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PEDIATRIC ANESTHESIA

Prophylactic Dexamethasone for Postoperative Nausea and Vomiting in Pediatric Strabismus Surgery: A Dose Ranging and Safety Evaluation Study

Rashmi Madan, MD^*, Anuj Bhatia, MD^*, Sajith Chakithandy, MBBS^*, Rajeshwari Subramaniam, MD^*, Gurram Rammohan, MBBS^*, Shrinivas Deshpande, MD^*, Manorama Singh, MD^*, and H. L. Kaul, MD^*

*Department of Anaesthesiology and Intensive Care, All India Institute of Medical Sciences, New Delhi, India; Department of Anaesthetics, Queen Elizabeth Hospital, Norfolk; and Department of Anesthetics, Addenbrookes Hospital, Cambridge, United Kingdom

Address correspondence and reprint requests to Dr. Anuj Bhatia, Department of Anaesthetics, Addenbrooke’s Hospital, Hills Rd., Cambridge CB2 2QQ, UK. Address e-mail to bhatiaanuj{at}hotmail.com.

	Abstract

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In this double-blind, randomized, placebo-controlled study, we evaluated the efficacy and safety of different doses of prophylactic IV dexamethasone for postoperative nausea and vomiting (PONV) in 168 children (aged 2–15 yr) scheduled for strabismus surgery. Patients received IV dexamethasone 0.25 mg/kg (D 0.25), 0.5 mg/kg (D 0.5), 1.0 mg/kg (D 1), or saline (S) immediately after induction of general anesthesia. Patients were discharged 24 h after surgery. Nausea and vomiting were assessed at 0–2, 2–6, and 6–24 h after surgery. Blood glucose was measured preoperatively and at 4 h after study drug administration. Wound healing and infection were assessed after 1 wk. More patients in group S had vomiting at 0–2, 2–6, and 6–24 h (P = 0.001, P = 0.003, and P = 0.04, respectively) and required larger doses of rescue antiemetics compared with the dexamethasone groups. Fewer patients in the dexamethasone groups (6, 3, and 6 in D 0.25, D 0.5, and D 1, respectively) had severe PONV compared with group S (P = 0.001). No significant increase in postoperative blood glucose levels was observed and wound healing was satisfactory in all four groups. The results suggest that dexamethasone 0.25 mg/kg is more effective than saline and equally effective compared with larger doses for preventing PONV for pediatric strabismus surgery.

	Introduction

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Pediatric strabismus surgery is associated with frequent early and late postoperative nausea and vomiting (PONV) (1). An antiemetic is routinely recommended for these patients but there is no consensus on either the choice or the optimal dose of the antiemetic (2). Dexamethasone, in large doses (1 mg/kg), is a cost-effective alternative to ondansetron in significantly reducing the incidence of PONV in pediatric patients undergoing strabismus surgery (3). Prophylactic dexamethasone in doses of 0.15–0.5 mg/kg has been found to be an effective antiemetic drug for children undergoing tonsillectomy and strabismus surgery (4–6). The efficacy of different doses of dexamethasone in children undergoing strabismus surgery has not been evaluated. This randomized, double-blind, placebo-controlled study was designed to evaluate the effect of different doses of prophylactic dexamethasone for prevention of PONV in pediatric patients undergoing strabismus surgery. Suspected side effects associated with the use of dexamethasone such as hyperglycemia, wound infection, and delayed wound healing were also studied.

	Methods

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After obtaining approval from the IRB and informed written consent from guardians, the study was conducted on 168 ASA physical status I–II children between the ages of 2 and 15 yr scheduled for elective strabismus repair under general anesthesia. Children who had a history of PONV and motion sickness or had received drugs known to have antiemetic effects (phenothiazines, scopolamine, corticosteroids, and tricyclic antidepressants) in the 24 h before surgery were excluded from the study. All children fasted for at least 6 h before surgery for solids but clear fluids were allowed until 3 h before anesthetic induction.

