A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication

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Zaki" }, { "@type": "Person", "name": "Mohamed Elgassim" }, { "@type": "Person", "name": "Eman E. Shaban" }, { "@type": "Person", "name": "Amina Ahmed" }, { "@type": "Person", "name": "Thamir Hashim" }, { "@type": "Person", "name": "Mazin Sharafeldien Elsayed Mohamed" }, { "@type": "Person", "name": "Amro Abdelrahman" }, { "@type": "Person", "name": "Kaleem Basharat" }, { "@type": "Person", "name": "Mohammed Abdurabu" }, { "@type": "Person", "name": "Ahmed Shaban" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Background Septic shock, is associated with a high mortality rate and increased expenses. Currently, the first-line therapy for septic shock entails administering resuscitation fluids followed by infusing vasopressors when the blood pressure goal is not achieved. The recommended first-line vasopressor is norepinephrine, followed by vasopressin, epinephrine, angiotensin II, and dopamine. There is still a controversy on when each vasopressor should be administered. Therefore, we conducted this review to determine the impact and implications of vasopressor timing in septic shock patients. Methods PubMed, Medline, Cochrane Library, Web of Science, and Google Scholar databases were comprehensively searched for potential studies until October 2023. The methodological quality and bias assessment of valid records was examined with the Newcastle Ottawa Scale and Cochrane’s risk of bias tool. Additionally, all the meta-analyses were performed with Review Manager software. Results Twelve articles were eligible for review and analysis. Pooled analyses of data from 7 of these studies demonstrated lower incidence of mortality and shorter duration to achieve target mean arterial pressure in the early vs. late epinephrine groups (OR:0.44; 95%CI: 0.35–0.55; p<0.00001 and MD:-1.17; 95%CI:-2.00– -0.34; p=0.0006). However, the length of ICU stay didn’t differ between the early and late norepinephrine group (MD:0.55; 95%CI: -0.52–1.62; p=0.31). The subgroup analyses show that early vasopressin is associated with a decreased mortality than late administration (OR:0.60; 95%CI:0.41–0.90; p=0.01). Similarly, the pooled analysis has shown that early concomitant administration of vasopressin and norepinephrine is associated with a shorter duration to achieve target MAP than norepinephrine alone (MD:-3.15; 95%CI:-4.40– -1.90;p<0.00001). Conclusion Early administration of norepinephrine has a mortality benefit and improves the duration taken to attain and sustain the goal MAP. Furthermore, early vasopressin possesses the potential to lower the fatality rate in individuals experiencing septic shock. However, further research is required to validate this finding. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-289/v1", "name": "A Systematic Review and Meta-Analysis of the Timing of Vasopressor..." } } ] } Home Browse A Systematic Review and Meta-Analysis of the Timing of Vasopressor... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Zaki HA, Elgassim M, Shaban EE et al. A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.12688/f1000research.144976.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] Hany A. Zaki https://orcid.org/0000-0002-3994-7088 1 , Mohamed Elgassim https://orcid.org/0009-0000-8454-132X 1 , Eman E. Shaban 2 , [...] Amina Ahmed 1 , Thamir Hashim 1 , Mazin Sharafeldien Elsayed Mohamed 1 , Amro Abdelrahman https://orcid.org/0009-0009-7983-422X 1 , Kaleem Basharat 1 , Mohammed Abdurabu 1 , Ahmed Shaban 3 Hany A. Zaki https://orcid.org/0000-0002-3994-7088 1 , Mohamed Elgassim https://orcid.org/0009-0000-8454-132X 1 , [...] Eman E. Shaban 2 , Amina Ahmed 1 , Thamir Hashim 1 , Mazin Sharafeldien Elsayed Mohamed 1 , Amro Abdelrahman https://orcid.org/0009-0009-7983-422X 1 , Kaleem Basharat 1 , Mohammed Abdurabu 1 , Ahmed Shaban 3 PUBLISHED 18 Apr 2024 Author details Author details 1 Emergency Medicine, Hamad Medical Corporation, Doha, Doha, Qatar 2 Cardiology, Al Jufairi Diagnosis and Treatment, MOH, Qatar, Doha, Qatar 3 Internal Medicine, Mansoura General Hospital, Cairo, Egypt Hany A. Zaki Roles: Conceptualization, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Mohamed Elgassim Roles: Conceptualization, Methodology, Project Administration, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Eman E. Shaban Roles: Conceptualization, Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Amina Ahmed Roles: Data Curation Thamir Hashim Roles: Writing – Original Draft Preparation, Writing – Review & Editing Mazin Sharafeldien Elsayed Mohamed Roles: Writing – Original Draft Preparation, Writing – Review & Editing Amro Abdelrahman Roles: Data Curation Kaleem Basharat Roles: Writing – Original Draft Preparation, Writing – Review & Editing Mohammed Abdurabu Roles: Writing – Original Draft Preparation, Writing – Review & Editing Ahmed Shaban Roles: Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Background Septic shock, is associated with a high mortality rate and increased expenses. Currently, the first-line therapy for septic shock entails administering resuscitation fluids followed by infusing vasopressors when the blood pressure goal is not achieved. The recommended first-line vasopressor is norepinephrine, followed by vasopressin, epinephrine, angiotensin II, and dopamine. There is still a controversy on when each vasopressor should be administered. Therefore, we conducted this review to determine the impact and implications of vasopressor timing in septic shock patients. Methods PubMed, Medline, Cochrane Library, Web of Science, and Google Scholar databases were comprehensively searched for potential studies until October 2023. The methodological quality and bias assessment of valid records was examined with the Newcastle Ottawa Scale and Cochrane’s risk of bias tool. Additionally, all the meta-analyses were performed with Review Manager software. Results Twelve articles were eligible for review and analysis. Pooled analyses of data from 7 of these studies demonstrated lower incidence of mortality and shorter duration to achieve target mean arterial pressure in the early vs. late epinephrine groups (OR:0.44; 95%CI: 0.35–0.55; p<0.00001 and MD:-1.17; 95%CI:-2.00– -0.34; p=0.0006). However, the length of ICU stay didn’t differ between the early and late norepinephrine group (MD:0.55; 95%CI: -0.52–1.62; p=0.31). The subgroup analyses show that early vasopressin is associated with a decreased mortality than late administration (OR:0.60; 95%CI:0.41–0.90; p=0.01). Similarly, the pooled analysis has shown that early concomitant administration of vasopressin and norepinephrine is associated with a shorter duration to achieve target MAP than norepinephrine alone (MD:-3.15; 95%CI:-4.40– -1.90;p<0.00001). Conclusion Early administration of norepinephrine has a mortality benefit and improves the duration taken to attain and sustain the goal MAP. Furthermore, early vasopressin possesses the potential to lower the fatality rate in individuals experiencing septic shock. However, further research is required to validate this finding. READ ALL READ LESS Keywords vasopressor, septic, shock Corresponding Author(s) Mohamed Elgassim ( [email protected] ) Close Corresponding author: Mohamed Elgassim Competing interests: No competing interests were disclosed. Grant information: Funding for this article is provided by Qatar National Library The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Zaki HA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Zaki HA, Elgassim M, Shaban EE et al. A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.12688/f1000research.144976.1 ) First published: 18 Apr 2024, 13 :289 ( https://doi.org/10.12688/f1000research.144976.1 ) Latest published: 18 Apr 2024, 13 :289 ( https://doi.org/10.12688/f1000research.144976.1 ) Introduction Sepsis is a health condition in which the body responds adversely to an infection. If it is overlooked or left untreated, it can quickly deteriorate into septic shock, characterized by persistent hypotension and the presence of tissue hypoperfusion. 