How Body Cooling How Body Cooling Affects the Affects the

Pharmacokinetics of Pharmacokinetics of MedicationsMedications

Annette L. Rickolt PCNS-BC, APN, RNC-NICAnnette L. Rickolt PCNS-BC, APN, RNC-NIC

&&

Barbara McKinney, PharmDBarbara McKinney, PharmD

Stated Learner ObjectivesStated Learner Objectives

Explain the mechanism of action of Explain the mechanism of action of Induced Hypothermia Therapy.Induced Hypothermia Therapy.

Describe appropriate adjustments in Describe appropriate adjustments in prescribing practices for patients receiving prescribing practices for patients receiving Induced Hypothermia TherapyInduced Hypothermia Therapy

  

Induced HypothermiaInduced Hypothermia

History of CoolingHistory of Cooling Indications Indications Standard treatment procedures for Standard treatment procedures for

neonates, pediatric and adult patientsneonates, pediatric and adult patients What happens when the body is cooled?What happens when the body is cooled? Latest research in adjunct treatmentsLatest research in adjunct treatments

When did cooling start ?When did cooling start ?

When did cooling start?When did cooling start?

1722 As early as 300 years ago an essay exists 1722 As early as 300 years ago an essay exists describing the manner of infant immersion from describing the manner of infant immersion from London/Holland London/Holland

1939 Dr. Fay at Temple Univ. School of 1939 Dr. Fay at Temple Univ. School of Medicine as treatment for metastatic disease Medicine as treatment for metastatic disease and to achieve pain controland to achieve pain control

1941 Used to treat schizophrenic symptoms1941 Used to treat schizophrenic symptoms 1940s and 1950s Dr. Wilfred Bigelow deep 1940s and 1950s Dr. Wilfred Bigelow deep

hypothermia for cardiopulmonary bypasshypothermia for cardiopulmonary bypass

History ContinuedHistory Continued

1954 to 1959 Dr. Hubert Rosomoff adjunct 1954 to 1959 Dr. Hubert Rosomoff adjunct treatment for traumatic brain injury and treatment for traumatic brain injury and cerebral vascular lesions at the Neurologic cerebral vascular lesions at the Neurologic Institute of New YorkInstitute of New York

Deep hypothermia was associated with Deep hypothermia was associated with lethal arrhythmias and increased infections lethal arrhythmias and increased infections which resulted in a decline in popularitywhich resulted in a decline in popularity

1990 to 1995 decreased ICP, reduced 1990 to 1995 decreased ICP, reduced mortality, and increased survival ratesmortality, and increased survival rates

Neonatal CoolingNeonatal Cooling

First reported in the therapy of infants after First reported in the therapy of infants after perinatal asphyxia in 1959perinatal asphyxia in 1959 No control groupNo control group Initiated after failed resuscitationInitiated after failed resuscitation No consistency on how it was applied (temp No consistency on how it was applied (temp

and timing)and timing) Safety and Efficacy could not be provenSafety and Efficacy could not be proven

Neonatal CoolingNeonatal Cooling

Gunn and Gluckman Gunn and Gluckman (2007) describe the (2007) describe the uncontrolled case uncontrolled case series in the 1950s series in the 1950s and 1960s Reported and 1960s Reported outcomes were better outcomes were better than historical than historical controls. (short term)controls. (short term)

Preceded active Preceded active resuscitationresuscitation

HIE: IncidenceHIE: Incidence

Peripartum asphyxia affects 2-5 per 1000 Peripartum asphyxia affects 2-5 per 1000 live births in technically- developed live births in technically- developed countriescountries

0.5-1 per 1000 live births have subsequent 0.5-1 per 1000 live births have subsequent moderate to severe HIEmoderate to severe HIE

Worldwide HIE results in death for 10-60% Worldwide HIE results in death for 10-60% of affected infantsof affected infants

25% of survivors have long term 25% of survivors have long term neurodevelopmental sequelae neurodevelopmental sequelae

Hypoxic-Ischemic EncephalopathyHypoxic-Ischemic Encephalopathy

Results from decreased oxygen levels Results from decreased oxygen levels during the birth processduring the birth process

The decreased oxygen before or during The decreased oxygen before or during birth can destroy cells in the infant’s brainbirth can destroy cells in the infant’s brain

Damage continues for some time after Damage continues for some time after initial insultinitial insult

HIE: Mechanism of InjuryHIE: Mechanism of Injury

Neuronal death occurs in two phases after Neuronal death occurs in two phases after a reversible hypoxic-ischemic global insulta reversible hypoxic-ischemic global insult

What are these insults?What are these insults? Cord prolapseCord prolapse Placental AbruptionPlacental Abruption Maternal hypotensionMaternal hypotension Asphyxia due to shoulder dystociaAsphyxia due to shoulder dystocia

