COOLING FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY

COOLING FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY Roger F. Soll H. Wallace Professor of Neonatology University of Vermont 19 th International Symposium on Neonatology Sao Paulo, Brazil

DISCLOSURE Roger F. Soll is the Coordinating Editor of the Cochrane Neonatal Review Group Supported by a contract from the NICHD

GOALS AND OBJECTIVES What evidence do we have for the use of hypothermia in the treatment of infants with moderate to severe hypoxic ischemic encephalopathy?

HYPOTHERMIA IS HOT

HYPOXIC ISCHEMIC ENCEPHALOPATHY Major predictor of neurodevelopmental disability 1-6/1000 live term births 15-20% die during newborn period 25% permanent neurologic deficits

ISCHEMIA

XX DELAYED PHASE OF INJURY REPERFUSION PERIOD INITIAL INJURY

XX Cell Death 6 hours 24 hours Injury Window of opportunity Time after injury VUNEO.org

HYPOTHERMIA IN THE TREATMENT OF HYPOXIC ISCHEMIC ENCEPHALOPATHY HYPOTHERMIA IN ANIMAL MODELS AFTER EXPERIMENTAL HYPOXIC ISCHEMIC INSULT mild hypothermia (cooling to 32 to 34 C) is neuroprotective brain cooling should be initiated as early as feasible (preferably within 2 hours) and not later than 6 hours cooling should be continued for 48 to 72 hours

XX Gunn, A. J. et al. Pediatrics 1998;102:1098-1106

Cooling for newborns with hypoxic ischemic encephalopathy. Jacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischemic encephalopathy. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003311. DOI: 10.1002/14651858.CD003311.pub2. Updated by M. Berg 2012

Cooling for newborns with hypoxic ischemic encephalopathy. Types of studies: All randomized and quasi-randomized studies comparing the use of therapeutic hypothermia with standard care were included.

Cooling for newborns with hypoxic ischemic encephalopathy. Types of participants Newborn infants Evidence of peripartum asphyxia, with each enrolled infant satisfying at least one of the following criteria: a. Apgar score of 5 or less at 10 minutes; b. mechanical ventilation or resuscitation at 10 minutes c. cord ph < 7.1, or an arterial ph < 7.1 or base deficit of 12 or more within 60 minutes of birth d. evidence of encephalopathy according to Sarnat staging No major congenital abnormalities recognizable at birth.

HYPOTHERMIA IN THE TREATMENT OF HYPOXIC ISCHEMIC ENCEPHALOPATHY: TRIALS IN NEONATES STUDIES Shankaran 2002 Akisu 2003 Eicher 2005 Cool Cap 2005 NICHD 2005 Lin 2006 TOBY 2009 European 2010 Zhou 2010 ICE 2011 Sun 2012 METHOD OF COOLING Whole body Selective Whole body Selective Whole body Selective Whole Body Whole body Selective Whole body Selective ENROLLED INFANTS 19 21 65 234 208 62 325 129 194 221 51

Selective Head Cooling with Mild Systemic Hypothermia to Improve Neurodevelopmental Outcome Following Neonatal Encephalopathy Peter D. Gluckman, FRS, John S. Wyatt, MBChB, Denis Azzopardi, MD, Roberta Ballard, MD, A. David Edwards, FMedScic, Donna M. Ferriero, MD, Richard A. Polin, MD, Charlene M. Robertson, MD, Marianne Thoresen, MD, PhD, Andrew Whitelaw, MD, Alistair J. Gunn, MBChB, PhD, on behalf of the CoolCap Study Group

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY Study objective: to examine whether a 72 hour period of selective head cooling with mild systemic hypothermia started within 6 hours of birth improves neurodevelopmental outcome at 18 months in infants with moderate or severe neonatal encephalopathy. GLUCKMAN 2005

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY Methods: - Infants enrolled at 25 perinatal centers - Study conducted between July 1999 to January 2002 - Infants 36 weeks gestation with acute encephalopathy were recruited if there was evidence of exposure to perinatal hypoxia-ischemia, an abnormal neurological examination and an abnormal aeeg recording. GLUCKMAN 2005

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY Study entry criteria: Apgar score of 5 at 10 minutes after birth, or continued need for resuscitation, including endotracheal or mask ventilation at 10 minutes after birth, or severe acidosis defined as either ph <7 00 or base deficit 16 mmol/l in an umbilical cord blood sample or an arterial or venous sample obtained within 60 minutes of birth. Infants were then assessed for evidence of moderate or severe encephalopathy.. GLUCKMAN 2005

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY Study entry criteria: Evidence of moderate or severe encephalopathy Criteria modified from Sarnat and Sarnat including lethargy, stupor or coma, with one or more of hypotonia, abnormal reflexes including oculomotor or pupillary abnormalities, an absent or weak suck or clinical evidence of seizures. Infants were then assessed for abnormal aeeg GLUCKMAN 2005

