Comparison of Ketamine and Fentanyl for Postoperative Pain Relief in Children Following Adenotonsillectomy

MATERIALS AND METHODS

Sixty children (ASA I or II), aged 3-12 years, were enrolled in this randomized, double-blind study. Institutional ethics committee approval and parental written consent were taken for all subjects. Children with systemic disease, metabolic and endocrine disorders, growth developmental, motor-mental retardation, a history of allergy to any of the study drugs, peritonsillar abscess, psychiatric disorders, chronic pain syndrome and those who had received analgesics were excluded from the study (Naderpour et al., 2011). Patients were fasted for 8 h prior to the surgery and received premedication of midazolam (0.05 mg kg^-1, IV) 5 min before anesthesia induction. Preoperative fluid administration was given with lactated Ringer’s solution (5 mL kg^-1) (Holte et al., 2003). Systolic Arterial Pressure (SAP), Diastolic Arterial Pressure (DAP), Heart Rate (HR) and peripheral oxygen saturation (SpO2) levels were monitored in the operation room.

Patients were randomized into one of two test groups by means of a computer-generated random number table with 30 patients in each group. An anesthesiologist prepared syringes containing either ketamine or fentanyl for each subject. Patients received dexamethasone (0.5 mg kg^-1) and either ketamine 0.5 mg kg^-1 (group 1) or fentanyl 1 μg kg^-1 (Ali and Maryam, 2007) (group 2) before induction.

Anesthesia was induced with propofol (2-3 mg kg^-1) (Mohammadi et al., 2006) and atracurium (0.5 mg kg^-1) (Mohammadi and Ghafari, 2007) and maintained with 1.2% isoflurane and 50% nitrous oxide in oxygen (Mohammadi et al., 2009). The same surgeon used the dissection and snare technique for every subject. Heart rate, SAP, DAP and SpO2 were recorded at 10 min intervals during the operation. At the end of the surgery, neuromuscular blockade was reversed by neostigmine (0.04 mg kg^-1, IV) and atropine (0.02 mg kg^-1, IV). Anesthesia was discontinued and the tracheal tube was removed in the operating room when airway reflexes had returned. After extubation, the patients were taken to the recovery room where an anesthetist and nurses who were unaware of the study drug, observed the patients. In the recovery room, pain assessment was performed using a modified Hannallah pain scale (Dal et al., 2007), an Observational Pain Score (OPS) developed and tested for validity and reliability in children. Different items of the modified Hannallah pain score are shown in Table 1. Pain scores were assessed by the blinded observer anesthetist on arrival and at 15th min. As supplementary analgesia, acetaminophen (40 mg kg^-1) was given for patients with OPS>4, on the patients’ request for pain medication, or in case of continuous crying for a 5 min period (Taheri et al., 2010). Nausea, vomiting, bleeding, sedation, SAP, HR, SpO2 were also recorded both on arrival in recovery room and at 15th min. Items and scores used to evaluate sedation, nausea and vomiting and bleeding are shown in Table 2 (Dal et al., 2007). Metoclopramide (0.1 mg kg^-1, IV) was administered to patients with nausea. Items of the post anesthesia recovery score (Aldrete score) (Aldrete, 1995), a 10-point post-anesthesia recovery score used to determine recovery room discharge readiness, are shown in Table 3.

Table 1:	Pain scoring table (modified hannallah score)

Table 2:	Nausea/vomiting scale, bleeding scale and sedation scale

Table 3:	The post anesthesia recovery score (Aldrete score)

The time at which the patient reached a post-anesthesia recovery score of at least 9 was noted. The time between anesthesia induction and extubation, between discontinuation of nitrous oxide and extubation and from tonsillectomy operation to the end of bleeding control was regarded as anesthesia duration, extubation time and operation time, respectively.

The postoperative OPS at 15th minute was considered the primary endpoint and was used to determine the sample size. It was calculated that sample size of 30 in each group would have an 80% power to detect a 20% difference in the OPS between two groups.

Statistical analysis: Data were presented as Mean±SD or as median (interquartile range). Statistical analysis was performed with SPSS for windows version 16.0 (Chicago, IL, USA) by using Chi-square test, Fisher’s exact test, Mann-whitney U test and Independent-Samples T test wherever appropriate. The Kolmogorov-Smirnov statistics was used for testing normality for continuous variables. A p-value less than 0.05 was considered statistically significant.

RESULTS AND DISCUSSION

Thirty four females and 26 males (age 3-12 years) were studied. No patient was excluded from the study. The demographic data as well as the analyses of the variables are shown in Table 4. There were no differences in gender, age, weight, duration of surgery and duration of anesthesia between the groups (Table 4, p>0.05). Furthermore, no statistically significant difference was observed between the groups in HR, SAP, DAP and SpO2 during the first 30 min of the surgery (p>0.05). Moreover, patients receiving ketamine (group 1) or fentanyl (group 2) had comparable OPS and sedation score both on arrival and at 15th minute in the recovery room (Table 4, p>0.05). Although rescue analgesics were similarly required in both groups (Table 4, p = 0.47), the time to reach rescue analgesia was shorter in group 1 (Table 4, p = 0.001). Post-anesthesia recovery scores (Aldrete scores) at 15th minute were not statistically different between the groups (9.13±0.68 in group 1 vs. 8.99±0.45 in group 2, Table 4, p>0.05). Only one patient in group 2 had nausea and vomiting in the first 15 minutes that needed antiemetic in the recovery room. In the first 15th minute in the recovery room, all patients had minimal or no bleeding; none of the patients required reoperation for bleeding.

