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InternalMed_Harrison. Hypertension At high altitudes, enhanced sympathetic activity may lead to a transient rise in blood pressure. Occasionally, nonhypertensive, healthy, asymptomatic trekkers have pathologically high blood pressure at high altitude that rapidly normalizes without medicines on descent. Sojourners should continue to take their antihypertensive medications at high altitudes. Hypertensive patients are not more likely than others to develop altitude illness. Because the probable mechanism of high-altitude hypertension is α-adrenergic activity, antiα-adrenergic drugs like prazosin have been suggested for symptomatic patients and those with labile hypertension. It is best to start taking the drug several weeks before the trip and to carry a sphygmomanometer if a trekker has labile hypertension. Sustained-release nifedipine may also be useful. For a common problem like hypertension, there is clearly inadequate knowledge on which to base appropriate recommendations.


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InternalMed_Harrison. Coronary Artery Disease Myocardial oxygen demand and maximal heart rate are reduced at high altitudes because the VO2 max (maximal oxygen consumption) decreases with increasing altitude. This effect may explain why signs of cardiac ischemia or dysfunction usually are not seen in healthy persons at high altitudes. Asymptomatic, fit individuals with no risk factors need not undergo any tests for coronary artery disease before ascent. For persons with ischemic heart disease, previous myocardial infarction, angioplasty, and/or bypass surgery, an exercise treadmill test is indicated. A strongly positive treadmill test is a contraindication for high-altitude trips. Patients with poorly controlled arrhythmias should avoid high-altitude travel, but patients with arrhythmias that are well controlled with antiarrhythmic medications do not seem to be at increased risk. Sudden cardiac deaths are not noted with a greater frequency in the Alps than at lower altitudes; although sudden cardiac deaths


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InternalMed_Harrison. with antiarrhythmic medications do not seem to be at increased risk. Sudden cardiac deaths are not noted with a greater frequency in the Alps than at lower altitudes; although sudden cardiac deaths are encountered every trekking season in the higher Himalayan range, accurate documentation is lacking.


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InternalMed_Harrison. Asthma Although cold air and exercise may provoke acute bronchoconstriction, asthmatic patients usually have fewer problems at high than at low altitudes, possibly because of decreased allergen levels and increased circulating catecholamine levels. Nevertheless, asthmatic individuals should carry all their medications, including oral glucocorticoids, with proper instructions for use in case of an exac-476e-5 erbation. Severely asthmatic persons should be cautioned against ascending to high altitudes. Pregnancy In general, low-risk pregnant women ascending to 3000 m are not at special risk except for the relative unavailability of medical care in many high-altitude locations, especially in developing countries. Despite the lack of firm data on this point, venturing higher than 3000 m to altitudes at which oxygen saturation drops steeply seems unadvisable for pregnant women.


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InternalMed_Harrison. Obesity Although living at a high altitude has been suggested as a means of controlling obesity, obesity has also been reported to be a risk factor for AMS, probably because nocturnal hypoxemia is more pronounced in obese individuals. Hypoxemia may also lead to greater pulmonary hypertension, thus possibly predisposing the trekker to HAPE. Sickle Cell Disease High altitude is one of the rare environmental exposures that occasionally provokes a crisis in persons with the sickle cell trait. Even when traversing mountain passes as low as 2500 m, people with sickle cell disease have been known to have a vasoocclusive crisis. Sickle cell disease needs to be considered when persons traveling to high altitudes become unwell and develop left-upper-quadrant pain. Patients with known sickle cell disease who need to travel to high altitudes should use supplemental oxygen and travel with caution.


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InternalMed_Harrison. Diabetes Mellitus Trekking at high altitudes may enhance sugar uptake. Thus, high-altitude travel may not pose problems for persons with diabetes that is well controlled with oral hypoglycemic agents. An eye examination before travel may be useful. Patients taking insulin may require lower doses on trekking/climbing days than on rest days. Because of these variations, diabetic patients need to carry a reliable glucometer and use fast-acting insulin. Ready access to sweets is also essential. It is important for companions of diabetic trekkers to be fully aware of potential problems like hypoglycemia.


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InternalMed_Harrison. Chronic Lung Disease Depending on disease severity and access to medical care, preexisting lung disease may not always preclude high-altitude travel. A proper pretravel evaluation must be conducted. Supplemental oxygen may be required if the predicted PaO2 for the altitude is <50–55 mmHg. Preexisting pulmonary hypertension may also need to be assessed in these patients. If the result is positive, patients should be discouraged from ascending to high altitudes; if such travel is necessary, treatment with sustained-release nifedipine (20 mg twice a day) should be considered. Small-scale studies have revealed that when patients with bullous disease reach ~5000 m, bullous expansion and pneumothorax are not noted. Compared with information on chronic obstructive pulmonary disease, fewer data exist about the safety of travel to high altitude for people with pulmonary fibrosis, but acute exacerbation of pulmonary fibrosis has been seen at high altitude. A handheld pulse oximeter can be


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InternalMed_Harrison. exist about the safety of travel to high altitude for people with pulmonary fibrosis, but acute exacerbation of pulmonary fibrosis has been seen at high altitude. A handheld pulse oximeter can be useful to check for oxygen saturation.


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InternalMed_Harrison. Chronic Kidney Disease Patients with chronic kidney disease can tolerate short-term stays at high altitudes, but theoretical concern persists about progression to end-stage renal disease. Acetazolamide, the drug most commonly used for altitude sickness, should be avoided by anyone with preexisting metabolic acidosis, which can be exacerbated by this drug. In addition, the acetazolamide dosage should be adjusted when the glomerular filtration rate falls below 50 mL/min, and the drug should not be used at all if this value falls below 10 mL/min.


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InternalMed_Harrison. Chronic mountain sickness (Monge’s disease) is a disease of long-term residents of altitudes above 2500 m that is characterized by excessive erythrocytosis with moderate to severe pulmonary hypertension leading to cor pulmonale. This condition was originally described in South America and has also been documented in Colorado and in the Han Chinese population in Tibet. Migration to a low altitude results in the resolution of chronic mountain illness. Venesection and acetazolamide are helpful.


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InternalMed_Harrison. High-altitude pulmonary hypertension is also a subacute disease in Tibet have presented with the adult and infantile forms, respectively. of long-term high-altitude residents. Unlike Monge’s disease, this High-altitude pulmonary hypertension bears a striking pathophysisyndrome is characterized primarily by pulmonary hypertension ologic resemblance to brisket disease in cattle. Descent to a lower alti(not erythrocytosis) leading to heart failure. Indian soldiers living at tude is curative. extreme altitudes for prolonged periods and Han Chinese infants born body exposure to pressures greater than 101.3 kPa (1 atmosphere or 760 mmHg). In practice, this almost always means the administration of hyperbaric oxygen therapy (HBO2T). The Undersea and Hyperbaric Medical Society (UHMS) defines HBO2T as: “a treatment in which a patient breathes 100% oxygen … while inside a treatment chamber at a pressure higher than sea level pressure (i.e., >1 atmosphere absolute or ATA).” The treatment chamber


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InternalMed_Harrison. as: “a treatment in which a patient breathes 100% oxygen … while inside a treatment chamber at a pressure higher than sea level pressure (i.e., >1 atmosphere absolute or ATA).” The treatment chamber is an airtight vessel variously called a hyperbaric chamber, recompression chamber, or decompression chamber, depending on the clinical and historical context. Such chambers may be capable of compressing a single patient (a monoplace chamber) or multiple patients and attendants as required (a multiplace chamber) (Figs. 477e-1 and 477e-2). Historically, these compression chambers were first used for the treatment of divers and compressed air workers suffering decompression sickness (DCS; “the bends”). Although the prevention and treatment of disorders arising after decompression in diving, aviation, and space flight has developed into a specialized field of its own, it remains closely linked to the broader practice of hyperbaric medicine.


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InternalMed_Harrison. hyperbaric and Diving Medicine Michael H. Bennett, Simon J. Mitchell WHAT IS HYPERBARIC AND DIVING MEDICINE? Hyperbaric medicine is the treatment of health disorders using whole-477e


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InternalMed_Harrison. Despite an increased understanding of mechanisms and an improving evidence basis, hyperbaric medicine has struggled to achieve widespread recognition as a “legitimate” therapeutic measure. There are several contributing factors, but high among them are a poor grounding in general oxygen physiology and oxygen therapy at medical schools and a continuing tradition of charlatans advocating hyperbaric therapy (often using air) as a panacea. Funding for both basic and clinical research has been difficult in an environment where the pharmacologic agent under study is abundant, cheap, and unpatentable. Recently, however, there are signs of an improved appreciation of the potential importance of HBO2T with significant National Institutes of Health (NIH) funding for mechanisms research and from the U.S. military for clinical investigation.


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InternalMed_Harrison. Increased hydrostatic pressure will reduce the volume of any bubbles present within the body (see “Diving Medicine”), and this is partly responsible for the success of prompt recompression in DCS and FIGuRE 477e-1 A monoplace chamber. (Prince of Wales Hospital, Sydney.) FIGuRE 477e-2 A chamber designed to treat multiple patients.


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InternalMed_Harrison. FIGuRE 477e-1 A monoplace chamber. (Prince of Wales Hospital, Sydney.) FIGuRE 477e-2 A chamber designed to treat multiple patients. (Karolinska University Hospital.) arterial gas embolism. Supplemental oxygen breathing has a dose-dependent effect on oxygen transport, ranging from improvement in hemoglobin oxygen saturation when a few liters per minute are delivered by simple mask at 101.3 kPa (1 ATA) to raising the dissolved plasma oxygen sufficiently to sustain life without the need for hemoglobin at all when 100% oxygen is breathed at 303.9 kPa (3 ATA). Most HBO2T regimens involve oxygen breathing at between 202.6 kPa and 283.6 kPa (2 and 2.8 ATA), and the resultant increase in arterial oxygen tensions to >133.3 kPa (1000 mmHg) has widespread physiologic and pharmacologic consequences (Fig. 477e-3).


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InternalMed_Harrison. One direct consequence of such high intravascular tension is to increase greatly the effective capillary-tissue diffusion distance for oxygen such that oxygen-dependent cellular processes can resume in hypoxic tissues. Important as this may be, the mechanism of action is not limited to this restoration of oxygenation in hypoxic tissue. Indeed, there are pharmacologic effects that are profound and long-lasting. Although removal from the hyperbaric chamber results in a rapid return of poorly vascularized tissues to their hypoxic state, even a single dose of HBO2T produces changes in fibroblast, leukocyte, and angiogenic functions and antioxidant defenses that persist many hours after oxygen tensions are returned to pretreatment levels.


