Hypoxic-ischemic encephalopathy
Anoxic-ischemic coma
Historical note

It was named "oxygen" (acid-former) by Antoine Lavoisier (1743-1794) of France
He made the greatest medical discoveries concerning oxygen's role in respiration.

In animal experiments, Lavoisier and others discovered that anoxia led to collapse and death.
In 1920 Barcroft introduced the terms "anoxic," "anemic," "histotoxic," and "stagnant" to designate the various forms of anoxia.

Barcroft J. Anoxemia. Lancet 1920;2:485-9.
Etiology
The brain utilizes oxygen to metabolize glucose. It cannot store oxygen and survives only for minutes after its oxygen supply is reduced below critical levels
Most vulnerable
1-Pyramidal cells of the third and fifth layers of the cerebral cortex
2-Pyramidal cells in Sommer sector of the hippocampus
3-Purkinje cells of the cerebellum
1-Pyramidal cells of the third and fifth layers of the cerebral cortex

3-Purkinje cells of the cerebellum all output of the cerebellum cortex carried by it to white matter
Lack of oxygen to the brain can be divided into :
Anoxic anoxia
Anemic anoxia
Ischemia anoxia
Ischemic anoxia
Describes a state of insufficient cerebral blood flow. "Low-flow states" may be secondary to cardiovascular collapse or conditions of increased vascular resistance as in stroke or migraine.
Anoxic anoxia
consists of low arterial oxygen content and tension. This may be secondary to decreased oxygen in the environment or inability for oxygen to enter the circulatory system as in pulmonary disease (P.E.).
Anemic anoxia
Consists of low oxygen content in the blood secondary to decreased hemoglobin content.
Brain normally consumes approximately 3.5 mL of oxygen for each 100 g of brain tissue per minute.
When this rate declines to 2.5 mL, delirium supervenes.
Rates of cerebral oxygen metabolism below 2 mL/100 g per minute are incompatible with a conscious state.
Epidemiology
Most of the time acute anoxic coma is a result of cardiac arrest .
Approximately 1.5 million people per year in the United States succumb to a cardiac death

Epidemiology
About 30% of the cardiac resuscitations attempted each year are considered "successful,"
Only 10% to 20% of survivors are able to resume their former lifestyles(Denton and Thomas 1997)
Epidemiology
Following cardiac arrest, individuals admitted to intensive care units in coma suffer a high mortality rate
Patients in coma for more than 48 hours have a 77% mortality rate By contrast, individuals not in coma have an 11% mortality rate (Teres et al 1982)
Prevention
Complications, such as hypoxic-ischemic encephalopathy, are closely linked to the time until the first defibrillatory shock is administered during cardiopulmonary resuscitation.
Increased survival rates with minimal complications are attained by reducing the time to initiation of cardiopulmonary resuscitation and defibrillation
In some cases, this can triple the chance of surviving a cardiac arrest outside of the hospital (Herlitz et al 1994)
Differential diagnosis
Severe degrees of anemia, congestive heart failure, hypotension, and pulmonary disease can lead to coma.
Occlusion of the pulmonary arteries during a pulmonary embolism produces an abrupt drop in cardiac output and cerebral blood flow.
Differential diagnosis
Fat embolism wherein pulmonary and cerebral vessels become occluded with lipid and fibrin debris can produce cerebral ischemia.
Anoxic coma also occurs in association with cardiac surgery (Hypotension).
Differential diagnosis
Hypertensive encephalopathy leads to diffuse cerebral ischemia. Alterations of the blood-brain barrier, arteriole necrosis, and diffuse infarcts and hemorrhages are present in this syndrome.

