Vasopressors in Sepsis

Abstract

Background:

Sepsis accounts for 10% of intensive care unit admissions and significant healthcare costs. Although the mortality rate from sepsis has been decreasing with better critical care, early identification of septic patients, and prompt interventions, the mortality rate remains 20%–30%.

Method:

Review of the English-language literature.

Results:

Norepinephrine is the first-line vasopressor in shock and is associated with a lower mortality rate as well as fewer adverse effects. Dopamine has similar actions but is associated with significantly more tachydysrhythmias and should be reserved for patients with bradycardia. Epinephrine and vasopressin are appropriate second-line vasopressors and may enable use of lower doses of norepinephrine while improving hemodynamics. Inotropes may be added in patients with cardiac dysfunction.

Conclusion:

Appropriate treatment of sepsis includes prompt identification, early antimicrobial drug therapy, appropriate fluid resuscitation, and initiation of vasopressors in the presence of continued septic shock. Further research needs to be done to better understand the ideal timing of the addition of a second agent and the optimal combinations of vasopressors for individual patients.

The clinical syndrome of sepsis has been recognized since the beginning of medicine, with the first mention appearing 2,700 years ago in Homer's poems. The term is derived from the Greek word sepein, which means “to rot.” Hippocrates and Galen also described the disease as a decay of tissues [1]. In 1914, Schottmueller wrote “Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes signs of an illness.”

Even with the long knowledge of this disease, many questions remain unanswered, and sepsis and septic shock still are a significant cause of death and morbidity in current medical care. Sepsis accounts for 10% of intensive care unit (ICU) admissions and significant healthcare costs [2,3]. Although the mortality rate from sepsis has been decreasing with improved critical care, prompt identification of septic patients, and early interventions, the mortality rate remains 20%–30% [4].

In 2016, the Third International Consensus provided updated definitions of sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection [5]. In the updated version, septic shock is defined as sepsis with profound circulatory, cellular, and metabolic abnormalities requiring a vasopressor to maintain the mean arterial pressure (MAP) >65 mm Hg [5]. Sepsis management has improved greatly in recent years, with an emphasis on early identification of septic patients and prompt source control and antibiotic initiation and appropriate resuscitation [6]. In addition to treating the cause of the sepsis (i.e., source control and antimicrobial drug therapy), restoration of adequate perfusion and oxygen delivery to tissues is the over-reaching goal of treatment. Adequate perfusion leads to less organ dysfunction and failure. In numerous studies, organ dysfunction was associated with a higher risk of death in septic patients [7,8], and it follows that preventing organ dysfunction could decrease the mortality rate.

Sepsis and septic shock lead to profound alterations in physiology. Infection can cause direct changes as a result of exotoxin or endotoxin release or indirectly through a maladaptive host response to the infection. These responses lead to vasodilation, decreased systemic vascular resistance (SVR), and endothelial damage. This endothelial damage in turn causes microvascular thrombosis [9], tissue hypoxia, and capillary leak [10]. These aberrations in normal physiology produce organ damage and dysfunction throughout the body—leading to kidney failure, respiratory failure, thrombocytopenia and disseminated intravascular coagulation, altered serum glucose control, changes in mental status, loss of intestinal barriers, hypovolemia because of leakage into the third space, and loss of vascular tone leading to shock. Restoration of intravascular volume with volume resuscitation is paramount to replace losses, but one should not lose sight of the importance of vasopressors to counteract the loss of vascular tone. Vasopressors are an integral part of supportive care in sepsis, the goal being maintenance of adequate organ perfusion and interruption of the progression of organ dysfunction.

