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. Author manuscript; available in PMC: 2013 Nov 22.
Published in final edited form as: J Am Coll Surg. 2010 Jun;210(6):10.1016/j.jamcollsurg.2010.01.036. doi: 10.1016/j.jamcollsurg.2010.01.036

The Influence of Alcohol on Mortality in Traumatic Brain Injury

Razvan C Opreanu 1, Donald Kuhn 2,3, Marc D Basson 1,2
PMCID: PMC3837571  NIHMSID: NIHMS201013  PMID: 20510810

Introduction

Traumatic brain injury (TBI) represents a major public health problem. Each year, 1.4 million people sustain TBI in the United States. 235,000 patients are hospitalized and 50,000 die. The leading cause of TBI in the general population is falls, where rates are highest among children ages 0 to 4 and among adults ages 75 or older. Falls are followed closely by motor vehicle crashes and assaults as overall causes of TBI. However, motor vehicle crashes result in the greatest number of TBI-related deaths and hospitalizations 1.

TBI injuries are extremely costly from a public health perspective since they require expenditures for hospital care, extended care, and other medical services, as well as the loss of productivity that may follow the permanent neurological consequences of TBI. For example, the Centers for Disease Control and Prevention estimated that at least 5.3 million patients have a long-term or lifelong need for help with activities of daily living because of TBI 2. As early as 1985, the annual economic burden of TBI in the United States was estimated at $37.8 billion 3, and over the past several years it has increased to almost $60 billion annually 4. One source estimated the cost of acute care and rehabilitation for new cases of TBI at $9 to $10 billion annually in 1999 5. In addition, the psychosocial burden borne by families of individuals with TBI must be taken in account even though it cannot be financially evaluated. Although not all of these figures are from the current decade, it is clear that TBI represents a prevalent and costly public health issue.

Alcohol contributes substantially to the morbidity and mortality of trauma patients, regardless of the type of injury suffered 6-9. Serum alcohol levels correlate closely with the extent of injury 10-12. In 2006, alcohol intoxication was involved in 32% of fatal motor-vehicle crashes in the United States 13. Approximately half of the alcohol-related deaths in trauma occur in pre-hospital settings 9, 14. Specifically in TBI, 35-81% of the injured patients are alcohol-intoxicated 15-16 and 42% of the TBI patients were heavy drinkers before injury 16. A study from the National Trauma Databank found similar rates 17.

In contrast to the strong correlation between alcohol and pre-hospital mortality in TBI victims, the effects of alcohol on the outcome of injured patients surviving the field and admitted to the hospital is less clear. Indeed, some clinical studies surprisingly seem to suggest a beneficial effect of alcohol in injured patients with TBI. This review will analyze basic research in animal models and available clinical information to provide a realistic perspective regarding the effect of alcohol on the outcome of patients admitted to the hospital with a diagnosis of TBI. The investigational literature can be categorized into studies of the effects of low- moderate doses of alcohol in TBI animal models, investigations into the effects of high doses of alcohol in such models, and experiments directed at elucidating the mechanisms of such effects. We will consider each in turn before moving to the clinical literature.

Experimental studies

No single experimental model of TBI can reproduce the clinical characteristics of TBI 18. Clinical TBI is complex, involving both focal and diffuse brain injuries. Moreover, most patients have secondary insults that contribute to the intricate TBI picture. For instance, systemic hemorrhage with hypotension can alter cerebral perfusion, as can intracranial bleeding that increases intracranial pressure and decreases cerebral perfusion despite the hypertension of Cushing’s reflex. Along with altered cerebral perfusion, changes in levels of inflammatory cytokines, differences in oxygenation, sepsis, and many other factors contribute to the complex global physiologic derangement observed after injury.

