Skip to main content
NCBI home page
BMJ Clinical Evidence logoLink to BMJ Clinical Evidence
. 2010 Jun 10;2010:1210.

Head injury (moderate to severe)

Ian Maconochie 1,#, Mark Ross 2,#
PMCID: PMC3217652  PMID: 21418686

Abstract

Introduction

Head injury in young adults is often associated with motor vehicle accidents, violence, and sports injuries. In older adults it is often associated with falls. Severe head injury can lead to secondary brain damage from cerebral ischaemia resulting from hypotension, hypercapnia, and raised intracranial pressure. Severity of brain injury is assessed using the Glasgow Coma Scale (GCS). While about one quarter of people with severe brain injury (GCS score less than 8) will make a good recovery, about one third will die, and one fifth will have severe disability or be in a vegetative state.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions to reduce complications of moderate to severe head injury as defined by Glasgow Coma Scale? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 17 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, anticonvulsants, corticosteroids, hyperventilation, hypothermia, and mannitol.

Key Points

Head injury in young adults is often associated with motor vehicle accidents, violence, and sports injuries. In older adults it is often associated with falls. This review covers only moderate to severe head injury.

  • Severe head injury can lead to secondary brain damage from cerebral ischaemia resulting from hypotension, hypercapnia, and raised intracranial pressure.

  • Poor outcome correlates with low post-resuscitation Glasgow Coma Scale (GCS) score, older age, eye pupil abnormalities, hypoxia or hypotension before definitive treatment, traumatic subarachnoid haemorrhage, and inability to control intracranial pressure.

  • Severity of brain injury is assessed using the GCS. While about one quarter of people with severe brain injury (GCS score less than 8) will make a good recovery, about one third will die, and one fifth will have severe disability or be in a vegetative state.

There is no strong evidence of benefit from any treatment in reducing the complications of moderate to severe head injury. Despite this, most clinicians implement various combinations of treatments discussed here.

Hyperventilation and mannitol are frequently used to lower intracranial pressure. Anticonvulsants, barbiturates, antibiotics, and hypothermia are less commonly implemented.

  • Evidence on hyperventilation, mild hypothermia, and mannitol has been inconclusive.

  • Carbamazepine and phenytoin may reduce early seizures in people with head injury, but they have not been shown to reduce late seizures, neurological disability, or death.

  • Barbiturates have not been shown to be effective in reducing intracranial pressure or in preventing adverse neurological outcomes after head injury.

  • Prophylactic antibiotics have not been shown to reduce the risk of death or meningitis in people with skull fracture.

CAUTION: Corticosteroids have been shown to increase mortality when used acutely in people with head injury.

  • One large RCT (the CRASH trial) found that death from all causes and severe disability at 6 months were more likely in people with head injury given methylprednisolone infusion than in those given placebo. Corticosteroids are no longer used in the treatment of head injuries.

About this condition

Definition

The basic operational components of a head injury are a history of blunt or penetrating trauma to the head — which may be followed by a period of altered consciousness — and the presence of physical evidence of trauma. The specific elements of a head injury are related to its severity. Some guidelines define head injury more broadly as any trauma to the head other than superficial injuries to the face. Head injuries are classified in a variety of ways: severity of injury as assessed by the Glasgow Coma Scale (GCS; mild, moderate, severe); mechanism (blunt or penetrating); or morphology (skull fractures or intracranial lesions). Since its introduction in 1974, the GCS has been widely used as an initial measure of the severity of brain injury. The scale incorporates neurological findings such as voluntary movements, speech, and eye movements, into a 3- to 15-point scale. GCS allows measurement of neurological findings, and it has been used to predict immediate and long-term outcome after head injury. A GCS of 8 or lower is considered representative of a severe brain injury, 9 to 13 of a moderate head injury, and 14 to 15 a mild head injury. The GCS is complicated by difficulties of communication and cooperation in the younger child. In children aged over 5 years, the adult GCS can be used. In younger children the verbal response is modified, and in very young children the motor response is also modified because these children are unable to obey commands. In this review, we cover only moderate to severe head injury as classified by GCS. Diagnosis and monitoring: The Advanced Trauma Life Support (ATLS) and Advanced Paediatric Life Support (APLS) guidelines contain standardised protocols for the initial assessment of traumatic head-injured adults and children, respectively. Most moderate to severe head injuries will require investigations after standard history and physical examination. Computed tomography (CT) scan is the investigation of choice in people with traumatic head injuries. Numerous organisations, including the National Institute for Health and Clinical Excellence, the Scottish Intercollegiate Guidelines Network, and the Royal College of Paediatrics and Child Health, have developed evidence-based pathways to provide physicians with guidance regarding whether a CT scan is required, and how urgently it should be performed. Monitoring of people with head injury may range from monitoring of intracranial pressure (ICP) with ventricular drains in people with severe head injuries to regular clinical neurological observations in people with less-severe head injuries.

Incidence/ Prevalence

Head injury remains the leading cause of death in trauma cases in Europe and the USA, and accounts for a disproportionate amount of morbidity in trauma survivors. Worldwide, several million people, mostly children and young adults, are treated each year for severe head injury. In the UK, 1.4 million people, 50% of whom are children, present to emergency departments every year after a head injury. This represents 11% of all new emergency department presentations. About 80% of people presenting to emergency departments can be categorised as having mild head injury, 10% as moderate, and 10% as severe.

Aetiology/ Risk factors

The main causes of head injury include injuries incurred from motor vehicle accidents (MVAs), falls, acts of violence, and sports injuries. MVAs account for most fatal and severe head injuries. Young adults (15–35 years old) are the most commonly affected group, reflecting increased risk-taking behaviour. A second peak occurs in older people (over 70 years), related to an increased frequency of falls. For most age groups, with the exception of extremes of age, there is a 2:1 male predominance. Severe head injury marks the beginning of a continuing encephalopathic process — secondary brain damage from ongoing cerebral ischaemia closely linked to factors such as hypotension, hypercapnia, and elevated ICP is a potential cause of morbidity and mortality.