1 , 2 Research indicates that up to 50% of septic shock patients experience mortality. 3 However, the death rate in this group might range from 30-50% depending on demographic characteristics such as age, sex, comorbid diseases, and the presence of organ dysfunction. 4 Moreover, the condition has been linked with higher medical expenses, with data revealing that in the United States alone, about $20 billion has been spent to manage it. 5 Therefore, updating the recommendations and improving the therapy of septic shock may assist in minimizing the mortality of susceptible patients and the expenses. Generally, the first-line treatment for septic shock entails administering intravenous fluids followed by vasopressor infusion when the blood pressure objective is not attained. 6 , 7 The recommended first-line vasopressor medication is norepinephrine. 6 Research has demonstrated that norepinephrine is an effective vasopressor. A recent meta-analysis of 2811 septic shock patients indicated that norepinephrine was associated with a lower death rate compared to dopamine alone. 8 However, the meta-analysis suggested that dopamine should not be ruled out as a therapy option since it may have a role in treating individuals who exhibit minimal risk of arrhythmias. Additionally, a meta-analysis of 43 randomized studies found minimal occurrences of arrhythmias among individuals taking norepinephrine (8.33%). 9 On the other hand, the Surviving Sepsis Campaign (SSC) guidelines have recommended vasopressin as a second-line vasopressor medication. 6 Data from preclinical and small clinical studies suggests that vasopressin may be superior in maintaining glomerular filtration rate and increasing creatinine clearance than norepinephrine. 10 , 11 In addition, a recent large clinical study indicated that using vasopressin as an adjuvant to norepinephrine had no significant difference in mortality compared to norepinephrine alone; however, the death rate was substantially minimized when vasopressin was used to treat patients with less severe shock. 12 Other vasopressors such as terlipressin (an analog of vasopressin), epinephrine, dopamine, and angiotensin II also have a place in managing different subsets of septic shock patients. Research has shown that terlipressin at low dosage is effective in attaining and maintaining target MAP and provides extra advantage of less severe impact on variceal hemorrhage in septic shock patients with an existing diagnosis of liver cirrhosis. 13 Furthermore, a combination therapy of terlipressin and norepinephrine has shown some promise in improving survival and achieving the objective MAP within a shorter duration than norepinephrine alone. 14 Epinephrine is also a second-line vasopressor recommended as an adjunct to norepinephrine. 6 , 7 Because to its formidable β 1 -adrenergic action, this vasopressor is frequently suggested in patients with heart dysfunction. However, it has been linked with more fatalities in the setting of cardiogenic shock. 15 Dopamine, which was prescribed in previous years as the primary vasopressor for septic shock patients, is currently recommended in case of bradycardia. 7 However, its use is limited due to the higher risk of arrhythmias. 16 , 17 Additionally, research has shown that angiotensin II has equal mortality benefit as norepinephrine without any increase in adverse events. 6 However, it does not qualify as the primary treatment but can be used as a supplementary vasopressor therapy. Despite the plethora of literature on the efficacy of various vasopressors, there is still an existing controversy on whether the timing of administration could impact patient outcomes. Therefore, the current systematic review was conducted to assess the implications and impact of vasopressor timing on the clinical outcomes of septic shock patients. Methods Information sources and searches PubMed, Medline, Cochrane Library, Web of Science, and Google Scholar databases were comprehensively searched for potential studies published from inception until October 2023. Moreover, the bibliographies of articles from these databases were scrutinized for additional studies. Articles were retrieved from the electronic databases if they had the following MeSH terms and keywords: (Timing OR timely OR delay OR early) AND (vasopressors OR vasopressor therapy OR norepinephrine OR vasopressin OR vasoconstrictor agents OR epinephrine OR dopamine) AND (Septic shock). Furthermore, to avoid publication bias and improve our scientific research, we did not retrieve grey literature. Eligibility criteria Two independent reviewers analyzed the potential studies according to the predefined eligibility criteria. Articles were included in the present review if they were non-randomized or randomized studies with full articles and published in English, included adult patients with septic shock, and compared any vasopressor therapy according to the timing of administration. On the other hand, research articles that did not meet these criteria or were designed as reviews, conference abstracts, case reports, and editorials were excluded. Any discrepancy during this process was resolved via constructive debates between the two reviewers. Data extraction and definitions The data used for review and analysis was abstracted into separate Excel files by two independent reviewers. The differences in extracted data was initially resolved via constructive debates between the two reviewers, and if they failed to agree, an additional reviewer was engaged. The data abstracted included Author ID (surname of the primary author and date of publication), Study design, Study location, pertinent characteristics of the included patients (sample size, distribution of sex, and the number of patients receiving early or delayed vasopressor therapy), Vasopressor agents used, timing of vasopressor administration and outcomes. The key endpoints of the current study were mortality rate and the duration needed to attain the goal mean arterial pressure (MAP) (≥65 mmHg), whereas the supplementary endpoints were the duration spent in ICUs and the incidence of new-onset arrhythmias. Mortality encompassed 28-day, 30-day, and in-hospital death rates. Quality appraisal The present review included randomized and non-randomized studies; therefore, assessment of methodological quality and risk of bias was performed using the Newcastle