Effects of reduction of the caudal morphine dose in paediatric circumcision on quality of postoperative analgesia and morphine-related side-effects.
Article Type: Clinical report
Subject: Morphine (Dosage and administration)
Morphine (Complications and side effects)
Pediatric anesthesia (Methods)
Circumcision (Complications and side effects)
Pain, Postoperative (Prevention)
Drugs (Adverse and side effects)
Drugs (Prevention)
Authors: Cesur, M.
Alici, H.A.
Erdem, A.F.
Yapanoglu, T.
Silbir, F.
Pub Date: 10/01/2007
Publication: Name: Anaesthesia and Intensive Care Publisher: Australian Society of Anaesthetists Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2007 Australian Society of Anaesthetists ISSN: 0310-057X
Issue: Date: Oct, 2007 Source Volume: 35 Source Issue: 5
Product: Product Code: 2834232 Morphine (Unit Dose) NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2834 Pharmaceutical preparations
Geographic: Geographic Scope: Turkey Geographic Code: 7TURK Turkey
Accession Number: 188847467
Full Text: SUMMARY

This study compared the efficacy and adverse effects of three low doses of morphine (10, 15 and 30A [micro]g.[kg.sup.1]) for caudal epidural analgesia in children undergoing circumcision. A total of 135 boys undergoing out-patient circumcision were randomly assigned to receive 10, 15 or 30 [micro]g.[kg.sup.1] of caudal morphine Anaesthesia was induced and maintained with propofol. After induction, the morphine was added to 0.5 ml.[kg.sup.1] 1% lignocaine solution with adrenaline 5 [micro]g.[ml.sup.-1] and injected caudally. Anaesthesia quality, postoperative pain and adverse events in a 24-hour period were evaluated. Paracetamol (20 mg.[kg.sup.1] orally) was used as rescue analgesia as required.

No patient required paracetamol in the first eight hours after the caudal injections In the first 24 hours postoperatively no further analgesia was required in 66.7, 77.8% and 91.1 % of the patients in the 10, 15 and 30 [micro]g.[kg.sup.1] groups, respectively (P=0.01 for 10 vs. 30 groups). All patients had excellent analgesia. No respiratory complications were observed. Nausea-vomiting occurred in 13.3%, 20% and 46.7% of the patients in the 10, 15 and 30 [micro]g.[kg.sup.1] groups(P=0.002 for 10 vs. 30 and 0.044 for 15 vs. 30). Pruritus occurred in 8.9%, 11 %and 15.6% in the 10, 15 and 30 [micro]g.[kg.sup.1] groups but was localised and did not require treatment.

This study was not powered to assess concerns that low dose epidural morphine may rarely be associated with delayed apnoea and is therefore considered unsuitable for outpatient use in many centres Increases in caudal morphine dose above 10[micro]g.[kg.sup.1] produce some paracetamol soaring' but no improvement in analgesia, some pruritus and a significant increase in nausea and vomiting.

Key Words: caudal, children, circumcision, morphine, pruritus, vomiting

Circumcision in children is a very common surgical procedure which may cause severe postoperative pain and distress and is usually performed in an outpatient setting. Single-dose caudal block for circumcision surgery in children is well established as a method for providing effective postoperative pain relief, while potentially decreasing the need for general anesthetic during the procedure (1). The duration of analgesia provided by a single injection caudal block with local anesthetic alone is limited. Adding an adjuvant to prolong the block may improve analgesia.

Caudal morphine is a potent analgesic drug and has a prolonged duration of action for postoperative analgesia with much smaller doses compared with the parenteral route (2). Epidural morphine is frequently associated with adverse effects, including nausea and/or vomiting, urinary retention, pruritus, sedation and respiratory depression (3-6). Because those adverse effects are usually dose dependent, it is rational to use a higher dose only if it provides a clinically significant benefit. The minimal effective dose of caudal morphine for post circumcision pain control has not previously determined.

In this study, we compared the efficacy and adverse effects of three low doses of morphine (30, 15 and 10 [micro]g.[kg.sup.-1] added to 0.5 ml.[kg.sup.-1] 1% lignocaine in children undergoing circumcision.

