Milrinone

Milrinone, one of the most important inodilators for cardiac anaesthesia and ICU. 

Milrinone is a phosphodiesterase-III inhibitor that increases cAMP → inotropy + lusitropy + vasodilation (“inodilator”). 

It’s β-independent, useful post-CPB or in β-blocked hearts, but causes hypotension and arrhythmia, prolonged in renal failure.

Load **50 mcg/kg over 10 min**, infuse **0.25–0.75 mcg/kg/min** (reduce if renal impairment). Combine with **norepinephrine** when needed to maintain MAP.

---

# 1) Receptor-level action → clinical effects

**Primary mechanism:**

* **Selective phosphodiesterase-III (PDE-3) inhibitor** → prevents breakdown of cyclic AMP (cAMP) in **cardiac myocytes** and **vascular smooth muscle**.

**Resulting downstream effects:**

* ↑ **cAMP** → ↑ intracellular **Ca²⁺** availability in myocardium → **positive inotropy**.

* ↑ cAMP in vascular smooth muscle → ↓ intracellular Ca²⁺ → **vasodilation** (both systemic & pulmonary).

* Also enhances **lusitropy** (myocardial relaxation) → improves diastolic filling.

**Net clinical effects:**

* ↑ cardiac contractility and stroke volume (inotropy).

* ↓ preload and afterload (inodilator).

* ↓ pulmonary artery pressure & PVR (helpful in RV failure, post-CPB, pulmonary hypertension).

* **No direct chronotropic or β-receptor stimulation** → safe in β-blocked patients.

* Can cause **hypotension** if preload low.

---

# 2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)

**Vials:** 10 mg/10 mL (1 mg/mL).

**Typical infusion preparation:**

* Dilute **10 mg in 100 mL** (0.1 mg/mL).

**Pharmacokinetics:**

* **Onset:** 5–15 min (after bolus).

* **Peak:** ~10 min.

* **Duration:** 2–4 h after stopping (depends on renal function).

* **Elimination:** **renal (unchanged drug)**.

* **Half-life:** 2.3 h (normal renal function), **up to 10 h** if renal failure.

**Disadvantages:**

* **Hypotension** from vasodilation (especially if preload inadequate).

* **Arrhythmia risk** (ventricular > atrial, though less than adrenaline/dobutamine).

* **Prolonged action in renal impairment.**

---

# 3) Practical dosing

## A. Anaesthesia / Cardiac theatre

**Indications:** post-CPB low cardiac output, RV dysfunction, pulmonary hypertension, weaning from bypass, β-blockade blunting.

* **Loading dose:** 50 mcg/kg IV over 10 min (may omit if hypotensive).

* **Maintenance infusion:** **0.25–0.75 mcg/kg/min**, titrate by 0.1–0.2 increments.

* Start low if systemic BP borderline or patient hypovolaemic.

* If significant hypotension, combine with **norepinephrine** or **vasopressin**.

**Typical 70-kg patient:**

* Load 3.5 mg over 10 min, then start 0.3 mcg/kg/min → 1.26 mg/h → **12.6 mL/h** (if 0.1 mg/mL solution).

## B. ICU

**Indications:**

* Post-cardiac surgery LCOS, RV failure, pulmonary hypertension crisis, or severe systolic heart failure refractory to catecholamines.

**Dosing:**

* **0.25–0.75 mcg/kg/min**, titrate to cardiac index, ScvO₂, lactate, and filling pressures.

* Avoid bolus in unstable hypotensive patients.

* Combine with **vasopressor** if MAP <65 mmHg.

---

# 4) Special populations — dosing cautions

### Pregnancy

* Limited data; use only if benefit outweighs risk (e.g., severe heart failure or pulmonary hypertension in obstetric anaesthesia).

### Lactation

* Unknown excretion; avoid breastfeeding during continuous infusion; safe after discontinuation due to short exposure.

### Hepatic impairment

* Metabolism minimal → no major adjustment.

### Renal impairment

* **Reduce dose:**

  * CrCl 30–50 mL/min → 0.23 mcg/kg/min

  * CrCl 10–30 → 0.2 mcg/kg/min

  * CrCl <10 → 0.13 mcg/kg/min

* Avoid loading dose. Monitor for prolonged hypotension and arrhythmia.

