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Midazolam anaphylaxis during general anesthesia

A case report
Yeon Su Jeon, MD, PhD, JinWoo Shim, MD, Eun Hwa Jun, MD, Seung Tae Choi, MD,
∗
Hong Soo Jung, MD, PhD

Abstract
Rationale: Midazolam is known as a safe drug and is widely used as a sedative and an anesthetic adjuvant. Therefore, there is a
lack of awareness that midazolam can cause anaphylaxis. Midazolam anaphylaxis is rare, and only a few cases have been reported,
but such a risk is always present. In this study, we report a case of midazolam anaphylaxis by an intravenous injection, in the prone
position, during general anesthesia.
Patient concerns: A 62-year-old woman was intravenously administered 1 mg midazolam during general anesthesia, and
sudden severe hypotension, bronchospasm, decreased oxygen saturation, erythema, and diarrhea occurred.
Diagnosis: Midazolam anaphylaxis was presumptively diagnosed by clinical symptoms and was confirmed by an intradermal test
after 9 weeks.
Interventions: The patient was treated with 100% oxygen, large volume of fluid, epinephrine, phenylephrine, ephedrine,
dexamethasone and prednisolone, ranitidine, and flumazenil.
Outcomes: Severe hypotension and decreased oxygen saturation were resolved within 20 minutes of the onset of anaphylaxis,
and the patient was discharged after 3 days without any sequelae.
Lessons: Midazolam anaphylaxis is very rare, but it can happen always. Therefore, the possibility of anaphylaxis due to midazolam
should be considered and always be prepared for treatment.
Abbreviations: BP = blood pressure, ETCO2 = end tidal carbon dioxide, HR = heart rate, IV = intravenous, SpO2 = peripheral
oxygen saturation.
Keywords: anaphylaxis, general anesthesia, midazolam

1. Introduction shock caused by 1 mg midazolam that was intravenously

administered as an adjuvant during general anesthesia.
Anaphylaxis is an acute, potentially life threatening, systemic
hypersensitivity reaction that occurs when a patient is re-exposed
to a previously sensitized antigen.[1,2] The most common causes of 2. Case presentation
perioperative anaphylaxis are muscle relaxants and antibiotics.[3] A 62-year-old woman, weight 46 kg, height 153 cm, was
Midazolam is known as a safe drug and is widely used as an scheduled for endoscopic discectomy due to the diagnosis of
anxiolytic, sedative, and adjuvant to general anesthetics in patients right L5S1 lateral stenosis.
with drug allergy.[4] Therefore, there is a lack of awareness that Her medical history showed that she underwent myomectomy
midazolam can cause anaphylaxis. Midazolam anaphylaxis is 20 years ago and had taken alprazolam and diazepam per os for 2
rare,[5] and only a few cases have been reported.[6–9] But such a risk months and underwent a colon polypectomy with midazolam 3
is always present. In this study, we report a case of anaphylactic mg intravenous (IV) 2 months ago. She had no history of a drug
or food allergy. The preoperative examination revealed no
Editor: N/A. specific findings and the intradermal test for the antibiotic
The authors have no conflicts of interest to disclose. cefotetan injection was negative.
Department of Anesthesiology and Pain Medicine, St’s Vincent Hospital, College On arrival to the operating room, electrocardiogram was
of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. normal and blood pressure (BP) 135/71 mmHg, heart rate (HR)
∗
Correspondence: Hong Soo Jung, Department of Anesthesiology and Pain 78 beats/min, peripheral oxygen saturation (SpO2) 98%, Bispec-
Medicine, St’s Vincent Hospital, College of Medicine, The Catholic University of tral index 99, and body temperature 36.5 °C were recorded.
Korea, 93 Jungbu daero, Paldal-gu, Suwon, Gyeonggi Province, 16247, Lidocaine 40 mg and 1% propofol 80 mg IV were administered to
Republic of Korea (e-mail: flood1@naver.com).
induce anesthesia, and tracheal intubation was performed after
Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. muscle relaxation with rocuronium 40 mg IV. Sevoflurane 1 to 2
This is an open access article distributed under the Creative Commons
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
vol%:O2:air was administered for maintenance of anesthesia.
reproduction in any medium, provided the original work is properly cited. Artificial ventilation was maintained at a tidal volume of 400 mL,
How to cite this article: Jeon YS, Shim J, Jun EH, Choi ST, Jung HS. Midazolam respiratory rate 11 breaths/min, and end tidal CO2 (ETCO2) 28
anaphylaxis during general anesthesia. Medicine 2019;98:41(e17405). to 30 mmHg. Remifentanil 0.5 to 1 ng/mL was continuously
Received: 25 April 2019 / Received in final form: 2 August 2019 / Accepted: 10 infused using target-controlled infusion pump from the anesthetic
September 2019 induction. After the anesthetic induction, BP 145/65 mmHg and
http://dx.doi.org/10.1097/MD.0000000000017405 HR 80 beats/min were noted.

