Perinatal asphyxia: Pathophysiology and therapy

Transcription

1 Perinatal asphyxia: Pathophysiology and therapy Peter Davis Melbourne Australia With thanks to Dr Sue Jacobs

2 Moderate or severe HIE Complicates ~1/1000 term live births: Mortality: >25% Major neurological sequelae: >25% Cerebral palsy, intellectual impairment, seizures Cognitive impairments at school-age, even without neuromotor deficits Associated behavioural & educational difficulties

3 A Little Basic Science Neuronal death occurs in 2 phases Severe insult Immediate neuronal death cellular hypoxia and primary energy failure Delayed neuronal death occurs at least 6 hours later i.e. allows a therapeutic window

4 A Little Basic Science Secondary phase accounts for a major proportion of cell loss Pathology - hyperemia, cytotoxic oedema, mitochondrial failure, accumulation of cytotoxins, apoptosis, nitric oxide synthesis, free radical damage Clinically encephalopathy, increased seizure activity

5 Mechanism of protection by hypothermia Survival of cells otherwise destined to die through apoptosis Reduced metabolic rate Reduced release of excitatory amino acids (glutamate, dopamine) Lower production of nitric oxide and free radicals

6 Methods of cooling newborns Selective head cooling with mild systemic hypothermia Rationale: Cool brain more than body Newborn brain produces 70% of total body heat Minimise adverse effects of systemic cooling Whole-body hypothermia Rationale: Reduce systemic temperature to achieve deep brain cooling Core body temperature & deep brain temperature are similar Mathematic modeling supports this

7 Potential Adverse Effects of Cooling Heart Lungs Contractility, BP Bradycardia Arrhythmias PPHN Pulmonary oedema Hypoxia Gastrointestinal NEC Hematological Coagulopathy & platelet dysfunction Metabolic Acidosis O 2 dissociation curve to left Hypokalaemia Hypoglycaemia Immunological Sepsis

8 Randomised Trials of Cooling for HIE

9 All RCTs included Term or near-term newborns < 6 hours of age with: Moderate or severe encephalopathy aeeg Peripartum hypoxia-ischaemia: e.g Apgar score < 5 at 10 minutes, and/or Mechanical ventilation or resuscitaiton at 10 minutes, and/or Cord ph < 7.1 or arterial ph < 7.1 or base deficit of 12 or more within 60 minutes of birth No congenital abnormality or active bleeding and not in extremis

10 RCTs Intervention Therapeutic hypothermia (whole body or selective head cooling) Or No cooling (standard care) Active (device) and/or Passive cooling

11 RCTs Outcomes Primary: death or long-term (>18 months) major neurodevelopmental disability Secondary: Death, major neurodevelopmental disability, CP, neuromotor delay, intellectual impairment, blindness, deafness Adverse effects of cooling: CVS, FBC, coagulation, hypoglycaemia, renal, culture proven sepsis

12 Larger published RCTs CoolCap NICHD TOBY Number aeeg Yes No Yes Method Selective head Systemic Systemic Primary outcome Death or severe disability at 18 months Death or moderate/severe disability at 18 months Death or severe disability at 18 months

13 Larger published RCTs Zhou Simbruner ICE Number aeeg No Yes No Method Selective head Systemic Systemic Primary outcome Death or severe disability at 18 months Survival free of handicap at 18 months Death or severe disability at 24 months

14 The ICE randomized trial of whole body hypothermia for hypoxic-ischemic encephalopathy (HIE) Sue Jacobs Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, Wright IMR, Kirpalani HM, Darlow BA, Doyle LW and The ICE Collaboration Arch Pediatr Adolesc Med Aug;165(8):

15 Background Most infants with moderate-to-severe HIE are born in non-tertiary settings Hypothermia should be started immediately after the insult for maximum benefit Gunn, 2000

16 ICE Infant Cooling Evaluation trial Aim: To determine the effectiveness and safety of whole body hypothermia to 33.5 C for 72 hours in term and near term newborns with moderate-to-severe HIE using: clinical eligibility criteria a simple method of hypothermia initiated within 6 hours of birth at the birth hospital by dedicated neonatal retrieval teams Prospective, multicenter, international, randomized controlled trial

