Journal of Clinical Anesthesia (2016) 35, 275–277

Case Report

Severe respiratory depression and bradycardia

before induction of anesthesia and onset
of Takotsubo cardiomyopathy after
cardiopulmonary resuscitation☆
Yuko Furuichi MD, PhD a,⁎, Ayaka Hamada MD a , Keiko Nakazato MD, PhD a ,
Katsuya Kobayashi MD, PhD b , Atsuhiro Sakamoto MD, PhD a
a
Department of Anesthesiology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
b
Intensive Care Unit, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan

Received 5 June 2015; revised 16 July 2016; accepted 9 August 2016

Keywords:
Abstract A 69-year-old woman undergoing treatment for hypertension and epilepsy was scheduled to un-
Remifentanil;
dergo cataract surgery. All preoperative examination results were within normal limits. Despite being tense,
Respiratory depression;
she walked to the operating room. Approximately 2 minutes after an intravenous line was established by an
Bradycardia;
anesthesia resident, severe hypoxia and bradycardia developed, and she lost consciousness. Cardiopulmo-
β-Blocker;
nary resuscitation was initiated immediately, and after 1 minute, she regained consciousness, and her breath-
Takotsubo cardiomyopathy;
ing and circulation recovered. After admission to the intensive care unit, emergency coronary angiography
Anesthesia induction
was performed. The blood flow in all the coronary arteries was normal. However, a decrease in the apical left
ventricular wall motion and an increase in the basal wall motion were observed. Based on these findings,
Takotsubo cardiomyopathy was diagnosed. The wall motion gradually improved and the patient was dis-
charged from the hospital on postoperative day 15. The respiratory depression and bradycardia were thought
to be due to an inadvertent bolus of remifentanil. We surmised that the patient had received a slight amount
of retained medication when the anesthesia resident established the intravenous line, which caused severe
respiratory depression. It is important to note that adverse effects such as severe respiratory depression
and bradycardia can be caused by even small doses of remifentanil.
© 2016 Elsevier Inc. All rights reserved.

1. Introduction

Opioids are among the most commonly used analgesic

☆
Disclosures: There was no financial support for this case report.
⁎ Corresponding author at: Department of Anesthesiology, Nippon Medi-
cal School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Tel.: +81
03 3822 2131.
E-mail address: yukof@nms.ac.jp (Y. Furuichi).
drugs for the treatment of perioperative pain [1,2]. Although
useful, these drugs can have adverse effects such as nausea,
vomiting, sedation, and respiratory depression [3]. Respiratory
depression can be fatal, and hence, medical staff must admin-
ister opioids with care. Remifentanil is an ultra–short-acting
μ-opioid receptor agonist that has been widely used in Japan

