L-Dopa in Hepatic Coma JOSEF E. FISCHER, M.D., JOSEF M. FUNOVICS, M.D., HORACIO A. FALCAO, M.D., ROBERT 1. C. WESDORP, M.D.
The use of L-Dopa in hepatic coma has been the subject of numerous reports since 1970. The following represents our experience with a rather heterogenous group of patients treated at the Massachusetts General Hospital over the past 4 years. Thirty-five patients with severe liver disease, a mean age of 53 ± 3.5 years, including nutritional cirrhosis with acute coma and acute hepatitis were treated. Four patients were judged grade III, 31 patients grade IV. All patients had previously been treated with protein restriction, orally administered non-absorbable antibiotics, fluid and electrolytes, and in some cases, steroids. L-Dopa was given orally in 21 patients, and as a retention enema in 14. Thirteen of the 35 patients did not respond to therapy. Seventeen responded, but did not survive, and 5 patients responded and survived. There was no difference between any of the groups as far as dosage of L-Dopa and clinical features. The one striking finding as the differences between groups was the time of initiation of L-Dopa therapy. In Group I, the survivors, therapy was started within 1.4 ± 0.8 days after the onset of coma. In Group II, there was an initiation of therapy at 6.7 ± 1.6 days, and in the non-responders 9.5 ± 1.6 days. These differences are highly significant. The results suggest that coma may pass from a reversible to an irreversible stage, and that L-Dopa therapy initiated early in the course of hepatic coma, may be of some benefit.
From the Departments of Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 a
controlled double blind study.6 Several studies of the
use of L-Dopa in hepatic coma are in progress, but stable
patients in hepatic encephalopathy are not common, and most of these studies have been hampered by the lack of sufficient numbers of patients. In the following report, 35 patients with hepatic encephalopathy were treated with Levo-Dopa, either orally or by retention enema. In spite of the variability
of the clinical condition and of the clinical course, which precluded inclusion in a prospective double blind study, certain features emerge which may help in the design of a prospective study of treatment of hepatic
encephalopathy.
Material Thirty-five patients, 15 males and 20 females ranging in S INCE the first report by Parkes, et al.31 on the use of L- age from 7 to 78 years, with a mean age of 53 + 3.5 Dopa in hepatic coma, several reports have appeared years were studied. All patients had severe liver disease suggesting that patients in previously unresponsive (Table 1). The etiology was alcoholic cirrhosis in 22 hepatic coma may awake following the administration (63%), acute hepatic necrosis in 7 (20%) (viral) of Levo-Dopa in amounts ranging from 50 mg/kg in hepatitis in 5 (14%) and undefined cirrhosis in 1 (3%). divided doses, to 5 gm given in a single dose. 1.14,15,28,33,36 Diagnosis was based on history, clinical findings, serial The mode of administration has included oral (naso- biochemical tests and liver biopsy, and was confirmed in 12 patients at necropsy. Clinical features of the gastric tube), rectal, as well as intravenous routes. The variability of consciousness in hepatic encephalop- hepatic disease included coma, which was grade III in athy is well known. Patients in grade IV coma may 4 patients (11%), grade IV in 31 patients (89%o), based on awake without demonstrable improvement in liver func- a classification originally suggested by Adams and Foley tion, and the efficacy of a given therapeutic agent in (2), with modifications of the criteria proposed by hepatic coma is difficult to prove. For example, Trey, et al.39 Grade I fluctuant mild confusion with euphoria the mainstay of therapy in hepatic encephalopathy, and/or depression, slurred speech, disorder "intestinal sterilization," have never been subjected to in sleep rhythm. Grade II (impending coma) accentuation of stage I with drowsiness, inappropriate behavior, Submitted for publication September 12, 1975. Supported in Part by Grant #AM-15347, U.S.P.H.S. but ability to maintain sphincter control. 386
VOl. 183.o NO. 4
L-DOPA IN HE]PATIC COMA TABLE 1. Etiology of Liver Disease
Alcoholic Cirrhosis Viral Hepatitis Acute Hepatic Necrosis Undefined Cirrhosis No. of Patients
Pts.
