Inotropes and vasopressors

Norepinephrine:

Receptors; α1 + α2 + mild β1

Effect: 

• SVR ↑↑ (powerful vasoconstrictor) 

• BP ↑ 

• CO slightly ↑

Indication: 

• First-line in septic shock (survival benefit)

• Restore MAP without tachycardia (good in tachyarrhythmia patients)

• Distributive shock (anaphylaxis after epi, neurogenic)

• Vasoplegia post-CPB

Contraindications:

• Cardiogenic shock with low EF (may ↑ afterload too much)

• Mesenteric ischemia risk

Dilution/rate

• 4 mg in 50 mL (0.08 mg/mL) or 16 mg in 50 mL (0.32 mg/mL, ICU conc)

• Start 0.02–0.1 μg/kg/min → titrate

Lactate after NE infusion:

• High lactate = shock is getting worse. However, after starting norepinephrine, a rise in lactate in the first 1–3 hours is often a GOOD sign.

• Before norepinephrine: Global hypoperfusion

  • • • Cardiac output is shunted to the heart and brain only, & Skin, muscle, and gut = ischemic --> the lactate in shock initially is from anaerobic metabolism + impaired clearance. However, the rate of production is still very low because tissues are dying and NOT metabolically active.

• After NE infusion

  • • • Norepi restores MAP and re-perfuses muscle and splanchnic beds --> Tissues start using glucose again --> Glycolysis kicks back to life → pyruvate production increases --> Mitochondria are still not fully recovered → more pyruvate converts to lactate

      • So lactate increases because metabolism is restarting, not because shock is worse.

      • More perfusion = more metabolism = more pyruvate = more lactate (temporarily). And lactate clears once mitochondria recover

• Timeline after starting NE

  • • • • 0-3 hours: Lactate ↑ (Perfusion returning, mitochondria still weak)

        • 3–12 hours: Lactate plateau (meaning improving)

        • 12 - 24 hours: Lactate ↓ (good prognosis)

• Clinical point: Patients whose lactate does NOT rise after norepinephrine actually do worse. Because:

  • • • • They may remain hypoperfused (no metabolic restart)

        • Lactate production machinery (glycolysis) is failing

        • The prognosis is worse

• Adrenaline also raises lactate, but for a metabolic reason, not perfusion alone: β₂ stimulation → ↑ glycolysis → ↑ pyruvate → ↑ lactate

• Lactate Trends After Norepinephrine: Early rise means perfusion is improving, cells are waking up and producing pyruvate again. But rising lactate despite good MAP after 6–12 hours is bad lactate.

Epinephrine:

Receptors; 

• Low dose  → β (inotropy + chronotropy)

• High dose → α (vasoconstriction)

Effect: 

• It behaves like an inotrope at low doses (0.01–0.05 µg/kg/min): β1 + β2  (↑ HR, ↑ contractility, bronchodilation, vasodilation)

• It acts as a vasopressor at high doses (>0.1 µg/kg/min): α1 (Vasoconstriction → ↑ SVR → ↑ BP)

Indication: 

1. Anaphylaxis (first line)

2. Cardiac arrest (ACLS)

3. Refractory septic shock (second line)

4. Cardiogenic shock with bradycardia

Contraindications:

• Severe tachyarrhythmias: Because β1 stimulaiton → risk of VF / VT

• Digoxin toxicity: It's a pro-arrhythmic condition

• LVOT obstruction (HOCM): ↑ contractility worsens LVOT obstruction

• Uncontrolled hyperthyroidism: Exaggerated response

Dilution/rate

• 4 mg in 50 mL (0.08 mg/mL) standard ICU

• Start 0.02–0.1 μg/kg/min, titrate

Clinical points:

• • Increases lactate because of β2 glycolysis — not always shock worsening

  • Lactate rises on epinephrine even if perfusion is good because β2 stimulation→ glycolysis --> generates lactate

  • Use in anaphylaxis BEFORE fluids if airway collapse suspicion: to prevent refractory shock

  • If BP drops on low-dose epi → increase dose (switch to α effect): β → α transition

  • Best drug for asthma peri-arrest: because it provides Bronchodilation + stabilises airway oedema

  • Epinephrine = β at low dose, α at high dose.

