Toronto Internal Medicine Review 2024

Citation preview

Toronto IMR 2024 Slides

good luck!

BONUS E-LECTURE: Allergy & Clinical Immunology With Contributions by Dr. Andrea Burke and Dr. David Fahmy Clinical Immunology & Allergy

Primary Immunodeficiency (PID) Ten Red Flags of Immunodeficiency: 1. ≥ 2 new ear infections within 1 year 2. ≥ 2 new sinus infections within 1 year, in the absence of allergy 3. One pneumonia per year for more than 1 year 4. Chronic diarrhea with weight loss 5. Recurrent viral infections (colds, herpes, warts, condyloma) 6. Recurrent need for IV antibiotics to clear infections 7. Recurrent, deep abscesses of the skin or internal organs 8. Persistent thrush or fungal infection on skin or elsewhere 9. Infection with normally harmless tuberculosis-like bacteria 10. A family history of Primary Immunodeficiency

2

Primary Immunodeficiency (PID) General Approach: • Rule out secondary causes of immunodeficiency: – DM, HIV infection, Cirrhosis, Nephrotic syndrome, Autoimmune disease, Malignancy, Splenectomy/Asplenia, Immunomodulatory drugs – Structural (obstructive tumours, urethral strictures), dermatitis, burns • Identify type of infections (see below) to direct investigation PREDOMINANT INFECTIONS Repeated pyogenic infections

TYPE OF IMMUNOInvestigations DEFICIENCY B- cell Lymphocyte count, Lymphocyte subsets, Immunoglobulins (IgG, IgA, IgM), vaccination titres T- cell Lymphocyte count, Lymphocyte subsets

Severe mycotic infection and opportunistic infections Abscess-forming infection with Neutrophil deficiency low-grade pathogens Repeated infections w/ Complement Neisseria sp. deficiency

Neutrophil count, Chronic Granulomatous Disease (CGD) Assay C3, C4, CH50

Immunodeficiency to know: CVID Combined Variable Immunodeficiency (CVID) • Most common symptomatic PID in adults – Recurrent sinopulmonary infections – Dx: LOW IgG + LOW IgA or IgM + poor response to vaccination; other immunodeficiency causes ruled out (e.g. CLL) – Tx: IVIG or SCIG (sub-cutaneous Immunoglobulin)

4

Urticaria (1) Acute Urticaria • Common antigens/triggers = antibiotics (PCN, Sulfa), NSAIDs, insects, food (shellfish in adults) - if there’s a trigger, there will be an obvious relationship • Lasts < 6 weeks • Work-up: Allergy referral for skin testing • First line treatment: STOP medication/AVOID trigger if identified, antihistamines PRN: ex. Cetirizine (Reactine) Red Flags of Urticaria: Last longer than 48hr Heal with a bruise, scar Burning, pain

Typical Urticaria: Last 6 weeks, most days of the week, “Spontaneous”: no clear trigger • Workup of CSU – CBC + diff, ESR/CRP • Workup of other causes of chronic urticaria – as directed by clinical picture: – Autoimmune work-up: ANA, ds-DNA, RF – Serum tryptase if systemic symptoms [Mastocytosis] – Biopsy [urticarial vasculitis] • Treatment of CSU – 1st line: Daily non-sedating antihistamine (cetirizine) – 2nd line: increased dose non-sedating antihistamine (4x – 3rd line: Omalizumab (Xolair) Physical Chronic Urticaria • Trigger = Pressure (aka dermatographism), Heat, Cold

Angioedema Angioedema + pruritus/urticaria = most likely Mast cell mediated Acute Treatment Angioedema: STOP offending agent/trigger, if possible • Related to a Specific Trigger (food, drug, insect bite, etc.) H1-Blocker: Diphenhydramine 25-50mg IV • Idiopathic Angioedema (can be part of CSU) H2-Blocker: Ranitidine 50mg IV Angioedema (NO pruritus/urticaria) = Mast cell OR Bradykinin-mediated Steroids: Methylprednisolone ~60-80mg IV • Differential diagnosis: *Anaphylaxis or oropharyngeal angioedema: Epi! – Related to Specific Trigger (see above) ACE Inhibitor Angioedema: Icatibant Known HAE: skip above treatment, instead: C1 – Idiopathic Angioedema • Chronic Tx: Frequent episodes : Daily antihistamine (Cetirizine) esterase inhibitor, Icatibant • Rare episodes: Prednisone + antihistamine for first sign of symptoms Investigations: Type C1 Inhibitor C1 Inhibitor C4 • Epinephrine Auto-injector Level Function – Hereditary Angioedema (HAE): C1 esterase inhibitor deficiency – Types I, II, III HAE Type I Low Low Low • PEARL: in general, a normal C4 level (in acute setting) rules OUT HAE Type II Normal/High Low Low HAE Type III Normal Normal Normal HAE Types I &II Acquired Low Low Low • Chronic Tx: Prophylactic C1 esterase Inhibitor ACE In Normal Normal Normal – Acquired Angioedema (lymphoproliferative or autoimmune disease) Idiopathic Normal Normal Normal – ACE Inhibitor Angioedema NEW: NEJM 2015: A Randomized Trial of Icatibant in ACE-Inhibitor–Induced Angioedema Conclusion: in this RCT involving patients with ACE-inhibitor–induced angioedema, complete resolution of edema was achieved significantly more quickly with SQ icatibant than with standard therapy consisting of glucocorticoids and antihistamines.

Anaphylaxis • • •

•

Common Triggers: food, medica2on, latex, insect venom Diagnosis: see next slide Acute Treatment – ABCs, MOIF – STOP drug/REMOVE trigger (if iden2fied) – Epinephrine IM: 1:1000 (1mg/mL) – DOSE: 0.01mg/kg (max 0.5mg) IM in anterolateral thigh, repeat q5-15min – Epinephrine IV: 1:10,000 (0.1mg/mL) – BOLUS: 0.05-0.1 mg IV over 5 min, then INFUSE: 2-10mcg/mL • Consider IV aXer several (i.e. 3) doses IM, profound hypotension, obese paZents

Adjunc2ve medica2ons: – – – – – –

•

H1-Blocker: Rani8dine 50mg IV q8hr PRN H2-Blocker: Diphenhydramine 25-50mg IV q4-6hr PRN Steroids: Methylprednisolone 125mg IV q6hr PRN Glucagon – paZents on beta-blockers Salbutamol – paZents with signs of bronchoconstricZon Vasopressors – for persisZng hypotension

Observe un2l symptoms improving, min. 4-6hr

IM EPINEPHRINE 0.01 mg/kg (max 0.5mg) IM Repeat q5-15 min PRN Note: 1:1000 solution = 1mg/mL IV EPINEPHRINE 0.05-0.1 mg IV over 5 min Then infuse 2-10 mcg/min titrated to BP Note: 1:10,000 solution = 0.1mg/mL

Discharge Plan: Prescribe Epinephrine Autoinjector 0.3mg IM PRN Anaphylaxis Action Plan Patient/Caregiver Education MedicAlert bracelet Referral to Allergist/Immunologist

ANAPHYLAXIS: Clinical Criteria for diagnosis

Kim & Fischer AACI 2011, 7(Suppl 1):S6

Anaphylaxis is highly likely when ANY ONE of the following 3 criteria is fulfilled following exposure to an allergen: 1.

Acute onset of an illness (min to several hours) with q Skin or mucosal tissue involvement (or both) • Generalized hives, itch/flushing, swelling of lips/tongue/uvula AND at least ONE of the following: q Respiratory compromise • Dyspnoea, wheeze, bronchospasm, stridor, reduced PEF, hypoxemia q Hypotension or associated symptoms of end-organ dysfunction • Hypotonia, syncope, incontinence 2. TWO or more of the following that occur rapidly (min to several hours) after exposure to a likely allergen for that patient q Skin or mucosal tissue involvement • Generalized hives, itch/flushing, swelling of lips/tongue/uvula q Respiratory compromise • Dyspnoea, wheeze, bronchospasm, stridor, reduced PEF, hypoxemia q Hypotension or associated symptoms of end-organ dysfunction • Hypotonia, syncope, incontinence q Persistent GI symptoms • Painful abdominal cramps, vomiting 3. Hypotension after exposure to a known allergen for that patient (min to several hours) q Adults: sBP 30% decrease from patient’s baseline

ANAPHYLAXIS = one of: 1. Possible allergen + Skin/mucosa + ≥ 1 of Resp HoTN/EOF 2. Likely Allergen + ≥ 2 of Skin/mucosa Resp HoTN/EOF GI 3. Known Allergen + HoTN

PEARL: As a general rule, any time you have more than one system involved, you should suspect anaphylaxis!

Penicillin Allergy Approach: – IgE-Mediated: pruritus, urticaria, angioedema, etc. – Non-IgE-Mediated: SJS-TENS (blistering, desquamation, conjunctivitis), DRESS (eosinophilia, fever, end-organ involvement), serum sickness (arthritis, fever)

Management: IgE-mediated Reactions – Allergy referral for Penicillin Skin Testing + Oral Challenge • ~90% “PCN allergic” patients will test negative – can safely receive beta-lactam and cephalosporin antibiotics • Positive skin test – AVOID penicillin, higher likelihood of reacting to 1st gen cephalosporins – Drug Desensitization (under close observation, OK to do even in Pregnant patient (eg) with syphilis)) • If penicillin is required acutely and no time for skin testing, or skin test positive • Note: this is a temporary induction of ‘tolerance’, and does NOT rule out allergy • Note: this is only used in cases of IgE-mediated drug reactions (NOT if any suspicion of serum sickness, SJS-TENS, DRESS, etc.) – Note: Aztreonam (monobactam) – generally tolerated in penicillin allergic patients • exception: if they have reacted to ceftazidime! Patient history not very reliable (JAMA 2001): PCN allergy history positive: LR+ 1.9 for +ve skin test PCN allergy history negative: LR- 0.5 for +ve skin test

Example Question A 30-year-old woman presents with a second pneumonia in the last six months. She has a past medical history of recurrent pneumonias and sinusitis. Investigations show: WBC 6, Neutrophils 3, Lymphocytes 2, Monocytes 1. What is most likely diagnosis? 1. Complement deficiency 2. Common variable immunodeficiency 3. HIV 4. Chronic granulomatous disease

Answer A 30-year-old woman presents with a second pneumonia in the last six months. She has a past medical history of recurrent pneumonias and sinusitis. Investigations show: WBC 6, Neutrophils 3, Lymphocytes 2, Monocytes 1. What is most likely diagnosis? 1. Complement deficiency 2. Common variable immunodeficiency 3. HIV 4. Chronic granulomatous disease

Example QuesEon A middle-aged female presents with a 6 month history of urticaria. She has never had any episodes of swelling. The urticaria resolve within 12hr, with no residual bruising or scarring. She reports that she has been eating out at restaurants more recently. She is otherwise well. Initial bloodwork is normal including a CBC, creatinine and liver profile. What is the most likely cause of this patient’s symptoms? 1. Chronic Idiopathic Urticaria 2. Food allergy 3. C1 esterase deficiency 4. Autoimmune Disease

Answer A middle-aged female presents with a 6 month history of urticaria. She has never had any episodes of swelling. The urticaria resolve within 12hr, with no residual bruising or scarring. She reports that she has been eating out at restaurants more recently. She is otherwise well. Initial bloodwork is normal including a CBC, creatinine and liver profile. What is the most likely cause of this patient’s symptoms? 1. Chronic Idiopathic Urticaria 2. Food allergy 3. C1 esterase deficiency 4. Autoimmune Disease

Example Question A pregnant patient with a history of asthma states she is allergic to penicillin. She developed wheeze the last time she took it, while admitted for an upper respiratory tract infection. She was referred for penicillin skin testing, which was negative. Penicillin is now indicated for a pregnancy acquired syphilis infection. Which drug would you use? 1. Penicillin 2. Second-Generation Cephalosporin 3. Doxycycline

Answer A pregnant patient with a history of asthma states she is allergic to penicillin. She developed wheeze the last time she took it, while admitted for an upper respiratory tract infection. She was referred for penicillin skin testing, which was negative. Penicillin is now indicated for a pregnancy acquired syphilis infection. Which drug would you use? 1. Penicillin 2. Second-Generation Cephalosporin 3. Doxycycline

Example QuesEon A young man presents with occasional angioedema of his lips and hands. Which of the following features make it least consistent with C1 esterase deficiency? 1. Occasional GI symptoms 2. Triggered by dental procedure 3. Presence of urticaria 4. Laryngeal involvement

Answer A young man presents with occasional angioedema of his lips and hands. Which of the following features make it least consistent with C1 esterase deficiency? 1. Occasional GI symptoms 2. Triggered by dental procedure 3. Presence of urticaria 4. Laryngeal involvement

Applied Scenarios & Ethics Primer ONLINE ONLY LECTURE NOTES © Internal Medicine Review 2024

Overview • Types of Applied Scenarios

– General Approach to Clinical Scenarios

• Ethics – – – – – – –

Patient Centred Communication Consent and Capacity Fitness to Drive Troubled Colleague / Professionalism End of life care Disclosure of medical error Confidentiality

• Patient Safety/QI àSee Online PRIMER with examples • Truth and Reconciliation in Canada – implications for physicians

Applied / Oral Scenarios In 2023, your applied / oral scenario will be done virtually. • Unless you have a medical exemption for accommodation, you will have to do this at one of 17 hotel test centres in Canada – On a computer, with examiner virtually

• What we know about virtual Applied/Oral Exams (https://www.royalcollege.ca/rcsite/documents/ibd/internal-medicine-examformat-e) – 7 virtual stations x 18 min each

• 1 rest station , 6 “work” stations • May have >1 case per station

– (eg) read stem 1-2 min, then 7 min scenario, read next stem 1-2 min, 7 min scenario

– Media provided can include videos [NB none reported in 2022] or documents (eg ECG – usually opens in a separate window) – Although the virtual format does not lend itself to physical exams, we have been told that knowledge of exam maneuvers may be tested (eg. – describe how to measure a pulsus paradoxus) 3

Feedback from IMR2023 Attendees “[Need to practice interruptions causing] stress that is experienced on exam day. I think that on the board exam the examiners do not really give you time to go over all the management including nonpharm treatment. You would get interrupted to move onto the next question. ” “There seems to be more of a focus on providing differential, investigations, management and answering specific questions in 7.5 minutes.”

“ On the real exam there were many doublet stations where we only had 1 min to read and were pressured to have a differential and plan ready to go right away. ” “The real exam has become very rapid fire. Long stem with HPI, P/E and initial Ix then after the prep time it’s really just “what’s your ddx and how would you manage, including further investigations?” They’d show you an EKG or X-ray if that was relevant to your workup. They cram so much into the stations … that you really can’t stray from the relevant points of the case (in an attempt to pick up extra points for nonpharm things, for example) some of the examiners were quite abrupt.” 4

Types of Applied Scenarios • Emergency Department / Ward on-call – (eg) Patient presenting after travel from Africa with fever and jaundice – workup and manage

• Pre- or Post-op patient

– (eg) Elective Orthopedic patient seen preop, asked to manage meds, calculate RCRI, manage MINS postop

• Pregnant patient

– (eG) L&D / ED – hypertension, pre-eclampsia diagnosis, admission, management

• Office Scenario

– (eg) Patient with diabetes – BP, A1C, Lipids all above target “how would you optimize”? • Prompts to cover counselling of patient – driving, eye exams, etc.

• Communication Station Unlikely

– In 2022 & 2023 no role-playing was reported however website still states Applied exam designed to test CANMEDs roles (including communicator). You may be asked how you would counsel a patient on a procedure or treatment (Indications, Contraindications, Risks, Benefits, Risks if you don’t have intervention…) – Ethics come up - Know Canadian Laws around medicolegal issues of care: Driving, end of life,consent & Capacity, withdrawal of care, MAID

Clinical Scenarios: General Approach 1.

2.

Understand the question

– If provided with a long stem, check the question at end first to tailor your reading – If your task is unclear from the written stem you are given, ask to clarify “Do you want me to counsel this patient on anticoagulation for atrial fibrillation only or other aspects of Afib management such as rate/rhythm control?” – –

Frame and Markup your “Pink Sheet” [you will be given a piece of paper to take notes on for each scenario] Your Differential – do this every time, may get asked by examiner what DDx is Management

• • •

3)

Tests for workup: many provided in stem if it is a management scenario Be prepared: ECG, CXR, PFTs are fair game for interpretation Non Pharm: SPEDD – Smoking, Pregnancy, Exercise, Driving, Diet Pharm: Acutely ill: ABC MOIF (monitor, oxygen, IV, foley) C&C (consults and code status)

Answer the Question – with new format, you will get pushed towards management 6

Clinical Scenarios: General Approach Management PEARLS: ACUTE MANAGEMENT • Use common sense – in an ED scenario with unstable patient, you must treat first, investigate later (like in real life!) – (eg) Afib –BP 70/40, HR 160, patient stuporous

• “This patient is presenting with acute unstable SVT/AFIB – I would like to move to appropriate resus area of the ER and begin ACLS measures” – Cardiovert first, ask questions later – (eg) ECG may suggest WPW but if unstable just cardiovert then think about next steps!

– (eg) ED Tox Scenario – patient starts to seize:

• Treat Seizure (position, suction available, oxygen, give appropriate order for benzodiazepine) • “While the nurse is preparing the lorazepam I would ask for the following stat labs including an immediate capillary glucose and ECG…”

– UNSURE? SAY WHO YOU WOULD CALL, WHAT YOU WOULD LOOK UP. (Like in real life.). This is a safety scenario – if you can demonstrate knowledge gap and where you would seek answer or help this is a PASS. 7

Clinical Scenarios – General Approach Management (continued) : SUBACUTE “C&C = Consult and Counsel” • Consult appropriate services – “I would consult a hematologist and ICU where plasma exchange is available for this patient with TTP for transfer…” – Pregnant Scenario: Don’t forget to consult OB +/- anesthesia +/- Paeds

• Counsel

– I would counsel the patient as to…

Medicolegal: Driving? Work restrictions? Communicable disease / Public Health reporting requirement? Risk of recurrence? (ex. DVT or HTN in pregnant pt) Consequences of disease (ex. Afib à Stroke risk) Consequences of treatment (ex. Afib à anti-arrhythmic side effects), Pregnancy implications if childbearing age. 8

Ethics In exams before 2020, there was usually a role-playing communication station. Now with virtual format, it is more likely a question of ethics will come up in a management question. (eg) question of consent/capacity in a patient with Jehovah’s witness faith refusing blood, driving restrictions post ICD or stroke • • • • • •

Patient Centred Communication – A Canadian Healthcare Priority Consent & Capacity Fitness to Drive Troubled Colleague / Professionalism End of life care – Medical Assistance in Dying (MAID) – Withdrawal of care

Disclosure of adverse events / medical error

– Patient Safety / Quality Improvement may be asked

• •

Confidentiality Patient Safety / QI

Patient Centred Communication • Meeting a patient “where they are” and acknowledging the socioeconomic and cultural influences on health (social determinants of health (#sdoh)). • FIFE –ask patients about their Feelings (fears) around illness, Ideas about what has caused illness, how it affects their Functioning, and Expectations of their encounter and treatment (eg) Creating a safe space for gender identity – inviting patients to express gender with preferred pronouns (eg) Being aware of non-visible aspects of culture – such as how emotions are managed, how modesty and physical distancing affect comfort with physical exam (eg) Writing “The patient is noncompliant with dietary recommendations for diabetes” does not acknowledge how food insecurity may make it impossible for patient to comply with your recommendations – screen for SDOH 10

Consent & Capacity Scenarios to consider: – The patient who is refusing life-saving therapy • Diabetic refusing above knee amputation • Jehovah’s Witness refusing transfusion – The family member who asks for a treatment for their cognitively impaired parent. • Variation: Family member who does not want you to disclose terminal diagnosis to their parent

Consent Requirements 1. Voluntary 2. Informed 3. Capable 4. Documented in the Chart* (*my lawyer added this) CMPA Consent and Capacity Module

https://www.cmpaacpm.ca/serve/docs/ela/goodpracticesguide/pages/communication/Informed_Consent/informed_consente.html Assent ≠ Consent (just because a patient lets you do a procedure (ex. ABG) does not mean that you have their consent.)

Consent: Voluntary • No compulsion – By physician – By other 3rd party • Police officer • Family member

Consent : Informed • Informed consent components – “Reasonable Patient Standard” – Supreme Court • What a reasonable patient in the particular patient's position would have expected to hear before consenting.

– Description of treatment – “Material Risks” • “A risk is thus material when a reasonable person in what the physician knows or should know to be the patient's position would be likely to attach significance to the risk or cluster of risks in determining whether or not to undergo the proposed therapy.”

– Alternates to treatment (and risks of alternate)

• Informed by MD carrying out procedure

– Can be delegated (ex. to a resident) if delegate has sufficient knowledge and experience to provide explanations

Consent : Capable patient • An individual who is able to understand – the nature and anticipated effect of proposed medical treatment and alternatives – Understand and appreciate the consequences of refusing treatment (Source: CMPA Guide to Consent)

• Capacity may fluctuate in hospital

Consent : INcapable patient If your patient is incapable – identify an appropriate substitute decision maker (SDM) – do not get fooled in a scenario! Ontario SDM Hierarchy: 1. 2. 3. 4. 5. 6.

Power of Attorney for Personal Care Spouse, Common-law spouse* or Partner Parent or adult (>16yrs) children Siblings Any other family member by blood, marriage or adoption Public Guardian & Trustee

If there is a CONFLICT between SDMs à PG&T should make decision in their stead (e.g. if SDMs are son and daughter who completely disagree on treatment)

*Common Law for Health Care • Ontario: – have cohabited for at least one year – have a child together – have entered into a cohabitation agreement together.

• Quebec: – ?? Different sources quote different laws (0-3 years cohabitation)

• Alberta: – Have cohabited for three years

• B.C.: – Have cohabited for two years 17

Consent & Capacity Scenarios to consider: • The patient who is refusing life-saving therapy – Diabetic refusing above knee amputation – Jehovah’s Witness refusing transfusion • The family member who asks for an opinion/treatment for their cognitively impaired parent. – Variation: Family member who does not want you to disclose diagnosis of cancer to their parent. – Patient who does not want to hear details of diagnosis, “Doctor do what you think is best”

Consent & Capacity Scenarios to consider: – Patient who does not want to hear details of diagnosis, “Doctor do what you think is best” CASE LAW: You can treat a patient without them being fully informed if they waive their autonomy with respect to consent – make sure their decision to waive this is properly informed + capable of course! [Ontario Health Care and Consent Act doesn’t make a ‘ruling’ on this – it is OK to say in your scenario to patient that you will need to speak to ethicist/CMPA, that you respect their decision and wishes and just need to be sure what your medico-legal obligations are.]

Fitness to Drive • Available for free to CMA Members

• Also note CCS 2023 published new guidelines on fitness to drive after cardiac illness – these are reviewed in Cardiology Lecture @ IMR2024 and summaries below. 20

Fitness to Drive Consider: • Truck Driver with visual field impairment • New Seizure – counsel on driving • Sleep Apnea – non compliant with CPAP

Fitness to Drive - CMA • Duty to report – Varies province to province including duty to report • Alberta, Nova Scotia, Quebec = reporting discretionary

– In Ontario (Exam is in Ottawa so default to Ontario rules if unsure) – MDs must fill out medical condition report and cannot be legally challenged for doing so: • “Medical Condition Report Ontario”

– Ontario Ministry of Transportation suggests the CMA guide be used by physicians in determining requirements to report

CMA Fitness to Drive:

https://joule.cma.ca/en/evidence/CMA-drivers-guide.html Category Cognitive

Private Car Hepatic Encephalopathy Dementia

Stroke

Alcohol Dependence

Commercial Driver (Truck, Bus) No Driving

UPDATED IN 2019 – SEE NEXT SLIDE

Psychiatric – acute psychosis, lack of coopertion w/ treatment or treatment too sedating

No driving

Untreated intracerebral aneurysm

No driving

Postop Aneurysm Rx

3 mos

6 mos

Other stroke, with normal VF, neuro exam

1 month

1 month

Alcohol Withdrawal Seizures

Seizure free, alcohol free for 6 months – Rehabilitated and Compliant

CMA Fitness to Drive:

https://joule.cma.ca/en/evidence/CMA-drivers-guide.html Category Sleep Problems

Private Car

Commercial Driver (Truck, Bus) Safe to Drive

OSA – mild or treated (TREATED = at least 4 hrs/d, 70% of last 30 days) OSA – mod/severe untreated

No driving

Narcolepsy

No driving

Endocrinology

Diabetes on insulin

May drive if: medic alert worn, no severe hypoglycemia last 6 mos

Seizure

Single, unprovoked, no epilepsy

3 months Full workup to ID cause

EEG, imaging required – if normal 12 mos

Epilepsy compliant on medications

6 mos seizure free

5 years seizure free

CMA Fitness to Drive : Dementia • Diagnosis of dementia alone not sufficient reason to suspend license. – Discuss a plan to “retire” from driving with patient – Physician is not the one to determine who is fit to drive, but to report clinical findings that raise concern about ability to drive

• Where fitness to drive not clear, refer for further functional testing (e.x. OT, DRIVEABLE assessment) • Ask : would I let a loved one get in the car… would I want a loved one crossing street in front of this individual’s car...? If answers are uncertain or “NO” then report and refer for further testing. 25

CMA Fitness to Drive: Dementia Excerpts

26

CMA Fitness to Drive: Dementia Excerpts

27

CMA Fitness to Drive:

https://joule.cma.ca/en/evidence/CMA-drivers-guide.html Category VISION

Private Car

Commercial Driver (Truck, Bus)

Visual Acuity

≥20/50 Corrected both eyes open

≥20/30 Corrected both eyes open

Visual Fields

120 continuous degrees along horizontal meridian 15 continuous degrees above and below fixation

120 continuous degrees along horizontal meridian 20 continuous degrees above and below fixation

CCS 2023 Fitness to Drive Guidelines Category

Coronary Artery Disease*

Private Car

Commercial Driver (Truck, Bus)

STEMI/NSTEMI with LVEF >40%

2 weeks post d/c

1 months post d/c

STEMI/NSTEMI with LVEF ≦ 40%

1 month post d/c

STEMI/NSTEMI with no PCI performed

1 month post d/c

3 months post d/c

UA (ACS without MI)

48h w/ PCI 7 d w/o PCI

7 d w/ PCI 1 month w/o PCI

PCI in non-ACS context

48h

48h

Asymptomatic CAD, stable angina

OK to drive

OK to drive

CABG

1 month post d/c

3 months post d/c

Category

3 months post d/c Heart Failure**

Private Car

Commercial Driver (Truck, Bus)

NYHA I

OK to drive

LVEF ≧ 30% OK

NYHA II

OK to drive

LVEF ≧ 30% OK

NYHA III

OK to drive

NO DRIVING

NYHA IV

NO DRIVING

NO DRIVING

Home inotropes

NO DRIVING

NO DRIVING

LVAD

2 months after implant if NYHA 1-2

NO DRIVING

Heart transplant

6 weeks after discharge + NYHA 1-2 + stable immunosuppression + followed annually

6 months post discharge + NYHA 1 + LVEF ≧ 50% + followed annually

*Updates focus on LVEF post MI, regardless of mechanism **Updates provide new recommendations for LVAD/TxP

CCS 2023 Fitness to Drive Guidelines Category Medically treated AS, AI, MS, MR, TR

Valvular Heart Disease

Post TAVI or SAVR for AS, AR

Private Car

Commercial Driver (Truck, Bus)

AS: OK if NYHA 1-2

Only OK if in the lowest risk group: NYHA 1, no syncope, LVEF ≧ 50%

MS, MR, AI, TR: OK if NYHA 1-3

1 month if stable QRS duration, no high grade AV block (2nd type II or 3rd) if no PPM and NYHA I-III

AS, AI: as above MR: also no pHTN or systemic embolism MS: no LVEF requirement TR: no RV dysfunction, symptomatic RV failure, RV arrhythmias 3 month if stable QRS duration, no high grade AV block (2nd type II or 3rd) if no PPM and NYHA I AR requires as above + LVEF ≧ 50%

AR requires as above + LVEF ≧ 50% Post TEER for MR or TR

48h post d/c if NYHA I-III

1 month post d/c if NYHA I and LVEF ≧ 50%

Post balloon valvuloplasty for MS

48h post d/c if NYHA I-III

1 month post d/c if NYHA I

Post TMVR, TTVR or surgical valve replacement

1 month post d/c if NYHA I-III

3 months post d/c if NYHA I and LVEF ≧ 50%

Updates provide new recommendations for TAVI, TEER, TMVR, TTVR

Category

Private Car

Impaired LOC or high grade AV block Pacemaker

No impairment in LOC/high grade AV block Generator change (also applies for ICD private driving)

Commercial Driver (Truck, Bus)

1 week post implant

ICD

Sinus node dysfunction

Private Car

Commercial Driver (Truck, Bus)

No impaired LOC: OK to drive Impaired LOC/symptomatic pauses: NO DRIVING until PPM

OK to drive

First degree, Wenckebach, isolated LBBB, LAFB, LPFB, RBBB, bifasicular block

OK to drive unless history of impaired LOC

OK to drive

Second degree type II, alternating BBB, 3rd degree AVB

NO DRIVING until PPM Exception: congenital 3rd AVB (only restricted if impaired LOC)

Lead upgrade/revision 1 week post implant if history (also applies for ICD of impaired LOC/high grade AV block private driving) Otherwise OK to drive Primary prophylaxis

Arrhythmia

1 week post implant

Secondary prophylaxis, impaired LOC

3 month

Secondary prophylaxis, no impaired LOC

1 week

NO DRIVING

SVT/AF/AFL

No impaired LOC: OK to drive Impaired LOC: NO DRIVING until treated

VF (no reversible causes)

3 months

VT/VF due to reversible cause (MI, drug, etc.)

NO DRIVING until underlying cause treated

Hemodynamically unstable VT or impaired LOC

3 months

VT with structural heart disease and no impaired LOC, no ICD VT with structurally normal heart (idiopathic VT)

3 months 1 week if well controlled

NO DRIVING

NO DRIVING

Category

Private Car

ICD shock or therapy, impaired LOC or disabling ICD therapy

Hypertrophic cardiomyopathy

ICD shock or therapy, NO impaired LOC or disabling

3 months Category 1 week

Inappropriate ICD therapies

No restriction

Electrical storm (3 or more VT/VF events in 24h)

3-6 months after event (expert reevaluation)

No high risk features High risk features**

NO DRIVING

Asymptomatic: OK to drive

3 months

NO DRIVING

Private Car

Single/recurrent vasovagal syncope

Syncope

OK to drive

Syncope: 3 months Prior sustained ventricular arrhythmia

CCS 2023 Fitness to Drive Guidelines

Commercial Driver (Truck, Bus)

Commercial Driver (Truck, Bus)

OK to drive

Reversible cause (orthostatic, dehydration) or avoidable trigger (micturition)

1 week

1 month

Single unexplained syncope

1 week

12 months

Recurrent unexplained syncope

3 months

12 months

Tachy/brady/device syncope

Refer to respective arrhythmia or device recommendation

**High risk features: think ICD recommendations i.e. wall thickness >30mm, unexplained syncope, apical aneurysm, LVEF 45 have 2X rate of diabetes • First Nations peoples 6X more likely to suffer alcohol-related death, 3X more likely to suffer drug related death • Suicide rate of First Nations communities >2X that of total Canadian population – 5-6X more likely for youth 19. We call upon the federal government, in consultation with Aboriginal peoples, to establish measurable goals to identify and close the gaps in health outcomes between Aboriginal and non-Aboriginal communities, and to publish annual progress reports and assess long term trends. Such efforts would focus on indicators such as: infant mortality, maternal health, suicide, mental health, addictions, life expectancy, birth rates, infant and child health issues, chronic diseases, illness and injury incidence, and the availability of appropriate health services. 20. In order to address the jurisdictional disputes concerning Aboriginal people who do not reside on reserves, we call upon the federal government to recognize, respect, and address the distinct health needs of the Métis, Inuit, and offreserve Aboriginal peoples. 50

TRC Healthcare Calls to Action 21. We call upon the federal government to provide sustainable funding for existing and new Aboriginal healing centres to address the physical, mental, emotional, and spiritual harms caused by residential schools, and to ensure that the funding of healing centres in Nunavut and the Northwest Territories is a priority. 22. We call upon those who can effect change within the Canadian health-care system to recognize the value of Aboriginal healing practices and use them in the treatment of Aboriginal patients in collaboration with Aboriginal healers and Elders where requested by Aboriginal patients. 23. We call upon all levels of government to: i. Increase the number of Aboriginal professionals working in the health-care field. ii. Ensure the retention of Aboriginal health-care providers in Aboriginal communities. iii. Provide cultural competency training for all healthcare professionals. 24. We call upon medical and nursing schools in Canada to require all students to take a course dealing with Aboriginal health issues, including the history and legacy of residential schools, the United Nations Declaration on the Rights of Indigenous Peoples, Treaties and Aboriginal rights, and Indigenous teachings and practices. This will require skills-based training in intercultural competency, conflict resolution, human rights, and anti-racism.

51

Education and Support Physicians should learn more per TRC calls to action.

INTERESTED IN READING MORE AS AN INTERNIST? THIS WEBSITE THROUGH THE NORTHERN ONTARIO SCHOOL OF MEDICINE HAS A DECENT COMPENDIUM OF OPENACCESS REFERENCES https://www.nosm.ca/education/rehabilitation-studies/resources/indigenous-health-learning-resources INDIGENOUS MENTAL HEALTH SUPPORTS INDIGENOUS MENTAL HEALTH SUPPORTS

The National Indigenous Residential School Crisis Line 24-hour crisis support line 1-866-925-4419 for Residential school students and their families Hope for Wellness support for any First Nation, Metis or Inuit 1-855-242-3310 /online chat at https://www.hopeforwellness.ca/

52

CARDIOLOGY December 2, 2023

Dr. Michael Ruiz

www.internalmedicinereview.ca

© Internal Medicine Review 2024

Guiding Principles Broad strokes: • Help symptomatic patients feel better • Help patients live longer • Identify and treat risk factors • Practice evidence-based medicine RC tips: • Use Canadian Guidelines (CCS) when possible • Do not worry about understanding advanced cardiovascular techniques (ablation, angiography, etc.) • Be safe!

Outline 1. Coronary artery disease 2. Heart failure / cardiomyopathy 3. Valvular heart disease 4. Aortopathy 5. Pericardial disease 6. Arrhythmias and implantable cardiac devices 7. Peripheral arterial disease NB. ECGs will be self study online

ACS

Acute Coronary Syndrome

CRT (D) vs. (P)

Cardiac Resynchronization Therapy (with Defibrillator) vs. (Pacing only)

CCTA

Coronary CT angiography

DAPT

Dual Antiplatelet Therapy (ASA + clopidogrel or prasugrel or ticagrelor)

EST

Exercise Stress Test

METs

Metabolic Equivalents

DOACs

Direct Oral Anticoagulants (ex apixaban, dabigatran, rivaroxaban)

NSTEACS

Non ST Elevation Acute Coronary Syndrome

OAC

Oral Anticoagulants (Includes VKA, DOAC)

OMT

Optimal Medical Therapy

POBA

Plain Old Balloon Angioplasty

PCI

Percutaneous Coronary Intervention

VKA

Vitamin K Antagonist (warfarin)

SAPT

Single Antiplatelet Therapy (ASA OR Clopidogrel)

SPECT

Single photon emission computed tomography

Coronary Artery Disease Key resources: • CCS 2014 Guidelines – Diagnosis and management of stable ischemic heart disease • ACC/AHA 2023 Guidelines – Chronic CAD

Coronary Artery Disease (CAD) Two major presentations: Chronic stable CAD 2014 CCS guidelines on stable ischemic heart disease 2023 ACC/AHA Guideline on Management of Patients with Chronic Coronary Disease

Acute coronary syndromes Various CCS/ACC/AHA guidelines on ACS, antiplatelets

How Do Patients Present? Ischemic cascade – with increasing ischemic time: 1. Blood flow changes (can be seen on myocardial perfusion) 2. Diastolic, then systolic dysfunction (wall motion abnormalities) 3. ECG changes 4. Symptoms 5. Myocardial necrosis

Diagnostic Tests for CAD • Functional Non-invasive stress tests: – STRESS = exercise, drugs (inotropes, vasodilators) – TEST = ECG, ECG+echo, ECG+nuclear

• Structural – Coronary angiography – CT coronary angiography

• STRESS: pick exercise whenever possible! – Provides prognostic info: e.g. duration of exercise, METs – Not possible if physical limitations or contraindications (e.g. critical aortic stenosis)

• TEST: consider functional imaging (e.g. nuclear) if: – Cannot accurately assess for ischemia on ECG • LBBB, paced rhythm, preexcitation, significant ST changes at rest à the ECG is not interpretable in these cases – RBBB interpretable generally

– Need specific anatomic correlation (e.g. prior revascularization)

Able to exercise and no contraindications?

YES

ECG Normal à Exercise Stress TEST

NO

NO LBBB or V- Paced rhythm Exercise myocardial perfusion Image

ECG normal or abnormal

ECG Abnormal

Exercise ECHO

LBBB or V paced rhythm

Vasodilator myocardial perfusion imaging

No LBBB or V paced Rhythm Vasodilator myocardial perfusion imaging Dobutamine or vasodilator echo

Principles of NonInvasive Testing LBBB or V paced rhythm Cardiac CT Angiography

Adapted from 2014 CCS – Stable Ischemic Heart Disease

Absolute Contraindications to EST • Acute MI (within 2 days) • Ongoing unstable angina • Uncontrolled hemodynamically-significant arrhythmia • Active endocarditis • Symptomatic severe AS • Decompensated heart failure • Acute PE, pulmonary infarction, DVT • Acute myocarditis, pericarditis • Acute aortic dissection • Physical limitations

Mnemonic: I – Inflammation D – Dissection O – Ongoing angina N – No consent O – Ongoing MI T – Thrombosis S – Severe AS T – Technical issues R – Rhythm E – Endocarditis S – Systolic dysfunction S – Slow

EST Results • • • •

Positive Negative Equivocal Uninterpretable

• Maximal vs. submaximal test – Patient should reach 85% of age predicted maximum heart rate – (Max HR = 220 – age)

EST Results Positive test – ≥ 1mm STE – ≥ 1 mm STD (horizontal or downsloping)

2013 AHA – Exercise standards for testing and training

High risk features* Duke Treadmill Score -11 or less 120, drop in BP >10, drop below baseline] – Ventricular arrhythmia

– – – – – – – –

2014 CCS – Stable Ischemic Heart Disease

Myocardial Perfusion Imaging • Radioactive tracer (e.g. 99mTc) is used that distributes into myocardium proportionally with blood flow • SPECT imaging detects decay of tracer • Stress = exercise vs. pharmacologic (e.g. dipyridamole) – Pharmacologic stress based on coronary perfusion mismatch after vasodilation

• dipyridamole (aka persantine) most commonly used for nuclear stress, less commonly adenosine • Dobutamine used commonly for stress echocardiography

– Diseased coronary vessels are already maximally dilated and develop perfusion mismatch – False negatives can be seen:

• Drug interactions with dipyridamole (caffeine, theophylline – hold before test!) • Severe flow limiting triple vessel or left main disease (“balanced” ischemia so no perfusion mismatch detected)

• Consider as a potential first-line test if patient cannot complete ECG stress test • Contraindications: active or severe asthma/COPD, as dipyridamole can cause bronchospasm – Reversal agent for dipyridamole is aminophylline

Coronary CT Angiography (CCTA) NB. CCTA is not the same as a Coronary Artery Calcium (CAC) Score from CT. - CAC scoring is recommended for further risk stratification of intermediate risk (FRS 10-19%) asymptomatic patients aged > 40 who are not candidates for statin based on other risk factors - Can consider CAC scoring for low risk patients with family hx premature CV Dz and genetic dyslipidemia - CAC score > 100 is basically a statin indicated condition; start therapy regardless of FRS

Coronary CT Angiography (CCTA) • Procedure specifics: – Low dose CT with beta blockade +/- IV nitro given (HR target 24h post ACS • Stopping P2Yi prior to CABG

– Limited evidence… “multidisc team” to decide, hold 2-7d pre-op

• Suggest hold Ticagrelor 2-3 days rather than 5-7d [weak, conditional]

• Postop Antiplatelet Regimen

– Off-pump – favour DAPT, with ASA + ticagrelor/prasugrel over ASA + Clopidogrel – On-pump – favor SAPT – AFIB? – consider OAC monotherapy

We think this is beyond scope of GIM – usually our exam questions pertain to NON CARDIAC SURGERY! 31

The Second Antiplatelet… Nuances • Ticagrelor is contraindicated if history of: – – – –

intracranial hemorrhage active pathological bleeding moderate-severe hepatic impairment combinations with CYP34A inhibitors (ketoconazole, clarithromycin, ritonavir) – Should consider avoiding in patients with evidence of heart block or bradycardia. – Dose: 180mg load then 90 mg bid x 12 months then 60mg bid thereafter

• Prasugrel is contraindicated if:

– active bleeding – prior TIA/stroke [even ISCHEMIC stroke] – hypersensitivity reaction

– Dose: 60mg load then 10mg daily (reduce to 5mg if 24h expected before cath, give second antiplatelet Elective angiogram: do not routinely treat with second antiplatelet

CCS 2023 Antiplatelet Guideline: AFIB + Antiplatelets

CCS Antiplatelet 2023

N.B. all of these recommendations are weak unless otherwise specified. Align w CCS AFIB guidelines.

• Antiplatelet and anticoagulation (i.e. patient on OAC for atrial fibrillation) – Dual pathway (clopidogrel+OAC) recommended over previous strategy of triple therapy for 1-30 days in most patients (but the small text says they need to receive 1 dose of ASA at PCI time, so it is like they only received 1 dose of triple therapy) – OAC monotherapy preferred over OAC+aspirin in stable CAD (from the AFIRE trial which showed rivaroxaban+ASA had more bleeding with no reduction on ischemic events compared to rivaroxaban alone)

High bleeding risk patient

*NEW* CCS 2023 Antiplatelet guidelines give clear guidance as to who is high risk of bleeding. Meeting 1 major or 2 minor should trigger you to consider a shorter duration or de-escalated regimen of DAPT

Need 1 major

Or 2 minor:

1.

Advanced CKD (eGFR55%, if LV is severely enlarged (cut off LV end systolic dimension >50mm or indexed to body surface area >25mm/m2) • Moderate AR undergoing other cardiac surgery Class IIb indications for surgery: • Asymptomatic, severe AR with LVEF >55% but progressive decline in LVEF on three serial studies to 55-60% or progressive increase in LV dilation (LV end diastolic dimension >65mm)

Aortic regurgitation causes a volume load on the left ventricle. Systolic dysfunction is a devastating consequence of volume loading (which is why it is a class I recommendation to intervene). Volume loading also causes LV dilation through remodeling, hence why LV enlargement is included in class IIa and IIb indications for intervention.

AHA 2020 Valve

Mitral Stenosis • Etiology is almost all rheumatic (other – MAC, radiation, autoimmune … ) – Often associated with AF – OAC with VKA if i) rheumatic MS and AF; ii) rheumatic MS and prior embolic event; iii) rheumatic MS and LA thrombus • INVICTUS trial: VKA vs. rivaroxaban in pts with rheumatic heart disease and AF

à VKA had ↓ stroke/systemic embolism/MI/death (i.e. DOAC harmful in this setting!) NEJM 2022

– Management considerations for AF and heart rate

• MS does not like high HRs à loss of diastolic filling time • MS does not like AF à loss of atrial kick

• Severe MS:

– MV area ≤1.5 cm2 (very severe = ≤1 cm2) – Pulmonary artery systolic pressure >50mmHg – Diastolic pressure half time (PHT) >150 ms

Echo criteria for severe MS in guidelines… but we don’t think you need to memorize!

AHA 2014, 2017, 2020 Valve

Mitral Stenosis - Intervention 2 types of interventions – percutaneous vs. surgical Percutaneous mitral balloon commissurotomy (PMBC) indicated if (Class I): • Severe, symptomatic MS + favourable valve anatomy + can be performed at a “Comprehensive Valve Centre” –

CONTRAINDICATED if: i) LA thrombus (need preop TEE) ii) >moderate MR

MV surgery (commissurotomy +/- repair OR replacement) indicated if (Class I): • Severe, symptomatic MS + acceptable surgical risk + contraindicated/failed PMBC • Severe MS and other cardiac surgery planned AHA 2014, 2017, 2020 Valve

BONUS Read on own

Mitral Stenosis - Intervention

• Percutaneous mitral balloon commissurotomy (PMBC) is reasonable if (Class IIa)*: – Asymptomatic, severe MS with pulmonary hypertension (PA systolic pressure > 50mmHg by echocardiography or right heart catheterization)

• Percutaneous mitral balloon commissurotomy (PMBC) can be considered if (Class IIb)*: – Asymptomatic, severe MS with new atrial fibrillation – Asymptomatic, severe MS with mean gradient >15 mmHg or wedge pressure >25 mmHg with exercise – Highly symptomatic patients (NYHA III-IV) with severe MS with unfavourable anatomy or high risk for surgery (as a palliative attempt to try to relieve symptoms)

An obstructed mitral valve leads to LA dilation, atrial arrhythmias and pulmonary hypertension. Therefore, think of pulmonary hypertension and atrial fibrillation as the “end organ” effects of mitral stenosis!

*All recommendations require the PMBC be performed at a “Comprehensive Valve Centre”. PMBC remains contraindicated if LAA thrombus or moderate or more MR 93

Mitral Regurgitation •

Acute MR

– VERY unstable patients – Ischemia à papillary muscle dysfunction – Chord rupture à patients with mitral valve prolapse may rupture a chord acutely, leading to a flailing mitral valve leaflet acute severe MR – Endocarditis – Trauma

•

Chronic MR

– PRIMARY (“degenerative”) à is the disease • • • •

Valve leaflet (MVP [myxomatous, fibroelastic deficiency], rheumatic) Annulus (calcification) Chordae (trauma, infection, idiopathic) Papillary muscle (trauma)

– SECONDARY (“functional”) à is the consequence

• Dilated or ischemic cardiomyopathy -> leaflet tethering (being pulled towards the apex) + annular dilatation -> leaflet malcoaptation leading to regurgitation

•

Severe MR is defined using specific echocardiographic parameters that you should not need to know

Mitral Regurgitation - Intervention PRIMARY MR – “the goal of therapy is to correct MR before onset of LV systolic dysfunction” Class I indications for surgery (repair when possible vs. replacement) for PRIMARY MR: • Severe, symptomatic 1o MR irrespective of LVEF • Severe, asymptomatic 1o MR + LV systolic dysfunction (LVEF ≤ 60%, LVESD ≥ 40mm) AHA 2014, 2017, 2020 Valve

BONUS Read on own

Mitral Regurgitation - Intervention

Class IIa indications for for PRIMARY MR (reasonable): • Asymptomatic patients with severe MR with preserved systolic function (LVEF ≥60%, LVESD 95% success and 12mmHg)

YES (ITP change exaggerates ventricular interdependence)

USUALLY NO NO (mechanism debated; ?related to (no ventricular lack of ITP transmission) interdependence)

Other features

Beck’s triad (low BP, high JVP, muffled heart sounds)

Pericardial knock (rapid early diastolic filling) +/- friction rub

Manifestations of systemic disease (amyloid, sarcoid)

Arrhythmias Key Resources: • +++ CCS AF Guidelines [NB. Most recent = 2020 update] • CCS 2020 Syncope Update • ACC/AHA 2018 Pacing Guidelines • ESC 2021 Pacing Guidelines • CCS VT Guidelines • ACLS Guidelines

Screening for Atrial Fibrillation (AF) • General Population – pulse-based screening or rhythm-based screening at all routine health assessments in people >65yrs – follow-up with ECG assessment if “irregularly irregular”

• Cardiac Implantable Electrical Device (PPM, ICD) – interrogate all high atrial rate episodes for possible AF

• Non-lacunar Embolic Stroke of Unknown Source – ”at least 24h of ambulatory ECG monitoring”

• Longer monitoring if AF is still suspected but not proven CCS 2020 AF Update

AF Etiology & Initial Investigations Major Guideline: CCS 2020 Major Considerations: • Always look for an etiology/precipitant (EtOH, drugs, withdrawal, ischemia, PE, valves, thyroid disease, OSA, infection, sleep deprivation, acute pulmonary disease … ) • Basic Workup for new AF: • • • • •

Document rhythm ECHO – assess LV size and function, LA size, valve .. CBC, lytes (Ca, Mg), Cr, Coags, TSH for all LFT before amiodarone prescription A1C, FBG, Fasting lipid profile as part of comprehensive cardiac risk assessment

• Always assess patient AF-related symptoms and quality of life (CCS-SAF), assess patients with AF for frailty, cog impairment, dementia, depression CCS 2020 AF Update

CCS – SAF Scale – Symptoms of AF Class 0

Asymptomatic

Class I

Minimal symptoms or 1 episode without syncope or CHF

Class II

Symptoms have minimal effect: Mild awareness if in persistent/permanent AF Rare episodes (“less than a few per year”) in those w/ paroxysmal AF.

Class III

Symptoms have moderate effect on QOL: Moderate awareness most days with persistent/perm AF More common episodes (”more than every few months”) or more severe symptoms in pts with paroxysmal AF

Class IV

Symptoms have severe effect on QOL: Syncope due to AF and / or CHF due to AF and / or Unpleasant symptoms in pts with persistent/perm AF and / or Frequent and highly symptomatic episodes in pts w paroxysmal AF

AF: Prevention and Treatment Major Considerations cont’d: • Prevention = modifiable risk factor management • Achieve rate control with bblocker, CCB, or digoxin • AF with pre-excitation (WPW): àDC cardioversion (or procainamide) • Rhythm control preferred if QoL impaired (symptomatic despite rate control) or hemodynamically unstable (DC cardioversion) CCS 2020 AF Update

This cutoff of 130/80 Is not mentioned in the CCS text anywhere, only in this figure! We suggest just go with HTN Canada guidelines for resting BP target.

CCS 2020 AF Update

What about Atrial Flutter (AFL)?

“It is recommended that patients with Atrial Flutter be stratified and treated in the same manner as patients with atrial fibrillation.”

126

Anticoagulation in AF/AFL •

DOACs are 1st line for almost everyone – VKA (i.e. warfarin) should be used instead of DOAC for valvular AF (CCS 2016, 2018 and 2020 definition): • Mechanical heart valves • Rheumatic mitral stenosis • Moderate-severe non-rheumatic mitral stenosis – Warfarin should also be considered (class IIa) in patients with new onset AF ≤ 3 months post-valve replacement (surgical or percutaneous)

*NEW* FRAIL-AF (Circulation, 2023) looked at elderly (>75) frail patients with AF who were already on VKA and randomized to change to DOAC vs stay on VKA. • Surprisingly, more bleeding was observed in those who were switched to DOAC (15.2%) compared to those who continued VKA (9.4%), trial stopped early.

– Criticisms – small trial (n=1330), bleeding events were self reported and the primary outcome was driven by minor bleeding, not major bleeding. No formal guideline recommendations have incorporated this trial. – No difference in ischemic/embolic events – Take Away #1 – if elderly frail patient stable on VKA can continue – Take Away #2 – caution in extrapolating results of other RCTs to populations excluded from enrolment (frail elderly) CCS 2020 AF, CCS 2020 Valve

Anticoagulation in CKD/ESRD Calculate CrCl using Cockroft – Gault at baseline, and at least annually: • Stage 3 CKD (eGFR >30) – A/C as usual •

•

Stage 4 CKD (eGFR >15 0 à OAC only – Prefer DOAC > VKA

*STABLE CAD = no PCI or ACS in preceding 12 months CCS 2020 AF Update

(2a) AFIB + PCI (elective or ACS) Individualize based upon thrombotic risk LOW RISK thrombotic events Elective PCI (no ACS)

HIGH RISK thrombotic events or ACS with PCI

CHADS65 = 0 à DAPT

CHADS65 = 0 à DAPT

–

DAPT for 6-12 months per CCS 2018 Antiplatelet Guidelines for non-AF patients

CHADS65 >0 à “Dual Pathway” –

SAPT with a P2Y inhibitor* + OAC for at least 1 month, up to 12 months after PCI, then OAC alone

CHADS65 >0 à “Triple Therapy”x1-30d THEN

“Dual Pathway Therapy” = clopidogrel + OAC up to 12 months post PCI THEN OAC only

**NEW** CCS 2023 Antiplatelet Guidelines says for PCI and need for OAC, dual pathway is recommended over triple therapy but specifies they receive 1 dose of ASA with PCI. Therefore it is as if they had “1 day of triple therapy.” If asked in an exam situation, minimizing triple therapy (1-30 days) or going straight to dual pathway would be guideline recommended durations. Talking with the interventionalist would also be an important step (i.e. how complex was the PCI). *P2Y inhibitor = Pick CLOPIDOGREL – lower bleeding risk

CCS 2020 AF Update

Who is HIGH RISK Post-Elective PCI?

•

Mitigate bleeding risk: Avoid prasugrel/ticagrelor – that’s why they say clopidogrel in guideline table

• • •

Consider PPI Avoid other NSAIDs if VKA target INR 2-2.5

CCS 2020 AF Update

(2a) AFIB + ACS – NO PCI /stent Individualize based upon thrombotic risk CHADS65 = 0 à DAPT = Dual Antiplatelet Therapy (ASA + P2Y inhibitor) CHADS65 > 0 à “Dual Pathway Therapy”: clopidogrel + OAC [apixaban1] for 1 to 12 months post ACS THEN OAC only 1TIP

– the only OAC studied after ACS without PCI is apixaban 5mg po bid. This is favoured in wording of guidelines for this scenario with clopidogrel. CCS 2020 AF Update

Prescribing notes – not all OAC the same dose in dual pathway, triple therapy: The OAC component of dual pathway regimens includes: normal dose edoxaban, apixaban, dabigatran BUT rivaroxaban only 15 mg PO daily (10 mg in patients with CrCl 30-50 mL/min). –

A DOAC is preferred over warfarin, however if warfarin is to be used the lower end of the recommended INR target range is preferred. All patients should receive a loading dose of ASA 160 mg at the time of PCI (if previously ASA-naïve).

The OAC component of triple therapy regimens includes: warfarin daily, rivaroxaban 2.5 mg PO BID, or apixaban 5 mg BID (reduced to 2.5 mg if they met two or more of the following dose reduction criteria: age > 80 years of age, weight < 60 kg, or Cr > 133 μmol/L). –

A DOAC is preferred over warfarin, however if warfarin is to be used the recommended INR target is 2.0-2.5. All patients should receive a loading dose of ASA 160 mg at the time of PCI (if previously ASA-naïve). Thereafter, ASA may be discontinued as early as the day following PCI or it can be continued longer. The timing of when to discontinue ASA will depend on individual patient’s ischemic and bleeding risk.

The dose of OAC beyond one year after PCI should be standard stroke prevention doses. A combination of an OAC and single antiplatelet therapy may be used only in highly selected patients with high-risk features for ischemic coronary outcomes, and who are also at low risk of bleeding CCS 2020 AF Update

CCS 2020 AF Update

AF – OAC in Special Populations Liver Disease

We recommend that OAC not be routinely prescribed in Child-Pugh class C or liver disease associated with significant coagulopathy

Cancer

Individualize OAC treatment in pts with active cancer. Consider DOAC> VKA.

Congenital Heart Disease

OAC for most patients with AF and HCM OAC if CHADS65 risk factors

Frail Elderly

OAC for most frail elderly – individualizing recommendations if high risk bleed

Secondary Atrial Fibrillation =clearly provoked by transient/ reversible risk factor such as severe sepsis, thyrotoxicosis

No OAC Exceptions: patient’s underlying ‘abnormal substrate’ and risk for recurrence estimated to be high and for “most patients during acute thyrotoxicosis until euthyroid state is restored”

Pregnancy (2021 CCS Pregnancy Heart Disease Update)

No DOACs (cross placenta). Consider LMWH, Warfarin (Tri2-3) in unique circumstances (see OB Med lecture for more details). Anticoag should be considered for pregnant women with AF and (1) structural heart disease or (2) no structural heart disease but CHADS >=1

High atrial events (i.e. PACs) WITHOUT AF

*NEW* NOAH-AFNET6 trial looked at patients with mean CHA2DS2VASC 4 and high atrial events (i.e. PACS) but no AF and started them on edoxaban vs. placebo. NO DIFFERENCE in stroke/systemic embolism. Don’t start DOACs for PACS!

Cardioversion of AF DOAC preferred

CCS 2020 AF Update

MCQ #4 2024 A 68yF is investigated for palpitations. She is a retired nurse and noticed that for the last two years her HR is irregularly irregular. 48h Holter reveals she is in Afib throughout the study, 95% of the time rates controlled /=3 weeks before planned cardioversion (chemical or electrical), continue DOAC indefinitely D) TEE, cardioversion (chemical or electrical), 3 weeks anticoagulation, then stop DOAC and change to ASA indefinitely E) None of the above

BONUS MCQ 23 A 37-year-old male with a history of HTN and recent cocaine use presents to the ED with ”tearing” chest pain radiating to the back. ECG reveals sinus tachycardia, SBP 160mmHg. He is in significant discomfort and agitated. A CT scan of the chest reveals aortic dissection involving the descending thoracic aorta. Which of the follow is the best next management strategy? A) STAT cardiac surgery consultation for urgent aortic surgery B) Admit patient to monitored unit; target HR first to < 60-80 bpm with IV labetalol; target SBP next with IV nitroprusside to < 120mmHg C) Admit patient to monitored unit; target HR first to < 60-80 bpm with IV calcium channel blocker; target SBP next with IV nitroprusside to < 120mmHg D) Admit patient to monitored unit; target SBP first with IV alpha blocker, then use nitroprusside as 2nd line agent as required

BONUS MCQ 24 A 42-year-old male presents to your clinic with exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea and dry cough for 4 months. He eventually developed peripheral and scrotal edema, which prompted him to seek evaluation. His ECG is shown below. His BNP is elevated. Tn is within normal range. He does not take any medications. His TTE reveals LVEF 22%, with severe RV dysfunction. In addition to coronary evaluation and lifestyle measures, which of the following best describes the next best therapy steps based on Canadian Guidelines? A) Beta blocker, ACEI, SGLT2i, MRA, furosemide as needed; consider device therapy after 3 months of optimal medical therapy B) ARNI, SGLT2i, MRA, furosemide as needed; consider ICD after 3 months of optimal medical therapy C) Beta blocker, ARNI, SGLT2i, MRA, ivabradine, furosemide as needed; consider device therapy after 3 months of optimal medical therapy D) ARNI, SGLT2i, MRA, furosemide as needed; refer to EP for ICD now

BONUS MCQ 25 – new 2024 A 55 year old man with a history of diabetes and hypertension has a lateral MI with PCI to his left circumflex artery. His transthoracic echocardiogram prior to discharge shows an LVEF of 52% with a lateral wall motion abnormality. He does not have any symptoms of heart failure. He asks about interventions he can do to reduce his cardiovascular risk. Based on the best available evidence all of the following interventions will reduce his risk of cardiovascular death or hospitalization EXCEPT: a. Add SGLT2 b. Flu shot c. Routine stress testing at 1 year d. Polypill of aspirin/statin/ACE inhibitor

228

BONUS MCQ 26 – new 2024 A 45yM is admitted with NSTEMI. He underwent an exercise myocardial perfusion scan which showed an anterior wall perfusion defect with stress, and subsequently underwent coronary angiography which showed a severe lesion of the LAD which was treated with 1 drug eluting stent. There is no other significant residual disease. His transthoracic echocardiogram shows normal LV function and wall motion. He feels well. No heart failure or arrhythmias. He works as a bus driver. He inquires if there are any restrictions to his ability to drive. You tell him prior to discharge: A) B) C) D)

No restrictions 48 hours post PCI for private driving, 1 week for commercial driving 2 weeks post PCI for private driving, 1 month for commercial driving 1 month post PCI for private driving, 3 months for commercial driving

229

BONUS MCQ 27 – new 2024 65yM with ischemic cardiomyopathy, previous anterior MI 2021 with primary PCI to the LAD. At the time he had residual moderate lesions in the circumflex and right coronary arteries. He is admitted to your care for decompensated heart failure and was found to have a significant troponin elevation which lead to a coronary angiogram which shows severe lesions of the proximal LAD, circumflex and RCA. A cardiac MRI was performed which shows a transmural infarction in the distal LAD territory, however there is otherwise good viability in all other territories. His LVEF is 30%. Home Meds: aspirin, valsartan, bisoprolol, spironolactone, atorvastatin. Which of the following interventions will NOT reduce his risk of cardiovascular death and hospitalization for heart failure? a. Coronary artery bypass grafting b. Percutaneous coronary intervention c. Change valsartan to combination sacubitril-valsartan d. SGLT-2 inhibition 230

BONUS MCQ 28 – new 2024 A 66 y F is seen in routine follow-up. PMH: HTN, T2DM, inferior MI 3 months ago where she received one drug eluting stent to the RCA. Her left ventricular systolic function is normal. She has been feeling well since leaving hospital except for experiencing intermittent palpitations over the last 2 weeks. She had called your office and a 48 hour Holter monitor was arranged prior to this visit. You review the Holter monitor with her which shows paroxysmal atrial fibrillation with the longest episode lasting 24 hours. Her current medications include aspirin 81mg daily, ticagrelor 90mg BID, ramipril 2.5mg daily, bisoprolol 5mg daily, metformin 500mg BID, dapagliflozin 5mg daily, rosuvastatin 10 mg daily. A) B) C) D)

Which of the following modifications do you make to her medications? Discontinue ticagrelor, start rivaroxaban 20 mg daily Discontinue aspirin, start rivaroxaban 15mg daily Discontinue aspirin and ticagrelor, start rivaroxaban 15mg daily Discontinue aspirin and ticagrelor, start clopidogrel 75mg daily and rivaroxaban 15mg daily

231

BONUS MCQ 29 – new 2024 50yM with a history of HTN, DLD, T2DM, CAD and HFmrEF. PCI to the RCA 3 years ago after an inferior MI with no recurrence of anginal symptoms. He has baseline NYHA II symptoms and his LVEF was 45% on TTE last month. Recently to ED with acute onset palpitations, found to be in atrial fibrillation and was electrically cardioverted. His aspirin was discontinued and he was prescribed for apixaban 5mg BID. He has since had 2 more episodes spontaneously converting to sinus. He finds these episodes bothersome and is interested in adjusting his medications to prevent these episodes. He is worried about starting amiodarone due to long term side effects, and is asking if there are other options. His current medications include apixaban 5mg BID, ramipril 2.5mg daily, bisoprolol 5mg daily, spironolactone 25mg daily, dapagliflozin 10mg daily, furosemide 40 mg daily. In addition to investigating etiology of his paroxysms of atrial fibrillation, which would be the most appropriate change to his medications? A) Discontinue bisoprolol, start sotalol

B) Continue bisoprolol, start flecainide C) Continue bisoprolol, start dronedarone D) Discontinue bisoprolol, start propafenone

232

BONUS MCQ 30 new 2024 A 75-year-old man presents to clinic regarding right leg pain that occurs with exertion present over the last 2 months. The symptoms are consistently relieved by rest. He notes decreased hair on his right leg. His right DP pulse is weaker than the left. You suspect peripheral arterial disease and intermittent claudication as a cause for symptoms. His comorbidities include diabetes and a 50 pack year smoking history for which he continues to smoke. He does not have any known cardiac disease. You discuss your thoughts including next steps to confirm your diagnosis. All of the following statements are true, EXCEPT: a)

If he were asymptomatic, performing an ABI would still be indicated in this patient to screen for PAD b) An ABI requires a continuous wave doppler and blood pressure cuff to be performed and is the diagnostic test of choice to diagnose PAD c) An ABI less than 0.9 indicates the presence of some degree of PAD d) If diagnosed with PAD, he should also be screened for CAD/carotid artery stenosis

233

BONUS MCQ #31 new 2024 All of these patients are bus drivers and have had syncope. Which of the following recommendations for private and commercial driving are correct for their clinical scenario? A. A 40 year old woman with no medical history who suffered an episode of syncope while donating blood, preceding by nausea and flushing prior to the needle draw. She has never had syncope before. Recommended to not drive for 1 week privately, 1 month commercially. B. A 50 year old man who presented to hospital after having a syncopal episode preceded by 2 days of severe diarrhea, with an orthostatic drop in blood pressure which resolved with fluid hydration. Recommended not to drive privately for 1 week, 1 month commercially. C. A 40 year old man who had an episode of syncope which after a thorough history, physical examination and investigations, no cause of syncope was identified. Recommended not to drive privately for 1 week, commercially for 12 months. D. The same 40 year old man in C but he has now had a second episode of unexplained syncope, 1 month after the first episode. Recommended not to drive privately for 3 months, commercially for 12 months.

234

BONUS MCQ #32 new 2024 A 45 year old man with diabetes and a strong family history of CAD presents with 1 month exertional chest pain. He undergoes a stress echocardiogram which shows wall motion abnormalities in the LAD and RCA territory at peak stress, concerning for multivessel coronary artery disease. He is admitted that day to undergo elective but expedited coronary angiography which shows severe lesions in the LAD, circumflex and RCA. He is recommended continued admission for planning for coronary artery bypass grafting (CABG) assessment. Based on the new CCS 2023 Antiplatelet Update, which of the following options is INCORRECT regarding management of this patient: A. A second antiplatelet like ticagrelor should not routinely be administered prior to elective coronary angiography B. Ticagrelor should be held 2-3 days prior to CABG C. Aspirin should be held 2-3 days prior to CABG D. DAPT, with aspirin and ticagrelor, should be started post-operatively when safe to do so from a bleeding perspective

235

BONUS MCQ ANSWERS MCQ 1: MCQ 2: MCQ 3: MCQ 4: MCQ 5: MCQ 6: MCQ 7: MCQ 8: MCQ 9: MCQ 10: MCQ 11: MCQ 12:

Answer D multivessel disease + diabetes would be associated with a mortality benefit with CABG. Answer C - Surgery may proceed without further delay for cardiac testing. B is wrong because the presence of LBBB means you cannot do stress echo (due to wall motion abnormalities) or exercise nuclear (due to septal perfusion defect artifact with exercise. Answer B - VALVE Question: refer to CV Surg LVESD is >40 Answer A change ramipril to sacubitril/valsartan, add empagliflozin – ok to do concurrently Answer C (3): Stop ASA and Clopidogrel and start warfarin alone. Answer 1 – start anticoagulation with a NOAC for at least 4 weeks. Answer D) refer to CV surg for potential valve repair/replacement. Answer (A) DC cardioversion Answer – (B) ASD Answer– (B) Transfer urgently to PCI centre for primary PCI Answer A Aortic regurgitation – acute AR causing heart failure secondary to aortic dissection Answer - C - Leg raise – HOCM murmur will get quieter. Recall: maneuvers that make HCM/MVP louder: Standing/Valsalva (decreased venous return) and Amyl Nitrate (decreased afterload)

BONUS MCQ ANSWERS MCQ 13: d Warfarin with goal INR 2.5-3.5 per new ACC/AHA Valve dz guideline For patients with a mechanical mitral valves, warfarin alone is not necessarily adequate. – The new ACC/AHA Guidelines no longer recommend routine use of ASA with mechanical valves… “For patients with a mechanical SAVR or mitral valve replacement who are managed with a VKA and have an indication for antiplatelet therapy, addition of aspirin 75 to 100 mg daily may be considered when the risk of bleeding is low.” - so for this patient with HTN only we would not otherwise prescribe ASA! – Patients with mitral valve prosthesis should be on warfarin with an with an international normalized ratio (INR) goal of 3 (2.5-3.5). – Patients with a ‘current generation’ aortic valve prosthesis should be on warfarin with an with an international normalized ratio (INR) goal of 2.5 (2-3). Patients with older AVR (ball-cage) may benefit from higher target 3.0. – Higher INR goals may be considered in patients who have thromboembolic events while anticoagulated within this INR range. This patient has not had a thromboembolic event therefore a higher INR goal would not be indicated.

