Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

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HIV INFECTION IN THE CRITICALLY ILL PATIENT

607

or soft tissue fluid collections, may be indicated. Imaging of

specific sites may include CT scan, ultrasonography, MRI,

or x-rays.

Septic patients with HIV infection and no obvious site of

infection require more generalized investigation. Urine cul-

ture for fungi and mycobacteria, blood cultures using the

lysis-centrifugation method for mycobacteria and fungi,

serum antigen for C. neoformans, sputum for acid-fast smear

and mycobacterial culture, and urine Histoplasma antigen

tests should be considered in patients with relevant exposure

histories. Patients with sepsis may have subtle CNS, pul-

monary, abdominal, soft tissue, or mucosal sources of infec-

tion. In these patients, CT scan of the head, abdomen, and

pelvis may be indicated. Lumbar puncture should be per-

formed in any HIV patient with unexplained sepsis or fever

with or without alteration in mental status or abnormal neu-

rologic findings. Cryptococcal meningitis and fungal and

mycobacterial infections of the CNS may be associated with

minimal symptoms and physical findings.

Biopsy of suspicious skin or mucosal lesions, lymph

nodes, spleen, liver, or bone marrow should be performed

expeditiously if results of other studies are unrevealing.

Special stains for microorganisms are necessary along with

traditional histologic examinations. Cultures from biopsy

specimens for many potential organisms may take 4–6 weeks

to yield results.

Treatment

Patients with sepsis accompanied by hypotension, altered

mental status, severe localized infection, or any organ system

dysfunction should receive immediate antimicrobial therapy

after appropriate cultures have been obtained. Empirical

antibiotic treatment should be directed at possible bacterial

pathogens; suspicion of fungal or mycobacterial dissemina-

tion should prompt initiation of appropriate targeted ther-

apy. The likelihood of bacterial infection is increased in

patients with either leukocytosis or neutropenia, those with

acute onset of chills and fever, those who have an identifiable

site of infection, and those who have higher CD4 lymphocyte

counts. Patients with very low CD4 lymphocyte counts are

susceptible to a wide variety of infections, including bacteria,

fungi, and mycobacteria. In such patients, antifungal and

antimycobacterial agents should be considered early; in addi-

tion, these antimicrobial regimens also should be considered

in any patient who is deteriorating clinically on antibacterial

therapy alone. Filgrastim (G-CSF) is indicated in patients

with significant neutropenia (<500–750 cells/μL).

Patients with disseminated tuberculosis can be treated

initially with regimens used for pulmonary tuberculosis (see

above). Treatment of MAC requires administration of a

macrolide such as clarithromycin (500 mg orally twice daily)

in conjunction with ethambutol (15 mg/kg per day orally)

with or without rifampin or rifabutin (600 or 300 mg/day,

respectively). If intravenous therapy is necessary, azithromycin

plus amikacin or ciprofloxacin should be considered.

Karakousis PC, Moore RD, Chaisson RE: Mycobacterium avium

complex in patients with HIV infection in the era of highly

active antiretroviral therapy. Lancet Infect Dis 2004;4:557–65.

[PMID: 15336223]

King MD et al: Emergence of community-acquired methicillin-

resistant Staphylococcus aureus USA 300 clone as the predomi-

nant cause of skin and soft-tissue infections. Ann Intern Med

2006;144:309–17. [PMID: 16520471]

Mrus JM, Braun L, Yi MS et al. Impact of HIV/AIDS on care and

outcomes of severe sepsis. Crit Care 2005;9:R623–30. [PMID:

16280060]

Proctor RA: Bacterial sepsis in patients with acquired immunode-

ficiency syndrome. Crit Care Med 2001;29:683–4. [PMID:

11379540]

Rosenberg AL et al: The importance of bacterial sepsis in intensive

care unit patients with acquired immunodeficiency syndrome:

Implications for future care in the age of increasing antiretrovi-

ral resistance. Crit Care Med 2001;29:548–56. [PMID: 11373418]



CNS Disorders In HIV-Infected Patients

HIV is a neurotropic virus; as a result, infection of the cen-

tral and peripheral nervous systems is likely to occur very

early in the disease course. However, severe CNS manifesta-

tions occur late in the course of HIV disease, when CD4

counts are very low. Neurologic disorders may result from

autoimmune phenomena (eg, vasculitis and demyelinating

inflammatory polyneuropathy), immunosuppression (eg,

opportunistic infections and CNS lymphoma), and direct

effects of HIV (eg, meningitis and dementia). In the ICU

patient with HIV disease, neurologic problems are the third

most common reason for admission. Severe CNS problems

leading to ICU admission include delirium and coma,

intracranial mass lesions from primary CNS lymphoma or

toxoplasmosis, meningitis (eg, bacterial, cryptococcal, tuber-

culous, aseptic, or viral), status epilepticus, and respiratory

failure owing to severe neuropathy or myopathy.

Focal CNS disorders include cerebral toxoplasmosis, pri-

mary CNS lymphoma (PCNS-L), and progressive multifo-

cal leukoencephalopathy (PML). Mass lesions can present

in a variety of ways, including symptomatic neurologic

deficits, altered mental status, or change in personality. In

conjunction with the clinical presentation, imaging studies

sometimes may be able to distinguish infection, malig-

nancy, or an inflammatory process. If a lumbar puncture

can be performed safely, CSF should be submitted for

cytology, Epstein-Barr virus (EBV) polymerase chain reac-

tion (PCR), and JC virus PCR, which may assist in the

diagnosis of PCNS-L and PML. Empirical therapy for tox-

oplasmosis should be initiated in critically ill patients with

focal ring-enhancing brain lesions pending results of serum

Toxoplasma titers. Patients with mass lesions and increased

intracranial pressure may require endotracheal intubation,

ventilatory support, corticosteroids to decrease cerebral

edema, antiseizure prophylaxis, and frequent neurologic

evaluation.

