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Post-Operative Hypotension: Notes & Stepwise Pharmacological Management

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1. Definition

• MAP < 65 mmHg (most commonly used threshold)
• SBP < 90 mmHg, OR
• A drop of >20-30% below the patient's individual baseline BP

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2. Pathophysiology - Why Does It Happen?

Vasodilation is the most common cause of POH after noncardiac surgery - Douglas et al., Br J Anaesth 2023 (PMID: 37778937)

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3. Clinical Recognition

• Low MAP/SBP on monitoring
• Tachycardia (compensatory) - but may be absent with beta-blockers or in vagally mediated states
• Oliguria / decreased urine output
• Altered consciousness, agitation
• Pale, cold, clammy skin (low CO states) vs. warm vasodilated peripheries (distributive)
• Narrow pulse pressure = low stroke volume / low CO
• Low diastolic pressure = vasodilation

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4. Causes to Actively Exclude (AABC Rule of Thumb)

• A - Arrhythmia / Anesthetic residual (volatile, neuraxial)
• A - Anaphylaxis / Adrenal crisis (pheochromocytoma post-resection, Addison's)
• B - Bleeding / Blood loss (surgical site, internal hemorrhage)
• C - Cardiac (STEMI, tamponade, tension pneumothorax, PE)
• C - Compression / obstruction

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5. Stepwise Pharmacological Management

Step 1 - Immediately Identify the Cause

• Get a quick history: surgical procedure, estimated blood loss, anesthetic used, pre-op meds (ACE inhibitors, beta-blockers, diuretics)
• Check: SBP trends, HR, urine output, SpO2, ECG
• Assess fluid responsiveness (passive leg raise, stroke volume variation if invasive monitoring available)

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Step 2 - Position + Oxygen

• Trendelenburg or passive leg raise (auto-transfusion effect, assess fluid responsiveness)
• 100% supplemental oxygen
• Call for help / escalate if needed

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Step 3 - Fluid Resuscitation (if hypovolemia is likely)

Do NOT fluid overload - assess response after each bolus (MAP, HR, UO). If no response after 1-2 boluses, move to vasopressors.

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Step 4 - Vasopressors (First-Line)

A. Phenylephrine

• Mechanism: Pure alpha-1 agonist -> increases SVR
• Dose: 50-200 mcg IV bolus; infusion 0.5-3 mcg/kg/min
• Indication: Anesthesia-induced vasodilation, spinal/epidural hypotension
• Cautions: Reduces cardiac output via reflex bradycardia; avoid in septic shock; avoid if CO is already low
• Note: Most commonly used vasopressor in the US for perioperative hypotension - Miller's Anesthesia, 10e

B. Ephedrine

• Mechanism: Mixed alpha + beta agonist (direct + indirect); increases both SVR and CO
• Dose: 5-10 mg IV bolus, repeat every 3-5 min (max ~50 mg)
• Indication: Hypotension + bradycardia (e.g., spinal anesthesia), preferred when cardiac stimulation is wanted
• Cautions: Tachyphylaxis with repeated dosing; avoid in tachycardia
• Note: Preferred over phenylephrine in patients on amitriptyline or where indirect-acting agents are inappropriate - Morgan & Mikhail, Clinical Anesthesiology, 7e

C. Norepinephrine (Noradrenaline)

• Mechanism: Potent alpha-1 + weak beta-1 agonist -> increases SVR while largely maintaining CO
• Dose: 0.01-0.5 mcg/kg/min IV infusion (start low, titrate)
• Indication: Most common vasopressor globally for POH; preferred when phenylephrine has failed or CO must be maintained; first-line in septic shock
• Cautions: Peripheral vasoconstriction; requires central line for prolonged use (peripheral short-term administration is acceptable in emergencies)
• Note: Norepinephrine was the most common vasopressor used for postoperative hypotension in the 2023 systematic review [PMID: 37778937]

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Step 5 - Second-Line Vasopressors

D. Vasopressin

• Mechanism: V1 receptor agonist -> vasoconstriction without catecholamine stimulation
• Dose: 0.03-0.04 units/min fixed-rate infusion (not titrated like catecholamines)
• Indication: Adjunct when norepinephrine is insufficient; catecholamine-refractory vasodilatory shock; may be particularly useful in adrenal insufficiency or post-cardiopulmonary bypass
• Cautions: Mesenteric and coronary vasoconstriction at high doses; reduces cardiac output

E. Epinephrine (Adrenaline)

• Mechanism: Alpha + beta-1 + beta-2 -> increases HR, CO, SVR
• Dose: 0.01-0.5 mcg/kg/min infusion; 0.1-1 mg bolus in cardiac arrest / anaphylaxis
• Indication: Cardiogenic shock with hypotension, anaphylaxis (IM 0.3-0.5 mg = drug of choice), severe refractory shock
• Cautions: Increases myocardial oxygen demand; arrhythmogenic; causes hyperglycemia

F. Dopamine

• Mechanism: Dose-dependent: low dose (1-5 mcg/kg/min) = dopaminergic; moderate (5-10) = beta-1; high (>10) = alpha-1
• Dose: 5-20 mcg/kg/min
• Indication: Less commonly used now; consider in POH with bradycardia and impaired cardiac function
• Cautions: More arrhythmogenic than norepinephrine; no longer preferred first-line

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Step 6 - Specific Scenarios

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Step 7 - Adjuncts for Refractory Hypotension

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6. Vasopressor Comparison Summary

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7. Monitoring Targets

• MAP > 65 mmHg (or within 10% of individual baseline)
• UO > 0.5 mL/kg/hr
• SpO2 > 95%, lactate trending down
• HR within normal range (avoid excessive tachycardia from aggressive beta stimulation)
• Avoid phenylephrine in low-output states - it may worsen splanchnic perfusion

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8. Special Notes

1. Chronic antihypertensive medications (ACE inhibitors, ARBs, diuretics) taken on the morning of surgery are a major risk factor for POH - delay restarting these postoperatively until clearly necessary. - APSF perioperative hypotension guidance
2. Even transient POH (MAP <65 for as little as 11-20 minutes) is associated with AKI, myocardial injury, and stroke. - Miller's Anesthesia, 10e
3. Neuraxial anesthesia (spinal/epidural) causes sympatholysis -> vasodilation + bradycardia. Treat with phenylephrine (if HR normal/high) or ephedrine (if bradycardia present).
4. Post-pheochromocytoma resection: Up to 20-70% of patients require postoperative vasopressor therapy. Ensure adequate volume loading pre-vein ligation to reduce post-resection hypotension severity. - Miller's Anesthesia, 10e
5. Fluids and vasopressors are complementary, not competing. Fluid responsiveness testing (passive leg raise, SV variation) guides rational use.

