Midazolam Plus Ketamine for Sedation in Laceration Repair
Midazolam Plus Ketamine for Sedation in Laceration Repair
This prospective, double-blind study did not demonstrate differences in pain reduction during local anaesthetic injection, between children treated with a combination of oral midazolam and ketamine, and children treated with oral midazolam alone. Nevertheless, the combination of midazolam and ketamine led to deeper sedation (as assessed by the sedation score) and higher success rates, with a smaller number of children requiring intravenous sedation. Time to discharge from the ED was longer in the combination of oral midazolam and ketamine group, compared with the midazolam group.
Sedation is often needed for young children undergoing minor procedures in the ED. Although much research has been conducted on different sedation methods in children, a 'golden' combination of sedation drugs has yet to be discovered.
Comparatively little research has been performed on the use of oral ketamine for sedation in children, and most of it dealt with non-painful procedures, such as parental separation or mask acceptance. Due to the scant data on the matter, the exact dosing of oral ketamine and its effect in combination with other drugs is not known.
The combination of oral ketamine and midazolam was described initially in 1993, in a study published only as an abstract by Lin et al who studied premedication for short surgical procedures. Their success rate using the combination was similar to that of each drug alone (~80%), though time to onset of sedation was shorter. No clinically significant adverse effects were noticed. Since then, several studies investigated the combination of ketamine and midazolam as premedication for short surgical procedures, for intravenous cannulation, and for invasive procedures in children with malignancies.
Younge et al compared the effect of high dose (10 mg/kg) oral ketamine with midazolam (0.7 mg/kg) during laceration repair in children. The study found better tolerance to local anaesthetics and deeper sedation in children treated with ketamine with no difference in the overall rate of adverse events. Pain was not assessed in this study.
To the best of our knowledge, the use of the oral combination, midazolam and ketamine, for sedation of children during laceration repair, has not been investigated yet.
Our study found no difference between either group in the time to onset of sedation. Inconsistent findings were evident in previous studies. Funk et al investigated the oral combination of ketamine and midazolam as premedication for short surgeries. They compared three study groups: midazolam group (0.5 mg/kg), ketamine group (6 mg/kg) and a combination group (midazolam 0.25 mg/kg and ketamine 3 mg/kg). The time course of the effect was similar in the three groups. Similar findings were shown by Ghai et al who compared the combination of midazolam (0.25 mg/kg) and ketamine (2.5 mg/kg) with midazolam 0.5 mg/kg alone, as premedication for short surgeries. Contrary to these findings, Darlong et al found that the time to achieve the best parental separation score was much shorter in the combination groups as compared with midazolam alone. At 30 min, the parental separation scores were comparable in all study groups.
Contrary to our hypothesis, no difference in VAS score assessment was detected between the two study groups during local anaesthetic injection This finding might be explained by the fact that we used an indirect tool to assess pain. Since the study was conducted in young children, many of them less than 4 years of age, we could not use pain scales that are based on the child's self reporting. Conversely, sedation activity score was lower (better), and might be considered in future as a better assessment tool for sedation success in very young children.
Additionally, we found that procedure time was longer in the research group. Procedure duration depends on many variables, such as laceration size, laceration location, the physician on call and so on. The exact reason for the longer procedure duration in patients treated with midazolam and ketamine in our study is not known. One possible explanation is that despite randomisation, the patients in the combination group had more complicated wounds. Unfortunately, although some characteristics of the wound were documented, the laceration size was not documented; therefore, this assumption cannot be tested. However, if true, it may also explain why, under better sedation, the VAS assessment was comparable between groups.
Failure of oral sedation, and the need for intravenous sedation, may cause distress for the child and his parents, and requires additional human and medical resources. In our study, there were more children who required intravenous sedation among those treated with midazolam alone. These findings suggests that adding oral ketamine to oral midazolam significantly reduced the need for intravenous sedation and, therefore, should be considered in certain cases, such as complex wounds or significant agitation prior to the procedure.
