MINISTRY OF HEALTH OF UKRAINE

Vinnitsa national medical university of N.I.Pirogova

“Approved"
At methodical meeting of chair
Internal medicine №1
Head of the department

____________ prof. Stanislavchuk M. A.

«30» August 2021

METHODICAL RECOMMENDATIONS
For students

Subject matter Internal medicine

Module Emergencies in the clinic of internal medicine
Substantial module № 1 Emergencies in the clinic of internal medicine
Subject of the lesson Management of a patient with a coma.
Course 6
Faculty Medical # 1

Vinnytsya 2021
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1. Topicality: Hepatic encephalopathy (HE) is a common, worrisome and sometimes difficult to manage
complication of end-stage liver disease. HE is often recurrent, requiring multiple hospital admissions. It
can have serious implications in terms of a patient’s ability to perform complex tasks (for example
driving), their earning capacity, their social and family roles.
Hepatic encephalopathy is also described in patients without cirrhosis with either spontaneous or
surgically created portosystemic shunts. The development of hepatic encephalopathy is explained, to
some extent, by the effect of neurotoxic substances, which occurs in the setting of cirrhosis and portal
hypertension.

2. Educational goal:

2.1. The student must know:

1. Determine main etiological factors of coma
2. Define the clinical symptoms of Hepatic encephalopathy
3. Make the plan of additional investigation of the patient and analyze their results.
4. Make the clinical diagnosis of the patient with Hepatic encephalopathy
5. Prescribe the proper treatment.

2.2. The student must be able:

1.To choose the symptoms of Hepatic encephalopathy
2. To make the scheme of investigation for the determination of the cause of coma.
4. To assess the result of lab tests.
5. To determinate the treatment depending on the cause of coma .
6. To prescribe the proper treatment for the patient with Hepatic encephalopathy, coma.

3. CONTENTS OF THE TRAINING MATERIALS:

Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver
dysfunction, after exclusion of brain disease. Hepatic encephalopathy is characterized by personality
changes, intellectual impairment, and a depressed level of consciousness. [An important prerequisite for
the syndrome is diversion of portal blood into the systemic circulation through portosystemic collateral
vessels.
Hepatic encephalopathy, accompanying the acute onset of severe hepatic synthetic dysfunction, is the
hallmark of acute liver failure (ALF). Symptoms of encephalopathy in ALF are graded using the same
scale used to assess encephalopathy symptoms in cirrhosis. The encephalopathy of cirrhosis and ALF
share many of the same pathogenic mechanisms. However, brain edema plays a much more prominent
role in ALF than in cirrhosis. The brain edema of ALF is attributed to increased permeability of the
blood-brain barrier, impaired osmoregulation within the brain, and increased cerebral blood flow. The
resulting brain cell swelling and brain edema are potentially fatal. In contrast, brain edema is rarely
reported in patients with cirrhosis.
A number of theories have been proposed to explain the development of hepatic encephalopathy in
patients with cirrhosis. Some investigators contend that hepatic encephalopathy is a disorder of astrocyte
function. Astrocytes account for about one third of the cortical volume. They play a key role in the
regulation of the blood-brain barrier. They are involved in maintaining electrolyte homeostasis and in
providing nutrients and neurotransmitter precursors to the neurons. They also play a role in the
detoxification of a number of chemicals, including ammonia. [13]
It is theorized that neurotoxic substances, including ammonia and manganese, may gain entry into the
brain in the setting of liver failure. These neurotoxic substances may then contribute to morphologic
changes in the astrocytes. In cirrhosis, astrocytes may undergo Alzheimer type II astrocytosis. Here,
astrocytes become swollen. They may develop a large pale nucleus, a prominent nucleolus, and
margination of chromatin. In ALF, astrocytes may also become swollen. The other changes of Alzheimer
type II astrocytosis are not seen in ALF. But, in contrast to cirrhosis, astrocyte swelling in ALF may be so
marked as to produce brain edema. This may lead to increased intracranial pressure and, potentially, brain
herniation.
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Grading of Hepatic encephalopathy

