Comparison of ketamine and fentanyl in pediatric tonsillectomy: Impact on pain control and emergence delirium

Abstract

Background:

Effective pain control following tonsillectomy in children remains challenging. Traditionally, opioids such as fentanyl have been used for pain control, but its adverse effect profile makes it a less ideal option for children, particularly those with obstructive sleep apnea. The curent study investigates the perioperative effects of ketamine on postoperative pain and delirium in children.

Methods:

In this prospective trials, patients 3–8 years of age were randomized to receive either fentanyl or ketamine for pain management. Pain was assessed using the face, legs, activity, crying, consolability (FLACC) scale, and emergence delirium was evaluated with the pediatric anesthesia emergence delirium (PAED) scale. Postoperative outcomes, including recovery time and analgesic requirements, were also recorded.

Results:

The study cohort include 59 pediatric patients. The ketamine group exhibited higher pain scores in the first 15 min post-surgery compared to the fentanyl group. However, pain scores between the two groups were comparable by 30 min. The incidence of emergence delirium was higher with ketamine than fentanul (19.35% versus 3.57%). The groups had similar recovery and post-anesthesia care unit (PACU) times, as well as supplemental analgesia requirements.

Conclusion:

Although ketamine demonstrated delayed pain relief and a higher incidence of emergence delirium, it showed potential as part of a multimodal analgesic approach. The combination of fentanyl and ketamine may optimize pain management in pediatric tonsillectomy, reducing opioid use while minimizing adverse effects. Further studies are needed to refine dosing strategies and assess long-term outcomes.

Introduction

Tonsillectomy is the common pediatric surgical procedure, but postoperative pain management remains a significant challenge. Effective pain control is crucial not only for patient comfort, but also to facilitate early discharge and reduce healthcare costs. Traditionally, opioids such as fentanyl have been the mainstay for post-tonsillectomy pain control, but their use is often limited by adverse effects such as respiratory depression, particularly concerning in children with obstructive sleep apnea (OSA).[1] In response to these challenges, there is a growing interest in opioid-sparing techniques that utilize multimodal analgesia to minimize opioid consumption and its associated risks. Recent studies have explored the efficacy of non-opioid analgesics, such as ketamine, which target different analgesic pathways and offer effective pain relief without the respiratory depression associated with opioids.[2] Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, provides analgesic effects and modulates central sensitization, making it a valuable component of multimodal regimens. These regimens have demonstrated reduced postoperative pain scores and opioid requirements in pediatric patients undergoing tonsillectomy.[3]

The use of an opioid-sparing technique, combining ketamine with other non-opioid medications, may offer a safer and more effective approach to pain management, while minimizing the risk of emergence agitation and respiratory depression. The current study compares the efficacy of ketamine versus fentanyl for postoperative pain control in pediatric patients following tonsillectomy, focusing on analgesic effectiveness, emergence characteristics, and potential adverse effects.

Methods

This study was approved by the Ethical Committee of Istanbul Medipol University (E-10840098-772.02-4354) and registered at ClinicalTrials.Gov (NCT06630364). It was a prospective, randomized clinical trial designed to evaluate the efficacy of ketamine versus fentanyl for postoperative pain control in pediatric patients undergoing tonsil-adenoidectomy. The study enrolled children, 3 to 8 years of age, classified as American Society of Anesthesiologists (ASA) physical status I–III. Exclusion criteria included ASA status ≥4, known hypersensitivity or allergy to acetaminophen, ketamine, or fentanyl, chronic opioid therapy, renal or hepatic disease, and obesity (BMI ≥99^th percentile for age).

All participants received premedication with oral midazolam (0.5 mg/kg to a maximum dose of 20 mg), administered approximately 30 minutes prior to induction. Anesthesia was induced with sevoflurane in nitrous oxide and oxygen, followed by the placement of a peripheral intravenous catheter. Participants were randomly assigned to one of two groups: Group I received propofol (1–1.5 mg/kg) and fentanyl (2 µg/kg) and group II received propofol (1–1.5 mg/kg) and ketamine (0.5 mg/kg). Endotracheal intubation was performed without the use of a neuromuscular blocking agent, and maintenance anesthesia was achieved with sevoflurane in a mixture of oxygen and air, titrated to maintain heart rate and blood pressure within 20% of baseline values. All patients received intravenous acetaminophen (15 mg/kg) perioperatively, along with ondansetron (0.15 mg/kg) and dexamethasone (0.25 mg/kg) for prevention of postoperative nausea and vomiting prophylaxis. Intraoperative fluid management consisted of 10–20 mL/kg of normal saline.

