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Anesth Analg 2001;92:907-912
© 2001 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

Prophylactically-Administered Rectal Acetaminophen Does Not Reduce Postoperative Opioid Requirements in Infants and Small Children Undergoing Elective Cleft Palate Repair

Dorothee H. Bremerich, MD, Gerd Neidhart, MD, Klaus Heimann, Paul Kessler, MD, and Michael Behne, MD

Clinics of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Johann Wolfgang Goethe-Universität Frankfurt, Germany

Address correspondence and reprint requests to Dorothee H. Bremerich, MD, Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Address e-mail to Bremerich{at}em.uni-frankfurt.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Rectal acetaminophen (Ac) is often administered prophylactically at anesthesia induction for postoperative pain management in small children and is thought to have an opioid-sparing effect. We assessed in this double-blinded, prospective, randomized study early opioid requirements after three doses of Ac (10, 20, and 40 mg/kg versus placebo) in 80 children (ASA physical status I, age 11.4 ± 9.9 mo) undergoing cleft palate repair. Single Ac plasma concentrations were measured. Pain scores assessed in the postanesthesia care unit of >=4 of 10 resulted in the IV administration of 25 µg/kg piritramide, a popular European µ receptor agonist (lockout time, 10 min; maximum 0.125 mg/kg). There were no significant differences between groups with regard to the early postoperative pain scores and the overall cumulative IV opioid requirements. Maximal plasma concentrations achieved were only subtherapeutic (Ac 10 mg/kg: 8 µg/mL; Ac 20 mg/kg: 13 µg/mL; Ac 40 mg/kg: 21 µg/mL after 122, 122, and 121 min, respectively). We conclude that rectal Ac up to 40 mg/kg has no opioid-sparing effect, does not result in analgesic Ac plasma concentrations, and lacks proof of its efficacy in infants and small children undergoing cleft palate repair, whereas titrated IV opioid boluses produced rapid and reliable pain relief.

Implications: Acetaminophen is widely used prophylactically for postoperative analgesia in children and is thought to have an opioid-sparing effect. We showed that rectal acetaminophen up to 40 mg/kg administered at anesthesia induction lacked proof of efficacy, whereas IV opioid boluses resulted in reliable pain relief in children undergoing cleft palate repair.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In infants and small children, rectal acetaminophen (Ac) is often administered prophylactically at anesthesia induction to provide postoperative analgesia and reduce supplementary opioid administration in the postoperative period. There is increasing evidence that the analgesic efficacy of rectal Ac is dose-dependent and directly related to its plasma concentration (1). Currently recommended single doses of rectal Ac exceed the manufacturers’ guidelines, and range from 10 to 70 mg/kg (2–4). Several investigators could not confirm an analgesic effect after single doses of rectal Ac (15–35 mg/kg) (5–7), whereas others established a significant opioid-sparing effect after 40 and 60 mg/kg (3). Pharmacokinetic data as well as pharmacodynamic data relating Ac plasma concentration to postoperative analgesia in children are scarce and conflicting. Doses of 10–45 mg/kg rectal Ac yield mainly subtherapeutic peak plasma concentrations associated with antipyresis (2,8,9). For satisfactory postoperative pain scores in children, Anderson et al. (10) determined an effective compartment concentration (ED50) of 10 µg/mL after the administration of 40 mg/kg rectal Ac. Surprisingly, in a previous study, this dosage did not result in adequate analgesia in the early postoperative period (1). Particularly if taking into consideration its potential adverse effects, e.g., accidental overdosage (11,12), hepatotoxicity (11,13), and nephrotoxicity (14), the role of prophylactically-administered rectal Ac for postoperative analgesia in infants and small children needs to be reevaluated.

The purpose of this study was to assess early postoperative pain scores and opioid requirements after three different doses of prophylactically-administered rectal Ac compared with placebo by using an observer-dependent Children’s and Infants Postoperative Pain Score (CHIPPS) (15,16). The analgesic effect of IV opioid administration on repeated CHIPPS ratings was determined. Ac plasma concentrations after the single administration of rectal Ac at anesthesia induction were measured and correlated to postoperative opioid requirements. Potential adverse effects and the incidence of vomiting within the first 24 h were recorded.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After we obtained institutional human investigation committee approval and written, informed consent of the parents, 80 infants and small children, ASA physical status I, undergoing elective cleft palate repair were included in the study. We assessed postoperative pain scores and opioid requirements after 3 different doses of Ac, compared with placebo, in a prospective, randomized, double-blinded study. Patients were excluded if they had an allergy to Ac, had renal or hepatic dysfunction, or were given Ac in the last 72 h. All patients fasted 4 h before surgery. All procedures were performed by the same surgeon. Routinely, 2–2.5 mL of 1% lidocaine containing 1:200 000 epinephrine was administered to create vasoconstriction in the surgical field and improved surgical conditions.