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InternalMed_Harrison. It is widely accepted that oxygen in high doses produces adverse effects due to the production of reactive oxygen species (ROS) such as superoxide (O2 -) and hydrogen peroxide (H2O2). It has become increasingly clear over the last decade that both ROS and reactive nitrogen species (RNS) such as nitric oxide (NO) participate in a wide range of intracellular signaling pathways involved in the production of a range of cytokines, growth factors, and other inflammatory and repair modulators. Such mechanisms are complex and at times apparently paradoxical. For example, when used to treat chronic hypoxic wounds, HBO2T has been shown to enhance the clearance of cellular debris and bacteria by providing the substrate for macrophage phagocytosis; stimulate growth factor synthesis by increased production and stabilization of hypoxia-inducible factor 1 (HIF-1); inhibit leukocyte activation and adherence to damaged endothelium; and mobilize CD34+ pluripotent vasculogenic progenitor cells from the


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InternalMed_Harrison. and stabilization of hypoxia-inducible factor 1 (HIF-1); inhibit leukocyte activation and adherence to damaged endothelium; and mobilize CD34+ pluripotent vasculogenic progenitor cells from the bone marrow. The interactions between these mechanisms remain a very active field of investigation. One exciting development is the concept of hyperoxic preconditioning in which a short exposure to HBO2 can induce tissue protection against future hypoxic/ ischemic insult, most likely through an inhibition of mitochondrial permeability transition pore (MPTP) opening and the release of cytochrome c. By targeting these mechanisms of cell death during reperfusion events, HBO2 has potential applications in a variety of settings including organ transplantation. One randomized clinical trial suggested that HBO2T prior to coronary artery bypass grafting reduces biochemical markers of ischemic stress and improves neurocognitive outcomes.


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InternalMed_Harrison. Hyperbaric oxygen Restoration of tissue normoxia Edema reduction Hyperoxic vasoconstriction ˜Wound growth factors Stem cell mobilization °˛2 integrin function Enhanced phagocytosis, angiogenesis, and fibroblast activity Ischemic preconditioning, e.g., HIF-1 HO-1 Wound healing, radiation tissue injury Threatened grafts/flaps cadaveric organ preservation Enhanced inert gas diffusion gradients between bubble, tissue, and lungs High arterial PO2 Hydrostatic compression Bubble volume reduction DCS CAGE Enhanced O2 diffusion Generation of ROS and RNS Osmotic effect Crush injury


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InternalMed_Harrison. FIGuRE 477e-3 Mechanisms of action of hyperbaric oxygen. There are many consequences of compression and oxygen breathing. The cell-signaling effects of HBO2T are the least understood but potentially most important. Examples of indications for use are shown in the shaded boxes. CAGE, cerebral arterial gas embolism; DCS, decompression sickness; HIF-1, hypoxia inducible factor-1; HO-1, hemoxygenase 1; RNS, reactive nitrogen species; ROS, reactive oxygen species. HBO2T is generally well tolerated and safe in clinical practice. Adverse effects are associated with both alterations in pressure (barotrauma) and the administration of oxygen.


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InternalMed_Harrison. Barotrauma occurs when any noncompliant gas-filled space within the body does not equalize with environmental pressure during compression or decompression. About 10% of patients complain of some difficulty equalizing middle-ear pressure early in compression, and although most of these problems are minor and can be overcome with training, 2–5% of conscious patients require middle-ear ventilation tubes or formal grommets across the tympanic membrane. Unconscious patients cannot equalize and should have middle-ear ventilation tubes placed prior to compression if possible. Other less common sites for barotrauma of compression include the respiratory sinuses and dental caries. The lungs are potentially vulnerable to barotrauma of decompression as described below in the section on diving medicine, but the decompression following HBO2T is so slow that pulmonary gas trapping is extremely rare in the absence of an undrained pneumothorax or lesions such as bullae.


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InternalMed_Harrison. The practical limit to the dose of oxygen, either in a single treatment session or in a series of daily sessions, is oxygen toxicity. The most common acute manifestation is a seizure, often preceded by anxiety and agitation, during which time a switch from oxygen to air breathing may avoid the convulsion. Hyperoxic seizures are typically generalized tonic-clonic seizures followed by a variable postictal period. The cause is an overwhelming of the antioxidant defense systems within the brain. Although clearly dose-dependent, onset is very variable both between individuals and within the same individual on different days. In routine clinical hyperbaric practice, the incidence is about 1:1500 to 1:2000 compressions.


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InternalMed_Harrison. Chronic oxygen poisoning most commonly manifests as myopic shift. This is due to alterations in the refractive index of the lens following oxidative damage that reduces the solubility of lenticular proteins in a process similar to that associated with senescent cataract formation. Up to 75% of patients show deterioration in visual acuity after a course of 30 treatments at 202.6 kPa (2 ATA). Although most return to pretreatment values 6–12 weeks after cessation of treatment, a small proportion do not recover. A more rapid maturation of preexisting cataracts has occasionally been associated with HBO2T. Although a theoretical problem, the development of pulmonary oxygen toxicity over time does not seem to be problematic in practice—probably due to the intermittent nature of the exposure.


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InternalMed_Harrison. There are few absolute contraindications to HBO2T. The most commonly encountered is an untreated pneumothorax. A pneumothorax may expand rapidly on decompression and come under tension. Prior to any compression, patients with a pneumothorax should have a patent chest drain in place. The presence of other obvious risk factors for pulmonary gas trapping such as bullae should trigger a very cautious analysis of the risks of treatment versus benefit. Prior bleomycin treatment deserves special mention because of its association with a partially dose-dependent pneumonitis in about 20% of people. These individuals appear to be at particular risk for rapid deterioration of ventilatory function following exposure to high oxygen tensions. The relationship between distant bleomycin exposure and subsequent risk of pulmonary oxygen toxicity is uncertain, however late pulmonary fibrosis is a potential complication of bleomycin, and any patient with a history of receiving this drug should be


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InternalMed_Harrison. subsequent risk of pulmonary oxygen toxicity is uncertain, however late pulmonary fibrosis is a potential complication of bleomycin, and any patient with a history of receiving this drug should be carefully counseled prior to exposure to HBO2T. For those recently exposed to doses above 300,000 IU (200 mg) and whose course was complicated by a respiratory reaction to bleomycin, compression should be avoided except in a life-threatening situation.


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InternalMed_Harrison. The appropriate indications for HBO2T are controversial and evolving. Practitioners in this area are in an unusual position. Unlike most branches of medicine, hyperbaric physicians do not deal with a range of disorders within a defined organ system (e.g., cardiology), nor are they masters of a therapy specifically designed for a single category of disorders. Inevitably, the encroachment of hyperbaric physicians into other medical fields generates suspicion from specialist practitioners in those fields. At the same time this relatively benign therapy, the prescription and delivery of which requires no medical license in most jurisdictions (including the United States), attracts both charlatans and well-motivated proselytizers who tout the benefits of oxygen for a plethora of chronic incurable diseases. This battle on two fronts has meant that mainstream hyperbaric physicians have been particularly careful to claim effectiveness only for those conditions where there is a reasonable body


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InternalMed_Harrison. diseases. This battle on two fronts has meant that mainstream hyperbaric physicians have been particularly careful to claim effectiveness only for those conditions where there is a reasonable body of supporting evidence.


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InternalMed_Harrison. In 1977, the UHMS systematically examined claims for the use of HBO2T in more than 100 disorders and found sufficient evidence to support routine use in only 12. The Hyperbaric Oxygen Therapy Committee of that organization has continued to update this list periodically with an increasingly formalized system of appraisal for new indications and emerging evidence (Table 477e-1). Around the world, other relevant medical organizations have generally taken a similar approach, although indications vary considerably—particularly those recommended by hyperbaric medical societies in Russia and China where HBO2T has gained much wider support than in the United States, Europe, and Australasia. Recently, several Cochrane reviews have examined the randomized trial evidence for many putative indications, including attempts to examine the cost-effectiveness of HBO2T. Table 477e-2 is a synthesis of these two approaches and lists the estimated cost of attaining health outcomes with the use of HBO2T.


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InternalMed_Harrison. including attempts to examine the cost-effectiveness of HBO2T. Table 477e-2 is a synthesis of these two approaches and lists the estimated cost of attaining health outcomes with the use of HBO2T. Any savings associated with alternative treatment strategies avoided as a result of HBO2T are not accounted for in these estimates (e.g., the avoidance of lower leg amputation in diabetic foot ulcers). Following are short reviews of three important indications currently accepted by the UHMS.


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InternalMed_Harrison. Radiotherapy is a well-established treatment for suitable malignancies. In the United States alone, approximately 300,000 individuals annually will become long-term survivors of cancer treated by irradiation. Serious radiation-related complications developing months or years after treatment (late radiation tissue injury [LRTI]) will significantly affect between 5 and 15% of those long-term survivors, although inci Current List of inDiCations for hyperBariC oxygen therapy 1. Air or gas embolism (includes diving-related, iatrogenic, and accidental causes) 2. 3. 4. Crush injury, compartment syndrome, and acute traumatic ischemias 5. 6. Arterial insufficiency Central retinal artery occlusion Enhancement of healing in selected problem wounds 7. Exceptional blood loss (where transfusion is refused or impossible) 8. 9. Necrotizing soft tissue infections (e.g., Fournier’s gangrene) 10. Osteomyelitis (refractory to other therapy) 11. 12. 13. 14.


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InternalMed_Harrison. 9. Necrotizing soft tissue infections (e.g., Fournier’s gangrene) 10. Osteomyelitis (refractory to other therapy) 11. 12. 13. 14. Sudden sensorineural hearing loss Source: The Undersea and Hyperbaric Medical Society (2013). dence varies widely with dose, age, and site. LRTI is most common in 477e-3 the head and neck, chest wall, breast, and pelvis.


