ARTIC LE Dexamethasone therapy for bacterial meningitis : Better never than late ?

A multicentre randomized controlled trial was conducted in children with bacterial meningitis using dexamethasone or placebo for four days within 24 h of starting antibiotics. Primary outcomes were hearing loss and neurological abnormalities at 12 months after meningitis. The dexamethasone (n=50) and placebo (n=51) groups were similar in age, severity of illness and etiological agent. Hearing loss occurred in 10% and 11% of the dexamethasone and placebo groups and neurological deficits occurred in 20% and 18% of patients, respectively. Duodenal perforation occurred in one dexamethasone-treated child. In conclusion, there was no significant benefit in those receiving dexamethasone. The lack of benefit may have been due to the delay in administration of dexamethasone (median delay of 11 h after antibiotics). Therefore, if dexamethasone is used for meningitis it should be given immediately with the antibiotic.


B ACTERIAL MENINGITIS REMAINS A RELATIVELY COMMON
and serious disease (1,2) .In Canada and the United Stales.the incidence is about three cases per 100.000 per year \vilh a case fatality rate of 5 lo 25% depen d ing on etiology and age.Alth ou gh lhe prognosis fo llo\vi ng bacterial meningitis improved dramatically after the inlro-duclion of anlibiolics.there has been no major decline in the morbidity and mortality in three decades (3).Slill .despite bacteriological cure there may be significant morbidity.The incidence of long term sequelae in child ren wh o survive bacterial meningitis is 25 to 50%, and hearing loss alone occurs in 10% (range 5 to 30%) (4)(5)(6).
Studies on th e pa thophysiology of bacte ria l m eningitis have s h O\'IT1 tha t the b ac teria in th e cerebros pina l fluid induce an infla mma tory res pon se in th e s ubarachnoid s pace.and this infla mma tory process contribu tes s ubstantia lly to the a dverse outcom e of m e ningiti s (7 -12) .Corti cos teroid s we re th e firs t a ntiinfla mma tory agents to b e s tudied .firs t in a nima l models and th en in clinical tria ls as a djunc tive th era py for meningitis.In th e a nima l mod els corticos teroids did decrease th e markers of infla mma tory resp on se in th e cerebrospinal flu id (1 3-15).In children dexamethason e a p pears to reduce the sequelae of meningitis (1 [6][7][8][9][10][11][12][13][14][15][16][17][18][19].In animal models.the effec t is dim inis h ed if d exam e thasone is given after an tibio tics (20)(21)(22).Since many children receive a dose of an tibiotic before th e diagn osis of men ingitis is confirmed o r before they are tran s ferred to a ped iatric h ospital.it is impor tant to evalu a te th e effi cacy of dexame thason e if given after t he initial dose of a ntib iotic.Th e use of d exameth asone in children wilh meningitis has been associa ted with gastrointestinal hemorrhage and.therefore.both Lh e ben efits a nd ris ks mu st be Laken in to cons ide ra tion wh en using dexamethasone as adjunctive thera py for meningitis (23.24).
The purpose of this s tudy was to determine the effect of dexameth ason e. in a ddition to standard a ntibiotic th erapy.on the outcome of bacterial m eningitis in infa n ts a nd c hildren whe n dexam ethason e was give n with in 24 h of the first dose of antibiotic.

