|Year : 2015 | Volume
| Issue : 1 | Page : 43-49
Pre-emptive intravenous ketorolac analgesia does not alter the risk of bleeding after tonsillectomy in children
Waleed M Abdelmageed1, Hesham F Soliman MD 2, Mohamed A Fatthallah3
1 Department of Anesthesia, Faculty of Medicine, Ain-Shams University, Cairo, Egypt; King Abdulaziz Naval Base Hospital, Jubail, Kingdom of Saudi Arabia, Egypt
2 Department of Anesthesia, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
3 Department of ENT, Faculty of Medicine, Alazhar University, Demiatte, Egypt
|Date of Submission||12-Sep-2014|
|Date of Acceptance||10-Dec-2014|
|Date of Web Publication||25-Mar-2015|
Hesham F Soliman
Alnoor Specialist Hospital, PO Box 6251, Makkah 21955
Source of Support: None, Conflict of Interest: None
NSAIDs inhibit platelet aggregation and prolong bleeding time, which may augment the risk of postoperative bleeding. We investigated the effects of pre-emptive analgesia with intravenous ketorolac on intraoperative and postoperative hemorrhage with pediatric tonsillectomy.
Patients and Methods
A total of 147 children, aged 2-7 years, scheduled for tonsillectomy with or without adenoidectomy were randomized to receive a slow intravenous infusion of either ketorolac 1 mg/kg (ketorolac group, n = 74) or paracetamol 15 mg/kg (paracetamol group, n = 73) after induction of anesthesia. Noninvasive hemoglobin was assessed preoperatively and several times after surgery. Bleeding times were measured before and after surgery. Intraoperative blood loss was estimated. Intensity of postoperative pain was measured using an objective pain score. The incidence and severity of post-tonsillectomy bleeding were recorded until the seventh postoperative day.
There was no statistically significant difference in the estimated intraoperative blood loss between ketorolac and paracetamol groups (2.4 ± 1.1 vs. 2.1 ± 0.8 ml/kg, respectively; P = 0.061). Bleeding time increased between preoperative and postoperative assessments in both groups, with significant postoperative elevation in the ketorolac group (P = 0.001). Both groups were comparable regarding the perioperative noninvasive hemoglobin measurements. The overall incidence of post-tonsillectomy bleeding was 5.4%, with no statistically significant difference between ketorolac and paracetamol groups [5 (6.75%) vs. 3 (4.1%) patients, respectively; P = 0.705]. Postoperative objective pain score were significantly lower in the ketorolac group on postanesthesia care unit admission and at 1, 2, and 6 postoperative hours (P < 0.05).
Pre-emptive ketorolac infusion during pediatric tonsillectomy provides superior postoperative analgesia with no effect on intraoperative or postoperative clinical bleeding.
Keywords: children, post-tonsillectomy bleeding, pre-emptive ketorolac analgesia, tonsillectomy
|How to cite this article:|
Abdelmageed WM, Soliman HF, Fatthallah MA. Pre-emptive intravenous ketorolac analgesia does not alter the risk of bleeding after tonsillectomy in children. Ain-Shams J Anaesthesiol 2015;8:43-9
|How to cite this URL:|
Abdelmageed WM, Soliman HF, Fatthallah MA. Pre-emptive intravenous ketorolac analgesia does not alter the risk of bleeding after tonsillectomy in children. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2021 May 6];8:43-9. Available from: http://www.asja.eg.net/text.asp?2015/8/1/43/153937
| Introduction|| |
Tonsillectomy is a common surgical procedure in childhood and is associated with severe postoperative pain  . Management of post-tonsillectomy pain in pediatric patients remains a challenge, as adequate pain control is crucial to minimize crying (which increases the risk of postoperative bleeding), ensure adequate hydration, and resume regular oral intake as soon as possible after surgery  . Traditionally, pain relief has been provided by opioid analgesics; however, the risk for postoperative nausea and vomiting (PONV), deep sedation, and respiratory depression limit their use, especially when the care of the child is the parents' responsibility after day-case surgery  . Paracetamol is a nonopioid analgesic and antipyretic medication that acts at both the central and peripheral components of the pain pathway, and is devoid of the detrimental effects of opioids  . The oral and rectal formulations of this agent have long been used to provide postoperative analgesia in children; however, irregular bioavailability of the paracetamol suppository  and the temporary prohibition of oral intake limit their use in the treatment of immediate post-tonsillectomy pain. An i.v. form of paracetamol with more predictable pharmacodynamic properties compared with its other formulations has become available  . The safety and efficacy of i.v. paracetamol in children have been investigated in several publications , .
