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

  1. Heikki Peltola1,
  2. Irmeli Roine3,
  3. Josefina Fernández4,
  4. Inés Zavala5,
  5. Silvia González Ayala7,
  6. Antonio González Mata10,
  7. Antonio Arbo12,
  8. Rosa Bologna8,
  9. Greta Miño6,
  10. José Goyo11,
  11. Eduardo López9,
  12. Solange Dourado de Andrade13, and
  13. Seppo Sarna2
  1. 1Helsinki University Central Hospital, Hospital for Children and Adolescents, Helsinki, Finland
  2. 2University of Helsinki, Department of Public Health, Helsinki, Finland
  3. 3University Diego Portales, Faculty of Health Sciences, Santiago, Chile
  4. 4Clinica Infantil Dr. Robert Reid Cabral, Santo Domingo, Dominican Republic, Guayaquil, Ecuador
  5. 5Hospital de Niños Dr. Roberto Gilbert, Guayaquil, Ecuador
  6. 6Hospital del Niño Dr. Francisco de Icaza Bustamante, Guayaquil, Ecuador
  7. 7Hospital de Niños Sor Marça Ludovica, La Plata
  8. 8Hospital de Pediatrça Dr. Juan P. Garrahan, Buenos Aires, Argentina
  9. 9Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, Argentina
  10. 10Hospital Pediatrico Dr. Agustin Zubillaga, Barquisimeto
  11. 11Hospital Universitario de los Andes, Mérida, Venezuela
  12. 12Instituto de Medicina Tropical, Universidad Nacional de Asunción, Asunción, Paraguay
  13. 13Fundaçao de Medicina Tropical do Amazonas, Institute for Tropical Diseases, Manaus, Brazil
  1. Reprints or correspondence: Prof. H. Peltola, HUCH, Hospital for Children and Adolescents, P.O. Box 281 (11 Stenbäck St.), 00029 HUS Helsinki, Finland (heikki.peltola{at}hus.fi).
 
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Abstract

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.

Despite successful Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae vaccinations in many parts of the world [1], childhood bacterial meningitis remains a challenge [2,3–4]. Even when seasonal meningococcal epidemics in Africa are excluded, >1 million people are affected annually; ∼350,000 die, and at least 30% of survivors experience sequelae. Death often follows neurological damage, especially in regions where rehabilitation facilities are virtually nonexistent [4, 5]. Globally, Hib, S. pneumoniae, and Neisseria meningitidis cause ∼90% of nonneonatal, nontuberculous cases of bacterial meningitis.

Except in cases of drug-resistant infection, the use of antimicrobials that are newer than third-generation cephalosporins has not improved outcomes [6]. As has been documented by biochemical parameters, dexamethasone dampens the inflammatory response [7,8,9–10], but no study of optimal antimicrobial therapy for childhood meningitis has shown a significant reduction in deafness, neurological sequelae, or mortality when these outcomes were examined separately. In Malawi, the first trial that was large enough to allow an examination of the individual outcomes failed to find any benefit [11]. Unfortunately, cephalosporins could not be used routinely in that pivotal study. Revised Cochrane analysis [12] supports the use of corticosteroids in high-income countries; however, as in meta-analysis in general, very dissimilar populations were directly compared, and the presenting status of the children was not taken into account.

Glycerol (glycerine, 1, 2, 3-propanetriol), which is a naturally occurring trivalent alcohol, an essential compound of the human cell membrane, a hyperosmolar agent, and an osmotic diuretic, was long used in neurosurgery, neurology, and ophthalmology to reduce raised tissue pressure [13,14,15,16–17]. Glycerol was given experimentally to treat bacterial meningitis in a few children in the United States in the 1970s [18], but the first systematic trial was performed in Finland during the period 1987–1991 [19]. Glycerol appeared to reduce profound hearing loss and persistent neurological abnormalities as efficaciously as dexamethasone, but the series was too small for definitive conclusions. To validate that finding, we launched a much larger study in Latin America, in which the potentials of glycerol and dexamethasone were examined in terms of different outcomes, and the results were compared with those of a placebo group.

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Patients and Methods

Setting and patients. This prospective multicenter, randomized, double-blind clinical trial examined the potential of intravenous dexamethasone, oral glycerol, or their combination as adjuvant medications to improve different outcomes of childhood bacterial meningitis. The series comprised children with bacterial meningitis who were aged 2 months through 16 years at 10 institutions in Argentina, Brazil, Dominican Republic, Ecuador, Paraguay, and Venezuela, during the period 1996–2003 (Santo Domingo and Manaus joined the trial in 2001).

