TITLE: Analgesic properties of a dexmedetomidine infusion after uvulopalatopharyngoplasty in patients with obstructive sleep apnea

  ABSTRACT.BACKGROUND:
Dexmedetomidine is an alpha2 -adrenergic agonist with sedative and analgesic properties. This study aimed to investigate if the use of a continuous dexmedetomidine infusion with i.v. morphine patient-controlled analgesia (PCA) could improve postoperative analgesia while reducing opioid consumption and opioid-related side effects.

ABSTRACT.METHODS:
In this prospective randomized, double-blinded, controlled study, 39 patients with obstructive sleep apnea syndrome undergoing uvulopalatopharyngoplasty were assigned to two groups. Group D (dexmedetomidine group) received a loading dose of dexmedetomidine 1 μg.kg-1 i.v., 30 minutes before the anticipated end of surgery, followed by infusion at 0.6 μg.kg-1 h-1 for 24 hours. Group P (placebo group) received a bolus and infusion of placebo. In both groups, postoperative pain was initially controlled by i.v. morphine titration and then PCA with morphine. Cumulative PCA morphine consumption, pain intensities, sedation scores, cardiovascular and respiratory variables and opioid-related adverse effects were recorded for 48 hours after operation.

ABSTRACT.RESULTS:
Compared with placebo group, patients in the dexmedetomidine group required 52.7% less PCA morphine during the first 24 hours postoperatively, with significantly better visual analogue scale scores, less incidence of respiratory obstruction (5 vs. 12 patients, respectively; P = .037) and longer time to first analgesic request (21 (11) vs. 9 (4) minutes; P = .002). Fewer patients in group D experienced nausea and vomiting than those in group P (7 vs. 24 patients, respectively; P < .05).

ABSTRACT.CONCLUSION:
Continuous dexmedetomidine infusion may be a useful analgesic adjuvant for patients susceptible to opioid-induced respiratory depression.

BODY.INTRODUCTION:
Obstructive sleep apnea (OSA) is a syndrome characterized by periodic, partial or complete upper airway obstruction resulting in the disruption of sleep and hypoxemia with potentially serious physiologic consequences.[1] It is identified as a major health problem, affecting 4% of men and 2% of women in middle age.[2]  Uvulopalatopharyngoplasty (UPPP) is the most commonly performed surgical procedure for the treatment of OSA;[3] it is effective and safe.[4] Despite the use of many analgesics, pain (which is usually severe and unacceptable throughout the first postoperative day)[5] is a major complication of UPPP and lasts till mucosal recovery is complete.[36]  Dexmedetomidine is an α2-adrenoreceptor agonist, with beneficial analgesic and sedative properties and limited respiratory depressant side effects. Thus it may be useful in the postoperative period for patients with OSA who are susceptible to opioid-induced respiratory depression and undergoing surgical procedures that are associated with significant postoperative pain.[78]  The aim of this study was to test the efficacy of a continuous dexmedetomidine infusion to provide effective analgesia and reduce the need for postoperative self-administration of i.v. morphine; and to assess if decreased morphine consumption is associated with a reduction in sedation, nausea and vomiting.

