Oral Pregabalin as Premedication on Anxiolysis and Stress Response to Laryngoscopy and Endotracheal Intubation in Patients Undergoing Laparoscopic Cholecystectomy: A Randomized Double-Blind Study.

BACKGROUND: Direct laryngoscopy and tracheal intubation lead to increase in heart rate and blood pressure. This can cause serious complications in patients with coronary artery disease, reactive airways, or intracranial neuropathology. Preoperative anxiety is associated with greater level of postoperative pain. Attenuation of anxiety and hemodynamic response to laryngoscopy and intubation are cornerstone of better anesthetic outcome. Gabapentinoids (gabapentin and pregabalin) have been known to possess anxiolytic, analgesic, and anticonvulsant properties. AIM: The aim of this study is to determine the effects of oral pregabalin on anxiolysis and attenuation of stress response to laryngoscopy and endotracheal intubation. STUDY
DESIGN: This was a prospective randomized double-blind placebo controlled study.
MATERIALS AND METHODS: A total of 60 patients ASA physical status Class I and II, undergoing elective laparoscopic cholecystectomy, were randomly allocated into two groups receiving either oral placebo or oral pregabalin 150 mg, 60 min before induction of anesthesia. Visual analog scale (VAS) for anxiety was recorded before, and 60 min after giving the drug. Hemodynamic parameters (heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure) were recorded before, and 60 min after giving drug, during and 2, 4, 6, 8, and 10 min after intubation.
RESULTS: During preinduction, pregabalin showed a decrease in VAS and attenuation of stress response to laryngoscopy and intubation compared to that of placebo. The premedicated patients were hemodynamically stable perioperatively without side effects.
CONCLUSION: Pregabalin is effective in attenuating preoperative anxiety and stress response to endotracheal intubation.

INTRODUCTION

Most patients awaiting elective surgery experience the preoperative anxiety. Anxiety influences patient's subjective perceptions,[1] and preoperative anxiety is associated with higher level of postoperative pain.[234] Although the use of preoperative benzodiazepines is the most common practice to decrease preoperative anxiety, they do not have a positive effect on the postoperative outcome.[56] Recently, an increasing emphasis has been placed on the use of nonopioid analgesic drugs as part of a multimodal regimen for preventing pain in the perioperative period.[789] Laparoscopic cholecystectomy has now replaced open cholecystectomy as the first choice of treatment for gallstones and inflammation of the gall bladder unless there are contraindications to the laparoscopic approach. Further laparoscopy results in stress hormone responses (cortisol, epinephrine, and norepinephrine), especially with Co2 pneumoperitoneum.[10] Manipulation of airway, particularly during laryngoscopy and endotracheal intubation is associated with sympathetic nervous system stimulation and catecholamine release. This can cause serious complications in patients with underlying abnormalities such as coronary artery disease,[11] reactive airways,[12] or intracranial neuropathology.[13] Both sympathetic and parasympathetic nervous system mediate cardiovascular responses to laryngoscopy and endotracheal intubation.[14] Various anesthetic drugs and techniques have been described to control the hemodynamic response to the laryngoscopy and intubation, such as omitting cholinergic medications,[15] deepening of anesthesia,[16] pretreatment with nitroglycerine,[17] administration of beta-blockers,[18] calcium channel blockers,[19] gabapentin,[20] clonidine,[21] and opioids such as fentanyl[10] and remifentanil.[22] Gabapentinoids (gabapentin and pregabalin) are the second generation of anticonvulsants that are effective in treatment of chronic neuropathic pain.[2324] Pregabalin is a structural and functional analog of gabapentin and effective in the treatment of nociceptive inflammatory pain that is resistant to gabapentin. Both drugs bind to the α2-δ subunit of voltage-sensitive Ca++ channels, which sustain the enhanced release of pain transmitters at the synapses between primary afferent fibers and second-order sensory neurons under the conditions of chronic pain. However, a growing body of evidence suggests that perioperative administration is efficacious for the postoperative analgesia, preoperative anxiolysis, attenuation of the hemodynamic response to laryngoscopy and intubation and preventing chronic postsurgical pain, postoperative nausea, vomiting, and delirium.[24] Only minimal evidence are available in our literature related to the attenuation of anxiety and cardiovascular properties of pregabalin in patients undergoing laparoscopic surgery. Hence, the present study was designed to evaluate the effects of oral pregabalin on anxiolysis and attenuation of stress response to laryngoscopy and endotracheal intubation.

