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Critical Care Update 2008:
implications of recent trials
Richard H. Savel, MD, FCCM
Co-Director, Surgical ICU
Maimonides Medical Center
Slide Sub-Title
New York, NY
Important trials in early 2008
• Corticus Trial
• VISEP study
• VASST trial
• And 2 trials looking at low/high PEEP in ALI/ARDS:
– Express trial
– LOVS trial
Slide 3
Corticus
Corticus Trial
• Still trying to answer the question:
– Is there a value to corticosteroids as part of therapy
for severe sepsis syndrome?
Slide 5NEJM
2008; 358: 111-24.
Corticus: the patients
• Age ≥ 18 yrs
• clinical evidence of infection
• evidence of a systemic response to infection
• the onset of shock within the previous 72 hours
– as defined by a systolic blood pressure of <90 mm Hg
despite adequate fluid replacement or a need for
vasopressors for at least 1 hour
• hypoperfusion or organ dysfunction attributable to sepsis
Slide 6
Corticus: the intervention
• Hydrocortisone was administered as:
– a 50-mg intravenous bolus every 6 hours for 5 days
– then tapered to 50 mg intravenously every 12 hours
for days 6 to 8
– 50 mg every 24 hours for days 9 to 11
– then stopped
Slide 7
Enrollment and Outcomes
Slide 8
Corticus: endpoints
• Primary endpoint:
– the rate of death at 28 days in patients who did not have a
response to corticotropin
• Secondary end-points were:
– the rates of death at 28 days in patients who had a response to
corticotropin and in all patients
– the rates of death in the ICU and in the hospital
– the rates of death at 1 year after randomization
– a reversal of organ system failure (including shock)
– and the duration of the stay in the ICU and the hospital
Slide 9
Corticus: primary outcome
Rate of death at 28 days in patients who did not have a response to
corticotropin (p=0.69)
45
40
35
30
25
39.2 %
N=125
36.1 %
N=108
20
15
10
5
0
placebo
hydrocortisone
Slide 10
Corticus: secondary outcome
Rate of death at 28 days in patients who did have a response to
corticotropin (p= 1.00)
35
30
25
20
28.7 %
N=136
28.8%
N=118
placebo
hydrocortisone
15
10
5
0
Slide 11
Corticus: secondary outcome
Rate of death at 28 days in all patients (p= 0.51)
40
35
30
25
34.3%
N=251
31.5 %
N=248
20
15
10
5
0
placebo
hydrocortisone
Slide 12
Corticus: other secondary
outcomes
• No other secondary outcomes were improved with
steroids
– rates of death in ICU, hospital, or at one year, as well
as duration of stay in ICU or hospital
• Reversal of organ system failure was improved with
steroids
Slide 13
Subgroup Outcomes
Slide 14
P=0.06
P<0.001
P<0.001
Slide 15
Corticus: adverse events
•
In the hydrocortisone group, there was an increased
incidence of superinfections, including new episodes of
sepsis or septic shock
•
There was also an increased incidence of
hyperglycemia and hypernatremia
Slide 16
Corticus: note on etomidate
• Post hoc analyses also revealed an increased rate of
death at 28 days among patients who received
etomidate before randomization in both groups:
– Etomidate/steroids:45.1%
– No etomidate/steroids:31.5%
– Etomidate/no steroids: 40.0%
– No etomidate/no steroids: 29.6%
– P=0.03
Slide 17
Overall mortality:
etomidate: 43%
no etomidate: 30.5%
Corticus: Conclusions
• In summary, the use of hydrocortisone did not decrease
mortality in a general population of patients with septic
shock, even though the drug hastened reversal of shock.
• This lack of improvement may be related to an increased
incidence of superinfection and new septic episodes.
Slide 18
Corticus: Conclusions
• No benefit was seen in a subgroup of patients who had
had no response to corticotropin, as had been
demonstrated previously for patients with severe septic
shock.
Slide 19
Corticus: Conclusions
• On the basis of these findings, hydrocortisone cannot be
recommended as general adjuvant therapy for septic
shock (vasopressor responsive), nor can corticotropin
testing be recommended to determine which patients
should receive hydrocortisone therapy.
Slide 20
Corticus: Conclusions
• Hydrocortisone may have a role among patients who are
treated early after the onset of septic shock who remain
hypotensive despite the administration of high-dose
vasopressors (vasopressor unresponsive).
Slide 21
VISEP
VISEP Study
Efficacy of Volume Substitution and Insulin Therapy in
Severe Sepsis (VISEP)
Slide 23
NEJM 2008; 358: 125-39.