MCQ 14: ASD (causes wide, fixed split S2) MCQ 15: Answer A - Super tough question J - He will decline functionally if delay surgery 12 mos. Delay 3 mos post PCI. Patients get spinal anesthesia for TKA so clopidogrel must be held7d preop. Per CCS 2020 guidelines should be on “Dual Pathway Therapy” – OAC + Clopidogrel, but recall that Xarelto dose for Dual Pathway is only 15mg not 20. Tricky tricky J

BONUS MCQ ANSWERS MCQ 16: Answer B. Similar to MCQ 1 but has LM disease. LM disease excluded from ISCHEMIA trial, so we don’t really know about the PCI vs OMT question. MCQ17: Answer D. Getting primary PCI. No prasugrel (hx stroke). E is Pericarditis dosing. This is not a pericarditis ECG. NB. There is an Emerging role for Colchicine post MI – 0.5mg/day reduces MACE compared to placebo [COLCOT Trial, NEJM Nov. 2019] MCQ18: Answer C. Note FAMILIAL ANGIOEDEMA = synonymous with HEREDITARY ANGIOEDEMA DAPA is now in the guidelines for non diabetic w EF 40%, antiarrhythmic options are limited to sotalol or amiodarone. Sotalol would be the preferred option to try as he is young and amiodarone will have cumulative side effects. Stop bisoprolol if starting another beta blocker; propafenone, flecainide and dronedarone are not appropriate in a patient with heart failure. Amiodarone could be considered for this patient with CAD and HF but is not a great long term solution due to side effects). MCQ #30: Answer D - PER NEW CCS 2022 PAD GUIDELINES, DO NOT SCREEN ASYMPTOMATIC PTS FOR CAD/CAS MCQ #31: Answer: A. Patients with vasovagal syncope, even recurrent episodes, have low of episodes while driving, therefore no driving restriction. Note if B was changed to have an avoidable trigger, like micturition syncope, this would have the same recommendation. The CCS 2020 syncope guidelines and CCS 2023 Fitness to Drive guidelines do not specify what is needed to diagnose unexplained syncope. The minimum work-up is history, examination and ECG followed by targeted investigations. MCQ #32: Answer C. Aspirin should be continued to day of surgery, while ticagrelor should be held 2-3 days before, clopidogrel 2-7 days before. DAPT is now (weakly) routinely recommended post CABG. Loading on DAPT for elective coronary angiography is not routinely recommended as this could delay timing of a CABG due to bleeding risk. 240

Critical Care Medicine & Toxicology Saturday, December 2, 2023 Dr. Jacob Michie www.internalmedicinereview.ca

© Internal Medicine Review 2024

BONUS Read on own • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •

Acronyms Used in this Talk

ABG – arterial blood gas Abs - antibodies ACS-Acute coronary syndrome AE - adverse events AG – anion gap AGMP-Aerosol generating medical procedure AKI-Acute kidney injury ARDS-Acute Respiratory Distress Syndrome A&O-Alert and oriented AVM – arteriovenous malformation b/l-Baseline BIPAP-Bilevel positive airway pressure BG-Blood glucose BP-Blood pressure CAM – confusion assessment method CCCS – Canadian Critical Care Society CI - Contraindication CO-Cardiac output COT-Conventional oxygen therapy CPAP-Continuous positive airway pressure CVP-Central venous pressure Ecmo-Extracorporeal Membrane Oxygenation ED-Emergency department EPAP-Expiratory positive airway pressure ETOH - ethanol ETT-Endotracheal tube EVD – external ventricular drain FiO2 – fraction of inspired oxygen FRC-Functional residual capacity GCS-Glascow coma scale

• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •

HFNC-High flow nasal cannula HR-Heart rate ICP – intracranial pressure ICU-Intensive care unit IFN - Interferon ILD – interstitial lung disease IPAP-Inspiratory positive airway pressure IMV-Invasive Mechanical Ventilation iNO-Inhaled nitric oxide IVC-Inferior vena cava I:E-Inspiratory Time to Expiratory Time Ratio JVP-Jugular venous pressure LOC-Level of consciousness LR-Likelihood ratio LV-Left ventricle MAP-Mean arterial pressure NAC - N-Acetylcysteine MEWS – Modified early warning score NEWS – National early warning score MG – myasthenia gravis NDD-Neurologic Determination of Death NIV-Non-invasive ventilation NMBA-Neuromuscular blocking agent NS-Normal Saline NYD-Not yet diagnosed OG – osmolar gap OSA – obstructive sleep apnea OHS – obesity hypoventilation syndrome Pplat-Plateau pressure PEEP-Positive end expiratory pressure PIP-Peak inspiratory pressure

• • • • • • • • • • • • • • • • • • • • • • • • • • •

PPE-Personal protective equipment PSILI – patient self induced lung injury PSV-pressure support ventilation RASS – Richmond agitation-sedation scale RM – Rumack-Matthew RCT – randomized control trial RL-Ringer’s lactate ROSC – return of spontaneous circulation RR-Respiratory Rate RSBI-Rapid shallow breathing index qSOFA-quick Sequential Organ Failure Assessment SBT-Spontaneous breathing trial SCC-Surviving Sepsis Campaign SIRS-Systemic Inflammatory Response Syndrome SUP-Stress Ulcer Prophylaxis SV-Stroke volume SVR-Systemic vascular resistance Sx-Surgery TFB – total fluid balance TCA-Tricyclic Antidepressant VBG – venous blood gas VF – ventricular fibrillation VT – ventricular tachycardia VTE-Venous thromboembolism Vt-Tidal volume VILI – ventilator induced lung injury V/Q-Ventilation/perfusion

2

OUTLINE • Extra slides for your reference: Shock and Sepsis – Acute hypoxia in the ICU Respiratory failure – Gas trapping Covid-19 in the Critically Ill – Maternal cardiac arrest Weaning from Mechanical Ventilation – Liver failure guidelines ICU Delirium, Sedation, Analgesia, – Hyperthermia & Hypothermia Sleep – Toxicology Bonus Slides • Targeted temperature management, – Bonus MCQs neuroprognostication, DNC, neuro Useful Resources! ICU • https://sccm.org/Home • https://emcrit.org/category/emcrit/ • Toxicology • https://litfl.com/ • • • • •

•

https://oncicu.com/Home

MCQ 1 2024 A 45y patient presents to the emergency department with a 2 day history of right upper quadrant abdominal pain, fever, rigors and vomiting. Initial vitals BP 79/50, HR 110, RR 26, SpO2 96% on RA, Temp 39.5C. Weight 70kg. Exam: abdominal tenderness in right upper quadrant but no signs of peritonitis, capillary refill time is prolonged. Laboratory : Hb 95, WBC 21, Plt 46, ALT 80, ALP 500, Bilirubin 50, Lactate 5. Abdominal ultrasound in the ED shows a hypoechoic structure in the common bile duct with biliary dilation, and a distended gall bladder with edematous walls. Treatment: Two large bore antecubital fossa peripheral intravenous lines are inserted, broad spectrum antibiotics and 3L of balanced crystalloid are administered. Subsequent vital signs are BP 80/50 (MAP 60), HR 80, RR 24, SpO2 94% RA, POCUS shows a distended IVC without respiratory variability, lactate is now 3. What is the next best step in this patient’s management? 1. Consult Interventional Radiology for consideration of biliary drainage 2. Start hydrocortisone IV 200mg/day in divided doses 3. Start norepinephrine infusion via peripheral intravenous line 4. Transfuse platelets and insert a central venous catheter 5. Change MAP target to ≥ 60

4

Circulatory Shock Syndromes

-

Distributive

Hypovolemic

Cardiogenic

Obstructive

Loss of Vascular Tone

Low Pre-load

PUMP failure

Excessive After-load

Sepsis Anaphylaxis SIRS (eg. pancreatitis) Mitochondrial Dysf. (eg. cyanide) Endocrine (thyroid, adrenal crisis) Others*

66%

-

Hemorrhage Trauma Burns Operative losses GI losses Renal losses Third space losses (Pancreatitis)

16%

-

ACS Arrythmia Acute Valvulopathy Cardiomyopathy (restrictive or dilated) Right or left sided heart failure

16%

-

Pulmonary Embolism Tamponade Tension pneumothorax

2%

*Other Distributive: HLH, medications, liver failure, post cardiopulmonary bypass vasoplegia, neurogenic shock

Vincent and De Backer. Circulatory Shock. N Engl J Med 2013; 369:1726-1734

5

Sepsis Defined (Surviving Sepsis Campaign, SCCM 2021) “Life threatening organ dysfunction secondary to dysregulated host response to infection” Use your clinical acumen, measure lactate, and a screening tool to diagnosis sepsis

Septic Shock = Sepsis + ü adequate volume resuscitation ü Persistent ↓BP requiring vasopressors to keep MAP ≥ 65 ü lactate > 2 mmol/L

Screening Tools recommended by SCCM SIRS, MEWS, NEWS (not qSOFA) SIRS is easiest tool to memorise for oral exam : HR >90 Temp >38 or 20 or PaCO2 12 or 80% corresponds with high flow states (eg. sepsis). Mitochondrial dysfunction leads to reduced O2 utilization • < 65% indicates poor forward flow: cardiogenic shock • Here, the heart isn’t strong enough to pump the oxygen out to the cells 7

Sepsis: IMMEDIATE Initial Resuscitation • If sepsis induced hypotension/shock, begin rapid administration of at least 30ml/kg (ideal body weight) crystalloid within the first 3h (2021 = Suggestion) • See next slide for guiding fluid resuscitation

• Use vasopressors if patient is hypotensive during or after fluid resuscitation to keep MAP≥65 – Norepinephrine (“levophed”) is first line vasopressor

• Give broad spectrum antibiotics within 1 hour – Obtain blood cultures prior to antibiotics if possible

Diagnosis of Sepsis unclear? DO : re-evaluate, perform diagnostic tests, can delay antibiotic start up to 3 h DON’T : measure procalcitonin to help with decision to start antibiotics

• If ICU level care needed, admit to ICU within 6 hours 1. Evans et al. Critical Care Medicine 2021; doi:

10.1097/CCM.0000000000005337

Sepsis: Antibiotic Choice • Broad spectrum antibiotics recommended (e.g. piperacillin-tazobactam) and consider individual risk of: – MRSA coverage empirically if high risk

• High risk: known MRSA colonized, recurrent skin/soft tissue infxn, PWID, central lines, dialysis

– Multi-Drug Resistant (MDR) organism – **double (2 antibiotic) GN coverage if high risk • High risk: previous abx within 3 months, known MDR colonization, local prevalence, travel to endemic country or hospitalization abroad **This is a weak recommendation with low quality evidence

– Fungal coverage if high risk

• High risk: neutropenia, immunocompromised, TPN, dialysis, chronic lines, PWID, HIV, Heme or solid organ transplant, emergency GI surgery or anastomotic leak

• Daily assessment for de-escalation of antibiotics • Rapidly identify if infection requires source control, remove source (including vascular access device) as soon as possible 1.

GN = Gram Negative

2.

SSC 2021. Intensive Care Med (2021) 47:1181–1247. doi.org/10.1007/s00134-021-06506-y CCM (2021) 49:11. DOI: 10.1097/CCM.0000000000005357

9

Sepsis: Guiding Resuscitation • Use DYNAMIC VARIABLES over physical examination and static parameters alone to guide resuscitation – – – –

Response to fluid bolus Response to passive leg raise (45o raise x 30-90sec = 15% increase in stroke volume) Pulse pressure variation (PPV) (>10%) Echocardiography • Stroke volume or Stroke volume variation (SVV) • IVC DI=(Dmax-Dmin)/Dmean – Intubated, fully ventilated-Distensibility Index >15-20% likely to be fluid responsive – Intubated breathing spontaneouslyà cannot use – Spontaneously breathing not intubated IVC 50%àlikely fluid responsive

• Lactate levels – if elevated aim to reduce with resuscitation • Capillary refill à Abnormal >3sec, Normal 200% above baseline)

? Suggest albumin in patients who received large volumes of crystalloid over crystalloid alone

❌ ❌

- Costly, no mortality benefit, did not define “large volume” – weak recommendation only Do not use starches (34 deaths per 1000) Do not use gelatin

HOW MUCH? • Guidelines: insufficient evidence to make recommendation • Titrate to fluid responsiveness • Judiciously give fluids to avoid excessive fluid overload • Restrictive Vs Liberal – CLASSIC Trial (NEJM 2022) failed to show difference in 90d mortality, but proof of concept that less fluid can be safe – CLOVERS (NEJM 2023): no 90d mortality difference, more vasopressor use in restrictive group 1. Semler, M. et al. NEJM 2018; DOI: 10.1056/NEJMoa1711584 2. PETAL Network and NHLBI. NEJM 2023; 388:499-510: DOI: 10.1056/NEJMoa2212663

Hemodynamic Management and Vasopressors Doses Norepinephrine/Epinephrine 0.05-0.5mcg/kg/min Vasopressin 2.4 units/hr Dobutamine 2.5-10 mcg/kg/min Add vasopressin when Norepinephrine approx 0.25 – 0.5 mcg/kg/min

Consider MAP target 60-65 in elderly patients. Trend towards possible mortality benefit with permissive hypotension in age > 65 and chronic hypertension.

1.

SSC 2021. Intensive Care Med (2021) 47:1181–1247. doi.org/10.1007/s00134-021-06506-y

Lamontagne F, et al. JAMA 2020: 323(10); 938-949

12

BONUS Read on own

BONUS: VASOPRESSOR PRIMER Drug

HR

SVR

CO

PCWP

Phenylephrine

ê

é

ê

é

Norepi

é

é

é/-

é

Dopamine

é

é

é

é

Epinephrine

é

é

é

ê

Dobutamine

é

ê

é

ê

Milrinone

é/-

ê

é

ê

Vasopressin

ê/-

é

ê/-

é

Steroid recommendations Theory: may help immune dysregulation, relative adrenal insufficiency • Consider for septic SHOCK with ongoing requirement for vasopressor – Hydrocortisone 200mg/d (typically 50 mg IV q6h) – Consider when norepinephrine 0.25mcg/kg/min for > 4hrs – Not recommended in sepsis without shock

• Duration unclear (caution if prolonged àmay need to taper) • No mortality benefit – considered a vasopressor sparing agent • Risks include potential hyperglycemia, hypernatremia, neuromuscular weakness

“Don’t Try these at Home”: Treatments to NOT give • • • • • • •

Immunoglobulins (IVIG) Polymyxin IV vitamin C (LOVIT trial – showed potential harm) Angiotensin II infusion Levosimendan Activated Protein C Liberal oxygen (target 94-96%, a sat >96% increases mortality in critically ill)

Best Practices in Sepsis: Summary of Guidelines Screening

Hospitals to improve screening processes, SIRS/MEWS/NEWS > qSOFA, admit to ICU < 6hrs

Resuscitation

30ml/kg balanced crystalloid, guide with dynamic measures, CRT, lactate

Infection

Abx in 1hr if probable or shock, cover resistant organisms if high risk, source control

Hemodynamics

MAP ≥65, Invasive BP monitoring, NE then Vaso, peripheral vasopressors for limited time

Steroids

Hydrocortisone 200mg/d when NE > 0.25mcg/kg/min for >4hrs

Ventilation

HFNC > NIV for Hypoxemic Resp Failure, LPV as per usual ARDS treatment (see slides on ARDS)

Best Practices

Restrictive Hb targets, VTE ppx, Stress ulcer prophylaxis, insulin for glucose > 10, Enteral feeding early

Long term outcomes

Address GOC early, integrate palliative care as needed, refer patient and family to support groups, involve social work, arrange follow up at discharge

CRT = Capillary Refill Time, Abx = antibiotics, NE = norepinephrine, Vaso = Vasopressin, HFNC = High flow nasal cannula, LPV = lung protective ventilation, ARDS = Acute Respiratory Distress Syndrome, NIV = Non-invasive ventilation, GOC = Goals of care, Hb = haemoglobin, VTE =Venous Thromboembolism

1.

SSC 2021. Intensive Care Med (2021) 47:1181–1247. 16 doi.org/10.1007/s00134-021-06506-y

MCQ 1 2024 A 45y patient presents to the emergency department C is correct.with a 2 day history of right upper quadrant abdominal pain, fever, rigors and vomiting. Vasopressors should be started for patients with septic shock (sepsis + adequate + MAPWeight < 65 + lactate Initial vitals BP 79/50, HR 110, RR 26, SpO2volume 96% onresuscitation RA, Temp 39.5C. 70kg. > 2). Not a: Source control should be achieved as soon as medically possible, whether that Exam: abdominal tenderness in right upper quadrant but no signs of peritonitis, capillary refill time is prolonged. viaALP consulting general 50, surgery or interventional radiology. However, this process Laboratory : Hb 95, WBC 21, Plt 46, ALTbe80, 500, Bilirubin Lactate 5. may take hours and resuscitation should be optimixed first with vasopressors Abdominal ultrasound in the ED showsNot a hypoechoic in theonce common bile duct biliary dilation, and a b: Consider structure hydrocortisone the patient is on with norepinephrine at distended gall bladder with edematous0.25mcg/kg/min walls. for > 4hrs. Vasopressors have not yet been started so this would not Two large bore antecubital fossa peripheral intravenous be suggested yet. lines are inserted, broad spectrum antibiotics and 3L of balanced crystalloid are administered. Not D: Guidelines suggest vasopressors can be started peripherally if central access Subsequent vital signs are BP 80/50 (MAP 60), HR 80,Moreover, RR 24, SpO2 RA, POCUS distended IVC without is not available. they94% suggest that youshows shouldanot delay vasopressor respiratory variability, lactate is now 3.initiation to gain central venous access. What is the next best step in this patient’s management? Not E: MAP targets in the initial resuscitation of sepsis should be >65. After initial resuscitation 60-65of could be considered 1. Consult Interventional Radiology for consideration biliary drainage for elderly patients with ongoing vasodilation (see Lamontagne study). 2. Start hydrocortisone IV 200mg/day in divided doses 3. Start norepinephrine infusion via peripheral intravenous line 4. Transfuse platelets and insert a central venous catheter 5. Change MAP target to ≥ 60

17

OUTLINE • Shock and Sepsis • Respiratory failure – HFNC, NIV, Invasive MV – ARDS – Covid-19 in the Critically Ill

• Weaning from Mechanical Ventilation • ICU Delirium, Sedation, Analgesia, Sleep • Targeted temperature management, neuroprognostication, DNC, neuro ICU • Toxicology

• Extra slides for your reference: – – – – – – –

Acute hypoxia in the ICU Gas trapping Maternal cardiac arrest Liver failure guidelines Hyperthermia & Hypothermia Toxicology Bonus Slides Bonus MCQs

BONUS Read on own

• • • •

High Flow Nasal Cannula (HFNC)

Humidified O2 Flow up to 60 L/min FiO2 up to 100% AGMP

Proposed Benefits: Heated / Humidified Gas

Increased secretion clearance Decreased bronchoconstriction

Washout C02 Upper Airways

Decreased dead space

High Nasal Insp. Flow

Decreased upper airway resistance

Positive Airway Pressure

Recruitment of atelectasis (gives minimal PEEP ~ 5 cmH2O)

Decreased entrainment ambient air

Increased FiO2

Decreased work of breathing, transpulmonary pressures

Decreased patient self-induced lung injury. Ozkowski et al. ERJ 2022;59:2101574. Goligher et al. AJRCCM 2017;195(9).19

HFNC Should Probably be Used For:

HFNC Should Probably Not be Used For:

• Hypoxemic resp failure (adults): HFNC over Conventional O2 Therapy (COT) or NIV • Patients taking Non-Invasive Ventilation (NIV) breaks: HFNC over COT • Post extubation (non-surgical patients) that are at a low/mod risk of extubation failure: HFNC over COT • Post-operative patient at low risk of respiratory complications: HFNC or COT • Post-operative patient at high risk of respiratory complications: HFNC or NIV

• Post extubation for patients at a high risk of extubation failure: NIV over HFNC (unless relative or absolute CI) • Acute hypercapnic resp failure secondary to COPD (pH < 7.35): trial NIV before HFNC

20

BONUS Read on own

Non-Invasive Ventilation

Mode

CPAP – Continuous Positive Airway Pressure

BiPAP – Bi-Level Positive Airway Pressure

What does the machine provide?

Constant pressure throughout expiration and inspiration (i.e. PEEP or EPAP)

- Expiratory Positive Airway Pressure (EPAP = PEEP) AND - Inspiratory Positive Airway Pressure (IPAP)

Physiological Benefits

- Reduced respiratory muscle oxygen consumption - Recruitment of alveoli – Improved V/Q matching - Reduced LV afterload - Reduced Preload

- All the same as CPAP AND - Increased alveolar ventilation

21

NIV Should Definitely be Used For: • •

BiPAP for mild-severe acidotic COPD patients (RR >20-24, pH≤7.35, and PaCO2>45) BiPAP/CPAP for Cardiogenic pulmonary edema* (not cardiogenic shock and acute MI) *Also in pre-hospital setting

NIV Should Probably Not be Used For: • • •

Treatment of post-extubation resp failure Prevention of post-extubation resp failure if not high risk Hypercapneic COPD patients who are NOT acidotic

NIV Should Probably be Used For: •

• •

No Recommendation for i) Asthma exacerbation ii) De novo respiratory failure-I.e hypoxemia NYD, ARDS iii) Acute Resp Failure due to viral illness during pandemic

Acute Respiratory Failure (ARF) if: • Post-operative patients (supra-diaphragmatic i.e. lung, abdominal, pelvic) • Chest trauma • Immunocompromised • Palliative patients if dyspneic from terminal cancers Prevention of post-extubation respiratory failure in high-risk patients (High risk = >65yo + underlying cardiac disease or respiratory disease)

Weaning from invasive mechanical ventilation if hypercapneic resp failure Eur Respir J 2017;50:1602426

22

Contraindications to NIV • Facial surgery, facial trauma, airway obstruction • Decreased LOC (*relative) • Inability to clear secretions • Respiratory arrest • Hemodynamic instability (reduces preload) • Other Indication for intubation (e.g. airway protection)

POST-Operative Patients OK to proceed with NIV if indicated (even if upper GI or thoracic surgery including esophageal - get blessing of surgeon if concern for anastomotic leak) ↓ reintubation ↓ invasive ventilation days

Intubating? Consider Video Laryngoscopy! DEVICE trial 2023 Prekker NEJM • Video Laryngoscope (VL) vs Direct Laryngoscope (DL) for 1st pass rate in intubation • Setting: ED or ICU • Higher 1st pass rate with VL • Subgroups favored DL if >100 prior intubations or < ¼ prior intubations with VL

Basic Modes of Mechanical Ventilation Mode

Type of Breath

Independent variable

Dependent variable

Best For

Notes

Volume Assist/ Control

Assist or Control

Tidal Volume (preset)

Peak inspiratory Pressure & Plateau Pressures

Lung Protection Post intubation with Low GCS pts

Control tidal volume for lung protection; can get breath stacking

Pressure assist/ Control

Assist or Control

Pressure

Adequate tidal volumes

Comfortable for patient; Used for decreased lung compliance

Control pressures to avoid barotrauma & breath stacking

Pressure Support

Supported

Pressure

Adequate tidal volumes

Patient comfort, used for weaning

All breaths initiated by pt.

24

Ventilator Hacks How to ê PaCO2 How to é SpO2 (PaO2) Example of “Vent Orders”

é RR é tidal volume (minute ventilation = RR * Vt) é FiO2 é PEEP é Inspiratory time Affect O2 delivery: é cardiac output, é Hb ê O2 consumption: treat fever, agitation Stop pulm vasodilators (eg nitroprusside)

RR 10-12, VT 6-8ml/kg (6 if ARDS) PEEP 5-20, PC 5-25

25

Lung and Airway Pressures • •

Peak inspiratory pressures (PIP) – Reflects airway resistance + lung compliance – Target 30l/min

Hypoxemia SpO2/FiO2

101-200

≦ 100

PEEP ≧ 5

PEEP ≧ 5

≦ 315 with SpO2 ≦ 97% 1. Riviello, Am J Respir Crit Care med 2016;193:52-9. 10.1164/rccm.201503-0584OC 2. Mathay et al., Am J Respir Crit Care Med, 2023, 10.1164/rccm.202303-0558WS.

28

ARDS Causes and Pathophysiology DIRECT LUNG INJURY • • • • • • •

Pneumonia Aspiration pneumonitis Drowning Thoracic trauma/pulmonary contusion Smoke or toxic inhalation Fat emboli Reperfusion injury (post lung transplant)

Pathophysiology: • Proteinaceous fluid fills alveoli • Neutrophils flood alveolar space • Hyaline membranes form on epithelial basement membrane • Microthrombi form • Fibrosis develops (late stage)

SYSTEMIC INFLAMMATION • • • •

Severe sepsis Transfusion reaction (TRALI) Shock Pancreatitis

Treatment: 1. Ventilation Strategies 2. Prone positioning 3. Neuromuscular Blockade 4. ECLS/ECMO 5. Corticosteroids 6. Inhaled Pulmonary Vasodilators

ARDS: Ventilation Mode: Tidal volume (Vt): Plateau pressure: PEEP:

Volume Control Initial Vt at 6ml/kg PBW à target 4-8 ml/kg PBW ≤ 30 cm H2O, Driving pressure (Pplat - PEEP) target < 15 cm H2O target higher PEEP in mod/severe ARDS, based on FiO2-PEEP Tables SpO2: target 88-93% or PaO2 55 - 80 mmHg (avoid hyperoxia – ↑s harm) CO2: permissive hypercapnia allowed, target pH > 7.25 • Deep sedation to achieve the above parameters • Lung Recruitment Maneuvers: Don’t use routinely (evidence of ↑ mortality). Can be considered. • High frequency oscillation: Do not use

Fi02

0.3-0.4

0.4

0.5

0.6

0.7

0.8

0.9

PEEP

5-8

8-14

8-16

10-20

10-20

14-22

16-22

No need to memorize this table! FYI only!

1. Am J Respir Crit Care Med Vol 195, Iss 9, pp 1253–1263, May 1, 2017 2. CMAJ 2021 May 25;193:E761-8. doi: 10.1503/cmaj.202661

ARDS Treatment Modalities Summary High PEEP

Recommended for in mod/sev ARDS. Mortality benefit in moderate-severe (ARDS, ALVEOLI, LOV, EXPRESS trials )

Prone positioning

Strong recommendation for severe ARDS. Mortality benefit if P/F < 150 (PROSEVA trial). Duration > 12hrs per day.

Neuromuscular blockade

No mortality benefit. Consider in severe ARDS after optimizing PEEP and ventilator settings. Reduces ventilator desynchrony, improves (ACURASYS, ROSE trials)

Inhaled INO

No mortality benefit. May improve oxygenation by improving VQ mismatching and reducing shunting. Bridge therapy.

Diuresis

Decreases duration on ventilator.

ECMO

No clear mortality benefit, acts as a bridge therapy. (EOLIA trial). See next slide.

Steroids

No benefit for ARDS. May be clinically indicated depending on underlying cause (ie. Covid pneumonia, concern of COP)

Statins

No benefit. Not indicated.

High frequency oscillation

Strong recommendation against routine use. May increase mortality 31

BONUS Read on own

ECMO Respiratory Considerations

Consider ECMO • • • • •

Severe ARDS Hypercapneic respiratory failure Bridge to lung transplantation Primary graft dysfunction after lung transplantation Status asthmaticus

Do NOT Consider ECMO Absolute • Disseminated malignancy • Known severe brain injury • Prolonged CPR without adequate tissue perfusion • Severe chronic organ dysfunction • Severe chronic pulmonary hypertension • Non-recoverable advanced comorbidity (ie. CNS damage or terminal malignancy)

Call for ECMO referral if: • P/F < 80 mmHg for > 6 hours OR P/F < 50 mmHg for > 3 hours • PaCO2 > 60 mmHg for > 6 hours (despite optimization of vent) • Mechanically ventilated < 7 days • BMI < 40 or weight < 125 kg • Age 18 - 65 ECMO Guidelines, CCSO 2020

32

Severe COVID-19 Respiratory Failure in the ICU Infection Control

Intubation or bronchoscopy – N95 + Standard PPE + Negative Pressure Room Refer to local Infection Control regarding length of isolation after severe COVID19 Pneumonia (21d Ontario)

Proning

Recommended in early pandemic to improve oxygenation. COVI-PRONE (JAMA 2022) compared awake proning to non proning, no change in rate of intubation at 30d. = PRONE if tolerated.

Intubation

Indication: usual indications (LOC, airway protection, resp failure), +/- failed trial of High flow nasal cannula Most Experienced Provider should intubate. Recommend video laryngoscopy to increase success on 1st pass.

Ventilator Mgmt

Identical to ARDS strategies (refer to those slides)

Dexamethasone

6 mg po/IV x 10 days if requiring O2 (↓ mortality ↓ need for mechanical ventilation)**

Remdesivir

200 mg IV x 1 then 100 mg IV x 4 days if requiring low flow O2 - May ↓ deaths in moderately ill (on low flow O2) , most trials done before routine steroids and Tocilizumab

Tocilizumab

400 mg IV if requiring HFNC, NIV or IMV. If on low flow O2 + systemic inflammation (CRP > 75) and worsening despite 24-48h of steroids. Must be within 14 days of Covid diagnosis. - ↓mortality in meta-analysis

Baricitinib

4 mg PO daily x 14d. If on appropriate steroid therapy or CI to steroids and NOT on IL-6 therapy

VTE prevention

Prophylactic dosing in critically ill patients (HFNC/NIV/IMV)

Do not pick on MCQ:

Colchicine, IFN, Vit D, hydroxychloroquine, ivermectin, lopinavir/ritonavir, neutralizing Abs, Paxlovid Not recommended. Antibiotics not required unless high suspicion co-infection

33

OUTLINE • Extra slides for your reference: Shock and Sepsis – Acute hypoxia in the ICU Respiratory failure – Gas trapping Weaning from Mechanical Ventilation – Maternal cardiac arrest ICU Delirium, Sedation, Analgesia, – Liver failure guidelines Sleep – Hyperthermia & Hypothermia • Targeted temperature management, – Toxicology Bonus Slides neuroprognostication, DNC, neuro – Bonus MCQs ICU • • • •

• Toxicology

Weaning from Mechanical Ventilation

Assess readiness for weaning from ventilator 1. Reversal of underlying reason for intubation and ventilation 2. Improvement of oxygenation (PaO2 > 60 mmHg, FiO2 < 40%, PEEP < 8) 3. Ability to perform work of breathing (Normal/compensated Co2, pH, adequate cardiac function, adequate diaphragm function)

Assess readiness for extubation 1. Adequate cough 2. Minimal secretions, ability to manage secretions 3. Awake/Alert, following commands, no sedation 4. No increased risk of airway obstruction – post-op swelling resolved, ETT cuff leak present

1. 2.

Boles et al., Eur Respir J 2007; 29: 1033–1056 DOI:10.1183/09031936.00010206 Fan et al., Ann Am Thorac Soc Vol 14, No 3, pp 441–443, Mar 2017. DOI: 10.1513/AnnalsATS.201612-993CME 35

Ventilator Weaning and Extubation: Best Practices Liberation Protocol

For patients intubated > 24hrs, standardised liberation protocols, nurse/RT driven

Spontaneous Breathing Trials

Should occur daily, if meeting screening criteria to perform

Early mobility

For patients intubated > 24hrs, protocolized rehabilitation to aid early mobilization

Sedation Liberation

Use protocols to minimize sedation use

Cuff Leak and steroids

If high risk (traumatic intubation, intubated > 6d, reintubation, female, large ETT) of postextubation stridor perform cuff leak. If fail and otherwise ready for extubation give steroids at least 4hrs before extubation (usually 24hrs before)

Prevention of post-extubation respiratory failure

If high risk (>65 + cardiac/resp disease) use NIV If low/mod risk use HFNC instead of COT (conventional O2 therapy)

1.

Fan et al., Ann Am Thorac Soc Vol 14, No 3, pp 441–443, Mar 2017. DOI: 10.1513/AnnalsATS.201612-993CME 36

Spontaneous Breathing Trial (SBT) • Mimics patient’s own ability to breathe independently • Perform on PSV for 30 minutes – PSV 5/5 vs. 0/0 vs. 5/0 à variable practices – Toronto standardized practice is 0/0

T-piece trial (JAMA 2019): - T-piece for 2 hours vs. PS 8/0 for 30 mins - Successful extubation higher for PS SBT over T-piece SBT

• Failure of SBT à tachypnea, increased work of breathing, tachycardia, hypotension, desaturation – Always ask ‘why’, and try to correct underlying cause of failure

• Rapid shallow breathing index (RSBI) à respiratory rate (breaths/min)/tidal volume (L/min) – RSBI > 105 is a predictor of extubation failure Yang and Tobin. NEJM 1991;324:1445-50. Meade et al. Chest 2001;120(6):400S-24S. 37

MCQ #2 –2023 A 56 year old male presents with ARDS secondary to acute smoke inhalation during a condominium fire. He is intubated on arrival to the ED and transferred to the ICU. He is diagnosed with ARDS and his ABG PaO2 on day 3 is 87, despite deep sedation, INO and paralysis. His vent settings are as follows: ACVC Vt 4ml/kg, PEEP 14, FiO2 100%, pPlat 30, driving pressure 14. • What is the next best step? a) Give methylprednisolone 125 mg daily b) Reduce PEEP to 10 and repeat an ABG c) Diurese with Lasix 40 mg IV BID d) Place patient in prone positioning for 16 hrs 38

MCQ #2 –2023 • What is the next best step? a) Give methylprednisolone 125 mg daily – no guideline based indication to give steroids for ARDS secondary to acute inhalation. b) Reduce PEEP to 10 and repeat an ABG – to optimize oxygenation you would want to INCREASE PEEP based on the FiO2/PEEP tables. c) Diurese with Lasix 40 mg IV BID – while we try to keep the lungs ‘dry’, this has not been shown to have a mortality benefit. d) Place patient in prone positioning for 16 hrs – based on the PROSEVA trials, there is a mortality benefit to proning patients if the P/F ratio is less than 150 despite optimizing deep sedation and ventilator settings (ie. PEEP, FiO2).

39

OUTLINE Shock and Sepsis Respiratory failure Weaning from Mechanical Ventilation ICU Delirium, Sedation, Analgesia, Sleep • Targeted temperature management, neuroprognostication, DNC, neuro ICU • • • •

• Toxicology

• Extra slides for your reference: – – – – – – –

Acute hypoxia in the ICU Gas trapping Maternal cardiac arrest Liver failure guidelines Hyperthermia & Hypothermia Toxicology Bonus Slides Bonus MCQs

Sedation SCCM 2018 Guidelines: • Target RASS -2 to +1 (light sedation) • Daily sedation interruptions and nurse titrated protocols can help achieve this • Propofol or dexmedetomidine are preferable to benzodiazepines – Reduced LOS, duration of IMV, delirium – Beware of bradycardia and hypotension

• Do not use dexmedetomidine if deep sedation is required 1. Devlin et al., Crit Care Med 2018; 46:e825–e873

4+

Combative, Violent, Dangerous

3+

Pulls/removes tubes or catheter, aggressive

2+

Frequent non-purposeful mvmt, dysynchronous

1+

Anxious, apprehensive, but not aggressive

0

Alert and calm

-1

Awakens to voice, eyes open > 10 seconds

-2

Lid sedation, briefly awakens < 10 seconds

-3

Moderate sedation, moves/eyes open

-4

Deep sedation, no response to voice, moves with physical stimulus

-5

Unrousable, no response to voice or stimulus 41

BONUS Read on own

A Note on Dexmedetomidine

• Alpha-2 agonist – acts on CNS receptors • Recent meta-analysis compared to Propofol and Benzodiazepines: – ↓risk of delirium (RR 0.67, 95% CI 0.55 to 0.81; moderate certainty) – ↓ duration of mechanical ventilation (MD - 1.8 h, 95% CI - 2.89 to - 0.71; low certainty) – ↓ ICU length of stay (MD - 0.32 days, 95% CI - 0.42 to - 0.22; low certainty) – Increased risk of bradycardia (RR 2.39, 95% CI 1.82 to 3.13; moderate certainty) and hypotension (RR 1.32, 95% CI 1.07 to 1.63; low certainty) Lewis et al. Intensive Care Med 2022; 48(7): 811-840 42

Delirium (2018 SCCM Guidelines) • Treatment of delirium in the ICU – Nonpharmacologic therapy:

• Optimize mobility, sleep, hearing, vision • Frequent orientation • Minimize modifiable risk factors – medications, transfusions

– Pharmacologic therapy • Pharmacological agents (statin, antipsychotics) should not be used to prevent delirium in ICU patients

• Do not routinely use Haldol, atypical antipsychotic or statin to treat delirium except if significant hallucinations, distress, agitation • Consider dexmedetomidine for intubated patients with delirium to help facilitate extubation/weaning

Risk factors:

– “modifiable”—benzodiazepine use and blood transfusions – “nonmodifiable”—greater age, dementia, prior coma, pre-ICU emergency surgery or trauma, and increasing Acute Physiology and Chronic Health Evaluation (APACHE) and ASA scores

• Screen with CAM-ICU • ICU-Delirium in ICU is associated with: – cognitive impairment at 3 & 12 months – longer ICU stay

AID-ICU NEJM 2023 Anderson-Randberg - Haloperidol vs placebo for delirium in ICU - Number of days alive/out of hospital no different at 90d - Number of rescue medications for agitation the same in both groups 43

Pain in the ICU (2018 SCCM Guidelines) Multimodal approach to pain management • Opioids are mainstay, especially post-op, but associated with side effects (respiratory depression, delirium, dependence) • Adjuncts should be used to reduce opioid requirements – Acetaminophen, NSAIDS (where appropriate) – Low dose ketamine (0.5 mg mg/kg bolus then 1-2 mcg/kg/min infusion) in post-operative patients – Gabapentin, pregabalin, carbamazepine for neuropathic pain – Do not routinely use lidocaine, local anesthetics or inhaled volatiles for pain adjuncts (may be effective for special circumstances – postoperative, trauma)

• Others recommended: cold therapy, relaxation techniques, music, massage

44

Sleep (2018 SCCM Guidelines) • Use non-pharmacologic component to improve sleep – Limit noise (ear plugs) – Light reduction (eye shades) – Avoid sleep disruption

• Do not use Propofol to promote sleep – Unable to make recommendations for dexmedetomidine or melatonin to promote sleep

• Consider assist-control over pressure support at night to improve sleep in appropriate (ventilated) patients 45

OUTLINE • Extra slides for your reference: Shock and Sepsis – Acute hypoxia in the ICU Respiratory failure – Gas trapping Weaning from Mechanical Ventilation – Maternal cardiac arrest ICU Delirium, Sedation, Analgesia, – Liver failure guidelines Sleep NEW! – Hyperthermia & Hypothermia • Targeted temperature management, • 2 new guidelines – Toxicology Bonus Slides • Canadian journal of Cardiology neuroprognostication, DNC, neuro • Neurocritical Society (American) – Bonus Care MCQs *Slides will focus on Canadian guidelines* ICU • • • •

• Toxicology

MCQ 3 -2024 75 year old patient is admitted to the ICU after an out-of-hospital cardiac arrest. The patient was found by bystanders. No CPR was initiated before paramedic arrival. The initial rhythm was ventricular fibrillation, they required multiple shocks for Vfib/VT, with a total downtime of approximately 20 minutes. In the ER: Intubated and diagnosed with a STEMI. They underwent PCI with angioplasty to the LAD. Postcardiac arrest management included therapeutic hypothermia targeting 35-36 degrees C. It is now 96 hrs since the arrest and the following information is available: Examination shows absent pupillary reflexes bilaterally, absent corneal reflexes bilaterally, M1 on motor examination. CT head shows subtle reduced grey-white matter differentiation with a ratio of 1.5. When considering neuroprognostication for this patient, which of the following results best predicts a poor neurological outcome (cerebroperformance categories 3-5)? 1. 2. 3. 4. 5.

Initial rhythm during cardiac arrest Duration of cardiac arrest Absent pupillary light reflexes at 72h CT head results Motor examination findings 47

Post Arrest Targeted Temperature Management 1. Continuous monitoring of core temperature in comatose patients after ROSC. 2. Actively prevent fever (T < 37.7oC) with antipyretics and cooling blankets set to 37.5oC. 3. Actively prevent fever for at least 72 hours. 4. Do not actively rewarm patients with mild hypothermia to achieve normothermia after ROSC.

2022 ERC-ESICM Guidelines 48

BONUS Read on own

Neurologic Outcomes

● Brain Death: ○ Irreversible cessation of cerebral and brainstem function

● Persistent Vegetative State: ○ Severe anoxic brain injury progressing to a state of wakefulness without awareness ○ No purposeful responses, sleep wake cycles intact

● Minimal Conscious State: ○ Limited interaction with environment with visually tracking +/- simple commands ○ Intelligible verbalization or sometimes yes/no but not always appropriate

● Locked In: ○ Retained alertness, cognitive abilities, can move eyes and blink voluntarily, paralysis of the limbs and oral structures 49

BONUS Read on own

Neuroprognostication

CPC

Disability

Conscious

Independent

Features

1

No, minor

Yes

Yes

Alert, able to work and lead a normal life with no/mild deficits.

2

Moderate

Yes

Yes

Independent in activities of daily life. May have hemiplegia, seizures, ataxia, memory impairment.

3

Severe

Yes

No

Limited cognition, dementia, locked in, minimally conscious. Usually requires institution level care.

4

Unconscious

No

No

Persistent vegetative state.

5

Dead

--

--

Certified brain death, circulation preserved

Cerebral Performance Categories. 1, 2 = Favourable outcome. 3, 4, 5 = Poor outcome

NEW: Neuroprognostication CJC 2023 NOT HELPFUL • Arrest rhythm • Patient’s age • Arrest duration

1.

Fordyce et al., CJC (2023) 39: 366-380

51

Summary of Neuroprognostication Guidelines Recommendation

Guideline: CJC 2023

Patient

1. Out-of-hospital Cardiac arrest age >18 with ROSC 2. GCS < 8 + unable to follow commands post cardiac arrest

Timing

Wait 24hrs after cardiac arrest before predicting outcome

Neurologic exam

Use absent PLR at 72hrs to predict poor outcome. Motor exam M1/M2 is unreliable (high false + rate). Absent corneal reflexes may be helpful at 72hrs, but confounded by residual sedation Ensure adequate time for sedatives, opioids, paralytics to be cleared

PLR = pupil light reflex Seizures/Status myoclonus

Status myoclonus < 7d after CA = marker of poor outcome when combined with other findings Treat status epilepticus as usual, delay neuroprognostication if prognosis favourable

Neurophysiological Testing

Use EEG as 1. part of multimodal assessment 2. to distinguish between SE and status myoclonus Use SSEPs as part of assessment. Bilaterally absent N20s > 24hrs after CA highly predictive of poor outcome Don’t use electrographic status epilepticus or absence of EEG activity as a marker of a poor outcome Don’t use routinely

SSEP = somatosensory evoked potentials

Serum biomakers Neuroimaging

CT ≤72hrs after ROSC. Reduced grey white matter differentiation = poor outcome MRI ≤ 7d after ROSC if uncertainty exists. Large diffusion restriction (high DWI) = poor outcome

Decisions

Use results from ≥2 different modalities before decision to withdraw life-sustaining therapies (modalities = Neurologic exam, EEG, SSEPs, Neuroimaging, Serum biomakers) 52

MCQ 3 -2024 75 year old patient is admitted to the ICU after an out-of-hospital cardiac arrest. The patient was found by bystanders. No CPR was initiated before paramedic arrival. The initial rhythm was ventricular fibrillation, they required multiple shocks for Vfib/VT, with a total downtime of approximately 20 minutes. In the ER: Intubated and diagnosed with a STEMI. They underwent PCI with angioplasty to the LAD. Postcardiac arrest management included therapeutic hypothermia targeting 35-36 degrees C. It is now 96 hrs since the arrest and the following information is available: Examination shows absent pupillary reflexes bilaterally, absent corneal reflexes bilaterally, M1 on motor examination. CT head shows subtle reduced grey-white matter differentiation with a ratio of 1.5. When considering neuroprognostication for this patient, which of the following results best predicts a poor neurological outcome (cerebroperformance categories 3-5)? 1. 2. 3. 4. 5.

Initial rhythm during cardiac arrest Duration of cardiac arrest Absent pupillary light reflexes at 72h CT head results Motor examination findings 53

MCQ 3 (new 2024) 1. Initial rhythm during cardiac arrest Do not use initial rhythm for neuroprognostication

2. Duration of cardiac arrest Do not use duration of cardiac arrest in neuroprognostication

3. Absent pupillary light reflexes Yes – absent bilateral pupillary light reflexes > 72 hrs (stem states 96hrs) has a < 5% false positive rate for a poor outcome (cerebral performance score 3-5)

4. CT head results Reduced grey white matter ratio below 1.15-1.2 has a false positive rate < 5%. The stem states the ratio is 1.5, so this is inconclusive.

4. Motor examination findings The CJC 2023 guidelines on neuroprognostication state that motor exam M1 or M2 (on Glasgow coma scale) has a high false positive rate, and is not included in the list of findings with a false positive rate < 5%.

54

HIGH YIELD

NEW: Criteria for Determination of Death

• Definitions • Clinical practice guidelines – Death by Neurological Criteria (DNC) – Death by Circulatory Criteria (DCC)

Shemie et al., Can J Anesth (2023) 70:483–557

55

Definitions • Death = Permanent cessation of brain function – Absence of consciousness – Absence of brainstem reflexes

• Death caused by cessation of blood flow to brain, due to: 1. 2.

Circulatory Arrest – Death by Circulatory Criteria (DCC) Devastating brain injury – Death by Neurological Criteria (DNC)

• Donation can occur after follow: 1. 2.

DNC DCC • •

Controlled circumstances – WLSM, MAiD Uncontrolled circumstances – i.e. unanticipated arrest. NPOD WLSM = withdrawal of life-sustaining measures, NPOD = non-perfused organ donation Shemie et al., Can J Anesth (2023) 70:483–557

56

Donation after Death by Circulatory Criteria (DCC) • DCC = absence of extracranial circulation leads to permanent absence of intracranial circulation • Use invasive arterial BP and continuous ECG for monitoring – Don’t use other monitoring of circulation – i.e. Echo, palpation, US

• Absence of circulation when pulse pressure < 5mmHg • Observation time after cardiac arrest to confirm permanence – 5 minutes in controlled circumstances (WLSM, MAiD) – 10 minutes in uncontrolled circumstances . al., Can J Anesth (2023) 70:483–557 Shemie et

57

NEW: Death by Neurologic Criteria (DNC) 3 pre-requisites before conducting DNC assessment 1. Mechanism causing devastating brain injury leading to death 2. Neuroimaging to support cause 3. Absence of confounders – – – – –

Temperature: core ≥ 36 celsius (rectal, esophageal, bladder, arterial, bladder, central venous) Time: wait ≥ 48hrs after arrest (unless imaging shows devastating injury) Drugs: Wait 5 half lives if drug is known (e.g. sedatives, neuromuscular blockers, Shock: Must be resuscitated appropriately (i.e. not un-resuscitated) Metabolic disorders*: Na 125-159, PO4 >0.4, Glucose 3-30, pH 7.28-7.5, PaCO2 < 60, Urea < 40 (if available), Cr < 400, bilirubin < 100

“If these derangements cannot be corrected and are judged to be potentially contributing to the loss of brain function, ancillary investigation should be considered. ” – Severe weakness: myasthenia, ALS, spinal cord injury – Decompressive craniectomy *Suggestions from Trillium Gift of Life Network (TGLN). Not exhaustive, not necessarily absolute contraindications but require call to donation support physician for advice.

Shemie et al., Can J Anesth (2023) 70:483–557 58

DNC Assessment 1. 2. 3.

3 criteria to confirm DNC Absence of consciousness – no wakefulness or response to stimuli Absence of brainstem function – no brainstem reflexes Absence of capacity to breathe

1. Motor examination - Central stimulation (supraorbital notch) - Peripheral stimulation

2. Brainstem Reflexes - Pupillary response to light - Corneal response - Cough - Gag - Vestibulo-ocular (cold calorics. Don’t use oculo-cephalic – dolls eyes)

3. Apnea testing - No respiratory effort - pH < 7.28, pCO2 > 60 AND pCO2 increase ≥20

Shemie et al., Can J Anesth (2023) 70:483–557 59

BONUS Read on own

Apnea Testing

• Pre-oxygenate and obtain ABG (Trillium Gift of Life Network recommends baseline ABG PaCO2 35-45, pH = 7.35-7.45) • Several options for apnea testing – CPAP – Passive oxygenation (O2 tubing down ETT, disconnected from ventilator) – Exogenous CO2 or Reduce minute ventilation by 50% if high risk of failing (i.e. from Hypoxaemia)

• Monitor for respiratory efforts • Serial ABGs at 0, 5, 10 and 15min Thresholds for completion: PaCO2 > 60 mmHg AND > 20 mmHg above the pre-apnea baseline AND pH ≤ 7.28. Shemie et al., Can J Anesth (2023) 70:483–557 60

BONUS Read on own

DNC: Ancillary Testing

• Required if DNC examination cannot be completed (i.e. confounder cannot be reversed, trauma to one eye prevents pupillary/corneal/vestibulo-ocular reflex testing)

• Ancillary tests used to support theory of cessation of brain function • Several modalities can be used – – – –

CT angiography (CTA) CT perfusion (CTP) Transcranial Doppler Radionuclide lipophillic perfusion study

• Don’t use: EEG, MRI, 4 vessel angiography, SSEP, BAEP, radionuclide liphophobic perfusion study SSEPs = somatosensory evoked potentials, BAEP = brainstem auditory evoked potentials

Shemie et al., Can J Anesth (2023) 70:483–557

61

BONUS Read on own

Donation Organ Support

• Respiratory: Vt 6-8ml/kg, PEEP ≥8, Recruitment manoeuvres • Cardiovascular: MAP > 65, inotropes (1st Vaso, 2nd Norepi, NO dopamine), crystalloids for fluid resuscitation • Endocrine: Steroids if on vasopressors, no recommendation for levothyroxine, glucose 6-10 • Diabetes insipidus: Na target 135-155, use vaso or DDAVP • GI: Continue enteral feeding • Core temperature 34-35 kidneys being considered • Coronary angiography if heart being considered Ball et al., CMAJ 2020 April 6;192:E3619.

62

Management of Neurological Injuries Types: traumatic brain injuries, subarachnoid hemorrhages, stroke, hypoxic injuries, etc. Principles of ICU management (Neuro lecture for specifics): • Intubation for airway protection (if GCS < 8) • Keep head of bed > 45 degrees • Target normothermia, euglycemia, normocapnia • Preferentially use normal saline for fluid management to avoid significant sodium shifts and avoid hyponatremia Increased ICP management: (in addition to above) • Hypertonic 3% saline (250 cc bolus) or mannitol (0.25 – 1 g/kg/dose, may repeat every 6-8 hrs) • Hyperventilation (target CO2 of 26 – 30) • ICP monitoring (goal to keep ICP < 20 mmHg) • Increase sedation (make sure airway is secured) • Blood pressure control (to maintain cerebral perfusion pressure > 60) • Avoid restrictive neck taping or excessive rotation/flexion of the neck • Treat seizures with anticonvulsant therapy if suspected • Surgical consultation for consideration of EVD placement (if hydrocephalus) or decompressive craniectomy

Devastating Brain Injury: *Incompatible with life or unlikely to make a meaningful recovery. CCCS 2020 Position Statement recommends waiting at least 72 hours before consideration of withdrawal of life support to establish greater confidence and accuracy in prognostication and recovery. This also allows time for conversations around and consideration of organ donation. Always remember to call Trillium Gift of Life! Healey et al. Can Journal of ED Medicine 2020; 22(5): 658-660. 63

BONUS Read on own

Critical Illness Associated Weakness

Critical illness myopathy

Critical illness polyneuropathy

Glucocorticoid-induced myopathy

Motor

Flaccid quadriparesis, proximal > distal muscles, failure to wean, normal CNs, weak facial muscles

Flaccid quadriparesis, failure to wean, normal CNs

-Gradual onset 1-3 months after starting steroids -Proximal muscle Lower>upper weakness, followed by atrophy of proximal muscle groups -Lower occurs before upper extremity weakness and is more severe

Sensory

Spared

Decreased pin prick/touch in distal extremities

Normal

Reflex

Normal or low

Low

Normal

Other

CK may be elevated Strongly associated with steroid use (starts several days after steroids) -Diagnose with nerve conduction studies/EMGs -No tx

Severe sepsis is the strongest risk factor

-Will get Cushing’s like syndrome with , DM, mood alteration, skin fragility, osteoperosis -Definitive dx=decrease steroid dose and see if improves in 3-4 weeks

64

TOXICOLOGY TIME! • Toxicology – – – – – – – – –

Approach TCA Toxic Alcohols Salicylate Acetaminophen Carbon Monoxide, Cyanide Methemoglobinaemia Lithium Hyperthermic Toxidromes

• Extra slides for your reference: – – – – – –

Acute hypoxia in the ICU Gas trapping Maternal cardiac arrest Liver failure guidelines Hyperthermia & Hypothermia Bonus MCQs

MCQ 4 2024 A 50 year old female presents to the emergency department after starting a new antibiotic for a UTI. She has a headache, dizziness, shortness of breath and confusion. On assessment vitals show BP 110/70, HR 110, RR 28, Sat 87%, temp 36.5. She appears cyanotic, tachypneic and drowsy. She is placed on a non-rebreather mask at 15L/min. Laboratory investigations show Hb 115, WBC 8, Plt 250, Cr 120, Na 137, K 4.8, Cl 105, bicarb 21, lactate 2.3, ABG 7.44, CO2 35, PaO2 170, SaO2 56%. What is the definitive next step in management? a. Hydroxycobalamin 5g IV b. Place on high-flow nasal cannula at FiO2 1.0 c. Methylene blue 2mg/kg IV d. CT head e. Transfuse 1 unit RBCs

66

Tox Quick Approach • History:

– What did the patient take? How long ago? How much?

• Co-ingestions (EtOH? ASA? Acetaminophen? Toxic alcohols?)

– Environmental exposures : Carbon monoxide risk factors – Past Medical History, Meds, Allergies, Social

• Physical: look for toxidromes – – – –

Vitals, GCS, capillary blood glucose Pupils (mydriasis, mioisis) Neuro (Reflexes, clonus, rigidity) Skin (dry, sweating, hot)

67

Tox Quick Approach STAT Investigations – CBC, Na, K, Cl, bicarb, BUN, Cr, Ca, Mg, PO4, LFTs, CK, troponin, glucose – ABG, lactate – Serum osmolality, urea – BHCG (if young female) – Urine/Serum Tox • ALWAYS ask for acetaminophen, salicylates, and EtOH level – 12-Lead ECG – Urinalysis (for pH), R+M (for crystals) – Consider CT head AND SOME QUICK MENTAL CALCULATIONS: - Anion gap= Na-Cl-Bicarb (normal < 12 with normal albumin) - Osmolar gap=Sosm-CalcOsm (normal < 10) --> if elevated, order toxic alcohols + start empiric treatment if high suspicion, not explained by ETOH level -Calc Osm=2Na+gluc+BUN (“2 salts and a sugar BUN”)

68

Management • • • •

ABC, IV access, Continuous Cardiac Monitors, O2, Foley C-collar if unwitnessed LOC Consider – Dextrose, oxygen, naloxone, thiamine Tox specific treatment (see next slide) – Decrease Absorption – Increase Elimination – Antidotes

• Call Poison Control (ALWAYS!) – And Psychiatry if intentional overdose, once pt is stable and talking – And Addictions medicine if applicable 69

Gastric lavage not used for decontamination

BONUS Read on own

Decontamination/Elimination Decontamination

Method

Single Dose Activated Charcoal (SDAC) (50-100g)

Whole Bowel Irrigation PEG 500ml + 1-2L/hr

Indications

Suitable toxin + 1-2hrs since ingestion >2hrs with drug that delays gastric emptying, massive ingestion, lethal drug

if ingestion large, deadly, long-acting i.e. buproprion, lithium, salicylates

Contraindications

High aspiration risk (reduced LOC, not protecting airway, seizures, vomiting) Poorly absorbed toxins • Metals (Fe, Pb, Li) • Alcohols • Salts (K, Na, Mg) • Hydrocarbons

High risk aspiration GI: Ileus, obstruction, perforation, bleeding

Elimination Method

Dialysis

Multidose-activated charcoal (12.5g q1h)

Indications

Dialysable drug (small, charged, not protein bound, small volume of distribution) EXTRIP – list of dialysable drugs i.e. Toxic alcohols, ASA, Lithium, Acetaminophen, metformin, CCBs, BBs

Drug cleared by enterohepatic circulation - Phenobarbitol, carbamazepine theophylline, caffeine, phenytoin, ASA, quinine, dapsone 70

BONUS Read on own

Common antidotes Drug

Antidote

Acetaminophen

NAC

ASA

HCO3

BB / CCB

High-Dose Euglycemic Insulin, glucagon, calcium, intralipid

Benzos

Flumazenil [caution – lasts up to an hour and if multiple drug ingestions or withdrawal seizure will make managing seizures a challenge!]

Cyanide

Hydroxycobalamin, sodium thiosulfate,

Iron

Deferoxamine

Isoniazid

Pyridoxine

Local anesthetics

Intralipid

Lipid soluble drugs (Atenolol, Buproprion, CCBs, Amitriptyline)

Intralipid

Methemobloginemia

Methylene blue

Organophosphates

Atropine, pralidoxime

TCA

HCO3, intralipid

Toxic alcohols (ethylene glycos, methanol)

Fomepizole, thiamine, folate

Valproate

L-carnitine

Sulfonylurea

Octreotide 71

TCA Overdose Signs and Symptoms • CVS – Hypotension – Arrhythmias • Sinus tach • VF/VT as QRS widens

• CNS – Dec LOC, agitation, psychosis, delirium – Seizures

Anticholinergic Toxicity RED as a beet DRY as a bone urinary retention MAD as a hatter sedation, confusion, delirium, hallucination BLIND as a bat (mydriasis) dilated pupils that DON’T respond to light HOT as a desert hyperthermic STUFFED as a turnip absent bowel sounds SEIZURES (since acts on GABA) 72

Labs • TCA serum levels are not helpful – Urine tox can detect TCA use, but beware of false positives (carbamazepine, diphenhydramine, cyclopenzaprine, quetiapine)

• Would expect to see a respiratory acidosis from decrease LOC • ECG is very helpful Diagnosis is made based on: 1. History of ingestion or TCA use 2. Physical findings of anticholinergic toxidrome 3. Characteristic ECG findings (see next slide)

73

• QRS >100 – >100-26% get seizures – >160-50% get arrhythmia

• Tall R in AVR • Deep slurred S in 1 and AVL • R/S ratio >0.7 AVR • Type 1 Brugada (RBBB, downslope ST depression V1-V3)

Treatment • ABCs, IV, O2, Monitors, Foley, Acute care area, Poison control • Decontamination – Can consider activated charcoal (1g/kg, max 50g) if present within 12hours unless they have a decreased LOC, gut perforation, bowel obstruction

• No increased elimination • No antidote • DO NOT use Physostigmine to counteract anticholinergic toxicity (will worsen cardiac instability, increases risk of cardiac arrest) 75

Symptom Specific Management • LOC – GCS 8, intubate – Agitation: benzodiazepines (Ativan or diazepam at 5 – 10 min intervals) – Seizures • • • •

Start with Ativan or diazepam, add midazolam infusion if refractory Then propofol infusion if refractory Then Barbiturates DO NOT USE PHENYTOINà Enhances Cardiac Toxicity

• Hypotension – NS or Na Bicarb bolus (up to 30ml/kg) – Norepi or phenylephrine if refractory – Consider hypertonic saline boluses 100 mg IV if refractory despite vasopressors 76

Treatment of Arrhythmias • Wide complex (ventricular) tachy OR prolonged QRS > 100

– Na Bicarb 1-2mEq/kg IV àif QRS narrows start infusion (3amps in a bag of D5W) at 250ml/h – If fails, give magnesium sulfate – If fails, lidocaine (class IB) 1.5mg/kg bolus then 1-4mg/min • Class IA, 1C, and III anti-arrhythmic are C/I

– If fail and unstableà lipid emulsion, VA ECMO

• Sodium Bicarb – Indication

• QRS>100, ventricular arrhythmia, or hypotension

– Goal pH 7.50-7.55 – Bolus 1-2 amps then run as an infusion at 250ml/h 77

Toxic Alcohols Ethylene Glycol

Methanol

Found in

Antifreeze, wiper fluid, cleaners, fuels, moonshine, solvents, hand sanitizer

S&S

-Decreased LOC -Frank hematuria, flank pain, oliguria -HypoCa

-Decreased LOC -Retinal injury leading to blindness

PE

-Cranial Nerve palsies -Tetany

-Afferent pupillary defect -Mydriasis (dilation) -Retinal sheen -Hyperemia of the optic disc

Labs

-Classically high AG and OG *see next slide -Lytes, Creatinine and Urine R&M -ECG (Watch QTc for ethylene glycol-à hypoCaàProlonged QT) 78

What if there is the right history but no Osmolar gap? • The osmoles get metabolized to anions! • This means there is no parent alcohol left to inhibit! There still may be a toxic alcohol ingestion with a low osmolar gap and high anion gap! Metabolites: • Methanol à formate • Ethylene glycol à Glycolate, glyoxylate, oxalate

The Toxicology Ddx of AG and Osm Gaps Anion Gap

Osm Gap

Ddx

High

No

Ketones Tylenol Salicylate High lactate (eg shock, status, ischemic gut) Late toxic alcohol ingestion

High

High

Ethylene Glycol Methanol Ethanol or diabetic Ketoacidosis Propylene Glycol ESRD with no IHD

Normal

High

Isopropyl Alcohol Ethanol Severe hyperproteinemia/hyperlipidemia

Treatment • ABCs, IV, O2, CCM, Foley, Monitored setting • Decontaminate – No role (can try NG aspirate if within 60min) • Enhanced elimination – Acidemia allows toxic metabolites to penetrate end-organ tissue, so give bicarb! – Give 1-2meq/kg then set up an infusion at 150-250 cc/h – The goal pH=7.35

Treatment Continued • Inhibition of alcohol dehydrogenase – Inhibition of alcohol dehydrogenase blocks degradation of the parent alcohol into its toxic metabolites – Fomepizole or ethanol with: • Folic acid 50 mg IV q6h for methanol • Thiamine 100 mg IV and pyridoxine 50 mg IV for ethylene glycole – Indications • Serum methanol >6.2mmol/L or ethylene glycol >3.2mmol/L OR • Documented recent history of ingestion of toxic amounts of methanol or ethylene glycol and an osmolar gap>10 OR • Suspicion of ingestion and 2 of the following:

– pH 7.2mmol/L – Hypoxemia requiring supplemental O2 – A change in mental status – Renal failure (and salicylate level >6.5mmol/L) – Progressive deterioration of vital signs – Severe acid –base or electrolyte imbalance despite appropriate treatment (pH 250 mg/kg or over 12g in 12 hour period • Severe liver toxicity occurs in doses greater than 350 mg/kg (AST and ALT > 1000) unless appropriately treated Signs and Symptoms: • Stage I (0.5 0 24 hrs) – nausea, vomiting, diaphoresis, pallor, lethargy, malaise, or asymptomatic • Stage II (24-72 hrs) – RUQ pain, jaundice, oliguria, rise in ALT & AST • Stage III (72 – 96 hrs) – jaundice, confusion (hepatic encephalopathy), marked elevation in AST & ALT, prolonged INR/PTT, bili > 68, hypoglycemia, lactic acidosis, hyperammonemia, bleeding diathesis, renal failure • Stage IV (96 hrs – 14 days) – recovery phase where hepatic necrosis may develop 91

Treatment • Acetaminophen levels should be drawn 4 hours after ingestion ideally and plotted on modified Rumack-Matthew nomogram • Not applicable in repeated supratherapeutic ingestion

92

Assessing Risk of Hepatotoxicity If ANY of the following occur: • Ingestion of greater than 7.5 – 10 g in 24 hours • Ingestion of greater than 4g in 24 hours AND increased risk of susceptibility to hepatotoxicity (ie. Chronic ETOH use) • Abdominal pain, liver tenderness, nausea, vomiting, jaundice • Supratherapeutic serum acetaminophen concentrations (> 130 mmol/L) • Elevated ALT or AST (> 50 U/L) on presentation 93

Treatment Principles Gastrointestinal decontamination: activated charcoal (1g/kg or 50g) in patients presenting within 4 hours of potentially toxic ingestion (single dose > 7.5 g) NAC protocol indications: • • • • • •

Serum concentration above treatment line on RM nomogram Single ingestion > 7.5 g (150 mg/kg) Unknown time of ingestion + concentration > 66 umol/L History of ingestion + liver injury Delayed presentation (>24 h) with evidence of liver injury Consider in acute undifferentiated liver failure Beware NAC infusion reactions. Mild flushing/urticaria – continue infusion with antihistamine/steroid. Severe anaphylaxis or angioedema – stop and treat as in allergy online slides

NAC Protocols 20 Hour: 150 mg/kg over 60 min; 50 mg/kg over 4 hrs; 100 mg/kg over 16 hrs. 72 Hour: 140 mg/kg PO loading dose; 70 mg/kg q4h for 17 doses. Target INR < 1.3, ALT < 100 U/L, acetaminophen < 132) before stopping.

94

After the Overdose… Required Recovery Reading Medication

Mechanism

Prescribing Notes

Naltrexone

Competitive antagonist of Mu- receptor

Use for both: Opioid Use Disorder Alcohol Use Disorder

Usual dose 50mg per day

With Opioid Use Disorder this is not first line, consider if pt unable/unwilling to use others below. Can improve retention in program and reduce incarceration. Must be OFF opioids 7-10d to avoid precipitated withdrawal. Can reduce frequency and amount of ETOH

Buprenorphine/Naloxone* (SUBOXONE) IM Buprenorphine (SUBLOCADE) q28d

High affinity partial agonist at mu-receptor; at high doses saturates receptor blocking effect of other opioids.

For Opioid Use Disorder

Methadone For Opioid Use Disorder

*Naloxone orally = ++hepatic first pass effect, so no significant systemic effect. BUT if Suboxone is INJECTED however naloxone component will ppte withdrawal. L-enantiomer binds mu-receptor, high intrinsic activity ~ opioid, low affinity; S-enantiomer acts as NMDA antagonist

Pt must be in withdrawal 12-24h opioid free to initiate. Standardized protocols using the Clinical Opioid Withdrawal Scale (COWS) to titrate dosing exist.

Can start immediately Need special license to prescribe **QT prolonging**

+ Social Work, Addictions Medicine referral + Harm Reduction: Naloxone kits, safe injection practices/sites

95

Methemoglobinemia

Carbon Monoxide

Cyanide Toxicity

Scenario

Dizzy/confused after exposure to dapsone/Septra/nitrates

Confused man w headache from his cabin in the winter, AGMA Lactic acidosis

“Caught in industrial fire, now looks very sick, coughing but sat is high”

Pathophysiology

Fe2+-Hgb is oxidized to Fe3+

Hb binds CO (CO-Hb) rather than O2; HbO2 dissociation curve L shifted. CO disrupts oxidative phosphorylation in mitochondria. CO causes neuronal death

CN binds cytC-oxidase in mitochondria – cannot do kreb’s cycle. Anaerobic glycolysis = AGMA

Causes

Many drugs – nitrates, sulfa…

Carbon combustion w/ poor ventilation

Combustion of plastic/wool/etc Toxic ingest (bitter almond, apricot pits)

Signs/ Symptoms

Cyanosis Chocolate brown blood

Cherry red skin Headache, dizzy, “flu like” Cardiac arrhythmias

Coma, Acidosis, Cardiac instability CNS symptom, sz, coma Severe lactic acidosis AGMA

Diagnosis

ABG, MetHb SpO2 80-85 w high PaO2 “PaO2-SpO2 mismatch” suggests hemoglobinopathy

SpO2 high AGMA with high lactate Carboxy-Hb level (>10% abnormal, Normal 1-2%, smokers 5-10%

VBG high venous sat ABG high SaO2, AGMA

Antidotes

Methylene Blue 1-2mg/kg

100% FiO2

Hydroxycobalamin 5g IV over 15. min

Other Rx

Supportive

Hyperbaric oxygen rarely (for severe cases eg seizure/coma or pregnancy related complications)

Sodium thiosulfate (enhances renal excretion) Nitrites (amyl nitrate/sodium nitrite) – induce MetHb which has higher affinity for CN than regular Hbg

Met-Hb can’t carry or release O2

96

Carbon Monoxide poisoning Pathophysiology HYPOXIA

Hb binds CO (COHb) rather than O2 HbO2 dissociation curve L shifted CO disrupts oxidative phosphorylation CO causes neuronal death

Causes

Carbon combustion + inadequate ventilation • (eg) gas stoves Others: Methylene chloride/bromide

Signs / Symptoms

Diagnosis

Early (10% abnormal SpO2 will over-estimate - i.e. will read 100% CT/MRI – bilateral opacities in globus pallidus

Sample scenario: “Confused elderly man comes with headache in winter from remote cabin with normal BP and unexplained AGMA lactic acidosis …” Treatment 1. Remove source, move to well ventilated area 2. 100% FiO2 – HFNC or Intubate (i.e. Coma) • COHb half lives

1.

– Room air: 250-320 minutes – 100% FiO2: 90 mins – Increased atmospheric pressure (2.5ATA): 20 mins

Consider Hyperbaric O2

– Conflicting evidence – expert consensus – Potential indications • • • • •

•

If within 6h of exposure is best CoHb > 25% Seizure or Coma Syncope Pregnant woman with >15% COHb or Fetal distress in pregnancy

If they are suffering CO poisoning after a smoke inhalation, treat for concurrent cyanide poisoning Juurlink Br J Clin Phamacol 2023:89.942-945

Cyanide (CN) Poisoning Pathophysiology HYPOXIA

Causes

Signs / Symptoms

Diagnosis

CN blocks cytochrome oxidase function Cells cannot use aerobic respiration (toxic to mitochondria) Anaerobic respiration = tissue hypoxia, lactic acidosis Inhalation of gases - combustion of plastic, rubber, wool, silk, polyurethane Ingestion: Casaver, apricot pits, bitter almonds Intravenous: Nitroprusside 3 hallmarks: Coma, Acidosis, Cardiac instability - ABRUPT onset (only delayed to hrs if ingestion) - H/A, Nausea, Dizziness, Confusion - Syncope, Seizure, Coma - Severe lactic acidosis, - Cardiac collapse, cardiac arrest, death - VBG: Venous arterialisation – high venous sat - ABG: High SaO2 (unlike CO toxicity), AGMA - Smell of bitter almonds - ECG: non-specific arrhythmias, blocks, brady, tachy Diagnosis is purely clinical – looks for hallmarks and high mixed/central venous sat (>90%) Cyanide levels - Take too long to come back so not used in emergency >2.4 coma. >3 death

Treatment 1. Supportive • • •

Control airway (intubate), 100% FiO2 Crystalloids and vasopressors for shock Bicarb for acidosis

2. Hydroxycobalamin • • •

Binds CN forming cyanocobalamin -> Urine 5g IV over 15mins, repeat x1 if needed A/E:anaphylactoid reaction, HTN

3. Nitrites •

MetHb higher affinity for CN than Hb -> induce methemobloginemia • Pre-hospital: amyl nitrate • Na nitrite 3% 10ml over 2-4mins IV • A/E: Hypotension, hypoxia (don’t give if COHb) 4. Sodium thiosulfate • Enhances renal excretion • 150-200mg/kg over 10-20mins • A/E: hypernatremia 1 and 2 are mainstay of management. 3 and 4 only if hydroxycobalamin unavailable

Methemoglobinaemia • Pathophysiology: – Iron in Hb oxidised to Fe3+ by precipitant – MetHb can’t carry O2 + O2 dissociation cure L shifted = Hypoxia Drugs

Local anesthetics (benzocaine, lidocaine) Dapsone Nitrates - Amyl nitrite - Nitric oxide - Nitroprusside - Nitroglycerin Chloroquine Sulfonamides (Sulfamethoxazole)

Clinical Features – based on MetHb level (%) 3-15

Pulse Ox low (90-95%) Slate gray skin discolouration

15-20

Cyanosis Chocolate brown blood Pulse ox approx 85%

20-50

Dizziness, syncope, fatigue, headache, weakness, dyspnea

>50

CNS depression/Coma Seizures Metabolic acidosis Arrhythmias Death

Hemolysis – any cause Genetic

Hemoglobin M NADH methemoglobin reductase deficiency

Fe2+ -> Fe3+ + ePaO2 – Saturation Gap - PaO2 will be high (pt being treated with O2) - SpO2 reads approx 8085% - PaO2-SpO2 mismatch is indicative of hemoglobinopathy

Methemoglobinaemia Treatment • Early recognition

– Stop offending agent – Draw MetHb level, ABG

• Supportive

– Coma: Airway protection, intubation – Cyanosis: Provide high-flow oxygen (if responds then unlikely MetHb)

• Methylene blue

– 1-2mg/kg, repeat at 30 mins if no response – Relative Contraindications: G6PD deficiency (may cause hemolysis), serotonin syndrome (serotonergic) – No clear cut off for when to use - potentially if symptomatic or MetHb > 30%. Liaise with poison centre.

• Cimetidine – can be used for dapsone induced MetHb • Ascorbic acid – Theoretically can be used if no response to methylene blue, although not typically used 100

Lithium Overdose Pharmacokinetics ● Lithium does not bind to proteins and is distributed freely throughout the body ● Therapeutic window 0.6-1.2mmol/L ○ However, can get sx of overdose in therapeutic window as well!

Treatment 1. Decontamination-Li is NOT absorbed by activated charcoal. Can try whole bowel irrigation if there is: - Sustained release ingestion -Symptomatic patients -Unknown amounts ingested ->40 mg/kg ingested, or 176umol/L orthostatic, lethargy, slurred speech, ataxia, 3. Restore fluid balance (NS at 1.5 maintenance) tremor, myoclonic jerks 4. Do NOT enhance elimination with forced diuresis -Get a small increase in elimination but then get salt/water Diagnosis depletion that leads to increased Li retention ● Li levels should be obtained on presentation + serially after ingestion of sustained release.

