Effect of Vasopressin and its Analogs versus Catecholamines on the Renal Outcomes in Septic Shock:A Systematic Review and Meta-Analysis of Randomized Trials

Background: This current systematic review and meta-analysis aimed to evaluate the association of Vasopressin and its analogs and adverse renal outcomes compared to Catecholamines in adult patients with septic shock. Method: We performed a systematic review of the literature published from inception to March 31, 2021, using online databases of PubMed, Embase, Cochrane Library. Randomized controlled trials reporting any renal function and comparing Vasopressin and its analogs with Catecholamines among adult septic shock patients. Our primary outcomes relating to acute renal failure were acute kidney injury incidence and the need for Renal replacement therapy. Our secondary outcomes were three: Renal replacement therapy free-days and 48h post-administration change in creatinine level and urine output. We applied a xed-effects model to estimate the risk ratio (RR) for (dichotomized outcomes) and standard mean difference (SMD) for (continues outcomes). Results: 18 trials met the inclusion criteria with a total of 4,024 patients. 13 studies were eligible for quantitative meta-analysis and 5 studies were eligible for qualitative data. For the primary outcome, Vasopressin or its agonist are associated with a lower AKI incidence (Risk ratio 0.93, 95% CI [0.86, 1.00], P = 0.04, I² = 5%) and a reduced need for renal replacement therapy (Risk ratio 0.84, 95% CI [0.73, 0.97], P = 0.02, I² = 11%). We found no statistical signicance in the pooled estimates for the secondary outcomes: RRT free-days (28 or 30 days) (P = 0.65, I² = 0%), 48h creatinine level (P = 0.81, I² = 39%), and 48h urine output (P = 0.46, I² = 8%). Conclusions: Vasopressin and its analogs are associated with a reduced AKI incidence and a lower RRT use rate in septic shock compared to catecholamines. Furthermore, we did not nd a signicant effect of Vasopressin on the number of RRT- free days (up to 28 or 30 days) or in creatinine


Introduction:
Septic shock is considered one of the most common causes of intensive care unit admission, and despite all new improvements in sepsis management, it continues to be one of the leading causes of Intensive Care Unit (ICU) mortality (1)(2)(3). Norepinephrine is the suggested rst-line vasopressor in septic shock by The Surviving Sepsis Campaign (SSC) guideline, and it is often the rst line of choice as a vasopressor because of its reliable effectiveness to achieve an adequate MAP in septic shock patients (4-7).
However, Norepinephrine has several adverse effects at high doses, including increased tissue oxygen demand, excessive vasoconstriction leading to decreased renal and mesenteric blood ow, increased pulmonary vascular resistance, alteration of the immune response, and coagulation (8-10). Notably, over a short time, a substantial number of patients become refractory to Norepinephrine, and vascular responsiveness to catecholamines like Norepinephrine diminishes, thus requiring increased doses, hence increasing the risk of side effects (11,12). Vasopressin, an endogenous peptide hormone produced by the hypothalamus and stored in the pituitary gland, has emerged as an adjunct to catecholamines. Vasopressin is relatively de cient during septic shock because of the depletion of vasopressin store from the pituitary gland and inhibition of synthesis and release (13).
Renal function impairment is a frequent complication of severe sepsis, and it is associated with high mortality [18,19] with an incidence of Sepsis-Acute kidney injury (S-AKI) ranging from 55 to 73% (14)(15)(16)(17)(18). Previous studies have demonstrated the bene cial effects of Vasopressin and analogs on renal function. Increased creatinine clearance, higher urinary output, lower acute kidney injury (AKI) incidence, and a reduced need for renal replacement therapy (RRT) in patients with septic shock treated with Vasopressin compared to other vasopressors were reported (19)(20)(21)(22)(23)(24)(25)(26). However, de nitive evidence analyzing the data only on patients with septic shock is lacking.
Therefore, the objective of this present study was to evaluate the association of Vasopressin and its analogs compared to Catecholamines alone on the reduction of adverse renal outcomes in adult patients with septic shock.

Methodology:
Our review and meta-analysis was performed in accordance to the 2020 preferred reporting items for Systematic reviews and Meta-analysis (PRISMA) statement (27).