Prognosis

Head injury can result in death or a lifelong impairment in physical, cognitive, and psychosocial functioning. Several factors have been shown to correlate with poor outcome — including low post-resuscitation GCS score, older age, eye pupil abnormalities, hypoxia or hypotension before definitive treatment, traumatic subarachnoid haemorrhage, and inability to control ICP. Data from the Traumatic Coma Data Bank found that people with an initial GCS score of 3 had 78% mortality, whereas those with a GCS score of 8 had 11% mortality. Overall, prognoses for people with severe head injury (GCS score 3–8) were: good recovery 27%, moderate disability 16%, severe disability 16%, vegetative 5%, and mortality 36%. Despite such data, the role of GCS in determining prognosis in head injury remains controversial. The impacts of head injury range from mild cognitive and psychosocial changes to severe physical disability and cognitive and sensory losses.

Aims of intervention

To reduce mortality and disability (neurological and other) from head injury; to reduce secondary physiological complications of head injury such as hypercapnia and intracranial hypertension; to reduce secondary clinical complications such as seizures and central nervous system infections; to reduce length of hospital stay; to maximise chances of full recovery (moderate to good recovery according to GCS score), with a minimum of adverse effects of treatment.

Outcomes

Mortality (including all-cause mortality, death), symptom severity (including severe neurological disability [according to GCS or other standardised functional scale, including psychological sequelae], seizures, mean ICP, mean arterial pressure, infection), adverse effects of treatment.

Methods

Clinical Evidence search and appraisal November 2009. For this review, the following sources were used for the identification of studies: Medline 1966 to November 2009, Embase 1980 to November 2009 and The Cochrane Library Issue 4, 2009. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and the National Institute for Health and Clinical Excellence (NICE). We also searched for retractions of studies included in the review. Abstracts of studies retrieved in the search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to evaluate relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition, we also use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for head injury (moderate to severe)

Important outcomes Symptom severity, mortality, adverse effects
Number of studies (participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of interventions to reduce complications of moderate to severe head injury as defined by the Glasgow Coma Scale?
4 (208) Mortality Antibiotics v placebo 4 0 0 –2 0 Low Directness points deducted for narrowness of population (only those with skull fracture) and for uncertainty about duration of study or time of measurement of outcome
4 (208) Symptom severity Antibiotics v placebo 4 0 0 –2 0 Low Directness points deducted for narrowness of population (only those with skull fracture) and for uncertainty about duration of study or time of measurement of outcome
1 (77) Mortality Hyperventilation v control 4 –2 –1 –1 0 Very low Quality points deducted for sparse data and for methodological flaws (blinding/randomisation). Consistency point deducted for conflicting results. Directness point deducted for use of a composite outcome
26 (2261) Mortality Hypothermia v normothermia 4 0 –1 –1 0 Low Consistency point deducted for conflicting results. Directness point deducted for variation in hypothermic regimens used
26 (2261) Symptom severity Hypothermia v normothermia 4 0 –1 –1 0 Low Consistency point deducted for conflicting results. Directness point deducted for variation in hypothermic regimens used
2 (61) Mortality Mannitol v placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and for possibility of RCTs being underpowered
1 (59) Mortality Mannitol v barbiturates 4 –2 0 0 0 Low Quality points deducted for sparse data and uncertainty about intention-to-treat analysis
6 (1156) Mortality Antiepileptic drugs v placebo 4 –2 0 –1 0 Very low Quality points deducted for poor follow-up and exclusion of one RCT in analysis. Directness point deducted for uncertainty about drug levels/dose
5 (992) Symptom severity Antiepileptic drugs v placebo 4 –1 –1 –2 0 Very low Quality point deducted for poor follow-up. Consistency point deducted for different results at different end points. Directness point deducted for inclusion of different disease states and uncertainty about drug levels/dose
3 (208) Mortality Barbiturates v placebo 4 0 0 –2 0 Low Directness point deducted for uncertainty about extent of head injury and duration of study or time of measurement of outcome
3 (208) Symptom severity Barbiturates v placebo 4 0 0 –2 0 Low Directness point deducted for uncertainty about extent of head injury and duration of study or time of measurement of outcome
at least 1 RCT (at least 9964 people) Mortality Corticosteroids v placebo 4 0 0 –1 0 Moderate Directness point deducted for composite outcome in one study
Open in a new tab

Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Therapeutic hypothermia

is the controlled lowering of core temperature (rectal, oesophageal, central venous). Mild-moderate hypothermia is lowering of temperatures to 32–35 °C. Systemic hypothermia is whole-body cooling using various techniques (cooling blankets, cooled fluids, ice, cooling beds/suits, bear huggers) to achieve the desired temperature. Regional or localised hypothermia, such as selective brain cooling is the process of cooling an extremity or specific organ/body part via the above techniques.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Ian Maconochie, Department of Paediatric Accident and Emergency, St Mary's Hospital, London, UK.

Mark Ross, Royal Prince Albert Hospital, Sydney, Australia.

