DR DR . E. SENTHIL KUMAR M.B.B.S

NATIONAL HOSPITAL

57 YEARS OLD MALE PATIENTADMITTED ON 8 / 2 / 09 WITH HISTORY OF

ALTERED SENSORIUM

NOT TAKING FEEDS 2 MONTHS

DROWSINESS ….. PAST ONE DAY

H / O ICU ADMISSION FOR SIMILAR COMPLAINTS …. LAST MONTH

HE WAS FULLY EVALUATED & TREATED .

AT THE TIME OF DISCHARGE …

PATIENT ABLE TO WALKSPEECH AND HIGHER FUNCTIONS .. NORMALICTERIC

PERSONAL HISTORY

ALCOHOLIC FOR THE PAST 37 YEARS

FAMILY HISTORY :

NOT CONTRIBUTORY

PAST HISTORY

INTERMITTENT JAUNDICE FOR THE PAST 4 YEARS (TREATED WITH NATIVE MEDICINES)

K / C / O CIRRHOSIS FOR PAST TWO YEARS AND ON RX

K / C / O HYPERTENSION FOR PAST 2 MONTHS AND ON RX

CLINICAL FINDINGS :

ICTERIC +++ PALLOR +

BILATERAL PITTING PEDAL EDEMA +

RS : BILATERAL CREPITUS +

CNS : GLASGOW COMA SCALE - E1 V 2 M 3 - 6 / 15

PUPILS ….. 4mm , PERLA

PLANTAR ….. WITHDRAWAL RESPONSE

B / L LIMB SPASTICITY ++ , REFLEXES

VITALS :

PULSE : 86 / minBP : 148 / 92 mm HgRR : 22 / minTEMP : N

spO2 : 98 %U / O : ADEQUATEBLOOD SUGAR : 209 mg %

NO INTUBATION DONE @ THE TIME OF ADMISSION

INVESTIGATIONS (9 / 2 / 09 )

TOTAL BILIRUBIN : 5.4 DIRECT : 2.3 INDIRECT : 3.1

URINE UROBILINOGEN : INCREASED

BLOOD AMMONIA : 79

PLATELETS : 1.02 LAKHS

INR : ELEVATED

SR POTASSIUM : REDUCED

CT BRAIN

GROSS AGE RELATED CEREBRAL ATROPHY

FEATURES S / O SMALL VESSEL ISCHEMIC CHANGE

USG ABDOMEN

COARSE ECHOGENIC LIVER S / O CIRRHOSIS

SPLENOMEGALY

MODERATELY DISTENDED BLADDER WITH DEBRIS (CYSTITIS)

CXR – PA VIEW

INHOMOGENEOUS OPACITIES IN RT UPPER AND MIDZONE

CARDIOMEGALY

ATHEROMATOUS AORTA

ECG : SB

DIFFERENTIAL DIAGNOSIS :

1. HYPOGLYCEMIA ….. RULED OUT { SUGAR @ ADMN – 209 }

2. HYPOXIA ….. RULED OUT { NO CYANOSIS , SATURATION – N }

3. UREMIA …. RULED OUT { NORMAL RFT }

4. KETO ACIDOSIS …. RULED OUT { SUGAR – NEAR NORMAL & URINE KETONE NEGATIVE }

5. ELECTROLYTE IMBALANCE …. POSSIBLE { LOW POTASSIUM }

6. HEPATIC COMA …. POSSIBLE { HIGH BILIRUBIN , RAISED INR HYPOKALEMIA LOW UREA LOW ALBUMIN MILDLY ELEVATED AMMONIA USG ABDOMEN .. S/O CIRRHOSIS }

7. ALCOHOL / OTHER INTOXICATION …. NO CONTRIBUTORY HISTORY

8. INTRA CRANIAL CAUSE { SDH, SOL,NEUROPSYCHIATRIC STATE, POST ICTAL ENCEPHALOPATHY , MENINGITIS, ENCEPHALITIS }

COURSE IN HOSPITAL : 8/2/09 … DATE OF ADMISSION

TREATMENT GIVEN :

PROTEIN RESTRICTION

TAB SPIRONOLACTONE , POTASSIUM INFUSIONS

INJ RANITIDINE

INJ MANNITOL

INJ VIT K

LACTULOSE

TAB RIFAXIMIN

RESOURCE HEPATIC POWDER

HEPAMERZ INFUSIONS

BACLOFEN , PHYSIOTHERAPY

14/2/09 … DROWSINESS TO HYPOTENSION18/2/09 HYPOKALEMIA (3.3) FEBRILE ++DAY 6 - 10 CRP , INR INCREASED BLOOD AMMONIA INCREASED ( 110 )

CLINICAL PICTURE :

