Vasopressor and inotropes are beneficial in shock states. Norepinephrine is considered the first-line vasopressor for patients with sepsis-associated hypotension. Dobutamine is considered the first-line inotrope in sepsis, and should be considered for patients with evidence of myocardial dysfunction or ongoing signs of hypoperfusion. Vasopressor and inotrope therapy has complex effects that are often difficult to predict; emergency providers should consider the physiology and clinical trial data. It is essential to continually reevaluate the patient to determine if the selected treatment is having the intended result.
Key points
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Vasopressors and inotropes are beneficial in shock states when they increase the systemic arterial pressure to allow autoregulation, increase venous return, augment abnormal cardiac contractility, or increase the coronary perfusion gradient.
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Norepinephrine should be administered within 6 hours in patients with sepsis-associated hypotension that does not correct with an initial 30 mL/kg crystalloid fluid bolus.
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Dobutamine should be considered in septic patients with evidence of myocardial dysfunction or signs of hypoperfusion despite restoration of adequate intravascular volume and mean arterial pressure with fluid and vasopressor therapy.
Introduction
The British physician George Oliver was among the first to investigate the vasoactive properties of the adrenal gland. In 1893, using his son as a research subject, Dr Oliver observed that ingestion of sheep adrenal extract produced narrowing of the radial artery diameter. Over the next 2 years, Dr Oliver, working with the physiologist Edward A. Schäfer from the University of London, described both the lethal effects of large amounts of the substance and the ability of lower doses to increase arteriolar blood pressure in animal models. Efforts to isolate a pure form of the active constituent of the adrenal gland extract, generically referred to as ‘epinephrine,’ would not be achieved until 1901, when the Japanese chemist Jokichi Takamine successfully marketed the substance under the proprietary name adrenalin . George Crile, the cardiovascular surgeon and Cleveland Clinic cofounder, would be among the first to demonstrate the clinical applications of synthetic adrenaline and its power to restore arterial blood pressure in surgical patients with various forms of shock. He would go on to describe adrenaline’s resuscitative effects in dogs with induced cardiac arrest. There would not, however, be a definitive thesis of the adrenoreceptor mechanism until Raymond Ahlquist published his seminal paper in 1948 proposing the existence of alpha- and beta-receptors.
Introduction
The British physician George Oliver was among the first to investigate the vasoactive properties of the adrenal gland. In 1893, using his son as a research subject, Dr Oliver observed that ingestion of sheep adrenal extract produced narrowing of the radial artery diameter. Over the next 2 years, Dr Oliver, working with the physiologist Edward A. Schäfer from the University of London, described both the lethal effects of large amounts of the substance and the ability of lower doses to increase arteriolar blood pressure in animal models. Efforts to isolate a pure form of the active constituent of the adrenal gland extract, generically referred to as ‘epinephrine,’ would not be achieved until 1901, when the Japanese chemist Jokichi Takamine successfully marketed the substance under the proprietary name adrenalin . George Crile, the cardiovascular surgeon and Cleveland Clinic cofounder, would be among the first to demonstrate the clinical applications of synthetic adrenaline and its power to restore arterial blood pressure in surgical patients with various forms of shock. He would go on to describe adrenaline’s resuscitative effects in dogs with induced cardiac arrest. There would not, however, be a definitive thesis of the adrenoreceptor mechanism until Raymond Ahlquist published his seminal paper in 1948 proposing the existence of alpha- and beta-receptors.
Physiologic rationale for vasoactive medications in patients with severe sepsis
Vasopressor and inotrope medications are vasoactive agents used in shock states to assist in the restoration of impaired perfusion. The physiologic effects these agents in sepsis-associated hypoperfusion are diverse and, often, overlap ( Table 1 ). Before reviewing the clinical application of individual vasoactive medications, it is useful to consider the primary therapeutic effects of each agent on the arterial, venous, and cardiac systems of patients in shock.
