Comparison of Enhanced Recovery After Surgery guideline-based multimodal analgesia with patient-controlled morphine analgesia for length of stay after spine instrumentation surgeries – A randomised controlled trial

Abstract

Background and Aims:

Despite the benefits of Enhanced Recovery After Surgery (ERAS) guidelines, there are still hesitations in implementing them. In this study, we compared the ERAS guideline-based multimodal analgesia protocol (ERAS-MMA) with patient-controlled morphine analgesia (PCA-Morphine) for single-level lumbar fusion surgeries. The primary objective was the length of hospital stay. The secondary objectives were the postoperative mobilisation time, time to start oral feeds, pain scores, complications, and re-admissions.

Methods:

This is a double-blinded, randomised controlled study, conducted on 60 participants who were randomised into two groups. Group T received the ERAS-MMA, and Group C received PCA-Morphine. An unpaired t-test was used to compare the continuous variables. The Mann–Whitney U test was used to compare discrete data. Regression analysis was used to identify the true effect of ERAS-MMA on the length of stay.

Results:

The difference in the mean length of the hospital stay was significant [Group T vs Group C, 4226.02 (Standard Deviation (SD): 522.21) min vs 7144.12 (SD: 592.11) min), P < 0.001]. Multiple linear regression model analysis showed that ERAS-MMA reduced the stay duration by 2 days (B = - 2871.8, P < 0.001) compared to the control group. Postoperative pain, opioid consumption, time to initiate oral feeds, time to mobilisation, and complications were less in Group T. There were no re-admissions in either group.

Conclusion:

Implementing ERAS-MMA for patients undergoing single-level spine fusion surgery significantly contributes to lesser hospital length of stay, faster time to oral feeding and mobilisation, lower opioid use with better pain scores, and reduced complications.

INTRODUCTION

Enhanced Recovery After Surgery (ERAS) guidelines for spine surgery were formulated with the aim of enhancing patient recovery and reducing length of hospital stay by focusing on multiple perioperative components of patient management, which include multimodal analgesia, early mobilisation, fluid management, nutrition, and patient education. Studies have reported the benefits of implementing ERAS protocols for spine surgeries, like reduced opioids, fewer complications in the postoperative period, faster recovery of functions, and higher patient satisfaction.[1,2,3] Despite the availability of evidence documenting the benefits of ERAS protocols for reducing the length of hospital stay, there are still hesitations in implementing these protocols in hospitals, especially in low- and mid-income countries. A few of the reasons identified were a lack of standardised protocols, myths about early mobilisation, and early feeding after spine surgery.[4]

Opioid-based analgesia remains the most common technique for postoperative pain management. Although patient-controlled analgesia with morphine provides adequate pain relief, they are associated with certain undesirable side effects that may delay recovery.[5] Studies have provided evidence that incorporating ERAS guideline-based multimodal analgesia regimes has significantly reduced the requirement of opioids and has enabled faster recovery.[5] In this study, we aimed to compare the effect of ERAS guideline-based multimodal analgesia protocol (ERAS-MMA) with patient-controlled morphine analgesia (PCA-Morphine) on the length of hospital stay in patients undergoing single-level open transforaminal lumbar interbody spine fusion (TLIF) surgeries.

The primary objective of the study was to compare the difference in length of hospital stay between the groups. The secondary objectives were to compare the time to mobilise postoperatively, time to start oral feeds postoperatively, postoperative pain scores, postoperative complications, and re-admission rates between the groups. We hypothesised that the ERAS guideline-based multimodal analgesia technique would help in decreasing the length of hospital stay.

METHODS

This is a randomised controlled study conducted in a tertiary care centre between May 2023 and October 2024. The participant recruitment for the study was commenced after obtaining Institutional Ethical Committee approval (vide approval number – SRMIEC-ST0922-190, dated 31 October 2022) and after Clinical Trials Registry- India registration (vide registration number CTRI/2023/03/050749, accessible at www.ctri.nic.in/). The study was conducted according to the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Humans and Good Clinical Practice guidelines.

