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PEDIATRIC ANESTHESIA

Prevention of Emergence Agitation After Sevoflurane Anesthesia for Pediatric Cerebral Magnetic Resonance Imaging by Small Doses of Ketamine or Nalbuphine Administered Just Before Discontinuing Anesthesia

Department of Anesthesiology, CHUL du Centre Hospitalier Universitaire de Québec, Québec, Canada

Address correspondence to Bernard J. Dalens, Department of Anesthesiology, CHUL du Centre Hospitalier Universitaire de Québec, 2705, boul. Laurier - Local 2206, Sainte-Foy, Québec, Canada, G1V 4G2. Address e-mail to bdalens{at}videotron.ca.

	Abstract

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Magnetic resonance imaging (MRI) requires long-lasting immobilization that frequently can only be provided by general anesthesia in pediatric patients. Sevoflurane provides adequate anesthesia but many patients experience emergence agitation. Small doses of ketamine and nalbuphine provide moderate sedation but their benefits have subsided at the time of emergence. We hypothesized that delaying their administration until the end of the procedure would prevent emergence agitation without prolonging patient wake-up and discharge times from the postanesthesia care unit. We performed a double-blind study involving 90 patients (aged 6 mo to 8 yr) randomly allocated to 1 of 3 groups receiving either saline (S-group), ketamine (0.25 mg/kg) (K-group), or nalbuphine (0.1 mg/kg) (N-group) at the end of an MRI procedure under sevoflurane anesthesia. We evaluated emergence conditions, sedation/agitation status and completion of discharge criteria at 30 min. The three groups were comparable in age, sex ratio, physical status, and associated medical disorders. Emergence conditions did not differ significantly. There were significantly more agitated children, at all times, in the S-group and more obtunded patients at early times (5 and 10 min) in both K- and N-groups. All patients met discharge criteria at 30 min but significantly more children were awake and quiet in the K-group and still more in the N-group. In conclusion, small doses of ketamine or nalbuphine administered at the end of an MRI procedure under sevoflurane anesthesia reduce emergence agitation without delaying discharge. Nalbuphine provided better results than ketamine.

	Introduction

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Magnetic resonance imaging (MRI) is a common diagnostic procedure in pediatric patients since it provides very discriminative anatomical details and accurate tissue identification while not subjecting the patient to ionizing radiation. MRI requires the patient to be immobilized and for this, many children need general anesthesia. In our institution, we use sevoflurane for both induction and maintenance of anesthesia. It has been reported that 30% to 80% of patients receiving sevoflurane general anesthesia develop emergence delirium (1,2). We tested the hypothesis that small-dose administration of either ketamine or nalbuphine just before discontinuing the administration of sevoflurane anesthesia would not delay patient awakening and would decrease the incidence of emergence agitation without delaying discharge from the postanesthesia care unit (PACU). In a pilot study, we evaluated the emergence conditions and discharge criteria 30 min after different doses of ketamine (1.0 to 0.25 mg/kg) and nalbuphine (0.3 to 0.1 mg/kg) and observed that the smaller dose regimens seemed most appropriate. Thus, we designed a prospective, randomized, double-blind study to determine whether small doses of saline, ketamine, or nalbuphine just before the discontinuation of anesthesia could affect emergence agitation in children undergoing MRI.

	Methods

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The study protocol received institutional approval from the Ethics Committee of our institution and because it involved pediatric patients, a copy was transmitted for registration to the Ministry of Health of the province of Québec (Canada). Written informed consent was obtained from at least one of the parents and verbal consent from the child was sought whenever possible. Between February and December 2004, 90 children aged 6 mo to 8 yr scheduled for cerebral MRI procedure under general anesthesia on an outpatient basis were enrolled in the study protocol. They were randomly allocated in a double-blind fashion to one of three groups receiving saline (S-group), ketamine (K-group), or nalbuphine (N-group). The study drug was administered at the end of the MRI procedure.

All infants and children ranging in age from 6 mo to 8 yr scheduled for elective cerebral MRI were eligible for inclusion in the study protocol. Exclusion criteria included hemodynamically or respiratory unstable patients, severe mental retardation and physical disabilities, patients under treatment with sedatives or anticonvulsants, emergency indications, extremely distressed and uncooperative children, and parental refusal.