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CHAPTER 27

608

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Cryptococcal Meningitis in HIV-Infected

Patients

Meningitis caused by C. neoformans is unusual in immuno-

competent patients but may occur in the presence of

advanced immunosuppression caused by HIV. Patients often

present with fever and headache, sometimes in conjunction

with nonspecific neurologic findings, including weakness,

fatigue, dizziness, lack of alertness, visual changes, and

seizures. Importantly, HIV patients with cryptococcal

meningitis have little or no meningeal irritation, and

meningismus is rare. Thus a lumbar puncture is warranted in

the patient with advanced HIV disease and any clinical suspi-

cion of a CNS process. CSF may be completely normal or may

reveal slightly elevated protein, decreased glucose, and/or a

mild lymphocytic response (up to 100/μL). In contrast to

these mild abnormalities, India ink preparations are positive

in 40–70%; positive cultures are the “gold standard” of diag-

nosis. CSF cryptococcal antigen is 95–98% sensitive and spe-

cific. Opening pressure always should be measured because it

has important prognostic significance. For example, elevated

opening pressure of the cerebrospinal fluid (>250 mm H

correlates with high cryptococcal polysaccharide antigen,

poor clinical response, and decreased short-term survival.

With treatment, failure of CSF opening pressure to fall has

been associated with poor outcome. Patients with cryptococ-

cal meningitis should be treated with amphotericin B,

0.7–1 mg/kg per day intravenously, with flucytosine, 100 mg/kg

daily orally for 2 weeks, followed by fluconazole 400 mg/day

orally for 8–10 weeks, and then 200 mg/day as suppressive

therapy. Elevated opening pressure should be managed with

serial (daily) lumbar punctures to reduce pressure to less

than 200 mm H

O, or 50% of opening pressure.

Antinori A et al: Prevalence, associated factors, and prognostic

determinants of AIDS-related toxoplasmic encephalitis in the

era of advanced highly active antiretroviral therapy. Clin Infect

Dis 2004;39:1681–91. [PMID: 15578371]

Benson CA et al: Treating opportunistic infections among HIV-

exposed and infected children: Recommendations from the

CDC, the National Institutes of Health, and the Infectious

Diseases Society of America. MMWR Recomm Rep 2004;53:

1–112. [PMID: 15841069]

Graybill JR et al: Diagnosis and management of increased intracra-

nial pressure in patients with AIDS and cryptococcal meningi-

tis. Clin Infect Dis 2000;30:47–54. [PMID: 10619732]

Mamidi A, DeSimone JA, Pomerantz RJ: Central nervous system

infections in individuals with HIV-1 infection. J Neurovirol

2002;8:158–67. [PMID: 12053271]

Offiah CE, Turnbull IW: The imaging appearances of intracranial

CNS infections in adult HIV and AIDS patients. Clin Radiol

2006;61:393–401. [PMID: 16679111]

Saag MS et al: Practice guidelines for the management of crypto-

coccal disease. Infectious Diseases Society of America. Clin

Infect Dis 2000;30:710–8. [PMID: 10770733]

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609

0028

Dermatologic Problems

in the Intensive Care Unit

Kory J. Zipperstein, MD

The skin plays an important role in maintaining homeosta-

sis. Thermoregulation, containment of body fluids, and pro-

tection of internal organs and structures from environmental

insults are some of the vital functions performed by the skin.

The skin is readily available for examination, so inspection

often provides important clues to underlying diseases. This

chapter focuses on the following categories of cutaneous dis-

orders in the critically ill patient: common skin disorders,

drug eruptions, purpura, life-threatening dermatoses, and

cutaneous manifestations of infections.

COMMON SKIN DISORDERS

Contact dermatitis, miliaria (heat rash), and candidiasis are

common in the critically ill patient as well as in the general

population. These conditions, as well as graft-versus-host

disease, are discussed in this section.



Contact Dermatitis

ESSENTIALS OF DIAGNOSIS



Circumscribed vesiculobullous eruptions on a base of

erythema, confined to the area of the contact.



Linear or sharply angulated pattern suggesting external

contact.



Pruritus may be a prominent symptom.



History of exposure or contact in involved areas.

General Considerations

Contact dermatitis is an eczematous eruption caused by

allergens or irritants coming in contact with the skin. The

latter type is more common and results from exposure to

irritating substances. Allergic contact dermatitis is a delayed

hypersensitivity reaction that affects individuals previously

exposed to the antigen. Any substance applied to the skin,

including tape, cleansing agents, and topical medications,

may be the offender. Even some topical steroids contain sen-

sitizing chemicals. An eruption that appears to improve but

subsequently becomes worse may be due to a contact der-

matitis from an applied medication. Occasionally, Candida

or bacteria are a secondary invader.

Clinical Features

The morphology and distribution of the lesions, as well as

the history of exposure, are diagnostic. Clinically, a circum-

scribed vesiculobullous eruption on a base of erythema, con-

fined to the area of the contact, is the hallmark of contact

dermatitis. Pruritus may be prominent. Contact dermatitis

often has a characteristic configuration—for example, linear

or sharply angulated patterns—that suggests that the erup-

tion is caused by external rather than internal stimuli.

Marked erythema, often with an eroded surface, suggests an

irritant contact dermatitis. Constant exposure to moisture,

urine, or fecal matter in areas such as the groin, perineum,

the backs of bedridden patients, and around a colostomy site

may produce such an eruption. The differential diagnosis of

contact dermatitis includes other eczematous eruptions,

impetigo, and candidiasis.

Treatment

The suspected irritant or allergen should be removed, and

cool tap water compresses can be applied to alleviate discom-

fort and remove crusts. Apply a high-potency topical steroid

such as fluocinonide cream twice daily to the affected area.

