Conditions: Bacterial Meningitis
Keywords: Bacterial meningitis infusion bolus paracetamol
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 375
Healthy volunteers: no

Brief summary:
The main purpose of this trial is to test if mortality of childhood bacterial meningitis can be reduced by slow, continuous infusion of cefotaxime initially, instead of the traditional bolus administration four times daily (qid), combined with high-dose paracetamol orally, when both treatments are executed for the first 4 days. The series will be collected at Hospital Pediátrico David Bernardino, Luanda, Angola.

The recruitment of patients begins, the conditions permitting, in early 2012. The criteria for patient participation is a child at the age of 2 months to 15 years who presents with the symptoms and signs suggestive of bacterial meningitis, for whom a lumbar puncture is performed, and the cerebrospinal fluid analysis suggests bacterial meningitis.

Detailed description:
The principal objective of the study is to examine if mortality of childhood bacterial meningitis can be reduced by slow continuous infusion of cefotaxime combined with high-dose paracetamol orally for the first 4 days (instead of the traditional qid administration of cefotaxime without concomitant paracetamol). Children qualifying for entry (see criteria below), whose guardian has given informed consent,will be randomized into 2 treatment arms (see details below)and receive the treatments in a double blind fashion (see details below). Primary and secondary outcomes (detailed below) will be evaluated according to predefined criteria and time points (see below).

Results will be analyzed for all patients in ITT datasets and in prespecified subgroups (etiology, nutritional status, etc.) in both crude and adjusted analysis. The efficacy results will be expressed as OR with 95% confidence intervals.

Arms:
arm 1: Cefotaxime is administered as 12 hourly infusions, together with high dose paracetamol (acetaminophen) arm 2: Cefotaxime is administered as bolus q.i.d. with a placebo of paracetamol

Interventions: intervention 1: Infusion with paracetamol intervention 2: Bolus without paracetamol
Intervention descriptions: intervention 1: The administration of 250 mg/kg/24 hours cefotaxime during the first 4 days as continuous intravenous infusion, each single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days. intervention 2: The control intervention consists of 250 mg/kg/24 hours cefotaxime administered traditionally with intermittent i.v. boluses and the place bo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.

Protocol document:
Prot_SAP_000.pdf: 
SLOW INITIAL β-LACTAM INFUSION WITH HIGH-DOSE PARACETAMOL TO 
IMPROVE THE OUTCOMES OF CHILDHOOD BACTERIAL MENINGITIS,  
       
          ESPECIALLY OF PNEUMOCOCCAL MENINGITIS, IN ANGOLA  
 
 
 
            
                      Prospective, Randomized, and Double-Blind Clinical Study   
 
                                           “INFU/PARA-BOLU/PLACE”                                                                               
               
                International standard randomized controlled trial number (to be registered) 
 
                                       Heikki Peltola, MD,1  with a Study Group* of   
   
Tuula Pelkonen, MD,2  Manuel Leite Cruzeiro, MD,2  Matti Kataja, PhD,3  Anne Pitkäranta, MD,4   
                                                       and Irmeli Roine, MD5   
 
1 Children’s Hospital, Helsinki University Central Hospital, and University of Helsinki, Helsinki, Finland 
2 Hospital Pediátrico David Bernardino, Luanda, Angola  
3 Institute of Health and Welfare, Helsinki, Finland  
4 Department of Otorhinolaryngology, Helsinki University Central Hospital, and University of Helsinki,     
  Helsinki, Finland 
5 Universidad Diego Portales, Facultad de Medicina, Santiago, Chile 
 
Correspondence with 
Prof Heikki Peltola, MD, DTM& H 
Children’s Hospital, Helsinki University Central Hospital 
PO Box 281 (11 Stenbäck Street)  
00029 HUS, Helsinki, FINLAND 
 
Tel:  +358-9-4717 2702 
Fax: +358-9-4717 4708  
E-mail: heikki.peltola@hus.fi 
________________________________________________________________________________ 
APPENDICES  
 
1.  Glasgow Coma Scale 
 
 
 
2.  Blantyre Coma Scale 
 
3.  Bayesian Luanda Score (includes also data for Simple Luanda Score) 
 
4.  Modified Glasgow Outcome Scale 
 
               5.  INFU/PARA - BOLU/PLACE follow-up sheets: 
    
5a: Admissão 
    
5b: Escala de coma de Glasgow & Blantyre  
   
5c:  Tratamento 
 
5d:  Laboratório e seguimento clínico 
 
5e:  Avaliacão do curso clínico 
    
5f:  Avaliacão e seguimento de sequelas 
 
6.  Informed Consent Form/Consentimento informado 
________________________________________________________________________________________ 
 
* The author names and order will likely change in different publications  
 


 
2
Summary of the Trial Protocol 
 
The main purpose of this trial is to test if mortality of childhood bacterial meningitis (BM) can be 
reduced by slow, continuous infusion of cefotaxime initially, instead of the traditional bolus 
administration qid, combined with high-dose paracetamol orally, when both treatments are executed 
for the first 4 days. The series will be collected at Hospital Pediátrico David Bernardino, Luanda, 
Angola.  
 
The recruitment of patients begins, the conditions permitting, in early 2012. The criteria for 
patient participation is a child at the age of 2 months to 15 years who presents with the symptoms 
and signs suggestive of BM, for whom a lumbar puncture is performed, and the cerebrospinal fluid 
(CSF) is cloudy, positive by Gram staining or latex agglutination, or shows at least 50 leukocytes 
per mm3.  
  
