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HBO therapy appears to be the treatment of choice for patients with significant CO exposures.178 But the most obvious effect, may not be the most important. One hundred percent oxygen at ambient pressure reduces the half-life of COHb from about 320 minutes to 85 minutes; at 2.5 atmospheres absolute (ATA), it is reduced to 20 minutes.141,197 Actual CO-poisoned victims treated with HBO have half-lives ranging from 4 to 86 minutes.126 HBO also increases the amount of dissolved oxygen by about 10 times, which is sufficient alone to supply metabolic needs in the absence of hemoglobin (Chap. 29).10 This is rarely an important clinical issue because most patients have already been stabilized and have appreciably decreased COHb with ambient oxygen alone before arrangements can be made for an HBO treatment.
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Therefore, HBO is more than just a modality to clear COHb more quickly than ambient oxygen (Antidotes in Depth: A38). More importantly, in rats after loss of consciousness from CO exposure, hyperbaric, but not normobaric, oxygen therapy prevents brain lipid peroxidation.166 HBO appears to prevent ischemic reperfusion injury by a variety of mechanisms. First, in animal models, HBO accelerates regeneration of inactivated cytochrome oxidase, which may be the initiating site for CO neuronal damage.12 Unlike 100% oxygen at room pressure, in clinical trials, HBO was much more effective at restoring mitochondrial function within peripheral white blood cells in CO poisoned patients.59 Second, HBO also prevents β-integrin mediated neutrophil adhesion to brain microvascular endothelium, a process essential for amplification of CNS damage from CO.178 This may explain why HBO, but not 100% oxygen at atmospheric pressure, prevented delayed deficits in a learning and memory maze model.170
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Clinical studies of the effectiveness of HBO in preventing neurologic damage from CO are not as convincing as basic science studies would suggest. In uncontrolled human clinical series, the incidence of persistent neuropsychiatric symptoms, including memory impairment, ranged from 12% to 43% in patients treated with 100% oxygen and was as low as 0% to 4% in patients treated with HBO.69,114,127,131
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More recently, several controlled clinical trials have evaluated the efficacy of HBO in CO poisoning (Table 125–3). The first randomized study of CO poisoning included more than 300 patients and failed to show a benefit from HBO in patients who had no initial loss of consciousness.144 Unfortunately, seriously ill patients were not randomized to surface pressure oxygen; they received either one or three treatments of HBO. Flaws in the study included significant delays to treatment and the use of suboptimal pressure of 2.0 ATA. A smaller (n = 60) controlled study avoided some of these flaws and showed that HBO decreased delayed neurologic sequelae at 3 to 4 weeks from 23% to 0% in CO-poisoned patients who presented without loss of consciousness.180 However, patients with syncope, a marker of serious poisoning, were excluded. A very small study (n = 26) of patients presenting with Glasgow Coma Scores (GCS) above 12 after CO poisoning included almost half with loss of consciousness.52 Randomization to HBO versus 100% normobaric oxygen resulted in decreased EEG abnormalities and less reduction in blood flow reactivity to acetazolamide at 3 weeks. Unfortunately, all of these studies failed to definitively study all CO-poisoned patients, including those with syncope or coma.