Eruptions on the face or intertriginous areas should be

treated with low- to medium-potency topical steroids.

Antihistamines may be administered to control itching. The

involved area should be observed for the development of sec-

ondary infection.

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610

Mark BJ, Slavin RG: Allergic contact dermatitis. Med Clin North

Am 2006;90:169–85. [PMID: 16310529]

Saary J et al: A systematic review of contact dermatitis treatment

and prevention. J Am Acad Dermatol 2005;53:845. [PMID:

16243136]

Scalf LA, Shenefelt PD: Contact dermatitis: Diagnosing and treat-

ing skin conditions in the elderly. Geriatrics 2007;62:14–9.

[PMID: 17547479]



Miliaria (Heat Rash)

ESSENTIALS OF DIAGNOSIS



Seen in bedridden patients with fever.



Miliaria crystallina: small, superficial, sweat-filled vesi-

cles without surrounding inflammation, giving the

appearance of clear dewdrops. The vesicles rupture

with the slightest frictional trauma.



Miliaria rubra (prickly heat): discrete, pruritic, erythe-

matous papules and vesiculopustules, especially on the

back, the antecubital and popliteal fossae, the chest,

and other regions prone to sweating and occlusion.

General Considerations

Miliaria is a common disorder characterized by retention of

sweat. It is seen in individuals exposed to warm or humid cli-

mates and in bedridden patients with fever and increased sweat-

ing. Increased moisture causes swelling of the stratum corneum,

with resulting occlusion of eccrine sweat ducts and pores and

eventual disruption of the sweat gland or duct. Leakage of sweat

into the surrounding tissue produces the lesions of miliaria.

Clinical Features

Two forms of miliaria may be seen in the febrile patient. In

miliaria crystallina, the sweat duct is occluded at the skin sur-

face, producing small and very superficial sweat-filled vesi-

cles without surrounding inflammation, giving the

appearance of clear dewdrops. The vesicles rupture with the

slightest frictional trauma. The eruption is asymptomatic

and self-limited.

A second form, miliaria rubra (prickly heat), is due to occlu-

sion of the intraepidermal portion of the sweat duct. The erup-

tion consists of discrete, pruritic, erythematous papules and

vesiculopustules. The erythema may be broad and diffuse

depending on the degree of inflammation. Areas such as the

backs of patients lying in bed, the antecubital and popliteal fos-

sae, the chest, and other regions prone to sweating and occlu-

sions are the sites of predilection; the palms and soles are spared.

Miliaria crystallina is clinically distinct. However, miliaria

rubra may resemble folliculitis, which usually can be

distinguished by its follicular papulopustules with penetrat-

ing hair shafts. A Gram stain or culture of the pustular con-

tents may help in distinguishing the two conditions.

Treatment

The patient should be kept cool and dry. The pruritus asso-

ciated with miliaria rubra may respond to oral antihista-

mines, such as hydroxyzine; medium-potency topical

steroids, such as triamcinolone acetonide 0.1%; or a topical

antipruritic lotion containing phenol and menthol (eg,

Sarna) or pramoxine hydrochloride.

Haas N, Martens F, Henz BM: Miliaria crystallina in an intensive

care setting. Clin Exp Dermatol 2004;29:32–4. [PMID:

14723716]



Candidiasis (Moniliasis)

ESSENTIALS OF DIAGNOSIS



Oral candidiasis: white curdlike plaques on the oral

mucosa, including the tongue, with a red, macerated

base and painful erosions.



Easily ruptured pustules commonly found in the groin,

between the buttocks, under overhanging abdominal

folds or pendulous breasts, and in the umbilicus. If rup-

tured, a bright red base with a fringe of moist scale at

the border and satellite pustules. Intense pruritus, irri-

tation, and burning are common.



In systemic candidiasis, may have acneiform pustules or

petechiae that may progress to necrotic ulcerative

lesions on the trunk and extremities.

General Considerations

The yeastlike fungus Candida albicans may cause infections

limited to the skin and mucous membranes in addition to

severe disseminated disease. Superficial candidiasis affects

warm, moist areas such as the vagina (vulvovaginitis), the

mouth (thrush), the uncircumcised penis (balanitis), the

intertriginous areas, and sites around fistulas and artificial

openings. Other predisposing factors include endocrine

abnormalities (especially diabetes), malignancies, and

immune-impaired states. Broad-spectrum antibiotics, preg-

nancy, incontinence, and skin maceration also may allow the

yeast to become pathogenic.

Clinical Features

A. Symptoms and Signs—Oral candidiasis, or thrush, com-

monly consists of white curdlike plaques on the oral mucosa,

including the tongue. The base of these plaques is red and

macerated, and painful erosions also may be seen.

Frequently, the infection will spread to the angles of the

mouth (ie, angular cheilitis or perlèche), resulting in macer-

ation and fissuring of the oral commissures.

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DERMATOLOGIC PROBLEMS IN THE INTENSIVE CARE UNIT

611

Candidiasis also tends to develop in intertriginous

regions, including the groin, between the buttocks, under

overhanging abdominal folds or pendulous breasts, and in

the umbilicus. In these areas, pustules form but are easily

ruptured by the friction of opposing surfaces, leaving a

bright red base with a fringe of moist scale at the border.

Coalescence of individual lesions results in spreading of the

erythema with satellite pustules at the edges. Intense pruri-

tus, irritation, and burning are common.

Oral candidiasis may spread to the esophagus or lungs.