 
 
 
Introduction 
 
Although large-scale vaccinations have virtually eliminated severe Haemophilus influenzae type b 
(Hib) infections from children in many parts of the world – albeit less so in the less privileged 
regions1 –, BM remains a major issue globally. Hib2 and pneumococcal3 conjugate vaccines can 
potentially prevent meningitis, but neither vaccine is much used in countries with limited 
resources.1,4 New (and expensive) antimicrobials have not improved the prognosis. Various other 
approaches5-9 are too costly to be used for most children with BM. High prevalence of HIV 
infection in countries adds to the gloomy prognosis of BM. Today, pneumococcal meningitis,4,10 the 
most deleterious type of childhood (and adulthood) BM, is of even greater relevance than before. 
 
 
 
Dexamethasone 
 
Thanks to some favorable biochemical effects in damping the host’s inflammatory response,11,12 
adjuvant dexamethasone has gained much attention, until the first sufficiently powered randomized 
trials proved it rather useless in childhood BM.13,14  In adult patients, though not in all studies,15 
dexamethasone has shown a salutary effect.16,17 Importantly, a large meta-analysis18 which used the 
individual patient data from 2029 subjects (of whom 833 children) from five trials confirmed the 


 
3
negative results; dexamethasone did not reduce death or neurological or audiological disability in 
children. The much-cited Cochrane analysis,19 in which dexamethasone is recommended in “high-
income countries”, is of minor relevance, because it totally neglected the single most important 
prognostic factor, the child’s presenting status.20,21 With this handicap, the conclusions became 
genuinely skewed.  
Of special concern are the data accumulating from a series of animal experiments and 
human autopsy studies which suggest that dexamethasone, not only being useless, likely harms the 
child with BM. In pneumococcal meningitis of rabbits, a single dose of corticosteroids potentiates 
neuronal toxicity in the dentate gyrus of hippocampus (a structure critical for memory function) rich 
in corticoid receptors.22 In an infant rat model, dexamethasone increases hippocampal cell injury, 
reduces learning capacity,23 and does not prevent hearing loss better than saline.24 As up to 90% of 
children with BM present with high serum cortisol levels,25 adding exogenous steroids, and thus 
potentially increasing the vulnerability of neurons possessing a high concentration of corticosteroid 
receptors,26 may be deleterious. This risk could, at most, be taken if the clinical benefits of 
dexamethasone would have been shown in a sufficiently-powered, randomized clinical study. This 
has not yet happened in childhood BM. 
  
 
 
Glycerol 
 
The potential of glycerol (glycerine, 1, 2, 3-propanetriol), a naturally occurring trivalent alcohol and 
an essential compound of the human cell-membrane, was studied in a large (N 654), prospective, 
randomized, four-arm, double-blind study in six countries of Latin America.14 The causative agent 
was identified in 74 % of cases, Hib, pneumococci, and meningococci being the three most 
common bacteria. Severe neurological sequelae (SeNeSe) were reduced by glycerol (OR 0.31; 95% 
CI 0.13-0.76; P=0.010), slightly less by the dexamethasone-glycerol combination (OR 0.39; 95% CI 
0.17-0.93, P=0.033), whereas dexamethasone failed to reach significance.  
 
When neurological sequelae and death (which may form a continuum)27,28 were 
examined together, again, glycerol proved effective (OR 0.44; 95% CI 0.25-0.76; P=0.003), the 
dexamethasone-glycerol combination did worse (OR 0.55; 95% CI 0.32-0.93; P=0.027), and the 
dexamethasone-only group did not reach significance. Aetiology did not affect the outcomes, nor 
did the timing between dexamethasone (or glycerol), and the institution of antimicrobial - not even 
in Hib meningitis. 14 


 
4
 
Although neither adjuvant (or their combination) prevented hearing loss,21 glycerol 
protected the children from SeNeSe so effectively14 that we deem it unethical not to use it in 
childhood BM. Therefore, in this trial, oral glycerol is administered routinely to all participants. 
Glycerol likely works by more than one mechanism, but essential is the quick increase in plasma 
osmolality.29 This improves rheology and contributes to improved cerebral circulation and brain 
oxygenation. Osmotic diuresis is of less importance, because urine output does not increase with the 
doses (6 ml/kg/day) used here.14,29 
 
 A recent study on adult meningitis patients in Malawi did not support the use of 
glycerol.30 However, glycerol in that trial was administered probably in too large quantities, and     –  
most importantly – too long (4 days).31 Glycerol must be discontinued after 48 hours; otherwise its 
effects will reverse.32,33 Of note is the finding from our own study in Angola:34 all children received 
glycerol, and SeNeSe developed less frequently (15%) than had been the case earlier (24%) in the 
same hospital. Convulsions were not associated with the use of glycerol. These findings fully 
agreed with those deriving from children in Latin America.14      
   
 
 
Non-steroidal anti-inflammatory drugs 
 
Paracetamol (acetaminophen, N-acetyl-p-aminophenol), disputably considered a non-steroidal anti-
inflammatory drug (NSAID), is used widely as an antipyretic, analgesic, and anti-inflammatory 
drug. Paracetamol is the most widely used antipyretic worldwide, because it is effective, safe, 
inexpensive, and available in different forms (syrup, tablet, effervescent, suppository and 
intravenous injection). It is suitable for all ages, and the effect is dose-dependent. There are only a 
few contraindications to its use (infrequent allergy). Hepatotoxicity has been described in adults, 
but in children, it is exceedingly rare.35 A placebo-controlled trial confirmed the safety in infants 
and children.36 In Plasmodium falciparum malaria – an important disease to be distinguished from 
meningitis in the tropics – paracetamol ostensibly prolongs parasite clearance time,37 but this 
finding only reflects delayed parasite development.38 Interestingly, paracetamol lowers antibody 
responses in childhood vaccinations.39 
 
 
Potential of NSAID’s to improve the prognosis of bacteremic infections 
NSAIDs relieve the host’s inflammatory response40 (demonstrated e.g. by lowering cytokine 
concentrations). The mechanisms are not well understood, but NSAIDs dampen inflammatory 


