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Pediatric Anesthesia 2008 18: 217–222 doi:10.1111/j.1460-9592.2008.02413.x Intravenous clonidine infusion in infants after cardiovascular surgery A N J A P O H L- S C H IC K IN GE R M D * , JU L IA LE M M E R M D †, M I C H A E L H Ü B L E R M D ‡, V L A D I M I R A L E X I - M E S K I S H V I L I M D , P h D ‡, M A T T H I A S R E D L I N M D § , F EL I X BE R G ER M D , P h D – A N D B R I G I T TE S T I L L E R M D , P h D # *Department of Neonatology, University Hospital Charité, †Department of Congenital Heart Disease, Deutsches Herzzentrum Berlin, ‡Department of Cardiothorathic and Vascular Surgery, Deutsches Herzzentrum Berlin, §Department of Anesthesia, Deutsches Herzzentrum Berlin and –Department of Congenital Heart Disease, Deutsches Herzzentrum Berlin and Charité, University Children¢s Hospital, Berlin, Germany, #Department of Congenital Heart Disease, Deutsches Herzzentrum Berlin and Childrens University Hospital, Freiburg, Germany Summary Background: The aim of this study was to investigate the hemodynamic profile and heart rhythm in infants who were given intravenous clonidine infusion after prolonged analgesia ⁄ sedation following cardiac surgery. Methods: This is a single center retrospective review. A total of 542 cardiovascular surgical procedures in infants aged 0–24 months with congenital heart disease were performed between 01 ⁄ 2003 and 12 ⁄ 2005 at the Deutsches Herzzentrum in Berlin. The majority received no long-term analgesia ⁄ sedation, but 50 (9%) of these infants received clonidine (dosed at 0.18–3.6 lgÆkg)1Æh)1) for sedation and to reduce withdrawal symptoms such as CNS hyperactivation, hypertension, tachycardia, and fever. The hospital records of these infants were studied. Results: Fifty infants (median age 5.0 months, median body weight 5.3 kg, 32 males ⁄ 18 females) received prolonged analgesia ⁄ sedation to ensure hemodynamic stability. Clonidine infusion started on day 5 (median) after surgery. During clonidine treatment we found an agerelated normalized profile of hemodynamic parameters with a reduction of heart rate and mean arterial pressure from the upper norm to the mean within 24 h (P < 0.001). In no case did clonidine cause low blood pressure resulting in additional therapy to reach the target blood pressure. There were no adverse effects on cardiac rhythm, especially no onset of atrioventricular block. Midazolam, fentanyl, and other opioids could be ended on day 4 of clonidine treatment. Conclusions: Although off-label, it is feasible to use clonidine infusions in infants in the PICU setting after cardiac surgery without hemodynamic problems arising. Keywords: cardiovascular surgery; clonidine; infants; withdrawal Correspondence to: Anja Pohl-Schickinger, Department of Neonatology, Campus Virchow Klinikum, University Hospital Charité, Augustenburger Platz 1, 13353 Berlin, Germany (email: [email protected]). 2008 The Authors Journal compilation 2008 Blackwell Publishing Ltd 217 2 18 A . P O H L - S C H I C K I N G E R ET AL . Introduction Cardiac surgery has achieved major improvements within the last decade. Nowadays, an increasing number of severe congenital cardiac diseases can be surgically corrected within the first year of life. Concurrently, the majority of patients can be extubated early after surgery without the need for prolonged analgesia ⁄ sedation. However, when procedures are complicated by longer duration of surgery, postoperative hemodynamic instability, pulmonary hypertensive crises, primary elective open sternum, capillary leak syndrome, or junctional ectopic tachycardia, the need for analgesia and sedation for several days to guarantee hemdynamic stability may be inevitable. Withdrawal is a common side-effect after prolonged administration of benzodiazepines and opioids for postoperative sedation and analgesia (1). Clonidine, a partial