Free
Perioperative Medicine  |   September 2009
Baroreflex Sensitivity Is Impaired in Patients with Obstructive Jaundice
Author Affiliations & Notes
  • Jian-gang Song, M.D.
    *
  • Yun-fei Cao, M.D.
  • Yu-ming Sun, M.D.
  • Yan-hu Ge, M.D.
    §
  • Xue-wu Xu, M.D.
  • Li-qun Yang, M.D.
  • Zhi-qiang Liu, M.D.
  • Shao-li Song, M.D., Ph.D.
    #
  • Wei-feng Yu, M.D.
    **
  • * Assistant Professor, Department of Anesthesiology, # Attending Physician, Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. † Associate Professor, ‡ Assistant Professor, § Resident, ** Professor and Director, Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. ∥ Associate Professor, Department of Anesthesiology, Shanghai First Maternity and Infant Health Hospital, Tongji University, Shanghai, China.
Article Information
Perioperative Medicine / Cardiovascular Anesthesia / Central and Peripheral Nervous Systems
Perioperative Medicine   |   September 2009
Baroreflex Sensitivity Is Impaired in Patients with Obstructive Jaundice
Anesthesiology 9 2009, Vol.111, 561-565. doi:10.1097/ALN.0b013e3181adf49f
Anesthesiology 9 2009, Vol.111, 561-565. doi:10.1097/ALN.0b013e3181adf49f
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 infection.1,2 Morbidity and mortality in jaundiced patients receiving surgical treatment are higher than in nonjaundiced patients.3,4 Reasons for this increased susceptibility are not well characterized at present. Potential mechanisms include extracellular water depletion,5,6 defective vascular reactivity,7,8 subclinical myocardial dysfunction,9,10 systemic endotoxemia that frequently accompanies obstructive jaundice,11,12 and exaggerated release of proinflammatory cytokines in response to endotoxin challenge.13,14 
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) limb.15 A reduction in sympathetic baroreflex sensitivity (BRS) results in greater hemodynamic liability when the patient is challenged with hypotension, hemorrhage, or general anesthesia.16,17 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 oxide,20,21 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 activity.25–28 Accordingly, we included these measures in the hope to find some underlying mechanisms for impaired baroreflex in jaundiced patients.
Materials 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 patients. Thirty-five consecutive men with obstructive jaundice (serum total bilirubin >20 μm) caused by a tumor in the bile duct or in the head of the pancreas were included in the study. Thirty men with asymptomatic gallbladder polypus without jaundice were recruited as controls. All participating patients were scheduled for elective surgery for the underlying diseases. Exclusion criteria were as follows: Age >70 yr or <50 yr; body mass index >30 kg/m2or <18 kg/m2; history of diabetes, cardiovascular, respiratory, or renal diseases; hepatic encephalopathy, psychiatric illnesses, or neuropathy; complication of acute cholangitis, gastrointestinal bleeding, or ascites; electrolyte or acid-base disturbance, sepsis, or cachexia defined as weight loss ≥2% in the past 2 months or ≥5% in the past 6 months; and use of medications that could interfere with cardiovascular function (e.g.  , β-blockers, calcium channel blockers, digoxin).
Baroreflex Sensitivity Measurement
Baroreflex sensitivity was measured using a modified Oxford pharmacological method29 before anesthesia on the day of surgery. On arriving at the operating room after an 8–10 h 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-1· h-1throughout 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 before the experiment. Testing was carried out using an intravenous bolus injection of 100–200 μg phenylephrine, followed by 100–250 μg sodium nitroprusside 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. Seven to 12 pairs of systolic blood pressure and 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. A liver function test was carried out using conventional methods and included total bilirubin, bile acids, alanine transaminase, and albumin. As for hormonal assays, a blood sample was collected into chilled tubes containing 2 mg/ml EDTA and 400 KIU/ml aprotinin (Trasylol; Sigma Chemical, St. Louis, MO). Samples were centrifuged at 3,000 g for 15 min at 4°C, and stored at −20°C until use. A radioimmunoassay kit was used to determine ANP (h-ANP, Cob. I-AR55 Co; Tokyo, Japan; reference value: 20–60 pg/ml).10 Because of 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). At 50% binding, the inter- and intraassay variation coefficient was 9.5% ± 0.5% and 6.8% ± 0.7%, respectively. The affinity of the antibody for methionine-enkephalin is 4 × 10−12pm.