 
5
reactions other than those mediated by inhibition of arachidonic acid metabolism.41 There are, 
however, differences between paracetamol and the other NSAIDs. While most NSAID’s inhibit 
cyclooxygenase enzyme (COX) in periphery, paracetamol inhibits also COX342 which is not seen 
outside the central nervous system. Furthermore, the COX enzymes are highly active only when 
appropriately oxidized, and since paracetamol reduces these forms, the concentration of pro-
inflammatory chemicals are reduced, too.43 
An important observation was made in a retrospective analysis of 809 adult patients 
with bacteremia in Finland:44 Whatever the causative agent of bacteremia - pneumococci, 
staphylococci or Gram negative agents -, patients having received paracetamol survived 
significantly better than those treated with other NSAIDs (a positive trend was observed for 
ibuprofen). Among the 220 patients with”rapidly fatal underlying disease” – classification for gram-
negative bacteremia45 – the case fatality rate among the paracetamol-recipients was 30% vs. 60% 
the non-recipients (OR 0.4; CI95% 0.18-0.67, P=0.001).46 A similar effect was seen in practically all 
subgroups.46,47  Interestingly, ibuprofen – a classical NSAID – did not improve survival in a 
randomized, placebo-controlled sepsis trial.48  
 
 
 
Slow infusion of -lactams 
 
-lactam antimicrobials are “time-dependent” agents whose effectiveness correlates with the time 
that plasma concentration exceeds the minimal inhibitory concentration (MIC).49 Now for some 
years, questions have been raised50,51  if -lactams are used sub-optimally when administered 
intermittently as boluses every 4-6 hours. This strategy triggers massive bacteriolysis and release of 
toxic cell wall components into the blood stream to which the host responds with a fierce 
inflammatory reaction. The great majority of patients are not sufficiently ill to be harmed by this 
inflammation; for them, the way of administration is not an issue. In contrast, the situation is 
profoundly different in life-threatening conditions, such as BM and severe sepsis,.  
 
Low-dose -lactams kill growing bacteria effectively also without major degradation,52 and 
this finding has been applied to the clinical practice. The evidence for the salutary effects of 
continuous -lactam infusion has not overwhelming, but a number of pharmacokinetic and other 
studies favor this approach.53-68 Importantly, lower clinical effectiveness has never been 
reported.65,67 As the -lactam infusion is safe, achieves sufficient tissue levels and sustains 
necessary serum concentrations long,68 allows a reduced daily dose, is cost-effective,58 and may be 


 
6
more active against resistant organisms and might slow the development of resistance,62,66,68  
sufficiently-powered clinical studies are ethically well justified.  
 
 
 
Encouraging results from Angola 
 
In 2005-2008, we carried out a randomized, prospective, double-blind study (2 x 2 factorial design) 
on childhood bacterial meningitis in Luanda, Angola.34 All patients at age 2 months to 15 years 
received oral glycerol and i.v. cefotaxime, but for the first 24 hours, this -lactam was administered 
intermittently qid (50% of patients), or by slow continuous infusion (thereafter qid). A further 
randomization (Fig 1) divided the children to receive high-dose paracetamol or placebo orally. No 
less than 723 children were gathered; most had pneumococcal or Hib meningitis. 
 
  
 
 
 
The key result was that while cefotaxime infusion or oral paracetamol alone did generally 
not much affect the outcomes, a significant reduction in initial mortality was achieved when these 
elements were combined,. The same phenomenon was observed across all etiology groups (Fig. 2, 
“PANEL B” 34). No treatment since chloramphenicol and ampicillin some 50 years ago has shown 
similar effect on mortality of childhood BM.  


 
7
 
 
 
However, this clear effect waned slowly. We had assumed that the deleterious effects of -
lactam (bacteriolysis and, hence, strong inflammation) would mostly be over within a day, but it 


 
8
looks like we probably discontinued the infusion + paracetamol treatment too early. Whatever the 
reason, this finding warrants a further study. If we can confirm the positive effect to be 
longstanding, the finding will benefit all children, also those in the resource-poor settings who have 
no access to expensive treatment modalities. 
 
 
 
Objectives 
 
Principal objective: 
To examine if mortality of childhood BM can be reduced by slow continuous infusion of 
cefotaxime combined with high-dose paracetamol orally for the first 4 days (instead of the 
traditional qid administration of cefotaxime without concomitant paracetamol). 
 
 
Secondary objectives: 
To compare the efficacy of the two treatment modalities in: 
 
1.  A potential reduction of the following outcomes:  
 
a) Severe neurological sequelae (SeNeSe), defined as blindness, quadriplegia/paresis,  
 
 
     hydrocephalus requiring a shunt, or severe psychomotor retardation) or death 
 
b) Deafness (better ear’s hearing threshold >80 dB) 
 
c)  Any adverse outcome 
2.  An improvement on the scale of the Glasgow Outcome Scale 
3.  The subgroup analyses regarding the etiology, disease severity, and the nutritional status. 
 
 
 
Methods 
 
Trial design: 
A randomized, double-blind, parallel-group clinical trial with the patients allocated in a 1 : 1 ratio.  
 
Participants: 
The patients are enrolled in Hospital Pediátrico David Bernardino, Luanda, Angola.  


 
9
 
 
Eligibility criteria: 
The study entry is assessed for all children at age 2 months - 15 years who present at the centre with 
the symptoms and signs suggestive of BM, and to whom lumbar puncture is performed.  
 
 
Inclusion criteria: 
All patients whose cerebrospinal fluid (CSF) turns out to be cloudy, positive by Gram staining or 
latex agglutination, or shows at least 50 leukocytes per mm3, will be enrolled in the study. 
 
