HYPOTHERMIA 3

FROSTBITE

Peripheral cold injuries include both freezing and nonfreezing injuries to tissue. Frostbite occurs when the tissue temperature drops below 0°C. Ice crystal formation subsequently distorts and destroys the cellular architecture. Once the vascular endothelium is damaged, stasis progresses rapidly to microvascular thrombosis. Tissue freezes quickly when in contact with thermal conductors such as metal or volatile solutions. Other predisposing factors include constrictive clothing or boots, immobility, or vasoconstrictive medications.

Clinically, it is most practical to classify frostbite as superficial or deep. Superficial does not entail tissue loss. Classically, frostbite is retrospectively graded like a burn once the resultant pathology is demarcated over time. First-degree frostbite causes only anesthesia and erythema. The appearance of superficial vesiculation surrounded by edema and erythema is considered second degree. Hemorrhagic vesicles reflect a serious injury to the microvasculature, and indicate third-degree frostbite. Fourth-degree injuries damage subcuticular, muscular, and osseous tissues.

PATHOPHYSIOLOGY

Peripheral cold injury involves a cascade of events. Endothelial cells are very susceptible to cold injury. In the prefreeze phase, plasma leaks and there is the development of microvascular vasoconstriction. The radiation of heat from underlying tissues initially prevents crystallization. The freeze phase usually begins with extracellular fluid crystallization. Water exits the cell and causes intracellular dehydration, hyperosmolality, and ultimately cellular shrinkage and demise. Damaged tissue releases thromboxane A2 and prostaglandin F2a, which produce platelet aggregation, leukocyte immobilization, and vasoconstriction.

After the tissue thaws, the second phase of the cascade causes progressive dermal ischemia. The microvasculature begins to collapse, arteriovenous shunting increases tissue pressures, and there is progressive formation of edema. Finally, thrombosis, ischemia, and superficial necrosis appear. The development of mummification and demarcation may take weeks to months.

CLINICAL PRESENTATION

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 complain of 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 boney prominences.

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 dry cold. Young females, particularly those with a history of Raynaud's phenomenon, are most at 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 (trench) 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 complain of hyperhidrosis, cold sensitivity, and painful ambulation for many years.

Various ancillary tests have been used in an attempt to diagnose the severity of peripheral cold injuries. None consistently predicts the extent of injury at presentation. For example, angiography and magnetic resonance imaging can demonstrate the patency of large vessels but not the microvasculature. Ultrasonography and digital plethysmography are also insensitive. Thermography and technetium scintigraphy help evaluate perfusion several days after rewarming.

TREATMENT

Frozen tissue should be rapidly and completely thawed by immersion in circulating water at 37° to 40°C. Rapid rewarming often produces an initial hyperemia. The early formation of clear distal large blebs is more favorable than 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.

Numerous experimental antithrombotic and vasodilatory treatment regimens have been evaluated. There is no conclusive evidence that dextran, heparin, steroids, calcium channel blockers, or hyperbaric oxygen salvage tissue. A treatment protocol for frostbite is summarized in Table 20-3.

Unless infection develops, any decision regarding debridement or amputation should be deferred until there is clear evidence of demarcation, mummification, and sloughing. The most common symptomatic sequelae reflect neuronal injury and the persistently abnormal sympathetic tone, including paresthesias, thermal misperception, and hyperhidrosis. Delayed findings include nail deformities, cutaneous carcinomas, and epiphyseal damage in children.

HYPOTHERMIA 2

DIAGNOSIS AND STABILIZATION

Hypothermia is confirmed by measuring 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 measurement will be falsely high during heated inhalation therapy. The probe should be placed 24 cm below the larynx. The greatest discordance between the readings is usually during the transition phase before effective rewarming. 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, one sequence of 3 defibrillation attempts (2 J/kg) should be administered. If unsuccessful, active rewarming should be continued past 30° to 32°C. Supplemental oxygenation is always warranted, since tissue oxygenation is adversely affected 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 pre-oxygenation will prevent ventricular arrhythmias.

Insertion of a gastric tube prevents dilatation secondary to decreased bowel motility. Indwelling bladder catheters facilitate monitoring of cold-induced diuresis. Dehydration is commonly encountered with chronic hypothermia, and most patients benefit from a bolus of crystalloid. Normal saline containing 5% dextrose is preferable to lactated Ringer's solution, as the liver in hypothermic patients inefficiently metabolizes lactate. The placement of a pulmonary artery catheter, although of potential value, risks perforation of the less compliant pulmonary artery. The use of a central venous catheter should be avoided because of right atrial irritability.

Arterial blood gases should not be corrected for temperature. This is termed the ectothermic or alpha-stat approach, which maximizes enzymatic function and maintains the normal distribution of charged metabolic intermediates. An uncorrected pH of 7.42 and a PCO2 of 40 mmHg reflects 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. When the PCO2 increases 10 mmHg at 28°C, it doubles the pH decline of 0.08 that is normally induced at 37°C.

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 most at risk for electrolyte disturbances.

Coagulopathies are common because cold inhibits the enzymatic reactions required for activation of the intrinsic cascade. In addition, the production of thromboxane B2 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 reported by the laboratory appear deceptively normal and contrast with the observed coagulopathy. This contradiction appears because all coagulation tests are routinely performed at 37°C, 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 covered, the rate of rewarming is usually 0.5° to 2.0°C per hour. This technique is ideal for previously healthy patients who develop acute, mild primary accidental hypothermia. The patient must have sufficient fuel and glycogen to support endogenous thermogenesis.

There are reservations about the application of heat directly to the extremities of patients with chronic severe hypothermia. Extinguishing peripheral vasoconstriction in the dehydrated patient may precipitate core temperature "afterdrop"¾the continual decline in the core temperature after removal of the patient from the cold. This phenomenon results from conductive temperature equilibration and a circulatory convective mechanism. Rewarming frostbitten extremities before stabilization of the core temperature causes a significant core temperature afterdrop. In contrast, truncal heat application may minimize the risk of afterdrop.

Active rewarming is necessary under the following circumstances: core temperature <32°C (poikilothermia), cardiovascular instability, age extremes, CNS dysfunction, endocrine insufficiency, or any suspicion of secondary hypothermia. Active external rewarming is best accomplished with forced-air heating blankets. Other options include 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. Widely available active core rewarming options include heated inhalation, heated infusion, and lavage (gastric, colonic, mediastinal, thoracic, pleural). The therapeutic options also include hemodialysis, venovenous, and continuous arteriovenous rewarming, in addition to formal cardiopulmonary bypass.

Arteriovenous anastomoses (AVA) rewarming provides exogenous heat by immersion of the hands, forearms, feet, and calves in 44° to 45°C water. Airway rewarming with heated humidified oxygen (40° to 45°C ) is a convenient option via mask or endotracheal tube. Although airway rewarming provides less heat than some other forms of active core rewarming, it eliminates respiratory heat loss and adds 1° to 2°C to the overall rewarming rate. Crystalloids should be heated to 40° to 42°C. The quantity of heat provided is significant only during massive volume resuscitations. 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 hemithoraces are irrigated through two large-bore thoracostomy tubes that are inserted into the left or both of the hemithoraces. 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° to 45°C 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 ingestions.

With extracorporeal venovenous rewarming, the blood is removed from a central venous catheter, heated to 40°C, and returned through a second central or peripheral venous catheter. Continuous arteriovenous rewarming involves the use of percutaneously inserted femoral arterial and contralateral femoral venous 8.5 Fr catheters. The blood pressure must be at least 60 mmHg. Heparin-bonded tubing obviates the need for systemic anticoagulation. Full circulatory support with an oxygenator can only be provided through formal cardiopulmonary bypass (CPB). Femoral flow rates of 2 to 3 L/min elevate the core temperature 1° to 2°C every 3 to 5 min. CPB should be considered in nonperfusing patients without documented contraindications to resuscitation. Circulatory support may also 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. The best strategy is usually a combination of passive, truncal active, and active core rewarming techniques.

