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Hepatic Coma
Hepatic Coma LESLIE ZIEVE, M.D., F.A.C.P. Chief, Radioisotope Service, and Associate Chief of Staff, Veterans Administration Hospital, ilfinneapolis, Minnesota; Associate Professor of Medicine, University of Minne80ta Medical School
HEPATIC COMA is a disorder of consciousness occurring in patients with severe liver disease; a neuropsychiatric disturbance with no striking or specific anatomic basis. The manifestations may be extreme, yet are entirely reversible, and the brain does not show pathologic changes that will account for the symptoms. Prior to the last decade there was little confusion regarding definition of this syndrome. Any patient with severe liver disease who was unconscious or somnolent or stuporous was said to be in hepatic coma or precoma. We now know that some of these episodes were instances of sodium or potassium deficit compounding the abnormalities of the decompensated liver. Others were the consequence of various and sundry therapeutic agents provided by the well-in tentioned physician in his treatment of the liver disease. Spontaneous hepatic coma is usually a terminal complication of cirrhosis or hepatitis with severe acute necrosis. The neuropsychiatric sequence is typically mental clouding, confusion, inappropriate behavior, increased psychomotor activity followed by decreased psychomotor activity, progressive somnolence, stupor and coma. Neurologically there is intermittency of muscle contractions with fluctuating rigidity of the limbs, flapping movement of the outstretched hands, arms and legs, grimacing, grasping, sucking, exaggerated reflexes, and occasionally convulsions. l Throughout hyperventilation is evident. It follows a crescendo course, and terminally the breathing is stertorous. The patient whose hepatic status has been deteriorating may lapse into coma spontaneously as a result of nearly complete destruction of his liver. Usually, however, some precipitating factor intervenes before this extremity is reached.
PRECIPITATING FACTORS
The ease with which coma is induced by various precipitating factors is directly correlated with the extent and acuteness of hepatic decompensation. Gastrointestinal bleeding, usually from esophageal varices, but also from peptic ulceration, is the most common precipitating factor.
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Blood protein breakdown products and ammonia, which ordinarily come in contact with hepatic cells and are processed before they can reach the systemic circulation, are shunted around the liver via the collateral circulation that is ordinarily present, or pass through areas of the damaged liver containing no functioning hepatic cells. Shock and anoxia following bleeding may contribute to the harmful cerebral effects of the intestinal nitrogenous products of protein breakdown, or shock may result from other causes and compromise cerebral blood flow sufficiently to precipitate coma. Severe infections, particularly bacteremias secondary to pneumonia or pyelonephritis, not infrequently usher in an episode of coma. Sedatives of any type may precipitate coma in the patient with severely decompensated liver disease, though they are tolerated well, as a rule, when he is not decompensated. Paraldehyde and chloral hydrate arc almost as noxious as narcotics and barbiturates in this respect. Excitement is frequent in the precomatose state of hepatic failure and the physician has to resist the temptation to quiet the patient with sedatives. Paracentesis was at one time the commonest immediate cause of hepatic coma. However, it is now generally realized that little is gained by massive paracenteses, and valuable protein and electrolytes are lost. Ascitic fluid is in dynamic equilibrium with the circulation and removal of large amounts of abdominal fluid causes rapid fluid and electrolyte shifts. Hyponatremia and hypokalemia with their attendant cerebral and renal effects are common consequences. Added to the abnormalities already present in the severe cirrhotic, they may precipitate a difficultly reversible chain of reactions leading to hepatic coma. Diuretics of any type may have effects similar to paracentesis if the diuresis and loss of electrolytes are massive. Chlorothiazide derivatives are particularly noxious because of the consequences of excessive potassium loss. Ammonia producers are recognized today as common precipitating agents in cirrhotics with prominent collateral circulation particularly. Ammonium chloride, ammonia-producing resins, and Diamox are very poorly tolerated. Chlorothiazide also seems to function as an ammonia producer and is poorly tolerated. Excessive protein in the gut, either as food or from internal bleeding, may precipitate coma. Methionine may also produce neurologic changes. Surgical procedures may lead to hepatic coma by a compounding of predisposing factors already mentioned, e.g., the effects of hypnotics and analgesics, anesthetics, hypoxia, trauma, blood loss, shock, and water and electrolyte imbalance. CLINICAL PICTURE
The usual sequence of development of symptoms and signs follows, more or less, the order of the tabulation in Table 1. The mental and
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Table 1.
Symptoms and Signs of Hepatic Coma
MEN'l'AL STATE
Clouding Confusion Restlessness Irritability Inappropriate behavior Sullen, paranoid, disobedient Picking and rearranging bedclothes Yawning Sucking Crying Agitation Disorientation Delirium Drowsiness Somnolence Lethargy Apathy Stupor Coma
NEUROMUSCULAR STA'l'E
Incoordination Tremor Dysarthria Grasping Hiccoughing Deliberate movement Cogwheel rigidity Masklike fascies Dilated pupils Roving eyes Muscle twitching Convulsions Flexion of legs Flapping tremor Hyperrefiexia Positive toe signs Nystagmus Ophthalmoplegia Incontinence
neuromuscular abnormalities develop in parallel fashion. The electroencephalogram shows a characteristic change in most patients. Bilaterally there are slow delta waves in bursts of 2 or 3 per second, most marked over the frontal areas.! The onset of precoma is most often insidious with quiet confusion, but may be abrupt and violent. Quiet confusion, lethargy, and stupor typically precede the coma of cirrhosis. However, the coma of acute atrophy is often preceded by mania, delirium and convulsionsY The sequence outlined is not inevitably progressive, there being swings up and down the scale of manifestations. Speed of progression is highly variable, from a few hours to a few weeks, to cite the extremes. Respirations are characteristically increased in rate and amplitude, though the hyperventilation may not be apparent in the earlier stages. As the precorna progresses into coma the breathing becomes stertorous. An amine-like odor, fetor hepaticus, is commonly exhaled by patients developing hepatic coma. It is much more prominent in the presence of acute atrophy than in cirrhosis. The cause of the odor is unknown, though there is reason to suspect some derivative of methyl mercaptan. 4 Once deep coma supervenes death usually follows in a matter of hours or a few days, though exceptions have been seen in which deep coma has lasted two to three weeks. BIOCHEMICAL CHANGES LIVER FUNCTION TESTS. Tests of liver function are generally severely deranged in the spontaneous cases of coma, but do not differ in this respect from patients with severe hepatic disease without coma. Bili-
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rubinemia often increases, but individual cases are observed that have practically no jaundice. Hypoglycemia is rare in hepatic coma, hyperglycemia being more frequent, since it is a common accompaniment of cirrhosis. When hypoglycemia occurs, it is usually in association with widespread acute necrosis. ELECTROLYTE ABNORMALITIES. Hyponatremia is common despite sodium retention. Values of serum sodium under 130 mEq./l. are frequent. If acute loss of sodium occurs, as after large paracenteses, a low salt syndrome may occur with transition into frank hepatic coma. Hypokalemia .and hypomagnesemia are common but not invariable. Values of serum potassium below 3.0 mEq./l. and of serum magnesium below 1.6 mEq.jl. are frequent. There is probably a severe intracellular deficit of these ions which mayor may not be reflected in the serum levels. In terminal phases of hepatic coma, the serum concentrations may actually be high as renal failure ensues. Correction of body potassium and magnesium deficits is usually difficult and requires care and persistence. During hepatic precoma patients will often perk up considerably simply upon improvement of their electrolyte deficiencies. Not uncommonly the deficit in sodium, potassium or magnesium is so extreme that a state of lethargy, apathy and stupor results which is entirely corrected by replacement therapy. Hypocalcemia and hypophosphatemia arc also frequent as a complication of decompensated cirrhosis. 2 Values of calcium below 4.2 mEq.jl. and of phosphorus below 1.2 mEq.jl. are not uncommon. ACID-BASE BALANCE. There is no characteristic acid-base picture in any given patient with hepatic coma. Depending upon the extent, duration and severity of his respiratory or electrolyte abnormality, one may find him in respiratory alkalosis, metabolic alkalosis or metabolic acidosis. Examples are shown in Figure 1. If hypopotassemia is not present, the patient will generally be in compensated or uncompensated respiratory alkalosis1s early in his course because of hypocapnia reSUlting from persistent hyperventilation which develops early in the interval of precoma. This results in a progressive accumulation of pyruvic and lactic acid (and probably other organic acids such as alpha-ketoglutaric acid) and a progressive bicarbonate deficit in the blood, which if severe enough results in metabolic acidosis. 6 This was the case with patient number 5 in Figure 1. Renal failure, which commonly supervenes, may compound this problem. In advanced coma, acidosis is probably more frequently seen than respiratory alkalosis. The rise in blood pyruvic and lactic acid in hepatic coma has been attributed to some unknown disturbance in intermediary metabolism associated with liver failure. We now know from the work of Eichenholz and collaborators5 that accumulation of these organic acids in hepatic failure, as in practically all other diseases in which they accumulate in
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Fig. 1. Examples of acidbase status in five patients with hepatic coma. Cases 1, 2 and 3 are examples of mixed respiratory and metabolic alkalosis. Case 4 is an example of compensated respiratory alkalosis; and Case 5 is an example of severe metabolic acidosis. (Data of Dr. A. Eichenholz.)
