Review question/objective

The objective of this review is to determine the effectiveness of intravenous remifentanil + propofol infusion for procedural sedation compared to intravenous propofol infusion in adult patients undergoing gastrointestinal endoscopic procedures.

Background

Gastrointestinal (GI) endoscopic procedures are essential diagnostic and therapeutic tools for evaluation and treatment of GI tract abnormalities. They are non-surgical procedures that enable a practitioner to identify and determine how to best treat conditions found in the upper and lower digestive system. Endoscopic procedures are complex, highly invasive and often painful procedures. Consequently, patient cooperation and procedural conditions can be adversely affected when discomfort and pain are not immediately alleviated. The provision of optimal sedation and analgesia is therefore a critical component of performing safe GI endoscopic procedures.1-3

Sedation is defined as a drug induced abatement of physiological function with concomitant changes in level of consciousness. There are four levels of sedation described as occurring in a continuum, ranging from minimal (anxiolysis), to moderate (conscious sedation), deep and general anesthesia.4 Analgesia is defined as a state of insensibility to pain without loss of consciousness.5 Procedural sedation is a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate an unpleasant procedure while maintaining cardiopulmonary function.6 The primary goal of procedural sedation in GI endoscopic procedures is the reduction of patient's anxiety, pain and discomfort, enabling the patient to tolerate the procedure and provide the endoscopist an ideal environment for a thorough examination. In addition, the administration of procedural sedation minimizes the patient's motion during the procedure, thus maximizing the chance of successfully completing the procedure.1,2 Interestingly, the provision and application of procedural sedation in GI endoscopic procedures varies greatly from country to country. In Canada, more than 90% of practitioners use sedation during colonoscopy7 while in Spain it is only 20%,8 in Greece 78%,9 in Germany 87%,10 in the US 98%11 and in Italy it is standard practice.12

The majority of procedural sedation administered for endoscopic procedures in adults, especially for relatively healthy patients who are undergoing simpler procedures such as esophagogastroduodenoscopy (EGD) or screening colonoscopy, consists of small doses of benzodiazepine in combination with opioid analgesics to reduce pain and anxiety.3 However, as the number of GI endoscopic procedures increase, patient expectations are changing and a growing number of patients expect a painless procedure and desire to be "knocked out" during the procedure. Several studies have shown that the anxiety and fear of pain during GI endoscopic procedures are associated with the unwillingness to participate in colorectal cancer screening.13 In addition, more GI endoscopic procedures are being performed as outpatient procedures at stand-alone ambulatory surgical centers (ASC). The location where these procedures are done has important ramifications on how sedation is provided, with implications on the capability for patient monitoring, management of complications, resuscitation efforts and efficiency. Furthermore, the increasing complexity and technical rigor of emerging advanced endoscopic procedures, such as endoscopic ultrasound (EUS) or endoscopic retrograde cholangio-pancreatography (ERCP) in the evaluation of pancreatic and biliary diseases, are more time consuming and necessitate a cooperative patient and procedural conditions that promote safe, comfortable and technically successful endoscopic procedures.13,14 Cohen et al. reported that patients with favourable endoscopic experiences from having optimal sedation are more likely to comply with medical advice and return for follow-up procedures in the future.1 Understandably, there is a growing interest in the use of other agents with unique pharmacologic properties designed to enhance sedation and analgesia, and reduce undesirable effects.

Currently, no single drug satisfies all the identified characteristics of an ideal sedative/analgesic such as rapid onset, short duration, lack of cumulative effects, minimal side effects and rapid recovery, for GI endoscopic procedures. However, the use of propofol for sedation in gastrointestinal endoscopic procedures is gaining widespread acceptance because of its favorable pharmacodynamics and pharmacokinetic characteristics that are ideal for short procedures that do not require extensive post procedure analgesia.13 Furthermore, studies have indicated that propofol as a sole agent for sedation in endoscopic procedures provides better sedation, faster recovery, greater efficiency and greater satisfaction levels for both the patient and endoscopist, when compared to an opioid/benzodiazepine combination.15-19 Propofol is an intravenous sedative hypnotic agent chemically described as 2,6-diisopropylphenol. It is used in the induction and maintenance of anesthesia and sedation. It has a rapid onset of approximately 30 seconds upon injection with a half time blood brain equilibration of approximately one to three minutes. The sedative effect of propofol is brought about by positive modulation of the inhibitory function of the neurotransmitter Gamma Amino Butyric Acid (GABA) through GABA_A receptors. The therapeutic effects of propofol are dose rate dependent and are proportional to the concentration in the blood. Propofol has a short duration of action due to rapid decline in plasma levels as a function of both distribution and metabolic clearance with an initial half life of two to four minutes followed by a rapid elimination phase, which explains the rapid recovery.20