Patients:
Infants and children on e monU1 lo 18 years of age who were ad mitted lo U1e Hospital for Sick Children in Toronto.On tario .the Izaak Walton Killa m Hospi tal in Halifax.Nova Scotia and the Health Sciences Centre in Winnipeg.Manitoba with the diagn osis of s u spected bacteria l meningitis we re e ligible for enrolment in the study.Th e study protocol was a pproved by each ins titution's research e thics review committee a nd informed consen t ob ta ined from the parents or gu a rdia n s of each patient before enrolm ent.Children were excl uded from the s tudy for any of the following : a hi s tory of a ntecedent hearing or neurological dis ord er: a previou s episode of meningiti s: con genita l or acquired immu nod efi cien cy syndromes; th e presen ce of a ven tri cula r s hu nt: o r current u se of s te roid s or a contra ind ication to th e u sc of steroids.s u ch as peptic ulcer disease.Patients were also excl u ded if th ey h a d received the fi rst dose of intraven ou s an tibi otic 24 h or m ore previou s ly.
Th e diagnosis of s u s pected m eningitis was made on clinical grounds by the a dmitting pediatricia n.Pa tients were eligib le if, as well as the clinical diagn osis.the cell count in the cerebros pinal fluid (csr-) was m ore tha n 1000x10 6 while blood cells/ L or between 100 and 1000x10 6 white b lood cells/ L with n eutropeni a or seps is.Patien ts were also eligible if Lh ey were assumed to have bacteria l me ningitis b ut were too uns ta bl e for a lumbar punct ure.ln a ll cases the lumbar punc ture was Dexamethasone therapy for bacterial meningitis pe rformed when s ta bility was attained.Confirmed cases of bac terial men ingitis h a d more U1an 1000x10 6 white blood cells/L in th e csr-and a t least one of th e following: bac teria s een on Gra m stain, recove ry of ba cteria or the presen ce of bac terial antigens.Patients were evalu a ble if the e tiological agent wa s Haemophilus injluenzae typ e b.Ne isseria m eningitidis.Slreplococcus pneumoniae or group 8 stre ptococcus.ln addition , cases were consid ered confirmed if there was csr-pleocytos is (greater than 1000x10 6 white blood cells/L) and on e of th e bact eria lis ted a b ove was recovered from b lood.Probable cases of b acte rial meningitis were those cases to wh om antibiotics were given before csr-was obtained and those in whom n o bacteria were identified b u t the csr-h a d greater tha n 1000x10 6 white blood ce ll s/L. of wh ic h m o r e t h a n 5 0 % we re p oly morphonu clear cells.Treatment: Patients were treated with empirical intrave no u s an ti b iotics in accordance with the guidelines of each ins tituti on.During the first two months of the s tudy cefuroxim e was u sed for empirical thera py and was received by s ix s ubj ects.For the remainder of the stu dy pe riod ceftriaxon e was u sed for empirical thera py except in infa nts under three months of age, for whom a mpicillin a nd cefotaxim e were u sed.The standard d ura tion of an timicrobial thera py for an uncomplicated case a t the pa rticipa ting ins iitutions is seven lo 10 days for H injiuenzae, five lo seven clays for N meningitidis, seve n to 14 days for S pnewnoniae and 14 to 21 clays for g ro up 8 s treptococcu s.
Patients were randomized to receive either d exameth ason e or an equa l volume of placebo (norma l saline) in a double-blind manner for four days.The randomization was s tra tified by centre and by age greater or less than five years.Dexamethas one sodium phospha te 0 .6mg /kg/day was given intravenously every 6 h.Addition a l s upportive care was a dministered according lo s tanda rd clinical practice a t each insti tution.Evaluation of therapy: Al e nrolment.pa tie nts were assessed a nd scored by a p edia tric s tudy nurse or investigator according lo th e pedia tric Glasgow coma scale a nd th e Herson -Todd m eningitis s everity score (25-27) .Ne urological s ta tu s a nd tempera ture were monitored daily throughout hos pita lization .Persistent feve r (tempera ture over 38.5°C orally) was defin ed as daily fever for more than five consecutive days .Secondary fever was defined a s a recurren ce of fever afte r a t least 24 h without fever.In a ddition , complete blood count, serum electrolytes.blood glucose and stool for occul t b lood were monitored daily for the first four h os pita l clays .
Hearing was assessed a t s ix weeks and one year after d isch arge .Hearing tests were selected according to the child's a bility to coopera te .Children under 24 to 30 month s of age were tested by beh a viour observa tional a udiome try or visual reinforced a udiometry (28,29).If clinically indicated , bra instem a uditory evoked re- Complete physical and n eurological examinations were performed by a pediatric infectiou s disease s pecialist a l six weeks, six months and one year.Patients were assessed by a pediatric neurologist and a clinical psychologist at six io 12 months after discharge.Children under 30 months of age were tested using the Bayley Scales of Infant Development (Mental Development Ind ex [M DI) and Psychomotor Development Ind ex [PD I)) , two-to four-year-olds using the Stanford-Binet and Wechsler Preschool and Primary Scale of Inte lligence.four-and five-year-olds using the Wide Range Achievement Test and ch ildren over six years old using the Wechsler Intelligence Scale for Children (Third Edition).Statistical analysis: Because the data were not always distributed in a statistically normal fashion, differences between the values for the two groups were tested for significance with the Mann-Whitney U lest.Differences for frequencies were compared either by the x 2 or Fisher's exact lest.P:S:0 .05 was considered to be slalis-Ucally s ignificant.

