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Open AcceStudy protocolProphylactic antibiotic for prevention of posttraumatic meningitis after traumatic pneumocephalus: design and rationale of a placebo-controlled randomized multicenter trial [ISRCTN71132784]Behzad Eftekhar*1, Mohammad Ghodsi1, Azar Hadadi2, Mousa Taghipoor3, Samira Zabihyan Sigarchi4, Vafa Rahimi-Movaghar5, Ehsan Sherafat Kazemzadeh3, Babak Esmaeeli7, Farideh Nejat8, Alireza Yalda6 and Ebrahim Ketabchi1

Address: 1Sina Trauma and Surgery Research Center and Department of Neurosurgery, Sina Hospital, Tehran University, Iran, 2Department of Infectious Diseases, Sina Hospital, Tehran University, Iran, 3Department of Neurosurgery, Namazi Hospital, Shiraz University, Iran, 4Department of Neurosurgery, Ghaem Hospital, Mashad University, Iran, 5Department of Neurosurgery, Khatam-ol-anbia Hospital, Zahedan University, Iran, 6Department of Infectious Diseases, Imam Hospital, Tehran University, Iran, 7Department of Neurosurgery, Hospital, Shahrood, Iran and 8Department of Neurosurgery, Children's Hospital Medical Center, Tehran University, Iran

Email: Behzad Eftekhar* - eftekhar@sina.tums.ac.ir; Mohammad Ghodsi - ghodsism@sina.tums.ac.ir; Azar Hadadi - Hadadiaz@sina.tums.ac.ir; Mousa Taghipoor - taghiporm@sums.ac.ir; Samira Zabihyan Sigarchi - zabihyan@yahoo.com; Vafa Rahimi-Movaghar - v_rahimi@yahoo.com; Ehsan Sherafat Kazemzadeh - sherafate@sums.ac.ir; Babak Esmaeeli - esmailibabak@yahoo.com; Farideh Nejat - Nejat@sina.tums.ac.ir; Alireza Yalda - AlirezaYalda@yahoo.com; Ebrahim Ketabchi - ebrahimketabchi@yahoo.com

* Corresponding author

AbstractBackground: The purpose of this study is to compare the efficacy of prophylactic antibiotic forprevention of meningitis in acute traumatic pneumocephalus patients.

Methods: In this prospective, randomized controlled clinical trial, 200 selected head injury patientswith traumatic pneumocephalus are randomly assigned to receive intravenous antibiotics (2 gramsCeftriaxone twice a day), oral antibiotics (Azithromycin) or placebo for at least 7 days after trauma.The patients will be followed for one month posttrauma.

Conclusion: The authors hope that this study helps clarifying the effectiveness and indications ofantibiotics in prevention of meningitis in traumatic pneumocephalus after head injury and in specificsubgroup of these patients.

BackgroundChemoprophylaxis with antibiotics is both feasible anddesirable for prevention of a potentially serious diseasewhen specific groups at risk can be defined and when asafe, effective, and affordable prophylactic agent is availa-

ble [1]. One of such potentially serious diseases is post-traumatic meningitis. The incidence of posttraumaticmeningitis after head trauma ranges from 0.2 to 17.8 percent and increases significantly in the presence of skull

Published: 18 January 2006

Trials 2006, 7:2 doi:10.1186/1745-6215-7-2

Received: 22 November 2005Accepted: 18 January 2006

This article is available from: http://www.trialsjournal.com/content/7/1/2

© 2006 Eftekhar et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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base fracture, pneumocephalus or cerebrospinal fluid(CSF) leak [2,3].

Considering the serious complications of the posttrau-matic meningitis, the idea of chemoprophylaxis with anti-biotics for prevention of posttraumatic meningitis hasalways been considered rational, but the efficacy of pro-phylactic antibiotic agents in the setting of posttraumaticCSF leakage is still controversial. The contrasting findingsreported by two large studies in which metaanalyses wereconducted reflect the general disagreement and lack ofsufficient power of the previous studies [4-6].

One possible reason for the inability of the previous stud-ies to demonstrate the efficacy of prophylactic antibioticsfor prevention of posttraumatic meningitis might havebeen inconsideration of those subsets of patients withspecific risk factors [5].