17 Inclusion criteria 1. Near term (> 35 weeks) 2. Encephalopathy (moderate or severe) 3. Peripartum hypoxia/ ischemia i.e., two of: a) Apgar score < 5 at 10 minutes b) Need for ventilation at 10 minutes c) Metabolic acidosis (ph <7.00 or BE >-12) within 1 hour of birth 4. Treatment at, or transport to, one of the participating centers

18 Exclusion criteria 1. Hypothermia unable to be started within 6 hours of birth 2. Birth weight <2 kg 3. Major congenital abnormalities: a) Suspected neuromuscular disorders b) Suspected chromosomal abnormalities c) Life threatening CVS or respiratory abnormalities d) Suspected coagulopathy e) Imperforate anus 4. Severe respiratory distress (FiO 2 >80%) 5. In extremis : hypotension or severe acidosis unresponsive to treatment 6. Any active cooling before consent

19 Methods All infants assessed for eligibility at birth hospital: Inborn infants by study investigator Outborn infants by retrieval team Obtained informed parental consent Randomized Initiated the intervention Continued the same hypothermia and monitoring protocol during transport to NICU as for inborns

20 Methods Control C (PR) Cool C (PR) for 72 hours Hypothermia protocol: Passive at ambient environmental temperature Radiant warmer turned off Active with 2 refrigerated gel packs placed: Under head + shoulders Over chest + abdomen Rewarm at < 0.5 C every 2 hours

21 Assessed for eligibility (n = 542) Randomized (n = 221) Excluded (n = 321) Not meeting inclusion criteria (n=207) Refused (n=33) Not approached (n=80) Consented, not randomised (n=1) Cool (n = 110) Control (n = 111) Lost to follow-up (n=3) Unable to contact (n=2) Refused (n=1) Died (n=27) Survivors assessed (n=80) Lost to follow-up (n=10) Withdrew, unable to contact (n=2) Refused (n=8) Died (n=42) Survivors assessed (n=59) Analyzed (n = 107) Analyzed (n = 101)

22 Neonatal baseline characteristics (1) Cool (n=110) Control (n=111) Gestation (weeks) - mean Birth weight (g) - mean Male 55% 60% Outborn 62% 60% Age at randomization (hours) - mean Temperature at randomization ( C) - mean

23 Neonatal baseline characteristics (1) Cool (n=110) Control (n=111) Gestation (weeks) - mean Birth weight (g) - mean Male 55% 60% Outborn 62% 60% Age at randomization (hours) - mean Temperature at randomization ( C) - mean

24 Neonatal baseline characteristics (2) Apgar score (median) 1 minute 5 minutes 10 minutes Resuscitation Ventilation Chest compressions Adrenaline Cool (n=110) % 63% 39% Control (n=111) % 62% 45%

25 Neonatal baseline characteristics (2) Apgar score (median) 1 minute 5 minutes 10 minutes Resuscitation Ventilation Chest compressions Adrenaline Cool (n=110) % 63% 39% Control (n=111) % 62% 45%

26 Neonatal baseline characteristics (3) Cool (n=110) Control (n=111) Peripartum hypoxia/ischaemia Apgar 5 at 10 mins Ventilation 10 mins Cord/gas within 1 hr (mean) ph Base excess 82% 96% % 96% Assessment encephalopathy Mild Moderate Severe 15% 57% 27% 23% 50% 27% Clinical seizures 33% 34%

27 Primary outcome Reported for 94% (208/221) Hypothermia significantly reduced death or major sensorineural disability at 2 years of age: Death or major disability Cool Control Risk Ratio (95% CI) P value 51% 66% 0.77 (0.62, 0.98) 0.03 Absolute reduction 15% NNT 7 (95%CI 4, 59)

28 Secondary outcomes: Mortality Hypothermia significantly reduced mortality Cool Control Risk Ratio (95% CI) P value Death 25% 39% 0.65 (0.43, 0.97) 0.04 Absolute reduction 14% NNT 7

29 Adverse effects of hypothermia 6 infants discontinued intervention 3 overt bleeding 1 parental request; 2 by clinicians Cool Control P-value Arrhythmia requiring treatment 0 0 Hypoxia in 100% oxygen 0 0 Overt bleeding 3% Death during intervention 12% 17% 0.26

30 Other effects of hypothermia Hypotension treated with inotropes Cool Control P-value 46% 47% 0.94 Treated coagulopathy 18% 11% 0.13 Thrombocytopaenia <150 x 10 9 /L 51% 45% 0.45 Oliguria 34% 27% 0.30 Hepatic dysfunction 35% 45% 0.14 Seizures (any) 77% 79% 0.94 Sepsis 5% 7% 0.59

