1. Vasopressors and inotropes
By:Dr. Amena Fatima

2. Vasopressors are a powerful class of drugs that induce vasoconstriction and thereby elevate mean arterial pressure (MAP).
Vasopressors differ from inotropes, which increase cardiac contractility; however, many drugs have both vasopressor and inotropic effects.
Although many vasopressors have been used since the 1940s, few controlled clinical trials have directly compared these agents or documented improved outcomes due to their use .
Thus, the manner in which these agents are commonly used largely reflects expert opinion, animal data, and the use of surrogate end points such as tissue oxygenation as a proxy for decreased morbidity and mortality.

3. CATECHOLAMINES
Catecholamines are drugs that promote blood flow and blood pressure by stimulating adrenergic receptors

4. Despite differences in adrenergic receptor activation and physiological responses, no catecholamine drug has proven superior to the others for improving clinical outcomes.

6. Dobutamine
Dobutamine is primarily a β1-receptor agonist, but also has weak β2- receptor agonist activity.
The β1-receptor stimulation produces an increase in heart rate and stroke volume, while the β2-receptor stimulation produces peripheral vasodilatation.
Because the increase in stroke volume is accompanied by a decrease in systemic vascular resistance, the blood pressure is usually unchanged or slightly increased .
The response to dobutamine, however, can vary widely in critically ill patients.

7. The cardiac stimulation produced by dobutamine is often accompanied by an increase in cardiac work and myocardial O2 consumption .
These effects can be deleterious in heart failure because cardiac work and myocardial energy needs are already heightened in the failing myocardium.

8. Dobutamine has been used to augment cardiac output in patients with decompensated heart failure due to systolic dysfunction.
However, the unfavorable effects of dobutamine on myocardial energetics has created a preference for other inodilators in decompensated heart failure.
Dobutamine remains the preferred inotropic agent for the treatment of myocardial depression associated with septic shock but it usually must be combined with a vasoconstrictor agent (e.g., norepinephrine) to raise the blood pressure.

9. Dosing Regimen
Dobutamine is started at an infusion rate of 3–5 μg/kg/min (without a loading dose), and this can be increased in increments of 3–5 μg/kg/min, if necessary, to achieve the desired effect.
The usual dose range is 5–20 μg/kg/min.
Therapy should be driven by hemodynamic end-points, and not by pre-selected dose rates.

10. Adverse Effects
Dobutamine produces only mild increases in heart rate (5-15 beats/min) in most patients, but it occasionally causes significant tachycardia (rate increases > 30 beats/min) , which can be deleterious in patients with coronary artery disease.
Like all positive inotropic agents, dobutamine is contraindicated in patients with hypertrophic cardiomyopathy.

11. Dopamine
Dopamine is an endogenous catecholamine that serves as a precursor for norepinephrine.
When given as an exogenous drug, dopamine produces a variety of dose-dependent effects, as described next.

12. Actions
At low infusion rates (≤ 3 μg/kg/min), dopamine selectively activates dopamine-specific receptors in the renal and splanchnic circulations, which increases blood flow in these regions .
Low-dose dopamine also directly affects renal tubular epithelial cells, causing an increase in both urinary sodium excretion (natriuresis) and urine output that are independent of the changes in renal blood flow .
The renal effects of low-dose dopamine are minimal or absent in patients with acute renal failure .

13. At moderate infusion rates (3 – 10 μg/kg/min), dopamine stimulates β- receptors in the heart and peripheral circulation, producing an increase in myocardial contractility and heart rate, along with peripheral vasodilatation.
The increase in stroke volume produced by dopamine is greater than dobutamine at equivalent infusion rates.

14. At high infusion rates (> 10 μg/kg/min), dopamine produces a dose dependent activation of α-receptors in the systemic and pulmonary circulations, resulting in progressive pulmonary and systemic vasoconstriction.
This vasopressor effect increases ventricular afterload, and can reduce the stroke volume augmentation produced by lower doses of dopamine.

15. Clinical Uses
Dopamine can be used to manage patients with cardiogenic shock and septic shock, although other measures are favored in these conditions (i.e., mechanical assist devices are preferred for cardiogenic shock, and norepinephrine is preferred for septic shock).
Low-dose dopamine is NOT recommended as a therapy for acute renal failure.

