Vasopressor Dosing in Septic Shock Clinical Trials: A Systematic Review and Meta-analysis
CCCF ePoster library. Teja B. 11/13/19; 283347; EP108
Dr. Bijan Teja
Dr. Bijan Teja
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Topic: Systematic Review, Meta-Analysis, or Meta-Synthesis

Teja, Bijan1; Bosch, Nicholas2; Walkey, Allan2; Pinto, Ruxandra​3; Wunsch, Hannah3,4
1. Interdisciplinary Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
2. The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
3. Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
4. Department of Anesthesia and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada

INTRODUCTION: Despite assessment of patient factors such as serum creatinine, presence or absence of vasopressors and Sequential Organ Failure Assessment score, there is large unexplained variation in mortality rate across septic shock clinical trials.

OBJECTIVE: To assess the relationship between norepinephrine equivalent doses on enrollment in septic shock clinical trials and 28/30-day mortality.
METHODS: We conducted a systematic review of all randomized controlled trials (RCTs) involving adult patients with septic shock published between 2006 and 2018. We limited our review to RCTs that used norepinephrine administration as an inclusion criterion and that reported 28/30-day, ICU, in-hospital or 90-day mortality. We first screened RCTs included in the systematic review by de Grooth, et al.and then extended their search strategy to identify RCTs published from January 2018 to August 2018. All stages of the review process were performed independently by two reviewers.
The primary exposure was the minimum total vasopressor dose required for study inclusion. The secondary exposure was the average (mean/median) total vasopressor dose given to patients on study inclusion. All vasopressor doses (i.e. non-norepinephrine vasopressors) were converted into norepinephrine equivalents using either equivalence calculations provided in the study, or the table from Ranieri et al.Doses of vasopressors reported as micrograms (µg)/min were divided by 70 kilograms (kg) to calculate the approximate dose in µg/kg/min for comparison. Our primary outcome was 28/30-day control-group mortality. When not present, 28/30-day mortality was estimated using previously published regression equations.1

We used random-effects meta-analysis to calculate overall control group mortality and rate of multiple vasopressors, and random-effects meta-regression to assess the association between vasopressor doses and mortality.
RESULTS: Twenty-eight septic shock RCTs met inclusion criteria (Figure 1).1,3 Nine trials specified a minimum fluid administration volume prior to enrollment ranging from 500ml to approximately 2000ml (30ml/kg); six trials required central venous pressure ≥8 mmHg or pulmonary artery occlusion pressure ≥12 mmHg prior to enrollment. 

Eighteen trials did not specify any minimum vasopressor dose for inclusion. Among 10 trials that specified a minimum requirement for norepinephrine, the range was 0.05-0.9 µg/kg/min (Table 1). Rate of use of multiple vasopressors on enrollment was 10.9% (95% CI 6.2-18.5%) of patients among 13 studies reporting these data.
Overall 28/30-day control-group mortality was 39.1% (95% CI 34.3-44.1%; range 14.3-80.5%) (Table 1). Minimum vasopressor dose required for inclusion did not correlate with 28/30-day mortality (regression coefficient (β)=0.54, p=0.47) (Figure 2A). Among 18 trials that reported actual vasopressor dose on enrollment, mean/median norepinephrine equivalent doses ranged from 0.16-1.16 µg/kg/min. Mean/median norepinephrine equivalent dose on enrollment also did not correlate with 28/30-day mortality (β=0.53, p=0.38) (Figure 2B).

CONCLUSION: There is wide variation in vasopressor dose inclusion criteria and vasopressor doses at baseline among septic shock trials; these doses do not correlate with short-term mortality. Despite perception that vasopressor doses are titrated based on degree of shock and are associated with expected mortality, the findings of this study suggest that vasopressor use and dosing may be more variable.

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1. de Grooth HJ, Postema J, Loer SA, Parienti JJ, Oudemans-van Straaten HM, Girbes AR. Unexplained mortality differences between septic shock trials: a systematic analysis of population characteristics and control-group mortality rates. Intensive Care Med. 2018;44(3):311-322.
2. Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin Alfa (Activated) in Adults with Septic Shock. New England Journal of Medicine. 2012;366(22):2055-2064.
3. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. New England Journal of Medicine. 2018;378(9):809-818.

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