Septic shock, defined by American College of Chest Physicians/Society of Critical Care Medicine as hypotension in sepsis that persists despite adequate fluid resuscitation, is one of the leading causes of death in intensive care units, with a high mortality rate1,2. Delayed treatment can lead to severe inadequacies in oxygen delivery to peripheral tissues and can ultimately result in organ failure and death. As with other medical emergencies, early identification and appropriate management will improve patient outcomes.
As recommended by the Surviving Sepsis Campaign (SSC), norepinephrine, a natural catecholamine neurotransmitter secreted by the adrenal glands, is the vasopressor of choice for patients in septic shock3. It has potent activity on both α-1 and α-2 receptors, causing vasoconstriction, as well as β-1 receptors, which increases heart rate and inotropy. Phenylephrine, a pure α-agonist with similar vasoconstrictive effects to norepinephrine, but without chronotropic or inotropic effects, is not recommended as an initial vasopressor due to its potential association with reduced splanchnic blood flow in septic shock patients4. These claims, however, are only based on a limited number of published readings.
Being that septic patients will typically present with tachycardia as a physiological reflex to hypotension, further iatrogenic increases in heart rate would theoretically decrease diastolic filling time and result in a decreased stroke volume5. In addition, the cardiac effects of norepinephrine are unfavorable in patients with significant cardiac comorbidities. Since few studies directly comparing the use of these 2 vasopressors exist, the objective of our study was to compare 28-day mortality and surgical intensive care unit (SICU) length of stay in septic shock patients treated with phenylephrine and norepinephrine. We hypothesized that patients receiving phenylephrine, especially those with significant cardiac history, would have improved outcomes compared with those receiving norepinephrine.
We performed an institutional review board-approved, retrospective chart review of septic shock patients admitted to the Northwell Long Island Jewish (LIJ) Medical Center SICU from January 2012 through June 2017 that received (i) phenylephrine, (ii) norepinephrine, (iii) phenylephrine for <24 hours, then received norepinephrine, or (iv) norepinephrine for <24 hours, then received phenylephrine. Patients that had been started on one of the study vasopressors and were subsequently switched to the other study drug within 24 hours of vasopressor initiation were considered a member of the latter drug group. Those that concomitantly received both phenylephrine and norepinephrine for >3 hours were excluded.
Patients aged 18–89 years old in septic shock with hypotension not responsive to intravenous fluid administration who were admitted to the SICU at LIJ were included in the study. Diagnosis of sepsis based on probable or confirmed infection and any 2 of the following systemic manifestations: (1) respiratory rate >20 breaths/min or PaCO2 <32 mm Hg on blood gas, (2) white blood count >12,000 cells/mm3 or <4000 cells/mm3, (3) heart rate >90 beats/min, or (4) body temperature >38°C or <36°C. Patients were said to be in septic shock if they met the Third International Consensus Definition of Septic Shock: requiring a vasopressor to maintain a mean arterial pressure of 65 mm Hg or greater with an initial serum lactate level >2 mmol/L after adequate volume resuscitation5. Vasopressor therapy was initiated within the first 6 hours of presentation as per Surviving Sepsis Guidelines on the basis of hemodynamic instability (meeting the criteria for septic shock described above), or according to the clinical judgment of the physician6.
Medical records of qualifying patients spanning these 5-year period were reviewed. Vasopressor use, duration of treatment, blood pressure, mean arterial pressure, heart rate, serum creatinine, age, sex, cardiac comorbidities, and concomitant cardiac medications were also assessed. The primary endpoint was an assessment of 28-day mortality, with a secondary endpoint of SICU length of stay. To determine if there was any benefit of phenylephrine over norepinephrine in patients with baseline cardiac disease, we studied the same endpoints specifically in those with documented heart failure, coronary artery disease with or without revascularization, and pre-existing arrhythmia. Data were analyzed using a log-rank test with a P-value set at 0.05 to determine statistical significance.
Thirty patients were included in the study aged 64±17 and 71±9 years for the norepinephrine and phenylephrine groups, respectively (P=0.12). Fifty-seven percent of all included patients were male. The sequential organ failure assessment scores were 8±4 for the norepinephrine group and 4±3 for the phenylephrine group (P>0.89). Length of SICU stay was 18.5±33.0 and 19.0±4.6 days for norepinephrine and phenylephrine, respectively (P=0.554). No statistically significant difference was observed in either 28-day mortality (P=0.200) or SICU length of stay (P=0.544) between the 2 vasopressor groups (Table 1).
