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PEDIATRIC ANESTHESIA

Low-Dose Intrathecal Morphine for Postoperative Analgesia in Children

Arjunan Ganesh, MBBS^*, Andrew Kim, MD, Pasquale Casale, MD, and Giovanni Cucchiaro, MD^*

From the *Department of Anesthesia and Critical Care Medicine, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine Philadelphia, Pennsylvania, Department of Surgery, Division of Urology, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania and Department of Anesthesiology, White Plains Hospital, White Plains New York.

	Abstract

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BACKGROUND: We evaluated the efficacy and safety profile of low-dose (4–5 mcg/kg) intrathecal morphine for postoperative pain management after various surgical procedures in children.

METHODS: We reviewed the pain management service database and the medical records of patients who received low-dose intrathecal morphine for postoperative analgesia at The Children's Hospital of Philadelphia between October 2003 and March 2006. Patients had been prospectively followed for 24–48 h after the intrathecal morphine administration.

RESULTS: The medical records of 187 patients were examined. The mean age was 5.6 ± 5.1 yr (median 4.0, interquartile range [IQR] 1.0–10.0). The median maximum pain score during the first 24 h in patients evaluated by the FLACC score and in those evaluated by the numeric verbal rating scale, was 0 (IQR 0–3) and 0 (IQR 0–4), respectively. The mean time to first rescue opioid was 22.4 ± 16.9 h (range: 0–48 h, 95% CI: 19.9–24.8 h). During the first 24 h after surgery, 70 patients (37%) did not receive any opioids (oral or IV). Of the 117 patients who received opioids, 59 (50%) were managed with oxycodone only. Pain was managed with ketorolac in 33% of patients, either alone (11%) or in combination with IV or oral opioids (22%). The incidence of nausea or vomiting, pruritus, and urinary retention was 32%, 37%, and 6% respectively. One patient had transient postdural puncture headache, while two patients received supplemental oxygen beyond the first 60 postoperative minutes to manage occasional episodes of hypoxemia. No severe respiratory depression requiring assisted ventilation or naloxone administration was observed.

CONCLUSION: We conclude that low-dose intrathecal morphine in the pediatric population can be a useful and safe adjunct for postoperative analgesia.

	Introduction

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Opioid therapy plays the most important role in the management of acute postoperative pain. Opiods can be administered orally, IV, in the epidural space or intrathecally (IT). The choice of the route of administration of opioids is based on the anesthesiologists' preferences, the anticipated degree of postoperative pain for the type of operation, and the duration of the hospital stay. Although Bier first described the use of a spinal anesthetic in 1899 (1), it was only in 1979 that intraspinal opioid administration was reported in humans (2). Although IT opioids have been widely administered to adults undergoing various surgical procedures, its reported use in the pediatric surgical population has been limited to spine, cardiac surgery, frontal encepholocele repairs, and in the long term management of cancer pain (3–5). The doses used in these studies usually ranged from 10–30 mcg/kg, and clinically significant side effects were common. We examined the efficacy and safety of low-dose IT morphine (4–5 mcg/kg) in a variety of surgical procedures in pediatric patients at our institution.

	METHODS

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The study was approved by IRB for Human Studies at The Children's Hospital of Philadelphia. We extracted data from the medical records and the Pain Service Database of children who had undergone IT administration of morphine for postoperative analgesia between October 2003 and March 2006. Demographic information and data on anesthetic and surgical procedures were obtained. These included the type of operation, doses of IT morphine, and use of supplemental intraoperative opioids. Follow-up data included the type, doses and time of administration of rescue analgesic medications, and pain scores over a period of 24–48 h after the operation. The incidence of side effects, including nausea or vomiting, pruritus, urinary retention, use of supplemental oxygen, and postdural puncture headache (PDPH) were also noted. These data were collected and recorded by nurses every 4 h during the postoperative period.

A numeric verbal rating scale (0 represented no pain and 10 was the worst pain ever experienced) was used to assess pain levels in children who were 7 yr of age or older. The FLACC scale (6) was used in children <7 yr or in any child who could not self-report pain levels. Both scales were graduated 0–10. These are the age appropriate scales used by the nursing staff at our institution for assessment of postoperative pain. The pain scores were recorded every 4 h by registered nurses who routinely cared for postoperative patients.

