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Postoperative Sedation and Analgesia After Pediatric Liver Transplantation
Postoperative Sedation and Analgesia After Pediatric Liver Transplantation R. Fumagalli, P. Ingelmo, and L.R. Sperti ABSTRACT The goal of sedation in the pediatric intensive care unit (PICU) is to produce a calm and comfortable child, free from pain and discomfort. Children receiving liver transplantation need analgesics to control pain from surgical incisions, drains, vascular access, or endotracheal suctioning. Sedatives are used to facilitate the delivery of nursing care, to prevent selfextubation, and to facilitate mechanical ventilation. Optimal sedation produces a state in which the patient is somnolent, responsive to the environment but untroubled by it, and with no excessive movements. A common problem in the PICU is the fluctuation in the delivery of sedatives and analgesics depending on the health care providers and on a breakdown in communication between physicians and nurses to define end points for pharmacological therapy. This variability more often leads to oversedation rather than undersedation. Oversedation delays extubation, promotes ventilator-associated pneumonia, and increases the risk of reintubation. The use of written sedation policies to guide practice at the bedside reduces the length of time for which patients require mechanical ventilation and the length of PICU stay. Protocols for drug administration practices increase patient safety during mechanical ventilation, promote nursing autonomy, and facilitate communication between nurses and physicians as well as between nurses.
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N CHILDREN RECEIVING liver transplantation, analgesics are used to control pain from surgical incisions, drains, vascular access or endotracheal suctioning. Sedatives are used to facilitate the delivery of nursing care, to prevent self-extubation and to facilitate mechanical ventilation.1 The goal of sedation in pediatric intensive care unit (PICU) is to produce a calm and comfortable child, free from pain and discomfort. Immediately after surgery, high levels of analgesia are required for pain relief or to reduce stress responses to surgery. If the patient remains ventilated, sedation may be required to relieve the discomfort and facilitate tolerance of an endotracheal tube. Optimal sedation will produce a state in which the patient is somnolent, responsive to the environment but untroubled by it, and with no excessive movements. Oversedation delays extubation, promotes ventilator associated pneumonia, and increases the risk of reintubation. Mechanical ventilation may have a negative impact on the hemodynamics of the transplanted liver.2 Daily discontinuation of sedative infusions in adults reduces the duration of mechanical ventilation and intensive care recovery.3 However, interruption of continuous sedative/analgesic infusion in children is less commonly © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 841– 843 (2006)
used. The care and evaluation of a child who has been allowed to completely wake up while on the ventilator is far more difficult than managing an older child or an adult.4 Critically ill children frequently exhibit unpredictable alterations in pharmacokinetic and pharmacodynamic profiles. Drug interaction profiles, renal and hepatic dysfunction, altered protein binding, impaired gastrointestinal absorption, and circulatory instability may contribute to this unpredictability.5 Morphine undergoes conjugation in the liver to two active metabolites, morphine-6-glucuronide and morphine3-glucuronide. Elimination occurs in the kidney. The elimination half-life of morphine during infusion is significantly longer in newborns than in older children. Adult levels of From the Anaesthesia and Intensive Care Department, Ospedali Riuniti di Bergamo, Dipartimento di Scienze Chirurgiche e Terapia Intensiva, Università degli Studi Milano Bicocca, Milano, Italy. Address reprint requests to Roberto Fumagalli, Anaesthesia and Intensive Care Department, Ospedali Riuniti di Bergamo, Dipartimento di Scienze Chirurgiche e Terapia Intensiva, Università degli Studi Milano Bicocca, 20100 Milano, Italy. E-mail: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.01.037 841
842
clearance are reached at 6 months of age.6 Decreased morphine requirements reported after liver transplantation are associated with increased peripheral metenkephalin levels, which may contributed to this decreased requirement.7 With prolonged continuous infusion, fentanyl suffers redistribution to peripheral tissues. When the infusion is stopped, the drug reenters the plasma where it can have a prolonged effect. Inactive products of hepatic metabolism are excreted by the kidney. The clearance of fentanyl under continuous infusion is highly variable and age related, with children under 6 months having the lowest clearance.6 Midazolam undergoes hepatic metabolism to an active metabolite (1-OH-midazolam) and renal excretion. After a 1-day infusion, it accumulates in peripheral tissues. After cessation of the infusion, patients with renal dysfunction are more prone to prolonged sedation (more than 3 days), because of the accumulation of the 1-OH-midazolam. Among children with liver failure or with concomitant administration of erythromycin and fentanyl, the elimination of midazolam is impaired due to reduced metabolism.8 Propofol is metabolized mainly in the liver to nonactive metabolites. Recently its use has been contraindicated in children, because of concerns associated with increased mortality and with a syndrome characterized by metabolic acidosis, dysrhythmia, heart