Grade 0 - Subclinical;
normal mental status, but minimal changes in memory, concentration, intellectual function, coordination
Grade 1 - Mild confusion, euphoria or depression, irritability.
Poor concentration, slurred speech, slow mentation, slowing of ability to perform mental tasks, disorder
of sleep rhythm (inverted sleep cycle - "day-night reversal"). Impairment in spatial perception (poor
ability to copy or draw simple images - cube).
Grade 2 - Lethargy or apathy, occasional inappropriate aggressive behaviour.
Subtle personality change; gross deficits in ability to perform mental tasks. Drowsiness
intermittent disorientation for time or place.
Ataxy, dysarthria, dysgraphia, asterixis, hyperreflexion appears.
Grade 3 - Somnolence to semistupor - sleepy but responds to pain and voice (to verbal stimuli);
Marked confusion;
Gross disorientation, unable to perform mental tasks, disorientation to time and place, amnesia, speech is
present but incomprehensible.
Jaundice, Hemorrhagy

Grade 4 - Coma - unconscious, unresponsive to painful, verbal or other stimuli.

With minimal hepatic encephalopathy, patients may have normal abilities in the areas of memory,
language, construction, and pure motor skills. However, patients with minimal hepatic encephalopathy
demonstrate impaired complex and sustained attention. They may have delay in the choice reaction time.
They may even have impaired fitness to drive. [27, 28, 29] Typically, patients with minimal hepatic
encephalopathy have normal function on standard mental status testing but abnormal psychometric
testing. Neurophysiologic tests in common use are the number connection test, the digit symbol test, the
block design test, and tests of reaction times to light or sound (eg, critical flicker test).
Patients with grade 1 hepatic encephalopathy typically demonstrate decreased short-term memory and
concentration on mental status testing. However, grade 1 hepatic encephalopathy may be difficult to
diagnose. The presence of disorientation and asterixis are characteristic of grade 2 hepatic
encephalopathy.
The borderline between covert and overt hepatic encephalopathy is being redrawn. Until recent years, the
term "overt" hepatic encephalopathy was applied to patients with grades 1 through 4 encephalopathy.
Now, patients with grades 0 and 1 hepatic encephalopathy are said to be "covert"; patients with grades 2
through 4 hepatic encephalopathy are said to be "overt."
In terms of the physical examination finding of asterixis, it must be emphasized that the flapping tremor
of the extremities is also observed in patients with uremia, pulmonary insufficiency, and barbiturate
toxicity.
Some patients with hepatic encephalopathy show evidence of fetor hepaticus, a sweet musty aroma of the
breath believed to be secondary to the exhalation of mercaptans.
Other potential physical examination findings include hyperventilation and decreased body temperature.
Extrapyramidal symptoms—including tremor, bradykinesia, cog-wheel rigidity, and shuffling gait—have
been described in patients with portosystemic shunting. These symptoms may or may not be associated
with hyperammonemia. It is postulated that manganese deposition in the basal ganglia may predispose
patients to develop these symptoms. However, some patients with the "Parkinsonian phenotype of hepatic
encephalopathy" may respond to treatment with rifaximin.
Another neurologic condition that may be seen in the setting of portosystemic shunting is hepatic
myelopathy. It is a rare condition that has been described in patients with cirrhosis of varying degrees of
severity, patients who have undergone portosystemic shunt surgery or the creation of a transjugular
intrahepatic portosystemic shunt (TIPS), and noncirrhotic patients with portosystemic shunts. Patients
may present with lower extremity weakness, difficulty walking, spastic paraparesis, and
hyperreflexia. Although patients typically have concomitant hepatic encephalopathy, this is not
invariable. Symptoms may be rapidly progressive in some patients. Neurologic deficits do not typically
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respond to standard medical therapies for hepatic encephalopathy. Neurologic improvement has been
described after TIPS closure and after liver transplantation.

Differential diagnoses of encephalopathy are as follows :

● Intracranial lesions, such as subdural hematoma, intracranial bleeding, stroke, tumor, and abscess
● Infections, such as meningitis, encephalitis, and intracranial abscess
● Metabolic encephalopathy, such as hypoglycemia, electrolyte imbalance, anoxia, hypercarbia, and
uremia
● Hyperammonemia from other causes, such as ureterosigmoidostomy and inherited urea cycle
disorders
● Toxic encephalopathy from alcohol intake, such as acute intoxication, alcohol withdrawal, and
Wernicke encephalopathy
● Toxic encephalopathy from drugs, such as sedative hypnotics, antidepressants, antipsychotic
agents, and salicylates
● Organic brain syndrome
● Postseizure encephalopathy

