Remifentanil in Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials

Article Outline

• Abstract
• Methods
  • Search Strategy
  • Study Selection
  • Data Abstraction and Study Characteristics
  • Internal Validity and Risk of Bias Assessment
  • Data Analysis and Synthesis
• Results
  • Study Characteristics
  • Quantitative Data Synthesis
• Discussion
  • Limitations
• Conclusions
• Acknowledgment
• Appendix 1
• References
• Copyright

Objective

The authors conducted a review of randomized controlled trials to identify advantages in clinically relevant outcomes in patients undergoing cardiac surgery with remifentanil.

Design

Meta-analysis.

Setting

Hospitals.

Participants

A total of 1,473 patients from 16 randomized trials.

Interventions

None.

Measurements and Main Result

PubMed, BioMedCentral, and conference proceedings were searched (updated May 2010) for randomized trials that compared remifentanil with fentanyl or sufentanil in cardiac anesthesia. Four independent reviewers performed data extraction, with divergences resolved by consensus. Overall analysis showed that the use of remifentanil was associated with a significant reduction in postoperative mechanical ventilation (WMD = −139 min [−244, −32], p for effect = 0.01, p for heterogeneity < 0.001, I₂ = 89%); length of hospital stay (WMD = −1.08 days [−1.60, −0.57], p for effect < 0.0001, p for heterogeneity = 0.004, I₂ = 71%); and cardiac troponin-I release (WMD = −2.08 ng/mL [−3.93, −0.24], p for effect = 0.03, p for heterogeneity < 0.02, I₂ = 74%). No difference was noted in mortality (3/344 [0.87%] in the remifentanil group vs [1.06%] the control group, OR 0.76 [0.17-3.38], p for effect = 0.72, p for heterogeneity = 0.35, I₂ = 5%).

Conclusions

Remifentanil reduces cardiac troponin release, time of mechanical ventilation, and length of hospital stay in patients undergoing cardiac surgery.

Key Words:  remifentanil , cardiac surgery , meta-analysis , comparative study , cardiac biomarker , inotropic drug , troponin , anesthesia , intensive care

THE ATTENUATION of neurohumoral responses to surgical stress always has been a main focus of cardiac anesthesia.¹ Remifentanil provides adequate protection against intraoperative stimuli and has advantageous pharmacokinetics.¹ Its rapid onset and offset of action, irrespective of the duration of its administration, plays a key role in facilitating rapid postoperative recovery. Fast-track anesthesia is an alternative to high-dose opioid (fentanyl or sufentanil) analgesia, which, while preserving hemodynamic stability, may also cause delayed recovery, respiratory depression, and the need for prolonged ventilatory support.²

A pivotal question is whether the effects of remifentanil are associated with an improvement of patients' clinically relevant outcomes. To address this question, the authors independently conducted a meta-analysis of data pooled from existing randomized trials to determine the impact of remifentanil compared with other opioids (fentanyl or sufentanil) on mechanical ventilation.

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Methods 

Search Strategy 

Pertinent studies were searched independently in BioMedCentral and PubMed (updated May 31, 2010) by 4 trained investigators. The full PubMed search strategy was developed according to Biondi-Zoccai et al³ and is available in Appendix 1. In addition, the authors used backward snowballing (ie, scanning of the references of retrieved articles and pertinent reviews) and contacted international experts for further studies. No language restriction was enforced and non–English-language articles were translated before further analysis.

Study Selection 

References obtained from database and literature searches were first examined independently at the title/abstract level by 4 investigators, with divergences resolved by consensus and, then, if potentially pertinent, retrieved as complete articles. The following inclusion criteria were used for potentially relevant studies: random allocation to treatment, comparison of remifentanil versus fentanyl or sufentanil, performed on cardiac surgical patients with no restriction in dose and time of administration, information on the primary or secondary outcomes. The exclusion criteria were duplicate publications (in this case only the article reporting the longest follow-up was abstracted), nonhuman experimental studies, and lack of data. Two investigators independently assessed compliance to selection criteria and selected studies for the final analysis with divergences finally resolved by consensus (Table 1).

Table 1. Description of the Studies Included in the Meta-analysis

Abbreviation: CABG, coronary artery bypass graft surgery.