a-2 adrenoreceptor agonist with antihypertensive, analgesic, and sedative properties (2), decreases the dose requirements of sedatives and facilitates opioid withdrawal (3). Several studies describe the beneficial effects of clonidine for premedication in pediatric anesthesia (4), prolongation of postoperative analgesia as a supplement to regional anesthesia (5) and treatment of emergence delirium (6,7). The safe use of oral clonidine for routine sedation in the pediatric intensive care unit in combination with morphine and lorazepam has been reported in children with respiratory failure (3). The objective of this retrospective study was to evaluate the efficacy of continuous intravenous (i.v.) clonidine infusion in reducing benzodiazepine and opioid withdrawal symptoms regarding hemodynamic safety in neonates and infants with congenital heart defects early after cardiac surgery. Methods Between 2003 and 2005 a total of 542 cardiovascular surgical procedures were performed in children aged 0–24 months with congenital heart disease at the Deutsches Herzzentrum in Berlin. While approximately 90% of these patients are extubated early postoperatively, long-term sedation and analgesia are occasionally unavoidable to ensure hemodynamic stability. Fifty of these children (32 males, 18 females) were treated with i.v. clonidine for symptoms of withdrawal (including agitation, hypersalivation, tachycardia, hypertension, and fever) after prolonged (>24 h) treatment with midazolam and fentanyl. Midazolam was used for premedication in all cases. General anesthesia and relaxation were induced with fentanyl, midazolam, and norcuronium. All patients were intubated and ventilated with normal blood gases. All had a urinary bladder catheter, a central venous catheter and a radial or a femoral artery catheter. In patients who required more complex monitoring, catheters were placed surgically in the left atrium and ⁄ or the pulmonary artery to enable continuous measurement for several days. The hospital records of these patients were reviewed. The data collected included demographics, anatomic diagnosis, details of surgery, and postoperative course. Means of heart rate, mean arterial blood pressure (MAP), core temperature, nutrition, infusion of midazolam, fentanyl and additional sedative or analgesic medication was documented on the day before clonidine was started, 2–4 h after the start of clonidine and daily during clonidine treatment, for a maximum of 5 days. Minimal heart rate and cardiac rhythm were documented for the whole time of clonidine usage. Descriptive statistics are reported as medians with 25–75th interquartile ranges (IQR). Statistical analysis was performed using SPSS 12.0 (Chicago, IL, USA). Nonparametric Friedman test was used to compare several samplings. The nonparametric Wilcoxon test was then applied to test for differences between the parameters before and during clonidine treatment. Significance was established at P < 0.05. Results Fifty infants and young children with a median age of 5.0 months (IQR, 3.0–9.0) received clonidine for a median of 3 days (IQR, 2–5). Clonidine treatment was started 5 days (IQR, 2–6) after cardiac surgery. At this time, 38 patients received midazolam with a median dosage of 7.58 lgÆkg)1Æmin)1 (IQR, 1.26– 11.22) and 17 patients fentanyl (median 0.0 lgÆkg)1Æ min)1, IQR, 0.0–0.1 lgÆkg)1Æmin)1). The highest infusion rate of midazolam was 16.9 lgÆkg)1Æmin)1 and the highest fentanyl infusion rate 0.27 lgÆkg)1Æmin)1. 