After induction of general anesthesia and endotracheal intubation, 174 of the 187 patients were turned in the lateral decubitus position and a 25-guage Whitacre needle was passed through a 19-guage introducer into the L3–4 or L2–3 lumbar intervertebral space until a free flow of cerebrospinal fluid was obtained and IT morphine 4–5 mcg/kg was administered. The remaining 13 patients underwent repair of a tethered spinal cord, and the surgeons inserted a canula into the subarachnoid space under direct vision and then injected the IT morphine before dural closure. After the injection, the canula was pulled out just as the last dural stitch was tightened. IV opioids (morphine or fentanyl) were used during the surgery in case of hemodynamic instability. Each patient received ondansetron (50 mcg/kg, maximum of 4 mg) for postoperative nausea/vomiting prophylaxis before emergence from general anesthesia.

Postoperatively, 172 of 187 patients were admitted on a regular hospital floor after achieving standard discharge criteria in the postanesthetic care unit (PACU) and were followed by the pain management service for at least 24 h. All medications for pain management and safety monitoring in these patients during the first 24 h after surgery were ordered only by the pain management service. Routine care for these patients included constant cardiorespiratory monitoring (continuous pulse oximetry and electrocardiogram, hourly respiratory rates and four-hourly arterial blood pressures) for the first 24 h. Pulse oximetry alarms were set to alarm when the oxygen saturation was <95%. The 13 neurosurgical patients were admitted into the Pediatric Intensive Care Unit as per hospital policy for all neurosurgical patients. An additional two patients aged 1.5 and 3.5 mo, respectively, who were in the Neonatal Intensive Care Unit before surgery, were transported back to the Neonatal Intensive Care Unit for postoperative care, after tracheal extubation in the operating room.

The protocol for rescue analgesic drugs was as follows:

1. During the first 12 h after the administration of IT morphine, ketorolac (500 mcg/kg; maximum 30 mg) for pain scores 3–5 (FLACC or numeric verbal scale) and nalbuphine (50 mcg/kg) for pain scores more than 5 (FLACC or numeric verbal scale) or whenever there was a clinical contraindication to the use of ketorolac. Use of other opioids during the first 12 h (for persistent pain despite the above intervention) required the approval of the pain management service.
   
2. After the first 12 h, ketorolac (0.5 mg/kg; maximum of 30 mg every 6 h PRN up to a maximum of eight doses) was administered for pain scores of 3–5 (FLACC or numeric verbal scale). When the use of ketorolac was contraindicated, oral oxycodone (0.1 mg/kg; maximum of 10 mg every 4 h PRN) was used for pain scores of 3–5. If oral medication could not be administered, IV nalbuphine (50 mcg/kg; maximum of 4 mg every 4 h) was administered for pain scores of 3–5 (FLACC or numeric verbal scale). IV morphine (50 mcg/kg; maximum of 4 mg every 3 h) was administered for pain scores >5 (FLACC or numeric verbal scale).
   

Ondansetron (50 mcg/kg; maximum of 4 mg every 8 h PRN IV) and metoclopromide (0.2 mg/kg; maximum of 10 mg every 6 h PRN IV) were ordered for treatment of nausea or vomiting.

All data were analyzed using descriptive statistics. Data are represented by mean ± sd unless stated otherwise. Pain scores (both FLACC and numeric) were represented as median scores with interquartile ranges (IQR). Kaplan-Meier survival analysis curves were obtained using JMP 5.01 software (SAS Institute, Cary NC) and box plot was obtained with STATA statistical software (STATA Corporation, College Station, TX). Student's t-test was used to compare independent variables.

	RESULTS

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One hundred eighty-seven patients, 97 men and 90 women, received a dose of 4–5 mcg/kg of IT preservative-free morphine. Table 1 shows the list of procedures. The mean age was 5.6 ± 5.1 (median 4.0, IQR 1.0–10.0) yr.

Pain scores (FLACC in 120 patients and numeric verbal scale in 67 patients) in the PACU and during the first 24 h are presented in Figures 1 and 2. Of 1309 possible pain score data points (seven data points per patient x 187), only 82 (6.2%) were missing. Also, no single patient had more than two data points missing. We determined that the data were missing at random and no further action was taken (7). Those data points were not filled. The median value of the maximum pain score during the first 24 h in patients evaluated by the FLACC score and in those evaluated by the numeric verbal scale, was 0 (IQR 0–3) and 0 (IQR 0–4), respectively. The use of rescue analgesic medications is presented in Table 2. When analyzing the percentage of patients receiving IV opioids in the postoperative period, we found that 81% of patients did not receive any (oral or IV) opioid rescue in the first 8 h and 37% of patients did not receive any opioids (oral or IV) in the first 24 h (Fig. 3). Pain was managed with only IV ketorolac in 11% of patients, while 22% received only oral rescue analgesic drugs, and 16% did not receive any additional analgesic medications in the first 24 postoperative hours.

