3627Hyperbaric and Diving Medicine CHAPTER 463

Transcutaneous

wound mapping on air

Transcutaneous mapping

on 100% oxygen 1 ATA

HBO2T unlikely to be

effective

Problem wound

referred for assessment

Suitable for

compression?

Contraindication, critical

major vessel disease, or

surgical option available

HBO2T indicated on

a case-by-case basis.

Consider alternatives.

PtcO2 35–100 mmHg

PtcO2 >100 mmHg

PtcO2 >200 mmHg

Transcutaneous mapping

on 100% oxygen 2.4 ATA HBO2T indicated

No

Yes

Not hypoxic

(PtcO2 >40 mmHg)

PtcO2 >100 but

<200 mmHg

PtcO2 <100 mmHg

PtcO2 <35 mmHg

unresponsive

PtcO2 <40 mmHg*

One schema for using

transcutaneous oximetry

to assist in patient

selection for HBO2T.

If the wound area is

hypoxic and responds to

the administration of

oxygen at 1 ATA or 2.4 ATA,

treatment may be justified.

FIGURE 463-4 Determining suitability for hyperbaric oxygen therapy (HBO2

T) guided by transcutaneous oximetry around the wound bed. *In diabetic patients, <50 mmHg

may be more appropriate. PtcO2

, transcutaneous oxygen pressure.

wound hypoxia and periwound 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 HBO2

T, 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.

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. 463-3). The result is a gradual improvement

in oxygen tension around the wound that reaches a plateau in experimental studies at ~20 treatments over 4 weeks. Improvements in oxygenation are associated with an eight- to ninefold increase in vascular

density over both normobaric oxygen and air-breathing controls.

Clinical Evidence The typical course of HBO2

T 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 HBO2

T for a wide range of problem wounds. Both retrospective and prospective cohort studies suggest

that 6 months after a course of therapy, ~70% of indolent ulcers will be

substantially improved or healed. Often these ulcers have been present

for many months or years, suggesting the application of HBO2

T has a

profound effect, either primarily or as a facilitator of other strategies.

A recent Cochrane review included 12 randomized controlled trials

(RCTs) and concluded that the chance of a diabetic ulcer healing

improved with HBO2

T (10 trials; RR, 2.35; 95% CI, 1.19–4.62; p = .01).

Although there was a trend to benefit with HBO2

T, there was no statistically significant difference in the rate of major amputations (RR, 0.36;

95% CI, 0.11–1.18).

■ CARBON MONOXIDE POISONING

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 >50,000 emergency department visits per year and

~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.

Pathology and Clinical Course The pathophysiology of CO

exposure is incompletely understood. CO binds to hemoglobin with

an affinity >200 times that of oxygen, directly reducing the oxygencarrying 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.

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

factors for poor outcome are age >35 years, exposure for >24 h, acidosis, and loss of consciousness.

Clinical Evidence The typical course of HBO2

T 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 HBO2

T—based largely on the obvious connection between exposure, tissue hypoxia, and the ability of HBO2

T to rapidly overcome

this hypoxia. CO is eliminated rapidly via the lungs on application of

HBO2

T, with a half-life of ~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 HBO2

T can be delivered in time to prevent either

3628 PART 15 Disorders Associated with Environmental Exposures

acute hypoxic death or irreversible global cerebral hypoxic injury. If

HBO2

T 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 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 RCTs of HBO2

T

for CO poisoning, although only four have been reported in full. While

a Cochrane review suggested there is insufficient evidence to confirm a

beneficial effect of HBO2

T on the chance of persisting neurocognitive

deficit following poisoning (34% of patients treated with oxygen at 1

atmosphere vs 29%, of those treated with HBO2

T; 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 HBO2

T 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 HBO2

T (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.

On this basis, HBO2

T 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 HBO2

T in this situation and call for

further well-designed studies.

CURRENT CONTROVERSIES IN

HYPERBARIC MEDICINE

The use of hyperbaric oxygen has been associated with controversy

since it was first instituted in the 1950s. A vigorous debate has recently

developed around the concept of performing sham controlled RCTs,

particularly when assessing outcomes where a placebo effect could significantly influence interpretation. The most popular method employed

to achieve blinding of both staff and patients is the exposure of patients

in the control arm to a modest pressure while breathing air in the chamber (between 1.1 and 1.3 ATA). While this strategy is effective in blinding the exposure, critics claim this exposure to air at pressure (equivalent

to breathing ~27% oxygen at 1.0 ATA) is therapeutic in a way yet to be

identified. These critics use this putative therapeutic effect to explain the

modest measured benefits in patients with a range of chronic neurologic

conditions including cerebral palsy, autism spectrum disorders, and

mild traumatic brain injury when exposed to either air at 1.1–1.3 ATA

or 100% oxygen at 2.0–2.4 ATA (HBO2

T) in a number of trials. These

benefits have traditionally been interpreted as the result of a participation or placebo effect, with the various authors concluding there was

no evidence of a specific effect for HBO2

T in any of these conditions.