Unlike previous studies, children treated with the combination of midazolam and ketamine remained in the ED much longer than children in the placebo group. This finding might be explained by drug dosing. Previous studies did not find any difference in recovery time when children were treated with the combination of midazolam 0.25–0.5 mg/kg and ketamine 2.5–3 mg/kg, whereas in our study, children were treated with higher doses of both midazolam (0.5 mg/kg) and ketamine (5 mg/kg.) The ketamine dose used in this study was based on the common dose for intramuscular ketamine. This relatively high dose was chosen because our study investigated sedation for a painful procedure, unlike previous studies. We should state that Younge et al used 10 mg/kg of oral ketamine for the same purpose with no clinically significant adverse effects. It is, however, important to remember that a longer stay in the ED means a higher cost for the health system. Therefore, one should consider the benefit of improving the depth of sedation versus the costs of observation for a longer time.
Our study demonstrated several limitations. First, although the combination of oral midazolam and oral ketamine was well tolerated, and adverse effects were mild and quickly resolved, due to the small number of patients, we cannot draw a definite conclusion regarding the safety of this combination.
Second, we did not review the child's and parents' overall satisfaction from the procedure. We only assessed the VAS score at the time of local anaesthetic injection, which is a very stressful event, both for the child and for the parents. In many situations, agitation of the child was noted only during the injection, with full cooperation of the child and parental contentment afterwards. Lastly, another limitation was that recovery time was not documented properly and, instead, time to discharge from the ED was chosen as the secondary outcome.
Time to discharge from the ED in our study was 121 min in the placebo group and 186 min in the research group, while in other studies the average recovery time ranged from 70 to 128 min in the midazolam groups, and from 70 to 120 min in the combination/ketamine groups. These studies are not comparable as they deal with different procedures and different dosing. It is important to note that our study documented the time from administration of sedation to discharge from the ED as a secondary outcome, and not the time to recovery, as we believed it is a more objective measure. Yet in many cases, full recovery was achieved long before the child was discharged from the ED, for both technical and religious reasons such as: waiting for Shabbat to end, waiting for a ride, and so on.
In summary, our randomised, double-blind study demonstrated that treatment with a combination of midazolam 0.5 mg/kg and ketamine 5 mg/kg did not lead to better pain reduction during laceration repair, compared with midazolam alone. However, the combination leads to a better sedation, reduces the need for intravenous sedation, and has no additional clinically significant adverse effects except for a longer stay in the ED. Further studies should be conducted in order to determine the optimal dose, and to establish safety of the combination therapy.
Discussion
This prospective, double-blind study did not demonstrate differences in pain reduction during local anaesthetic injection, between children treated with a combination of oral midazolam and ketamine, and children treated with oral midazolam alone. Nevertheless, the combination of midazolam and ketamine led to deeper sedation (as assessed by the sedation score) and higher success rates, with a smaller number of children requiring intravenous sedation. Time to discharge from the ED was longer in the combination of oral midazolam and ketamine group, compared with the midazolam group.
Sedation is often needed for young children undergoing minor procedures in the ED. Although much research has been conducted on different sedation methods in children, a 'golden' combination of sedation drugs has yet to be discovered.
Comparatively little research has been performed on the use of oral ketamine for sedation in children, and most of it dealt with non-painful procedures, such as parental separation or mask acceptance. Due to the scant data on the matter, the exact dosing of oral ketamine and its effect in combination with other drugs is not known.
The combination of oral ketamine and midazolam was described initially in 1993, in a study published only as an abstract by Lin et al who studied premedication for short surgical procedures. Their success rate using the combination was similar to that of each drug alone (~80%), though time to onset of sedation was shorter. No clinically significant adverse effects were noticed. Since then, several studies investigated the combination of ketamine and midazolam as premedication for short surgical procedures, for intravenous cannulation, and for invasive procedures in children with malignancies.
Younge et al compared the effect of high dose (10 mg/kg) oral ketamine with midazolam (0.7 mg/kg) during laceration repair in children. The study found better tolerance to local anaesthetics and deeper sedation in children treated with ketamine with no difference in the overall rate of adverse events. Pain was not assessed in this study.
To the best of our knowledge, the use of the oral combination, midazolam and ketamine, for sedation of children during laceration repair, has not been investigated yet.