Postoperatively, the patients were transferred to the recovery room, where pain was assessed using the face, legs, activity, crying, consolability (FLACC) scale every 15 min until discharge. A minimum Aldrete score of eight was required for discharge. Patients with a pain score >4 were administered intravenous meperidine (0.5 mg/kg) as needed and the total postoperative meperidine dose was recorded. Emergence delirium was evaluated using the pediatric anesthesia emergence delirium (PAED) scale every 30 min in the recovery room. Discharge criteria from the post-anesthesia care unit (PACU) included stable vital signs, adequate pain control, and the ability to maintain oral intake. After discharge, patients were instructed to take weight-based oral acetaminophen every 6 hours as needed for pain.

Data collection included demographic variables (age, weight, and height), intraoperative parameters, and postoperative outcomes. The following parameters were evaluated:

1. Duration of surgery (minutes): The time from the first surgical incision to the completion of the surgical procedure.

2. Recovery time (minutes): The time from the end of anesthesia to the patient regaining full consciousness and meeting discharge criteria from the PACU.

3. PACU time (minutes): The time from the end of surgery to the patient’s discharge from the PACU to the service room.

4. Postoperative outcomes included pain scores using the FLACC scale and delirium scores using the PAED scale.

5. Hemodynamic parameters (heart rate, blood pressure, and oxygen saturation) assessed at multiple time points (0, 15, 30, and 60 minutes postoperatively)

Categorical variables were summarized as frequencies and percentages and analyzed between study arms using Chi-Square tests, while continuous variables were presented as mean ± standard deviation and compared via the Wilcoxon-Mann-Whitney test. Statistical significance was set at P less than 0.05 without adjustment for multiple comparisons. Analyses were conducted using SAS® Version 9.4 (Cary, NC, USA).

Results

The study cohort included 59 patients, randomized to receive either fentanyl (n = 28) or ketamine (n = 31). The demographic and baseline characteristics were comparable between groups, with no significant differences in age (fentanyl: 5.6 ± 1.57 years vs. ketamine: 5.3 ± 1.55 years, P = 0.36), weight (fentanyl: 21.9 ± 5.90 kg vs. ketamine: 21.6 ± 7.41 kg, P = 0.44), and height (fentanyl: 116.5 ± 10.40 cm vs. ketamine: 114.5 ± 14.37 cm, P = 0.22) [Table 1].

Table 1.

Distribution of continuous variables by study groups

Demographic parameter		Number	Minimum	Q1	Median	Q3	Maximum	Mean±SD
Age (years)	All	59	3.0	4.0	5.0	7.0	9.0	5.5±1.56
	Fentanyl	28	3.0	4.0	6.0	7.0	8.0	5.6±1.57
	Ketamine	31	3.0	4.0	5.0	7.0	9.0	5.3±1.55
Weight (kilograms)	All	59	12.0	16.0	21.0	24.0	41.0	21.7±6.68
	Fentanyl	28	12.0	18.0	21.0	24.5	37.0	21.9±5.90
	Ketamine	31	14.0	16.0	21.0	23.0	41.0	21.6±7.41
Height (centimeters)	All	53	95.0	106.0	112.0	124.0	150.0	115.4±12.80
	Fentanyl	22	96.0	110.0	117.0	126.0	133.0	116.5±10.40
	Ketamine	31	95.0	105.0	110.0	123.0	150.0	114.5±14.37

Comorbid conditions

Although not statistically significant due to random allocation, the ketamine group showed a higher prevalence of comorbid conditions (87.10%) compared to the fentanyl group (87.10% versus 67.86%, P = 0.075). Oxygen saturation levels and sevoflurane requirements remained stable and comparable between the study arms throughout the procedure, with no significant differences observed at any time point. The recovery time was comparable between the groups (fentanyl: 6.5 ± 3.82 min vs. ketamine: 8.0 ± 6.43 min, P = 0.28), with no significant differences observed in surgery duration (fentanyl: 50.3 ± 21.66 min vs. ketamine: 47.1 ± 25.56 min, P = 0.38) or PACU time (fentanyl: 20.7 ± 2.62 min vs. ketamine: 21.5 ± 6.08 min, P = 0.99). These data are outlined in Table 2.