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Quick Reference - Stepwise Algorithm

Recognize POH (MAP <65 or SBP <90)
       ↓
ABCDE assessment + 12-lead ECG
       ↓
Identify cause: Hemorrhage? Vasodilation? Pump failure? Obstruction?
       ↓
  ┌─────────────────────────────────────────────┐
  │  Fluid responsive? → IV bolus 250-500 mL   │
  │  (Repeat x1-2, reassess)                   │
  └─────────────────────────────────────────────┘
       ↓ (No response / contraindicated)
  ┌─────────────────────────────────────────────┐
  │  VASODILATION → Phenylephrine or NE         │
  │  BRADYCARDIA + vasodilation → Ephedrine     │
  │  ANAPHYLAXIS → Epinephrine IM 0.5 mg        │
  │  CARDIOGENIC → NE + Dobutamine              │
  │  ADRENAL → Hydrocortisone 100 mg IV         │
  └─────────────────────────────────────────────┘
       ↓ (Refractory)
  ┌─────────────────────────────────────────────┐
  │  Add Vasopressin 0.03 units/min             │
  │  Consider Angiotensin II / Methylene Blue   │
  └─────────────────────────────────────────────┘
       ↓
  Target MAP >65, UO >0.5 mL/kg/hr, Lactate ↓

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• Douglas et al., Vasopressors to treat postoperative hypotension, Br J Anaesth 2023 (PMID: 37778937) - systematic review; norepinephrine most common vasopressor used; vasodilation most common mechanism
• Miller's Anesthesia, 10e - perioperative blood pressure management, pheo resection
• Morgan & Mikhail's Clinical Anesthesiology, 7e - agent selection in neuraxial/valvular anesthesia
• APSF perioperative hypotension guidance

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Post-Operative Nausea & Vomiting (PONV): Comprehensive Notes

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1. Definition

• Incidence: 20-30% in general surgical patients; up to 70-80% in high-risk populations
• One of the most common and distressing post-operative complications
• Leads to: dehydration, wound dehiscence, aspiration, delayed discharge, unplanned hospital admission

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2. Pathophysiology - The Vomiting Reflex

"The CTZ contains opioid, serotonin (5HT3), histamine, dopamine (D2), and muscarinic acetylcholine receptors. The CTZ, vagal nerve, and vestibular organs all send neural projections to the vomiting center in the medulla." - Barash, Cullen & Stoelting's Clinical Anesthesia, 9e

• Volatile anesthetic agents (most important intraoperative cause)
• Opioids (act directly on CTZ and increase vestibular sensitivity)
• Type/duration/site of surgery (gynecological, laparoscopic, ENT, strabismus)
• Patient-specific factors

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3. Risk Stratification - Apfel Score (Adults)

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4. Non-Pharmacological Risk Reduction (Baseline Mitigation)

• Use propofol TIVA instead of volatile anesthetics (reduces PONV by ~25%)
• Prefer regional/neuraxial anesthesia over general anesthesia
• Minimize intraoperative and postoperative opioids (use NSAIDs, acetaminophen, regional blocks)
• Adequate IV hydration intraoperatively
• Avoid nitrous oxide
• Use dexmedetomidine as opioid-sparing adjunct
• Minimize neostigmine (anticholinesterase use) - stimulates muscarinic receptors in GI tract
• Acupressure at P6 (Neiguan) point has modest evidence

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5. Treatment Guidelines - Stepwise Approach

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Step 1: Assess Risk (Apfel Score)

Step 2: Risk Mitigation (Non-pharmacological)

Step 3: Prophylaxis Based on Risk Tier

Guideline: "Patients with 1-2 risk factors should receive 2 agents; patients with >2 risk factors should receive 3-4 agents." - APSF/ASER 2025

Step 4: Rescue Treatment (if prophylaxis fails or none given)

• Use an antiemetic from a different pharmacological class than what was used for prophylaxis
• Do NOT re-dose the same class within 6 hours (no additional benefit vs. placebo)
• Exception: if >6 hours have passed, a 5-HT3 antagonist or butyrophenone may be re-dosed if no alternatives available

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6. Pharmacological Drugs - Mechanism, Dose, Side Effects

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CLASS 1: 5-HT3 RECEPTOR ANTAGONISTS (Serotonin Antagonists)

A. Ondansetron (Zofran) - First-Line

• Selectively blocks 5-HT3 (serotonin type 3) receptors in the CTZ (area postrema) and on vagal afferents in the GI tract
• Prevents serotonin (released from enterochromaffin cells of GI mucosa after surgical stress) from triggering the vomiting reflex via vagal and CTZ pathways
• Does NOT block dopamine or muscarinic receptors

• Headache (most common, ~9%)
• QTc prolongation (dose-dependent; ECG monitoring if high-risk)
• Constipation
• Dizziness, flushing
• Rare: anaphylaxis
• Serotonin syndrome risk if combined with other serotonergic drugs (rare)

• Most commonly used antiemetic globally for PONV
• Palonosetron (0.075 mg IV) is a newer 2nd-generation agent with longer half-life (~40h vs 3-4h for ondansetron)
• Granisetron 1 mg IV and tropisetron 5 mg IV are alternatives

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CLASS 2: CORTICOSTEROIDS

B. Dexamethasone

• Exact antiemetic mechanism is not fully established
• Proposed: reduces prostaglandin synthesis and release of serotonin from the gut; inhibits neuronal activation in the nucleus tractus solitarius; possible anti-inflammatory effect on the vomiting center
• Also provides adjunct analgesia (opioid-sparing) and mood-elevating effect

• Hyperglycemia (especially in diabetics; monitor blood glucose)
• Perineal burning/itching with rapid IV injection (use slow infusion)
• Risk of wound infection with repeated high doses (single-dose prophylaxis considered safe)
• Adrenal suppression (single dose - minimal risk)
• Insomnia (when given early)
• Immunosuppression concerns with repeated dosing

• Highly cost-effective; widely available
• Timing at induction is important (effect onset is delayed ~60 min)
• Combination with ondansetron is synergistic and superior to either alone (evidence A1)
• Fourth Consensus Guidelines, ASER 2025

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CLASS 3: DOPAMINE (D2) ANTAGONISTS / BUTYROPHENONES

C. Droperidol (Inapsine)

• D2 receptor antagonist in the CTZ (area postrema)
• Blocks dopaminergic transmission at the CTZ, preventing dopamine-mediated emetic signaling
• Also has mild alpha-1 adrenergic blocking activity

• QTc prolongation - FDA issued Black Box Warning in 2001 (risk of sudden cardiac death at doses >25 mg, NOT at antiemetic doses of 0.625 mg)
• Sedation
• Extrapyramidal symptoms (EPS): akathisia, dystonia (rare at antiemetic doses)
• Dysphoria
• Hypotension

• Multiple studies confirm antiemetic doses (0.625 mg) are safe and cause only transient QTc change comparable to ondansetron
• Comparable efficacy to ondansetron 4-8 mg at rescue doses of 1-1.25 mg
• Available and inexpensive

D. Haloperidol (Haldol)

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CLASS 4: NEUROKININ-1 (NK-1) RECEPTOR ANTAGONISTS

E. Aprepitant (Emend) / Fosaprepitant

• Selectively blocks Neurokinin-1 (NK-1) receptors in the brain (cerebral cortex and brainstem)
• Substance P (released during surgery/stress) acts on NK-1 receptors to trigger nausea and vomiting
• Blocking NK-1 receptors interrupts this pathway at a different site from 5-HT3 or D2 receptors - hence excellent in combination therapy and for refractory PONV
• Half-life: ~40 hours (much longer than 5-HT3 agents)

• Fatigue/asthenia
• Hiccups
• Constipation
• Drug interactions - aprepitant is a moderate CYP3A4 inhibitor; reduces efficacy of warfarin, oral contraceptives; levels altered by CYP3A4 inducers/inhibitors
• Headache

• Aprepitant 40 mg + dexamethasone is superior to ondansetron + dexamethasone for preventing vomiting especially in high-risk patients (neurosurgery)
• Amisulpride 5 mg IV (Barhemsys) - newest agent approved 2020; also a D2/D3 antagonist with NK-1 activity, given at induction; minimal QT effect

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CLASS 5: ANTICHOLINERGICS (MUSCARINIC ANTAGONISTS)

