Skin and collagen disorders

Acanthosis nigricans

Acanthosis nigricans refers to thickened, darkened, velvety skin that is usually a manifestation of an underlying medical condition. Based on the underlying medical condition, there are five types of acanthosis nigricans: familial, endocrine (diabetes mellitus), metabolic (obesity), chemical (drug related), and neoplastic. Skin manifestations of acanthosis nigricans are thought to be due to activation of insulin-like growth factor (IGF) receptors in the skin leading to proliferation of keratinocytes and fibroblasts, which produce the skin lesions, especially in skinfolds. The clinical significance of acanthosis nigricans lies mainly in determining its underlying cause and providing appropriate therapy. Some of the most common underlying conditions include insulin resistance and gastrointestinal (GI) cancers ( Figs. 24.1 and 24.2 ). Anesthetic implications of acanthosis nigricans are related to the underlying medical condition and associated therapies.

Atopic dermatitis

Atopic dermatitis, also known as atopic eczema, is the cutaneous manifestation of an atopic state (i.e., a type 1 hypersensitive allergic reaction), whose manifestations may include eczema, asthma, food allergies, or hay fever. Skin manifestations of atopic dermatitis vary according to age. Diagnostic criteria must include pruritus, typical morphology and distribution of skin lesions, onset in childhood, and chronicity. Atopic dermatitis is thought to be the result of interaction between genetic predisposition and exposure to allergens, including skin colonization with Staphylococcus aureus . Treatment is symptomatic with topical steroids and systemic antihistamines, plus lifestyle modifications to remove suspected allergens. Anesthetic implications consist of protecting the eczematous skin from trauma or infection, managing the systemic manifestations of the atopic state (asthma, hay fever, otitis media, sinusitis), and therapeutic adjustments based on the medications used in the treatment of atopic dermatitis (corticosteroids, antihistamines, and immunosuppressants).

Epidermolysis bullosa

Epidermolysis bullosa refers to a group of hereditary disorders, whose manifestations are apparent since birth or early childhood and are characterized by easy blistering of both the skin and mucous membranes, including the oropharynx and esophagus. The painful blisters are produced by minor friction or trauma and can lead to serious complications, including esophageal narrowing, skin cancer, digit amputation, or death. Epidermolysis bullosa has three different types that are divided into nonscarring (simplex and junctional) and scarring (dystrophic).

Epidermolysis bullosa simplex has an age of onset from birth to early childhood. It affects mainly the epidermis, has a relatively benign course, allows normal development of the affected person, but still may result in premature death.

Junctional epidermolysis bullosa has an age of onset at birth. Its lesions extend to the dermal-epidermal junction, producing a more severe form of the disease, and results in premature death in early childhood mostly due to sepsis but also due to metastatic squamous cell cancer. Features of junctional epidermolysis bullosa include early blistering since birth, absence of scar formation, and mucosal involvement of the GI, genitourinary, and respiratory tracts.

Dystrophic epidermolysis bullosa may appear at birth through recessive inheritance or during infancy through dominant inheritance. Its manifestations are varied in scope and severity and include dystrophic changes in the skin and mucous membranes, scarring and fusion of the digits, constriction of the oral aperture, esophageal stricture, dysplastic teeth, malnutrition, anemia, electrolyte derangements, hypoalbuminemia, chronic infection, general debilitation, renal dysfunction, and premature death in the second decade of life. Subtypes of dystrophic epidermolysis bullosa include epidermolysis bullosa pruriginosa and albopapuloid epidermolysis bullosa.

Other types of epidermolysis bullosa include epidermolysis bullosa acquisita and acral peeling. Systemic diseases that can be associated with epidermolysis bullosa include porphyria cutanea tarda, amyloidosis, multiple myeloma, diabetes mellitus, and hypercoagulable states. Treatment of epidermolysis bullosa includes symptomatic relief, skin protection, treatment of secondary infection, support of organ function, corticosteroids, intravenous granulocyte colony-stimulating factor (G-CSF), and transplanting skin derived from genetically modified stem cells.