Randomisation was done using a computer-based random number generator, followed by allocation concealment using a sequentially numbered opaque sealed envelope technique to ensure confidentiality in allocation. This was a double-blinded study where the patients were blinded to the group allocation, and the principal investigator who collected the data was also blinded to the allocation. The first anaesthesiologist was allotted for preoperative optimisation and post-operative follow-up of patients for pain management and nutrition. The first orthopaedician was involved in preoperative education and counselling; the second orthopaedician, who was blinded to the group allocation, was involved in postoperative mobilisation. The second anaesthesiologist was involved in monitoring the adherence to study protocols. The patient and the principal investigator were blinded to the group allocation. All the data were collected by the blinded principal investigator from the records and case files at a time point after the participants were assessed and announced ready for discharge after the treatment.

The patients who were diagnosed with single-level lumbar disease and advised fusion surgery as an elective procedure were screened for eligibility to participate in the study. Patients aged between 18 and 65 years of age of both genders, belonging to American Society of Anesthesiologists – Physical Status I and II, and with a preoperative pain score of not more than six as assessed by the Visual Analogue Scale (VAS) were included in the study. Patients who were taking opioid drugs previously; patients who had diabetes mellitus, neurological deficit, cognitive impairment, or previous history of spine surgery; and pregnancy and lactating mothers were excluded from the study. Informed written consent was obtained for participation in the study and use of the patient data for research and educational purposes. The participants were randomised into Group T and Group C. In Group T, ERAS guideline-based multimodal analgesia was followed. The ERAS guideline-based multimodal analgesia, which was followed in this study, was in large part derived from the ERAS Society for spine surgeries[3], and the details are shown in Table 1. There were a few modifications made to match the locoregional patient needs, like inclusion of video-based preoperative education, telephonic follow-up, and addition of coconut water instead of carbohydrate drink. In the control group (Group C), patient-controlled morphine analgesia was used, and the patients were treated as per the institutional protocol for anaesthesia and surgery.

Table 1.

Patient management protocol

		GROUP T (ERAS guideline-based Multimodal analgesia)	GROUP C (PCA-Morphine analgesia)
Preoperative period	Education and Counselling	Through video demonstration of the procedure and oral elaboration to the patient and family members.	Oral elaboration to patient and family members.
	Smoking	Advised to stop 4 weeks prior to surgery and compliance followed up every day by telephone enquiry.	Advised to stop 4 weeks before surgery
	Alcohol	Advised to stop 4 weeks prior to surgery and compliance followed up every day by telephone enquiry.	Advised to stop 4 weeks before surgery
	Anaemia	Haemoglobin (Hb) levels were checked and anaemia (male Hb <13g/dl, female Hb <12 g/dL) corrected by iron supplementation 3–4 weeks before surgery.	Haemoglobin levels were checked before surgery, and anaemia was corrected by transfusion.
	Fasting	Solids stopped 8 hours before surgery. 200 ml of clear coconut water is given 4 hours before surgery. 100 ml of plain water is given 2 hours before surgery.	All oral intake stopped 8 hours before surgery. IV fluids given at 100ml per hour.
	Medications	T. Alprazolam 0.25 mg, T. Ranitidine 150 mg, T. Metoclopramide 10 mg, T. Paracetamol 1 g oral, T. Baclofen 10 mg oral, T. Gabapentin 300 mg oral. Given with sips of water 1 hour before surgery.	T. Alprazolam 0.25 mg T. Ranitidine 150 mg, T. Metoclopramide 10 mg Given sips of water 1 hour before surgery.
Intraoperative period	Medications	Inj. Glycopyrrolate 10 μg/kg IV, Inj. Dexamethasone 0.1 mg/kg IV, Inj. Propofol 2 mg/kg IV, Inj. Vecuronium 0.1 mg/kg IV, Inj. Neostigmine 50 μg/kg IV. Inj. Lignocaine 1.5 mg/kg as a bolus dose 3 minutes before intubation, and a maintenance dose is given at 2 mg/kg/h till the end of surgery. Inj. Dexmedetomidine infusion 0.4 mcg/kg/h and stopped approximately 45 minutes before completion of surgery. Inj. Tranexamic acid 10 mg/kg as a bolus dose followed by 1 mg/kg/h till the end of surgery.	As per the individual preference of the attending anaesthesiologist.
	Regional technique	Ultrasound-guided Transforaminal Lumbar Interbody Fusion Block using 20 ml of 0.5% ropivacaine on each side was given.	As per the individual preference of the attending anaesthesiologist.
	Temperature maintenance	Continuous body temperature monitoring using a nasopharyngeal temperature probe was done, and perioperative temperature was maintained around 36 degrees Celsius. Warm air blankets and warm intravenous fluids were used.	As per the individual preference of the attending anaesthesiologist.
	Fluid management	The Holiday segar formula was used to calculate fluids, and Ringer’s lactate was used accordingly.	As per the individual preference of the attending anaesthesiologist.
	Antimicrobial prophylaxis	First-generation cephalosporins and Metronidazole for anaerobic coverage.	As per the individual preference of the operating surgeon.
	Drainage tube and urinary catheter placement	Use of drain tubes and urinary catheters was limited only to cases deemed deserving due to conditions during surgery.	As per the individual preference of the operating surgeon.
Postoperative period	Pain management	T. Baclofen 10 mg oral TDS, T. Gabapentin 300 mg oral HS, T. Paracetamol 650 mg oral 6thhourly Rescue analgesia: Inj. Morphine in PCA: No basal infusion Bolus dose – 1 mg Lockout interval – 10 minutes.	Inj. Paracetamol 1000 mg IV TDS. Inj. Morphine in PCA: 1 mg basal infusion, Bolus dose – 1 mg Lockout interval – 10 minutes.
	Mobilisation and Physical Therapy	Made to sit within 6 hours postop, walking with support within 12–24 hours of surgery. Knee bending was encouraged for every hour. Made to sit on a chair for at least 1 hour continuously, and made to walk as per patient comfort once every 6 hours.	As per the individual preference of the operating surgeon.
	Oral nutrition	Was started on sips of water 1 hour after surgery. Solids started after 6–12 hours as per patient tolerance.	As per the individual preference of the operating surgeon.