No premedication was given. Children were randomly assigned using a randomization table to 4 groups of 42 patients to receive saline (group S) or dexamethasone doses of 0.25 mg/kg (group D 0.25), 0.5 mg/kg (group D 0.5), or 1 mg/kg (group D 1). All of the study drugs were prepared and given in equal volumes of 5 mL so that investigators and observers were blinded to the drug and dose given. Anesthesia was induced with halothane and nitrous oxide in oxygen via facemask or IV thiopentone in a sleep dose. After induction and establishment of venous access, tracheal intubation was facilitated with 0.1 mg/kg IV vecuronium. The study drug was administered immediately after tracheal intubation. Anesthesia was maintained with 0.5% halothane, 66% nitrous oxide in oxygen, and IV boluses of vecuronium were given on the basis of train-of-four neuromuscular monitoring. Intraoperative analgesia was provided with IV pethidine 0.75 mg/kg. The stomach was aspirated soon after induction and at the end of surgery before tracheal extubation.

Intraoperatively, lactated Ringer’s solution was given IV according to our routine practice—half of the preoperative fluid deficit in the first hour followed by maintenance fluids according to body weight. The number of muscles operated and the duration of anesthesia and surgery were also recorded. The incidence and duration of oculocardiac reflex (decrease in heart rate to <50 min^–1) were also recorded along with atropine administration (7 µg/kg IV) if persistent and severe oculocardiac reflex was present (>30 s and/or heart rate <50 min^–1). At the end of the procedure, neuromuscular blockade was antagonized in all patients with 0.05 mg/kg neostigmine and 0.01 mg/kg glycopyrrolate after ensuring that at least 1 response was present to train-of-four stimulation. Residual neuromuscular blockade was detected by using double burst stimulation in case of any doubt. Blood glucose levels were checked at induction and 4 h after injection of study drug.

Postoperatively, children were monitored in the postanesthesia care unit. Time to achieve complete recovery, i.e., a score of 10 (as per Steward scoring system), was recorded. Analgesia was provided with oral ibuprofen 10 mg/kg as a drug of first choice. For treatment of pain in children who had PONV in the immediate postoperative period in the postanesthesia care unit, 0.5 mg/kg pethidine IV was administered as the analgesic of second choice by the anesthesiologist who provided intraoperative care. As per institutional practice, patients were discharged 24 h after surgery.

All episodes of PONV in the first 24 postoperative hours were evaluated at 3 time periods: 0–2, 2–6, and 6–24 h using a numeric scoring system for PONV by the staff nurse aware of the study but blinded to the group to which the patient belonged. The scoring system used was: 0 = no nausea or vomiting, 1 = nausea but no vomiting, 2 = 1 vomiting episode in 30 min, 3 = persistent nausea (>30 min) or 2 or more vomiting episodes in 30 min (3). PONV severity in the first 24 postoperative hours was calculated by taking the highest value of PONV score in this period. We did not assess nausea in children <6 yr of age. In older children, nausea was assessed by an observer and by self report. Children with a PONV score of 3 were treated with IV metoclopramide 150 µg/kg as a rescue antiemetic. Any adverse effects such as headache, sedation, or weakness were noted.

Patients were followed up in the ophthalmic out-patient department at 1 wk after surgery by an ophthalmologist for occurrence of possible side effects accompanying dexamethasone usage such as wound infection or delayed wound healing. Conjunctival scar healing and any inflammation or discharge from the wound were evaluated. The examining ophthalmologist was not aware of the group to which the patient belonged.

