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The Safety of Concurrent Administration of Opioids via Epidural and Intravenous Routes for Postoperative Pain in Pediatric Oncology Patients
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Journal of Pain and Symptom Management
Vol. 35 No. 4 April 2008
Original Article
The Safety of Concurrent Administration of Opioids via Epidural and Intravenous Routes for Postoperative Pain in Pediatric Oncology Patients Doralina L. Anghelescu, MD, Catherine E. Ross, BA, Linda L. Oakes, RN, MSN, C CCNS, and Laura L. Burgoyne, BM, BS Division of Anesthesia and Pain Management Service, Division of Patient Care Services, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
Abstract Supplementation of epidural opioid analgesia with intravenous opioids is usually avoided because of concern about respiratory depression. However, the choice of adjunct analgesic agents for pediatric oncology patients is limited. Antipyretic drugs may mask fever in neutropenic patients, and nonsteroidal anti-inflammatory agents may exert antiplatelet effects and interact with chemotherapeutic agents. We examined the safety of concurrent use of epidural and intravenous opioids in a consecutive series of 117 epidural infusions in pediatric patients and compared our findings to those reported by other investigators. We observed a 0.85% rate of clinically significant respiratory complications. The single adverse event was associated with an error in dosage. In our experience, the supplementation of epidural opioid analgesia with intravenous opioids has been a safe method of postoperative pain control for pediatric patients with cancer. J Pain Symptom Manage 2008;35:412e419. Ó 2008 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Epidural opioids, postoperative pain, patient-controlled analgesia, respiratory depression, pediatric oncology, cancer
Introduction
This work was supported in part by U.S. Public Health Service grant CA21765, NIH grant 5 R25 CA23944 and by the American Lebanese Syrian Associated Charities (ALSAC). Address correspondence to: Doralina L. Anghelescu, MD, Division of Anesthesia, Mail Stop 130, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA. E-mail: [email protected] Accepted for publication: June 9, 2007. Ó 2008 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
The combination of opioids and local anesthetics has become the standard of care for epidural analgesia, because its analgesic effects are greater, and its adverse effects are less, than those of local anesthetics alone.1 However, administration of epidural opioids incurs the risk of respiratory depression and sedation. Epidural analgesia is typically supplemented with nonopioid analgesic agents such as acetaminophen and nonsteroidal anti-inflammatory drugs; intravenous opioids are usually avoided because of early reports of an increased incidence of respiratory depression.2 0885-3924/08/$esee front matter doi:10.1016/j.jpainsymman.2007.06.010
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The choice of adjunct analgesic agents for pediatric cancer patients is limited. Antipyretic agents may mask fever in neutropenic patients, and nonsteroidal anti-inflammatory drugs can exert an antiplatelet effect and interact with chemotherapeutic agents.3 Consequently, epidural analgesia is frequently supplemented with intravenous opioids at our institution. Here we report the safety of this practice in our institution’s recent experience and discuss our findings in the context of the available literature.
Methods Patients This study was approved by the St. Jude Children’s Research Hospital Institutional Review Board, which waived informed consent. Data had been prospectively collected on all patients consecutively treated for postoperative pain by continuous epidural infusion between September 2004 and July 2006 as part of a Quality Improvement project led by the Pain Management Service. We identified all cases in which opioids were administered concurrently by epidural and intravenous routes. Patients were excluded from analysis if they were older than 18 years or if they received opioids by only one route.
Pain Management Postoperative analgesia was provided by continuous epidural infusion of bupivacaine 0.1%e0.125% and fentanyl 2e5 mcg/mL, at an hourly rate calculated to deliver 0.5e1 mcg/kg of fentanyl per hour. Orders for supplemental analgesia consisted of nurse administered intravenous doses of opioid as needed (IV PRN). Dose ranges for supplemental analgesia were 0.05e0.1 mg/kg of morphine, 0.5e1 mcg/kg of fentanyl, and 0.01e0.02 mg/kg hydromorphone every 1e2 hours as needed. If patients had a history of opioid tolerance and difficult-to-control pain, or if IV PRN analgesia failed to control pain, opioid IV patient-controlled analgesia (IV PCA) was provided. The first-line intravenous opioid was morphine; fentanyl and hydromorphone were used as alternatives. The recommended starting PCA bolus doses were morphine 0.02 mg/kg, hydromorphone 0.004 mg/kg, and fentanyl 0.5 mcg/kg, with
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a 15-minute lockout interval. If a background infusion was added, the starting dose per hour was equal to the bolus dose. Patients were admitted to the general oncology floor or the intensive care unit depending on the postoperative status, as decided by the anesthesiologist and the surgeon. The presence of an epidural catheter did not influence admission to a higher acuity floor. Vital signs (blood pressure, heart rate, respiratory rate, and temperature) were monitored every four hours (every two hours in the intensive care unit). Pain intensity, level of consciousness, and motor function were monitored every four hours while patients were awake, and pulse oximetry was monitored continuously. The patient’s level of consciousness was categorized as alert, drowsy, confused, asleep, or unarousable. Pulse oximetry values were displayed at the nursing station via a central monitoring system. It is our hospital policy to notify the physician of oxygen saturations <95%, which may prompt an order for supplemental oxygen. For oxygen saturation <90%, there are standing orders to administer supplemental oxygen by simple face mask at 5 L/min.
Data Collection The medical records of each patient receiving continuous epidural analgesia were examined daily, and relevant information was stored in the Quality Improvement database. These data included the name and concentration of opioid and local anesthetics, the rate of epidural infusion, and any adjustments to those parameters. Data collected on supplemental intravenous opioid analgesia (IV PRN or IV PCA) included the drug, dose, and time interval. If the method of opioid administration (IV PRN vs. IV PCA) changed during the 3e4 days of concomitant continuous epidural infusion, we counted each patient in the category in which he/she was placed initially (as IV PRN or PCA). Each patient’s pain score (median and range) was summarized daily in the Quality Improvement database. Age-appropriate pain scales were used: the numeric pain scale for children older than 13 years, the FACES pain scale for those 5e13 years of age, and the FLACC behavioral scale for those younger than 5 years. Any change in respiratory status, including decreased respiratory rate, respiratory amplitude,
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or pulse oximetry values, was recorded in the database, as were any neurological changes, such as sedation, confusion, hallucination, or seizure. Corrective interventions were also recorded. We examined any adjustments in the epidural infusion rates or composition of the epidural infusate prompted by changes in respiratory or neurological status.
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epidural infusion, which is typically three days. In the PCA group, five patients had basal opioid infusions augmented by patient-controlled boost doses, and nine had patient-controlled doses only. The anatomic level of catheter placement and the types of surgical intervention are presented in Table 1. The dermatomal level of the block is not routinely assessed and was not reported.
