A38: Antidotes in Depth

Hyperbaric oxygen (HBO) is used therapeutically in poisoning by carbon monoxide (alone or if complicated by cyanide poisoning), methylene chloride, hydrogen sulfide, and carbon tetrachloride. It is also a recognized therapy for air or gas embolism, such as may arise from ingestion of hydrogen peroxide, and for anemia, a functional form of which arises from oxidants that induce methemoglobinemia.

Hyperbaric medicine became established as a clinical discipline in the later half of the 20th century with a focus on treatment of decompression sickness. Utilization of hyperbaric chambers has expanded in the past 60 years with improved understanding of basic mechanisms of action. The first case reports of HBO for documented CO poisoning appeared in 1960,¹⁹² and the consistent application of HBO in CO poisoning began in many centers at that time.¹⁹⁰ The first report presenting statistical evidence of the superiority of HBO compared to normobaric oxygen in CO poisoning, as well as a description of the “late syndrome,” was published in 1969.⁷⁴

Chemistry and Preparation

In hyperbaric oxygen (HBO) therapy the patient breathes 100% O₂ while exposed to increased atmospheric pressure. Treatments are performed in either a monoplace (single patient) or a multiplace (typically 2–14 patients) chamber. Pressures applied while patients are in the chamber usually are 2 to 3 atmospheres absolute (ATA), where sea level air pressure equals 1 ATA. Treatments generally last for 1.5 to 8 hours, depending on the indication, and may be performed one to three times daily. Monoplace chambers usually are compressed with pure oxygen. Multiplace chambers are pressurized with air, and patients breathe pure oxygen through a tight fitting face mask, a head tent, or endotracheal tube as clinically indicated.

Mechanisms of Action

Therapeutic mechanisms of action for HBO are based on elevation of both hydrostatic pressure and the partial pressure of oxygen. Elevation of the hydrostatic pressure reduces the volume of a gas according to Boyle’s law (within a closed system, absolute pressure and volume of a given mass of a confined gas are inversely proportional, if the temperature remains unchanged). This action has direct relevance to pathologic conditions in which gas bubbles are present in the body, such as arterial gas embolism, decompression sickness, and ingestion of concentrated solutions of hydrogen peroxide (H₂O₂). During treatment, the arterial oxygen tension typically exceeds 1500 mm Hg and achieves tissue oxygen tensions of 200 to 400 mm Hg—over fivefold higher than when breathing air.²⁰³ While one is breathing air under normal environmental conditions, hemoglobin is saturated with oxygen on passage through the pulmonary microvasculature, and the primary effect of HBO is to increase the dissolved oxygen content of plasma. In addition, HBO affects neutrophil adhesion to blood vessels and restores mitochondrial, neutrophil, and immunologic disturbances caused by CO poisoning.

Pharmacokinetics

Oxygen inhaled at hyperbaric pressure is rapidly absorbed. Application of each additional atmosphere of pressure while breathing 100% oxygen increases the dissolved oxygen concentration in the plasma by 2.2 mL O₂/dL (vol%) (Chap. 29). In five human subjects performing breath holds during compression to 20 m, oxygen consumption also significantly increased, which was attributed to increased cardiac output.¹²⁵ Animal models of focal ischemia suggest that hyperbaric oxygen rapidly distributes to target organs to improve penumbral oxygenation.¹⁹⁹ HBO increases tissue oxygen concentration and wound oxygen delivery in humans.¹⁷² Regarding pharmaceutical interactions, hyperbaric hyperoxia does not appear to produce appreciable alterations in the pharmacokinetics of pentobarbital, salicylate, or theophylline in canine models^{111, 112, and 113} or gentamicin in healthy human volunteers.¹⁴²