ERAS=Enhanced Recovery After Surgery; PCA=Patient-Controlled Analgesia; IV=Intravenous; TDS=ter die sumendum, three times a day; HS=hora somni, at bedtime

The patients allocated to Group T were followed preoperatively for a period of 3 weeks, through regular telephonic calls for ensuring compliance with optimisation advice and in person during their time of weekly review visit to the orthopaedic outpatient department. The patients in the control group were followed from their time of admission to the hospital till the surgery, and the pre-operative assessment, optimisation, and baseline data documentation were done. The follow-up was done by two investigators not involved in the data collection. The optimisation of the comorbid conditions was done for all patients involved in the study, irrespective of the group allocation. All patients underwent open transforaminal lumbar body fusion surgery using a posterior approach by a surgeon with more than 10 years of spine surgical experience. The details of the management protocol done for the two groups are mentioned in Table 1.

In the intraoperative period, for Group C, pain management was done using morphine 0.2 mg/kg body weight, and in cases of tachycardia (heart rate more than 10% of baseline) and hypertension (mean arterial pressure more than 10% of baseline). IV morphine was supplemented at a dose of 0.05mg/kg body weight. In the postoperative period, morphine was administered using a patient-controlled analgesic (PCA) pump as the rescue analgesic for both groups in case of a VAS pain score of more than four. In Group T, no basal infusion was set in the PCA pump. The bolus on demand dose was one milligram with a lock-out interval of 10 min, with a maximum of five milligrams for 1 hour. In Group C, basal morphine infusion was set at one milligram per hour infusion rate, and the on-demand dose and lock-out intervals were set the same as Group T. Patients were discharged from the hospital when they satisfied all the criteria for discharge, like VAS less than three for more than 24 hours, haemodynamic stability, able to walk without support, able to take oral food, normal bladder and bowel function, and no signs of surgical site infection. All patients in both groups were discharged to their homes and were advised to undergo physical therapy and pain medications. Patients were followed for a period of 3 months postoperatively for re-admissions.

The primary outcome measured in the study was the length of hospital stay, which was defined as the time from the day of the surgery to the day of discharge. The secondary outcomes measured were the time to start oral feeds, time to mobilise, postoperative pain score, and the rate of re-admission after discharge. The time to oral feed was defined as the time from the end of surgery to the time when the patient was able to eat solid food. The time to mobilise was defined as the time from the end of surgery to the time when the patient was able to walk four steps with support. The post-operative pain was measured using the VAS at different settings like pain at rest, pain at first attempt to sit, pain at first attempt to stand, and pain at first attempt to walk four steps. Pain at rest was taken every 4 hours from the end of surgery till the twelfth hour, and then once every 12 hours till the 72 hours post-operative period. The rate of re-admission was defined as the number of patients who were admitted to the hospital after discharge for a period of 3 months for any reason related to or not related to the spine surgery.