Definition of Adverse Events If neurological or respiratory changes were noted, we examined each incident to determine its clinical significance and identify possible contributory factors, such as significant comorbidity or additional sedative drugs (e.g., benzodiazepines and phenothiazines). Clinically significant episodes of respiratory depression were defined as any occurrence of apnea or requirement for aggressive intervention (naloxone administration or intubation) in addition to discontinuation of opioids. Minor respiratory events were defined as a respiratory rate lower than 10 breaths per minute or oxygen saturation less than 90% on room air, requiring minimal interventions such as stimulation, supplemental oxygen, and adjustment of the epidural infusion rate or substitution of PRN opioids for PCA opioids.
Results Patients One hundred forty oncology patients received postoperative epidural analgesia after thoracotomy, exploratory laparotomy, and lower-extremity surgery. Twenty patients were excluded because of age >18 years and three patients were excluded because they received opioids by only one route. Therefore, we examined 117 consecutive cases of postoperative pain management given by continuous epidural opioid infusion and concomitant intravenous opioid infusion. Thirty patients (25.6%) were 1e2 years, 35 patients (30%) were 3e10 years, and 52 patients (44.4%) were 11e18 years of age. The mean age was 8 years (range, 8 months to 18 years). The intravenous opioids were administered initially as IV PRN doses in 103 cases and by IV PCA in 14 cases. The patients were categorized on the basis of initial therapy, but 10 ‘‘crossed over’’ (nine from IV PRN to IV PCA and one from IV PCA to IV PRN) during the course of the continuous
Efficacy of Analgesia Pain was scored as mild (pain score 0e3), moderate (4e6), and severe (>7) on a 0e10 scale. The distribution of pain scores on postoperative Days 1e3 is shown in Table 2.
Adverse Events One clinically significant respiratory adverse event was recorded (0.85%). A 10-month-old infant experienced recurrent apnea and bradycardia after inadvertent administration of 5 mg of morphine rather than the 0.5 mg prescribed, while receiving supplemental oxygen. This complication resolved with stimulation, supplemental oxygen, and discontinuation of the epidural infusion. Minor respiratory events were observed in two patients, 14 and 17 years of age, who experienced respiratory rates of 7 and 9 breaths per minute, respectively. Neither patient required supplemental oxygen and were managed by substituting IV PRN morphine for the IV PCA in the former case and by decreasing the rate of epidural infusion in the latter. Naloxone was not required for any episode of opioid-mediated respiratory depression and neither route of opioid administration had to be discontinued.
Safety Analysis No neurological complications were observed. Of the three respiratory complications observed, two (including the drug error Table 1 Type of Surgery and Location of Epidural Catheter Type of Surgery Level of Catheter Placement (n) Thoracic (32) Lumbar (84) Caudal (1) Total (117)
Exploratory Thoracotomy Laparotomy 18 6 0 24
14 32 1 47
Lower Extremity Surgery 0 46 0 46
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Table 2 Distribution of Pain Scores on Postoperative Days 0e4 Maximum Pain Scores 0 to 3 Day Day Day Day
0 1 2 3
(n ¼ 101) (n ¼ 108) (n ¼ 104) (n ¼ 67)
42 46 59 43
(41.6%) (42.6%) (56.7%) (64.1%)
4 to 6 34 39 26 17
(33.7%) (36.1%) (25%) (25.4%)
described above) occurred in the IV PRN opioid group and one occurred in the IV PCA group in a patient receiving a basal opioid infusion. Only one respiratory adverse event was clinically significant and was noted in the IV PRN opioid group. We also examined the records of the three patients who received opioids via only one route. Two of these patients experienced adverse respiratory events. One patient receiving epidural fentanyl and bupivacaine after a thoracotomy had arterial oxygen desaturation to 75% while receiving supplemental oxygen and had a pleural effusion. The other patient had a respiratory rate of five breaths per minute while receiving IV PCA opioid and epidural analgesia with local anesthetic only; his lowest oxygen saturation was 94% and he did not receive supplemental oxygen. Epidural infusion rates were decreased in six cases (6 of 117). Two cases are presented above, and a further four cases did not meet the study criteria for either clinically significant or minor respiratory events. No adjustments to the concentration of opioid in the epidural infusate were prompted by respiratory or neurological changes; rather, they were prompted by pruritis, hypotension, or bradycardia.
Discussion Only one of the 117 consecutive pediatric patients who received concomitant epidural and intravenous opioids (0.85%) had a clinically significant respiratory complication, which was the result of a drug error. Two other respiratory events were minor and did not result in discontinuation of the epidural or intravenous opioids. Continuous epidural analgesia (bupivacaine 0.1%e0.125% and fentanyl 2e5 mcg/mL for 72 hours) is the standard postoperative practice at our institution. Although epidural
Median Pain Scores 7 to 10 25 23 19 7
(24.7%) (21.3%) (18.3%) (10.5%)
0 to 3 69 83 85 55
(68.3%) (76.9%) (81.7%) (82.1%)
4 to 6 22 15 14 10
(21.8%) (13.9%) (13.5%) (14.9%)
7 to 10 10 10 5 2
(9.9%) (9.2%) (4.8%) (3%)
opioid analgesia is not ordinarily supplemented with IV opioids, it is used for our pediatric oncology patients for several reasons. First, the choice of agents is limited. Our clinicians are concerned that acetaminophen may mask fever in neutropenic patients. Nonsteroidal anti-inflammatory drugs are contraindicated for patients with thrombocytopenia and they interact with chemotherapeutic agents. Second, most of our patients require chronic opioid pain control and have some degree of opioid tolerance at the time of surgery. The high rate of supplemental parenteral opioid analgesia in this study is not necessarily a reflection of the failure of the epidural analgesia, rather an institutional approach to provide liberal ‘‘back-up’’ analgesia plans for all patients receiving regional or neuraxial analgesia. The first-line intravenous opioid supplementation in our practice is PRN administration of IV opioid doses. The rationale for choosing IV PRN doses as the preferred modality is that our low nurse to patient ratio of 1:2 allows frequent clinical observation and prompt provision of PRN opioids as necessary. The PRN doses of opioids are ordered with a range of doses, the higher dose being one that would be administered in the absence of epidural opioids as a ‘‘full dose’’ and the lower dose being a ‘‘half dose.’’ The nurses frequently choose the lower dose first, and then escalate the dose as necessary. IV PCA is used for selected patients with a history of opioid tolerance and pain that is difficult to manage. IV PCA opioids can also be a contingency strategy for patients whose pain is not adequately controlled by intermittent IV doses. However, because one of our 14 patients receiving IV PCA with a basal infusion experienced a minor respiratory complication, basal infusion is no longer used in conjunction with IV PCA and epidural opioids, as it may carry a risk of complications. Patients were not randomized to either IV PRN or IV PCA groups, and crossover
