HYPOXIC ISCHEMIC ENCEPHALOPATHY AND I have nothing to disclose and - - PowerPoint PPT Presentation

HYPOXIC ISCHEMIC ENCEPHALOPATHY AND THE OBSTETRICIAN

Michael P. Nageotte, M.D.

DISCLOSURE

• I have nothing to disclose and have no real or

potential conflicts with this presentation and its content. CASE: 27 y.o. G2 P0 at 38 4/7 wks in spontaneous labor at 0830. Subsequent AROM by MD at 1230-- 4/80%/0 station; moderate meconium; pitocin begun at 1245. Category I-II FHR; cervical exam at 1545: vtx/8/90%/+2; pitocin infusion at 4 mu/min; external FHR/UC monitors; IV analgesia PRN. Management by nurses other than the single MD exam (AROM) at 1230--physician in his patient office; called at 1609 to L&D STAT. Arrives at bedside at 1620.

DELIVERY ROOM DATA

• Emergency primary L/T C/S under general anesthesia

with skin incision at 1630 and delivery at 1632

• 2310 gm SGA male; tight NC x3 with thin cord; thick

meconium; Apgars 1/4/4 at one, five and ten minutes

• Cord gases: Artery 6.99/115/10/-12; Vein 7.04/84/15/-8
• Several intubations and full CPR in Delivery Room
• In NICU, early onset seizures; unable to oxygenate well

and requiring intubation; Admit Dx: “Hypoxic Ischemic Encephalopathy”; transfer to Level III for total body cooling despite IUGR

Question

Should the admitting diagnosis to the NICU be hypoxic ischemic encephalopathy?

• A. Yes
• B. No

Y e s N

• 82%

18%

NOMENCLATURE

• Hypoxia
• Acidosis
• Asphyxia
• Neonatal Encephalopathy
• Hypoxic Ischemic Encephalopathy (HIE)
• Cerebral Palsy
• Negligence

What do these terms mean, are they different, what causes them and can they be prevented?

It is critical to understand that the diagnostic labels applied to the neurologically depressed neonate have potentially profound consequences for the child, the family, the physicians for both mother and baby, the nurses and the hospital.

Hypoxia : Reduced amount of oxygen delivered to tissues;

encephalopathy or brain injury unlikely in the fetus or newborn

Hypoxemia: Reduced oxygen concentration in blood; associated

with hypoxia but injury unlikely if adequate cerebral blood flow

Hypoxia-Ischemia: Reduced oxygen and inadequate volume

• f blood delivered to tissues; can cause brain injury if both

intracellular oxygen and glucose remain below critical levels

Metabolic Acidosis: Low pH due to increased lactic acid in the

blood reflecting severity of asphyxia and/or hypoxia-ischemia

Respiratory Acidosis: Low pH due to increased carbon dioxide

in blood; may protect the fetal/neonatal brain due to reflex cerebral vasodilation and increased cerebral blood flow

Mixed Acidosis: Low pH reflecting both increased carbon

dioxide (respiratory) and lactic acid (metabolic); most common form of clinically significant neonatal acidosis

ASPHYXIA

• Condition of impaired gas exchange leading, if it

persists, to progressive hypoxemia and hypercapnia with a significant metabolic acidosis resulting (World Federation of Neurology, 1993)

• This term describes a process of varying severity and

duration rather than an endpoint and should not be applied to birth events unless specific evidence of markedly impaired intrapartum or immediate postnatal gas exchange can be linked to neurologic illness in the neonate (Low, 1997)

NEONATAL ENCEPHALOPATHY

NEONATAL ENCEPHALOPATHY

• A clinically defined syndrome of disturbed

neurologic function in the earliest days of life in a neonate at or beyond 35 weeks of gestation, manifested by subnormal level of consciousness or seizures often accompanied by difficulty with initiating and maintaining respiration and with various degrees of depression of both muscle tone and reflexes.

NEONATAL ENCEPHALOPATHY

• Applied in various clinical settings with altered

neurologic signs in neonates born > 35 weeks

• Descriptive term which is often erroneously

interchanged with such terms as hypoxia, acidosis and asphyxia particularly during the immediate neonatal period and continued throughout the medical chart

• Generally classified as mild, moderate or severe

(Sarnat classification) with death or developmental impairment usually confined to infants with moderate or severe NE

Potential Etiologies of Neonatal Encephalopathy

• Chronic persistent or acute fetal

hypoxemia/ischemia

• Maternal/Fetal(FIRS)/Neonatal Infection
• Inborn errors of metabolism; genetics
• Trauma (skull fracture, CNS bleeding)
• Coagulation disorders, acute anemia
• Fetal/Neonatal Stroke; anomalies
• Unknown