BODY.METHODS:
This study took place in King Abdulaziz Navel Base Hospital, Jubail, Kingdom of Saudi Arabia, from July 2007 to August 2009. The study was approved by the Hospital Ethics Committee and registered with the Australian New Zealand Clinical Trials Registry (ANZCTR). URL and unique identification number: http://www.ANZCTR.org.au/ACTRN12609000731291.aspx. Written informed consent was obtained from each patient. We studied 43 ASA I-II patients, aged 38-55 years, with OSA and scheduled for UPPP. Inclusion criteria included frequent loud snoring, history of airway obstruction and frequent arousal from sleep. All patients were subjected to physical examination for tonsillar size, palate tongue position and degree of hypertrophy of the lateral sides of the oropharynx; fiber-optic endoscopy with Muller's maneuver; nasoendoscopy; and polysomnography; and positive diagnosis of OSA was obtained before surgery. Apnea-hypopnea index ranged from 20 to 40.  The surgical procedure included tonsillectomy and resection of excess fat and mucosa in the soft palate, including uvula, with preservation of palpable musculature. Several sutures approximated the anterior and posterior pillars.  Patients were excluded if there was a history of ischemic heart disease, conduction disturbance, long-term use of certain medications (β-blockers, analgesics, sedatives or tricyclic antidepressants); if they had impaired renal, hepatic or pulmonary function; if they had a history of allergy to opioids or any other drug used in the study; or if they were unable to use the patient-controlled analgesia (PCA) system.  During the preoperative visit, the patients were taught how to represent their postoperative pain on a 10-cm visual analogue scale (VAS), on which 0 cm indicated no pain; and 10 cm, the worst imaginable pain. The use of a PCA system (Fresenius vial, Brezins, France) was also explained at that time. No premedication was given, and the anesthetic technique was standardized. Heart rate (HR), noninvasive mean arterial pressure (MAP) and oxygen saturation (SpO2) were noted before induction and repeated at regular intervals thereafter. Anesthesia was induced with propofol 2 mg.kg-1 ; morphine sulfate 0.1 mg.kg-1; and atracurium 0.5 mg.kg-1 to facilitate tracheal intubation. The lungs were ventilated to maintain normocapnia [end-tidal carbon dioxide (ETCO2) pressure between 4.5 and 5.6 kPa], with 1-2% sevoflurane in 60% nitrous oxide and 40% oxygen for maintenance of anesthesia. Supplemental boluses of atracurium 0.1 mg.kg-1 were administrated as required to maintain muscle relaxation during surgery.  Patients were randomized by using a sealed-envelope technique to one of two groups, 30 minutes before the anticipated end of surgery. Dexmedetomidine group received a loading dose of dexmedetomidine 1 μg.kg-1 in 100 mL of normal saline (Precedex, Abbott Laboratories Inc., Abbott Park, IL, USA) over 20 minutes, followed by an infusion of 0.6 μg.kg-1 h-1. This rate was maintained uninterrupted for 24 hours (until the end of the first postoperative day). Placebo group received the same volume of normal saline as a loading dose, followed by a continuous saline infusion. Blinding was carried out by a technician not involved in data collection, who made up identical syringes and infusions of dexmedetomidine and normal saline under sterile conditions.  At the end of surgery, atropine 20 μg.kg-1 and neostigmine 50 μg.kg-1 were used to antagonize the residual neuromuscular block. The trachea was extubated after recovery of adequate spontaneous ventilation. Extubation time was noted.  Following surgery, patients were transferred to the post-anesthesia care unit (PACU), where they were monitored and received oxygen via a face mask at 6 L.min-1 for 1 hour; and then at 4 L.min-1 until discharge to the surgical ward, 4 hours after extubation.  Pain intensity was assessed by the patients during swallowing using a VAS, and the first analgesic medication was administered by nurses who were blinded to the treatment group, when the VAS reached 4 cm after extubation. Intravenous morphine 2 mg at 10-minute intervals was titrated until the VAS decreased to <4 cm, at which time, morphine consumption was recorded and the patients had access to a PCA device. This device was set to deliver morphine 1 mg as an i.v. bolus with a lockout interval of 5 minutes, without background infusion. Patients were advised to push the analgesic-demand button when they felt pain, and to repeat this until pain relief. This PCA regimen was discontinued when no longer needed.  If pain scores remained higher than 4, lornoxicam 8 mg i.v. was used as a rescue analgesic. Cumulative doses of morphine given by PCA were recorded at 12, 24, 36, 48 hours postoperatively.  Pain scores were recorded after being measured using a VAS scale every 30 minutes during the first 2 hours, every 60 minutes during the next 10 hours and every 4 hours during the next 36 hours. The time between extubation and the first administration of analgesic medication was recorded.  Samples for arterial blood gases analysis were drawn at extubation and every 8 hours thereafter and when clinically indicated. Respiratory depression was defined as a persistent respiratory rate <10 bpm, oxygen partial pressure (PaO2) < 9.0 kPa or a carbon dioxide partial pressure (PaCO2) > 7.5 kPa.  The degree of sedation was monitored using a four-point scale (0 = awake and alert, 1 = drowsy, 2 = mostly sleeping, 3 = difficult or impossible to awaken).  Sedation scores were recorded at regular intervals after surgery.  The presence of nausea and vomiting was noted using a four-point scale (0 = no nausea or vomiting, 1 = mild nausea, 2 = severe nausea, 3 = retching or vomiting). Patients with a nausea score of 2 or 3 were initially given an i.v. bolus of metoclopramide 10 mg, followed by ondansteron 4 mg if metoclopramide was unsuccessful.  Other side effects (bradycardia, bradypnea, urinary retention and pruritus) possibly attributed to morphine or dexmedetomidine administration were recorded for each patient.  Assessment of patients' satisfaction with postoperative pain control for the following 24 hours after surgery was carried out using a four-point scale (0 = totally dissatisfied, 1 = moderately dissatisfied, 2 = reasonably satisfied, 3 = totally satisfied with pain relief).  The estimated sample size indicated that 23 patients per group would give a β risk of 80% at an α level of 0.05 for detecting a difference in morphine consumption of at least 30%. Statistical analysis was performed using Kruskal-Wallis ANOVA and Mann-Whitney U tests for pain scores, t tests for parametric data, and Chi-square test for categorical data. Statistical calculations were carried out using computer programs Microsoft Excel version 7 (Microsoft Corporation, New York, USA) and statistical package for the social sciences (SPSS Inc., Chicago, IL, USA). P < .05 was considered statistically significant.  