31 Strengths of ICE Whole body therapeutic hypothermia is beneficial No major adverse effects Results consistent with other RCTs & meta-analyses Only larger RCT to report safety & outcomes of hypothermia initiated at the birth hospital, continued during retrieval & transport to the tertiary NICU

32 ICE Conclusions ICE method is effective, safe and widely applicable: Identifies infants with HIE at risk of adverse outcome soon after birth Uses a simple, inexpensive method of whole body hypothermia Could be used in non-tertiary settings whilst awaiting retrieval and during transport to the regional NICU

33 Systematic reviews & meta-analyses 7 reviews published Cochrane review Cooling for newborns with HIE updated July 2007 Today updated to include 12 RCT s & 1504 term newborns with moderate or severe HIE 7 trials of whole-body cooling 5 trials of selective head cooling

34 Death or major disability in survivors (8 studies, n=1344) Study or Subgroup Selective head cooling with mild systemic hypothermia Gunn 1998 Gluckman 2005 Zhou 2010 Subtotal (95% CI) Total events Heterogeneity: Chi² = 2.46, df = 2 (P = 0.29); I² = 19% Test for overall effect: Z = 2.78 (P = 0.005) Hypothermia Standard care Risk Ratio Risk Ratio Events Total Events Total Weight 1.1% 17.6% 11.5% 30.3% M-H, Fixed, 95% CI 1.26 [0.46, 3.44] 0.82 [0.66, 1.02] 0.63 [0.44, 0.91] 0.77 [0.64, 0.92] M-H, Fixed, 95% CI Whole body cooling Eicher 2005 Shankaran 2005 Azzopardi 2009 Simbruner 2010 Jacobs 2002 Subtotal (95% CI) % 15.5% 21.0% 11.2% 16.8% 69.7% 0.62 [0.41, 0.92] 0.71 [0.54, 0.93] 0.86 [0.68, 1.07] 0.62 [0.46, 0.82] 0.77 [0.62, 0.98] 0.75 [0.66, 0.84] Total events 215 Heterogeneity: Chi² = 4.25, df = 4 (P = 0.37); I² = 6% Test for overall effect: Z = 4.80 (P < ) 286 Total (95% CI) % 0.75 [0.68, 0.83] Total events Heterogeneity: Chi² = 6.89, df = 7 (P = 0.44); I² = 0% Test for overall effect: Z = 5.53 (P < ) Favors hypothermia Favors standard care

35 Death or major disability in survivors (8 studies, n=1344) Study or Subgroup Selective head cooling with mild systemic hypothermia Gunn 1998 Gluckman 2005 Zhou 2010 Subtotal (95% CI) Total events Heterogeneity: Chi² = 2.46, df = 2 (P = 0.29); I² = 19% Test for overall effect: Z = 2.78 (P = 0.005) Hypothermia Standard care Risk Ratio Risk Ratio Events Total Events Total Weight 1.1% 17.6% 11.5% 30.3% M-H, Fixed, 95% CI 1.26 [0.46, 3.44] 0.82 [0.66, 1.02] 0.63 [0.44, 0.91] 0.77 [0.64, 0.92] M-H, Fixed, 95% CI Whole body cooling Eicher 2005 Shankaran 2005 Azzopardi 2009 Simbruner 2010 Jacobs 2002 Subtotal (95% CI) % 15.5% 21.0% 11.2% 16.8% 69.7% 0.62 [0.41, 0.92] 0.71 [0.54, 0.93] 0.86 [0.68, 1.07] 0.62 [0.46, 0.82] 0.77 [0.62, 0.98] 0.75 [0.66, 0.84] Total events 215 Heterogeneity: Chi² = 4.25, df = 4 (P = 0.37); I² = 6% Test for overall effect: Z = 4.80 (P < ) 286 Total (95% CI) % 0.75 [0.68, 0.83] Total events Heterogeneity: Chi² = 6.89, df = 7 (P = 0.44); I² = 0% Test for overall effect: Z = 5.53 (P < ) Favors hypothermia Favors standard care