Candidal proctitis may develop with or without concurrent

perianal infection. Systemic candidiasis is an opportunistic

infection that tends to occur in patients with AIDS (rarely),

hematologic malignancies, indwelling intravenous catheters,

or malnutrition. Widespread dissemination may produce

fever and proximal muscle tenderness, but any organ may be

affected. Skin findings occur in about 10% of patients with

candidal sepsis and consist of acneiform pustules or

petechiae that may progress to necrotic ulcerative lesions on

the trunk and extremities. Ophthalmoscopy may be helpful

to look for candidal endophthalmitis. Concurrent superficial

candidiasis may not be present and, by itself, is not helpful in

establishing the diagnosis of systemic infection.

Superficial candidiasis is usually distinctive, but it may be

confused with eczematous eruptions, dermatophytosis, and

pus-producing bacterial skin infections (ie, pyodermas).

Systemic candidiasis must be distinguished from other

septicemias.

B. Laboratory Findings—For superficial candidiasis, a

potassium hydroxide preparation demonstrating budding

yeast or spores and pseudohyphae establishes the diagnosis.

Culture on Sabouraud’s agar shows growth in 3–4 days. The

diagnosis of systemic candidiasis is made by discovery of

microorganisms in cutaneous biopsy or a positive culture

from fluids (eg, blood or cerebrospinal fluid) or tissues nor-

mally sterile for candida in a patient in whom clinical find-

ings are compatible.

Treatment

A. Superficial Candidiasis—Moist areas should be kept

clean and dry. If the skin is weeping, a wet compress should

be applied for 10–20 minutes twice daily. Topical anticandi-

dal creams (eg, clotrimazole) applied twice daily are effective.

Adding a low-potency topical steroid to the anticandidal

agent may reduce the inflammatory component and speed

healing. Creams should be rubbed into the area gently but

thoroughly. This should be followed with an anticandidal

powder (eg, miconazole).

The patient should be evaluated for predisposing factors

such as diabetes, fecal and urinary incontinence, and

immunosuppression.

B. Systemic Candidiasis—Systemic candidiasis requires

more aggressive therapy with systemic agents such as ampho-

tericin B, fluconazole, itraconazole, or an echinocandin.

Mays SR, Bogle MA, Bodey GP: Cutaneous fungal infections in the

oncology patient: Recognition and management. Am J Clin

Dermatol 2006;7:31–43. [PMID: 16489841]

Sobel JD, Vazquez J: Candidiasis in the intensive care unit. Semin

Respir Crit Care Med 2003;24:99–112. [PMID: 16088529]



Graft-Versus-Host Disease

ESSENTIALS OF DIAGNOSIS



Prior allogeneic transplant containing immunologically

competent cells, particularly bone marrow.



Acute (days to weeks after transplant): pruritic macular

and papular erythema, frequently progressing to a gen-

eralized erythroderma with bullae in severe cases.



Chronic (50–100 days after transplant): widespread

scaly plaques and desquamation. Cicatricial alopecia

and dystrophic nails. In severe forms, sclerodermatous

changes supervene.

General Considerations

Graft-versus-host disease occurs when tissues containing

immunologically competent cells (eg, blood products, bone

marrow, and solid organs) are introduced into an antigeni-

cally foreign person who is incapable of mounting an effec-

tive response to destroy the transplanted cells. It is the chief

complication of allogeneic transplantation. Two forms are

recognized: an acute form that can occur within days or as

late as 1–2 months after transplantation and a chronic form

that typically presents from 50–100 days or more after trans-

plantation. Both forms are associated with significant mor-

bidity and a high mortality rate.

Clinical Features

A. Symptoms and Signs—In acute graft-versus-host dis-

ease, the skin is the most commonly affected organ. The

cutaneous eruption is characterized by a pruritic macular

and papular erythema, often on the palms, soles, ears, and

upper trunk, frequently progressing to a generalized erythro-

derma. In severe cases, bullae may develop, resembling the

lesions of toxic epidermal necrolysis. The intestines, liver,

and immune system are the other principally involved organs

in acute graft-versus-host disease, with manifestations of

diarrhea, hepatitis, and delayed immunologic recovery usu-

ally appearing after the skin eruption. The incidence of acute

graft-versus-host disease ranges from 10–80%.

Chronic graft-versus-host disease may occur with or

without preceding acute disease. However, any manifestation

of acute graft-versus-host disease increases the chance of

developing the chronic form. The incidence ranges from

30–60%. Cutaneous abnormalities occur in about 80% of



CHAPTER 28

612

patients with chronic graft-versus-host disease and usually

resemble lichen planus, with widespread scaly plaques and

desquamation. Destruction of skin appendages leads to cica-

tricial alopecia and dystrophic nails. In severe forms, sclero-

dermatous changes supervene. This may remain localized

but more often is generalized, producing induration, dyspig-

mentation, atrophy, telangiectases, and chronic skin ulcers.

Vitiligo also may occur. Other target organs include the

mucosal surfaces, the eyes, the hematopoietic and immune

systems, the liver, and the lungs.

B. Laboratory Findings—Skin biopsy may be useful for

confirming the diagnosis and grading the severity of acute

cutaneous graft-versus-host disease but does not help in dif-

ferentiating acute graft-versus-host disease from drug erup-

tions. Laboratory studies are not specific but are important

for monitoring other organ system involvement, the severity

of illness, and the response to treatment. Key values are total

bilirubin and stool output, which, when evaluated with the

extent of rash and stage of disease, are prognostic for early

acute graft-versus-host disease. Circulating autoantibodies

and elevated immunoglobulins may be present in chronic

graft-versus-host disease.

Differential Diagnosis

The skin abnormalities in acute graft-versus-host disease may

be confused with toxic epidermal necrolysis, drug-induced

eruptions, infectious exanthems, and other causes of palmar

erythema—including cirrhosis, pregnancy, and other hypere-

strogen states—and chemotherapy-related acral erythema. Of

these, drug eruptions may be the most difficult to exclude.

