Pathophysiology Review. Hypoxic-Ischemic Encephalopathy & Therapeutic Hypothermia. Objectives. What is Hypoxic-Ischemic Encephalopathy?

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1 Hypoxic-Ischemic Encephalopathy & Therapeutic Hypothermia Nancy Couto Nurse Practitioner, NICU London Health Sciences Centre, Children s Hospital nancy.couto@lhsc.on.ca Objectives Review Pathophysiology of Hypoxic-Ischemic Encephalopathy (HIE) Identify Criteria for initiating Therapeutic Hypothermia for presumed HIE Review Therapeutic Hypothermia Discuss evidence supporting Therapeutic Hypothermia for HIE Application to Clinical Practice What is Hypoxic-Ischemic Encephalopathy? Hypoxic: diminished amount of oxygen Ischemic: diminished blood perfusion Encephalopathy: dysfunction of the brain HIE is an abnormal neurological state as a result of a hypoxicischemic insult. HIE occurs when there is impaired cerebral blood flow, thus reducing oxygen delivery to the brain followed by cerebral dysfunction. (The ACoRN Neonatal Society, 2010; Deacon & O Neill, 1999; Fetus and Newborn Committee & CPS, 2012) Factors that Affect Fetal Oxygenation that may contributing to the development of HIE Maternal factors seizures, trauma, smoking, sepsis, vasculopathies, severe preecclampsia, antepartum hemorrhage Uteroplacental factors placental abruption, placental infarction/dysfunction, oligohydramnios, abnormal doppler studies or chorioamnionitis Fetal Factors cord compression, cord prolapse, entanglement, significant anaemia (e.g. maternal-fetal hemorrhage) (Liston, Sawchuck & Young, 2007) Incidence of HIE 1 to 6 per 1000 live births It is often unanticipated HIE infants are often initially cared for in community hospitals Pathophysiology Review (Fetus and Newborn Committee & CPS, 2012) 1

2 HIE Pathophysiology Primary Phase (primary neuronal death & energy failure ) Evolving Process Latent Period 6 hours Secondary Phase (delayed neuronal death) reperfusion injury begins INSULT.. Window of opportunity for.continued Therapeutic Hypothermia Neuron Cell Intervention Death (Fetus and Newborn Committee & CPS, 2011; Higgins et al., 2006; Jacobs et al., 2007; Gomella, Cunningham & Eyal, 2009) How does Therapeutic Hypothermia fit into this clinical picture? If infant cooling is initiated within the 6 hour window, the extent of neuronal damage may be decreased. Therapeutic Hypothermia is a neuroprotective intervention intended to prevent severe neurological sequelae. (Fetus and Newborn Committee, CPS, 2012; Higgins et al., 2006; Cunningham & Eyal, 2009, Jacobs, 2007; Shah, 2010) How do we decide which infants should receive Therapeutic Hypothermia? Canadian Pediatric Society (2012) Practice Point Infants > 36 weeks gestation with HIE who are <6 hours of age and who meet the following criteria: Criteria A (any two): APGAR score <5 at 10 minutes of age Continued need for ventilation & resuscitation at 10 min. of age ph<7 or base deficit >16 mmol/l in cord blood OR arterial blood gases measured within 1 hour of birth. AND Criteria B: Moderate (Sarnat stage II) or Severe (Sarnat stage III) encephalopathy demonstrated by the presence of SEIZURES OR at least ONE SIGN IN AT LEAST THREE OF THE CATEGORIES shown in Table 1 Clinical Criteria for HIE Exclusion Criteria < 36 weeks gestation based on CPS statement OR < 35 weeks gestation based on some current research Significant hemorrhage Major congenital or genetic abnormalities and no further aggressive treatment is planned * presence of seizures or at least one sign in at least three of the categories (Fetus and Newborn Committee & CPS, 2012, pp. 3; modified from original Sarnat & Sarnat, 1976) (Fetus and Newborn Committee, CPS, 2012; Shah, 2010) 2

