Vasopressin versus norepinephrine as the first-line vasopressor in septic shock: A systematic review and meta-analysis

Background and Aim: Norepinephrine is currently the first-line vasopressor for septic shock. We conducted this meta-analysis to examine the outcomes of adult patients with septic shock who received vasopressin instead of norepinephrine. Methods: We selected studies in adults with septic shock that compared the outcomes of patients treated with vasopressin versus norepinephrine. Cochrane ROB 2.0 and the Joanna Briggs Institute quality assessment tools were used to assess the risk of bias in RCTs and observational studies. Meta-analysis was conducted using RevMan 5.4. Results: Eight studies were included in this meta-analysis. There were no significant differences in 28-day mortality rates (OR, 1.07; CI, 0.80–1.44) and intensive care unit (ICU) mortality (OR, 0.74; CI, 0.21–2.67) between the two groups. Similarly, length of ICU stay, length of hospital stay, mean arterial pressure at 24 h, urine output at 24 h, and serious adverse events also did not differ significantly. However, the odds of renal replacement therapy (RRT) requirement in the vasopressin group were substantially lower than in the norepinephrine group (OR, 0.68; CI, 0.47–0.98). Conclusion: There were no differences in mortality, duration of hospitalization, and adverse effects in adults with septic shock across the two groups. However, the patients treated with vasopressin had lower chances of requiring RRT. Relevance for Patients: Vasopressin use as the first-line vasopressor in septic shock showed a significant reduction in RRT, though there were no significant differences in terms of mortality and other adverse events. Therefore, vasopressin can be considered as a first-line vasopressor in septic shock patients with other risk factors which may contribute to renal failure requiring RRT.


Introduction
Septic shock is the leading cause of mortality in intensive care units (ICUs) [1,2]. In 2015, it was estimated that there were more than 230,000 cases of septic shock in the United States which directly caused more than 40,000 deaths per year [3]. Septic shock management revolves around timely source control and hemodynamic resuscitation, ensuring end-organ perfusion. Crystalloids are used to expand the intravascular volume and catecholamine infusions, that is, norepinephrine, to provide cardiovascular support. Catecholamines, however, may reduce blood flow to end organs despite adequate perfusion pressure [4,5]. Vasopressin is an endogenously released peptide hormone that has been used as an adjunct to catecholamines for patients with septic shock not responding to fluids. Studies have shown that septic shock patients have relative vasopressin deficiency [6,7]. Vasopressin use restores vascular tone and decreases norepinephrine requirements [6,7]. Two small randomized and controlled trials (RCTs) showed that vasopressin improved mean arterial pressure (MAP) and expedited norepinephrine withdrawal [8,9]. Furthermore, vasopressin maintained glomerular filtration rate and creatinine clearance compared with norepinephrine [8,10]. The VASST trial, the largest multicenter, double-blind RCT, compared vasopressin, and norepinephrine in patients with septic shock; no mortality benefit was demonstrated in the trial [11]. In the subsequent VANISH trial, early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days [12]. Yet, the trial mentioned that the confidence interval included a potential clinically meaningful benefit for vasopressin and the need for further large-scale trials, highlighting a persistent knowledge gap.
In light of the knowledge gap regarding the benefits of vasopressin in septic shock, we sought to conduct this systematic review and meta-analysis to appraise the available evidence fully and compare the use and benefits of vasopressin compared to norepinephrine in patients with septic shock.

Objectives
The objectives of the study are as follows: • To compare mortality and length of stay in patients with septic shock receiving norepinephrine compared to vasopressin • To compare MAP and urine output in patients with septic shock receiving norepinephrine compared to vasopressin • To compare serious adverse events and renal replacement therapy (RRT) among patients with septic shock receiving norepinephrine compared to vasopressin.

Methods
Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guidelines were used for our systematic review [13]. The protocol for review was published in PROSPERO (CRD42021226012) [14].

Types of studies
We included studies focusing on mortality, clinical improvement, length of hospital stays, adverse effects, mean difference of clinical improvement, and recovery among patients receiving vasopressin compared to norepinephrine for septic shock.

Types of participants
We included all adult patients suffering from septic shock who are more than 18 years of age who received vasopressin or norepinephrine.

Types of Interventions
The treatment arm consists of patients receiving vasopressin for septic shock, while the control arm consists of patients receiving norepinephrine for septic shock.

Types of outcome measures
For our quantitative analysis, mortality, length of stay, MAP, urine output, RRT, and serious adverse effects rates were the outcomes of interest.