Statistical Analysis
Data are presented as mean ± SD, and analyzed using an unpaired Student’s t  test. P  < 0.05 was considered to be statistically significant. A multivariate analysis was performed to identify factors associated with changes of BRS in the group of jaundiced patients. Candidate factors included significantly altered liver biochemistry and/or hormones, as compared with 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 nonjaundiced patients were taken in the preliminary trial. The vagal BRS of jaundiced patients and control patients were 5.14 ± 2.63 and 7.21 ± 2.98 ms/mmHg, respectively; and the sympathetic BRS were 3.07 ± 1.78 and 4.64 ± 2.16 ms/mmHg, respectively. 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.
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 patients. No arrhythmia was observed during the testing.
Table 1. Demographic Data 
Image not available
Table 1. Demographic Data 
×
Representative responses to phenylephrine and nitroprusside are shown in figure 1. In control patients, BRS was 8.98 ± 2.86 and 5.81 ± 2.53 ms/mmHg 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/mmHg, P  < 0.001; fig. 2).
Fig. 1. (  A  ) Sensitivity of the vagal component of arterial baroreflex in representative subjects. Patients received a bolus phenylephrine injection. Pulse interval was plotted against systolic blood pressure (SBP). The slope of the curve reflects the sensitivity of the vagal response. Closed circles: Control subject; pulse interval = 11.7 SBP −909, R2= 0.92,  P  < 0.001; SBP range = 137–161 mmHg. Triangles: Subject with obstructive jaundice. Pulse interval = 3.87 SBP + 159, R2= 0.92,  P  < 0.001; SBP range = 132–158 mmHg. (  B  ) 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: Control subject; pulse interval = 6.31 SBP + 56, R2= 0.96,  P  < 0.001; SBP range = 124 mmHg–103 mmHg. Triangles: Subject with obstructive jaundice; pulse interval = 1.65 SBP + 538, R2= 0.91,  P  < 0.001; SBP range = 126 mmHg–90 mmHg. 
Fig. 1. (  A  ) Sensitivity of the vagal component of arterial baroreflex in representative subjects. Patients received a bolus phenylephrine injection. Pulse interval was plotted against systolic blood pressure (SBP). The slope of the curve reflects the sensitivity of the vagal response. Closed circles: Control subject; pulse interval = 11.7 SBP −909, R2= 0.92,  P  < 0.001; SBP range = 137–161 mmHg. Triangles: Subject with obstructive jaundice. Pulse interval = 3.87 SBP + 159, R2= 0.92,  P  < 0.001; SBP range = 132–158 mmHg. (  B  ) 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: Control subject; pulse interval = 6.31 SBP + 56, R2= 0.96,  P  < 0.001; SBP range = 124 mmHg–103 mmHg. Triangles: Subject with obstructive jaundice; pulse interval = 1.65 SBP + 538, R2= 0.91,  P  < 0.001; SBP range = 126 mmHg–90 mmHg. 
Fig. 1. (  A  ) Sensitivity of the vagal component of arterial baroreflex in representative subjects. Patients received a bolus phenylephrine injection. Pulse interval was plotted against systolic blood pressure (SBP). The slope of the curve reflects the sensitivity of the vagal response. Closed circles: Control subject; pulse interval = 11.7 SBP −909, R2= 0.92,  P  < 0.001; SBP range = 137–161 mmHg. Triangles: Subject with obstructive jaundice. Pulse interval = 3.87 SBP + 159, R2= 0.92,  P  < 0.001; SBP range = 132–158 mmHg. (  B  ) 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: Control subject; pulse interval = 6.31 SBP + 56, R2= 0.96,  P  < 0.001; SBP range = 124 mmHg–103 mmHg. Triangles: Subject with obstructive jaundice; pulse interval = 1.65 SBP + 538, R2= 0.91,  P  < 0.001; SBP range = 126 mmHg–90 mmHg. 
