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Management of hepatorenal syndrome and associated outcomes: a systematic review
  1. Jamshid Roozbeh1,2,
  2. Shahrokh Ezzatzadegan Jahromi1,2,
  3. Mohamad Hossein Rezazadeh1,2,
  4. Anahid Hamidianjahromi1,2,
  5. Leila Malekmakan1,2
  1. 1 Shiraz University of Medical Sciences, shiraz, Iran (the Islamic Republic of)
  2. 2 Shiraz Nephro-Urology Research Center, Shiraz, Iran
  1. Correspondence to Dr Leila Malekmakan; malekmakan_l{at}yahoo.com

Abstract

Background Hepatorenal syndrome (HRS), a multiorgan condition of acute kidney injury, is seen in advanced liver disease. This study aims to evaluate the current treatment for HRS.

Methods The authors searched PubMed, Scopus and Google Scholar literature. After quality assessment, 31 studies were included in this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology and the population, intervention, comparison and outcome scheme were used. We included human-controlled trials that evaluate the current treatment for HRS. Two authors independently screened articles for inclusion, extracted data and assessed the quality of included studies.

Results This study investigated the studies conducted on the effects of different treatments on follow-up of HRS patients. We gathered 440 articles, so 31 articles remained in our study. Of which 24 articles were conducted on terlipressin versus placebo or other treatments (midodrine/octreotide, norepinephrine, etc) that showed the higher rate of HRS reversal was detected for terlipressin in 17 studies (10 of them were significant), 2 studies achieved an insignificant lower rate of the model for end-stage liver disease score for terlipressin, 15 studies showed a decreased mortality rate in the terlipressin group (4 of them were significant).

Conclusion This review showed that terlipressin has a significantly higher reversal rate of HRS than the other treatments. Even the results showed that terlipressin is more efficient than midodrine/octreotide and norepinephrine as a previous medication, in reverse HRS, increasing patient survival.

  • HEPATORENAL SYNDROME
  • ACUTE LIVER FAILURE
  • CIRRHOSIS

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Hepatorenal syndrome (HRS) is a multiorgan condition of acute kidney injury, which is seen in advanced liver disease. However, there are still many controversial areas concerning HRS management.

WHAT THIS STUDY ADDS

  • This systematic review sought to provide information in the decision in management process; terlipressin has a significantly higher rate of HRS reversal than other treatments. More patients achieving HRS reversal with terlipressin were alive at 3 months compared with other treatments.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • Since the treatment of these patients has always been a challenge, some researches are being done in this regard. The current study has looked at the details of the included studies and focused on a brief discussion of the challenges in deciding the most appropriate medication regimens to give the reader the justification for the better management of these patients.

Introduction

Hepatorenal syndrome (HRS) is a type of acute kidney dysfunction in patients with advanced liver disease. Recent changes in the definition of HRS have caused it to be known in two ways: acute with acute kidney injury (AKI)-HRS1–3 and chronic with chronic kidney disease-HRS.4 AKI-HRS is characterised by a severe kidney function impairment due to vasoconstriction of renal arteries in the absence of significant abnormalities in kidney tissue.5 6 There are two types of HRS with different characteristics and prognoses. HRS type 1 is characterised by the sudden onset of acute kidney failure and the rapid deterioration of the function of other organs. HRS type 2 has slow and progressive deterioration of renal function due to cirrhosis and portal hypertension and is associated with refractory ascites.7

Pathogenetic mechanisms include circulatory dysfunction due to dilation of splanchnic arterial vessels, which activates vasoconstrictor factors.8 A severe systemic inflammatory reaction is one of the main triggers of AKI-HRS.6 7 9

The only definitive treatment for HRS is a liver transplant. There are controversial results about the administration of different pharmacological therapeutic regimens have been used, including octreotide/midodrine as traditional treatment, norepinephrine, dopamine, vasopressin and vasopressin analogues (ornipressin, terlipressin, etc).4 5 7 Administration of intravenous albumin is an established coadjuvant therapy.10

This systematic review assesses the current treatment for HRS and discusses the challenges in deciding the most appropriate medication regimens. We have also evaluated the effect of different treatments on the follow-up of HRS patients.