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InternalMed_Harrison. Pathology and Clinical Course With time, tissues undergo a progressive deterioration characterized by a reduction in the density of small blood vessels (reduced vascularity) and the replacement of normal tissue with dense fibrous tissue (fibrosis). An alternative model of pathogenesis suggests that rather than a primary hypoxia, the principle trigger is an overexpression of inflammatory cytokines that promote fibrosis, probably through oxidative stress and mitochondrial dysfunction, and a secondary tissue hypoxia. Ultimately, and often triggered by a further physical insult such as surgery or infection, there may be insufficient oxygen to sustain normal function, and the tissue becomes necrotic (radiation necrosis). LRTI may be life-threatening and significantly reduce quality of life. Historically, the management of these injuries has been unsatisfactory. Conservative treatment is usually restricted to symptom management, whereas definitive treatment traditionally entails surgery to


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InternalMed_Harrison. the management of these injuries has been unsatisfactory. Conservative treatment is usually restricted to symptom management, whereas definitive treatment traditionally entails surgery to remove the affected part and extensive repair. Surgical intervention in an irradiated field is often disfiguring and associated with an increased incidence of delayed healing, breakdown of a surgical wound, or infection. HBO2T may act by several mechanisms to improve this situation, including edema reduction, vasculogenesis, and enhancement of macrophage activity (Fig. 477e-3). The intermittent application of HBO2 is the only intervention shown to increase the microvascular density in irradiated tissue.


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InternalMed_Harrison. Clinical Evidence The typical course of HBO2T consists of 30 once-daily compressions to 202.6–243.1 kPa (2–2.4 ATA) for 1.5–2 h each session, often bracketed around surgical intervention if required. Although HBO2T has been used for LRTI since at least 1975, most clinical studies have been limited to small case series or individual case reports. In a review, Feldmeier and Hampson located 71 such reports involving a total of 1193 patients across eight different tissues. There were clinically significant improvements in the majority of patients, and only 7 of 71 reports indicated a generally poor response to HBO2T. A Cochrane systematic review with meta-analysis included six randomized trials published since 1985 and drew the following conclusions (see Table 477e-2 for numbers needed to treat): HBO2T improves healing in radiation proctitis (relative risk [RR] of healing with HBO2T 2.7; 95% confidence interval [CI] 1.2–6) and after hemimandibulectomy and reconstruction of the mandible


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InternalMed_Harrison. HBO2T improves healing in radiation proctitis (relative risk [RR] of healing with HBO2T 2.7; 95% confidence interval [CI] 1.2–6) and after hemimandibulectomy and reconstruction of the mandible (RR 1.4; 95% CI 1.1–1.8); HBO2T improves the probability of achieving mucosal coverage (RR 1.4; 95% CI 1.2–1.6) and the restoration of bony continuity with osteoradionecrosis (ORN) (RR 1.4; 95% CI 1.1–1.8); HBO2T prevents the development of ORN following tooth extraction from a radiation field (RR 1.4; 95% CI 1.08–1.7) and reduces the risk of wound dehiscence following grafts and flaps in the head and neck (RR 4.2; 95% CI 1.1–16.8). Conversely, there was no evidence of benefit in established radiation brachial plexus lesions or brain injury.


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InternalMed_Harrison. A problem wound is any cutaneous ulceration that requires a prolonged time to heal, does not heal, or recurs. In general, wounds referred to hyperbaric facilities are those where sustained attempts to heal by other means have failed. Problem wounds are common and constitute a significant health problem. It has been estimated that 1% of the population of industrialized countries will experience a leg ulcer at some time. The global cost of chronic wound care may be as high as U.S. $25 billion per year.


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InternalMed_Harrison. U.S. $25 billion per year. Pathology and Clinical Course By definition, chronic wounds are indolent or progressive and resistant to the wide array of treatments applied. Although there are many contributing factors, most commonly these wounds arise in association with one or more comorbidities such as diabetes, peripheral venous or arterial disease, or prolonged pressure (decubitus ulcers). First-line treatments are aimed at correction of the underlying pathology (e.g., vascular reconstruction, compression bandaging, or normalization of blood glucose level), and HBO2T is an adjunctive therapy to good general wound care practice to maximize the chance of healing. Estimated Cost to Produce Outcome (number of


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InternalMed_Harrison. Estimated Cost to Produce Outcome (number of Radiation tissue injury More information is required on the subset of disease severity, the affected tissue type that is most likely to benefit, and the time over which benefit may persist. Resolved proctitis (30) 3 22,392 Large ongoing multicenter trial 2–11 14,928–82,104 Healed mandible (30) 4 29,184 Based on one poorly reported study 2–8 14,592–58,368 Mucosal cover in ORN (30) 3 29,888 Based on one poorly reported study 2–4 14,592–29,184 Bony continuity in ORN (30) 4 29,184 Based on one poorly reported study 2–8 14,592–58,368 Prevention of ORN after dental 4 29,184 Based on a single study extraction (30) 2–13 14,592–94,848 Prevention of dehiscence (30) 5 36,480 Based on one poorly reported study 3–8 21,888–58,368


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InternalMed_Harrison. Prevention of dehiscence (30) 5 36,480 Based on one poorly reported study 3–8 21,888–58,368 Chronic wounds More information is required on the subset of disease severity or classification most likely to benefit, the time over which benefit may persist, and the most appropriate oxygen dose. Economic analysis is required. Diabetic ulcer healed at 2 14,928 Based on one small study, more 1 year (30) 1–5 7464–37,320 Diabetic ulcer, major 4 29,856 Three small studies; outcome over a amputation avoided (30) 3–11 22,392–82,104 ISSNHL No evidence of benefit more than 2 weeks after onset. More research is required to define the role (if any) of HBO2T in routine therapy. Improvement of 25% in hearing 5 18,240 Some improvement in hearing, but loss within 2 weeks of onset 3–20 10,944–72,960


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InternalMed_Harrison. Improvement of 25% in hearing 5 18,240 Some improvement in hearing, but loss within 2 weeks of onset 3–20 10,944–72,960 Acute coronary More information is required on the subset of disease severity and timing of therapy most likely to result in benefit. Given syndrome the potential of HBO2T in modifying ischemia-reperfusion injury, attention should be given to the combination of HBO2T and thrombolysis in early management and in the prevention of restenosis after stent placement. Episode of MACE (5) 4 4864 Based on a single small study; more research required 3–10 3648–12,160 Incidence of significant 3–24 3648–29,184 Based on a single moderately powered dysrhythmia (5) study in the 1970s Traumatic brain injury Limited evidence that for acute injury HBO2T reduces mortality but not functional morbidity. Routine use not yet justified. Mortality (15) 7 34,104 Based on four heterogeneous studies 4–22 19,488–58,464


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InternalMed_Harrison. Enhancement of There is some evidence that HBO2T improves local tumor control, reduces mortality for cancers of the head and neck, and radiotherapy reduces the chance of local tumor recurrence in cancers of the head, neck, and uterine cervix. Decompression illnessa Reasonable evidence for reduced number of HBO2T sessions but similar outcomes when NSAID added. Abbreviations: CI, confidence interval; HBO2T, hyperbaric oxygen therapy; ISSNHL, idiopathic sudden sensorineural hearing loss; MACE, major adverse cardiac events; N/R, not remarkable; NNT, number needed to treat; NSAID, nonsteroidal anti-inflammatory drug; ORN, osteoradionecrosis; USD, U.S. dollars. Source: M Bennett: The evidence-basis of diving and hyperbaric medicine—a synthesis of the high level evidence with meta-analysis. http://unsworks.unsw.edu.au/vital/access/manager/ Repository/unsworks:949.


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InternalMed_Harrison. For most indolent wounds, hypoxia is a major contributor to failure to heal. Many guidelines to patient selection for HBO2T include the interpretation of transcutaneous oxygen tensions around the wound while breathing air and oxygen at pressure (Fig. 477e-4). Wound healing is a complex and incompletely understood process. While it appears that in acute wounds healing is stimulated by the initial hypoxia, low pH, and high lactate concentrations found in freshly injured tissue, some elements of tissue repair are extremely oxygen dependent, for example, collagen elaboration and deposition by fibroblasts, and bacterial killing by macrophages. In this complicated interaction between wound hypoxia and peri-wound oxygenation, successful healing relies on adequate tissue oxygenation in the area surrounding the fresh wound. Certainly, wounds that lie in hypoxic tissue beds are those that most often display poor or absent healing. Some causes of tissue hypoxia will be reversible with HBO2T,


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InternalMed_Harrison. surrounding the fresh wound. Certainly, wounds that lie in hypoxic tissue beds are those that most often display poor or absent healing. Some causes of tissue hypoxia will be reversible with HBO2T, whereas some will not (e.g., in the presence of severe large vessel disease). When tissue hypoxia can be overcome by a high driving pressure of oxygen in the arterial blood, this can be demonstrated by measuring the tissue partial pressure of oxygen using an implantable oxygen electrode or, more commonly, a modified transcutaneous Clarke electrode.


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InternalMed_Harrison. The intermittent presentation of oxygen to those hypoxic tissues facilitates a resumption of healing. These short exposures to high oxygen tensions have long-lasting effects (at least 24 h) on a wide range of healing processes (Fig. 477e-3). The result is a gradual improvement in oxygen tension around the wound that reaches a plateau in experimental studies at about 20 treatments over 4 weeks. Improvements in oxygenation are associated with an eightto ninefold increase in vascular density over both normobaric oxygen and air-breathing controls.


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InternalMed_Harrison. Clinical Evidence The typical course of HBO2T consists of 20–30 once-daily compressions to 2–2.4 ATA for 1.5–2 h each session, but is highly dependent on the clinical response. There are many case series in the literature supporting the use of HBO2T for a wide range of problem wounds. Both retrospective and prospective cohort studies suggest that 6 months after a course of therapy, about 70% of indolent ulcers will be substantially improved or healed. Often these ulcers have been present for many months or years, suggesting that the application of HBO2T has a profound effect, either primarily or as a facilitator of other strategies. A recent Cochrane review included nine randomized controlled trials (RCTs) and concluded that the chance of ulcer healing improved about fivefold with HBO2T (RR 5.20; 95% CI 1.25–21.66; p = .02).


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InternalMed_Harrison. Although there was a trend to benefit with HBO2T, there was no sta-477e-5 tistically significant difference in the rate of major amputations (RR 0.36; 95% CI 0.11–1.18). Carbon monoxide (CO) is a colorless, odorless gas formed during incomplete hydrocarbon combustion. Although CO is an essential endogenous neurotransmitter linked to NO metabolism and activity, it is also a leading cause of poisoning death, and in the United States alone results in more than 50,000 emergency department visits per year and about 2000 deaths. Although there are large variations from country to country, about half of nonlethal exposures are due to self-harm. Accidental poisoning is commonly associated with defective or improperly installed heaters, house fires, and industrial exposures. The motor vehicle is by far the most common source of intentional poisoning.