HYPOXIC ISCHEMIC ENCEPHALOPATHY

Hypoxic Ischemic Encephalopathy

• Assumptions on the role of intrapartum events on

newborn and neonatal status have given rise to the term hypoxic ischemic encephalopathy (HIE)

• HIE (post-asphyxial encephalopathy, birth asphyxia,

perinatal asphyxia) describes a subset of NE present in the first week of life in term/near term infants believed to have experienced significant hypoxemia/asphyxia prior to or during labor and delivery

• Findings: altered consciousness, tone and reflexes; the

most severe state characterized by hypotonia, apnea/respiratory depression, coma and seizures

• Diagnosis confirmed with specific MRI changes

CEREBRAL PALSY

Question

Since the introduction of continuous fetal heart rate monitoring in, the reported rate of cerebral palsy in the developed world has:

• A. increased
• B. decreased
• C. remained unchanged

i n c r e a s e d d e c r e a s e d r e m a i n e d u n c h a n g e d

17% 80% 3%

CEREBRAL PALSY

Cerebral palsy describes a group of conditions specifically involving motor disability of early onset which, despite a wide range of possible abilities and disabilities, must satisfy the following: 1) motor disorder (specifically, spasticity, dyskinesia, ataxia, mixed or hypotonia) is present by age of four 2) cerebral not peripheral nerve or muscular abnormality 3) arises early in development 4) is not progressive or degenerative but life-long and with no known cure 5) may or may not be associated with other neurological

• r intellectual abnormalities

6) if fetal asphyxia is implicated, the CP must be of the spastic quadriparetic or dyskinetic type

CEREBRAL PALSY

• Associated impairments including vision, hearing,

cognition, speech, epilepsy and behavioral disorders

• ften accompany the motor impairment.
• The more severe the motor impairment, the more

likely that a number of these impairments will add to the complexity of the disorder.

• For term and near term infants, if CP is present it is

generally a more severe form with milder CP evident

• nly in surviving preterm infants.

CEREBRAL PALSY

• The risk of CP increases substantially as gestational

age at birth decreases with < 32 weeks gestation being the strongest risk factor for CP.

• While death and CP in the very preterm have declined

steadily since the mid 1990s, this has had little impact

• n the overall prevalence of CP as births < 34 weeks

comprise only 2% of all births.

• Term and late preterm infants are at low risk for CP

yet comprise 60% of CP cases (term/late preterm neonates account for 98% of all births).

• Term CP rates have remained remarkably stable with

the rate of 2/1000 consistent throughout the developed world for the past several decades.

Elective and Emergency C-Sections and Live Births with Cerebral Palsy in Western Australia, 1980-2009

THREE ETIOLOGICAL GROUPS OF NEONATAL ENCEPHALOPATHY

• In a minority of cases, encephalopathy is likely due

to hypoxia-ischemia, with specific MRI established abnormalities, following a recognized obstetrical sentinel event (e.g. uterine rupture, cord prolapse, maternal cardiac arrest).

• In such incontrovertible cases, HIE is frequently

the accepted cause of encephalopathy but not all sentinel events result in HIE and one cannot implicate hypoxia-ischemia with 100% certainty because it is not possible to document blood flow and oxygenation of the fetal brain.

THREE GROUPS OF NEONATAL ENCEPHALOPATHY

• In a second subset of encephalopathy cases, an etiology

different from hypoxia-ischemia is identified (e.g. trauma, infection or specific metabolic disorder).

• The third group is the largest and presents a clinical

conundrum as there is a lack of an obvious cause of the neurologic abnormalities identified.

• Different etiologies of encephalopathy must be kept in

mind in all cases and a clear history of hypoxia- ischemia associated with a sentinel event does not rule

• ut other causes or contributors to the findings.

PRIMATE MODE OF TERM NEONATAL BRAIN INJURY (R.

Myers, 1972, 1975)

• Specific regional distribution of injury

associated with different durations and severities of experimental ischemia (rhesus)

• Prolonged partial asphyxia: cerebral white

matter injury

• Acute profound asphyxia: deep gray nuclei

(basal ganglia and thalamus) injury rarely with extension to white matter

Magnetic Resonance Imaging

• Dramatically improved technology with visualization
• f myelination and changes in cerebral structures
• More sensitive and specific than U/S or CT
• Shows heterogeneous pattern, ranging from cortical

dysplasia to focal infarcts and atrophy or basal ganglion lesions (related to insult timing/severity)

• Better anatomical resolution, particularly in the

basal ganglia, thalamus and periphery of the cerebral cortex

• Detects discrete lesions in cerebellum and brain stem

MRI PATTERNS OF INJURY-HIE AND ITS PRESUMED ETIOLOGIES

1) Selective neuronal necrosis of the cortex,

predominantly the hippocampus and also the grey matter nuclei 2) Leucomalacia of periventricular to subcortical white matter 3) Focal or more generalized infarction  There is dynamism to the MRI pattern until the final pattern is achieved.

