Prediction of blood pressure change during surgical incision under opioid analgesia using sympathetic response evoking threshold

概要

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Prediction of blood pressure
change during surgical incision
under opioid analgesia using
sympathetic response evoking
threshold
Satoshi Kamiya1, Ryuji Nakamura1*, Noboru Saeki1, Takashi Kondo1, Hirotsugu Miyoshi1,
Soushi Narasaki1, Atsushi Morio1, Masashi Kawamoto2, Harutoyo Hirano3, Toshio Tsuji4 &
Yasuo M. Tsutsumi1
Opioid inhibition of nociceptive stimuli varies in individuals and is difficult to titrate. We have reported
the vascular stiffness value (K) as a standard monitor to quantify sympathetic response with high
accuracy. On the contrary, among individuals, a considerable variation in the rate of change in K for
constant pain has been observed. In this study, we proposed a new index, the minimum stimulus
intensity value that evoked the response on K ­(MECK: Minimum Evoked Current of K), and evaluated
its accuracy in predicting sympathetic response to nociceptive stimuli under constant opioid
administration. Thirty patients undergoing open surgery under general anesthesia were included.
After anesthetic induction, remifentanil was administered at a constant concentration of 2 ng/ml at
the effect site followed by tetanus stimulation. ­MECK was defined as the minimal current needed to
produce a change in K. ­MECK significantly (P < 0.001) correlated with the rate of change of systolic
blood pressure during skin incision ­(ROCBP). Bland–Altman plot analysis using the predicted ­ROCBP
calculated from ­MECK and the measured ­ROCBP showed that the prediction equation for ­ROCBP was
highly accurate. This study showed the potential of ­MECK to predict blood pressure change during
surgical incision under opioid analgesia.
Clinical trial registration Registry: University hospital medical information network; Registration
number: UMIN000041816; Principal investigator’s name: Satoshi Kamiya; Date of registration: July
9th, 2019.
The International Association for the Study of Pain defines pain as an aversive sensory and emotional experience.
Patients under general anesthesia are unconscious and do not have an aversive experience. However, anesthesiologists commonly use analgesics in addition to sedatives because nociceptive stimuli can cause noxious autonomic reflexes. Opioids are the most commonly used analgesics during general anesthesia due to their lack of a
ceiling effect. Opioids exert their analgesic effects mainly by inhibiting sensory nerve transmission in the spinal
cord and by inhibiting the excitation of pain conduction pathways in the brain. When opioids are administered
during general anesthesia, noxious autonomic reflexes are suppressed and multiple parameters such as heart
rate, blood pressure, electrocardiogram, and respiratory rate are affected. During surgery, anesthesiologists rely
on these parameters to estimate pain levels and adjust the opioid dosage. However, this nociceptive stimuliinduced sympathetic response varies among individuals, and therefore, so do individual anesthetic requirements.
Adverse events, either as an unexpected increase in blood pressure due to underdosing or delayed arousal due to
overdosing, are common. Thus, if the individual’s opioid requirement can be accurately quantified in advance,
more stable general anesthesia can be performed.

1

Department of Anesthesiology and Critical Care, Hiroshima University, 1‑2‑3 Kasumi, Minami,
Hiroshima 734‑8551, Japan. 2Medical Corporation JR Hiroshima Hospital, Hiroshima, Japan. 3Academic Institute,
College of Engineering, Shizuoka University, Hamamatsu, Japan. 4Graduate School of Advanced Science and
Engineering, Hiroshima University, Hiroshima, Japan. *email: r-nacamura@hiroshima-u.ac.jp

Scientific Reports |

(2021) 11:9558

| https://doi.org/10.1038/s41598-021-87636-7

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Vol.:(0123456789)