Anesthetic implications of epidermolysis bullosa are related to the primary disease process affecting the skin and mucous membranes, the associated systemic complications, and ongoing therapies.

Throughout the perioperative period, protection of the skin and mucous membranes from even minor trauma is crucial. Blood pressure cuffs should be padded with a loose cotton dressing. Electrocardiogram (ECG) electrodes should have the adhesive portion removed and be held in place using petroleum jelly gauze. A nonadhesive pulse oximetry sensor should be used. Intravenous and intraarterial catheters should be either sutured or held in place with gauze wraps rather than tape. A soft foam, sheepskin, or gel pad should be placed under the patient. Linen creases should be removed. Anesthetic face mask should be gently applied against the face. Lubrication of the face and mask with cortisol ointment or another lubricant can be helpful.

Upper airway instrumentation should be minimized because the squamous epithelium lining the oropharynx and esophagus is very susceptible to trauma, bullae formation, and extensive hemorrhage. Hemorrhage from ruptured oral bullae can be treated by topical application of epinephrine-soaked gauze. In epidermolysis bullosa dystrophica, endotracheal intubation has not been associated with laryngeal or tracheal complications due to greater resistance of laryngotracheal columnar epithelium in comparison with oropharyngeal squamous epithelium. Still, generous lubrication of the laryngoscope blade with cortisol ointment or petroleum jelly and selection of a smaller-than-usual endotracheal tube are recommended. Video laryngoscopy intubation is recommended in cases of small mouth opening due to chronic scarring.

After intubation, the tube must be positioned so that it does not exert pressure at the corners of the mouth and should be immobilized with soft cloth bandages and not taped to the skin. Oropharyngeal suctioning should be avoided as it can lead to life-threatening bulla formation. Aspiration precautions should be implemented in the presence of esophageal stricture.

Epidermolysis bullosa is associated with increased occurrence of porphyria cutanea tarda, which is the type of porphyria that does not precipitate attacks of acute porphyria. Therefore commonly used anesthetic agents, including volatile anesthetics, can be safely used. Skeletal muscle dystrophy of epidermolysis bullosa dystrophica is not associated with excessive hyperkalemic response to succinylcholine. Regional anesthesia (spinal, epidural, brachial plexus block) is an acceptable technique in these patients. Epidermolysis bullosa patients who are on long-term therapy with corticosteroids should receive supplemental corticosteroids therapy to compensate for the needs of the perioperative surgical stress.

Pemphigus

Pemphigus refers to autoimmune vesiculobullous lesions that involve the skin and mucous membranes. Pemphigus is caused by autoantibodies to adherence molecules in the skin called desmogleins, which results in frictional bulla formation in the skin and mucous membranes, leading to fluid and protein loss through the skin and increased risk of infection. The protein loss through the skin is compounded by decreased food intake by mouth due to painful oropharyngeal lesions, which are present in 50% of cases ( Fig. 24.3 ). There are a dozen subtypes of pemphigus, including a drug-induced form. Pemphigus vulgaris is the most common and most significant form of pemphigus because of its high incidence of oropharyngeal lesions. Paraneoplastic pemphigus is a complication of many forms of cancer, including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), thymoma, spindle cell tumors, and Waldenström macroglobulinemia.

Untreated pemphigus can be fatal due to secondary infection and hypoproteinemia. Immunosuppression therapy is the mainstay of treatment, in conjunction with symptomatic and supportive therapy. High-dose corticosteroid therapy is the first line of treatment and has decreased the associated mortality rates from 70% to 5%. Other immunosuppressive therapy includes mycophenolate mofetil, azathioprine, methotrexate, and cyclophosphamide. Resistant disease may respond well to rituximab, intravenous immunoglobulin (IVIG), or plasmapheresis.

