17. St.Galler IPS-Symposium 2013 Weiter- und Fortbildungstag … · 2018-04-11 · St.Galler...

Coma hepaticum – intensivmedizinische Aspekte

Dr. med. Roger Lussmann Leitender Arzt CHIPS

Kantonsspital St.Gallen

17. St.Galler IPS-Symposium 2013 Weiter- und Fortbildungstag

Dienstag, 15. Januar 2013, 10.00 – 18.00 Uhr

15.01.2013 Dr. Roger Lussmann 1

Vorbemerkungen

• Keine Ausführungen bezüglich akutes oder akut auf chronisches Leberversagen

• Keine Ausführungen bezüglich Behandlung des Leberzirrhotikers auf der Intensivstation

• Keine Ausführungen zu spezifischen Behandlungen spezifischer Ursachen des akuten Leberversagens

• Worüber wird gesprochen?

Inhalt

• Vorbemerkungen zur Pathophysiologie des akuten Leberversagens

• Definition der hepatischen Encephalopathie

• Pathophysiologie des coma hepaticum (intrazerebrale Hypertension)

• Therapie des coma hepaticums in der Intensivstation

• Verlegung des Patienten in ein Leberzentrum für die OLTx

Hepatic Encephalopathy

Hepatic encephalopathy reflects a spectrum of

neuropsychiatric abnormalities seen in patients with

liver dysfunction after exclusion of other known

brain disease.

Hepatic Encephalopathy – West Haven Criteria

for Grading Mental State Grade 1

• Trivial lack of awareness

• Euphoria or anxiety

• Shortened attention span

• Impaired performance of addition

Grade 2

• Lethargy or apathy

• Minimal disorientation for time or place

• Subtle personality change

• Inappropriate behavior

• Impaired performance of subtraction

Grade 3

• Somnolence to semi-stupor but responsive to verbal stimuli

• Confusion

• Gross disorientation

Grade 4

• Coma, unresponsive to verbal or noxious stimuli

516 | SEPTEMBER 2010 | VOLUME 7 www.nature.com/ nrgastro

reason, recognition of the complications of cirrhosis

(including HE) and the need for improved management

of patients affected by this disease is imperative.7–9 HE

has a substantial negative effect on quality of life, even

in patients with minimal disease.10 Prasad et al.11 were

the first group to show that treatment of MHE improves

patients’ quality of life. Moreover, patients with HE

have poor navigational skills and an impaired ability to

drive.12–15 This impairment places these individuals at an

increased risk of road traffic violations and accidents.15,16

Apart from these negative effects on quality of life and

daily functioning, patients with HE also have increased

mortality.9,17 Furthermore, diagnosis of MHE has a prog-

nostic implication with regard to the risk of progression

Key points

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of ■

acute and chronic liver disease

Inflammation and raised levels of ammonia in the blood (owing to diminished ■

clearance of ammonia by the liver) underlie the pathogenesis of HE

Some degree of cerebral edema is observed in all grades of HE ■

The occurrence of any neuropsychiatric manifestation in patients with liver ■

disease should be treated as HE unless proven otherwise

An acute episode of HE is managed by a tripartite strategy: ruling out other ■

causes of encephalopathy, identifying the precipitating cause and initiating

empiric therapy

Rifaximin and lactulose are the only two medications approved by FDA for long- ■

term treatment of HE

Work-up for liver transplantation must be initiated as early as possible ■

to OHE.17 With increased awareness and improved

diagnostic methods, the burden of HE is likely to attain

epidemic proportions. This Review therefore considers

the pathogenesis, diagnosis and management of HE. The

therapies that are effective in the treatment of HE are also

discussed along with the available options for long-term

management of this disorder.

PathogenesisThe pathogenesis of HE has not been clearly defined. The

general consensus is that elevated levels of ammonia

and an inflammatory response work in synergy to cause

astrocytes to swell and fluid to accumulate in the brain

(cerebral edema), which is thought to explain the symp-

toms of HE. The precise molecular mechanisms that

result in these morphological changes in the brain are

yet to be identified.

Ammonia

Ammonia is a byproduct of the metabolism of nitrogen-

containing compounds and is involved in a number

of metabolic reactions. However, ammonia is toxic at

elevated concentrations and must be removed from the

body.18,19 In mammals, ammonia is most commonly

eliminated through the formation of urea in the liver.

This nontoxic metabolite is water soluble and can be

excreted by the kidneys. In patients with acute liver

failure, however, brain and muscle cells are involved in the

metabolism of ammonia to a greater extent than normal.19

These ‘ammonia sinks’ utilize the amino acid glutamate to

detoxify ammonia by converting it to glutamine.20,21

Accumulation of ammonia has received considerable

attention as an explanation for the pathogenesis of HE.

