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CASE REPORTParadoxical increase in the photoplethysmography amplitude
in response to nociceptive stimulation induced by tracheal
intubation : A case report
Satoshi Kamiya, Ryuji Nakamura, Noboru Saeki, and Yasuo M Tsutsumi
Department of Anesthesiology and Critical Care, Hiroshima University, Hiroshima, Japan

Abstract : Background : Although an increase in sympathetic nerve activity is generally associated with a decrease in the photoplethysmography (PPG) amplitude, the present case study demonstrates that nociceptivestimuli, such as tracheal intubation, paradoxically induce an increase in PPG amplitude. To the best of ourknowledge, this is the first study to capture an increase in the PPG amplitude in response to sympathetic nerve
activation. Case presentation : A 73-year-old woman underwent open surgery. Following anesthesia induction,
tracheal intubation was performed, which resulted in increased heart rate and raised blood pressure. Whilenociception usually decreases the PPG amplitude, the opposite was found. Conversely, the vascular stiffness
K value, our research group’s unique monitoring method to quantify the strength of sympathetic activity,increased reflecting increased peripheral vascular resistance. Conclusions : We report a paradoxical case ofincreased PPG amplitude following tracheal intubation. It is important to note that the PPG amplitude does
not always decrease with nociceptive stimuli. J. Med. Invest. 68 : 383-385, August, 2021
Keywords : Photoplethysmography, sympathetic response, vascular stiffness

BACKGROUND
Nociceptive stimuli are known to provoke sympathetic responses, resulting in increased inotropic and chronotropic effects(cardiac index), systemic vascular resistance (SVR), and bloodpressure (BP). Thus, it is important to accurately evaluate these
sympathetic responses to estimate the intensity of nociceptive
stimuli. However, although heart rate (HR) and BP are simple
monitoring methods of sympathetic responses, they are greatly
influenced by cardioactive agents and changes in circulating
blood volume in addition to nociception. On the other hand,
photoplethysmography (PPG) is a widely used technique toquantify the nociceptive stimulus, as increase in SVR decreases
skin blood flow and amplitude (1). Therefore, recently proposedmonitoring devices for quantifying nociception during surgery,such as the Surgical Pleth Index and Nociception Level, often
use SVR measurement based on the PPG amplitude as anindex of peripheral sympathetic nerve activity (2, 3). The PPG
amplitude can be easily measured with a pulse oximeter, whichis indispensable in anesthesia management, and can be used asa simple method to monitor SVR. Nociceptive stimuli theoretically increase SVR and decrease the PPG amplitude. However,nociceptive stimuli may increase the PPG amplitude when themagnitude of the stroke volume increase overcomes that of thevascular constriction increase (4). There have been several reports of cases where increased SVR increases the cardiac output(CO) (5). However, to the best of our knowledge, no case has beenreported in which nociceptive stimuli actually increased thePPG amplitude. Here, we present a paradoxical increase in thePPG amplitude in response to noxious stimuli, i.e., tracheal intubation in a patient scheduled to undergo open hepatectomy under
Received for publication February 16, 2021 ; accepted June 30, 2021.
Address correspondence and reprint requests to Ryuji Nakamura
M.D., Ph.D., Department of Anesthesiology and Critical Care, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551,
Japan.

general anesthesia. In addition, we simultaneously recorded thechanges in PPG and SVR (or vascular stiffness) and compared
them. Prior written consent was obtained from the patient whosecase is reported in this study. This study fully adheres to theCARE guidelines.

VASCULAR STIFFNESS VALUE K
Previously, our research group succeeded in quantifying SVR
using the vascular stiffness value (K) by fitting the beat-tobeat PPG and Lissajous curves of invasive arterial BP (ABP)
waveforms to a mechanical impedance model (6). Details of
the calculation of K have been reported previously (7). K is thecoefficient of a function in which the arterial waveform is estimated from the function of the PPG waveform, and calculated
by a least square fitting of all waveforms in each heartbeat. K isadopted only when the coefficient of determination of the fittingis ≥ 0.95 ; therefore, it has a high reliability. K is more sensitive
to changes in peripheral vascular resistance than PPG, as it is
not affected by stroke volume. Furthermore, K was reported toquantitatively measure pain and reflect sympathetic nerve activity (8, 9). K is calculated by using the data from electrocardiography (ECG), ABP, and PPG. In our hospital, ECG, ABP, PPG,
and other data are recorded not only numerically, but also as
waveform data for all patients. Because of the rare phenomenonof a paradoxical increase in the PPG during tracheal intubation,
we analyzed these waveform data postoperatively.