With this concept in mind, the authors tried to clarifythose subgroups at risk in two subsequent studies since1994. In the first study done in our hospital (Ghodsi M,Nejat F, Eftekhar B, unpublished data), the efficacy of pro-phylactic antibiotics in head injury patients with skullbase fracture were studied. Although no statistically signif-icant differences were found between those with andwithout prophylactic antibiotics, 12% of patients withskull base fractures had pneumocephalus and the inci-dence of meningitis was considerably higher (20%) inthis subgroup of the head injury patients. In the secondstudy we selected only patients with posttraumatic pneu-mocephalus. The overall meningitis rate in head injurypatients with pneumocephalus was 21.5% [5]. That studyagain did not approve the prophylactic administration ofceftriaxone (2 grams daily) in the pneumocephaluspatients. But it showed that CSF rhinorrhea and intracra-nial hemorrhage might be considered as primary risk fac-tors and in the absence of them, intradural location of airand air volume greater than 10 cc as secondary risk factorsfor developing meningitis in posttraumatic pneumoceph-alus patients [5]. Even in those patients with CSF rhinor-rhea or intracranial hemorrhage, prophylactic ceftriaxone(2 grams daily) did not prove to be effective on preventionof meningitis.

Selection of drugsIn posttraumatic meningitis after traumatic pneumoceph-alus, the microorganisms enter the CSF from the outsidemainly air sinuses. This is the reason why pneumococciare the major causative microorganisms. In order to pre-vent posttraumatic meningitis in pneumocephaluspatients, we should either clear the air sinuses from thepotential microorganisms or make the CSF defense strongenough to control those pathogenic microorganisms thathave passed the blood brain barrier. This simple strategy

has not worked favorably so far. There might be variousreasons. We thought that the dosage of the antibioticsmight have been less than enough due to lack of inflam-mation of the blood brain barrier. So based on the mostcommon microorganisms in microbiological studies ofthe posttraumatic meningitis it has been decided toadminister antibiotics with full antimeningitic dosage (2grams Ceftriaxone twice a day) prophylactically.

Another reason for inability of the previous studies todemonstrate the efficacy of prophylactic antibiotics mighthave been lack of enough coverage of the normal flora ofthe air sinuses. These sinuses should be considered thepotential source of the secondary infection in majority ofcases. In order to cover these, we selected Azithromycin asan oral regimen. Penetration of drugs into the cerebrospi-nal fluid, minimal gastrointestinal side effects, patient tol-erance and cost-effectiveness of medications were otherimportant factors in selection of drugs.

In our previous studies meningitis happened almostalways in the first week post trauma, so both regimens arecontinued for 7 days.

ObjectivesPrimary objectiveThe primary objective of this prospective study is to com-pare the efficacy of prophylactic antibiotics (either intra-venous Ceftriaxone 2 grams BID or oral Azithromycin) forprevention of bacterial meningitis in acute traumaticpneumocephalus.

Secondary objectives- To determine the relative frequency of rhinorrhea andintracranial hemorrhage in each of the IV, O and P groups

- To determine the GCS, age and volume of intracranial airin each of the IV, O and P groups

- To determine if the volume or location of the air affectsthe rate of meningitis.

- To determine the rate of presence and location of theskull base fracture in each of the IV, O and P groups

- To determine the short term (during the treatment) com-plications of the administration of the antibiotics in eachof the IV, O and P groups

- To compare the microbiological findings in meningiticpatients among IV, O and P groups

- To determine the frequency of meningitis caused byresistant bacteria.

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Outcome measuresPrimary outcome measureThe frequency of bacterial meningitis in IV, O and Pgroups

Secondary outcome measures- The frequency of rhinorrhea, intracranial hemorrhageand skull base fracture, volume and location of intracra-nial air in the population study and each of the IV, O andP groups.

- The mortality rate in study population and each of theIV, O and P groups.

MethodsStudy PopulationThe study is intended to be a randomized placebo-con-trolled clinical trial study.

Sample sizeThe frequency rate of meningitis among our traumaticpneumocephalus patients was 21.5% (p1). What weexpect to be an intended (or at least acceptable) effect ofthe prophylactic antibiotics is 5 %(p2) frequency of men-ingitis in the patients with antibiotics. To detect this dif-ference with a sensitivity of 80% and an error probabilityof 5%, at least 62 patients per randomization group willbe required using the following formula:

n = 7.84 * [p1(1 - p1) + p2 (1 - p2)]/[p1 - p2]2

Considering only comparing the placebo group with eachone of the antibiotics group, our sample size should be atleast 186 cases. To account for the possibility of loss to fol-low-up, our estimated sample size is 200 cases.

Ethical approvalThis study has been ethically approved by Sina Traumaand Surgery Research Center, Tehran University.

Inclusion criteriaThe entry criterion to this study is traumatic pneumoceph-alus verified by brain CT scan. The patients should beolder than 15 years old, admitted less than 24 hours aftertrauma and we should be able to start the antibiotics inless than 24 hours after trauma.