 
 
Exclusion criteria: 
1.  Trauma, or relevant underlying illness such as intracranial shunt, previous neurological   
      abnormality (cerebral palsy, Down's syndrome, meningitis) 
2.  Previous hearing impairment (if known) 
3.   Immunosuppression, except HIV infection 
4.   More than one parenteral dose of a pretreatment antimicrobial. Children with oral antimicrobials  
     are included, this information being marked in the FOLLOW-UP sheet. 
5.  Active tuberculosis (if tuberculotic meningitis is diagnosed during trial, it will be included in     
     intention-to-treat (ITT) analysis) 
6. Known hepatic disease. 
 
 
ITT vs. PP datasets 
The patients fulfilling the inclusion criteria and showing no exclusion criterion comprise in the ITT 
dataset. The per-protocol (PP) analysis includes those with one or more of the following criteria: 
 
1.  Positive CSF culture. 
2.  Positive PCR from CSF. 
3. Symptoms and signs compatible with BM, and positive blood culture. 
4. Symptoms and signs compatible with BM, and at least 2 of the following criteria: CSF  
     pleocytosis 100 cells/mm3 (predominantly polymorphs), a positive Gram-stain result, positive  
     latex agglutination test, or serum CRP  40 mg/L14   
 


 
10
 
 
Study interventions 
 
All patients will receive cefotaxime in a dose of 250 mg/kg/24 hours69 for 7 days,34 except in 
salmonella meningitis for which the duration is ≥14 days (because of proneness to relapse).70   
Cefotaxime is chosen because it is a β-lactam that covers most relevant agents, is one of the 
recommended third-generation cephalosporins,71 is pharmacodynamically suitable for infusion 
(recommended also by manufacturer), and was used in our previous trial in Angola.34 It is also 
effective against penicillin-resistant pneumococci.   
 
The general course of  7 days of antimicrobial should not be extended, because even this 
duration is unnecessarily long to sterilize CSF which occurs with cefotaxime in 1-2 days.71 Long 
persisting neck stiffness, fever, subdural effusion etc.72 do not warrant prolongation of antimicrobial 
therapy; these events call for anti-inflammatory, not antibacterial medication.    
 
 
Experimental intervention: 
The administration of cefotaxime during the first 4 days as continuous intravenous infusion, each 
single infusion lasting for 12 hours (to prevent degradation of the agent), combined with high-dose 
paracetamol orally; the first dose is 30 mg/kg, then 20 mg/kg every 6 hours for 4 full days.   
 
The total amount of paracetamol is 90 mg/kg per day during hours 0-24, and 80 mg/kg per 
day during hours 25 - 96 (4 days). Thereafter, paracetamol is discontinued. When the effervescent 
tablet is dissolved in 50 ml of water, the solution contains 10 mg/ml of paracetamol (child of 10 kg 
needs 30 ml of the ready-to-use solution). Paracetamol/placebo is given at the same time with 
glycerol. Which agent is given first, is not considered important.  
 
 
 
NB !  During the first 4 days, no other antipyretic should be used, unless fever continues high 
and/or pain is a problem. To lower high fever, physical means should primarily be used. If 
medication is deemed absolutely necessary, oral ibuprofen with a dose of 15 mg/kg every 12 hours 
is the drug of choice, but the course should be kept as short as possible. All details should be 
marked in the follow-up sheet. After 4 days, paracetamol can be used openly to any child with 
temperature exceeding 39 C.  
 
 


 
11
 
Control intervention: 
The control intervention consists of cefotaxime administered traditionally with intermittent i.v. 
boluses and the placebo of paracetamol orally, both repeated every 6 hours (qid) for 4 days.   
The allocation and masking of treatments is depicted in Figure 3: 
 
 
Outcomes 
 
The primary outcome is mortality on day 7 from the institution of treatment. All patients should 
stay in hospital ≥7 days. This time frame is twice longer than the duration of the modified treatment. 
 
The secondary outcomes are the following:  
1. 
Mortality on days 14, 21, and 28 from the institution of treatment. 
 
The other secondary outcomes are examined on days 7, 14, 21, and 28.  
2. 
SeNeSe or death 
3. 
Profound hearing loss (defined as the better ear’s threshold >80 dB) 
4. 
Status on the modified Glasgow Outcome Scale73 (see Appendix) 


 
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5. 
Death or any neurological sequelae (SeNeSe, hemi- or monoparesis, ataxia, or psychomotor 
 
retardation of any degree), or any hearing impairment. Hearing is deemed impaired if 
 
the better ear fails to detect a threshold of 40 dB. The cut-off levels for moderate and 
 
severe hearing impairment are 60 dB and 80 dB, respectively. 
6. 
A change in hearing threshold compared to the first test result 
 
 
 
Sample size  
 
Assuming in confirmed meningitis a 13% decrease (from 27% to 14%, based on our experience 
from Angola) in mortality,34 and accepting a 5% error after adjustment for multiple testing in one-
tailed test with a power of 80%, at least 165 patients are required in both arms (CTX-BOLUSES + 
ORAL PLACEBO vs. CTX-INFUSION + ORAL PARACETAMOL). Because several confounding factors, 
such as dissimilar age, severity on admission, malnutrition, malaria, are to be included in the 
adjusted efficacy calculations, we intend to enrol 400 patients.  
 
It is possible that one treatment will be significantly better than the other. Therefore, an 
external Data Safety Monitoring Board (DSMB) obtains the 7-day results after each 100 patients 
have been evaluated. If an indisputable significance between treatments will be found, DSMB shall 
interrupt enrolment for ethical reasons. 
 
 
 
Randomization (Fig. 3, p. 11) 
 
Sequence generation  
A randomization sequence is accomplished by uninvolved persons for 500 patients by means of a 
computer generated list of random numbers in blocks of 20. The patients are allocated 1:1 to one of 
the two alternative treatments. The code is kept in a sealed envelope, a copy being sent to DSMB 
for the interim analyses. For emergency purposes, the key for opening the code is kept sealed also 
in Helsinki. 
 
