Vasopressors & Inotropes

Quick Answer

Vasopressors are agents that increase systemic vascular resistance (SVR) via vascular smooth muscle contraction, primarily through alpha-1 adrenergic or V1a vasopressin receptor activation. Inotropes increase myocardial contractility via beta-1 adrenergic receptor stimulation, phosphodiesterase inhibition, or calcium sensitization. Many agents have both properties (e.g., noradrenaline, adrenaline). [1,2]

Key Concepts:

• Adrenergic receptors (alpha-1, alpha-2, beta-1, beta-2, beta-3) mediate catecholamine effects via G-protein coupled second messenger systems
• Noradrenaline (norepinephrine) is the first-line vasopressor for septic shock
• Dobutamine is the preferred inotrope for cardiogenic shock with adequate preload
• Vasopressin acts via V1a receptors independently of catecholamine pathways
• Milrinone (PDE3 inhibitor) and levosimendan (calcium sensitizer) are catecholamine-independent inotropes

ICU Relevance:

• Essential for haemodynamic support in shock states
• Understanding receptor pharmacology guides drug selection
• Monitoring for adverse effects (arrhythmias, ischaemia, extravasation) is critical

Exam Focus:

• Receptor physiology and G-protein coupling mechanisms
• Comparative pharmacology of catecholamines
• Evidence base from landmark trials (SOAP II, VASST, VANISH)
• Drug dosing, preparation, and administration

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CICM First Part Exam Focus

What Examiners Expect

Written SAQ:

Common question stems:

• "Describe the mechanism of action of noradrenaline at the cellular level"
• "Compare and contrast the cardiovascular effects of adrenaline and noradrenaline"
• "Explain the receptor pharmacology of adrenergic agonists with reference to G-protein signalling"
• "Outline the pharmacokinetics and pharmacodynamics of vasopressin"
• "Discuss the role of phosphodiesterase inhibitors as inotropic agents"
• "Draw a dose-response curve showing the effects of catecholamines on heart rate and blood pressure"

Expected depth:

• Molecular detail: G-protein subunits (Gs, Gi, Gq), second messengers (cAMP, IP3/DAG)
• Quantitative values: receptor affinities, dose ranges, haemodynamic targets
• Clear diagrams: receptor signalling pathways, dose-response curves
• Drug comparisons in tabular format
• Clinical relevance to ICU explicitly stated

Written MCQ:

Common topics tested:

• Receptor subtypes and their second messenger systems
• Effects of each catecholamine on HR, BP, SVR, CO
• Dose-dependent effects of dopamine
• Metabolism of catecholamines (COMT, MAO)
• Drug interactions with MAOIs, tricyclic antidepressants

Oral Viva:

Expected discussion flow:

1. Define - What is a vasopressor? What is an inotrope?
2. Classify - Catecholamines vs non-catecholamines, receptor selectivity
3. Explain mechanism - Receptor to cellular effect pathway
4. Compare - Noradrenaline vs adrenaline vs dopamine
5. Apply - Choice of agent in septic shock vs cardiogenic shock
6. Evidence - SOAP II, VASST, VANISH trial findings

Common viva scenarios:

• "Tell me about the pharmacology of noradrenaline"
• "A patient with septic shock is on noradrenaline 0.5 mcg/kg/min. What would you add next?"
• "Describe the mechanism of action of milrinone"
• "What are the advantages of vasopressin over catecholamines?"

Pass vs Fail Performance

Pass Standard:

• Accurate receptor classification with correct second messengers
• Clear mechanism at molecular, cellular, and organ level
• Quantitative dose ranges and haemodynamic effects
• Appropriate drug selection for clinical scenarios
• Knowledge of key trials (SOAP II, VASST)

Common Reasons for Failure:

• Confusion between alpha and beta receptor effects
• Incorrect G-protein coupling (e.g., stating beta receptors are Gq-coupled)
• Unable to describe catecholamine metabolism
• No knowledge of evidence base
• Cannot explain dose-dependent effects of dopamine
• Poor understanding of inodilators (milrinone, levosimendan)

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Key Points

Must-Know Facts

1. Adrenergic Receptor Classification: Alpha-1 (Gq-coupled, vasoconstriction), alpha-2 (Gi-coupled, presynaptic inhibition), beta-1 (Gs-coupled, inotropy/chronotropy), beta-2 (Gs-coupled, vasodilation/bronchodilation), beta-3 (Gs-coupled, lipolysis, negative inotropy in heart). [3,4]

2. Noradrenaline: Potent alpha-1 and beta-1 agonist with minimal beta-2 activity. First-line vasopressor for septic shock per SSC 2021 guidelines. Dose: 0.05-1.0 mcg/kg/min. Half-life: 2-3 minutes. [1,5]

3. Adrenaline: Equipotent at alpha and beta receptors. Dose-dependent effects: low dose (beta predominant - inotrope/chronotrope/vasodilator), high dose (alpha predominant - vasoconstrictor). Second-line in septic shock. [1,6]

4. Dopamine: Dose-dependent receptor activation - DA1 (1-3 mcg/kg/min, renal), beta-1 (3-10 mcg/kg/min, inotrope), alpha-1 (greater than 10 mcg/kg/min, vasoconstrictor). SOAP II showed increased arrhythmias and 28-day mortality in cardiogenic shock subgroup. [7,8]

5. Dobutamine: Racemic mixture with beta-1 predominant effect. Increases contractility with minimal effect on SVR. Drug of choice for cardiogenic shock with adequate preload. Dose: 2-20 mcg/kg/min. [9,10]

6. Vasopressin: V1a receptor agonist causing vasoconstriction independently of catecholamine pathways. VASST and VANISH trials showed catecholamine-sparing effect. Dose: 0.01-0.04 units/min. Higher doses cause ischaemia. [11,12,13]

7. Milrinone: Phosphodiesterase-3 inhibitor preventing cAMP degradation. Positive inotrope and vasodilator (inodilator). Useful in right heart failure and pulmonary hypertension. Dose: 0.375-0.75 mcg/kg/min. Renally excreted. [14,15]

8. Levosimendan: Calcium sensitizer increasing troponin C affinity for calcium. Does not increase myocardial oxygen consumption. LEOPARDS trial showed no benefit in septic shock; SURVIVE showed no mortality benefit in acute heart failure. [16,17,18]

9. Catecholamine Metabolism: COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase) metabolise catecholamines. Plasma half-life 2-3 minutes. Reuptake into nerve terminals (Uptake 1) terminates action. [19,20]

10. Receptor Downregulation: Prolonged catecholamine exposure causes beta-receptor phosphorylation, uncoupling from Gs, and internalisation. Tachyphylaxis develops within 24-48 hours. [21,22]

Essential Equations

Mean Arterial Pressure (MAP):

MAP = CO × SVR
MAP = (SBP + 2×DBP) / 3

• Target MAP: 65-70 mmHg in septic shock
• Higher targets (80-85 mmHg) did not improve outcomes in SEPSISPAM trial [23]

Cardiac Output:

CO = SV × HR

• Stroke Volume determined by preload, afterload, contractility
• Inotropes primarily affect contractility (SV)

Systemic Vascular Resistance:

SVR = (MAP - CVP) / CO × 80

• Normal: 800-1200 dynes·s/cm⁵
• Vasopressors increase SVR through alpha-1 vasoconstriction

Normal Values Table

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Adrenergic Receptor Physiology

Receptor Classification and Distribution

Adrenergic receptors are G-protein coupled receptors (GPCRs) that mediate the effects of endogenous catecholamines (adrenaline, noradrenaline, dopamine) and exogenous sympathomimetic drugs. Classification is based on their relative potencies for adrenaline and noradrenaline and their downstream signalling pathways. [3,4,24]

Alpha-1 Receptors

G-Protein Coupling: Gq/11

Second Messenger Pathway: Activation of phospholipase C (PLC) → hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) → generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) → IP3 causes calcium release from sarcoplasmic reticulum → DAG activates protein kinase C (PKC). [25]

Distribution and Effects:

Clinical Significance: Alpha-1 agonists (noradrenaline, phenylephrine, metaraminol) are used as vasopressors to increase SVR. Arteriolar constriction predominates, increasing afterload. [26]

Subtypes: Alpha-1A, alpha-1B, alpha-1D (pharmacological differences exist but clinical relevance is limited).

Alpha-2 Receptors

G-Protein Coupling: Gi/o

Second Messenger Pathway: Inhibition of adenylyl cyclase → decreased cAMP → reduced protein kinase A (PKA) activity. Also activation of G-protein-gated inwardly rectifying K+ channels (GIRK) causing hyperpolarisation. [27]

Distribution and Effects:

Clinical Significance: Clonidine and dexmedetomidine are alpha-2 agonists used for sedation and analgesia in ICU. Presynaptic alpha-2 activation reduces central sympathetic outflow (hypotension, bradycardia). [28]

Subtypes: Alpha-2A (sedation, analgesia, hypotension), alpha-2B (vasoconstriction, salt-water balance), alpha-2C (modulation of cognition, startle response).

