Norepinephrine

Norepinephrine has pharmacologic effects on both α ₁ – and β ₁ -adrenergic receptors. In low dosage ranges, the β effect is noticeable, and there is a mild increase in cardiac output. In most dosage ranges, vasoconstriction and increased MAP are evident. Norepinephrine does not increase heart rate. The main beneficial effect of norepinephrine is to increase organ perfusion by increasing vascular tone. Studies that have compared norepinephrine to dopamine head to head have favored the former in terms of overall improvements in oxygen delivery, organ perfusion, and oxygen consumption.

Marik and Mohedin randomized 20 patients with vasoplegic septic shock to dopamine or norepinephrine, titrated to increase the MAP to greater than 75 mm Hg and measured oxygen delivery, oxygen consumption, and gastric mucosal pH (pHi, determined by gastric tonometry) at baseline and after 3 hours of achieving the target MAP. Dopamine increased the MAP largely by increasing the cardiac output, principally by driving up heart rate, whereas norepinephrine increased the MAP by increasing the peripheral vascular resistance while maintaining the cardiac output. Although oxygen delivery and oxygen consumption increased in both groups of patients, the pHi increased significantly in those patients treated with norepinephrine, whereas the pHi decreased significantly in those patients receiving dopamine ( P < .001, for corrected 3-hour value). Similar data were reported by Ruokenen and associates.

DeBacker and colleagues randomized 1679 patients to receive dopamine (maximum, 20 μg/kg/min) or norepinephrine (maximum, 0.19 μg/kg/min) as first-line vasopressor therapy to restore and maintain blood pressure at a MAP of greater than 65 mm Hg. The primary endpoint was 28-day mortality, and secondary outcomes included organ-support-free days and adverse events. Although 28-day mortality was nonsignificant between dopamine and norepinephrine (52.5% vs. 48.5% respectively, P = .10), a significantly higher incidence of arrhythmias—principally atrial fibrillation—occurred in the dopamine group (24.1% vs. 12.4%, P < .001). Of note, subgroup analysis of patients with cardiogenic shock showed a significantly higher mortality in the dopamine versus the norepinephrine group ( P = .03 for cardiogenic shock, P = .19 for septic shock, and P = .84 for hypovolemic shock).

Norepinephrine is less metabolically active than epinephrine and reduces serum lactate. Norepinephrine significantly improves renal perfusion and splanchnic blood flow in sepsis, particularly when combined with dobutamine.

Martin and colleagues undertook a prospective, observational cohort study of 97 patients with septic shock to look at outcome predictors using stepwise logistic regression analysis. The 57 patients treated with norepinephrine had significantly lower hospital mortality rates (62% vs. 82%; P < .001; relative risk, 0.68; 95% confidence interval [CI], 0.54 to 0.87) than the 40 patients treated with vasopressors other than norepinephrine (high-dose dopamine, epinephrine, or both). This study was weakened by several factors, including observational nonblinded status, probable selection bias, and a weak endpoint (hospital mortality). However, at the time, the study was significant because many practitioners thought that norepinephrine administration resulted in organ hypoperfusion in critical illness. These data confirmed the work by Goncalves and colleagues.

Does the timing of norepinephrine administration make a difference? Bai and colleagues performed a retrospective analysis of timing of initiation of norepinephrine in 213 patients with septic shock in two intensive care units (ICUs). Patients were divided into two groups: If norepinephrine was started within 2 hours of onset of septic shock, then this was considered early (Early-NE); norepinephrine administered after 2 hours was considered late (Late-NE). The time to initial antimicrobial therapy was not different between the groups. There was significantly higher 28-day mortality in the Late-NE group versus the Early-NE group (for >2 hours delay odds ratio [OR] for death = 1.86; 95% CI, 1.04–3.34; P = .035). Every 1-hour delay in norepinephrine initiation during the first 6 hours after septic shock onset was associated with a 5.3% increase in mortality. The duration of hypotension and norepinephrine administration was significantly shorter and the quantity of norepinephrine administered in a 24-hour period was significantly less for the Early-NE group compared with the Late-NE group.

How is this outcome difference explained? Early administration of norepinephrine likely reflects the presence of greater expertise at the bedside. Patients likely reached their resuscitation goals earlier and required less fluid (∼500 mL less in the first 24 hours). In the Rivers’ study, patients in the late resuscitation group required more fluid over the first 72 hours than in the intervention group, and this may be part of the etiology for poor control group outcomes.

In conclusion, norepinephrine rapidly achieves hemodynamic goals, particularly when administered early in septic shock. It is the agent of choice in septic shock.