failure, hyperkalemia, rabdomyolysis, and death. Most PICUs used propofol for pediatric sedation from a few hours up to overnight with maximum doses ranging from 3 to 4 mg/kg/h. Long-term sedation of children with propofol cannot be supported.9 Oral clonidine may be a safe and effective sedative in combination with morphine and lorazepam for young children with respiratory failure. Using a dose of 3 to 5 g/kg every 8 hours, this agent may also exhibit opioid- and benzodiazepine-sparing effects.10 At a dose of 0.25 g/kg/h, dexmedetomidine was approximately equivalent to midazolam at 0.22 mg/kg/h. At 0.5 g/kg/h, dexmedetomidine provided more effective sedation during mechanical ventilation in infants and children.11 Tolerance, physical dependency, and withdrawal can occur after the prolonged administration of any agent used for sedation and analgesia. Identifiable risk factors are the total dose and duration of drug administration. More than 9 days of fentanyl infusion and a total dose of 2.5 mg/kg were 100% predictive of a withdrawal syndrome. A total dose of midazolam greater than 60 mg/kg is significantly associated with occurrence of withdrawal symptoms. For children receiving sedative and analgesic drugs for prolonged periods, gradual weaning (10% to 15% per day reduction) over several days to weeks is recommended.12 Epidural drug delivery can interrupt nociception, providing safe and effective pain control after major abdominal surgery. However, epidural hematoma formation can be a catastrophic complication of epidural catheterization. The risk is increased in patients with impaired hemostasis because of coagulopathy or therapeutic anticoagulation and antiaggregation effects as observed in liver transplant patients.
FUMAGALLI, INGELMO, AND SPERTI
A common problem in the PICU is the fluctuation in the delivery of sedatives and analgesics depending on the health care providers with a breakdown of communication between physicians and nurses in defining endpoints for pharmacological therapy. This variability more often leads to oversedation rather than undersedation.4 The use of written sedation policies to guide practices at the bedside reduces the length of time for which patients require mechanical ventilation and the length of PICU stay. Protocols for drug administration practices may increase patient safety during mechanical ventilation, promote nursing autonomy, and facilitate communication between nurses and physicians as well as among nurses during various shifts.13 The use of a scoring system to routinely assess pain and sedation may guide therapy. The most commonly used scoring system in the PICU is the COMFORT score, an observational tool developed specifically for ventilated children.14 The cardiac analgesic assessment scale was developed to evaluate pain and response to analgesia in children sedated and intubated after cardiac surgery. A combination of physiological and behavioral indicators significantly reflect changes in pain status over time.15 Sedation/analgesia score must be performed regularly to monitor the adequacy of sedation and comfort. If the major component of the discomfort is judged to be pain, then the analgesic component of the drug combination should be increased. If the major component is restlessness, then sedative drugs may be needed. Often simple nonpharmacological approaches alone are sufficient to calm a distressed infant. REFERENCES 1. Polaner DM: Sedation-analgesia in the pediatric intensive care unit. Pediatr Clin North Am 48:695, 2001 2. Glanemann M, Langrehr JM, Muller AR, et al: Incidence and risk factors of prolonged mechanical ventilation and causes of reintubation after liver transplantation. Transplant Proc 30:1874, 1998 3. Kress MH, Pohlman A, O’Connor MF, et al: Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471, 2000 4. Twite MD, Rashid A, Zuk J, et al: Sedation, analgesia, and neuromuscular blockade in the pediatric intensive care unit: survey of fellowship training programs. Pediatr Crit Care Med 5:521, 2004 5. Tobias JD: Sedation and analgesia in paediatric intensive care units: a guide to drug selection and use. Paediatr Drugs 1:109, 1999 6. Kost-Byerly S: New concepts in acute and extended postoperative pain management in children. Anesthesiol Clin North America, 20:115, 2002 7. Donovan KL, Janicki PK, Striepe VI, et al: Decreased patient analgesic requirements after liver transplantation and associated neuropeptide levels. Transplantation 63:1423, 1997 8. De Wildt SN, De Hoog M, Vinks AA, et al: Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Crit Care Med 31:1952, 2003 9. Playfor SD, Venkatesh K: Current patterns of propofol use in PICU in the United Kingdom and North America. Pediatr Anaesth 14:501, 2004 10. Arenas-Lopez S, Riphagen S, Tibby SM, et al: Use of oral clonidine for sedation in ventilated paediatric intensive care patients. Intensive Care Med 30:1625, 2004 11. Tobias JD, Berkenbosch JW: Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. South Med J 97:451, 2004
POSTOPERATIVE SEDATION AND ANALGESIA 12. Tobias JD: Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med 28:2122, 2000 13. Popernack ML, Thomas NJ, Lucking SE: Decreasing unplanned extubations: utilization of the Penn State Children’s Hospital sedation algorithm. Pediatr Crit Care Med 5:58, 2004
843 14. Ambuel B, Hamlett KW, Marx CM, et al: Assesing distress in pediatric intensive care enviroments: the COMFORT scale. J Pediatr Psychol 17:95, 1992 15. Suominen P, Caffin C, Linton S, et al: The cardiac analgesic assessment scale (CAAS): a pain assessment tool for intubated and ventilated children after cardiac surgery. Pediatr Anesth 14:336, 2004
I
