Assessment of stress response due to C-Mac D-blade guided videolaryngoscopic endotracheal intubation and docking of da Vinci surgical robot using perfusion index in patients undergoing transoral robotic oncosurgery

Clinical utility of perfusion index (PI) has entered a new realm as a non-invasive, quantitative index of stress response to endotracheal intubation. Transoral robotic surgery (TORS) involves F-K retractor aided docking of the surgical robot producing haemodynamic and stress responses akin to laryngoscopy. We compared the stress response to videolaryngoscopy with that due to docking of da Vinci surgical robot using PI, heart rate and mean arterial pressure evaluated at specific time points post-laryngoscopy and post-docking. Twenty-six adult patients, scheduled for TORS under general endotracheal anaesthesia were included in this prospective, observational, single-centric cohort study. Statistical analysis included paired samples t-test, dotted box-whisker plots, trendlines and correlograms for comparative analysis of two stressors, laryngoscopy and docking. Baseline PI was 4.14. PI values increased post-midazolam (4.23), 1 min (5.69) and 3 min (6.25) post anaesthetic-induction, plummeted at laryngoscopy (3.24), remained low at 1 min (3.68), 3 min (4.69) thereafter, and were highest at 10 min (6.17) post-laryngoscopy and predocking (6.84). Docking witnessed a fall in PI (4.1), which remained low at 1 min (4.02), 3 min (4.31) and 10 min (4.79) post-docking. PI was significantly higher at laryngoscopy compared with PI at docking (p = 0.0044). At 1 min and 3 min post-laryngoscopy and post-docking, respectively, the differences in PI were statistically insignificant. PI at 10 min post-laryngoscopy was significantly lower than PI at 10 min post-docking (p < 0.0001). As non-invasively quantified by PI, videolaryngoscopic stress response is more intense but shorter-lived versus that due to docking. PI displays a negative correlation with haemodynamic variables. PI at laryngoscopy is a good predictor of PI at docking, enabling pre-emptive measures (fentanyl bolus; deepening of volatile anaesthesia from MAC-maintenance to MAC-intubation) anticipating the docking-induced stress response. Trial registrationhttp://ctri.nic.in; Identifier: CTRI/2019/11/022091.


Introduction
Non-invasive techniques for predicting the haemodynamic responses to anaesthetic drugs, airway intubation techniques, invasive procedures, intraoperative stimuli and post operative pain constitute welcome advances in anaesthetic practice. A practical and user-friendly method of quantitative evaluation of sympathetic tone or stress response would be of extreme clinical utility. Perfusion Index (PI) is a promising non-invasive tool for detection of stress response to supraglottic airway and endotracheal tube insertion during propofol, fentanyl and isoflurane anaesthesia and acute postoperative pain [1,2]. PI is a dimensionless number indicative 1 3 of the strength of infrared rays (940 nm) returning from the site housing the co-oximeter probe (hand, finger, toe). PI represents an indirect, non-invasive and accurate index of peripheral perfusion calculated by co-oximetry by expressing the pulsatile signal (during arterial inflow) as a percentage of the non-pulsatile signal and ranges from 0.02% (very feeble pulse) to 20% (very strong pulse strength) [3][4][5]. Feyh-Kastenbauer retractor (F-K retractor; Olympus Medical Systems, Tokyo Japan) aided docking of surgical robot for transoral robotic surgery (TORS) is another intraoperative stressor (akin to laryngoscopy) [6] which has so far not been evaluated quantitatively (Fig. 1).
We correlated PI changes with conventional haemodynamic criteria in 26 adult patients undergoing C-Mac D-blade guided videolaryngoscopic endotracheal intubation for transoral robotic oncosurgeries (TORS). Definition of stress response in context of this study is any one or more of these three criteria: 10% increase in heart rate (HR), 20% increase in mean arterial pressures (MAP) and ≥ 10% decrease in PI from baseline values.
Our primary outcome measure was the perfusion index (PI) in the upper limb at specified time points during anaesthetic induction, laryngoscopy and docking of the da Vinci Xi surgical robot (Intuitive Surgical; Sunnyvale; CA; USA). Our secondary outcome measures were the HR, and MAP measured during induction, laryngoscopy and docking of surgical robot. Our primary objective was to compare the PI changes during C-Mac D-blade guided videolaryngoscopic intubation and FK-retractor aided docking of da Vinci surgical robot in patients undergoing TORS. Our secondary objective was to ascertain if any correlation exists between PI and non-invasive haemodynamic parameters (HR and MAP) measured at specific time points during anaesthetic induction, videolaryngoscopic endotracheal intubation and FK-retractor aided docking of surgical robot.