### Obesity

* Dose on **Ideal/Adjusted Body Weight**; avoid overshoot due to hypotension risk.

### Paediatrics

* **Bolus:** 50 mcg/kg over 10 min.

* **Infusion:** 0.25–0.75 mcg/kg/min (same range).

* Neonates: prolonged half-life; start lower (0.25 mcg/kg/min).

---

# 5) Drug interactions (clinically key)

* **Loop diuretics (furosemide):** precipitate in same line — use separate lumen.

* **Other vasodilators (nitroglycerin, nitroprusside):** additive hypotension.

* **Catecholamines (dobutamine, adrenaline):** synergistic for inotropy—common combination in LCOS.

* **Beta-blockers:** effects preserved (not receptor-mediated).

* **Norepinephrine:** balances systemic BP; often co-infused.

* **Dopamine/dobutamine:** may further increase arrhythmia risk if used together long-term.

* **Digoxin:** additive arrhythmogenicity possible.

---

# 6) Significant complications & management

| Complication                          | Mechanism / Features                       | Management                                                                       |

| ------------------------------------- | ------------------------------------------ | -------------------------------------------------------------------------------- |

| **Hypotension**                       | Peripheral vasodilation from ↑ cAMP in VSM | Volume resuscitate; reduce rate; start vasopressor (norepi/vasopressin).         |

| **Ventricular arrhythmias**           | Excess cAMP, Ca²⁺ overload                 | Reduce/stop infusion; correct K⁺, Mg²⁺, acid-base; antiarrhythmics if sustained. |

| **Tachycardia / palpitations**        | Mild β₁ stimulation                        | Usually self-limiting; adjust dose.                                              |

| **Thrombocytopenia (rare)**           | Idiosyncratic                              | Stop drug; monitor platelets.                                                    |

| **Prolonged effect in renal failure** | Accumulation                               | Adjust dose; extend interval; consider CRRT clearance if severe.                 |

---

Adrenaline (Epinephrine)

Adrenaline is a potent **β₁/β₂/α₁ agonist** with **dose-dependent** inotropy, chronotropy, bronchodilation, and vasoconstriction. 

It’s the **drug of choice for anaphylaxis**, a powerful **inopressor** for LCOS/post-CPB or refractory septic vasoplegia, and the standard **ALS** vasopressor. 

Typical ICU/OR infusion **0.02–0.2 (up to 0.5) mcg/kg/min**; use central access and be vigilant for **arrhythmias, ischaemia, lactate rise, hypokalaemia**, and **extravasation injury.

# 1) Receptor-level action → clinical effects

**Primary receptors (dose-dependent):**

* **β₁ agonist** → ↑ inotropy, ↑ chronotropy, ↑ dromotropy → ↑ **CO**.

* **β₂ agonist** → **bronchodilation**, skeletal-muscle vasodilation, **↓ mast-cell mediator release**; metabolic effects (↑ glucose, **↓ K⁺** via cellular shift).

* **α₁ agonist** (more prominent at higher doses) → **arterial/venous vasoconstriction** → ↑ **SVR/MAP**.

**Clinical phenotype by dose (rule of thumb):**

* **Very low–low** (≤0.02–0.05 mcg/kg/min): β₁/β₂ dominant → ↑ CO, mild ↓ SVR.

* **Moderate** (0.05–0.2): balanced β + α → ↑ CO **and** ↑ SVR.

* **High** (>0.2): α₁ predominant → marked vasoconstriction; risk of ↑ afterload, ischaemia, lactate rise.

**Key bedside effects**

* **Heart:** powerful inotrope/chronotrope; may precipitate **AF/VT/VF**, ↑ myocardial O₂ demand → **ischaemia**.

* **Vessels:** dose-dependent vasoconstriction (skin/splanchnic) or vasodilation (muscle) → net MAP usually rises with moderate–high doses.

* **Lungs:** **bronchodilation**; cornerstone for **anaphylaxis**.