Meningitis was defined by (1) CSF culture positive for a bacterial agent known to cause meningitis, (2) characteristic CSF findings and positive blood culture results, (3) characteristic CSF findings and a CSF sample with a positive latex agglutination test result, and (4) symptoms and signs that were compatible with bacterial meningitis and at least 3 of the following criteria: CSF pleocytosis (WBC count, ⩾1000 cells/mm3), decreased CSF glucose level (<40 mg/dL), increased CSF protein concentration (⩾40 mg/dL), increased serum C-reactive protein level (⩾40 mg/L) [20, 21], or occasionally, when data regarding C-reactive protein level was not available, blood leukocyte count >15,000 cells/mm3. Bacteriological analysis was performed at each institute's laboratory and was standardized by training where necessary.

The exclusion criteria were a history of recent head injury, previous neurosurgical precedure (e.g., intracranial shunt placement), previous neurological disease (e.g., cerebral palsy and Down syndrome), immunosuppression, and known hearing impairment. Pretreatment antimicrobial therapy was registered in detail but did not prevent study enrollment if oral therapy or ⩽1 parenteral dose had been administered.

Study drugs. All children received intravenous ceftriaxone at a dosage of 80–100 mg per kg of body weight once daily for 7–10 days. Ceftriaxone was bought locally, although for the centers in Guayaquil, Ecuador, and Asunción, Paraguay, ceftriaxone was purchased from Chile. Antipyretics were given as needed, and convulsions were treated according to local practice. No fluid restriction was used [22, 23], but in patients with hypovolemia, deficits were restored before changing to maintenance fluids with isotonic crystalloids.

The patients were randomized to 1 of the following adjuvant medication groups: intravenous dexamethasone and oral placebo, intravenous dexamethasone and oral glycerol, oral glycerol and intravenous placebo, or intravenous placebo and oral placebo. The dosing of dexamethasone was 0.15 mg/kg administered every 6 h for 48 h [24], the first dose being administered 15 min prior to administration of ceftriaxone (if possible).

Oral 85% glycerol (1 mL of which contained 1 g of glycerol) was given for 48 h at a dosage of 1.5 g (1.5 mL) per kg every 6 h; the maximum volume was 25 mL per dose. The first dose was given 15 min prior to ceftriaxone administration. At most study centers, a nasogastric tube was inserted routinely. If the child vomited within 30 min, the dose was repeated immediately.

Randomization and blinding. Stratified block randomization took place in blocks of 20, except at 2 hospitals in Buenos Aires, Argentina, in which the placebo-placebo group was not allowed; at these hospitals, the block size was 24. All treatment kits were packaged according to the randomization lists in Santiago, Chile. Saline and carboxymethylcellulose were the placebo preparations for dexamethasone and glycerol, respectively. The agents were provided in identical ampoules or bottles and were labeled only with a study code. Because all patients had an intravenous line and received a test agent orally, the blinding was complete. Each treatment kit, marked only with the study number, contained the medication or placebo and a sealed envelope. The envelope disclosed the medication and was to be opened in an emergency (no envelopes were opened during the course of the study). Persons treating the patients, the study monitor (I.R.), and the scientific advisor (H.P.) were not aware of the specific treatments until the code was broken. This was done after the study was completed.

Sample size. The sample size was calculated assuming that a given adjuvant medication would decrease the rate of sequelae from 20% to 5%. Accepting a 5% error in a 2-tailed test and a power of 80%, at least 88 patients in each arm were required. To be able to adjust for possible confounding factors, the sample size was doubled. However, enrollment was to be stopped on 31 December 2003, whatever the number of patients.

Follow-up. All findings at presentation were recorded on specially designed forms by the physician in charge. Records included exact information on the nature and route of all antimicrobials and of the test agents, the age-adjusted Glasgow Coma Scale [25], and the Denver Developmental Score [26]. A child was assessed for neurological, developmental, and hearing sequelae on hospital discharge. If any deficits were found, he or she was scheduled for a follow-up visit 1–2 months later.

After 200 patients had been enrolled and again after 400 patients had been enrolled, an ethicist and a statistician who were not involved in the study reviewed the data to ensure that there was no statistical difference between groups with respect to case-fatality rate. The study protocol was approved by all local ethical committees. Because not all mothers were literate, an oral consent was accepted, after full information had been given. The study was designed, conducted, and analyzed independently of any funding source.