The present study revealed that children receiving intravenous fentanyl (1 μg kg^-1) before adenotonsillectomy had prolonged time to first request for analgesia when compared to those receiving intravenous ketamine (0.5 mg kg^-1).

Table 4:	Patient’s demographic data and intra- and post-operative characteristics (Mean±SD) (n = number of patients)
OPS: Observational Pain Score. *Statistically significant (p<0.05)

However, no difference was found between ketamine and fentanyl groups with respect to OPS, sedation score, post-anesthesia recovery score and rescue analgesics. In contrast to our findings, Kennedy et al. (1998) found that children on ketamine/midazolam had lower pain scores than those on fentanyl/midazolam in pediatric orthopedic emergency room. To the best of our knowledge, the present study is the first investigation to compare ketamine and fentanyl for postoperative pain relief in children following adenotonsillectomy.

Recent studies on ketamine have reported contrasting results regarding its analgesic characteristics in adenotonsillectomy. A number of previous studies indicated that intravenous ketamine could reduce postoperative pain scores in children undergoing adenotonsillectomy without significant side effects (Dal et al., 2007; Marcus et al., 2000; Aydin et al., 2007; Murray et al., 1987). Furthermore, Marcus et al. (2000) and Aspinall and Mayor (2001) found that intravenous ketamine (0.5 mg kg^-1) might be a safe and effective alternative to morphine in providing postoperative analgesia after adenotonsillectomy. In contrast, Umuroglu et al. (2004) concluded that due to its positive chronotropic effect, high sedative and low analgesic effects, ketamine might not be a good analgesic in adenotonsillectomy when compared to morphine and tramadol. Moreover, O’Flaherty and Lin (2003) failed to demonstrate a decrease in pain and analgesic consumption in children undergoing tonsillectomy when pretreated with intravenous ketamine (0.15 mg kg^-1). Although our dosage was three times higher (0.5 mg kg^-1), we found no difference in analgesic effect between ketamine and fentanyl in our subjects. Ketamine is believed to be accompanied with undesirable psychological reactions occurring during awakening from ketamine anesthesia (emergence reactions; vivid dreaming, extracorporeal experiences and illusions) (Mistry and Nahata, 2005; Chen et al., 2010). Nevertheless, Treston and colleagues concluded that emergency physicians should not be deterred from using ketamine for pediatric procedural sedation (Treston et al., 2009).

A few studies have been targeted at analgesic characteristics of fentanyl in pediatric adenotonsillectomy. Davis et al. (2000) investigated the effect of remifentanil, an ultra-short acting synthetic opioid (Mohammadi et al., 2006), versus fentanyl on post-operative pain in children undergoing tonsillectomy and adenoidectomy (Davis et al., 2000). They concluded that remifentanil was associated with higher postoperative pain scores (Davis et al., 2000). In addition, pain scores in recovery and over the next 24 h were similar between fentanyl and morphine groups following pediatric adenotonsillectomy in the study by Mukherjee et al. (2001). In the present report, children in fentanyl group had prolonged time to first analgesia.

Postoperative nausea and vomiting following adenotonsillectomy may be due to swallowed blood, pain, opioid administration and direct oropharyngeal irritation (Dal et al., 2007). Although intravenous ketamine has been shown to accompany with significant postoperative vomiting in the study by Kennedy et al. (1998), rectally administered fentanyl-droperidol in children resulted in higher rate of postoperative nausea and vomiting than ketamine group (Zanette et al., 2010). In our study, there was no difference in the incidence of vomiting between two groups. We believe that administration of propofol, dexamethasone and fluid at the start of anesthesia might have decreased the incidence of vomiting in our study.

This study has certain limitations. We did not have a placebo group in the present study. We believed that providing no pain relief following adenotonsillectomy would be unethical. In addition, an intravenous Non-opioid analgesic drug such as paracetamol was not available as a rescue analgesic at our center. This clarifies why acetaminophen suppository was used for rescue analgesic in the recovery room. Furthermore, difficulties of pain assessment in children and refinement of follow-up period to 15-30 min should be considered as limitations of the present report. Moreover, the present investigation has focused on the effect of ketamine without considering the timing of the drug administration. The effect of the ketamine dose used at the start of the surgical procedure could diminish as time elapses. This would allow noxious stimuli from surgical area to reach the central nervous neurons. However, tonsillectomy is considered as a relatively short procedure in which, we believe, the diminishing effect of drug with time could not be of significance. In addition, the use of midazolam as a premedication could add to postoperative sedation and complicate scoring (Fakheri et al., 2010). On the other hand, the Hannallah pain score was originally described for use in unpremedicated patients (Hannallah et al., 1987), however we used modified Hannallah score which has been applied to premedicated patients in a number of previous studies (Dal et al., 2007; Pappas et al., 2003).

In conclusion, intravenous fentanyl (1 μg kg^-1) compared with intravenous ketamine (0.5 mg kg^-1) might provide extended time to first analgesic in children undergoing adenotonsillectomy. Interestingly, fentanyl and ketamine did not differ in post-operative vomiting.