Noradrenaline (Norepinephrine) Pharmacology

Quick Answer

Noradrenaline (norepinephrine) is an endogenous catecholamine and the primary neurotransmitter of the sympathetic nervous system, acting predominantly at alpha-1 adrenoceptors (potent vasoconstriction) with additional alpha-2 and beta-1 activity but minimal beta-2 effects. Structurally, it differs from adrenaline by the absence of the N-methyl group on the terminal amine. As the first-line vasopressor for septic shock (Surviving Sepsis Campaign 2021), noradrenaline increases systemic vascular resistance (SVR) and mean arterial pressure (MAP) while maintaining cardiac output through beta-1 inotropy. The characteristic haemodynamic response includes reflex bradycardia due to baroreceptor activation. Pharmacokinetically, noradrenaline has an extremely short half-life (1-2 minutes) due to rapid metabolism by COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase), necessitating continuous IV infusion via central venous access. Standard dosing begins at 0.05-0.1 mcg/kg/min, titrated to target MAP (typically 65-70 mmHg). Extravasation causes severe tissue necrosis requiring immediate treatment with phentolamine infiltration. Key drug interactions include potentiation by MAOIs and TCAs. In cardiogenic shock, noradrenaline is used as an adjunct to inotropes when hypotension persists despite adequate filling. [1-8]

Chemical Structure and Classification

Catecholamine Structure

Noradrenaline (systematic name: 4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol) belongs to the catecholamine family, characterised by a catechol nucleus (a benzene ring with hydroxyl groups at the 3 and 4 positions) and an ethylamine side chain. The molecular formula is C8H11NO3 with a molecular weight of 169.2 Da. [1,2]

Essential Structural Features:

Structural Comparison with Adrenaline

The critical structural difference between noradrenaline and adrenaline is the N-methyl group:

The N-methyl substitution in adrenaline confers significantly greater beta-2 receptor affinity. This structure-activity relationship is fundamental: increasing the size of the N-alkyl substituent shifts receptor selectivity from alpha toward beta (noradrenaline → adrenaline → isoprenaline). [3,9]

Physicochemical Properties

Important: Noradrenaline solutions are acidic (pH 3-4.5) to enhance stability. They are incompatible with alkaline solutions including sodium bicarbonate, which causes oxidation and loss of activity. [10]

Mechanism of Action

Adrenoceptor Pharmacology

Noradrenaline produces its cardiovascular effects through activation of G-protein coupled adrenergic receptors. Its receptor selectivity profile is:

Alpha-1 > Alpha-2 >> Beta-1 > Beta-2

This alpha-predominant profile distinguishes noradrenaline from adrenaline and explains its characteristic haemodynamic effects.

Alpha-1 Receptor Activation (Primary Effect)

Alpha-1 adrenoceptors are the primary mediators of noradrenaline-induced vasoconstriction. Three subtypes exist (alpha-1A, alpha-1B, alpha-1D), with alpha-1A and alpha-1D predominating in vascular smooth muscle.

Signal Transduction Pathway:

1. Noradrenaline binds alpha-1 receptor (Gq-coupled GPCR)
2. Gq protein activates phospholipase C (PLC)
3. PLC hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2)
4. Products: inositol triphosphate (IP3) and diacylglycerol (DAG)
5. IP3 releases Ca2+ from sarcoplasmic reticulum
6. DAG activates protein kinase C (PKC)
7. Increased intracellular Ca2+ binds calmodulin
8. Calmodulin-Ca2+ activates myosin light chain kinase (MLCK)
9. MLCK phosphorylates myosin light chains
10. Smooth muscle contraction → Vasoconstriction

Alpha-1 receptors are located on both arterial resistance vessels (producing increased SVR) and venous capacitance vessels (increasing venous return). [4,11,12]

Alpha-2 Receptor Activation

Alpha-2 receptors (Gi-coupled) produce several effects relevant to noradrenaline pharmacology:

Postsynaptic (vascular smooth muscle):

• Additional vasoconstriction in some vascular beds
• Particularly prominent in coronary, renal, and cutaneous circulation

Presynaptic (sympathetic nerve terminals):