Eligibility criteria
The study must evaluate adult patients at least 18 years of age with septic shock and must be randomized controlled trials. Included studies must compare the administration of Vasopressin or analogs with or without concomitant of Catecholaminergic vasopressors vs. administration of Catecholaminergic vasopressors alone, or placebo irrespective of dose, duration, or co-intervention. Reports at least one renal outcome related to acute renal failure, e.g., AKI incidence, and the need for RRT, RRT-free days, urine output, or creatinine level. We complied with the original authors' de nitions of each of these endpoints.
The exclusion criteria were: age < 18 years, Case reports, letters, comments, duplicate publications, reviews, case-control studies, cohort studies, or animal studies.

Information source and search strategy
We conducted a comprehensive electronic search using various (MeSH) terms like "septic shock," "Arginine Vasopressin," "Vasopressin," "Sepsis." The following electronic databases were searched PubMed, Embase, and Cochrane Library databases. Relevant studies in databases were searched from their inception up to March 31, 2021. The search strategy for PubMed is described in (Additional le 1).

Study selection process
Trials selection was done by two reviewers (WH, and RY) independently. We set no language restrictions. Full papers of the potentially eligible studies were retrieved. The same two reviewers then independently screened full texts in duplicate and recorded the main reason for exclusion. Any discrepancy was solved by discussion until consensus was reached or discussion with a third reviewer. The reference data of retrieved publications were manually searched for potentially relevant bibliographies of studies.

Data collection process
Two reviewers (WH and RY) independently extracted data using a predesigned form. The primary outcomes were acute kidney injury incidence and the need for renal replacement therapy. The secondary outcomes were renal replacement therapy Free-days (28 or 30 days), 48h Creatinine level, and 48h urine output. The data about the studies were recorded according to the rst author, year of publication, study design, clinical setting, the total number of participants, type of intervention, and the number of events in each group for each of the assessed outcomes. Similarly, any disagreements were resolved by discussion until consensus was reached.

Study quality and risk of bias assessment
To assess the risk of bias of included studies, in each trial, the review authors (AEY, WH) assessed by using the Cochrane Risk of Bias Tool Version 5.4. The following domains were evaluated: sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other sources of bias. The risk of bias was labeled as high, unclear, or low.

DATA SYNTHESIS AND ANALYSIS
All statistical analyses were performed using Review Manager Version 5.3 (Nordic Cochrane Center, Copenhagen, Denmark). For Dichotomous data, we expressed the pooled effect estimates using the risk ratio (RR) of each study using the number of events on each arm if data were available as absolute numbers. In contrast, mean differences (MD) were used for pooling continuous data. The pooled results were calculated with 95% con dence intervals (CI). A non-signi cant chi-square test result (a p-value ≥ of 0.1 and an I2 value ≤ of 50%) only suggested that there was no evidence of heterogeneity. A xed-effects model with Mantel-Haenszel weighting was used for all analyses. Publication bias was evaluated using funnel plots of the primary endpoint by visually inspecting publication bias and small-study effects. Results:

Study Selection
The electronic search yielded 2040 relevant studies in total for further assessment. There were no additional studies identi ed by hand searching reference list that were not already found in the electronic search. After removing duplicates and complete screening of reference based on titles and abstract, and text screening, 18 trials met our inclusion criteria and were eligible for nal analysis, 13 trials for quantitative analysis, and ve trials for qualitative analysis. (See Fig. 1) for study selection and exclusion owchart.