MATERIAL AND METHODS

Following approval by the Ataturk University Hospital Ethics Committee, this randomised, double-blind study was conducted at Ataturk University Hospital. A total of 135 boys aged 7 to 12 years and of ASA class I-II undergoing elective day case circumcision surgery, were randomly and equally assigned to receive 10, 15 or 30 [micro]g.[kg.sup.-1] of caudal morphine for postoperative analgesia by a computer randomisation program. Informed written consent was obtained from the parent or legal guardian of all boys and the consent of the boys if able to understand. Patients were excluded if they had severe systemic disease, pre-existing neurological or obvious spinal disease, bleeding diathesis, a history of seizure disorder or a known hypersensitivity to amide-type local anesthetics.

On arrival in the operating room, the patients were monitored with electrocardiogram, pulse oximetry and noninvasive arterial blood pressure, and baseline values were recorded. No premedication was administered. Anaesthesia was induced with an intravenous bolus of propofol 1-2 mg.[kg.sup.-1] and maintained with a propofol infusion at 1-2 mg.[kg.sup.-1].[h.-sup.-1]. Ventilation was spontaneous and oxygen was administered via a face mask throughout the surgical procedure.

A blinded assistant prepared solutions for caudal injection to contain 10, 15 or 30 [micro]g.[kg.sup.-1] morphine with 1% lignocaine and adrenaline 5 [micro]g.[ml.sup.-1] Injection volumes were calculated as 0.5 ml.[kg.sup.-1] according to the Armitage formula (7). All caudal blocks were performed by one of two anaesthesiologists experienced in the procedure. Following induction of anaesthesia, the patients were placed in the lateral position. After sterile skin preparation, the sacral hiatus was identified and a local anesthesia was administered: a 25-gauge needle was advanced about 3 to 4 mm through the sacrococcygeal ligament into the epidural space. After a negative aspiration test for blood or cerebrospinal fluid, 2 ml of the prepared solution was injected through the needle as a test dose. The syringe was then disconnected in order to observe for drip back. The patients were also observed for any increase in heart rate which would indicate intravascular injection of adrenaline. If these responses were negative after two minutes, the remainder of the full dose of local anaesthetic solution was injected in three divided doses.

Surgical stimulus was applied 15 minutes after caudal injection. Criteria for inadequate anaesthesia were: gross motor movement, or an increase in respiratory rate or heart rate of more than 25% from baseline.

After completion of surgery, the children were assessed in the recovery room by an independent blinded observer. For pain assessment, a scale from 0 to 2 (0: calm, no pain expressed verbally, 1: pain expressed if questioned, but appeared to be comfortable and 2: pain expressed verbally spontaneously, with crying or restlessness) (8) was used. This scale was taught to the parent or the guardian of subjects for continuing observations at home.

Patients were allowed to go home and to eat and drink four hours after completion of surgical procedures. If the pain score reached 1 or greater, a rescue dose of paracetamol (20 mg.[kg.sup.-1] orally) was administered by the parent or the guardian. The time of the first dose and repeated doses of paracetamol were recorded. The duration of analgesia was measured by the time from caudal injection to the first dose of paracetamol. Urinary retention was considered to be present when boys could not void spontaneously six hours after the caudal injection. The following day, the children's parents or guardians were contacted by telephone to enquire of the postoperative pain, paracetamol requests and adverse events, including respiratory depression, nausea, vomiting, pruritus and urinary retention in the 24-hour period. In patients for whom no rescue paracetamol was required, the time to first analgesia was set to 24 hours.

The primary outcomes were numbers of patients who did not need rescue analgesic and frequency of nausea and/or vomiting. A 25% difference between groups in either parameters was considered to be clinically important. According to a priori power analysis, 43 patients were sufficient in each group to provide 80% power to detect these differences between the groups, accepting a two-tailed (alpha) error of 5%.

Statistical analysis was performed by SPSS for Windows (version 10.0) statistical package (SPSS Inc., Chicago, IL, U.S.A.). Differences in age, weight and duration of operation and analgesia were evaluated statistically among the groups using one-way ANOVA and paired Student's t-test. The frequencies of side-effects and number of patients who did not need rescue analgesic were compared using a [chi square]-test or Fisher's exact test. A P value < 0.05 was accepted as statistically significant.

