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Cerebral autoregulation in patients with cirrhosis and ascites
Journalof Hepatologg ISSN 016&h’.?7
Cerebral autoregulation in patients with cirrhosis and ascites A transcranial Doppler study Alfonso Lagi’, Giorgio La Villa, Giuseppe Barletta 2, Simone Cencetti' , Stefano Bacalli’ , Marcello Cipriani’, Marco Foschi. Chiara Lazzeri, Riccarda Del Bene2. Paolo Gentilini and Giacomo
Background/Aims: Patients with cirrhosis and ascites usually show alterations of systemic hemodynamics and are thus prone to develop arterial hypotension, which might result in cerebral hypoperfusion if cerebral autoregulation is impaired. Methods: We evaluated cerebral autoregulation in 15 patients with cirrhosis and ascites and 15 healthy subjects by monitoring mean blood flow velocity in the middle cerebral artery and arterial pressure during supine rest and passive tilting. Results: Tilt provoked a drop of arterial pressure in both groups. Control subjects had a prompt recovery of mean flow velocity and a progressive recovery of arterial pressure, so that, after 120 s, both parameters had returned to baseline: at 20 s the recovery of flow
R
EACTIVE dilation
or constriction of cerebral resistance vessels allows cerebral blood flow (CBF) to remain virtually constant despite changes in perfusion pressure. This functional adaptation is commonly referred to as cerebral autoregulation (CA) (l-3). Patients with cirrhosis and ascites usually have a hyperdynamic circulation, with increased cardiac output and reduced peripheral vascular resistance, often leading to arterial hypotension (4,5). They have also been claimed to have an impaired autonomic regulation of cardiovascular homeostasis (6-8). As a consequence, in these patients CBF might fall, because of the reduced perfusion pressure, if CA were also impaired. Transcranial Doppler ultrasonography (TCD) has been widely used as a suitable tool to investigate CA in man (9%12), Recriwl
7 h’owmhrr 1996: rrvisud 3 Fehruavy; u cepted 7 Fehruor~~1997
Correspondence: Giacomo Laffi, MD, Istituto di Medicina Interna, viale Morgagni, 85, I/50134 Florence. Italy. Tel: 391551416635. Fax: 391551417123.
114
Laffi
velocity was faster (p
allowing cerebral we used ing in a
real time recordings of functional indexes of hemodynamics (10,13). In the present study, this method to assess CA during dynamic testgroup of patients with cirrhosis and ascites.
Materials
and Methods
Subjects Fifteen patients with cirrhosis (eight men and seven women, mean age 64k7, range 45-74 years) and 15 age- and sex-matched healthy subjects (eight men and seven women. mean age 64?7, range 45-73 years) gave their informed consent to participate in the study, which was approved by the local Ethics Committee. Diagnosis of cirrhosis was established by history, physical examination, laboratory findings and liver biopsy. when not contraindicated. Cirrhosis was HBVrelated in five patients, HCV-related in eight and alcoholic-related in two. All patients had esophageal varices and ascites, as recognized by physical examination and ultrasound. Ascites was graded as mild or moder-
Cerebral autoregulation in cirrhosis
ate/tense and scored 2 or 3, according to Pugh et al. (14). No patient had renal failure, hepatocellular carcinoma or other malignancies, recent (~6 weeks) gastrointestinal bleeding, encephalopathy, cardiac, pulmonary or renal diseases, diabetes or arrhythmias. Study protocol
All subjects received a 40 mmol/day sodium diet and no drugs on the 7 days before and throughout the study. Smoking and consumption of caffeine-containing foods and beverages were not allowed in the 2 days before and throughout the study. On the first day of the study, blood samples and a 24-h urine collection were obtained to evaluate liver and renal function, urinary sodium excretion (UNaV), plasma renin activity and plasma levels of aldosterone, norepinephrine and atria1 natriuretic peptide. On the following day, systemic hemodynamics was evaluated using a noninvasive echocardiographic method. Echocardiography was performed in supine left lateral decubitus, using an SSA 270A HG (Toshiba, Tokyo, Japan) echocardiograph. The M-mode left ventricular dimensions were obtained from a parasternal long axis view, just below the mitral leaflets, according to the recommendations of the American Society of Echocardiography (15). Left ventricular volumes were calculated from ventricular dimensions according to Teichholz et al. (16). Cardiac output was obtained from stroke volume (end-diastolic volume minus end-systolic volume) and heart rate and corrected for the subject’s body surface area to obtain the cardiac index. Blood pressure was simultaneously measured using a semiautomatic oscillometric method (Sirecust 888, Siemens, Erlangen, Germany). Mean arterial pressure (MAP) was calculated as diastolic pressure + l/3 pulse pressure and peripheral vascular resistance as MAPX go/cardiac output. On the same day, after 60-min supine resting, all subjects underwent TCD examination. Recordings from the main basal intracranial arteries were performed with a 2 MHz probe (Multidop S, DWL, Sipplingen, Germany), according to the accepted criteria (17). Vasomotor reactivity was assessed by calculating the percent change in time-averaged mean flow velocity (mV) in the right middle cerebral artery before and at the end of breath holding (18,19). Cerebral autoregulation
testing
Each subject was then placed on a tilt-table (ElektroWerke, Type 1.73-006, Hanning, Germany) in the supine position. Room temperature was kept constant at 22°C. Non-invasive monitoring was performed for the following parameters: arterial pressure, recorded from
