|Year : 2018 | Volume
| Issue : 3 | Page : 198-204
Ketamine–propofol versus ketamine–midazolam for procedural sedation and analgesia in children with hematological malignancies: a randomized, open-labeled, cross-over trial
Oyebola O Adekola1, Edamisan O Temiye2, Gabriel K Asiyanbi3, Nurudeen O Akanmu1, Ibironke Desalu1
1 Department of Anesthesia, College of Medicine, Lagos University Teaching Hospital, University of Lagos, Lagos, Nigeria
2 Hematology and Oncology Unit, Department of Pediatric, College of Medicine, Lagos University Teaching Hospital, University of Lagos, Lagos, Nigeria
3 Department of Anesthesia, Lagos University Teaching Hospital, University of Lagos, Lagos, Nigeria
|Date of Submission||16-May-2017|
|Date of Acceptance||27-Oct-2017|
|Date of Web Publication||31-Aug-2018|
Oyebola O Adekola
Department of Anaesthesia, College of Medicine, Lagos University Teaching Hospital, University of Lagos, PMB 12003 Surulere, Lagos
Source of Support: None, Conflict of Interest: None
Background The use of procedural sedation and analgesia for painful procedures in children with hematological malignancies has become a standard practice in recent time. We compared the occurrence of hypoxia, apnea, and pain between ketamine–propofol and ketamine–midazolam combination.
Patients and methods This randomized, open-labeled cross-over study was conducted in 60 children aged 1–15 years scheduled for bone marrow aspiration and, or intrathecal chemotherapy. They were divided into two groups of 30 to receive either ketamine–propofol or ketamine–midazolam. Sedation was performed by trained anesthetists according to the study protocol. Data were analyzed with independent t-test, χ2-test and Fisher’s exact test. P value 0.05 or less was considered significant.
Results A total of 120 procedures were performed. One (1.7%) patient in each group had hypoxia, (P=0.8). The oxygen saturation decreased to 83 and 88% in ketamine–propofol and ketamine–midazolam groups, respectively. This was accompanied by bradycardia with a heart rate of 56 and 58 beats/min, respectively. Both events responded to oxygen therapy. There was no episode of apnea, and all maintained spontaneous respiration. The number of patients with a pain score of at least 5 during the procedure was comparable; ketamine–propofol group [6 (10%)] versus ketamine–midazolam group [4 (6.7%)] (P=0.4). Hallucinations were more common in the ketamine–propofol group [4(6.7%)] than the ketamine–midazolam group [0 (0%)] (P=0.05).
Conclusion The occurrence of hypoxia, apnea, and pain was comparable following the administration of ketamine–propofol and ketamine–midazolam combination.
Keywords: apnea, hematological malignancies, hypoxia, ketamine–midazolam, ketamine–propofol, pain, procedural sedation
|How to cite this article:|
Adekola OO, Temiye EO, Asiyanbi GK, Akanmu NO, Desalu I. Ketamine–propofol versus ketamine–midazolam for procedural sedation and analgesia in children with hematological malignancies: a randomized, open-labeled, cross-over trial. Res Opin Anesth Intensive Care 2018;5:198-204
|How to cite this URL:|
Adekola OO, Temiye EO, Asiyanbi GK, Akanmu NO, Desalu I. Ketamine–propofol versus ketamine–midazolam for procedural sedation and analgesia in children with hematological malignancies: a randomized, open-labeled, cross-over trial. Res Opin Anesth Intensive Care [serial online] 2018 [cited 2018 Nov 19];5:198-204. Available from: http://www.roaic.eg.net/text.asp?2018/5/3/198/240269
| Introduction|| |
Bone marrow aspiration, biopsy, lumbar puncture, and intrathecal chemotherapy are short, frequent, and painful procedures performed in the management of hematological malignancies . The inadequate relief of pain and distress affects the experience of the children and their parents, and adversely impact the success of such procedure . The treatment for hematological malignancies at our institution requires about 15–30 painful procedures for diagnosis and intervention depending on the type of leukemia.