RESULTS

All 45 patients in each group completed the study and were fully evaluated. Demographic data and operation durations were similar for the three groups (Table 1). Heart, respiratory rate and blood pressure did not diverge by more than 20% from baseline and gross body movement was not noted during the operation. No respiratory or haemodynamic therapy was needed for any patient during surgery or the postoperative period.

The data for quality of analgesia are summarised in Table 2. No patient in any group required any paracetamol for the first eight hours after the caudal injections. Throughout the 24 hours postoperatively, 30 (66.7%), 35 (77.8%) and 41(91.1%) of the patients given 10, 15 and 30 [micro]g.[kg.sup.-1] morphine, respectively, experienced excellent postoperative analgesia (score = 0, i.e. calm, no pain expressed verbally) without any rescue paracetamol. For those subjects requiring no paracetamol, there was a difference between the 10 and 30 [micro]g.[kg.sup.-1] groups (P=1.010), but there were no differences between the 15 and 30 [micro]g.[kg.sup.-1] groups, or between the 10 and 15 [micro]g.[kg.sup.-1] groups. Rescue oral paracetamol was needed for 11 of the 10 [micro]g.[kg.sup.-1] group, eight of the 15 [micro]g.[kg.sup.-1] group and four of the 30 [micro]g.[kg.sup.-1] Four patients in the 10 [micro]g.[kg.sup.-1] group and two in the 15 [micro]g.[kg.sup.-1] group needed two doses of paracetamol during the 24-hour study period, but no patient required more than two doses. Thirty minutes after paracetamol, the pain score was 0 in all patients. There was a trend toward to a longer time interval to the first additional analgesia in the 30 [micro]g.[kg.sup.-1] group compared with the two lower doses, but this difference was not statistically significant (Table 2).

All patients in the three groups were awake and alert approximately 20 minutes after completion of the procedure and they were transferred from the recovery room and discharged from the hospital about two hours later. At discharge, all boys could stand and walk without assistance. The incidence of nausea-vomiting and pruritus for each group is noted in Table 2. Urinary retention and respiratory depression were not observed in any patient.

Nausea-vomiting was observed in six (13.3%), 10 (20%) and 20 (46.7%) boys in the 10, 15 and 30 [micro]g.[kg.sup.-1] groups respectively. Although there were no statistically significant differences between the 10 and the 15 [micro]g.[kg.sup.-1] groups, there were differences between the 10 and 30 [micro]g.[kg.sup.-1] groups and between the 15 and 30 [micro]g.[kg.sup.-1] groups (P=0.002 and P=0.044, respectively). Pruritus was observed in four (8.9%), five (11.1%) and seven (15.6%) boys in the 10, 15 and 30 [micro]g.[kg.sup.-1] groups respectively. Pruritus, when it occurred, was localised to the nose or face and not generalised to the body and treatment was not necessary. There was no significant difference among the groups for the incidence of postoperative pruritus.

DISCUSSION

Circumcision is performed as outpatient surgery and may be associated with significant postoperative pain, which is not only distressing but also is associated with delayed discharge and unanticipated admission or readmission (9). Effective postoperative analgesia for circumcision must include planning for the immediate postoperative period and after discharge. Neuraxial morphine provides prolonged analgesia with small doses (compared with systemic administration). Unfortunately, studies reported that caudal morphine causes a high incidence of postoperative nausea and/or vomiting even with doses as small as 33 [micro]g.[kg.sup.-1] (10). Nausea and vomiting can be a major problem in outpatient surgery both during the hospital stay and later at home (9) and another cause of unexpected admission or readmission. Thus pain management in outpatient procedures which precipitates nausea and vomiting may be unacceptable, even if the analgesia is excellent.

