Circulatory Failure and Inotropic Drugs

Circulatory Failure and Inotropic Drugs

Posted by Kai Knudsen, Senior Physician in Anesthesia & Intensive Care. Sahlgrenska University Hospital.
Updated 2018-12-21


Inotropic treatment refers to intravenous vasopressor therapy with potent cardiovascular vasoactive drugs. The drugs commonly used are synthetic fast-acting catecholamines. These drugs are administered intravenously intermittently or in a continuous infusion via a CVC or a peripheral venous catheter (PVC). The treatment usually results, but not always in elevated blood pressure, increased heart volume and increased oxygen transport. The catecholamines activate α and β receptors i vital organs and peripheral vessels. Αlfa1 receptors are predominantly in peripheral blood vessels postsynaptically, β1 receptors are present in the heart, β2 receptors are found in the heart, blood vessels, uterus and respiratory tract. DA1 receptors are found primarily in splanchnicus and kidneys. Vasopressor drugs have short-term sympathomimetic effects on circulation with positive effects on blood pressure and oxygen delivery, but may in prolonged use damage vessels, extremities and vital organs such as the heart and kidneys. There is an increased risk of cardiac arrhythmias and ischemia but the risk depends on how the medication is used. Common vasopressors are dopamine, adrenaline, norepinephrine and dobutamine. Long-term use may present a risk of an exhausted heart with cardiac failure and increased risk of intestinal ischemia and peripheral ischemia. In case of moderate hypotension, short-acting drugs like ephedrine and phenylephrine should be used primarily, but if necessary for long-term effects, continuous infusion of more potent drugs is recommended.

Suggested treatment for hypotension that does not respond to initial fluid supply;

At low heart rate <90 bpm and low blood pressure: First-hand therapy Ephedrine 5-10 mg iv, secondary therapy Dopamine, 2-10 μg/kg/min dose after pulse and blood pressure response, third-hand therapy Epinephrine 0.1-1.0 mg iv, then in continuous infusion, 0.05-0.1-0.30 μg/kg/min as measured after pulse and blood pressure response.

At high heart rate> 90 beats/min and low blood pressure: First-hand therapy in addition to fluid therapy is Phenylephrine 0.1-0.2 mg i v. Secondary therapy is Dobutamine, 2-10-15 μg/kg/min alt. Norepinephrine which is dosed after pulse, blood pressure, CO and SvO2. Norepinephrine is given in a continuous infusion, 0.01-0.1- (0.5) μg/kg/min = 3-40 ml/h for 70 kg. Normal starting dose noradrenaline 0.05 μg/kg/min, is dosed after blood pressure. Norepinephrine may also be used as a first-aid kit in a severely ill patient, but should preferably not be given in peripheral venous canal due to risk of hemodynamic instability.

Physiological effects of Inotropic Drugs

Inotropic Agentα 1β 1β 2DA- 1SVRCOHRBP
Epinephrine (Adrenaline)+++++++++++
Norepinephrine (Noradrenaline)+++++++zero+/-↑↑
Dobutamine +++++++zero+/-
Dopamine +++++++++++
Ephedrine++++++zero
Phenylephrine+++zerozerozero+/-+/-
Isoprenalinezero++++++++zero
Levosimendan ----
Milrinone ---
Vasopressin----+/-↑↑
Vasopressor therapy in anesthesia induced hypotension
 Low blood pressure and low heart rateLow blood pressure and high heart rate
First choice medicationEphedrine 5-10 mg i v. intermittentlyPhenylefrine 0,1 mg i v. intermittently
Second choice medicationDopamin 2-10-15 μg/kg/minPhenylefrine in continuous infusion, 0,05-0,15 μg/kg/min
Third choice medicationEpinephrine 0,01-0,1-(0,5) μg/kg/minNorepinephrine in continuous infusion, 0.01-0.1- (0.5) μg /kg/min

 


Argipressin

Argipressin is a synthetic analogue to pitressin. Argipressin causes systemic vasoconstriction, and thus elevated peripheral vascular tone with elevated blood pressure. It can also be administered locally and results in decreased bleeding in laparoscopic surgery of ectopic pregnancy and in myoma extirpation.

Indication: Reported hypotension due to vasoplegia (refractory hypotension). Treatment failure with other inotropic drugs at low peripheral vascular resistance.

Dosage: 2.4-4.8 E/hour (which usually becomes 6-12 ml/h)

Concentration: 20 U/ml. Dilution of Argipressin is done by diluting 1 ml of 1 ampoule (1 ml = 20 U) with 49 ml of Glucose 5% in a 50 ml syringe giving a concentration of 0.4 U/ml.

Side effects: Headache, flush, hypotension, pain in extremities, peripheral edema, blurred vision, nasal congestion, nightly sweating.