The skin in chronic graft-versus-host disease may have the

appearance of collagen-vascular diseases such as scleroderma,

lupus erythematosus, and dermatomyositis. The diagnosis is

suspected when a characteristic skin eruption occurs in the

presence of typical involvement in other organs.

Treatment

Over the past several years, major efforts have been focused

on prophylaxis against graft-versus-host disease using corti-

costeroids, cyclosporine, tacrolimus, mycophenolate mofetil,

and methotrexate. Posttransfusion graft-versus-host disease

can be prevented by irradiating blood products prior to

transfusion. The immunosuppressive agents used for pre-

venting graft-versus-host disease are also useful in treating

established acute disease. Antithymocyte globulins (ATGs),

monoclonal antibodies such as anti-interleukin 2 receptor

(anti-IL2R), extracorporeal photopheresis, and psoralen

with ultraviolet A (PUVA) may be useful in refractory cases.

Patients with localized chronic graft-versus-host disease

do well without intervention. In generalized chronic dis-

ease, immunosuppressive agents are the mainstays of treat-

ment. In addition, thalidomide, etretinate, extracorporeal

photopheresis, PUVA, and hydroxychloroquine are some-

times used.

Bolanos-Meade J et al : Acute graft-versus-host disease. Clin Adv

Hematol Oncol 2004;2:672–82. [PMID: 16163254]

Gilman AL, Serody J: Diagnosis and treatment of chronic graft-

versus-host disease. Semin Hematol 2006;43:70–80. [PMID:

16412791]

Hymes SR et al: Cutaneous manifestations of chronic graft-versus-

host disease. Biol Blood Marrow Transplant 2006;12:1101–13.

[PMID: 17085303]

Marra D et al: Tissue eosinophils and the perils of using skin

biopsy specimens to distinguish between drug hypersensitivity

and cutaneous graft-versus-host disease. J Am Acad Dermatol

2004;51:543–6. [PMID: 15389188]

Penas PF, Fernandez-Herrera J, Garcia-Diez A: Dermatologic treat-

ment of cutaneous graft versus host disease. Am J Clin

Dermatol 2004;5:403–16. [PMID: 15663337]

Vargas-Diez E et al: Life-threatening graft-vs-host disease. Clin

Dermatol 2005;23:285–300. [PMID: 15896544]

DRUG REACTIONS

A drug reaction is defined as any adverse response temporally

related to the administration of a drug. Unwanted drug reac-

tions have been estimated to occur in 15–30% of hospitalized

patients. Cutaneous eruptions are among the most common

adverse reactions to drugs, affecting 2–3% of hospitalized

patients. Patients receiving many different drugs, such as the

critically ill, are more likely to develop a drug eruption. The

cutaneous manifestations vary in severity from mild and

transient to the occasional development of severe systemic

disease and even death, and often mimic other dermatoses,

both clinically and histologically. In this section, drug erup-

tions with distinctive morphologic characteristics will be dis-

cussed, with emphasis on some common or life-threatening

conditions encountered in critically ill patients. Special

forms of drug reactions are also discussed in the sections on

contact dermatitis, vasculitis, anticoagulant necrosis, and

exfoliative erythroderma.



Morbilliform, Urticarial, & Bullous Drug

Eruptions

ESSENTIALS OF DIAGNOSIS



Exposure to drugs commonly associated with drug

eruptions, especially antibiotics, anticonvulsants, and

blood products—but may be due to any medication.



Onset of rash temporally related to drug administration,

most often 5–10 days after exposure to a new drug or

1–2 days as a reaction to a drug to which the patient

has been previously sensitized.



Eruptions are usually symmetric and widespread,

appear suddenly, and are not associated with systemic

symptoms other than pruritus and mild fever.



Improvement with cessation of drug supports diagnosis.

General Considerations

Adverse reactions that involve immune mechanisms, such as

IgE-mediated urticaria and anaphylaxis, and cell-mediated con-

tact reactions are true drug allergies. Reactions involving sus-

pected immune mechanisms of unknown or mixed

pathogenesis include the erythematous maculopapular or mor-

billiform rashes, bullous eruptions, erythema multiforme and

Stevens-Johnson syndrome, and exfoliative erythrodermas.

Nonimmune mechanisms and idiosyncratic reactions may lead

to skin abnormalities via activation of effector pathways,

direct toxicity, drug interactions, and overdosage. Drug-

induced urticaria can be produced by several mechanisms:

IgE-mediated anaphylactic hypersensitivity, immune

complex–induced urticaria associated with serum sickness–like

reactions (eg, urticaria, fever, hematuria, and arthralgias), non-

immunologic release of mast cell mediators, and direct stimula-

tion of the complement cascade. Unfortunately, the pathogenic

mechanisms in the majority of drug eruptions remain unknown.

Clinical Features

A. History of Medications—When a drug eruption is sus-

pected, it is important to document each medication cur-

rently being given or recently discontinued, the duration of

its use, and the timing of drug exposure in relation to onset

of the rash. As a rule, a recently started medication is more

apt to be responsible for a drug eruption. Rarely will a med-

ication that has been taken regularly for months to years

stimulate the immune system to produce an eruption. It typ-

ically takes 5–10 days following exposure to a new drug—or

1–2 days after previous sensitization—for a drug eruption to

appear. However, the rash may appear suddenly, as seen in

urticaria and anaphylaxis. Prior history of an adverse reac-

tion is the only clinically helpful risk factor.

B. Symptoms and Signs—The morphology of the rash and

the reported frequency of adverse cutaneous reactions to a

given drug may assist in identifying the offending agent.

Some drugs are rarely associated with skin eruptions

(Table 28–1). In the ICU setting, the most frequently impli-

cated medications are antibiotics (eg, ampicillin, semisyn-

thetic penicillins, and trimethoprim-sulfamethoxazole),

anticonvulsants, and blood products. Certain drugs are more

commonly associated with specific morphologic patterns,

thus helping to identify the causative agent when multiple

drug exposures have occurred (Table 28–2).