End points and statistical analysis. The 3 primary end points were death, severe neurological sequelae, and profound hearing loss (inability to detect sounds with the better ear at 80 dB, determined with brain stem evoked response audiometry or traditional audiometry). Severe neurological sequelae were defined as blindness, quadriparesis or quadriplegia, hydrocephalus requiring a shunt, or severe psychomotor retardation (in which the patient does not sit or walk, does not speak or establish contact, or requires institutionalization). Because severe neurological sequelae and death may form a continuum [4, 5], these 2 outcomes formed a composite end point. Because it was unlikely that all patients would report for follow-up, assessments were performed primarily at hospital discharge.

Dexamethasone has been reported to be especially beneficial in treating Hib meningitis [8,9–10]. Therefore, we planned a subgroup analysis for Hib versus non-Hib meningitis, taking into account the receipt or nonreceipt of pretreatment antimicrobial drugs. The 2 centers in Buenos Aires that did not include the placebo-only arm were included in the analysis, provided that their results did not change the results of the 4-arm study.

The χ2 test was used to test the heterogeneity of proportions between groups. To compare the main outcome measures, a multivariable binary logistic model with and without covariates was used. The treatment effects were taken into account by applying a reference coding system using the (0.1)-indicator variables, with the placebo recipients serving as the reference group. All analyses were performed on an intention-to-treat basis and were checked by per-protocol analysis.

Receipt of potential pretreatment antimicrobial drugs and the timing of their administration with respect to the initiation of adjuvant therapy were included as covariates in the post hoc analysis for Hib meningitis versus other meningitides. We also checked whether the findings remained the same when the etiologically unconfirmed cases were excluded from analysis. Finally, the entire series was divided into dexamethasone or glycerol recipients and nonrecipients; this rough division was intended to identify differences that were so small that they would remain undetected in direct comparisons with the placebo-placebo group.

The results are expressed as ORs, 95% CIs, and P values. An OR <1.0 indicated a beneficial effect, and it was also considered to be statistically significant if the upper value of the 95% CI was <1.0. P values of <.05 were considered to be statistically significant.

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Results

General. As shown by the patient characteristics at hospital admission (table 1), there was no significant difference between the 4 groups, and there was no major differences in enrollment of patients or outcomes during the study period. Of the 763 patients who were assessed for eligibility, 109 did not fulfill the criteria of bacterial meningitis. Thus, 654 children (figure 1) had data analyzed; of these, 166 received dexamethasone and placebo, 159 received dexamethasone and glycerol, 166 received glycerol and placebo, and 163 received placebo-placebo adjuvant treatment. Per-protocol analysis, which did not change the results, used data from 640 children; the reasons for excluding data from 14 children from this analysis are given in figure 1. Eighty-six patients (13%) died. Of the remaining 568 children, 556 (98%) underwent a full neurological evaluation, whereas 534 (94%) were tested for deafness (bilateral hearing threshold, ⩾80 dB).

Figure 1
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Figure 1

Study profile. DXM, dexamethasone; GLY, glycerol.

In all, 37% of patients had received prior antimicrobial treatment. Because inclusion of the 86 children from Buenos Aires did not change the results, our data represent all 654 patients. Their characteristics during the hospital stay are shown in table 2.

Table 1
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Table 1

Patient characteristics at presentation to the hospital.

Table 2
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Table 2

Patient characteristics during hospital stay for the intention-to-treat population.

The causative agent was identified for 484 patients (74%). Hib was the most common pathogen (found in 221 patients), followed by S. pneumoniae (132 patients) and N. meningitidis (110 patients); 21 patients had cases that were caused by other bacteria (mostly Escherichia coli or Salmonella enteritidis). For 170 patients, 80 (47%) of whom had received pretreatment antimicrobials, no causative agent was identified. In total, 174 patients were enrolled in Argentina, 143 in Ecuador, 122 in Venezuela, 120 in the Dominican Republic, 80 in Paraguay, and 15 in Brazil.

