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Published ahead of print on August 16, 2007, doi:10.1164/rccm.200702-290OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 1001-1006, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200702-290OC

Original Article

Apolipoprotein E Genotype and Response of Carbon Monoxide Poisoning to Hyperbaric Oxygen Treatment

Ramona O. Hopkins1,2, Lindell K. Weaver2,3, Karen J. Valentine4, Chrissa Mower5, Susan Churchill2 and John Carlquist5

1 Psychology Department and Neuroscience Center, Brigham Young University, Provo, Utah; 2 Pulmonary and Critical Division, Department of Medicine, LDS Hospital, Salt Lake City, Utah; 3 University of Utah School of Medicine, Salt Lake City, Utah; 4 Institute for Health Care Delivery Research, Intermountain Healthcare, Salt Lake City, Utah; and 5 Department of Cardiology, LDS Hospital, Salt Lake City, Utah

Correspondence and requests for reprints should be addressed to Ramona O. Hopkins, Ph.D., Critical Care Medicine, LDS Hospital, Eighth Avenue and C Street, Salt Lake City, UT 84143. E-mail: ramona.hopkins{at}intermountainmail.org


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Hyperbaric oxygen (HBO2) reduced the incidence of cognitive sequelae 6 weeks after carbon monoxide (CO) poisoning compared with normobaric oxygen (NBO2). The apolipoprotein (APOE) {epsilon}4 allele predicts unfavorable neurologic outcome after brain injury and stroke.

Objectives: To assess the effects of the {epsilon}4 allele on 6-week cognitive sequelae after CO poisoning.

Methods: We tested APOE genotypes in 86 of 152 CO-poisoned patients from our randomized trial. Logistic regression was used to control for risk factors while testing for effects with the {epsilon}4 allele or interactions with {epsilon}4 and treatment on 6-week and 6- and 12-month cognitive sequelae.

Measurements and Main Results: We enrolled 86 patients: 44 received HBO2 and 42 NBO2 therapy. A total of 31 (36%) patients had at least one {epsilon}4 allele. Six-week cognitive sequelae rates for patients treated with HBO2 and NBO2, respectively: {epsilon}4 allele absent, 11% (3/27) and 43% (12/28); {epsilon}4 allele present, 35% (6/17) and 29% (4/14). The {epsilon}4 allele was not associated with 6-week cognitive sequelae, 27% (15/55) without and 32% (10/31) with the {epsilon}4 allele (P = 0.323). The interaction between the {epsilon}4 allele and treatment was significantly associated with 6-week cognitive sequelae (P = 0.048). The interaction between the {epsilon}4 allele and treatment was not associated with 6- and 12-month cognitive sequelae.

Conclusions: HBO2 therapy reduces cognitive sequelae after CO poisoning in the absence of the {epsilon}4 allele. Because apolipoprotein genotype is unknown at the time of poisoning, we recommend that patients with acute CO poisoning receive HBO2.

Key Words: apolipoprotein • carbon monoxide • cognitive • genotype • outcomes



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
There is no information regarding the role of the APOE 4 allele on cognitive outcomes or its affect on hyperbaric oxygen (HBO2) treatment after acute CO poisoning.

What This Study Adds to the Field
HBO2 therapy reduced cognitive sequelae in the absence of the APOE 4 {epsilon}4 allele.

 
Carbon monoxide (CO) poisoning can result in cognitive sequelae (1). The precise mechanism(s) of brain injury that results in cognitive impairments is unknown. Numerous pathophysiologic mechanisms have been proposed for CO-related brain injury, including hypoxia (2), lipid peroxidation resulting in oxidative injury (3), damage to the vascular endothelium due to deposition of peroxynitrite (4), inflammation (5), excitotoxicity (6), apoptosis or programmed cell death (7, 8), and inhibition of mitochondrial function (9). The degree of CO poisoning, magnitude of physiologic derangements (hypoxemia, hypotension, etc.), and markers of poisoning severity (e.g., carboxyhemoglobin levels or loss of consciousness) do not necessarily correlate with the presence, development, or severity of the observed cognitive deficits (10). The lack of predictability of outcome based upon poisoning severity raises the possibility of individual susceptibility to brain injury after CO poisoning. That is, certain CO-poisoned patients may be genetically predisposed to poor cognitive outcomes based on the presence or absence of various genotypes, such as apolipoprotein E (APOE).