Standardized Anesthesia Procedure
Infants younger than 6 mo received no premedication, infants and small children 6 mo and older received 0.5 mg/kg midazolam rectally, 30 min before their arrival in the operating room. Standard monitoring was applied, including electrocardiogram, pulse oximetry, and noninvasive arterial pressure. After IV cannulation, 0.01 mg/kg atropine was administered and anesthesia was induced by using 3 mg/kg methohexital. Endotracheal intubation was facilitated with a single dose of 1–1.5 mg/kg succinylcholine. Patients were ventilated to normocapnia with 30% oxygen in nitrous oxide. General anesthesia was maintained with 1–2 minimum al-veolar concentration desflurane. All patients received 10 mL · kg-1 · h-1 Ringer’s lactate solution intraoperatively. After surgery, a nasogastric tube was placed in all patients. They were tracheally extubated when fully awake and transferred to the postanesthesia care unit (PACU). No opioids or antiemetics were administered either pre- or intraoperatively.

Administration of Ac
After the anesthesia induction, all patients received either placebo or a single dose of 10, 20, or 40 mg/kg Ac in a stearate-based suppository according to the randomized group assignment (sealed-envelope method).

Blood Sampling and Ac Assay
At the end of the surgical procedure, a single blood sample from each patient was drawn by using the indwelling IV cannula. Plasma was separated by centrifugation and stored at –20°C until analysis. The plasma concentration of Ac was determined by using a commercially available colorimetric assay (ACET®; Vitros Chemistry ProductsTM; Johnson & Johnson, Norderstedt, Germany) and the Johnson & Johnson Ectachem Analyzer model 250 according to the manufacturer’s instructions. The Ac detection range of the assay is 4–350 µg/mL (conversion factor equals 6.6 µmol/mg).

Pain Assessment and Opioid Administration
Early postoperative pain was assessed by using a five-item observational CHIPPS proven to be valid and reliable, especially in preverbal children (15,16). Immediately after emergence and on arrival in the PACU, an independent observer blinded to the treatment group evaluated the items "crying," "facial expression," "positioning of the trunk," "positioning of the legs," and "motor restlessness" every 5 min (a minimum of 13 observational time points). A pain score < 4 of 10 (10 representing the worst imaginable pain to the patient) was considered satisfactory, pain scores of 4 and higher resulted in the administration of 25 µg/kg piritramide (Pi; lockout time, 10 min; 5 boluses maximum = 0.125 mg/kg). The individual dose required to achieve satisfactory analgesia was established by IV titration. Respiration, oxygen saturation, and heart rate were continuously monitored. The observational period in the PACU was 70–90 min. Vomiting and adverse effects were recorded within the first 24 h after surgery.

Statistical Analysis
Multiple comparisons were made by using two-way repeated measures of analysis of variance followed by Newman-Keuls Test for post hoc tests probabilities. Two-tailed Student’s t-test was used where appropriate. Correlations were determined by using Pearson’s correlation.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The four groups were comparable with respect to age, weight, sex, use of premedication, time of blood sampling, and duration of surgery ( Table 1). CHIPPS ratings at different observational time points were not significantly different among groups ( Fig. 1). The shortest observation period in the PACU was 70 min. The use of titrated Pi resulted in satisfactory analgesia (CHIPPS < 4) in the majority of the patients after an average of 15 to 20 min after admittance to the PACU.


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  		Table 1. Demographic Data and Characteristic Operative Times
 


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  		Figure 1. Children and Infants Postoperative Pain Scale (CHIPPS) rating at different observational time points (0 = postextubation, PACU = on arrival in the recovery room, further CHIPPS assessments at 5-min intervals). Shortest observation period in the PACU was 70 min. Use of this regimen resulted in satisfactory analgesia (CHIPPS < 4) in the majority of the patients after an average of 15 to 20 min. Data are expressed as mean ± SD; n = 20 in each group. There was no statistically significant difference among groups. For clarity, error bars have been omitted.