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occurred between the two groups. For both of these reasons, no conclusion can be drawn regarding the safety of one rescue technique over the other. Data about epidural opioid-induced respiratory depression in children are limited. Overall, the reported incidence of respiratory depression associated with epidural opioids is 0%e1.9% in adults (Table 3)1,4e17 and 0%e25% in children (Table 4).18e28 The rates most commonly reported in children are 0.5%e1%.28 The lack of consistent reporting criteria limits the meaningful comparison of studies about neuraxial opioids. Some investigators report respiratory depression on the basis of requirement for naloxone reversal,2,8,11,29 indicating a relatively severe complication. When this definitive criterion is used, the reported rate of respiratory depression with epidural opioids is 0.2%e0.4%.2,8,11 However, when reduced respiratory rate and oxygen saturation are included as criteria, rates of 0.07%e1.2% are reported in adults (Table 3).5e9,12,14e16 Similarly, pediatric studies of epidural analgesia have used two broad definitions of respiratory
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depression: (1) clinically significant episodes such as reintubation, use of naloxone or apnea18,20,26,27 and (2) definitions that include minor events such as respiratory rate <10 per minute or oxygen saturation <90%.21,23 One potential criticism of our study is that it did not use age-specific respiratory rates, which may be relevant in small children and babies. Our definitions of adverse respiratory events were designed to be as inclusive as possible, while maintaining comparability to other studies. The respiratory depression rates associated with epidural and intravenous opioids have been compared. Although morphine administered epidurally appeared to be associated with a lower rate of respiratory depression (0.4%e0.6%) than IV PCA morphine (1.2%e1.9%),9,14 a systematic review of randomized controlled studies found comparable cumulative respiratory depression rates of 1.9% for epidural opioids and 1.8% for IV PCA.4 In the case of PCA opioid administration in adults, respiratory depression rates of 1.2%e 11.5% have been found with meta-analysis
Table 3 Incidence of Respiratory Depression with Epidural AnalgesiadAdult Data Study, Year, Ref #; (n) 1
Wheatley, 2001 ; (1,014e>1.3 million) Wheeler, 20024; (1,596) Fischer, 198813; (107)
Study Design Review of RCTs Review of RCTs Prospective
Epidural Opioid
0.24%e1.6%
Various
Various
E: 1.9%; IV PCA: 1.8%; IV/IM: 2.4% 0%
Various
0.2% 0.9% 0.07%
Naloxone use RR < 10/min RR < 10/min; prompted use of naloxone per protocol RR < 8; Naloxone use
Ready, 1991 ; (1,106) Stuart-Taylor, 19927; (800) de Leon-Casasola, 1994a,16; (4,227) Scott, 19958; (1,014)
Prospective Prospective Prospective Prospective
Fentanyl
Rygnestad, 199710; (2,000)
Prospective
Morphine
Liu, 1998 ; (1,030) Flisberg, 200314; (2,696) Shapiro, 20059; (1,524)
Prospective Prospective Prospective
Fentanyl Morphine Morphine
Burstal, 199817; (1,062)
Various
Fuller, 199015; (4,880) Tsui, 19976; (1,466)
Prospective survey Retrospective Retrospective
Wigfull, 2001b,5; (1,057)
Retrospective
b,12
Criteria
Various
Morphine, fentanyl Morphine Diamorphine Morphine
11
Incidence of Respiratory Depression
Morphine Morphine, fentanyl Fentanyl
RR < 8/min: 1.2%, Naloxone: 0.4% Overall: 1.6%; Severe: 0.15% 0.3% IV PCA: 1.2%; PCEA: 0.4% Overall: 1.2%; IV PCA: 1.9%; E: 0.6%; IT: 0.7% 0.32% 0.25% IV PCA: 1.97%; E: 0.6% 0.19%
‘‘Clinically evident’’
Considered severe if infusion was stopped RR < 8/min RR < 8/min RR < 10/min RR < 8 and sedation RR < 10/min RR < 10/min; SpO2 < 90% PCO2 > 7 kPa RR < 8/min
RCT ¼ Randomized controlled trial; E ¼ Epidural; IV ¼ Intravenous; PCA ¼ Patient-controlled analgesia; IM ¼ Intramuscular; RR ¼ Respiratory rate; PCEA ¼ Patient-controlled epidural analgesia; IT ¼ Intrathecal; SpO2 ¼ Arterial oxygen saturation; pCO2 ¼ Arterial carbon dioxide partial pressure. a Used intravenous morphine as supplementary analgesia. b Used patient-controlled epidural analgesia.
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Table 4 Incidence of Respiratory Depression with Epidural AnalgesiadPediatric Data Study, Year, Ref #; (n) 24
Study Design
Opioid
Incidence of Respiratory Depression
Criteria
Krane, 1989 ; (32) Kart, 1997a,22; (31) Goodarzi, 199921; (90)
RCT RCT RCT
Morphine Fentanyl, morphine Morphine, fentanyl, hydromorphone
Attia, 198618; (20) Krane, 198723; (46) Lovstad, 199725; (100)
Prospective Prospective Prospective
Morphine Morphine Fentanyl
3.1% 0% Morphine: 25% (none severe); fentanyl: 0%; hydromorphone: 0% 0% 0% 0%
Giaufre, 1996b,20; (15,013) Shayevitz, 199626; (54)
Prospective survey
Various
0.006%
Retrospective case control
Morphine
E: 0%; IV: 0%
Valley, 199127; (138)
Retrospective
Morphine
8%
Flandin-Blety, 199519; (7,200) Williams, 200328
Retrospective questionnaire Retrospective questionnaire
Various
0%
Delayed extubation, reintubation, naloxone use Apnea, desaturation, bradycardia, decreased RR, treated with stimulation, intubation, or nalaxone Various, not specified
Various
Overall: 0.1%e5%
Various, not specified
Not specified Not specified RR < 10/min, SpO2 < 90% Apnea RR < 10/min Treatment with rescue medication Apnea
RCT ¼ Randomized controlled trial; IV ¼ Intravenous; RR ¼ Respiratory rate; SpO2 ¼ Arterial oxygen saturation; E ¼ Epidural. a Used intravenous morphine as supplementary analgesic. b Used mostly caudal blocks.