BONUS Read on own

Hyperthermia

Serotonin Syndrome

NMS

Malignant Hyperthermia

1. Autonomic (tachy, hypertension, vomit, fever, diarrhea, diaphoretic) 2. Neuromuscular hyperactivity (tremor, muscle rigidity lower>upper, myoclonus, hyperreflexia, bilateral babinskis, ocular clonus) 3. Change in mental status (anxiety, agitated, restless, disoriented)

Tetrad “FARM” 1. Fever-Temp>38, may be >40 2. Autonomic-Tachy, labile BP, arrythmia, diaphoresis 3. Rigidity-Lead pipe/cogwheel increase tone NO CLONUS –They are HYPOREFLEXIVE 4. Change in mental status Agitated delirium, Catatonia, coma

Rare genetic (autosomal dominant) condition

Onset

Within 24h

Days to weeks

Time from drug - 30min – 24h

Off

24h

2 weeks

S&S

VERY HIGH temp (>42oC often) with diaphoresis Extreme Rigidity Hyporeflexia

102

Inciting Meds

Diagnos tic criteria

Tx

Serotonin Syndrome

Neuroleptic Malignant Syndrome

Malignant Hyperthermia

-SSRIs -Amphetamines, Cocaine, MDMA, Levodopa -TCA, SNRI, NDRI -Tramadol, Meperidine -St John’s wart, VPA -MAOI -Direct serotonin agonistsàTriptans, Ergot, Fentanyl, buspirone

-All classes of neuroleptic drugs can be implicated (Quetiapine, clozapine, risperidone, olanzapine, etc) -Antiemetic agents (domperidone, metoclopramide, prochlorperazine)

Reaction to inhaled volatile anesthetics and depolarizing NM blockers (succinylcholine)

Hunter Criteria: Needs to take a serotonergic agent and ONE of -Spontaneous clonus -Ocular clonus -Inducible clonus + diaphoresis or agitation -Tremor + Hyperreflexia -Hypertonic + temp>38 PLUS ocular or inducible clonus

No criteria

-Stop the agent, support -Sedate with benzos (goal is to eliminate agitation, hypertonia, normalize vitals) -If failsàcyproheptadine

-Stop the agent, Support, Cooling blankets -Benzos are mainstay -Dantrolene and Bromocriptine are adjuncts

Acute withdrawal of L-dopa therapy in pt w severe Parkinson’s has also been reported to trigger NMS

Can occur after 1st exposure but more likely after 3rd exposure

Anesthesia will notice this intra=op – rise in ETCO2, rigidity, Temp >1oC higher Genetic tests (RYR1 gene most commonly or muscle biopsy – beyond scope of Gim exam )

DANTROLENE And rapid cooling , supportive measures

•

•

• •

•

Organophosphate Poisoning

Typically found in insecticides • Also have applications in medical uses such as reversing neuromuscular blockade (neostigmine/physostigmine), or treating myasthenia gravis and alzheimer's (pyridostigmine, donepezil, edrophonium) MOA • Bind acetylcholinesterase and render it nonfunctioning • This will lead to an overabundance of acetylcholine at the neuromuscular junction S&S • Onset within 3 hours if oral or resp exposure • Dermal may be up to 12h Muscarinic effects: DUMBELS • Diaphoresis, Diarrhea • Urination • Miotic pupils (SMALL) • Bronchospasm, bradycardia, bronchorrhea • Emesis • Lacrimation • Salivation Nicotinic effects: MATCH • Muscle weakness (paralysis)/fasiculations • Adrenergic stimulation…mydriasis (large pupils) • Tachycardia • CNS-lethargy, seizures, coma, resp depression • HTN

• • •

Dx

•

CV: QTc prolongation, MI’s, CV collapse (? Secondary to vasodilation) Resp: Resp failure secondary to CNS depression, neuromuscular weakness (diaphragmatic weakness), resp secretions, bronchoconstriction Neuro: • Nicotinic effects • “intermediate syndrome” • 24-96h after exposure • Neck flexion, decreased reflexes, CN abnormalities, prox muscle weakness and resp insufficiency • Organophosphate agent induced delayed neuropathy • 1-3 weeks after ingestion • Painful stocking and glove paresthesia followed by a symmetrical motor polyneuropathy characterized by flaccid weakness of the lower extremities Based off history

Treatment

A/B

Antidote

•

100% FiO2 Intubate (constant reassessment of ability to protect airways and resp insufficiency from diaphragmatic weakness) • Avoid succs as it is cleared by acetylcholinesterase (which is inhibited by OP) • Can use roc, but will need high doses C-Usually hypotension and brady-fluids • Can cause HTN and Tachy with sympathetic stimulation D-Decontaminate-Wash patient, medical personnel should wear full protection, be in well vented area • •

Atropine • Atropine competes for acetylcholine, preventing cholinergic activation • Fixes muscarinic symptoms • Indications: • Miosis • Excessive sweating • Hypotension • Resp distress (poor air entry, bronchorrhea, bronchospasm/wheeze) • Bradycardia • Start at doses 2mg IV, double dose q3-5 minutes until pulmonary signs and symptoms are alleviated • Once atropinization, start infusion 10-20% of total dose required to atropinize patient per hour (to max 3g/h) • S/E • Agitation, urinary retention, ileus, hyperthermia, tachy causing MI if pre-existing heart disease • Tachy is NOT a C/I to cholinergic toxicity-may be tachy from hypoxia…which will resolve!

MCQ 4 2024 A 50 year old female presents to the emergency department after starting a new antibiotic for a UTI. She has a headache, dizziness, shortness of breath and confusion. On assessment vitals show BP 110/70, HR 110, RR 28, Sat 87%, temp 36.5. She appears cyanotic, tachypneic and drowsy. She is placed on a non-rebreather mask at 15L/min. Laboratory investigations show Hb 115, WBC 8, Plt 250, Cr 120, Na 137, K 4.8, Cl 105, bicarb 21, lactate 2.3, ABG 7.44, CO2 35, PaO2 170, SaO2 56%. What is the best next step in management? 1. Hydroxycobalamin 5g IV

This would be appropriate if the stem was suggesting cyanide toxicity. There is not clear exposure to cyanide, no cardiac instability, no severe lactic acidosis.

2. Place on high-flow nasal cannula at FiO2 1.0

This could be done as part of supportive management but will not treat the cause. The PaO2 is already 170 so additional inspired oxygen is not going to help significantly. If the stem was suggesting Carbon monoxide poisoning then this would be appropriate – the SpO2 would be higher (i.e. 100%), and there would be evidence of a cause (carbon combustion).

3. Methylene blue 2mg/kg IV

This is the appropriate treatment for methemoglobinemia. The stem is likely pointing at sulfamethoxazole (Septra) that was used to treat the UTI.

4. CT head

This could be used part of a work up for confusion/drowsiness, but should not delay administering methylene blue.

5. Transfuse 1 unit RBCs

Increasing Hb available to bind to O2 may make sense theoretically, but there is not evidence/guidelines suggesting to do this in MetHb.

106

Thank You! Shock and Sepsis Respiratory failure & ARDS Covid-19 in the Critically Ill Extubation ICU Delirium, Sedation, Analgesia, Sleep • Targeted temperature management, neuroprognostication, NDD, neuro ICU • Toxicology • • • • •

• Extra slides for your reference: – – – – –

Acute hypoxia in the ICU Gas trapping Maternal cardiac arrest Hyperthermia & Hypothermia Bonus MCQs

BONUS Read on own

Acute Desaturation/Hypoxia

1. Check the ventilator – all connections intact? Is the oxygen connected? 2. Disconnect ETT from vent àBag-ventilate – is there increased resistance? – – – –

3. 4. 5. 6. 7.

AIRWAY = blocked ETT, bronchoconstriction Airspace = Blood, Pus, Water, Cells, Protein Pleura = Pneumothorax, effusion, hemothorax Vascular = Pulmonary Embolism

Deep suction Auscultate, check that trachea is midline** Check other vitals – hypotension, tachycardia = could it be hypoperfusion? Chest X-ray à check ETT placement (right mainstem intubation?) Review history: New Line? (pneumo]) New blood? (TRALI/TACO) ACS/bolus? (acute pulmonary edema) Off DVT proph? (PE) Fevers? (VAP)

BONUS Read on own

Acute Respiratory Distress in the ICU

Auscultate and Check that Trachea is midline: Diagnosis

Trachea Displacement

Air Entry

Percussion

ETT migrated (commonly to R mainstem bronchus)

To LEFT (if R mainstem intubation)

Decreased on L

Decreased on Left

Pneumothorax

Away from affected Decreased on lung affected side

Increased on affected side

Collapse (mucous plug)

Towards affected side

Decreased on affected side

Decreased on affected side

Other

May have SubQ emphysema if trauma induced

BONUS Read on own

Gas Trapping

• Aka auto-peep or intrinsic-peep • What is it – Occurs when the expiratory time on the vent is shorter than the actual time needed to fully deflate the lungs

• How to detect – Do an end-expiratory breath hold

110

BONUS Read on own

• • • • • • •

Gas Trapping

Signs and Symptoms

Causes

Increased work of breathing Wheeze Increased chest distension Decreased chest expansion Bilateral decreased air entry Increased CO2 Increased intrathoracic pressures – Dec venous return and hemodynamic instability

• Machine factors – Kinked ETT – ETT clogged by sputum – Patient biting on ETT • Vent settings – High RR – High I:E ratio • Patient – Bronchospasm – Increased RR

111

BONUS Read on own

Patient changed

Gas Trapping Vent changes

• Reverse anything reversible • Need long I:E ratio (1:4 or 1:5) (i.e. give more time to exhale) (bronchodilators/steroids) • Lower the resp rate • Suction ETT and make sure patent

• Decrease the Vt • Apply PEEP to counter the increased work of breathing • Last line measures – – – –

Disconnect from vent and press on chest Heliox ECCOR2 High frequency oscillation

112

BONUS Read on own

Maternal cardiac arrest

• • •

Run ACLS as one would non-pregnant patient Detach all fetal monitors If it is a shockable rhythm-defibrillate! – A delay in defibrillation decreases chance of survival

•

Must move the gravid uterus off the IVC once fundus is at or above umbilicus (20 weeks)

• •

– IVC compression reduced SV and COàManual left lateral uterine displacement – IV must be above the diaphragm – If getting IV Mg, stop and give calcium chloride or gluconate Focus on early intubation as ++hypoxia (either ETT or supraglottic devise) Resuscitation should not be overshadowed by postmortem cesarean delivery – PMCD should be considered in the later half of pregnancy – Consider PMCD at 5 minutes of resuscitation

BONUS Read on own

Hypothermia

Brown D et al., N Engl J Med 2012; 367:19301938

114

BONUS Read on own

Hypothermia

Brown D et al., N Engl J Med 2012; 367:1930-1938

BONUS Read on own

Central line placement and Platelets

• Van Baarle N Engl J Med 2023; 388:1956-1965 • Pts with Plt 10-50 in ICU or Hematology ward requiring CVC • Intervention: Prophylactic plt transfusion before CVC insertion vs no transfusion • Non-inferiority study – outcome catheter related bleeding • Withholding plt transfusion before CVC insertion if plt 10-50 was NOT non-inferior (i.e. more catheter related bleeding in the control group)

MCQ #1 – 2023 A 70 year old male presents with a one day history of fevers, chills, and right flank pain. He was previously well, and has a past medical history of hypertension, dyslipidemia and BPH. On exam: he is drowsy, but rousable, GCS 14, confused to date. His BP is 79/40 (MAP 53), HR 120 sinus tach, resp rate 18, satting 99% on room air. His physical exam is notable for costovertebral angle tenderness on the right. Labs: WBC 18, plt 475, Hgb 118, Cr is elevated to 365 (baseline 90), lactate 5, VBG: 7.25/25/12. Urinalysis is positive for leukocytes and nitrites. All else is normal. Blood cultures are pending. Imaging: An abdo X-ray was unremarkable and a CT abdo is pending. The patient has been given 2.5L of balanced crystalloid and was started on empiric antibiotics. You perform a bedside ultrasound, which shows a grade I LV (by visual estimation), no pericardial effusion, no B-lines, and a non-collapsible IVC (on inspiration) measuring 2.5 cm. • Which of the following is the next best course of treatment a) b) c) d)

Give 2L of NS Give 500 cc of 5% albumin Start norepinephrine infusion Start dopamine infusion 117

MCQ #1 • Which of the following is the next best course of treatment a)

b)

c)

d)

Give 2L of NS – based on your dynamic measurements of fluid responsiveness using bedside US, this patient is likely fluid replete and would not benefit from additional boluses. Give 500 cc of 5% albumin – albumin is not a first line resuscitation fluid, and if patient required additional fluid, would recommend additional balanced crystalloid bolus. Start norepinephrine infusion – given the IVC is non-collapsible and measuring greater than 2cm, patient would likely not respond to further fluid boluses and should start on vasopressors due to the presence of shock. Start dopamine infusion – not a first line vasopressor, norepinephrine would be the appropriate choice.

118

MCQ#2 2023 A 25 year old female presents with an out of hospital cardiac arrest due to a cocaine overdose. After a prolonged resuscitation by EMS, return of spontaneous circulation is achieved after 40 minutes. The patient is then admitted to ICU for further management. The patient does not respond to painful stimuli, has an absent pupillary response and absent corneal reflex. There is no cough or gag reflex detectable. You are concerned about potential brain death. What prevents you from making this diagnosis? a) Norepinephrine required to maintain a MAP of 65 b) Cardiac arrest occurred less than 24 hours ago c) Serum sodium of 158 d) Propofol infusion that stopped only 12 hours ago 119

MCQ#22023 What prevents you from making this diagnosis? a) Norepinephrine required to maintain a MAP of 65 – vasopressors and IV fluids are appropriate to ensure MAP greater than 65, not contraindicated in DNC. b) Cardiac arrest occurred less than 24 hours ago – need at least 48 hours as per 2023 Canadian guidelines unless neuroimaging shows devastating neurological injury c) Serum sodium of 158 – guidelines mandate serum sodium of less than 160 and greater than 125. d) Propofol infusion that stopped only 12 hours ago – always check medication half-lives. Propofol is short acting with short half-life (~40 mins), 12 hours for a short duration infusion is more than enough time.

120

MCQ #3 – old 2023 37 yF presents with altered LOC after being found by her partner with an empty bottle of amitriptyline (recently filled 2 days ago). The bottle contained 25 mg tablets, with approximately 150 tablets missing. It was estimated she ingested the pills about 4 hours before presentation. On exam: Temp 40, HR 135, BP 125/78, RR 16, normal oxygen saturation. CBG 7.5. She has mydriasis, diffuse erythema. A foley is placed and 2L of urine immediately drains. GCS is currently 10. Investigations: CBC, lytes, VBG and creatinine are all WNL. ECG shows a wide complex regular tachyarrhythmia with a QRS of 140. • What is the next best step? a) Give 2 amps of bicarbonate immediately b) Administer physostigmine to counteract the anticholinergic toxicity c) Give Dilantin for seizure prevention d) Cardiovert the patient 121

MCQ #3 • What is the next best step? a) Give 2 amps of bicarbonate immediately – indicated for a QRS duration > 100 msec in TCA overdose. If QRS narrows then start bicarb infusion. b) Administer physostigmine to counteract the anticholinergic toxicity – contraindicated in TCA overdose due to the risk of cardiac arrest. c) Give Dilantin for seizure prevention – no indication for seizure prevention, but even for seizure treatment, avoid Dilantin due to the sodium channel blockade that could worsen cardiac arrhythmias. Mainstay is benzodiazepines for seizures and agitation. d) Cardiovert the patient – not indicated at this point, especially if patient responds to bicarbonate therapy. 122

BONUS Read on own

MCQ #4 (2023)

A 45 year old male with morbid obesity is admitted for respiratory failure secondary to pneumonia. He has a prolonged course on the ventilator and underwent tracheostomy 5 days ago. He becomes agitated and today he pulls out his trach. What do you do? a) Reinsert the trach b) Orotracheal intubation c) Crichothyroidotomy d) Place on nasal prongs and monitor 123

BONUS Read on own

MCQ#4 (2023)

What do you do? a) Reinsert the trach – do not reinsert a trach, unless the tract is mature (7-10 days minimum). This could lead to subcutaneous emphysema when placed on the vent and rapid respiratory/cardiac arrest. b) CORRECT - Orotracheal intubation – this is the first step, intubate from above to secure the airway. c) Crichothyroidotomy – consider this if unable to intubate or ventilate. d) Place on nasal prongs and monitor – not recommended for a patient who failed previous extubation and was unable to wean from the vent. 124

BONUS Read on own

MCQ #5 (2023)

A 25 year old female presents with an acute Tylenol overdose. She ingested 8.5 g four hours before presentation. She is asymptomatic currently, and was given activated charcoal. Her GCS is 15 and she is vitally stable. Her exam is remarkable for mild right upper quadrant tenderness. Her labs are unremarkable, AST and ALT are within normal limits. Her Tylenol level is above the treatment line on the RM nomogram. She is started on a NAC infusion. Thirty minutes into the infusion she develops urticaria and flushing. The infusion is stopped, she is given benadryl and the reaction subsides. What is the best course of action? a) Do not restart the infusion and consult Nephro for hemodialysis b) Switch to PO NAC c) Reduce the dose by half and uptitrate if the infusion is tolerated d) Restart the infusion and monitor for airway compromise or signs of anaphylaxis

125

BONUS Read on own

MCQ #5 (2023)

What is the best course of action? a) Do not restart the infusion and consult Nephro for hemodialysis – there is no role for hemodialysis in Tylenol overdose if you are able to continue with NAC therapy. Hemodialysis may be considered to lower Tylenol concentrations if NAC is not available or if there is a concurrent renal failure. b) Switch to PO NAC – no indication to switch routes of administration. c) Reduce the dose by half and uptitrate if the infusion is tolerated – dose reduction is not recommended by guidelines, instead you should continue the recommended NAC protocol dosing regimen. d) CORRECT - Restart the infusion and monitor for airway compromise or signs of anaphylaxis – this is appropriate to optimize Tylenol toxicity treatment and for liver protection. 126

BONUS Read on own

MCQ #6 (2023)

A 66 year old obese male is admitted to the ICU with acute hypercarbic respiratory failure secondary to a severe COPD exacerbation. He presents with a CO2 of 85, and with this has a GCS of 10. He is started on steroids, routine puffers, and trialed on BiPAP, and after 2 hours his GCS is 8 and his CO2 has climbed to 105. The decision is made to intubate the patient. His initial vent settings are: ACPC 14/5, 40% FiO2, RR 18. Peak pressures are 35 cm H2O, plateau pressures are 20 cm H2O, driving pressure is 15 cm H2O, and tidal volume is 8 ml/kg. You are called to his bedside 3 hours later because the patient has acutely desaturated, and is requiring an FiO2 of 80%. His SpO2 is now 85%. How would you advise adjusting the ventilator settings to improve his oxygenation? a) Increase the FiO2 to 100% b) Increase the respiratory rate to 25 breaths per minute c) Switch to volume control ventilation d) Increase the PEEP to 10 cm H2O

127

BONUS Read on own

MCQ #6 (2023)

How would you advise adjusting the ventilator settings to improve his oxygenation? a) Increase the FiO2 to 100% - this would not be recommended before optimizing the PEEP due to the negative effects of hyperoxia on lung tissue (increase in free radicals). b) Increase the respiratory rate to 25 breaths per minute – this would increase minute ventilation, which would improve ventilation (CO2 clearance), but would not impact oxygenation. c) Switch to volume control ventilation – this would be recommended in lung protective ventilation (for ARDS), but in other clinical situations pressure control is appropriate, unless concern of ventilator dysynchrony. d) CORRECT Increase the PEEP to 10 cm H2O – this would be indicated to optimize oxygenation by improving recruitment and reducing atelectasis to optimize gas exchange. Likely in this scenario the patient de-recruited from having too little PEEP in the context of his underlying obesity and COPD.

128

MCQ 7 (2024) 45 year old patient is admitted to the general internal medicine ward with acute respiratory failure secondary to influenza. Their medical history includes hypertension. They were initially managed with conventional oxygen therapy, with nasal prongs 4L/min. On repeat assessment their hypoxemia is worsening with O2 sats 85% on nonrebreather mask at 12L/min and they have increased work of breathing. They are following commands and speaking in short sentences. VBG shows pH 7.42, CO2 35, Bicarb 24. What is the best next step in management? 1. Non-Invasive Ventilation 2. High-Flow Nasal Cannula 3. Intubation 4. Proning 5. Hydrocortisone 100 mg IV

129

MCQ 7 (2024) 1. Non-Invasive Ventilation Non-invasive ventilation should be used for hypoxemia secondary to cardiogenic pulmonary edema, and can be considered for acute respiratory failure in patients with chest trauma, immunocompromised state, post-operative, palliative with dyspnea. There is no recommendation made for de novo respiratory failure without these conditions.

2. High-Flow Nasal Cannula Strong indication for hypoxemic respiratory failure OVER conventional oxygen therapy

3. Intubation There is no strong indication for intubation yet. Airway is protected (patient is talking, alert) and work of breathing/hypoxemia may improve on HFNC.

4. Proning Self proning can be considered for hypoxemia in setting of covid in non-intubated patients. However, HFNC would be used first.

5. Steroids Steroids have a benefit in treating Severe COMMUNITY ACQUIRED PNEUMONIA (data covered in ID lecture) and with COVID 19 (Dexamethasone) – however can actually be harmful (more nosocomial infection, possibly more mortality) with influenza. Even if you didn’t know this data, in this setting next best step (ABCs!) is to administer more oxygen if you were choosing best answer on MCQ.

130

MCQ 8 (2024) 65 year old patient is admitted to the ICU after an unwitnessed out-of-hospital cardiac arrest secondary to fentanyl overdose. It is now 60hrs since the arrest. CT head shows diffuse greywhite matter loss in keeping with a hypoxemic-ischemic brain injury, with cerebral edema and tonsillar herniation. Post-cardiac arrest management included therapeutic hypothermia targeting 35-36 degrees C. Passive rewarming has started and the current core temperature is 35.6 degrees C. The patient was sedated with propofol and ketamine which were stopped 24hrs after the cardiac arrest. No neuromuscular blockers were used. MAP is currently 70 with vasopressin, ABG showing pH 7.33, PaCO2 45, lactate 1.7. Bicarb 24. Further labs show Na 150, K 3.4, Cr 140, Urea 15, Calcium 2.1, Mg 0.8, Phosphate 0.7, Bilirubin 20, ALT 60, ALP 80. Which of the following would prevent death by neurological criteria assessment? 1. Time since cardiac arrest 2. Core temperature 3. Metabolic derangement 4. Shock 5. Sedative medication 131

MCQ 8 (2024) 1. Time since cardiac arrest Updated canadian guidelines 2023 state to wait at least 48hrs since cardiac arrest before completing DNC assessment.

2. Core temperature Core temperature must be ≥36 degrees C in latest guidelines (previously 34) before completing DNC assessment

3. Metabolic derangement Metabolic derangements that are severe should be corrected before completing DNC assessment. However, none of the metabolic derangements in this case would be considered severe enough.

4. Shock Shock is resuscitated in this case with vasopressor support and a normal lactate. Only un-resuscitated shock prevents DNC assessment (i.e. high lactate, end organ ischemia/dysfunction, MAP < 65 despite vasopressors).

5. Sedative medication New guidelines suggest waiting 5 half lives of medications. 60hrs would be long enough for fentanyl (1/2 life approx 4-7hrs) and ketamine/propofol (stopped approx 40hrs ago).

132

MCQ 9 (2024) 80 year old patient presents to the emergency department with nausea and vomiting secondary to a small bowel obstruction. Past medical history includes chronic pain, depression, cholecystectomy. Home medications are citalopram, hydromorphone contin, senna. The patient undergoes an urgent laparotomy with resection of adhesions for management of the small bowel obstruction. They are admitted to the ICU for post-operative management. Issues during the ICU stay include post-operative ileus, delirium and pain. ICU medications include hydromorphone CR, IV fentanyl, IV gravol, IV metoclopramide, lansoprazole, citalopram, dalteparin 5000 u sc daily. On post-operative day 3 the patient develops a temperature of 39 degrees C. Vitals shows BP 130/80, HR 110, RR 20, Sats 96% 2L NP. Examination shows pupils 5mm and equal, diaphoresis, agitation, lower limb rigidity with brisk reflexes, ankle clonus x 12 beats bilaterally. Which syndrome most likely explains the findings? 1. Sympathomimetic toxidrome 2. Anti-cholinergic toxidrome 3. Serotonin syndrome 4. Neuroleptic malignant syndrome 5. Malignant hyperthermia

133

MCQ 9 (2024) 1. Sympathomimetic toxidrome No inciting cause. Rigidity not expected. Patient would have significant hypertension.

2. Anti-cholinergic toxidrome Excessive levodopa could cause this, but would expect dilated pupils. Does not explain hypertonia.

3. Serotonin syndrome Fentanyl and citalopram (SSR) could cause serotonin syndrome; addition of metoclopramide to the mix can worsen risk of serotonin syndrome in patients on SSRIs!! He has fever, rigidity, hyperreflexia and clonus so this fits the bill.

4. Neuroleptic malignant syndrome There are features of NMS (hyperthermia, rigidity,) and an inciting cause potentially (metoclopramide) – however the hyperreflexia doesn’t fit with this syndrome and is better explained by serotonin syndrome.

5. Malignant hyperthermia Too long since volatile anaesthetic. This would occur minutes/hrs after exposure.

134

MCQ 10 (2024) A patient has been admitted to the intensive care unit after a motor vehicle collision. Their injuries include a severe traumatic brain injury (TBI), rib fractures, splenic laceration, and facial fractures including an orbital fracture with disruption of the ocular muscles resulting in fixed abduction of the right eye. The patient remains GCS 3 48hrs into admission with CT evidence of severe cerebral edema, mass effect and herniation. Examination reveals no brainstem reflexes. No further options are available for management of the TBI. Review of the chart shows no confounders to death by neurologic criteria (DNC) assessment. What is the appropriate next step? 1. Wait a further 24hrs hours before completing DNC assessment 2. Order an MRI 3. Proceed with DNC assessment 4. Order a CTA head and neck as an ancillary test 5. Order SSEPs 135

MCQ 10 (2024) 1. Wait a further 24hrs hours before completing DNC assessment

DNC assessment can occur ≥48 hrs after a cardiac arrest, or earlier if neuroimaging shows a devastating injury. There has been no cardiac arrest and imaging shows a devastating injury so there is no need to wait longer.

2. Order an MRI to characterise the cause of coma

MRI is useful in neuroprognostication, but is not an accepted ancillary test

3. Proceed with DNC assessment

Cannot proceed with DNC because the ocular injury and persistent lateral abduction prevents assessment of brainstem reflexes. For example, vestibulo-ocular requires assessment of eye movement (nystagmus).

4. Order a CTA head and neck as an ancillary test An ancillary test is required. CTA is an accepted option.

5. Order SSEPs for neuroprognostication

SSEPs are useful in neuroprognostication, but is not an accepted ancillary test

136

MCQ 11 (2024) A patient presents 4 hours after an ingestion of an unknown quantity of pills and clear liquid. They are initially confused and agitated, and subsequently become drowsy. Bloodwork shows Na 140, K 4.5, Cl 105, bicarb 21, urea 10, glucose 5, VBG pH 7.30 pco2 40, lactate 2.4, serum etoh 30 mmol/l, plasma osmolality 395, serum/urine ketones positive, acetaminophen 80 micromol/l (upper limit normal < 66, rumack-mathew treatment threshold >800 micromol/l at 6hrs) What is the next best step in management? 1. D10 infusion 2. NAC infusion 3. Dialysis 4. Fomepizole 5. Single Dose Activated Charcoal

137

MCQ 11 (2024) 1. D10 infusion

This can be used for salicylate toxicity to prevent cerebral hypoglycemia despite normal serum blood glucose levels. There is no respiratory alkalosis to suggest salicylate toxicity.

2. NAC infusion

The acetaminophen level given is below the treatment threshold at this time post ingestion so NAC is not the next best step. In scenarios where the time of ingestion is uncertain or there are risk factors for hepatotoxicity then NAC can still be given.

3. Dialysis

Acetaminophen is dialyzable (See EXTRIP for indications), but this scenario is not in keeping with a massive overdose. Dialysis could be indicated for a toxic alcohol ingestion in this scenario, but there is no evidence of a clear indication (severe acidosis, known high parent alcohol level, renal failure).

4. Fomepizole

This scenario shows a mild anion gap metabolic acidosis (AG 14) with high osmolar gap (calculate osmolality = 2x Na (280) + glucose (5) + urea (10) + 1.25xetoh (45) = 340, measured 395, osmolar gap 55). Although the this could be due to isopropyl alcohol, an early ethylene glycol/methanol ingestion which has not yet had time to convert into toxic metabolites and cause a severe metabolic acidosis cannot be ruled out. Therefore the best next step is to give fomepizole while awaiting volatile screen results.

5. Single Dose Activated Charcoal

The risk of aspiration is high (uncooperative, drowsy, not intubated) so this would not be of benefit. SDAC does not work for toxic alcohols. It could be used for acetaminophen but the risk of aspiration does not outweigh the benefit in this case.

138

ENDOCRINOLOGY Sunday, December 3rd, 2023 Dr. Jessica Mak

Outline (Lecture) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Hypercalcemia – **NEW Endo Society Hyper/Hypopara Guidelines 2022** MEN Syndromes Hyperthyroidism Hypothyroidism Thyroid Disease in Pregnancy Osteoporosis & Metabolic Bone Disease – **NEW CMAJ Guidelines 2023** Diabetes Adrenal & Pituitary Obesity Guidelines Lipid Guidelines – **NEW CCS Guidelines 2021** Care for Transgender Patients Reproductive Endocrinology Thyroid Nodules & Cancer 2

Endocrinology 101 Before we start… Interpreting Labs:

*Normal or inappropriately normal? Always think critically about what the pattern of hormones should be, not only whether a value is in the normal range

3

1. Hypercalcemia Resources: 2022 Hyperparathyroidism Guidelines from the Fifth International Workshop https://asbmr.onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4677 Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus: https://pubmed.ncbi.nlm.nih.gov/27613721/

4

Question 1 A 85yoF is referred for hypercalcemia. She is complaining of severe bone pain. A CT scan done shows lytic lesions. sPEP, uPEP, FLC assay are normal, malignant workup is normal. BMD do not have any T-scores 250mg/d) in women or >7.5 mmol/d in men (>300mg/d) Stones or nephrocalcinosis by x-ray, ultrasound, or CT Suggest Surgery in those being monitored in follow-up if: • Serum calcium consistently >0.25 mmol/L above upper limit Creatinine clearance < 60 mL/min (stage 3 CKD) • Low trauma fracture (+/- VFA if indicated) JBMR 2022

• • •

A kidney stone (abdo imaging if indicated) Significant reduction in BMD (every 1-2 yrs) to T-score 3ml/min annually to 0.02 Urine Calcium (mmol/l) x [Serum Creatinine (umol/l) / 1000] Serum Calcium (mmol) x Urine Creatinine (mmol/l)

11

1o Hyperparathyroidism (PHPT):Medical Management If patient NOT a candidate for surgery (e.g. per ENT, or too frail for surgery) : Medical Management* • ! Correct vitamin D deficiency/insufficiency: target serum 25-OH vit D to >75 nmol/L • Calcium intake should be consistent with nutritional guidelines (1000-1200 mg/d) • Bisphosphonates and denosumab if indication to improve BMD • Cinacalcet ($) is effective in reducing serum Ca and should be considered for symptomatic PHPT if surgery is not an option. May combine w BP or denosumab in selected pts (to reduce Ca AND increase BMD). *Bottom Line: Surgery is the only cure for PHPT. Never use medical mgmt as an alternative to surgery when patient is fit for OR. There is no fracture data (only BMD improvement) with the existing medical treatments. 12

2o & 3o Hyperparathyroidism Secondary Hyperparathyroidism

– Appropriate increase in PTH release in hypocalcemia or vitamin D deficiency (most common) – PTH is appropriately working to absorb all the urine calcium/salvage calcium level – TIP #1 : Postop Gastic Surgery (ex. gastric bypass/bilroth/whipples surgery where a portion of stomach is removed) • You CANNOT use Calcium Carbonate as a supplement (there is no acidity to absorb this!) = use Calcium Citrate

– TIP #2: Pt w Renal disease (CKD)

• treat with Vitamin D, phosphate restriction, non-calcium phosphate binders • Cinacalcet for 2o HPT in CKD on dialysis (with target PTH levels depending on CKD stage; often in consultation with Nephrology)

Tertiary Hyperparathyroidism

– Longstanding hypocalcemia (appropriate stimulus for PTH release) à parathyroid glands can become autonomous – Usually in the setting of end-stage renal disease or post-transplant

Indications for Surgery in Tertiary Hyperparathyroidism • Refractory hyperPTH despite vit D analogues/ calcimimetics (No absolute #/PTH cutoff, KDIGO defines as PTH still rising, symptomatic)

• Hypercalcemia severe / symptomatic Remarkably the KDIGO 2017 • Calciphylaxis guidelines don’t give a lot of • Progressive bone disease

guidance here, largely because there are no high quality RCTs showing difference in outcome of medical vs surgical therapy in this population. 14

*

BONUS Read on own

Hypoparathyroidism Guidelines 2022

Diagnosis: • Hypocalcemia in the presence of undetectable, low or inappropriately normal PTH • measured on two occasions >2 weeks apart • Supported by high phosphorus and low (1,25)OH2 vitamin D • Permanent postsurgical hypoPTH is defined as persisting >12 months after surgery Management: • 1st line = Conventional therapy w/ oral calcium & active vitamin D (calcitriol or alfacalcidol) • PTH therapy can be considered if conventional therapy insufficient

*

Hypoparathyroid Differential

BONUS Read on own

• Acquired – Hypomagnesemia à PTH resistance – Hypermagnesemia à reduce PTH synthesis/secretion – Post-surgical (common complication post-total thyroidectomy) or postradiation – Infiltrative disease (sarcoid, amyloid, cancer metastasis) – Autoimmune polyglandular syndrome type 1 (APS-1)

(Whitaker’s Triad: chronic mucocutaneous candidiasis, Addison’s disease, & hypoparathyroidism) AIRE mutation

• Congenital

– Pseudohypoparathyroidism (genetic mutation in GNAS gene) – DiGeorge Syndrome / 22q11.2 deletion syndrome : parathyroid agenesis – Note: Hypocalcemia outside of hypoparathyroidism can also occur in

Extravascular sequestration – Hyperphosphatemia, Pancreatitis, Osteoblastic metastases

Question 1

Lytic lesions caused by HyperPTH = “Brown tumors”

A 85yo is referred for hypercalcemia. She is complaining of severe bone pain. A CT scan done shows lytic lesions. sPEP, uPEP, FLC assay are normal, malignant workup is normal. BMD do not have any T-scores 90 or CVD”) • It takes 4-6 weeks to see full effect of antithyroid drugs (e.g. methimazole or propylthiouracil) 25

Hyperthyroidism – Pearl # 5 Treatment Options for Graves: thionamides, surgery (total thyroidectomy), or RAI ablation; latter two renders the patient hypothyroid à need levothyroxine replacement lifelong Medical Management: • Use MMZ instead of PTU because less hepatotoxic EXCEPT in the following situations: Ø First trimester of pregnancy (risk of aplasia cutis & cleft palate) Ø Thyroid storm Ø Minor MMZ reactions (if severe, then shouldn’t use anti-thyroid drugs at all)

26

Counselling on Anti-Thyroid Drugs

Drug Reaction

MMZ

PTU

Action

Management Notes

Hepatotoxicity*

YES

YES (worse)

STOP & can’t switch

Discontinue if transaminases reach >3x ULN * *some transaminitis often also a result of thyrotoxicosis before ATD, but typically not 3x ULN

Agranulocytosis (look out for fever/sore throat!)

YES (more likely dose related)

YES (not dose related)

STOP & can’t switch

Vasculitis (polyarthritis, purpuric skin lesions, pulmonary +/or renal)

YES

YES

STOP & can’t switch

Serious allergic rxn

YES

YES

STOP & can’t switch

Assess and treat for anaphylaxis

Minor reactions

YES (be careful that it isn’t vasculitis)

YES (be careful that it isn’t vasculitis)

Can try switching (but probably not helpful)

Rx anti-histamine for minor rashes

(e.g. minor rash, GI symptoms, myalgias & arthralgias)

Granulocyte colony stimulating factor, steroids, antibiotics (if febrile) and/or supportive care Rx - Glucocorticoids or other immunosuppressive therapy

27

Other Graves’ Treatment Options • RAI

– Single dose of ablative radioactive iodine. – Contraindications: Pregnancy, breastfeeding, moderate-severe orbitopathy, thyroid cancer – Adverse effects: Worsened Orbitopathy, Thyroiditis – Delay pregnancy for 6 months after tx – If giving RAI with orbitopathy, should give steroids – Should be off methimazole for at least 2-3 days before radioactive iodine ablation

• Surgery

- Patient should be euthyroid prior to surgery

Grave's Orbitopathy Treatment - Mild • Artificial tears or ophthalmic gels • Selenium supplementation x 6 months (fasting intake)

Bartalena et al. 2021 Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for Management of 29 Graves’ orbitopathy

GO Treatment: Mod to Severe • IV glucocorticoids + mycophenolate is the EUGOGO first-line treatment for those with ACTIVE GO if no contraindications (ie CHF, severe hyperglycemia). • Alternative first-line regimen is IV glucocorticoids alone at higher doses • Surgery only offered for stable INACTIVE GO (must be inactive >6 months) “EUGOGO” Guidelines, 2021

30

Thyroid Storm Think of this with a very sick patient with thyrotoxicosis (tachycardia, confusion, hyperthermia) The degree of T4 excess is not necessarily more than with other forms of hyperthyroidism

Burch-Wartofsky Scale https://www.mdcalc.com/burch-wartofsky-point-scale-bwps-thyrotoxicosis *don’t memorize the calculations, know the clinical picture* COMPONENTS: • Fever • Neurological symptoms • GI symptoms/hepatic dysfunction • Tachycardia • A. fib • Heart failure • Precipitants (infection, surgery, trauma, iodine load, pregnancy; most common is medication nonadherence/discontinuation) 31

Thyroid Storm Treatment • ABCs – get ICU involved early! • Supportive care

• Beta-blockers (careful with hemodynamic status!!)

• E.g. Propranolol 60-80mg PO q4-6h, if unsure, start at lower Propranolol dose 20-40mg po q4-6hr [the intention is to reduce adrenergic drive]

• PTU* (usually 200 mg PO q4h) THEN • Iodine

• Lugol’s iodine 10 drops q8h • Should be given 1 hour after the loading dose of PTU

• Glucocorticoids (often AI co-exists, also helps to reduce fT4à fT3 conversion) *In Real Life: There is a shortage of PTU since 2020. PTU is preferred in Thyroid storm vs MMI because it blocks some peripheral conversion of T4 à T3. If unavailable at your hospital : give MMI 20mg q4-6h

32

MCQ - 2 2024 A 46 year old female is seen by General Surgery in the ER for abdominal pain. She has known history of hyperthyroidism with her current TSH being 10 mIU/L * 1.6mcg x weight (kg) = typical starting dose; titrate every 4-6 weeks ** if cardiac disease (CAD) or frail elderly, can start at lowest possible dose (e.g. 25mcg po daily or 50mcg po daily to avoid risk of inducing AFib)

Consider treatment when: Ø Ø Ø Ø

Symptomatic Goiter Pregnancy/pregnancy-planning Positive anti-TPO antibodies

Double-blind RCT of adults > 65 years with subclinical hypothyroidism (Stott DJ et al. NEJM 2017): No apparent benefits to treating older persons with subclinical hypothyroidism Choosing Wisely: routinely, we do not test for anti-TPO (also called anti-microsomal Ab), but in subclinical, can test to push your treatment decision 35

Myxedema Coma • Severe hypothyroidism leading to: – – – – – –

Altered LOC / lethargy Life-threatening SLOWING of Hypothermia function in multiple organs! Hypotension Bradycardia Diagnosis is clinical – but often Hyponatremia see very low/undetectable FT4, Hypoventilation high TSH

36

Myxedema Coma Treatment • IV levothyroxine load 200-400mcg x1 followed by 1.6mcg/kg/d (this is the PO dose, multiple by 75% if given IV) – Lower dose should be considered if cardiac history or elderly – PO levothyroxine ~75% as potent as IV form

• IV glucocorticoids (HC 100mg IV Q8H) until AI ruled out • IV liothyronine load 5-20mcg x1 followed by 2.5-10mcg Q8H • Supportive measures (ICU monitoring, mechanical ventilation, fluids, warming) 37

5. Thyroid Disease in Pregnancy • • • •

Subclinical Hypothyroidism Pre-existing Hypothyroidism Grave’s Disease Gestational Thyrotoxicosis

38

Question 3 - 2023 A 34 year-old woman with Graves disease, who has been euthyroid on methimazole 5mg PO daily for the past year, recently tested positive for pregnancy. She is referred for thyroid management in pregnancy. Which of the following is NOT appropriate? a) b) c) d)

Discontinue all anti-thyroidal meds to avoid teratogenicity Check thyroid function tests every 4 weeks during pregnancy Switch to PTU 300mg PO BID and continue until GA 16 weeks Check TRAb titre immediately and check again at GA 18-22 weeks

39

Subclinical Hypothyroidism in Pregnancy Simplified version of the 2017 ATA Guidelines TSH ≤ 2.5 (-)TPO Ab

Do not treat

TSH ≥ 4.0

TSH 2.5 – 4.0

Do not treat

(+)TPO Ab

Treat

(-)TPO Ab

Consider treat 4-10, definitely treat if >10

(+)TPO Ab

Treat

v Pregnant women with TSH >2.5 mU/L should be evaluated for TPO-Ab

v Once on treatment, target TSH ≤ 2.5 throughout the pregnancy v In Canada, we do not routinely screen TSH in asymptomatic pregnant women 40

Pre-existing Hypothyroidism in Pregnancy Need ~30-35% more LT4 as soon as pregnant = take an extra LT4 pill on Saturdays and Sundays (two extra pills/week = 9 pills/week) as soon as they are pregnant Ø e.g. If she is on LT4 75 mcg PO daily before pregnancy, take LT4 75 mcg PO q M-F and 150 mcg S/S Ø Upon delivery, go back to pre-pregnancy dose Ø Target TSH ≤ 2.5 throughout the pregnancy 41

Graves’ in Pregnancy Special Considerations:

1. Anti-thyroidal medications are teratogenic.

Mild subclinical hyperthyroidism = monitor, does not require automatic anti-thyroid drugs considering risk to fetus. a) If treating for symptoms, use PTU in the first trimester (conversion ~1mg MMZ:20mg PTU), MMZ after that (or discontinue all ATDs if possible!) - Patients on MMZ 5 mg daily) • Falls, ≥ 2 in the last year • Parent fractured hip • Body mass index < 20 kg/m2 • Secondary osteoporosis. • Current smoking • Alcohol ≥ 3 drinks/d

55

When to Treat: High Risk • • •

Hip, vertebra or ≥ 2 osteoporosis-related fractures 10-yr major osteoporotic fracture risk ≥ 20% ≥ 70 yo and have a T-score ≤ –2.5 (femoral neck, total hip or lumbar spine) o Before initiating pharmacotherapy, assess for secondary causes of osteoporosis: ALP (Paget's), PTH, Calcium/Alb/PO4 (parathyroid), Cr/eGFR (renal disease), TSH (hyperthyroidism), 25OH vitamin D (deficiency, malabsorption), Meds/Alcohol SPEP – vertebral #, anemia (MM), Eating disorders, Bariatric Surgery Hx, testosterone (hypogonadism), CRP (IBD), tTG-IGA (Celiac) etc.

56

Suggest Treatment: Moderate Risk • 10-yr major osteoporotic fracture risk between 15% and 19.9% • < 70 yr and have a T-score ≤ –2.5 (femoral neck, total hip or lumbar spine) Other treatment decision factors to consider: • a fracture in the last 2 years (risk of subsequent fracture highest) • ongoing risk factors

57

Pharmacotherapy for Osteoporosis CLASS

Drugs

Side effects

Contraindications

Rx Notes

Bisphosphonate

Alendronate Risedronate Zoledronic acid (5mg IV annually)

Esophageal / GI intolerance MSK arthralgias Flu-like infusion reaction (IV Zole) Rare: AFF, ONJ

CrCl= 30ml/min

↓calcemia/↓phosphatemia/↑PTH

Zoledronic acid

5mg IV every 1-2 years

eGFR >= 35ml/min

↓calcemia/↓phosphatemia

Teriparatide

20-40ug sc OD

eGFR >=30ml/min

↑or↓ calcemia ↑calciuria

Denosumab

60mg sc q 6mo

Any eGFR

↓↓calcemia/↓phosphatemia

Romosozumab

210mg sc q1mo

Not studied w/CKD

Unknown

Adapted from: Khairallah & Nickolas 2018 CJASN 13:962

60

Treatment Duration • Bisphosphonates: initial therapy for 3–6 yr, Reassess during drug holiday with BMD/FRAX in 3 years (or sooner if clinical indication) • Denosumab: long-term uninterrupted therapy (should not delay Q6month dosing by more than 1 mo) may be re-assessed after 6–10 yr • If stop at ≤ 4 doses, transition to bisphosphonate 6 mo after the last dose of denosumab (reduces risk of rapid bone loss. Bisphosphonate therapy for 1 yr and then reassessing). • If stop at ≥ 5 doses (risk of rapid bone loss or vertebral fractures is high): refer to OP expert

• Teriparatide (24 mos)/Romo (12 mos): one course then transition to antiresorptive agent to maintain bone density gains

61

BMD Monitoring Frequency Not a candidate for pharmacological treatment: – 5–10 yr: if risk of major osteoporotic fracture (MOF) is < 10% – 5 yr if risk of MOF is 10%–15% – 3 yr if the risk of MOF is > 15% • Those on Therapy: – 3 yr after starting Rx • Those on Bisphosphonate Drug Holiday: – 3 yrs after stopping *BMD measurement may be repeated sooner/more frequently in people with new fracture, secondary causes of osteoporosis, or new clinical risk factors associated with rapid bone loss •

62

Atypical Femoral Fractures (AFF) Thigh or groin pain on bisphosphonates = need to rule out AFF! (bilateral femur X-rays, if these negative consider bone scan / MRIcharacteristics: if high index suspicion)** Clinical • • •

• Radiographic Characteristics • Lateral cortical thickening • Transverse fracture lines • Beaking

• • •

Proximal femoral shaft fracture Atraumatic Chronic bisphosphonate use (risk increases as early as 3 years) Asian women high risk Prodromal thigh pain (in up to 70%) Can occur with denosumab and romosozumab as well

Absolute risk increase is small, ~1:1000 patient years on bisphosphonate, versus 1:50000 patient years off bisphosphonate

Management of AFF PREVENTION • Drug holiday for oral/?IV bisphosphonate for 3-6 years TREATMENT • Orthopedic surgery consult (for IM nail insertion) • Make sure contralateral femur is imaged (early fractures may be asymptomatic) • Stop bisphosphonate • Ensure adequate vitamin D and calcium intake • Start teriparatide (if still meet OP treatment criteria) 64

Osteonecrosis of the Jaw ONJ • Nonhealing wound in oral mucosa with exposed bone that lasts >8 weeks • Risk 1 fracture or substantial bone density decline (e.g. ≥ 5%) • adherence to an adequate course of treatment (typically >1 yr) • Consider : secondary causes of osteoporosis, falls, BMD imprecision errors • Do not use bone turnover markers or FRAX/CAROC for monitoring What to do: • •

extend or switch therapy reassess for secondary causes and refer to OP expert

66

Treatment Summary

67

Evidence based Non-Pharm Interventions •

Exercise • • •

•

Nutrition • • •

•

Functional & Balance Training (twice weekly) : ↓ fall related fractures Resistance Training (twice weekly): In combination with functional !Caution: Twisting or Flexion of the spine in repetitive, rapid way

Vitamin D: 400 IU/d minimum, dosing to target 25-OH vitamin D level *75- 125 mmol/L Ca: 1000 mg/d (males aged 51–70 yr) and 1200 mg/d (females > 50 yr & males > 70 yr), dietary sources preferred Supplemental Protein, vitamin K, magnesium: low evidence

Other •

Smoking cessation, alcohol moderation

68

When to refer • To Consultant with OP expertise/Fracture Liasion Service:

Recent fracture Uncertainty about fracture risk or treatment Possible secondary causes of osteoporosis Comorbidities that complicate management (e.g. CKDMBD) • Significant adverse effects from pharmacotherapy • Inadequate treatment response • • • •

69

BONUS Read on own •

•

•

• •

*Paget’s Disease of Bone

Pathophysiology: focal ↑ in bone resorption by

very large osteoclasts, then ↑ osteoblastic activity producing a high rate of bone formation/turn-over. Initial Labs: ↑ serum total alkaline phosphatase (ALP) +/- bone specific ALP, without other

abnormalities Imaging: do plain film XRs first of suspicious areas, if asymptomatic do skeletal survey/series (look for thickened cortices with tunnelling & accentuated trabeculae) If the diagnosis is confirmed à, bone scan should be done to determine the extent of the disease. Associated illness: – Hearing loss, compressive neuropathies, osteoarthritis, osteosarcoma

Indications for Treatment: – Symptoms – pain, compression, fracture – Evidence of active disease with impending symptoms (high risk for fracture) – Hypercalcemia (usually should only happen if immobile) – ALP >2x ULN – Pre-orthopedic surgery at or near site (i.e. femoral Paget’s lesion for hip replacement) • First Line Treatment: IV zoledronic acid 5mg IV q1yr is treatment of choice or Oral bisphosphonate can be used **NOTE DOSING** – alendronate 40 mg/day x 6 months – Risedronate 30mg/day x 2 months •

•

2nd Line Agent (if intolerant to bisphos) is Calcitonin Paget's Disease of Bone: An Endocrine Society Clinical Practice Guideline (2014)

MCQ 4 - 2024 A 65 year old female with bipolar disorder on valproate and osteoporosis on alendronate, calcium, and vitamin D presents with leg pain after stumbling. She is found on X-ray to have an atypical femoral fracture. Secondary osteoporosis work-up was negative and her vitamin D level normal. Which of the following would be the next best step? 1. Stop oral bisphosphonate and start yearly IV Management of AFF: bisphosphonate 2. Continue oral bisphosphonate 1. Stop bisphosphonate 2. Treatment with teriparatide 3. Stop alendronate and start denosumab for fracture healing, especially if still high risk 4. Stop alendronate and start teriparatide osteoporosis on BMD. 3.

Should also involve ortho assessment especially if complete fracture. 71

7. Diabetes Highest yield resource: 2018 Diabetes Canada Guidelines http://guidelines.diabetes.ca/cpg + 2020 Diabetes Canada Updates: http://guidelines.diabetes.ca/2020-Update (Pharmacologic glycemic management of T2DM in adults) + 2021 Diabetes Canada Updates: http://guidelines.diabetes.ca/2021-Update (BG monitoring in adults & children with diabetes) + 2022 Diabetes Canada Updates: https://guidelines.diabetes.ca/2022-Update (T2DM Remission) + 2023 Diabetes Canada Updates: https://guidelines.diabetes.ca/2023-Update (Diabetes and mental health)

Note: The chapter summaries are concise. 72

MCQ 5 - 2024 A 46 year old female comes in with epigastric pain radiating to back. CT Abdo showing calcified pancreas and she admits to chronic drinking. She is discharged from the hospital, and gains weight on pancreatic enzyme supplements. She is referred to you for elevated blood glucose (fasting 13.4). You look back to her hospital records and find that her in-hospital morning blood glucose has always been elevated. Her A1C is 8.8%. What medications would you start? a. Insulin b. TZD c. Metformin d. Metformin + gliclazide

73

Diabetes - Diagnosis Diagnosis of Diabetes with any of : • Fasting glucose ≥ 7mmol/L • HbA1c ≥ 6.5% • 2h 75g OGTT ≥ 11.1 mmol/L • Random glucose ≥ 11.1 mmol/L

(Prediabetes: 6.1-6.9) OR (Prediabetes: 6.0-6.4%) OR (Impaired glucose tolerance: 7.8-11.0) OR

Type of Diabetes: • Type1: insulin deficiency (pancreatic β cell destruction), DKA prone, Usually Anti-GAD/Anti-Islet Cell + • Type 2: insulin resistance (tissue resistance, secretory defect), metabolic syndrome • Latent autoimmune diabetes in adults (LADA): type 2 diabetes who also have immune-mediated loss of pancreatic β cells • Monogenic: familial autosomal dominant mutation leading to beta cell defects, neonatal or 30 and diabetes duration > 15 years Ø Microvascular disease Ø Other CV risk factors Note: If LDL is not at target with statin therapy alone, a second line agent may be used. In patients with clinical CVD, ezetimibe or evolocumab may be added to reduce CV events (IMPROVE-IT and FOURIER trials). SEE CCS LIPID UPDATES

99

Drugs for Vascular Protection – Indications ACEi/ARB Ø Clinical CVD Ø Age ≥ 55 with an additional CV risk factor or end organ damage (albuminuria, retinopathy, LVH) Ø Microvascular disease Note: Should use doses shown to provide CV protection (perindopril 8 mg daily, ramipril 10 mg daily, telmisartan 80 mg daily) ASA Ø Established CV disease only Ø We no longer recommend ASA for primary prevention of CVD in people with diabetes (10). 100

Microvascular Complications Retinopathy

Neuropathy

Nephropathy

When to start?

How to screen?

Frequency?

Treatment?

T1DM

5y after diagnosis > age 15 At diagnosis

If retinopathy present – screen per Ophtho If no retinopathy: q1y (T1DM) q1-2y (T2DM)

Tight BG + BP control.

T2DM

Dilated fundoscopy, fundus photography by optometrist

T1DM

5y of post-pubertal T1DM

Annual

Tight BG cntrl

T2DM

At time of diagnosis

10g monofilament test OR 128 Hz Vibration

T1DM

5y after diagnosis of T1DM

Annual

T2DM

At time of diagnosis

Random Urine ACR >20, OR 2 of 3 rpt ACRs >2mg/mmol and/or eGFR Antidepressants > Opioid > topical

• • •

ACE inhibitor or ARB first line SGLT2i !Finerenone 101

Microvascular Complications - Retinopathy Screening: T1D: Start 5 years after diagnosis after age 15 T2D: Start at diagnosis for all patients Dilated fundoscopy, fundus photography 1. If present: Further monitoring and treatment as determined by ophthalmology.

2. If not present:

Rescreen q1yr (T1DM), q1-2yr (T2DM)

Microvascular Complications - Neuropathy Annual Screening: Start after 5 years’ duration of post-pubertal Type 1 diabetes All patients with Type 2 diabetes 10g monofilament test OR 128 Hz Vibration Treatment: 1. Intensify glycemic control 2. Anticonvulsants > Antidepressants > Opioid > topical

Microvascular Complications - Nephropathy Annual Screening: 5 years after diagnosis of Type 1 Diabetes At diagnosis of Type 2 Diabetes Dx: Random Urine ACr >20mg/mmol, OR eGFR 2mg/mmol Treatment: ACE inhibitor or ARB Refer if: chronic progressive loss of renal function, ACR persistently >60, eGFR 21 SU level ++

>=5

>=0.2

1.4

Negative

Insulin autoimmune Ab

>>21

>>5

>>0.2

1.4

Positive

IGF2

5

2000, treatment is case by case decision

– – – –

Extra-hepatic manifestations HBeAg positive, ↑ ALT, HBV DNA ≥ 2,000 IU/ml (CASL) HBeAg negative,↑ ALT, HBV DNA ≥ 2,000 IU/ml Pregnancy

• End 2nd/ Start of 3rd trimester + high DNA levels (HBV DNA >200,000 IU/ml i.e. 5 logs, 2x105) à treat to prevent fetal transmission [tenofovir] • Baby should also get HBIG + HBV vaccine after birth

• Do not treat

– Immune-tolerant phase or inactive CHB phase (normal ALT) – Acute infection is generally managed supportively

See excellent summary table on who treat in: 2018 CASL-AMMI HBV Guidelines: https://hepatology.ca/publications/guidelines/current-guidelines/

12

Chronic Hepatitis B (sAg + >6 mos) Hep B Status

sAg

sAb

eAg

HBV DNA ALT

Fibroscan

Treat?

HBeAg+ infection (immune tolerant)

✔

-

✔

Often >10 7

Normal

Normal

No

HBeAg + hepatitis (immune active)

✔

-

✔

104 - 107

⬆ or fluctuabng

Abnormal

Yes

HBeAg –ve chronic infection

✔

-

-

membranous glomerulopathy Derm: Porphyria cutanea tarda, leukocytoclastic vasculitis Heme: lymphoma (NHL), autoimmune hemolytic anemia, ITP, Cryoglobulinemia Other: Insulin resistance / Diabetes mellitus 16

Approach to HCV Treatment 1) Treat ALL patients with chronic hep C EXCEPT those with short life expectancy due to comorbidities – Sometimes if decompensated may treat after liver transplant (to avoid MELD purgatory) – Ongoing IV drug use is not a contraindication to treatment; need concurrent Addiction Medicine – Not enough evidence to recommend treatment during pregnancy or breastfeeding

2)

Check HCV RNA (and genotype, especially if cirrhosis), check for co-infections (Hep B, HIV)

3)

Fibrosis Assessment – – – –

4)

If simple HCV (no cirrhosis, co-infection), choose one of 2 pan-genotypic regimens: –

5)

Can use APRI score/ FIB-4 score to exclude clinically significant fibrosis. If > F2 fibrosis à proceed to fibroscan. Fibroscan > 12.5 kPa = cirrhosis. Ultrasound is insensitive for cirrhosis. Only needed IF cirrhotic, to exclude HCC. If cirrhosis, consider transplant assessment (MELD ≥ 15). Sofosbuvir/ Velpatasvir (Epclusa; 1 pill once daily x 12 wks) or Glecaprevir/ Pibrentasvir (Maviret; 3 pills once daily x 8 wks)

Check viral load 12-weeks post treatment completion. If negative, the patient is likely CURED (termed SVR12, sustained virological response) 17

Alcohol-associated Hepatitis • • • •

Acute onset hepa//s associated with ongoing alcohol intake (within 8 wks) AST > 50, AST/ALT > 1.5-2, and both values < 400, Tbili > 51 Clinical diagnosis; Biopsy rarely needed (consider if AST/ALT > 400, other Dx suspected) Treatment – Assess eligibility for steroids: Severe AH i.e. Maddrey Discriminant Funcaon≥ 32 (or MELD >20) or presence of encephalopathy à Prednisolone 40mg PO daily (⬆28d mortality; max benefit at MELD 25-39) • If Lille score at 4 or 7 days < 0.45 à condnue pred x 28d then taper; if ≥ 0.45 à stop; consider early liver transplantadon (no longer requirement for minimum period of absdnence; case-by-case)

– – – – –

Assess for contraindicaaons to steroids: Uncontrolled infecaon, uncontrolled GI bleed, AKI EtOH cessaaon and nutriaon (high calorie, high protein diet) are vital NAC can be considered in addiaon to steroids – “may improve 30 d survival in severe AH” NO role for pentoxifylline in addiaon to steroids per ACG/AASLD; trend toward benefit in HRS No mortality benefit for prophylacac anabioacs in Alc hep (Louvet et al. JAMA. 2023) 2019 AASLD Guidelines: https://www.aasld.org/practice-guidelines/alcohol-associated-liver-disease

18

Metabolic-Associated Fatty Liver Fast Facts – NEW terminology faiy liver disease: • MASLD (NAFLD): Faiy liver with no hepatocellular injury • MASH (NASH): + hepatocellular injury • Met-ALD: MASLD + increased EtOH intake – MASLD Diagnosis à 1) evidence of steatosis, 2) rule out 2° causes (i.e. EtOH) – MASH can only by diagnosed definiavely on Bx – Associated with T2DM (most imp RF), ↑lipids, HTN, obesity, metabolic syndrome, OSA – Most common cause of death in MASLD is ♥ – Many cases of cryptogenic cirrhosis are likely “burned out” MASLD

– Screen for clinically significant fibrosis: – T2DM, medically comorbid obesity, 1st degree relative with MASH cirrhosis, pts with alcohol use – FIB-4 score for everyone à if > 1.3 à fibroscan

– Treatment • Weight loss (diet + moderate intensity exercise) ≥ 3-5% ↓ to improve steatosis, 7-10% to improve fibrosis

• Identify + manage CV risk factors – Statins are safe in MASLD/MASH, including compensated cirrhosis

• Pharmacotherapy – Semaglutide for MASH + T2DM/ obesity » Also studied: (1) pioglitazone for Bx-proven MASH + T2DM, but risk of edema, CHF, (2) vitamin E 800 IU OD for Bx-proven MASH w/o T2DM, but may increase risk of adverse CV outcomes

• Bariatric surgery if obese

2023 AASLD Guidelines: https://www.aasld.org/practice-guidelines/clinical-assessment-and-management-nonalcoholic-fatty-liver-disease New terminology 2023: https://journals.lww.com/hep/fulltext/9900/a_multi_society_delphi_consensus_statement_on_new.488.aspx 19

Approach to Cirrhosis: Causes •

Determine etiology – (1) Viral (2) Fatty liver [EtOH, NASH], (3) Autoimmune/ cholestatic [AIH, PBC, PSC], (4) Genetic [Wilson, HH, A1AT], (5) Chronic biliary disease, (6) Vascular [R CHF, Budd Chiari] – Labs, abdominal imaging (+ doppler), and consider biopsy if indeterminate cause

•

Assess severity – Child-Pugh score – predicts perioperative mortality for open abdominal surgery (based on old data, likely overestimates risk): – CP A (score 5-6) – 10% – CP B (score 7-9) – 30% – CP C (score 10-15) – 80% – MELD ≥ 15 – refer for liver transplant assessment • 6 mo of EtOH abstinence no longer a rule in Ontario (case by case)

– For perioperative liver-related mortality, can use the Mayo clinic surgical risk score or the VOCAL-Penn score (both online, more refined + current than the childs-pugh score; but know CP for exam)

Child Pugh Score

*Don’t memorize, but helpful to have a sense of ‘A’ vs ‘C’! Ascites • Absent (1), slight (2), moderate (3) Bilirubin • 51.3 (3) Coagulopathy (INR) • < 1.7 (1), 1.7 – 2.2 (2), > 2.2 (3) Albumin • >35 (1), 28 – 35(2), < 28 (3) Encephalopathy • None (1), grade 1-2 (2), grade 3-4 (3) 20

Approach to Cirrhosis: Complications + Counseling •

Assess for complications: – – – – – –

•

Varices à EGD at diagnosis, then interval based on findings Ascites/SBP à Paracentesis at diagnosis, any inpatient presentation, and if concern for SBP Hepatic encephalopathy à History/ exam Hepato-renal syndrome, Hep-pulmonary Syndrome/porto-pulmonary hypertension à History/exam/labs HCC à Abdominal U/S at diagnosis and q6mo Screen for FRAILTY, MALNUTRITION in clinic (new – ACG 2021 Guideline on Frailty, Sarcopenia and Malnutrition in Cirrhosis)

Counseling:

Abstinence from alcohol, adequate nutrition, weight loss for NAFLD Limit acetaminophen to ≤ 2g/day Avoid sedatives, NSAIDs, ACEI/ARBs HAV, HBV, COVID 19, TdAP, Pneumococcal, flu vaccinations (+zoster if age >50, MMR and Varicella where applicable) – Refer to multidisciplinary team if frailty, sarcopenia or malnutrition (ACG 2021 Guidelines) – Refer to palliative care team if decompensated cirrhosis at any point in journey (AASLD 2022 Guidance statement àimproves symptoms, quality of life, caregiver stress) – – – –

21

Approach to Varices • Primary prophylaxis (never bled) – Screen every patient at diagnosis of cirrhosis or at time of decompensation – Patients receive: NSBB OR EVL – Detailed algorithm on next slide

• Secondary prophylaxis (after bleed) – Patients receive: NSBB AND EVL NSBB: non selective beta blocker ex. nadolol, propranolol; OR carvedilol | titrate to HR 55-60 and maintain SBP>90 EVL: endoscopic variceal ligation AASLD guideline: Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management (Hepatology. 2017 Jan;65(1):310-335)

22

Screening and Management of Varices (Primary Prophylaxis = has never bled) Initial gastroscopy No varices

Small varices

Med/Large varices

compensated

decompensated

Low risk

EGD q2-3y

EGD at time of decomp. and then q1y

High risk (CP-C, stigmata)

EGD q1-2y

NSBB

Stigmata: Red wale sign, red spot IF you do EVL, need to repeat q2-8 weeks until obliteration of varices. Then, repeat EGD 3-6 months after eradication and every 6-12 months thereafter.

No need to repeat EGD if on NSBB

NSBB OR EVL No need to repeat EGD if on NSBB

AASLD guideline: Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management (Hepatology. 2017 Jan;65(1):310-335)

23

Ascites • Etiology – SAAG >11 = ‘transudative’ (e.g., portal HTN) – SAAG < 11 = ‘exudative’ (e.g., malignancy, pancreatitis, infection (TB), nephrotic syndrome)

• For ascites related to portal HTN – Initial management

• Treat underlying liver disease (stop alcohol, treat HCV, etc.) • Salt restriction (< 2 g or 88 mmol/day) – Water restriction not necessary unless [Na] < 125 • Diuretics (start with Spironolactone 100mg and Lasix 40mg daily, titrate as needed – monitor for : hypotension, AKI, electrolyte imbalance)

– Failing medical therapy

• Serial therapeutic paracentesis; give albumin 6-8 g/L of fluid removed for taps > 4L • TIPS if no contraindications (encephalopathy, HCC)

– Liver transplant

AASLD guideline: Management of Adult Patients with Ascites Due to Cirrhosis (Hepatology. 2013 Apr;57(4):1651-3.)

24

Ascites • Patients with ascites should be Na restricted (78 mmol à NON-COMPLIANT > 78 mmol, but gold standard(eg 2) Start diuretics if ongoing ascites or unable to comply on exam) remains 24h urine Na 3) For patients on diuretics, do 24-hour urine Na collection • 24-hr uNa 78 mmol AND patient not losing weight à NON-COMPLIANT with Na restriction à reinforce Na restriction • 24-hr uNa >78 mmol AND weight loss à patient is adherent to sodium restriction and diuretic sensitive à stay the course 25

Spontaneous Bacterial Peritoni8s • Perform diagnostic paracentesis in every patient with new ascites AND in every cirrhotic with ascites who presents to hospital • SBP classically presents with abdominal pain and fever (can also present with encephalopathy, hypotension, AKI, or worsening liver function) • Diagnosis of SBP – Neutrophils in ascitic fluid > 250 cells/mm3 OR culture-positive ascitic fluid • culture-negative ascites still requires complete course of treatment – Rule out secondary cause of peritonitis (e.g., bowel perforation or recent surgery)

AASLD guideline: Management of Adult Patients with Ascites Due to Cirrhosis (Hepatology. 2013 Apr;57(4):1651-3.)

26

Spontaneous Bacterial Peritonitis • Treatment of confirmed SBP – Ceftriaxone (or Fluoroquinolone if Pen allergic) x 5 days – HRS prophylaxis à Day 1: Albumin 1.5g/kg; Day 3: Albumin 1 g/kg • In practice almost everyone gets albumin, but guidelines suggest only if Cr > 88, BUN > 10.7, or bili > 68 • Post SBP: lifelong prophylaxis with Norfloxacin, Septra DS, or Cipro. • Indications for SBP prophylaxis 1) Patients who have previously had SBP à Indefinite SBP prophylaxis 2) Patients with cirrhosis who present with upper or lower GI bleeding (don’t need to have ascites) à SBP prophylaxis x 7 days 3) Cirrhotic with ascitic fluid protein is 18 years old (Guideline suggests for offspring of affected individual to screen their other parent w HFE testing; avoids testing all offspring if other parent negative.) As per Choosing Wisely Canada: TS ≥ 45% AND elevated SF. USE THIS Tsat < 45% AND ferriDn < 300 (M)/ 200 (F) rules out HH with good NPV 97%!

ACG 2019 HH Algorithm

Ferritin >1000 should suspect end-organ damage Ferritin > 300 (M), >200 (F)

30

HH Treatment • Who + when to treat: – C282Y homozygotes if ferritin > 300 (men) or > 200 (women) AND Tsat > 45% – C282Y/H63D heterozygotes/ other à Evaluate for other causes of iron overload/ liver dz + consider MRI/ Bx to estimate hepatic iron concentration (HIC) à Treat other causes 1st, then, if high HIC à treat

• Treatment: – 1st-line = phlebotomy targeting ferritin 50 – 100 – 2nd- line (when patient refractory to phlebotomy e.g. anemia, high output CHF) = chelation (i.e. desferoxamine, deferiprone, deferasirox) •

• •

Risks of retinal/auditory toxicity (desferoxamine), agranulocytosis (deferiprone), liver/renal toxicity (deferasirox).