Differential diagnosis
Migraine headaches can result in coma. The mechanism is believed secondary to vascular insufficiency of the tributaries of the basilar artery.
Symptoms range from confusion, fever, meningismus, ataxia, syncope, and amnesia, to coma. Most episodes of coma resolve within 24 hours, but can persist for days and can be precipitated by head trauma, work, and angiography.
-Familial migraine coma: a case study Journal of Neurology February 1990 Issue: Volume 237, Number 1
-Coma associated with migraine .Rev Neurol. 1999 Dec 1-15;29(11):1048-51
Basilar migraine:
Usually during childhood and teenage years
Throbbing Occipital headache
Aura 10-40 minutes, visual changes
Tingling and numbness of hand and feet's
Ataxia of gait and speech, vertigo and tinnitus
Involvement of brainstem reticular formation can cause loss of consciousness
Bradley 2075

Diagnostic workup
…
CT or MRI are useful in determining the etiology of coma. These studies can differentiate between an ischemic infarct, intracerebral hemorrhage, and a mass lesion involving the cortex or the brainstem
Diagnostic workup
CT scan and global hypoxic injury :
There is a loss and reversal of normal grey-white matter differentiation with expanded grey matter showing lower attenuation. The basal ganglia are not sharply defined. There is also generalized effacement of cerebral sulci.


Diagnostic workup
MRI with the apparent diffusion coefficient of water is becoming a sensitive tool of neuronal physiology and may represent a reliable indicator of progressive neuronal injury following cerebral ischemia.
White matter demyelization and necrosis
Sub cortical u fibers
Corpus calusum
Int/ext capsules
Gray matter
Neuroradiology, Grossman 353-4
Diagnostic workup
EEG can be a sensitive indicator of cerebral function.
the EEG can be used to assess cerebral function and to guide therapy.
Coma Patterns
Alpha Coma, Burst Suppression
Periodic spiking , Triphasic waves
Electrocerebral inactivity





Diagnostic workup
EEG has been used to assess prognosis. In patients with terminal coma, onset of abnormal EEG changes may sometimes be suggestive of a poor outcome :
(Rothstein et al 1991)
Burst suppression pattern
Periodic pattern( Generalized periodic discharges, periodic lateralized epileptiform discharges.)
Diagnostic workup
BURST SUPRESSION

Diagnostic workup
Periodic lateralizing epileptiform discharges may occur following focal cerebral insults such as infarction, but do not necessarily indicate active epileptic activity.

Diagnostic workup
Alpha coma is frequently associated with cardiac arrest, but its prognostic significance is unclear.
EEG pattern does not change with stimulation.
( ? Extremely poor prognosis PEDLEY,358)




Diagnostic workup
If seizures develop and aggressive management is desired for the patient, then epileptic activity should be treated to reduce further neuronal cell loss in the cortex. Status epilepticus, status myoclonus, and myoclonic statusepilepticus are associated with inability to recover consciousness in cardiac arrest survivors (Krumholz et al 1988)
ICU? – Consult ! – Prognosis?
Prognosis and complications
Prediction of outcome following coma has been the subject of multiple clinical studies
Earlier reports have noted that post-arrest coma longer than 3 days carried an unfavorable prognosis (Bell and Hodgson 1974)

Prognosis and complications
Several studies even report some permanent neurologic sequelae if coma duration is greater than 6 hours (Maiese et al 1988)
Others have correlated outcome with the pattern of motor responses and the presence or absence of particular brainstem reflexes.
( Levy et al , predicting outcome from hypoxemic-ischemic coma 1985)


Levy examined 210 patients in whom cardiopulmonary failure was the cause of coma and correlated clinical signs with outcome at 1 year .
Patient age, sex, location of the initial insult, etiology of the coma, and the presence of generalized seizures did not influence the degree of recovery.
Levy et al 1985
In contrast, the clinical examination did correlate with recovery. Individuals without pupillary light reflexes at the initial examination never regained independence. Absence of corneal reflexes following the first day was also a poor prognosis.
Levy et al 1985
Prognosis and complications
Increased numbers of brainstem reflex abnormalities were associated with reduced survival
Snyder et al 1977 ,Rudolf et al 2000
The most favorable sign of a good outcome
(can be rare at day 1):
Any form of speech, orienting spontaneous eye movements, intact oculocephalic or oculovestibular responses, ability to follow commands, and normal skeletal tone.



