Septic Shock: Steroids/Vasopressin

CORTICUSCORTICUS

Corticosteroid Therapy in Septic ShockCorticosteroid Therapy in Septic Shock Sprung CL, et. al. NEJM, 2008;358:111-24.Sprung CL, et. al. NEJM, 2008;358:111-24.

http://content.nejm.org/cgi/reprint/358/2/111.pdfhttp://content.nejm.org/cgi/reprint/358/2/111.pdf

CORTICUSCORTICUS BackgroundBackground

Hydrocortisone is widely used in patients with septic shock even Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who though a survival benefit has been reported only in patients who remained hypotensive after fluid resuscitation and vasopressor remained hypotensive after fluid resuscitation and vasopressor institution and whose plasma cortisol levels did not rise appropriately institution and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin. after the administration of corticotropin.

Trial designTrial design Multicenter, randomized, double-blind, placebo-controlled trialMulticenter, randomized, double-blind, placebo-controlled trial

Primary outcomePrimary outcome: death at 28 days among patients with septic : death at 28 days among patients with septic shock who did not have a response to a corticotropin stimulation shock who did not have a response to a corticotropin stimulation test (CST)test (CST)

Failure to respond defined as Failure to respond defined as ≤9 ≤9 μμg/dL increase in serum cortisol g/dL increase in serum cortisol level 60 minutes after IV administration of synthetic corticotropinlevel 60 minutes after IV administration of synthetic corticotropin

Sprung C et al. N Engl J Med 2008;358:111-124

Enrollment and Outcomes

CORTICUSCORTICUS

499 total patients499 total patients

233 (46.7%) did NOT have a response to CST233 (46.7%) did NOT have a response to CST 125 received supplemental hydrocortisone125 received supplemental hydrocortisone 108 placebo108 placebo

266 had positive response266 had positive response 126 received supplemental hydrocortisone126 received supplemental hydrocortisone 140 received placebo140 received placebo

Steroid regimen: 50mg hydrocortisone every 6hr x 5d, then Steroid regimen: 50mg hydrocortisone every 6hr x 5d, then tapered off over 6 days (tapered via increasing time between tapered off over 6 days (tapered via increasing time between doses, not reducing the dose)doses, not reducing the dose)

Supported by a contract (QLK2-CT-2000-00589) from the Supported by a contract (QLK2-CT-2000-00589) from the European Commission, the European Society of Intensive Care European Commission, the European Society of Intensive Care Medicine, the European Critical Care Research Network, the Medicine, the European Critical Care Research Network, the International Sepsis Forum, and the Gorham Foundation. Roche International Sepsis Forum, and the Gorham Foundation. Roche Diagnostics provided the Elecsys cortisol immunoassay. Diagnostics provided the Elecsys cortisol immunoassay.

Drug was provided by Rotexmedica, and no authors claimed Drug was provided by Rotexmedica, and no authors claimed affiliation with this companyaffiliation with this company

ResultsResults

At 28 days, there was At 28 days, there was no significant differenceno significant difference in in

mortalitymortality between patients in the two study groups between patients in the two study groups

Mortality in those with no response to CSTMortality in those with no response to CST 49 of 125 (39.2%) in the hydrocortisone group 49 of 125 (39.2%) in the hydrocortisone group

95% CI, 30.5 to 47.995% CI, 30.5 to 47.9 39 of 108 (36.1%) in the placebo group39 of 108 (36.1%) in the placebo group

95% CI, 26.9 to 45.3; 95% CI, 26.9 to 45.3; P=0.69P=0.69

Mortality in those with positive CSTMortality in those with positive CST 34 of 118 (28.8%) in the hydrocortisone group34 of 118 (28.8%) in the hydrocortisone group

95% CI, 20.6 to 3795% CI, 20.6 to 37 39 of 136 (28.7%) in the placebo group39 of 136 (28.7%) in the placebo group

