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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Recombinant bactericidal/permeability-increasing protein (rBPI₂₁) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial.

Levin M, Quint PA, Goldstein B, et al.

Lancet 2000; 356: 961 - 967. [abstract]

Reviewed by Steven Cray, Birmingham Children's Hospital, UK

Review posted October 7, 2000

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I. What is being studied?:

The study objective:

To establish whether a recombinant 21-kDa modified fragment of human bactericidal/permeability-increasing protein (rBPI₂₁), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability in children with severe meningococcal sepsis

The study design:

Multicenter randomized, double-blind, controlled trial

The patients included:

393 children aged from 2 weeks to 18 years presenting to 22 centers in the UK and North America with a clinical picture suggestive of meningococcal sepsis (fever or petechial or purpuric rash) and with evidence of severe disease (Glasgow meningococcal sepsis prognostic score [1] (GMSPS) of 8 or greater). Subsequently 365 children were confirmed to have N meningitidis infections and in only 3 was non-meningitidis infection confirmed.

The patients excluded:

1287 children were screened for study eligibility. 825 failed to meet the inclusion criteria (619 because of GMSPS < 8). A further 67 children who met the inclusion criteria were excluded for the following reasons: 41 met criteria for imminent death [*footnote], 16 died before enrolment and 10 for unspecified reasons. Of the 395 children enrolled, two died (one in each group) before receiving any study drug and were excluded from the data analysis.

The interventions compared:

Patients received infusions of rBPI₂₁ (n = 190) (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (n = 203) (an equal volume of 0.2 mg/ml human albumin solution). Study medication was administered within 8 hours of the first dose of parenteral antibiotics active against N meningitidis.

The outcomes evaluated:

Primary outcomes:

1. 60-day mortality
2. amputations ("severe" defined as below-the-knee, or below-the-elbow, or higher)
3. change in pediatric overall performance category (POPC) scale from before illness to day 60

Secondary outcomes:

1. duration of stay in ICU
2. duration of hospital stay
3. time on ventilator
4. use of blood products

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Patients were randomized (by SAS software) and stratified within each center into high (12-15) and low (8-11) GMSPS groups

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

Was followup complete?

Patients were followed up for 60 days or until death if sooner. However the table for 60 day outcome (see below) would appear to include some of the placebo, but not of the rBPI₂₁ patients, who died in the change in POPC category. Alternatively POPC data may not have been obtained for all survivors.

	rBPI21 (n=190)	Placebo (n=203)
Mortality	14	20
Change in POPC	(n=176)	(n=190)
Return to baseline	136	126
1 point deterioration	17	27
2 point deterioration	23	37

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

Yes. Analysis was by intention to treat.

Secondary questions:

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

Yes.

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

Yes, with regard to age, weight, GMSPS, PRISM III score, time from first dose of antibiotics to study entry and confirmed N meningitidis infection.

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

Unclear. The authors only state that patient management was according to the standard practices of each participating institution. The authors state that despite vigorous attempts to limit the use of other experimental treatments during the study period, 4 patients in the rBPI₂₁ group and 9 in the placebo group received antithrombin III and/or protein C concentrate. This does not seem to have affected mortality.

III. What were the results?

1. How large was the treatment effect?

There was no difference in mortality between the groups (rBPI₂₁ 14/190 (7.4%), placebo 20/203 (9.9%) p = 0.48). Six children (3.2%) in the rBPI₂₁ group required "severe" amputations (below-the-knee, or below-the-elbow, or higher) compared to 15 (7.4%) in the placebo group (p=0.067). In terms of functional outcome as measured by the POPC scale, 28.4% of children in the rBPI₂₁ group and 37.9% of those in the placebo group did not return to their pre-illness status (p < 0.05). However the previously mentioned problem with the POPC data should be considered when interpreting these results.

There were no differences between the two groups in duration of mechanical ventilation, ICU stay or hospital stay. However the use of some blood products (cryoprecipitate and platelets) was reduced in the rBPI₂₁ group and they received fewer blood products in total.

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

60 day mortality with rBPI21 treatment		95% confidence interval
absolute risk reduction	2.5%	8% to —3%
relative risk reduction	25%	61% to —43%
number needed to treat	40	12 to -33

 

Severe amputations with rBPI21 treatment		95% confidence interval
absolute risk reduction	4.2%	8.6% to —0.2%
relative risk reduction	57%	83% to —7%
number needed to treat	24	12 to -540

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

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

Yes. The study group represents a typical group of children with severe meningococcal disease requiring intensive care.

2. Were all clinically important outcomes considered?

Yes, with the exception of long term follow-up.

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

In terms of the most important outcome measure of 60-day mortality, the present study is inconclusive. There could be either considerable benefit (1 life saved for every 12 children given rBPI₂₁) or appreciable harm (1 extra death for every 33 children given rBPI₂₁) associated with rBPI₂₁ treatment in children with meningococcal septicemia. The chief difficulty facing these researchers was the extremely rapid deterioration and progression to death that occurs in fulminant meningococcemia. Of 462 children who met eligibility criteria, there were 93 deaths (assuming all those classified as having signs of imminent death did in fact die) (20% mortality). However, most of these children died before they could receive any study drug. In order to demonstrate a beneficial effect of rBPI₂₁ on mortality in meningococcemia, either a very large study (c 4000 patients) would be required or perhaps the drug would need to be administered very early after diagnosis, before transfer to a tertiary center.

Although there were benefits associated with rBPI₂₁ treatment in terms of some of the other outcome measures (functional outcome, use of blood products), these do not justify its use at present outside the context of further clinical trails. We should also bear in mind the failure to show benefit in trials of other adjunctive treatments in sepsis [2]. The authors did not identify any specific safety concerns or adverse events associated with rBPI₂₁.

Footnote

*Criteria for imminent death:

1. meeting clinical criteria for suspected brain death
2. receiving continuous ineffective CPR
3. hemodynamic deterioration or collapse despite maximum doses of vasopressors/inotropes
4. clearly equivalent evidence of imminent death

References

1. Castellanos-Ortega A, Delgado-Rodriguez M Comparison of the performance of two general and three specific scoring systems for meningococcal septic shock in children. Crit Care Med 2000;28:2967-2973. [abstract]
2. Derkx B, Wittes J, McCloskey R. Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. European Pediatric Meningococcal Septic Shock Trial Study Group. Clin Infect Dis 1999;28:770-777. [abstract]

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