F. Transdermal Scopolamine (Hyoscine Patch)

• Muscarinic (M1) receptor antagonist at the vestibular nuclei and vomiting center
• Blocks cholinergic input from the vestibular apparatus to the vomiting center
• Particularly effective for motion-related and vestibular-mediated PONV
• Acts on M1 receptors in the CTZ and brainstem

• Dry mouth (very common)
• Blurred vision, mydriasis (do NOT use in narrow-angle glaucoma)
• Sedation, confusion, dizziness
• Urinary retention
• Tachycardia
• Skin irritation at patch site
• Risk of anticholinergic syndrome in elderly

• Primarily for high-risk patients; excellent as an add-on agent (different MOA from 5-HT3/NK-1)
• Remove before MRI
• Wash hands after application to avoid inadvertent eye contact

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CLASS 6: PHENOTHIAZINES / D2 ANTAGONISTS

G. Promethazine (Phenergan)

• Blocks D2 receptors in the CTZ
• Also blocks H1 histamine receptors and muscarinic receptors (anticholinergic effect)
• This dual D2/H1 blockade makes it effective for opioid-induced PONV and vestibular PONV

• Sedation (significant)
• Extrapyramidal symptoms (EPS) - akathisia, dystonia, tardive dyskinesia with prolonged use
• Anticholinergic effects (dry mouth, blurred vision, urinary retention)
• Tissue necrosis with inadvertent intra-arterial injection (IV only, never intra-arterial)
• QTc prolongation
• Respiratory depression (use caution with opioids)

• Lower dose (6.25 mg IV) is as effective as higher doses with fewer side effects per guidelines
• Useful as rescue agent when 5-HT3 antagonists fail

H. Prochlorperazine (Compazine)

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CLASS 7: PROKINETIC / D2 ANTAGONIST

I. Metoclopramide (Maxolon, Reglan)

• D2 receptor antagonist in the CTZ - antiemetic effect
• Also acts peripherally: enhances gastric emptying by increasing lower esophageal sphincter tone and accelerating gastric motility (prokinetic)
• Weak 5-HT3 antagonism at higher doses
• Weak 5-HT4 agonist - accelerates GI motility

• Extrapyramidal symptoms (EPS) - akathisia (restlessness), acute dystonia, tardive dyskinesia (with prolonged use)
• Sedation
• QTc prolongation
• FDA Black Box Warning: risk of tardive dyskinesia with prolonged use
• Diarrhea
• Headache

• As monotherapy, 10 mg metoclopramide has modest efficacy (evidence A1)
• Significantly inferior to ondansetron and droperidol as rescue therapy
• Not recommended for PONV prophylaxis as a standalone agent per 2025 guidelines
• Higher doses (25-50 mg) improve efficacy but increase EPS risk
• Avoid in patients with Parkinson's disease

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CLASS 8: ANTIHISTAMINES

J. Dimenhydrinate (Dramamine) / Diphenhydramine

• H1 histamine receptor antagonist in the vestibular nuclei and vomiting center
• Also has anticholinergic (muscarinic) activity
• Particularly effective for vestibular-mediated and motion sickness-associated PONV

• Dimenhydrinate: 25-50 mg IV or 0.5 mg/kg in children
• Diphenhydramine: 25-50 mg IV

• Sedation (prominent)
• Dry mouth (anticholinergic)
• Urinary retention
• Blurred vision
• Confusion (especially in elderly)

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CLASS 9: MISCELLANEOUS / ADJUNCTS

K. Dexmedetomidine (alpha-2 agonist)

L. Olanzapine (Zyprexa) - Atypical Antipsychotic

M. Propofol (sub-anesthetic dose)

N. Ephedrine

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7. Drug Combination Strategies (ASER 2025 Guidelines)

Triple therapy (ondansetron + dexamethasone + droperidol 0.625 mg) vs. placebo significantly reduces PONV 0-6 hours postoperatively.

Aprepitant 40 mg as 4th agent (added to ondansetron + dexamethasone + TIVA) further reduces PONV in highest-risk patients.

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8. Rescue Treatment Algorithm (When Prophylaxis Fails)

PONV occurs in PACU
       ↓
Did patient receive prophylaxis?
  ├─ NO → Give 5-HT3 antagonist (ondansetron 4 mg IV) as first-line
  └─ YES → Give drug from a DIFFERENT class
           (If got ondansetron → give droperidol or dexamethasone or promethazine)
       ↓
< 6 hours since prophylaxis dose?
  └─ YES → DO NOT re-dose same class (ineffective, same as placebo)
  └─ NO (>6h) → May re-dose 5-HT3 antagonist or butyrophenone if no alternatives
       ↓
Still refractory?
  → Propofol 20-40 mg IV (in monitored setting)
  → Olanzapine 10 mg PO (if available)
  → Consider NK-1 antagonist (aprepitant/fosaprepitant)

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9. Quick Reference - All Drugs Summary Table

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10. Special Populations

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• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e - pathophysiology, CTZ, opioid-induced PONV
• Barash Clinical Anesthesia, 9e (Pediatric PONV section)
• Fourth Consensus Guidelines for the Management of PONV, ASER 2025 - drug doses, combination therapy, rescue treatment
• APSF PONV Guidelines Podcast - algorithm summary
• SAMBA Consensus Guidelines (archived, ASHP)

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Post-Operative Delirium & Emergence Agitation: Comprehensive Notes

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PART 1: POST-OPERATIVE DELIRIUM (POD)

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1. Definition

• Reduced awareness and attention
• Disorganized thinking
• Fluctuating course (often worse at night)
• Onset: hours to 5 days after surgery (most often starts in the PACU or POD 1-3)

• Incidence: 4-53% (varies widely by patient population and surgery type)
• Most common in elderly hip fracture patients; also common after cardiac, thoracic, and major abdominal surgery
• Associated with: longer hospital stay, increased mortality, functional decline, institutionalization, accelerated cognitive decline

"POD is defined as an acute and fluctuating alteration of mental state of reduced awareness and disturbance of attention. POD often starts in the recovery room and can occur up to 5 days after surgery." - Miller's Anesthesia, 10e

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2. Subtypes of Delirium

"The hypoactive subtype may easily go unnoticed, be therefore untreated, and potentially linked to a worse outcome." - Miller's Anesthesia, 10e

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3. Pathophysiology

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4. Risk Factors

Predisposing (Patient) Factors:

• Age >65 years (most important)
• Pre-existing cognitive impairment (dementia, MCI)
• Severe illness / high comorbidity burden (ASA 3-4)
• Sensory impairment (hearing loss, visual impairment)
• History of prior delirium
• Frailty, malnutrition
• Alcohol use disorder (especially withdrawal risk)
• Baseline functional impairment
• Presence of infection / fever

Precipitating (Perioperative) Factors:

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5. Diagnosis & Screening Tools

Gold Standard: Confusion Assessment Method (CAM)

1. Acute onset and fluctuating course
2. Inattention (difficulty focusing)
3. Disorganized thinking
4. Altered level of consciousness

Other Tools:

"The Confusion Assessment Method is the gold standard for delirium diagnosis. Other instruments exist that are easier to administer like the 3-Minute Diagnostic Confusion Assessment Method (3D-CAM)." - Barash Clinical Anesthesia, 9e

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6. Prevention Strategies

A. Non-Pharmacological (MOST EFFECTIVE - Evidence Grade A)

B. Pharmacological Prevention

"Dexmedetomidine sedation decreases delirium risk in mechanically ventilated ICU patients and cardiac surgery patients." - Barash Clinical Anesthesia, 9e