Outcomes
We compared mortality, length of stay, MAP, urine output, RRT, and serious adverse effects among septic shock patients receiving vasopressin compared to those receiving norepinephrine.

Search strategies
PubMed, PubMed Central, Embase, and Scopus were independently searched, and the quality of the studies done in the past decade was evaluated. Finally, we filtered the studies using Covidence and extracted data for quantitative and qualitative synthesis [15]. Any potential conflict was solved by taking the final opinion of another reviewer.

Electronic searches
We have documented the detailed search strategy in Supplementary File 1.

Data collection and analysis
We extracted the data for quantitative synthesis through Covidence and did the analysis using RevMan5.4 [15,16]. We used a random/fixed effect to pool selected studies based on heterogeneity.

Selection of studies
We have included RCTs, prospective, observational studies, and cohort studies for septic shock, comparing the outcomes of those receiving vasopressin with norepinephrine. We excluded studies in the entire study population in which vasopressin was used for the treatment among the pediatric age group, pregnant women, and shock other than septic shock. In addition, we excluded metaanalyses, reviews, editorials, commentary, and the studies with no data required for quantitative analysis.

Data extraction and management
We evaluated the quality of studies thoroughly and considered only the outcomes in our interest.

Assessment of risk of bias in included studies
We used the Cochrane ROB 2.0 tool to analyze our RCTs ( Figure 1) and the Joanna Briggs Institute (JBI) quality assessment tools to assess the risk of bias in our prospective and retrospective observational studies (Table 1) [17,18]. We used RevMan 5.4 for creating a summary of biases for RCTs using the Cochrane ROB 2.0 tool.

Assessment of heterogeneity
The I-squared (I 2 ) test was used for the assessment of heterogeneity [22]. We interpreted the I-squared (I 2 ) test done based on the Cochrane Handbook for Systematic Reviews of Interventions [22].

Assessment of reporting biases
Reporting bias was checked by prefixed reporting of the outcome.

Data synthesis
Statistical analysis was performed using RevMan 5.4 software. Odds ratio (OR) was used for outcome estimation with a 95% confidence interval (CI). The fixed/random-effects model was used according to heterogeneities. Mean and standard deviation were formulated based on median and interquartile range. We used mean differences for outcomes such as the length of stay, MAP, and urine output using the mean and standard deviation values obtained from the study [23].

Subgroup analysis and investigation of heterogeneity
We used the random effect model in cases of heterogeneity.

Sensitivity analysis
Non-randomized studies were excluded for sensitivity analysis to find any alterations in the outcomes after removal.

Results
A total of 2442 studies were imported after a comprehensive database search. After removing duplicates, the title and abstracts of 2417 studies were screened, followed by the exclusion of 2382 studies. Thirty-five full-text studies were assessed for eligibility, and 27 studies were excluded for definite reasons. Eight studies were included in the narrative summary (Table 2), and seven studies were included in the quantitative analysis. The following is represented in the PRISMA flow diagram ( Figure 2).
Patel et al. randomized patients to vasopressin to norepinephrine infusion for 4 h [8]. In the study, vasopressin decreased the catecholamine use in septic shock and achieved significantly higher urine output and creatinine clearance than norepinephrine. However, since Patel et al. were a short duration study, the outcomes were not reported beyond 4 h, and it could not be included in the quantitative synthesis.
Lauzier et al. randomized patients to high-dose vasopressin or norepinephrine in early septic shock [10]. Vasopressin in the high dose (o.2U/min) could not attain Map in all the patients in the study and required d additional epinephrine. However, the patients achieved less modified sofa in the vasopressin arm than norepinephrine arm at 48 h. Russell et al. (VASST) were the largest RCT with 778 patients, which randomized patients to vasopressin or norepinephrine in septic shock [11]. The primary endpoint of the study was death at 28 days. There was no difference in mortality at 28 days and severe adverse effects in both arms. However, in the patients with less severe septic shock (those who required NE <15 ug/min), vasopressin provided a mortality benefit compared to norepinephrine. Gordon et al. (VANISH trial) were conducted to study the renal effects of vasopressin versus norepinephrine in patients with septic shock [12]. The primary endpoint was the number of kidney-free days. Vasopressin did not increase the number of kidney-free days in septic shock compared to norepinephrine.
The TERLIVAP study (Morelli et al.) was a randomized control trial with three arms: A continuous terlipressin arm, a continuous vasopressin arm, and a fixed-dose norepinephrine arm [24]. The primary endpoint was the additional requirement of norepinephrine. Terlipressin required lower norepinephrine as compared to the vasopressin arm. There was no difference in hemodynamic differences achieved by vasopressin, norepinephrine, and terlipressin.

