Abstract
Background
Postoperative nausea and vomiting (PONV) is one of the most common and distressing side effects of general anesthesia. According to the Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting, patients at high risk of PONV should be given at least three prophylactic antiemetic agents. As previous studies have reported antiemetic effects of sub-hypnotic doses of midazolam, a benzodiazepine, we investigated the efficacy of remimazolam, an ultra-short-acting benzodiazepine, as a third prophylactic antiemetic agent when administered at a low target dose.
Methods
Hundred and eight patients were randomly allocated to either remimazolm group (group R) or control group (group C). Sevoflurane was used to maintain anesthesia and the group R additionally received remimazolam (0.3 mg/kg/hr). All patients received ramosetron 0.3 mg and dexamethasone 5 mg. The incidence of PONV, quality of recovery score, and pain score at postoperative 24 h were evaluated.
Result
The groups did not have significantly different incidences and severities of PONV at postoperative 24 h. However, the group C had a statistically significantly higher incidence of nausea than the group R at postoperative 6 h (52.9% vs. 31.5%, P = 0.026). The group C had a statistically significantly higher incidence of dizziness than the group R in the post anesthesia care unit (19.6% vs. 1.9%, P = 0.008).
Conclusion
Low-dose remimazolam infusion did not reduce the incidence of PONV at postoperative 24 h. It was associated with a lower incidence of nausea at postoperative 6 h and dizziness in the PACU.
Trial registration
Clinicaltrials.gov. NCT05439057 on June 27, 2022 (retrospectively registered).
Keywords: Postoperative nausea vomiting (PONV), Remimazolam, Laparoscopic cholecystectomy
Introduction
Postoperative nausea and vomiting (PONV) is a prevalent and distressing postoperative complication, affecting approximately 30% of surgical patients with higher rates observed in high-risk groups of PONV [1]. PONV significantly reduces patient satisfaction and increases the risk of complications, such as electrolyte imbalances, aspiration pneumonia, and wound dehiscence, leading to extended hospital stays and higher healthcare costs [2, 3].
The Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting recommend administering at least three prophylactic antiemetic agents to patients at high risk of PONV [4]. Our center uses two prophylactic agents—5-HT3 receptor antagonists and dexamethasone—in female patients undergoing laparoscopic cholecystectomy. Female patients undergoing general anesthesia with inhalational agents and receiving opioids are at high risk for PONV, particularly if they have a history of PONV or are non-smokers. In addition, laparoscopic surgery can cause peritoneal distension, which stimulates mechanoreceptors and increases serotonin levels, further elevating the risk of PONV [5]. Therefore, this patient population requires at least three prophylactic antiemetic agents to effectively manage PONV risk.
Administering a sub-hypnotic dose of midazolam, a benzodiazepine, effectively prevents PONV [6]. Remimazolam, an ultra-short-acting benzodiazepine, has an antiemetic effect when used alone as an anesthetic agent. However, it has limited analgesic properties, making it less suitable as a primary anesthetic agent for laparoscopic cholecystectomy in non-elderly adults. Thus, we investigated the efficacy of low-dose remimazolam infusion as the third prophylactic agent for PONV prevention by adding it to our center’s standard balanced anesthesia protocol. Given that remimazolam shares pharmacological properties with midazolam, which has been shown to reduce PONV incidence in various surgical procedures at sub-hypnotic doses, we hypothesized that low-dose remimazolam may decrease PONV rates.