The experimental-clinical translation of knowledge can be limited by the size and anatomic complexity of the animal model. Most experimental TBI studies use rodents. Few studies have used sheep or pigs, perhaps because of financial or animal welfare considerations. The different brain geometry among diverse species is likely a confounding factor, and findings in animal studies might not translate in the same fashion to humans 19. The mechanism by which TBI is created also varies among studies, and is necessarily more standardized and different from human TBI mechanisms. Three types of animal TBI model have been described: focal, diffuse and combined focal and diffuse brain injury 18. In most clinical cases, the human brain suffers a combined diffuse and focal form of injury. Weight drop, fluid percussion, impact acceleration or controlled cortical impact models have been created to replicate the characteristics of human TBI. These forces have been applied on the lateral cortex or over the midline. Each causes different cortical cellular pathophysiology that to a variable extent resembles the injury suffered by the human brain.

In addition, clinical studies generally focus on severe TBI, defined as a Glasgow Coma Score (GCS) below eight. In contrast, experimental studies cannot accurately replicate such severe brain injury because of the high resulting fatality rate, so most animal studies model less severe TBI. Anesthetic management also varies between clinical settings, in which propofol or benzodiazepines are commonly used after TBI, and experimental models in which anesthesia is typically applied prior to TBI because of animal welfare considerations, and in particular propofol or benzodiazepines are associated with the poorest outcomes 19.

Clinical data suggests the potential importance of demographic variables in TBI outcomes, in a manner not necessarily consistent with animal data. Such factors as gender and age have been identified as important in clinical TBI. Although the clinical opinion is that women experience better outcomes than men 20, some research studies were not able to prove this. In one study, female patients with head injury had significantly worse intracerebral pressure reactivity and higher mortality than men 21. However, a metaanalysis yielded contradictory results with no clear conclusions on this subject 20. Although male rats exhibit better cognitive recovery than females rats 22, no gender differences were found in humans 5. Increased mortality is expected in older patients, probably because of associated comorbidities 23. Most animal studies use either healthy female or male rats with narrow age ranges. Such homogenous groups of animals cannot reflect the demographic, genetic, and clinical variability of humans injured in TBI trauma.

Differences in pharmacokinetics, dosing, or cell susceptibility to alcohol among models or species could also add to the complexity of the translation between experimental models and humans. Alcohol metabolism in the liver depends on the amount of alcohol dehydrogenase present. This varies among humans, and has genetic determinants 24. Alcohol absorption and metabolism are influenced by ingested food and gender. Alcohol is three times more slowly absorbed if there is food in the stomach 25 and women consuming similar amounts of alcohol as men are more susceptible to brain or heart muscle damage 26-27. Body weight also critically influences alcohol effects. For example, a 70kg man would have to consume three drinks of alcohol to reach a blood concentration of 0.10% (100mg/dL). A 100kg man would have to consume five drinks to reach the same blood concentration. However, these metabolic features are common to humans and variation among species would also probably be expected.

Effects of low to moderate doses of alcohol in experimental TBI

Bearing such concerns in mind, numerous basic science studies have sought to define the effect of alcohol on the outcome of TBI in rats or swine to establish experimental models that can generate hypotheses to be further tested in humans. Although published reports seem in conflict on first reading, further analysis suggests that exposure to low doses of alcohol exerts qualitatively different results in TBI models than exposure to high dose alcohol. We will consider first the results of studies in which alcohol was administered orally or intragastrically by gavage or injected intraperitoneally at low to moderate doses (less than 1g/kg or 100 mg/dL, approximately 0.1%) (Table 1). Behavioral tests for characterization of motor or cognitive deficits 28-31, histopathology testing of neuronal layers 32 and various physiologic parameters 33-34 were used to determine the outcome in animals after administration of alcohol and experimental TBI in comparison to their respective controls.

Table 1.