| Agent | Indication | Activity in Sepsis and Septic Shock | Receptor Binding | Typical Dose | Adverse Effects | |
|---|---|---|---|---|---|---|
| Norepinephrine | Shock (septic, cardiogenic) | Inoconstriction, mobilizes unstressed venous blood volume; provides some direct inotropic support |
|
| 0.02–0.3 μg/kg/min | Tachyarrhythmias, cardiac myocyte apoptosis, limb ischemia |
| Epinephrine | Shock (septic, cardiogenic), cardiac arrest, symptomatic bradycardia, anaphylaxis | Inoconstriction, mostly β 1 effects at doses up to 0.1 μg/kg/min; α 1 effects predominate at higher doses |
|
| 0.01–0.20 μg/kg/min | Ventricular arrhythmias, severe hypertension leading to cerebrovascular events, limb ischemia, metabolic acidemia, and lactic acidosis |
| Vasopressin | Shock (septic, vasoplegic), ± cardiac arrest | Vasoconstriction of the pulmonary and systemic vasculature, adjunctive |
| 0.01–0.04 U/min | Tachyarrhythmias, digital ischemia | |
| Dopamine | Symptomatic bradycardia, shock (septic, cardiogenic) | Inoconstriction, vasodilatory via DA receptors at doses <2 μg/kg/min; β 1 effects from 2–5 μg/kg/min; α 1 predominate at higher doses |
|
| 2–20 μg/kg/min | Tachyarrhythmias, cardiac ischemia, severe hypertension |
| Phenylephrine | Acute hypotension (vagal, medication related), aortic stenosis w/hypotension, HCM with LVOT gradient | Vasoconstriction, adjunctive |
|
| 100–180 μg/min initial, 40–60 μg/min maintenance; boluses 50–200 μg q20 min | Worsening cardiac function, baroreflex bradycardia |
| Dobutamine | Shock (cardiogenic, septic cardiomyopathy), ADHF/low CO states | Inodilatation, mostly β 1 and β 2 effects <15 μg/kg/min; mild α 1 at higher doses but offset by β 2 |
|
| 5–15 μg/kg/min | Ventricular arrhythmias, cardiac ischemia, hypotension as a known β 2 effect |
| Milrinone | Low CO states refractory to dobutamine and/or in chronically β-blocked patients, or in RV failure with pHTN | Inodilatation, decreases pulmonary vascular resistance |
|
| 0.25–0.75 μg/kg/min | Profound vasodilatory effects mediated through PDE3 inhibition, torsades and other ventricular arrhythmias |
Effect of Vasopressors and Inotropes on the Systemic Arterial System
In general, vasopressors induce vasoconstriction within the arterial system, whereas inotropes increase cardiac contractility. In reality, most vasoactive agents produce both effects. The most commonly used vasopressor and inotrope medications are synthetic catecholamines that stimulate alpha, beta, and dopaminergic receptors in the arteries and arterioles. Typically, the alpha effects predominate in these vessels, especially at standard doses. Specifically, stimulation of alpha-1 receptors on vascular smooth muscle cells leads to an increase in intracellular calcium, and, consequently, intense vasoconstriction and increased systemic blood pressure.
The small arterioles supply most of the resistance in the high-pressure systemic arterial circulation. This is essential for autoregulation, the process by which tissues control their own blood flow. Tissues that require increased perfusion can dilate their arterioles and admit additional blood flow into their capillary beds. Autoregulation, therefore, improves the distribution of blood flow within the arterial system. Importantly, autoregulation requires that the pressure in systemic arteries exceed a minimum threshold. If systemic arterial blood pressure falls below this minimum threshold, there can be an insufficient pressure gradient for perfusion. Agents with vasoconstrictive activity can therefore help to increase the resistance and pressure in the systemic arteries and arterioles above the threshold required to enable autoregulation, restoring critical perfusion to regional vascular beds.
Effect of Vasopressors and Inotropes on the Systemic Venous System
Normally, the compliant systemic venous system contains two-thirds of the total blood volume. Smooth muscle in the walls of systemic veins constrict in response to activation of alpha and vasopressin (a noncatecholamine vasoconstrictor) receptors. This feature allows the systemic veins to serve as an adjustable blood reservoir that is under autonomic control. The venous reservoir has an average pressure that is independent of the pressure generated by the heart’s pumping, and is determined by both the circulating volume of blood and the intrinsic stiffness of the vessel walls. This pressure, called the mean systemic filling pressure (MSFP), is normally around 7 mm Hg. For blood to return to the heart, the MSFP must be greater than the right atrial pressure, which is normally 0 mm Hg in early diastole. The rate of venous return to the heart depends on the pressure gradient between the MSFP and the right atrium. Endogenous vasopressors play an essential role in regulating venous return through their ability to increase MSFP, increase this pressure gradient, and drive blood into the heart. A normal heart responds to increased venous return by increasing its output by the Frank–Starling mechanism and autonomic reflexes. Importantly, this mechanism of increasing cardiac output occurs independent of direct cardiac stimulation, and is similar to the effect of a fluid bolus.
