1. How Body Cooling Affects the Pharmacokinetics of Medications Annette L. Rickolt PCNS-BC, APN, RNC-NIC & Barbara McKinney, PharmD

2. Stated Learner Objectives  Explain the mechanism of action of Induced Hypothermia Therapy.  Describe appropriate adjustments in prescribing practices for patients receiving Induced Hypothermia Therapy

3. Induced Hypothermia  History of Cooling  Indications  Standard treatment procedures for neonates, pediatric and adult patients  What happens when the body is cooled?  Latest research in adjunct treatments

4. When did cooling start ?

5.  1722 As early as 300 years ago an essay exists describing the manner of infant immersion from London/Holland  1939 Dr. Fay at Temple Univ. School of Medicine as treatment for metastatic disease and to achieve pain control  1941 Used to treat schizophrenic symptoms  1940s and 1950s Dr. Wilfred Bigelow deep hypothermia for cardiopulmonary bypass

6. History Continued  1954 to 1959 Dr. Hubert Rosomoff adjunct treatment for traumatic brain injury and cerebral vascular lesions at the Neurologic Institute of New York  Deep hypothermia was associated with lethal arrhythmias and increased infections which resulted in a decline in popularity  1990 to 1995 decreased ICP, reduced mortality, and increased survival rates

7. Neonatal Cooling  First reported in the therapy of infants after perinatal asphyxia in 1959 No control group No control group Initiated after failed resuscitation Initiated after failed resuscitation No consistency on how it was applied (temp and timing) No consistency on how it was applied (temp and timing)  Safety and Efficacy could not be proven

8. Neonatal Cooling  Gunn and Gluckman (2007) describe the uncontrolled case series in the 1950s and 1960s Reported outcomes were better than historical controls. (short term)  Preceded active resuscitation

9. HIE: Incidence  Peripartum asphyxia affects 2-5 per 1000 live births in technically- developed countries  0.5-1 per 1000 live births have subsequent moderate to severe HIE  Worldwide HIE results in death for 10-60% of affected infants  25% of survivors have long term neurodevelopmental sequelae

10. Hypoxic-Ischemic Encephalopathy  Results from decreased oxygen levels during the birth process  The decreased oxygen before or during birth can destroy cells in the infant’s brain  Damage continues for some time after initial insult

11. HIE: Mechanism of Injury  Neuronal death occurs in two phases after a reversible hypoxic-ischemic global insult  What are these insults? Cord prolapse Cord prolapse Placental Abruption Placental Abruption Maternal hypotension Maternal hypotension Asphyxia due to shoulder dystocia Asphyxia due to shoulder dystocia

12. HIE: Second Phase  “Delayed neuronal death” Secondary phase believed to begin after a latent period of approximately 6 hours as originally identified in animal studies Secondary phase believed to begin after a latent period of approximately 6 hours as originally identified in animal studies Mechanisms causing the delayed death Mechanisms causing the delayed death HyperemiaHyperemia Cytotoxic edema and mitochondrial failureCytotoxic edema and mitochondrial failure Accumulation of excitotoxinsAccumulation of excitotoxins Active cell deathActive cell death Nitric Oxide synthesisNitric Oxide synthesis Free radicalsFree radicals

13. Ischemia Induced Neuronal Death Lee et al. (2000)

14. What happens when the body is cooled?  Peripheral constriction and shunting of blood to the core organs  Decreased inflammatory response  The brain is protected by inhibiting depolarization and therefore by-products  Decreased Cerebral Metabolic Rate  Decreased Cerebral Edema  Decreased Intracranial Pressure

16. Neuroprotection for the Neonate  Precise Mechanisms ?  Programmed cell death (Apoptosis)  Inflammatory Second Messengers  Excitotoxity after Hypoxic- Ischemia

17. When else is hypothermia used in the Pediatric population  Post cardiac arrest Survival to hospital discharge 2%-28% out of hospital CA Survival to hospital discharge 2%-28% out of hospital CA 14-42% after in-hospital CA 14-42% after in-hospital CA Many survivors have severe neurological disability Many survivors have severe neurological disability  Traumatic brain injury

18. Cardiac Arrest and Brain Injury  Period of increased sensitivity of the brain to secondary injury  Pediatric cardiac arrest is usually related to asphyxia instead of VF/VT as in adults  Brain injury is different based on cause of arrest Hickey, R. & Painter, M. (2006). Brain injury from cardiac arrest in children. Neurologic Clinics, 24, 147-158.

19. Post Cardiac Arrest Treatment in Children  Avoid hypotension  Maintain normoxia  Maintain euglycemia  Avoid hyperventilation  Avoid hyperthermia  Avoid rewarming  Consider induced hypothermia Hickey & Painter (2006)Hickey & Painter (2006)

20. Protocol in Children Fink et al. (2010) Children’s Hospital of Pittsburgh After 2002 publications of adult randomized controlled trials began cooling children who were comatose after Cardiac Arrest After 2002 publications of adult randomized controlled trials began cooling children who were comatose after Cardiac Arrest Cooling blanket, ice packs, fan, lowering room temp., gastric lavage with iced saline. One case iced IV saline. Cooling blanket, ice packs, fan, lowering room temp., gastric lavage with iced saline. One case iced IV saline. Target- 34 (33.5-34.8) Target- 34 (33.5-34.8) Reached in 7 hours (5-8) Reached in 7 hours (5-8) Maintained for 24 hrs (16- 48hrs) Maintained for 24 hrs (16- 48hrs) Rewarming for 6 hrs (5-8hrs) Rewarming for 6 hrs (5-8hrs)