The search continues for a convincing sham exposure that is universally

regarded as inactive. Some workers claim this is not possible and that

patient-blinded trials are therefore similarly unachievable. This impasse

needs resolution, and there is some hope that the restriction of pressure

exposure to short periods of modest compression at the start and end

of each sham session may be convincing for both sides of the argument.

DIVING MEDICINE

■ INTRODUCTION

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 10.1-m increase in depth of seawater, the

ambient pressure (Pamb) increases by 101.3 kPa (1 atmosphere) so that,

for example, a diver at 20 m depth is exposed to a Pamb of 303.9 kPa

(3 ATA), made up of 1 ATA due to atmospheric pressure and 2 ATA

generated by the water column.

■ BREATHING EQUIPMENT

Most diving is undertaken using 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

comprise a closed or semi-closed breathing circuit with a carbon

dioxide scrubber and an oxygen addition 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”

cable from the surface.

All these systems must supply gas to the diver at the Pamb of the surrounding water or inspiration would be impossible against the water

pressure. For most recreational diving, the respired gas is air. Pure

oxygen is rarely used because there is a dose-dependent risk (where

“dose” is a function of exposure time and inspired Po2

) that oxygen

may provoke seizures above an inspired Po2

 of 130 kPa (1.3 ATA).

The maximum acceptable inspired Po2

 in diving is often considered to

be 161 kPa (1.6 ATA), which would be achieved when breathing pure

oxygen at 6 m or air at 66 m. This is a conspicuously lower Po2

 than

routinely used for hyperbaric therapy (see earlier), reflecting a higher

risk of oxygen toxic seizures during immersion and exercise. In order

to avoid dangerous oxygen exposures, very deep diving requires the

use of inspired oxygen fractions lower than in air (Fo2

 0.21), and divers

tailor the oxygen content of their gases to remain within recommended

exposure guidelines. Deep-diving gases include helium as a substitute

for some or all of the nitrogen to reduce both the narcotic effect and

high gas density that result from breathing nitrogen at high pressures.

■ SUITABILITY FOR DIVING

The most common reason for physician consultation in relation to diving is for the evaluation of suitability for diver training or continuation

of diving 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 an approach in which each case is considered on its own merits and

an individualized evaluation of risk is made. Such evaluations require

integration of diving physiology, the impact of associated medical

problems, and knowledge of the specific medical condition(s) of the

candidate. A detailed discussion is beyond the scope of this chapter, but

several important principles are outlined below.

There are three primary questions that should be answered in

relation to any medical condition reported by a prospective diver: (1)

Could the 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 of positive answers to these questions (respectively):

epilepsy is usually considered to imply high risk because there are epileptogenic stimuli such as high inspired oxygen pressures encountered

in diving that could make a seizure (and drowning) more likely; active

3629Hyperbaric and Diving Medicine CHAPTER 463

asthma is considered to increase risk because it could predispose to air

trapping and pulmonary barotrauma (see below); and ischemic heart

disease increases risk 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 their

impact on suitability for diving. There may follow an equally complex

discussion about whether such interactions impart a disqualifying

risk, and this may be influenced by the individual candidate’s level of

risk acceptance and the extent to which others involved (such as dive

partners) might be affected. Guidelines are occasionally published

on assessment of diving candidates with risk factors for important

comorbidities like cardiovascular disease or who have suffered topical

problems such as COVID-19 infection (see “Further Reading” list).

Physicians interested in regularly conducting such evaluations should

obtain relevant training. Short courses providing relevant training are

offered by specialist groups in most countries.

BAROTRAUMA

Barotrauma is essentially tissue injury arising as a result of ambient

pressure changes. Middle-ear barotrauma (MEBT) in 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 surrounding 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 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.

Much less commonly, divers may suffer inner ear 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 result in transmission of pressure to the perilymph via the cochlear aqueduct and outward rupture

of the round window, which is 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.

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 within minutes after surfacing.

The management is the same as for DCS described below. 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 re-embolization can occur. Unsurprisingly, these events can be

misdiagnosed as typical strokes or transient ischemic attacks (TIAs)

(Chap. 427) when patients are seen by clinicians 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.

DECOMPRESSION SICKNESS

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

~1:10,000 recreational dives.

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

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

allow time for gas washout (“decompression stops”). Although a breach

of these protocols increases the risk of DCS, adherence does not guarantee that it will be prevented. DCS should be considered in any diver

manifesting postdive symptoms not readily explained by an alternative

mechanism.

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,

almost certainly forming in capillary beds 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 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 bubbles

can cause harm, perhaps by disrupting flow in the microcirculation of

target organs. Circulating microparticles, which are elevated in number

and size after diving, are currently under investigation as indicators of

decompression stress and as injurious agents in their own right. How

they arise and their exact role in DCS remain unclear.