Caution: Caution in angina pectoris, cardiac decompensation, renal failure, poorly controlled hypertension, anaphylaxis or hypersensitivity to vasopressin.


Epinephrine (Adrenaline)

Adrenaline is a sympathomimetic catecholamine. The positive inotropic effect is based primarily on the agonistic effect on the heart’s beta1-receptors, but also on the heart’s alpha1 receptors.

Concentration: Normal concentration is 0.05 mg/ml alt. 0.1 mg/ml for continuous infusion. For manual injections, 0.1 mg/ml or a “weak” solution at 0.01 mg/ml are common concentrations.

Receptor activity: α1 ++++, β1 ++++, β2 +++

Physiological effects: SVR ↑, CO ↑, HR ↑, BP ↑, bronchodilation

Indication: Circulatory shock, refractory hypotension, allergic shock, anaphylaxis, cardiac arrest, severe cardiac failure, cardiogenic shock, severe poisoning, severe bronchospasm, status asthmaticus, severe stridor.

Dosage: 0.05-0.1- (0.30) μg/kg/min = 3-40 ml/h for 70 kg. Normal starting dose 0.1 μg/kg/min, dose adjusted to blood pressure. Anaphylaxis/asthma: 0.3-0.5 mg i.m., CPR 1 mg i v. At established circulation but congestive heart failure 0.1 mg i.v. at a time. At circulation collapse 0.1-1.0 mg i v, titrate after blood pressure, avoid overdose.

Dosage activity: <0.05 μg/kg/min – usually moderate effect on blood pressure, 0.05-0.1 μg/kg/min β1 effect, increased cardiac output,> 0.1 μg/kg/min – mostly α1 effect

Adverse reactions: Tachycardia, arrhythmias, uncontrolled blood pressure increase.


Dobutamine (Dobutamin Hameln®)

Positive inotropic drug with weak vasodilating effect. Dobutamine is a synthetic, sympathomimetic amine. The positive inotropic effect is based primarily on the agonistic effect on the heart’s beta1-receptors, but also on the heart’s alpha-receptors.

Concentration: Standard solution 2 mg/ml.

Receptor activity: α1 +, β1 ++++, β2 ++, DA-1 zero.

Physiological effects: SVR ↓, CO ↑, HR ↑, BP +/-. Binds to and stimulates beta1 receptors in the heart. Provides increased contraction force.

Indication: Low cardiac output, low heart rate, cardiac failure, sepsis.

Dosage: 2-10-15 μg/kg/min = 5-40 ml/h for 70 kg.

Dose activity: <3 μg/kg/min – usually no effect on blood pressure or blood pressure drop, 5-10 μg/kg/min β1 effect, increased cardiac output >10 μg/kg/min – α1 effect. Increased heart rate.

Adverse reactions: Tachycardia, hypotension in hypovolemia.


Dopamine (Intropin®, Abbodop®, Giludop®)

Dopamine is a sympathomimetic catecholamine. The positive inotropic effect is based primarily on the agonistic effect on the heart’s beta1-receptors, but also on the heart’s alpha-receptors. Significant chronotropic effect.

Concentration: Standard solution 2 mg/ml

Receptor activity: α1 ++, β1 ++++, β2 ++, DA-1 +++

Indication: Refractory hypotension, low cardiac output, heart failure, oliguria, sepsis.

Dosage: 3-15 μg/kg/min = 7-40 ml/h for 70 kg.

Dose activity: <3 μg/kg/min – DA effect, 5-10 μg/kg/min β1 effect, increased heart rate, > 10 μg/kg/min – mostly α1 effect.

Adverse reactions: Tachycardia, arrhythmias, renal and intestinal hypoperfusion, mental symptoms, pituitary dysfunction.


Ephedrine

Ephedrine is a naturally occurring alkaloid. Ephedrine acts as a blood pressure enhancer through stimulation of adrenergic alpha and beta receptors. Ephedrine acts directly on the receptors, but mainly by releasing endogenous noradrenaline, which in turn affects the receptors. The positive inotropic effect is based primarily on the agonistic effect on the heart’s beta1 receptors, but also to some extent on the heart’s alpha1 receptors.

Receptor activity: α1 +, β1 +++, β2 ++, DA-1 zero.

Physiological effects: Slightly increased inotropy, chronotropy and blood pressure increase. Releases noradrenaline. Increased cardiac output (CO), increased blood pressure and mean arterial pressure. Increased SVR, decreased CO, increased HR, increased BP. Short-term effect for 5-15 minutes during intravenous administration. Slightly more prolonged effect after subcutaneous or intramuscular administration.

Indication: Temporary drop in blood pressure, vasodilation, bradycardia, blood pressure drop after spinal anesthesia and epidural anesthesia, blood pressure drop after anesthesia induction, bronchial asthma.

