J'ournal ofNeurology, Neurosurgery, and Psychiatry 1995;58:753-755 753

FOR DEBATE J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.6.753 on 1 June 1995. Downloaded from

Prescribing of potentially harmful to patients admitted to hospital after head injury

Larry B Goldstein

Abstract tion. It is clear, however, from recent labora- Fundamental studies in laboratory ani- tory studies that recovery after focal brain mals show that certain drugs influence injury can be affected by certain drugs that behavioural recovery after brain injury. influence the activities of specific central neuro- Although some drugs have the potential transmitters.45 Even small doses of some to enhance recovery, others may be drugs given after brain injury can have long detrimental. The purpose of the present lasting beneficial or harmful effects on recov- study was to determine how often these ery. -8 For example, amphetamine is among potentially detrimental drugs are used in the most extensively studied drugs with the the management of patients with trau- capacity to facilitate recovery after focal brain matic brain injury. The medical records injury.6 9 Coadministration of of 100 patients with head trauma admit- blocks amphetamine promoted recovery and ted to a university hospital during one haloperidol impairs recovery when given year were reviewed and the frequencies alone.616 Treatment with a centrally acting a, of prescriptions during the () stay in hospital were recorded. Only 14% interferes with motor recovery after focal sen- of patients with head injury were taking sorimotor cortex injury in rats.17 Postlesion at the time of injury. All of systemic administration of an a, adrenergic the patients were prescribed medications receptor antagonist (, idazoxan) during their stay in hospital. Seventy two is beneficial'7-20 whereas the a2 adrenergic per cent of the patients received one or a receptor agonist impairs motor combination of the drugs (neuroleptics recovery when given soon after brain injury7 and other central receptor and reinstates motor deficits in recovered antagonists, benzodiazepines, and the rats.'7202' Intracortical infusion of the anticonvulsants phenytoin and pheno- inhibitory y aminobutyric barbitone) that animal studies suggest acid (GABA) increases the hemiparesis pro- http://jnnp.bmj.com/ may impair recovery. Until the true duced by a small motor cortex lesion in rats." impact of these classes of drugs on the The deleterious effect of GABA is increased recovery process is better understood, by the systemic administration of phenytoin,'3 care should be exercised in their use. which may act through a GABA mediated mechanism.'4 The short term administration (3 Neurol Neurosurg Psychiatry 1995;58:753-755) of diazepam, a benzodiazepine that acts as an

indirect GABA agonist, permanently impedes on October 1, 2021 by guest. Protected copyright. recovery from the sensory asymmetry caused Keywords: head trauma; recovery by anteromedial neocortex damage in rats.8 Phenobarbitone administration to rats recov- Traumatic brain injury affects 200 to 400 ering from cortical injury is also detrimental25 Department of persons per 100 000 population in the United whereas carbamazepine does not influence Medicine (Neurology) States and has a peak incidence in the second the recovery process.'6 Drugs affecting and Center for Health acetyl- Policy Research and and third decades of life.' A second peak in choline and glutamate may also influence Education, Duke incidence occurs in the sixth decade.' recovery.'7-" Certain of the new experimental University, Durham Although 5%-10% of traumatic brain injury neuroprotective agents may actually be harm- NC27719, USA and cases are fatal Durham Department (overall mortality of 25 per ful if given at particular times during the of Veterans Affairs 100 000 population), most people have only recovery process.303' Medical Center, minor injuries and do not come to medical Preliminary clinical evidence suggests that Durham NC 27705 attention.' USA Moderate head injury (Glasgow the same drugs that influence recovery in lab- L B Goldstein coma scale 9-12) affects 60-75 000 persons oratory animals may also affect recovery in Correspondence to: each year.' Of patients with moderate trau- humans after both stroke32-36 and traumatic Dr Iarry B Goldstein, Box matic brain injury, two thirds are moderately brain of the 3651, Duke University injury.37-39 Many possibly harmful Medical Center, Durham, to severely disabled three months after the drugs identified through laboratory investiga- NC 27710, USA. injury.3 tions (the antihypertensives clonidine and Received 7 October 1994 Potential interventions for traumatic brain prazosin, neuroleptics and other and in revised form central 5 January 1995 injury generally consist of primary prevention, dopamine receptor antagonists, benzodi- Accepted 10 January 1995 reduction of acute sequelae, and rehabilita- azepines, and the anticonvulsants phenytoin 754 Goldstein

