Irmeli Roine

Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data

Summary Background Dexamethasone improves outcome for some patients with bacterial meningitis, but not others. We aimed to identify which patients are most likely to benefit from dexamethasone treatment. Methods We did a meta-analysis of individual patient data from the randomised, double-blind, placebo-controlled trials of dexamethasone for bacterial meningitis in patients of all ages for which raw data were available. The pre-determined outcome measures were death at the time of first follow-up, death or severe neurological sequelae at 1 month follow-up, death or any neurological sequelae at first follow-up, and death or severe bilateral hearing loss at first follow-up. Combined odds ratios (ORs) and tests for heterogeneity were calculated using conventional Mantel-Haenszel statistics. We also did exploratory analysis of hearing loss among survivors and other exploratory subgroup analyses by use of logistic regression. Findings Data from 2029 patients from five trials were included in the analysis (833 [41·0%] aged <15 years). HIV infection was confirmed or likely in 580 (28·6%) patients and bacterial meningitis was confirmed in 1639 (80·8%). Dexamethasone was not associated with a significant reduction in death (270 of 1019 [26·5%] on dexamethasone vs 275 of 1010 [27·2%] on placebo; OR 0·97, 95% CI 0·79–1·19), death or severe neurological sequelae or bilateral severe deafness (42·3% vs 44·3%; 0·92, 0·76–1·11), death or any neurological sequelae or any hearing loss (54·2% vs 57·4%; 0·89, 0·74–1·07), or death or severe bilateral hearing loss (36·4% vs 38·9%; 0·89, 0·73–1·69). However, dexamethasone seemed to reduce hearing loss among survivors (24·1% vs 29·5%; 0·77, 0·60–0·99, p=0·04). Dexamethasone had no effect in any of the prespecified subgroups, including specific causative organisms, pre-dexamethasone antibiotic treatment, HIV status, or age. Pooling of the mortality data with those of all other published trials did not significantly change the results. Interpretation Adjunctive dexamethasone in the treatment of acute bacterial meningitis does not seem to significantly reduce death or neurological disability. There were no significant treatment effects in any of the prespecified subgroups. The benefit of adjunctive dexamethasone for all or any subgroup of patients with bacterial meningitis thus remains unproven. Funding Wellcome Trust UK.

Adjuvant Glycerol and/or Dexamethasone to Improve the Outcomes of Childhood Bacterial Meningitis: A Prospective, Randomized, Double- Blind, Placebo-Controlled Trial

BACKGROUND Despite favorable meta-analyses, no study involving third-generation cephalosporins for the treatment of childhood bacterial meningitis has documented a benefit of adjuvant dexamethasone therapy if the outcomes are examined individually. METHODS We conducted a prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Ceftriaxone was administered to all children; children were randomized to also receive dexamethasone intravenously, glycerol orally, both agents, or neither agent. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. A subgroup analysis for Haemophilus influenzae type b meningitis was undertaken. Intention-to-treat analysis was performed using binary logistic regression models. RESULTS H. influenzae type b, pneumococci, and meningococci were the main agents found among 654 patients; dexamethasone was given to 166, dexamethasone and glycerol were given to 159, glycerol was given to 166, and placebo was given to 163. No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the odds ratios were 0.31 (95% confidence interval [95% CI], 0.13-0.76; P=.010) and 0.39 (95% CI, 0.17-0.93; P=.033), respectively. For neurological sequelae and death, the odds ratios were 0.44 (95% CI, 0.25-0.76; P=.003) and 0.55 (95% CI, 0.32-0.93; P=.027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (odds ratio, 0.27; 95% CI, 0.09-0.77; P=.014). CONCLUSION Oral glycerol therapy prevents severe neurological sequelae in patients with childhood meningitis. Safety, availability, low cost, and oral administration also add to its usefulness, especially in resource-limited settings.

Serial serum C-reactive protein to monitor recovery from acute hematogenous osteomyelitis in children

Serial C‐reactive protein (CRP) and erythrocyte sedimentation rate determinations were compared with clinical course and outcome at 1 to 2 months in 63 children with acute hematogenous osteomyelitis. High CRP values (163 \pm 108 mg/liter) on admission began to descend after the second day of treatment. From the fourth day on higher (P = 0.03 to P = 0.0001) CRP values distinguished a complicated from an uneventful course of acute hematogenous osteomyelitis and the patients symptomatic at follow‐up (P = 0.003 to P = 0.0001) from asymptomatic ones. Children who developed extensive radiographic changes had elevated CRP values for a longer time (32 \pm 13 days) than children with typical changes (11 \pm 6 days, P = 0.0001). Erythrocyte sedimentation rates did not identify the type of clinical course but higher values on Days 4 to 7 distinguished children symptomatic at follow‐up (P = 0.02) from asymptomatic ones. Monitoring serial CRP values can alert the physician to complications and predict outcome earlier than clinical signs or roentgenograms.

