Prolonged opioid therapy in the Critically Ill Pediatric Patient

Transcription

1 PBLD Table #22 Prolonged opioid therapy in the Critically Ill Pediatric Patient Arlyne K. Thung, M.D. Assistant Professor, Anesthesiology & Shu-Ming Wang, M.D. Associate Professor, Anesthesiology Yale University, Yale New Haven Children s Hospital Goals 1. Understand the complications associated with prolonged opioid therapy 2. Understand potential risk factors for opioid withdrawal 3. Appreciate various scales for opioid/benzodiazepine withdrawal assessment 4. Understand various opioid tapering regimens and the pharmacological agents used Case A 6 month old child weighing 6.5 kg with a history of AV canal and pulmonary hypertension requires high dose levels of analgesia and sedation for mechanical ventilation. Now the patient is extubated and tolerating oral feeds but is without IV access. IV fentanyl dose is changed to oral morphine with cross tolerance considered in the calculation. Morphine doses cause oversedation, however subsequent withholding of morphine administration leads to signs and symptoms consistent with opioid withdrawal. We will discuss complications associated with prolonged opioid use, appropriate assessments for opioid withdrawal, opioid conversion and management strategies for opioid tapering in the critically ill child. Hospital course The patient s hospital course consisted of a 6 week PICU admission which was notable for AV canal repair, permanent pacemaker for complete AV block and several reintubation for increased work of breathing and respiratory distress. The patient was initially started on an infusion of 2 mcg/kg/hr of fentanyl that was increased over 4 weeks to 7 mcg/kg/hr of fentanyl and 0.5mg/kg/hr of midazolam with the patient extubated to high flow nasal cannula. Two days following the patient s extubation the patient s central line was discontinued for infection prevention and preservation of vascular access for future surgical procedures. Peripheral access or a PICC line was unable to be obtained.

2 Questions: Discussion 1. What are the differences between tolerance, dependence, withdrawal and addiction? Opioid and benzodiazepine therapy has long been a mainstay of analgesic and sedative treatment for pediatric patients requiring mechanical ventilation in the intensive care unit. Morphine and fentanyl along with benzodiazepines such as midazolam and lorazepam are the most commonly administered pharmacological agents in the pediatric intensive care unit. Given the widespread use of opioids in the pediatric population, practitioners are faced with the ramifications of their prolonged use, particularly that of tolerance, dependence, withdrawal and rarely addiction. Tolerance occurs when repeated exposure to a particular drug results in a diminished therapeutic effect that requires increasing doses to maintain the same effect. Opioid tolerance has been reported in both the neonatal and pediatric population with studies suggesting that tolerance may be related to opioid type and mode of administration e.g. the use of synthetic opioids such as fentanyl and remifentanil and continuous intravenous infusions. Physiological dependence is defined as the potential for withdrawal after abrupt cessation or reduction of the drug. Withdrawal or abstinence syndrome is a group of symptoms that occur with the abrupt cessation or reduction of a drug. Although the exact prevalence of sedative induced withdrawal in pediatric patients is unknown, published reports of opioid and opioid + benzodiazepine withdrawal has ranged from 13-57% with the onset of occurring anywhere between 1 hour to 6 days after a decrease in sedative and analgesic agents. Addiction is a complex behavioral pattern of drug use characterized by overwhelming involvement and compulsive use of the drug and associated antisocial and criminal behavior obtaining the drug and is considered a rare occurrence with pediatric patients. 2. What are potential risk factors for opioid/benzodiazepine withdrawal? Purported risk factors for opioid withdrawal in published reports include the use of synthetic opioids (i.e. fentanyl), cumulative opioid/dose, opioid duration and mode of administration (i.e. continuous infusion). With regard to patients in the pediatric intensive care unit, a combination of an opioid and benzodiazepine infusion for sedation and analgesia, prolonged infusion and associated accumulative doses make these critically ill patients a population at risk for withdrawal. As the patient s medical status stabilizes, medical practitioners are then faced with the challenge of weaning these patients off sedation and analgesia without triggering withdrawal symptoms and converting between different types of opioids +/- benzodiazepine that may result in unexpected under treatment of withdrawal prevention or over-sedation by pharmacological agents. Of note, patients in the PICU frequently have complex physiological and pathological conditions, which are known to affect the rate of drug metabolism. In addition, the interactions between opioids/benzodiazepine and other medications which patients are also receiving can delay the clearance of these drugs.