Prestudy power analysis showed that 42 children were required in each group to have a 95% chance (ß = 0.05) of detecting a 50% reduction in PONV at 95% confidence interval limits ( = 0.05). A series of one-way analysis of variance tests were conducted to examine differences in the mean values of the variables among the four groups. If a significant difference was found, t-test with Bonferroni correction was applied to detect the intergroup differences. Student’s t-test or Mann-Whitney rank sums test was used for continuous and ordinal variables, respectively. Nominal variables were analyzed using ² tests to detect differences among the four groups and intergroup differences. Nausea, vomiting, and severity of PONV were analyzed separately. A probability value <0.05 was considered significant. The positive number needed to prevent (NNTP) for severe PONV indicates how many patients must be exposed to different doses of dexamethasone in order to prevent severe PONV in one patient who would have developed it had the patient received placebo. It was calculated as the reciprocal of the absolute risk reduction from baseline (placebo) incidence.

	Results

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One-hundred-sixty-eight patients were enrolled in the study and divided into 4 groups, 42 each in groups S, D 0.25, D 0.5, and D 1. One patient each in groups S and D 1 was lost to follow-up. Patient characteristics such as age, weight, ASA physical status, sex distribution, induction technique, duration of anesthesia and surgery, number of muscles repaired, recovery time, and intraoperative fluid requirement were similar in the 4 groups (Table 1). There was no significant difference among groups with respect to intraoperative and postoperative analgesic requirements (Table 1).

The number of patients having no nausea and vomiting (highest PONV score = 0) in the first 24 h postoperatively was significantly larger in the dexamethasone groups as compared with group S (Table 2, P = 0.003). However, there was no significant difference among patients in the different dexamethasone groups. Relatively more patients had nausea in the dexamethasone groups compared with group S but the difference was not significant (Table 2). More patients in group S had vomiting in all 3 postoperative periods in the first 24 postoperative hours: 0–2, 2–6, and 6–24 (P = 0.001, P = 0.003, and P = 0.04 respectively, Table 2) as compared with the dexamethasone groups. The number of patients in the dexamethasone groups who experienced vomiting was similar (Table 2). More patients in group S had severe PONV (highest PONV score = 3) and required antiemetics in the first 24 h as compared with the dexamethasone groups (P = 0.001) but there was no significant difference among the patients of the dexamethasone groups (Table 2).

The mean rescue antiemetic (IV metoclopramide) requirement was larger for group S compared with the dexamethasone groups (2.5 ± 2.6 mg compared with 0.7 ± 1.8 mg for D 0.25, 0.1 ± 0.5 mg for D 0.5, and 1 ± 1.1 mg for D 1; P < 0.001) but there was no significant difference among dexamethasone groups. There was a significant reduction in the incidence of vomiting 0–2 h (66% to 26%; P = 0.001), 2–6 h (52% to 26%; P = 0.003) and severity (51% to 14%; P = 0.001) of PONV in the first 24 postoperative hours in patients who received dexamethasone 0.25 mg/kg (Table 2). Patients who received dexamethasone 0.5 and 1.0 mg/kg showed similar but no additional benefit (Table 2).

No patients experienced wound infection or delayed wound healing at follow-up after 1 wk. Preoperative blood glucose was similar in all groups (Table 3). There was no significant increase in blood glucose levels recorded at the end of 4 h after baseline levels in any of the groups and there were no significant differences among the 4 groups. No discernible side effects accompanying dexamethasone usage were observed. The positive NNTP for severe PONV were comparable in the 3 dexamethasone groups and varied between 2.2 to 2.7 (Table 3). Age stratification of patients with severe PONV did not reveal age as an independent risk factor for PONV (Table 4).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The incidence of PONV after strabismus surgery may be as much as 80% in pediatric patients who have not received antiemetic prophylaxis (7). In our institution, most of the previous studies had a 70%–80% incidence of PONV in patients who did not receive any antiemetic prophylaxis (8,9). In the present study, the incidence of severe PONV in the first 24 hours was 51% in the placebo group with an incidence of vomiting in the early postoperative period of 66%. Risk factors, such as possible existence of oculoemetic reflex (traction on the extraocular muscles stimulates the afferent pathway) (10), postoperative distortion of vision (1), postoperative pain (11), and use of opioid analgesia in the perioperative period, (12) may have contributed to this incidence. We controlled these factors by our study design. The duration of anesthesia and surgery, anesthetic drugs used, and number of muscles operated were similar among groups; hence, we believe that the use of dexamethasone is the primary reason for the difference in the occurrence of PONV between the saline and dexamethasone groups.