Ottawa Scale (NOS) and Cochrane’s risk of bias (RoB) tool, respectively. Using the NOS, articles were assessed according to the selection, comparability, and outcome domains. For each domain, a maximum of one star was assigned to each criterion fully addressed; otherwise, no star was assigned. For the selection domain, a maximum of four stars could be achieved, while the maximum number of stars that could be attained under the comparability and outcome domains were 2 and 3, respectively. On the other hand, risk of bias assessment was performed according to the risk of selection, attrition, performance, reporting, and other biases. A low risk of bias was assigned to a domain that was sufficiently addressed within the study, while a high and unclear risk was assigned to domains not addressed entirely or with insufficient information to make a judgment. Data synthesis All quantitative statistical analyses in the present systematic review were conducted using the Review Manager software (RevMan 5.4.1). These analyses were pooled together using the DerSimonian and Laird random-effect model, which provides conservative effect sizes and counteracts the interstudy heterogeneity. Moreover, the dichotomous outcomes, such as mortality and incidences of new-onset arrhythmias, were pooled together using the simple odds ratio (OR), while continuous outcomes, such as ICU stay and time taken to achieve target MAP (≥65 mmHg), were pooled using the mean difference (MD) calculations. For studies in which the continuous outcomes were presented as median, interquartile ranges, and ranges, the formula provided by Hozo and colleagues was used to calculate the mean and standard deviations. 18 In addition, the 95% confidence interval was employed for calculations, and a p-value of less than 0.05 was considered significant. Interstudy heterogeneity was calculated using the I2 statistics, of which values greater than 50% were considered high or significant. During the analyses, we grouped the outcomes according to the type of vasopressor therapy used, and whenever possible, subgroup analyses were performed. Results Study selection With the predefined keywords and MeSH terms, 2021 potential studies were identified from the electronic databases. A review of these articles led to the exclusion of 989 close or exact duplicates. Afterward, the remaining studies were screened based on their titles and abstracts, of which 917 deemed to be unrelated to our topic were excluded. Eventually, 12 studies were deemed eligible for review and analysis, while the remaining 64 articles were excluded as follows: 8 were animal studies, 12 did not have comparative groups, 4 included pediatric patients, 7 included patients with other conditions such as hemorrhagic shock and sepsis without evidence of shock, and 26 compared various vasopressin without showing the effect of the time of administration ( Figure 1 ). Figure 1. PRISMA flow chart. Summary of study characteristics Twelve studies with 2721 septic shock patients were included in the present review. Four of these studies were randomized controlled trials (RCT), and 8 were cohort studies. Furthermore, seven studies evaluated the timing of norepinephrine, and 5 assessed the timing of vasopressin as an adjunct treatment ( Table 1 ). Table 1. Summary of study characteristics. Author ID Study design Study location Patients’ characteristics Vasopressor agents Definition of early and delayed vasopressor administration Outcomes Sample (n) M/F Early/Delayed Ospina-Tascon et al., 2020 19 Prospective study Colombia 337 93/93 Norepinephrine Early: Vasopressor initiated within 1 hour of septic shock or before first fluid load Delayed: Vasopressor initiated >1 hour after fluid loading Mortality and length of ICU stay Reardon et al., 2014 20 Retrospective cohort study USA 71 35/36 35/36 Early addition of Vasopressin to catecholamine therapy. Early: vasopressin initiated within 6 hours of catecholamine therapy Delayed: vasopressin initiated after 6 hours but before 48 hours of catecholamine therapy Mortality, new-onset arrhythmias, and length of ICU stay Permpikul et al., 2019 21 Single-center, double-blind, RCT. Thailand 310 148/162 155/155 Norepinephrine NR Mortality, length of ICU stay, and time to achieve target MAP Gordon et al., 2016 22 Multicenter, double-blind RCT UK 409 238/171 NA Early vasopressin and Norepinephrine NR Mortality, length of ICU stay, and kidney failure incidence Hammond et al., 2018 23 Prospective, single-center, open-label RCT USA 82 40/42 NA Early vasopressin plus norepinephrine and norepinephrine alone. Early: vasopressin initiated as soon as available at the patient’s bedside. Mortality, length of ICU stay, new-onset arrhythmias, and time to achieving target MAP Hammond et al., 2017 24 Retrospective cohort study USA 96 47/49 NA Early vasopressin plus norepinephrine and norepinephrine alone. Early: Addition of vasopressin within 4 hours of septic shock onset Mortality, length of ICU stay, new-onset arrhythmias, and time to achieving target MAP Elbouhy et al., 2019 25 Prospective RCT Egypt 101 58/43 57/54 Norepinephrine NR Mortality and time to achieving target MAP Hidalgo et al., 2018 26 Retrospective single-center cohort study USA 119 59/60 76/43 Norepinephrine Early: vasopressor therapy initiated within 6 hours of septic shock onset. Delayed: vasopressor therapy initiated after 6 hours Mortality, length of ICU stay, and time to achieve target MAP Bai et al., 2014 27 Retrospective cohort study China 213 116/97 86/127 Norepinephrine Early: vasopressor therapy initiated within 2 hours of septic shock onset Delayed: vasopressor therapy initiated after 2 hours Mortality and ICU stay Li et al., 2023 28 Prospective cohort study China 120 85/35 42/78 Norepinephrine Early: vasopressor therapy initiated within 1 hour of septic shock onset Delayed: vasopressor therapy initiated after 1 hour Mortality, length of ICU stay, and time to achieving target MAP Jouffroy et al., 2022 29 Retrospective study France 478 NR 143/335 Norepinephrine Early: vasopressor therapy was initiated in the prehospital setting. Mortality and length of ICU stay Rydz et al., 2022 30 Multicenter, retrospective cohort study USA 385 NR 189/196 Early addition of vasopressin to catecholamine therapy (norepinephrine only) Early: vasopressor therapy initiated within 7 hours of septic shock onset Delayed: vasopressor therapy initiated after 7 hours Mortality, length of ICU stay, and incidence of new-onset arrhythmias Quality appraisal outcomes The risk of bias outcomes are summarized in Figure 2 . The bias assessment showed that most of the studies had a high risk of other bias because they were performed in single institutions. On the other hand, methodological quality of cohort studies is presented in Table 2 . Most of the studies were carried out in single institutions; therefore, the could not attain maximum stars in the selection domain. Furthermore, two of the studies did not attain any stars in the comparability domain because they did not adjust any cofounders. Figure 2. Risk of bias summary. Table 2. Methodological quality using the Newcastle Ottawa Scale. Study Selection (/4) Comparability (/2) Outcome (/3) Overall methodological quality Ospina-Tascon et al., 2020 3 1 2 