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The first randomized trial to directly address the issue of HBO efficacy in seriously CO-poisoned patients evaluated 191 CO-poisoned patients referred for HBO treatment.152 Patients were randomized to a minimum of three daily treatments of HBO (2.8 ATA for 60 minutes) or 100% oxygen at 1.0 ATA for 3 days. Although the HBO group had a higher incidence of persistent neurologic sequelae at one month, there was no significant difference between the two groups; more than two-thirds of each group had persistent problems. This study, although the largest controlled, randomized study to date, suffered from several flaws. Fewer than half of the patients had follow-up at one month. Disproportionate numbers of suicide cases (about two-thirds) and drug toxicity (44%), with accompanying neuropsychologic defects, could have confounded any beneficial effect from HBO. Finally, HBO treatment was delayed for 6 hours, making it much less likely to be effective.69,144
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A more recent randomized, double-blind, placebo-controlled study identified a beneficial effect of HBO in CO-poisoned patients.196 Most of these patients were ill, with a mean initial COHb level of 25% and a 50% incidence of loss of consciousness. Patients were all treated within a 24-hour window after exposure, but the success of the study might be partially attributable to the rapid mean time to treatment of less than 2 hours. Patients received HBO three times at intervals of 6 to 12 hours, each at 2.0 ATA, except for the first hour of the first treatment, which was at 3.0 ATA. Control patients received sham treatments in the HBO chamber with 100% oxygen at 1.0 ATA. At 6 weeks, the HBO group had a 24% incidence of cognitive sequelae versus 46% in the control group. Based on these data, the number of patients needed to treat to prevent one case of cognitive impairment is only five. Critics of this study point out that the neuropsychiatric tests were not significantly different between the groups except for digit spam and trail making, and there was no difference in activities of daily living. However, untreated patients had increased self-reported memory problems at 6 weeks (28% vs. 51%), and the beneficial effect on cognitive sequelae lasted well into 12 months.
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A more recent study of 179 patients with transient loss of consciousness after CO poisoning showed no benefit from a single HBO treatment.4 Neurological recovery at one month was approximately 60% regardless of HBO or normobaric oxygen. However, the study was done only at 2.0 ATA, which is below the customary initial dose for CO in positive studies. In addition, over 20% of patients were lost to follow-up.
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Based on the strong animal and basic science experience, the positive human studies mentioned above, and few adverse effects, it is not surprising that the Underwater and Hyperbaric Medical Society (UHMS) recommends HBO for all CO patients with signs of serious toxicity.195 With the low risk of this procedure,151,156 almost 1500 patients are treated with HBO for CO poisoning in the United States each year.72 Therefore, HBO has become the standard of care for serious CO poisoning, even though there is substantial disagreement in the interpretation of the existing evidence.83,109,201
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Indications for Hyperbaric Oxygen Therapy.
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Although specific indications for HBO after acute CO poisoning are listed (Table 125–4), they have not been prospectively evaluated. The patients most likely to benefit are those most at risk for persistent or delayed neurologic sequelae, such as those presenting in coma or with a history of syncope.198 These may be clinical markers for the episode of hypotension that are necessary for causing neuronal damage from CO-induced ischemic–reperfusion injury in animal models.65,133 However, syncope is neither particularly sensitive nor specific marker for cognitive sequelae. Patients with long exposures, or “soaking” periods, typically longer than 6 hours, are also at greater risk for neurologic sequelae.11 The presence of a significant metabolic acidosis may be a surrogate marker.157,186 Patients who present with decreased level of consciousness, a GCS <9 in one series, had an odds ratio of 7.0 for development of neurological sequelae.140 Some authors advocate ongoing myocardial ischemia as an indication for HBO; however, in our experience, these patients usually already meet neurologic criteria for treatment, such as loss of consciousness or ongoing mental status changes. Isolated cardiac ischemia, more importantly, deserves immediate proven myocardial salvaging therapy rather than delayed treatment with an unproven therapy such as HBO.
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Some authors advocate treating all patients with COHb levels of 40% or greater with HBO. Many HBO centers arbitrarily use a more conservative level of 25% as an indication for HBO.78 More important than actual level are patient history and examination. Further analysis of data from the most recent controlled trial demonstrates that in patients not treated with HBO, there were no reliable factors (COHb level, loss of consciousness, or base excess) for predicting who progressed to cognitive sequelae.198 This recent multivariate analysis showed that of all factors (loss of consciousness, age, exposure time, and COHb levels) only age of 36 years or older and CO exposure duration of 24 hours or longer predicted cognitive dysfunction at 6 week follow-up. More problematic is the incidence of cognitive sequelae in patients without those risk factors: 32% in those younger than age 36 years and 36% in those with less than 24 hours of exposure. In conclusion, it appears that there are no reliable predictors for screening out patients who will do well and not develop cognitive sequelae, and therefore can avoid HBO treatment with mild CO poisoning.