References

  • 1.Dandie G, Curtis J, Dexter M. Head injuries. In: Sherry E, Trieu L, Templeton J, editors. Trauma. Oxford, UK: Oxford University Press: 2003. [Google Scholar]
  • 2.National Institute for Health and Clinical Excellence. Head injury: triage, investigation, assessment, and early management of head injury in infants, children, and adults. 2007. Available online at: http://guidance.nice.org.uk/CG56 (last accessed 13 May 2010). [Google Scholar]
  • 3.Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81–84. [DOI] [PubMed] [Google Scholar]
  • 4.American College of Surgeons. Advanced trauma life support for doctors. Chicago, IL: American College of Surgeons, 1997. [Google Scholar]
  • 5.Scottish Intercollegiate Guidelines Network. Early management of patients with a head injury. Available online at: http://www.sign.ac.uk/guidelines/fulltext/110/index.html (last accessed 12 May 2010). [Google Scholar]
  • 6.Royal College of Paediatrics and Child Health. Guidelines for good practice: early management of patients with a head injury. Available online at: http://www.sign.ac.uk/guidelines/fulltext/46/index.html (last accessed 14 May 2010). [Google Scholar]
  • 7.Finfer SR, Cohen J. Severe traumatic brain injury. Resuscitation 2000;48:77–90. [DOI] [PubMed] [Google Scholar]
  • 8.Moulton C, Yates D. Lecture notes on emergency medicine. Head injury, 2nd edition. Oxford, UK: Blackwell Science Ltd. 1999. [Google Scholar]
  • 9.Gentleman D. Preventing secondary brain damage after head injury: a multidisciplinary challenge. Injury 1990;21:305–308. [DOI] [PubMed] [Google Scholar]
  • 10.Eisenberg HM, Jane JA, Luerssen TG, et al. The outcome of severe closed head injury. J Neurosurg 1991;75:S28–S36. [Google Scholar]
  • 11.Eisenberg HM, Gary HE, Aldrich EF, et al. Initial CT findings in 753 patients with severe head injury. A report of the NIH Traumatic Coma Data Bank. J Neurosurg 1990;73:688–690. [DOI] [PubMed] [Google Scholar]
  • 12.Ratilal B, Costa J, Sampaio C. Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005. [Google Scholar]
  • 13.Samuel V, Berger SA, Ramaswamuy G. Pneumococcal meningitis despite cloramphenicol prophylaxis. Arch Intern Med 1981;141:808. [PubMed] [Google Scholar]
  • 14.Bryan CS, Jernigan FE. Posttraumatic meningitis due to ampicillin-resistant Haemophilus influenzae. J Neurosurg 1979;51:240–241. [DOI] [PubMed] [Google Scholar]
  • 15.Roberts I, Schierhout G. Hyperventilation therapy for acute traumatic brain injury. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2008. [Google Scholar]
  • 16.Muizelaar JP, Marmarou A, Ward J, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomised clinical trial. J Neurosurg 1991;75:731–739. [DOI] [PubMed] [Google Scholar]
  • 17.Marion DW, Puccio A, Wisniewski SR, et al. Effect of hyperventilation on extracellular concentrations of glutamate, lactate, pyruvate and local cerebral blood flow in patients with severe traumatic brain injury. Crit Care Med 2002;30:2619–2625. [DOI] [PubMed] [Google Scholar]
  • 18.Sydenham E, Roberts I, Alderson P. Hypothermia for head injury. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2009. [Google Scholar]
  • 19.Zhi D, Zhang S, Lin X. Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury. Surg Neurol 2003;59:381–385. [DOI] [PubMed] [Google Scholar]
  • 20.Qui W, Liu W, Shen H, et al. Therapeutic effect of mild hypothermia on severe traumatic head injury. Chinese J Traumatol 2005;8:27–32. [PubMed] [Google Scholar]
  • 21.Gal R, Cundrle I, Zimova I, et al. Mild hypothermia therapy for patients with severe brain injury. Clin Neurol Neurosurg 2002;104:318–321. [DOI] [PubMed] [Google Scholar]
  • 22.Liu WG, Qiu WS, Zhang Y, et al. Effects of selective brain cooling in patients with severe traumatic brain injury: a preliminary study. J Int Med Res 2006;34:58–64. [DOI] [PubMed] [Google Scholar]
  • 23.Qiu W-S, Wang W-M, Du H-Y, et al. Thrombocytopenia after therapeutic hypothermia in severe traumatic brain injury. Chin J Traumatol 2006;9:238–241. [PubMed] [Google Scholar]
  • 24.Shen H, Shen MW. Application of mild hypothermia in treatment of severe brain injury. Heibel Med J 2000;6:498–500. [Google Scholar]
  • 25.Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2006. [Google Scholar]
  • 26.Feig PU, McCurdy DK. The hypertonic state. N Engl J Med 1977;297:1449. [DOI] [PubMed] [Google Scholar]
  • 27.Brain Trauma Foundation. The use of mannitol in severe head injury. J Neurotrauma 1996;13:705–709. [DOI] [PubMed] [Google Scholar]
  • 28.Cruz J, Minoja G, Okuchi K, et al. Successful use of the new high-dose mannitol treatment in patients with Glasgow Coma Scores of 3 and bilateral abnormal pupillary widening: a randomized trial. J Neurosurg 2004;100:376–383. [DOI] [PubMed] [Google Scholar]
  • 29.Cruz J, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with emergency preoperative administration of high doses of mannitol: a randomized trial. Neurosurgery 2001;49:864–871. [DOI] [PubMed] [Google Scholar]
  • 30.Cruz C, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: a randomized trial. Neurosurgery 2002;51:628–638. [PubMed] [Google Scholar]
  • 31.Schierhout G, Roberts I. Anti-epileptic drugs for preventing seizures following acute traumatic brain injury. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002. [DOI] [PubMed] [Google Scholar]
  • 32.Young KD, Okada PJ, Sokolove PE, et al. A randomized, double-blinded, placebo-controlled trial of phenytoin for the prevention of early posttraumatic seizures in children with moderate to severe blunt head injury. Ann Emerg Med 2004;43:435–446. [DOI] [PubMed] [Google Scholar]
  • 33.Roberts I, Sydnenham E. Barbiturates for acute traumatic brain injury. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2009. [Google Scholar]
  • 34.Smith KR, Goulding P, Wilderman D, et al. Neurobehavioural effects of phenytoin and carbamazepine in patients recovering from brain trauma: a comparative study. Arch Neurol 1994;51:653–660. [DOI] [PubMed] [Google Scholar]
  • 35.Alderson P, Roberts I. Corticosteroids for acute traumatic brain injury. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2008. [Google Scholar]
  • 36.CRASH trial collaborators. Effect of intravenous corticosteroids on death within 14 days in 100 008 adults with clinically significant head injury (MRC CRASH trial): randomized placebo-controlled trial. Lancet 2004;364:1321–1328. [DOI] [PubMed] [Google Scholar]
  • 37.CRASH trial collaborators. Final results of MRC CRASH, a randomized placebo-controlled trial of intravenous corticosteroids in adults with head injury: outcomes at 6 months. Lancet 2005;365:1957–1959. [DOI] [PubMed] [Google Scholar]
  • 38.Ratilal B, Costa J, Sampaio C. Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005. [Google Scholar]
  • 39.Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. DARE 2007; Issue 1. [DOI] [PubMed] [Google Scholar]
BMJ Clin Evid. 2010 Jun 10;2010:1210.