Anesthetic considerations are similar to those of epidermolysis bullosa. Preoperative evaluation must include assessment for dehydration, electrolyte derangements, and current immunosuppression therapy. Supplemental stress-dose corticosteroids are often required. Airway management may be difficult and can result in bulla formation, airway obstruction, and bleeding. Regional anesthesia is an acceptable alternative with meticulous sterile and antiseptic conditions, and avoidance of skin infiltration with a local anesthetic solution.

Mastocytosis

Mastocytosis refers to the accumulation of defective mast cells (mastocytes) and mast cell precursors in body tissues, resulting in cutaneous and systemic manifestations. Cutaneous manifestations of mastocytosis include urticaria pigmentosa, which commonly starts at childhood and improves with aging. Urticaria pigmentosa manifests as pruritic rash with dermatographia on the trunk and extremities.

Systemic mastocytosis spares the central nervous system (CNS) and ranges in severity from indolent to aggressive. It may progress to myelodysplastic disorders, myeloproliferative disorders, or mast cell leukemia, with mast cell proliferation in parenchymal organs, especially bone marrow, which is usually biopsied to categorize the type of systemic mastocytosis. Many of the symptoms of systemic mastocytosis are the result of mast cell degranulation, which can be triggered spontaneously or by nonimmune factors, including temperature changes, exercise, psychological stimuli, alcohol, spicy foods, and histamine-releasing drugs.

Mast cell degranulation results in the release of many cell products, including histamine, leukotrienes, prostaglandins, proteases (tryptases, hydrolases), and proteoglycans (heparin and chondroitin sulfate). Clinical symptoms of mast cell degranulation include pruritus, urticaria, flushing, nausea and vomiting, abdominal cramping, diarrhea, bronchospasm, tachycardia, and hypotension, which may be life threatening.

Medications used for the prevention and treatment of systemic mastocytosis include histamine (H ₁ and H ₂ ) receptor blockers, mast cell stabilizers, leukotriene receptor–binding inhibitors, proton pump inhibitors (PPIs), adrenergic β ₂ agonists, and corticosteroids. In most severe cases, cytoreductive therapy as well as allogenic stem cell transplantation have been used.

Anesthetic implications of mastocytosis include preoperative plan formulation through discussions with the patient, surgeon, and allergist; possible preoperative skin testing to determine the potential of commonly used anesthetic drugs to trigger mast cell degranulation; possible preoperative administration of H1- and H2-receptor antagonists and oral cromolyn sodium; and perioperative avoidance of triggers of mast cell degranulation, including temperature changes, histamine-releasing drugs, emotional distress, and unblocked surgical stress response.

Means for dealing with life-threatening anaphylactoid reactions should be made readily available. Measuring serum tryptase concentration, up to 3 hours after a suspected anaphylactoid reaction, may be useful for detecting mast cell degranulation, but it cannot differentiate between nonimmunologic mast cell degranulation or classic anaphylaxis. Similar precautions should be taken before procedures involving administration of radiocontrast, including pretreatment with H1- and H2-receptor antagonists and corticosteroids.

Urticaria

Urticaria refers to itchy, red, raised skin rash that is also known as hives. Urticaria is commonly categorized into acute, chronic, or physical. Acute urticaria can be encountered in 10% to 20% of the US population at one time or another. Most cases of acute urticaria have undefined cause and resolve within hours, either spontaneously or after administration of antihistamines.

Chronic urticaria is characterized by hives, localized edema, and intense pruritus that last less than 24 hours, whereas urticaria lasting longer than 24 hours raises the possibility of urticarial vasculitis. Chronic urticaria affects approximately twice as many women as men. It follows a remitting and relapsing course, with symptoms typically increasing at night. Its pathophysiology involves stimulation of mast cells and basophils either by nonimmunologic or by immunologic factors, which results in release of histamine and other vasoactive substances such as bradykinin, leading to localized vasodilation, edema, and pruritus. The trigger of chronic urticaria is often unidentified (idiopathic). Treatment aims at dealing with the underlying cause, when identified, and alleviation of symptoms through physical and chemical means, such as tepid showers, antihistamines (H1-receptor antagonists), terfenadine, systemic corticosteroids (≤21-day course), and omalizumab (Xolair), which is an antiimmunoglobulin E (anti-IgE) antibody that binds to IgE and lowers free IgE levels. Acute treatment of oropharyngeal edema includes topical spray with 2% ephedrine and, in severe cases, subcutaneous injection of epinephrine. Chronic urticaria patients should be advised to avoid angiotensin-converting enzyme (ACE) inhibitors, aspirin, and nonsteroidal antiinflammatory drugs (NSAIDs).