Adverse reactions: Tachycardia, extravasation, arrhythmias, atrial fibrillation, cardiovascular disease.

Concentration: Solution 50 mg/ml. The usual concentration is 5 mg/ml (diluted) or 50 mg/ml.

Dosage: 5-10 mg i v. Normal starting dose 5 mg i v, adjusted for blood pressure and pulse. 25-50 mg can be given i m. Intramuscular dose can be given at the same time as intravenous administration, e.g. 5 mg i v plus 25 mg intramuscularly associated with spinal anesthesia.

Dose activity: 5 – 10 mg usually produces moderate effect on blood pressure, with unchanged CO, > 10 mg also gives increased CO.


Phenylephrine

Phenylephrine is a sympathomimetically substituted phenethylamine. Pure alpha receptor agonist. Provides vasoconstriction and blood pressure increase. Reduced cardiac output (CO), increased diastolic blood pressure and mean arterial pressure (MAP).

Receptor activity: α1 +++, β1 zero, β2 zero, DA-1 zero.

Physiological effects: Increased SVR, decreased CO, decreased HR, increased BP, reflective bradycardia.

Indication: Hypotension, vasodilation, drop in blood pressure after spinal anesthesia and epidural anesthesia.

Side effects: Bradycardia, cardiac failure, pulmonary edema.

Concentration: Standard solution 0.1 mg/ml. A common concentration is 0.1 mg/ml or (0.2 mg/ml). Also available in the concentration of 10.0 mg/ml that may be diluted.

Dosage: 0.1-0.2 mg i v. Normal starting dose 0.1 mg i v, adjusted for blood pressure. Phenylephrine is usually given in repeated bolus doses, but can also be given in continuous infusion at 0.1 mg/ml strength. The usual dose is 0.05-0.15 μg/kg/min = about 3 – 20 ml/h for 70 kg.

Dosage activity: < 0.3 mg: usually moderate effect on blood pressure, CO unchanged, > 0.5 mg reduced CO, vasoconstriction.


Isoprenaline

Isoprenaline is a sympathomimetic amine. The positive inotropic effect is based primarily on the agonistic effect on the heart’s beta1 receptors and beta2 receptors, but also on the heart’s alpha1 receptors. Isoprenaline is vasodilatory with pronounced positive chronotropic effect.

Concentration: Standard concentration at 0.2 mg/ml.

Receptor activity: α1 zero, β1 ++++, β2 ++++, DA-1 zero. Positive chronotropic and inotropic effects on the heart. Potent vasodilation and increased heart rate. Increased cardiac output (CO), diastolic blood pressure and mean arterial pressure.

Physiological effects: Decreased SVR, CO ↑↑, HR ↑↑, decreased BP, bronchodilation.

Indication: Circulatory shock, bradycardia, AV block III, refractory hypotension, cardiac arrest, severe heart failure with low CO, cardiogenic shock, some severe poisoning.

Dosage: 0.01-0.15 μg/kg/min, 15-30 ml/h for 70 kg. Normal starting dose 0.05 μg/kg/min, adjusted for blood pressure.

Dosage activity: < 0.05 μg/kg/min – usually moderate effect on blood pressure, possibly blood pressure fall, increased CO, 0.05-0.1 μg/kg/min β1 effect, increased cardiac output, increased heart rate.

Adverse reactions: Tachycardia, blood pressure fall, arrhythmias.


Levosimendan (Simdax®)

Levosimendan enhances the calcium sensitivity of the contractile proteins through a calcium-dependent binding to cardiac troponin C. In addition, levosimendan opens ATP-sensitive potassium channels in vascular smooth muscle, resulting in vasodilation of systemic and coronary resistor vessels and systemic venous capacitor vessels.

Receptor activity: Calcium sensitizer in the myocardium.

Concentration: Solution at 2.5 mg/ml. Normal concentration at 0.025 mg/ml or 0.05 mg/ml.

Physiological effects: Increased contractile force, CO↑, HR↑, vasodilation, increased ejection fraction, hypotension, decreased SVR.

Indication: Circulatory shock, severe cardiac failure, cardiogenic shock, stunned myocardium.

Dosage: 6-12 μg/kg/min for 10 minutes followed by a continuous infusion at 0.1 μg/kg/min for 24 hours.  Normal starting dose at 6 μg/kg/min, adjusted for blood pressure.

Dosage activity: 0.05-2 μg/kg/min – usually moderate effect on blood pressure, blood pressure drop.

Contraindications: Reported hypotension, hypokalaemia, hypovolemia, tachycardia, left ventricular mechanical obstruction, Torsade de Pointes arrhythmias, renal impairment.

Adverse reactions: Tachycardia, blood pressure fall, headache, atrial fibrillation, ventricular extrasystoles, arrhythmias, hypokalaemia.