Prognosis and complications
Additional investigations seek to identify cellular markers that may signal a poor neurologic prognosis, such as elevated levels of S-100B and interleukin-8 ,(Mussack et al 2002)
Mussack et al 2002
Serum S-100B and interleukin-8 as predictive markers for comparative neurologic outcome analysis of patients after cardiac arrest and severe traumatic brain injury
Significantly elevated S-100B and interleukin-8 serum levels 12 hrs after cardiac arrest suggest that primary brain damage and systemic inflammatory response are comparably serious with that of traumatic brain injury. In both collectives, increased S-100B values measured 12 hrs after insult correlated well with an unfavorable neurologic outcome after 12 months.





Decorticate or flexor responses occur after damage to the hemispheres, or in cases of diffuse depression of cortical function following cerebral ischemia. Decerebrate or extensor responses correlate with destructive lesions of the midbrain and upper pons, but also may be present in anoxic encephalopathy. The absence of motor response, especially if flaccidity and areflexia are present, indicates severe brainstem depression and is frequently found in terminal coma or in severe sedative intoxication. Withdrawal and localizing responses imply purposeful or voluntary behavior. Obeying commands is the best response and marks the return of consciousness.

Hypoxic-ischemic encephalopathy

Hypoxic-ischemic encephalopathy

Neurology

Anti Epileptics


Na channel blockers:

Depakore- valproike acid: ( VPA )
Enz inhibitor Pro binding 95%
increase INR ! hypoglycemia
side effect fat , pco,hairy , pancreatitis , no rash !
increase ammonia level ,don't freak out if asymptomatic
asprine displace it from pro/ and increase its level.

Lamictal-lamotrigine ( LTG )
first line generalized sz
Rash
Pregnancy precaution

Keppra-levetiracetam ( LTC )
renal excretion
UMOA

Topomax-topiramate (TPM )
Enz inducer hperglycemia (metformin),decrease INR (Coumadin)
Diamox (used for NPH) like effect tingling and numbness


Dilantin-phenytoin ( PHT )
pro binding 90% increase INR ! hypoglycemia
Enz inducer decrease INR, hperglycemia
Half life 22h
Side effect : megaloblastic anemia,dupuytran contracture, rash
PHT decrease CBZ level to one third !!! , but CBZ increase dilanine level !!!

Tegretol-carbatrol-carbamazepine ( CBZ )
may induce absence status
Enz inducer decrease INR, hperglycemia
typical case: nursing home pt on this drug, physican prescrib darvocet or propoxiphen for pain and pt goes to coma (altered mental status) !!( increase level )
Side effect :hyponatremia , 10% rash ,diplopia
PHT decrease level to third !!
Cimetedine, verapamil,diltiazem, propoxyphen ,erythromycine isoniiazide increase the level.

trileptal-oxacarbamazepine
worse than carbamazepin in hyponatremia induction !
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CA channel blocker-only one !

zarontyn-ethosuximide absence sz
side effect : ataxia, rash
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GABAERGICS (most have ga, ba in their names ), (chloride chane GABA 1 , K increase and Ca decrease GABA2)

Primidone-Mysoline ( PRM ). Will metabolize to PB and other metabolites
Side effect : impotence,….
felbatol-felbamateside effect aplastic anemia and liver dysfunction
tiagan-tiagabine-gabatril
neurontin-gabapentinrenal excretion
Phenobarbital ( PB )hard to taper offEnz induce decrease INR, hyperglycemia
Side effect : dupuytran contracture , rash
Zonegram-zonisamide ( ZNS )diamox like effect tingling and numbnessSulfa allergy
Vigabatrinretinal deposition

which medication can normaliz the EEG:Depakote and PHB can normalize the EEG don't get full

case:if 21 year old pt with generalized sz new onset no etiology find, is geneticand need to be on med for the rest of life , don't full with sz free episodes or normal EEG
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Therapeutic levels
Carbamazapin 5-10 ug/ml ,
Dilantin 10-20
Phenobarbital 20-40 , 90-120mg po phs, could start iv 300-800 mg iv. load for status epilepticus could use 10-20 mg/kg iv
Valporate 50-100, 10-60mg/kg TID (250cap),
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LOADING
Only : PHT/VPA/PB
Loading for pht and vpa the same 10-15 mg/kg
Expect for each gram the level raise 10
PB : don’t load more than 200 the first time (respiratory distress and ..), but you can reload 100 or 60 till level therapeutic later on /


H/F LIFE