  • First-line for anaphylaxis — IM, not IV.

  • Raises lactate, not always due to shock — β2 metabolic effect.

  • Great for bradycardic shock, bad for tachyarrhythmias.

Dobutamine:

Receptors: β1 (++), β2 (+)

Effect: 

• CO ↑↑ 

• SVR ↓ 

• HR ↑

Indications

• Cardiogenic shock with high SVR

• Acute heart failure with low output

• Bradycardic heart failure when pacing is unavailable

Contraindications

• Hypotension without vasopressors (needs NE support)

• Septic shock without cardiac dysfunction

Dilution/rate

• 250 mg in 50 mL (5 mg/mL)

• Start 2.5–10 μg/kg/min, titrate slowly; arrhythmias are dose-dependent.

Clinical points

• If BP drops on dobutamine → add norepinephrine, don’t stop dobutamine

• Improves pulmonary oedema by increasing LV forward flow

• In recent years, the practice for Cardiogenic Shock (CS) has shifted such that Norepinephrine is increasingly recommended as the first-line vasoactive agent rather than Dopamine or even Dobutamine in many scenarios; The SOAP‑II trial. The recommended strategy is 

  • • • First: start norepinephrine to achieve an adequate MAP (>65)

      • Then: add dobutamine if hypoperfusion persists due to low contractility

Typical bedside markers prompting dobutamine addition

• • • • • • • • 1. Cold extremities, low urine output despite MAP >65

                2. Echo: low EF / low LV contractility

                3. High lactate despite restored BP

Dopamine:

Receptors: dose-dependent

• Low 1–3 μg/kg/min → dopaminergic (renal)

• Medium 3–10 → β1 (inotropy)

• High >10 → α1 (vasoconstriction)

Indications

• Almost obsolete

• Only niche: bradycardic shock if pacing/epi unavailable

Contraindications

• AF / tachyarrhythmias

• Cardiogenic shock with high filling pressures

• Never for “renal dose dopamine” — harmful

Clinical points

• Higher arrhythmia risk than any other catecholamine

• Higher mortality vs norepinephrine in septic shock (SOAP II trial)

Vasopressin:

Receptor: 

• V1 (vascular smooth muscle), 

• V2 (renal water retention)

Effect: 

• Intense vasoconstriction independent of pH + adrenergic receptors

Indications

• Septic shock after NE 0.2–0.3 μg/kg/min

• Vasoplegia post-cardiac surgery

• ACE-i induced refractory shock

• Anaphylaxis resistant to epinephrine

Contraindications

• Coronary or mesenteric ischemia (pure vasoconstrictor)

Dose

• Not weight-based

• 0.01–0.04 units/min (fixed rate)

Clinical points:

• Never give bolus → cardiac arrest

• Works even in severe acidosis & beta-blocker therapy

Pressor choice: (Shock type and best choice)

1. 1. Septic: Norepi → add Vasopressin → Epi

   2. Cardiogenic (cold, high SVR): Dobutamine ± Norepi

   3. Cardiogenic (warm, vasodilated): Norepi + Dobutamine

   4. Anaphylaxis: Epinephrine

   5. Neurogenic: Norepinephrine

   6. Bradycardic shock: Epi / Dopamine

   7. Acidosis, β-blocker on board: Vasopressin

Clinical pearls:

• • Norepinephrine is the MAP-restoring agent, dobutamine is the CO-restoring agent

  • If dobutamine drops BP → add norepi, don’t stop dobutamine

  • Rising lactate on adrenaline can mean good perfusion

  • Never use dopamine for kidneys — it kills kidneys

  • Vasopressin NEVER bolus

  • Vasopressin is an add-on, not a starter

  • Never use dopamine for kidneys.

  • Never treat all shock with fluids.

  • In shock + severe acidosis (pH < 7.1) → vasopressin works when catecholamines fail

  • Don’t run pressors through peripheral lines if >4 hours → necrosis risk

  • In cardiogenic shock with hypotension, dobutamine is not first-line. Norepinephrine → stabilise MAP → then add dobutamine only to fix poor pump function.

  • Central line preferred after 4 hours 

  • Dobutamine often needs NE support to maintain BP

Shock:

Treat shock by restoring FLOW — not just by raising blood pressure (MAP is not FLOW). If you look at MAP only → you will kill the patient. If you look at FLOW and organ perfusion → you save them. 