Morbilliform eruptions, or toxic erythemas, are the most

common type of drug-induced rashes. These eruptions are

usually symmetric, widespread, and consist of erythematous

macules or papules that often become confluent. The rash

typically begins on the trunk or in dependent areas; involve-

ment of the palms and soles is variable. Pruritus and mild

fever may accompany the reaction. Signs and symptoms usu-

ally regress within a few days after treatment is stopped.

Exceptionally, the eruption fades despite continued intake of

the drug.

Urticaria represents the second most common type of

drug eruption. Urticaria is a vascular reaction of the skin

characterized by wheals, which are pinkish, edematous, pru-

ritic lesions that vary in size and shape. Individual lesions are

transient, rarely lasting longer than 24 hours. Angioedema

refers to urticarial swelling of deep dermal and subcutaneous

tissues. Angioedema may involve the mucous membranes

and may be life-threatening. Urticaria may occur alone or in

conjunction with angioedema or anaphylaxis. The reaction is

usually self-limited, lasting a few days to a few weeks.

Blisters may accompany a variety of drug-induced erup-

tions, including fixed-drug eruptions, erythema multiforme,

Stevens-Johnson syndrome, toxic epidermal necrolysis, vas-

culitis, and anticoagulant necrosis. Some drugs can produce

blistering eruptions that are indistinguishable from primary

bullous dermatoses such as bullous pemphigoid and por-

phyria cutanea tarda. Coma bullae—blisters over pressure

areas—are seen in patients in coma from various causes,

including narcotics, barbiturates, and carbon monoxide poi-

soning. Some bullous drug eruptions do not fit into any of

these diagnostic classes.

C. Laboratory Findings—Laboratory tests are rarely helpful

in diagnosis. Morbilliform reactions are occasionally associ-

ated with eosinophilia, antinuclear antibody titers are posi-

tive in drug-induced lupus, and there may be evidence of

liver, kidney, and hematologic abnormalities in the pheny-

toin hypersensitivity syndrome (see next). Skin biopsy find-

ings are usually nonspecific. Tissue eosinophils may help to

differentiate drug eruptions from the dermatoses they

mimic. However, a few specific eruptions, including coma

bullae, fixed drug eruptions, erythema multiforme, toxic epi-

dermal necrolysis, and vasculitis, may show distinctive

histopathologic changes.

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613

Acetaminophen Isosorbide dinitrate

Aminophylline Laxatives

Antacid Lidocaine

Atropine Meperidine

Chloral hydrate Morphine

Chloramphenicol Multivitamins

Chlorpromazine Nitroglycerin

Dexamethasone Potassium iodide

Digoxin Prednisolone

Diphenhydramine Prednisone

Ferrous sulfate Promethazine

Flurazepam Propranolol

Folic acid Spironolactone

Hydrochlorothiazide Tetracycline

Hydroxyzine Theophylline

Insulin Thyroid hormones

Table 28–1. Drugs infrequently associated with adverse

skin reactions.



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614

Differential Diagnosis

Drug eruptions sometimes may be distinguished clinically

from the dermatoses they simulate by their sudden appear-

ance, symmetry, widespread distribution, and paucity of

associated systemic symptoms. Medication history and

improvement of the skin after the medication is stopped may

support the diagnosis.

The principal causes of morbilliform eruptions are drug

reactions and infections, especially viral exanthems.

Occasionally, a morbilliform drug rash may be confused with

a bacterial or rickettsial infection or collagen-vascular dis-

ease. Although the diagnosis of urticaria is usually apparent

because of the presence of evanescent wheals, the cause may

be difficult to discern. In addition to drugs, other common

causes of urticaria include food allergies, insect bites and

stings, and parasitic infections. If the urticarial lesions persist

longer than 24–36 hours, are tender, or have a purpuric com-

ponent, an urticarial vasculitis or serum sickness–like reac-

tion should be considered. Bullous drug eruptions may

resemble primary blistering dermatoses.

Treatment

The challenges to the clinician faced with a suspected drug

rash are to consider alternative explanations for the rash,

identify the offending drug, predict progression to serious or

life-threatening eruptions, and decide whether or not to

intervene.

A. Review Medications—When feasible, discontinue likely

causative agents and substitute chemically unrelated drugs. If

the medication is not essential, it may be stopped without

substitution. If the eruption is mild and relatively asympto-

matic and a particular drug is necessary, the drug may be

continued with cautious observation. However, urticaria,

erythema multiforme, vasculitis, or generalized erythema

(erythroderma) requires a search for alternative therapy.

B. General Measures—Treatment of drug eruptions is usu-

ally supportive and symptomatic because most eruptions

resolve within 2–5 days of stopping the offending drug.

Pruritus can be treated with oral antihistamines, such as

hydroxyzine, and a topical antipruritic lotion (eg, Sarna or

Pramosone). Treatment of severe urticarial reactions associ-

ated with angioedema or anaphylaxis consists of supportive

measures to maintain vital functions, epinephrine, antihista-

mines, and if all else fails, systemic corticosteroids. Blistering

eruptions may require decompression of large bullae, topical

antibiotics to denuded areas, and baths or wet compresses to

remove exudate or crusts. Drug-induced erythroderma may

require systemic corticosteroid therapy.