Experimental Studies of the Impact of Alcohol Intoxication (Low to Moderate Doses) on Outcomes of Subsequent Traumatic Brain Injury

First author Year Animal
model
Main findings
 Dash 28 2004 Rats Caffeine and alcohol reduced cortical tissue loss and
improved working memory
 Janis 29 1998 Rats Alcohol provided better results on memory probe tests in rats,
reducing the severity of cognitive impairments caused by
 Kelly 30 1997 Rats Less mortality and severe beam-walking impairment in the
low and moderate dose alcohol groups
 Taylor 31 2002 Rats Alcohol attenuated induced hyperthermia and deficits in
spatial learning
 Tureci 32 2004 Rats Less vacuolar degeneration in the pyramidal cell layer in the
low and moderate dose alcohol groups
Gottesfeld 33 2002 Rats Decrease in proinflammatory cytokine production
 Kelly 34 2000 Rats Less reduction in cerebral blood flow and a decreased degree
of uncoupling between glucose metabolism and cerebral
blood flow

Tureci et al. demonstrated less vacuolar degeneration in the pyramidal cell layer in rats with TBI in which alcohol was administered at low to moderate doses and concluded that alcohol may have a neuroprotective role 32. Low dose alcohol was associated with marked attenuation of immediate post-injury hyperglycolysis in rats, with more normal glucose metabolism and less reduction of the cerebral blood flow in the injury penumbra over the contusion site 34. Alcohol pretreatment lowered cytokine levels in the cortex, hippocampus and hypothalamus of rats, while serum corticosterone levels were higher after TBI induction with a low-moderate dose of alcohol compared to controls with corticosterone only 33. Both lower cytokine levels and higher corticosterone levels might contribute to alcohol neuroprotection. Indeed, less impairment of motor and cognitive functions was found in rats that had been administered low-moderate doses of alcohol after TBI generation 28-31. Thus, at least some investigations suggest that low to moderate doses of alcohol may be neuroprotective in experimental animal models of TBI.

Effects of high doses of alcohol in experimental TBI

In contrast to the studies above, some TBI investigators have administered higher alcohol doses above 3g/kg body or 200 mg/dL by the same techniques, exceeding 0.2% blood levels (Table 2). Respiratory impairment is one of the most adverse effects associated with the use of high dose alcohol in swine 35-37. Zink et al. reported increased lactic acid in the brain and decreased organ blood flow in intoxicated swine 36. The same author separately reported multiple hemodynamic changes including decreased mean arterial pressure and cerebral blood flow after administering high dose alcohol 37. Increased brain edema and negative effects on neurobehavioral function have been described in TBI rats receiving higher doses of alcohol as opposed to TBI rats exposed without alcohol 38-39.

Table 2.

Experimental Studies of the Impact of Alcohol Intoxication (High Doses) on Outcomes of Subsequent Traumatic Brain Injury

First author Year Animal
model
Main findings
Zink 35 1995 Pigs Impairment in respiratory control following TBI
Zink 36 1999 Swine Increased in concentration of brain and cerebral venous
blood lactate
Zink. 37 1993 Swine Increased hemodynamic (decreased mean arterial and
cerebral perfusion pressure) and respiratory depression
Katada 38 2009 Rats Increased volume of cytotoxic brain edema after TBI
Yamakami 39 1995 Rats Significantly increased mortality

Exploring the apparent contrast between the effects of low and high dose alcohol on animal TBI, some researchers have employed more than one experimental group, comparing high dose alcohol with low and/or moderate dose alcohol along with control animals not receiving alcohol. Yamakami et al. demonstrated significantly increased mortality and markedly worsened neurological deficits in the high dose alcohol group compared to rats receiving low or moderate doses of alcohol 39. Gottesfeld et al. similarly reported that levels of IL1-β or TNF-α in the cortex, hippocampus or hypothalamus varied depending on whether the experimental rats received low or high dose alcohol 33. Kelly et al. observed that TBI-injured rats receiving low and moderate dose alcohol had significantly less severe behavioral outcomes compared to either rats without alcohol or rats receiving high dose alcohol 30.