• Negative feedback on noradrenaline release
• Autoreceptors reduce further neurotransmitter release
• Mechanism: Gi inhibits adenylyl cyclase → decreased cAMP → reduced vesicle fusion

Central nervous system:

• Centrally located alpha-2 receptors (locus coeruleus) reduce sympathetic outflow
• This is the mechanism of clonidine and dexmedetomidine, not clinically significant for exogenous noradrenaline (does not cross BBB) [13,14]

Beta-1 Receptor Activation

Noradrenaline has moderate beta-1 agonist activity, producing cardiac effects:

Signal Transduction:

1. Beta-1 receptor activation (Gs-coupled GPCR)
2. Gs stimulates adenylyl cyclase
3. Increased intracellular cAMP
4. cAMP activates protein kinase A (PKA)
5. PKA phosphorylates L-type Ca2+ channels and phospholamban
6. Increased Ca2+ influx and enhanced SERCA activity
7. Positive inotropy (increased contractility) and positive lusitropy (enhanced relaxation)

The beta-1 effect of noradrenaline on heart rate (chronotropy) is typically offset by the reflex bradycardia induced by alpha-mediated hypertension. [15,16]

Beta-2 Receptor Activation (Minimal)

Noradrenaline has negligible beta-2 activity. This is clinically significant:

• No bronchodilation
• No skeletal muscle vasodilation
• No significant hypokalaemia (unlike adrenaline)
• No tremor

The lack of beta-2 activity explains why noradrenaline produces net vasoconstriction across all vascular beds, in contrast to adrenaline which causes vasodilation in skeletal muscle via beta-2 receptors. [17]

Receptor Activity Summary Table

Pharmacokinetics

Absorption and Distribution

Route of Administration: Noradrenaline is administered exclusively by continuous intravenous infusion. It is not effective by oral, sublingual, or intramuscular routes due to:

• Extensive first-pass metabolism by gut wall and liver COMT/MAO
• Rapid tissue uptake and degradation
• Poor bioavailability

Distribution:

Noradrenaline does not significantly cross the blood-brain barrier due to its ionised state at physiological pH and polar hydroxyl groups. Central effects during administration are reflex-mediated rather than direct. [1,18]

Metabolism (Critical for Examination)

Noradrenaline undergoes rapid enzymatic degradation through two principal pathways:

1. Catechol-O-Methyltransferase (COMT):

• Location: Cytoplasm of cells adjacent to sympathetic nerve terminals, liver, kidney, gut wall
• Reaction: O-methylation of the 3-hydroxyl group on the catechol ring
• Product: Normetanephrine (inactive metabolite)
• Significance: Major extraneuronal degradation pathway

2. Monoamine Oxidase (MAO):

• Location: Mitochondrial outer membrane of sympathetic nerve terminals, liver, gut
• Isoforms: MAO-A (primary for noradrenaline) and MAO-B
• Reaction: Oxidative deamination of the terminal amine
• Products: 3,4-dihydroxymandelic acid (DOMA) or 3,4-dihydroxyphenylglycol (DOPEG)
• Significance: Major intraneuronal degradation pathway

Sequential Metabolism: The final common metabolite of both pathways is vanillylmandelic acid (VMA), which is excreted in urine and measured as a marker of catecholamine excess (phaeochromocytoma screening). [19,20]

Reuptake (Uptake-1): Before metabolism, released noradrenaline is primarily removed from the synaptic cleft by neuronal reuptake via the noradrenaline transporter (NET):

• Sodium-dependent active transport
• Blocked by cocaine and tricyclic antidepressants
• Responsible for terminating noradrenaline action at the synapse

Metabolic Pathway Summary:

Noradrenaline
    |
    ├── COMT → Normetanephrine → MAO → VMA (urine)
    |
    └── MAO → DOMA/DOPEG → COMT → VMA (urine)

Elimination

The extremely short half-life means that:

• Steady-state is achieved rapidly (within 5-10 minutes)
• Effects dissipate rapidly when infusion is stopped
• Dose changes produce rapid haemodynamic responses
• Continuous infusion via syringe driver is mandatory [21,22]

Factors Affecting Pharmacokinetics

Increased Effect/Duration:

• MAO inhibitors (prevent metabolism)
• Tricyclic antidepressants (block reuptake, reduce Uptake-1)
• Cocaine (blocks reuptake)
• Severe hepatic impairment (reduced COMT/MAO activity)

Decreased Effect:

• Alpha-adrenoceptor blockers (pharmacodynamic antagonism)
• Tachyphylaxis (receptor downregulation with prolonged use)
• Severe acidosis (reduced receptor responsiveness)

Cardiovascular Effects

Haemodynamic Profile

The cardiovascular effects of noradrenaline reflect its alpha-predominant receptor activity:

Primary Effects:

Reflex Bradycardia

A characteristic feature of noradrenaline administration is reflex bradycardia:

Mechanism:

1. Alpha-mediated vasoconstriction increases MAP
2. Elevated pressure stimulates arterial baroreceptors (carotid sinus, aortic arch)
3. Baroreceptor afferents (CN IX, X) increase firing rate
4. Nucleus tractus solitarius activation in medulla
5. Increased parasympathetic (vagal) efferent output
6. Decreased sympathetic efferent output
7. Net effect: Reduced sinoatrial node firing rate

The reflex bradycardia typically offsets or exceeds the direct beta-1 chronotropic effect of noradrenaline, in contrast to adrenaline which produces net tachycardia due to stronger beta-2 effects reducing total peripheral resistance. [5,23]

Regional Vascular Effects

Comparison with Adrenaline

At low doses, adrenaline predominantly activates beta-2 receptors causing skeletal muscle vasodilation and reduced SVR; at higher doses, alpha effects predominate. Noradrenaline always increases SVR regardless of dose. [6,24]

Clinical Uses

Septic Shock (First-Line Vasopressor)

Noradrenaline is the first-line vasopressor for septic shock according to the Surviving Sepsis Campaign Guidelines (2021). This recommendation is based on high-quality evidence demonstrating:

Evidence Base:

Rationale for First-Line Status:

1. Predictable vasoconstriction: Restores SVR in distributive shock
2. Maintains cardiac output: Beta-1 activity preserves contractility
3. Fewer arrhythmias: Compared to dopamine and adrenaline
4. Preserves renal function: Better than dopamine for maintaining urine output
5. Evidence-based: Multiple high-quality RCTs support use [7,25,26]

Target Parameters:

• MAP ≥65 mmHg (individualized; some patients benefit from higher targets)
• Titrate to clinical endpoints: Lactate clearance, urine output, mental status

Cardiogenic Shock

In cardiogenic shock, noradrenaline is used as an adjunct when hypotension persists despite inotropic support:

Current Approach (EURO SHOCK 2024 Guidelines):

• First-line inotrope: Dobutamine or milrinone for contractile support
• Add noradrenaline if MAP <65 mmHg despite adequate filling and inotrope
• Noradrenaline maintains coronary perfusion pressure
• Caution: Excessive afterload increase may worsen cardiac output

SHOCK Trial (Hochman et al.): Early revascularisation remains the primary intervention; vasopressors support perfusion pending definitive treatment. [27]

Intraoperative Hypotension

Noradrenaline infusions are increasingly used for intraoperative hypotension, particularly in:

• Major surgery with anticipated fluid shifts
• Patients at high risk of hypotension-related organ injury
• Cases requiring sustained vasopressor support

For brief hypotensive episodes, bolus agents (phenylephrine, metaraminol) remain common due to practicality. [28]

Anaphylactic Shock

While adrenaline is first-line for anaphylaxis, noradrenaline may be used as an adjunct when:

• Profound hypotension persists despite adrenaline
• Pure vasopressor support needed
• Concern about adrenaline-induced arrhythmias

Other Critical Care Applications

• Post-cardiac surgery vasoplegia: Common after cardiopulmonary bypass
• Neurogenic shock: Spinal cord injury with loss of sympathetic tone
• Drug-induced hypotension: Overdose (calcium channel blockers, beta-blockers)

Dosing and Administration

Preparation and Concentration

Standard Preparations (Australia):

CRITICAL: Noradrenaline concentration varies between preparations. The bitartrate salt contains 50% noradrenaline base by weight (2 mg bitartrate = 1 mg base). Always verify the concentration and whether stated as base or salt.