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Jeon et al. Medicine (2019) 98:41 Medicine

The patient was positioned in the prone position for surgery, The day after the anaphylactic shock, the patient was
and the vertebra level of the surgical site was checked with a C- transferred to the general ward. The main complaint, back pain,
arm x-ray. While simultaneously administering sevoflurane 2 vol was treated with medication and physical therapy. After 2 days,
% and remifentanil 0.5 ng/mL, BP 125/68 mmHg, HR 55 beats/ the patient and her family were informed again about midazolam
min, and ETCO2 29 mmHg were maintained. However, even anaphylaxis and the patient was discharged without any
after 25 minutes of anesthetic induction, Bispectral index was sequelae. After 9 weeks of anaphylaxis, the patient showed a
constantly maintained above 60 (64–68). Subsequently, we positive reaction for midazolam in the intradermal test.
decided to inject midazolam 1 mg IV to prevent awareness of the The study was approved by the Institutional Review Board of
patient without decrease of BP during general anesthesia. our University Hospital. Written informed consent was obtained
One minute after administering midazolam 1 mg IV, Bispectral from the patient for the publication of this case report.
index decreased from 68 to 54. At the same time, BP 41/30
mmHg, HR 46 beats/min, SpO2 96%, and ETCO2 15 mmHg had
3. Discussion
declined and capnography showed an obstructive pattern.
Wheezing sound in both lungs was noted on auscultation and Anaphylaxis causes a very fast life-threatening condition and can
some small erythema appeared on the back. Sevoflurane and involve multiple organs,[10] so proper diagnosis and treatment by
remifentanil were discontinued and 100% O2 and ephedrine 10 the physician is very important.
mg IV were administered twice. However, BP 53/35 mmHg, HR Severe hypotension after the onset of anaphylaxis is due to
74 beats/min, and SpO2 91% were noted. SpO2 further reduced vasodilation and increased vascular permeability by preformed
to 89% and BP was not detected. Ringer lactate solution at a high mediators such as histamine, neutral protease (tryptase,
rate, 2 times of epinephrine 100 mg IV, and phenylephrine 100 mg chymase), and proteoglycans (heparin) released from mast cells
IV were administered twice. BP 58/38 mmHg, HR 98 beats/min, or basophils. Due to increased vascular permeability, 35% of the
and SpO2 92% were noted. intravascular volume shifts to the interstitial space.[11] In this
The patient was changed to supine position, followed by case, the vena cava compression due to the prone position
Trendelenburg position. Based on the suspicion of anaphylaxis due reduced the venous return and induced more severe hypotension.
to midazolam, we injected flumazenil 0.25 mg, dexamethasone 5 Therefore, it was recommended to change to a Trendelenburg
mg, methylprednisolone 125 mg, and ranitidine 100 mg intrave- position or supine position with leg elevation. The patient also
nously. However, BP 73/48 mmHg, HR 104 beats/min, SpO2 developed fever on the day of anaphylaxis. This was due to the
94%, and ETCO2 25 mmHg were noted, and phenylephrine 100 m inflammatory reaction by newly formed proinflammatory
g IV was administered. Vital signs improved to BP 86/61 mmHg, phospholipid-derived mediators such as prostaglandin D2,
HR 110 beats/min, and SpO2 98% after 20 minutes of the leukotrienes, thromboxane A2, and platelet activating factor.[10]
anaphylactic shock. We then explained to the family the possibility Treatments for anaphylactic reaction are administration of
of side effects due to midazolam and decided to postpone the 100% oxygen, large volume of fluid, epinephrine, corticosteroid,
operation. Glycopyrrolate 0.2 mg IV and pyridostigmine 10 mg IV and antihistamine. Epinephrine should be administered as early
were administered to reverse muscle relaxation. The wheezing as possible and carefully. Epinephrine, in addition to vasocon-
sound disappeared and self-respiration of the patient gradually striction, has b2 agonist action, including bronchial dilatation,
