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PEDIATRIC ANESTHESIA

Premedication with Midazolam Delays Recovery After Ambulatory Sevoflurane Anesthesia in Children

Hanna Viitanen, MD^*, Päivi Annila, MD, PhD, Matti Viitanen, MD^*, and Pekka Tarkkila, MD, PhD

*Department of Surgery and Anaesthesia, Central Hospital of Seinäjoki, Seinäjoki; Department of Anaesthesiology, Tampere University Hospital and Tampere University Medical School, Tampere; and Department of Anaesthesia, Ear Hospital, Helsinki University Central Hospital, Helsinki, Finland

Address correspondence and reprint requests to Hanna Viitanen, MD, Department of Surgery and Anaesthesia, Central Hospital of Seinäjoki, 60220 Seinäjoki, Finland. Address e-mail to msv{at}sci.fi

	Abstract

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We studied the effect of oral premedication with midazolam on the recovery characteristics of sevoflurane anesthesia in small children. In a randomized, double-blinded study, 60 children (1–3 yr, ASA physical status I or II) undergoing ambulatory adenoidectomy received either midazolam 0.5 mg/kg (Group M) or placebo (Group P) PO approximately 30 min before the induction of anesthesia. All children received atropine 0.01 mg/kg IV and alfentanil 10 µg/kg IV before the induction of anesthesia with sevoflurane up to 8 vol% inspired concentration in N₂O 67% in O₂. Tracheal intubation was facilitated with mivacurium 0.2 mg/kg. Anesthesia was continued with sevoflurane adjusted to maintain hemodynamic stability. In the postanesthesia care unit, predetermined recovery end points (emergence, recovery, discharge) were recorded. A pain/discomfort scale was used to determine the quality of recovery. A postoperative questionnaire was used to evaluate the well-being of the patient at home 24 h after surgery. Emergence (spontaneous eye opening), recovery (full points on the modified Aldrete scale), and discharge were achieved later in Group M than in Group P (15 ± 6 vs 11 ± 3 min [P = 0.002], 25 ± 17 vs 16 ± 6 min [P = 0.01], and 80 ± 23 vs 70 ± 23 min [P = 0.03]). Side effects, postanesthetic excitement, and analgesic treatment did not differ significantly between groups. At home, more children in Group P (30%) experienced disturbed sleep during the night compared with those in Group M (4%) (P = 0.007).

Implications: In this randomized, double-blinded, placebo-controlled study, premedication with midazolam 0.5 mg/kg PO delayed recovery in children 1–3 yr of age after brief (<30 min) sevoflurane anesthesia. Except for more peaceful sleep at home, premedication did not affect the quality of recovery.

	Introduction

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Midazolam is a benzodiazepine derivative that is widely used as a premedicant in both adults and children (1). Midazolam's elimination half-life (1.17 h) (2) makes it particularly suitable for brief procedures. In children, premedication with oral midazolam seems to provide satisfactory anxiolysis before anesthesia (3,4) and to reduce the psychological impact of hospitalization after surgery (5). However, the routine use of anxiolytic premedication before anesthetic induction is controversial (6). Furthermore, premedication may significantly delay recovery from anesthesia (5,6), a vital consideration in a busy ambulatory surgery unit. However, several studies have reported no effect on recovery characteristics after midazolam premedication when using inhaled anesthesia with halothane only (3,4).

The effect of midazolam premedication on recovery from ambulatory sevoflurane anesthesia is not known. We therefore designed this randomized, double-blinded, placebo-controlled study to test the hypothesis that midazolam delays recovery after brief sevoflurane anesthesia in small children.

	Methods

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After institutional approval and informed, written parental consent, we studied 60 children, ASA physical status I or II, aged 1–3 yr, scheduled for ambulatory adenoidectomy. Children were excluded if they were allergic to the drugs being used or if they were taking medication that could interact with midazolam (e.g., antibiotics, anti-epileptics, sedatives). All patients were fasted 4–6 h before surgery. All children were randomized according to a computer-generated random numbers program in a double-blinded fashion to receive either 0.5 mg/kg midazolam (Group M) or placebo (Group P) approximately 30 min before the induction of anesthesia. All observers, as well as the children and their parents, were unaware of the contents of the oral premedicant.