DRUG THERAPY

When a patient is hypothermic, target organs and the cardiovascular system respond minimally to most medications. Moreover, cumulative doses can cause toxicity during rewarming because of increased binding of drugs to proteins, and impaired metabolism and excretion. As an example, the administration of repeated doses of digoxin or insulin would be ineffective while the patient is hypothermic, and the residual drugs are potentially toxic during rewarming.

Any pharmacologic manipulation of the depressed and vasoconstricted cardiovascular system should generally be avoided. If the hypotension does not respond to crystalloid infusion and rewarming, low-dose dopamine (2 to 5 ug/kg per min) support should be considered. Atrial arrhythmias should initially be monitored without intervention, as the ventricular response will be slow, and most will convert spontaneously during rewarming. When indicated, bretylium tosylate is the class III ventricular antiarrhythmic of choice. During ventricular fibrillation, it should initially be administered at a dose of 10 mg/kg. Bretylium uniquely increases the ventricular arrhythmia threshold at low temperatures, although the wisdom of prophylaxis is unresolved.

Initiating empirical therapy for adrenal insufficiency is usually not warranted unless there is a history suggesting steroid dependence, hypoadrenalism, or a failure to rewarm with standard therapy. However, the administration of parenteral levothyroxine to euthyroid patients with hypothermia is potentially hazardous. Because laboratory results can be delayed and confounded by the presence of the sick euthyroid syndrome , historical 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 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.

Preventive measures should be discussed with high-risk individuals, such as the elderly or 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.

HYPOTHERMIA 1

HYPOTHERMIA AND FROSTBITE

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 to 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 those patients who develop secondary hypothermia as a complication of a serious systemic disorder.

CAUSES

Primary accidental hypothermia is geographically and seasonally pervasive. Although most cases occur in the winter months and in colder climates, it is surprisingly common in warmer regions as well. In the United States, hypothermia accounts for more than 700 deaths each year, half of which occur in people age 65 or older.

Multiple variables make individuals at the extremes of age, the elderly and neonates, particularly vulnerable to hypothermia. The elderly have diminished thermal proprioception 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. In addition, malnutrition can contribute to heat loss because of diminished subcutaneous fat and because of its association with depleted energy stores used for thermogenesis.

Individuals whose occupations or hobbies entail extensive exposure to cold weather are clearly 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 vasodilatation (which increases heat loss), reduces thermogenesis and gluconeogenesis, and may impair judgment or lead to obtundation. Hypothermia is not an uncommon feature in Wernicke's encephalopathy and may mask its other manifestations. A number of medications are associated with altered thermal regulation. Phenothiazines, barbiturates, benzodiazepines, cyclic antidepressants, and many other medications reduce centrally-mediated vasoconstriction. Up to one-quarter of patients admitted to an intensive care unit because of drug overdose are hypothermic. Anesthetics can block the shivering responses; their effects may be compounded when patients are not covered adequately in the operating or recovery rooms.

Several types of endocrine dysfunction can lead to hypothermia. Hypothyroidism¾particularly when extreme, as in myxedema coma¾reduces the metabolic rate and impairs thermogenesis and behavioral responses. Myxedema is more common in women than in men and may be occult. Adrenal insufficiency and hypopituitarism can also increase susceptibility to hypothermia. Hypoglycemia, most commonly caused by insulin or oral hypoglycemic drugs, is associated with hypothermia, in part the result 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, or hypothalamic lesions increases susceptibility to hypothermia. Agenesis of the corpus callosum, or Shapiro syndrome, is one cause of episodic hypothermia, characterized by profuse perspiration 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 stores 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 to 65% of heat loss), conduction (10 to 15% of heat loss, but much greater in cold water), convection (increase in the wind), respiration, and evaporation (which are affected by the ambient temperature and the relative humidity).

The preoptic anterior hypothalamus normally orchestrates thermoregulation. 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 converse heat. Prolonged exposure to cold also stimulates hypothalamic release of thyrotropin releasing hormone; this leads to increased levels of thyroid stimulating hormone (TSH), which stimulates the thyroid gland to produce thyroxine, a hormone that increases metabolic rate.

CLINICAL PRESENTATION

In most cases of hypothermia, the history of exposure to environmental factors, such as prolonged exposure to the outdoors without adequate clothing, makes the diagnosis straightforward. In urban settings, however, the presentation is often more subtle and the clinician may focus on other disease processes, toxin exposures, or psychiatric diagnoses.

After initial stimulation by hypothermia, there is progressive depression of all organ systems. The timing of the appearance of these clinical manifestations varies widely. Without knowing the core temperature, it can be difficult to interpret other vital signs. For example, a 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 should raise suspicion of an overdose or CNS dysfunction due to infection or trauma.

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 injury. Patients with hypothermia may be confused or combative; these symptoms abate more rapidly with rewarming than with the use of restraints. 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.

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 exceeding 10 mEq/L. Other findings that may preclude continuing resuscitation include a core temperature <12°C, a pH <6.5, or evidence of intravascular thrombosis with a fibrinogen value <50 mg/dL. The decision to terminate resuscitation before rewarming the patient to 35°C is extremely difficult. 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.

ACUTELY ILL INFECTED FEBRILE PATIENT 3

NEUROLOGIC INFECTIONS WITH OR WITHOUT SEPTIC SHOCK

Bacterial Meningitis Bacterial meningitis is one of the most common infectious emergencies involving the central nervous system. Although hosts with cell-mediated immune deficiency, including transplant recipients, diabetic patients, the elderly, and cancer patients treated with certain chemotherapeutic agents, are at particular risk for Listeria monocytogenes meningitis, most cases in adults are due to S. pneumoniae (30 to 50%) and N. meningitidis (10 to 35%). An early presentation of headache, meningismus, and fever is classic but is seen in only half of patients. The elderly can present without fever or meningeal signs despite lethargy and confusion. Cerebral dysfunction is evidenced by confusion, delirium, and lethargy that can progress to coma. The presentation is fulminant, with sepsis and brain edema, in some cases; papilledema at presentation is unusual and suggests another diagnosis (e.g., an intracranial lesion). Focal signs, including cranial nerve palsies (IV, VI, VII), can be seen in 10 to 20% of cases; 50 to 60% of patients have bacteremia. A poor neurologic outcome is associated with coma at any time during the course or with a CSF glucose level of <0.6 mmol/L (<10 mg/dL). Mortality is associated with coma, respiratory distress, shock, a CSF protein level of >2.5 g/L, a peripheral white blood cell count of <5000/uL, and a serum sodium level of <135 mmol/L.

Suppurative Intracranial Infections Other rare intracranial lesions that present with sepsis and hemodynamic instability are subdural empyema, septic cavernous sinus thrombosis, and septic superior sagittal sinus thrombosis. Rapid recognition of the toxic patient with central neurologic signs is crucial to improvement of the dismal prognosis of these entities.

Subdural Empyema This infection arises from the paranasal sinus in 60 to 70% of cases. Microaerophilic streptococci and staphylococci are the predominant etiologic organisms. The patient is toxic, with fever, headache, and nuchal rigidity. Of all patients, 75% have focal signs and 6 to 20% die.

Septic Cavernous Sinus Thrombosis This condition follows a facial or sphenoid sinus infection; 70% of cases are due to staphylococci and the remainder to aerobic or anaerobic streptococci. A unilateral or retroorbital headache progresses to a toxic appearance and fever within days. Three-quarters of patients have unilateral periorbital edema that becomes bilateral and then progresses to ptosis, proptosis, ophthalmoplegia, and papilledema. The mortality rate is as high as 30%.

Septic Thrombosis of the Superior Sagittal Sinus This infection spreads from the ethmoid or maxillary sinuses. Its bacterial causes include S. pneumoniae, other streptococci, and staphylococci. The fulminant course is characterized by headache, nausea, vomiting, rapid progression to confusion and coma, nuchal rigidity, and brainstem signs. If the sinus is totally thrombosed, the mortality rate exceeds 80%.