3 3. What are available sedative withdrawal assessment tools for the pediatric patient? Since withdrawal symptoms may occur with the abrupt reduction of sedative medications, an objective assessment tool can certainly beneficial for clinicians. Various assessment scales have been used thus far in pediatric patients. Examples include: A. Neonatal Abstinence Scoring tool (NAST) One of the oldest assessment tools for opioid withdrawal consisting of 20+ signs of opioid withdrawal with scores > 8 indicative of withdrawal and need for treatment Signs are categorized as neurological, sympathetically mediated and gastrointestinal Pros: Well known and commonly used assessment tool, validated in neonates with an 82% inter-observer reliability coefficient Cons: Not validated in older pediatric patients. Inclusion of Moro reflex as a sign of opioid withdrawal may not be applicable in older patients as the reflex disappears after 3-4 months. Requires q4 hour observations. Scoring tool may be more relevant to opioid withdrawal rather than benzodiazepine withdrawal. B. Sedation Withdrawal Score (SWS) Scoring system incorporating 12 clinical features of withdrawal (derived from NAST) with a score given for each feature (0=absent, 1=mild, 2=severe) with 24 as the maximum score Based on the calculated score the authors provide instructions to continue the current regimen, revert to another regimen or seek advice Pros: Does not include Moro reflex in the list of features Cons: Scoring appears subjective and SWS report is descriptive. Reasons for score cut offs, score validity, specificity and sensitivity of scoring system are lacking. Instructions following the calculated score are vague. Q6 hourly scoring. C. Opioid Benzodiazepine Withdrawal Scale (OBWS) 21 item checklist that rates frequency and severity of withdrawal symptoms OBWS score > 8 moderate to severe withdrawal Pros: Prospective validation performed with an inter-observer reliability of 80% and specificity of 87%. Scale encompasses both opioid and benzodiazepine withdrawal. Cons: Prospective validation showed a sensitivity of 50%. Q4hr scoring. Tapering regimens were variable among patients. Potential subjectivity with OBWS scoring by the nurses. D. Withdrawal Assessment Tool-1 (WAT-1) Consists of 19 withdrawal symptoms based from the OBWS Validation and reliability performed on 11 item reduced version Patient assessed for symptoms 2 minutes pre stimulus (i.e.verbal or physical), during stimulus and post stimulus in which the State behavioral

4 scale used (SBS) to determine level of sedation/agitation Pros: Multi-center (n=2) prospective study. Prospective validation performed with a 87% sensitivity and 88% specificity for WAT-1 scores > 3 and NRS > 4. Scoring is twice daily. Cons: Withdrawal symptoms based from OWBS which showed 50% sensitivity with prospective validation. Variable tapering regimens used. Authors state WAT-1 may be better at detecting symptoms for opioid withdrawal than benzodiazepine withdrawal. Lack of benzodiazepine withdrawal symptoms in WAT-1. Why authors included SBS into WAT-1 is not clarified. E. Sophia Observation withdrawal Symptoms-Scale (SOS) Derived from 24 withdrawal symptoms (selected from literature review) and reduced to 15 following multidimensional scaling and expert panel judgement. Patients prospectively observed Pros: Incorporates the opinion of an expert panel (physicians/nurses). Prospective observation. Assessment requires 2 minutes. List of symptoms may be more encompassing for both opioid and benzodiazepine withdrawal. Cons: Variable weaning protocols among patients. 4. What strategies could you use to avoid opioid withdrawal/sedation in critical ill pediatric patients? What pharmacological agents (primary or adjunct) can be used for the treatment of withdrawal prevention? The use of tapering regimens is a common practice for the prevention of opioid withdrawal. Opioid tapering allows for the gradual removal of opioids without the excessive excitation of physiologically dependent neurons which could lead to opioid withdrawal. Goals of opioid tapering as previously outlined by Anand et al are to: A. Decrease the severity of the withdrawal syndrome to a clinically tolerable degree. B. Ensure that the patient is not agitated or distressed or displaying signs and symptoms of withdrawal C. Ensure that the patient is able to sleep undisturbed for adequate amounts of time. To date, multiple tapering regimens have been described and are usually decided at the discretion of the caring medical team. Suggested strategies for opioid/benzodiazepine tapering may include distinguishing patients who have been on short term (<3-4 days) vs long term opioid/benzodiazepine therapy (>4-7 days), deciding on specific tapering agent/s, deciding on an oral conversion dose if the patient is without IV access, deciding on the percentage reduction of the daily opioid/benzodiazepine dose to be weaned, deciding on whether to wean opioid/benzodiazepine simultaneously or in isolation and deciding on a withdrawal assessment tool which is familiar to the medical team during tapering period as discussed above.