So When Does the Injury Occur?

Question

The majority of cases of cerebral palsy following a term gestation have an identifiable intrapartum sentinel event:

• A. True
• B. False

T r u e F a l s e

91% 9%

Timing of Ischemic Brain Injury

• 80% to 90% before labor

– Multiple pregnancy/chorionicity – 3rd Trimester bleeding; cord entrapment – Intrauterine infection/drugs – Fetal coagulation disorders/stroke

• 10% to 20% intrapartum
• Rate of term stillbirth is 3x rate of NE; birth

may be interrupting a fetal continuum to death in utero with recurrent or near fatal insults

(Yudkin PL, Ped Perinatal Epidemiol 1988; 156:170)

Antepartum Associations with Neonatal Encephalopathy

Antepartum Risk Factors for Neonatal Encephalopathy in Term Neonates

(N=164; Controls=400)

• Fam Hx Seizures

2.55 1.3-4.9

• Fam Hx neurol. dis.

2.73 1.2-6.4

• Infertility Rx

4.43 1.1-17.6

• Mat. Thyroid dis.

9.7 2.0-47.9

• Severe Pre-eclampsia

6.3 2.3-17.7

• Bleeding in Pregnancy

3.6 1.3-9.9

• Viral Illness

3.0 1.5-5.8

• Abnormal placenta

2.97 1.2-3.7

• IUGR < 3rd %

38.2 9.4-154.8

• Postmaturity

13.2 5.0-34.8 (Badawi, N, et al 1998;BMJ 317:1554)

O.R. 95% C.I.

Antepartum and Intrapartum Risk Factors for Neonatal Encephalopathy

• 69% had only antenatal risk factors
• 24% had antepartum and intrapartum

risk factors

• 5% had only intrapartum risk factors

(Badawi, N, et al 1998;BMJ 317:1554)

IUGR and Neonatal Encephalopathy in Term Neonates

• > 90% ile

1 1

• 10-90%

1.5 .66-3.6

• 3rd-9%

4.4 1.4-13.4

• < 3rd%

38.23 9.4-154.8

(Badawi, N, et al 1998;BMJ 317:1554)

O.R. 95% C.I.

Gestational Age and Neonatal Encephalopathy in Term Neonates

(N=164 Controls=400)

• 37 weeks

2.4 1.1-5.0

• 38 weeks

1.1 0.9-1.6

• 39 weeks

1 1

• 40 weeks

1.4 1.2-1.7

• 41 weeks

3.3 2.1-5.4

• 42 weeks

13.2 5.0-34.8

O.R. 95% C.I.

MRI/MRS TIMING OF INJURY

• There are no tools currently available to

pinpoint the time of injury with any degree of

• accuracy. Although appropriate neonatal

neuroimaging is the best method available, brain MRI/MRS can only implicate a time window that spans days, not hours or minutes.

(Wu, Yvonne; Editorial, Annals of Neurology 2012 V.72: 151-2)

Summary

• Intrapartum hypoxia-ischemia associated with about

30% of cases of neonatal encephalopathy.

• The majority of cases of HIE result in normal children.
• Approximately 15-20% of all cases of cerebral palsy are

associated with clear intrapartum hypoxia-ischemia.

• In the vast majority of encephalopathic infants,

including those who meet the clinical and MRI criteria for HIE, the exact mechanism and timing of brain injury remains unknown and unknowable.

• Regarding neonatal encephalopathy, there is a lot we

do not know and we do not know how to prevent neonatal brain injury.

RECOMMENDATIONS

• Correct and consistent usage of nomenclature
• Documentation of umbilical artery/vein pH in all

preterm, multiples or depressed neonates

• Early assessment/triage of neonate for cooling therapy
• Clear and consistent language in the diagnoses and

communication among all health care providers

• Careful fetal/neonatal evaluations for birth defects/IUGR
• Early MRI/MRS (24-96 hours if possible) and repeat

before discharge to assess nature and general timing of injury with interpretation by skilled neuroradiologists

• Involvement of family in evaluation and management
• Multidisciplinary intensive assessment of all HIE cases

THANK YOU!