• Benzodiazepines (except for EtOH/benzo withdrawal)
• Anticholinergics (atropine, scopolamine, diphenhydramine, promethazine)
• Meperidine - clear delirium risk factor; avoid entirely
• Ketamine (mixed evidence; can cause psychoactive effects)

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7. Treatment of Established POD

Step 1: Immediate Assessment - Identify Reversible Causes (THINK DELIRIUM mnemonic)

Step 2: Non-Pharmacological Management (FIRST-LINE always)

Step 3: Pharmacological Treatment

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Pharmacological Drugs for POD Treatment

A. Haloperidol (Haldol) - Traditional First-Line

• Potent D2 (dopamine receptor 2) antagonist in the mesolimbic and mesocortical pathways
• Reduces excess dopaminergic activity thought to underlie hallucinations, agitation, and disorganized thinking
• Increases central acetylcholine levels indirectly
• Has anti-hallucinatory, anti-delusional, and anti-agitation effects

• Extrapyramidal symptoms (EPS): Akathisia, dystonia, Parkinsonism (especially in elderly)
• QTc prolongation - risk of Torsades de Pointes; monitor ECG
• Tardive dyskinesia (prolonged use)
• Hypotension (IV administration)
• Neuroleptic Malignant Syndrome (NMS) - rare but life-threatening
• Do NOT use in Parkinson's disease or Lewy Body Dementia (severe worsening of rigidity)
• Sedation
• Lowered seizure threshold

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B. Quetiapine (Seroquel) - Atypical Antipsychotic

• D2 and D1 antagonist (weaker D2 than haloperidol - fewer EPS)
• 5-HT2A, 5-HT2C antagonist - contributes to sedation and anxiolysis
• H1 antihistamine effect - promotes sleep
• Alpha-1 adrenergic blockade
• Broad receptor binding makes it effective for mixed and hypoactive delirium

• Sedation (beneficial in agitated patients)
• Orthostatic hypotension
• Mild QTc prolongation
• Hyperglycemia (chronic use)
• EPS rare at low doses
• Avoid in Lewy Body Dementia (caution)

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C. Risperidone (Risperdal) - Atypical Antipsychotic

• D2 + 5-HT2A receptor antagonist
• Less sedating than quetiapine
• Alpha-2 adrenergic blocking effects

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D. Dexmedetomidine (Precedex) - PREFERRED in ICU/Post-Op Agitated Delirium

• Highly selective Alpha-2 adrenergic receptor agonist (alpha-2:alpha-1 selectivity ratio = 1600:1)
• Acts on locus coeruleus (LC) in the brainstem - reduces norepinephrine release and sympathetic outflow
• Produces arousable sedation mimicking natural sleep (NREM Stage 2) without respiratory depression
• Opioid-sparing and analgesic properties via alpha-2 receptors in spinal cord
• Anti-inflammatory effects: reduces microglial activation, decreases pro-inflammatory cytokines
• Reduces requirement for benzodiazepines (which worsen delirium)
• Dexmedetomidine given postoperatively is more effective than intraoperatively for POD prevention (neuroinflammatory processes continue postoperatively)

• Bradycardia (dose-dependent; most common)
• Hypotension (especially with loading dose)
• Dry mouth
• Rebound hypertension with abrupt discontinuation
• Nausea

---

E. Lorazepam / Benzodiazepines - RESTRICTED USE ONLY

• ONLY indicated for delirium due to alcohol or benzodiazepine withdrawal (CIWA protocol)
• NOT for general delirium management - worsens and prolongs delirium
• Acceptable for procedural sedation if brief

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F. Olanzapine (Zyprexa) - Adjunct

---

G. Melatonin / Ramelteon - Circadian Adjunct

• Melatonin: 0.5-3 mg PO at bedtime
• Ramelteon: 8 mg PO at bedtime (prescription)

---

8. Drugs to AVOID in Delirium

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PART 2: EMERGENCE AGITATION (EA) / EMERGENCE DELIRIUM

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9. Definition

• Distinct from POD: EA occurs immediately on emergence (within 0-30 minutes), while POD occurs hours to days later
• Duration: usually 5-15 minutes, resolves as full consciousness returns
• Incidence: up to 21% in adults; 10-67% in children (especially with sevoflurane)

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10. Pathophysiology of Emergence Agitation

• Confusion, fear, and disorientation without full cortical awareness
• Pain or discomfort without the ability to communicate effectively
• Possibly: residual anesthetic in limbic circuits causing dysphoria/excitation before cortex clears

• Rapid wash-out (fast wake-up) before limbic/cortical reintegration is complete
• Possible GABA-A and glycine receptor dysregulation during offset

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11. Risk Factors for Emergence Agitation

"Risk factors for ED may include volatile anesthetic exposure (particularly sevoflurane), certain types of surgery including ophthalmology and otorhinolaryngology procedures, patient age around 3 to 7 years old, patient anxiety." - Barash Clinical Anesthesia, 9e

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12. Assessment Tools for EA

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13. Management - Stepwise Approach

Step 1: SAFETY FIRST

• Protect patient from self-injury (fall from bed, dislodging lines, wound disruption)
• Protect staff
• Protect airway - ensure adequate oxygenation and ventilation
• Do NOT physically restrain (worsens agitation)
• Call for help; two-person management

Step 2: Identify and Treat Reversible Causes (FAST check)

• Pain - inadequate analgesia is the most common cause; treat with IV opioid bolus
• Hypoxia/hypercapnia - check SpO2, ETCO2; give oxygen
• Full bladder - check and catheterize if needed
• Residual neuromuscular blockade - check train-of-four; reverse if needed
• Hypothermia - warm the patient
• Hypoglycemia - check BGL
• Anticholinergic syndrome - from atropine, scopolamine
• ETT discomfort - consider extubation if ready

Step 3: Calm the Environment

• Reduce noise, dim lights
• Speak calmly, reorient the patient: "You're safe, the surgery is over, you're in the recovery room"
• Parent presence for children
• Remove restraints if possible

Step 4: Pharmacological Treatment (if steps 1-3 insufficient)

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14. Pharmacological Treatment of Emergence Agitation

A. Adequate Analgesia First

• Mechanism: Mu-opioid receptor agonist - potent analgesia; reduces pain-driven agitation
• Dose: 0.5-1 mcg/kg IV bolus; titrate to effect
• Side Effects: Respiratory depression, nausea, chest wall rigidity (high doses)
• Note: Fentanyl 2.5 mcg/kg intraoperatively significantly reduces EA after adenotonsillectomy

• Longer-acting alternatives for sustained pain control; no superiority over fentanyl for delirium

---

B. Dexmedetomidine - FIRST-LINE pharmacological treatment (EA and POD)

• 0.5-1 mcg/kg IV over 10 minutes (slow infusion)
• Can repeat carefully if needed

---

C. Propofol - Rapid Rescue

• 0.5 mg/kg IV bolus (adults)
• Can use 0.5-1 mg/kg; titrate carefully

---

D. Ketamine - Low-Dose Adjunct

---

E. Midazolam - Cautious Use in Adults; Limited Pediatric Role

• Benzodiazepines as premedication do NOT reduce EA in pediatric patients
• May help in adult EA when pain is excluded and sedation is required; however, avoid in elderly
• Indicated for alcohol/benzo withdrawal-associated agitation

