Remifentanil Is Associated With Increased Length-Of-Stay After Abdominal Surgery: A Single-Center Retrospective Propensity-Matched Cohort Study

Abstract

Perioperative remifentanil infusions have been postulated to help with recovery after surgery due to their rapid offset and predictable metabolism. However, evidence on patients undergoing abdominal surgery suggests an association between intraoperative remifentanil and longer length of stay in the post-anesthetic care unit, increased postoperative pain and analgesic requirement.

We retrospectively evaluated 3648 adult patients who underwent major abdominal surgeries from 2013 to 2020 in a tertiary single center. Propensity score matching was conducted to balance 12 specific covariates between the treatment and control groups prior to further statistical analysis. We found that intraoperative remifentanil infusion was associated with an increased average hospital length of stay (10.62 in treatment group vs 10.13 in control group, 95% CI 0.048 - 0.088, P<0.001) and increased length of stay in the high dependency ward (1.89 days in treatment group vs 1.52 days in control group, 95% CI 0.126 - 0.223 P <0.001), but a shorter stay in the intensive care unit (4.03 hours in treatment group vs 7.01 hours in control group, 95% CI -0.509 - 0.452, P <0.001). Consistent with current evidence, there was no significant difference between the treatment and control groups for death in 3 months and 2 years post-surgery.

In conclusion, our study suggests that remifentanil may not promote postoperative recovery as expected. Its role in enhancing recovery is debatable and further studies are needed to determine the cost effectiveness of remifentanil use in abdominal surgery.

Introduction

Remifentanil is a pure agonist of the mu-opioid receptor that has become an essential component of anesthetic practice since its development in the 1990s. Unlike other drugs in the same category, its ultra-short onset and offset allows it to be highly titratable to intraoperative surgical stimuli, allowing for precise physiological control. Furthermore, metabolism of remifentanil is rapid, predictable and independent of renal or liver function. It does not accumulate despite long infusion durations, allowing for more rapid awakening after surgery and minimizing the risk of long-acting opioid overdose. Theoretically, this leads to a decreased risk of opioid-induced side effects, such as vomiting, drowsiness, respiratory depression and delayed gastric transit times. Furthermore, previous data suggests a decreased incidence of postoperative delirium in the Post-Anesthesia Care Unit (PACU) and on postoperative day (POD) 1 [1] (Radtke et al. 2010), as well as the avoidance of Intensive Care Unit (ICU) admission in borderline patients [2] (Park et al. 2000). Hence, its purported benefits in enhancing postoperative recovery could theoretically lead to a decrease in hospital length-of-stay and healthcare costs. 

However, remifentanil also frequently increases intraoperative bradycardia and hypotension [3] (Schüttler et al. 1997), contributing to hemodynamic instability. Moreover, an association with opioid-induced hyperalgesia [4] (Santonocito et al. 2018) has also been found, with increased acute postoperative pain and the use of rescue analgesia [5] (Yamashita et al. 2016). There is also a potential increased incidence of chronic pain, suggested by an increase in pain and analgesic requirements in cardiac patients at 1 year after surgery [6] (van Gulik et al. 2012). A recent large, multicentre, cross-sectional study which looked into remifentanil-associated postoperative pain, analgesic requirements, time to extubation and length of stay in the recovery room suggested higher postoperative pain scores and opioid-related side effects with no change in the duration spent by the patient in PACU [7] (Niedermayer et al. 2020). These findings suggest that remifentanil may not facilitate recovery as previously believed. Although in theory, the effects of remifentanil should be short-lived, its observed role in long-term neuropathic dysfunction suggests that this assumption may not be entirely valid [8] (Salengros et al. 2010). As remifentanil is significantly more costly than its other opioid counterparts, it is currently uncertain if the additional cost of using the drug is justified. 

Given these findings, we sought to investigate the downstream impact of remifentanil on the rest of the hospital stay. In our literature review, we found a lack of studies investigating the longer-term impact of intraoperative remifentanil.  

The primary objective of this study was to investigate whether patients who received remifentanil intraoperatively during abdominal surgery (defined as operative procedures that involve the abdomen, including urological and gynecological procedures) have a different hospital length of stay, and time spent in the high-dependency wards. We also sought to look into other secondary outcomes such as hospital readmission rate, ICU admission rate and death at 3 months and 2 years post-surgery. 

