- Email: [email protected]
Impairment of psychomotor responses after conscious sedation in cirrhotic patients undergoing therapeutic upper GI endoscopy
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2002 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 97, No. 7, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(02)04187-4
Impairment of Psychomotor Responses After Conscious Sedation in Cirrhotic Patients Undergoing Therapeutic Upper GI Endoscopy A. E. Vasudevan, M.B.B.S., M. Med., K. L. Goh, M.B.B.S., F.R.C.P., M.D., F.A.C.G., and A. M. Bulgiba, M.B.B.S., M.P.H. Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
OBJECTIVES: The aim of this study was to determine whether the number connection test (NCT) times of a group of cirrhotic patients without clinically overt hepatic encephalopathy and a group of healthy patients without liver disease who were undergoing endoscopy were prolonged after sedation with short acting i.v. benzodiazepines. METHODS: All patients were administered the NCT in a standard fashion for 30 min before sedation for an upper GI endoscopy and then 2 h after sedation postprocedure. Two NCTs were carried out before and 2 h after sedation, and the mean of the tests pre- and postsedation calculated. Based on the upper limit of the 95% CI of the presedation NCT of patients without liver disease as the cut-off level for hepatic encephalopathy, the proportion of cirrhotic patients with subclinical encephalopathy before and after sedation were also determined. RESULTS: A total of 61 consecutive cirrhotic patients who underwent therapeutic upper GI endoscopy completed the study. The mean presedation NCT time was 43.5 s (95% CI ⫽ 39.0 – 48.1 s) and the mean postsedation NCT time 60.0 s (95% CI ⫽ 50.7– 69.3 s). The difference between the mean pre- and postsedation NCT times was 16.4 s (95% CI ⫽ 9.8 –23.1 s; p ⬍ 0.001). A total of 38 consecutive patients without clinical or biochemical evidence of liver disease who presented for upper GI endoscopy completed the NCT as described for the group of cirrhotic patients. The mean (⫾ SD) baseline NCT time was 34.7 ⫾ 7.9 s (95% CI ⫽ 32.1–37.2 s), whereas the mean postsedation NCT time was 33.7 ⫾ 8.5 s (95% CI ⫽ 30.9 –36.5 s). This difference was not statistically significant (p ⫽ 0.177). Using the upper limit of the 95% CI of the mean (37.4 s) of the presedation time in the patients without liver disease as the cut-off between normal and encephalopathy, the number of cirrhotic patients with abnormal presedation NCT times was 33 patients (54.1%), and this number rose to 46 patients (75.4%) after sedation with midazolam. This increase in proportion of cirrhotic patients with prolonged NCT time was statistically significant (p ⬍ 0.001).
CONCLUSIONS: Sedation with i.v. midazolam prolongs NCT times in cirrhotic patients but not in healthy individuals without liver disease. The proportion of patients with prolonged NCT times increased in patients with cirrhosis following sedation, whereas this did not occur in those without liver disease. (Am J Gastroenterol 2002;97:1717–1721. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION Conscious sedation in the form of an i.v. preparation of a short acting benzodiazepine (1) is routinely administered to patients undergoing GI endoscopy. In patients with liver disease, this may impair psychomotor responses and precipitate or unmask hepatic encephalopathy (2, 3). Not infrequently, this impairment may be subclinical and can only be detected when formal psychometric tests are carried out (4, 5). The number connection test (NCT) has been used in clinical practice for the purpose of detecting subclinical hepatic encephalopathy. The objectives of this study were: 1) to determine whether sedation with midazolam resulted in prolongation in NCT times in cirrhotic patients without clinically overt hepatic encephalopathy undergoing therapeutic upper GI endoscopy; and 2) to determine whether sedation prolonged the NCT times in a group of patients without evidence of liver disease. We also sought to set a cut-off level of normality based on the NCT times of patients without liver disease and, based on this cut-off level, to determine the proportion of cirrhotic patients with abnormal NCT times suggestive of subclinical hepatic encephalopathy (SHE) pre- and postsedation.
MATERIALS AND METHODS Study Subjects Consecutive patients presenting to the University Malaya Medical Center Endoscopy Unit for elective variceal ligation or sclerotherapy between January, 2000, and Septem-
1718
Vasudevan et al.
ber, 2000, who fulfilled the inclusion and exclusion criteria were prospectively recruited for the study. Inclusion Criteria Patients with a firm diagnosis of liver cirrhosis based on clinical, radiological, or histological evidence but without clinically overt hepatic encephalopathy were included. Only patients with a minimum literacy level with the ability to recognize numbers easily and confidently were recruited. Exclusion Criteria Patients who were medically unstable, i.e., with active GI bleeding, concurrent medical illnesses such as chest infections, renal disease, or overt hepatic encephalopathy, as well as those with a history of recent (within the last 4 wk) alcohol consumption, drug addiction, psychiatric illness, or recent (within the last 4 wk) consumption of neuroactive medication or drugs (benzodiazepines, phenothiazines, cimetidine, azoles, or antiepileptics) that would interfere with midazolam clearance and metabolism were excluded. Those who were aged ⬎70 yr or who had visual impairment or any other disability that would interfere with the ability to complete the NCT were also excluded. Patients who required more sedation (i.e., increased dosage of midazolam or the addition of pethidine) or who required reversal of sedation with flumazenil were also not considered for the study. Written informed consent was obtained from recruited patients before the commencement of the NCT. A physical examination of the patients was carried out to establish the severity of ascites and presence of encephalopathy. These parameters were documented in addition to the liver function test results and prothrombin time. Components of these tests such as the Child-Pugh score (6) were used to grade the severity of liver disease (grades A, B, and C, and numerical scores). The presence of esophageal or gastric varices was noted. Patients Without Liver Disease (Healthy Subjects) Patients undergoing upper GI endoscopy for dyspepsia who had no clinical or biochemical evidence of liver disease and who were otherwise healthy were also recruited consecutively studied. The exclusion criteria were the same as in the cirrhotic group and the NCTs were carried out in a similar manner and with the same dose of midazolam. Study Design THE NUMBER CONNECTION TEST. The patients were initially shown an example of the NCT to illustrate how the numbered circles should be connected with a pen. An example of randomly arranged circles numbered from 1 to 8 was shown and the patient was instructed on the method to connect them. Subsequently, a trial or demonstration test was administered to allow the patients to become accustomed to the procedure. Only after this was the length of time spent completing the four different variations of the NCT recorded. The reason for this was to eliminate the effect of the learning curve (3–5, 7, 8).