The administration of benzodiazepines and propofol is limited by their lack of analgesic effect; therefore, they are often used in combination with opioids. The addition of opioids can result in oversedation, respiratory distress, nausea, and vomiting . Ketamine has been suggested as an alternative because it provides good analgesia even at subanesthetic doses, it stimulates the cardiovascular system, maintains airway reflexes, and spontaneous respiration when compared with opioids . A combination of ketamine and propofol mixed in the same syringe (ketofol) is gaining ground as the agent of choice for procedural sedation and analgesia (PSA) in hematological oncology interventions ,,. The reported advantages of ketofol include analgesia, decrease in incidences of hypotension, bradycardia, and respiratory depression ,,. There have been reports of respiratory depression, oxygen desaturation, and delayed recovery following large dose midazolam during PSA . However, the combination of ketamine and midazolam provides faster analgesia, amnesia, and fewer side effects . We compared the occurrence of hypoxia, apnea, and pain following the administration of ketamine–propofol and ketamine–midazolam combinations during PSA in the pediatric oncology ward.
| Patients and methods|| |
Our institution is a University Teaching Hospital with a 770-bed tertiary-care institution with a special pediatric oncology service for children with cancer and other life-threatening diseases. The facility has a children’s emergency unit, oncology outpatient clinics and 20 inpatient beds.
This prospective cross-over open-labeled study included patients aged 1–15 years undergoing treatment for acute leukemia or lymphoma. They were expected to undergo at least two combined unilateral bone marrow aspiration and, or lumbar puncture procedure for intrathecal chemotherapy. Eligible patients were American Society of Anesthesiologist (ASA) I and II patients with a platelet count of more than 50 000/mm3 .
Exclusion criteria included previous allergic reaction to ketamine, midazolam, propofol. Children with hypotension, increased intracranial or intraocular pressure or those who have been involved in another study in the last 30 days were excluded. In addition, those with symptomatic thrombocytopenia, platelet count less than 50 000/mm3 , age less than 1 year or over 15 years, and ASA III–V children were exempted.
The study was approved by the Human Research Ethic Committee of our institution, and written informed consent was obtained from parents or guardians, and assent was obtained from the patients, as appropriate. The trial was registered with Pan African Clinical Trial Registry PACTR201403000762218.
The study was in two phases; at the end of the first phase, the children were switched to the other agent. In phase one of the study, children were randomly selected into two groups of 30 through the use of computer-generated random numbers; ketamine–propofol group received ketofol 0.5 ml/kg [1 : 1 mixture of propofol (10 mg/ml) and ketamine (10 mg/ml)], and ketamine–midazolam group received a mixture of midazolam (0.05 mg/kg) and ketamine (1.5 mg/kg). Each phase consists of one session of sedation procedure, at 3 weeks interval per patient. In phase two of the study, the patients in the ketamine–propofol combination were switched to ketamine–midazolam combination, and vice versa.
All children abstained from solid food for 6 h and clear fluid for 2 h. An automated Omron noninvasive blood pressure apparatus (Omron Healthcare. Inc., Lake Forest, Illinios, USA) and a Lifebox Pulse oximeter (Acare Technology Co. Ltd, New Taipei City, Taiwan) were attached to monitor the blood pressure, pulse rate, and oxygen saturation (SPO2) before sedation and every 2 min till the end of sedation. If SPO2 fell below 90% for 30 s, oxygen was given through a Hudson face mask. Respiratory rate was monitored continuously, and spontaneous respiration was maintained during the study. Eutectic mixture of local anesthetics cream was applied to the dorsum of nondominant hand 1 h before intravenous cannulation. Thereafter, a 22- or 24-G venous cannula was inserted in the dorsum of the same hand. All patients received intravenous infusion, ringer lactate solution at 4 ml/kg/h for the first hour.
Preparation and dilution of ketamine, midazolam, and propofol
Ketofol was prepared as a 1 : 1 mixture of 10 mg/ml propofol and 10 mg/ml ketamine; the children who received ketofol were administered 0.5 ml/kg of ketofol .
Both study drugs were administered at 60 s interval at the discretion of the attending anesthetist, with a target of moderate sedation or Ramsay 4.
Presedation behavior was assessed on a four-point scale by the attending anesthetist , (1=calm, cooperative; 2=anxious but reassurable; 3=anxious and not reassurable; 4=crying or resisting by a team member).
Categories 1 and 2 were classed as undistressed and categories 3 and 4 as distressed.
The depth of sedation was measured using the Ramsay sedation scale by evaluating response to sound, verbal commands or tactile stimulation by an anesthetist.