×
Fig. 2. Sympathetic and vagal baroreflex sensitivity in patients with obstructive jaundice  versus  the controls. Values are mean ± SD. *  P  < 0.05  versus  the control group. 
Fig. 2. Sympathetic and vagal baroreflex sensitivity in patients with obstructive jaundice  versus  the controls. Values are mean ± SD. *  P  < 0.05  versus  the control group. 
Fig. 2. Sympathetic and vagal baroreflex sensitivity in patients with obstructive jaundice  versus  the controls. Values are mean ± SD. *  P  < 0.05  versus  the control group. 
×
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 as compared with controls. The concentrations of plasma nitrate and albumin did not differ between the two 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 (ms/mmHg) = 5.0951–0.0156 ANP (pg/ml), with R2of 0.1938 (fig. 3). No parameter was associated with vagal BRS.
Table 2. Liver Biochemistry and Hormone Levels 
Image not available
Table 2. Liver Biochemistry and Hormone Levels 
×
Fig. 3. Correlation between the serum atrial natriuretic peptide (ANP) and sympathetic baroreflex sensitivity in patients with obstructive jaundice (  P  = 0.008). 
Fig. 3. Correlation between the serum atrial natriuretic peptide (ANP) and sympathetic baroreflex sensitivity in patients with obstructive jaundice (  P  = 0.008). 
Fig. 3. Correlation between the serum atrial natriuretic peptide (ANP) and sympathetic baroreflex sensitivity in patients with obstructive jaundice (  P  = 0.008). 
×
Discussion
It is well established that the autonomic function of regulating the cardiovascular system is impaired in primary biliary cirrhosis, a chronic cholestatic liver disease with a probable autoimmune etiology.31 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 as compared with 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 dysfunction,32 stringent criteria were adopted in the current study to minimize this factor. Also, the normal plasma albumin of the 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.
The 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 perioperative 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 as a result of increased endotoxin absorption from the intestinal lumen and decreased clearance by the hepatic reticuloendothelial system.11,12 Furthermore, in obstructive jaundice, endotoxins produce more severe organ damage, mainly through exaggerated release of proinflammatory cytokines.13,14 Using a rodent model, Tracey et al.  recently discovered that an efferent vagus nerve attenuates the development of endotoxin-induced shock by inhibiting the release of proinflammatory cytokines such as tumor necrosis factor.33 Su et al.  observed a significant correlation between vagal BRS and survival time in rat models of experimental sepsis induced by lipopolysaccharide18 or cecal ligation and puncture.19 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 diseases.34 
Consistent with previous human and animal studies,10,24 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 nerves.35,36 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 response.37,38 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. Regarding the cause of increased ANP, a previous study by Martínez-Ródenas et al.  24 in rabbits with a biliovenous shunt suggests that 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 jaundice.10 
In addition, we also found an 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 reflexes,26,27 elevated methionine-enkephalin may have 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 methionine-enkephalin. In addition, we did not find changes in plasma nitrate levels in patients with obstructive jaundice. This result is consistent with the findings by Padillo et al.  in jaundiced patients,40 but not studies using rodent models of acute cholestasis.20,21 
Somewhat surprisingly, we did not find a 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 pathologic 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 the perioperative period. The underlying mechanisms for such a change may be associated with increased level of plasma ANP.
