An Evidence-Based Approach to Pressors in Shock: Part II
- Feb 26th, 2018
- Sarah Brubaker
Author: Sarah Brubaker, MD (EM Resident, San Antonio, TX) // Edited by Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit, EM Attending, San Antonio, TX)
This is the second article in a discussion about the use of pressors in circulatory shock. Part I discussed basic guidelines for pressor management, in addition to specific literature regarding “inopressors” (norepinephrine, epinephrine, and dobutamine). Part II will discuss “pure inotropes” (dobutamine and milrinone) and “pure vasopressors” (vasopressin and phenylephrine).
Inotropes work primarily to increase cardiac output; they increase stroke volume by improving cardiac contractility, as opposed to vasopressors, which increase blood pressure by increasing peripheral resistance (1). Inotropes can lead to peripheral vasodilation and have a variable effect on blood pressure; their use often results in hypotension. For this reason, inotropes should only be used in patients after complete fluid resuscitation. In addition, increased cardiac contractility leads to increased myocardial oxygen consumption (2), which can result in increased in-hospital mortality (3) and risk for myocardial infarction (1). Because inotrope use is rife with complications, research is currently underway in an attempt to find alternative options (4, 5).
There are only two inotropes frequently used in the United States: dobutamine and milrinone. Levosimendan is a calcium-channel sensitizer with equivalent efficacy to the dopamine and milrinone, and possibly lower morbidity and mortality (6). It is used in several European countries, but it is not FDA-approved for use in the United States. Therefore, this article will focus on dobutamine and milrinone.
Clinical Case #1:
A 79-year-old female with a history of CHF presents to your emergency department in acute respiratory distress. Her vital signs are: heart rate 104, blood pressure 84/58, respiratory rate 45, and oxygen saturation 84%. Exam reveals decreased lung sounds with diffuse crackles bilaterally, in addition to 2+ pitting edema to the knees. Bedside cardiac ultrasound demonstrates marked global hypokinesis. You give a dose of IV Lasix and initiate BiPAP. Several minutes after initiation of these treatments, the patient’s blood pressure is 75/45. You are unable to wean the patient off BiPAP, so you decided to continue positive pressure ventilation while starting a pressor. Which pressor should you use?
MECHANISM OF ACTION
Dobutamine is a synthetic catecholamine derivative (7) that stimulates beta-1 and beta-2 receptors (7, 8), at approximately a 3:1 ratio (9). At high doses (greater than 15 ug/kg/min), dobutamine also becomes a mild alpha-1 agonist. Because it primarily stimulates beta-1 receptors, dobutamine confers predominantly inotropic effects, with less pronounced chronotropic effects.
Dobutamine’s stimulation of beta-2 receptors can result in peripheral vasodilation, though the magnitude of this effect is variable (1). Therefore, dobutamine can lead to decreased blood pressure in some (but not all) patients. Due to its vasodilatory effects, dobutamine has been shown to improve capillary perfusion independent of changes in blood pressure and cardiac index (10).
As a catecholamine analog, dobutamine may be used through a peripheral catheter (7). However, central access is strongly preferred.
Dobutamine was developed in an attempt to decrease the rates of myocardial ischemia associated with epinephrine and dopamine use. However, despite minimal chronotropic effects, studies have demonstrated increased myocardial oxygen demand and malignant arrhythmias (8, 11, 12). Although these adverse events typically occur at doses higher than 15 ug/kg/min, they can happen at any dose. Dobutamine use was found to substantially increase mortality at 180 days when compared with placebo in the CASINO study (13).
As noted above, many patients experience hypotension associated with dobutamine use. It should be used with caution in patients with systolic blood pressure less than 90 mmHg. In addition, dobutamine use often requires concomitant inopressor/vasopressor use. For this reason, dobutamine should only be used in patients with adequate fluid resuscitation (14).
It is important to note that dobutamine’s onset of action is 1-2 minutes (2), and the half-life is also approximately 2 minutes. Therefore, negative effects of dobutamine are theoretically rapidly reversible. In addition, dobutamine infusions lasting longer than 72 hours can lead to pharmacologic tolerance (1).
