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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Prevention of infection in multiple trauma patients by high-dose intravenous immunoglobulins

Douzinas EE, Pitaridis MT, Louris G, Andrianakis I, Katsouyanni K, Karmpaliotis D, Economidou J, Sfyras D, Roussos C.

Crit Care Med 2000; 28: 8-15. [abstract]

Reviewed by Scot Bateman MD, Boston Medical Center

Review posted December 18, 2000

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I. What is being studied?:

The study objective:

To investigate the use of intravenous immunoglobulin (IVIG) as prophylaxis against infection in multiple trauma patients.

The study design:

Prospective, randomized, double-blind, placebo-controlled trial

The patients included:

39 trauma patients with injury severity scores (ISS) of 16-50.

The patients excluded:

ISS score < 16 because the risk of infection was low, ISS > 50 because the risk of death was high, admission to ICU after more than 12 hours in the hospital, known immunosuppression or corticosteroid treatment, IVIG within 6 mo, IVIG hypersensitivity, connective tissue disease, pregnancy, pencillin allergy.

The interventions compared:

IVIG or human albumin at 1 g/kg in four divided doses (days 1, 2, 3 and 6) in patients who were also treated with prophylactic penicillin.

The outcomes evaluated:

Primary outcomes: Infection rate, serum bactericidal activity (SBA) percent change over time

Secondary outcomes: ICU stay, mortality, specific pathogens isolated from various sites, serum immunoglobin levels.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. The patients who were enrolled were randomized, although the specific technique of randomization was not mentioned. BUT: They enrolled only 42 of 196 trauma patients admitted to the ICU during the time mentioned. Most of the patients were excluded (89 pts) because of ISS scores < 16 or > 50.

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

Was followup complete?

Unclear. There is no confirmation of the number of patients available for analysis at day 7. They report that the protocol was violated if the patient was discharged prior to day 7 of hospitalization. Two patients were excluded from analysis in the control group because they required other antibiotics during the first three days after trauma; another was dropped from the control group due to the need for corticosteroids for a spinal cord injury.

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

Yes. There were no crossovers in the study.

Secondary questions:

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

Yes for the MD's, unclear for the rest of the staff. Physicians not caring for the patients did the administration of IVIG or albumin. It is unclear if the nursing staff was blinded.

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

No. They used the injury severity score (ISS) as there inclusion criteria but the IVIG group had a significantly higher score at baseline (26.3 vs. 21.5 in the control group). The groups had similar APACHE II scores and Glasgow coma scores. I'm not sure why they chose the ISS as their measure. The IVIG group has 19/21 "open injuries" versus 14/18 in the control group, and the IVIG group had a total of 20 operations versus 11 operations in the control group. The groups were similar in age and gender.

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

No. The median number of days patients in the control group received chemical paralysis was 13 days vs. zero days in the IVIG group. Mechanical ventilation was used for a median of 15 days in the control group patients versus a median of 11 days for the IVIG patients.

III. What were the results?

1. How large was the treatment effect?

They report a significant reduction in the number of patients who developed infection other than catheter-related infections (33% in IVIG group vs. 61% in control group, p < 0.04). This gives an absolute risk reduction (ARR) of 28%, and a relative risk reduction (RRR) of 46%. This significance was after controlling for ISS through multiple regression. They report a significant decrease in nosocomial pneumonias (10% in IVIG group vs. 61% in control group, p < 0.003, ARR 51%, RRR 84%) The significance of these findings is unclear because for some reason the control group had more days of mechanical ventilation and significantly more days of paralysis, both of which could influence nosocomial pneumonia rates. Conversely, the catheter related infection rate was 43% in the IVIG group vs. 28% in the control group (p = NS).

There was no difference in number of ICU days (23.5 days vs. 26.3 days in control group) or antibiotic days (50 days vs. 57 days in control group).

The IVIG group has a significant difference in SBA on day 4 and 7 compared to controls. The control group had no difference over time but the IVIG group showed an improvement. The authors report that SBA has been used as an index of adequacy of antimicrobial therapy. Decreased SBA has also been associated with increased susceptibility to the subsequent development of infections and increased SBA has been found to correlate with favorable clinical outcomes. Patients who developed pneumonia had significantly worse SBA on days 1,4 and 7 (data was not shown).

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

The precision of the results is weakened by the decision to analyze the data in subgroups of infection rate. There was no statistically significant difference in the total infection rate.. The 95% CI for the decrease absolute risk reduction in non-catheter related infections was -0.02 to 0.58. That the lower 95% confidence interval crosses zero suggests there may be a slight increase in infection in the treated group, making the results "not statistically significant." The p value of the difference between the mean infection rates, however, appears to attain statistical significance at 0.04.

For nosocomial pneumonia the 95% CI was for the ARR was 0.26 to 0.76. They do not report the SBA levels that were "predictive" of getting a pneumonia so we cannot assess the precision of those results.

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

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

Unclear. No children were included in the study. It is difficult to determine from the data what type of trauma patient would benefit from the therapy (i.e. they did not mention if their high rate of "open" injuries 19/21 patients in the IVIG group and 14/18 in the control group influenced their results). All of the patients were treated with prophylactic high dose penicillin. Using penicillin as standard therapy makes an analysis of infection rates difficult. There is no compelling data presented to encourage routine SBA level analysis. They do not present the interesting point that low initial SBA level was predictive of pneumonia. A further study should be done just to look at that relationship.

2. Were all clinically important outcomes considered?

No. There is no report about adverse reactions to IVIG. There is an infectious risk of giving IVIG that was not addressed. They also did not comment on the timing of infections. These patients were in the ICU for approx. 25 days and it would be interesting to note when the infections developed. Significantly more patients in the control group were paralyzed and on mechanical ventilation than the IVIG group. The impact of longer mechanical ventilation days on the development of nosocomial pneumonias cannot be overlooked.

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

Not at this point. There was a small but significant decrease in non-catheter-related infections but no decrease in overall infection rates or mortality or ICU days or antibiotic days. The paper demonstrated the improvement in SBA levels with IVIG administration but the clinical significance of that remains to be elucidated.

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