Antibiotics

Summary

MORTALITY Compared with placebo: Antibiotics may be no more effective at reducing mortality in people with head injury ( low-quality evidence ). SYMPTOM SEVERITY Compared with placebo: Antibiotics may be no more effective at reducing the risk of meningitis in people with head injury (low-quality evidence).

Benefits

Antibiotics versus placebo:

We found one systematic review (search date 2005, 4 RCTs, 17 observational studies, 2376 people with base-of-skull fractures) comparing antibiotics versus placebo. All studies assessed meningitis as their primary outcome. Meta-analysis of the RCTs identified by the review found no significant difference in all-cause mortality, meningitis-related mortality, or meningitis between antibiotics and placebo (4 RCTs, 208 people; all-cause mortality: 5/109 [5%] with antibiotics v 3/99 [3%] with placebo; OR 1.68, CI 0.41 to 6.95; meningitis-related mortality: 1/109 [1%] with antibiotics v 1/99 [1%] with placebo; OR 1.03, CI 0.14 to 7.40; meningitis: 10/109 [9%] with antibiotics v 14/99 [14%] with placebo; OR 0.69, CI 0.29 to 1.21). The review did not report trial duration and time to assessment of outcome. The review found similar reductions in rates of meningitis in the subgroup of people with cerebrospinal fluid leakage. The review also meta-analysed results for the retrospective controlled studies it identified (2168 people with basal skull fracture) and found similar results.

Harms

Antibiotics versus placebo:

The review gave no information on adverse effects. There have been case reports of meningitis developing despite antibiotic prophylaxis, and of meningitis caused by drug-resistant organisms in people given antibiotics.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Jun 10;2010:1210.

Hyperventilation

Summary

MORTALITY Compared with control: We don't know whether hyperventilation, alone or in combination with a buffer, is more effective than normal ventilation at reducing mortality or at improving neurological recovery in adults and children with intracranial lesions ( very low-quality evidence ). NOTE Hyperventilation may worsen cerebral ischaemia by increasing cerebral tissue concentrations of toxic metabolites.

Benefits

We found one systematic review (search date 2008), which identified one RCT of sufficient quality (113 people aged at least 3 years with intracranial lesions, Glasgow Coma Scale [GCS] score less than 8) comparing three interventions: hyperventilation alone, hyperventilation plus buffer (tris-hydroxy-methyl-amino methane [THAM]), or normal ventilation. All participants also received intracranial pressure-lowering agents such as mannitol, and barbiturates. The RCT found that, compared with normal ventilation, hyperventilation alone or combined with a buffer reduced mortality at 1 year, although the difference between groups in each comparison did not reach significance (9/36 [25%] with hyperventilation alone v 14/41 [34%] with normal ventilation; RR 0.73, CI 0.36 to 1.49; 11/36 [31%] with hyperventilation plus buffer v 14/41 [34%] with normal ventilation; RR 0.89, CI 0.47 to 1.72). However, this reduction in mortality did not correlate with an improvement in neurological recovery: there was no significant difference between groups in the combined outcome of death or disability (25/36 [69%] with hyperventilation alone v 25/41 [61%] with normal ventilation; RR 1.14, 95% CI 0.82 to 1.58; 19/36 [53%] with hyperventilation plus buffer v 25/41 [61%] with normal ventilation; RR 0.87, 95% CI 0.58 to 1.28). People receiving hyperventilation with higher GCS scores (4–5), suggesting a better initial prognosis, did significantly worse (P = 0.05) at 3- and 6-month follow-up than did other subgroups. The RCT had some weaknesses in its methods; it was not double blind, and randomisation was compromised early in the RCT, because people in whom informed consent could not be obtained were automatically assigned to control. This practice was stopped as soon as the authors became aware of it.

Harms

The review gave no information on adverse effects. One prospective cohort study (20 adults with severe head injury) evaluated potential adverse effects of hyperventilation. Assessments of the effects of 30 minutes of hyperventilation on extracellular metabolites associated with cerebral ischaemia and on local cerebral blood flow were done 24 to 36 hours and 3 to 4 days after injury. The study found that hyperventilation increased extracellular glutamate at 24 to 36 hours (at least 10% increase in 14/20 [70%] people; P less than 0.05) and lactate (at least 10% increase in 7/20 [35%] people; P less than 0.05), and decreased local cerebral blood flow (at least 10% decrease in 5/20 [25%] people; significance not reported). Results at 3 to 4 days were similar.

Comment

None.

Substantive changes

Hyperventilation: One updated systematic review found no new evidence on the effects of hyperventilation. Categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2010 Jun 10;2010:1210.

Hypothermia (therapeutic)

Summary

MORTALITY Compared with normothermia: We don't know whether hypothermia is more effective at reducing mortality at 6 months to 2 years in people with head injury ( low-quality evidence ). SYMPTOM SEVERITY Compared with normothermia: We don't know whether hypothermia is more effective at improving neurological outcomes and cerebral perfusion, and at reducing intracranial pressure, in people with head injuries (low-quality evidence). NOTE Immediate hypothermia has been associated with increased rates of pneumonia, pulmonary complications, and thrombocytopenia.