Studies and patients' characteristics
The 18 trials reported on 4,024 septic shock patients. The number of patients included in these randomized controlled trials ranged from 10 to 828. The included trials were published from 1999 to 2019. Eight studies were double-blind, nine were open-label, and one was single-blind. Eight enrolled trials were designed as multicenter studies, and one study was published in conference abstract form (28). Thus, further details were not available for this review. All included studies characteristics are presented in (Table 1).
2,179 subjects received Vasopressin or analogs as the study group, and 1,825 received catecholamine mainly (Norepinephrine) as the control group. The AKI de nition varied among the included trials. Only One study considered the renal outcome (AKI free-days) as the primary outcome. Vasopressin and Terlipressin dosage and administration varied between trials. Vasopressin was administered in 10 studies and Terlipressin in 6 studies. One study used both Vasopressin and Terlipressin, and one study used Selepressin as the vasopressor of choice. Evaluated renal outcomes for the included trials are described in (Additional le 2).  Fig. 2 for Forest plot evaluating AKI incidence).
Funnel plot visual inspection did not lead to concerns about potential publication bias. (Additional le 5).
Six RCTs (20,23,25,36,37,39) Table 2 for secondary outcomes). Discussion: The ndings of this systematic review, and meta-analysis of randomized clinical trials, showed that the administration of Vasopressin or its analogs compared to Catecholamines alone is marginally associated with a signi cant reduction of AKI incidence and reduces the need for RRT in patients with septic shock (moderatequality evidence). Meanwhile, there was no evidence of a statistically signi cant effect on RRT-free days, 48h urine output, or 48h creatinine concentration.
To our knowledge, this is the rst comprehensive meta-analysis on this topic focusing on the renal outcomes solely in septic shock patients. Catecholamines like Norepinephrine reduces urine ow by preferentially binding to α1-adrenoreceptors, mainly located on renal afferent arterioles, contributing to decreased glomerular ltration rate (GFR), creatinine clearance, and urine output (40,41). In contrast, Vasopressin results in increased urine output and improved glomerular ltration rate by binding to V1a receptors on efferent glomerular arterioles without constricting afferent arterioles (41)(42)(43).
Although several studies reported an overall higher creatinine clearance or urine output in patients treated with Vasopressin (20,23,25,30,33), we failed to show a signi cant effect when we pooled the data. We think this could be due to the small sample size affected by the predetermined time point. Hemodynamic changes in the microcirculation and renal microcirculation have been implicated in the pathogenesis of septic AKI and in ammation, but interventions that reduce in ammatory states have not been successful in reducing septic AKI.
However, when Vasopressin is added to Norepinephrine in septic shock, it results in decreased Norepinephrine requirement. Thus, reducing their adverse effect. This reduction trend for the primary outcomes in this review is likely due to vasopressin association with reduced progression to renal failure or loss for patients at risk of kidney injury, therefore, reducing renal replacement therapy requirements (20).
A meta-analysis by (Nedel and colleagues) evaluated the renal outcomes in Distributive shock (septic, postcardiac, post-operative). It concluded with a high risk of bias due to heterogeneity that Vasopressin and its analogs use reduced acute kidney injury incidence and the need for renal replacement therapy in distributive shock but failed to demonstrate a signi cant effect on septic shock patients when analyzed separately in both outcomes (44).
Two recent systematic reviews with meta-analyses evaluating Vasopressin and its analogs compared to solely using catecholamines found con icting data on the reduction of 28 days mortality (22,45). Nonetheless, there was a pronounced trend for increased risk of digital ischemia in the vasopressin or analogs group. Terlipressin, a synthetic analog of Vasopressin with a high a nity to V1a receptors, demonstrated in several clinical studies a greater urinary output and creatinine clearance in septic patients with hepatorenal syndrome. However, the evidence was based on a few studies with low quality. Altogether, further, large RCTs are needed to strengthen the evidence of the renal bene t of Vasopressin and Terlipressin use in septic shock.
There are several limitations in our review. First, the AKI de nition varied among the included studies. Second, due to the different time points reported in the studies for creatinine level and urinary output, our subgroup analysis of these outcomes was restricted to measure up to 48 hours. Third, the dose and usage were different across trials, and open-label Norepinephrine was allowed if needed to reach the target MAP. Finally, although our search protocol was prespeci ed before we conducted this review, we did not pre-register our review protocol.

Conclusion:
Vasopressin and its analogs are associated with a reduced AKI incidence and a lower RRT use rate in septic shock compared to catecholamines. Furthermore, we did not nd a signi cant effect of Vasopressin on the number of RRT-free days (up to 28 or 30 days) or in creatinine level and urinary output in 48 hours. However, due to the high mortality associated with S-AKI, large blinded RCTs addressing renal function impairment in septic shock are warranted.

Declarations
Ethics approval and consent to participate Not applicable.

Availability of data and material
The data supporting the conclusion of this article are included within this article and its additional les. Figure 1 Flowchart for study selection process