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the blood, is directly correlated with a reduction in CO 2 tension resulting from hyperventilation. If hypopotassemia is prominent, a metabolic alkalosis will be found which responds to correction of the potassium deficit. Since all of the etiologic factors affecting the blood pH are present to varying degree, it is less common to see pure examples of acid-base imbalance than confusing mixtures. The contribution of acid-base imbalance to the mortality from hepatic coma has never been adequately assessed. I suspect it plays a central role. As clinicians it behooves us to secure routinely in these cases the three measurements-pH, pC02, and bicarbonate concentration--essential to an understanding of acid-base status. Therapy for the acid-base disturbance cannot be safely undertaken without knowing precisely where a patient's value falls on a three-variable plot such as that of Figure 1. To take an extreme example, treatment of a patient such as Case 5 with CO 2 inhalations, without first correcting the bicarbonate deficit, would be rapidly fatal, since the plotted point would move, roughly, to the ordinate of 10 mM';l. and pH of 6.95 as the pC02 returned to normal. Similarly the fully compensated value for Case 4 would move approximately to the ordinate of 17.5 mM./l. and pH of 7.25 as the pC0 2 returned to normal, the patient meanwhile becoming sicker. It is evident that CO 2 inhalation is not a very satisfactory form of therapy for hepatic coma. By contrast one would anticipate that bicarbonate replacement would be valuable if the plotted point falls below the normal buffer slope and potassium replacement valuable if the plotted point falls above the normal buffer slope. In addition to a lowering of the carbon dioxide tension in the blood, patients in hepatic coma commonly have a reduced oxygen tension and a decreased saturation of hemoglobin. This decrease in oxygen saturation
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(hypoxemia) is not specific to hepatic coma, being present in the same patients (with cirrhosis) before they develop hepatic failure. Warren and Schenker23 recently showed in mice that hypoxia directly potentiated the toxic effect of ammonia on the brain. BLOOD AMMONIA. The first major study of blood ammonia in liver disease was by Esben Kirk in 1936.1° He observed very small amounts of preformed ammonia in normal persons and abnormal concentrations in cirrhotics. Parnas and Klisieckjl4 had shown in 1926 that large amounts of ammonia are formed in the gastrointestinal tract by baeterial action and that portal vein blood contains two to eight times as much ammonia as the systemic circulation. Kirk performed ammonia tolerance tests, feeding 10 grams of ammonium citrate. There were at most slight rises in blood ammonia concentration in normal subjeets, but considerable increases in mo,;t patients with cirrhosis. A good correlation between blood ammonia value,; and ,;everity of the cirrhosis was not observed. Kirk suggested the observed abnormality of blood ammonia was probably correlated with the collateral circulation developed in cirrhosi,; rather than hepatoedlular dysfunetion per se. These observations have been verifif~d repeatedly since the rediscovery in 1952 of the importance of ammonia and protein breakdown products in paticnts with portal-systemif: venou,; ::;hunting of blood. B, 15 In hepatic precoma or coma the blood ammonia is frequently devated but may be normal. The correlation between blood ammonia concentration and severity of the coma is significant but not high.1 6 Whether or not a high correlation exists between brain (intracellular) ammoma concentration and severity of hepatic coma is unknown. AMINO ACIDS. Aminoaciduria, especially cystinuria, IS common. Walshe 19 ,21 observed an increase in urine content of all the commOIl amino acids in advanced liver disease. Generally, plasma concentratiom; were only slightly elevated. The amino acids excreted in largest amounts were cystine, {:J-aminoisobutyric acid, methylhistidine and taurine. Uro(:anic acid, a metabolic product of histidine and an intermediate in the conversion of histidine to glutamic acid, has been found in increased amounts in the urine of a patient in hepatic comaY In three patients in coma, Walshe 21 observed increased blood amino acids and an abnormal pattern of amino acids in the spinal fluid. An excess of glutamine was found in the spinal fluid of all three and glutamic acid and methionine sulfoxide were present in two. Flock and co-worken;7 have also observed increased concentrations of glutamine in the brain of hepatectomized dogs. Gilon and co-workers 9 recently found the spinal fluid glutamine concentration elevated in all of 26 patients with hepatic coma studied. Only in patients with hepatic coma did values exceed 35 mg./lOO m!. (23 of 26 cases). A good correlation was observed within a given patient between the glutamine level and the severity of coma.
