Vancomycin Associated Red Man Syndrome (RMS)

Genetic Polymorphisms Associated With Histamine Disposition in Children With Vancomycin Associated Red Man Syndrome (RMS)

This study proposes to identify patients who developed RMS with vancomycin infusion, and determine presence or absence of variant alleles involved in histamine biotransformation. The implications of this study are important, as identification of variant alleles in these patients, may alter the current standard of care for vancomycin infusions.

The hypothesis of this study is that the development of red man syndrome (RMS) during receipt of intravenous vancomycin is associated with the presence of variant alleles for genes involved in the histamine pathway. The primary outcome that will be measured will be the history of RMS and the presence or absence of variant alleles for the genes responsible for histamine metabolism (i.e. histamine n-methyltransferase and diamine oxidase). As a secondary endpoint, the study will also attempt to determine the incidence of RMS in pediatric patients.

Study Overview

• Status: Completed
• Conditions: Red Man Syndrome

Detailed Description

Vancomycin has been utilized as an antimicrobial therapeutic agent for serious gram positive infections for more than half a century.The pharmacokinetics of vancomycin has been well studied, and in general there are few side effects from this medication. The most common side effect that occurs with receipt of vancomycin is red man syndrome (RMS), which is also known as red neck, or red person syndrome.1 RMS encompasses a spectrum that ranges from a mild reaction such as flushing, urticarial rash, pruritis, to a severe reaction that includes generalized erythema,intense pruritis, and even hypotension. RMS has been estimated to occur in 5- 50% of hospitalized patients who receive this drug.

RMS is considered an anaphylactoid type of reaction that is due to mast cell degranulation with a concomitant rise in blood histamine levels. The resultant symptomatology varies from mild itching and erythematous rash to a more generalized reaction with hypotension. This reaction has been shown to be modified by pre-treatment with various types of antihistamines including diphenhydramine and cimetidine.

There is now evidence to suggest that altered histamine metabolism contributes to the pathogenesis of various disorders. Histamine is almost exclusively metabolized by the enzymes histamine N-methyltranserase (HNMT)and diamine oxidase (DAO) both of which are polymorphically expressed in people with varying frequencies.HNMT catalyzes the N- methylation of histamine. This is the predominant pathway for histamine metabolism,accounting for 50-80% of its biotransformation. Diamine oxidase (DAO) likely contributes in a significant manner of the remaining metabolism of histamine as only 2-3% of this autocoid is excreted unchanged in the urine. It is plausible that allelic variants of HNMT and/or DAO may contribute to histmaminergic reactions in a given patient with resultant propagation of its pharmacologic effects, and that polymorphically expressed enzymes primarily responsible for terminating the pharmacologic activity of histamine (via biotransformation)may play a crucial role in determining disease phenotype for disorders (e.g., RMS) where histamine is a key mediator.

This is a prospective study that will be conducted over a one year period of time. Eligible patients will be identified by a search of patients who are receiving vancomycin therapy throughout the study period. Chart review/patient interview will then be performed to identify patients who developed symptomatology consistent with RMS while receiving vancomycin infusion. For the purposes of this study, red man syndrome (RMS) will be defined as: erythematous rash, flushing of the face, neck, or torso, itching, or a lowering of systolic or diastolic blood pressure by >10mm/hg. A subset of patients who remained asymptomatic throughout their vancomycin therapy will also be evaluated as a control group.

• Study Type: Observational
• Enrollment (Actual): 544

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital & Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Eligible patients will be identified by a search of patients who are receiving vancomycin therapy throughout the study period. Chart review/patient interview will then be performed to identify patients who developed symptomatology consistent with RMS while receiving vancomycin infusion. For the purposes of this study, red man syndrome (RMS) will be defined as: erythematous rash, flushing of the face, neck, or torso, itching, or a lowering of systolic or diastolic blood pressure by >10mm/hg. A subset of patients who remained asymptomatic throughout their vancomycin therapy will also be evaluated as a control group.

Description

Inclusion Criteria:

• Patients must have received vancomycin

Exclusion Criteria:

• Patients who have received antihistamines at the time of vancomycin administration or
• Patients who have been on steroids or tricyclic antidepressants within 30 days prior to the vancomycin administration
• People receiving ECMO or have multiorgan failure
• Currently receiving dialysis

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
1; Children greater than 6 months receiving at least one dose of Vancomycin and Red Man Syndrome
2; Children greater than 6 months receiving at least one dose of Vancomycin and has not had Red Man Syndrome

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Presence or abscence of genetic polymorphisms in the histamine pathway in patients with vancomycin related RMS.	During Hospital Admission

Collaborators and Investigators

• Sponsor: Children's Mercy Hospital Kansas City
• Collaborators: Katherine Berry Richardson Foundation
• Investigators: Principal Investigator: Angela Myers, MD, MPH, Children's Mercy Hosptials and Clinics

Publications and helpful links

General Publications

• Myers AL, Gaedigk A, Dai H, James LP, Jones BL, Neville KA. Defining risk factors for red man syndrome in children and adults. Pediatr Infect Dis J. 2012 May;31(5):464-8. doi: 10.1097/INF.0b013e31824e10d7.

Study record dates

Study Major Dates

• Study Start: January 1, 2008
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: January 14, 2009
• First Submitted That Met QC Criteria: January 14, 2009
• First Posted (Estimate): January 16, 2009

Study Record Updates

• Last Update Posted (Estimate): October 12, 2011
• Last Update Submitted That Met QC Criteria: October 11, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Disease; Endocrine Gland Neoplasms; Genetic Diseases, Inborn; Neoplastic Syndromes, Hereditary; Neoplasms, Multiple Primary; Syndrome; Multiple Endocrine Neoplasia
• Other Study ID Numbers: 10914

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No