Callen JP: Newly recognized cutaneous drug eruptions. Dermatol

Clin 2007;25:255–61. [PMID: 17430762]

Greenberger PA: Drug allergy. J Allergy Clin Immunol

2006;117:S464–70. [PMID: 16455348]

Maculopapular eruptions Toxic epidermal necrolysis and

Oral hypoglycemic agents Stevens-Johnson syndrome

Thiazides Allopurinol

Enalapril Penicillins

Allopurinol Chlormezanine

Ampicillin Corticosteroids

Barbiturates Felbamate

Blood products Lamotrigine

Captopril Phenylbutazone

Gentamicin Valporic acid

Isoniazid Barbiturates

Phenytoin Carbamazepine

Sulfonamides Dapsone

Urticaria Phenytoin

Azole antifungals Sulfonamides

Cephalosporins Allopurinol

Proton pump inhibitors Purpura

Oral hypoglycemic agents

Thrombocytopenic

Aminoglycosides Carbamazepine

Barbiturates NSAIDs

Blood products

Vasculitis

Chlorpromazine Allopurinol

Hydralazine Barbiturates

Morphine Clindamycin

NSAIDs Furosemide

Penicillins Hydralazine

Phenytoin Penicillins

Radiographic contrast Phenytoin

Salicylates Salicylates

Sulfonamides Sulfonamides

Bullous eruptions

Miscellaneous

Barbiturates (coma bullae) Corticosteroids

Captopril Heparin

Heparin Warfarin

Pencillamine (pemphigus- Serum sickness

like) Antithymocyte globulin

Piroxicam Blood products

Phenytoin Beta-blockers

Sulfonamides Bupropion

Warfarin Minocycline

Erythema multiforme major Cephalosporins

Barbiturates Penicillins

NSAIDs Phenytoin

Penicillins Radiographic contrast

Phenytoin Sulfonamides

Rifampin Exfoliative erythroderma

Sulfonamides Barbiturates

Sulfonylureas Captopril

Carbamazepine

Cefoxitin

Cimetidine

Furosemide

Isoniazid

Phenytoin

Salicylates

Sulfonamides

Sulfonylureas

Table 28–2. Some morphologic patterns of drug

eruptions and commonly incriminated agents.

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DERMATOLOGIC PROBLEMS IN THE INTENSIVE CARE UNIT

615

Knowles SR, Shear NH: Recognition and management of severe

cutaneous drug reactions. Dermatol Clin 2007;25:245–53.

[PMID: 17430761]

Litt JZ: Drug Eruption Reference Manual, 10th ed. New York: Taylor

and Francis Group, 2004.



Erythema Multiforme

ESSENTIALS OF DIAGNOSIS



Erythema multiforme minor: prodrome of low-grade

fever, malaise, and upper respiratory symptoms, fol-

lowed by a nonspecific symmetric eruption of erythe-

matous macules, papules, and urticarial plaques.



Evolves into concentric rings of erythema with papular,

dusky, necrotic, or bullous centers (target lesions) over

1–2 days but also may be annular, polycyclic, or pur-

puric (multiforme).



Erythema multiforme with mucous membrane involve-

ment: high fever, headache, myalgias, and sore throat,

with more than one mucosal surface affected. Stomatitis

is conspicuous, beginning with vesicles on the lips,

tongue, and buccal mucosa. The vesicles rapidly evolve

into erosions and ulcers covered by hemorrhagic crusts.

General Considerations

Historically, erythema multiforme (EM), Stevens-Johnson

syndrome (SJS), and toxic epidermal necrolysis (TEN) were

lumped into the same diagnostic group erythema multi-

forme because they shared clinical and histologic features.

In recent years, a new classification scheme has been pro-

posed that distinguishes EM from SJS and TEN. This new

scheme is based on the observation that EM is triggered by

herpes simplex virus (HSV) infection in nearly all cases,

and SJS and TEN are adverse reactions to medications. EM

may present with a wide range of severity. Patients with

herpes simplex–associated EM (HAEM) and mild or no

mucosal involvement are classified as having EM minor.

Some patients with EM have more severe disease called

erythema multiforme with mucous membrane involvement

(also called EM major). EM major is caused by HSV in

about half the cases. There is a long list of other suspected

etiologic triggers that have been reported to trigger EM

major (Table 28-3), but only Mycoplasma pneumoniae and

radiation therapy have been reproducibly documented

associations.

EM minor is an acute, self-limited, recurrent inflamma-

tory disease of the skin or mucous membranes. EM major is

a severe and occasionally fatal form characterized by marked

oral and ocular mucosal involvement. Erythema multiforme

occurs in all age groups.

The pathogenesis of erythema multiforme is not fully

understood. According to one hypothesis, foreign antigens

are sequestered in the epithelium, leading to immune-

mediated apoptosis and epithelial damage. Polymerase chain

reaction (PCR) studies have demonstrated HSV DNA in the

skin lesions of many patients, even in patients with no obvi-

ous clinical association with HSV.

Clinical Features

A. Symptoms and Signs—Both EM minor and EM major

have similar skin lesions that characteristically appear 1–3

weeks after an HSV infection, although some episodes will

not be preceded by an obvious outbreak of herpes. In EM

minor, a prodrome of low-grade fever, malaise, and upper

respiratory symptoms may develop. In EM major, high fever,

headache, myalgias, and sore throat develop abruptly, often

associated with coryza, vomiting, diarrhea, and joint pains.

This is followed by a nonspecific symmetric eruption of ery-

thematous macules, papules, and urticarial plaques that

evolve into target lesions over a 1–2-day period. The classic

target or iris lesions are concentric rings of erythema with

papular, dusky, necrotic, or bullous centers. The lesions also

may be annular, polycyclic, or purpuric, demonstrating the

polymorphous (multiforme) nature of the eruption. The

extensor surfaces of the forearms, the face, the neck, the legs,

and the palms and soles are the most commonly involved

sites. The lesions appear in crops over 1–2 weeks and usually

resolve within 4 weeks, often with residual hyperpigmenta-

tion. The mucous membranes commonly reveal hemor-

rhagic crusting of the lips, painful oral erosions, and

purulent conjunctivitis.