3 How do you provide Therapeutic Hypothermia? Decreasing a newborn temperature to a rectal or esophageal temperature of C for 72 hrs. Head/ whole body cooling. Provision at a Level III NICU/ Paediatric Critical Care Unit with trained personal to diagnose and treating seizures, multi-organ failure, arrhythmias, coagulopathy and other complications that may develop. (American Heart Association & American Academy of Pediatrics, 2011; Cunningham & Eyal, 2009; Fetus and Newborn Committee, CPS, 2012; Jacobs, 2007; Shah, 2010) What can be done until the transport team arrives? Initiate passive cooling in the peripheral hospital as per direction of accepting physician at tertiary centre Turn off the overhead warmer Remove infant hat, un-swaddle infant *maintain boundaries around infant for comfort* Monitor temperature very closely to avoid excessive hypothermia Establish venous/arterial access if possible prior to the cooling process Monitor vital signs & for signs of seizure activity Intervene as clinically indicated *Update family prior to transport!* Infant Cooling System Possible Multi-organ Involvement: Pathophysiology Review Multi-organ Involvement Cerebral edema, ischemia, cerebral hemorrhage, spinal cord injury Monitor: seizures, altered suck, swallow, gag, spontaneous breathing, neurological assessment, motor function Pulmonary Edema (related to cardiac dysfunction and increased pulmonary capillary permeability), RDS (surfactant deactivation), MAS, PPHN Monitor: pulmonary hemorrhage, acidemia (may lead to pulmonary vessels remaining constricted thus leading to PPHN), hypoxemia Ischemia of cardiac muscle and reduced contractility Monitor: hypotension, bradycardia, arrhythmia, decreased perfusion, cardiovascular shock (Gomella 1999; The ACoRN Neonatal Society, 2010; Wachtel, E. & Hendricks-Muñoz, k., 2011) Multi-organ Involvement Altered synthesis, excretory and detoxifying functions of the liver Monitor: LFTs, ammonia levels (hyperammonemia), coagulopathies Necrotizing enterocolitis, delayed gastric emptying, ileus, GI bleed Monitor: Abdominal status, stooling/ stool, cautious initiation of feeds Decreased GFR, acute tubular necrosis (ATN), impaired Na & H2O regulation, fluid shifts, SIADH, DI Monitor: Electrolytes, BUN, Cr, accurate ins and outs (Gomella 1999; The ACoRN Neonatal Society, 2010; Wachtel, E. & Hendricks-Muñoz, k., 2011 ) 3

4 Multi-organ Involvement Hematological: Coagulopathy, impaired synthesis of clotting factors, thrombocytopenia Monitor: CBC, Platelets counts, INR, Fibrinogen; may need volume replacement; blood products (e.g. platelets, PRBCs, cryoprecipitate) Metabolic: Hypokalemia, hypo/ hypermagnesemia, Hypocalcemia, Hypoglycemia, Acidosis (Gomella 1999; The ACoRN Neonatal Society, 2010; Wachtel, E. & Hendricks-Muñoz, k., 2011 ) Clinical Management Considerations: Venous/Arterial Access: venous/arterial access prior to the cooling process! Fluid and Nutritional Requirements: metabolic activity is reduced prevention of excess fluids ; TFI 40-70mls/kg/day Analgesia / Sedative treatment: Indications for analgesia include agitation, pain or shivering response. Shivering leads to increased peripheral muscle oxygenation consumption. Remember hypothermia may have reduced drug clearance, potentially toxic serum concentrations may occur with moderate hypothermia. (E.g. Morphine infusion rates should not be >10 mcg/kg/hr Therapeutic Drug Level Monitoring: Metabolism by the liver and pharmcokinteics may be significantly altered during the cooling process. Skin At risk of subcutaneous fat necrosis, monitoring skin integrity closely (Gomella1999; Wachtel, E. & Hendricks-Muñoz, k., 2011 ) Possible Seizure Activity While cooling what do we monitor? Peak time for seizure occurrence is 6-48 hrs Why do we monitor for this? If seizures are untreated negative sequelae can occur How? Bedside Amplitude-integrated electroencephalography (aeeg) e.g. BrainZ aeeg is a tool for monitoring both normal and severely abnormal background patterns and seizure activity Seizures detected by aeeg should be evaluated by a min sensor Conventional Electroencephalography (ceeg) done by a ceeg technician. What else do we monitor & when? On Admission: CBC, coagulation, electrolytes, LFTs, ammonia, urea & creatinine, calcium, glucose, phosphate and alkaline phosphatase, gas, lactate 1st 24 hours: Arterial blood gas, electrolyes, glucose & lactate q6-8h 24 hours to end of cooling phase: CBC, coagulation, electrolytes, LFTs, bilirubin, urea & creatinine, ammonia, calcium, phosphate and alkaline phosphatase Lipid level if receiving IV lipid Arterial blood gas, electrolytes, glucose and lactate q6-8h aeeg, 12 lead EEG, MRI Paediatric Neurology Consultation Consider: Echocardiogram if hemodynamically unstable What supporting literature exists for Therapeutic Hypothermia? 4