recovered. We performed tracheal extubation after 55 minutes of gastrointestinal smooth muscle relaxation, inhibition of further
anesthesia induction. BP 121/60 mmHg, HR 110 beats/min, and mediator release from mast cell and basophil, and inotropic/
SpO2 98% were noted at the time of extubation. chronotropic effects.[12]
In the recovery room, oxygen 5 L/min was supplied and the The recognition of anaphylaxis during anesthesia is usually
patient’s legs were elevated, and BP 90 to 100/53 to 55 mmHg, confusing because hypotension and bronchospasm can develop
HR 85 to 100 beats/min, and SpO2 99% were noted. The patient due to other reasons and because many drugs, including muscle
complained of diarrhea. After 15 minutes of arrival at the relaxants and propofol, are administered during general
recovery room, BP and HR decreased again to 78/45 mmHg and anesthesia. In this case, the chief clinical factors of diagnosing
85 beats/min, respectively, and phenylephrine 100 mg IV was anaphylaxis were sudden severe hypotension, bradycardia, SpO2
injected. On evaluation, BP was 88–92/48–50 mmHg and HR decrease, abrupt drop in ETCO2, obstructive pattern on
was 48 to 50 beats/min. Arterial blood gas analysis was capnography, and erythema. Many drugs have been adminis-
performed, but there were no specific findings. After 80 minutes tered at various stages of anesthetic induction, but only
in the recovery room, BP, HR, and SpO2 were maintained at 92– midazolam was injected immediately before the anaphylactic
100/51–52 mmHg, 51 beats/min, and 99%, respectively. The skin response. We clinically suspected midazolam as the causative
erythema disappeared, and the patient was transferred to the agent because anaphylactic signs appeared after 1 minute of IV
intensive care unit after 2 hours in the recovery room. The total injection of midazolam. An acute serum tryptase test within 2
amount of injected Ringer lactate solution was 1800 mL. hours after the onset of anaphylaxis was recommended.[13]
Examinations for serum b-tryptase and serum immunoglobulin However, it is difficult to sample acute serum tryptase due to
E were not performed. insufficient equipment or other practical limitations in urgent
In the intensive care unit, BP was maintained at 80/50 mmHg clinical situations. We also did not perform the test and it is a
and HR at 60 beats/min. After 1 hour (5 hours after initial limitation of this case. Buka et al[14] reported that, using a cutoff
hypotension), the vital signs were recorded as BP 126/66 mmHg of 12.4 ng/mL (75th centile), sensitivity, specificity, positive
and HR 60 beats/min. The body temperature rose from 36.9 to predictive value, and negative predictive value of acute serum
37.6 °C and was normalized after supportive care for 2 days. We tryptase were 28%, 88%, 93%, and 17%, respectively. It means
examined Troponin-T, creatine kinase-MB isoenzyme, and acute serum tryptase is a poor indicator for anaphylaxis.
echocardiogram to rule out the cardiovascular problem, which Nonetheless, acute serum tryptase is useful in clinical circum-
was normal. stances to distinguish from its mimics. In the cause analysis with

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Jeon et al. Medicine (2019) 98:41 www.md-journal.com

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[9] Bernardini R, Bonadonna P, Catania P, et al. Perioperative midazolam
Investigation: JinWoo Shim, Eun Hwa Jun, Seung Tae Choi.
hypersensitivity in a seven-year-old boy. Pediatric Allergy Immunol
Writing – original draft: Yeon Su Jeon. 2017;28:400–1.
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Seung Tae Choi orcid: 0000-0003-2041-5580. [12] Schwartz LB, Bradford TR, Rouse C, et al. Development of a new, more
Hong Soo Jung orcid: 0000-0002-6812-1955. sensitive immune-assay for human tryptase: use in systemic anaphylaxis.
J Immunol 1994;14:190–204.
[13] Harper NJ, Dixon T, Dugue P, et al. Suspected anaphylactic reactions
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