Table 463-3 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 >24 h after diving are very unlikely to

be DCS. The presentation may be confusing and nonspecific, and there

are no useful diagnostic investigations. Diagnosis is based on integration of findings from examination of the dive profile, the nature and

3630 PART 15 Disorders Associated with Environmental Exposures

TABLE 463-3 Manifestations of Decompression Sickness

ORGAN SYSTEM MANIFESTATIONS

Musculoskeletal Limb pain

Neurologic

Cerebral Confusion

Visual disturbances

Speech disturbances

Spinal Muscular weakness

Paralysis

Upper motor neuron signs

Bladder and sphincter dysfunction

Dermatomal sensory disturbances

Abdominal pain

Girdle pain

Vestibulocochlear Hearing loss

Vertigo and ataxia

Nausea and vomiting

Peripheral Patchy nondermatomal sensory disturbance

Pulmonary Cough

Dyspnea

Cardiovascular Hemoconcentration

Coagulopathy

Hypotension

Cutaneous Rash, itch

Lymphatic Soft tissue edema, often relatively localized

Constitutional Fatigue and malaise

■ 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

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 or injury.

464 Hypothermia and

Peripheral Cold Injuries

Daniel F. Danzl

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.

TREATMENT

Diving Medicine

First aid for either DCS or CAGE 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 alone—an option that may be invoked by experienced diving

physicians 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 ATA.

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

may ameliorate some of the proinflammatory effects of bubbles.

Various recompression protocols have been advocated, but there

are no data that define the optimum approach. Recompression typically begins with oxygen administered at 2.8 ATA, 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 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 intubation, ventilation, and high-level intensive care.

The presentation of sick divers to physicians or hospitals without

diving medicine expertise creates a risk of misinterpretation of

nonspecific manifestations and of consequent mistakes in diagnosis and management. Physicians finding themselves in this situation are strongly advised to expeditiously contact the 24-h diving

emergency advisory service provided by the Divers Alert Network

(DAN). This can be accessed at +1-919-684-9111, and there are

subsidiary or related services in virtually all jurisdictions globally.

■ FURTHER READING

Bennett MH et al: Hyperbaric oxygen therapy for late radiation tissue

injury. Cochrane Database Syst Rev 4:CD005005, 2016.

Edmonds C et al: Diving and Subaquatic Medicine, 5th ed. Boca Raton,

FL, Taylor and Francis, 2015.

Francis A, Baynosa R: Ischaemia-reperfusion injury and hyperbaric

oxygen pathways: A review of cellular mechanisms. Diving Hyperb

Med 47:110, 2017.

Gorenstein SA et al: Hyperbaric oxygen therapy for COVID-19

patients with respiratory distress: Treated cases versus propensity

-matched controls. Undersea Hyperb Med 47:405, 2020.

Jepson N et al: South Pacific Underwater Medicine Society guidelines

for cardiovascular risk assessment of divers. Diving Hyperb Med

50:273, 2020.

Kranke P et al: Hyperbaric oxygen therapy for chronic wounds.

Cochrane Database Syst Rev 6:CD004123, 2015.

Mitchell SJ et al: Pre-hospital management of decompression illness:

Expert review of key principles and controversies. Diving Hyperb

Med 48:45, 2018.

Moon RE (ed): Hyperbaric Oxygen Therapy Indications, 14th ed. North

Palm Beach, FL, Best Publishing Company, 2018.

Oley MH et al: Effects of hyperbaric oxygen therapy on vascular endothelial growth factor protein and mRNA in crush injury patients: A

randomized controlled trial study. Int J Surg Open 29:33, 2021.

Sadler C et al: Diving after SARS-CoV-2 (COVID-19) infection: Fitness to dive assessment and medical guidance. Diving Hyperb Med

50:278, 2020.

Vann RD et al: Decompression illness. Lancet 377:153, 2011.

Weaver LK et al: Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 347:1057, 2002.

Whelan HT, Kindwall EP (eds): Hyperbaric Medicine Practice,

4th ed. Palm Beach, FL, Best Publishing Company, 2017.

3631Hypothermia and Peripheral Cold Injuries CHAPTER 464

disrupts the autonomic pathways that lead to shivering and will prevent

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.

■ THERMOREGULATION

Heat loss occurs through five mechanisms: radiation (55–65% of heat

loss), conduction (10–15% of heat loss, 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 thermoregulation (Chap. 18). 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.

■ CLINICAL PRESENTATION

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.

Predicting the core temperature based on the clinical presentation is

very difficult.

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 464-2). 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

an organic acidosis. A markedly depressed level of consciousness in a

patient with mild hypothermia suggests an overdose or CNS dysfunction due to infection or trauma.

Physical examination findings will also be altered by hypothermia.

For instance, the assumption that areflexia is solely attributable to

hypothermia can obscure 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. 15).

When a patient in hypothermic cardiac arrest is first discovered,

cardiopulmonary resuscitation (CPR) is indicated unless (1) a do-notresuscitate status is verified, (2) obviously lethal injuries are identified,

or (3) the depression of a frozen chest wall is not possible. Continuous

CPR is normally recommended, and interruptions should be avoided if

possible. In the field, when the core temperature is <28°C, intermittent

CPR may also be effective.

