Methadone: Who Tapers, When, Where, and How?* Joseph D. Tobias, MD Department of Anesthesiology & Pain Medicine Nationwide Children’s Hospital; Department of Anesthesiology & Pain Medicine The Ohio State University; and Department of Pediatrics The Ohio State University Columbus, OH
O
ver the past 10–20 years, data demonstrating the potential deleterious physiologic effects of untreated pain combined with ongoing humanitarian concerns have led to the increased use of sedative and analgesic agents in the ICU. These initiatives have resulted in an increased number of patients that may be at risk for physical dependency, tolerance, and withdrawal. The first reported experiences with opioid dependency and withdrawal in neonates and infants occurred in the 1970s and 1980s when pediatricians and neonatal ICU physicians cared for infants of drug-addicted mothers (1–3). Issues related to iatrogenic opioid dependency were subsequently noted in two studies performed by Arnold et al (4, 5). In a retrospective review, these investigators sought to identify the signs and symptoms of the neonatal abstinence syndrome (NAS) and risk factors for its occurrence in 37 neonates who received IV fentanyl for sedation during extracorporeal membrane oxygenation for respiratory failure. Tolerance was clearly demonstrated as fentanyl infusion requirements and the plasma concentration to achieve the desired level of sedation increased from 11.6 ± 6.9 µg/kg/hr on day 1 to 52.5 ± 19.4 µg/kg/hr on day 8. The authors noted that the prevalence of NAS was related to both the total fentanyl dose and the duration of the infusion. Shortly after this, the potential for using oral methadone to treat or prevent opioid withdrawal after the prolonged administration of fentanyl in the PICU patient was first suggested (6). Advantages of methadone include its longer half-life allowing for maintenance dosing at 2–3 times per day, generally high oral bioavailability, and availability as a liquid thereby allowing its use in younger patients. These properties allowed for patients to be transitioned to an oral medication thereby alleviating the need for IV access. Once the use of methadone became more routine, many centers were facile enough with its use to allow these patients to be discharged home on methadone with subsequent weaning performed
*See also p. 206. Key Words: dependency; methadone; opioids; tolerance; withdrawal The author has disclosed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000080
268
www.pccmjournal.org
on an outpatient basis (7). Although the first report regarding the use of methadone suggested a starting dose of 0.1 mg/ kg every 12 hours, the three patients in the series were receiving relatively low opioid doses and therefore, higher doses of methadone were not needed (6, 7). The subsequent clinical experience has demonstrated that higher doses of methadone may be needed based on the IV doses of opioids that the patient was receiving. Considerations during the transition from IV fentanyl to oral methadone include the differences in the potency and half-life of the two medications and cross-over tolerance (7). Once the appropriate enteral/oral dose is initiated, the IV administration is tapered, generally over a 24- to 48-hour period. Despite such benefits, the use of methadone in this clinical scenario is far from routine as demonstrated by the significant variation in the literature with regard to dosing, the transition from IV opioids to oral methadone, and the subsequent weaning process. This is clearly demonstrated by the variable protocols reported in the literature which include variations in the conversion ratios from fentanyl to methadone, dosing intervals, and most importantly weaning schedules (8–11). In this issue of Pediatric Critical Care Medicine, another option is presented by Steineck et al (12) from Amplatz Children’s Hospital. They take advantage of a growing and incredibly useful trend in the PICU, the availability of healthcare providers with Doctor of Pharmacy degrees. Even for those of us who have practiced in the PICU setting for decades, the addition of specialized clinical pharmacists on daily rounds has greatly improved the quality of care and in many settings and decreased the potential for morbidity. In this retrospective review, Steineck et al (12) report their preliminary experience with a pharmacist-managed methadone taper. At their institution, a new pharmacy consult for opioid withdrawal was available as of May 2010, therefore allowing for a retrospective comparison of outcomes before and after the availability of this process. With the new pharmacy consult service, the initial dosing of methadone, its tapering, patient assessment during weaning, and the entire process of methadone use was in accordance with a protocol, which Steineck et al (12) outline in an appendix to their article. The primary and secondary outcomes evaluated included the length of the methadone taper, number of additional doses of opioid used during the taper, the number of days that patients remained on an opioid infusion once methadone was started, withdrawal scores, and the length of hospital stay. Following the institution of the pharmacy consult weaning program, there was a decrease in the length of the methadone taper from a mean of 24.7 to 15 days (p = 0.003) and a decrease in the length of time that patients received IV opioids after the methadone was started (3.32 d vs 1.78 d; p = 0.004). There was no difference noted in number of additional opioid doses required during weaning and equivalent withdrawal scores during weaning. Most March 2014 • Volume 15 • Number 3
Editorials