Benefits

We found one systematic review (search date 2009, 23 RCTs, 1614 people, primarily adults, with head injuries requiring admission to hospital, mechanism and morphology of injury unclear) and five additional RCTs. The review compared mild therapeutic hypothermia (34–35 °C) for at least 12 hours versus normothermia.Cooling may have begun immediately or have been deferred until intracranial pressure (ICP) was uncontrollable. Results were stratified by trial quality. The review found no significant difference between hypothermia and normothermia for mortality. The review also assessed nine RCTs with good allocation concealment in a subgroup analysis, which also found no significant difference between groups for mortality. The review found that hypothermia significantly reduced the risk of unfavourable outcomes (composite outcome including death, vegetative state, or severe disability) compared with normothermia; however, a subgroup analysis of nine high-quality RCTs included in the review found no significant difference between groups for unfavourable outcomes (see table 1 ).

Table 1.

Summary of RCTs on hypothermia as a treatment for head injury (moderate to severe).

Reference Population Intervention and comparison Outcome assessed Result Significance
Mortality
21 RCTs, 1587 people Immediate hypothermia v normothermia Mortality after the end of treatment NS 214/803 (27%) with hypothermia v 233/784 (30%) with normothermia; OR 0.85, 95% CI 0.68 to 1.06; P = 0.15
9 high-quality RCTs, 891 people Immediate hypothermia v normothermia Mortality after the end of treatment NS 116/450 (25%) with hypothermia v 105/441 (24%) with normothermia; OR 1.11, 95% CI 0.82 to 1.51; P = 0.51
396 people aged 15 to 65 years, with GCS score less than 8 Immediate (within 24 hours of injury) hypothermia (32–35 °C) v normothermia for 1 to 7 days Mortality at the end of treatment Significant difference 51/198 (26%) with hypothermia v 72/198 (36%) with normothermia; P less than 0.05
86 people aged 14 to 65 years with GCS score less than 8 Hypothermia (33–35 °C) immediately after hospital admission or 3 to 5 days after craniotomy v normothermia Mortality Significant difference 11/43 (26%) with hypothermia v 22/43 (51%) with normothermia; P less than 0.05
66 adults with GCS score 8 or less, mean age 40.6 years Selective brain cooling (brain surface temperature maintained at 33–35 °C for 0–6 hours/day) v systemic cooling (rectal temperature maintained between 36.5 and 37.5 °C) v normothermia for 3 days Mortality at 2 years Significant reduction with selective brain hypothermia and systemic hypothermia v normothermia 5/22 (23%) with selective brain hypothermia v 6/21 (29%) with systemic hypothermia v 12/23 (52%) with normothermia; P value for both comparisons less than 0.05
Neurological outcome
21 RCTs, 1587 people Immediate hypothermia v normothermia Unfavourable outcomes (including death, vegetative state, or severe disability Significant risk reduction with hypothermia 323/803 (40%) with hypothermia v 362/784 (46%) with normothermia; OR 0.77, 95% CI 0.62 to 0.94; P = 0.011
9 high-quality RCTs, 891 people Immediate hypothermia v normothermia Unfavourable outcomes (including death, vegetative state, or severe disability NS 189/450 (42%) with hypothermia v 191/441 (43%) with normothermia; OR 0.93, 95% CI 0.70 to 1.23; P = 0.60
396 people aged 15 to 65 years, with GCS score less than 8 Immediate (within 24 hours of injury) hypothermia (32–35 °C) v normothermia for 1 to 7 days Good neurological outcome Significant difference 77/198 (39%) with hypothermia v 39/198 (20%) with normothermia; P less than 0.05
86 people aged 14 to 65 years with GCS score less than 8 Hypothermia (33–35 °C) immediately after hospital admission or 3 to 5 days after craniotomy v normothermia Mild or no disability at 2 years Significant difference 23/43 (53%) with hypothermia v 12/43 (28%) with normothermia; P less than 0.05
30 adults with GCS score less than 8, mean age 35 years Immediate hypothermia (34 °C, within 15 hours of head injury) v normothermia Good neurological outcome (GCS 4 or 5) between treatments at 6 months NS 13/15 (87%) with hypothermia v 7/15 (47%) with normothermia; P = 0.08
66 adults with GCS score 8 or less, mean age 40.6 years Selective brain cooling (brain surface temperature maintained at 33–35 °C for 0–6 hours/day) v systemic cooling (rectal temperature maintained between 36.5 and 37.5 °C) v normothermia for 3 days Good neurological outcome (GCS score 4 or 5) at 2 years Significant increase in proportion of people with a good neurological outcome with selective brain and systemic hypothermia 16/22 (73%) with selective brain hypothermia v 12/21 (57%) with systemic hypothermia v 8/23 (35%) with normothermia; P value for both treatments v normothermia less than 0.05
96 adults, mean age 41.3 years and with a GCS score of 8 or less Selective brain cooling (24 people) v mild systemic hypothermia (30 people) v normothermia (42 people) Good neurological outcome (GCS score 4 or 5) Significantly smaller proportion of people with a good neurological outcome with selective brain and systemic hypothermia 7/18 (39%) with selective brain hypothermia v 8/23 (35%) with mild systemic hypothermia v 12/15 (80%) with normothermia; P value for both treatments v normothermia less than 0.01
Intracranial pressure
396 people aged 15 to 65 years, with GCS score less than 8 Immediate (within 24 hours of injury) hypothermia (32–35 °C) v normothermia for 1 to 7 days ICP at 24 hours, 3 days, and 1 week Significant difference P less than 0.05 for all comparisons
30 adults with GCS score less than 8, mean age 35 years Immediate hypothermia (34 °C, within 15 hours of head injury) v normothermia ICP Significant difference P = 0.00007
66 adults with GCS score 8 or less, mean age 40.6 years Selective brain cooling (brain surface temperature maintained at 33–35 °C for 0–6 hours/day) v systemic cooling (rectal temperature maintained between 36.5 and 37.5 °C) v normothermia for 3 days ICP at 24, 48, and 72 hours Significant decrease in ICP with selective brain and systemic hypothermia at 24, 48, and 72 hours P less than 0.05 for all comparisons
Adverse effects
11 RCTs, 559 people Immediate hypothermia v normothermia Rate of pneumonia NS 111/281 (39%) with hypothermia v 90/278 (32%) with normothermia; OR 1.35, 95% CI 0.95 to 1.91; P = 0.09
4 high-quality RCTs, 306 people Immediate hypothermia v normothermia Rate of pneumonia NS 51/149 (34%) with hypothermia v 60/157 (38%) with normothermia; OR 0.84, 95% CI 0.52 to1.35; P = 0.47
86 people aged 14 to 65 years with GCS score less than 8 Hypothermia (33–35 °C) immediately after hospital admission or 3 to 5 days after craniotomy v normothermia Pulmonary infection and thrombocytopenia Significant difference Pulmonary infection: 26/43 (61%) with hypothermia v 14/43 (33%) with normothermia; P less than 0.05Thrombocytopenia: 27/43 (63%) with hypothermia v 17/43 (40%) with normothermia; P less than 0.05
30 adults with GCS score less than 8, mean age 35 years Immediate hypothermia (34 °C, within 15 hours of head injury) v normothermia Cerebral perfusion pressure Significant difference P = 0.00007
66 adults with GCS score 8 or less, mean age 40.6 years Selective brain cooling (brain surface temperature maintained at 33–35 °C for 0–6 hours/day) v systemic cooling (rectal temperature maintained between 36.5 and 37.5 °C) v normothermia for 3 days Thrombocytopenia Increase in thrombocytopenia with selective brain and systemic hypothermia compared with normothermia 16/22 (73%) with selective brain hypothermia v 14/21 (67%) with systemic hypothermia v 9/23 (39%) with normothermia; significance not assessed
96 adults, mean age 41.3 years and with a GCS score of 8 or less Selective brain cooling (24 people) v mild systemic hypothermia (30 people) v normothermia (42 people) Thrombocytopenia Significant difference 18/24 (75%) with selective brain hypothermia v 23/30 (77%) with mild systemic hypothermia v 15/42 (36%) with normothermia; P less than 0.01
Open in a new tab