Our study found no difference between either group in the time to onset of sedation. Inconsistent findings were evident in previous studies. Funk et al investigated the oral combination of ketamine and midazolam as premedication for short surgeries. They compared three study groups: midazolam group (0.5 mg/kg), ketamine group (6 mg/kg) and a combination group (midazolam 0.25 mg/kg and ketamine 3 mg/kg). The time course of the effect was similar in the three groups. Similar findings were shown by Ghai et al who compared the combination of midazolam (0.25 mg/kg) and ketamine (2.5 mg/kg) with midazolam 0.5 mg/kg alone, as premedication for short surgeries. Contrary to these findings, Darlong et al found that the time to achieve the best parental separation score was much shorter in the combination groups as compared with midazolam alone. At 30 min, the parental separation scores were comparable in all study groups.
Contrary to our hypothesis, no difference in VAS score assessment was detected between the two study groups during local anaesthetic injection This finding might be explained by the fact that we used an indirect tool to assess pain. Since the study was conducted in young children, many of them less than 4 years of age, we could not use pain scales that are based on the child's self reporting. Conversely, sedation activity score was lower (better), and might be considered in future as a better assessment tool for sedation success in very young children.
Additionally, we found that procedure time was longer in the research group. Procedure duration depends on many variables, such as laceration size, laceration location, the physician on call and so on. The exact reason for the longer procedure duration in patients treated with midazolam and ketamine in our study is not known. One possible explanation is that despite randomisation, the patients in the combination group had more complicated wounds. Unfortunately, although some characteristics of the wound were documented, the laceration size was not documented; therefore, this assumption cannot be tested. However, if true, it may also explain why, under better sedation, the VAS assessment was comparable between groups.
Failure of oral sedation, and the need for intravenous sedation, may cause distress for the child and his parents, and requires additional human and medical resources. In our study, there were more children who required intravenous sedation among those treated with midazolam alone. These findings suggests that adding oral ketamine to oral midazolam significantly reduced the need for intravenous sedation and, therefore, should be considered in certain cases, such as complex wounds or significant agitation prior to the procedure.
Unlike previous studies, children treated with the combination of midazolam and ketamine remained in the ED much longer than children in the placebo group. This finding might be explained by drug dosing. Previous studies did not find any difference in recovery time when children were treated with the combination of midazolam 0.25–0.5 mg/kg and ketamine 2.5–3 mg/kg, whereas in our study, children were treated with higher doses of both midazolam (0.5 mg/kg) and ketamine (5 mg/kg.) The ketamine dose used in this study was based on the common dose for intramuscular ketamine. This relatively high dose was chosen because our study investigated sedation for a painful procedure, unlike previous studies. We should state that Younge et al used 10 mg/kg of oral ketamine for the same purpose with no clinically significant adverse effects. It is, however, important to remember that a longer stay in the ED means a higher cost for the health system. Therefore, one should consider the benefit of improving the depth of sedation versus the costs of observation for a longer time.
Our study demonstrated several limitations. First, although the combination of oral midazolam and oral ketamine was well tolerated, and adverse effects were mild and quickly resolved, due to the small number of patients, we cannot draw a definite conclusion regarding the safety of this combination.
Second, we did not review the child's and parents' overall satisfaction from the procedure. We only assessed the VAS score at the time of local anaesthetic injection, which is a very stressful event, both for the child and for the parents. In many situations, agitation of the child was noted only during the injection, with full cooperation of the child and parental contentment afterwards. Lastly, another limitation was that recovery time was not documented properly and, instead, time to discharge from the ED was chosen as the secondary outcome.
Time to discharge from the ED in our study was 121 min in the placebo group and 186 min in the research group, while in other studies the average recovery time ranged from 70 to 128 min in the midazolam groups, and from 70 to 120 min in the combination/ketamine groups. These studies are not comparable as they deal with different procedures and different dosing. It is important to note that our study documented the time from administration of sedation to discharge from the ED as a secondary outcome, and not the time to recovery, as we believed it is a more objective measure. Yet in many cases, full recovery was achieved long before the child was discharged from the ED, for both technical and religious reasons such as: waiting for Shabbat to end, waiting for a ride, and so on.
In summary, our randomised, double-blind study demonstrated that treatment with a combination of midazolam 0.5 mg/kg and ketamine 5 mg/kg did not lead to better pain reduction during laceration repair, compared with midazolam alone. However, the combination leads to a better sedation, reduces the need for intravenous sedation, and has no additional clinically significant adverse effects except for a longer stay in the ED. Further studies should be conducted in order to determine the optimal dose, and to establish safety of the combination therapy.