NSAIDs are effectively used for pain relief following tonsillectomy in children, with a lower risk for PONV  . They act by reducing prostaglandin synthesis through inhibition of cyclo-oxygenase (COX) enzymes I and II, with subsequent inhibition of platelet aggregation; thus, NSAIDs may be linked to increased incidence of post-tonsillectomy bleeding (PTB)  . Ketorolac is an intravenous NSAID that has been found to be as effective as morphine for relief of moderate to severe postoperative pain  . However, its effect on platelet aggregation with the anticipated increased risk for PTB is still a subject of debate among surgeons and anesthesiologists who have been unwilling to use NSAIDs for post-tonsillectomy analgesia. Therefore, the purpose of this study was to evaluate the effect of the pre-emptive i.v. ketorolac analgesia versus i.v. paracetamol on intraoperative and postoperative clinical bleeding in children undergoing tonsillectomy.
| Patients and Methods|| |
This prospective, randomized, double-blind, controlled study took place in King Abdulaziz Naval Base Hospital, Jubail, Kingdom of Saudi Arabia, from December 2011 to May 2013. The protocol was approved by the Hospital Ethics Committee and registered with the Australian New Zealand Clinical Trials Registry (http://www.ANZCTR.org.au/ACTRN12613001203741.aspx). Written informed consent was obtained from the guardian of each child. We studied 147 children of ASA physical status I, of both sexes, aged 3-7 years, scheduled for tonsillectomy with or without adenoidectomy. All patients enrolled in this study had normal blood counts, with normal coagulation profile [prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time (BT)]. Exclusion criteria included the use of paracetamol or NSAIDs within 6 h, or any other analgesic medication within 12 h before surgery, and a known allergy to any of the study drugs. Hemoglobin (Hb) level was measured in the laboratory as part of the routine preoperative preparation for tonsillectomy at the hospital. In addition, noninvasive hemoglobin level (SpHb) was assessed at the same time when blood was drawn from the child for the routine preoperative laboratory investigations, using multiwavelength pulse oximetry (MASIMO Radical-7 Signal Extraction Pulse Co-Oximeter; Masimo Corporation, Parker Irvine, California, USA).
No premedication was given, and all children had been fasting from solid food for 8 h before operation, with clear liquids permitted until 3 h before surgery. At the operating theatre, monitors to record intraoperative vital measurements [ECG, noninvasive systolic and diastolic blood pressure, and peripheral oxygen saturation (SpO 2 )] were attached. All children received standardized general anesthesia, started by inhalational induction with sevoflurane, and 60% nitrous oxide in oxygen, followed by placement of an i.v. cannula. Tracheal intubation was facilitated with 0.5 mg/kg atracurium. An oxygen and nitrous oxide mixture (40 : 60% respectively) with sevoflurane 1.5-2.5 volume% in 3 l/min fresh gas flow was used for maintenance of anesthesia, and mechanical ventilation was started with pressure-controlled ventilation at 15-20 cm H 2 O to keep the end-tidal carbon dioxide at 30-35 mmHg. Sevoflurane concentration was adjusted to maintain the child's heart rate and blood pressure within 30% of the preoperative values.
After induction of anesthesia and before surgical incision, the children were randomized, by using a computer generated random list, into one of two groups - the ketorolac group (group K) and the paracetamol group (group P) - to receive a slow i.v. infusion over 15 min of either ketorolac 1 mg/kg (ketorolac tromethamine; Hospira Inc., Lake Forest, Illinois, USA) (group K) or paracetamol 15 mg/kg (Perfalgan; UPSA, Bristol Myers Squibb, 304, avenue du Docteur Jean Bru 47000 AGEN, France) (group P). Both medications were diluted with 0.9% saline to a total volume of 40 ml. This volume was deducted from the total i.v. fluid administered (dextrose 5% in 0.45% saline, at a rate of 7 ml/kg/h). The anesthesia technician, who was not involved in the data collection, prepared identical infusions under aseptic conditions.