APOE is a 299–amino acid lipid-binding protein with three human isoforms, designated {epsilon}2, {epsilon}3, and {epsilon}4, which are encoded by three different alleles mapped to a single gene locus on chromosome 19. The {epsilon}4 polymorphism allele frequency occurs in approximately 14–25% of the population (11), the {epsilon}3 in 78% (12), and the {epsilon}2 in about 8% of the population (12). In the nervous system, APOE is involved in the distribution of cholesterol in the brain for membrane synthesis and neuritic growth and repair (13). APOE synthesis is up-regulated by astrocytes and oligodendrocytes after central nervous system injury, and is postulated to be involved in neural injury and/or repair (14). The {epsilon}4 allele is a risk factor for the development of Alzheimer's disease (15), and predicts poor neurologic outcomes after traumatic brain injury (16), hemorrhagic stroke (17), and cardiac bypass surgery (18). The {epsilon}4 isoform generally has detrimental central nervous system effects (15), whereas {epsilon}2 may be neuroprotective (19). Given that the presence of the {epsilon}4 allele is associated with poor neurologic outcomes in other disorders raises the question as to whether the {epsilon}4 allele contributes to the development of unfavorable cognitive sequelae after acute CO poisoning. The purpose of this study was to determine if the APOE genotype modified the effect of hyperbaric oxygen (HBO2) therapy in preventing cognitive sequelae in patients with acute CO poisoning. Preliminary data from this study were previously published in abstract form (20).


   METHODS
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Of the 152 patients in our randomized clinical trial of acute CO poisoning (1), 86 were enrolled in this ancillary prospective APOE genotyping study. The APOE study began after our randomized clinical trial. A total of 66 of the patients were ineligible for the study, as we were unable to obtain blood for genotyping because we began to store blood after these patients were already enrolled in the clinical trial. Patients were eligible for the parent randomized clinical study if they had a documented (elevated carboxyhemoglobin levels or ambient CO concentrations), or obvious CO exposure and any of the following: loss of consciousness, confusion, headache, malaise, fatigue, forgetfulness, dizziness, visual disturbances, nausea, vomiting, cardiac ischemia, or metabolic acidosis (calculated base excess less than –2.0 mEq/L, or a lactate greater than 2.5 mmol/L). Patients were excluded if: more than 24 hours had elapsed since the CO exposure had ended; age was less than 16 years at the time of CO poisoning; patient was moribund; informed consent could not be obtained; or the patient was pregnant. Patients were recruited from Utah, Idaho, and Wyoming from November 1992 through February 1999. The institutional review board at LDS Hospital approved this prospective outcome and APOE genotyping study. Written, informed consent was obtained from patients or their surrogates before study enrollment.

The oxygen therapy of randomized trial patients was described previously (1). Briefly, patients breathed nonrebreather reservoir facemask oxygen followed by HBO2 or continued facemask oxygen. Intubated patients breathed 100% oxygen before and during HBO2 or the normobaric oxygen (NBO2) sessions. The mean duration of total high-concentration oxygen therapy through chamber session one was 6.9 hours for the NBO2 group and 7.0 hours for the HBO2 group (1). The patients treated with HBO2 were initially compressed to 3.0 atmospheres absolute (atm abs) (304 kPa) for 50 minutes followed by 60 minutes at 2.0 atm abs (203 kPa). In 6- to 12-hour intervals, they received two additional HBO2 sessions at 2.0 atm abs for 90 minutes. Five-minute air breathing periods were provided every 25 minutes while at 3.0 atm abs and every 30 minutes while at 2.0 atm abs (1).

Data Collection
At enrollment in the randomized clinical trial, data concerning demographics, physiology, comorbid conditions, oxygen therapy, and medications, together with details of CO poisoning, were recorded. Neuropsychological data were obtained 6 weeks after CO poisoning. A battery of neuropsychological tests was conducted, consisting of general orientation, digit span (21), Trail Making (parts A and B) (22), digit-symbol (21), block design (21), and story recall (23). All tests were reliable and valid, and were administered using standardized formats (24), in private, quiet examination rooms. A priori, cognitive sequelae were considered to be present if any 6-week neuropsychological subtest T score was greater than 2 SD below the mean of demographically corrected standardized T scores, or if two or more subtest T scores were each greater than 1 SD below the mean of demographically corrected standardized T scores (mean = 50; SD = 10) (25, 26). If the patient complained of memory, attention, or concentration difficulties, the required neuropsychological test decrement was decreased to greater than 1 SD below the mean of demographically corrected standardized T scores on any one subtest (25, 26).