importantly, there was a decrease in the length of hospital stay by 38% from a mean of 108.7 to 67.25 days (p = 0.023) with no change in the length of PICU stay (see below). The authors note that the use of a protocol driven by the pharmacy service eliminated the variability due to attending physicians’ views regarding opioid tapering. The authors are to be congratulated for the significant impact that their process had on the patients in their care. Obviously, there is the potential for the usual problems based on the retrospective nature of the study, which are clearly outlined by the authors. However, the real question is whether it is truly the presence of the consult service that resulted in their findings or rather a more formal and standardized protocol for weaning opioids, identifying withdrawal, and appropriately intervening. As noted, the number of patients with documented withdrawal scores increased from 37% to 95% following the institution of their new process thereby suggesting that there was a wide range effect of their protocol on the entire process. Regardless of this, it is evident that significant improvements in patient care can occur by the use of such protocols when weaning opioids and transitioning to methadone rather than leaving such processes to the potential random variation in our clinical practices. Other potential issues of the current study are nicely outlined by the authors including their use of a modified Finnegan score. Although common practice in their institution, the scale has not been validated in the pediatric population and is being replaced by other validated scores such as the Withdrawal Assessment Tool developed by Franck et al (13–18). The score assigns a value of 0 for no or 1 for yes to the following questions: loose or watery stools; vomiting, retching or gagging; and temperature more than or equal to 37.8°C. The patient is then observed for 2 minutes to assess their state (asleep, awake, or calm vs distressed), the presence of a tremor, sweating, uncoordinated or repetitive motion, and yawning or sneezing. These are also scored as 0 for no and 1 for yes. The patient is then observed following a stimulus and during recovery for startle to touch as well as time to regain a calm state. These components result in a score from 0 to 12. Most importantly, these newer scores were developed for use in patients along the entire continuum of the pediatric age range and should therefore be encouraged for use not only during routine clinical care but also for prospective clinical research initiatives. The most dramatic result noted by Steineck et al (12) is a dramatic decrease in length of hospitalization. As they clearly indicate, it is unknown what impact their protocol had on this as other initiatives had also been started at their hospital which may have impacted length of hospitalization. It is difficult to fully appreciate the impact on their protocol on the length of hospitalization as true severity of illness scores are not provided and length of hospitalization is provided as the mean and not the median thereby introducing the possibility that outliers may have affected the results. It may be more important to recognize that the length of PICU stay was not impacted. Pediatric Critical Care Medicine
Despite these issues, the study adds to our knowledge regarding the use of methadone in this difficult management scenario. The authors clearly demonstrate the benefits of weaning using a standardized protocol. They also provide further evidence for the immense benefit that our pharmacist colleagues provide us in the PICU setting. These benefits extend well beyond the dosing and use of methadone. As we continue our investigations into methadone use for iatrogenic opioid dependency, we are confronted with additional challenges. Regardless of the protocol used, close observation during the conversion period is necessary to avoid adverse effects from oversedation or to recognize the early symptoms of withdrawal. This practice continues to evolve with more institutions using formal scoring systems. Given the potential for the lay public to have concerns regarding the use of methadone, a thorough discussion with the parents is necessary to discuss why methadone is being used and to outline the differences between addiction and physical dependency. Although methadone offers some pharmacokinetic advantages over other agents, there is significant interpatient variability in its oral bioavailability and half-life. As with many drugs in the pediatric-aged patient, there are limited data regarding its pharmacokinetics and the impact that critical illness may have. Additionally, given its metabolic fate, metabolism may be affected by genetic factors and the coadministration of other medications. More recently concern has been expressed in the adult population, who are on maintenance methadone for drug addiction, regarding the potential for methadone to result in QT prolongation and arrhythmias (19). Although limited to the adult population to date, these concerns have led to the consideration of obtaining periodic electrocardiograms prior to and after instituting therapy with methadone. Physical dependency and withdrawal remain a common problem following prolonged admission to the PICU. These problems are not limited to opioids but have been reported with every sedative and analgesic agent used in the ICU setting (20). These problems and the use of sedative and analgesic agents in the PICU may have long-lasting effects which may impact length of PICU stay, length of hospitalization, and even eventual outcomes. Given that, ongoing clinical trials are needed to further delineate these issues. The current report by Steineck et al (12) is an excellent step in the right direction demonstrating the efficacy of their protocol for methadone administration. The use of such protocols minimizes non– evidence-based medicine practices which are inherent in the variability of clinical practices. They also serve to eliminate variation which may negate the validity of prospective, clinical trials.