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 (10–12 meq/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

TABLE 464-1 Risk Factors for Hypothermia

Age extremes

Elderly

Neonates

Environmental exposure

Occupational

Sports-related

Inadequate clothing

Immersion

Toxicologic and pharmacologic

Ethanol

Anesthetics

Antipsychotics

Antidepressants

Anxiolytics

Benzodiazepines

Neuromuscular blockers

Insufficient fuel

Malnutrition

Marasmus

Kwashiorkor

Endocrine-related

Diabetes mellitus

Hypoglycemia

Hypothyroidism

Adrenal insufficiency

Hypopituitarism

Neurologic

Cerebrovascular accident

Hypothalamic disorders

Parkinson’s disease

Spinal cord injury

Multisystemic

Trauma

Sepsis

Shock

Hepatic or renal failure

Carcinomatosis

 Burns and exfoliative dermatologic

disorders

Immobility or debilitation

■ CAUSES

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 464-1). 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. 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.

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. Some antipsychotics, antidepressants, anxiolytics, benzodiazepines, and other medications reduce centrally mediated vasoconstriction. Many hypothermic patients are admitted to intensive care

because of drug overdose. Anesthetics can block shivering responses;

these effects are compounded when patients are not insulated adequately in the operating or recovery units.

Several types of endocrine dysfunction cause hypothermia.

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 agents, 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.

Neurologic injury from trauma, cerebrovascular accident, subarachnoid hemorrhage, and a hypothalamic lesion increases susceptibility to

hypothermia. Agenesis of the corpus callosum (Shapiro’s syndrome) is

one cause of episodic hypothermia. In this syndrome, profuse perspiration is followed by a rapid fall in temperature. Acute spinal cord injury

3632 PART 15 Disorders Associated with Environmental Exposures

before rewarming the patient past 33°C (91°F) should be predicated

on the type and severity of the precipitants of hypothermia. Survival

has occurred with a cardiac arrest time over 7 h. There is an ongoing

search for validated prognostic indicators for recovery from hypothermia. The Swiss grading system considers core body temperature

and the clinical findings. Other scoring systems also consider age,

albumin, and lactate levels. A history of asphyxia, as in an avalanche,

with secondary cooling is the most important negative predictor of

survival.

■ DIAGNOSIS AND STABILIZATION

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

can 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 biphasic attempt below 30°C is warranted. Further defibrillation

attempts should usually be deferred until some rewarming (1°–2°C)

is achieved and ventricular fibrillation is coarser. Although cardiac

pacing for hypothermic bradydysrhythmias is rarely indicated, the

transthoracic technique is preferable. The J or Osborn wave at the

junction of the QRS complex and ST segment suggests the diagnosis.

Obvious J waves are routinely misdiagnosed by automated readings as

injury current.

Supplemental oxygenation is always warranted, since tissue oxygenation is affected adversely by the leftward shift of the oxyhemoglobin

dissociation curve. Pulse oximetry is often 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 and can provide an ancillary approach for

temperature monitoring. Dehydration is encountered commonly with

chronic hypothermia, and most patients benefit from an intravenous

or intraosseous crystalloid bolus. Normal saline is preferable to 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, similar to transvenous pacing, can precipitate refractory arrhythmias.

Arterial blood gases should not be corrected for temperature

(Chap. 55). 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).

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 are often obscured by hypothermia. Patients

with renal insufficiency, metabolic acidosis, or rhabdomyolysis are at

greatest risk for electrolyte disturbances.

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. Coagulation studies 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.

■ REWARMING STRATEGIES

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

TABLE 464-2 Physiologic Changes Associated with Accidental Hypothermia

SEVERITY BODY TEMPERATURE

CENTRAL NERVOUS

SYSTEM CARDIOVASCULAR RESPIRATORY

RENAL AND

ENDOCRINE NEUROMUSCULAR

Mild 35°C (95°F)–32.2°C

(90°F)

Linear depression of

cerebral metabolism;

amnesia; apathy;

dysarthria; impaired

judgment; maladaptive

behavior

Tachycardia,

then progressive

bradycardia; cardiac

cycle prolongation;

vasoconstriction;

increase in cardiac output

and blood pressure

Tachypnea, then

progressive decrease

in respiratory minute

volume; declining

oxygen consumption;

bronchorrhea;

bronchospasm

Diuresis; increase

in catecholamines,

adrenal steroids,

triiodothyronine, and

thyroxine; increase

in metabolism with

shivering

Increased

preshivering muscle

tone, then fatiguing

Moderate <32.2°C (90°F)–28°C

(82.4°F)