Pharmacodynamics

There are transient benefits from HBO for reducing bubble volume in disorders such as air embolism and also oxygenating tissues in conditions where hemoglobin-based O₂ delivery is impaired. These rather straightforward mechanisms form the basis for using HBO for patients with massive ingestions of hydrogen peroxide (H₂O₂) associated with intravascular gas embolism and for life-threatening poisonings from cyanide (CN), hydrogen sulfide (H₂S), and exposure to oxidizers causing methemoglobin. HBO is also used for carbon tetrachloride (CCl₄) poisoning, where acute application of oxygen and pressure may inhibit the cytochrome P450 oxidase system responsible for producing hepatotoxic free radicals.^30,136 HBO also has well described vasoconstriction effects,^38,197,216 compared to dynamic CO-associated effects on cerebral vasodilation.¹²²

Recent years have shown that benefits persisting beyond the short period when a patient is in a hyperbaric chamber are related to production of reactive oxygen species (ROS) and reactive nitrogen species (RNS).^206,207 Reactive species can have positive and negative effects that depend on the concentration of reactant generated and its intracellular localization. Hence, with regard to HBO as with any drug, the precise dose may define the risks and benefits of therapy. Because exposure to hyperoxia in typical clinical HBO protocols is rather brief, most studies show that antioxidant defenses are adequate to avoid tissue injuries.^{52,53,173,220}

There are at least three separate therapeutic mechanisms supporting the use of O₂ when treating carbon monoxide (CO) poisoning. Administration of supplemental O₂ is a historical cornerstone for treatment based on reducing body burden of carboxyhemoglobin (COHb). Elevated COHb can result in tissue hypoxia, and exogenous O₂ both hastens dissociation of CO from hemoglobin and provides enhanced tissue oxygenation directly through the increased PO₂. HBO causes COHb dissociation to occur at a rate greater than that achievable by breathing 100% O₂ at sea level pressure.¹⁵⁸ Additionally, HBO accelerates restoration of mitochondrial oxidative processes.²⁸ Among the earliest events observed in both an animal model and in humans suffering CO poisoning is platelet-neutrophil interactions that mediate intravascular neutrophil activation. These changes precipitate neutrophil adherence to blood vessel walls that initiate vascular changes and a cascade of events leading to neurological dysfunction (Fig. A38–1).^96,208,213 Immunological responses to altered myelin basic protein (MBP) cause neurological dysfunction in animals, and presence of MBP in cerebrospinal fluid of CO poisoned patients is suggested as a predictive marker for onset and persistence of CO-mediated encephalopathy.^{17, 18, and 19,94,95,102}

Animals poisoned with CO then treated with HBO have more rapid improvement in cardiovascular status,⁵⁸ lower mortality,¹⁶¹ and lower incidence of neurological sequelae.^84,205 Benefits are likely based on improved oxygenation and mitochondrial function as well as inhibition of neutrophil adhesion. Exposure to 2.8 to 3.0 ATA O₂ for 45 minutes temporarily inhibits neutrophil adherence to endothelium mediated by the activation-dependent β₂-integrins on the neutrophil membrane in both rodents and humans.^{41,101,114,204,214} The ability of HBO to inhibit function of neutrophil β₂-integrin adhesion molecules in animal models forms the basis for amelioration of encephalopathy resulting from CO poisoning and decompression sickness, smoke-induced lung injury, as well as reperfusion injuries of brain, heart, lung, liver, and skeletal muscle.^{8,105,135,200,201,204,217,221,226,240, 241, and 242} HBO inhibits neutrophil β₂ integrin expression but not its expression on other circulating leukocytes due to RNS generation by type-2 nitric oxide synthase and myeloperoxidase present in neutrophil-specific α-granules. That is, it is the presence of both enzymes within the same granules that is required to generate the requisite RNS to impair neutrophil adherence. The reaction leads to excessive S-nitrosylation of cytoskeletal β actin, which in turn impedes the function of β₂ integrins.²¹⁰ This leads to modifications in cytoskeletal regulation of a number of proteins.^211,212 It is important to comment that HBO does not reduce neutrophil viability, and functions such as degranulation and oxidative burst in response to chemoattractants remain intact.^204,211,214 This contrasts with alternative interventions such as monoclonal antibodies which can inhibit β₂ integrins and ameliorate ischemia-reperfusion injuries but cause profound immunocompromise.^144,145