Although propofol possess the ideal characteristics of a fast onset/fast offset hypnotic sedative for endoscopic procedures, it has very limited analgesic properties. This limitation is demonstrated clearly when propofol is solely used for GI endoscopic procedures as evidenced by the larger doses required to produce optimal sedation.1 Some may argue that some minor discomfort or pain is acceptable during these procedures because it is unlikely that the patient will remember due to the amnestic effect of propofol. However, the amnesia associated with propofol is dose dependent and not guaranteed. Although pain is a physiologic response to tissue damage, the emotional and behavioural component associated with the distressing experience may leave the patient with a lasting memory of a traumatic experience.21 The pain and discomfort associated with these procedures are acute and visceral in nature. In lower GI procedures, acute visceral pain results from activation of sensory afferent nerves that innervate the intestines and can be due to stretching of the sigmoid wall and mesenteric attachments from looping of the colonoscope shaft and overinsufflation.22 Visceral pain often triggers autonomic responses such as sweating, bradycardia, dizziness, hypotension and nausea.21-24 Unfortunately, propofol lacks vagolytic quality and has been associated with reports of bradycardia and asystole. In clinical trials, hypotension and transient apnea were noted in 75% of patients during the induction of propofol.20 Consequently, dose related side effects are common when propofol is used as the sole agent for procedural sedation in GI endoscopic procedures.1

Some studies have shown that propofol in sub-hypnotic plasma concentrations may actually increase the perception of pain.26 To ameliorate the limited analgesic property, hyperalgesic effect and adverse effects of large dose propofol intravenous infusion while maintaining an ideal procedural condition, the pharmacologic concept of balanced anesthesia can be applied for procedural sedation. The concept of balanced anesthesia posits that when small doses of several drugs that possess desirable pharmacologic properties are combined, the synergistic interaction of the drug combination "maximizes the therapeutic actions of each drug while minimizing the likelihood of a dose related adverse reaction."1 This can be achieved in procedural sedation for GI endoscopic procedures by combining propofol with small doses of short acting opioid analgesic. Short acting opioid analgesics are preferred over non opioid analgesics because of their potent blocking mechanism of incoming nociceptive signals to the brain and their direct action to the higher brain centers, thus controlling the affective components of pain.27 The combination of propofol with a short acting opioid analgesic not only decreases the amount of each drug needed to achieve optimal sedation, but also reduces the risks associated with each medication, for example respiratory depression, hypotension and arrhythmias.27

There are several short acting opioid analgesics available that can be combined with propofol to achieve optimal sedation, including meperidine, fentanyl, alfentanil and remifentanil. The therapeutic effects of these opioids are due to their actions on both M[mu] and K receptors.5 Although these short acting opioid narcotics belong to the same family of phenylpiperidines and are structurally similar, they differ primarily in their potency, relative rates of redistribution and clearance.28 Each of these analgesic options offer perceived advantages and disadvantages when it comes to onset and analgesia effect times, depth of analgesia and safety profile. However, among these short acting opioids, remifentanil is the only ultra-short acting opioid that allows a lower propofol dose to be used for maintenance of sedation due to the rapid onset and predictable offset of its opioid effect with propofol.28,29 It differs from all other opioids in that it possesses an ester linkage that undergoes rapid hydrolysis by non-specific tissue and plasma esterase resulting in very predictable pharmacokinetics and short elimination half-life that is independent of the duration of infusion.30,31 The termination of the therapeutic effect of remifentanil mostly depends on metabolic clearance rather than redistribution, which explains the rapid and predictable elimination from the body as opposed to being shunted from compartment to compartment as seen with other opioid analgesics. The short context sensitive half-life of remifentanil makes it an ideal opioid analgesic for intense pain of short duration.28-31