Approach Considerations
The approach to a patient with hepatic encephalopathy depends upon the severity of mental status
changes and upon the certainty of the diagnosis. As an example, a patient with known cirrhosis and mild
complaints of decreased concentration might be served best by an empiric trial of rifaximin or lactulose
and a follow-up office visit to check its effect. However, a patient presenting to the emergency
department with severe hepatic encephalopathy requires a different approach. General management
recommendations include the following:
● Exclude nonhepatic causes of altered mental function.
● Consider checking an arterial ammonia level in the initial assessment of a hospitalized patient
with cirrhosis and with impaired mental function. Ammonia levels have less use in a stable outpatient.
● Precipitants of hepatic encephalopathy, such as hypovolemia, metabolic disturbances,
gastrointestinal bleeding, infection, and constipation, should be corrected.
● Avoid medications that depress central nervous system function, especially benzodiazepines.
Patients with severe agitation and hepatic encephalopathy may receive haloperidol as a sedative. Treating
patients who present with coexisting alcohol withdrawal and hepatic encephalopathy is particularly
challenging. These patients may require therapy with benzodiazepines in conjunction with lactulose and
other medical therapies for hepatic encephalopathy.
● Patients with severe encephalopathy (ie, grade 3 or 4) who are at risk for aspiration should
undergo prophylactic endotracheal intubation. They are optimally managed in the intensive care unit.
Most current therapies are designed to treat hyperammonemia that is a hallmark of most cases of hepatic
encephalopathy.
Treatments to Decrease Intestinal Ammonia Production
Diet
Diets containing vegetable proteins appear to be better tolerated than diets rich in animal protein,
especially proteins derived from red meats. This may be because of increased content of dietary fiber, a
natural cathartic, and decreased levels of aromatic amino acids. Aromatic amino acids, as precursors of
the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic
neurotransmission and worsen hepatic encephalopathy.
The author recommends that patients consume well-cooked chicken and fish in addition to vegetable
proteins. Malnourished patients are encouraged to add commercially available liquid nutritional
supplements to their diet. Patients rarely require specialized treatment with oral or enteral supplements
rich in branched-chain amino acids.
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Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable

disaccharides that have been in common clinical use since the early 1970s (the latter is not available in
the United States). They are degraded by intestinal bacteria to lactic acid and other organic acids.
Lactulose appears to inhibit intestinal ammonia production by a number of mechanisms. The conversion
of lactulose to lactic acid and acetic acid results in the acidification of the gut lumen.
This favors conversion of ammonia (NH3) to ammonium (NH4+); owing to the resultant relative
impermeability of the membrane, the NH4+ ions are not easily absorbed, thereby remaining trapped in the
colonic lumen, and there is a reduction in plasma NH3.
Gut acidification inhibits ammoniagenic coliform bacteria, leading to increased levels of
nonammoniagenic lactobacilli.
Lactulose also works as a cathartic, reducing colonic bacterial load.
Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may be increased as tolerated.
Patients should be instructed to reduce lactulose dosing in the event of diarrhea, abdominal cramping, or
bloating. Patients should take sufficient lactulose as to have 2-4 loose stools per day.

Antibiotics
Neomycin and other antibiotics, such as metronidazole, oral vancomycin, paromomycin, and oral
quinolones, are administered in an effort to decrease the colonic concentration of ammoniagenic bacteria.
Initial neomycin dosing is 250 mg orally 2-4 times a day. Doses as high as 4000 mg/d may be
administered. Neomycin is usually reserved as a second-line agent, after initiation of treatment with
lactulose. Long-term treatment with this oral aminoglycoside runs the risks of inducing ototoxicity and
nephrotoxicity because of some systemic absorption.
Rifaximin a nonabsorbable derivative of rifampin, has been used in Europe for more than 20 years for a
wide variety of gastrointestinal indications. Multiple clinical trials have demonstrated that rifaximin at a
dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactitol at improving hepatic
encephalopathy symptoms.

Treatments to Increase Ammonia Clearance

L-ornithine L-aspartate (LOLA)
LOLA (Hepa-Merz) is available in Europe in both intravenous formulations and oral formulations. It is
not available in the United States. LOLA is a stable salt of the two constituent amino acids. L-ornithine
stimulates the urea cycle, with resulting loss of ammonia. Both l-ornithine and l-aspartate are substrates
for glutamate transaminase. Their administration results in increased glutamate levels. Ammonia is
subsequently used in the conversion of glutamate to glutamine by glutamine synthetase.

