RECENT ADVANCES IN TREATMENT OF HIE

BYDR. TAUHID IQBALIMBBS(JIPMER)MD PED. (PMCH)

DEFNITION OF HIE

NEONATAL ENCEPHALOPATHY

FOLLOWING SEVERE BIRTH ASPHYXIA OR PERINATAL HYPOXIA IS REFERED TO AS HIE

PATHOPHYSIOLOGY OF HIE

Pathogenesis of HIE involves cascades of events. And it consist of:

1. Primary energy failure 2. Latent phase 3. Reperfusion injury 4 .Secondary phase

PRIMARY ENERGY FAILURE SEVERE HYPOXIA

DEPLETON OF HIGH ENERGY PHOSPHATE COMPOUNDS

INCREASE RELEASE OF GLUTAMATE AT SYNAPTIC LEVEL

FAILURE OF Na+-k+ ATPase

DEPOLARIZATION OF CELL MEMBRANE

INFLUX OF Na+ INFLUX OF Ca++

OSMOTIC INFLUX OF WATER

CYTOTOXIC NEURONAL EDEMA

ACTIVATION OF INTRACELLULAR PROTEASES AND LIPASES

PRODUCTION OF:XANTHINE OXIDASENOPROSTAGLANDINS

FREE RADICAL GENERATION

NMDA RECEPTOR ACTIVATION

Ca ++ INFLUX

NEURONAL NOS ACTIVATION

INCREASE NO RELEASE

NO AND FREE RADICALS COMBINE TO FORM PEROXYNITRITE ( A HIGHLY TOXIC OXIDAND )

NECROTIC CELL DEATH OF NEURONS

LATENT PHASE

PHASE WHERE CEREBRAL METABOLISM TRANSIANTLY RECOVERS

REPERFUSION PHASE

1.ACTIVATION OF : Cyclooxygenase Xanthine oxidase Lipoxygenase

INCREASE PRODUCTION OF FREE RADICAL

2. ACCUMULATION OF NO

SECONDARY PHASE

IT INVOLVES CONTRIBUTIONS OF:

MITOCHONDRIAL DYSFUNCTION

CASPASE ACTIVATION

INFLAMATORY MEDIATORS

EXCITO TOXIC – OXIDATION CASCADES

APOPTOTIC CELL DEATH

PATHOPHYSIOLOGY OF HIE CONT. TIME LINE

SO NOW AS WE UNDERSTOOD THE CURRENT MECHANISM OF HIE !!

OUR STRATEGIES WOULD BE TO: DECREASE CEREBRAL METABOLIC RATE

BLOCK NMDA RECEPTOR CHANNEL

DECREASE GLUTAMATE RELEASE

INHIBIT VOLTAGE GATED Ca++ CHANNELS

DECREASE FREE RADICAL REACTIONS

PREVENT FREE RADICAL FORMATIONS

DECREASE INFLAMATORY RESPONSE

ATTENUATE APOPTOSIS CASCADES

THIS IS WHAT GIVES US HUNTING

GROUND FOR ADVANCED THERAPUTIC MODALITIES IN HIE

HYPOTHERMIA THERAPYMILD HYPOTHERMIA (3-4 degree below baseline temperature) IS

NEUROPROTECTIVE

MECHANISM OF ACTION:

1.DECREASE CEREBRAL METABOLICRATE AND ENERGY DEPLETION

2.DECREASE EXCITATORY NEUROTRANSMITTER RELEASE

3.DECREASE APOPTOSIS

4.DECREASE VASCULAR PERMEABILITY AND EDEMA

What is the optimal timing of initiation of hypothermia therapy?

Cooling must begin early, within 6 hours of injury. However, experimental evidence strongly suggest that the earlier the better.

What is the optimal duration of hypothermia therapy?

The greater the severity of the initial injury, the longer the duration of hypothermia needed.

But it should be at least used for 72 hours

What is the best method? Two methods have been used in clinical trials:

Selective head cooling

Whole body cooling

In selective head cooling, a cap (Cool Cap) with channels for circulating cold water is placed over the infant's head, and a pumping device facilitates continuous circulation of cold water. Nasopharyngeal or rectal temperature is then maintained at 34-35°C for 72 hours

In whole body hypothermia, the infant is placed on a commercially available cooling blanket, through which circulating cold water flows, so that the desired level of hypothermia is reached quickly and maintained for 72 hours.

What is the optimal rewarming method?

Rewarming is a critical period. In

clinical trials, rewarming was carried out gradually, over 6-8 hours.