CASE PRESENTATION
The patient described here was a 73-year-old woman(height : 144 cm ; weight : 44 kg) who was scheduled to undergo hepatic S7 subsegment resection due to hepatocellular
carcinoma secondary to hepatitis C and gallbladder resection.
Her medical history included thrombocytopenia (83,000 / µL),
hypertension, and diabetes. Her indocyanine green retention

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S. Kamiya, et al. Paradoxical increase in the PPG amplitude

rate at 15 minutes was 14.6%, and Child-Pugh classification
was grade A, indicating that liver damage was relatively mild.
Oral medications included omega-3-acid ethyl esters, nicardipinehydrochloride, sitagliptin phosphate hydrate, and teprenone.
Without premedication, laxatives were administered on the day
before surgery as preoperative treatment, which caused a reaction stool. The patient had her last meal and drink 14 hours and
12 hours, respectively, before entering the operating room. In
the operating room, the equipment was attached and monitoring
was started. This included : a photoplethysmography probe (TL271T, Nihon Kohden, Tokyo, Japan) was placed on her left middle
finger ; ECG and electroencephalogram probes (EEG ; Entropy,GE Healthcare UK Ltd., Buckinghamshire, UK) were placed onher chest and anterior forehead, respectively ; a neuromuscular
blockade monitoring device (NMT- Neuromuscular Transmission, GE Healthcare UK Ltd., Buckinghamshire, UK) wasplaced on the ulnar side of her right forearm ; and a non-invasive blood pressure cuff was placed on her right upper arm. A
preoperative dosing plan was developed to achieve a predicted effect-site concentration of 2 ng / mL remifentanil. Minto’s
pharmacokinetic model (10) was used to calculate predictedeffect-site concentrations. Before anesthesia induction, her HR
was 52 bpm, BP was 139 / 58 mmHg, oxygen saturation (SpO2)
was 100%, axillary temperature was 35.8℃, and she had cold
extremities. Remifentanil was administered as per the dosing
plan, and propofol was used to induce anesthesia using a target-controlled infusion (TCI) pump with built-in ‘Diprifusor’(TE-371, Terumo, Tokyo, Japan). After the patient became unconscious, 50 mg of rocuronium were administered, and a 22 G
catheter was secured in the left radial artery for measuring arterial blood pressure (ABP). ECG, ABP, and PPG waveform data
were monitored by a bedside patient monitor (BSS-9800, Nihon
Kohden, Tokyo, Japan), and outputted to a personal computer
for the calculation of K. When the target blood concentrations ofpropofol and predicted effect-site concentration of remifentanil
reached a steady state at 2.2 μg / mL and 2 ng / mL, respectively,
the patient’s ABP decreased (58 / 35 mmHg). This was promptly
followed by tracheal intubation using a Macintosh laryngoscope.
Figure shows the waves and trends of each parameter during
tracheal intubation. Briefly, significant increases in the patient’s
HR and ABP were observed in response to tracheal intubation,
and K increased as a normal response to noxious stimuli, reflecting vasoconstriction. However, despite the noxious stimuli, her
PPG amplitude paradoxically reached a peak, which was several
seconds behind the ABP and K value peaks and continued evenafter those returned to their basal values.

DISCUSSION
Here, we reported the case of a patient scheduled to undergo
open hepatectomy under general anesthesia who showed paradoxical increase in the PPG amplitude in response to noxious
stimuli. Previous literature suggests that an unpleasant stimulus produces a sympathetic response that increases SVR, resulting in an increase in BP and a decrease in the PPG amplitude(4). Many of the currently proposed nociceptive monitoring methods utilize this phenomenon and are designed so that the indexof nociception decreases with increase in the PPG amplitude (2,3). Therefore, it should be noted that nociceptive monitors usingthe PPG amplitude as the primary signal will provide erroneous
readings in cases that show paradoxical changes in the PPG
amplitude, as observed here.
In the present case, a cold sensation in the periphery of the patient’s extremities was observed before anesthesia induction. Inaddition, her BP was extremely low after anesthesia induction.