Dopamine

Dopamine has predominantly β-adrenergic effects in low to moderate dose ranges (up to 10 μg/kg/min), although there is much interpatient variability. This effect may be due to its conversion to norepinephrine in the myocardium and activation of adrenergic receptors. In higher dose ranges, α-adrenergic receptor activation increases and causes vasoconstriction. Thus the agent is a mixed inotrope and vasoconstrictor. At all dose ranges, dopamine is a potent chronotrope. Dopamine may be a useful agent in patients with compromised systolic function, but it causes more tachycardia and may be more arrhythmogenic than norepinephrine. There has been much controversy about the other metabolic functions of this agent. Dopamine is a potent diuretic (i.e., it neither saves nor damages the kidneys). Dopamine has complex neuroendocrine effects; it may interfere with thyroid and pituitary function and may have an immunosuppressive effect. Whether these affect outcomes, in terms of morbidity or mortality, is unknown.

A high-quality prospective trial and a meta-analysis have displayed ample evidence to discourage the use of “renal-dose” dopamine because it does not change mortality, risk for developing renal failure, or the need for renal replacement therapy.

The Sepsis Occurrence in Acutely Ill Patients (SOAP) study was a prospective, multicenter, observational study that was designed to evaluate the epidemiology of sepsis in European countries and was initiated by a working group of the European Society of Intensive Care Medicine. It has been the subject of various database mining exercises, one of which looked at dopamine and outcomes. Of the 3147 patients included in the SOAP study, 1058 (33.6%) had shock at any time; 462 (14.7%) had septic shock. Norepinephrine was the most commonly used vasopressor agent (80.2%), used as a single agent in 31.8% of patients with shock. Dopamine was used in 35.4% of patients with shock, as a single agent in 8.8% of patients, and combined most commonly with norepinephrine (11.6%). Epinephrine was used less commonly (23.3%) but rarely as a single agent (4.5%). Dobutamine was combined with other catecholamines in 33.9% of patients, mostly with norepinephrine (15.4%). All four catecholamines were administered simultaneously in 2.6% of patients. The authors divided patients into those who received dopamine alone or in combination and those who never received dopamine. The dopamine group had higher ICU (42.9% vs. 35.7%; P = .02) and hospital (49.9% vs. 41.7%; P = .01) mortality rates. A Kaplan-Meier survival curve showed diminished 30-day survival in the dopamine group (log rank, 4.6; P = .032). Patients treated with epinephrine had a worse outcome, but this may represent evidence of worse outcomes in patients with more severe shock. This study was observational and nonrandomized, and the original database was not designed to prove that one intervention would be associated with better outcomes than another because of the huge number of confounders.

Finally, why use dopamine? Dopamine is a natural precursor of norepinephrine, converted through β-hydroxylation. When dopamine is administered, serum norepinephrine levels increase. Because dopamine is a neurotransmitter and has metabolic activity in many organ systems, there appears to be little benefit to using dopamine over norepinephrine. Furthermore, a syndrome of dopamine-resistant septic shock (DRSS) has been described, defined as a MAP of less than 70 mm Hg despite administration of dopamine at 20 μg/kg/min. Levy and colleagues investigated DRSS in a group of 110 patients in septic shock. The incidence of DRSS was 60%, and those patients had a mortality rate of 78%, compared with 16% in the dopamine-sensitive group. Thus, in the highest risk group of patients, the use of dopamine may be associated with delay in achieving hemodynamic goals.

In conclusion, dopamine is an effective inotrope and vasopressor, but it is associated with excess complications and should not be used as first-line therapy in septic shock.

Dobutamine

Dobutamine is a potent β ₁ -adrenergic receptor agonist, with predominant effects in the heart, where it increases myocardial contractility and thus stroke volume and cardiac output. Dobutamine is less chronotropic than dopamine. In sepsis, dobutamine, although a vasodilator, increases oxygen delivery and consumption. Dobutamine appears particularly effective in splanchnic resuscitation, increasing pHi and improving mucosal perfusion in comparison with dopamine. As part of an early goal-directed resuscitation protocol that combined close medical and nursing attention and aggressive fluid and blood administration, dobutamine was associated with a significant reduction in the risk for mortality. However, it is unclear whether any of this benefit was derived from dobutamine, and the follow-up studies failed to demonstrate outcome benefit with this protocol versus conventional therapy.