Apolipoprotein E Genotyping
APOE genotyping was performed on blood and plasma. Whole blood samples were collected and the plasma removed after centrifugation and stored at –70°C. DNA was extracted using QIAamp DNA Mini Kit (Qiagen, Valencia, CA) using a modified spin protocol for blood or body fluids. Genotyping on plasma samples used five times the normal quantity of plasma due to the low concentration of DNA in the plasma samples. Proteinase K-AL buffer and ethanol quantities were adjusted accordingly. The region of the APOE gene bracketing codons 112 and 158 was amplified by polymerase chain reaction using the after primers: forward, 5'- GGCACGGCTGTCCAAGGA-3' and reverse 5'-CTCGCGGATGGCGTGAG-3'. Amplified products were cycle sequenced in the forward direction by employing the same forward primer as for amplification. Sequencing used ABI Big Dye chemistry, v3.1 (University of Utah Core Sequencing Facility, Salt Lake City, UT). Thirteen samples were also sequenced in the reverse direction to resolve equivocal results. Any subject with a T-to-C substitution at the first base of codon 112 was determined to carry the {epsilon}4 allele, and a C-to-T substitution at the first position of codon 158, the {epsilon}2 allele. For each subject, the APOE genotypes were reported as {epsilon}2/{epsilon}2, {epsilon}2/{epsilon}3, {epsilon}2/{epsilon}4, {epsilon}3/{epsilon}3, {epsilon}3/{epsilon}4, and {epsilon}4/{epsilon}4.

Statistical Analysis
Descriptive statistics, including means (±SD) and percents, were calculated for medical, neuropsychological, and treatment type by the presence or absence of the APOE {epsilon}4 allele. The geometric mean (±SD) from log-transformed data was calculated for skewed continuous factors. To test if there were differences in baseline characteristics of CO-poisoned patients with and without the {epsilon}4 allele, two-sample t tests were performed on continuous factors, Fisher's exact tests were performed on dichotomous categorical factors, and chi-square tests were performed on nondichotomous categorical factors. Baseline characteristics were tested at the two-sided 5% significance level.

Primary outcome.
Logistic regression analysis was performed to determine if {epsilon}4 or the interaction with {epsilon}4 and treatment (HBO2 vs. NBO2) were associated with cognitive sequelae 6 weeks after CO poisoning while adjusting for treatment and risk factors. Cognitive sequelae 6 weeks after CO poisoning was the primary outcome and dependent variable for the logistic regression. Independent factors were {epsilon}4 (present or absent), treatment (HBO2 vs. NBO2), the interaction between {epsilon}4 and treatment, and risk factors (age >= 36 yr, intermittent exposure [27]). A two-sided P value of less than 0.05 was considered statistically significant.

Secondary outcomes.
Logistic regression analyses were repeated in order determine if {epsilon}4 or the interaction with {epsilon}4 and treatment (HBO2 vs. NBO2) were associated with cognitive sequelae 6 months and 12 months after CO poisoning while adjusting for treatment and risk factors.

Additional outcomes.
For the primary outcome, logistic regression analyses were repeated using the presence or absence of {epsilon}2 or {epsilon}3 instead of {epsilon}4.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 86 patients were enrolled in this APOE outcome study: 44 received HBO2 therapy and 42 received NBO2 (1). APOE genotypes for the CO-poisoned patients are shown in Table 1. A total of 31 of 86 patients (36%) had at least one {epsilon}4 allele, whereas only 3 patients were homozygous {epsilon}4/{epsilon}4. Baseline characteristics of the patients are shown in Table 2. There was no difference in any baseline characteristic for CO-poisoned patients with the {epsilon}4 allele compared with patients without the {epsilon}4 allele. Of all patients, unfavorable cognitive sequelae were present in 29% (25/86) 6 weeks after acute CO poisoning. For patients without the {epsilon}4 allele, 27% (15/55) had cognitive sequelae compared with 32% (10/31) with the {epsilon}4 allele 6 weeks after acute CO poisoning.