Potential mechanisms of alcohol protection in TBI

Thus, although high dose alcohol can worsen TBI, low or moderate doses of alcohol may be neuroprotective. Various mechanisms have been suggested for this neuroprotective effect, including inhibition of NMDAr (N-methyl-D-aspartic acid receptors) or sympathetic response. We will review the extant data in support of these theories.

Blunting of N-methyl-D-aspartic acid receptors

One of the most postulated mechanisms of alcohol neuroprotection is bunting of the NMDAr. NMDAr overactivation increases levels of extracellular excitatory amino acids, glutamate and aspartate. A major release of excitatory neurotransmitters is common after TBI and is believed to be a proximate cause of a series of neurochemical sequelae of cortical injury 40-44. This chain reaction was demonstrated to promote neuronal cell death through calcium influx which activates Ca2+-dependent enzymes that cause mitochondrial lysis 45-47. There is also evidence that the neuronal cell death occurs through sodium influx, which promotes massive cellular swelling 48-49.

This neurochemical reaction has been successfully counteracted using competitive or non-competitive antagonists targeting the binding sites of the NMDAr. Numerous basic science studies have demonstrated that the pharmacologic blockade of NMDAr improves brain metabolic status, attenuates cortical damage and overall limits neurological dysfunction after TBI 41, 50-54.

However, clinical trials of different competitive or non-competitive NMDAr antagonists 55-58 have been uniformly disappointing. None of these trials has shown any benefit for NMDAr blockade in intoxicated TBI patients. The most commonly invoked reason for this failure was the poor pharmacokinetics of these drugs and poor design of the trials 59-61. NMDAr antagonists also have adverse effects including increase in blood pressure, hallucinations or catatonia 62. These effects are encountered mainly with nonselective NMDAr antagonists and limit the dose that can be used clinically. Hardingham et al. showed that synaptic and extra-synaptic NMDAr elicit opposing effects in hippocampal neuron cultures 63. Their study established that stimulation of synaptic NMDAr is anti-apoptotic, whereas extrasynaptic NMDAr stimulation causes loss of mitochondrial membrane potential and neuronal death. Thus, the development of selective antagonists for extrasynaptic NMDAr could prove useful in TBI in the future.

More recently, Ikonomidou and Turski 61 have offered another explanation for the failure of these clinical trials, introducing the concept of a short neuroprotective window. All of the benefits described in animal models of TBI were obtained when administration of the NMDAr antagonists was conducted prior or immediately after the TBI. In fact, neuroprotection is lost when NMDAr antagonist were started 7-10 hours after TBI 52. The overactivation of NMDAr after TBI is short-lived (less than one hour) and is followed by a more chronic upturn of receptor function that lasts more than seven days 64-65. Thus, Ikonomidou and Turski 61 suggested that the NMDAr are indeed overactivated immediately after TBI in experimental models, but only for a short period of time. It would therefore seem that the ideal system to provide neuroprotection against NMDAr overactivation in intoxicated TBI patients would be to administer the antagonists before or immediately after the TBI, when the antagonists appear most efficacious in animal studies 64. This is especially true since some published experimental studies oppose the neuroprotection concept behind the NMDAr blockage. They actually demonstrate that synaptic transmission mediated by NMDAr is essential for neuronal survival and that administration of NMDAr antagonists during the critical period after TBI, when neurodegeneration occurs, exacerbates the neuronal damage 66-67. Similarly to the NMDAr antagonists, alcohol acts by inhibiting the NMDAr synaptic current 68-72.

This short therapeutic time window may explain the failure of clinical trials of NMDAr antagonists. Infusion of NMDAr antagonists was typically started within 8-12 hours after TBI in human trials and continued for 4-6 days after the initial injury. NMDAr blockade was achieved beyond the NMDAr blockade therapeutic window with subsequent impact on the neurological outcome. In conclusion, the short-window of overactivation of NMDAr theoretically explains why low dose alcohol inhibition of NMDAr in the initial period after TBI could be neuroprotective, since the alcohol is metabolized quickly, allowing the NMDAr to return to its normal physiologic function. This same concept might also explain negative outcomes in TBI with high dose alcohol, because of the more prolonged metabolism of higher alcohol levels, proportionally to ingested amounts, in which case prolonged inhibition of NMDAr would be detrimental.

