Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study.

Briegel J, Forst H, Haller M, et al.

Crit Care Med. 1999; 27:723-32. [abstract]

Reviewed by David Vaughan MD, Childrens Hospital and Regional Medical Center, Seattle

Review posted December 11, 1999

I. What is being studied?:

The study objective:

To test whether stress doses of hydrocortisone reverse hyperdynamic septic shock

The study design:

A prospective, randomized, double blind, single-center study in an academic center.

The patients included:

Consecutive patients who met the ACCP/SCCM criteria for septic shock.(1) These criteria require a documented positive blood culture or infection and at least two of the following; a) fever (temperature > 38°) or hypothermia (body temperature < 36°), b) tachycardia (> 90 beats/minute), c) tachypnea (> 20 breaths/minute) or hyperventilation (Paco2 < 32 torr), d) abnormal white blood cell count; e) evidence of organ dysfunction or hypoperfusion abnormality, e) hypotension persisting despite adequate fluid resuscitation or the use of vasopressor or inotropic support.

Those who met these criteria, who were on vasopressor support, and had high output circulatory failure with a cardiac index (CI) > 4 L/min/m2 (> 55 years: 3.5 L/min/m2) after fluid resuscitation to achieve a pulmonary capillary wedge pressure (PCWP) of 12 to 15 mm Hg were enrolled. The hyperdynamic state had to present without the use of positive inotropic agents (dobutamine or dopexamine).

The patients excluded:

Patients aged < 18 or > 75 years old, those who were pregnant, or who had irreversible underlying diseases were excluded. Other exclusion criteria included those who were treated with vasopressors for greater than 72 hours or with glucocorticoids. Organ transplant recipients, patients with burns or hemorrhagic shock, and those who suffered myocardial infarction in the six months preceding the study were also excluded.

The interventions compared:

The treatment group received hydrocortisone at a dose of 100 mg over 30 minutes, followed by 0.18 mg/kg/hr as long as vasopressor therapy continued. When septic shock had been reversed, as defined by cessation of vasopressor support, the dose of hydrocortisone was reduced to 0.08 mg/kg/hr. This dose was kept constant for six days. The hydrocortisone infusions were then tapered off in steps of 24 mg per day. The control group received physiological saline solution in an identical manner.

The outcomes evaluated:

The primary study end point was time to shock reversal as defined by cessation of vasopressor support (alpha-adrenergic support). Vasopressor support was defined a priori as epinephrine or norepinephrine at any dose and/or dopamine at > 6 mcg/kg/min. Secondary study end points were the evolution of hemodynamics and the multiple organ dysfunction syndrome. All patients were followed until death or discharge from the ICU. All those discharged from hospital were subsequently contacted by phone to determine long term outcome.

II. Are the results of the study valid?

1. Is there a strong, independent, consistent association between the surrogate end point and the clinical end point?

No. There is an association between various surrogate end points including cessation of pressors, evolution of hemodynamics (mean arterial pressure [MAP], systemic vascular resistance index [SVRI], and oxygen delivery index [DO2I) and improvement in organ dysfunction as measured globally by the SOFA score and specifically in the case of cardiovascular, respiratory, central nervous system and hepatic dysfunction scores. However only in the case of MAP, SVRI and DO2I did these changes achieve significance.

2. Is there evidence from randomized trials in other drug classes that improvement in the surrogate end point has consistently led to improvement in the target outcome?

There is evidence that a good outcome is correlated with improvement in surrogate markers such as hemodynamic variables and biochemical indices of tissue perfusion such as lactate. (2-6) There is little data that supports the hypothesis that an intervention, which improves indirect or surrogate markers of illness severity correlates with an improved outcome. Indeed, there is little data available to show a beneficial effect of any recent experimental therapy in altering the outcome of septic shock.

3. Is there evidence from randomized trials in the same drug class that improvement in the surrogate end point has consistently led to improvement in the target outcome?

Sprung et al. demonstrated early shock reversal in a group treated with high dose methylprednisolone and dexamethasone compared to a placebo group. However there was no difference in mortality between the two groups. (7) More recent work by Bollaert has demonstrated that late septic shock may be reversed by supraphysiologic doses of hydrocortisone and that shock reversal within seven days was a strong predictor of survival. (8) Bone et al found no effect of steroids on either shock reversal or outcome. (9)

IIa. Validity Questions for Therapy Articles:

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were assigned to random permuted blocks.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete? and were patients analyzed in the groups to which they were randomized?

Yes. All survivors who were discharged from the ICU were followed for one year after enrollment. Follow up was by means of phone to assess long-term outcome. All non-survivors were followed until death supervened. No patient crossed over to the other group.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

It is not stated explicitly that caregivers were blinded to the treatments received in the text. However this is implied in both the title and abstract. The drugs, apparently identical in appearance, were prepared by research assistants who were not involved in the study or the care of the patients.

4. Were the groups similar at the start of the trial?

Yes. Specifically there was no difference at the start of the trial between the two groups in demographics, disease severity as defined by Apache 2, simplified acute physiology score (SAP 2) and simplified organ failure assessment (SOFA). There was no significant difference between the two groups in their underlying infections or causative organisms. There was no difference in degree of cardiovascular dysfunction or pressor requirements. There was no significant difference in other organ dysfunction as measured by PaO2/Fi02 ratio, serum creatinine, serum bilirubin, platelets, lactate and C-reactive protein.