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InternalMed_Harrison. Pathology and Clinical Course The pathophysiology of carbon monoxide exposure is incompletely understood. CO binds to hemoglobin with an affinity more than 200 times that of oxygen, directly reducing the oxygen-carrying capacity of blood, and further promoting tissue hypoxia by shifting the oxyhemoglobin dissociation curve to the left. CO is also an anesthetic agent that inhibits evoked responses and narcotizes experimental animals in a dose-dependent manner. The associated loss of airway patency together with reduced oxygen carriage in blood may cause death from acute arterial hypoxia in severe poisoning. CO may also cause harm by other mechanisms including direct disruption of cellular oxidative processes, binding to myoglobin and hepatic cytochromes, and peroxidation of brain lipids.


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InternalMed_Harrison. The brain and heart are the most sensitive target organs due to their high blood flow, poor tolerance of hypoxia, and high oxygen requirements. Minor exposure may be asymptomatic or present with vague constitutional symptoms such as headache, lethargy, and nausea, whereas higher doses may present with poor concentration and cognition, short-term memory loss, confusion, seizures, and loss of consciousness. While carboxyhemoglobin (COHb) levels on admission do not necessarily reflect the severity or the prognosis of CO poisoning, cardiorespiratory arrest carries a very poor prognosis. Over the longer term, surviving patients commonly have neuropsychological sequelae. Motor disturbances, peripheral neuropathy, hearing loss, vestibular abnormalities, dementia, and psychosis have all been reported. Risk One schema for using transcutaneous oximetry to assist in patient selection for HBO2T. If the wound area is Suitable for compression?


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InternalMed_Harrison. One schema for using transcutaneous oximetry to assist in patient selection for HBO2T. If the wound area is Suitable for compression? hypoxic and responds to the administration of oxygen at 1 ATA or 2.4 ATA, treatment may be justified. Contraindication, critical major vessel disease or surgical option available HBO2T indicated on a case by case basis. Consider alternatives Transcutaneous mapping on 100% oxygen 2.4 ATA FIGuRE 477e-4 Determining suitability for hyperbaric oxygen therapy (HBO2T) guided by transcutaneous oximetry around the wound bed. *In diabetic patients, <50 mmHg may be more appropriate. PtcO2, transcutaneous oxygen pressure. factors for poor outcome are age >35 years, exposure for >24 h, acidosis, and loss of consciousness.


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InternalMed_Harrison. Clinical Evidence The typical course of HBO2T consists of two to three compressions to 2–2.8 ATA for 1.5–2 h each session. It is common for the first two compressions to be delivered within 24 h of the exposure. CO poisoning is one of the longest-standing indications for HBO2T— based largely on the obvious connection between exposure, tissue hypoxia, and the ability of HBO2T rapidly to overcome this hypoxia. CO is eliminated rapidly via the lungs on application of HBO2T, with a half-life of about 21 min at 2.0 ATA versus 5.5 h breathing air and 71 min breathing oxygen at sea level. In practice, however, it seems unlikely that HBO2T can be delivered in time to prevent either acute hypoxic death or irreversible global cerebral hypoxic injury. If HBO2T is beneficial in CO poisoning, it must reduce the likelihood of persisting and/or delayed neurocognitive deficit through a mechanism other than the simple reversal of arterial hypoxia due to high levels of COHb. The difficulty in


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InternalMed_Harrison. it must reduce the likelihood of persisting and/or delayed neurocognitive deficit through a mechanism other than the simple reversal of arterial hypoxia due to high levels of COHb. The difficulty in accurately assessing neurocognitive deficit has been one of the primary sources of controversy surrounding the clinical evidence in this area. To date there have been six randomized controlled trials of HBO2T for CO poisoning, although only four have been reported in full. While a Cochrane review suggested that overall there is insufficient evidence to confirm a beneficial effect of HBO2T on the chance of persisting neurocognitive deficit following poisoning (34% of patients treated with oxygen at 1 atmosphere vs 29%, of those treated with HBO2T; odds ratio [OR] 0.78; 95% CI 0.54–1.1), this may have more to do with poor reporting and inadequate follow-up than with evidence that HBO2T is not effective. The interpretation of the literature has much to do with how one defines neurocognitive


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InternalMed_Harrison. have more to do with poor reporting and inadequate follow-up than with evidence that HBO2T is not effective. The interpretation of the literature has much to do with how one defines neurocognitive deficit. In the most methodologically rigorous of these studies (Weaver et al.), a professionally administered battery of validated neuropsychological tests and a definition based on the deviation of individual subtest scores from the age-adjusted normal values was used; if the patient complained of memory, attention, or concentration difficulties, the required decrement was decreased. Using this approach, 6 weeks after poisoning, 46% of patients treated with normobaric oxygen alone had cognitive sequelae compared to 25% of those who received HBO2T (p = .007; number needed to treat [NNT] = 5; 95% CI 3–16). At 12 months, the difference remained significant (32% vs 18%; p = .04; NNT = 7; 95% CI 4–124) despite considerable loss to follow-up.


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InternalMed_Harrison. On this basis, HBO2T remains widely advocated for the routine treatment of patients with moderate to severe poisoning—in particular in those older than 35 years, presenting with a metabolic acidosis on arterial blood-gas analysis, exposed for lengthy periods, or with a history of unconsciousness. Conversely, many toxicologists remain unconvinced about the place of HBO2T in this situation and call for further well-designed studies.


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InternalMed_Harrison. Underwater diving is both a popular recreational activity and a means of employment in a range of tasks from underwater construction to military operations. It is a complex activity with unique hazards and medical complications arising mainly as a consequence of the dramatic changes in pressure associated with both descent and ascent through the water column. For every 10.13 m increase in depth of seawater, the ambient pressure (Pamb) increases by 101.3 kPa (1 atmosphere) so that a diver at 20 m depth is exposed to a Pamb of approximately 303.9 kPa (3 ATA), made up of 1 ATA due to atmospheric pressure and 2 ATA generated by the water column.


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InternalMed_Harrison. Most diving is undertaken using a self-contained underwater breathing apparatus (scuba) consisting of one or more cylinders of compressed gas connected to a pressure-reducing regulator and a demand valve activated by inspiratory effort. Some divers use “rebreathers,” which are scuba devices that are closed or semiclosed circle systems with a carbon dioxide scrubber and a system designed to maintain a safe inspired PO2. Exhaled gas is recycled, and gas consumption is limited to little more than the oxygen metabolized by the diver. Rebreathers are therefore popular for deep dives where expensive helium is included in the respired mix (see below). Occupational divers frequently use “surface supply” equipment where gas, along with other utilities such as communications and power, is supplied via an umbilical from the surface.


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InternalMed_Harrison. All these systems must supply gas to the diver at the Pamb of the surrounding water or inspiration would be impossible against the surrounding water pressure. For most recreational diving, the respired gas is air. Pure oxygen is rarely used because oxygen may provoke seizures above an inspired PO2 of 162 kPa (1.6 ATA) in aquatic environments, limiting the practical safe depth to 6 m. This is a conspicuously lower PO2 than routinely used for hyperbaric therapy, reflecting a higher risk of both seizures and pulmonary toxicity during immersion. For the same reason, very deep diving requires the use of oxygen fractions lower than in air (FO2 0.21). This is because breathing air at 66 m means inspiring 1.6 ATA of oxygen, the maximum allowable pressure. To dive any deeper, breathing gases must contain less oxygen than air. Deep-diving gases often include helium instead of nitrogen to reduce both the narcotic effect and high gas density that result from breathing nitrogen at high pressures.


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InternalMed_Harrison. The most common reason for physician consultation in relation to diving is for the evaluation of suitability for diver training or after a health event. Occupational diver candidates are usually compelled to see doctors with specialist training in the field, both at entry to the industry and periodically thereafter, and their medical evaluations are usually conducted according to legally mandated standards. In contrast, in most jurisdictions prospective recreational diver candidates simply complete a self-assessment medical questionnaire prior to diver training. If there are no positive responses, the candidate proceeds directly to training, but positive responses mandate the candidate see a doctor for evaluation of the identified medical issue. Prospective divers will often present to their family medicine practitioner for this purpose. In the modern era, such consultations have evolved from a simple proscriptive exercise of excluding those with potential contraindications to a more


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InternalMed_Harrison. family medicine practitioner for this purpose. In the modern era, such consultations have evolved from a simple proscriptive exercise of excluding those with potential contraindications to a more “risk analysis” approach in which each case is evaluated on its own merits. Such analyses require integration of diving physiology, the impact of associated medical problems, and a detailed knowledge of the specific medical condition of the candidate. A detailed discussion of the subject is beyond the scope of this chapter, but a few important principles are outlined below.


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InternalMed_Harrison. There are three primary questions that should be answered: (1) Could the underlying condition be exacerbated by diving? (2) Could the condition make a diving medical problem more likely? (3) Could the condition prevent the diver from meeting the functional requirements of diving? As examples, epilepsy is usually considered a contraindication because there are epileptogenic stimuli encountered in diving that could make a seizure more likely (such as thermal stress and exercise). Active asthma is a relative contraindication because it could predispose to pulmonary barotrauma (see below), and untreated ischemic heart disease is a contraindication because it could prevent a diver from exercising sufficiently to get out of a difficult situation such as being caught in a current. It can be a complex matter to recognize the relevant interactions between diving and medical conditions and to determine the impact on suitability for diving. Physicians interested in regularly conducting such


InternalMed_Harrison

InternalMed_Harrison. a complex matter to recognize the relevant interactions between diving and medical conditions and to determine the impact on suitability for diving. Physicians interested in regularly conducting such evaluations should obtain relevant training. Short courses providing relevant training are offered by specialist groups in most countries.


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InternalMed_Harrison. The problem of middle-ear barotrauma (MEBT) with diving is similar to the problem that may occur during descent from altitude in an airplane, but difficulties with equalizing pressure in the middle ear are exaggerated underwater by both the rapidity and magnitude of pressure change as a diver descends or ascends. Failure to periodically insufflate the middle-ear spaces via the eustachian tubes during descent results in increasing pain. As the Pamb increases, the tympanic membrane (TM) may be bruised or even ruptured as it is pushed inward. Negative pressure in the middle ear results in engorgement of blood vessels in the mucous membranes and leads to effusion or bleeding, which can be associated with a conductive hearing loss. MEBT is much less common during ascent because expanding gas in the middle-ear space tends to open the eustachian tube easily and “automatically.” Barotrauma may also affect the respiratory sinuses, although the sinus ostia are usually widely patent and allow


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InternalMed_Harrison. in the middle-ear space tends to open the eustachian tube easily and “automatically.” Barotrauma may also affect the respiratory sinuses, although the sinus ostia are usually widely patent and allow automatic pressure equalization without the need for specific maneuvers. If equalization fails, pain usually results in termination of the dive. Difficulty with equalizing ears or sinuses may respond to oral or nasal decongestants.