Good Reardon et al., 2014 3 0 2 Poor Hammond et al., 2017 3 0 2 Poor Hidalgo et al., 2018 3 1 2 Good Bai et al., 2014 4 1 2 Good Li et al., 2023 3 2 2 Good Jouffroy et al., 2022 3 2 2 Good Rydz et al., 2022 4 1 2 Good Does the timing of Norepinephrine administration improve outcomes of septic shock? Of the 12 studies, 7, including 1678 septic shock patients, evaluated the impact of administering norepinephrine early or late on the clinical outcomes. The pooled data from these studies showed that patients receiving norepinephrine in the early stage had significantly lower mortality rates than those who received norepinephrine late (OR: 0.44; 95% CI: 0.35 – 0.55; p<0.00001) ( Figure 3 ). Similarly, the data pooled from 4 studies showed that patients in the early group took significantly less time (in hours) to achieve the target MAP than those in the late group (MD: -1.17; 95% CI: -2.00 – -0.34; p=0.0006) ( Figure 4 ). However, the length of ICU stay did not differ statistically between the two groups (MD: 0.55; 95% CI: -0.52 – 1.62; p=0.31) ( Figure 5 ). Figure 3. A forest plot comparing mortality rates between patients receiving early and late norepinephrine. Figure 4. A forest plot comparing time taken to achieve target MAP between patients receiving early and late norepinephrine. Figure 5. A forest plot comparing length of ICU stay between patients receiving early and late norepinephrine. Does the timing of Vasopressin administration improve outcomes of septic shock? Five studies, including 1043 patients, assessed the impact of vasopressin as an adjunct therapy for septic shock. Data pooled from two studies showed that the early addition of vasopressin to norepinephrine has no significant mortality benefit compared to monotherapy norepinephrine (OR: 0.87; 95% CI: 0.48 – 1.58; p=0.65) ( Figure 6 ). Similarly, data from the study in which vasopressin was administered in combination with hydrocortisone showed that early administration has no significant mortality benefit compared to norepinephrine in combination with hydrocortisone (OR: 1.20; 95% CI: 0.79 – 1.82; p=0.39) ( Figure 6 ). However, the pooled data from two studies showed that early initiation of vasopressin significantly reduces mortality of septic shock patients compared to late initiation (OR: 0.60; 95% CI: 0.41 – 0.90; p=0.01) ( Figure 6 ). Figure 6. Forest plot for mortality rate after early vasopressin initiation. In addition, our statistical analyses show that early addition of vasopressin to norepinephrine is associated with a significant reduction in the time taken to achieve target MAP compared to monotherapy norepinephrine (MD: -3.15; 95% CI: -4.40 – -1.90; p<0.00001) ( Figure 7 ). However, this early addition shows no significant difference compared with norepinephrine alone on the incidence of new-onset arrhythmias (OR: 1.31; 95% CI: 0.45 – 3.78; p=0.62) or ICU length of stay (MD: -0.45; 95% CI: -3.25 – 2.36; p=0.75) ( Figures 8 & 9 ). Figure 7. Forest plot for time taken to achieve target MAP after early vasopressin initiation. Figure 8. Forest plot for incidence of new-onset arrhythmias after early vasopressin initiation. Figure 9. Forest plot for length of ICU stay after early vasopressin initiation. The statistical analyses also suggest that early vasopressin in combination with hydrocortisone shows no significant difference compared to norepinephrine on the incidence of new-onset arrhythmias (OR: 0.39; 95% CI: 0.08 – 2.04; p=0.27) ( Figure 8 ) and length of ICU stay (MD: 0.50; 95% CI: -0.01 – 1.01; p=0.05) ( Figure 9 ). Similarly, patients receiving early or late vasopressin have statistically equal length of ICU stays (MD: -0.41; 95% CI: -3.64 – 2.82; p = 0.80) ( Figure 9 ) and incidences of new-onset arrhythmias (OR: 0.69; 95% CI: 0.18 – 2.58; p=0.58) ( Figure 8 ). Discussion The present review sought to determine whether the time of vasopressor administration impacts the clinical outcomes of septic shock patients. We found that early norepinephrine initiation resulted in a mortality decrease and shorter time to achieve target MAP than delayed administration. However, the duration of ICU stay did not vary statistically among patients receiving norepinephrine early or late. Furthermore, timely addition of vasopressin to norepinephrine considerably decreases the time to attain goal MAP than monotherapy norepinephrine. Early addition of vasopressin to catecholamine therapy also results in a considerable decrease in mortality than late addition. Impact of norepinephrine timing on the clinical outcomes of septic shock The SSC guidelines have recommended using norepinephrine as the first-line vasopressor for septic shock. 6 , 7 The goal of this therapy is usually to attain and maintain a MAP of above 65 mmHg. 31 , 32 MAP is a crucial measure of pressure because if it goes excessively low, it can cause organs not to be perfused, causing the cells to start dying and organs not function properly. 7 Furthermore, MAP below 65mmHg results in an elevated mortality risk because of the inadequate amount of oxygen delivered to the organs. 7 Therefore, it is essential to assess how the timing of norepinephrine initiation affects MAP. Our statistical analysis indicated that early initiation of norepinephrine significantly decreases the time to achieve target MAP. This finding collaborates with what was already reported in a previous meta-analysis of 5 studies. According to that study, the duration it took to attain target MAP was shorter with early administration of norepinephrine (MD: -1.39; 95% CI: -1.81 – -0.96; p<0.00001). 33 Similarly, Hamzaoui and colleagues found that among patients with severe shock, early norepinephrine (within 6 hours of septic shock) was effective in obtaining the target MAP. 34 This decrease in the duration to attain MAP goal is particularly important as studies have shown that MAP is a key determinant of patients’ outcomes. 35 , 36 The current research has also revealed that early shock treatment with norepinephrine results in a considerable reduction in mortality. In similar fashion, Li and colleagues discovered that short-term mortality was lower when norepinephrine was administered early as opposed to late (p<0.00001). 33 The survival benefit reported in these studies can be attributed to faster achievement of MAP with early norepinephrine administration. In contrast, a 2019 double-blinded RCT recorded an insignificant difference in crude 28-day mortality between early and late norepinephrine use (p=0.15). 21 However, the mortality benefit of early norepinephrine cannot be inferred from this study due to various limitations. First, the trial was not designed to assess mortality. Secondly, the fluid resuscitation rate was not controlled, and this might have affected the mortality outcomes. Finally, the trial was performed in a single center, and its findings cannot be generalized to other care facilities. Early administration of norepinephrine also displays other benefits over late administration. Research has shown that early norepinephrine can boost cardiac output via multiple methods. One of these methods is the elevation of cardiac preload and reduction of preload reliance 34 , 37 during the initial stages septic shock by elevating mean systemic filling pressure and dispersing blood out of the disproportionately bumped unstressed volume to the stressed volume via α-adrenergic-mediated reduction of venous capacitance. 