Effect of Vasopressors and Inotropes on the Heart
Vasoactive agents that stimulate beta-receptors, specifically beta-1 receptors, increase cardiac myocyte contractility; an effect mediated by an increase in intracellular cyclic adenosine monophosphate (cAMP) and intracellular calcium. The enhanced contractility that results can increase stroke volume and reduce ventricular end-diastolic volume and filling pressures. Beta agonists, however, typically cause only a modest increase in cardiac output because the unstimulated heart is normally able to eject almost all of the blood that has returned to it. Significant increases in cardiac output will only occur if the end-diastolic volume is abnormally increased, as occurs in the setting of myocardial dysfunction. Beta agonists may also improve cardiac performance through increased chronotropy (beta-1) and enhanced lusitropy (beta-2). Activation of beta-2 receptors also results in relaxation of vascular smooth muscle and, consequently, peripheral arterial vasodilation. In certain clinical scenarios, this can offset the work imposed on the heart by the vasculature and improve cardiac performance.
Vasopressors also improve cardiac performance by augmenting coronary artery perfusion. The coronary arteries carry nutrient blood flow from the aorta to the myocardium. During systole, the high pressure generated by ventricular contraction compresses the coronary arteries within the walls of the myocardium, resulting in both anterograde and retrograde flow. The relative proportion of anterograde and retrograde flow depends on the pressure gradient between the aorta and the ventricles. Coronary perfusion to either ventricle can decrease precipitously if intraventricular pressures increase at the same time systemic arterial pressure decreases. A vicious and potentially rapidly fatal cycle of low cardiac output reducing coronary perfusion ensues, which further reduces cardiac performance. This can occur in multiple clinical scenarios ( Box 1 ). In these settings, vasopressors can serve to increase vascular tone, restore systemic arterial pressure, and preserve the coronary perfusion gradient, thereby minimizing myocardial ischemia. This approach has been shown to be effective in experimental models of pulmonary embolism, tamponade, and cardiogenic shock from left ventricular ischemia.
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Cardiac tamponade
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Aortic stenosis
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Hypertrophic obstructive cardiomyopathy
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Pulmonary embolism
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Pulmonary hypertension
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Systolic heart failure
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Cardiopulmonary resuscitation
Vasopressors and inotropes have multiple effects on cardiac performance and perfusion in shock states. The net effect will vary depending on the clinical situation. In general, benefit will be realized when use of vasoactive agents (1) increases the systemic arterial pressure to greater than the threshold to allow autoregulation, (2) increases venous return, (3) augments abnormal cardiac contractility, or (4) increases the coronary perfusion gradient.
Other Physiologic Effects of Vasopressors and Inotropes
Vasoactive agents exert a multitude of other significant physiologic effects. Select agents result in pulmonary artery constriction and increased pulmonary vascular resistance. However, the right ventricular strain this effect can produce is typically offset by a simultaneous improvement in both cardiac contractility and the coronary perfusion gradient. Vasoactive agents also have important metabolic effects. Beta agonists, particularly epinephrine, can increase blood glucose and lactate concentrations. Both epinephrine and norepinephrine increase kaliuresis and urine output independent of their effect on blood pressure and cardiac output.
Initiating vasopressor therapy in severe sepsis
The Surviving Sepsis Campaign (SSC) recommends vasopressor therapy in patients with severe sepsis within 6 hours if hypotension, defined as a mean arterial blood pressure (MAP) of less than 65 mm Hg, persists after a 30 mL/kg crystalloid fluid bolus. In practice, many patients whose hemodynamics and physical examination findings improve with appropriate initial volume resuscitation will, nevertheless, receive additional volume before vasopressor therapy is started. Accurate estimation of intravascular volume status is challenging in an emergency department setting. What is considered ‘adequate’ volume resuscitation is often determined at the point of volume unresponsiveness, or the failure of additional fluid boluses to further augment indices of cardiac output. This approach, however, can lead to overresuscitation with large volumes of crystalloid and the sequelae of acute renal insufficiency, cardiac insufficiency, pulmonary edema, and prolonged ventilator dependency.