16. Dosing Regimen
Dopamine is usually started at a rate of 3 – 5 μg/kg/min (without a loading dose), and the infusion rate is increased in increments of 3 – 5 μg/kg/min to achieve the desired effect.
The usual dose range is 3 – 10 μg/kg/min for increasing cardiac output, and 10 – 20 μg/kg/min for increasing blood pressure.
Dopamine infusions should be delivered into large, central veins, because extravasation of the drug through peripheral veins can produce extensive tissue necrosis.

17. Adverse Effects
Sinus tachycardia and atrial fibrillation are reported in 25% of patients receiving dopamine infusions .
Other adverse effects of dopamine include increased intraocular pressure , splanchnic hypoperfusion, and delayed gastric emptying, which could predispose to aspiration pneumonia.

18. EXTRAVASATION OF VASOPRESSORS:
The risk of tissue necrosis from extravasation of dopamine is a concern with all vasopressor (vasoconstrictor)drug infusions, and eliminating this risk is the reason that large, central veins are recommended for all vasopressor drug infusions.
If dopamine or any other vasopressor drug escapes from a peripheral vein into the surrounding tissues, the tendency for ischemic tissue necrosis can be reduced by injecting phentolamine (an α-receptor antagonist) into the involved area.
The recommended injectate is a solution containing 5 – 10 mg phentolamine in 15 mL of isotonic saline.

19. Epinephrine
Epinephrine is an endogenous catecholamine that is released by the adrenal medulla in response to physiological stress.
It is the most potent natural β-agonist.

20. Actions
Epinephrine stimulates both α-adrenergic and β-adrenergic receptors (β1 and β2 subtypes), and produces dose-dependent increases in heart rate, stroke volume, and blood pressure.
Epinephrine is a more potent β1- receptor agonist than dopamine, and produces a greater increase in stroke volume and heart rate than comparable doses of dopamine.
The α-receptor stimulation produces a nonuniform peripheral vasoconstriction, with the most prominent effects in the subcutaneous, renal, and splanchnic circulations.
Epinephrine also has several metabolic effects, including lipolysis, increased glycolysis, and increased lactate production (from β-receptor activation), and hyperglycemia from α-receptor-mediated inhibition of insulin secretion.

21. Clinical Uses
Epinephrine plays an important role in the resuscitation of cardiac arrest and it is the drug of choice for hemodynamic support in anaphylactic shock.
Epinephrine is also used for hemodynamic support in the early postoperative period following cardiopulmonary bypass surgery.
Although epinephrine is as effective as other catecholamines in septic shock concerns about side effects have limited its popularity in septic shock.

22. Dosing Regimen
The dosing regimens for epinephrine in cardiac arrest is 1 mg IV every 3–5 minutes.
Vasopressor effect can increase coronary perfusion pressure, but cardiac stimulation is counter productive.
Dosing for anaphylactic shock is:

24. Epinephrine infusions are not preceded by a loading dose.
The initial infusion rate is usually 1 – 2 μg/min (or 0.02 μg/kg/min), and the rate is then increased in increments of 1 – 2 μg/min to achieve the desired effect .
The usual dose range for augmenting cardiac output or correcting hypotension is 5 – 15 μg/min.

25. Adverse Effects
Epinephrine creates a greater risk of unwanted cardiac stimulation (which can be deleterious in patients with coronary artery disease) than the other catecholamine drugs .
Other adverse effects include hyperglycemia, increased metabolic rate, and splanchnic hypoperfusion (which can damage the mucosal barrier in the bowel).
Epinephrine infusions are accompanied by an increase in serum lactate levels but this is not an adverse effect because it reflects an increased rate of glycolysis (not tissue hypoxia), and the lactate can be used as an
alternative fuel source.