The Ramsay scale assigns a score of 1–6 based on the clinical assessment of the level of sedation (1=anxious, agitated, restless; 2=awake, but cooperative, tranquil, orientated; 3=responds to verbal commands only). Scores 4–6 apply to sleeping patients and are graded according to the response to loud noise or a glabella tap (4=brisk response; 5=sluggish response; 6=no response). The procedure was commenced after a Ramsay score of 4 and hemodynamic and respiratory stability were achieved. If a Ramsay score of 4 was not achieved additional hypnotic agent was given. At the end of the procedure, the children were allowed to recover from the sedation, and monitoring was continued until full recovery (Ramsay scale of 2).
The primary study outcome was the presence of hypoxia and apnea. The secondary outcome was the occurrence of severe pain (pain score ≥5) and adverse events during the procedure. During the sedation period, pain was measured by an anesthetist. Scales were applied according to the developmental ability of the participant: Wong-Baker Faces scale or FLACC pain scale (a score based on behaviors observed: face, legs, activity, cry, and consolability). All two scales were scored from 0–10 U, and are interchangeable for comparison purposes. Pain score of 0 coded as ‘no pain, score 1–4 as ‘mild pain’, and score of more than or equal to 5 as ‘moderate to severe pain’.
In addition, the onset, sedation, procedure and recovery time and the total dose of ketamine were determined by the research associate.
The attending anesthetist registered all data in a standard data collection record, which included age, weight, sex, diagnosis, procedure performed, duration of the procedure, and recovery time. The presence of hypoxia, apnea and pain were documented, as well as changes in the heart rate, blood pressure and SPO2.
Statistical analysis was performed using the statistical package for the social sciences (SPSS) version 20.0 for Windows computer programe (SPSS Inc., Chicago, Illinois, USA). Intergroup statistical analyses were performed using the independent t-test, and nonparametric data were analyzed using the χ2-test. Statistical significance was set P value less than or equal to 0.05. Results were presented as mean±SD, frequency or percentile.
For the purpose of this study the following definitions were used:
- PSA described as the safe and effective control of pain, anxiety, and motion so as to allow the necessary procedure to be performed and to provide an appropriate degree of memory loss or decrease awareness ,.
- Time of onset: the time from the administration of induction agent to the time it takes to achieve a Ramsay score of 4 .
- Sedation time: the time from Ramsay score of 4 till the end of the procedure.
- Procedure time: starting with the first attempt at either bone marrow, and or intrathecal administration of chemotherapy, and ending with completion of the procedure(s).
- Recovery time: the time between the end of the procedure, to the time to reach a Ramsay score of 2.
Adverse events were defined as ,:
- Apnea occurred if there was no breath for 6 s.
- Oxygen desaturation (O2): a decrease in O2 saturation resulting in intervention.
- Hypoxia: oxygen saturation less than 90% after administration of the intravenous induction agent or within 4 min of the end of the dose ,.
- Partial or complete upper airway obstruction: stridor or snoring or ventilatory effort with no air exchange, with response to intervention ,.
- Laryngospasm: partial or complete upper airway obstruction, with O2 desaturation caused by involuntary and sustained closure of the vocal cord not responding to intervention ,.
- Clinically apparent pulmonary aspiration: the presence before the end of the recovery phase of new physical symptom, or need for supplemental O2 to maintain baseline oxygenation, or chest radiograph findings of focal infiltrate, consolidation, or atelectasis ,.
- Paradoxical reaction: sustained irritability or combativeness lasting for more than 30 min after sedation.
- The requirement for airway intervention included respiratory rate less than 8 breaths/min of more than or equal to 10 s in duration, or apnea greater than 6 s (defined as no visible respiratory effort) ,.
- The requirement for oxygen therapy included SPO2 less than or equal to 90% of more than or equal to 10 s in duration.
- Success of sedation: successful completion of bone marrow aspiration, bone marrow biopsy, and lumbar puncture with or without intrathecal chemotherapy administration without movement by the patient .
| Results|| |
A total of 120 procedures were performed in 60 children; the mean age, weight, male : female ratio and acute lymphoblastic leukemia : lymphoblastic leukemia ratio were comparable. Likewise, the mean onset, duration of procedure/sedation, and recovery time were similar. In addition, the mean dose of ketamine between the groups was similar; ketamine–propofol group 1.74±1.0 mg/kg versus ketamine–midazolam group 2.23±1.58 mg/kg (P=0.9, [Table 1]). However, more patients required an additional dose of sedative in the ketamine–propofol group [25 (41.7%)] than the ketamine–midazolam group [15 (25%)] (P=0.01).
