Penetration of ceftriaxone and cefoperazone into bile and gallbladder tissue in patients with acute cholecystitis

The penetration of ceftriaxone and cefoperazone into bile and gallbladder tissue was prospectively studied in 21 adult patients undergoing early surgery for acute cholecystitis. Comparable tissue, bile, and serum concentrations of the drugs were demonstrable; however, significantly fewer preoperative doses of ceftriaxone were required for adequate perioperative treatment. In view of its higher serum half-life and superior antibacterial activity toward common biliary pathogens, ceftriaxone appears to be a useful drug for the perioperative management of acute cholecystitis.     

胆道梗阻诱发急性胆囊炎对豚鼠胆囊平滑肌收缩的影响

目的探讨胆道梗阻早期胆囊平滑肌的收缩障碍,并初步探究其相关机制。方法胆总管结扎方法构建豚鼠急性非结石性胆囊炎(AAC)模型,HE染色后光镜下观察各组胆囊病理改变。采用灌流法加药,利用张力换能器记录豚鼠离体胆囊肌条张力的变化,观察8肽胆囊收缩素(CCK-8)、乙酰胆碱(Ach)及氯化钾(KCl)对正常豚鼠离体胆囊肌条(A组)、假手术组(B组)、胆总管结扎1天(C组)、胆总管结扎2天(D组)豚鼠离体胆囊肌条的影响。结果A、B组未见明显炎性改变;C组炎症改变较轻;D组炎性改变明显。加入CCK-8、Ach和KCl后,A组、B组、C组及D组收缩振幅均增加,呈浓度依赖性;C、D两组振幅效应值同A组和B组相比变小,起作用时间慢(P0.05)。结论利用胆总管结扎方法可成功构建AAC模型。离体胆囊肌条肌张力降低在AAC的发生发展中有重要作用。模型组肌条收缩力降低,可能与CCK受体、胆碱能受体相关。     

Hydrophilic bile salts and liposomes inhibit hydrophobic bile salt-induced release of glycoprotein by guinea-pig gall-bladder

Abstract Bile salts can be cytotoxic to mucosal surfaces, because of their detergent properties. This is not normally seen under physiological circumstances in the gall-bladder. To further study normal mucosal defence mechanisms, the present study was performed to examine the effects of liposomes and hydrophilic bile salts on hydrophobic bile salt-induced release of radiolabelled glycoproteins from explants of guinea-pig gall-bladder. Glycoprotein release was correlated with the degree of hydrophobicity of bile salts, as determined by the retention factor in reversed-phase high-performance liquid chromatography. Hydrophobic bile salt-induced release of glycoproteins was reduced by liposomes and hydrophilic bile salts. The inhibitory effect of liposomes was directly related to the degree of saturation of their fatty acyl chains, and that of hydrophilic bile salts was related to the degree of hydrophilicity. These findings suggest that vesicles and hydrophilic bile salts may play a cytoprotective role against membrane damage passively caused by hydrophobic bile salts in the biliary system, and that such damage may occur according to the quantitative and qualitative imbalance among these factors.     

Smooth muscle function and dysfunction in gallbladder disease

The gallbladder epithelium and smooth muscle layer are exposed to concentrated biliary solutes, including cholesterol and potentially toxic hydrophobic bile salts, which are able to influence muscle contraction. Physiologically, gallbladder tone is regulated by spontaneous muscle activity, hormones, and neurotransmitters released into the muscle from intrinsic neurons and extrinsic sympathetic nerves. Methods to explore gallbladder smooth muscle function in vitro include cholecystokinin (CCK) receptorbinding studies and contractility studies. In human and animal models, studies have focused on cellular and molecular events in health and disease, and in vitro findings mirror in vivo events. The interplay between contraction and relaxation of the gallbladder muscularis leads in vivo to appropriate gallbladder emptying and refilling during fasting and postprandially. Defective smooth muscle contractility and/or relaxation are found in cholesterol stone-containing gallbladders, featuring a type of gallbladder leiomyopathy; defects of CCKA receptors and signal transduction may coexist with abnormal responses to oxidative stress and inflammatory mediators. Abnormal smooth musculature contractility, impaired gallbladder motility, and increased stasis are key factors in the pathogenesis of cholesterol gallstones.     

Clinical predictors of severe gallbladder complications in acute acalculous cholecystitis