Death, severe neurological sequelae, and hearing loss. Table 3 shows the number of deaths (86 [13%] of 654), severe neurological sequelae (44 [8%] of 556), deaths and severe neurological sequelae combined (130 [20%] of 642), and profound hearing loss (43 [8%] of 534) in the 4 groups. Poor outcomes were most common in the placebo-placebo group, but statistical significance was reached only with respect to severe neurological sequelae and the category of severe neurological damage or death. Profound hearing loss occurred with similar frequency in all 4 groups (detailed audiological analysis will be presented separately). For any end point, no significant interaction was observed between glycerol and dexamethasone.

Table 3
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Table 3

Death, severe neurological sequelae, the composite end point of death or severe neurological sequelae, and profound hearing loss, by treatment group.

The results with respect to outcome in the 3 adjuvant groups tested against the placebo group are shown in table 4; this table also gives data for children with information regarding the timing of ceftriaxone therapy compared with that of adjuvant therapy and data regarding etiologically confirmed cases. The incidence of severe neurological sequelae was significantly reduced among patients who received glycerol alone (OR, 0.31 [95% CI, 0.13–0.76]; P = .01) and patients who received the dexamethasone-glycerol combination (OR, 0.39 [95% CI, 0.17–0.93]; P = .033), whereas among those who received dexamethasone alone, no more than a tendency towards a reduction in severe neurological sequelae was observed. On the other hand, a tendency towards lowered mortality rate was observed in the group that received only glycerol. Receipt or nonreceipt of pretreatment antimicrobials and the timing of their administration with respect to the initiation of an adjuvant medication left the results essentially unchanged.

Table 4
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Table 4

Risk of death, severe neurological sequelae, the composite end point of death or severe neurological sequelae, and profound hearing loss in the 3 adjuvant therapy groups, compared with the placebo only group.

For the composite end point group (those who experienced severe neurological sequelae or death), the results were similar. The OR for the glycerol-only group was 0.44 (95% CI, 0.25–0.76; P = .003), and for the dexamethasone-glycerol group, the OR was 0.55 (95% CI, 0.32–0.93; P = .027). Including the timing of antimicrobial administration in the analysis or excluding the patients for whom an etiological agent was not identified did not change the observation that the glycerol-only group had the best outcomes, followed by the dexamethasone-glycerol group; the group that received dexamethasone alone had the worst outcomes.

Hib versus non-Hib meningitis. Effects of the adjuvant therapies on Hib versus non-Hib meningitis are presented in table 5. All statistically significant differences were found in the glycerol-only group. The incidence of severe neurological sequelae was reduced in patients with Hib meningitis, regardless of whether all cases were examined (OR, 0.11 [95% CI, 0.01–0.95]; P = .045) or only those cases with information on pretreatment antimicrobials and the timing of adjuvant therapy (OR 0.11 [95% CI, 0.01–0.96]; P = .046).

Table 5
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Table 5

Risk of death, severe neurological sequelae, the composite end point of death or severe neurological sequelae, and profound hearing loss among the 3 adjuvant therapy groups, compared with the placebo group, in patients with Haemophilus influenzae type b (Hib) meningitis and patients with non-Hib meningitis.

Examining severe neurological sequelae and death together, the effect of treatment with glycerol remained statistically significant among patients with Hib meningitis with information on prior receipt of antimicrobials and the timing of adjuvant therapy (OR, 0.33 [95% CI, 0.12–0.92]; P = .035) and among children with non-Hib meningitis (OR, 0.46 [95% CI, 0.23–0.91]; P = .025). Among children with non-Hib meningitis, even the mortality rate was somewhat reduced by receipt of glycerol (OR, 0.49 [95% CI, 0.21–1.13]; P = .094).

When the data were analyzed taking into consideration only whether glycerol or dexamethasone was or was not given, the only new finding was with respect to Hib meningitis. Analyzing all 181 cases together and neglecting the timing between dexamethasone and ceftriaxone administration, treatment with dexamethasone prevented profound hearing loss (OR, 0.27 [95% CI, 0.09–0.77]; P = .014). Statistical significance was lost if data from patients with cases of Hib meningitis who had not received pretreatment antimicrobials (123 patients) were examined separately.

Safety. Few adverse effects attributable to either adjuvant medication were observed. Visible blood in the stool was noted in 6 (5%) of 111 patients in the dexamethasone group and in 5 (5%) of 101 patients in the dexamethasone-glycerol group but in only 1 (1%) of 113 patients in the glycerol-only group and 2 (2%) of 99 patients in the placebo group (table 2). The difference between the dexamethasone recipients and those who did not receive dexamethasone was statistically significant (P = .032). Vomiting or diarrhea were not more common in the glycerol group, and massive gastrointestinal hemorrhage or other severe adverse events were not found in any child.