Methods
Participants
This study is a single-center, prospective, randomized, controlled trial and was approved by the Institutional Review Board of Sanggye paik Hospital (IRB No. 2022-03-007-008). The study was conducted in accordance with the Declaration of Helsinki. The report of this study adheres to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Written informed consent was obtained from all participants. We enrolled 142 female patients aged 19 to 65 years with ASA physical status I–III undergoing laparoscopic cholecystectomy in Sanggye Paik Hospital, Seoul, South Korea between May 13, 2022 and October 31, 2024. Patients with moderate-to-severe liver dysfunction, defined as total bilirubin ≧ 3.0 mg/dL; aspartate aminotransferase or alanine aminotransferase 2.5 times more than the normal range; moderate-to-severe renal dysfunction, defined as serum creatinine ≧ 2.0 mg/dL or in end-stage renal disease undergoing hemodialysis; tolerance to benzodiazepines; history of hypersensitivity to anesthetic drugs, namely benzodiazepines, propofol, remifentanil, fentanyl, rocuronium, and flumazenil; alcohol dependence; galactose intolerance; lactase deficiency; glucose-galactose malabsorption; body mass index ≥ 35 kg/m²; uncontrolled diabetes mellitus; or acute closed-angle glaucoma; patients who were pregnant or breast feeding; or who refused were excluded. A total of 34 patients were excluded of whom 9 were excluded because of moderate liver dysfunction, 1 because she had a body mass index of 36, and 24 because they refused to participate. The remaining 108 patients were randomly allocated to either the remimazolm group (R group) or control group (C group). In the C group, 3 patients stopped receiving the intervention, so 51 patients in the C group and 54 patients in the R group were analyzed.
This study was conducted as a double-blinded study. Patients were randomly assigned to one of two groups in 1:1 ratio using a random sequence generated by Microsoft Excel. Group allocation information was concealed in sequentially numbered, opaque, sealed envelopes. When a patient arrived at the preanesthesia holding area, an anesthesiologist not involved in data collection opened the patient’s envelope and assigned them to the group noted in the envelope. The patients did not know the group they belonged to until the end of the study. The outcome assessor was an anesthesiologist not involved in the surgical procedure and did not know which group the patient was assigned to.
Anesthesia and monitoring
All patients received glycopyrrolate (0.2 mg intramuscularly) for premedication and received dual antiemetic prophylaxis regimen (ramosetron 0.3 mg, dexamethasone 5 mg) during surgery. On arrival of the operation room, the patients were monitored with standard monitoring devices and received general anesthesia uniformly. Anesthesia was induced with propofol (2 mg/kg). After loss of consciousness, sevoflurane was started and rocuronium (0.6 mg/kg) was administered followed by a remifentanil infusion (0.1 mcg/kg/min). The R group received remimazolam (0.3 mg/kg/hr) (Byfavo, Hana Pharmaceuticals, Seoul, South Korea) after loss of consciousness and stopped receiving it 20 min before the end of anesthesia. The remimazolam dose (0.3 mg/kg/hr) was determined based on a pilot study, in which all patients were able to awaken without the need for flumazenil reversal. Instead of remimazolam, the C group received an equivalent volume of normal saline. The remimazolam and saline were injected using a transparent 50 ml syringe, so their appearance was indistinguishable. After endotracheal intubation, dexamethasone (5 mg) was administered intravenously to all patients. Anesthesia was maintained with sevoflurane (1.5–2.5 vol%) with the bispectral index (Aspect Medical Systems, Inc., Natick, MA, USA) kept at 40–60. At the end of surgery, ramosetron (0.3 mg) and fentanyl (1 mcg/kg) were administered. Sugammadex (2–4 mg/kg) was administered for neuromuscular reversal. If the patient did not regain consciousness in 15 min after stopping of remimazolam, flumazenil (0.3 mg) was administered repeatedly.
Measurements
The patients’ demographics (age, height, weight, body mass index, hypertension, American Society of Anesthesiologists classification, and Apfel score) and perioperative characteristics (operation duration, anesthesia duration, PACU time, crystalloid amount, colloid amount, and estimated blood loss) were recorded. The Apfel scores were calculated based on four variables (female, nonsmoker, history of motion sickness or PONV, and use of postoperative opioids). The patients’ quality of recovery scores (QoR-15) were measured preoperatively and at postoperative 24 h to assess changes in recovery quality after anesthesia and surgery. We used the Korean version of the QoR-15, which has a total possible score of 150. All patients filled out the QoR-15 form themselves. Additionally, the total hospital stay and the use of analgesics and antiemetics were recorded.