Survivors of CO poisoning are faced with potential impairments to cardiac and neurological functions. CO poisoning can cause acute cardiac compromise, and survivors exhibit an increased risk for cardiovascular related death in the subsequent 10 years.^88,175 Some patients exhibit acute abnormalities wherein they have impaired consciousness and or focal neurological findings from the time of initial presentation and never recover.^3,47,50,69 Other patients seemingly recover from acute poisoning but then manifest neurological or neuropsychiatric abnormalities from 2 days to about 5 weeks after poisoning.^{42,55,73,92,131,139,143,152,166,183,186,215,235} Events occurring after a clear or “lucid” interval are termed “subacute or delayed” neurological sequelae. These terms have gained popularity and may have some clinical utility, but animal studies suggest neuropathology is more of a continuum. That is, various pathways of injury occur in close proximity, and in some cases they occur concomitantly.^{68,97,140,153,208,209,213}

Since 1960, HBO has been used with increasing frequency for severe CO poisoning because clinical recovery appeared to improve beyond that expected with ambient pressure oxygen therapy. Support for HBO use comes from this experience.^{73,74,93,115,138,152,155,171} The clinical efficacy of HBO for acute CO poisoning has been assessed in six prospective, randomized trials published in peer-reviewed journals. Only one clinical trial satisfies all items deemed to be necessary for the highest quality of randomized controlled trials.²³⁵ This double-blinded, placebo-controlled clinical trial involved 152 patients, who received treatment with either three sessions of HBO therapy or normobaric O₂ with sham pressurization to maintain blinding. The group treated with HBO had a lower incidence of cognitive sequelae than the group treated with NBO after adjustment for pre-treatment cerebellar dysfunction and stratification (odds ratio 0.45, 95% confidence interval 0.22–0.92, p= 0.03).

The only other blinded, prospective, randomized trial was published in 1999, and it involved 191 patients of different severity treated with either daily HBO (2.8 ATA for 60 minutes) with intervening high flow oxygen for 3 or 6 days versus high flow normobaric oxygen for 3 or 6 days.¹⁷⁸ Additional HBO treatments (up to six daily) were performed in patients without adequate neurological recovery. The primary outcome measure for this trial was testing performed at completion of treatment (3–6 days) and not from long term follow-up. This study had a high rate of adverse neurological outcomes in all patients, regardless of treatment assignment. Neurological sequelae were reported in 74% of HBO treated patients and in 68% of controls. No other clinical trial has described this magnitude of neurological dysfunction. The high incidence may be related to the assessment tool which could not discern true neurological impairments from poor test taking related to depression.¹⁷⁹ Suicide attempts with CO represented 69% of cases in this trial. Moreover, 54% of subjects were lost to follow-up. Outcomes at one month were not reported, but were stated to show no difference. Multiple statistical comparisons were reported without apparent planning or the requisite statistical correction. Both treatment arms received continuous supplemental mask O₂ for 3 days between their hyperbaric treatments (both true HBO and “sham”), resulting in greater overall O₂ doses than conventional therapy. Multiple flaws in the design and execution of this study are discussed in the literature, so it is impossible to draw meaningful conclusions from the data.^80,148 Despite these issues, conclusions from this trial have been accepted in systematic reviews.^29,238

Other randomized trials of HBO for CO poisoning were not blinded. The first prospective clinical trial involving HBO therapy did not demonstrate therapeutic benefits.¹⁶⁶ This study was criticized because the authors used a low oxygen partial pressure (2 ATA) versus the more usual protocols with 2.5 to 3 ATA, an unvalidated questionnaire to assess neurological function, and because nearly half of the patients received hyperbaric treatments more than 6 hours after they were identified.²⁷ This 1989 study protocol was used again in a more recent trial with no modifications despite the criticisms voiced over a decade earlier. Not surprisingly, the outcome was virtually the same. If study results are expressed on an intention-to-treat basis, patients with transient loss of consciousness had an incidence of neurological sequelae based on the self-assessment questionnaire of 48%, and those treated with HBO had an incidence of 51%. Patients with initial coma who were treated once with HBO had an incidence of sequelae of 47%; patients who were treated with two HBO treatments had an incidence of sequelae of 60% (not significantly different from any of the other groups).⁶