View larger version (12K): [in this window] [in a new window]   Figure 1. Maximal FLACC pain scores (n = 120) in the postanesthesia care unit (PACU) and in the 24 h follow-up period. The boxes represent the 25th-75th percentile, the thick line in the box represents the median, and the extended bars the 10th-90th percentile. Note that the median maximal pain score for PACU arrival, 4, 8, 12, and 16 h was zero. The dots represent the outliers.

View larger version (11K): [in this window] [in a new window]   Figure 3. Kaplan-Meier survival curve showing the fraction of patients who did not receive any opioid (oral or IV) rescues over a period of 24 h. (Time zero is recorded at initial assessment in the postanesthesia care unit).

View larger version (15K): [in this window] [in a new window]   Figure 2. Maximal numeric pain scores (n = 67) in the postanesthesia care unit (PACU) and in the 24 h follow-up period. The boxes represent the 25th-75th percentile, the thick line in the box represents the median, and the extended bars the 10th-90th percentile. Note that the median maximal pain score at 4, 8, 12, and 16 h was zero. The dots represent the outliers.

The mean time to first opioid rescue was 22.4 ± 16.9 h (range: 0–48 h, 95% CI: 19.9–24.8 h) (Fig. 2), while the mean time to first IV ketorolac rescue was 35 ± 18 h (range: 0–48 h, 95% CI: 32.4–37.5 h).

Four patients received IV morphine within 12 h of IT morphine injection, as the other rescue medications did not control the pain adequately. Two patients received morphine by IV patient-controlled analgesia devices (PCA) starting at 6 and 10 h, respectively after the administration of IT morphine. One of these two patients had undergone a nephrectomy; the other underwent thoracoscopy. The pain management service directly supervised the PCA administration and a baseline infusion of morphine was avoided in these two patients.

Intraoperative opioids were used in 130 patients (70%). Fentanyl (1–2 mcg/kg) was administered to 105 (56%) patients, morphine (50–100 mcg/kg) to 22 (12%) patients, and remifentanil infusion (0.1–1 mcg·kg^–1· min^–1) was used in three (2%) patients. The mean time to first opioid rescue in these patients was 20.1 ± 16.7 h when compared with 27.6 ± 16.2 h in those who did not receive intraoperative opioids (P < 0.05). Table 3 shows the list of procedures, the use of intraoperative opioids, and the mean time to first opioid rescue.

The side effect profile is presented in Table 4. In the PACU, vomiting was observed in 19 patients (10%) and 17 received ondansetron, metoclopromide or a combination of metoclopromide, ondansetron, and dexamethasone. On the floor, 60 patients (32%) had symptoms of nausea or vomiting. Twenty-nine patients (16%) received ondansetron, nine (5%) received metoclopromide, and one (0.5%) received both ondansetron and metoclopromide. Seventy patients (37%) had pruritus, and 24 of these (13%) received nalbuphine treatment.

Urinary catheters were placed during the intraoperative period in 106 patients (57%) for surgical reasons (66% of our patients had urological procedures). The remaining 81 patients did not have an indwelling catheter postoperatively. Five of these patients (6%, 95% confidence limits 2.3%–13.8%) were diagnosed to be in urinary retention in the postoperative period, and were managed with a one-time straight catheterization of the bladder.

Three patients had unintended dural puncture with the 19-guage introducer needle. One of them developed symptoms of PDPH on postoperative day 2, which resolved in 24 h with conservative management that included hydration, IV caffeine, and ibuprofen. Supplemental oxygen was administered via nasal canula to two patients (1%) for brief periods in the postoperative period because of hypoxemia (O₂ saturation <95%). In these two patients, the episodes occurred at 6 h in one (8 yr old) and at 12 h in the other (4 yr old) after surgery. The episodes were self-limited and no patient received assisted ventilation or naloxone administration. The first patient received fentanyl (1 mcg/kg) intraoperatively, while the other did not receive any intraoperative opioids. However, neither of the above two patients received any supplemental opioid after surgery, before the desaturation episodes. The first patient (desaturation at 6 h) received the first rescue opioid only 18 h after surgery and the second patient (desaturation at 12 h) received the first opioid rescue 28 h after surgery.

