Upload
changezkn
View
927
Download
2
Embed Size (px)
DESCRIPTION
Citation preview
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
Sprung C et al. N Engl J Med 2008;358:111-124
Outcomes According to Subgroup
Sprung C et al. N Engl J Med 2008;358:111-124
Kaplan-Meier Curves for the Time to Reversal of Shock
Sprung C et al. N Engl J Med 2008;358:111-124
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
Russell J et al. N Engl J Med 2008;358:877-887
Analysis of the Rates and Risks of Death from Any Cause and Secondary Outcomes
Russell J et al. N Engl J Med 2008;358:877-887
Kaplan-Meier Survival Curves for Patients Who Underwent Randomization and Infusion
Russell J et al. N Engl J Med 2008;358:877-887
Serious Adverse Events in Patients Who Had Septic Shock
Russell J et al. N Engl J Med 2008;358:877-887
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?
Russell J et al. N Engl J Med 2008;358:877-887
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?