HBO was found effective in several other prospective investigations. In a trial involving mildly to moderately poisoned patients, 23% of patients (7/30) treated with ambient pressure oxygen developed neurologic sequelae, whereas no patients (0/30; p<0.05) who were treated with HBO (2.8 ATA) developed sequelae.²¹⁵ In another prospective, randomized trial, 26 patients were hospitalized within 2 hours of discovery and were equally divided between two treatment groups: ambient pressure oxygen or 2.5 ATA O₂.⁵⁵ Three weeks later, patients treated with HBO had significantly fewer abnormalities on electroencephalogram, and single-photon emission computed tomography (SPECT) scans showed that cerebral vessels had nearly normal reactivity to carbon dioxide, in contrast to diminished reactivity in patients treated with ambient pressure oxygen.

In conclusion, efficacy of HBO for acute CO poisoning is supported in animal trials, and studies provide a mechanistic basis for treatment. In this era of evidence-based medicine a great deal of emphasis has been placed on systematic reviews, which have stressed the need for new studies because of the range in quality of published clinical trials.^29,238 Practice recommendations are published based on existing studies with the best design that most closely address the actual practical handling of patients.⁸³ HBO should at least be considered in all cases of serious acute CO poisoning and normobaric 100% oxygen continued until the time of HBO administration. CO poisoned patients who receive three HBO treatments within 24 hours following presentation manifest approximately one half the rate of cognitive sequelae at 6 weeks, 6 months, and 12 months following treatment as those treated with only normobaric oxygen. Risk factors for long term cognitive impairment in patients not treated with hyperbaric oxygen include age >36 years, exposure >24 hours, loss of consciousness, and COHb >25%. Recommendations for children can pose special challenges, but in clinical series there appear to be no marked differences in clinical manifestations compared to those reported in adults.^{62,82,108,162} Pregnancy poses another special situation in that CO readily crosses the placenta and may cause fetal distress and fetal death. HBO has been administered safely to pregnant women, but there are no prospective studies of efficacy, so standard adult guidelines for treatment are often utilized.

Another study has shown that HBO is only beneficial in reducing neurological sequelae among patients who do not possess the apolipoprotein ε4 allele.⁸⁹ Because genotype is typically unknown, this report does not alter existing treatment guidelines, but it may become important for future research. Although the basic mechanisms are unknown, it is well established that the apolipoprotein genotype can have profound effects on risk for a variety of neuropathological events.^1,64,141,176 Whether apolipoprotein ε4 modifies the primary pathophysiological insults of CO or the mechanisms of HBO are currently unknown. As of yet, no objective method is available for staging the severity of CO poisoning, although preliminary reports suggest plasma markers may be used in the future.²⁰⁹ Psychometric screening tests have not proved reliable because abnormalities during the initial screening do not correlate with development of delayed sequelae.²¹⁵

Methylene chloride (CH₂Cl₂) is an organic solvent used commercially in aerosol sprays, as a solvent in plastics manufacturing, in photographic film production, in food processing as a degreaser, and as a paint stripper (eg, for bathtub refinishing).³⁹ It is readily absorbed through the skin or by inhalation. Immediate effects of methylene chloride are attributable to the direct depressant actions of this solvent on the CNS and resulting hypoxia. There are two metabolic pathways involved in its metabolism: an oxidative one mediated by cytochrome P450s, mainly CYP2E1 that may involve a metabolic-switch or two-active site process, and another pathway mediated by glutathione (GSH) that involves mainly glutathione S-transferases (GST).^59,195 The P450 pathways generate formyl chloride and CO, with a secondary conjugation of formyl chloride to GSH. The separate GSH/GST pathway involves conjugation of methylene chloride, primarily by metabolism through GST-theta, to generate CO₂ as well as DNA adducts. These GSH/GST conjugation pathway DNA adducts play a role in late-onset carcinogenesis.^228,229 Acute methylene chloride toxicity can have many of the same manifestations as CO poisoning.¹⁹¹ Production of CO is slow, and peak COHb levels of 10% to 50% may not be reached for 8 hours or more.^{37,40,60,103,116,131,132,185,195} Effects that are present after one hour or more, particularly if the COHb level is elevated, may be partially caused by CO toxicity. Anecdotal reports of HBO treatment for methylene chloride poisoning report both success and failure, which may reflect an additional component due to solvent toxicity.^{35,109,170,174} HBO treatment recommendations, using a standard three treatment protocol, follow those in patients meeting the aforementioned considerations in CO poisoning. Additional treatments in the setting of ongoing CO production or persistent symptoms may be required.¹¹⁷ Prolonged normobaric 100% oxygen therapy may be used in patients with HBO contraindicatons.^90,167