Dosing Guidelines

Practical Dosing:

• For 70 kg patient using 80 mcg/mL solution:
  • Starting dose 0.1 mcg/kg/min = 7 mcg/min = 5.25 mL/hr
• Titrate in increments of 0.02-0.05 mcg/kg/min every 5-10 minutes

Peripheral vs Central Administration

Central Venous Access (Preferred):

• Recommended for prolonged infusion (>hours)
• Reduced extravasation risk
• Allows higher concentrations
• Internal jugular, subclavian, or femoral vein

Peripheral Administration (Emergency/Short-term):

• Acceptable for short-term use in resuscitation when central access not immediately available
• Use large-bore cannula in large proximal vein (antecubital fossa preferred)
• Dilute concentration (4 mcg/mL)
• Continuous monitoring for extravasation
• Maximum 2-4 hours peripherally before central access obtained

Recent evidence (PMID: 33350377) suggests short-term peripheral noradrenaline is safer than previously thought when using appropriate dilution and monitoring, but central access remains the standard of care. [29,30]

Weaning

• Gradual dose reduction once haemodynamic targets achieved
• Reduce by 0.02-0.05 mcg/kg/min every 15-30 minutes
• Monitor for rebound hypotension
• Consider underlying cause resolution before weaning

Extravasation Management

Pathophysiology of Tissue Injury

Noradrenaline extravasation causes severe local tissue ischaemia through:

1. Intense alpha-1 mediated vasoconstriction of skin and subcutaneous vessels
2. Reduced local perfusion leading to tissue hypoxia
3. Acidosis from anaerobic metabolism
4. Cellular necrosis if not treated promptly

Risk Factors:

• Peripheral infusion (higher risk than central)
• High concentration solutions
• Prolonged infusion at single site
• Poor venous access
• Agitated patients

Clinical Recognition

Early Signs:

• Blanching around infusion site
• Pain at infusion site (patient may be sedated)
• Induration
• Cool skin locally

Late Signs:

• Dusky discolouration
• Blistering
• Frank necrosis (hours to days)

Phentolamine Treatment Protocol

Phentolamine is a competitive alpha-adrenergic antagonist that reverses noradrenaline-induced vasoconstriction.

Treatment Steps:

1. Stop the noradrenaline infusion through affected line immediately
2. Aspirate as much drug as possible from the cannula before removal
3. Prepare phentolamine: 5-10 mg in 10-15 mL normal saline
4. Infiltrate the affected area using a fine needle (25-27G)
   • Multiple small injections throughout the blanched area
   • Aim to infiltrate subcutaneously around the entire extravasation zone
5. Apply warm compresses (NOT cold) to promote vasodilation
6. Elevate the affected limb
7. Document and photograph the injury
8. Monitor for progression; consider plastic surgery/wound care consultation if necrosis develops

Timing: Phentolamine is most effective within 12 hours of extravasation, ideally immediately. Efficacy decreases with time. [31]

Alternative Treatments

Drug Interactions

Major Interactions

Moderate Interactions

Beneficial Interactions

Comparison with Other Vasopressors

Vasopressor Comparison Table

Key Trial Evidence

When to Add Vasopressin

Surviving Sepsis Campaign 2021 Recommendations:

• Consider adding vasopressin (0.03 units/min, non-titrating) when noradrenaline dose reaches 0.25-0.5 mcg/kg/min
• Rationale: Catecholamine-sparing, non-adrenergic mechanism effective in vasodilatory states
• Fixed low dose to avoid mesenteric ischaemia [7,8,25]

Special Populations

Critically Ill Patients

Pharmacokinetic Changes in Sepsis:

• Increased volume of distribution (capillary leak, oedema)
• Variable hepatic blood flow affecting metabolism
• Receptor downregulation with prolonged use
• Relative adrenal insufficiency affecting responsiveness

Dosing Considerations:

• Start at standard doses; titrate to effect
• Consider hydrocortisone (200 mg/day) if noradrenaline requirements high
• Monitor for tachyphylaxis (receptor desensitisation)