and 1.8 % in a systematic review of randomized controlled trials. In children, the incidence of respiratory depression associated with the use of PCA opioids is 0%e7%30e33 and at our institution 0.56%.30 The respiratory depression rate (0.85%) found in our investigation of dual-route opioids is comparable to that reported for single-route epidural opioid administration or PCA in adults and children. It is also comparable to our institutional complication rate of 0.56% with PCA opioids alone.30 This result indicates an acceptable level of safety. However, we acknowledge that a second route of opioid administration introduces an additional venue for error. The only clinically significant respiratory event in our study was caused by a drug overdose due to human error. One investigator has reported routine concurrent administration of IV and epidural opioids in adult oncology patients.16 Intravenous morphine given concurrently with epidurally infused bupivacaine and morphine for postoperative pain was associated with a 0.07% rate of respiratory depression requiring reversal with naloxone. This low incidence of respiratory complications, as in our patient population, may reflect the increased likelihood of opioid
tolerance caused by opioid administration for chronic cancer pain.34 There are few reported studies of concurrent opioid administration via two routes in nononcology patient populations. A pediatric study comparing continuous epidural infusion of fentanyl and bupivacaine vs. intermittent epidural morphine for postoperative pain control found no episodes of respiratory depression, despite the concomitant use of IV opioids in 7% and 40% of cases, respectively.22 In a landmark study, Gustafsson et al. identified concomitant use of intravenous opioids or sedatives, residual anesthesia, supine position, and thoracic level of the epidural infusion as risk factors for respiratory depression with epidural opioids.2 Other investigators established a direct correlation between intraoperative IV fentanyl and postoperative respiratory depression when epidural opioids were given postoperatively.9 Our observation of respiratory complications in two of the three patients who received opioids via only one route (epidurally or intravenously) suggests that patients’ overall medical condition, comorbid conditions, and other individual factors may contribute more significantly to the risk of respiratory complications
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than the concurrent administration of opioids by epidural and intravenous routes. It has been often recommended that sedativehypnotic drugs not be used together with neuraxial opioids as it may increase the risk of respiratory depression. Two minor respiratory events in our series were in cases in which systemic opioids were combined with additional CNS depressant medications (an antihistaminic and a benzodiazepine, respectively). However, to place this in context, the use of benzodiazepines and sedative antihistamines in our institution is almost universal. We believe that the opioid tolerance of our patients increases the margin of safety of dual-route opioids and that our results cannot necessarily be extrapolated to a more general, opioid-naive patient population. Moreover, our patients and their families tend to be medically sophisticated because of their prolonged hospital stays and cancer treatment and may be more alert to subtle changes. Other institutional factors may increase the safety of dual-route opioid administration. Our nurse-to-patient ratio for patients with epidural catheters rarely exceeds one to two, and all nurses complete an epidural competency program that emphasizes the need for careful monitoring. Further, patients are monitored continuously by pulse oximetry, which is connected to a central monitoring system with alarms at the nursing station. These advantages may not be available in all institutions. Our data suggest that in an appropriate environment, it is safe to use intravenous opioids, given either PRN or via PCA, to supplement postoperative opioid-containing epidural anesthesia in pediatric oncology patients.
Acknowledgments The authors thank Sharon Naron for editorial advice and Poorna Gajjar, RN, for assistance with data collection.
References 1. Wheatley RG, Schug SA, Watson D. Safety and efficacy of postoperative epidural analgesia. Br J Anaesth 2001;87:47e61. 2. Gustafsson LL, Schildt B, Jacobsen K. Adverse effects of extradural and intrathecal opiates: report of a nationwide survey in Sweden. Br J Anaesth 1982;54:479e486.
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3. Litalien C, Jacqz-Aigrain E. Risks and benefits of nonsteroidal anti-inflammatory drugs in children: a comparison with paracetamol. Paediatr Drugs 2001;3:817e858. 4. Wheeler M, Oderda GM, Ashburn MA, Lipman AG. Adverse events associated with postoperative opioid analgesia: a systematic review. J Pain 2002;3:159e180. 5. Wigfull J, Welchew E. Survey of 1057 patients receiving postoperative patient-controlled epidural analgesia. Anaesthesia 2001;56:70e75. 6. Tsui SL, Irwin MG, Wong CM, et al. An audit of the safety of an acute pain service. Anaesthesia 1997; 52:1042e1047. 7. Stuart-Taylor ME, Billingham IS, Barrett RF, Church JJ. Extradural diamorphine for postoperative analgesia: audit of a nurse-administered service to 800 patients in a district general hospital. Br J Anaesth 1992;68:429e432. 8. Scott DA, Beilby DS, McClymont C. Postoperative analgesia using epidural infusions of fentanyl with bupivacaine. A prospective analysis of 1,014 patients. Anesthesiology 1995;83:727e737. 9. Shapiro A, Zohar E, Zaslansky R, et al. The frequency and timing of respiratory depression in 1524 postoperative patients treated with systemic or neuraxial morphine. J Clin Anesth 2005;17:537e542. 10. Rygnestad T, Borchgrevink PC, Eide E. Postoperative epidural infusion of morphine and bupivacaine is safe on surgical wards. Organisation of the treatment, effects and side-effects in 2000 consecutive patients. Acta Anaesthesiol Scand 1997;41: 868e876. 11. Ready LB, Loper KA, Nessly M, Wild L. Postoperative epidural morphine is safe on surgical wards. Anesthesiology 1991;75:452e456. 12. Liu SS, Allen HW, Olsson GL. Patient-controlled epidural analgesia with bupivacaine and fentanyl on hospital wards: prospective experience with 1,030 surgical patients. Anesthesiology 1998;88: 688e695. 13. Fischer RL, Lubenow TR, Liceaga A, McCarthy RJ, Ivankovich AD. Comparison of continuous epidural infusion of fentanyl-bupivacaine and morphine-bupivacaine in management of postoperative pain. Anesth Analg 1988;67:559e563. 14. Flisberg P, Rudin A, Linner R, Lundberg CJ. Pain relief and safety after major surgery. A prospective study of epidural and intravenous analgesia in 2696 patients. Acta Anaesthesiol Scand 2003;47: 457e465. 15. Fuller JG, McMorland GH, Douglas MJ, Palmer L. Epidural morphine for analgesia after caesarean section: a report of 4880 patients. Can J Anaesth 1990;37:636e640. 16. de Leon-Casasola OA, Parker B, Lema MJ, Harrison P, Massey J. Postoperative epidural bupivacaine-morphine therapy. Experience with 4,227
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surgical cancer patients. Anesthesiology 1994;81: 368e375. 17. Burstal R, Wegener F, Hayes C, Lantry G. Epidural analgesia: prospective audit of 1062 patients. Anaesth Intensive Care 1998;26:165e172. 18. Attia J, Ecoffey C, Sandouk P, Gross JB, Samii K. Epidural morphine in children: pharmacokinetics and CO2 sensitivity. Anesthesiology 1986;65: 590e594. 19. Flandin-Blety C, Barrier G. Accidents following extradural analgesia in children. The results of a retrospective study. Paediatr Anaesth 1995;5:41e46. 20. Giaufre E, Dalens B, Gombert A. Epidemiology and morbidity of regional anesthesia in children: a one-year prospective survey of the FrenchLanguage Society of Pediatric Anesthesiologists. Anesth Analg 1996;83:904e912. 21. Goodarzi M. Comparison of epidural morphine, hydromorphone and fentanyl for postoperative pain control in children undergoing orthopaedic surgery. Paediatr Anaesth 1999;9:419e422. 22. Kart T, Walther-Larsen S, Svejborg TF, et al. Comparison of continuous epidural infusion of fentanyl and bupivacaine with intermittent epidural administration of morphine for postoperative pain management in children. Acta Anaesthesiol Scand 1997;41:461e465.