CO and CN poisonings can occur concomitantly from smoke inhalation.^{4,5,12, 13, 14, and 15,21,44,49,128,130,146,184,188,231,236} Experimental evidence suggests that they can produce synergistic toxicity.^{10,149,156,158,163} Animal studies demonstrate that ambient pressure 100% O₂ can protect against CN toxicity¹⁸¹ and also can enhance CN metabolism to thiocyanate when thiosulfate is used concomitantly.²³ HBO may have either direct effects on reducing CN toxicity^{48,98,99,120,189,202} or augment other antidotes.^{33,121,181,233} However, animal studies have not uniformly found that HBO improved outcome,²³² and clinical experience regarding CN treatment with HBO is sparse.^3,72,180 In a series of symptomatic smoke inhalation victims with elevated concentrations of both CO and CN who received HBO and treatment for CN involving sodium nitrite and sodium thiosulfate, four of five patients survived without apparent neurologic damage.⁸⁶ Clinical case reports where HBO was used along with standard antidote treatment (sodium nitrite plus sodium thiosulfate) for isolated CN poisonings are equivocal regarding benefit.^{72,126,180,218} One case showed dramatic improvement,²¹⁸ but another showed none.¹²⁶ Methemoglobin formation with the standard antidote treatment involving nitrite is not thought to generate concerningly high methemoglobin concentrations, but in the setting of concomitant COHb the additional reduction of oxygen carrying capacity may pose a risk.^107,78 Hence, there is a special advantage for hydroxycobalamin use in combined poisonings. Further research in this area is necessary. Because CN is among the most lethal poisons and toxicity is rapid, standard antidotal therapy for isolated CN poisoning is of primary importance. Hyperbaric oxygen should be considered in any case of dual (CO and CN) poisoning and in CN poisoning when vital signs and mental status do not improve with antidote treatment. Possible use of HBO therapy may change as data on alternative antidotes such as hydroxycobalamin are investigated. Some evidence suggests each offers supportive effects on brain metabolism.^120,121

Hydrogen sulfide (H₂S) binds to cytochrome a-a₃. This is similar to CN, although it is more readily dissociated by O₂.¹⁹⁶ Clinical manifestations of toxicity are also similar to those with CO and CN.¹⁹⁶ Management of patients with serious H₂S poisoning principally involves oxygenation and cardiovascular support, as well as consideration of antidotal therapy with sodium nitrite to induce methemoglobinemia.^66,76,79,154 HBO may be more effective than sodium nitrite in preventing mortality in animals.²² Several clinical reports indicate that HBO, sometimes in conjunction with supplemental oxygen and blood pressure support, appears to be beneficial.^{7,16,32,77,123,191,237} Relatively late treatment with HBO (eg, over 10 hours after poisoning) is reported to be beneficial in some²²⁵ but not all cases.^2,193 No definitive data regarding use of HBO for H₂S poisoning are available, but HBO should be considered in cases where altered mental status or unstable vital signs persist after standard resuscitation measures.