Methodology
This prospective, observational, single centric clinical study was carried out in accordance with the Helsinki Protocol after taking written informed consent from all the patients, and approval from the scientific committee and institutional review board. It is prospectively registered with the Clinical Trial Registry of India. Ethical approval for this study (RGCIRC/IRB/255/2018) was obtained from Ethical Committee of Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India (Chairperson Dr. A Rao) on 4 February 2019. It was conducted from November 2019 to January 2022 in the Major Operation Theatre of a tertiary care oncology centre in accordance with the Helsinki Protocol and included 26 adult patients. All ASA I-II patients aged between 35 and 70 y, weighing 40-85 kg with mouth opening greater than two fingers and Mallampati grade 1-3 patients undergoing elective oral robotic oncosurgery were included in this study. Exclusion criteria comprised patient refusal, patients with mouth opening less than two fingers and Mallampati Grade-4 patients. Fidelity to protocol to eliminate performance-bias and data analyst blinding to avoid detection-bias was employed.

Sample size calculation
Taking difference in mean PI values between two groups as 0.47 and standard deviation in first and second group as 0.44 and 0.56 respectively from a previous study [1] comparing PI values at endotracheal intubation with PI values at I-gel insertion, and fixing Type-1/alpha error at 0.05 and power of the study at 0.9 we arrived at a sample size of 26 patients (since in our study laryngoscopy and robotic docking were performed on the same patient).

Statistical analysis
Descriptive summary is presented for both types of variables i.e., categorical and continuous. Data was subjected to statistical analysis using Medcalc statistical software (version 18.9.1; released 2018; MedCalc Software bvba, Ostend, Belgium) Paired samples t-test for equality of means and dotted box-whisker plots were utilized. To find the association between PI and haemodynamic variables Pearsons's correlation test was used and a correlogram created.

Anaesthetic technique
After application of standard monitors, patients were premedicated with intravenous glycopyrrolate 4 μg.kg, −1 midazolam 0.03 mg.kg, −1 and fentanyl 2 μg.kg. −1 Anaesthesia was induced with fentanyl 2 μg.kg −1 and propofol 1.5-2.5 mg.kg −1 and endotracheal intubation was facilitated with atracurium 0.6 mg.kg. −1 Anaesthesia was maintained with Bispectral Index guided sevoflurane, nitrous oxide, fentanyl boluses and peripheral nerve stimulator guided atracurium infusion. The PI values were assessed using a Radical-7™ finger pulse oximetry device (Masimo Corp., Irvine, CA, USA) clipped onto the right upper limb of the oral cancer patients. PI is a dimensionless number indicative of the strength of infrared rays (940 nm) returning from the site housing the co-oximeter probe (hand, finger, toe). PI represents an indirect, non-invasive and accurate index of peripheral perfusion calculated by co-oximetry by expressing the pulsatile signal (during arterial inflow) as a percentage of the non-pulsatile signal and ranges from 0.02% (very feeble pulse) to 20% (very strong pulse strength) [3][4][5]. The haemodynamic parameters (heart rate (HR) and mean arterial pressure (MAP) were continuously recorded. Data was evaluated at baseline (1 min after midazolam), 1 min and 3 min post-induction, 0,1,3 and 10 min post-laryngoscopy and 0,1,3 and 10 min post-docking. Sevoflurane was started post-intubation. Intravenous diltiazem 5 mg bolus for MAP ≥ 20% above baseline despite sevoflurane; i.v. esmolol 5 mg bolus for increase in HR ≥ 20% above baseline, i.v. ephedrine 3 µg bolus for 20% fall in MAP below baseline.