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Discussion

This prospective, double-blind, randomized trial from 6 Latin American countries that involved 654 patients is, to our knowledge, the largest clinical study of childhood bacterial meningitis to date. Oral glycerol improved outcomes especially by reducing severe neurological sequelae. The study was performed in conditions similar to those in which the great majority of children with meningitis worldwide are treated [3, 4, 27,28–29]. Many of the children in our study presented late in the course of disease, many were anemic, and many had previously been given oral antimicrobials. A few of these children may have been infected with HIV, although the prevalence of HIV infection in Latin America was low during the study period [30].

Because most children could not be expected to return for a control visit, we were forced to use the outcome data that were available at hospital discharge. Some subtle sequelae may, therefore, have remained undetected, but this shortcoming probably did not distort the results, because most of the sequelae described in our study were very unlikely to resolve with time. Children with these sequelae probably died or remained permanently disabled. Other limitations of the study were the inclusion of patients who had received pretreatment antimicrobial drugs (which are administered indiscriminately in Latin America) and patients with etiologically unidentified cases; however, the study design distributed such patients evenly to each arm. Because the details of antimicrobial administration were recorded meticulously, we could also examine children who did not receive a single dose of any antimicrobial before hospitalization.

The comprehensiveness of the series allowed us to analyze the adjuvant effects separately for each outcome. Except for 2 earlier studies that were sufficiently powered—one from Africa, involving children [11], and the other from Europe, involving adults who received dexamethasone for 4 days [31]—this has not been possible before. By keeping the outcomes separated, potential benefits between adjuvants could be examined specifically. Glycerol not only reduced severe neurological sequelae but was also beneficial when severe neurological sequelae and mortality were examined together [4, 5]. Nevertheless, prevention of severe neurological sequelae alone was a major achievement; many clinicians classify survival with severe sequelae and death as poor outcomes of equal importance [4]. Reducing the impact of meningitis on the family and on society clearly requires more than merely increasing the survival rate [32].

How does glycerol work? One-third of the children with bacterial meningitis experience significantly impaired cerebral blood flow [33, 34] and intracranial edema. Oral glycerol increases plasma osmolality, which, among other effects, lowers intraocular pressure within 30 min [17]. Oral glycerol also increases plasma osmolality in children with bacterial meningitis (S. Singhi, personal communication), as it does in adult healthy volunteers [35]. This change in osmolality reduces edema and enhances cerebral circulation by reducing the excretion of CSF [36]. As water moves by osmosis back into the plasma, extravascularization of water and subsequent occult hypovolemia are reduced. Decrease of the intracranial pressure by glycerol-induced osmotic diuresis seems to be less important [37], because a gradient between the body compartments requires an intact or almost intact blood-brain barrier, and this is not the case in patients with bacterial meningitis. Glycerol is also a scavenger of free oxygen radicals, and this action may further alleviate meningeal inflammation.

Our glycerol dosage (6 g per kg of body weight per day divided into 4 doses) was not evidence-based but was derived from dosages recommended earlier [38] in neurology and neurosurgery. Our practice of keeping to a single maximum dose of 25 mL was based on our previous experience [19], which showed that some children vomited if they received a larger total dose. In our study, vomiting was not more common among glycerol recipients. No data suggest the substitution of another osmotic diuretic, such as mannitol, for glycerol; in fact, intravenous mannitol may be harmful in patients with bacterial meningitis [39].

Further studies on adjuvant glycerol to treat bacterial meningitis are clearly warranted. Interestingly, although the Malawi trial [11] found no advantage associated with dexamethasone treatment, some of our patients benefited. This was best shown among patients with Hib meningitis when the dexamethasone recipients were compared with the non-recipients and the timing of antimicrobial administration was not taken into account. Unfortunately, we cannot easily identify patients who likely would benefit from adjuvant dexamethasone. Evidently, they are not simply those patients with nonpretreated Hib meningitis for whom cephalosporin therapy was initiated after giving dexamethasone.

In conclusion, oral glycerol reduced the incidence of severe neurological sequelae associated with childhood bacterial meningitis. Five properties of glycerol make its widespread use possible and desirable: it can be taken orally, is inexpensive, is easily available, has no special storage requirements, and is safe [18, 19, 37, 40]. Glycerol is a common ingredient of ingested (e.g., chewing gum) and topical (e.g., shampoo) substances. Some patients have received intravenous glycerol for 1 week [14]; we gave 8 oral doses over a 48-h period.

