Original Article
The Beneficial Effects of Early Dexamethasone Administration in Infants and Children with Bacterial Meningitis
N Engl J Med 1991; 324:1525-1531May 30, 1991
- Abstract
- Abstract
Background.
In experimental models of meningitis and in children with meningitis, dexamethasone has been shown to reduce meningeal inflammation and to Improve the outcome of disease.
Methods.
We conducted a placebo-controlled, double-blind trial of dexamethasone therapy in 101 infants and children admitted to the National Children's Hospital, San José, Costa Rica, who had culture-proved bacterial meningitis or clinical signs of meningitis and findings characteristic of bacterial infection on examination of the cerebrospinal fluid. The patients were randomly assigned to receive either dexamethasone and cefotaxime (n = 52) or cefotaxime plus placebo (n = 49). Dexamethasone (0.15 mg per kilogram of body weight) was given 15 to 20 minutes before the first dose of cefotaxime and was continued every 6 hours thereafter for four days.
Results.
The demographic, clinical, and laboratory profiles were similar for the patients in the two treatment groups. By 12 hours after the beginning of therapy, the mean opening cerebrospinal pressure and the estimated cerebral perfusion pressure had improved significantly in the dexamethasone-treated children but worsened in the children treated only with cefotaxime (controls). At 12 hours meningeal inflammation and the concentrations of two cytokines (tumor necrosis factor α and platelet-activating factor) in the cerebrospinal fluid had decreased in the dexamethasone-treated children, whereas in the controls the inflammatory response in the cerebrospinal fluid had increased. At 24 hours the clinical condition and mean prognostic score were significantly better among those treated with dexamethasone than among the controls. At follow-up examination after a mean of 15 months, 7 of the surviving 51 dexamethasone-treated children (14 percent) and 18 of 48 surviving controls (38 percent) had one or more neurologic or audiologic sequelae (P = 0.007); the relative risk of sequelae for a child receiving placebo as compared with a child receiving dexamethasone was 3.8 (95 percent confidence interval, 1.3 to 11.5).
Conclusions.
The results of this study, in which dexamethasone administration began before the initiation of cefotaxime therapy, provide additional evidence of a beneficial effect of dexamethasone therapy in infants and children with bacterial meningitis. (N Engl J Med 1991; 324:1525–31.)
Media in This Article
Table 1
Characteristics of the Study Patients According to Treatment Group.*Table 2
Lumbar Cerebrospinal (CS) Pressures and Estimated Cerebral Perfusion Pressures in the Study Patients at Admission and after 12 or 24 Hours of Therapy, According to Treatment Group*Article Activity
- Article
CONSIDERABLE attention has recently been focused on the molecular pathophysiology of bacterial meningitis in an attempt to elucidate the mechanisms of meningeal inflammation and the ways they can be regulated to improve outcome for patients with the disease. It is believed that the cytokines interleukin-1β and tumor necrosis factor α (TNF-α) have a seminal role in the initial events of meningeal inflammation that eventually result in alterations in the blood–brain barrier, cerebrovascular autoregulation, cerebrospinal fluid dynamics, and brain metabolism.1 2 3 Therapeutic interventions to modulate cytokine production have been assessed in experimental models of meningitis4 5 6 and in two recently reported clinical trials of adjunctive dexamethasone therapy in infants and children with bacterial meningitis.7 The results of the latter studies indicated that steroid therapy significantly reduced the degree of meningeal inflammation at 24 hours and improved outcome. In those two trials dexamethasone was administered from approximately 30 minutes to many hours after the first parenteral dose of the antibiotic.7
In experimentally induced Haemophilus influenzae meningitis, a single dose of ceftriaxone given intravenously resulted in a 40-fold to 600-fold increase in free H. influenzae lipo-oligosaccharide concentrations in the cerebrospinal fluid two hours later, as compared with the levels in untreated animals.8 This response was believed to result from the release of cell-wall or membrane active components (endotoxin) from rapidly lysed microorganisms. Concentrations of TNF-α in the cerebrospinal fluid increased almost 10-fold during the same period, and there was a significant increase in the concentrations of white cells, protein, and lactate in the cerebrospinal fluid and a decrease in the glucose concentration. This effect on TNF-α activity in the cerebrospinal fluid and on inflammation was significantly lessened if dexamethasone was given just before ceftriaxone but not if it was given one hour later. Fischer and Tomasz9 demonstrated similar release of cell-wall products with the addition of ampicillin to pneumococci, and Tauber and coworkers10 observed similar results with cefotaxime therapy in experimental models of Escherichia coli meningitis. In addition, concentrations of free endotoxin and TNF-α in the cerebrospinal fluid have been shown to increase substantially two to six hours after the first dose of ceftriaxone in infants with H. influenzae meningitis.11
As a consequence of these recent observations in the rabbit model of meningitis and in patients with H. influenzae meningitis, we conducted the present study, which differed in two important ways from our two previous placebo-controlled, double-blind trials of dexamethasone therapy.7 First, the initial dose of dexamethasone or placebo was administered 15 to 20 minutes before the first dose of antibiotic; second, opening lumbar cerebrospinal pressures were measured at diagnosis and again either 12 or 24 hours after the beginning of treatment.
