|Year : 2020 | Volume
| Issue : 2 | Page : 135-141
Analgesic efficacy of intramuscular ketamine/ketorolac versus fentanyl/ketorolac for children undergoing bone marrow biopsy and aspiration
Enas A. Abd El Motlb
Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||10-Apr-2019|
|Date of Acceptance||30-Apr-2019|
|Date of Web Publication||27-Jun-2020|
Enas A. Abd El Motlb
Department of Anesthesia and surgical intensive care, Faculty of medicine, Mansoura University
Source of Support: None, Conflict of Interest: None
Background Bone marrow aspiration and/or biopsy (BMAB) in children with hematological disorders is a painful procedure, is required to be repeated at regular intervals, and is under researched.
Objective To compare intramuscular administration of fentanyl/ketorolac (F) versus ketamine/ketorolac (K) as an analgesic regimen in pediatric population undergoing BMAB under general anesthesia. A total of 80 children underwent BMAB under general anesthesia, who were randomized into two equal groups: group K received ketamine 0.5 mg/kg/ketorolac 1 mg/kg and group F received fentanyl 1.5 μg/kg/ketorolac 1 mg/kg. The study drugs are injected intramuscularly after induction of general anesthesia.
Result No statistically significant difference was found between groups regarding patient characteristics, duration of procedure or duration of anesthesia, pain score, time to first analgesic request, emergence-agitation score, or incidence of vomiting. There was a significant decrease in heart rate, systolic blood pressure, and respiratory rate in both groups at 15 and 20 min compared with basal values.
Conclusion Ketamine 0.5 mg/kg+ketorolac 1 mg/kg and fentanyl 1.5 μg/kg+ketorolac 1 mg/kg administered intramuscular are similarly effective analgesic regimens in pediatric population undergoing BMAB under general anesthesia without adverse effects.
Keywords: bone marrow biopsy, fentanyl, ketamine, ketorolac
|How to cite this article:|
El Motlb EA. Analgesic efficacy of intramuscular ketamine/ketorolac versus fentanyl/ketorolac for children undergoing bone marrow biopsy and aspiration. Res Opin Anesth Intensive Care 2020;7:135-41
|How to cite this URL:|
El Motlb EA. Analgesic efficacy of intramuscular ketamine/ketorolac versus fentanyl/ketorolac for children undergoing bone marrow biopsy and aspiration. Res Opin Anesth Intensive Care [serial online] 2020 [cited 2020 Sep 29];7:135-41. Available from: http://www.roaic.eg.net/text.asp?2020/7/2/135/287989
| Introduction|| |
Bone marrow aspiration and/or biopsy (BMAB) is the cornerstone in diagnosis of many malignant and benign hematological disorders . Despite the great revolution in medicine, limited effort has been put to develop methods for more pain control in patients undergoing this procedure ,. Most of the pain experienced during the procedure originates from the needle puncture to gain access into the marrow cavity, and aspiration of marrow fluid participates also to a large extent, one which is not controlled by local anesthetic .
Although most of the pain is experienced during the procedure of BMAB, there is some recollection afterward. The used analgesic drugs should have minimal adverse effects and can be given by other routes in case of poor venous access. Detailed studies assessing the efficacy of combination analgesic therapies on BMAB pain are limited.
Vanhelleputte et al.  reported a good response of pain arises from vacuum aspiration of bone marrow fluid to opioids. Fentanyl is a potent opioid narcotic, used effectively in combination with propofol for controlling pain during BMAB in pediatrics . However, another study in adults documented a similar pain score of placebo and sublingual single-agent fentanyl .
Ketamine is a noncompetitive antagonist at the N methyl-d-aspartate receptor. These receptors are involved in central sensitization to painful stimuli, and ‘wind up’, and this accounts for the analgesic properties of ketamine at subanesthetic doses . Ketofol, a combination of ketamine and propofol in varying concentrations, was used successfully in children undergoing BMAB for sedation analgesia .
One of NSAIDs is ketorolac. It is used effectively in pediatric patients for post-traumatic, intraoperative, and postoperative analgesia with low incidence of adverse effects .
This prospective, randomized, double-blind study aims to compare two analgesic regimens involving the intramuscular administration of fentanyl/ketorolac (F) versus ketamine/ketorolac (K).
We hypothesize that both regimen are comparable as an analgesic regimen in pediatrics undergoing BMAB under general anesthesia.
The primary outcome
Time to first analgesic request was the primary outcome.
Children’s Hospital of Eastern Ontario Pain Scale (CHEOP), hemodynamic changes during the procedure, emergence behavior score, and incidence of vomiting were the secondary outcomes.
| Patients and methods|| |
After approval of the Ethical Committee of Faculty of Medicine, Mansoura University (R.18.06.213), and registration in clinical trials.gov (NCT 03649334), this randomized double-blinded study was carried out in the Department of Pediatric oncology in cooperation with the Anesthesiology Department over two months. All collected data were used for the scientific purpose only. Parents of each child were enrolled in this study, and they had the complete right to withdraw at any time with no negative consequences on the medical service provided to his/her child.