References
Green J, Better OS: Systemic hypotension and renal failure in obstructive jaundice-mechanistic and therapeutic aspects. J Am Soc Nephrol 1995; 5:1853–71Green, J Better, OS
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; 181:567–81Kimmings, AN van Deventer, SJ Obertop, H Rauws, EA Gouma, DJ
Rege RV: Adverse effects of biliary obstruction: Implications for treatment of patients with obstructive jaundice. AJR Am J Roentgenol 1995; 164:287–93Rege, RV
Sewnath ME, Karsten TM, Prins MH, Rauws EJ, Obertop H, Gouma DJ: A meta-analysis on the efficacy of preoperative biliary drainage for tumors causing obstructive jaundice. Ann Surg 2002; 236:17–27Sewnath, ME Karsten, TM Prins, MH Rauws, EJ Obertop, H Gouma, DJ
Sitges-Serra A, Carulla X, Piera C, Martínez-Ródenas F, Franch G, Pereira J, Gubern JM: Body water compartments in patients with obstructive jaundice. Br J Surg 1992; 79:553–6Sitges-Serra, A Carulla, X Piera, C Martínez-Ródenas, F Franch, G Pereira, J Gubern, JM
Gillett DJ: The effect of obstructive jaundice on the blood volume in rats. J Surg Res 1971; 11:447–9Gillett, DJ
Finberg JP, Syrop HA, Better OS: Blunted pressor response to angiotensin and sympathomimetic amines in bile-duct ligated dogs. Clin Sci (Lond) 1981; 61:535–9Finberg, JP Syrop, HA Better, OS
Utkan ZN, Utkan T, Sarioglu Y, Gönüllü NN: Effects of experimental obstructive jaundice on contractile responses of dog isolated blood vessels: Role of endothelium and duration of bile duct ligation. Clin Exp Pharmacol Physiol 2000; 27:339–44Utkan, ZN Utkan, T Sarioglu, Y Gönüllü, NN
Lumlertgul D, Boonyaprapa S, Bunnachak D, Thanachaikun N, Praisontarangkul OA, Phornphutkul K, Keoplung M: The jaundiced heart: Evidence of blunted response to positive inotropic stimulation. Ren Fail 1991; 13:15–22Lumlertgul, D Boonyaprapa, S Bunnachak, D Thanachaikun, N Praisontarangkul, OA Phornphutkul, K Keoplung, M
Padillo J, Puente J, Gómez M, Dios F, Naranjo A, Vallejo JA, Miño G, Pera C, Sitges-Serra A: Improved cardiac function in patients with obstructive jaundice after internal biliary drainage: Hemodynamic and hormonal assessment. Ann Surg 2001; 234:652–6Padillo, J Puente, J Gómez, M Dios, F Naranjo, A Vallejo, JA Miño, G Pera, C Sitges-Serra, A
Papakostas C, Bezirtzoglou E, Pitiakoudis M, Polychronidis A, Simopoulos C: Endotoxinemia in the portal and the systemic circulation in obstructive jaundice. Clin Exp Med 2003; 3:124–8Papakostas, C Bezirtzoglou, E Pitiakoudis, M Polychronidis, A Simopoulos, C
Pain JA, Bailey ME: Measurement of operative plasma endotoxin levels in jaundiced and non-jaundiced patients. Eur Surg Res 1987; 19:207–16Pain, JA Bailey, ME
Sewnath ME, Van Der Poll T, Ten Kate FJ, Van Noorden CJ, Gouma DJ: Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin. Hepatology 2002; 35:149–58Sewnath, ME Van Der Poll, T Ten Kate, FJ Van Noorden, CJ Gouma, DJ
Sewnath ME, van der Poll T, van Noorden CJ, ten Kate FJ, Gouma DJ: Cholestatic interleukin-6-deficient mice succumb to endotoxin-induced liver injury and pulmonary inflammation. Am J Respir Crit Care Med 2004; 169:413–20Sewnath, ME van der Poll, T van Noorden, CJ ten Kate, FJ Gouma, DJ
Eckberg DL, Sleight P: Human Baroreflexes in Health and Disease. Oxford, England: Clarendon Press; 1992; pp 3–57Eckberg, DL Sleight, P Oxford, England Clarendon Press
Chesterton LJ, McIntyre CW: The assessment of baroreflex sensitivity in patients with chronic kidney disease: Implications for vasomotor instability. Curr Opin Nephrol Hypertens 2005; 14:586–91Chesterton, LJ McIntyre, CW