– No need to limit red meat/dietary iron if undergoing phlebotomy – Avoid consuming vitamin C supplements (↑iron absorption) – Avoid uncooked seafood (Listeria, Yersinia, and Vibrio ♥ Fe) – Liver transplantation for decompensated cirrhosis/focal HCC HCC screening: Only if cirrhosis. ACG recommends against screening if fibrosis ≤ stage 3. Other Heterozygotes: Monitor iron indices annually + assess for organ damage, no treatment needed 31

QuesQon 1: Liver A 54 year-old female patient born in Vietnam with a history of lung cancer currently on her third cycle of chemotherapy presents with new onset ascites in the emergency room. Previous Mantoux testing was positive. A paracentesis was done showing ascitic albumin of 12. Her serum albumin is 28. What is the likely etiology of her ascites? A. Portal vein thrombosis B. Nephrotic syndrome C. Peritoneal TB D. Omental carcinomatosis

SAAG > 11 --> 'Transudative' i.e. Portal HTN o Total protein < 2.5 g/dL --> cirrhotic ascites o Total protein ≥ 2.5 g/dL --> post-sinusoidal ascites e.g. cardiac ascites (CHF, constrictive pericarditis)

SAAG < 11 --> ‘Exudative’ (e.g., malignancy, malnutrition, infection (TB), inflammation (pancreatitis, SLE, eosinophilic GE), nephrotic syndrome) o Total protein < 2.5 g/dL --> nephrotic ascites o Total protein ≥ 2.5 g/dL --> peritoneal carcinomatosis, TB 32

Question 2: Celiac A 43yM with Down’s Syndrome lives in a group home setting. He has hyperphagia and is known to eat large quantities of food from kitchen particularly when stressed; this has worsened with pandemic related restrictions on activities and visitors. Group home staff say it is difficult to police his foods. He presents with a 2 month history of progressive severe pruritic blistering rash on his knees, hands, buttocks, elbows (inset). Which of the following tests would you not initiate? a) TTG-IgA b) HLADQ2, -DQ8 testing c) G6PD Assay d) Skin biopsy e) Skin scraping for microscopy 33

Celiac Disease Celiac disease is an immune-mediated enteropathy due to gluten hypersensidvity • Risk Factors: – Northern European descent, + family history (1st degree reladve), T1DM, autoimmune disease, Down(6x risk) + Turner’s syndrome, IgA deficiency •

•

Symptoms & Signs: – Diarrhea/ steatorrhea, abdo pain, bloadng, weight loss, anemia, osteoporosis, enamel defects, elevated transaminases (mild), inferdlity – Vitamin + mineral deficiencies – A, D, E, B12, Fe, Ca – Dermadds herpedformis Diagnosis: – And-TTG IgA & quandtadve immunoglobulins (r/o ↓ IgA) +/- and-deamidated gliadin pepdde [DGP] IgG (if ↓ IgA) +/- and-endomysial andbody [EMA] – Upper endoscopy with small-bowel biopsy – Marsh Classificadon [High risk, posidve serology] ACG 2023 Celiac Dx and Mgmt guidelines: https://journals.lww.com/ajg/Fulltext/2023/01000/American_College_of_Gastroenterology_Guidelines.17.aspx?context=FeaturedArticles&collectionId=2 AGA 2019 guidelines: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.gastrojournal.org/article/S0016-5085(18)35408-8/pdf 34

Celiac Disease •

HLA DQ2/DQ8 Testing

– POSITIVE in almost all patients with Celiac disease – NEGATIVE test rules out Celiac disease • Sensitivity - 100% • Specificity – 57% • Negative predictive value – 100%

– Should NOT be routinely ordered (poor PPV) – Consider if… • Equivocal histology in seronegative patients • Evaluation in patients on a gluten-free diet where testing can be falsely negative • Discordant serology and histology • Suspicion of refractory Celiac or when Diagnosis in question • Patients with Down’s syndrome • Patients with a history diagnosis of Celiac (especially as very young children before introduction of TTG-IgA testing) ACG 2023 Celiac Dx and Mgmt guidelines: https://journals.lww.com/ajg/Fulltext/2023/01000/American_College_of_Gastroenterology_Guidelines.17.aspx?context=FeaturedArticles&collectionId=2 AGA 2019 guidelines: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.gastrojournal.org/article/S0016-5085(18)35408-8/pdf 35

ACG 2023 Diagnos9c Algorithm

36

Celiac Disease • Treatment: Lifelong gluten-free diet • Follow-up – Ensure adherence – Diet history – ↓ antibody titres +/- improvement of histology – Follow-up serology 6 and 12 months post diagnosis, then annually* • Patients with persistent symptoms despite negative serology should undergo repeat biopsy to determine healing*

Gluten Containing Foods – ‘BROW’ • • • •

Barley Rye Oats *often contaminated Wheat

ACG 2023 Celiac Dx and Mgmt guidelines: https://journals.lww.com/ajg/Fulltext/2023/01000/American_College_of_Gastroenterology_Guidelines.17.aspx?context=FeaturedArticles&collectionId=2 AGA 2019 guidelines: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.gastrojournal.org/article/S0016-5085(18)35408-8/pdf 37

Celiac Disease • Further workup: – Micronutrient measurements (Fe, folate, Vit D, B12) – BMD per guidelines

• Complications of celiac disease: – – – – –

Nutritional deficiencies and anemia TIP: Consider refractory celiac disease and Osteopenia/osteoporosis progression to EATL if a celiac patient stops responding to a gluten-free diet Elevated liver enzymes Dermatitis herpetiformis Enteropathy-associated T cell lymphoma (EATL) 38

Celiac Disease Dermatitis Herpetiformis (DH) • > 90% DH patients have CD • Up to 25% of patients with CD have DH • Responds to: – Gluten-free diet (Takes months to work) – Dapsone (must R/O G6PD deficiency) Who to screen for Celiac Disease? 1) Insufficient evidence to recommend screening in asymptomatic

Grouped, pruritic papules and vesicles on extensor surfaces

2) Lower threshold for screening in those predisposed: +FHx in first degree relative, DM-I, autoimmune thyroid disease, Down’s syndrome, Turner’s syndrome USPSTF Statement: Screening for Celiac Disease (JAMA. 2017 Mar 28;317(12):1252-1257.)

39

QuesQon 2 A 43yM with Down’s Syndrome lives in a group home setting. He is known to eat large quantities of food from kitchen particularly when stressed; this has worsened with pandemic related restrictions on activities and visitors. Group home staff say it is difficult to police his foods. He presents with a 2 month history of progressive severe pruritic blistering rash on his knees, hands, buttocks, elbows (inset). Which of the following tests would you not initiate? This is a high probability scenario for Celiac disease (DH!). a) TTG-IgA b) HLADQ2, -DQ8 testing Living in a group home with itchy rash, also need to think about scabies which can clinically appear as pruritic papular c) G6PD Assay rash in same distribution so scraping for microscopy not a bad d) Skin biopsy idea (absence of burrows on exam also helpful). Skin biopsy e) Skin scraping for microscopy will be diagnostic of DH. G6PD assay needed as this pt will need dapsone – adherence to strict gluten free diet will be a challenge. 40

Question 3: IBD A 29F @ 6 weeks pregnant with a new diagnosis of ulcerative pancolitis is admitted to hospital with a flare. She was admitted with worsening bloody diarrhea up to 7 BMs/ day, and was found to a Hgb 101, WBC 13, and Plt 489. Stool studies were negative and she was started on IV methylprednisone on day 2 of admission. On Day 4 of admission, her nurse calls you for fever with a Tmax 38.1C, HR 120, and BP 100/62. Bedside Ultrasound: No free air. Dilated loops of bowel with maximal diameter of 7cm at the transverse colon. What is the best next step? a) Give her an induction dose of infliximab b) Consult General Surgery c) Schedule sigmoidoscopy with biopsies to rule out CMV colitis d) Start IV ciprofloxacin and flagyl e) Start Lovenox 40mg daily thromboprophylaxis 41

Crohn’s Disease • Inflammatory bowel disease characterised by transmural inflamma/on, strictures and fistulas, that can affect anywhere in the GI tract from ‘gum to bum’. • Common disease loca0ons: – – – –

Small bowel - terminal ileal involvement is most common Ileocolids Colonic Mouth + upper GI tract

• Clinical Manifesta0ons: – Abdominal pain, diarrhea, weight loss, fever, peri-anal symptoms – ↑ CRP, anemia, ↓ Albumin, ↓ Fe, ↓ B12, ↑ fecal calprotecdn

• Diagnosis: – Ileocolonoscopy & biopsy • Patchy inflammadon, skip lesions, aphthous ulcers, cobble-stone mucosa • Rectal involvement + circumferendal condnuous inflammadon less common in CD vs UC – Small bowel imaging (CT/MR-enterography, capsule endoscopy) +/- EGD – No role for serology in diagnosis of IBD (e.g. ANCA/ ASCA) Roda et al. Crohn’s Disease. Nature Reviews. April 2020. 42

Crohn’s Treatment Options • Induction

• Maintenance

– Mild • 5-ASA (Guidelines recommend AGAINST this, but still used for mild colonic Crohn’s) • Budesonide (Entocort, Cortimet)

– Moderate to Severe Budesonide Prednisone/methylpred MTX Anti-TNF – Infliximab (Remicade), Adalimumab (Humira) • Anti-Integrin – Vedolizumab (Entyvio) • Anti-IL12/23 – Ustekinumab (Stelara) • • • •

– Mild • Thiopurine (AZP, 6-MP)

Thiopurines take ~8-12 weeks to have effect

– Moderate to Severe • • • • • •

MTX Thiopurine (AZP, 6-MP) Anti-TNF – Infliximab, Adalimumab Anti-integrin – Vedolizumab Anti-IL-12/23 – Ustekinumab Anti-IL 23 – Risankizumab (FDA approved Jun 2022; not yet in Canada)

• More severe Crohn’s = Affecting lifestyle, high CRP, low alb, complications, deep ulceration on endoscopy • When starting anti-TNF, combine with a thiopurine (AZP/ 6-MP) – SONIC trial

43

General Patterns in CD Treatment – Sulfasalazine can be considered only for mild colonic Crohn’s disease. 5-ASAs are NOT effective for Crohn’s ileitis, fistulizing or moderate-severe disease. – Fistulas (any kind) à Biologic (anti-TNF e.g. infliximab have the most evidence, then vedolizumab) – Perianal disease (abscesses or fistulae) à Anti-TNF (+/- antibiotics if concern for infection) – Do not use antibiotics alone to induce or maintain remission – Tofacitinib not approved for CD (only UC) – Once remission achieved, generally continue the agent that induced remission (except steroids) – Indications for surgery in Crohn’s disease: Intestinal obstruction, refractory/ fulminant disease, highgrade dysplasia/ cancer, severe perianal disease/ fistulas/ abscess, perforation.

Alternative therapies CAG Recommends against: Probiotics, Marijuana, Dietary modification, Omega fatty acids. 44

Crohn’s Disease Complications If a Crohn’s pafent has pain + fever à look for a collecfon/ abscess!

– Abscess: • Drain (IR or I+D or surgery) and antibiotics (Cipro/Flagyl or CTX/ flagyl), prior to immunosuppression

– Fistula: • Characterize perianal fistulae w/ EUS (endoscopic ultrasound) or MRI pelvis +/- EUA (exam under anesthesia) • Anti-TNF preferred to induce a symptomatic response and maintain remission • Other options: Vedolizumab/ ustekinumab or surgery

– Stricture: • ‘Cold’ stricture: – Fibrostenotic disease, no active inflammation on imaging or endoscopy – Conservative mgmt. (i.e. bowel rest, NG tube), endoscopic dilation or surgery • ’Hot’ stricture – Active inflammation (may be overlying area of fibrosis/ cold stricture) – Steroid bridge to maintenance therapy (usually biologics)

AGA 2021: https://gastro.org/clinicalguidance/medicalmanagement-of-moderateto-severe-luminal-andperianal-fistulizing-crohnsdisease/ 45

Ulcerative Colitis • Immune-mediated condition of the colon often associated with rectal inflammation, extending proximally to involve the adjacent colon in a continuous manner. • Disease Location: – Proctitis – w/in 18 cm from the anal verge – Left-sided colitis – sigmoid to splenic flexure – Extensive/ ‘pan’ colitis – beyond the splenic flexure

• Clinical Manifestations:

– ‘Proctitis’ – small volume + frequent BMs w/ blood, tenesmus, urgency, crampy abdominal pain – Fever, fatigue, weight loss – Inflammatory markers: Anemia, ↓ Albumin, ↑ ESR/CRP, ↑ fecal calprotectin

• Diagnosis:

– Ileocolonoscopy + biopsies • Continuous inflammation from rectum proximally • Granular, friable mucosa • Bx – i.e. crypt abscesses, lamina propria cellularity

1. 2. 3. 4. 5. 6.

Truelove & Witts Criteria for Severe UC: Bowel movements ≥ 6 Visible blood in stool Pyrexia T ≥ 37.8C* Pulse > 90bpm* Anemia Hgb ≤ 105* ESR>30*

Severe UC when criteria for frequency of bowel movement and ≥1 features of systemic upset (*) are satisfied. 46

Ulcerative Colitis Treatment Options • Induction – Mild

• 5ASA PO (extensive), PR (proctitis) (suppository < 18cm, enema – to splenic flexure) • Budesonide

– Moderate to Severe

“small molecules”, oral agents

• Budesonide • Prednisone/methylpred • Anti-TNF – Infliximab, Adalimumab, Golimumab • Anti-Integrin – Vedolizumab • Anti-IL-12/23 – Ustekinumab • JAK-inhibitor – Tofacitinib, upadacitinib (Approved 2023) • Sphingosine 1-phosphate receptor modulator – Ozanimod (Approved 2022)

• Maintenance – Mild

• 5ASA PO, PR

– Moderate to Severe • Thiopurine (AZP, 6-MP) • Anl-TNF – Infliximab, Adalimumab, Golimumab • Anl-Integrin – Vedolizumab • Anl-IL-12/23 – Ustekinumab • JAK-inhibitor – Tofacilnib, upadacilnib • Sphingosine 1-phosphate receptor modulator – Ozanimod • When starting anti-TNF, combine with a thiopurine -UC SUCCESS Trial • Thiopurine/MTX monotherapy is not recommended 47

IBD – General Principles • No role for serology (ASCA/ANCA/anti-OmpC etc.) in diagnosis • Pre-Biologic Work-up: – – – –

HBV, HCV TB skin test; If BCG vaccinated à CXR and/ or IGRA VZV titres; certain biologics require this Strongyloides serology if high pretest probability*

IBD is associated with ↑ risk of colorectal cancer *See Med Onc lecture for more details

• Before starting AZA/6MP – check TMPT • Fecal calprotectin used as a marker of disease activity • Treatment target – Clinical (symptoms, steroid free), biochemical (inflammatory markers), and endoscopic (mucosal healing) remission *Briosh Society of Gastroenterology Consensus guidelines on management of IBD in adults, BMJ GUT, 2019 and ECCO 2013 consensus guidelines on prevenoon, diagnosis, and management of opportunisoc infecoons in IBD discuss screening of strongyloides in paoents returning from endemic areas or who have travelled for “long” periods of ome. NOT clearly menooned in Canadian or American guidelines. 48

Inpatient IBD • IBD flares commonly overlap with infection 1.

Rule out C. diff/ other infection if worsening diarrhea (even if no recent antibiotics)

2.

Rule out abscess in a Crohn’s patient with fever and abdominal/perianal pain • Use appropriate imaging (CT abdo, MR pelvis, EUS, etc.)

3.

Withhold immunosuppression until (1+2) are addressed. • If the patient looks septic, cover with antibiotics

4.

CMV colitis can co-exist with IBD and requires colonic biopsies to diagnose (CMV blood PCR is not enough; look for “owl-eye inclusion bodies” on pathology and CMV+ immunohistochem off biopsy)

• Don’t stop DVT prophylaxis even if patient having bloody diarrhea

– Risk of thrombosis > risk of life-threatening hemorrhage in hospitalized IBD patients with acute flare

• Bile-salt diarrhea

– Occurs with ileitis or after ileal resection – ALWAYS assess for (CT or C Scope) and treat active IBD before treating for bile salt diarrhea • cholestyramine (bile acid sequestrant)

49

Inpatient IBD • Work-up: – – – –

Labs – CBC, lytes, extended lytes, Cr, AST/ALT/ALP, bilirubin, INR, albumin, ESR/CRP Stool tests – Stool C&S, Stool O&P, C. diff toxin, +/- fecal calprotectin Imaging – AXR, +/- CT abdomen, +/- CT/MR enterography (i.e. small bowel imaging) Endoscopy – for diagnosis, to assess disease severity, rule out mimics (ischemia, CMV), can send aspirates for micro

• Management: – – – – –

IV fluids, bowel rest, VTE prophylaxis Minimize narcotics, NSAIDS Start IV steroids once infection is ruled out If minimal response after ~ 72h IV steroids à Infliximab Consider general surgical consultation for treatment refractory colitis, toxic megacolon, perianal/intra-abdominal abscess, complex fistulizing Crohn’s 50

Acute Severe UC Management

•

IndicaUons for colectomy: Toxic megacolon, colonic perforaaon, severe refractory hemorrhage, refractoriness to medical therapy

•

Muladisciplinary care with early surgical involvement is important 51

Question 3: IBD A 29F 6 weeks pregnant with a new diagnosis of ulcerative pancolitis is admitted to hospital with a flare. She was admitted with worsening bloody diarrhea up to 7 BMs/ day, and was found to a Hgb 101, WBC 13, and Plt 489. Stool studies were negative and she was started on IV methylprednisone on day 2 of admission. On Day 4 of admission, her nurse calls you for fever with a Tmax 38.1C, HR 120, and BP 100/62. Bedside Ultrasound: No free air. Dilated loops of bowel with maximal diameter of 7cm at the transverse colon. What is the best next step? a) b) c) d)

Give her an induction dose of infliximab Consult General Surgery Schedule sigmoidoscopy with biopsies to rule out CMV colitis Start IV ciprofloxacin and flagyl

e)

Start Lovenox 40mg daily thromboprophylaxis

Toxic Megacolon

• Radiographic megacolon (>6cm) • PLUS at least 3 of: • Fever (>38C) • HR >120 • Neutrophils >10.5 • Anemia • PLUS at least 1 of: • Dehydration • Altered sensorium • Electrolyte disturbances • Hypotension

Tricky Question! - Don’t give a blood thinner until you know she’s not going for surgery (reasonable to start once Gen Surg has seen if not for OR tonight!) - Don’t give fluoroquinolones in pregnancy when other reasonable alternatives available (eg could give her Pip/Tazo, Ceft/Flagyl…) In versions of this question where you have to choose between antibiotics and surgery as next step, we feel the point of question is know when to call surgeon, you would also give antibiotics in real life!) 52

Upper GI Bleeding UGIB

Variceal

Non-Variceal IV PPI * IV octreotide

IV PPI

IV antibiotics (if cirrhosis) Use *IV PPI even if you suspect variceal etiology – you don’t know until you scope and PUD is always possible!

Endoscopy within 12-24 hours Endoscopy within 12 hours

Ongoing PPI depending on lesion

Assess medications, H. pylori status 53

UGIB • Pre-endoscopy (**POSSIBLE ORAL SCENARIO**) – ABC’s, monitoring, O2, 2-large bore IV’s, fluids (ABC-MOIF) – [Apply Glasgow-Blatchford score to identify low-risk patients that can be discharged with outpatient follow up] – CBC, urea, Cr, cross and type, INR/PTT, Liver enzyme and function tests – Transfuse • Hb > 70; consider higher target (>80) if symptomatic/ active cardiac ischemia, or unstable Tranexamic Acid does not reduce • Plts > 50 if actively bleeding/unstable mortality in UGI Bleed – do not use

– Reverse anticoagulation

• See slide on antithrombotic mgmt. in GI bleed

– PPI therapy (IV bolus + infusion or BID dosing)

routinely!

(HALT-IT Trial - Effects of a high-dose 24-h infusion of TXA on death and thromboembolic events in patients with acute gastrointestinal bleeding The Lancet. 2020.) 54

UGIB in patient with Cirrhosis • UGIB (variceal or not) + Cirrhosis (or suspected non-cirrhoGc portal HTN) 1. 2. 3. 4. 5.

Restric]ve transfusion strategy (target 70-90 g/dL)

• No FFP

IV vasoac]ve drug (octreobde, somatostabn, terlipressin [not yet in Canada] or vasopressin) as soon as variceal bleed is suspected; conbnue x 5 days postendoscopy if variceal bleed IV PPI unbl varices ruled out Endoscopy within 12h of presentabon An]bio]c prophylaxis is indicated for any GI bleed in a pabent with cirrhosis

• Cetriaxone 1g/24h x 5-7 days

• Following variceal bleed + EVL:

– Inibate NSBB when vasoacbve drugs stopped • NSBB not required if pt had a TIPS placed; TIPS is rescue if bleed despite NSBB+EVL Diaz-Soto MP, Garcia-Tsao G. Therap Adv Gastroenterol. 2022;15:17562848221101712. AASLD guideline: Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management (Hepatology. 2017 Jan;65(1):310-335)

55

Variceal Bleeding

for 3-5 days

(NSBB not required if pt had a TIPS placed) Modified slightly from Diaz-Soto MP, Garcia-Tsao G. Therap Adv Gastroenterol. 2022;15:17562848221101712.

56

Non-variceal UGIB • Endoscopic management – Erythromycin 250 mg IV suggested 30 min before endoscopy – Endoscopy should be performed within 24 hours (or within 12 hours in high-risk patients, including suspected variceal bleeds) – Endoscopic therapy only for high-risk ulcers (Forest IA, IB, IIA ulcers)

• If ongoing/ re-bleeding: repeat EGD, consider IR embolization or surgical management • Consider radiation for tumor bleeds Barkun et al. Management of Nonvariceal Upper Gastrointestinal Bleeding: Guidelines Recommendations from the International Consensus Group. Annals of Internal Medicine. Dec. 2019.

ACG Guideline: Upper Gastrointes`nal and Ulcer Bleeding. Am J Gastroenterol. 2021 May 1;116(5):899-917. doi: 10.14309/ajg.0000000000001245. 57

Non-variceal UGIB •

Post-endoscopy – High-risk ulcers à IV PPI BID or PPI infusion x 72 hours, then oral PPI BID for at least the first 2 weeks after endoscopy – Low-risk ulcers à Oral PPI (no guidelines; typically BID x 2-4 weeks then stop) – Restart anti-platelets and anticoagulation as soon as possible (see ACG-CAG guidelines next slide) • Restarting OAC or antiplatelets (or both) not associated with increased GI bleed risk compared to not restarting but IS associated with a reduction in all cause mortality (Witt DM Hematology ASH education Program 2016:620).

• Timing – variable decision incorporating patient factors and endoscopic findings (Forrest class)

•

Consider risk factors – Test all patients with PUD or gastritis for H. pylori – can biopsy at time of EGD or check serology • Treat with quadruple therapy if positive • After treatment and confirmation of eradication, PPI therapy can be stopped – Stop all unnecessary NSAIDs, stop ASA for primary prophylaxis – For CV patients requiring ongoing ASA and/or Plavix, consider indefinite PPI prophylaxis – Indefinite PPI if unclear cause of PUD (conditional recommendation) ACG Guideline: Upper Gastrointestinal and Ulcer Bleeding. Am J Gastroenterol. 2021 May 1;116(5):899-917. doi: 10.14309/ajg.0000000000001245. CAG Guideline: Intl. Consensus on Mgt of Patients with NVUGIB (Ann Intern Med. 2010 Jan 19;152(2):101-13) 58

Anti-thrombotic management (Joint ACG-CAG Guideline April 2022)

Acute GI Bleeding – All guidance “suggest” due to low level of evidence à use your clinical judgement! i) Patient stable, “hospitalized or under observation for GI Bleed [upper or lower]” ASA 81-325 mg for 2o cardiovascular prevention à Suggest no interruption; if interrupted à re-start on the day that hemostasis is endoscopically confirmed. Anticoagulation reversal? – Warfarin à Suggest AGAINST vitamin K and FFP use. No recommendation for/ against PCC.

• •

• Do not routinely give Vitamin K unless low dose to correct supratherapeutic INR

– DOAC à Suggest AGAINST reversal with PCC/ idarucizumab/ andaxnet alpha

ii) Life threatening hemorrhage, “major clinically overt or apparent bleeding, resulting in hypovolemic shock, or severe hypotension requiring pressors or surgery”, ↓Hgb >50, transfusion ≥5u PRBC, or causing death” –

Warfarin à PCC “could be considered” (or in patients in whom massive transfusion is undesirable) •

– –

Uncertain re use of vitamin K – see above, conditional recommendation to not use if INR in target range and intervention planned

DOAC à selective use of PCC (for anti-Xa DOAC) or idarucizumab (for Dabigatran) for those who took DOAC within 24h who have life threatening bleed “may be appropriate” No Platelet transfusions to reverse effect of antiplatelet! ACG-CAG Guideline April 2022: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period https://journals.lww.com/ajg/Fulltext/2022/04000/American_College_of_Gastroenterology_Canadian.16.aspx

An0-thrombo0c management (Joint ACG-CAG Guideline April 2022)

Anti-thrombotic management in the elective endoscopy setting*: • • • • •

ASA 81-325 mg for 2o preventionà Suggest no interruption DAPT à Suggest interrupting only the P2Y12 inhibitor; Re-start 0-7d post-endoscopy (no consensus) P2Y12 monotherapy à No consensus for or against interruption*, or when to restart DOACs à Suggest interruption⌃; Re-start 0-7d post-endoscopy (no consensus) Warfarin à Suggest no interruption#, and if interrupted à Suggest no need to bridge

*Individualize risk of thrombosis versus bleeding in setting of high risk endoscopic procedures: (eg) high risk examples: >1cm polypectomy, ERCP w sphincterotomy, PEG/PEJ tube, ampullary resection, treatment of varices incl band ligation … ⌃ In line w thrombosis Canada – see Periop Medicine Lecture In an Oral scenario “I will liaise with my GI/Gen Surg colleague and their heme/cardio”… # Based

on a single observational study, depends on what you’re expecting to find on endoscopy

ACG-CAG Guideline April 2022: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period https://journals.lww.com/ajg/Fulltext/2022/04000/American_College_of_Gastroenterology_Canadian.16.aspx

H. pylori Fast Facts – H. Pylori ↑ risk of gastric cancer • Controversial whether to treat patients solely to prevent cancer, but most recent ACG guidelines (2017) seem to err on the side of offering treatment to everyone testing positive

– Who to test? • PUD, MALT lymphoma, resected early gastric cancer, uninvestigated dyspepsia*, long-term NSAIDs/ASA, otherwise unexplained iron deficiency, ITP • Do not test those with GERD without dyspepsia or PUD Treatment of H. Pylori will generally not improve (and can worsen) symptoms of GERD

– MALT lymphoma – treatment of HP alone will cure most cases! – *Only a minority of patients with dyspepsia and H. Pylori will have symptomatic improvement with eradication

ACG Guideline: Treatment of H. pylori Infec`on (Am J Gastroenterol 2017; 112: 212–238) CAG Guideline: The Toronto Consensus for the Treatment of Helicobacter pylori in adults (Gastroenterology. 2016 Jul;151(1):51-69.e14.)

61

H. pylori Diagnosis – Testing to detect current infection • Stool Antigen (SN 94% / SP 92%) • Histology (SN 96% / SP 99%) • Biopsy Culture (SN 88-95% / SP 95-100%) • Urea Breath Test (SN 90-95% / SP 95-100%) – Testing to detect current or prior infection • Serology i.e. serum IgG (SN 85% / SP 80%) –

If negative in a patient with bleeding ulcer, repeat testing is recommended when acute bleeding episode resolves

62

H. pylori Treatment 2016 Canadian Guidelines (Toronto Consensus): • Triple therapy no longer recommended unless local resistance to clarithromycin is < 15% • Suggested treatment: – First line: PBMT or PAMC x 14 days • •

PPI/Bismuth/Metronidazole/Tetracycline (PBMT) PPI/Amoxicillin/Metronidazole/Clarithromycin (PAMC)

– Treatment failure: • •

PBMT (if prior triple-therapy) x 14 days OR PPI/Amoxicillin/Levofloxacin (PAL) x 14 days

• Confirm eradication in all treated patients

– Urea breath test, stool antigen test, or repeat gastric biopsy

Wait ≥ 4 weeks a{er compledng andbiodc therapy and ≥ 1-2 weeks a{er PPI therapy before tesdng for H. pylori to improve test accuracy!

ACG Guideline: Treatment of H. pylori Infection (Am J Gastroenterol 2017; 112: 212–238) CAG Guideline: The Toronto Consensus for the Treatment of Helicobacter pylori in adults (Gastroenterology. 2016 Jul;151(1):51-69.e14.)

63

GERD – ACG 2021 Guideline • Alarm symptoms (dysphagia, weight loss, GI bleed) à EGD – Recommend against barium studies – poor SN/SP for GERD and miss mucosal lesions w alarm symptoms

• No alarm symptoms?

– Non pharm mgmt. (weight loss, avoid trigger foods, quit smoking, elevate HOB, etc) – Trial PPI once daily 30-60min before a meal x 8 weeks • Symptoms improve? Try to wean PPI, if unable: lowest dose PPI • Symptoms refractory? à Ensure optimization of PPI therapyà Sx refractory despite optimizationà EGD off PPI, if normal à reflux monitoring à if negative, discontinue PPI, consider other causes – Recommend AGAINST other medical therapies (prokinetics, sucralfate, baclofen, H2RA) in PPI nonresponders (Exception: sucralfate in pregnancy OK, H2RA prn at night if objective nocturnal acid reflux on pH monitoring despite PPI)

• Extra-esophageal symptoms (cough, asthma, chest pain) need usual workup (PFT, cardiac w/u) – Can consider BID PPI x 8-12 weeks for typical GERD w/ extraesophageal symptoms; failing this àendoscopy off PPI

• Surgery – only for objective evidence of GERD – Fundoplication, Roux en Y bypass for eligible obese patients – Transesophageal incisionless fundoplication if unwilling to undergo classic lap fundo ACG Clinical guideline for Dx and Mgmt of GERD. Am J Gastroenterology 2021; 00-:1 online Nov 22, 2021

64

Barrett’s Esophagus •

Diagnosis: – Metaplasia of normal squamous epithelium to salmon-colored columnar epithelium ≥ 1 cm proximal to the gastroesophageal junction. – Biopsy confirmation of columnar intestinal metaplasia, +/- goblet cells.

•

Malignant potential: – 30 fold ↑ risk of esophageal adenocarcinoma vs average population – Low overall annual risk (0.1% – 3%) – Dysplastic > Non-dysplastic; long segment > short segment

•

ACG Guideline: Diagnosis and Management of Barrei’s Esophagus (Am J Gastroenterol 2022; 117 (4): 559-587).

Risk Factors: 1. 2. 3. 4. 5. 6. 7.

Chronic GERD (weekly symptoms for ≥ 5 years) Age > 50 Male gender Tobacco use Central obesity Caucasian Family history of Barrett’s esophagus/ esophageal adenocarcinoma

Alcohol is not known to ↑ risk of Barrett’s or esophageal adenocarcinoma! Only SCC

65

Screening for Barrett’s Esophagus ACG April 2022 Guidelines (strength of recommendation: conditional; quality of evidence: very low): •

Single screening endoscopy (or capsule + biomarker) for patients with chronic GERD and ≥ 3 risk factors for Barrett’s including: Age > 50, male, white race, obesity, tobacco smoking, 1st degree relative with Barrett’s or esophageal adenocarcinoma (moderate risk).

Canadian Task Force 2020: • “We recommend not screening adults (≥ 18 years) with chronic GERD for esophageal adenocarcinoma or precursor conditions (Barrett esophagus or dysplasia) (strong recommendation; very low-certainty evidence” • Go with this for your exam, considering ACG was a conditional recommendation re screening

66

Management of Barrett’s Esophagus (ACG 2022 Guidelines)

Obtain ≥8 biopsies if >1cm salmon mucosa extending from GE jxn - INTESTINAL METAPLASIA: - No Dysplasia = EGD in 3y if >3cm segement, otherwise in 5 yrs - Indefinite Dysplasia = PPI BID*, repeat EGD w biopsy in 6 mos - Dysplasia = Get Expert Path Review, see next slide

- No metaplasia – Repeat endo w biopsy in 1-2 yrs

*For all other padents with Barre|’s: • Once daily PPI • No role for roudne BID PPI unless refractory GERD/esophagids 67

Management of Barrett’s Esophagus (ACG 2022 Guidelines)

Low Grade Dysplasia – discuss risk/benefit of surveillance vs EET • Surveillance endoscopy q6mos x 2 then annually •

Endoscopic eradication therapy à complete eradication à surveillance endo 1 year then q2y after

High Grade Dysplasia or intramucosal carcinoma (T1a) • Endoscopic eradication therapy à complete eradication à surveillance endo 3, 6, 12mo then q1y Submucosal cancer (T1b) • Surgical referral for esophagectomy • ”consider” Endoscopic eradication only if low risk features ( 50 yo, odynophagia, vomiting, bleeding, weight loss

69

Dysphagia • Step 2 Imaging and/or Endoscopy – Oropharyngeal à Video fluoroscopy swallowing study – Esophageal • Alarm symptoms? à Endoscopy – Weight loss – Anemia – Vomilng

• No alarm symptoms and age < 50, Sx GERD, à Trial of PPI

• Key Concepts from CAG 2018 Guideline – EGD is recommended > barium swallow for inveskgakon of esophageal dysphagia. *Can biopsy for EoE on endoscopy! – Manometry is recommended > barium swallow for inveskgakon of esophageal moklity disorders 70

Achalasia • •

Esophageal motility disorder defined by loss of esophageal peristalsis and incomplete relaxation of lower esophageal sphincter Signs & Symptoms: – – – – –

•

•

Progressive solid and liquid dysphagia Regurgitation + reflux symptoms Chest pain Weight loss Symptoms refractory to PPI therapy

Epidemiology:

Okwara C, Cangemi D. Achalasia with Megaesophagus. N Engl J Med 2015; 373:e30 DOI: 10.1056/NEJMic 1502835.

– M=F – Age 30 – 60 years – All ethnicities

Complications:

– Megaesophagus > 6cm – Sigmoid esophagus – Esophageal squamous cell carcinoma >>>> adenoCA *NB* - Esophageal involvement from chagas is indistinguishable from achalasia on endoscopy! It is diagnosed via serology. Biopsies are not helpful! Treatment is the same.

71

Achalasia • Diagnosis: – Step 1 – EGD • Rule out pseudoachalasia + obstrucdon • ‘Puckered’ GE juncdon • Dilated, fluid filled esophagus as disease progresses

– Step 2 - High resoluUon manometry +/- barium swallow • Manometry – Gold standard test for achalasia – Measures pressures and peristaljc waveform throughout esophagus – Impaired relaxajon of LES and abnormal peristalsis are diagnosjc – ID’s muljple subtypes of achalasia (Updated Chicago Classificajon v4.0, 2021) – Don’t need to know for IM exam!!

• Barium Swallow – ‘Bird’s beak esophagus’

Barium swallow: Dilated esophagus, narrow GEJ with “bird-beak” appearance, poor barium emptying 72

Achalasia ACG Guideline (2020) Diagnosis and Management of Achalasia • Poor surgical candidates – Endoscopic botox injection – 1st line – Smooth muscle relaxants – CCB, nitrates • Ex. Nifedipine 10-30mg SL TID, ISDN 5mg SL TID • *Least effective therapy •

*NB – Achalasia ↑ risk of esophageal SCC. Poor esophageal emptying à stasis of food/liquid à inflammation à dysplasia à malignancy.

Good surgical candidates However, current guidelines do – Pneumatic dilatation st not recommend routine • 1 line option endoscopic surveillance for SCC. • Risk of tear/perforation – Laparoscopic Heller Myotomy • 1st line option • Often performed with fundoplication (anti-reflux surgery) – Peroral endoscopic myotomy (POEM) • 1st line option (especially type 3 achalasia) • Often complicated by GERD – patients need lifelong acid suppression – Esophagectomy • For patients with megaesophagus, sigmoid esophagus, failure of above treatments

73

Eosinophilic Esophagitis (EoE) •

Immune-mediated disease characterized by esophageal symptoms and eosinophilic infiltraaon (>15 eos/hpf) of the esophageal mucosa in absence of secondary causes of eosinophilia**.

•

Risk factors: – M > F (3:1). Peak incidence at 30-44 yo. – History of atopy (asthma, eczema, allergic rhiniDs), food allergies, autoimmune disease

• • •

Clinical presentaSon: Intermigent solid food dysphagia, food bolus obstrucDon Endoscopic findings: ‘TrachealizaDon’ of the esophagus (‘Feline Esophagus’), linear furrows, white

exudates/ papules, ‘Crate-paper’ esophagus, strictures

Treatment goal = SymptomaSc and histologic improvement – Non-pharmacologic Rx: 6 food eliminaDon diet (eggs, soy, cow’s milk, wheat, tree nuts, seafood). New evidence that animal milk eliminaDon equivalent to 6 food eliminaDon. – Pharmacologic Rx: • 1st line: PPI, topical steroids (swallowed fluDcasone/budesonide, or orodispersible budesonide [Jorveza]) • 2nd line: Prednisone • Approved by Health Canada Fall 2022: Dupilumab (anD-IL 4 and IL13) – Endoscopic treatment for symptomaDc strictures: DilaDon

**Secondary causes of esophageal eosinophilia: GERD, achalasia, connective tissue diseases, hypermobility syndromes, pill esophagitis, pemphigus, hyper IgE syndrome

AGA 2020 guideline: https://gastro.org/clinical-guidance/management-of-eosinophilic-esophagitis-eoe/

74

Acute Pancreatitis • Definition (need 2/3 criteria for diagnosis): 1. Abdominal pain consistent with disease (acute severe epigastric/ LUQ, radiates to back, better leaning forward) 2. Lipase and/or amylase ≥ 3x ULN 3. Characteristic findings on imaging

• Etiology: #1: Gall stones - always order U/S to rule out gallstones (Endoscopic ultrasound [EUS] or MRCP if high clinical suspicion and U/S negative) #2: EtOH #3: Other – triglycerides (> 11 mmol/L), hypercalcemia, drugs (GLP1 Rc agonists, 5-ASA, thiazides, azathioprine), autoimmune, post-ERCP, trauma, viruses, malignancy, hereditary, smoking, scorpion bite, vasculitis ACG Guideline: Management of Acute Pancreatitis (Am J Gastroenterol 2013; 108:1400–1415)

75

Acute PancreaQQs • Severity: (APACHE II and SIRS are the best) – Useful to assess adequacy of resuscitation and disposition (ward vs. ICU) – CT scan NOT required for diagnosis or prognosis (early CT can be misleading)

• Management: – IV fluids are the only effective therapy for pancreatitis in the first 24-48h • IV fluids within the first 12-24h are associated with reduced mortality • Current evidence favors moderate fluid resuscitation (1.5 mL/kg/hour with a 10 mL/kg bolus in patients with hypovolemia) over aggressive fluid resuscitation (20 mL/kg bolus followed by 3 mL/kg/hour), which resulted in more volume overload – WATERFALL trial 2022

• Generally Ringer’s Lactate (trials ongoing), but avoid in hypercalcemic patients – Analgesia – Nutrition • Start clear fluids or low fat diet early (within 24h), advance as able • If unable to take PO, enteral nutrition preferred (NG=NJ) – Empiric/ prophylactic antibiotics are not recommended (unless evidence of cholangitis or sepsis) ACG Guideline: Management of Acute Pancreatitis (Am J Gastroenterol 2013; 108:1400–1415)

76

If Clinical deterioration 48-72hrs after diagnosis à CT scan to assess for complications

Pancreatic necrosis: suspected of infection If patient systemically well

Obtain CT-guided FNA Negative gram stain + culture STERILE Necrosis: supportive care + consider repeat FNA every 5-7 days if clinically indicated Clinically stable Continue antibiotics and observe. Delayed minimally invasive surgical, endoscopic or radiologic debridement OR if asymptomatic consider no debridement.

If patient septic

Empiric necrosis-penetrating antibiotics [IF SEPTIC] Positive gram stain +/- culture Infected necrosis

Choice of antibiotics: Carbapenem (or Quinolone + Metronidazole). No role for empiric anti-fungals as per IDSA Clinically unstable

Prompt surgical debridement ACG Guideline: Management of Acute Pancrea``s (Am J Gastroenterol 2013; 108:1400–1415) 77

Approach to Acute Pancreatitis • Gallstone pancreatitis – Role of urgent ERCP (48 hours if not clinically improving with evidence of persistent stone – Ideally, cholecystectomy before discharge • Hypertriglyceridemia-induced pancreatitis – Generally only if TG very high (> 11) – If sick à IV insulin, strict NPO +/- plasmapheresis – Long term à Fibrates, restrict dietary fat, treat secondary causes of hyperTG (diabetes, ETOH) 78

BONUS Read on own

Classifica9on and Complica9ons of Acute Pancrea99s The Atlanta Classifica/on

Early ( 60 yo )

– Type II isolated to pancreas and associated with IBD • M = F; > 40 yo

It can mimic pancreatic cancer – But unlike cancer, it responds to steroids! Workup • CT/MRCP + EUS – “Sausage pancreas” – Biopsy (EUS + FNA or CT-guided Bx of retroperitoneal mass); histology = lymphoplasmacytic infiltrate + fibrosis – Biliary strictures (IgG4-associated cholangitis) • Serum IgG4 > 2x ULN suggestive of Type I AIP (but can be negative!) Treatment • Prednisone 40mg daily x 4-6 weeks, then taper – If relapse à retrial steroids or AZA or Rituximab • Look for radiologic improvement 80

Chronic Pancreatitis •

ACG 2020 Clinical Guideline – Chronic Pancreatitis Etiology: “TIGAR-O” – Toxic/metabolic: CHRONIC alcohol use, hyperTG, Smoking, hyper Ca, Medications, Toxins…Cystic Fibrosis – Idiopathic – Genetic – CF, and others PRSS1, CTRC… – Autoimmune pancreatitis – Recurrent Acute Pancreatitis (RAP) – Obstructive: i.e. pancreatic divisum (2 distinct pancreatic ducts, not one), stricture, stone, tumor

•

Clinical Manifestations: – Severe abdominal pain – Fat-soluble vitamin deficiency (ADEK) – Exocrine pancreatic insufficiency à steatorrhea, maldigestion, weight loss – Endocrine pancreatic insufficiency à Diabetes

•

•

Diagnosis: – 1st line – cross-sectional imaging (CT or MRI) à EUS if uncertain – Role of pancreatic exocrine function testing (eg 72h fecal fat) unclear in diagnosis of CP. Work-up: – Ca2+, Triglycerides (≥ 5.6 mmol/L) – Med review – i.e. AZA, cyclosporine – IgG subclass – IgG4 disease – Recurrent acute: • Consider MRCP – r/o divisum, stricture, tumor, stone • Consider genetics workup “if etiology unclear, especially in younger patients” – PRSS1, CFTR, CTRC, SPINK1 81

Chronic Pancreatitis - Treatment • Lifestyle Modification: – Alcohol and smoking cessation for all

• Pancreatic enzymes

– No evidence for relieving pain – Use for patients with exocrine pancreatic insufficiency – ↑ weight, ↑ fat-soluble vitamin absorption

• Pain management

– Antioxidants (limited benefit) i.e. selenium, ascorbic acid, methionine – Opioids – if other pain control methods exhausted – Celiac plexus block - ↓ pain x 3-6 mo.

• Obstructive cause – trial of ERCP, EUS. If patient has chronic pain failing endoscopic therapy, “surgical intervention for long term pain relief” – CAVEAT: “Performing procedures on individuals using alcohol should be considered cautiously”

• Total pancreatectomy + islet cell autotransplant – highly select pts.

82

BONUS Read on own

Choosing Wisely Canada

1) Don’t maintain long-term PPI therapy for GI symptoms without an attempt to stop/reduce PPI once a year (Patients with Barrett’s, severe esophagitis, or GI bleeding would be exempt) 2) Avoid using an upper GI series to investigate dyspepsia 3) Avoid performing an endoscopy for dyspepsia without alarm symptoms for patients under the age of 60 years 4) Avoid performing colonoscopy for constipation in those under the age of 50 without family history of colon cancer or alarm features 5) Do not routinely perform colonoscopy in IBS patients < 50 years of age without alarm features 6) Do not use steroids to maintain remission in IBD 7) Do not use opioids long-term for the management of pain in IBD 8) Don’t use abdominal computed tomography (CT) scan to assess inflammatory bowel disease (IBD) in the acute setting unless there is suspicion of a complication (obstruction, perforation, abscess) or a non-IBD etiology for abdominal symptoms. 83

Questions?

84

BONUS Slides: GI ‘Poo-Pourri’ • • • • • • • • •

PPI fast facts LGIB, SB bleeding IBD bonus slides Acute Cholangitis Microscopic colitis IgG4-Related disease ERCP/EUS AIH/ PSC/PBC Paracentesis + cirrhosis complications – Check out 2018 Online Video for this!

• Coagulation + cirrhosis • BONUS MCQs 85

BONUS Read on own

PPI Fast Facts

– Should be taken 30-60 min before breakfast (and dinner if BID) – Has clear benefits in the treatment of GERD, PUD, ZES, H. pylori – BUT PPIs have also been implicated in: • • • • • • •

C. diff, pneumonia HypoMg, Low B12 AIN/CKD Dementia Low BMD Gastric cancer Death?!

– Keep in mind: based on observational data so can’t establish a convincing causal relationship between PPIs and any of the above – For RC be ready to counsel patients on potential risks – Ensure there’s a clear indication for PPIs whenever they’re used • Barrett’s, refractory GERD, UGIB needing lifelong antiplatelet/anticoagulant • As per Choosing Wisely, reassess at least annually 86

BONUS Read on own

Lower GI Bleeding

• Rule out brisk UGIB or other source of bleeding • DDx of rectal bleeding – Painless • Diverticular bleed (most common), hemorrhoids, angiodysplasia, polyp/ post-polypectomy, cancer, ulcers (NSAIDs, stercoral), radiation proctitis, Meckel’s diverticulum

– Painful • Ischemic colitis (sudden, cramping abdo pain followed by bloody bowel movement) – Work-up cause: Cardio-embolic? (AFIB? Endocarditis? LV Thrombus) ATHERO-embolic (?AAA, dissection…), Shock/low flow, Segmental – think vasculitis / PAN – Risk factors for poor outcome: Male, sBP < 90, HR > 100, abdominal pain without rectal bleeding, BUN >20 mg/dL, Hb < 120, LDH >, Na 15 – Mgmt: Most resolve with supportive care (IV fluids, analgesia), empiric antibiotics if moderatesevere (strong recommendation, low quality evidence), Gen Sx if pancolitis or isolated right-sided • Hemorrhoid (if thrombosed) ACG 2015 colonic ischemia guidelines: https://journals-lww• Anal fissure

– Other (may be associated with cramping) • Inflammatory (IBD), Infectious

com.myaccess.library.utoronto.ca/ajg/fulltext/2015/01000/acg_clinical _guideline__epidemiology,_risk.8.aspx 87

BONUS Read on own

Lower GI Bleeding

• ABC-MOIF: (Monitor Oxygen IV, Foley) Resuscitation and management identical to UGIB • Consider EGD for suspected rapid UGIB (usually BRBPR with hemodynamic instability, elevated urea) – NG tube can rule in UGIB (coffee grounds/blood per NG) but cannot rule it out

• Rapid preparation for colonoscopy within 24 hours WITH FULL BOWEL PREP – If recurrent bleeding consider repeating colonoscopy

• Early referral to surgery or IR for embolization for unstable patients or those unable to tolerate colonic preparation • Stop NSAIDs or primary prevention ASA ACG Guideline: Management of Patients with Acute Lower Gastrointestinal Bleeding (Am J Gastroenterol 2016; 111:459–474)

88

BONUS Read on own

Small Bowel Bleeding

• Suspect in patients with ongoing overt GI bleeding with normal EGD and colonoscopy • Diagnostic algorithm if ongoing bleed despite negative EGD/ colonoscopy (in this order): 1. 2. 3.

Second-look EGD +/- push enteroscopy (to look up to proximal jejunum) +/-colonoscopy Video capsule endoscopy (VCE); must have regular CT/ AXR to r/o obstruction CT enterography (CTE) • CTE before VCE if concern for tumors, SB IBD, strictures or other obstructive process that the capsule would get stuck in Ø CTA if brisk, active bleeding; tagged RBC scan if slow bleed (>0.1 mL/minute) Ø Conventional angiography in IR suite for massive, unstable bleeding Ø Intraoperative enteroscopy (invasive; rarely done)

• Treatment options: – Double-balloon enteroscopy, surgery, IR embolization – Supportive management with transfusions and iron replacement ACG Guideline: Diagnosis and Management of Small Bowel CAG Guideline: Clinical Practice Guideline for Use of Bleeding (Am J Gastroenterol 2015; 110:1265–1287) VCE (Gastroenterology. 2017 Feb;152(3):497-514)

89

BONUS Read on own

CD vs. UC Disease features

Crohn’s disease

Ulcerative colitis

Pathology

Transmural Non-caseating granulomas (characteristic but only in < 30% of pts) Lymphoid aggregates

Mucosal/submucosal Cryptitis/ architectural distortion,crypt abscesses, atrophy Shallow, broad-based ulcers

Distribution

Skip lesions, “gum to bum,” UGI involvement possible (rare) Most common: ileocecal region

Contiguous colonic inflammation starts in rectum

Complications

Obstruction (strictures), fistula, abscess, perianal dz

Toxic megacolon

Cancer risk

Colorectal CA (colitis only)

Colorectal CA If PSC à risk of hepatobiliary cancers incl HCC, cholangioca, GB cancer

Serology *routine use of

ASCA (anti saccharomyces cereviscae Antibodies), Anti-OmpC, Anti-CBir1

P-ANCA

serology is NOT recommended because poor SN/SP

90

BONUS Read on own

IBD Therapy: Reference Table

Drugs

Indication

Side Effects

Caution / CI

5-ASA

Little role in Crohn’s UC: induction, maintenance -Suppository if up to 18cm disease only -Enema if beyond this but distal to splenic flexure

Headache, diarrhea, nausea, pancreatitis interstitial nephritis

Allergy

Steroids

Topical steroids (ie: budesonide) can be used longer-term

Less steroid S/E (high first pass effect)

Non-TI or R Colon disease

Systemic steroids only in the short term – “steroid bridge”

Usual steroid S/E

Azathioprine

Crohn’s or UC maintenance

Hepatotoxicity, leukopenia, lymphoma

TPMT deficiency

Methotrexate

Crohn’s induction/maintenance

Cytopenias, hepatotoxicity, ILD (See rheum slides for more)

Women of childbearing age

Biologics

First-line for fistulizing disease, perianal disease, or severe disease

Infections, lymphoma, other malignancy

TB reactivation, HBV reactivation

Tofacitinib

Moderate-severe UC with loss of response/lack of response/intolerance of conventional therapy or anti-TNF

Infections, lymphoma, other malignancy, leukopenia, anemia, MACE, thrombosis (arterial/ venous)

CAD, thrombosis HZV, TB reactivation GI perforation

Antibiotics (Cipro/Flagyl)

Some evidence for use, but for RC purposes limit to Tx of abscess, active infections, or fistulas

Neuropathy (Flagyl) Achilles tendonitis (Cipro)

Allergy

Cyclosporine

Failure of steroids in UC, alternative to Remicade/Infliximab

AKI, hyperK, hirsutism, infection 91

BONUS Read on own

• •

Bacterial infection of biliary tree usually due to partial/complete obstruction Etiology of obstruction – – – – – – –

•

Acute Cholangitis Stones (choledocholithiasis, Mirizzi syndrome) Strictures (malignant/benign) Clot Masses/tumors (i.e. pancreatic head, Klatskin tumor, metastases) PSC, HIV cholangiopathy Biliary stent obstruction (stones/sludge) Worms (Ascaris lumbricoides, tapeworm)

Clinical Presentation – ‘Charcot’s Triad, Reynaud’s Pentad’

↑ bilirubin + ALP are NOT common in acute cholecystitis. Have a high index of suspicion for cholangitis!

– Fever, abdominal pain + jaundice +/- hypotension and confusion – Labs: • WBC > 10 or < 4 • ALP/GGT > 1.5x ULN, ALT > 1.5x ULN • Bilirubin > 34 – Imaging: • Biliary dilatation +/- stones - U/S, CT, MRCP or EUS (↑ sensitivity, respectively) – Predisposition – PSC, stricture, stent, recent ERCP, etc… Ahmed M. Acute Cholangi`s – An Update. World J Gastrointest Pathophysiol. 2018 Feb 15; 9(1): 1–7.

92

BONUS Read on own

Acute Cholangitis - Management

• Investigations: – CBC, lytes, creatinine, INR/PTT – AST, ALT, ALP, GGT, total + direct bilirubin – Blood cultures

• Empiric Antibiotics: – Cover common biliary pathogens – CTX/flagyl, piptazo, cipro/flagyl, carbapenem

• ‘Source control’ – ERCP + stone removal +/- sphincterotomy (*↑ bleeding risk! Ensure INR < 1.5, PLT >50, anticoagulants held) +/- stent placement – Percutaneous transhepatic biliary drainage – IR-guided, if failed ERCP or ++ comorbidities, bleeding risk etc. – Surgical biliary drainage – rarely required Ahmed M. Acute Cholangitis – An Update. World J Gastrointest Pathophysiol. 2018 Feb 15; 9(1): 1–7.

93

BONUS Read on own

Microscopic colitis

• Two types: lymphocybc or collagenous colibs • Epidemiology, risk factors

– Older women (mean age 65) – Comorbid autoimmune diseases – thyroid, celiac, RA – Associated medicaaons: NSAIDs, PPIs (specifically lansoprazole), SSRIs, pembrolizumab, others

• Symptoms

– Relapsing/remi{ng watery, non-bloody diarrhea; may be severe – Weight loss, abdominal pain are common

• Diagnosis – Normal-appearing colonoscopy, biopsies confirm diagnosis

• Treatment – Imodium, stop NSAIDs/ other offending meds – 1st line: Budesonide PO, 2nd line: 5-ASA PO 94

BONUS Read on own

IgG4-related disease

• Epidemiology

– Mostly older men (age > 60)

• In contrast, Type II (non-IgG4) AIP is diagnosed at age > 40, M=F

• Disease manifestations

– Autoimmune pancreatitis, biliary sclerosis, retroperitoneal fibrosis, chronic sclerosing aortitis, thyroiditis, interstitial pneumonitis, tubulointerstitial nephritis

• Diagnosis – Measure serum IgG4 levels (can help but not diagnostic) – Imaging of affected organ and ruling out other causes (i.e., cancer) – Gold-standard Dx is made upon tissue biopsy of affected organ

• Treatment – Prednisone 40mg daily and then taper over 2 months – If unable to taper, consider rituximab, AZA, or MMF – Follow response to treatment symptomatically and radiologically 95

BONUS Read on own

Autoimmune Hepatitis (AIH) Type 1 AIH

Type 2 AIH

Antibodies

ANA > 1:80, ASMA > 1:80 ANA, AAA, Anti-soluble liver/ liver pancreas antigen

Anti-LKM1 > 1:80 Anti-liver cytosol

Age of presentation

Any age

Children and young adults

Associated disorders

Autoimmune thyroid disease, Grave’s, UC, celiac, T1DM

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

Clinical presentation: – F >> M (5:1) – May be asymptomatic, or acute hepatitis, acute liver failure, or chronic hepatitis and cirrhosis – Drug-induced AIH (e.g. infliximab, adalimumab, nitrofurantoin, minocycline, atorvastatin, others) Diagnosis: – Constellation of clinical, lab (antibodies and elevated IgG), and histology (interface hepatitis) – Exclude other causes of chronic hepatitis (NASH, viral, hereditary etc.) – Can use the simplified AIH score to aid diagnosis Treatment – Depends on presentation severity and presence of cirrhosis: – Typically steroids (prednisone or budesonide) +/- azathioprine (not used in severe acute AIH) *See excellent chart in guidelines – Screen all patients for celiac disease and thyroid diseases 2019 AASLD Guidelines on Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: https://doi.org/10.1002/hep.31065 96

BONUS Read on own

Primary Sclerosing Cholangitis (PSC)

•

Chronic, cholestatic, immune-mediated disease of intra & extrahepatic bile ducts (radiologic diagnosis)

•

Clinical presentation: – M >> F, 2/3rd of patients have IBD (most have ulcerative colitis phenotype). – Up to 50% asymptomatic at presentation. Symptoms include abdominal pain, pruritus, fatigue.

•

Diagnosis: – (1) Elevated ALP, (2) multifocal biliary strictures “beads on a string” (usually on MRCP), (3) exclude secondary sclerosing cholangitis, (4) liver Bx if PSC-AIH overlap of small duct PSD suspected.

•

Differential diagnosis: – IgG4 related disease (exclude since this entity is steroid-responsive) – PSC-autoimmune overlap syndrome (respond partially to immunosuppressants)

•

Treatment: – – – – –

ERCP as needed for symptomatic strictures MRCP +/- CA 19-9 q1 year to screen for GB cancer and cholangiocarcinoma Colonoscopy with surveillance biopsies at diagnosis and q1-2 years If cirrhotic, screen for HCC/EoV Ursodeoxycholic acid has NO evidence but frequently used; liver transplant for liver failure The 6 C’s of PSC: DOI: 10.1016/j.jhep.2020.06.033

97

BONUS Read on own

•

Primary Biliary Cholangitis (PBC)

Disease of intrahepatic biliary tree

• Clinical presentation – Usually middle-aged women (>95% of cases) – Present with jaundice, pruritus, fatigue, elevated ALP (usually get imaging – either U/S or MRCP to rule out obstruction) – Associated with Sjogren’s, celiac disease, and autoimmune thyroid disease

• Diagnosis requires 2 of 3: 1. Persistent ALP elevation > 6 months 2. Positive AMA >1:40 (95% sensitive, 98% specific) or specific ANAs (e.g. gp 210/sp 100) 3. Liver biopsy (only needed when diagnosis unclear)

• Treatment – Bone density testing, lipid profile derangements, monitor for cirrhosis – Ursodeoxycholic acid 15mg/kg has benefit; liver transplant for liver failure 98

BONUS Read on own

Cholestatic liver diseases

Primary Biliary Cholangitis (PBC)

Primary Sclerosing Cholangitis (PSC)

Older women, autoimmune diseases

Younger men, ulcerative colitis

AMA positive in >95%

No antibodies (rarely IgG4-related)

Urso can alter natural history

No treatment is effective

Benign course in 2/3 of patients

Progressive disease

Screening only if evidence of cirrhosis

Annual MRI to look for GB cancer or cholangiocarcinoma

Only affects intrahepatic bile ducts, histologic diagnosis

Affects intra and extrahepatic bile ducts, radiologic diagnosis

Rarely require ERCP

Cholangitis common, may require ERCP for dilation of dominant strictures 99

BONUS Read on own

Paracentesis (Oral Scenario)

• Diagnostic

– cell count, culture and sensitivity, biochemistry including albumin (to calculate SAAG), cytology, AFB, etc. – Risks: bleeding, infection, perforation, organ injury

• Therapeutic – Purpose is to reduce ascites for symptomatic patients – Can take off unlimited amount of fluid as one time (suggest replace with 100cc of 25% albumin for each 4L of fluid removed) – Avoid therapeutic paracentesis for patients with SBP, UGIB, active infection, or acute kidney injury (may worsen renal function) – Risks are same as diagnostic paracentesis AND risk of hypotension, AKI, encephalopathy

100

BONUS Read on own

Cirrhosis Decompensation

Problem

Diagnostic

Treatment

Hepatic Encephalopathy

Clinical (confusion, asterixis) Look for precipitant (meds, GI bleed, electrolyte abn, HCC, SBP…)

Treat precipitants à Lactulose +/- Rifaximin

Hepatorenal syndrome Suspect in liver patients with AKI. Need to rule out other causes of AKI, have a low UNa, and be refractory to albumin 1g/kg X 2d after stopping diuretics

Treat underlying liver disease à Albumin + (1) Midodrine & Octreotide; (2) Terlipressin; (3) Norepi (if in ICU) à Transplant

Hepatopulmonary Syndrome

Suspect in liver patients with dyspnea, Supportive à Transplant paltypnea/orthodeoxia, or hypoxemia otherwise (PaO215). TTE bubble study = shunt Rule out other causes hypoxemia!

Hepatocellular Carcinoma

Screening in Med Oncology lecture

Curative – Transplant, Surgery, RFA; Palliative – TKI/Chemo, XRT, TACE

101

BONUS Read on own

Hepatic Encephalopathy (HE)

• Etiology – Accumulation of glutamine from increased ammonia levels – Patients can present with day-night sleep reversal, drowsiness, agitation, confusion

• Diagnosis • Clinical diagnosis! (no role for ammonia levels) • Look for precipitating causes (SBP, infection, GI bleeding, alcohol, drugs, HCC, stroke, constipation, dehydration, portal or hepatic vein thrombus, electrolyte abnormalities, TIPS )

• Treatment – – – –

Treat underlying cause (stop benzos, opioids, anti-chol) Lactulose +/- Rifaximin (typically added if patient had episode of HE while on lactulose) Ensure high-calorie, high-protein diet Recurrent intractable HE, together with liver failure, is an indication for liver transplant Hepatic Encephalopathy. AASLD guidelines. 2014

102

BONUS Read on own

• • •

•

•

Hepatorenal Syndrome

HRS: Functional renal injury in pts with portal HTN 2º cirrhosis/ acute cause (alc hep, fulminant liver failure) Pathophysiology: Portal HTN à splanchnic arterial vasodilation à AKI HRS classification (based on the rapidity of renal impairment): – HRS-AKI (formerly type 1 HRS): more severe; Abrupt (< 48h) ↑ Cr ≥ 0.3 mg/dl (~ 26 umol/L) or ↑ Cr ≥ 50% (from b/l in past 3 mo) or urine output < 0.5 ml/kg/h for ≥ 6h. – HRS-NAKI [non-AKI] (formerly type 2 HRS): less severe; gradual decline in kidney function assoc. w/ refractory ascites • HRS-AKD (HRS-acute kidney disease) if eGFR < 60 mL/min/1.73m2 for < 3 months • HRS-CKD (HRS-chronic kidney disease) if eGFR < 60 mL/ min/1.73m2 for > 3 months HRS-AKI Diagnostic criteria: 1. Cirrhosis/ acute portal HTN with ascites 2. ↑ Cr ≥ 0.3 mg/dl (~ 26 umol/L) or ↑ Cr ≥ 50% (from b/l within past 3 mo) or UO < 0.5 ml/kg/h for ≥ 6h. 3. Other causes ruled out (ATN, shock, drugs, obstructive) 4. No improvement with diuretic withdrawal + 1g/kg IV albumin x 2 days 5. Suggestion of renal vasoconstriction with a FENa < 0.2% (with levels < 0.1% being highly predictive) Treatment – Definitive = liver transplant – ICU = Norepinephrine and IV albumin – Ward = terlipressin + albumin > octreotide + midodrine + albumin • Teripressin now approved by FDA (CONFIRM trial NEJM. 2021 Mar 4;384(9):818-828) Wong and Kwo. Am J Gastroenterol 2023;118:915–920.

103

BONUS Read on own

Hepatopulmonary Syndrome

• Etiology – Patients with cirrhosis or portal hypertension can get hypoxemia from intrapulmonary vasodilation – Classic presentation: dyspnea, platypnea, hypoxemia

• Diagnosis: – Suspect HPS if ABG reveals PaO2 < 80, A-a gradient ≥15 – TT Echo with agitated saline (i.e. bubble study) demonstrates evidence of intrapulmonary shunting – Need to exclude other causes

• Treatment – Supplemental oxygen, liver transplant reverses HPS 104

BONUS Read on own

Coagulation + Cirrhosis

• Compensated cirrhosis à balance of clotting + bleeding but easily shifted! – – – – – –

↓ production of clotting factors: VII, intrinsic + extrinsic pathway ↓ production of coagulation inhibitors (protein C/S, antithrombin) ↑ intravascular coagulation + fibrinolysis à premature clot dissolution ↓ TPO à ↓ PLT production from bone marrow ↓ PLT from hypersplenism often countered by ↑ VWF INR correlates poorly with bleeding risk – paracentesis still safe to perform w/o specific INR cutoff

• Sepsis, hypothermia, renal failure…à all can easily shift the balance, especially in decompensated patients! 105

BONUS Read on own

Bonus 1– 2023

32F presents with two months of dysphagia to solids that occurs 3-5x per week. She has had to visit the emergency room for a food impact once in the past. She sometimes forces herself to vomit to resolve obstruction. She is otherwise healthy except for allergic rhinoconjunctivitis for which he takes sublingual immunotherapy and nasal spray. Physical exam is normal. What diagnostic test would you order? A. B. C. D.

CT chest Endoscopy Esophageal manometry Cine esophagram 106

BONUS Read on own

Bonus Question 2 – Liver 2023

A 51F born in Canada is admitted to with a 3 day history of melena and is suspected to have liver disease based upon clinical examination revealing mild edema, scleral icterus, palmar erythema. She is on no medications. She has no family history of liver or autoimmune disease. No viral hepatitis risk factors. Vaccines up to date. She does not drink alcohol. She has been feeling unwell with weight loss, anorexia and fatigue for the past 12 months. Vitals: BMI: 24 BP 102/68, HR 90, afebrile. She is fatigued but oriented, attentive, ambulatory in ER. Labs available show Hgb 109 WBC 10 Plt 102 Na 128 Cr 72 AST 927 ALT 1034 ALP 168 INR 1.5 Alb 32 Bili 49. Quantitative immunoglobulins show elevated IgG. Ultrasound reveals normal appearing liver with perihepatic and pelvic ascites, no obvious masses in liver. No portal venous thrombus. CT abdomen reveals evidence of portal hypertensive gastropathy and esophageal varices on CT. Which of the following should be initiated most urgently? a)Ultrasound guided paracentesis to rule out SBP b)Carvedilol 6.25 mg once daily c)Nadolol 40 mg po and endoscopic variceal ligation d)Prednisone 50 mg po daily e)Ceftriaxone 1g IV f)Octreotide 50mg IV 107

BONUS Read on own

Bonus Question 3 2023

67F with a recent STEMI was started on clopidogrel and ASA. She had been on ranitidine 150 mg PO for years after a remote UGIB related to an H. pylori positive ulcer. She remembers receiving antibiotics for her H. pylori. She has had no recent GI bleeding. Which of the following do you recommend for her therapy? A. B. C. D.

Continue ranitidine Double ranitidine dose to 300 mg Change ranitidine to a pantoprazole Treat for H pylori with PBMT

108

BONUS Read on own

Bonus Question 4 2023

48M with a 15-year history of ileocolonic Crohn’s disease is admitted with a flare. He is not responsive to high dose IV steroids and plan to start infliximab as he does not want surgery. He had his normal vaccinations in childhood and has not had any vaccinations since then. What would you do in regards to vaccinations? A. B. C. D.

Provide an MMR booster Now Provide the TdAP booster when steroids tapered to >DBP) – ê innervation of detrusor muscle

• Gait: – 10-20% reduction in gait velocity and stride length. Increased stance width, increased time in double support phase. 94

Normal Aging • Cardiovascular system: – – – –

HTN: isolated systolic; pulse pressure widens valves thicken, LV stiffens… less tolerance to increased workload. Systolic function preserved LA enlargement by 50%; No significant changes to RV or RA Maximum HR decreased by 5-6 beats per decade

• Respiratory system: – Functional changes: • éRV, ERV, FRC due to gas trapping • ê VC, FVC, FEV, compliance, FEV1/FVC, dlco

– – – –

Anatomical changes: increased dead space (30% of surface area per lung volume lost over lifespan) Increased V-Q mismatch Changes in surfactant + decreased ciliary function and elasticity Decline in diffusion capacity (5% per decade)

95

Normal Aging • Renal: – – – – – –

30% decline in mass functional decline with CrCl decrease of 7.5 – 10 mL/min/decade 30% of glomeruli sclerosed by age 75 ability to maximally dilute urine decreased hydroxylation of vitamin D decreased erythropoietin production preserved

• GI:

– reflux d/t reduced tone at LES – preserved nutrient absorption in small intestine – colonic changes in motility with decreased myenteric neurons; diverticuli formation, greater water absorption and subsequently harder stool – Liver: decreased mass and blood flow – Phase 1 reactions: decreased oxidation – Phase 2: no change to glucuronidation 96

Normal Aging • MSK: êmuscle & bone mass

– sarcopenia - appendicular muscle mass • loss in legs greater than arms

• Immune:

– immunosenescence, êefficiency, infections more severe w/ slower recovery

• Endo: – – – –

menopause in women, êestrogen à vulvovaginal atrophy ê GH and testosterone, ê DHEA secretion Mean 24h cortisol concentrations higher – 30 to 50% àê bone density, fractures, memory loss Vasopressin response to volume increases, less to osmolality à less renal response, less thirst

• Sleep:

– longer to initiate, êsleep efficiency (time in bed that is spent asleep), phase shift of circadium rhythm (go to bed earlier, get up earlier), increased napping 97

Pharmacodynamics & Aging “What drug does to body” • Additive: A+B = AB – ex: ASA & SSRI (for platelet inhibition)

• Antagonistic: A+B < AB – ex: oxybutynin & ChEI (for cholinergic effect)

Minimal change w/ age, ñsensitivity

98

Pharmacokinetics & Aging “What body does to drug” • Absorption: relatively unaffected • Distribution: Less muscle & water, more fat – Water soluble drugs – increased serum concentrations – Fat soluble drugs – increased half life

• Metabolism: Reduced hepatic metabolism – Enzymatic transformations:

• Demethylation • Phase 1 (CYP450) oxidation (decreased) • Phase 2 glucuronidation (less affected)

• Elimination: Reduced GFR – less clearance Significant changes w/ age

99

Considerations in Med Review Reason to stop or D/C

Selected examples

Non compliance w/o negative health effect

Anti-HTN Oral diabetic medication

Takes incorrectly w/o negative effect or benefit

Puffers

Not indicated or relative contraindication

Statin, ASA for primary prevention Docusate CCB in pt with systolic heart failure

No longer indicated

Bisphosphonate after 5 yrs* Benzos, NSAIDs, PPIs ChEI (consider if fully dependent)

Inappropriate dose for geriatric patient

Digoxin Amitryptiline

Not aligning with goals of care, life expectancy

Statins ( overflow), and MORE Holroyd-Leduc. JAMA RCE. 2008

110

Incontinence Management • Non-Pharmacological First line treatment for all types: – LIFESTYLE modifications: limit fluids, caffeine and EtOH; weight loss; treat constipation; bladder training (cog intact), pelvic floor muscle training (cog intact), prompted/timed voiding (cog impaired), functional intervention training, or pessary (stress)

• Stress: • Pessary for prolapse, no pharmacotherapy, surgical options • Effective, but trials do not represent older adult population. Health Canada warning re: mid urethral sling due to complications. •

Urge: • Beta-agonist (Mirabegron): s.e. headache, tachycardia afib, HTN, nasopharyngitis effectiveness low (535 umol/L), no response to allopurinol (NOT in G6PD def) Zuckerman et al. How I Treat Hematology Emergencies in Adults with Acute Leukemia. Blood, 2012.

2. Leukostasis (AML>ALL>CML>>CLL): • Rigid sticky blasts ↓flow → organ dysfunction • Can affect any/all organ systems • Lungs (dyspnea/hypoxia) • CNS (confusion/visual changes) • In AML if WBC >50-100 • At higher WBC in CML/ALL, rare in CLL Treatment: 1. IVF 2. Cytoreduction (e.g hydroxyurea, leukapheresis, induction chemo) 3. TLS prophylaxis 4. Avoid transfusion

Clinical Practice Guideline From the AABB; Ann Int Med 2015 Wada et al. Journal of Intensive Care 2014 Rolling and Ehniger. How I Treat Hyperleukocytosis in AML. Blood, 2015.

13

Acute Leukemia Associated Emergencies (2) 3. DIC

Non-APL: 1. Platelets (see “cytopenias”) 2. FFP (15 cc/kg) • Indication: If bleeding and PT or PTT > 1.5 x ULN 3. Fibrinogen concentrate (4g) • Indication: If bleeding and fibrinogen 165/160 g/L (M/F) or HCT > 49%/48% (M/F) (interferon if young or pregnant) 2. BM: hypercellular for age, trilineage growth • Second line: JAK inhibitor (Ruxolitinib) – resistant 3. JAK2 V617F (or JAK2 exon 12) mutation /intolerant of Hydroxyurea (RESPONSE trial) Minor: Low serum EPO • Venous thrombosis history: anticoagulation • Arterial thrombosis history: consider ASA BID NCCN MPN Guidelines; ASH-SAP; AJH 2024 Update

20

Essential Thrombocythemia (ET) Presentation • •

CBC: ↑PLTs Vasomotor sx, thrombosis, bleeding (acquired VWD with plt ≥ 1000)

Diagnosis: 4 major or first 3 major + minor Major

1. Sustained ↑ PLT (≥ 450) 2. BMBx: ↑ mature hyperlobulated megakaryocytes 3. r/o other WHO diseases 4. Presence of JAK2 (50%) or CALR (25%) or MPL (5%) mutation* Minor: NO reactive cause

Risk stratification (IPSET): thrombosis hx, age, JAK2 status Treatment:

Very low risk (no thrombosis, age CALR > MPL mutation* 3. Rule out other MPN/MDS

Minor:

Presentation:

– Massive spleen, early satiety, B symptoms – CBC: cytopenias Peripheral blood film: – Leukoerythroblastic = nucleated RBC + left-shift – “Teardrop” RBC cells – 50% of patients with Budd Chiari have an MPN *there are other clonal markers WHO 2016/2023 Guidelines; ASH-SAP.

1. 2. 3. 4. 5.