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  		TABLE 1. APOLIPOPROTEIN E GENOTYPE ANALYSIS (n = 86)

 

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  		TABLE 2. BASELINE CHARACTERISTICS OF THE PATIENTS

 
Outcome for the four individuals with {epsilon}2/{epsilon}4 were as follows: one patient was treated with HBO2 and three were treated with NBO2. Two patients had cognitive sequelae, one treated with NBO2 and one with HBO2.

The incidence of 6-week cognitive sequelae for patients treated with HBO2 of 11% (3/27; 95% confidence interval [CI], 2.4–29.2%) was lower than that of those treated with NBO2, 43% (12/28; 95% CI, 24.5–62.8%), in patients without the {epsilon}4 allele (Figure 1). The incidence of 6-week cognitive sequelae for patients treated with HBO2 was 35% (6/17; 95% CI, 14.2–61.7%), and for those treated with NBO2 was 29% (4/14; 95% CI, 8.4–58.1%), in patients when the {epsilon}4 allele was present.


Figure 1
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  		Figure 1. The percent of patients with cognitive sequelae 6 weeks after carbon monoxide poisoning (± SEM). Patients without the {epsilon}4 allele (APOE4) treated with hyperbaric oxygen (HBO2) had significantly lower incidence of cognitive sequelae compared with patients treated with normobaric oxygen (NBO2) (*P = 0.014). There was no significant difference in the incidence of cognitive sequelae for patients with the {epsilon}4 allele treated with HBO2 compared with NBO2.

 
Primary Outcome
When controlling for treatment and risk factors, the presence of {epsilon}4 was not significantly associated with cognitive sequelae 6 weeks after acute CO poisoning (P = 0.32) (Table 3). However, the interaction between the presence of the {epsilon}4 allele and treatment was significantly associated with 6-week cognitive sequelae at the two-sided 5% significance level (P = 0.048).


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  		TABLE 3. LOGISTIC REGRESSION RESULTS FOR THE PRIMARY OUTCOME: COGNITIVE SEQUELAE AT 6 WEEKS (n = 86)

 
Secondary Outcomes
The interaction between the presence of {epsilon}4 and treatment (HBO2 vs. NBO2) with cognitive sequelae was not statistically significant at 6 months (P = 0.15; n = 74) or at 12 months (P = 0.97; n = 77).

Additional Outcomes
When controlling for treatment and risk factors, the presence of {epsilon}2 or {epsilon}3 (P = 0.96 and 0.71, respectively), along with their corresponding interactions (P = 0.83 and 0.99, respectively), was not significantly associated with cognitive sequelae 6 weeks after acute CO poisoning.


   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Among patients without the {epsilon}4 allele, the incidence of neurologic sequelae at 6 weeks was 11% in those treated with HBO2 and 43% for those treated with NBO2. However, among patients with the {epsilon}4 allele, the incidence of cognitive sequelae was 35% in those treated with HBO2 and 29% in those treated with NBO2. Our finding of an APOE–by-treatment interaction for the development of cognitive sequelae after acute CO poisoning is unique, and unexpected. Consistent with previous reports (1), unfavorable cognitive sequelae were common 6 weeks after acute CO poisoning. Importantly, the incidence of cognitive sequelae is 3.9 times lower for CO-poisoned patients treated with HBO2 compared with NBO2 in patients without the {epsilon}4 allele. Patients that possess the {epsilon}4 allele appear to develop brain injury that is not amenable to reduction or palliation by HBO2 therapy.

There was no statistical difference in the incidence of cognitive sequelae for CO-poisoned patients treated with HBO2 compared with NBO2 in patients with the {epsilon}4 allele at 6 and 12 months. The loss of effect at 6 and 12 months may be due to a smaller sample size and decreased rate of cognitive sequelae over time, resulting in insufficient power to detect an effect and instability in the models, or it may be due to smaller or absent effect of the {epsilon}4 allele over time. Replication of this study in a larger sample is needed to determine if the effect of the {epsilon}4 allele remains over time. There was no statistical difference in the incidence of cognitive sequelae for CO-poisoned patients treated with HBO2 compared with NBO2 in patients with the {epsilon}2 or {epsilon}3 alleles at any time point.

