The appropriate route and drug for premedication in contemporary paediatric anaesthetic practice is still a controversial subject.
The risk of developing behavioural or personality disorders is higher following a traumatic induction . Therefore an effective premedication may reduce psychobehavioural sequel resulting from the surgical experience.
Many premedicant agents administered via various routes exist; intramuscular (i.m.), nasal, oral and rectal; among these the oral route appears to be the simplest and the least traumatic [2-5].
In this study the oral route, the least traumatic, was used to study the effect and safety of ketamine 3 or 6 mg kg−1, an agent commonly used in paediatric anaesthesia practice.
Patients and methods
After receiving the approval of the 'Ethics Committee of Ankara University Medical Faculty Hospital' 43 children undergoing ophthalmic surgery were included in the study group, informed consent was also obtained. No operation was for strabismus surgery.
Children were randomly allocated to three groups; 14 children in Group I, 15 in Group II and 14 in Group III. An ECG monitor and a pulse oximeter were attached to all the children after their arrival in the premedication room adjacent to the operation theatre. The basal emotional state of the children was evaluated before premedication was administered using the Emotional State Scale (Table 1). Approximately 20-25 min before the induction of anaesthesia, ketamine (50 mg mL−1, parenteral formulation) in the following doses, mixed in a commercial form of cola (0.2 mL kg−1), were administered orally; 3 mg kg−1 in Group I (3K), 6 mg kg−1 in Group II (6K). Plain cola was given to Group III; the control group. Solutions prepared for premedication were administered by an anaesthetist blinded to the medications given. Anaesthetists who administered the anaesthetic were also not informed about the type of premedication. Premedication was administered while the children were still with their parents and any dislike for its taste was questioned. Expression on their faces were recorded in the cases of children too young to make verbal comments. Following premedication; at 1, 3, 5, 10, 15 and 20 min intervals heart rate, blood pressure, respiration rate, arterial haemoglobin oxygen saturation (SpO2) were recorded and the sedation of the patients was also evaluated using the Sedation Scale (Table 1). Patients receiving scores 1, 2, 3 were considered to be sedated and 4, 5 were not sedated. Fasciculation of the tongue muscles and nystagmus if present was also noted.
Twenty min after premedication the children were separated from their parents and taken into the operating theatre. Their reactions were recorded using a separation from the family scale (Table 1).
Anaesthesia was induced with Halothane 1.5% and N2O 50% in oxygen. The child's reaction to the mask was evaluated by a Mask Acceptance Scale (Table 1). Venous cannulation was not performed until induction was completed. Following venous cannulation the patients were intubated by following succinylcholine 1-1.5 mg kg−1. Just before intubation the amount of secretion was recorded to be increased , normal , or decreased  and the presence of airway obstruction or laryngospasm was noted.
Anaesthesia was maintained with Halothane 1.5%, N2O 50% in oxygen. Heart rate, systemic arterial pressure, breathing rate and SpO2 were recorded throughout the operation and at 5 min intervals until the 20th min post-operatively. Patients were observed closely until they had fully recovered. Nausea, vomiting, nystagmus, fasciculation of the tongue muscles and the time to verbal contact were recorded. The emotional state of the patients was assessed during recovery using the Emotional State Scale, after the children were responsive to verbal commands.
All the children were observed closely for the signs of 'emergence phenomena'. One day after surgery the families were contacted by telephone and asked what was the last thing their child remembered before they were anaesthetized, in particular did they remember the mask being applied and had they suffered any nightmares.
Post-operative analgesic requirements were not recorded.
χ2-test was utilized to analyse data about mask recall, nightmares, nystagmus, pre- and post-operative fasciculation and scores obtained from the evaluation scales. Other results and demographic data were analyzed using a paired Student's t-test. The values were recorded as mean ± standard deviation. A value of P<0.05 was considered significant.
The groups were similar in terms of age, weight and basal emotional states (Table 2).
Five children from group 3K and three children from group 6K complained about the taste of the premedication solution, but none spat out the drug.
There was no difference in the sedation scores at 1, 3 and 5 min between the groups but sedation was observed in group 6K at the 10th min (P<0.05). The children in both ketamine groups were sedated at the 15th and 20th min compared with the control group (P<0.05). There was no significant difference between 3K and 6K groups. Twenty min after premedication no sedation was observed in the control group, however 40% of the children in group 3K and 71% of the children in group 6K were sedated (Table 2).
Following sedation no pre-operative nystagmus was noted in the control and group 3K but it was observed in 26% of the children in group 6K (P<0.05). Fasciculation of the tongue muscles was observed in 13 and 7% of the children in group 3K and group 6K respectively. The difference was not significant (Table 2).
Following separation from their families 50, 80 and 79% of the children were calm (scores 1, 2) in the control, 3K and 6K groups respectively (Table 2).
When the face mask was applied 36% of the children in the control group, 80% in group 3K and 71% in group 6K remained calm (mask acceptance test 1, 2) (Table 2).
Induction times were shorter in group 6K compared with the other groups (P<0.05) (Table 2).
No difference was detected between the groups in the incidence of increased salivation and laryngospasm did not occur in any of the patients (Table 2). Anaesthesia was significantly prolonged in the group 6K (P<0.05).