http://dx.doi.org/10.1016/j.jclinane.2016.08.007
0952-8180/© 2016 Elsevier Inc. All rights reserved.
276
for general anesthesia in recent years. We report our experi-
ences with a patient who developed severe hypoxia and brady-
cardia before the induction of anesthesia, possibly relating to
an inadvertent bolus of remifentanil.
2. Case report
A 69-year-old woman measuring 54 kg in weight, 152 cm
in height, and with a body mass index of 23.4 kg·m−2 was
scheduled to undergo cataract surgery. Usually, cataract sur-
gery is performed with the aid of topical anesthesia in our hos-
pital; however, general anesthesia was chosen at her request.
She was undergoing treatment for hypertension and epilepsy.
The results of the preoperative laboratory tests, chest radiogra-
phy, and electrocardiography (ECG) were normal. The epilep-
sy was characterized by several minutes of nausea and
glossolalia. She was prescribed carvedilol for hypertension,
and zonisamide, clobazam, and lamotrigine for epilepsy from
another hospital. She had no history of heart failure, and the
reason for the choice of carvedilol as the antihypertensive drug
was unknown.
One hour before entering the operating room, she took car-
vedilol 2.5 mg, zonisamide 100 mg, clobazam 10 mg, and
lamotrigine 25 mg orally. Although she was very tense, she
was able to walk to the operating room. Her baseline heart rate
was 51 beats/min with an oxygen saturation of 98%. Electro-
cardiography showed regular sinus rhythm with no ST-T
changes. Her blood pressure has not yet been measured. After
the ECG and oxygen saturation monitoring were initiated, the
anesthesia resident established an intravenous line with a
22-gauge intravenous cannula on the side opposite to the
blood pressure cuff.
The intravenous infusion line was a closed system contain-
ing 2 stopcocks with Q-Syte (Becton Dickinson and Compa-
ny, Franklin Lakes, NJ), connected to the remifentanil-
primed extension line (100 cm, priming volume 1.2 mL)
with the 3-way stopcock opened. The priming volume of
Q-Syte is 0.36 mL. The remifentanil syringe was placed in
the syringe pump, but the pump had not been started. The
concentration of remifentanil was 100 μg/mL, and it was filled
in a 50-mL syringe.
After the resident established an intravenous line, the at-
tending physician was called to induce anesthesia, and she ar-
rived approximately 2 minutes later. By that time, although
preinduction oxygen was administered by the resident, the
patient's oxygen saturation was 77%, and she was cyanotic.
The attending physician asked, “Are you OK?” and she an-
swered “OK” in a faint voice. While the physicians checked
for equipment errors, the ECG showed bradycardia (heart rate
20 beats/min) with the patient becoming unresponsive and
deeply cyanotic. Chest compressions and 100% oxygen via
mask ventilation were initiated, and 1 mg of epinephrine was
administered via the venous line connected to remifentanil.
The cyanosis quickly resolved with manual ventilation. After
Y. Furuichi et al.
approximately 1 minute, the patient began to move, raised
her arms to push aside the chest compressions, and started
breathing. She quickly recovered full consciousness and the
cardiopulmonary resuscitation was stopped. Radial artery can-
nulation was held, and the systolic blood pressure was mea-
sured to be 180 mm Hg. Arterial blood gas analysis, post–
cardiopulmonary resuscitation, with an O2 6-L per minute by
face mask showed a pH of 7.273, PaCO2 of 53 mm Hg, PaO2
of 274 mm Hg, bicarbonate of 24 mmol·L−1, and a base excess
of −3.4 mmol·L−1. The hemoglobin level was 13.1 g·dL−1;
Na+, 139 mmol·L−1; K+ , 3.77 mmol·L−1; glucose, 143
g·dL−1; and lactate, 0.75 mmol·L−1. Twelve-lead ECG
showed premature ventricular contractions.
Her systolic blood pressure decreased to around 80-
100 mm Hg in several minutes. The patient reported chest pain
and ischemic heart disease was considered a possibility. Treat-
ment with nicorandil was initiated, and the patient was trans-
ferred to the intensive care unit.
Again, a 12-lead ECG showed unchanged results. Howev-
er, 1 hour after admission to the intensive care unit, the ECG
showed negative T waves in leads V3 through V6, and trans-
thoracic echocardiography revealed asynergy in the left anteri-
or ventricular wall, with serum troponin T levels (collected
about 3 hours after cardiopulmonary resuscitation) elevated
to 0.478 ng·dL−1. Because acute coronary syndrome was sus-
pected, an emergency coronary angiogram was performed.
The blood flow in all coronary arteries was normal, but the left
ventricular apical wall motion was decreased, and the basal
wall motion was increased. Takotsubo cardiomyopathy was
diagnosed. By postoperative day (POD) 3, the left ventricular
wall motion had gradually improved. On POD 10, the trans-
thoracic echocardiography revealed a left ventricular ejection
fraction of 55%. Throughout the admission period, no cardiac
event occurred and she was discharged from the hospital on
POD 15.
3. Discussion
Remifentanil is an ultra–short-acting μ-opioid receptor ag-
onist with a very fast onset and an ultra-short duration of action
as a result of rapid hydrolysis to an inactive metabolite [4].
Manufacturer recommended dose of remifentanil before start
of anesthesia is 0.5-1 μg kg−1 min−1, and if tracheal intubation
is to occur within b10 minutes, an initial dose of 1 μg/kg may
be given for 30-60 seconds. Inadvertent bolus doses contain-
ing minute amounts of remifentanil result in overdose.
Although used only intraoperatively in Japan, remifentanil
patient-controlled analgesia is used during labor in some other
countries. In recent years, cases of cardiorespiratory arrest re-
lated to remifentanil patient-controlled analgesia have been re-
ported [5-7]. Remifentanil has a greater potential for causing
respiratory depression than other opioids [8].
Anilidopeptide opioids such as alfentanil, fentanyl, remi-
fentanil, and sufentanil may enhance the bradycardiac and
Respiratory depression and bradycardia
hypotensive effect of β-blockers [9-11]. Some studies have
suggested remifentanil to have more potent cardiovascular ef-
fects than other anilidopeptide opioids [10,11] and have cau-
tioned the use of remifentanil as a bolus [11]. Considering
the time of onset and symptoms, we believe that the near-
fatal respiratory depression occurred due to the adverse effects
of remifentanil, and consecutively, bradycardia occurred due
to hypoxia. There is a possibility that the cardiodepressant ac-
tion resulted from the interaction between remifentanil and
carvedilol, which led to severe bradycardia.
When the resident established the intravenous line, the
remifentanil-primed extension line was connected with the 3-
way stopcock open, and the syringe pump had not been
started. The position of the syringe pump was unspecified.
We surmised that either the 3-way stopcock and intravenous
line had been primed with a slight amount of remifentanil be-
fore the intravenous line was established or, resulting from the
difference between the height of the syringe pump and the
patient's height, the patient was flushed with a slight amount
of remifentanil when the resident established the intravenous
line, causing the severe respiratory depression. To prevent in-
advertent delivery of a bolus of remifentanil, the remifentanil-
primed extension line should only be connected to the 3-way
stopcock after the intravenous line has been established and
adequate preparations have been made for the induction of an-
esthesia. Before starting the syringe pump, the attending phy-
sician should ensure that the 3-way stopcock is opened to the
remifentanil-primed extension line. The syringe pump should
not be positioned at a considerably higher level compared with
the position of the patient. Finally, before the patient leaves the
operating room, any residual remifentanil should be removed
from the 3-way stopcock. In our hospital, these rules are abid-
ed by all the anesthesiologists.
In this case, we believe that there was no relationship be-
tween bradycardia and Takotsubo cardiomyopathy. The pa-
tient had no primary cardiac problems that could have
caused severe bradycardia. Although nervous and tense on ad-
mission to the operating room, she did not complain of dys-
pnea or chest pain, and the ECG findings were normal. In
this case, we concluded that the Takotsubo cardiomyopathy
had been caused by epinephrine administered during cardio-
277
pulmonary resuscitation. There is a possibility that myocardial
stunning had occurred because of a massive afterload increase
from a big dose of epinephrine and chest compressions. Be-
cause we had assessed the patient was to be in a state of pulse-
less electrical activity, 1 mg of epinephrine was administered.
However, because the patient did not experience cardiac arrest,
a chronotropic agent like atropine should have been used.
In conclusion, close attention should be paid to prevent pro-
viding an inadvertent bolus of remifentanil and while adminis-
tering remifentanil in patients receiving β-blockers.
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