Knowledge is limited regarding the role of APOE genotype in modification of responses to a number of therapies. For example, the attention and memory of patients with Alzheimer's disease with the {epsilon}4 allele improved after donepezil treatment (28). Consumption of fatty fish reduced risk of dementia in patients without the {epsilon}4 allele (29). In patients with cerebral amyloid angiopathy, the {epsilon}2 allele is associated with increased warfarin-associated intracerebral hemorrhage (30). Cholesteryl ester transfer protein Taq1B polymorphism predicts reduced death from myocardial infarction (31) and angiographic lesion progression (32) after statin therapy. Although the influence of the APOE {epsilon}4 allele has been identified after brain injury and dementia, the impact related to development of CO-related cognitive sequelae and efficacy of HBO2, or lack there of, is novel. Thus, the risk associated with the {epsilon}4 allele in CO poisoning is only manifest after treatment with HBO2.

In vitro studies find isoform differences in the ability of {epsilon}3 and {epsilon}4 to stimulate neurite outgrowth (33), bind to amyloid (34) and cytoskeletal proteins (35), and protect against oxidative stress (36). The {epsilon}4 allele has the least antioxidant properties (36), likely due to reduced free radical scavenging abilities (37). The APOE distributes cholesterol and phospholipids to neurons after injury, and aids in clearance of cholesterol and lipid debris at the injury site (38). The APOE also modifies neurologic outcome after brain injury, conferring neuroprotection, in some cases, and increased risk of neural injury when the {epsilon}4 allele is present. For example, intraneuronal APOE is markedly increased after brain injury (39), which influences neuronal repair, regeneration, and survival (14).

Data are lacking regarding APOE genotype effects on CO poisoning pathophysiology, cognitive outcomes, or efficacy of HBO2 treatment. The {epsilon}4 allele may somehow inhibit the mechanisms of action of HBO2. Alternatively, the absence of the {epsilon}4 allele may alter CO pathophysiologic pathways, and thus affect the severity of CO poisoning. Recent data suggest apolipoproteins modify central nervous system inflammatory responses and glial activation (40–42). The {epsilon}4 allele may predispose patients to central nervous system inflammation, including glial activation and release of inflammatory mediators, such as IL-6, IL-1beta, and tumor necrosis factor (43), leading to blood–brain barrier disruption, microvascular injury, and cerebral edema. Furthermore, CO poisoning causes brain inflammation (44), for which HBO2 is protective (45). It is possible that the favorable effect of HBO2 on inflammation is APOE {epsilon}4 dependent. Although we do not know how HBO2 reduces cognitive sequelae after CO poisoning, possible beneficial mechanisms include reduced lipid peroxidation (46), reduced oxidative stress (46), preserved ATP activity (47), and favorable modulation of brain inflammation (45). It is conceivable that HBO2 exerts benefit in patients without the {epsilon}4 allele by enhancing oxidative stress mechanisms, or by mechanisms that are presently unknown.

The beneficial reduction in cognitive sequelae with HBO2 occurred in patients without the {epsilon}4 allele. Although methods for point-of-care testing are currently being developed for many genetic markers, current technology does not permit rapid APOE genotyping in the emergency medicine setting. Furthermore, there may be unfavorable ramifications to revealing a patient's genotype (48). Therefore, the clinical implications of our findings support treating patients with acute CO poisoning with HBO2.

The strengths of our study include an adequate sample size and similar baseline characteristics (age, education, CO poisoning variables, etc.) between patients with the presence and absence of the {epsilon}4 genotype. A weakness of our study was an insufficient sample size to determine if the {epsilon}4 allele was detrimental if homozygous, as only three patients were homozygous {epsilon}4 in our study. This suggests that our study had insufficient power to detect differences in these patients. In addition, a smaller or absent effect of the {epsilon}4 allele and/or the smaller sample size and decrease in the rate of cognitive sequelae at 6 and 12 months resulted in insufficient power to determine if the {epsilon}4 allele–by-HBO2 treatment interaction persisted over time.

In summary, HBO2 therapy reduces cognitive sequelae after acute CO poisoning in patients without the APOE {epsilon}4 allele. A poisoned patient's genotype is likely to be unknown at presentation to the hospital. As such, and given the significant adverse effects of cognitive impairments for the patients and their families, and the benefit of HBO2 in reducing cognitive sequelae, we recommend that patients with acute CO poisoning receive HBO2.


   FOOTNOTES
 
Supported by grants 247, 305, and 403 from the Deseret Foundation, LDS Hospital.

Originally Published in Press as DOI: 10.1164/rccm.200702-290OC on August 16, 2007

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form February 20, 2007; accepted in final form August 15, 2007


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 METHODS
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 DISCUSSION
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