26. Norepinephrine
Norepinephrine is an endogenous catecholamine that normally functions as an excitatory neurotransmitter.
When used as an exogenous drug, norepinephrine functions as a vasopressor

27. Actions
The principal action of norepinephrine is α-receptor-mediated peripheral vasoconstriction.
However, the adrenergic response to norepinephrine is altered in patients with septic shock .
For example, norepinephrine infusions are usually accompanied by a decrease in renal blood flow but in patients with septic shock, renal blood flow is increased by norepinephrine infusions .
Similar alterations may also occur with splanchnic blood flow (i.e., normally reduced, but not in septic shock)
Norepinephrine is also a weak β1-receptor agonist, but the effects of norepinephrine on stroke volume and heart rate can be comparable to dopamine (a more potent β1-receptor agonist) in patients with septic
Shock.

28. Clinical Uses
Norepinephrine is the preferred catecholamine for circulatory support in patients with septic shock.
This preference is not based on improved outcomes, because the mortality rate in septic shock is the same regardless of the catecholamine used for circulatory support.
Instead, norepinephrine is favored in septic shock because it has fewer adverse effects
than dopamine or epinephrine .

29. Dosing Regimen
Norepinephrine infusions are usually started at a rate of 8 – 10 μg/min, and the dose rate is then titrated upward or downward to maintain a mean blood pressure of at least 65 mm Hg.
The effective dose rate in septic shock varies widely in individual patients, but is usually below 40 μg/min.
Hypotension that is refractory to norepinephrine usually prompts the addition of dopamine or vasopressin, but there is no evidence that this practice improves outcomes

30. Adverse Effects
Adverse effects of norepinephrine include local tissue necrosis from drug extravasation, and intense systemic vasoconstriction with organ dysfunction when high dose rates are required.
However, whenever high doses of a vasoconstrictor drug are required to correct hypotension, it is difficult to distinguish between adverse drug effects and adverse effects of the circulatory shock.

31. Phenylephrine
Phenylephrine is a potent vasoconstrictor that has very few applications in the ICU.
Actions
Phenylephrine in a pure α-receptor agonist that produces widespread vasoconstriction.
The consequences of this vasoconstriction can include bradycardia, a decrease in cardiac stroke output (usually in patients with cardiac dysfunction), and hypoperfusion of the kidneys and bowel

32. Clinical Uses
The principal use of phenylephrine is for the reversal of severe hypotension produced by spinal anesthesia.
However, pure α-receptor agonists are not universally favored in this situation because they can aggravate the decrease in cardiac stroke output that occurs in spinal shock .
Phenylephrine is not recommended for hemodynamic support in septic shock, although a clinical study comparing phenylephrine and norepinephrine for the early management of septic shock showed no differences in hemodynamic effects or clinical outcomes with the use of either drug.

33. Dosing Regimen
Phenylephrine can be given as intermittent IV doses. The initial IV dose is 0.2 mg, which can be repeated in increments of 0.1 mg to a maximum dose of 0.5 mg .
Adverse Effects
The principal adverse effects of phenylephrine are bradycardia, low car-diac output, and renal hypoperfusion.
These effects are magnified in hypovolemic patients.

34. ADJUNCTIVE VASOPRESSORS
The following drugs can be added to vasopressor therapy with catecholamines in selected situations.
Vasopressin
Antidiuretic hormone (ADH) is an osmoregulatory hormone that is also called vasopressin because it produces vasoconstriction.

35. Actions
The vasoconstrictor effects of vasopressin are mediated by specialized vasopressin (V1) receptors located on vascular smooth muscle.
Vasoconstriction is most prominent in skin, skeletal muscle, and splanchnic circulations .
Exogenous vasopressin does not increase blood pressure in healthy volunteers, but it can produce significant increases in blood pressure in patients with hypotension caused by peripheral vasodilatation.
This type of hypotension occurs in septic shock, anaphylactic shock, autonomic insufficiency, and the hypotension associated with spinal and general anesthesia.

36. Other actions of vasopressin include enhanced water reabsorption in the distal renal tubules (mediated by V2 receptors), and stimulation of ACTH release by the anterior pituitary gland (mediated by V3 receptors).
These actions are clinically silent when vasopressin is administered in the recommended doses.

