Non-opioid versus Opioid Peri-operative Analgesia In Neurosurgery (NOPAIN): Study protocol for a multi-centric randomised controlled trial.

Background and Aims: Many patients suffer from post-operative pain after neurosurgery despite using intra-operative opioids. Opioid side effects are problematic in neurosurgical patients. Hence, non-opioid alternatives for the management of nociception and pain are needed. Previous studies comparing opioids with non-opioids in the neurosurgical population were few, from single centres, of small sample sizes and were equivocal in findings, which prevented change in clinical practice. To overcome these limitations, we are conducting a multi-centre trial with objectives to compare intra-operative rescue opioid requirements and post-operative pain scores (primary objectives), adverse events, quality of recovery from anaesthesia, quality of sleep and patient satisfaction during hospital stay, and persistent post-surgical pain and quality of life at 3 and 6 months (secondary objectives) in patients receiving opioid and non-opioid analgesia for brain tumour surgeries. Methods: This study protocol describes the methodology of a multi-centre randomised controlled trial. Ethics committee approval has been obtained from all five centres, the trial has been registered with the Clinical Trial Registry- India, and insurance has been obtained for this investigator-initiated funded study. In patients undergoing supra-tentorial brain tumour surgery (population), we will compare fentanyl (intervention) 1 µg/kg/h with dexmedetomidine (comparator) 0.5 µg/kg/h administered during surgery with regards to intra-operative rescue opioid requirement and post-operative pain (primary outcomes). Results: We describe the study protocol of the multi-centre trial (protocol version 2, dated 29/01/2022). The first patient was recruited on 19/10/2022, and we will complete recruitment before March 2024. Conclusion: We expect our study to establish dexmedetomidine as an effective non-opioid analgesic vis-à-vis opioids in the neurosurgical population.

Comparison of Tracheal Intubation Using King Vision (Non-channeled Blade) and Tuoren Video Laryngoscopes in Patients With Cervical Spine Immobilization by Manual In-Line Stabilization: A Randomized Clinical Trial.

BACKGROUND: Glottic visualization on cervical immobilization with manual in-line stabilization (MILS) might be challenging in individuals with cervical spine injuries. We compared non-channeled King Vision video laryngoscope (VL) (Ambu GmbH, Bad Nauheim, Germany) with Tuoren video laryngoscope (Henan Tuoren Medical Device, Zhengzhou, China) for endotracheal intubation in patients with cervical spine immobilization. METHODS: A total of 124 patients undergoing elective surgery under general anesthesia were included in this study. After induction of general anesthesia, patients were randomized into two groups (62 each): group K (non-channeled blade of King Vision video laryngoscope) and group T (Tuoren video laryngoscope). Cervical spine immobilization was achieved with manual in-line stabilization. The success of the first pass intubation, the time required to intubate, glottic visualization, and intubation difficulty score (IDS) were recorded. RESULTS: The first-attempt success rate of intubation was 95.2% (59 out of 62 patients) in group K and 90.3% (56 out of 62 patients) in group T, which were comparable. The mean glottic visualization time was significantly less with group T (12.74 ± 6.32 seconds) compared to group K (17.92 ± 4.24 seconds). Intubation time was significantly faster with group K (18.79 ± 5.857 seconds) compared to group T (27.21 ± 8.514 seconds). Both video laryngoscopes provided good grades of glottic visualization. CONCLUSIONS:  We conclude that the performance of the Tuoren video laryngoscope is similar to the King Vision video laryngoscope in terms of first-attempt intubation success rate and glottic visualization score in patients with cervical spine immobilization by manual in-line stabilization. Although glottic visualization time was shorter with Tuoren VL, we could achieve faster intubation with King Vision VL.

Is optic nerve sheath diameter a promising screening tool to predict neurological outcomes and the need for secondary decompressive craniectomy in moderate to severe head injury patients? A prospective monocentric observational pilot study.