Levy and colleagues compared the combination of norepinephrine and dobutamine to epinephrine in septic shock. After 6 hours, the use of epinephrine was associated with an increase in lactate levels (from 3.1 ± 1.5 to 5.9 ± 1.0 mmol/L; P < .01), whereas lactate levels decreased in the norepinephrine-dobutamine group (from 3.1 ± 1.5 to 2.7 ± 1.0 mmol/L). The ratio of lactate to pyruvate increased in the epinephrine group (from 15.5 ± 5.4 to 21 ± 5.8; P < .01), but it did not change in the norepinephrine-dobutamine group (13.8 ± 5 to 14 ± 5.0). pHi decreased (from 7.29 ± 0.11 to 7.16 ± 0.07; P < .01), and the partial pressure of carbon dioxide (P co ₂ ) gap (tonometer P co ₂ – arterial P co ₂ ) increased (from 10 ± 2.7 to 14 ± 2.7 mm Hg; P < .01) in the epinephrine group. In the norepinephrine-dobutamine group, pHi (from 7.30 ± 0.11 to 7.35 ± 0.07) and the P co ₂ gap (from 10 ± 3 to 4 ± 2 mm Hg) were normalized within 6 hours ( P < .01). Thus, compared with epinephrine, dobutamine and norepinephrine were associated, presumably, with better splanchnic blood flow and a reduction in catecholamine-driven lactate production. Whether this is of clinical significance is unclear. Moreover, the decrease in pHi and the increase in the ratio of lactate to pyruvate in the epinephrine group returned to normal within 24 hours. The serum lactate level normalized in 7 hours.

Annane and colleagues performed a multicentre, randomized, double-blind trial that included 330 patients with septic shock. Participants were assigned to receive epinephrine (n = 161) or norepinephrine plus dobutamine (n = 169), titrated to maintain mean blood pressure at 70 mm Hg or more. There was no difference in mortality at 28 days between the groups ( P = ·31; relative risk, 0.86; 95% CI, 0.65 to 1.14), nor was there any difference in serious side effects, time to pressor withdrawal, or time to achieve hemodynamic goals.

Epinephrine

Epinephrine has potent β ₁ -, β ₂ -, and α ₁ -adrenergic activity, although the increase in MAP in sepsis is mainly from an increase in cardiac output (stroke volume). There are three major drawbacks from using this drug: (1) epinephrine increases myocardial oxygen demand; (2) epinephrine increases serum glucose and lactate, which is largely a calorigenic effect (increased release and anaerobic breakdown of glucose); and (3) epinephrine appears to have adverse effects on splanchnic blood flow, peripherally redirecting blood as part of the fight-and-flight response. As we have seen, factors 2 and 3 are of undetermined significance and are transient. Whether increasing myocardial oxygen consumption in sepsis is a good thing or a bad thing is unknown.

Many data support the hypothesis that epinephrine reduces splanchnic blood flow, at least initially. Seguin and colleagues studied laser Doppler flow in a small group of ICU patients to prospectively determine the effects of different vasopressors on gastric mucosal blood flow (GMBF). The studies showed that a combination of dopexamine-norepinephrine enhanced GMBF more than epineprhine alone did. Conversely, the same group had previously shown that GMBF was increased more with epinephrine than with the combination of dobutamine and norepinephrine. Both studies only looked at GMBF for 6 hours and were unable to demonstrate differences in hepatic blood flow or oxidative stress.

Myburgh and colleagues performed a prospective, multicentered, double-blind, randomized controlled trial of 280 ICU patients comparing epinephrine with norepinephrine. They found no difference in time to achieve target MAP. There was also no difference in the number of vasopressor-free days between the two drugs. However, several patients receiving epinephrine were withdrawn from this study because of a significant but transient tachycardia, increased insulin requirements, and lactic acidosis.

Obi and colleagues performed a meta-analysis of inotropes and vasopressor in patients with septic shock. Fourteen studies with a total of 2811 patients were included in the analysis. Norepinephrine and norepinephrine plus low-dose vasopressin but not epinephrine were associated with significantly reduced mortality compared with dopamine (OR, 0.80 [95% CI, 0.65 to 0.99], 0.69 [0.48 to 0.98], and 0.56 [0.26 to 1.18], respectively).

In summary, epinephrine, although not currently recommended by international organizations as first-line vasopressor therapy in sepsis, is a viable alternative. There are few data to distinguish epinephrine from norepinephrine in achievement of hemodynamic goals, and epinephrine is a superior inotrope. Concern about the effect of epinephrine on splanchnic perfusion may be misguided. It has been assumed that a lower pHi and increased P co ₂ gap correlate with hypoperfusion; however, the opposite may be the case. Epinephrine may increase splanchnic oxygen use and carbon dioxide (CO ₂ ) production through a thermogenic effect, especially if gastric blood flow does not increase to the same extent, inducing a mismatch between splanchnic oxygen delivery and splanchnic oxygen consumption. This is supported by data from Duranteau and colleagues. Concern about the effect of increased serum lactate and hyperglycemia has limited the use of epinephrine. However, it is unclear whether lactate is harmful in sepsis, and concern regarding hyperglycemia appears to be fading.