On arrival in the operating room, routine monitoring was applied, and preinduction heart rate, blood pressure, and hemoglobin oxygen saturation (SpO₂) were recorded. An IV cannula was inserted (facilitated by EMLA® cream; Astra, Södertälje, Sweden), and an infusion of lactated Ringer's solution containing 2.5% dextrose was started. Atropine 0.01 mg/kg IV and alfentanil 10 µg/kg IV were administered before the induction of anesthesia. All children received a standard inhaled induction with sevoflurane with gradual increase every few breaths up to 8 vol% inspired concentration with N₂O 67% in O₂ via a face mask. Tracheal intubation was facilitated with a single dose of mivacurium 0.2 mg/kg IV. Anesthesia was continued with sevoflurane in N₂O 67% in O₂. The inspired sevoflurane concentration was adjusted to maintain mean arterial blood pressure within 20% of initial readings. A semiclosed circle system was used throughout anesthesia, and ventilation was controlled to maintain normocapnia. Immediately after intubation, a suppository of acetaminophen 20 mg/kg was administered. SpO₂, end-tidal carbon dioxide, and heart rate were monitored continuously. Blood pressure was measured before intubation, after intubation, and every 5 min during surgery. At the end of surgery, all anesthetics were discontinued, and extubation was performed when spontaneous breathing was regarded as adequate.

In the postanesthesia care unit (PACU), vital signs (heart rate, blood pressure, SpO₂) were monitored until the child was fully awake. Parents of the children were allowed to enter the PACU once the child was awake. A trained nurse who was blinded to the premedication protocol evaluated every patient during the recovery period. The following recovery times (from discontinuation of sevoflurane and nitrous oxide) were recorded: time to opening eyes spontaneously (emergence); time to responding to the nurse or parent (interaction); time to a score of 8 on the modified Aldrete score (7); time to elective drinking; time to ambulate according to age; and time to achieving discharge criteria. The discharge criteria were: fully awake, stable vital signs for at least 30 min, no bleeding, no signs of excessive pain, no vomiting, and able to ambulate according to age.

Any postoperative side effects (vomiting, pain, airway difficulties) were recorded. The quality of recovery was evaluated using the three objective components (crying, movement, and agitation) in the pain/discomfort scale reported by Hannallah et al. (8), each variable scoring 0–2 points (best to worst). If the total score on the pain/discomfort scale at any evaluation point exceeded 3 (e.g., the child was crying inconsolably, thrashing, or severely agitated), the child was regarded as suffering from postanesthetic excitement. IV oxycodone 0.05 mg/kg was given for postoperative pain relief at the discretion of the recovery nurse; the time to administration of the first dose and the total amount of analgesic needed were recorded.

The parents were asked to record (in a postoperative questionnaire) the well-being (pain, vomiting, tiredness, sleep) of the child at home until 24 h after anesthesia.

Analyses were performed using Statistical Package for the Social Sciences (v. 6.0; SPSS, Chicago, IL). Results are presented as mean ± SD, 95% CI, or number (percentage) where appropriate. Demographic data were analyzed by using Student's t-test. Differences in premedication and recovery times and time to first analgesic were assessed by using the Mann-Whitney U-test. The number of children with postoperative sequelae were compared by using 2 test and Fisher's exact test, where approppriate. A P value of <0.05 was considered significant. To detect a 15-min difference in the discharge time between the groups, with an estimated discharge time of 80 min and a SD of 20 min in the placebo group, a minimum of 28 patients would be required in each group. This would give the study an 80% power at a significance level of 5%.

	Results

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The two groups did not differ in age, weight, duration of surgery or anesthesia, or times from premedication to the induction of anesthesia and end of anesthesia (Table 1).

View larger version (15K): [in this window] [in a new window]   Figure 1. Percentage of children with postanesthetic excitement in the midazolam group (Group M) and placebo group (Group P) at different time points in the postanesthesia care unit.

	Discussion

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Our hypothesis was confirmed. Oral premedication with midazolam 0.5 mg/kg delayed recovery after brief (<30 min) sevoflurane anesthesia in small children. All recovery end points were achieved later with midazolam than with placebo. However, the quality of recovery was not affected by premedication, except for more peaceful sleep during the night after surgery.