EEG abnormalities;

progressive depression

of level of consciousness;

pupillary dilation;

paradoxical undressing;

hallucinations

Progressive decrease in

pulse and cardiac output;

increased atrial and

ventricular arrhythmias;

suggestive (J-wave) ECG

changes

Hypoventilation: 50%

decrease in carbon

dioxide production

per 8°C (17.6°F)

drop in temperature;

absence of protective

airway reflexes

50% increase in renal

blood flow; renal

autoregulation intact;

impaired insulin

action

Hyporeflexia;

diminishing

shivering-induced

thermogenesis; rigidity

Severe <28°C (<82.4°F) Loss of cerebrovascular

autoregulation; decline

in cerebral blood flow;

coma; loss of ocular

reflexes; progressive

decrease in EEG

abnormalities

Progressive decrease

in blood pressure, heart

rate, and cardiac output;

reentrant dysrhythmias;

maximal risk of ventricular

fibrillation; asystole

Pulmonic congestion

and edema; 75%

decrease in oxygen

consumption; apnea

Decrease in renal

blood flow that

parallels decrease

in cardiac output;

extreme oliguria;

poikilothermia; 80%

decrease in basal

metabolism

No motion; decreased

nerve-conduction

velocity; peripheral

areflexia; no corneal

or oculocephalic

reflexes

Abbreviations: ECG, electrocardiogram; EEG, electroencephalogram.

Source: From DF Danzl, RS Pozos: Accidental hypothermia. N Engl J Med 331:1756, 1994. Copyright © 1994 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.

3633Hypothermia and Peripheral Cold Injuries CHAPTER 464

after removal of the patient from the cold. Truncal heat application

reduces the risk of afterdrop.

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.

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 (2.2°–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.

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 use of endovascular temperature control catheters.

Extracorporeal blood rewarming options (Table 464-3) should be

considered in severely hypothermic patients, especially those with

primary accidental hypothermia. Extracorporeal life support, including

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 perfusing patients.

TREATMENT

Hypothermia

When a patient is hypothermic, target organs and the cardiovascular system respond minimally to most medications. Generally,

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, but the residual drugs would be

potentially toxic during rewarming.

Achieving a mean arterial pressure of at least 60 mmHg should

be an early objective. If the hypotension is disproportionate for

temperature and 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 improve 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 prophylaxis and treatment of ventricular arrhythmias

is complex. Preexisting ventricular ectopy may be suppressed by

hypothermia and reappear during rewarming. None of the class I

agents is proven to be safe and efficacious.

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. 382), 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.

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.

FROSTBITE

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.

TABLE 464-3 Options for Extracorporeal Blood Rewarming

EXTRACORPOREAL

REWARMING TECHNIQUE CONSIDERATIONS

Continuous venovenous (CVV)

rewarming

Circuit: CV catheter to CV, dual-lumen CV, or

peripheral catheter

No oxygenator/circulatory support

Flow rates 150–400 mL/min

ROR 2°–3°C (4.4°–6.6°F)/h

Hemodialysis Circuit: single- or dual-vessel cannulation

Stabilizes electrolyte or toxicologic

abnormalities

Exchange cycle volumes 200–500 mL/min

ROR 2°–3°C (4.4°–6.6°F)/h

Continuous arteriovenous

rewarming (CAVR)

Circuit: percutaneous 8.5-Fr femoral catheters

Requires systolic blood pressure of 60 mmHg

No perfusionist/pump/anticoagulation

Flow rates 225–375 mL/min

ROR 3°–4°C (6.6°–8.8°F)/h

Cardiopulmonary bypass (CPB) Circuit: full circulatory support with pump and

oxygenator

Perfusate-temperature gradient 5°–10°C

(11°–22° F)

Flow rates 2–7 L/min (average 3–4 L/min)

ROR up to 9.5°C (20.9°F)/h

Venoarterial extracorporeal

membrane oxygenation

(VA-ECMO)

Decreased risk of post-rewarming

cardiorespiratory failure

Improved neurologic outcome

Abbreviations: CV, central venous; ROR, rate of rewarming.

3634 PART 15 Disorders Associated with Environmental Exposures

CLINICAL PRESENTATION

The initial presentation of frostbite can be deceptively benign. The

symptoms always include a sensory deficiency affecting light touch,

pain, or 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.

Clinically, frostbite is 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. 464-1). Hemorrhagic vesicles reflect

a serious injury to the microvasculature and indicate severe frostbite.

Damages in subcuticular, muscular, or osseous tissues may result in

amputation. An alternative classification establishes grades based on

the location of presenting cyanosis; that is grade 1, absence of cyanosis;

grade 2, cyanosis on the distal phalanx; grade 3, cyanosis up to the

metacarpophalangeal (MP) joint; and grade 4 cyanosis proximal to the

MP joint.

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

damp cold above the freezing point. 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

TABLE 464-4 Treatment for Frostbite

BEFORE THAWING DURING THAWING AFTER THAWING

Remove from

environment.

Consider parenteral

analgesia and ketorolac.

Gently dry and protect part;

elevate; place pledgets

between toes, if macerated.

Prevent partial

thawing and

refreezing.

Administer ibuprofen

(400 mg PO).

If clear vesicles are intact,

aspirate sterilely; if broken,

debride and dress with

antibiotic or sterile aloe vera

ointment.

Stabilize core

temperature and treat

hypothermia.

Immerse part in

37°–40°C (99°–104°F)

(thermometer-monitored)

circulating water

containing an antiseptic

soap until distal flush

(10–45 min).