The occurrence and the severity of PONV were assessed every 10 min in the PACU and at postoperative 6 and 24 h. The severity of nausea and pain were measured using the 11-point verbal numeric rating scale (VNRS) (none: 0, mild: 1–3, moderate: 4–6, severe: 7–10). All patients were prescribed fentanyl-based intravenous patient-controlled analgesia (IV-PCA) (100 mL) that consisted of fentanyl (15 mcg/kg), ramosetron (0.6 mg), and 0.9% normal saline. The IV-PCA device was set to deliver 1 mL per hour with an additional 1 mL on patient demand and a lock-out time of 15 min. IV-PCA was started when the patient entered the PACU. Fentanyl, acetaminophen, or ketorolac was administered as a rescue analgesic. If patients reported PONV, IV-PCA was discontinued. If PONV persisted, metoclopramide (10 mg) was administered.
The primary outcome was the incidence of PONV at postoperative 24 h. The secondary outcomes were QoR-15 and VNRS pain scores at postoperative 24 h.
Statistical analysis
In a previous study, 40% of female patients who undergo laparoscopic surgery with two prophylactic antiemetics experienced PONV at 24 h after surgery [7]. When an additional third prophylactic antiemetic is administered, this incidence decreased to 15% [7]. In the present study, we assumed that remimazolam has an antiemetic effect if PONV was reduced by more than 60% when remimazolam was infused after administering two prophylactic antiemetic agents. G Power version 3.1.9.4 (Franz Faul, Universitat Kiel, Germany) was used to determine that 49 patients were required per group (α = 0.05, β = 0.8). Considering a 10% dropout rate, a total of 108 patients were enrolled.
Statistical analyses were performed using SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA). All tests were two-sided. A P-value of < 0.05 was considered statistically significant. The Kolmogorov-Smirnov test was used to assess the normality of continuous variables. Data are presented as mean ± standard deviation for normally distributed data and as median (interquartile range) for non-normally distributed data. Continuous variables were compared using the independent sample t-test for normally distributed data and the Mann-Whitney U-test for non-normally distributed data. Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate.
Results
A total of 142 patients who underwent laparoscopic cholecystectomy under general anesthesia were eligible for participation in this study. Thirty-four patients were excluded due to not meeting the inclusion criteria. Nine were excluded for having moderate liver dysfunction, 1 because of a body mass index of 36, and 24 because they refused to participate. The remaining 108 patients were randomly assigned to either the group C or group R. Three patients in the group C were discontinued during the study, so 51 in the C group and 54 in the group R were analyzed (Fig. 1).
Fig. 1.
Flow diagram of the study
The groups did not have statistically significantly different demographic or perioperative characteristics (Table 1). The groups’ perioperative non-opioid and opioid analgesic doses were not statistically significantly different (Table 2). Overall incidence of PONV (from PACU to postoperative 24 h) was not different between the groups (66.6% vs. 57.4%, P = 0.329). The groups did not have statistically significantly different incidences and severities of PONV at postoperative 24 h (43.1% vs. 35.2%, P = 0.404; 1.8 ± 2.6 vs. 1.3 ± 2.1, P = 0.245). However, the group C had a statistically significantly higher incidence of dizziness than the group R in the PACU (P = 0.008). The group C had a statistically significantly higher incidence of nausea than the group R at postoperative 6 h (P = 0.026) (Table 3). Table 4 shows univariate and multivariate regression analysis for the incidence of PONV at postoperative 24 h. Only the IV-PCA fentanyl dose administered during the first 24 postoperative hours was associated with the development of PONV. No adverse events were recorded for either group during the study period.
Table 1.
Patient demographics
| Control group (n = 51) | Remimazolam group (n = 54) | P | ||
|---|---|---|---|---|
| Age (years) | 46.4 ± 11.8 | 44.7 ± 10.5 | 0.437 | |
| Weight (kg) | 61.9 ± 12.1 | 62.2 ± 9.2 | 0.891 | |
| Height (cm) | 159.1 ± 5.7 | 159.5 ± 5.6 | 0.692 | |
| Body mass index (kg/m2) | 24.3 ± 4.1 | 24.4 ± 3.6 | 0.928 | |
| Hypertension | 5 (9.8) | 6 (11.1) | 1.000 | |
|
ASA classification I, II III |
51 (100.0) 0 (0) |
53 (98.1) 1 (1.9) |
1.000 | |
| Apfel score (0–4) | 0.742 | |||
|
3 4 |
47 (92.2) 4 (7.8) |
48 (88.9) 6 (11.1) |
||
Data are shown as mean ± standard deviation or median (interquartile range) or number (%). ASA: American Society of Anesthesiologists
Table 2.
