Combination of norepinephrine with phenylephrine versus norepinephrine with vasopressin in critically ill patients with septic shock: A retrospective study

Highlights

• The outcomes of therapy of septic shock with a combination of norepinephrine with phenylephrine were compared to norepinephrine with vasopressin

• Mortality was not significantly different with a combination of norepinephrine with phenylephrine compared to norepinephrine with vasopressin

• There was also no difference in ICU length of stay and hospital length of stay

• Phenylephrine used as a second-line vasoactive agent combined with norepinephrine may be a reasonable option compared to vasopressin

Abstract

Purpose

To evaluate the outcomes of patients with septic shock treated with a combination of norepinephrine with phenylephrine compared to norepinephrine with vasopressin.

Materials and methods

This was a retrospective cohort study including adults admitted between 2002 and 2017 with septic shock according to the Sepsis 3 criteria. We compared outcomes of patients treated with norepinephrine with phenylephrine to those treated with norepinephrine with vasopressin. Multivariate analysis was carried out to evaluate the association of norepinephrine with phenylephrine compared to norepinephrine with vasopressin with in-hospital mortality.

Results

During the study period, 158 patients with septic shock were treated with norepinephrine with phenylephrine and 129 with norepinephrine with vasopressin. Crude in-hospital mortality was not different between the two groups [91/158 (57.6%) versus 80/129 (62.5%), p = 0.40]. There was also no difference in ICU length of stay or hospital length of stay. Multivariate analysis demonstrated no significant association of norepinephrine with phenylephrine with in-hospital mortality compared to norepinephrine with vasopressin (OR 0.62 (95% confidence interval 0.31, 1.23, p = 0.17).

Conclusion

Phenylephrine used as a second-line vasoactive agent combined with norepinephrine may be a reasonable option compared to vasopressin. However, this finding needs to be validated in a randomized controlled trial.

Introduction

Septic shock is associated with high mortality [1,2]. Norepinephrine is recommended as a first-line vasoactive agent for the hemodynamic support of septic shock as per the Surviving Sepsis Campaign (SSC) guidelines [[3], [4], [5]]. In patients with severe and refractory septic shock despite increased catecholamine requirements, it is recommended to add vasopressin as a second vasoactive agent [3]. Vasopressin deficiency was identified in patients with septic shock in the late 1990s and vasopressin infusion has been used in refractory septic shock based on the results of multiple clinical trials [[6], [7], [8]]. Phenylephrine is a pure vasoconstrictor that works as a selective α1 receptor agonist targeting larger arterioles [9]. The hemodynamic effects of phenylephrine have been studied in several small studies. A before and after phenylephrine infusion study showed that phenylephrine increased cardiac index and stroke index in patients with septic shock (n = 7) but decreased cardiac index in patients with heart failure (n = 8) [10]. Another study conducted on hyperdynamic septic shock patients showed that phenylephrine compared to norepinephrine decreased splanchnic blood flow although it did not affect other hemodynamic parameters [11]. There is a limited number of studies that assessed the effectiveness of phenylephrine as a first-line vasoactive agent in patients with septic shock on clinical outcomes; existing data have demonstrated no significant difference in survival when compared to norepinephrine as a first-line vasoactive agent [10,12,13]. A network metanalysis found no trials directly comparing phenylephrine to vasopressin. However, the indirect comparison suggested no difference in mortality between phenylephrine and vasopressin (odds ratio (OR) = 1.35, 95% CI 0.20–4.55) [14].

In practice, vasopressin is commonly used as a second agent to norepinephrine in patients with septic shock, and phenylephrine is utilized but less extensively [15,16]. The relative effectiveness of phenylephrine compared to vasopressin as a second agent is a relevant question, as a shortage of vasopressin drug supply may occur, such as what happened during the coronavirus 2019 (COVID-19) pandemic [17,18]. The aim of our study is to evaluate the association of phenylephrine compared to vasopressin as a second-line agent added to norepinephrine on in-hospital mortality of patients admitted to the ICU with septic shock.