Krane et al (10) studied caudal morphine in doses of 33-100 [micro]g.[kg.sup.-1] and demonstrated that caudal morphine in a dose of 33 [micro]g.[kg.sup.-1] provided excellent analgesia in children following major surgical procedures below the diaphragm. In that study, the frequency of nausea and/or vomiting and pruritus was 33 to 56% and 22 to 57% respectively and there was no difference among the doses of caudal morphine. They recommended future dose-response studies in order to determine the minimum effective dose below 33 [micro]g.[kg.sup.-1]. In the literature only Leong et al (11) studied smaller doses and they compared 25 [micro]g.[kg.sup.-1] and 50 [micro]g.[kg.sup.-1] caudal morphine in children after major urogenital surgery and found that 25 [micro]g.[kg.sup.-1] of caudal morphine was as effective as 50 [micro]g.[kg.sup.-1] for providing postoperative analgesia.

The present study suggested that both 10 and 15 [micro]g.[kg.sup.-1] caudal morphine provided analgesia following circumcision as satisfactory as 30 [micro]g.[kg.sup.-1] morphine with a lower incidence of nausea-vomiting.

Paracetamol, which is very safe and effective, is the most widely used analgesic in paediatric practice. A multimodal approach to postoperative analgesia is recommended (12). Combining paracetamol with a regional technique is a very attractive option.

In the present study, nausea and/or vomiting was the most common side-effect of morphine and was dose-dependent. All findings of the study are specific to minor penile surgery in school-age boys, breathing spontaneously under propofol anesthesia. These specifications may effect the incidence of nausea and vomiting. Postoperative nausea and vomiting is a significant problem resulting in patient suffering and prolonged recovery. School-age children, as surgical inpatients, have a higher incidence of postoperative nausea and vomiting (34 to 50%) compared to adults (13-15. The overall incidence of nausea and/or vomiting following day case paediatric surgery is 20 to 30% (16). There are numerous factors related to this complication. Some of these relate to the patient, including age, gender, history of previous nausea or vomiting, and some factors are also related to the nature and the duration of the surgery (17). These factors are out of the control of the anaesthetist. The factors under the control of the anaesthetist are anaesthetic agents, neuromuscular blockade antagonists, premedication and postoperative pain management. In addition, severe pain itself may also precipitate postoperative nausea and vomiting (18,19). The use of propofol for induction and maintenance reduces the incidence of postoperative nausea and vomiting to 35% compared with 70% following sevoflurane anesthesia (20).

The incidence of pruritus ranged from 8 to 15% but was not statistically significantly different in the groups. Others have found pruritus to be dose-related (21). No patient had respiratory depression or urinary retention.

In the present study, lignocaine was chosen as the local anesthetic due to its fast onset and brief duration of action. The combination of lignocaine for early and profound local anaesthesia and morphine for prolonged analgesia seems a potentially good one. All patients could walk without help within two hours of completion of the surgery.

Due to the rostra] spread of caudally administered morphine and the potential for delayed respiratory depression, caudal morphine is considered by some to be unsuitable in the paediatric outpatient setting. Although respiratory depression due to epidural morphine is measurably dose-related (22) and low doses of morphine appear to have minimal potential for respiratory depression, the risk of unexpected bulk cerebrospinal flow from lumbar to brainstem with unpredictable delayed respiratory depression with potentially catastrophic outcome has dampened enthusiasm for the technique in many centres.

Valley and Bailey (23) administered 70 [micro]g.[kg.sup.-1] of caudal morphine to 138 children. Clinically significant respiratory depression occurred in 11 (< 8%). Ten of the children with respiratory depression were less than one year of age and weighed less than 9 kg. Seven of the 11 patients also received intravenous opioids. Krane et al (10) did not show any evidence of delayed respiratory depression even with 100 [micro]g.[kg.sup.-1] of caudal morphine in children aged one to 16 years. These studies indicate increased risk of respiratory depression after epidural morphine associated with patients under one year of age, high doses and concominant opioid administration by other routes. As the potential for delayed respiratory depression is related to the rostral spread of caudal morphine, higher blocks with larger volumes of caudal epidural injection may be at greater risk. In the present study, all patients were school-age children, both the absolute morphine doses and injection volume were low and no supplemental opioid was used. We would consider that the risk of delayed respiratory depression was minimal. The published data is inadequate to assess what the incidence of a possible low frequency complication such as delayed severe respiratory depression is. We believe that, using our protocol, the potential benefits of low dose caudal morphine balance what we consider are largely theoretical concerns about delayed respiratory depression.