Nonresp
Resp
22 5 7 1 35
11
2
9 5 3
13
17
387
steroids. Failure to improve or further deterioation in Resp + Surv mental status was considered an indication for L-Dopa (Laro-Dopa 500 mg tablet, kindly donated by Dr. Clif2 ford Joseph of Hoffman-LaRoche Laboratories, Inc., Nutley, New Jersey). 2 I 5
Grade III (stupor), sleep most of the time, but arousable. Marked confusion is present with lack of knowledge of surroundings. Grade IV (coma), physical responses to painful stimuli may or may not be present.
Cardiovascular and Renal Thirty-three of the 35 patients were thought to manifest stigmata of high cardiac output, either by direct measurement or as manifestation of warm skin, bounding pulses, heaving and active precordia and decreased peripheral resistance. When cardiac outputs were measured, cardiac index was considered elevated, if a value of greater than 4.25 1/min/m2 was obtained. Hypotension, defined as a blood pressure 20 mm Hg systolic less than previously known or recorded blood pressure, was present in most patients. Thirty-three of the 35 patients had a urinary output less than 20 cc/hr with a urinary sodium lower than 10 mEq/liter immediately before therapy, but some were not oliguric on the basis of 24 hr urine volume. Clinical Accompaniments Gastrointestinal bleeding (defined as requiring more than 2 units of blood over a total course) occurred in 26 patients (74%), ascites in 26 (74%) and jaundice in 33 (94%). Six patients had a total bilirubin between 1.5-5 mg/100 ml, 11 had a bilirubin greater than 5, and 17 patients had a bilirubin in excess of 25 mg/100 ml.
Etiology Major surgery, including aortic valve replacement, cholecystectomy, craniotomy and mastectomy had been performed in 5 patients before coma developed, and in an additional 12 patients after the onset of coma because of uncontrolled bleeding from esophageal varices, where various decompressive or ablative procedures were carried out in an effort to arrest bleeding. Prior to initiation of L-Dopa therapy, all patients had been treated with "maximal standard therapy," including protein restriction, orally and rectally administered nonabsorpable antibiotics (neomycin or humatin) intravenous administration of dextrose and electrolytes, cathartics and enemas, and in some patients, cortico-
Administration of L-Dopa L-Dopa was given as a suspension in water, orally via a nasogastric tube in 21 patients (30 minutes after antacid) or as a retention enema in 14 patients. In all patients, response was assessed by clinical and neurological examination, serial hemodynamic evaluation of blood pressure, central venous pressure, cardiac index and urinary output, by laboratory analysis of urinary sodium, and where possible, serial creatinine clearances and daily determinations of parameters of renal and hepatic function, including venous blood ammonia, performed by the method of Seligson, et al.37 Initial dosage was 500 mg suspended in water given rectally at 6 hourly intervals or per nasogastric tube (30 minutes after antacid) and repeated at 4 hourly intervals. Results Thirteen of the 35 patients did not respond to therapy at all (37% NONRESP, Group 3), 17 responded but did not survive (49%6 RESP, Group 2) and 5 patients responded and survived (14% SURV, Group 1). Thus, 63% of all patients responded. Neurological: There was by definition no obvious response in 13 patients (37% NONRESP) and the response in the remaining 22 (63%) was variable. The level of consciousness improved in all these patients within I to 5 days to the degree indicated in Fig. 1. All survivors improved to grade I within 2 to 5 days, in the RESP group 5 patients improved to grade II and 6 to grade III within 24 hrs, 2 patients to grade I and 2 to grade III in 48 hrs, and 2 patients to grade II within 5 days (Fig. 1). TABLE 2. Clinical Picture
Resp
Patients
+
Nonresp
Resp
Surv
No
%
1 12 17 10 11 13
2 15 13 14 14 15
1 4 3 2 1 5
4 31 33 26 26 33
11.5 88.5 94.2 74.3 74.3 94.2
Hepatic Coma I II III IV Renal Manifestations*
GI-Bleeding Ascites Jaundice
* Urine Output < 20 cc/hr or
Urine Na < 10 mEq/liter.