The sample size was calculated using the G*Power version 3.1.9.4. The two-tailed independent samples t-test was used to compare the mean difference between the two groups from a previous study,[6] and the estimated effect size was 1.53. With the alpha as 0.05 and the power of the study as 80%, the calculated sample size was more than ten participants in each group. Since the estimated effect size (Cohen’s d = 1.53) was too large, we re-calculated the sample size using a realistic effect size of 0.8, while retaining the alpha and the power of the study. The estimated sample size was 26 in each group, and further taking into account a ten percentage of drop-outs, we included 30 patients in each group. The total sample size was 60.

Data were entered in an MS Excel spreadsheet (2019) and analysed using the Statistical Package for Social Sciences (SPSS) statistics software version 22 (International Business Machines Corporation (IBM Corp), Armonk, NY, USA). The Kolmogorov–Smirnov test was used to test the normal distribution of the collected data. Mean and standard deviation (SD) were used to express the normally distributed continuous variables like age, BMI, fluid administration, duration of surgery, blood loss, time to start oral feeds, time to mobilisation, and length of hospital stay. The unpaired t-test was used to compare the groups. The median with an interquartile range was used to express the non-normally distributed discrete data, like intraoperative opioid dose and PCA-Morphine use. The Mann–Whitney U test was used to compare medians. Categorical variables like gender, ASA physical status, dexamethasone use, ondansetron use, placement of urinary catheter, drainage tube, regional anaesthesia technique, post-operative nausea and vomiting, pruritus, urinary retention, respiratory depression, and re-admission rate were reported as frequency, and the Chi-square test or Fisher’s exact test was used to determine statistical significance. Regression analysis was used to identify the true effect of the ERAS guideline-based multimodal analgesia technique on the length of stay after correction for other confounding factors. Wherever the P was less than 0.05, the difference between groups was considered to be significant.

RESULTS

The study was conducted on 60 participants and flow of the participants in the study is shown in the CONSORT flow diagram [Figure 1].

Figure 1.

Consolidated standards of reporting trial statement flow diagram. PCA-Morphine = Patient Controlled Analgesia–Morphine, ERAS-MMA = Enhanced Recovery After Surgery guidelines based on multimodal analgesia

The demographic variables were comparable between the two groups [Table 2]. The details of intraoperative variables are shown in Table 2. The mean difference in the length of the hospital stay in minutes was statistically significant between the groups [Group T vs Group C, 4226.02 (SD: 522.21) minutes vs 7144.12 (SD: 592.11) minutes, P < 0.001] [Table 2].

Table 2.

Demography, intraoperative profile, and postoperative patient profile

		Group T (n=30)	Group C (n=30)	P
Demographic profile	Age (years)	48.6 (10.0)	45.3 (8)	0.163
	Gender (female/male) (n)	13/17	12/18	0.79
	BMI (Kg/m2)	27.72 (2.32)	28.96 (3.29)	0.10
	ASA I/II (n)	12/18	10/20	0.78
Intraoperative profile	Fluid administration (millilitres)	2018.04 (885.75)	2010.13 (634.62)	0.97
	Duration (minutes)	136.80 (50.01)	137.50 (41.12)	0.95
	Morphine (milligram) (Median (IQR))	0 (0-0)	10 (12-14)	0.001
	Dexamethasone (n)	30	4	0.001
	Ondansetron (n)	30	30	>0.99
	Blood loss (mL)	313.00 (28.00)	329.00 (29.00)	0.034
	Placement of urinary catheter (n)	3	30	0.001
	Placement of drainage tube (n)	2	22	0.001
	Regional anaesthesia technique (n)	30	18	0.001
Postoperative recovery profile	Time to start oral feeds (minutes)	772.02 (102.13)	1560.10 (162.01)	0.001
	Time to mobilisation (minutes)	1242.00 (198.03)	2704.04 (200.11)	0.001
	Postop Nausea and Vomiting (n)	2	10	0.02
	Pruritus (n)	0	6	0.02
	Urinary Retention (n)	0	1	>0.99
	Respiratory depression (n)	0	3	0.24
	PCA-Morphine (milligram) (Median (IQR);[Range])	0 (0-0);[0-0]	5 (5-6);[3-7]	0.001
	Length of hospital stay (min)	4226.02 (522.21)	7144.12 (592.11)	0.001
	Re-admission rate	0	0

