Introduction

Surgical interventions for cancers are often extensive and traumatic. Therefore, adequate postoperative pain relief and sedation are essential [1, 2]. According to the concept of multimodal analgesia, various drugs with different mechanisms of action are used in lower doses to achieve pain relief with minimal side effects [3]. An important role in nociception and hyperalgesia is assigned to N-methyl-D-aspartate (NMDA) receptors. Their activation is enhanced by glutamate and biologically active substances (neurokines). Xenon as an inhalation anesthetic agent inhibits glutamate NMDA receptors [4]. Analgesic effect of xenon is realized at the spinal, supraspinal and cortical levels, and xenon blocks hyperalgesia [5]. Xenon can be used as a part of combined anesthesia or monoanesthesia for minor surgical interventions [6]. One of the indications for xenon is the need to enhance narcotic and analgesic effects of other general anesthetics (including postoperative analgesia), as well as various pain syndromes such as acute coronary insufficiency, myocardial infarction, acute pancreatitis and traumatic shock (prevention).

At the same time, analgesic effect of xenon and influence on psycho-vegetative component of pain syndrome in analgesia are unclear. Also, effectiveness of xenon pain relief depending on psycho-emotional characteristics of patients has not been studied. It is important at low xenon concentrations, which are used for pain relief outside of general anesthesia.

Obviously, various methods for pain measurement are necessary to determine the influence of xenon on severity of pain syndrome. Pain rating scales are a convenient and informative instrument for clinicians. However, subjective self-assessment of pain by patients influences these scores. Objective methods for pain measurement can probably give a more correct assessment of clinical status. One of these methods is pupillometry, i.e. dynamic measurement of pupil size.

Pupillary reactions as an objective criterion for assessing the autonomic nervous system were analyzed in various studies [7, 8]. Pupillometry can also be used for assessing pain syndrome during anesthesia and in postoperative period, since the pupil enlarges under activation of sympathetic nervous system and narrows under parasympathetic reactions [9—11].

Some authors found the relationship between pupillometry data and interhemispheric asymmetry, as well as features of mental processes [12, 13]. Considering an important role of psycho-emotional component of pain syndrome, we assumed possible relationship between individual psychological characteristics and pain intensity.

The purpose of the study was to study the effect of xenon-oxygen inhalations on psychovegetative component of pain syndrome after abdominal surgery in cancer patients.

Material and methods

An open randomized blind placebo-controlled study included 60 patients aged 45—75 years with abdominal malignancies. All patients underwent open surgical treatment at the Moscow Cancer Research Institute named after P.A. Herzen between 2019 and 2021.

All patients were randomized into 2 groups: main group (n=31) — xenon-oxygen inhalations, control group (n=29, placebo) — oxygen-air inhalations. Randomization was carried out using random number method so that patients with No. 1—60 were evenly divided into 2 groups. All patients signed an informed consent. The local ethics committee approved the study (protocol No. 444 dated 11/01/2019).

Surgical interventions are summarized in Table 1.

Table 1. Characteristics of surgeries in both groups

Technique of xenon inhalation procedure

Xenon-oxygen inhalations were carried out through a closed respiratory circuit (KTK-01, Fig. 1). This device included gas analyzer to control concentration of xenon and oxygen in respiratory mixture and adsorber with soda lime to absorb carbon dioxide. The content of xenon in inhaled mixture was 25±5%.

Fig. 1. Xenon therapeutic device “KTK-01” (XeMed Ltd, Russia).

As soon as target xenon concentrations were achieved, its supply was reduced to 0 l/min. Total xenon consumption for the procedure did not exceed 3 liters. Amount of oxygen was adequate to ensure sufficient tidal volume. We used medical xenon (XeMed®, LLC “AKELA-N”, Russia, registration certificate LS-000121) and gaseous medical oxygen (GOST 5583). Inhalation time was 10 min. In the placebo group, patients inhaled mixture of 50% oxygen and 50% air. Treatment was started in 2—3 postoperative days after transferring to surgical department before the next injection of anesthetic drug.

