Diffuse rashes

Red man syndrome: Red man syndrome results from vancomycin administration. The incidence increases at higher doses (>1 g) and faster rates of infusion (<1 hour).^[1] The syndrome presents as an erythematous rash mainly of the face, neck, and upper chest. Pruritus often accompanies the rash, while hypotension and angioedema are less frequent. Onset usually appears 4 to 10 minutes following initiation of infusion, but can be delayed in patients on vancomycin for longer than 7 days.^[1] When infusions are less than 1 hour, the incidence of the syndrome is 5% to 13%.^[2] Healy and colleagues noted symptoms in 8 of 10 volunteers given 1 g over 1 hour, but in only 3 of 10 volunteers given the same dose over 2 hours.^[3] Mast cell and basophil degranulation releases histamines, leading to the syndrome’s signs and symptoms; thus, pretreatment with diphenhydramine will decrease the occurrence.^[2] Upon diagnosis, the vancomycin infusion should be stopped immediately and oral or intravenous IV diphenhydramine (50 mg) administered. Upon resolution of the rash and pruritus, the infusion can be restarted at a slower rate. If the rash and pruritus are accompanied by significant hypotension, give fluids liberally and monitor for signs of anaphylaxis. In this instance, an alternative antibiotic should be selected instead of restarting the infusion.

Urticaria: The prevalence of drug rashes among hospitalized patients is 3.6 per 1,000. Fifty-five percent of these rashes are the result of antibiotics, most commonly amoxicillin, trimethoprim-sulfamethoxazole, and ampicillin. The two most common presentations of drug rashes are urticarial and maculopapular.^[4]

The lesions of urticaria are smooth, erythematous, blanchable red papules that are often intensely pruritic. Regardless of the cause of urticaria, the lesions are established following the release of histamine and tryptase from basophils and mast cells.^[5] Urticaria can be divided into two categories based upon presentation. Acute urticaria is IgE mediated and presents less than an hour following exposure to antigen. It can be accompanied by angioedema, bronchospasm, and anaphylaxis. Chronic urticaria is T-cell mediated, occurs at least an hour after exposure, and lasts up to a week.^[5]

The prevalence of upper respiratory infection in acute urticaria is 28% to 62%. Other causes include aspirin, NSAIDs, vancomycin, quinolones, and radiocontrast, with antibiotics, radiocontrast, and NSAIDs also triggering chronic urticaria.^[5]

Treatment for urticaria is second-generation H₁ blockers and observation for 4 to 6 hours to monitor the resolution of the rash.^[5] If the rash is resolving appropriately, this observation can be continued, assuming that good communication and a designated physician for follow-up are available.

In 1993, Gadde et al. found that the result of penicillin skin testing performed on those with a stated history of penicillin allergy was positive in only 7.1%. Of note, 1.7% of patients with a negative history tested positive.^[6] Owing to their shared β-lactam ring, it is recommended practice to avoid the administration of cephalosporins to patients with a known penicillin allergy. Cephalosporins will cause a reaction in 4.4% of people with a positive skin allergy test to penicillin.^[4]

Blood transfusion also causes urticaria. Host mast cells degranulate in response to allergens in the donated plasma. Pretreatment with antihistamines is only indicated in those patients with a history of an allergic reaction to blood transfusion. Urticaria may be accompanied by pruritus and localized edema. In the event of a reaction, the blood transfusion should be stopped. If antihistamines lead to symptom resolution, the infusion can be restarted. Caution must be observed in patients with a known IgA deficiency as they are more prone to anaphylaxis from donor serum.

Blistering disorders: The spectrum of blistering skin disorders progresses in severity from erythema multiforme (EM) to Stevens–Johnson syndrome (SJS) to toxic epidermal necrolysis (TEN). The rash can result from drugs, graft-versus-host disease (GVHD), viral infection, usually herpes, or Mycoplasma pneumoniae.^[7] Hundreds of drugs have been linked to this disease spectrum. The most commonly implicated medications are sulfonamides, cephalosporins, imidazole, anticonvulsants, and NSAIDs. Differentiating between the types of blistering disorders is important because their treatment varies. In all of these cases, an early dermatology consult is recommended.