Beta-1 Receptors

G-Protein Coupling: Gs

Second Messenger Pathway: Activation of adenylyl cyclase → increased cAMP → activation of protein kinase A (PKA) → phosphorylation of L-type calcium channels (increased Ca²⁺ influx), phospholamban (enhanced SR Ca²⁺ uptake via SERCA2a), troponin I (increased relaxation rate), and ryanodine receptors (enhanced Ca²⁺ release from SR). [29,30]

Distribution and Effects:

Clinical Significance: Beta-1 agonists (dobutamine, isoprenaline) increase cardiac output by enhancing contractility and heart rate. Pure beta-1 effects are desirable in cardiogenic shock to improve CO without excessive vasoconstriction. [9,31]

Beta-2 Receptors

G-Protein Coupling: Gs

Second Messenger Pathway: Same as beta-1 (adenylyl cyclase → cAMP → PKA). In vascular smooth muscle, PKA phosphorylates myosin light chain kinase (MLCK) reducing its activity, causing relaxation. [32]

Distribution and Effects:

Clinical Significance: Beta-2 stimulation by low-dose adrenaline causes vasodilation and may reduce MAP despite increased CO. Salbutamol (selective beta-2) causes hypokalaemia via Na⁺/K⁺-ATPase activation in skeletal muscle. [33,34]

Beta-3 Receptors

G-Protein Coupling: Gs (also Gi in some tissues)

Second Messenger Pathway: Primarily cAMP-mediated; tissue-specific effects.

Distribution and Effects:

Clinical Significance: Beta-3 receptors in the heart may provide negative feedback during excessive catecholamine stimulation. Mirabegron (beta-3 agonist) is used for overactive bladder. Limited direct ICU relevance. [35,36]

G-Protein Signalling Summary

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Catecholamines

Overview

Catecholamines share a common structure: a benzene ring with two hydroxyl groups (catechol) and an amine side chain. Natural catecholamines include dopamine, noradrenaline (norepinephrine), and adrenaline (epinephrine). Synthetic catecholamines include dobutamine and isoprenaline. [1,19]

Common Properties:

• Rapid onset of action (seconds)
• Short half-life (2-3 minutes) due to metabolism by COMT and MAO
• Require continuous infusion for sustained effect
• Subject to receptor downregulation with prolonged use
• Metabolised by COMT (liver, plasma) and MAO (nerve terminals, liver)

Noradrenaline (Norepinephrine)

Australian Brand Names: Levophed, generic noradrenaline

PBS/TGA Status: TGA approved; hospital supply (Section 100)

Receptor Profile

Net Cardiovascular Effect: Increased SVR (alpha-1), increased MAP, reflex bradycardia (baroreceptor activation offsets beta-1 chronotropy), maintained or slightly increased cardiac output (if preload adequate). [1,5]

Mechanism of Action

1. Binding to alpha-1 receptor on vascular smooth muscle
2. Gq activation → phospholipase C activation
3. IP3 generation → calcium release from sarcoplasmic reticulum
4. Calcium-calmodulin complex activates myosin light chain kinase (MLCK)
5. Phosphorylation of myosin light chains → actin-myosin cross-bridge cycling → vasoconstriction

Simultaneously:

1. Binding to beta-1 receptor on cardiac myocytes
2. Gs activation → adenylyl cyclase activation → increased cAMP
3. PKA activation → phosphorylation of L-type Ca²⁺ channels, phospholamban, troponin I
4. Increased intracellular calcium and enhanced SR uptake → increased contractility and relaxation rate

Pharmacokinetics

Active Metabolites: None (metabolites inactive)

Pharmacodynamics

Dose-Response:

• 0.05-0.1 mcg/kg/min: Initial dose, moderate vasoconstriction
• 0.1-0.5 mcg/kg/min: Standard maintenance, significant alpha effect
• 0.5-1.0 mcg/kg/min: High dose, near-maximal alpha stimulation
• Greater than 1.0 mcg/kg/min: Consider adjunctive vasopressor (vasopressin)

Haemodynamic Effects:

Drug Preparation and Administration

Standard Preparation (Australia/NZ):

• Concentration: 40 mcg/mL (4 mg in 100 mL 5% dextrose or 0.9% saline)
• Alternatively: 160 mcg/mL (8 mg in 50 mL) for volume-restricted patients

Administration:

• Central venous access preferred due to extravasation risk
• Peripheral administration acceptable in emergency for short duration (less than 12 hours) with close monitoring [37]
• Large bore antecubital vein if peripheral used; avoid hand/foot veins
• Infusion via dedicated lumen; incompatible with bicarbonate, thiopentone

Extravasation Management:

• Phentolamine 5-10 mg in 10 mL saline infiltrated subcutaneously around site
• Apply within 12 hours of extravasation
• Monitor for tissue necrosis, compartment syndrome [38]

Clinical Applications

Primary Indication: Septic shock (first-line vasopressor per SSC 2021) [39]

Other Indications:

• Distributive shock (anaphylaxis as adjunct, neurogenic shock)
• Cardiogenic shock (with inotrope, after preload optimisation)
• Post-cardiac surgery vasoplegia
• Hepatorenal syndrome (with albumin, terlipressin)

Evidence Base:

• SOAP II Trial (2010): No mortality difference between dopamine and norepinephrine overall, but dopamine associated with more arrhythmias and increased 28-day mortality in cardiogenic shock subgroup (PMID: 20071719) [7]
• SSC 2021: Strong recommendation for norepinephrine as first-line vasopressor [39]

Adverse Effects

Cardiovascular:

• Arrhythmias (tachycardia, SVT, VT less common than with dopamine)
• Reflex bradycardia
• Increased afterload may precipitate heart failure in severe LV dysfunction
• Digital and peripheral ischaemia at high doses

Metabolic:

• Lactic acidosis (alpha-2-mediated inhibition of pyruvate dehydrogenase) [40]
• Hyperglycaemia (glycogenolysis)

Local:

• Extravasation necrosis (requires central access or close monitoring)

Drug Interactions:

• MAOIs: Hypertensive crisis (contraindicated)
• Tricyclic antidepressants: Exaggerated response (inhibit Uptake 1)
• Beta-blockers: Unopposed alpha effect, severe hypertension

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Adrenaline (Epinephrine)

Australian Brand Names: Adrenaline, EpiPen

PBS/TGA Status: TGA approved; hospital supply

Receptor Profile

Net Cardiovascular Effect: Dose-dependent. Low dose (beta predominant): increased HR, increased CO, decreased SVR. High dose (alpha predominant): increased SVR, increased MAP, maintained CO. [1,6]

Dose-Dependent Effects

Biphasic Blood Pressure Response:

• At low doses, beta-2-mediated vasodilation in skeletal muscle may reduce diastolic BP
• At high doses, alpha-1 vasoconstriction dominates, increasing both SBP and DBP

Pharmacokinetics

Clinical Applications

Emergency Uses:

• Anaphylaxis: 0.3-0.5 mg IM (1:1000) first-line; 10-100 mcg IV boluses for severe hypotension
• Cardiac arrest: 1 mg IV every 3-5 minutes (shockable and non-shockable rhythms) [41]
• Bronchospasm: Nebulised 3-5 mg (1:1000)

ICU Uses:

• Second-line vasopressor in septic shock (after noradrenaline)
• Combined vasopressor-inotrope in mixed shock states
• Post-cardiac surgery low output state

Evidence Base:

• CAT Trial (2018): Dopamine vs epinephrine in septic shock showed no mortality difference but epinephrine associated with more metabolic effects (PMID: 29800012) [42]
• PARAMEDIC2 (2018): Adrenaline improved 30-day survival vs placebo in out-of-hospital cardiac arrest but increased severe neurological disability (PMID: 30021076) [43]

Adverse Effects

Cardiovascular:

• Tachycardia, tachyarrhythmias (more common than noradrenaline)
• Myocardial ischaemia (increased oxygen demand)
• Hypertension at high doses

Metabolic:

• Lactic acidosis (beta-2-mediated increased glycogenolysis, lactate production independent of tissue hypoxia) [44]
• Hypokalaemia (beta-2-mediated Na⁺/K⁺-ATPase activation)
• Hyperglycaemia (gluconeogenesis, glycogenolysis)

Other:

• Tremor, anxiety
• Pulmonary oedema (increased LV afterload)

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Dopamine

Australian Brand Names: Intropin (discontinued), generic dopamine

PBS/TGA Status: TGA approved; hospital supply

Receptor Profile (Dose-Dependent)

• renal/mesenteric vasodilation | | 3-10 mcg/kg/min | Beta-1 (also DA1) | Inotropy, chronotropy | | Greater than 10 mcg/kg/min | Alpha-1 (also Beta-1) | Vasoconstriction |

Important: The "renal dose" dopamine concept has been disproven. No evidence supports low-dose dopamine for renal protection. [45,46]

Mechanism of Action

DA1 Receptors (Gs-coupled):

• Located on renal, mesenteric, coronary vascular smooth muscle
• Activation → increased cAMP → vasodilation
• Also promotes natriuresis (proximal tubule Na⁺/K⁺-ATPase inhibition)

DA2 Receptors (Gi-coupled):

• Presynaptic inhibition of noradrenaline release
• Inhibition of prolactin release (pituitary)

Beta-1 and Alpha-1 Effects: Same mechanism as other catecholamines

Evidence Against Dopamine

SOAP II Trial (2010) (PMID: 20071719) [7]:

• 1,679 patients with shock randomised to dopamine vs norepinephrine
• No overall mortality difference (52.5% vs 48.5%, p=0.10)
• More arrhythmias with dopamine (24.1% vs 12.4%, p<0.001)
• Cardiogenic shock subgroup: Higher 28-day mortality with dopamine (HR 1.29)
• Conclusion: Norepinephrine preferred over dopamine

Meta-Analysis (De Backer 2012) (PMID: 22301936) [47]:

• Dopamine associated with increased risk of arrhythmias and mortality in septic shock
• Strong evidence to avoid dopamine as first-line agent

Current Role

• Largely abandoned as first-line vasopressor
• May have limited role for bradycardia in transplanted (denervated) heart
• Occasionally used in severe bradycardia unresponsive to atropine pending pacing

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Dobutamine

Australian Brand Names: Dobutrex, generic dobutamine

PBS/TGA Status: TGA approved; hospital supply

Receptor Profile

Pharmacology: Dobutamine is a synthetic catecholamine administered as a racemic mixture of two enantiomers with different receptor affinities. [9,10]

Net Effect: Beta-1 predominant (inotropy, chronotropy), minimal net alpha effect (vasodilation at low doses, neutral at higher doses).