Time to initiation of vasopressors may prove to be an independent predictor of mortality. A recent retrospective cohort study in patients with septic shock found that mortality rates increased with increasing time to norepinephrine initiation; this was true even when vasopressors were begun within the SSC’s recommended 6-hour window. Patients who received norepinephrine within 2 hours of onset of septic shock had significantly lower 28-day mortality rates compared with patients who received vasopressors after 2 hours of shock (30% vs 43%). In this study, mortality rates increased by 5.3% for every hour delay in vasopressor initiation once shock was recognized. Earlier administration of norepinephrine also led to shorter duration of vasopressor use and lower total doses of the drug administered. Patients in whom norepinephrine was started after 2 hours also took significantly longer to achieve goal MAPs than patients in the early initiation group (6.1 vs 4.6 hours; P <.001). Importantly, both groups received similar volumes of fluid within the first 6 hours, and there were no differences in time to antibiotic initiation or corticosteroid use.
Vasopressor use typically requires a central venous catheter. The time and effort required for catheter insertion, as well as the known complications of the procedure, may contribute to provider delay in initiating vasopressor therapy. Central venous catheter placement and use is associated with infectious, thrombotic, and mechanical complications. The safety of peripherally administered vasopressors, however, remains a subject of debate, with tissue necrosis, gangrene, or limb ischemia resulting from vasopressor extravasation being primary concerns. The first randomized controlled trial comparing mechanical, infectious, and thrombotic complication rates in patients in the intensive care unit (ICU) receiving vasopressor therapy via peripheral or central venous catheters demonstrated a trend toward increased complications in the peripheral catheter group. The majority of complications were attributed to difficulty with peripheral catheter insertion, insertion-site erythema, and subcutaneous extravasation with subsequent blistering, or local tissue necrosis. There were no differences in mortality between the central and peripheral catheter groups; however, more than one-half of the peripheral catheter group eventually required central venous catheter placement because of increasing vasopressor requirements or because peripheral access could not be obtained.
A more recent single-arm study in 734 ICU patients who received peripheral norepinephrine, dopamine, or phenylephrine for a median of 49 hours demonstrated the safety of administering these agents peripherally when local phentolamine and nitroglycerin paste were used in combination to treat incidences of peripheral extravasation. No cases of tissue injury resulted. Importantly, the study protocol mandated the use of at least 20-G catheters placed in vessels with diameters of greater than 4 mm, as determined on bedside ultrasonography. Importantly, the integrity of the catheters was assessed every 2 hours by nursing staff.
A recent systematic review composed of mostly case reviews and case studies concluded that the peripheral administration of vasopressors is safe for short durations (<2 hours) via larger bore catheters that are placed proximal to the antecubital and popliteal fossae. This review recommended the use of peripherally administered vasopressors only as a temporizing measure while central access is obtained.
When using vasopressors, it is important to remember that local derangements of the microcirculation (ie, perfusion of regional capillary beds) may persist despite optimization of surrogate macrocirculatory variables. Boerma and Ince cite in vitro studies demonstrating that capillary hematocrits vary dynamically, from 6.8% to 38%, despite a systemic hematocrit of 50%, depending on whether there is upstream vasoconstriction or dilatation of the contributing arterioles. Vasoconstriction also increases the diffusion distance of oxygen, which is inversely proportional to oxygen delivery at the cellular level. Various imaging and detection modalities have been used to capture the state of the microcirculation in severe sepsis and have underscored the heterogeneity of flow to different microvascular beds despite optimization of macrocirculatory variables. Although it is clear that a functioning microcirculation requires a minimum MAP, it is not always the case that meeting threshold MAPs will be sufficient to normalize flow to these low-pressure vascular beds.
Norepinephrine
Norepinephrine is the first-line vasopressor in patients with sepsis or septic shock. It is a hydroxylated derivative of dopamine and stimulates both alpha and beta receptors. Its alpha-1 effects predominate at therapeutic doses. As noted, the venous effects of norepinephrine (augmentation of MSFP) act similarly to a fluid bolus, and can provide preload support during simultaneous fluid resuscitation. Norepinephrine also provides moderate inotropic support via its beta-1 activity.
At therapeutic doses, norepinephrine carries a lesser risk of serious adverse events than dopamine in the treatment of septic shock, with an absolute risk reduction of 11% in mortality compared with dopamine in a recent systematic review. Dopamine also doubled the risk of cardiac arrhythmias in this analysis and in an earlier metaanalysis by De Backer and colleagues, who reported a relative risk of arrhythmias of 2.34 when dopamine was used instead of norepinephrine in patients with septic shock. Prolonged use of norepinephrine, however, can be directly toxic to cardiac myocytes and may result in reflex bradycardia, cardiac arrhythmia, and tissue ischemia as a result of profound vasoconstriction.
