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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.57 no.6 Campinas Nov./Dec. 2007
Perioperative analgesia with continuous epidural infusion of morphine combined with clonidine in children undergoing abdominal surgeries*
Analgesia perioperatoria con infusión peridural continua de la combinación de morfina y clonidina en niños sometidos a procedimientos quirúrgicos abdominales
Jyrson Guilherme Klamt, TSAI; Magaly SantoniII; Luis Vicente Garcia, TSAI; Renato Mestriner Stocche, TSAIII
da Disciplina de Anestesiologia do Departamento de Biomecânica, Medicina
e Reabilitação do Aparelho Locomotor, FMRP-USP
IIMédica Assistente, Hospital São Vicente de Paulo (Jundiaí-SP); Doutor em Ciências Médicas pela FMRP-USP
IIIMédico Assistente do Serviço de Anestesiologia do HCFMRP-USP; Doutor em Ciências Médicas pela FMRP-USP
OBJECTIVES: The present study was developed to evaluate the analgesic effects
of the epidural administration of a combination of morphine and clonidine, whose
efficacy has been demonstrated in adults, on the consumption of isoflurane and
postoperative consumption of analgesics in children.
METHODS: Twenty-six children scheduled for intra-abdominal surgeries were randomly divided in two groups. Both groups received an epidural bolus of morphine (8 µg.kg-1) and clonidine (0.8 µg.kg-1) before the surgery, followed by the continuous infusion of clonidine (0.12 µg.kg-1.h-1) plus morphine (1.2 µg.kg-1.h-1) in Group I, and twice those dosages in Group II, during 24 hours. Inspiratory concentrations of isoflurane were measured during the surgery, as well as the number of doses (1 mg.kg-1) of tramadol during 24 hours in the postoperative period.
RESULTS: The concentrations of isoflurane were significantly smaller after 60 and 90 minutes than the concentrations before the incision in Groups II and I, respectively, but those differences were not statistically significant. The consumption of tramadol was significantly lower in Group II, and 7 (53.8%) patients in this group did not need rescue analgesia, but we observed an increase in the incidence of sedation and hypotension. Respiratory depression was not observed in either group.
CONCLUSIONS: Epidural infusion of low doses of clonidine combined with morphine reduced the intraoperative need of isoflurane and postoperative analgesia
Key Words: ANALGESIA, Regional: spinal; ANALGESICS: morphine, clonidine; SURGERY, pediatrics.
Y OBJETIVOS: El presente estudio fue desarrollado para evaluar el efecto
analgésico de la combinación de morfina y clonidina administrada
por vía peridural, cuya eficacia fue demostrada en pacientes adultos,
sobre el consumo de isoflurano y el consumo de medicación analgésica
en el período postoperatorio en niños.
MÉTODO: Veinte y seis niños destinados a operaciones intra-abdominales fueron ubicados aleatoriamente en de los grupos. Los de los grupos recibieron, por vía peridural, bolus de morfina (8 µg.kg-1) y de clonidina (0,8 µg.kg-1) antes del inicio de la intervención quirúrgica, seguidos de infusión continua de clonidina (0,12 µg.kg-1.h-1) más morfina (1,2 µg.kg-1.h-1) en el Grupo I y el doble de esa dosis en el Grupo II, durante 24 horas. Fueron medidas las concentraciones inspiratorias de isoflurano durante la operación y el número de dosis (1 mg.kg-1) de tramadol durante 24 horas en el postoperatorio.
RESULTADOS: Las concentraciones de isoflurano fueron significativamente menores con relación a los valores observados antes de la incisión quirúrgica después 60 y 90 minutos en los grupos II y I, respectivamente, sin embargo no hubo diferencia entre los de los grupos. El consumo de tramadol fue significativamente menor en el grupo 2, siendo que 7 (53,8%) no necesitaron analgesia de rescate, sin embargo fueron observadas mayor sedación e hipotensión arterial. No fue observada depresión respiratoria en los de los grupos.
CONCLUSIÓN: La infusión peridural de la combinación de bajas dosis de clonidina y morfina promovieron reducción de la necesidad de isoflurano en el período intraoperatorio y analgesia postoperatoria de buena calidad.