Perioperative data
| Control group (n = 51) | Remimazolam group (n = 54) | P | ||
|---|---|---|---|---|
| Operation duration (min) | 61.0 ± 28.2 | 55.6 ± 27.5 | 0.321 | |
| Anesthesia duration (min) | 93.6 ± 28.1 | 90.8 ± 26.8 | 0.596 | |
| Crystalloid amount (mL) | 578.7 ± 185.1 | 545.4 ± 157.3 | 0.323 | |
| Estimated blood loss (mL) | 16.3 ± 72.0 | 4.5 ± 8.9 | 0.250 | |
| PACU time (min) | 44.9 ± 12.3 | 48.1 ± 16.6 | 0.273 | |
| Sevoflurane (%) | 1.8 ± 0.3 | 1.7 ± 0.3 | 0.026 | |
| remifentanil dose (µg) | 410.8 ± 223.7 | 398.2 ± 196.7 | 0.760 | |
| fentanyl dose in PACU (µg) | 49.3 ± 37.4 | 48.2 ± 41.4 | 0.880 | |
| Non-opioid in PACU | 12 (23.5) | 12 (22.2) | 1.000 | |
| Analgesic at ward on POD0 | 20 (39.2) | 24 (44.4) | 0.730 | |
| Analgesic at ward on POD1 | 16 (31.4) | 19 (35.2) | 0.836 | |
| Antiemetic POD0 | 0 | 0 | ||
| Antiemetic POD1 | 1 (2.0) | 3 (5.6) | 0.618 | |
| IV-PCA fentanyl dose during postoperative 24 h (µg) | 310.2 ± 183.6 | 290.3 ± 149.7 | 0.545 | |
| IV-PCA stop | 22 (43.1) | 19 (35.2) | 0.526 | |
| QoR15 score-preoperation | 128.7 ± 23.1 | 128.8 ± 19.9 | 0.976 | |
| QoR15 score-postoperation | 113.7 ± 23.1 | 120.0 ± 20.9 | 0.146 | |
| Hospital stay (day) | 5.8 ± 3.9 | 5.7 ± 2.1 | 0.824 | |
Data are shown as mean ± standard deviation or number (%). PACU: postanesthesia care unit, POD: post operative day, PCA: patient controlled analgesia, QoR15: Quality of Recovery Score
Table 3.
Comparison of PONV and postoperative symptoms
| Control group (n = 51) | Remimazolam group (n = 54) | P | |
|---|---|---|---|
| Overall PONV | 34 (66.6) | 31 (57.4) | 0.329 |
| [PACU] | |||
| Nausea | 16 (31.4) | 10 (18.5) | 0.194 |
| Nausea severity (0/1/2/3) | 35/6/6/4 | 44/4/3/3 | 0.478 |
| Vomit | 0 (0) | 0 (0) | 1.000 |
| Retch | 2 (3.9) | 0 (0.0) | 0.234 |
| Pain score (0-10) | 7.2 ± 1.4 | 7.5 ± 1.9 | 0.292 |
| Headache | 3 (5.9) | 0 (0) | 0.111 |
| Dizziness | 10 (19.6) | 1 (1.9) | 0.008 |
| [postoperative 6 hour] | |||
| Nausea | 27 (52.9) | 17 (31.5) | 0.026 |
| Nausea severity (0/1/2/3) | 24/7/9/11 | 37/7/5/5 | 0.108 |
| Vomit | 3 (5.9) | 5 (9.3) | 0.717 |
| Retch | 8 (15.7) | 5 (9.3) | 0.482 |
| Pain score (0-10) | 6.6 ± 2.5 | 6.1 ± 2.4 | 0.382 |
| [postoperative 24 hour] | |||
| Nausea | 22 (43.1) | 19 (35.2) | 0.404 |
| Nausea severity (0/1/2/3) | 29/11/7/4 | 35/12/5/2 | 0.677 |
| Vomit | 3 (5.9) | 2 (3.7) | 0.672 |
| Retch | 6 (11.8) | 7 (13.0) | 1.000 |
| Pain score (0-10) | 3.7 ± 2.0 | 3.6 ± 1.8 | 0.687 |
Data are shown as mean ± standard deviation, or number (%). PONV postoperative nausea and vomiting, PACU postanesthesia care unit
Table 4.
