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\begin{document}

\title{Experience of general anesthesia in a patient with menstrual-associated
coronary spasm}



\author[1]{AYA KAWACHI}%
\author[1]{Saho Sudo}%
\author[1]{Yusuke Ishida}%
\author[1]{Koichi Nakazawa}%
\affil[1]{Tokyo Medical University}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\textbf{Experience of general anesthesia in a patient with
menstrual-associated coronary spasm}

Aya Kawachi, Saho Sudo, Yusuke Ishida and Koichi Nakazawa

Department of Anesthesiology, Tokyo Medical University, 6-7-1
Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

\textbf{Corresponding author}

Aya Kawachi

Department of Anesthesiology

Tokyo Medical University Hospital

6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

Tel.: +81-03-3342-6111; Fax: +81-03-5381-6650

Email: ayalpaca1929k@gmail.com

\textbf{Abstract}

\textbf{Background}

Coronary angina due to low estrogen is relatively common around
menopause, with almost no reports associated with the menstrual cycle or
anesthetic management at younger ages.

\textbf{Case presentation}

The patient was a 22-year-old woman who had developed ventricular
fibrillation due to coronary spasm, resulting in cardiopulmonary arrest.
She was resuscitated, and underwent ICD implantation. As her symptoms
appeared at specific times during her menstrual cycle, she was diagnosed
as having menstrual-associated coronary spasm, and started taking
estrogen/progesterone medication. An endometrial ablation was scheduled
for endometrial hyperplasia that was caused by the medicine. The surgery
was scheduled in consideration of the patient's menstrual cycle, and
general anesthesia was selected as the method of anesthesia. The surgery
and perioperative management were uneventful, and her postoperative
course was favorable.

\textbf{Conclusion}

Our case is the first to our knowledge of general anesthesia performed
on a patient with menstrual-associated coronary spasm.

\textbf{Keywords:}

menstruation, coronary spasm, general anesthesia

\textbf{Background}

Coronary spasm is a rare condition that occurs in premenopausal women in
association with phases of the menstrual cycle, and is thought to be
associated with a decrease in estrogen levels. To our knowledge, there
have been no reports to date of anesthesia management of patients with
menstrual-associated coronary spasm. We encountered a case of a patient
with a history of coronary spasm induced by hormonal changes in the
menstrual cycle, who was treated with intraoperative prophylaxis and
appropriate anesthesia to prevent coronary spasm attacks during surgery
for endometrial ablation. We here report a review of the anesthetic
management of this rare case.

\textbf{Case presentation}

The patient was a 22-year-old woman (height: 165 cm; weight: 86.5 kg;
BMI: 31.8 kg/m\textsuperscript{2}). She was scheduled to undergo
endometrial ablation for endometrial hyperplasia. Regarding her medical
history, she experienced a cardiopulmonary arrest owing to ventricular
fibrillation at the age of 15, at which time she was diagnosed as having
coronary spasm via a coronary angiogram and acetylcholine stress test.
She underwent ICD implantation, together with the initiation of
treatment with a Ca\textsuperscript{2+} blocker and coronary dilators.
The ICD was activated 4 times in 6 years, and the patient resumed a
self-paced heartbeat. After a careful interview regarding the
circumstances of the onset of her symptoms, we strongly suspected
menstrual-associated coronary spasm, as her symptoms occurred from just
before menstruation to the middle of menstruation. Estrogen/progesterone
replacement therapy was started, and her ICD activation and angina
attacks ceased. When she was 22 years old, we decided to perform an
endometrial ablation with tissue biopsy for endometrial hyperplasia that
was thought to be caused by the estrogen/progesterone medication. Her
family history included coronary angina pectoris in the father. Her oral
medications were diltiazem (120 mg/day), nifedipine (40 mg/day),
nicorandil (25 mg/day), and isosorbide mononitrate (40 mg/day), and an
isosorbide mononitrate patch (80 mg/day). She had no history of smoking.
Her first menstrual period was at 11 years old, and her menstrual cycle
was 30 days and regular. Her last menstrual period was 14 days before
the scheduled surgery. Blood test findings were normal. Chest X-ray
displayed no cardiac enlargement or abnormal shadows, except for the
presence of an ICD device. Preoperative estradiol levels were 63.1 pg/mL
in the follicular phase, and 42.9 pg/mL in the ovulatory phase, which
were within the normal ranges for these phases in nonpregnant women. Her
ECG results were normal, with a pulse of 55 beats/min, sinus rhythm, and
a corrected QTc of 403 ms. Transthoracic echocardiography displayed an
ejection fraction of 65\%, no abnormal wall motion, no systolic or
diastolic dysfunction, and no apparent valvular disease. There were
load-induced right ventricular abnormalities, and she had a NYHA
classification of grade I. Anesthesia was induced with remifentanil (0.3
\selectlanguage{greek}µ\selectlanguage{english}g/kg/min) and propofol TCI (4.0 \selectlanguage{greek}µ\selectlanguage{english}g/mL), and muscle relaxation was
achieved with rocuronium bromide (50 mg). After endotracheal intubation
using a McGrath MAC\selectlanguage{ngerman}® video laryngoscope (Medtronic Co., Minneapolis, MN,
USA), anesthesia was maintained with propofol TCI (4.0 \selectlanguage{greek}µ\selectlanguage{english}g/mL),
continuous infusion of remifentanil (0.1--0.2 \selectlanguage{greek}µ\selectlanguage{english}g/kg/min), and rocuronium
bromide\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}50mg, and sedation levels were monitored using the patient
state index measured with a Sedline\selectlanguage{ngerman}® monitor (Masimo Co., Irvine, CA,
USA), and maintained at scores between 30 and 50. In addition, an
observation arterial pressure line was taken. Intraoperative and
postoperative nicorandil (1 \selectlanguage{greek}µ\selectlanguage{english}g/kg/min) and diltiazem (1 \selectlanguage{greek}µ\selectlanguage{english}g/kg/min) were
continuously administered intravenously. The patient remained unchanged
and her blood pressure did not decrease, and no antihypertensive or
antiarrhythmic medications were administered during the surgery. Surgery
time was 13 minutes, and anesthesia time was 49 minutes. Bleeding was
minimal. The surgery was completed without any complications, and the
patient was extubated and returned to the ICU after surgery. The patient
was discharged on the day after the surgery.