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SPINAL FLUID. A rise in bilirubin content which is not well correlated with blood levels is often seen. Protein content also rises. The amino acid content also rises and glutamine particularly is present in excess. The ammonia content is variable. Rl<~NAL FUNCTION. In decompensated cirrhosis the glomerular filtration rate and renal blood flow are reduced, markedly in the presence of ascites. In hepatic coma oliguria is frequent, and with progression azotemia is common. Occasionally the picture of acute renal insufficiency is very prominent. TYPES OF HEPATIC COMA AND PATHOGENESIS
Episodes of hepatic coma may be classified as spontaneous or induced. The clinical manifestations of both types are similar, a fact that often makes their differentiation difficult. The spontaneous cases have no evident precipitating factor, being simply the final consequence of practically complete liver cell destruction. The induced cases are precipitated by known agents or abnormalities. The difference between the two types is easily stated, but often in practical fact very slight. As liver destruction proceeds, metabolic and circulatory alterations are produced which enhance the susceptibility of the individual to inducing agents. So the patient who is most likely to lapse into spontaneom; hepatic coma is also most likely to have his coma induced by an exogenous agent. However, this is not necessarily so, and coma is often induced in patients with fairly good hepatic function. The predisposition to coma from exogenous agents is a result of the development of portal-systemic collaterals (shunts), electrolyte and add-base imbalances, and hypoxemia and hypoxia. Of greatest importance are the portal-systemic shunts which develop naturally in the eourf'e of progression of cirrhosis or are exaggerated surgically (portacaval or splenorenal connections) in an attempt to decompress the portal venous system. In fact, hepatic coma may be looked upon as an encephalopathy resulting from shunting of blood around the liver as a whole or around the viable hepatic cells during passage through the badly damaged liverY The liver is thus unable to modify a cerebrotoxic substance or substances originating in the intestine. The precise nature of this toxicant is not known, though it is most probably a nitrogenous breakdown product of protein whose formation is associated with the release of ammonia, and it may be ammonia itself. What has been called ammonia ini;oxication (but should perhaps more properly be called nitrogenous factor intoxication) is the most common form of induced coma. It is produced acutely by gastrointestinal bleeding, excessive protein ingestion, and ingestion of various ammonia producers such as ammonia chloride, Diamox, etc. Susceptibility to ammonia intoxication is directly related to both the severity of the liver disease
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and the magnitude of the portal-systemic shunting, and the occurrence of symptoms is dependent upon the load of ammonia producers processed by the intestine. The greater the load the less severe the hepatocellular dysfunction need be, and the less extensive the portal-systemic collateral need be before cerebral manifestations appear. Patients without advanced liver disease who have extensive shunting of portal blood into systemic channels are susceptible to ammonia intoxication which is easily reversed by removing the noxious agent. Such cases are more responsive to treatment, and very likely account for most of the spontaneous remissions from hepatic coma observed in the past. The varying proportions of such cases in various published series is probably responsible for the varying proportions of remissions observed. Prior to the development of acute ammonia intoxication the brain is being continuously exposed to the cerebrotoxic substance(s). This underlying state of chronic ammonia intoxication undoubtedly plays a role in the increased susceptibility of the patient to other exogenous factors such as sedatives, electrolyte deficiencies and acid-base imbalances. The strongest argument against the concept that ammonia per se is the cerebrotoxicant producing hepatic coma is the lack of a high correlation between blood concentration of ammonia and the mental state of the patient. A significant correlation between these variables does exist, but there are many exceptions. Patients have been observed in deep hepatic coma with normal blood ammonia, and others with elevated blood ammonia levels have been observed who were not in coma. This has led to the hypothesis that cerebral intracellular ammonia content may be the important factor and that the pH of the blood influences the passage of ammonia into the brain. It has in fact been suggested recently that, as the blood pH rises, more un-ionized or free ammonia is formed which enters the brain more readily.22 Still lacking, however, is evidence bearing on the correlation between mental state and brain content of ammonia. One cannot escape the conclusion that disturbed cerebral ammonia metabolism is in some way related to the syndrome of hepatic coma. However, it may not be the primary or the only abnormality. Walshe 2! suggested that an associated abnormality in cerebral metabolism of amino acids, particularly glutamic acid, plays a role. Glutamic acid is unique in its binding of ammonia and in its support of brain respiration. It is involved in amination by the brain wherein it binds NHa to form glutamine. It is involved in deamination wherein NHa is split off to form alpha-ketoglutaric acid. In the presence of an excess of NHa, amination of ketoglutarate to form glutamate and of the latter to form glutamine predominates. Ketoglutarate is used up and may be in short supply in the Krebs cycle,a and glutamine accumulates in the brain and cerebrospinal fluid. So far the best correlation bet,'.een mental statc in hepatic precoma or coma and anyone biochemical abnormality is that
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reported by Gilon and co-workers 9 with spinal fluid glutamine concentration. Glutamic acid also influences the brain's permeability to potassium and may play a role in cerebral uptake of potassium in the presence of deficiency of this ion. Except for these circumstantial bits of evidence no consistent mechanism can be written at present which involves these amino acids and accounts for all cases of hepatic coma. Walshe 20 and others have been able to reverse the course of hepatic coma in selected cases by use of large doses of glutamate intravenously. Arginine is another amino acid which has been used successfully in individual patients with hepatic coma. 12 Its effect was presumably to bind NH3 in the Krcbs-Henseleit urea cycle taking place in the liver. Significantly, only the absence of arginine from an intravenous infusion of a mixture of amino acids leads to cerebral toxicity.6 The possibility that arginine may have direct effects upon the brain in hepatic coma has apparently not been studied. DIFFERENTIAL DIAGNOSIS
Confusion of hepatic coma with other comatose states such as occur with uremia, hypoglycemia and trauma is infrequent since the antecedent course of events quite clearly delineates the type of case one is dealing with. The comatose or precomatose alcoholic may present a diagnostic problem, particularly if he has coexisting hepatic decompensation. The acute alcoholic psychoses are not a source of confusion, with the exception of delirium tremens. The state of increased psychomotor activity in a fully conscious patient who is anxious and fearful, speaks rapidly, is aggressive and destructive, hallucinates, has a fine tremor, and has great muscle strength characterizes the patient with delirium tremens and differentiates him from the patient with hepatic coma. A greater source of confusion are the patients with advanced liver disease who lapse into a stuporous state as a result of severe deficits of sodium or potassium, which is promptly corrected by replacement of these electrolytes. Unlike the typical case of hepatic coma, these patients usually lie quietly in stupor without hyperventilating. Since deficiencies of these ions commonly occur in patients following the path to hepatic coma, and often hasten them along the way, it may seem artificial to segregate the group in whom electrolyte deficiencies predominate. However, in these patients, the liver disease is probably not at the moment an essential component leading to the stuporous state, and much confusion has resulted from calling them instances of hepatic coma. TREATMENT
Preventive measures are of major importance since most episodes of hepatic coma are avoidable. The following list of precautions will minimize the likelihood of an induced coma:
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1. Avoid all sedation in the severely decompensated patient with liver disease. If absolutely necessary, use with circumspection. 2. Avoid ammonia-producing substances such as ammonium chloride, Diamox, chlorothiazide and excessive protein where tolerance is limited. :). A void large paracenteses and vigorous diuresis. 4. Correct hypokalemia and hypomagnesemia assiduously, and persist with therapy since the eellular deficiency of K+ and Mg++ is usually marked . .5. Treat gastrointestinal bleeding vigorously. Avoid shock and anoxia at all costs. 6. Nip infections in the bud. Use antibiotics prophylactically in the early precoma period. 7. If surgery is contemplated in any patient with liver disease Wie anesthetics, hypnoties and narcotics gingerly, minimize trauma and blood loss, avoid shock and hypoxia at all costs, give particular care to electrolyte balance, minimize operating time and avoid massive tram.;fusions. The patient in hepatic precoma or coma requires meticulous nursing care and attention to details of intake and output. A sequential tabulation of clinical, laboratory and therapeutic data is as valuable as in diabetic coma. Particular and continuous attention is given to the patient's state of hydration and the correction of electrolyte deficits, especially of potassium and magnesium. Parenteral glucose in large amounts (300 to 500 grams per day) is the primary source of calories, and is possibly of specific therapeutic value. A convenient method of administration is via a small catheter introduced through a needle in an arm vein into the vena cava. Protein is withheld until improvement is definite. An absorbable broad-spectrum antibiotic such as tetracycline is recommended, to accomplish two objectives: (1) prophylacticaJly to prevent infection, of the lungs and urinary tract particularly; and (2) to sterilize the intestinal tract and reduce ammonia production. Oral neomycin has been used to accomplish the second of these purposes, but will of course not provide systemic protection against infection. Najarian and coworkers l3 have found neomycin enemas valuable in controlling ammonia production. In their procedure a cleansing enema is followed by a 1 per cent neomycin retention enema each day for several days. They noted clinical improvement in patients with shunt encephalopathy, which was not observed following ordinary cleansing enemas. Steroids have been of value in acute hepatitis with acute necrosis, but of little value in cirrhosis with coma. The earliest evidences of neuropsychiatric abnormalities in acute hepatitis is an indication for vigorous therapy with steroids in large dosage. Once coma ensues it is generally too late, and therapy is usually ineffective. Two amino acids, sodium or potassium glutamate and arginine hydro-
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chloride, have proved valuable adjuncts to therapy if given in appropriate fashion and large eXlOugh dosage. Patients with coma induced by an exogenous agent are most responsive to this type of therapy, as they are to any other. Large doses are necessary, 50 to 150 grams of glutamate or arginine being the rule. Simultaneous administration of glucose and correction of electrolyte deficits (K+ and Mg++ particularly) may be important for the action of these agents. In order to avoid the excessive alkalinizing effect of sodium glutamate and the excessive acidifying effect of arginine hydrochloride, a combination of the two agents, arginine-glutamate, has been developed which is to be preferred. In my own experience arginine hydrochloride and arginine-glutamate are about equally effective in hepatic coma, and both seem to be more effective than glutamate alone. A satisfactory procedure is to give 50 grams of arginine-glutamate ill lOOO m!. of 10 to 15 per ccnt glucose in distilled water intravenously over a period of six to eight hours, repeating the sequence several times if the paticnt fails to respond or responds inadequately. Parenteral potassium and magnesium are given simultaneously, if urine flow it-i adequate, as long as the serum levels of these ions are normal or low. Potassium chloride may be added to one or more of the arginine-glutamate solutions so as to provide 40 to 120 mEq. of K+ per day, depending upon the need. Magnesium sulfate may also be added to the solutions so as to provide 4 to 8 grams of magnesium sulfate per day depending upon the need. A total dosage of 150 grams of arginine-glutamate given consecutively will generally produce a favorable response if the patient is capable of responding. An occasional partial response will become complete with a repetition of this sequence until as much as 300 gramt-i of arginine-glutamate has been given. If the patient does not respond to this dose he will probably not respond to a larger dose. It is important to realize that there is usually an appreciable lag between the institution of therapy and complete restoration of consciousness; however, other clinical signs such as the stertorousness and regularity of respirations and the response to painful stimuli indicate the progress of the patient. Those reporting these agents to be without effect in hepatic coma have by and large given small doses or ignored the simultaneous requirement for glucose and electrolytes. Unfortunately, patients requiring such therapy are seriously ill and frequently progress to death because of some other coexisting or unremitting complication. The therapeutic effectiveness of any drug under such circumstances is difficult to establish. PROGNOSIS
The outlook for the unconscious patient with hepatic coma is at best very poor. In the spontaneous eases the patients almost invariably die, as might be expected, since the liver is largely, destroyed. In the induced
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cases therapeutic measures such as those outlined above may help. The eventual mortality is high, even in those responding to the treatment of the immediate episode, because serious unremitting or rapidly recurrent complications, such as bleeding, commonly coexist. Vigorous therapy of the kind outlined has led to a significant improvement in the mortality rate, particularly among patients who do not progress to frank coma. However, part of the answer to the improved mortality statistics lies in our increased awareness of ammonia toxicity, and inclusion in the group of hepatic comas of many patients, previously excluded, who have readily reversible shunt encephalopathy in the presence of comparatively good liver function. The variable mortality figures reported undoubtedly reflect variable composition of the groups labeled hepatic coma. We thus have no basis for specifying a precise mortality percentage except to say it is still very high indeed. REFERENCES 1. Adams, R. D. and Foley, J. M.: The Neurological Disorders Associated with Liver Disease. A. Res. Nerv. & Ment. Dis. Proc. 32: 198, 1953.
2. Amatuzio, D. S., Stutzman, F., Shrifter, N. and Nesbitt, S.: A Study of Serum Electrolytes (Na, K, Ca, P) in Patients with Severely Decompensated Portal Cirrhosis of the Liver. J. Lab. & Clin. Med. 39: 26, 1952. 3. Bessman, S. P.: Role of Ammonia in Clinical Syndromes. Ann. Int. Med. 44: 1037, 1956. 4. Challenger, F. and Walshe, J. M.: Foetor Hepaticus. Lancet 1: 1239, 1955. 5. Eichenholz, A., Anderson, W. E. and MacDonald, F. M.: Primary HypocapniaA Cause of Metabolic Acidosis. Clin. Res. 8: 287, 1960. Also Eichenholz, A. and Mulhausen, R. 0.: Unpublished observations. 6. Fahey, J. L.: Toxicity and Blood Ammonia Rise Resulting from Intravenous Amino Acid Administration in Man: The Protective Effect of L-Arginine. J. Clin. Invest. 36: 1647, 1957. 7. Flock, E. V., Block, M. A., Grindlay, J. H., Mann, F. C. and 13o11man, J. L.: Changes in Free Amino Acids of Brain and Muscle After Total Hepatectomy. J. Biol. Chem. 200: 529, 1953. 8. Gabuzda, G. J., Phillips, G. B. and Davidson, C. S.: Reversible Toxic Manifestations in Patients with Cirrhosis of the Liver. New England J. Med. 246: 124,1952. 9. Gilon, E., Szeinberg, A., Tauman, G. and Bodonyi, E.: Glutamine Estimation in Cerebrospinal Fluid in Cases of Liver Cirrhosis and Hepatic Coma. J. Lab. & Clin. Med. 53: 714, 1959. 10. Kirk, E.: Amino Acid and Ammonia Metabolism in Liver Disease. Acta med. scandinav. 89: Supp. 77, 1936. 11. McIsaac, W. M. and Page,!. H.: Urocanicaciduria Associated with Hepatic Coma. Nature 190: 347, 1961. 12. Najarian, J. S. and Harper, H. A.: A Clinical Study of the Effect of Arginine on Blood Ammonia. Am. J. Med. 21: 832,1956. 13. Najarian, J. S., Jew, J., Dakin, R. L., Harper, H. A., Quinnell, C. M. and McCorkle, H. J.: Control of Ammonia Production in the Colon with Neomycin Enemas. Arch. Surg. 78: 844, 1959. 14. Parnas, J. K. and Klisiecki, A.: Dber den Ammoniakgehalt und die Ammoniakbildung im Blute. VI. Bioch. Ztschr. 173: 224, 1926. 15. Phillips, G. B., Schwartz, R., Gabuzda, G. J. Jr. and Davidson, C. S.: The Syndrome of Impending Hepatic Coma in Patients with Cirrhosis of the Liver Given Nitrogenous Substances. New England J. Med. 247: 239, 1952. 16. Sherlock, S.: Pathogenesis and Management of Hepatic Coma. Am. J. Med. 24: 805,1958.
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17. Hherlock, H., SUlllmerskill, W. H. J., White, L. P. and Phear, E. A.: PortalSystemic Encephalopathy. Neurological Complications of Liver Disease. Lancet 2: 458, 1954. 18. Vanamee, P., Poppell, J. W., Glicksman, A. H., Randall, H. T. and RClberts, K. E.: Respiratory Alkalosis in Hepatic Coma. Arch. Int. Med. 97: 762, 1956. 19. Walshe, J. M.: Disturbances of Aminoacid Metabolism Following Liver Injury: A Htudy by Means of Paper Chromatography. Quart. J. Med. 22: 488,1958. 20. Walshe, J. M.: Glutamic Acid in Hepatic Coma. Lancet 1: 1285, 1955. 21. Walshe, J. M.: Observations on the Hymptomatology and Pathogenesis of Hepatic Coma. Quart. J. Med. 20: 421, 1951. 22. Warren, K. S.: The Differential Toxicity of Ammonium Salts. J. Clin. Invest. 87: 497, 1958. 28. Warren, K. S. and Schenker, S.: Hypoxia and Ammonia Toxicity. Am. J. Physiol. 199: 1105, 1960.