The epidural administration of clonidine, a a2-adrenergic agonist, produces analgesia 1 and prolongs the analgesia produced by epidural caudal ropivacaine in children 2. Since it has a limited action after a bolus administration, continuous infusion is necessary to prolong postoperative analgesia. There are few reports, even in adults, in the literature on the doses of the epidural infusion of clonidine 3,4. Recently, two reports confirmed the safety and efficacy of the epidural infusion of clonidine associated with small doses of bupivacaine in children 5,6. A preliminary study 7 demonstrated that the epidural administration of a bolus of clonidine, associated or not with ropivacaine, followed by the epidural infusion of the same drugs, promoted analgesia of good quality against pain at rest in children undergoing intracavitary abdominal surgeries. However, the safety of the epidural administration of clonidine is limited by the sedation and hypotension it causes 7.
Several studies in adults demonstrated the potent interaction of the concomitant epidural administration of morphine and clonidine on the relief of postoperative pain in abdominal surgeries 8-12.
The administration of small doses of morphine and clonidine reduces, significantly, the risk of severe side effects of epidural morphine (respiratory depression, urinary retention, vomiting, pruritus, and sedation) and epidural clonidine (sedation and hypotension). Besides, clonidine does not intensify the late respiratory depression, the most feared side effect after the epidural administration of morphine. The short duration of action of both drugs makes continuous infusion more adequate for prolonged pain relief after major surgeries when compared with intermittent injections 13. Despite the proven efficacy of the combination of morphine and clonidine in adults, there are no studies evaluating different regimens of continuous epidural administration of morphine combined with clonidine for pain control in the pediatric population. In addition, the possibility of reduced need of intraoperative general anesthetics could be an added benefit resulting from the combination of morphine and clonidine 1,12,14-16. Thus, the present study evaluated the efficacy of the epidural infusion of low doses of morphine and clonidine in children undergoing major abdominal surgeries.
After approval by the Ethics Committee on Research of the Hospital das Clínicas of the Faculdade de Medicina de Ribeirão Preto USP, and after parents or legal guardians signed an informed consent, 26 children, ages ranging from 4 to 48 months, physical status ASA I to III, scheduled for major abdominal surgeries, such as Nissen fundoplication, excision of intra-abdominal tumors, splenectomy, or intracavitary urologic surgeries, were enrolled in the study. Patients were electronically allocated, at random (Microsoft Excel, Windows), in two non-blind treatment groups of postoperative analgesia. Both groups received continuous infusion of a mixture of clonidine (1.2 µg.mL-1) and morphine (12 µg.mL-1) in normal saline for 24 hours via an epidural catheter, preceded by a bolus dose of clonidine (0.8 µg.kg-1) and morphine (8 µg.kg-1) approximately 5 minutes before the incision. The infusion was administered at 0.1 and 0,2 mL.kg-1.h-1 in Groups I and II, respectively. Exclusion criteria included refusal by parents or legal guardians of the epidural anesthesia, neurologic disorders, cardiovascular disorders, or hemodynamic instability.
The children were placed in lateral decubitus and an epidural catheter (20G, Becton-Dickinson) was inserted using the lumbar (L1-L5) or caudal (sacral hiatus) approach through a Touhy needle (18G, Becton-Dickinson) about 5 cm into the epidural space. Only children in whom the catheter was easily introduced and met normal resistance to the injection were included in the study.
General anesthesia was induced with midazolam (0.1 mg.kg-1), lidocaine (1.5 mg.kg-1), propofol (3-5 mg.kg-1), fentanyl (5 µg. kg-1), dexamethasone (1 mg.kg-1), ondansentron (0.2 mg.kg-1), and pancuronium (0.15 mg.kg-1), and maintained with N2O (N2O/O2, 1:1) and isoflurane. The inspired concentration of isoflurane was titrated to maintain hemodynamic stability, which was defined as a change in systolic blood pressure and heart rate of no more than 20% of baseline parameters. Inspired concentrations of isoflurane were recorded immediately before the incision, and 10, 20, 30, 40, 50, 60, and 90 minutes after the incision, and during closure of the aponeurosis and the skin. During the surgery, Ringer's lactate (12-15 mL.kg-1.h-1) and D5W (5 mg.kg-1.mm-1) were administered intravenously. An orogastric tube was introduced during the surgery for continuous gastric drainage.