GCS, Glasgow Coma Scale; ICP, intracranial pressure; NS, not significant.

The first additional RCT (396 people) compared immediate (within 24 hours of injury) hypothermia (32–35 °C) versus normothermia for 1 to 7 days. It found that, compared with normothermia, immediate hypothermia significantly reduced mortality and improved the proportion of people with a good neurological outcome at the end of treatment. ICP was significantly lower in the hypothermia group at 24 hours, 3 days, and 1 week compared with the normothermia group.

The second additional RCT (86 people) compared mild to moderate hypothermia (33–35 °C) immediately after hospital admission or 3 to 5 days after craniotomy versus normothermia. It found a significant reduction in mortality and a significant improvement in the proportion of people who had mild or no disability at 2 years with hypothermia compared with normothermia.

The third additional RCT (30 adults) compared immediate hypothermia (34 °C, within 15 hours of head injury) versus normothermia. The RCT found no significant difference in good neurological outcome (Glasgow Coma Scale [GCS] score 4 or 5) at 6 months between hypothermia and normothermia. Hypothermia significantly decreased ICP and increased cerebral perfusion pressure. However, these observations are of questionable clinical value because they were not compared with parameters obtained from people receiving normothermia.

The fourth and fifth additional RCTs compared three interventions: immediate selective brain hypothermia, systemic hypothermia, and normothermia for 3 days. The fourth RCT found that hypothermia of either type significantly increased the proportion of people with a good neurological outcome, and also significantly reduced mortality (see table 1 ). However, the fifth RCT found that the proportion of people with good neurological outcome was significantly smaller with either hypothermic treatment compared with normothermic treatment. The method of randomisation in this RCT was unclear.

Harms

The review found no significant difference between hypothermia and normothermia for pneumonia (11 RCTs; 111/281 [39%] people with hypothermia v 90/278 [32%] with normothermia; OR 1.35, 95% CI 0.95 to 1.91; P = 0.09). A subgroup analysis of high-quality trials also found no significant difference between groups for pneumonia (4 RCTs; 51/149 [34%] with hypothermia v 60/157 [38%] with normothermia; OR 0.84, 95% CI 0.52 to 1.35; P = 0.47). Other complications of hypothermia were not analysed in the review. Four additional RCTs found that, compared with normothermia, hypothermia significantly increased complications (pulmonary infection, thrombocytopenia, cerebral perfusion pressure). In one of the RCTs, all platelet counts during both hypothermia treatments normalised within 3 days of hypothermia cessation. One additional RCT gave no information on adverse effects. See table 1 for full results .

Comment

One original citation was identified by the review as being potentially relevant, but the authors of the review were unable to retrieve the article for assessment.

Substantive changes

Hypothermia (therapeutic): One systematic review updated. The review found no significant difference between hypothermia and normothermia in rates of mortality. The review found conflicting evidence on unfavourable outcomes (including death, vegetative state, or severe disability). In a meta-analysis of RCTs of any quality, the review found that hypothermia reduced the risk of unfavourable outcomes compared with normothermia. However, a subgroup analysis of high-quality RCTs found no significant difference between groups for unfavourable outcomes. Categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2010 Jun 10;2010:1210.

Mannitol

Summary

MORTALITY Compared with placebo or hypertonic saline: Mannitol may be no more effective at reducing mortality at 3 months in people with moderate to severe intracranial lesions ( low-quality evidence ). Compared with barbiturates: We don't know how mannitol and barbiturates compare at reducing mortality at 3 months in people with severe head injuries and raised intracranial pressure (low-quality evidence).

Benefits

We found one systematic review (search date 2006, 4 RCTs, 120 adults with moderate to severe intracranial lesions, Glasgow Coma Scale [GCS] score 8 or lower in most RCTs) comparing mannitol versus placebo, hypertonic saline, or phenobarbitone.