 
Allocation concealment  


 
13
Numbered and sealed envelopes, each disclosing the specific treatment, are kept in a box in the 
institution. 
 
 
Allocation implementation 
Once a patient is included into the study by the attending physician, an auxiliary person, who does 
not otherwise participate in the study, takes the next sealed envelope, prepares cefotaxime and the 
placebo as ordered by the card, and gives both preparations for 96 hours (4 days). The assignment 
of any given patient into one of the treatment groups is not known beforehand by the auxiliary 
person who prepares the antimicrobial(s) and paracetamol/placebo(s).  
 
  
 
 
 
Blinding (masking) 
 
To mask the experimental vs. control interventions, all children receive both an infusion and a bolus 
treatment for the entire 4-day course (see page 11). Since the ready-to-use cefotaxime is slightly 
yellowish liquid, yellow i.v. linesBecton-Dickinson GmbH, Art.No. 300326, black 50 ml syringesB Braun, Ref No 
8728828F, are used with a foil covering on the 3-way stopcock’s B Braun Smallbore T-Port Extension Set, Ref No 
471954 short end which leads to the skin-penetrating needle (for boluses). This setup allows the use of 
the same one line for the antimicrobial and placebo administrations, each always given as infusion 
or boluses. 
 
 
Placebo preparations 
Since black syringes and yellow i.v. lines are used, saline is an appropriate placebo preparation for 
cefotaxime, no matter whether administered as infusion or boluses. Since paracetamol effervescent 
tablets are used, regular drinking water serves as its placebo. Once bubbles have disappeared, the 
practically tasteless solution looks like plain water. Each tablet (Panadol®) contains 500 mg of 
paracetamol. Dissolved in 50 ml of water, the solution contains 10 mg/ml of paracetamol (child of 
10 kg needs 30 ml of the ready-to-use solution). Paracetamol/placebo(s) is given at the same time 
with glycerol. 
 
 
 


 
14
 
 
Statistical methods, analysis plan 
 
Comparability of the study groups prior to therapy will be checked by Student’s t-test, whereas chi-
square test is applied to the qualitative variables.  
 
 
Primary (crude, unadjusted) analyses 
The primary endpoint (mortality on day 7), and the secondary endpoints are examined by using 
Fisher’s exact test (because of directed hypothesis). The extent of the potential decrease in mortality 
by the experimental intervention is measured with logistic regression, and the results are expressed 
as risk ratios (RR) with 95% confidence intervals, both for the ITT and PP datasets.  
 
The time of death from the institution of therapy is registered, and a survival analysis 
between groups is done. Kaplan-Meier analysis assesses mortality, whereas Fisher’s exact and sign 
tests are used when analyzing the time of death.  
 
All data are analyzed with StatView (version 5.1), and the trial will be registered in the 
International Standard Randomized Controlled Trial Number Register (ISRCTN). 
 
 
Adjusted efficacy analyses 
Multiple logistic regression is used when testing the influence of various known (severity of 
disease, age, malnutrition, malaria, etc.) and likely unknown variables in the crude efficacy ratio. If 
a confounding variable is detected – e.g., once included in analysis, the crude efficacy ratio changes 
≥ 10% –, the adjusted efficacy ratios are calculated for each endpoint by combining all confounding 
variables with the treatment variables. Should some data be missing (which would drop the case 
from logistic regression), Bayesian multivariate analysis is used.  
 
 
 
Subgroup analyses 
Subgroup analyses, for both crude (unadjusted) and adjusted efficacy, are needed because of 
potential heterogeneity in the treatment effect due to dissimilar patient and etiological 
characteristics. Provided the series is large enough, the subgroup analyses will likely cover  
 


 
15
a) Severity of disease, using different gradings of the Glasgow Coma Scale 
b) The causative agents: S. pneumoniae, H. influenzae, N. meningitidis, and other agents 
c) The nutritional status, using the z-score grading of “normal” weight/age (+1 to -1),      
    “malnourished” (below -1), and “severely malnourished” (below -3)74  
d) The child’s HIV status 
e) Time of death   
f) Different categories identified by the indices of inflammation or sequential CRP determinations 
g) Sickle-cell disease 
 
 
 
Sequential analysis   
The statistician of study group, permanently located in Finland, will get regularly the core result  
data and analyse the mortality in the sense of sequential analysis.75  
 
 
 
Supplementary analysis   
Since a very similar study will be carried out in Santo Domingo, Dominican Republic, the data will 
be examined also combined, provided the results are in the same direction. Were this the case, the 
statistical power of the results would increase considerably. 
 
 
 
Other medications and management 
 
Glycerol  
Because 85% glycerol proved so beneficial in Latin-America,14 its omission would raise ethical 
questions. Therefore, it is given to all patients in a quantity of 6.0 g (6.0 ml) per kg/day divided in   
4 equal daily doses ad 25 ml per dose. If it induces vomiting (rare), a nasogastric tube is inserted, 
and the same dose is repeated immediately. Glycerol is given for 2 days [8 doses 1.5 g/kg (1.5 
ml/kg) ad 25 g (25 ml) per dose]. Some authors recommend giving glycerol chilly. An old report76 
tells how best to disguise the slightly sweet taste: “Orange juice immediately before and after 
glycerol leaves virtually nothing but the taste of orange.”  
 


 
16
 
 
Dexamethasone 
For reasons explained before,14,18,21 dexamethasone is not used in this study. Notably, the Ethics 
Committee in Luanda did not approve its use in our previous meningitis study in Angola.34    
 
 
 
Convulsions  
Seizures are treated as usual in each center. Paraldehyde is often used with a dose of 0.2 ml/kg 
intramuscularly; the dose can be repeated at least once. In Malawi, intranasal lorazepam 100 µg/kg 
has proved very useful.77  
 
 
 
 
 
 
Malaria 
In many tropical regions malaria is a major disease to be distinguished form BM. It is diagnosed 
and treated as is the practice in the institution.  
 