HIE: Second PhaseHIE: Second Phase

““Delayed neuronal death” Delayed neuronal death” Secondary phase believed to begin after a latent Secondary phase believed to begin after a latent

period of approximately 6 hours as originally period of approximately 6 hours as originally identified in animal studiesidentified in animal studies

Mechanisms causing the delayed deathMechanisms causing the delayed death• HyperemiaHyperemia• Cytotoxic edema and mitochondrial failureCytotoxic edema and mitochondrial failure• Accumulation of excitotoxins Accumulation of excitotoxins • Active cell deathActive cell death• Nitric Oxide synthesisNitric Oxide synthesis• Free radicalsFree radicals

Ischemia Induced Neuronal DeathIschemia Induced Neuronal Death

Lee et al. (2000)Lee et al. (2000)

What happens when the body is What happens when the body is cooled?cooled?

Peripheral constriction and shunting of Peripheral constriction and shunting of blood to the core organsblood to the core organs

Decreased inflammatory responseDecreased inflammatory response The brain is protected by inhibiting The brain is protected by inhibiting

depolarization and therefore by-productsdepolarization and therefore by-products Decreased Cerebral Metabolic RateDecreased Cerebral Metabolic Rate Decreased Cerebral EdemaDecreased Cerebral Edema Decreased Intracranial PressureDecreased Intracranial Pressure

Neuroprotection for the NeonateNeuroprotection for the Neonate

Precise Mechanisms ?Precise Mechanisms ?

Programmed cell death Programmed cell death (Apoptosis)(Apoptosis)

Inflammatory Second Inflammatory Second MessengersMessengers

Excitotoxity after Hypoxic-Excitotoxity after Hypoxic-IschemiaIschemia

When else is hypothermia used in When else is hypothermia used in the Pediatric populationthe Pediatric population

Post cardiac arrestPost cardiac arrest Survival to hospital discharge 2%-28% out of Survival to hospital discharge 2%-28% out of

hospital CAhospital CA 14-42% after in-hospital CA14-42% after in-hospital CA Many survivors have severe neurological Many survivors have severe neurological

disabilitydisability Traumatic brain injuryTraumatic brain injury

Cardiac Arrest and Brain InjuryCardiac Arrest and Brain Injury

Period of increased sensitivity of the brain Period of increased sensitivity of the brain to secondary injuryto secondary injury

Pediatric cardiac arrest is usually related Pediatric cardiac arrest is usually related to asphyxia instead of VF/VT as in adultsto asphyxia instead of VF/VT as in adults

Brain injury is different based on cause of Brain injury is different based on cause of arrestarrest

Hickey, R. & Painter, M. (2006). Brain injury from cardiac Hickey, R. & Painter, M. (2006). Brain injury from cardiac arrest in children. arrest in children. Neurologic ClinicsNeurologic Clinics, 24, 147-158., 24, 147-158.

Post Cardiac Arrest Treatment in Post Cardiac Arrest Treatment in ChildrenChildren

Avoid hypotensionAvoid hypotension Maintain normoxiaMaintain normoxia Maintain euglycemiaMaintain euglycemia Avoid hyperventilationAvoid hyperventilation Avoid hyperthermiaAvoid hyperthermia Avoid rewarmingAvoid rewarming Consider induced hypothermiaConsider induced hypothermia

• Hickey & Painter (2006)Hickey & Painter (2006)

Protocol in ChildrenProtocol in Children

Fink et al. (2010) Children’s Hospital of PittsburghFink et al. (2010) Children’s Hospital of Pittsburgh After 2002 publications of adult randomized controlled After 2002 publications of adult randomized controlled

trials began cooling children who were comatose after trials began cooling children who were comatose after Cardiac ArrestCardiac Arrest

Cooling blanket, ice packs, fan, lowering room temp., Cooling blanket, ice packs, fan, lowering room temp., gastric lavage with iced saline. One case iced IV gastric lavage with iced saline. One case iced IV saline.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)

Conclusions for Hypothermia as Conclusions for Hypothermia as Treatment Post Cardiac ArrestTreatment Post Cardiac Arrest

Hypothermia was not associated with Hypothermia was not associated with survivalsurvival

Hypothermia patients needed more Hypothermia patients needed more electrolyte replacementelectrolyte replacement

Hypothermia patients overcooled had Hypothermia patients overcooled had greater mortalitygreater mortality

Current American Heart Assoc. guidelines Current American Heart Assoc. guidelines recommend consideration of use of HT for recommend consideration of use of HT for comatose survivors of pediatric CAcomatose survivors of pediatric CA

Induced Hypothermia for AdultsInduced Hypothermia for Adults

IndicationsIndications Cardiac surgeryCardiac surgery Intracranial hypertensionIntracranial hypertension Ischemic StrokeIschemic Stroke Post Cardiac ArrestPost Cardiac Arrest

