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Baroreflex sensitivity is impaired in patients with obstructive jaundice
时间：2010-08-24 09:11:30 来源： 作者：
Introduction Patients with obstructive jaundice are prone to hypotensive shock, acute renal failure, sepsis, and multiple organ failure under a wide range of conditions, such as anesthesia, surgery, hemorrhage, and infection1, 2.Morbidity and mortality in jaundiced patients receiving surgical treatment are higher than non-jaundiced subjects3, 4. Reasons for this increased susceptibility are not well characterized at present. Potential mechanisms include extracellular water depletion5, 6, defective vascular reactivity7, 8, subclinical myocardial dysfunction9, 10, systemic endotoxemia that frequently accompanies obstructive jaundice11, 12, and exaggerated release of pro-inflammatory cytokines in response to endotoxin challenge13, 14. Arterial baroreflex is an important short-term neural control mechanism that maintains cardiovascular stability. The reflex consists of two parts: a sympathetic and a vagal (parasympathetic) limb15. A reduction in sympathetic baroreflex sensitivity (BRS) results in greater hemodynamic liability when the subject is challenged with hypotension, hemorrhage or general anesthesia16, 17. An intact vagal baroreflex recently has been found to be necessary for improving survival in sepsis 18, 19. Based on these findings, we hypothesized that arterial baroreflex function may be compromised in patients with obstructive jaundice, which may help to explain the enhanced susceptibility to those well-known perioperative complications. The current study was designed to test this hypothesis. Besides cholestasis and liver damage, overproduction of nitric oxide20, 21, accumulation of endogenous opioid peptides (methionine-enkephalin) 22, and elevated plasma level of atrial natriuretic peptides (ANP) 10, 23, 24, are frequently observed in patients with obstructive jaundice or in animal models of biliary obstruction. These factors are implicated in the regulation of arterial baroreflex function and/or autonomic nervous system activity25-28. Accordingly, we included these measures in the hope to find some underlying mechanisms for impaired baroreflex in jaundiced patients.  Figure 1A. Sensitivity of the vagal component of arterial baroreflex in representative subjects. Patients received a bolus phenylephrine injection. Pulse interval was plotted against SBP. The slope of the curve reflects the sensitivity of the vagal response. Closed circles: a control subject. Pulse interval = 11.7SBP-909, R2 = 0.92, P<0.001; SBP range: 137-161 mmHg. Triangles: a subject with obstructive jaundice. Pulse interval = 3.87SBP+159, R2 = 0.92, P<0.001; SBP range: 132-158 mmHg. SBP = systolic blood pressure.  Figure 1B. Sensitivity of the sympathetic component of arterial baroreflex in representative subjects. Patients received a bolus nitroprusside injection. Pulse interval was plotted against SBP. The slope of the curve reflects the sensitivity of the sympathetic response. Closed circles: a control subject. Pulse interval = 6.31SBP+56, R2 = 0.96, P<0.001; SBP range: 124-103 mmHg. Triangles: a subject with obstructive jaundice. Pulse interval = 1.65SBP+538, R2 = 0.91, P<0.001; SBP range: 126-90 mmHg. Patients and Methods Patients The study was approved by the Institutional Ethics Committee (Eastern Hepatobiliary Surgery Hospital; Shanghai, China). Informed consent was obtained from all participating subjects. Thirty-five consecutive male patients with obstructive jaundice (serum total bilirubin >20 μmol/L) caused by a tumor in the bile duct or in the head of the pancreas were included in the study. Thirty male patients with asymptomatic gallbladder polypus without jaundice were recruited as controls. All participating subjects were scheduled for elective surgery for the underlying diseases. Exclusion criteria were: (1) age >70 yr or <50 yr; (2) body mass index >30 kg/m2, or <18 kg/m2; (3) history of diabetes, cardiovascular, respiratory, or renal diseases; (4) hepatic encephalopathy, psychiatric illnesses, or neuropathy; (5) complication of acute cholangitis, gastrointestinal bleeding, or ascites; (6) electrolyte or acid-base disturbance, sepsis, or cachexia defined as weight loss ≥ 2% in the past 2 months or ≥ 5% in 6 months; (7) use of medications that could interfere with cardiovascular function (e.g., b-blockers, calcium channel blockers, digoxin). Baroreflex Sensitivity Measurement Baroreflex