N CHILDREN RECEIVING liver transplantation, analgesics are used to control pain from surgical incisions, drains, vascular access or endotracheal suctioning. Sedatives are used to facilitate the delivery of nursing care, to prevent self-extubation and to facilitate mechanical ventilation.1 The goal of sedation in pediatric intensive care unit (PICU) is to produce a calm and comfortable child, free from pain and discomfort. Immediately after surgery, high levels of analgesia are required for pain relief or to reduce stress responses to surgery. If the patient remains ventilated, sedation may be required to relieve the discomfort and facilitate tolerance of an endotracheal tube. Optimal sedation will produce a state in which the patient is somnolent, responsive to the environment but untroubled by it, and with no excessive movements. Oversedation delays extubation, promotes ventilator associated pneumonia, and increases the risk of reintubation. Mechanical ventilation may have a negative impact on the hemodynamics of the transplanted liver.2 Daily discontinuation of sedative infusions in adults reduces the duration of mechanical ventilation and intensive care recovery.3 However, interruption of continuous sedative/analgesic infusion in children is less commonly © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 841– 843 (2006)
used. The care and evaluation of a child who has been allowed to completely wake up while on the ventilator is far more difficult than managing an older child or an adult.4 Critically ill children frequently exhibit unpredictable alterations in pharmacokinetic and pharmacodynamic profiles. Drug interaction profiles, renal and hepatic dysfunction, altered protein binding, impaired gastrointestinal absorption, and circulatory instability may contribute to this unpredictability.5 Morphine undergoes conjugation in the liver to two active metabolites, morphine-6-glucuronide and morphine3-glucuronide. Elimination occurs in the kidney. The elimination half-life of morphine during infusion is significantly longer in newborns than in older children. Adult levels of From the Anaesthesia and Intensive Care Department, Ospedali Riuniti di Bergamo, Dipartimento di Scienze Chirurgiche e Terapia Intensiva, Università degli Studi Milano Bicocca, Milano, Italy. Address reprint requests to Roberto Fumagalli, Anaesthesia and Intensive Care Department, Ospedali Riuniti di Bergamo, Dipartimento di Scienze Chirurgiche e Terapia Intensiva, Università degli Studi Milano Bicocca, 20100 Milano, Italy. E-mail: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.01.037 841
842
clearance are reached at 6 months of age.6 Decreased morphine requirements reported after liver transplantation are associated with increased peripheral metenkephalin levels, which may contributed to this decreased requirement.7 With prolonged continuous infusion, fentanyl suffers redistribution to peripheral tissues. When the infusion is stopped, the drug reenters the plasma where it can have a prolonged effect. Inactive products of hepatic metabolism are excreted by the kidney. The clearance of fentanyl under continuous infusion is highly variable and age related, with children under 6 months having the lowest clearance.6 Midazolam undergoes hepatic metabolism to an active metabolite (1-OH-midazolam) and renal excretion. After a 1-day infusion, it accumulates in peripheral tissues. After cessation of the infusion, patients with renal dysfunction are more prone to prolonged sedation (more than 3 days), because of the accumulation of the 1-OH-midazolam. Among children with liver failure or with concomitant administration of erythromycin and fentanyl, the elimination of midazolam is impaired due to reduced metabolism.8 Propofol is metabolized mainly in the liver to nonactive metabolites. Recently its use has been contraindicated in children, because of concerns associated with increased mortality and with a syndrome characterized by metabolic acidosis, dysrhythmia, heart failure, hyperkalemia, rabdomyolysis, and death. Most PICUs used propofol for pediatric sedation from a few hours up to overnight with maximum doses ranging from 3 to 4 mg/kg/h. Long-term sedation of children with propofol cannot be supported.9 Oral clonidine may be a safe and effective sedative in combination with morphine and lorazepam for young children with respiratory failure. Using a dose of 3 to 5 g/kg every 8 hours, this agent may also exhibit opioid- and benzodiazepine-sparing effects.10 At a dose of 0.25 g/kg/h, dexmedetomidine was approximately equivalent to midazolam at 0.22 mg/kg/h. At 0.5 g/kg/h, dexmedetomidine provided more effective sedation during mechanical ventilation in infants and children.11 Tolerance, physical dependency, and withdrawal can occur after the prolonged administration of any agent used for sedation and analgesia. Identifiable risk factors are the total dose and duration of drug administration. More than 9 days of fentanyl infusion and a total dose of 2.5 mg/kg were 100% predictive of a withdrawal syndrome. A total dose of midazolam greater than 60 mg/kg is significantly associated with occurrence of withdrawal symptoms. For children receiving sedative and analgesic drugs for prolonged periods, gradual weaning (10% to 15% per day reduction) over several days to weeks is recommended.12 Epidural drug delivery can interrupt nociception, providing safe and effective pain control after major abdominal surgery. However, epidural hematoma formation can be a catastrophic complication of epidural catheterization. The risk is increased in patients with impaired hemostasis because of coagulopathy or therapeutic anticoagulation and antiaggregation effects as observed in liver transplant patients.