the third finger of the left hand (Finapres, Ohmeda, Englewood, CO, USA), blood oxygen saturation, from the second finger of the left hand (Spacelabs 90603A, Redmond, WA, USA), heart rate, on the RR interval of ECG tracing (Spacelabs 90603A, Redmond, WA, USA), respiratory activity, by means of a piezoelectric transducer (OS-9000SRS, GoldStar, Cerritos, CA, USA), as previously described (20), and mV in the right middle cerebral artery, using the above described TCD scanner. The position of the 2 MHz probe was kept constant on the right temporal bone with an elastic band, fastened around the skull, equipped with a mechanical holding device. Insonation depth was set between 52 and 60 mm, depending on the position that ensured maximum signal intensity; sample volume axial length was 10 mm, and horizontal sweep speed was 10 s. To avoid accidental shifts of the probe along the temporal skin, and thus changes in the insonation angle, no contact was allowed between the probe holder and the surface of the tilt table thanks to a supporting device of appropriate dimensions placed on the table and supporting the occipital skull of the subjects without touching the elastic band of the probe holder. After 20-min resting, the tilt table was turned up to 60” for 2 min twice, at 5-min intervals, to let the subjects become acquainted with the test and minimize emotional influences on cerebral hemodynamics. Neither light nor verbal stimuli were given in the following 10 min or during dynamic testing. After 10 min, the CA test started. Continuous recordings were made in the supine position for at least 2 min. Afterwards, each subject was tilted up to 60”. No recording was obtained during the 20 s of the mechanical movement of the tilt table. Recordings were made for 2 min during head-up tilt. Data of mV and MAP were stored in a personal computer (Zenith Z-486/33 ET, Zenith Data System, Buffalo, NY, USA) for subsequent statistical analysis. Results of mV and MAP were evaluated as the mean values over three consecutive cardiac cycles, at intervals of 20 s each, according to the following scheme: baseline values (mean of the last three cycles in the supine position), end of mechanical movement of the tilt table (TO), 20 s (T20), 40 s (T40), 60 s (T60), 80 s (T80), 100 s (TlOO) and 120 s (T120) after TO. Values of MAP and mV obtained during the tilt test were expressed as percent values with respect to baseline. Blood samples were obtained just before and at the end of the CA test to measure hematocrit. CA was considered to be adequate when the recovery of mV was higher than that of MAP at T20 (11). To assess whether the slight downward shift of brain structures occurring during the tilt test might cause significant changes in the insonation angle, we evaluated, 115
TABLE
1
Child-Pugh class and results of baseline measurements in the 15 patients with cirrhosis and ascites and the 15 healthy subjects Patients Child Class (B-C) Ascites (mild/moderate) Serum bilirubin (mg/dl) Serum albumin (g/l) Prothrombin activity (l/u) Serum creatinine (mg/dl) Serum sodium (mmol/l) UNaV (mmoli24 h) Cl,, (ml/min) Hematocrit Fibrinogen (mg/dl) PRA(ng.mll’.h-~‘) Plasma aldosterone (nmol/l) Plasma NE (nmolil) Plasma ANP (pmolil) CI (l.min-’ rn- ‘) MAP (mmHg) PVRI (dyne’s’cm m5.mm2)
5--10 87 1.82t0.91 28.0?4.1 6224 0.91 -to.22 13621 20.422.1 802 15 0.3320.05 2891134 5.3322.82 4.7810.71 3.27k0.51 10.80t1.53 4.97-+ 1.79 9428 16322433
Healthv
subiects
0.57zo.07 (*) 41.21~1.12 (*) 9712 (*)
1.0210.05 140t1 (*) 41.011.8 (*) 11525 0.43+0.02 (*) 307278 1.18kO.13 (*) 0.71~0.10 (*) 0.88to.11 (*) 6.1521.79 (*) 3.3720.88 (#) 9328 23342526 (*)
UNaV: urinary sodium excretion. Cl,,: creatinine clearance., PRA: plasma renin activity. NE: norepinephrine. ANP: atria1 natriuretic peptide. CI: Cardiac index. MAP: mean arterial pressure. PVRI: peripheral vascular resistance index. ‘_n
in a preliminary set of experiments, the differences between the mV values recorded with the probe fixed with an elastic device during a tilt test and the ones obtained with manual search of the best signal intensity at the same depth during another tilt test in 12 healthy volunteers. The maximum difference noted between the two measurements was 7%: indicating that this mechanical factor can cause only minimal errors in mV measurements. Measurements Plasma renin activity was estimated by radioimmunoassay for angiotensin I (Rianen Angiotensin I Generation Kit, New England Nuclear, Boston, MA, USA). Aldosterone, norepinephrine and ANP were measured using commercial kits (ALDO kit, RADIM, Rome, Italy; CAT-A-KIT, Amersham, Buckinghamshire, UK; ANP ria kit, Peninsula Laboratories, St. Helens, UK. respectively) as previously described (21). Statistical analysis Data are expressed as meant SD. Results of baseline measurements in healthy subjects and patients with cirrhosis and in the two subgroups of patients, respectively with normal and impaired CA, were analyzed with the t-test for unpaired data. Statistical analysis of the sets of percent values of MAP and mV obtained in patients with cirrhosis and healthy subjects was performed using repeated measure 2-way analysis of vari116
ance (ANOVA). Comparisons between the two groups at each stage for arterial pressure and mV were performed using one-way ANOVA, followed by t-test with Bonferroni correction. Distribution of Child class and ascites score in patients with normal or impaired CA was performed using Fisher’s exact test. A /Ivalue<0.05 was considered significant. Data were analyzed by using the SPSS Inc. (Chicago, istical package.
IL, USA) stat-
Results Results of baseline measurements performed in patients with cirrhosis and healthy subjects are shown in Table 1. Cirrhotic patients with ascites had impaired liver function, sodium retention, hyperdynamic circulation, as indicated by a high cardiac index and low peripheral vascular resistance, activation of the reninaldosterone and sympathetic nervous systems and high plasma levels of atria1 natriuretic peptide. Patients also had significantly lower values of hematocrit than healthy controls. Fibrinogen levels were lower in patients than in controls, but the difference was not significant. Cerebral autoregulation testing No significant differences were observed between healthy subjects and cirrhotic patients with ascites with respect to any of the measured parameters during supine rest (Table 2). Both control subjects and patients with cirrhosis had adequate ultrasonic windows, mean blood flow velocity and pulsatility index within the normal limits (22-24), and no interhemispheric asym-
TABLE
2
Results of baseline transcranial Doppler measurements in the 15 patients with cirrhosis and ascites and the 15 healthy subjects Patients
Healthy
MCA mV (cm/s) PI
531-14 O.XOirO.16
54-L 14 0.83-+0.18
ACA mV (cm/s) PI
431-18 0.7820. I1
45215 0.82kO.09
ICA mV (cmi’s) PI
4429 0.92t0.23
42211 0.941-0.20
PCA mV (cm/s) PI
3627 0.8X10.12
345.5 0.84?0.15
BA mV (cm/s) PI
41z12 0.9lr0.08
40513 0.90to. 13
VMR (‘k)
301-12
subjects
342 I1
MCA=middle cerebral artery. ACA: anterior cerebral artery. ICA: internal carotid artery: PCA: posterior cerebral artery. BA: basilai artery. mV: mean blood few velocity. PI: pulsatility index. VMR: vasomotor reactivity (‘!it increase in mV in the middle cerebral arteries at the end of breath holding).