VISEP study
• Two-by-two factorial design:
• Evaluate safety and efficacy of intensive insulin therapy
compared with conventional insulin therapy
• Evaluate safety and efficacy of hydroxyethyl starch
(HES) compared with Ringer’s lactate (RL) in patients
with severe sepsis syndrome or septic shock
Slide 24
VISEP study
• Randomized patients with severe sepsis to either :
– intensive insulin therapy, or conventional insulin
therapy
AND
– 10% pentastarch, a low-molecular weight
hydroxyethyl starch, or modified Ringer’s lactate for
fluid resuscitation
Slide 25
VISEP study
• The trial was stopped for safety reasons.
• 537 patients evaluated:
– Intensive insulin: 112 mg/dL
– Conventional therapy: 151 mg/dL
– P<0.001
Slide 26
VISEP study
• At 28 days, no difference between the 2 groups in rate of
death, or organ failure score
• Rate of severe hypoglycemia (≤40 mg/dL) was higher in
intensive insulin group (17.0% vs. 4.1%, p< 0.001)
Slide 27
VISEP study
• Rate of serious adverse reactions were also higher in
intensive insulin therapy group (10.9% vs. 5.2%, p=0.01)
Slide 28
VISEP study
• HES therapy was associated with higher rates of acute
renal failure (34.9% vs. 22.8%, p=0.002) and renalreplacement therapy (RRT) (31% vs. 18.8%, P=0.001)
Slide 29
VISEP study
• Direct correlation between cumulative dose of HES and
both need for RRT and rate of death at 90 days…not
true for cumulative dose of RL.
• Cox regression analysis identified the occurrence of
hypoglycemia as an independent risk factor for death
from any cause.
Slide 30
VISEP study
• Overall conclusions from this study:
– “Taken together, our study and the medical ICU study
by Van den Berghe et al. establish that intensive
insulin therapy has no measurable, consistent benefit
in critically ill patients in a medical ICU, regardless of
whether the patients have severe sepsis, and that
such therapy increases the risk of hypoglycemic
episodes.”
Slide 31
VISEP study
• Overall conclusions from this study:
– “Fluid resuscitation with 10% HES 200/0.5 is harmful
in patients with severe sepsis. At recommended
doses, it causes renal impairment, and at high doses,
it impairs long-term survival. Since adverse effects
have been attributed to various HES solutions… HES
solutions should be avoided.”
Slide 32
VASST
Vasopressin and Septic Shock Trial:
VASST
Slide 34
NEJM 2008; 358: 877-87.
VASST trial
• 778 patients with septic shock (receiving at least
5mcg/min of norepinephrine) underwent randomization
to either
– Low-dose vasopressin (0.01-0.03 U/min)
• Or
– Norepinephrine (5-15 mcg/min)
Slide 35
Enrollment and Outcomes
Slide 36
VASST trial
• Primary endpoint:
– Death from any cause at 28 days
• Secondary endpoints:
– 90-day mortality
– ICU and hosp length-of-stay
– Days alive and free of :
• organ dysfunction, vasopressor use, mechanical ventilation,
renal replacement therapy, SIRS, corticosteroid use
Slide 37
VASST trial
• No significant differences in any of the primary or
secondary endpoints when comparing the vasopressin
with the “placebo” (i.e., norepinephrine) group
Slide 38
Anaylsis of Death Rates & Risks
Slide 39
VASST trial: Conclusions
• “We did not find a significant reduction in mortality rates
with vasopressin.”
Slide 40
PEEP in ALI / ARDS
• Recent randomized trials on high vs. low Positive EndExpiratory Pressure (PEEP) for Acute Lung Injury/ARDS
Slide 41
JAMA 2008
• LOVEs trial
– Meade et al. JAMA. 2008;299(6):637-645
• Express trial
– Mercat et al. JAMA. 2008;299(6):646-655
• Looking at high vs. low PEEP
• Not better…not worse…
Slide 42
LOVs Trial
JAMA. 2008;299(6):637-645 Meade et al.
Slide 43
LOVs Trial
Slide 44
LOVs Trial
Slide 45
LOVs Trial
LOVs Trial
Slide 46
Outcomes
Slide 47
Express Trial
JAMA. 2008;299(6):646-655 Mercat et al.
Slide 48
EXPRESS trial
Slide 49
Express Trial
Slide 50
Express Trials
Slide 51
Express Trials
Slide 52
Conclusions
• There is great consensus that low tidal volumes are
beneficial in ALI/ARDS
• Recent studies are trying to answer the question about
low vs. high peep
Slide 53