Red Man Syndrome

Article Author:
Thomas Martel
Article Author (Archived):
Radia Jamil
Article Editor:
Kevin King
Updated:
6/6/2019 5:31:28 PM
PubMed Link:
Red Man Syndrome

Introduction

Red man syndrome (RMS) is an anaphlylactoid reaction caused by the rapid infusion of the glycopeptide antibiotic Vancomycin.  RMS consists of a pruritic erythematous rash to the face, neck, and upper torso which may also involve the extremities to a lesser degree. Symptoms may include weakness, angioedema, and chest or back pain. RMS is caused by Vancomycin through the direct and non immune mediated release of histamine from mast cells and basophils. The amount of histamine release is generally related to the dose of Vancomycin infused and the rate of infusion. RMS is generally associated with more rapid infusion rates but can be seen following slower infusion rates and after several days of transfusion.  Practitioners using vancomycin should be aware of this known drug reaction, its prevention and treatment.[1][2][3]

Etiology

RMS most frequently occurs with IV vancomycin but may rarely occur from oral or intraperitoneal vancomycin.[4][5][6] It 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. RMS most often begins 4 to 10 minutes from the start of the first dose of IV vancomycin. It may occur later during the infusion or begin shortly after dose completion. RMS may occur from later doses as far out as 7 days.[1][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.[7][2]

There are case studies of RMS occurring from other antibiotics such as rifampin, cefepime, teicoplanin, ciprofloxacin, and amphotericin B.[3][8][9][1]

Epidemiology

RMS is the most frequent adverse reaction to IV vancomycin. It occurs in 4% to 50% of infected patients treated with IV vancomycin. Patients under 40 years of age are at greatest risk of severe RMS reactions. 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. RMS usually is mild and easily managed. There are rare cases of life-threatening RMS reactions.[1]

Pathophysiology

Vancomycin was discovered in 1952 in soil obtained from the jungles of Borneo. Initial preparations of the antibiotic lacked purification and were brown. Therefore, many referred to vancomycin as "Mississippi mud." Clinicians initially thought RMS, otic, and renal toxicity were secondary to impurities in vancomycin. However, even after vancomycin was purified RMS continued to be observed. 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 RMS and suggest histamine metabolism may also be delayed due to inhibition of histamine N-methyltransferase and diamine oxidase enzymes.[7][1]

History and Physical

The clinical presentation of RMS 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 RMS. The signs and symptoms of RMS include:[1][2]

  • 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

Evaluation

The diagnosis of RMS is made clinically and does not depend on laboratory or other tests. Severe cases should be differentiated from IgE-mediated anaphylactic reactions.[2]

Treatment / Management

When a patient develops RMS, 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 RMS. Future doses of vancomycin may be given at decreased infusion rates in most cases.[1]

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.[10]

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 RMS 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.[11][12]

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. [11][12]  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 RMS is maintaining infusion rates below 10 mg/min.[13][14]

Differential Diagnosis

RMS should be differentiated from an anaphylactic reaction. Both RMS 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. RMS is a rate-related anaphylactoid adverse reaction which most often occurs during the first exposure to IV vancomycin.[11][12]

Prognosis

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

Pearls and Other Issues

Key Points

  • RMS is a common adverse reaction seen with IV vancomycin use.
  • The increased use of vancomycin will likely cause an increase in the number of RMS 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.

Enhancing Healthcare Team Outcomes

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

References

[1] Red man syndrome., Sivagnanam S,Deleu D,, Critical care (London, England), 2003 Apr     [PubMed PMID: 12720556]
[2] Bruniera FR,Ferreira FM,Saviolli LR,Bacci MR,Feder D,da Luz Gon´┐Żalves Pedreira M,Sorgini Peterlini MA,Azzalis LA,Campos Junqueira VB,Fonseca FL, The use of vancomycin with its therapeutic and adverse effects: a review. European review for medical and pharmacological sciences. 2015 Feb;     [PubMed PMID: 25753888]
[3] Red man syndrome adverse reaction following intravenous infusion of cefepime., Panos G,Watson DC,Sargianou M,Kampiotis D,Chra P,, Antimicrobial agents and chemotherapy, 2012 Dec     [PubMed PMID: 22948884]
[4] Domis MJ,Moritz ML, Red man syndrome following intraperitoneal vancomycin in a child with peritonitis. Frontiers in pediatrics. 2014;     [PubMed PMID: 24926475]
[5] Possible red-man syndrome associated with systemic absorption of oral vancomycin in a child with normal renal function., Bergeron L,Boucher FD,, The Annals of pharmacotherapy, 1994 May     [PubMed PMID: 8068993]
[6] Bailey P,Gray H, An elderly woman with 'Red Man Syndrome' in association with oral vancomycin therapy: a case report. Cases journal. 2008 Aug 18;     [PubMed PMID: 18710566]
[7] Griffith RS, Introduction to vancomycin. Reviews of infectious diseases. 1981 Nov-Dec     [PubMed PMID: 7043707]
[8] Dubettier S,Boibieux A,Lagable M,Crevon L,Peyramond D,Milon H, Red man syndrome with teicoplanin. Reviews of infectious diseases. 1991 Jul-Aug     [PubMed PMID: 1833809]
[9] Ellis ME,Tharpe W, Red man syndrome associated with amphotericin B. BMJ (Clinical research ed.). 1990 Jun 2     [PubMed PMID: 2379017]
[10] Korman TM,Turnidge JD,Grayson ML, Risk factors for adverse cutaneous reactions associated with intravenous vancomycin. The Journal of antimicrobial chemotherapy. 1997 Mar     [PubMed PMID: 9096187]
[11] Irani AM,Akl EG, Management and Prevention of Anaphylaxis. F1000Research. 2015     [PubMed PMID: 26918144]
[12] Simons FE,Ebisawa M,Sanchez-Borges M,Thong BY,Worm M,Tanno LK,Lockey RF,El-Gamal YM,Brown SG,Park HS,Sheikh A, 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. The World Allergy Organization journal. 2015     [PubMed PMID: 26525001]
[13] Healy DP,Sahai JV,Fuller SH,Polk RE, Vancomycin-induced histamine release and "red man syndrome": comparison of 1- and 2-hour infusions. Antimicrobial agents and chemotherapy. 1990 Apr     [PubMed PMID: 1693055]
[14]     [PubMed PMID: 2572652]