Red man syndrome

Red man syndrome is also called idiopathic erythroderma, is the most common anaphlylactoid reaction caused by the rapid infusion of the glycopeptide antibiotic vancomycin, but it is rarely life-threatening ¹. However, there are rare cases of life-threatening red man syndrome reactions ². Red man syndrome consists of red itchy rash to the face, neck, and upper torso which may also involve the extremities to a lesser degree after intravenous administration of vancomycin ³. Severe reactions include angioedema, hypotension, tachycardia, weakness, muscle spasms, and chest or back pain in addition to a rash of the face, neck, and upper torso. red man syndrome usually is mild and easily managed. Patients under 40 years of age are at greatest risk of severe red man syndrome reactions.

Red man syndrome is the most frequent adverse reaction to IV vancomycin. It occurs in 4% to 50% of infected patients treated with IV vancomycin. Red man syndrome is caused by vancomycin through the direct and non immune mediated release of histamine from mast cells and basophils ⁴. The amount of histamine release is generally related to the dose of vancomycin infused and the rate of infusion. red man syndrome is generally associated with more rapid infusion rates but can be seen following slower infusion rates and after several days of transfusion. Physicians using vancomycin should be aware of this known drug reaction, its prevention and treatment ⁵.

Red man syndrome key points

• Red man syndrome is a common adverse reaction seen with IV vancomycin use.
• The increased use of vancomycin will likely cause an increase in the number of red man syndrome reactions.
• Healthcare providers should be aware of this common reaction, its signs and symptoms, and how to manage cases when they occur.
• The rapid infusion of vancomycin should be avoided as this most often is a rate-related adverse drug reaction.
• Facilities should establish infusion protocols to limit infusion rates of vancomycin to 1 gram/hour or slower at 10 mg/min.

To help maximize patient care and patient safety it is important for the health care team is to:

• Recognize early if a patient needs pre-treatment for vancomycin – remember to ask the patient if they have any issues with Vancomycin infusion in the past
• Ensure that there is ongoing surveillance of patient response to treatment and an appropriate handover at shift change to minimize errors during ongoing transfusion
• If there is a question about the patient’s response to treatment, medication dose ask you supervisor or the physician or healthcare provider who prescribed the medication
• Pharmacists are often available to answer any questions about the medication and how it should be restarted
• Be familiar with the infusion protocols for the healthcare facility in which you work

Red man syndrome causes

Red man syndrome most frequently occurs with IV vancomycin but may rarely occur from oral or intraperitoneal vancomycin ⁶. Red man syndrome usually is related to a rapid infusion rate of vancomycin (1 gram in less than 1 hour). Current treatment recommendations are to administer vancomycin at a rate no faster than 1 gram/hour or 10 mg/min. red man syndrome most often begins 4 to 10 minutes from the start of the first dose of IV vancomycin ⁴. Red man syndrome may occur later during the infusion or begin shortly after dose completion. red man syndrome may occur from later doses as far out as 7 days ⁵.

Animal and several human studies indicate vancomycin activates the degranulation of mast cells and basophils increasing histamine release. The amount of histamine release has been correlated with the dose and the rate of vancomycin infusion. However, not all studies correlate elevated histamine levels with severe cases of red man syndrome and suggest histamine metabolism may also be delayed due to inhibition of histamine N-methyltransferase and diamine oxidase enzymes ².

The increased incidence of methicillin/oxacillin-resistant Staphylococcus aureus, multiresistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae, and metronidazole-resistant Clostridium difficile has led to an increase in the use of vancomycin. Vancomycin is commonly used to treat bacterial endocarditis, abscesses with cellulitis, postoperative wound infections, infected surgically placed devices, and central line-associated bloodstream infections ⁵.

There are case studies of red man syndrome occurring from other antibiotics such as rifampin, cefepime, teicoplanin, ciprofloxacin, and amphotericin B ⁷.

Red man syndrome symptoms

The clinical presentation of red man syndrome can vary, ranging from minor pruritus to occasionally life-threatening symptoms. Symptoms may occur as soon as 4 minutes after initiating the first dose until up to 7 days after dose completion. Patients with infections treated with IV vancomycin are at risk of developing red man syndrome. The signs and symptoms of red man syndrome include ⁵:

• Erythematous rash to the face, neck, and upper torso
• Pruritus
• Nausea, vomiting
• Hypotension
• Fever, chills
• Weakness, dizziness
• Chest or back pain, trunk muscle spasms
• Angioedema
• Tachycardia
• Rash on the extremities may occur but is typically less severe than the rash on the face, neck, and upper torso

Red man syndrome diagnosis

The diagnosis of red man syndrome is made clinically and does not depend on laboratory or other tests. Severe cases should be differentiated from IgE-mediated anaphylactic reactions ⁵.

Red man syndrome differential diagnosis

Red man syndrome should be differentiated from an anaphylactic reaction. Both red man syndrome and anaphylactic reactions will have similar findings of pruritus, erythematous rash, and tachycardia. Anaphylactic reactions involve stridor, angioedema, hives, and wheezing from bronchospasm. Anaphylactic reactions are IgE mediated and require prior exposure. red man syndrome is a rate-related anaphylactoid adverse reaction which most often occurs during the first exposure to IV vancomycin ⁸.

Red man syndrome treatment

When a patient develops red man syndrome, the IV antibiotic infusion should be stopped immediately. Supportive care should be provided. H1 (diphenhydramine) and H2 antihistamines (ranitidine or cimetidine) are used in the management of red man syndrome. Future doses of vancomycin may be given at decreased infusion rates in most cases ².

Mild cases (mild flushing and mild pruritus) can be managed with with antihistamines such as diphenhydramine 50 mg by mouth or intravenously and ranitidine 50 mg intravenously. Most episodes will resolve within 20 minutes, and the vancomycin may be restarted at 50% of the original rate. Future doses should be given at the new, slower rate, typically over 2 hours ⁹.

Moderate to severe cases (severe rash, hypotension, tachycardia, chest pain, back pain, muscle spasms, weakness, angioedema) should be managed according to severity. Patients with severe symptoms should be evaluated for anaphylaxis or other serious cause for their symptoms before assuming is red man syndrome. If after careful evaluation of the patient is determined to have red man syndrome antihistamines such as diphenhydramine and ranitidine can both be started intravenously. Normal saline IV boluses are used to treat hypotension. After the symptoms resolve, the vancomycin can be restarted and given over 4 hours. If alternative antibiotics to vancomycin are available, they should be used. If vancomycin must be continued, patients should be premedicated with diphenhydramine 50 mg intravenously and ranitidine 50 mg intravenously 1 hour before each dose, and vancomycin should be administered over 4 hours under close observation ¹⁰.

If the symptoms of anaphylaxis are present, such as altered mental status, hypotension, stridor, difficulty breathing, wheezing and hives, treatment should be started immediately for anaphylaxis and the patient needs emergency care. Epinephrine should be given early and the patient may have an epinephrine auto injector on them which can be used ¹⁰. Emergency medical services, if available, should be activated immediately to expedite further patient treatment and transport to definitive care.

Patients requiring a rapid infusion of vancomycin may be pre-treated with diphenhydramine and ranitidine. However, the best preventive measure to avoid red man syndrome is maintaining infusion rates below 10 mg/min ¹¹.

Red man syndrome prognosis

The prognosis for patients with red man syndrome is excellent with appropriate management. Vancomycin may be used again after an episode of red man syndrome. Appropriate precautions and treatment guidelines should be followed. Normal IV saline should be used to treat hypotension. Other supportive care measures should be provided.

References

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