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Multiple studies have looked for serum markers after acute CO poisoning that would predict neurological sequelae. COHb, although confirming exposure, does not correlate with future outcome, let alone acute symptoms.75,198 Multiple serum markers, including cytokines, do increase after CO poisoning, but their predictive accuracy is unclear.172 Although impaired mitochondrial cytochrome function and elevated lipid peroxidation are seen in peripheral lymphocytes and monocytes after clinical CO poisoning, they only confirm CO exposure and are too nonspecific to use as predictors of neurological sequelae.59
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Therefore, at this time, it is prudent to refer for HBO treatment those patients with the most serious neurologic symptoms, regardless of their COHb level. Such symptoms include coma, seizures, focal neurologic deficits, altered mental status (GCS <15), and although controversial, loss of consciousness. Patients who have had cardiac arrest from CO poisoning and had the return of spontaneous circulation may be poor candidates for HBO therapy because all these cases have been fatal.81 In fact, such deaths from CO poisoning are no contraindication to organ donation.
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Excluding patients from HBO with milder symptoms after CO poisoning may be problematic because even they are susceptible to neurocognitive sequelae. One series of 55 patients with mild poisoning as defined by absence of loss of consciousness and maximum measured COHb level less than 15% found that even one-third of these individuals had neurocognitive sequelae up to 12 months after exposure.30 This was no different than that occurring in the severely poisoned group, although the milder group had a much longer duration of exposure as well as a greater delay to COHb level drawn. Brain imaging studies have confirmed that mild exposures, marked by no LOC and COHb levels lower than 15%, may result in visible changes.58,143 Taken to its logical but impractical conclusion, because even apparently mild cases of CO poisoning may have poor neurocognitive outcomes, HBO treatment of every CO-exposed patient, regardless of severity, could be justified.
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It is still unclear if mild neurologic symptoms, such as confusion, headache, dizziness, visual blurring, or abnormal mental status testing on initial presentation after CO poisoning, are prognostic for cognitive sequelae, which would necessitate HBO treatment. These symptoms simply represent CO poisoning, which, at COHb levels approaching 10% in volunteers, may cause temporary impairment of learning and memory.3 In one prospective clinical trial of CO poisoning, the incidence of cerebellar dysfunction portended a higher incidence of cognitive sequelae (odds ratio, 5.7 {95% confidence interval, 1.7–19.3}).196 Therefore, difficulty with finger-to-nose, heel-to-shin, rapid alternating hand movements, or even ataxia, should be considered indications for HBO. Patients with other mild neurologic findings, such as headache, warrant at least several hours of oxygen by non-rebreather facemask until symptoms resolve. If symptoms do not resolve, HBO may be considered; however, any delay in HBO may decrease its efficacy.
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A more promising method to discern patients who may respond to HBO may be the genotype, apolipoprotein E, specifically the isoform ε4.89 This particular polymorphism allele is present in up to one-quarter of the population, and it is associated with worse neurologic outcome from trauma and stroke. In the presence of CO poisoning, it is associated with lack of response to HBO for preventing neurocognitive sequelae. Further studies may support not treating patients with this particular allele, focusing on those with the potential for response to HBO therapy.