After closure of the abdominal wall, the residual neuromuscular blockade was reversed with atropine (25 µg.kg-1), and neostigmine (50 µg.kg-1) and spontaneous ventilation was allowed if patients maintained SpO2 > 95% and PETCO2 < 55 mmHg. The interval between surgery and the beginning of spontaneous ventilation, and the duration of general anesthesia maintained only with N2O, in minutes, were recorded. The children were extubated when they presented a strong reaction to the tracheal tube, had normal respiratory rate and pattern, SpO2 > 97% (FiO2 = 1.0), and PETCO2 < 45 mmHg, opened their eyes, and moved all four limbs. After the surgery, the children were transferred to the recovery room or to the Pediatric Intensive Care Unit (PICU) (patients younger than 6 months) when they were able to maintain SpO2 > 95% after five minutes breathing room air and achieved recovery scores (modified Aldrete-Kroulik scale 14) > 7, and sedation scores (scale from 0-5) > 3. The length of time necessary for extubation and transference to the recovery room or PICU was recorded.
The nursing staff was oriented to administer intravenous (rescue analgesia) tramadol (1 mg.kg-1, a maximum of 3 mg.kg-1 in a 6-hour period) when they identified pain or discomfort in the patient: non-consolable crying and agitation, complaint of pain, difficulty to cough, and difficulty mobilize in bed due to pain, or presented systolic blood pressure or heart rate 20-30% greater than preoperative values. Tramadol solutions (1 mg.mL-1) were always available for immediate administration, as prescribed by the anesthesia team, and administered according to the evaluation of the nurse responsible for the patient. Parents or guardians were instructed on possible signs of pain/discomfort and stimulated to communicate to the nursing staff if they felt their child was experienced pain and/or discomfort. The quality of postoperative anesthesia was evaluated by the number of doses of tramadol requested in the first 24-postoperative hours, and it was considered the second efficacy parameter in the study. Patients in this study did not receive morphine and/or dypirone during those 24 hours.
Sedation, blood pressure (BP), heart rate (HR), recovery from anesthesia (modified Aldrete-Kroulik scale), and respiratory rate (RR) were recorded at 30-minute intervals in the recovery room and PICU up to 120 minutes. Children who remained in the recovery room were discharged to the room 120 minutes after their arrival to this unit. In the room, vital signs (BP, HR, RR, and temperature) were recorded at 2-hour intervals, while patients were awake, and 4-hour intervals when they were sleeping. Heart rate and SpO2 (pulse oximetry) were recorded continuously for 24 hours. Sedation was evaluated using a 6-point scale: 5 awake and alert; 4 sleepy, but easily aroused; 3 sleepy, but opens eyes when called several times or answers to light tactile stimulation; 2 sleepy, difficult to arouse, has to be shaken; 1 responds only to pain stimuli; and 0 no response. Recovery from general anesthesia was evaluated by the modified Aldrete-Kroulik scale, and sleep quality was evaluated by a 3-point scale: 3 excellent; sleeps without interruption; 2 good: wakes occasionally, but not due to pain; 1 poor: awakes frequently.
Hypotension and bradycardia were defined as systolic BP and HR less that 70% of pre-anesthetic values. Respiratory depression was defined as a RR below 20 bpm in children 1-year old or younger, and below 14 bpm in older children, or SpO2 < 95%. Infusion was interrupted for 2 hours if the child seemed too sedate (score < 2), SpO2 was consistently below 94%, or developed respiratory depression. In case of severe respiratory depression (patient with cyanosis and bradycardia), patients were treated with a bolus of naloxone (5 to 10 µg.kg-1) followed by continuous infusion (5 µg.kg.h-1). Adverse events and strange behavior were recorded. The anesthesia team involved in the study remained available for 24 hours in case the child developed any complication related with the analgesic treatment or its eventual lack of efficacy.
Data are presented as mean ± SD or, when mentioned, median. Sedation and sleep quality scores, demographic data, BP, HR, RR, number of doses of tramadol during 24 hours, and time until extubation, to transfer to the recovery room or PICU, to begin spontaneous ventilation, and period anesthesia was maintained with N2O were compared in both groups by the Mann-Whitney test. Differences in inspiratory concentration of isoflurane were compared by non-parametric Analysis of Variance for repeated measurements (Friedman test), followed by Dunn's post test (GraphPad Prism 4). The Chi-square test was used to compare the gender distribution, ASA status, and the occurrence of adverse events. A p < 0.05 was considered significant.
Both groups were similar regarding the demographic data and duration of surgical interventions (Table I). There was a tendency for lower weight and age in Group I, and this group had two patients with ASA III. However, this difference was not statistically significant.