\textbf{Discussion}

Coronary spasm is defined as a transient abnormal contraction of the
coronary arteries. Factors known to contribute to the onset of the
disease include smoking, alcohol consumption, abnormal lipid and sugar
metabolism, stress and hyperventilation, genetic factors, and female
hormone deficiency\textsuperscript{1)}. The female hormone estrogen is
known to have cardioprotective effects\textsuperscript{2)}. The
mechanism is thought to be vasodilation via estrogen receptors in
vascular endothelial cells, vascular smooth muscle cells, and the heart,
suppression of neointimal proliferation, and suppression of angiotensin
1 receptor expression, which has a myocardial hypertrophic
effect\textsuperscript{3-5)}. Premenopausal women have a late luteal to
menstrual phase when blood estrogen levels are low, and a follicular and
ovulatory phase, and early luteal phase when estrogen levels are high.
For this reason, it has been noted that coronary spasms and acute
coronary syndromes are more common during the late luteal phase and
menstrual phase, when estrogen levels are low\textsuperscript{6)}. In
the present patient, life-threatening arrhythmias due to coronary spasm
occurred during the luteal phase to the menstrual phase.

The frequency of coronary spasm attacks and anginal symptoms improved
after treatment with estrogen (Duphaston\selectlanguage{ngerman}®) and progesterone (Premarin®)
was started. Sugiura et al. reported that oral contraceptives and
low-dose estrogen/progesterone products, regardless of their type, are
associated with a significant increase in deep vein
thrombosis\textsuperscript{7)}. In the perioperative period, it is
recommended that medication be withdrawn 4 weeks prior to surgery for
surgeries lasting longer than 45 minutes, and postoperatively until
immobility is resolved\textsuperscript{8)}. In the present case, both
drugs were withdrawn 30 days prior to surgery. Considering that the
scheduled surgery time for this case was 30 minutes, and the patient was
scheduled to be discharged the day after surgery, there may have been no
need for drug withdrawal. The timing of the surgery was appropriate
because it was scheduled around the time of ovulation, 2 weeks after the
last menstrual period. Problems with estrogen/progesterone therapy
include an increased risk of breast cancer owing to high progesterone
levels\textsuperscript{9)}, increased incidence of coronary vascular
disease, and abnormal vaginal bleeding. However, it has been pointed out
that estrogen monotherapy increases the risk of developing endometrial
hyperplasia and endometrial cancer. The frequency of endometrial
hyperplasia coexisting with or progressing to cancer is reported to be
about 1\% to 30\%\textsuperscript{10)}, and if the patient is required
to take oral contraceptive pills from a young age, as in this patient,
the risk of developing cancer in the future may be high. In the present
patient, intravenous diltiazem hydrochloride and nicorandil were started
at the time of induction of anesthesia for the prevention of coronary
spasms, and was continued during and after surgery, until just before
discharge. According to the Guidelines for the Diagnosis and Treatment
of Coronary Angina Pectoris, the Ca\textsuperscript{2+} antagonist
diltiazem hydrochloride is extremely effective in preventing coronary
spasms, and is recommended as class I drug. Nicorandil has selective
coronary vasodilation and anticoronary spasm effects, and is classified
as a class II drug that is recommended with a high likelihood of
efficacy when used in combination with a
Ca\textsuperscript{2+}antagonist for seizures that are difficult to
control with the antagonist alone.\textsuperscript{11)}