---

F. Physostigmine - Specific Use: Anticholinergic Syndrome

---

G. Clonidine - Alpha-2 Agonist (older alternative to dexmedetomidine)

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15. Prevention of Emergence Agitation - Drug Summary

---

16. Key Comparison: POD vs EA

---

17. Quick Drug Reference

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• Miller's Anesthesia, 10e - POD definition, risk factors, prophylaxis/management
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e - CAM, diagnosis, EA in pediatrics, dexmedetomidine
• ESAIC 2024 Guideline on POD (PMID: 37599617) - Evidence-based consensus guideline; multicomponent prevention; neuroinflammation pathogenesis
• Liu et al., Haloperidol meta-analysis BMC Anesthesiology 2024 - perioperative haloperidol reduces POD in elderly
• Deblois et al., J Patient Saf 2025 (PMID: 39907462) - systematic review of POD prevention and treatment in elderly

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Oxygen Therapy in PACU & Anaesthesia: Comprehensive Notes

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1. Why Oxygen Therapy Matters in the Perioperative Period

"The pulse oximeter is a standard monitor in the PACU for the detection of hypoxemia, but it does not reflect the adequacy of ventilation... it does not reliably detect hypoventilation in patients breathing oxygen." - Miller's Anesthesia, 10e

1. Maintain adequate tissue oxygenation
2. Prevent hypoxic organ injury (brain, heart, kidneys)
3. Treat specific disease states where oxygen is therapeutic
4. Avoid oxygen toxicity from unnecessary hyperoxia

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2. Physiology of Oxygen - Key Concepts

DO2 = CO x (Hb x 1.34 x SaO2 + PaO2 x 0.0031)

1. Cardiac output (CO) - perfusion
2. Haemoglobin - oxygen carrier
3. Arterial oxygen saturation (SaO2) - loading

• PaO2: 80-100 mmHg (room air)
• SaO2 target: 94-98% (general population); 88-92% (COPD / risk of hypercapnia)
• PaO2/FiO2 (P/F ratio): normal >400; ARDS mild 200-300; moderate 100-200; severe <100

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3. Causes of Post-Operative Hypoxaemia

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4. Target Oxygen Saturations

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5. Oxygen Delivery Devices

LOW-FLOW SYSTEMS

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A. Nasal Cannula (Prongs) - Standard Low Flow

"Each liter per minute of oxygen flow through nasal cannula increases the FiO2 by 0.04, with 6 L/min delivering an FiO2 of approximately 0.44." - Miller's Anesthesia, 10e

• Max flow: 6 L/min (beyond this, no further FiO2 increase; causes nasal drying and discomfort)
• Advantages: Comfortable; allows eating, talking; well-tolerated long-term
• Disadvantages: FiO2 unreliable (varies with mouth breathing, RR); cannot deliver high FiO2
• PACU use: Standard initial device for mild-moderate post-operative hypoxaemia; preferred in elderly (less delirium risk than face mask); preferred after head/neck surgery where masks cannot be used

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B. Simple Face Mask

• Minimum flow: 5 L/min - to flush CO2 from mask and prevent rebreathing
• Advantages: Higher FiO2 than nasal cannula; quick to apply; useful for moderate hypoxaemia
• Disadvantages: Claustrophobic; must be removed for eating/talking; FiO2 variable; not suitable after face/ENT surgery
• PACU use: Moderate hypoxaemia; short-term post-anaesthesia O2 supplementation

"Simple face masks are generally used in the postoperative setting in patients who are breathing spontaneously yet require a higher oxygen flow rate and/or concentration." - Miller's Anesthesia, 10e

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C. Partial Rebreather Mask (with reservoir bag, no one-way valve)

• Flow: 6-10 L/min
• FiO2: 0.60-0.80
• Mechanism: Reservoir bag fills with pure O2; first 1/3 of exhaled gas (dead space gas, O2-rich) re-enters bag; remaining 2/3 exits via side holes
• Keep reservoir bag inflated at all times; increase flow if bag deflates on inspiration
• Disadvantages: CO2 rebreathing possible if flow too low; FiO2 still variable

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D. Non-Rebreather Mask (NRM) - Highest FiO2 via non-invasive route

• Flow: 10-15 L/min
• FiO2: 0.90-1.00
• Mechanism: One-way valve between reservoir bag and mask prevents exhaled gas re-entering bag; side exhalation valves allow exhaled gas to escape but prevent room air entry
• Advantages: Delivers highest possible FiO2 without intubation; near-100% O2 achievable
• Disadvantages: Uncomfortable; cannot talk or eat; masks must be tight-fitting; not tolerated long-term; CO2 accumulates if valve fails
• PACU use: Severe acute hypoxaemia (SpO2 <85%), PE, carbon monoxide poisoning, anaphylaxis, trauma

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HIGH-FLOW SYSTEMS

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E. Venturi Mask (Air-Entrainment Mask) - Fixed, Precise FiO2

• Uses the Bernoulli principle (Venturi effect): O2 passes through a narrow jet, entraining room air through side ports in a fixed ratio
• Different coloured inserts/adaptors entrain different air:O2 ratios, giving precise FiO2 regardless of breathing pattern

• Advantages: Most accurate and predictable FiO2; ideal for COPD and patients needing controlled O2 titration; increasing flow through Venturi does NOT increase FiO2 (only changes total flow - important to note)
• Disadvantages: Cumbersome; must be removed for eating; cannot deliver >60% FiO2
• PACU use: COPD patients; any patient where precise FiO2 control is needed

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F. High-Flow Nasal Cannula (HFNC) - Optiflow, AirVo

• Delivers heated, humidified O2 at 40-60 L/min with adjustable FiO2 from 0.21-1.0
• Key therapeutic effects:
  1. Precise FiO2 delivery (flow exceeds patient's inspiratory demand at all times)
  2. Small CPAP effect (~1-2 cmH2O per 10 L/min of flow) - recruits alveoli and reduces work of breathing
  3. Flushing of nasopharyngeal dead space - reduces CO2 rebreathing, improving ventilation
  4. Mucociliary clearance improved by warm humidified gas
  5. Reduced metabolic work of breathing (gas does not need to be warmed/humidified)

• When increasing support: Increase flow first, then FiO2
• When weaning: Decrease FiO2 first (to 0.40), then reduce flow

"HFNC devices can comfortably deliver oxygen at 40-60 L/min with 40%-100% O2 at 37°C and 99.9% relative humidity... HFNC is an appropriate alternative in patients with hypoxemic respiratory failure without hypercapnia." - Miller's Anesthesia, 10e

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G. CPAP (Continuous Positive Airway Pressure)

• Applies constant positive pressure throughout respiratory cycle (both inspiration AND expiration)
• Prevents alveolar collapse, recruits atelectatic lung, increases FRC
• Reduces work of breathing; improves V/Q matching
• Does NOT provide respiratory support (no pressure support on inspiration)

• CPAP: 5-10 cmH2O
• FiO2: titrated to SpO2 target

• Obstructive sleep apnoea (OSA) - patients should resume their home CPAP
• Post-obese surgery (bariatric)
• Atelectasis-driven hypoxaemia
• Pre-extubation recruitment

"A large percentage of patients who are obese and undergoing Roux-en-Y gastric bypass surgery have OSA and stand to benefit significantly from postoperative CPAP therapy." - Miller's Anesthesia, 10e

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H. BiPAP / NIPPV (Bi-level / Non-Invasive Positive Pressure Ventilation)

• Delivers two levels of positive pressure:
  • IPAP (Inspiratory Positive Airway Pressure): assists inspiration, increases tidal volume, reduces PaCO2
  • EPAP (Expiratory Positive Airway Pressure): same as CPAP; prevents alveolar collapse, recruits lung