Brain Abscess Brain abscess often occurs without systemic signs. Almost half of patients are afebrile, and presentations are more consistent with a space-occupying lesion in the brain; 70% have headache, 50% have focal neurologic signs, and 25% have papilledema. Abscesses can present as single or multiple lesions resulting from contiguous foci or hematogenous infection, such as unrecognized endocarditis. The infection progresses over several days from cerebritis to an abscess with a mature capsule. Abscesses arising hematogenously are especially apt to rupture into the ventricular space, causing a sudden and severe deterioration in clinical status and high mortality. Otherwise, mortality is low but morbidity is high (30 to 55%). Patients presenting with stroke and a parameningeal infectious focus, such as sinusitis or otitis, may have a brain abscess, and physicians must maintain a high level of suspicion. Prognosis worsens in patients with a fulminant course, delayed diagnosis, abscess rupture into the ventricles, multiple abscesses, or abnormal neurologic status at presentation.

Cerebral Malaria This entity should be urgently considered if patients who have recently traveled to areas endemic for malaria present with a febrile illness and lethargy or other neurologic signs. Fulminant malaria is caused by Plasmodium falciparum and is associated with temperatures of >40°C (>104°F), hypotension, jaundice, adult respiratory distress syndrome, and bleeding. By definition, any patient with a change in mental status or repeated seizure in the setting of fulminant malaria has cerebral malaria. In adults this nonspecific febrile illness progresses to coma over several days; occasionally, coma occurs within hours and death within 24 h. Nuchal rigidity and photophobia are rare. On physical examination, symmetric encephalopathy is typical, and upper motor neuron dysfunction with decorticate and decerebrate posturing can be seen with advanced disease. Unrecognized infection results in a 30% mortality rate.

Spinal Epidural Abscesses Patients with spinal epidural abscesses often present with back pain and develop neurologic deficits late in their course. At-risk patients include those with diabetes mellitus; intravenous drug use; recent spinal trauma, surgery, or epidural anesthesia; and other comorbid conditions, such as HIV infection. The thoracic or lumbar spine is the most common location, and staphylococci are the most common etiologic agents; in HIV-infected intravenous drug users, therapy must cover gram-negative rods and methicillin-resistant S. aureus. If a patient gives a history of antecedent back pain and has new neurologic symptoms, this diagnosis must immediately be considered. Almost 60% of patients have fever and almost 90% have back pain. Paresthesia, bowel and bladder dysfunction, radicular pain, and weakness are frequent neurologic complaints, and examination of the patient may reveal abnormal reflexes and motor and sensory deficits. Rapid recognition and treatment, including immediate drainage, can prevent or minimize permanent neurologic sequelae.

FOCAL SYNDROMES WITH A FULMINANT COURSE

Infection at virtually any primary focus (e.g., osteomyelitis, pneumonia, pyelonephritis, or cholangitis) can result in bacteremia and sepsis. TSS has been associated with focal infections such as septic arthritis, peritonitis, sinusitis, and wound infection. Death occurs secondary to septic shock or toxin production with hemodynamic instability and multiorgan failure. Rapid clinical deterioration and death can be associated with destruction of the primary site of infection, as is seen in endocarditis and in necrotizing infections of the oropharynx (in which edema suddenly compromises the airway).

Rhinocerebral Mucormycosis Patients with diabetes or malignancy are at risk for invasive rhinocerebral mucormycosis. Patients present with low-grade fever, dull sinus pain, diplopia, decreased mental status, decreased ocular motion, chemosis, proptosis, dusky or necrotic nasal turbinates, and necrotic hard-palate lesions that respect the midline. Without rapid recognition and intervention, the process continues an inexorable invasive course with high mortality.

Acute Bacterial Endocarditis This entity presents with a much more aggressive course than subacute endocarditis. Bacteria such as S. aureus, S. pneumoniae, L. monocytogenes, Haemophilus spp., and streptococci of groups A, B, and G attack native valves. Mortality rates range from 10 to 40%. The host may have comorbid conditions such as underlying malignancy, diabetes mellitus, intravenous drug use, or alcoholism. The patient presents with fever, fatigue, and malaise <2 weeks after onset of infection. On physical examination, a changing murmur and congestive heart failure may be noted. Hemorrhagic macules on palms or soles (Janeway lesions,) sometimes develop. Petechiae, Roth's spots, splinter hemorrhages, and splenomegaly are unusual. Rapid valvular destruction, particularly of the aortic valve, results in pulmonary edema and hypotension. Myocardial abscesses can form, eroding through the septum or into the conduction system and causing life-threatening arrhythmias or high-degree conduction block. Large friable vegetations can result in major arterial emboli, metastatic infection, or tissue infarction. Emboli can lead to stroke, change in mental status, visual disturbances, aphasia, ataxia, headache, meningismus, brain abscess, cerebritis, spinal cord infarct with paraplegia, arthralgia, osteomyelitis, splenic abscess, septic arthritis, and hematuria. Rapid intervention is crucial for a successful outcome.

DIAGNOSTIC WORKUP OF THE ACUTELY ILL PATIENT

After a quick clinical assessment, diagnostic material should be obtained rapidly and antibiotic and supportive treatment begun. In the sepsis syndromes, blood (for cultures; baseline complete blood count with differential; measurement of serum electrolytes, blood urea nitrogen, serum creatinine, and serum glucose; and liver function tests) can be obtained at the time an intravenous line is placed and before antibiotics are administered. For patients with possible acute endocarditis, three sets of blood cultures should be performed. Asplenic patients should have a blood smear examined to confirm the presence of Howell-Jolly bodies (indicating the absence of splenic function) and a buffy coat examined for bacteria; these patients can have >106 organisms per milliliter of blood (compared to 104/mL in patients with an intact spleen). Blood smears from patients with possible cerebral malaria or babesiosis must be examined for the diagnosis and quantitation of parasitemia. Blood smears may also be diagnostic in ehrlichiosis.

Patients with meningitis should have CSF obtained before the initiation of antibiotic therapy. If focal neurologic signs, abnormal mental status, or papilledema mandates brain imaging before a lumbar puncture, antibiotics should be administered prior to imaging but after blood for cultures has been drawn. If CSF cultures are negative, laboratory examination of CSF by latex agglutination or immunoprecipitation can be attempted to make an etiologic diagnosis. However, blood cultures will provide the diagnosis in 50 to 70% of cases.

Focal abscesses necessitate immediate computed tomography or magnetic resonance imaging as part of an evaluation for surgical intervention. Other diagnostic procedures, such as cultures of wounds or scraping of skin lesions, should not delay the initiation of treatment for more than minutes. Once emergent evaluation, diagnostic procedures, and (if appropriate) surgical consultation (see below) have been completed, other laboratory tests can be conducted. Appropriate radiography, computed axial tomography, magnetic resonance imaging, urinalysis, erythrocyte sedimentation rate determination, and transthoracic or transesophageal echocardiography may all prove important.

TREATMENT

lists first-line treatments for the infections considered in this chapter. (For a more detailed discussion of treatment, see specific chapters.) In addition to the initiation of parenteral antibiotic therapy, several of these infections require urgent surgical attention. General surgery for possible necrotizing fasciitis or myonecrosis, neurosurgical evaluation for subdural empyema or spinal epidural abscess, otolaryngologic surgery for possible mucormycosis, and cardiothoracic surgery for critically ill patients with acute endocarditis are as important as the rapid commencement of antibiotic therapy. For infections such as necrotizing fasciitis and clostridial myonecrosis, rapid surgical intervention supercedes other diagnostic or therapeutic maneuvers.

Acutely ill febrile patients require close observation, aggressive supportive measures, and¾in most cases¾admission to intensive care units. Adjunctive treatments, such as intravenous immunoglobulin administration for TSS, can be considered after initial stabilization. The most important task of the physician is to recognize the acute infectious emergency and proceed with appropriate urgency.

ACUTELY ILL INFECTED FEBRILE PATIENT 2

SEPSIS WITH SKIN MANIFESTATIONS

Maculopapular rashes may reflect early meningococcal or rickettsial disease but are usually associated with nonemergent infections. Exanthems are usually viral.

Petechiae Petechial rashes caused by viruses are seldom associated with hypotension or a toxic appearance, although severe measles can be an exception. In other settings, petechial rashes require more urgent attention.