Material and methods

This review was based on Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement.11

The population, intervention, comparison and outcome framework was used to structure the research question.2 Specifically, the population is humans who are diagnosed with HRS. The intervention is different regimens as trials in the diagnosed cases of HRS. The comparison is a trial regimen, placebo and standard/routine treatments for HRS. The outcomes were differences in related variables to the efficacy of the treatment compared with the study groups, including HRS reversal, mortality and model for end-stage liver disease (MELD ) score.

Two coauthors searched the electronic databases (PubMed, Scopus and Google Scholar) to collect all papers relevant to treating HRS.

The primary outcome was to evaluate the current treatment for HRS and discuss the challenges in deciding the most appropriate medication regimens. The secondary outcome was to determine the effect of different treatments on the follow-up of HRS patients.

The keywords searched were “HRS” and/or “hepatorenal syndrome” combined with the general term “liver diseases” and “kidney diseases,” “AKI-HRS,” “CKD-HRS,” “KDIGO criteria,” “HRS type 1 & 2”, “ terlipressin,” “albumin,” “hemodialysis” and “liver transplant.” At this step, data were collected based on the study titles. All in vivo clinical trial studies on human studies in English, regardless of the age or sex of cases from 1999 to 2023, were included.

Literature selection and data extraction: After collecting the papers, two researchers briefly read each paper to exclude the irrelevant and duplicate studies. Next, the relevant studies were reviewed carefully, and the references were explored to collect more papers (figure 1). We prepared a data gathering form containing the title, author’s name, year of study, population, sample size and the study results (table 1). Researchers reread the articles to extract and document the data required to complete the form.

Figure 1

PRISMA flow chart. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1

Detailed review of studies

Quality assessment and risk of bias: The authors independently assessed the risk of bias using the Cochrane Risk of Bias Tool12 and resolved disagreements through the consensus method.

Results

This study investigated the studies conducted on the effects of different treatments on follow-up of HRS patients. Initially, we gathered 440 articles. After reading their abstracts and references, 31 articles remained in our study. From these studies, 9 articles studied HRS types 1 and 2, 19 HRS type 1, 1 HRS type 2 and 2 articles did not specify. The studies included in this review were assessed in different treatment regimen subgroups.