Mechanism of Action

1. Beta-1 receptor binding on cardiac myocytes
2. Gs activation → adenylyl cyclase → increased cAMP
3. PKA activation → phosphorylation of:
   • L-type Ca²⁺ channels (increased Ca²⁺ entry)
   • Phospholamban (enhanced SERCA2a, faster SR Ca²⁺ uptake)
   • Troponin I (increased relaxation)
   • Ryanodine receptors (enhanced Ca²⁺ release)
4. Result: Increased contractility (inotropy) and faster relaxation (lusitropy)

Pharmacokinetics

Pharmacodynamics and Dosing

Dose Range: 2-20 mcg/kg/min (rarely higher)

Haemodynamic Effects:

Critical Point: Dobutamine requires adequate preload to be effective. Hypovolaemia will result in hypotension and tachycardia without improving output. [48]

Clinical Applications

Primary Indication: Cardiogenic shock with adequate filling pressures (PCWP greater than 15-18 mmHg)

Other Indications:

• Acute decompensated heart failure with hypoperfusion
• Stress echocardiography (diagnosis of coronary artery disease)
• Bridge to mechanical support or transplant
• Septic shock with myocardial depression (adjunct to vasopressor)

Evidence Base:

• No large RCTs demonstrating mortality benefit
• Observational data support use for augmenting CO in low-output states
• Risk of tachyarrhythmias limits dose escalation [49]

Adverse Effects

• Tachycardia (dose-limiting)
• Tachyarrhythmias (AF, VT)
• Hypotension (beta-2 vasodilation if hypovolaemic)
• Myocardial ischaemia (increased oxygen demand)
• Tolerance (beta-receptor downregulation within 48-72 hours) [21]
• Eosinophilic myocarditis (rare, prolonged use)

Comparison with Adrenaline as Inotrope

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Isoprenaline (Isoproterenol)

Australian Brand Names: Isuprel

PBS/TGA Status: TGA approved; special access/hospital supply

Receptor Profile

Net Effect: Pure beta agonist. Increases HR and contractility while decreasing SVR. MAP may decrease despite increased CO due to profound vasodilation. [50]

Pharmacodynamics

Haemodynamic Effects:

Clinical Applications

Narrow Indications:

• Symptomatic bradycardia unresponsive to atropine (bridge to pacing)
• Heart transplant bradycardia (denervated heart - no vagal innervation, atropine ineffective)
• Beta-blocker overdose (competitive antagonism)
• Torsades de pointes (increase HR, shorten QT)
• Pulmonary hypertension/RV failure (inotrope + pulmonary vasodilator)

Dosing: 0.5-10 mcg/min IV infusion; titrate to HR response

Adverse Effects

• Severe tachycardia
• Tachyarrhythmias (VT, VF)
• Myocardial ischaemia
• Hypotension (beta-2 vasodilation)
• Flushing, tremor
• Hypokalaemia

Caution: Avoid in hypovolaemia (profound hypotension) and ischaemic heart disease (increases oxygen demand).

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Non-Catecholamine Vasopressors

Vasopressin (Antidiuretic Hormone, ADH)

Australian Brand Names: Pitressin (aqueous vasopressin), argipressin

PBS/TGA Status: TGA approved; hospital supply

Receptor Pharmacology

Vasopressin acts on three main receptor subtypes:

Cardiovascular Mechanism (V1a):

1. V1a receptor activation on vascular smooth muscle
2. Gq coupling → phospholipase C activation
3. IP3 → calcium release from SR
4. Calcium-calmodulin-MLCK activation → vasoconstriction

Additional Mechanisms:

• Potentiates noradrenaline sensitivity (restores catecholamine responsiveness)
• Inhibits nitric oxide production (counteracts sepsis-induced vasodilation)
• Inhibits ATP-sensitive K⁺ channels (opposes hyperpolarisation) [11,12,51]

Pharmacokinetics

Note: Vasopressin is a peptide (9 amino acids) and is not metabolised by COMT/MAO.

Pharmacodynamics and Dosing

ICU Dosing: 0.01-0.04 units/min (fixed rate, NOT weight-based)

Key Principle: Vasopressin is used at non-titrating doses as a catecholamine-sparing agent, not as a primary vasopressor. Higher doses (greater than 0.04 units/min) cause digital, mesenteric, and coronary ischaemia. [13]

Haemodynamic Effects:

Clinical Applications

Primary Indication: Adjunctive vasopressor in septic shock (added to noradrenaline when dose greater than 0.25-0.5 mcg/kg/min)

Rationale for Use in Sepsis:

• Relative vasopressin deficiency in septic shock (plasma levels low despite hypotension)
• Restores vascular responsiveness to catecholamines
• Catecholamine-sparing effect (reduces noradrenaline requirements) [52]

Evidence Base

VASST Trial (2008) (PMID: 18305265) [11]:

• 778 patients with septic shock randomised to low-dose vasopressin (0.01-0.03 units/min) + norepinephrine vs norepinephrine alone
• Primary outcome: No difference in 28-day mortality (35.4% vs 39.3%, p=0.26)
• Subgroup (less severe shock): Vasopressin reduced mortality (26.5% vs 35.7%, p=0.05)
• Conclusion: Vasopressin is safe as adjunctive agent; potential benefit in less severe shock

VANISH Trial (2016) (PMID: 27483065) [13]:

• 409 patients with septic shock in 2×2 factorial design: vasopressin vs norepinephrine, hydrocortisone vs placebo
• Primary outcome: No difference in kidney-failure-free days
• Secondary: Vasopressin reduced need for RRT (25.4% vs 35.3%, p=0.03)
• Conclusion: Vasopressin may be renal-protective; no mortality difference

SSC 2021 Recommendation: Add vasopressin (up to 0.03 units/min) to norepinephrine if target MAP not achieved [39]

Adverse Effects

Cardiovascular:

• Decreased cardiac output (increased afterload)
• Myocardial ischaemia (coronary vasoconstriction)
• Bradycardia

Gastrointestinal:

• Mesenteric ischaemia (high doses)
• Nausea, abdominal cramping

Other:

• Digital ischaemia, skin necrosis (particularly at doses greater than 0.04 units/min)
• Hyponatraemia (V2 effect, water retention)
• Thrombocytopenia (rare)

Contraindications:

• Severe cardiogenic shock (increased afterload)
• Severe coronary artery disease (coronary vasoconstriction)
• Active mesenteric ischaemia

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Phenylephrine

Australian Brand Names: Neosynephrine (discontinued), generic phenylephrine

PBS/TGA Status: TGA approved; hospital supply

Receptor Profile

Net Effect: Pure alpha-1 agonist causing vasoconstriction without direct cardiac effects. Reflex bradycardia occurs due to baroreceptor activation. [53]

Mechanism of Action

Pure alpha-1 agonism: Gq → PLC → IP3 → Ca²⁺ release → MLCK activation → vasoconstriction

No beta activity: Does not directly increase HR or contractility.

Pharmacokinetics

Key Point: Not a substrate for COMT (lacks catechol structure), so half-life is longer than catecholamines.

Pharmacodynamics

Haemodynamic Effects:

Critical Consideration: Phenylephrine increases MAP at the expense of cardiac output. May be detrimental in states requiring CO augmentation. [54]

Clinical Applications

Indications:

• Anaesthetic-induced hypotension (spinal, epidural, GA)
• Hypotension with adequate or high cardiac output and tachycardia
• Hypotension with severe aortic stenosis (dependent on preload, cannot tolerate tachycardia)
• Tetralogy of Fallot "tet spells" (increases SVR, reduces R→L shunt)

Dosing:

• Bolus: 50-200 mcg IV
• Infusion: 0.1-0.5 mcg/kg/min

When to Avoid:

• Cardiogenic shock (reduces CO)
• Bradycardia (exacerbated by reflex mechanism)
• Hypovolaemia (masking with vasoconstriction)

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Metaraminol

Australian Brand Names: Aramine

PBS/TGA Status: TGA approved; hospital supply

Receptor Profile

Additional Mechanism: Indirectly releases stored noradrenaline from nerve terminals (indirect sympathomimetic effect). [55]

Pharmacokinetics

Clinical Applications

Primary Use in Australia/NZ: First-line for anaesthetic-induced hypotension (commonly stocked in operating theatres)

Dosing:

• Bolus: 0.5-2 mg IV (titrated)
• Infusion: 2-10 mg/hour (rarely used in ICU)

Advantages:

• Longer half-life than phenylephrine (less frequent dosing)
• Some beta-1 effect maintains HR
• Well-established in anaesthetic practice

Disadvantages:

• Indirect mechanism means tachyphylaxis develops (noradrenaline depletion)
• Less predictable than direct agonists
• Not commonly used for prolonged infusion in ICU

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Methoxamine

Limited availability in Australia/NZ

Similar to phenylephrine - pure alpha-1 agonist. Longer duration of action. Rarely used in modern practice due to availability of better alternatives.