REFERENCES
1. Collett BJ: Opioid tolerance: The clinical perspective. Br J Anaesth 1998; 81:58–68 2. Finnegan LP: Effects of maternal opiate abuse on the newborn. Fed Proc 1985; 44:2314–2317 3. Finnegan LP, Connaughton JF Jr, Kron RE, et al: Neonatal abstinence syndrome: Assessment and management. Addict Dis 1975; 2:141–158 www.pccmjournal.org
269
Editorials 4. Arnold JH, Truog RD, Orav EJ, et al: Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology 1990; 73:1136–1140 5. Arnold JH, Truog RD, Scavone JM, et al: Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr 1991; 119:639–643 6. Tobias JD, Schleien CL, Haun SE: Methadone as treatment for iatrogenic opioid dependency in pediatric intensive care unit patients. Crit Care Med 1990; 18:1292–1293 7. Tobias JD: Outpatient therapy of iatrogenic drug dependency following prolonged sedation in the pediatric intensive care unit. Intensive Care Med 1996; 11:284–287 8. Robertson RC, Darsey E, Fortenberry JD, et al: Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatr Crit Care Med 2000; 1:119–123 9. Meyer MM, Berens RJ: Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients. Pediatr Crit Care Med 2001; 2:329–333 10. Siddappa R, Fletcher JE, Heard AM, et al: Methadone dosage for prevention of opioid withdrawal in children. Paediatr Anaesth 2003; 13:805–810 11. Berens RJ, Meyer MT, Mikhailov TA, et al: A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients. Anesth Analg 2006; 102:1045–1050 12. Steineck KJ, Skoglund AK, Carlson MK, et al: Evaluation of a Pharmacist-Managed Methadone Taper. Pediatr Crit Care Med 2014; 15:206–210
13. Ista E, van Dijk M, Gamel C, et al: Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: A literature review. “Assessment remains troublesome.” Intensive Care Med 2007; 33:1396–1406 14. Cunliffe M, McArthur L, Dooley F: Managing sedation withdrawal in children who undergo prolonged PICU admission after discharge to the ward. Paediatr Anaesth 2004; 14:293–298 15. Franck LS, Naughton I, Winter I: Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients. Intensive Crit Care Nurs 2004; 20:344–351 16. Ista E, van Dijk M, Gamel C, et al: Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: A first evaluation. Crit Care Med 2008; 36:2427–2432 17. Franck LS, Scoppettuolo LA, Wypij D, et al: Validity and generalizability of the Withdrawal Assessment Tool-1 (WAT-1) for monitoring iatrogenic withdrawal syndrome in pediatric patients. Pain 2012; 153:142–148 18. Franck LS, Harris SK, Soetenga DJ, et al: The Withdrawal Assessment Tool-1 (WAT-1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Pediatr Crit Care Med 2008; 9:573–580 19. Atkinson D, Dunne A, Parker M: Torsades de pointes and self-terminating ventricular fibrillation in a prescription methadone user. Anaesthesia 2007; 62:952–955 20. Tobias JD: Tolerance, withdrawal, and abstinence syndromes following long term sedation and analgesia of children in the pediatric ICU. Crit Care Med 2000; 28:2122–2132
Minding the Brain* Erika L. Fink, MD Pediatric Critical Care Medicine Children’s Hospital of Pittsburgh Pittsburgh, PA
I
nfants with congenital heart disease (CHD) are at increased risk of preoperative and acquired brain disease and subsequent long-lasting disability, especially if surgery involves cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) (1, 2). Brain lesion types commonly include congenital cortical folding disorders, focal and global hypoxic-ischemic insults, and white matter degeneration (3– 7). Identifying new brain disease early is imperative but can be clinically difficult to detect, especially in infants where the Glasgow Coma Scale score is insensitive (8). New injury often presents clinically with altered mental status or seizures (which may also be nonconvulsive). Diagnostic tools such as brain ultrasound and CT often miss early ischemic lesions, and MRI typically requires lengthy transport of a critically ill patient outside the ICU. Serum brain biomarkers have potential to be
*See also p. 229. Key Words: biomarker; brain; calpain; cell death; congenital heart disease Dr. Fink received support for article research from the National Institutes of Health (NIH). Her institution received grant support from the NIH. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000074
270
www.pccmjournal.org