Leukoerythroblastic film LDH > ULN Anemia Leukocytosis ≥ 11 Palpable splenomegaly

Risk stratification: DIPSS, MIPSS70 Treatment (based on risk stratification) Low risk: supportive (e.g. anemia – EPO, danazol) High risk: allogenic hematopoietic stem cell transplant For splenomegaly à hydroxyurea, JAK-inhibitors (e.g. Ruxolitinib), splenectomy For B Sx à JAK inhibitors Radiotherapy for extra-medullary hematopoiesis 22

Chronic MyeloMonocytic Leukemia (CMML) Both an MPN and MDS Diagnosis: – – – –

Peripheral blood monocytosis ≥ 1 x 109/L and ≥ 10% of total WBC for >3mo Blasts 10 cm or symptomatic – Splenomegaly > 6 cm below CM or symptomatic – Progressive cytopenias à BM failure (Hb < 100, plts < 100) – AIHA/ITP with poor steroid response – Extranodal involvement (skin, lung, kidney, spine) – Significant constitutional symptoms – Treatment choices based on pt values, disease risk stratification •

Chemoimmunotherapy (FCR, V-O) vs. tyrosine kinase inhibitors i.e. Ibrutinib (SE = bleeding, A.fib) ASH SAP

26

History/Workup for Lymphoma Risk factors: •

Infections – – – – –

HIV (Hodgkin’s, NHL: DLBCL, 1⁰CNS lymphoma, Burkitt, 1⁰ effusion lymphoma) EBV (Burkitt’s) H. pylori (gastric MALT) C. psittaci (ocular MALT) Hepatitis C (NHL)

• Immunosuppression : Post-transplant lymphoproliferative disease (PTLD), ↑ risk with certain DMARDs and biologics • Chronic inflammation: Sjögren's (salivary gland MALT), Celiac or Crohn’s (GI lymphoma), SLE & RA associated with NHL

B-symptoms:

- Weight loss (>10% in 6 mo) - Unexplained fevers (>38.3 ⁰C x ≥2 weeks, no infection) - Night sweats

Diagnosis: -

- NEED EXCISIONAL LYMPH NODE BIOPSY FOR DIAGNOSIS 27

Lymphoma Staging/Prognosis Staging: • (PET)-CT neck/chest/abdo/pelvis • BMBx/aspirate • +/-LP

• Ann-Arbor Staging System (older) •

•

•

•

•

•

Stage 1: Single lymph node region Stage 2: Lymph node regions on the same side of the diaphragm Stage 3: Lymph node regions on both sides of the diaphragm Stage 4: One or more extralymphatic organs (includes bone marrow) A: no symptoms; B: B-symptoms; E: contiguous extranodal site; S: splenic involvement Disease-specific prognostic scores Lugano Staging (newer)

28

Lymphoma Classification + Treatment • •

↑ lymphoid cells in LN / lymphatic organs (spleen) Aggressive [curative, high mortality] vs. indolent [slow growing, not curative]

Hodgkin (HL)

Non-Hodgkin (NHL)

Bimodal age distribution

Typically older

Reed-Sternberg cells

No Reed-Sternberg cells

All forms are ”aggressive”

Indolent: follicular, marginal zone Aggressive: diffuse large B cell (DLBCL), Burkitt

Lymphadenopathy +/- mediastinal mass +/- B sx

Nodal +/- extranodal dx +/- B symptoms

Tx: Chemo + rads (e.g. ABVD* vs. AAVD +/radiation)

Tx: - Indolent: watch and wait vs. rituximab + chemo (e.g. BR) - Treatment based on tumor burden and Sx, not on stage or grade - Aggressive: - DLBCL: Ritux + chemo (e.g. R-CHOP) - Burkitt’s: chemo (e.g. Magrath)

*ABVD: Adriamycin, bleomycin, vinblastine, dacarbazine *AAVD: brentuximab, doxorubicin, vinblastine, dacarbazine Emerging: PD-1 blockade (Nivolumab) RCHOP for Nodular Lymphocyte–Predominant HL: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone

29

Lymphoid Disorders • Acute Lymphocytic Leukemia (ALL) – Too many immature lymphoid blasts

• Lymphoproliferative disorders (LPDs) – Too many mature lymphoid cells

• CLL: burden of disease is in the peripheral blood • Lymphoma: burden of disease is in lymph node

• Plasma cell dyscrasias

– Too many plasma cells → overproduction of single antibody * MGUS → smoldering myeloma → multiple myeloma * Primary amyloidosis

30

Work up (1) 1. Protein electrophoresis 3. Serum free light chain (FLC) assay • Serum (SPEP) and 24 hr urine (UPEP) • Normally k & λ light chains present in ~ equal amount • Quantity of M protein present » k : λ ratio varies around 1 (0.26-1.65) Normal protein electrophoresis

M spike = M protein

» Free light chains filtered by kidney but resorbed » Monoclonal excess light chains supercede resorption capacity à urinary excretion

• Renal failure (not MM): ↓light chain excretion, k ↑ ↑, λ ↑ » E.g. k : λ ratio ~2

• Myeloma: clonal FLC will skew ratio

» E.g. IgG-k myeloma → k : λ ratio = 35

4. BMBx, aspirate 2. Immunofixation • Qualitative: determine “type” of M-protein (eg: IgG /IgA/IgM, k vs. λ)

• Plasma cell burden; normally 100mg/L MRI: > 1 focal bone lesions that are ≥ 5 mm on MRI [Ca2+ ]: > 2.75 or > 0.25 mmol/L above ULN Renal: Cr > 177 μmol/L or CrCl < 40 (attributable to MM) Anemia: Hb < 100 g/L or 20g/L below the LLN Bone: ≥ 1 osteolytic lesion (skeletal survey, CT or PET/CT)

IMWG Diagnostic Criteria 2014

34

Management MGUS - based on risk of transformation into MM/waldenstrom/amyloidosis High Risk (any 1 of): 1. M-protein ≥ 15 g/L 2. Non-IgG M-protein 3. Abnormal free light chain (FLC) ratio Low risk MGUS: 2% risk of transform’n @ 20y à no BM biopsy/bone imaging à CBC, SPEP, FLC, Ca, Cr in 6 mo à if stable FU if new symptoms or q2-3y High risk MGUS: >20% risk of transform’n @20 yrs à BMBx, whole body CT, CT abdo if IgM à CBC, SPEP, FLC, Ca/Cr in 6 monà stableàrpt q1y lifelong

Smoldering Myeloma • BM biopsy/aspirate & imaging to rule out bony lesions (CT or MRI) à rule out MM • If no MM à monitor closely (+ annual re-imaging) Myeloma: • No cure • Transplant (auto-HSCT) eligible (~≤70 yo, fit): chemo à auto-HSCT à maintenance therapy • Transplant ineligible: chemo à maintenance therapy

Auto-HSCT: autologous hematopoietic stem cell transplant

Kyle et al., IMWG 2014 Go & Rajkumar, Blood 2018 ASH MGUS Pocket guide 2016

35

AL (Light Chain) Amyloidosis Definition: Plasma cell dyscrasia (or lymphoma) with 2o monoclonal light chain deposition in organs (e.g. renal, cardiac, liver, peripheral nerves, GI, soft tissue infiltration, coagulopathy) Diagnosis: IMWG criteria [diagnosis requires all 4] 1. Clonal plasma cell disorder (eg: evidence of M protein or abnormal FLC or clonal plasma cells in BM) 2. Presence of amyloid related systemic syndrome (eg renal, cardiac, GI, liver, neuropathy) 3. Amyloid on bone marrow or tissue biopsy à “apple green birefringence” on Congo red stain 4. Prove amyloid is light chain restricted (mass-spectrometry or electron microscopy) Treatment: Similar to myeloma Rajkumar et al. Lancet Oncol 2014

36

Waldenstrom’s Macroglobulinemia Definition: 1. Lymphoplasmacytic lymphoma

(an indolent lymphoma with features between B-cells & plasma cells)

AND 2.

Monoclonal IgM in the peripheral blood

Presentation: 1. Symptoms 2o to infiltration → Anemia (BM infiltration), (order CT Abdo) hepatosplenomegaly, lymphadenopathy 2. Symptoms 2o to autoimmune processes → Neuropathy à Autoimmune hemolytic anemia à Cold agglutinin disease

3. Symptoms 2o to monoclonal IgM:

→ Type I cryoglobulinemia → Hyperviscosity syndrome – Headaches, neurologic symptoms, mucocutaneous bleeding à Bleeding Management: – Treat when symptomatic – PLEX for hyperviscosity syndrome (removes serum IgM) – Chemoimmunotherapy with rituximab 37

MCQ 2 2024 A 63 year old female with history of ER/PR positive breast cancer treated with chemotherapy and radiation 2 years prior presents with fatigue, worsening exercise capacity including dyspnea on exertion, and overall decreased functional status. She continues on hormonal therapy currently. Her exam demonstrates no breast masses, and no localizing bony pain. She appears pale, and a grade 3/6 systolic ejection murmur can be heard over left sternum border, and no other pertinent exam findings. Her blood work shows Hgb 72, MCV 108, WBC 2 with ANC 0.8, platelet 75, with blood film demonstrating hypolobulated neutrophils with poor granulation. What is the most likely cause of the patient’s presentation? 1) 2) 3) 4) 5)

Acute myeloid leukemia Myelofibrosis Myelodysplastic syndrome Metastatic breast cancer to the bone Vitamin B12 deficiency

38

Bone Marrow Failure Syndromes • Myelodysplastic Syndrome (MDS) – Cytopenia(s) + dysplastic cells/genetic abnormalities/blasts

• Aplastic anemia (AA)

– Hypocellular bone marrow – Primary vs. secondary

NOTE: THESE CAN OVERLAP

• Paroxysmal nocturnal hemoglobinuria (PNH) – Bone marrow failure – Hemolysis – Thrombosis

39

Myelodysplastic Syndrome (MDS) Pathophysiology: • •

Clonal, dysplastic cells à dysfunctional blood cells à risk of progression to AML Etiology: idiopathic vs 2o to DNA damage (rads/chemo/hydrocarbons)

Definition: Cytopenia

Dysplasia

AND 30

Antidote?

Idarucizumab (PRAXBIND)

Not in Canada PCC 2000 units

Not in Canada PCC 2000 units

Not in Canada PCC 2000 units

(ROCKET-AF)

(ARISTOTLE)

(ENGAGE –AF) 60mg OD, see 30mg dose

Health Canada Approved Indications (Clinical Trial)

Non-valvular Afib

Acute DVT

Prophylaxis post TKA/THA

(RELY)

*dose 110bid if: age ≧80, or ≧75 w/ bleeding risk incl CrCl30-50, P-gp inhib

*dose 15mg OD if CrCl 30-49

*dose 2.5bid if 2 of: Cr≧133, age≧80, wt60= 60mgOD. CrCl 30-60 or weight 3cm from SFJ/SPJ + 9: hold warfarin + VitK 2.5-5 mg po • INR 4.5-9: hold warfarin + decrease dose Non life-threatening bleed: • Vit K + supportive Life threatening bleed/imminent procedure: • IV Vit K + prothrombin complex (PCC) – PCC dosing per INR: INR 1.5-3: PCC 1000U; INR 3-5: PCC 2000U; INR> 5: PCC 3000U

LMWH Life threatening bleed: • Protamine 25-50 mg

DOACs Consider TXA Non life-threatening: supportive Life-threatening bleed: supportive + • Dabigatran: • Idarucizumab (Praxbind) 2.5g x 2 doses; consider dialysis (~65% removal in 4 h) •

Apixaban/Rivaroxaban/Edoxaban: • 4 factor PCC (e.g. Octaplex, Beriplex); 2000U (can be repeated) • Andexanet alfa (not available in Canada) Thrombosis Canada: “Warfarin: Management of Out-of-Range INRs” Thrombosis Canada: “NOACS/DOACS: Management of Bleeding” Thrombosis Canada: UFH and LMWH ASH 2018 Guideline Blood Advances 2018 2:3257-3291 The AABB Choosing Wisely Campaign of ABIM RE-VERSE AD. NEJM. 2015;373:511-20 UPRATE Trial. ASH 2017; 130: 1706-12.

57

Unusual Sites of Thrombosis Anatomic location

Symptom

Risk factor(s)

Anticoagulation duration

Cerebral venous sinus

Sinus thrombosis (mass effect): headache, visual loss, papilledema, sz, hydrocephalus Cortical vein thrombosis (venous ischemia/hemorrhage): neuro deficit May need neurosx if severe ↑ICP

Smoking; estrogen: OCP/pregnancy; MPN; PNH; Heritable thrombophilia; APLA; Parameningeal infection; VITT

Provoked: 6 mns Unprovoked: consider indefinite Thrombophilia: indefinite

Splanchnic : portal, mesenteric

Often clinically silent Acute with rapid extension: portal hypertension, acute GI bleeding, decompensation of previously stable cirrhosis, intestinal ischemia

Cirrhosis; MPN (JAK2?); cancer; APLA; PNH; IBD; intra-abdominal infection; trauma; cancer; surgery

Acute PVT: 3-6 mns or longer Chronic PVT: dependent on RFs, case by case, consider treatment to avoid extension and increased portal hypertension

Splanchnic: splenic

Abdominal pain

Embolic: cardiac, vasculature (aorta) In situ: APLA, sickle cell, cancer Congestion: heme cancer, Gaucher’s

Treat underlying cause; antithrombotic if embolic

Splanchnic: hepatic vein

Fulminant liver failure: acute liver failure, encephalopathy, ascites, portal hypertension

MPN; PNH; APLA; IBD; cancer

Acute: consider thrombolysis, TIPS; indefinite anticoagulation

Upper arm: brachial, axillary, cephalic, axillary - NOT basilic

Pain, erythema, swelling

Majority provoked (ie. catheter) Unprovoked: “effort” thrombosis ie thoracic outlet syndrome

Duration: 3-6 mns Thoracic outlet: vascular surgery

ISTH Anticoagulant therapy for splanchnic vein thrombosis; ASH Treatment of unusual thrombotic manifestations

58

Hypercoaguable States Thrombophilia

Population prevalence

Mechanism

Relative risk first VTE

Relative risk recurrent VTE

Factor V leiden (FVL)

Caucasian 5% (hetero); 0.060.25% (homo)

Resistance to inactivation by protein C

3-5

1.4

Prothrombin gene mutation

Caucasian 3% (hetero); 65 Score 0-1 – Outpatient Score > 2 – Likely needs admission Bauer et al, 2006 Mandell LA et al, 2007

33

CAP – Pathogens • Common pathogens: – – – – –

S. pneumoniae (most common) M. pneumoniae C. pneumoniae H. influenzae Respiratory viruses (Influenza, RSV, parainfluenza, rhinovirus, adenovirus, coronaviruses…)

• Severe disease – Legionella pneumophila

• In patients with increasing comorbidities, antibiotic and hospital exposures: – Increasing gram negatives e.g. K. pneumoniae, Pseudomonas (PsA) – S. aureus (including MRSA) • post-influenza pneumonia

• Travel (Always ask in respiratory syndromes!) – Influenza, COVID-19 most common – Legionella (including non-pneumophila species) – MERS and other emerging viruses – need to be aware of outbreaks – TB, Coccidiomycosis, Histoplasmosis if right epi – Less common: Hantavirus, Q fever, parasitic 34 infection

CAP – Diagnostics IDSA/ATS CAP 2019 Guidelines: - Do not obtain sputum or blood C&S on outpatients (yield low) - Consider for inpatients if severe CAP / intubated/ being treated empirically for MRSA or Pseudomonas

- Consider urine pneumococcal + legionella Ag +/- lower tract Legionella NAAT in severe CAP or when indicated by epidemiological factors (e.g. outbreak) - Send rapid influenza molecular assay (NAAT) when influenza virus is circulating in community - In severe CAP or immunocompromised patients, can also send NAAT for non-influenza viruses ** Not included in 2019 guidelines, but current standard of care would include COVID-19 PCR

- Do not send procalcitonin levels to distinguish between viral and bacterial pathogens 35

CAP – Outpatient Treatment • Healthy outpatients without comorbidities or risk factors – Amoxicillin 1 g TID (strong, moderate) – Doxycycline 100 mg BID (conditional, low) – Azithromycin 500 mg and then 250 mg (or Clarithromycin) - only in areas with pneumococcal resistance < 25% (conditional, moderate) • Not appropriate for majority of Canada

• Outpatients with comorbidities (chronic heart, lung, liver, renal, diabetes, alcoholism, malignancy, or asplenia) – Amox-clav OR Cephalosporin (Cefpodoxime, cefuroxime) PLUS macrolide (strong, moderate) OR Doxy (conditional, low) – Resp FQ ie. levofloxacin/moxifloxacin(strong, moderate) • Adds additional coverage for H. flu and M. catarrhalis (both produce beta-lactase frequently) and as well provides coverage for S. aureus and gram negatives, which are particularly high risk in COPD

36

CAP – Inpatient Treatment • Inpatients, non-severe, without risk factors for MRSA or PsA – Beta-lactam (CTX, amp-sulbactam, cefotaxime, or ceftaroline) PLUS Macrolide (strong, high). • Beta-lactam + Doxy is a third line option as alternative if unable to macrolide or FQ (conditional, low), but this is not first line because legionella has higher rates of resistance to doxycycline than Macrolide or FQ

– Resp FQ (levofloxacin, moxifloxacin)

• Inpatients, severe CAP, without risk factors for MRSA or PsA – Beta-lactam PLUS Macrolide (strong, moderate) – Beta-lactam PLUS Resp FQ (strong, low) • Evidence that macrolide containing combination had lower risk of death, and evidence that combination of beta-lactam and Resp FQ had higher mortality (but poor quality evidence/small number of observational trials)

• Aspiration Pneumonia – recommend AGAINST adding empiric anaerobic coverage unless empyema or abscess present (conditional, low quality) 37

CAP – Other

Mandell et al, 2007 Uranga et al, 2016 Siemieniuk RAC et al, 2015

Consider MRSA coverage based upon local risk factors – Vancomycin 15 mg/kg IV q12h or linezolid 600 mg q12h – Consider severe post-influenza pneumonia, mechanical ventilation/ICU, significant recent antibiotic

Consider Pseudomonas coverage based upon locally validated risk factors – Pip-Tazo or Cefepime 2g q8h or Ceftaz 2g q8h or Aztreonam or Meropenem 1g q8h – Usually recent mechanical ventilation OR prior isolation of organism.

Transition to PO

– Hemodynamically stable, improving, tolerated PO/absorbing from GI

Duration of Treatment

– 5 days if afebrile x 48 hrs with ≤ 1 sign of CAP clinical instability (HR>100, RR>24, SBP10% resistance to base drug, or if risk factor for Pseudomonas resistance

• • • •

Ceftazidime/Cefepime/PipTazo/Mero/Imipenem Ciprofloxacin/Levofloxacin Aminoglycoside (less preferred) Colistin (less preferred)

*Unreliable Pseudomonas coverage, never use for targeted Tx

Generally, duration of antibiotics = 7 days Kalil et al, 2016

40

Flu and Covid cannot be differentiated clinically

Influenza

Who to Test? •

•

When Influenza is circulating in community: – Symptomatic outpatients if will influence treatment – All inpatients with acute respiratory illness When influenza is not circulating: – Symptomatic inpatients with epidemiologic link to influenza case – Consider in high-risk patients with acute respiratory symptoms

Who to Treat? • •

Any patient hospitalized with influenza Any Outpatients with severe/progressive illness or risk factors – >65, pregnant or 2 weeks post-partum, immunocompromise, comorbidities

•

Consider in other outpatients 65 Pregnancy Immunocompromise Obesity Smoking Diabetes Heart Disease/ HTN

• • • • • • •

Chronic Lung Disease Cerebral Palsy Intellectual Disability Sickle Cell Disease CKD Liver Disease Mental Health Disorders

Complications: ARDS, myocarditis, CM, myocarditis, cytokine storm, shock, AKI, thrombosis, multisystem-inflammatory syndrome 44

BONUS Read on own

COVID-19 – Infection Control PHAC Guidelines Last Updated 2021 (Each Province has own)

Avoid nebulized medications (increased airborne spread) Droplet + contact isolation + Respirator Ventilation is a key factor in infection control COVID Positive patients in hospital should be on precautions for a minimum 10 days or until symptoms improving (may differ between hospitals) • High risk exposures (unvaccinated persons with close, prolonged contact with a positive patient without appropriate precautions): PHAC recommend isolation for 14 days (not updated) • Low risk exposures (vaccinated persons or using appropriate precautions): monitor for symptoms for 14 days but do not require isolation • • • •

PHAC Coronavirus disease (COVID-19): Guidance documents https://www.canada.ca/en/public-health/services/diseases/2019novel-coronavirus-infection/guidance-documents.html#hp 45

COVID-19 Therapies in Mild Illness Different Guidelines with different recommendations!

Treatment Options •

To reduce risk of hospitalization; no evidence for reducing symptoms burden or duration

• •

Studies in unvaccinated high-risk patients; limited evidence in other patients Generally recommended in high-risk patients but definition varies between guidelines –

Severe immunocompromise (Active cancer treatment, HSCT or CAR-T, primary immunodeficiency, advanced HIV, high dose steroids, transplant, TNF-inhibitor or immunosuppressive biologics)

– – –

Unvaccinated Pregnant Patients* Long-Term Care (variable recommendations) Other patients dependent on age, vaccine status and comorbidities (Obesity, Diabetes, heart disease, lung disease, intellectual disability, sickle cell, kidney disease, liver disease)

Nirmatrelvir/Ritonavir 300/100mg BID x 5 days *Start within 5 days Remdesivir 200mg IV x 1 day followed by 100mg daily x 2 days *Start within 7 days Variably Recommended Therapies: Budesonide, Fluvoxamine, Molnupiravir, Convalescent Plasma

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 COVID-19 Science Table (April 2022) Clinical Practice Guideline Summary: Recommended Drugs and Biologics in Adults Patients with COVID-19 BC Clinical Practice Guide for the Use of Therapeutics in Mild-Moderate COVID-19 *remdesivir in pregnancy – if immunocompornise or unvaccinated, caution re lack of data on safety *Molnupiravir contraindicated in pregnancy (animal studies showing harm)

46

Nirmatrelvir/Ritonavir

Ontario COVID-19 Drugs and Biologics Clinical Practice Guidelines Working Group on behalf of the Ontario COVID-19 Science Advisory Table and University of Waterloo School of Pharmacy https://doi.org/10.47326/ocsat.202 2.03.58.3.0

• Requires Dose adjustment for CKD and cannot be used in severe liver disease • Many Many Drug Interactions: always check with pharmacy – Amiodarone contraindication – Many statins and antihypertensives need to be held or dose adjusted – Rivaroxaban cannot be coadministered; Apixaban, Edoxaban and Dabigatran can be given at a reduced dose 47

BONUS Read on own

COVID-19: Therapies

MODERATE (Low Flow Oxygen)

SEVERE (IMV, ECMO)

Dexamethasone 6mg PO daily x 10 days

Dexamethasone 6mg PO daily x 10 days

Remdesivir 200mg x 1 then 100mg daily x 4

Immunomodulators (one of): • Tocilizumab • Baricitinib • Sarilumab

Immunomodulators if not improving (one of): • Tocilizumab • Baricitinib • Tofacitinib • Sarilumab NOT RECOMMENDED: Antibiotics, Colchicine, IFN, Vitamin D, Hydroxychloroquine, Ivermectin, Lopinavir/ritonavir, Casirivimab+imdevimab or sotrovimab, Ivermectin, Famotidine, Anakinra

48

BONUS Read on own

COVID-19 Vaccines (NACI Guidance) Type of vaccine

Age

Primary Series

Side effects

Janssen (Johnson & Johnson)

Viral vectorbased

18+

1 dose

Local site reactions and systemic S/E VTE, capillary leak syndrome, GBS, anaphylaxis

Moderna Spikevax (Original, Bivalents, XBB.1.5)

mRNA

6m+

2 doses 4-8 weeks apart

Local site reactions and systemic S/E

Pfizer-BioNTech Comirnaty (Original, Bivalents)

mRNA

6m+

2 doses 3-8 weeks apart

myocarditis/pericarditis, Bell’s palsy, anaphylaxis

Novavax Nuvaxovid

Protein subunit

18+

2 doses 3-8 weeks apart

Local site reactions and systemic S/E

• •

Unvaccinated Individuals >5 should be immunized with a primary series of mRNA vaccine For vaccinated individuals: Booster dose if >6 months from last vaccine dose or known COVID infection

– Particularly: Age >65, LTC or congregate living, high risk comorbidities, pregnancy, Indigenous, Racialized communities, providers of essential community services Contraindications to COVID-19 vaccine: Severe allergic reaction – Current Vaccine is XBB.1.5 mRNA vaccine Canadian Immunization Guide

(anaphylaxis) or immediate allergic reaction to any ingredient (ie polyethylene glycol), severe or immediate allergic reaction after first dose. 49

MCQ 2 - 2024 An 80yM with mild dementia is referred from his LTC facility to ER due to progressively worsening respiratory symptoms for the past 5 days. There is an influenza outbreak at his facility. He is currently requiring 2L of oxygen via nasal prongs. His CXR does not show a focal consolidation. He has normal kidney function. What is the most appropriate treatment? a) Moxifloxacin 400 mg po daily b) Amoxicillin-Clavulanic acid 875 mg BID + azithromycin 500 mg po daily c) Ceftriaxone 1g IV q24h + Oseltamivir 75mg PO BID d) Oseltamivir 75mg PO BID All Patients hospitalized with suspected or confirmed influenza should receive antivirals regardless of symptom duration. Since there is no signs of bacterial infection or severe illness, it is reasonable to forego antibiotic coverage

50

5. Infectious Diarrhea References: • Shane AL, Mody RK, Crump JA, et al. Infectious Disease Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis 2017;65(12):e45-80. • Loo VG, Davis I, Embil J, et al. Association of medical microbiology and infectious disease Canada treatment practice guidelines for Clostridium difficile infection. JAMMI 2018. 3.2, 71-92. • Johnson et al IDSA & SHEA 2021 Focused Update Guidelines on Management of Clostridioides difficile infection in adults. CID, Volume 73, Issue 5, 1 September 2021, Pages e1029-e1044 , https://doi.org/10.1093/cid/ciab549 • Kelly et al. ACG Clinical Guidelines: Prevention, Diagnosis and Treatment of Clostridioides difficile Infections Am J Gastroenterol 2021;116;1124-1147. https://doi.org/10/14309/ajg.0000000000001278 51

Diarrhea: Diagnosis • Stool cultures for Salmonella, Shigella, Campylobacter, Yersinia, STEC in patients with diarrhea AND: – Fever – – – –

Bloody or mucoid stools Severe abdominal pain Sepsis Immunocompromise or outbreak exposure

– (V. Cholerae in large volume rice water stools)

• C. difficile testing in patients with:

• Blood cultures in patients with: – Immunocompromise – Sepsis – Suspicion of enteric fever

• Stool for Ova and Parasites in patients with: – Diarrhea ≥ 14 days – Immunocompromise e.g. HIV – Travel – *Increased yield if ordered daily x 3 days* – Repeat up to 3x to increase yield if high suspicion

– Recent antibiotics – Work in healthcare/LTC or prison – Compatible syndrome – IBD flare 52

Diarrhea - Treatment • Empiric therapy in adults with bloody diarrhea not recommended UNLESS:

1. Sick immunocompetent patients with bacillary dysentery (frequent scant bloody stools, abdominal pain, tenesmus, fevers), suggestive of Shigella 2. Recent travel with high fever (≥ 38.5) and/or sepsis 3. Sick immunocompromised patients

Ciprofloxacin

Azithromycin

• Empiric antibiotic choice: ciprofloxacin or azithromycin • May use loperamide; caution if bloody stool, fever

53

Diarrhea – Treatment • Modified treatment for specific pathogens (while awaiting sensitivities): Indication

Campylobacter

First Choice

Azithromycin

Alternative

Ciprofloxacin

S. enterica typhi or Ceftriaxone OR ciprofloxacin paratyphi

Ampicillin OR TMP-SMX OR azithromycin

Shigella

Azithromycin OR ciprofloxacin OR ceftriaxone

TMP-SMX OR ampicillin

Vibrio cholerae

Doxycycline

Ciprofloxacin, azithromycin, or ceftriaxone

Yersina enterocolitica

TMP-SMX

Cefotaxime or ciprofloxacin

Non-typhoidal S. enterica, STEC (inc. O157)

Not indicated

N/A

54

C. difficile Infection (CDI) Diagnosis • Testing: – Stool toxin test - combinations • EIA for GDH, toxin • NAAT PCR for toxin – Pseudomembranes on colonoscopy

• Clinical Syndrome: – Unexplained new-onset ≥3 unformed stools in 24 hours • C. difficile colonization: Positive C. diff stool test in absence of clinical syndrome

• Criteria for severe C. difficile: – WBC > 15 OR serum Cr 1.5 x premorbid level – Other risk factors: Age > 65, immunosuppression, T > 38, Albumin < 30 • Fulminant C. difficile: – Sepsis, Shock, Ileus, perforation, toxic megacolon (colon dilation >6cm) Johnson et al. CID 2021 Loo et al. JAMMI 2018

C. difficile Infection First Episode Treatment • Determine colonization vs infection (based on clinical picture) • STOP non-essential antibiotics! Stop PPI if not needed! No evidence for probiotics. • Fidaxomicin similar response but less recurrence after 1st episode, but expensive (not often covered) Disease

Therapy

1st episode Fidaxomicin 200 mg PO BID x 10d (non-fulminant) Vancomycin 125mg PO QID x 10d (10-14d for AMMI)

Metronidazole 500mg PO TID x 1014d (non-severe only) 1st episode (Fulminant)

Recommendations First line: IDSA, ACG Alternative: AMMI First line: ACG, AMMI Alternative: IDSA First line: ACG in low-risk pts Alternative: IDSA, AMMI

Vancomycin 500 mg PO/NG QID + IV IDSA, ACG, AMMI metronidazole 500 mg Q8H +/- PR vancomycin

For paralytic ileus or bowel in discontinuity

+/- Total colectomy Johnson et al. CID 2021 56 Kelly et al ACG 2021

Johnson et al. CID 2021 Kelly et al ACG 2021

C. difficile Infection Recurrence Treatment Disease

Therapy

Notes

First relapse (Within 3 months of previous infection)

Fidaxomicin 200mg PO BID x 10d OR BID x 5d then q2d x 20d

First Line: IDSA, ACG, AMMI (if severe) Alternative: AMMI (if mild)

Vancomycin Taper + Pulse

First Line: ACG Alternative: IDSA

Vancomycin 125mg PO QID x 10d (14d)

First Line: AMMI Alternative: IDSA

Metronidazole 500mg PO TID x 10-14d

Alternative: AMMI (if non-severe)

Bezlotoxumab 10mg/kg IV x 1

Adjunctive: IDSA, ACG (if risk factors)

Fidax 200mg PO BID x 10d OR BID x 5d then q2d x 20d

First Line: IDSA

Vancomycin Taper + Pulse

First Line: IDSA, AMMI

Vanco 125mg PO QID x 10d then Rifaximin 400mg x 20d

First Line: IDSA

Bezlotoxumab 10mg/kg IV x 1

Adjunctive: IDSA, ACG

FMT (≥3 episodes)

IDSA, ACG, AMMI

Oral Vancomycin Suppression

ACG (if high risk and ongoing abx; 57 unable to have FMT, relapse after FMT)

≥2nd relapse Risk factors for recurrence •

Recurrent CDI in last 6m

• • •

age>65 Immunocompromised severe CDI on presentation

6. Intraabdominal Infections (IAIs) • Adequate source control is #1 principle of management

– Percutaneous if possible, laparotomy otherwise. – Collections 3cm or smaller can be attempted to be managed with antibiotics alone

• Initial antimicrobial coverage

– Community-acquired, no previous hospitalization (E. coli, B. fragilis) -> Ceftriaxone or ciprofloxacin PLUS metronidazole (OR Amox-Clav) – Healthcare-associated or critically ill (Pseudomonas coverage) -> Piptazo, meropenem, ceftazidime OR cipro PLUS metronidazole • Enterococcal coverage for healthcare-associated or severe biliary infection, immunocompromise, post-operative infection or intravascular prosthesis/valvular heart disease. (Amox-Clav, PipTazo, Imipenem, Vanco)

– Targeted antifungal coverage recommended for severe or nosocomial IAI if Candida isolated from intraabdominal or blood cultures. Empiric coverage otherwise dose not improve mortality.

• STOP-IT Trial (2015): If source control achieved, 3-5 days of antibiotics has similar outcomes to continuing until 2 days after resolution of fever, leukocytosis, and ileus. AMMI Canadian practice guidelines for surgical intra-abdominal infections (2010) 58 STOP-IT trial (2015)

7. Genitourinary Infections References: • Gupta, K et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. (2011) 52 (5):e103-e120.doi: 10.1093/cid/ciq257 • Nicolle, L et al. Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the IDSA. Clin Infect Dis. (2019) 69(10):e83-110 • Blondel-Hill, E et al. AMMI Canada position statement on asymptomatic bacteriuria. AMMI Canada Position statement. JAMMI (2018) 3(1) doi:10.3138/jammi.3.1.02 59

UTI – Diagnosis

BONUS Read on own

• Clinical diagnosis, supported by urinalysis, culture +/- imaging – – – –

Cystitis Symptoms: Dysuria, suprapubic pain, frequency, hematuria Pyelonephritis Symptoms: Fever, chills, flank pain, nausea/vomiting Cloudy, smelling urine is NOT a symptom of UTI Delirium without other symptoms is not considered symptomatic UTI

• Uncomplicated ONLY if simple cystitis in non-pregnant woman with no urinary tract abnormalities OR catheter/instrumentation • Do NOT treat asymptomatic bacteruria UNLESS: – Pregnant – Urologic procedure with mucosal transection

60

UTI – Empiric Treatment Syndrome

First Line Treatment

Alternatives

Acute Simple Cystitis

Nitrofurantoin 100mg BID x 5 days

Ciprofloxacin 250mg BID x 3 days

TMPSMX 1 DS BID x 3 days

Levofloxacin 250mg daily x 3 days

Fosfomycin 3g PO X 1

Amox-Clav 500/125mg BID x 5-7 days

Huttner et al. JAMA 2018 • Nitrofurantoin TID v. Fosfomycin for uncomplicated UTI • 28d resolution: 70% v. 58%, p=0.004 • AEs comparable • Bottom line: Prefer Nitrofurantoin

Cephalexin 250-500mg QID x 5-7 days

Complicated UTI OR Pyelonephritis (Oral)

Ciprofloxacin 500mg x 7 days

Complicated UTI OR Pyelonephritis (IV)

Base on local antibiogram

Pip-Tazo 3.375g q6h if history of resistance

Ceftriaxone 1g q24h

Carbapenem if history or resistance

Amox-Clav 875/125 mg BID x 10-14 days

TMPSMX 1 DS BID x 7-14 days

Ciprofloxacin 400mg BID Gentamicin +/- Ampicillin

61

BONUS Read on own

• • • •

Prostatitis

E. coli, Other Enterobacteriaceae, Pseudomonas Occasionally Enterococci, S. Aureus Do not treat if asymptomatic unless elevated PSA, planning for biopsy or infertility Acute: fever, dysuria, pelvic pain, tender and edematous prostate – Obtain urinalysis + culture prior to abx – Abx – empiric piptazo, 3rd gen ceph, FQ – Duration 2-4 weeks

• Chronic, bacterial: Subtle. Recurrent UTIs, obstructive symptoms. – Ucx with prostatic massage – Abx – FQ or TMPSMX based on susceptibility – Duration 4-6 weeks if FQ, 8-12 weeks if other abx Can Urol Assoc J 2011;5(5):306-15; DOI:10.5489/cuaj.11211 62

8. Sexually Transmitted Infections (STI) References: • CDC (July 23, 2021)Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Vol. 70 No. 4 https://www.cdc.gov/std/treatment-guidelines/default.htm • Public Health Agency of Canada. Sexually transmitted and bloodborne infections. PHAC; Ottawa (ON): PHAC; [updated 2023]. https://www.canada.ca/en/public-health/services/infectiousdiseases/sexual-health-sexually-transmittedinfections/canadian-guidelines.html

63

Gonorrhea/Chlamydia

BONUS Read on own

Neisseria gonorrhea (NG)

History Incubation 2-7 days. Rectal/pharynx infx more likely to be asymptomatic.

Men: usually symptomatic

Urethral discharge, dysuria, urethral itch, testicular pain/epididymitis, rectal pain/proctitis

Women: Often asymptomatic

Chlamydia trachomatis (CT)

Vaginal/cervical discharge, low abdo pain, dysuria, dyspareunia, rectal pain/proctitis

Incubation ~2-6 weeks after infection. May persist for months if untreated 50% of Men and 70% of women are asymptomatic Genital infection symptoms similar to gonorrhea above LGV More invasive

Investigations NAAT/Culture from appropriate anatomical site -

Urine Cervical swab Rectal Swab Pharyngeal swab

For DGI: -

Screen ALL exposed sites (above) AND all disseminated sites E.g. Synovial Fluid/Blood culture +/- pustule swab

*Culture preferred for resistance testing.

NAAT from appropriate specimens -

Urine Cervical swab Rectal Swab Pharyngeal swab

Complications M: Urethral strictures with fistulas, epididymitis (Chlamydia > gonorrhea), infertility (rare) F: PID, infertility, ectopic pregnancy, Fitz-Hugh-Curtis syndrome Both: Re-infection, reactive arthritis, DGI = arthritis, dermatitis, endocarditis, meningitis (more common in pregnant women or MSM), increased risk of HIV

Send specimen for genotyping if concern for LGV (e.g. rectal infection)

64

Gonorrhea/Chlamydia Treatment Gonorrhea

Anogenital or Pharyngeal: PHAC 2021

Anogenital or Pharyngeal: CDC 2021

Other:

Ceftriaxone 250mg IM x 1 (Alt: Cefixime 800mg PO x 1)

Ceftriaxone 500mg IM x 1

For DGI: Ceftriaxone 1-2g IM/IV q24h x 7 days

PLUS

(Doxycycline added only if Chlamydia cannot be ruled out)

Azithromycin 1g PO x 1 (Alt: Doxycycline 100mg PO BID x 7d)

Chlamydia

Azithromycin 1g PO x 1 OR Doxycycline 100mg PO x 7 days

Doxycycline 100mg PO BID x 7d (Alt: Azithromycin 1g PO x 1)

Notes: 1) CDC changed preferred treatment in 2021, PHAC continued with previous treatment recommendations 2) Doxycycline contraindicated in pregnancy (azithro is OK) 3) Test/Treat partner! 4) Counsel patient to abstain from sex x 7d AND partner treated

TOC of cure 2 weeks after treatment for all infections (PHAC)

For LGV: Doxycycline 100mg PO BID x 21 days Indications for TOC (3-4w after treatment) : - LGV - Unclear compliance - Alternative regimen - Pregnancy 65

Syphilis Stage

Manifestations

Treatment

Primary (3 weeks, up to 90d)

Painless chancre, regional LN

PRIMARY, SECONDARY, EARLY LATENT: Benzathine penicillin G 2.4 mU IM x 1

Secondary (12w - 6 months)

Fever, malaise, rash, alopecia, uveitis, meningitis, LN, hepatitis, arthralgias, condylomata lata

Latent Early (< 1 year) Late (> 1 year), or unknown duration

Positive serology No clinical manifestations

ALTERNATIVE (limited evidence): Doxycycline 100mg BID x 14d Ceftriaxone 1g IM/IV x 10d •

•

LATE LATENT or UNKNOWN DURATION, TERTIARY SYPHILIS: Benzathine penicillin G 2.4 mU IM weekly x3

ALTERNATIVE: Doxycycline 100mg BID x 28d Ceftriaxone 1g IM/IV x 10d *if carefully monitored* •

•

Tertiary Neurosyphilis can occur at any stage! Asymptomatic, meningitis, otic symptoms, headaches ocular symptoms, ArgylRobertson pupil, dementia…

1. Cardiovascular • Aortitis 2. Gummatous 3. Late neurosyphilis • Tabes dorsalis • General paresis

NEUROSYPHILIS Aqueous penicillin 4mU q4 hours IV x 14 days

ALTERNATIVE: Preferably desensitize Ceftriaxone 1-2g IM/IV x 10-14d *With specialist* •

•

For PCN allergy, consider desensitization for: **Pregnancy**, Neurosyphilis

66

Syphilis Test Interpretation (Reverse Algorithm) •

TT = Treponemal test (immunoassays, TPPA, FTA-ABS) – Specific antibody against T. pallidum, persist over lifetime

•

NTT = Non-treponemal tests (VDRL, RPR)

• • • •

Indications for LP: Neurologic, ocular, or auditory symptoms Inadequate serologic response to treatment Tertiary syphilis (HIV with CD4 < 350 or RPR >1:32 maybe)

– Non-specific antibody released during infection

Clinical history and past results is important for test interpretation!

Screening CMIA (TT)

Confirmatory RPR (NTT)

Confirmatory TPPA (TT)

Interpretation

-

Not Done

Not Done

Negative or early incubating syphilis

+

-

-

False positive early infection, late latent/tertiary, previously treated

+

+

-

+

-

Indeterminate

+

+

Indeterminate

+

-

+

Previously treated, early infection, late latent/tertiary

+

+

+

Current or previously treated infection

Inconclusive, repeat

67

Extra STIs

BONUS Read on own

Notes

Treatment

M. Genitalium

Persistent or recurrent urethritis/cervicitis with negative G/C NAAT

Azithromycin 500mg PO x 1 then 250mg daily on day 2-5 Moxifloxacin 400mg PO daily x 7 days

Chancroid (H. ducreyi)

Painful ulcer with granulomatous base that bleeds, painful inguinal LN

Azithromycin 1g PO X 1, CTX 250mg IM x1, or Ciprofloxacin 500mg PO BID x 3d

LGV (Chlamydia)

Serovars (L1-L3) are more invasive; painful LN, hemorrhagic Doxycycline 100mg PO BID X 21d; proctitis Rx partner(s)!

Genital HSV

HSV-1/2, painful vesicles/ulcers with prodrome (itch/tingling/burning)

Acyclovir, valacyclovir, famciclovir

Anogenital warts (HPV)

Strains 6,11; asymmetric, polymorphic lesions

Spontaneous resolution; consider imiquimod/cryotherapy. VACCINE!

Trichomonas vaginalis

Vaginal pH > 4.5; neg whiff; yellow, frothy discharge; “strawberry cervix”

Metronidazole 2g PO X 1 dose (M) OR 500mg PO X 7 days (F); Rx partner(s)!

Vulvovaginal candidiasis

Vaginal pH < 4.5; neg whiff; wet mount with 10% KOH – budding yeast

Clotrimazole, miconazole cream OR Fluconazole 150mg PO X 1 dose

Bacterial vaginosis

Vaginal pH > 4.5; pos whiff; clue cells on gram stain; fishy odor

Metronidazole 500mg PO BID X 7days OR 0.75% (5g) application PV x 5 days 68

9. Skin and Soft Tissue Infections References:

• Stevens DL, Bisno AL, Chambers HF, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. Clin Infect Dis 2014.

• Canadian Immunization Guide http://www.phac-aspc.gc.ca/naci-ccni/ • Public Health Agency of Canada. Guidelines for the Prevention and Control of Invasive Group A Streptococcal Disease. CCDR 2006;32S2:1-26.

69

Skin and Soft Tissue Infections (SSTIs) PURULENT • Folliculitis: Infection of isolated hair follicle • Furuncle: Infection on hair follicle extending into dermis + SC tissue • Carbuncle: Coalescence of several infected follicles • Abscess: Collection of pus within dermis + SC tissue

NON-PURULENT • Impetigo: Most often caused by S. aureus • Erysipelas: Most often caused by GAS, infecting epidermis + dermis • Cellulitis: Most often caused by GAS, infecting epidermis + dermis + SC tissue • Necrotizing fasciitis: see later slides

Stevens DL et al, 2014

70

Managing SSTIs: Purulent • Purulent (Furuncle/Carbuncle/Abscess) – I&D and C&S should be performed

**Although 2014 IDSA guidelines suggested forgo antibiotics in mild abscesses with source control, multiple RCTs have since shown that a short course of antibiotics is associated with higher rates of cure and lower rates of recurrence (regardless of size, organism or severity).

Severity Mild

Empiric Rx Defined Rx Consider antibiotics based on clinical context**

Moderate (systemic signs of infection)

Cephalexin* or TMP/SMX or Doxycycline

Severe Vancomycin (IC, failed prior antibiotics or I&D, systemic signs of infection)

MRSA → TMP/SMX MSSA → Cephalexin MRSA → Vancomycin MSSA → Cefazolin

* Do not use cephalexin if high MRSA prevalence Stevens DL et al, 2014

71

Managing SSTIs: Non-Purulent • Non-Purulent (Impetigo/Erysipelas/Cellulitis) – Think Strep! Severity

Abx

Duration

Mild (no systemic signs of infection; no focus of purulence)

Oral cephalosporin (cephalexin)

Moderate (systemic signs of infection)

IV cephalosporin (cefazolin)

Generally 5 days, extend up to 14 if no improvement at completion (not if simply persistent redness)

* Treat predisposing trauma, tinea pedis, xerosis, lymphedema etc. ** Consider antimicrobials effective against MRSA (and streptococci) if cellulitis is associated with penetrating trauma, evidence of MRSA infection elsewhere, nasal colonization with MRSA, PWID *** If patient is severely immunocompromised, consider broadening coverage to Vanco + PipTazo OR Vanco + Meropenem/Imipenem Stevens DL et al, 2014

72

BONUS Read on own

Recurrent Cellulitis Trials

PATCH I Trial (2013) •

Oral penicillin daily for at least 1 year was effective in preventing subsequent episodes of cellulitis in patients with at least 2 episodes of cellulitis in the past 3 years

•

Patients with BMI > 33, ≥3 episodes per year, and lymphedema may have less effect

•

BOTTOM LINE: Guidelines suggest considering trial of oral penicillin if ≥3/ year DESPITE controlling other risk factors (e.g. revascularization, wound care, foot wear, compression, tinea)

Compression Stockings (2020) •

In patients with chronic leg edema and recurrent cellulitis, compression therapy was associated with reduced recurrence compared to conservative treatment

•

BOTTOM LINE: Compression therapy for patients with chronic leg edema and recurrent cellulitis as part of first line prevention measures

(Web et al, 2020)

(Thomas et al, 2013) 73

Necrotizing Fasciitis (NF)

Stevens DL et al, 2014

Erythema with systemic toxicity, gangrene/anesthesia, hard induration, hemorrhagic bullae, pain-out-of-proportion and extending beyond erythema – EMERGENT surgical inspection/debridement to rule out necrotizing process (SURGERY CONSULT – This is a surgical emergency) – EMPIRIC Abx: PipTazo + Vancomycin + Clindamycin – Consider IVIG if shock or pre-operative

CANNOT CLINICALLY DISTINGUISH TYPES!

Pathogen

Defined Abx

Additional Notes

GAS (S. pyogenes) PCN + clindamycin (TYPE 2 NF)

Usually younger, following minor trauma/bruise, may have DM/PAD/PWID, NSAIDs

Polymicrobial (TYPE 1 NF)

PipTazo + vancomycin or carbapenem

Usually older, DM, pelvic wounds

Clostridium spp.

PCN + clindamycin

Trauma-associated, Colon Ca

Vibrio vulnificus

Doxy + ceftazidime

Saltwater exposure; consider if underlying liver dz, seafood ingestion

Aeromonas hydrophila

Doxy + ceftazidime

Freshwater exposure/injury

74

Toxic Shock Syndrome (TSS): Group A Strep (and sometimes S. aureus – tampons, nasal packing)

Diagnostic Criteria: • Hypotension (sBP < 90) AND • Isolation of GAS from normally sterile site AND at least two of the following: •

– Renal impairment (Cr > 177) – Coagulopathy (plt < 100 or DIC) – Liver fx abnormality (ALT/AST/Tbili 2X Upper limit of normal) – ARDS – Generalized erythematous macular rash that may desquamate

•

• • • • • • •

Management: Contact and droplet precautions* Volume resuscitation Surgical source control (especially if necrotizing SSTI suspected) Antibiotics: Beta lactam PLUS clindamycin IVIG – limited evidence but consider if severe infection Hyperbaric O2 (HBO)–efficacy unknown Chemoprophylaxis – cephalexin x10d (clinda if PCN allergy)* *For all invasive GAS

Guidelines for prevention and control of invasive GAS disease (CCDR, 2006)

75

BONUS Read on own

SSTI Miscellaneous Exposures/Syndromes

Clinical picture

Microbiology – classic association

Diabetes

Polymicrobial, often Pseudomonas and anaerobes

Water exposure

Vibrio vulnificus (salt water), Aeromonas spp. (fresh water), M. marinum (fish tank exposure), M. fortuitum, (hot tub exposure)

Rose gardens

Sporothrix schenckii

Meat, butchers, veterinarians

Erysipelothrix rhusiopathiae

Ecthyma gangrenosum; malignant/invasive otitis externa; hot tub folliculitis; green nail syndrome

Pseudomonas aeruginosa

“Herpetic” whitlow

HSV-1, HSV-2

Burrows, pruritic and tracks seen in web spaces

Scabies

Black eschar in nasal mucosa or palate of diabetic/ elevated glucose

Mucormycosis (Rhizopus spp.) 76

10. Bone & Joint Infections References:

• Senneville É, Albalawi Z, van Asten SA, et al. IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes-related foot infections (IWGDF/IDSA 2023) [published online ahead of print, 2023 Oct 1]. Diabetes Metab Res Rev. 2023;e3687. doi:10.1002/dmrr.3687 • Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015. • Butalia S, Palda VA, Sargeant RJ, et al. Does this patient with diabetes have osteomyelitis of the lower extremity? JAMA 2008;299:806-13. • American Academy of Orthopaedic Surgeons Evidence Based Clinical Practice Guideline for Diagnosis and Prevention of Periprosthetic Joint Infections https://www.aaos.org/pjicpg Published March 11, 2019

NOTE: Septic Arthritis is covered in the RHEUMATOLOGY LECTURE** 77

Osteomyelitis Etiology • Hematogenous (more common in children [long bones] vs. adults [vertebrae]) à monomicrobial • Contiguous from SSTI, trauma, or surgery (more common in adults) à polymicrobial Patient Population

Organism

All patients Foreign body, prosthetic infection Nosocomial Diabetes Immunocompromised

S. aureus CNST, Cutibacterium acnes Pseudomonas, Enterobacterales, Candida Streptococcus, Gram negative bacilli, anaerobes Candida, Aspergillus, Mycobacterium

78

Non-Vertebral Osteomyelitis (w/o hardware) Non-hematogenous Investigations

Hematogenous Blood Cultures Appropriate Imaging CRP Bone Biopsy/OR Specimen if possible

Surgical Management

Debridement of necrotic material. Send for culture Soft tissue coverage of site of infection required for successful cure

Empiric Therapy

Usually not required. Consider if subperiosteal collection, necrotic bone, concomitant joint infection.

Ceftriaxone +/- Vancomycin (if MRSA risk factors) +/- Metronidazole (if sacral) Tailor based on organism if possible

Duration

6 weeks from last debridement if residual infection

4-6 weeks

48 hours post complete source control • •

For Diabetic Foot infection, see separate slide For periprosthetic infections, see slide on PJI 79

BONUS Read on own

Chronic Wounds

ORAL EXAM

• What type of foot ulcer is it?

– Neuropathic: Pressure points, punched out appearance, deep ulcer, minimal pain, warm and dry foot – Arterial: Lateral malleolus, dry and punctate, decreased pulses, cold and dry foot – Venous: Medial malleolus, irregular margins, shallow depth, mildly painful, venous stasis dermatitis/lipodermatosclerosis

• Is the ulcer infected?

– Pain in chronic wound (LR 11-20) – Foul odour (LR 1-3) – Purulence, exudate, erythema, warmth, and edema (LR < 1.0) 80

BONUS Read on own

JAMA: Does this patient with diabetes have OM of the lower extremity? Clinical Findings

LR+

LR-

Ulcer area > 2cm2

7.2

0.48

Positive ‘probe to bone’

6.4

0.39

Bone exposure

9.2

0.70

Investigations that may increase likelihood ESR > 70 mm/h

11

0.34

Abnormal X-ray

2.3

0.63

Role of MRI Positive MRI

3.8

0.14

- Gold standard = bone biopsy and culture - Presence or absence of ulcer inflammation (erythema, swelling, pus) does not modify probability of dz - Superficial swab cultures do not reliably predict bone microorganisms or diagnose infection Butalia S et al, 2008 81

ORAL EXAM

Diabetic Foot Infection Diagnosis: Diagnose soft tissue infection clinically • CRP +/- ESR +/- Procalcitonin if equivocal exam • Combination of probe-to-bone, plain x-rays and CRP/ESR to diagnose osteomyelitis; send MRI if diagnosis in doubt • If possible obtain samples from tissue specimen (soft tissue) or bone biopsy (osteomyelitis) for culture • •

Antibiotic Management • Agent: Select based on likely or proven causative pathogens, severity of infection, evidence of efficacy and risk of adverse effects Mild DFI

Stage using the IWGDF/IDSA classification (do not memorize!) Consider hospitalizing patients with severe infection or mod infection w/ comorbidities

Surgery and Debridement • Urgent Surgical consult if severe or moderate DFI with complications, early surgery to remove infected and necrotic tissue • •

Consider surgery in patients with osteomyelitis or PAD with ulcer, gangrene Exception: Forefoot osteomyelitis only, no PAD, no exposed bone and no need for surgery to control infection

Revascularization •

•

Obtain vascular consult for DFI w/ PAD for consideration of revascularization

Other Pillars of Multidisciplinary Management • Wound Care • •

Glycemic Control Off-loading + Foot care (Chiropodist, shoe care)

New IDSA Guideline Senneville et al, 2023

•

Mod-

Severe

DFI

No recent Abx

Aerobic GPC

(eg) Cephalexin, Septra, Doxycycline, Moxifloxacin

Recent Abx

GPC + GNB

Amox-clav, septra, moxifloxacin

No complications

GPC + GNB

Amox-clav, Ceftriaxone

Ischemia/ necrosis

GPC + GNB + anaerobes

Amox-clav, PipTazo, Ceftriaxone + Clindamycin

Macerated ulcer

GPC + GNB + Pseudomonas

PipTazo, Cephalexin + Cipro

Duration: – Soft Tissue: 1-2 wks, up to 3-4 wks if extensive/slow to resolve – Osteomyelitis: 48hrs (complete amputation), 3 weeks (amputation/resection with positive margins), or 6 weeks (no resection) Oral Stepdown 82

FYI Only : IWGDF/IDSA Diabetic Foot Infection Severity Classification

83

Native Vertebral Osteomyelitis

Berbari, 2015

•

Etiology: hematogenous seeding disc à bone

•

Microbiology: – Most common S. aureus* – Beta-hemolytic streptococci, GNB – TB, Brucella, fungi much less common

•

Risk factors: – Elderly, immunocompromised, IDU, PICC/Ports

•

Signs and symptoms: – New/worsening back pain and suggestive b/w – Fever (only 45% of patients)

•

Diagnosis: – Blood cultures (50% Pos if S. aureus), biopsy – ESR, CRP (sensitivity 94-100%) – MRI (SN 97%, Sp 93%) *If S. aureus bacteremia in prior 3 months, biopsy likely not needed

•

Treatment: – Hold ABx until biopsy result if no sepsis/neuro compromise (dx 50-60% of time with 1st bx) – Empiric: ceftriaxone + vancomycin – Duration: 6 weeks – Surgery if neuro deficits, spinal cord compression, progression/recurrence despite appropriate antibiotics

•

Follow-up: – Monitor clinically and repeat inflammatory markers – Repeat MRI ONLY if poor clinical response after ABx

84

BONUS Read on own

PJI for the Internist

Principles: 1) Make micro diagnosis. –

Empiric Abx in a scenario:

Vanco + CTX Tailor based on culture Add Rifampin for Staphylococcal

Withhold antibiotics if stable pending arthrocentesis / OR to ensure pathogen determined.

2) Surgical Management 3) Duration dependent on surgery + organism Retained Hardware

1 Stage Revision

2 Stage Revision

Staphylococcal

2-6 weeks IV followed by PO for total 6m (knee) or 3m (all else)

2-6w IV followed by PO for total 3m

4-6w IV/PO

Other

4-6 weeks IV/PO

4-6 weeks IV/PO

4-6 weeks IV/PO

PJI = Prosthetic Joint Infection

Osmon et al, 2012 85

BONUS Read on own

OVIVA Trial (2019)

• Oral versus Intravenous Antibiotics for Bone and Joint Infection. NEJM 2019 – 1054 patients with bone and joint infections randomized to IV vs. oral therapy. – Primary endpoint was definitive treatment failure within 1 year after randomization. – Treatment failure occurred in 74/506 (14.6%) of IV group and 67/509 (13.2%) of oral group showing non-inferiority. – Caveat – majority surgically managed with identified organisms and were able to use highly bioavailable oral antibiotics

Bottom Line: Highly bioavailable oral therapy can be used for bone and joint infections 86

11. HIV References: • Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. 2023. Available at https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv. • Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. National Institutes of Health, Centers for Disease Control and Prevention, HIV Medicine Association, and Infectious Diseases Society of America. 2023. Available at https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection. • Gandhi RT, Bedimo R, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2022 recommendations of the International Antiviral Society-USA Panel. JAMA. 2022; doi:10.1001/jama.2022.22246. • Thompson et al. Primary Care Guidance for Persons With Human Immunodeficiency Virus: 2020 Update by the HIV Medicine Association of the Infectious Diseases Society of America. CID. 2020; DOI: 10.1093/cid/ciaa1391

• Wood E, Kerr T, Roswell G, et al. Does this adult patient have early HIV infection? JAMA 2014;312:278-85. • Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States. Department of Health and Human Services. 2023. Available at https://clinicalinfo.hiv.gov/en/guidelines/perinatal. 87

ORAL EXAM

Approach to the New HIV Diagnosis 1.

Stage the HIV Infection q q q q q

2.

Confirm positive test CD4 count/OI screen Viral load (RNA) Genotype (resistance) Tropism testing (CCR5)

q

4.

q q q q

q Prophylaxis / Treatment Depending on CD4 count

3.

Assess for Co-Infections

TB: TST/IGRA, CXR (active pulmonary TB) q Serologies q CMV IgG q Toxoplasma IgG q Hepatitis B/C serology

q

q

•

5.

6.

Hepatitis A (only at risk)

Hepatitis B (if non-immune) Annual influenza + COVID HPV PCV-13 then PPV-23 eight weeks later (Hib, meningococcus)

Initiate ARV q q q

Immunizations q

Assess for Opportunistic Infx (OI)

STI and sexual health: q Syphilis screen q Chlamydia, gonorrhea NAATs +/- cultures q Pap test (cervical) +/anal

7.

Drug safety screening: HLA-

B5701 (ABC hypersensitivity), G6PD level ASAP ARV start (see slides) Side effects of therapy

Follow-up & Counselling q q q q

Prognosis Safe Sex, U=U HIV in pregnancy Duty to disclose HIV status

*Caution with live vaccines (varicella, VZV, MMR) if CD4 < 200

Assess general health q q q

CBC, lytes, Cr, PO4 Non-fasting lipids/gluc Urinalysis/ BHCG

Thompson et al, 2020 AIDS Info Guidelines, 2023 Ghandi et al 2020

88

BONUS Read on own

ORAL EXAM

BONUS: JAMA: Does this patient have early HIV infection? (*check out our 2015 video demonstrating this exam online!*)

• Primary HIV infection (Acute retroviral syndrome) → fever, nausea, emesis, weight loss, arthralgia/myalgia, pharyngitis, oral ulcers, rash and LN

***Limited utility of clinical examination to detect or rule out early HIV infection highlights the importance of routine testing for HIV infection among adults (current recommendation is yearly screening for all adults, although practically this is not done)

Clinical Findings

LR+

LR-

Symptoms that increase likelihood Genital ulcers

5.4

Weight loss

4.7

Vomiting

4.6

Swollen LNs

4.6

Fever

3.4

0.74

Physical exam signs that increase likelihood Presence of lymphadenopathy

3.1

0.70

Wood et al, 2014 89

HIV – Initiation of ARV Assess readiness for treatment ARV recommended for all individuals with HIV, regardless of CD4 count to reduce morbidity and mortality associated with HIV infection • ARV regimen should include TWO (sometimes one) NRTIs PLUS INSTI OR NNRTI OR PI

• •

First Line Therapy: • Bictegravir/tenofovir alafenamide/emtricitabine • Ø Ø Ø

Dolutegravir PLUS: Tenofovir alafenamide/emtricitabine Tenofovir disoproxil fumarate/emtricitabine Tenofovir disoproxil fumarate/lamivudine

Tenofovir alafenamide (TAF) has fewer bone and renal toxicities, whereas tenofovir disoproxil fumarate (TDF) is associated with lower lipid levels and lower cost

• Dolutegravir/lamivudine *with caveats* • (Dolutegravir/Abacavir/Lamivudine *with caveats*) AIDS Info Guidelines, 2023 Ghandi et al. 2020

90

BONUS Read on own

HIV – Opportunistic Infections

91

HIV – OI Primary Prophylaxis (1) CD4

OI

200 for at least 3 months 92

HIV – OI Primary Prophylaxis (2) CD4

OI

Preferred

Alternative

30 Oral lead in to assess tolerability is optional, no longer mandatory Injection site reactions common and decrease over time Injectable Cabotegravir for PrEP not yet approved in Canada 101

12. Tuberculosis and non-tuberculous mycobacteria References: • Canadian TB Standards – 8th Edition (2022). – Covers diagnosis and treatment for both latent and active TB

• www.tstin3d.com – Great tool to assist in determining likelihood of latent TB based upon TST/IGRA results, epidemiology and BCG status

• IDSA Guidelines for a) Diagnosis and b) Treatment – 2016 – NOTE: IDSA published a guideline for Multi-Drug Resistant Tb Nov 2019 – this is beyond scope of GIM exam – first line of guideline states they recommend if MDR-Tb suspected to “consult with a Tb expert!”

• http://bcgatlas.org – Determining likelihood of BCG vaccination based on geographic origin 102

MCQ 3 - 2024 You are in clinic seeing a 37-year-old nurse who recently immigrated from Zimbabwe where he worked in the TB ward. He was referred by occupational health because his TB skin test is positive, confirmed with positive IGRA. There is no evidence of active tuberculosis. He is an active smoker but has no other medical history or medications. What do you recommend? A. Isoniazid+B6 daily x 9 months B. Isoniazid+B6 daily x 6 months C. Rifampin daily x 4 months D. No therapy 103

TB Exposure Risk Primary disease Exposure to transmissible TB with infection

Pulmonary disease

(5%) Latent TB

Reactivation of TB

(95%)

(5%)

Updated Terminology:

Extra-pulmonary disease

No disease (95%)

Latent TB = TB Infection Active TB = TB Disease

104

Latent TB – Diagnosis • Two accepted tests: TST and IGRA • Neither can separate LTBI from active TB Decision to test= decision to treat – only check if high risk/occupationally indicated TST – Tuberculin Skin Test

IGRA – Interferon Gamma Release Assay

In vivo May be affected by BCG after infancy 2 patient visits Inter-reader variability Sensitivity 90%; Specificity >95% if no BCG, 60% with BCG • Cheap - use if repeat testing required • May be (-) if immunosuppressed

• • • • • • •

• • • • •

In vitro Not affected by BCG - use if prior BCG 1 patient visit - use if unlikely to return Minimal inter-reader variability Sensitivity 80-90%; Specificity >95% Often not covered ($$ to patient) May be (-) if immunosuppressed 105

Latent TB – Diagnosis Who should be tested? Those likely to be exposed and/or at elevated risk of developing TB Disease and would therefore benefit from treatment. E.g. • Contacts of active case of pulmonary TB • Immigrants from countries with high TB incidence with risk factors for reactivation • Planned future start of immunocompromising medications (e.g. chemotherapy, TNF-a inhibitors, steroids), especially if other risk factors • People living with HIV

Sometimes may also test those with elevated risk of exposure and contact with vulnerable populations e.g. healthcare workers 106

Latent TB – Diagnosis TST Result 0-4mm 5mm (higher pre-test probability)

Situation in which reaction is considered positive Generally considered negative People living with HIV Contact with infectious TB case within past two years Presence of fibronodular disease on CXR (evidence of healed, untreated Tb) Prior to Organ transplantation (ie. Immunosuppressive rx) Planned Biologic use including TNF-alpha inhibitor use or DMARDs Planned other immunosuppressive drugs (incl corticosteroids >= 15 mg per day for at least 1 mon.) Stage 4 or 5 CKD (with or without dialysis)

> 10mm

All other situations (ie. DM even if well controlled, malnutrition ( 3 drinks/d), TST conversion (within 2 years)

BOLD = Very High or High reactivation risk Underline = moderate reactivation risk

107

Latent TB – Treatment (Updated 2022) 1. Interpret TST (Positive Predictive Value) 2. Exclude active disease DRUG

3. Determine risk of re-activation 4. Consider risk of AEs

AgeDependent

SCHEDULE

DURATION

CONSIDERATIONS

Rifampin (4R)

Daily

4 Months

Rash, Drug Interactions

Rifapentine + Isoniazid (3HP)

Weekly

3 Months

Flu-like effects, drug interactions

Daily

9 Months

Hepatotoxicity, peripheral neuropathy

Isoniazid (6H)

Daily

6 Months

Hepatotoxicity, peripheral neuropathy

Isoniazid

Twice Weekly

9 Months

Hepatotoxicity, peripheral neuropathy

Isoniazid + Rifampin (3HR)

Daily

3 Months

Hepatotoxicity, peripheral neuropathy, Drug interactions

FIRST LINE REGIMENS

SECOND LINE REGIMEN Isoniazid (9H) ALTERNATIVE REGIMENS

TB Standards, 2022

108

TB DISEASE Treatment

Standard Regimen for Suspected* Drug Susceptible TB INTENSIVE PHASE (2 Months) INH

5 mg/kg (up to 300mg)

RMP

10 mg/kg (up to 600mg)

PZA

20-25 mg/kg

EMB

15-20 mg/kg

Intensive Phase = 3 or 4 active drugs for rapid killing Continuation Phase = at least 2 active drugs, duration dependent on regimen, adherence, site of infection, response

CONTINUATION PHASE (min 4 Months)

*If known susceptible, INH/RMP/PZA x 2 months followed by INH/RMP for 4 months If suspect susceptible, but no susceptibility results available, add EMB

Add B6 (pyridoxine) to prevent peripheral neuropathy *Usually start RIPE, then drop EMB once susceptibility *Add Steroids for TB meningitis or pericardial disease results return 109

Active TB - Side Effects

BONUS Read on own

Isoniazid (INH) - rash3, hepatitis2, neuropathy Rifampin (RMP) - drug interaction, rash1, hepatitis3 Pyrazinamide (PZA) - hepatitis1, rash2, arthralgia * Number implies likelihood 4 Ethambutol (EMB) - eye toxicity, rash out of all first-line TB meds Neuropathy Prevention: 50mg VitB6 in at risk patients (etoh, DM, seizure, malnutrition, HIV, CKD, all pregnant and breastfeeding women… practically most programs put everyone on b6) If neuropathy develops: 100mg daily

110

BONUS Read on own

Active TB in Pregnancy • Elevated risk of TB disease and significant associated morbidity to both woman and fetus • Risk of untreated active TB to a pregnant woman and her fetus outweighs risk of adverse effects of drugs used in its treatment • INH, RIF, EMB are considered SAFE in pregnancy, so all three should be used as initial treatment – Category C due to lack of controlled studies in pregnancy but lack track records of safety in pregnancy

• PZA added if extensive disease, smear-positive pulmonary disease, disseminated TB, intolerance of other agents – No formal studies on safety in pregnancy but no reports of teratogenicity – WHO recommends use in pregnancy

• Do not treat latent TB until after delivery unless high risk of TB reactivation, and use 4R regimen

111

Latent TB and HIV • Anyone with TB should have HIV test (and vice versa) – Significant increase in risk of reactivation, up to 5% per year (compared to 5% annually)

• Preferred regimens: – 3HP: Weekly INH + Rifapentine for 3 months – 3HR: Daily INH + Rifampin for 3 months – (Alternative: INH x 6-9 months)

* Need to adjust ART for drug interactions with Rifamycins Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic112 infectionc

Active TB and HIV • With lower CD4 counts, CXR findings are different (e.g. increased cavitation) and extrapulmonary disease is more common • Treatment is the same as for TB in HIV-negative patients • ART must be adjusted for interactions with Rifamycins – Initiation of ART in ART-Naïve Patients: • • • •

If CD4 < 50 → within 2 weeks If CD4 > 50 → within 8 weeks Pregnancy → ASAP regardless of CD4 If TB meningitis → defer for ~8 weeks given ↑ risk of IRIS (especially if low CD4 count

• IRIS: Increased risk if low CD4, high viral load, disseminated TB – Pre-emptive steroids if high risk for IRIS

• Steroids for TB meningitis* (similar to non-HIV patients) but not TB pericarditis

– *Recent small RCT suggests benefit less pronounced – many caveats (small trial, not in highly resourced countries, patients with severe immunosuppression from HIV) – on exam still give steroids for meningitis per guidelines! [NEJM 2023; 389:1357-1367] Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunisticinfectionc 113

Non-tuberculous Mycobacteria Over 190 species and subspecies: M avium complex, M. kansasii, M xenopi, M abscessus Diagnostic criteria (NTM pulmonary disease): Both clinical (pulmonary or systemic sx) AND radiologic (nodular or cavitary lesions on CXR, or CT with bronchiectasis) Plus one of: • 2 or more sputum positive for same species NTM • 1 BAL/bronch culture positive for NTM • Biopsy with mycobacterial histology (AFB/granuloma) and positive culture Treatment: Requires discussion around clinical factors, infecting species and patient priorities. • Ideally susceptibility-based therapy (not empiric) • Minimum 3-drug regimen (macrolide, ethambutol, +/-rifampicin +/- aminoglycoside)

Daley et al 2020 Treatment of NTM Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline

114

MCQ 3 - 2024 You are in clinic seeing a 37-year-old nurse who recently immigrated from Zimbabwe where he worked in the TB ward. He was referred by occupational health because his TB skin test is positive, confirmed with positive IGRA. There is no evidence of active tuberculosis. He is an active smoker but has no other medical history or medications. What do you recommend? A. B. C. D.

Isoniazid+B6 daily x 9 months Isoniazid+B6 daily x 6 months Rifampin daily x 4 months No therapy

With known contact with TB cases and active smoker, this patient has a high lifetime risk of activation, and treatment is indicated. In updated 2022 guidelines, Rifampin x 4 months is preferred treatment. (In years prior to 2023, A would have been correct answer)

115

13. Travel & Tropical Infections References

• Canadian Recommendations for the Prevention and Treatment of Malaria. An Advisory Committee Statement (ACS) committee to advise on tropical medicine and travel (CATMAT). PHAC 2020. • Taylor SM, Molyneux ME, Simel DL, et al. Does this patient have malaria? JAMA 2010;304:2048-56. • Zika Working Group on behalf of the Committee to Advice on Tropical Medicine and Travel (CATMAT). Canadian recommendations on the prevention and treatment of Zika virus: Update. March 2020.

116

MCQ 4 - 2024 You are seeing a 25 year old woman with a flare of lupus for whom course of prednisone is planned. She is originally from Thailand and immigrated to Canada 15 years ago. She has no infectious symptoms. Her rheumatologist has performed a TB skin test as well as Hepatitis B, Hepatitis C and HIV serologies. What additional testing is indicated? A. B. C. D.