388
FISCHER AND OTHERS
the index remained within the normal range (3.75 + 0.5 1/min/m2) and increased in 2 patients from 4.7 to 5.7 I/min/m2 (t = 1.59, P = NS) (paired t-test). Hepatic and Renal Function: In the SURV, the mean urinary output in 24 hours was 697 (+352) ml before treatment with L-Dopa and increased to 2440 (+440) and after initiation of therapy (P < 0.02). In the RESP, the mean daily output increased from 758 (+181) to 1098 (±219), P < 0.05. The mean urinary sodium output in the RESP increased from 10.6 (+3) to 40 (+7) mEq/1 (P < 0.001) and from 34 (+20) to 103 (± 14) mEq/l in the SURV (P < 0.05). In the NONRESP, mean urinary output (228 + 70 ml) and urinary sodium (19 + 12 mEq) remained uninfluenced by L-Dopa (Table 3). Creatinine Cleardnce: In those patients in whom creatinine clearance was measured serially, it increased. Changes in renal function will be the subject of a subsequent more detailed report. Liver Chemistries: The mean level of ammonia in the RESP was 178 (+25 ug%o) before and 193 (+43) after administration of L-Dopa; in the SURV, there was a statistically insignificant decrease from 224 (±+57) to 124 (+21 ,ug%o), (P = NS). Total serum bilirubin, transaminase, total protein and albumin remained unchanged during the treatment period with L-Dopa.
RESPONDERS COMA IV
m
ALERT
Ann. Surg. * April 1976
I IlI
-RESPONDERS SURVIVORS COMA IS
m
U. ALERT I
Duration of Coma
L 1
2
3
4
5
DA YS FIG. 1. Graphic representation of response to L-Dopa in patients with hepatic encephalopathy. Improvement in coma state is graphed against time. Definition of stage of coma is given in text.
Cardiovascular: The mean diastolic blood pressure increased from 76 (+4) to 90 (+4.4) P = NS) mm Hg in the SURV and from 60 (±4.4) to 85 (+4.2) (P < 0.001) mm Hg in the RESP. In the NONRESP, a slight decrease from 67 (+11) was observed (P = NS). The mean central venous pressure decreased from 10.4 (+3) to 7 (+2) in the SURV and from 20.3 (+7) to 8.3 (±+1.5) mm Hg in the RESP (P < 0.05). Insufficient information is available in the NONRESP. The mean cardiac index decreased from 6.6 (±1.2) to 4.5 (±0.5) 1/min/m2 in 6 patients of the RESP, in 8 patients of the same group,
The initiation of L-Dopa therapy (Table 4) was variable. In the survivors, therapy was started within 1.4 (+0.8) days after the onset of coma (group 1), whereas there was a delay of 6.7 (± 1.6) days in the responders (group 2) and 9.5 (± 1.6) days in the nonresponders (group 3). The difference between the SURV and the RESP is significant to P < 0.01, the difference between the SURV and the NONRESP to P < 0.001. Duration of treatment with L-Dopa varied again to a great extent: While mean duration in the SURV was 10.2 (±2.0) days, it was 6.1 (±1.4) days in the RESP and only 3.0 (±1.6) days in the NONRESP. Four patients in this latter group received only one single dose for various reasons. There is no statistical difference in duration of therapy between the SURV and the RESP, while the difference between SURV and NONRESP is significant to P < 0.01.