BODY.RESULTS:
We studied 43 ASA I-II patients, aged 38-55 years, with OSA and scheduled for UPPP. Two patients were withdrawn from the study because of tracheal intubation difficulty. Another patient was excluded from the analysis as he was unable to use the PCA because of severe vomiting and requested alternative analgesia 7 hours after operation. One more patient was excluded due to severe postoperative bleeding. The remaining 39 patients completed the study. Patient characteristics were similar in the two groups [Table 1].   Table 1 Patients characteristics   Postoperative hemodynamic monitoring revealed no significant differences between the two groups. No patient required intervention as a result of cardiovascular problems.  The durations of anesthesia and surgery were similar in the two groups. The median (SD) extubation time was significantly prolonged in the dexmedetomidine group as compared to the placebo group [16 (7) vs. 9 (5.9) minutes, respectively; P = .015] [Table 2].  Table 2 Duration of anesthesia and surgery, extubation time and postoperative morphine titration   Figure 1 demonstrates the VAS scores of the two groups during the first 12 hours after surgery. VAS scores were significantly greater during the first 2 hours after tracheal extubation in the placebo group and were similar in the two groups thereafter. The mean VAS scores were never >5 cm in the dexmedetomidine group during the first 2 hours after surgery.  Figure 1VAS pain scores (0-10 cm) in the two groups during the first 12 hours after surgery. Values are presented as mean. Asterisks indicate statistically significant difference between the two groups (P < .05)  The period between extubation and the first analgesic request in the PACU was significantly longer in the dexmedetomidine group as compared to the placebo group [21 (11) vs. 9 (4) minutes, respectively; P = .002] [Table 2]. The cumulative dose of morphine given by nurses in the PACU for titration was significantly greater in the placebo group [21.7 (11.1) mg] than in the dexmedetomidine group [9.4 (5.2) mg] (P = .002) [Table 2]. PCA morphine consumption was significantly greater at 12 hours and 24 hours after surgery in the placebo group than in the dexmedetomidine group [12 hours, 34 (16.7) and 18.1 (10) mg, respectively; 24 hours, 65 (29) and 34.3 (16.4) mg, respectively; P < .05] [Figure 2]. The cumulative morphine dose used during titration and PCA throughout the study period (48 hours) was significantly greater in the placebo group than in the dexmedetomidine group [135.7 (37.4) vs. 86.4 (26.1) mg, respectively, P = .001]. In addition, 13 patients in the placebo group needed rescue analgesia in contrast to only 6 patients in the dexmedetomidine group (P = .037).  Figure 2Cumulative postoperative PCA morphine consumption in the two groups during the 48 hours after surgery. Data are presented as mean. Asterisks indicate statistically significant difference between the two groups (P < .05)  There was a statistically significant difference in the mean respiratory rate and SpO2 between the two groups during the first 6 hours after surgery. Twelve patients in the placebo group and 5 patients in the dexmedetomidine group experienced a respiratory rate <10 bpm with desaturation between 89% and 92% {PaO2 between 7.8 and 8.6 kPa} (P = .037) without significant changes in the PaCO2 . Two more patients in the dexmedetomidine group experienced a respiratory rate <10 bpm without desaturation below 95%. All these patients recovered without any specific treatment. The sedation scores did not differ significantly between the two groups during the 48 hours after surgery [Table 3].  Table 3 Sedation scores and incidence of nausea and vomiting   Postoperative nausea and vomiting were the most prevalent adverse events. The incidence of nausea and vomiting requiring treatment was significantly reduced in the dexmedetomidine group during the first 24 hours after surgery [Table 3], although the severity scores were unchanged. Significantly more patients in the placebo group experienced pruritus in comparison with the dexmedetomidine group (14 vs. 6, respectively; P = .016).  No other side effects related to morphine or dexmedetomidine were noted.  Patient satisfaction scores were significantly higher in group D [median, 4 (range, 2-4)] compared to group P [median, 3 (range, 1-4)] (P < .05).