• Intact mental status
• Able to cooperate
• Moderate hypercarbia (PaCO2 45-92 mmHg) + mild acidosis (pH 7.10-7.35)
• Physiologic improvement within 2 hours

"Greater success with NIPPV is associated with patients who are able to cooperate and tolerate PPV, those with an intact mental status, moderate hypercarbia and acidemia (PaCO2 45-92, pH 7.1-7.35)." - Miller's Anesthesia, 10e

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I. Bag-Valve-Mask (BVM) / Self-Inflating Bag

• Without O2 reservoir: 0.40
• With O2 reservoir at 15 L/min: 0.90-1.00
• With 2-person technique and good seal: most effective

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Summary Table - Oxygen Devices

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6. Oxygen Therapy by Disease - PACU and Anaesthesia Context

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1. COPD (Chronic Obstructive Pulmonary Disease)

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2. Asthma (Acute Exacerbation)

• Oxygen combined with bronchodilators (nebulised salbutamol ideally driven by AIR not O2 in COPD; in pure asthma, O2 as nebuliser carrier is acceptable)
• Severe attack: high-flow O2 + IV magnesium + IV hydrocortisone
• Near-fatal: consider HFNC, NIV, or intubation

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3. Pneumonia

• Mild: Nasal cannula 2-4 L/min
• Moderate: Simple face mask 5-8 L/min
• Severe (CAP/HAP/VAP with hypoxaemia): HFNC first-line (reduces intubation rate in non-COPD pneumonia vs. standard O2 - FLORALI trial)
• Failure of HFNC → NIV → intubation + mechanical ventilation

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4. ARDS (Acute Respiratory Distress Syndrome)

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5. Cardiogenic Pulmonary Oedema (CPO)

• Mild: Nasal cannula or simple face mask
• Moderate-severe: CPAP 5-10 cmH2O - reduces preload and afterload, recruits alveoli, improves oxygenation dramatically
• BiPAP if hypercapnia present

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6. Obstructive Sleep Apnoea (OSA)

• Failure to apply CPAP in PACU increases risk of post-operative apnoeas, desaturations, re-intubation
• If patient's home CPAP is unavailable: use supplemental O2 with close monitoring
• PACU protocols: High-risk OSA patients: continuous pulse oximetry x 24h; lateral or semi-upright positioning; minimise opioids

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7. Post-Thoracic Surgery (Pneumonectomy / Lobectomy)

• Reduced respiratory reserve; risk of bronchopleural fistula; avoid high airway pressures
• Nasal cannula or simple face mask preferred initially
• Avoid high PEEP if bronchopleural fistula risk
• HFNC or NIV for respiratory failure (monitoring for anastomotic disruption risk)

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8. Carbon Monoxide (CO) Poisoning

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9. Cluster Headache

• Mechanism: Vasoconstriction of intracranial vessels; counteracts trigeminal-autonomic pathway activation
• Aborts attacks in 60-70% of patients within 15-20 minutes
• Avoid nasal cannula (insufficient FiO2)

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10. Sickle Cell Disease (Vaso-occlusive Crisis)

• Hypoxia promotes HbS polymerisation → sickling → vaso-occlusion
• Nasal cannula or simple face mask during painful crises
• No benefit to hyperoxia once SpO2 normalised; avoid excessive O2 beyond target
• Intraoperatively: maintain high FiO2 (0.5-1.0); avoid hypoxia, hypothermia, acidosis, dehydration

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11. Pulmonary Embolism (PE)

• Mechanism: Dead space ventilation + RV strain + atelectasis → V/Q mismatch
• Supplemental O2: nasal cannula or face mask initially
• Massive PE with haemodynamic compromise: 100% O2 via NRM + urgent anticoagulation/thrombolysis
• Avoid positive pressure ventilation where possible (reduces RV preload)

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12. Pneumothorax

• High-flow O2 (100% NRM) accelerates nitrogen reabsorption from pneumothorax space (by creating a nitrogen gradient across the pleural membrane) - can increase reabsorption rate 4-fold
• Caution in COPD
• Definitive treatment: needle decompression (tension) or chest drain

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13. Post-Laryngospasm Pulmonary Oedema (Negative Pressure PE)

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14. Anaesthetic Induction - Preoxygenation

• Head-up 20-30° positioning (increases FRC; especially useful in obese patients)
• HFNC 60 L/min during apnoea (apnoeic oxygenation) extends safe apnoea time - O2 diffuses into alveoli via mass flow from pharynx
• NIPPV in morbidly obese, high-risk patients

"Current evidence does not support the use of HFNC for preoxygenation before intubation. At this time, HFNC for preoxygenation should only be considered for those cases of mild hypoxemia, with NIV used for more severe cases." - Murray & Nadel's Respiratory Medicine

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7. Hazards of Oxygen Therapy

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8. PACU-Specific Oxygen Protocol (Practical Summary)

Patient arrives in PACU from OR
         ↓
Apply O2 (standard: nasal cannula 2-4 L/min or simple face mask)
         ↓
Connect pulse oximeter + continuous monitoring
         ↓
Check SpO2 target (94-98% general / 88-92% COPD)
         ↓
SpO2 within target?
  YES → Continue; titrate down to lowest effective flow; consider d/c O2
  NO  → Escalate
         ↓
SpO2 88-93% (general patient)
  → Increase nasal cannula to 4-6 L/min
  → Assess cause: pain/splinting? opioid excess? NMB residual? atelectasis?
         ↓
SpO2 <88% or deteriorating
  → Simple face mask 5-8 L/min OR non-rebreather mask
  → Assess airway; call for help
  → Consider HFNC, CPAP, or BiPAP
         ↓
Persistent hypoxaemia / rising PaCO2 / haemodynamic compromise
  → Senior clinician; ABG
  → Consider reintubation

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9. Key Rules to Remember

1. Venturi mask = precision - always use in COPD, never exceed FiO2 target of 28% to start
2. HFNC - warm humidified high-flow; treats hypoxaemic failure without hypercapnia; superior comfort; small CPAP effect
3. CPAP - recruits alveoli; ideal for OSA, pulmonary oedema, post-bariatric atelectasis
4. BiPAP - treats hypercapnic failure; two pressures = ventilatory assist + expiratory support
5. NRM - 100% O2; for emergencies, CO poisoning, cluster headache, severe acute hypoxaemia
6. Pulse oximetry alone is not enough in PACU: a patient on O2 can have severe hypoventilation (PaCO2 rising) with "normal" SpO2. Use capnography if available.
7. Absorption atelectasis: avoid prolonged 100% O2 unnecessarily; HFNC and PEEP help
8. Never hyperoxigenate COPD: target 88-92% strictly; serial ABGs

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• Miller's Anesthesia, 10e - PACU oxygen therapy, supplemental O2 devices, CPAP, NIPPV
• Murray & Nadel's Respiratory Medicine, 2e - HFNC perioperative use, preoxygenation evidence
• British Thoracic Society (BTS) Oxygen Guidelines - target saturations, COPD management
• TSANZ Acute Oxygen Guidelines - FiO2 tables, device selection by SpO2
• Open Anesthesia Journal - Oxygen Delivery Devices - device comparison table

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Post-Operative Shivering: Comprehensive Notes

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1. Definition

1. Thermoregulatory shivering - a thermogenic response to hypothermia (most common)
2. Non-thermoregulatory / Normothermic shivering - occurs despite a normal or near-normal core temperature (unique to the post-anaesthetic context)