Phenylephrine

Phenylephrine is an almost pure α ₁ -adrenergic agonist with moderate potency. Phenylephrine is a less-effective vasoconstrictor than norepinephrine or epinephrine, but it is the adrenergic agent least likely to cause tachycardia. Although widely used in anesthesia to treat iatrogenic hypotension, phenylephrine is considered a less-effective agent in sepsis. Previous concerns regarding reduced hepatosplanchnic blood flow appear to have been allayed. Morelli et al. conducted a prospective, randomized controlled trial on 32 septic shock patients using either phenylephrine or norepinephrine as the initial vasopressor. MAP was maintained between 65 and 75 mm Hg and measurements conducted over the first 12 hours. Cardiac output, gastric tonometry, acid base balance, creatinine clearance, and troponin “leaks” were all primary endpoints. Phenylephrine did not worsen hepatosplanchnic perfusion as compared with norepinephrine. It had similar effects as norepinephrine on cardiopulmonary performance and global oxygen transport, but it was less effective than norepinephrine to counteract sepsis-related arterial hypotension as reflected by the higher dosages required to achieve the same goal MAP.

In summary, phenylephrine is not harmful in septic shock, but it is less potent than norepinephrine. Although not addressed by the authors, potential peripheral, rather than central, administration of this agent may increase its utility in early septic shock while central line insertion is planned or taking place.

Vasopressin

Arginine-vasopressin is an endogenous hormone that is released in response to decreased intravascular volume and increased plasma osmolality. Vasopressin directly constricts vascular smooth muscle through V1 receptors. It also increases the responsiveness of the vasculature to catecholamines.

Vasopressin has emerged as an additive vasoconstrictor in septic patients who have become resistant to catecholamines. There appears to be a quantitative deficiency of this hormone in sepsis, and administration of vasopressin in addition to norepinephrine increases splanchnic blood flow and urinary output. Vasopressin offers theoretical advantages over epinephrine in that it does not significantly increase myocardial oxygen demand and its receptors are relatively unaffected by acidosis.

Early studies demonstrated that the most efficacious dose was 0.04 U/min, and this was not titrated. This relatively low dose has little or no effect on normotensive patients. Several small early studies demonstrated the potential utility of vasopressin (or its analogs) in sepsis, although there were few compelling supportive data.

Russell and colleagues performed a multicenter randomized double-blind trial of patients in septic shock who were already receiving 5 μg of norepinephrine per minute (VASST [Vasopressin and Septic Shock Trial]). Three hundred ninety-six patients were randomized to receive vasopressin (0.01 to 0.03 U/min), and 382 were randomized to receive norepinephrine (5 to 15 μg/min) in addition to open-label vasopressors. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P = .26), in 90-day mortality rate (43.9% and 49.6%, respectively; P = .11), or in organ dysfunction. Heart rate and total norepinephrine dose, early in the course of critical care, were lower in the vasopressin group. A subgroup analysis suggested a survival benefit for vasopressin in less severe sepsis (i.e., those patients who required a lower overall dose of norepinephrine to achieve MAP targets) at 28 days (35.7% vs. 26.5%; number needed to treat [NNT] 11) and 90 days (46.1% vs. 35.8%; NNT 10) but not for more severe sepsis. In patients whose vasopressin levels were measured, those levels were very low at baseline (median, 3.2 pmol/L; interquartile range, 1.7 to 4.9) and increased in the vasopressin group but not in the norepinephrine group.

Several significant limitations of this study should be noted. This study looked at dose escalation of norepinephrine versus norepinephrine plus complementary vasopressin: the objective was to determine whether the catecholamine-sparing effect of vasopressin improved outcomes. It was not a head-to-head study of vasopressin versus norepinephrine, nor was it a study of vasopressin in early septic shock. There was significant lead-time delay in recruitment (12 hours) before patients were randomized. The VASST study was underpowered; an expected mortality rate of 60% was used for the sample size planning. The actual mortality rate in the control group was 39%. Finally, the dose of vasopressin used in the study (up to 0.03 U/min) may have been inadequate to show a response in the patients with more severe septic shock.

A subsequent retrospective analysis of the VASST study database suggested a beneficial synergy between vasopressin and corticosteroids in patients who had septic shock and were also treated with corticosteroids. Vasopressin, compared with norepinephrine, was associated with significantly decreased mortality (35.9% vs. 44.7%, respectively; P = .03) if patients were simultaneously receiving corticosteroids. In patients who received vasopressin infusion, administration of corticosteroids significantly increased plasma vasopressin levels by 33% at 6 hours ( P = .006) to 67% at 24 hours ( P = .025) compared with patients who did not receive corticosteroids.

In conclusion, patients in septic shock are depleted of vasopressin. Replacement therapy with arginine vasopressin may be catecholamine sparing in septic shock, particularly in moderate disease.