There have been no reports on the anesthesia of patients with
menstrual-associated coronary angina pectoris. The present patient
required an endometrial ablation, and the attending physician,
cardiologist, and anesthesiologist discussed whether the procedure
should be performed under general anesthesia or spinal anesthesia.

Anesthesia management with spinal anesthesia was initially considered,
but there were concerns regarding side effects from the use of various
drugs, and the risk of suppression of cardiac function. However, there
have been many previous reports of coronary spasms induced by relative
parasympathetic dominance due to sympathetic blockade by epidural or
spinal anesthesia\textsuperscript{12)13)}.Therefore, in this case, the
patient was managed under general anesthesia, considering the
possibility that coronary spasms might occur due to sympathetic blockade
by spinal anesthesia.



\textbf{References}

1) Yasue H, Takizawa A, Nagao M, et al. Long-term prognosis for patients
with variant angina and influential factors. Circulation 1988;78:1-9.

2) Mendelsohn ME, Karas RH.The protective effects of estrogen on the
cardiovascular system. N Engl J Med 1999;340:1801-1811.

3) Meyer MR, Barton M. ERalpha, ERbeta, and gpER: novel aspects of
oestrogen receptor signalling in atherosclerosis. Cardiovasc Res
2009;83:605-610.

4) Orshal JM, Khalil RA: Gender, sex hormones, and vascular tone. Am J
Physiol Regul Integr Comp Physiol 2004;286:R233-R249.

5) Nickenig G, Bäumer AT, Grohè C et al: Estrogen modulates AT1 receptor
gene expression in vitro and in vivo. Circulation1998;97:2197-2201.

6) Kawano H, Motoyama T, Ohgushi M et al: Menstrual cyclic variation of
myocardial ischemia in premenopausal women with variant angina. Ann
Intern Med 2001;135: 977-981.

7) Kazuko S,Takao K,Toshiyuki O : The epidemiological characteristics of
thromboembolism related to oral contraceptives in Japan: Results of a
national surgery 2021;47:198-207

8) Japanese Society of Obstetrics and Gynecology, ed. Low-Dose Oral
Contraceptives, Low Estrogen-Progestin Combination Drug Guide Line 2020
Edition

9) Trabert B, Sherman E, Kannnan N : Progesterone and Breast Cancer
2020, 41:320-344

10) Antunes CM, Strolley PD, Rosenshein NB et al : Endmetrial cancer and
estrogen use. Report of a large case-control study: N Engl J Med
1979,300:9-13

11) Guidelines for Diagnosis and Treatment of Patients with Vasospastic
Angina \selectlanguage{english}(Coronary Spastic Angina\selectlanguage{english})JCS2013

12) Koshiba K, Hoka S. Clinical characteristics of perioperative
coronary spasm: reviews of 115 case reports in Japan. J Anesth.
2001;15(2):93--99.

13) Easley RB, Rosen RE, Lindeman KS. Coronary artery spasm during
initiation of epidural anesthesia. Anesthesiology. 2003;99(4):1015--7.

\textbf{List of abbreviations}

BMI: body mass index

ICD: implantable cardioverter defibrillator

ECG: electrocardiogram

QTc: corrected QT

NYHA: New York Heart Association

TCI: target controlled infusion

ICU: Intensive Care Unit



\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

Not applicable

\textbf{Consent for publication}

Written informed consent was obtained from the patient for publication
of this case report and the accompanying images.

\textbf{Availability of data and material}

Not applicable

\textbf{Competing interests}

The authors declare that they have no competing interests associated
with this manuscript.

\textbf{Funding}

None

\textbf{Contributions}

AK contributed to the anesthesia management of the patient,
conceptualization of the case report, and writing of the original draft.
SS and YI contributed to the anesthesia management of the patient. YI
and KN edited the manuscript. KN was the overall supervisor of this
case. All authors read and approved the final manuscript.

\textbf{Acknowledgements}

We would like to thank Helena Akiko Popiel for English language editing.

\textbf{Author information}

\textbf{Affiliation}

Department of Anesthesiology

Tokyo Medical University Hospital

6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

Aya Kawachi, Saho Sudo, Yusuke Ishida and Koichi Nakazawa

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