AJG – Vol. 97, No. 7, 2002
All patients in the study population performed the number connection test (NCT-A) at least 30 min before sedation and 2 h after the sedation was administered. The repetition of the NCT at 2 h was carried out because patients undergoing endoscopy are usually discharged between 1.5 and 2 h at our endoscopy unit. This time frame was also intended to eliminate the effects of hypoxemia, which could influence judgment, and to obviate the effect of antegrade amnesia (3). After the initial demonstrations, of which time was taken for the demonstration NCT but discarded, the patients then took two presedation NCT tests (NCT-1 and NCT-2). Subsequently, at 2 h patients were required to repeat the demonstration NCT to reaccustom them to the procedure, before completing two additional NCTs of different arrangement (NCT-3 and NCT-4). The time taken to complete NCT-1 and NCT-2 (mean 1) was averaged and taken as the presedation NCT time. Similarly, the times taken for NCT-3 and NCT-4 (mean 2) values were also averaged and the mean taken as the postsedation NCT time. Errors were pointed out to patients as they were carrying out the test, and they were instructed to start from the last number that they had missed. The time for errors was included into the NCT time. The NCTs were conducted on all patients by the principal investigator so as to eliminate variability in the conduct of the test. The tests were carried out in a quiet side room in the endoscopy unit for all subjects. We arbitrarily chose the upper limit of the 95% CI of the mean for healthy subjects without liver disease as the cut-off level between normal and abnormal NCT times. SEDATION. Sedation was standardized to 5 mg of midazolam for all patients in this study, as this is the dose most frequently used in our patients who are undergoing therapeutic upper GI endoscopy. In our practice locally, droperidol and narcotics are not routinely used. Flumazenil (a competitive benzodiazepine receptor antagonist) was available if the need arose to reverse sedation in case of respiratory depression in an overly sedated patient. As is standard practice in our endoscopy unit, oxygen saturation, pulse rate, and blood pressure were measured continuously during the procedure. Approval was obtained to carry out this study from the University Malaya Medical Center Ethics Sub-Committee and the Medical Research Committee of the University of Malaya. Statistical Analyses Differences between the mean pre- and postsedation NCT times were determined using the paired t test in patients with cirrhosis as well as in those without liver disease. The Mann-Whitney U test was used to assess the differences in age as well as pre- and postsedation NCT time between the cirrhotic and control patients. The 2 test was used to compare educational levels between the two groups. All results were considered significant at a 5% level (p ⬍ 0.05).
AJG – July, 2002
Psychomotor Responses After Conscious Sedation
Table 1. Comparison of Parameters Between Cirrhotic Patients and Patients Without Liver Disease Parameter
Cirrhotic Patients
Patients Without Liver Disease
Mean age, yr* Educational level† Primary Secondary Tertiary
50.61 (SD ⫾ 10.52)
50.35 (SD ⫾ 9.62)
19 35 7
6 22 6
*p ⫽ 0.608. †p ⫽ 0.314.
RESULTS Demographic Characteristics of Cirrhotic Patients A total of 63 consecutive patients who underwent therapeutic upper GI endoscopy were recruited. Two patients were unable to complete the NCT postsedation, as one required flumazenil to reverse respiratory depression and the other patient developed overt hepatic encephalopathy. The final analyses in this study was carried out on 61 patients. The mean (⫾ SD) age was 50.6 ⫾ 10.5 yr with an age range of 20 – 68 yr. The majority of the patients were men (n ⫽ 53, 86.9%), with eight women (13.1%). The mean length of time spent in school was 9.3 ⫾ 3.5 yr. The main cause of cirrhosis was chronic viral hepatitis; 24 patients (45.9%) had hepatitis B and four had hepatitis C infections. A total of 16 patients (26.2%) had alcoholrelated cirrhosis, whereas 12 patients (19.7%) had cirrhosis of unknown etiology. Other causes of cirrhosis were autoimmune hepatitis (four patients, 6.6%) and primary sclerosing cholangitis (one patient). The mean Child-Pugh score was 7.7 ⫾ 2.2, with a minimal score of 5 and a maximal score of 13. A total of 23 patients (37.7%) were classified as Child-Pugh A, 26 patients (42.6%) Child-Pugh B, and 12 patients (19.7%) ChildPugh C. The mean total bilirubin was 33.9 ⫾ 29.5 mol/L, the mean albumin level 30.4 ⫾ 7.5 g/L, mean ALT level 59.7 ⫾ 26.3 IU/L, and the mean AST level 59.7 ⫾ 34.3 IU/L. The mean INR was 1.4, with a range of 1.0 –2.2. Demographic Characteristics of Patients Without Liver Disease A total of 38 consecutive patients without clinical or biochemical evidence of liver disease who presented for upper GI endoscopy completed the NCT as described for the group of cirrhotic patients. There were no dropouts in this group. The mean age was 50.9 ⫾ 9.6 yr, and the mean length of education 9.3 ⫾ 3.6 yr.