The frequency of procedures performed was similar between the groups; ketamine–propofol group [bone marrow only 20 (33.33%), intrathecal chemotherapy only 18 (30%), bone marrow+intrathecal chemotherapy 20 (33.33%), and lumbar puncture 2 (3.33%)] versus ketamine–midazolam group [bone marrow only 24 (40%) intrathecal chemotherapy only 21 (35%) and bone marrow+intrathecal chemotherapy 15 (25%)] (P=0.5). Similarly, the number of attempts, and frequency of movement during PSA were comparable ([Table 2]).
There was no difference in the presedation level of anxiety in both groups; in the ketamine–propofol group, 31 (51.7%) were calm cooperative, 16 (26.7%) were anxious but reassurable, five (8.3%) were anxious not reassurable, and eight (13.3%) were crying or restrained by a team member, while in ketamine–midazolam group, 34 (56.7%) were calm cooperative, 23 (38.3%) were anxious but reassurable, zero (0%) anxious not reassurable, and three (5%) were crying or restrained by a team member (P=0.3).
One patient in each group had hypoxia with a decrease in SPO2 to 83 and 88% in ketamine–propofol and ketamine–midazolam groups, respectively. This was associated with bradycardia of 56 and 58 beats/min, respectively. The clinical conditions responded to oxygen therapy. All children maintained spontaneous respiration during the course of sedation. The frequency of increase in the heart rate was higher in ketamine–midazolam group [26 (43.3%)] than in ketamine–propofol group [11(18.3%)]. A similar trend was observed with the blood pressure, nystagmus, and hypersalivation [25 (41.7%), 6 (10%), and 10 (16.7%), respectively, and 13 (21.7%), 2 (3.3%), and 4 (6.7%), respectively]. However, hypotension was more common in the latter group [7 (11.7%)] than in the former group [4 (6.7%)] ([Table 3]). There was no incidence of laryngospasm, apnea, and aspiration pneumonitis in either group.
The number of patients with a mean pain score of more than or equal to 5 during the procedure was comparable between the groups; ketamine–propofol group [6 (10%)] versus ketamine–midazolam group [4(6.7%)] (P=0.4).
| Discussion|| |
We have demonstrated that either ketamine–propofol or ketamine–midazolam combination was effective for PSA in hematological malignancies. The proportion of patients who experienced moderate to severe pain during the sedation was comparable between the groups. The frequency of moderate to severe pain (pain score ≥5) in our study in both groups (3.3–10%) is close to the value reported in a similar study where fentanyl–propofol topical combination was used (3.45–8.45%) . However, in the fentanyl combination there were associated nausea and vomiting. This is not surprising because postoperative nausea and vomiting have been a short coming of opioid administration for PSA in children with leukemia . Our observation shows that ketamine in combination with either propofol or midazolam is as effective as fentanyl–propofol topical anesthetic in minimizing the severity of pain in children with leukemia undergoing painful procedures .
The onset, duration of sedation and procedure and recovery time were similar in both groups. Since the propofol and midazolam in our study were premixed with ketamine in syringes before administration, this may account for the similarity in the duration of action of the studied agents. A previous study observed that propofol alone provided a faster onset of sedation, achieved the appropriate sedation level more quickly and recovery was faster than midazolam alone in PSA for imaging studies . This may suggest that a combination of ketamine to either propofol or midazolam modified the onset and recovery time.
However, the mean recovery time in ketamine, propofol, and midazolam groups (10 min) in our study was lower than the 25–27 min reported in adult patients undergoing PSA for endobronchial ultrasound guided transbronchial needle aspiration using both agents . In the later study, the authors concluded that the ketamine–propofol combination provided rapid recovery from procedural sedation. The variation in recovery time between the two studies we attribute to the difference in patients’ population. The shorter duration of recovery in our study may be due to the relatively larger extracellular fluid volume and small muscle mass in children when compared to adults.