HEPATIC COMA is a disorder of consciousness occurring in patients with severe liver disease; a neuropsychiatric disturbance with no striking or specific anatomic basis. The manifestations may be extreme, yet are entirely reversible, and the brain does not show pathologic changes that will account for the symptoms. Prior to the last decade there was little confusion regarding definition of this syndrome. Any patient with severe liver disease who was unconscious or somnolent or stuporous was said to be in hepatic coma or precoma. We now know that some of these episodes were instances of sodium or potassium deficit compounding the abnormalities of the decompensated liver. Others were the consequence of various and sundry therapeutic agents provided by the well-in tentioned physician in his treatment of the liver disease. Spontaneous hepatic coma is usually a terminal complication of cirrhosis or hepatitis with severe acute necrosis. The neuropsychiatric sequence is typically mental clouding, confusion, inappropriate behavior, increased psychomotor activity followed by decreased psychomotor activity, progressive somnolence, stupor and coma. Neurologically there is intermittency of muscle contractions with fluctuating rigidity of the limbs, flapping movement of the outstretched hands, arms and legs, grimacing, grasping, sucking, exaggerated reflexes, and occasionally convulsions. l Throughout hyperventilation is evident. It follows a crescendo course, and terminally the breathing is stertorous. The patient whose hepatic status has been deteriorating may lapse into coma spontaneously as a result of nearly complete destruction of his liver. Usually, however, some precipitating factor intervenes before this extremity is reached.
PRECIPITATING FACTORS
The ease with which coma is induced by various precipitating factors is directly correlated with the extent and acuteness of hepatic decompensation. Gastrointestinal bleeding, usually from esophageal varices, but also from peptic ulceration, is the most common precipitating factor.
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Blood protein breakdown products and ammonia, which ordinarily come in contact with hepatic cells and are processed before they can reach the systemic circulation, are shunted around the liver via the collateral circulation that is ordinarily present, or pass through areas of the damaged liver containing no functioning hepatic cells. Shock and anoxia following bleeding may contribute to the harmful cerebral effects of the intestinal nitrogenous products of protein breakdown, or shock may result from other causes and compromise cerebral blood flow sufficiently to precipitate coma. Severe infections, particularly bacteremias secondary to pneumonia or pyelonephritis, not infrequently usher in an episode of coma. Sedatives of any type may precipitate coma in the patient with severely decompensated liver disease, though they are tolerated well, as a rule, when he is not decompensated. Paraldehyde and chloral hydrate arc almost as noxious as narcotics and barbiturates in this respect. Excitement is frequent in the precomatose state of hepatic failure and the physician has to resist the temptation to quiet the patient with sedatives. Paracentesis was at one time the commonest immediate cause of hepatic coma. However, it is now generally realized that little is gained by massive paracenteses, and valuable protein and electrolytes are lost. Ascitic fluid is in dynamic equilibrium with the circulation and removal of large amounts of abdominal fluid causes rapid fluid and electrolyte shifts. Hyponatremia and hypokalemia with their attendant cerebral and renal effects are common consequences. Added to the abnormalities already present in the severe cirrhotic, they may precipitate a difficultly reversible chain of reactions leading to hepatic coma. Diuretics of any type may have effects similar to paracentesis if the diuresis and loss of electrolytes are massive. Chlorothiazide derivatives are particularly noxious because of the consequences of excessive potassium loss. Ammonia producers are recognized today as common precipitating agents in cirrhotics with prominent collateral circulation particularly. Ammonium chloride, ammonia-producing resins, and Diamox are very poorly tolerated. Chlorothiazide also seems to function as an ammonia producer and is poorly tolerated. Excessive protein in the gut, either as food or from internal bleeding, may precipitate coma. Methionine may also produce neurologic changes. Surgical procedures may lead to hepatic coma by a compounding of predisposing factors already mentioned, e.g., the effects of hypnotics and analgesics, anesthetics, hypoxia, trauma, blood loss, shock, and water and electrolyte imbalance. CLINICAL PICTURE
The usual sequence of development of symptoms and signs follows, more or less, the order of the tabulation in Table 1. The mental and
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509
Table 1.
Symptoms and Signs of Hepatic Coma
MEN'l'AL STATE
Clouding Confusion Restlessness Irritability Inappropriate behavior Sullen, paranoid, disobedient Picking and rearranging bedclothes Yawning Sucking Crying Agitation Disorientation Delirium Drowsiness Somnolence Lethargy Apathy Stupor Coma
NEUROMUSCULAR STA'l'E
Incoordination Tremor Dysarthria Grasping Hiccoughing Deliberate movement Cogwheel rigidity Masklike fascies Dilated pupils Roving eyes Muscle twitching Convulsions Flexion of legs Flapping tremor Hyperrefiexia Positive toe signs Nystagmus Ophthalmoplegia Incontinence
neuromuscular abnormalities develop in parallel fashion. The electroencephalogram shows a characteristic change in most patients. Bilaterally there are slow delta waves in bursts of 2 or 3 per second, most marked over the frontal areas.! The onset of precoma is most often insidious with quiet confusion, but may be abrupt and violent. Quiet confusion, lethargy, and stupor typically precede the coma of cirrhosis. However, the coma of acute atrophy is often preceded by mania, delirium and convulsionsY The sequence outlined is not inevitably progressive, there being swings up and down the scale of manifestations. Speed of progression is highly variable, from a few hours to a few weeks, to cite the extremes. Respirations are characteristically increased in rate and amplitude, though the hyperventilation may not be apparent in the earlier stages. As the precorna progresses into coma the breathing becomes stertorous. An amine-like odor, fetor hepaticus, is commonly exhaled by patients developing hepatic coma. It is much more prominent in the presence of acute atrophy than in cirrhosis. The cause of the odor is unknown, though there is reason to suspect some derivative of methyl mercaptan. 4 Once deep coma supervenes death usually follows in a matter of hours or a few days, though exceptions have been seen in which deep coma has lasted two to three weeks. BIOCHEMICAL CHANGES LIVER FUNCTION TESTS. Tests of liver function are generally severely deranged in the spontaneous cases of coma, but do not differ in this respect from patients with severe hepatic disease without coma. Bili-
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rubinemia often increases, but individual cases are observed that have practically no jaundice. Hypoglycemia is rare in hepatic coma, hyperglycemia being more frequent, since it is a common accompaniment of cirrhosis. When hypoglycemia occurs, it is usually in association with widespread acute necrosis. ELECTROLYTE ABNORMALITIES. Hyponatremia is common despite sodium retention. Values of serum sodium under 130 mEq./l. are frequent. If acute loss of sodium occurs, as after large paracenteses, a low salt syndrome may occur with transition into frank hepatic coma. Hypokalemia .and hypomagnesemia are common but not invariable. Values of serum potassium below 3.0 mEq./l. and of serum magnesium below 1.6 mEq.jl. are frequent. There is probably a severe intracellular deficit of these ions which mayor may not be reflected in the serum levels. In terminal phases of hepatic coma, the serum concentrations may actually be high as renal failure ensues. Correction of body potassium and magnesium deficits is usually difficult and requires care and persistence. During hepatic precoma patients will often perk up considerably simply upon improvement of their electrolyte deficiencies. Not uncommonly the deficit in sodium, potassium or magnesium is so extreme that a state of lethargy, apathy and stupor results which is entirely corrected by replacement therapy. Hypocalcemia and hypophosphatemia arc also frequent as a complication of decompensated cirrhosis. 2 Values of calcium below 4.2 mEq.jl. and of phosphorus below 1.2 mEq.jl. are not uncommon. ACID-BASE BALANCE. There is no characteristic acid-base picture in any given patient with hepatic coma. Depending upon the extent, duration and severity of his respiratory or electrolyte abnormality, one may find him in respiratory alkalosis, metabolic alkalosis or metabolic acidosis. Examples are shown in Figure 1. If hypopotassemia is not present, the patient will generally be in compensated or uncompensated respiratory alkalosis1s early in his course because of hypocapnia reSUlting from persistent hyperventilation which develops early in the interval of precoma. This results in a progressive accumulation of pyruvic and lactic acid (and probably other organic acids such as alpha-ketoglutaric acid) and a progressive bicarbonate deficit in the blood, which if severe enough results in metabolic acidosis. 6 This was the case with patient number 5 in Figure 1. Renal failure, which commonly supervenes, may compound this problem. In advanced coma, acidosis is probably more frequently seen than respiratory alkalosis. The rise in blood pyruvic and lactic acid in hepatic coma has been attributed to some unknown disturbance in intermediary metabolism associated with liver failure. We now know from the work of Eichenholz and collaborators5 that accumulation of these organic acids in hepatic failure, as in practically all other diseases in which they accumulate in
Hepatic Coma
511 35
Fig. 1. Examples of acidbase status in five patients with hepatic coma. Cases 1, 2 and 3 are examples of mixed respiratory and metabolic alkalosis. Case 4 is an example of compensated respiratory alkalosis; and Case 5 is an example of severe metabolic acidosis. (Data of Dr. A. Eichenholz.)