* **Metabolic:** **hyperglycaemia**, **lactataemia** (β-driven glycolysis; not always tissue hypoperfusion), **hypokalaemia** (β₂ shift).

---

# 2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)

**Common presentations**

* **1 mg/mL** (1:1000) amp (IM use; can be diluted for infusions).

* **0.1 mg/mL** (1 mg in 10 mL; 1:10,000) prefilled syringe (IV bolus for ALS).

* Infusion mixes (ICU/OR): **4 mg in 50 mL** (80 mcg/mL) or **1 mg in 50 mL** (20 mcg/mL). Central line preferred.

**PK**

* **Onset IV:** < 1 min; **peak:** minutes; **offset:** 1–3 min after stop.

* **t½:** ~2–3 min; **metabolism:** MAO & COMT → inactive; **excretion:** renal metabolites.

**Disadvantages from PK/PD**

* Requires **continuous infusion**; narrow titration window.

* **Tachyarrhythmias**, **lactate rise**, **hyperglycaemia**.

* **Peripheral extravasation** can cause **ischaemic necrosis**.

---

# 3) Practical dosing

## A. Anaesthesia / Cardiac theatre

**Indications:** post-CPB myocardial stunning/LCOS, anaphylaxis under anaesthesia, refractory hypotension with low CO.

* **Post-CPB/LCOS infusion:** start **0.02–0.05 mcg/kg/min**, titrate q2–5 min by 0.01–0.02; typical **0.02–0.2 mcg/kg/min** (higher if refractory).

* **Rescue bolus (careful):** 10–20 **mcg** IV aliquots (0.1–0.2 mL of 1:10,000) for transient hypotension while starting infusion.

* **Math example (70 kg @ 0.1 mcg/kg/min = 7 mcg/min):** with **80 mcg/mL** → **5.25 mL/h**.

## B. ICU

**Indications:** vasodilatory shock with low CO (septic/post-CPB vasoplegia), cardiogenic shock as an inopressor when dobutamine/milrinone insufficient.

* **Start:** **0.02–0.05 mcg/kg/min**; **range:** **0.02–0.5 mcg/kg/min**.

* Combine with **norepinephrine** when SVR is very low; or with **inodilator** (dobutamine/milrinone) if afterload high and contractility poor.

## C. Life-threatening emergencies (for completeness)

* **Adult cardiac arrest (ALS):** **1 mg IV** (1:10,000) every 3–5 min cycles.

* **Anaphylaxis (adult):** **0.5 mg IM** (1:1000) mid-outer thigh; repeat q5 min PRN. Refractory → **IV infusion** (e.g., 1–4 mcg/min then titrate) under monitoring.

---

# 4) Special populations — dosing cautions

### Pregnancy

* First-line for **anaphylaxis** in pregnancy (maternal life priority); can reduce uterine blood flow at high IV doses—use **IM first** when appropriate and titrate IV carefully intra-op.

### Lactation

* Minimal oral bioavailability for infant; short t½; single/emergency doses acceptable.

### Hepatic impairment

* Widely metabolised extrahepatically; **no formal adjustment**—**titrate to effect**.

### Renal impairment

* Metabolites renally excreted but inactive; **no adjustment**. Watch perfusion and urine output.

### Obesity

* Start with **IBW/AdjBW-based** rates to avoid overshoot; titrate to haemodynamics.

### Paediatrics

* **Anaphylaxis IM:** **0.01 mg/kg** (1:1000), max **0.5 mg**.

* **Infusion:** **0.02–1 mcg/kg/min** titrated in specialist setting.

* **Cardiac arrest:** **0.01 mg/kg IV** (1:10,000 = 0.1 mL/kg).

---

# 5) Drug interactions (clinically key)

* **MAO inhibitors / TCAs / SNRIs:** **exaggerated pressor** and arrhythmic responses → start at **very low doses** or avoid.

* **Non-selective β-blockers** (e.g., propranolol): **unopposed α₁ vasoconstriction** → severe hypertension/bradycardia; bronchospasm risk persists (β₂ blocked).

* **Halogenated volatiles (esp. halothane):** myocardial sensitisation → **ventricular arrhythmias**.

* **Digoxin:** arrhythmia risk ↑.