Conclusions can thus be drawn from experimental studies of alcohol impact on NMDAr and the neurophysiology of brain injury, along with data derived from clinical trials of NMDAr blockade. An alternative mode of treatment might administer NMDAr antagonists only in the immediate one hour period after TBI to block the receptor only in the short-window of overactivation of NMDAr. At the same time, consideration should be offered for the extrasynaptic NMDAr activation concept and other pitfalls associated with the use of NDMAr antagonists before further clinical trials should be restarted.

Alcohol blunting of the adrenergic response in TBI

The sympathetic nervous system is central to the stress response to injury. An initial surge in catecholamine levels is common after TBI, followed by a prolonged hyperadrenergic state 73-78. The response of circulating hormonal levels correlates proportionally with the neurological impairment reflected by the admission GCS or Injury Severity Score 74-76. In a clinical study, Hamill et al. found that patients with severe brain injury (GCS 3-8) had a five-fold increase in plasma norepinephrine and epinephrine levels after TBI 74. Furthermore, catecholamine levels predicted the neurological outcome and recovery in these patients. Patients who had an unchanged neurological status one week after the injury consistently showed markedly elevated plasma norepinephrine levels. Woolf et al. found that 12 out of 15 patients with twice normal norepinephrine levels and severe brain injuries (GCS 3-6) either failed to improve neurologically or died, and that norepinephrine and epinephrine levels correlated with the length of hospitalization 75. In a different study, Woolf et al. compared polytrauma patients with and without brain injuries and found that circulating norepinephrine levels significantly correlated with the severity of injury only in patients with brain injury 76.

Studies in mice have investigated the adrenergic contribution to the neurological changes that occur after TBI using β-blockers. By microPET imaging, Ley et al. demonstrated improved cerebral perfusion and decreased cerebral hypoxia in mice treated with propranolol compared to a placebo group 79. In a similar animal study, non-selective β-blockers lessened the volume of brain edema compared to placebo 80. Improved outcomes have been also reported in retrospective clinical studies with the use of β-blockers in TBI, with greatest effect in the elderly and more severely injured. These studies provide Level III evidence that β-blockers improve mortality in injured patients with TBI 81-85.

There is good evidence that alcohol intoxication blunts the sympathetic surge that is observed after TBI since increased alcohol levels are associated with decreased circulating norepinephrine and epinephrine response and improved GCS scores in patients with TBI 86-87. However, only retrospective studies have addressed the potential beneficial effect of sympathetic blockade in TBI. The potential benefits of β-blockers in the prevention of TBI complications and death could be better defined by prospective studies in the future.

Clinical studies of the effect of alcohol in TBI

There has recently been increased interest in research on the effects of alcohol in specific TBI populations, driven by a combination of attractive basic science data, the failure of most clinical trials, and the contradictory results of retrospective studies of mortality in alcohol-intoxicated patients with multiple injuries with or without TBI. It is important to distinguish here between studies that examined mortality in patients with or without TBI and other associated injuries and studies that were limited to patients with TBI with or without associated injuries.

When the study population comprised traumatized patients that did not necessarily have TBI, various researchers have demonstrated increased, decreased or no difference in mortality in intoxicated patients admitted to the hospital. For instance, Luna et al. found a fourfold increase in mortality in intoxicated compared with unintoxicated motorcyclists 88. Moreover, the protective effect of the helmet was lost in intoxicated patients. Similarly, in a more heterogeneous population with polytrauma resulting from motor vehicle crashes, falls or sports injuries, Pories et al. reported increased mortality in intoxicated patients 11.