Cerebral autoregulation in cirrhosis
70’
0
20
1 40
1 60
80
100
120
time after tilting (set) Fig. I. Mean arterial pressure (MAP) in healthy subjects (dottedline) andpatients with cirrhosis (straight line) in the 120 s after tilting. Measurements were performed at the end of the mechanical movement of the tilt table. Data are expressed as percentage of baseline MAP (9328 mmHg in healthy subjects and 9428 mmHg inpatients with cirrhosis). Statistical analysis: 2-way AN0 VA tilt time anddisease: F= 34.54, p
metry (25), intracranial stenoses and hemodynamic patterns of collateral flow in the intracranial circulation. The cerebrovascular reactivity in response to breath-holding was present in both groups, thus allowing evaluation of CA. Baseline values of MAP and mV (mean of the last three cycles measured in the supine position, just before the tilt test) were 93 +8 mmHg and 54? 13 cm/s in healthy subjects and 9458 mmHg and 53-14 cm/s in patients with cirrhosis. Percent values of MAP and mV observed in patients and healthy subjects at the different times of acquisition are shown in Fig. 1 and 2. In the first determination performed after tilting (TO), MAP was reduced in both groups. Thereafter, control subjects showed a progressive increase in MAP, up to a complete recovery of basal values at T120. On the contrary, patients with cirrhosis had an incomplete recovery of MAP, with significant differences with respect to control subjects at T4CLT120. The behavior of MAP in response to passive tilting was therefore significantly different between the two groups (2-way ANOVA tilt time and disease: F=34.54,p<0.001, Fig. 1). Passive tilting induced a decrement of mV in both groups, no significant differences being observed between patients with cirrhosis and healthy subjects with respect to mV values in the first recording (TO) after tilt (Fig. 2). In the following steps, mV promptly returned to baseline values in healthy subjects, whereas patients showed a delayed and incomplete recovery of mV, so that
mV values were significantly lower in patients than in control subjects in all but the first measurement. The difference between the two groups was therefore significant (2-way ANOVA: tilt time and disease: F=5.53,p<0.01). In healthy subjects, the percent increment of mV after the first 20 s (o/omV at T20 minus %mV at TO) was significantly greater (ANOVA: F=9.73,p<0.01) than that of MAP, indicating that the recovery of mV was faster than that of MAP A similar phenomenon was not observed in patients with cirrhosis. When data of MAP and mV obtained in each individual during the tilt test were analyzed, and adequacy of CA was evaluated using the criteria of higher percent recovery of mV than that of MAP at T20, CA was found to be adequate in all control subjects, while eight out of 15 cirrhotic patients with ascites showed an impaired CA. These patients had a worse liver function than the seven patients with adequate autoregulation, since they were all in class C, according to Pugh et al. (14) whereas five out of the seven patients with normal CA were in class B (Fisher’s Exact test p=O.O3). Furthermore, cirrhotic patients with impaired CA had lower albumin levels (25.8k3.6 vs 3O.lk2.2 g/l, p
0
20
40
60
80
100
120
time after tilting (set) Fig. 2. Mean flow velocity in the right middle cerebral artery (mV) observed in healthy subjects (dotted line) and patients with cirrhosis (straight line) in the 120 s after tilting. Measurements were performed at the end of the mechanical movement of the tilt table. Data are expressed as percentage of baseline mV (54~13 cm/s in healthy subjects and 53+-14 cm/s in patients with cirrhosis). Statistical analysis: 2-way ANOVA: tilt time and disease: F=5..53, p
A. Lqi
et 01.
dyne. s. cm-5*m-2, pcO.05). Despite a trend towards higher PRA levels in patients with impaired autoregulation, no significant differences were observed between the two subgroups of cirrhotic patients with respect to any of the endocrine parameters measured in this study. During the test, neither patients nor control subjects showed heart rates over 120 beats per minute, hypo- or hyperventilation, which could give unreliable mV data due to the corresponding changes in arterial pC02. Passive tilting did not induce any appreciable changes in hematocrit in either healthy subjects (from 0.437t0.028 to 0.433+0.031) or patients with cirrhosis (from 0.342+0.041 to 0.339t0.042).
Discussion Patients with cirrhosis and ascites usually show a peculiar derangement of systemic hemodynamics, with increased plasma volume and cardiac output and reduced peripheral vascular resistance (4,5,26). These patients have also been demonstrated to have an impaired ability to maintain cardiovascular homeostasis and arterial pressure during postural changes, as indicated by previous studies that evaluated the response to tilting (7,27,28). More recently, an altered 24-h pressure profile has been observed in patients with cirrhosis, characterized by the lack of blood pressure increase during daytime, while patients are attending their daily activities, mainly in the standing position (29). In patients with cirrhosis and ascites, therefore, maintenance of CBF critically depends on the adequacy of CA. Cerebral autoregulation was usually studied by using a static approach, based on the collection of data on CBF under different consecutive steady-state conditions (30,31). This approach has led to the wellknown autoregulation curve, where CBF is constant within defined pressure limits and declines or increases when arterial pressure is below or above these limits. Transcranial Doppler recording of mV in the middle cerebral artery is a recently developed method to evaluate cerebral hemodynamics reliably in man (9--13), which allows a dynamic study of CA (10,32) in response to various stimuli, such as postural changes. In this regard, head-up tilt proved to be a useful tool to investigate the physiological response to alterations in cerebral perfusion pressure in humans (33) because it introduces transient changes in cerebral perfusion pressure by shifting a consistent amount of blood towards the lower limbs. Dynamic methods for the assessment of CA displayed a high correlation with static methods (32). The two approaches, however, evaluate different effects of the autoregulatory action, since the static method evaluates the overall effect, whereas the