36 Mortality (12 studies, n=963)

37 Disability in survivors assessed (8 studies, n=917)

38 Infants with severe encephalopathy: Death or major disability

39 Outcome Hypothermia Standard RR NNT (%) (%) (95% CI) p-value Death or major disability in survivors 46% 61% 0.77 (0.66,0.90) Mortality 25% 34% 0.77 (0.66,0.90) Major disability 19% 25% 0.78 (0.64,0.96) Major disability in survivors 26% 39% 0.67 (0.55,0.80)

40 Outcome in survivors Hypothermia Standard RR NNT (%) (%) (95% CI) p-value Cerebral palsy 23% 35% 0.66 (0.54, 0.82) Neuromotor delay (BSID PDI <70) Developmental delay (BSID MDI <70) 26% 35% 0.75 (0.59, 0.94) 22% 34% 0.65 (0.53, 0.81) Blindness 6% 10% 0.62 (0.38, 1.01) 0.06 Deafness 4% 6% 0.66 (0.35, 1.26) 0.21

41 Cochrane review summary When used within strict protocols in tertiary NICUs, therapeutic hypothermia is beneficial to near-term newborns with moderate or severe HIE. Cooling reduces mortality and major disability. The benefits of cooling on survival and neurodevelopment outweigh the short term adverse effects (sinus bradycardia, thrombocytopaenia). Whole-body and selective head cooling both effective.

42 In Hypothermia is the most promising option for a clinically feasible neural rescue therapy in encephalopathic newborns following acute perinatal asphyxia Thoresen and Wyatt. Acta Paediatr 1997;86:

43 In 2014 Therapeutic hypothermia improves outcome after moderate or severe HIE. But, 46% of cooled infants still die or survive with major disability. Further strategies are needed: Regional guidelines to facilitate earlier induction of cooling Refinement of current hypothermia methods Synergistic neuroprotective therapies

44 ILCOR 2010 Treatment Recommendation Term and near-term with moderate to severe HIE should be offered cooling Whole body and selective head cooling are both appropriate Cooling should be initiated and conducted in neonatal intensive care facilities using the protocols used in the RCTS (begin within 6 hours of birth, continue for 72 hours after birth, and rewarm over at least 4 hours). Monitor for adverse effects: thrombocytopenia and hypotension All treated infants should be followed up longitudinally

45

46

47

48

49 Gaps in newborn resuscitation in resource-limited settings Gaps in the evidence Cord clamping Timing Positive pressure ventilation Best interface Optimal ventilation parameters Others Simple ways to administer blended oxygen Thermal management of asphyxiated infant

50 Problems and solutions Most of the burden of illness occurs in resource limited settings Most of the evidence comes from the developed world

51 So... Should facilitate/support research in the developing world Community based interventions are very important But once NMR < per 1000 live births hospital based therapies are required to gain further improvements Small part of the puzzle use what we know to improve their outcomes

52 Barriers to application in resource limited settings Lack of suitable cooling equipment ($) Lack of skilled personnel Higher rates of sepsis (neutrophil function) Lack of facilities for disabled children Lack of ventilatory support

53 Effectiveness vs efficacy Can accurate/reliable cooling be achieved with ice packs and passive cooling? Does this method of cooling improve long term outcomes? Is it safe? Infection Coagulopathy...

54 What is resource limited? A continuous rather than dichotomous variable e.g. China, South Africa... Self defined? All of us? What resources are needed to safely cool?

55 4 RCTs Evidence pertinent to resource limited settings ICE Trial: gel packs, advanced setting Bharadwaj (2012) India: gel packs Thayyil (2013) India: phase changing material mattress Robertson (2011, 2008) Uganda: water bottles

56 Rectal temperature: Bharadwaj

57 Rectal temperature: Thayyil

58 Simple whole body cooling: Death

59 Death or disability

60 *Bharadwaj assessed at 6 months Disability

61 Results Simple cooling delivers reasonably precise and accurate whole body hypothermia The technique reduces death (and death or disability) in a developed world setting (ICE) No evidence of benefit or harm (mortality) in resource limited setting

62 Conclusions Insufficient evidence for effectiveness or safety in resource limited settings -- therefore cooling not recommended outside RCT (opportunity cost=money spent on cooling could be spent better on prevention)

63 OR

64 Conclusions The treatment is efficacious and safe(ish). No evidence of harm, small trials underpowered, therefore cool and audit the results.

65 OR

66 Conclusions Define the resources required to safely cool and let units decide where they fit Intravenous fluids Supplemental oxygen Anticonvulsants Antibiotics Adequate trained staff Pathology: glucose, electrolytes, coagulation studies

67