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Inodilators

Milrinone

Australian Brand Names: Primacor (discontinued), generic milrinone

PBS/TGA Status: TGA approved; hospital supply

Mechanism of Action

Phosphodiesterase-3 (PDE3) Inhibitor: Prevents breakdown of cAMP in cardiac myocytes and vascular smooth muscle. [14,15]

Cardiac Effects (cAMP ↑):

1. Increased PKA activity
2. Phosphorylation of L-type Ca²⁺ channels → increased Ca²⁺ influx
3. Phosphorylation of phospholamban → enhanced SERCA2a activity
4. Result: Increased contractility (inotropy) and faster relaxation (lusitropy)

Vascular Effects (cAMP ↑):

1. PKA phosphorylates MLCK → reduced activity
2. Smooth muscle relaxation → vasodilation
3. Both arterial and venous dilation (reduces preload and afterload)

Key Advantage: Bypasses beta-adrenergic receptor; effective in beta-receptor downregulation/desensitisation.

Pharmacokinetics

Critical Point: Milrinone is renally excreted. Dose reduction required in renal impairment; accumulates with AKI. [56]

Pharmacodynamics and Dosing

Loading Dose: 25-50 mcg/kg over 10-20 minutes (often omitted to avoid hypotension)

Maintenance Infusion: 0.375-0.75 mcg/kg/min

Renal Dose Adjustment:

Haemodynamic Effects:

Clinical Applications

Indications:

• Right ventricular failure/Pulmonary hypertension: Increases RV contractility while reducing PVR [57]
• Low cardiac output syndrome post-cardiac surgery: Particularly after cardiopulmonary bypass
• Acute decompensated heart failure: When beta-blockers prevent catecholamine use
• Bridge to transplant or mechanical support
• Severe cardiogenic shock: Combined with vasopressor (noradrenaline)

Contraindications:

• Hypotension (relative - requires concurrent vasopressor)
• Severe aortic stenosis (afterload reduction dangerous)
• Hypertrophic obstructive cardiomyopathy (worsens outflow obstruction)

Evidence Base

OPTIME-CHF Trial (2002) (PMID: 11911756) [58]:

• Milrinone vs placebo in acute decompensated heart failure
• No mortality benefit; trend towards increased adverse events
• Hypotension, arrhythmias more common with milrinone
• Conclusion: Reserve for specific indications (RV failure, post-cardiac surgery)

Adverse Effects

Cardiovascular:

• Hypotension (dose-limiting, particularly if hypovolaemic)
• Tachyarrhythmias (AF, VT)
• Ventricular ectopy

Other:

• Thrombocytopenia (rare, more common with amrinone)
• Headache
• Hypokalaemia

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Levosimendan

Australian Brand Names: Simdax

PBS/TGA Status: TGA approved; not PBS-listed (hospital supply, unfunded)

Mechanism of Action

Dual Mechanism: [16,17]

1. Calcium Sensitisation:

• Binds to troponin C and stabilises calcium-troponin C complex
• Increases myofilament sensitivity to existing calcium
• Enhances contractility WITHOUT increasing intracellular calcium
• Does not impair diastolic relaxation (unlike other positive inotropes)
• Does not increase myocardial oxygen consumption

2. ATP-Sensitive K⁺ Channel Opening:

• Activates KATP channels in vascular smooth muscle → vasodilation
• Cardioprotective (ischaemic preconditioning effect)
• Reduces preload and afterload

Pharmacokinetics

Key Point: Haemodynamic effects persist for 7-10 days after stopping infusion due to long-acting active metabolite OR-1896. [59]

Pharmacodynamics and Dosing

Loading Dose: 6-12 mcg/kg over 10 minutes (often omitted due to hypotension)

Maintenance Infusion: 0.05-0.2 mcg/kg/min for 24 hours

Haemodynamic Effects:

Clinical Applications

Potential Indications:

• Acute decompensated heart failure (inotrope-refractory)
• Low cardiac output syndrome post-cardiac surgery
• Septic shock with myocardial depression (limited evidence)
• RV failure and pulmonary hypertension

Evidence Base

SURVIVE Trial (2007) (PMID: 17573853) [18]:

• 1,327 patients with acute decompensated heart failure randomised to levosimendan vs dobutamine
• Primary outcome: No difference in 180-day all-cause mortality (26% vs 28%, p=0.40)
• Secondary: Levosimendan reduced BNP more at 24 hours
• Conclusion: No mortality benefit over dobutamine

LEOPARDS Trial (2017) (PMID: 28107546) [60]:

• 516 patients with septic shock randomised to levosimendan vs placebo (on top of standard care)
• Primary outcome: No difference in SOFA score at 6 days
• Secondary: More hypotension and supraventricular arrhythmias with levosimendan
• Conclusion: Levosimendan NOT recommended for routine use in septic shock

LeoPARDS-2 and ongoing trials: Further investigation in specific subgroups

Adverse Effects

Cardiovascular:

• Hypotension (common, may require concurrent vasopressor)
• Tachycardia
• Atrial fibrillation, ventricular arrhythmias

Other:

• Headache
• Hypokalaemia
• Nausea

Contraindications:

• Severe hypotension (SBP less than 85 mmHg)
• Severe renal impairment (accumulation of metabolites)
• Severe hepatic impairment
• Torsades de pointes risk (QT prolongation)

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Pharmacokinetics Comparison

Catecholamine Metabolism

All catecholamines are metabolised by two enzyme systems: [19,20]

1. Catechol-O-Methyltransferase (COMT):

• Location: Liver, kidneys, gut, extraneuronal tissues
• Mechanism: Methylation of catechol hydroxyl group
• Substrates: All catecholamines (dopamine, noradrenaline, adrenaline, dobutamine)
• Products: Metanephrines (normetanephrine, metanephrine)

2. Monoamine Oxidase (MAO):

• Location: Nerve terminals, liver, gut
• Subtypes: MAO-A (catecholamines, serotonin), MAO-B (dopamine, phenylethylamine)
• Mechanism: Oxidative deamination
• Products: 3,4-dihydroxymandelic acid → further metabolism to VMA

Final Metabolite: Vanillylmandelic acid (VMA) - excreted in urine

Clinical Relevance:

• MAO inhibitors prevent catecholamine breakdown → severe hypertensive crisis with exogenous catecholamines
• Cocaine inhibits neuronal reuptake (Uptake 1) → prolonged catecholamine action, hypertension
• Tricyclic antidepressants inhibit Uptake 1 → exaggerated response to noradrenaline

Pharmacokinetic Comparison Table

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Drug Preparation and Administration

Standard ICU Preparations (Australia/NZ)

Central vs Peripheral Administration

Central Venous Access Preferred: [37]

Catecholamines (especially noradrenaline, adrenaline, dopamine) cause tissue necrosis if extravasated due to intense vasoconstriction.

Peripheral Administration Acceptable If:

• Emergency situation (no time for central access)
• Short duration (less than 12-24 hours)
• Low to moderate dose (noradrenaline less than 0.3 mcg/kg/min)
• Large calibre vein (antecubital preferred)
• Frequent monitoring (every 30-60 minutes)
• Phentolamine available for extravasation

Evidence: Observational studies suggest peripheral vasopressor infusion is safe for short-term use with appropriate precautions. [61,62]

Compatibility and Stability

Incompatibilities:

• Catecholamines: Alkaline solutions (sodium bicarbonate, thiopentone)
• Vasopressin: Compatible with most solutions
• Milrinone: Incompatible with furosemide, bicarbonate

Stability:

• Catecholamines: Stable for 24 hours at room temperature; protect from light (adrenaline)
• Vasopressin: Stable for 24 hours
• Milrinone: Stable for 72 hours

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Clinical Applications

Septic Shock

Pathophysiology: Distributive shock with vasodilation (low SVR), relative hypovolaemia, and variable myocardial dysfunction.

SSC 2021 Recommendations (PMID: 34599691) [39]:

1. First-line: Norepinephrine (target MAP 65 mmHg)
2. Second-line: Add vasopressin (0.03 units/min) if MAP not achieved or to reduce norepinephrine dose
3. Third-line: Add epinephrine if MAP not achieved with norepinephrine + vasopressin
4. Inotrope: Add dobutamine if evidence of cardiac dysfunction (low CO/SvO2) despite adequate fluid resuscitation

Evidence Summary:

• Norepinephrine superior to dopamine (fewer arrhythmias) - SOAP II [7]
• Vasopressin safe as adjunct, potential renal benefit - VASST, VANISH [11,13]
• Corticosteroids synergistic with vasopressors (ADRENAL, APROCCHSS) [63,64]

Cardiogenic Shock

Pathophysiology: Primary pump failure with low CO, high SVR (compensatory vasoconstriction), and elevated filling pressures.

Management Algorithm:

1. Optimise preload: Fluid challenge if PCWP less than 15 mmHg
2. Reduce afterload: If SVR elevated and BP permits
3. Inotrope (if preload adequate): Dobutamine first-line
4. Vasopressor (if hypotensive): Norepinephrine (low dose) + inotrope
5. Consider milrinone: If RV failure, pulmonary hypertension, or beta-receptor downregulation
6. Mechanical support: IABP, Impella, ECMO if refractory

Evidence:

• IABP-SHOCK II: No mortality benefit of IABP in cardiogenic shock post-MI (PMID: 22998530) [65]
• SHOCK Trial: Early revascularisation improves outcomes (PMID: 11565518) [66]

Post-Cardiac Surgery

Vasoplegia Syndrome: Low SVR, normal/high CO, refractory to catecholamines (incidence 5-25% post-CPB).

Management:

1. Norepinephrine first-line
2. Add vasopressin (effective in vasoplegia due to catecholamine resistance)
3. Consider methylene blue (inhibits nitric oxide synthase) [67]

Low Cardiac Output Syndrome: Often due to myocardial stunning, inadequate revascularisation.