Leave hemorrhagic vesicles

intact to prevent desiccation

and infection.

Protect frozen

part—no friction or

massage.

Encourage patient to

gently move part.

Continue ibuprofen

(400–600 mg PO [12 mg/kg

per day] q8 to 12h).

Address medical or

surgical conditions.

If pain is refractory,

reduce water

temperature to 35°–37°C

(95°–99°F) and administer

parenteral narcotics.

Consider tetanus and

streptococcal prophylaxis;

elevate part.

Administer hydrotherapy at

37°C (99°F).

Consider dextran or

phenoxybenzamine or, in

severe cases, thrombolysis

rt-PA (IV or intraarterial).

FIGURE 464-1 Frostbite with vesiculation, surrounded by edema and erythema. Abbreviation: rt-PA, recombinant tissue plasminogen activator.

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.

TREATMENT

Peripheral Cold Injuries

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)

for 30–60 min and not by using hot air. 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 treatment regimens have

been evaluated. The prostacyclin analogue iloprost given within

48 h after rewarming is an option. There is no conclusive evidence

that sympathectomy, steroids, calcium channel blockers, or hyperbaric oxygen salvages tissue.

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 may help evaluate the injury and monitor the progress

of tissue plasminogen activator therapy (rt-PA). 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 464-4.

Unless infection develops, any decision regarding debridement or amputation should generally be deferred. Angiography or

3635Heat-Related Illnesses CHAPTER 465

technetium-99 bone scan may assist in the determination of surgical margins. Magnetic resonance angiography may also demonstrate the line of demarcation earlier than does clinical demarcation.

The most common symptomatic sequelae reflect neuronal injury

and persistently abnormal sympathetic tone, including paresthesia, thermal misperception, and hyperhidrosis. Delayed findings

include nail deformities, cutaneous carcinomas, and epiphyseal

damage in children.

Management of the chilblain syndrome is usually supportive.

With refractory perniosis, alternatives include nifedipine, steroids,

and limaprost, a prostaglandin E1

 analogue.

■ FURTHER READING

Cauchy E et al: A controlled trial of a prostacyclin and rt-PA in the

treatment of severe frostbite. N Engl J Med 364:189, 2011.

McIntosh SE et al: Wilderness Medical Society practice guidelines for

the prevention and treatment of frostbite. Wilderness Environ Med

25(4 suppl):S43, 2014.

Ohbe H et al: Extracorporeal membrane oxygenation improves outcomes of accidental hypothermia without vital signs: A nationwide

observational study. Resuscitation 144:27, 2019.

Okada Y et al: The development and validation of a “5A” severity scale

for predicting in-hospital mortality after accidental hypothermia

from J-point registry data. J Intensive Care 7:27, 2019.

Zafren K: Out-of-hospital evaluation and treatment of accidental

hypothermia. Emerg Med Clin North Am 35:261, 2017.

Heat-related illnesses include a spectrum of disorders ranging from

heat syncope, muscle cramps, and heat exhaustion to medical emergencies such as heatstroke. The core body temperature is normally

maintained within a very narrow range. Although significant levels of

hypothermia are tolerated (Chap. 464), multiorgan dysfunction occurs

rapidly at temperatures >41°–43°C. In contrast to heatstroke, the far

more common sign of fever reflects intact thermoregulation.

■ THERMOREGULATION

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 central integrative 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.

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.

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.

465 Heat-Related Illnesses

Daniel F. Danzl

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.

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.

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 deacclimatization occurs within weeks.

■ PREDISPOSING FACTORS AND

DIFFERENTIAL DIAGNOSIS

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 among 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. 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 with lack of acclimatization, and mild dehydration.

Cardiovascular inefficiency is a common feature of heat illness. Any

physiologic or pharmacologic impediment to cutaneous perfusion

impairs 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

and heterocyclic antidepressants also have anticholinergic properties

that interfere with the function of the preoptic nucleus of the anterior

hypothalamus due to central depletion of dopamine.

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. Neuroleptic malignant syndrome can

be triggered by certain antipsychotic medications, including selective

serotonin reuptake inhibitors. A variety of infectious and endocrine

disorders as well as toxicologic or CNS etiologies may mimic heatstroke (Table 465-1).

■ MINOR HEAT-EMERGENCY SYNDROMES

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

3636 PART 15 Disorders Associated with Environmental Exposures

or lotion provides some relief. In adults, localized areas may benefit

from 1% salicylic acid TID, with caution taken to avoid salicylate

intoxication. Clothing with breathable fabric should be clean and loose

fitting, and activities or environments that induce diaphoresis should

be avoided.

Heat syncope (exercise-associated collapse) can follow endurance

exercise or 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.

Hyperventilation tetany occurs in some individuals when exposure

to heat stimulates hyperventilation, producing respiratory alkalosis,

paresthesia, 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

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.

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 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. Rhabdomyolysis is very rare with routine exercise-associated muscle cramps.

Heat cramps that are not accompanied by significant dehydration

can be treated with commercially available electrolyte solutions.