FUMAGALLI, INGELMO, AND SPERTI
A common problem in the PICU is the fluctuation in the delivery of sedatives and analgesics depending on the health care providers with a breakdown of communication between physicians and nurses in defining endpoints for pharmacological therapy. This variability more often leads to oversedation rather than undersedation.4 The use of written sedation policies to guide practices at the bedside reduces the length of time for which patients require mechanical ventilation and the length of PICU stay. Protocols for drug administration practices may increase patient safety during mechanical ventilation, promote nursing autonomy, and facilitate communication between nurses and physicians as well as among nurses during various shifts.13 The use of a scoring system to routinely assess pain and sedation may guide therapy. The most commonly used scoring system in the PICU is the COMFORT score, an observational tool developed specifically for ventilated children.14 The cardiac analgesic assessment scale was developed to evaluate pain and response to analgesia in children sedated and intubated after cardiac surgery. A combination of physiological and behavioral indicators significantly reflect changes in pain status over time.15 Sedation/analgesia score must be performed regularly to monitor the adequacy of sedation and comfort. If the major component of the discomfort is judged to be pain, then the analgesic component of the drug combination should be increased. If the major component is restlessness, then sedative drugs may be needed. Often simple nonpharmacological approaches alone are sufficient to calm a distressed infant. REFERENCES 1. Polaner DM: Sedation-analgesia in the pediatric intensive care unit. Pediatr Clin North Am 48:695, 2001 2. Glanemann M, Langrehr JM, Muller AR, et al: Incidence and risk factors of prolonged mechanical ventilation and causes of reintubation after liver transplantation. Transplant Proc 30:1874, 1998 3. Kress MH, Pohlman A, O’Connor MF, et al: Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471, 2000 4. Twite MD, Rashid A, Zuk J, et al: Sedation, analgesia, and neuromuscular blockade in the pediatric intensive care unit: survey of fellowship training programs. Pediatr Crit Care Med 5:521, 2004 5. Tobias JD: Sedation and analgesia in paediatric intensive care units: a guide to drug selection and use. Paediatr Drugs 1:109, 1999 6. Kost-Byerly S: New concepts in acute and extended postoperative pain management in children. Anesthesiol Clin North America, 20:115, 2002 7. Donovan KL, Janicki PK, Striepe VI, et al: Decreased patient analgesic requirements after liver transplantation and associated neuropeptide levels. Transplantation 63:1423, 1997 8. De Wildt SN, De Hoog M, Vinks AA, et al: Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Crit Care Med 31:1952, 2003 9. Playfor SD, Venkatesh K: Current patterns of propofol use in PICU in the United Kingdom and North America. Pediatr Anaesth 14:501, 2004 10. Arenas-Lopez S, Riphagen S, Tibby SM, et al: Use of oral clonidine for sedation in ventilated paediatric intensive care patients. Intensive Care Med 30:1625, 2004 11. Tobias JD, Berkenbosch JW: Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. South Med J 97:451, 2004
POSTOPERATIVE SEDATION AND ANALGESIA 12. Tobias JD: Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med 28:2122, 2000 13. Popernack ML, Thomas NJ, Lucking SE: Decreasing unplanned extubations: utilization of the Penn State Children’s Hospital sedation algorithm. Pediatr Crit Care Med 5:58, 2004
843 14. Ambuel B, Hamlett KW, Marx CM, et al: Assesing distress in pediatric intensive care enviroments: the COMFORT scale. J Pediatr Psychol 17:95, 1992 15. Suominen P, Caffin C, Linton S, et al: The cardiac analgesic assessment scale (CAAS): a pain assessment tool for intubated and ventilated children after cardiac surgery. Pediatr Anesth 14:336, 2004