www.nature.com/scientificreports/
Nociceptive stimuli input to the central nervous system is output to effector organs such as the heart and
blood vessels via the sympathetic nervous system. Opioids inhibit the input of nociceptive stimuli to the central
nervous system. Therefore, the administration of opioids blunts the sympathetic response to nociceptive stimuli.
In other words, by accurately quantifying the sympathetic response to a given nociceptive stimulus under opioid
administration, we can determine the relationship between the opioid dose and the response to the nociceptive
stimulus and quantify opioid sensitivity. Photoplethysmography (PPG), an increasingly popular tool, has recently
begun to be used to measure sympathetic cutaneous blood flow responses for quantifying sympathetic nerve
activity in peripheral v­ asculature1–4. However, PPG measures blood flow at the measurement site and does not,
in principle, directly indicate the degree of sympathetic response. Therefore, we proposed a method to extract
only the degree of vasoconstriction from sympathetic cutaneous blood flow responses to PPG and quantify it
as vascular stiffness value (K)5. We reported that K could be used to quantify pain and reflect the activity of
the sympathetic nervous ­system6,7. Moreover, we reported that K value reflects changes in pain caused by the
administration of opioids during general anesthesia and that the response of K to pain was attenuated with
increasing doses of ­opioids8–10.
On the contrary, among individuals, a considerable variation in the rate of change in K for constant pain has
been ­observed9,10. We speculated that this may have been due to the fact that the pathway of nociceptive stimuli,
which travel from the peripheral nerves through the central nervous system to effector organs such as peripheral
blood vessels, is strongly influenced by autonomic changes due to aging and coexisting diseases. While opioids
inhibit the afferent pathway of pain perception, the rate of change of K represents the intensity of the sympathetic response or the efferent pathway. In other words, the rate of change in K includes information from both
efferent and afferent pathways, so the measurement results may vary depending on the sensitivity of the effector.
Therefore, we hypothesized that the “intensity of nociceptive stimuli" at which sympathetic responses appear is
a better indicator of opioid sensitivity than the "intensity of sympathetic responses" to nociceptive stimuli (that
is, the rate of change in K) because it exclusively extracts only information regarding afferent pathways.
In this study, we proposed a new index, the minimum stimulus intensity value that evoked the response
(MEC: Minimum Evoked Current ) on each parameter, and evaluated its accuracy in predicting sympathetic
response to nociceptive stimuli under constant opioid administration. The primary objective of this study was
to compare the prediction accuracy of R
­ OCBP by MEC for each parameter, and the secondary objective was to
compare the prediction accuracy of R
­ OCBP between ­MECK and ­KR80.

Patients and methods

Patients.  Prior to the study, we received approval from the Ethics Committee of Hiroshima University (‘Hi’-

226, ‘E’-1523-1) and registered the clinical trial (registry: university hospital medical information network, registration number: UMIN000041816, principal investigator’s name: Satoshi Kamiya, Date of registration: July 9th,
2019). This study was conducted in accordance with the Declaration of Helsinki and STROBE statement. The
study population consisted of patients over 20 years of age who underwent open surgery under general anesthesia from July 2019 to October 2019. A total of 30 patients gave their written informed consent before the study.
All procedures were conducted at the Hiroshima University Hospital. We excluded patients with irregular R-R
via electrocardiogram (ECG), inability to perform invasive arterial pressure measurements in the radial artery,
significant hemodynamic or neurological impairment in the upper extremity, and severe stenosis or occlusive
lesions in the coronary arteries or cerebral vessels. If, for a patient, the mean blood pressure remained below
50 mmHg for more than 3 min during the study time, the study protocol for that patient was discontinued.

Measurement and protocol.  Before induction of anesthesia, a photoplethysmography probe (TL-271T,

NIHON KODEN, Tokyo, Japan) on the middle finger of the left hand, ECG on the chest, electroencephalogram
(EEG; Entropy, GE HEALTHCARE UK LTD., Buckinghamshire, UK) on the anterior forehead, neuromuscular
blockade monitoring device (NMT- Neuromuscular Transmission, GE HEALTHCARE UK LTD., Buckinghamshire, UK) on the ulnar side of the forearm of the right hand, and a non-invasive blood pressure cuff on the right
upper arm were placed. In all patients, a preoperative dosing plan was developed to achieve a predicted effectsite concentration of 2 ng/ml remifentanil. Minto’s pharmacokinetic ­model11 was used to calculate predicted
effect-site concentrations. Administration of remifentanil was initiated as per the dosing plan, and propofol
3 μg/ml was used to induce anesthesia using a target-controlled infusion (TCI) pump with built-in ‘Diprifusor’
(TE-371, TERUMO, Tokyo, Japan). After the patient was unconscious, 50 mg of rocuronium was administered
and a 22 G catheter was secured in the left radial artery for measuring arterial blood pressure (ABP). Data from
ECG, ABP, and PPG were output to a personal computer from a bedside patient monitor (BSS-9800, NIHON
KODEN, Tokyo, Japan) and were used to calculate K values in real-time.
After the predicted effect-site concentration of remifentanil reached a steady state at 2 ng/ml, tetanus stimuli at
50 Hz for 5 s were delivered through a two-pole body surface electrode on the ulnar side of the right hand using
the INNERVATOR 252 (FISHER & PAYKEL HEALTHCARE, Auckland, New Zealand). The current value was
initially 10 mA and increased in increments of 10 mA until 80 mA, the maximum output of the INNERVATOR
252, was reached. Thus, a total of eight tetanus stimulation sessions were performed. ...

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