a useful tool for early detection of brain insults, leading to neuroprotective interventions and prevention of evolution into more severe disease. Serum S100b and neuron-specific enolase (NSE) show promise in a preliminary study in infants with CHD, but interpretation is hindered by the fact that normal S100b concentrations change during early development and NSE increases with hemolysis, which commonly occurs on bypass (9, 10). In this issue of Pediatric Critical Care Medicine, Jain et al (11) performed a prospective, single-center study using serial (preoperative, 6, 24, 48, 72, and 96 hr) serum measurements of alpha II-spectrin breakdown products (SBDPs) 120 kDa and 150 kDa in neonates with CHD. Alpha II-spectrin is a protein located in brain and non-CNS tissue and functions in cell cytoskeleton maintenance (12). Cleavage of calpains occurs after cellular insults, producing specific patterns of alpha II-SBDPs depending on the type of cleavage enzyme (12). The primary outcome demonstrated that neither SBDP was increased in children receiving closed-heart surgery (CHS). However, unlike the previously demonstrated predominance of fragments associated with necrosis in experimental models of stroke and CPB, both 120 kDa (apoptosis associated) and 150 kDa (necrosis associated) fragments were increased in children after open-heart surgery (CBP ± deep hypothermia), peaking at 24 and 6 hours postoperatively, respectively (12). The young brain is particularly vulnerable to apoptosis during development (13). The 120-kDa fragment decreased over time and did not return to baseline by the 96-hour timepoint while the 150-kDa fragment peaked in bimodal fashion, March 2014 • Volume 15 • Number 3
O
ver the past 10–20 years, data demonstrating the potential deleterious physiologic effects of untreated pain combined with ongoing humanitarian concerns have led to the increased use of sedative and analgesic agents in the ICU. These initiatives have resulted in an increased number of patients that may be at risk for physical dependency, tolerance, and withdrawal. The first reported experiences with opioid dependency and withdrawal in neonates and infants occurred in the 1970s and 1980s when pediatricians and neonatal ICU physicians cared for infants of drug-addicted mothers (1–3). Issues related to iatrogenic opioid dependency were subsequently noted in two studies performed by Arnold et al (4, 5). In a retrospective review, these investigators sought to identify the signs and symptoms of the neonatal abstinence syndrome (NAS) and risk factors for its occurrence in 37 neonates who received IV fentanyl for sedation during extracorporeal membrane oxygenation for respiratory failure. Tolerance was clearly demonstrated as fentanyl infusion requirements and the plasma concentration to achieve the desired level of sedation increased from 11.6 ± 6.9 µg/kg/hr on day 1 to 52.5 ± 19.4 µg/kg/hr on day 8. The authors noted that the prevalence of NAS was related to both the total fentanyl dose and the duration of the infusion. Shortly after this, the potential for using oral methadone to treat or prevent opioid withdrawal after the prolonged administration of fentanyl in the PICU patient was first suggested (6). Advantages of methadone include its longer half-life allowing for maintenance dosing at 2–3 times per day, generally high oral bioavailability, and availability as a liquid thereby allowing its use in younger patients. These properties allowed for patients to be transitioned to an oral medication thereby alleviating the need for IV access. Once the use of methadone became more routine, many centers were facile enough with its use to allow these patients to be discharged home on methadone with subsequent weaning performed
*See also p. 206. Key Words: dependency; methadone; opioids; tolerance; withdrawal The author has disclosed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000080
268
www.pccmjournal.org
on an outpatient basis (7). Although the first report regarding the use of methadone suggested a starting dose of 0.1 mg/ kg every 12 hours, the three patients in the series were receiving relatively low opioid doses and therefore, higher doses of methadone were not needed (6, 7). The subsequent clinical experience has demonstrated that higher doses of methadone may be needed based on the IV doses of opioids that the patient was receiving. Considerations during the transition from IV fentanyl to oral methadone include the differences in the potency and half-life of the two medications and cross-over tolerance (7). Once the appropriate enteral/oral dose is initiated, the IV administration is tapered, generally over a 24- to 48-hour period. Despite such benefits, the use of methadone in this clinical scenario is far from routine as demonstrated by the significant variation in the literature with regard to dosing, the transition from IV opioids to oral methadone, and the subsequent weaning process. This is clearly demonstrated by the variable protocols reported in the literature which include variations in the conversion ratios from fentanyl to