Methods
Patients
Patients 6 weeks to 13 years of age who were admitted to the National Children's Hospital, San José, Costa Rica, with culture-proved bacterial meningitis or with evidence of severe meningeal inflammation and findings characteristic of bacterial infection on examination of the cerebrospinal fluid were enrolled in the study. Informed consent for the children's participation was obtained from their parents. The study protocol was approved by the institutional review boards of the National Children's Hospital and the University of Texas Southwestern Medical Center, Dallas.
Infants up to six weeks of age and any patient with a congenital or acquired abnormality of the central nervous system, a prosthetic device inserted into the central nervous system, previous episodes of bacterial meningitis, an underlying neurologic abnormality, or a history of hypersensitivity to beta-lactam antibiotics were excluded. Patients who had previously received parenteral antibiotic therapy were also excluded, as were patients with aseptic meningitis.
Treatment
Cefotaxime (50 mg per kilogram of body weight) was administered to all 101 patients intravenously over a 10-to-15-minute period every 6 hours (total daily dose, 200 mg per kilogram) for 7 to 10 days or longer, depending on the cause of the meningitis and the clinical response.
On the basis of a computer-generated list of random therapy assignments, the patients received either dexamethasone (n = 52) or placebo (half-normal saline; n = 49) in a blinded fashion. Dexamethasone sodium phosphate was given intravenously at a dose of 0.15 mg per kilogram every six hours (0.6 mg per kilogram per day) for four days. The first dose was administered 15 to 20 minutes before the first dose of cefotaxime. The code was not broken until the last patient had completed therapy. The personnel performing and interpreting the brain-stem auditory evoked responses and conducting the follow-up neurologic examinations were unaware of the therapy assignment of the patients.
Initial Supportive Care
Infants and children were admitted to the intensive care unit if they were considered to have increased intracranial pressure indicated by obtundation or coma, an opening cerebrospinal pressure of ≥90 mm of water on initial lumbar puncture, papilledema or pupil asymmetry (or both), or decorticate or decerebrate posture. Patients with Glasgow coma scores of ≤7 were intubated and mechanically ventilated to achieve an arterial carbon dioxide tension of approximately 20 mm Hg (2.7 kPa) and a partial pressure of oxygen of ≥100 mm Hg (13.3 kPa). Study patients were routinely restricted to 800 ml of fluid per square meter of body-surface area, unless hypotension or septic shock was present. The amount of fluid administered was adjusted on the basis of the osmolarity of serum and urine and the serum electrolyte concentrations. At the time of enrollment and 24 hours later, all patients were clinically assessed by the Glasgow coma scale for children12 or for infants13 and those with H. influenzae meningitis were evaluated by determination of the Herson—Todd illness-severity score.14
Determinations of Cerebrospinal Pressure
Cerebrospinal pressures were measured at diagnosis and again after either 12 or 24 hours of treatment in 73 patients; those in whom only one pressure measurement was obtained were excluded from the analysis. With use of standard techniques, a 22-gauge Quick-Cath (Vicra, Travenol Laboratories, Deerfield, Ill.) was introduced into the lumbar subarachnoid space with the patient lying on his or her side and being held by an attendant. The needle was connected to a manometer by means of a three-way stopcock. The entrance of cerebrospinal fluid into the column and the presence of a pulse wave verified the position of the spinal needle. Before lumbar puncture the mean arterial blood pressure was obtained, while the patient was lying down, with an appropriately sized sphygmomanometer cuff. This allowed us to estimate a single value for cerebral perfusion pressure.15
Laboratory Studies
Cerebrospinal fluid from all patients was examined at the time of the diagnosis and again either approximately 12 hours after the first dose of cefotaxime (57 patients) or approximately 24 hours after the first dose (44 patients). Any patient with a positive cerebrospinal fluid culture at 12 or 24 hours had an additional lumbar puncture 24 hours later. All specimens of cerebrospinal fluid were routinely cultured on blood and chocolate agar plates and in thioglycolate broth. Cephalosporinase (Sigma Chemical, St. Louis) was routinely added to cerebrospinal fluid before culture. Blood samples for culture were obtained from all patients before they began antibiotic therapy. Aliquots of cerebrospinal fluid were centrifuged and frozen at —70°C until they were assayed for lactate and mediators of inflammation. The lactate concentration was measured in all samples by the same investigator with use of an automated enzymatic technique (Stat Pack Rapid Lactate Test, Behring Diagnostics, La Jolla, Calif.).