5 Jacobs et al., 2007 The Cochrane Library, 4 Cochrane Review included 8 RCTs (n=638) comparing hypothermia treatment to normothermia treatment for newborns with moderate or severe HIE. Objective: Determine the effect of therapeutic hypothermia on mortality, long-term neurodevelopmental disability (18 months) and clinical side effects. Jacobs et al., 2007 The Cochrane Library, 4 Conclusion: Death or major disability, mortality and neurodevelopmental disability in survivors are all reduced. It is important to note that there is some evidence of harm from therapeutic hypothermia. These risks include increased thrombocytopenia & hypotension, however the benefits on survival and neurodevelopment outweighed these short-term adverse effects. Seminars in Fetal & Neonatal Medicine 15; 5 A systematic review and meta-analysis was conducted to including 13 RCTs comparing hypothermia treatment to normothermia treatment for newborns with HIE. The Metaanalysis included n=1440 newborns >35 weeks gestation. Seminars in Fetal & Neonatal medicine 15; 5 Objective: To evaluate the effectiveness and safety of therapeutic hypothermia use in newborns with HIE. Fig. 3. Efficacy outcomes. ND, neurodevelopmental; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index. Seminars in Fetal & Neonatal medicine 15; 5 Seminars in Fetal & Neonatal Medicine 15; 5 Conclusion: Hypothermia is a safe and effective treatment of neonatal HIE in term and near-term newborn infants. Therapeutic hypothermia reduced mortality and neurological disability at months of age. Fig. 4. Safety outcomes. 5

6 Systematic Reviews Favour Therapeutic Hypothermia & Governing Bodies Endorse this Therapy. Edwards, D., Brocklehurst, P., Gunn, A. J., Halliday, H., Juszczak, E., Levene, M., Strohm, B., & Thoresen, M. (2010). Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. British Medical Journal, 1-7. doi: /bmj.c363 What do we do after 72 hours of cooling? Shah, P. S., Ohlsson, A., & Perlman, M. (2007). Hypothermia to treat neonatal hypoxic ischemic encephalopathy [Systematic Review]. Archives of Paediatric and Adolescent Medicine, 161(10), Tagin, M. A., Woolcott, C. G., Vincer, M. J., Whyte, R. K., & Stinson, D. A. (2012, June). Hypothermia for neonatal hypoxic ischemic encephalopathy: An updated systematic review and meta-analysis. Archives of Pediatric and Adolescent Medicine, 166(6), doi: /archpediatrics CPS, AAP Rewarming after Therapeutic Hypothermia Increase rectal temperature by 0.5 C every 1-4 hours. The consensus is rewarm infant VERY SLOWLY! Why do an MRI at hrs post warming? Edema secondary to hypoxic ischemic insult usually subsides so patterns of injury that are irreversible may be identified as restricted diffusion BEFORE lysis of cerebral cells occurs. Aids in prognostic counselling (Fetus and Newborn Committee & CPS, 2012; Prakesh, 2007; Shah, 2007; Tagin, 2012; Jacobs, 2011) (The ACoRN Neonatal Society, 2010; Cheong, Coleman & Hunt et al., 2012) Conclusions Morality and neurodevelopmental disability are reduced when therapeutic hypothermia is utilized for moderate to severe HIE. Questions/ Comments Mortality is without major disability (Edwards et al., 2010;Fetus and Newborn Committee & CPS, 2012; Jacobs et al., 2007; Tagin et al., 2012; Shah, 2010) 6

