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:

Please visit the new Evidence Based Journal Club Reviews

Effects of ibuprofen on the physiology and survival of hypothermic sepsis.

Arons MM, Wheller AP, Bernard GR, et al.

Crit Care Med 1999; 27:699-707. [abstract]

Reviewed by Waleska Arias, M.D., Section of Critical Care at Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.

Review posted May 7, 2003

---

I. What is being studied?:

The study objective:

The study objective was to compare the clinical and physical characteristics of febrile septic patients with hypothermic septic patients. The article wanted to report the effect of Ibuprofen treatment on vital signs, organ failure and mortality in hypothermic sepsis. Also the investigators examined the plasma levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), thromboxane B2 and prostacyclin in hypothermic septic patients versus febrile patients.

The study design:

The paper is a subset analysis of a randomized controlled trial of ibuprofen in sepsis (1).

The patients included:

The recruitment of patients began in October 1989 and was completed in March 1995. It was performed in seven medical centers in the United States and Canada. Four hundred and fifty five patients who met the criteria for severe sepsis and were suspected of having a serious infection were included in the trial. Forty four (9.6%) patients in the original trial were hypothermic (< 35.5°C); 24 of these received ibuprofen and 20 received placebo. The subgroup analysis of the effect of ibuprofen in hypothermic sepsis was performed on these 44 patients. All the patients included should have all of group A criteria and one of the group B criteria. The Group A criteria were: a) core temperature of ≥ 38.3°C or ≤ 35.5°C, b) heart rate ≥ 90 beats/min and c) respiratory rate ≥ 20 breaths/min or if mechanically ventilated, a minute ventilation > 10L/min. The group B inclusion criteria were: a) cardiovascular system: hypotension (systolic blood pressure ≤ 90 mmHg or a decrease of ≥ 40 mmHg for 1 hour in the with adequate pulmonary artery wedge pressure (≥ 12 mmHg ) or after ≥ 500 ml of saline, b) renal system: urine output ≤ 30 ml/hr or ≤ 0.5 ml/kg for ≥ 1 hour, c) pulmonary system: PaO2 ≤ 70 torr while on room air or a PaO2/ FIO2 ≤ 333 torr or if on supplemental oxygen d) ARDS: PaO2/FIO2 ≤ 200 torr with acute bilateral infiltrates, e) central nervous system; significant alteration in mental status (decrease of ≥ 2 points on the Glasgow Coma Scale).

The patients excluded:

The patients were excluded from the trial if: a) pregnant, b) < 18 years old, c) known or suspected hypersensitivity to cyclooxygenases inhibitors, d) had received cyclooxygenases inhibitors in the past 12 hours, e) were enrolled in another experimental protocol or if consent could not be obtained. Also excluded were patients with: a) known or suspected brain death, b) advanced acute or chronic renal or hepatic failure, c) core temperature of < 90° F, d) platelet count < 20,000 cells/mm3, e) granulocyte count < 1,000 cells/mm3, f) receiving a major immunosuppressive drug, g) known HIV, h) gastrointestinal bleeding, i) life expectancy of less than 6 hours, j) lack of commitment to life support.

The interventions compared:

Patients in the treatment group received intravenous Ibuprofen at a dose of 10 mg/kg (maximum of 800 mg) infused over 30 to 60 minutes every six hours for eight doses. The placebo group received a glycine buffer vehicle using the same volume and administration regimen as the treatment group.

The outcomes evaluated:

The primary outcome evaluated was mortality rate over a 30 day period after treatment with Ibuprofen. Also was evaluated the effect of this drug on vital signs, organ failure (failure-free days), time alive and out of the ICU (ICU-free days) and time alive and off ventilatory support (ventilator-free days).

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. All eligible patients were randomized to receive either Ibuprofen or placebo using a blinded permuted-block randomization algorithm.

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

Was followup complete?

Yes; all deaths occurring within 30 days of randomization were recorded.

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

Yes; on an "intention to treat basis", all patients were analyzed in each of the groups to which they were randomized. There was no cross over.

Secondary questions:

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

Yes, all personnel involved in the patient's care, as well as the patient and patient's family were blinded to the treatment assignment.

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

The most important baseline differences in baseline characteristics within the hypothermic group (control vs. treated) were:1) age of almost 10 yrs between groups (p = 0.05) and 2) a difference in positive blood cultures, 50% in the ibuprofen group vs. 20% in the placebo group (p < .05). Other baseline differences such as APACHE II scores of 18 in the ibuprofen group and 19 in the placebo group were not statistically significant.

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

Maybe; it is likely that the groups were treated equally because the study was blinded, but there were no data in the article to confirm this fact.

III. What were the results?

1. How large was the treatment effect?

The mortality rate in the hypothermic patients treated with Ibuprofen was significantly smaller than the hypothermic placebo group.

A) Ibuprofen effect on mortality in hypothermic patients:

Risk without Ibuprofen Treatment (Baseline risk): x	18/20 = 0.9 or 90%.	CI: (0.7 to 0.97)
Risk with Ibuprofen Treatment: y	13/24=0.54 or 54%	CI: (0.4 to 0.7)
Absolute Risk Reduction (ARR) of Mortality with Ibuprofen Treatment: X-Y	0.90-0.54 = 0.36	CI: (0.12 to 0.6)
Relative Risk (RR) of Mortality with Ibuprofen Treatment: Y/X	0.54/0.9 = 0.6	CI: (0.4 to 0.9)
Relative Risk Reduction (RRR) of Mortality with Ibuprofen Treatment: [1-Y/X] x 100 or [(X-Y) / X] x 100	[0.35/0..9] x 100 = 40%	CI: (0.1 to 0.6)
Number needed to treat (NNT): (1/ARR)	1/0.36 = 3	CI: (2 to 8)

The relative risk reduction (RRR) of mortality after treatment was 40%. This means that the effect of treatment with Ibuprofen in hypothermic patients reduced the risk of mortality by 40% when compared to controls. The number needed to treat (NNT) was 3, meaning that 3 patients would have to be treated in order to have one possible survival with treatment. The mortality rate between treated and controls overall (hypothermic and febrile together) was not different (37% for treated vs.40% for controls).

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

The absolute risk reduction is 36% with a 95% CI of 12% to 60%. The difference in the risk of death between hypothermic patients treated with Ibuprofen and those who had the placebo will range between 12 to 60%. The number needed to treat with Ibuprofen instead of placebo to prevent one death, could be as few as 2 patients or as high as 8 patients. These confidence intervals confirm that the point estimate is significant.

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

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

No. Although the article intended to include patients above 18 years, the mean age of the patients at the study entry was around 50 years old. We have to remember that the physiologic responses to diseases in the pediatric population are different to that of the adult population, so we should expect different outcomes. I think that further studies should be done in the pediatric population in order to be able to apply this treatment in our intensive care units.

2. Were all clinically important outcomes considered?

Mortality is the most important outcome to be evaluated given the patient population being studied in this article.

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

The results presented in the article as well as the statistical analysis were strong enough to consider the use of Ibuprofen in the treatment of septic hypothermic patients. A reduction in mortality from 90% in the placebo group to 54% in the treatment group is significant enough to try the use of Ibuprofen as a measure to improve outcome of hypothermic patients despite the costs of this drug.

References:

1. Bernard GR, Wheeler AP, Russel JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 1997;336:912-918. [abstract]
2. CEBM Stats calculator, University Health Network, Mount Sinai Hospital.
3. HyperStat Statistics Textbook, David Lane, Rice University, Houston, Texas.

Comments

Back to the EB Journal Club Index