Mannitol versus placebo or hypertonic saline:

The review identified two RCTs. The first RCT (41 adults with moderate to severe head injury) compared mannitol given before hospital admission versus placebo. It found no significant difference in mortality at 3 months between mannitol and placebo (5/20 [25%] with mannitol v 3/21 [14%] with placebo; RR 1.75, CI 0.48 to 6.38). The width of the confidence interval suggests that the RCT is likely to have been underpowered to detect a clinically important difference between groups. The second RCT (20 people with head injury and persistent coma requiring ongoing treatment for refractory intracranial hypertension) identified by the review compared mannitol versus hypertonic saline. It also found no significant difference between mannitol and hypertonic saline in mortality at 3 months (5/10 [50%] with mannitol v 4/10 [40%] with placebo; RR 1.25, 95% CI 0.47 to 3.33). The RCT was too small to draw reliable conclusions.

Mannitol versus barbiturates:

The review identified one RCT (59 adults with severe head injury, GCS score less than 8, and raised intracranial pressure [ICP]) comparing mannitol versus phenobarbitone. It found no significant difference in mortality at 3 months between mannitol and phenobarbitone (15/31 [48%] with mannitol v 16/28 [57%] with phenobarbitone; RR 0.85, 95% CI 0.52 to 1.38). The RCT is likely to have been underpowered to detect a clinically important difference between groups. In the RCT, some participants later received the alternative treatment if the allocated treatment did not control ICP. It is unclear from the review whether the analysis was by intention to treat.

Harms

The review gave no information on adverse effects. Physiological and animal studies have found an increased risk of acute renal failure with large doses of mannitol. Multiple doses of mannitol may accumulate in the brain, causing a reverse osmotic shift and raising brain osmolarity, thus theoretically increasing ICP.

Comment

Clinical guide:

There were very few adequate RCTs of mannitol in people with moderate to severe head injury. The review excluded three RCTs that compared high- versus low-dose mannitol because of ongoing concerns about the validity of the original data they report. Current clinical use of mannitol is based on its pharmacological mode of action, and on observational human and animal studies that show a potential beneficial effect.

Substantive changes

No new evidence

BMJ Clin Evid. 2010 Jun 10;2010:1210.

Anticonvulsants

Summary

MORTALITY Antiepileptic drugs compared with placebo: Antiepileptic drugs may be no more effective at reducing mortality at 3 months to 2 years in people with head injuries ( very low-quality evidence ). Barbiturates compared with placebo: Barbiturates may be no more effective at reducing mortality in people with head injuries ( low-quality evidence ). Barbiturates compared with mannitol: We don't know how barbiturates and mannitol compare at reducing mortality at 3 months in people with severe head injuries and raised intracranial pressure (low-quality evidence). SYMPTOM SEVERITY Compared with placebo: Antiepileptic drugs may be more effective at reducing early seizures, but we don't know whether they are more effective at improving neurological outcomes (including a composite outcome of mortality or neurological disability) at 30 days to 2 years (very low-quality evidence). Barbiturates compared with placebo: Barbiturates may be less effective at reducing adverse neurological outcomes and intracranial pressure in people with head injuries (low-quality evidence).

Benefits

Antiepileptic drugs versus placebo:

We found one systematic review and one subsequent RCT. The review (search date 2002, 6 RCTs, 1218 adults and children; severity, mechanism, and morphology of head injury unclear) compared antiepileptic drugs or barbiturates versus placebo. The RCTs identified by the review assessed phenytoin (4 RCTs, 903 people), carbamazepine (1 RCT, 151 people), and pentobarbital (1 RCT, 164 people) commenced within 8 weeks of acute head injury. The RCTs had several weaknesses in methods: in the largest trial of phenytoin (586 people), 50% of people withdrew, and therapeutic drug levels were often not attained or even reported in some RCTs. The RCT of the barbiturate phenobarbital was not included in most of the meta-analyses. The RCTs found no significant difference in mortality over 2 years between antiepileptic drugs and placebo (5 RCTs: 95/540 [18%] with antiepileptic drugs v 78/514 [15%] with placebo; RR 1.15, CI 0.89 to 1.51). One RCT of phenytoin and one of carbamazepine assessed the combined outcome of death or neurological disability. One RCT found that, compared with placebo, carbamazepine was associated with a significantly higher risk of death or neurological disability at 2 years (RR 1.49, CI 1.06 to 2.08 for carbamazepine v placebo), but the other RCT found no significant difference between phenytoin and placebo for this outcome (RR 0.96, CI 0.72 to 1.26 for phenytoin v placebo). The review found that carbamazepine or phenytoin significantly reduced early seizure (within 1 week) compared with placebo (4 RCTs: 22/456 [5%] with antiepileptics v 65/434 [15%] with placebo; RR 0.34, 95% CI 0.21 to 0.54). The subsequent RCT (102 children aged up to 16 years with Glasgow Coma Scale [GCS] score 10 or lower) compared phenytoin versus placebo. The primary outcome assessed was incidence of post-traumatic seizures within 48 hours. It found no significant difference between phenytoin and placebo in the proportion of children with seizures (3/46 [7%] with phenytoin v 3/56 [5%] with placebo; mean difference –0.015, 95% CI –0.127 to +0.091; mean increase +1.5%, 95% CI –9.1% to +12.7%). The RCT also found no significant difference at 30 days between groups in the secondary outcomes of mortality or neurological outcome. However, the RCT was underpowered to detect clinically important differences between groups — the study authors had legal difficulties with waiving consent, and so they were unable to enrol the required number of participants.