All patients received standard postoperative pain relief: epidural analgesia, ropivacaine 8 mg/h, non-steroidal anti-inflammatory drugs, lornoxicam 16 mg, and tramadol 100 mg as required.

We assessed pain syndrome using numeric rating scale (NRS) and pupillometry data.

NRS scores of pain syndrome were assessed as follows: 0 — no pain, 1—3 — mild pain, 4—6 — moderate pain, 7—9 — severe pain, 10 — unbearable pain.

Pupillometry was carried out using the IriCAMM binocular pupillometric hardware-software complex (Sambon P&E, Republic of Korea). This device records pupil size changes in response to light flashes. This complex is based on synchronous video recording of pupillary reactions of both eyes to suprathreshold light stimulus, automatic processing of video sequences of eye images, calculation of pupillographic parameters and analysis of results.

Examination was performed under uniform background artificial lighting (70±20 lux) with obligatory preliminary adaptation of subjects to lighting for 5 min. At this time, we instructed patients on the procedure (no motions, no changes in gaze direction and not blinking). To enter the video sequence, the patient’s eyes were illuminated with invisible infrared light. Duration of visible (white) light flash was 30 ms, intensity — 45 lux, distance between the camera lens and the eye — 12±1 cm. Light flash was bilateral and synchronous. Registration of data from both eyes was carried out synchronously with an error of up to 200 microseconds. Shooting time was 2.5 seconds.

Pupillogram was automatically created for each eye after processing the video sequence (Fig. 2). The graph is presented in the following coordinates: abscissa axis (t) — time in milliseconds, ordinate axis (R) — pupil size (relative radius) as a percentage of iris radius. This approach excludes the correlation of results with the distance between the eye and video camera, as well as scale of the camera’s field of view.

Fig. 2. Pupillometry parameters.

rLat — baseline pupil size (size in latent section of contraction); tLat — duration of latent section before the start of reaction; rMin — pupil size at the minimum point (minimum size); tMin — time for the minimum point; Para — duration of contraction phase (duration of parasympathetic phase of reaction); Contr and Contr2 — pupil contraction in %: Contr — pupil contraction in percent relative to iris area, Contr2 — pupil contraction in percent relative to baseline size, i.e. pupil size in latent section is taken as 100%; UgLat — criterion for activity of parasympathetic phase of reaction (contraction phase); UG40 — criterion for activity of sympathetic phase of reaction (recovery phase) calculated for the pupillogram point at a distance of 667 ms from the minimum point. Duration of this section is similar to mean duration of active recovery phase, i.e. pupil dilation with positive speed; Plato — duration of latent section before recovery; Speed — pupil contraction speed.

t1SpdCntr and t2SpdCntr characterize parasympathetic phase of reaction (pupil contraction). Contraction phase is divided into 3 sections: 1 — contraction process picks up speed; 2 — pupil constriction at a constant speed, 3 — slowing down the contraction up to complete stop at the minimum point. The 1^st section characterizes training of pupillomotor system. The 2^nd section determines the depth of reaction to unexpected stimulus. The length of parasympathetic phase (Para) is equal to the sum of 3 sections + half of Plato. t1SpdCntr corresponds to the time when acceleration of constriction process ends. t2SpdCntr is the end of contraction at a constant speed.

t1Crk, t2Crk and t3Crk characterize pupil dilation, where t1Crk is onset of pupil dilation at a constant speed, t2Crk — the middle of pupil dilation at a constant speed, t3Crk — the end of pupil dilation at a constant rate, i.e. end of active recovery.

Pupillometry parameters make it possible to evaluate 3 phases of pupillary reaction. The first phase is latent period of pupillary reaction and corresponds to the time of nerve impulse passage along conduction pathways (speed of nervous processes). The second phase characterizes pupillary sphincter and activity of parasympathetic nervous system. The third phase characterizes the state of pupil dilator and activity of sympathetic nervous system.