The occurrence of hypoxia in either group was low (1.7%) in our study, with a reduction in the SPO2 in ketamine–propofol to 83% with and in ketamine–midazolam to 88%. This resulted in a reduction in the heart rate to 56 and 58 beats/min, respectively; however, both the heart rate and the SPO2 increased after the commencement of oxygen therapy. There was no episode of apnea, all the children maintained spontaneous respiration, hence there was no need for airway adjuvants and assisted ventilation. On the contrary, in a similar study in children who received fentanyl–propofol topical combination there was no report of hypoxia . This may be because all the children were given oxygen through a face mask for at least 1 min before the administration of the study drug and throughout the sedation . In another study in adults scheduled for endobronchial ultrasound guided transbronchial needle aspiration, the SPO2 values were not below 90%. The authors also administered oxygen through a nasal cannula during the procedure . This has led to the recommendations by some scholars for the routine administration of supplemental oxygen during PSA . This recommendation may not be feasible in a poor resource environment, considering the low occurrence of hypoxia in our study. However, we suggest that routine use of supplemental oxygen be discouraged during PSA. Nevertheless, a mean of oxygen delivery and appropriate airway devices should be readily available when the need arises.
An increase in the heart rate, blood pressure, salivation was observed in the ketamine–midazolam group, this we relate to the sympathomimetic effect of ketamine. The dose of ketamine has, however, been reported not to have any influence on the increase in heart rate and blood pressure after administration ,. The sympathomimetic effect is obtunded by the addition of propofol or midazolam, thereby resulting in a stable hemodynamics ,,. Propofol when compared to midazolam has a pronounced depressant effect on the cardiovascular system, this may account for the lower incidence of tachycardia and hypertension observed by us.
We observed that more children in the ketamine–propofol group experienced hallucination than the ketamine–midazolam group. This was in agreement with an earlier study in children using the same sedative agents . The lower incidence in the midazolam combination may be due to the anxiolytic and amnesic properties of midazolam. On the contrary, Hashemi et al.  observed that the incidence of hallucination reduced with increasing concentration of propofol and decreasing concentration of ketamine when they compared different combinations of ketofol during bone marrow aspiration and lumbar puncture in children with acute lymphoblastic leukemia. They reported that in patients who received ketofol (1 : 1) combination, 12 (50%) patients experienced hallucinations compared to six (24%) patients in ketofol (2 : 1) combination. The authors suggested that ketofol 2 : 1 combination was better than ketofol 1 : 1 combination, because it minimized the psychomimetic side effects of ketamine and shortens the recovery time . In a recent study by the authors, they observed that ketofol (3 : 1) (one part of ketamine and three parts of propofol) resulted in less hallucination with one patient than ketofol (2 : 1) (one part of ketamine and two parts of propofol) with seven patients . The authors concluded that the adjunctive use of a smaller dose of ketamine in ketofol combination minimized the psychomimetic side effects and shortens the recovery time. However, they suggested a large-scale study to confirm their assertion. Other authors have also demonstrated that ketofol 4 : 1 (propofol 8 mg to ketamine 2 mg) is better than ketofol 1 : 1 (ketamine 5 mg/ml to propofol 5 mg/ml) , while ketofol 5 : 1 (one part of ketamine and five parts of propofol) is better than ketofol 3 : 1 (one part of ketamine and three parts of propofol) in terms of recovery profile and occurrence of hallucination ,. Other researchers have suggested that the administration of low dose ketamine increases thalamic sensory output and arousal, and result in electroencephalographic stimulation .This may be responsible for our observations and that of other researchers in the administration of ketofol. Nevertheless, the overall incidence of hallucination is less in the pediatric population ,.Increased salivation and nystagmus was more common in the ketamine–midazolam group in our study; however, the increased secretion was tolerated with frequent aspiration, and there was no incident of laryngospasm, apnea, or aspiration pneumonitis. Other authors also reported minimal salivation with ketamine combinations with no sequelae . It is concluded that the occurrence of hypoxia, apnea, and moderate to severe pain was comparable following the administration of ketamine–propofol and ketamine–midazolam combination. However, hallucination and hypotension was commoner in the ketamine–propofol group, while ketamine–midazolam group was associated with an increase in the heart rate and blood pressure. The limitations to our study include it being a single center investigation with a relatively small sample size. Due to the similarity in the outcome of both agents, we recommend future studies with a larger population, and, or a multicenter trial, with further monitoring and recovery score.
Adekola O.O. contributed to the conception and design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Temiye E.O. contributed to the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Gabriel K.A. contributed to the data collection, revising the work critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Akanmu N.O. contributed to the revising of the work critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Desalu I. contributed to revising the work critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]