In conclusion, all doses (10, 15 and 30 [micro]g.[kg.sup.-1]) of caudal morphine studied, with paracetamol available as 'rescue' analgesia, provided excellent analgesia. Nausea and/or vomiting was frequent but significantly decreased with decreasing doses of morphine. Whether caudal epidural local anaesthesia without morphine supplementation and with oral paracetamol 'rescue' available would achieve similar satisfactory analgesia with even less nausea or vomiting and pruritus is worthy of further study.

Accepted for publication on May 15, 2007.

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(19.) Romsing J, Ostergaard D, Drozdziewicz D, Schultz P, Ravn G. Diclofenac or acetaminophen for analgesia in paediatric tonsillectomy outpatients. Acta Anaesthesiol Scand 2000; 44:291-295.

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M. CESUR *, H. A. ALICI ([dagger]), A. F. ERDEM ([dagger]), T. YAPANOGLU ([double dagger]), F. SILBIR ([section])

Departments of Anesthesiology and Reanimation and Urology, Ataturk University, Medical Faculty, Erzurum, Turkey

Presented in part at the 8th National Algology Congress, Istanbul, Turkey, May 18 to 21, 2005.

* M.D., Assistant Professor of Anesthesiology, Department of Anesthesiology and Reanimation.

([dagger]) M.D., Assistant Professor, Department of Anesthesiology and Reanimation.

([double dagger]) M.D., Assistant Professor, Department of Urology.

([section]) M.D., Staff Anesthesiologist, Department of Anesthesiology and Reanimation.

Address for reprints: Dr M. Cesur, Yunus Emre Mah. Tomurcuk Sok, Ikizler Apt. B Blok No: 7/7, 25080 Yenisehir/Erzurum, Turkey.
TABLE 1
Patient data and operation duration as mean [+ or -] SD or median
(range)

                     10 [micro]g.[kg.sup.-1]   15 [micro]g.[kg.sup.-1]
                     morphine                  morphine
                     (n= 45)                   (n= 45)

Age (y)              9 (7-12)                  9 (7-12)

Weight (kg)          23 (18-38)                24 (19-40)

Operation duration   22.0[+ or -]3.4           22.2[+ or -]3.3
(min)

                         30 [micro]g.[kg.sup.-1]
                         morphine
                         (n= 45)

Age (y)                  9 (7-12)

Weight (kg)              25 (19-36)

Operation duration       21.6[+ or -]3.3
(min)

TABLE 2
Analgesia and side-effects of morphine (number (%) of mean
[+ or -] SD)

                          10                      15
                          [micro]g.[kg.sup.-1]    [micro]g.[kg.sup.-1]
                          morphine (n=45)         morphine (n=45)

Patients not requiring    30 (66.7%)              35 (77.8%)
'rescue' paracetamol

Patients requiring one    11 (24.4%)              8 (17.8)
dose of paracetamol

Patients requiring two    4 (8.9%)                2 (4.4%)
doses of paracetamol

Duration of analgesia     1165.4[+ or -] 401.7    1287.8[+ or -] 320.7
(min)

Recovery time (min)       9.4[+ or -] 1.3         9.6[+ or -] 1.2

Nausea-vomiting           6 (13.3%)               10 (20%)

Pruritus                  4 (8.9%)                5 (11.1%)

                               30
                               [micro]g.[kg.sup.-1]
                               morphine (n=45)

Patients not requiring         41 (91.1%) (a)
'escue' paracetamol

Patients requiring one         4 (8.9%)
dose of paracetamol

Patients requiring two         0
doses of paracetamol

Duration of analgesia          1386.5[+ or -] 188.0
(min)

Recovery time (min)            9.5[+ or -]1.4

Nausea-vomiting                20 (46.7% ) (b)

Pruritus                       7 (15.6%)

(a): P=0.010 between 10 and 30 [micro]g.[kg.sup.-1] morphine groups.
(b): P=0.002 between 10 and 30 [micro]g.[kg.sup.-1] morphine groups,
P=0.044 between 15 and 30 [micro]g.[kg.sup.-1] morphine groups.
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