38 Additionally, norepinephrine can elevate cardiac output by boosting the ventricular contractility. 39 Hamzaoui and colleagues found that early norepinephrine administration in septic shock patients receiving adequate intravenous fluid might enhance the left ventricular ejection fraction and other indicators of left and right systolic function. 39 This effect was attributed to an improvement in coronary perfusion pressure via an increased diastolic blood pressure and β-adrenergic stimulation of cardiomyocytes at the initial stages of septic shock when the β-adrenergic receptors are poorly controlled. Early norepinephrine administration can also prevent fluid overload. Research has shown that positive fluid balance is independently associated with poor outcomes in septic shock. 40 , 41 Therefore, early initiation of norepinephrine can result in a reduced amount of infused fluids, thus lowering the risk of fluid overload. This hypothesis is evident in the study by Li and colleagues, where patients receiving early norepinephrine had significantly lower amounts of infused fluids within the first 24 hours than those receiving norepinephrine late (p=0.03). 28 Similarly, Bai and colleagues found that the volume of intravenous fluids at 24 hours was significantly lower in patients receiving norepinephrine within 2 hours of septic shock onset than those receiving the therapy after 2 hours (p<0.001). 27 In contrast, permpikul and colleagues found that the amount of infused resuscitation fluids did not differ between patients in the early and late norepinephrine groups. 21 This insignificant difference can be explained by the fact the study was performed during the 2013 – 2017 period when the SSC guidelines were used, meaning that fluid was given towards a target intravascular volume and central venous pressure. Additionally, early initiation of norepinephrine in cases of severe hypotension might recruit microvessels and improve microcirculation by increasing organ perfusion pressure. This is evident in the study by Georger and colleagues, who found that early norepinephrine significantly improved the tissue muscle oxygen saturation alongside MAP in septic shock patients. 42 Although we have shown that early administration of norepinephrine may be beneficial in septic shock patients, it is not without consequences. One of the well-known adverse events associated with vasopressor therapy is the development of arrhythmias. Permpikul et al. reported that early norepinephrine was associated with significantly lower incidences of new-onset arrhythmias and cardiogenic pulmonary edema than late norepinephrine (p=0.03 and 0.004, respectively). 21 However, no other study has collaborated this finding, meaning that further high-quality trials are required to investigate whether administering norepinephrine in the early phase of septic shock might reduce the occurrence of new-onset arrhythmias and other adverse events. Impact of vasopressin timing on the clinical outcomes of septic shock Vasopressin is an antidiuretic drug that attaches onto the arginine vasopressin receptors. Currently, this medication is recommended as a supplementary treatment option for septic shock patients who are incapable of attaining or maintaining a MAP goal of more than 65mmHg on norepinephrine alone. In our analysis, we observed that the prompt addition of vasopressin to norepinephrine resulted to a considerable decrease in the time taken to achieve target MAP than norepinephrine alone. This faster achievement of target MAP suggests that resolving vasopressin insufficiency sooner could lessen the duration spent on the initial stages of septic shock. Since prior research has revealed that delay in obtaining objective MAP can raise the overall mortality of septic shock patients, the findings of this meta-analysis might provide clinicians with a therapy that can be employed to attain and sustain the target MAP within a shorter period. However, subsequent studies should concentrate on a precision therapeutic strategy to identify patients more likely to benefit from the early addition of vasopressin. The pooled analyses have also shown that despite early vasopressin reducing the time to target MAP, it has no significant difference to norepinephrine alone in terms of mortality, ICU stay, and incidence of new-onset arrhythmias. These findings are collaborated by a previous meta-analysis of 5 studies which found that early vasopressin did not improve short-term mortality (p=0.60), length of ICU stay (p=0.77), and incidence of new-onset arrhythmias (p=0.10). 43 Therefore, there is still a need for further large-scale trials to evaluate the benefit of early concomitant vasopressin and norepinephrine therapy in septic shock patients. In addition, evidence suggests that early induction of vasopressin as a supplement to norepinephrine might aid in resolving organ dysfunction. A 2017 study noted that patients who were managed with concomitant early vasopressin and norepinephrine had considerable decreases in Sequential Organ Failure Assessment (SOFA) scores within 72 hours than those who received the initial norepinephrine monotherapy (-4 vs. -1; p=0.12, respectively). 24 However, a 2018 randomized trial did not demonstrate any substantial variations in SOFA scores among patients receiving early vasopressin combined with norepinephrine and those receiving norepinephrine alone (p=0.29). 23 The evidence in these trials has shown contradictions, meaning that the early initiation of vasopressin to norepinephrine has the potential to decrease morbidity and time taken to resolve septic shock phase by resolving organ failure, but this potential benefit should be investigated further in large high-quality randomized trials. Our subgroup analysis has also shown that early initiation of vasopressin as an adjunct therapy for septic shock patients receiving catecholamines is associated with a significant decrease in mortality than late initiation. However, the analyses have indicated a high interstudy heterogeneity, which suggests variation in outcomes. Reardon et al. 20 found no significant difference in mortality rate between the early and late vasopressin groups. On the other hand, Rydz and colleagues found that the in-hospital mortality was significantly higher in patients receiving vasopressin after 7 hours. 30 The difference between these studies may be attributed to the fact that Rydz and colleagues administered vasopressin at lower doses of norepinephrine, which might have statistically reduced the composite outcome of in-hospital mortality. This hypothesis is supported by a previous study which found that for every 10 ug/min increase in norepinephrine dose equivalents, less than 60 ug/min at the time of vasopressin initiation was associated with an increase in mortality by 20.7%. 44 The present study has also demonstrated a negligible variation in the occurrence of new-onset arrhythmias between the early and delayed vasopressin groups. In contrast, Reardon and colleagues reported a significantly lower incidence of new-onset arrhythmias when vasopressin was administered in the initial stages of septic shock. 