AIM: To evaluate the relationship between clinical information (including age, laboratory data, and sonographic findings) and severe complications, such as gangrene, perforation, or abscess, in patients with acute acalculous cholecystitis (AAC). METHODS: The medical records of patients hospitalized from January 1997 to December 2002 with a diagnosis of acute cholecystitis were retrospectively reviewed to find those with AAC, confirmed at operation or by histologic examination. Data collected included age, sex, white blood cell count, AST, total bilirubin, alkaline phosphatase, bacteriology, mortality, and sonographic findings. The sonographic findings were recorded on a 3-point scale with 1 point each for gallbladder distention, gallbladder wall thickness >3.5 mm, and sludge. The patients were divided into 2 groups based on the presence (group A) or absence (group B) of severe gallbladder complications, defined as perforation, gangrene, or abscess. RESULTS: There were 52 cases of AAC, accounting for 3.7% of all cases of acute cholecystitis. Males predominated. Most patients were diagnosed by ultrasonography (48 of 52) or computed tomography (17 of 52). Severe gallbladder complications were present in 27 patients (52%, group A) and absent in 25 (group B). Six patients died with a mortality of 12%. Four of the 6 who died were in group A. Patients in group A were significantly older than those in group B (mean 60.88 y vs. 54.12 y, P=0.04) and had a significantly higher white blood cell count (mean 15,885.19 vs. 9,948.40, P=0.0005). All the 6 patients who died had normal white blood cell counts with an elevated percentage of band forms. The most commonly cultured bacteria in both blood and bile were E. coli and Klebsiella pneumoniae. The cumulative sonographic points did not reliably distinguish between groups A and B, even though group A tended to have more points. CONCLUSION: Older patients with a high white cell count are more likely to have severe gallbladder complications. In these patients, earlier surgical intervention should be considered if the sonographic findings support the diagnosis of AAC.     

Ursodeoxycholic acid and in vitro vasoactivity of hydrophobic bile acids

Lipophilic bile acids, such as deoxycholic acid (DCA), are nonspecific endothelium-independent vasorelaxants whose underlying basis is complex, involving membrane calcium channels blockade and receptor antagonism. The vasorelaxant action of these acids has also been linked to the generation of reactive oxygen species and an increased extent of lipid peroxidation. Ursodeoxycholic acid (UDCA) is a naturally occurring tertiary dihydroxy hydrophilic acid whose mechanism of action has been attributed to minimizing the effects of lipophilic bile acids. Hence, we considered UDCA might be a useful pharmacological tool to delineate the role of enhanced lipid peroxidation in lipophilic bile acid-induced vasorelaxation. UDCA abrogates in vitro DCA-induced vasorelaxation in rat aortic rings and can suppress DCA-initiated lipid peroxidation in vascular smooth muscle microsomal membrane fractions prepared from the rat aortae. Three different studies were performed. In study 1, the ability of UDCA to restore the DCA-blunted contractile response to the ₁-adrenoceptor, phenylephrine in rat aortic rings, was evaluated. In study 2, the ability of UDCA to restore DCA-induced vasorelaxation in precontracted rat aortic rings was assessed. In study 3, the ability of UDCA to suppress the increased extent of lipid peroxidation effected by DCA in vascular smooth muscle microsomal membrane fractions prepared from rat aortae was measured using the thiobarbituric acid reactive substance (TBARS) assay. UDCA, at a concentration equivalent to that seen in the plasma of patients with cholestatic liver disease treated with the bile acid, partially restored DCA-induced impaired contractility, prevented DCA-induced vasorelaxation, and abolished DCA-induced increases in the extent of lipid peroxidation. In conclusion, these data suggest that DCA-induced vasorelaxation is mediated by increasing the extent of lipid peroxidation in vascular tissue.     

Acute hemorrhagic pancreatic necrosis in mice bile acids in gallbladder bile, serum and pancreas

Mice develop acute hemorrhagic pancreatic necrosis with fat necrosis after 4 days of feeding on a choline deficient-ethionine supplemented (CDE) diet. The diameter, weight and histopathology of the gallbladder were determined in mice fed laboratory chow (LC), a choline-supplemented (CS) diet, a choline-deficient (CD) diet, or the CDE diet for 1, 2 or 3 days. A progressive distension of the gallbladder due to accumulation of bile, was observed in mice fed the CS, CD and CDE diets. An analysis of the bile acid composition of the pancreas, serum and gallbladder bile of mice fed the same diets for 3 days was performed. No differences between control and experimental animals were seen in the concentration and distribution of bile acids in the pancreas. It is concluded that: 1) alterations in bile acid constituents are produced by the diets; and, 2) regurgitation of bile into the pancreas of mice fed the CDE diet does not occur. Thus, bile acids do not seem to initiate or participate in the extensive cellular damage that precedes and accompanies the onset of acute hemorrhagic pancreatic necrosis with fat necrosis in mice fed the CDE diet.     

Sildenafil enhances systolic adaptation, but does not prevent diastolic dysfunction, in the pressure-loaded right ventricle

