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

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

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A randomized and controlled trial of the effect of treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic shock.

Alia I, Esteban A, Gordo F, et al.

Chest 1999;115:453-61. [abstract]

Reviewed by Priya Prabhakaran, MD and Tracy Butler, MD, Baylor College of Medicine and Texas Children's Hospital, Houston, TX

Review posted August 3, 2000

I. What is being studied?:

The study objective:

The primary objective of this study was to evaluate the effect of increased oxygen delivery on the mortality and morbidity of patients with severe sepsis or septic shock. The secondary objective was to evaluate the factors contributing to mortality in these patients.

The study design:

Prospective randomized controlled trial

The patients included:

63 patients admitted to the medical-surgical ICU of a tertiary care hospital during a 30 month period from January 1993 to June 1995. Information about the total number of eligible patients is not available. Patients were included in the study cohort when they had a documented or strongly suspected infection and two of the following: tachycardia (HR > 90/min), tachypnea (RR > 20 or requiring mechanical ventilation), fever (core temp > 38C) or hypothermia (core temp < 35.6C) in addition to hypotension (SBP < 90mmHg, or drop in SBP > 40 from baseline) and or any signs of organ dysfunction in the absence of any obvious explanation other than sepsis. These included metabolic acidosis (pH < 7.3 or plasma lactate > 2mmol/L), arterial hypoxemia (PaO2/FiO2 < 250), oliguria (UOP < 0.5cc/kg/hr), coagulopathy (prolonged prothrombin time or a drop in platelet count by 50%), or encephalopathy in the absence of sedatives or intracranial injury. Shock was defined as hypotension lasting more than an hour despite the administration of fluids to expand intravascular volume associated with signs of organ dysfunction or hypoperfusion.

The patients excluded:

Patients < 18 years old, pregnancy, shock > 24 hours prior to enrollment in the study.

The interventions compared:

Normal oxygen delivery was compared to supranormal oxygen delivery. Normal DO2 was values of > 330 ml/min/m2 in controls compared to supranormal DO2 of > 600 ml/min/m2 in the treatment group. The supranormal DO2 was achieved with dobutamine administration.

The outcomes evaluated:

Mortality and the number of organ dysfunctions.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, a table of random numbers was used and patients were allocated to one of the two groups using opaque sealed envelopes that were opened only after a patient fulfilled the entry criteria.

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

Was followup complete?

Yes.

Were patients analyzed in the groups to which they were randomized?

Yes, the intention to treat principle was followed.

Secondary questions:

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

No, the amount of inotrope a patient was on would be known by all caregivers.

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

More patients in the control group were bacteremic (34% vs.13%. p = 0.04) The treatment group appeared to have sicker patients with higher APACHE scores (25 vs 22, p = 0.08). Aside from these two factors, the groups were similar.

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

Unknown. There is no comment about other aspects of management.

III. What were the results?

1. How large was the treatment effect?

The mortality rate in the control group was 66% versus 74% in the treatment group (p = 0.46). The number of dysfunctional organs per patient was also similar in both groups. A relative increase of 13% in the mortality rate of the treatment group patients was observed (RR =1.13 or 13% increase; 95% CI, -18% to 57%).

2. How precise was the estimate of the treatment effect?

The results of this study are not very precise for the following reasons: (a)The number of patients needed to detect a statistically significant difference between the two groups is 540 (as pointed out by the authors) versus the 63 subjects actually enrolled. (b) The targeted goal of DO2I of > 600 ml/min/m2 was only achieved in 28% of the treatment group. (c) The confidence intervals for the relative risk of increased mortality include 0, negating any treatment effect. The confidence interval shows that the treatment group could have 18% less to 57% greater mortality than the control group. The Absolute Risk Reduction of mortality in the treatment group was -0.08, indicating that the treatment group actually did worse than the control group.

3. 3. Did the treatment effect differ in subgroups of patients?

Yes, the mortality rate was 100% in bacteremic patients regardless of which group they were randomized. The non-bacteremic patients in the treatment group had a higher mortality rate than those in the control group (70% vs. 48%, p = 0.1)

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

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

The results are not applicable to pediatric patients since there were no children enrolled in this study. Most pediatric patients tolerate higher inotropic drug doses and the resultant tachycardia better than adults. With this in mind, pediatric patients would more likely to achieve the goal of supranormal oxygen delivery > 600 ml/min/m2.

2. Were all clinically important outcomes considered?

Yes.

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

From the results of this study - increased mortality in the treatment group - it is not worth subjecting patients to interventions aimed at achieving supranormal oxygen delivery.

Discussion

The mortality rate from septic shock in both the treatment and control group (66% and 74% respectively) Ñ and adults in general is much higher than the mortality seen in pediatric septic shock (20%) (1). As stated above, children are better able to tolerate higher doses of inotropes without extreme tachycardia and could therefore be more likely to achieve the goal of DO2I of 600 ml/min/m2. The fact that the investigators were able to achieve their goal of supranormal oxygen delivery in only 28% of the treatment group with an almost equal number in the control group reaching supranormal oxygen delivery diminishes any real treatment effect. The crossover phenomenon has been seen in previous studies as well. Despite the problem of crossover, previous studies have shown an overall trend towards lower mortality in the treatment group.

References

1. Ceneviva G, Paschall JA, Maffei F, Carcillo JA. Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics. 1998;102(2):e19. [abstract] [full-text]

    

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