20 This finding may be attributed to the fact that most patients in the early group were younger than those in the late group and were not necessarily at equal risk for developing arrhythmias. However, the outcomes of this research might not be applied to other healthcare institutions since it was undertaken in only one institution. Therefore, more RCTs are required to validate these findings. Although we did not assess the effect of vasopressin timing on organ dysfunction, it is worth noting the effect on acute kidney injury (AKI), which is a common complication of sepsis and septic shock. A previous meta-analysis focusing on the clinical outcomes of septic shock patients receiving early vasopressin found that patients receiving vasopressin had a reduced need for renal replacement therapy (RRT). 43 Similarly, Rydz and colleagues reported that the incidence of AKI and the need for RRT was significantly lower for patients receiving adjunct vasopressin within 7 hours of stroke onset. 30 On the other hand, a previous meta-analysis focusing on the renal outcomes of distributive shock patients found that vasopressin and its analogs is associated with reduced AKI incidences and the need for RRT. 45 Therefore, vasopressin administration seems to be beneficial in resolving organ dysfunction, especially AKI. However, further large-scale RCTs are still needed to validate this important finding. Implications for clinical care and future research From a practical standpoint, early administration of norepinephrine can rapidly increase MAP and lower the death rate of septic shock patients. Therefore, expedited norepinephrine infusion may be a logical therapy for improving organ perfusion, and we can recommend that norepinephrine is initiated concurrently with resuscitation fluids at the initial stages of septic shock. However, this technique ought not to hinder sufficient fluid resuscitation as clinicians should be aware of the ‘vasoconstrictor-masked hypovolemia’. 46 Timely infusion of vasopressin as an additional treatment in septic shock might decrease mortality. However, further randomized trials are needed to validate this finding. Furthermore, early introduction of vasopressin as a supplement to norepinephrine rapidly improves the achievement of target MAP than norepinephrine alone. Therefore, we recommend early concomitant administration of vasopressin and norepinephrine in patients who are unable to attain the goal MAP or those with presumed or proven deficit of vasopressin. Our contemporary qualitative review has also identified gaps that should be addressed in future research. First, the definition of early vasopressor initiation varied across the studies. In studies on norepinephrine, early initiation was either referenced to the onset of septic shock or administration of loading fluid, while for studies on vasopressin, early initiation referred to the time between administration of first-line vasopressor to the addition of vasopressin. Therefore, future studies should look to harmonize the definition of early initiation to determine the optimal time at which vasopressor therapy can have improved outcomes. Secondly, evidence suggests that early initiation of norepinephrine might reduce the incidences of new-onset arrhythmias; however, further research is required to establish this finding. Finally, there is a suggestion that early administration of vasopressin might aid in resolving organ dysfunction; however, rigorous reporting is still required to validate this finding. Limitations The present review article has several limitations that should be accounted for when interpreting our findings. First, we observed high heterogeneity in some of the statistical analyses. This heterogeneity might be a result of varied sample sizes, different dosages, and methodological designs. However, the random effect model employed in our analyses was justified and countered the heterogeneity to provide conservative outcomes. Second, our eligibility criteria excluded articles of pediatric patients; hence, our findings can only be inferred for adult septic shock patients. Thirdly, due to limited data, we were unable to carry out a meta-analysis on organ dysfunction, which is an important clinical outcome in septic shock. However, we have addressed this outcome by reviewing the literature qualitatively. Fourth, our study was designed to evaluate the effect of various vasopressor timing on clinical outcomes; however, we only identified articles reporting the timing of norepinephrine and vasopressin. Finally, most of the studies in this review were non-randomized and conducted in single centers; hence, the bias that comes with such study designs was transferred to our analyses. Conclusion Early initiation of norepinephrine in septic shock patients is associated with a significant reduction in mortality and a shorter duration to achieve the MAP goal. However, it does not reduce the duration spent in ICU compared to late admission. 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In Review.2023. Publisher Full Text 29. Jouffroy R, Hajjar A, Gilbert B, et al. : Prehospital norepinephrine administration reduces 30-day mortality among septic shock patients. BMC Infect. Dis. 2022; 22 : 345. PubMed Abstract | Publisher Full Text | Free Full Text 30. Rydz AC, Elefritz JL, Conroy M, et al. : EARLY INITIATION OF VASOPRESSIN REDUCES ORGAN FAILURE AND MORTALITY IN SEPTIC SHOCK. Shock. 2022; 58 : 269–274. PubMed Abstract | Publisher Full Text 31. Dellinger RP, Levy MM, Rhodes A, et al. : Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013; 39 : 165–228. PubMed Abstract | Publisher Full Text | Free Full Text 32. Dellinger RP, Levy MM, Carlet JM, et al. : Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008; 34 : 17–60. PubMed Abstract | Publisher Full Text | Free Full Text 33. Li Y, Li H, Zhang D: Timing of norepinephrine initiation in patients with septic shock: a systematic review and meta-analysis. Crit. Care. 2020; 24 : 488. PubMed Abstract | Publisher Full Text | Free Full Text 34. Hamzaoui O, Georger J-F, Monnet X, et al. : Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension. Crit. Care. 2010; 14 : R142. PubMed Abstract | Publisher Full Text | Free Full Text 35. Varpula M, Tallgren M, Saukkonen K, et al. : Hemodynamic variables related to outcome in septic shock. Intensive Care Med. 2005; 31 : 1066–1071. Publisher Full Text 36. Vincent J-L, Nielsen ND, Shapiro NI, et al. : Mean arterial pressure and mortality in patients with distributive shock: a retrospective analysis of the MIMIC-III database. Ann. Intensive Care. 2018; 8 : 107. PubMed Abstract | Publisher Full Text | Free Full Text 37. Monnet X, Jabot J, Maizel J, et al. : Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients. Crit. Care Med. 2011; 39 : 689–694. PubMed Abstract | Publisher Full Text 38. Persichini R, Silva S, Teboul J-L, et al. : Effects of norepinephrine on mean systemic pressure and venous return in human septic shock. Crit. Care Med. 2012; 40 : 3146–3153. PubMed Abstract | Publisher Full Text 39. Hamzaoui O, Jozwiak M, Geffriaud T, et al. : Norepinephrine exerts an inotropic effect during the early phase of human septic shock. Br. J. Anaesth. 