RESULTS
Study patients: Between March 1989 and June 1991.118 patients were enrolled in the study. of whom l 7 were excluded -nine from th e dexamethasone group and eight from the placebo g roup.The diagnoses of excluded cases were aseptic meningitis (seven).enterovira l meningitis (three).recurrent meningitis (one) , 212  1).The gro ups were also similar in the proportion who were baclere mic and in the causative agent of meningitis.with on ly 56% overa ll of the cases due to H injluenzae type b.Six patients in each group had no organism isolated and were classified as probable cases of bacterial meningitis.There were no slatislically s ignificant differences between the groups in their clini ca l characteristics or in their CSF at enrolment (Table 2).In both groups the median lime from the first dose of intravenous antibiotic to admini stration of the study drug was ll h.Only eight patients in the dexamethasone group and seven in the placebo group received the study drug within 4 h of the first dose of antibiotic.Most children received a third -gen eration ceph alosporin as empirical therapy -92% in the dexamethasone group and 88% in the placebo group.The antibiotic was ch anged to a penicillin in 62 and 67% of the groups.respectively, when the etiological agent was identified as sensitive to penicillin or ampicillin.
Response to therapy -Long term sequelae: Ninety three per cent oflhe children had one or more audiological assessments (Table 3).Eighty-five per cent had a second a udiological assessment at one year after men- Th ere were no statistically s ignificant d ifferences between the two grou ps in the incidence of one or more types of ne u ro logical sequ elae.The numbers of children with any long term sequelae after meningitis were 10 (20%) and n ine (17 .6%) in the dexamethasone and placebo grou ps.respectively (Table 3).There was a single death during th e stu dy . in the placebo group on day 2. Ninety per cent of the children had neurological assessments at six to 12 months after meningitis.Th e 10 ch ildren not retu r ning for neurological evaluation were neurologically nor mal at the lime of discharge from hospital .Five children in th e dexamethasone group had persisten t n eu rological abn ormalities: m ultiple handicaps of h emiparesis.vis u a l loss.seizures and severe developm ental delay (one); ataxia (one): m ild hypotonia (one); and s peech delay (two).Three child ren in the placebo grou p had persistent neurological abnormalities : multi ple h andicaps of h emiparesis.seizures and severe developmen tal delay (one): gross motor delay (one); and m ild hypotonia (one).An additional five  children had neurological abnormalities at six weeks after meningitis but were normal at 12 months after men ingitis .The abnormali ties that resolved were mi ld hemiparesis (two): sixth cranial nente palsy (one): ataxia (one); and developmental delay (one).Seventy-two per cent of the children had psychometric assessments.In the dexamethasone group there were four children with abnormali ties: developmental delay (one) and language delay (three).In the placebo group there were three children with abnormalities: developmental delay (one).gross motor delay (one) and language delay (one) .
The outcome of meningitis for each etiological agent and for probable cases is shown in Table 4 .Table 5 summarizes the h earing outcome by age group.antib iotic group and interval to the intervention.None of the proportions were significantly different.although.given the small numbers in each subgroup.there wou ld be limited power to detect even major differences in incidence.Course i n hospital: As shown in Table 6.Lhe median number of clays of fever was one clay in the dexamethasone group and 1.5 days in the placebo group (P>0.05).Fewer chi ldren in the dexamethasone group had prolonged primary fever-three (6%) compared with eight (16%) in th e placebo group (P<0.01).The incidence of secondary fever was similar in both groups.
No s ignificant differences were obsenred between the groups in the incidence of electrolyte abnormalities, hyperglycemia or hypertension .The percentage of children whose stools were positive for occull b lood were 29 and 23%, respectively.One child in the dexamethasone group developed gastrointestinal bleeding with duodenal perforation on the second hospital day .This child had no antecedent history.no family history and no findings on physical exan1ination that would have suggested that she was at increased risk for gastrointestinal b leeding.One child in the placebo group had r KING eta!The median length of stay in hospital was eight days for both groups (range seven to 40).