37. Clinical Uses
Vasopressin can be used in the following clinical situations.
In the resuscitation of cardiac arrest, vasopressin can be given as a single IV dose (40 units) to replace the first or second dose of epinephrine.
In cases of septic shock that are resistant, or refractory, to hemodynamic support with norepinephrine or dopamine, a vasopressin infusion can be used to raise the blood pressure and reduce the catecholamine requirement (catecholamine sparing effect) . Unfortunately, there is no survival benefit associated with the this practice .
In cases of hemorrhage from esophageal or gastric varices, vasopressin infusions can be used to promote splanchnic vasoconstriction and reduce the rate of bleeding.

38. Dosing Regimen
The plasma half-life of exogenous vasopressin is 5 – 20 min , so vasopressin must be given by continuous infusion to produce prolonged effects.
In septic shock, the recommended infusion rate is 0.01 – 0.04 units/min, and a rate of 0.03 units/min is most popular.

39. Adverse Effects
Adverse effects are uncommon with infusion rates < 0.04 units/hr .
At higher infusion rates, unwanted effects can include consequences of excessive vasoconstriction (e.g., impaired renal and hepatic function), along with excessive water retention and hyponatremia.

40. Terlipressin
Terlipressin is a vasopressin analogue that has two advantages over vasopressin.
First, it is a selective V1 receptor agonist, and does not produce the
side effects associated with stimulation of the other vasopressin receptors.
Secondly, terlipressin has a much longer duration of action than vasopressin, and a single IV dose of 1 – 2 mg can raise the blood pressure for 5 hours .

41. The long duration of action allows terlipressin to be given by intermittent IV dosing.
Terlipressin is a potent splanchnic vasoconstrictor, and may prove valuable in the management of variceal bleeding.
However, there is an increased risk of splanchnic ischemia with terlipressin, and ischemic effects cannot be reversed for 5 hours after the drug is administered.
Like vasopressin, there is no survival advantage associated with the addition of terlipressin in patients with septic shock

42. Select inotrope or vasopressors
Despite adequate volume replacement, if the patient is hypotensive and perfusion of vital organs is jeopardized, vasoactive agents may be administered to improve cardiac output and blood pressure.
It is useful to understand the receptors through which adrenergic agents exert their effect.
• Three broad groups of agents may be identified:
1. Predominant b -agonists (dobutamine, dopexamine, isoprenaline)
2. Predominant a -agonists (phenylephrine)
3. Those with mixed b - and a -effects (adrenaline and noradrenaline).

43. In general, when the heart is failing, and the peripheral vascular resistance is normal, an agent with predominant inotropic effect (especially a b -1 selective agent) would be a good choice.
If there is vasodilatation, a vasoconstrictor with predominant a -agonist activity is appropriate.
Familiarize with doses and effects of commonly used inotropes and vasopressors.
Consider practical aspects of vasopressor infusion:
– Infuse through large veins preferably central veins.
– Use multi-lumen catheters and use dedicated lumen for vasopressor infusion.
– No other drug bolus or infusion should be given through the same lumen.

44. Use infusion or syringe pumps or other infusion controllers.
Invasive arterial pressure should be measured.
Dobutamine and other inodilators may be given through peripheral line.
Volume defi cit should always be corrected as much as possible before resorting to vasopressors which would lead to a false sense of security by increasing blood pressure while underlying hypovolemia and resultant low perfusion will lead to subsequent organ dysfunction.

45. Titrate inotropes and vasopressors
All inotropes and vasopressors should be titrated so that tissue perfusion is restored with the lowest dose of drug and to the desired end points with minimal or no side effects:
– Titrate to clinical improvements in heart rate (HR) and mean arterial pressure (MAP).
– Titrate inotropes to desired cardiac output.