There were no significant changes in heart rate, blood pressure, respiratory rate or SpO2 values within and between the groups at any time (Fig 1).
Nystagmus occurred in 13 and 20% of the children in group 3K and 6K respectively during recovery but not in the control group, the differences were not significant (Table 2). Nausea and vomiting rates were 13, 7 and 33% in the control, 3K and 6K groups respectively, the difference between 6K and 3K groups was significant (P<0.05) (Table 2). The scores for post-operative and pre-operative fasciculation of the tongue muscles were similar.
One child in group 6K developed a generalized rash and fever (not exceeding 38°C). Surface cooling was applied and the signs disappeared. Emergence phenomena was not observed in any of the children.
Time to responsiveness was significantly longer in both ketamine groups (P<0.05) (Table 2). When the emotional states were re-evaluated after the children were responsive there was a significant difference between the control and the ketamine groups, the latter having better scores (Table 2).
Children older than 2.5 years of age were asked post-operatively if they remembered the mask being used, 75% of the children in the control group and 58% in the 3K stated that they remembered the mask whereas only 22% (P<0.05) in the 6K group recalled the mask (Table 2).
Two children from the control group, one from 3K and two from 6K groups complained about nightmares on the first post-operative night. One of the children in the ketamine 6 mg group too young to be questioned about nightmares, was also considered to have had nightmares as his mother described his as crying all night long. There was no statistical significance between the groups in this result. One child from the control group and one from 3K group exhibited desperate anxiety towards the doctors.
The oral route has been assessed and recommended as the least traumatic method for paediatric pre-medication. Opioids, benzodiazepines and ketamine have all been studied [5-9].
Ketamine is of particular interest in anaesthetic practice as it may be administered by multiple routes. In this study the intention was to introduce this drug into routine anaesthetic practice by the least traumatic route.
The results demonstrate that oral ketamine pre-medication at both dose levels produced not only sedation but an easier separation from the families and also an easier face mask application. Improved emotional state scores were observed following both the ketamine doses during the recovery phase compared with the placebo group. In addition; the mask application was recalled less frequently in the ketamine groups. Although a significant number of patients in group 3K remembered the mask, as long as the induction was not performed by force and the child accepted the mask without struggle, that memory of the mask would not result in psychological trauma post-operatively.
Ketamine was administered with cola, a favourite drink for most of children. The pH of cola was found to be 3.0 in a pilot study. This value was higher than the levels of pH (2.5) reported to cause pulmonary damage in the case of aspiration . The volume of the cola solution was 0.2 mL kg−1 and was below the critical volume for residual gastric content .
Ketamine's bioavailability varies with the route of administration. The bioavailability of oral ketamine is 10-15% [3,11]. Studies in which the pharmacokinetics of ketamine have been evaluated reported that maximum blood concentration was obtained in a mean time of 40 min (30-60 min) following both oral or rectal use . However, two studies concluded that oral ketamine produces uniform, predictable sedation within 20-25 min of administration [3-5]. Therefore in the present study, ketamine plasma levels may not have reached in 20-25 mins the maximum blood concentration, but were high enough to cause sedation.
Although in a previous study oral ketamine 6 mg kg−1 was shown to sedate 100% of children , in the present study sedation was obtained in 71% and 40% in the 6K and 3K groups respectively. Comparison of the results presented here with those of Gutstein et al. has revealed that, although the ketamine doses were identical, the results were different in some respects. Cultural differences may be relevant and alter the results especially when dealing with qualitative values such as emotional states, sedation and reaction to parental separation.
Nystagmus, fasciculation of the tongue muscles, increased secretions, nausea and vomiting are the adverse effects of ketamine. The incidence of nystagmus within 20 min of premedication was 22.6% in the 6K group but not seen in the 3K group.
Fasciculation of the tongue muscles and nystagmus were observed during recovery, but they were not upsetting. Increased secretions in the 3K and 6K groups were also present but none of the patients developed an SpO2 less than 95%. Twenty per cent of the control group had increased secretions which may have been because of their crying in the absence of sedation.
Incidence of nausea and vomiting have been reported to be 33% following i.v. administration of ketamine and found to be significantly more prolonged and more frequent in older children . The incidence was 33% in the 6K group reported here. Duration of anaesthesia may also be another factor contributing to adverse effects, and nystagmus, increased secretions and nightmares were also more prominent in this group.
The incidence of nightmares and hallucinations have been reported to be higher in older children [12,13]. Mean age in the present study population was five and incidence of nightmares was low.
In conclusion the results presented here suggest that ketamine 3 mg kg−1 or 6 mg kg−1 given orally as premedication for children allows easier separation from parents, easier acceptance of a facemask and a better emotional state during recovery. These advantages were observed in both ketamine groups compared with the placebo group. However, the incidence of increased secretions and vomiting in children pre-medicated with ketamine 6 mg kg−1 suggests that ketamine 3 mg kg−1 orally is the more suitable dose.
Administration of oral ketamine can be regarded as a safe and efficient means of premedication in children. However, these patients should be kept under close supervision following this medication.
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