MATERIALS AND METHODS

With approval of the Ethics Committee and informed consent of the patients, a randomized double-blind placebo-controlled study was conducted in the Department of Anesthesia, Uttar Pradesh University of Medical sciences Saifai, U. P., India, from January 2018 to December 2018. A total 60 patients of either sex and ASA physical status classification I and II, aged 18–65 years scheduled to undergo laparoscopic cholecystectomy under general anesthesia were enrolled in the study. Patients with ASA physical status classification III and IV, anticipated difficult intubation, multiple intubation (>1) attempts at laryngoscopy, severe renal or hepatic disease, allergic, chronic hypertension, ischemic heart disease, left ventricular failure, major cardiac disorders, and obesity were excluded from the study. Patients were randomly allocated in two groups of 30 each using sealed opaque envelopes. After thorough preanesthetic evaluation, patients were randomly allocated and provided either envelope containing formulations by another staff nurse in the preoperative room 60 min before surgery. Group A received oral placebo in the form of oral multivitamin capsules, and Group B received oral pregabalin 150 mg.

On arrival in the operating room, 18G intravenous (IV) cannula was inserted in a peripheral vein, and Ringer's lactate solution was started at 6 mL/kg. A uniform anesthetic technique was used in all groups. After 3 min of preoxygenation, anesthesia was induced with IV thiopentone 5 mg/kg; IV succinylcholine 1.5 mg/kg to facilitate endotracheal intubation. The duration of laryngoscopy and intubation was limited to <15 s for all patients. Monitoring of vitals was done by an anesthetist, who was blinded to the drug used in each group. Heart rate (bpm) and noninvasive systolic blood pressure (mmHg), diastolic blood pressure (mmHg), and mean arterial pressure (MAP) (mmHg) were recorded preoperatively (baseline), 60 min after administration of study drug, during laryngoscopy and intubation, and at 2, 4, 6, 8, and 10 min after intubation, after extubation and in the postoperative room. Following endotracheal intubation, a nasogastric tube (14 F) was placed. Maintenance of anesthesia was carried out using 67% N20 in 33% O2 and halothane 0.5% using controlled ventilation. Neuromuscular blockade was achieved using vecuronium 0.08–0.12 mg/kg. Intraoperative analgesia was provided with 1–1.5 μg/kg fentanyl. At the end of surgery, residual neuromuscular blockade was reversed with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg intravenously.

Statistical analysis

The sample size was calculated using the formula:

(n = [z(1-α/2)]2 × SD2/d2)

Where

z(1-α/2)= standard normal deviate for 95% confidence = 1.96

SD = Standard deviation of MAP = 14 mmHg

d = precision = 5%

n = 1.962 × 142/52

n = 30

The sample size obtained is 30 patients in each group.

At the end of the study, results were represented as (mean ± SD) and percentage changes. The statistical analysis of quantitative data (mean ± SD) between the groups was performed using the Student's “t”-test. The statistical analysis of qualitative data between the groups was performed using the Chi-square test. A value of P < 0.05 was considered to be statistically significant. All the analysis was performed using SPSS statistical package version 20.0 (IBM, Armonk, NY).

RESULTS

A total of 60 patients were recruited for the study, and none were excluded as shown in consort chart [Chart 1]. Both groups were comparable in terms of age, weight, sex, duration of surgery, ASA physical status classification [Table 1]. Table 2 shows intergroup comparison of mean VAS score with respect to time whereas Table 3 shows intragroup comparisons of VAS score in both the groups. Tables 4 and 5, Figure 1 shows the comparison of change in heart rate across time periods. Tables 6 and 7, Figure 2 shows the comparison of change in systolic blood pressure across time periods. Tables 8 and 9, Figure 3 shows the comparison of change in diastolic blood pressure across time periods. Tables 10 and 11, Figure 4 shows the comparison of change in mean arterial pressure across time periods. Mean VAS score and hemodynamic parameters were found significant in pregabalin group compared to placebo group.