Meningococcemia Almost three-quarters of patients with bacteremic N. meningitidis infection have a rash. Meningococcemia most often affects young children (i.e., those 6 months to 5 years old, often in daycare). However, sporadic cases and outbreaks occur in schools (grade school through college) and army barracks. Between 10 and 20% of all cases have a fulminant course, with shock, DIC, and multiorgan failure. Of these patients, 50 to 60% die, and survivors often require extensive debridement or amputation of gangrenous extremities. Patients may exhibit fever, headache, nausea, vomiting, myalgias, change in mental status, and meningismus. However, the rapidly progressive form of disease is not usually associated with meningitis. The rash is initially pink, blanching, and maculopapular, appearing on the trunk and extremities, but then becomes hemorrhagic, forming petechiae. Petechiae are first seen at the ankles, wrists, axillae, mucosal surfaces, and palpebral and bulbar conjunctiva, with subsequent spread to the lower extremities and trunk. A cluster of petechiae may be seen at pressure points, e.g., where a blood pressure cuff has been inflated. In rapidly progressive meningococcemia, the petechial rash quickly becomes purpuric and patients develop DIC. Hypotension with petechiae for <12 h is associated with significant mortality. The mortality rate can exceed 90% in patients without meningitis who have rash, hypotension, and a normal or low white blood cell count and erythrocyte sedimentation rate. A better prognosis has been reported in cases where antibiotics are given before admission by the primary care provider. This observation suggests that early initiation of treatment may be life-saving.

Rocky Mountain spotted fever RMSF occurs throughout the United States. A history of tick bite is common; however, if such a history is lacking, a history of travel or outdoor activity (e.g., camping in tick-infested areas) can be ascertained. RMSF is caused by Rickettsia rickettsii. For the first 3 days, headache, fever, malaise, myalgias, nausea, vomiting, and anorexia are present. By day 3, half of patients have skin findings. Blanching macules develop initially on the wrists and ankles and then spread over the legs and trunk. The lesions become hemorrhagic and are frequently petechial. The rash spreads to palms and soles later in the course (Plate IID-45). The centripetal spread is a classic feature of RMSF. However, 10 to 15% of patients with RMSF never develop a rash. The patient can be hypotensive and develop noncardiogenic pulmonary edema, confusion, lethargy, and encephalitis progressing to coma. The cerebrospinal fluid (CSF) contains 10 to 100 cells/uL, usually with a predominance of mononuclear cells. The CSF glucose level is often normal; the protein concentration may be slightly elevated. Renal and hepatic injury and bleeding secondary to vascular damage are noted. Untreated infection has a mortality rate of 30%.

Purpura Fulminans This is the cutaneous manifestation of DIC and presents as large ecchymotic areas and hemorrhagic bullae. Progression of petechiae to purpura and ecchymoses is associated with congestive heart failure, septic shock, acute renal failure, acidosis, hypoxia, hypotension, and death. Purpura fulminans has primarily been associated with N. meningitidis but, in the splenectomized patient, has been described in association with S. pneumoniae and H. influenzae.

Ecthyma Gangrenosum Septic shock caused by P. aeruginosa and A. hydrophila can be associated with ecthyma gangrenosum: hemorrhagic vesicles surrounded by a rim of erythema with central necrosis and ulceration. These gram-negative bacteremias are most common among patients with neutropenia, extensive burns, and hypogammaglobulinemia.

Other Emergent Infections Associated with Rash Vibrio vulnificus and other noncholera Vibrio bacteremic infections can cause focal skin lesions and overwhelming sepsis in the host with liver disease. After ingestion of contaminated shellfish, there is a sudden onset of malaise, chills, fever, and hypotension. The patient develops bullous or hemorrhagic skin lesions, usually on the lower extremities, and 75% of patients have leg pain. The mortality rate can be as high as 50%. Capnocytophaga canimorsus can cause septic shock in asplenic patients. Infection with this fastidious gram-negative rod typically presents after a dog bite as fever, chills, myalgia, vomiting, diarrhea, dyspnea, confusion, and headache. Findings can include an exanthem or erythema multiforme, cyanotic mottling or peripheral cyanosis, petechiae, and ecchymosis. About 30% of patients with this fulminant form die of overwhelming sepsis and DIC, and survivors may require amputation to treat gangrene.

Erythroderma TSS is usually associated with erythroderma. The patient presents with fever, malaise, myalgias, nausea, vomiting, diarrhea, and confusion. There is a sunburn-type rash that may be subtle and patchy but is usually diffuse and is found on the face, trunk, and extremities. Erythroderma, which desquamates after 1 to 2 weeks, is more common in Staphylococcus-associated than in Streptococcus-associated TSS. Hypotension develops rapidly after onset of symptoms, often within hours. Multiorgan failure is seen. Often there is no indication of a primary focal infection. Colonization rather than overt infection of the vagina or a postoperative wound, for example, is typical with staphylococcal TSS, and the mucosal areas appear hyperemic but not infected. Early renal failure may distinguish this syndrome from other septic shock syndromes. Clinical evaluation constitutes the diagnosis because TSS is defined by the clinical criteria of fever, rash, hypotension, and multiorgan involvement. The mortality rate is 5% for menstruation-associated TSS, 10 to 15% for nonmenstrual TSS, and 30 to 70% for streptococcal TSS.

SEPSIS WITH A SOFT TISSUE/MUSCLE PRIMARY FOCUS

Necrotizing Fasciitis This infection may arise at a site of minimal trauma or postoperative incision and may also be associated with recent varicella, childbirth, or muscle strain. The most common causes of necrotizing fasciitis are group A streptococci alone and a mixed facultative and anaerobic flora. Diabetes mellitus, peripheral vascular disease, and intravenous drug use are associated risk factors. Use of nonsteroidal anti-inflammatory agents adversely affects granulocyte chemotaxis, phagocytosis, and bacterial killing, allowing progression of skin or soft tissue infections. The patient may have bacteremia and hypotension without other organ-system failure. Physical findings are minimal compared to the severity of pain and the degree of fever. The examination is often unremarkable except for soft tissue edema and erythema. The infected area is red, hot, shiny, swollen, and exquisitely tender. In untreated infection, the overlying skin develops blue-gray patches after 36 h, and cutaneous bullae and necrosis develop after 3 to 5 days. Necrotizing fasciitis due to a mixed flora, but not that due to group A streptococci, can be associated with gas production. Without treatment, pain decreases because of thrombosis of the small blood vessels and destruction of the peripheral nerves¾an ominous sign. The mortality rate is >30% overall, >70% in association with TSS, and nearly 100% without surgical intervention. Life-threatening necrotizing fasciitis may also be due to Clostridium perfringens; in this condition, the patient is extremely toxic and the mortality rate is high. Within 48 h, rapid tissue invasion and systemic toxicity associated with hemolysis and death ensue. The distinction between this entity and clostridial myonecrosis is made by muscle biopsy.

Clostridial Myonecrosis Myonecrosis is often associated with trauma or surgery but can be spontaneous. The incubation period is usually 12 to 24 h long, and massive necrotizing gangrene develops within hours of onset. Systemic toxicity, shock, and death can occur within 12 h. The patient's pain and toxic appearance are out of proportion to physical findings. On examination, the patient is febrile, apathetic, tachycardic, and tachypneic and may express a feeling of impending doom. Hypotension and renal failure develop later, and hyperalertness is evident preterminally. The skin over the affected area is bronze-brown, mottled, and edematous. Bullous lesions with serosanguineous drainage and a mousy or sweet odor can be present. Crepitus can occur secondary to gas production in muscle tissue. The mortality rate is >65% with spontaneous myonecrosis, which is often associated with C. septicum and underlying malignancy. The mortality rates associated with trunk and limb infection are 63% and 12%, respectively, and any delay in surgical treatment increases the risk of death.

ACUTELY ILL INFECTED FEBRILE PATIENT 1

APPROACH TO THE ACUTELY ILL INFECTED FEBRILE PATIENT

The physician treating the acutely ill febrile patient must be able to recognize infections that require emergent attention. If such infections are not adequately evaluated and treated at initial presentation, the opportunity to alter an adverse outcome may be lost. In this chapter, the clinical presentations of and approach to patients with relatively common infectious disease emergencies are discussed. These infectious processes are discussed in detail in other chapters.