Data Abstraction and Study Characteristics 

Baseline, procedural, and outcome data were abstracted independently by 4 trained investigators with divergences resolved by consensus (Table 1). Specifically, the authors extracted study endpoints, and main outcomes were study design, population, clinical setting, remifentanil dosage and treatment duration, and length of follow-up (Table 2). At least 2 separate attempts at contacting original authors were made in case of missing data. The primary endpoint of the present review was time on mechanical ventilation. Secondary endpoints were represented by cardiac biomarkers, myocardial infarction, use of inotropic drugs, intensive care unit (ICU) and hospital length of stay (LOS), and mortality.

Table 2. Number of Patients and Interventions of Included Studies

Internal Validity and Risk of Bias Assessment 

The internal validity and risk of bias of included trials were appraised according to The Cochrane Collaboration methods⁴ by 2 independent reviewers, with divergences resolved by consensus.

Data Analysis and Synthesis 

Computations were performed with RevMan 5 (a freeware available from The Cochrane Collaboration).⁴ Binary outcomes from individual studies were analyzed in order to compute individual and pooled odds ratios (ORs) with pertinent 95% confidence intervals (CIs, with equivalence set at 1, OR <1 favoring the first treatment, and OR >1 favoring the second treatment) with the Peto method. Weighted mean differences (WMDs) and the 95% CI were computed for continuous variables by means of the inverse variance fixed- or random-effect method.⁴ Mortality, the need for inotropic drugs, and myocardial infarction were dichotomous outcomes, whereas continuous variables were ventilation time, LOS, ICU stay, and cardiac biomarker release. Statistical heterogeneity and inconsistency were measured using the Cochran Q test and I², respectively. In both the continuous and binary outcomes, the analysis was performed by means of the random-effect method (which better accommodates clinical and statistical variations) in case of high statistical inconsistency (ie, ventilation time and cardiac biomarker release)⁵ and by means of the fixed-effect method in case of low or moderate statistical inconsistency (other outcomes).⁵ Statistical significance was set at the 2-tailed 0.05 level for hypothesis testing and at 0.10 for heterogeneity testing; unadjusted p values are reported throughout. This study was performed in compliance with The Cochrane Collaboration and the Quality of Reporting of Meta-Analyses guidelines.⁶, ⁷

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Results 

Database searches, snowballing, and contacts with experts yielded a total of 193 articles. Excluding 171 nonpertinent titles or abstracts, 22 studies were retrieved in complete form and assessed according to the selection criteria (Fig 1). A total of 6 studies were further excluded because there were no outcome data and further details could not be obtained by the authors⁸, ⁹, they were a duplicate publication,¹⁰ they were not randomized,¹¹ and neuraxial anesthesia was adopted.¹², ¹³ Sixteen eligible randomized clinical trials were identified and included in the final analysis², ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸ (Table 1).

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• Fig 1. 

  A flow diagram of the systematic review process.

Study Characteristics 

The 16 included trials randomized 1,473 patients (573 to remifentanil and 664 receiving control) (Table 2). All but 2 studies², ¹⁴ included only patients who underwent isolated coronary artery bypass graft surgery. One author¹⁴ administered a bolus of the study drug, and 15 authors used a continuous infusion,², ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸ 4 of them¹⁵, ¹⁸, ²⁷, ²⁸ after bolus. The dose varied between 0.3 and 5 μg/kg (as an intravenous bolus) or between 0.025 and 4 μg/kg/min (as a continuous infusion). Two studies were multicentric.¹⁶, ²³ Control was represented by fentanyl in 12 studies¹⁴, ¹⁵, ¹⁶, ¹⁹, ^21-18 and by sufentanil in 4 trials.², ¹⁷, ¹⁸, ²⁰

Study quality appraisal showed that some studies appeared of suboptimal quality, as testified by the common lack of details on the method used for allocation and by the lack of blinding in many studies (Table 3). Although 5 randomized controlled trials (RCTs) were of high quality, many others lacked important details to appraise the risk of selection, performance, attrition, or detection biases.

