CBL CPK QUESTION 4

Red Man Syndrome (RMS) primarily occurred with parenteral administration. It was
associated with histamine-mediated flushing during or immediately after infusion with
vancomycin. The extent of histamine release depends on the amount of medication
administered as well as the rate of infusion (Martel, Jamil, & King, 2019). RMS is characterized
by flushing, erythema, and pruritus, at usually back of neck, arms, upper portion of the body,
back and even in the face. Pains and muscle spasms in the back and chest, dyspnea, and
hypotension may also occur.(Sivagnanam & Deleu, 2003)

Vancomycin lead to the degranulation of the mast cells, thus directly release it in the
circulation. Besides, the pathogenesis of RMS also was believed due to the altered histamine
metabolism. Histamine is synthesized from L-histidine and primarily metabolized by histamine
N-methyltransferase (HNMT) and diamine oxidase (DAO). It is believed that certain single
nucleotide polymorphisms (SNPs) expressed on the mast cells lead to the altered function of
the H1 and H2 receptors thus interrupt the metabolism of histamine causing an excessive
amount of histamine in the circulation (Chalo Mutiso, Camilla, & Mutiso Chalo, 2016). Higher
doses and faster infusion times lead to elevated level of histamine in the blood circulation thus
lead to red man syndrome.

Vancomycin should be administered at an infusion rate of not higher than 10 mg/minute

or for a one gram dose, over a minimum of 100 minutes (whichever results in a slower infusion)
in order to avoid RMS (Choi & Weller, 2016).

Although optimal regimen had not been determined, pre-treatment with anti-histamine was
found beneficial in reducing the prevalence of RMS.

• RMS was completely prevented in a group of patients receiving 1 g of vancomycin over

1 hour in which the hypersensitivity reaction was observed in 47% of the placebo group
while zero in patients pre-treated with 50 mg diphenhydramine orally (Wallace,
Mascola and Oldfield, 1991).

• In a randomized trial in 30 presurgical patients administered with very rapid infusions

(1 gram over 10 minutes) as well as premedication with both H1 and H2 antihistamines,
it is reported that the incidence of RMS were significantly lower than the placebo group.
Fifty percent of the placebo group also developed hypotension which was not observe
in group pre-treated with antihistamine (Renz, et. al, 1998)
 The management of RMS would require the uses of antihistamines as primary treatment.
Firstly, the IV Vancomycin must be stopped immediately when the RMS symptoms present.
In mild cases of RMS, manifested by having mild flushing and pruritus, diphenhydramine 50
mg orally or intravenously and ranitidine 50 mg intravenously can be initiated. The symptoms
may resolve in 20 minutes and vancomycin can be restarted at 50% of the original rate.
However, the future doses should be administered in a slower rate, at least over 2 hours with
close monitoring of the patient condition (Simons et al., 2015).

On the other hand, patient with moderate to severe cases should be managed according to
severity. The patient may experience symptoms of severe rash, hypotension, tachycardia, chest
pain, back pain, muscle spasms, weakness, angioedema. Before assuming it was the red man
syndrome, the patient should be evaluated for anaphylaxis or other serious cause for their
symptom. If it confirmed to be RMS, antihistamines such as IV diphenhydramine and IV
ranitidine should be initiated immediately. Patient with hypotension can be treated using
Normal saline IV boluses. Vancomycin can be restarted once the symptom resolved and should
be given over 4 hours. Alternative antibiotic to vancomycin can be used if available. However,
pre-treatment with diphenhydramine 50 mg intravenously and ranitidine 50
mg intravenously 1 hour before each dose are necessary if vancomycin still to be continued
and vancomycin should be administered at slower rate of at least over 4 hours under close
observation (Irani & Akl, 2015; Simons et al., 2015).

REFERENCES

Chalo Mutiso, D., Camilla, B., & Mutiso Chalo, P. (2016). An ethnobotanical study of
medicinal plants used by the Masaai people of Losho, Kenya. International Journal of
Pharmacological Research, 6(02), 68–74. https://doi.org/10.7439/ijpr
Choi, E. I., & Weller, P. . (2016). Vancomycin hypersensitivity. UpToDate. Retrieved from
http://www.uptodate.com/contents/vancomycin-hypersensitivity
Irani, A.-M., & Akl, E. G. (2015). Management and Prevention of Anaphylaxis.
F1000Research, 4. https://doi.org/10.12688/f1000research.7181.1
Martel, T. J., Jamil, R. T., & King, K. C. (2019). Red Man Syndrome. StatPearls. StatPearls
Publishing. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/29494112
Renz, C. L, Thurn, J. D, Finn, H. A. (1998). Oral antihistamines reduce the side effects from
rapid vancomycin infusion. Anesth Analg. 87:681.
Simons, F. E. R., Ebisawa, M., Sanchez-Borges, M., Thong, B. Y., Worm, M., Tanno, L. K.,
… Sheikh, A. (2015). 2015 update of the evidence base: World Allergy Organization
anaphylaxis guidelines. The World Allergy Organization Journal, 8(1), 32.
https://doi.org/10.1186/s40413-015-0080-1
Sivagnanam, S., & Deleu, D. (2003). Red man syndrome. Critical Care (London, England),
7(2), 119–120. https://doi.org/10.1186/CC1871
Wallace, M. R, Mascola, J. R, Oldfield E. C. (1991). Red man syndrome: incidence,
etiology, and prophylaxis. J Infect Dis. 164:1180.