ADVERSE EFFECTS:THOUGH THEORETITAL IT INCLUDESCOAGULATION DEFECT

LEUKOCYTES MALFUNCTION

PULMONARY HYPERTENSION

WORSENING OF METABOLIC ACIDOSIS

ABNORMALITIES OF CARDIAC RHYTHM

2013 Cochrane review says

Significant adverse effect is limited to only SINUS BRADYCARDIA and THROMBOCYTOPENIA

LONG TERM OUTCOME:2012 NICHD trial Combined outcome of death and IQ score

below 70 occurred in62% of patient in control group47% of patient in hypothermia therapy group Death Control group 48%Hypothermia therapy group 28% Severe disabilityControl group 60%Hypothermia therapy group 41%

STUDIES ON THERAPUTIC HYPOTHERMIA IN HIE

A decrease in the combined outcomes of mortality/major neurodevelopmental disability at 18 months (8 studies)

A reduction in mortality (11 studies)

A reduction in neurodevelopmental disability in survivors (8 studies)

9 independent meta-analyses have confirmed a consistent and robust beneficial effect of therapeutic hypothermia for moderate-to-severe encephalopathy

OTHER NEW THERAPUTIC MODALITIESOXYGEN FREE RADICAL INHIBITOR AND SCAVENGERS

DIRECT INHIBITORS:SUPEROXIDE DISMUTASE

ENDOPEROXIDASE

CATALASE

SCAVENGERS:VITAMIN E

VITAMIN C

MANNITOL

INDIRECT INHIBITORS:INDOMETHACIN

ALLOPURINOL

CYCLOOXYGENASE

N-ACETYL CYSTEINE

MELATONIN

Study have shown promising results but their use will depend on the ability to develop appropriate delivery system that will allow action at the cellular and specific tissue site

CALCIUM CHANNEL BLOCKERSFLUNARIZINE

NIMODIPINE

These two drugs appears mot efficacious on animal study

Results of clinical trial is awaited

ERYTHROPOIETINIts neuroprotective mechanism is mediated

through:1.Direct neurotropic effect

2.Decrease susceptibility to glutamate toxicity

3. Release of antiapoptotic factors

4.Reduce inflamation

5. Decrease nitric oxide mediated injury

6.Direct antioxidant effect

Epo 5000 u/kg have shown to provide significant neuroprotection and improved outcome

EXCITATORY AMINO ACID ANTAGONISTINHIBITOR OF GLUTAMATE RELEASE:BACLOFEN

ADENOSINE

ADENOSINE AGONIST

NMDA RECEPTOR BLOCKER:MAGNESIUM

PHENCYCLIDINE

DEXTROMETHORPHAN

KETAMINE

MK- 801 EAA antagonist MK-801 , has shown promising results in experimental animals and in

a limited number of adult trials. However, this drug has serious cardiovascular adverse effects

HOWEVER

MAGNESIUM SULFATE IS A NATURAL ANTAGONIST OF NMDA WITH LESS SIDE EFFECTS SO ROLE OF MS AS A NEUROPROTECTIVE AGENT IN PREVENTION OF BRAIN DAMAGE IN HIE DESERVE ACTIVE CONSIDERATION AND EVALUATION IN FUTURE

PREVENTION OF EXCESS NITRIC OXIDE FORMATION

NOS INHIBITOR:NITROARGININE

Administration of nitroarginine in immature rats caused prolonged inhibition of NOS and thus reduction in the extent of brain injury

Agents decreasing inflamatory response:AllopurinolInflamatory antagonist IL1 blocker TNF alfa blocker

ATTENUATE APOPTOSIS PATHWAYCASPASE INHIBITORS

STEM CELL TRANSPLANTATION THERE IS EVIDENCE THAT SUGGEST NEONATE BRAIN IS

ENDOWED WITH THE CAPABILITY FOR ENDOGENOUS NEUROGENESIS FLOWING HIE

INFACT MANY EXPERIMENTAL EVIDENCES SUGGEST SCT MAY REPAIR THE DAMAGED NEURONSIN BRAIN

SEVERAL TYPES OF STEM CELLS HAVE BEEN USED IN RODENTS INCLUDING NEURONAL STEM CELLS MESNCHYMAL STEM CELLS AND HEMATOPOIETIC STEM CELLS

THERE IS EVIDENCE THAT SUGGEST THAT GENETICALLY MODIFIED STEM CELLS MAY BE MORE EFFECTIVE THAN UNMODIFIED STEM CELLS

THUS SCT HAS POTENTIAL TO BECOME A FUTURE NEUROPROTECTIVE AND REGENERATIVE THERAPY FOR HIE

THANK YOU