Table 3. Risk of Bias Assessment of Included Studies

Quantitative Data Synthesis 

Overall analysis showed that the use of remifentanil was associated with a significant reduction in postoperative mechanical ventilation (WMD = −139 minute [−244, −32], p for effect = 0.01, p for heterogeneity <0.001, I² = 89% with 480 patients included) (Fig 2) and LOS (WMD = −1.08 days [−1.60, −0.57], p for effect <0.0001, p for heterogeneity = 0.004, I² = 71% with 306 patients included) (Fig 3). Furthermore, patients receiving remifentanil had a reduction in cardiac troponin-I release (WMD = −2.08 ng/mL, [−3.93, −0.24], p for effect 0.03, p for heterogeneity = 0.02, I² = 74% with 144 patients included) (Fig 4). No difference was noted in ICU stay (WMD = −0.24 hours, [−1.49, 1.00], p for effect = 0.70, p for heterogeneity = 0.72, I² = 0% with 416 patients included) or in mortality (3/344 [0.87%] in the remifentanil group v 4/377 [1.06%] in the control group, OR = 0.76 [0.17-3.38], p for effect = 0.72, p for heterogeneity = 0.35, I² = 5% with 721 patients included).

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• Fig 2. 

  Pooled estimates of mechanical ventilation comparing remifentanil versus control (minutes). df, degrees of freedom; MD, mean difference.

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• Fig 3. 

  Pooled estimates of hospital stay comparing remifentanil versus control (days). df, degrees of freedom; MD, mean difference.

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• Fig 4. 

  Pooled estimates of peak serum troponin I (ng/mL) comparing remifentanil versus control (days). df, degrees of freedom; OR, odds ratio.

An increase in the use of inotropic drugs was found in patients receiving remifentanil, (70/140 [50%] in the remifentanil group v 56/167 [33%] in the control group, OR = 1.75, [1.05, 2.90], p for effect = 0.03, p for heterogeneity = 0.01, I² = 69% with 307 patients included). No reduction in the incidence of perioperative myocardial infarction was noted (11/496 [2.2%] in the remifentanil group v 19/528 [3.5%] in the control group, OR = −0.62, [−0.30, 1.28], p for effect = 0.20, p for heterogeneity = 0.70, I² = 0% with 1,024 patients included).

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Discussion 

In this meta-analysis of randomized controlled trials, the authors showed that the use of remifentanil reduces the time of mechanical ventilation in patients undergoing cardiac surgery when compared with other opioids (fentanyl or sufentanil). Remifentanil is a well-known ultra–short-acting opioid, a piperidine derivative. It has the ability to provide a strong analgesia causing a decreased sympathetic and increased vagal tone, allowing maintenance of physiologic heart rate and arterial pressure during surgery. Moreover, remifentanil possesses an ester linkage that allows predictable pharmacokinetics. Infusion has an onset of 1 minute and rapidly achieves steady-state plasma levels. Its action dissipates within 3 to 10 minutes after infusion discontinuation.²⁹ Remifentanil is metabolized directly in the plasma by nonspecific esterases. Its primary metabolite is remifentanil acid, which has negligible pharmacologic activity. Remifentanil action is not prolonged by renal or hepatic dysfunction.

Thanks to these unique properties, remifentanil has been evaluated in surgical populations. Komatsu et al,³⁰ in a recent meta-analysis, compared remifentanil with short-acting opioids (fentanyl, alfentanil, or sufentanil) during general anesthesia. Eighty-five trials were identified, and a total of 13,057 patients were included. Intraoperatively, remifentanil was associated with clinical signs of deeper analgesia and anesthesia, such as statistically significantly fewer responses to noxious stimuli, significantly more frequent episodes of bradycardia, significantly more hypotension, and less hypertension. In the postoperative period, remifentanil presented a significantly faster recovery and less respiratory depression. Times to obeying a command, to extubation, to initiation of spontaneous ventilation, and to adequate ventilation were shorter in remifentanil-treated patients than in other opioid-treated patients. Remifentanil presented more frequent postoperative analgesic requirements and shivering and no overall impact on postoperative nausea or vomiting.³⁰