Glycerol is a novel tool for the treatment of bacterial meningitis, which is a life-threatening disease that ∼5000 children per day contract worldwide. Oral glycerol is also an agent that is cheap enough and simple enough for treatment of the poorest patients. Since the advent of chloramphenicol and ampicillin ∼40 years ago, no other medication has improved the prognosis of childhood meningitis, especially Hib meningitis, as much as glycerol.

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Study Contributors

Jesús Feris-Iglesias and Chabela Peña (Santo Domingo, Dominican Republic); Mariella Chang and Ruth Flor (Guayaquil, Ecuador); Marça Rosa Agosti (La Plata, Argentina); Miriam Maitin and Lesbia Colina (Barquisimeto, Venezuela); Dolores Lovera (Asunción, Paraguay); Marça Teresa Rosanova, Ilse Villaroel, and Mari Carmen Cifró (Buenos Aires, Argentina); Magdalena Correa (Mérida, Venezuela); and Marcos Fernandes and Vania Prazeres (Manaus, Brazil).

Bacteriological and other laboratory investigations were directed by Jacqueline Sanchez (Santo Domingo, Dominican Republic); Rafael Roas (Barquisimeto, Venezuela); Cecilia Vescina, Marta Altschuler, and Patricie Lazarte (La Plata, Argentina); Wilma Basualdo (Asunción, Paraguay); Maria del Carmen Ceinos (Buenos Aires, Argentina); and Rossicleia Monte (Manaus, Brazil).

Audiological examinations were performed by Clemente Terrero (Santo Domingo, Dominican Republic); Beila Pire (Barquisimeto, Venezuela); Pedro Toledo (Guayaquil, Ecuador); Luis Pedersoli, Alicia Calcaterra, and Silvia Jury (La Plata, Argentina); Arturo Campos (Asunción, Paraguay); and Marça E. Prieto (Buenos Aires, Argentina).

The formula for the placebo of glycerol was developed by Pedro Valora (Buenos Aires, Argentina).

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Acknowledgments

We thank Dr. Ralf Clemens, who organized the initial grant for this nonprofit study, and Dr. Elizabeth Molyneux, who revised the text. Ossi Hiltunen (Orion Diagnostica) kindly provided the equipment for quantitative C-reactive protein measurements.

Financial support. GlaxoSmithKline, Alfred Kordelin, Päivikki and Sakari Sohlberg, and Sigfrid Jusélius Funds. Farmacia Ahumada donated glycerol and both placebo preparations. Laboratorio de Chile partly donated ceftriaxone.

Potential conflicts of interest. H.P. is currently a scientific consultant of Serum Institute of India. All other authors: no conflicts.

  • Received March 2, 2007.
  • Accepted July 24, 2007.
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References