Milrinone (Corotrop®)

Milrinone is a bipyridine derivative with both positive inotropic and vasodilating effect, but with little chronotropic effect.

Receptor activity: Phosphodiesterase-III inhibitor.

Physiological effects: SVR↓, CO↑, HR↑, BP+/-. Provides increased cardiac contraction force and increased stroke volume, vascular dilator.

Indication: Severe cardiac failure, cardiogenic shock.

Concentration: Solution at 1 mg/ml. The usual concentration for continuous infusion is 0.1 mg/ml (100 μg/ml) alt. 0.15 mg/ml (150 μg/ml).

Dosage: Initially a slow (10 minute) intravenous injection of 50 μg/kg. Thereafter a continuous infusion of 0.37-0.75 μg/kg/min. Normal starting dose at 0.5 μg/kg/min, adjusted for blood pressure. In the vast majority of patients, hemodynamic improvement is noted within 5-15 minutes. Doses in the range of 0.375-0.50 μg/kg/min tend to maximize the initial improvement in cardiac output, while doses in the range of 0.50-0.75 μg/kg/min tend to maximize the improvement in the pre- and afterload parameters such as pulmonary capillary wedge (PCW) pressure, mean arterial pressure and systemic vessel resistance (SVR).

Dosage activity: <0.375 μg/kg/min – usually moderate effect on circulation, 0.5-0.75 μg/kg/min β1 effect, blood pressure increase, increased CO and EF.

Contraindications: Hypovolemia, obstructive aorta or pulmonary valve. In case of acute myocardial infarction observe caution.

Side effects: hypotension, increased cardiac oxygen consumption, tachycardia, VES, VT.


Norepinephrine (Noradrenaline)

Norepinephrine (Noradrenaline) is a sympathomimetic amine. The positive inotropic effect is based primarily on the agonistic effect on the heart’s beta1 receptors, but also on the heart’s alpha1 receptors.

Concentration: Normal concentration for continuous infusion at 0.1 mg/ml. “Double strength” 0.2 mg/ml. “Weak” strength 0.05 mg/ml. Receptor activity: α1 +++, β1 +++, β2 +. DA-1 zero. Physiological effects: SVR ↑, CO +/-, HR ↑, BP ↑↑,

Indication: Circulatory shock, refractory hypotension, sepsis, anaphylaxis, severe hypotension with vasodilation, cardiogenic shock, severe poisoning.

Side effects: Tachycardia, arrhythmias, renal and intestinal hypoperfusion, peripheral ischemia, intestinal ischemia, splanchnicus ischemia.

Dosage: 0.01-0.1- (0.5) μg/kg/min = 3-40 ml/h for 70 kg. Normal starting dose 0.05 μg/kg/min, adjusted for blood pressure.

Dosage activity: <0.05 μg/kg/min – usually moderate effect on blood pressure, 0.0-5 0.1 μg/kg/min β1 effect, blood pressure increase, > 0.1 μg/kg/min – α1 effect with blood pressure increase, vasoconstriction, tachycardia.

Contraindications: Hypertension, pronounced hypovolemia, hyperthyroidism, peripheral hypoxia, peripheral vasoconstriction, hyperadrenergic conditions.


Vasopressin

Vasopressin is an antidiuretic hormone that regulates the resorption of water into the renal distal tubules. Regulates water balance, resulting in increased urinary osmolarity. Provides increased peripheral vasoconstriction and elevated blood pressure.

Concentration: Normal concentration for continuous infusion at 0.1 mg/ml. “Double strength” 0.2 mg/ml. Weak strength 0.05 mg/ml.

Receptor activity: α1 +++, β1 +++, β2 +. DA-1 zero.

Physiological effects: SVR ↑, CO +/-, HR ↑, BP ↑↑.

Indication: Circulatory shock, refractory hypotension, sepsis, anaphylaxis, severe hypotension with vasodilation, cardiogenic shock, severe poisoning.

Side effects: Tachycardia, arrhythmias, renal and intestinal hypoperfusion, peripheral ischemia, intestinal ischemia, splanchnicus ischemia.

Dosage: 0.01-0.1- (0.5) μg/kg/min = 3-40 ml/h for 70 kg. Normal starting dose 0.05 μg/kg/min, adjusted for blood pressure.

Dosage activity: <0.05 μg/kg/min – usually moderate effect on blood pressure, 0.0-5 0.1 μg/kg/min β1 effect, blood pressure increase,> 0.1 μg/kg/min – α1 effect , blood pressure increase, vasoconstriction, tachycardia.

Contraindications: Hypertension, hypovolemia, hyperthyroidism, peripheral hypoxia, peripheral vasoconstriction, hyperadrenergic conditions.