COOLING FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY · NEONATAL ENCEPHALOPATHY Study objective: to examine...

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


Types of studies:

All randomized and quasi-randomized studies comparing the use of therapeutic hypothermia

with standard care were included.


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 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.


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……..


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………………


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).


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%


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%


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%


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%


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.


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


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.


“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%


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%


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


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)


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


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?

COOLING FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY · NEONATAL ENCEPHALOPATHY Study objective: to examine...

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