Results
The demographic parameters exhibited a normal distribution ( Table 1).
Out of 30 potentially eligible patients, all were assessed for eligibility but only 26 were confirmed eligible and included in the study. Four patients did not fit the inclusion criteria (age > 70 y (n = 2), Mallampati Grade-4 on airway assessment (n = 1); henna application on all her fingernails and toenails that confounded the co-oximetric readings (n = 1). Data from 26 patients was analysed. The study being an entirely intraoperative one, there was no missing data and none of the patients was lost to follow up.
Mean PI values at baseline and post midazolam were 4.1 and 4.2 which increased to 5.7 and 6.3 at 1 min and 3 min post induction of anaesthesia. Thereafter, PI reached the nadir (3.2) at laryngoscopy and increased to 3.7, 4.7, and 6.2 at 1 min, 3 min, and 10 min post laryngoscopy, respectively. PI peaked at pre-docking (6.8) and a second trough was seen at docking (4.1) and 1 min post-docking (4.0). At 3 min and 10 min post-docking, PI was 4.3 and 4.8 respectively (Fig. 2).
The mean PI, standard deviation, range and 95% confidence intervals at each time point are detailed in Table 1 of appendix section.
Application of the paired t-test for PI on laryngoscopy (3.2 ± 1.0) and PI on application of F-K retractor/beginning of docking (4.1 ± 1.6) produced statistically significant results (p = 0.0044). Mean ± SD for PI at 1 min post intubation and PI at 1 min post docking was 3.7 ± 1 and 4.0 ± 1.5 respectively (p = 0.25). Similarly, mean ± SD for PI at 3 min post-intubation and PI at 3 min post-docking was 4.7 ± 1.2 and 4.3 ± 1.6 respectively (p = 0.299). At 10 min post-intubation and 10 min post-docking PI was 6.2 ± 1.1 and 4.8 ± 1.5 respectively (p < 0.0001) Fig. 3. PI at laryngoscopy showed a strong corelation with PI at docking (Pearson correlation coefficient r = 0.52; p = 0.01). Difference between PI at laryngoscopy and PI 1 min prior to laryngoscopy (DifPIL) and difference between PI at docking and PI 1 min prior to docking (DifPID) exhibited an even stronger correlation (r = 0.76; p < 0.0001).
DifPIL had a negative corelation (r = − 0.31;p = 0.12) with difference between HR at laryngoscopy and HR 1 min prior to laryngoscopy (DifHRL). This correlation was statistically highly significant (r = − 0.85; p < 0.0001) after exclusion of a solitary patient in whom heart rate decreased in response to both laryngoscopy and docking (Table 2). DifPIL had a statistically significant negative corelation (r = − 0.43; p = 0.03) with difference between MAP at laryngoscopy and MAP 1 min prior to laryngoscopy (DifMAPL). DifPID had a statistically significant negative correlation with both difference between HR at docking and HR 1 min prior to docking DifHRD (r = − 0.6; p = 0.002) and difference between MAP at docking and MAP 1 min prior to docking DifMAPD (r = − 0.59; p = 0.002) ( Table 2).
The MAP peaked at laryngoscopy and progressively declined at 1 min and 3 min post laryngoscopy to reach baseline levels at 10 min post-laryngoscopy. The MAP rose again on docking but the second peak occurred at 1 min post docking. The MAP declined thereafter at 3 min and 10 min post initiation of docking but did not return to baseline even at 10 min post docking. The second peak was lower than the first one but the rise in MAP was more sustained since the laryngoscope blade was withdrawn immediately after intubation but the FK-retractor provided a continued source of stimuli (Fig. 4).