In contrast, some researchers reported decreased mortality among intoxicated patients with any type of injury, not necessarily TBI. Plurad et al. found decreased mortality in victims of motor vehicle crashes with high dose compared to low dose alcohol 89. Other researchers have also reported decreased mortality after alcohol intoxication with various mechanisms of injuries such as assaults, burns or stabbing resulting in a high preponderance of blunt over penetrating injuries, and again without necessarily including TBI 90-91.

In the setting of some reports of increased mortality and some of decreased mortality in intoxicated trauma patients, it is important to recognize that many investigators have found no statistically significant differences in mortality of alcohol intoxicated injured patients in either direction 92-96. These studies included patients with any type of injury and not necessarily with TBI. For example, Jurkovich et al. performed a subgroup analysis based on time of death, i.e. in the field, trauma bay, within 24 hours of admission, or after longer hospitalization 93. Although there were was no evidence that alcohol affected mortality in these groups of patients, subgroup analysis based on mechanism of injury, magnitude of hemodynamic or inflammatory alterations, or type of TBI could be more revealing.

In contrast to these studies of patients with any type of injury, some researchers have aimed to test mortality in a specific cohort of patients with TBI without or with other associated injuries. Studies restricted to TBI patients still demonstrate some inconsistencies, but may be more readily understandable (Table 3). One of the first studies of the association between alcohol and mortality in TBI was published in 2004 by Alexander et al. This study found no impact of alcohol levels at admission on mortality 97. However, the small sample size of this study may have obscured a significant difference between the patient groups, if present. Tien et al in 2006 were the first to report significant differences in mortality in TBI patients depending upon alcohol levels 98. In this seminal study, the authors divided the patients into three groups based on admission alcohol levels. These groups were no alcohol (0 mg/dL), low-moderate alcohol (less than 230 mg/dL), and high alcohol (above 230 mg/dL). The low-moderate alcohol group exhibited better survival than the no alcohol group. In contrast, compared to the same no alcohol reference group, the high alcohol group demonstrated worse survival rates. O’Phelan et al. reported similar findings in 2008 in a more diverse population including patients with substance abuse as well as alcohol intoxication 99.

Table 3.

Clinical Studies of the Impact of Alcohol Intoxication on Outcomes of Subsequent Traumatic Brain Injury

First author Year No. pts
included
No. pts
excluded
Patient groups Mortality outcomes
Alexander 97 2004 80 (42%) 108 (58%) Three groups
0 mg/dL; 1-100 mg/dL; >100
mg/dL
No difference in mortality
among the three groups of
patients
Tien 98 2006 3675
(89.7%)
424
(10.3%)
Three groups
0 mg/dL; 0-230 mg/dL; >230
mg/dL
Increased mortality in the
>230 mg/dL group when
compared to the 0 mg/dL
group
Decreased mortality in the
0-230 mg/dL group when
compared to the 0 mg/dL
group
O’Phelan 99 2008 255 (52.8%) 228
(47.2%)
Two groups
Alcohol negative or positive*
Decreased mortality in the
alcohol positive group
Salim 101 2009 482 (47%) 543 (53%) Two groups
Alcohol negative or positive
Decreased mortality in the
alcohol positive group
Salim 17 2009 38019
(52.6%)
34275
(47.4%)
Two groups
Alcohol negative or positive
Decreased mortality in the
alcohol positive group
Shandro 100 2009 836 (54.6%) 693
(45.4%)
Three groups
0.1-100 mg/dL; 101-230
mg/dL; >230 mg/dL
No significant difference in
mortality among these
groups, but a clear trend
toward lower mortality in
the 101-230 mg/dL and
>230 mg/dL groups

All studies had a retrospective design and used abbreviated injury score of three or more for head to select for severe traumatic brain injury. The number of patients included represents the final population used in the analysis. In these studies, patients were excluded due to missing data on blood alcohol levels.