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major orthopaedic surgery. A prospective evaluation of efficacy and side effects. Eur J Anaesthesiol 1997; 14:583e589. 26. Shayevitz JR, Merkel S, O’Kelly SW, Reynolds PI, Gutstein HB. Lumbar epidural morphine infusions for children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1996;10:217e224. 27. Valley RD, Bailey AG. Caudal morphine for postoperative analgesia in infants and children: a report of 138 cases. Anesth Analg 1991;72:120e124. 28. Williams DG, Howard RF. Epidural analgesia in children. A survey of current opinions and practices amongst UK paediatric anaesthetists. Paediatr Anaesth 2003;13:769e776. 29. Krane EJ. Delayed respiratory depression in a child after caudal epidural morphine. Anesth Analg 1988;67:79e82. 30. Anghelescu DL, Burgoyne LL, Oakes LL, Wallace DA. The safety of patient-controlled analgesia by proxy in pediatric oncology patients. Anesth Analg 2005;101:1623e1627. 31. Beaulieu P, Cyrenne L, Mathews S, Villeneuve E, Vischoff D. Patient-controlled analgesia after spinal fusion for idiopathic scoliosis. Int Orthop 1996;20: 295e299.
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32. Berde CB, Lehn BM, Yee JD, Sethna NF, Russo D. Patient-controlled analgesia in children and adolescents: a randomized, prospective comparison with intramuscular administration of morphine for postoperative analgesia. J Pediatr 1991;118: 460e466.
24. Krane EJ, Tyler DC, Jacobson LE. The dose response of caudal morphine in children. Anesthesiology 1989;71:48e52.
33. Marchetti G, Calbi G, Villani A. [PCA in the control of acute and chronic pain in children]. Pediatr Med Chir 2000;22:9e13.
25. Lovstad RZ, Halvorsen P, Raeder JC, Steen PA. Post-operative epidural analgesia with low dose fentanyl, adrenaline and bupivacaine in children after
34. de Leon-Casasola OA. Postoperative pain management in opioid-tolerant patients. Reg Anesth 1996;21:114e116.
Journal of Pain and Symptom Management
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Original Article
The Safety of Concurrent Administration of Opioids via Epidural and Intravenous Routes for Postoperative Pain in Pediatric Oncology Patients Doralina L. Anghelescu, MD, Catherine E. Ross, BA, Linda L. Oakes, RN, MSN, C CCNS, and Laura L. Burgoyne, BM, BS Division of Anesthesia and Pain Management Service, Division of Patient Care Services, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
Abstract Supplementation of epidural opioid analgesia with intravenous opioids is usually avoided because of concern about respiratory depression. However, the choice of adjunct analgesic agents for pediatric oncology patients is limited. Antipyretic drugs may mask fever in neutropenic patients, and nonsteroidal anti-inflammatory agents may exert antiplatelet effects and interact with chemotherapeutic agents. We examined the safety of concurrent use of epidural and intravenous opioids in a consecutive series of 117 epidural infusions in pediatric patients and compared our findings to those reported by other investigators. We observed a 0.85% rate of clinically significant respiratory complications. The single adverse event was associated with an error in dosage. In our experience, the supplementation of epidural opioid analgesia with intravenous opioids has been a safe method of postoperative pain control for pediatric patients with cancer. J Pain Symptom Manage 2008;35:412e419. Ó 2008 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Epidural opioids, postoperative pain, patient-controlled analgesia, respiratory depression, pediatric oncology, cancer
Introduction
This work was supported in part by U.S. Public Health Service grant CA21765, NIH grant 5 R25 CA23944 and by the American Lebanese Syrian Associated Charities (ALSAC). Address correspondence to: Doralina L. Anghelescu, MD, Division of Anesthesia, Mail Stop 130, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105-2794, USA. E-mail: [email protected] Accepted for publication: June 9, 2007. Ó 2008 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
The combination of opioids and local anesthetics has become the standard of care for epidural analgesia, because its analgesic effects are greater, and its adverse effects are less, than those of local anesthetics alone.1 However, administration of epidural opioids incurs the risk of respiratory depression and sedation. Epidural analgesia is typically supplemented with nonopioid analgesic agents such as acetaminophen and nonsteroidal anti-inflammatory drugs; intravenous opioids are usually avoided because of early reports of an increased incidence of respiratory depression.2 0885-3924/08/$esee front matter doi:10.1016/j.jpainsymman.2007.06.010
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The choice of adjunct analgesic agents for pediatric cancer patients is limited. Antipyretic agents may mask fever in neutropenic patients, and nonsteroidal anti-inflammatory drugs can exert an antiplatelet effect and interact with chemotherapeutic agents.3 Consequently, epidural analgesia is frequently supplemented with intravenous opioids at our institution. Here we report the safety of this practice in our institution’s recent experience and discuss our findings in the context of the available literature.
Methods Patients This study was approved by the St. Jude Children’s Research Hospital Institutional Review Board, which waived informed consent. Data had been prospectively collected on all patients consecutively treated for postoperative pain by continuous epidural infusion between September 2004 and July 2006 as part of a Quality Improvement project led by the Pain Management Service. We identified all cases in which opioids were administered concurrently by epidural and intravenous routes. Patients were excluded from analysis if they were older than 18 years or if they received opioids by only one route.