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InternalMed_Harrison. Much less commonly the inner ear may suffer barotrauma (IEBT). Several explanations have been proposed, of which the most favored holds that forceful attempts to insufflate the middle-ear space by Valsalva maneuvers during descent cause sudden transmission of pressure to the perilymph via the cochlear aqueduct and outward rupture of the round window already under tension because of negative middle ear pressure. The clinician should be alerted to possible IEBT after diving by a sensorineural hearing loss or true vertigo (which is often accompanied by nausea, vomiting, nystagmus, and ataxia). These manifestations can also occur in vestibulocochlear DCS (see below) but should never be attributed to MEBT. Immediate review by an expert diving physician is recommended, and urgent referral to an otologist will often follow.


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InternalMed_Harrison. The lungs are also vulnerable to barotrauma but are at most risk during ascent. If expanding gas becomes trapped in the lungs as Pamb falls, this may rupture alveoli and associated vascular tissue. Gas trapping may occur if divers intentionally or involuntarily hold their breath during ascent or if there are bullae. The extent to which asthma predisposes to pulmonary barotrauma is debated, but the presence of active bronchoconstriction must increase risk. For this reason, asthmatics who regularly require bronchodilator medications or whose airways are sensitive to exercise or cold air are usually discouraged from diving. While possible consequences of pulmonary barotrauma include pneumothorax and mediastinal emphysema, the most feared is the introduction of gas into the pulmonary veins leading to cerebral arterial gas embolism (CAGE). Manifestations of CAGE include loss of consciousness, confusion, hemiplegia, visual disturbances, and speech difficulties, appearing immediately or


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InternalMed_Harrison. leading to cerebral arterial gas embolism (CAGE). Manifestations of CAGE include loss of consciousness, confusion, hemiplegia, visual disturbances, and speech difficulties, appearing immediately or within minutes after surfacing. The management is the same as for DCS described below. It is notable that the natural history of CAGE often includes substantial or complete resolution of symptoms early after the event. This is probably the clinical correlate of bubble involution and redistribution with consequent restoration of flow. Patients exhibiting such remissions should still be reviewed at specialist diving medical centers because secondary deterioration or reembolization can occur. Unsurprisingly, these events can be misdiagnosed as typical strokes or transient ischemic attacks (TIAs) (Chap. 455) when patients are seen by those unfamiliar with diving medicine. All patients presenting with neurologic symptoms after diving should have their symptoms discussed with a specialist in


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InternalMed_Harrison. (Chap. 455) when patients are seen by those unfamiliar with diving medicine. All patients presenting with neurologic symptoms after diving should have their symptoms discussed with a specialist in diving medicine and be considered for recompression therapy.


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InternalMed_Harrison. DCS is caused by the formation of bubbles from dissolved inert gas (usually nitrogen) during or after ascent (decompression) from a compressed gas dive. Bubble formation is also possible following decompression for extravehicular activity during space flight and with ascent to altitude in unpressurized aircraft. DCS in the latter scenarios is probably rare in comparison with diving, where the incidence is approximately 1:10,000 recreational dives.


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InternalMed_Harrison. Breathing at elevated Pamb results in increased uptake of inert gas into blood and then into tissues. The rate at which tissue inert gas equilibrates with the inspired inert gas pressure is proportional to tissue blood flow and the blood-tissue partition coefficient for the gas. Similar factors dictate the kinetics of inert gas washout during ascent. If the rate of gas washout from tissues does not match the rate of decline in Pamb, then the sum of dissolved gas pressures in the tissue will exceed Pamb, a condition referred to as “supersaturation.” This is the prerequisite for bubbles to form during decompression, although other less well-understood factors are also involved. Deeper and longer dives 477e-7 result in greater inert gas absorption and greater likelihood of tissue supersaturation during ascent. Divers control their ascent for a given depth and time exposure using algorithms that often include periods where ascent is halted for a prescribed period at different depths to


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InternalMed_Harrison. during ascent. Divers control their ascent for a given depth and time exposure using algorithms that often include periods where ascent is halted for a prescribed period at different depths to allow time for gas washout (“decompression stops”). Although a breach of these protocols increases the risk of DCS, adherence does not guarantee against it. DCS should be considered in any diver manifesting symptoms not readily explained by an alternative mechanism.


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InternalMed_Harrison. Bubbles may form within tissues themselves, where they cause symptoms by mechanical distraction of pain-sensitive or functionally important structures. They also appear in the venous circulation as blood passes through supersaturated tissues. Some venous bubbles are tolerated without symptoms and are filtered from the circulation in the pulmonary capillaries. However, in sufficiently large numbers, these bubbles are capable of inciting inflammatory and coagulation cascades, damaging endothelium, activating formed elements of blood such as platelets, and causing symptomatic pulmonary vascular obstruction. Moreover, if there is a right-to-left shunt such as through a patent foramen ovale (PFO) or an intrapulmonary shunt, then venous bubbles may enter the arterial circulation (25% of adults have a probe-patent PFO). The risk of cerebral, spinal cord, inner ear, and skin manifestations appears higher in the presence of significant shunts, suggesting that these “arterialized” venous


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InternalMed_Harrison. have a probe-patent PFO). The risk of cerebral, spinal cord, inner ear, and skin manifestations appears higher in the presence of significant shunts, suggesting that these “arterialized” venous bubbles can cause harm, perhaps by disrupting flow in the microcirculation of target organs. Circulating endothelial microparticles, which are elevated in number and size after diving, are currently under investigation as indicators of decompression stress or possibly as injurious agents in their own right. How they arise, and their role in DCS, remain unclear.


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InternalMed_Harrison. Table 477e-3 lists manifestations of DCS grouped according to organ system. The majority of cases present with mild symptoms, including musculoskeletal pain, fatigue, and minor neurologic manifestations such as patchy paresthesias. Serious presentations are much less common. Pulmonary and cardiovascular manifestations can be life-threatening, and spinal cord involvement frequently results in permanent disability. Latency is variable. Serious DCS usually manifests within minutes of surfacing, but mild symptoms may not appear for several hours. Symptoms arising more than 24 h after diving are very unlikely to be DCS. The presentation may be confusing and nonspecific, and there are as yet no useful diagnostic investigations. Diagnosis is based on integration of findings from examination of the dive profile, the nature and temporal relationship of symptoms, and the clinical examination. Some DCS presentations may be difficult to separate from CAGE following pulmonary barotrauma, but from


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InternalMed_Harrison. dive profile, the nature and temporal relationship of symptoms, and the clinical examination. Some DCS presentations may be difficult to separate from CAGE following pulmonary barotrauma, but from a clinical perspective the distinction is unimportant because the first aid and definitive management of both conditions are the same.


InternalMed_Harrison

InternalMed_Harrison. First aid includes horizontal positioning (especially if there are cerebral manifestations), intravenous fluids if available, and sustained 100% oxygen administration. The latter accelerates inert gas washout from tissues and promotes resolution of bubbles. Definitive treatment of DCS or CAGE with recompression and hyperbaric oxygen is justified in most instances, although some mild or marginal DCS cases may be managed with first aid measures, an option that may be invoked under various circumstances, but especially if evacuation for recompression is hazardous or extremely difficult. Long-distance evacuations are usually undertaken using a helicopter flying at low altitude or a fixed wing air ambulance pressurized to 1 atmosphere pressure.


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InternalMed_Harrison. Recompression reduces bubble volume in accordance with Boyle’s law and increases the inert gas partial pressure difference between a bubble and surrounding tissue. At the same time, oxygen administration markedly increases the inert gas partial pressure difference between alveoli and tissue. The net effect is to significantly increase the rate of inert gas diffusion from bubble to tissue and tissue to blood, thus accelerating bubble resolution. Hyperbaric oxygen also helps oxygenate compromised tissues and appears to ameliorate some of the proinflammatory effects of bubbles. Various recompression protocols have been advocated, but there are no data that define the optimum approach. It typically begins with oxygen administered at 2.8 atmospheres absolute, the maximum pressure at which the risk of oxygen toxicity remains acceptable in a hyperbaric chamber. There follows a stepwise decompression over variable periods adjusted to symptom response. The most widely used algorithm is the


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InternalMed_Harrison. risk of oxygen toxicity remains acceptable in a hyperbaric chamber. There follows a stepwise decompression over variable periods adjusted to symptom response. The most widely used algorithm is the U.S. Navy Table 6, whose shortest format lasts 4 h and 45 min. Typically, shorter “follow-up” recompressions are repeated daily while symptoms persist and appear responsive to treatment. Adjuncts to recompression include intravenous fluids and other supportive care as necessary. Occasionally, very sick divers require high-level intensive care.


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InternalMed_Harrison. hypothermia and Frostbite Daniel F. Danzl HYPOTHERMIA Accidental hypothermia occurs when there is an unintentional drop in the body’s core temperature below 35°C (95°F). At this temperature, many of the compensatory physiologic mechanisms that conserve heat 478e begin to fail. Primary accidental hypothermia is a result of the direct exposure of a previously healthy individual to the cold. The mortality rate is much higher for patients who develop secondary hypothermia as a complication of a serious systemic disorder.


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InternalMed_Harrison. Primary accidental hypothermia is geographically and seasonally pervasive. Although most cases occur in the winter months and in colder climates, this condition is surprisingly common in warmer regions as well. Multiple variables render individuals at the extremes of age— both the elderly and neonates—particularly vulnerable to hypothermia (Table 478e-1). The elderly have diminished thermal perception and are more susceptible to immobility, malnutrition, and systemic illnesses that interfere with heat generation or conservation. Dementia, psychiatric illness, and socioeconomic factors often compound these problems by impeding adequate measures to prevent hypothermia. Neonates have high rates of heat loss because of their increased surface-to-mass ratio and their lack of effective shivering and adaptive behavioral responses. At all ages, malnutrition can contribute to heat loss because of diminished subcutaneous fat and as a result of depleted energy stores used for thermogenesis.


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InternalMed_Harrison. Individuals whose occupations or hobbies entail extensive exposure to cold weather are at increased risk for hypothermia. Military history is replete with hypothermic tragedies. Hunters, sailors, skiers, and climbers also are at great risk of exposure, whether it involves injury, changes in weather, or lack of preparedness. Ethanol causes vasodilation (which increases heat loss), reduces thermogenesis and gluconeogenesis, and may impair judgment or lead to obtundation. Phenothiazines, barbiturates, benzodiazepines, heterocyclic antidepressants, and many other medications reduce centrally mediated vasoconstriction. Up to 25% of patients admitted to an intensive care unit because of drug overdose are hypothermic. Anesthetics can block shivering responses; their effects are compounded when patients are not insulated adequately in the operating or recovery units.