Terlipressin

Wong et al investigated the effect of terlipressin (0.5 mg intravenous/5.5–6.5 hours) over 14 days on HRS 1 patients. HRS reversal was 39.1% in the treatment and 17.8% in the control group (p<0.001). Mortality at 3 months of follow-up was 50.7% compared with 44.5% in the control group. The MELD score in the treatment and control groups was 32.7±6.6 and 33.1±6.2, respectively.13 Sanyal et al investigated the effect of terlipressin (1–2 mg intravenous/6 hours) over 14 days on HRS 1 patients. The HRS reversal was 27.4% in the treatment group vs 14.1% in the control group (p=0.004). Mortality at 3 months of follow-up was 47.0% vs 50.3% in the control group (p=0.716). The MELD score in the treated and control groups was 33.4±6.1 and 32.9±5.8, respectively (p<0.001).14 Boyer et al evaluated the effects of terlipressin (1 mg intravenous/6 hour) for 14 days on HRS 1 patients. HRS reversal was 23.7% in terlipressin vs 15.1% in another group (p=0.130). The mortality rate after 3 months of follow-up was 41.2% compared with 43.4% in the control group (p<0.001). The MELD scores in the treatment and control groups were 33.5±6.2 and 32.6±5.5, respectively (p=0.36).15 Zafar et al evaluated the effects of terlipressin (1 mg intravenous/4 hours) for 7–10 days on HRS types 1 and 2 patients. HRS reversal was 40.0% in the trial compared with 16.0% in the other group (p<0.05). The mortality rate after 3 months of follow-up was 76.0% compared with 80.0% in the control group (p>0.05). MELD scores were not provided in this study.16 Llahi et al 17 studied the effect of terlipressin (1–2 mg intravenous/6 hours) over 15 days on HRS types 1 and 2 patients. The HRS reversal was 43.4% in the treatment group vs 8.6% in the control group (p=0.017). Mortality at 3 months of follow-up was 73.9% vs 82.6% in the control group (p=0.7). The MELD score in the treated and control groups was 30.0±9.0 and 28.0±8.0, respectively (p=0.001).17 Neri et al investigated the effect of terlipressin (0.5–1 mg intravenous/8 hours) over 14 days on HRS 1 patients. The HRS reversal was 7.6% in the treatment group vs 0.0% in the control group (p<0.001). Mortality after 3 months of follow-up was 50.0% compared with 84.6% in the control group (p<0.0001). The MELD score was not reported in this study.18 Solanki et al evaluated the effects of terlipressin (1 mg intravenous/12 hours) for 15 days on HRS 1 patients. The mortality rate after 15 days of follow-up was 58.3% compared with 100% in the control group (p<0.05). This study did not provide MELD score and HRS reversal.19 von Kalckreuth et al examined the effect of increasing the terlipressin dose. HRS types 1 and 2 patients received terlipressin (intravenous bolus of 1 mg/6 hours), and after 72 hours of not responding to treatment, the dose doubled. Response was defined as serum creatinine <1.5 mg/dL. This study showed terlipressin is effective in more than two-thirds of HRS patients (p<0.01). Prolonging treatment beyond 7 days up to 20 days may increase response rates.20 Cavallin et al investigated the effect of a continuous terlipressin infusion (2–12 mg intravenous/24 hours) compared with a bolus (0.5–2 mg intravenous/4 hour) over 15 days on HRS 1 patient. HRS reversal was 55.8% in the continuous infusion group vs 18%.9% in the bolus group (p>0.05). Mortality at 3 months of follow-up was 55.8% in the continuous infusion group vs 29.7% in the bolus group (p<0.001). The MELD score in the continuous infusion and bolus group was 29.26±7.8 and 29.8±6.4, respectively (p>0.05).21 Mujtaba et al reported that in type-1 HRS patients HRS reversal was almost two times higher in terlipressin-treated patients compared with placebo (31.5% vs 16.7%; p=0.143), Overall survival through day 90 was similar in both study groups (p=0.538); 55.6% patients in the terlipressin and 52.8% in the placebo group died through 90 days.22