Quantitative analysis
A total of seven studies were included in the meta-analysis (four RCTs and three cohorts).

Length of Stay
Length of ICU stays outcome was reported by five studies. Pooling of results using the mean difference in length of ICU stay in days showed some reduction in length in the vasopressin group; however, it did not reach the level of significance (MD, −0.24; 95% CI, −1.35-0.86; n=1445; I 2 =41%). Similarly, length of hospital stay was reported in four studies and there was no significant difference across two groups (MD, −0.49; 95% CI, −3.12-2.14; n=1415; I 2 =0%) ( Figure 4). Further, no significant differences were seen while analyzing for ICU-LOS and LOHS after excluding nonrandomized studies (Supplementary File 2, Figure 2).

Serious adverse effect
Three studies reported serious adverse events. Pooling of the data showed no significant differences in its occurrence across two

Discussion
We analyzed eight studies in our study. When both medications were compared, neither showed survival benefit over the other. Furthermore, no statistical difference was found between norepinephrine and vasopressin in terms of length of ICU stay, MAP, severe adverse effects, and urine output. Norepinephrine was the first-choice vasopressor for managing hypotension in septic shock. In contrast, vasopressin has been used as one of the first add-on vasopressors to norepinephrine to attain the target MAP or decrease the norepinephrine dosage [25]. Our study found no significant difference between hospital mortality and 28-day mortality among patients treated with either medication. This finding is consistent with other meta-analyses, which have also compared the mortality outcome [26,27]. Similarly, there was no significant difference in the length of ICU stay among the patients. A previous meta-analysis had also reached a similar conclusion [28].
Septic shock is a state of relative vasopressin deficiency attributed to impaired baroreceptor-mediated vasopressin secretion [29]. However, all the clinical implications of the relative deficiency state are not known. A short-term study has shown that the microcirculation effects of vasopressin in patients are dependent on the baseline norepinephrine dose [30]. Regarding the hemodynamic parameters, many hemodynamic parameters were not reported in the studies; however, they were reported with inconsistent time duration. We compared the effect of vasopressin versus norepinephrine on MAP, on which a significant difference could not be found. The previous meta-analysis has reported multiple hemodynamic parameters and MAP, such as heart rate, cardiac index, systemic vascular resistance index, and oxygen consumption, which have no significant differences [26]. The study found no significant difference in the occurrence of major side effects. While vasopressin may increase the incidence of digital ischemia, prior meta-analyses have shown no increase in the incidence of major adverse effects [28,31,32].  Patel et al. have shown that vasopressin increases urine output and decreases serum creatinine compared to norepinephrine in the early hours of administration [8]. However, there seems to be no difference in kidney failure-free days in patients treated with vasopressin than norepinephrine. Although we did not find any significant difference in urine output in our study, there were lower odds of RRT with vasopressin. Our findings of the decreased requirement for RRT align with the findings of prior clinical studies that have found improvement in glomerular filtration rate and creatinine clearance in the vasopressin group compared to norepinephrine [8,10]. Further studies are necessary to evaluate the implications of possible renal benefits seen with vasopressin compared to norepinephrine.

Limitations
Our meta-analysis has several limitations, including the small number of available studies and the heterogeneity of study designs and demographics. Included studies have their inherent limitations. The included studies have been conducted from 2002 to 2018 and represent a contemporary cohort of septic shock patients. Treatment protocol, formulations, and drug dosage are comparable and offer granularity of data in assessing individual influence. The presence of organ dysfunction and comorbidities could have influenced the clinical outcomes [33]. We could only report adverse effects and the need for RRT based on a few studies. We could not report various other parameters of interest as there was wide variation in reporting among studies.
Furthermore, we have only included studies published in English, which could have excluded studies published in other languages. Further studies are warranted to uncover the pathophysiology of vasopressin in septic shock and its potential role in therapeutics.

Conclusion
This comprehensive meta-analysis reports no mortality benefit when comparing vasopressin to norepinephrine in septic shock patients. Yet, the need for RRT was significantly lower in the vasopressin group. In addition, we found no difference in adverse   events and duration of hospitalization in septic shock patients receiving vasopressin compared to norepinephrine. Therefore, further large-scale randomized clinical trials are required to uncover the renal benefit of vasopressin in septic shock.