Oxidation of ferrous (2⁺) heme to the ferric (3⁺) form renders hemoglobin nonfunctional, and the presence of oxidized hemoglobin varieties causes a left shift of the oxyhemoglobin dissociation curve.¹⁹⁸ Hence, the manifestations of toxicity from acquired methemoglobinemia are usually more severe than those produced by a corresponding degree of anemia. In healthy people, when the fraction of methemoglobin is 10% to 20% (~1.5 g/dL) patients may appear cyanotic, but otherwise asymptomatic. With approximately 30% methemoglobin, there may be vague, nonspecific symptoms such as headache, fatigue, dyspnea, tachycardia, and dizziness. Unconsciousness is common at levels above 50% and death at 70%. There are numerous anecdotal accounts of clinical improvement with HBO in patients suffering from life-threatening methemoglobinemia.^{54,70,71,75,100,119,124,177,230} Ongoing exposure to any oxidants and the potential need for methylene blue to treat methemoglobinemia (Antidotes in Depth: A42) should also be addressed.

Carbon tetrachloride (CCl₄) induced hepatotoxicity may be diminished by HBO. Mortality was decreased in a number of animal studies,^{20,31,147,168} and there are several case reports of patients surviving potentially lethal ingestions with HBO therapy.^{118,194,219,243} Because there are no proven antidotes for CCl₄ poisoning, HBO should be used for patients with large CCl₄ exposures. However, there may be a delicate balance between oxidative processes that are therapeutic and those that mediate hepatotoxicity.²⁴ Therefore, when HBO is being considered, it should be instituted before the onset of liver function abnormalities. More recently, N-Acetylcysteine (NAC) is effective in limiting liver damage in animals and appears of clinical benefit in humans with massive ingestions.^{133,137,222,239} Additive benefit from concomitant use of NAC and HBO was shown in an animal model demonstrating a diminution of toxicity in l-arginine induced pancreatitis, but there is no experience with CCl₄ poisoning.¹⁵⁷

Ingestion of concentrated hydrogen peroxide (H₂O₂) solutions (eg, 35%) can result in venous and arterial gas embolism due to liberation of large volumes of O₂. Exposure to household concentrations of H₂O₂(3%) has resulted in symptomatic portal venous air embolism on rare occasion.¹³⁴ At standard temperature and pressure, ingestion of 1 mL of household 3% H₂O₂ liberates approximately 10 mL oxygen gas; by comparison, each milliliter of 35% hydrogen peroxide yields 115 mL of oxygen gas.¹⁵⁰ Symptoms vary with the affected organ. Seizures, alterations in mental status, and strokelike manifestations occur with CNS involvement from arterial emboli and nausea, vomiting, hematemesis, and abdominal pain with gastrointestinal and hepatic venous involvement, acute obstruction of the portal vein, portal venous hypertension, and bowel edema.^{43,91,127,160,182} HBO has been a successful intervention for portal venous gas and in some cases of impaired ­consciousness and or focal neurological findings.^{9,63,134,150,160,169,224} HBO reduces the volume of offending gas and improves solubility of gas into tissues and plasma.¹⁶⁰ A history of inadvertent ingestion of concentrated H₂O₂, significant signs or symptoms, or radiologic evidence of gas embolism should prompt patient placement in a Trendelenburg, left lateral decubitus position, administration of 100% oxygen and sufficient fluids to sustain perfusion, and consideration for immediate transportation to the nearest hyperbaric facility. HBO to treat gas embolism has demonstrated benefit even if delayed beyond 20 hours.⁵⁶

Many HBO facilities have equipment and treatment protocols and abilities analogous to those found in an intensive care unit.^104,227,234 The possible capabilities will vary and interventions with HBO should never be undertaken if standard patient support cannot also be achieved. The inherent toxicity of O₂ and potential for injury resulting from elevations of ambient pressure must be addressed whenever HBO is used therapeutically. Preexisting conditions that require evaluation for possible management before initiation of HBO include claustrophobia, sinus congestion, and patients with scarred or noncompliant structures in the middle ear, such as otosclerosis.¹⁰⁶ Middle ear barotrauma is the most common adverse effect of HBO treatment,³⁷ and it occurs in 1.2% to 7% of patients.^46,164,220 When autoinsufflation fails, puncturing the ear drum or tympanostomy tube placement will resolve the problem. Pneumothorax is a rarely reported complication.²⁵ Toxicity resulting from O₂ can be manifested by injuries to the CNS, lungs, and eyes. CNS O₂ toxicity manifests as a generalized seizure and occurs at an incidence of approximately 1-4/10,000 patient treatments.^51,85,164 Pulmonary oxygen toxicity typically does not arise when standard treatment protocols are followed.^45,61,87,165 Progressive myopia may occur in patients undergoing prolonged daily therapy, but typically reverses within 6 weeks after treatments are terminated.¹²⁹ Nuclear cataracts can form with excessive treatments, exceeding a total of 150 to 200 hours, and they may rarely develop with standard treatment protocols.^67,159 Absent on-site hyperbaric capability, the risks of interfacility transportation (clinical decompensation, vehicle crashes, etc) also will factor into decision making.