A patient can have: good BP + bad perfusion,  or stable MAP + dying organs => This is why targeting MAP alone is not enough. Resuscitation should target macro + micro perfusion

Shock = poor perfusion + cellular hypoxia

Septic shock = vasoplegia + often cardiomyopathy.

Warm shock: high cardiac output, low SVR (vasodilation), with warm extremities. bounding pulse, wide pulse pressure, typically represents a hyperdynamic, distributive state early in septic shock; 

Cold shock: describes CO is low, and SVR is high (vasoconstricted) -> peripheral perfusion is poor: extremities become cold. It is often considered a later, decompensated phase in sepsis

Fix the FLOW using 4 levers.

1. 1. • • 1. 1. 1. • Preload --> fluids

                   • Afterload (SVR) --> Pressors

                   • Contractility --> Inotropes

                   • Oxygen extration --> Oxygen (hypoxemia)/Hb (transfusion)/Acid-base

Fluids increase preload; pressors increase afterload; inotropes increase contractility; oxygen/Hb improve DO₂; acid–base fixes drug responsiveness

Any shock is fixed by targeting the failing component — not treating all components blindly.

Perfusion Markers

Treat shock based on perfusion markers — not BP alone. If BP is okay but perfusion markers are worsening, → patient is in shock. If BP is low but perfusion markers are improving → you’re winning the resuscitation.

Macro markers (Large-scale hemodynamics:)

1. MAP

2. CO index

3. Stroke volume/ SVV

4. SVR

5. Echo IVC / LVOT VTI

Micro markers (Actual delivery of oxygen to tissues and cells)

1. CRT

2. Skin temp

3. Urine output

4. Lactate

Macro markers show flow into the body.

Micro markers show flow into cells.

Monitor (without compromise)

1. MAP (target ≥65)

2. CRT (capillary refill)

3. Skin temp: warm vs cold

4. Urine output

5. Lactate

Shock approach:

• 1. Identify shock type 

     • • Cold? Warm? Bradycardic? Hypoxic? Anaphylaxis? (ABC assessment)

       • First, divide into fluid-responsive vs fluid-unresponsive shock

  2. Give fluids only if volume loss is suspected

     • • Sepsis? 20–30 mL/kg once

       • Cardiogenic shock? Fluids worsen → avoid

  3.  Choose pressor:

     • • Septic shock → Norepinephrine

       • If NE > 0.3 μg/kg/min → ADD Vasopressin

       • If CO low → ADD Dobutamine

       • Cardiogenic shock

         • • • Low output & high SVR → Dobutamine ± NE

             • Low output & vasodilated → NE + Dobutamine

• Anaphylaxis → IM Epinephrine → IV infusion if shock

• Neurogenic shock → Norepinephrine

• Bradycardic shock → Epinephrine or Dopamine

4. Reassess every 15 minutes

• 1. MAP > 65?  (In septic shock, diastolic pressure collapses early, so MAP falls before systolic does)

  2. Urine > 0.5 mL/kg/hr?

  3. Lactate falling after 6–12 h?

Early norepinephrine saves lives. Because giving repeated fluid boluses and waiting for BP to “crash” causes:

• Dilutional acidosis

• Pulmonary edema

• Worsening shock

Fluid-responsive shocks and fluid-unresponsive shocks;

A patient is fluid responsive if: A fluid bolus would increase stroke volume / cardiac output by ≥ 10–15%

If not → don’t give more fluid → start vasopressors or inotropes.

Fluid-responsive shocks:

1. Hypovolemia

2. Sepsis early phase

3. Pancreatitis

4. Burns (first 24h)

5. Massive GI loss

6. Trauma (before haemorrhage control)

Fluid-unresponsive shocks:

7. Cardiogenic

8. Obstructive

9. Late sepsis (vasoplegia)

10. Pulmonary hypertension crisis

11. End-stage heart failure

Shock management;

1. First line fluid if the patient is likely fluid-responsive; use balanced crystalloids. Not NS. 

Choice 1 — Plasma-Lyte (best), Choice 2 — Ringer’s Lactate (excellent)

Dose:

1. 1. • • 30 ml/kg in septic shock

        • 10–20 ml/kg in hypovolemia

        • 250–500 ml aliquots with reassessment in CHF/CKD

Stop giving fluids when any of these appear:

• MAP ≥ 65

• POCUS shows full IVC

• Rising lactate clears / cap refill improves

• Pulmonary oedema / B-lines on lung US

• Right ventricular strain

1. If still hypotensive after adequate fluids, go to vasopressors, not more fluids.

First choice: Norepinephrine; starts even through a peripheral line if needed.