Physical urticaria is characterized by hives, itching, and possible angioedema in response to physical stimulation of the skin, such as by cold temperatures. Cold urticaria accounts for 3% to 5% of all physical urticarias and may be either familial or acquired in origin ( Table 24.1 ). It is characterized by development of urticaria and angioedema following exposure to cold air, rain, aquatic activities, snow, consumption of cold foods and beverages, and contact with cold objects. Severe cold urticaria may be life threatening due to laryngeal edema, bronchospasm, and hypotension. The diagnosis is based on skin stimulation at a temperature of 0°C to 4°C for a period of 1 to 5 minutes (cold stimulation test). In cold urticaria, cutaneous mast cells rather than intravascular basophils seem to be the target cells for degranulation, and serum IgE concentrations may be increased. Treatment consists of avoidance of known triggers and administration of systemic antihistamines and topical doxepin.

Urticarial vasculitis may be a presenting symptom of immunologic disorders such as systemic lupus erythematosus (SLE) and Sjögren syndrome.

Management of anesthesia in patients with urticaria focuses on avoiding any known triggers, including histamine-releasing drugs, cold intravenous fluids and drugs, cold ambient temperature, as well as the preoperative prophylactic administration of H1- and H2-receptor antagonists and corticosteroids.

Patients with cold urticaria undergoing cardiac surgery have been managed in three ways: off-pump coronary artery bypass grafting (in patients with suitable coronary anatomy), use of cardiopulmonary bypass under normothermic conditions with isothermic cardioplegia, and cardiopulmonary bypass with systemic hypothermia and cold cardioplegia. If the patient is exposed to cold, clinical manifestations of cold urticaria typically become apparent during rewarming rather than during cooling.

Erythema multiforme

Erythema multiforme is a recurrent disease of the skin and mucous membranes characterized by lesions ranging from edematous macules and papules to vesicles (≤0.5 cm) and bullae (>0.5 cm), which may ulcerate. Erythema multiforme attacks can be triggered by infection (especially herpes simplex, hemolytic streptococci), cancer, collagen vascular disease, and drug-induced hypersensitivity.

Stevens-Johnson syndrome and toxic epidermal necrolysis are severe manifestations of erythema multiforme that are associated with multisystem dysfunction, including fever, tachycardia, tachypnea, and skin sloughing ( Figs. 24.4 and 24.5 ). Skin surface area involved in SJS is typically less than 10% of total body surface area, in SJS/TEN overlap syndrome about 10% to 30%, and in TEN more than 30%. Mortality correlates with the surface area of skin involved and is less than 5% for SJS and up to 50% for TEN. Drug triggers of SJS and TEN include antibiotics, analgesics, and certain over-the-counter medications. Corticosteroids are used in the management of severe cases.

Anesthetic risks and precautions in patients with SJS or TEN are similar to those in patients with epidermolysis bullosa or pemphigus, including those related to airway management and tracheal intubation. Patients with moderate to severe SJS and TEN are best treated as a burn patient in a closed burn unit.