Pain Management Postoperative analgesia was provided by continuous epidural infusion of bupivacaine 0.1%e0.125% and fentanyl 2e5 mcg/mL, at an hourly rate calculated to deliver 0.5e1 mcg/kg of fentanyl per hour. Orders for supplemental analgesia consisted of nurse administered intravenous doses of opioid as needed (IV PRN). Dose ranges for supplemental analgesia were 0.05e0.1 mg/kg of morphine, 0.5e1 mcg/kg of fentanyl, and 0.01e0.02 mg/kg hydromorphone every 1e2 hours as needed. If patients had a history of opioid tolerance and difficult-to-control pain, or if IV PRN analgesia failed to control pain, opioid IV patient-controlled analgesia (IV PCA) was provided. The first-line intravenous opioid was morphine; fentanyl and hydromorphone were used as alternatives. The recommended starting PCA bolus doses were morphine 0.02 mg/kg, hydromorphone 0.004 mg/kg, and fentanyl 0.5 mcg/kg, with
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a 15-minute lockout interval. If a background infusion was added, the starting dose per hour was equal to the bolus dose. Patients were admitted to the general oncology floor or the intensive care unit depending on the postoperative status, as decided by the anesthesiologist and the surgeon. The presence of an epidural catheter did not influence admission to a higher acuity floor. Vital signs (blood pressure, heart rate, respiratory rate, and temperature) were monitored every four hours (every two hours in the intensive care unit). Pain intensity, level of consciousness, and motor function were monitored every four hours while patients were awake, and pulse oximetry was monitored continuously. The patient’s level of consciousness was categorized as alert, drowsy, confused, asleep, or unarousable. Pulse oximetry values were displayed at the nursing station via a central monitoring system. It is our hospital policy to notify the physician of oxygen saturations <95%, which may prompt an order for supplemental oxygen. For oxygen saturation <90%, there are standing orders to administer supplemental oxygen by simple face mask at 5 L/min.
Data Collection The medical records of each patient receiving continuous epidural analgesia were examined daily, and relevant information was stored in the Quality Improvement database. These data included the name and concentration of opioid and local anesthetics, the rate of epidural infusion, and any adjustments to those parameters. Data collected on supplemental intravenous opioid analgesia (IV PRN or IV PCA) included the drug, dose, and time interval. If the method of opioid administration (IV PRN vs. IV PCA) changed during the 3e4 days of concomitant continuous epidural infusion, we counted each patient in the category in which he/she was placed initially (as IV PRN or PCA). Each patient’s pain score (median and range) was summarized daily in the Quality Improvement database. Age-appropriate pain scales were used: the numeric pain scale for children older than 13 years, the FACES pain scale for those 5e13 years of age, and the FLACC behavioral scale for those younger than 5 years. Any change in respiratory status, including decreased respiratory rate, respiratory amplitude,
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or pulse oximetry values, was recorded in the database, as were any neurological changes, such as sedation, confusion, hallucination, or seizure. Corrective interventions were also recorded. We examined any adjustments in the epidural infusion rates or composition of the epidural infusate prompted by changes in respiratory or neurological status.
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epidural infusion, which is typically three days. In the PCA group, five patients had basal opioid infusions augmented by patient-controlled boost doses, and nine had patient-controlled doses only. The anatomic level of catheter placement and the types of surgical intervention are presented in Table 1. The dermatomal level of the block is not routinely assessed and was not reported.
Definition of Adverse Events If neurological or respiratory changes were noted, we examined each incident to determine its clinical significance and identify possible contributory factors, such as significant comorbidity or additional sedative drugs (e.g., benzodiazepines and phenothiazines). Clinically significant episodes of respiratory depression were defined as any occurrence of apnea or requirement for aggressive intervention (naloxone administration or intubation) in addition to discontinuation of opioids. Minor respiratory events were defined as a respiratory rate lower than 10 breaths per minute or oxygen saturation less than 90% on room air, requiring minimal interventions such as stimulation, supplemental oxygen, and adjustment of the epidural infusion rate or substitution of PRN opioids for PCA opioids.
Results Patients One hundred forty oncology patients received postoperative epidural analgesia after thoracotomy, exploratory laparotomy, and lower-extremity surgery. Twenty patients were excluded because of age >18 years and three patients were excluded because they received opioids by only one route. Therefore, we examined 117 consecutive cases of postoperative pain management given by continuous epidural opioid infusion and concomitant intravenous opioid infusion. Thirty patients (25.6%) were 1e2 years, 35 patients (30%) were 3e10 years, and 52 patients (44.4%) were 11e18 years of age. The mean age was 8 years (range, 8 months to 18 years). The intravenous opioids were administered initially as IV PRN doses in 103 cases and by IV PCA in 14 cases. The patients were categorized on the basis of initial therapy, but 10 ‘‘crossed over’’ (nine from IV PRN to IV PCA and one from IV PCA to IV PRN) during the course of the continuous
Efficacy of Analgesia Pain was scored as mild (pain score 0e3), moderate (4e6), and severe (>7) on a 0e10 scale. The distribution of pain scores on postoperative Days 1e3 is shown in Table 2.
Adverse Events One clinically significant respiratory adverse event was recorded (0.85%). A 10-month-old infant experienced recurrent apnea and bradycardia after inadvertent administration of 5 mg of morphine rather than the 0.5 mg prescribed, while receiving supplemental oxygen. This complication resolved with stimulation, supplemental oxygen, and discontinuation of the epidural infusion. Minor respiratory events were observed in two patients, 14 and 17 years of age, who experienced respiratory rates of 7 and 9 breaths per minute, respectively. Neither patient required supplemental oxygen and were managed by substituting IV PRN morphine for the IV PCA in the former case and by decreasing the rate of epidural infusion in the latter. Naloxone was not required for any episode of opioid-mediated respiratory depression and neither route of opioid administration had to be discontinued.
Safety Analysis No neurological complications were observed. Of the three respiratory complications observed, two (including the drug error Table 1 Type of Surgery and Location of Epidural Catheter Type of Surgery Level of Catheter Placement (n) Thoracic (32) Lumbar (84) Caudal (1) Total (117)
Exploratory Thoracotomy Laparotomy 18 6 0 24
14 32 1 47
Lower Extremity Surgery 0 46 0 46
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Table 2 Distribution of Pain Scores on Postoperative Days 0e4 Maximum Pain Scores 0 to 3 Day Day Day Day
0 1 2 3
(n ¼ 101) (n ¼ 108) (n ¼ 104) (n ¼ 67)
42 46 59 43
(41.6%) (42.6%) (56.7%) (64.1%)
4 to 6 34 39 26 17
(33.7%) (36.1%) (25%) (25.4%)
described above) occurred in the IV PRN opioid group and one occurred in the IV PCA group in a patient receiving a basal opioid infusion. Only one respiratory adverse event was clinically significant and was noted in the IV PRN opioid group. We also examined the records of the three patients who received opioids via only one route. Two of these patients experienced adverse respiratory events. One patient receiving epidural fentanyl and bupivacaine after a thoracotomy had arterial oxygen desaturation to 75% while receiving supplemental oxygen and had a pleural effusion. The other patient had a respiratory rate of five breaths per minute while receiving IV PCA opioid and epidural analgesia with local anesthetic only; his lowest oxygen saturation was 94% and he did not receive supplemental oxygen. Epidural infusion rates were decreased in six cases (6 of 117). Two cases are presented above, and a further four cases did not meet the study criteria for either clinically significant or minor respiratory events. No adjustments to the concentration of opioid in the epidural infusate were prompted by respiratory or neurological changes; rather, they were prompted by pruritis, hypotension, or bradycardia.