Surviving sepsis campaign guidelines recommend the use of dobutamine in patients with septic shock who display evidence of decreased cardiac output in the presence of adequate preload (15). This includes patients with known decreased ejection fracture and those who are persistently hypotensive despite adequate fluid administration and use of vasopressors.
Current ACC/AHA guidelines recommend using dobutamine as a first-line agent in management of hypotension associated with acute myocardial infarction (9, 16). However, because dobutamine can lower blood pressure, it should only be used if systolic blood pressure is between 70-100 mmHg, with norepinephrine ready (or already infusing) as well. Dobutamine is typically recommended as the first line agent in cardiogenic shock (17), but this is not a strong recommendation because several studies have demonstrated benefits to norepinephrine in this setting (18, 19). If dobutamine is used as a first-line agent, then norepinephrine should be second-line or already infusing, followed by milrinone.
Dobutamine can be started at 2 mcg/kg/min and titrated to effect, with a maximum dose of 20 mcg/kg/min.
Clinical Case #2:
You are treating a 79-year-old female in acute decompensated heart failure. You have given a dose of IV Lasix and initiated BiPAP. You are currently attempting to provide positive pressure ventilation while using pressors to maintain hemodynamic stability. You previously initiated a dobutamine drip, and then added norepinephrine. However, despite escalating doses of both pressors, the patient’s hemodynamic status does not improve. What can do you do now?
MECHANISM OF ACTION
Milrinone is a phosphodiesterase-3 (PDE3) inhibitor. PDE3 is present in cardiac myocytes and vascular smooth muscles; it ultimately leads to cardiac smooth muscle relaxation and peripheral vasoconstriction (1, 9). Therefore, PDE3 inhibition results in potent inotropy, in addition to diastolic relaxation and vasodilation. This leads to reduced preload, afterload, and systemic vascular resistance (SVR). In addition to increased cardiac contractility, this results in improved cardiac output. Milrinone has no beta-adrenergic activity, resulting in minimal chronotropic effects.
Because milrinone decreases preload (and therefore often leads to hypotension), it should only be used in patients who have undergone appropriate fluid resuscitation (8). In addition, the use of milrinone often necessitates concurrent vasopressor administration. The OPTIME-CHF study, an RCT involving 951 patients with systolic heart failure who did not require inotropic support, demonstrated increased rates of sustained hypotension and dysrhythmias (20).
Because milrinone is metabolized in the kidneys, it should be avoided in patients with renal disease (1).
In addition, milrinone has a substantially longer half-life compared to the other pressors. Because its half-life is approximately 1-2 hours (8), milrinone’s adverse effects can last for several hours. Milrinone should never be given as a bolus, and it should be slowly titrated from the lowest starting dose.
There are few studies directly comparing milrinone and dobutamine, so the exact indication for milrinone is unclear. However, because milrinone exerts its effects via PDE inhibition, it bypasses the catecholamine pathway. Therefore, it is recommended for use in patients with daily beta-blocker use and in patients with long-standing heart failure who have developed resistance to catecholamine derivatives (8).
Due to PDE’s vasodilatory effect on pulmonary vasculature, one would expect an advantage in patients with pulmonary hypertension (1). However, the use of milrinone in this setting has not been thoroughly studied.
The starting dose of milrinone should ideally be chosen based on that patient’s renal function. The general range is 0.25-0.75 mcg/kg/min. Avoid its use in patients with creatinine clearance less than 50 mL/min. Because of its long onset of action and half-life, milrinone should be titrated every 2 hours (or slower, in the presence of renal disease).
Pure Inotrope Summary
-Inotropes have traditionally been avoided due to their increased risk of arrhythmia and myocardial ischemia.
-Inotropes are indicated in septic shock when there is evidence of decreased cardiac function (echocardiogram with evidence of decreased ejection fraction, failure of blood pressure to improve with pressors, known CHF).
-Inotropes are first-line for cardiogenic shock.
-Dobutamine is generally preferred over milrinone, but milrinone is preferred in patients who take daily beta-blockers.