The delay in emergence time may have been due to the residual sedation of midazolam after a brief anesthetic. The mean time from premedication to end of anesthesia was 68 ± 16 min in Group M. Although the maximal sedative effect after oral midazolam administration occurs at 30 min (3), the serum concentration peaks at 50–60 min and can remain above the suggested therapeutic level for anxiolysis and light sedation (40 mg/mL) until 2 h after administration (2,9). That the peak serum midazolam concentration coincided with the end of anesthesia could partly explain the delayed early recovery. However, it is possible that the use of alfentanil also contributed to the delayed emergence, as even subanalgesic doses of alfentanil have been shown to potentiate midazolam-induced unconsciousness (10). In addition, the use of oxycodone for postoperative pain relief may have contributed to the prolongation of later recovery.

Our findings are in agreement with previous studies, in which oral premedication with midazolam delayed both early recovery and discharge (5,6) when halothane or isoflurane anesthesia was induced with thiopentone or propofol. In contrast, two other studies reported no effect on recovery when using inhaled anesthesia with halothane only (3,4). These conflicting findings may be due to the variable dosage of the premedicant (0.5–1.0 mg/kg) and differing anesthetic times (23–60 min). The induction technique used (5,6) may also have affected recovery; synergistic interaction with regard to hypnosis have been demonstrated between midazolam and thiopentone (11) or propofol (12).

All the differences between the groups in achieving the recovery end points were statistically significant, although the implication of this in clinical practice is debatable. The fact that emergence occurred 4 min sooner in Group P may seem clinically irrelevant, but the interval between extubation and the moment the child starts to awaken is crucial with regard to airway maintenance. Obstruction of the airway is always a possibility, and the rapid return of protective reflexes on awakening is therefore an important aspect of recovery. However, the clinical relevance of a 10-min delay in discharge time is questionable; it may have a negligible impact on the turnover rate of patients in an ambulatory surgery unit.

Many children in both groups (47%–60%) experienced postanesthetic excitement, at incidences consistent with previous studies (13,14). This may have been partly due to pain in the immediate recovery period. A currently held opinion is that traditional doses of rectal acetaminophen (10–20 mg/kg) are too small to provide adequate postoperative pain control (15,16). In addition, because of its very rapid elimination in children (17), the analgesic effect of alfentanil may not have extended to the recovery period. The highest incidence of postanesthetic excitement was seen during the first 20 min after anesthesia. Most of the children received the rescue analgesic during this time, which could explain the subsequent decrease in the pain/discomfort scores. However, some children were clearly comforted by the presence of a parent, which indicates that pain may not have been the only factor contributing to the occurrence of postanesthetic excitement in these children.

Our results revealed no benefit from midazolam on the incidence of postanesthetic excitement, although findings to the contrary have been reported (18). However, premedication with midazolam significantly improved the quality of sleep the night after surgery. Night disturbances during the first 2 weeks after anesthesia have been reported to occur in 17%–52% of children aged 1–10 years (5,19). In some children, these disturbances have extended beyond 4 weeks (20,21). Similarly to our findings, McCluskey and Meakin (5) and Payne et al. (19) found that premedication decreased the incidence of night waking and nightmares. However, in the study by McGraw and Kendrick (20) in children aged 1–10 years, midazolam increased adverse behavioral changes, of which nightmares and night terrors were the most common, during the first postoperative week. These researchers suggested that midazolam may disrupt the pattern of sleep and could also increase postoperative anxiety through its amnestic properties. Our high incidence of sleep disturbances (30%) in the unpremedicated group may reflect the young age of the children and the time of observation. Negative behavioral changes after surgery occur most often among children 1–3 years of age (21,22), the worst day being the day of surgery (22).

In conclusion, oral premedication with midazolam 0.5 mg/kg delayed recovery from brief (<30 min) sevoflurane anesthesia in children 1–3 years of age. Emergence from anesthesia and early recovery (Aldrete score of 8) occurred later with midazolam than with placebo, and discharge time was slightly delayed. Except for the improved quality of sleep the night after surgery, premedication did not affect the quality of recovery.

	Acknowledgments

 
This study was supported by the Medical Research Fund of Tampere University Hospital.

We thank Riitta Kataja-Rahko, RN, Aila Autio, RN, and the personnel of the Central Hospital of Seinäjoki for their help and cooperation during this study.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999