 
HIV infection 
All efforts will be done to materialize HIV-testing for all participants, and the test results should be 
marked in the FOLLOW-UP sheet. HIV infection is treated according to the lines of each institution.  
 
 
Fluid therapy 
Most children with meningitis have alterations in their fluid and electrolyte homeostasis, which may 
lead to death, if not corrected in time. Capillary leak because of sepsis and shock add to the 
problems.  
More children suffer from fluid depletion than overload.78,79 In spite of overwhelming 
reasons for hypovolemia, many children are still deemed to have the Syndrome of Inappropriate 
Antidiuretic Hormone secretion (SIADH),80,81 because hyponatremia, hypernatriuria (U-Na >20 
mmol/l), and high plasma arginine-vasopressin (ADH) are found in more than 50% of children with 
BM. Thus, ‘SIADH’ is considered the cause of free-water retention, hypo-osmolality and 
hyponatremia. Then, death is explained by fluid overload, hyponatremia and oliguria, which 
worsened the intracranial pressure. With this reasoning, fluid restriction to two-third of normal 
maintenance was previously recommended.82  


 
17
However, clinical evidence has not supported fluid restriction,83 because, actually, an 
increased ADH level is probably a very appropriate response to hypovolemia; the ADH levels 
return to normal when fluids are administered rather freely.84 Elevated plasma ADH represents a 
compensatory mechanism to overcome raised intracranial pressure and to maintain adequate 
cerebral blood flow.85 This in turn depends on the main arterial pressure, which is adversely 
affected by hypovolemia. Therefore, restriction of fluids can be dangerous, and might enhance 
cerebral ischemia. In experimental meningitis, fluid restriction did not relieve brain oedema,86 but 
lowered the blood pressure, cerebral blood flow, and increased the CSF lactate concentration 
(suggesting increasing hypoxia).87 Prospective, randomized clinical study in India showed that, 
instead of being beneficial, fluid restriction was harmful;88 children with reduced extracellular 
volume (10 ml/kg or more) within first 48 hrs had significantly lower intact survival. This 
experience is further corroborated by another randomized trial from Papua-New Guinea.27  
Fluid restriction affects cerebral edema minimally (if at all) and, if pursued to excess, 
may induce hypotension and cerebral hypoxia, and then, further increase intracranial pressure. 
Normal maintenance fluids with isotonic crystalloids are justified. Widely used 50% Darrow or 
Ringer fluid, with added glucose (5%), are appropriate fluids for this purpose. If the patient is 
hypovolemic (dry mouth, tachypnea, sunken eyes, or shocked), fluid replacement will be rapid 
according to WHO shock and severe dehydration protocols. 
Monitoring of the hydration status, intravascular volume, electrolytes, and osmolality 
are the guides for fluid management, with the aim of maintaining normovolemia, iso-osmolality and 
normal blood pressure - and thereby adequate cerebral perfusion. Glycerol probably adds to these 
positive effects.29  Monitoring of serum glucose 3-4 times a day is mandatory, resources permitting, 
for unconscious patients, because  severe hypoglycemia is one of the insidious risks during the 
acute phase of meningitis. Monitoring of the hydration status, intravascular volume, electrolytes, 
and osmolality are the guides for the fluid management, aiming at maintaining the normovolemia, 
iso-osmolality and normal blood pressure – and thereby adequate cerebral perfusion.  
 
 
Blood transfusion 
A 10 cc/kg of transfusion of packed red blood cell (in two parts, if deemed necessary) will be 
administered to all children with an admission hemoglobin of <5 g/dL. If the child is in a poor 
condition, a transfusion may be given when the hemoglobin is higher, e.g.  <6 g/dL.  
 
 
 


 
18
 
 
Data collection and samples taken during hospital stay 
 
Data collection 
All data will be collected with the 3 forms (APPENDICES) which were modified from those we used 
previously.14,34 Hence, comparable data on the history of patient, presenting status, and the course 
and outcomes of illness will be obtained. At discharge, the forms are e-mailed to the Study 
Coordinator, the original data being kept at the centre. The results from the check-up are sent later.  
 
 
Disease severity 
The severity of disease is graded by the Glasgow Coma Scale (adjusted for age), the Blantyre 
Coma89 and the Bayesian Luanda and the Simple Luanda Scales (APPENDICES).90  
 
 
 
 
Audiology 
Special attention is paid to measure hearing at presentation, and on days 7, 14, 21, and 28. The 
child’s cooperation permitting, traditional pure tone audiometry is preferred, but this is rarely 
possible. Hence, brain stem evoked response audiometry (BERA, ABR, BSA) is the main method 
used in this study. The equipment (Madsen Octavus, Windows XP/2000 compatible) will be 
provided.  
 
Otitis media or other benign reason for reduced hearing should be excluded with pneumatic 
otoscopy or tympanometry. If impairment is likely/confirmed, the child will be retested a few 
months later. All test documents are sent to an audiology expert who is kept blinded from other 
patient details. Three threshold levels, 40 dB (mild impairment), 60 dB (moderate impairment), and 
80 dB (severe impairment, social deafness) are used. The data are given for the better ear and both 
ears separately. 
 
 
Samples 
 
CSF 


 
19
A CSF sample is taken on admission, and if needed, preferably after 12 or 24 hours (precisely) from 
the institution of antimicrobial. The sample should be cultured immediately on fresh blood and 
sugar agar plates. Good-quality plates ready should be kept on site, and by letting the first CSF 
drops to fall directly onto the plates.  
Conditions permitting, a CSF sample (≥1 ml) for further analyses should be kept at       
-20 °C. Because the agent may later be identified by PCR, a CSF sample should always be collected 
also on a filter paper strip91 (circles throughout moistened with CSF). The strips, provided by the 
study, are left to dry in room air, placed in an envelope and sent to Finland by regular mail. 
Resources permitting, the isolated bacterial strain is lyophilized. All samples must be clearly 
marked with the name, date, and the time of the day, using deep freeze-resisting ink.  
Routine biochemistry and cytology are done as routinely. Resources permitting, 
inflammatory mediators, mycobacteria and viruses are investigated (details in Sub-study protocols). 
 