PATIENT DEVELOPED

MILD NECK STIFFNESS SPASTIC QUADRIPARESIS

NEURO CALL OVER GIVEN

EEG :

BACKGROUND ACTIVITY NORMALRESPONSE TO EYE OPENING NORMAL DURING HYPER VENTILATION SLOW WAVES PRESENT IN ANTI HEAD REGION

ed

CSF ANALYSIS :

PROTEIN – 31

GLUCOSE – 90

CHLORIDE – 117

APPEARANCE – CLEAR

AFB – NEGATIVE

CULTURE – NO GROWTH

VDRL - NEGATIVE

HIV - NEGATIVE

NORMAL CT BRAIN , NORMAL EEG , NORMAL CSF PROFILE , NORMAL VDRL & HIV

RULES OUT INTRA CRANIAL CAUSES , MENINGO ENCEPHALITIS , POST ICTAL STATES

BASED ON THESE , A DIAGNOSIS OF HEPATIC COMA WAS MADE

“ HEPATIC ENCEPHALOPATHY - ESSENTIALLY A DIAGNOSIS OF EXCLUSIONHEPATIC ENCEPHALOPATHY - ESSENTIALLY A DIAGNOSIS OF EXCLUSION “

BUT DESPITE H.E. DIRECTED INTENSIVE MEDICAL CARE

28 / 2 /09 … FURTHER DETERIORATION IN GCS ( E 1 V2 M 1)DAY 20

1/3/09 … CENTRAL VENOUS LINE SECURED

2/3/09 … PATIENT INTUBATED AND PLACED IN MECHANICAL VENTILATORDAY 22 FALLING PLATELET COUNT

TREATMENTTREATMENT RESISTANTRESISTANT HEPATIC HEPATIC COMA …COMA …

??? CAUSE

CAUSES OF PERSISTENT HEPATIC COMA DESPITE TREATMENTCAUSES OF PERSISTENT HEPATIC COMA DESPITE TREATMENT

INFECTION ….. SBP , LRI { VAP } , SEPTICEMIA , UTI

ELECTROLYTE IMBALANCE … PERSISTENT HYPOKALEMIA

ASSOCIATED RENAL FAILURE …. RULED OUT { NORMAL RFT , OUTPUT }

HYPOGLYCEMIA …. RULED OUT { PATIENT WAS ON > 2000 Kcal / Day SUGARS WERE STABLE }

UPPER GI BLEED …. RULED OUT { RT ASPIRATES – NOT BLOOD STAINED STOOL NEGATIVE FOR BLOOD , HB % - N }

CONSTIPATION …. RULED OUT { PT ON LACTULOSE & PASSING 2-4 STOOLS PER DAY}

DEHYDRATION ….. RULED OUT { ADEQUATE FLUID INTAKE PULSE , BP , U / O – NORMAL }

ACID BASE IMBALANCE …. POSSIBLE ( ABG NOT DONE )

DRUGS ….. POSSIBLE { BDZ GIVEN FOR SEDATION IN EARLY STAGES LASIX , PSYCHOTROPIC MEDICINES , NARCOTICS WERE AVOIDED}

FEVER WORK UP DONE :

BLOOD C/S … NON FERMENTING GNB

SPUTUM C/S … KLEBSIELLA

URINE C/S … ENTEROCOCCI & PNEUMOCOCCI

TREATMENT :

DOPAMINE DRIP STARTED

POTASSIUM INFUSIONS MAINTAINED

APPROPRIATE ANTIBIOTICS ADDED ( MEROPENEM , VANCOMYCIN , PIPERACILLIN – TAZOBACTAM )

BACLOFEN AND PHYSIOTHERAPY GIVEN

BDZ STOPPED

OTHER TREATMENT CONTINUED

12/3/09 … TRACHEOSTOMY DONEDAY 32

18/3/09 … PATIENT IMPROVED AND WEANED OFF THE VENTILATORDAY 38 ON NOR ADRENALINE DRIP (DUE TO PERSISTENT HYPOTENSION)

AS ON 25/3/09 : …DAY 45

ICTERIC ++

AFEBRILE

VITALS … STABLE

BLOOD NH3 … STABLE

SERUM K + … STABLE

INR , PLATELETS … STABLE

DISCHARGE BEING PLANNED ON 30 / 3 / 09 ….. DAY 50

SUMMARY SUMMARY

57 YEARS OLD MALE ADMITTED WITH

FLUCTUATING CONSCIOUSNESS LEVEL (FOR WHICH TREATED AT OUTSIDE HOSPITALS FOR PAST FEW MONTHS)

SEVERE HEPATIC DYSFUNCTION AS EVIDENCED BY

HIGH BILIRUBIN & AMMONIA ,HIGH BILIRUBIN & AMMONIA , LOW ALBUMIN , POTASSIUM & UREA LOW ALBUMIN , POTASSIUM & UREA VIT K RESISTANT COAGULOPATHYVIT K RESISTANT COAGULOPATHY