dynamic
one evaluates
the latency
and the fast com-
ponents of CA (32). We studied a group of cirrhotic patients with ascites and hyperdynamic circulation, as indicated by the presence of high cardiac index and reduced peripheral vascular resistance (Table 1). and used the head-up tilt combined with TCD measurements of mV to investigate CA during the dynamic period of the recovery from the stepwise hypotensive stimulus applied. The validity of TCD measurements in the assessment of CA during tilting has been debated (3436) because of concerns about the possibility that the diameter of the middle cerebral artery might change during the orthostatic stress (34). However. further studies showed that variations in intracranial pressure induced by stepwise hypotensive stimuli. such as the leg-cuff method (10,35). the lower body negative pressure test (37) and the squatting/standing test (3X), have minimal influence on the cross-sectional area of the insonated artery. Moreover, modifications of mV due to changes in the caliber of the main trunk of the middle cerebral artery during head-up tilt were found to be negligible (39). In the present study no significant differences were observed between patients and control subjects with respect to baseline TCD measurements. The finding that patients had similar mV in the main cerebral vessels as healthy subjects does not allow the assumption that CBF of our patients with cirrhosis was normal. because they had low values of hematocrit (Table 1) and a wide variability in plasma fibrinogen levels, two parameters that are known to influence mean blood flow velocity (40,41). On the other hand, this study was not aimed at estimating CBF, but at evaluating CA in cirrhosis with ascites. For this purpose, we performed repeated measurements of MAP and mV before and during the first 2 min of head-up tilt. a maneuver that did not induce any appreciable modification of hematocrit. Passive tilting induced the expected transient hypotension in healthy subjects (42) and in patients with cirrhosis. In control subjects, however, MAP progressively increased and returned to baseline values at Tl20. By contrast, in patients with cirrhosis the recovery of MAP was delayed and incomplete, confirming that these patients have an altered cardiovascular response to tilt (7,27,28). The main finding of the current study was that CA was impaired in cirrhotic patients with ascites. In healthy subjects, mV, after the initial drop, recovered more rapidly than MAP and promptly returned to baseline levels, while in cirrhotic patients with ascites the recovery of mV was delayed and incomplete (Fig. 2), so that significant differences between patients and
Cerebral autoregulation
controls were observed with respect to mV measurements. Carbon dioxide is a powerful regulator of CBF and thus of mV (43). We monitored respiratory activity in both patients and control subjects and did not find either differences in baseline conditions or any modification during the tilt test, ruling out the possibility that our results might have been influenced by hypo- or hyperventilation-induced changes in arterial pCOz. In this study MAP of control subjects and patients with cirrhosis never fell below the lower limit of CA during passive tilting. Both groups also experienced an initial drop in mV when the hypotensive stimulus was given. This result is not in contradiction with the presence and adequacy of CA. In fact, previous dynamic studies on CA showed that after a transient change in MAP a latency is requested before CA takes place, as demonstrated by the slope of the mV/MAP regression (10,32,44,45) and the phase differences between oscillations in MAP and mV (3 1,46). However, mV would recover faster than MAP in the presence of an adequate CA, as it did occur in healthy subjects. By contrast, eight out of 15 cirrhotic patients with ascites were unable to promptly recover their mV values when submitted to passive tilting. Noteworthy, the delay of mV recovery in cirrhotic patients with impaired CA did not depend on the delay of MAP recovery, as demonstrated by the fact that mV at T20 was lower in this subset than in the control group, despite similar values of MAP measured at the same time after tilting. All these data indicate that CA was impaired in a substantial proportion of cirrhotic patients with ascites. Interestingly, the impairment of CA was observed in patients with a more severe reduction of liver function and more marked alterations of systemic hemodynamics. An impaired CA has been observed in humans (4749) and animals (50) with hepatic failure, and it is considered to play a major role in the development of cerebral edema. Recently, Larsen et al. (51) used TCD to investigate CBF autoregulation in 10 patients with liver cirrhosis, mostly without ascites, and found that it was impaired in only two of them. In this study, however, a static methodology was used, and changes in perfusion pressure were induced by combining mechanical and pharmacological stimuli. Different from this study (51) we investigated CA in a group of cirrhotic patients with ascites who had a more severe derangement of liver function and systemic hemodynamics, and used a physiological test, like the head-up tilt, so avoiding any pharmacological interference with systemic and cerebral hemodynamics. In conclusion, an impairment of CBF autoregulation in response to passive head-up tilting is often observed
in cirrhosis
in patients with cirrhosis and ascites. This alteration may predispose these patients to cerebral hypoperfusion and ischemia when they have to face pathological conditions that lead to an abrupt fall of arterial pressure, such as bleeding, infections, anesthesia or coma.
Acknowledgements This work was supported by grants from the Italian Liver Foundation and the Italian Minister0 per l’Universita e la Ricerca Scientifica e Tecnologica (1994, 1995).