No further testing is required Malaria Blood Smear Schistosoma and Strongyloides Serologies Strongyloides Serologies alone

117

Fever in Returned Traveler

BONUS Read on own

Pre-Travel

• Past medical history, medications • History of a pre-travel consultation • Travel immunizations (Hep A/B, yellow fever, typhoid, rabies, meningitis, influenza) • Adherence to malaria chemoprophylaxis

Travel • • • • •

Purpose of travel (VFR greatest risk) Itinerary (dates/locations, incl. layovers), season Type of accommodations (urban versus rural) Insect precautions taken (repellant, bed nets) Individual exposures – – – – –

raw meat, seafood, street foods, unclean water, unpasteurized dairy products Freshwater exposure (e.g. swimming, rafting) Visits to farms, slaughterhouses, funerals, hospitals Animal bites, insect or arthropod bites, hiking/caving Body fluid exposures (e.g. tattoos, sexual activity)

• Medical care while overseas

ORAL EXAM

Post-Travel • Timing of fever / clinical symptoms in relation to international travel – Short incubation periods < 2 weeks = Malaria, Dengue, Chikungunya, traveller’s diarrhea, viral URTI, influenza – Longer incubation periods > 2 weeks = Malaria, TB, hepatitis, HIV, enteric fever due to Salmonella spp. • Pattern of fever – Daily: Malaria, traveller’s diarrhea, viral RTI, enteric fever – Biphasic: Malaria, Dengue – Relapsing: Malaria, enteric fever

118

Fever in Returned Traveler Differential Diagnosis •

•

•

Infectious – Travel-related – Malaria, malaria, malaria!!! – Typhoid /enteric fever – Dengue, Chikungunya, Zika virus – Viral hepatidities – Others: Rickettsiae, Brucellosis, Leptospirosis, Q-fever, Ebola – STIs, acute HIV Infectious – Non-travel related – UTI, CAP, mono, meningitis, C. diff, influenza, COVID-19 Non-infectious (travel or non-travel) – VTE, drug fever, illicit drugs S/E

Investigations • CBC + diff, peripheral smear • Electrolytes, Cr, urea, glucose • ALT, AST, ALP, Bili, INR/PTT • Blood cultures x2, urine culture • CXR • Malaria smears x3 (over 24h) – RDT (e.g. Binax) +/- Stool C&S; Stool O&P; C. difficile +/- Dengue/chikungunya/zika PCR or serology +/- Hepatitis serology +/- HIV, STI screen +/- NP swab for viral PCR (including SARS-COV2 and Influenza)

Malaria – Diagnosis Species: • Plasmodium falciparum – Can be severe – Present within 3 months – Infects RBCs of all stages

• P. ovale and P. vivax – May present years later due to hypnozoites in liver

•

Others: – P. malariae – P. knowlesi – P. simiun

CATMAT, 2020

Diagnostic Techniques: Thick and thin blood smear x3, separated by at least 6 hours over 24 hour period - Thick smear: Looks for any parasite (sensitivity 87%) - Thin smear: Identifies parasitemia (%) and speciation by stain

Rapid detection test (RDT) Separate tests for P. falciparum and others; highest Sn for P. falciparum

120

Malaria – Severity Criteria •

•

Criteria for Severe Malaria: Essentially any end organ dysfunction

• Neurologic = confusion, prostration (severe weakness), seizures • Respiratory = ARDS, pulmonary edema • Hematologic = DIC (anemia, thrombocytopenia, elevated LDH), jaundice, hemoglobinuria à Black water fever

CATMAT, 2020

• • • • • •

Severe anemia (Hgb < 50) Hypoglycemia (glucose < 2.2) Acidosis (pH < 7.25, HCO3 < 15) Renal impairment (Cr > 265) Lactic Acidosis Hyperparasitemia – ≥5% for non-immune adults – ≥10% for semi-immune adults

If Severe: 1. Admit to ICU 2. Start tx (see following slide) 3. Supportive Care 4. Serial Glucose Checks 121

Malaria – Management

CATMAT, 2020

Severity

Species

Resistance

Treatment

Uncomplicated

P. falciparum

CS

Chloroquine

CR (most common)

Atovaquone-proguanil OR Quinine + doxycycline OR Quinine + clindamycin

CS (most common)

Chloroquine

CR

Atovaquone-proguanil OR Quinine + doxycycline

N/A

IV artesunate X 48h then PO

(can treat with oral meds)

Complicated

Unsure if CS on MCQ? Based on local epi but generally for Falciparum assume resistant and for non-falciparum assume sensitive (exception is New Guinea)

Non-falciparum spp.*

N/A

• Atovaquone-proguanil OR • Doxycycline OR • Clindamycin * If P. vivax or P. ovale, add primaquine (check G6PD level first) to treat hypnozoite stage - Repeat smears q6-12h to monitor parasitemia - If artesunate not available for complicated malaria, give IV quinine as alternative (monitor QT and for hypoglycemia) CS = chloroquine sensitive region; CR = chloroquine resistant region

122

BONUS Read on own

Malaria – Chemoprophylaxis

CATMAT, 2020

Drugs

Notes

Chloroquine/ Hydroxychloroquine

Only use in sensitive areas (e.g. Haiti, DR, central America, etc.). Weekly dosing; start 1w prior and stop 4w post. Safe in pregnancy

Atovaquone-proguanil Daily dosing; start 1d prior and stop 7d post. Insufficient data regarding use in (Malarone) pregnancy. Well-tolerated Doxycycline

Daily dosing; start 1d prior and stop 4w post. GI upset, photosensitivity. Contraindicated in pregnancy

Mefloquine

Weekly dosing; start 2-3w prior and stop 4w post. Associated with bizarre dreams and can cause severe neuro-psychiatric symptoms (sz/psychosis); QT prolongation. Safe in pregnancy; check to ensure no resistance in destination

Primaquine

Use only if others contra-indicated. Daily dosing; start 1d prior and stop 7d post Need to check G6PD level. Contraindicated in pregnancy/breastfeeding

123

BONUS Read on own

JAMA: Does This Returned Traveler Have Malaria? Clinical Findings

LR+

Taylor SM et al, 2010

LR-

Signs and symptoms (for returned travelers) Fever

5.1

0.12

Splenomegaly

6.5

0.79

Jaundice/icterus

4.5

0.91

Pallor

2.8

0.80

Hepatomegaly

2.4

0.95

Chills/rigors

1.7

0.47

Headache

1.8

0.40

Diarrhea

0.60

1.1

Cough

0.04

1.3

Laboratory findings (for returned travelers) Hyperbilirubinemia

7.3

0.65

Thrombocytopenia

5.6

0.32

124

BONUS Read on own

Some other infections to know…

Dengue (mosquito-borne)

Zika virus (mosquitoborne)

Chikungunya (mosquito-borne)

Typhoid (Salmonella typhi/ paratyphi)

Leptospirosis (animal waste à soil, water exposure)

Incubation: < 2 wks Features: fever, maculopapular rash, retro-orbital pain, myalgias (“break bone” fever), cytopenias (thrombocytopenia). Rx: supportive care; avoid NSAIDs

Incubation: < 2 wks Features: fever, rash, arthralgias, myalgias, conjunctivitis, HA, retro-orbital pain; association with microcephaly and GBS Rx: supportive care

Incubation: < 2 wks Features: fever, polyarthralgia (NOT arthritis usually), lymphopenia, maculopapular rash Rx: supportive care

Incubation: 5-21 d Features: fever, flu-like illness, salmon-coloured spots, constipation, abdominal pain, relative bradycardia Rx: IV ceftriaxone, ciprofloxacin or azithromycin *increasing resistance with FQs in SE Asia

Incubation: 2-26 d, ~10 d Features: fever, myalgias, HA, conjunctivitis, hypokalemia, cytopenias, sterile pyuria. Rare severe: jaundice + renal failure (Weil’s dz.), ARDS, pulm. Hemorrhage. Rx: Mild disease: doxycycline or azithromycin Severe: IV ceftriaxone, Penicillin or doxycycline Supportive care

125

Parasites Simplified

BONUS Read on own

Protozoa

Amoebae

Apicomplexans

Acanthamoeba • Granulomatous Amebic Encephalitis • Contact lens related Keratitis • Treatment Uncertain

Plasmodium See Malaria Slides

Naegleria Fowleri • Primary Amebic Encephalitis • Warm Fresh Water inhalation • No Canadian Cases • Fatal, No treatment

Toxoplasma See HIV slides

Entamoeba Histolytica • Luminal disease, liver abscess • Microscopy (can’t differentiate from non-pathogenic), Antigen, PCR • Paromomycin (luminal) +/Metronidazole (for systemic)

Babesia See Bonus Slides

Cryptosporidium • Fecal-oral • Self-limited diarrhea in immunocompetent • Chronic, life threatening in immunocompromise • Microscopy • Nitazoxanide • Reduce Immunosuppression

Flagellates Trypanosoma • Brucei – African Sleeping Sickness • Cruzi – Chagas (central/south America) Leishmania • Sand Fly Vector • Cutaneous ulcers, mucocutaneous and visceral forms • Can give topical treatment for mild cutaneous, Amphotericin for others Giardia • Fecal-Oral • Day-care, drinking/swimming in lake or river, MSM • Diarrheal infection • Microscopy • Metronidazole x 14d

Parasites Simplified Helminths

Flat Worms (Platyhelminths)

Flukes (Trematodes) Schistosoma Fasciola Paragonimus

Opisthorchis Clonorchis

• Microscopy: O&P x 3 from relevant site • +/- Serology • Praziquantel EXCEPT Fasciola (Triclabendazole)

Tapeworm (Cestodes) Roundworm (Nematodes) Taenia Solium Taenia Saginata

Echinococcus Diphyllobothrium

Ascaris Strongyloides Trichinella

Trichuria Enterobius Cutaneous LM

• Microscopy: O&P x 3 (stool) • Serology • Imaging for Echinococcus or Taenia solium

• Microscopy: O/P x 3 • Serology • Some (Cutaneous larva migrans) clinical diagnosis

• In gut: Praziquantel • In tissue: Albendazole • Echinococcus treatment is dependent on stage (from imaging) but can involve albendazole or surgery/ aspiration

• In gut: Mebendazole • In tissue: Albendazole (ivermectin is alternative sometimes)

Microfilaria W. Bancrofti Onchocerca

127

Blood Smear

BONUS Read on own

Helminths (worms) 101

• 1000s, many low yield for exam. Don’t waste time studying them all • Clue is eosinophilia (Helminths contained to GI tract may not have eosinophilia). • Dx with stool/urine/sputum microscopy (ova and parasites), +/- serology • Echinococcus (granulosus/multilocularis): Liver cysts, sometimes lung cysts. Diagnosed with combo imaging + serology/Antigen. Staged based on imaging, tx depends on stage but may include albendazole, aspiration, surgery or monitoring. • Schistosoma (mansoni/haematobium etc): Water/snail host, subtropical and tropical areas, chronic infection, can cause liver/bladder CA. Dx. Tx. Praziquantel • Taenia solium(pork): Can cause taeniasis (eating infected/undercooked meat), or neurocysticercosis (eating eggs). Tx neurocysticercosis with albendazole +/praziquantel +/- steroids • Trichinella spiralis (trichinosis) from eating undercooked wild animal meat (bear/pork). GI symptoms, muscle pain (cysts). Tx. Albendazole/mebendazole. https://www.cdc.gov/parasites/az/index.html 128

Strongyloides Stercoralis • From skin contact with soil in tropical and subtropical regions (e.g. walking on a beach) – assume exposure in anyone living for >1 month in endemic areas • Can cause lifelong asymptomatic infection where host continuously reinfects self • Symptomatic infection may be eosinophilia, diarrhea, itching and respiratory symptoms (may diagnose with O/P or serology) • With glucocorticoids or other immunosuppression can get disseminated disease which can cause recurrent gram-negative infections (including meningitis) and is highly fatal • Screen exposed patients with serology prior to starting immunosuppression • Treatment is Ivermectin (1 or 2 doses) 129

MCQ 4 - 2024 You are seeing a 25 year old woman with a flare of lupus for whom course of prednisone is planned. She is originally from Thailand and immigrated to Canada 5 years ago. She has no infectious symptoms. Her rheumatologist has performed a TB skin test as well as Hepatitis B, Hepatitis C and HIV serologies. What additional testing is indicated? A. B. C. D.

No further testing is required Malaria Blood Smear Schistosoma and Strongyloides Serologies Strongyloides Serologies alone Persons from tropical and subtropical regions

should be presumed to be exposed to strongyloides and screened prior to starting immunosuppression. Neither malaria or schistosoma screening is indicated in asymptomatic persons before starting immunosuppression. 130

14. Fungal Infections References:

• Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016. • Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016 Aug 15;63(4):e1-e60. doi: 10.1093/cid/ciw326. Epub 2016 Jun 29. • Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis 2008;46:1801-12. • Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-825. • Galgiani JN, Ampel NM, Blair JE, et al. 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clin Infect Dis. 2016;63(6):e112-e146. doi:10.1093/cid/ciw360

131

Species

Candidemia Fluconazole

Echinocandins

Amphotericin B

C. albicans/dubliniensis/tropicalis

S

S

S

C. glabrata

Variable**

S

S

C. krusei

R

S

S

C. parapsilosis

S

Variable***

S

C. lusitaniae

S S R Management: • Stable, no recent azole exposure → fluconazole • Unstable, neutropenic, or recent azole exposure → echinocandin • Pregnancy → amphotericin B • CNS infections à amphotericin B +/- flucytosine

Risk Factors:

Use of broad-spec antibiotics ICU admission CVC TPN Neutropenia Immunosuppressive agents (steroids, chemo, etc.) • Intra-abdominal surgical procedures • Necrotizing pancreatitis • Candida colonization x 3 sites

• • • • • •

(IV=PO)

(not for CNS/eyes)

(liposomal preferred)

**Higher rates of resistance to Fluc. When susceptible, requires higher dose ***Tends to have higher MICs to echinocandins

Remove central lines (especially if prolonged candidemia) Treat for two weeks from first negative blood culture (if no metastatic focus) * Consult ophthalmology to r/o endophthalmitis * Consider TTE or Abdo US if persistent candidemia to rule out IE 132 Pappas PG et al, 2016

Aspergillus Syndrome

Additional Details and Treatment

ABPA/Allergic Rhinosinusitis

Hyper-sensitivity response to Aspergillus allergens/precipitans Elevated IgE, asthma, brown sputum, eosinophilia, bronchiectasis Rx: Steroids/anti-IgE +/- itraconazole (anti-fungal controversial)

Aspergilloma

Mycetoma that forms within a pre-existing cavity Solitary lesion = Rx surgical resection +/- antifungal Multiple lesions = Rx antifungal x 6 months

Chronic Cavitary Pulmonary Aspergilosis (CCPA)

Pre-existing structural lung disease (most commonly COPD) à progression of above Weight loss, worsening cough +/- hemoptysis Rx antifungal x 6 months

Invasive aspergillosis

Opportunistic infection seen in neutropenia/cellular immunocompromise Diagnosis using imaging (CT chest), indirect tests (galactomannan of serum and sputum), or direct tests (fungal culture or pathology) Rx: Voriconazole x ≥6 weeks or longer CID, 2016 133

Dimorphic/(Endemic) Fungi

BONUS Read on own

Dimorphic Fungi

Notes and Treatment

Blastomyces dermatitidis ie. Blastomycosis

• Border of Great Lakes (incl. Northern Ontario), Southeastern/central USA, and St. Lawrence River (now sometimes seen in GTA) • Pneumonia, skin/joint infections • Dx: Fungal cx, PCR, path, urine/serum antigen • Rx: Itraconazole (mild to moderate), Amphotericin B (severe) Chapman SW et al, 2008 • Duration 6-12 months, or 3 months after complete resolution

Histoplasma capsulatum ie. Histoplasmosis

St. Lawrence, Ohio rivers Self-limited pneumonia, mTB mimicker Dx: Fungal cx, PCR, path, urine antigen Rx: None (mild), Itraconazole (moderate), Amphotericin B (severe) Duration ~12 weeks

Coccidioides spp. ie. Coccidiodomycosis

New Mexico, Arizona, Mexico, Central America (valley fever) Suspect in returned traveler with pneumonia, meningitis Dx: Fungal cx, path, antigen; LP if symptoms Rx: None (asymptomatic), Itraconazole (symptomatic)

• • • • Wheat LJ et al, 2007 •

• • • Galgiani JN et al, 2016 •

134

Questions? DON’T FORGET CHECK OUT THE BONUS MATERIAL FOR MORE READING ON

• Extra material on: – AMMI Canada Duration of Antibiotics Practice Point – Emerging pathogens – Lyme Disease and Tick Borne infections – Fever of unknown origin – Infections in immunocompromised hosts – Nosocomial infections

– IPAC – Exposure management (bites, needlesticks) – Adult immunizations including vaccine primer

– Choosing Wisely

**Bonus questions available online!

135

BONUS Read on own

AMMI Duration of Abx: GU Infections

Syndrome

Duration of Treatment

Comments

Acute Simple Cystitis

Nitrofurantoin 100mg BID x 5 days

Young non-pregnant women or young adults with normal GU anatomy and normal renal function

TMPSMX 1 DS BID x 3 days Fosfomycin 3g PO X 1

Complicated UTI OR Pyelonephritis (Oral)

Quinolone or Beta Lactam x 7 days

Excludes patients with urogenital abnormalities or stents. Duration depends on rapidity of improvement

SOURCE: ASSOCIATION OF MEDICAL MICROBIOLOGISTS AND INFECTIOUS DISEASE CANADA Grant, J et al. JAMMI 6(3); 2021: 181-197 Practice Point “ Shorter is better” – endorsed by med micro and ID docs of Canada 136

BONUS Read on own

AMMI Guidelines: Respiratory Tract

Syndrome

Duraiton of Treatment

Comments

Strep pharyngitis

Pen V x 10 days

Most data from peds, they still say 10 days here on guideline.

Acute Otitis Media or sinusitis , uncomplicated

5 days

Should meet diagnostic criteria Doesn’t include Complicated sinusitis eg epidural or orbital abscess

Community Acquired Pneumonia

5 days

Excludes immunocompromised or underlying lung disease ex emphysema. Pt must be improving w normal vital signs for 2 d

HAP/VAP

< or = 7 days

Generally. RCT of 8 vs 15 d showed no difference in important outcomes, pts receiving less antibiotics had less re-infection w resistant organisms. IDSA recommends 7 d for VAP.

AECOPD

5-7 days

5 days for most if they meet criteria for antibiotics

137

BONUS Read on own

AMMI Guidelines: Skin Bone GUT

Syndrome

Duration of Treatment

Comments

Uncomplicated cellulitis

5 – 7 days

Ususally due to GAS or S aureus

Acute vertebral osteomyelitis in 6 weeks adults

Not associated w implantable device; Assumes S aureus is pathogen but Rx duration could be longer if Salmonella or brucella infection.

2 weeks if small joint after Adults with native joint osteoarticular infections (septic surgical drainage 4 weeks if small joint after arthritis)

Only applies to postop pts w causal organism and susceptibility profile

surg drainage

Bowel Perforation: Traumaticà Gastro-duodenal (eg PUD)à

No more tan 24h postop

Intraabdominal infection

papules -> vesicles -> pustules -> ulcers -> scab Lesions tend to evolve synchronously Painful lesions (may be pruritic during healing) Infectious: Symptom onset until scabs fall off 140

BONUS Read on own

Viral Hemorrhagic Fevers

• Group of severe diseases caused by 4 virus families: – – – –

• • • • •

Arenaviridae (E.g. Lassa Fever) Filoviridae (E.g. Ebola, Marburg) Bunyaviridae (E.g. Crimean-Congo hemorrhagic fever) Flaviviruses (E.g. Yellow Fever, Dengue Fever) – arthropod transmission

All VHFs can progress to severe disease but likelihood varies Severe disease usually hemorrhagic or vascular leak manifestations Natural hosts are animals or arthropods and outbreaks occur where host is present Several outbreaks over the world in recent years Important thing is to alert IPAC immediately if symptomatic patient arrives who travelled to outbreak zone in past 21 days and start droplet/contact + N95 precautions (except flaviviruses)

141

BONUS Read on own

Ebola Virus

• Incubation: 2-21 days (avg 8-12) – Most recent Uganda Outbreak Sept 2022-Jan 2023 – Prior outbreaks Dem. Rep. of Congo, Guinea, West Africa

• Syndrome: – Fever, myalgias à GI symptoms, anorexia – Bleeding < 20%

• Infection control: – call IPAC, droplet/contact with N95

CATMAT, 2023 PHAC, 2023

until further notice – Impermeable neck to toe, with N95 and face shield, trained observer

• Diagnosis: – Viral culture, NAAT, viral antigens, serology from appropriate sites

• Supportive care – Essential procedures/bloodwork only – Do not forget DDx -> MALARIA! – Monoclonal antibody treatments

• Case fatality rate 60% NB: Investigational vaccine not available in Canada 142

Measles Virus

BONUS Read on own

• Outbreaks, waning vaccination, airborne transmission • Incubation: – ~14 days post exposure

• Syndrome: – fever, cough, coryza, conjunctivitis, Koplik spots, rash (centrifugal)

• Infection Control: – Airborne precautions, contact tracing (4 days prior to rash, 4 days after rash)

• Diagnosis: – PCR of pharynx/NP/urine; serology can be false negative early

• Complications: – Pneumonia, encephalitis, subacute sclerosing panencephalitis (SSPE)

• Post-exposure prophylaxis: – MMR, Measles immunoglobulin if susceptible, based on time from exposure

Canada, 2023

143

Tick-borne Disease References: • Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease. Arthritis and Rheumatology 2020: 1-9. DOI 10.1002/art.41562 • Krause PJ, Auwaerter PG, Bannuru RR, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis and Management of Babesiosis [published correction appears in Clin Infect Dis. 2021 Jul 1;73(1):172-173]. Clin Infect Dis. 2021;72(2):e49-e64. doi:10.1093/cid/ciaa1216 • Lyme Disease. Public Health Agency of Canada. 2023. https://www.canada.ca/en/publichealth/services/diseases/lyme-disease/health-professionals-lyme-disease.html • Diseases Transmitted By Ticks. CDC. 2023. https://www.cdc.gov/ticks/diseases/index.html

144

Arthropod Infections in Canada • Ixodes Scapularis

– Lyme (Borrelia burgdorferi) – Anaplasmosis – Babesiosis – Powassan Virus – Borrelia Miyamotoi

• Ixodes Pacificus – Lyme (Borrelia burgdorferi) – Borrelia Miyamotoi

• Other Ticks – Tick Borne Relapsing fever – Rocky Mountain Spotted Fever – Tularemia – Colorado Tick Fever

• Lice – Louse Borne Relapsing Fever – Bartonella Quintana

• Fleas – Bartonella Henselae

• Mosquitos – West Nile Virus – Western equine Virus – Eastern Equine Virus – St. Louis Virus

145

BONUS Read on own

Lyme Disease - Dx PHAC, 2023

DO NOT TEST ASYMPTOMATIC PATIENTS

146

Lyme Disease – Rx

BONUS Read on own

Stage

Lantos et al, 2020

Syndrome

Presentation

Rx

High risk bite

Confirmed Ixodes spp. In highly Doxycycline 200mg PO x1 within 72 hrs of tick endemic area, attached >36 hours removal*

Early Localized

Erythema migrans “target lesion” at site of tick bite

Doxycycline X 10d; Amoxicillin or Cefuroxime x 14d

Early Disseminated

Multiple Multiple target lesions Erythema Migrans

Doxycycline X 10d; Amoxicillin or Cefuroxime x 14d

Early neuroborreliosis

CN palsy, Meningitis, radiculopathy, neuropathy

Doxycycline, ceftriaxone, Cefotaxime, pen G X 14-21d

Carditis

Heart block, myocarditis, pericarditis

Ceftriaxone step down to oral once well Total X 14-21d

Arthritis

Mono/oligo/polyarthritis

Doxycycline X 28d

Late neuroborreliosis

Encephalopathy, encephalitis, peripheral neuropathy

Ceftriaxone X 14d

Late

*Doxycycline single dose prophylaxis okay for pregnant women, with risk-benefit discussion

147

BONUS Read on own

Lyme Disease Management Pearls

• Erythema Migrans: Typical Lesions are clinical diagnosis. If atypical, acute and convalescent serology • For early disseminated and late manifestations, serology for diagnosis rather than PCR (including neuro and arthritis) • Screen with ECG if early lyme disease and symptoms of carditis (dyspnea, edema, palpitations, lightheadedness, chest pain, and syncope) • Indications for Admission: significant PR prolongation (PR > 300 milliseconds), other arrhythmias, or clinical manifestations of myopericarditis • For telemetry, may require temporary pacing • Post Treatment Lyme Disease Syndrome: persistent symptoms after treatment. Usually, non-infectious. • Clinical signs of ongoing infection (e.g. arthritis): consider second course of tx with IV • If ongoing arthritis after 2nd tx course: refer to rheumatology for DMARDs • If no arthritis or objective signs of infection: recommend against further antibiotics • Consider coinfection (Babesia, Anaplasma), especially if ongoing fevers while on antibiotics IDSA/ACR Lyme Guidelines 2020

148

Other Ixodes Infections Anaplasmosis

Babesiosis

• Rickettsial Bacteria: Anaplasma Phagocytophilum • Geography: South Central and eastern Canada • Incubation: 5-14 days • Manifestations:

• Protozoa: Babesia Microti • Geography: South central and eastern Canada • Incubation: 1-4 weeks • Manifestations:

• Diagnosis: Serology +/- PCR • Treatment: Doxycycline x 7-10 days

• Diagnosis: Blood Smear, PCR, Serology

– fever, malaise, myalgia, and headache – DIC, Rhabdo, Resp compromise, hemorrhage

– Fever, fatigue, malaise, hemolytic anemia – Severe disease associated with severe anemia and multiple complications – Tetrad (Maltese cross)

• Treatment: Azithromycin + Atovaquone x 7-10 days 149

BONUS Read on own

Fever of Unknown Origin (FUO) References: • Haidar G, Singh N. Fever of Unknown Origin. N Engl J Med. 2022;386(5):463-477. doi:10.1056/NEJMra2111003 • Mourad O, Palda V, and Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med 2003; 163:545-51. • Hersch EC and Oh RC. Prolonged febrile illness and fever of unknown origin in adults. American Family Physician 2014;90:91-96.

150

FUO

BONUS Read on own

• Classic Definition: T > 38.3C over 3 wks, with 1 wk investigations – Core features are prolonged fever without clear source despite reasonable investigations (rather than rigid definition)

• Differential Diagnosis: Infection (30%)

Abscess (intra-abdominal) Endocarditis Sinusitis TB and Others – CMV, EBV HIV

Inflammatory (20%)

GCA (age >50) Still’s Disease IBD + other seropos

Malignancy (15%)

Lymphoma/leukemia Renal Cell Colorectal

Drugs / miscellaneous (10%)

VTE, Drugs à AEDs, antimicrobilas, NSAIDs, Allopurinol

Idiopathic (25%)

Good prognosis, spon recovery in most pts

BONUS Read on own

FUO

• First line investigations: – History and physical exam, comprehensive fever diary – CBC + diff, blood film, lytes, Cr, LDH, TSH, CK, LFTs, SPEP – Blood cultures (X 3 sets), urine C&S – HIV, CMV IgM, Hepatitis serology – CXR, abdominal U/S [or CT Chest/abdo/pelvis if available] – ANA, RF, ANCA – +/- EBV, monospot, Q-fever serology in right setting •

Second line investigations/steps (in order): – Discontinue non-essential Rx; fever diary – CT abdomen – Nuclear imaging – TTE (IE) and Duke Criteria – Doppler U/S – lower extremities (DVT) – Temporal Artery biopsy (if ESR >50 and patient >50) – Liver biopsy

*Empiric trials of steroids/Abx discouraged as they rarely establish diagnosis Mourad O et al,2003

Hersch EC et al, 2014

Hairdar G et al, 2022

BONUS Read on own

Infections in Immunocompromised Hosts References: • Fever and Neutropenia in Adults with Cancer: 2018 Update by the Infectious Diseases Society of America; CID 2018 (covered by med onc) • Shafran et al. Reducing the risk of infection in a 74-year-old man who is to receive prednisone. CMAJ. 2014

153

BONUS Read on own

Immunomodulating Therapy Work-up

• LTBI: TST/IGRA if >1 TB risk factor* and either TNF-a or Prednisone >15mg/d for >4 weeks (or equivalent). – * Close contact w TB, recent immigration high risk country, high risk work/life exposure etc. – If positive, rule out active TB and treat latent TB. (can give immunosuppression once treatment started)

• Hepatitis B: Screen w/ HBsAg (+/- coreAb) if biologic or Prednisone > 7.5mg/d – Consider need for treatment/prophylaxis – **Rituximab is high risk for reactivation, must start prophylaxis with entecavir or Tenofovir

• Hepatitis C: Some risk of reactivation, screen with serology for TNF-a or long-term steroids • PJP: Consider TMP-SMX prophylaxis if Prednisone > 20mg/d for > 4-8 weeks • Strongyloides: Screen with serology if planned immunosuppression in anyone who lived (usually >1m) in tropic or subtropic area. – Treatment with/ Ivermectin 200 mcg/kg PO day 1, 14

• *HIV: Although no evidence for worsening infection, individuals are usually screened for HIV alongside Hepatitis B and C when starting immunocompromising treatment 154

BONUS Read on own

Antimicrobial Prophylaxis in Oncology

• Prophylaxis with Ciprofloxacin recommended in those at high risk for FN or prolonged profound neutropenia (> 7d and ANC < 0.1) • Antifungal (oral triazole or echinocandin) recommended if prolonged and profound neutropenia such as in AML/MDS, HSCT. Not recommended for solid tumour. • PJP prophylaxis recommended if chemotherapy risk of PJP > 3.5% e.g. those with > 20 mg pred daily for > 1 mo • HSV positive undergoing allo-HSCT or leukemia induction should get acyclovir for prophylaxis • NRTI (e.g. entecavir or tenofovir) if high risk of Hep B reactivation • Yearly influenza vaccine recommended • Those with neutropenia from cancer therapy should avoid prolonged contact with environments that have high concentration with fungal spores

155

BONUS Read on own

Nosocomial Infections and IPAC

References: • IDSA/SHEA/APIC/AHA Compendium of strategies to prevent healthcareassociated infections in acute care hospitals: 2022 updates. https://www.idsociety.org/practice-guideline/compendium-of-strategies-toprevent-hais/#StrategiestoPreventVAP/VAE/NV-HAP20May2022 • Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. (2009) 49 (1): 1-45.doi: 10.1086/599376 • Public Health Agency of Canada. Routine Practices and Additional Precautions for Preventing the Transmission of Infection in Healthcare Settings. 2017. https://www.canada.ca/en/public-health/services/publications/diseasesconditions/routine-practices-precautions-healthcare-associated-infections.html 156

BONUS Read on own

Line Infections Diagnosis – Fever + Indwelling line - consider diagnosis – Blood cultures from separate sites at same time (line and periphery) – If shock, removal of line and culture tip Treatment – Remove line if possible – ALWAYS for S. aureus, Candida spp, complicated infection (ie. thrombophlebitis, IE, OM) – Directed therapy x 7d (minimum 14 days if S. aureus / Candida) Rosenthal et al, 2009

157

BONUS Read on own

Other Nosocomial Infx

Surgical Infection • can be superficial, deep or organ space • similar ABx to Cellulitis if superficial • drainage if deep/organ space +/- ABx

Catheter-Associated Urinary Tract Infx (CAUTI)

• only obtain Cx if pt symptomatic • Rx x 7d if positive Cx and symptomatic • removal/change catheter if possible

158

Prevention Strategies

BONUS Read on own

VAP • Avoid intubation if possible • Minimize sedation • Maintain physical conditioning • Keep head of bed between 30 to 45 degrees • Oral care with toothbrush, no chlorhexidine • Early enteral nutrition • Change ventilator circuit only if visibly soiled/malfunctioning

CLABSI • • • • • • • • • • • • • •

Evidence based list of indications Provide education to providers Daily chlorhexidine baths Hand hygiene prior to catheter insertion Subclavian > jugular > femoral Procedure checklist and all-inclusive kit Ultrasound guidance Use maximal sterile barrier precautions chlorhexidine skin prep Appropriate nurse-to-patient ratio Chlorhexidine dressings; change q7d Disinfect before accessing catheter Remove nonessential catheters Surveillance for infection

CAUTI • Hand hygiene; insert catheter using aseptic technique and sterile equipment • Use smallest catheter possible • Maintain sterile, continuously closed drainage system • Keep collection bag below level of bladder • Empty collection bag regularly • Daily discussion of indication for catheter (consider alternatives) • Avoid unnecessary re-insertion Yokoe DS et al, 2014

159

BONUS Read on own

Infection Control

References: • Routine practices and additional precautions for preventing the transmission of infection in healthcare settings (PHAC, 2013) Donning/Doffing: • Droplet Demonstration - 2015 video on website under course materials; available for various clinical scenarios depending on level of PPE required

DROPLET DONNING Sequence: http://www.cdc.gov/hai/pdfs/ppe/PPESequence.pdf

160

BONUS Read on own

Precautions

Precaution

What’s involved

Airborne (A)

Negative pressure isolation with own washroom, mask (N95)

Droplet (D)

Mask, eye protection/face shield if respiratory illness

Contact (C)

Gown, gloves, dedicated equipment, single room if possible, own toilet if diarrhea

Since COVID, consensus understanding that Aerosols/Droplets are on continuum rather than mutually exclusive categories. There is significant overlap and respiratory infections may have more or less of both categories

List of aerosol generating medical procedures (AGMP) • Intubation/extubation, manual ventilation • Open endotracheal/deep suction • CPR (*not chest compressions, but airway manipulation) • Bronchoscopy and bronchoalveolar lavage • Tracheostomy/laryngoscopy • Sputum induction • Nebulized therapy (not MDI therapy) • High flow nasal cannula (e.g. Venturi, Optiflow) • Non-invasive positive-pressure ventilation (CPAP/BiPAP) • Some dental procedures (drilling, ultrasonic scaling)

Routine practices and additional precautions for preventing the transmission of infection in healthcare settings (PHAC, 2017)

Precautions

BONUS Read on own

Pathogen

Precaution s

Duration of precautions

TB (pleural/laryngeal)

A

Until received 2 weeks of effective treatment and is clinically improving, and 3 consecutive negative sputums for AFB

Disseminated VZV

A+C

Until all lesions have crusted/dried

Primary or disseminated, extensive varicella

A+C

Until all lesions have crusted/dried

Measles

A

4d after start of rash

SARS-CoV 2/ COVID-19

D+C+ respirator

10d following resolution of symptoms with minimum 24h symptom free if at home, 21d if immunocompromised/ICU admission/severe disease

Mumps

D

Until 5d after onset of parotitis

Meningococcus

D

Until 24h of effective rx has been received

VHF (including Ebola)

C+D

Until symptoms resolve

Interim COVID-19 infection prevention and control in the health care setting when COVID-19 is suspected or confirmed (PHAC, Dec 2021) Routine practices and additional precautions for preventing the transmission of infection in healthcare settings (PHAC, 2016)

162

Precautions

BONUS Read on own

Pathogen

Precautions Duration of precautions

Invasive GAS (TSS/NF/pneumonia/meningitis)

D+C

Until 24h of appropriate abx received

C. difficile

C

Duration of symptoms

Disseminated/primary extensive HSV

C

Until all lesions dried/crusted

Diphtheria (pharyngeal)

D

Until 2 neg cultures from nose and throat

Seasonal influenza

D+C

Duration of symptoms

Norovirus

C

48h after resolution of illness

Scabies

C

Until 24h after initiation of appropriate therapy

Antibiotic resistant organisms (MRSA, VRE, ESBL, CRE, CPO)

C

As directed by ICP

Routine practices and additional precautions for preventing the transmission of infection in healthcare settings (PHAC, 2013)

163

Bites

BONUS Read on own

• Wound cleaning and irrigation • Prophylactic or pre-emptive antibiotics – Consider in the following individuals: • • • • • •

Immunocompromised Asplenic Advanced liver disease Pre-existing or resultant edema of affected area Moderate to severe injury (esp. to hand or face) Penetrating injuries to periosteum or joint capsule

Stevens DL et al, 2014

164

Bites

BONUS Read on own

Microbiology Animal Bite (cats, Pasteurella multocida, dogs) Capnocytophaga canimorsus, staphylococci, streptococci, anaerobes

Examples of Abx Regimens •

•

•

•

Human Bite

Eikenella corrodens, streptococci, S. aureus, anaerobes

•

•

•

•

Amoxicillin-clavulanic acid 2nd or 3rd gen cephalosporin + metronidazole Moxifloxacin Doxy + clindamycin Amoxicillin-clavulanic acid 2nd or 3rd gen cephalosporin + metronidazole Moxifloxacin Doxy + clindamycin

Stevens DL et al, 2014

165

Bites

BONUS Read on own

• Tetanus prophylaxis in wound management Clean, minor wounds

Hx of tetanus immunization

All other wounds

Toxoidcontaining vaccine

TIg

Toxoidcontaining vaccine

TIg

< 5 years since last booster and completed series

✖

✖

✖

✖

> 5 years but < 10 years since last booster and completed series

✖

✖

✔

✖

> 10 years since last booster and completed series

✔

✖

✔

✖

Unknown or incomplete series (< 3 doses) (e.g. immigrant populations)

✔

✖

✔

✔

Canadian Immunization Guide (PHAC, 2023)

166

Bites

BONUS Read on own

• Rabies post exposure prophylaxis – Immediate cleaning and flushing X 15min, avoid suturing – Call public health to assist in risk assessment – Ask about animal species, type of exposure, circumstances, behavior and vaccination status of animal, domestic vs stray, unprovoked vs provoked attack, location and severity of bite – If exposure to rabies is considered highly likely, administer post-exposure prophylaxis Rabies Immunoglobulin

Rabies Vaccine

Not vaccinated, immunocompetent

✔

✔- 4 Doses

Not vaccinated, immunocompromised

✔

✔- 5 Doses

Vaccinated

✖

✔- 2 Doses

Canadian Immunization Guide (PHAC, 2023)

167

BONUS Read on own

1.

Bloodborne Pathogen Exposure Management Source Patient • • •

2.

Status of HBV, HCV, and HIV. If positive, treated or untreated? Controlled or not controlled? If negative, risk factors (ie. MSM, multiple partners, PWID, etc.)

Exposure Factors •

3.

–

• •

p24 antigen-HIV antibody assay Hepatitis B sAg Hepatitis C Ab

–

High Risk: Percutaneous (large hollow bore needles) Moderate Risk: Splash to eyes, nose, mouth Low Risk: Contact through non-intact skin

Host Patient

Immunization history

Exposed Patient • • • • • • •

High Risk: Blood, semen, vaginal secretions, visceral fluid (pleural, peritoneal, pericardial, amniotic) Low Risk: Saliva, sputum, feces, urine, vomit, sweats, tears, nasal secretions

Type of injury – –

•

•

Type of fluid –

•

Source Patient

p24 antigen-HIV antibody assay Hepatitis B sAg, sAb Hepatitis C Ab Pregnancy test CBC, creatinine, ALT STI testing Repeat in 6 weeks and 3 months

Time to positive serology

Time to positive NAAT

HIV

22 days

5-10 days

HCV

38-94 days

6-9 days

HBV

38-50 days

20-25 days

168

ORAL EXAM

Bloodborne Pathogen Management

BONUS Read on own

Infection

Risk of transmission if percutaneous exposure

Management/PEP

HIV

0.23% (up to 1.3%) Truvada PLUS Dolutegravir (OR Raltegravir) x 28days (within 72 hours of exposure)

Hepatitis B

6-30%

Immune (confirmed anti-HBs > 10mIU/mL): No further management Nonimmune (never vaccinated or anti-HBs < 10mIU/mL) or Unknown: Vaccine series +/- HBIG

Hepatitis C

3-10%

None. Repeat testing in 4-6 months.

169

Immunizations

BONUS Read on own

References: • Refer to National Advisory Committee on Immunization (NACI) Canadian Immunization Guide for further information: – http://www.phac-aspc.gc.ca/naci-ccni/ » Click on ‘Canadian Immunization Guide’ for key updates and information regarding specific vaccines

Great resource for patient education and up to date immunization schedule endorced by PHAC, CMA, CFPC, AMMI Canada…:

Immunize.ca 170

BONUS Read on own

Vaccine Counselling

• Ask patient if they are opening to discussing the vaccine, and what questions they may have – For vaccine hesitant patient, explore their reasons which may be multifactorial – Focus on what your patient’s specific concerns are and not make assumptions – Respect differences in opinion, and adopt a patient-centred approach Benefits Principles of Effective Communication about Vaccines: • Adopt a vaccine-recipient approach • Respect differences of opinion • Represent the risks and benefits of vaccines fairly and openly • Clearly communicate current knowledge using an evidence-based approach

ORAL EXAM PHAC. Communicating effectively about immunization: Canadian Immunization Guide. 2016

• Discuss risks of vaccine preventable illness • Discuss available vaccines, how they work, and their efficacy • Be upfront about potential side effects

• Effective at protecting against preventable diseases • Safe • Community/herd immunity indirectly protects those who cannot be vaccinated (newborns, elderly, immunocompromised) • Cost savings to individual, healthcare system and society in prevention of illness

Risks • Adverse reactions, generally minor and resolve quickly (fever, local injection reaction, • Serious adverse reactions are rare (anaphylaxis, severe asthma exacerbation) • Guillain-Barre syndrome within 6 weeks of immunization (influenza, tetanus toxoid, rare) 171

Types of Vaccines 101

BONUS Read on own

•

ORAL EXAM

Whole Vaccines:

Non-live (may also be called inactivated):Cannot cause disease

– Live Attenuated: weakened live pathogen. Caution in immunocompromise (MMR, Varicella, Rotavirus, Immavune) – Inactivated: killed pathogen, cannot cause disease but often requires multiple doses. (Polio, Flu, Hep A)

•

Component Vaccines: Uses part of pathogen. Often require repeat doses and adjuvants – Subunit Vaccine: Uses antigenic component of vaccine • Protein: Uses antigenic protein • Polysaccharide: Uses polysaccharide from bacteria. Less immune response (Pneumovax) • Conjugate: Polysaccharide attached to protein, to produce longer lasting immunity to polysaccharide (Prevnar, Men ACYW) • Toxoid: Inactivated toxins produced by bacteria (Tetanus, Diphtheria)

– mRNA/DNA: Viral RNA/DNA which is translated into protein in human cells (COVID Pfizer/moderna) – Recombinant Vaccines: Insertion of viral gene into yeast/virus cell to produce pure antigen (Hep B, HPV)

• •

Viral Vector (replicating or non-replicating): Non-pathogenic viral vector carries gene for antigen, and produces protein inside body (COVID AstraZeneca) Virus-like particles: Molecules that closely resemble viruses (COVID Covifenz) Canadian Immunization Guide (PHAC, 2020) https://www.cdc.gov/vaccines/pubs/pinkbook/prinvac.html

172

Adult Immunizations

BONUS Read on own

Vaccine

Age 18-26 yrs

Td

27-49 yrs

50-59 yrs

60 yrs

> 65 yrs

Booster q10 years

Pneu-P-23 Shingrix Inf

(

)

Annually

HPV Pertussis

1 dose as an adult and during each pregnancy

COVID-19

Fall 2023: XBB.1.5 mRNA booster if >6m from last vaccine or infection

Recommended immunizations, adults (18 years of age and older), previously immunized with primary series for diphtheria, tetanus, pertussis, polio, Hib, measles, mumps, rubella, meningococcal prior to age 24 • • •

VZV – Shingrix (recombinant) for all over age 50 if no contraindication, consider Zostavax (live) if Shingrix contraindicated or unavailable HPV – Recommended for males and females ages 9 to 26 (and older) HepA and HepB – If at risk developing it Canadian Immunization Guide (PHAC, 2023) 173

BONUS Read on own

Adult Immunizations – Specific Populations

Vaccine

Examples of populations at risk

Schedule

Hib

Asplenia/hyposplenism, HIV, malignant hematologic disorders, PID, SOT, cochlear implant

1 dose regardless of prior immunization hx

Meningo

Asplenia/hyposplenism, HIV, complement deficiency Travelers to meningitis belt, pilgrims to Hajj, military personnel, lab workers, close contacts of case

Men-C-ACYW X 2 doses, 8 wks apart; consider 4CMenB X 2 doses, at least 4 wks apart

Pneumo

Asplenia/hyposplenism, sickle cell dz, hemoglobinopathies, HIV, nephrotic syndrome, SOT, leukemia, lymphoma, immunocompromising therapy (steroids, chemo, RT, etc.), complement deficiency

Pneu-C-13 followed by Pneu-P-23, 8 wks later; single re-immunization with Pneu-P-23 five years later

Age > 65 Other - Chronic CSF leak, chronic cardiac/ pulmonary disease, DM, CKD, CLD, EtOH, smokers, homeless, LTC, PWID

1 dose of Pneu-P-23 (at least 8 weeks after Pneu-C-13, if received); reimmunization after 5 yrs in some cases

Canadian Immunization Guide (PHAC, 2020)

174

BONUS Read on own

Choosing Wisely and ID

• Don’t routinely prescribe IV forms of highly bioavailable antimicrobial agents for patients who can reliably take and absorb oral meds (ciprofloxacin, metronidazole, fluconazole) • Don’t prescribe alternate second-line antimicrobials to patients reporting non-severe reactions to PCN when beta-lactams are recommended first-line therapy • Don’t routinely repeat CD4 counts in patients with HIV and undetectable VL > 2 years and CD4 > 500 unless virologic failure or intermittent OI • Don’t routinely repeat imaging in patients with OM demonstrating clinical improvement following adequate antimicrobial rx • Don’t prescribe aminoglycosides for synergy to patients with bacteremia or NV IE caused by S. aureus 175

Bonus MCQ 1 + 2 Bonus 1 Endocarditis 40 year old male with S. mitis endocarditis on a bicuspid aortic valve. Echo shows mild AI and small vegetations on both cusps. Treated with ceftriaxone. 10 days after initiating therapy he develops a cold, ischaemic pale leg. Symptoms last 6 hours then resolve. Next step: A. Change antibiotics to vancomycin B. CT head C. Consult CV surgery for surgical assessment D. IV heparin followed by warfarin E. Continue present management

Bonus 2 Diarrhea A 30 year old female presents with diarrhea and abdominal pain. She has had 5 days of fever. She returned from Cambodia 9 days ago. On examination her temperature is 39.6 and she has a palpable spleen tip. She also has a rash consisting of 1-4mm erythematous macules on her trunk. Which antibiotics would you give? A. Ampicillin B. No Antibiotics C. Metronidazole D. Ceftriaxone

176

MCQ Bonus 3 + 4 BONUS 3 - HIV 68 y M from Saudi Arabia living with HIV admitted with PJP pneumonia confirmed by bronchoscopy. ABG shows PaO2 62. He has a severe allergy to sulfa reported. In addition to prednisone, management should include: a. TMP-SMX 15mg/kg IV b. IV foscarnet c. IV pentamidine d. PO dapsone e. Clindamycin and Primaquine

BONUS 4 – STI You are seeing a 25yo MSM for HIV pre-exposure prophylaxis. As part of routine screening, you diagnose pharyngeal gonorrhea by NAAT testing. He weighs 52kg. How do you treat? A. Ceftriaxone 250 mg IM x1 and doxycycline 100mg PO BID x 10d B. Ceftriaxone 250 mg IM x1 and Azithromycin 1 g PO x1 and test of cure C. Ceftriaxone 500 mg IM x1 and test of cure D. Ceftriaxone 250 mg IM x1, Azithromycin 1 g PO x1 and Pen G 2.4MU IM x 1

177

MCQ Bonus 5 + 6 BONUS 5 – STI You are are asked to see a 22-year-old female college student with diffuse pustular skin lesions, and migratory arthralgias. Last week, she was seen in the ED for a swollen knee which has now resolved. What is the best way to make the diagnosis? A. Wound swab or lesions B. Blood cultures x 2 C. HIV serology D. Urine, cervical, rectal and pharynx testing for C+G

BOUS 6 – STI You have been referred a 78M patient for positive syphilis serology (RPR 1:32), ordered in the context of work-up for dementia. They do not have a previous history of syphilis have never been previously tested, and are asymptomatic aside from some intermittent ringing in their ears. They have already been given one dose of benzathine pen G by their family physician last week. The remainder of screening of STIs is negative. What further work-up do you recommend? A. No further work-up or treatment. B. Continue benzathine pen G 2.4 million units IM x 2 more doses 1 week apart, for total 3 doses C. Repeat syphilis serology now to assess RPR titre for decrease to further guide treatment D. Follow-up in 3 months with repeat serology at that point. Repeat penicillin dose then if titre has not decreased 3-fold E. Lumbar puncture 178

BONUS MCQ 7+ 8 BONUS 7 - Malaria A young man presents to the ED with fevers and confusion, after returning from a trip to visit his relatives in Nigeria for summer break. He is icteric, and bloodwork reveals a Hgb 52, Plat 44, Creat 150, lactate 4.5, INR 3.3. He has a blood smear that confirms P. falciparum with 8% parasitemia. Which of the following is part of your management.

A. B. C. D.

Admit to hospital ward Start double-dose atovaquone-proguanil Lumbar puncture IV artesunate

BONUS 8 - Lyme You have seen a fisherman in southern Nova Scotia who presents with a large rash on their leg with central clearing. They do not feel unwell, but do not know how long it has been there. There are no other rashes, and you do not see a tick anywhere. They have no joint pain, or neurologic findings. What is your treatment approach? A. Lyme serology, and start treatment if positive B. Doxycycline 200mg PO x 1 now, Lyme serology and reassess in 1 week. C. Lyme serology, doxycycline 100mg PO BID x 10d D. Doxycycline 100mg PO BID x 10d E. Lyme serology, Cephalexin 500mg PO BID x 7 d for potential cellulitis

179

Bonus 9 – COVID-19 2024 A 87 year old woman with 4 previous mRNA vaccine doses, but no booster in the past 12 months, presents with cough and fever. She is found to be COVID positive. Her oxygen saturation is 97% on room air. Her medical history includes T2DM, HTN and chronic kidney disease (eGFR 50), and her current medications are metformin and ramipril. She is fatigued, but comfortable going home. What do you recommend? A. Amoxicillin-Clavulanate for 5 days B. Remdesivir for 3 days C. Nirmatrelvir/Ritonavir x 5 days D. No treatment 180

BONUS MCQ 10 + 11 BONUS MCQ 10 – CNS Infection You have just confirmed a case of N. meningitidis meningitis in a 21 year old university student. What should you NOT do? A. Call public health at 3AM to alert them. B. Give prophylaxis to all ICU staff caring for this patient as he was not on isolation initially. C. Place patient on droplet precautions as still febrile. D. Give vaccine and prophylaxis for his university roommate.

BONUS MCQ 11 – Resistant Organisms A 67 year old man is intubated in the ICU after a traumatic brain injury 2 weeks ago. Over the past 24 hours he has required increasing FiO2 and pressure support. A sputum sample is taken and grows Enterobacter Cloacae. The report indicates it is susceptible to all betalactams. What antibiotic do you treat with? A. Vancomycin B. Ertapenem C. Piperacillin-Tazobactam D. Ceftriaxone

181

BONUS MCQ 12 + 13 BONUS MCQ 12 – Travel You are seeing a 27 year old man on the ward with pneumonia. He returned from Thailand 8 days ago, where he was staying at a hostel. He has a left lobe infiltrate on CXR. He has been on Ceftriaxone for 4 days without improvement. What pathogen do you suspect? A. Legionella B. S. Pneumoniae C. Mycoplasma D. Tuberculosis

BONUS MCQ 13 – Immunocompromise A 60 year old women with AML was admitted with febrile neutropenia and treated with Meropenem and vancomycin. She is also on Ganciclovir due to a positive blood CMV PCR. 1 week into therapy she has a repeat fever and is found to have candidemia and is started on fluconazole for 2 weeks. She initially improves. She has been neutropenic for the past month, but her neutrophils are now beginning to improve. 1 week later, she becomes febrile again. Bloodwork shows Neutrophils 1.5, ALT 100, ALP 400, Bilirubin 20. What is the cause of her fever? A. B. C. D.

CMV viremia Hepatic Abscess Drug Fever Hepatosplenic Candidiasis

182

Bonus MCQ 14+15 BONUS MCQ 14: Tb + HIV You have just diagnosed active pulmonary TB. In which patient would the likelihood of MDR-TB be lowest?

A. Patient with thoracotomy 20 years ago for TB B. Patient with well controlled HIV C. Patient from a northern First Nations community with recent contact with MDR TB patient D. Patient from South Africa

MCQ 15: GU Infections You are seeing a post-menopausal female patient in the ED. She has fever, flank pain and nausea. You suspect pyelonephritis. She had an episode of cystitis one month ago secondary to ESBL E coli (S FQ, TMPSMX, nitrofurantoin, fosfomycin). It was treated with nitrofurantoin. After sending off supportive testing, how do you initially treat? A. B. C. D.

Fosfomycin PO TMP-SMX PO Moxifloxacin IV Ertapenem IV

183

Bonus 16- IPAC - 2024 You are seeing a 25 year old man in the ED with new fever, cough and hypoxia without any abnormalities on CT chest; it is not influenza season. He was placed on droplet/contact precautions by the ED for suspected COVID and an NP swab was sent. During your interview, he mentions that he works at a poultry farm. What should you do next? A. Contact IPAC and Public Health B. Start Ceftriaxone C. Contact Respirology for a BAL D. Prophylaxis for all household contacts 184

MCQ Bonus 17 + 18 BONUS 17 – HIV A young man is seen in clinic for a new diagnosis of HIV. On physical examination, you do not note any abnormalities, but he points out some “bruises” on his arms that appeared months ago and have not healed. There are three, all less than 1cm in diameter. On bloodwork, his CD4 count is 47, viral load is pending. Which treatment will you arrange for these lesions? A. Intralesional chemotherapy B. Surgical excision C. Start atovaquone D. Start bictegravir/FTC/TAF

BONUS 18 – IA Infections An 67 year old man undergoes a colectomy for perforation secondary to colon cancer. He is placed on ceftriaxone and metronidazole. He develops a fever on post op day 2, but is otherwise stable. Abdominal ultrasound reveals a 5cm abdominal abscess. What is the next step in management? A. Laparotomy B. Percutaneous Drainage C. Change antibiotics to PiperacillinTazobactam D. Add Fluconazole

185

BONUS MCQ BONUS MCQ 19 - endocarditis You see a 72yF with bioprosthetic aortic valve for shortness of breath on exertion. She reports some night sweats for past few weeks and recalls it started after her tooth became infected a month ago, and she had a delay until could be seen by dentist. On your physical examination the patient is stable, 37.8C, BP 110/60, HR 80. She has splinter hemorrhages and diastolic blowing murmur in LLSB. Which of the following is not appropriate initial management? a) Blood cultures b) Transthoracic echocardiogram c) No empiric antibiotics d) IV Ceftriaxone and Ampicillin

BONUS MCQ 20 – Bone/joint You are seeing a patient in follow-up for congestive heart failure and hyperglycemia after a recent hospital admission. They ask you to assess an ulcer on their foot, as they are worried that it might have become infected since their last admission to hospital. Which of the following is most indicative of infection? A. Bad odour B. Increased redness C. Purulence at the site D. Increased pain

186

Bonus 21 - Fever in Traveller You are asked to see a 22 year old woman in emerge who had returned from Vietnam 22 days ago. They present with 3 days of fever, headache, maculopapular rash and thrombocytopenia. Which of the following is LEAST likely? A. B. C. D. E.

Dengue Malaria Typhoid HIV COVID-19 187

Bonus 22 – Parasitic Infection - 2024 You are seeing a 53 year old man with who returned 4 weeks ago from visiting relatives in India for 6 months. For the last two weeks he has been experiencing fevers and night sweats and has a dull pain in his right upper quadrant. You notice some RUQ tenderness on exam and order an ultrasound which shows well-defined hypoechoic abscess in the posterior right lobe. Which amoeba causes amebic liver abscesses? A. Naegleria Fowleri B. Acanthamoeba C. Entamoeba Histolytica D. Entamoeba Dispar 188

BONUS MCQ Answers 1) C -This is one of the indications for consideration of surgical approach (emboli despite antibiotic therapy). Know these for your exam. No indication to change antibiotics (strep universally susceptible). 2) D - Typhoid is common in southeast Asia. Presentation includes fever, “rose spots”, abdominal pain and can develop hepatosplenomegaly. Constipation is most common presentation but can present with diarrhea. Preferred treatment, particularly in inpatients, is ceftriaxone. 3) C - He is Sulfa Allergic so TMP-SMX is off the table. For second line – clinda/primaquine usually preferred but being from Saudi Arabia higher chance this man has G6PD deficiency so would recommend PENTAMIDINE instead. 4) B - Depending on whether you read PHAC or CDC guidelines. Would follow PHAC guidelines for exam, but would not likely be faulted for saying C in the oral exam. Increasing CFTx resistance is the reason for dosing increase from CDC, whereas PHAC chose dual coverage to overcome resistance. Note: Pharyngeal gonorrhea requires test of cure in both guidelines. 5) D - Clinically this is suspicious for disseminated gonococcal infection. Can try to swab the skin lesions, but this may be lower yield than performing NAAT PCR at all sites of sexual contact (cervical, urine, +/- rectum/pharynx). HIV serology would also be indicated for risk factor screening. Yield of blood cultures is low, despite likely hematogenous spreading of bacteria. 6) E - E – at minimum this is late latent syphilis of unknown origin, but sx of dementia, + ringing in ears could be findings of neurosypihilis/otic syphilis. This requires LP, and treatment with IV penicillin x 14d. If this was negative, then continue treatment for late latent as in option B but need to rule out neuro first. Repeating serology now is too early, but goal is 4-fold drop within 6 months (if latent) or 1 year (if neuro). 7) D - This patient has severe malaria (anemia, potentially DIC, high parasite burden assuming he is non-immune). He requires admission to ICU for IV artesunate. His current coagulopathy precludes safe LP. 8) D - Nova Scotia has +++ Lyme disease. This sounds like uncomplicated Lyme, or erythema migrans. Serology is NOT needed to diagnose, and should not delay treatment. Should be treated up front with doxycycline x 10 days as long as no evidence of disseminated disease 9) C - In a patient over 70 with >3 high risk comorbidities presenting with mild COVID, treatment can be offered regardless of vaccine status (although benefit is not totally clear). Due to her CKD she will need a dose reduction for Nirmatrelvir/Ritonavir; however she has no medication interactions. Remdesivir is IV and not convenient for outpatients. 189

BONUS MCQ Answers 10) B- In this case B is the best answer because prophylaxis is not warranted for all ICU staff, only those who who have had intensive unprotected contact (eg. intubating, resuscitating, closely examining oropharynx without a mask). The others you should do. 11) B - Enterobacter is a high risk SPICE/AmpC organism that may induce resistance to penicillins and cephalosporins that isn’t present at the time of initial culture results. Preferred treatment is Carbapenem or non-beta lactam (however Vancomycin does not cover gram negative organisms) 12) A - Legionella outbreaks occasionally occur in hotels/hostels in water supply. There have previously been outbreaks in travellers to Thailand. It would not respond to Ceftriaxone. S. Pneumoniae expect response to Ceftriaxone. Mycoplasma rarely can cause mild pneumonia with bilateral infiltrates, not likely to be severe. TB uncommon in travellers, uncommon to present with bilateral infiltrates. 13) D - Hepatosplenic Candidiasis typically occurs in patients with heme malignancy and prolonged neutropenia. Candida gets into the bloodstream and seeds the liver/spleen. Lesions are often not visible while neutropenic, but emerge once the neutrophil count recovers. May be accompanied by an elevated ALP. Suspect in someone who either is not improving on antifungals or improves then worsens again especially after neutrophil recovery. Drug fever could also cause fever and elevated ALP, but overall pattern consistent with hepatosplenic candidiasis 14) B is the best answer based on the guidelines as known risk factors for MDR include previously treated TB (anti-TB medications would have been used 20 years ago), known contact with an MDR case and being born in an endemic country . 15) D- Moxifloxacin has a lower concentration in the urine so not approved for this indication (Pick levofloxacin or ciprofloxacin for urinary infections instead). 16) A - This exposure is concerning for a possible H5N1. Contact IPAC and public health for further guidance. The patient is already on contact/droplet precautions however some hospitals will request airborne precautions. While you could consider empiric treatment, prophylaxis for contacts would not be done unless the diagnosis confirmed 190

BONUS MCQ Answers

17) D - D- Sounds like Kaposi’s sarcoma. Usual treatment is initiation of ART, and follow up as this generally regresses with treatment. Intralesional chemotherapy can be considered for large lesions, especially if not improved on ART. 18) B - Percutaneous drainage is mainstay of treatment for abdominal abscess. For community acquired abdominal infections, Ceftriaxone and Metronidazole would be reasonable coverage (no indication he is on chemo in question), so no urgency to switch. Empiric candida coverage not required after only 2 days. 19) D - This patient does not yet have a diagnosis of endocarditis (does not meet Duke Criteria based on provided info alone – 3 minor criteria). If a patient is stable, empiric antibiotic should be held until A) diagnosis is made based on Duke criteria and B) at least 3 sets of blood cultures have been obtained. Generally continue to hold antibiotics until blood cultures are resulted and either organism is obtained or culture negative endocarditis is diagnosed. For patient with suspected endocarditis who are a) acutely ill (e.g. septic) or b) show high risk signs (e.g. concern for embolization) and no organism yet obtained, empiric therapy should be started after initial blood cultures taken, following the guidelines for culture negative endocarditis. Based on IDSA: 1. Acute native valve endocarditis: S. Aureus, B-hemolytic streptococci, and aerobic GNB 2. Subacute native valve endocarditis: S. Aureus, VGS, HACEK and enterococci 3. Prosthetic Valve Endocarditis 1 from placement: staphylococci, VGS, enterococci *Vancomycin + Ceftriaxone is reasonable coverage for all of these 20) D - JAMA RCE: Pain in chronic wound (LR 11-20), Foul odour (LR 1-3), Purulence, exudate, erythema, warmth, and edema (LR < 1.0) 21) A. DENGUE - Incubation periods critical. Symptom onset > 14 days after travel essentially rules out dengue 22) C - The travel history and appearance is suggestive of an amebic liver abscess. Amebic liver abscesses are caused by Entamoeba Histolytica. Entamoeba Dispar is a non-pathogenic species that resembles E. Histolytica on microscopy. Naegleria and Acanthamoeba primarily cause CNS related disease. Naegleria is also not found in Canada. The incubation period is 5 days and death usually follows 5 days after symptom onset, so it is unlikely that a case even in a traveller would occur be seen in Canada.

191

Nephrology Friday, December 1st, 2023 Dr. Fatema Zaidi

www.internalmedicinereview.ca

© Internal Medicine Review 2024

Overview • • • • • • •

Acid Base Hypo/Hypernatremia Hypo/Hyperkalemia Hypertension Glomerular Disease & AIN CKD Complications DM2 and CKD 2022

• BONUS Nephro Nuggets – – – – – – – – –

•

“Lumps” in the kidney ADPKD Choosing Wisely Nephrolithiasis HTN (practical) When to biopsy Urine lytes/Hypokalemia (bonus) Hematologic malignancies and the kidney Landmark trials

Bonus MCQ Cases

2

Acronyms Used in this Talk AOBP

Automated Office Blood Pressure

ABPM

Ambulatory Blood Pressure Monitor (usually 24 hr)

AG ( UAG)

Anion Gap (Urinary Anion Gap)

AIN

Acute Interstitial nephritis

CHEP

Canadian Hypertension Education Program

ESA

Erytropoietin Stimulating Agent

EGPA

Eosinophilic Granulomatosis w/ Polyangiitis (Churg-Straus)

FSGS

Focal Segmental Glomerulosclerosis

GPA

Granulomatosis with Polyangiitis (Wegner’s)

HTN

Hypertension

HBPM

Home Blood Pressure Measurement

MBD

Metabolic Bone Diseases

MPA

Microscopic Polyangiitis

OBPM

Office Blood Pressure Measurement

RAS

Renal Artery Stenosis

RTA

Renal Tubular Acidosis

3

Guidelines reviewed • Hypertension – CHEP 2020-25, C-CHANGE 2022 • KDIGO (kdigo.org) – CKD – KDIGO 2022 management of DM with CKD – AKI – MBD – GN –2021 GN guidelines, 2023 lupus nephritis guidelines – Anemia 4

Acid/Base and Electrolytes

5

Approach to Nephro Labs • Acid/Base Disorders • Hyponatremia • Hypernatremia

There are several practice MCQs and scenarios in the bonus slides to cement the concepts herein!

• Hyperkalemia • Hypokalemia 6

Case 1 - 2024 32 year old male presents with nausea, vomiting and confusion. He was seen to be drinking antifreeze yesterday. His labs show Na 135, Cl 95, Hco3 12. Urea is 20, glucose 10. Measured serum osm is 290. Creatinine is 300. What is the next best step for the likely ingestion? a) IV ethanol b) IV fomepizole c) Hemodialysis d) Supportive care 7

Acid-base: H2O + CO2 ↔ H2CO3 ↔ HCO3 - + H+

pH

7.4

HCO3 is DOWN PCO2 is UP = MIXED

HCO3 is UP PCO2 normal or UP = METABOLIC alkalosis

PCO2 is DOWN HCO3 normal or down = RESPIRATORY alkalosis

8

Acid/Base Disorders ΔpCO2 : ΔHCO3

1. Determine the primary disorder:

a) Look at the pH b) Then look at the HCO3 (24) & pCO2 (45)

RESPIRATORY ACIDOSIS

RESPIRATORY ALKALOSIS

ACUTE

10:1

10:2

CHRONIC

10:3-4

10:4-5

For every rise of 10 of pCO2 the HCO3 will rise by 1 (or 3-4) ΔpCO2 : ΔHCO3

For every fall of 10 of pCO2 the HCO3 will fall by 2 (or 45) ΔpCO2 : ΔHCO3

2. Compensation?

-Metabolic Acidosis 1:~1 (↓ HCO3 :↓ CO2) *winter’s formula/last 2 digits of pH ± 2 -Metabolic Alkalosis 1:0.7 (↑ HCO3 : ↑ CO2)

-Respiratory Alkalosis (↓ CO2 : ↓ HCO3). Chronic (10:4-5) / Acute (10:2) -Respiratory Acidosis (↑ CO2 : ↑ HCO3). Chronic (10: 3-4)/ Acute (10:1) 9

Metabolic Acidosis 1. Calculate the anion gap: Na – Cl – HCO3 –

Adjust for albumin (every decrease in albumin by 10, add 2.5mEq/L to the AG)

2. Calculate the “delta-delta”: ΔAG (12-AG):Δbicarb(24-bicarb) – –

The delta AG (from normal = 12) should be equal to the change in bicarb (from normal = 24) when pure AGMA See next slide

3. Calculate the osmol gap: [calculated osm: 2xNa + Gluc + BUN] – [serum measured osm] – –

Normal osmolar gap = 10; higher means additional unmeasured osmoles− think EtOH or toxic alcohol (dangerous to miss!) Could have high osmolar gap with normal anion gap early in toxic alcohol Calculated osm= 2 salts and a sticky Bun!

10

Delta:Delta

Delta:Delta ΔAG :ΔHCO3

Interpretation

∆AG >>∆HCO3

>2, bicarb doesn’t change enough, meaning a secondary alkalosis is opposing the acidosis Concurrent Metabolic alkalosis (HCO3 higher than expected) with anion gap metabolic acidosis

∆HCO3 ≈ ∆AG

0.8-2, Pure AG acidosis

∆AG 25: (will not be chloride/NS responsive) – High BP: • Hyperaldosterone (htn, hypoK, alkalosis, high aldo) • Liddle’s (htn, hypoK, alkalosis, low aldo) • Cushings

– Low BP:

• Barter’s (mimics Loops – low K, low Mg) • Gittleman’s (mimics thiazides – low K, low Na, high Ca)

– Excess bicarb ingestion

17

Case 1 32 year old male presents with nausea, vomiting and confusion. He was seen to be drinking antifreeze yesterday. His labs show Na 135, Cl 95, Hco3 12. Urea is 20, glucose 10. Measured serum osm is 290. Creatinine is 300. What is the next best step for the likely ingestion? a) IV ethanol - This person likely had ethylene glycol intoxication b) IV fomepizole - He has a high anion gap metabolic acidosis - Anion gap is high at 28 (135-95-12 = 28) - Osm gap is 10 (2x135 + 20+ 10 = 300. 300-290=10) c) Hemodialysis - Likely he has metabolized all of his ethylene glycol thus there is no role for ethanol or fomepizole d) Supportive care - You would provide supportive care until he requires dialysis 18

Hyponatremia • The most important questions to answer on initial assessment:

– Is this a medical emergency? TBW= Total Body Water – Is this symptomatic or asymptomatic? – Is this acute, chronic, or acute-on-chronic? Female- 50% of Wt (Kg) or Wt (Kg) x 0.5 • Acute bolus and repeat levels • If they are hypovolemic -> 1ml/kg/hr 21

Hyponatremia • Hyponatremia is a problem of too much water in the body Too much water comes from 1. Too much water intake compared to salt – Psychogenic polydipsia, beer potomania, D5W – ADH off à pee out excess water à dilutes urine à low urine osm (300) + hyponatremia ADH is on because of appropriate and inappropriate reasons

22

High Water:Solute intake • •

ADH is appropriately off (U osm 40) 1. SIADH •

Nausea/vomiting, Pain, Drugs- TCAs, SSRIs, carbamazepine, ecstasy/MDMA, Thiazides, CNS disorders, tumors (SCC lung), Pneumonia/ lung infections, adrenal insufficiency, hypoT4 – Treatment: fluid restriction (next step is to add salt tablets 1 g BID/TID and/or urea 15 mmol BID)

24

Over correction • Want to avoid rapid correction in chronic HypoNa to prevent osmotic demyelination

– Risk factors for demyelination: hypokalemia, malnutrition, alcoholism, liver disease, low starting Na

–

Tip: “If urine output exceeds 150 ml/hr page MD”

– Indicates that ADH has turned off and patient will suddenly start

peeing free water thus raising serum sodium faster than expected Risk Factors Change in Na per Day for chronic

–

IF overcorrected: – DDAVP – D5W – Call nephro

HypoNa

Target

Maximum

None

6

8

Any risk factor

4

6 25

BONUS Read on own

Hyponatremia pearls

Isotonic hyponatremia (sOsm 280-295): Pseudohyponatremia -hypertriglyeridemia -paraproteinemia (multiple myeloma) -obstructive jaundice Hypertonic (sOsm >295) hyponatremia -hyperglycemia -mannitol -Immunoglobulins (IVIG) Hyponatremia in the dialysis population: they’re drinking too much water inbetween sessions! Treatment : fluid restriction (not salt restriction)

26

Case 2 - 2024 A 45 year old female recently had a showering of strokes from infective endocarditis. A few days later you notice sodium trending up to 155. You initiate increased po intake of water but her sodium won’t improve. Urine osm is 100. What is the next best step? a) Water deprivation test b) DDAVP trial c) ½ NS @ 45 cc/hour d) Supportive care 27

Management of Hypernatremia Dehydration or Free Water Deficit Calculate Water Deficit= % change in [Na] x TBW

1.

Where % change in [Na] = Serum Na- 140 140 Water Deficit= % change in [Na] x TBW

– –

2.

