Conscious Sedation with Remifentanil During Painful Medical Procedures☆

Introduction 

In recent years, it has become standard practice in most medical centers to routinely provide conscious or deep sedation to patients undergoing painful medical procedures. Initially, the combination of an intravenous (IV) opioid (e.g., fentanyl) and a benzodiazepine (e.g., midazolam) was used mainly because of their relatively short onset of action and duration of effect. However, more recently, many anesthesiologists and intensivists have utilized IV propofol,1 a short-acting hypnotic agent, because of its ability to maintain spontaneous ventilation at therapeutic levels in most patients.2 Despite its record of safety, propofol administration invariably results in a loss of consciousness at levels required to maintain patient immobility during painful stimuli. These levels, in fact, result in a state of deep sedation that is often indistinguishable from general anesthesia. Thus the use of propofol is restricted to practitioners who are adequately trained in airway management and maintenance of general anesthesia.

Remifentanil, an ultra-short-acting μ-opioid, was recently released for use during general anesthesia.3 Unlike other natural or synthetic opioids, remifentanil is rapidly hydrolyzed by nonspecific plasma and tissue esterases that impart brevity of action (terminal elimination half-life 8–10 minutes) and rapid, precise titratability when used as a continuous IV infusion. Discontinuation of remifentanil results in an extremely rapid return to the patient's baseline mental and cardiorespiratory status (within 10 minutes in most cases) regardless of the duration of the infusion.4 Because of these desirable properties, over an 18 month period, remifentanil was used in combination with a benzodiazepine to provide analgesia and anxiolysis, while maintaining consciousness, to 31 patients undergoing painful procedures. The objective of this report is to describe the efficacy and complications of these sedations.

Methods 

The research subjects' review board of the University of Rochester approved this retrospective chart review study. The anesthetic records of 30 patients who underwent 40 medical procedures and who received remifentanil as part of a conscious sedation technique between January 1, 1997 and June 30, 1998 were examined. The following factors were recorded: age, weight, gender, procedure, duration of the procedure, dose of remifentanil required, other anesthetics used, time to discharge, and complications. Complications included hypoxemia (SpO2 < 90%), hypotension (systolic blood pressure < 30% of baseline), bradycardia (heart rate < 60 beats per minute), and emesis. The majority of the procedures were performed in an area with standard emergency equipment immediately available in accordance with the recommendations in the American Academy of Pediatrics' (AAP) guidelines for sedation of pediatric patients.5 All patients were monitored continuously with an electrocardiograph and pulse oximeter, and blood pressure measurements were taken at least every 3 minutes. Respiratory rates were continuously monitored by visual or tactile inspection. Oxygen was administered either by a nasal cannula at 3 L/min, or the “blow-by” technique using oxygen tubing connected to an oxygen source at 15 L/min. Data are presented as mean ± SD where appropriate.

Results 

Thirty patients received remifentanil as the major component of conscious sedation during 40 painful medical procedures. There were 17 males and 13 females, whose ages ranged from 1 to 25 years. The medical procedures were bone marrow aspiration or biopsy (22), bone marrow harvest (2), bronchoscopy (2), burn debridement (1), chest tube insertion (1), closed fracture reduction (1), endoscopy (1), colonoscopy (1), steroid injection in hips (1), lumbar puncture (2), and renal biopsy (6). All but 2 patients received premedication with midazolam by either the oral (0.5 mg/kg) or IV (0.05 mg/kg) route; the others received oral diazepam, 0.25 mg/kg. Additional benzodiazepines were not administered during the procedures. One child (bone marrow harvest) had induction of general anesthesia with halothane and nitrous oxide and was then switched over to remifentanil. For the first two patients, the remifentanil was initially started as an infusion of 0.05 μg/kg/min (via infusion pump) and increased by 0.025 μg/kg/min every 5 minutes. However, it quickly became apparent that this dosage regimen was considerably below that needed to provide analgesia during the painful procedure in a reasonable period of time. Therefore, all subsequently reported patients received an initial bolus dose of 1 μg/kg/min, followed by an infusion dose of 0.1 μg/kg/min. Approximately every five minutes, the patients' reactions to injection of local anesthesia were observed. If, in the opinion of the practitioners, sufficient analgesia was not attained, the infusion dose was doubled and this process continued until the patient was comfortable during the procedure or if complications intervened.