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book of Physiology. sect. 2: The Cardiovascular System, vol. 3. Bethesda: American Physiological Society, 1983. 131-82. 34. Mailer HR. Flow and velocity during autoregulation testing in humans (letter). Stroke 1994; 25: 1296-7. 35. Aaslid R, Newell DW Flow and velocity during autoregulation testing in humans (letter, reply). Stroke 1994: 25: 1297. 36. Miiller HR, Casty M. Moll R. Zehnder R. Response of middle cerebral artery volume flow to orthostasis. Cerebrovast Dis 1091; 1: 82--9. 37. Levine BD, Giller CA. Lane LD. Buckey JC. Blomqvist CG. Cerebral versus systemic hemodynamics during graded orthostatic stress in humans. Circulation 1994; 90: 298-306. 38. Birch AA, Dirnhuber MJ. Hartley-Davis R, Iannotti F, NeilDwyer G. Assessment of autoregulation by means of periodic changes in blood pressure. Stroke 1995; 26: 834-7. 39. Daffertshofer M. Diehl RR, Ziems GU, Hennerici M. Orthostatic changes of cerebral blood flow velocity in patients with autonomic dysfunction. J Neurol Sci 1991; 104: 32-8. 40. Brass LM. Pavlakis SG, DeVivo D, Piomelli S. Mohr JI? Transcranial doppler measurements in the middle cerebral artery. Effect of hematocrit. Stroke 1988; 19: 1466-9. 41. Ameriso S, Paganini-Hill A, Meiselman HJ. Fisher M. Correlates of middle cerebral artery blood velocity in the elderly. Stroke 1990: 21: 1579.--83. 42. Wieling W. van Lieshout JJ. Maintenance of postural normotension in humans. In: Low PA. ed. Clinical Autonomic Disorders. Boston: Little. Brown, 1993: 69-77. 43. Ringelstein EB. Sievers C, Ecker S, Schneider PA, Otis SM. Noninvasive assessment of CO?-induced vasomotor response in normal individuals and in patients with internal carotid artery occlusion. Stroke 1988; 19: 963-9. 44. Aaslid R, Newell DW, Stoos R, Sorteberg W. Lindegaard KF. Assessment of cerebral autoregulation dynamics by simultaneous arterial and venous transcranial Doppler. Stroke 1991: 22: 1148-54. 45. Aaslid R. Cerebral hemodynamics. In: Newell DW, Aaslid R. eds. Transcranial Doppler. New York: Raven Press, 1992: 57.66. 46. Diehl RR. Linden D, Lucke D, Berlit P Phase relationship between cerebral blood flow velocity and blood pressure. Stroke 1995: 26: 18014. 47. Larsen FS. Ejlersen E. Hansen BA. Knudsen GM, Tygstrup N. Secher NH. Functional loss of cerebral blood flow autoregulation in patients with fulminant hepatic failure. J Hepatol 1995; 23: 212.-7. 48. Larsen FS. Hansen BA, Jorgensen LG. Secher NH, Bondesen S. Linkis P. et al. Cerebral blood velocity during high volume plasmapheresis in fulminant hepatic failure. Int J Art Org 1994; 17: 301-9. 49. Ejlersen E, Larsen FS. Pott E Gyrtrup HJ, Kirkegaard I? Secher NH. Hepatectomy corrects cerebral hyperperfusion in fulminant hepatic failure. Transplant Proc 1994; 26: 1794.-5. 50. Larsen FS. Knudsen GM. Paulson OB. Vilstrup H. Cerebral blood flow autoregulation is absent in rats with thioacetamide-induced hepatic failure. J Hepatol 1994; 21: 491-5. 51. Larsen FS. Olsen KS, Ejlersen E, Hansen BA, Paulson OB, Knudsen GM. Cerebral blood flow autoregulation and transcranial doppler sonography in patients with cirrhosis. Hepatology 1995; 22: 7X&6.
Cerebral autoregulation in patients with cirrhosis and ascites A transcranial Doppler study Alfonso Lagi’, Giorgio La Villa, Giuseppe Barletta 2, Simone Cencetti' , Stefano Bacalli’ , Marcello Cipriani’, Marco Foschi. Chiara Lazzeri, Riccarda Del Bene2. Paolo Gentilini and Giacomo
Background/Aims: Patients with cirrhosis and ascites usually show alterations of systemic hemodynamics and are thus prone to develop arterial hypotension, which might result in cerebral hypoperfusion if cerebral autoregulation is impaired. Methods: We evaluated cerebral autoregulation in 15 patients with cirrhosis and ascites and 15 healthy subjects by monitoring mean blood flow velocity in the middle cerebral artery and arterial pressure during supine rest and passive tilting. Results: Tilt provoked a drop of arterial pressure in both groups. Control subjects had a prompt recovery of mean flow velocity and a progressive recovery of arterial pressure, so that, after 120 s, both parameters had returned to baseline: at 20 s the recovery of flow
R
EACTIVE dilation
or constriction of cerebral resistance vessels allows cerebral blood flow (CBF) to remain virtually constant despite changes in perfusion pressure. This functional adaptation is commonly referred to as cerebral autoregulation (CA) (l-3). Patients with cirrhosis and ascites usually have a hyperdynamic circulation, with increased cardiac output and reduced peripheral vascular resistance, often leading to arterial hypotension (4,5). They have also been claimed to have an impaired autonomic regulation of cardiovascular homeostasis (6-8). As a consequence, in these patients CBF might fall, because of the reduced perfusion pressure, if CA were also impaired. Transcranial Doppler ultrasonography (TCD) has been widely used as a suitable tool to investigate CA in man (9%12), Recriwl
7 h’owmhrr 1996: rrvisud 3 Fehruavy; u cepted 7 Fehruor~~1997
Correspondence: Giacomo Laffi, MD, Istituto di Medicina Interna, viale Morgagni, 85, I/50134 Florence. Italy. Tel: 391551416635. Fax: 391551417123.
114
Laffi
velocity was faster (p
allowing cerebral we used ing in a
real time recordings of functional indexes of hemodynamics (10,13). In the present study, this method to assess CA during dynamic testgroup of patients with cirrhosis and ascites.
Materials
and Methods
Subjects Fifteen patients with cirrhosis (eight men and seven women, mean age 64k7, range 45-74 years) and 15 age- and sex-matched healthy subjects (eight men and seven women. mean age 64?7, range 45-73 years) gave their informed consent to participate in the study, which was approved by the local Ethics Committee. Diagnosis of cirrhosis was established by history, physical examination, laboratory findings and liver biopsy. when not contraindicated. Cirrhosis was HBVrelated in five patients, HCV-related in eight and alcoholic-related in two. All patients had esophageal varices and ascites, as recognized by physical examination and ultrasound. Ascites was graded as mild or moder-
Cerebral autoregulation in cirrhosis
ate/tense and scored 2 or 3, according to Pugh et al. (14). No patient had renal failure, hepatocellular carcinoma or other malignancies, recent (~6 weeks) gastrointestinal bleeding, encephalopathy, cardiac, pulmonary or renal diseases, diabetes or arrhythmias. Study protocol