*

In addition to alcohol intoxication, the patients enrolled in this study were under the influence of other various substances (methamphetamine, cocaine or marijuana).

The study by Shandro and colleagues did not demonstrate a statistical significant difference between the different groups of patients but did show a trend toward lower mortality in patients with higher alcohol levels.

Shandro et al. found no statistically significant difference in mortality among patient groups with TBI in 2009, but the data did demonstrate a clear trend toward a beneficial outcome and lower mortality in intoxicated patients with higher blood alcohol levels 100, and so this study may be also consistent with the concept of alcohol neuroprotectivity in clinical TBI. In contrast to previous studies, these authors did not exclude patients who did not have blood alcohol levels measured at admission. Instead, they used a multiple imputation technique to represent the missing data, trying to exclude the bias pertaining to missing values using a modern statistical technique. This method might have contributed to their indefinite result. Salim et al. recently published two other important studies, one using data from the national trauma data bank, and the other focusing on patients from a major trauma center. In each case, alcohol-intoxicated patients regardless of blood levels were compared with patients who tested negative for alcohol. Each study found lower mortality in intoxicated patients with TBI 17, 101. Thus, clinical studies tend to suggest a protective effect of pre-traumatic alcohol intoxication on TBI outcomes, but such studies also have significant limitations.

Influence of pre-TBI alcohol on neuropsychological testing

Besides mortality and morbidity, neuropsychological outcomes have also been investigated in patients with TBI and prior alcohol use. Patients with alcohol abuse and/or alcohol dependence were followed for different periods of time after TBI and neuropsychological/cognitive outcomes were compared with those of sober patients with TBI. Most researchers who have studied individuals with alcohol abuse and alcohol dependence prior to TBI have found inferior performance on neuropsychological/cognitive testing in alcohol-intoxicated patients with TBI 102-105. In contrast, Lange et al. reported that sober patients with TBI performed more poorly in neuropsychological/cognitive testing than intoxicated patients 106. A key difference is that Lange et al. enrolled only alcohol-intoxicated patients at the time of injury and without any history of alcohol dependence. It is important to separate these types of patients into different groups based on the presence of alcohol abuse or dependence since their outcomes may be dissimilar. Whether alcohol intoxication at the time of injury can mitigate the neurological effects of subsequent TBI remains to be determined. In contrast, such neurologic sequelae may promote self-medication with alcohol in TBI patients. Such patients may need alternative strategies to ameliorate their TBI if alcohol cessation is to be achieved.

Limitations of Clinical Studies

Understanding the limitations of the clinical studies that have investigated the effects of alcohol on mortality in TBI patients is important to design more effective research in the future. Such clinical studies are unavoidably retrospective since prospective trials offering alcohol to an intervention group would probably be unethical unless strong evidence can be developed first for a protective effect. The same guidelines for control of confounding variables should be considered with regard to medications or other potential treatments. For example, future research designs should take into consideration the potential neuroprotective affect of β-blockers.

One discrepancy among extant clinical studies is the definition of the study groups. Some researchers have ascertained only the presence or absence of blood alcohol, while others 98, 100 have categorized patients into upon the magnitude of their blood alcohol levels. Future studies should incorporate these considerations in their design for the same purpose as stated above.

Another concern about the inclusion criteria for many previous studies is that some patients did not have blood alcohol levels measured at admission and therefore were excluded from analysis in most studies. The selection bias introduced by the exclusion of this type of data would likely be eliminated by prospective measurements of blood alcohol levels in injured patients. Trauma centers that have incorporated routine alcohol determination in injured patients into routine screening guidelines would be able to perform such a research study without this particular type of bias.

It is also important to distinguish acute alcohol intoxication from chronic alcoholism. Chronic alcoholism is associated with immunosuppression 107-109, and increased risk of infection, particularly pneumonia because of impairment of lung cytokine production 110. Chronic alcoholism might thus be an important factor in mortality and morbidity of patients with TBI that should be considered in these types of research. Serum levels of γ-glutamyltransferase closely correlate with chronic alcohol consumption 111-112 and may be useful in differentiating chronic alcoholism from the trauma victim with acute intoxication.