Timing of Vasopressor Initiation

The appropriate timing of vasopressor initiation remains unclear and is most often left to physician discretion. Early goal-directed resuscitation was popularized by Rivers et al. in 2001, emphasizing administration of fluid boluses until a set of defined resuscitation goals were met [11]. These goals included central venous pressure (CVP) ≥8–12 mm Hg, MAP ≥65 mm Hg, urine output >0.5 mL/kg/h, and ScvO₂ ≥70%. The initial study demonstrated a significant improvement in outcomes in patients who had aggressive goal-directed resuscitation rather than the usual therapy. However, the subsequent ARISE, PROMISE, and PROCESS trials were unable to demonstrate a mortality benefit [12 –14], bringing into question whether it was necessary to resuscitate to these set goals. However, it seems clear that restoring circulatory volume early in the patient's course is necessary to ensure adequate perfusion of distal organs. Early fluid resuscitation clearly is important to improve perfusion, but at some point, more fluid is not the answer. However, currently, there is a paucity of evidence guiding us as to when exactly in a patient's resuscitation vasopressors should be initiated to improve perfusion. Morimatsu et al. found, in a retrospective review of 142 patients with septic shock treated with early initiation of norepinephrine (NE) (median 1.3 hours after ICU admission; range 0.3–5 hours), that the mortality rate of 34.5% was less than predicted by the illness severity score (40.8%) [15]. Waechter and the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group published a retrospective review of 2,849 patients at 24 hospitals in three countries [16]. They found that the mortality rate was lowest when patients received >1 L of fluids in the first hour, and vasopressors were started one to six hours after admission to the ICU. Bai et al. found an even greater association between death and the timing of vasopressor initiation [17]. This group reported an increase in the mortality rate by 5.3% for each hour of delay in starting vasopressors. They also found that early initiation was associated with a shorter duration of vasopressor need, as well as lower total vasopressor doses. Currently, the Surviving Sepsis Guidelines recommend starting vasopressors within six hours of the start of hypotension after a crystalloid fluid bolus of 30 mL/kg [6].

Norepinephrine versus Dopamine

The ideal vasopressor for the treatment of septic shock would improve perfusion to distal organs by increasing MAP and venous return and thereby increasing preload, via venous constriction, while limiting side effects. Dopamine (DA) and NE have historically been the most common initial vasopressors used in septic shock. Both have pharmacologic profiles that are beneficial in combating the effects of sepsis; both have various degrees of alpha-agonist vasoconstriction effects, as well as beta-agonist effects causing greater contractility and heart rate (Table 1). However, until recently, there have been limited data from which to decide which drug to use as first-line treatment. Norepinephrine has more potent alpha-1 agonist activity, which historically led to concern that it may cause excessive vasoconstriction, especially in the splanchnic and renal vascular beds, producing organ hypoperfusion and greater damage [18,19]. However, studies looking specifically at NE's effect on renal blood flow during sepsis have demonstrated that supporting the MAP with NE during septic pathologic vasodilation actually increases the renal blood flow and glomerular filtration rate [19]. In addition, in the early 2000s, multiple observational studies reported that the use of NE in septic patients was associated with a lower mortality rate than was seen in patients receiving DA [20 –22]. Following these reports, The Sepsis Occurrence in Acutely Ill Patients (SOAP II) group performed a multicenter randomized study directly comparing DA and NE in patients with shock [23]. In the subgroup of patients with septic shock, 502 patents received NE and 542 received DA. There was no difference in the 28-day mortality rate in the two groups (53% with DA versus 49% with NE; p = 0.1); however, there were significantly more cardiac dysrhythmias with DA. The most common dysrhythmia was atrial fibrillation, which occurred in 24% of patients treated with DA and 14% of patients treated with NE (p < 0.001). The same group then performed a meta-analysis of 11 published trials (six randomized and five observational) [24]. In this analysis, after exclusion of one observational study because of its significant heterogeneity, use of DA was associated with a significantly greater risk of death as well as a higher rate of dysrhythmias. This study was limited by the lack of continuity of reported endpoints, time of outcome measurement, and poor reporting of adverse events, which were documented in only two studies. These findings have been echoed in repeat analyses, including the most recent Cochrane review, published in 2016 [25 –27]. Currently, NE is recommended as the first-line agent for treatment of septic shock, with DA reserved for patients with significant bradycardia in the setting of hypotension.

Table 1.