All subjects received a 40 mmol/day sodium diet and no drugs on the 7 days before and throughout the study. Smoking and consumption of caffeine-containing foods and beverages were not allowed in the 2 days before and throughout the study. On the first day of the study, blood samples and a 24-h urine collection were obtained to evaluate liver and renal function, urinary sodium excretion (UNaV), plasma renin activity and plasma levels of aldosterone, norepinephrine and atria1 natriuretic peptide. On the following day, systemic hemodynamics was evaluated using a noninvasive echocardiographic method. Echocardiography was performed in supine left lateral decubitus, using an SSA 270A HG (Toshiba, Tokyo, Japan) echocardiograph. The M-mode left ventricular dimensions were obtained from a parasternal long axis view, just below the mitral leaflets, according to the recommendations of the American Society of Echocardiography (15). Left ventricular volumes were calculated from ventricular dimensions according to Teichholz et al. (16). Cardiac output was obtained from stroke volume (end-diastolic volume minus end-systolic volume) and heart rate and corrected for the subject’s body surface area to obtain the cardiac index. Blood pressure was simultaneously measured using a semiautomatic oscillometric method (Sirecust 888, Siemens, Erlangen, Germany). Mean arterial pressure (MAP) was calculated as diastolic pressure + l/3 pulse pressure and peripheral vascular resistance as MAPX go/cardiac output. On the same day, after 60-min supine resting, all subjects underwent TCD examination. Recordings from the main basal intracranial arteries were performed with a 2 MHz probe (Multidop S, DWL, Sipplingen, Germany), according to the accepted criteria (17). Vasomotor reactivity was assessed by calculating the percent change in time-averaged mean flow velocity (mV) in the right middle cerebral artery before and at the end of breath holding (18,19). Cerebral autoregulation
testing
Each subject was then placed on a tilt-table (ElektroWerke, Type 1.73-006, Hanning, Germany) in the supine position. Room temperature was kept constant at 22°C. Non-invasive monitoring was performed for the following parameters: arterial pressure, recorded from
the third finger of the left hand (Finapres, Ohmeda, Englewood, CO, USA), blood oxygen saturation, from the second finger of the left hand (Spacelabs 90603A, Redmond, WA, USA), heart rate, on the RR interval of ECG tracing (Spacelabs 90603A, Redmond, WA, USA), respiratory activity, by means of a piezoelectric transducer (OS-9000SRS, GoldStar, Cerritos, CA, USA), as previously described (20), and mV in the right middle cerebral artery, using the above described TCD scanner. The position of the 2 MHz probe was kept constant on the right temporal bone with an elastic band, fastened around the skull, equipped with a mechanical holding device. Insonation depth was set between 52 and 60 mm, depending on the position that ensured maximum signal intensity; sample volume axial length was 10 mm, and horizontal sweep speed was 10 s. To avoid accidental shifts of the probe along the temporal skin, and thus changes in the insonation angle, no contact was allowed between the probe holder and the surface of the tilt table thanks to a supporting device of appropriate dimensions placed on the table and supporting the occipital skull of the subjects without touching the elastic band of the probe holder. After 20-min resting, the tilt table was turned up to 60” for 2 min twice, at 5-min intervals, to let the subjects become acquainted with the test and minimize emotional influences on cerebral hemodynamics. Neither light nor verbal stimuli were given in the following 10 min or during dynamic testing. After 10 min, the CA test started. Continuous recordings were made in the supine position for at least 2 min. Afterwards, each subject was tilted up to 60”. No recording was obtained during the 20 s of the mechanical movement of the tilt table. Recordings were made for 2 min during head-up tilt. Data of mV and MAP were stored in a personal computer (Zenith Z-486/33 ET, Zenith Data System, Buffalo, NY, USA) for subsequent statistical analysis. Results of mV and MAP were evaluated as the mean values over three consecutive cardiac cycles, at intervals of 20 s each, according to the following scheme: baseline values (mean of the last three cycles in the supine position), end of mechanical movement of the tilt table (TO), 20 s (T20), 40 s (T40), 60 s (T60), 80 s (T80), 100 s (TlOO) and 120 s (T120) after TO. Values of MAP and mV obtained during the tilt test were expressed as percent values with respect to baseline. Blood samples were obtained just before and at the end of the CA test to measure hematocrit. CA was considered to be adequate when the recovery of mV was higher than that of MAP at T20 (11). To assess whether the slight downward shift of brain structures occurring during the tilt test might cause significant changes in the insonation angle, we evaluated, 115
TABLE
1
Child-Pugh class and results of baseline measurements in the 15 patients with cirrhosis and ascites and the 15 healthy subjects Patients Child Class (B-C) Ascites (mild/moderate) Serum bilirubin (mg/dl) Serum albumin (g/l) Prothrombin activity (l/u) Serum creatinine (mg/dl) Serum sodium (mmol/l) UNaV (mmoli24 h) Cl,, (ml/min) Hematocrit Fibrinogen (mg/dl) PRA(ng.mll’.h-~‘) Plasma aldosterone (nmol/l) Plasma NE (nmolil) Plasma ANP (pmolil) CI (l.min-’ rn- ‘) MAP (mmHg) PVRI (dyne’s’cm m5.mm2)
5--10 87 1.82t0.91 28.0?4.1 6224 0.91 -to.22 13621 20.422.1 802 15 0.3320.05 2891134 5.3322.82 4.7810.71 3.27k0.51 10.80t1.53 4.97-+ 1.79 9428 16322433
Healthv
subiects
0.57zo.07 (*) 41.21~1.12 (*) 9712 (*)
1.0210.05 140t1 (*) 41.011.8 (*) 11525 0.43+0.02 (*) 307278 1.18kO.13 (*) 0.71~0.10 (*) 0.88to.11 (*) 6.1521.79 (*) 3.3720.88 (#) 9328 23342526 (*)
UNaV: urinary sodium excretion. Cl,,: creatinine clearance., PRA: plasma renin activity. NE: norepinephrine. ANP: atria1 natriuretic peptide. CI: Cardiac index. MAP: mean arterial pressure. PVRI: peripheral vascular resistance index. ‘_n
in a preliminary set of experiments, the differences between the mV values recorded with the probe fixed with an elastic device during a tilt test and the ones obtained with manual search of the best signal intensity at the same depth during another tilt test in 12 healthy volunteers. The maximum difference noted between the two measurements was 7%: indicating that this mechanical factor can cause only minimal errors in mV measurements. Measurements Plasma renin activity was estimated by radioimmunoassay for angiotensin I (Rianen Angiotensin I Generation Kit, New England Nuclear, Boston, MA, USA). Aldosterone, norepinephrine and ANP were measured using commercial kits (ALDO kit, RADIM, Rome, Italy; CAT-A-KIT, Amersham, Buckinghamshire, UK; ANP ria kit, Peninsula Laboratories, St. Helens, UK. respectively) as previously described (21). Statistical analysis Data are expressed as meant SD. Results of baseline measurements in healthy subjects and patients with cirrhosis and in the two subgroups of patients, respectively with normal and impaired CA, were analyzed with the t-test for unpaired data. Statistical analysis of the sets of percent values of MAP and mV obtained in patients with cirrhosis and healthy subjects was performed using repeated measure 2-way analysis of vari116
ance (ANOVA). Comparisons between the two groups at each stage for arterial pressure and mV were performed using one-way ANOVA, followed by t-test with Bonferroni correction. Distribution of Child class and ascites score in patients with normal or impaired CA was performed using Fisher’s exact test. A /Ivalue<0.05 was considered significant. Data were analyzed by using the SPSS Inc. (Chicago, istical package.