	DISCUSSION

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This review shows that low-dose IT morphine can provide adequate analgesia in the first 24 h after several types of operations, with 80% of our patients not receiving supplemental rescue opioids in the first 8 h and 52% receiving only oral rescue analgesics in the first 24 h. As this was a retrospective study, we cannot state with certainty that rescue analgesics were always administered when needed. However, we believe that the possibility of inadequate rescue analgesia would be small, as pain in these patients was actively managed by the pain service using a specifically developed protocol. There are clear advantages to an approach where a single intraoperative administration of a drug is accompanied by a minimal requirement for additional interventions for supplemental analgesia in the postoperative period. The rapid transition to the oral route of analgesic therapy has obvious implications in reducing costs and improving patient satisfaction. In contrast, there are increased personnel and equipment costs with alternative analgesic regimens, such as continuous epidural infusions or IV PCA therapy.

There have been studies evaluating the use of IT opioids in the pediatric population, but many were limited to spine and cardiothoracic surgical procedures (8–15) and used doses up to 10–30 mcg/kg of IT morphine (8–10,12,14). We chose a dose of 4–5 mcg/kg based on a previous study (11), where 5 mcg/kg was found be an effective dose balancing potency and side effects in children undergoing spine fusion surgery, a procedure associated with severe postoperative pain.

In our study we noted that the use of intraoperative opioids was associated with a significantly shorter time to first opioid rescue. The most likely reason for this is that intraoperative opioids were more commonly used in more painful surgical procedures. The data in Table 3 seem to support this reasoning.

We observed a relatively low incidence of side effects when compared with previous studies. Many reports in adults demonstrate that IT morphine, although very effective with respect to postoperative analgesia, can cause severe side effects. The incidence of pruritus, emesis, and respiratory depression is dose-dependant and with a reported incidence varying from 60% to 80% for emetic symptoms (16–18), 20%–100% for pruritus (19,20), and 0.36% (21) for respiratory depression. In our study the incidence of side effects was also lower when compared with that reported in other studies where higher doses of IT morphine were used in children (10). In many of these studies, patients received IV opioids via a PCA device in the postoperative period. Hence, it is difficult to establish the exact role of IV PCA and IT morphine in causing the observed side effects. In the only published study in which postoperative analgesia was provided solely by IT morphine (10), the incidence of nausea or vomiting (57%–86%) was significantly higher than that in our report. However, patients in that study received a higher dose of IT morphine than those in our study (10–30 mcg/kg vs 4–5 mcg/kg, respectively).

There are major concerns about the potential for delayed life-threatening respiratory depression after IT morphine administration. The reported incidence of respiratory depression in adult patients who have received an IT opiate is 0.36% (21), but respiratory depression has been variously defined in different studies (22), making it difficult to determine its true incidence even in systematic reviews. In our study no patient developed life-threatening respiratory depression when positive pressure ventilation or naloxone therapy was administered, although two patients did receive supplemental oxygen after the first postoperative hour. As we had 187 patients in our study, we can only state that the upper 95% CI of the incidence of life-threatening respiratory depression after this dose of IT morphine is <3 in 187 (1.6%) (23). We believe that most of these patients can be safely monitored (with well placed protocols) on the regular floor as the incidence of serious side effects, with small dose IT morphine, is low.

Although we used IT morphine in two children less than 6 mo of age, the safety of neuraxial opioids in this age group has not been proven. It may be more prudent to admit these very young patients to a high observation setting such as an intensive care unit until more data are available about the safety of this route of administration. There are data supporting that the ventilatory response to carbon dioxide is depressed for up to 18 h after IT morphine administration in children, but infants do not exhibit greater ventilatory depression than older children (24). The concomitant use of IV opioids increases the risk of serious ventilatory depression (25), reinforcing the need for strict protocols limiting the use of supplemental IV opioids in patients receiving IT morphine.

Most of our patients had a urinary catheter inserted during the intraoperative period as part of the surgical procedure. The incidence of urinary retention was only 6% in patients who did not have a urinary catheter, suggesting that routine urinary catheterization may not be necessary for all patients receiving IT morphine. There was only a single case of PDPH, which probably resulted from the documented wet tap with the introducer needle (19-guage) and resolved with only conservative measures.

We conclude that low-dose IT morphine in the pediatric patient can provide an effective and safe option for postoperative analgesia after many surgical procedures and need not be limited to the cardiothoracic, oncology, or spine surgeries. Additional information is required about the potential for rarer adverse events and protocols must be in place for adequate postoperative monitoring and for limiting the use of IV opioids after IT morphine.

	Footnotes

 
Accepted for publication October 16, 2006.

Address for correspondence and reprint requests to Arjunan Ganesh, MBBS, Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104-4399. Address e-mail to ganesha{at}email.chop.edu.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION 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 PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Ganesh, A. Articles by Cucchiaro, G. Search for Related Content PubMed PubMed Citation Articles by Ganesh, A. Articles by Cucchiaro, G. Related Collections Pediatrics Pharmacology

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