1719
Mean serum albumin was 38.9 ⫾ 3.4 g/L, mean serum total bilirubin 11.4 ⫾ 5.9 mol/L, mean ALT 47.5 ⫾ 14.7 IU/L, and mean AST 28.7 ⫾ 8.4 IU/L. These parameters were all within the normal reference range for our laboratory. NCT Results Before and After Sedation for Cirrhotic Patients The mean presedation time for the completion of the NCT-1 and NCT-2 was 43.5 s (95% CI ⫽ 39.0 – 48.1 s), whereas the mean postsedation time for the completion of NCT-3 and NCT-4 was 60.0 s (95% CI ⫽ 50.7– 69.3 s). The difference between the mean pre- and postsedation NCT times was 16.4 s (95% CI ⫽ 9.8 –23.1 s). This difference of the mean times was highly significant (p ⬍ 0.001). NCT Results Before and After Sedation for Patients Without Liver Disease The mean (⫾ SD) baseline NCT time was 34.7 ⫾ 7.9 s (95% CI ⫽ 32.1–37.2 s), whereas the mean postsedation NCT time was 33.7 ⫾ 8.5 s (95% CI ⫽ 30.9 –36.5 s). Although, there was a numerical improvement in NCT time postsedation, this difference was not statistically significant (p ⫽ 0.177). Cirrhotic Patients Versus Healthy Subjects The cirrhotic patients and those without liver disease were comparable with respect to age and educational level (Table 1). There was, however, a significant difference in both the presedation (p ⫽ 0.013) and postsedation NCT (p ⬍ 0.001) times between the patients with cirrhosis and those without liver disease (Table 2). Prevalence of Subclinical Hepatic Encephalopathy Using the upper limit of the 95% CI of the mean (31.7–37.4 s) of the presedation time in the patients without liver disease as the arbitrary cut-off between normal and encephalopathy, the number of cirrhotics with abnormal presedation NCT times was 33 patients (54.1%), whereas this number rose to 46 patients (75.4%) after sedation with midazolam. This increase in proportion of cirrhotic patients with prolonged NCT time was statistically significant (p ⬍ 0.001).
DISCUSSION This study shows that the time to complete the NCT is impaired 2 h after sedation when i.v. midazolam is administered to cirrhotic patients without clinically overt hepatic encephalopathy. There were no prolongation in NCT times
Table 2. NCTs Pre- and Postsedation for Cirrhotic and Normal Patients Patients Cirrhotic Normal Post ⫽ postsedation; Pre ⫽ presedation.
NCT Pre (95% CI)
NCT Post (95% CI)
p Value
43.5 (39.0–48.1) 34.6 (32.1–37.2) p ⫽ 0.013
59.9 (50.7–69.3) 33.7 (30.9–36.5) p ⬍ 0.001
⬍0.001 0.177
1720
Vasudevan et al.
in a comparable group of patients who did not have clinical nor biochemical evidence of liver disease and who served as controls. Using the upper limit of the 95% CI of the mean baseline NCT of the patients without liver disease presedation as the cut-off level, more than half of the patients (54.1%) in the cirrhotic group had abnormal NCT times presedation, and this proportion increased to 75.4% postsedation. By implication, this group of cirrhotic patients who did not have overt clinical encephalopathy had SHE, which was further unmasked in some cirrhotic patients after sedation. NCT times can be influenced by various factors such as age (4, 5, 9), level of education (4, 5), and severity of liver disease (8, 10 –12). In our study, these potential confounding factors are obviated, as each patient serves as his or her own control. The NCT test itself, if carried out improperly or casually, may lead to inaccurate NCT times. In our study, we have taken stringent measures to ensure that the test was performed as accurately as possible and in as standard a manner for all patients and subjects. The test was performed in quiet room to optimize performance. The choice of a cut-off level was arbitrary and was based on the NCTs of the group of healthy patients without liver disease. These patients were clearly shown to have no prolongation of their NCTs with sedation, and we believed that their NCT times were a fairly accurate representation of a normal NCT time. Furthermore, this group of patients was subjected to the same circumstances for testing as was the cirrhotic group and, therefore, serves as a reliable comparator group. SHE may be subtle and difficult to detect on clinical examination. Often the patient will have normal mental and neurological function, and will only exhibit abnormalities on specific psychometric testing indicating impairment of psychomotor skills. Several pyschometric tests are available such as the NCT, block design test, and digit symbol test. The most popular of such tests is the NCT, which we used in our study. Although these tests are generally easy to perform, interpretation of test scores has been noted to be difficult (6). The definition of abnormal NCT test has been quite arbitary. Zeegen et al. (10) in 1970 were the first to apply objective psychometric tests in the assessment of cerebral dysfunction patients with liver cirrhosis. In their study, Zeegen et al. use the sum total of Reitan trail-making test A and B (the predecessor of our present day NCT) of ⬎130 s as abnormal. Rikkers et al. (13) and Groenweg et al. (7) used the mean ⫹ 2 SD as the cut-off level between abnormal and normal test results. As with ourselves, Marchesini et al. have used the upper limit of the 95% CI as the cut-off (14). By definition, subjects with test results above these cut-off levels were classified as having SHE. Conn (12) has arbitrarily classified hepatic encephalopathy according to stated times, as follows: 15–30 s ⫽ non (0), 31–50 s ⫽ mild (1⫹), 51– 80 s ⫽ moderate (2⫹), 81–120 s ⫽ severe (3⫹), and ⬎120 s ⫽ coma (4⫹). The definition of a cut-off level of
AJG – Vol. 97, No. 7, 2002
normal/abnormal for all these various tests is necessarily arbitrary, as there is no “gold standard” against which these tests can be compared. Clearly, patients with cirrhosis without overt hepatic encephalopathy do poorly after sedation. If we arbitrarily define subclinical encephalopathy as patients having NCT times exceeding the cut-off level that we have set, then we have an alarming 75.4% of cirrhotic patients in this category, 2 h after benzodazepine sedation was administered. Studies have shown that benzodiazepine metabolism is affected in patients with advanced or chronic liver disease, leading to a prolonged drug effect and action (2, 15). This is clearly demonstrated in this study, in which there was no impairment in NCTs after i.v. midazolam in patients without liver disease. MacGilchrist et al. (2) demonstrated that midazolam causes psychomotor deficits in patients with severe alcoholic cirrhosis and that midazolam was detectable in plasma up to 6 h after administration. The sedative-hypnotic actions of benzodiazepines such as midazolam, which bind to benzodiazepine receptor ligands in the brain, are mediated by the ␥-aminobutyric acid (GABA) neurotransmitter system (16). GABA is the principal inhibitory neurotransmitter in the mammalian brain. Within the neural membrane of the GABA postsynaptic receptor is a supramolecule complex that has binding