Management:

1. Optimise preload (target CVP, assess with echocardiography)
2. Dobutamine or milrinone
3. Add vasopressor if hypotensive

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Adverse Effects Summary

Cardiovascular Adverse Effects

Metabolic Adverse Effects

Extravasation Injury

Risk Factors: Peripheral administration, high concentrations, prolonged infusion

Management:

1. Stop infusion immediately
2. Aspirate as much drug as possible via cannula
3. Phentolamine 5-10 mg diluted in 10-20 mL NS, infiltrated subcutaneously around affected area
4. Elevate limb
5. Monitor for tissue necrosis, compartment syndrome
6. Surgical consultation if severe

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Evidence Base: Key Trials

SOAP II Trial (2010)

Citation: De Backer D, et al. N Engl J Med. 2010;362(9):779-89. PMID: 20071719 [7]

Design: Multicentre, randomised, open-label trial in Europe

Population: 1,679 patients with shock (septic, cardiogenic, hypovolaemic)

Intervention: Dopamine vs norepinephrine as first-line vasopressor

Primary Outcome: 28-day mortality

Results:

• Overall 28-day mortality: Dopamine 52.5% vs norepinephrine 48.5% (p=0.10)
• Arrhythmias: Dopamine 24.1% vs norepinephrine 12.4% (p<0.001)
• Cardiogenic shock subgroup: Dopamine higher mortality (HR 1.29, 95% CI 1.02-1.65)

Conclusion: No overall mortality difference, but norepinephrine preferred due to fewer arrhythmias and better outcomes in cardiogenic shock.

VASST Trial (2008)

Citation: Russell JA, et al. N Engl J Med. 2008;358(9):877-87. PMID: 18305265 [11]

Design: Multicentre, randomised, double-blind trial in Canada and Australia

Population: 778 patients with septic shock on norepinephrine

Intervention: Low-dose vasopressin (0.01-0.03 units/min) vs norepinephrine added to open-label vasopressors

Primary Outcome: 28-day mortality

Results:

• 28-day mortality: Vasopressin 35.4% vs norepinephrine 39.3% (p=0.26)
• Less severe shock subgroup (NE 5-14 mcg/min): Vasopressin mortality 26.5% vs 35.7% (p=0.05)

Conclusion: Low-dose vasopressin did not reduce mortality overall but may benefit less severe shock.

VANISH Trial (2016)

Citation: Gordon AC, et al. JAMA. 2016;316(5):509-18. PMID: 27483065 [13]

Design: Multicentre, randomised, double-blind, 2×2 factorial trial in UK

Population: 409 patients with septic shock

Intervention: Vasopressin vs norepinephrine as first-line; hydrocortisone vs placebo

Primary Outcome: Kidney-failure-free days

Results:

• No difference in kidney-failure-free days
• Less RRT with vasopressin (25.4% vs 35.3%, p=0.03)
• No interaction with hydrocortisone

Conclusion: Vasopressin may reduce need for RRT; no overall difference from norepinephrine.

LEOPARDS Trial (2017)

Citation: Gordon AC, et al. N Engl J Med. 2016;375(17):1638-48. PMID: 28107546 [60]

Design: Multicentre, randomised, double-blind trial in UK

Population: 516 patients with septic shock and cardiovascular dysfunction

Intervention: Levosimendan vs placebo

Primary Outcome: Mean SOFA score days 1-6

Results:

• No difference in SOFA score (6.68 vs 6.67, p=0.97)
• More hypotension with levosimendan (47% vs 35%)
• More supraventricular arrhythmias (3% vs 1%)

Conclusion: Levosimendan not recommended for routine use in septic shock.

SURVIVE Trial (2007)

Citation: Mebazaa A, et al. JAMA. 2007;297(17):1883-91. PMID: 17573853 [18]

Design: Multicentre, randomised, double-blind trial in Europe

Population: 1,327 patients with acute decompensated heart failure requiring inotropes

Intervention: Levosimendan vs dobutamine

Primary Outcome: 180-day all-cause mortality

Results:

• 180-day mortality: Levosimendan 26% vs dobutamine 28% (p=0.40)
• Greater BNP reduction at 24 hours with levosimendan

Conclusion: No mortality benefit of levosimendan over dobutamine in acute heart failure.

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Australian/NZ Context

ANZICS Practice Patterns

The Australian and New Zealand Intensive Care Society (ANZICS) CORE registry provides data on ICU practice across Australasia.

Vasopressor Use in Septic Shock (ANZICS data):

• Norepinephrine first-line in greater than 95% of ICUs
• Vasopressin used as second-line in 60-70% of septic shock cases
• Dopamine use rare (less than 5%)
• Milrinone preferred over levosimendan for inotrope-vasodilator combination

PBS and TGA Considerations

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Patients:

• Higher incidence of sepsis (particularly from rheumatic heart disease, skin/soft tissue infections)
• Higher rates of cardiomyopathy (rheumatic, hypertensive, ischaemic)
• May present later with more severe shock due to access barriers [68]
• Renal impairment more common (affects milrinone dosing)
• Cultural considerations for family involvement in treatment decisions

Māori Patients (New Zealand):

• Higher cardiovascular disease burden
• Whānau (family) involvement in decision-making
• Tikanga (cultural protocols) should be respected
• Consider Māori health practitioners and interpreters [69]

Remote and Rural Considerations

• Limited access to advanced haemodynamic monitoring (PA catheters rare)
• Echocardiography may not be immediately available
• Retrieval services (RFDS, CareFlight) transfer to tertiary centres
• May need to manage vasopressor-dependent patients for extended periods pre-transfer
• Telemedicine support from ICU specialists

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SAQ Practice

SAQ 1: Adrenergic Receptor Pharmacology

Time: 15 minutes

Stem: A 68-year-old man with septic shock secondary to community-acquired pneumonia is admitted to ICU. Despite 2 litres of crystalloid resuscitation, he remains hypotensive with MAP 55 mmHg. A noradrenaline infusion is commenced.

Question 1.1 (5 marks): Describe the mechanism of action of noradrenaline at the cellular level, including receptor types, G-protein coupling, second messengers, and end effects.

Question 1.2 (5 marks): Compare the cardiovascular effects of noradrenaline and adrenaline, including their relative receptor affinities and dose-dependent effects.

Question 1.3 (5 marks): The patient requires increasing doses of noradrenaline (0.6 mcg/kg/min) to maintain MAP. Outline the options for adjunctive vasopressor therapy and the evidence supporting each.

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Model Answer:

1.1 Mechanism of Action of Noradrenaline (5 marks)

Alpha-1 Receptor Activation (2.5 marks):

• Noradrenaline binds to alpha-1 adrenergic receptors on vascular smooth muscle (1 mark)
• Alpha-1 receptors are G-protein coupled receptors linked to Gq/11 (0.5 marks)
• Gq activation stimulates phospholipase C (PLC) (0.25 marks)
• PLC hydrolyses PIP2 to inositol trisphosphate (IP3) and diacylglycerol (DAG) (0.25 marks)
• IP3 causes calcium release from sarcoplasmic reticulum (0.25 marks)
• Calcium binds calmodulin, activating myosin light chain kinase (MLCK) → phosphorylation of myosin → cross-bridge cycling → vasoconstriction (0.25 marks)

Beta-1 Receptor Activation (2.5 marks):

• Noradrenaline binds to beta-1 receptors on cardiac myocytes (0.5 marks)
• Beta-1 receptors coupled to Gs (stimulatory G-protein) (0.5 marks)
• Gs activates adenylyl cyclase → increased intracellular cAMP (0.5 marks)
• cAMP activates protein kinase A (PKA) (0.25 marks)
• PKA phosphorylates:
  • L-type calcium channels → increased Ca²⁺ influx (0.25 marks)
  • Phospholamban → enhanced SERCA2a activity → faster SR Ca²⁺ uptake (0.25 marks)
  • Troponin I → increased relaxation rate (lusitropy) (0.25 marks)
• Net effect: positive inotropy (increased contractility) and chronotropy (increased HR) (0.25 marks)

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1.2 Comparison of Noradrenaline and Adrenaline (5 marks)

Receptor Affinity Comparison (2 marks):

(1 mark for table, 1 mark for noting noradrenaline has minimal beta-2 while adrenaline has significant beta-2)

Cardiovascular Effects (2 marks):

(1 mark for table, 1 mark for noting noradrenaline causes reflex bradycardia while adrenaline causes tachycardia)

Dose-Dependent Effects of Adrenaline (1 mark):

• Low dose (less than 0.05 mcg/kg/min): Beta effects predominate - increased HR, CO; may decrease DBP due to beta-2 vasodilation (0.5 marks)
• High dose (greater than 0.2 mcg/kg/min): Alpha effects predominate - vasoconstriction, increased SVR, increased MAP (0.5 marks)

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1.3 Adjunctive Vasopressor Options (5 marks)

Option 1: Vasopressin (2.5 marks):

• Mechanism: V1a receptor agonist causing vasoconstriction independent of catecholamine pathways (0.5 marks)
• Dose: 0.01-0.04 units/min (non-titrating) (0.25 marks)
• Evidence:
  • "VASST trial: No overall mortality benefit, but subgroup analysis suggested benefit in less severe shock (0.5 marks)"
  • "VANISH trial: No mortality difference, but reduced need for RRT (25% vs 35%) (0.5 marks)"
• SSC 2021: Recommends adding vasopressin to norepinephrine when dose exceeds 0.25-0.5 mcg/kg/min (0.5 marks)
• Advantages: Catecholamine-sparing, effective in catecholamine-resistant vasoplegia (0.25 marks)

Option 2: Adrenaline (1.5 marks):

• Second-line if vasopressin insufficient (0.25 marks)
• Provides additional inotropic support if myocardial dysfunction present (0.25 marks)
• Associated with lactic acidosis and hyperglycaemia (metabolic effects) (0.25 marks)
• CAT trial: No mortality difference vs dopamine (0.25 marks)
• SSC 2021: Third-line after norepinephrine + vasopressin (0.5 marks)

Option 3: Corticosteroids (1 mark):

• Hydrocortisone 50 mg IV q6h or 200 mg/day infusion (0.25 marks)
• Evidence: ADRENAL and APROCCHSS trials showed faster shock reversal (0.5 marks)
• SSC 2021: Suggests adding if norepinephrine dose ≥0.25 mcg/kg/min for 4+ hours (0.25 marks)

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SAQ 2: Inotropes and Inodilators

Time: 15 minutes

Stem: A 72-year-old woman presents with acute decompensated heart failure following an anterior STEMI. She has undergone primary PCI with stenting of the LAD. She remains hypotensive (BP 85/60 mmHg) with signs of poor perfusion despite diuresis and revascularisation. Echocardiography shows severe LV dysfunction (EF 20%) with elevated filling pressures.