BODY.DISCUSSION:
This study demonstrated that patients receiving continuous dexmedetomidine infusion for pain relief following UPPP consumed 52.7% less morphine by PCA in the first 24 hours postoperatively, compared with the placebo group receiving only morphine.  Dexmedetomidine stimulates α2-adrenergic receptors and couples in an inhibitory fashion to the L-type calcium channels. The agent induces analgesia via receptors in the spinal cord; sedation and anxiolysis, via receptors in the locus ceruleus; and attenuation of the stress response without significant respiratory depression.[9] The relatively high ratio of α2:α1 activity (1620:1 as compared with 220:1 for clonidine) accounts for the potent sedative effect of dexmedetomidine without unwanted cardiovascular effects from α1-receptor activation.[10] However, its use in large doses is complicated by transient hypertension and bradycardia via activation of α2B-adrenoceptor located on smooth muscle cells in the resistance vessels and inhibition of cardiac sympathetic drive.[11] Because no particular dose of dexmedetomidine is strongly supported in the literature, in this study we used a dose of dexmedetomidine that was predicated to have no or minimal cardiovascular effects but still might be sufficient to produce sedation and analgesia.  The loading dose was administrated approximately 30 minutes before the end of the procedure (over 20 minutes to minimize the effects on heart rate and blood pressure) in an attempt to attain a therapeutic level before the completion of surgery. Arain and colleagues[7] administrated dexmedetomidine at an initial loading dose of 1 μg.kg-1 (over 10 minutes) followed by an infusion at 0.4 μg.kg-1 h-1 initiated 30 minutes before the end of elective inpatient surgery. They observed lower mean heart rates in the dexmedetomidine-treated group during the early postoperative period, with transient significant increase in MAP that lasted several minutes immediately after the initial loading dose of dexmedetomidine. The transient increase in MAP could be attributed to the direct effects of α2-receptor stimulation of vascular smooth muscle followed by an inhibition of sympathetic outflow that overrode the direct effects of dexmedetomidine on the vasculature. This might be an unavoidable effect of infusion of α2 agonists, because the time differential between directly binding to vascular receptors and diffusion into the central nervous system to decrease sympathetic outflow during i.v. infusions might be ever present.[10] However, in our study we did not observe this transient hypertension in the dexmedetomidine-treated patients, probably due to the relatively long period of infusion of the loading dose.  Obstructive sleep apnea is an increasingly common sleep disorder, which is of particular concern to anesthesiologists because it is associated with increased perioperative morbidity and mortality, including respiratory obstruction after extubation or respiratory depression after opioid administration.[1] Pain is one of the most important complications of UPPP (the most common surgical procedure performed by most otolaryngologists for treatment of OSA). Analgesics must be administrated judiciously after UPPP as there is much evidence to suggest that anesthetic and opioid agents increase the tendency for upper airway collapse; these agents also impair normal arousal mechanisms and may therefore worsen the severity of OSA.[12]  Several studies have demonstrated the analgesic effects of dexmedetomidine. Gurbet and colleagues[13] investigated the efficacy of dexmedetomidine vs. placebo for postoperative analgesia after total abdominal hysterectomy. The two groups had similar pain scores, but the patients who received dexmedetomidine required a lower cumulative amount of morphine during the first 48 hours after surgery. Arain and colleagues[7] examined 34 patients scheduled for elective inpatient surgery and randomized them equally to receive either dexmedetomidine (initial loading dose of 1 μg.kg-1 over 10 minutes followed by 0.4 mg.kg-1 h-1, discontinued at the end of surgery) or morphine sulfate (0.08 mg.kg-1) 30 minutes before the end of surgery. The groups had similar pain scores, but the morphine group required 66% more morphine to achieve the same analgesic effect. Hofer and colleagues[8] reported a 433-kg morbidly obese patient with OSA and pulmonary hypertension who underwent Roux-en-Y gastric bypass. They substituted the intraoperative use of opioids with a continuous infusion of dexmedetomidine (0.7 μg.kg-1 h-1) that was continued uninterrupted throughout the end of the