Terlipressin compared with norepinephrine

Alessandria et al investigated the effect of terlipressin (1–2 mg intravenous/4 hours) compared with norepinephrine (0.1–0.7 µg/kg/min intravenous) over 14 days on HRS types 1 and 2 patients. The HRS reversal was 83.3% in the treated group vs 70.0% in the norepinephrine group (p>0.05). The 6-month follow-up mortality was 33.3% vs 30.0% in the norepinephrine group (p>0.05). The MELD scores in the treatment and norepinephrine groups were 26.0±2.0 and 26.0±1.0, respectively (p>0.05).23 Badawy et al investigated the effect of terlipressin (3–12 mg IV/24 hours) compared with norepinephrine (0.5–3 µg/kg/min intravenous) over 15 days on HRS 1 patients. HRS reversal was 48.0% in the treatment group vs 38.4% in the norepinephrine group (p<0.05). After 1 month of follow-up, mortality was 48.0% vs 50.0% in the norepinephrine group (p>0.05). The MELD score was not reported in this study.24 Arora et al investigated the effects of terlipressin (2–12 mg intravenous/24 hours) compared with norepinephrine (0.5–3 µg/kg/min intravenous) over 7 days on HRS 1 patients. HRS reversal was 40.0% in the treatment group compared with 16.6% in the norepinephrine group (p=0.004). Mortality after 28 days of follow-up was 51.6% compared with 80.0% in the norepinephrine group (p=0.001). His MELD scores in the treatment and norepinephrine groups were 33.3±5.0 and 33.7±5.0, respectively (p=0.60).25 Saif et al evaluated the efficacy of terlipressin (0.5–2 mg intravenous/6 hours) compared with norepinephrine (0.5–3 µg/kg/min intravenous) for 14 days on HRS 1 patients. HRS reversal was 56.6% in the treatment group compared with 53.3% in the norepinephrine group (p>0.05). Mortality after 3 months of follow-up was 80.0% compared with 96.6% in the norepinephrine group (p value not provided). The MELD scores in the treatment and norepinephrine groups were 29.1±5.8 and 30.4±9.2, respectively (p=0.526).26 Sharma et al investigated the effect of terlipressin (0.5–2 mg intravenous/6 hours) compared with norepinephrine (0.5–3 µg/kg/min intravenous) over 15 days on HRS 1 patients. The HRS reversal was 40.0% in the treatment group compared with 50.0% in the norepinephrine group (p=0.741). No deaths occurred in any group during this time interval of 15–30 days. The MELD score was not provided.27 Singh et al investigated the effect of terlipressin (0.5–2 mg intravenous/6 hours) compared with norepinephrine (0.5–3 µg/kg/min intravenous) over 14 days on HRS 1 patients. HRS reversal was 39.1% vs 43.4% in the treatment group compared with the norepinephrine group (p=0.764). Mortality after 1 month of follow-up was 69.5% vs 65.2% in the norepinephrine group (p>0.05). The MELD score in the treatment and norepinephrine group was 26.4±3.1 and 24.6±5.3, respectively (p=0.294).28 Ghosh et al investigated the effects of terlipressin (0.5–2 mg intravenous/6 hours) compared with norepinephrine (0.5–3 µg/kg/min intravenous) over 15 days on HRS 2 patients. The HRS recovery rate was 73.9% for both groups (p=1.000). Mortality at 3 months follow-up was 34.7% compared with 39.1% in the norepinephrine group. MELD scores in the treatment and norepinephrine groups were 21.3±2.8 and 21.0±3.3, respectively.29 Goyal et al evaluated the efficacy of terlipressin (0.5–2 mg intravenous/6 hours) compared with norepinephrine (0.5–3 µg/kg/min intravenous) for 14 days on HRS 1 patients. HRS reversal was 45.0% in the treatment group compared with 47.6% in the norepinephrine group (p=1.00). The 14-day mortality rate was 55.0% compared with 52.3% in the norepinephrine group (p>0.05). The MELD scores in the treatment and norepinephrine groups were 30.1±5.9 and 29.2±6.1, respectively (p=0.536).30 Indrabi et al investigated the effect of terlipressin compared with norepinephrine on HRS 1 patients. The HRS reversal in the treatment group was 56.6% compared with 53.3% in the norepinephrine group (p=0.797). Mortality was 66.6% in the treatment vs 93.3% in the norepinephrine group (p=0.257). MELD results, dosage and duration of treatment were not reported in this study.31

In the study of Singh et al, 60 patients with type 1 HRS were randomised to receive either terlipressin (started at 2 mg/day and increased by 1 mg/day) or a combination of terlipressin and norepinephrine infusion (a constant dose of terlipressin 2 mg/day and norepinephrine infusion started at 0.5 mg/hour and increased to 3 mg/hour) at 15 days. There was no significant difference in the response rate between the groups (50% vs 76.7%, p=0.06). In addition, 30-day survival was similar (36.7% vs 53.3%, p=0.13).32

Terlipressin compared with dopamine

Silawat et al evaluated the efficacy of terlipressin (0.5–2 mg intravenous/12 hours) compared with dopamine (4 µg/min) in non-specified HRS patients. HRS reversal was 66.6% in the terlipressin vs 33.3% in the dopamine group (p>0.05). Mortality at maximum follow-up was 20.0% in the terlipressin group compared with 26.6% in the dopamine group (p=0.02). This study did not provide MELD scores or the duration of treatment.33

Terlipressin compared with dopamine and furosemide

Srivastava et al investigated the effect of terlipressin (0.5 mg intravenous/6 hours) against dopamine (2 µg/kg/min) and furosemide (0.01 mg/kg/hour) for 5 days on HRS types 1 and 2 patients. Significantly more patients in the terlipressin group achieved HRS reversal than the placebo group (33.9% vs 12.5%; p=0.008), mortality at 1 month of follow-up was 77.5% vs 80.0% in the dopamine and furosemide groups (p>0.200). MELD score was not reported.34