Certain pupillography parameters clearly correlate with dynamic mental characteristics. Thus, duration of latent period of reaction (tLat) negatively correlates with mobility of nervous processes. Duration of parasympathetic phase of pupillary response (Para) and pupillary contraction relative to iris size (Contr) positively correlate with force. Pupillary constriction speed (Speed) is also correlated with mobility of nervous processes.

Duration of latent period, amplitude and speed of sympathetic and parasympathetic phases of pupillograms of each eye provide information on desynchronization, sensorimotor interhemispheric functional asymmetry and degree of impairment of autonomic regulation of both hemispheres.

Psychological testing was carried out using individual typological questionnaire (ITQ) and color test (Sobchik L.N.).

The ITQ methodology is based on the theory of leading tendencies by L.N. Sobchik [14, 15]. Leading tendencies determine the main type of response, strength and direction of motivation, styles of interpersonal communication and cognitive processes. The questionnaire consists of 91 statements, and the subject should evaluate them as true or false in relation to himself. The questionnaire contains confidence scales to identify motivational distortions of results (Appendix 1).

Factor scales:

— lie (insincerity, tendency to show oneself in the best light);

— aggravation (the desire to emphasize the existing problems and complexity of one’s own character);

— extraversion (turning to the world of real objects and values, openness, desire to expand the circle of contacts, sociability);

— spontaneity (lack of thought in statements and actions);

— aggressiveness (active self-realization, stubbornness and willfulness in defending one’s interests);

— rigidity (inertia, stiffness) of attitudes, subjectivism, an increased desire to defend one’s views and principles, criticism of other opinions;

— introversion (turning to the world of subjective ideas and experiences, tendency to go into the world of illusions, fantasies and subjective ideal values, restraint, isolation);

— sensitivity (sensibility, tendency to reflection, pessimism in assessing prospects);

— anxiety (emotionality, susceptibility, insecurity);

— lability (mood variability, motivational instability, sentimentality, desire for emotional involvement).

Data analysis was performed by using of a computer program.

Interpretation of results:

— 0—1 point — reduced emotions, poor self-understanding or lack of frankness during examination;

— 3—4 points (norm) — harmonious personality;

— 5—7 points (moderate) — accentuated features;

— 8—9 points (excessive) — emotional tension, difficult adaptation.

The norm is within 4 points. Increased values indicate emotional tension.

Color test is an adapted version of the eight-color Luscher test [16]. This technique allows you to identify unconscious reactions of subject regardless of subjective attitude to any color. This feature determines projective nature of this test. Color test provides a “slice” of psycho-emotional state at a certain moment. The patient is asked to choose the most pleasant color among color cards without thinking about how much he likes this color in general but only taking into account preferences at this moment. The researcher records the number of each selected color card.

Numbers of color standards: dark blue — 1, blue-green — 2, orange-red — 3, yellow — 4, violet — 5, brown — 6, black — 7, gray — 0. Selection procedure is repeated twice. Normally, bright colors should be in the first positions, achromatic — in the last ones. We interpreted data using a computer program and calculated the number of anxiety points depending on position of color in each choice.

Statistical analysis

Considering Shapiro-Wilk test (α=0.05), we concluded abnormal distribution of data and used nonparametric statistical methods.

Statistical analysis was performed using non-parametric Wilcoxon tests for within-group comparison and Mann-Whitney for between-group comparison. Correlation analysis (non-parametric Kendal correlation coefficient) was applied too. Differences were significant at p-value <0.05.

Results

NRS scores demonstrated significant differences in pain syndrome between baseline values and after 2—3 postoperative days. Postoperative pain score was about 4 out of 10 points (moderate pain). Xenon-oxygen inhalation significantly reduced pain syndrome (Table 2).

Table 2. NRS scores of pain syndrome in both groups

Note. Wilcoxon test for within-group analysis, p<0.05.

Noteworthy is significant decrease of pain syndrome in the placebo group (to a lesser extent compared to the main group).