 
Pi was titrated up to a maximum dose of 0.125 mg/kg in the early postoperative period. To achieve adequate analgesia, an average of 3.1 ± 1.3 (Placebo: 2.7 ± 1.6; Ac 10: 3.0 ± 1.2; Ac 20: 3.2 ± 1.3; Ac 40: 3.4 ± 1.1) doses were administered, corresponding to an average cumulative dose of 76.4 ± 32.5 µg/kg (Placebo: 65.5 ± 40 µg/kg; Ac 10: 75.0 ± 30 µg/kg; Ac 20: 80.0 ± 32.5 µg/kg; 85.0 ± 27.5 µg/kg) Pi in the early postoperative period. There was no statistically significant difference among groups ( Fig. 2). The percentage (%) of patients treated with Pi at each observational time point was not significantly different among groups ( Fig. 3).



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  		Figure 2. Cumulative IV dose of piritramide (25 µg/kg; maximum of 5 doses; lockout time, 10 min between doses) throughout the period of observation. Piritramide was titrated to a satisfactory level of analgesia up to a maximum dose of 0.125 mg/kg in the early postoperative period. To achieve a satisfactory level of analgesia, an average of 3.5 ± 1.3 doses were administered, corresponding to a cumulative dose of 87.5 ± 32.5 µg/kg piritramide in the early postoperative period. Data are expressed as mean ± SD; n = 20 in each group. There was no statistically significant difference among groups. For clarity, error bars have been omitted.

 


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  		Figure 3. Percentage of patients treated with piritramide 25 µg/kg at each observational time point. Lockout time between administration was 10 min; maximum dose administered was 0.125 mg/kg (0 = post extubation, PACU = on arrival in the recovery room, further CHIPPS assessments at 5-min intervals). Data are expressed as mean ± SD; n = 20 in each group. There was no statistically significant difference among groups. For clarity, error bars have been omitted.

 
To demonstrate the effect of opioid administration on postoperative pain scores, we assessed changes in CHIPPS ratings at each observational time point (minimum, 13 per patient), with and without Pi administration over 10-min intervals (equivalent to the lockout period). After the administration of Pi (n = 240), CHIPPS ratings were decreased by 3.2 ± 4.9, whereas CHIPPS ratings were only reduced by 0.2 ± 2.1 without the Pi administration (n = 560). There was a statistically significant difference among groups (P < 0.00001).

Blood samples for Ac plasma concentrations were taken from the indwelling venous cannulae; because of technical difficulties (e.g., venoconstriction), sampling from all patients was not possible. Fifty blood samples were collected for analysis ( Table 2). There was no statistically significant difference in the time of blood sampling among groups. Ac 0 and 10 mg/kg produced only subtherapeutic plasma levels (<10 µg/mL). Maximum plasma concentrations of 13 and 21 µg/mL were achieved after 20 and 40 mg/kg, respectively. There were no statistically significant differences among groups. In addition, there was no correlation between Ac plasma concentrations achieved and postoperative opioid requirements (20 mg/kg Ac: r = -0.33; 40 mg/kg Ac: r = 0.45).


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  		Table 2. Plasma Acetaminophen (Ac) Concentrations
 
There was no incidence of bradycardia, respiratory depression <= 10 breaths/min, or oxygen desaturation <= 93% in the PACU. Furthermore, there was no incidence of vomiting or other adverse effects within the first 24 h after surgery.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major findings of this study were that rectal Ac up to 40 mg/kg administered at anesthesia induction in infants and small children undergoing elective cleft palate repair (I) had no effect on early postoperative pain scores, (II) had no opioid-sparing effect in the early postoperative period, and (III) did not result in analgesic plasma concentrations, whereas (IV) carefully titrated IV opioid boluses produced rapid and reliable pain relief.