Discussion
As non-invasively quantified by PI, videolaryngoscopic stress response is more intense but shorter-lived versus that due to docking. Smoking/chewing tobacco and alcohol addiction (leading cause of oral cancer) is rampant in Indian males. Therefore, in our study, sex ratio was sharply skewed towards the male gender [7]. The rise in PI following anaesthetic induction, observed in our patients, is ascribed to peripheral vasodilatation and enhanced peripheral perfusion with accompanying fall in arterial blood pressure upon general anaesthetic induction using propofol and opioids. Mizuno et al. have reported a similar significant rise in PI from 2.1 to 3.8 in their study on PI changes with anaesthestic induction in 21 adult patients [8].
PI values dipped both at laryngoscopy and docking, with a steeper and deeper trough pertaining to laryngoscopy. In comparison the slope of the second trough (caused by docking) was gentler and PI at 1 min post docking was lower than PI at docking. Stress response was observed at both videolaryngoscopy and docking. Although the stress response was greater in intensity at laryngoscopy, it was more prolonged during docking. This is supported by the statistically significant lower PI at 10 min post-docking as compared to 10 min post-laryngoscopy, although PI was lower at laryngoscopy as compared to docking. A plausible explanation lies in the fact that while the laryngoscope is removed immediately after intubation, the F-K retractor remains in situ for as long as TORS continues. In clinical conditions, a fentanyl bolus and deepening of anaesthesia by increasing the MAC value of sevoflurane (from MAC maintenance to MAC intubation) should prophylactically be accomplished in anticipation of the stress response due to F-K retractor aided docking. PI at laryngoscopy showed a strong corelation with PI at docking. Similarly, difPIL and difPID exhibited a stronger correlation. Hence patients who exhibit a high stress response at laryngoscopy will behave in a similar fashion at docking and it follows that PI at laryngoscopy can be a useful predictor of stress response likely to be generated by docking. Preventive measures like additional fentanyl, esmolol or lignocaine boluses can be administered to these patients, just before docking, anticipating the magnitude of stress response due to docking.
Correlation between difHRL and difPIL became statistically significant after exclusion of a single patient in whom heart rate decreased in response to both laryngoscopy and docking. PI is a superior measure of stress response because although HR increases with laryngoscopy most of the times [9], paradoxical bradycardia due to vagal stimulation occurs in a few patients. Mean HR increased from 82.8 min −1 to only 87.6 min −1 on laryngoscopy in a study by Xue et al. because HR may have actually decreased after laryngoscopy in some of their patients [10]. Nasotracheal intubation can evoke the nasocardiac reflex, which depresses the tachycardiac response to laryngoscopic nasotracheal intubation [11]. Moreover, videolaryngoscopes (including C-Mac D-Blade) result in lower increases in HR and MAP compared to classic laryngoscopy [12][13][14][15][16]. Some videolaryngoscopes exert less pressure on upper incissors than other videolaryngoscopes, but all classic laryngoscopes produce the highest MAPs and HRs [17][18][19][20][21]. It is our institutional protocol to use the D-Blade for intubating TORS patients.
PI consistently decreases on laryngoscopy. Change in PI/ HR/MAP is a better indicator of stress response than magnitude of a solitary PI/HR/MAP value per se, be it at laryngoscopy or at docking. Hence, we chose difPI, difHR and DifMAP as parameters for ascertaining corelation.
The fact that 'haemodynamic variable-PI' pairs (dif-MAPL and difPI; difHRL and difPI; difHRD and difPID; difMAPD and difPID), have a high negative correlation coefficient indicates that PI and haemodynamic parameters move in opposite directions but in same proportions. PI plummets in response to stressors like laryngoscopy and docking while the haemodynamic parameters like HR and MAP shoot up by similar extents. Atef et al. [1] reported a significant decrease in PI by 10 in 40%, 100% and 100% patients on insertion of an Igel, Classic LMA and MacIntosh laryngoscope aided endotracheal tube respectively which corroborates with our findings. They also recorded a 10 beats/min increase in HR and > 15mmHG rise in systolic and diastolic blood pressures in 0%, 30% and 60% patients, Table 2 Colour coded correlograms depicting relationship between haemodynamic variables and perfusion index; Red = Maximum positive correlation (1), Orange = (0.75); Yellow = 0.5, Green = No correlation(0), Light blue = (− 0.5), Deep Blue = Maximum negative correlation(− 1); (DifMAPL = Difference in mean arterial pressure at laryngoscopy and 1 min prior to laryngoscopy; DifMAPD = Difference in mean arterial pressure at docking and 1 min prior to dock-ing; DifHRD = Difference in heart rate at docking and 1 min prior to docking; DifHRL = Difference in heart rate at laryngoscopy and 1 min prior to laryngoscopy; DifPID = Difference in perfusion index at docking and 1 min prior to docking; DifPIL = Difference in perfusion index at laryngoscopy and 1 min prior to laryngoscopy) The second correlogram shows data of the patient with bradycardia (outlier) excluded from DifHRL and DifHRD
The major strength of our study is that stress response due to F-K retractor aided docking of surgical robot for TORS has not been quantified by any previous study. Moreover, since laryngoscopy and docking (the two stressors compared) were performed in the same patient, potentially confounding factors like difficult airway, hypertension, antihypertensive medication and other co-morbidities were neutralized. We have demonstrated that combination of PI, HR, and MAP provides value addition for monitoring stress response during various moments in anaesthesia. A limitation of our study is that PI values were not compared beyond 10 min of docking.

Conclusion
As non-invasively quantified by PI, stress response due to videolaryngoscopy is more intense but shorter lived than that due to docking of surgical robot. Although of a lower magnitude, the duration of stress response is prolonged to greater than 10 min post-docking. We advocate a prophylactic fentanyl bolus and deepening of anaesthesia by increasing the MAC-value of sevoflurane (from MAC maintenance to MAC intubation) in anticipation of the stress response due to F-K retractor aided docking.