Remifentanil was the sole analgesic in 31 cases. The infusion dose required for these patients was 0.5 ± 0.3 μg/kg/min. The duration of the sedation was 22.5 ± 12.6 minutes and the time to discharge for these patients was 11.3 ± 4.7 minutes. Nine patients required supplemental hypnotic agents (propofol or ketamine) to provide comfort and analgesia. In these 9 cases, remifentanil was abandoned because of the lack of analgesia at doses that caused apnea.

In the 31 cases where remifentanil was the sole analgesic, 10 patients developed hypoxemia (SpO2 48–89%) during the course of the procedure. Most were easily corrected with verbal or mild physical stimulation, but one patient (closed fracture reduction in a 9 year-old) required ventilatory assistance with bag and mask positive pressure ventilation for approximately 1 minute. Of the 20 patients who did not develop hypoxemia, 15 developed apnea during the procedure and required continuous verbal prompting to breathe.

One patient (endoscopy in a 1 year-old) developed bradycardia and hypotension, which was promptly corrected by administration of atropine. The initial five patients had post-procedure nausea or emesis. Therefore, subsequent patients received IV ondansetron, 1–2 mg as prophylaxis, and none of these patients developed nausea or emesis.

Discussion 

The major finding of this analysis was that although remifentanil resulted in sufficient analgesia and rapid times to discharge in the majority of the patients, in many cases the dose required for comfort was higher than the dose causing apnea. This is not entirely surprising because remifentanil does not differ from other opioids with regard to its side effect profile.4 Opioids characteristically cause dose-dependent depression of the ventilatory response to hypercarbia and blunting of the ventilatory response to hypoxia.6 When used as sole agents, benzodiazepines demonstrate variable and unpredictable ventilatory effects.7 However, when a benzodiazepine is combined with an opioid, synergism occurs, and the likelihood of ventilatory depression is increased.8, 9 In a study that investigated the effect of combining midazolam and fentanyl on the slope of the ventilatory response to hypercarbia, the incidence of apnea was significantly increased when fentanyl was added to midazolam.9 A theoretic advantage, however, of using remifentanil is the rapid return of ventilatory drive once the infusion is discontinued.

Other important side effects of opioids include emesis and difficult ventilation resulting from opioid-induced glottic spasm (also referred to as chest wall rigidity).10 Glottic spasm did not occur in any of the patients reported here. It is possible that pretreatment with midazolam attenuated this effect. The episodes of hypoxia that were frequently encountered appeared to be due to central apnea alone. Emesis was easily controlled by the addition of ondansetron, a 5-HT3 antagonist used commonly for postoperative emesis.

Since using remifentanil for these 30 patients, this institution has discontinued remifentanil use in favor of propofol, the previous anesthetic of choice. In general, patients, parents, and medical practitioners who had been using propofol expressed their desire to use it for future procedures because of its ability to rapidly induce unconsciousness and the low incidence of apnea or airway obstruction at most therapeutic levels, despite longer recovery times. Remifentanil, however, can be advantageous to those patients or families whose priorities differ. For example, in our clinic, an 8 year-old who receives bone marrow aspirations every 2 months continues to receive remifentanil at his and his parents' request because his rapid recovery and desire to remain conscious during the procedure are important priorities. However, we have not had similar requests from other patients or parents whose children received remifentanil successfully. Although the use of remifentanil resulted in a more rapid return to full consciousness and times to recovery than if propofol were used, these were not important priorities.

The one circumstance in which the remifentanil technique was preferred was in the radiology suite during renal biopsies. Since the kidney remained stationary during apnea, it provided the radiologists an easier target to hit. In addition, the radiology staff appreciated the patient's rapid return to their baseline state of consciousness because only minimal postoperative care was then required and the patient returned to the hospital ward shortly after completion of the procedure.

In summary, the major finding of this review is that the combination of a benzodiazepine and remifentanil was not a useful conscious sedation technique for painful procedures because of a high incidence of respiratory depression at subtherapeutic doses and frequent need for additional sedatives to provide patient comfort. We have since discontinued the use of remifentanil for conscious sedation in favor of a propofol-based technique. Although times to discharge are generally shorter when using remifentanil, the use of propofol rarely results in apnea or hypoxemia at therapeutic doses.1 If one chooses to use remifentanil, patients and families should be selected based on their comprehension that apnea will likely occur, and they will be frequently prompted to breathe throughout the procedure. Thus, this technique is generally contraindicated in children under the age of 4 or 5, or older children with cognitive impairment who cannot respond appropriately to verbal command.