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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Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis, Ibuprofen in Sepsis Study Group.

Mangialardi RJ, Martin GS, Bernard GR, et al.

Crit Care Med. 2000;28(9):3137-45. [abstract]

Reviewed by Nesreen Faqih MD, Baylor College of Medicine

Review posted September 5, 2002

I. What is being studied?:

The study objective:

To determine if an association exists between low serum protein levels and the presence and severity of ARDS.

The study design:

A retrospective cohort study. The authors used data obtained from a recently completed prospective multi-center clinical trial investigating sepsis and ibuprofen. Data was collected over a six- year period between Oct 1989 and March 1995. While 3311 patients were screened, only 455 patients were included given the numerous exclusion criteria. All but 14 patients that were enrolled in the original Ibuprofen study had serum protein levels measured at the study entry.

The patients included:

The patients included were those who met the original study inclusion criteria and had initial serum protein values. Initial study inclusion criteria were:

If patients had a known site of infection and if they met all group A criteria and at least one of the group B criteria

Group A criteria

1. Core temperature >38.3C (101F) or < 35.5C (96F)
2. Heart rate > 90 beats /min (in the absence of beta adrenergic blockers)
3. Respiratory rate > 20 breaths /minute, or if mechanically ventilated, a minute ventilation > 10L/minute.

Group B criteria

1. Cardiovascular system: Systolic blood pressure < 90mm Hg or fall of > 40 mm Hg for more than one hour in the face of adequate pulmonary occlusion pressures ( 12mm Hg) or intravenous infusion of 500 cc of saline solution.
2. Renal system: urine output < 30ml/hr or < 0.5 ml/kg for 1 hr.
3. Pulmonary system: Pa02 < 70 mm Hg while breathing room air or a Pa02/Fi02 ratio < 333 if receiving supplemental oxygen.
4. ARDS: Pa02/Fi02 < 200 mm Hg in the presence of acute bilateral diffuse lung infiltrates on frontal chest X-rays.
5. CNS: mental status decrease of 2 points on the Glasgow Coma Scale.

The patients excluded:

Excluded were patients that did not have initial protein values and those not meeting the original study exclusion criteria and these were patients that were less than 18 yrs old, had suspected hypersensitivity to cyclooxygenase inhibitors, had received a cyclooxygenase inhibitor within 12 hours, were enrolled in another study protocol, consent could not be obtained, or had suspected brain death, advanced renal or hepatic system disease, core temperature < 32.2 C, platelet count less than 20,000, granulocyte count < 1,000 as a result of causes other than sepsis, HIV infection, GI bleeding, administration of major immunosuppressive drugs, life expectancy, 6 hours, or lack of aggressive life-support plans. Patients were also excluded if they could not receive the first dose of the study drug within 24 hours of meeting entry criteria.

The outcomes assessed:

1. ARDS development
2. 30 day survival rates
3. Ventilator free days
4. serum protein levels on day 5 and weight gain on day 5.

II. Are the results in the study valid?

Primary questions:

1. Was there a representative and well-defined sample of patients at a similar point in the course of the disease?

Partially. The numerous exclusion criteria of the original study made this sample of patients relatively restricted compared to the diversity in most ICUs. Again, of the 3311 screened, only 455 were enrolled. It would be interesting to see if the association holds true in a more diverse population of patients including those with renal and hepatic disease, HIV, and GI bleeding. It was not mentioned in the study whether the patients were at the same point in the course of their illness. There was also a difference in the management of patients with low and normal protein values, although the different protein values might have resulted from this management differences , patients with low protein had a higher rate of intravenous fluid administration compared to patients with normal protein (307 vs. 176 cc/hr respectively; p < 0.001).

It should be noted that the patients selected were only those with sepsis. Patients with other etiologies of ARDS were not included. There were also a higher percentage of surgical patients with low serum protein values in comparison to those with normal and borderline protein levels. Again, this raises the question of cause and effect. Their levels might have been lower because they had surgery.

2. Was follow-up sufficiently long and complete?

Traditionally speaking yes. The patients in the study were followed for 30 days from date of study entry to determine ventilator free days and 30-day survival. While 30 days is a traditional time frame to follow patients, a recent study presented as an abstract at SCCM meeting held in San Diego this January, showed that 20% of patients succumbed to their original illness beyond 28 days (1). This raises the question that mortality during the total hospital stay may represent a more accurate assessment of outcome.

Secondary questions:

3. Were objective and unbiased outcome criteria used?

Yes. The criteria for outcome used were objective defined as ventilator free days and survival. No subjective outcomes criteria were used.

4. Was there adjustment for important prognostic factors?

There was partial adjustment. They adjusted for Apache score and other factors in baseline health status. They did not adjust for patients who received Ibuprofen versus those who did not, although that likely would not have an affect on initial serum protein levels. The other variables entered into the regression analysis were age, bilirubin, urine output, estimated glomerular filtration rate, number of blood transfusions, gender, race, patient type (medical vs. surgical), infection site (peritoneal or other), hemoglobin, platelet count, white blood cell count, intravenous fluid rate, mean arterial pressure, shock (yes or no). [see first column page 3139].

III. What are the results?

1. How large is the likelihood of the outcome event(s) in a specified period of time?

	low protein	Border line protein	Normal protein	P value
ARDS incidence	45%	45%	22%	.001
Mortality rate	41%	42%	26%	.03

The odds ratio (OR) for developing ARDS for each decrease in serum protein level by 2 gm/dl was 2.8 with a 95% confidence interval (CI) of 1.5-4.8. And the OR for death in ARDS for each decrease in serum protein level of 2 gm/dl is 3.3 with a CI of ∼1.2 - 7.

2. How precise are the estimates of likelihood?

Reasonably precise. The confidence intervals are narrow for the risk of developing ARDS and also for the risk of mortality. Based on this study, one could say with 95% confidence that the true likelihood increase, for each 2gm/dl reduction in serum protein, for developing ARDS is between 1.5 and 4.8. One could also say with 95% confidence that the increased likelihood for mortality in ARDS for each reduction in serum protein of 2 gm/dl is between 1.2 and 7 . (Note: all confidence intervals reported here are approximate; they are numbers estimated from viewing the graphic results of the logistic regression. )

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

1. Were the study patients and their management similar to my own?

All patients in this study are adults, and our patient population is pediatric. However, the diagnosis and causes of sepsis and ARDS are similar to most pediatric patients. It would be reasonable to expect baseline nutrition levels were similar to my patients.

2. Will the results lead directly to selecting or avoiding therapy?

Maybe. Given the strong association between low protein levels and ARDS and mortality, maybe we should focus more on early nutrition and explore whether synthetic albumin would be useful in those patients with low albumin.

3. Are the results useful for reassuring or counseling patients?

Maybe. Patients with low protein levels could be expected to have a worse prognosis based on the results of this study.

References

1. Morita S et al. Twenty-Eight Day Mortality : A Medical Truism. Crit Care Med 2002; 30.

 

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