Patient demographics including age, gender, and weight were recorded. Past and current medical records were carefully checked for associated medical disorders as well as concomitant medication intake. The neurodevelopmental status and social abilities of the children were recorded.

All patients underwent inhaled induction of anesthesia with 6% sevoflurane in 100% oxygen. After the patient’s loss of consciousness, a peripheral venous catheter was inserted and 10 mL/kg of lactated Ringer’s solution was infused over 20 min followed by standard fluid maintenance therapy according to the patient’s weight. A laryngeal mask was inserted and maintenance of anesthesia was maintained with 3% sevoflurane (delivered concentration) in oxygen/air (Fio₂ between 0.3 and 0.5 depending on Sao₂ values). Ear plugs were inserted in all patients. Spontaneous breathing was allowed provided ETco₂ remained below 50 mm Hg; if ETco₂ had exceeded 50 mm Hg, the patient would have been excluded from the protocol and assisted ventilation would have been performed. No sedative, muscle relaxant or narcotic was administered during the procedure. At the end of the procedure, the patients randomly received saline, ketamine 0.25 mg/kg, or nalbuphine 0.1 mg/kg in a blinded fashion.

The vials used for the study were prepared by the pharmacy of our institution. All the vials were identical and contained the same volume of transparent and unidentifiable fluid. The patient’s anesthesiologist and the nursing staff were all unaware of the drug administered, and the administered drug was only revealed after completion of the protocol study. Sevoflurane administration was discontinued immediately after the study drug injection, the anesthetic circuit was set to 100% oxygen, and the laryngeal mask was removed precisely 60 s later.

The following variables were evaluated for all patients:

-Duration of anesthesia,

-Effect of IV injection on respiratory rate (apnea?),

-Tolerance of laryngeal mask removal and occurrence of adverse effects: cough, laryngospasm, desaturation (Sao₂ below 95%),

-Need for respiratory assistance, especially assisted mask ventilation if Sao₂ was below 91% or tracheal intubation,

-Behavioral status (sedation, alertness or agitation) and adverse reactions.

Recovery monitoring was performed for all patients during their stay in the PACU according to the standard protocol of our institution. No patient was returned to the ambulatory unit earlier than 30 min after completion of the procedure.

In the PACU, all patients were evaluated 5, 10, 15, and 30 min after the removal of the laryngeal mask for the following:

-Occurrence of postoperative nausea and vomiting according to a 4-degree scale (3): 0 = absence of nausea and vomiting; 1 = nausea only; 2 = 1 single emetic episode; 3 = multiple emetic episodes

-Alertness and spontaneous behavior, according to a 3-step scale (Recovery Mental State Scale) (3): 1 = alert and awake; 2 = drowsy; 3 = agitated and distressed

-Sedation/agitation according to the 5-step Emergence Agitation Scale (4): 1 = obtunded with no response to stimulation; 2 = asleep (i.e., not initiating interaction with the observer) but responsive to movement or stimulation; 3 = awake and responsive; 4 = crying; 5 = thrashing behavior that requires restraint

Any undesired or unexpected effects were reported on the postanesthetic recovery chart.

The same standard discharge criteria were used during the study protocol as for patients not included in the study protocol. The anesthesiologist who provided anesthesia signed the discharge form after controlling:

-Restoration of complete autonomy of vital functions, especially respiratory and cardiovascular

-Restoration of a state of alertness close to that observed before the procedure had begun

-State of quietness sufficient to ensure that the child is not distressed and will not harm him/herself or the attendants

The sample size was determined assuming that the probability of sevoflurane agitation was 30% or more. We wanted to find a significant difference (P < 0.05) ( = 0.05, one-tailed) with a power of 80% (ß error = 0.2) to detect a difference of 25%. Twenty-five patients per group would have been sufficient but we expected some exclusions from the protocol (which did not happen) and increased this number to 30 (which allowed finding the same significant difference with a power of 90%). The random list was established by the department of Epidemiology and Human Statistics of our institution; allocation of each patient to one of the three groups was blind and did not take into account the results of previous allocations, thus resulting in an uneven number of patients in each group.

Continuous variables (age, weight, duration of anesthesia) were expressed as means and standard deviations. Comparisons among groups were made by using Kruskal-Wallis test (nonparametric analysis of variance) and Dunn’s multiple comparison test.