Inspiratory concentrations of isoflurane necessary to maintain general anesthesia reduced progressively and were significantly lower at 90 and 60 minutes after the beginning of the procedure in groups I and II, respectively; however, there was no difference between both groups (Figure 1). The period general anesthesia was maintained only with N2O/O2 was similar in both groups (Figure 2). The length of time until the beginning of spontaneous ventilation, extubation, and discharge from the operating room were similar in both groups (Figure 2).
Recovery from anesthesia was also similar in both groups (Figure 3). Severe sedation was observed in patients in Group II after 2 hours in the recovery room or PICU (Figure 4). The morning after the surgery, patients in Group II were visibly more sedated and had better sleep quality than patients in Group I (Figure 5). The number of doses of tramadol during 24 hours was significantly lower in Group II, in which only 5 patients (38.4%) needed one or two doses of tramadol in the first 24 hours of the postoperative period. (Figure 6).
Three patients in Group II needed volume expansion (with Ringer's lactate, 10 mL.kg-1) to increase their blood pressure after the surgery. Bradycardia and respiratory depression were not observed in both groups. One patient in Group II and 2 in Group I required catheterization of the bladder. Pruritus was observed in 4 patients in Group II. Most patients tolerated well the nasogastric tube, especially patients who received the highest doses. Only one child in Group II developed vomiting.
This study demonstrated that continuous epidural infusion of low doses of clonidine and morphine, administered before beginning major abdominal surgery, in children aged 4 to 48 months promoted good quality analgesia with both doses. Intraoperative analgesia obtained with both infusion regimens was consistently demonstrated by the progressive reduction in the consumption of isoflurane. The higher dose (Group II) promoted good quality analgesia, confirmed by the reduced consumption of tramadol, apparent analgesia in 53.8% of the patients, and better sleep quality. The present study also provided evidence of the safety of the combination of epidural morphine and clonidine in children, despite prolonged sedation and the risk of postoperative hypotension, which responded promptly to volume replacement. Immediate or late respiratory depression and high incidence of vomiting were not observed.
Concentrations of isoflurane necessary to maintain intraoperative cardiovascular stability were reduced in both groups. Reduction in blood pressure, an indicator of the level of anesthesia, was not accompanied by a significant reduction in heart rate. The reduction in the consumption of isoflurane was maintained throughout the surgery and, in most patients, general anesthesia during the closure of the skin could be maintained with N2O/O2 only. On the other hand, immediate recovery from general anesthesia was similar in both groups. It is possible that, due to the nature, intensity of the surgical stimulation, and the effects of fentanyl, the latency of the isoflurane sparing effect in both groups was greater than those reported in the literature for installation of analgesia after the epidural administration of clonidine and morphine in adults 12. However, the latency for the reduction in the need of isoflurane observed in this study coincided with the peak concentration in the cerebrospinal fluid of both drugs after epidural administration17 and also coincided with the time between the epidural administration of clonidine and the maximal reduction of blood pressure observed in a previous study 7 and that reported by other two studies 18,19. Low attack doses of clonidine (0.8 µg.kg-1) and morphine (8 µg.kg-1) were chosen because hypotension associated with tachycardia was observed after doses higher then 1 and 10 µg.kg-1, respectively, in children younger than 6 months.
Titration of the doses (or concentrations) of general anesthetics according to hemodynamic changes provoked by the surgical stimulation is a common and acceptable method of managing general anesthesia. The hemodynamic stability, reflected by the reduction in the need of isoflurane, could have resulted by a specific anti-hypertensive effect of the combination of epidural clonidine-morphine that masked the hemodynamic response to the surgical stress. Thus, it is possible that its cardiovascular and analgesic effects might not be dissociated. The nociceptive stimulation is an important determinant of the need of general anesthetics, and any reduction to that effect can be attributed to a potent analgesic effect 14. A strong general anesthetics-sparing effect of clonidine, or clonidine associated with opioids, regardless of the route of administration, is well documented 1,12,14-16.The impression of the authors is that the reduction in the need of isoflurane produced by the continuous epidural administration was a result of the analgesic effect. In fact, despite the very superficial levels of the general anesthesia administered (concentration of isoflurane) and complete recovery of the neuromuscular transmission (TOF > 3 and a normal pattern of spontaneous ventilation) at the end of the surgery, patients showed no signs of pain (tearing, salivation, or rude movements). Such effectiveness is similar to the effects obtained with the routine use of epidural/caudal 0.25% bupivacaine in children. This result is also consistent with the report that the general anesthetics-sparing effects of the intraoperative administration of epidural clonidine was more effective than sufentanil13, or even 0.25% bupivacaine using the same route, although with relatively elevated doses of clonidine.