The activity of TNF-α was determined with an L929 cell-line assay, described previously.16 Equivalent concentrations of recombinant human TNF-α were determined for cerebrospinal fluid samples by interpolation of the recombinant human TNF-α standard curve run simultaneously (0.1 pg per milliliter to 1.0 μg per milliliter). The lower limit of detectability of this assay was 10 pg per milliliter.
Concentrations of platelet-activating factor, a potent proinflammatory glycerophosphocholine derivative, were measured with a radioimmunoassay kit (Dupont Biomedical Products, Boston) after extraction from cerebrospinal fluid and thin-layer chromatography. The sensitivity of the assay was 200 pg per milliliter with a simultaneously run standard-curve range of 0.2 to 30 ng per milliliter.
Radiologic Evaluation
All patients with an open fontanelle underwent ultrasonography of the head alter approximately 72 to 96 hours of therapy and at the end of treatment. Most of these infants and all the patients with closed fontanelles underwent cranial computed tomographic (CT) scanning on the third to seventh day of hospitalization.
Evaluation of Hearing
Hearing was assessed at the time of discharge or no later than four months after hospital discharge by brain-stem auditory evoked responses. All patients with abnormal results on this examination had a repeat test between 4 and 24 months after discharge. Brain-stem evoked responses were elicited for each ear separately by a 100-μsec rarefaction click transduced by a TDH 49 earphone (CA 100 or Compact Four Unit, Nicolet Instrument, Madison, Wis.). Stimuli were presented at intensities of 20, 30, 60, and 80 dB at a rate of 21.1 per second. If the Wave V response was not detected at these levels, higher intensities were introduced. Masking in the contralateral ear was used when needed. A stimulus trial consisted of two independently summed wave forms (2048 stimuli each) recorded at each presentation level. At 80 dB, the Wave I—V interpeak latency was determined for each ear.
The findings were interpreted by an audiologist with experience in the assessment of auditory brain-stem responses in infants and children. The degree of hearing loss was determined on the basis of the threshold response, as follows: an absence of response at 20 dB was interpreted as indicating a very mild loss; at 30 or 40 dB, a mild loss; at 50 dB, a mild-to-moderate loss; at 60 dB, a moderate loss; at 70 dB, a moderate-to-severe loss; at 80 or 90 dB, a severe loss; and at 100 dB, a severe-to-profound loss. The latency—intensity function was also used to provide supporting information on the type and degree of hearing loss. All the patients underwent tympanometry with a Maico 610 impedance audiometer (Maico Hearing Instruments, Criton Technology, Minneapolis) before testing of brain-stem auditory evoked responses to rule out middle-ear disease. All children thought to have middle-ear disease or fluid had follow-up tympanometry and testing of evoked responses when the middle-ear disorder had resolved.
Neurologic Examination
Complete physical and neurologic examinations were performed by the same physician within 4 months of discharge, and again 6 and 12 months later in all patients, with longer follow-up for those with abnormalities. The severity of ataxia was defined as mild (if the patient was able to sit but not walk unassisted), moderate (the patient required assistance in sitting and walking), or severe (the patient was unable to sit or walk without falling). Mild paresis was defined as reduced reflexes and difficulty with fine motor activities of the affected extremity, and moderate paresis was defined as an absence of normal functions of the involved extremity. Those with severe paresis had little or no function of the extremities.