 
 
Serum, urine, and saliva 
A 4-5 ml sample of blood is collected on admission for basic hematological and biochemical 
determinations (such as hemoglobin, blood-leukocyte and platelet counts, glucose concentration,  
electrolytes), CRP and/or serum procalcitonin with other inflammatory mediators, malaria parasites, 
and testing for HIV and sickle-cell disease. A few drops of serum (or blood) should be collected on 
filter strips. The same procedure applies to saliva samples, too, because those render possible 
examining the inflammatory mediators. Urine analysis and tuberculin test by the Mantoux 
technique are done as is the routine of the institution.   
 
 
 
Check-up samples during medications 
Besides potential second CSF sample at 12 or 24 hours, monitoring of blood glucose 2-4 times per 
24 hours is highly desirable especially for patients with lessened consciousness. Severe 
hypoglycaemia is an under-recognized risk in the acute phase of meningitis. For easy measuring, a 
handy gadget (Contour, Bayer) is provided.  
 
The only check-up blood sample, appr. 3 ml, is taken on day 4 (1) from the institution of 
therapy. From this specimen, plasma hemoglobin, CRP and/or procalcitonin are measured. A serum 
(or blood) sample should also be collected on filter strips for later determination of a set of other 
inflammatory mediators. Urine and saliva samples are an option. 


 
20
 
Serial serum CRP measurements are very useful in monitoring the course of illness. Ideally, 
CRP is measured (from a finger-prick) every 24 hours, 5 times in total (days 1-5), beginning on 
admission. At least CRP should be measured on admission and on day 4 from the institution of 
therapy. 
 
 
 
Follow-up visits 
 
All randomized patients should stay in hospital for at least 7 days to be included in the survival 
dataset. Thereafter, the participants will be discharged according to their clinical condition.  
 
A control visit on day 21 (±2 days) from the institution of therapy, unless the child is still in 
hospital, is of paramount importance. And especially so is the case if any hearing, neurological, or 
other abnormality was found before. Special attention is paid to all potential short- or long-term 
sequelae, whatever their nature. The follow-up sheet is filled, using also the Modified Glasgow 
Outcome Scale. 
 
 
 
Launch and duration of study, registration 
 
The study is launched in early 2012, once the ethics committee has approved the protocol. One can 
expect the enrolment to last approximately three years. The enrolment ends once 400 patients have 
been gathered, or five years have elapsed. The study will be registered in an international register. 
 
 
 
Persons in charge, publication politics, and the study group meetings  
 
Drs Tuula Pelkonen and Manuel Leite Cruzeiro are the Principal Co-investigators, headed by Prof 
Luis Bernardino. These persons have the right to make all decisions, such as to change the 
antimicrobial in case of resistance to cefotaxime and, in emergency, to open the code. Dr Irmeli 
Roine is the General Study Coordinator, whereas Prof Heikki Peltola is the Director and Scientific 
Advisor. Dr Matti Kataja is the statistician, whereas Prof Anne Pitkäranta is the oto-audiological 


 
21
consultant. All data will be published as collaborative papers at a national and international level. - 
Resources permitting, meetings of the Study Group are organized annually.  
 
 
Ethical issues 
 
Informed consent 
The protocol and the informed consent form should be approved by the relevant ethics committee. 
The Helsinki and Tokyo Declarations will be followed. Before a child enters the study, the 
attending physician describes the study to the legal guardian, asks him/her to read the Informed 
Consent, and addresses all potential questions. If the guardian agrees the study, he/she should sign 
the form. Only children with a signed consent enter the study. If the guardian is illiterate, the text is 
read to him/her. Then the guardian may express his/her acceptance with a finger-mark or by 
drawing a cross in the consent form. If participation is refused, the child is treated as is the routine 
of hospital. 
 
 
Data Safety Monitoring Board, DSMB 
DSMB comprises 3 experienced scientists, Professor Markku Koskenvuo (epidemiologist, 
University of Helsinki), Docent Marjo Renko (pediatric infectious disease specialist, University of 
Oulu), and Docent Terho Heikkinen (pediatric infectious disease specialist, University of Turku). 
As the Board’s responsibility is to follow-up the study from the scientific and ethical points of view, 
it has an access to the treatment code at any time. Dr Roine keeps the study group up-to-dated of the 
trial’s status.  
 
Not being involved in the treatment, Dr Kataja (statistician) is the only person in the study 
group who is familiar with the treatment of each patient. By sequential analysis, conditions 
permitting, he checks the situation every weekend, or at least, after each 100 patients have entered 
the study. If a crude significance appears between groups, he immediately contacts DSMB to 
discuss if the trial should be terminated because of ethical reasons.   
 