Relative Agonist Action of Each Vasopressor on Selected Receptors

	Alpha-1	Beta-1	Beta-2	Dopamine	Vasopressin
Norepinephrine	↑↑↑↑↑	↑↑↑	↑↑	0	0
Dopamine	↑↑↑	↑↑↑↑	↑↑	↑↑↑↑↑	0
Epinephrine	↑↑↑↑↑	↑↑↑↑	↑↑↑	0	0
Phenylephrine	↑↑↑↑↑	0	0	0	0
Vasopressin	0	0	0	0	↑↑↑↑↑
Dobutamine	↑	↑↑↑↑↑	↑↑	0	0

Low-dose DA (≤2 mcg/kg/min) had been touted as “renal-dose dopamine” and was thought to improve renal perfusion via actions on DA receptors in the renal vascular beds. However, in 2000, Bellomo et al. performed a randomized controlled trial comparing low-dose DA and placebo [28] and found no difference in the rate of progression of kidney injury or need for renal replacement therapy. Marik et al. performed a second randomized controlled trial, again looking at patients in septic shock with oliguria who were treated with low-dose, high-dose, or no DA and again demonstrated no difference in the rates of kidney injury, renal replacement therapy, or survival. The use of low-dose DA for renal protection is no longer recommended [29].

Epinephrine

Epinephrine (EPI) also has potent non-selective agonist action on alpha- and beta-adrenergic receptors and functions as both a vasopressor and an inotrope, increasing MAP by increasing both cardiac output and arterial constriction. At lower doses (up to 0.1 mcg/kg/min), beta effects predominate, with a rise in cardiac contractility and rate, whereas at higher doses, EPI alpha-1 vasoconstriction effects predominate [30]. Fewer studies have compared EPI and NE efficacy in septic shock, with the majority having compared EPI with NE combined with dobutamine. The only randomized controlled trial comparing NE and EPI was performed by Mygurg et al. This study looked at all patients in shock and analyzed the subgroup of patients with septic shock [31]. In 158 patients, there was no difference in the mortality rate, time to MAP goal, duration of vasopressor use, or 28- or 90-day mortality rate between patients treated with NE and those receiving EPI. More patients were withdrawn from the EPI group (18 versus 4); the reasons for withdrawal in the EPI group included tachycardia, lactic acidosis, and failure to meet study goals. Lactic acidosis is a common reported side effect of EPI treatment, which may represent local ischemia from vasoconstriction; however, as this finding does not correlate with outcomes, it is increasingly thought to be attributable to beta-2 activation of the aerobic glycolytic pathways [32].

Three studies compared outcomes in septic shock using either EPI or combination of NE and dobutamine [33 –35]. Neither the mortality rate nor adverse events were different in the two groups. Arterial pH was significantly lower and the serum lactate concentration significantly higher in patients treated with EPI; however, as discussed above, these changes were not associated with organ dysfunction, death, or other adverse events and are thought to be secondary to epinephrine's stimulation of aerobic glycolysis in skeletal muscle.

Following these studies, an obvious question that comes to mind is which agent should be added to NE—dobutamine, EPI, or something else? Mahmoud et al. addressed this question with a randomized double-blind study in 2012 comparing NE + dobutamine and NE + EPI in patients with septic shock [36]. Patients with hypotension after resuscitation were started on NE; if a dose of 0.1 mcg/min was reached and the MAP was still <70 mm Hg, patients were randomized to receive the addition of either EPI or dobutamine. There was no difference in the mortality rates in the two groups; however, EPI was associated with significantly better heart rates, MAP, cardiac index, oxygen delivery, and urine output. Again, EPI use was associated with an increased lactate concentration. The authors hypothesized that although both EPI and dobutamine have ionotropic effects, the additional vasoconstrictive effects of EPI helped to improve the hemodynamic response, whereas the mild vasodilatory effects of dobutamine may have been less beneficial.