These findings suggest that the patient’s circulating blood volume was very low. In addition, the vasodilator action and heart
deterrent effect of propofol may have contributed to the hypovolemia before tracheal intubation. Based on the change in K aftertracheal intubation, SVR is likely to have increased because oftracheal intubation in this patient. However, the PPG amplitude
paradoxically increased. Similar to studies showing that elevated SVR during hypovolemia increases venous return and CO (5),sympathetic responses associated with tracheal intubation likely
caused the increase in SVR, venous return, and CO. The PPG
amplitude is determined by the balance of the forces between theblood supply (CO) and SVR (11). When comparing the increase in
the cardiac index and SVR due to tracheal intubation, the former
may have had a greater effect, resulting in an increase in thePPG amplitude. It is important to note that nociceptive stimuli
may paradoxically increase the PPG amplitude under conditionsof reduced circulating blood volume.
In contrast to PPG, K displayed a normal response and increased with the noxious stimulus. Given that K is the coefficientof the first derivative of the displacement of the vascular wall
against the force applied on the vascular wall itself, it is lessaffected than PPG by the change in blood volume and accuratelyreflects changes in SVR. In our previous studies, the direction of
the response to tracheal intubation of the K value and PPG wereoften the same (12). However, the amount of change in K waslarger than that in the PPG amplitude. This may be because theincreased PPG amplitude due to the increased CO induced by
nociception offsets the effect of increased SVR.
It is noteworthy that the PPG amplitude trend during tracheal
intubation was different from that of K. Specifically, vasoconstriction, represented by K, increased and returned to baseline
after intubation, while PPG continued to increase. As a result,
the timing of PPG amplitude maximization lagged behind ABP
by approximately 40 seconds, with K reaching maximum values(Fig. 1). This temporal change in the PPG amplitude is similar
to the report that phenylephrine causes an increase in venous
return and CO approximately 20–30 seconds after the rise in BP(5). When a nociceptive stimulus is applied, the PPG amplitude issusceptible to changes in SVR (4). However, it seems likely that
the PPG amplitude in this case showed a change that was more
greatly influenced by the change in CO than SVR. Conversely,
K increased quickly after tracheal intubation and was a moreaccurate estimate of SVR change than the PPG amplitude.

LIMITATIONSFirst, considering that the effective circulating blood volume
was not measured, determining the change in CO before andafter anesthesia induction was not possible. Therefore, we
assumed that CO was at a decreased level after anesthesia
induction with the given standard clinical signs (e.g., bowel
preparation, cold skin, and hypotension). Second, atropine was
not administered, as it may modify the sympathetic response.
Although the vagal reflex caused by tracheal intubation should
be considered, it was thought to be less likely, since the HR did
not change and BP was increased by intubation. Finally, we
performed tracheal intubation at an effect-site concentration of
2 ng / mL of remifentanil. Our research group has previously
reported that this concentration of remifentanil suppresses
some sympathetic responses to tracheal intubation in a subsetof patients (12). In addition, we did not increase the dose toavoid exacerbating hypotension. While it is possible that the low
remifentanil concentration resulted in a strong sympathetic response, in light of the actual changes in HR and BP, it is unlikelythat the sympathetic response was stronger than the ones inThe Journal of Medical Investigation Vol. 68 August 2021

385

Figure 1. Changes in parameters before and after the tracheal intubation.

The measured values of K, HR, PPG amplitude, and raw waveforms of PPG and ABP are presented. The time at
the start of tracheal intubation was set to zero. While the HR and ABP increased following tracheal intubation, PPG
also simultaneously increased.
HR, heart rate ; PPG, photoplethysmography ; ABP, arterial blood pressure

routine clinical practice.

CONCLUSION
We suggest that the PPG amplitude does not always correctlyreflect changes in peripheral vascular resistance when special
circulatory dynamics occur, e.g., when the effective circulating
blood volume is extremely low. In the present case, K was foundto be more accurate for reflecting changes in SVR due to nociceptive stimuli, as it correctly showed an increase in vascular tone.

CONFLICTS OF INTEREST
Satoshi Kamiya declares no conflict of interest associated withthis manuscript.
Ryuji Nakamura declares no conflict of interest associatedwith this manuscript.
Noboru Saeki declares no conflict of interest associated withthis manuscript.
Yasuo M Tsutsumi declares no conflict of interest associatedwith this manuscript.

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