Background: Optic nerve sheath diameter (ONSD) has been shown to be a noninvasive and quick method to calculate intracranial pressure (ICP) and subsequent neurologic outcomes, although with variable cutoffs. ICP can be indirectly assessed by noninvasive methods such as transcranial Doppler, ONSD, tympanic membrane displacement, and fundoscopy. Knowledge regarding the diagnostic accuracy of ONSD for predicting unfavorable outcomes within 72 hours (h) of moderate and severe head injury is limited. The objective of this study was to measure ONSD measurements at 24-h intervals in moderate to severe head injury patients and to find its association with clinical outcomes in the target population. Methods: This prospective observational study was done on moderate to severe head injury patients. ONSD was measured twice at 24-h intervals over 48 h. The clinical outcome was divided into the favorable group (patients who were in conservative treatment with a stable Glasgow Coma Scale [GCS] score and discharged following treatment) and the unfavorable group (patients who had a drop in GCS motor score of one or more, or expired or underwent surgical intervention) within 72 h following traumatic brain injury. The Kruskal-Wallis test, Mann- Whitney test, and receiver operating characteristic curves were used to establish the association between ONSD and clinical outcomes. Results: ONSD values measured at 24-h intervals >6.1 mm (P < 0.0146) and 6.2 mm (P < 0.0001) were found to be predictors of unfavorable outcomes (expired or underwent surgery), and hence the need for a secondary decompressive craniectomy (DC). Conclusion: ONSD is an efficient screening tool to assess neurological outcomes in severe head injury patients. It can reliably predict the need for secondary DC at an earlier stage before secondary brain damage ensues in these patients.

Trigeminal Somatosensory Evoked Potentials During Neurosurgical Procedures Using Electrical Stimulation of the Lips Under General Anesthesia.

Background Intraoperative neurophysiology monitoring is rapidly evolving with the advent of newer modalities. Long latency sensory evoked potentials from the trigeminal nerve distribution have rarely been demonstrated during neurosurgical procedures. Trigeminal sensory evoked potential (TSEP) can be used to prevent nerve injury during surgical procedures, such as those for trigeminal neuralgia and tumors involving the trigeminal nerve and pathway. Methodology We attempted to record TSEP from 12 subjects who underwent various neurosurgical procedures with low doses of inhalational anesthetic agents. We stimulated the upper and lower lip and recorded from C6 and Fz locations. We used 14-17 mA current stimuli with a pulse width of 50-150 microseconds and a stimulation rate of 2.1 Hz. Results We could obtain a clear, reproducible TSEP response in two out of 12 subjects. We observed a TSEP waveform with negative peaks at 13 and 27 milliseconds and a positive wave at around 19 milliseconds. Conclusions The TSEP produced by the electrical stimulation of the upper and lower lip can be detected from the scalp C5, C6, and Fz area even during neurosurgical procedures, even if inhalational anesthesia was used at induction, but only in a small proportion of cases. It appeared to reflect the activity of trigeminal cortical response. Avoiding the notch filter and turning off the inhalational agents are essential for a good response.

Comparison of Dexmedetomidine Versus Fentanyl-Based Anesthetic Protocols Under Patient State Index Guidance in Patients Undergoing Elective Neurosurgical Procedures with Intraoperative Neurophysiological Monitoring.

Objectives The study was designed to elucidate the effects of dexmedetomidine as an anesthetic adjunct to propofol in total intravenous anesthesia (TIVA) on anesthetic dose reduction, the quality of intraoperative neurophysiological monitoring (IONM) recordings, analgesic requirements, and recovery parameters in patients undergoing neurosurgical procedures with neurophysiological monitoring. Methods A total of 54 patients for elective neurosurgical procedures with IONM were randomized to group D (dexmedetomidine) and group F (fentanyl). A loading dose of the study drug of 1µg/kg followed by 0.5 µg/kg/h infusion was used in two groups. Propofol-based TIVA with a Schneider target-controlled infusion model was used for induction and maintenance with effect site concentration of 4-5 and 2.5-4 µg/mL, respectively, titrated to a Patient State Index (PSI) of 25-40. Baseline IONM recordings were obtained after induction. The mean propofol consumption, number of patient movements, quality of IONM recordings, number of fentanyl boluses, hemodynamic characteristics, and recovery parameters were recorded. Results The mean propofol consumption was significantly lower in group D when compared to group F (101.4 ± 13.5 µg/kg/min vs 148.0 ± 29.8 µg/kg/min). Baseline IONM recordings were acquired in all patients without any difficulty. The two groups were comparable with respect to the number of additional boluses of fentanyl, patient movements, and recovery characteristics. Conclusion Dexmedetomidine as an adjuvant to propofol in TIVA reduces the requirement of the latter, without affecting the IONM recordings. The addition of dexmedetomidine also ensures stable hemodynamics and decreases the requirement of opioids with similar recovery characteristics.