Methods

This was a single-center retrospective cohort study conducted in Singapore General Hospital (SGH). SGH is an 1800-bedded tertiary academic hospital in Singapore. The study was granted an exemption by SingHealth’s Centralized Institutional Review Board (CIRB Reference number 2021/2496), with a waiver of patient consent and waiver for approval due to the use of anonymized routinely collected clinical data. All research was performed in accordance with relevant institutional guidelines and regulations.

Our study cohort was extracted from the Singapore General Hospital’s Perioperative and   Anesthesia Subject Area (PASA), a curated electronic medical records database containing the clinical records of all operative procedures performed under anesthetic care in the institution since 2013. [9] (Chiew et al. 2020) Information on patient demographics, anthropometric parameters, and preoperative comorbidities had been assessed by the attending anesthetist as part of the structured clinical notes for routine clinical care and were included. All laboratory results for 30 days prior to the procedure and 7 days after were also available. Laboratory investigations were conducted in our institution’s College of American Pathologists accredited clinical laboratory. Hematological parameters were processed with the Sysmex XN Automated Hematology Analyzer (Sysmex Corporation, Kobe, Japan) and ADVIA 2120i Hematology System (Siemens Healthcare Diagnostics Inc, Malvern, PA, USA) while biochemical parameters were processed using the Roche Cobas c501 analyzer (Roche Diagnostics). Intraoperative data were collected as part of the routine electronic Anesthesia Information Management System (Mortality data in the system was synchronized with the National Electronic Health Record, which includes mandatory registration of all deaths), thus ensuring near-complete all-cause mortality follow up). A full list of the extracted variables can be found in Appendix 1. 

Inclusion Criteria

Adult patients aged 18 and above undergoing elective abdominal surgeries (gastrointestinal, colorectal, hepatopancreaticobiliary, urological, gynecological) under general anesthesia between 2013 and 2020 in the PASA dataset were included in this study. No patients with COVID-19 were included.

Exposure

The primary independent variable was the use of remifentanil intraoperatively. The induction and maintenance of general anesthesia in our institute are anesthetist-dependent and not performed based on a standardized protocol. The decision to use remifentanil too was made by the individual anesthetic specialist without any standardized dosing protocol. However, popular indications for remifentanil use include the presence of renal impairment, obstructive sleep apnea and other comorbidities leading to concerns with opioid accumulation, and expected large swings in haemodynamics requiring precise titration of ongoing anaesthetic agents. We included remifentanil infusions in mcg/kg/min as well as ng/ml by target controlled infusion (Minto model).

Missing data were cross-checked and corrected. Missing data that could not be corrected were coded as a dummy missing variable. To minimize the risk of false associations being drawn between remifentanil treatment and the outcomes investigated in our retrospective observational study, we used propensity score matching (PSM) to reduce the distribution of measured baseline covariates between our treatment and control subjects, simulating attributes of a randomized controlled trial.

Outcome Measures

The primary outcomes were length of stay in hospital, high dependency (HD)/ intermediate care area (ICA) and intensive care unit (ICU). Secondary outcomes included all-cause death at 90-days and 2 years post-surgery. 

In our institution, HD wards nurse patients who are seriously ill but do not require intensive care. Our ICA wards are a step above the HD wards, and nurse critically ill patients who do not yet need invasive mechanical ventilation.

Statistical Analysis

We aimed to investigate the effect of remifentanil on the following outcomes:

1. Average length of stay, the average number of days that patients spend in hospital post-abdominal surgery

2. Length of stay in the High Dependency and Intermediate Care Area, wards that manage patients with complex conditions requiring more medical attention than a general ward

3. Intensive care unit (ICU) admission rates and hours spent in the ICU

4. Death at 3 months and 2 years post-surgery

Propensity Score Matching and Association Testing

To model the propensity score, we identified 12 potential confounders and performed the matching of treatment and control groups based on a generalized linear model. Matched pairs were formed by nearest-neighbor matching, with 1:1 matching without replacement and a caliper width of 0.1. The level of balance between the treatment of control groups was evaluated based on a comparison of pre-matching and post-matching statistical data including visual analysis and evaluating standardized differences.