2008 The Authors Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222 I .V . C L O N I D I N E A F T E R C A R D I A C S U R G E R Y Table 1 shows general patient data and the number of patients receiving clonidine on each of the 5 days. Diagnoses and surgical procedures are listed in Table 2. There were six patients with Down syndrome, one with Williams-Beuren syndrome and six former preterm infants. Clonidine was reduced when symptoms of withdrawal such as agitation, hypersalivation, vomiting, tachycardia, hypertension, and fever diminished. The shortest duration of clonidine administration was 14 h. Six patients received clonidine for longer than 5 days, the longest duration of clonidine administration being 18 days. The reason for termination of clonidine was improvement of withdrawal symptoms in nearly all patients. In two patients clonidine was stopped after reintubation and in one patient after sinus bradycardia (55 bpm) that resolved spontaneously within seconds. Before clonidine was started, sinus rhythm was present in 47 patients. Three patients had external pacemaker treatment for slow atrioventricular node rhythm, atrioventricular dissociation, and first-degree atrioventricular block, respectively. There was no adverse effect of clonidine on the cardiac rhythm, in particular no new onset of atrioventricular block. The one patient with atrioventricular dissociation regained sinus rhythm during treatment with clonidine. In no case did clonidine cause low blood pressure resulting in additional inotropic need to reach the target blood pressure. 219 Table 2 Diagnoses and surgical procedures Cardiac diagnoses d-TGA CAVSD TOF ⁄ DORV TA VSD ± ASD Cc-TGA, AS, PS, VSD, ASD CoA CoA, ASD, VSD HLHS, CoA HLHS ALCAPA CAVSD, TGA, PS AS, PS, PFO Aortopulmonary window PA PA, VSD, TGA DAA Cardiomyopathy MVR, TVR Number of patients 1 9 10 4 11 1 1 1 1 2 1 1 1 1 1 1 1 1 1 Surgical procedures Arterial switch Correction Correction Glenn ⁄ shunt Closure PABa End-to-end repaira End-to-end repair, closure Aortic arch repair, Damus-Kaye-Stansel operation, A-P-shunt Norwood I ⁄ II Correction, Berlin Heart Glenn Correction Correction Correction A-P-shunt Correctiona Berlin Heart TR, MR a Operations without cardiopulmonary bypass. d-TGA, d-transposition of great arteries; CAVSD, complete atrioventricular septal defect; TOF, tetralogy of fallot; DORV, double outlet right ventricle; TA, tricuspid atresia; VSD, ventricular septal defect; ASD, atrial septal defect; Cc-TGA, congenitally corrected transposition of great arteries; AS, aortic stenosis; PS, pulmonary stenosis; CoA, coarctation of the aorta; HLHS, hypoplastic left heart syndrome; A-P-shunt, aortopulmonary shunt; ALCAPA, anomalous left coronary artery from pulmonary artery; PFO, patent foramen ovale; PA, pulmonary atresia; DAA, doubled aortic arch; MVR, mitral valve regurgitation; TVR, tricuspid valve regurgitation; PAB, pulmonary arterial banding; AP, aortopulmonary; TR, tricuspid reconstruction; MR, mitral reconstruction. Table 1 Description of the study group Age (months), median (IQR) Body weight (kg), median (IQR) Body height (cm), median (IQR) Sex (male ⁄ female) Days on ventilation, median (IQR) Days on ventilation with clonidine, median (IQR) Postoperative start of clonidine treatment (day), median (IQR) Duration of clonidine treatment (days), median (IQR) Number of patients on clonidine 2–4 h Day 1 Day 2 Day 3 Day 4 Day 5 IQR, interquartile range. 5.0 5.3 61.0 32 7 2 (3.0–9.0) (4.0–6.6) (55.0–68.8) ⁄ 18 (5–9) (1–3) 5 (2–6) 3 (2–5) 50 49 39 27 19 14 The effects of clonidine on MAP, heart rate, and core temperature are shown in Table 3. Milk intake rose from 22 mlÆkg)1 day)1 before clonidine treatment to 54 mlÆkg)1 day)1 on day 5 (P < 0.009 for each day of treatment, data not shown). Nineteen patients were extubated during clonidine treatment. Reintubation was necessary in four of them. Seven patients received clonidine while already breathing spontaneously. There was a significant reduction in midazolam (2–4 h after start of clonidine until day 2, Table 4), fentanyl (2–4 h after start of clonidine until day 4, P < 0.05) and other opioids (day 1 and day 2, P < 0.05). The number of patients receiving midazolam infusion diminished from 38 before clonidine treatment to 16 on day 1. In the further