* **Insulin/oral hypoglycaemics:** hyperglycaemia from epi may necessitate higher insulin.

* **Inhaled β₂-agonists:** additive hypokalaemia—monitor K⁺.

---

# 6) Significant complications & management

| Complication                                           | Mechanism / Features                                 | Management                                                                                                                                       |

| ------------------------------------------------------ | ---------------------------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------ |

| **Tachyarrhythmias (AF/VT/VF)**                        | β₁ excess, esp. hypoxia/acidosis                     | Reduce/stop; correct K⁺/Mg²⁺; antiarrhythmics/defibrillate per ACLS.                                                                             |

| **Myocardial ischaemia**                               | ↑ MVO₂ + ↑ afterload                                 | Lower dose; add inodilator; ensure adequate MAP/CPP and treat pain/anaemia.                                                                      |

| **Severe hypertension / limb or mesenteric ischaemia** | α₁ vasoconstriction at high dose                     | Titrate down; reconsider target MAP; balance with inodilator.                                                                                    |

| **Lactataemia** (β-driven)                             | Accelerated glycolysis—not necessarily hypoperfusion | Interpret with context; check ScvO₂/echo; don’t chase lactate alone.                                                                             |

| **Hypokalaemia**                                       | β₂-mediated intracellular shift                      | Monitor K⁺; replace if needed.                                                                                                                   |

| **Hyperglycaemia**                                     | Glycogenolysis/gluconeogenesis                       | Adjust insulin.                                                                                                                                  |

| **Extravasation necrosis**                             | Intense local α₁ vasoconstriction                    | **Stop infusion, leave cannula**, **phentolamine 5–10 mg** in 10–15 mL saline infiltrated around site; warm compress; surgical review if severe. |

| **Pulmonary oedema**                                   | Afterload ↑ + tachycardia                            | Reduce dose; diuretics/vasodilator if appropriate; optimise ventilation.                                                                         |

---

Norepinephrine

Norepinephrine is a potent **α₁ agonist** and moderate **β₁ agonist**, producing **powerful vasoconstriction** and modest inotropy. 

It is the **first-line vasopressor** in septic, cardiogenic, and post-cardiac bypass vasodilatory shock.

Dose **0.02–0.3 mcg/kg/min**, titrated to MAP 65–75 mmHg; always via central line; treat extravasation with **phentolamine.

---

# 1) Receptor-level action → clinical effects

**Primary receptor activity:**

* **α₁ agonist (dominant):** intense arterial & venous vasoconstriction → ↑ SVR, ↑ MAP.

* **β₁ agonist (moderate):** ↑ contractility and heart rate *slightly* but offset by baroreflex-mediated bradycardia.

* **β₂ agonist (minimal):** clinically negligible.

**Net effects:**

* ↑ MAP primarily via **↑ SVR**.

* Slight ↑ myocardial contractility & CO in moderate doses (depends on preload).

* Reflex **bradycardia** common due to baroreceptor activation.

* Improves coronary and cerebral perfusion pressure.

**Clinical summary of effects:**

* **Vascular:** potent vasoconstrictor, preserves perfusion pressure.

* **Cardiac:** improves inotropy modestly; no direct chronotropy in intact baroreflex.

* **Renal/splanchnic:** vasoconstriction; at adequate MAP, **net renal perfusion improved** by higher pressure.

* **Metabolic:** can cause mild hyperglycaemia, hyperlactataemia (β-effect on metabolism).

---

# 2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)

**Formulation:**

* Standard ampoule: **4 mg/4 mL (1 mg/mL)**.

* Common ICU dilution: **4 mg in 50 mL** → **80 mcg/mL** (1 mL/h = 1.33 mcg/min).

  * Alternative: **8 mg/50 mL** (160 mcg/mL) for central use.

**Pharmacokinetics:**

* **Onset:** <1 min.

* **Duration:** 1–2 min (terminated rapidly by reuptake/metabolism).

* **Metabolism:** MAO & COMT → inactive metabolites.

* **Half-life:** ~2.5 min.

* **Elimination:** renal excretion of metabolites.

**Disadvantages:**

* **Requires continuous infusion**, short half-life.