Using the matched data, we tested outcome differences between the treatment and control groups with the Poisson regression model for continuous outcomes and chi-square test for categorical data. In view of the multiple comparisons being performed, the Bonferroni correction was applied to decrease the risk of type 1 error.

All analysis, statistical computing and visualizations were carried out in the R environment version 4.3.1 (The R Foundation for Statistical Computing, Vienna, Austria). The Love Plot (Figure 2) and Propensity-adjusted density plot (Figure 3) were performed with the “Cobalt” R library package [10] (Greifer 2021).  

Results

Characteristics of the study data pre- and post-matching

Of the 194,946 medical records, we identified 54,622 (26%) patients who had undergone abdominal surgery (both elective and emergency) and who met our inclusion and exclusion criteria. Patients with greater than 30% missing values were excluded from any analysis. 13,601 patients (25%) did not have a recorded BMI and 15,757 (29%) had missing information regarding the duration of surgery. For the rest of the variables identified, the amount of missing data was less than 10%.

2277 patients had received remifentanil intraoperatively. Of these cases, 1824 were matched to a control group without remifentanil, yielding an analyzed sample of 3648 observations. (Figure 1)

After PSM, the confounders were balanced between the control and treatment group. Table 1 illustrates the proportion of participant characteristics post-matching, based on our 12 identified covariates (gender, age, Body Mass Index (BMI), preoperative renal function and hemoglobin concentration, operation duration in minutes, American Society of Anesthesiologists (ASA) class, type of surgery and operation risk, presence of ischemic heart disease and presence of cerebral vascular disease). We obtained a standardized difference of less than 0.1 in all matched categories except operative risk (0.11).  

Results of Outcome Measures

Table 2 illustrates the results of our primary and secondary outcome measures, before and after univariate analysis and propensity score matching.

Primary Outcomes

There was a prolonged postoperative length of stay in HD and ICA wards in patients who received remifentanil (1.89 days in treatment group vs 1.52 days in control group, 95% CI 0.126 - 0.223 P <0.001). This difference was more significant prior to matching (1.91 days in treatment group vs 0.78 days in control group).

Patients who received intravenous remifentanil had a slightly shorter average stay in ICU compared to those who did not (4.03 hours in treatment group vs 7.01 hours in control group, 95% CI -0.509 - 0.452, P <0.001). 

The postoperative average hospital length of stay was slightly increased in the remifentanil group  (10.62 in the treatment group vs 10.13 in the control group, 95% CI 0.048 - 0.088, P<0.001). Again, this difference was more significant prior to matching (7.32 in treatment group vs 3.54 in control group).

Secondary Outcomes

There was no statistically significant difference between the treatment and control groups for death in 3 months and 2 years post-surgery. 

Discussion

Remifentanil has the advantages of a rapid wash-in and wash-out period, non-organ dependent metabolism and clearance, and lack of active metabolites. This has led to its increasing popularity in the operating theatre. However, it has also been shown to be associated with increased postoperative pain and need for rescue analgesia [7] (Niedermayer et al. 2020). In this study, we found a possible association between intraoperative remifentanil use and increased hospital length of stay and time spent in the high dependency ward. 

The postoperative average hospital length of stay was slightly increased in the remifentanil group  (10.62 in the treatment group vs 10.13 in the control group, 95% CI 0.048 - 0.088, P<0.001). Remifentanil has previously been shown to be associated with increased postoperative acute pain, nausea and vomiting, and the need for rescue opioids in the PACU. This is likely due to its pharmacokinetics, which may lead to a washout of its analgesic effects before longer-acting pain control has been adequately administered. This may also be compounded by the development of opioid-induced hyperalgesia if large doses of remifentanil were administered intraoperatively.  Apart from pain control, there has been conflicting data regarding the effect of remifentanil on other factors that affect postoperative recovery. Its effect on postoperative nausea and vomiting (PONV) has been debatable and some studies have suggested that it could be considered an independent risk factor for PONV [11] (Hozumi et al. 2016). Hence, the increase in postoperative pain, nausea, vomiting and use of opioids could have impeded the recovery of patients and their readiness for discharge home. This may not be clinically significant due to the small difference of less than 1 day in the hospital length of stay, but raises questions about the benefits of using a more expensive opioid when recovery does not seem to be significantly enhanced.