Although the flavored electrolyte solutions are far more palatable, two

650-mg salt tablets dissolved in 1 quart of water produce a 0.1% saline

solution. Individuals should avoid the ingestion of undissolved salt

tablets, which are a gastric irritant and may induce vomiting.

■ HEAT EXHAUSTION

The physiologic hallmarks of heat exhaustion—in contrast to

heatstroke—are the maintenance of thermoregulatory control and

CNS function. The core temperature is usually elevated but is generally

<40.5°C (<105°F). The two physiologic precipitants are water depletion

and sodium depletion, which often occur in combination. Laborers,

athletes, and elderly individuals exerting themselves in hot environments, without adequate fluid intake, tend to develop water-depletion

heat exhaustion. Persons working in the heat frequently consume only

two-thirds of their net water loss and are voluntarily dehydrated. In

contrast, salt-depletion heat exhaustion occurs more slowly in unacclimated persons who have been consuming large quantities of hypotonic

solutions.

TABLE 465-1 Heat-Related Illness: Predisposing Factors and

Differential Diagnosis

ILLNESS PREDISPOSING FACTORS

Cardiovascular inefficiency Age extremes

Beta/calcium channel blockade

Congestive heart failure

Dehydration

Diuresis

Obesity

Poor physical fitness

Central nervous system illness Cerebellar injury

Cerebral hemorrhage

Hypothalamic cerebrovascular accident

Psychiatric disorders

Status epilepticus

Impaired heat loss Antihistamines

Heterocyclic antidepressants

Occlusive clothing

Skin abnormalities

Endocrine and immune-related

illness

Diabetic ketoacidosis

Multiple-organ dysfunction syndrome

Pheochromocytoma

Systemic inflammatory response syndrome

Thyroid storm

Excessive heat load Environmental conditions

Exertion

Fever

Hypermetabolic state

Lack of acclimatization

Infectious illness Cerebral abscess

Encephalitis

Malaria

Meningitis

Sepsis syndrome

Tetanus

Typhoid

Toxicologic illness Amphetamines

Anticholinergic toxidrome

Cocaine

Dietary supplements

Hallucinogens

Malignant hyperthermia

Neuroleptic malignant syndrome

Salicylates

Serotonin syndrome

Strychnine

Sympathomimetics

Withdrawal syndromes (ethanol, hypnotics)

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. Simple

leg elevation or compression stockings will usually suffice. Diuretics

are not effective and, in fact, predispose to volume depletion and the

development of more serious heat-related illnesses.

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 in a light cream

3637Heat-Related Illnesses CHAPTER 465

Heat exhaustion is usually a diagnosis of exclusion because of the

multitude of nonspecific symptoms. If any signs of heatstroke are

present, rapid cooling and crystalloid resuscitation should be initiated

immediately during stabilization and evaluation. Mild neurologic

and gastrointestinal influenza-like symptoms are common. These

symptoms may include headache, vertigo, ataxia, impaired judgment,

malaise, dizziness, nausea, and muscle cramps. Orthostatic hypotension and sinus tachycardia develop frequently. More significant CNS

impairment suggests heatstroke or other infectious, neurologic, or

toxicologic diagnoses.

Hemoconcentration does not always develop, and rapid infusion of

isotonic IV fluids should be guided by frequent electrolyte determinations and perfusion requirements. Most cases of heat exhaustion reflect

mixed sodium and water depletion. Sodium-depletion heat exhaustion is characterized by hyponatremia and hypochloremia. Hepatic

aminotransferases are mildly elevated in both types of heat exhaustion.

Urinary sodium and chloride concentrations are usually low.

Some patients with heat exhaustion develop heatstroke after removal

from the heat-stress environment. Aggressive cooling of nonresponders is indicated until their core temperature is 39°C (102.2°F). Except

in mild cases, free water deficits should be replaced slowly over 24–48 h

to avoid a decrease of serum osmolality by >2 mOsm/h.

The disposition of younger, previously healthy heat-exhaustion

patients who have no major laboratory abnormalities may include

hospital observation and discharge after IV rehydration. Older patients

with comorbidities (including cardiovascular disease) or predisposing

factors often require inpatient fluid and electrolyte replacement, monitoring, and reassessment.

■ HEATSTROKE

The clinical manifestations of heatstroke reflect a total loss of thermoregulatory function. Typical vital-sign abnormalities include tachypnea, various tachycardias, hypotension, and a widened pulse

pressure. Although there is no single specific diagnostic test, the historical and physical triad of exposure to a heat stress, CNS dysfunction,

and a core temperature >40.5°C helps establish the preliminary diagnosis. Some patients with impending heatstroke will initially appear lucid.

The definitive diagnosis should be reserved until the other potential

causes of hyperthermia are excluded. Many of the usual laboratory

abnormalities seen with heatstroke overlap with other conditions. If

the patient’s mental status does not improve with cooling, toxicologic

screening may be indicated, and cranial CT and spinal fluid analysis

can be considered.