Table 2.

Distribution of outcome variables

Outcome variable		Number	Minimum	Q1	Median	Q3	Maximum	Mean±SD
Recovery time (minutes)	All	57	3.0	5.0	5.0	10.0	35.0	8.0±6.43
	Fentanyl	27	3.0	5.0	5.0	7.0	20.0	6.5±3.82
	Ketamine	30	3.0	5.0	5.0	10.0	35.0	9.3±7.94
Duration of surgery (minutes)	All	59	3.0	30.0	45.0	60.0	105.0	48.6±23.64
	Fentanyl	28	15.0	35.0	52.5	60.0	102.0	50.3±21.66
	Ketamine	31	3.0	30.0	40.0	55.0	105.0	47.1±25.56
PACU time (minutes)	All	59	15.0	20.0	20.0	20.0	50.0	21.1±4.74
	Fentanyl	28	20.0	20.0	20.0	20.0	30.0	20.7±2.62
	Ketamine	31	15.0	20.0	20.0	20.0	50.0	21.5±6.08

PACU - post-anesthesia care unit

Pain and delirium scores

PACU-FLACC pain scores were significantly higher in the ketamine group at both 0 min (ketamine: 2.9 ± 2.26 vs. fentanyl: 1.6 ± 2.50, P = 0.012) and 15 min (ketamine: 2.4 ± 1.50 vs. fentanyl: 1.2 ± 1.85, P = 0.0032). By 30 min, pain scores were comparable between the groups (ketamine: 1.0 ± 1.26 vs. fentanyl: 1.4 ± 1.67, P = 0.78) [Figure 1]. Regarding the need for additional analgesics, a total of 26 of 59 patients (44.07%) required supplemental analgesia including 42.86% in the fentanyl group (12 of 28) and 45.16% in the ketamine group (14 of 31, P = 0.86). There was a higher incidence of delirium at 30 min postoperatively showed, with higher rates in the ketamine group (19.35%) compared to the fentanyl group (3.57%, P = 0.061) [Figure 2].

Figure 1.

Differences in pain scores over time between the fentanyl and the ketamine groups. FLACC scores at 0, 15, and 30 min in the post-anesthesia care unit. FLACC - Face, legs, activity, crying, consolability

Figure 2.

Delirium scores over time at 0, 30, and 60 min postoperatively for both groups

Hemodynamic parameters

The initial heart rates tended to be higher in the fentanyl group (123.5 ± 17.11 beats/minute vs. 115.3 ± 18.27 beats/minute, P = 0.067) [Figure 3]. Systolic blood pressure at 15 min showed a trend toward higher values in the ketamine group (103.9 ± 13.20 mmHg vs. 97.8 ± 10.49 mmHg, P = 0.074) [Figure 4]. Other hemodynamic parameters, including diastolic blood pressure and mean arterial pressure, remained comparable between groups throughout the observation period [Figures 5 and 6].

Figure 3.

Heart rate changes over time at 0, 15, and 30 min postoperatively for both groups

Figure 4.

Systolic blood pressure over time at 0, 15, and 30 min postoperatively for both groups

Figure 5.

Diastolic blood pressure over time at 0, 15, and 30 min postoperatively for both groups

Figure 6.

Mean arterial pressure over time at 0, 15, and 30 min postoperatively for both groups

Discussion

This study explores the perioperative effects of fentanyl and ketamine on postoperative pain and emergence delirium (EA) in children undergoing tonsillectomy, with a focus on reducing opioid use through multimodal pain management. We found that EA was more common in the ketamine group (19.35%) compared to the fentanyl group (3.57%). This effect may have been related to the ketamine itself or a result of inadequate pain control early in the recovery phase, which can worsen agitation. Children in the ketamine group also had higher PACU-FLACC scores in the first 15 min after surgery, suggesting that the pain-relieving effects of ketamine may be less than those seen with fentanyl of may take longer to set in, contributing to the increased agitation. These findings highlight the importance of early assessment of pain and delirium, as well as managing pain effectively immediately after surgery to help reduce EA and improve recovery.