Zinc deficiency is common in cirrhosis. Even in patients who are not zinc deficient, zinc administration
has the potential to improve hyperammonemia by increasing the activity of ornithine transcarbamylase,
an enzyme in the urea cycle.
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Adult Glasgow Coma Scale

The Glasgow Coma Scale (GCS) is used to describe the general level of consciousness in
patients with traumatic brain injury (TBI) and to define broad categories of head injury. [1] The
GCS is divided into 3 categories, eye opening (E), motor response (M), and verbal response
(V). The score is determined by the sum of the score in each of the 3 categories, with a
maximum score of 15 and a minimum score of 3, as follows:
GCS score = E + M + V
Glasgow Coma Scale Calculator.
Eye opening scores
See the list below:
● 4: Spontaneously
● 3: To verbal command
● 2: To pain
● 1: No response
Best motor response scores
See the list below:
● 6: Obeys command
● 5: Localizes pain
● 4: Flexion withdrawal
● 3: Flexion abnormal (decorticate)
● 2: Extension (decerebrate)
● 1: No response
Best verbal response scores
See the list below:
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● 5: Oriented and converses

● 4: Disoriented and converses
● 3: Inappropriate words; cries
● 2: Incomprehensible sounds
● 1: No response
Interpretation
Patients who are intubated are unable to speak, and their verbal score cannot be assessed.
They are evaluated only based on eye opening and motor scores, and the suffix T is added to
their score to indicate intubation. In intubated patients, the maximum GCS score is 10T and
the minimum score is 2T. The GCS is often used to help define the severity of TBI. Mild head
injuries are generally defined as those associated with a GCS score of 13-15, and moderate
head injuries are those associated with a GCS score of 9-12. A GCS score of 8 or less defines
a severe head injury. These definitions are not rigid and should be considered as a general
guide to the level of injury.

Management of patient with coma

Situation task 1.

Patient K., 31, nurse, sick more than 10 years with chronic hepatitis after viral hepatitis B. Her status had
was worsened after flu 16.09.09: malaise, nausea, vomiting, pain in the joints were appeared. In 09/21/2009
urea became darkened, jaundice appears. In 1/09/2009 she was hospitalized.
Physical exam: the state of moderate gravity, t ° body - 38,2 ° C, expressed jaundice of skin and mucous
membranes, liver edge + 3 cm below the rib arch, spleen is enlarged. 26/9/2009 abdominal pain and sleep
abnormality appeared. 9/27/2009 hematomas appear in injection places with single petehiyi, liver breath
odor; pitting edema of feet and lumbar area.
1. Your diagnosis
2. Additional investigations
3. Treatment of the patient

Situation task 2.
The patient T., 48 years, was admitted to ICU. The patient doesn’t understand the purpose of his
hospitalization.
Patient is aggressive, poorly understands the questions put to him, and gives in inadequate answers. He is
untidy; there is a flapping tremor of his hands, horizontal nystagmus, and sickly-sweet smell. RR -24/min.
Above the lungs - vesicular breathing. BP - 110/70 mm Hg, HR -120/min. Abdomen enlarge due to
bloating and ascites, on the anterior abdominal wall there are dilated veins, the liver + 5 cm from the
costal arch.
On the eve of the patient did not drink alcohol, but ate meat. The disease began with sleep disorders. The
patient could not sleep at night and become somnolent during the day. The patient abused alcohol for
many years.
1. Make a diagnosis.
2. Emergency treatment.
3. Which groups of medicine are contraindicated to patient?

Recommended literature for students:

А. Main:
1. Davidson’s Principles and Practice of Medicine, 22nd Edition, 2014.
2. Harrison's Principles of Internal Medicine, 20e J. Larry Jameson, Anthony S. Fauci, Dennis L. Kasper,
Stephen L. Hauser, Dan L. Longo, Joseph Loscalzo) – part 10 -chapter 337.
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B. Additional:
1 - https://www.dldjournalonline.com/article/S1590-8658(18)31274-X/fulltext
2 - https://reference.medscape.com/article/186101-overview

Methodical recommendation made by Ph.D. Berko G.K.

Ph.D Ostapchuk O.I