Scleroderma

Scleroderma (also known as systemic sclerosis) is an autoimmune disorder that involves the skin in addition to other body tissues and organs. It is characterized by three interrelated processes: (1) inflammation and autoimmunity, (2) vascular injury with eventual vascular obliteration, and (3) fibrosis and accumulation of excess matrix in many organs and tissues. The etiology is unclear, but triggers may include exposure to toxins, drugs, and microbial pathogens. Pathophysiology consists of irreversible vascular endothelial cell injury that produces capillary loss, vascular obliteration, leakage of serum proteins into the interstitial space, tissue edema, lymphatic obstruction, and ultimately tissue fibrosis and organ sclerosis. In some patients the disease evolves into CREST syndrome (calcinosis, Raynaud phenomenon, esophageal hypomotility, sclerodactyly, telangiectasia).

The prognosis is poor and is related to the extent of visceral involvement. No drugs or treatments have proved safe and effective in altering the underlying disease process. The typical age at onset is 20 to 40 years, and women are most often affected. Pregnancy accelerates the progression of scleroderma in about half of patients. The incidence of spontaneous abortion, premature labor, and perinatal mortality is high. Manifestations of scleroderma occur in the skin, musculoskeletal system, nervous system, cardiovascular system, lungs, kidneys, and GI tract.

Skin manifestations include thickening, edema, and decreased elasticity to the point of producing flexion contractures, especially in the fingers. Muscular manifestations include myopathy, proximal weakness, and increased plasma creatine kinase concentration. Skeletal manifestations include mild inflammatory arthritis and avascular necrosis of the femoral head. Neuronal manifestations include autonomic, peripheral, and cranial neuropathy, including trigeminal neuralgia. Ocular manifestations include keratoconjunctivitis sicca and corneal abrasions. Cardiovascular manifestations include sclerosis in the small coronary arteries and the conduction system, fibrosis in the cardiac muscle, systemic and pulmonary hypertension, cardiac dysrhythmias, cardiac conduction abnormalities, congestive heart failure, cor pulmonale, pericarditis, pericardial effusion, cardiac tamponade, intermittent vasospasm in the small arteries of the digits, Raynaud phenomenon, and oral or nasal telangiectasias.

Pulmonary manifestations are a major cause of morbidity and mortality and include diffuse interstitial pulmonary fibrosis, with resulting arterial hypoxemia and decreased pulmonary compliance. Renal manifestations include renal artery stenosis, decreased renal blood flow and systemic hypertension, and irreversible renal failure, which used to be the most common cause of death in patients with scleroderma until the introduction of ACE inhibitors, which helped control the hypertension and improve the associated impaired renal function and effectively treat the 10% to 15% of patients who develop a scleroderma renal crisis. It should be noted that corticosteroids can precipitate a renal crisis in patients with scleroderma.

GI manifestations include dryness of the oral mucosa (xerostomia), dysphagia, hypomotility of the lower esophagus, decreased lower esophageal sphincter (which increases the risk of reflux of gastric fluid into the esophagus), and hypomotility of small intestine, which can lead to pseudoobstruction as well as bacterial-induced malabsorption syndrome, including malabsorption of vitamin K, which might lead to coagulation disorders. Broad-spectrum antibiotics are effective in treating bacterial-induced malabsorption syndrome. Somatostatin analogues such as octreotide are effective in improving small intestine hypomotility, whereas prokinetic drugs such as metoclopramide are not.

The only treatment that has been shown to alter the course of scleroderma is the use of ACE inhibitors to treat scleroderma renal crisis. Other aspects of therapy are aimed at monitoring disease activity, alleviating symptoms, and managing complications such as pulmonary hypertension.

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum is a rare hereditary disorder that causes mineralization of elastic fibers in the skin, eyes, and blood vessels, with the latter leading to premature arteriosclerosis. Cutaneous manifestations are among the earliest clinical features and include the appearance of leathery cobblestone-like skin in skinfolds such as the axilla, neck creases, and groin. Ocular manifestations, which are often the basis of diagnosis, include retinal angioid streaks and vitreous hemorrhage, resulting in loss of visual acuity. Vascular manifestations include hypertension, ischemic heart disease, occlusive peripheral arterial disease of radial and ulnar arteries, which leads to loss of pulses, and degenerative changes of gastrointestinal arteries, which leads to gastrointestinal hemorrhage in about 10% of patients. Cardiac manifestations include endocardial calcification, including the valves, conduction abnormalities, dysrhythmias, and sudden death. Interestingly, some tissues rich in elastic fibers (e.g., lungs, aorta, palms, soles) are not affected by this disease process.