sites for the synergistic ligands, GABA, benzodiazepines, and barbiturates. Activation of the GABA neurotransmitter system opens chloride-ion channels in postsynaptic membranes, resulting in hyperpolarization and reduced excitability of the neurone (17, 18), resulting in an inhibitory postsynaptic potential. This stimulation of GABA-ergic activity by midazolam is responsible for the ability of benzodiazepine class of drugs to reduce anxiety, reduce muscle tone, mediate amnesia and sedation, and act as an anticonvulsant (17). It is postulated that in patients with liver cirrhosis, there is up-regulation of benzodiazepine receptor sites, thus enhancing sensitivity to benzodiazepines. In one study (19), it was found that rabbits with induced hepatic coma had an approximately 40% increase in the number of benzodiazepine binding sites on GABA receptors, leading to the conclusion that the increased sensitivity to benzodiazepines is mediated by the increased binding sites for this drug, and thus permitting enhancement of its side effects. This provides an animal model for the possible elucidation of increased sensitivity of benzodiazepines in cirrhotic patients. Bakti et al. (20) studied cirrhotic patients using triazolam and found that triazolam levels were comparable in cirrhotic patients and controls, whereas cirrhotic patients exhibited abnormal psychometric testing after triazolam. They suggested that hypersensitivity to benzodiazepines may contribute to the prolonged drug effect. The clinical significance of subclinical encephalopathy has generated great interest, as it is said to impair driving (21) and daily functioning (7). Schomerus et al. (21) showed in 1981 that cirrhotic patients exhibited defective cerebral
AJG – July, 2002
functions in psychomotor functioning, reaction time, and visual retention. These functions are relevant to driving; and, in fact, only 15% of 40 cirrhotic patients evaluated in their study were found to be fit to drive a car, whereas 60% were considered completely unfit to drive. However, there is as yet no absolute cut-off time for the NCT by which a patient can be deemed unfit to drive. Groenweg et al. (7) studied 179 patients and found that 27% of outpatient cirrhotics had subclinical encephalopathy. Using a Sickness Impact Profile questionnaire, these investigators concluded that these patients with subclinical encephalopathy had impaired daily functioning and warranted some form of treatment. These cirrhotic patients with subclinical encephalopathy had sleep disturbances, impaired calculation, shortened attention span, and mild personality change. More recently, Hartmann et al. (22) studied subclinical hepatic encephalopathy in greater detail with regard to the prognosis of this condition. They found that the patients with subclinical hepatic encephalopathy as diagnosed with psychometric tests or with spectral electroencephalography had more episodes of clinical hepatic encephalopathy, however, survival was similar to that in patients without subclinical hepatic encephalopathy. It is evident from this study that sedation with midazolam has an adverse effect on patients with liver cirrhosis even at 2 h (i.e., at discharge), whereas this effect was not seen in patients without evidence of liver disease. These findings suggest that caution should be exercised when procedures requiring sedation with benzodiazepines, even short acting ones such as midazolam, are undertaken in cirrhotic patients. It is conceivable that this impairment in NCT times may be present in cirrhotic patients for up to 6 h (2), as stated earlier. The clinical significance of subclinical hepatic encephalopathy needs further evaluation. In any case, all patients who undergo upper GI endoscopy with sedation should be accompanied on discharge, especially those patients who are cirrhotic. Reprint requests and correspondence: K. L. Goh, Department of Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. Received Aug. 6, 2001; accepted Feb. 15, 2002.
Psychomotor Responses After Conscious Sedation
3.
4. 5. 6.
7.
8.
9. 10.
11. 12.
13.
14.
15. 16.
17. 18. 19.
20.
21.
REFERENCES 1. Keefe EB. Sedation and analgesia for endoscopy. Gastroenterology 1995;108:932– 4. 2. MacGilchrist AJ, Birnie JJ, Cook A, et al. Pharmacokinetics
22.
1721
and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986;27:190 –5. Assy N, Rosser BG, Grahame GR, et al. Risk of sedation for upper GI endoscopy exacerbating subclinical hepatic encephalopathy in patients with cirrhosis. Gastrointest Endosc 1999; 49:690 – 4. Gitlin N. Subclinical portal-systemic encephalopathy. Am J Gastroenterol 1988;82:8 –11. Quero JC, Scalm SW. Subclinical hepatic encephalopathy. Semin Liver Dis 1996;16:321– 8. Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transection of the esophagus for bleeding esophageal varices. Br J Surg 1973;60:646 –9. Groeneweg M, Quero JC, De Bruijn I, et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 1998;28:45–9. Conn HO. Trailmaking and number connection tests in the assessment of mental state in portosystemic encephalopathy. Dig Dis Sci 1977;22:541–50. Davies ADM. The influence of age on Trailmaking Test performance. J Clin Psychol 1968;24:96 – 8. Zeegen R, Drinkwater JE, Dawson AM. Method for measuring cerebral dysfunction in patients with liver disease. Br Med J 1970;2:633– 6. Jones EA, Weissenborn K. Neurology and the liver. J Neurol Neurosurg Psychiatry 1997;63:279 –93. Conn HO, Lieberthal MM. Assessment of mental state. In: Conn HO, Lieberthal MM, eds. The hepatic coma syndromes and lactulose. Baltimore: Williams & Wilkins, 1979:169 – 88. Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: Detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 1978;75:462–9. Marchesini G, Zoli M, Dondi C, et al. Prevalence of subclinical hepatic encephalopathy in cirrhotics and relationship to plasma amino acid imbalance. Dig Dis Sci 1980;25:763– 8. Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther 1981;30:653– 61. Schafer DF, Jones EA. Hepatic encephalopathy and the gamma-aminobutyric-acid neurotransmitter system. Lancet 1982; 1:18 –20. Mullen KD, Jones EA. Natural benzodiazepines and hepatic encephalopathy. Semin Liver Dis 1996;16:255– 64. Wilkinson SJ. GABA, benzodiazepines and hepatic encephalopathy. Eur J Gastroenterol Hepatol 1995;7:323– 4. Fowler JM, Schafer DF. A mechanism for the sensitivity to benzodiazepines in hepatocellular failure: Evidence from an animal model. Gastroenterology 1981;80:1359 (abstract). Bakti G, Fisch HU, Karlagans G, et al. Mechanism of excessive sedative response of cirrhotics to benzodiazepines: Model experiments with triazolam. Hepatology 1987;7:629 –38. Schomerus H, Hamster W, Blunck H, et al. Latent portosystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive. Dig Dis Sci 1981;26:622– 30. Hartmann IJC, Groeneweg M, Quero JC, et al. The prognostic significance of sub clinical hepatic encephalopathy. Am J Gastroenterol 2000;95:2029 –34.
