So, skeptics interpreted that there was no benefit of vasopressin, some authors [ 7 , 24 , 25 ] and the Surviving Sepsis Campaign [ 8 , 26 ] recommended vasopressin for patients not responding to norepinephrine, and others likely used vasopressin in patients who had less severe shock based on the VASST stratum results.
The authors have been on record as recommending 0. One meta-analysis suggested efficacy of vasopressin vs. Randomized controlled trials such as VASST and VANISH assess efficacy of a drug in a highly selected group of patients carefully selected to test whether the drug can decrease the primary endpoint under trial conditions. Efficacy trials should be followed by effectiveness trials to better assess benefits and risks of drugs such as vasopressin in the broader range of patients in clinical practice.
Indeed, despite inherent methodological limitations lack of randomization and blinding , comparative effectiveness research is ramping up in the USA [ 19 , 27 , 28 ] and has shown effectiveness of drugs and devices e. Physicians may not widely adapt new evidence into clinical practice when new evidence is reported so outcomes do not improve as soon or as well as expected.
Furthermore, there had been no propensity-matched cohort studies of use of vasopressin vs. In our current study, before VASST was published, vasopressin was associated with increased mortality compared to norepinephrine and our study suggests—but does not prove—that after publication of VASST, physicians were more selective in prescribing vasopressin such that the difference in mortality between vasopressin- and norepinephrine-treated patients disappeared after VASST.
Finally, if we assume that randomized controlled trial results align most closely with the true effects of vasopressin in septic shock, then it is satisfying to see that our propensity-matched efficiency study post-VASST aligned well with the overall negative results of the two large randomized controlled trials of vasopressin in septic shock, VASST [ 23 ] and VANISH [ 9 ].
These randomized controlled trials found no difference in mortality between vasopressin and norepinephrine. It is an important first step in moving from the VASST efficacy trial to an efficiency trial in the VASST coordinating center, which could be followed by a broader multi-center efficiency trial to compare vasopressin versus norepinephrine in clinical practice of septic shock.
We speculate that our current study results could apply to other hospitals that also use vasopressin vs. How did the clinical equipoise regarding vasopressin in septic shock translate into practice in other studies?
Lower age and respiratory dysfunction were clinical features associated with use of vasopressin as was hospital of admission [ 11 ]. Although the reasons for changes in mortality rates of vasopressin vs. The day 1 vasopressin dose in SPH 1 vs.
Higher dose vasopressin is associated with increased risk of adverse events [ 25 , 30 , 31 ] such as vital organ and digital ischemia, which may have contributed to increased mortality in our propensity-matched efficiency study. The differences in mortality between vasopressin-treated vs. SPH2 could be related to the differences in vasopressin benefits lowering norepinephrine dose, decreasing organ dysfunction vs.
We did not assess these possible mechanisms in this clinical study. The strengths of our study are efficiency evaluation of vasopressin vs. The limitations of the study are the lack of control by randomization and blinding so there could be remaining confounding by indication , the single-center design the single-center design of our study limits generalizability , the use of the sepsis 2.
We do not know how many patients were self-reported NYHA class IV heart failure but did not have confirmation such as by echocardiography or cardiac catheterization.
We only included patients who had all of the data required for the current study, and so there was no missing data. The difference in day 1 vasopressin dose between SPH1 vs.
SPH2 0. Another limitation is that we do not have other clinical variables including use of corticosteroids, need for positive pressure ventilation, time to first appropriate antibiotic, other concomitant vasopressor use, fluid volume during resuscitation, and transfusion s. After the VASST results were known, there was no difference in mortality between vasopressin- and norepinephrine-treated patients.
This is the first propensity-matched cohort study of a sepsis treatment in a center that had previously coordinated a large pivotal randomized controlled trial of that treatment—this approach may be useful for other sepsis therapies. Vasopressin deficiency contributes to the vasodilation of septic shock. Vasopressin pressor hypersensitivity in vasodilatory septic shock.
Crit Care Med. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma. Beneficial effects of short-term vasopressin infusion during severe septic shock.
Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. Parrillo JE. Septic shock—vasopressin, norepinephrine, and urgency. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. Potential for overuse of corticosteroids and vasopressin in septic shock.
Crit Care. Article Google Scholar. Epidemiology of vasopressin use for adults with septic shock. Ann Am Thorac Soc. Russell JA. Physician culture and vasopressin use in septic shock. PubMed Google Scholar. Comparative effectiveness of second vasoactive agents in septic shock refractory to norepinephrine. J Intensive Care Med. The Septic Shock 3. Comparisons are norepinephrine vs.
Jump to: navigation , search. Russel JA, et al. The New England Journal of Medicine. Categories : Usable articles Critical Care. Navigation menu Personal tools Create account Log in. Namespaces Page Discussion. We also analyzed whether fluid balance was predictive of central venous pressure and furthermore whether a guideline-recommended central venous pressure of mm Hg yielded a mortality advantage.
After correcting for age and Acute Physiology and Chronic Health Evaluation II score, a more positive fluid balance at both at 12 hrs and day 4 correlated significantly with increased mortality. Figure 1 shows the flow of patients through the trial. The most frequent reason for screening failure was exceeding the 6-hour recruitment window.