Similar to its effect on the average hospital length of stay, there was a prolonged postoperative length of stay in HD and ICA wards in patients who received remifentanil (1.89 days in treatment group vs 1.52 days in control group, 95% CI 0.126 - 0.223 P <0.001) (Figure 3). Patient discomfort, gastrointestinal side effects and other opioid-related adverse events could have resulted in delayed transfers to the general ward. Furthermore, gastrointestinal side effects such as nausea, vomiting, increased nasogastric aspirates and prolonged intestinal transit time may also be harbingers of post-surgical combinations, especially in abdominal surgery. Given this, their transfer to the general ward may be held off as surgeons may choose to take a cautious approach in monitoring for any further change in the patient’s clinical status. The difference of slightly less than half a day may seem inconsequential, but may be significant as it impacts the decision of whether planned surgery should proceed when beds with additional monitoring capabilities are in scarcity, and has downstream effects on optimising operation list scheduling. Elective list cancellations have been shown to be financially costly with a significant waste in resources [12] (Haana et al. 2009), with waiting lists being prolonged to accommodate cancelled operations. Late cancellations also result in significant dissatisfaction to patients and their families. [13] (Nasr et al. 2004)

Patients who received intravenous remifentanil had a slightly shorter average stay in ICU compared to those who did not (4.03 hours in treatment group vs 7.01 hours in control group, 95% CI -0.509 - 0.452, P <0.001). This is consistent with what has been found in studies that investigated the relationship between remifentanil and duration of mechanical ventilation and ICU length of stay. [14] (Rozendaal et al. 2009) When administered over several days, conventional sedative agents such as propofol and fentanyl may accumulate or redistribute, resulting in their unpredictable pharmacodynamics. The prolonged effect of these agents may have a role to play in a decreased respiratory drive and extend the process of weaning patients off the mechanical ventilator. In contrast, remifentanil does not accumulate and may improve the speed of weaning, facilitate extubation and hence the total ICU length of stay. Pain and gastrointestinal side effects may be adequately managed in the high dependency ward, and not impede the discharge of the patient from ICU. Despite the seemingly marginal benefit of a few hours’ difference in the ICU length of stay, this may be financially meaningful as the mean ICU cost has been shown to be the greatest on day 1, at an average of more than 10000 dollars for mechanically ventilated patients. [15] (Dasta et al. 2005)

There was no statistically significant difference between the treatment and control groups for death in 3 months and 2 years post-surgery. This is consistent with the current available evidence. [16] (Tan and Ho 2009) Despite postulations that postoperative pain may intensify the sympathoadrenergic response and result in undue stress to multiple organ systems, the clinical significance of this is unclear and there has been a lack of studies reporting an association between postoperative pain and long-term mortality.

 The findings from our study suggests that the cost-effectiveness of using remifentanil intraoperatively for major abdominal surgeries is questionable. Although remifentanil has been shown to be no more expensive than fentanyl-based anesthesia in some countries [17] (Nakada et al. 2010), it is still considered cost-prohibitive in comparison to fentanyl [18] (Tabing et al. 2015). In our institution, a vial of 1g of remifentanil costs 30 times more than a 500mcg vial of fentanyl. Compounded with our findings no significant decrease in average hospital length of stay and time spent in the high dependency ward, this may result in an undesirable increase in healthcare costs without any apparent benefit. In patients who are highly likely to require postoperative ICU admission, there may be some benefit in administering remifentanil along with other types of analgesia. However, in a significant proportion of patients, the choice of disposition after major abdominal surgery is not clear-cut.

Strengths

Our study involved the initial use of a large dataset of nearly 200,000 patients, with cases spanning 7 years. Despite the large amount of missing data, we were still able to include 3648 patients in our analysis. 

Furthermore, the impact of remifentanil in actual patients undergoing surgery in a real-world setting was measured, compared to the limited generalizability of small randomized controlled trials in restricted, targeted patient groups. All intermediate to high risk abdominal surgeries were evaluated, allowing the conclusions drawn to be applicable to a large variety of patients.

Limitations

As our data was based on a medical records database, several limitations should be acknowledged and considered in the interpretation of our results. 

