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?
15.01.2013 Dr. Roger Lussmann 2
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
15.01.2013 Dr. Roger Lussmann 3
15.01.2013 Dr. Roger Lussmann 4
15.01.2013 Dr. Roger Lussmann 5
15.01.2013 Dr. Roger Lussmann 6
Hepatic Encephalopathy
Hepatic encephalopathy reflects a spectrum of
neuropsychiatric abnormalities seen in patients with
liver dysfunction after exclusion of other known
brain disease.
15.01.2013 Dr. Roger Lussmann 7
15.01.2013 Dr. Roger Lussmann 8
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
15.01.2013 Dr. Roger Lussmann 9
15.01.2013 Dr. Roger Lussmann 10
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
Yes
Yes
Yes
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
Mild
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
© 20 Macmillan Publishers Limited. All rights reserved10
15.01.2013 Dr. Roger Lussmann 11
15.01.2013 Dr. Roger Lussmann 12
15.01.2013 Dr. Roger Lussmann 13
15.01.2013 Dr. Roger Lussmann 14
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)
15.01.2013 Dr. Roger Lussmann 15
Hepatic Encephalopathy
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.
15.01.2013 Dr. Roger Lussmann 16
15.01.2013 Dr. Roger Lussmann 17
15.01.2013 Dr. Roger Lussmann 18
15.01.2013 Dr. Roger Lussmann 19
15.01.2013 Dr. Roger Lussmann 20
15.01.2013 Dr. Roger Lussmann 21
Hirnödem und intrakranielle Hypertonie
15.01.2013 Dr. Roger Lussmann 22
15.01.2013 Dr. Roger Lussmann 23
15.01.2013 Dr. Roger Lussmann 24
15.01.2013 Dr. Roger Lussmann 25
conclusions
15.01.2013 Dr. Roger Lussmann 26
Hepatic Encephalopathy
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
15.01.2013 Dr. Roger Lussmann 27
Hepatic Encephalopathy
Cerebral Edema
Clinical signs of increased ICP (may not be present until late)
• Increased muscle tone
• Dilated sluggish pupils
• Hyperventilation
• Cushing reflex (very late)
15.01.2013 Dr. Roger Lussmann 28
Inflammation und Infektion
15.01.2013 Dr. Roger Lussmann 29
15.01.2013 Dr. Roger Lussmann 30
15.01.2013 Dr. Roger Lussmann 31
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
15.01.2013 Dr. Roger Lussmann 32
Cerebraler Blutfluss
15.01.2013 Dr. Roger Lussmann 33
15.01.2013 Dr. Roger Lussmann 34
Noradrenalin Terlipressin
Noradrenalin Terlipressin
15.01.2013 Dr. Roger Lussmann 35
Behandlung
15.01.2013 Dr. Roger Lussmann 36
15.01.2013 Dr. Roger Lussmann 37
15.01.2013 Dr. Roger Lussmann 38
Hepatic Encephalopathy
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
15.01.2013 Dr. Roger Lussmann 39
15.01.2013 Dr. Roger Lussmann 40
15.01.2013 Dr. Roger Lussmann 41
15.01.2013 Dr. Roger Lussmann 42
Hepatic Encephalopathy
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.
15.01.2013 Dr. Roger Lussmann 43
Hepatic Encephalopathy
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
15.01.2013 Dr. Roger Lussmann 44
15.01.2013 Dr. Roger Lussmann 45
15.01.2013 Dr. Roger Lussmann 46
Hepatic Encephalopathy
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
15.01.2013 Dr. Roger Lussmann 47
15.01.2013 Dr. Roger Lussmann 48
Correlation between sodium and ICP
15.01.2013 Dr. Roger Lussmann 49
Effective for sodium increase in serum
15.01.2013 Dr. Roger Lussmann 50
Less Norepinephrine
15.01.2013 Dr. Roger Lussmann 51
Better ICP control
15.01.2013 Dr. Roger Lussmann 52
Better ICP control
15.01.2013 Dr. Roger Lussmann 53
Hepatic Encephalopathy
Treatment
Get better liver
or
Get liver better
15.01.2013 Dr. Roger Lussmann 54
15.01.2013 Dr. Roger Lussmann 55
Indikationen zur Verlegung in ein Leberzentrum
15.01.2013 Dr. Roger Lussmann 56
15.01.2013 Dr. Roger Lussmann 57
15.01.2013 Dr. Roger Lussmann 58
15.01.2013 Dr. Roger Lussmann 59
15.01.2013 Dr. Roger Lussmann 60
15.01.2013 Dr. Roger Lussmann 61
15.01.2013 Dr. Roger Lussmann 62
15.01.2013 Dr. Roger Lussmann 63
15.01.2013 Dr. Roger Lussmann 64
15.01.2013 Dr. Roger Lussmann 65
15.01.2013 Dr. Roger Lussmann 66
15.01.2013 Dr. Roger Lussmann 67
15.01.2013 Dr. Roger Lussmann 68
15.01.2013 Dr. Roger Lussmann 69
15.01.2013 Dr. Roger Lussmann 70
15.01.2013 Dr. Roger Lussmann 71
15.01.2013 Dr. Roger Lussmann 72
Take home messages
15.01.2013 Dr. Roger Lussmann 73
15.01.2013 Dr. Roger Lussmann 74
Dr. Roger Lussmann
Any questions ?
15.01.2013 Dr. R. Lussmann