Vasopressin

Vasopressin has been used increasingly as a vasopressor in septic shock. Vasopressin has a multitude of functions in the body. It is a peptide hormone synthesized by the posterior hypothalamus and secreted by the posterior pituitary gland. This hormone binds to V1 receptors in vascular smooth muscle causing contraction, as well as functioning as an antidiuretic. During hypotension, secretion of vasopressin increases 10 to 100 fold [37]. Intrinsic vasopressin stores can become depleted quickly in times of shock, and in this setting, external supplementation can lead to significant improvements in blood pressure [38,39]. Current Surviving Sepsis Guidelines recommend use of vasopressin as an adjunct to catecholamines in septic shock, most commonly in conjunction with NE. The Vasopressin and Septic Shock Trial (VASST) study was a randomized double-blind multicenter study evaluating 778 patients with septic shock requiring vasopressor support to maintain MAP [39]. The goal of the study was to compare NE alone with NE combined with vasopressin. Patients were stratified prior to randomization based on their NE dose (less severe shock was defined as an NE dose of 5–14 mcg/kg/min and severe shock as an NE dose >15 mcg/kg/min). The addition of vasopressin at a low dose (0.03 U/min) led to significantly lower dose requirements for NE, although it did not affect the number of adverse events. There was no mortality rate difference in the groups; however, this study was underpowered to detect a difference in this rate. During the planning, the study was powered with the expectation of a 60% mortality rate in the NE alone group, but the actual mortality rate was only 39%. To detect a 4% difference, more than 2,000 patients would have had to be enrolled. Interestingly, in subgroup analysis of patients with less severe shock, treatment with NE and vasopressin did confer a mortality rate benefit (26.5% with both compared with 35.7% with NE alone; p = 0.05). Later post hoc analysis of the data from the VASST study found that patients in the “Risk” category, as defined by the Risk, Injury, Failure, Loss and End-stage kidney disease (RIFLE) criteria, NE + vasopressin was associated with a lower rate of renal replacement therapy (17% versus 38%; p = 0.02) and a trend toward less progression to renal failure [40]. Another subsequent ad hoc analysis found that patients treated with corticosteroids who received vasopressin had a significant decrease in the mortality rate compared with those receiving NE alone. (36% versus 45%; p = 0.03) [41]. This group of investigators also reported significant increases in the serum vasopressin concentration in patients treated with both steroids and vasopressin, leading the authors to theorize that the corticosteroids improve vasopressin activity.

In 2014, Gordon et al. performed a pilot randomized controlled trial to evaluate the interaction of vasopressin and corticosteroids in sepsis [42]. This study looked at 61 patients with septic shock, 31 treated with vasopressin and hydrocortisone and 30 with vasopressin and placebo. Patients receiving steroids and vasopressin had significantly shorter durations of vasopressin therapy as well as a lower total dose of the drug. However, the investigators did not find any difference in plasma vasopressin concentration. A recent meta-analysis of nine trials evaluating vasopressin or its analog terlipressin found that the addition of vasopressin to NE was associated to an improvement in the mortality rate (42.5% versus 49%; relative risk [RR] 0.85; 95% confidence interval [CI] 0.75–1.0; p = 0.05), as well as a significant decrease in NE dose requirements. Heart rates also were slower in the patients treated with NE + vasopressin without an effect on the cardiac output.

There have been only a few studies of vasopressin as the sole drug to treat septic shock, and currently, the Surviving Sepsis Campaign does not recommend the use of vasopressin as a single agent. However, it may be a useful adjunct in septic shock, with the goal of adding it to NE to either reduce the NE dose or increase the MAP further if NE is not meeting the goal.

Phenylephrine

Phenylephrine is a potent alpha-1 agonist with pure vasoconstrictive properties and no direct cardiac effects. This isolated increase in afterload can lead to severe reductions in stroke volume and therefore cardiac output. Likely because of these findings, there are minimal data on phenylephrine use in septic shock. A small randomized controlled trial by Morelli et al. compared NE and phenylephrine in septic shock (16 patients in each group) [43]. This study found no difference in patient hemodynamics or outcomes between treatment with NE and that with phenylephrine. Currently, use of phenylephrine in septic shock is not recommended as a primary treatment because of these concerns; however, it may be useful in patients with tachycardia or who do not tolerate NE because of its cardiogenic effects [6].