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InternalMed_Harrison. Several types of endocrine dysfunction can lead to hypothermia. 478e-1 Hypothyroidism—particularly when extreme, as in myxedema coma— reduces the metabolic rate and impairs thermogenesis and behavioral responses. Adrenal insufficiency and hypopituitarism also increase susceptibility to hypothermia. Hypoglycemia, most commonly caused by insulin or oral hypoglycemic drugs, is associated with hypothermia, in part because of neuroglycopenic effects on hypothalamic function. Increased osmolality and metabolic derangements associated with uremia, diabetic ketoacidosis, and lactic acidosis can lead to altered hypothalamic thermoregulation.


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InternalMed_Harrison. Neurologic injury from trauma, cerebrovascular accident, subarachnoid hemorrhage, and hypothalamic lesion increases susceptibility to hypothermia. Agenesis of the corpus callosum (Shapiro syndrome) is one cause of episodic hypothermia; in this syndrome, profuse perspiration is followed by a rapid fall in temperature. Acute spinal cord injury disrupts the autonomic pathways that lead to shivering and prevents cold-induced reflex vasoconstrictive responses. Hypothermia associated with sepsis is a poor prognostic sign. Hepatic failure causes decreased glycogen storage and gluconeogenesis as well as a diminished shivering response. In acute myocardial infarction associated with low cardiac output, hypothermia may be reversed after adequate resuscitation. With extensive burns, psoriasis, erythrodermas, and other skin diseases, increased peripheral-blood flow leads to excessive heat loss.


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InternalMed_Harrison. Heat loss occurs through five mechanisms: radiation (55–65% of heat loss), conduction (10–15% of heat loss, much increased in cold water), convection (increased in the wind), respiration, and evaporation; both of the latter two mechanisms are affected by the ambient temperature and the relative humidity. The preoptic anterior hypothalamus normally orchestrates thermo-regulation (Chap. 23). The immediate defense of thermoneutrality is via the autonomic nervous system, whereas delayed control is mediated by the endocrine system. Autonomic nervous system responses include the release of norepinephrine, increased muscle tone, and shivering, leading to thermogenesis and an increase in the basal metabolic rate. Cutaneous cold thermoreception causes direct reflex vasoconstriction to conserve heat. Prolonged exposure to cold also stimulates the thyroid axis, leading to an increased metabolic rate.


InternalMed_Harrison

InternalMed_Harrison. In most cases of hypothermia, the history of exposure to environmental factors (e.g., prolonged exposure to the outdoors without adequate clothing) makes the diagnosis straightforward. In urban settings, however, the presentation is often more subtle, and other disease processes, toxin exposures, or psychiatric diagnoses should be considered.


InternalMed_Harrison

InternalMed_Harrison. After initial stimulation by hypothermia, there is progressive depression of all organ systems. The timing of the appearance of these clinical manifestations varies widely (Table 478e-2). Without knowing the core temperature, it can be difficult to interpret other vital signs. For example, tachycardia disproportionate to the core temperature suggests secondary hypothermia resulting from hypoglycemia, hypovolemia, or a toxin overdose. Because carbon dioxide production declines progressively, the respiratory rate should be low; persistent hyperventilation suggests a central nervous system (CNS) lesion or one of the organic acidoses. A markedly depressed level of consciousness in a patient with mild hypothermia raises suspicion of an overdose or CNS dysfunction due to infection or trauma.


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InternalMed_Harrison. Physical examination findings can also be altered by hypothermia. For instance, the assumption that areflexia is solely attributable to hypothermia can obscure and delay the diagnosis of a spinal cord lesion. Patients with hypothermia may be confused or combative; these symptoms abate more rapidly with rewarming than with chemical or physical restraint. A classic example of maladaptive behavior in patients with hypothermia is paradoxical undressing, which involves the inappropriate removal of clothing in response to a cold stress. The cold-induced ileus and abdominal rectus spasm can mimic or mask the presentation of an acute abdomen (Chap. 20). Mild 35°C (95°F)– 32.2°C (90°F) Moderate <32.2°C (90°F)–28°C (82.4°F) Severe <28°C (<82.4°F)


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InternalMed_Harrison. Mild 35°C (95°F)– 32.2°C (90°F) Moderate <32.2°C (90°F)–28°C (82.4°F) Severe <28°C (<82.4°F) Linear depression of Tachycardia, then pro-Tachypnea, then Diuresis; increase in cerebral metabolism; gressive bradycardia; progressive decrease catecholamines, adreamnesia; apathy; dysar-cardiac cycle prolonga-in respiratory minute nal steroids, triiodothythria; impaired judgment; tion; vasoconstriction; volume; declining ronine, and thyroxine; maladaptive behavior increase in cardiac out-oxygen consumption; increase in metabolism


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InternalMed_Harrison. EEG abnormalities; pro-Progressive decrease Hypoventilation; 50% 50% increase in renal gressive depression of in pulse and cardiac decrease in carbon blood flow; renal level of consciousness; output; increased atrial dioxide production autoregulation intact; pupillary dilation; para-and ventricular arrhyth-per 8°C (46°F) drop in impaired insulin action doxical undressing; hal-mias; suggestive (Jtemperature; absence lucinations wave) ECG changes of protective airway Loss of cerebrovascular Progressive decrease in Pulmonic conges-Decrease in renal blood autoregulation; decline blood pressure, heart tion and edema; 75% flow that parallels in cerebral blood flow; rate, and cardiac out-decrease in oxygen decrease in cardiac coma; loss of ocular put; reentrant dysrhyth-consumption; apnea output; extreme olireflexes; progressive mias; maximal risk of Abbreviations: ECG, electrocardiogram; EEG, electroencephalogram. Source: Modified from DF Danzl, RS Pozos: N Engl J Med 331:1756, 1994.


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InternalMed_Harrison. When a patient in hypothermic cardiac arrest is first discovered, cardiopulmonary resuscitation is indicated unless (1) a do-not-resuscitate status is verified, (2) obviously lethal injuries are identified, or (3) the depression of a frozen chest wall is not possible. As the resuscitation proceeds, the prognosis is grave if there is evidence of widespread cell lysis, as reflected by potassium levels >10–12 mmol/L (10–12meq/L). Other findings that may preclude continuing resuscitation include a core temperature <10–12°C (<50–54°F), a pH <6.5, and evidence of intravascular thrombosis with a fibrinogen value <0.5 g/L (<50 mg/ dL). The decision to terminate resuscitation before rewarming the patient past 33°C (91°F) should be predicated on the type and severity of the precipitants of hypothermia. There are no validated prognostic indicators for recovery from hypothermia. A history of asphyxia with secondary cooling is the most important negative predictor of survival.


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InternalMed_Harrison. Hypothermia is confirmed by measurement of the core temperature, preferably at two sites. Rectal probes should be placed to a depth of 15 cm and not adjacent to cold feces. A simultaneous esophageal probe should be placed 24 cm below the larynx; it may read falsely high during heated inhalation therapy. Relying solely on infrared tympanic thermography is not advisable. After a diagnosis of hypothermia is established, cardiac monitoring should be instituted, along with attempts to limit further heat loss. If the patient is in ventricular fibrillation, it is unclear at what core temperature ventricular defibrillation (2 J/kg) should first be attempted. One attempt below 30°C is warranted. Further defibrillation attempts should be deferred until some rewarming (1°–2°C) is achieved and ventricular fibrillation is coarser. Although cardiac pacing for hypothermic bradydysrrhythmias is rarely indicated, the transthoracic technique is preferable.


InternalMed_Harrison

InternalMed_Harrison. Supplemental oxygenation is always warranted, since tissue oxygenation is affected adversely by the leftward shift of the oxyhemoglobin dissociation curve. Pulse oximetry may be unreliable in patients with vasoconstriction. If protective airway reflexes are absent, gentle endotracheal intubation should be performed. Adequate preoxygenation will prevent ventricular arrhythmias. Insertion of a gastric tube prevents dilation secondary to decreased bowel motility. Indwelling bladder catheters facilitate monitoring of cold-induced diuresis. Dehydration is encountered commonly with chronic hypothermia, and most patients benefit from an intravenous or intraosseous bolus of crystalloid. Normal saline is preferable to


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InternalMed_Harrison. Increased preshivering muscle tone, then fatiguing lactated Ringer’s solution, as the liver in hypothermic patients inefficiently metabolizes lactate. The placement of a pulmonary artery catheter can cause perforation of the less compliant pulmonary artery. Insertion of a central venous catheter deeply into the cold right atrium should be avoided since this procedure can precipitate arrhythmias. Arterial blood gases should not be corrected for temperature (Chap. 66). An uncorrected pH of 7.42 and a Pco2 of 40 mmHg reflect appropriate alveolar ventilation and acid-base balance at any core temperature. Acid-base imbalances should be corrected gradually, since the bicarbonate buffering system is inefficient. A common error is overzealous hyperventilation in the setting of depressed CO2 production. When the Pco2 decreases by 10 mmHg at 28°C (82°F), it doubles the pH increase of 0.08 that occurs at 37°C (99°F).


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InternalMed_Harrison. The severity of anemia may be underestimated because the hematocrit increases 2% for each 1°C drop in temperature. White blood cell sequestration and bone marrow suppression are common, potentially masking an infection. Although hypokalemia is more common in chronic hypothermia, hyperkalemia also occurs; the expected electrocardiographic changes can be obscured by hypothermia. Patients with renal insufficiency, metabolic acidoses, or rhabdomyolysis are at greatest risk for electrolyte disturbances.


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InternalMed_Harrison. Coagulopathies are common because cold inhibits the enzymatic reactions required for activation of the intrinsic cascade. In addition, thromboxane B2 production by platelets is temperature dependent, and platelet function is impaired. The administration of platelets and fresh-frozen plasma is therefore not effective. The prothrombin or partial thromboplastin times or the international normalized ratio can be deceptively normal and contrast with the observed in vivo coagulopathy. This contradiction occurs because all coagulation tests are routinely performed at 37°C (99°F), and the enzymes are thus rewarmed.


InternalMed_Harrison

InternalMed_Harrison. The key initial decision is whether to rewarm the patient passively or actively. Passive external rewarming simply involves covering and insulating the patient in a warm environment. With the head also covered, the rate of rewarming is usually 0.5°–2°C (1.10°–4.4°F) per hour. This technique is ideal for previously healthy patients who develop acute, mild primary accidental hypothermia. The patient must have sufficient glycogen to support endogenous thermogenesis. The application of heat directly to the extremities of patients with chronic severe hypothermia should be avoided because it can induce peripheral vasodilation and precipitate core temperature “afterdrop,” a response characterized by a continual decline in the core temperature after removal of the patient from the cold. Truncal heat application reduces the risk of afterdrop.