Discussion Only one of the 117 consecutive pediatric patients who received concomitant epidural and intravenous opioids (0.85%) had a clinically significant respiratory complication, which was the result of a drug error. Two other respiratory events were minor and did not result in discontinuation of the epidural or intravenous opioids. Continuous epidural analgesia (bupivacaine 0.1%e0.125% and fentanyl 2e5 mcg/mL for 72 hours) is the standard postoperative practice at our institution. Although epidural
Median Pain Scores 7 to 10 25 23 19 7
(24.7%) (21.3%) (18.3%) (10.5%)
0 to 3 69 83 85 55
(68.3%) (76.9%) (81.7%) (82.1%)
4 to 6 22 15 14 10
(21.8%) (13.9%) (13.5%) (14.9%)
7 to 10 10 10 5 2
(9.9%) (9.2%) (4.8%) (3%)
opioid analgesia is not ordinarily supplemented with IV opioids, it is used for our pediatric oncology patients for several reasons. First, the choice of agents is limited. Our clinicians are concerned that acetaminophen may mask fever in neutropenic patients. Nonsteroidal anti-inflammatory drugs are contraindicated for patients with thrombocytopenia and they interact with chemotherapeutic agents. Second, most of our patients require chronic opioid pain control and have some degree of opioid tolerance at the time of surgery. The high rate of supplemental parenteral opioid analgesia in this study is not necessarily a reflection of the failure of the epidural analgesia, rather an institutional approach to provide liberal ‘‘back-up’’ analgesia plans for all patients receiving regional or neuraxial analgesia. The first-line intravenous opioid supplementation in our practice is PRN administration of IV opioid doses. The rationale for choosing IV PRN doses as the preferred modality is that our low nurse to patient ratio of 1:2 allows frequent clinical observation and prompt provision of PRN opioids as necessary. The PRN doses of opioids are ordered with a range of doses, the higher dose being one that would be administered in the absence of epidural opioids as a ‘‘full dose’’ and the lower dose being a ‘‘half dose.’’ The nurses frequently choose the lower dose first, and then escalate the dose as necessary. IV PCA is used for selected patients with a history of opioid tolerance and pain that is difficult to manage. IV PCA opioids can also be a contingency strategy for patients whose pain is not adequately controlled by intermittent IV doses. However, because one of our 14 patients receiving IV PCA with a basal infusion experienced a minor respiratory complication, basal infusion is no longer used in conjunction with IV PCA and epidural opioids, as it may carry a risk of complications. Patients were not randomized to either IV PRN or IV PCA groups, and crossover
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occurred between the two groups. For both of these reasons, no conclusion can be drawn regarding the safety of one rescue technique over the other. Data about epidural opioid-induced respiratory depression in children are limited. Overall, the reported incidence of respiratory depression associated with epidural opioids is 0%e1.9% in adults (Table 3)1,4e17 and 0%e25% in children (Table 4).18e28 The rates most commonly reported in children are 0.5%e1%.28 The lack of consistent reporting criteria limits the meaningful comparison of studies about neuraxial opioids. Some investigators report respiratory depression on the basis of requirement for naloxone reversal,2,8,11,29 indicating a relatively severe complication. When this definitive criterion is used, the reported rate of respiratory depression with epidural opioids is 0.2%e0.4%.2,8,11 However, when reduced respiratory rate and oxygen saturation are included as criteria, rates of 0.07%e1.2% are reported in adults (Table 3).5e9,12,14e16 Similarly, pediatric studies of epidural analgesia have used two broad definitions of respiratory
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depression: (1) clinically significant episodes such as reintubation, use of naloxone or apnea18,20,26,27 and (2) definitions that include minor events such as respiratory rate <10 per minute or oxygen saturation <90%.21,23 One potential criticism of our study is that it did not use age-specific respiratory rates, which may be relevant in small children and babies. Our definitions of adverse respiratory events were designed to be as inclusive as possible, while maintaining comparability to other studies. The respiratory depression rates associated with epidural and intravenous opioids have been compared. Although morphine administered epidurally appeared to be associated with a lower rate of respiratory depression (0.4%e0.6%) than IV PCA morphine (1.2%e1.9%),9,14 a systematic review of randomized controlled studies found comparable cumulative respiratory depression rates of 1.9% for epidural opioids and 1.8% for IV PCA.4 In the case of PCA opioid administration in adults, respiratory depression rates of 1.2%e 11.5% have been found with meta-analysis
Table 3 Incidence of Respiratory Depression with Epidural AnalgesiadAdult Data Study, Year, Ref #; (n) 1
Wheatley, 2001 ; (1,014e>1.3 million) Wheeler, 20024; (1,596) Fischer, 198813; (107)
Study Design Review of RCTs Review of RCTs Prospective
Epidural Opioid
0.24%e1.6%
Various
Various
E: 1.9%; IV PCA: 1.8%; IV/IM: 2.4% 0%
Various
0.2% 0.9% 0.07%
Naloxone use RR < 10/min RR < 10/min; prompted use of naloxone per protocol RR < 8; Naloxone use
Ready, 1991 ; (1,106) Stuart-Taylor, 19927; (800) de Leon-Casasola, 1994a,16; (4,227) Scott, 19958; (1,014)
Prospective Prospective Prospective Prospective
Fentanyl
Rygnestad, 199710; (2,000)
Prospective
Morphine
Liu, 1998 ; (1,030) Flisberg, 200314; (2,696) Shapiro, 20059; (1,524)
Prospective Prospective Prospective
Fentanyl Morphine Morphine
Burstal, 199817; (1,062)
Various
Fuller, 199015; (4,880) Tsui, 19976; (1,466)
Prospective survey Retrospective Retrospective
Wigfull, 2001b,5; (1,057)
Retrospective
b,12
Criteria
Various
Morphine, fentanyl Morphine Diamorphine Morphine
11
Incidence of Respiratory Depression
Morphine Morphine, fentanyl Fentanyl
RR < 8/min: 1.2%, Naloxone: 0.4% Overall: 1.6%; Severe: 0.15% 0.3% IV PCA: 1.2%; PCEA: 0.4% Overall: 1.2%; IV PCA: 1.9%; E: 0.6%; IT: 0.7% 0.32% 0.25% IV PCA: 1.97%; E: 0.6% 0.19%
‘‘Clinically evident’’
Considered severe if infusion was stopped RR < 8/min RR < 8/min RR < 10/min RR < 8 and sedation RR < 10/min RR < 10/min; SpO2 < 90% PCO2 > 7 kPa RR < 8/min
RCT ¼ Randomized controlled trial; E ¼ Epidural; IV ¼ Intravenous; PCA ¼ Patient-controlled analgesia; IM ¼ Intramuscular; RR ¼ Respiratory rate; PCEA ¼ Patient-controlled epidural analgesia; IT ¼ Intrathecal; SpO2 ¼ Arterial oxygen saturation; pCO2 ¼ Arterial carbon dioxide partial pressure. a Used intravenous morphine as supplementary analgesia. b Used patient-controlled epidural analgesia.