Univariate and multivariate regression analysis of potential risk factors of PONV at postoperative 24 h
| Variable | Univariate OR (95% CI) | P value | Multivariate OR (95% CI) | P value |
|---|---|---|---|---|
| Age (years) | 1.01 (0.97, 1.05) | 0.62 | ||
| Weight (kg) | 0.99 (0.95, 1.03) | 0.57 | ||
| Height (cm) | 0.95 (0.88, 1.02) | 0.144 | ||
| Body mass index (kg/m2) | 1 (0.9, 1.11) | 0.97 | ||
| Hypertension (1 vs. 0) | 1.4 (0.4, 4.94) | 0.597 | ||
| Apfel score (4 vs. 3) | 1.09 (0.29, 4.14) | 0.896 | ||
| Anesthesia duration (min) | 1.02 (1, 1.03) | 0.022 | 1.02 (1, 1.05) | 0.089 |
| Remimazolam (1 vs. 0) | 0.66 (0.3, 1.46) | 0.302 | ||
| Sevoflurane (%) | 1.91 (0.43, 8.47) | 0.395 | ||
| Crystalloid amount (mL) | 1 (1, 1) | 0.722 | ||
| Estimated blood loss (mL) | 1 (0.99, 1.01) | 0.793 | ||
| Remifentanil dose (µg) | 1 (1, 1) | 0.083 | 1 (1, 1) | 0.93 |
| fentanyl dose in PACU (µg) | 1 (0.99, 1.01) | 0.764 | ||
| IV-PCA fentanyl dose during postoperative 24 h (µg) | 1 (0.99, 1) | 0.015 | 1 (0.99, 1) | 0.007 |
Values are presented as ORs (95% CIs). OR: odds ratio, CI: confidence interval
Discussion
This study explored the effect of adding low-dose remimazolam by continuous intravenous infusion to standard anesthesia protocols on PONV. While previous studies compared remimazolam to balanced anesthesia as the main anesthetics, our study was the first to examine remimazolam’s role as the third antiemetic agent of a multimodal PONV prophylaxis regimen [8, 9].
Studies have examined the antiemetic effect of benzodiazepines. Previous studies have shown the antiemetic effect of remimazolam in the early postoperative period. In a previous study, the incidence of PONV at postoperative 2 h was significantly lower in the remimazolam group (27%) than the desflurane group (60%, P = 0.02) [10]. Another study reported that administering remimazolam produced a statistically significantly lower PONV incidence 0–12 h postoperatively (28.9%) than administering sevoflurane (57.9%, P = 0.011) [11]. Also, there was a report of a comparable PONV incidence between patients receiving remimazolam (30%) and patients receiving propofol at 2 h after surgery (30%, P > 0.99), while propofol is well known for its antiemetic effect [12]. In a recent meta-analysis of 11 randomized controlled trials, remimazolam reduced PONV incidence more than volatile agents (OR: 0.25, 95% CI: 0.13–0.47, P = 0.0000) and a similar amount as propofol (OR: 1.04, 95% CI: 0.70–1.56; P = 0.8332) [13]. Midazolam, another benzodiazepine, has shown to reduce PONV [14]. There are reports that midazolam has antiemetic effects at low doses [6, 15, 16] and systematic reviews show that midazolam lowers the incidence of PONV by up to 55% [17, 18].