It seems evident that the epidural infusion of low doses of clonidine and morphine (Group I) promoted good control of postoperative pain, and doubled the dose (Group II) promoted almost complete analgesia for most children undergoing major abdominal surgeries. Tramadol has been used in our institution for the management of postoperative pain in children older than 3 months as an alternative to morphine. The cumulative doses of rescue analgesics (tramadol), one of the parameters of efficacy used in this study, which depends on the severity of the pain and sleep quality can be a sensitive and objective evaluation of the effectiveness of the method used to control postoperative pain in children 10. Thus, the results demonstrated a clear dose-effect relationship in both groups. The regimen with greater dose and the ratio morphine/clonidine for continuous infusion were obtained, and modified, from a study by Motsch et al. 8 and from a previous study from our institution 7. Even in the higher-dose regimen (Group II) the total dose of morphine in 24 hours (64.4 µg.kg-1) is equivalent to the lower range of safety recommended for the pediatric population 6,14,20,21 that seem to have low probability of late respiratory depression. In fact, we did not detect any indication of respiratory depression in both groups. These results are also similar to those of De Negri et al. 5 and Cecchiaro et al. 6, who reported that the continuous epidural infusion of clonidine associated with ropivacaine promoted analgesia of good quality in children. Coincidently, the doses of clonidine considered effective were exactly the same (0.12 and 0.24 µg.kg-1.h-1) used in the present study. There are no current data available on the epidural infusion of the combination of morphine and clonidine in children.
Similar to fentanyl, the continuous epidural infusion of clonidine produces greater cephalad dispersion in the cerebrospinal fluid than a single dose and, for this reason, it can have analgesic effects in all segments of the spinal cord, regardless of the position of the catheter in the epidural space 22. Another potential benefit of continuous epidural infusion is the constant good quality analgesia since patients are maintained in a "analgesic corridor" between inadequate analgesia and adverse effects, and it should be accompanied by peaks of low amplitude of the cerebrospinal fluid and plasma concentration, therefore reducing the potential risk of adverse effects 13. Except for the prolonged sedation and three temporary episodes of postoperative hypotension, some acceptable side effects caused by epidural morphine, such as pruritus and urinary retention, were detected. Continuous epidural infusion of morphine and clonidine seems to be a promising analgesic treatment, coherent with the principle of multimodal analgesia ("balanced analgesia") advocated by Kehlet 23. Addition of drugs with different mechanisms and sites of action (different pathways), such as non-steroidal anti-inflammatories, could improve pain relief and safety. Further studies are needed to establish the precise doses of the combination of epidural morphine and clonidine that produce effective analgesia with acceptable side effects, by classifying patients by age, type of surgery, clinical conditions, and scores of the stress level.
The present study demonstrated that two regimens of continuous epidural infusion of the combination of morphine and clonidine (clonidine, 0.12 µg.kg-1.h-1, plus morphine, 1.2 µg.kg-1.h-1 and clonidine 0.24 µg.kg-1.h-1, plus morphine, 2.4 µg.kg-1.h-1) in the first 24 postoperative hours, preceded by a bolus of clonidine (0.8 mg.kg-1), and morphine (8 µg.kg-1) before the surgery, reduced the intraoperative need of isoflurane and promoted postoperative dose-related analgesia in children ages 4 months to 48 months undergoing major abdominal surgery. Higher doses of analgesics promoted good quality analgesia in most children, and were associated with marked sedation and the occurrence of temporary hypotension without respiratory depression.
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Dr. Jyrson Guilherme Klamt
Serviço de Anestesiologia Hospital das Clínicas
Av. Bandeirantes 3.900 Monte Alegre
14048-900 Ribeirão Preto, SP
Submitted em 22
de maio de 2006
Accepted para publicação em 06 de agosto de 2007
* Received from Serviço de Anestesiologia do Hospital das Clínicas de Ribeirão Preto da Faculdade de Medicina de Ribeirão Preto Universidade de São Paulo (HCFMRP-USP)