– –

TBW= Total Body Water

Female= 50% of Wt (Kg) or Wt (Kg) x 0.5 Male= 60% of Wt (Kg) or Wt (Kg) x 0.6

Determine rate of correction of water deficit:

Acute (e.g. postop central DI, nephrogenic DI): Correct quickly (rare) Chronic (e.g. dementia LTC patients): Correct water deficit slowly: maximum 0.5 mmol/L per hour/ 12 points over 24 hours (Avoid cerebral edema!)

• •

IF POSSIBLE USE ENTERAL ROUTE (If NG, give free water flushes)

Large volumes of D5 à hyperglycemia à glucosuria & a solute diuresis, worsening polyuria and hypernatremia 28

Diabetes Insipidus (DI) • Clinical clues: polyuria + hypernatremia – (and polydipsia if patient is able to drink) • Types of DI: – Central DI (brain can’t make/secrete ADH) – Nephrogenic DI (kidney can’t respond to ADH) – causes: Lithium, hypercalcemia, hereditary, resolution of obstructive nephropathy

• Diagnosis: – Step 1: One of: • Labs: high serum Na with inappropriately low urine osmolality confirms diagnosis • Water deprivation test: Urine osmolality does not rise appropriately despite –

rising serum osmolality/ serum Na

Step 2: DDAVP (2-4 mg IV/SC) test to differentiate between central and nephrogenic DI 29

Diabetes Insipidus Diagnostic Criteria

Response to DDAVP

Central DI

• • •

Serum Osm > 295, Na > 145 But Urine Osm is low, (< Serum Osm) After water deprivation test, urine osm remains low

Responds! Urine osm increases (by 50%) Urine output decreases

Nephro DI

• • •

Serum Osm > 295, Na > 145 But Urine Osm is low, (< Serum Osm) After water deprivation test, urine osm remains low

Complete nephro DI: no change Partial: outside the scope of this exam!

Psychogenic Polydipsia

• •

Sosm6 mos age 65

Outline • • • • • • •

Hypertension & Pre-eclampsia VTE and ITP in pregnancy Diabetes in pregnancy COVID-19 in pregnancy High Yield GI disorders of pregnancy High Yield Cardio in pregnancy BONUS SLIDES – – – –

CCS 2021 Update: Clinical Practice Update on CV Management of the Pregnant Patient ACC/AHA 2023 Chronic CAD Guideline with pregnancy recomendations

High Yield Infections in pregnancy High Yield Heme disorders of pregnancy Drugs in Pregnancy Approach to the Obstetric Patient in a Scenario

• Pre-pregnancy counselling for women with chronic conditions

– Normal Labs in Pregnancy

•

COVERED ELSEWHERE:

– Thyroid à ENDO – Asthma Treatment à RESP – HIV and others in pregnancy à ID 66

Cardiovascular diseases in pregnancy • Congenital heart disease + mechanical valves requires management in specialized centres • As our demographics change, cardiovascular diseases need to be included in standard differentials of pregnancy related complaints • As general internists, remember to counsel women of childbearing age appropriately + discuss contraception + refer for subspecialty mgmt if planning preg CCS 2021 Clinical practice update on cardiovascular management of the pregnant patient. 67 Similar to ACC/AHA Chronic CAD Guideline 2023 which has nice section on Pregnancy

ACC/AHA 2023 Chronic CAD Guideline – Pregnancy Notes • Be aware that a history of heart disease puts women at very high risk of cardiac events in pregnancy • Women with Chronic CAD have high rate of adverse maternal, fetal, neonatal events in pregnancy Statins … FDA recently (2021) removed black box warning re statins in pregnancy (still C/I in lactation). Limited data re safety but maternal risks must be considered if discontinuing.

68

Peripartum Cardiomyopathy • Normal Pregnancy physiology – Cardiac output and plasma volume increases by 50%, peak in T2, decline by 2 weeks postpartum but can be up to 6 months post partum – Common physiologic symptoms in pregnancy: dizziness, palpitations, dyspnea, orthopnea, peripheral edema – Physiologic dyspnea of pregnancy (up to 75%), due to progesterone causing hyperventilation, onset first or second trimester, mild and not progressive, not activity limiting • Hypoxia is abnormal!

– Sinus tachycardia, prominent or mildly elevated JVP, displaced apex (due to elevated diaphragm), S3 common (up to 80% of women), occasional S4, soft systolic flow murmur, varicose veins and peripheral edema

• Definition: – Systolic dysfunction EF40% = 20% recurrence of peripartum cardiomyopathy – If EF remains 5mg:

– dose-adjusted LMWH trimester 1 followed by warfarin Trimester 2, 3 (Class IIa) or – dose adjusted LMWH all three trimesters (Class IIb)

• Delivery:

– All patients need a planned delivery – Avoid delivery on VKA, due to high risk of fetal intracerebral hemorrhage. VKA should switch to doseadjusted bid LMWH or IV UFH at least 1 week before planned delivery (CLASS I) – Women on LMWH must be switched to IV UFH at least 36h prior to planned delivery (CLASS I) – Stop UFH at least 6h prior to planned vaginal delivery (CLASS I) – If labour begins or urgent delivery required in woman on VKA, cesarean section should be performed after reversal of anticoagulation (CLASS I) – Bridge back to Warfarin postpartum (safe during breastfeeding)

BONUS Read on own

Valvular Heart Disease (VHD) in Pregnancy (AHA/ACC Valve 2020)

• Severe stenotic VHD = High risk of heart failure, arrhythmia, intrapartum instability. • Pre-pregnancy evaluation (TTE + consult with cardiologist expert in managing VHD in pregnancy) recommended (Class I) for all women with known or suspected valvular disease considering pregnancy – Symptomatic severe STENOTIC lesions should have surgery pre-preg (Class I) – Asymptomatic severe STENOTIC lesions and asymptomatic severe MR suitable for repair should be considered for intervention pre-pregnancy (Class II) – REGURGITANT lesions are generally better tolerated in pregnancy

76

Respiratory Disorders in Pregnancy •

Community Acquired Pneumonia – Increased risk of preterm birth, pre-eclampsia, low birth weight – First-line antibiotics : Macrolide or beta-lactam, Oseltamivir and flu, pneumococcal vaccines safe • FQs in animal model associated w/ cartilage problems – Where appropriate (ex exacerbations in pts with CF!), you can use these however!! Counsel. – No increased SA or Fetal malformations in cohort of women exposed to FQ in Tri 1. Non signif increase in malformation in moxifloxacin group; cipro gati levo no difference. » Antimicrob Agents Chemoth 2014 58:8(4392-4398).

• •

• Tetracyclines – fetal teeth staining, bone growth suppression • Sulfa - kernicterus Asthma – same treatment as non-pregnant, steroids are safe (po and inhaled) OSA in pregnancy – gets worse due to N physiologic changes of pregnancy; associated with adverse maternal outcomes. No guidelines on screening/treatment in pregnancy (consensus = treat modsevere, consider screening if at-risk pregnancy (ex early 30)

FETAL: higher rates of some fetal anomalies (Neural Tube), SA MATERNAL: GDM, HTN, OSA, preeclampsia, increased risk of C-Section, VTE

Prior Preeclampsia

1/6 chance repeat Preeclampsia If Prior SEVERE preeclampsia 25% if 150min moderate intensity activity / week – ASA to prevent preeclampsia if other maternal risks exist – Folic acid >1mg/day, Vitamin D >400 IU / day – Closer surveillance (OB to discuss with patient, + consider delivery 39-40weeks to reduce risk of stillbirth if BMI >40… details for OB to know, not internist) Post-partum – Higher risk of PP Depression, anxiety, recommended to screen for same – Higher rates of breastfeeding discontinuation – lactation support recommended – Thromboprophylaxis if C-Section

Labs in Pregnancy • What is the abnormal lab in a pregnant patient in 3rd trimester? a) Hgb 110 b) WBC 12.9 (8.9 neutrophils) c) Plt 124 d) Cr 96 e) BG 3.7 f) ALT 45 g) ALP 172 h) Bilirubin 8 86

Labs in Pregnancy • a) b) c) d) e) f) g) h)

What is the abnormal lab in a pregnant patient in 3rd trimester? Hgb 110 – Hb cut-offs in pregnancy: >110 in first trimester, >105 in second and third trimesters, >100 post partum WBC 12.9 (8.9 neutrophils) – elevated WBC predominantly neutrophils seen in pregnancy due to demargination (like stress response to steroids). WBC up to 13 common and not reflective of infection. Plt 124 – gestational thrombocytopenia common in third trimester due to hemodilution, usually >100. Cr 96 - Cr should drop in pregnancy due to increase in GFR by 40%! Usually Cr of 50 or less in healthy women without renal disease. BG 3.7 – normal fasting blood glucose 3.9 +/- 0.4. Due to glucose and amino acids preferentially diverted to the fetus, decrease hepatic gluconeogenesis, and increase in peripheral glucose consumption. ALT 45 ALP 172 - ALP is made by the placenta, so is normally elevated 2nd, 3rd trimester. AST, ALT, Bilirubin, GGT should be within normal limits in pregnancy. Bilirubin 8

87

Infections in Pregnancy • Special clinical scenarios – Asymptomatic bacteriuria à Associated w/ PTL, LBW; progression to pyelo à TREAT

– Genital infections peripartum à active HSV lesions warrant C-section to reduce

neonatal exposure. For women with HSV in pregnancy or hx recurrent disease, consider acyclovir 36+ wks to suppress outbreak.

– Listeria à Suspect if sepsis or meningitis, cover with ampicillin – Syphilis à even if PCN allergic, best to desensitize and treat w/ PCN (alternatives ex. doxy C/I in pregnancy)

– HIV à Indication to start ART. PJP can be treated with Septra, ensure high-dose folate. C-section unless VL Decide on further treatment 15

Breast Cancer: Staging Stage I Small tumor, no nodes

Stage II

Stage III

Stage IV

Large tumor/ + nodes ( Mediastinal -> Supraclav/ Scalene • Ipsilateral vs Contralateral

AJCC 8th edition TNM staging

High Yield

Non-Small Cell Lung Cancer: Early Stage Management Stage 1

Stage 2 and 3 (Resectable)

Definitive Treatment

Fit for surgery: Surgery Unfit: Radiation (SBRT*) 12

Surgery

Adjuvant Treatment

None * Caveat for 1B- NoE

Adjuvant chemo

Stage 3 (Unresectable) Concurrent chemoradiation Immunotherapy (Durvalumab) x1 yr13

*SBRT = Stereotactic Body Radiation Treatment NoE- 2023 Update: • Neoadjuvant Chemo+ Immuno becoming standard of care for resectable lung cancer • For resectable stage 2 and 3 lung cancer with EGFR mutation- Adjuvant Osimertinib x 3 years • For resectable stage 2 and 3 lung cancer withOUT EGFR mutation- Adjuvant Atezolizumab x 1 year

25

Lung Cancer: Note on Radiation Pneumonitis • •

•

•

•

Typically 4-12 weeks (1-3 months post radiation) Corresponds to radiation field, depends on dose of radiation and presence of concurrent chemotherapy Mimics pneumonia in radiographic and clinical presentation – Ground glass – Interstitial changes Typically by the time patients present, no longer immunosuppressed by chemo (beyond day 7 to 14 post-chemo) Treat with steroids.

Source: Dr McKenna – used with permission of patient (who did very well on steroids!)

26

**High Yield**

Non-Small Cell Lung Cancer: Metastatic Management

First Line Treatment RC Pearl

EGFR mutation positive

Other driver mutations

Driver mutation negative

Osimertinib first line

Chemotherapy +/- IO

Immunotherapy +/- Chemo14

(ex. KRAS,MET, NTRK, ALK, etc)

aside from ALK which has first-line targeted therapy- NoE

Early Referral to palliative care= Mortality benefit (Patient feels better, tolerate treatment better) 15

NoE- 2023 Update: • Amivantamab for EGFR exon 20 insertion mutation

27

**HIGH YIELD **

Small Cell Lung Cancer: Workup & Management Limited Stage Definition

Confined to 1 hemithorax/1 radiation field

Treatment

Curative Intent

Concurrent chemoradiation ± prophylactic cranial irradiation

Extensive Stage Beyond 1 radiation field (i.e. mets) or presence of malignant effusion

Incurable/ Palliative Intent

Chemotherapy + Immunotherapy + Prophylactic Cranial Radiation

(Moving away from brain rad since 2022)

• Highly chemo/radio-sensitive, but frequently relapse • Surgery is generally NOT a part of SCLC treatment unless very early stage

NoE • Chemo regimen: Cisplatin/ Carboplatin + Etoposide • Immunotherapy: Atezolizumab OR Durvalumab 28

**HIGH YIELD **

Lung Cancer: Paraneoplastic Syndromes Paraneoplastic Syndromes Highlights

Cancer Type SCLC

• • • •

SIADH Lambert-Eaton Myasthenic Syndrome (LEMS) o Anti-VGCC Ab* : reduced presynaptic ACh release o Similarities to myasthenia gravis, but notably absent/decreased reflexes Encephalomyelitis & sensory neuropathy o Anti-Hu Ab* cross reacts w/ both SCLC antigens and neuron-specific RNA-binding nuclear proteins Cushing’s syndrome o Ectopic ACTH production. NOT suppressed by dexamethasone supp test

Adeno NSCLC

•

Hypertrophic osteoarthropathy o Clubbing + periosteal new bone formation of tubular bones o Symmetrical, painful arthropathy (ankles, knees, wrists, elbows)

Squamous NSCLC

•

Hypercalcemia o PTHrP production (NOT measured in modern assays for PTH)

*Only order antibodies (serum + CSF) if suspecting the clinical syndrome. NOT used as a screening test for paraneoplastic syndromes

29

MCQ 3 Ms. Sega Rett is a 55F with LUL lung cancer, received concurrent chemoradiation. 7 weeks post treatment presents with 2 weeks of non-productive cough and low grade fever. Appears well on exam, satting 94% on room air but desat to 88% with exertion, no wheezing on exam, crackles LUL. Chest x-ray showed LUL consolidation. CT thorax shows LUL lung mass with surrounding ground glass. There’s no evidence of pleural effusion or lymphadenopathy. What is the treatment of choice? A. B. C. D. E.

Ceftriaxone + Azithromycin Azithromycin Apixaban Fluticasone/Salmeterol Prednisone

30

MCQ 3 Ms. Sega Rett is a 55F with LUL lung cancer, received concurrent chemoradiation. 7 weeks post treatment presents with 2 weeks of non-productive cough and low grade fever. Appears well on exam, satting 94% on room air but desat to 88% with exertion, no wheezing on exam, crackles LUL. Chest x-ray showed LUL consolidation. CT thorax shows LUL lung mass with surrounding ground glass. There’s no evidence of pleural effusion or lymphadenopathy. What is the treatment ofWrong answers: choice? • A and B – While pneumonia is on the differential, the key here A. B. C. D. E.

Ceftriaxone + Azithromycin Azithromycin Apixaban Fluticasone/Salmeterol Prednisone

is to recognize radiation pneumonitis C – There is no evidence of PE in the stem D – Puffers are helpful for airway disease. However this would not be the best treatment in this setting. Correct answer: • E – Oral steroids are needed to treat radiation pneumonitis so this is the best answer. In real life however, would cover both pneumonia and radiation pneumonitis.

• •

31

**HIGH YIELD **

Colorectal Cancer: Workup Diagnosis • Full colonoscopy to terminal ileum (all patients, pre-op) with biopsy Staging • CT chest, abdomen and pelvis (all patients, pre-op) Tumour and molecular markers • Carcinoembryonic antigen (CEA)

bowelcanceruk.org.uk 32

Colorectal Cancer: Management Stages I-III • Surgery upfront • Adjuvant chemotherapy for stage 3 and selected stage 2 Stage IV (metastatic) • Oligometastatic (isolated liver or lung lesions, undefined number of mets) o Metastectomy + chemotherapy (curative-intent)16 • Non-operable o Chemotherapy ± either VEGF Inhibitor (Bevacizumab) or EGFR inhibitor (Panitumumab/Cetuximab) Typical regimens: • Post-op: FOLFOX/CAPOX (5-FU/Capecitabine, Leucovorin, Oxaliplatin) • Metastatic: FOLFOX/FOLFIRI (Irinotecan instead of Oxaliplatin) ± Bevacizumab/Panitumumab/Cetuximab 33

Colorectal Cancer: Surveillance

Marked with ⌘

• Stage 1 o Colonoscopy 1 year post resection o Subsequent colonoscopies based on findings of previous scope (not annually), if negative, every 5 years. ⌘ • Stage 2-3 o Colonoscopy 1 year post resection o Years 1-3: Q6 month history, physical exam, CEA, CT C/A/P o Year 4-5: Annual history, physical exam, CEA, CT C/A/P

34

**HIGH YIELD **

Gastroesophageal Cancer Common location: Risk factors:

Squamous cell

Adenocarcinoma

Upper-mid esophagus

Distal esophagus

• EtOH • Caustic injury • Smoking

• • • •

Barrett’s esophagus GERD Obesity Smoking

W&W: Leser-Trelat sign- sudden eruption of seborrheic keratosis. Most commonly implicating GI cancers- out of those gastric most common. Also seen in breast. Treatment • Localized – Pre-op Chemo+radiation (concurrent) -> Surgery • Metastatic – NoE 35

**HIGH YIELD **

Prostate Cancer: Workup • Biology o Like Breast Cancer feeds on Estrogen, Prostate Cancer feeds on Androgen (Hence backbone treatment is Androgen Deprivation Therapy- ADT) o Mets primarily to LN and bone o W&W: associated with coagulopathy. DIC most common in metastatic setting/ post-operatively • Diagnosis o Digital rectal examination o Prostate biopsy with calculation of Gleason Score • Tumour Markers o Serum PSA • Staging Imaging (if symptomatic or “high-risk”- NoE) o Imaging = Bone scan, CT chest/abdomen/pelvis

36

Prostate Cancer: Management

Marked with ⌘

Castrate Sensitive- Responds to lowering Androgen

Castrate Resistant

Early/ Localized

1.

Active surveillance (PSA monitoring, intervene if progression) • Choosing Wisely: “Do NOT initiate management in patients with lowrisk prostate cancer without first discussing active surveillance” ⌘ 2. Radical prostatectomy ± lymph node dissection 3. Radiation (Brachytherapy or External Beam)

NoE

Metastatic

1. ADT + CYP17 inhibitor (shuts down androgen production) (Abiraterone) 2. ADT + second-generation antiandrogen (Enzalutamide, Apalutamide) 3. ADT + Chemotherapy + second-generation antiandrogen (Darolutamide)

NoE

*ADT = GnRH agonist (Lupron) or antagonist (Degarelix) 37

Prostate Cancer: Treatment side effects Androgen Deprivation Therapy Osteoporosis Decreased libido Gynecomastia Hot flashes Fatigue

Docetaxel (chemo)

Non-steroidal antiandrogen

Peripheral neuropathy Abiraterone (+ Prednisone) N/V • Hyperaldosteronism Hair loss o HTN o Hyperglycemia o Hypokalemia • CV disease Enzalutamide/Apalutamide • •

Seizure/ Cognitive issues/ Falls DRUG-DRUG INTERACTIONS

ALL patients on ADT should be on Calcium (if needed), Vitamin D supplementation, and a Bisphosphonate for metastatic disease or low bone mineral density 38

BONUS Read on own

Testicular Cancer

**HIGH YIELD **

Imaging: Scrotal ultrasound, CT chest/abdomen/pelvis Diagnosis: Made by radical orchiectomy, (NEVER biopsy testicular mass due to risk of tumor seeding) Tumour markers: β-hCG, AFP, LDH Typical chemo regimen: BEP Management (Bleomycin, Etoposide, Cisplatin) • Localized – Surgical orchiectomy • Metastatic – Chemotherapy (highly curable, chemo-sensitive, good prognosis) Tumour type 1)

2)

β-hCG

AFP

Germ cell tumour (95%) • Seminoma (1hr AND ANC ≤0.5 OR 7 days) and/or prolonged Abx use Diagnosis • Investigations – Blood culture x2 PIV + CVC (if present), Urine culture, Skin exam, Sputum (if present), Stool sample + C. diff (if diarrhea), CXR and Other imaging/tests as indicated Treatment • Broad spectrum antibiotics IMMEDIATELY (often institution-dependent) o Examples: Piptazo to start, if still febrile add Vancomycin

G-CSF used as 2o prophylaxis – but does NOT improve outcomes

41

Outpatient management of Febrile Neutropenia in adults16 •

• •

Based on MASCC score (DO NOT memorize MASCC) o e.g. no hypotension, no active COPD, no volume depletion, no or mild symptoms, solid tumor rather than heme malignancy, age 6mo

Avoid chemotherapy in those who are unlikely to benefit (patients ECOG 3-4) ⌘

Marked with ⌘

ECOG score Score

Description

0

Asymptomatic

1

Symptomatic Completely ambulatory Able to do light house work

2

50% day spent in bed/chair Only limited self-care

4

Bedbound

5

Dead

62

Pain Control Options • Non-opioids – Acetaminophen, NSAIDs • Opioids – Morphine, Hydromorphone, Fentanyl, etc. • Adjuvants – Pregabalin, Gabapentin, TCAs

Nociceptive pain

Neuropathic pain

Opioid titration Goal to address most of the baseline pain with long-acting formulations 1. Start with immediate release (IR) formulation Q1-Q4H PRN (q4h PRN for opioid naïve) 2. Low dose à increase to effect/side effects 3. Allow for steady state (~24hrs = 5 half lives) 4. Once steady state achieved, calculate total use in past 24 h 5. Divide 24hr dose into distributed doses of long acting formula 6. Order breakthroughs (= 10% of total daily dose in IR tabs) Cannabinoids Nabilone > placebo, but benefits compared to other analgesics not proven (CADTH 2011) 63

**HIGH YIELD **

Pain Control

Picking an opioid • No comorbidities – No one right answer. Usually based on physician comfort • Renal dysfunction – Hydromorphone, Methadone, Fentanyl ”No Morphine with No Urine” o Do NOT use: Morphine, Codeine, Tramadol, Demerol • Hepatic dysfunction – Hydromorphone, Morphine, Fentanyl “No Meth with Failing Heps” o Do NOT use: Codeine, Methadone • Excess opioid-induced itching/urticaria – Fentanyl Opioid side effects • Common: Constipation, Nausea, Vomiting, Sedation **Important, lesser-known side effect • Rare: Confusion, hallucination, Myoclonus • Methadone specific: QT prolongation, Drug-drug interactions (CYP3A4 metabolism) • If treatment addresses source of pain, need to decrease opioids to prevent toxicity 64

**HIGH YIELD **

1. 2. 3. 4. 5.

Opioid Rotation

Calculate total daily dose (TDD) of drug Convert TDD to ORAL MORPHINE EQUIVALENT using equianalgesic table19 below Convert TDD to drug of choice Calculate regular/interval dosing – long-acting (BID) or short-acting (q4h) Calculate PRN dose (q1h) based on 10% of TDD or 50% of q4h dose Equivalence to 30 mg oral morphine

To convert to PO morphine, multiply by

PO : IV/SC

Effect Duration

Morphine

30 mg

1

2:1

2-4 hrs

Oxycodone

20 mg

1.5

N/A

3-4 hrs

Hydromorphone

6 mg

5

2:1

2-4 hrs

Transdermal Fentanyl

60-130 mg morphine = 25 mcg/hr (~100mg = 25mcg/hr) 135-179 mg morphine = 37.5 mcg/hr 180-224 mg morphine = 50 mcg/hr 225-269 = 75 mcg/hr

48-72 hrs

Clinical Pearl: If switching meds due to toxicity (i.e. myoclonus), consider 25-30% dose reduction to allow for cross tolerance à BUT, if pain is not well-controlled, then no need to decrease dose 65

Symptom Management

Marked with ⌘

Dyspnea • Stepwise approach: Non-pharmacologic therapies (i.e. fan, open window) à oxygen (if hypoxic) à Opioids20 • Oxygen ineffective for non-hypoxemic dyspnea⌘ Nausea and Vomiting • Direct treatment towards etiology • Unknown etiology – Dopamine antagonist favored (haloperidol, olanzapine) or agents used for chemotherapy-induced nausea and vomiting Delirium • Risperidone/haloperidol do not alleviate distress at end of life and tend towards harm (JAMA 2017) o May slightly worsen delirium symptoms (low quality evidence, Cochrane Review 2020) o May increase adverse side effects (EPS symptoms) (low-mod quality) Cachexia: • Refer for counseling + assessment re: high protein, nutrient dense food, advise against extreme diets/fad diets • Do NOT offer enteral tube feeding or parenteral nutrition to manage cancer cachexia • Evidence insufficient to strongly endorse any pharmacologic agent 66

Symptom Management

Marked with ⌘

Constipation • Considerations o Disease and drug effects o Check calcium & TSH o Counsel on bowel regimen if starting opioids • Medications o Stimulant laxative (Senna) – Consider giving alongside opioids as prophylaxis o Osmotic laxatives (Lactulose, PEG) o Enema o Selective opioid antagonist – Methylnaltrexone SC (Relistor©), Naldemidine PO (Symproic ©) o Chloride-channel agonist (Lubiprostone) o Do NOT use stool softeners (Colace) alone for opioid induced constipation (no better than placebo)⌘ 67

End-of-Life Discussion

Marked with ⌘

• For patients with limited life-expectancy begin end-of-life discussion and advanced care planning early ⌘ o Involve Palliative Care early, even if patient is pursuing disease-directed treatment (i.e. chemo) • Assess understanding of disease and treatment as well as goals • Address emotional, social, and spiritual needs (Comfort Care for Patients Dying in the Hospital, NEJM 2015) • Discontinue statins (JAMA Int Med 2015: safe, improves QOL and saves money) • Do not transfuse RBC at arbitrary cut-off w/o symptoms ⌘

68

Medical Assistance In Dying – the law changed March, 2021 & changes again March 2024

**HIGH YIELD **

Eligibility (must meet ALL of the following…) 1. Be eligible for health services funded by government (i.e. have a health card) Pt must be capable: Cannot be 2. Be ≥ 18 years old and have decision making capability in delirium, advanced dementia 3. Have a grievous and irremediable* medical condition • “Have a serious and incurable illness, disease or disability” • Excludes Mental Illness… **until March 17, 2024** then law changes •

https://www.camh.ca/en/camh-news-and-stories/maid-and-mental-illness-faqs has a nice summary

Mental Illness includes conditions primarily in domain of psychiatry (ie depression), but does NOT include neurocognitive or neurodevelopmental disorders. Make a voluntary request for MAID, free from outside pressure or influence Provide informed consent to receive MAID •

4. 5.

*Grievous and irremediable definition • Does not need to be a fatal or terminal condition • Must be a serious illness, disease, disability in an advanced, irreversible state • As of March 2021 – Supreme Court removed requirement that death is reasonably foreseeable, created 2 track approach!

69

Stream 2: Death is NOT foreseeable

Stream 1: Death is reasonably Foreseeable • • •

•

Request in writing, signed by independent witness 2 independent MD/NPs must confirm all eligibility criteria met Person must be given opportunity to withdraw consent, and confirm consent expressly before receiving MAID

•

•

*10 day reflection period is now REMOVED for those whose death is reasonably foreseeable*

•

•

MAID

Request in writing, signed by independent witness 2 independent MD/NPs must confirm all eligibility criteria met AND consult with expert in the medical condition (if MD/NP is unfamiliar with it) The person must be informed of means to alleviate suffering and be offered consults with experts in this (incl. counselling, pall care…) The eligibility assessments must take at least 90d, but this period can be shortened if pt about to lose capacity Person must be given opportunity to withdraw consent, and confirm consent expressly before receiving MAID

MAID: Changes to Final Consent Requirement • Pt does not have to provide consent immediately before provision of MAID if : o Pt has been assessed and approved for MAID o Pt was at risk of losing decision making capability prior to receiving MAID and was made aware of that risk o Person makes arrangement in writing with their practitioner to waive final consent, and according to which their practitioner will provide MAID on their preferred date if they have lost capacity (“Audrey’s amendment” )

71

MCQ 5. Pain Management Mr. T Pain, a 48yM with metastatic lung CA presents with an acute pathological T8 fracture. He rates his pain as 10/10. He is nauseous and vomiting. AKI with Cr 200. He was taking M-Eslon 90 mg po BID for pain plus 20 mg morphine IR for breakthrough, 3 doses per day before the Opioid Rotation Calculation fracture occurred. In=addition to dexamethasone, what treatment will 1) TDD 240 mg morphine po 2 to get sc/IV equiv: 120mg you initiate for2)hisDivide painbycontrol? Due to renal toxicity, convert to non-morphine (eg) hydromorphone – divide a) Morphine3)IV by 20mg q4h prn 5 = 24mg total daily iv/sc dose 4) WhenContin converting dose reduce to avoid toxicity AKI =prn 3mg q4 (18mg per b) Hydromorphone 12mg po BID + 5 mg IRwq1h day) c) Hydromorphone 3mg sc q4h + 2mg sc q1h prn 5) Calculate PRN = 10% TDD Answer C:5mg Hydromorphone sc q4h 2mgprn sc q1h prn d) Hydromorphone sc q4h +3mg 3 mg sc +q1h Wrong Answers: Morphine shouldn’t be used in AKI. Patient is vomiting so po e) Fentanyl patch 50 mcg q 72h + hydromorphone 2mg sc q1h PRN hydromorphone not good. Fentanyl patch takes 12h to ‘kick in’ so not ideal in this setting of severe acute pain 72

Questions? Many practice MCQs available in your BONUS materials for self-study and on FLEXIQUIZ online

73

REFERENCES 1. 2. 3. 4. 5. 6. 7.

8 9. 10.

11.

Canadian Task Force on Preventative Health Care: Breast Cancer Update (2018) – Klarenbach S, et al. Recommendations on screening for breast cancer in women aged 40-74 years who are not at increased risk for breast cancer. CMAJ. 2018; 190(49):E1441-E1451. Canadian Task Force on Preventative Health Care. Recommendations on screening for lung cancer. CMAJ. 2016; 188(6):425-432. Canadian Task Force on Preventative Health Care. Recommendations on screening for colorectal cancer in primary care. CMAJ. 2016; 188(5):340-348. Cancer Care Ontario. Guidelines & Advice. Colorectal Cancer Screening Recommendations Summary. Canadian Association of Gastroenterology Banff Consensus. Leddin et al. Gastroenterology 2018;155:1325–1347 CASL/AMMI – Coffin CS, et al. Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of the Liver and Association of Medical Microbiology and Infectious Diseases Canada. Canadian Liver Journal. 1.4, 2018. Terrault et al. Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance. Clinical Liver Disease. 12. 33-34. AND Singal AG et al. AASLD Practice Guideline on the Diagnosis, prevention and management of hepatocellular carcinoma. Hepatology. 2023. Accessed online Nov 4, 2023. Canadian Task Force on Preventative Health Care. Recommendations on screening for cervical cancer. CMAJ. 2013; 185(1):35-45. Canadian Task Force on Preventative Health Care. Guideline on screening for esophageal adenocarcinoma in patients with chronic gastroesophageal reflux disease. CMAJ. 2020;192(27) E768-E777 Van Poznak C, Somerfield MR, Barlow WE, Biermann JS, Bosserman LD, Clemons MJ, Dhesy-Thind SK, Dillmon MS, Eisen A, Frank ES, Jagsi R, Jimenez R, Theriault RL, Vandenberg TA, Yee GC, Moy B. Role of Bone-Modifying Agents in Metastatic Breast Cancer: An American Society of Clinical Oncology-Cancer Care Ontario Focused Guideline Update. J Clin Oncol. 2017 Dec 10;35(35):3978-3986. doi: 10.1200/JCO.2017.75.4614. Epub 2017 Oct 16. PMID: 29035643. Cancer Care Ontario. Guidelines & Advice. Breast Screening for Survivors of Breast Cancer 74

REFERENCES 12. 13. 14. 15. 16. 17. 18. 19. 20.

Baumann P, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol. 2009; 27(20):3290-3296. Antonia SJ, et all. Durvalumab after Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 377:1919-1929. Hanna et al. Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update Summary. JCO Oncol Pract. 2020 16(8):e844-e848. Temel JS, et al. Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2010; 363:733-742. Zimmer and Freifeld. Optimal Management of Neutropenic Fever in Patients With Cancer. Journal of Oncology Practice. 2019;15(1): 19-24 Yu et al. Superior Vena Cava Syndrome—A Proposed Classification System and Algorithm for Management. JTO. 2008. 8(3): P811-814 Cancer Care Ontario. Immune Checkpoint Inhibitor Toxicity Management: Clinical Practice Guideline. https://www.cancercareontario.ca/sites/ccocancercare/files/guidelines/full/ImmuneCheckpointInhibitor.pdf Reddy A, et al. The Conversion Ratio From Intravenous Hydromorphone to Oral OPIOIDS IN Cancer Patients. J Pain Symptom Manage. 2017; 54(3):280-288. Hui D, et al. Management of Dyspnea in Advanced Cancer: ASCO Guideline. J Clin Oncol.2021; 39:1389-1411. 75

BONUS Read on own

**HIGH YIELD **

Self study: High Yield List

Lymph Node Metastases • Right supraclavicular nodes o Lung, Esophageal • Left supraclavicular nodes (“Virchow’s node”) o Abdominal malignancies (via the thoracic duct) – Gastric, gallbladder, pancreas, kidneys, testicles, ovaries, prostate o Ipsilateral breast & lung • Umbilical nodes (“Sister Mary Joseph Node”) = Intra-abdominal/pelvic metastases o GI – Gastric, colon, pancreas o Gynecologic – Ovarian, endometrial o Unknown primary

76

**HIGH YIELD **

Self study: Stage IV Peculiarities (i.e. Exam Fodder)

• Lung Cancer o Pleural effusion in lung cancer = Stage IV (i.e. incurable) • Colorectal Cancer o “Few” liver or lung metastases = Stage IV, but may be curable with metastatectomy • Bladder/Prostate Cancer o Any positive lymph nodes in bladder or prostate cancer = Stage IV • Testicular Cancer o NO stage 4 in testicular cancer (i.e. all potentially curable) • Ovarian Cancer o Malignant fluid = Stage IV in all cancers EXCEPT ovarian • Malignant ASCITES with peritoneal deposits = Stage III, high risk of recurrence (attempt cytoreduction, adjuvant chemo) à curative intent • Malignant PLEURAL EFFUSION = Stage IV, but may still undergo neoadjuvant chemotherapy, debulking surgery ± chemotherapy à NOT curative intent

77

BONUS Read on own

**HIGH YIELD **

Self study: High Yield Lists

Bone metastases • Osteoblastic (ie. Sclerotic) o Prostate, SCLC, Carcinoid, Hodgkin lymphoma • Osteolytic o Multiple myeloma, NSCLC, RCC, Melanoma, Thyroid, Non-Hodgkin lymphoma • Mixed o Breast, GI, Squamous cell carcinomas (NSCLC, H&N, Cervical ca)

78

BONUS Read on own

**HIGH YIELD **

Self-Study: Cancer of Unknown Primary

Histology

Clinical Features

Work-Up

Suggested treatment

“Adenocarcinoma”

Woman, Axillary adenopathy

Mammo, MRI breast

Treat as breast ca

Woman, Peritoneal carcinomatosis

CA-125, TVUS

Treat as ovarian ca

Man, Elevated PSA, Bone metastases

PSA, Bone scan

Treat as prostate ca

Cervical adenopathy

Pan-endoscopy, PET

Treat as H&N ca

Man, Inguinal adenopathy

Lower endoscopy

Treat as anal cancer

Woman, Inguinal adenopathy

Pap smear, TVUS, endoscopy

Treat as cervical cancer or anal cancer

Young man, Midline tumour, Elevated hCG/AFP

Scrotal ultrasound

Treat as testicular primary

“Squamous cell carcinoma”

“Poorlydifferentiated carcinoma”

79

Adapted from UpToDate

BONUS Read on own

Self Study: Renal Cell Carcinoma

RCC once called “The Internist’s Tumor” due to variety of paraneoplastic phenomenons. Remember to consider as a ddx if you see any or constellation of the following: • • • • • • • • •

Hypercalcemia Hypertension Polycythemia Cushing’s Classic Triad (occurs in less than 15% of patients) • palpable mass Galactorrhea • Hematuria Amyloidosis • Flank pain Anemia Coagulopathy/ Thrombosis etc Management of Localized disease- Nephrectomy. Metastatic- NoE. 80

BONUS Read on own

Self-study: Genetics: BRCA 1 & 2 (JAMA)12

• BRCA 1 = ↑ Lifetime risk of Breast ca (70%) and Ovarian ca (45%) • BRCA 2 = ↑ Lifetime risk of Breast CA (70%), Ovarian Ca (20%), Prostate Ca, Pancreatic Ca, Gastric Ca • Criteria for genetic testing (LOW YIELD- Always changing): o Ashkenazi Jewish + breast ca at age < 50 o Breast cancer at age < 35 o Male breast cancer o Triple negative breast cancer age < 60 o Serous ovarian ca at any age o Breast + ovarian ca in same patient o Gastric, prostate or pancreatic ca in patient with significant family history of other BRCA 2-associated malignancies • Therapeutic considerations: Prophylactic mastectomy, Oophorectomy 81

Cancer type

Risk group

Screening age

Screening test(s)

Frequency

Breast ca

Average risk women

50-74 yrs

Mammogram

Q2-3 yrs

High risk women • Germline mutation • Personal Hx breast/ovarian ca • Rads to chest < 30yrs

30-69 yrs

Mammogram + MRI breasts

Q1 yr

Lung ca

At risk • ≥ 30 py smoking • Current smoker or quit ≤ 15 yrs ago

55-74 yrs

Low dose CT chest

Q1 yr x3 yrs

Colorectal ca

Average risk

50-74 yrs

FIT/gFOBT Sigmoidoscopy

Q2 yrs Q10 yrs

Increased risk • ≥ 1o relative with colon ca

40-50 yrs OR 10 years earlier than age of relative’s Dx

Colonoscopy

Q5-10 years

High risk - HNPCC

20 yrs OR 10yrs earlier than age of relative’s Dx

Colonoscopy

Q1-2 yrs

• High risk – FAP

10yrs

Sigmoidoscopy

Q1 yr

• High risk – IBD

8 yrs after Dx (pancolitis) 10-12 yrs after Dx (lef-sided colitis

Colonoscopy

Q1-3 yrs

BONUS Read on own

82

BONUS ReadCancer on own type HCC

Cervical ca

Risk group

Screening age

Screening test(s)

Frequency

At risk - Cirrhosis • Any etiology • Exclude Child-Pugh Class 4 or other severe life limiting comorbidity (1 yr mortality from liver / comorbidity negates benefit of screening)

From time of Dx

U/S + AFP

Q6months

At risk – Hep B • Endemic country (Hep BsAg prevalence >2%) • = (Asia): males ≥40, females ≥50 • African or North American blacks ≥20 yrs • FHx of HCC in 1st degree relative (start at age 40) • CASL = All HIV co-infected patients (start at age 40) • AASLD= All Hep D co-infected patients

See previous column – depends on circumstance.

Average risk

25-69yrs

(addition of AFP = new AASLD 2023)

20yrs for Blacks per CASL 2018 irrespective of gender

U/S + AFP

Q6months

(addition of AFP = new AASLD 2023)

Cervical cytology

Q3 yrs STOP if ≥ 3 negative tests after 70 yrs

83

BONUS Q1 2024 50F with Diffuse Large B Cell Lymphoma, recently received prednisone 4 days. She comes into ER feeling unwell. HR is 132, BP 90/68, Temp 38.5, RR 20. Bloodwork: Neutorphils 5, K 6.3, Ca 2.1, Cr 180, PO4 2.2, Uric acid 380, LFT normal. CT shows shrinking lymph nodes compared to the scan a month ago . She has no other significant past medical history and takes no medications. What should you do next? A.

Start IV fluids and send off G6PD testing

B.

Start IV fluids and start Allopurinol

C.

Start IV fluids and start Rasburicase

D.

Start IV fluids and Piptazo

84

BONUS Q2 2024 A 55M with recently identified large RUL lung mass, with a small right pleural effusion presents to your clinic for further workup. He is currently asymptomatic. What is the next best step? A. B. C. D.

Thoracic surgery for thoracentesis Consult early palliative care as early referral has survival advantage. Urgent referral to medical oncology to get opinion on treatment. IR for lung mass biopsy

85

BONUS Q3 2024 The same 55M, now diagnosed with unresectable stage 3 lung cancer presents to clinic with worsening shortness of breath. The effusion was sampled and was negative for malignancy. He’s ECOG 1. He has a history of anxiety and depression and is asking for your support in transitioning to end of life as this cancer can no longer be cut out. What is the next best step? A. B. C. D.

Consult MAID provider as this is a grievous and irremediable condition. Consult early palliative care as early referral has survival advantage. Urgent referral to medical oncology to get opinion on treatment. Consult psychiatry to help with anxiety and depression which is likely driving his shortness of breath.

86

BONUS Q4 2024 A 56F with triple negative breast cancer is currently on first-line treatment with pembrolizumab and chemotherapy. She presents to clinic 8 days after treatment, feeling very fatigued after 2 cycles of treatment. Her HR is 100, BP is 95/50, 100% RA, febrile. Her BW shows Na 129, K 5.2, Cr 85, TSH 1.5, LFT normal, ANC 1.0, Hb 100, Plt 180. What’s the next best thing to do? A. B. C. D.

Give Amox-Clav and a fluid bolus as outpatient. Bring back to clinic in 1 week Get random cortisol and start hydrocortisone. Bring back to clinic in 1 week Give piptazo and a fluid bolus. Admit to inpatient Get random cortisol and fluid bolus, start hydrocortisone. Admit to inpatient

87

BONUS Q5 2024 The same 56F with triple negative breast cancer, currently on first-line treatment with pembrolizumab and chemotherapy, presents now after another cycle, this time 14 days after treatment, feeling very fatigued after now 3 cycles of treatment. Her HR is 100, BP is 95/50, 100% RA, afebrile. Her BW shows Na 127, K 5.8, Cr 85, TSH 1.5, LFT normal, ANC 2, Hb 130, Plt 180. What’s the next best thing to do? A. B. C. D.

Give Amox-Clav and a fluid bolus as outpatient. Bring back to clinic in 1 week Get random cortisol and start hydrocortisone. Bring back to clinic in 1 week Give piptazo and a fluid bolus. Admit to inpatient Get random cortisol and fluid bolus, start hydrocortisone. Admit to inpatient

88

BONUS Q6 2024 A 34 premenopausal female with breast cancer on tamoxifen recently presented to clinic for routine check-up. She is having intermittent vaginal bleeding that is not part of her period. She wants to switch over to Letrozole. What would you advise her, assuming her medical oncologist is not available? A. B. C. D.

Switch to letrozole. Stop the tamoxifen. Organize an endometrial biopsy Reassure her that tamoxifen confers cardiovascular benefit, and to continue the tamoxifen Stop the tamoxifen. Organize a pap smear

89

BONUS Q7 2024 A 35M plumber presents with flushing, and a new left leg pain and swelling. HR 95, BP 165/85, O2 100%RA, 37.3 degrees Celsius. CBC shows Hb of 175, WBC 9, Plt 230. Na 132, K 4.2, Cr 250. Ca 2.9, Mg 0.74, PO4 1.25. He reports feeling tired over the last 1 year with 15 lb weight loss. He denies any SOB, cough, hematuria, but does have some back ache that is sustained in the last 3 months which he attributed to mechanical back pain. What is the next best test to assess his potential malignancy? A. B. C. D. E.

CT Abdomen and Pelvis with contrast Ultrasound KUB CT chest PET scan Upper Endoscopy with Colonoscopy

90

BONUS Q8 2024 A 34F with triple negative breast cancer on chemotherapy. She came into ER with dizziness, vomiting and ataxia. On brain MRI she was found to to have a left cerebellar lesion and bilaterally enlarged ventricles with obstructive hydrocephalus. What is the next best step? A. B. C. D.

Lumbar puncture to relieve the pressure Dexamethasone Acetazolamide Neurosurgery for shunt

91

9. Bonus MCQ Screening – (2023) A 72yF lawyer executive presents after her best friend was diagnosed with metastatic cancer and wants to be sure she doesn’t have cancer herself. She reports a family history of colon cancer in her paternal grandfather, and cervical cancer in her sister, though she says her last pap test 4 years ago was normal and never had an abnormal pap. She smoked ½ ppd from age 30-60. What cancer screening do you recommend? a) mammogram, pap smear, FIT testing b) Mammogram, pap smear, colonoscopy c) Mammogram, pap smear, colonoscopy, low dose CT Thorax d) Mammogram, FIT testing, low dose CT Thorax e) Mammogram, FIT testing 92

BONUS 2024 MCQ ANSWERS

1. C- She’s a female so not likely G6PD. She’s unwell, hemodynamic unstable, there’s signs of treatment response with biochemical features of TLS. Treat! 2. D- Need bx of primary to identify the malignancy first (Effusion can wait. May be reactive). In addition, thoracic surgery doesn’t do paracentesis. No pathology so don’t refer to med onc yet. Palliative care not appropriate- we don’t even know if this is cancer yet. 3. C- Stage 3 unresectable lung cancer can potentially be cured with chemoradiation -> durvalumab. He’s symptomatic so needs to see med onc urgently. Early palliative care referral only applies in advanced/ metastatic setting- as internist we need to know how to manage symptoms when patients are getting cured of their cancer. MAID is not appropriate as this is not an irremediable condition. This is his cancer growing likely so psychiatry at this point is not appropriate. 4. C- Day 8 post-chemo = entering period of nadir. She’s febrile and ANC 1. This is feb neut and she’s hemodynamically not great. The lower Na and K could be any reason- perhaps a little dehydrated, ate a banana too many, etc. Adrenal insufficiency is on the list but right now sepsis is what’s going to kill her. 5. D- She’s afebrile, ANC normal, day 14 is well out of nadir. With the lower Na and higher K, one has to think about adrenal insufficiency from immunotherapy. While sepsis is still on the differential, you need ot make sure you don’t miss the AI. 6. B- While tamoxifen has theoretical CV benefit, the risk of endometrial cancer is real. Biopsy is the gold standard. Pap smear is for cervical cancer screening. Need to stop the tamoxifen but can’t start AI as this now boosts estrogen in pre-menopausal woman! 7. B- While CT scan would be ideal, he has a kidney injury so it’s best to at least get an ultrasound first to rule out hydro but also evaluate for the culprit- Likely an RCC, an internist’s tumor given the thrombosis, HTN, hypercalcemia, and the polycythemia 8. B- Leptomeningeal disease is deadly and often occurs with breast cancer and lung cancer. Shunting doesn’t work well as the cancer cells just plug up the shunt. LP will cause herniation. Dexamethasone would be first line to help reduce some swelling and buy time for chemo. 9. E - mammo + FIT are correct. Last pap was age 68, not required after age 70. 15pk yr smoker so doesn’t qualify for CT chest; no 1o relative w CRC so ‘avg risk’ doesn’t need colonoscopy . 93

BONUS MCQ (2023): Pain Management A 56yF with metastatic ovarian CA presents with a malignant bowel obstruction. She has been vomiting for 3 days and unable to keep anything down. She has an acute kidney injury, Cr 217. She rates her pain as 10/10. She was taking M-Eslon 60 mg po BID for pain plus 10mg morphine IR for breakthrough, taking 4 doses per day before this bowel obstruction occurred. In addition to IV hydration and anti-emetics, what treatment will you initiate for her pain control? a) Morphine IV 10mg q4h prn b) Hydromorphone CR 6mg po BID + 2mg IR q2h prn c) Hydromorphone 2mg sc q4h + 1mg sc q1h prn d) Hydromorphone 2.5 mg sc q4h + 1.5 mg sc q1h PRN e) Fentanyl patch 37.5 mcg q 72h + hydromorphone 2mg sc q1h PRN 94

BONUS MCQ (2023): Pain Management Opioid Rotation Calculation

A 56yF with metastatic ovarian CA presents1)with bowel TDDa =malignant 160mg morphine po obstruction. She has been vomiting for 3 days and unable to keep anything 2) Divide by 2 to get sc/IV equiv: 80mg down. She has an acute kidney injury, Cr 217. She rates her pain as 10/10. 3) Due to renal toxicity, convert to non- She was taking M-Eslon 60 mg po BID for pain plusmorphine 10mg morphine IR for – divide by 5 (eg) hydromorphone = 16mg totalobstruction daily iv/sc dose breakthrough, taking 4 doses per day before this bowel occurred. 4) what Whentreatment converting dose to avoid In addition to IV hydration and anti-emetics, willreduce you initiate toxicity w AKI = 2mg q4 (12mg per day) for her pain control? 5) Calculate PRN = 10% TDD a) Morphine IV 10mg q4h prn Answer C b) Hydromorphone CR 6mg po BID + 2mgNBIRFentanyl q2h prn patch – takes 12h to ‘kick in’ so not this setting of severe acute pain c) Hydromorphone 2mg sc q4h + 1mg scideal q1hinprn d) Hydromorphone 2.5 mg sc q4h + 1.5 mg sc q1h PRN e) Fentanyl patch 25 mcg q 72h + hydromorphone 2mg sc q1h PRN 95

Approach to studying solid tumor oncology

BONUS Read on own

1. 2. 3. 4.

Relevant Biology Diagnosis and Staging Method Staging Management- Early Stage 1. 2. 3.

Underlined = Extra Important

Neoadjuvant therapy Definitive Treatment Adjuvant therapy

5. Management- Metastatic Disease 6. Important systemic therapy side effects 7. Surveillance

96

General TIPS to studying solid tumor oncology

BONUS Read on own

1. 2. 3. 4.

Relevant Biology- rarely tested Underlined = Extra Important Diagnosis- Can be tested Staging Method- Rarely tested Stages of Cancer- Rarely tested except for a few special cases (will be addressed) –

Know what stages require what treatment, rather than memorizing which TNM contributes to which prognostic stage

5. Management- Early Stage 1. 2. 3.

Neoadjuvant therapy- Never tested- WILL NOT COVER Definitive Treatment- Can be tested in broad overview Adjuvant therapy- Can be tested in broad overview

6. Management- Metastatic Disease- Can be tested in broad overview 7. Important systemic therapy side effects- Expect to be tested 8. Surveillance- Can be tested in broad overview Remember these are general overview of managements. There are caveats EVERYWHERE that we won’t be addressing. 97

BONUS Read on own

Current Screening Algorithms to know

• Breast Cancer – Low-risk vs High risk

• Colon Cancer – Average risk vs Increased risk

• Cervical Cancer – One screening algorithm for the general population

• Hepatocellular Carcinoma – One screening algorithm for selected population

• Lung Cancer – One screening algorithm for selected population 98

BONUS Read on own Oncologic Site

Breast Cancer

Chemotherapy Toxicities by Disease Site Chemotherapy Agent

Anthracyclines (FEC-D, ddAC-T) Doxorubicin (Adriamycin), Epirubicin Cyclophosphamide (FEC-D, ddAC-T)

Colon Cancer

Testicular Cancer

Taxanes (FEC-D, ddAC-T) • Docetaxel • Paclitaxel Antimetabolite (FOLFOX/FOLFIRI) 5-Fluourouracil, Capecitabine Topoisomerase inhibitors (FOLFIRI) Irinotecan Platinums (FOLFOX) • Oxaliplatin Bleomycin(BEP) Topoisomerase inhibitors (BEP) • Etoposide

**HIGH YIELD **

High Yield Toxicities

Irreversible cardiomyopathy Secondary leukemias) Hemorrhagic cystitis, bladder CA Secondary malignancies (MDS, AML, bladder Ca) Infertility Peripheral neuropathy Fluid retention (Docetaxel) Diarrhea, mucositis, hand-foot syndrome, coronary vasospasm Diarrhea, Cholinergic Reaction Peripheral Neuropathy Cold-induced neuropathy (Oxaliplatin-specific) Pneumonitis Myelosuppression, Hypersensitivity reaction, diarrhea

99

BONUS Read on own Oncologic Site

Lung Cancer

Ovarian Cancer

Chemotherapy Toxicities by Disease Site

Chemotherapy Agent

Platinums (Platinum Doublet Chemotherapy) • Cisplatin • Carboplatin Vinca alkaloids (Cis+ Vinorelbine) • Vincristine, Vinorelbine Taxanes (Carboplatin+ Paclitaxel) • Paclitaxel • Docetaxel Platinums (Platinum Doublet Chemotherapy) • Carboplatin Taxanes (Carboplatin+ Paclitaxel) • Paclitaxel • Docetaxel

**HIGH YIELD **

High Yield Toxicities

All – Peripheral neuropathy Cisplatin-specific – Highly emetogenic, nephrotoxic, ototoxic, hypoMg/Ca/K Carboplatin- Gentle version of Cisplatin- Less ematogenic. Peripheral neuropathy Peripheral neuropathy Fluid retention (Docetaxel) Peripheral neuropathy Carboplatin- Gentle version of Cisplatin- Less ematogenic. Peripheral neuropathy Fluid retention (Docetaxel)

100

BONUS Read on own

Screening for Esophageal Cancer (CTFPHC)11

• Do NOT screen adults (≥18) with chronic GERD without alarm symptoms for o Esophageal adenocarcinoma or o Precursor conditions (Barrett esophagus or dysplasia)

• These guidelines DO NOT apply to o Patients with alarm symptoms (dysphagia, odynophagia, recurrent vomiting, unexplained weight loss, anemia, loss of appetite, or GI bleed) o Those with Barrett esophagus (with or without dysplasia)

101

TAKE OUT

BONUS Read on own

Immunotherapy: Use in Solid Tumours

• Checkpoint inhibition allows re-activation of quiescent T-cells to attack tumour cells o PD-1 inhibitors: Pembrolizumab, nivolumab o CTLA-4 inhibitors: Ipilimumab

• Indications in multiple tumors: o Melanoma, Lung, bladder, renal cell, colon, Hodgkin’s lymphoma, breast, head and neck, gastric ….

https://www.medgadget.com/

• Side effects- Any organitis! o Rash (most common), endocrine (hypothyroid, panhypopituitarism, adrenal insufficiency, diabetes), GI (colitis, hepatitis), pneumonitis, uveitis, myocarditis, nephritis, MSK (synovitis, arthritis), hematologic, encephalitis 102

TAKE OUT

BONUS Read on own

Erythropoietin stimulating agents in Solid Tumor Malignancies18

•

Chemo-associated anemia (Hgb < 100) o If treatment is CURATIVE – Do NOT use erythropoietin stimulating agents (ESAs) o If treatment is PALLIATIVE – MAY use ESAs if Hgb persistently low

•

Cancer-associated anemia (Hgb < 100), NOT on therapy o Do NOT use ESAs if anemia is solely due to solid-tumor malignancy

•

Factors to consider when starting ESAs o Rule out non-cancer/chemo associated causes for anemia (i.e. Fe deficiency) o Discuss risks of thromboembolism o There is no “target” Hgb for this population. Target Hgb to avoid need for recurrent transfusions o ESAs should be discontinued if not working after 6-8 weeks o Iron supplementation may be ADDED to ESAs to increase efficacy, even if not iron deficient 103

Perioperative Medicine Dr. Ann Marie McKenna Friday, December 1, 2023

© Internal Medicine Review 2024

Outline • • • • •

Components of a pre-op assessment Cardiac risk stratification Delirium and Frailty risk Assessment Medication management Anticoagulation – When to stop, when to bridge – Postop VTE prophylaxis regimens

• Perioperative Miscellany – Blood sugar control peri-op – Anemia / Blood product management – Respiratory risk stratification • BONUS SLIDES

2

List of Short Forms Used in this Talk DASI

Duke Activity Status Index https://www.mdcalc.com/duke-activity-status-index-dasi

CPET

CardioPulmonary Exercise Testing

CCS

Canadian Cardiovascular Society

METS

Measurement of Exercise Tolerance Study (or metabolic equivalents – depends on context!)

RCRI

Revised Cardiac Risk Index https://www.mdcalc.com/revised-cardiac-risk-index-pre-operative-risk

POBA

Plain Old Balloon Angioplasty (No Stent)

BMS

Bare Metal Stent

DES

Drug-Eluting Stent

LMWH

Low Molecular Weight Heparin

LDUH

Low Dose Unfractionated Heparin 3

The Pre-op Assessment • The Checklist: qCardiac risk assessment

q+ Don’t forget endocarditis prophylaxis

qDelirium Risk and Frailty qMedications and withdrawal qAnticoagulants qAntiplatelets qHeme considerations: qVTE prophylaxis qAnemia optimization qCoagulopathies (liver, ITP, VWD etc.) qMetabolic: Diabetes, stress steroids

Focused Physical Exam: Watch them walk into your exam room CNS: Delirium Risk - Executive function - Check pills and bottles Cardiac: AS, HCM, Pulmonary HTN Lungs: Clear? Pulm HTN? Peripheral vascular exam (+Diabetic foot pre TKA/THA) 4

Cardiac Risk Assessment (AKA – “medicine to clear patient prior to OR”)

Key Guidelines: 2016 CCS Guideline – Need to KNOW this one Be aware of 2021 AHA Statement – major authors are Canadian

5

Cardiac Risk Assessment

(AKA – “medicine to clear patient prior to OR”)

“We don’t clear – we counsel, optimize, and follow" – We DON’T delay emergent/urgent surgery • Exceptions? … Active ACS, decompensated HF, unstable arrhythmia (things you can emergently optimize)

– We DO delay purely elective surgery for medical optimization • Example: patient with poorly controlled diabetes before elective TKA

MCQ #1 2024 A 72y M is referred for preop assessment. The surgeon wonders if they can stop clopidogrel prior to upcoming elective laparoscopic cholecystectomy for symptomatic gallstones. PMH: Lacunar stroke 2 years ago. HTN, Dyslipidemia, ex-smoker. No history of cardiac disease or Afib. Osteoarthritis. Last known LVEF 65%. Meds: Clopidogrel 75mg daily, Indapamide 2.5mg daily, Simvastatin 40 mg daily, vitamin D, Ibuprofen PRN arthritis. On exam: Alert, oriented. Using his iPhone he shows you his BP and HR trend for past 2 years which he tracks meticulously. BP 128/72, HR 68. Cardiac exam normal. ECG shows normal sinus rhythm with ECG LVH. With regards to his pre-operative management, which is the next best recommendation? a) Measure NT-pro BNP b) Order post-operative ECG and Troponin c) Order exercise stress test d) Advise to hold clopidogrel 5 days preoperatively 7

CCS 2016: Preop Cardiac Risk Evaluation Duceppe et al. Perioperative Cardiac Risk Assessment & Management

Patients Timing of surgery‡

Preoperative assessment

19

Patients age ≥45 years or 18-44 years with known significant cardiovascular disease* undergoing noncardiac surgery requiring overnight hospital admission Emergency surgery

Urgent/semiurgent surgery

Requiring overnight hospital stay Proceed to surgery without additional preoperative cardiac assessment

Proceed to surgery; only undertake preoperative cardiac assessment if unstable cardiac condition or suspected undiagnosed severe PHTN or obstructive £ cardiac disease

If patient’s age ≥65 years or 18-64 years with significant cardiovascular disease*

Postoperative monitoring

Elective surgery

Assessment of perioperative cardiac risk Risk stratification with RCRI§ If a patient’s age ≥65 years, RCRI ≥1, or age 45-64 years with significant cardiovascular disease* order NT-proBNP/BNP Positive NT-proBNP ≥300 mg/L or BNP ≥92 mg/L

Measure troponin daily x 48-72 hrs Obtain ECG in PACU Consider in-hospital shared-care management**

NT-proBNP or BNP not available

Negative NT-proBNP 65 or 18-64 w/ major CVD : - postop Trop X 48-72h - PACU ECG - “shared care management”

Elective Surgery

*requiring overnight hospital stay BNP Normal

Calculate RCRI score to assess risk of MACE Measure BNP if: ≧65y or RCRI≧1 or 45-64y w/ major CVD

= no additional routine postop monitoring

BNP Abnormal or BNP unavailable: -postop trop x 48-72h -PACU ECG “shared care management”

BNP Cutoffs: NT-proBNP≧300mg/L or BNP ≧92 mg/L

Revised Cardiac Risk Index : CCS 2016 High Risk Surgery

Intraperitoneal, intrathoracic, supra-inguinal vascular

Ischemic Heart Disease

History of MI, positive exercise stress test, current angina or nitrate use, ECG w Q waves. Note: If pt has revascularization w PCI or CABG does NOT get a point in absence of above – e.g. if patient had CABG and is asymptomatic, no nitro, with normal ECG, stress test does not get a point.

CHF History

HISTORY of CHF, pulm edema, PND OR exam showing bilat crackles, S3 gallop OR vascular redistribution on CXR

History of stroke or TIA

Score 0-6 ~ risk of infarct, arrest or death 30 d postop 0 ~ 4% 1 ~ 6% 2 ~ 10% 3+ ~ 15%

Diabetes on Insulin Pre-op Creat >177 umol/L

12

BONUS Read on own

• • • • • •

High risk features of non-invasive stress testing that prompt periop testing

> 2mm ST depression ST elevation VT/VF sBP not greater than 120 or decrease >10 mmHg EF < 35% Severe stress induced LV dysfunction - EF 65% of patients suffering a perioperative myocardial infarction do not experience ischemic symptoms

• “MINS” myocardial injury after noncardiac surgery • In CCS defined as elevation of Troponin T (4th generation Tn) > 0.03 ng/mL • Myocardial injury due to ischemic mechanism – supply-demand mismatch… not due to other cause (renal failure, PE etc.)

– Asymptomatic MIs / MINS are associated with a similar increased risk of 30-day mortality (adjusted OR, 4.00; 95% CI, 2.65-6.06) as symptomatic myocardial infarctions • Incidence of MINS up to 20% (Cardiol Rev. 2019; 27:267–273)

VISION study Lancet 2012

CCS 2016: treating MINS Periop Scenario: Counsel patients, & optimize meds for known cardiac conditions EVERY patient should be appraised of their cardiac risk for “shared decision making” • How do you treat someone with an asymptomatic post-op troponin elevation?

– 2016 Guideline less prescriptive about what to DO with the ↑troponin

• Start ASA, statin (Strong Recommendation) • “Shared care”, Close follow-up by the thorough internist • “Area of ongoing research” – MANAGE Trial (Lancet, 2018) – dabigatran 110 mg BID ↓MACE (NNT 25) in postop MINS • Follow-up mean 16 months. Nearly ½ discontinued meds in both groups. • No increased risk in MAJOR bleeding • Rates of MACE 11% in dabigatran group, 15% in placebo

MINS 2021 Management AHA Screening: adults >=65yrs, or adults >= 45yrs w established CAD/PAD – HOW: preop baseline troponin and postop 48-72h

• ↑ troponin >99th %le of ULN within 30d of surgery (most within 72h) – TnT (4th gen) >30 ng/L ; hsTnT 20-65 ng/L with an abs change of >5, or any abs change >14 or any elevation over 65 ng/L – Clinical symptoms may be masked by perioperative treatments (sedation, analgesia)= symptoms and ECG changes not required to diagnose MINS Canadians who author CCS guidelines…

19

AHA 2021 Statement on treating MINS • MINS Treatment = Consider etiology: • atherosclerotic plaque disruption (type 1 MI) – consider revascularization, DAPT, high intensity STATIN, BB, ACE/ARB • supply-demand mismatch (type 2 MI) : (eg) bleeding triggering demand ischemia. – Rx antithrombotic if appropriate, statin, non-invasive testing.

Everyone: non pharm and pharm mgmt.

2023 data – what DOESN’T Work to prevent MINS – MCQ Fodder

❌ Colchicine (Does not ↓MINS or POAF [COP-AF, 2023]) ❌ TXA (2022 POISE 3 – but it does prevent major bleeding!) ❌ Periop Vit C IV, N-Acetylcysteine, high FiO2 (80% in OR) don’t prevent MINS. ❌ High intraop MAP >80 vs >60 no difference in MINS in adults >45y with CV disease and chronic HTN (POISE3 – Ann Int Med 2023) ❌ Warming intraop to Temp>37oC vs standard 35.5oC in adults >45 w/ 1+ CV risk factor undergoing noncardiac surgery did not reduce endpoint of MINS, arrest, death at 30 d. (PROTECT – lancet 2022) 20

Example: Mr. Uh-Oh – 71y diabetic no hx CAD/PAD, POD#2 ECG (radical cystectomy and L nephrectomy, non-cancer). Mildly nauseous, BP 110/60.

PREOP ECG

POSTOP ECG. TnI POD#1 0.02 ug/L à 7.4 ug/L POD#3

Dx: “asymptomatic” INFERIOR STEMI. Bleeding risk = very, very high. Given ASA, IV heparin, Atorvastatin 80. Added Plavix once we were sure he wasn’t bleeding via ileal conduit (POD#4). TFR for cath : 70% distal LM and severe 3VD; underwent CABG x 4 ,14 days later.

21

MCQ #1 2024 A 72y M is referred for preop assessment. The surgeon wonders if they can stop clopidogrel prior to upcoming elective laparoscopic cholecystectomy for symptomatic gallstones. PMH: Lacunar stroke 2 years ago. HTN, Dyslipidemia, ex-smoker. No history of cardiac disease or Afib. Osteoarthritis. Last known LVEF 65%. Meds: Clopidogrel 75mg daily, Indapamide 2.5mg daily, Simvastatin 40 mg daily, vitamin D, Ibuprofen PRN arthritis. On exam: Alert, oriented. Using his iPhone he shows you his BP and HR trend for past 2 years which he tracks meticulously. BP 128/72, HR 68. Cardiac exam normal. ECG shows normal sinus rhythm with ECG LVH. With regards to his pre-operative management, which is the next best recommendation? a) Measure NT-pro BNP This is low risk OUTPATIENT laparoscopic b) Order post-operative ECG and Troponin surgery. Does not need BNP. c) Order exercise stress test Remote stroke. No other indication for d) Advise to hold clopidogrel 5 days preoperatively antiplatelet. 22

Valvular Disease • Request Echo if clinically suspected moderate-severe stenosis/regurgitation • If meet standard criteria for valve intervention, should delay elective non-cardiac surgery for cardiology assessment / valve replacement/repair • If need for urgent/emergent OR, and suspicion of severe AS/MR/AR/MS

– Get Echo and inform anesthesia, get intra-op monitoring and post-op monitored bed AHA Valve Guidelines 2020 23

Criteria for Valve Intervention to know: • See Cardio Slides for high yield summaries for AS, MS, MR, AR surgical indications Severe AS on echo Abnormal systolic AV opening with Vmax ≥ 4m/s or Pmean gradient ≥ 40mmHg

• Class 1 indications for AVR – Class 1 indications to replace: • Severe AS with symptoms • OR Severe AS without symptoms, but EF 48 hrs of a. fib and CHA2DS2-VASC is ≥ 2 – J Am Coll Surg. 2014, 219(4), 831-841. – J Thromb Haemost 2015; 13 (Suppl. 1): S304–S12.

• A recent retrospective study found that POAF portends similar risk of embolism compared to non-valvular AF – J Am Coll Cardiol. 2018, 72(17):2027-2036.