Besides the important findings published by Komatsu et al,³⁰ the specific condition of cardiac anesthesia required a special investigation. Protection against noxious stimuli is particularly important in cardiac surgery because tachycardia and hypertension can trigger perioperative myocardial ischemia. For this reason, high-dose opioids, like sufentanil or fentanyl, frequently are used. However, they may accumulate in the body because of their pharmacokinetics, causing delayed recovery, respiratory depression, and the need for prolonged ventilatory support.¹, ²

On the contrary, the advantages of short-acting opioids like remifentanil must be balanced with the increased risk of postoperative pain, leading to hemodynamic deterioration, which may increase the risk of ischemic events. Adequate analgesia with other drugs or techniques may be needed to avoid these complications.³¹, ³² However, results from this study failed to show an increased risk in myocardial infarction or mortality in patients treated with remifentanil and may be reassuring to clinicians.

In this meta-analysis of RCTs, the authors showed that the use of remifentanil reduced the time of mechanical ventilation in patients undergoing cardiac surgery when compared with other opioids (fentanyl or sufentanil). These data could be of particular relevance in cardiac surgery in which early tracheal extubation might be hindered by accumulation of high-dose opioids. The present meta-analysis also suggests a reduced hospital stay in patients receiving remifentanil, with possible cost reduction. However, this finding is not confirmed by a reduction in the length of ICU stay.

Even if there might have been some concern about fast-track protocols because of the risk of myocardial ischemia, the authors showed that remifentanil reduced cardiac troponin release after cardiac surgery when compared with fentanyl and/or sufentanil. Interestingly, a recent study by Wong et al²⁸ suggested that remifentanil preconditioning has cardiac protective properties in coronary artery bypass graft surgery patients receiving a standard fentanyl and propofol anesthesia. The addition of remifentanil reduced the degree of myocardial damage in terms of postoperative cardiac troponin release, MB isoenzyme of creatine kinase, heart-type fatty-acid–binding protein, and the reduction of ischemia-modified albumin.

An increase in consumption of inotropes was found in the present results. Hypotension is a common side effect of opioids like sufentanil and remifentanil³⁰ although the use of remifentanil already has been described in patients with poor cardiovascular function and is correlated with drug administration rate. The initial concerns of remifentanil's detrimental effect on hemodynamic stability probably were caused by high doses of drug infusion (1-5 μg/kg/min) and bolus administration. However, lower rates of infusions have reduced concerns, and in recent studies remifentanil has been regarded as standard of care in patients with severely reduced left ventricular function undergoing implantation of a cardiovascular defibrillator and high-risk patients undergoing transcatheter aortic valve implantation.³³, ³⁴, ³⁵ On the basis of the data from the literature and of the results of the meta-analysis, the authors suggest that remifentanil administration should not be avoided because of the potential hypotensive effect but should be adjusted according to the patient's characteristics and the necessity of strong intraoperative analgesia. Nonetheless, low-dose remifentanil infusion and the avoidance of bolus injection could be recommended in order to maintain hemodynamic stability.

Limitations 

Drawbacks of systematic reviews and meta-analyses are well known and include the post hoc design with a potential increase in α error, the risk of small study bias, and the inability to overcome limitations in the primary studies included.⁶, ⁷, ³⁶ Many RCTs included in this systematic review were of suboptimal quality (ie, at least at moderate risk of bias), thus potentially undermining the validity of the results. Limitations in the total number of patients included and in consistency between studies may restrict some of the findings of the present meta-analysis. Although a higher number of patients included in the analysis could lead to the nonsignificant trend in reduction in ICU stay to statistical significance, no difference in the length of ICU stay may also suggest that the reduction in LOS is caused by chance (type I error).

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Conclusions 

This meta-analysis of randomized controlled trials suggests that remifentanil could be beneficial in cardiac surgery with a reduced time on mechanical ventilation, cardiac biomarker release, and hospital stay.

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Acknowledgment 

The authors wish to acknowledge Paola Zuppelli and Lara Sussani for their constant support and cooperation.

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Appendix 1 

Search Strategy for PubMed Developed According to Biondi-Zoccai et al³ (remifentanil OR remifentanyl) AND (sulfentanil OR sulfentanyl OR fentanyl OR fentanyl) AND coronary.

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