Latson TW, Ashmore TH, Reinhart DJ, Klein KW, Giesecke AH: Autonomic reflex dysfunction in patients presenting for elective surgery is associated with hypotension after anesthesia induction. Anesthesiology 1994; 80:326–37Latson, TW Ashmore, TH Reinhart, DJ Klein, KW Giesecke, AH
Shen FM, Guan YF, Xie HH, Su DF: Arterial baroreflex function determines the survival time in lipopolysaccharide-induced shock in rats. Shock 2004; 21:556–60Shen, FM Guan, YF Xie, HH Su, DF
Shi KY, Shen FM, Liu AJ, Chu ZX, Cao YL, Su DF: The survival time post-cecal ligation and puncture in sinoaortic denervated rats. J Cardiovasc Pharmacol 2007; 50:162–7Shi, KY Shen, FM Liu, AJ Chu, ZX Cao, YL Su, DF
Ebrahimi F, Tavakoli S, Hajrasouliha AR, Shafaroodi H, Sadeghipour H, Riazi K, Borhani AA, Houshmand G, Ahmadi SH, Dehpour AR: Contribution of endogenous opioids and nitric oxide to papillary muscle contractile impairment in cholestatic rats. Eur J Pharmacol 2005; 31:93–100Ebrahimi, F Tavakoli, S Hajrasouliha, AR Shafaroodi, H Sadeghipour, H Riazi, K Borhani, AA Houshmand, G Ahmadi, SH Dehpour, AR
Gaskari SA, Mani AR, Ejtemaei-Mehr S, Namiranian K, Homayoun H, Ahmadi H, Dehpour AR: Do endogenous opioids contribute to the bradycardia of rats with obstructive cholestasis? Fundam Clin Pharmacol 2002; 16:273–9Gaskari, SA Mani, AR Ejtemaei-Mehr, S Namiranian, K Homayoun, H Ahmadi, H Dehpour, AR
Swain MG, Rothman RB, Xu H, Vergalla J, Bergasa NV, Jones EA: Endogenous opioids accumulate in plasma in a rat model of acute cholestasis. Gastroenterology 1992; 103:630–5Swain, MG Rothman, RB Xu, H Vergalla, J Bergasa, NV Jones, EA
Gallardo JM, Padillo J, Martín-Malo A, Miño G, Pera C, Sitges-Serra A: Increased plasma levels of atrial natriuretic peptide and endocrine markers of volume depletion in patients with obstructive jaundice. Br J Surg 1998; 85:28–31Gallardo, JM Padillo, J Martín-Malo, A Miño, G Pera, C Sitges-Serra, A
Martínez-Ródenas F, Pereira JA, Jiménez W, Gubern JM, Sitges-Serra A: Circulating bile is the main factor responsible for atrial natriuretic peptide release in experimental obstructive jaundice. Br J Surg 1998; 85:480–4Martínez-Ródenas, F Pereira, JA Jiménez, W Gubern, JM Sitges-Serra, A
Li Z, Chapleau MW, Bates JN, Bielefeldt K, Lee HC, Abboud FM: Nitric oxide as an autocrine regulator of sodium currents in baroreceptor neurons. Neuron 1998; 20:1039–49Li, Z Chapleau, MW Bates, JN Bielefeldt, K Lee, HC Abboud, FM
Szilagyi JE: Endogenous opiate modulation of baroreflexes in normotensive and hypertensive rats. Am J Physiol 1988; 255:H987–91Szilagyi, JE
Miyawaki T, Goodchild AK, Pilowsky PM: Activation of mu-opioid receptors in rat ventrolateral medulla selectively blocks baroreceptor reflexes while activation of delta opioid receptors blocks somato-sympathetic reflexes. Neuroscience 2002; 109:133–44Miyawaki, T Goodchild, AK Pilowsky, PM
Luchner A, Schunkert H: Interactions between the sympathetic nervous system and the cardiac natriuretic peptide system. Cardiovasc Res 2004; 63:443–9Luchner, A Schunkert, H
Tanaka M, Nagasaki G, Nishikawa T: Moderate hypothermia depresses arterial baroreflex control of heart rate during, and delays its recovery after, general anesthesia in humans. Anesthesiology 2001; 95:51–5Tanaka, M Nagasaki, G Nishikawa, T