first postoperative day. They found that the patient had lower opioid requirement during the first postoperative day (48 mg of morphine by PCA) while still receiving dexmedetomidine compared to the second postoperative day (148 mg of morphine by PCA), with similar pain scores. In another study involving 100 women undergoing total abdominal hysterectomy, Lin and colleagues[14] added dexmedetomidine to PCA morphine for one of their patient groups. The authors observed that the patients in the dexmedetomidine group required 29% less morphine and reported significantly lower pain scores from the second postoperative hour onwards and throughout the study. In agreement with these trials, the patients in our study who received dexmedetomidine required a lower cumulative amount of morphine during the first 24 hours after surgery, which strongly supports the presence of dexmedetomidine-induced opioid-sparing effect.  The analgesic effect of dexmedetomidine was also evident in our research, by the significantly lower VAS scores observed during the first 2 hours after surgery in the dexmedetomidine-treated patients compared to the placebo group.  Previous animal studies have concluded that systemic administration of α2-adrenergic receptor agonists resulted in dose-dependent antinociception and sedation responses,[15] whereas human data revealed a clear dose-response relationship for sedation but not for analgesia.[16] A possible explanation of the variances between animal and human studies is that many of the animal experiments involved drug doses several orders of magnitude larger than those used in human trials.[17] In humans, a continuous dexmedetomidine infusion was found to maintain a unique level of sedation (patients appear to be asleep but are readily arousable) without affecting respiration.[18]  Dexmedetomidine is currently approved by the U.S. Food and Drug Administration for sedation of adults in the intensive care setting for up to 24 hours during mechanical ventilation.[19] Patients receiving dexmedetomidine can typically respond to commands and perform psychomotor tests when lightly aroused from their sedate state without a need to decrease or stop the dexmedetomidine infusion.[10] In our study, we found that the dexmedetomidine-treated patients were sedated; they appeared to be asleep but were easily aroused with verbal or physical stimuli. This is in agreement with the previous report by Gurbet and colleagues,[13] who did not observe clinically important sedation in any of their patients who received dexmedetomidine infused at the rate of 0.5 μg.kg-1 h-1.  In this study, we found a statistically significant difference regarding the ventilatory parameters between the two groups. More patients in the placebo group developed respiratory obstruction in comparison with the dexmedetomidine group. Of note, the respiratory effects of dexmedetomidine have been greatly debated.[10] Venn and colleagues[18] demonstrated that, when used in spontaneously breathing patients in the intensive care unit after cardiac surgery and general surgery, dexmedetomidine reduced morphine requirements by over 50% while at the same time had no effect on respiratory rate, SpO2 , arterial pH and PaCO2 . Moreover, the PaO2:FiO2 ratios were statistically higher in the dexmedetomidine group compared with their patients receiving morphine and midazolam boluses. On the other hand, Belleville and colleagues[20] reported that dexmedetomidine could be associated with episodes of obstructive apnea, and this was increasingly common at doses of 1 and 2 μg.kg-1 that were given for 2 minutes; and presumably associated with a rapid increase in sedation. There was a mild decrease in minute ventilation and an increase in PaCO2 . Although all these effects are much less pronounced than those of opioids and other intravenous and volatile anesthetic agents, and appear to be similar in order of magnitude to those seen during profound sleep, we cannot exclude the possibility that more rapid loading doses might cause irregular breathing or obstructive apnea.[10]  To conclude, we found that continuous infusion of dexmedetomidine for pain relief after uvulopalatopharyngoplasty significantly reduces the amount of PCA morphine used by the patients postoperatively without affecting their ventilatory parameters and was associated with fewer morphine-related side effects.

Question: Compared to Placebo what was the result of Dexmedetomidine  on Time to first analgesic request ?
Evidence: less incidence of respiratory obstruction (5 vs. 12 patients, respectively; P = .037)
Answer: significantly increased