Add:

2. 1. • Vasopressin if NE dose ≥ 0.3 μg/kg/min

      • Epinephrine if still hypotensive, or bradycardic vasoplegia

When to consider colloids (Albumin 5%)

• Not first line — but indicated in these situations:

• Hypotension persists after fluids + pressor

• Severe hypoalbuminemia (<2.5) + edema + hypotension

• Cirrhosis with shock

• Nephrotic syndrome with shock

• Do not use HES colloids in ICU — AKI + mortality risk

Perfusion Endpoints in Shock Resuscitation:

• Mental status improving

• UO > 0.5–1 mL/kg/hr

• Cap refill < 3 sec

• Warm extremities OR improving temperature gradient

• Lactate falling / clearance ≥ 20% every 2 hrs

In endpoints of shock resuscitation, MAP (>65) is not included: Patients don’t die because MAP was low — they die because tissues didn’t get oxygen. That’s why shock resuscitation emphasises micro-perfusion markers, not just macro numbers. Examples that prove it:

• MAP 80 but lactate rising → dying tissues

• MAP 70 but UO zero → kidneys starved

• MAP 75 + cold extremities + confused → poor perfusion

• MAP 90 on high-dose norad + no lactate clearance → catecholamine-induced false stability

That is called “numerical success, biological failure.

• MAP 62, but warm extremities, mental status clear, UO good, lactate falling → patient recovering

(This is the basis of permissive hypotension during haemorrhage and septic shock de-escalation).

So MAP is the starting target, & Micro-perfusion is the ending target.

• Macro success without micro success = patient dies.

• Micro success even before macro perfection = patient survives.

• MAP 65 = survival threshold

• Perfusion micro markers = survival outcome

Shock cannot be reversed without addressing oxygen debt.

High lactate = oxygen debt until proven otherwise

Rising urine output = best early sign of adequate perfusion.

Falling lactate = the strongest biochemical sign of shock reversal.

Oxygen & Hb decide how much oxygen the tissues receive.

Acid–base decides how well vasopressors and inotropes work.

Shock cannot be reversed without addressing oxygen debt.

A patient can die with a MAP of 80 if DO₂ is low.

A patient can die with NE 1.5 if pH is low.

High lactate = oxygen debt until proven otherwise

Rising urine output = the best early sign of adequate perfusion.

Falling lactate = the strongest biochemical sign of shock reversal.

Summary;

When do we resuscitate: (to restore circulation and organ perfusion fast)

• MAP < 65 (Not systolic BP. Systolic can mislead because it fluctuates; MAP reflects organ perfusion. If SBP seems okay, ≥90 but MAP <65, start norepinephrine. Delaying means ongoing organ ischemia. In sepsis->  Fluids + vasopressor go together, not “fluids first then pressor

• Shock (tachy, cool peripheries, low urine)

• Altered mental status due to perfusion failure

• High lactate

• CRT > 3s

Approach:

• Shock recognised ➜ Give 500 ml balanced crystalloid (PL/RL)

• Improves? ➜ Continue until targets met.

• No? ➜ Start norepinephrine.

• If persistent hypotension on NE 0.3 ➜ Add vasopressin.

• If albumin <2.5 OR oedema + hypotension ➜ Give albumin 5%.

• If bleeding ➜ Stop crystalloids ➜ Blood products.

• If cardiogenic ➜ Stop fluids ➜ Add dobutamine + NE.

Don'ts:

•  Do not give NS as routine resuscitation (hyperchloremic AKI)

• Do not keep giving fluids after the patient stops being fluid-responsive (fluid-refractory shock)

• Do not delay vasopressors waiting for “more fluids”

•  Do not use HES colloids

• Do not give RL in the same line simultaneously with citrate blood transfusion