Vol. 97, No. 7, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(02)04187-4
Impairment of Psychomotor Responses After Conscious Sedation in Cirrhotic Patients Undergoing Therapeutic Upper GI Endoscopy A. E. Vasudevan, M.B.B.S., M. Med., K. L. Goh, M.B.B.S., F.R.C.P., M.D., F.A.C.G., and A. M. Bulgiba, M.B.B.S., M.P.H. Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
OBJECTIVES: The aim of this study was to determine whether the number connection test (NCT) times of a group of cirrhotic patients without clinically overt hepatic encephalopathy and a group of healthy patients without liver disease who were undergoing endoscopy were prolonged after sedation with short acting i.v. benzodiazepines. METHODS: All patients were administered the NCT in a standard fashion for 30 min before sedation for an upper GI endoscopy and then 2 h after sedation postprocedure. Two NCTs were carried out before and 2 h after sedation, and the mean of the tests pre- and postsedation calculated. Based on the upper limit of the 95% CI of the presedation NCT of patients without liver disease as the cut-off level for hepatic encephalopathy, the proportion of cirrhotic patients with subclinical encephalopathy before and after sedation were also determined. RESULTS: A total of 61 consecutive cirrhotic patients who underwent therapeutic upper GI endoscopy completed the study. The mean presedation NCT time was 43.5 s (95% CI ⫽ 39.0 – 48.1 s) and the mean postsedation NCT time 60.0 s (95% CI ⫽ 50.7– 69.3 s). The difference between the mean pre- and postsedation NCT times was 16.4 s (95% CI ⫽ 9.8 –23.1 s; p ⬍ 0.001). A total of 38 consecutive patients without clinical or biochemical evidence of liver disease who presented for upper GI endoscopy completed the NCT as described for the group of cirrhotic patients. The mean (⫾ SD) baseline NCT time was 34.7 ⫾ 7.9 s (95% CI ⫽ 32.1–37.2 s), whereas the mean postsedation NCT time was 33.7 ⫾ 8.5 s (95% CI ⫽ 30.9 –36.5 s). This difference was not statistically significant (p ⫽ 0.177). Using the upper limit of the 95% CI of the mean (37.4 s) of the presedation time in the patients without liver disease as the cut-off between normal and encephalopathy, the number of cirrhotic patients with abnormal presedation NCT times was 33 patients (54.1%), and this number rose to 46 patients (75.4%) after sedation with midazolam. This increase in proportion of cirrhotic patients with prolonged NCT time was statistically significant (p ⬍ 0.001).
CONCLUSIONS: Sedation with i.v. midazolam prolongs NCT times in cirrhotic patients but not in healthy individuals without liver disease. The proportion of patients with prolonged NCT times increased in patients with cirrhosis following sedation, whereas this did not occur in those without liver disease. (Am J Gastroenterol 2002;97:1717–1721. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION Conscious sedation in the form of an i.v. preparation of a short acting benzodiazepine (1) is routinely administered to patients undergoing GI endoscopy. In patients with liver disease, this may impair psychomotor responses and precipitate or unmask hepatic encephalopathy (2, 3). Not infrequently, this impairment may be subclinical and can only be detected when formal psychometric tests are carried out (4, 5). The number connection test (NCT) has been used in clinical practice for the purpose of detecting subclinical hepatic encephalopathy. The objectives of this study were: 1) to determine whether sedation with midazolam resulted in prolongation in NCT times in cirrhotic patients without clinically overt hepatic encephalopathy undergoing therapeutic upper GI endoscopy; and 2) to determine whether sedation prolonged the NCT times in a group of patients without evidence of liver disease. We also sought to set a cut-off level of normality based on the NCT times of patients without liver disease and, based on this cut-off level, to determine the proportion of cirrhotic patients with abnormal NCT times suggestive of subclinical hepatic encephalopathy (SHE) pre- and postsedation.
MATERIALS AND METHODS Study Subjects Consecutive patients presenting to the University Malaya Medical Center Endoscopy Unit for elective variceal ligation or sclerotherapy between January, 2000, and Septem-
1718
Vasudevan et al.
ber, 2000, who fulfilled the inclusion and exclusion criteria were prospectively recruited for the study. Inclusion Criteria Patients with a firm diagnosis of liver cirrhosis based on clinical, radiological, or histological evidence but without clinically overt hepatic encephalopathy were included. Only patients with a minimum literacy level with the ability to recognize numbers easily and confidently were recruited. Exclusion Criteria Patients who were medically unstable, i.e., with active GI bleeding, concurrent medical illnesses such as chest infections, renal disease, or overt hepatic encephalopathy, as well as those with a history of recent (within the last 4 wk) alcohol consumption, drug addiction, psychiatric illness, or recent (within the last 4 wk) consumption of neuroactive medication or drugs (benzodiazepines, phenothiazines, cimetidine, azoles, or antiepileptics) that would interfere with midazolam clearance and metabolism were excluded. Those who were aged ⬎70 yr or who had visual impairment or any other disability that would interfere with the ability to complete the NCT were also excluded. Patients who required more sedation (i.e., increased dosage of midazolam or the addition of pethidine) or who required reversal of sedation with flumazenil were also not considered for the study. Written informed consent was obtained from recruited patients before the commencement of the NCT. A physical examination of the patients was carried out to establish the severity of ascites and presence of encephalopathy. These parameters were documented in addition to the liver function test results and prothrombin time. Components of these tests such as the Child-Pugh score (6) were used to grade the severity of liver disease (grades A, B, and C, and numerical scores). The presence of esophageal or gastric varices was noted. Patients Without Liver Disease (Healthy Subjects) Patients undergoing upper GI endoscopy for dyspepsia who had no clinical or biochemical evidence of liver disease and who were otherwise healthy were also recruited consecutively studied. The exclusion criteria were the same as in the cirrhotic group and the NCTs were carried out in a similar manner and with the same dose of midazolam. Study Design THE NUMBER CONNECTION TEST. The patients were initially shown an example of the NCT to illustrate how the numbered circles should be connected with a pen. An example of randomly arranged circles numbered from 1 to 8 was shown and the patient was instructed on the method to connect them. Subsequently, a trial or demonstration test was administered to allow the patients to become accustomed to the procedure. Only after this was the length of time spent completing the four different variations of the NCT recorded. The reason for this was to eliminate the effect of the learning curve (3–5, 7, 8).