Exclusion criteriaThose patients who have received antibiotic therapy forother reasons within the prior 2 weeks, are on corticoster-oids or allergic to the specified medications, individualswith penetrating traumatic brain injury, open skull frac-tures or operated for any causes, those who are dischargedfrom hospital with personal consent, all cases with lifethreatening lesions including severe brain, abdominal or

vascular injuries and death due to other causes will beexcluded from this study.

RandomizationThe randomization list was generated by using the websiteRandomization.com http://www.randomization.com.The permuted block method of randomization for a blocksize of three was used. According to this list patients wereallocated to each of the three groups in the trial: intrave-nous antibiotics, oral antibiotics and placebo.

BlindingSince providing both the antibiotics and placebo in iden-tical containers for participating centers is not practicallypossible for us, this study is not double-blinded.

Study designThe patients should be observed in the hospital, untiloccurrence of meningitis or at least 7 days after trauma. Inthe case of concomitant Cerebrospinal Fluid (CSF) leak-age and need for close observation in the hospital, theywill be hospitalized until recovery from leakage. After dis-charge the patients will be followed up until one monthafter trauma.

The following data is registered: age, sex, time intervalbetween trauma and admission, time interval betweenadmission and antibiotic therapy, the cause of trauma,GCS upon admission, intracranial air volume (at the timeof admission and three days later), intracranial air loca-tion, presence of CSF rhinorrhea, CSF otorrhea, presenceand location of the radiological signs of skull base frac-tures, presence and volume of the intracranial hemor-rhage(at the time of admission and three days later),presence of meningitis, CSF findings, treatment and com-plications in the case of meningitis and one month fol-low-up note.

Intracranial air and hemorrhage volume are calculated inthe CT scan using the formula ABC/2, where A is the great-est mass diameter by CT, B is the diameter 90° to A, andC is the approximate number of CT slices with mass mul-tiplied by the slice thickness. In the case of air in the sub-arachnoid space, this formula is not easily applicable andan approximate volume is calculated and determinedwhether the volume is less than 10 cc or not [7].

The patients are divided into three groups; with intrave-nous antibiotics (IV), oral antibiotics (O) and placebo(P), according to the randomization list. In IV group,Ceftriaxone 2 grams BID plus oral placebo and in Ogroup, Azithromycin 500 mg in the first day followed by250 mg daily plus intravenous placebo for the rest will becontinued for 7 days. Antibiotics should be started in lessthan 24 hours after trauma. Since antibiotics may mask

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the clinical presentation of the meningitis, these patients(IV and O) will remain hospitalized two more days forclose clinical observation. In the case of meningitis,appropriate antibiotics are continued until patients'recovery. Corticosteroids should not be prescribed for thepatients for any reason.

The physicians caring for the patients are not blinded tothe regimen that is used.

Intracranial hemorrhages included subarachnoid hemor-rhage, epidural and subdural hematoma and cerebral con-tusion or hematoma.

The diagnosis of bacterial meningitis is based upon CSFfindings (increase in leukocyte count, decrease in CSF glu-cose [<60% of the level simultaneously measured inblood] increase in the CSF protein > 45 mg/dL and posi-tive CSF smear or culture) in patients with compatibleclinical findings (fever, headache, nausea and vomiting,change in the level of consciousness and/or meningismusnot explainable with other causes). Probable meningitis isdefined when positive CSF smear or culture is not availa-ble. In rare cases with relative contraindications for lum-bar puncture (accompanying intracranial hemorrhageand clinically suspected raised intracranial pressure), thepossible diagnosis of meningitis is based upon clinicalfindings and ruling out other causes.

Statistical analysisIntention to treat analysis will be used.

Categorical variables are compared using a chi-square test,and the Student t-test is used to compare continuous var-iables between groups. Logistic regression with adjust-ment for other possible risk factors for meningitis is usedto estimate the odds ratios and 95% confidence intervals.

DiscussionThis study can be a major step forward solving one of thecontroversial issues in the management of traumaticpneumocephalus. Considering our circumstances thedesign of the study is not double-blinded. This may beone of the potential shortcomings of the study.

ConclusionIn conclusion, this study is aimed to study the effective-ness and indications of prophylactic antibiotics in preven-tion of meningitis in traumatic pneumocephalus patientsafter mild head injury.

Competing interestsThe author(s) declare that they have no competing inter-ests.

Authors' contributionsBE conceived the trial design, involved in subsequentadaptations and drafted the manuscript. MG, AH MT, SZS,VRM, ESK, BE, FN, AY and EK have contributed to adapta-tions from the original design.

All authors read and approved the final manuscript.

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