Clinical Case #3:
An 86-year-old man with a history of COPD, CHF, CAD, and ESRD presents to your emergency department via EMS for decreased mental status. When he arrives, he is alert but confused, with a rectal temperature of 102.4F, heart rate of 113, and blood pressure of 75/55. You immediately treat for sepsis, administering a fluid bolus, antipyretics, and broad-spectrum antibiotics. His hemodynamic status does not improve, so you initiate a norepinephrine drip. You titrate to 20 mcg/min, with minimal effect. You decide to initiate a second pressor. Which one should you choose?
MECHANISM OF ACTION
Vasopressin is an endogenously released hormone (also known as anti-diuretic hormone) that directly stimulates vasopressin receptors, located in the kidneys, to selectively constrict the efferent arterioles of the glomeruli. There are also vasopressin receptors on the peripheral vasculature, which directly stimulate vasoconstriction. It is believed that vasopressin also causes coronary and cerebral vasodilation (21).
Based on its mechanism of action, one would expect vasopressin to improve GFR. Several small RCTs and case studies have investigated this supposition, and each demonstrates improved renal function with vasopressin use (21-23). However, the VANISH trial (2016), which was the first large-scale RCT to compare the renal effects of vasopressin versus norepinephrine, failed to demonstrate a statistically significant difference between number of kidney-failure-free days for the first month after randomization (24). However, patients in the vasopressin group were less likely to require dialysis while hospitalized. Therefore, there is currently not enough evidence to suggest a renal-protective effect associated with vasopressin use.
There was once concern that vasopressin increases the risk of cardiac arrest. However, several studies have since disproven this belief. Most notably, two large, multicenter trials demonstrated equivalent mortality and complication rates between both vasopressin and norepinephrine. The first large RCT to investigate vasopressin, the VASST trial (2008), found lower mortality in the vasopressin group (26.5%) compared to the norepinephrine group (35.0%) in “less severe septic shock,” but equivalent mortality in “more severe septic shock” (25). The rates of adverse events were equivalent in both groups. The VANISH trial (2016) corroborated these findings.
Although serious adverse event rates were equivalent between both vasopressin and norepinephrine, vasopressin increases the risk of digital ischemia more significantly than the catecholamine derivatives. In addition, the risk of digital ischemia increases dramatically when epinephrine and vasopressin are given in combination (26).
It is important to note that because previous studies regarding the safety of peripheral intravenous access for pressors did not include vasopressin (27), there is not enough evidence to support the use of vasopressin through a peripheral intravenous line. In addition, unlike catecholamine derivatives, vasopressin does not have an antidote if extravasation does occur.
It has been proposed that vasopressin deficiency leads to the vasodilation associated with septic shock (28), as demonstrated by the vasopressin depletion that occurs with the progression of shock (29). Therefore, vasopressin was historically a first-line pressor for septic shock. However, current surviving sepsis guidelines recommend vasopressin as a second-line agent, after norepinephrine (15). Several studies have demonstrated similar efficacy between vasopressin and norepinephrine (30, 31). In addition, the VASST and VANISH trials demonstrate similar complication and mortality rates between vasopressin and the catecholamine derivatives. Therefore, vasopressin may become more highly recommended as further studies continue to support its use. However, at this time it is unclear which patients may benefit from vasopressin use. Vasopressin may be preferable to epinephrine in incidences of hyperkinetic cardiac function, severe tachycardia, and renal failure. Due to its increased risk for digital ischemia, it may be best to avoid vasopressin in patients with known peripheral vascular disease or other such risk factors.
It has been proposed that because vasopressin leads to coronary vasodilation, it may be a preferable agent in cardiogenic shock. One retrospective study in 2005 demonstrated favorable hemodynamic effects associated with vasopressin use, compared to norepinephrine (32). However, studies on this subject are contradictory, with several retrospective studies demonstrating increased mortality in vasopressin use during cardiogenic shock (33). There are few RCTs investigating vasopressin use in cardiogenic shock.
Because vasopressin may not lead to pulmonary vasoconstriction, it may be an ideal pressor choice in hypotension secondary to pulmonary hypertension. While a small number of studies in limited clinical scenarios have proposed the superiority of vasopressin in this setting (34), there have only been case reports on the topic (35). Therefore, there is not enough literature to support vasopressin’s routine use in pulmonary hypertension.