Recent advancements in the practice of neuroanaesthesia and neurocritical care: An update.

The practice of neuroanaesthesia has expanded significantly in recent years to keep up with various challenges posed in the perioperative care of patients for neurosurgical, interventional, neuroradiological, and diagnostic procedures. Technological advancements in neuroscience include the intraoperative use of computed tomography scans and angiograms for vascular neurosurgery, magnetic resonance imaging, neuronavigation, expansion of minimally invasive neurosurgery, neuroendoscopy, stereotaxy, radiosurgery, the performance of increasingly complex procedures, advancements in neurocritical care, etc. Recent advancements in neuroanaesthesia that can meet these challenges include the resurgence of ketamine, opioid-free anaesthesia, total intravenous anaesthesia, techniques to facilitate intraoperative neuromonitoring, awake neurosurgical and spine surgeries, etc. The current review provides an update on the recent advancements in neuroanaesthesia and neurocritical care.

Comparison of two techniques of goal directed fluid therapy in elective neurosurgical patients - a randomized controlled study.

BACKGROUND: Goal directed fluid therapy (GDFT) may be a rational approach to adopt in neurosurgical patients, in whom intravascular volume optimization is of utmost importance. Most of the parameters used to guide GDFT are derived invasively. We postulated that the total volume of intraoperative intravenous fluid administered during elective craniotomy for supratentorial brain tumours would be comparable between two groups receiving GDFT guided either by the non-invasively derived plethysmography variability index (PVI) or by stroke volume variation (SVV). METHODS: 60 ASA category 1, 2 and 3 patients between 18 and 70 years of age were randomized to receive intraoperative fluid guided either by SVV (SVV group; n = 31) or PVI (PVI group; n = 29). The total volume of fluid administered intraoperatively was recorded. Serum creatinine was measured before the surgery, at the end of the surgery, 24 h after surgery and on the fifth post-operative day. Arterial cannulation was performed before induction in all patients. Serum lactate was measured before induction, once in 2 h intraoperatively, at the end of the surgery and 24 h after the surgery. Brain relaxation score was assessed by the surgeon during dural opening and dural closure. Patients were followed up till discharge or death. The duration of mechanical ventilation and the duration of hospital stay was noted for all patients. RESULTS: The volume of fluid given intraoperatively was significantly higher in the SVV group (p = 0.005). The two groups were comparable with respect to serum lactate and serum creatinine measured at pre-determined time intervals. Brain relaxation score was also comparable between the groups. SVV and PVI displayed moderate to strong correlation intraoperatively. The duration of mechanical ventilation and the length of the hospital stay were comparable between the two groups. CONCLUSIONS: PVI and SVV are equally effective in guiding GDFT in adults undergoing elective craniotomy for supratentorial brain tumours.

Comparison of the Analgesic Efficacy of Ultrasound-Guided Superficial Serratus Anterior Plane Block With Deep Serratus Anterior Plane Block in Patients Undergoing Modified Radical Mastectomy: A Randomized Clinical Trial.

Background Acute postoperative pain after breast cancer surgery adversely affects recovery and is an independent predictor of chronic postsurgical pain in these patients. Serratus plane blocks have been found to provide analgesia to the anterior hemithorax. However, trials comparing superficial serratus plane block and deep serratus block in breast cancer surgery patients are sparse. Methodology A total of 74 female patients with American Society of Anesthesiologists physical status I and II scheduled for elective modified radical mastectomy for breast cancer were randomized into two groups. Group A patients received a superficial serratus plane block with 30 mL of 0.25% bupivacaine, and group B patients received a deep serratus plane block with 30 mL of 0.25% bupivacaine. Postoperatively, the Numerical Rating Scale (NRS) score was measured during the immediate postoperative period, after 30 minutes and at one, four, eight, 16, and 24 hours, as well as on the second and third day. After discharge, the NRS scores were recorded in the second and third weeks and then monthly once for three months. All patients received patient-controlled analgesia with intravenous (IV) morphine. The duration of analgesia, pain scores, and 24-hour morphine consumption were also noted. Results In group A, the mean duration of analgesia (hours) was 5.51 ± 1.42, whereas in group B the mean duration of analgesia (hours) was 6.69 ± 1.18 (p < 0.01). NRS scores for pain during rest at 12 and 16 hours and NRS scores for pain during cough at eight, 12, and 16 hours, as well as at the third month were significantly lower in group B. However, morphine consumption was comparable between the groups. Conclusions Deep serratus plane block was associated with better NRS scores for pain on rest and coughing and prolonged duration of analgesia after a modified radical mastectomy. We conclude that the deep serratus plane block provides superior and extended analgesia than the superficial serratus plane block after a modified radical mastectomy.