46. – Titrate vasopressors to MAP of 65–70 mmHg.
Do not aim for supranormal cardiac output:
– Titrate vasopressors to MAP of 65–70 mmHg.
– In patients with long-standing hypertension, renal failure, recent cerebral infarct, and increased intra-abdominal pressure, a higher MAP may be desirable.
– In trauma with active bleeding, a lower MAP till bleeding source is controlled is advisable.
– Aiming for higher MAP than desired may result in unnecessary vasoconstriction.
– Titrate to achieve adequacy of organ perfusion
• Urine output more than 0.5 mL/Kg/h
• ScvO 2 more than 70%
• Reduction in lactate levels over time (e.g., 20% over 2 h)
• Watch for side effects: tachycardia, arrhythmias, cardiac ischemia

47. Doses and effects of commonly used inotropes and vasopressors

50. Levosimendan
– It is a myo fi lament calcium sensitizer. It increases myocardial contractility without increasing myocardial ATP consumption, thereby improving contraction at low energy cost.
– It causes normal or improved diastolic relaxation and vasodilatation.
– It has been studied in acute decompensated heart failure, during and after cardiac surgery, and postmyocardial infarction.

51. MILRINONE: Milrinone is a phosphodiesterase inhibitor that enhances myocardial contractility and relaxation via the same mechanism as dobutamine (i.e., cyclic AMP-mediated calcium influx into cardiac myocytes).
Milrinone has similar effects on cardiac performance as dobutamine, but
is more likely to produce hypotension .

52. Digitalis glycosides
– The digitalis glycosides have long been used as inotropic agents.
– However, today their role in the treatment of acute heart failure or cardiogenic shock is limited to control of the ventricular rate response in fast atrial fi brillation.
– The onset of action of effects of digoxin takes 90 min after an intravenous loading dose, and peak effect occurs at 2–6 h.
– The effects of digoxin are modest and unpredictable, and it has a narrow therapeutic index

53. • Agents used in septic shock
The Surviving Sepsis Campaign makes the following evidence-based recommendations in patients with sepsis:
– Vasopressors
• Recommend to maintain MAP ³ 65 mmHg.
• Recommend noradrenaline centrally administered as the initial vasopressors of choice.
• Suggest that dopamine, adrenaline, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock.
• Vasopressin at dose of 0.03 unit/min may be subsequently added to noradrenaline with anticipation of an effect equivalent to noradrenaline alone

54. Use adrenaline as the fi rst alternative agent in septic shock when blood pressure is poorly responsive to noradrenaline
Recommend not to use low-dose dopamine for renal protection.
Recommend to insert an arterial catheter in patients requiring vaso pressors, as soon as practical.
– Inotropic therapy
• Recommend the use of dobutamine in patients with myocardial dysfunction as supported by elevated cardiac fi lling pressures and low cardiac output.
• Do not increase cardiac index to predetermined supranormal levels.

55. Understand limitations of vasopressor and inotrope therapy
• All inotropic and vasopressor drugs may increase myocardial oxygen demand. • Increasing blood pressure by use of vasopressors does not lead to increased perfusion all the time; in certain circumstances like hypovolemia, it might lead to decreased fl ow to end organs. • Tachycardia may occur, especially in volume-depleted patients. • Arrhythmias. • Catecholamines also have signi fi cant neurohumoral and metabolic effects, which might be deleterious, for example, hyperglycemia and hyperlactatemia induced by adrenaline and suppression of prolactin by dopamine.

56. Wean inotropes and vasopressors
All attempts should be made to treat underlying cause of low perfusion state whenever feasible and vasopressors should be weaned off at the earliest.
• If necessary, additional fl uid challenges may be used judiciously in order to wean off vasopressors

57. The following broad recommendations can be made:
Smaller combined doses of inotropes and vasopressors may be advantageous over a single agent used at higher doses to avoid dose-related adverse effects.
The use of vasopressin at low to moderate doses may allow catecholamine sparing, and it may be particularly useful in settings of catecholamine hyposensitivity and after prolonged critical illness.
In cardiogenic shock complicating AMI, current guidelines based on expert opinion recommend dopamine or dobutamine as first-line agents with moderate hypotension (systolic blood pressure 70 to 100 mm Hg) and norepinephrine as the preferred therapy for severe hypotension (systolic blood pressure 70 mm Hg).

58. Routine inotropic use is not recommended for end-stage HF
Routine inotropic use is not recommended for end-stage HF. When such use is essential, every effort should be made to either reinstitute stable oral therapy as quickly as possible or use destination therapy such as cardiac transplantation or LV assist device support.
Large randomized trials focusing on clinical outcomes are needed to better assess the clinical efficacy of these agents

59. THANK-YOU