The most important finding of this study is that prophylactic IV dexamethasone in a dose of 0.25 mg/kg is a safe and effective choice for significantly reducing the incidence (66%–26%) and severity (51%–14%) of PONV in the first 24 hours postoperatively after pediatric strabismus repair. Larger doses of dexamethasone (0.5 and 1.0 mg/kg) are equally effective but offer no additional benefits.

The first clinical trial using dexamethasone for PONV found that dexamethasone decreased pain, swelling, and vomiting after extraction of third molar teeth in adults (13). The mechanism of dexamethasone’s antiemetic effect is not clear. Theories include prostaglandin antagonism, release of endorphins resulting in mood elevation, a sense of well-being, reduced levels of serotonin in neural tissue, and prevention of release of serotonin in the gut (14).

Dexamethasone, in a dose of 1 mg/kg, has been shown to be a cost-effective alternative to ondansetron in preventing PONV after pediatric strabismus repair in a previous study from our institute (3) but efficacy of varying doses was not compared. Studies of dexamethasone use in the surgical setting such as gynecologic surgery, have found doses as small as 2.5 mg to be effective in preventing PONV (15). However, no attempt was made in these studies to correlate the administered dose of dexamethasone to the patient’s body weight. The effect of dexamethasone on blood glucose levels was also not studied.

Our study is the first to make a recommendation of dexamethasone dose based on comparison among three different doses in terms of patient’s weight. This is especially important in pediatric patients, because the use of predetermined doses irrespective of body weight may lead to administration of either an inadequate or an excessive dose of dexamethasone resulting in lack of efficacy or adverse effects.

In our study, follow-up of patients at 7 days after surgery revealed that none of the patients experienced wound infection or delayed wound healing. There was no significant increase of blood glucose levels measured four hours later over baseline levels. In the D 1 group, 9 patients received dexamethasone doses of >20 mg and none of them had any adverse effects. This further testifies to the safety of relatively large doses of dexamethasone. A quantitative systematic review of the use of dexamethasone for prevention of PONV also found no evidence of adverse effects (14).

The timing of prophylactic antiemetic administration is important. We administered the drugs at the beginning of the procedure. It has been shown that dexamethasone is more effective when administered at induction than when given at the end of anesthesia (16). We included a placebo group for calculating the absolute risk reduction in PONV and thereby NNTP. NNTP severe PONV in this study for different doses of dexamethasone was in the range of 2.2–2.7 which indicates that dexamethasone prevented severe emesis in at least every third patient. This is in contrast to the NNTP of 4 reported in a meta-analysis of dexamethasone for prevention of PONV (14). This larger NNTP in the meta-analysis could have been the result of the heterogeneous patient population and defects in the meta-analysis of PONV (17).

In conclusion, IV dexamethasone in a dose of 0.25 mg/kg was as effective as 0.5 and 1 mg/kg and more effective than saline control for preventing PONV in children undergoing strabismus surgery. There were no side effects of dexamethasone usage such as increase of blood glucose, delayed wound healing, and wound infection. We recommend that, until further clinical trials evaluating efficacy of doses of dexamethasone smaller than 0.25 mg/kg are conducted, this dose is adequate for prevention of PONV after pediatric strabismus surgery.

	Footnotes

 
Accepted for publication November 3, 2004.

	References

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7. Hardy JF, Charest J, Girouard G, Lepage Y. Nausea and vomiting after strabismus surgery in preschool children. Can Anaesth Soc J 1986;33:57–62.[ISI][Medline]
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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