Clinical utility of ultrasonography, pulse oximetry and arterial line derived hemodynamic parameters for predicting post-induction hypotension in patients undergoing elective craniotomy for excision of brain tumors - A prospective observational study.

Background: Hypotension, which is a common adverse effect of induction of anesthesia, may be especially detrimental in neurosurgical patients. Hence, it is important to investigate hemodynamic parameters which may be useful in identifying patients at risk of hypotension, following induction. Our study was designed to assess the utility of parameters derived from ultrasonography, pulse oximeter and arterial line for predicting post-induction hypotension. Methods: The study was designed as a prospective, observational trial. Written informed consent was obtained from 100 American Society of Anesthesiologists (ASA) 1 and 2 patients, between 18-60 years of age, scheduled for elective craniotomy for brain tumors. Arterial cannula was inserted before induction of anesthesia and connected to Vigileo cardiac output monitor. Baseline stroke volume variation (SVV), stroke volume (SV), cardiac index (Ci), cardiac output (CO) and pulse pressure variation (PPV) were recorded. Plethysmography variability index (PVI) and perfusion index (PI) were obtained from the Masimo rainbow SET® Radical-7® pulse oximeter. Ultrasonographic assessment of the inferior vena cava (IVC) was performed before induction of anesthesia and again within 15 min after induction. Maximum and minimum IVC diameters (dIVCmax and dIVCmin) and collapsibility index (CI) were measured. All the other aforementioned parameters were recorded every minute starting at induction, until the 15th minute following induction. Results: PI, CI and dIVCmax were found to have the largest AUCROC for the prediction of post-induction hypotension (AUCROC 0.852, 0.823 and 0.781 respectively). Multiple logistic regression analysis revealed CI to be the most significant independent factor for the prediction of post-induction hypotension. Conclusion: Non-invasively derived hemodynamic parameters like dIVCmax, CI and PI were more accurate for the prediction of post-induction hypotension, compared to invasively derived parameters.

Preoperative Vascular Function Assessment and Perioperative Vascular Events in Patients Posted for Elective Non-cardiac Surgeries.

Background Coronary atherosclerosis is usually asymptomatic until a major cardiac event occurs. Surgery is one of the major stress factors that play a role in hastening vascular deterioration in susceptible patients. Non-invasive tests to detect atherosclerosis and endothelial dysfunction have started gaining popularity nowadays, and of the several options, carotid artery intima-media thickness (IMT) and radial artery flow-mediated dilation (FMD) are two promising tests for detecting cardiovascular impairment. Methods This was a pilot study that was undertaken on 100 patients in a tertiary care medical center (Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry) between June 2015 and August 2016 with the aim of studying the prevalence of endothelial dysfunction and early atherosclerosis in the given population, and to find out the predictive power of preoperative vascular functional assessment in the prediction of perioperative cardiovascular events in the same population. We had selected patients who had at least two risk factors for endothelial dysfunction and were posted for elective non-cardiac surgical procedures via convenience sampling. Flow-mediated vasodilatation of the radial artery (FMD) and carotid intima-media thickness (CIMT) were measured on the previous day of surgery, while a fasting lipid profile was collected from the patients on the morning of the surgery. Endothelial dysfunction was defined as FMD<4.5%, while atherosclerosis was defined as CIMT>0.07 cm. Demographic details and baseline hemodynamic parameters of the patients were also noted preoperatively as well as intra-operatively, and patients were followed up for any major clinical adverse cardiovascular event post-operatively till they were discharged from the hospital. Results It was found that the prevalence of endothelial dysfunction was 23%, while the prevalence of early atherosclerosis was 33% in our study population. However, it was found that FMD and CIMT did not correlate with each other significantly, nor did they correlate significantly with perioperative cardiovascular events. The risk factors of the patients also did not correlate with the FMD and CIMT values of the patients in which they were impaired. Moreover, they did not have any significant correlation with the perioperative events that occurred. Conclusion The prevalence of endothelial dysfunction in our tertiary center was found to be 23%, and the prevalence of atherosclerosis was 33% in patients posted for elective non-cardiac surgery who had multiple risk factors. It was also found that non-invasive preoperative vascular assessment was not quite effective as hypothesized in predicting perioperative cardiovascular events.