First, this is a non-randomized, retrospective observational study. With this in mind, we applied propensity score matching to ensure an even distribution of 12 baseline characteristics known to be associated with remifentanil use and our measured outcomes. However, there may have been unmeasured confounders that were unevenly distributed between the treatment and control groups, resulting in bias of the results. This included surgical complexity, as not all procedures were coded according to the requirements of the Surgical Complexity Classification Index or other complexity classification systems. There was also a significant proportion of missing data, particularly for BMI and the duration of surgery. This resulted in the loss of nearly one-third of the cases that could have been matched, and our eventual analyzed sample was less than 10% of the original number of cases who underwent abdominal surgery. Certain measures of patient comorbidity, such as the Charlson comorbidity index, could not be calculated as Singapore has strict rules on the access to potentially sensitive data (including Human Immunodeficiency Virus infections). Nevertheless, we were still able to evaluate a very large number of patients, with a significantly larger cohort compared to other studies on remifentanil.

Second, an increased length of stay in the hospital or high dependency ward may be due to various factors which may not be associated with intravenous remifentanil. Even if remifentanil has further unexplored implications on postoperative recovery, it is difficult to draw definite causality between the use of remifentanil and other contributors to a prolonged hospital stay. For example, surgical complications, new medical issues such as infections and other adverse events may have a tenuous link to our subject of interest. Caregiver training and preparation of the home for these patients may also delay discharge, but are unlikely to be due to remifentanil. Unfortunately, the reason for delayed discharge was not documented in our database, making it extremely difficult to investigate. A prospective study would be more appropriate to study this particular issue.

Third, there was a likelihood that the use of remifentanil may have been influenced by factors that we were unable to measure, such as the patient’s general preoperative physiological status. The pharmacokinetics and pharmacodynamics of remifentanil may mean that its benefits are more pronounced in patients at risk of opioid accumulation, or undergoing long, intermittently stimulating procedures. Hence, patients in the remifentanil group with admissions to HD or ICA may be self-selecting; higher-risk procedures with a need for closer postoperative monitoring would encourage the use of remifentanil in the first place. As the decision to  use remifentanil and the general intraoperative management was dependent on each individual anesthetist, all these other variances in perioperative management may have influenced our final outcomes and it is difficult to conclusively attribute our findings to remifentanil alone.

Conclusion

Despite the theoretical benefits of remifentanil, several large studies have shown that its effects on both immediate and longer-term recovery may not reflect the purported advantages of its metabolic profile. In addition to delaying discharge from the PACU, we have also found that it may prolong both the high dependency ward and the overall hospital length-of-stay, with downstream implications on operating list management and patient satisfaction. However, it may be beneficial in enhancing recovery in patients originally admitted to the intensive care unit postoperatively and minimizing the time these patients spend in the ICU. The equivocal role that remifentanil has to play in post-operative recovery, combined with its potential contribution to chronic post-surgical pain, and its significantly increased cost, makes its cost-effectiveness in abdominal surgery debatable. 

Taking all this into consideration, there is insufficient definitive evidence to reconsider the use of remifentanil in major abdominal surgery, but this should prompt further, multi-centre definitive research to do so.

Declarations

Data Availability

The datasets used/or analyzed during the current study may be made available from the corresponding author on reasonable request

Acknowledgements

The authors would like to thank Dr Daniel Lim Yan Zheng, Ms Chia Sing Yi, Ms Hanis Abdul Kadir and Ms Nur Nasyitah from the Health Services Research Unit, Singapore General Hospital, for their help in curating the primary data used in the study. 

Author Contributions

SKT Chan - literature search, writing of manuscript and formatting of tables

MYF Chong - editing of manuscript and edits for submission

YH Ke - data processing

HR Abdullah - conceptualisation of database and supervisor

Additional Information ((including a Competing Interests Statement)

The authors have no conflicts of interests to declare.

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Tables

Table 1: Post-propensity score matching patient demographics stratified by remifentanil infusion

BMI: Body Mass Index

ASA class: American Society of Anesthesiologists Physical Status Classification System
RCRI: Lee’s Revised Cardiac Risk Index, with 1 score allocated for each of the following: high risk surgery, history of ischemic heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative treatment with insulin, preoperative creatinine >176.8μmol/L

HD: High dependency ward

ICA: Intermediate care area ward

ICU: Intensive Care Unit

 Table 2: Results of Outcome Measures