Chart 1

Consort Flow Diagram. Group A=Placebo; Group B=Pregabalin

Table 1

Distribution of demographic data among the studied groups

Parameters	Mean±SD		P
	Group A (n=30)	Group B (n=30)
Age (years)	36.3±11.9	40.9±12.2	0.14
Sex (%)
Male	15 (50)	15 (50)	1.00
Female	15 (50)	15 (50)
Weight (kg)	57.3±6.5	59.9±4.9	0.08
Duration of surgery (min)	60.6±4.5	62.6±5.2	0.12
ASA grade (%)
I	8 (53)	7 (47)	1.00
II	7 (47)	8 (53)

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. SD=Standard deviation, ASA=American Society of Anesthesiologists

Table 2

Mean visual analog scale anxiety score in the studied groups

	Mean±SD		P
	Group A (n=30)	Group B (n=30)
Before drug administration (BL)	68.3±14.2	66.6±17.6	0.89
60 min after giving drug (preinduction)	58.6±14.4	49.3±14.1	<0.001

SD=Standard deviation, P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. SD=Standard deviation, BL=Baseline

Table 3

Intragroup comparison of visual analog scale anxiety scores

	Group A (n=30)				Group B (n=30)
	Mean±SD	Difference from BL	Percentage difference	P	Mean±SD	Difference from BL	Percentage difference	P
Before giving drug (BL)	68.3±14.2	-	-	-	66.6±17.6	-	-	-
Preinduction	58.6±14.4	9.7	14	<0.01	49.3±14.1	17.3	26	0.01

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. BL=Baseline, SD=Standard deviation, DL=Direct laryngoscopy

Table 4

Intragroup comparison of change in heart rate across time periods among the groups

Heart rate (beats per min)	Group A (n=30)				Group B (n=30)
	Mean±SD	Difference from BL	Percentage difference	P	Mean±SD	Difference from BL	Percentage difference	P
BL	87.3±9.8	-	-	-	89.6±5.7	-	-	-
60 min after drug administration	88.5±8.7	1.2	1	0.61	90.0±9.2	0.4	0.4	0.84
During DL	118.5±6.7	31.2	36	0.0001	98.4±5.8	8.8	10	0.0001
2nd min	116.4±5.3	29.1	33	0.0001	99.0±5.6	9.4	10	0.0001
4th min	117.8±8.4	30.5	35	0.0001	98.5±6.6	8.9	10	0.0001
6th min	112.2±7.9	24.9	28	0.0001	97.2±8.2	7.6	8	0.0001
8th min	110.1±8.8	22.8	26	0.0001	97.1±6.3	7.5	8	0.0001
10th min	106.8±9.2	19.5	22	0.0001	96.3±8.4	6.7	7	0.0006

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. BL=Baseline, SD=Standard deviation, DL=Direct laryngoscopy

Table 5

Intergroup comparison of change in heart rate across time periods among the studied groups

Heart rate (beats per min)	Mean±SD		P
	Group A (n=30)	Group B (n=30)
BL	87.3±9.8	89.6±5.7	0.27
60 min after drug administration	88.5±8.7	90.0±9.2	0.51
During DL	118.5±6.7	98.4±5.8	0.0001
2nd min	116.4±5.3	99.0±5.6	0.0001
4th min	117.8±8.4	98.5±6.6	0.0001
6th min	112.2±7.9	97.2±8.2	0.0001
8th min	110.1±8.8	97.1±6.3	0.0001
10th min	106.8±9.2	96. 3±8.4	0.0001

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. BL=Baseline, SD=Standard deviation, DL=Direct laryngoscopy

Figure 1

Line diagram showing comparison of change in heart rate across time periods among the study groups

Table 6

Intragroup comparison of changes of mean systolic blood pressure across the time periods among the study groups