Terlipressin compared with midodrine/octreotide

Cavallin et al investigated the effects of terlipressin (3–12 mg intravenous/24 hours) compared with midodrine (7.5–12.5 mg orally/8 hours) and octreotide (100–200 µg subcutaneously/8 hours) over 14 days on HRS types 1 and 2 patients. HRS reversal was 4.7% in the midodrine-octreotide groups compared with 55.5% in the treatment group (p=0.01). Mortality at 3 months follow-up was 40.7% in the treatment group compared with 52.3% in the midodrine-octreotide groups (p>0.05). MELD scores for treatment and other groups were 31.2±5.8 and 29.1±8.1, respectively (p>0.05).35 Copaci et al evaluated the efficacy of terlipressin (1–2 mg IV/6 hours) compared with octreotide (100–200 µg SC/8 hours) for 10 days on HRS 1 patients. HRS reversal was 55.0% in the treatment vs 20.0% in the midodrine-octreotide groups (p=0.010). MELD scores and mortality were not provided.36

Norepinephrine compared with midodrine/octreotide

Tavakkoli et al investigated the effect of noradrenalin (0.1–0.7 µg/kg/min intravenous) compared with midodrine (5–15 mg orally/three times per day) and octreotide (100–200 µg subcutaneously/three times per day) over 15 days on HRS types 1 and 2 patients. The HRS reversal was 72.7% in the noradrenalin group vs 75.0% in the midodrine-octreotide group (p>0.05). The 3-month follow-up mortality was 45.4% in the norepinephrine vs 50.0% in the other group. The MELD score in the noradrenalin midodrine/octreotide groups was 32.9±6.0 and 34.5±5.7, respectively (p>0.05).37 El-Desoki Mahmoud et al investigated the effect of norepinephrine (0.5–3 mg/hour) vs midodrine (5–12 mg/three times per day) and octreotide (100–200 µg intravenous/6 hours) over 10 days on non-specified HRS patients. HRS reversal was 57.6% in the trial vs 20.0% in the other group (p=0.006). After 30 days of follow-up, mortality was 63.3% in the norepinephrine vs 80.0% (p=0.166). The MELD score was not reported.38

Dopamine compared with midodrine/octreotide

Angeli et al evaluated the effects of midodrine (7.5 to 12.5 mg orally/three times per day) and octreotide (100–200 µg subcutaneous/three times per day) compared with dopamine (2–4 µg/kg/min) on HRS types 1 and 2 patients. Mortality at the month of the follow-up was lower in the midodrine/octreotide group. This study did not report MELD score, duration of therapy and HRS reversal.39

Midodrine and octreotide

Pomier-Layrargues et al administered octreotide 50 µg/hour intravenous for 4 days on HRS types 1 and 2 patients and the placebo in the second group. The HRS reversal rate was 42.8% in the first vs 33.3% in the second group (p>0.05). After 4 days of follow-up, mortality was 28.5% in the first group compared with 55.5% in the second group (p value not provided). MELD scores were not provided in this study.40

Pentoxifylline and midodrine/octreotide

Stine et al studied the effects of pentoxifylline (PTX) (400 mg hree times per day) or placebo with midodrine and octreotide therapy over 14 days on HRS 1 patients. HRS recovery was about 16.6% in both groups (p=1.000). Mortality after 6 months was 50.0% compared with 83.3% in the control patients (p=0.221). The MELD scores in the treatment and control groups were 26.0 and 27.0, respectively (p=0.042).41

The molecular adsorbent recirculating system

Molecular adsorbent recirculating system (MARS) is a modified dialysis method using an albumin-containing dialysate. Mitzner et al estimated the MARS group at 6–8 hours, 5.2±3.6 treatments per HRS 1 patient daily. Significant reductions in bilirubin and creatinine levels, increases in sodium levels and prothrombin activity were seen in the MARS patients. Mortality was 100% on day 7 in the control, 62.5% on the end of the first week and 75.0% on day 30 in the MARS group (p<0.01).42