Epinephrine
Epinephrine is a potent nonselective alpha and beta agonist recommended by the SSC for use in sepsis-associated hypotension as either a first alternative or in addition to norepinephrine when norepinephrine fails to achieve hemodynamic goals. It is also the first-line vasopressor in cardiac arrest and, like dopamine, is recommended for use in symptomatic bradycardia that does not respond to atropine.
Epinephrine is typically administered at doses of 0.01 to 0.20 μg/kg/min. Its beta effects predominate at lower doses, up to 0.1 μg/kg/min, and it has powerful effects on cardiac contractility and heart rate in this range. At higher doses, epinephrine’s alpha-1–mediated vasoconstrictive effects predominate, and its inoconstricting properties begin to approximate those of combined norepinephrine and dobutamine. A multicenter, randomized, controlled, double-blind study of 330 patients with septic shock showed no differences in the duration of vasopressor dependency, ICU or hospital duration of stay, or 28- and 90-day mortality when vasopressor therapy with epinephrine plus placebo was compared with combined norepinephrine and dobutamine. There was no increase in adverse events in the epinephrine group; however, the epinephrine group did have significantly lower arterial pH values over the first 4 days, with significantly higher arterial lactate values on day one. Although these findings had no effect on the primary outcomes of interest, epinephrine’s acid–base and metabolic effects are well-documented, and may reflect local ischemia from alpha-1–mediated vasoconstriction, although it is increasingly believed that these effects result from the beta-2–mediated activation of the aerobic glycolytic pathway.
Vasopressin
Vasopressin is an endogenous peptide hormone that produces contraction of vascular smooth muscle via V 1 receptors, which are ubiquitous in the systemic circulation, especially the skin and splanchnic vessels. It is considered a nonadrenergic vasopressor adjunct in the treatment of sepsis-associated hypotension. Under normal physiologic conditions, vasopressin is primarily responsible for free water homeostasis. In healthy subjects, it is associated with only moderate vasoconstriction in the pulmonary and renal arterial systems and, at very low doses, can actually lead to pulmonary vasodilatation via release of endothelial nitric oxide. The latter effect may be helpful in specific instances of acute right ventricular failure. Vasopressin’s effects on arterial tone becomes more significant in instances of acute hypotension, when it is released from the neurohypophysis in concentrations that are tens to hundreds of times greater than basal levels. Endogenous vasopressin stores can become depleted within hours of shock onset. In this setting, normalization of circulating concentrations with exogenous administration can result in marked peripheral vasoconstriction and increased systolic and diastolic pressures.
At the standard therapeutic dose, vasopressin is considered a “catecholamine-sparing” agent in severe sepsis, and is used most often in conjunction with norepinephrine. The SSC does not recommended its use as a single agent. The VASST (Vasopressin and Septic Shock Trial) study was a multicenter, randomized controlled, double-blind study of 778 septic patients who were dependent on vasopressor therapy to maintain goal MAPs. The study was designed to evaluate the use of the combination of vasopressin and norepinephrine compared with norepinephrine alone. Patients were stratified by disease severity based on their vasopressor requirements 1 hour before randomization; patients requiring 5 to 14 μg/min and greater than or equal to 15 μg/min of norepinephrine (or the equivalent) were considered to have less and more severe forms of septic shock, respectively. The use of low-dose vasopressin (0.03 U/min) significantly decreased the requirement for norepinephrine over the first 4 days of treatment, although this did not result in fewer adverse events. The study authors did report a trend toward improved 28- and 90-day mortality among patients with less severe shock in the combined therapy group, although the vasopressin group also demonstrated a trend toward higher incidence of digit ischemia ( P = .11). Importantly, the study was neither powered to detect a mortality difference between combination vasopressin and norepinephrine therapy and single-agent norepinephrine, nor was it a study of vasopressor-refractory shock.
Dopamine
Dopamine is no longer considered first-line treatment for hypotension in sepsis or septic shock. Its recommended use in sepsis is limited to a subset of patients at low risk for tachyarrhythmias or with bradycardia. In the 2013 American Heart Association guidelines, dopamine was also no longer recommended as the first-line vasoactive medication in cardiogenic shock. Dopamine remains an important component of the Advanced Cardiac Life Support protocol for the treatment of symptomatic bradycardia.