Systolic blood pressure (mmHg)	Group A (n=30)				Group B (n=30)
	Mean±SD	Difference from BL	Percentage difference	P	Mean±SD	Difference from BL	Percentage difference	P
BL	128.6±6.5	-	-	-	129.8±7.1	-	-	-
60 min after drug administration	130.6±5.3	2.0	1.5	0.19	130.1±6.2	0.3	0.2	0.86
During DL	147.2±8.4	18.6	14	0.0001	136.5±8.8	6.7	5	0.002
2nd min	148.4±7.6	19.8	15	0.0001	136.9±9.1	7.1	5	0.001
4th min	150.1±9.2	21.5	17	0.0001	137.5±6.7	7.7	6	0.0001
6th min	149.3±7.5	20.7	16	0.0001	134.3±9.4	4.5	3	0.04
8th min	146.8±7.1	18.2	14	0.0001	133.8±7.9	4.0	3	0.04
10th min	140.0±6.2	11.4	9	0.0001	132.3±6.6	2.5	2	0.16

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. BL=Baseline, SD=Standard deviation, DL=Direct laryngoscopy

Table 7

Intergroup comparison of change in systolic blood pressure across time periods among the study groups

Systolic blood pressure (mm Hg)	Mean±SD		P
	Group A (n=30)	Group B (n=30)
BL	128.6±6.5	129.8±7.1	0.50
60 min after drug administration	130.6±5.3	130.1±6.2	0.73
During DL	147.2±8.4	136.5±8.8	0.0001
2nd min	148.4±7.6	136.9±9.1	0.0001
4th min	150.1±9.2	137.5±6.7	0.0001
6th min	149.3±7.5	134.3±9.4	0.0001
8th min	146.8±7.1	133.8±7.9	0.0001
10th min	140.0±6.2	132.3±6.6	0.0001

P>0.05=Not significant, P<0.05=Significant; P<0.001=Highly significant. BL=Baseline, SD=Standard deviation, DL=Direct laryngoscopy

Figure 2

Line diagram showing comparison of change in systolic blood pressure across time periods among the study groups

Table 8

Intragroup comparison of change in diastolic blood pressure across time periods among the study groups

Diastolic blood pressure (mmHg)	Group A (n=30)				Group B (n=30)
	Mean±SD	Difference from BL	Percentage difference	P	Mean±SD	Difference from BL	Percentage difference	P
BL	84.6±6.0	-	-	-	85.2±5.3	-	-	-
60 min after drug administration	86.3±6.9	1.7	2	0.31	85.3±5.5	0.1	0.1	0.94
During DL	98.4±7.9	13.8	16	0.0001	89.7±7.7	4.5	5	0.01
2nd min	98.6±7.2	14.0	16	0.0001	89.5±6.8	4.3	5	0.008
4th min	99.0±8.5	14.4	17	0.0001	89.5±7.2	4.3	5	0.01
6th min	97.6±6.8	13.0	15	0.0001	89.2±7.5	3.8	4	0.02
8th min	97.2±7.2	12.6	15	0.0001	89.0±8.3	3.6	4	0.04
10th min	96.5±6.3	11.9	14	0.0001	87.6±7.8	2.4	3	0.16

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. SD=Standard deviation, DL=Direct laryngoscopy, BL=Baseline

Table 9

Intergroup comparison of change in diastolic blood pressure across time periods among the study groups

Diastolic blood pressure (mmHg)	Mean±SD		P
	Group A (n=30)	Group B (n=30)
BL	84.6±6.0	85.2±5.3	0.68
60 min after drug administration	86.3±6.9	85.3±5.5	0.53
During DL	98.4±7.9	89.7±7.7	0.0001
2nd min	98.6±7.2	89.5±6.8	0.0001
4th min	99.0±8.5	89.5±7.2	0.0001
6th min	97.6±6.8	89.2±7.5	0.0001
8th min	97.2±7.2	89.0±8.3	0.0001
10th min	96.5±6.3	87.6±7.8	0.0001

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. SD=Standard deviation, DL=Direct laryngoscopy, BL=Baseline

Figure 3

Line diagram showing comparison of change in diastolic blood pressure across time periods among the groups

Table 10

Intragroup comparison of change in mean arterial pressure across time periods among the groups