sensitivity was measured using a modified Oxford pharmacological method 29 prior to anesthesia on the day of surgery. On arriving at the operating room after an 8-10 hour fast, an electrocardiography monitor (lead Ⅱ), a central intravenous catheter, and an arterial (radial) blood pressure catheter were placed. Electrocardiogram and blood pressure were continuously monitored. Acetate Ringer’s solution was administered intravenously at a rate of 2 ml/kg/h throughout the entire procedure. The patients did not receive any premedication that could otherwise interfere with the subsequent baroreflex testing, and were allowed to rest in a supine position for at least 20 min prior to the experiment. Testing was carried out using intravenous bolus injection of phenylephrine (100-200 mg) followed by sodium nitroprusside (100-250 mg) to increase/decrease systolic blood pressure by 15-30 mmHg, respectively. The pressor and the depressor tests were separated by a period of stabilization, usually 5 min, for the heart rate and systolic blood pressure to return to 95%-105% of the pretest level. The slope of the linear portion of the relationship curve between the pulse interval and the preceding systolic blood pressure was analyzed using a least-square regression as an index for baroreflex sensitivity. 7-12 pairs of systolic blood pressureand pulse intervals were used for each test. Squared correlation coefficient was greater than 0.8 for all samples. Patients proceeded to anesthesia and surgery after the BRS experiment was completed. The observers were unaware of the study design or the study purpose. Blood Sampling and Hormonal Assays Before the BRS test, a sample of venous blood was collected. Arterial gas analysis was performed using samples of arterial blood collected during the BRS test. Liver function test was carried out using conventional methods, and included total bilirubin, bile acids, alanine transaminase, and albumin. As for hormonal assays, blood sample was collected into chilled tubes containing EDTA (2 mg/mL) and aprotinin (Trasylol 400 KIU/mL; Sigma Chemical, St. Louis, MO). Samples were centrifuged at 3,000 g for 15 minutes at 4°C, and stored at -20°C until use. Radioimmunoassay kit was used to determine ANP (h-ANP, Cob. I-AR55 Co; Tokyo, Japan; reference value: 20–60 pg/mL)10. Due to the extremely short half-life of nitric oxide, its production was estimated by measuring the plasma nitrate concentration using a gas chromatography-mass spectrometry method 30. Plasma met-enkephalin was determined using a radioimmunoassay kit (Peninsula Laboratories, Inc., San Carlos, CA, U.S.A). At 50% binding, the inter- and intra-assay variation coefficient was 9.5% ± 0.5% and 6.8% ± 0.7%, respectively. The affinity of the antibody for methionine-enkephalin is 4×10 -12 pmol/L. Statistical Analysis Data are presented as mean ± SD, and analyzed using an unpaired Student t-test. P < 0.05 was considered statistically significant. A multivariate analysis was performed to identify factors associated with changes of BRS in the group of jaundiced patients. Candidate factors included those significantly altered liver biochemistry and/or hormones compared with that of controls. Variables with P > 0.1 were excluded from the regression analysis using a stepwise method [SPSS 11 for Windows (SPSS Inc., Chicago, IL)]. The BRS measurements of eight jaundiced patients and eight non-jaundiced ones were taken in the preliminary trial. The vagal BRS of jaundiced patients and control subjects were 5.14±2.63 and 7.21±2.98 ms mm Hg-1, respectivly; and the sympathetic BRS were 3.07±1.78 and 4.64±2.16 ms mm Hg-1, respectivly. Based on the difference between two groups, the formula for normal theory, and assuming a two-sided type I error rate of 0.05 and a power of 0.80, 30 patients in each group were required to reveal a statistically significant difference.  Figure 2. Sympathetic and vagal baroreflex sensitivity in patients with obstructive jaundice vs. the controls. Values are mean±SD. *P<0.05 vs. the control group.  