Schimke I, Richter N, Wauer H, Rohr U, Petersson AS, Wennmalm A, Kuppe H, Kox WJ: High and low response in relation to nitric oxide formation but not to lipid peroxidation in patients with sepsis. Crit Care Med 2003; 31:65–72Schimke, I Richter, N Wauer, H Rohr, U Petersson, AS Wennmalm, A Kuppe, H Kox, WJ
Newton JL, Hudson M, Tachtatzis P, Sutcliffe K, Pairman J, Burt JA, Jones DE: Population prevalence and symptom associations of autonomic dysfunction in primary biliary cirrhosis. Hepatology 2007; 45:1496–505Newton, JL Hudson, M Tachtatzis, P Sutcliffe, K Pairman, J Burt, JA Jones, DE
Walsh D, Nelson KA: Autonomic nervous system dysfunction in advanced cancer. Support Care Cancer 2002; 10:523–8Walsh, D Nelson, KA
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405:458–62Borovikova, LV Ivanova, S Zhang, M Yang, H Botchkina, GI Watkins, LR Wang, H Abumrad, N Eaton, JW Tracey, KJ
Hendrickse MT, Thuluvath PJ, Triger DR: Natural history of autonomic neuropathy in chronic liver disease. Lancet 1992; 339:1462–4Hendrickse, MT Thuluvath, PJ Triger, DR
Ebert TJ, Cowley AW Jr: Atrial natriuretic factor attenuates carotid baroreflex-mediated cardioacceleration in humans. Am J Physiol 1988; 254:R590–4Ebert, TJ Cowley, AW
Ebert TJ: Reflex activation of sympathetic nervous system by ANF in humans. Am J Physiol 1988; 255:H685–9Ebert, TJ
Imaizumi T, Takeshita A, Higashi H, Nakamura M: alpha-ANP alters reflex control of lumbar and renal sympathetic nerve activity and heart rate. Am J Physiol 1987; 253:H1136–40Imaizumi, T Takeshita, A Higashi, H Nakamura, M
Thorén P, Mark AL, Morgan DA, O’Neill TP, Needleman P, Brody MJ: Activation of vagal depressor reflexes by atriopeptins inhibits renal sympathetic nerve activity. Am J Physiol 1986; 251:H1252–9Thorén, P Mark, AL Morgan, DA O’Neill, TP Needleman, P Brody, MJ
Thornton JR, Losowsky MS: Plasma methionine enkephalin concentration and prognosis in primary biliary cirrhosis. BMJ 1988; 297:1241–2Thornton, JR Losowsky, MS
Padillo FJ, Cruz A, Briceño J, Martin-Malo A, Pera-Madrazo C, Sitges-Serra A: Multivariate analysis of factors associated with renal dysfunction in patients with obstructive jaundice. Br J Surg 2005; 92:1388–92Padillo, FJ Cruz, A Briceño, J Martin-Malo, A Pera-Madrazo, C Sitges-Serra, A
Newton JL, Allen J, Kerr S, Jones DE: Reduced heart rate variability and baroreflex sensitivity in primary biliary cirrhosis. Liver Int 2006; 26:197–202Newton, JL Allen, J Kerr, S Jones, DE
Keresztes K, Istenes I, Folhoffer A, Lakatos PL, Horvath A, Csak T, Varga P, Kempler P, Szalay F: Autonomic and sensory nerve dysfunction in primary biliary cirrhosis. World J Gastroenterol 2004; 10:3039–43Keresztes, K Istenes, I Folhoffer, A Lakatos, PL Horvath, A Csak, T Varga, P Kempler, P Szalay, F
Fig. 1. (  A  ) Sensitivity of the vagal component of arterial baroreflex in representative subjects. Patients received a bolus phenylephrine injection. Pulse interval was plotted against systolic blood pressure (SBP). The slope of the curve reflects the sensitivity of the vagal response. Closed circles: Control subject; pulse interval = 11.7 SBP −909, R2= 0.92,  P  < 0.001; SBP range = 137–161 mmHg. Triangles: Subject with obstructive jaundice. Pulse interval = 3.87 SBP + 159, R2= 0.92,  P  < 0.001; SBP range = 132–158 mmHg. (  B  ) 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: Control subject; pulse interval = 6.31 SBP + 56, R2= 0.96,  P  < 0.001; SBP range = 124 mmHg–103 mmHg. Triangles: Subject with obstructive jaundice; pulse interval = 1.65 SBP + 538, R2= 0.91,  P  < 0.001; SBP range = 126 mmHg–90 mmHg. 