Some intensivists have suggested using epinephrine and vasopressin in combination, in an attempt to minimize the deleterious effects of both pressors while harnessing the strength of each. In theory, epinephrine has fewer peripheral effects, but would stimulate cardiac contraction, while vasopressin would improve renal microcirculation. However, this is not a well-established practice.
Because vasopressin is an endogenous hormone with a limited number of receptors, there is no utility to titrating vasopressin. Therefore, vasopressin is used at a set dose of 0.04 U/min, regardless of weight.
Clinical Case #4:
A 37-year-old male presents to the trauma bay after jumping off a bridge. His initial vital signs are heart rate 56, blood pressure 70/50, respiratory rate 30, and temperature 96.5F. His GCS is 14. He is alert but oriented only to person and place. He complains of severe neck pain. On exam, he has obvious deformities that are consistent with closed fractures of his upper and lower extremities. Upon examination of his spine, you note palpable midline tenderness and step-offs at multiple levels. Despite the administration of 2 units of packed red blood cells, the patient’s pressure is still 70/50. You initiate a norepinephrine drip and titrate to 20 mcg/min, but the patient’s capillary refill is still delayed and the blood pressure is only 80/54. You decide to initiate a second pressor. What should you choose?
MECHANISM OF ACTION
Phenylephrine is a pure alpha-1 agonist. It primarily affects large arterioles, with little effect on terminal arterioles (36, 37). In addition, because phenylephrine is solely an alpha agonist, it does not confer any inotropic effects.
Because phenylephrine is a pure vasopressor, it induces substantial increases in arterial and venous tone, without concomitant increases in cardiac function. This leads to rapid changes in MAP and baroreflex-mediated bradycardia (8), in addition to digital ischemia and possibly end-organ hypoperfusion. Several studies have demonstrated worsened cardiac function associated with phenylephrine use (37, 38).
Phenylephrine is no longer recommended in septic shock. In addition, it should also be avoided in other forms of shock. Phenylephrine’s role should ideally be limited to rapidly correcting vasodilatory hypotension, such as is seen in medication-overdose (8). In addition, it may be indicated in neurogenic shock, if the patient is known to have normal cardiac function. However, due to the possibility of reflex bradycardia, phenylephrine should only be initiated as an adjunct to norepinephrine (39, 40).
Phenylephrine can be initiated at 100-180 mcg/min initially, then titrated to 40-60 mcg/min as a maintenance dose. Boluses of 50-200 mcg can be used every 20 minutes as needed.
Pure Vasopressor Summary
-Pure vasopressors increase peripheral vasoconstriction, with minimal effects on heart rate and cardiac contractility.
-Current guidelines suggest using vasopressin as a second-line agent for septic shock, after norepinephrine.
-Vasopressin has a myriad of potential uses, including cardiogenic shock and pulmonary hypertension, but currently there is not enough literature to support its use in these settings.
–Vasopressin is associated with a high risk for digital ischemia, especially when used in combination with epinephrine.
-Phenylephrine should never be used in isolation, due to high risk for reflex bradycardia.
-Phenylephrine use should generally be avoided, but it may be useful as an adjunct to norepinephrine in neurogenic shock.
To bring everything together in an easy-to-use format, emDocs has a downloadable summary chart here: Inopressor Summary_chart
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3 thoughts on “An Evidence-Based Approach to Pressors in Shock: Part II”
Great review, very thorough and well researched. Only comment would be the norepi dosing on the supplementary chart. You have 2-4 mcg/min whereas all the other agents seem to have the overall dosing range and the norepi “dose” that’s listed is maybe the starting dose?
Hi Scott, thanks for reading and the comment! You are correct in that 2-4 mcg/min IV is the starting dose. The chart states “titrate to effect”, which is one of the most important components of the chart. Norepinephrine infusion requires monitoring to ensure patient hemodynamic response with titration.
Enjoyed reading both part 1+2. Very clear and informative.
Thankyou for your hardwork.