Data presented as mean (Standard Deviation) for continuous variables; median (Interquartile Range); [Range (minimum-maximum)] for non-parametric variables, frequency (n) for categorical variables. BMI=body mass index; ASA=American Society of Anesthesiologists; IQR=Interquartile range

Among the postoperative profiles, none of the patients in Group T required the PCA-Morphine rescue analgesia. In Group C, the total median dose of on-demand PCA-morphine consumed in mg was 5 (IQR: 5–6);[Range: 3-7]. Also, in Group C, six patients experienced pruritus, one patient had respiratory depression, and one patient had urinary retention. In Group T, there were no incidences of complications like pruritus, respiratory depression, and urinary retention. In both groups, there were no re-admissions for a period of 3 months post-discharge. Other details of the postoperative period are shown in Table 2.

In order to analyse the true effect of the intervention on the length of stay, a multiple linear regression model analysis was performed with all the confounding variables as covariates. The results showed that 87.9% of the difference was explained by the covariates (adjusted R² = 0.879). It also showed that when compared with the control group, the ERAS guideline-based multimodal analgesia intervention had a significant effect on the length of stay and that it reduced the stay duration by 2871 minutes, which was approximately two days (B = - 2871.8, P < 0.001) [Table 3]. No other covariates influenced the length of stay (P > 0.05) [Table 3].

Table 3.

Multiple linear regression coefficient table for length of stay

Predictor	B	β	P
Age	-1.248	-0.008	0.872
Gender	85.985	0.028	0.610
BMI	-68.634	-0.126	0.098
ASA class	290.373	0.089	0.220
Duration of Surgery	1.200	0.035	0.468
Blood Loss	-2.184	-0.041	0.436
ERAS-MMA	-2871.751	-0.921	0.001
PONV	-352.627	-0.090	0.135
Pruritus	64.976	0.013	0.881
Urinary Retention	168.276	0.014	0.798
Respiratory Depression	1005.548	0.083	0.136
Postop Morphine Use	163.026	0.043	0.605
Use of Regional block	-304.313	-0.078	0.258

Data presented as regression outputs. B=Unstandardised regression coefficient; β=standardised regression coefficient. BMI=body mass index; ASA=American Society of Anesthesiologists; ERAS-MMA=ERAS guideline-based multimodal analgesia protocol; PONV=Postoperative nausea and vomiting

Postoperative pain scores assessed by VAS showed that pain at rest and pain at sitting, standing, and walking were significantly less in Group T compared to Group C [Table 4].

Table 4.

Post-operative pain scores

		Group T	Group C	P
Pain at rest (VAS) Median (IQR); [Range]	4 h	2(2-3); [1-3]	3(2-4); [2-5]	<0.001
	8 h	2(2-3); [1-4]	3(2-3); [1-5]	0.010
	12 h	2(1-2); [1-3]	3(2-4); [2-5]	<0.001
	24 h	1(1-2); [1-3]	3(2-3); [1-5]	<0.001
	36 h	2(1-2); [1-3]	2(2-2); [1-3]	0.020
	48 h	1(1-2); [1-3]	2(1-2); [0-3]	0.013
Pain during movement (VAS) Median (IQR); [Range]	Sitting	2(2-2); [1-3]	3(2-3); [1-3]	<0.001
	Standing	3(2-3); [2-4]	4(3-4); [2-5]	<0.001
	Walking 4 steps	3(2-4); [2-4]	4(3-5); [3-5]	0.001

Data presented as pain scores, median (first interquartile – third interquartile); [range (minimum – maximum)]. VAS=visual analogue scale. IQR=Interquartile range

DISCUSSION

In this study, we have implemented ERAS guideline-based multimodal analgesia (ERAS-MMA), and we have derived evidence that this approach reduced the length of hospital stay. In our study, the duration of hospital stay was reduced by 2 days in the ERAS-MMA group. This duration correlates with numerous other studies that were conducted globally.[7,8,9,10] Also, we were able to derive that patients in the ERAS-MMA group had less post-operative pain, less opioid consumption, early mobilisation, early oral feeds, and fewer post-operative complications.