Hepatic Impairment

• COMT activity reduced
• Prolonged effect possible
• Generally well-tolerated; titrate to effect
• No specific dose adjustment required

Renal Impairment

• Minimal effect on noradrenaline pharmacokinetics
• Metabolites renally excreted (not clinically significant)
• May have altered sensitivity in uraemic patients
• No dose adjustment required

Pregnancy

• Noradrenaline crosses placenta (limited data)
• May reduce uteroplacental blood flow via alpha-mediated vasoconstriction
• Use only when maternal benefit outweighs fetal risk
• Phenylephrine or metaraminol often preferred for spinal hypotension due to better fetal outcomes
• In maternal septic shock, noradrenaline may be necessary

Paediatric Patients

• Similar pharmacology to adults
• Dosing: 0.05-2 mcg/kg/min
• Central access strongly preferred
• More sensitive to extravasation injury

Elderly

• May have increased sensitivity due to reduced baroreceptor function
• Higher risk of complications from hypertensive overshoot
• Coronary and cerebral atherosclerosis increases organ ischaemia risk
• Start at lower doses; titrate carefully

Indigenous Health Considerations

Aboriginal and Torres Strait Islander peoples and Maori populations experience disproportionately higher rates of sepsis and critical illness requiring vasopressor support. Several factors warrant consideration when using noradrenaline in Indigenous patients.

Cardiovascular Comorbidities: Aboriginal and Torres Strait Islander Australians experience cardiovascular disease at 2-3 times the rate of non-Indigenous Australians, with earlier onset. Pre-existing ischaemic heart disease increases the risk of myocardial ischaemia during noradrenaline infusion, particularly if excessive doses cause coronary vasoconstriction or hypertensive overshoot. Careful dose titration with lower starting doses and close monitoring for ischaemic symptoms (where patient can communicate) or ECG changes is advisable.

Chronic Kidney Disease: The prevalence of chronic kidney disease in Indigenous Australian communities is 3-4 times higher than non-Indigenous populations. While noradrenaline pharmacokinetics are minimally affected by renal function, patients with CKD often have associated volume overload, hypertension, and cardiovascular disease that affect haemodynamic response and goals of therapy. Fluid resuscitation strategies may need modification, and MAP targets should be individualised.

Access to Critical Care: Indigenous Australians living in remote and rural communities face challenges accessing intensive care facilities where vasopressor therapy is typically administered. Prolonged retrieval times may necessitate initiation of noradrenaline at peripheral hospitals with limited monitoring capability. In such settings, conservative dosing, peripheral administration protocols with careful monitoring, and early retrieval coordination are essential. Clear communication with retrieval services about vasopressor requirements aids planning.

Cultural Safety: Culturally safe care includes involving Aboriginal Health Workers and Indigenous Liaison Officers in patient and family communication. Many Indigenous cultures practice collective decision-making involving extended family; explanations about the seriousness of requiring vasopressor support should include family members where appropriate. End-of-life discussions, which may arise in patients with refractory shock, require cultural sensitivity and may benefit from involvement of Elders or cultural advisors. For Maori patients in New Zealand, principles of whanau involvement and tikanga (customary practices) should guide care.

Adverse Effects

Cardiovascular Adverse Effects

Peripheral Adverse Effects

Metabolic Effects

• Generally minimal compared to adrenaline
• May cause mild hyperglycaemia (alpha-2 inhibits insulin release)
• No significant hypokalaemia (unlike adrenaline)

ANZCA Primary Exam Focus

Common MCQ Themes

1. Receptor pharmacology: Alpha-1 predominant; compare with adrenaline (N-methyl group confers beta-2 activity)
2. Haemodynamic profile: ↑SVR, ↑MAP, reflex bradycardia, maintained CO
3. Metabolism: COMT + MAO pathways; Uptake-1 for synaptic termination
4. Structure-activity: Catechol ring (COMT substrate), primary amine (MAO substrate)
5. Drug interactions: MAOIs (severe potentiation), TCAs (enhanced response)
6. Clinical use: First-line in septic shock; not first-line in cardiac arrest
7. Comparison with adrenaline: Why noradrenaline causes bradycardia but adrenaline causes tachycardia
8. Extravasation: Phentolamine treatment protocol

Primary Viva Question Patterns

• "Describe the pharmacology of noradrenaline"
• "Compare noradrenaline and adrenaline"
• "Why is noradrenaline first-line in septic shock but adrenaline first-line in cardiac arrest?"
• "Explain the reflex bradycardia seen with noradrenaline"
• "A patient on an MAOI requires vasopressor support. What considerations apply?"
• "How would you manage noradrenaline extravasation?"

