The effects of vasopressin on acute kidney injury in septic shock.

TLDR: Vasopressin may reduce progression to renal failure and mortality in patients at risk of kidney injury who have septic shock and the interaction of treatment group and RIFLE category was significant in predicting mortality.

Abstract: To compare the effects of vasopressin versus norepinephrine infusion on the outcome of kidney injury in septic shock Post-hoc analysis of the multi-center double-blind randomized controlled trial of vasopressin versus norepinephrine in adult patients who had septic shock (VASST) Seven hundred seventy-eight patients were randomized to receive a blinded infusion of either low-dose vasopressin (001–003 U/min) or norepinephrine infusion (5–15 μg/min) in addition to open-label vasopressors and were included in the outcome analysis All vasopressors were titrated and weaned to maintain a target blood pressure RIFLE criteria for acute kidney injury were used to compare the effects of vasopressin versus norepinephrine In view of multiple simultaneous comparisons, a p value of 001 was considered statistically significant Kidney injury was present in 464 patients (596%) at study entry In patients in the RIFLE “Risk” category (n = 106), vasopressin as compared with norepinephrine was associated with a trend to a lower rate of progression to renal “Failure” or “Loss” categories (208 vs 396%, respectively, p = 003), and a lower rate of use of renal replacement therapy (170 vs 377%, p = 002) Mortality rates in the “Risk” category patients treated with vasopressin compared to norepinephrine were 308 versus 547%, p = 001, but this did not reach significance in a multiple logistic regression analysis (OR = 033, 99% CI 010–109, p = 002) The interaction of treatment group and RIFLE category was significant in predicting mortality Vasopressin may reduce progression to renal failure and mortality in patients at risk of kidney injury who have septic shock

Figures

Figure 2. Mean serum creatinine (and 95%CI) over the first 20 days from start of study drug infusion in A – “Non-AKI” category, B – “Risk” category, C – “Injury” category, D – “Failure” category of RIFLE. Grey circles represent norepinephrine group, black squares represent vasopressin group. Serum creatinine values recorded whilst receiving renal replacement therapy have been excluded from the analysis.

Table 1. RIFLE criteria definitions used in this study [6]

Figure 3. Median (±IQR) norepinephrine infusion rates are shown (Panel A) for patients receiving open-label norepinephrine at baseline in vasopressin and in norepinephrine treatment groups of patients in VASST who were in the “Risk” category of acute kidney injury according to RIFLE. Vasopressin-treated patients (black squares) had significantly reduced norepinephrine infusion rates compared to

Figure 1. Kaplan Meier survival curves for at “Risk” patients in the vasopressintreated group, solid black line, and the norepinephrine-treated group, dotted line (p = 0.007). P value was calculated using the log rank statistic.

Table 2. Baseline characteristics at time of study drug infusion, 28 day mortality rates and other outcomes according to RIFLE categories, and comparing the vasopressin and norepinephrine treatment groups according to RIFLE category.

Table 3. Multivariate logistic regression model for 28-day mortality in “Risk” category patients

Full text

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THE EFFECTS OF VASOPRESSIN ON ACUTE KIDNEY INJURY IN
SEPTIC SHOCK
Anthony C. Gordon
1
, James A. Russell
2
, Keith R. Walley
2
, Joel Singer
3
, Dieter
Ayers
3
, Michelle M. Storms
2
, Cheryl L. Holmes
4
, Paul C. Hébert
5
, D. James Cooper
9
,
Sangeeta Mehta
6
, John T. Granton
7
, Deborah J. Cook
8
, Jeffrey J. Presneill
10
, for the
Vasopressin and Septic Shock Trial (VASST) Investigators
From: 1. Imperial College NHS Trust, London, UK; 2. iCAPTURE centre, St Paul’s
Hospital, 3. Epidemiology and Biostatistics, St. Paul’s Hospital, 4. Kelowna General
Hospital, University of British Columbia; 5. Ottawa Hospital, General Campus
University of Ottawa; 6. Mount Sinai Hospital, 7. Toronto General and Toronto
Western Hospital, University of Toronto; 8. St. Joseph’s Hospital, McMaster
University, Canada; 9. Alfred Hospital, Monash University; 10. Royal Melbourne
Hospital, University of Melbourne, Australia.
Address for correspondence and reprints:
Anthony C Gordon, MD, FRCA
Intensive Care Unit,
Charing Cross Hospital, Imperial College NHS Trust
Fulham Palace Road, London
W6 8RF, UK
Tel: +44 (0)20 8383 0657
Fax: +44 (0)20 8846 1975
anthony.gordon@imperial.ac.uk
Support:

2
Canadian Institutes of Health Research, Grant number: MCT 44152
Registration: ISRCTN94845869, http://www.controlled-trials.com
Anthony C. Gordon is grateful for support from the NIHR Biomedical Research
Centre funding scheme. Keith R. Walley is a Michael Smith Foundation for Health
Research Distinguished Scholar. Deborah J. Cook is a Chair of the Canadian
Institutes of Health Research.
Short title: VASOPRESSIN AND KIDNEY INJURY
Title character and spaces count: 66
Abstract word count: 249
Word count: 2664