To better distinguish between pain-related and non-pain-related agitation, future research should incorporate combined pain and agitation assessment abilities, such as FLACC and PAED scores. While this study relied on FLACC scores to assess pain, this approach does not fully capture the behavioral components of EA. Including PAED scores would provide a more comprehensive evaluation and address a potential limitation of the methodology in our current study. Standardizing these abilities across studies would enhance consistency and comparability, as differences in assessment timing and methods may explain discrepancies in EA rates reported in previous research.[4]

While fentanyl’s ability to reduce EA strengthens its utility in pediatric tonsillectomy patients, future studies should further explore its potential impact on postoperative respiratory function and postoperative respiratory adverse effects especially in children with OSA. The use of various adjunctive agents including acetaminophen, dexmedetomidine, non-steroidal anti-inflammatory agents, and ketamine have been suggested as means to decrease or eliminate the need for opioids following tonsillectomy. It may be that adjustments in dosing or administration timing of opioids can mitigate their potential impact on postoperative outcomes in patients with OSA. The somewhat delayed analgesic effect of ketamine, as reflected in higher early PACU-FLACC scores that equalized by 30 min, suggest its potential role in multimodal analgesia. It may be that the two agents can be combined to take advantage of the rapid onset of fentanyl and the more prolonged and potential opioid-sparing effects of ketamine throughout the recovery period. This aligns with previous findings suggesting that a multimodal regimen including ketamine and dexmedetomidine provided effective pain control without the need for opioids.[2]

Our study found no significant differences in postoperative nausea and vomiting (PONV) between the ketamine and fentanyl groups, consistent with previous findings.[5] This provides additional support that ketamine, whether administered intravenously or via peritonsillar infiltration, does not increase the risk of PONV, making it a viable option in multimodal pain management. Earlier studies reporting differing PONV rates between ketamine and fentanyl groups may have been due to variations in intraoperative antiemetic protocols, adjunctive agents, and study methodologies.[4] These findings highlight the importance of standardized antiemetic regimens to ensure reliable comparisons of opioid-sparing techniques.

The variability in age ranges and pain assessment abilities across studies further complicates cross-study comparisons. While our reliance on FLACC scores aligns with common practices, adopting combined modalities such as FLACC and PAED scores could improve the interpretability of findings. Future research should also consider age-stratified analyses to address differences in pain perception and reporting across pediatric age groups. Our current study evaluated patients only during the initial in-hospital postoperative period. Examining longer-term outcomes would provide valuable insights into the sustained effects of different analgesic strategies and their impact on recovery. Lee et al. reported that ketamine reduced EA in pediatric tonsillectomy patients under sevoflurane anesthesia, which contrasts with our findings of higher EA rates in the ketamine group.[6] This discrepancy may be attributed to differences in the timing and dosage of ketamine administration. Nevertheless, their results reinforce the importance of managing early postoperative pain to prevent EA and highlight the potential benefits of combining ketamine and fentanyl. This aligns with our proposal to explore multimodal analgesia strategies, leveraging the complementary effects of these agents to optimize pain control while minimizing opioid use.

In conclusion, the current study further supports the critical relationship between pain control and EA, emphasizing the need for tailored strategies to optimize postoperative outcomes, especially in the immediate postoperative period. There was a modest improvement in pain scores in the immediate postoperative period with fentanyl with an increase in EA with ketamine. The latter may have been related to pain or a direct effect of ketamine. These differences were likely of limited clinical significance and did not impact postoperative outcomes including discharge times. Future research should focus on standardizing pain and agitation assessment abilities, investigating optimal drug administration timing, determining optimal drug regimens or combinations, conducting age-stratified analyses, and examining longer-term pain outcomes. Future work is needed to further define the efficacy of potential opioid-sparing techniques in various pediatric surgical procedures, emphasizing the need for larger studies to validate these findings across diverse surgical populations. These steps will address current gaps in evidence and provide more definitive guidance for pediatric tonsillectomy pain management protocols

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.