The premonitory clinical characteristics may be nonspecific and

include weakness, dizziness, disorientation, ataxia, and gastrointestinal

or psychiatric symptoms. These prodromal symptoms often resemble

heat exhaustion. The sudden onset of heatstroke occurs when the maintenance of adequate perfusion requires peripheral vasoconstriction to

stabilize the mean arterial blood pressure. As a result, the cutaneous

radiation of heat ceases. At this juncture, the core temperature rises

dramatically. Since many patients with heatstroke also meet the criteria

for systemic inflammatory response syndrome (SIRS) and have a broad

differential diagnosis, rapid cooling is essential during the extensive

diagnostic evaluation. Heat-induced SIRS reflects the responses of both

the innate and the adaptive immune systems (Table 465-1).

There are two forms of heatstroke with significantly different manifestations (Table 465-2). Classic (epidemic) heatstroke (CHS) usually

occurs during long periods of high ambient temperature and humidity,

as during summer heat waves. Patients with CHS commonly have

chronic diseases that predispose to heat-related illness, and they may

have limited access to oral fluids. Heat dissipation mechanisms are

overwhelmed by both endogenous heat production and exogenous heat

stress. Patients with CHS are often compliant with prescribed medications that can impair tolerance to a heat stress. In many of these dehydrated CHS patients, sweating has ceased and the skin is hot and dry.

If cooling is delayed, severe hepatic dysfunction, renal failure, disseminated intravascular coagulation, and fulminant multisystem organ

failure may occur. Hepatocytes are very heat sensitive. On presentation, the serum level of aspartate aminotransferase (AST) is routinely

elevated. Eventually, levels of both AST and alanine aminotransferase

(ALT) often increase to >100 times the normal values. Coagulation studies commonly demonstrate decreased platelets, fibrinogen,

and prothrombin. Most patients with CHS require cautious crystalloid resuscitation, electrolyte monitoring, and—in certain refractory

cases—consideration of central venous pressure (CVP) measurements.

Hypernatremia is secondary to dehydration in CHS. Many patients

exhibit significant stress leukocytosis, even in the absence of infection.

Patients with exertional heatstroke (EHS), in contrast to those with

CHS, are often young and previously healthy, and their diagnosis is

usually more obvious from the history. Athletes, laborers, and military recruits are common victims. Unlike those with CHS, many EHS

patients present profusely diaphoretic despite significant dehydration.

As a result of muscular exertion, rhabdomyolysis and acute renal failure are more common in EHS. Studies to detect rhabdomyolysis and

its complications, including hypocalcemia and hyperphosphatemia,

should be considered. Hyponatremia, hypoglycemia, and coagulopathies are frequent findings. Elevated creatine kinase and lactate dehydrogenase levels also suggest EHS. Oliguria is a common finding. Renal

failure can result from direct thermal injury, untreated rhabdomyolysis,

or volume depletion. Common urinalysis findings include microscopic

hematuria, myoglobinuria, and granular or red cell casts.

With both CHS and EHS, heat-related increases in cardiac biomarker

levels may be present and reversible. Heatstroke often causes thermal

cardiomyopathy. As a result, the CVP may be elevated despite significant dehydration. In addition, the patient often presents with potentially deceptive noncardiogenic pulmonary edema and basilar rales

despite being significantly hypovolemic. The electrocardiogram commonly displays a variety of tachyarrhythmias, nonspecific ST-T wave

changes, and heat-related ischemia or infarction. Rapid cooling—not

the initial administration of antiarrhythmic medications—is essential.

Above 42°C (107.6°F), heat can rapidly produce direct cellular

injury. Thermosensitive enzymes become nonfunctional, and eventually, there is irreversible uncoupling of oxidative phosphorylation. The

production of heat-shock proteins increases, and cytokines mediate

a systemic inflammatory response. The vascular endothelium is also

damaged, and this injury activates the coagulation cascade. Significant

shunting away from the splanchnic circulation produces gastrointestinal ischemia. Endotoxins further impair normal thermoregulation. As

a result, if cooling is delayed, severe hepatic dysfunction, permanent

renal failure, disseminated intravascular coagulation, and fulminant

multisystem organ failure may occur.

■ COOLING STRATEGIES

Before cooling is initiated, endotracheal intubation and continuous core-temperature monitoring should be considered. Peripheral

methods to measure temperature are not reliable. Hypoglycemia is

TABLE 465-2 Typical Manifestations of Heatstroke

CLASSIC EXERTIONAL

Older patient Younger patient

Predisposing health factors/

medications

Healthy condition

Epidemiology (heat waves) Sporadic cases

Sedentary Exercising

Anhidrosis (possible) Diaphoresis (common)

Central nervous system dysfunction Myocardial/hepatic injury

Oliguria Acute renal failure

Coagulopathy (mild) Disseminated intravascular

coagulation

Mild lactic acidosis Marked lactic acidosis

Mild creatine kinase elevation Rhabdomyolysis

Normoglycemia/calcemia Hypoglycemia/calcemia

Normokalemia Hyperkalemia

Normonatremia Hyponatremia