AJG – Vol. 97, No. 7, 2002
All patients in the study population performed the number connection test (NCT-A) at least 30 min before sedation and 2 h after the sedation was administered. The repetition of the NCT at 2 h was carried out because patients undergoing endoscopy are usually discharged between 1.5 and 2 h at our endoscopy unit. This time frame was also intended to eliminate the effects of hypoxemia, which could influence judgment, and to obviate the effect of antegrade amnesia (3). After the initial demonstrations, of which time was taken for the demonstration NCT but discarded, the patients then took two presedation NCT tests (NCT-1 and NCT-2). Subsequently, at 2 h patients were required to repeat the demonstration NCT to reaccustom them to the procedure, before completing two additional NCTs of different arrangement (NCT-3 and NCT-4). The time taken to complete NCT-1 and NCT-2 (mean 1) was averaged and taken as the presedation NCT time. Similarly, the times taken for NCT-3 and NCT-4 (mean 2) values were also averaged and the mean taken as the postsedation NCT time. Errors were pointed out to patients as they were carrying out the test, and they were instructed to start from the last number that they had missed. The time for errors was included into the NCT time. The NCTs were conducted on all patients by the principal investigator so as to eliminate variability in the conduct of the test. The tests were carried out in a quiet side room in the endoscopy unit for all subjects. We arbitrarily chose the upper limit of the 95% CI of the mean for healthy subjects without liver disease as the cut-off level between normal and abnormal NCT times. SEDATION. Sedation was standardized to 5 mg of midazolam for all patients in this study, as this is the dose most frequently used in our patients who are undergoing therapeutic upper GI endoscopy. In our practice locally, droperidol and narcotics are not routinely used. Flumazenil (a competitive benzodiazepine receptor antagonist) was available if the need arose to reverse sedation in case of respiratory depression in an overly sedated patient. As is standard practice in our endoscopy unit, oxygen saturation, pulse rate, and blood pressure were measured continuously during the procedure. Approval was obtained to carry out this study from the University Malaya Medical Center Ethics Sub-Committee and the Medical Research Committee of the University of Malaya. Statistical Analyses Differences between the mean pre- and postsedation NCT times were determined using the paired t test in patients with cirrhosis as well as in those without liver disease. The Mann-Whitney U test was used to assess the differences in age as well as pre- and postsedation NCT time between the cirrhotic and control patients. The 2 test was used to compare educational levels between the two groups. All results were considered significant at a 5% level (p ⬍ 0.05).
AJG – July, 2002
Psychomotor Responses After Conscious Sedation
Table 1. Comparison of Parameters Between Cirrhotic Patients and Patients Without Liver Disease Parameter
Cirrhotic Patients
Patients Without Liver Disease
Mean age, yr* Educational level† Primary Secondary Tertiary
50.61 (SD ⫾ 10.52)
50.35 (SD ⫾ 9.62)
19 35 7
6 22 6
*p ⫽ 0.608. †p ⫽ 0.314.
RESULTS Demographic Characteristics of Cirrhotic Patients A total of 63 consecutive patients who underwent therapeutic upper GI endoscopy were recruited. Two patients were unable to complete the NCT postsedation, as one required flumazenil to reverse respiratory depression and the other patient developed overt hepatic encephalopathy. The final analyses in this study was carried out on 61 patients. The mean (⫾ SD) age was 50.6 ⫾ 10.5 yr with an age range of 20 – 68 yr. The majority of the patients were men (n ⫽ 53, 86.9%), with eight women (13.1%). The mean length of time spent in school was 9.3 ⫾ 3.5 yr. The main cause of cirrhosis was chronic viral hepatitis; 24 patients (45.9%) had hepatitis B and four had hepatitis C infections. A total of 16 patients (26.2%) had alcoholrelated cirrhosis, whereas 12 patients (19.7%) had cirrhosis of unknown etiology. Other causes of cirrhosis were autoimmune hepatitis (four patients, 6.6%) and primary sclerosing cholangitis (one patient). The mean Child-Pugh score was 7.7 ⫾ 2.2, with a minimal score of 5 and a maximal score of 13. A total of 23 patients (37.7%) were classified as Child-Pugh A, 26 patients (42.6%) Child-Pugh B, and 12 patients (19.7%) ChildPugh C. The mean total bilirubin was 33.9 ⫾ 29.5 mol/L, the mean albumin level 30.4 ⫾ 7.5 g/L, mean ALT level 59.7 ⫾ 26.3 IU/L, and the mean AST level 59.7 ⫾ 34.3 IU/L. The mean INR was 1.4, with a range of 1.0 –2.2. Demographic Characteristics of Patients Without Liver Disease A total of 38 consecutive patients without clinical or biochemical evidence of liver disease who presented for upper GI endoscopy completed the NCT as described for the group of cirrhotic patients. There were no dropouts in this group. The mean age was 50.9 ⫾ 9.6 yr, and the mean length of education 9.3 ⫾ 3.6 yr.
1719
Mean serum albumin was 38.9 ⫾ 3.4 g/L, mean serum total bilirubin 11.4 ⫾ 5.9 mol/L, mean ALT 47.5 ⫾ 14.7 IU/L, and mean AST 28.7 ⫾ 8.4 IU/L. These parameters were all within the normal reference range for our laboratory. NCT Results Before and After Sedation for Cirrhotic Patients The mean presedation time for the completion of the NCT-1 and NCT-2 was 43.5 s (95% CI ⫽ 39.0 – 48.1 s), whereas the mean postsedation time for the completion of NCT-3 and NCT-4 was 60.0 s (95% CI ⫽ 50.7– 69.3 s). The difference between the mean pre- and postsedation NCT times was 16.4 s (95% CI ⫽ 9.8 –23.1 s). This difference of the mean times was highly significant (p ⬍ 0.001). NCT Results Before and After Sedation for Patients Without Liver Disease The mean (⫾ SD) baseline NCT time was 34.7 ⫾ 7.9 s (95% CI ⫽ 32.1–37.2 s), whereas the mean postsedation NCT time was 33.7 ⫾ 8.5 s (95% CI ⫽ 30.9 –36.5 s). Although, there was a numerical improvement in NCT time postsedation, this difference was not statistically significant (p ⫽ 0.177). Cirrhotic Patients Versus Healthy Subjects The cirrhotic patients and those without liver disease were comparable with respect to age and educational level (Table 1). There was, however, a significant difference in both the presedation (p ⫽ 0.013) and postsedation NCT (p ⬍ 0.001) times between the patients with cirrhosis and those without liver disease (Table 2). Prevalence of Subclinical Hepatic Encephalopathy Using the upper limit of the 95% CI of the mean (31.7–37.4 s) of the presedation time in the patients without liver disease as the arbitrary cut-off between normal and encephalopathy, the number of cirrhotics with abnormal presedation NCT times was 33 patients (54.1%), whereas this number rose to 46 patients (75.4%) after sedation with midazolam. This increase in proportion of cirrhotic patients with prolonged NCT time was statistically significant (p ⬍ 0.001).