In the early 18th century, Nencki, Pavlov and Zaleski

demonstrated the development of neuropsychiatric

changes in dogs after experimental portacaval fistula

surgery (termed Eck fistula) induced the symptoms of

HE.22 The neuropsychiatric symptoms worsened if the

dogs were fed meat, which led to the term ‘meat intoxica-

tion syndrome’.23 Behavioral alterations in patients with

liver dysfunction were formally described later in the 20th

century by Phillips and colleagues.24 In 1991, Lockwood

and colleagues demonstrated direct evidence for the role

of ammonia in the pathogenesis of HE by using radio-

labeled nitrogen in PET imaging studies of patients with

severe liver disease and MHE.25

Astrocytes are the only cells in the brain that can

metabolize ammonia.19 The enzyme glutamine syn-

thetase (present in the endoplasmic reticulum of astro-

cytes) is responsible for the conversion of equimolar

concentra tions of glutamate and ammonia to glut-

amine.21 Intracellular levels of glutamine, therefore,

increase enormously as the ambient ammonia concentra-

tions rise owing to liver failure.26 As glutamine is an

osmolyte, water moves inside the astrocyte causing it to

swell. This swelling leads to cerebral edema and intra-

cranial hypertension.27,28 Administration of methionine

sulfoximine (an inhibitor of glutamine synthase) pre-

vents astrocyte swelling in experiments in animals.29,30

Sudden exposure of astrocytes to high concentrations of

HE associated with

acute liver failure

HE in patients with

portosystemic bypass

and no intrinsic

hepatocellular disease

Type A

Type B

Type C

HE associated with

cirrhosis or por tal

hypertension or

portosystemic shunts

Episodic HE

Persistent HE

Minimal HE

Precipitated

Spontaneous

Recurrent

Severe

Treatment-

dependent

Figure 1 | Classification of hepatic encephalopathy (HE) proposed by the Working

Party at the 1998 World Congress of Gastroenterology, Vienna, Austria.

The Working Party proposed a classification system for HE to standardize the

nomenclature used in HE diagnosis. HE can be graded into three types: type A HE

is associated with acute liver failure; type B HE is found in patients with

portosystemic bypass and no intrinsic hepatocellular disease; type C HE is

associated with cirrhosis or portal hypertension or portosystemic shunts. Type C

HE can be further divided into three categories: episodic HE (precipitated;

spontaneous; recurrent); persistent HE (mild; severe; treatment-dependent);

minimal HE.

REVIEWS

nrgastro_116_SEP10.indd 516 11/8/10 15:48:52

Hepatic Encephalopathy Pathogenesis

Only partly understood

Clinical and experimental evidence: important role for raised concentrations of circulating neurotoxins, especially ammonia (109) (decreased liver clearence)

Laboratory studies: ammonia-induced changes in neurotransmitter synthesis and release, neuronal oxydative stress, impaired mitochondrial function, osmotic disturbances resulting from astrocytic metabolism of ammonia to glutamine

Change in cerebral function and astrocytic swelling (109-111)

Neurotoxins

• Ammonia -- correlates poorly with encephalopathy • Amino acids --aromatic and straight chain aa are

increased in liver failure -- tryptophan may be preferentially transported into CNS

• Methionine, mercaptans • Gamma aminobutyric acid (GABA) -- this is an

inhibitory neurotransmitter. GABA receptor is site of benzodiazepine action. GABA levels and endogenous benzodiazepines are elevated in hepatic failure. Enteric bacteria produce GABA and this may be absorbed across gut. Flumazenil anecdotally improves encephalopathy.

Hirnödem und intrakranielle Hypertonie

conclusions

Cerebral Edema

• Etiology uncertain -- Correlated with degree of encephalopathy. Occurs in 50 - 85% of patients with late grade 3 to grade 4 encephalopathy.

• Evidence of altered blood brain barrier

• Impaired cellular Na+K+ -ATP pump resulting in glial cell edema

• Inappropriate cerebral vasodilatation

Cerebral Edema

Clinical signs of increased ICP (may not be present until late)

• Increased muscle tone

• Dilated sluggish pupils

• Hyperventilation

• Cushing reflex (very late)

Inflammation und Infektion

Inflammation and Infection

• 60% aller Patienten mit ALF erfüllen die SIRS Kriterien

• Progression der HE sowie Verschlechterung der Prognose

• Eingeschränkte Immunabwehr prädisponiert zu bakteriellen und fungalen Infektionen mit weiterer Verschlechterung der HE

• Prophylaktische AB-Regimes reduzieren Inzidenz an Infektionen

Cerebraler Blutfluss

Noradrenalin Terlipressin

Behandlung

Treatment

– Protect airway -- Most patients with grade III to IV should be intubated.

– Adequate sedation (Propofol preferred)

– Relaxation with Atracurium

– Avoid secondary brain injuries

– Treat precipitating factors for hepatic encephalopathy vigorously

Treatment

– Prevent hypotension

– Lactulose -- although not shown to work well in FHF and felt to be less effective than in chronic liver disease.

– Branch chain amino acids -- theoretically appealing but studies are mixed results -- most authors feel they are not helpful.

Treatment – Beware and intervene for cerebral edema – ICP monitoring -- somewhat controversial because

studies have not shown altered outcome and risk is significant because of coagulopathy. Reasons favoring monitoring: • Intracranial hypertension is erratic and can develop

rapidly with few clinical signs • Monitoring allows for early detection and minute-to-

minute titration of therapy • Cerebral perfusion pressure is prognostic sign and would

spare poor risk patients a transplant (CPP < 50 for 2 hrs) • Allows management of intraoperative events

Treatment

– Mannitol -- shown to be effective in improving outcome, hypertonic saline probably preferred

– Hyperventilation -- probably useful for acute spikes in ICP. Has not been shown to be effective in hepatic failure. Concerns about effect on cerebral perfusion warrant consideration.

– Elevation of head -- ?? What is effect on CPP? Keep head midline, perhaps 20 - 30 degrees of elevation.

– Pentobarbital coma, hypothermia -- unproven, occasionally may be indicated.

– Steroids -- no good, may worsen outcome

Correlation between sodium and ICP

Effective for sodium increase in serum

Less Norepinephrine

Better ICP control

Treatment

Get better liver

Get liver better

Indikationen zur Verlegung in ein Leberzentrum

Take home messages

Dr. Roger Lussmann

Any questions ?

15.01.2013 Dr. R. Lussmann

17. St.Galler IPS-Symposium 2013 Weiter- und Fortbildungstag … · 2018-04-11 · St.Galler...

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