Further analysis of the 2 study drugs in patients considered to be at higher cardiac risk was also performed. Of the 30 patients included in the study, 18 were considered to be at higher cardiac risk (age <70 years with pre-existing cardiac disease). When the of norepinephrine and phenylephrine was compared in this subset patients, there were still no statistically significant differences detected in either 28-day mortality (P=0.464) or SICU length of stay (P=0.735).
Two patients required substitution with dobutamine due to low cardiac output, both of whom were on norepinephrine therapy before making the change. Thirty-three percent of patients in the norepinephrine group required vasopressin to increase MAP, whereas 13% needed vasopressin in the phenylephrine group. Of the patients that were switched from one of the study drugs to the other, a switch from norepinephrine to phenylephrine was more common (9 patients vs. 6 patients). The most common reason for a change to norepinephrine from phenylephrine was bradycardia, and the most common reason for changing to phenylephrine from norepinephrine was new-onset atrial fibrillation.
Septic shock is one of the major causes of morbidity and mortality in the intensive care unit.7 Early hemodynamic stabilization is vital in reducing sepsis-related mortality, with vasopressor therapy recommended to maintain tissue perfusion and oxygenation when hypovolemia is not responsive to adequate fluid resuscitation8. A 2011 Cochrane review of 6 vasopressors alone or in combination with dobutamine found no sufficient evidence to prove that any of the vasopressors were superior to the others9. While no definitive consensus on appropriate therapy has yet been established, the SSC published international guidelines for appropriate fluid resuscitation, early and appropriate antibiotics, timely initiation of vasopressor support with signs of fluid unresponsiveness.3,7,10 While there is a trend toward improved outcomes with these goal-directed therapies, few clinical trials directly compare all relevant treatment options, notably in regard to the optimal primary vasopressor to start in patients that remain hypotensive despite adequate fluid resuscitation9.
As such, we aimed to directly compare the use of norepinephrine and phenylephrine in septic shock patients admitted to the SICU, as few similar studies had previously been performed. Our study focused on differences in 28-day mortality and length of stay in the SICU as key outcomes, as opposed to drug effects on initial hemodynamic parameters, which have been previously reported on in other studies4,11.
Norepinephrine increases heart rate and inotropy via its beta-adrenergic effects. Several previous studies have correlated beta-adrenergic agents with adverse effects such as tachycardia, additional arrhythmias, and worsening type-2 lactic acidosis. This was further highlighted in a placebo-controlled randomized control trial by Morelli and colleagues, showing that esmolol, a rapid-acting beta-blocker, seemed to decrease mortality in septic shock9,12–14. As such, it was hypothesized that patients with pre-existing cardiac disease, would have more detrimental side effects from norepinephrine therapy versus phenylephrine which lacks bate adrenergic effects.
Our literature searches aimed at comparing phenylephrine and norepinephrine yielded only 2 pertinent results. In the study by Morelli et al15, there was no significant difference in systemic hemodynamics in septic shock patients who received phenylephrine or norepinephrine. Similar data were obtained in a randomized controlled trial by Jain and Singh using either phenylephrine or norepinephrine in septic shock patients resistant to dopamine. They found that phenylephrine infusions were comparable to norepinephrine in stabilizing hemodynamic parameters and yielded a statistically significant reduction in heart rate16. Its lack of chronotropic or inotropic activity is why we hypothesized that phenylephrine would be preferable over norepinephrine, and selected it as the comparative drug in this study.
The major limiting factor with regards to the routine use of phenylephrine is the risk of reduction in splanchnic blood flow and oxygen delivery in septic shock patients, which has not been substantially reported in the existing literature.
Phenylephrine use was not found to have a significant difference in 28-day mortality or SICU length of stay in septic shock patients when compared with norepinephrine, the current drug of choice per the SSC guidelines. In general, when used in patients without cardiac disease, drugs with beta-adrenergic activity are well tolerated and increase both cardiac output and peripheral perfusion. However, myocardial ischemia and dysrhythmias are serious adverse effects that may arise in patients with pre-existing cardiomyopathies, congestive heart failure, coronary artery disease, or other underlying disease states who are exposed to beta-receptor stimulation. On the basis of its pharmacology, the use of phenylephrine was thought to be preferred in patients at a higher risk of cardiac complications. As a pure alpha agonist, phenylephrine works solely as a vasoconstrictor and exerts no effect on cardiac activity, thereby increasing mean arterial pressure without increasing myocardial oxygen demand. Norepinephrine has vasoconstrictive properties very similar to that of phenylephrine, but will additionally stimulate beta-adrenoceptors on cardiac tissue. Although from a pharmacologic standpoint, phenylephrine would appear to be a more beneficial option in patients with a positive cardiac history, no statistical difference was observed in this patient population in our study.