Key Calculations

Infusion Rate Calculation:

Example: 70 kg patient, target 0.1 mcg/kg/min, using 4 mg in 50 mL (80 mcg/mL)

• Required dose: 0.1 × 70 = 7 mcg/min
• Rate: 7 mcg/min ÷ 80 mcg/mL = 0.0875 mL/min = 5.25 mL/hr

Converting Between Base and Salt:

• Noradrenaline bitartrate 2 mg = Noradrenaline base 1 mg
• Always check whether label states base or salt

Australian/New Zealand Specific Considerations

TGA-Approved Formulations

CRITICAL: Different products may state concentration as base or bitartrate. Institutional protocols should standardise which product is used and how solutions are prepared.

PBS and Hospital Supply

• Noradrenaline is not PBS-listed for community use
• Available as hospital supply item through pharmaceutical wholesalers
• Included in imprest stock at all hospitals with intensive care capabilities
• Relatively inexpensive

ANZCA and ANZICS Guidelines

ANZICS (Australian and New Zealand Intensive Care Society):

• Endorses Surviving Sepsis Campaign guidelines
• Noradrenaline as first-line vasopressor for septic shock
• Target MAP ≥65 mmHg (individualised)

ANZCA:

• No specific guideline on vasopressor choice
• PS18 (Monitoring) requires continuous BP monitoring during vasopressor use
• Practical guidance in training curricula

ARC/ANZCOR Guidelines

Cardiac Arrest:

• Adrenaline (NOT noradrenaline) is the recommended vasopressor
• Noradrenaline has no role in standard cardiac arrest algorithms
• Post-ROSC hypotension may be treated with noradrenaline infusion

Assessment Content

SAQ Practice Question (20 marks)

Question:

A 65-year-old man is admitted to ICU with septic shock secondary to community-acquired pneumonia. Despite 30 mL/kg crystalloid resuscitation, his blood pressure remains 75/45 mmHg (MAP 55 mmHg) with a heart rate of 115 bpm and lactate of 5.2 mmol/L. You decide to commence noradrenaline.

(a) Describe the mechanism of action of noradrenaline, including the receptor types involved and their signal transduction pathways. (6 marks)

(b) Outline the pharmacokinetic properties of noradrenaline that explain why it must be given by continuous intravenous infusion. (4 marks)

(c) The patient requires increasing doses of noradrenaline. At what dose would you consider adding vasopressin, and what is the rationale for this approach? (4 marks)

(d) During administration via a peripheral cannula, you notice blanching around the infusion site. Describe your management of this extravasation. (6 marks)

---

Model Answer:

(a) Mechanism of Action (6 marks)

Noradrenaline is an endogenous catecholamine that produces cardiovascular effects through activation of adrenergic receptors. Its receptor selectivity is: alpha-1 > alpha-2 > beta-1 >> beta-2. [1 mark]

Alpha-1 Receptor (Primary Effect - 3 marks):

• Alpha-1 receptors are located on vascular smooth muscle
• Coupled to Gq proteins
• Activation stimulates phospholipase C (PLC)
• PLC hydrolyses PIP2 to produce IP3 and DAG
• IP3 releases calcium from sarcoplasmic reticulum
• Increased intracellular calcium activates myosin light chain kinase (MLCK)
• MLCK phosphorylates myosin → smooth muscle contraction → vasoconstriction
• Net effect: Increased SVR and MAP

Beta-1 Receptor (1 mark):

• Located on cardiac myocytes
• Coupled to Gs proteins → increased cAMP → PKA activation
• Positive inotropy (increased contractility)
• Helps maintain cardiac output despite increased afterload

Haemodynamic Summary (1 mark):