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2. Why Shivering Is Clinically Important

"Oxygen consumption and CO2 production can increase 200%. Associated increases in minute ventilation and cardiac output might precipitate ventilatory failure in patients with limited reserve or myocardial ischemia." - Barash Clinical Anesthesia, 9e

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3. Normal Thermoregulation - The Baseline

• Normal core temperature: 36.5-37.5°C
• Interthreshold range (no thermoregulatory response triggered): 0.2°C
• Above threshold → Heat loss responses: sweating, peripheral vasodilation, behavioural cooling
• Below threshold → Heat gain responses: peripheral vasoconstriction, non-shivering thermogenesis (brown fat in neonates), shivering (skeletal muscle)

• Originates in the posterior hypothalamus (cold-sensing area)
• Signal descends via the brainstem reticular formation and anterior horn cells to skeletal muscles
• Results in rhythmic, synchronised muscle contractions (out-of-phase cycling of antagonist muscle groups)
• The kappa-opioid receptor system in the hypothalamus and spinal cord plays a key role in modulating the shivering response

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4. Perioperative Heat Loss - The 3-Phase Model

Phase 1: Redistribution (0-1 hour) - Largest drop

• Mechanism: Anaesthetic agents (both volatile and intravenous) cause peripheral vasodilation, opening arteriovenous shunts
• Warm blood from the body core redistributes to the cold periphery
• Core temperature drops rapidly by 1-1.5°C in the first 30 minutes
• The periphery is typically 2-4°C cooler than the core before induction
• This is largely not preventable by surface warming alone once vasodilation occurs

Phase 2: Linear Cooling (1-3 hours)

• Heat loss exceeds metabolic heat production
• Four routes of heat loss from skin surface:
  • Radiation (40%): infrared emission from skin to cooler surroundings
  • Convection (30%): heat carried away by air currents; amplified by operating room ventilation
  • Conduction (5%): direct skin-to-cold surface contact (OR table, cold infusions)
  • Evaporation (25%): via respiratory tract and open surgical wounds

Phase 3: Plateau (>3 hours)

• Core temperature stabilises as thermoregulatory vasoconstriction eventually reactivates (incomplete due to anaesthetic suppression)
• Equilibrium between heat production and heat loss

"Anesthetic-induced vasodilation redistributes blood from the core to the periphery, where heat is rapidly lost via radiation to the surrounding environment. Heat is also lost via conduction, convection, and evaporation." - Sabiston Textbook of Surgery

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5. How Anaesthesia Disrupts Thermoregulation

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6. Causes of Shivering in PACU

A. Thermoregulatory Shivering (most common)

• Direct result of intraoperative hypothermia (core temp <36°C)
• Hypothalamus triggers shivering during emergence to restore core temperature
• Accentuated by tremors from emergence from volatile anaesthesia
• "Tremors exhibit clonic and tonic components, and likely reflect decreased cortical influence on spinal cord reflexes." - Barash Clinical Anesthesia, 9e

B. Non-Thermoregulatory / Normothermic Shivering (occurs despite normal temperature)

1. Emergence tremors from volatile anaesthesia:
   • Sevoflurane, desflurane, and isoflurane cause cortical and spinal cord excitability during offset
   • Reduced cortical inhibition of spinal cord reflexes → exaggerated clonic/tonic movements resembling shivering
   • NOT a true thermoregulatory response - occurs even when core temperature is 37°C
2. Pain-triggered non-thermoregulatory tremors:
   • Acute pain (especially from poorly controlled post-op pain) activates spinal cord nociceptive pathways
   • These overlap with thermoregulatory efferent pathways → tremor-like activity
   • Postoperative pain facilitates non-thermoregulatory tremor even in normothermic patients
3. Acute opioid withdrawal tremors:
   • Use of short-acting intraoperative opioids (remifentanil, fentanyl) → rapid offset
   • Acute opioid withdrawal effect generates hyperexcitability of spinal cord and brainstem
   • Creates tremors resembling shivering; responds to opioid supplementation
4. Neuraxial-specific shivering:
   • Spinal and epidural anaesthesia block afferent cold signals from below the block
   • Hypothalamus receives false signals of warmth → does NOT trigger vasoconstriction
   • However, peripheral vasodilation causes rapid heat redistribution and true hypothermia
   • Additionally, cool intrathecal fluid directly stimulates spinal thermoreceptors → paradoxical shivering signal without cortical integration
   • Can occur even when core temperature is near-normal (due to altered temperature sensing)
5. Pyrogen-induced shivering:
   • Blood transfusion reactions, sepsis, drug reactions
   • Cytokine (IL-1, IL-6, TNF-alpha) release raises the hypothalamic set-point
   • Shivering is triggered to raise core temperature to the new (elevated) set-point
6. Sympathetic activation / stress response:
   • Surgical stress hormones increase metabolic rate; autonomic fluctuations can trigger tremors

"Shivering that occurs even in normothermic patients during the perioperative period... Another potential mechanism is pain and acute opioid withdrawal (especially with the use of short-acting narcotics)." - Sessler, PMC5931188

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7. Risk Factors for Post-Operative Shivering

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8. Assessment - Grading Shivering

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9. Prevention Strategies (Non-Pharmacological)

"The Surgical Care Improvement Project... requires maintaining patients' temperatures above 36°C. The PACU has a 15-minute period from admission to have a measured patient temperature of at least 36°C." - Barash Clinical Anesthesia, 9e

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10. Pharmacological Treatment of Post-Operative Shivering

FIRST-LINE DRUGS

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A. MEPERIDINE (Pethidine) - Most Efficacious Drug for POS

• Kappa (κ) opioid receptor agonism - the key distinguishing feature:
  • κ receptors are densely located in the hypothalamus (POAH), brainstem, and spinal cord dorsal horn
  • κ receptor activation specifically lowers the shivering threshold (reduces the core temperature at which shivering is triggered) by ~1.2°C
  • κ receptors also modulate thermoregulatory vasoconstriction threshold
  • This is why other opioids (fentanyl, morphine, alfentanil) - which are primarily μ agonists - are FAR LESS effective at stopping shivering at equianalgesic doses
• Mu (μ) opioid receptor agonism - provides additional CNS depression, reduces pain-triggered non-thermoregulatory tremors, and contributes to the anti-shivering effect
• Additional mechanism: Meperidine may also inhibit serotonin and norepinephrine reuptake (weak SNRI activity), which contributes to its anti-shivering effect via descending monoaminergic thermoregulatory pathways

• Nausea and vomiting (common; gives PONV)
• Sedation
• Respiratory depression (dose-dependent)
• QTc prolongation
• Serotonin syndrome risk - when combined with MAOIs, SSRIs, or serotonergic drugs (due to SNRI activity)
• Normeperidine toxicity (active metabolite): with repeated dosing or renal impairment - causes CNS excitation, tremors, seizures (paradoxical effect)
• Histamine release (mild)
• Tachycardia (anticholinergic-like effect; unlike other opioids)
• Drug interactions: ABSOLUTELY CONTRAINDICATED with MAOIs (risk of fatal serotonin syndrome); caution with SSRIs

• MAOIs or recent MAOI use within 14 days
• Seizure disorders (normeperidine lowers seizure threshold)
• Renal impairment (normeperidine accumulates)
• Patients on serotonergic medications

"Many medications have been recommended to suppress shivering, but meperidine is most efficacious in conjunction with rewarming... Fentanyl has also been used with patients in whom meperidine is contraindicated." - Barash Clinical Anesthesia, 9e