IL, USA) stat-
Results Results of baseline measurements performed in patients with cirrhosis and healthy subjects are shown in Table 1. Cirrhotic patients with ascites had impaired liver function, sodium retention, hyperdynamic circulation, as indicated by a high cardiac index and low peripheral vascular resistance, activation of the reninaldosterone and sympathetic nervous systems and high plasma levels of atria1 natriuretic peptide. Patients also had significantly lower values of hematocrit than healthy controls. Fibrinogen levels were lower in patients than in controls, but the difference was not significant. Cerebral autoregulation testing No significant differences were observed between healthy subjects and cirrhotic patients with ascites with respect to any of the measured parameters during supine rest (Table 2). Both control subjects and patients with cirrhosis had adequate ultrasonic windows, mean blood flow velocity and pulsatility index within the normal limits (22-24), and no interhemispheric asym-
TABLE
2
Results of baseline transcranial Doppler measurements in the 15 patients with cirrhosis and ascites and the 15 healthy subjects Patients
Healthy
MCA mV (cm/s) PI
531-14 O.XOirO.16
54-L 14 0.83-+0.18
ACA mV (cm/s) PI
431-18 0.7820. I1
45215 0.82kO.09
ICA mV (cmi’s) PI
4429 0.92t0.23
42211 0.941-0.20
PCA mV (cm/s) PI
3627 0.8X10.12
345.5 0.84?0.15
BA mV (cm/s) PI
41z12 0.9lr0.08
40513 0.90to. 13
VMR (‘k)
301-12
subjects
342 I1
MCA=middle cerebral artery. ACA: anterior cerebral artery. ICA: internal carotid artery: PCA: posterior cerebral artery. BA: basilai artery. mV: mean blood few velocity. PI: pulsatility index. VMR: vasomotor reactivity (‘!it increase in mV in the middle cerebral arteries at the end of breath holding).
Cerebral autoregulation in cirrhosis
70’
0
20
1 40
1 60
80
100
120
time after tilting (set) Fig. I. Mean arterial pressure (MAP) in healthy subjects (dottedline) andpatients with cirrhosis (straight line) in the 120 s after tilting. Measurements were performed at the end of the mechanical movement of the tilt table. Data are expressed as percentage of baseline MAP (9328 mmHg in healthy subjects and 9428 mmHg inpatients with cirrhosis). Statistical analysis: 2-way AN0 VA tilt time anddisease: F= 34.54, p
metry (25), intracranial stenoses and hemodynamic patterns of collateral flow in the intracranial circulation. The cerebrovascular reactivity in response to breath-holding was present in both groups, thus allowing evaluation of CA. Baseline values of MAP and mV (mean of the last three cycles measured in the supine position, just before the tilt test) were 93 +8 mmHg and 54? 13 cm/s in healthy subjects and 9458 mmHg and 53-14 cm/s in patients with cirrhosis. Percent values of MAP and mV observed in patients and healthy subjects at the different times of acquisition are shown in Fig. 1 and 2. In the first determination performed after tilting (TO), MAP was reduced in both groups. Thereafter, control subjects showed a progressive increase in MAP, up to a complete recovery of basal values at T120. On the contrary, patients with cirrhosis had an incomplete recovery of MAP, with significant differences with respect to control subjects at T4CLT120. The behavior of MAP in response to passive tilting was therefore significantly different between the two groups (2-way ANOVA tilt time and disease: F=34.54,p<0.001, Fig. 1). Passive tilting induced a decrement of mV in both groups, no significant differences being observed between patients with cirrhosis and healthy subjects with respect to mV values in the first recording (TO) after tilt (Fig. 2). In the following steps, mV promptly returned to baseline values in healthy subjects, whereas patients showed a delayed and incomplete recovery of mV, so that
mV values were significantly lower in patients than in control subjects in all but the first measurement. The difference between the two groups was therefore significant (2-way ANOVA: tilt time and disease: F=5.53,p<0.01). In healthy subjects, the percent increment of mV after the first 20 s (o/omV at T20 minus %mV at TO) was significantly greater (ANOVA: F=9.73,p<0.01) than that of MAP, indicating that the recovery of mV was faster than that of MAP A similar phenomenon was not observed in patients with cirrhosis. When data of MAP and mV obtained in each individual during the tilt test were analyzed, and adequacy of CA was evaluated using the criteria of higher percent recovery of mV than that of MAP at T20, CA was found to be adequate in all control subjects, while eight out of 15 cirrhotic patients with ascites showed an impaired CA. These patients had a worse liver function than the seven patients with adequate autoregulation, since they were all in class C, according to Pugh et al. (14) whereas five out of the seven patients with normal CA were in class B (Fisher’s Exact test p=O.O3). Furthermore, cirrhotic patients with impaired CA had lower albumin levels (25.8k3.6 vs 3O.lk2.2 g/l, p
0
20
40
60
80
100
120
time after tilting (set) Fig. 2. Mean flow velocity in the right middle cerebral artery (mV) observed in healthy subjects (dotted line) and patients with cirrhosis (straight line) in the 120 s after tilting. Measurements were performed at the end of the mechanical movement of the tilt table. Data are expressed as percentage of baseline mV (54~13 cm/s in healthy subjects and 53+-14 cm/s in patients with cirrhosis). Statistical analysis: 2-way ANOVA: tilt time and disease: F=5..53, p
A. Lqi
et 01.
dyne. s. cm-5*m-2, pcO.05). Despite a trend towards higher PRA levels in patients with impaired autoregulation, no significant differences were observed between the two subgroups of cirrhotic patients with respect to any of the endocrine parameters measured in this study. During the test, neither patients nor control subjects showed heart rates over 120 beats per minute, hypo- or hyperventilation, which could give unreliable mV data due to the corresponding changes in arterial pC02. Passive tilting did not induce any appreciable changes in hematocrit in either healthy subjects (from 0.437t0.028 to 0.433+0.031) or patients with cirrhosis (from 0.342+0.041 to 0.339t0.042).