and phenobarbitone) are commonly pre- P < 0-001). There were no differences in

scribed for stroke patients for the treatment of survival based on racial group, sex, age, or J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.6.753 on 1 June 1995. Downloaded from coincident medical problems.40 The purpose whether craniotomy or other surgical proce- of the present retrospective study was to dures were performed during the stay in determine how often these potentially detri- hospital (P > 0 05 for each comparison). mental drugs are used in the management of a The mean duration of stay in hospital of group of patients with traumatic brain injury. the 85 survivors was 21 (range 1-129) days. Seventy per cent of survivors were male and 64% were white. Seventy one per cent had Patients and methods closed head injury, 27% had an associated Patients with head trauma admitted to Duke skull fracture, and 2% had a gunshot wound. University Hospital between 1 January and Twenty one per cent of these patients under- 31 December 1990 were identified through a went craniotomy and 23% had other opera- prospective registry. A retrospective chart tions. Eight per cent of patients had a history review was then carried out to determine of seizures and 16% had seizures during the what drugs were prescribed for these patients postinjury period in hospital. There was no during their stays in hospital. A variety of significant difference in the incidence of clinical variables were also recorded including seizures after injury between those with and age, sex, race, medical history, admission without a history of seizures (2% v 11%, Glasgow coma score (GCS),4' brain CT find- P = 0-7). ings, the occurrence of postinjury seizures, Only 14% of patients with head injury and whether craniotomy or other surgery was were noted in their hospital records to have performed. been taking medications at the time of injury. X2 tests were used for statistical compar- All of the patients were prescribed medica- isons of categorical data. The Mann-Whitney tions during the stay in hospital. The table U test was used for ordinal, non-continuous gives the frequency of prescription by class data. Student's t test was used for continu- for drugs given to more than 10% of the ous, normally distributed data. patients. Anaesthetic agents used during sur- gical procedures and drugs used for the treatment of cerebral edema (mannitol, Results frusemide) are excluded from the list. The One hundred and five patients were identified benzodiazepines were the drugs most often through the registry. Hospital charts could prescribed which, based on laboratory stud- not be located for five patients. Of the ies, might impair recovery after brain injury remaining 100 patients, there were 72 men (given to 40% of the patients). Almost half of and 28 women. Sixty six per cent of the the patients were given either a neuroleptic or patients were white. Most of the remainder another centrally acting dopamine receptor (31% of the total) were African-American. antagonist. Of the 20 patients given anticon- The mean age of the patients was 38 years. vulsants, 17 received phenytoin and three Fourteen patients died while in hospital and received phenobarbitone (alone or in combi- one was prematurely discharged against the nation with other anticonvulsant medica- advice of his physicians. As expected, the tions). Thus a total of 72% of patients