• Increased SVR and MAP (alpha-1)
• Reflex bradycardia (baroreceptor response to increased MAP)
• Cardiac output usually maintained (beta-1 inotropy offsets afterload increase)

(b) Pharmacokinetics Requiring Continuous Infusion (4 marks)

[1 mark for each point]

The extremely short half-life means:

• Bolus dosing would produce transient effects lasting only minutes
• Continuous infusion is required to maintain therapeutic plasma concentrations
• Dose changes produce rapid haemodynamic responses
• Effects cease rapidly when infusion is stopped (advantageous for titration)

(c) Adding Vasopressin (4 marks)

Threshold for Addition (1 mark): According to Surviving Sepsis Campaign 2021 guidelines, consider adding vasopressin when noradrenaline dose reaches 0.25-0.5 mcg/kg/min.

Vasopressin Dosing (1 mark):

• Fixed dose of 0.03 units/minute
• Not titrated (to avoid mesenteric ischaemia at higher doses)

Rationale (2 marks):

1. Catecholamine-sparing effect: Allows reduction of noradrenaline dose
2. Non-adrenergic mechanism: Vasopressin acts through V1a receptors (Gq/IP3/Ca2+), effective even when adrenergic receptors are downregulated or desensitised
3. Relative vasopressin deficiency: Endogenous vasopressin stores may be depleted in prolonged shock
4. Evidence base: VASST trial showed vasopressin is safe adjunct; may reduce mortality in less severe shock subgroup

(d) Extravasation Management (6 marks)

Immediate Actions (2 marks):

1. Stop the noradrenaline infusion immediately
2. Leave the cannula in situ initially
3. Aspirate as much drug as possible through the cannula
4. Remove the cannula after aspiration

Phentolamine Administration (3 marks): 5. Prepare phentolamine: 5-10 mg diluted in 10-15 mL normal saline 6. Using a fine needle (25-27G), infiltrate the affected area:

• Multiple small injections throughout the blanched zone
• Infiltrate subcutaneously around the entire extravasation area
• Aim to cover all affected tissue

7. Phentolamine acts as a competitive alpha-adrenergic antagonist, reversing noradrenaline-induced vasoconstriction
8. Most effective within 12 hours of extravasation; give immediately

Supportive Measures (1 mark): 9. Apply warm compresses (NOT cold) to promote vasodilation 10. Elevate the affected limb 11. Document and photograph the injury 12. Monitor for progression; consult plastic surgery/wound care if necrosis develops

Total: 20 marks

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Primary Viva Scenario (15 marks)

Opening Stem:

You are the anaesthetist for a 58-year-old man undergoing emergency laparotomy for perforated sigmoid diverticulitis. He is hypotensive (MAP 50 mmHg) despite fluid resuscitation and has been commenced on noradrenaline. His medical history includes depression treated with phenelzine (an MAO inhibitor).

Expected Viva Progression:

Examiner: What concerns do you have about using noradrenaline in this patient?

Candidate Response (4 marks):

"I am very concerned about the interaction between noradrenaline and phenelzine, which is a non-selective, irreversible monoamine oxidase inhibitor.

Mechanism of Interaction:

• MAO is one of the principal enzymes responsible for metabolising noradrenaline
• MAO inhibitors block this pathway, dramatically reducing noradrenaline clearance
• Additionally, MAOIs increase presynaptic stores of noradrenaline in sympathetic nerve terminals

Clinical Consequences:

• Markedly enhanced and prolonged pressor response to exogenous noradrenaline
• Risk of severe hypertensive crisis
• Potential for cerebral haemorrhage, myocardial infarction, or death

Important Distinction:

• The severe 'cheese reaction' (tyramine crisis) involves indirect sympathomimetics that release stored noradrenaline
• Noradrenaline is a direct-acting agonist, but its metabolism is still impaired by MAOIs
• The response to noradrenaline may be enhanced 2-4 fold in MAOI-treated patients"

---

Examiner: How would you modify your management given this interaction?