Mean arterial pressure (mmHg)	Group A (n=30)				Group B (n=30)
	Mean±SD	Difference from BL	Percentage difference	P	Mean±SD	Difference from BL	Percentage difference	P
BL	97.3±9.1	-	-	-	99.2±5.6	-	-	-
60 min after drug administration	98.6±7.2	1.3	1	0.54	99.3±8.1	0.1	0.1	0.95
During DL	119.4±9.8	22.1	23	0.0001	108.3±6.3	9.1	9	0.0001
2nd min	120.5±9.6	23.2	24	0.0001	110.5±6.8	11.3	11	0.0001
4th min	120.2±8.9	22.9	23	0.0001	110.8±6.5	11.6	12	0.0001
6th min	120.2±7.6	22.9	23	0.0001	106.7±7.6	7.5	7	0.0001
8th min	118.3±7.9	20.7	21	0.0001	105.5±7.5	6.3	6	0.0005
10th min	115.8±8.2	18.5	19	0.0001	103.8±8.2	4.3	4	0.01

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. SD=Standard deviation, DL=Direct laryngoscopy, BL=Baseline

Table 11

Intergroup comparison of changes in mean arterial pressure across time periods among the study groups

Mean arterial pressure (mmHg)	Mean±SD		P
	Group A (n=30)	Group B (n=30)
BL	97.3±9.1	99.2±5.6	0.33
60 min after drug administration	98.6±7.2	99.3±8.1	0.72
During DL	119.4±9.8	108.3±6.3	0.0001
2nd min	120.5±9.6	110.5±6.8	0.0001
4th min	120.2±8.9	110.8±6.5	0.0001
6th min	120.2±7.6	106.7±7.6	0.0001
8th min	118.3±7.9	105.5±7.5	0.0001
10th min	115.8±8.2	103.8±8.2	0.0001

P>0.05=Not significant, P<0.05=Significant, P<0.001=Highly significant. SD=Standard deviation, DL=Direct laryngoscopy, BL=Baseline

Figure 4

Line diagram showing comparison of changes in mean arterial pressure across time periods among the study groups

DISCUSSION

The augmented cardiovascular reflexes in the form of tachycardia and hypertension brought about by the noxious stimulus of laryngoscopy and intubation can prove to be detrimental for patients with cardiovascular and cerebrovascular diseases.[25] For decreasing anxiety and the intubation response, use of nonopioid drugs has become a part of the multimodal regimen. Many recent studies show that drugs such as gabapentin and pregabalin are known to decrease stress response due to laryngoscopy and intubation. Pregabalin is a drug with analgesic, anticonvulsant, and anti-anxiety effects mainly used for the management of neuropathic pain, neuralgia occurring postherpes infection, and as adjuvant for the treatment of partial onset seizures. Gabapentin and pregabalin were initially developed for the treatment of epilepsy and also for the effective management of neuropathic pain. They are also used in the perioperative period to provide pain relief. Recently, these drugs are being used in the preoperative setting to decease the anxiety and blunt the cardiovascular stress response occurring to laryngoscopy and tracheal intubation but with different doses and conflicting results.[262728]

In this study, the demographic data with respect to age, sex, ASA physical status classification, and duration of surgery were comparable among all the groups [Table 1]. Several investigators have used different scales for measuring preoperative anxiety, i.e., state-trait anxiety inventory,[29] visual analog scale (VAS),[29] and 5-Point scale. We choose VAS scale because it is easy to assess and reliable. Recently, de-Paris et al. demonstrated that gabapentin attenuated anxiety associated “with simulated public speaking” in volunteers.[30] A study in patients with generalized anxiety disorders found that chronic use of pregabalin was significantly more effective than the benzodiazepine alprazolam in improving somatic anxiety symptoms.[31] Preoperatively, we observed decrease in anxiety in the pregabalin group by 26% compared to that of the placebo group (14%). This is in contrast to the findings observed by White et al. where they studied 75, 150, and 300 mg of pregabalin and compared it with placebo. Anxiety levels remained unchanged in their study during the preoperative evaluation period and did not differ among all the groups.[32] Table 4 and Figure 1 show intragroup comparison of change in heart rate from baseline up to 10 min after tracheal intubation among the study groups. Throughout the monitoring and reporting of data, mean heart rate value rises to a maximum of 36% and 10% in the Group A and Group B, respectively, during direct laryngoscopy and intubation and found to be statistically significant (P = 0.0001). When Group A was compared with Group B, throughout the study period, there was a statistically significant difference in the mean heart rate value. Table 6 and Figure 2 show intragroup comparison of change in systolic blood pressure from baseline up to 10 min after tracheal intubation among the study groups. In Group A, throughout the monitoring and reporting of data during direct laryngoscopy and intubation, mean systolic blood pressure value rises to 14% in Group A and 5% in Group B, respectively, and found to be statistically significant. However, the maximum increase is 17% in Group A and 6% in Group B observed 4 min after direct laryngoscopy and intubation and remained statistically significant throughout the duration of study except at 10 min in Group B.