Ehlers-Danlos syndrome

Ehlers-Danlos syndrome refers to a group of inherited disorders that affect an estimated 1 in 5000 people and result in abnormal production of procollagen and collagen, which affects all body tissues, including the skin, musculoskeletal, vasculature, and smooth muscles. The most common symptoms are skin fragility and hyperelasticity, easy bruising and scarring, musculoskeletal discomfort, joint hypermobility, and susceptibility to osteoarthritis. There are about a dozen forms of Ehlers-Danlos syndrome, of which the vascular form is most markedly associated with increased risk of death due to increased risk of rupture of blood vessels, intestines, or uterus—structures that are rich with type III collagen. Arterial ruptures are notoriously difficult to repair due to marked fragility of the affected arterial wall. Pregnant Ehlers-Danlos syndrome patients are more prone to premature labor, rupture of uterus or large arteries, and excessive bleeding during delivery. Additional complications encountered in various forms of Ehlers-Danlos syndrome include tracheal dilation, spontaneous pneumothorax, mitral regurgitation, cardiac conduction abnormalities, and easy bruisability.

Marfan syndrome

Marfan syndrome is an autosomal dominant genetic disorder that is caused by a mutation in the fibrillin-1 (FBN1) gene, which leads to production of defective large glycoprotein fibrillin-1 proteins, which leads to defective connective tissues. It affects about 1 of 20,000 live births. Clinical manifestations include increased length of tubular bones, high-arched palate, pectus excavatum or carinatum, kyphoscoliosis, joint hyperextensibility, emphysema, and increased risk of spontaneous pneumothorax. Ocular manifestations occur in 50% of patients and include myopia, lens dislocation, and retinal detachment. Cardiovascular abnormalities are responsible for nearly all premature deaths in patients with Marfan syndrome. They include dilation, dissection or rupture of the thoracic aorta, mitral valve prolapse or regurgitation, bacterial endocarditis, and conduction abnormalities. For patients with dilated thoracic aorta, prophylactic β blocker therapy is recommended throughout life as it slows the rate of aortic dilation and decreases the risk of aortic dissection. Surgical replacement of the aortic valve and ascending aorta is indicated in Marfan syndrome when the diameter of the ascending aorta exceeds 4.5 cm and substantial aortic regurgitation is present. Pregnancy increases the risk of aortic dissection and rupture.

Inflammatory myopathies

Muscular dystrophy

Muscular dystrophy refers to a hereditary muscular disorder characterized by degeneration of muscle fibers due to breakdown of the dystrophin-glycoprotein protein complex, which binds myofibrils to the matrix and stabilizes the sarcolemma during contraction and relaxation ( Box 24.1 ). Loss of this protein complex leads to myonecrosis, fibrosis, and increased skeletal muscle membrane permeability. The main clinical manifestation is progressive symmetric skeletal muscle weakness and wasting, with no abnormalities in motor or sensory innervation or deep tendon reflexes. In order of decreasing frequency, muscular dystrophy types include pseudohypertrophic muscular dystrophy (Duchenne muscular dystrophy), limb-girdle, facioscapulohumeral muscular dystrophy (Landouzy-Dejerine dystrophy), and oculopharyngeal muscular dystrophy.

Inherited myopathies

Congenital myopathies are primarily muscle disorders that are characterized by structural abnormalities of muscle fibers and accumulation of abnormal proteins in the sarcoplasm ( Box 24.2 ). In contrast to congenital muscular dystrophies, these disorders do not show muscle necrosis or fibrosis on muscle biopsy. Some of these muscle disorders involve abnormal chloride, sodium, and calcium channel genes.