Comparing postgraduate anaesthesia education in India and abroad: Strengths and scope.

The quality of training is a major contributor to workforce proficiency in healthcare, and there is a definite need to achieve a uniform level of knowledge and skill in medical education programmes. There is a paucity of literature comparing postgraduate anaesthesia medical education training structure and requirements across the globe. In a zeal to achieve uniform competencies and technical skills, the strengths and scope of training programmes need to be identified. In this article, we describe the core elements of postgraduate training in various countries while proposing an amalgamation of strengths of each programme and providing a roadmap to evolve further the competency-based comprehensive curriculum proposed by the National Medical Commission of India.

Ease of lumbar epidural catheter insertion with prepuncture ultrasound as guidance compared with conventional palpatory technique when performed by anesthesiology residents: A randomized controlled trial.

BACKGROUND AND AIMS: Lumbar epidural catheter insertion is conventionally performed by anesthesia residents by palpation of anatomical landmarks with relatively blind localization of epidural space which may lead to an increase in failure rate. We aim to compare the ease of lumbar epidural catheterization using prepuncture ultrasound as guidance with that of conventional palpatory technique. Comparisons were made with reference to number of insertion attempts, total time taken for the procedure, frequency of dural puncture, and overall satisfaction score as assessed by Likert's scale. MATERIAL AND METHODS: Eighty, ASA 1-3, patients undergoing elective surgeries requiring lumbar epidural catheterization were recruited for the study. Study participants were randomized into two groups. In group P, epidural catheterization was performed using the conventional palpatory method and in group U, it was performed with the help of ultrasound determined parameters. Number of insertion attempts, total time taken for successful insertion of epidural catheter, frequency of dural puncture, and overall satisfaction of ease of insertion as determined by Likert's scale were compared between both the groups. Data were analyzed using SPSS statistical software version 17 and P value <0.05 was considered statistically significant. RESULTS: The number of insertion attempts was significantly lesser in Group U (P = 0.019). The total procedure time was significantly higher in group U (P < .001). There was no significant difference in ease of insertion score, as measured by Likert's scale between both the groups (P = 0.45). CONCLUSION: Prepuncture ultrasound guidance improves the first attempt success rate of lumbar epidural catheterization with reduced incidence of dural puncture with similar overall satisfaction score but increases the total time taken for the procedure when compared to conventional palpatory technique.

Variation in therapeutic strategies for the management of severe COVID-19 in India: A nationwide cross-sectional survey.

AIM: During the pandemic of coronavirus disease 2019 (COVID-19), the physicians are using various off-label therapeutics to manage COVID-19. We undertook a cross-sectional survey to study the current variation in therapeutic strategies for managing severe COVID-19 in India. METHODS: From January 4 to January 18, 2021, an online cross-sectional survey was conducted among physicians involved in the management of severe COVID-19. The survey had three sections: 1. Antiviral agents, 2. Immunomodulators, and 3. Adjuvant therapies. RESULTS: 1055 respondents (from 24 states and five union territories), of which 64.2% were consultants, 54.3% working in private hospitals, and 39.1% were from critical care medicine completed the survey. Remdesivir (95.2%), antithrombotics (94.2%), corticosteroids (90.3%), vitamins (89.7%) and empirical antibiotics (85.6%) were the commonly used therapeutics. Ivermectin (33%), convalescent plasma (28.6%) and favipiravir (17.6%) were other antiviral agents used. Methylprednisolone (50.2%) and dexamethasone (44.1%) were preferred corticosteroids and at a dose equivalent of 8 mg of dexamethasone phosphate (70.2%). There was significant variation among physicians from different medical specialities in the use of favipiravir, corticosteroids, empirical antibiotics and vitamins. CONCLUSION: There is a considerable variation in the physicians' choice of therapeutic strategies for the management of severe COVID-19 in India, as compared with the available evidence.