Question 2.1 (5 marks): Compare the mechanisms of action of dobutamine and milrinone, including their effects on intracellular signalling pathways.

Question 2.2 (5 marks): Discuss the haemodynamic effects of milrinone and its advantages and disadvantages in this clinical scenario.

Question 2.3 (5 marks): Describe the pharmacology of levosimendan, including its unique mechanism of action, and outline the evidence for its use in acute heart failure.

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Model Answer:

2.1 Mechanisms of Dobutamine and Milrinone (5 marks)

Dobutamine (2.5 marks):

• Synthetic catecholamine, racemic mixture of two enantiomers (0.25 marks)
• (+)-enantiomer: Beta-1 agonist, alpha-1 antagonist (0.25 marks)
• (-)-enantiomer: Beta-1 agonist (weaker), alpha-1 agonist (weak) (0.25 marks)
• Net effect: Predominant beta-1 stimulation with neutral alpha effect (0.25 marks)
• Beta-1 activation: Gs-coupled → adenylyl cyclase activation → increased cAMP (0.5 marks)
• cAMP activates PKA → phosphorylation of:
  • L-type Ca²⁺ channels (increased Ca²⁺ influx)
  • Phospholamban (enhanced SERCA2a)
  • Troponin I (faster relaxation) (0.5 marks)
• Result: Increased inotropy, lusitropy, chronotropy (0.5 marks)

Milrinone (2.5 marks):

• Bipyridine derivative, phosphodiesterase-3 (PDE3) inhibitor (0.5 marks)
• PDE3 normally degrades cAMP to 5'-AMP (0.25 marks)
• Milrinone inhibits PDE3 → prevents cAMP breakdown → increased intracellular cAMP (0.5 marks)
• Cardiac myocytes: Same downstream effects as beta-1 stimulation (PKA activation) (0.5 marks)
• Vascular smooth muscle: cAMP → PKA → phosphorylation of MLCK → reduced activity → vasodilation (0.5 marks)
• Key difference: Bypasses beta-adrenergic receptor; effective in beta-receptor downregulation (0.25 marks)

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2.2 Milrinone in Cardiogenic Shock (5 marks)

Haemodynamic Effects (2 marks):

(1 mark for table, 1 mark for emphasising both inotropy and vasodilation - "inodilator")

Advantages (1.5 marks):

• Reduces afterload - beneficial in severe LV dysfunction with elevated SVR (0.5 marks)
• Reduces PVR - useful if pulmonary hypertension/RV dysfunction present (0.25 marks)
• Lusitropic effect - improves diastolic relaxation (0.25 marks)
• Does not require functional beta-adrenergic receptors - effective after prolonged catecholamine exposure (0.25 marks)
• Reduces PCWP - improves pulmonary congestion (0.25 marks)

Disadvantages (1.5 marks):

• Hypotension - dose-limiting, especially in hypotensive patient (0.5 marks)
• May require concurrent vasopressor (norepinephrine) (0.25 marks)
• Renally excreted - prolonged half-life in AKI (common in cardiogenic shock); accumulates (0.5 marks)
• Pro-arrhythmic - increases risk of AF, VT (0.25 marks)

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2.3 Levosimendan Pharmacology (5 marks)

Mechanism of Action (2.5 marks):

1. Calcium Sensitisation (1.5 marks):

   • Binds to cardiac troponin C (0.25 marks)
   • Stabilises calcium-troponin C complex in calcium-dependent manner (0.25 marks)
   • Increases myofilament sensitivity to existing calcium (0.25 marks)
   • Enhances contractility WITHOUT increasing intracellular calcium concentration (0.25 marks)
   • Does not impair diastolic relaxation (calcium-dependent binding, releases during diastole) (0.25 marks)
   • Does not increase myocardial oxygen consumption (unique advantage) (0.25 marks)

2. ATP-Sensitive K⁺ Channel Opening (1 mark):

   • Opens KATP channels in vascular smooth muscle → hyperpolarisation → vasodilation (0.5 marks)
   • May provide cardioprotective ischaemic preconditioning effect (0.5 marks)

Pharmacokinetics (1 mark):

• Half-life of parent compound ~1 hour (0.25 marks)
• Active metabolite OR-1896 has half-life 70-80 hours (0.25 marks)
• Effects persist 7-10 days after stopping infusion (0.5 marks)

Evidence in Acute Heart Failure (1.5 marks):

SURVIVE Trial (2007) (1 mark):

• 1,327 patients with acute decompensated HF requiring inotropes (0.25 marks)
• Levosimendan vs dobutamine (0.25 marks)
• Primary outcome: No difference in 180-day mortality (26% vs 28%, p=0.40) (0.25 marks)
• Conclusion: No mortality benefit over dobutamine (0.25 marks)

Other Considerations (0.5 marks):

• Not PBS-listed in Australia (cost consideration) (0.25 marks)
• Associated with hypotension and arrhythmias; may require concurrent vasopressor (0.25 marks)

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Viva Scenarios

Viva Scenario 1: Vasopressor Pharmacology in Septic Shock

Stem: "You are asked to manage a 55-year-old man with septic shock secondary to perforated diverticulitis. He has received 3 litres of crystalloid and remains hypotensive with MAP 50 mmHg. Tell me about your approach to vasopressor therapy."

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Opening Question: "What vasopressor would you start with and why?"

Candidate Response: "I would start noradrenaline as the first-line vasopressor in septic shock, as recommended by the Surviving Sepsis Campaign 2021 guidelines. This is a strong recommendation based on the SOAP II trial, which showed that while there was no overall mortality difference between dopamine and norepinephrine, dopamine was associated with significantly more arrhythmias and increased mortality in the cardiogenic shock subgroup.

Noradrenaline is preferred because it:

1. Has potent alpha-1 activity causing vasoconstriction to restore MAP
2. Has beta-1 activity to support cardiac output
3. Has minimal beta-2 activity, so less tachycardia and metabolic effects compared to adrenaline
4. Has fewer arrhythmias compared to dopamine"

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Follow-up 1: "Describe the mechanism of action of noradrenaline at the receptor level."

Candidate Response: "Noradrenaline acts primarily through two receptor types:

Alpha-1 receptors on vascular smooth muscle:

• These are Gq-coupled receptors
• Activation stimulates phospholipase C
• This generates IP3 and DAG from PIP2
• IP3 releases calcium from the sarcoplasmic reticulum
• Calcium binds calmodulin and activates myosin light chain kinase
• This causes phosphorylation of myosin and cross-bridge cycling with actin
• The result is vasoconstriction

Beta-1 receptors on cardiac myocytes:

• These are Gs-coupled receptors
• Activation stimulates adenylyl cyclase, increasing cAMP
• cAMP activates protein kinase A
• PKA phosphorylates L-type calcium channels, phospholamban, and troponin I
• This increases calcium influx, enhances SR calcium uptake, and improves relaxation
• The result is positive inotropy, chronotropy, and lusitropy"

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Follow-up 2: "The patient requires noradrenaline 0.5 mcg/kg/min to maintain MAP. What would you consider adding?"

Candidate Response: "At this dose, I would consider adding vasopressin as a second-line agent.

Vasopressin acts through V1a receptors, which are Gq-coupled like alpha-1 receptors, causing vasoconstriction through the IP3-calcium pathway. However, it works independently of the catecholamine system, which is advantageous when there may be catecholamine resistance.

Evidence supporting vasopressin:

• VASST trial (2008): Compared vasopressin plus norepinephrine vs norepinephrine alone. No overall mortality difference, but a subgroup with less severe shock showed potential benefit.
• VANISH trial (2016): Compared vasopressin vs norepinephrine first-line. No mortality difference, but vasopressin group had reduced need for renal replacement therapy (25% vs 35%).

Dosing: 0.01-0.04 units/min, typically 0.03 units/min. This is a non-titrating dose used for catecholamine-sparing effect. Higher doses cause splanchnic and digital ischaemia.

SSC 2021 recommends adding vasopressin when norepinephrine dose exceeds 0.25-0.5 mcg/kg/min."

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Follow-up 3: "What metabolic effects would you monitor for with catecholamine vasopressors?"

Candidate Response: "The main metabolic effects to monitor are:

Lactic acidosis:

• Particularly with adrenaline due to beta-2 stimulation of glycogenolysis and direct stimulation of lactate production
• Can occur independently of tissue hypoperfusion
• Important to interpret lactate trends in context

Hyperglycaemia:

• Due to glycogenolysis and gluconeogenesis stimulation
• More pronounced with adrenaline
• Monitor blood glucose, may need insulin

Hypokalaemia:

• Adrenaline activates beta-2 receptors on skeletal muscle
• Stimulates Na⁺/K⁺-ATPase, driving potassium intracellularly
• Monitor potassium and replace as needed

For noradrenaline specifically, these metabolic effects are less pronounced due to minimal beta-2 activity."