5. Aside from the experimental intervention, were the groups treated equally?

Yes. Patients were treated according to a previously defined protocol. This included fluid resuscitation to achieve a PCWP of 12-15 mm Hg. Packed red blood cells were given for a hematocrit below 27%. Vasopressor therapy was titrated to achieve a mean arterial pressure of > 70 mm Hg. When dopamine exceeded 10 mcg/kg/min, norepinephrine combined with dopamine in low dose was the proposed regimen. Following randomization, additional catecholamines were permitted. There was no difference between the two groups in the use of these additional agents (dobutamine, dopexamine or epinephrine) following randomization. There was also no difference in the use of concomitant therapies, including mechanical ventilation, hemofiltration, immunoglobulins or antithrombin III. It is unclear whether there were significant differences in the antimicrobial therapies received.

III. What were the results?

1. How large, precise, and lasting was the treatment effect? (Effect should be large, precise, and lasting to consider a surrogate trial as possible basis for offering patients the intervention.)

Median time of vasopressor support was 2 days in the hydrocortisone group vs. 7 days in the placebo group (p=0.005). Shock reversal was achieved in 90% of the hydrocortisone group, vs. 80 % in the placebo group (no significant difference). No difference in mortality between the two groups was observed to hospital discharge (20% in the hydrocortisone group; 30% in the placebo group) or in one-year mortality between the 2 groups; (p=0.69, log rank test).

There was a trend toward improvement in organ dysfunction as judged by components of the sepsis related organ failure assessment (SOFA), with respect to cardiovascular, respiratory and CNS function. Again, these failed to reach statistical significance. It should be noted however that the SOFA score was applied retrospectively as it was first published in 1996 after commencement of the trial. Improvement in respiratory function was reflected in a (non-significant) trend toward a shorter duration of mechanical ventilation; 18 days in the hydrocortisone group vs. 38 days in the placebo group, (log rank test p=0.19)

The estimate was reasonably precise in that time of pressor support (1st and 3rd quartiles) in the treatment group was 1-6 days and 3-19 days in the placebo group, p < 0.005. Standard confidence intervals are not offered for these continuous data.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

No. The patient population consisted entirely of adults. Also, the numbers (20 per group) were quite small and the study was confined to a single center. However, this paper is consistent with others who have recently showed an effect of steroids in septic shock as defined by shock reversal. (8) There is also recent data showing evidence of adrenal insufficiency in a pediatric population with septic shock. (10) However as against this, there remains a very large body of evidence that shows steroids are either of no benefit or may be harmful in the treatment of shock. Clearly much work remains to be done, specifically a large randomized multi center trial and also determining the optimal timing, dose and type of steroid replacement.

2. Were all clinically important outcomes considered?

It is also unclear how many patients were post-operative and whether steroids had any effect on subsequent wound healing. Otherwise all major relevant outcomes were accounted for. However, the study was insufficiently powered to detect differences in major clinical outcomes, e.g., mortality.

3. Are the likely treatment benefits worth the potential harms and costs?

It remains unclear. A cost benefit analysis was not performed, weighing potential savings of reduced vasopressor drugs vs. the cost of steroid replacement. In view of the fact that there were no significant differences in outcome, the major benefits of this therapy would seem to be cost savings from reduced pressor requirements and possibly reduced length of ICU stay. There was a statistically non-significant though clinically and fiscally significant trend toward reduced ICU stay (median length of stay 27 days in the hydrocortisone group vs. 44 days in the placebo group, p=0.27). As against this there was no obvious increased incidence of major side effects seen in the treatment group. 7/20 patients in the hydrocortisone group had sodium concentration > 155 mmol/L. One patient had a GI hemorrhage.

References

1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-874. [abstract]
2. Pollack MM, Fields AI, Ruttimann UE. Distributions of cardiopulmonary variables in pediatric survivors and nonsurvivors of septic shock. Crit Care Med 1985;13:454-459. [abstract]
3. Bernardin G, Pradier C, Tiger F, Deloffre P, Mattei M. Blood pressure and arterial lactate level are early indicators of short-term survival in human septic shock. Intensive Care Med 1996;22:17-25. [abstract]
4. Tuchschmidt J, Fried J, Swinney R, Sharma OP. Early hemodynamic correlates of survival in patients with septic shock. Crit Care Med 1989;17:719-723. [abstract]
5. Groeneveld AB, Nauta JJ, Thijs LG. Peripheral vascular resistance in septic shock: its relation to outcome. Intensive Care Med 1988;14:141-147. [abstract]
6. Nishijima H, Weil MH, Shubin H, Cavanilles J. Hemodynamic and metabolic studies on shock associated with gram negative bacteremia. Medicine 1973;52:287-294. [abstract]
7. Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984;311:1137-1143. [abstract]
8. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645-650. [abstract]
9. Bone RC, Fisher CJJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317:653-658. [abstract]
10. Hatherill M, Tibby SM, Hilliard T, Turner C, Murdoch IA. Adrenal insufficiency in septic shock. Arch Dis Child 1999;80:51-55. [abstract]

     

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