Multimodal analgesia has been shown to have many advantages over traditional opioid-based analgesia for various types of surgeries.[11,12,13,14] In our study, the patients who received multimodal analgesia had a reduced length of hospital stay, compared to the traditional PCA morphine analgesia for management, which is consistent with many studies.[15,16,17,18,19] ERAS pathway significantly resulted in early postoperative oral intake, early postoperative mobilisation, and a lesser incidence of postoperative nausea and vomiting. All these claims are well supported by studies.[20,21,22,23]

Preoperative anxiety leads to the activation of the sympathetic system and neuroendocrine response, and affects the postoperative patient recovery.[24,25,26] By adopting the patient education through the health literacy education method[27] in our study, we were able to mitigate these effects.

Prolonged fasting in the perioperative period leads to increased endoplasmic reticulum stress and downregulation of glucose transporter in skeletal muscles, which leads to increased insulin resistance, immune dysfunction, and muscle fatiguability in the postoperative period.[28] ERAS protocol includes the administration of carbohydrate drinks 2 hours before surgery to mitigate these adverse effects.[29] In our study, we have included clear coconut water as the carbohydrate source due to reasons like the additional presence of electrolytes along with simple sugar, easy availability, and the cultural acceptance among the population in our region.

Some of the other perioperative factors apart from surgical stress and anaesthesia related stress that contribute to an altered immune system due to inflammation are blood transfusion, indwelling catheters, drain tubes, and intraoperative hypothermia.[30,31,32] All these factors lead to activation of cytokine response, and this in turn leads to delayed wound healing, increases the chances of postoperative infection, and delays recovery. ERAS-MMA protocol advocates strict measures like preoperative optimisation of anaemia, advocating intraoperative tranexamic acid prophylaxis to reduce blood loss, maintaining normothermia, and minimising placement of urinary catheter and drain tubes. In our study, since the interventions in the ERAS-MMA group were protocol based, we had a significantly lower incidence of drainage tube, urinary catheter, and blood loss. ERAS protocol also emphasises early post operative mobilisation and early feeding of patients, and as a consequence, there are reduced muscle fatiguability, reduced adverse effects of fasting, and reduced risk of thromboembolism, again promoting enhanced recovery.

There are a few limitations in this study. Since there was no institutional protocol in place during the time of the study, the risk of performance bias may not have been eliminated. Secondly, in our study, the majority of the patients in the control group received urinary catheters and drain tubes, which may have introduced a possible violation in blinding. Third, we measured the impact of the implementation of the ERAS protocol through subjective and indirect outcomes. Future studies may utilise objective outcomes like blood level of catecholamines, cytokines, and other inflammatory markers to correlate with clinical outcomes to provide more definite evidence of enhanced recovery. Finally, the results may be specific to single-level spine instrumentation surgery, and more research may be needed to test the broader applicability of the intervention in other population groups.

Even though there are certain limitations, this is one of the few studies that were conducted in a prospective, randomised, double-blinded study. This study puts emphasis on the importance of protocol-based patient management. This study also sets a precedent for tertiary care hospitals in developing nations, where there is a limitation of resource availability on how ERAS protocols can be implemented effectively.

CONCLUSION

We conclude that implementing the Enhanced Recovery After Surgery (ERAS) guideline-based multimodal analgesia for patients undergoing single-level spine fusion surgery significantly reduces the hospital length of stay. A multiple linear regression analysis verified that the reduction in length of stay was mainly due to the combined ERAS guideline-based multimodal analgesia protocol intervention without the influence of other confounding variables.

Presentation at conferences/CMEs and abstract publication

Part of this work was presented at the ISACON 2024, held at Yercaud, Tamil Nadu, dated 21 July 2024.

Study data availability

De-identified data may be requested with reasonable justification from the authors (email to the corresponding author) and shall be shared after approval as per the authors’ institution’s policy.

Disclosure of use of artificial intelligence (AI)-assistive or generative tools

The AI tools or language models (LLM) have not been utilised in the manuscript, except that software has been used for grammar corrections and references.

Declaration of use of permitted tools

NIL

Authors contributions

GM: was involved in Concepts, Design, Definition of intellectual content, literature search, conduct of cases, data acquisition, data analyses, manuscript preparation, editing, review and approval. RV: was involved in Concepts, Design, Definition of intellectual content, literature search, conduct of cases, data analyses, manuscript preparation, editing, review and approval. SY: was involved in the conduct of cases, data analyses, manuscript review and approval. VB: was involved in Concepts, Design, Definition of intellectual content, conduct of cases, manuscript review and approval. SP: was involved in the conduct of cases, data analyses, manuscript review and approval.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.