GENERAL CONSIDERATIONS

APPEARANCE

A physician must have a consistent approach to acutely ill patients. Even before the history is elicited and a physical examination performed, an immediate assessment of the patient's general appearance yields valuable information. The perceptive physician's subjective sense that a patient is septic or toxic often proves accurate. Visible agitation or anxiety in a febrile patient can be a harbinger of critical illness.

HISTORY

Presenting symptoms are frequently nonspecific. In addition to a general description of symptoms, it is important to obtain a sense of disease progression. Detailed questions should be asked about the onset and duration of symptoms and about changes in severity or rate of progression over time. Host factors and comorbid conditions may enhance the risk of infection with certain organisms or of a more fulminant course than is usually seen. Lack of splenic function, alcoholism with significant liver disease, intravenous drug use, HIV infection, diabetes, malignancy, and chemotherapy all predispose to specific infections and frequently to increased severity. The patient should be questioned about factors that might help identify a nidus for invasive infection, such as recent upper respiratory tract infections, influenza, or varicella; prior trauma; disruption of cutaneous barriers due to lacerations, burns, surgery, or decubiti; and the presence of foreign bodies, such as nasal packing after rhinoplasty, barrier contraceptives, tampons, arteriovenous fistulas, or prosthetic joints. Travel, contact with pets or other animals, or activities that might result in tick exposure can lead to diagnoses that would not otherwise be considered. Recent dietary intake, medication use, social contact with ill individuals, vaccination history, and menstrual history may be relevant. A review of systems should focus on any neurologic signs or sensorium alterations, rashes or skin lesions, and focal pain or tenderness and should also include a general review of respiratory, gastrointestinal, or genitourinary symptoms. It is especially important to determine the duration and progression of these symptoms in order to gain an appreciation of the pace and urgency of the process.

PHYSICAL EXAMINATION

A complete physical examination should be performed, with special attention to some areas that are sometimes given short shrift in routine examinations. Assessment of the patient's general appearance and vital signs, skin and soft tissue examination, and the neurologic evaluation are of particular importance.

The patient may appear either anxious and agitated or lethargic and apathetic. Fever is usually present, although the elderly and compromised hosts, such as those who are uremic or cirrhotic and patients who are taking glucocorticoids or nonsteroidal anti-inflammatory agents, may be afebrile despite serious underlying infection. Measurement of blood pressure, heart rate, and respiratory rate helps determine the degree of hemodynamic and metabolic compromise. The patient's airway must be evaluated to rule out the risk of obstruction from an invasive oropharyngeal infection.

The etiologic diagnosis may become evident in the context of a thorough skin examination. Petechial rashes are typically seen with meningococcemia or Rocky Mountain spotted fever (RMSF); erythroderma is usual with toxic shock syndrome (TSS) and drug fever. The soft tissue and muscle examination is critical. Areas of erythema or duskiness, edema, and tenderness may indicate underlying necrotizing fasciitis, myositis, or myonecrosis. The neurologic examination must include a careful assessment of mental status for signs of early encephalopathy. Evidence of nuchal rigidity or focal neurologic findings should be sought. Focal findings, depressed mental status, or papilledema should be evaluated by brain imaging prior to lumbar puncture, which, in this setting, could initiate herniation.

SPECIFIC PRESENTATIONS

For most infections, there is time for careful evaluation, diagnostic testing, and consultation with other physicians. However, the infections considered below according to common clinical presentation can have rapidly catastrophic outcomes, and their immediate recognition can be life-saving. Recommended therapeutic regimens are presented in.

SEPSIS WITHOUT AN OBVIOUS FOCUS OF PRIMARY INFECTION

These patients initially have a brief prodrome of nonspecific symptoms and signs that progresses quickly to hemodynamic instability with hypotension, tachycardia, tachypnea, or respiratory distress. A patient may display altered mental status. Disseminated intravascular coagulation (DIC) with clinical evidence of a hemorrhagic diathesis is a poor prognostic sign.

Septic Shock Patients with bacteremia leading to septic shock may have a primary site of infection (e.g., pneumonia, pyelonephritis, or cholangitis) that is not evident initially. Elderly patients with comorbid conditions, hosts compromised by malignancy and neutropenia, or patients who have recently undergone a surgical procedure or hospitalization are at increased risk for an adverse outcome. Gram-negative bacteremia with organisms such as Pseudomonas aeruginosa, Aeromonas hydrophila, or Escherichia coli and gram-positive infection with organisms such as Staphylococcus aureus or group A streptococci can present as intractable hypotension and multiorgan failure. Treatment can usually be initiated empirically on the basis of the presentation.

Overwhelming Infection in Asplenic Patients Patients without splenic function are at risk for overwhelming bacterial sepsis. Asplenic patients succumb to sepsis at 600 times the rate of the general population; 50 to 70% of cases occur within the first 2 years after splenectomy, with a mortality rate of up to 80%. However, in the asplenic individual, an increased risk of overwhelming sepsis continues throughout life. In asplenia, encapsulated bacteria cause the majority of infections, and adults are at lower risk than children because they are more likely to have antibody to these organisms. Streptococcus pneumoniae infection is most common, but the risk of infection with Haemophilus influenzae or Neisseria meningitidis is also high. Severe clinical manifestations of infections due to E. coli, S. aureus, group B streptococci, P. aeruginosa, Capnocytophaga, Babesia, and Plasmodium have been described.

Babesiosis A history of recent travel to endemic areas should raise the possibility of infection with Babesia. Between 1 and 4 weeks after a tick bite, the patient experiences chills, fatigue, anorexia, myalgia, arthralgia, nausea, and headache; ecchymosis and/or petechiae are occasionally seen. The tick that most commonly transmits Babesia, Ixodes scapularis, also transmits Borrelia burgdorferi (the agent of Lyme disease) and Ehrlichia, and co-infection can occur, resulting in more severe disease. Infection with the European species Babesia divergens is more frequently fulminant than that due to the U.S. species B. microti, causing a febrile syndrome with hemolysis, jaundice, hemoglobinemia, and renal failure and a mortality rate of >50%. Severe babesiosis is especially common in asplenic hosts but does occur in hosts with normal splenic function.

Other Sepsis Syndromes Tularemia is seen throughout the United States, but primarily in Arkansas, Oklahoma, and Missouri, in association with wild rabbit, tick, and tabanid fly contact. The uncommon typhoidal form can be associated with gram-negative septic shock and a mortality rate of >30%. In the United States, plague is found primarily in New Mexico, Arizona, and Colorado after contact with ground squirrels, prairie dogs, or chipmunks. The septic form is particularly rare and is associated with shock, multiorgan failure, and a 30% mortality rate. These rare infections should be considered in the appropriate epidemiologic setting.

FEVER AND RASH 2

Peripheral Eruptions These rashes are alike in that they are most prominent peripherally or begin in peripheral (acral) areas before spreading centripetally. Early diagnosis and therapy are critical in RMSF because of its grave prognosis if untreated. Lesions evolve from macular to petechial, start on the wrists and ankles, spread centripetally, and appear on the palms and soles only later in the disease. The rash of secondary syphilis, which may be diffuse but is prominent on the palms and soles, should be considered in the differential diagnosis of pityriasis rosea, especially in sexually active patients. Atypical measles is seen in individuals contracting measles who received the killed measles vaccine between 1963 and 1967 in the United States and who were not subsequently protected with the live vaccine. Hand-foot-and-mouth disease is distinguished by tender vesicles distributed peripherally and in the mouth; outbreaks commonly occur within families. The classic target lesions of erythema multiforme appear symmetrically on the elbows, knees, palms, and soles. In relatively severe cases, these lesions may spread diffusely and involve mucosal surfaces. Lesions may develop on the hands and feet in endocarditis.