ADMITTED WITH STAGE 3 H.E. WHICH WAS RESISTANT TO TREATMENT

COMPLICATED BY MULTI FOCAL SEPSIS , ELECTROLYTE IMBALANCE , ? BDZ USE PROGRESSED TO STAGE 4 - PATIENT PLACED IN MV

AFTER SUSTAINED TREATMENT WITH DIETARY MGT , ANTIBIOTICS ,HEPAMERZ , VIT K , POTASSIUM INFUSIONS , LACTULOSE , BACLOFEN AND PHYSIOTHERAPY PATIENT IMPROVED TO PRESENT CONDITION

THIS IS THE FIRST CASE OF SEVERE TREATMENT RESISTANT STAGE 3 / 4 HEPATIC COMA ADMITTED IN NATIONAL HOSPITAL

PATIENT – IN ICU FOR NEARLY 50 DAYS WITH CONSTANT MONITORINGAND MANAGEMENT OF THE ENCEPHALOPATHY , MULTI FOCAL SEPSIS, PERSISTENT HYPOTENSION , HYPO KALEMIA , HYPER AMMONEMIA ,HYPER BILIRUBINEMIA & COAGULOPATHY

PATIENT – IN VENTILATOR FOR 14 DAYS

PATIENT - SUCCESSFULLY REVIVED AFTER NEARLY 50 DAYS OF INTENSIVE MEDICAL CARE

ALL OF THIS POSSIBLE ONLY BECAUSE HIS COMPANY AGREED TO PAY FOR THE EXPENSES

HEPATIC ENCEPHALOPATHY

Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction characterized bypersonality changes, intellectual impairment, and a depressed level ofconsciousness

Type A hepatic encephalopathy associated with A cute liver failure.

Type B hepatic encephalopathy associated with portal-systemic B ypass

Type C hepatic encephalopathy associated with C irrhosis and portal hypertension or portal-systemic shunts.

Type C hepatic encephalopathy is, in turn, subcategorized as episodic, persistent, or minimal.

PATHOGENESIS

Endogenous Neurotoxins

AmmoniaMercaptansPhenolsShort-medium fatty acids

Increased Permeability of Blood-Brain Barrier

Change in Neurotransmitters and Receptors

GABAMet enkephalin

Altered BCAA/AAA ratio

Zinc deficiency

Manganese deposits

PRECIPITATING FACTORS

DrugsBenzodiazepinesNarcotics, opioidsAnti psychoticsAnti depressantsAlcoholdiuretics

Portosystemic ShuntingRadiographic or surgically placed shuntsSpontaneous shuntsVascular OcclusionPortal or Hepatic Vein Thrombosis

DehydrationVomitingDiarrheaHemorrhageDiureticsLarge volume paracentesis

Increased Ammonia Production, Absorption or Entry Into the BrainExcess Dietary Intake of ProteinRenal failureGI BleedingInfectionElectrolyte Disturbances (ie., hypokalemia)ConstipationMetabolic alkalosisPrimary Hepatocellular

Carcinoma

CLINICAL PICTURE

MINIMAL H.E.

EARLY SYMPTOM ….. ALTERATION OF SLEEP PATTERNEARLY SIGN ….. CONSTRUCTIONAL APRAXIA

OTHER FEATURES …

UNAWARENESS OF CLINICAL SUBJECTIVE SYMPTOMS

ABSENT EEG FINDINGS

PSYCHOMETRIC/NEUROSPYCHOLOGICAL TESTS CAN DISCLOSE DEFICITS

HYPER VENTILATION

REDUCED BODY TEMPERATURE

NEJM Volume 337:473-479

ASTERIXIS IS ABSENT IN STAGES 0 & 4

IT IS SEEN IN OTHER ORGANFAILURES ALSO

EG : RENAL FAILURE PULMONARY FAILURE

ALSO OBSERVED IN BARBITURATETOXICITY

LAB DIAGNOSIS :

PSYCHOMETRIC / NEUROPSYCHOLOGICAL TESTSPSYCHOMETRIC / NEUROPSYCHOLOGICAL TESTS

ELECTRO PHYSIOLOGIC STUDIESELECTRO PHYSIOLOGIC STUDIES

IMAGE TECHNIQUESIMAGE TECHNIQUES

CLINICAL LABORATORY TESTSCLINICAL LABORATORY TESTS

PSYCHOMETRIC / NEUROPSYCHOLOGICAL TESTS

Retelling and interpretation a fable

Forward / backward digit span

Reproduction of simple figures

Block design test

Critical flicker test

WAIS performance IQ

Line tracing tests: LTT

Number connecting test: NCT

Digital-symbol test: DST

EEG :

Classic EEG changes associated with hepatic encephalopathy are high-amplitude , low-frequency waves and tri phasic waves

VEP …. Useful in detecting early H.E.