Inotropes

Currently, pure inotropes are used less commonly in the treatment of septic shock; however, they remain an adjunct in certain cases. Although the majority of patients in septic shock have high cardiac output and hyperdynamic cardiac function, septic cardiomyopathy occurs in as many as 60% of patients [44]. Cardiac dysfunction can present as elevated troponin, decrease in contractility, or ventricular dilation [45]; and cardiac dysfunction in sepsis is associated with more deaths [46]. Dobutamine is a strong beta-1 agonist, as well as a moderate beta-2 agonist, which leads to higher concentrations of cAMP and greater release of calcium, causing a higher force of cardiac contraction [47]. Milrinone functions via a separate mechanism, inhibiting the breakdown of cAMP and again leading to more calcium release and greater contractile force and cardiac output.

The difference in the pharmacology of these inotropes leads to their respective side effects. Dobutamine's beta-agonist effect can cause tachycardia and also increases myocardia oxygen demand, making it less attractive for use in patients with recent myocardial infarction or who are prone to tachyarrhythmias. Milrinone's inhibition of cAMP breakdown leads to a higher cAMP concentration in the peripheral vascular system as well, which causes vasodilation that can be detrimental in patients already hypotensive secondary to septic shock. In addition, milrinone is metabolized by the kdineys, and in patients with renal dysfunction, the half-life of milrinone is increased significantly, which can create supratherapeutic doses. Currently, there are no studies comparing dobutamine and milrinone in patients with septic shock.

In the Early Goal Directed Therapy (EGDT) study on septic shock by Rivers et al., dobutamine was an integral part in the resuscitative strategy. In this study, after CVP, MAP, and hemoglobin were optimized via fluid resuscitation, blood transfusion, or vasopressors, dobutamine was started if the central venous oxygen saturation remained <70% [11]. After six hours of resuscitation, significantly more patients were on dobutamine if they were in the EGDT group than in the usual care group (14% vs 1%; p < 0.001). This aggressive, goal-directed early treatment was associated with a significantly lower mortality rate. Subsequent large multi-center randomized controlled studies, ProCESS, PROMISE, and ARISE, attempted to replicate this study's lower mortality rate with its aggressive EGDT [6]. All studies found no mortality benefit for EGDT compared with protocolized standardized therapies, which included fluids and vasopressors to achieve a MAP >65 mm Hg. Patients in the ProCESS trial EGDT group were significantly more likely to need dobutamine (15% vs. 3%; p < 0.001) and had higher MAPs than those on standardized therapy, but there was no difference in the mortality rate. Although these studies have at times been interpreted to mean that the addition of dobutamine to reach a goal central venous oxygen saturation of >70% does not benefit patients with septic shock. However, we know that the addition of inotropes can be of use in patients with cardiac dysfunction. The Surviving Sepsis Campaign as well as the European Society of Intensive Care Medicine recommend use of dobutamine in patients with cardiac dysfunction, inadequate cardiac output, and signs of tissue hypoperfusion after optimization of preload and MAP [6,48].

Conclusion

Sepsis and septic shock remain a cause of death and morbidity in the current era. Early recognition and rapid treatment of septic shock improves outcomes, and vasopressors are an integral part of appropriate treatment, leading to correction of the inappropriate vasodilation and reversal of hypoperfusion of distal tissues. Norepinephrine is recommended as the first-line vasopressor in septic shock, being associated with a lower mortality rate and a lower rate of dysrhythmias. Epinephrine and vasopressin can be added as second-line drugs, either in an attempt to meet MAP goals and distal perfusion or to augment NE and lead to a need for lower doses. Dopamine can be useful in patients with bradycardia or at low risk of tachydysrhythmias. The ideal second agent is still unclear and should be tailored to the patient's physiology. Inotropes can be useful in patients with septic myocardial dysfunction or baseline cardiac dysfunction. Further research needs to be done to determine the most beneficial timing for adding a second agent and the optimal combinations of vasopressors for individual patients.

Footnotes

Author Disclosure Statement

All authors have no financial disclosures.

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