Figure 3. Correlation between the serum ANP and sympathetic baroreflex sensitivity in patients with obstructive jaundice ( P=0.008 ). Results The two groups did not differ in age, weight, body temperature, baseline blood pressure, and heart rate (Table 1). Blood pH, arterial oxygen and carbon dioxide, sodium, potassium, ionized calcium, and glucose were all within the normal range in all participants. No arrhythmia was observed during the testing. Representative responses to phenylephrine and nitroprusside are shown in Figure 1. In control subjects, BRS was 8.98±2.86 and 5.81±2.53 ms mm Hg-1 for the vagal and sympathetic limbs, respectively. Both measures were significantly reduced in patients with jaundice (5.28±2.68 and 3.19±1.52 ms mm Hg-1, P <0.001; Figure 2). As expected, serum concentrations of total bilirubin, bile acids, and alanine transaminase were significantly higher in patients with jaundice. Plasma concentrations of methionine-enkephalin and ANP were higher in patients with jaundice in comparison to the controls. The concentrations of plasma nitrate and albumin did not differ between the 2 groups (Table 2). Consequently, plasma total bilirubin, bile acids, alanine transaminase, methionine-enkephalin and ANP were chosen as possible candidate risk factors associated with impaired BRS of jaundice patients for a multivariate regression analysis. As a result, a significant inverse correlation between the plasma ANP concentration and sympathetic BRS in patients with obstructive jaundice was found, and the equation of the regression line was sympathetic BRS (msec/mmHg) = 5.0951-0.0156 · ANP (pg/ml), with R2 of 0.1938 (Figure 3). No parameter was associated with vagal BRS. Discussion It is well established that the autonomic function of regulating cardiovascular system is impaired in primary biliary cirrhosis, a chronic cholestatic liver disease with a probable autoimmune etiology31. Results from the current study for the first time extended these findings to patients with obstructive jaundice. Specifically, we found significantly decreased sensitivity in both sympathetic and vagal baroreflex in comparison to aged match controls. A potential confounding factor in the current study is the presence of tumor in the jaundiced group but not the control group. Since cachexia caused by neoplasm has been reported to be associated with autonomic dysfunction32, stringent criteria were adopted in the current study to minimize this factor.Also, the normal plasma albuminof jaundiced group indicated a relatively good condition.Consequently, it is reasonable to attribute impaired BRS in jaundiced patients to extrahepatic biliary obstruction, and not the systemic effects of the tumors. rte ved in The theThe current study did not confirm the cause-effect relationship between reduced BRS in patients with obstructive jaundice and their susceptibility to hypotensive shock, acute renal failure, sepsis, or multiple organ failure. However, it is only reasonable to assume that impaired sympathetic BRS would lead to insufficient compensatory responses to hypotension, blood loss, or other hemodynamic disturbances in the peri-operative period, which may predispose jaundiced patients to organ hypoperfusion or ischemic events. Decreased vagal BRS may also be a critical contributing factor to the greater susceptibility of these patients to sepsis. Endotoxemia is a frequent condition that accompanies obstructive jaundice due to increased endotoxin absorption from the intestinal lumen and decreased clearance by the hepatic reticuloendothelial system11, 12. Furthermore, in obstructive jaundice endotoxin produce severer organ damage mainly through exaggerated release of pro-inflammatory cytokines13, 14.Using a rodent model, Tracey et al. recently discovered that efferent vagus nerve attenuates the development of endotoxin-induced shock by inhibiting the release of pro-inflammatory cytokines such as tumor necrosis factor33. Su et al. observed a significant correlation between vagal BRS and survival time in rat models of experimental sepsis induced by lipopolysaccharide 18 or cecal ligation and puncture19. Based on these findings, we hypothesize that decreased vagal BRS in jaundiced patients may, at least in part, result in an endotoxin hypersensitivity state of cholestatic host that eventually leads to multiple organ damage. This hypothesis is consistent with the previous findings that the presence of vagal neuropathy is an independent predictor for reduced survival in patients with chronic liver diseases34. Consistent with previous human and animal studies10, 24, we found increased plasma ANP concentration in patients with obstructive jaundice. In addition, a multivariate analysis revealed an inverse relation between plasma ANP and sympathetic BRS in jaundiced patients. In addition to diuresis and vasodilation, ANP also influences sympathetic nervous outflow 28. Several human studies demonstrated that infusion