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY Study entry criteria (continued): aeeg Infants who met the previous criteria were selected for randomization if they had: moderately or severely abnormal background aeeg voltage (moderate: upper margin of aeeg activity above 10 mv and lower margin below 5 mv; severe: upper margin below 10 mv) and/or electroencephalographically determined seizures (identified by a sudden increase in voltage accompanied by narrowing of the band of aeeg activity and followed by a brief period of suppression). GLUCKMAN 2005

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY

INFANT CHARACTERISTICS N Mean birth weight (gms) Mean gestational age (wks) Emergency C/S Median Apgar score <3 at 5 minute <3 at 10 minutes COOLED GROUP 116 3399 +/- 663 38.9 +/- 1.6 69% 77% 70% CONTROL GROUP 118 3504 +/- 625 39.1 +/- 1.4 64% 68% 55%

STATUS AT ENROLLMENT N Seizures aeeg Moderately Abnormal Severely Abnormal Age at enrollment (hrs) COOLED GROUP 116 59% 54% 36% 4.8 (2.6-6.0) CONTROL GROUP 118 64% 64% 27% 4.7 (2.1-6.1)

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY MORTALITY IN ALL INFANTS % INFANTS 50% 40% 30% 20% 10% 0% ODDS RATIO 0.81 (95% CI 0.47-1.41) 33% 38% MORTALITY COOLING CONTROL GLUCKMAN 2005

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY SEVERE MOTOR DISABILITY AT 18 MONTHS % INFANTS 40% 30% 20% 10% 19% ODDS RATIO 0.54 (95% CI 0.25-1.17) 31% 0% SEVERE MOTOR DISABILITY COOLING CONTROL GLUCKMAN 2005

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY DEATH OR SEVERE DISABILITY AT 18 MONTHS IN ALL INFANTS % INFANTS 70% 60% 50% 40% 30% 20% 10% 0% ODDS RATIO 0.61 (95% CI 0.34-1.09) 66% 55% DEATH OR DISABILITY COOLING CONTROL GLUCKMAN 2005

SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY DEATH OR SEVERE DISABILITY AT 18 MONTHS INTERMEDIATE aeeg GROUP % INFANTS 70% 60% 50% 40% 30% 20% 10% 0% ODDS RATIO 0.47 (95% CI 0.26-0.87) 66% 48% DEATH OR DISABILITY COOLING CONTROL GLUCKMAN 2005

Whole-Body Hypothermia for Neonates with Hypoxic Ischemic Encephalopathy Seetha Shankaran, M.D., Abbot R. Laptook, M.D., Richard A. Ehrenkranz, M.D., Jon E. Tyson, M.D., M.P.H., Scott A. McDonald, B.S., Edward F. Donovan, M.D., Avroy A. Fanaroff, M.D., W. Kenneth Poole, Ph.D., Linda L. Wright, M.D., Rosemary D. Higgins, M.D., Neil N. Finer, M.D., Waldemar A. Carlo, M.D., Shahnaz Duara, M.D., William Oh, M.D., C. Michael Cotten, M.D., David K. Stevenson, M.D., Barbara J. Stoll, M.D., James A. Lemons, M.D., Ronnie Guillet, M.D., Ph.D., Alan H. Jobe, M.D., Ph.D., for the National Institute of Child Health and Human Development Neonatal Research Network

WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY Study objective: To evaluate whether whole body hypothermia initiated before six hours of age and continued for 72 hours in term infants with moderate or severe encephalopathy would reduce death or disability at 18-72 months of age as compared with infants given the usual care.

WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY The patients included: Infants at six hours of age or less were eligible if they met the following criteria: - A blood gas PH of 7 or less or base deficit of 16 mmol per liter or more in a sample of umbilical cord or blood taken during the first hour of life. Additional criteria if blood gas unavailable or did not meet the above values: - Acute perinatal event with a 10 minute Apgar less than 5 or assisted ventilation for more than 10 minutes. - Evidence of seizure and/or encephalopathy. The patients excluded: - Inability to enroll by six hours of age. - Major congenital abnormality. - Severe growth restriction (birth weight equal or less than 1800 grams). - Moribund infant in whom no further aggressive treatment was planned.

CRITERIA FOR DEFINING MODERATE OR SEVERE ENCEPHALOPATHY

WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY INTERVENTION HYPOTHERMIA: whole body cooling within six hours of age; achieved by the use of a blanket servomechanism (water blanket) pre-cooled to 5 C to a target esophageal temperature of 33.5 C for 72 hours following enrollment CONTROL: maintenance of normothermia in the control group. In the hypothermia group infant were rewarmed no faster than 0.5 C per hour. In both groups all skin and esophageal temperature were recorded using a standard protocol, and all infants received standard and same monitoring of vital signs and surveillance for organ dysfunction.

WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY The infant lies supine on the infant-size blanket. The adult-size blanket is suspended vertically alongside the cooling unit. Both blankets are attached to the cooling unit with water circulating through them simultaneously. Shankaran

INFANT CHARACTERISTICS N Mean birth weight (gms) Emergency C/S Median Apgar score <5 at 5 minute <5 at 10 minutes HYPOTHERMIA GROUP 102 3385 +/- 617 71% 91% 84% CONTROL GROUP 106 3370 +/- 655 75% 92% 77%

STATUS AT ENROLLMENT N Seizures Moderate Encephalopathy Severe Encephalopathy Age at enrollment (hrs) HYPOTHERMIA GROUP 102 43% 68% 32% 4.3 +/- 1.3 CONTROL GROUP 106 48% 62% 38% 4.3 +/- 1.2

WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY MORTALITY % INFANTS 50% 40% 30% 20% 10% 24% RR 0.68 (95% CI 0.44-1.05) 37% 0% MORTALITY COOLING CONTROL SHANKARAN 2005

WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY DEATH OR MODERATE OR SEVERE DISABILITY % INFANTS 70% 60% 50% 40% 30% 20% 10% 0% RR 0.72 (95% CI 0.54-0.95) 62% 44% DEATH OR DISABILITY COOLING CONTROL SHANKARAN 2005

WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY: ESOPHAGEAL TEMPERATURE A

X Distribution of control infants among strata of esophageal temperatures - mean of the highest quartile (A) - median (B) - mean of the lowest quartile (C) Laptook, A. and coworkers Pediatrics 2008;122:491-499

COOLING Esophageal Temperatures and Adverse Outcomes in control infants Esophageal Death or Disability Death Disability Temperature (N = 99) (N = 99) (N = 65) Highest quartile 4.0 (1.5 11.2) 6.2 (2.1 17.9) 1.8 (0.4 8.2) Median 3.2 (0.9 11.2) 5.9 (1.5 22.7) 1.0 (0.2 5.1 Lowest quartile 1.5 (0.6 3.5) 1.4 (0.6 3.3) 1.1 (0.3 3.5) Each regression included values from each control infant (mean of the highest quartile, median, and mean of the lowest quartile of temperature) for death or disability, death alone, and disability alone. Results are Odd Ratios per 1 C increase, adjusted for level of encephalopathy, gender, gestational age, and race.

HYPOTHERMIA FOR THE TREATMENT OF HYPOXIC ISCHEMIC ENCEPHALOPATHY Total Body Cooling Trial (TOBY) Infants from Cool Cap + Total Body Cooling from NICHD = TOBY

TOTAL BODY COOLING TRIAL (TOBY) Infants with moderate-to-severe HIE are randomized to receive whole body cooling or standard intensive care. The trial design and entry criteria for the TOBY trial are similar to those of the selective head cooling (CoolCap) trial. Upon completion, the findings from the TOBY trial can be effectively compared with those of CoolCap to assess the relative benefits from whole body vs. selective head cooling in HIE. Enrolled 325 infants

WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY Whole Body Cooling in TOBY Trial (UK) Edwards

TOTAL BODY COOLING TRIAL (TOBY) MORTALITY AND SEVERE DISABILITY IN ALL INFANTS % INFANTS 50% 40% 30% 20% 10% RR 0.95 (95% CI 0.66-1.36) 26% 27% RR 0.74 (95% CI 0.50-1.10) 26% 35% 0% MORTALITY SEVERE DISABILITY COOLING CONTROL TOBY 2008

HYPOTHERMIA FOR THE TREATMENT OF HYPOXIC ISCHEMIC ENCEPHALOPATHY The ICE Trial Treatment of hypoxic ischemic encephalopathy in infants from a wide geographic region, using simplified protocols. Hypothermia is achieved by turning off the ambient heating systems and by applying Hot-Cold gel packs (at 10 C) around the infant s head and over the chest, so that the rectal temperature is reduced to 33 34 C. Planned enrollment: 276 infants from 15 participating centers in Australia, New Zealand and Canada

ICE TRIAL MORTALITY IN ALL INFANTS % INFANTS 50% 40% 30% 20% 10% 24% RR 0.64 (95% CI 0.42-0.97) 37% 0% MORTALITY COOLING CONTROL ICE 2008

COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY MORTALITY

COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY MAJOR NEURODEVELOPMENTAL DISABILITY

COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY DEATH OR MAJOR DISABILITY

