COOLING FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY
Roger F. Soll H. Wallace Professor of Neonatology University of Vermont 19th 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
INITIAL INJURY
REPERFUSION PERIOD
DELAYED PHASE OF INJURY
XX
VUNEO.org
Cell Death
Window of opportunity
Injury
Time after injury
6 hours 24 hours
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
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
STUDIES Shankaran 2002 Akisu 2003 Eicher 2005 Cool Cap 2005 NICHD 2005 Lin 2006 TOBY 2009 European 2010 Zhou 2010 ICE 2011 Sun 2012
HYPOTHERMIA IN THE TREATMENT OF HYPOXIC ISCHEMIC ENCEPHALOPATHY: TRIALS IN NEONATES
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
STUDIES Shankaran 2002 Akisu 2003 Eicher 2005 Cool Cap 2005 NICHD 2005 Lin 2006 TOBY 2009 European 2010 Zhou 2010 ICE 2011 Sun 2012
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
GLUCKMAN 2005
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
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.
SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY
GLUCKMAN 2005
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……..
SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY
GLUCKMAN 2005
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………………
SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY
GLUCKMAN 2005
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).
SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY
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)
0%
10%
20%
30%
40%
50%
MORTALITY
% I
NF
AN
TS
COOLING CONTROLGLUCKMAN 2005
MORTALITY IN ALL INFANTS
33% 38%
SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY
ODDS RATIO 0.81 (95% CI 0.47-1.41)
0%
10%
20%
30%
40%
SEVERE MOTOR DISABILITY
% I
NF
AN
TS
COOLING CONTROL
GLUCKMAN 2005
SEVERE MOTOR DISABILITY AT 18 MONTHS
19% 31%
SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY
ODDS RATIO 0.54 (95% CI 0.25-1.17)
0%
10%
20%
30%
40%
50%
60%
70%
DEATH OR DISABILITY
% I
NF
AN
TS
COOLING CONTROL
GLUCKMAN 2005
DEATH OR SEVERE DISABILITY AT 18 MONTHS IN ALL INFANTS
55% 66%
SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY
ODDS RATIO 0.61 (95% CI 0.34-1.09)
0%
10%
20%
30%
40%
50%
60%
70%
DEATH OR DISABILITY
% I
NF
AN
TS
COOLING CONTROL GLUCKMAN 2005
DEATH OR SEVERE DISABILITY AT 18 MONTHS INTERMEDIATE aEEG GROUP
48% 66%
SELECTIVE HEAD COOLING IN NEONATAL ENCEPHALOPATHY
ODDS RATIO 0.47 (95% CI 0.26-0.87)
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
0%
10%
20%
30%
40%
50%
MORTALITY
% I
NF
AN
TS
COOLING CONTROL
SHANKARAN 2005
MORTALITY
24% 37%
WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY
RR 0.68 (95% CI 0.44-1.05)
0%
10%
20%
30%
40%
50%
60%
70%
DEATH OR DISABILITY
% I
NF
AN
TS
COOLING CONTROL
SHANKARAN 2005
DEATH OR MODERATE OR SEVERE DISABILITY
44%
62%
WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY
RR 0.72 (95% CI 0.54-0.95)
WHOLE BODY HYPOTHERMIA FOR NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY: ESOPHAGEAL TEMPERATURE
A
X
Laptook, A. and coworkers Pediatrics 2008;122:491-499
Distribution of control infants among strata of esophageal
temperatures
- mean of the highest quartile (A) - median (B) - mean of the lowest quartile (C)
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
Edwards
Whole Body Cooling in TOBY Trial (UK)
0%
10%
20%
30%
40%
50%
MORTALITY SEVERE DISABILITY
% I
NF
AN
TS
COOLING CONTROLTOBY 2008
MORTALITY AND SEVERE DISABILITY IN ALL INFANTS
26% 27%
TOTAL BODY COOLING TRIAL (TOBY)
RR 0.74 (95% CI 0.50-1.10)
26% 35%
RR 0.95 (95% CI 0.66-1.36)
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
0%
10%
20%
30%
40%
50%
MORTALITY
% I
NF
AN
TS
COOLING CONTROLICE 2008
MORTALITY IN ALL INFANTS
24% 37%
ICE TRIAL
RR 0.64 (95% CI 0.42-0.97)
COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY MORTALITY
COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY MAJOR NEURODEVELOPMENTAL DISABILITY
COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY DEATH OR MAJOR DISABILITY
DEATH OR MAJOR DISABILITY (5) -0.16 (-0.22, -0.10)
MAJOR DISABILITY (5) -0.05 (-0.11 -0.00)
DEATH (6) -0.10 (-0.16, -0.04)
WHOLE BODY COOLING
DEATH OR MAJOR DISABILITY (3) -0.13 (-0.22, -0.04)
MAJOR DISABILITY (3) -0.06 (-0.14, 0.00)
DEATH (5) -0.06 (-0.14, 0.01)
Typical Relative Risk and 95% CI
0.5 1.0 2.0 4.0 0.2
HYPOTHERMIA FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY
WHOLE BODY COOLING AND SELECTIVE HEAD COOLING
SELECTIVE HEAD COOLING
OUTCOMES (N STUDIES) Typical Risk Difference
(95% CI) 0.5 1.0 2.0 4.0 0.2 Decreased Increased Risk
Modified from Jacobs 2007; updated M. Berg 2012
COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY: MRI ABNORMALITIES
COAGULOPATHY /DIC (7) 0.03 (-0.02, 0.08)
THROMBOCYTOPENIA (7) 0.06 (0.01, 0.10)
LEUKOPENIA (3) 0.02 (-0.00, 0.05)
INHALED NITRIC OXIDE (3) 0.04 (-0.02, 0.05)
PPHN (4) 0.05 (-0.01, 0.10)
HYPOTENSION REQUIRING RX (4) 0.04 (-0.04, 0.12)
ARRTHYMIA REQUIRING RX (6) -0.00 (-0.01, 0.01)
Relative Risk and 95% CI
0.5 1.0 2.0 4.0 0.2
HYPOTHERMIA FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY
DEATH
OUTCOMES (N STUDIES) Risk Difference ( 95% CI ) 0.5 1.0 2.0 4.0 0.2
Decreased Increased Risk
COMPLICATIONS OF COOLING
Modified from Jacobs 2007; updated M. Berg 2012
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
Pfister. PAS. 2013
Whole Body 74% Selective Head 17% Both 9%
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 HYPOTHERMIN THERAPY
Locations of Hypothermic Therapy 2008
Preliminary Data November 2009
Community Hospital
Transfer Hospital
Reporting Hospital
101 8 11 28 4
QUESTIONS/DISCUSSION?