2018; 120 : 517–524. PubMed Abstract | Publisher Full Text 40. Vincent J-L, Sakr Y, Sprung CL, et al. : Sepsis in European intensive care units: results of the SOAP study. Crit. Care Med. 2006; 34 : 344–353. PubMed Abstract | Publisher Full Text 41. Boyd JH, Forbes J, Nakada T, et al. : Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit. Care Med. 2011; 39 : 259–265. PubMed Abstract | Publisher Full Text 42. Georger J-F, Hamzaoui O, Chaari A, et al. : Restoring arterial pressure with norepinephrine improves muscle tissue oxygenation assessed by near-infrared spectroscopy in severely hypotensive septic patients. Intensive Care Med. 2010; 36 : 1882–1889. PubMed Abstract | Publisher Full Text 43. Huang H, Wu C, Shen Q, et al. : The effect of early vasopressin use on patients with septic shock: A systematic review and meta-analysis. Am. J. Emerg. Med. 2021; 48 : 203–208. PubMed Abstract | Publisher Full Text 44. Sacha GL, Lam SW, Wang L, et al. : Association of Catecholamine Dose, Lactate, and Shock Duration at Vasopressin Initiation With Mortality in Patients With Septic Shock. Crit. Care Med. 2022; 50 : 614–623. PubMed Abstract | Publisher Full Text 45. Nedel WL, Rech TH, Ribeiro RA, et al. : Renal Outcomes of Vasopressin and Its Analogs in Distributive Shock: A Systematic Review and Meta-Analysis of Randomized Trials. Crit. Care Med. 2019; 47 : e44–e51. PubMed Abstract | Publisher Full Text 46. Hinder F, Stubbe HD, Van Aken H, et al. : Early multiple organ failure after recurrent endotoxemia in the presence of vasoconstrictor-masked hypovolemia. Crit. Care Med. 2003; 31 : 903–909. PubMed Abstract | Publisher Full Text 47. Elgassim M, Zaki HA, Shaban E, et al. : A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication. figshare. 2024. Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 18 Apr 2024 ADD YOUR COMMENT Comment Author details Author details 1 Emergency Medicine, Hamad Medical Corporation, Doha, Doha, Qatar 2 Cardiology, Al Jufairi Diagnosis and Treatment, MOH, Qatar, Doha, Qatar 3 Internal Medicine, Mansoura General Hospital, Cairo, Egypt Hany A. Zaki Roles: Conceptualization, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Mohamed Elgassim Roles: Conceptualization, Methodology, Project Administration, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Eman E. Shaban Roles: Conceptualization, Project Administration, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Amina Ahmed Roles: Data Curation Thamir Hashim Roles: Writing – Original Draft Preparation, Writing – Review & Editing Mazin Sharafeldien Elsayed Mohamed Roles: Writing – Original Draft Preparation, Writing – Review & Editing Amro Abdelrahman Roles: Data Curation Kaleem Basharat Roles: Writing – Original Draft Preparation, Writing – Review & Editing Mohammed Abdurabu Roles: Writing – Original Draft Preparation, Writing – Review & Editing Ahmed Shaban Roles: Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information Funding for this article is provided by Qatar National Library The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 18 Apr 2024, 13:289 https://doi.org/10.12688/f1000research.144976.1 Copyright © 2024 Zaki HA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Zaki HA, Elgassim M, Shaban EE et al. A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.12688/f1000research.144976.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 18 Apr 2024 Views 0 Cite How to cite this report: Innocenti F. Reviewer Report For: A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.5256/f1000research.158848.r276798 ) The direct URL for this report is: https://f1000research.com/articles/13-289/v1#referee-response-276798 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 29 Aug 2024 Francesca Innocenti , High-Dependency Unit, Department of Clinical and Experimental Medicine, Careggi University Hospital, Florence, Italy Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.158848.r276798 I thank for having the opportunity to review this paper. The topic is hot and large areas of debate persist. I would have some concerns. The review seems unbalanced in the sense of recognizing ... Continue reading READ ALL I thank for having the opportunity to review this paper. The topic is hot and large areas of debate persist. I would have some concerns. The review seems unbalanced in the sense of recognizing a survival benefit of early noradrenaline use. The paper by Permpikul is undervalued and the paper by Yeo and coll, "Vasopressor Initiation Within 1 Hour of Fluid Loading Is Associated With Increased Mortality in Septic Shock Patients: Analysis of National Registry Data" in Critical Care Medicine 2022 was not included. I was not able to understand the reasons for this choice. It has to be demonstrated if results are confirmed by the inclusion of this prospective multicenter study, which included one of the largest populations among those included in the present meta-analysis. I would invite the authors to detail what they intend for early NA and early vasopressin, also considering differences among different studies. The discussion is very long and repetitive; it should be shortened and focused on the main finding of the study. For example, the long explanation about pathophysiology of MAP is not so pertinent. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Partly Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Sepsis, management of the critical patient in the Emergency Medicine Setting I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Innocenti F. Reviewer Report For: A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.5256/f1000research.158848.r276798 ) The direct URL for this report is: https://f1000research.com/articles/13-289/v1#referee-response-276798 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Zhang Z. Reviewer Report For: A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.5256/f1000research.158848.r271514 ) The direct URL for this report is: https://f1000research.com/articles/13-289/v1#referee-response-271514 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 May 2024 Zhongheng Zhang , Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.158848.r271514 This systematic review found that early administration of norepinephrine has a mortality benefit and improves the duration taken to attain and sustain the goal MAP. Furthermore, early vasopressin possesses the potential to lower the fatality rate in individuals experiencing septic ... Continue reading READ ALL This systematic review found that early administration of norepinephrine has a mortality benefit and improves the duration taken to attain and sustain the goal MAP. Furthermore, early vasopressin possesses the potential to lower the fatality rate in individuals experiencing septic shock. However, further research is required to validate this finding. I have several comments as follows: 1. In the abstract, the key component of a systematic review should be reported in PICO, at least, the intervention and control should be explicitly described. 2. There can be heterogenous definitions for early versus late use of epinephrine. 3. "Pooled analyses of data from 7 of these studies demonstrated lower incidence of mortality and shorter duration to achieve target mean arterial pressure in the early vs. late epinephrine groups (OR:0.44; 95%CI: 0.35–0.55; p<0.00001 and MD:-1.17; 95%CI:-2.00– -0.34; p=0.0006)."