A total of 80 children aged 2–7 years scheduled for bone marrow biopsy and aspiration with American Society of Anesthesiologists physical status II were included. Exclusion criteria included a known allergy to the studied drugs, any cardiac problems, any bleeding disorders or abnormal international normalized ratio, bleeding time, or platelet count, use of psychotropic drugs, and mental retardation.
Patients were randomly allocated into two groups of 40 patients each according to computer-generated randomization program. Each patient was assigned to K or F group, according to his or her group, followed by a number from 1 to 80 according to his or her order.
Patients belonging to group K received ketamine 0.5 mg/kg plus ketorolac 1 mg/kg intramuscularly, whereas those of group F received fentanyl 1.5 μg/kg plus ketorolac 1 mg/kg intramuscularly (all drugs were undiluted, and in the smallest possible equivalent volume). All study drugs were prepared by an anesthesiologist who was not involved in data collection. Drugs were packed in identical syringes and labeled with code numbers that refer to its content. An anesthesiologist, who was blinded to the given drug, recorded the parameters.
Anesthesia was induced using 8% sevoflurane in 100% oxygen. When adequate depth of anesthesia was reached, appropriate laryngeal mask airway (LMA) was placed, and the patient was left to breath spontaneously. Patients were maintained on 3–4% sevoflurane in 60% air and 40% oxygen. Standard monitoring was done by using ECG, noninvasive blood pressure, respiratory rate, pulse-oximeter, and capnograph. Then, the study drugs were injected intramuscularly in either quadriceps or deltoid muscle just before insertion of biopsy needle.
After the end of the procedure, sevoflurane was discontinued to 0% and re-placed with O2 100% (4 l/min). LMA was removed when the patient is awake, and then he or she was transferred to the recovery room.
- Heart rate and systolic blood pressure were recorded at the baseline (after the induction of anesthesia and before administration of the drugs) and then every 5 min till the end of the procedure.
- Postoperative pain was assessed by the CHEOP scale .
- The pain score was assessed on arrival to PACU and 5, 10, 15, 30, 45, and 60 min later. When the postoperative pain score exceeded four, rescue analgesia was given with a 20 mg/kg paracetamol suppository.
- The time to the first analgesic request and the total number of participants who required postoperative rescue analgesic during the 24-h period were recorded.
- Emergence behavior was evaluated every 5 min during the first 30 min using Aono’s four-point scale  as follows: (a) asleep, (b) awake but calm, (c) agitated but consolable, and (d) severely agitated and difficult to console. The highest-recorded value was documented during the PACU stay. For purposes of analysis, grades 1 and 2 of the scale were considered as no agitation and grades 3 and 4 were considered as the presence of agitation.
- Complications such as nausea, vomiting, or respiratory problems were recorded.
- All the variables studied were recorded by observer who was unaware of the assignment of the study group.
- Participants were considered ready for discharge when they met an Aldrete score of 9–10.
The sample size was based on the assumption that the pain score in intramuscular ketamine group will be similar to similar to those in previously published data . A total of 40 children would be required per group to detect a difference of 30% in CHEOP scale pain scores with a power of 90% (α=0.05, β=0.1).
Data were analyzed through statistical package for the social sciences (SPSS), Program version 22 (IBM Crop, Armonk, NY). Distribution of data was first tested by Shapiro test. Data were presented as mean and SD, median and range, or numbers and percentages. For normally distributed data, unpaired t-test was used to compare between mean values of both groups. For pain and sedation scores, Mann–Whitney U-test was used. Fisher’s exact test was used for comparison of categorical data. The P value up to 0.05 was considered as the level of statistical significance.
| Results|| |
A total of 80 children were enrolled in this study ([Figure 1]). The two groups of participants did not show statistically significant difference regarding patient characteristics, duration of procedure, or duration of anesthesia ([Table 1]). A significant decrease in heart rate, systolic blood pressure, and respiratory rate was recorded in both groups at 15 and 20 min compared with basal values ([Table 2]). There was no significant difference between groups regarding incidence of vomiting, time to first analgesic request ([Table 3]), or emergence-agitation (EA) score ([Table 4]). Only one (2.5%) case in group F and two (5%) cases in group K needed rescue analgesic in the form of paracetamol suppository, but there was no significant difference between groups regarding CHEOP scale ([Figure 2]).
|Table 1 Demographic data of the studied groups, duration of surgery, and satisfaction score|
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|Table 2 Hemodynamic variables, oxygen saturation, and respiratory rate of the studied groups|
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|Table 3 Incidence of emesis and time to first analgesic request of the studied groups|
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|Figure 2 Children’s Hospital of Eastern Ontario Pain Scale of studied groups. F group, fentanyl–ketorolac; K group, ketamine–ketorolac.|
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| Discussion|| |
This study aimed to compare the analgesic efficacy of two regimens that include dual-agents (fentanyl and ketorolac vs. ketamine and ketorolac). We documented that both regimens appear similarly effective with no adverse effects.