The Ethics Committee has to be informed biannually about the progress of the study, and can reunite 
always when considered necessary 
 
 
Jan 21, 2012 
 


 
22
 
Heikki Peltola, MD, Professor 
 
 
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26
 
 
 
 
 
 
 
APPENDIX 1          
 
                                                             GLASGOW COMA SCALE  
 
 
                                  Infants and children <2 yrs                     Older children  
______________________________________________________________________________ 
 
Eye opening 
 
 
  
Spontaneous 
4  
Spontaneous                        
  
To verbal stimuli   
3 
To verbal stimuli  
 
 
  
To pain only 
2 
To pain only  
 
  
No response 
1 
No response  
 
 
 
Verbal response 
Coos and babbles 
5 
Oriented, appropriate  
 
  
Irritable, cries 
4 
Confused 
 
 
 
  
Cries to pain     
3 
Inappropriate words  
 
  
Moarns to pain 
2 
Incomprehensible words 
 
           
 
 
                     or nonspecific sounds  
  
 
  
No response 
1 
No response  
 
 
 
Motor response 
Moves spontaneously 
   6 
Obeys commands 
 
  
 
 
 
and purposefully 
  
 
  
Withdraws to touch 
   5 
Localizes painful stimulus             
          
 
  
Withdraws in response to pain  4 
Withdraws in response to pain 
  
 
  
Decorticate posturing* in       3 
Flexion in response to pain 
  
response to pain  
  
 
                                        
Decerebrate posturing** in     2 
Extension in response to pain 
  
response to pain  


 
27
  
  
No response 
    1 
No response 
________________________________________________________________________________ 
 * abnormal flexion          ** abnormal extension 
 
 
 
 
 
 
APPENDIX 2 
 
 
 
                  BLANTYRE COMA SCALE FOR YOUNG CHILDREN [scores from 0 to 5]89 
 
______________________________________________________________________________ 
 
 
Best motor response 
 Localizes painful stimulus*  
 
 
 
 
2 
 Withdraws limb from painful stimulus** 
 
 
 
1 
 No response, or inappropriate response 
 
 
 
0 
 
Best verbal response 
 Cries appropriately with painful stimulus* or, if verbal, speaks 
2 
 Moan or abnormal cry with painful stimulus  
 
 
1 
 No vocal response to painful stimulus 
 
 
 
0 
 
Eye movement 
 Watches or follows (e.g. mother’s face) 
 
 
 
1 
 Fails to watch or follow 
 
 
 
 
 
0 
___________________________________________________________________ 
 
*   Presssure with blunt end of pencil on sternum or supraorbital ridge 
 
** Pressure with horizontal pencil on nailed, or finger, or toe 
 
 
                
 
                
 
 
 
 


 
28
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 3 a 
 
 
 
                                               BAYESIAN LUANDA SCALE [scores from 0 to 5]90 
 
______________________________________________________________________________ 
 
                                   
           Variable 
 
 
Electricity at home 
 
 
 
Yes 
 
 
□  
  
No    
 
 
□ 
 
Days of illness 
 
≤3 
 
 
 
□ 
 
 
 
4-7 
 
 
 
□ 
 
 
≥8 
 
 
 
□ 
 
Convulsion at home 
  
No 
 
 
 
□ 
  
Yes, focal 
 
 
□ 
  
Yes, generalized  
□ 
 
 
Consciousness 
  
Normal 
 
 
 
□ 
  
Altered 
 
 
 
□ 
  
Coma 
 
 
 
□ 
 
Dyspnoea 
  
None or slight 
 
 
□ 
  
Moderate 
 
 
 
□ 
  
Grave 
 
 
 
□ 
 
Blood glucose on admission, mg/dL (lowest value) 
  
      -40 
 
 
□ 
 
   


 
29
  
41-100 
 
 
□ 
 
 
  
101-120 
 
 
□ 
 
 
  
121- 
 
 
□ 
 
 
 
 
 
 
APPENDIX 3 b 
 
 
 
                                               SIMPLE LUANDA SCALE [scores from 0 to 10]90 
 
______________________________________________________________________________ 
 
 
Electricity at home 
  
Yes 
0 
  
No    
2 
  
Unknown 
1 
 
Days of illness 
  
≤3  
0 
  
4-7  
1 
 
≥8  
3 
 
Convulsion on admission 
  
No  
0 
  
Yes, focal 
1 
  
Yes, generalized 
2 
  
Unknown 
1 
 
Consciousness 
  
Normal 
0 
  
Altered 
5 
  
Coma 
10 
  
Unknown 
1 
Dyspnoea 
  
None or slight 
0 
  
Moderate 
1 
  
Grave 
2 


 
30
  
Unknown 
1 
 
 
 
 
APPENDIX 4             
 
 
 
 
                 MODIFIED GLASGOW OUTCOME SCALE [scores from 5 to 1]73 
____________________________________________________________________________ 
 
 
Death 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
Vegetative state 
 
 
 
 
 
 
 
 
2 
 Unable to interact with the environment  
 
 
 
Severe disability 
 
 
 
 
 
 
 
 
3 
 Unable to live independently (if grown), but can follow commands 
 
    IN SMALL (appr. <2 yrs) CHILDREN: Better ear’s hearing >80 dB, blindness,  
   quadriplegia/paresis, severe psychomotor retardation (does not sit or  
   walk, speak, or establish contact, or requires institutionalization)   
 
 
 
Moderate disability 
 
 
 
 
 
 
 
 
4 
 Capable of living independently (if grown), but unable to go to school 
 
    IN SMALL (appr. <2 yrs) CHILDREN: Better ear’s hearing 61-80 dB, hemiparesis,  
   mild-to-moderate psychomotor retardation 
 
 
 
Mild or no disability  
 
 
 
 
 
 
 
5 
 Able to go to school 
 
   IN SMALL (appr. <2 yrs) CHILDREN: Better ear’s hearing 41-60 dB, ataxia, 
  monoparesis 
 
___________________________________________________________________ 
 
 
 
 


 
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APPENDIX 5 
 
 
          
 INFU/PARA - BOLU/PLACE follow-up sheets in Portuguese (separate sheets): 
 
 
 
5a: Admission 
 
5b: The Glasgow & Blantyre & Bayesian Luanda Scores 
 
5c: Treatment 
 
5d:  Laboratory results, and the Clinical follow-up 
 
5e:  Assessment of the clinical course 
 
5f: Assessment and follow-up of sequelae 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
32
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 6 
 
 
          
          Informed Consent Form (in Portuguese) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
33