HBO in pregnant patients presents the additional risks of fetal CNS, ocular, pulmonary, and cardiac toxicity.¹¹ In CO poisoning, these must be weighed against the potentially devastating fetal outcomes such as spontaneous abortion, intrauterine fetal demise, anatomic malformations, CNS injury, respiratory distress, and neonatal jaundice, which may occur even in only mildly symptomatic CO poisoned mothers.^36,110 For these reasons, carboxyhemoglobin thresholds (eg, 15%–20%) for HBO therapy are often set lower for the pregnant patients than for other adults in HBO treatment algorithms. Normal fetal outcomes have followed HBO, even in the setting of severe maternal toxicity, whereas significant adverse fetal outcomes have followed normobaric oxygen therapy.¹¹⁰ A summary of over 700 Russian patients treated with HBO for various hypoxemic states did not find any detrimental HBO effects.²²³ HBO was used safely in a prospective study of 44 pregnant women poisoned by CO.⁵⁷ Multiple other case reports document successful maternal and fetal outcomes in CO poisoned pregnant patients.^26,65,187 HBO has also been employed successfully in patients with obstetrical procedures complicated by gas embolism.¹⁵¹ Treatment decisions will ultimately be made on an individual case basis after weighing potential risks and benefits. There are no data regarding HBO effects on lactation.

Rodent and human studies demonstrate that exposure to 2.8 to 3.0 ATA O₂ for 45 minutes is required to temporarily inhibit neutrophil adherence to endothelium mediated by the activation-dependent β₂-integrins on the neutrophil membrane.^{41,101,114,204,214} Clinical trials employing HBO at only 2 ATAs have been unable to demonstrate a benefit of HBO.^6,166 Multiple trials using HBO (2.5 ATA or above) have demonstrated efficacy.^{55,139,215,235} One trial using HBO (2.8 ATA) was unable to demonstrate benefit, subject to the previously discussed limitations.¹⁷⁸ If undertaken, HBO therapy (2.5–3.0 ATA, weighted toward the latter) should be provided as early as possible, as a mortality benefit is demonstrated if HBO is administered within 6 hours.⁷⁴ Clinical trials have initiated therapy within 24 hours of the end of carbon monoxide exposure.²³⁵ The use of more than one treatment is supported by retrospective and prospective analysis,^73,235 although clinical practice is highly variable in this regard.^34,81

HBO therapy is provided in monoplace or multiplace chambers, which are considered class II medical devices. For sites not possessing HBO ­capacity, various online organizational and professional directories may assist in locating hyperbaric facilities in the absence of preexisting HBO transfer protocols.

• Mechanisms of action and efficacy of HBO are complex and remain an area of active investigation. Research findings are provocative because they highlight the fact that traditional assessments of mechanisms for toxicity of some xenobiotics are incomplete.

• While the efficacy of HBO for acute CO poisoning is supported in animal trials, questions persist on many issues, including patient selection, optimal dose, and session frequency.

• HBO merits consideration in serious acute CO poisoning, particularly in those cases with end organ manifestations, recognizing highly ­varied clinical practice scenarios and preferences.

• Further investigation is required to discern those cases where clear benefit arises with HBO treatment and to define the constraints that may limit its efficacious use.

• Anecdotal evidence supports HBO therapy in hydrogen sulfide and carbon tetrachloride poisoning, in oxidant induced methemoglobinemia, and in hydrogen peroxide ingestion.

References