All operations were performed by one of three surgeons (two consultants and one senior registrar) following a standardized surgical technique, with bilateral dissection of the tonsils and bipolar diathermy for hemostasis. Intraoperative blood loss was estimated by recording the volume of blood in the calibrated suction canister and counting the blood-soaked gauzes that had been used for packing the bleeding sites after tonsil removal (one soaked gauze equalled 5 ml of blood). On completion of surgery, sevoflurane administration was stopped, and atropine 20 μg/kg with neostigmine 50 μg/kg was used to antagonize the residual neuromuscular block. The trachea was extubated after recovery of adequate spontaneous ventilation.
Following surgery, the patients were kept on oxygen supplementation through a face mask at 6 l/min and were transferred to the postanesthesia care unit (PACU) for continuous monitoring. SpHb measurement was assessed on arrival at the PACU and repeated at 12 and 24 h postoperatively, and another measurement was obtained on the seventh postoperative day (POD7). On admission to the PACU, BT test using Ivy's method was also performed by a laboratory technician who was blinded to the treatment group.
In the PACU and the surgical ward, pain intensity was assessed by an anesthesiologist blinded to the treatment group using an objective pain score (OPS) immediately upon PACU admission, followed by 30 min, 1, 2, 4, and 6 h postoperatively. The OPS used was a modification of the pain score described by Hannallah et al.  and took into account the child's blood pressure, crying, movement, and agitation, with each variable scoring 0-2 points (0 being the best and 2 being the worst). This scale had been previously used for pain scoring after pediatric tonsillectomy  . Rescue analgesic medication consisting of i.v. meperidine 0.25 mg/kg, to a total dose of 1 mg/kg, was administered if OPS was greater than 4 and the pain score was reassessed every 10 min until a score less than 4 was achieved. The time to administer the first rescue analgesics (defined as the period between tracheal extubation to the first administration of meperidine) and the total amount of meperidine given were recorded. If still in pain despite receiving the maximum dose of meperidine, the child was given a paracetamol suppository of 35 mg/kg and excluded from the study. At 3 h after surgery, the parent or a nurse started to offer the child oral liquids, and once he/she was able to tolerate oral fluids pain was treated every 6 h with oral paracetamol at 20 mg/kg every 6 h. The time to first oral intake was also recorded.
The incidence of postoperative vomiting was documented throughout the first 24 h after surgery. If a child had two or more episodes of vomiting, ondansetron 50 μg/kg i.v. (maximum 4 mg) was used as a rescue antiemetic. The incidence of PTB was recorded over a 7-day period. Bleeding severity was assessed and classified as mild (mild oozing of blood or spitting of blood-tinged saliva reported by the parents), moderate (active bleeding that required hospital admission for conservative treatment), or severe (persistent bleeding; the child has to be taken to the operative room for bipolar diathermy and/or suture ligature under general anesthesia). The children were discharged from hospital on the second postoperative day and were followed up for 7 days postoperatively. The parents were instructed to contact the Emergency Department in case of postoperative bleeding, and PTB was defined to them as spitting or oozing of blood from the mouth. At POD7, the patients arrived at the outpatient department, where they were examined and the last SpHb measurement was taken. Any other postoperative adverse effects were recorded.
The required sample size was calculated using G*Power© software, version 3.1.0 (Institut fόr Experimentelle Psychologie, Heinrich Heine Universitδt, Dόsseldorf, Germany).
The primary outcome measures were the difference between the two groups as regards the pain scores and Hb level. It was estimated that a sample of 70 patients per group would have a power of 82% to detect a medium effect size (d) of 0.5 as regards the outcome measures using a two-sided U-test and setting the type I error at 0.05.
Data were analyzed on a personal computer using the IBM© SPSS© Statistics, version 21 (IBM© Corp., Armonk, New York, USA). The Shapiro - Wilk test was used to test the normality of numerical data distribution.
Normally distributed data were presented as mean (SD) and the unpaired t-test was used for intergroup comparisons. Skewed data were presented as median (interquartile range) and the Mann-Whitney U-test was used to compare between-group differences. For comparison of paired skewed data, the Wilcoxon signed rank test was used. Repeated-measures analysis of variance was used to compare differences among serial measures.
Categorical data were presented as ratio or number (percentage) and differences between the two groups were compared using the χ2 -test or Fisher's exact test, when appropriate.