Confluent Desquamative Erythemas These eruptions consist of diffuse erythema frequently followed by desquamation. The eruptions caused by group A Streptococcus or Staphylococcus aureus are toxin mediated. Certain disease features may provide diagnostic clues. Scarlet fever usually follows pharyngitis; patients have a facial flush, a "strawberry" tongue, and accentuated petechiae in body folds (Pastia's lines). Kawasaki disease presents in the pediatric population as fissuring of the lips, a strawberry tongue, conjunctivitis, adenopathy, and sometimes cardiac abnormalities. Streptococcal toxic shock syndrome manifests with hypotension, multiorgan failure, and often a severe group A streptococcal infection (e.g., necrotizing fasciitis,. Staphylococcal toxic shock syndrome also presents with hypotension and multiorgan failure, but usually only S. aureus colonization¾not a severe S. aureus infection¾is documented. Staphylococcal scalded-skin syndrome is seen primarily in children and in immunocompromised adults. Generalized erythema is often evident during the prodrome of fever and malaise; profound tenderness of the skin is distinctive. In the exfoliative stage, the skin can be induced to form bullae with light lateral pressure (Nikolsky's sign). In a mild form, a scarlatiniform eruption mimics scarlet fever, but the patient does not exhibit a strawberry tongue or circumoral pallor. In contrast to the staphylococcal scalded-skin syndrome, in which the cleavage plane is superficial in the epidermis, toxic epidermal necrolysis involves sloughing of the entire epidermis, resulting in severe disease. Exfoliative erythroderma syndrome is a serious reaction associated with systemic toxicity that is often due to eczema, psoriasis, mycosis fungoides, or a severe drug reaction.

Vesiculobullous Eruptions Varicella is highly contagious, often occurring in winter or spring. At a given time within a given region of the body, varicella lesions are in different stages of development. In immunocompromised hosts, varicella vesicles may lack the characteristic erythematous base or may appear hemorrhagic. Rickettsialpox is often documented in urban settings and is characterized by vesicles. It can be distinguished from varicella by an eschar at the site of the mouse-mite bite and the papule/plaque base of each vesicle. Disseminated Vibrio vulnificus infection or ecthyma gangrenosum due to Pseudomonas aeruginosa should be considered in immunosuppressed individuals with sepsis and hemorrhagic bullae.

Urticarial Eruptions Individuals with classic urticaria ("hives") usually have a hypersensitivity reaction without associated fever. In the presence of fever, urticarial eruptions are usually due to urticarial vasculitis. Unlike individual lesions of classic urticaria, which last up to 48 h, these lesions may last up to 5 days. Etiologies include serum sickness (often induced by drugs such as penicillins, sulfas, salicylates, or barbiturates), connective-tissue disease (e.g., systemic lupus erythematosus or Sjogren's syndrome), and infection (e.g., with hepatitis B virus, coxsackievirus A9, or parasites). Malignancy may be associated with fever and chronic urticaria .

Nodular Eruptions In immunocompromised hosts, nodular lesions often represent disseminated infection. Patients with disseminated candidiasis (often due to Candida tropicalis) may have a triad of fever, myalgias, and eruptive nodules. Disseminated cryptococcosis lesions may resemble molluscum contagiosum. Necrosis of nodules should raise the suspicion of aspergillosis or mucormycosis. Erythema nodosum presents with exquisitely tender nodules on the lower extremities. Sweet's syndrome should be considered in individuals with multiple nodules and plaques, often so edematous that they give the appearance of vesicles or bullae. Sweet's syndrome may affect either healthy individuals or persons with lymphoproliferative disease.

Purpuric Eruptions Acute meningococcemia classically presents in children as a petechial eruption, but initial lesions may appear as blanchable macules or urticaria. RMSF should be considered in the differential diagnosis of acute meningococcemia. Echovirus 9 infection may mimic acute meningococcemia; patients should be treated as if they have bacterial sepsis since prompt differentiation of these conditions may be impossible. Large ecchymotic areas of purpura fulminans reflect severe underlying disseminated intravascular coagulation, which may be due to infectious or noninfectious causes. The lesions of chronic meningococcemia may have a variety of morphologies, including petechial. Purpuric nodules may develop on the legs and resemble erythema nodosum but lack its exquisite tenderness. Lesions of disseminated gonococcemia are distinctive, sparse, countable hemorrhagic pustules, usually located near joints. The lesions of chronic meningococcemia and those of gonococcemia may be indistinguishable in terms of appearance and distribution. Viral hemorrhagic fever should be considered in patients with an appropriate travel history and a petechial rash. Thrombotic thrombocytopenic purpura is a noninfectious cause of fever and petechiae. Cutaneous small-vessel vasculitis (leukocytoclastic vasculitis) typically manifests as palpable purpura and has a wide variety of causes.

Eruptions with Ulcers or Eschars The presence of an ulcer or eschar in the setting of a more widespread eruption can provide an important diagnostic clue. For example, the presence of an eschar may suggest the diagnosis of scrub typhus or rickettsialpox in the appropriate setting. In other illnesses (e.g., anthrax), an ulcer or eschar may be the only skin manifestation.

FEVER AND RASH 1

FEVER AND RASH

The acutely ill patient with fever and rash often presents a diagnostic challenge for physicians. The distinctive appearance of an eruption in concert with a clinical syndrome may facilitate a prompt diagnosis and the institution of life-saving therapy or critical infection-control interventions.

Approach to the Patient

A thorough history of patients with fever and rash includes the following relevant information: immune status, medications taken within the previous month, specific travel history, immunization status, exposure to domestic pets and other animals, history of animal or arthropod bites, existence of cardiac abnormalities, presence of prosthetic material, recent exposure to ill individuals, and exposure to sexually transmitted diseases. The history should also include the site of onset of the rash and its direction and rate of spread.

A thorough physical examination entails close attention to the rash, with an assessment and precise definition of its salient features. First, it is critical to determine the type of lesions that make up the eruption. Macules are flat lesions defined by an area of changed color (i.e., a blanchable erythema). Papules are raised, solid lesions <5 mm in diameter; plaques are lesions >5 mm in diameter with a flat, plateau-like surface; and nodules are lesions >5 mm in diameter with a more rounded configuration. Wheals (urticaria, hives) are papules or plaques that are pale pink and may appear annular (ringlike) as they enlarge; classic (nonvasculitic) wheals are transient, lasting only 24 to 48 h in any defined area. Vesicles (<5 mm) and bullae (>5 mm) are circumscribed, elevated lesions containing fluid. Pustules are raised lesions containing purulent exudate; vesicular processes such as varicella or herpes simplex may evolve to pustules. Nonpalpable purpura is a flat lesion that is due to bleeding into the skin; if <3 mm in diameter, the purpuric lesions are termed petechiae; if >3 mm, they are termed ecchymoses. Palpable purpura is a raised lesion that is due to inflammation of the vessel wall (vasculitis) with subsequent hemorrhage. An ulcer is a defect in the skin extending at least into the upper layer of the dermis, and an eschar (tache noire) is a necrotic lesion covered with a black crust.

Other pertinent features of rashes include their configuration (i.e., annular or target), the arrangement of their lesions, and their distribution (i.e., central or peripheral).

CLASSIFICATION OF RASH

This chapter reviews rashes that reflect systemic disease but does not include localized skin eruptions (i.e., cellulitis, impetigo) that may also be associated with fever. Rashes are classified herein on the basis of the morphology and distribution of lesions. For practical purposes, this classification system is based on the most typical disease presentations. However, morphology may vary as rashes evolve, and the presentation of diseases with rashes is subject to many variations. For instance, the classic petechial rash of Rocky Mountain spotted fever (RMSF) may initially consist of blanchable erythematous macules distributed peripherally; at times, the rash associated with RMSF may not be predominantly acral, or a rash may not develop at all.

Diseases with fever and rash may be classified by type of eruption: centrally distributed maculopapular, peripheral, confluent desquamative erythematous, vesiculobullous, urticarial, nodular, purpuric, ulcerated, or eschars. For a more detailed discussion of each disease associated with a rash, the reader is referred to the chapter dealing with that specific disease.