InternalMed_Harrison

InternalMed_Harrison. Active rewarming is necessary under the following circumstances: core temperature <32°C (<90°F) (poikilothermia), cardiovascular instability, age extremes, CNS dysfunction, hormone insufficiency, and suspicion of secondary hypothermia. Active external rewarming is best accomplished with forced-air heating blankets. Other options include devices that circulate water through external heat exchange pads, radiant heat sources, and hot packs. Monitoring a patient with hypothermia in a heated tub is extremely difficult. Electric blankets should be avoided because vasoconstricted skin is easily burned.


InternalMed_Harrison

InternalMed_Harrison. There are numerous widely available options for active core rewarming. Airway rewarming with heated humidified oxygen (40°–45°C [104°–113°F]) via mask or endotracheal tube is a convenient option. Although airway rewarming provides less heat than do some other forms of active core rewarming, it eliminates respiratory heat loss and adds 1°–2°C (1.1°–4.4°F) to the overall rewarming rate. Crystalloids should be heated to 40°–42°C (104°–108°F), but the quantity of heat provided is significant only during massive volume resuscitation. The most efficient method for heating and delivering fluid or blood is with a countercurrent in-line heat exchanger. Heated irrigation of the gastrointestinal tract or bladder transfers minimal heat because of the limited available surface area. These methods should be reserved for patients in cardiac arrest and then used in combination with all available active rewarming techniques.


InternalMed_Harrison

InternalMed_Harrison. Closed thoracic lavage is far more efficient in severely hypothermic patients with cardiac arrest. The hemithoraxes are irrigated through two inserted large-bore thoracostomy tubes. Thoracostomy tubes should not be placed in the left chest of a spontaneously perfusing patient for purposes of rewarming. Peritoneal lavage with the dialysate at 40°–45°C (104°–113°F) efficiently transfers heat when delivered through two catheters with outflow suction. Like peritoneal dialysis, standard hemodialysis is especially useful for patients with electrolyte abnormalities, rhabdomyolysis, or toxin ingestion. Another option involves the central venous insertion of a rapid endovascular warming device.


InternalMed_Harrison

InternalMed_Harrison. Extracorporeal blood rewarming options (Table 478e-3) should be considered in severely hypothermic patients, especially those with primary accidental hypothermia. Cardiopulmonary bypass should be considered in nonperfusing patients without documented contraindications to resuscitation. Circulatory support may be the only effective option in patients with completely frozen extremities or those with significant tissue destruction coupled with rhabdomyolysis. There is no evidence that extremely rapid rewarming improves survival in per-fusing patients. The best strategy is usually a combination of passive, truncal active, and active core rewarming techniques.


InternalMed_Harrison

InternalMed_Harrison. When a patient is hypothermic, target organs and the cardiovascular system respond minimally to most medications. Generally, IV medications are withheld below 30°C (86°F). In contrast to antiarrhythmics, low-dose vasopressor medications may improve the intra-arrest rates of return of spontaneous circulation. Because of increased binding of drugs to proteins as well as impaired metabolism and excretion, either a lower dose or a longer interval between doses should be used to avoid toxicity. As an example, the administration of repeated doses of digoxin or insulin would be ineffective while the patient is hypothermic, and the residual drugs would be potentially toxic during rewarming.


InternalMed_Harrison

InternalMed_Harrison. Achieving a mean arterial pressure of at least 60 mmHg should be an early objective. If the hypotension does not respond to crystalloid/ colloid infusion and rewarming, low-dose dopamine support (2–5 μg/ kg per min) should be considered. Perfusion of the vasoconstricted cardiovascular system also may be improved with low-dose IV nitroglycerin. Atrial arrhythmias should be monitored initially without intervention, as the ventricular response should be slow and, unless preexistent, most will convert spontaneously during rewarming. The role of Continuous venovenous Circuit: CV catheter to CV, dual-lumen CV, or Hemodialysis Circuit: singleor dual-vessel cannulation Continuous arteriove-Circuit: percutaneous 8.5-Fr femoral catheters nous rewarming (CAVR) Requires systolic blood pressure of 60 mmHg Cardiopulmonary Circuit: full circulatory support with pump and bypass (CPB) oxygenator ROR up to 9.5°C (49°F)/h


InternalMed_Harrison

InternalMed_Harrison. Requires systolic blood pressure of 60 mmHg Cardiopulmonary Circuit: full circulatory support with pump and bypass (CPB) oxygenator ROR up to 9.5°C (49°F)/h Extracorporeal Decreased risk of post-rewarming cardiorespiratory membrane oxygenation failure (ECMO) Abbreviations: CV, central venous; ROR, rate of rewarming. prophylaxis and treatment of ventricular arrhythmias is problematic. Preexisting ventricular ectopy may be suppressed by hypothermia and reappear during rewarming. None of the class I agents has proved to be safe and efficacious. There is also insufficient evidence that the class III ventricular antiarrhythmic amiodarone is safe.


InternalMed_Harrison

InternalMed_Harrison. Initiating empirical therapy for adrenal insufficiency usually is not warranted unless the history suggests steroid dependence or hypoadrenalism or efforts to rewarm with standard therapy fail. The administration of parenteral levothyroxine to euthyroid patients with hypothermia, however, is potentially hazardous. Because laboratory results can be delayed and confounded by the presence of the sick euthyroid syndrome (Chap. 405), historic clues or physical findings suggestive of hypothyroidism should be sought. When myxedema is the cause of hypothermia, the relaxation phase of the Achilles reflex is prolonged more than is the contraction phase.


InternalMed_Harrison

InternalMed_Harrison. Hypothermia obscures most of the symptoms and signs of infection, notably fever and leukocytosis. Shaking rigors from infection may be mistaken for shivering. Except in mild cases, extensive cultures and repeated physical examinations are essential. Unless an infectious source is identified, empirical antibiotic prophylaxis is most warranted in the elderly, neonates, and immunocompromised patients. Preventive measures should be discussed with high-risk individuals, such as the elderly and people whose work frequently exposes them to extreme cold. The importance of layered clothing and headgear, adequate shelter, increased caloric intake, and the avoidance of ethanol should be emphasized, along with access to rescue services.


InternalMed_Harrison

InternalMed_Harrison. Peripheral cold injuries include both freezing and nonfreezing injuries to tissue. Tissue freezes quickly when in contact with thermal conductors such as metal and volatile solutions. Other predisposing factors include constrictive clothing or boots, immobility, and vasoconstrictive medications. Frostbite occurs when the tissue temperature drops below 0°C (32°F). Ice-crystal formation subsequently distorts and destroys the cellular architecture. Once the vascular endothelium is damaged, stasis progresses rapidly to microvascular thrombosis. After the tissue thaws, there is progressive dermal ischemia. The microvasculature begins to collapse, arteriovenous shunting increases tissue pressures, and edema forms. Finally, thrombosis, ischemia, and superficial necrosis appear. The development of mummification and demarcation may take weeks to months.


InternalMed_Harrison

InternalMed_Harrison. The initial presentation of frostbite can be deceptively benign. The symptoms always include a sensory deficiency affecting light touch, pain, and temperature perception. The acral areas and distal extremities are the most common insensate areas. Some patients describe a clumsy or “chunk of wood” sensation in the extremity. Deep frostbitten tissue can appear waxy, mottled, yellow, or violaceous-white. Favorable presenting signs include some warmth or sensation with normal color. The injury is often superficial if the subcutaneous tissue is pliable or if the dermis can be rolled over bony prominences. Frostnip may precede frostbite. Frostnip is a nonfreezing cold injury resulting from intense vasoconstriction of exposed acral skin.


InternalMed_Harrison

InternalMed_Harrison. Frostnip may precede frostbite. Frostnip is a nonfreezing cold injury resulting from intense vasoconstriction of exposed acral skin. Clinically, it is most practical to classify frostbite as superficial or deep. Superficial frostbite does not entail tissue loss but rather causes only anesthesia and erythema. The appearance of vesiculation surrounded by edema and erythema implies deeper involvement (Fig. 478e-1). Hemorrhagic vesicles reflect a serious injury to the microvasculature and indicate severe frostbite. Damages in subcuticular, muscular, or osseous tissues may result in amputation. The two most common nonfreezing peripheral cold injuries are chilblain (pernio) and immersion (trench) foot. Chilblain results from neuronal and endothelial damage induced by repetitive exposure to FIGURE 478e-1 Frostbite with vesiculation, surrounded by edema and erythema.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 478e-1 Frostbite with vesiculation, surrounded by edema and erythema. dry cold. Young females, particularly those with a history of Raynaud’s phenomenon, are at greatest risk. Persistent vasospasticity and vasculitis can cause erythema, mild edema, and pruritus. Eventually plaques, blue nodules, and ulcerations develop. These lesions typically involve the dorsa of the hands and feet. In contrast, immersion foot results from repetitive exposure to wet cold above the freezing point. The feet initially appear cyanotic, cold, and edematous. The subsequent development of bullae is often indistinguishable from frostbite. This vesiculation rapidly progresses to ulceration and liquefaction gangrene. Patients with milder cases report hyperhidrosis, cold sensitivity, and painful ambulation for many years.


InternalMed_Harrison

InternalMed_Harrison. When frostbite accompanies hypothermia, hydration may improve vascular stasis. Frozen tissue should be thawed rapidly and completely by immersion in circulating water at 37°–40°C (99°–104°F). Rapid rewarming often produces an initial hyperemia. The early formation of large clear distal blebs is more favorable than that of smaller proximal dark hemorrhagic blebs. A common error is the premature termination of thawing, since the reestablishment of perfusion is intensely painful. Parenteral narcotics will be necessary with deep frostbite. If cyanosis persists after rewarming, the tissue compartment pressures should be monitored carefully. Many antithrombotic and vasodilatory primary and adjunctive treatment regimens have been evaluated. The prostacyclin analogue iloprost in combination with aspirin may prove useful. There is no conclusive evidence that sympathectomy, steroids, calcium channel blockers, or hyperbaric oxygen salvages tissue.