Discussion

The treatment strategies of HRS have been mainly focused on renal function improvement. While liver transplantation has remained the only definitive treatment for HRS,7 considering long waiting times on the liver transplantation list, different pharmacological therapeutic options have been recommended.4 Traditional and routine treatment was octreotide/midodrine, besides albumin. However, HRS management has approved vasopressin and vasopressin analogues (ornipressin, terlipressin).3 43 Which bind to V1 receptors on vascular smooth muscle, affecting vasoconstriction, primarily of the splanchnic and extrarenal circulations that affects the increased effective circulating volume and renal perfusion pressures.44

In this study, 24 articles were conducted on terlipressin alone or compared with placebo/other treatments.13–36 A higher rate of HRS reversal was detected for terlipressin in 17 studies, which was significant in 10 of them. Two studies achieved an insignificant lower rate of the MELD score in the terlipressin groups versus placebo/other treatments; however, in six studies, this score was higher in the terlipressin group (two were significant). The efficacy results of 15 studies showed a decreased mortality rate in the terlipressin group versus placebo/other treatments, which was significant in four. In addition, a study showed that a continuous terlipressin infusion insignificantly increased the HRS reversal compared with a bolus type.21

Moreover, terlipressin therapy may improve clinical outcomes in senior patients with HRS.22 Karvellas et al reported that patients who received terlipressin were more likely to achieve renal function improvement and had significantly shorter lengths of intensive care unit (ICU) stay than the placebo group.45 Despite limited data, terlipressin may be more effective than norepinephrine and is likely more effective than the combination of midodrine/octreotide.46 It seems that more patients experiencing HRS reversal with terlipressin had less mortality.14–21 23–27 30 31 33 Also, patients with lower MELD scores had lower mortality and more HSR reversal.13 26

There are controversial results about the administration of midodrine/octreotide in the literature in contrast with some studies that demonstrated that its long-term use was effective and harmless in these patients39; another one showed that octreotide infusion is ineffective in this setting. However, they found that octreotide does not improve systemic haemodynamics in cirrhotic patients while impairing renal function.40 Nevertheless, adding midodrine can ameliorate the hyperdynamic circulation without inducing renal dysfunction.47 Also, it was shown that noradrenalin has the same efficacy in complete response with midodrine/octreotide in HRS treatment, so the use of noradrenalin in HRS treatment might be suggested.37 Even another study reported that noradrenalin is significantly superior to midodrine/octreotide in improving kidney function among HRS.38 Norepinephrine works on alpha-1-adrenergic receptors in vascular smooth muscle cells and could improve urine production and renal function. In HRS patients admitted to ICU, norepinephrine plus albumin is the first choice for treatment.44

On the other hand, adding some medication to the standard of volume expansion with albumin and vasoconstriction with midodrine/octreotide in treating HRS is recommended, including PTX and captopril.41 44 48 Another study concluded that removing albumin-bound substances with the MARS method can contribute to treating type I HRS.42

In addition, there is rising evidence that inflammation contributes to HRS. Bacterial infection and systemic inflammation can cause decompensation in cirrhosis. However, a prophylactic antibiotic is controversial in this setting.43 44

This study has some strengths and limitations. First, we included articles with controversial results about different management methods for HRS patients. Second, since our focus is on the challenges of current therapeutic regimens, we did not perform a meta-analysis in drug subtitles. Furthermore, some uncertainties remain since the availability of some data was limited due to unpublished data, non-English language and not full-text availability. In addition, since all studies inserted were human-controlled trials, we could not evaluate the descriptive studies.

Conclusion

This systematic review showed that terlipressin has a significantly higher rate of HRS reversal than placebo/other treatments. More patients achieving HRS reversal with terlipressin were alive at 3 months compared with placebo/other treatments. Current results showed terlipressin is more efficient than other vasoactive agents in HRS reversal and improves short-term survival.

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

Ethics statements

Patient consent for publication

Ethics approval

The project number of this study was 27776, which the local ethics committee approved with the code of IR.SUMS.REC.1401.706.

Acknowledgments

This study was conducted at Shiraz University of Medical Sciences by research project number 27776.

References

Footnotes

  • Contributors JR and LM conceived and designed the study and drafted the manuscript. SE and MHR contributed to the edited the manuscript and revised the manuscript. LM and AH helped with data collection and management. JR and LM are contributors as being responsible for the overall content as guarantors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.