EM is a cell-mediated hypersensitivity that presents as acrally distributed, pleomorphic cutaneous eruptions, or target lesions. The major form of EM includes mucosal involvement, while the minor form does not. EM may also arise following radiation therapy in patients receiving phenytoin for seizure prophylaxis.^[8] Early treatment of EM minor with systemic corticosteroids may prevent progression to the major form and SJS.

Differentiating SJS from the major form of EM is controversial, and overlap is inevitable. Patients with SJS have a purpuric macular rash with more extensive blistering (up to 10%) of the trunk and oral mucosa. Ocular involvement is common. Systemic corticosteroid treatment is controversial. If initiated late (3 to 4 days after onset) it may assist in progression to TEN. TEN is a more significant form of SJS with over 30% blistering of the skin. Patients with TEN must be treated in a burn unit. Corticosteroids are contraindicated. Mortality is as high as 50%.^[8]

Jaundice: Postoperative jaundice has an incidence of less than 1%. The majority of cases resolve spontaneously causing few, if any, ill effects. However, its presence requires evaluation as it may be a marker of massive hemolysis, hepatic hypoperfusion, or impending multi-organ failure. Severe hepatocellular dysfunction causes jaundice in 2% of patients following trauma-induced shock.^[9]

Hereditary sources of jaundice can cause postoperative jaundice without the presence of severe hepatocellular dysfunction. Gilbert’s syndrome affects 3% to 10% of the population.^[10] Following surgical stress, it can cause an unconjugated hyperbilirubinemia with normal liver function tests and without overt hemolysis. Dubin–Johnson disorder is a rare autosomal recessive disorder of impaired hepatic storage and excretion of bromsulphalein, as well as impaired urinary excretion of coproporphyrin. It is most common in Israeli Jews of Iranian origin, 1:1,300.^[9]

G6PD deficiency is an X-linked recessive disorder of red blood cell metabolism in which oxidative stress from drugs (aspirin, acetaminophen, diphenhydramine, sulfa, and vitamin K), metabolic derangement, or infection can lead to intraoperative and postoperative hemolysis. Infection is the most common trigger – an acute fall in hemoglobin occurred in 20% of G6PD patients with pneumonia.^[11] Acidosis and hyperglycemia may also precipitate hemolysis in those with G6PD.^[12] In vitro, the inhaled anesthetics isoflurane and sevoflurane, inhibited G6PD enyzyme activity but its clinical significance is unknown.^[13] Postoperative care of patients with G6PD is centered on avoiding oxidative stress. Pain and anxiety should be treated with benzodiazepines, codeine, and fentanyl, all of which are proven to be safe with G6PD. Acute hemolysis from G6PD deficiency is usually self-limited, but in rare instances will require blood transfusion.

With the discontinuation of halothane as an inhaled agent, anesthetic-induced postoperative jaundice has reduced markedly. Halothane was thought to have caused an immune-mediated hepatitis in patients. Two of today’s commonly used agents, isoflurane and desflurane, are metabolized in the liver to a metabolite similar to that formed from halothane metabolism. The reduced incidence of hepatitis with these agents is due to their reduced hepatic metabolism (halothane 20% vs. isoflurane 0.2% and desflurane 0.01%). Patients with a history of a previous halothane anesthetic may be sensitized and prone to hepatitis from today’s anesthetics.^[14]

In patients with jaundice, liver function tests and blood counts should be ordered. If abnormal and/or no obvious cause for jaundice can be identified, a gastroenterology consult is recommended. If the cause is apparent and the patient is stable, continued supportive care is indicated.

Papulopustular rash: Since their approval by the FDA in 2003 for solid tumor chemotherapy, epidermal growth factor receptor inhibitors (EGFRIs) have gained in popularity. EGFRIs are less likely than their cytotoxic counterparts to cause myelosuppression, infection, nausea, vomiting, and diarrhea. They do, however, have an alarmingly high rate of papulopustular eruptions in a folliculocentric pattern. The incidence ranges from 44% in those treated with gefitinib, to 49% to 75% with erlotinib, and 90% with cetuximab and panitumumab. There is not an agreed treatment, but oral tetracyclines and mild to moderate topical steroids have been used. It is important to keep the skin clean and dry because the potential for staph superinfection is high.^[15]