30 25
E
~
~
~
15
10
5 7.0
7.1
7.2
7.3
7.4
7.5
7.6'
7.7
pH
the blood, is directly correlated with a reduction in CO 2 tension resulting from hyperventilation. If hypopotassemia is prominent, a metabolic alkalosis will be found which responds to correction of the potassium deficit. Since all of the etiologic factors affecting the blood pH are present to varying degree, it is less common to see pure examples of acid-base imbalance than confusing mixtures. The contribution of acid-base imbalance to the mortality from hepatic coma has never been adequately assessed. I suspect it plays a central role. As clinicians it behooves us to secure routinely in these cases the three measurements-pH, pC02, and bicarbonate concentration--essential to an understanding of acid-base status. Therapy for the acid-base disturbance cannot be safely undertaken without knowing precisely where a patient's value falls on a three-variable plot such as that of Figure 1. To take an extreme example, treatment of a patient such as Case 5 with CO 2 inhalations, without first correcting the bicarbonate deficit, would be rapidly fatal, since the plotted point would move, roughly, to the ordinate of 10 mM';l. and pH of 6.95 as the pC02 returned to normal. Similarly the fully compensated value for Case 4 would move approximately to the ordinate of 17.5 mM./l. and pH of 7.25 as the pC0 2 returned to normal, the patient meanwhile becoming sicker. It is evident that CO 2 inhalation is not a very satisfactory form of therapy for hepatic coma. By contrast one would anticipate that bicarbonate replacement would be valuable if the plotted point falls below the normal buffer slope and potassium replacement valuable if the plotted point falls above the normal buffer slope. In addition to a lowering of the carbon dioxide tension in the blood, patients in hepatic coma commonly have a reduced oxygen tension and a decreased saturation of hemoglobin. This decrease in oxygen saturation
.512
LESLIE ZIEVE
(hypoxemia) is not specific to hepatic coma, being present in the same patients (with cirrhosis) before they develop hepatic failure. Warren and Schenker23 recently showed in mice that hypoxia directly potentiated the toxic effect of ammonia on the brain. BLOOD AMMONIA. The first major study of blood ammonia in liver disease was by Esben Kirk in 1936.1° He observed very small amounts of preformed ammonia in normal persons and abnormal concentrations in cirrhotics. Parnas and Klisieckjl4 had shown in 1926 that large amounts of ammonia are formed in the gastrointestinal tract by baeterial action and that portal vein blood contains two to eight times as much ammonia as the systemic circulation. Kirk performed ammonia tolerance tests, feeding 10 grams of ammonium citrate. There were at most slight rises in blood ammonia concentration in normal subjeets, but considerable increases in mo,;t patients with cirrhosis. A good correlation between blood ammonia value,; and ,;everity of the cirrhosis was not observed. Kirk suggested the observed abnormality of blood ammonia was probably correlated with the collateral circulation developed in cirrhosi,; rather than hepatoedlular dysfunetion per se. These observations have been verifif~d repeatedly since the rediscovery in 1952 of the importance of ammonia and protein breakdown products in paticnts with portal-systemif: venou,; ::;hunting of blood. B, 15 In hepatic precoma or coma the blood ammonia is frequently devated but may be normal. The correlation between blood ammonia concentration and severity of the coma is significant but not high.1 6 Whether or not a high correlation exists between brain (intracellular) ammoma concentration and severity of hepatic coma is unknown. AMINO ACIDS. Aminoaciduria, especially cystinuria, IS common. Walshe 19 ,21 observed an increase in urine content of all the commOIl amino acids in advanced liver disease. Generally, plasma concentratiom; were only slightly elevated. The amino acids excreted in largest amounts were cystine, {:J-aminoisobutyric acid, methylhistidine and taurine. Uro(:anic acid, a metabolic product of histidine and an intermediate in the conversion of histidine to glutamic acid, has been found in increased amounts in the urine of a patient in hepatic comaY In three patients in coma, Walshe 21 observed increased blood amino acids and an abnormal pattern of amino acids in the spinal fluid. An excess of glutamine was found in the spinal fluid of all three and glutamic acid and methionine sulfoxide were present in two. Flock and co-worken;7 have also observed increased concentrations of glutamine in the brain of hepatectomized dogs. Gilon and co-workers 9 recently found the spinal fluid glutamine concentration elevated in all of 26 patients with hepatic coma studied. Only in patients with hepatic coma did values exceed 35 mg./lOO m!. (23 of 26 cases). A good correlation was observed within a given patient between the glutamine level and the severity of coma.