In the subgroup of patients that were switched from one study vasopressor to the other for hemodynamic stabilization, most were initially receiving norepinephrine and were switched to phenylephrine with the development of tachycardia or new-onset atrial fibrillation. The duration of the vasopressor requirement was similar in both study groups, indicating similar efficacy between the 2 drugs, as previously reported.
A general limitation of this retrospective review was a small sample size. However, similar numbers of patients were studied in previous trials directly comparing phenylephrine to norepinephrine15,16. The retrospective nature of our study was also a limitation. Vasopressor selection was based on physician preference and the patient’s clinical presentation at the time of initiation; patients were not randomized to their respective study drugs. As such, potential confounding factors could not be controlled.
Our data suggest that phenylephrine can safely be used for the treatment of septic shock. Although additional studies comparing these two vasopressors are needed, our findings further suggest that vasopressor selection in septic shock should be made with the patient’s comorbidities, current hemodynamics, and vital signs in mind. The clinical significance of these findings must be substantiated with a larger, controlled trial.
Although the pure alpha agonism of phenylephrine could theoretically make it a preferential drug choice in the critically ill, our study found no significant difference in 28-day mortality or overall SICU length of stay among patients in septic shock receiving either phenylephrine or norepinephrine. This also held true when looking at higher risk patients, specifically the elderly and patients with existing cardiac comorbidities.
This editorial did not require IRB approval.
Sources of funding
Dr. R.B. was the principal investigator for the study and oversaw the entirety of the study. He contributed to the background of the manuscript and was responsible for editing the manuscript. Dr. L.S. wrote the manuscript. Dr. D.A. edited the manuscript. The remaining authors all contributed equally to the project design, data collection and analysis, and production of the manuscript.
Conflict of interest disclosures
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identifying number (UIN)
The authors would like to acknowledge the efforts of the pharmacists and pharmacy students who contributed immensely to the thorough data collection and analysis required for this project
1. Ferrario M, Cambiaghi A, Brunelli L, et al. Mortality prediction in patients with severe septic shock: a pilot study using a target metabolomics approach. Scientific Reports 2016;6:20391.
2. Friedman G, Silva E, Vincent JL. Has the mortality of septic shock changed with time? Crit Care Med 1998;26:2078–86.
3. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Surviving Sepsis
Campaign: international guidelines for management of sepsis
and septic shock: 2016. Intensive Care Med 2017;43:304–77.
4. Beale RJ, Hollenberg SM, Vincent JL, et al. Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med 2004;32(suppl):S455–65.
5. Singer M, Deutschman CS, Seymour C. The Third International Consensus Definitions for Sepsis
and Septic Shock (Sepsis
-3). JAMA 2016;315:801–10.
6. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis
campaign: international guidelines for the management of severe sepsis
and septic shock, 2012. Intensive Care Med 2013;39:165–228.
7. Oba Y, Lone NA. Mortality benefit of vasopressor and inotropic agents in septic shock: a Bayesian network meta-analysis of randomized controlled trials. JCC 2014;29:706–10.
8. Jhanji S, Stirling S, Patel N, et al. The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock. Crit Care Med 2009;37:1961–66.
9. Gelinas JP, Russel JA. Vasopressors
: Selection and targets. Clin Chest Med 2016;37:251–62.
10. Belletti A, Benedetto U, Biondi-Zoccai G, et al. The effect of vasoactive drugs on mortality in patients with severe sepsis
and septic shock: a network meta-analysis of randomized trials. JCC 2017;37:91–8.
11. Kimmoun A, Wei C, Levy B, et al. Heart rate reduction may be a major determinant of vascular tone in esmolol-treated septic shock patients—although still remains to be confirmed!. J Thorac Dis 2016;8:E829–E832.
12. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med 2014;371:2309–19.
13. Levy B, Desebbe O, Montemont C, et al. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock 2008;30:417–21.
14. Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock; a randomized clinical trial. JAMA 2013;310:1683–91.
15. Morelli A, Ertmer C, Rehberg S, et al. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial. Crit Care 2008;12:R143.
16. Jain G, Singh DK. Comparison of phenylephrine and norepinephrine in the management of dopamine-resistant septic shock. Indian J Crit Care Med 2010;14:29–34.