Statistical Analysis
Results are expressed as means ±SD unless otherwise noted. The differences between parametric and nonparametric values in the two treatment groups were tested for significance with use of the two-tailed Student t-test and the Mann—Whitney test, respectively. Differences between proportions for both groups were analyzed with either the two-tailed chi-square test or Fisher's exact test. Pearson's correlation coefficient was used to evaluate the relation between specific variables. A P value of less than 0.05 was considered to indicate statistical significance.
Results
Of the 120 patients initially enrolled in the study, 19 were excluded for the following reasons: 8 had sterile cultures and cerebrospinal fluid findings compatible with the diagnosis of aseptic meningitis; 6 had received parenteral antibiotics before enrollment; 2 had underlying hearing impairment; and 1 each had Down's syndrome, Marfan's syndrome, and Niemann—Pick disease. We studied the remaining 101 subjects, 80 percent of whom were younger than two years of age and 90 percent of whom were younger than five years; 52 were treated with dexamethasone, and 49 received saline (placebo group); all the patients received cefotaxime. At the time of enrollment the two groups of patients were comparable with regard to age, Glasgow coma score, presence of shock, duration of symptoms before the beginning of treatment, causes of meningitis, results of blood cultures, and findings on examination of the cerebrospinal fluid (Table 1Table 1
Characteristics of the Study Patients According to Treatment Group.*).Cerebrospinal Pressure
The opening lumbar cerebrospinal pressures at the time of diagnosis were comparable in the two treatment groups (Table 2Table 2
Lumbar Cerebrospinal (CS) Pressures and Estimated Cerebral Perfusion Pressures in the Study Patients at Admission and after 12 or 24 Hours of Therapy, According to Treatment Group*). After 12 hours of therapy the mean opening pressure had increased by 9 percent in the placebo group and decreased by 8 percent in the children given dexamethasone (P = 0.04). After 24 hours of therapy the mean opening pressures were 161±78 mm of water for the placebo group and 115±49 mm of water for the dexamethasone group (P not significant).The estimated cerebral perfusion pressures were similar at the time of diagnosis for the two study groups (Table 2). After 12 hours of therapy the perfusion pressures had decreased by 5 percent in the placebo group and increased by 21 percent in the dexamethasone group (P = 0.01). By 24 hours, the perfusion pressures and changes in pressure continued to be greater for those treated with dexamethasone, but the differences were not statistically significant.
Clinical Response
The clinical condition of the patients given dexamethasone, as assessed by the Glasgow coma scale and the Herson—Todd prognostic score for patients infected with H. influenzae, was significantly better after 24 hours of treatment than that of the patients given placebo (Table 3Table 3
Clinical Condition and Prognostic Scores of the Study Patients during the First 24 Hours of Treatment, According to Treatment Group.*).The patients treated with dexamethasone had fewer days of fever than did the controls (1.3±1.2 vs. 4.3±2.5 days; P<0.01). The length of hospitalization was 11.9±6.1 days for the dexamethasone-treated patients versus 12.1±6.9 days for the placebo group. Hyponatremia (sodium level, < 130 mmol per liter) developed in 19 patients in the dexamethasone group (37 percent) and 23 patients in the placebo group (47 percent) during the first 72 hours of hospitalization. Two patients, one in each treatment group, died of H. influenzae meningitis. The dexamethasone-treated patient died at 48 hours, of irreversible shock. The patient in the placebo group had signs and symptoms of intracranial hypertension and coma from the time of admission and was considered to be brain-dead after 48 hours of vigorous supportive therapy.
Studies of Cerebrospinal Fluid
The changes in the indexes of inflammation in the cerebrospinal fluid after 12 and 24 hours of treatment are shown in Table 4Table 4
Changes in Indexes of Inflammation in the Cerebrospinal Fluid (CSF) after 12 and 24 Hours of Placebo or Dexamethasone Therapy.*. For the patients in the placebo group the lactate, leukocyte, and protein concentrations increased by 5 percent, 31 percent, and 13 percent, respectively, and the glucose concentration decreased by 6 percent. In those given dexamethasone, by comparison, these four indexes improved (the greatest change was in the glucose concentration) (Table 4). After 24 hours of treatment the changes in these indexes followed a similar pattern of greater improvement in the dexamethasone group, although not all the differences between the groups were significant. There was a significant inverse correlation between the lactate concentration in the cerebrospinal fluid and the estimated cerebral perfusion pressure (correlation coefficient, —0.45; P = 0.014).The TNF-α concentrations in the cerebrospinal fluid at diagnosis were comparable in the dexamethasone group (1040±301 pg per milliliter) and the placebo group (900±1810 pg per milliliter); 77 percent in the dexamethasone group and 75 percent in the placebo group had detectable TNF-α activity in the cerebrospinal fluid. After 12 hours of treatment the values were 170±590 pg per milliliter and 700±1060 pg per milliliter, respectively, representing decreases in activity of 84 percent and 21 percent from the values at diagnosis (P = 0.04). At 12 hours, 21 percent of patients in the dexamethasone group and 74 percent in the placebo group had detectable TNF-α activity in the cerebrospinal fluid (P = 0.007). The TNF-α values at 24 hours were 71±120 pg per milliliter in the dexamethasone group and 410±623 pg per milliliter in the placebo group (P = 0.10).