BRAIN IMAGING

MRI / CT are used mainly to rule out other causes . MRI has the additionaladvantage of being able to demonstrate hyperintensity of the globus palliduson T1-weighted images, a finding that is commonly described in hepatic encephalopathy

LAB PARAMETERS

RENAL FUNCTION DISORDERSELECTROLYTE IMBALANCE { ESP SR POTASSIUM LEVELS }ACID-BASE EQUILIBRIUMLIVER FUNCTIONINFLAMMATORY PARAMETERS

BLOOD AMMONIA LEVELS

Clinical assessment more reliable than serial ammonia estimation

Arterial sample is preferable

Blood drawn from an extremity to which a tourniquet has been appliedmay provide a falsely elevated ammonia level

NORMAL RANGE : 18 TO 60

May also be elevated in other states of hyper ammonemia such as

uretero sigmoidostomyurea cycle disorders

AMMONIA HAS NO RELATION TO CLINICAL STATUS

THIS PATIENT HAD ONLY MILD ELEVATION ( < 120 ) INSPITE OF SEVERE ENCEPHALOPATHY

MANAGEMENT OF H.E.

TREATMENT OF PRECIPITATING FACTORS

DIETARY MANAGEMENT

INTESTINAL CLEANSING

ROLE OF FLUMAZENIL , ZINC , MANGANESE

AMMONIA DETOXIFICATION

TRANSPLANTATION

TREATMENT OF PRECIPITATING FACTORS :

ADEQUATE HYDRATION

HYPOGLYCEMIA : ADEQUATE CARBOHYDRATE SUPPLEMENT

GI BLEEDINGS : STOP BLEEDING AND AVOID ANEMIA

INFECTIONS { ESP. SBP } : ANTIMICROBIALS

ACIDOSIS / ALKALOSIS : TO BE CORRECTED

DIURETICS : ESP LASIX TO BE AVOIDED

SEDATIVES : DISCONTINUED

CONSTIPATION : TO BE CORRECTED WITH LACTULOSE

UREMIA : TO BE CORRECTED

DIETARY MANAGEMENT :

ENSURE ADEQUATE CALORIE & FLUID INTAKE

RESTRICT PROTEINS TO LESS THAN 30 gm PER DAY

PLANT PROTEIN IS BETTER THAN ANIMAL PROTEIN

BRANCHED CHAIN AMINO ACID SUPPLEMENTATION

ZINC SUPPLEMENTATION

INTESTINAL CLEANSING :

LACTULOSE

NEOMYCIN , METRONIDAZOLE , AMPICILLIN , PAROMOMYCIN

RIFAXIMIN

ROLE OF FLUMAZENIL , ZINC , MANGANESE :

FLUMAZENIL IS HIGHLY USEFUL IN THOSE CASES TREATED WITH BDZ

EVEN IN OTHER CASES , IT MAY HAVE A ROLE

ZINC DEFICIENCY IS IMPLICATED IN THE PATHOGENES OF H.E. AND HENCE ITS SUPPLEMENTATION IS HELPFUL IN SOME CASES

MANGANESE EXCESS IS ALSO A PRESUMED PREDISPOSING FACTOR AND THIS IS SAID TO BE RESPONSIBLE FOR THE HYPER DENSITY OF GLOBUS PALLIDUS ON MRI

SO MANGANESE CHELATORS MAY BE USED IN FUTURE

Others :

Modification of intestinal flora : (replacing ammoniagenic coliforms with non ammoniagenic bacilli)

Methionine sulfoximine.

AMMONIA DETOXIFICATION :

Protein restriction

Lactulose

Neomycin , metronidazole , Ampicillin , paromomycin , Rifaximin

L-ornithine L-aspartate (LOLA)

Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate

L-carnitine

Dialysis

LIVER TRANSPLANTATION

SEVERE AND TREATMENT REFRACTORY H.E.

ACUTE LIVER FAILURE WITH H.E.

APPROACH TO A PATIENT WITH H.E.

Exclude nonhepatic causes of altered mental function.

Periodic estimation of blood ( preferably arterial ) ammonia

Precipitants of hepatic encephalopathy, such as metabolic disturbances, gastrointestinal bleeding, infection, and constipation, should be corrected.

Avoid CNS depressants especially BENZODIAZEPINES{ but they may be used in co existing alcohol withdrawal + H.E.}

Prophylactic intubation for grade 3 & 4 H.E. cases to prevent aspiration

Treatment of hyper ammonemia

Zinc , Vit K supplementation

Supportive care & nutrition