course, the 2008 The Authors Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222 2 20 A . P O H L - S C H I C K I N G E R ET AL . MAP (mmHg) Previous day 2–4 h Day 1 Day 2 Day 3 Day 4 Day 5 60 53 55 55 55 59 55 (55–68) (50–59) (50–60) (50–64) (52–64) (51–63) (52–63) Heart rate (bÆmin)1) P 138 124 120 120 120 120 125 0.000 0.000 0.005 0.291 0.080 0.221 (125–152) (111–140) (112–130) (111–129) (112–130) (106–130) (108–131) P 0.000 0.000 0.000 0.000 0.007 0.054 Temperature (C) 37.3 37.1 37.1 37.2 37.2 37.2 37.5 (36.9–37.7) (36.6–37.3) (36.8–37.5) (36.8–37.4) (37.0–37.5) (36.8–37.7) (37.3–37.8) P Table 3 Parameters in the course of clonidine treatment 0.004 0.001 0.013 0.579 0.527 0.482 The median and interquartile range of mean arterial blood pressure, heart rate (bÆmin)1) and central temperature the day before and up to 5 days after the start of clonidine infusion are shown. The P-values indicate the level of significance for a decrease between the day before infusion and the given day. Table 4 Doses of clonidine and midazolam in the course of clonidine treatment Clonidine (lgÆkg)1Æh)1) Previous day 2–4 h Day 1 Day 2 Day 3 Day 4 Day 5 1.50 1.44 1.37 1.20 1.34 1.14 (1.20–1.80) (0.63–1.80) (0.71–1.80) (0.81–1.80) (0.63–2.33) (0.69–2.19) Midazolam (lgÆkg)1Æmin)1) 7.58 3.01 0.00 0.00 0.00 0.00 0.00 (1.26–11.22) (0.00–8.01) (0.00–3,76) (0.00–0.00) (0.00–0.00) (0.00–0.00) (0.00–0.00) P 0.000 0.000 0.000 0.000 0.000 0.003 The doses of clonidine and midazolam are shown as median and interquartile range. The P-values indicate the level of significance for a decrease of the midazolam dose between the day before clonidine treatment and the given day. number of patients receiving midazolam further decreased and there was no patient with midazolam treatment on day 5. Two patients still had fentanyl infusion on day 1; there was no patient with fentanyl infusion from day 3 to day 5. There was no influence of clonidine on the administration of nonopioid analgesics. Discussion Oral clonidine given as premedication causes anxiolysis and sedation and provides perioperative hemodynamic stability in adults. Nishina et al. (8,9) reproduced these beneficial effects in children aged 5 years and older. It was shown that oral clonidine given in a dose of 4 lgÆkg)1 significantly reduced the intraoperative instability of blood pressure and heart rate. While the majority of studies examined the use of clonidine as coanalgesic prior to surgery (3), its use in children as an i.v. sedative in the postoperative course has not been sufficiently investigated. Ambrose et al. (2) found that i.v. clonidine in combination with midazolam can provide dose-dependent sedation in ventilated critically ill children without adverse effects on cardiovascular performance. Children enrolled in their study were aged 10 years and under. Our study confirms their findings in younger children. The onset of withdrawal symptoms with a median of 5 days (IQR, 2–6) after surgery is comparable with recently published data on current UK sedation practice in pediatric intensive care units (10). This study reports an incidence of withdrawal of between 5% (intubated patients after cardiac surgery, median age 0.42 years, IQR: 0.06–3) and 15% (intubated noncardiac patients, median age 1.5 years, IQR: 0.42–7). We observed an incidence of 9% in our study group, which has a median age of 5 months (IQR, 3–9). The consensus guidelines on sedation and analgesia in critically ill children recommend a dose of i.v. clonidine of 0.1–2 lgÆkg)1Æh)1 (11). Our findings suggest that continuous i.v. clonidine in 0- to 24month-old postoperative cardiac surgical patients may be safe and efficacious. It provides hemodynamic stability in this group of patients at high risk for cardiac failure because of complex congenital heart defects. We showed that i.v. clonidine facilitates a quick and significant reduction of midazolam, fentanyl, and