7 Thank You References American Heart Association & American Academy of Pediatrics. (2011). Neonatal Resuscitation Textbook. (6th ed.). United States of America: American Academy of Pediatrics. Cincinnati Sub-zero Medical, (2011) Retrieved from III.aspx Cheong, J., Coleman L., FRANZCR, Hunt R., Lee K., Doyle L., Inder T. & Jacobs S. (2012). Prognostic Utility of Magnetic Resonance Imaging in Neonatal Hypoxic-Ischemic Encephalopathy: Substudy of a Randomized Trial. Arch Pediatr Adolesc Med. 2012;166(7): doi: /archpediatrics Deacon, J. & O Neil, P. (1999). Core curriculum for neonatal intensive care nursing (2nd ed.). Philadelphia,PA: W.B. Saunders Company. Edwards, D., Brocklehurst, P., Gunn, A. J., Halliday, H., Juszczak, E., Levene, M., Strohm, B., & Thoresen, M. (2010). Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischemic encephalopathy: synthesis and meta-analysis of trial data. British Medical Journal, 1-7. doi: /bmj.c363 Fetus and Newborn Committee, Canadian Paediatric Society. (2012). Hypothermia for newborns with hypoxic ischemic encephalopathy. Retrieved from Canadian Pediatric Society: Gomella, T. L., Cunningham, M. D., & Eyal, F. G. (2009). Neonatology: management, procedures, on-call problems, diseases and drugs (6th ed.). New York, NY: The McGraw-Hill Companies, Inc. Higgins, R., Raju, T., Perlman, J., Azzopardi, D., Blackmon, L., Clark, R., Edwards, D., & Ferriero, D. (2006). Hypothermia and perinatal asphyxia: Executive summary of the national institute of child health and human development workshop. Journal of Pediatrics, 148, doi: /j.jpeds Jacobs, S. E., Hunt, R., Tarnow-Mordi, W., Inder, T., & Davis, P. (2007). Cooling for newborns with hypoxic ischemic encephalopathy [Systematic Review]. The Cochrane Library, Retrieved from Jacobs, S. E., Morley, C. J., Inder, T. E., Stewart, M. J., Smith, K. R., McNamara, M. P., Wright, I. M., & Kirpalani, H. M. (2011, Aug). Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: A randomized control trial. Archives of Paediatric and Adolescent Medicine, 165(8), References Lavery, S. & Randall, K. (2008). Cerebral monitoring of the term neonate Neonatal Network, 27(5) Liston, R., Sawchuck, D., & Young, D. (2007). Fetal health surveillance: Antepartum and intrapartum consensus guideline [SOGC Clinical Practice Guideline]. Journal of Obstetrics and Gynecology Canada, 29(9), Perrone, S., Szabo, M., Bellieni, C., Longini, M., Bango, M., Kelen, D., Treszl, A., & Negro, S. (2010, May 6). Whole body hypothermia and oxidative stress in babies with hypoxic-ischemic brain injury. Pediatric Neurology, 43(4), doi: /.pediatrneurol Sarnat, H. & Sarnat, M. (1976). Neonatal encephalopathy following fetal distress. A clinical and electrencephalographic study. Archives of Neurology, 33, Shah, P. S. (2010). Hypothermia: a systematic review and meta-analysis of clinical trials [Systematic Review]. Seminars in Fetal & Neonatal Medicine, 15, doi: /j.siny Shah, P. S., Ohlsson, A., & Perlman, M. (2007). Hypothermia to treat neonatal hypoxic ischemic encephalopathy [Systematic Review]. Archives of Paediatric and Adolescent Medicine, 161(10), Shankaran, S., Laptook, A., Ehrenkranz, R., Tyson, J., McDonald, S., Donovan, E., Fanaroff, A., & Kenneth, W. (2005). Wholebody hypothermia for neonates with hypoxic-ischemic encephalopathy. The New England Journal of Medicine, 353(15), Tagin, M. A., Woolcott, C. G., Vincer, M. J., Whyte, R. K., & Stinson, D. A. (2012, June). Hypothermia for neonatal hypoxic ischemic encephalopathy: An updated systematic review and meta-analysis. Archives of Pediatric and Adolescent Medicine, 166(6), doi: /archpediatrics The ACoRN Neonatal Society (2010). ACoRN: Acute care of at-risk newborns (1st ed.). Edmonton, AB: McCallum Printing Group, Inc. Wachtel, E. & Hendricks-Muñoz, k. (2011). Current Management of the Infant Who Presents with Neonatal Encephalopathy. Curr Probl Pediatr Adolesc Health Care, 41,