--in this sentence, the epinephrine should be norepinephrine? 4. Early use of norepinephrine means less fluid infusions in the resuscitation phase. The fluid volume should also be compared between the two groups. 5. It should also be acknowledged that the septic shock population can be heterogenous and some may respond well to early use of NE and others are better suited for late NE. The heterogeneity of the study population should be acknowledged so that future work are needed to explore how subgroups of patients can have different results/conclusions 1 . There has been numerous studies in this field and the authors may need to discuss this issue in interpreting current findings. 6. I do not think non-randomized studies can be pooled with RCTs because the level of evidence is far different. 7. "However, the length of ICU stay did not differ statistically between the two groups (MD: 0.55; 95% CI: -0.52 – 1.62; p=0.31)"--the unit should be added to the length of ICU stay, since it is a mean difference. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Partly Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes References 1. Yang J, Zhang B, Hu C, Jiang X, et al.: Identification of clinical subphenotypes of sepsis after laparoscopic surgery. Laparoscopic, Endoscopic and Robotic Surgery . 2024; 7 (1): 16-26 Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: critical care I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Zhang Z. Reviewer Report For: A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.5256/f1000research.158848.r271514 ) The direct URL for this report is: https://f1000research.com/articles/13-289/v1#referee-response-271514 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 18 Apr 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 18 Apr 24 read read Zhongheng Zhang , Zhejiang University School of Medicine, Hangzhou, China Francesca Innocenti , Careggi University Hospital, Florence, Italy Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Innocenti F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 29 Aug 2024 | for Version 1 Francesca Innocenti , High-Dependency Unit, Department of Clinical and Experimental Medicine, Careggi University Hospital, Florence, Italy 0 Views copyright © 2024 Innocenti F. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I thank for having the opportunity to review this paper. The topic is hot and large areas of debate persist. I would have some concerns. The review seems unbalanced in the sense of recognizing a survival benefit of early noradrenaline use. The paper by Permpikul is undervalued and the paper by Yeo and coll, "Vasopressor Initiation Within 1 Hour of Fluid Loading Is Associated With Increased Mortality in Septic Shock Patients: Analysis of National Registry Data" in Critical Care Medicine 2022 was not included. I was not able to understand the reasons for this choice. It has to be demonstrated if results are confirmed by the inclusion of this prospective multicenter study, which included one of the largest populations among those included in the present meta-analysis. I would invite the authors to detail what they intend for early NA and early vasopressin, also considering differences among different studies. The discussion is very long and repetitive; it should be shortened and focused on the main finding of the study. For example, the long explanation about pathophysiology of MAP is not so pertinent. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Partly Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Sepsis, management of the critical patient in the Emergency Medicine Setting I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Innocenti F. Peer Review Report For: A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.5256/f1000research.158848.r276798) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-289/v1#referee-response-276798 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Zhang Z. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 May 2024 | for Version 1 Zhongheng Zhang , Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China 0 Views copyright © 2024 Zhang Z. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This systematic review found that early administration of norepinephrine has a mortality benefit and improves the duration taken to attain and sustain the goal MAP. Furthermore, early vasopressin possesses the potential to lower the fatality rate in individuals experiencing septic shock. However, further research is required to validate this finding. I have several comments as follows: 1. In the abstract, the key component of a systematic review should be reported in PICO, at least, the intervention and control should be explicitly described. 2. There can be heterogenous definitions for early versus late use of epinephrine. 3. "Pooled analyses of data from 7 of these studies demonstrated lower incidence of mortality and shorter duration to achieve target mean arterial pressure in the early vs. late epinephrine groups (OR:0.44; 95%CI: 0.35–0.55; p<0.00001 and MD:-1.17; 95%CI:-2.00– -0.34; p=0.0006)."--in this sentence, the epinephrine should be norepinephrine? 4. Early use of norepinephrine means less fluid infusions in the resuscitation phase. The fluid volume should also be compared between the two groups. 5. It should also be acknowledged that the septic shock population can be heterogenous and some may respond well to early use of NE and others are better suited for late NE. The heterogeneity of the study population should be acknowledged so that future work are needed to explore how subgroups of patients can have different results/conclusions 1 . There has been numerous studies in this field and the authors may need to discuss this issue in interpreting current findings. 6. I do not think non-randomized studies can be pooled with RCTs because the level of evidence is far different. 7. "However, the length of ICU stay did not differ statistically between the two groups (MD: 0.55; 95% CI: -0.52 – 1.62; p=0.31)"--the unit should be added to the length of ICU stay, since it is a mean difference. Are the rationale for, and objectives of, the Systematic Review clearly stated? Yes Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Partly Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Yes References 1. Yang J, Zhang B, Hu C, Jiang X, et al.: Identification of clinical subphenotypes of sepsis after laparoscopic surgery. Laparoscopic, Endoscopic and Robotic Surgery . 2024; 7 (1): 16-26 Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise critical care I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Zhang Z. Peer Review Report For: A Systematic Review and Meta-Analysis of the Timing of Vasopressor Therapy in Patients with Septic Shock: Assessing Clinical Outcomes and Implication [version 1; peer review: 2 approved with reservations] . F1000Research 2024, 13 :289 ( https://doi.org/10.5256/f1000research.158848.r271514) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-289/v1#referee-response-271514 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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