* **Peripheral extravasation → severe tissue necrosis.**

* Excessive vasoconstriction → impaired peripheral, mesenteric, or renal flow if MAP overshoot.

* **Arrhythmia risk** lower than dopamine, but possible with high doses.

---

# 3) Practical dosing

## A. Anaesthesia / Post–cardiac bypass

**Indications:** hypotension due to vasodilation, vasoplegia, or low SVR after CPB, sepsis, or anaesthetic-induced vasodilation.

* **Starting dose:** **0.02–0.05 mcg/kg/min**.

* **Titrate up:** by 0.01–0.02 mcg/kg/min increments.

* **Typical range:** **0.02–0.3 mcg/kg/min** (occasionally higher in refractory vasoplegia).

* **Usual ICU practice:** aim for **MAP 65–75 mmHg** (individualised).

**Preparation examples (for 70 kg):**

* 70 × 0.1 mcg/kg/min = 7 mcg/min.

  Using 80 mcg/mL solution → rate = **5.25 mL/h.**

**Peripheral use (if emergency):**

* Use **max 15–20 min** only through **large antecubital vein**; monitor closely; change to central line ASAP.

---

# 4) Special populations — dosing cautions

### Pregnancy

* Used for **maternal hypotension** during spinal/epidural anaesthesia; maintains **better fetal acid–base status** than phenylephrine (lower reflex bradycardia).

* Crosses placenta minimally; **safe in obstetric anaesthesia** when titrated carefully.

### Lactation

* Short t½ and poor oral absorption → minimal transfer risk.

### Hepatic impairment

* Metabolised widely (not dependent on hepatic clearance). No dose adjustment required; **titrate to effect**.

### Renal impairment

* Metabolite excretion renal but inactive; **safe**.

* Improves renal perfusion indirectly via better MAP.

### Obesity

* Dose by **ideal body weight** to avoid excessive pressor effect.

### Paediatrics

* **Starting:** 0.05 mcg/kg/min; titrate to 1–2 mcg/kg/min if required (specialist monitoring).

---

# 5) Drug interactions (clinically key)

* **MAOIs:** marked pressor response → start at **1/10th** normal dose or avoid.

* **TCAs / SNRIs:** exaggerated BP response.

* **Halogenated volatiles (esp. halothane):** myocardial sensitisation → **ventricular arrhythmia risk.**

* **β-blockers:** may cause unopposed α-stimulation → **severe hypertension/bradycardia**.

* **Ergot alkaloids, oxytocin:** additive vasoconstriction.

* **Phosphodiesterase inhibitors (milrinone):** synergistic—useful combination for inodilator + vasopressor balance.

* **General anaesthetics / propofol:** counteract vasodilation; titrate slowly.

---

# 6) Significant complications & management

| Complication                              | Mechanism / Features                       | Management                                                                                                                                     |

| ----------------------------------------- | ------------------------------------------ | ---------------------------------------------------------------------------------------------------------------------------------------------- |

| **Peripheral extravasation necrosis**     | α₁ vasoconstriction → ischaemia            | Stop infusion, leave cannula, **phentolamine 5–10 mg in 10–15 mL saline** infiltrated around site; warm compress; surgical review if necrosis. |

| **Digital/mesenteric ischaemia**          | Excess vasoconstriction                    | Lower dose, reassess MAP goal, switch/add inodilator.                                                                                          |

| **Arrhythmia (AF/VT)**                    | β₁ effect, usually in high dose or hypoxia | Correct electrolytes, reduce dose; antiarrhythmics as indicated.                                                                               |

| **Reflex bradycardia**                    | Baroreceptor response                      | Often mild; if MAP adequate, observe. Severe → **atropine/glycopyrrolate** if symptomatic.                                                     |

| **Metabolic acidosis / hyperlactataemia** | From high β-stimulation (non-hypoxic)      | Usually benign; evaluate perfusion if severe.                                                                                                  |

---

Dopamine

Dopamine is a **dose-dependent catecholamine**: D₁/D₂ at low dose, **β₁ inotropy** at moderate dose, and **α₁ vasoconstriction** at high dose. 