Adult ProtocolsAdult Protocols

32-34 degrees C32-34 degrees C 12-24 hours12-24 hours Cooling Caps, Vests, BlanketsCooling Caps, Vests, Blankets Cooled FluidsCooled Fluids

Adverse Effects of HypothermiaAdverse Effects of Hypothermia

Suppression of Immune FunctionSuppression of Immune Function Prolongation of Clotting TimesProlongation of Clotting Times Metabolic EffectsMetabolic Effects Cardiovascular Adaptation during coolingCardiovascular Adaptation during cooling Skin disturbancesSkin disturbances

Fat Tissue NecrosisFat Tissue Necrosis

PharmacologyPharmacology

Altered PharmacokineticsAltered Pharmacokinetics Altered Altered

PharmacodynamicsPharmacodynamics Alterations in enzyme Alterations in enzyme

functionfunction

Zanelli et al., 2011Zanelli et al., 2011

MorphineMorphine FentanylFentanyl MidazolamMidazolam VecuroniumVecuronium PhenobarbitalPhenobarbital PhenytoinPhenytoin TopiramateTopiramate GentamicinGentamicin

Effects of the AlterationsEffects of the Alterations

ClearanceClearance Serum concentrationsSerum concentrations EfficacyEfficacy Volume of distributionVolume of distribution Hepatic metabolismHepatic metabolism Excretion of Unchanged drugExcretion of Unchanged drug

RecommendationsRecommendations

Lower Starting dosesLower Starting doses Conservative dose titrationConservative dose titration Periodic discontinuation Periodic discontinuation Monitor serum concentrations and adjustMonitor serum concentrations and adjust Change timing of dosingChange timing of dosing

Pharmacologic Considerations Pharmacologic Considerations of Rewarmingof Rewarming

Monitor for increased responseMonitor for increased response Break through SeizuresBreak through Seizures Break through PainBreak through Pain Increased oxygen consumptionIncreased oxygen consumption Increased Heart rateIncreased Heart rate Decreased blood pressureDecreased blood pressure

Current Research on Adjunct Current Research on Adjunct TreatmentsTreatments

Stem Cell TreatmentStem Cell Treatment XenonXenon ErythropoietinErythropoietin

Our GoalOur Goal

ReferencesReferencesAllen, K & Brandon, D (2011). Hypoxic ischemic encephalopathy: Allen, K & Brandon, D (2011). Hypoxic ischemic encephalopathy:

Pathophysiology and experimental treatments. Pathophysiology and experimental treatments. Newborn & Infant Nursing Newborn & Infant Nursing ReviewsReviews, 11(3), 125-133., 11(3), 125-133.

Anderson, M., Longhofer,T., et al.(2007). Passive cooling to initiate Anderson, M., Longhofer,T., et al.(2007). Passive cooling to initiate hypothermia for transported encephalopathic newborns. hypothermia for transported encephalopathic newborns. Journal of Journal of PerinatologyPerinatology, 27, 592-593., 27, 592-593.

Arpino,P.A. & Greer D.M. (2008). Practical pharmacologic aspects of Arpino,P.A. & Greer D.M. (2008). Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest. therapeutic hypothermia after cardiac arrest. PharmacotherapyPharmacotherapy, 28(1), 102-, 28(1), 102-111.111.

Battin, M., Dezoete,A., et al. (2001). Neurodevelopmental outcome of infants Battin, M., Dezoete,A., et al. (2001). Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. treated with head cooling and mild hypothermia after perinatal asphyxia. PediatricsPediatrics, 107(4), 480-484., 107(4), 480-484.

Bayir,H., Adelson, D., et al. (2009). Therapeutic hypothermia preserves Bayir,H., Adelson, D., et al. (2009). Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and antioxidant defenses after severe traumatic brain injury in infants and children. children. Critical Care MedicineCritical Care Medicine, 37(2), 689-695., 37(2), 689-695.

De Mos, N., van Litsenberg, R., et al.(2006). Pediatric in-intensive care unit De Mos, N., van Litsenberg, R., et al.(2006). Pediatric in-intensive care unit cardiac arrest: Incidence, survival, and predictive factors. cardiac arrest: Incidence, survival, and predictive factors. Critical Care Critical Care MedicineMedicine, 34, 1209-1215., 34, 1209-1215.

References cont.References cont.Fink, E., Clark, R., et al. (2010). A tertiary care center’s experience with Fink, E., Clark, R., et al. (2010). A tertiary care center’s experience with

therapeutic hypothermia after pediatric cardiac arrest. therapeutic hypothermia after pediatric cardiac arrest. Pediatric Critical Care Pediatric Critical Care MedicineMedicine, 11(1), 66-74., 11(1), 66-74.