median admission Glasgow coma score of received one or a combination of potentially http://jnnp.bmj.com/ those who died was significantly lower detrimental medications. Twenty nine than for those who survived (3.0 v 13-5, patients (34%) were prescribed a single and 32 (38%) were prescribed a combination of these agents. Drugs prescribedfor more than 10% ofpatients in hospital after head injury (n = 85) Patients Discussion prescribed on October 1, 2021 by guest. Protected copyright. class (n (%)) The primary finding of the present study is that certain classes of drugs found to impair Narcotic 71 (84) Paracetamol 70 (82) recovery after brain injury in studies with lab- Antibiotic 62 (73) oratory animals are often prescribed for Neuroleptic/dopamine antagonist* 41 (48) 21 (25) patients with head injury (neuroleptics and Metoclopramide 9 (11) other central dopamine receptor antagonists, Haloperidol 6 (7) Combination 4 (5) benzodiazepines, and the anticonvulsants 1 (1) phenytoin and phenobarbitone). Whether the Ranitidine 37 (44) Benzodiazepine* 34 (40) detrimental effects of specific drugs antici- Miscellaneous antacid 30 (35) pated from laboratory studies also occurs in Anticonvulsant 20 (24) Phenytoin t 16 (19) humans recovering from brain injury is diffi- Carbamazepine 1 (1) cult to determine. One study found that long Phenytoint + phenobarbitonet 1 (1) Carbamazepine + phenobarbitonet 2 (2) term administration of phenytoin for prophy- Cimetidine 14 (16) laxis of post-traumatic seizures may be Other sedative-hypnotic 13 (15) Other non-narcotic analgesic 13 (15) detrimental.39 Both phenytoin and carba- 9 (11) mazepine may have negative effects on cogni- *Entire classes of drugs and tindividual drugs that laboratory tive performance in patients recovering from studies suggest may impair behavioural recovery after brain brain trauma.4' The duration of post-trau- injury (neuroleptics and other central dopamine receptor antagonists, benzodiazepines, and the anticonvulsants pheny- matic amnesia and agitation was longer in toin and phenobarbitone; see text) patients treated with haloperidol than in Prescribing ofpotentially harmrful drugs to patients admitted to hospital after head injury 755

16 Hovda DA, Feeney DM. Haloperidol blocks ampheta- those managed without this drug.43 Clinical mine induced recovery of binocular depth perception data relating to the potential beneficial effects after bilateral visual cortex ablation in the cat. Proc West J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.6.753 on 1 June 1995. Downloaded from Pharmacol Soc 1985;28:209-1 1. of certain drugs on recovery after traumatic 17 Feeney DM, Westerberg VS. and brain brain injury is also limited. Anecdotal reports damage: alpha noradrenergic pharmacology alters func- indicate that treatment with amphetamine tional recovery after cortical trauma. Can J Psychol 1990;44:233-52. improves cognitive function in young adults 18 Goldstein LB. Amphetamine-facilitated functional recov- ery after stroke. In: Ginsberg MD, et al, eds. with post-traumatic organiic brain syndrome.38" Cerebrovascular diseases, sixteenth research (Princeton) con- Both amantadine45 and levodopa37 have been ference. New York: Raven Press, 1989:303-8. 19 Goldstein LB, Poe HV, Davis JN. An animal model of used in the treatment of small groups of recovery of function after stroke: facilitation of recovery patients with severe traumatic brain injury. by an a2- antagonist. Ann Neurol In summary, it is clear that certain drugs 1989;26: 157. 20 Sutton RL, Feeney DM. a-Noradrenergic agonists and influence behavioural recovery in laboratory antagonists affect recovery and maintenance of beam- animals after brain injury. These drug effects walking ability after sensorimotor cortex ablation in the rat. Restorative Neurology and Neuroscience 1992;4: 1-11. can be either beneficial or detrimental. 21 Stephens J, Goldberg G, Demopoulos JT. Clonidine rein- states deficits following recovery from sensorimotor cor- Similar drug effects may occur in humans. tex lesion in rats. Arch Phys Med Rehabil 1986;67:666-7. Certain of the drugs found to be harmful in 22 Brailowsky S, Knight RT, Blood K. y-aminobutyric acid- laboratory studies are commonly employed in induced potentiation of cortical hemiplegia. Brain Res 1986;362:322-30. the management of the patient with head 23 Brailowsky S, Knight RT, Efron R. Phenytoin increases Whenever clinically feasible, drugs not the severity of cortical hemiplegia in rats. Brain Res injury. 1986;376:71-7. known to impair recovery should be used in 24 Chweh AY, Swinyard EA, Wolf HH. Involvement of a those with potentially detrimental GABAergic mechanism in the pharmacologic action of place of phenytoin. Pharmacol Biochem Behav 1986;24:1301-4. effects (for example, carbamazepine could be 25 Hernandez TD, Holling LC. 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