DISCUSSION This study shows that the time to complete the NCT is impaired 2 h after sedation when i.v. midazolam is administered to cirrhotic patients without clinically overt hepatic encephalopathy. There were no prolongation in NCT times
Table 2. NCTs Pre- and Postsedation for Cirrhotic and Normal Patients Patients Cirrhotic Normal Post ⫽ postsedation; Pre ⫽ presedation.
NCT Pre (95% CI)
NCT Post (95% CI)
p Value
43.5 (39.0–48.1) 34.6 (32.1–37.2) p ⫽ 0.013
59.9 (50.7–69.3) 33.7 (30.9–36.5) p ⬍ 0.001
⬍0.001 0.177
1720
Vasudevan et al.
in a comparable group of patients who did not have clinical nor biochemical evidence of liver disease and who served as controls. Using the upper limit of the 95% CI of the mean baseline NCT of the patients without liver disease presedation as the cut-off level, more than half of the patients (54.1%) in the cirrhotic group had abnormal NCT times presedation, and this proportion increased to 75.4% postsedation. By implication, this group of cirrhotic patients who did not have overt clinical encephalopathy had SHE, which was further unmasked in some cirrhotic patients after sedation. NCT times can be influenced by various factors such as age (4, 5, 9), level of education (4, 5), and severity of liver disease (8, 10 –12). In our study, these potential confounding factors are obviated, as each patient serves as his or her own control. The NCT test itself, if carried out improperly or casually, may lead to inaccurate NCT times. In our study, we have taken stringent measures to ensure that the test was performed as accurately as possible and in as standard a manner for all patients and subjects. The test was performed in quiet room to optimize performance. The choice of a cut-off level was arbitrary and was based on the NCTs of the group of healthy patients without liver disease. These patients were clearly shown to have no prolongation of their NCTs with sedation, and we believed that their NCT times were a fairly accurate representation of a normal NCT time. Furthermore, this group of patients was subjected to the same circumstances for testing as was the cirrhotic group and, therefore, serves as a reliable comparator group. SHE may be subtle and difficult to detect on clinical examination. Often the patient will have normal mental and neurological function, and will only exhibit abnormalities on specific psychometric testing indicating impairment of psychomotor skills. Several pyschometric tests are available such as the NCT, block design test, and digit symbol test. The most popular of such tests is the NCT, which we used in our study. Although these tests are generally easy to perform, interpretation of test scores has been noted to be difficult (6). The definition of abnormal NCT test has been quite arbitary. Zeegen et al. (10) in 1970 were the first to apply objective psychometric tests in the assessment of cerebral dysfunction patients with liver cirrhosis. In their study, Zeegen et al. use the sum total of Reitan trail-making test A and B (the predecessor of our present day NCT) of ⬎130 s as abnormal. Rikkers et al. (13) and Groenweg et al. (7) used the mean ⫹ 2 SD as the cut-off level between abnormal and normal test results. As with ourselves, Marchesini et al. have used the upper limit of the 95% CI as the cut-off (14). By definition, subjects with test results above these cut-off levels were classified as having SHE. Conn (12) has arbitrarily classified hepatic encephalopathy according to stated times, as follows: 15–30 s ⫽ non (0), 31–50 s ⫽ mild (1⫹), 51– 80 s ⫽ moderate (2⫹), 81–120 s ⫽ severe (3⫹), and ⬎120 s ⫽ coma (4⫹). The definition of a cut-off level of
AJG – Vol. 97, No. 7, 2002
normal/abnormal for all these various tests is necessarily arbitrary, as there is no “gold standard” against which these tests can be compared. Clearly, patients with cirrhosis without overt hepatic encephalopathy do poorly after sedation. If we arbitrarily define subclinical encephalopathy as patients having NCT times exceeding the cut-off level that we have set, then we have an alarming 75.4% of cirrhotic patients in this category, 2 h after benzodazepine sedation was administered. Studies have shown that benzodiazepine metabolism is affected in patients with advanced or chronic liver disease, leading to a prolonged drug effect and action (2, 15). This is clearly demonstrated in this study, in which there was no impairment in NCTs after i.v. midazolam in patients without liver disease. MacGilchrist et al. (2) demonstrated that midazolam causes psychomotor deficits in patients with severe alcoholic cirrhosis and that midazolam was detectable in plasma up to 6 h after administration. The sedative-hypnotic actions of benzodiazepines such as midazolam, which bind to benzodiazepine receptor ligands in the brain, are mediated by the ␥-aminobutyric acid (GABA) neurotransmitter system (16). GABA is the principal inhibitory neurotransmitter in the mammalian brain. Within the neural membrane of the GABA postsynaptic receptor is a supramolecule complex that has binding sites for the synergistic ligands, GABA, benzodiazepines, and barbiturates. Activation of the GABA neurotransmitter system opens chloride-ion channels in postsynaptic membranes, resulting in hyperpolarization and reduced excitability of the neurone (17, 18), resulting in an inhibitory postsynaptic potential. This stimulation of GABA-ergic activity by midazolam is responsible for the ability of benzodiazepine class of drugs to reduce anxiety, reduce muscle tone, mediate amnesia and sedation, and act as an anticonvulsant (17). It is postulated that in patients with liver cirrhosis, there is up-regulation of benzodiazepine receptor sites, thus enhancing sensitivity to benzodiazepines. In one study (19), it was found that rabbits with induced hepatic coma had an approximately 40% increase in the number of benzodiazepine binding sites on GABA receptors, leading to the conclusion that the increased sensitivity to benzodiazepines is mediated by the increased binding sites for this drug, and thus permitting enhancement of its side effects. This provides an animal model for the possible elucidation of increased sensitivity of benzodiazepines in cirrhotic patients. Bakti et al. (20) studied cirrhotic patients using triazolam and found that triazolam levels were comparable in cirrhotic patients and controls, whereas cirrhotic patients exhibited abnormal psychometric testing after triazolam. They suggested that hypersensitivity to benzodiazepines may contribute to the prolonged drug effect. The clinical significance of subclinical encephalopathy has generated great interest, as it is said to impair driving (21) and daily functioning (7). Schomerus et al. (21) showed in 1981 that cirrhotic patients exhibited defective cerebral