methadone, dosing intervals, and most importantly weaning schedules (8–11). In this issue of Pediatric Critical Care Medicine, another option is presented by Steineck et al (12) from Amplatz Children’s Hospital. They take advantage of a growing and incredibly useful trend in the PICU, the availability of healthcare providers with Doctor of Pharmacy degrees. Even for those of us who have practiced in the PICU setting for decades, the addition of specialized clinical pharmacists on daily rounds has greatly improved the quality of care and in many settings and decreased the potential for morbidity. In this retrospective review, Steineck et al (12) report their preliminary experience with a pharmacist-managed methadone taper. At their institution, a new pharmacy consult for opioid withdrawal was available as of May 2010, therefore allowing for a retrospective comparison of outcomes before and after the availability of this process. With the new pharmacy consult service, the initial dosing of methadone, its tapering, patient assessment during weaning, and the entire process of methadone use was in accordance with a protocol, which Steineck et al (12) outline in an appendix to their article. The primary and secondary outcomes evaluated included the length of the methadone taper, number of additional doses of opioid used during the taper, the number of days that patients remained on an opioid infusion once methadone was started, withdrawal scores, and the length of hospital stay. Following the institution of the pharmacy consult weaning program, there was a decrease in the length of the methadone taper from a mean of 24.7 to 15 days (p = 0.003) and a decrease in the length of time that patients received IV opioids after the methadone was started (3.32 d vs 1.78 d; p = 0.004). There was no difference noted in number of additional opioid doses required during weaning and equivalent withdrawal scores during weaning. Most March 2014 • Volume 15 • Number 3
Editorials
importantly, there was a decrease in the length of hospital stay by 38% from a mean of 108.7 to 67.25 days (p = 0.023) with no change in the length of PICU stay (see below). The authors note that the use of a protocol driven by the pharmacy service eliminated the variability due to attending physicians’ views regarding opioid tapering. The authors are to be congratulated for the significant impact that their process had on the patients in their care. Obviously, there is the potential for the usual problems based on the retrospective nature of the study, which are clearly outlined by the authors. However, the real question is whether it is truly the presence of the consult service that resulted in their findings or rather a more formal and standardized protocol for weaning opioids, identifying withdrawal, and appropriately intervening. As noted, the number of patients with documented withdrawal scores increased from 37% to 95% following the institution of their new process thereby suggesting that there was a wide range effect of their protocol on the entire process. Regardless of this, it is evident that significant improvements in patient care can occur by the use of such protocols when weaning opioids and transitioning to methadone rather than leaving such processes to the potential random variation in our clinical practices. Other potential issues of the current study are nicely outlined by the authors including their use of a modified Finnegan score. Although common practice in their institution, the scale has not been validated in the pediatric population and is being replaced by other validated scores such as the Withdrawal Assessment Tool developed by Franck et al (13–18). The score assigns a value of 0 for no or 1 for yes to the following questions: loose or watery stools; vomiting, retching or gagging; and temperature more than or equal to 37.8°C. The patient is then observed for 2 minutes to assess their state (asleep, awake, or calm vs distressed), the presence of a tremor, sweating, uncoordinated or repetitive motion, and yawning or sneezing. These are also scored as 0 for no and 1 for yes. The patient is then observed following a stimulus and during recovery for startle to touch as well as time to regain a calm state. These components result in a score from 0 to 12. Most importantly, these newer scores were developed for use in patients along the entire continuum of the pediatric age range and should therefore be encouraged for use not only during routine clinical care but also for prospective clinical research initiatives. The most dramatic result noted by Steineck et al (12) is a dramatic decrease in length of hospitalization. As they clearly indicate, it is unknown what impact their protocol had on this as other initiatives had also been started at their hospital which may have impacted length of hospitalization. It is difficult to fully appreciate the impact on their protocol on the length of hospitalization as true severity of illness scores are not provided and length of hospitalization is provided as the mean and not the median thereby introducing the possibility that outliers may have affected the results. It may be more important to recognize that the length of PICU stay was not impacted. Pediatric Critical Care Medicine