Foreman, S. & Thorngate, L. (2011). Amplitude-integrated Foreman, S. & Thorngate, L. (2011). Amplitude-integrated electroencephalography: A new approach to enhancing neurologic nursing electroencephalography: A new approach to enhancing neurologic nursing care in the neonatal intensive care unit. care in the neonatal intensive care unit. Newborn & Infant Nursing ReviewsNewborn & Infant Nursing Reviews, , 11(3), 134-140.11(3), 134-140.

Gunn,A. & Gluckman P. (2007). Head cooling for neonatal encephalopathy: Gunn,A. & Gluckman P. (2007). Head cooling for neonatal encephalopathy: The state of the art. The state of the art. Clinical Obstetrics and GynecologyClinical Obstetrics and Gynecology, 50(3), 636-651., 50(3), 636-651.

Hickey, R. & Painter, M. (2006). Brain injury from cardiac arrest in children. Hickey, R. & Painter, M. (2006). Brain injury from cardiac arrest in children. Neurologic ClinicsNeurologic Clinics, 24, 147-158., 24, 147-158.

Jacobs, S., Hunt, R. et al. (2007). Cooling for newborns with hypoxic ischaemic Jacobs, S., Hunt, R. et al. (2007). Cooling for newborns with hypoxic ischaemic encephalopathy. encephalopathy. Cochrane Database for Systematic Reviews,4Cochrane Database for Systematic Reviews,4. retrieved . retrieved January 15, 2008, from http:gateway.tx.ovid.com/gw2/ovidweb.cgiJanuary 15, 2008, from http:gateway.tx.ovid.com/gw2/ovidweb.cgi

Keough, J.M. (2007). Determinants of outcome after head cooling for neonatal Keough, J.M. (2007). Determinants of outcome after head cooling for neonatal encephalopathy. encephalopathy. PediatricsPediatrics,120(1), 171-172. ,120(1), 171-172.

References cont.References cont.Long,M. & Brandon, D. (2007). Induced hypothermia for neonates with hypoxic-Long,M. & Brandon, D. (2007). Induced hypothermia for neonates with hypoxic-

ischemic encephalopathy. ischemic encephalopathy. The Journal of Obstetric, Gynecologic, and The Journal of Obstetric, Gynecologic, and Neonatal NursingNeonatal Nursing, 36(3), 293-298., 36(3), 293-298.

Merchant, R.,Abella, B., et al. (2006). Therapeutic hypothermia after cardiac Merchant, R.,Abella, B., et al. (2006). Therapeutic hypothermia after cardiac arrest: Unintentional overcooling is common using ice packs and arrest: Unintentional overcooling is common using ice packs and conventional cooling blankets. conventional cooling blankets. Critical Care MedicineCritical Care Medicine, 34(12), S490-S494., 34(12), S490-S494.

Navarani-Meury,S., Schneider,J., & Buhrer,C. (2007). Sclerema neonatorum Navarani-Meury,S., Schneider,J., & Buhrer,C. (2007). Sclerema neonatorum after therapeutic whole-body hypothermia. after therapeutic whole-body hypothermia. Archives of Disease in Child, Archives of Disease in Child, Fetal, and Neonatal EducationFetal, and Neonatal Education, 92, F307., 92, F307.

Newman, K. & DeLoach, D. (2011). Neonatal Hypothermia: A method to Newman, K. & DeLoach, D. (2011). Neonatal Hypothermia: A method to provide neuroprotection after hypoxic ischemic encephalopathy. provide neuroprotection after hypoxic ischemic encephalopathy. Newborn & Newborn & Infant Nursing ReviewsInfant Nursing Reviews, 11(3), 113-124., 11(3), 113-124.

Shankaran,S. & Laptook,A. (2007). Hypothermia as a treatment for birth Shankaran,S. & Laptook,A. (2007). Hypothermia as a treatment for birth asphyxia. asphyxia. Clinical Obstetrics and Gynecology,Clinical Obstetrics and Gynecology, 50(3), 624-635. 50(3), 624-635.

Tortorici,M., Kochanek, P., Poloyac, S. (2007). Effects of hypothermia on drug Tortorici,M., Kochanek, P., Poloyac, S. (2007). Effects of hypothermia on drug disposition, metabolism, and response: A focus of hypothermia-mediated disposition, metabolism, and response: A focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. alterations on the cytochrome P450 enzyme system. Critical Care MedicineCritical Care Medicine, , 35(9), 2196-2204.35(9), 2196-2204.

Zanelli,S., Buck,M., Fairchild, K. (2011). Physiologic and pharmacologic Zanelli,S., Buck,M., Fairchild, K. (2011). Physiologic and pharmacologic considerations for hypothermia therapy in neonates. considerations for hypothermia therapy in neonates. Journal of Journal of PerinatologyPerinatology, 31, 377-386., 31, 377-386.