BMAB in children with hematological disorders is a painful procedure, is required to be repeated at regular intervals, and is under researched . As the problem of poor venous access and exhaustion of peripheral veins is common in this group of patients , so the intramuscular injection route may be a good alternative.
Vanhelleputte et al.  reported that younger age group and those exposed to lengthy procedures of bone marrow biopsy showed higher pain scores. The use of different analgesic agents working through different mechanisms provides a rational approach for controlling postoperative pain with reduction of the adverse effects .
Fentanyl as a potent narcotic analgesic has a role in controlling of postoperative pain especially in younger children who might awaken agitated after sevoflurane-based anesthesia . So, whatever the cause of immediate postoperative discomfort, either agitation, pain, or both, fentanyl has an effective role in this setting ,,. Intramuscular fentanyl has an onset of action within 7– 8 min and duration of action 1–2 h .
Ketorolac is a NSAID. Many studies have documented a potent postoperative analgesic effect of ketorolac in children with relatively low adverse effects. There is no published report about pharmacokinetics of intramuscular ketorolac, but pharmacokinetics of intravenous ketorolac is similar to adults. Intramuscular ketorolac has an onset of action of 20–25 min in adults. A t1/2 of 60-mg intramuscular ketorolac is ∼5.3 h .
Numerous clinical trials in adult and pediatric patients documented that synergism of ketorolac and opioid resulted in better pain relief with fewer incidences of opioid-related adverse effects such as respiratory depression, nausea, and vomiting .
The analgesic effect of combined intramuscular fentanyl and ketorolac was assessed by Stricker et al.  through a large retrospective cohort study in pediatric patients undergoing bilateral myringotomy. This combination achieved less postoperative pain score and less requirement of rescue analgesic compared with the use of either agent alone. The study did not record any significant delay in discharge following this dual-agent regimen even with higher doses of fentanyl. However, other authors reported that doses of fentanyl more than 2 μg/kg were associated with increased incidence of emesis without any analgesic benefit .
Results of this study were in accordance of this retrospective cohort. We used a combination of 1 mg/kg ketorolac plus 1.5 μg/kg fentanyl, which achieved stable intraoperative hemodynamics, low pain score, low incidence of postprocedure emesis, and only one case requested a rescue analgesic.
Ketamine is a safe intravenous anesthetic with potent analgesic effects that continue till a plasma concentration much less than the hypnotic concentration. The noncompetitive antagonism of N methyl-d-aspartate receptors by ketamine accounts for its analgesic effects .
Children have faster absorption after intramuscular injection than adult; this can be explained by muscle weakness and different regional blood flow. Elimination half-life of ketamine is ∼100 min in pediatrics .
Ketamine was used successfully as pain reliever after adenotonsillectomy in pediatric patients by many routes either intravenous, intramuscular, peritonsillar, or rectal administration .
Marcus et al.  compared 0.5 mg/kg ketamine intramuscular with 0.1 mg/kg morphine intramuscular for postoperative analgesia in pediatric patients undergoing tonsillectomy, and they documented that both drugs were comparable regarding rescue analgesic requirement and incidence of dreaming and vomiting. However, the authors noted that ketamine group showed a higher pain score only at 30 min after extubation, and then both groups became similar.
In this study, a combination of intramuscular ketorolac/ ketamine achieved a comparable pain scores with that of intramuscular ketorolac/ fentanyl, with no significant difference in time to first request of rescue analgesic. This can be attributed to concurrent use of ketorolac with onset of analgesic action 20 min after administration and duration of action extends beyond that of fentanyl or ketamine,
Many studies documented the efficacy of either ketamine ,, or fentanyl ,, on decreasing the incidence of EA following sevoflurane anesthesia. Abdelhalim and Alarfaj  studied EA in children undergoing tonsillectomy under inhaled sevoflurane general anesthesia. They reported that ketamine 0.5 mg/kg or fentanyl 1 µg/kg was similarly effective in reducing the incidence of EA without delay in PACU discharge.
This study did not record any postoperative hallucinations or nightmares in patients who received ketamine. This can be attributed to the low dose of ketamine (0.5 mg/kg) used in this study. This findings are in accordance with that of Dich-Nielsen et al.  who documented a low incidence of such adverse effects with doses of ketamine less than 1 mg/kg.
In this study, there was no significant difference between both groups regarding incidence of vomiting. Previous reports did not record vomiting as a problem on using the analgesic doses of ketamine ,,.
Although nor-ketamine, which is the active metabolite of ketamine, reaches its maximum plasma concentration after more than 1 h following intramuscular injection of ketamine, sedation was unlikely at the used dose .
The combination of ketamine and ketorolac used in this study seems a good analgesic cocktail for pediatrics with no adverse effects, so further studies are needed to try this cocktail in a larger number of patients and in other painful procedures in patients with pediatric cancer.
| Conclusion|| |
Ketamine 0.5 mg/kg/ketorolac 1 mg/kg and fentanyl 1.5 μg/kg/ketorolac 1 mg/kg administered intramuscular are similarly effective as analgesic regimens in pediatrics undergoing BMAB under general anesthesia without adverse effects.
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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]