  1. ↵
    1. Peltola H
    . Worldwide Haemophilus influenzae type b disease at the beginning of the 21st century; global analysis of the disease burden 25 years after the use of polysaccharide vaccine and a decade after the advent of conjugates. Clin Microbiol Rev 2000;13:302-17.
    Abstract/FREE Full Text
  2. ↵
    1. Daoud AS,
    2. Al-Sheyyab M,
    3. Batchoun RG,
    4. et al
    . Bacterial meningitis: still a cause of high mortality and severe neurological morbidity in childhood. J Trop Med Paed 1995;41:308-10.
  3. ↵
    1. Goetghebuer T,
    2. West TE,
    3. Wermenbol V,
    4. et al
    . Outcome of meningitis caused by Streptococcus pneumoniae and Haemophilus influenzae type b in children in The Gambia. Trop Med Int Health 2000;5:207-13.
    CrossRefMedlineWeb of Science
  4. ↵
    1. Duke T,
    2. Mokela D,
    3. Frank D,
    4. et al
    . Management of meningitis in children with oral fluid restriction or intravenous fluid at maintenance volumes: a randomized trial. Ann Trop Paediatr 2002;22:145-57.
    CrossRefMedlineWeb of Science
  5. ↵
    1. Principi N,
    2. Esposito S
    . Dexamethasone in acute bacterial meningitis. Lancet 2002;360:1610-0000.
    MedlineWeb of Science
  6. ↵
    1. Peltola H,
    2. Anttila M,
    3. Renkonen O-V
    . The Finnish Study Group. Randomised comparison of chloramphenicol, ampicillin, cefotaxime, and ceftriaxone for childhood bacterial meningitis. Lancet 1989;1:1281-7.
    MedlineWeb of Science
  7. ↵
    1. Mustafa MM,
    2. Ramilo O,
    3. Mertsola J,
    4. et al
    . Modulation of inflammation and cachectin activity in relation to treatment of experimental Haemophilus influenzae type b meningitis. J Infect Dis 1989;160:818-25.
    Abstract/FREE Full Text
  8. ↵
    1. Lebel MH,
    2. Freij BJ,
    3. Syrogiannopoulos GA,
    4. et al
    . Dexamethasone therapy for bacterial meningitis: results of two double-blind, placebo-controlled trials. N Engl J Med 1988;319:964-71.
    MedlineWeb of Science
  9. ↵
    1. Odio CM,
    2. Faingezicht I,
    3. Paris M,
    4. et al
    . The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med 1991;324:1525-31.
    MedlineWeb of Science
  10. ↵
    1. Schaad UB,
    2. Lips U,
    3. Gnehm HE,
    4. Blumberg A,
    5. Wedgwood J
    . Dexamethasone therapy for bacterial meningitis in children. The Swiss Meningitis Study Group. Lancet 1993;342:457-61.
    CrossRefMedlineWeb of Science
  11. ↵
    1. Molyneux EM,
    2. Walsh AL,
    3. Forsyth H,
    4. et al
    . Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002;360:211-8.
    CrossRefMedlineWeb of Science
  12. ↵
    Cochrane Database Syst Rev. 2007. Corticosteroids in acute bacterial meningitis. CD004405.
  13. ↵
    1. Buckell M,
    2. Walsh L
    . Effect of glycerol by mouth on raised intracranial pressure in man. Lancet 1964;2:1151-2.
    MedlineWeb of Science
  14. ↵
    1. Gilsanz V,
    2. Rebollar JL,
    3. Buencuerpo J,
    4. Chantres MT
    . Controlled trial of glycerol versus dexamethasone in the treatment of cerebral oedema in acute cerebral infarction. Lancet 1975;1:1049-51.
    MedlineWeb of Science
  15. ↵
    1. Rottenberg DA,
    2. Hurwitz BJ,
    3. Posner JB
    . The effect of oral glycerol on intraventricular pressure in man. Neurology 1977;27:600-8.
    Abstract/FREE Full Text
  16. ↵
    1. Bayer AJ,
    2. Pathy MSJ,
    3. Newcombe R
    . Double-blind randomised trial of intravenous glycerol in acute stroke. Lancet 1987;1:405-8.
    CrossRefMedlineWeb of Science
  17. ↵
    1. McCurdy DK,
    2. Schneider B,
    3. Scheie HG
    . Oral glycerol: the mechanism on intraocular hypotension. Am J Ophthalmol 1966;61:1244-9.
    MedlineWeb of Science
  18. ↵
    1. Herson VC,
    2. Todd JK
    . Prediction of morbidity in Haemophilus influenzae meningitis. Pediatrics 1977;59:35-9.
    Abstract/FREE Full Text
  19. ↵
    1. Kilpi T,
    2. Peltola H,
    3. Kallio MK,
    4. et al
    . Oral glycerol versus intravenous dexamethasone in preventing hearing impairment due to childhood bacterial meningitis. Pediatr Infect Dis J 1995;14:270-8.
    MedlineWeb of Science
  20. ↵
    1. Peltola HO
    . C-reactive protein in rapid monitoring of infections of the central nervous system. Lancet 1982;1:980-2.
    MedlineWeb of Science
  21. ↵
    1. Roine I,
    2. Banfi A,