The agreement between arterial and venous lactate in patients with sepsis.

BACKGROUND: Arterial sampling, which is the gold standard for measuring lactate levels in sepsis, is more painful, requires experience and is associated with a higher incidence of morbidity, when compared with venous sampling. This study attempted to measure the correlation and agreement between arterial and peripheral venous (PV) lactate and between arterial and central venous (CV) lactate, with the objective to test interchangeability of the two and possibly support the use of venous lactate levels in resuscitating patients with sepsis. METHODS: Eighty-seven patients admitted to the critical care unit of our hospital with the diagnosis of sepsis or septic shock were included in the study after taking informed consent. The arterial, PV and CV samples were taken within the first 24 hours following admission and within 10 minutes of each other. Lactate levels, CV oxygen saturation (ScvO2 ) and base excess of each sample type were reported within 15 minutes of collection. Patients were followed up for a period of 28 days to record the need for organ support (newly diagnosed renal failure, need for renal replacement therapy [RRT], liver failure, coagulopathy and need for ventilation) and mortality. RESULTS: Pearson correlation for arterial versus PV lactate was 0.76 and for arterial versus CV lactate was 0.992. The mean difference between arterial and PV lactate was found to be -0.30 (95% confidence interval [CI], -0.38 to -0.21). The upper and lower limits of agreement were 0.51 and -1.10, respectively. Mean difference between arterial and CV lactate was found to be -0.13 (95% CI, -0.21 to -0.05). Upper and lower limits of agreement were 0.63 and -0.89, respectively. CONCLUSION: Our study demonstrates a high level of agreement in the lactate levels as measured on venous samples and arterial samples. Venous lactate levels are reliable in resuscitation of patients with sepsis.

Intraoperative neurophysiological monitoring in paediatric neurosurgery.

Intraoperative neurophysiological monitoring (IONM) is commonly used in various surgical procedures in adults, but with technological and anaesthetic advancements, its use has extended to the paediatric population. The use of IONM in children poses a unique set of challenges considering the anatomical and physiological differences in this group of patients. The use of IONM aids in the localization of neural structures and enables surgeons to preserve the functional neural structures leading to decreased incidence of postoperative neurological deficits and better patient outcomes. In this article, we review the use of IONM in paediatric patients undergoing various spinal and cranial neurosurgical procedures. We discuss the patient characteristics, type of surgeries, and technical and anaesthetic considerations about IONM in this population.

Comparison of total intravenous anesthesia vs. inhalational anesthesia on brain relaxation, intracranial pressure, and hemodynamics in patients with acute subdural hematoma undergoing emergency craniotomy: a randomized control trial.

BACKGROUND: The major goals of anesthesia in patients with severe traumatic brain injury (TBI) are-maintenance of hemodynamic stability, optimal cerebral perfusion pressure, lowering of ICP, and providing a relaxed brain. Although both inhalational and intravenous anesthetics are commonly employed, there is no clear consensus on which technique is better for the anesthetic management of severe TBI. METHODS: Ninety patients, 18-60 years of age, of either gender, with GCS < 8, posted for emergency evacuation of acute subdural hematoma were enrolled in this prospective trial, and they were randomized into two groups of 45 each. Patients in group P received propofol infusion at 100-150 mg/kg/min for maintenance of anesthesia and those in group I received ≤ 1 MAC of isoflurane. Hemodynamic parameters were monitored in all patients. ICP was measured at the dural opening and brain relaxation was assessed by the operating surgeon on a four-point scale (1-perfectly relaxed, 2-satisfactorily relaxed, 3-firm brain, and 4-bulging brain) at the dural opening. It was reassessed at dural closure. RESULTS: Brain relaxation, both at dural opening and closure, was significantly better in patients who received propofol compared to those who received isoflurane. ICP was significantly lower (25.47 ± 3.72 mmHg vs. 23.41 ± 3.97 mmHg) in the TIVA group. Hemodynamic parameters were well maintained in both groups. CONCLUSIONS: In patients with severe TBI, total intravenous (Propofol)-based anesthesia provided better brain relaxation, maintained a lower ICP along with better hemodynamics when compared to inhalational anesthesia. CLINICAL TRIAL REGISTRATION: Clinical trials registry (NCT03146104).