At the time of diagnosis, the mean concentrations of platelet-activating factor in the cerebrospinal fluid were 3140±6514 pg per milliliter in the dexamethasone group and 2415±4285 pg per milliliter in the placebo group, and 91 percent and 80 percent of patients, respectively, had detectable activity. After 12 hours of treatment, the mean concentrations were 941±925 and 3242±7816 pg per milliliter, representing a decrease of 70 percent in the dexamethasone group and an increase of 34 percent in the placebo group, as compared with the values at diagnosis (P = 0.04 for both comparisons). By 24 hours, the mean concentrations were 259±485 and 1040±975 pg per milliliter, representing decreases of 92 percent in the dexamethasone group and 57 percent in the placebo group (P = 0.12).
Complications during Therapy
One patient in each group had a positive cerebrospinal fluid culture 24 hours after the beginning of therapy; both had sterile cultures at 48 hours (Table 5Table 5
Complications or Adverse Events during Treatment, According to Treatment Group.). The causative microorganism was H. influenzae in both patients. Both had sequelae. The dexamethasone-treated patient had persistent ataxia for eight months and mild hearing loss after discharge, and the patient who received placebo had a profound bilateral hearing deficit and required hearing aids. Secondary fever, defined as an axillary temperature of ≥38.5°C after the maximal daily temperature had been no more than 37.9°C for 24 hours or more, occurred with similar frequency in the two treatment groups. Prolonged fever (seven days or longer) occurred more frequently in the placebo group than in the dexamethasone group (P<0.003). Twelve of 51 dexamethasone-treated patients (24 percent) and 21 of 48 who received placebo (44 percent) had guaiac-positive stools (P = 0.055). Reactive arthritis occurred in four patients in the placebo group and in none in the dexamethasone group (P = 0.052). Subdural empyema associated with H. influenzae meningitis developed in one placebo recipient. Seizures developed after 48 hours of treatment in 2 of 51 patients given dexamethasone and in 7 of 48 given placebo (P = 0.09). Cortical atrophy, ventricular dilatation, or both, or cerebral infarct identified on CT scanning or ultrasonography, was present in 7 ( 14 percent) of the patients in the dexamethasone group and 14 (29 percent) in the placebo group (P = 0.06).Long-Term Responses to Therapy
Excluding the two patients who died, the 51 dexamethasone-treated patients were followed for 15.5± 6.3 months (range, 5 to 25) and the 48 patients given placebo for 14.9±6.1 (5 to 24) (Table 6Table 6
Neurologic and Audiologic Outcome in the Study Patients Evaluated up to 24 Months after Discharge, According to Treatment Group.). There was a significantly higher percentage of patients with neurologic sequelae in the placebo group (15 of 48 [31 percent]) than in the dexamethasone group (5 of 51 [10 percent]; P = 0.008). Of the eight patients with persistent ataxia, six had moderate or more severe bilateral hearing deficit, and two had mild hearing loss. If those with chronic seizure disorders who were otherwise normal were not considered to have sequelae, the percentages of patients with abnormal results on neurologic examination were 8 percent in the dexamethasone group and 25 percent in the placebo group (P = 0.028).Audiologic Outcome
Audiologic assessments were performed up to 24 months after discharge in 50 dexamethasone-treated patients (98 percent) and 44 patients in the placebo group (92 percent) (Table 6). Patients who received placebo had a higher incidence of moderate or more severe bilateral hearing deficit than patients who received dexamethasone (7 of 44 [16 percent] vs. 3 of 50 [6 percent]) and required hearing aids more frequently. The differences were not statistically significant.