It raises **CO** and **HR**, but carries **higher arrhythmia risk** than dobutamine/norepinephrine. 

Dose **2–20 mcg/kg/min**, central line preferred; **avoid** for “renal protection,” and **treat extravasation with phentolamine.

# 1) Receptor-level action → clinical effects

**Receptors (dose-dependent):**

* **D₁/D₂ (≈1–3 mcg/kg/min)** → renal/mesenteric vasodilation, natriuresis (the classic “renal dose” effect).

  **Clinical reality:** renal-protective strategy **not recommended**—no outcome benefit.

* **β₁ (≈3–10 mcg/kg/min)** → ↑ inotropy/chronotropy → ↑ CO, modest ↑ MAP.

* **α₁ (≥10–20 mcg/kg/min)** → vasoconstriction → ↑ SVR/MAP; tachyarrhythmia risk rises.

**Clinical effects from the above:**

* **Heart:** ↑ contractility (β₁), ↑ HR; may precipitate **AF/VT**.

* **Vessels:** low dose vasodilation (splanchnic/renal), moderate → little net change, high dose **vasoconstriction**.

* **Kidney:** ↑ diuresis at low dose in some, **but no proven renal protection**.

* **Metabolic:** can raise blood glucose, lactate (β-agonism).

---

# 2) Vial strength, preparation & basic PK (+ disadvantages)

**Supply / prep**

* Common vials/amps: **200 mg/5 mL** (40 mg/mL).

* Typical infusions: **200 mg/50 mL (4 mg/mL)** or **400 mg/50 mL (8 mg/mL)** in 0.9% saline or 5% dextrose. Use **central line** if possible; guard against extravasation.

**PK you feel at the bedside**

* **Onset:** 2–5 min; **peak** ~10 min.

* **Offset:** 5–10 min after stopping.

* **Metabolism:** MAO & COMT (hepatic, renal, plasma) → inactive metabolites.

* **t½:** ~2 min.

**Disadvantages (from PD/PK)**

* **Tachyarrhythmias**, ↑ myocardial O₂ demand, **variable BP response** (esp. hypovolaemia).

* High-dose **vasoconstriction** may impair splanchnic perfusion.

* **Less predictable** than norepinephrine; higher arrhythmia rates in shock.

---

# 3) Practical dosing

## A. Anaesthesia / OR (post-CPB or LV dysfunction)

* **Start:** **2–5 mcg/kg/min**, titrate q5–10 min by 2–5 mcg/kg/min.

* **Typical range:** **2–20 mcg/kg/min** (rarely higher).

* If hypotension with low SVR → may need **norepinephrine** adjunct rather than pushing dopamine high.

## B. ICU (shock, LCOS-Low Cardiac Output Syndrome)

* **Low cardiac output with relative bradycardia:** dopamine reasonable if you want **inotropy + HR** in one drug.

* **Septic shock:** **not first-line** (use **norepinephrine**); dopamine only if **bradycardic, low arrhythmia risk**, and limited access to other agents.

* **Cardiogenic shock:** can be used, but **arrhythmia risk > dobutamine**; many centres prefer **dobutamine ± norepinephrine**.

**Handy rate example (70 kg, 5 mcg/kg/min):**

* Using **8 mg/mL** (8000 mcg/mL): mL/h = (70×5×60) / 8000 ≈ **2.6 mL/h**.

---

# 4) Special populations — dosing cautions

### Pregnancy

* Use only if benefits outweigh risks (maternal shock). Can reduce uterine blood flow at high doses (α₁ vasoconstriction).

### Lactation

* Poor oral bioavailability; clinically minimal infant exposure with short maternal use.

### Hepatic impairment

* Metabolised by MAO/COMT widely (not solely hepatic). No strict adjustment; **titrate to effect**.

### Renal impairment

* Metabolites renally excreted; haemodynamics guide dosing. **Do not use** for “renal protection.”

### Obesity

* Start low; titrate to haemodynamic targets. (Most dose to **actual body weight**, but watch for excessive tachycardia.)

### Paediatrics

* **Start 2–5 mcg/kg/min**, titrate to 20 mcg/kg/min max under specialist monitoring (more arrhythmia-prone).