P values less than 0.05 were considered statistically significant.
| Results|| |
A total of 147 children completed the study. The flowchart of patients throughout the study is presented in [Figure 1]. The groups were comparable for patient characteristics and duration of surgery and anesthesia. There was no statistically significant difference in the estimated intraoperative blood loss between the two groups (P = 0.061) ([Table 1]). The mean heart rate, blood pressure, and SpO2 values throughout the study period were statistically similar in the two groups. Perioperative BTs are shown in [Table 2]. The values increased between preoperative and postoperative assessments in both groups, with statistically significant elevation in the ketorolac group (P = 0.001). However, all postoperative BT values were still within the normal range in the two groups.
Analysis of the postoperative pain scores revealed significantly lower OPS in the ketorolac group on admission to the PACU and at 1, 2, and 6 h after surgery (P < 0.05) ([Table 3]). The cumulative postoperative meperidine consumption was statistically higher in the paracetamol group than in the ketorolac group (7.5 ± 3.1 vs. 6.4 ± 2.9 mg, respectively; P = 0.012), with significantly shorter time to first analgesic administration compared with group K (28 ± 12.1 vs. 32.4 ± 8.7 min, respectively; P = 0.012). The ketorolac-treated patients tolerated oral fluids faster than did those receiving paracetamol with a significantly lower mean time to first oral intake (4.9 ± 1.5 vs. 5.6 ± 2.0 h, respectively; P = 0.018).
There was no significant difference between preoperative laboratory Hb level and SpHb obtained at the same preoperative time (P > 0.05) in the two groups. There were no statistically significant differences in the perioperative SpHb assessments between the two groups until POD7 ([Table 4] [Table 5] [Table 6] and [Figure 2]). The overall incidence of PTB in this study was 5.4%. In the ketorolac group, 5 (6.8%) patients suffered from PTB compared with 3 (4.1%) patients in paracetamol group, with no statistically significant difference between the two groups (P = 0.705). In the ketorolac group, one child had persistent bleeding on the day of surgery and returned to the operative room for hemostasis under general anesthesia; the other four patients developed mild secondary hemorrhage on POD5 to POD7, which required no treatment. Three patients receiving paracetamol developed PTB; one had primary hemorrhage that necessitated surgical intervention, and two others experienced moderate bleeding that occurred between POD4 and POD7 and needed conservative management. All eight patients bled only once and none of them needed allogeneic blood transfusion.
|Figure 2: Change in perioperative noninvasive hemoglobin in the two study groups. T1, baseline; T2, at PACU; T3, at 24 h after surgery; T4, at 7 days after surgery. Bars represent mean. Error bars represent 95% CI. CI, confi dence interval; PACU, postanesthesia care unit; SpHb, noninvasive hemogl obin.|
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|Table 5 Repeated-measures analysis of variance for change in perioperative noninvasive hemoglobin level|
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|Table 6 Pairwise comparisons of noninvasive hemoglobin level in the two study groups|
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The overall incidence of postoperative emesis was 24.5%. Postoperative vomiting occurred in 16 (21.6%) patients in the ketorolac group versus 20 (27.4%) patients in the paracetamol group, with no statistically significant difference between the two groups (P = 0.448), in addition to a statistically similar number of patients who were given ondansetron for multiple emesis episodes [9 (12.2%) vs. 14 (19.2%) patients, respectively; P = 0.265].
| Discussion|| |
In this study, the effect of pre-emptive intraoperative ketorolac infusion of 1 mg/kg on intraoperative and postoperative bleeding in pediatric tonsillectomy was evaluated and compared with 15 mg/kg i.v. paracetamol infusion, and no significant statistical difference was recorded between the groups regarding the estimated intraoperative blood loss, perioperative SpHb values, or frequency and severity of PTB. Moreover, our results revealed that patients treated with ketorolac had enhanced postoperative analgesia with lower consumption of rescue analgesics and faster resumption of oral intake.
Despite the fact that all NSAIDs have antiplatelet effect and prolong the BT, published data regarding their effect on intraoperative and postoperative bleeding during tonsillectomy have been conflicting ,,, . It should be noted that most anesthesiologists are aware that the skill and experience of the surgeon, together with the operative technique used, are important factors to be considered whenever PTB is a concern. In addition, the reversible effect of ketorolac on platelet function is short-lived, and limited to the time the drug is present in high blood concentration. Because of the short half-life of ketorolac (~5-6 h), platelet function is expected to return to normal within 24 h of a single dose administration of the drug (after 5 to 6 drug half-lives)  , and any bleeding episode that could be related to a single intraoperative dose of ketorolac would have to occur in the immediate postoperative period, or within the first 24 h. Therefore, the episodes of secondary hemorrhage that occurred in the patients treated with ketorolac in the current study between POD5 and POD7 might not be due to a single intraoperative dose of ketorolac as they occurred at a time well after the drug had been eliminated from the body. Those bleeding events might be caused by dehiscence of the eschar occurring several days after surgery.