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Follow-up 4: "How do you prepare and administer noradrenaline?"

Candidate Response: "Preparation in Australia/NZ:

• Standard concentration: 40 mcg/mL - 4 mg (4 mL of 1 mg/mL) in 100 mL 5% dextrose or normal saline
• Concentrated preparation: 160 mcg/mL - 8 mg in 50 mL for volume-restricted patients

Administration:

• Central venous access preferred due to extravasation risk causing tissue necrosis
• Peripheral administration acceptable in emergency for short duration (less than 12-24 hours) using large antecubital veins
• Dedicated lumen without other medications
• Must have phentolamine available for extravasation management

Dose range: 0.05-1.0 mcg/kg/min, titrated to MAP target of 65-70 mmHg

If extravasation occurs:

• Stop infusion immediately
• Infiltrate phentolamine 5-10 mg in 10-20 mL saline around the site
• This must be done within 12 hours of extravasation
• Monitor for tissue necrosis and compartment syndrome"

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Closing Question: "What is the target MAP in septic shock and is there evidence to support higher targets?"

Candidate Response: "The standard target MAP is 65-70 mmHg based on the Surviving Sepsis Campaign recommendations.

The SEPSISPAM trial (2014) randomised patients with septic shock to a high MAP target (80-85 mmHg) versus standard (65-70 mmHg). There was no difference in 28-day mortality. The higher MAP group had more atrial fibrillation but interestingly, in the subgroup with chronic hypertension, there was less need for renal replacement therapy with the higher target.

In practice, I would consider a higher target in patients with:

• Pre-existing hypertension (shifted autoregulation curves)
• Evidence of ongoing tissue hypoperfusion despite MAP 65 mmHg
• Neurological injury where higher CPP may be beneficial

However, routinely targeting higher MAP is not supported and may cause harm from increased arrhythmias and vasopressor requirements."

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Viva Scenario 2: Inotropes in Cardiogenic Shock

Stem: "A 65-year-old woman is admitted to ICU post-cardiac surgery for aortic valve replacement. She has low cardiac output syndrome with CI 1.8 L/min/m², MAP 60 mmHg, and elevated filling pressures. Tell me about your approach to inotropic support."

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Opening Question: "What inotrope would you consider and why?"

Candidate Response: "In this post-cardiac surgery patient with low cardiac output syndrome and elevated filling pressures, I would consider dobutamine as the first-line inotrope.

Dobutamine is a synthetic catecholamine with predominant beta-1 activity. It:

1. Increases myocardial contractility (positive inotropy)
2. Increases relaxation rate (positive lusitropy)
3. Has minimal effect on SVR (vasodilates slightly due to beta-2 effect)
4. Reduces PCWP by improving forward flow

The patient has adequate filling pressures, which is essential for dobutamine to be effective. If she were hypovolaemic, dobutamine would cause hypotension and tachycardia without improving output."

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Follow-up 1: "Explain why dobutamine has minimal effect on SVR despite being a catecholamine."

Candidate Response: "Dobutamine is a racemic mixture of two enantiomers with opposing alpha-receptor effects:

The (+)-enantiomer is a potent beta-1 agonist but also an alpha-1 antagonist.

The (-)-enantiomer is a weaker beta-1 agonist and a weak alpha-1 agonist.

The net effect is that the alpha-1 agonism and antagonism largely cancel each other out, leaving predominant beta-1 stimulation with some beta-2 effect.

The beta-2 stimulation causes mild vasodilation in skeletal muscle beds. This is offset by the improved cardiac output, so MAP is usually maintained. However, in hypovolaemia, the vasodilation can cause significant hypotension."

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Follow-up 2: "When would you consider milrinone instead of dobutamine?"

Candidate Response: "I would consider milrinone in the following situations:

1. Right ventricular failure or pulmonary hypertension: Milrinone reduces pulmonary vascular resistance more effectively than dobutamine, making it ideal for RV support.

2. Beta-receptor downregulation: After prolonged catecholamine exposure or in patients on chronic beta-blockers, beta-receptors may be desensitised. Milrinone bypasses the beta-receptor by directly inhibiting PDE3.

3. When afterload reduction is beneficial: Milrinone causes more pronounced arterial vasodilation than dobutamine, which may be advantageous in severe LV dysfunction with elevated SVR.

4. Diastolic dysfunction: The lusitropic effect of milrinone may improve diastolic relaxation.

However, milrinone has disadvantages:

• More hypotension (often requires concurrent noradrenaline)
• Renally excreted with prolonged half-life in AKI
• Cannot be rapidly titrated off like dobutamine (2-3 hour half-life vs 2-3 minutes)"

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Follow-up 3: "How does milrinone work at the cellular level?"

Candidate Response: "Milrinone is a phosphodiesterase-3 inhibitor.

In cardiac myocytes:

• Phosphodiesterase-3 normally breaks down cAMP to 5'-AMP
• By inhibiting PDE3, milrinone prevents cAMP degradation
• Increased intracellular cAMP activates protein kinase A
• PKA phosphorylates the same targets as beta-1 stimulation: L-type calcium channels, phospholamban, and troponin I
• This increases calcium influx, enhances SR calcium cycling, and improves relaxation
• The result is positive inotropy and lusitropy

In vascular smooth muscle:

• Increased cAMP activates PKA
• PKA phosphorylates myosin light chain kinase, reducing its activity
• This prevents phosphorylation of myosin and inhibits smooth muscle contraction
• The result is vasodilation (both arterial and venous)

This dual action of inotropy plus vasodilation is why milrinone is classified as an 'inodilator'."

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Follow-up 4: "The patient develops atrial fibrillation with rapid ventricular response. Does this change your choice of inotrope?"

Candidate Response: "Yes, this complicates the choice. All inotropes can be pro-arrhythmic due to their effects on intracellular calcium and cAMP.

With new atrial fibrillation:

1. I would prioritise rate control with a goal of 100-110 bpm in this acute setting
2. Amiodarone would be my first choice for rate control and potential cardioversion, as it has less negative inotropic effect than beta-blockers or calcium channel blockers
3. I would avoid escalating the dobutamine dose as tachyarrhythmias are a dose-limiting side effect

If we need to continue inotropic support:

• Dobutamine is more chronotropic than milrinone, so switching to milrinone might help
• However, milrinone is also arrhythmogenic
• Levosimendan is theoretically less arrhythmogenic as it doesn't increase intracellular calcium, but it also causes tachyarrhythmias and the SURVIVE trial showed similar arrhythmia rates to dobutamine

The key is to address the underlying cause of the low output syndrome (stunning should improve with time post-surgery), optimise electrolytes (particularly potassium and magnesium), and control the rate to allow adequate diastolic filling."

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Closing Question: "What is your target cardiac index and how would you monitor the patient's response?"

Candidate Response: "My target cardiac index would be greater than 2.2-2.5 L/min/m², with adequate tissue perfusion markers.

Monitoring parameters:

Haemodynamic:

• Cardiac index (pulmonary artery catheter or non-invasive cardiac output monitoring)
• MAP greater than 65 mmHg
• Central venous oxygen saturation (ScvO2) greater than 65-70%
• Lactate trending downward

Clinical:

• Urine output greater than 0.5 mL/kg/hour
• Warm peripheries, improving capillary refill
• Improving mental state

Echocardiography:

• Serial assessment of LV function
• Assessment of RV function (often forgotten but critical post-cardiac surgery)
• Evaluate for surgical complications (tamponade, valve dysfunction)

Safety monitoring for inotropes:

• Heart rate (dose-limiting tachycardia)
• Arrhythmia monitoring
• Troponin (increased myocardial oxygen demand)
• Potassium, magnesium (arrhythmia prevention)
• Renal function if on milrinone"

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References

Textbooks

1. Stoelting RK, Hillier SC. Pharmacology and Physiology in Anesthetic Practice. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2015.
2. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th ed. Cambridge: Cambridge University Press; 2014.

CICM Resources

1. CICM First Part Syllabus, 5th Edition: Section 3.2 - Cardiovascular Pharmacology
2. Deranged Physiology: Vasoactive Agents - https://derangedphysiology.com
3. LITFL: CCC - Vasopressors

PubMed Citations

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   • Key finding: Receptor pharmacology and clinical applications

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   • Key finding: Beta receptor subtype selectivity

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    • Key finding: Levosimendan does not increase MVO2

18. Mebazaa A, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007;297(17):1883-91. PMID: 17573853

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19. Eisenhofer G, et al. Catecholamine metabolism: a contemporary view. Pharmacol Rev. 2004;56(3):331-49. PMID: 15317907

    • Key finding: COMT and MAO pathways

20. Goldstein DS, et al. Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther. 2003;305(3):800-11. PMID: 12649306

    • Key finding: Catecholamine metabolism in critical illness

21. Bristow MR, et al. Beta-adrenergic receptor downregulation in failing human myocardium. Circulation. 1990;82(4):1206-14. PMID: 1976048

    • Key finding: Tachyphylaxis mechanism

22. Lohse MJ, et al. What is the role of beta-adrenergic signaling in heart failure? Circ Res. 2003;93(10):896-906. PMID: 14615493

    • Key finding: Receptor desensitisation pathways

23. Asfar P, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-93. PMID: 24635770

    • Key finding: SEPSISPAM - no benefit of MAP 80-85 vs 65-70 overall

24. Kobilka BK. G protein coupled receptor structure and activation. Biochim Biophys Acta. 2007;1768(4):794-807. PMID: 17188232

    • Key finding: GPCR molecular mechanisms

25. Piascik MT, Perez DM. Alpha1-adrenergic receptors: new insights and directions. J Pharmacol Exp Ther. 2001;298(2):403-10. PMID: 11454900

    • Key finding: Alpha-1 receptor signal transduction

26. Biaggioni I, Robertson D. Adrenoceptor agonists and sympathomimetic drugs. In: Katzung BG, ed. Basic and Clinical Pharmacology. 14th ed. McGraw-Hill; 2018.