A systematic review by Komatsu etal. comparing remifentanil to fentanyl, alfentanil and sufentanil for general anesthesia concluded that remifentanil was associated with clinical signs of deeper analgesia and anesthesia, faster recovery and fewer respiratory events as compared to the other short acting opioids.31 Leong etal. compared the effectiveness of pain control with remifentanil during labor to that of meperidine and concluded that remifentanil is a better analgesic and provided better satisfaction scores.32 These reviews suggest that remifentanil is most suitable for short procedures that produce intense but brief and intermittent pain in comparison to the other short acting opioids. The similarity in the pharmacologic profile of remifentanil to that of propofol makes it an ideal short acting opioid analgesic that can attenuate the pain and discomfort associated with GI endoscopic procedures when combined with the hypnotic properties of propofol.

A preliminary search of the literature revealed several systematic reviews that examined the effectiveness and safety profile of remifentanil and propofol.31,19 However, no systematic review was located for the proposed topic. Two studies were found that examined whether there is any benefit in combining remifentanil with propofol for procedural sedation during GI endoscopic procedures.33,34 Although the results of these studies reflect a trend for better procedural conditions and lower incidence of complications when propofol alone is used, the difference was not statistically significant. A systematic review is therefore proposed to pool all existing evidence as means of clarifying and focusing the body of knowledge concerning the potential benefits of combining remifentanil with propofol as a technique for procedural sedation in GI endoscopic procedures.

Inclusion criteria

Types of participants

This review will consider studies that include adult patients 18 years and older with American Society of Anaesthesiologists (ASA) physical status I-III for GI endoscopic procedures, such as colonoscopy, EGD, flexible sigmoidoscopy, ERCP or EUS.

Types of intervention(s)/phenomena of interest

This review will consider studies that evaluate intravenous remifentanil + propofol combination in comparison to intavenous propofol alone for procedural sedation.

Types of outcomes

This review will consider studies that include the following outcome measures:

Patients' satisfaction with quality of sedation using a 100-mm visual analog scale (VAS) or Likert Scale

Incidence of adverse effects of sedation such as hypotension, decreased oxygen saturation, arrhythmias and nausea/vomiting

Post procedure recovery using the Observer Assessment of Alertness Sedation (OAAS) score or the modified Aldrete Scale score

Types of studies

This review will consider any existing evidence generated by study designs of prospective randomized control trials (RCT) and quasi-randomized control trials. In the absence of RCTs and quasi RCTs, observational studies including cohort designs and case controlled designs will be included.

Search strategy

The search strategy aims to find both published and unpublished studies in the English language and other languages with English translation, between 1991 and February 2015, as 1991 was the year remifentanil was brought to clinical trial. A three step search strategy will be utilised in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies.

The databases to be searched include:

CINAHL

Embase

PubMed

mailto:Nursing@OVID

Cochrane Central Trials Register

Web of Science

ProQuest

The search for unpublished studies will include:

New York Academy of Medicine Gray Literature

MEDNAR

Initial keywords to be used will be:

Propofol AND Remifentanil AND Gastrointestinal Endoscopy OR Colonoscopy OR Esophagogastroduodenoscopy

OR Endoscopic Retrograde Cholangio-Pancreatography OR Endoscopic Ultrasound AND Sedation OR Monitored Anesthesia Care

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.

Data collection

Data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives.

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes, expressed as odds ratio (for categorical data, e.g. incidence of cardio-pulmonary adverse events or incidence of post-procedure nausea/vomiting), weighted mean differences (for continuous data, e.g. patient satisfaction scores using VAS scores or post procedure recovery using the OAAS score) and their 95% confidence intervals, will be calculated for analysis. Heterogeneity will be assessed statistically using the standard Chi-square and variations in treatment effect will be explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Conflicts of interest

No conflict of interest exists.

Acknowledgements

This systematic review will contribute to the primary reviewer's degree in Doctor of Nursing Practice (DNP) at Texas Christian University (TCU), in Fort Worth, Texas.

References