In EM major, patients appear extremely ill and may have

tachycardia and tachypnea. More than one mucosal surface is

Drugs: See Table 28–2.

Infection

Herpes simplex

M. pneumoniae

Streptococcus

Yersinia

Tuberculosis

Histoplasmosis

Other conditions

Irradiation of tumors

Sarcoidosis

Pregnancy

Carcinomas

Leukemias

Collagen-vascular diseases

Inflammatory bowel disease

Idiopathic

Table 28–3. Common causes of erythema multiforme

major.



CHAPTER 28

616

affected. Stomatitis is conspicuous, beginning with vesicles

on the lips, tongue, and buccal mucosa. The vesicles evolve

rapidly into erosions and ulcers, covered by hemorrhagic

crusts. Bilateral catarrhal conjunctivitis, corneal ulcers, ero-

sive rhinitis, balanitis, and vulvovaginitis may develop. The

urethra, larynx, esophagus, trachea, and bronchi also may be

involved. Occasionally, the skin is spared, but in most

instances a vesiculobullous or erythematous eruption

appears on the face and distal extremities. Complications

include dehydration resulting from the ulcerative stomatitis

and blindness resulting from the corneal ulcers. In patients

with extensive disease, the mortality rate approaches 5%,

with deaths usually a result of sepsis.

B. Laboratory Findings—There are no specific laboratory

abnormalities. Leukocytosis, elevated erythrocyte sedi-

mentation rate, abnormal liver function tests, proteinuria,

and occasionally, hematuria are seen. The diagnosis is

based on characteristic clinical features with histopatho-

logic confirmation.

Underlying causative factors should be sought.

Evaluation of the patient with EM major should include the

following: complete blood count, erythrocyte sedimentation

rate, urinalysis, and a purified protein derivative (PPD) test.

Other tests may include cold agglutinin titers; chest, sinus,

and dental x-rays; hepatitis B serologic tests; cultures for bac-

teria, viruses, and fungi; and antinuclear antibody (ANA)

and rheumatoid factor determinations. Other tests for the

evaluation of diseases such as sarcoidosis or occult malignan-

cies also should be considered.

Differential Diagnosis

EM may resemble many other skin disorders, especially when

the classic target lesions are absent. The presence of target

lesions and characteristic histopathologic features helps to

distinguish EM from urticaria, viral exanthems, and vasculi-

tis, as well as from other mucocutaneous disorders such as

Reiter’s syndrome, Behçet’s syndrome, herpes gingivostom-

atitis, and Kawasaki’s disease. When blisters are present, EM

must be differentiated from bullous impetigo, bullous pem-

phigoid, pemphigus vulgaris, SJS, and TEN. The skin lesions

in SJS are characteristically purpuric macules and atypical

target lesions on the torso, face, and extremities, involving

less than 10% of the body surface

Treatment

If the specific cause is identified, treatment directed at that

cause is indicated. In most cases, therapy is supportive and

symptomatic. The patient should be monitored closely for

potential progression to secondary infection and sepsis. Cool

compresses, followed by the application of mupirocin oint-

ment, are useful for crusting and secondary infection.

For patients with compromised oral intake or extensive

erosions, proper attention must be paid to fluids, electrolytes,

and nutrition. An antiseptic mouthwash or hydrogen peroxide

should be used to keep the oral cavity clean. Viscous lidocaine

or a mixture of equal parts of diphenhydramine hydrochloride

and an oral antacid may alleviate pain on swallowing.

Eye involvement should be managed in consultation with

an ophthalmologist. Avoid sulfonamide-containing eye

drops because they can cause or exacerbate sulfonamide-

induced reactions. Topical or systemic steroids have not been

proved to prevent ocular sequelae or progression of cuta-

neous disease, and they may be harmful. However, some

authorities advocate systemic steroids early in the course of

the reaction (within 48 hours).

Auquier-Dunant A et al: Correlations between clinical patterns

and causes of erythema multiforme majus, Stevens-Johnson

syndrome, and toxic epidermal necrolysis: Results of an

International Prospective Study. Arch Dermatol

2002;138:1019–24. [PMID: 12164739]



Stevens-Johnson Syndrome & Toxic

Epidermal Necrolysis

ESSENTIALS OF DIAGNOSIS



Severe, acute blistering diseases associated with signif-

icant morbidity and mortality.



Often a recent history of drug ingestion.



Prodrome of fever, nausea, vomiting, diarrhea, malaise,

headache, cough, sore throat, myalgia, and arthralgia

1–14 days before the skin eruption.



SJS: widespread red or purpuric macules or flat atypical

target lesions with subepidermal detachment over less

than 10% of body surface at worse; mucosal erosions

frequent; no correlation between extent of mucosal

involvement and extent of epidermal detachment;

subepidermal separation of skin (Nikolsky’s sign).



TEN: variant of same process with epidermal detach-

ment greater than 30% of surface; features of SJS:

stomatitis, blotchy eruption with target lesions.

General Considerations

SJS and TEN are acute, severe blistering diseases of the skin

and mucous membranes caused by drugs or infections. The

mortality rate of SJS approaches 5%, but the mortality rate of

TEN may be closer to 30%. TEN is a rare, life-threatening

syndrome characterized by skin tenderness, erythema, and

exfoliation of the epidermis and mucous membranes remi-

niscent of a scald injury. The pathophysiology is not known,

but these disorders are believed to be immunologically medi-

ated. Most cases are drug-induced by such agents as

antiepileptics (eg, phenytoin, phenobarbital, and carba-

mazepine), sulfonamides, sulfones, nonsteroidal anti-

inflammatory drugs (especially pyrazolone derivatives),

allopurinol, and ampicillin. Identification of the causative

drug is often difficult because many patients are treated with