At low doses, dopamine acts primarily through presynaptic and postsynaptic dopaminergic DA2 and DA1 receptors, respectively. These receptors are scattered throughout the coronary, cerebral, renal, and splanchnic vascular beds. In healthy subjects, dopamine has been shown to directly increase effective renal plasma flow and natriuresis in a dose-dependent fashion, via a noncatecholaminergic pathway and independent of any changes in cardiac output. For this reason, ‘renal dose’ dopamine was once thought to restore renal perfusion and protect septic patients from risk of acute kidney injury. However, one of the first randomized controlled trials on the subject demonstrated no benefit for progression to severe kidney injury or need for renal replacement therapy when low-dose dopamine was compared with placebo. Similarly, Marik and Iglesias showed no difference in progression to acute renal failure, the need for renal replacement therapy, or 28-day survival when low-dose dopamine, high-dose dopamine, and no dopamine strategies were compared in 395 oliguric patients with septic shock. The study authors postulated that renal afferent arteriolar dilatation is already maximized under septic conditions, thus limiting low-dose dopamine’s potential renovascular protective effects. In another prospective, double-blind, randomized controlled study of 40 ICU patients, low-dose dopamine resulted in decreased renal vascular resistance in patients with preserved renal function; the same doses, however, worsened resistive indices and renal perfusion in patients greater than 55 years of age with preexisting renal insufficiency. The physiologic basis for this finding is not clear, but the study authors suggest that increased levels of endogenous dopamine in older patients with underlying renal insufficiency may predispose to higher tissue-specific concentrations of dopamine when the drug is administered exogenously. As a result of these and other studies, the use of low-dose dopamine for renal protection in sepsis is no longer recommended.
At doses of 2 to 10 μg/kg/min, dopamine’s beta-1 effects become more apparent, and its effects on inotropy, dromotropy, and chronotropy predominate. In chronically beta-blocked patients, however, dopamine’s DA1- and DA2-mediated effects may continue to have significant effect even at these doses, and vasodilatation of the renal and splanchnic vasculature can precipitate worsening hypotension.
At doses between 10 and 20 μg/kg/min, dopamine’s alpha-1 effects predominate, increasing peripheral vascular resistance and MAP. Administration of doses of greater than 20 μg/kg/min can result in profound vasoconstriction, lead to limb ischemia, and worsen end-organ perfusion. Doses in this range are not recommended.
In a predefined subgroup analysis of the SOAP (Sepsis Occurrence in Acutely Ill Patients) II trial, a 2010 randomized controlled trial comparing dopamine and norepinephrine use in all forms of shock, there were no apparent differences in 28-day mortality in patients with septic shock; dopamine use was, however, associated with worse survival curves in patients with cardiogenic shock. The reason for the increased mortality risk in these patients is unclear, but study investigators surmised that dopamine-mediated increases in heart rate were contributory. Notably, the median dopamine doses for all patients over the first 7 days fell within the medium to high dose range, but did not exceed 17 μg/kg/min.
Phenylephrine
Phenylephrine is a pure alpha-1 agonist whose use in sepsis is not recommended except in very circumscribed conditions that include when norepinephrine use leads to or can be expected to exacerbate serious cardiac arrhythmias, when cardiac output is known to be high despite persistent hypotension, or as a vasopressor adjunct in refractory hypotension. Its use is more ideally suited to the purpose of rapidly correcting vasodilatory hypotension (eg, medication related or vagally mediated). Phenylephrine increases both arterial and venous tone at therapeutic doses and leads to rapid changes in MAP and a baroreflex-mediated bradycardia.
Randomized, controlled trials comparing the use of phenylephrine with norepinephrine in septic shock have explicitly excluded patients with underlying cardiac dysfunction, or only included patients with baseline normal-to-high cardiac indices. These studies failed to demonstrate any worsening of cardiac output when phenylephrine was used for hemodynamic support in septic shock. A study using animal models of septic shock with sepsis-induced cardiomyopathy, however, demonstrated worsening ventricular performance when phenylephrine was used. A study of 18 nonseptic patients with underlying cardiac insufficiency demonstrated that single dose phenylephrine, in boluses of 50 to 200 μg, increased the MAP within 20 to 40 seconds of the infusion, with a concurrent and predictable worsening of cardiac output. Negative effects on cardiac output were greatest in the patients with the poorest baseline cardiac function. Given the prevalence of sepsis-associated cardiomyopathy and the challenges of appreciating the full complexity of an acutely ill patient’s medical history in an emergency department setting, phenylephrine should be used rarely and with extreme caution.
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