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B. TRAMADOL - Effective Alternative with Better Side Effect Profile

1. Weak Mu (μ) opioid receptor agonism (primary metabolite O-desmethyltramadol / M1 is 200x more potent at μ receptor):
   • Contributes to analgesia and modest antishivering effect
   • Much weaker than meperidine at kappa receptor
2. Serotonin reuptake inhibition (SERT blockade):
   • Tramadol blocks the serotonin transporter → increases synaptic serotonin in POAH and brainstem
   • Serotonin acts on 5-HT2 receptors in the hypothalamus → modulates thermoregulatory set point
   • Lowers both the vasoconstriction threshold AND the shivering threshold
   • Serotonergic activity in the POAH is thought to be a key anti-shivering pathway
3. Norepinephrine reuptake inhibition (NET blockade):
   • Increases norepinephrine in thermoregulatory circuits (hypothalamus, locus coeruleus)
   • Noradrenergic pathways have a modulatory role in shivering and vasoconstriction thresholds
   • This SNRI-like activity (also shared with meperidine) contributes significantly to anti-shivering effect
   • Clonidine and dexmedetomidine (alpha-2 agonists) work via related noradrenergic pathways - consistent with this mechanism
4. Combined effect: The dual monoamine reuptake inhibition (serotonin + norepinephrine) of tramadol is considered responsible for its anti-shivering efficacy, distinguishing it from pure μ-opioid agonists that are far less effective.

• No risk of normeperidine accumulation
• Lower risk of PONV (less emetogenic)
• No absolute contraindication with renal impairment (though caution needed)
• Lower addiction potential
• Can be given orally (not just IV)

• Nausea and vomiting (less than meperidine but present)
• Dizziness, sedation
• Seizure risk - lowers seizure threshold; caution in epilepsy
• Serotonin syndrome risk (especially with SSRIs, SNRIs, MAOIs, triptans) - due to serotonin reuptake inhibition
• Respiratory depression (less than meperidine)
• Urinary retention

• MAOIs (absolute - fatal serotonin syndrome risk)
• Severe epilepsy
• Caution with other serotonergic drugs

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11. Other Pharmacological Options

C. Clonidine - Alpha-2 Agonist

• Alpha-2 adrenergic receptor agonist at locus coeruleus and hypothalamus
• Reduces sympathetic norepinephrine release → lowers vasoconstriction and shivering thresholds
• Sedative and analgesic properties provide additional benefit
• Does NOT provide kappa opioid or serotonergic anti-shivering effects

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D. Dexmedetomidine - Alpha-2 Agonist (more selective than clonidine)

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E. Ketamine - NMDA Antagonist

• NMDA receptor blockade in the hypothalamus and spinal cord
• Also has mild sympathomimetic effects and some opioid receptor activity
• Disrupts the ascending nociceptive/thermoregulatory signals that trigger shivering

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F. Ondansetron - 5-HT3 Antagonist

• Blocks 5-HT3 serotonin receptors in the preoptic anterior hypothalamus (POAH)
• The POAH contains thermosensitive neurons regulated by serotonin via 5-HT3 receptors
• Blocking these receptors interferes with the serotonin-mediated thermoregulatory signalling that triggers shivering
• Additional action: inhibits serotonin reuptake in thermosensitive pathways

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G. Magnesium Sulphate

• NMDA receptor antagonism (similar to ketamine)
• Calcium channel blockade → reduces neuronal excitability and skeletal muscle contraction
• Reduces sympathetic nervous system activation

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H. Doxapram

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I. Nefopam - Non-Opioid Analgesic

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12. Normothermic Shivering - Key Concept

• Standard rewarming alone will NOT resolve it (patient is already normothermic)
• It is often mistakenly attributed only to hypothermia
• Requires specific pharmacological treatment regardless of temperature

Causes of Normothermic Shivering:

"Shivering occurs even in normothermic patients during the perioperative period. The aetiology of shivering is not understood sufficiently... Another potential mechanism is pain and acute opioid withdrawal (especially with the use of short-acting narcotics)." - Sessler et al., PMC5931188

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13. Stepwise Management of POS in PACU

Patient in PACU - shivering noted
         ↓
Grade shivering (Crossley & Mahajan Scale)
         ↓
Check core temperature
  ├─ <36°C → Hypothermic shivering
  │           Apply forced-air warming blanket
  │           Warm IV fluids; warm oxygen
  │           Supplemental O2 (SpO2 >95%)
  │           Pharmacological if Gr 3-4
  └─ ≥36°C → Normothermic shivering
              Exclude: pain, opioid offset, pyrexia, transfusion reaction
              Pharmacological treatment needed
         ↓
Grade 1-2 AND hypothermic:
  → Rewarming + reassurance; no drug needed
         ↓
Grade 3-4 OR normothermic shivering:
  → PHARMACOLOGICAL TREATMENT

FIRST-LINE CHOICE:
  ┌─────────────────────────────────────────┐
  │ Meperidine 25-50 mg IV (slow push)      │
  │ OR Tramadol 0.5-1 mg/kg IV (if contra-  │
  │    indicated to meperidine)              │
  └─────────────────────────────────────────┘
         ↓ No response in 10-15 min
  ┌─────────────────────────────────────────┐
  │ Repeat meperidine 25 mg OR              │
  │ Dexmedetomidine 0.5 mcg/kg IV or        │
  │ Clonidine 75-150 mcg IV                 │
  └─────────────────────────────────────────┘
         ↓
Continue O2; monitoring; reassurance
Transfer from PACU when:
  - Temperature >36°C
  - Shivering resolved or Grade 0-1

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14. Drug Comparison Summary

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15. Key Points to Remember

1. Meperidine is unique among opioids - its kappa receptor agonism is responsible for superior anti-shivering efficacy. Other opioids (fentanyl, morphine) have minimal anti-shivering action at equianalgesic doses.
2. Tramadol's SNRI mechanism (serotonin + norepinephrine reuptake inhibition) is the basis of its anti-shivering action - not its weak opioid activity. This is why it works in normothermic shivering.
3. Normothermic shivering requires pharmacological treatment - rewarming alone is insufficient as the patient is already at normal temperature.
4. Prevention > Treatment - pre-warming with forced-air blankets for 30-60 minutes before surgery is the single most effective intervention and should be routine for all high-risk patients.
5. Supplemental O2 is mandatory during shivering in PACU - O2 consumption rises 200-400%; failure to supplement O2 during shivering can cause life-threatening hypoxaemia.
6. Neuraxial shivering (spinal > epidural) has a unique mechanism - blocked afferent signals + core-to-peripheral redistribution + cold intrathecal drug effects. More refractory to warming alone.
7. Serotonin syndrome risk - both meperidine and tramadol have serotonergic activity. Never use with MAOIs. Use caution with SSRIs/SNRIs.

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• Barash, Cullen & Stoelting's Clinical Anesthesia, 9e - PACU shivering, meperidine first-line, thermoregulation during emergence
• Morgan & Mikhail's Clinical Anesthesiology, 7e - perioperative hypothermia, normothermia importance
• Sabiston Textbook of Surgery - heat loss mechanisms, radiation/conduction/convection
• Sessler et al., "Postanaesthetic shivering - from pathophysiology to prevention," PMC5931188 - meperidine κ mechanism, tramadol SNRI mechanism, normothermic shivering
• Pharmacological Approach to Prevention of POS, AJA - systematic review; tramadol vs meperidine vs dexmedetomidine