Hepatic Coma
513
SPINAL FLUID. A rise in bilirubin content which is not well correlated with blood levels is often seen. Protein content also rises. The amino acid content also rises and glutamine particularly is present in excess. The ammonia content is variable. Rl<~NAL FUNCTION. In decompensated cirrhosis the glomerular filtration rate and renal blood flow are reduced, markedly in the presence of ascites. In hepatic coma oliguria is frequent, and with progression azotemia is common. Occasionally the picture of acute renal insufficiency is very prominent. TYPES OF HEPATIC COMA AND PATHOGENESIS
Episodes of hepatic coma may be classified as spontaneous or induced. The clinical manifestations of both types are similar, a fact that often makes their differentiation difficult. The spontaneous cases have no evident precipitating factor, being simply the final consequence of practically complete liver cell destruction. The induced cases are precipitated by known agents or abnormalities. The difference between the two types is easily stated, but often in practical fact very slight. As liver destruction proceeds, metabolic and circulatory alterations are produced which enhance the susceptibility of the individual to inducing agents. So the patient who is most likely to lapse into spontaneom; hepatic coma is also most likely to have his coma induced by an exogenous agent. However, this is not necessarily so, and coma is often induced in patients with fairly good hepatic function. The predisposition to coma from exogenous agents is a result of the development of portal-systemic collaterals (shunts), electrolyte and add-base imbalances, and hypoxemia and hypoxia. Of greatest importance are the portal-systemic shunts which develop naturally in the eourf'e of progression of cirrhosis or are exaggerated surgically (portacaval or splenorenal connections) in an attempt to decompress the portal venous system. In fact, hepatic coma may be looked upon as an encephalopathy resulting from shunting of blood around the liver as a whole or around the viable hepatic cells during passage through the badly damaged liverY The liver is thus unable to modify a cerebrotoxic substance or substances originating in the intestine. The precise nature of this toxicant is not known, though it is most probably a nitrogenous breakdown product of protein whose formation is associated with the release of ammonia, and it may be ammonia itself. What has been called ammonia ini;oxication (but should perhaps more properly be called nitrogenous factor intoxication) is the most common form of induced coma. It is produced acutely by gastrointestinal bleeding, excessive protein ingestion, and ingestion of various ammonia producers such as ammonia chloride, Diamox, etc. Susceptibility to ammonia intoxication is directly related to both the severity of the liver disease
514
LESLIE ZIEVE
and the magnitude of the portal-systemic shunting, and the occurrence of symptoms is dependent upon the load of ammonia producers processed by the intestine. The greater the load the less severe the hepatocellular dysfunction need be, and the less extensive the portal-systemic collateral need be before cerebral manifestations appear. Patients without advanced liver disease who have extensive shunting of portal blood into systemic channels are susceptible to ammonia intoxication which is easily reversed by removing the noxious agent. Such cases are more responsive to treatment, and very likely account for most of the spontaneous remissions from hepatic coma observed in the past. The varying proportions of such cases in various published series is probably responsible for the varying proportions of remissions observed. Prior to the development of acute ammonia intoxication the brain is being continuously exposed to the cerebrotoxic substance(s). This underlying state of chronic ammonia intoxication undoubtedly plays a role in the increased susceptibility of the patient to other exogenous factors such as sedatives, electrolyte deficiencies and acid-base imbalances. The strongest argument against the concept that ammonia per se is the cerebrotoxicant producing hepatic coma is the lack of a high correlation between blood concentration of ammonia and the mental state of the patient. A significant correlation between these variables does exist, but there are many exceptions. Patients have been observed in deep hepatic coma with normal blood ammonia, and others with elevated blood ammonia levels have been observed who were not in coma. This has led to the hypothesis that cerebral intracellular ammonia content may be the important factor and that the pH of the blood influences the passage of ammonia into the brain. It has in fact been suggested recently that, as the blood pH rises, more un-ionized or free ammonia is formed which enters the brain more readily.22 Still lacking, however, is evidence bearing on the correlation between mental state and brain content of ammonia. One cannot escape the conclusion that disturbed cerebral ammonia metabolism is in some way related to the syndrome of hepatic coma. However, it may not be the primary or the only abnormality. Walshe 2! suggested that an associated abnormality in cerebral metabolism of amino acids, particularly glutamic acid, plays a role. Glutamic acid is unique in its binding of ammonia and in its support of brain respiration. It is involved in amination by the brain wherein it binds NHa to form glutamine. It is involved in deamination wherein NHa is split off to form alpha-ketoglutaric acid. In the presence of an excess of NHa, amination of ketoglutarate to form glutamate and of the latter to form glutamine predominates. Ketoglutarate is used up and may be in short supply in the Krebs cycle,a and glutamine accumulates in the brain and cerebrospinal fluid. So far the best correlation bet,'.een mental statc in hepatic precoma or coma and anyone biochemical abnormality is that
Hepatic Coma
.515
reported by Gilon and co-workers 9 with spinal fluid glutamine concentration. Glutamic acid also influences the brain's permeability to potassium and may play a role in cerebral uptake of potassium in the presence of deficiency of this ion. Except for these circumstantial bits of evidence no consistent mechanism can be written at present which involves these amino acids and accounts for all cases of hepatic coma. Walshe 20 and others have been able to reverse the course of hepatic coma in selected cases by use of large doses of glutamate intravenously. Arginine is another amino acid which has been used successfully in individual patients with hepatic coma. 12 Its effect was presumably to bind NH3 in the Krcbs-Henseleit urea cycle taking place in the liver. Significantly, only the absence of arginine from an intravenous infusion of a mixture of amino acids leads to cerebral toxicity.6 The possibility that arginine may have direct effects upon the brain in hepatic coma has apparently not been studied. DIFFERENTIAL DIAGNOSIS
Confusion of hepatic coma with other comatose states such as occur with uremia, hypoglycemia and trauma is infrequent since the antecedent course of events quite clearly delineates the type of case one is dealing with. The comatose or precomatose alcoholic may present a diagnostic problem, particularly if he has coexisting hepatic decompensation. The acute alcoholic psychoses are not a source of confusion, with the exception of delirium tremens. The state of increased psychomotor activity in a fully conscious patient who is anxious and fearful, speaks rapidly, is aggressive and destructive, hallucinates, has a fine tremor, and has great muscle strength characterizes the patient with delirium tremens and differentiates him from the patient with hepatic coma. A greater source of confusion are the patients with advanced liver disease who lapse into a stuporous state as a result of severe deficits of sodium or potassium, which is promptly corrected by replacement of these electrolytes. Unlike the typical case of hepatic coma, these patients usually lie quietly in stupor without hyperventilating. Since deficiencies of these ions commonly occur in patients following the path to hepatic coma, and often hasten them along the way, it may seem artificial to segregate the group in whom electrolyte deficiencies predominate. However, in these patients, the liver disease is probably not at the moment an essential component leading to the stuporous state, and much confusion has resulted from calling them instances of hepatic coma. TREATMENT
Preventive measures are of major importance since most episodes of hepatic coma are avoidable. The following list of precautions will minimize the likelihood of an induced coma:
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1. Avoid all sedation in the severely decompensated patient with liver disease. If absolutely necessary, use with circumspection. 2. Avoid ammonia-producing substances such as ammonium chloride, Diamox, chlorothiazide and excessive protein where tolerance is limited. :). A void large paracenteses and vigorous diuresis. 4. Correct hypokalemia and hypomagnesemia assiduously, and persist with therapy since the eellular deficiency of K+ and Mg++ is usually marked . .5. Treat gastrointestinal bleeding vigorously. Avoid shock and anoxia at all costs. 6. Nip infections in the bud. Use antibiotics prophylactically in the early precoma period. 7. If surgery is contemplated in any patient with liver disease Wie anesthetics, hypnoties and narcotics gingerly, minimize trauma and blood loss, avoid shock and hypoxia at all costs, give particular care to electrolyte balance, minimize operating time and avoid massive tram.;fusions. The patient in hepatic precoma or coma requires meticulous nursing care and attention to details of intake and output. A sequential tabulation of clinical, laboratory and therapeutic data is as valuable as in diabetic coma. Particular and continuous attention is given to the patient's state of hydration and the correction of electrolyte deficits, especially of potassium and magnesium. Parenteral glucose in large amounts (300 to 500 grams per day) is the primary source of calories, and is possibly of specific therapeutic value. A convenient method of administration is via a small catheter introduced through a needle in an arm vein into the vena cava. Protein is withheld until improvement is definite. An absorbable broad-spectrum antibiotic such as tetracycline is recommended, to accomplish two objectives: (1) prophylacticaJly to prevent infection, of the lungs and urinary tract particularly; and (2) to sterilize the intestinal tract and reduce ammonia production. Oral neomycin has been used to accomplish the second of these purposes, but will of course not provide systemic protection against infection. Najarian and coworkers l3 have found neomycin enemas valuable in controlling ammonia production. In their procedure a cleansing enema is followed by a 1 per cent neomycin retention enema each day for several days. They noted clinical improvement in patients with shunt encephalopathy, which was not observed following ordinary cleansing enemas. Steroids have been of value in acute hepatitis with acute necrosis, but of little value in cirrhosis with coma. The earliest evidences of neuropsychiatric abnormalities in acute hepatitis is an indication for vigorous therapy with steroids in large dosage. Once coma ensues it is generally too late, and therapy is usually ineffective. Two amino acids, sodium or potassium glutamate and arginine hydro-
517
Hepatic Coma
chloride, have proved valuable adjuncts to therapy if given in appropriate fashion and large eXlOugh dosage. Patients with coma induced by an exogenous agent are most responsive to this type of therapy, as they are to any other. Large doses are necessary, 50 to 150 grams of glutamate or arginine being the rule. Simultaneous administration of glucose and correction of electrolyte deficits (K+ and Mg++ particularly) may be important for the action of these agents. In order to avoid the excessive alkalinizing effect of sodium glutamate and the excessive acidifying effect of arginine hydrochloride, a combination of the two agents, arginine-glutamate, has been developed which is to be preferred. In my own experience arginine hydrochloride and arginine-glutamate are about equally effective in hepatic coma, and both seem to be more effective than glutamate alone. A satisfactory procedure is to give 50 grams of arginine-glutamate ill lOOO m!. of 10 to 15 per ccnt glucose in distilled water intravenously over a period of six to eight hours, repeating the sequence several times if the paticnt fails to respond or responds inadequately. Parenteral potassium and magnesium are given simultaneously, if urine flow it-i adequate, as long as the serum levels of these ions are normal or low. Potassium chloride may be added to one or more of the arginine-glutamate solutions so as to provide 40 to 120 mEq. of K+ per day, depending upon the need. Magnesium sulfate may also be added to the solutions so as to provide 4 to 8 grams of magnesium sulfate per day depending upon the need. A total dosage of 150 grams of arginine-glutamate given consecutively will generally produce a favorable response if the patient is capable of responding. An occasional partial response will become complete with a repetition of this sequence until as much as 300 gramt-i of arginine-glutamate has been given. If the patient does not respond to this dose he will probably not respond to a larger dose. It is important to realize that there is usually an appreciable lag between the institution of therapy and complete restoration of consciousness; however, other clinical signs such as the stertorousness and regularity of respirations and the response to painful stimuli indicate the progress of the patient. Those reporting these agents to be without effect in hepatic coma have by and large given small doses or ignored the simultaneous requirement for glucose and electrolytes. Unfortunately, patients requiring such therapy are seriously ill and frequently progress to death because of some other coexisting or unremitting complication. The therapeutic effectiveness of any drug under such circumstances is difficult to establish. PROGNOSIS
The outlook for the unconscious patient with hepatic coma is at best very poor. In the spontaneous eases the patients almost invariably die, as might be expected, since the liver is largely, destroyed. In the induced
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cases therapeutic measures such as those outlined above may help. The eventual mortality is high, even in those responding to the treatment of the immediate episode, because serious unremitting or rapidly recurrent complications, such as bleeding, commonly coexist. Vigorous therapy of the kind outlined has led to a significant improvement in the mortality rate, particularly among patients who do not progress to frank coma. However, part of the answer to the improved mortality statistics lies in our increased awareness of ammonia toxicity, and inclusion in the group of hepatic comas of many patients, previously excluded, who have readily reversible shunt encephalopathy in the presence of comparatively good liver function. The variable mortality figures reported undoubtedly reflect variable composition of the groups labeled hepatic coma. We thus have no basis for specifying a precise mortality percentage except to say it is still very high indeed. REFERENCES 1. Adams, R. D. and Foley, J. M.: The Neurological Disorders Associated with Liver Disease. A. Res. Nerv. & Ment. Dis. Proc. 32: 198, 1953.
2. Amatuzio, D. S., Stutzman, F., Shrifter, N. and Nesbitt, S.: A Study of Serum Electrolytes (Na, K, Ca, P) in Patients with Severely Decompensated Portal Cirrhosis of the Liver. J. Lab. & Clin. Med. 39: 26, 1952. 3. Bessman, S. P.: Role of Ammonia in Clinical Syndromes. Ann. Int. Med. 44: 1037, 1956. 4. Challenger, F. and Walshe, J. M.: Foetor Hepaticus. Lancet 1: 1239, 1955. 5. Eichenholz, A., Anderson, W. E. and MacDonald, F. M.: Primary HypocapniaA Cause of Metabolic Acidosis. Clin. Res. 8: 287, 1960. Also Eichenholz, A. and Mulhausen, R. 0.: Unpublished observations. 6. Fahey, J. L.: Toxicity and Blood Ammonia Rise Resulting from Intravenous Amino Acid Administration in Man: The Protective Effect of L-Arginine. J. Clin. Invest. 36: 1647, 1957. 7. Flock, E. V., Block, M. A., Grindlay, J. H., Mann, F. C. and 13o11man, J. L.: Changes in Free Amino Acids of Brain and Muscle After Total Hepatectomy. J. Biol. Chem. 200: 529, 1953. 8. Gabuzda, G. J., Phillips, G. B. and Davidson, C. S.: Reversible Toxic Manifestations in Patients with Cirrhosis of the Liver. New England J. Med. 246: 124,1952. 9. Gilon, E., Szeinberg, A., Tauman, G. and Bodonyi, E.: Glutamine Estimation in Cerebrospinal Fluid in Cases of Liver Cirrhosis and Hepatic Coma. J. Lab. & Clin. Med. 53: 714, 1959. 10. Kirk, E.: Amino Acid and Ammonia Metabolism in Liver Disease. Acta med. scandinav. 89: Supp. 77, 1936. 11. McIsaac, W. M. and Page,!. H.: Urocanicaciduria Associated with Hepatic Coma. Nature 190: 347, 1961. 12. Najarian, J. S. and Harper, H. A.: A Clinical Study of the Effect of Arginine on Blood Ammonia. Am. J. Med. 21: 832,1956. 13. Najarian, J. S., Jew, J., Dakin, R. L., Harper, H. A., Quinnell, C. M. and McCorkle, H. J.: Control of Ammonia Production in the Colon with Neomycin Enemas. Arch. Surg. 78: 844, 1959. 14. Parnas, J. K. and Klisiecki, A.: Dber den Ammoniakgehalt und die Ammoniakbildung im Blute. VI. Bioch. Ztschr. 173: 224, 1926. 15. Phillips, G. B., Schwartz, R., Gabuzda, G. J. Jr. and Davidson, C. S.: The Syndrome of Impending Hepatic Coma in Patients with Cirrhosis of the Liver Given Nitrogenous Substances. New England J. Med. 247: 239, 1952. 16. Sherlock, S.: Pathogenesis and Management of Hepatic Coma. Am. J. Med. 24: 805,1958.
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17. Hherlock, H., SUlllmerskill, W. H. J., White, L. P. and Phear, E. A.: PortalSystemic Encephalopathy. Neurological Complications of Liver Disease. Lancet 2: 458, 1954. 18. Vanamee, P., Poppell, J. W., Glicksman, A. H., Randall, H. T. and RClberts, K. E.: Respiratory Alkalosis in Hepatic Coma. Arch. Int. Med. 97: 762, 1956. 19. Walshe, J. M.: Disturbances of Aminoacid Metabolism Following Liver Injury: A Htudy by Means of Paper Chromatography. Quart. J. Med. 22: 488,1958. 20. Walshe, J. M.: Glutamic Acid in Hepatic Coma. Lancet 1: 1285, 1955. 21. Walshe, J. M.: Observations on the Hymptomatology and Pathogenesis of Hepatic Coma. Quart. J. Med. 20: 421, 1951. 22. Warren, K. S.: The Differential Toxicity of Ammonium Salts. J. Clin. Invest. 87: 497, 1958. 28. Warren, K. S. and Schenker, S.: Hypoxia and Ammonia Toxicity. Am. J. Physiol. 199: 1105, 1960.