    3. Bosch P,
    4. Ledermann W,
    5. Contreras C,
    6. Peltola H
    . Serum C-reactive protein in childhood meningitis in countries with limited laboratory resources: a Chilean experience. Pediatr Infect Dis J 1991;10:923-8.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Tureen JM,
    2. Täuber MG,
    3. Sande MA
    . Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis. J Clin Invest 1992;89:947-53.
    CrossRefMedlineWeb of Science
  23. ↵
    1. Singhi SC,
    2. Singhi PD,
    3. Srinivas B,
    4. et al
    . Fluid restriction does not improve the outcome of acute meningitis. Pediatr Infect Dis J 1995;14:495-503.
    MedlineWeb of Science
  24. ↵
    1. Syrogiannopoulos GA,
    2. Lourida AN,
    3. Theodoridou MC,
    4. et al
    . Dexamethasone therapy for bacterial meningitis in children: 2- versus 4-day regimen. J Infect Dis 1994;169:853-8.
    Abstract/FREE Full Text
  25. ↵
    1. Teasdale G,
    2. Jennett B
    . Assessment of coma and impaired consciousness: a practical scale. Lancet 1974;2:81-4.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Glascoe FP,
    2. Byrne KE,
    3. Ashford LK,
    4. Johnson KL,
    5. Chang B,
    6. Strickland B
    . Accuracy of the Denver-II in developmental screening. Pediatrics 1992;89:1221-5.
    Abstract/FREE Full Text
  27. ↵
    1. Peltola H
    . Haemophilus influenzae type b disease and vaccination in Latin America and the Caribbean. Pediatr Infect Dis J 1997;16:780-7.
    CrossRefMedlineWeb of Science
  28. ↵
    1. Basualdo W,
    2. Arbo A
    . Invasive Haemophilus influenzae type b infections in children in Paraguay. Arch Med Res 2004;35:126-33.
    CrossRefMedlineWeb of Science
  29. ↵
    1. Peltola H
    . Burden of meningitis and other severe bacterial infections of children in Africa: implications for prevention. Clin Infect Dis 2001;32:64-75.
    Abstract/FREE Full Text
  30. ↵
    1. Salooje H,
    2. Violari A
    . HIV infection in children. BMJ 2001;323:670-4.
    FREE Full Text
  31. ↵
    1. de Gans J,
    2. van de Beek D
    . European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549-56.
    CrossRefMedlineWeb of Science
  32. ↵
    Dexamethasone therapy for bacterial meningitis. New Engl J Med 1989;320:463-5.
    MedlineWeb of Science
  33. ↵
    1. Ashwal S,
    2. Stringer W,
    3. Tornasi L,
    4. Schneider S,
    5. Thompson J,
    6. Perkin R
    . Cerebral blood flow and carbon dioxide reactivity in children with bacterial meningitis. J Pediatr 1990;117:523-30.
    CrossRefMedlineWeb of Science
  34. ↵
    1. Møller K,
    2. Larsen FS,
    3. Qvist J,
    4. et al
    . Dependency of cerebral blood flow on mean arterial pressure in patients with acute meningitis. Crit Care Med 2000;28:1027-32.
    CrossRefMedlineWeb of Science
  35. ↵
    1. Sommer S,
    2. Nau R,
    3. Wieland E,
    4. Prange HW
    . Pharmacokinetics of glycerol administered orally in healthy volunteers. Arzneimittelforschung 1993;43:744-7.
    Medline
  36. ↵
    1. Zoghbi HV,
    2. Okumura S,
    3. Laurent JP,
    4. Fishman MA
    . Acute effect of glycerol on net cerebrospinal fluid production in dogs. J Neurosurg 1985;63:759-62.
    MedlineWeb of Science
  37. ↵
    1. Nau R,
    2. Prins F-J,
    3. Kolenda H,
    4. Prange HW
    . Temporary reversal of serum to cerebrospinal fluid glycerol concentration gradient after intravenous infusion of glycerol. Eur J Clin Pharmacol 1992;42:181-5.
    CrossRefMedlineWeb of Science
  38. ↵
    1. Frank MSB,
    2. Nahata MC,
    3. Hilty MD
    . Glycerol: a review of its pharmacology, phamacokinetics, adverse reactions, and clinical use. Pharmacotherapy 1981;1:147-60.
    MedlineWeb of Science
  39. ↵
    1. Syrogiannopoulos GA,
    2. Olsen KD,
    3. McCracken GH
    . Mannitol treatment in experimental Haemophilus influenzae type b meningitis. Pediatr Res 1987;22:118-22.
    MedlineWeb of Science
  40. ↵
    1. Tourtelotte WW,
    2. Reinglass JL,
    3. Newkirk TA
    . Cerebral dehydration action of glycerol. I. Historical aspects with emphasis on the toxicity and intravenous administration. Clin Pharmacol Ther 1972;13:159-71.
    MedlineWeb of Science
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  1. Clin Infect Dis. (2007) 45 (10): 1277-1286. doi: 10.1086/522534
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