other opioids, and can significantly minimize symptoms of withdrawal by normalizing MAP, heart rate, and core temperature. As our patients suffer from cardiac disease, the body temperature was lowered by antipyretics and 2008 The Authors Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222 I .V . C L O N I D I N E A F T E R C A R D I A C S U R G E R Y mechanical cooling to prevent elevated oxygen demand and higher cardiac index. The appearance of atrioventricular block has been repeatedly described as a side-effect of clonidine (12,13). In our study, we did not experience any serious adverse effects of clonidine in a dose of 0.18– 3.6 lgÆkg)1Æh)1 on cardiac rhythm and in particular no higher degree of atrioventricular block. Only one patient developed sinus bradycardia during clonidine treatment; this lasted only a few seconds and resolved spontaneously. As clonidine elimination half-time ranges from 6 to 24 h, a causal relationship between clonidine and bradycardia seems unlikely in this context. The reduction of MAP and core temperature was highly significant until the third day after the start of clonidine, the decrease and normalization of the heart rate until the fourth day. For patients with a good response to clonidine the treatment usually lasted <5 days. For later days the statistics do not exhibit a significant decrease, because the number of patients still receiving clonidine decreased from 50 to 19. The respiratory depressant effect has been described in clonidine poisoning of children (12–15) but clonidine does not potentiate opioid-induced respiratory depression (16). Although randomized studies have shown that clonidine administered via the caudal route does not affect respiratory function (17– 20), there are several case reports describing apnea in preterm infants, ex-preterm infants and neonates in connection with caudal clonidine (21–24). In adults, clonidine infusion has no statistically significant effect on cardiorespiratory variables (25). We found no major respiratory depressant effect, as the reintubation rate was not higher than that normally found in this patient group. Other drugs used for treating withdrawal in pediatric intensive care units are morphine, chloral hydrate, paracetamol or other NSAID, diazepam, fentanyl with midazolam and odanstron with dexamethason, named in descending frequency (10). Also there is growing interest in the use of dexmedetomidine, a complete a-2 adrenoreceptor agonist that has a shorter half-life (2–3 h) and limited effects on hemodynamic and respiratory function (26). To summarize, we studied the use of i.v. clonidine in 0- to 24-month-old children for the treatment of 221 withdrawal after cardiac surgery. Clonidine decreased the symptoms of withdrawal by lowering MAP, heart rate, and core temperature. There was a significant effect in terms of reduction of opioid analgesics and no side-effects on cardiac rhythm. Therefore, we consider the use of continuous i.v. clonidine for the treatment of withdrawal to be safe. There are several limitations. As this study was not conceived in prospective form, no validated scores have been used to quantify withdrawal symptoms. It lacks a placebo-matched control group, which makes it impossible to discriminate the natural process after surgery in these children. Nevertheless, the hemodynamic profile of these young and hemodynamically critical clonidinetreated infants may provide helpful information, especially as clonidine, often used in pediatric intensive care units, is still off-label. Prospective, randomized studies are needed to corroborate our conclusions. Acknowledgement We thank Ms. Anne Gale, medical editor, for editorial assistance. References 1 Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med 2000; 28: 2122–2132. 2 Ambrose C, Sale S, Howells R et al. Intravenous clonidine infusion in critically ill children: dose-dependent sedative effects and cardiovascular stability. Br J Anaesth 2000; 84: 794–796. 