Discontinuous variables (nausea/vomiting, quality of early awakening after removal of the laryngeal mask, items of the Recovery Mental State and Emergence Agitation Scale) were compared using both Pearson ² test with Yates’s continuity correction, when applicable, and Fisher’s exact test. Differences were considered significant at P < 0.05.

	Results

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Ninety patients (34 girls and 56 boys) ranging in age from 6 mo to 8 yr were enrolled in the study protocol, 28 patients (10 girls and 18 boys) in the S-group, 33 (14 girls and 19 boys) in the K-group, and 29 (10 girls and 19 boys) in the N-group. The main clinical variables are detailed in Table 1. MRI indications were for cerebral examinations in all patients and both cerebral and lumbar spinal evaluation in the 7 patients with spina bifida (the duration of the procedure was longer in these 7 patients). Other clinical conditions were similar in the three groups.

The three groups did not differ significantly in terms of age, weight, ASA physical status, or duration of anesthesia. In all patients enrolled in the study, the protocol was achieved with no intraoperative incident or secondary exclusion from the protocol. All patients breathed spontaneously with ETco₂ below 50 mm Hg throughout the procedure. Physiological status and behavioral conditions after removal of the laryngeal mask performed 60 s after injection of saline, ketamine, or nalbuphine are displayed in Table 2. Differences among the three groups were not significant. No apnea was observed and the 5 patients who developed mild desaturation (1 in K-group and 2 in both S-group and N-group) were easily managed using assisted facemask ventilation in 100% oxygen for <1 min. No additional measures were necessary and all patients breathed spontaneously throughout the recovery phase.

In the PACU, only 1 patient experienced nausea without vomiting, at the tenth minute in the S-group. No other clinically relevant adverse effect was observed in any group.

Alertness and spontaneous behavior of the patients according to the Recovery Mental State are displayed in Figure 1. The number of patients quietly alert did not differ significantly in the 3 groups at 5, 10 and 15 min but was significantly increased in the N-group and K-group as compared with the S-group at 30 min. More patients were drowsy in the K-group and S-group at 5, 10, and 15 min, but the difference was not statistically significant. There were more agitated children in the S-group as compared to the K-group or to the N-Group, at all times: the difference was only significant at 15 and 30 min using the Recovery Mental State Scale but was significant at all times using the Emergence Agitation Scale. More patients from the K-group developed agitation as compared with the N-group but the difference reached significance only at 15 min.

View larger version (19K): [in this window] [in a new window]   Figure 1. Recovery mental state in the three groups of patients. *Significant difference (P < 0.05) between saline (S)-group and both ketamine (K)-group and nalbuphine (N)-group. **Significant difference (P < 0.05) between K-group and N-group.

Assessment of patients according to the Emergence Agitation Scale is displayed in Figure 2. More patients were obtunded in the K-group and N-group at 5 and 10 min (P < 0.05) but not at 15 and 30 min. Thirty minutes after discontinuation of anesthesia, significantly more patients were awake, quiet, and responsive in both the K-group and N-group as compared with the S-group. Significantly more crying and thrashing children (score of 4 or 5) were observed in the S-group as compared with the 2 other groups, at all times, especially at 30 min (one third of the patients). In the K-group, the number of patients who were crying or thrashing was significantly less than in the S-group (0 versus 18%, 10 versus 25%, 15 versus 29%, and 12 versus 36%, respectively, at 5, 10, 15, and 30 min). In the N-group, only 1 patient was crying at 15 and 30 min, a result significantly better than that observed in the S-group (all times) and in the K-group at 10, 15, and 30 min.

View larger version (22K): [in this window] [in a new window]   Figure 2. Distribution of patients according to the Emergence Agitation Scale. *Significant difference (P < 0.05) between saline (S)-group and both ketamine (K)-group and nalbuphine (N)-group. **Significant difference (P < 0.05) between K-group and N-group.

In the same day unit, nausea and vomiting were reported in 2, 3, and 2 children of the S-group, K-group, and N-group, respectively (difference not significant). All patients from the K-group and N-groups were discharged from hospital in <3 h (1.7 ± 0.50 and 1.5 ± 0.52, respectively, versus 2.2 ± 1.32 in the S-group) after leaving the PACU. Five patients from the S-group had to stay longer (3 to 6 h), mostly as a result of agitation (4/5).