InternalMed_Harrison

InternalMed_Harrison. Patients who have deep frostbite injuries with the potential for significant morbidity should be considered for intravenous or intraarterial thrombolytic therapy. Angiography or pyrophosphate scanning should help evaluate the injury and monitor the progress of tissue plasminogen activator therapy. Heparin is recommended as adjunctive therapy. Intraarterial thrombolysis may reduce the need for digital and more proximal amputations when administered within 24 h of severe injuries. A treatment protocol for frostbite is summarized in (Table 478e-4). Unless infection develops, any decision regarding debridement or amputation should generally be deferred. Angiography or Remove from environment. Prevent partial thawing and refreezing. Stabilize core temperature and treat hypothermia. Protect frozen part—no friction or massage. Consider parenteral analgesia and ketorolac. Administer ibuprofen (400 mg PO).


InternalMed_Harrison

InternalMed_Harrison. Stabilize core temperature and treat hypothermia. Protect frozen part—no friction or massage. Consider parenteral analgesia and ketorolac. Administer ibuprofen (400 mg PO). Immerse part in 37°–40°C (99°–104°F) (thermometermonitored) circulating water containing an antiseptic soap until distal flush (10–45 min). Encourage patient to gently move part. Gently dry and protect part; elevate; place pledgets between toes, if macerated. If clear vesicles are intact, aspirate sterilely; if broken, debride and dress with antibiotic or sterile aloe vera ointment. Leave hemorrhagic vesicles intact to prevent desiccation and infection. Continue ibuprofen (400 mg PO [12 mg/kg per day] q12h). Address medical or If pain is refractory, reduce Consider tetanus and surgical conditions. water temperature to streptococcal prophylaxis; 35°–37°C (95°–99°F) and elevate part. administer parenteral Administer hydrotherapy narcotics. at 37°C (99°F).


InternalMed_Harrison

InternalMed_Harrison. Administer hydrotherapy narcotics. at 37°C (99°F). Consider dextran or phenoxybenzamine or, in severe cases, thrombolysis heat-related Illnesses Daniel F. Danzl Heat-related illnesses include a spectrum of disorders ranging from heat syncope, muscle cramps, and heat exhaustion to medical emer-gencies such as heatstroke. The core body temperature is normally maintained within a very narrow range. Although significant levels 479e of hypothermia are tolerated (Chap. 478e), multiorgan dysfunction occurs rapidly at temperatures >41°–43°C. In contrast to severe hyperthermia, the far more common sign of fever reflects intact thermoregulation.


InternalMed_Harrison

InternalMed_Harrison. Humans are capable of significant heat generation. Strenuous exercise can increase heat generation twentyfold. The heat load from metabolic heat production and environmental heat absorption is balanced by a variety of heat dissipation mechanisms. These dissipation pathways are orchestrated by the central thermostat, which is located in the preoptic nucleus of the anterior hypothalamus. Efferent signals sent via the autonomic nervous system trigger cutaneous vasodilation and diaphoresis to facilitate heat loss.


InternalMed_Harrison

InternalMed_Harrison. Normally, the body dissipates heat into the environment via four mechanisms. The evaporation of skin moisture is the single most efficient mechanism of heat loss but becomes progressively ineffective as the relative humidity rises to >70%. The radiation of infrared electromagnetic energy directly into the surrounding environment occurs continuously. (Conversely, radiation is a major source of heat gain in hot climates.) Conduction— the direct transfer of heat to a cooler object—and convection—the loss of heat to air currents—become ineffective when the environmental temperature exceeds the skin temperature.


InternalMed_Harrison

InternalMed_Harrison. Factors that interfere with the evaporation of diaphoresis significantly increase the risk of heat illness. Examples include dripping of sweat off the skin, constrictive or occlusive clothing, dehydration, and excessive humidity. While air is an effective insulator, the thermal conductivity of water is 25 times greater than that of air at the same temperature. The wet-bulb globe temperature is a commonly used index to assess the environmental heat load. This calculation considers the ambient air temperature, the relative humidity, and the degree of radiant heat.


InternalMed_Harrison

InternalMed_Harrison. The regulation of this heat load is complex and involves the central nervous system (CNS), thermosensors, and thermoregulatory effectors. The central thermostat activates the effectors that produce peripheral vasodilation and sweating. The skin surface is in effect the radiator and the principal location of heat loss, since skin blood flow can increase 25–30 times over the basal rate. This dramatic increase in skin blood flow, coupled with the maintenance of peripheral vasodilation, efficiently radiates heat. At the same time, there is a compensatory vasoconstriction of the splanchnic and renal beds.


InternalMed_Harrison

InternalMed_Harrison. Acclimatization to heat reflects a constellation of physiologic adaptations that permit the body to lose heat more efficiently. This process often requires one to several weeks of exposure and work in a hot environment. During acclimatization, the thermoregulatory set point is altered, and this alteration affects the onset, volume, and content of diaphoresis. The threshold for the initiation of sweating is lowered, and the amount of sweat increases, with a lowered salt concentration. Sweating rates can be 1–2 L/h in acclimated individuals during heat stress. Plasma volume expansion also occurs and improves cutaneous vascular flow. The heart rate lowers, with a higher stroke volume. After the individual leaves the hot environment, improved tolerance to heat stress dissipates rapidly, the plasma volume decreases, and de-acclimatization occurs within weeks.


InternalMed_Harrison

InternalMed_Harrison. When there is an excessive heat load, unacclimated individuals can develop a variety of heat-related illnesses. Heat waves exacerbate the mortality rate, particularly among the elderly and poor and among 479e-1 persons lacking adequate nutrition and access to air-conditioned environments. Secondary vascular events, including cerebrovascular accidents and myocardial infarctions, occur at least 10 times more often in conditions of extreme heat. Exertional heat illness continues to occur when laborers, military personnel, or athletes exercise strenuously in the heat. A variety of common factors predispose to heat illness. In addition to the very young and very old, preadolescents and teenagers are at risk since they may use poor judgment when vigorously exercising in high humidity and heat. Other risk factors include obesity, poor conditioning and lack of acclimatization, and mild dehydration.


InternalMed_Harrison

InternalMed_Harrison. Cardiovascular inefficiency is a common feature of heat illness. Any physiologic or pharmacologic impediment to cutaneous perfusion will impair heat loss. Many patients are unaware of the heat risk associated with their medications. Anticholinergic agents impair sweating and blunt the normal cardiovascular response to heat. Phenothiazines also have anticholinergic properties that interfere with the function of the preoptic nucleus of the anterior hypothalamus due to central depletion of dopamine.


InternalMed_Harrison

InternalMed_Harrison. Calcium channel blockers, beta blockers, and various stimulants also inhibit sweating by reducing peripheral blood flow. To maintain the mean arterial blood pressure, increased cardiac output must be capable of compensating for progressive dehydration. A variety of stimulants and substances of abuse also increase muscle activity and heat production. Careful consideration of the differential diagnosis is important in the evaluation of a patient for a potential heat-related illness. The clinical setting may suggest other etiologies, such as malignant hyperthermia after general anesthesia or neuroleptic malignant syndrome in a patient taking certain antipsychotic medications. A variety of infectious and endocrine disorders as well as conditions with toxicologic or CNS etiologies may initially mimic heatstroke (Table 479e-1).


InternalMed_Harrison

InternalMed_Harrison. Heat edema is characterized by mild swelling of the hands, feet, and ankles during the first few days of significant heat exposure. The principal mechanism involves cutaneous vasodilation and pooling of interstitial fluid in response to heat stress. Heat also increases the secretion of antidiuretic hormone and aldosterone. Systemic causes of edema, including cirrhosis, nephrotic syndrome, and congestive heart failure, can usually be excluded by the history and physical examination. Heat edema generally resolves without treatment in several days. Diuretics are not effective and, in fact, predispose to volume depletion and the development of more serious heat-related illnesses.


InternalMed_Harrison

InternalMed_Harrison. Prickly heat (miliaria rubra, lichen tropicus) is a maculopapular, pruritic, erythematous rash that commonly occurs in clothed areas. Blockage of the sweat pores by debris from macerated stratum corneum causes inflammation in the sweat ducts. As the ducts dilate, they rupture and produce superficial vesicles. The predominant symptom is pruritus. In addition to antihistamines, chlorhexidine may provide some relief. Localized areas may benefit from 1% salicylic acid, with caution taken to avoid salicylate intoxication. Clothing should be clean and loose fitting, and activities or environments that induce diaphoresis should be avoided.


InternalMed_Harrison

InternalMed_Harrison. Heat syncope (exercise-associated collapse) can follow endurance exercise or can occur in the elderly. Other common clinical scenarios include prolonged standing while stationary in the heat and sudden standing after prolonged exposure to heat. Heat stress routinely causes relative volume depletion, decreased vasomotor tone, and peripheral vasodilation. The cumulative effect of this decrease in venous return is postural hypotension, especially in nonacclimated elderly individuals. Many of those affected also have comorbidities. Therefore, other cardiovascular, neurologic, and metabolic causes of syncope should be considered. After removal from the heat source, most patients will recover promptly with cooling and rehydration.


InternalMed_Harrison

InternalMed_Harrison. Hyperventilation tetany occurs in some individuals when exposure to heat stimulates hyperventilation, producing respiratory alkalosis, paresthesias, and carpopedal spasm. Unlike heat cramps, heat tetany causes very little muscle-compartment pain. Treatment includes providing reassurance, moving the patient out of the heat, and addressing the hyperventilation. Heat cramps (exercise-associated muscle cramps) are intermittent, painful, and involuntary spasmodic contractions of skeletal muscles. They typically occur in an unacclimated individual who is at rest after vigorous exertion in a humid, hot environment. In contrast, cramps that occur in athletes during exercise last longer, are relieved by stretching and massage, and resolve spontaneously. Of note, not all muscle cramps are related to exercise, and the differential diagnosis includes many other disorders. A variety of medications, myopathies, endocrine disorders, and sickle cell trait are other possible causes.


InternalMed_Harrison

InternalMed_Harrison. The typical patient with heat cramps is usually profusely diaphoretic and has been replacing fluid losses with copious water or other hypotonic fluids. Roofers, firefighters, military personnel, athletes, steel workers, and field workers are commonly affected. Other predisposing factors include insufficient sodium intake before intense activity in the heat and lack of heat acclimatization, resulting in sweat with a high salt concentration. The precise pathogenesis of heat cramps is unclear but appears to involve a relative deficiency of sodium, potassium, and fluid at the intracellular level. Coupled with copious hypotonic fluid ingestion, large amounts of sodium in the diaphoresis cause hyponatremia and hypochloremia, resulting in muscle cramps due to calcium-dependent muscle relaxation. Total-body depletion of potassium may be observed during the period of heat acclimatization. Rhadomyolysis is very rare with routine exercise-associated muscle cramps.