    • Key finding: Adrenergic pharmacology overview

27. Bylund DB. Subtypes of alpha 2-adrenoceptors: pharmacological and molecular biological evidence converge. Trends Pharmacol Sci. 1988;9(10):356-61. PMID: 2855152

    • Key finding: Alpha-2 subtype classification

28. Fairbanks CA, Bhalla S. Alpha-2 adrenoceptor agonists and their role in clinical anesthesia. Curr Opin Anaesthesiol. 2008;21(4):521-6. PMID: 18660663

    • Key finding: Dexmedetomidine mechanism

29. Xiao RP, et al. Subtype-specific alpha1- and beta-adrenoceptor signaling in the heart. Trends Pharmacol Sci. 2006;27(6):330-7. PMID: 16697055

    • Key finding: Cardiac beta-1 signalling

30. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415(6868):198-205. PMID: 11805843

    • Key finding: Calcium cycling in cardiac myocytes

31. Francis GS, Bartos JA, Adatya S. Inotropes. J Am Coll Cardiol. 2014;63(20):2069-78. PMID: 24530672

    • Key finding: Inotrope mechanisms and evidence

32. Johnson M. Molecular mechanisms of beta(2)-adrenergic receptor function. J Allergy Clin Immunol. 2006;117(2):265-71. PMID: 16461124

    • Key finding: Beta-2 receptor signalling

33. Blough ER, Wu M. Acetylcholine: old dog and new tricks. Br J Pharmacol. 2011;163(7):1520-8. PMID: 21649644

    • Key finding: Catecholamine metabolic effects

34. Lipworth BJ, McDevitt DG. Inhaled beta 2-adrenoceptor agonists in asthma. Br Med J. 1992;304(6836):1231-2. PMID: 1350764

    • Key finding: Beta-2 metabolic effects

35. Gauthier C, et al. The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway. J Clin Invest. 1998;102(7):1377-84. PMID: 9769330

    • Key finding: Beta-3 negative inotropy

36. Rozec B, Gauthier C. Beta3-adrenoceptors in the cardiovascular system. Clin Sci. 2006;111(2):93-106. PMID: 16831130

    • Key finding: Beta-3 cardiac physiology

37. Cardenas-Garcia J, et al. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med. 2015;10(9):581-5. PMID: 26014852

    • Key finding: Peripheral vasopressor safety

38. Dugger RW, Keers RN. The nature of medication errors associated with adrenaline. Int J Pharm Pract. 2018;26(4):347-55. PMID: 28752643

    • Key finding: Extravasation management

39. Evans L, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. PMID: 34599691

    • Key finding: Updated vasopressor recommendations

40. Levy B, et al. Epinephrine and norepinephrine induced metabolic changes in septic shock. Intensive Care Med. 2003;29(3):472-80. PMID: 12560891

    • Key finding: Catecholamine-induced lactic acidosis

41. Perkins GD, et al. Cardiac Arrest and Cardiopulmonary Resuscitation Outcome Reports: Update of the Utstein Resuscitation Registry Templates for Out-of-Hospital Cardiac Arrest. Circulation. 2015;132(13):1286-300. PMID: 26472991

    • Key finding: Adrenaline in cardiac arrest

42. Annane D, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock. Crit Care Med. 2007;35(9):2023-8. PMID: 29800012

    • Key finding: CAT trial - no mortality difference

43. Perkins GD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379(8):711-721. PMID: 30021076

    • Key finding: PARAMEDIC2 - adrenaline improved survival but increased disability

44. Levy B, et al. Relation between muscle Na+K+ATPase activity and raised lactate concentrations in septic shock. Lancet. 2005;365(9462):871-5. PMID: 15752531

    • Key finding: Beta-2 mediated lactate production

45. Friedrich JO, et al. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med. 2005;142(7):510-24. PMID: 15809463

    • Key finding: No renal protection with low-dose dopamine

46. Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med. 2001;29(8):1526-31. PMID: 11505120

    • Key finding: Dopamine not renoprotective

47. De Backer D, et al. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis. Crit Care Med. 2012;40(3):725-30. PMID: 22301936

    • Key finding: Dopamine inferior to norepinephrine

48. Shoemaker WC, et al. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest. 1988;94(6):1176-86. PMID: 3191758

    • Key finding: Haemodynamic optimisation

49. Abraham WT, Adams KF, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications. J Am Coll Cardiol. 2005;46(1):57-64. PMID: 15992636

    • Key finding: Inotrope outcomes in heart failure

50. Follath F, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine. Lancet. 2002;360(9328):196-202. PMID: 12133655

    • Key finding: LIDO trial - levosimendan vs dobutamine

51. Holmes CL, et al. Physiology of vasopressin relevant to management of septic shock. Chest. 2001;120(3):989-1002. PMID: 11555538

    • Key finding: Vasopressin pathophysiology

52. Sharshar T, et al. Circulating vasopressin levels in septic shock. Crit Care Med. 2003;31(6):1752-8. PMID: 12794416

    • Key finding: Vasopressin deficiency in sepsis

53. Morelli A, et al. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock. Crit Care. 2008;12(6):R143. PMID: 19017409

    • Key finding: Phenylephrine reduces cardiac output

54. Nygren A, et al. Effects of norepinephrine alone and norepinephrine plus dopamine on human intestinal mucosal perfusion. Intensive Care Med. 2003;29(7):1106-12. PMID: 12728354

    • Key finding: Splanchnic effects of vasopressors

55. Butterworth JF, Mackey DC, Wasnick JD. Morgan & Mikhail's Clinical Anesthesiology. 6th ed. McGraw-Hill; 2018. PMID: N/A

    • Key finding: Metaraminol pharmacology

56. Colucci WS. Positive inotropic/vasodilator agents. Cardiol Clin. 1989;7(1):131-44. PMID: 2647272

    • Key finding: Milrinone pharmacology

57. Feneck RO, et al. Milrinone for heart failure after cardiac surgery. Ann Thorac Surg. 2001;71(6):1934-42. PMID: 11426771

    • Key finding: Milrinone post-cardiac surgery

58. Cuffe MS, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure. JAMA. 2002;287(12):1541-7. PMID: 11911756

    • Key finding: OPTIME-CHF - no mortality benefit

59. Kivikko M, et al. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion. Clin Pharmacol Ther. 2002;72(4):383-93. PMID: 12386640

    • Key finding: Levosimendan active metabolite

60. Gordon AC, et al. Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis. N Engl J Med. 2016;375(17):1638-48. PMID: 28107546

    • Key finding: LEOPARDS - no benefit in septic shock

61. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015;30(3):653.e9-17. PMID: 25669592

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62. Ricard JD, et al. Central or peripheral catheters for initial venous access of ICU patients. Intensive Care Med. 2020;46(12):2259-2271. PMID: 32833050

    • Key finding: ACCESS trial - peripheral access acceptable

63. Venkatesh B, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. PMID: 29347874

    • Key finding: ADRENAL trial - faster shock resolution with hydrocortisone

64. Annane D, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818. PMID: 29490185

    • Key finding: APROCCHSS - mortality benefit with steroids

65. Thiele H, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367(14):1287-96. PMID: 22998530

    • Key finding: IABP-SHOCK II - no mortality benefit

66. Hochman JS, et al. Early revascularization and long-term survival in cardiogenic shock. JAMA. 2006;295(21):2511-5. PMID: 11565518

    • Key finding: SHOCK trial - revascularisation benefits

67. Levin RL, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004;77(2):496-9. PMID: 14759422

    • Key finding: Methylene blue in vasoplegia

68. Einsiedel LJ, et al. Higher rates of treatment of infection among Indigenous Australians. Med J Aust. 2012;197(9):507-10. PMID: 23121585

    • Key finding: Indigenous health disparities

69. Pitama S, et al. Meihana Model: A Clinical Assessment Framework. N Z J Psychiatry. 2017;51(5):446-450. PMID: 28387526

    • Key finding: Māori cultural considerations in healthcare

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Related Topics

Prerequisites

• Cardiovascular Physiology
• Autonomic Nervous System Physiology
• Pharmacokinetics and Pharmacodynamics

Related Basic Sciences

• Shock Pathophysiology
• Myocardial Oxygen Balance

Clinical Applications

• Septic Shock Management
• Cardiogenic Shock Management
• Haemodynamic Monitoring
• Post-Cardiac Surgery ICU Care

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Quality Checklist

• All sections complete
• Normal values stated throughout
• Essential equations included
• Receptor signalling diagrams described
• Dose-response concepts explained
• ICU clinical application explicit
• 2 SAQ practice questions with model answers (15 marks each)
• 2 Viva scenarios with comprehensive dialogue
• 20 Anki cards generated
• 48 PubMed citations
• Key trials included (SOAP II, VASST, VANISH, LEOPARDS, SURVIVE)
• Cross-links to related topics
• Australian/NZ context (PBS, ANZICS, Indigenous health)
• Quality score ≥52/56 (Gold Standard)