Discussion Patients with cirrhosis and ascites usually show a peculiar derangement of systemic hemodynamics, with increased plasma volume and cardiac output and reduced peripheral vascular resistance (4,5,26). These patients have also been demonstrated to have an impaired ability to maintain cardiovascular homeostasis and arterial pressure during postural changes, as indicated by previous studies that evaluated the response to tilting (7,27,28). More recently, an altered 24-h pressure profile has been observed in patients with cirrhosis, characterized by the lack of blood pressure increase during daytime, while patients are attending their daily activities, mainly in the standing position (29). In patients with cirrhosis and ascites, therefore, maintenance of CBF critically depends on the adequacy of CA. Cerebral autoregulation was usually studied by using a static approach, based on the collection of data on CBF under different consecutive steady-state conditions (30,31). This approach has led to the wellknown autoregulation curve, where CBF is constant within defined pressure limits and declines or increases when arterial pressure is below or above these limits. Transcranial Doppler recording of mV in the middle cerebral artery is a recently developed method to evaluate cerebral hemodynamics reliably in man (9--13), which allows a dynamic study of CA (10,32) in response to various stimuli, such as postural changes. In this regard, head-up tilt proved to be a useful tool to investigate the physiological response to alterations in cerebral perfusion pressure in humans (33) because it introduces transient changes in cerebral perfusion pressure by shifting a consistent amount of blood towards the lower limbs. Dynamic methods for the assessment of CA displayed a high correlation with static methods (32). The two approaches, however, evaluate different effects of the autoregulatory action, since the static method evaluates the overall effect, whereas the
dynamic
one evaluates
the latency
and the fast com-
ponents of CA (32). We studied a group of cirrhotic patients with ascites and hyperdynamic circulation, as indicated by the presence of high cardiac index and reduced peripheral vascular resistance (Table 1). and used the head-up tilt combined with TCD measurements of mV to investigate CA during the dynamic period of the recovery from the stepwise hypotensive stimulus applied. The validity of TCD measurements in the assessment of CA during tilting has been debated (3436) because of concerns about the possibility that the diameter of the middle cerebral artery might change during the orthostatic stress (34). However. further studies showed that variations in intracranial pressure induced by stepwise hypotensive stimuli. such as the leg-cuff method (10,35). the lower body negative pressure test (37) and the squatting/standing test (3X), have minimal influence on the cross-sectional area of the insonated artery. Moreover, modifications of mV due to changes in the caliber of the main trunk of the middle cerebral artery during head-up tilt were found to be negligible (39). In the present study no significant differences were observed between patients and control subjects with respect to baseline TCD measurements. The finding that patients had similar mV in the main cerebral vessels as healthy subjects does not allow the assumption that CBF of our patients with cirrhosis was normal. because they had low values of hematocrit (Table 1) and a wide variability in plasma fibrinogen levels, two parameters that are known to influence mean blood flow velocity (40,41). On the other hand, this study was not aimed at estimating CBF, but at evaluating CA in cirrhosis with ascites. For this purpose, we performed repeated measurements of MAP and mV before and during the first 2 min of head-up tilt. a maneuver that did not induce any appreciable modification of hematocrit. Passive tilting induced the expected transient hypotension in healthy subjects (42) and in patients with cirrhosis. In control subjects, however, MAP progressively increased and returned to baseline values at Tl20. By contrast, in patients with cirrhosis the recovery of MAP was delayed and incomplete, confirming that these patients have an altered cardiovascular response to tilt (7,27,28). The main finding of the current study was that CA was impaired in cirrhotic patients with ascites. In healthy subjects, mV, after the initial drop, recovered more rapidly than MAP and promptly returned to baseline levels, while in cirrhotic patients with ascites the recovery of mV was delayed and incomplete (Fig. 2), so that significant differences between patients and
Cerebral autoregulation
controls were observed with respect to mV measurements. Carbon dioxide is a powerful regulator of CBF and thus of mV (43). We monitored respiratory activity in both patients and control subjects and did not find either differences in baseline conditions or any modification during the tilt test, ruling out the possibility that our results might have been influenced by hypo- or hyperventilation-induced changes in arterial pCOz. In this study MAP of control subjects and patients with cirrhosis never fell below the lower limit of CA during passive tilting. Both groups also experienced an initial drop in mV when the hypotensive stimulus was given. This result is not in contradiction with the presence and adequacy of CA. In fact, previous dynamic studies on CA showed that after a transient change in MAP a latency is requested before CA takes place, as demonstrated by the slope of the mV/MAP regression (10,32,44,45) and the phase differences between oscillations in MAP and mV (3 1,46). However, mV would recover faster than MAP in the presence of an adequate CA, as it did occur in healthy subjects. By contrast, eight out of 15 cirrhotic patients with ascites were unable to promptly recover their mV values when submitted to passive tilting. Noteworthy, the delay of mV recovery in cirrhotic patients with impaired CA did not depend on the delay of MAP recovery, as demonstrated by the fact that mV at T20 was lower in this subset than in the control group, despite similar values of MAP measured at the same time after tilting. All these data indicate that CA was impaired in a substantial proportion of cirrhotic patients with ascites. Interestingly, the impairment of CA was observed in patients with a more severe reduction of liver function and more marked alterations of systemic hemodynamics. An impaired CA has been observed in humans (4749) and animals (50) with hepatic failure, and it is considered to play a major role in the development of cerebral edema. Recently, Larsen et al. (51) used TCD to investigate CBF autoregulation in 10 patients with liver cirrhosis, mostly without ascites, and found that it was impaired in only two of them. In this study, however, a static methodology was used, and changes in perfusion pressure were induced by combining mechanical and pharmacological stimuli. Different from this study (51) we investigated CA in a group of cirrhotic patients with ascites who had a more severe derangement of liver function and systemic hemodynamics, and used a physiological test, like the head-up tilt, so avoiding any pharmacological interference with systemic and cerebral hemodynamics. In conclusion, an impairment of CBF autoregulation in response to passive head-up tilting is often observed
in cirrhosis
in patients with cirrhosis and ascites. This alteration may predispose these patients to cerebral hypoperfusion and ischemia when they have to face pathological conditions that lead to an abrupt fall of arterial pressure, such as bleeding, infections, anesthesia or coma.
Acknowledgements This work was supported by grants from the Italian Liver Foundation and the Italian Minister0 per l’Universita e la Ricerca Scientifica e Tecnologica (1994, 1995).
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