21. Conclusions for Hypothermia as Treatment Post Cardiac Arrest  Hypothermia was not associated with survival  Hypothermia patients needed more electrolyte replacement  Hypothermia patients overcooled had greater mortality  Current American Heart Assoc. guidelines recommend consideration of use of HT for comatose survivors of pediatric CA

22. Induced Hypothermia for Adults  Indications Cardiac surgery Cardiac surgery Intracranial hypertension Intracranial hypertension Ischemic Stroke Ischemic Stroke Post Cardiac Arrest Post Cardiac Arrest

23. Adult Protocols  32-34 degrees C  12-24 hours  Cooling Caps, Vests, Blankets  Cooled Fluids

24. Adverse Effects of Hypothermia  Suppression of Immune Function  Prolongation of Clotting Times  Metabolic Effects  Cardiovascular Adaptation during cooling  Skin disturbances

25. Fat Tissue Necrosis

26. Pharmacology  Altered Pharmacokinetics  Altered Pharmacodynamics  Alterations in enzyme function Zanelli et al., 2011  Morphine  Fentanyl  Midazolam  Vecuronium  Phenobarbital  Phenytoin  Topiramate  Gentamicin

27. Effects of the Alterations  Clearance  Serum concentrations  Efficacy  Volume of distribution  Hepatic metabolism  Excretion of Unchanged drug

28. Recommendations  Lower Starting doses  Conservative dose titration  Periodic discontinuation  Monitor serum concentrations and adjust  Change timing of dosing

29. Pharmacologic Considerations of Rewarming  Monitor for increased response  Break through Seizures  Break through Pain  Increased oxygen consumption  Increased Heart rate  Decreased blood pressure

30. Current Research on Adjunct Treatments  Stem Cell Treatment  Xenon  Erythropoietin

31. Our Goal

32. References Allen, K & Brandon, D (2011). Hypoxic ischemic encephalopathy: Pathophysiology and experimental treatments. Newborn & Infant Nursing Reviews, 11(3), 125-133. Anderson, M., Longhofer,T., et al.(2007). Passive cooling to initiate hypothermia for transported encephalopathic newborns. Journal of Perinatology, 27, 592-593. Arpino,P.A. & Greer D.M. (2008). Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest. Pharmacotherapy, 28(1), 102- 111. Battin, M., Dezoete,A., et al. (2001). Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics, 107(4), 480-484. Bayir,H., Adelson, D., et al. (2009). Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children. Critical Care Medicine, 37(2), 689-695. De Mos, N., van Litsenberg, R., et al.(2006). Pediatric in-intensive care unit cardiac arrest: Incidence, survival, and predictive factors. Critical Care Medicine, 34, 1209-1215.

33. References cont. Fink, E., Clark, R., et al. (2010). A tertiary care center’s experience with therapeutic hypothermia after pediatric cardiac arrest. Pediatric Critical Care Medicine, 11(1), 66-74. Foreman, S. & Thorngate, L. (2011). Amplitude-integrated electroencephalography: A new approach to enhancing neurologic nursing care in the neonatal intensive care unit. Newborn & Infant Nursing Reviews, 11(3), 134-140. Gunn,A. & Gluckman P. (2007). Head cooling for neonatal encephalopathy: The state of the art. Clinical Obstetrics and Gynecology, 50(3), 636-651. Hickey, R. & Painter, M. (2006). Brain injury from cardiac arrest in children. Neurologic Clinics, 24, 147-158. Jacobs, S., Hunt, R. et al. (2007). Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database for Systematic Reviews,4. retrieved January 15, 2008, from http:gateway.tx.ovid.com/gw2/ovidweb.cgi Keough, J.M. (2007). Determinants of outcome after head cooling for neonatal encephalopathy. Pediatrics,120(1), 171-172.

34. References cont. Long,M. & Brandon, D. (2007). Induced hypothermia for neonates with hypoxic- ischemic encephalopathy. The Journal of Obstetric, Gynecologic, and Neonatal Nursing, 36(3), 293-298. Merchant, R.,Abella, B., et al. (2006). Therapeutic hypothermia after cardiac arrest: Unintentional overcooling is common using ice packs and conventional cooling blankets. Critical Care Medicine, 34(12), S490-S494. Navarani-Meury,S., Schneider,J., & Buhrer,C. (2007). Sclerema neonatorum after therapeutic whole-body hypothermia. Archives of Disease in Child, Fetal, and Neonatal Education, 92, F307. Newman, K. & DeLoach, D. (2011). Neonatal Hypothermia: A method to provide neuroprotection after hypoxic ischemic encephalopathy. Newborn & Infant Nursing Reviews, 11(3), 113-124. Shankaran,S. & Laptook,A. (2007). Hypothermia as a treatment for birth asphyxia. Clinical Obstetrics and Gynecology, 50(3), 624-635. Tortorici,M., Kochanek, P., Poloyac, S. (2007). Effects of hypothermia on drug disposition, metabolism, and response: A focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Critical Care Medicine, 35(9), 2196-2204. Zanelli,S., Buck,M., Fairchild, K. (2011). Physiologic and pharmacologic considerations for hypothermia therapy in neonates. Journal of Perinatology, 31, 377-386.