Aim Right ventricular (RV) failure due to pressure or volume overload is a major risk factor for early mortality in congenital heart disease and pulmonary hypertension, but currently treatments are lacking. We aimed to demonstrate that the phosphodiesterase 5A inhibitor sildenafil can prevent adverse remodelling and improve function in chronic abnormal RV overload, independent from effects on the pulmonary vasculature. METHODS AND RESULTS: In rat models of either pressure or volume overload, we performed pressure-volume studies to measure haemodynamic effects and voluntary exercise testing as clinical outcome after 4 weeks of sildenafil (or vehicle) administration. In the pressure-loaded right ventricle, sildenafil enhanced contractility [end-systolic elastance (mmHg/mL) 247 ±68 vs.155 ±71, sildenafil vs. vehicle, P < 0.05], prevented RV dilatation [end-diastolic volume (μL) 733 ±50 vs. 874 ±39, P < 0.05], reduced wall stress [peak wall stress (mmHg) 323 ±46 vs. 492 ±62, P < 0.05], and partially preserved exercise tolerance [running distance (%) -33 ±15 vs. -62 ±12, P < 0.05]. Protein kinase A was not activated by sildenafil and thus did not mediate the observed effects. In contrast, protein kinase G-1 was activated by sildenafil, but hypertrophy was not inhibited. Importantly, sildenafil did not prevent diastolic dysfunction, whereas RV fibrosis appeared to be increased in sildenafil-treated rats. In the volume-loaded right ventricle, sildenafil treatment did not show any beneficial effects. CONCLUSION: We demonstrate sildenafil to have beneficial, afterload-independent effects on the pressure-loaded right ventricle, but not on the volume-loaded right ventricle. These results indicate that sildenafil may offer a specific treatment for the pressure-loaded right ventricle, although persistent diastolic dysfunction and RV fibrosis could be of concern.     

Preconditioning does not prevent postischemic dysfunction in aging heart

Objectives. This study was performed to investigate the effect of single or multiple brief periods of ischemia and the administration of exogenous norepinephrine before a more prolonged ischemic period and after reperfusion in adult and senescent isolated and perfused rat hearts.

Background. The mortality rate for coronary artery disease is greater in the elderly. Ischemic preconditioning has been proposed as an endogenous form of protection against ischemia-reperfusion injury. However, the role of preconditioning in aging heart is unknown.

Methods. Compared the protective effect of preconditioning transient ischemic and norepinephrine stimuli against 20 min of global normothermic ischemia and 40 min of reperfusion in isolated perfused hearts of adult (6 months old) and senescent (24 months old) rats. Norepinephrine release in coronary effluent was determined by high performance liquid chromatography.

Results. Final recovery of percent developed pressure were improved after single preconditioning transient ischemic and norepinephrine stimuli in adult hearts (87.7 ± 9% and 82.3 ± 8.7%) versus unconditioned control hearts (50.6 ± 4.8%, p < 0.01 [mean ± SD]). The effect of preconditioning on developed pressure recovery was not present in senescent hearts after transient ischemic stimulus (39.8 ± 4.9% vs. 41.6 ± 5.8%, P = NS) but was present after norepinephrine stimulus (74.3 ± 10.5, p < 0.01). Norepinephrine release significantly increased after preconditioning transient ischemic stimulus in adult but not in senescent hearts (p < 0.01 vs. adult). Transient ischemic- and norepinephrine-induced preconditioning was blocked by alpha-adrenergic receptor antagonists in both adult and senescent hearts. Multiple transient ischemic stimuli were able to reduce postischemic dysfunction in adult but not in senescent hearts.

Conclusions. Preconditioning transient ischemic stimulus significantly reduces postischemic dysfunction in adult but not in senescent hearts, whereas exogenous norepinephrine is able to mimic preconditioning in both adult and senescent hearts. Ischemic preconditioning induces an increase in norepinephrine release in adult but not in senescent hearts. Preconditioning induced by transient ischemic stimulus and norepinephrine was abolished by alpha-adrenergic receptor blockade in both adult and senescent hearts. Thus, our data demonstrate that preconditioning is absent in aging heart and is probably related to the reduction of norepinephrine release and alpha-adrenergic receptor stimulation in response to ischemic preconditioning.     

Percutaneous gallbladder drainage in emphysematous cholecystitis

Emphysematous cholecystitis is a serious disorder with a high mortality and morbidity. We report successful drainage of the gallbadder in a male diabetic patient with emphysematous cholecystitis in whom surgery was considered contraindicated because of his poor cardiac status.     

Bacteriological analysis of bile in acute cholecystitis according to the Tokyo guidelines

Background

We performed bacteriological analysis of bile in acute cholecystitis (AC) patients graded in severity according to the Tokyo guidelines.

Methods

We enrolled 163 AC patients in whom bacteriological analysis of bile was performed.

Results

Significant differences in age (60 vs. 67 years), body temperature (BT) (37.2 vs. 37.6°C), white blood cell count (13,033 vs. 15,177/mm³), and serum C-reactive protein (CRP) (8.9 vs. 16.9 mg/dL) were found between the Mild and Moderate severity groups. The prevalence of bactibilia differed significantly between Mild and Moderate patients (45.3 vs. 67.0%, P = 0.0107); however, there were no significant differences in the bacterial strains, prevalence of antimicrobial resistance, or polymicrobial isolation frequency between the 2 groups. Our local antibiogram revealed that several microorganisms showed higher resistance rates; these were also isolated even in Mild cases. Advanced age, high BT, high serum CRP, and presence of marked local infection were identified as being significantly associated with high risk of bactibilia. Receiver operating characteristic curve analysis indicated the optimal cutoff value of age to be 65 years, of BT to be 37.5°C, and of serum CRP to be 13.4 mg/dL.

Conclusion

Adequate broad-spectrum antimicrobial therapy should be administered perioperatively even for Mild patients classified according to the current Tokyo guidelines. These results suggest that more precise severity grades may need to be established, including age and CRP as additional parameters.