HYPOTHERMIA FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY WHOLE BODY COOLING AND SELECTIVE HEAD COOLING OUTCOMES (N STUDIES) Typical Risk Difference Decreased Risk Increased (95% CI) 0.2 0.5 1.0 2.0 4.0 SELECTIVE HEAD COOLING DEATH (5) -0.06 (-0.14, 0.01) MAJOR DISABILITY (3) -0.06 (-0.14, 0.00) DEATH OR MAJOR DISABILITY (3) -0.13 (-0.22, -0.04) WHOLE BODY COOLING DEATH (6) -0.10 (-0.16, -0.04) MAJOR DISABILITY (5) -0.05 (-0.11-0.00) DEATH OR MAJOR DISABILITY (5) -0.16 (-0.22, -0.10) Modified from Jacobs 2007; updated M. Berg 2012 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk and 95% CI

COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY: MRI ABNORMALITIES

HYPOTHERMIA FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY COMPLICATIONS DEATH OF COOLING OUTCOMES (N STUDIES) Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 ARRTHYMIA REQUIRING RX (6) -0.00 (-0.01, 0.01) HYPOTENSION REQUIRING RX (4) 0.04 (-0.04, 0.12) PPHN (4) 0.05 (-0.01, 0.10) INHALED NITRIC OXIDE (3) 0.04 (-0.02, 0.05) LEUKOPENIA (3) 0.02 (-0.00, 0.05) THROMBOCYTOPENIA (7) 0.06 (0.01, 0.10) COAGULOPATHY /DIC (7) 0.03 (-0.02, 0.08) Modified from Jacobs 2007; updated M. Berg 2012 0.2 0.5 1.0 2.0 4.0 Relative Risk and 95% CI

HYPOTHERMIA FOR THE TREATMENT OF HYPOXIC ISCHEMIC ENCEPHALOPATHY ILCOR recommendations Intensive care nurseries should now consider adopting one of the validated protocols for the selection of term infants with HIE, be appropriately equipped and train staff to offer hypothermia according to the protocol of the currently published large hypothermia trials Because HIE is a relatively uncommon condition, it would be highly desirable where possible to centralize this treatment to larger intensive care units. With the data presently available, there is no longer any reasonable justification to deny this apparently efficacious treatment for those who most urgently need it. Hoehn and coworkers. Resuscitation 2008

COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY What are we supposed to do?

DIFFICULTY OF TRANSLATING EVIDENCE TO PRACTICE Efficacy: The benefit of using an intervention for a particular problem under ideal conditions, for example, in a laboratory setting, within the protocol of a carefully managed randomized controlled trial, or at a center of excellence. Effectiveness: The extent to which a specific intervention, procedure, regimen of service does what it is intended to do for a defined population. Efficiency: The extent to which objectives are achieved by minimizing the use of resources.

HYPOTHERMIA FOR THE TREATMENT OF HYPOXIC ISCHEMIC ENCEPHALOPATHY: WHAT ANSWERS DO WE HAVE? PROMISING THERAPY IN A HIGHLY SELECTED POPULATION WITH MODERATE TO SEVERE HYPOXIC ISCHEMIC ENCEPHALOPATHY WHEN TREATED BEFORE 6 HOURS OF AGE - UNKNOWN IF WORTHWHILE IN THE MOST AFFECTED INFANTS, OR IN CASES WHERE INJURY IS LESS SEVERE - UNKNOWN WHETHER CLINICALLY EFFECTIVE OUTSIDE OF RESTRICTED TIME WINDOW - UNKNOWN IF SELECTIVE OR WHOLE BODY HYPOTHERMIA CONVEYS GREATEST ADVANTAGE - UNKNOWN RELATIONSHIP TO OTHER THERAPEUTIC INTERVENTIONS - UNKNOWN SCHOOL AGE FOLLOW UP

ENCEPHALOPATHY REGISTRY: Hypothermic Therapy 2006 to 2011 99 participating centers 2457 infants treated with hypothermia 726 (30%) did not meet criteria from RCTs 40% with mild encephalopathy 60% treated after 6 hours 17% of all infants < 36 weeks gestation Whole Body 74% Selective Head 17% Both 9% Pfister. PAS. 2013

ENCEPHALOPATHY REGISTRY: Hypothermic Therapy: Complications Cardiac arrhythmia 21.8% PPHN 24.4% ino 18.2% Severe hypotension 32.8% Thrombocytopenia 33.8% DIC 28.7% Mortality 16.9% Pfister. Preliminary Data 2012

Locations of Hypothermic Therapy 2008 LOCATIONS OF HYPOTHERMIN THERAPY 11 101 8 28 4 Community Hospital Reporting Hospital Transfer Hospital Preliminary Data November 2009

QUESTIONS/DISCUSSION?