Centrally Distributed Maculopapular Eruptions Centrally distributed rashes, in which lesions are primarily truncal, are the most common type of eruption. The rash of measles (rubeola) starts at the hairline 2 to 3 days into the illness and moves down the body, sparing the palms and soles. It begins as discrete erythematous lesions, which become confluent as the rash spreads. Koplik's spots (1- to 2-mm white or bluish lesions with an erythematous halo on the buccal mucosa) are pathognomonic for measles and are generally seen during the first 2 days of symptoms. They should not be confused with Fordyce's spots (ectopic sebaceous glands), which have no erythematous halos and are found in the mouth of healthy individuals. Koplik's spots may briefly overlap with the measles exanthem.

German measles (rubella) also spreads from the hairline downward; unlike that of measles, however, the rash of rubella tends to clear from originally affected areas as it migrates and may be pruritic. Forchheimer spots (palatal petechiae) may develop but are nonspecific since they also develop in mononucleosis and scarlet fever. Postauricular and suboccipital adenopathy and arthritis are common among adults with German measles. Exposure of pregnant women to ill individuals should be avoided, as rubella causes severe congenital abnormalities. Numerous strains of enteroviruses .primarily echoviruses and coxsackieviruses, cause nonspecific syndromes of fever and eruptions that may mimic rubella or measles. Patients with infectious mononucleosis caused by Epstein-Barr virus or with primary infection caused by HIV may exhibit pharyngitis, lymphadenopathy, and a nonspecific maculopapular exanthem.

The rash of erythema infectiosum (fifth disease), which is caused by human parvovirus B19, primarily affects children 3 to 12 years old; it develops after fever has resolved as a bright blanchable erythema on the cheeks ("slapped cheeks") with perioral pallor. A more diffuse rash (often pruritic) appears the next day on the trunk and extremities and then rapidly develops into a lacy reticular eruption that may wax and wane (especially with temperature change) over 3 weeks. Adults with fifth disease often have arthritis, and fetal hydrops can develop in association with this condition in pregnant women.

Exanthem subitum is most common among children under 3 years of age. As in erythema infectiosum, the rash usually appears after fever has subsided. It consists of 2- to 3-mm rose-pink macules and papules that rarely coalesce, occur initially on the trunk and sometimes on the extremities (sparing the face), and fade within 2 days.

Though drug reactions have many manifestations, including urticaria, exanthematous drug-induced eruptions are most common and are often difficult to distinguish from viral exanthems. Eruptions elicited by drugs are usually more intensely erythematous and pruritic than viral exanthems, but this distinction is not reliable. A history of new medications and an absence of prostration may help to distinguish a drug-related rash from an eruption of another etiology. Rashes may persist for up to 2 weeks after administration of the offending agent is discontinued. Certain populations are more prone than others to drug rashes. Of HIV-infected patients, 50 to 60% develop a rash in response to sulfa drugs; 50 to 100% of patients with mononucleosis due to Epstein-Barr virus develop a rash when given ampicillin.

Rickettsial illnesses should be considered in the evaluation of individuals with centrally distributed maculopapular eruptions. The usual setting for epidemic typhus is a site of war or natural disaster in which people are exposed to body lice. A diagnosis of recrudescent typhus should be considered in European immigrants to the United States. However, an indigenous form of typhus, presumably transmitted by flying squirrels, has been reported in the southeastern United States. Endemic typhus or leptospirosis (the latter caused by a spirochete; may be seen in urban environments where rodents proliferate. Outside the United States, other rickettsial diseases cause a spotted-fever syndrome and should be considered in residents of or travelers to endemic areas. Similarly, typhoid fever, a nonrickettsial disease caused by Salmonella typhi, is usually acquired during travel outside the United States.

Some centrally distributed maculopapular eruptions have distinctive features. Erythema chronicum migrans (ECM), the rash of Lyme disease, typically manifests as singular or multiple annular plaques. Untreated ECM lesions usually fade within a month but may persist for more than a year. Erythema marginatum, the rash of acute rheumatic fever, has a distinctive pattern of enlarging and shifting transient annular lesions.

Collagen vascular diseases may cause fever and rash. Patients with systemic lupus erythematosus typically develop a sharply defined, erythematous eruption in a butterfly distribution on the cheeks (malar rash) as well as many other skin manifestations. Still's disease manifests as an evanescent salmon-colored rash on the trunk and proximal extremities that coincides with fever spikes.

FEVER AND HYPERTHERMIA 3

TREATMENT

The Decision to Treat Fever Most fevers are associated with self-limited infections, most commonly of viral origin. In these cases, the general cause of the fever is easily identified. The routine use of antipyretics given automatically as "standing," "routine," or "prn" orders to treat low-grade fevers in adult patients on hospital wards is entirely unacceptable. This practice masks not only fever but also other important clinical indicators of a patient's course. The assumption underlying any decision to reduce fever with antipyretics is that there is no diagnostic benefit to be gained by allowing the fever to persist. However, there may be such a diagnostic benefit. For example, the daily highs and lows of normal temperature are exaggerated in most fevers, but the usual times of peak and trough temperatures may be reversed in typhoid fever and disseminated tuberculosis. Temperature-pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, and factitious fever. In newborns, the elderly, patients with chronic renal failure, and patients taking glucocorticoids, fever may not be present despite infection, or core temperature may be hypothermic. Hypothermia is observed in patients with septic shock.

Some febrile diseases have characteristic patterns. With relapsing fevers, febrile episodes are separated by intervals of normal temperature; when paroxysms occur on the first and third days, the fever is called tertian. Plasmodium vivax causes tertian fevers. Quartan fevers are associated with paroxysms on the first and fourth days and are seen with P. malariae. Other relapsing fevers are related to Borrelia infections and rat-bite fever, which are both associated with days of fever followed by a several-day afebrile period and then a relapse of days of fever. Pel-Ebstein fever, with fevers lasting 3 to 10 days followed by afebrile periods of 3 to 10 days, is classic for Hodgkin's disease and other lymphomas. Another characteristic fever is that of cyclic neutropenia, in which fevers occur every 21 days and accompany the neutropenia. There is no periodicity of fever in patients with familial Mediterranean fever.

Mechanisms of Antipyretic Agents The synthesis of PGE2 depends on the constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic acid released from the cell membrane, and this release is the rate-limiting step in the synthesis of PGE2. Inhibitors of cyclooxygenase are potent antipyretics. The antipyretic potency of various drugs is directly correlated with the inhibition of brain cyclooxygenase. Acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and is without noteworthy anti-inflammatory activity; in the brain, however, acetaminophen is oxidized by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity.

Oral aspirin and acetaminophen are equally effective in reducing fever in humans. Nonsteroidal anti-inflammatory agents (NSAIDs) such as indomethacin and ibuprofen are also excellent antipyretics. Chronic high-dose therapy with antipyretics such as aspirin or the NSAIDs used in arthritis does not reduce normal core body temperature. Thus, PGE2 appears to play no role in normal thermoregulation.

As effective antipyretics, glucocorticoids act at two levels. First, similar to the cyclooxygenase inhibitors, glucocorticoids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2, which is needed to release arachidonic acid from the cell membrane. Second, glucocorticoids block the transcription of the mRNA for the pyrogenic cytokines.

Drugs that interfere with vasoconstriction (phenothiazines, for example) can act as antipyretics, as can drugs that block muscle contractions. However, these agents are not true antipyretics since they can also reduce core temperature independently of hypothalamic control.

Indications and Regimens for the Treatment of Fever The objectives in treating fever are first to reduce the elevated hypothalamic set point and second to facilitate heat loss. There is no evidence that fever itself facilitates the recovery from infection or acts as an adjuvant to the immune system. In fact, peripheral PGE2 production is a potent immunosuppressant. Hence, treating fever and its symptoms does no harm and does not slow the resolution of common viral and bacterial infections. Reducing fever with antipyretics also reduces systemic symptoms of headache, myalgias, and arthralgias.

Oral aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and the gastrointestinal tract. Therefore, acetaminophen is preferred to all of these agents as an antipyretic. In children, acetaminophen must be used because aspirin increases the risk of Reye's syndrome. If the patient cannot take oral antipyretics, parenteral preparations of NSAIDs and rectal suppository preparations of various antipyretics can be used.