Further assessment of pain syndrome revealed significantly shorter duration of analgesic effect in the placebo group (1 (0—3) vs. 5 (4.00—8.75) hours, p=0.0003) (Fig. 3).

Fig. 3. Duration of analgesia in both groups.

Note. * — significant between-group differences, p=0.0003.

Assessment of psycho-emotional state by using of color test revealed no significant between-group differences (Fig. 4, Table 3).

Fig. 4. Color test data in both groups.

Note. 1 — baseline values, 2 — before inhalation, 3 — after inhalation.

Table 3. Changes in color test indicators (the 2^nd choice) under the influence of xenon-oxygen and oxygen-air inhalations

Note. data are presented as a median, interquartile range; differences were analyzed using the Wilcoxon test, p <0.05.

All changes in color test were insignificant in both groups. We also analyzed the difference between the first and second choice in color test, as it reflects changes in psycho-emotional state (decrease or increase of anxiety) (Table 4). These changes were insignificant too.

Table 4. Color test changes (∆ between both choices) in both groups

Importantly, color test is largely determined by actual situation and can describe various influences. Therefore, the ITQ test was used to assess the relationship between personality traits and pain perception. These results in the form of pooled psychological profile of cancer patients are shown in Fig. 5. Sensitivity combined with anxiety and emotional lability prevailed among personality traits. This is typical for the so-called “weak” type of response to a stressful situation. In general, the profile was similar to increased emotional tension. We determined the correlations between these results and NRS score of pain syndrome (Table 5).

Fig. 5. Properties of cancer patients according to individual typology questionnaire.

Table 5. Correlations between personal properties and pain syndrome before and after xenon-oxygen and oxygen-air inhalations

Note. NRS — numeric rating scale, ITQ — individual typological questionnaire, *p<0.05.

We found significant negative correlations between NRS scores and introversion, sensitivity, lability, anxiety and aggressiveness. Positive correlation was observed between NRS scores and lie, rigidity. Duration of analgesic effect correlates positively with lability and negatively with introversion.

Each patient underwent pupillometry 3 times: before inhalation, immediately after inhalation and after 30 minutes. We obtained correlations between pupillometric parameters and NRS scores. Moreover, all data were divided into the groups considering inhalation (xenon or placebo) and stage of the study. We identified significant correlations between NRS score of pain syndrome and pupillometric parameters describing the state of autonomic nervous system (Table 6).

Table 6. Correlations between pupillometry parameters and pain syndrome in both groups

Note. correlations between NRS scores and pupillometry parameters are presented. Data are obtained before, immediately after and 30 minutes after xenon-air and oxygen-air inhalation, *p<0.05.

Importantly, correlation qualities are the same for all groups in the tables. Correlations are mostly stronger for the xenon group. In the placebo group, significant correlations (p < 0.05) were obtained only for tests before inhalation. All other tests showed no significant correlations in the placebo group.

We obtained direct correlations with NRS scores for the following parameters:

— rLat (baseline pupil size);

— rMin (pupil size at the minimum point);

— Contr and Contr2 (pupil constriction (%) in different values);

— UgLat (activity of parasympathetic phase of reaction — constriction phase);

— UG40 (activity of sympathetic reaction phase — recovery phase);

— Speed (pupil constriction speed).

These parameters are higher in patients with more severe pain. At the same time, higher UgLat and UG40 characterize lower activity of appropriate phase (sympathetic or parasympathetic).

Negative correlations with NRS scores were obtained for the following parameters:

— tLat (duration of latent region before the start of reaction);

— tMin (time for the minimum point);

— Para (duration of parasympathetic phase of reaction);

— Plato (duration of latent area before recovery);

— t1SpdCntr, t2SpdCntr (parameters characterizing parasympathetic phase of reaction);

— t1Crk, t2Crk, t3Crk (parameters characterizing activity of pupil dilation process).