• Bottom line: Weigh risk benefit on each case – Prolonged outpatient monitoring/clinic follow-up might be most prudent – No wrong answer on oral exam [”weigh risk/benefits and follow-up”] 28

Peri-op Scenario: Cardiovascular Bottom Line • Good history and physical (AS? MS? HOCM? Pulm HTN? OSA?) • Counsel patient on their patient & surgery specific risk

– Use RCRI to give risk of adverse outcomes – Engage in “shared decision making” with patient and surgeon prior to truly elective procedures

• Don’t order unnecessary pre-op tests in asymptomatic/stable patients – ECHO if you suspect obstructive lesion – “Consider BNP testing if available” for elective OR

• Put on OMT where indicated by known cardiovascular conditions • Plan to monitor patient closely pre / post-op with clinical exam (+/- Tn) and put on OMT

Outline • • • • •

Components of a pre-op assessment Cardiac risk stratification Delirium and Frailty risk Assessment Medication management Anticoagulation – When to stop, when to bridge – Postop VTE prophylaxis regimens

• Perioperative Miscellany – Blood sugar control peri-op – Anemia / Blood product management – Respiratory risk stratification • BONUS SLIDES

3 0

Pre-op Optimization Scenario You are asked to see 75yF w history of remote MI and stenting (PCI x 1 DES) in 2015 prior to R hip arthroplasty (THA) for AVN of hip. The surgeon wants to know if she can come off her clopidogrel. The patient wants to know about her risk of heart attack if she does this. PMH: CAD, Stable, no symptoms within limits of her activity. She is slowed up by her hip so needs help with housekeeping and outside work. She used to prepare simple meals but her partner has taken this over. Independent for ADLs (supervision w bathing due to fall risk). Needs blister pack or will mix up meds. She and her husband note memory is gradually getting worse. She has a history of MVA causing R leg trauma (hence AVN). She had a traumatic subdural and long stay in ICU for delirium following this in 2014. Meds: Clopidogrel 75mg daily, Rosuvastatin 20mg daily, Bisoprolol 5 mg daily, lorazepam 1mg QHS prn sleep, perindopril 4mg daily, vitamin d 1000 IU daily, nitro PRN (not requiring), celecoxib 100 mg BID Social: Retired school principal. Married, lives in house with 10 stairs, non smoker, rare ETOH. Exam: BP 138/78, HR 64, normal cardiac exam, no CHF. Wt: 80kg BMI 28. ECG: sinus w old inferior Qs Labs: NT pro BNP 422 mg/L, Hgb 110 MCV 84, Plt 290, Cr 92, ferritin 30 Please discuss her fitness for surgery and strategies to reduce postoperative morbidity. What tests (if any) will you order? How will you counsel patient with regards to her risk of perioperative complications? 31

Frailty and Surgical Outcomes • Clinical Measures of Frailty that predict adverse postop outcomes: • Clinical Frailty Score (Rockwood et al – see Bonus slides of Geri Lecture) • Modified Frailty Index (This is what NSQIP is using (US))

• Could a Frailty Index be a better predictor of perioperative morbidity/mortality than RCRI Index? – Very frail patients have higher mortality post-op [even after cystoscopy!] – Perioperative morbidity ↑ in frail patients. • ↑ LOS, ↑ discharge to LTC, ↑ major complications post-op (all surgeries)

• Interventions targeting frail adults may be helpful to reduce morbidity – Multicomponent interventions, comprehensive geriatric assessments, pre/post op exercise protocols 32

Delirium and Elective Surgery • There are validated tools to estimate preop risk of delirium for elective non cardiac surgery • There are validated screening tools to detect delirium post-op (CAM) • There are interventions that reduce risk of post operative delirium in at-risk patients – Pre-op Comprehensive Geriatric Assessment 1 – Multicomponent interventions: Effect of the Tailored, Family-Involved Hospital Elder Life Program on Postoperative Delirium and Function in Older Adults RCT2 • Addressed patients’ orientation, nutrition, hydration, sleep, and mobility, involved family to help. NNP = 6

1Anaesthesia. 2JAMA

2014 Mar;69(3):259-69. Intern Med. Pub. online Oct 21, 2019 33

Delirium workup post-op… consider stroke • NEUROVISION Cohort studyLancet. 2019 – Patients: >65y elective non cardiac surgery – Intervention: MRI on everyone postop, pre and postop neurocognitive testing – FINDINGS: • 7% of patients had a ‘covert stroke’ (seen on MRI but not clinically apparent) • Covert stroke increased risk of perioperative delirium (HR 2.24) and overt stroke/TIA at 1 yr (HR 4.13)

34

Scenario Wrap UP • Perioperative CV Risk = high (BNP ↑) • CFS = 6 = Moderately Frail • Delirium risk = high

– Med review – deprescribe BZD – Comprehensive Geriatric Ax – Counsel, establish DNR/POA, think of discharge barriers (stairs at home) – Multicomponent interventions like pre-postop exercise protocols

AND – answer the surgeon’s question! • Switch clopidogrel to ASA periop (more on that later), hold NSAID/ACE preop • postop TnI/ECG, Med consult • Anemia – preop IV iron, ESA (more on that later) 35

Outline • • • • •

Components of a pre-op assessment Cardiac risk stratification Delirium and Frailty risk Assessment Medication management Anticoagulation – When to stop, when to bridge – Postop VTE prophylaxis regimens

• Perioperative Miscellany – Blood sugar control peri-op – Anemia / Blood product management – Respiratory risk stratification • BONUS SLIDES

3 6

Medication Management • Starting and/or stopping:

–Beta-blockers –ASA and other antiplatelets –Statin –ACEi –DMARDs & Biologics

37

MCQ #2 (2024) You are seeing a 78y patient who broke their hip today and they are going to the OR tomorrow evening. They have a history of stable coronary artery disease with 3 stents 10 years ago and remote TIA. Diabetes on oral agents. Known L carotid stenosis 60%. Hypertensive. He is on azathioprine for severe mixed connective tissue disease with arthritis. He is in pain. BP 108/72, HR 62. Medication reconciliation is listed here: ASA 81 mg daily, clopidogrel 75 mg daily, atorvastatin 80 mg daily, ramipril 5mg daily, metoprolol 25mg bid, metformin 1g bid, azathioprine 75mg daily. With regards to admission medication reconciliation, which of the following is incorrect: a) Hold antiplatelets b) Hold ramipril c) Hold metformin d) Hold azathioprine e) Increase metoprolol to 100 mg BID

38

Beta-Blockers- CCS Guidelines 2016 2016 CCS guidelines: – DON’T start β-blocker within 24 hours of noncardiac surgery (ref: POISE, 2008) – DO CONTINUE β-blocker perioperatively if patients taking chronically

THE EXCEPTIONS: In scenarios where a beta-blocker is clearly indicated (ex. Angina or arrhythmia like rapid AFIB… give beta blockade as you usually would, proceed to OR when appropriate)

39

Beta-blockade Trial to Know POISE 1 (Perioperative Ischemic Evaluation) Lancet 2008

8351 at-risk patients randomized to receive 100 mg metoprolol XR or placebo 2-4 hrs pre-op; 30 d outcomes • More death (3.1 > 2.3%) • More stroke (1.0 > 0.5%) • Less MI (4.2 < 5.7%) – Most in first week after OR – Most asymptomatic – “MINS” TnI elevation only

Bottom Line: Don’t start high dose beta-blockers on the day of major non-cardiac surgery! 40

ASA – CCS Guidelines (2016, 2018) • We recommend against initiation of ASA for the prevention of perioperative cardiac events • Physicians should discontinue ASA at least 3 days before noncardiac surgery to reduce the risk of major bleeding. – UNLESS: recent coronary stent or pre-op major vascular surgery (or CVSx) – “Recent” = 6 weeks BMS, 3-12 months DES [depends on stent generation] “Ask their cardiologist*” REAL WORLD : Continue ASA with history of coronary stent even >1 year “wherever possible (unless procedure very very high risk bleeding ex. neurosurgery)”… per CCS 2018 Antiplatelet Guidelines 41

Why Continue ASA if history of stent? POISE-2 trial (NEJM 2014)

– 10,010 intermediate-high risk patients randomized 2x2 to ASA or placebo, and clonidine or placebo • 4% had stents – excluded DES 1 week of surgery

High risk aspiration with induction

Insulin

✓*

Hold prandial when fasting

Dose reduce basal insulin

DMARDs

✓

Biologics

❌

NO Severe poor control HTN

24h preop (risk of intraop Hypotension/AKI)

Per Periop THA/TKA SLE with organ threatening disease

1 dosing cycle 52

MCQ #2 (2024) You are seeing a 78y patient who broke their hip today and they are going to the OR tomorrow evening. They have a history of stable coronary artery disease with 3 stents 10 years ago and remote TIA. Diabetes on oral agents. Known L carotid stenosis 60%. Hypertensive. He is on azathioprine for severe mixed connective tissue disease with arthritis. He is in pain. BP 108/72, HR 62. Medication reconciliation is listed here: ASA 81 mg daily, clopidogrel 75 mg daily, atorvastatin 80 mg daily, ramipril 5mg daily, metoprolol 25mg bid, metformin 1g bid, azathioprine 75mg daily. With regards to admission medication reconciliation, which of the following is incorrect: a) Hold antiplatelets Answer: E b) Hold ramipril The patient is going for high risk bleeding surgery tomorrow and is already ”on” DAPT. You can reassess c) Hold metformin antiplatelets postop. Anesthesia should be aware of d) Hold azathioprine clopidogrel exposure = No epidural. e) Increase metoprolol to 100 mg BID His HR and BP are low so per CCS recommendations and knowing results of POISE high dose metoprolol not wise 53

Outline • • • • •

Components of a pre-op assessment Cardiac risk stratification Delirium and Frailty risk Assessment Medication management Anticoagulation – When to stop, when to bridge – Postop VTE prophylaxis regimens

• Perioperative Miscellany – Blood sugar control peri-op – Anemia / Blood product management – Respiratory risk stratification • BONUS SLIDES

5 4

Anticoagulation – General Approach Patient Thrombosis Risk

Procedural Bleeding Risk Does anticoagulation need to be held? (eg cataract surgery = NO!)

Are they High risk thrombosis if anticoagulants held?

Patient bleeding risk (ie. HAS-BLED score, need for antiplatelet if stent, thrombocytopenia / uremia / cirrhosis)?

Is bridging needed? [WARFARIN ONLY] If so, how to bridge? Stopping and restarting OACs – tables to memorize now, forget later

Decision to interrupt antithrombotic therapy for an invasive procedure should balance the risks of a thromboembolic event with those of a periprocedural bleeding event - CCS 2020 AFIB Guideline

55

Procedural Risk: Low Bleeding Risk, anticoagulation can be continued • Minor dental procedure:

– Up to 2 teeth removal; root canal; periodontal surgery; teeth cleaning – Continue VKA and use oral prohemostatic agent

• Minor dermatologic procedure: skin biopsy • Cataracts • Minor procedures with small bore needles (ex paracentesis, thoracentesis) • Endoscopic procedures not requiring biopsy: sigmoidoscopy for Crohn’s 56

Procedural risk: High bleeding risk, must HOLD anticoagulants • Any procedure involving neuraxial anesthesia = Regional block, epidural, spinal

Neurosurgery (intracranial or spinal surgery) Cardiac surgery (e.g. CABG, heart valve replacement) Major vascular surgery (e.g. aortic aneurysm repair, aortofemoral bypass) Major urological surgery (e.g. prostatectomy, bladder tumour resection) Major lower limb orthopedic surgery (e.g. hip/knee joint replacement or fracture surgery) • Lung resection surgery • Intestinal anastomosis surgery. • Selected procedures (e.g. kidney biopsy, prostate biopsy, cervical cone biopsy, pericardiocentesis, colonic polypectomy) • • • • •

57

Who to Bridge? (VKA ONLY**) • Who takes VKA still? – – – – –

Mechanical valves APLAS CKD/ESRD with VTE or AFIB Patient preference with VTE or AFIB (+breastfeeding) LV Thrombus (sometimes)

BRIDGE Trial (NEJM 2015) - No bridging anticoagulation in patients with A. Fib on warfarin was non-inferior to bridging in prevention of arterial thromboembolic events and decreased the risk of major bleeding (NNH = 50). Periop2 Trial (BMJ 2021) – AFIB or mech valve patients given preop bridge; randomized to postop bridgeà no benefit to postop bridging (incl >300 Mech Valves, 1/3 mitral)

• Which of these patients should* be bridged? – Mechanical MVR or older AVR (ballcage, tilting) – DVT, PE or Arterial TE 1 year ago No other risk factors

59

BONUS Read on own

Example of How to Bridge – Warfarin and LMWH (assumes normal CrCl)

Day

-5 -4 -3 -2 -1 Day of OR POD1

Stop Warfarin

POD2 POD3

Warfarin (1.5X usual dose) + LMWH

Start full dose LMWH (eg enoxaparin 1mg/kg sc bid) Last dose of LMWH 24h before OR, administer ½ the dose Start warfarin (1.5X usual dose) at least 12h after OR and full dose LMWH 24h after OR Warfarin (usual dose) + LMWH. Check INR and continue LMWH until INR therapeutic then stop LMWH

60

When to hold OAC : ELECTIVE surgery Anticoagulant Anti Xa Drugs* Apixa, Edoxa, Rivaroxa AND

Dabigatran**CrCl >50

Bleeding Risk

Day -5

Day -4

Day -3

Day -2

Day -1

SURGERY

POD #1

Low / Moderate

✓

✓

✓

✓

❌

❌

✓ 24h postop

HIGH Risk

✓

✓

✓

❌

❌

❌

❌

* Assumes CrCl >30 for Anti Xa Drugs. If CrCl is reduced due to AKI – “hold an extra day” ** Assumes CrCl > 50 for Dabigatran. If it is 12h postop

✓ VKA ✓LMWH

Not Bridging

❌

❌

❌

❌

Bridging

❌

❌

LMWH

LMWH

61

When to restart DOAC post-op • Moderate risk bleeding surgery – Generally resume 24 h postop

• High risk bleeding surgery – Resume 48-72h postop – Consider alternative anticoagulation until resume DOAC • DVT prophylaxis if low/mod risk thrombosis • IV heparin or LMWH if high risk thrombosis

Moderate Risk: [think: DAY SURGERIES ] General surgery without anastomosis (eg breast, chole, hernia repair, not cutting bowel) Arthroscopic Ortho procedures Multiple dental extractions (>2) GI endoscopy with biopsies/polypectomy Non cataract Ophtho surgery

TALK TO SURGEON!

Ex. cancer surgery and a LMWH

14-35d

Preferences ASH: DOACs are preferred. If DOAC not used, LMWH preferred over VKA.

*DOAC = Choose any one of Extended prophylaxis (>3 Apixaban 2.5 bid, dabigatran 220mg weeks) recommended over OD, rivaroxaban 10mg OD short (up to 14 d) Do not be tricked by ASA alone (CRISTAL Trial JAMA 2022 –ASA **Rivaroxaban 10mg x 5 d then ASA 100 inferior to enoxaparin) 81mg x 9-30d an optional regimen 14-35 d Extended prophylaxis (>3 weeks) recommended over short (up to 14 d)

LMWH or LDUH recommended over all other agents. DOACs are not studied or recommended for this indication!

Until Discharge including Rehabilitation

IPC up front if high risk of bleeding

Hip Fracture Surgery

LMWH

Major Trauma/leg amp/admitted

LMWH LDUH (e.g. if CrCl1-2 hours) • Prolonged OR in insulin dependent patient • Intrapartum – diabetics on insulin in pregnancy (see OB Med Lecture)

71

Diabetes Management Peri-Op: What to do with everyone else Home Diabetes Regimen

Perioperative Regimen

Oral agents

Hold morning of OR, use sliding scale

GLP1 agonists (ex liraglutide)

Hold/skip injection 1 week prior to surgery **

SGLT2 inhibitor*

Hold 3 days before OR [FDA – 4 days for ertugliflozin]

Long-acting insulin Lantus/Tuojeo, Tresiba, Levemir,NPH

1/2 to full usual dose [70-100% dose if night before surgery injection, but ½ dose if morning of surgery injection]

Twice daily (mix insulin, eg 30/70)

½ usual AM dose as NPH

3, 4, 5 injections daily

Omit short acting, give 2/3 to full basal dose

DISCLAIMER – this is a guideline. Ask 10 internists and you’ll get 10 different answers. Consider risks of hypoglycemia: age, renal fxn, “brittle”/”labile” sugars, etc. You will not get asked to counsel a patient in high detail on periop glucose mgmt due to lack of evidence base! Modified from Dhatariya K et al: Management of adults with diabetes undergoing surgery and elective procedures: improving standards. NHS Diabetes April 2011. *(1) Can J Anesth. 2018; 65: 188-93; (2) AACE/ACE Position Statement. 2016; 22: 753-762

**Am soc Anesthesia 2023: Increased aspiration risk due to delayed gastric emptying; hold 1 week preop. If 72 urgent OR, intubate w aspiration precautions

Anemia and Blood Product Management (More in BONUS SLIDES)

• Preop optimization of Hgb if anemic (women: 60%, standard risk) No “exact cutoff of FEV1” for lobectomy/pneumonectomy… It is more nuanced [not testable in MCQ, and NOT for GIM, it is for thoracic surgeon to know!]

Management of Resp Risk

BONUS Read on own

• Interventions: – Pre-op: • Optimization of COPD/Asthma (continue puffers) • Smoking Cessation: – Strongly recommended (CCS 2016) – > 4 weeks cessation shows increased benefit

• Recent URTI – no good evidence to inform mgmt (delay if active infection) • Route of anesthesia – to discuss with Anesthesia non-GA options

– Post-op: Note: Weak evidence and modest effect for all of these…But easy to mention! Deep-breathing exercises or incentive spirometry Early mobilization Good pain control (esp. upper abdominal surgery – epidural anesthesia is your friend!), NG Decompression • DVT prophylaxis • Home CPAP machine • • • •

BONUS Read on own

Resp Risk Assessment

• Less data vs. cardiac risk assessment – Most guidelines have to do with risk of resp failure (eg intubation prolonged) • Complications: – Respiratory failure, Infection, Atelectasis, Exacerbation, VTE, pneumothorax

• Patient related risks: • Clinical=COUGHS (COPD, Older than 60, Underlying disease- ASA >II, General health (functional class), Heart failure, Smoking)*ACP 2006 • Biochemical: Albumin 4 METS). Consequently, she cannot reliably achieve 4 METs. No angina or cardiac Sx at baseline. Slowed up by arthritis, Needs help with some of her outside work (shovelling, raking) due to arthritis. Drives, does her own banking, is a bookkeeper on the side. • Meds: ASA 81 mg daily, Bisoprolol 2.5 mg daily, Ramipril 5 mg daily, Atorvastatin 10 mg qhs, Prednisone 10 mg daily, Methotrexate 25 mg weekly, Folic Acid 5mg weekly, and occasional Acetaminophen. No change in her steroid dose in the past year. • Physical exam: normal vital signs with HR 65. She is not obese or Cushingoid. There are no active joints but does have deformity from prior active RA. Her neck ROM is normal, although she reports slight pain. Cardiac and respiratory exam is normal except for decreased lower limb pulses and findings of PVD. • Investigations reveal normal CBC (Hgb 130) and electrolytes. Creatinine is 90. INR is 1.0. She has a normal CXR and an ECG showing old lateral Q waves. • PLEASE OUTLINE YOUR APPROACH AND MANGEMENT

Example Pre-Op • The “Pre-Flight” Checklist: – Cardiac risk assessment • RCRI = 2, peri-op risk of MACE is approximately 10% • Would NOT suggest an echo or stress testing • Would complete a pre-op BNP à daily troponins, ECG starting in PACU, post-op for 48 hours – Clinical Frailty Scale 4 – Respiratory risk assessment

• This patient does NOT have findings to suggest pulmonary HTN or ILD • Does not require pre-op PFTs • Would proceed to surgery with routine measures including early mobilization post-op, and appropriate analgesia

Example Pre-Op Medications – CONTINUE ASA (*vascular surgeons are special), CONTINUE Bisoprolol, HOLD Ramipril 24 hours before Steroids/Adrenal Insufficiency – This patient is at risk of adrenal insufficiency given her chronic steroid use – Would provide Hydrocortisone IV 50 mg q8h on day of surgery and then taper to usual home dose over 24-48 hours – Ensure care team is aware that hypotension post-operatively could be adrenal insufficiency Prophylaxis – This patient does not require IE prophylaxis – VTE prophylaxis (usually LMWH) Delirium prevention – Early mobilization, pain control, bowel regimen, avoidance of anticholinergic drugs

Example Pre-Op • Special: – This patient has Rheumatoid Arthritis – I would alert my surgery and anesthesia colleagues regarding RA status and obtain pre-operative consultations – I would contact this patient’s rheumatologist • Make a decision regarding holding or continuing methotrexate

– I would obtain pre-operative C-spine Xrays • Consideration of surgery/neurosurgical referral if: C1-C2 separation 9 mm, posterior atlanto-dental distance < 14 mm, or any symptoms • I would consider it reasonable to say you would defer this assessment to Anesthesia

Example Post-Op Scenario • Keep in mind that the post-op scenarios can often take you anywhere…… • Beware of scenarios that start with an operative scenario then lead into a separate topic (ie. read cues from your examiners to make sure you are focusing on what you need to cover) • Eg. The post-operative patient with delirium who you subsequently diagnose with hypercalcemia

Steroids • •

Not evidence based AT ALL Clinical gestalt / consensus – HPA Axis likely NOT suppressed: • Prednisone < 5 mg/d • Any dose < 3 wks – Uncertain • 5-20 mg prednisone > 3 wks (*some say > 5 mg for 3 wks = probably suppressed) • Consider ACTH stim test/consult Endo, or just give steroids as if suppressed (esp. if no time for testing and major surgical stress) – HPA Axis Suppressed: Prednisone ≥ 20 mg/d for 3+ weeks or Cushingoid – STRESS DOSE (this is “art of medicine” not evidence based – pick a number 50 or 100 and you will be fine in oral exam ;) • Major surgery – Usual AM dose + HC 100 mg IV X 1 pre-op, then 50 mg q8h X 3 doses, then 25 mg q8h X 3 doses then back to usual dose • Moderate surgery – Usual AM dose + HC 50 mg X 1 pre-op, 25 mg q8h X 3, then usual dose • Minor surgery – Usual AM dose SOURCE: “In the Clinic: Pre-operative medicine consult” Annals of Internal Medicine 2009 and UpToDate “The surgical patient taking glucocorticoids”

85

Pre-Op Blood Product Management What if Hb was 95 and patient is a devout Jehovah’s Witness who would not want transfusion…… • Discuss patient preferences: involve surgeon, determine likelihood and magnitude of blood loss and discuss whether or not these risks can be mitigated surgically • Clearly express possible consequences of NOT having transfusion and inquire if patient understands risks (ie. complications up to and including death) • Document strategies and treatments available for this surgery (based on discussion with patient), delay surgery where possible to optimize anemia. – DECREASE PHLEBOTOMY (frequency, pediatric tubes) – Autologous blood donation pre-operatively [most pts with Jehovah’s faith do not accept this practice, however you can discuss if available at your institution] – Tranexamic acid Pre-op and postop if bleeding complications or concerns re hemostasis – Acute Normovolemic Hemodilution (defer to anesthesia) – RBC Salvage

• Establish SDM. If you get “down to the wire” with life threatening bleed it is helpful to verify with SDM the patient really would NOT want blood in that scenario.

Anemia and Blood Product Management “All patients undergoing [high bleeding risk] surgery OR DELIVERY should be screened for anemia at least 6 weeks prior to OR date” • If there is a high bleeding risk associated with surgery (major Ortho, Gyne, GU, Vascular, CV surgery) – Preop CBC – add ferritin, Tsat, CRP if possible, consider Cr and B12

• If anemia (Hgb F, 6th or 7th decade (rare 1mg/kg po daily) and empiric antimicrobials Dismal prognosis – generally 50% in-hospital mortality

CTS 2018 ILD Position Statement Summary • Accurate diagnosis is key • Rx IPF w/ anti-fibrotics (pirfenidone, nintedanib), consider immunosuppression in non-IPF • Pulmonary rehab is recommended – ↓ dyspnea,↑ walking distance and QOL

• There is a role for supplemental oxygen in:

– Resting hypoxemia – Same criteria as COPD – Exertional hypoxemia (sat 2/3 the upper limit of normal value for serum LDH. Suspect Malignant Effusion? Beware - sensitivity of pleural fluid for cytology only 46%!

Pleural Fluid Differentials • Chylothorax – (TGs >1.24mmol, +CM)

– Malignancy #1 (most commonly lymphoma) – Trauma/surgery, TB, LAM (young woman with cystic lung disease/PTX)

• Pleural fluid eosinophilia - (>10%)

– Etiology depends on history • Asbestos related (BAPE), drugs (ex. nitrofurantoin), malignancy (lung), infection (parasites), PE, eGPA

• Low glucose - (glc> Others (CF, TB, PCP) • Even small SSP can lead to significant symptoms; often requires admission • Most likely will require chest drain given underlying lung abnormalities and risk of air leak. Unlikely to spontaneous resolve. • Consult Resp/Thoracic Surgery 73

MCQ 4 (2024) A 21-year-old male presents to the ED given abnormal imaging results. As part of required TB screening at work, he had a CXR demonstrating a 3.5cm right apical pneumothorax. He is asymptomatic and is a nonsmoker. His vitals are normal, and your exam is unremarkable except for decreased air entry in right apex. You would now recommend: a) Insertion of a right small bore chest tube and admit to hospital b) Insertion of ambulatory pneumothorax device and discharge with close follow-up c) Needle aspiration and then discharge with close follow-up intervention required for asymptomatic d) Discharge home with close follow up No pneumothoraces even if large.

Do not discharge home without appropriate follow-up! May consider short period of 74 observation in ED.

Sarcoid • Multisystem granulomatous disease of unknown etiology

– Pathology reveals noncaseating granulomas in involved organs – Usually involves the lungs (>90%) but up to 30% of patients present with extrapulmonary sarcoid including:

Heart, CNS, eyes* need urgent treatment! • Other: liver, spleen, musculoskeletal system, kidney • Most are asymptomatic •

Guideline ATS 2020 Guidelines on the Diagnosis and Detection of Sarcoidosis ERS 2021 Clinical Practice Guidelines on Treatment of Sarcoidosis (NEW)

– Two thirds of patients will have remission at a decade – After one year of spontaneous remission relapse is very uncommon

Sarcoid Syndromes • Lofgren Syndrome – – – – – –

Bilateral hilar adenopathy Erythema nodosum Migratory polyarthralgias Fever Seen primarily in women High likelihood of spontaneous remission

– – – –

Anterior uveitis Parotid enlargement Fever (uveoparotid fever) Facial palsy

• Heerfordt Syndrome

ATS Recommends: 1. Lofgren syndrome, Heerfordt syndrome, lupus pernio: No biopsy required for diagnosis. (Conditional recommendation, very low quality of evidence) 2. Asymptomatic bilateral hilar adenopathy: no recommendations for/against. Close clinical follow up required if no biopsy. 3. EBUS guided lymph node sampling, rather than mediastinoscopy, is recommended as the sampling method of choice (Conditional recommendation, low quality of evidence)

Sarcoid: Pulmonary Involvement • 90% have pulmonary involvement – often asymptomatic hilar lymphadenopathy

• Stage reflects chance of spontaneous remission • Symptoms can vary: dyspnea, cough, chest pain, wheeze • PFTs can show anything: normal, restriction, obstruction, or both (+/- reduced DLCO) Stage Rate of Chest X Ray Findings spontaneous • Co-existent asthma is common remission 55-90% [75%] Bilateral adenopathy • Pulmonary hypertension is rare 1 2 40-70% [50%] Adenopathy + parenchymal but described lesions 3

10-30% [25%] Parenchymal lesions with no adenopathy

4

0-5%

[0%]

Fibrosis

77

Sarcoidosis: Extrapulmonary Involvement • Cutaneous: Common (about 1/3 of patients), lupus pernio, erythema nodosum, others • Liver and Spleen: ~10% of patients, elevated liver enzymes, cholestasis, rarely liver failure, can see liver and spleen lesions on imaging • Neurologic: Cranial nerve palsy, headache, ataxia, weakness, LP nonspecific lymphocytic inflammation, MRI imaging chest of choice • Ocular: Anterior uveitis most common • Cardiac: ~5% of patients clinically (more at autopsy), cardiomyopathy, arrhythmia, heart block, screen with ECG +/- echo, then cardiac MRI and PET scan if concern • Hypercalcemia: Common, rule out other causes of hypercalcemia, due to increased conversion of 25-OHD3 to 1,25-D3.

Lupus Pernio

nose/cheeks/lips/ ears/digits Source: Dermnetnz.org

Erythema Nodosum

Panniculitis usually anterior shins Source: Dr McKenna office 78

Investigations • • • • •

CXR +/- CT, PFTs Tissue biopsy: LN or transbronchial biopsy CBC: anemia of chronic disease, lymphopenia, thrombocytopenia Calcium, Alb, LFTs, Cr ECG

– If cardiac disease suspected – Cardiac MRI is preferred, or cardiac PET if unavailable – If PH suspected – do TTE

• 1,25- OH Vitamin D • Ophtho referral to r/o sarcoid ocular Rule out: HIV serology, Rule out TB • Bronchoscopy/BAL: low CD8, elevated CD4/CD8 ratio • 24 hour urine (hypercalciuria) • Serum ACE level is not necessary

– increased ACE is ~70% sensitive and 90% specific with active disease; – Reflects granulomatous load and can be false positive in other granulomatous disease

Sarcoidosis Treatment •

Most patients will not require treatment – Most patients with stage 1 or 2 disease will have spontaneous remission, with low recurrence (4-5%) – Steroids accelerate remission at the cost of higher risk of recurrence (60-70%) – indicated if end-organ failure from granulomatous inflammation. Dose is 20-40 mg (higher if life threatening inflammation).

•

Indications for treatment

*fatigue alone is not indication for treatment*

– Pulmonary: Bothersome symptoms (cough and dyspnea), deteriorating lung function as measured with PFTs, or development of pulmonary hypertension. ICS can be used for mild symptoms and stable PFTs. – Extrapulmonary: Eye disease, CNS disease, cardiomyopathy/active cardiac involvement *, severe skin disease, hypercalcemia, symptomatic liver disease are usually treated (for skin disease refractory to steroids, consider INFLIXIMAB)

•

Duration of treatment – Usually 1-3 months at initial dose, SLOW taper to ~10 mg/d (total treatment for 1 year) – If relapse can consider other agents like MTX (less commonly HCQ, LEF, TNF alpha inhibitors)

• • •

Erythema nodosum usually good response to NSAIDs alone Cutaneous sarcoid – if low burden can try topical steroids, intralesional steroids (Derm helpful here) Pulmonary rehab is 1st line treatment for fatigue. European Respiratory Society Clinical Practice Guidelines, Nov 2021

Pulmonary Hypertension (PH) Relevant guidelines: CCS/CTS 2020 Position Statement on Pulmonary Hypertension 2022 ESC/ERS Guidelines for the diagnosis and treatment of Pulmonary Hypertension • Defined as: mean pulmonary artery pressure >20mmHg on right heart catheterization and PVR >2WU (previously PVR > 3WU), is consistent with pre-capillary PH – PVR = Pulmonary Vascular Resistance ((mPAP – PCW) / Q ) • PCW = Pulm Cap wedge P and Q = Cardiac output

– Hx: slowly progressive dyspnea on exertion and eventually right ventricular failure

•

Suspect in dyspnea on exertion, isolated reduced DLCO

– Most important screening is echocardiogram – Assess how RV is doing!

•

Initial work up directed at identifying PH etiology – Classify into a WHO group (determines management)

•

Everyone should get: – – – – – –

CBC -lytes -LFTs -TSH -BNP screening connective tissue disease, viral hepatitis HIV Transthoracic echo -PFTs -6MWT CT pulmonary angiogram. ( + V/Q scan if unexplained PH to rule out CTEPH) Abdo US to screen for portal HTN sleep study if suspicious clinical features right heart catheterization 81

Pulmonary Hypertension Group 1: (mPAP>20 with PVR > 2WU) – Idiopathic (IPAH) – Heritable – Drug/toxin induced – Associated with: CTD, HIV, portal HTN, schistosomiasis – (Group 1’: PVOD)

TREATMENT: Should be referred to a PH centre – Vasoreactivity testing to determine if candidate for CCB – PDE5 inhibitor or riociguat (soluble guanylate cyclase inhibitor) – Endothelin receptor antagonist – Prostanoid – Influenza/pneumococcal/COVID etc vaccines – Supervised Exercise – Women – pregnancy counselling (avoid pregnancy)

Group 2: – Pulmonary hypertension due to left heart disease • Systolic dysfunction, diastolic dysfunction, valvular disease • Treat underlying cause Group 3: – Due to lung disease/hypoxemia (COPD, ILD, etc) – Treat underlying cause Group 4 – Chronic thromboembolic pulmonary hypertension *APLAS testing for all. If + à warfarin* (ERS 2022) Refer for pulmonary thromboendarterectomy, anticoagulation Group 5: – PH with unclear mechanisms – Treat underlying disease • Heme disorders (myeloproliforative disease, splenectomy) • Systemic disorders (sarcoid, LCH, LAM) 82

Pulmonary Hypertension – ERS 2022 • •

Patients with a diagnosis of PH should be evaluated/treated at a specialized PH centre! Notes from this guideline applicable to GIM: – Screen patients with scleroderma annually for PH with echo and DLCO – Echo to screen for PH in patients with portal hypertension undergoing transplant w/u – If dyspnea or exercise intolerance after at least 3 months of uninterrupted anticoagulation post acute PE assess for CTEPH with echo and V/Q lung scan – Patients with CTEPH – test for APLAS

For your Reference only! Clues for PH on ECHO: RVSP (not a hard cutoff/not sensitive) but ≥40 mmHg ”RV enlargement” “RV overload” “IVS flattening”, or TR jet velocity ≥ 2.8, TAPSE < 1.7 cm, FAC < 35% – GIM do not need to know ECHO criteria, just when to suspect/refer.

83

PH guidelines • Treatment goals

– Achieving low-risk profile based on 2015 ERS Risk Assessment Table (combination of factors including WHO functional class, 6MWD, BNP, and hemodynamics on F/U RHC)

• General therapies – – – –

Diuretics for volume overload Physical activity/rehab contraception Oxygen if hypoxemic

ERS 2022 Recommendations

Class

Level

Echocardiography recommended first-line nonI invasive diagnostic investigation in suspicion of PH

C

VQ Scan recommended in unexplained PH to exclude CTEPH

I

C

Routine biochem, CBC, immunology, HIV testing and TSH recommended in all patients with PAH to identify an associated condition

I

C

Abdo U/S recommended to screen for portal htn

I

C

PFT + DLCO recommended in the initial evaluation I of patients with PH

C

Patients with Scleroderma should be evaluated annually for the risk of PH.

I

C

In patients with SSc and unexplained dyspnea following non-invasive assessment, RHC is recommended to exclude PAH

I

C

Consider HRCT in all patients with PH

IIa

C

Pulmonary angiography should be considered in workup of CTEPH

IIa

C

Open/thorascopic lung biopsy not recommended in PAH

III

C 84

Hypoxemia Assessing Hypoxemia: A-a Gradient: PAO2 estimated from alveolar gas equation

– PaO2 measured from ABG

A-a =[FiO2 * (Patm – PH2O) – (PaCO2/R)] – PaO2 On room air at sea level the first term simplifies to approximately 150 Respiratory Quotient (R) Depends on carbohydrate metabolism but usually 0.8 is used A-a = [150- (PaCO2/0.8)]– PaO2 Approximate Normal A-a Gradient for reference: (Age (yrs)/4)+4

Hypoxemia Normal A-a gradient (normal gas exchange) – Hypoventilation • CNS depression (drugs, stroke, tumour, bleed, meningitis), spinal cord injury, chest wall abnormality, diaphragm dysfunction (ie phrenic nerve injury or myopathy), neuromuscular disorder, obesity hypoventilation • Check PaCO2 – if elevated think of hypoventilation – Low inspired FiO2 (e.g. altitude) Widened A-a gradient – V/Q mismatch (improves with 100% FiO2) • E.g. COPD, PE – Shunt (does not improve completely with administration of 100% FiO2) • CAUSE: intracardiac with R->L shunt (eg PFO, ASD, VSD), intrapulmonary (ie pulmonary AVM), physiologic (ie severe pneumonia with perfused alveoli that are not ventilated) – Diffusion Abnormality • E.g. ILD

Hypoxemia • When to prescribe Home O2 PaO2 ≤ 55 or (Resting SaO2 ≤ 88%) or PaO2 = 55-59 with:

• Cor pulmonale or • Pulmonary hypertension or • Persistent erythrocytosis (Hct >55%)

• Based trials from the early 1980s showing mortality benefit in COPD, extrapolated to all lung disease • FYI - Other funded criteria (Ontario - varies by province) – Nocturnal hypoxemia [needs sleep study] – Exercise criteria (beyond scope of this exam*) – Palliative setting (90 d funding)

*Long Term Oxygen Therapy Trial (NEJM 2016) Pts: stable COPD, SpO2 >88% at rest with exercise induced desaturation. Results: No improvement in any measurement – mortality, hospitalization, symptoms, exercise…

Respiratory Blood Gases RESPIRATORY ACIDOSIS

RESPIRATORY ALKALOSIS

Reflects a decrease in alveolar ventilation. Reflects an increase in alveolar ventilation If marked limitation in pulmonary reserve (i.e., pain, fever, anxiety, liver disease, pregnancy) (increased deadspace), or hypoventilation In the presence of mechanical ventilation, decreased carbon dioxide production (i.e., will lead to consequent acidosis. sedation, skeletal muscle paralysis, hypothermia) can cause respiratory alkalosis Metabolic compensation

RESPIRATORY ACIDOSIS ΔpCO2 : ΔHCO3

RESPIRATORY ALKALOSIS ΔpCO2 : ΔHCO3

ACUTE

10:1

10:2

CHRONIC

10:3-4

10:4-5

For every rise of 10 of pCO2 the HCO3 will rise by 1 (or 3-4)

For every fall of 10 of pCO2 the HCO3 will fall by 2 (or 4-5)

88

Hemoptysis Differential Infection

Bronchitis, TB, bronchiectasis Young non-smoker with lung collapse (endobronchial tumors, can fill lumen) Carcinoid

Preop Workup: if suspect carcinoid syndrome, TTE to rule out carcinoid heart disease (TR)

Malignant

NSCLC or SCLC

Tumour Hemoptysis (GI and upper airway ruled out)

CTD Drugs/Toxin Vascular

Goodpasture's (antiGBM), GPA (or other vasculitis), SLE Cocaine, anticoagulation

Approach depends on whether massive or nonmassive hemoptysis

Pulmonary AVM, bronchial art. aneurysm, PE, florid CHF 89

Hemoptysis • Massive (variable definitions; ~200-600 cc/24 hours) – Acute management à Airway, Breathing, Circulation – If able to localize bleeding side

• position patient in decubitus position to protect unaffected lung

– Hold anti-coagulation/ correct coagulopathy – CBC, coagulation profile, ABG – Cross-type, IV fluids, oxygen

• Investigations

– Need imaging if patient is stable enough (CXR/CT) – Flexible bronchoscopy can be used for localization prior to IR guided embolization

• Management dependent on local center

– Interventional Radiology – Arterial embolization #1 if available – Thoracic Surgery – Ability for rigid bronchoscopy/Resection – Patients die of asphyxiation NOT exsanguination ATS Guidelines. 2003

QUESTIONS? • Be Sure to Check out BONUS Slides in Your Course Pack! – – – – – – – – – –

COVID and Pulmonary Diseases Choosing Wisely CTS Chronic Cough Approach (ACCP) OSA Lung Nodules (Fleischer 2017 guidelines) Smoking Cessation Counselling ** HIGH YIELD for Oral Scenarios** (VAPING has made it newsworthy) A Couple more slides on less high yield ILD subtypes Relevant Asthma and COPD trials Clubbing **PFT Approach, Some PFT “CLANG ASSOCIATIONS” to know ** • Our ONLINE MODULE also covers this, but some like a paper copy of notes

– CXR Approach

91

COVID-19 and Respiratory Diseases • Asthma: Patients at no increased risk of acquiring COVID, but may be at risk of triggering an exacerbation/more severe illness. Those with well-controlled asthma do not have this risk. No evidence that inhaled/oral steroids or biologics adversely affect patients. Avoid/use caution with nebulizers (GINA 2022). • COPD: Emphasis on advanced care planning. No increased risk of acquiring COVID, but 5-fold increased risk of severe disease. Treat COPD exacerbations with prednisone—no evidence of harm, expectation of low risk of harm (CHEST 2020). • ILD: Patients without prior lung disease develop imaging features of ILD after COVID-19 disease, but no data on long-term prognosis (CJRCCSM 2020, Lancet 2021). • Sleep Disordered Breathing: If suspected/confirmed COVID and using PAP device, must use a separate room/bathroom and sterilize mask daily. Caregivers at risk. If admitted to hospital with mild-moderate OSA, may be reasonable to withhold CPAP for infection control (CRJCCM 2020). If suspected/confirmed COVID case need to follow local infection control protocols and consider risk/benefit of withholding PAP device. • Pulmonary rehabilitation: Virtual programs developed, in 2022 many programs back to in person with appropriate precautions. 92

“Long COVID” – CTS 2021 Position statement on rehab for COVID-19 and Ontario Science Table statement “We suggest that all pts with COVID-19 be assessed for persistent or new symptoms and functional limitations 6-8 wks after their acute infection.” • Long COVID / post-COVID condition / Post-Acute-Sequelae of SARS COV2 (PASC)

– No firm definition, variable prevalence – >50 different long-term effects reported, fatigue, dyspnea, and neurocog sx most common – No specific therapies

• For referral to Pulmonary Rehab they suggest the following criteria be used:

New / ongoing respiratory symptoms (dyspnea and/or cough and/or exercise intolerance) and functional limitations after resolution of acute COVID-19 AND New or ongoing requirement for supplemental O2 OR At least 1 of: i) Persistent radiographic pulm. Abnormality (eg new or persistent reticular changes or fibrosis) ii) PFTs showing new/persistent reduction in lung volumes, airflow limitation and/or decrease in DLCO 93

Choosing Wisely Resp 2021 Update 1. 2. 3. 4. 5. 6. 7.

Don’t initiate long term maintenance inhalers in stable patients with suspected COPD if they have not had confirmation of post bronchodilator airflow obstruction with spirometry. Don’t perform CT screening for lung cancer among patients at low risk for lung cancer. Don’t perform CTA or VQ scan to evaluate for PE in patients with low clinical probability and negative D-dimer. Don’t treat adult cough with antibiotics even if it lasts more than 1 week, unless bacterial pneumonia suspected (mean viral cough duration 18d). Don’t initiate asthma treatment in patients who have not had reversible airflow limitation with spirometry or positive methacholine, or sufficient expiratory flow variability. Don’t use antibiotics for asthma exacerbations without clear signs of bacterial infection. Don’t delay conversations about wishes and goals with patients who have serious or progressive chronic respiratory illness, such as COPD, IPF, PH, or CF. Unnecessary and potentially harmful treatments can be avoided by having discussions and documenting these conversations. (NEW 2021)

94

Cough (ACCP) Acute (8 weeks)

• Life threatening: Pneumonia, COPDE, asthma,PE,heart failure, other serious disease • Non-life threatening: Infectious (URTI or LRTI), Environmental / occupational (RADS) • Post infectious: Pneumonia, bronchitis, pertussis, worsening asthma, GERD, UACS, COPD, NAEB • Non-infectious (same as chronic ddx) • UACS – upper airway cough syndrome, asthma, NAEB, GERD, smoking, ACEi use

95

Cough Approach • •

CXR and exclude ACE-inhibitors In this order, test and treat for: – UACS • Confirmed by response to Tx with 1st generation antihistamine/ decongestant (bronpheniramine/SR pseudoephedrine) • Sinus imaging if does not improve – Asthma • Methacholine challenge and/or empiric ICS (may treat NAEB as well) – GERD • If “clinical profile” fits (not necessarily GI symptoms), treat empirically – Lifestyle: coffee, chocolate, citrus, smoking ,etc. – H2RA/PPI – Prokinetic • 24h pH monitoring on therapy if cough persists • Antireflux surgery if refractory – NAEB • Sputum eosinophils, if available, or an empiric trial of corticosteroids

96

Obstructive Sleep Apnea • Go to resource: 2011 CTS Guideline on Sleep Disordered Breathing, JAMA RCE for OSA, 2019 AASM Guideline on OSA and PAP • Defined by presence of both: – Symptoms (sleepiness, choking, awakenings etc) and – Objective testing (> 5 apnea/hypopnea events during sleep monitoring) • Mild 5-15 (events/h) / Moderate 15-30 / Severe >30

• Physical Exam: (JAMA 2013 – Does this patient have OSA) – Most helpful finding was nocturnal choking/gasping (LR 3.3) – Snoring is non-specific – No findings on history or physical are good enough to rule in or out OSA, hence patients require sleep study 97

Obstructive Sleep Apnea • Treatment Indications

– Patients with symptoms of excessive sleepiness or impaired sleep-related QOL – Comorbid HTN – Asymptomatic patients with severe OSA

• Treatments – Weight loss (see endocrinology Bonus slides re Obesity) – PAP (CPAP or APAP) • All patients should be offered therapy, asymptomatic patients should be treated if have comorbidities (ie. HTN), AHI >30, critical occupation – Oral appliances – for mild-moderate disease – Surgery (rare) – Tonsillectomy if appropriate, uvulopalatopharyngoplasty in select patients • Recent Evidence: CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea, NEJM 2016 (RCT). Use of CPAP DID NOT reduce cardiovascular events for asymptomatic patients with moderate-severe OSA. Significance of this result still heavily debated. 98

CTS OSA 2014 / CMA 2019 Driving Guidelines – Severity of OSA alone is not a reliable predictor of collision risk and should not be used in isolation to assess fitness to drive • Consider co-morbidities, meds, sleep schedule and history of collisions in addition to severity • Mostly up to respirologist discretion in non-commercial drivers. • In commercial drivers with AHI > 20, patients generally need to be “treated adequately” i.e. compliant with therapy – Defined as >= 4hrs >70% of nights in past 30 days

– CMA Driver’s Guide 2019 (9.1 edition) now reflects these changes Know:

CTS 2014

99

Solid Lung Nodules – Fleischner 2017 Guidelines Simplified for IMR SOLID NODULE

Risk?

8mm

Single Solid Nodule

Low Risk

No routine f/u

CT at 6-12 mos then consider 18-24mos

High Risk

Optional CT at 12 mos

CT at 6-12 mos, AND CT at 18-24 mos.

Consider CT at 3 mos, PET – CT or biopsy

Low Risk patient

No routine f/u

CT at 3-6 mos, then consider CT at 18-24 mos*

High Risk Patient

Optional CT @ 12mos

CT at 3-6 mos, and CT at 18-24 mos*

Multiple Solid Nodules

This guideline applies to Adults >35 years and Pertains to incidental nodules, NOT in lung cancer screening population, patients with history of primary cancer, or immunosuppression *With multiple nodules, use most suspicious nodule to guide interval for followup. High risk = estimated risk of cancer >5%. (use clinical and radiographic risk – older age, heavy smoking, irregular nodule, spiculated, upper lobe location … there is ambiguity in guideline about this) 100

Subsolid Lung Nodules – Fleischner 2017 Guidelines Simplified for IMR SUBSOLID NODULE

Description of nodule

= 6mm

Notes

Single nodule

Ground Glass

No routine f/u

CT at 6-12 mos then if every 2h til 5yr

Partsolid

No routine F/U

CT at 6-12 mos, then if persistent annual CT to 5 yrs

Increase in nodule by >=2mm significant

Low risk

CT at 6-12 mos

High risk

CT at 6-12 mos then at 2y , 4y if high risk

Multiple subsolid Nodules

CT at 3-6 mos then depends on most suspicious nodule

This guideline applies to Adults >35 years and Pertains to incidental nodules, NOT in lung cancer screening population, patients with history of primary cancer, or immunosuppression *With multiple nodules, use most suspicious nodule to guide interval for followup.

101

Clubbing Clubbing is enlargement of the terminal segments of the fingers due to proliferation of the connective tissue between the nail matrix and the distal phalynx •

•

• •

• •

Neoplastic Intrathoracic Disease – Bronchogenic Carcinoma – Mesothelioma Suppurative Intrathoracic Disease – Lung Abscess or Empyema – Bronchiectasis, CF Diffuse Pulmonary Disease ex Pulmonary Fibrosis Cardiac Disease – Cyanotic CHD – Infective Endocarditis Gastrointestinal Disease (IBD) Metabolic Disease (grave’s)

1. 2.

MEASURING CLUBBING: (no longer high yield now that applied eam doesn’t include physicals!) Phalangeal depth ratio (DPD/PPD) > 1.0 Profile angle (defined by the angle made by nail as it exists from the proximal nail fold) > 176 Hyponychial angle (constructed by drawing a line from distal digital crease to the cuticle and another line from the cuticle to hyponychium which is the thickened stratum corneum of epidermis lying under the free edge of the nail) > 192 degrees is abnormal • Schamroth & palpation not validated

Spirometry Glossary of Terms

•

FEV1: Forced Expired Volume in 1 second (in litres) FVC: Forced Vital Capacity: maximum volume of gas that can be expired when a subject exhales as forcefully and rapidly as possible after maximal inspiration. (in litres). VC: Vital Capacity (or Slow Vital Capacity): the volume of gas measured from a slow, complete exhalation. Look at patient demographics!

•

Look at the Curve! Obstructive vs. restrictive

• • •

PFT Approach

A. Fixed upper-airway obstruction (intrathoracic or extrathoracic) • Glotic stenosis (prolonged intubation), subglotic stenosis (Wegner’s, sarcoid, polychondritis) B. Variable extrathoracic obstruction • Flattening of inspiratory curve • Vocal cord dysfunction/paralysis C. Variable intrathoracic obstruction • Flattening of expiratory curve • E.g. tracheomalacia of intrathoracic airway

PFT Approach Spirometry: • Is there Obstruction? (FEV1/FVC12% + 200cc)? Is there reduction in FVC suggesting restriction or gas trapping

– –

Volumes: • Is there restriction? TLC < LLN

If yes, is it parenchymal (reduced DLCO) or extra parenchymal (normal DLCO)

–

• •

Is there gas trapping? RV/TLC >ULN Is there hyperinflation? TLC>ULN

DLCO: • Is there a diffusion impairment? DLCO < LLN (DLCO < 75% in some institutions) – –

•

Isolated decreased DLCO? Increased DLCO?

Is there concomitant obstructive or restrictive physiology?

105

PFT Clang Associations and Pitfalls • Restrictive pattern varying with position

– Vital Capacity decreases when lying down by >10% • Gravity eliminated therefore unmasks diaphragm dysfunction, confirm with MIPs/MEPs • May be presented as a post-op scenario (e.g. CABG) or NMD (e.g. ALS)

• Isolated decrease in DLCO?

– Classically pulmonary hypertension, also early ILD/emphysema, anemia

• Increased DLCO

– Pulmonary hemorrhage/polycythemia, LV failure, asthma, obesity

• More than one process can occur in the same patient!

– Mixed obstructive and restrictive process: Obese smoker, bronchiectasis, sarcoidosis, HP

• Ask for full PFTs including lung volumes and DLCO if possible:

– If “what you see is what you get”, interpret based on the best of your ability: • “Mild obstructive lung disease. I would ask for further testing to evaluate for a bronchodilator response and measure lung volumes and DLCO to help with my differential diagnosis.”

PFT Contraindications • Contraindications to PFTs: (BMJ) • • • • • • •

1. Hemoptysis 2. Pneumothorax 3. Unstable cardiovascular status including recent MI 4. Aneurysms – thoracic, abdominal or cerebral 5. Recent eye surgery – eg. Cataracts 6. Recent thoracic or abdominal surgery 7. Presence of acute illness that may interfere with test performance

• Contraindications to Methacholine Challenge: (ATS)

– Absolute: • 1. Severe airflow limitation FEV1 abdominal) 2. Age, prexisting lung disease Preventing post op complications – Epidural analgesia decreases atelectasis and pneumonia (Ann Surg 2014)

Diaphragmatic Weakness • Often idiopathic, often unilateral (and may be entirely asymptomatic) • Causes include:

– Trauma or surgery (C3-5 injury during trauma, phrenic nerve injury during cardiac surgery) – Mechanical ventilation – Myopathy/neuropathy • ALS, MG, critical illness myopathy/neuropathy

@IMR we often get asked: What is the most specific and most sensitive test for diagnosis of diaphragm weakness/paralysis? Most SENSITIVE = MIP. Most SPECIFIC: There isn't really a good specific test on PFTs for diaphragmatic weakness. Proceed to ultrasound if you want specificity. If forced to choose we “guess” FVC… because it's associated with poor prognosis in diaphragmatic dysfunction as per the ALS CTS guidelines. 109

Approach to CXR Think ABCDEFGH… •

•

•

•

Assess quality: – Position: Supine? AP? Lateral? – Inspiration: count ribs – Exposure: do you see interverbral discs – Rotation: position of spinous process to the medial aspect of clavicle Bones and soft tissue – Symmetry, fractures, osteoporosis, lesions – Soft tissue, foreign body, swelling, subcutaneous air Cardiac – Heart 60min) Worse with rest, better with activity Night pain (esp. latter half of night) Swelling Mono-arthritis: 1 joint Oligo-arthritis: 2-4 joints Poly-arthritis: 5 or more joints

Acute: < 6 weeks duration vs Chronic: > 6 weeks Extra-articular features Synovial Fluid Analysis 5

Synovial Fluid Analysis Type of Arthritis

Fluid Appearance

WBC Count (mm^3)

% PMNs

Crystals

Noninflammatory (OA)

Clear

≦ 2000

50%

No

Inflammatory/ Crystals

Cloudy

>2000-50,000

>50%

- birefring = Gout + birefring = CPPD

Cloudy/pus

>50,000 bacterial 10k-30k fungal/mycobacterial

>75% PMH indicative of bacterial infection

+/-

Septic

(crystals can co-exist with septic arthritis don’t be fooled await culture) CMAJ. 2009: 180(1): 59-65.

6

Approach to Arthritis Arthritis

Poly

Mono

*not an exhaustive list

Acute

Chronic

Acute

Chronic

(< 6 weeks)

(> 6 weeks)

(< 6 weeks)

(> 6 weeks)

Infection, Crystal, Trauma, Hemarthrosis, New IA

OA, IA, Infection (fungal, TB), AVN

Infectious (viral, IE), New IA

Inflammatory, Crystal, Reactive, Paraneoplastic 7

Chronic Inflammatory Arthritis Sero-positive

Sero-negative : “PEAR”

Rheumatoid Arthritis (RA)

Psoriatic Arthritis (PsA)

Systemic Lupus Erythematosus

Enteropathic (IBD) arthritis

Scleroderma (systemic sclerosis)

Ankylosing Spondylitis (AS)

Sjogren’s Syndrome

Reactive Arthritis

Dermatomyositis (DM)

Undifferentiated

Polymyositis Mixed Connective Tissue Disease 8

MCQ #1 2024 A 27-year-old female who works in a daycare presents with a 3-month history of joint pain and swelling. Examination reveals swelling of the bilateral MCP 2-3 and wrists as well as tenderness to palpation of MTP 2-4 bilaterally. X-rays of the hands and feet show no evidence of erosions or other pathology. ROS is otherwise negative. Which of the following lab tests is most specific for the diagnosis? A. HFE genetic testing and iron studies B. Rheumatoid Factor C. Anti-CCP antibodies D. Parvovirus IgM and IgG titers 9

Rheumatoid Arthritis Symmetric small joint polyarthritis of synovial joints (MCPs, PIPs, wrists) • ≥6 weeks of arthritis • Serology: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) Ø 25% RA are RF negative (RF is not diagnostic) Ø Anti-CCP: 95% specificity, can precede arthritis, predicts more erosive disease (in association with smoking = major RF) Ø Elevated CRP, ESR • XR – periarticular osteopenia, joint space narrowing, marginal erosions • Do not need serology or X-rays for diagnosis, especially with early disease 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria. Arthritis Rheum. 62(9):2569-2581.

DDx of + RF : -Other CTD -Hepatitis C/ cryoglobulinemia -Endocarditis -Malignancy (B cell neoplasms most common) -Age -Normal variation

10

RA Extra-articular Manifestations Cardiac • Pericarditis (+/- effusion), myocarditis • Coronary artery disease àRA is independent RF for developing CAD due to accelerated atherosclerosis Lung • Interstitial lung disease (NSIP, UIP) – usually anti-CCP positive • Pleural effusion (sterile exudate with low glucose) • Pulmonary nodules • Bronchiolitis obliterans Hematologic • Anemia, reactive thrombocytosis • Felty’s syndrome (rare) = Seropositive RA + splenomegaly + neutropenia • Lymphoproliferative conditions

Neurologic • Carpal tunnel syndrome (one of the earliest signs of RAà know for oral) • C1-C2 instability/subluxation = lifethreatening (pre-op oral scenario) Other • Rheumatoid nodules • Vasculitis – variable vessel involvement • Often occurs in “burnt out” disease • Secondary Amyloidosis • Scleritis/Episcleritis, corneal melt • Sicca symptoms (dry eyes, dry mouth) • Raynaud’s phenomenon • Sweet’s syndrome • Neutrophilic dermatosis 11

RA Management: Overview of DMARD Conventional synthetic DMARD (csDMARD) • Methotrexate (MTX) • Hydroxychloroquine (HCQ, PLQ) • Sulfasalazine (SSZ) • Leflunomide (LEF) Biologic DMARD (bDMARD) • TNF Inhibitors – Adalimumab, infliximab, certolizumab, etanercept, golimumab • Tocilizumab (IL-6) • Abatacept (T cell inhibitor) • Rituximab (anti-CD20) Small molecules/targeted synthetic DMARD (tsDMARD) • Tofacitinib* (Xeljanz) • Baricitinib* (Olumiant) • Upadacitinib* (Rinvoq) • Apremilast (Otezla) • JAKi – significantly increased risk of HZ

*ORAL Surveillance Study - 2022: • Large post-marketing safety study revealed increased risk of all-cause mortality, MACE, VTE & cancer in tofacitinib vs TNFi (patients had RA, age >50 with >1 CV risk factor) • FDA issued black box warning Sep 2021 against all JAK inhibitors for all indications (approved if failed/intolerant to >1 anti-TNF) RELATION Study – Tofa vs TNFi, similar risk of MACE. Tofa not associated with increased risk of cancer excluding NMSC

2022 CRA guideline for the pharmacologic management of RA. J Rheum 39 (8) 1559-1582. 2021 ACR guidelines for the mgmt. of RA. Arthritis Care Res. 73(7):924-939. Cardiovascular & Cancer Risk w Tofacitinib in RA. NEJM, 2022. 386(4):316-326.

12

RA Management

Note: 2023 CRA guideline for RA is a living guideline that updates as new evidence emerges!

• “Bridge” Therapy/Symptomatic Treatment (NOT disease modifying) • Steroids (PO, IM, IA) ≦ 3 months – use lowest dose for shortest possible time • NSAIDs, Analgesics Treat to Target strategy = Treat • Long Term Therapy (Disease modifying) until patients reach a low disease activity state or remission based on • Step 1: Conventional DMARD • • •

validated disease severity indices Low disease activity: Hydroxychloroquine Moderate to high disease activity: MTX monotherapy Note: Triple therapy (MTX + PLQ + SFZ) no longer recommended as a preferred strategy

• Step 2: Biologic or Small Molecule

Use when failed MTX monotherapy (preferred over triple therapy) Usually start with TNF inhibitor and continue MTX • MTX is used for synergistic effects but also to prevent formation of anti-drug Ab • Change medication classes to alternate biologic or small molecule if not at target Dose can be reduced in patients with low disease activity or remission for >6 months • •

•

2021 ACR guidelines for the management of Rheumatoid Arthritis. Arthritis Care Res. 73(7):924-939. 2022 CRA living guidelines for the pharmacological management of Rheumatoid Arthritis. J Rheum.

13

RA Management: Special Considerations •

• • •

•

Pulmonary disease : Screen at baseline with PFTs and High Resolution CT [not CXR – new- ACR 2023] • MTX can cause pneumonitis (rare complication) • If patient has at baseline parenchymal lung disease that is incidental/mild/stable then can still use MTX over other DMARDs for arthritis particularly if moderate to severe RA disease activity Heart Failure • Don’t start TNFi if history of NYHA Class III or IV heart failure • If patient develops heart failure on TNFi switch to another agent (non-TNF biologic) Lymphoproliferative Disorder • Use rituximab first line if patient has moderate to severe disease activity and a lymphoproliferative disorder in which rituximab is indicated Hepatitis B • If Hep B core Ab Positive, SAg + à prophylactic antiviral therapy while starting all biologic dMARD. • If starting rituximab à prophylactic antiviral therapy even if surface antigen neg if core Ab + Metabolic-dysfunction associated steatotic liver disease (formerly NAFLD): Can still use MTX if liver enzymes normal, liver function tests normal, no advanced liver fibrosis, and patient has moderate to severe disease activity, with more frequent (q4-8wk) monitoring of LFTs • MTX can be hepatotoxic 2021 ACR guidelines for the management of Rheumatoid Arthritis. Arthritis Care Res. 73(7):924-939.

14

Conventional DMARD Key Points DMARD Methotrexate (MTX) (weekly medication)

Side Effects Hepatotoxicity, nausea, pancytopenia, pulmonary (hypersensitivity pneumonitis, fibrosis), oral ulcers, alopecia, teratogenic Prescribe with folic acid to reduce s/e

Monitoring -Baseline CXR, HCV, HBV, CBC, LFTs, Cr -Initial CBC, LFTs, Cr q2-4 weeks, then q12 weeks after 3 months - ESR and CRP for disease monitoring

Hydroxychloroquine

Retinal toxicity, rash, photosensitivity, myotoxicity (rare), cardiotoxicity (rare)

- Baseline and annual ophthalmologic exam (retinal toxicity)

Leflunomide

GI (nausea, GI pain, dyspepsia, diarrhea), hepatotoxicity, HTN, myelosuppression (rare), peripheral neuropathy, teratogenic

-Baseline CBC, LFTs, Cr, HBV, HCV

Sulfasalazine

GI toxicity, headache, rash Contraindicated if sulfa allergy

-Initial CBC, LFTs, Cr q2-4 weeks, then q12 weeks after 3 months -Initial CBC, LFTs, Cr q2-4 weeks, then q12 weeks after 3 months

2012 CRA Guidelines for management of RA. J Rheum. 39(8): 1559-1582. 2015 ACR Guidelines for treatment of RA. Arth Care Res. 68(1): 1-25.

15

Management of low-dose MTX toxicity Toxicity

Management

Nausea

• • •

Increase folic acid to 5mg daily Trial H2 blocker or PPI Add leucovorin post MTX dose

Stomatitis

• • •

Increase folic acid to 5mg daily Add leucovorin If folic acid/leucovorin ineffective or ulcers severe: ↓ MTX dose

Hepato-toxicity

• Mildly elevated LFTs= reduce MTX dose • Elevated LFTs > 2x ULN = hold MTX dose then resume at lower dose 1-2 weeks after normalization

Rash

• Dose reduce MTX • If non-resolving, discontinue MTX

Cytopenias

• Dose reduce or discontinue MTX depending on severity

Pneumonitis

• Discontinue MTX, do not re-start

2021 ACR guidelines for the mgmt. of RA. Arthritis Care Res. 73(7):924-939. 2008 ACR Guidelines for treatment of RA. Arth Care Res. 59(6): 762-784.

For patients not tolerating oral methotrexate, try: - Split dose (eg 10mg bid once weekly instead of 20mg po weekly) - Change to Sc injection - Increase dose folic/folinic acid BEFORE stopping MTX and switching to another DMARD

16

Biologics Key Points • •

•

•

Risks of Biologics: Infection (new or reactivation), drug induced SLE/antibodies (get baseline ANA), local skin reactions, malignancy risk Baseline Testing (prior to starting biologic): • Hepatitis B surface Ag, Surface Ab, Core Ab, Hepatitis C serology (treat concurrently if positive) • TB skin test, IGRA, and/or CXR as appropriate (see algorithm slide) Special Situations/Controversial to use if: • NYHA Class III or IV heart failure (TNFi can worsen CHF) • Active hepatitis (start hepatitis treatment first, consult GI) • Prior lymphoproliferative malignancy – use Rituximab • Prior solid organ malignancy – consult Oncologist prior to starting • Prior skin cancer – csDMARDs preferred (avoid TNFi as increased risk nonmelanoma skin ca) • Prior serious infection – considering using csDMARDs if serious infection w/i 12 months If flare, modify frequency rather than dose first ** DO NOT COMBINE BIOLOGICS ** 17

TB Screening for Biologics or Tofacitinib HIGH Risk includes: Ø Close contacts of persons known/ suspected to active TB Ø Born in endemic (e.g., Africa, Asia, Eastern Europe, Latin America, and Russia) or visit areas with high prevalence Ø Residents/employees of congregate settings (e.g., correctional facilities, long-term care facilities, and homeless shelters)

2015 ACR Guidelines for treatment of RA. Arth Care Res. 68(1): 1-25.

18

BONUS Read on own

• • • • •

• •

Vaccination Recommendations

Yearly Influenza • High dose recommended for all RMD patients >65 and patients between 18-65 on immunosuppressants Pneumococcal • Recommended for patients aged 18 on immunosuppressants • Shingrix (non-live, recombinant) preferred • Live attenuated can be administered to high-risk patients not on biologics • If starting biologics administer live attenuated at least 4 weeks prior to initiation HPV • Recommended for patients aged >26 - 2 weeks • Prednisone: Give influenza vaccine; Defer other vaccines if on > 20 mg Prednisone until tapered • Other immunosuppressives: Continue unchanged

•

Medication management around live-attenuated vaccines: • Deferring live-attenuated vaccines is conditionally recommended, but can be considered with caution • Hold treatment for period before (below) and 4 weeks after necessary live-attenuated vaccines • • • • •

•

Glucocorticoids, conventional DMARDs (except IV CYC): Hold 4 weeks prior Biologics (except rituximab + IVIG), IV CYC: Hold 1 prior dosing interval Rituximab: Hold 6 months prior IVIG: Hold for 8-11 months prior (dose dependent) JAKi: Hold 1 week prior

Live-attenuated rotavirus vaccine in infants exposed to immunosuppressants in utero

Anti-TNF: Controversial à ACR 2022 – ”can be given within 1st 6 months”, EULAR 2019 - “should be avoided within 1st 6 months”, PHAC 2021 – “data around vaccine safety is limited - Individual risk assessment recommended” • Rituximab: Rotavirus vaccine should be avoided within 1st 6 months 2022 ACR Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal diseases. Summary published ahead of print (expected late 2022). 20 2019 EULAR Recommendations for vaccination of patients with rheumatic disease on immunosuppressive therapies. Ann Rheum Dis. 79: 39-52. •

Management during Pregnancy •

•

•

•

Pre-Pregnancy: Ideal if in remission • Stabilize disease on medication that is safe to take in pregnancy • Discontinue MTX at least 1-3 months prior to conception • Ideally avoid leflunomide in patients with the possibility of pregnancy; if on leflunomide, measure leflunomide levels and treat with cholestyramine washout if detectable • Taper prednisone to 6mo) • Treatment: • NSAIDs, intra-articular corticosteroids • Consider DMARDs in recurrent/chronic disease, e.g. MTX, sulfasalazine; rarely TNFi • No role for antibiotics (unless evidence of active infection) 31

Septic Arthritis •

Most commonly monoarthritis of hip or knee

•

S. aureus #1 in both native and prosthetic joints

•

Salmonella #1 in osteomyelitis and septic arthritis in Sickle Cell Disease

•

Crystal arthritis can co-exist with infection – don’t be fooled!

•

Definitive management requires source control (i.e. ortho consult for washout) GRAM STAIN

NOTE: IDSA Guidelines on Prosthetic Joint Infections in BONUS slides of ID lecture.

EMPIRIC TREATMENT

Gram + community acquired

Cefazolin 1-2g IV q8h

Gram + hospital / LTC acquired

Vanco 1 g IV q12h

Gram – bacilli

Ceftriaxone 2g IV q24h + anti-pseudomonal if risk (DM, hospitalized, IVDU) Ceftriaxone 2g IV q24 h (+ treat for chlamydia) Vanco + Ceftriaxone

Gram – cocci (eg Neisseria) Nothing on Gram stain

JAMA. 2007; 297(13):1478-1488. 32

Gonococcal Arthritis 2 common syndromes: 1.

Triad of tenosynovitis, vesiculopustular skin lesions, migratory polyarthralgias without purulent arthritis 2. Purulent arthritis without skin lesions à requires longer course of antibiotics • Occurs in 6 months post infection), oligoarthritis with synovitis and swelling most commonly affecting the knee. Symptoms can fluctuate – swelling and erythema without significant pain. Synovial fluid inflammatory. Diagnosis • Lyme Serology + Clinical Picture • Where diagnosis needs confirmation, PCR of synovial fluid or tissue Treatment • Oral antibiotics x 28 days (doxycycline or amoxicillin) • Treatment failure with objective severe synovitis – ceftriaxone 2-4 weeks IV if other diagnoses excluded • Post-antibiotic Lyme Arthritis: Referral to Rheumatology for consideration of DMARD or biologic therapy (repeated courses of IV antibiotics not recommended) 2020 IDSA/AAN/ACR Guidelines for Lyme Disease. Arth & Rheum. 73(1):12-20. 34

MCQ #3 2024 Concerning for Adult Onset Still’s Disease (see

A 35-year-old female previously healthy bonus presents with recurrent criteria) fevers (Twith max slides for Yamaguchi 39.1) and arthralgias after URTI over 1 month ago. On examination, she is febrile recurrent fever, truncal rash, synovitis, liver with left wrist synovitis and a truncal rash. Bloodelevation, work demonstrates the Common to enzyme ferritin elevation. present after infection. following: Hb 110, WBC 10.1, Plts 220. ALT 60, AST Tx: 80,AOSD ALP 22. Ferritin 2080. Serology • Mild/moderate disease can start with NSAIDS. negative for ANA, RF, anti-CCP, dsDNA, and normal complements. You proceed • Severe disease or failure of NSAIDS, consider with an arthrocentesis of her wrist. steroids or Anakinra (IL-1) Which of the following is NOT appropriate initial management? While waiting results of joint aspiration cover A. Naproxen with antibiotics, d/c when gram stain/culture B. Ceftriaxone neg. This is not Lyme disease, doxy is not appropriate first choice. C. Vancomycin D. Doxycycline 35

Crystal Arthritis: Gout Gout • • • •

Monosodium urate crystals (needle shaped, negatively birefringent) Acute self limited inflammatory arthritis (mono>oligo>poly) Gold standard – arthrocentesis with SF demonstrating MSU crystals Presence of crystals on arthrocentesis does NOT rule out septic arthritis

Risk Factors: • Hyperuricemia – may be increased production (purine rich diet, TLS, hemolysis, polycythemia) or reduced clearance (renal insufficiency, diuretics) • •

• •

Meds: thiazides, low dose ASA, allopurinol, pyrazinamide Diet: beer, red meat, seafood

Demographics: male, post-menopausal females, obesity Estrogen has protective effect (so not in young healthy females!)

Source: ACR image gallery

Monoarticular in ~80% of initial attacks with predilection to lower extremities, most commonly 1st MTP or knee **Uric acid level is not diagnostic** but is a target for therapy • Look for tophi on cool extremities (especially helix/elbows) •

36

Crystal Arthritis: Pseudogout Calcium pyrophosphate dihydrate disease (CPPD, aka pseudogout) • Various presentations: • • •

Pseudogout –acute mono/oligo-arthritis “RA-like” – chronic inflammatory arthritis OA with CPPD – atypical OA distribution (lateral knees, wrists, elbows)

Chondrocalcinosis is radiographic diagnosis (may be asx) CPPD crystals = rhomboid shaped, positively birefringent • If present on synovial fluid, then patient has CPPD • Secondary Causes: hypothyroidism, hypomagnesemia, hypophosphatemia, hemochromatosis (2nd, 3rd MCP arthritis with hooked osteophytes), hyperparathyroidism, Wilson’s (rare) Calcific Tendinitis / Milwaukee Shoulder (basic calcium phosphate/hydroxyapatite crystals) • Older female patients • Acute onset, destructive shoulder arthropathy • •

Crowned Dens Syndrome: acute or subacute onset upper neck pain (usually with limited ROM), elevated inflammatory markers and often fever Diagnostic of CPPD if clinical/imaging features of CDS present 37

Treatment of Gout: Acute NSAIDs Colchicine • 1.2mg load then 0.6mg an hour later then 0.6mg BID until symptoms resolve – Requires dose reduction for CKD – CrCl 535 • Urolithiasis

Allopurinol vs. Febuxostat* - some early studies suggested increased CV events w febuxostat ; FDA issued black box warning re CV safety. Since then - FAST trial (Lancet, 2020) à “Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its longterm use is not associated with an increased risk of death or serious adverse events compared with allopurinol.”

ULT Treatment Options: 1) Allopurinol: 1st line • Start at 100mg/d (or 50mg if CKD 4) and up-titrate until reach target uric acid level < 356umol/L or 0.5g/24h Renal bx class II or V lupus nephritis Renal bx class III or IV lupus nephritis

4 8 10

Anti-cardiolipin antibodies OR Anti-B2GP1 antibodies OR Lupus anticoagulant

Wt

2019 SLE Classification Criteria

2

Complement proteins Low C3 OR low C4 Low C3 AND low C4

3 4

SLE-specific antibodies Anti-dsDNA antibody* OR Anti-Smith antibody

6

Cutoffs for Criteria: • Fever >38.3oC • Leukopenia WBC 1/160 = 5%) • Not used to follow disease activity (do not repeat over time) Anti-dsDNA • Specific (97-98%), but not sensitive (present in 60-80% of SLE patients) • Associated with lupus nephritis • Can be used for monitoring disease activity, along with serum complements (C3, C4) in concordant individuals – –

Concordance = When flare, high anti-dsDNA, low complements Discordance = When flare, above pattern doesn’t apply

45

Lupus Labs: ENA • Anti-Sm: Specific but not sensitive (30-40%) • Anti-histone: Drug-induced lupus; SLE (50-70%) • Anti-RNP: Required for diagnosis of MCTD; SLE (30-40%) • Anti-Ro (SSA): Risk of congenital heart block and neonatal cutaneous lupus; also seen in Sjogren’s syndrome • Anti-La (SSB): seen in Sjogren’s syndrome 46

Management of Non-Renal SLE Mild* Constitutional symptoms, mild arthritis, rash 0.5g/24h or UPCR >500 mg/g - Unexplained dec in GFR +Check APLA in all with SLE Nephritis

Overview of Management Class I: Minimal Mesangial LN Class II: Mesangial Proliferative LN Class III: Focal LN (3g/day Aggressive immunosuppression Anti-proteinuric/anti-hypertensive agents +/- Immunosuppression if refractory Supportive Therapy +/- Treat extra-renal manifestations Measure ADAMSTS if you suspect SLE-TMA Measure APLAS Experienced heme needed…Treat underlying cause (PLEX, steroids, anticoag, eculizumab, etc)

Feng et al. Redefining lupus nephritis: clinical implications of pathophysiologic subtypes. Nat Rev Neph. 2017; (13):483-495. 2003 ISN/RPC Classification of Lupus Nephritis. Kidney Int. 2004; (65): 521-530.

49

Management of Lupus Nephritis

Targets: 3mo: ≥25% reduction in Upr 6mo: ≥50 reduction in Upr to