3 Arenas-Lopez S, Riphagen S, Tibby SM et al. Use of oral clonidine for sedation in ventilated paediatric intensive care patients. Intensive Care Med 2004; 30: 1625–1629. 4 Bergendahl H, Lonnqvist PA, Eksborg S. Clonidine in paediatric anaesthesia: review of the literature and comparison with benzodiazepines for premedication. Acta Anaesthesiol Scand 2006; 50: 135–143. 5 Nishina K, Mikawa K, Shiga M et al. Clonidine in paediatric anaesthesia. Paediatr Anaesth 1999; 9: 187–202. 6 Malviya S, Voepel-Lewis T, Ramamurthi RJ et al. Clonidine for the prevention of emergence agitation in young children: efficacy and recovery profile. Pediatr Anesth 2006; 16: 554–559. 7 Tesoro S, Mezzetti D, Marchesini L et al. Clonidine treatment for agitation in children after sevoflurane anesthesia. Anesth Analg 2005; 101: 1619–1622. 8 Nishina K, Mikawa K, Maekawa N et al. Clonidine decreases the dose of thiamylal required to induce anesthesia in children. Anesth Analg 1994; 79: 766–768. 9 Nishina K, Mikawa K, Maekawa N et al. The efficacy of clonidine for reducing perioperative haemodynamic changes 2008 The Authors Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222 2 22 10 11 12 13 14 15 16 17 18 A . P O H L - S C H I C K I N G E R ET AL . and volatile anaesthetic requirements in children. Acta Anaesthesiol Scand 1996; 40: 746–751. Jenkins IA, Playfor SD, Bevan C et al. Current United Kingdom sedation practice in pediatric intensive care. Pediatr Anesth 2007; 17: 675–683. Playfor S, Jenkins I, Boyles C et al. Consensus guidelines on sedation and analgesia in critically ill children. Intensive Care Med 2006; 32: 1125–1136. Olsson JM, Pruitt AW. Management of clonidine ingestion in children. J Pediatr 1983; 103: 646–650. Anderson RJ, Hart GR, Crumpler CP et al. Clonidine overdose: report of six cases and review of the literature. Ann Emerg Med 1981; 10: 107–112. Litovitz TL, Normann SA, Veltri JC. 1985 Annual Report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1986; 4: 427–458. Nichols MH, King WD, James LP. Clonidine poisoning in Jefferson County, Alabama. Ann Emerg Med 1997; 29: 511–517. Bailey PL, Sperry RJ, Johnson GK et al. Respiratory effects of clonidine alone and combined with morphine, in humans. Anesthesiology 1991; 74: 43–48. Jamali S, Monin S, Begon C et al. Clonidine in pediatric caudal anesthesia. Anesth Analg 1994; 78: 663–666. Lee JJ, Rubin AP. Comparison of a bupivacaine–clonidine mixture with plain bupivacaine for caudal analgesia in children. Br J Anaesth 1994; 72: 258–262. 19 Ivani G, Mattioli G, Rega M et al. Clonidine–mepivacaine mixture vs plain mepivacaine in paediatric surgery. Paediatr Anaesth 1996; 6: 111–114. 20 Dupeyrat A, Goujard E, Muret J et al. Transcutaneous CO2 tension effects of clonidine in paediatric caudal analgesia. Paediatr Anaesth 1998; 8: 145–148. 21 Galante D. Preoperative apnea in a preterm infant after caudal block with ropivacaine and clonidine. Pediatr Anesth 2005; 15: 708–709. 22 Breschan C, Krumpholz R, Likar R et al. Can a dose of 2 lgÆkg)1 caudal clonidine cause respiratory depression in neonates? Paediatr Anaesth 1999; 9: 81–83. 23 Fellmann C, Gerber AC, Weiss M. Apnoea in a former preterm infant after caudal bupivacaine with clonidine for inguinal herniorrhaphy. Paediatr Anaesth 2002; 12: 637–640. 24 Bouchut JC, Dubois R, Godard J. Clonidine in preterm-infant caudal anesthesia may be responsible for postoperative apnea. Reg Anesth Pain Med 2001; 26: 83–85. 25 Hall JE, Uhrich TD, Ebert TJ. Sedative, analgesic and cognitive effects of clonidine infusions in humans. Br J Anaesth 2001; 86: 5–11. 26 Tobias JD. Dexmedetomidine: applications in pediatric critical care and pediatric anesthesiology. Pediatr Crit Care Med 2007; 8: 115–131. Accepted 18 October 2007 2008 The Authors Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222