Slow initial β-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial

BACKGROUND New antimicrobials or adjunctive treatments have not substantially reduced mortality from acute childhood bacterial meningitis. Paracetamol seems to have beneficial effects in bacteraemic adults and some experts recommend initial slow β-lactam infusion. We investigated whether these treatments had benefits in children with bacterial meningitis. METHODS We did a prospective, double-blind, single-centre study with a two-by-two factorial design in Luanda, Angola. 723 participants aged 2 months to 13 years were randomly assigned two 12 h intravenous infusions, without loading doses, of 125 mg/kg bodyweight cefotaxime (total dose 250 mg/kg) given over 24 h, or 250 mg/kg bodyweight cefotaxime given as four boluses, one every 6 h over 24 h. Patients also received oral paracetamol at an initial dose of 30 mg/kg then 20 mg/kg every 6 h for 48 h or placebo. Two primary endpoints, death or severe neurological sequelae and deafness, were analysed by intention to treat. The study was registered as ISRCTN62824827. FINDINGS 183 patients were assigned cefotaxime infusion plus paracetamol and 180 patients to each of the other three treatment groups. Causative agents were identified in 63% of cases and were mostly Haemophilus influenzae type b, Streptococcus pneumoniae, or Neisseria meningitidis. Death or severe neurological sequelae were seen in 340 (47%) of 723 children and deafness in 45 (12%) of 374 tested, both distributed similarly across treatment groups. In a predefined subgroup analysis of death or any sequelae, by causative agent, a benefit was seen in favour of infusion over bolus in children with pneumococcal meningitis (infusion plus placebo, odds ratio 0·18, 95% CI 0·03-0·90, p=0·04). A similar effect was seen for children receiving cefotaxime infusion plus paracetamol, but the difference was not significant (OR 0·22, 95% CI 0·04-1·09, p=0·06). A post-hoc analysis suggested that cefotaxime infusion plus paracetamol lowered mortality at least during the first 3 days, irrespective of cause. INTERPRETATION Although no tested regimen improved the final outcomes of these very ill children, studies of longer courses of β-lactam infusion plus paracetamol seem warranted. FUNDING The Päivikki and Sakari Sohlberg, the Sigrid Jusélius, and the Paediatric Research Foundations, and the daily newspaper Helsingin Sanomat.

Risk Factors for Death and Severe Neurological Sequelae in Childhood Bacterial Meningitis in Sub-Saharan Africa

We report a morality rate of 33% among 403 children with bacterial meningitis in Angola. A fatal outcome was associated with impaired consciousness, severe dyspnea, and seizures, and severe neurological sequelae (found in 25% of our patients) was associated with delayed presentation to the hospital, impaired consciousness, and seizures. Being underweight was of secondary importance. Treatment with ceftriaxone, rather than with penicillin plus chloramphenicol, did not improve outcome.

Influence of Admission Findings on Death and Neurological Outcome from Childhood Bacterial Meningitis

A post hoc analysis of 654 children with bacterial meningitis showed that the level of consciousness is the most important predictor of death and/or neurological sequelae, more than is etiology per se. This finding emphasizes the need of including a measurement of the presenting status in all studies examining treatment efficacy.

Hearing Impairment in Childhood Bacterial Meningitis Is Little Relieved by Dexamethasone or Glycerol