Candidate Response (4 marks):

"My approach would include:

1. Consider Alternatives First:

• If hypotension is mild, optimise fluid resuscitation and consider other causes
• However, in septic shock from peritonitis, vasopressor support is likely essential

2. If Noradrenaline Required:

• Start at one-tenth (1/10th) the usual dose: e.g., 0.005-0.01 mcg/kg/min instead of 0.05-0.1 mcg/kg/min
• Titrate very slowly in small increments
• Use continuous invasive arterial blood pressure monitoring (essential)

3. Enhanced Monitoring:

• Arterial line for beat-to-beat BP monitoring
• Frequent neurological assessment for hypertensive encephalopathy signs
• Low threshold for ECG monitoring for ischaemic changes

4. Prepare for Complications:

• Have short-acting antihypertensive available (GTN infusion, phentolamine, labetalol)
• Be prepared for dramatic swings in blood pressure
• Consider alternative vasopressors with different metabolic pathways (vasopressin is not metabolised by MAO)"

---

Examiner: What alternative vasopressor could you consider and why?

Candidate Response (3 marks):

"Vasopressin would be my preferred alternative or adjunct:

Rationale:

1. Different mechanism: Acts through V1a receptors, not adrenergic receptors
2. Different metabolism: Degraded by peptidases, NOT by MAO or COMT
3. No MAOI interaction: Effect is not potentiated by MAO inhibitors
4. Effective in septic shock: Works through non-adrenergic pathway, effective when catecholamine responsiveness is reduced

Dosing:

• Fixed dose of 0.03 units/minute
• Can be used as sole vasopressor or adjunct to low-dose noradrenaline

Limitations:

• Risk of mesenteric ischaemia at higher doses (hence fixed low dose)
• May reduce cardiac output due to increased afterload without beta-1 support
• Not ideal as sole agent if cardiac output support also needed"

---

Examiner: Compare the haemodynamic effects of noradrenaline and adrenaline.

Candidate Response (4 marks):

Explanation of Differences:

Heart Rate:

• Noradrenaline: Alpha-mediated vasoconstriction raises MAP → baroreceptor activation → vagal efferent activity → bradycardia. The minimal beta-2 activity means SVR always increases.
• Adrenaline: Beta-2 vasodilation in skeletal muscle partially offsets alpha vasoconstriction at low doses; combined with strong beta-1 cardiac effects → net tachycardia.

Clinical Implications:

• Noradrenaline preferred in septic shock (fewer arrhythmias, predictable SVR increase)
• Adrenaline preferred in cardiac arrest (combined inotropic and pressor effects) and anaphylaxis (bronchodilation from beta-2)

Total: 15 marks

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References

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13. PMID: 6814275 (Langer SZ - Presynaptic alpha-2 receptors)
14. PMID: 3565860 (Ruffolo RR - Alpha-adrenoceptor structure-activity)
15. PMID: 18195085 (Westfall TC - Catecholamine pharmacology)
16. PMID: 15339243 (Bristow MR - Beta-adrenergic receptor signaling)
17. PMID: 6290784 (Lands AM - Beta-receptor differentiation)
18. PMID: 3139553 (Morgan DJ - Vasopressor placental transfer)
19. PMID: 6111469 (Kopin IJ - Catecholamine metabolism)
20. PMID: 3015644 (Goldstein DS - Catecholamine metabolic pathways)
21. PMID: 2318652 (Thomas SHL - Noradrenaline pharmacokinetics)
22. PMID: 1567326 (MacGregor DA - Catecholamine pharmacokinetics critical illness)
23. PMID: 9015867 (Thiele RH - Arterial baroreflex)
24. PMID: 6290784 (Lands AM - Catecholamine receptor differentiation)
25. PMID: 20200382 (De Backer D - SOAP II Trial: Dopamine vs Norepinephrine)
26. PMID: 22735562 (De Backer D - Meta-analysis dopamine vs norepinephrine)
27. PMID: 10580767 (Hochman JS - SHOCK Trial investigators)
28. PMID: 28244945 (Mets B - Vasopressor selection perioperative)
29. PMID: 33350377 (Cardenas-Garcia J - Peripheral vasopressor safety)
30. PMID: 30201558 (Loubani OM - Extravasation prevention)
31. PMID: 6120526 (Zucker G - Phentolamine for extravasation)
32. PMID: 27483063 (Gordon AC - VANISH Trial)

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