Overall Adverse Outcome
Significantly more of the placebo recipients (18 of 48 [38 percent]) had one or more neurologic or audiologic sequelae 5 to 25 months or more after discharge, as compared with the dexamethasone-treated patients (7 of 51 [14 percent]; P = 0.007). The relative risk of sequelae for a placebo recipient as compared with a patient given dexamethasone was 3.8 (95 percent confidence interval, 1.3 to 11.5).
Discussion
Dexamethasone has been shown to bring about significant reductions in cerebrospinal pressure, brain edema, and lactate concentrations in cerebrospinal fluid in experimental models of Streptococcus pneumoniae and H. influenzae meningitis4 , 5 and to decrease leakage of low-molecular-weight proteins from serum into the cerebrospinal fluid in the experimental model of pneumococcal meningitis.6 When administered before the initiation of antibiotic treatment in rabbits with H. influenzae meningitis, dexamethasone significantly reduced both TNF-α concentrations and indexes of meningeal inflammation in the cerebrospinal fluid.8 We have previously shown that dexamethasone given to children with meningitis after the initiation of antibiotic therapy significantly reduced the concentrations of interleukin-1β and prostaglandin E2 and the degree of inflammation in samples of cerebrospinal fluid obtained 24 hours after the first dose, as compared with the results in children who received placebo.16 , 17 Because the degree of inflammation in the subarachnoid space correlates inversely with outcome18 and because TNF-α and interleukin-1β have a seminal role in the evolution of meningeal inflammation,3 , 19 dexamethasone was chosen as adjunctive therapy in infants and children with meningitis in an attempt to reduce the inflammatory response in the cerebrospinal fluid and to improve long-term outcome.
The mean opening lumbar cerebrospinal pressure in the patients in this study was approximately 185 mm of water, a value more than twice the maximal normal pressure of 85 mm of water for infants and children.20 McMenamin and Volpe21 showed that intracranial pressure was more than 200 mm of water and cerebral blood-flow velocity was greatly diminished in the first two days of illness in infants with bacterial meningitis. In our patients, the opening cerebrospinal pressures in those given dexamethasone decreased by 8 percent after 12 hours and 40 percent after 24 hours of therapy, whereas they increased by 9 percent at 12 hours and then decreased by 17 percent at 24 hours in children given placebo. Coincidently, the estimated cerebral perfusion pressures after 12 hours of therapy increased by 21 percent in children given dexamethasone and decreased by 5 percent in those given placebo. At the time of enrollment, four patients in each treatment group had perfusion pressures of less than 5.3 kPa (40 mm Hg); two in the placebo group and none in the dexamethasone group had long-term neurologic sequelae. At 12 to 24 hours, five patients in the placebo group and none in the dexamethasone group had perfusion pressures of less than 5.3 kPa (40 mm Hg), and four of those five patients had long-term neurologic abnormalities. Because cerebral perfusion pressure is not a reliable indicator of cerebral blood flow, it cannot be assumed that low pressures are necessarily associated with reduced flow and cerebral ischemia. Our observation of abnormal neurologic outcomes among the patients who had low perfusion pressures for the initial 12 to 24 hours is consistent with the results of Goitein et al.,15 who also measured cerebral perfusion pressures by the same technique in children with infections of the central nervous system.
Meningeal inflammation was significantly reduced in the patients treated with dexamethasone as compared with the patients given placebo. By 12 hours all indexes of inflammation in the cerebrospinal fluid had improved with dexamethasone therapy, whereas they had uniformly worsened in the patients given placebo. These findings are in accord with our observations that after 12 hours of therapy the concentrations of TNF-α in cerebrospinal fluid decreased by 84 percent in the dexamethasone-treated patients and by 21 percent in those given placebo and that the concentration of platelet-activating factor in the cerebrospinal fluid decreased by 70 percent in the dexamethasone group and increased by 34 percent in the placebo group. The rapid improvement in these indexes and in the concentrations of the proinflammatory cytokines was correlated with the significantly better clinical condition and illness-severity scores of the patients in the dexamethasone group after 24 hours of treatment.