Despite these issues, the study adds to our knowledge regarding the use of methadone in this difficult management scenario. The authors clearly demonstrate the benefits of weaning using a standardized protocol. They also provide further evidence for the immense benefit that our pharmacist colleagues provide us in the PICU setting. These benefits extend well beyond the dosing and use of methadone. As we continue our investigations into methadone use for iatrogenic opioid dependency, we are confronted with additional challenges. Regardless of the protocol used, close observation during the conversion period is necessary to avoid adverse effects from oversedation or to recognize the early symptoms of withdrawal. This practice continues to evolve with more institutions using formal scoring systems. Given the potential for the lay public to have concerns regarding the use of methadone, a thorough discussion with the parents is necessary to discuss why methadone is being used and to outline the differences between addiction and physical dependency. Although methadone offers some pharmacokinetic advantages over other agents, there is significant interpatient variability in its oral bioavailability and half-life. As with many drugs in the pediatric-aged patient, there are limited data regarding its pharmacokinetics and the impact that critical illness may have. Additionally, given its metabolic fate, metabolism may be affected by genetic factors and the coadministration of other medications. More recently concern has been expressed in the adult population, who are on maintenance methadone for drug addiction, regarding the potential for methadone to result in QT prolongation and arrhythmias (19). Although limited to the adult population to date, these concerns have led to the consideration of obtaining periodic electrocardiograms prior to and after instituting therapy with methadone. Physical dependency and withdrawal remain a common problem following prolonged admission to the PICU. These problems are not limited to opioids but have been reported with every sedative and analgesic agent used in the ICU setting (20). These problems and the use of sedative and analgesic agents in the PICU may have long-lasting effects which may impact length of PICU stay, length of hospitalization, and even eventual outcomes. Given that, ongoing clinical trials are needed to further delineate these issues. The current report by Steineck et al (12) is an excellent step in the right direction demonstrating the efficacy of their protocol for methadone administration. The use of such protocols minimizes non– evidence-based medicine practices which are inherent in the variability of clinical practices. They also serve to eliminate variation which may negate the validity of prospective, clinical trials.
REFERENCES
1. Collett BJ: Opioid tolerance: The clinical perspective. Br J Anaesth 1998; 81:58–68 2. Finnegan LP: Effects of maternal opiate abuse on the newborn. Fed Proc 1985; 44:2314–2317 3. Finnegan LP, Connaughton JF Jr, Kron RE, et al: Neonatal abstinence syndrome: Assessment and management. Addict Dis 1975; 2:141–158 www.pccmjournal.org
269
Editorials 4. Arnold JH, Truog RD, Orav EJ, et al: Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology 1990; 73:1136–1140 5. Arnold JH, Truog RD, Scavone JM, et al: Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr 1991; 119:639–643 6. Tobias JD, Schleien CL, Haun SE: Methadone as treatment for iatrogenic opioid dependency in pediatric intensive care unit patients. Crit Care Med 1990; 18:1292–1293 7. Tobias JD: Outpatient therapy of iatrogenic drug dependency following prolonged sedation in the pediatric intensive care unit. Intensive Care Med 1996; 11:284–287 8. Robertson RC, Darsey E, Fortenberry JD, et al: Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatr Crit Care Med 2000; 1:119–123 9. Meyer MM, Berens RJ: Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients. Pediatr Crit Care Med 2001; 2:329–333 10. Siddappa R, Fletcher JE, Heard AM, et al: Methadone dosage for prevention of opioid withdrawal in children. Paediatr Anaesth 2003; 13:805–810 11. Berens RJ, Meyer MT, Mikhailov TA, et al: A prospective evaluation of opioid weaning in opioid-dependent pediatric critical care patients. Anesth Analg 2006; 102:1045–1050 12. Steineck KJ, Skoglund AK, Carlson MK, et al: Evaluation of a Pharmacist-Managed Methadone Taper. Pediatr Crit Care Med 2014; 15:206–210
