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Original Investigation |

Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock The VANISH Randomized Clinical Trial

Anthony C. Gordon, MD1; Alexina J. Mason, PhD2; Neeraja Thirunavukkarasu, MSc3; Gavin D. Perkins, MD4; Maurizio Cecconi, MD5; Magda Cepkova, MD6; David G. Pogson, MB BCh7; Hollmann D. Aya, MD5; Aisha Anjum, BSc3; Gregory J. Frazier, MSc3; Shalini Santhakumaran, MSc3; Deborah Ashby, PhD3; Stephen J. Brett, MD8 ; for the VANISH Investigators
[+] Author Affiliations
1Section of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
2Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom
3Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, United Kingdom
4Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, United Kingdom
5Anaesthesia and Intensive Care Medicine, St George's University Hospitals National Health Service Foundation Trust, London, United Kingdom
6Intensive Care Unit, Whittington Health National Health Service, London, United Kingdom
7Academic Department of Critical Care, Portsmouth Hospitals National Health Service Trust, Portsmouth, United Kingdom
8Centre for Perioperative and Critical Care Research, Imperial College Healthcare National Health Service Trust, London, United Kingdom
JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485.
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Importance  Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative.

Objective  To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock.

Design, Setting, and Participants  A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock.

Interventions  Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103).

Main Outcomes and Measures  The primary outcome was kidney failure–free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes.

Results  A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, −2.3% [95% CI, −13.0% to 8.5%]). The median number of kidney failure–free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to –24) in the vasopressin group and 13 days (IQR, 1 to –25) in the norepinephrine group (difference, −4 days [95% CI, −11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, −9.9% [95% CI, −19.3% to −0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, −3.3% to 8.2%]).

Conclusions and Relevance  Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure–free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further.

Trial Registration  clinicaltrials.gov Identifier: ISRCTN 20769191

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Figure 1.
Recruitment, Randomization, and Patient Flow in the VANISH Trial

ICU indicates intensive care unit.

aPatients could meet more than 1 exclusion criteria.

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Figure 2.
Mean Arterial Pressure and Maximum Total (Study and Open-Label) Norepinephrine Dose Over the First 7 Days by Study Drug 1

Squares and circles indicate the median. The error bars indicate the interquartile range. Day 1 runs from the time of randomization to the end of the “ICU calendar day” and is therefore less than 24 hours and varies in duration between patients.

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Figure 3.
Kidney Failure–Free Days by Randomized Treatment Group

The column at 28 days represents survivors who never developed kidney failure, other columns represent patients who did not survive, who experienced kidney failure, or both at any time.

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Figure 4.
Serum Creatinine and Urine Output Over the First 7 Days by Study Drug 1

aNo. of patients with data included.

Squares and circles indicate the median. The error bars indicate the interquartile range. Day 0 = baseline (most recent measurement prior to randomization up to a maximum of 24 hours). Day 1 runs from the time of randomization to the end of the “ICU calendar day” and is therefore less than 24 hours and varies in duration between patients.

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