Fig. 1. (  A  ) Sensitivity of the vagal component of arterial baroreflex in representative subjects. Patients received a bolus phenylephrine injection. Pulse interval was plotted against systolic blood pressure (SBP). The slope of the curve reflects the sensitivity of the vagal response. Closed circles: Control subject; pulse interval = 11.7 SBP −909, R2= 0.92,  P  < 0.001; SBP range = 137–161 mmHg. Triangles: Subject with obstructive jaundice. Pulse interval = 3.87 SBP + 159, R2= 0.92,  P  < 0.001; SBP range = 132–158 mmHg. (  B  ) 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: Control subject; pulse interval = 6.31 SBP + 56, R2= 0.96,  P  < 0.001; SBP range = 124 mmHg–103 mmHg. Triangles: Subject with obstructive jaundice; pulse interval = 1.65 SBP + 538, R2= 0.91,  P  < 0.001; SBP range = 126 mmHg–90 mmHg. 
Fig. 1. (  A  ) Sensitivity of the vagal component of arterial baroreflex in representative subjects. Patients received a bolus phenylephrine injection. Pulse interval was plotted against systolic blood pressure (SBP). The slope of the curve reflects the sensitivity of the vagal response. Closed circles: Control subject; pulse interval = 11.7 SBP −909, R2= 0.92,  P  < 0.001; SBP range = 137–161 mmHg. Triangles: Subject with obstructive jaundice. Pulse interval = 3.87 SBP + 159, R2= 0.92,  P  < 0.001; SBP range = 132–158 mmHg. (  B  ) 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: Control subject; pulse interval = 6.31 SBP + 56, R2= 0.96,  P  < 0.001; SBP range = 124 mmHg–103 mmHg. Triangles: Subject with obstructive jaundice; pulse interval = 1.65 SBP + 538, R2= 0.91,  P  < 0.001; SBP range = 126 mmHg–90 mmHg. 
×
Fig. 2. Sympathetic and vagal baroreflex sensitivity in patients with obstructive jaundice  versus  the controls. Values are mean ± SD. *  P  < 0.05  versus  the control group. 
Fig. 2. Sympathetic and vagal baroreflex sensitivity in patients with obstructive jaundice  versus  the controls. Values are mean ± SD. *  P  < 0.05  versus  the control group. 
Fig. 2. Sympathetic and vagal baroreflex sensitivity in patients with obstructive jaundice  versus  the controls. Values are mean ± SD. *  P  < 0.05  versus  the control group. 
×
Fig. 3. Correlation between the serum atrial natriuretic peptide (ANP) and sympathetic baroreflex sensitivity in patients with obstructive jaundice (  P  = 0.008). 
Fig. 3. Correlation between the serum atrial natriuretic peptide (ANP) and sympathetic baroreflex sensitivity in patients with obstructive jaundice (  P  = 0.008). 
Fig. 3. Correlation between the serum atrial natriuretic peptide (ANP) and sympathetic baroreflex sensitivity in patients with obstructive jaundice (  P  = 0.008). 
×
Table 1. Demographic Data 
Image not available
Table 1. Demographic Data 
×
Table 2. Liver Biochemistry and Hormone Levels 
Image not available
Table 2. Liver Biochemistry and Hormone Levels 
×