Barbiturates versus placebo:

We found one systematic review (search date 2009, 3 RCTs, 208 adults and children, GCS score 7 or lower, mechanism and morphology of head injury unclear), which compared barbiturates (phenobarbital or pentobarbital) or barbiturates plus an anaesthetic (pentobarbital plus etomidate) versus no barbiturates. The review found no significant difference in mortality between barbiturates and no barbiturates (48/105 [46%] with barbiturates v 43/103 [42%] with placebo; RR 1.09, 95% CI 0.81 to 1.47). It also found no significant difference in the proportion of people with an adverse neurological outcome (death, vegetative state, or severe disability) between phenobarbitone or pentobarbital and placebo (34/68 [50%] with barbiturates v 29/67 [43%] with placebo; RR 1.15, 95% CI 0.81 to 1.64). Two RCTs (126 adults with severe head injury) examined the effect of barbiturates on intracranial pressure (ICP) and found no significant difference between barbiturates and placebo, although results were better in people taking barbiturates (first RCT, people with uncontrolled ICP: 25/37 [68%] with barbiturates v 30/36 [83%] with placebo; RR for uncontrolled ICP 0.81, 95% CI 0.62 to 1.06; second RCT: WMD in ICP –1.00, 95% CI –7.77 to +5.77). Trial duration and time to assessment of outcome were not reported by the review.

Barbiturates versus mannitol:

See benefits of mannitol.

Harms

Antiepileptic drugs versus placebo:

The review gave little information on adverse effects. One RCT (586 people) identified by the review found that antiepileptic drugs were associated with negative cognitive effects (no further data reported). Two RCTs identified by the review found that phenytoin significantly increased the incidence of skin rashes compared with placebo (30/292 [10%] with phenytoin v 18/276 [7%] with placebo; RR 1.57, 95% CI 0.90 to 2.75). One additional RCT (80 people) compared discontinuation versus continuation of phenytoin or carbamazepine, in people recovering from head injury who had received either drug for the previous 6 months to 3.5 years. The RCT assessed neurological adverse effects, and found that people had significantly improved performance in motor and speed tasks and reduced anxiety when either drug was discontinued (absolute numbers tabulated; P less than 0.05 for all outcomes). However, practice and acquired learning could not be excluded as causative factors of these apparent improvements in performance upon drug withdrawal.

Barbiturates versus placebo:

The review found that barbiturates significantly increased hypotension compared with placebo (2 RCTs: 37/64 [60%] with barbiturates v 20/62 [32%] with placebo; RR 1.80, CI 1.19 to 2.70). One RCT (53 people) identified by the review found that mean body temperature was significantly lower in people taking barbiturates compared with placebo (WMD –3.20, CI –4.66 to –1.74).

Barbiturates versus mannitol:

See harms of mannitol.

Comment

Clinical guide:

Barbiturates:

The hypotensive effect of barbiturates is likely to offset the beneficial effect on cerebral perfusion pressure, or of any barbiturate-related reduction in ICP.

Substantive changes

Anticonvulsants versus placebo: One updated systematic review identified no new evidence on the effects of barbiturates in the treatment of head injury. Categorisation unchanged (Unlikely to be beneficial).

BMJ Clin Evid. 2010 Jun 10;2010:1210.

Corticosteroids

Summary

MORTALITY Compared with placebo: Corticosteroids seem less effective at reducing mortality at 2 weeks to 6 months in adults with mild, moderate, or severe head injuries ( moderate-quality evidence ).

Benefits

We found one systematic review (search date 2008, 20 RCTs, 12,303 adults and children with head injury) comparing corticosteroids versus placebo or no corticosteroids in people with acute traumatic brain injury treated within 7 days of injury. The review did not meta-analyse results for the outcome of death, because of significant statistical heterogeneity among the trials (P value not reported) — probably as a result of the inclusion of the largest trial (Corticosteroid Randomisation After Significant Head Injury [CRASH]). The CRASH trial was 27 times larger than any of the previous RCTs identified by the review, and accounted for about 80% of all people included in the entire review. The RCT (10,008 adults with head injury, Glasgow Coma Scale [GCS] score 14 or lower, about 70% with moderate to severe head injury, mechanism and morphology of injury unclear) compared intravenous methylprednisolone for 48 hours versus placebo. It found that the risk of death from all causes within 2 weeks was significantly higher in people taking corticosteroids compared with people taking placebo (1052/4985 [21%] with corticosteroids v 893/4979 [18%] with placebo; RR 1.18, 95% CI 1.09 to 1.27; P = 0.0001). The relative increase in mortality in people receiving corticosteroids did not differ by injury severity (P = 0.22) or by time since injury (P = 0.05). Data collected at 6 months (9673 adults, 97% of participants) were consistent with earlier results. Mortality was higher in people taking corticosteroids compared with those taking placebo (1248/4985 [26%] with corticosteroids v 1075/4979 [22%] with placebo; RR 1.15, 95% CI 1.07 to 1.24; P = 0.0001), as was death or severe disability (1828/4985 [38%] with corticosteroids v 1728/4979 [36%] with placebo; RR 1.05, 95% CI 0.99 to 1.10; P = 0.079). Nine RCTs (1628 adults and children, proportion of children not reported, most with severe head injury) identified by the review assessed the combined outcome of death or disability, and found no significant difference between corticosteroids and placebo (9 RCTs; 505/927 [54%] with corticosteroids v 340/701 [49%] with placebo or no corticosteroids; RR 1.01, 95% CI 0.91 to 1.11). This analysis did not include data from the CRASH trial.

Harms

Five RCTs (10,798 adults and children) identified by the review, including the CRASH trial, assessed infectious complications and found no significant difference between corticosteroids and placebo or no corticosteroids (2586/5347 [48%] with corticosteroids v 2560/5451 [47%] with placebo or no corticosteroids; RR 1.03, 95% CI 0.99 to 1.11). There was also no significant difference in gastrointestinal bleeding between corticosteroids and placebo or no corticosteroids (10 RCTs, including CRASH; 95/5722 [1.6%] with corticosteroids v 72/5580 [1.3%] with placebo or no corticosteroids; RR 1.23, 95% CI 0.91 to 1.67).

Comment

In the CRASH trial, the main cause of death was not analysed. The mechanism remains uncertain, but is unlikely to be related to corticosteroid complications. Neither the CRASH trial nor the systematic review reported data on hypotension, which is known to be strongly associated with mortality after traumatic brain injury.

Substantive changes

Corticosteroids: One updated systematic review identified no new evidence on the effects of corticosteroids. Categorisation unchanged (Likely to be ineffective or harmful).

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

RESOURCES