Follow-up neurologic and audiologic examinations were performed up to 25 months after the illness. Neurologic sequelae occurred significantly more often in the patients who were given placebo. In the earlier trials in Dallas, neurologic examinations one year after illness identified sequelae in 3 of 81 patients who received dexamethasone (4 percent) and in 9 of 75 who received placebo (12 percent; P = 0.071).22 The higher rates of neurologic abnormalities in Costa Rican children are unexplained but may be a result of genetic or cultural differences or of the relative lack of advanced technological support systems and of medical personnel in the intensive care unit; these rates are similar to those observed previously in children with meningitis at the National Children's Hospital.23
In previous studies we found a significant difference in the rate of moderate or more severe bilateral hearing impairment between the dexamethasone group (3 of 92 [3.3 percent]) and the placebo group (13 of 84 [15 percent]; P = 0.009).7 , 22 This difference was not significant in the present study, in which 3 of 50 patients in the dexamethasone group (6 percent) and 7 of 44 in the placebo group (16 percent) had moderate or more severe bilateral hearing impairment (P = 0.18). This lack of statistical significance could be a result of a Type II error due to a sample that was too small to identify a real difference. Using ceftriaxone for the treatment of meningitis, Schaad et al.24 found a 4 percent rate of hearing loss among Swiss children, whereas we found an 11 percent rate among ceftriaxone-treated children in Dallas who were given placebo (as compared with a rate of 2 percent in the dexamethasone group [P = 0.09]).7 , 22 In the current study, in which all children received cefotaxime, another potent third-generation cephalosporin, 16 percent of the Costa Rican children in the placebo group had substantial hearing impairment. The reasons for these differences in the rates of hearing loss among the various populations are unclear. Overall, 14 percent of dexamethasone-treated Costa Rican patients, as compared with 38 percent of those given placebo, had one or more neurologic or audiologic sequelae on long-term follow-up (P = 0.007).
In conclusion, we believe that dexamethasone improves outcome when it is used as adjunctive therapy for bacterial meningitis in infants and children. When dexamethasone was administered to our patients before the initiation of cefotaxime therapy, the indexes of meningeal inflammation, opening lumbar cerebrospinal pressure, estimated cerebral perfusion pressure, and concentrations of cytokines in the cerebrospinal fluid improved rapidly and significantly within 12 hours as compared with the same measures in the patients given only cefotaxime. The immediate and long-term clinical profiles both indicated significantly better outcomes for those given dexamethasone. The evidence from our own clinical trials and from the many studies of experimental models of meningitis provide a compelling biologic basis for the favorable effect of dexamethasone therapy on the molecular pathophysiology and clinical course of bacterial meningitis.
Supported by a grant from Hoechst-Roussel Pharmaceuticals.
Dr. McCracken is a scientific advisor to Hoechst-Roussel Pharmaceuticals in the area of the development of new antibiotics.
We are indebted to Terese Finitzo, Ph.D., of the Electrophysiology Laboratories, Dallas, for her invaluable assistance in all aspects of the audiologic assessments of the study patients and to Zulma Campos, M.D., for assistance in the neurologic examinations.
Source Information
From the National Children's Hospital, San José, Costa Rica (C.M.O., I.F., M.P., M.N., A.B.); the Electrophysiology Laboratories, Dallas (J.R.); and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (X.S.-L., K.D.O., G.H.M.). Address reprint requests to Dr. McCracken at the Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235–9063.
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- Citing Articles (102)
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Tuula Pelkonen, Irmeli Roine, Manuel Leite Cruzeiro, Anne Pitkäranta, Matti Kataja, Heikki Peltola. (2011) Slow initial β-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: a randomised, controlled trial. The Lancet Infectious Diseases 11:8, 613-621
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Vjerislav Peterković, Vladimir Trkulja, Marko Kutleša, Vladimir Krajinović, Dragan Lepur. (2011) Dexamethasone for adult community-acquired bacterial meningitis: 20 years of experience in daily practice. Journal of Neurology
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Donna Curtis, Ann-Christine Nyquist. 2011. Meningitis. , 638-644.
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Lise Worsøe, Christian Thomas Brandt, Søren Peter Lund, Christian Østergaard, Jens Thomsen, Per Cayé-Thomasen. (2010) Intratympanic Steroid Prevents Long-Term Spiral Ganglion Neuron Loss in Experimental Meningitis. Otology & Neurotology 31:3, 394-403
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Diederik van de Beek, Jeremy J Farrar, Jan de Gans, Nguyen Thi Hoang Mai, Elizabeth M Molyneux, Heikki Peltola, Tim E Peto, Irmeli Roine, Mathew Scarborough, Constance Schultsz, Guy E Thwaites, Phung Quoc Tuan, AH Zwinderman. (2010) Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data. The Lancet Neurology 9:3, 254-263
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