Postoperative Pain Scores and Opioid Requirements
Rectal Ac, given at anesthesia induction, is very popular in the treatment of mild-to-moderate postoperative pain in infants and small children. As an analgesic adjuvant, it reduces postoperative opioid requirements (3). The currently suggested rectal Ac dose recommendations for the treatment of postoperative pain in infants and children exceed the age-related manufacturer’s guidelines (Drugdex Drug Evaluations: Acetaminophen). Still, data about the efficacy of rectal Ac in the treatment of postoperative pain are conflicting. Rectal Ac 20 mg/kg (6) and 40 mg/kg (1) administered at anesthesia induction failed to adequately treat postoperative pain in up to 46% (1) and 90% (6) of the children undergoing adenotonsillectomies. Morton and O’Brien (5) demonstrated that 15–20 mg/kg rectal Ac had no significant morphine-sparing effect in children undergoing appendectomies. In contrast to these results, both 40 and 60 mg/kg rectal Ac significantly reduced pain and postoperative opioid requirements in children undergoing outpatient surgery in a dose-dependent way (3).

Our results differ from those of Korpela et al. (3), demonstrating that prophylactically-administered rectal Ac in the dose-range studied had no beneficial impact on postoperative pain scores and no opioid-sparing effect in infants or small children undergoing elective cleft palate repair. One possible reason for these conflicting results could be that the type of surgery performed has a significant effect on the analgesic efficacy of rectal Ac and on the additional postoperative opioid requirements. After the administration of rectal Ac, sufficient postoperative pain control was achieved after herniorrhaphies, whereas the analgesic demand was significantly increased after orchidopexies (17). In the study presented by Korpela et al. (3), depending on the group assignment, up to 80% of the patients underwent herniorrhaphies, possibly resulting in low postoperative pain intensities not requiring further opioid administration. Furthermore, patients’ demographics may significantly affect the postoperative pain intensity and opioid requirement. In contrast to investigations studying very heterogeneous age groups and mixed surgical procedures (1,3,10), the patients enrolled in the current study are very homogenous with respect to age, weight, sex, and surgical procedure. As a further standardization of the study design, in all patients, anesthesia, surgery, and postoperative pain assessment were performed by the same personnel.

Ac Plasma Concentrations
In this study, Ac plasma concentrations obtained after the rectal administration of 10, 20, and 40 mg/kg were mainly subtherapeutic (i.e., below the antipyretic range of 10–20 µg/mL) and did not exceed 21 µg/mL in any patient. Recently, Hansen et al. (8) determined Ac plasma concentrations in neonates and young infants. Similar to our results, after the rectal administration of 24 mg/kg Ac, mean peak plasma concentrations achieved were 11 µg/mL only (8). In children, mean peak plasma concentrations of 5.5, 8.8, and 14.2 µg/mL were obtained after rectal Ac doses of 10, 20, and 30 mg/kg at 107, 288, and 210 minutes, respectively (2). Even the administration of large-dose rectal Ac of 45 mg/kg yielded only peak plasma concentrations associated with antipyresis (9).

In 1999, a plasma concentration-analgesic effect relationship of rectal Ac in children was first established (10). Mean posttonsillectomy pain scores of <4 of 10 are achieved at an effect compartment concentration of 10 µg/mL. Using doses up to 40 mg/kg Ac, however, still results in pain scores more than 4 of 10 in the first 2 h postoperatively (10), whereas only pain scores of <4 of 10 are commonly considered satisfactory in children (7).

In addition to the Ac dosages used, the time and route of Ac administration are important. The bioavailability of rectal Ac is lower (18) and the time to peak plasma concentrations is longer than when compared with the same dose given orally (19). Thus, despite the current increase in recommended Ac dosage, the absorption after rectal administration remains erratic (9), and bioavailability is highly variable. Peak plasma concentration occurs in an average of 2 to 3 hours after insertion of rectal suppository (2,8–10). Therefore, after mean blood sampling times between 122 and 129 minutes in this study, analgesic Ac plasma concentrations should have been reached at anesthesia emergence.

The accuracy of the Ac plasma concentrations determined in our study may be limited because of technical difficulties (i.e., venoconstriction) and the study design (i.e., blood sampling from the indwelling cannulae). Only a limited number of blood samples were obtained. Furthermore, because blood samples were collected only once, we cannot exclude the possibility that we might have missed earlier peak Ac plasma concentrations.

