Slow initial beeta-lactam infusion, and high-dose paracetamol to improve the prognosis of childhood bacterial meningitis, especially of pneumococcal meningitis

• Register: ISRCTN
• Last refreshed on: 13 January 2015
• Main ID: ISRCTN62824827
• Date of registration: 04/10/2005
• Prospective Registration: No
• Primary sponsor: Luanda Hospital (Angola)
• Public title: Slow initial beeta-lactam infusion, and high-dose paracetamol to improve the prognosis of childhood bacterial meningitis, especially of pneumococcal meningitis
• Date of first enrolment: 27/06/2005
• Target sample size: 750
• Recruitment status: Completed
• URL: http://isrctn.com/ISRCTN62824827
• Study type: Interventional
• Study design: Randomised controlled trial (Treatment)

Countries of recruitment

Angola

Contacts

• Name: Heikki Peltola

Key inclusion & exclusion criteria

Inclusion criteria: [Added as of 22/01/2008: All children aged at least 2 months with suspected or confirmed bacterial meningitis.]

Diagnosis:
BM is defined as a case with:
1. Positive CSF culture, or
2. Symptoms and signs compatible with bacterial meningitis, and positive blood culture, or
3. Symptoms and signs compatible with bacterial meningitis, and at least two of the following criteria:
3.1. CSF pleocytosis more than or equal to 100 cells/mm^3
3.2. A positive Gram-stain result
3.3. Positive latex agglutination test
3.4. Serum C-Reactive Protein (CRP) more than or equal to 40 mg/l, or
4. Symptoms and signs compatible with bacterial meningitis, and positive CSF antigen detection by Polymerase Chain Reaction (PCR)
Exclusion criteria: The exclusion criteria comprise the age less than two months, trauma, or relevant underlying illness such as intracranial shunt, previous neurological disease (cerebral palsy, Down's syndrome, meningitis), previous hearing impairment if known, and immunosuppression, except Human Immunodeficiency Virus (HIV) infection.

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Childhood bacterial meningitis
Infections and Infestations
Meningitis

Intervention(s)

All children will receive cefotaxime 250 mg/kg/day for seven days, except salmonella meningitis for which antimicrobial treatment should last for 14 days or more. Regardless of etiology, the children are randomised in a double-blind fashion in two groups for the first 24 hours: 50% receive cefotaxime in two 12-hour infusions, the other 50% getting cefotaxime in four boluses.

Added as of 22/01/2008:
In addition to the intervention of cefotaxime bolus versus cefotaxime infusions:
During the first 48 hours, 50% of the patients are randomised to receive high dose paracetamol (first dose 30 mg/kg, then 20 mg/kg every six hours for 42 hours) and the other 50% an oral placebo.

Thus the four treatment alternatives are:
1. Cefotaxime boluses + oral high dose paracetamol
2. Cefotaxime boluses + oral placebo
3. Cefotaxime infusions + oral high dose paracetamol
4. Cefotaxime infusions + oral placebo

Analysis plan:
Analysis by intention to treat will include all children in whom bacterial meningitis was suggested and a study medication was instituted. The patients in whom meningitis was confirmed (greater than or equal to 1 diagnostic criterium fulfilled) will be analysed per protocol.

Chi square test is used to test potential differences in the primary endpoints comparing the groups of infusion versus bolus dosing, and those receiving versus not receiving paracetamol. The secondary endpoints are examined similarly.

Primary Outcome(s)

Current primary endpoints as of 22/01/2008:
1. Death (measuring the exact time from institution of antimicrobial) OR severe neurological sequelae (blindness, quadriplegia, hydrocephalus requiring a shunt, or severe psychomotor retardation) at discharge
2. Profound hearing loss (more than 80 dB in both ears) at discharge

Previous primary endpoints:
1. Death (measuring the exact time from institution of antimicrobial)
2. Severe neurological sequelae (blindness, quadriplegia, hydrocephalus requiring a shunt, or severe psychomotor retardation)
3. Profound hearing loss (more than 80 dB in both ears), as found at discharge from hospital and dismal outcome denotes death, severe neurological sequelae and/or profound hearing loss.

Because severe neurological sequelae and death may form a continuum, their combination is taken as a composite endpoint. Various patient characteristics are taken into account as covariates, those being essentially the age, etiology (pneumococcus, Hib, meningococcus, other agents, and unidentified etiology), blood hemoglobin level, potential HIV- and/or malaria-infection, and the presenting status. This is graded by Glasgow Coma Scale (adjusted for age), the Blantyre Coma Scale, and the Herson-Todd Score. Also blood hemoglobin concentration will be related to the outcome, which is assessed with the modified Glasgow Outcome Scale.

Secondary Outcome(s)

Current secondary endpoints as of 22/01/2008:
1. Death or any audiological or any neurological sequelae: any neurological sequelae are, in addition to severe neurological sequelae : hemiparesis, monoparesis moderate psychomotor retardation, or ataxia. Psychomotor retardation is graded by (according to the Denver-II developmental screening test). Hearing is deemed impaired if a threshold of 40 dB remains unrecognized by the better ear, the cut-off levels for moderate and severe hearing impairment being 60 dB and 80 dB, respectively
2. Glasgow Outcome Scale
3. Potential differences in the indices of inflammation such as serum C-reactive protein (CRP) will also be examined

Previous secondary endpoints:
The secondary endpoints comprise any audiological or neurological sequelae (according to
the Denver-II developmental screening test). Hearing is deemed impaired if a threshold of 40 dB is not recognized by the better ear. The cut-off levels for moderate and severe hearing impairment are 60 dB and 80 dB, respectively. Potential differences in the indices of inflammation such as serum C-Reactive Protein (CRP) will also be examined.

Source(s) of Monetary Support

The Pediatric Research Foundation (Finland), Sigrid Juselius Foundation (Finland), Helsinki University Central Hospital Research (Finland)