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Because of the confusion in determining which CO poisoned patients really need HBO treatment, several professional societies have developed evidence-based guidelines. As alluded to previously, the American College of Emergency Physicians has noted that no clinical variable can be used to predict patients at risk of cognitive sequelae and therefore most likely to benefit from HBO.201 Similarly, the Cochrane Collaboration review on the use of HBO in CO poisoning concluded that because of so much conflicting data, there is insufficient evidence to support HBO for CO poisoning at this time.16 The collective odds ratio for protective effect at 4 to 6 weeks with HBO versus normobaric oxygen was 0.78 [95% CI 0.54–1.12] based on a collective experience of 1361 patients in six studies. The most recent guideline from the UHMS states that CO-poisoned patients should be referred for HBO if they have serious poisoning, such as unconsciousness, whether it is transient or persistent; age 36 years or older; or CO exposure duration of 24 hours or longer, even if intermittent.195 This is all consistent with the prior studies discussed earlier. The UHMS guidelines also state that many physicians treat when neuropsychologic testing is abnormal or COHb levels are greater than 25% to 30%.
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Some authors recommend selective use of HBO because of cost and difficulties in transport if the primary facility lacks a chamber. However, complications that may make such transfers and treatment unsafe are rare.156 At the present time, we routinely recommend HBO for selected patients poisoned by CO based on the indications in Table 125-4. Fortunately, even without HBO, anywhere from one-third to three-quarters of cases with persistent cognitive sequelae resolve over the subsequent year.34,196
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Delayed Administration of Hyperbaric Oxygen.
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The optimal timing and number of HBO treatments for CO poisoning is unclear. Patients treated later than 6 hours after exposure tend to have worse outcomes in terms of delayed sequelae (30% vs. 19%) and mortality (30% vs. 14%).69 This may explain the failure of one of the first randomized trials on HBO in CO, which had a mean time to treatment of over 6 hours after poisoning.152 Meanwhile, HBO treatments delivered within 6 hours after poisoning in patients with loss of consciousness after CO seem to almost completely prevent neurologic sequelae.207 However, patients may benefit if they are treated even later. In the most recent randomized clinical trial showing beneficial effects of HBO, although all patients were treated within 24 hours of exposure, 38% of patients were treated later than 6 hours after exposure. Therefore, it is not unreasonable to consider HBO, contingent on transport limitations, within 24 hours of presentation for symptomatic acute poisoning.
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One case series suggests beneficial effects for HBO used up to 21 days after exposure, even after patients have developed neuropsychologic sequelae.127 The problem with studies showing HBO benefits days after an acute poisoning or after chronic poisoning is that these cases are all anecdotal and lack control subjects. In fact, delayed neurocognitive sequelae frequently resolve within 2 months in patients with mild CO poisoning,180 and in those with serious CO poisoning who survive to HBO treatment, one-third resolve within one year.196 It is possible that these delayed or chronic cases may simply represent the placebo effect of HBO.
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Repeat Treatment with Hyperbaric Oxygen.
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A randomized clinical trial demonstrated that three HBO treatments within the first 24 hours improved cognitive outcome.196 Unfortunately, there was no group treated with only one or two HBO sessions in that study. Regardless, multiple treatments are advocated for patients who have persistent symptoms, particularly coma, and do not clear after their first HBO session. In a pilot study, one hyperbaric oxygen treatment was enough to promote almost total mitochondrial cytochrome activity, as measured in peripheral lymphocytes, after CO poisoning.59 In a nonrandomized retrospective study, CO-poisoned patients who received a second HBO treatment had a reduction in delayed neurologic sequelae from 55% to 18% compared with control subjects who had only one treatment.68
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It is not clear that more HBO treatments are better. A large recent study showed that in seriously poisoned CO patients, two hyperbaric treatments resulted in a worse outcome than one treatment, with complete recovery 47% versus 68% respectively.4 There were serious flaws in that study, including lack of formal neuropsychological testing and the use of only 2.0 ATA of pressure, well below the 3.0 ATA used initially in favorable studies. With the lack of prospective studies comparing single versus multiple courses of HBO therapy, multiple treatments cannot be recommended routine at this time. The most recent clinical guidelines from the UHMS state that the optimal number of HBO treatments for CO poisoning is unknown and that one should consider reserving multiple treatments for patients who fail to fully recover after one treatment.195