Adverse Effects of Ac
In children, hepatotoxicity from Ac poisoning is an exceedingly rare event, with most of the reported cases resulting from chronic administration and not acute overdosage (11). However, Ac may be potentially hepatotoxic in doses twice those recommended by the manufacturer and close to those often prescribed for its antipyretic properties (12). As a precaution, especially in the outpatient surgical setting, parents should be advised about the potential liver damage from Ac in doses exceeding weight-based recommendations (11). Based on the recommendations of Birmingham et al. (2) and Anderson et al. (1,10) the maximum single dose of rectal Ac in this study was limited to 40 mg/kg leading to a safe maximum Ac plasma concentration of 21 µg/mL.

By using a pharmacokinetic dynamic simulation model, larger rectal Ac doses for satisfactory postoperative pain control than used in this study are effective (4). A loading dose of 70 mg/kg and a maintenance dose of 50 mg/kg every 8 hours is predicted to provide adequate postoperative analgesia in children. However, this model has not been used clinically. The potential hepatotoxic effect of Ac in daily doses above 150 mg/kg (4) and the maximum daily cumulative dose restriction of 90 mg/kg (20) should be adhered to. With respect to this safety margin, we feel that an increase in rectal Ac dosage is not advantageous for postoperative pain management in infants and small children, especially if equipotent (7) or even superior (5) clinical alternatives are available. Further investigations using different nonsteroidal antiinflammatory drugs are required to study their suitability and potential opioid-sparing effect in postoperative pain management after elective cleft palate repair.

Observational Scoring Systems for Postoperative Pain Assessment
Various observational scoring systems are available for postoperative pain assessment in preverbal infants and children (15,16,21,22). One of the shortcomings of these systems, however, is the potential inability to differentiate true pain from other forms of perioperative discomfort such as fear, hunger, and separation anxiety. The CHIPPS as a measure of postoperative pain especially in preverbal children is economic and suitable for most clinical settings, controlled data on the sensitivity, specificity, reliability, and validity of the CHIPPS have been presented (16). Explicitly, there was a significant interaction between repeated CHIPPS measurements and the supply of analgesics, whereas sedatives had no effect on CHIPPS scores. The CHIPPS ranges from no pain (0 of 10) to the worst imaginable pain (10 of 10). In our study, the effect of titrated opioid administration on CHIPPS ratings was determined, and a significant correlation between repeated pain assessments and the administration of analgesics was established. Pi significantly decreased CHIPPS ratings by 2.8, whereas no opioid administration reduced CHIPPS ratings by only 0.3, indicating that CHIPPS is actually assessing pain.

Opioid Administration
Postoperative IV opioid administration may be associated with the risk of respiratory depression and oversedation. Yet, these adverse effects constitute no rationale to deny infants and small children postoperative opioids if adequate monitoring is guaranteed and administration is titrated by need. In parts of Europe, the IV opioid Pi is the "gold standard" for postoperative pain management in adults (23). Its safe and efficient use in pediatric postoperative pain management has been described (24). Compared with morphine, the analgesic potency of Pi is 0.7, and it is associated with a decreased incidence of nausea and vomiting as well as less histamine liberation (23). When administered in equipotent doses, its respiratory depressant effect equals that of morphine (23). Compared with pethidine, it is characterized by remarkable cardiovascular stability (23). Compared with other opioids, Pi’s pharmacodynamic properties most closely matched those of the study design: After IV administration, it has a fast onset of action (2–5 minutes) with peak effect after 10 minutes. The mean duration of action is six hours (23).

Vomiting is a potential adverse effect of opioid administration; however, postoperative pain also seems to be a clear predictor of nausea and vomiting in children (25). In our study, there was no incidence of vomiting within the first 24 hours despite oral feeding via the nasogastric tube when fully awake. Furthermore, no other untoward effects from either Ac or Pi were observed.

Based on our results, we conclude that, in infants and small children undergoing elective cleft palate repair, rectally-administered Ac at anesthesia induction in the dose range studied lacks proof of its analgesic efficacy, has no opioid-sparing effect, and does not result in analgesic plasma concentrations in the early postoperative period, whereas carefully titrated IV opioid boluses produced rapid and reliable pain relief.


   Footnotes
 
Presented, in part, at the International Anesthesia Research Society 74th Clinical and Scientific Congress, Honolulu, HI, March 2000 (S349, S350) and the European Society of Anaesthesiologists 8th Annual Meeting with the Austrian International Congress, Vienna, Austria, April 2000 (A-485).


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 Discussion
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Accepted for publication December 7, 2000.




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Lippincott, Williams & Wilkins 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 HighWire Press