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417
Table 4 Incidence of Respiratory Depression with Epidural AnalgesiadPediatric Data Study, Year, Ref #; (n) 24
Study Design
Opioid
Incidence of Respiratory Depression
Criteria
Krane, 1989 ; (32) Kart, 1997a,22; (31) Goodarzi, 199921; (90)
RCT RCT RCT
Morphine Fentanyl, morphine Morphine, fentanyl, hydromorphone
Attia, 198618; (20) Krane, 198723; (46) Lovstad, 199725; (100)
Prospective Prospective Prospective
Morphine Morphine Fentanyl
3.1% 0% Morphine: 25% (none severe); fentanyl: 0%; hydromorphone: 0% 0% 0% 0%
Giaufre, 1996b,20; (15,013) Shayevitz, 199626; (54)
Prospective survey
Various
0.006%
Retrospective case control
Morphine
E: 0%; IV: 0%
Valley, 199127; (138)
Retrospective
Morphine
8%
Flandin-Blety, 199519; (7,200) Williams, 200328
Retrospective questionnaire Retrospective questionnaire
Various
0%
Delayed extubation, reintubation, naloxone use Apnea, desaturation, bradycardia, decreased RR, treated with stimulation, intubation, or nalaxone Various, not specified
Various
Overall: 0.1%e5%
Various, not specified
Not specified Not specified RR < 10/min, SpO2 < 90% Apnea RR < 10/min Treatment with rescue medication Apnea
RCT ¼ Randomized controlled trial; IV ¼ Intravenous; RR ¼ Respiratory rate; SpO2 ¼ Arterial oxygen saturation; E ¼ Epidural. a Used intravenous morphine as supplementary analgesic. b Used mostly caudal blocks.
and 1.8 % in a systematic review of randomized controlled trials. In children, the incidence of respiratory depression associated with the use of PCA opioids is 0%e7%30e33 and at our institution 0.56%.30 The respiratory depression rate (0.85%) found in our investigation of dual-route opioids is comparable to that reported for single-route epidural opioid administration or PCA in adults and children. It is also comparable to our institutional complication rate of 0.56% with PCA opioids alone.30 This result indicates an acceptable level of safety. However, we acknowledge that a second route of opioid administration introduces an additional venue for error. The only clinically significant respiratory event in our study was caused by a drug overdose due to human error. One investigator has reported routine concurrent administration of IV and epidural opioids in adult oncology patients.16 Intravenous morphine given concurrently with epidurally infused bupivacaine and morphine for postoperative pain was associated with a 0.07% rate of respiratory depression requiring reversal with naloxone. This low incidence of respiratory complications, as in our patient population, may reflect the increased likelihood of opioid
tolerance caused by opioid administration for chronic cancer pain.34 There are few reported studies of concurrent opioid administration via two routes in nononcology patient populations. A pediatric study comparing continuous epidural infusion of fentanyl and bupivacaine vs. intermittent epidural morphine for postoperative pain control found no episodes of respiratory depression, despite the concomitant use of IV opioids in 7% and 40% of cases, respectively.22 In a landmark study, Gustafsson et al. identified concomitant use of intravenous opioids or sedatives, residual anesthesia, supine position, and thoracic level of the epidural infusion as risk factors for respiratory depression with epidural opioids.2 Other investigators established a direct correlation between intraoperative IV fentanyl and postoperative respiratory depression when epidural opioids were given postoperatively.9 Our observation of respiratory complications in two of the three patients who received opioids via only one route (epidurally or intravenously) suggests that patients’ overall medical condition, comorbid conditions, and other individual factors may contribute more significantly to the risk of respiratory complications
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than the concurrent administration of opioids by epidural and intravenous routes. It has been often recommended that sedativehypnotic drugs not be used together with neuraxial opioids as it may increase the risk of respiratory depression. Two minor respiratory events in our series were in cases in which systemic opioids were combined with additional CNS depressant medications (an antihistaminic and a benzodiazepine, respectively). However, to place this in context, the use of benzodiazepines and sedative antihistamines in our institution is almost universal. We believe that the opioid tolerance of our patients increases the margin of safety of dual-route opioids and that our results cannot necessarily be extrapolated to a more general, opioid-naive patient population. Moreover, our patients and their families tend to be medically sophisticated because of their prolonged hospital stays and cancer treatment and may be more alert to subtle changes. Other institutional factors may increase the safety of dual-route opioid administration. Our nurse-to-patient ratio for patients with epidural catheters rarely exceeds one to two, and all nurses complete an epidural competency program that emphasizes the need for careful monitoring. Further, patients are monitored continuously by pulse oximetry, which is connected to a central monitoring system with alarms at the nursing station. These advantages may not be available in all institutions. Our data suggest that in an appropriate environment, it is safe to use intravenous opioids, given either PRN or via PCA, to supplement postoperative opioid-containing epidural anesthesia in pediatric oncology patients.
Acknowledgments The authors thank Sharon Naron for editorial advice and Poorna Gajjar, RN, for assistance with data collection.
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24. Krane EJ, Tyler DC, Jacobson LE. The dose response of caudal morphine in children. Anesthesiology 1989;71:48e52.
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25. Lovstad RZ, Halvorsen P, Raeder JC, Steen PA. Post-operative epidural analgesia with low dose fentanyl, adrenaline and bupivacaine in children after
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