13. Ista E, van Dijk M, Gamel C, et al: Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: A literature review. “Assessment remains troublesome.” Intensive Care Med 2007; 33:1396–1406 14. Cunliffe M, McArthur L, Dooley F: Managing sedation withdrawal in children who undergo prolonged PICU admission after discharge to the ward. Paediatr Anaesth 2004; 14:293–298 15. Franck LS, Naughton I, Winter I: Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients. Intensive Crit Care Nurs 2004; 20:344–351 16. Ista E, van Dijk M, Gamel C, et al: Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: A first evaluation. Crit Care Med 2008; 36:2427–2432 17. Franck LS, Scoppettuolo LA, Wypij D, et al: Validity and generalizability of the Withdrawal Assessment Tool-1 (WAT-1) for monitoring iatrogenic withdrawal syndrome in pediatric patients. Pain 2012; 153:142–148 18. Franck LS, Harris SK, Soetenga DJ, et al: The Withdrawal Assessment Tool-1 (WAT-1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Pediatr Crit Care Med 2008; 9:573–580 19. Atkinson D, Dunne A, Parker M: Torsades de pointes and self-terminating ventricular fibrillation in a prescription methadone user. Anaesthesia 2007; 62:952–955 20. Tobias JD: Tolerance, withdrawal, and abstinence syndromes following long term sedation and analgesia of children in the pediatric ICU. Crit Care Med 2000; 28:2122–2132
Minding the Brain* Erika L. Fink, MD Pediatric Critical Care Medicine Children’s Hospital of Pittsburgh Pittsburgh, PA
I
nfants with congenital heart disease (CHD) are at increased risk of preoperative and acquired brain disease and subsequent long-lasting disability, especially if surgery involves cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) (1, 2). Brain lesion types commonly include congenital cortical folding disorders, focal and global hypoxic-ischemic insults, and white matter degeneration (3– 7). Identifying new brain disease early is imperative but can be clinically difficult to detect, especially in infants where the Glasgow Coma Scale score is insensitive (8). New injury often presents clinically with altered mental status or seizures (which may also be nonconvulsive). Diagnostic tools such as brain ultrasound and CT often miss early ischemic lesions, and MRI typically requires lengthy transport of a critically ill patient outside the ICU. Serum brain biomarkers have potential to be
*See also p. 229. Key Words: biomarker; brain; calpain; cell death; congenital heart disease Dr. Fink received support for article research from the National Institutes of Health (NIH). Her institution received grant support from the NIH. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000074
270
www.pccmjournal.org
a useful tool for early detection of brain insults, leading to neuroprotective interventions and prevention of evolution into more severe disease. Serum S100b and neuron-specific enolase (NSE) show promise in a preliminary study in infants with CHD, but interpretation is hindered by the fact that normal S100b concentrations change during early development and NSE increases with hemolysis, which commonly occurs on bypass (9, 10). In this issue of Pediatric Critical Care Medicine, Jain et al (11) performed a prospective, single-center study using serial (preoperative, 6, 24, 48, 72, and 96 hr) serum measurements of alpha II-spectrin breakdown products (SBDPs) 120 kDa and 150 kDa in neonates with CHD. Alpha II-spectrin is a protein located in brain and non-CNS tissue and functions in cell cytoskeleton maintenance (12). Cleavage of calpains occurs after cellular insults, producing specific patterns of alpha II-SBDPs depending on the type of cleavage enzyme (12). The primary outcome demonstrated that neither SBDP was increased in children receiving closed-heart surgery (CHS). However, unlike the previously demonstrated predominance of fragments associated with necrosis in experimental models of stroke and CPB, both 120 kDa (apoptosis associated) and 150 kDa (necrosis associated) fragments were increased in children after open-heart surgery (CBP ± deep hypothermia), peaking at 24 and 6 hours postoperatively, respectively (12). The young brain is particularly vulnerable to apoptosis during development (13). The 120-kDa fragment decreased over time and did not return to baseline by the 96-hour timepoint while the 150-kDa fragment peaked in bimodal fashion, March 2014 • Volume 15 • Number 3