OBJECTIVE. Several studies have evaluated dexamethasone for prevention of hearing loss in childhood bacterial meningitis, but results have varied. We compared dexamethasone and/or glycerol recipients with placebo recipients, and measured hearing at 3 threshold levels. METHODS. Children aged 2 months to 16 years with meningitis were treated with ceftriaxone but were double-blindly randomly assigned to receive adjuvant dexamethasone intravenously, glycerol orally, both agents, or neither agent. We used the Glasgow coma scale to grade the presenting status. The end points were the better ears ability to detect sounds of >40 dB, ≥60 dB, and ≥80 dB, with these thresholds indicating any, moderate-to-severe, or severe impairment, respectively. All tests were interpreted by an external audiologist. Influence of covariates in the treatment groups was examined by binary logistic regression. RESULTS: Of the 383 children, mostly with meningitis caused by Haemophilus influenzae type b or Streptococcus pneumoniae, 101 received dexamethasone, 95 received dexamethasone and glycerol, 92 received glycerol, and 95 received placebo. Only the presenting condition and young age predicted impairment independently through all threshold levels. Each lowering point in the Glasgow scale increased the risk by 15% to 21% (odds ratio: 1.20, 1.21, and 1.15 [95% confidence interval: 1.06–1.35, 1.07–1.37, and 1.01–1.31]; P = .005, .003, and .039) for any, moderate-to-severe, or severe impairment, respectively. Each increasing month of age decreased the risk by 2% to 6% (P = .0001, .0007, and .041, respectively). Neither dexamethasone nor glycerol prevented hearing loss at these levels regardless of the causative agent or timing of antimicrobial agent. CONCLUSIONS: With bacterial meningitis, the childs presenting status and young age are the most important predictors of hearing impairment. Little relief is obtained from current adjuvant medications.

Randomized trial of four vs. seven days of ceftriaxone treatment for bacterial meningitis in children with rapid initial recovery.

Background. Seven days or more of antimicrobial treatment is the standard for bacterial meningitis, although third generation cephalosporins are usually able to sterilize cerebrospinal fluid within 24 h. The limited experience from shorter regimens in children is encouraging, and we hypothesized that in rapidly recovering patients older than 3 months of age it would pose no risk for adverse outcome. Methods. Strict clinical and laboratory criteria were used to define rapid initial recovery, in which case ceftriaxone therapy was either stopped after 4 days (4 injections) in children born on even dates (N = 53) or continued for 7 days in patients born on odd dates (N = 47). Outcomes were compared on Day 7 of hospitalization and at 1 to 3 months after discharge. Results. On Day 7 no differences (P > 0.05 for each criteria) were observed between the 4‐day and the 7‐day groups regarding fever, clinical signs or serum C‐reactive protein concentration. At the follow‐up visit 1 to 3 months after discharge the 4‐day group had fewer sequelae than the 7‐day group (0%vs. 5% neurologic sequelae, P = 0.39 and 3%vs. 9% hearing loss, P = 0.49, respectively). One child in the 4‐day group who had fully recovered was subsequently readmitted 53 days after the first hospitalization with recurrent Haemophilus influenzae meningitis. Conclusions. Four days of ceftriaxone therapy proved to be a safe alternative in patients with rapid initial recovery from bacterial meningitis. A 4‐day course of treatment is particularly beneficial for countries with limited resources.

Microalbuminuria: an index of severity in childhood meningitis.

Urinary albumin excretion (AE) was determined by a sensitive method (below dipstick positive values, 15 to 300 μg/minute) in 68 children with meningitis during 48 hours after hospital admission; 51 children had bacterial meningitis (BM) and 17 had aseptic meningitis. AE (results as mean ± SD) during 0 to 24 hours was higher (P ≤ 0.001) in patients with BM (36 ± 40 μg/minute) than with aseptic meningitis (7 ± 5 μg/minute), albeit no cutoff value distinguished the two conditions accurately. In BM the clinical course (uneventful, intermediate, complicated, fatal) correlated with AE of 0 to 24 hours (r = 0.34, P ≤ 0.05) and AE of 25 to

Serum C-reactive protein in childhood meningitis in countries with limited laboratory resources : a Chilean experience

&NA; Quantitative C‐reactive protein (CRP) was determined sequentially by nephelometry and photometry from a finger prick serum sample in 67 children with bacterial meningitis (BM) and 16 children with aseptic meningitis (AM). The initial mean CRP value of 180 mg/liter in children with BM differed significantly from the 12 mg/liter found in those with AM (P < 0.001). In BM a slow descent instead of rapid normalization or a secondary increase in sequential CRP values were early indicators of complications during recovery, such as resistance to the antibiotic. A significant difference in the mean CRP values between uneventful and complicated courses of BM was observed from the fourth day on (P < 0.001). The measurements obtained with nephelometry correlated reliably with the more widely available photometry (r = 0.99). Easily performed rapid CRP determinations can considerably improve the quality of care in meningitis patients, especially in those situations where facilities for performing bacterial cultures or antibiotic susceptibility testing are not available.