---

# 5) Drug interactions (clinically key)

* **MAO inhibitors** (or within 14 days): **massively potentiated** effect → severe hypertension/arrhythmias; **avoid or start at tiny doses with extreme caution**.

* **TCAs / SNRIs:** enhance pressor responses.

* **β-blockers:** blunt inotropy/chronotropy; unopposed α may ↑ SVR (context-dependent).

* **Inhalational anaesthetics (esp. halothane)**: **sensitise myocardium** to catecholamine-induced arrhythmias—use the lowest effective dose.

* **Other pressors/inotropes:** additive effects; coordinate with norepinephrine/dobutamine rather than stacking high dopamine alone.

---

# 6) Significant complications & management

| Complication                                       | Mechanism / Features                   | What to do                                                                                                                                                |

| -------------------------------------------------- | -------------------------------------- | --------------------------------------------------------------------------------------------------------------------------------------------------------- |

| **Tachyarrhythmias (AF/VT), myocardial ischaemia** | β₁ stimulation ↑ HR/O₂ demand          | Reduce/stop; correct electrolytes; consider **esmolol** (careful), switch to **dobutamine** or **norepinephrine** strategy.                               |

| **Hypertension with low output**                   | Excess α₁ tone                         | Titrate down; balance with inodilator (e.g., dobutamine/milrinone) if needed.                                                                             |

| **Extravasation → local ischaemia/necrosis**       | Intense α₁ vasoconstriction in tissues | **Stop infusion, leave cannula**, **infiltrate phentolamine 5–10 mg in 10–15 mL saline** around site ASAP; elevate/heat pack; surgical consult if severe. |

| **Gut/limb hypoperfusion** (high dose)             | Vasoconstriction                       | Lower dose; switch agent; ensure MAP/flow balance.                                                                                                        |

| **Endocrine effects (rare clinically)**            | Dopaminergic pituitary inhibition      | Usually not limiting; note possible ↓ prolactin transiently.                                                                                              |

---

Dobutamine

Dobutamine is a synthetic **β₁-adrenergic agonist** with mild β₂ and α₁ effects producing **inotropy > chronotropy** and mild vasodilation. It increases cardiac output, reduces filling pressures, and is ideal for **low-output heart failure** and **post-cardiac-surgery inotropy**. Dose **2–20 mcg/kg/min**, titrated to haemodynamics; combine with norepinephrine if hypotensive.

# 1) Receptor-level action → clinical effects

**Primary receptor targets:**

* **β₁-adrenergic agonist** (predominant) → ↑ **inotropy** (contractility) and modest ↑ **chronotropy** (HR).

* **β₂-adrenergic agonist** (mild) → **vasodilation** (↓ SVR).

* **α₁-adrenergic agonist** (weak) → mild vasoconstriction, balancing β₂ effects.

* **Net effect:** ↑ cardiac output with **slight fall in SVR** and **modest rise in HR**.

**Clinical effects from receptor activity:**

* ↑ myocardial contractility → ↑ stroke volume, ↑ cardiac output.

* Mild ↑ HR (may precipitate tachyarrhythmias in some).

* ↓ LV filling pressures and pulmonary capillary wedge pressure (improved forward flow).

* **Coronary flow** ↑ (secondary to ↑CO).

* **BP**: may rise, fall, or stay unchanged depending on baseline SVR and dose.

* **No significant effect on oxygenation or renal perfusion** beyond increased cardiac output.

---

# 2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)

**Formulation:**

* 250 mg/20 mL vial (12.5 mg/mL).

* Dilute to **250 mg/250 mL** (1 mg/mL) or **500 mg/250 mL** (2 mg/mL) for infusion.

**Pharmacokinetics:**

* **Onset:** 1–2 min (rapid).

* **Peak effect:** 10 min.

* **Duration:** 5–10 min after stopping infusion.

* **Metabolism:** hepatic + tissue **catechol-O-methyltransferase (COMT)** → inactive metabolites.

* **Elimination half-life:** 2–3 min.

* **Excretion:** renal (as metabolites).

**Disadvantages (from above PK/PD):**

* Short half-life → requires **continuous infusion**.