HIE--Clinical Aspects

• Dominated by the ultimate occurrence of brain

ischemia from diminished blood flow usually but not necessarily preceded or accompanied by hypoxemia (diminished amount of oxygen in the blood supply)

• Brain injury results from hypoxemia causing

myocardial disturbance leading to the critically important loss of CNS vascular autoregulation resulting in ischemia (hypoperfusion injury)

• Timing and severity of hypoxemia/ischemia as well

as the gestational age, presence of co-morbidities and potentially preceding events strongly influence the presence and degree of resultant neuropathology

DIAGNOSIS OF HIE

• Established when cerebral blood flow is sufficiently

reduced that oxygen content of the blood delivered to the brain is below the level needed to avoid energy failure in brain cells; metabolism is disturbed, neuronal cell integrity is not maintained and cellular injury, dysfunction or neuronal cell death results.

• Reliable measures of such changes in fetal/newborn

CNS are not available in current clinical settings.

• Poor surrogates include base deficit (>12 mmol/L),

biomarkers, EFM, scalp/umbilical artery pH, etc.

• The argument that location and appearance of brain

lesions establishes timing, severity and etiology remains open to debate as sentinel events are not always followed by specific MRI abnormalities.

CEREBRAL PALSY

• 96% of singletons are born at or after 35

weeks and account for 2/3 of CP cases

• This group has been less extensively studied
• Much of the medical and lay literature on

the causes of CP remains focused on the contribution of birth asphyxia

• EFM introduced to identify fetal asphyxia

but has had no impact on decreasing CP

Partial (Chronic) Asphyxia

• In the < 34 week fetus, partial (chronic) asphyxial injury

typically noted in the periventricular white matter, the region with the most tenuous perfusion, sparing the subcortical white matter and cortex

• In the > 34 week fetus, partial asphyxial injury is noted

in the mature intervascular boundary zones (“watershed”) which include the periventricular white matter, subcortical white matter and cerebral cortex in the boundary regions. The deep gray matter structures

• f the cerebrum are typically spared in such patients.
• Periventricular white leukomalacia (PVL) is an imaging

finding (ultrasound or MRI) of preterm fetuses at risk for CP from in utero/intrapartum/perinatal injury

Profound (Acute) Asphyxia

• Profound acute insult lasting 25 minutes or greater

damages nearly the entire brain with no useful patterns detected by any modality of imaging.

• Arrests of shorter duration show specific patterns

that vary with the state of brain maturity.

• Such profound acute events when <32 weeks result

in injury primarily to the lateral thalami.

• At 34-36 weeks, hippocampus, lentiform nucleus,

and perirolandic cortex may be injured.

• By 40 weeks, the corticospinal tracts are affected

from the internal capsule to the perirolandic cortex within the basal ganglia (likely due to the higher metabolic activity in these areas of the brain).

5 Minute Apgar Score and Neonatal Encephalopathy in Term Neonates (N=164 Controls=400)

0.00% 20.00% 40.00% 60.00% 80.00% 100.00% Cases Controls 5 M in Apgar <3 5 M in Apgar 3-6 5 M in Apgar >6

(Badawi, N, et al 1998;BMJ 317:1554)

Intrapartum Risk Factors for Neonatal Encephalopathy in Term Neonates

(N=164 Controls=400)

• Maternal Pyrexia

3.82 1.4-10.1

• Persistent OP

4.29 1.7-10.5

• Acute event

4.40 1.3-15.2

• Oper Vag Del

2.34 1.2-4.7

• Emergent C/S

2.17 1.1-4.64

O.R. 95% C.I.

(Badawi, N, et al 1998;BMJ 317:1554)

Mode of Delivery and Relative Risk for NE

(N=164 Controls=400)

• Mode of delivery

RR p-value

– Spontaneous Vag 1.0 1.0 – Elective C/S 0.17 0.05-0.56

(Badawi, N, et al 1998;BMJ 317:1554)

• Torfs (1990) 1

3.8 1.6-9.1

• Krebs 2

1.6 0.9-2.4 Nelson et al--CP increased with breech CP not related to route of delivery

O.R. C.I.

Malpresentation and CP

• 1. Torfs et al J Pediatr 1990; 116:615-19
• 2. Nelson et al JAMA 1984; 251:1843-48
• 3. Krebs et al BR J Ob Gyn 1999; 106:943-7

Seizures and CP in Dublin Randomized EFM Study

• Total live births

6527 6552

• Seizures

12 (.018%) 27(.041%)*

• NND after seizures

3 (.005%) 6(.009%)

• Survival after seizures 9 (.014%)

21(.032%)

• CP at age 4

3(0.005%) 3(0.005%)

• Total with CP

12 (.018%) 10(.015%) EFM I.A. (Grant A, Lancet: Nov. 25, 1989)

Insurance Status and Neonatal Encephalopathy in Term Neonates

(N=164 Controls=400)

• Private

1 1

• Public

3.5 1.3-9.6

O.R. C.I.