A total of patients were randomized. Seven patients were found to be ineligible after randomization but before receiving any study drug and 5 patients or legal representatives withheld or withdrew consent after inclusion in the trial; these patients were excluded from all analyses. One patient refused ongoing participation in the trial after inclusion, including day follow-up, but allowed existing data to be included in the analyses.
Therefore, patients were included at baseline for safety data and some secondary outcome analyses as indicated and patients were included in the primary intention-to-treat analysis. The patients who did not receive study drug 2 Figure 1 were allocated to the placebo group in the as-treated analysis.
All crossovers and patients not receiving the second study drug were excluded from the per-protocol analysis. The treatment groups were well balanced at baseline Table 1.
The study drugs were started at a median of 3. The MAP in all treatment groups was similar at baseline and over the first 7 days Figure 2 A; eFigure 1A in Supplement 2 and vasopressin spared the total dose of norepinephrine required to maintain the blood pressure Figure 2 B. Similar results were obtained when using the serum creatinine values and urine output values separately to define kidney failure eTable 2 in Supplement 2 , and the as-treated and per-protocol analyses gave similar results eTable 3 in Supplement 2.
Similar quantities of intravenous fluid were given to all groups, and total fluid balance, serum lactate levels, and heart rate were similar in all groups eTables in Supplement 2. Serum creatinine levels were lower and urine output slightly higher over the first 7 days in the vasopressin group compared with the norepinephrine group Figure 4 and eTables 8A and 9A in Supplement 2 and the rate of renal replacement therapy use was There was no significant difference in mortality rates between vasopressin and norepinephrine groups day mortality, There were no differences in rates of other new organ failures or organ failure—free days between vasopressin and norepinephrine groups eTable 10 in Supplement 2.
In the vasopressin group 22 patients had a total of 29 serious adverse events and 17 patients in the norepinephrine group had 19 events. The breakdown of all serious adverse events by treatment group is given in Table 2. Rates of vasopressin and norepinephrine infusion are shown in eFigures 1B-D and 2 in Supplement 2.
There was no difference in serum creatinine, urine output, rates of kidney failure, use of renal replacement therapy, mortality, or serious adverse events between the hydrocortisone group and the placebo group eTables 8B, 9B, and 11 and eFigures 3A-B and 4B in Supplement 2. Mortality rates were similar between all groups and there was no interaction on outcome between vasopressin and corticosteroids.
Possible explanations for the VASST result might be 1 that vasopressin was more effective when used earlier before patients had become too sick the mean time to study drug initiation was approximately 12 hours after meeting eligibility , 2 that the patients with more severe shock might have required a higher dose of vasopressin because the maximum rate of vasopressin was limited to 0.
Further analyses from VASST suggested that vasopressin might improve kidney function in patients at risk of kidney failure and reduce rates of progression to kidney failure and loss, but that it had no effect if acute kidney failure was already established at the time of study inclusion.
Similarly in VASST, patients enrolled in the first 12 hours tended to have better outcomes with vasopressin treatment compared with norepinephrine, but not if enrolled after 12 hours. Despite this early recruitment, a number of patients already had developed acute kidney failure at the time of inclusion.
However, there was no significant difference in the number of patients who had kidney failure at any time or progressed to kidney failure after randomization.
Although there was no significant difference in rates of kidney failure, there was a lower rate of use of renal replacement therapy in the patients treated with vasopressin. The use of renal replacement therapy was not controlled in this trial, and it was started based on local clinical decision.
It is therefore not possible to know why renal replacement therapy was or was not started. Because the trial was double-blinded, it is unlikely to be due to any obvious clinician bias. It is possible the difference in rates of renal replacement therapy reflects the slightly lower creatinine values and higher urine outputs seen in the patients treated with vasopressin, particularly on days 3 through 6.
Although use of renal replacement therapy was not the primary outcome of this trial, it is an important patient-centered outcome, and therefore this result may be important when planning patient treatment strategies. To ensure that patients with more severe shock were treated with an adequate dose of vasopressin, the dose of vasopressin was titrated up to 0.
In another randomized clinical trial, a dose of 0. The mean dose of vasopressin was 0. In view of the uncertainty about what is the ideal blood pressure to target in septic shock, 18 clinicians need to balance the potential benefits of an increased blood pressure against the risk of vasopressor-related adverse events, particularly at high dose and should set blood pressure targets for individual patients.
The other potentially important finding from VASST that informed this trial was the potential interaction with corticosteroids. There are several possible biological interactions including that vasopressin binds to V1b receptors in the anterior pituitary that then leads to adrenocorticotropin hormone release 19 and corticosteroids have been shown to restore cytokine-mediated down-regulation of vasopressin receptors. In contrast with patients who did not receive corticosteroids, patients treated with norepinephrine had better outcomes.
As in the pilot study, 11 corticosteroids reduced vasopressin requirements but there was no difference in mortality rates and no evidence of an interaction between vasopressin and corticosteroids on outcome.
Although not all patients required study drug 2 hydrocortisone or placebo , the results were similar in the as-treated and the per-protocol analyses. However, because many patients did not require or receive study drug 2, the power to assess an interaction was limited and restricts the interpretation of this finding.
Limitations of this study need to be considered.
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