TABLE 3. Renal Function Following L-Dopa
Urinary Volume
Urinary Na
Group
Before
After
Before
After
1. Survivors 2. Responders 3. NonResponders
697 352 758 ± 181 228 ± 70
2440 ± 440t 1098 ± 219* 240 ± 67
34 ± 20 10.6 ± 3 19 ± 12
103 ± 14§ 40 ± 7t 23 ± 6
*P
The use of L-Dopa in hepatic coma has been the subject of numerous reports since 1970. The following represents our experience with a rather heterogenous group of patients treated at the Massachusetts General Hospital over the past 4 years. Thirty-five patients with severe liver disease, a mean age of 53 ± 3.5 years, including nutritional cirrhosis with acute coma and acute hepatitis were treated. Four patients were judged grade III, 31 patients grade IV. All patients had previously been treated with protein restriction, orally administered non-absorbable antibiotics, fluid and electrolytes, and in some cases, steroids. L-Dopa was given orally in 21 patients, and as a retention enema in 14. Thirteen of the 35 patients did not respond to therapy. Seventeen responded, but did not survive, and 5 patients responded and survived. There was no difference between any of the groups as far as dosage of L-Dopa and clinical features. The one striking finding as the differences between groups was the time of initiation of L-Dopa therapy. In Group I, the survivors, therapy was started within 1.4 ± 0.8 days after the onset of coma. In Group II, there was an initiation of therapy at 6.7 ± 1.6 days, and in the non-responders 9.5 ± 1.6 days. These differences are highly significant. The results suggest that coma may pass from a reversible to an irreversible stage, and that L-Dopa therapy initiated early in the course of hepatic coma, may be of some benefit.
From the Departments of Medicine and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 a
controlled double blind study.6 Several studies of the
use of L-Dopa in hepatic coma are in progress, but stable
patients in hepatic encephalopathy are not common, and most of these studies have been hampered by the lack of sufficient numbers of patients. In the following report, 35 patients with hepatic encephalopathy were treated with Levo-Dopa, either orally or by retention enema. In spite of the variability
of the clinical condition and of the clinical course, which precluded inclusion in a prospective double blind study, certain features emerge which may help in the design of a prospective study of treatment of hepatic
encephalopathy.
Material Thirty-five patients, 15 males and 20 females ranging in S INCE the first report by Parkes, et al.31 on the use of L- age from 7 to 78 years, with a mean age of 53 + 3.5 Dopa in hepatic coma, several reports have appeared years were studied. All patients had severe liver disease suggesting that patients in previously unresponsive (Table 1). The etiology was alcoholic cirrhosis in 22 hepatic coma may awake following the administration (63%), acute hepatic necrosis in 7 (20%) (viral) of Levo-Dopa in amounts ranging from 50 mg/kg in hepatitis in 5 (14%) and undefined cirrhosis in 1 (3%). divided doses, to 5 gm given in a single dose. 1.14,15,28,33,36 Diagnosis was based on history, clinical findings, serial The mode of administration has included oral (naso- biochemical tests and liver biopsy, and was confirmed in 12 patients at necropsy. Clinical features of the gastric tube), rectal, as well as intravenous routes. The variability of consciousness in hepatic encephalop- hepatic disease included coma, which was grade III in athy is well known. Patients in grade IV coma may 4 patients (11%), grade IV in 31 patients (89%o), based on awake without demonstrable improvement in liver func- a classification originally suggested by Adams and Foley tion, and the efficacy of a given therapeutic agent in (2), with modifications of the criteria proposed by hepatic coma is difficult to prove. For example, Trey, et al.39 Grade I fluctuant mild confusion with euphoria the mainstay of therapy in hepatic encephalopathy, and/or depression, slurred speech, disorder "intestinal sterilization," have never been subjected to in sleep rhythm. Grade II (impending coma) accentuation of stage I with drowsiness, inappropriate behavior, Submitted for publication September 12, 1975. Supported in Part by Grant #AM-15347, U.S.P.H.S. but ability to maintain sphincter control. 386
VOl. 183.o NO. 4
L-DOPA IN HE]PATIC COMA TABLE 1. Etiology of Liver Disease
Alcoholic Cirrhosis Viral Hepatitis Acute Hepatic Necrosis Undefined Cirrhosis No. of Patients
Pts.