Most clinical studies on the effects of pre-existing alcohol on TBI have used mortality as the primary endpoint. Other outcome variables including intensive care unit and hospital length of stay, ventilator days or complications have also been considered. Unfortunately, no specific functional neurological outcomes were addressed in these studies. This represents another opportunity for further research.

Another important limitation of these studies is the lack of analysis based on specific types of injuries. Blunt or penetrating injuries might have different outcomes in terms of morbidity and mortality which could be specific to each type. It is probably also important to seek specific outcome patterns based on the location of the injury, i.e. frontal, temporal or occipital lobes. Moreover, interplay with other associated injuries can obscure the influence of alcohol on TBI, and should be carefully tracked in future studies.

Alcohol consumption after TBI

Patterns of alcohol consumption following TBI have recently received considerably more attention in the literature. In general, after TBI, alcohol drinking varies over time. Early in the recovery period, alcohol use tends to decline 113-116. Indeed, 20-80% of the patients with previous alcohol abuse problems tend to stop abusing alcohol for at least a short period of time after TBI 113-114, 117. However, many of these patients that initially overcome alcohol abuse after TBI then relapse into the alcohol abuse patterns of their pre-injury period. Indeed, heavy drinking increases with time after TBI 114, 116, 118. Moreover, it appears that a history of alcohol drinking prior to injury is a strong predictor of heavy drinking after TBI 119. Not unexpectedly, patients with less education tend to have higher relapse drinking rates 102. In contrast, higher alcohol levels on admission also may predict a decrease in drinking after TBI 116. A more severe TBI, as defined by initial GCS, seems to also predict decreased drinking after TBI. The last two variables may actually be covariates since a higher alcohol level is associated with more severe injuries in trauma patients 10-12. These findings could be explained by the psychological effect of the injury or limited finances of these patients. In addition, more of the patients with initially lower GCS would seem likely to need placement in extended care facilities where alcohol availability would be limited.

The period of time over which these patients abstain from alcohol is short,. varying from one month to one year after TBI 116. Secondary prevention programs would probably have the greatest success when implemented during this opportunity window, as described by Bombardier et al. 115, especially since during this period of time, patients frequently contemplate changing their alcohol habits 120.

Consumption of alcohol after TBI is associated with several complications. Patients are at increased risk of recurrent TBI upon returning to their pre-injury alcohol habits 121. Continuation of alcohol drinking after TBI is also associated with more atrophy of the cerebral cortex 122, development of post-traumatic seizures 123-124 and deterioration of behavioral functioning 125-126. Overall, the data suggests that secondary prevention of subsequent complications resulting either directly from recurrent TBI or from effects of alcohol on a previously injured cortex, should be implemented early after TBI.

Conclusion

Considerable progress has been made to elucidate the role of alcohol in TBI by both experimental and clinical studies. That the resulting data is somewhat contradictory is probably not surprising, considering the complexity of the pathophysiologic response that accompanies TBI and any other associated injuries. Secondary prevention of alcohol abuse after TBI is as important as primary prevention and should be emphasized in the first month after the injury. There is a substantial need for further clinical and experimental research with regards to the mechanisms responsible for the neurophysiology of TBI. For clinical studies in particular, a systematic approach might be beneficial in which details about possible confounders are taken into account. Potential mechanisms of alcohol effects on TBI including blockage of NMDAr and sympathetic surge need to be investigated in detail to be able to identify new opportunities for treatments to decrease mortality and morbidity in clinical settings. In the interim, screening for alcohol intake in trauma patients, good clinical care to prevent TBI, and subsequent counseling regarding the dangers of further alcohol intake are definite weapons available to the practicing trauma surgeon today.

Footnotes

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