Treatment of fever in some patient groups is recommended. Fever increases the demand for oxygen (i.e., for every increase of 1°C over 37°C, there is a 13% increase in oxygen consumption) and can aggravate preexisting cardiac, cerebrovascular, or pulmonary insufficiency. Elevated temperature can induce mental changes in patients with organic brain disease. Children with a history of febrile or nonfebrile seizure should be aggressively treated to reduce fever, although it is unclear what triggers the febrile seizure and there is no correlation between absolute temperature elevation and onset of a febrile seizure in susceptible children.

In hyperpyrexia, the use of cooling blankets facilitates the reduction of temperature; however, cooling blankets should not be used without oral antipyretics. In hyperpyretic patients with central nervous system disease or trauma, reducing core temperature mitigates the ill effects of high temperature on the brain.

Treating Hyperthermia A high core temperature in a patient with an appropriate history (e.g., environmental heat exposure or treatment with anticholinergic or neuroleptic drugs, tricyclic antidepressants, succinylcholine, or halothane) along with appropriate clinical findings (dry skin, hallucinations, delirium, pupil dilation, muscle rigidity, and/or elevated levels of creatine phosphokinase) suggests hyperthermia. The attempt to lower the already normal hypothalamic set point is of little use. Physical cooling with sponging, fans, cooling blankets, and even ice baths should be initiated immediately in conjunction with the administration of intravenous fluids and appropriate pharmacologic agents (see below). If insufficient cooling is achieved by external means, internal cooling can be achieved by gastric or peritoneal lavage with iced saline. In extreme circumstances, hemodialysis or even cardiopulmonary bypass with cooling of blood may be performed.

Malignant hyperthermia should be treated immediately with cessation of anesthesia and intravenous administration of dantrolene sodium. The recommended dose of dantrolene is 1 to 2.5 mg/kg of body weight given intravenously every 6 h for at least 24 to 48 h¾until oral dantrolene can be administered, if needed. Procainamide should also be administered to patients with malignant hyperthermia because of the likelihood of ventricular fibrillation in this syndrome. Dantrolene at similar doses is indicated in the neuroleptic malignant syndrome and in drug-induced hyperthermia and may even be useful in the hyperthermia of thyrotoxicosis. The neuroleptic malignant syndrome may also be treated with bromocriptine, levodopa, amantadine, or nifedipine or by induction of muscle paralysis with curare and pancuronium. Tricyclic antidepressant overdose may be treated with physostigmine.

FEVER AND HYPERTHERMIA 2

Approach to the Patient

History It is in the diagnosis of a febrile illness that the science and art of medicine come together. In no other clinical situation is a meticulous history more important. Painstaking attention must be paid to the chronology of symptoms in relation to the use of prescription drugs (including drugs or herbs taken without a physician's supervision) or treatments such as surgical or dental procedures. The exact nature of any prosthetic materials and/or implanted devices should be ascertained. A careful occupational history should include exposures to animals; toxic fumes; potential infectious agents; possible antigens; or other febrile or infected individuals in the home, workplace, or school. A history of the geographic areas in which the patient has lived and a travel history should include locations during military service. Information on unusual hobbies, dietary proclivities (such as raw or poorly cooked meat, raw fish, and unpasteurized milk or cheeses), and household pets should be elicited, as should that on sexual orientation and practices, including precautions taken or omitted. Attention should be directed to the use of tobacco, marijuana, intravenous drugs, or alcohol; trauma; animal bites; tick or other insect bites; and prior transfusions, immunizations, drug allergies, or hypersensitivities. A careful family history should include information on family members with tuberculosis, other febrile or infectious diseases, arthritis or collagen vascular disease, or unusual familial symptomatology such as deafness, urticaria, fevers and polyserositis, bone pain, or anemia. Ethnic origin may be critical. For example, blacks are more likely than persons in other groups to have hemoglobinopathies. Turks, Arabs, Armenians, and Sephardic Jews are especially likely to have familial Mediterranean fever.

Physical Examination A meticulous physical examination should be repeated on a regular basis. All the vital signs are relevant. The temperature may be taken orally or rectally, but the site used should be consistent. Axillary temperatures are notoriously unreliable. Particular attention should be paid to daily (or sometimes more frequent) physical examination, which should continue until the diagnosis is certain and the anticipated response has been achieved. Special attention should be paid to the skin, lymph nodes, eyes, nail beds, cardiovascular system, chest, abdomen, musculoskeletal system, and nervous system. Rectal examination is imperative. The penis, prostate, scrotum, and testes should be examined carefully and the foreskin, if present, retracted. Pelvic examination must be part of every complete physical examination of a woman, with a search for such causes of fever as pelvic inflammatory disease and tubo-ovarian abscess.

Laboratory Tests Few signs and symptoms in medicine have as many diagnostic possibilities as fever. If the history, epidemiologic situation, or physical examination suggests more than a simple viral illness or streptococcal pharyngitis, then laboratory testing is indicated. The tempo and complexity of the workup will depend on the pace of the illness, diagnostic considerations, and the immune status of the host. If findings are focal or if the history, epidemiologic setting, or physical examination suggests certain diagnoses, the laboratory examination can be focused. If fever is undifferentiated, the diagnostic nets must be cast farther, and certain guidelines are indicated, as follows.

CLINICAL PATHOLOGY The workup should include a complete blood count; a differential count should be performed manually or with an instrument sensitive to the identification of eosinophils, juvenile or band forms, toxic granulations, and Dohle bodies, the last three of which are suggestive of bacterial infection. Neutropenia may be present with some viral infections, particularly parvovirus B19 infection; drug reactions; systemic lupus erythematosus; typhoid; brucellosis; and infiltrative diseases of the bone marrow, including lymphoma, leukemia, tuberculosis, and histoplasmosis. Lymphocytosis may occur with typhoid, brucellosis, tuberculosis, and viral disease. Atypical lymphocytes are documented in many viral diseases, including infection with Epstein-Barr virus, cytomegalovirus, or HIV; dengue; rubella; varicella; measles; and viral hepatitis. This abnormality also occurs in serum sickness and toxoplasmosis. Monocytosis is a feature of typhoid, tuberculosis, brucellosis, and lymphoma. Eosinophilia may be associated with hypersensitivity drug reactions, Hodgkin's disease, adrenal insufficiency, and certain metazoan infections. If the febrile illness appears to be severe or is prolonged, the smear should be examined carefully for malarial or babesial pathogens (where appropriate) as well as for classic morphologic features, and the erythrocyte sedimentation rate should be determined. Urinalysis, with examination of urinary sediment, is indicated. It is axiomatic that any abnormal fluid accumulation (pleural, peritoneal, joint), even if previously sampled, merits reexamination in the presence of undiagnosed fever. Joint fluids should be examined for bacteria as well as crystals. Bone marrow biopsy (not simple aspiration) for histopathologic studies (as well as culture) is indicated when marrow infiltration by pathogens or tumor cells is possible. Stool should be inspected for occult blood; an inspection for fecal leukocytes, ova, or parasites also may be indicated.

CHEMISTRY Electrolyte, glucose, blood urea nitrogen, and creatinine levels should be measured. Liver function tests are usually indicated if efforts to identify the cause of fever do not point to the involvement of another organ. Additional assessments (e.g., measurement of creatinine phosphokinase or amylase) can be added as the workup progresses.

MICROBIOLOGY Smears and cultures of specimens from the throat, urethra, anus, cervix, and vagina should be assessed when there are no localizing findings or when findings suggest the involvement of the pelvis or the gastrointestinal tract. If respiratory tract infection is suspected, sputum evaluation (Gram's staining, staining for acid-fast bacilli, culture) is indicated. Cultures of blood, abnormal fluid collections, and urine are indicated when fever is thought to reflect more than uncomplicated viral illness. Cerebrospinal fluid should be examined and cultured if meningismus, severe headache, or a change in mental status is noted.

RADIOLOGY A chest x-ray is usually part of the evaluation for any significant febrile illness.

Outcome of Diagnostic Efforts In most cases of fever, either the patient recovers spontaneously or the history, physical examination, and initial screening laboratory studies lead to a diagnosis. When fever continues for 2 to 3 weeks, during which time repeat physical examinations and laboratory tests are unrevealing, the patient is provisionally diagnosed as having fever of unknown origin.