5 At the authors institution an example of a tapering regimen is reducing the opioid and/or benzodiazepine dose by 25% in patients on short term therapy (<7 days) and reducing the opioid and/or benzodiazepine dose by 10% in patients on long term therapy (>7 days) as tolerated. Given the lack of evidence based studies advocating standardized tapering regimens and the nebulous status of what withdrawal assessment tool to be used, tapering regimens are variable. If IV access is unable to be obtained and the patient is able to tolerate orals, an oral formulation of the opioid/benzodiazepine should be used. If converting to one opioid to another, a reduction of incomplete cross tolerance should be calculated into the actual dose. Apart from conventional opioids, the following drugs have been used for withdrawal prevention (primary or adjuvant) and opioid tapering: A. Methadone Liquid formulation available and easily digested Long half life, % bioavailability and equipotent with morphine Previous report shows successful weaning in pediatric patients in 5 days in 80% patients B. Buprenorphine Synthetic partial µ opioid agonist with low abuse potential and strong safety profile Previously used with adolescent patients in out patient substance abuse programs Sublingual and transdermal (new) formulation available Validated assessment tool Clinical Opioid Withdrawal Scale (COWS) Role in the treatment of iatrogenic opioid withdrawal for pediatric patients is unknown C. Clonidine/Dexmedetomidine Alpha 2 agonist. Sympatholytic effects reported to mitigate hyperadrenergic state associated with opioid withdrawal Dexmedetomidine administered IV/SQ Clonidine PO Use of clonidine/dexmedetomidine in pediatric withdrawal treatment limited to case reports and small case series D. Ketamine NMDA receptor antagonist noted to attenuate opioid dependence and withdrawal in adults Use of ketamine for opioid withdrawal in pediatric patient limited to case report. 5. What causes could account for over-sedation in the patient? In this patient, potential causes of over-sedation may include: A. Airway/Breathing/Cardiovascular issues

6 B. Drug error C. Dosing error D. Drug-drug interactions E. Systemic (i.e. renal/hepatic/cardiac) impairment causing altered pharmacokinetics of drug F. CNS etiologies G. Benzyl alcohol (present in IV midazolam) causing neurological abnormalities Anand KJ, Ingraham J. Pediatric. Tolerance, dependence and strategies for compassionate withdrawal of analgesics and anxiolytics in the pediatric ICU. Crit Care Nurse 1996; 16(6): Arnold JH, Troug RD, Orav EL. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology 1990; 73: 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: Cunliffe M, McArthur L, Dooley F. Managing sedation withdrawal in children who 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 2008; 9(6): Franck LS, Naughton I, Winter I. Opioid and benzodiazepine withdrawal symptoms in pediatric intensive care patients. Intensive and Crit Care Nursing 2004; 20: French JP, Nocera M. Drug withdrawal symptoms in children after continuous infusions of fentanyl. J Pediatr Nurs 1994; 9(2): Ista E, van Djik 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(8): Ista E, van Djik M, de Hoog et al. Construction of the Sophia Observation withdrawal Symptoms-scale (S0S) for critically ill children. Intensive Care Med 2009; 35: Katz R, Kelly HW, His A. Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion. Crit Care Med 1994; 22: ( ) Jenkins IA, Playfor SD, Bevan C et al. Current United Kingdom sedation practices in pediatric intensive care. Paediatr Anesth 2007; 17:

7 Levy SM, Vaughan BL, Angulo M et al. Buprenorphine Replacement Therapy for Adolescents with Opioid Dependence: Early Experience from a Children s Hospital- Based Outpatient Treatment Program. J of Adolesc Health 2007; 40: Tobias JD. Dexmedetomidine to treat opioid withdrawal in infants and children following prolonged sedation in the PICU. J Opioid Manag 2006; 2: 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;