	Discussion

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Sevoflurane is a safe, well accepted, and easily manageable anesthetic for induction and maintenance anesthesia in pediatric patients. It has been proven to be suitable in spontaneously breathing neonates and infants (5,6), but when it is used as the sole anesthetic it generally results in emergence agitation, often long-lasting, in a number of patients (7). These episodes of agitation may result in physical harm (8) and paranoid ideation (9). To avoid this undesirable complication, many adjuvants have been used: propofol (10,11), narcotics (4), ₂–agonists such as clonidine (12) or dexmedetomidine (13–15), and other sedatives (16–19). Other techniques of anesthesia have also been explored (20), usually using deep general anesthesia with tracheal intubation. Because cerebral MRI is a rather lengthy procedure (typically 45 to 60 minutes in duration), the administration of large doses of sedatives at induction of anesthesia is necessary to maintain a pharmacodynamic effect at the end of the procedure. These large doses usually require that the airway and ventilation of the patient be controlled: consequently, an otherwise noninvasive pain-free examination such as an MRI requires deep general anesthesia and tracheal intubation with their attendant drawbacks in terms of potential morbidity and costs. Both ketamine (21,22) and nalbuphine (23,24) can provide mild to moderate safe sedation when administered in small doses. We tested the hypothesis that administering these sedative drugs just before discontinuing the anesthesia would not delay patient awakening and would significantly decrease the incidence of emergence agitation. The duration of anesthesia was the same in the three groups of patients and emergence conditions when sevoflurane administration was discontinued were similar in all groups. Episodes of coughing and desaturation were unusual and mild, and could be resolved in <2 minutes in the 3 groups. Brief facemask-assisted ventilation with oxygen was sufficient to overcome the transient breathing difficulty.

Patients given ketamine or nalbuphine were more sedated during the first 15 minutes, but at 30 minutes more than 50% of children were awake and quiet in the K-group and N-group versus fewer than 30% in the S-group. All patients could be discharged from the PACU 30 minutes after discontinuation of anesthesia.

One third of patients presented with emergence agitation in the S-group, a result comparable to other clinical studies (3,4). Patients from the K-group experienced significantly fewer episodes of delirium than those in the S-group, and this complication was almost completely absent in the N-group.

Evaluation using the Emergence Agitation Scale (4) confirmed that fewer patients were crying or thrashing in the K-group and still fewer in the N-group. Irrespective of the level of sedation at early evaluation times in these two groups, more patients were also awake, quiet, and alert 30 minutes after discontinuation of anesthesia, and none required either additional sedation or prolonged stay in the PACU.

A limitation of the study is that as nalbuphine is an opioid agonist/antagonist, nausea and vomiting could represent a significant adverse effect after hospital discharge even though the three groups did not differ in this regard during the evaluation time.

In conclusion, the IV administration of either 0.25 mg/kg of ketamine or 0.1 mg/kg of nalbuphine in sevoflurane-anesthetized children at the end of a MRI examination did not delay awakening and removal of the laryngeal mask. Immediate and delayed postanesthetic conditions were improved with significantly fewer episodes of agitation in the K-group and virtually none in the N-group versus more than 30% in patients given saline. The stay in the PACU was not prolonged in those patients who received either ketamine or nalbuphine. There were significantly more patients awake, quiet, and alert at the time of discharge from the PACU in both the K-group and the N-group as compared with the S-group. Because of its excellent efficacy in preventing emergence agitation with no additional adverse effects, IV nalbuphine at the end of the procedure at a dose of 0.1 mg/kg seems to offer the highest benefit/risk ratio when sevoflurane has been used as the sole anesthetic.

The authors thank Dr. Russel A. Rarity, MA FRCA, Consultant Anaesthetist, Department of Anaesthetics, Timaru Hospital, Private Bag 911, Timaru (New Zealand) for his assistance in the editing of the manuscript.

	Footnotes

 
Supported, in part, by the Department of Anesthesiology, CHUL du Centre Hospitalier Universitaire de Québec.

Accepted for publication December 1, 2005.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Dalens, B. J. Articles by Truchon, R. J. Y. Search for Related Content PubMed PubMed Citation Articles by Dalens, B. J. Articles by Truchon, R. J. Y. Related Collections Pediatrics Pharmacology