95% CI, 21.1 to 36.3; 95% CI, 21.1 to 36.3; P=0.51P=0.51

ResultsResults

mortalitymortality at 28 days at 28 days

Hydrocortisone groupHydrocortisone group 86 of 251 (34.3%)86 of 251 (34.3%)

Placebo Placebo 78/248 (31.5%)78/248 (31.5%)

P = 0.51P = 0.51


Outcomes According to Subgroup


Kaplan-Meier Curves for the Time to Reversal of Shock


Kaplan-Meier Curves for Survival at 28 Days

ResultsResults

The use of low-dose hydrocortisone had no The use of low-dose hydrocortisone had no significant effect on the rate of death in patients significant effect on the rate of death in patients with septic shock at 28 days, regardless of with septic shock at 28 days, regardless of adrenal responsiveness to corticotropin adrenal responsiveness to corticotropin

Although shock was reversed more quickly in Although shock was reversed more quickly in the hydrocortisone group, there were more the hydrocortisone group, there were more episodes of superinfection, including new episodes of superinfection, including new sepsis and septic shocksepsis and septic shock

ResultsResults

A modest increase in the rate of death at 28 days was A modest increase in the rate of death at 28 days was seen in patients who did not have a response to seen in patients who did not have a response to corticotropin (38%), as compared with those who had a corticotropin (38%), as compared with those who had a response (29%). response (29%). However, there was no difference in outcome in either However, there was no difference in outcome in either

subgroup of the hydrocortisone group subgroup of the hydrocortisone group

Only 4.2% of pt’s were given open-label corticosteroidsOnly 4.2% of pt’s were given open-label corticosteroids

CritiquesCritiques

Etomidate was the paralytic used in 26% of patients at Etomidate was the paralytic used in 26% of patients at time of intubationtime of intubation Known to cause ~24hr period of adrenal suppressionKnown to cause ~24hr period of adrenal suppression May have caused false negative CST in some pt’sMay have caused false negative CST in some pt’s

The study was ended prematurely, and thus was The study was ended prematurely, and thus was underpowered (target 800 pt’s)underpowered (target 800 pt’s) Slow recruitmentSlow recruitment Loss of fundingLoss of funding Expiry of study drugExpiry of study drug

Final Rec’sFinal Rec’s

Corticosteroid supplementation can not be routinely Corticosteroid supplementation can not be routinely recommended for treatment of septic shockrecommended for treatment of septic shock May have a role in those who are unresponsive to both early May have a role in those who are unresponsive to both early

adequate fluid resuscitation and high-dose vasopressorsadequate fluid resuscitation and high-dose vasopressors

Corticotropin stimulation testing is not reliable nor Corticotropin stimulation testing is not reliable nor diagnostically useful in patients who are critically illdiagnostically useful in patients who are critically ill

The above are also supported by the latest “Surviving The above are also supported by the latest “Surviving Sepsis” guidelines…for whatever that’s worthSepsis” guidelines…for whatever that’s worth Crit Care Med, Jan 2008. Vol. 36, p296-327Crit Care Med, Jan 2008. Vol. 36, p296-327

Comments?Comments?

http://content.nejm.org/cgi/reprint/358/9/877.pdfhttp://content.nejm.org/cgi/reprint/358/9/877.pdf

BackgroundBackground Vasopressin is commonly used as an adjunct to Vasopressin is commonly used as an adjunct to

catecholamines to support blood pressure in refractory septic catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) who were being treated with conventional (catecholamine) vasopressors. vasopressors.