* **Tachyphylaxis** possible with prolonged use.

* ↑ myocardial O₂ consumption → risk of **ischaemia** in CAD patients.

* May cause **tachyarrhythmias** and **hypotension** if hypovolaemic or at high dose.

---

# 3) Practical dosing

## A. Anaesthesia / Perioperative

**Indications:** low cardiac output state after CPB, myocardial stunning, heart failure, or to support weaning from bypass.

* **Starting dose:** 2.5 mcg/kg/min.

* **Titrate up:** 2.5–5 mcg/kg/min increments q10–15 min.

* **Typical range:** **2–20 mcg/kg/min** (rarely up to 40 mcg/kg/min in refractory cases).

* **Target:** improved CO/CI, MAP, urine output, lactate trend.

* Reduce if HR >120 bpm, new arrhythmia, or hypotension.

**Example (70 kg):**

* Start 2.5 mcg/kg/min → 10.5 mg/h → **10.5 mL/h** if 1 mg/mL solution.

* Double rate for 5 mcg/kg/min = 21 mL/h.

## B. ICU

**Indications:**

* Low-output heart failure (esp. systolic dysfunction).

* Cardiogenic shock (in combination with vasopressors like norepinephrine).

* Post-cardiac surgery LCOS.

* Bridge to more definitive therapy (IABP, ECMO, LVAD).

**Dosing:** same as above (2–20 mcg/kg/min).

* Start low and titrate to CO, ScvO₂, urine output, and lactate.

* Use **norepinephrine adjunct** if hypotension develops.

* Avoid in severe dynamic LVOT obstruction or hypertrophic obstructive cardiomyopathy (worsens gradient).

---

# 4) Special populations — dosing cautions

### Pregnancy

* Crosses placenta; limited data. Use only if benefits outweigh risk (e.g., maternal shock).

* No known teratogenicity.

### Lactation

* Insufficient data; short t½ and poor oral absorption → unlikely harmful.

### Hepatic impairment

* Metabolised by COMT in tissues → minimal hepatic dependence; **no major adjustment needed**.

### Renal impairment

* Excreted as inactive metabolites; **safe in renal failure** but monitor for volume status and arrhythmias.

### Obesity

* Dose based on **actual body weight** (drug acts in plasma, not lipophilic).

* However, **start at lower end** and titrate cautiously for HR and MAP.

### Paediatrics

* **Starting dose:** 1–5 mcg/kg/min IV infusion; titrate q10–15 min up to 20 mcg/kg/min.

* Monitor HR, BP, rhythm closely (more sensitive to tachycardia).

---

# 5) Drug interactions (clinically key)

* **β-blockers:** blunt inotropic effect → may require higher doses or switch agent (e.g., milrinone).

* **Volatile anaesthetics:** additive myocardial depression → exaggerated hypotension if combined.

* **MAOIs / COMT inhibitors:** unpredictable pressor or tachycardic responses—avoid or titrate very slowly.

* **Norepinephrine / dopamine:** synergistic for MAP support.

* **Amiodarone or other antiarrhythmics:** increased risk of bradyarrhythmia.

* **Tricyclic antidepressants:** may enhance chronotropy/arrhythmia risk.

---

# 6) Significant complications & management

| Complication                             | Mechanism / Features                          | Management                                                              |

| ---------------------------------------- | --------------------------------------------- | ----------------------------------------------------------------------- |

| **Tachycardia / arrhythmia**             | β₁ stimulation                                | Reduce dose; ensure euvolaemia; consider β-blocker (esmolol) if severe. |

| **Hypotension**                          | β₂-mediated vasodilation esp. in hypovolaemia | Fluid resuscitation; add vasopressor (norepi).                          |

| **Myocardial ischaemia**                 | ↑ O₂ demand                                   | Reduce dose; nitrates; ensure adequate coronary perfusion pressure.     |

| **Tolerance (tachyphylaxis)**            | β-receptor desensitisation                    | Alternate with other inotropes (milrinone).                             |

| **Eosinophilic myocarditis (very rare)** | Hypersensitivity after prolonged use          | Stop drug; supportive care; steroids if severe.                         |

---