AJG – July, 2002
functions in psychomotor functioning, reaction time, and visual retention. These functions are relevant to driving; and, in fact, only 15% of 40 cirrhotic patients evaluated in their study were found to be fit to drive a car, whereas 60% were considered completely unfit to drive. However, there is as yet no absolute cut-off time for the NCT by which a patient can be deemed unfit to drive. Groenweg et al. (7) studied 179 patients and found that 27% of outpatient cirrhotics had subclinical encephalopathy. Using a Sickness Impact Profile questionnaire, these investigators concluded that these patients with subclinical encephalopathy had impaired daily functioning and warranted some form of treatment. These cirrhotic patients with subclinical encephalopathy had sleep disturbances, impaired calculation, shortened attention span, and mild personality change. More recently, Hartmann et al. (22) studied subclinical hepatic encephalopathy in greater detail with regard to the prognosis of this condition. They found that the patients with subclinical hepatic encephalopathy as diagnosed with psychometric tests or with spectral electroencephalography had more episodes of clinical hepatic encephalopathy, however, survival was similar to that in patients without subclinical hepatic encephalopathy. It is evident from this study that sedation with midazolam has an adverse effect on patients with liver cirrhosis even at 2 h (i.e., at discharge), whereas this effect was not seen in patients without evidence of liver disease. These findings suggest that caution should be exercised when procedures requiring sedation with benzodiazepines, even short acting ones such as midazolam, are undertaken in cirrhotic patients. It is conceivable that this impairment in NCT times may be present in cirrhotic patients for up to 6 h (2), as stated earlier. The clinical significance of subclinical hepatic encephalopathy needs further evaluation. In any case, all patients who undergo upper GI endoscopy with sedation should be accompanied on discharge, especially those patients who are cirrhotic. Reprint requests and correspondence: K. L. Goh, Department of Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. Received Aug. 6, 2001; accepted Feb. 15, 2002.
Psychomotor Responses After Conscious Sedation
3.
4. 5. 6.
7.
8.
9. 10.
11. 12.
13.
14.
15. 16.
17. 18. 19.
20.
21.
REFERENCES 1. Keefe EB. Sedation and analgesia for endoscopy. Gastroenterology 1995;108:932– 4. 2. MacGilchrist AJ, Birnie JJ, Cook A, et al. Pharmacokinetics
22.
1721
and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986;27:190 –5. Assy N, Rosser BG, Grahame GR, et al. Risk of sedation for upper GI endoscopy exacerbating subclinical hepatic encephalopathy in patients with cirrhosis. Gastrointest Endosc 1999; 49:690 – 4. Gitlin N. Subclinical portal-systemic encephalopathy. Am J Gastroenterol 1988;82:8 –11. Quero JC, Scalm SW. Subclinical hepatic encephalopathy. Semin Liver Dis 1996;16:321– 8. Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transection of the esophagus for bleeding esophageal varices. Br J Surg 1973;60:646 –9. Groeneweg M, Quero JC, De Bruijn I, et al. Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 1998;28:45–9. Conn HO. Trailmaking and number connection tests in the assessment of mental state in portosystemic encephalopathy. Dig Dis Sci 1977;22:541–50. Davies ADM. The influence of age on Trailmaking Test performance. J Clin Psychol 1968;24:96 – 8. Zeegen R, Drinkwater JE, Dawson AM. Method for measuring cerebral dysfunction in patients with liver disease. Br Med J 1970;2:633– 6. Jones EA, Weissenborn K. Neurology and the liver. J Neurol Neurosurg Psychiatry 1997;63:279 –93. Conn HO, Lieberthal MM. Assessment of mental state. In: Conn HO, Lieberthal MM, eds. The hepatic coma syndromes and lactulose. Baltimore: Williams & Wilkins, 1979:169 – 88. Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: Detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 1978;75:462–9. Marchesini G, Zoli M, Dondi C, et al. Prevalence of subclinical hepatic encephalopathy in cirrhotics and relationship to plasma amino acid imbalance. Dig Dis Sci 1980;25:763– 8. Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther 1981;30:653– 61. Schafer DF, Jones EA. Hepatic encephalopathy and the gamma-aminobutyric-acid neurotransmitter system. Lancet 1982; 1:18 –20. Mullen KD, Jones EA. Natural benzodiazepines and hepatic encephalopathy. Semin Liver Dis 1996;16:255– 64. Wilkinson SJ. GABA, benzodiazepines and hepatic encephalopathy. Eur J Gastroenterol Hepatol 1995;7:323– 4. Fowler JM, Schafer DF. A mechanism for the sensitivity to benzodiazepines in hepatocellular failure: Evidence from an animal model. Gastroenterology 1981;80:1359 (abstract). Bakti G, Fisch HU, Karlagans G, et al. Mechanism of excessive sedative response of cirrhotics to benzodiazepines: Model experiments with triazolam. Hepatology 1987;7:629 –38. Schomerus H, Hamster W, Blunck H, et al. Latent portosystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive. Dig Dis Sci 1981;26:622– 30. Hartmann IJC, Groeneweg M, Quero JC, et al. The prognostic significance of sub clinical hepatic encephalopathy. Am J Gastroenterol 2000;95:2029 –34.