Nonresp
Resp
22 5 7 1 35
11
2
9 5 3
13
17
387
steroids. Failure to improve or further deterioation in Resp + Surv mental status was considered an indication for L-Dopa (Laro-Dopa 500 mg tablet, kindly donated by Dr. Clif2 ford Joseph of Hoffman-LaRoche Laboratories, Inc., Nutley, New Jersey). 2 I 5
Grade III (stupor), sleep most of the time, but arousable. Marked confusion is present with lack of knowledge of surroundings. Grade IV (coma), physical responses to painful stimuli may or may not be present.
Cardiovascular and Renal Thirty-three of the 35 patients were thought to manifest stigmata of high cardiac output, either by direct measurement or as manifestation of warm skin, bounding pulses, heaving and active precordia and decreased peripheral resistance. When cardiac outputs were measured, cardiac index was considered elevated, if a value of greater than 4.25 1/min/m2 was obtained. Hypotension, defined as a blood pressure 20 mm Hg systolic less than previously known or recorded blood pressure, was present in most patients. Thirty-three of the 35 patients had a urinary output less than 20 cc/hr with a urinary sodium lower than 10 mEq/liter immediately before therapy, but some were not oliguric on the basis of 24 hr urine volume. Clinical Accompaniments Gastrointestinal bleeding (defined as requiring more than 2 units of blood over a total course) occurred in 26 patients (74%), ascites in 26 (74%) and jaundice in 33 (94%). Six patients had a total bilirubin between 1.5-5 mg/100 ml, 11 had a bilirubin greater than 5, and 17 patients had a bilirubin in excess of 25 mg/100 ml.
Etiology Major surgery, including aortic valve replacement, cholecystectomy, craniotomy and mastectomy had been performed in 5 patients before coma developed, and in an additional 12 patients after the onset of coma because of uncontrolled bleeding from esophageal varices, where various decompressive or ablative procedures were carried out in an effort to arrest bleeding. Prior to initiation of L-Dopa therapy, all patients had been treated with "maximal standard therapy," including protein restriction, orally and rectally administered nonabsorpable antibiotics (neomycin or humatin) intravenous administration of dextrose and electrolytes, cathartics and enemas, and in some patients, cortico-
Administration of L-Dopa L-Dopa was given as a suspension in water, orally via a nasogastric tube in 21 patients (30 minutes after antacid) or as a retention enema in 14 patients. In all patients, response was assessed by clinical and neurological examination, serial hemodynamic evaluation of blood pressure, central venous pressure, cardiac index and urinary output, by laboratory analysis of urinary sodium, and where possible, serial creatinine clearances and daily determinations of parameters of renal and hepatic function, including venous blood ammonia, performed by the method of Seligson, et al.37 Initial dosage was 500 mg suspended in water given rectally at 6 hourly intervals or per nasogastric tube (30 minutes after antacid) and repeated at 4 hourly intervals. Results Thirteen of the 35 patients did not respond to therapy at all (37% NONRESP, Group 3), 17 responded but did not survive (49%6 RESP, Group 2) and 5 patients responded and survived (14% SURV, Group 1). Thus, 63% of all patients responded. Neurological: There was by definition no obvious response in 13 patients (37% NONRESP) and the response in the remaining 22 (63%) was variable. The level of consciousness improved in all these patients within I to 5 days to the degree indicated in Fig. 1. All survivors improved to grade I within 2 to 5 days, in the RESP group 5 patients improved to grade II and 6 to grade III within 24 hrs, 2 patients to grade I and 2 to grade III in 48 hrs, and 2 patients to grade II within 5 days (Fig. 1). TABLE 2. Clinical Picture
Resp
Patients
+
Nonresp
Resp
Surv
No
%
1 12 17 10 11 13
2 15 13 14 14 15
1 4 3 2 1 5
4 31 33 26 26 33
11.5 88.5 94.2 74.3 74.3 94.2
Hepatic Coma I II III IV Renal Manifestations*
GI-Bleeding Ascites Jaundice
* Urine Output < 20 cc/hr or
Urine Na < 10 mEq/liter.