DISCUSSION
Early studies of the use of dexamethasone in children with bacterial meningitis suggested lack of efficacy (30.31) but animal studies confirmed ils anti-inflammatory effect in meningitis (13)(14)(15)(20)(21)(22).Before the start of this study two trials conducted at the same centre found a beneficial effect of dexamethasone on hearing loss after meningitis ( 16).However. in those trials the rate of hearing loss was high compared with previous studies (32)(33)(34).Based on the animal studies dexamethasone would more likely be expected to be beneficial if given early and.preferably, before administration of antibiotic (20 .21).However.antibiotics are frequenUy administered to children before the diagnosis of meningitis has been made and, therefore, the clinician must decide whether dexamethasone would be beneficial after the administration of antibiotic.This study was conducted to determine whether dexamethasone given within 24 h of antibiotic administration would decrease hearing loss and neurological sequelae after meningitis.No benefit was observed in long term sequelae.
This study was stopped early on the recommendation of the steering committee because of a conflict between research and clinical practice.As approved by each of the participating centre's institutional ethics review board, children were enrolled after informed consent was obtained.Since antibiotics were a lways started as soon as meningitis was diagnosed , but the study drug was given after specific consent for the study was obtained, a time interval was necessary between administration of antibiotic and study drug.During the present study the results of another simil ar randomized controlled trial of dexamethasone in meningitis were published (19).Many clinicians were con-vincecl that if steroids were to be given they shou ld be given early.wh ich is the recommendation of the American Academy of Pediatrics (23) .Therefore.continuation of the present study wou ld have meant delay in the administration of steroids, which wou ld have been in con fli ct with the new standard clinical practice.
The role of dexamethasone in children with meningitis remains controversia l (23 .24).In two subsequent randomized conlrollecl tria ls.one supported ( 18) and the other refuted (19) the benefit of dexamethasone.Two factors that may have contributed to the di fferences in results among studies are the timing of administration of dexamethasone and varying etiological bacterial agents over lime.The present study differed from others in that the antibiotic was changed from a third-generation cephalosporin to penicillin or ampicillin if a penicillin-or ampicillin-sensitive organism was identified.This management difference is unlikely to have had an impact on the effect of steroids.since any effect of steroids wou ld likely have occurred early.before the change in antibiotic.
In this study the median lime between antibiotic and clexameU1asone administration was 11 h .with only eight of the 50 cases in the dexamethasone group receiving dexamethasone within 4 h.In the four trials reporting efficacy, dexamethasone was given immediately before antibiotics in two (17,18) but the interval was not reported for the other trials (16).In the trial reporting lack of benefit, dexamethasone was administered within 4 h (19).When hearing was assessed within 24 h of admission hearing loss was found fre-quenUy to be an early event (19).This is consistent with previous literature on hearing loss in meningitis (35,36).In the eight-year period over which these trials were conducted (1984 to 1992).U1e introduction of the H iryl.uenzae type b (Hib) vaccine has resulted in a decreased incidence of Hib disease (37).In early trials the proportions of cases clue to H injl.uenzae were 77 to 78% (16) and in recent trials 56 to 58% (17 -19).CurrenUy U1e proportion of cases clue to H ir!fl.uenzae is even lower and, therefore, generalizing the results of these studies to current practice must be done with caution.
Given the potentially life-threatening adverse complication of gastrointestinal bleeding in up to 2% of dexamethasone recipients in these trials without any observed evidence of benefit of therapy, there is no basis for administering dexamethasone after intravenous antibiotics have been started.The power of this study is limited and a larger randomized controlled tria l would be necessary to determine the relative efficacy of dexamethasone before and after antibiotics.In the face of a decreasing incidence of disease due to H injl.uenzae such a u;al is probably not feasible.A meta-analysis of the trials to date may be useful in evaluating the relationship between the lime of administration of dexamethasone and efficacy in reducing hearing loss and neurological sequelae .
CAN J INFECT DIS VOL 5 No 5 SEPTEMBER/OCTOBER 1994 CAN J INFECT DIS VOL 5 No 5 SEPTEMBER/OCTOBER 1994 Dexamethasone therapy for bacterial meningitis

TABLE 1
Characteristics of the study patients on admission by treatment group Hea~ing impairment was defined as mild if the auditory threshold was 21 io 40 dB.moderate if 41 to 70 dB.severe if 71 to 90 dB and profound if greater than 90 dB.The diagnosis of sensmineural hearing loss was based on the results of at least two hearing evaluations .

TABLE 2
Laboratory characteristics of the study patients by treatment group 'Means are given± SO pineal tumour (on e) and other bacterial causes of meningitis (five), including Esche richia coli (two) , salmonella (one).en lerobacier (one) and H injlltenzae non type b (one).During the study period 12 eligible children were inadverten Uy missed.nine parents refused consent and . in two cases, U1e treating physicians refused because they wanted to treat with dexamethasone.Of the remaining l 0 l patients, 50 were assigned to the dexamethasone group and 51 to the placebo group .Clinical and laboratory features: The two groups of patients were similar in age, sex and race (Table

TABLE 3
Sequelae in study patients by treatment group D Dexamethasone; P Placebo ingitis.All ch ildren with equivocal or abnormal initial assessments had at least one fu rther assessment.Five children in each group h ad h aring loss with moderate to severe losses in five cases -two in the dexamethasone group and three in the placebo group.One child in each group required a hearing aid .

TABLE 5
Outcome of hearing loss after meningitis grouped by age, empirical antibiotic and time to dexamethasone or placebo