Table 7 shows intergroup comparison of change in systolic blood pressure between Group A and Group B and found to be statistically significant throughout the study period. Table 10 and Figure 4 show intragroup comparison of change in MAP from baseline up to 10 min after tracheal intubation among the groups. In Group A, throughout the monitoring and reporting data, MAP value rises to a maximum of 24%, 2 min after direct laryngoscopy and intubation which was statistically significant, whereas in Group B, MAP value rises to a maximum of 12%, 4 min after laryngoscopy and intubation which was statistically significant. Table 11 shows intergroup comparison of changes in MAP across time periods among the groups and found a statistically significant difference in MAP value between the groups. This is in consistent to the study done by Chakraborty et al.,[33] who concluded that premedication with 150 mg of oral pregabalin safely attenuates hemodynamic response to laryngoscopy and intubation. Sundar et al.[34] conducted a study to see the effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass graft and concluded that pregabalin 150 mg succeeded in suppressing reflex tachycardia related to laryngoscopy and intubation. In another similar study done by Singh et al.[35] to evaluate the effects of oral pregabalin as premedication for attenuation of pressor response during laryngoscopy and endotracheal intubation and found that magnitude of rise in heart rate is lower and it is falling to less than the basal value at 10 min in the pregabalin group, but in the control group, it has not reached the basal value even by 10 min following laryngoscopy and intubation. Saxena et al.[36] conducted a study to see the effect of pregabalin premedication on laryngoscopic response and intraoperative hemodynamic variables in laparoscopic cholecystectomy and observed that 150 mg and 300 mg pregabalin were equally effective in attenuating the increase in heart rate during laryngoscopy and intubation. Raichurkar et al.[37] conducted a comparative study on oral pregabalin and clonidine for attenuation of hemodynamic responses to laryngoscopy and tracheal intubation and concluded that pregabalin and clonidine successfully attenuated the hemodynamic response to laryngoscopy and tracheal intubation, but pregabalin better attenuates pressor response, and clonidine better attenuates tachycardia response. Eren et al.[38] used pregabalin to know its effectiveness in blunting the hemodynamic response to intubation in lumbar surgeries among 50 patients undergoing elective lumbar disc surgery, and found MAP values are significantly low in the pregabalin 150 group compared to the placebo group (108.3 ± 6.3 vs. 119.4 ± 9.8, P = 0.0001) during laryngoscopy and intubation even up to 10th min, i.e., a rise of mean MAP from baseline was 9% in pregabalin 150 mg as compared to 23% in the placebo group. Rastogi et al.[39] conducted prospective randomized controlled study using two various doses of pregabalin to find out the clinically effective and safe dose during airway manipulation to maintain the hemodynamics and observed the attenuation of MAP in the premedicated group was statistically significant, i.e., in pregabalin 75 mg group (97.80 ± 2.52 vs. 110.70 ± 4.94, P = 0.001) and in pregabalin 150 mg group (92.06 ± 3.37 vs. 110.70 ± 4.94, P = 0.001) to as compared with control group, in dose-related fashion.

CONCLUSION

From the present study, we conclude that pregabalin 150 mg seems to be an effective and safe drug for anxiolysis, analgesia, and hemodynamic stability during laryngoscopy and intubation and can be useful for patients with comorbid conditions preoperatively.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.