388
FISCHER AND OTHERS
the index remained within the normal range (3.75 + 0.5 1/min/m2) and increased in 2 patients from 4.7 to 5.7 I/min/m2 (t = 1.59, P = NS) (paired t-test). Hepatic and Renal Function: In the SURV, the mean urinary output in 24 hours was 697 (+352) ml before treatment with L-Dopa and increased to 2440 (+440) and after initiation of therapy (P < 0.02). In the RESP, the mean daily output increased from 758 (+181) to 1098 (±219), P < 0.05. The mean urinary sodium output in the RESP increased from 10.6 (+3) to 40 (+7) mEq/1 (P < 0.001) and from 34 (+20) to 103 (± 14) mEq/l in the SURV (P < 0.05). In the NONRESP, mean urinary output (228 + 70 ml) and urinary sodium (19 + 12 mEq) remained uninfluenced by L-Dopa (Table 3). Creatinine Cleardnce: In those patients in whom creatinine clearance was measured serially, it increased. Changes in renal function will be the subject of a subsequent more detailed report. Liver Chemistries: The mean level of ammonia in the RESP was 178 (+25 ug%o) before and 193 (+43) after administration of L-Dopa; in the SURV, there was a statistically insignificant decrease from 224 (±+57) to 124 (+21 ,ug%o), (P = NS). Total serum bilirubin, transaminase, total protein and albumin remained unchanged during the treatment period with L-Dopa.
RESPONDERS COMA IV
m
ALERT
Ann. Surg. * April 1976
I IlI
-RESPONDERS SURVIVORS COMA IS
m
U. ALERT I
Duration of Coma
L 1
2
3
4
5
DA YS FIG. 1. Graphic representation of response to L-Dopa in patients with hepatic encephalopathy. Improvement in coma state is graphed against time. Definition of stage of coma is given in text.
Cardiovascular: The mean diastolic blood pressure increased from 76 (+4) to 90 (+4.4) P = NS) mm Hg in the SURV and from 60 (±4.4) to 85 (+4.2) (P < 0.001) mm Hg in the RESP. In the NONRESP, a slight decrease from 67 (+11) was observed (P = NS). The mean central venous pressure decreased from 10.4 (+3) to 7 (+2) in the SURV and from 20.3 (+7) to 8.3 (±+1.5) mm Hg in the RESP (P < 0.05). Insufficient information is available in the NONRESP. The mean cardiac index decreased from 6.6 (±1.2) to 4.5 (±0.5) 1/min/m2 in 6 patients of the RESP, in 8 patients of the same group,
The initiation of L-Dopa therapy (Table 4) was variable. In the survivors, therapy was started within 1.4 (+0.8) days after the onset of coma (group 1), whereas there was a delay of 6.7 (± 1.6) days in the responders (group 2) and 9.5 (± 1.6) days in the nonresponders (group 3). The difference between the SURV and the RESP is significant to P < 0.01, the difference between the SURV and the NONRESP to P < 0.001. Duration of treatment with L-Dopa varied again to a great extent: While mean duration in the SURV was 10.2 (±2.0) days, it was 6.1 (±1.4) days in the RESP and only 3.0 (±1.6) days in the NONRESP. Four patients in this latter group received only one single dose for various reasons. There is no statistical difference in duration of therapy between the SURV and the RESP, while the difference between SURV and NONRESP is significant to P < 0.01.
TABLE 3. Renal Function Following L-Dopa
Urinary Volume
Urinary Na
Group
Before
After
Before
After
1. Survivors 2. Responders 3. NonResponders
697 352 758 ± 181 228 ± 70
2440 ± 440t 1098 ± 219* 240 ± 67
34 ± 20 10.6 ± 3 19 ± 12
103 ± 14§ 40 ± 7t 23 ± 6
*P