Due to remimazolam’s and midazolam’s pharmacological similarities, we hypothesized that low-dose remimazolam would have comparable antiemetic properties to low-dose midazolam. Although it is not yet clear how benzodiazepine agents have antiemetic effects, it is postulated that this mechanism includes modulation of GABA-A receptors that suppress serotonin release, stabilize the central nervous system, augment benzodiazepines’ adenosinergic effects, inhibit dopamine release, and augment the adenosine-mediated inhibition of dopamine in the chemoreceptor trigger zone [19–21]. Unlike midazolam, remimazolam is a short-acting benzodiazepine and is organ-independently metabolized by non-specific tissue esterase. Flumazenil, as an antagonist of remimazolam, accelerates patient awakening [22] and its effect on PONV remains controversial. In a previous retrospective study, authors reported no significant difference in PONV between patients who did and did not receive flumazenil after remimazolam [23]. Also, there were no significant difference in PONV incidence with remimazolam-flumazenil when compared to propofol anesthesia in different clinical contexts [24–26]. On the other hand, it has been questioned whether flumazenil may antagonize antiemetic effects of benzodiazepines, with one study reporting an increased incidence of PONV after flumazenil [27]. In our study, no patient failed to awaken within 15 min that flumazenil was not administered. Nonetheless, the role of flumazenil in modulating the antiemetic effects of remimazolam remains controversial and warrants further investigation.
We used remimazolam in low dose rather than as a sole anesthetics, as we assumed its limited analgesic properties make it less suitable as a primary anesthetic agent for laparoscopic cholecystectomy in non-elderly adults with ASA I and II. Remimazolam as a main anesthetic frequently leads to significant blood pressure fluctuations and requires frequent redosing, which can be burdensome for clinicians. In the present study, low-dose remimazolam did not reduce the incidence of PONV at postoperative 24 h but was associated with a lower incidence of nausea at postoperative 6 h. Although PONV at postoperative 24 h was not statistically significantly different between the groups, our results are promising since it lowered PONV incidence at postoperative 6 h and patients commonly experience PONV in the early postoperative period. Further research is needed to determine the optimal dosing strategy.
The group R (1.9%) had statistically significantly less dizziness than the group C in the PACU (19.6%, P = 0.008). There is no evidence that benzodiazepines directly reduce postoperative dizziness. However, in our study, remimazolam reduced the amount of sevoflurane compared to the group C (1.8 ± 0.3%, 1.7 ± 0.3%, P = 0.026) which may have reduced postoperative dizziness since higher concentration of inhaled anesthetics cause postoperative dizziness and PONV. In addition, benzodiazepines may indirectly alleviate dizziness by increasing hemodynamic stability by reducing autonomic nervous system activity [28].
This study had some limitations. First, the sample size was relatively small and only included women aged 19 to 65 years, so our results may not be applicable to other patient populations. Second, we only examined the effects of a single low-dose regimen of remimazolam. Further research should include more patients with increased statistical power and a broader range of remimazolam doses to validate our findings.
Conclusion
Low-dose remimazolam infusion did not reduce the incidence of PONV at postoperative 24 h in patients at high risk for PONV. However, it was associated with a lower incidence of nausea at postoperative 6 h and dizziness in the PACU. Further trials with different doses, are warranted to assess remimazolam’s efficacy at reducing PONV.
Acknowledgements
None.
Abbreviations
- PONV
postoperative nausea and vomiting
- ASA
American society of anesthesiology
- QoR-15
quality of recovery scores
- VNRS
verbal numeric rating scale
- PCA
patient controlled analgesia
- PACU
postanesthesia care unit
Author contributions
S.P. and I.J.J. started with conceptualization and took part in data collection. J.H.Y. and I.J.J. reviewed the result and performed formal analysis. S.P. and I.J.J. wrote original draft of the manuscript. S.L. and K.M.K. reviewed and edited the manuscript. J.H.Y. supervised the final version of the manuscript. Funding acquisition was done by J.H.Y. and I.J.J. All authors have read and agreed to the final version of the manuscript.
Funding
This study was financially supported by Hana pharmaceutical. (SGPAIK 2022-03-007). The funder had no role in the design, conduct, analysis and reporting of the trial.
Data availability
The datasets used or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and received ethical approval from the Institutional Review Board of Sanggye paik Hospital (IRB No. 2022-03-007-008). Written informed consent was obtained from every participants prior to study enrollment.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Seongho Park, Jun Heum Yon, Sangseok Lee and Kye-Min Kim contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used or analysed during the current study are available from the corresponding author on reasonable request.