Trial designTrial design Multicenter, randomized, double-blind trialMulticenter, randomized, double-blind trial

Primary end pointPrimary end point: mortality 28 days after the initiation : mortality 28 days after the initiation of infusionsof infusions

Methods Methods

Target MAP was set at 65-75mm HgTarget MAP was set at 65-75mm Hg Open-label vasopressors were allowed in addition to the study drugOpen-label vasopressors were allowed in addition to the study drug

Vasopressin started at 0.01 U/min and titrated to 0.03 U/min over Vasopressin started at 0.01 U/min and titrated to 0.03 U/min over 1 hour 1 hour

Norepi started at 5 Norepi started at 5 μμg/min and titrated to 15 g/min and titrated to 15 μμg/min g/min

778 pt’s randomized778 pt’s randomized 396 received vasopressin396 received vasopressin 382 received norepinephrine382 received norepinephrine

Methods Methods

Calculated 776 pt’s were required to Calculated 776 pt’s were required to detect a 10% difference in mortalitydetect a 10% difference in mortality Assuming a 60% death rate in the norepi Assuming a 60% death rate in the norepi

group and a 2-sided alpha error of 0.05 and group and a 2-sided alpha error of 0.05 and a power of 80%a power of 80%

Russell J et al. N Engl J Med 2008;358:877-887

12.8%

97%

ResultsResults

There was no significant difference in the primary There was no significant difference in the primary outcome (rate of death 28 days after initiation of outcome (rate of death 28 days after initiation of infusions)infusions) 35.4% in vasopressin group35.4% in vasopressin group 39.3% in norepi group39.3% in norepi group P=0.26P=0.26 95% CI for absolute RR in vasopressin group, -2.9 to 10.7%95% CI for absolute RR in vasopressin group, -2.9 to 10.7%

Additionally there was no significant difference at 90 Additionally there was no significant difference at 90 days (43.9% vs 49.6% respectively; P=0.11)days (43.9% vs 49.6% respectively; P=0.11)

These results also remained non-significant after These results also remained non-significant after multivariate logistic-regression analysismultivariate logistic-regression analysis

There were also no differences in the rates of serious There were also no differences in the rates of serious adverse eventsadverse events Was a trend toward higher incidence of MI in norepi groupWas a trend toward higher incidence of MI in norepi group

There were no difference in the percentage of patients There were no difference in the percentage of patients receiving corticosteroidsreceiving corticosteroids


Analysis of the Rates and Risks of Death from Any Cause and Secondary Outcomes


Kaplan-Meier Survival Curves for Patients Who Underwent Randomization and Infusion


Serious Adverse Events in Patients Who Had Septic Shock


Rates and Risks of Death from Any Cause According to the Severity of Shock

CritiquesCritiques

The overall mortality rate from septic shock The overall mortality rate from septic shock was 37% - lower than the normal reported was 37% - lower than the normal reported range of 50-60%range of 50-60% Was there sampling bias?Was there sampling bias?


Enrollment and Outcomes

12.8%

CritiquesCritiques

The overall mortality rate from septic shock The overall mortality rate from septic shock was 37% - lower than the normal reported was 37% - lower than the normal reported range of 50-60%range of 50-60% Was there sampling bias?Was there sampling bias? Is this applicable to more “real-world” pt’s?Is this applicable to more “real-world” pt’s?

CritiquesCritiques

MAP at baseline was 72mm Hg on MAP at baseline was 72mm Hg on catecholamine therapy alonecatecholamine therapy alone Effectively making the trial an evaluation of Effectively making the trial an evaluation of

vasopressin as a catecholamine-sparing agentvasopressin as a catecholamine-sparing agent

Average time of initiation of therapy after Average time of initiation of therapy after diagnosis of septic shock was 12hrsdiagnosis of septic shock was 12hrs Several studies already report on the necessity of Several studies already report on the necessity of

early intervention of fluid resuscitation and early intervention of fluid resuscitation and antimicrobial therapy (Rivers, Kumar respectively)antimicrobial therapy (Rivers, Kumar respectively)

ConclusionsConclusions

There seems to be no advantage to There seems to be no advantage to vasopressin in the management of septic vasopressin in the management of septic shockshock

Timing of effective therapy (regardless of Timing of effective therapy (regardless of actual drug used) still seems to be the most actual drug used) still seems to be the most important factor in the management of septic important factor in the management of septic shockshock

Comments?Comments?

Technology

Septic Shock: Steroids/Vasopressin