of exogenous ANP lowers the activity of sympathetic but not parasympathetic nerves35, 36. Animal studies have also shown that reflex tachycardia and sympathoexcitation did not occur during hypotension caused by ANP, whereas similar levels of hypotension produced with nitroglycerin provoked an appropriate reflex tachycardic response37, 38. Thus, negative correlation between sympathetic BRS and plasma ANP suggested that increased ANP may produce a relative sympatho-inhibitory action, which, at least in part, results in impaired sympathetic BRS in jaundiced patients. With regards to the cause of increased ANP, a previous study by Martínez-Ródenas et al.24rabbits with biliovenous shunt suggests the passage of bile components to the circulation may be responsible. The presence of bile products in the blood may diminish cardiac contractility, which in turn may result in increased ANP synthesis through stretching of the atria. Indeed, a correlation between subclinical myocardial dysfunction and increased ANP was found in patients with obstructive jaundice10. In addition, we also found increased level of circulating methionine-enkephalin in patients with obstructive jaundice, which is consistent with previous reports in cholestatic rodents and patients 22, 39, Since endogenous opioids have been implicated in the central inhibition of sympathetic tone and baroreceptor reflexes26, 27, elevated methionine-enkephalin may also contributed to observed BRS dysfunction in patients with obstructive jaundice in the current study. However, we were unable to detect a direct correlation between BRS and plasma met-enkephalin. Additionally, we did not find changes in plasma nitrate level in patients with obstructive jaundice. This result is consistent with the findings by Padillo et al. in jaundiced patients40, but not studies using rodent models of acute cholestasis20, 21. Somewhat surprisingly, we did not find significant correlation between impaired BRS and blood biochemical measures indicative of liver damage and/or the degree of jaundice, such as serum alanine transaminase, bilirubin, or bile acids, in patients with obstructive jaundice. In fact, in chronic cholestatic liver diseases, association between autonomic dysfunction and disease severity has not been confirmed. For example, Newton et al.41 suggested that abnormalities of heart rate variability and BRS in primary biliary cirrhosis are not specific to advanced disease but associated with fatigue severity. Keresztes et al.42 showed that risk factors for autonomic dysfunction include duration and severity of primary biliary cirrhosis but not markers of cholestasis. The lack of relationship between BRS and liver function in patients with obstructive jaundice suggests that reduced BRS may be the result of pathological processes (such as increased ANP in circulation) to which obstructive jaundice acts as a permissive factor or cofactor in some way, rather than a direct consequence of jaundice itself. In other words, the changes secondary to liver damage and/or cholestasis may contribute more to autonomic dysfunction than liver damage and/or cholestasis per se.It should be pointed out that the strategy of including only the significant or known variables in the multivariate analysis carries the risk of excluding some potential confounding relations, but also minimizes unexplainable or spurious associations. Consequently, risk factors underpinning the impairment of BRS warrant further study. In conclusion, the present study demonstrated that both the sympathetic and vagal components of arterial baroreflex are depressed in patients with obstructive jaundice. Reduced BRS may, at least in part, contribute to enhanced susceptibility to hypotensive shock, renal failure, and sepsis in patients with obstructive jaundice during peri-operative period. The underlying mechanisms for such a change may be associated with increased level of plasma ANP.   References 1. Green J, Better OS. Systemic hypotension and renal failure in obstructive jaundice-mechanistic and therapeutic aspects. J Am Soc Nephrol 1995; 5:1853-71. 2. Kimmings AN, van Deventer SJ, Obertop H, Rauws EA, Gouma DJ. Inflammatory and immunologic effects of obstructive jaundice: pathogenesis and treatment. J Am Coll Surg 1995; 181:567-81. 3. Robert V. Rege. Adverse effects of biliary obstruction: implications for treatment of patients with obstructive jaundice. Am J Roentgenol 1995;164:287-93. 4. 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