These parameters describing the state of parasympathetic and sympathetic phases are characterized by inverse dependence on exhaustion of appropriate part of autonomic nervous system.

Discussion

We found analgesic effect of xenon-oxygen inhalations and similar short-term effect after oxygen-air inhalations. Duration of placebo effect was short-term and did not exceed 1 hour, while duration of pain relief after xenon-oxygen inhalations was more than 5 hours.

There were negative correlations between NRS scores and introversion, sensitivity, lability, anxiety and aggressiveness, as well as positive correlations between NRS scores and lie, rigidity. Duration of analgesic effect correlates positively with lability and negatively with introversion.

Sensitivity, lability, anxiety and aggressiveness characterize figurative style of thinking with predominant reliance on intuition that is typical for the right hemispheric type [14]. People with right hemispheric type of perception are characterized by milder postoperative pain syndrome. Pain was more severe in rigid personalities with predominant abstract-logical thinking (left hemispheric type of intelligence).

Considering obvious narcotic properties of xenon and potential impact on consciousness in low concentrations, we assessed the results using other methods. Pupillometry is currently used in anesthesiology and intensive care for monitoring of pain sensations [11, 17]. This method does not allow continuous measurements due to necessary pupillary response testing for assessing pain. Moreover, the limitation of this method is effect of opioids on pupil size. Therefore, pupillometry can characterize narcotic effect rather severity of nociception. At the same time, some authors have shown that pupillometric response to standardized pain stimulus (tetanic nerve stimulation with a current of 20 mA) was a predictor of response to tracheal sanitation in intensive care unit [18, 19].

Pupillary reaction to stimulus (light, sound, logical, pain, etc.) is an unconditioned reflex that cannot be controlled by the cortex and consciousness. At the same time, it is a sensitive indicator of various physiological processes depending on sympathetic-parasympathetic balance. This reaction is valuable to analyze functional state of central nervous system.

Pupillary reaction to light stimulus is described by 3 main phases, and this process characterizes interaction of both components of autonomic nervous system. Since autonomic nervous system is anatomically and physiologically connected with higher parts of central nervous system, parameters of pupillary reactions are largely determined by mental state. That is, dynamics of pupillary reaction makes it possible to assess the features of psychophysiological state during examination.

NRS score of pain positively correlates with pupil size. However, pain proportionally decreases activity of both sympathetic and parasympathetic systems (UgLat, UG40). Severe pain syndrome is accompanied by fast exhaustibility of autonomic nervous system (short latent sections of both phases of reaction, high constriction rate with low potential for both constriction and recovery of pupil).

Xenon-oxygen inhalations changed reactions of autonomic nervous system to painful stimuli, in particular, duration of parasympathetic phase of pupillary reaction. Impact on parasympathetic system changed responses to painful stimuli that results negative correlation between NRS score, Para and Tmin.

Pain relief after xenon inhalations was approximately twice as large as for the placebo group. This group was characterized by significant changes of rLat (decrease by 0.37%), tLat (increase by 13.9 ms), and Para (decrease by 17.76 ms) andContr (decrease by 1.21%). This indicates inhibitory effect of xenon on parasympathetic phase of reaction. There was another dynamics in the placebo group: the pupil enlarged by 0.5%, duration of constriction phase increased by 18.86 ms, activity of parasympathetic phase increased (UgLat decreased by 1.26º). These are signs of stimulation of parasympathetic phase by oxygen-air inhalation.

Conclusions

1. Xenon-oxygen inhalations promote pain relief after abdominal surgery for cancer.

2. Mean duration of analgesic effect after xenon-oxygen inhalations was 5 hours and significantly exceeded duration of placebo effect.

3. There were significant correlations between pupillometry parameters and NRS scores of pain syndrome.

4. We found the relationship between personal characteristics, effect of xenon inhalation on pain syndrome and duration of analgesic effect. More severe pain syndrome was observed in rigid personalities, less pronounced — in sensitive and emotionally labile ones.

The authors declare no conflicts of interest.