BT is one of the first-line screening tests of platelet function with a wide normal range of 2-7 min  . This test is subjected to a lot of confounding factors, including the type of technique and the skill and experience of the technician performing it. A normal BT does not imply normal hemostasis and the result of the test has been shown not to correlate with bleeding at other sites  . In the current study, the postoperative BT tests were significantly prolonged in the patients treated with ketorolac versus those receiving paracetamol, although all postoperative BT values in the groups were still within the normal range. Nevertheless, prolongation of BT in the patients receiving ketorolac in this study, which probably indicates affection of platelet aggregation, was not reflected on the intraoperative clinical bleeding and was not associated with hemodynamic compromise or increased risk for postoperative bleeding events. The agreement of SpHb measurements with laboratory Hb levels was verified to ensure the accuracy and precision of the pulse co-oximeter in offering an accurate, real-time, and noninvasive assessment of Hb. The ease in obtaining perioperative Hb values noninvasively enabled us to perform frequent postoperative assessments in this study to determine any decrease in Hb level that could be related to intraoperative or postoperative hemorrhage, to detect clinical bleeding based on objective laboratory values.
The use of i.v. paracetamol for postoperative pain control is gradually increasing, and several studies in the literature have demonstrated the analgesic and opioid-sparing effect of this agent  . However, when paracetamol is used alone for post-tonsillectomy pain, it often provides insufficient analgesia  . In the present study, analysis of OPS revealed significantly higher values in children receiving paracetamol following surgery, with shorter time to first analgesic administration and significant increase in the postoperative meperidine consumption compared with the other group of patients. We therefore share the view of other authors , that paracetamol, although safe, is not effective as a sole analgesic in pediatric tonsillectomy.
Further, the use of ketorolac in this study was associated with shorter time to first oral intake. A delay in starting and tolerating postoperative oral fluids, as well as inadequate oral feeding because of pain and vomiting, can prolong the hospital stay and increase the risk of dehydration in the postoperative period. NSAIDs decrease the levels of inflammatory mediators generated locally at the site of tissue disruption through direct inhibition of the COX enzyme activity, thus blocking the conversion of arachidonic acid to prostaglandins and leukotriene. These mediators, in addition to initiating the inflammatory cascade, sensitize the pain nerve endings to various noxious stimuli  . Therefore, by decreasing the inflammatory response and providing adequate postoperative analgesia, ketorolac can play a role in the process of re-establishment of the normal physiological mechanisms of swallowing. In contrast, paracetamol has been shown to have a weak anti-inflammatory action  .
PONV are common side effects after tonsillectomy. As our results showed, the overall incidence of postoperative vomiting in this study was lower than that reported in several previous studies , . This could be partly attributed to the absence of opioids in our anesthetic regimen; besides, a possible central antiemetic effect of both drugs used in this study could not be ruled out. There is a lot of evidence that NSAIDs have a central mechanism of action that augments the peripheral mechanism. This effect may be the result of interference with the formation of prostaglandins or by blocking the release of serotonin (5-hydroxytryptamine; 5-HT) within the central nervous system  . A similar central effect of paracetamol had been described  .
We believe that, despite the availability of various therapeutic approaches to treat post-tonsillectomy pain in children, NSAIDs remain an attractive choice, although the perioperative use of COX-2-selective NSAIDs had been shown to provide similar analgesic effects to conventional NSAIDs when used for acute pain, with minimal side effects. However, the use of NSAIDs selective for COX-2 for pain management in the pediatric population is rare, and the previously raised controversies regarding the involvement of these drugs in ischemic heart disease in adults have limited their use  .
| Conclusion|| |
In conclusion, we found that the pre-emptive use of a single dose of i.v. ketorolac during pediatric tonsillectomy provided superior postoperative analgesia and was not associated with increased incidence of intraoperative or postoperative bleeding.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]