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ABSTRACT
Objective: To compare the effects of vasopressin versus norepinephrine infusion on
the outcome of kidney injury in septic shock.
Design and Setting: Post-hoc analysis of the multi-centre double-blind randomized
controlled trial of vasopressin versus norepinephrine in adult patients who had septic
shock (VASST).
Patients and Intervention: 778 patients were randomized to receive a blinded
infusion of either low-dose vasopressin (0.01-0.03U/min) or norepinephrine infusion
(5-15µg/min) in addition to open-label vasopressors and were included in the outcome
analysis. All vasopressors were titrated and weaned to maintain a target blood
pressure.
Measurement and results: RIFLE criteria for acute kidney injury were used to
compare the effects of vasopressin versus norepinephrine. In view of multiple
simultaneous comparisons a p-value of 0.01 was considered statistically significant.
Kidney injury was present in 464 patients (59.6%) at study entry. In patients in the
RIFLE “Risk” category (n=106) vasopressin as compared with norepinephrine was
associated with a trend to a lower rate of progression to renal “Failure” or “Loss”
categories (20.8% v 39.6% respectively, p=0.03), and a lower rate of use of renal
replacement therapy (17.0% v 37.7%, p=0.02). Mortality rates in the “Risk” category
patients treated with vasopressin compared to norepinephrine were 30.8% v 54.7%,
p=0.01, but this did not reach significance in a multiple logistic regression analysis
(OR=0.33, 99%CI 0.10-1.09, p=0.02). The interaction of treatment group and RIFLE
category was significant in predicting mortality.
Conclusions: Vasopressin may reduce progression to renal failure and mortality in
patients at risk of kidney injury who have septic shock.
Key words: Sepsis; kidney failure; vasopressins; shock, septic

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INTRODUCTION
Acute kidney injury is a common complication of sepsis that is associated with high
mortality [1]. The incidence ranges from 15-50% [2-4], and is associated with a
mortality rate of 30-75% [2-5]. This variation in reported incidence and outcome is
partly due to heterogeneous patients and different definitions of kidney injury used in
these studies. Recently, the acute dialysis quality initiative (ADQI) group
recommended a consensus definition for kidney injury called the RIFLE criteria [6].
Patients are defined as being at “Risk” of kidney injury, having renal “Injury” or
“Failure”, having “Loss” of renal function or having “End-stage” renal failure based
on decreased glomerular filtration rate (or increased serum creatinine) and urine
output.
Despite the high prevalence of acute kidney injury during critical illness in general,
and severe sepsis specifically, success has been limited in improving the outcome of
this complication [7]. The mainstays of prevention and treatment include avoidance of
nephrotoxins and ensuring adequate renal perfusion. In addition to its potent
vasoconstrictor effects, vasopressin may also have specific beneficial effects on renal
function secondary to its binding to a family of vasopressin receptors [8]. In several
small studies of vasodilatory shock, vasopressin increased glomerular filtration rate,
urine output and creatinine clearance [9-12]. However, to date no large studies have
assessed the effect of vasopressin, as compared with norepinephrine, on the outcome
of acute kidney injury.
Therefore, we studied patients who had septic shock recruited to the randomized
controlled trial of vasopressin versus norepinephrine (VASST: Vasopressin and
Septic Shock Trial) to compare the effects of vasopressin versus norepinephrine on

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the outcome of acute kidney injury using the RIFLE criteria. Some of this data has
been presented in the form of an abstract at the American Thoracic Society
International Conference, San Francisco, in 2007 [13].

Frequently asked questions

Q1. How many patients were still dependent on renal replacement therapy at day 28?

Nineteen (4.1%) of the 466 survivors without pre-existing end-stage renal failure were still dependent on renal replacement therapy at day 28. 

Q2. How many patients were treated with continuous renal replacement therapy?

Of the 49 patients who had end-stage renal failure at baseline, 19 were managed with continuous renal replacement therapy, 8 with intermittent hemodialysis and 22 with both, during the study period. 

Q3. How many patients were included in the outcome analysis?

One patient in the vasopressin group was lost to follow up at day 28 and therefore only 778 patients were included in the outcome analysis. 

Q4. What was the p-value of the analyses?

As the analyses were repeated in each of the five RIFLE classes at baseline a Bonferroni correction for multiple testing was applied and a p-value of 0.01 was considered statistically significant. 

Q5. What was the effect of adjusting for the baseline characteristics in a multiple logistic regression model?

Adjusting for these baseline characteristics in a multiple logistic regression model resulted in the mortality rates within the “Risk”category no longer reaching statistical significance. 

Q6. What was the classification of the patients with end-stage renal failure?

Patients without end-stage renal failure who were receiving renal replacement therapy at study baseline were assigned to the “Failure” category as previously described [16].