Predicting Persistent Acute Respiratory Failure in Acute Pancreatitis: The Accuracy of Two Lung Injury Indices.

BACKGROUND/AIMS: Early and accurate identification of patients with acute pancreatitis (AP) at high risk of persistent acute respiratory failure (PARF) is crucial. We sought to determine the accuracy of simplified Lung Injury Prediction Score (sLIPS) and simplified Early Acute Lung Injury (sEALI) for predicting PARF in ward AP patients. METHODS: Consecutive AP patients in a training cohort from West China Hospital of Sichuan University (n = 912) and a validation cohort from The First Affiliated Hospital of Nanchang University (n = 1033) were analyzed. PARF was defined as oxygen in arterial blood/fraction of inspired oxygen < 300 mmHg that lasts for > 48 h. The sLIPS was composed by shock (predisposing condition), alcohol abuse, obesity, high respiratory rate, low oxygen saturation, high oxygen requirement, hypoalbuminemia, and acidosis (risk modifiers). The sEALI was calculated from oxygen 2 to 6 L/min, oxygen > 6 L/min, and high respiratory rate. Both indices were calculated on admission. RESULTS: PARF developed in 16% (145/912) and 22% (228/1033) (22%) of the training and validation cohorts, respectively. In these patients, sLIPS and sEALI were significantly increased. sLIPS ≥ 2 predicted PARF in the training (AUROC 0.87, 95% CI 0.84-0.89) and validation (AUROC 0.81, 95% CI 0.78-0.83) cohorts. sLIPS was significantly more accurate than sEALI and current clinical scoring systems in both cohorts (all P < 0.05). CONCLUSIONS: Using routinely available clinical data, the sLIPS can accurately predict PARF in ward AP patients and outperforms the sEALI and current existing clinical scoring systems.

Development of a refined ex vivo model of peritoneal adhesion formation, and a role for connexin 43 in their development.

Despite many advances across the surgical sciences, post-surgical peritoneal adhesions still pose a considerable risk in modern-day procedures and are highly undesirable. We have developed a novel mouse peritoneal strip ex vivo adhesion model which may serve to bridge the gap between single cell culture systems and in vivo animal drug testing for the assessment of potential anti-adhesion agents, and study of causality of the process. We investigated the optimal conditions for adhesion formation with mouse peritoneal tissue strips by modifying an existing ex vivo rat model of peritoneal adhesions. We assessed the impact of the following conditions on the formation of adhesions: contact pressure, abrasions, and the presence of clotted blood. Macroscopic adhesions were detected in all mouse peritoneal strips exposed to specific conditions, namely abrasions and clotted blood, where peritoneal surfaces were kept in contact with pressure using cotton gauze in a tissue cassette. Adhesions were confirmed microscopically. Interestingly, connexin 43, a gap junction protein, was found to be upregulated at sites of adhesions. Key features of this model were the use of padding the abraded tissue with gauze and the use of a standardised volume of clotted blood. Using this model, peritoneal strips cultured with clotted blood between abraded surfaces were found to reproducibly develop adhesion bands at 72 h. Our goal is to develop a model that can be used in genetically modified mice in order to dissect out the role of particular genes in adhesion formation and to test drugs to prevent adhesion formation.

Hemoconcentration is associated with early faster fluid rate and increased risk of persistent organ failure in acute pancreatitis patients.

BACKGROUND: Controversies existed surrounding the use of hematocrit to guide early fluid therapy in acute pancreatitis (AP). The association between hematocrit, early fluid therapy, and clinical outcomes in ward AP patients needs to be investigated. METHODS: Data from prospectively maintained AP database and retrospectively collected details of fluid therapy were analyzed. Patients were stratified into three groups: Group 1, hematocrit < 44% both at admission and at 24 h thereafter; Group 2: regardless of admission level, hematocrit increased and >44% at 24 h; Group 3: hematocrit >44% on admission and decreased thereafter during first 24 h. "Early" means first 24 h after admission. Baseline characteristics, early fluid rates, and clinical outcomes of the three groups were compared. RESULTS: Among the 628 patients, Group 3 had a higher hematocrit level, greater baseline predicted severity, faster fluid rate, and more fluid volume in the first 24 h compared with Group 1 or 2. Group 3 had an increased risk for persistent organ failure (POF; odds ratio 2, 95% confidence interval [1.1-3.8], P = 0.03) compared with Group 1 after adjusting for difference in baseline clinical severity scores, there was no difference between Group 2 and Group 3 or Group 1. Multivariate regression analyses revealed that hemoconcentration and early faster fluid rate were risk factors for POF and mortality (both P < 0.05). CONCLUSIONS: Hemoconcentration is associated with faster fluid rate and POF in ward AP patients. Randomized trials comparing standardized early fast and slow fluid management is warranted.

Aqueous extraction from dachengqi formula granules reduces the severity of mouse acute pancreatitis via inhibition of pancreatic pro-inflammatory signalling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Dachengqi decoction (DCQD) belongs to a family of purgative herbal formulas widely used in China for the treatment of acute pancreatitis (AP). AP is a prevalent digestive disease currently without an effective pharmacological intervention. Formula granules have become the preferred method for delivery of herbal formulation in China given its benefit of potency retention, dosing precision and ease of use. The efficacy of DCQD formula granules (DFGs) in experimental AP models has not been investigated. AIM OF THE STUDY: To analyse and compare the differences in chemical composition of DFGs, with their aqueous extraction (AE) and chloroform extraction (CE) derivatives. To assess their efficacy on severity and targeted pancreatic pro-inflammatory signalling pathways in freshly isolated acinar cells and two models of experimental AP. MATERIAL AND METHODS: UPLC-Q-TOF-MS was used to analyse chemical components of DFGs and their extractions. Freshly isolated mouse pancreatic acinar cells were treated with taurolithocholic acid 3-sulphate disodium salt (TLCS, 500 µM) with or without DFGs, AE and CE. Apoptotic and necrotic cell death pathway activation was measured by caspase 3/7 (10 µl/mL) and propidium iodide (PI, 1 µM), respectively, using a fluorescent plate reader. Necrotic acinar cells were also counted by epifluorescence microscopy. Mice received either 7 intraperitoneal injections of caerulein (50 µg/kg) at hourly intervals or retrograde infusion of TLCS (3 mM, 50 µl) to induce AP (CER-AP and TLCS-AP, respectively). In CER-AP, mice received oral gavage of DFGs (2.1, 4.2 and 5.2 g/kg), AE (0.6, 1.2, and 2.4 g/kg) and CE (4, 9 and 17 mg/kg), or matched DFGs (1.8 g/kg) and AE (1 g/kg) for 3 times at 2-hourly intervals, or a single intraperitoneal injection of DCQD-related monomers rhein (20 mg/kg), narigeinine (25 mg/kg), and honokiol (5 mg/kg) begun at the 3rd injection of caerulein. In TLCS-AP, DFGs (4.2 g/kg) were given orally at 1, 3 and 5 h post-surgery. Disease severity and pancreatic pro-inflammatory markers were determined. RESULTS: The main effective anthraquinones and their glycosides, flavonoids and their glycosides, polyphenols and lignans were found in the DFGs. A higher proportion of polar components including glycosides attached to anthraquinones, phenols and flavonoids was found in AE. Conversely, lower polar components containing methoxy substituted flavonoids and anthraquinones were more abundant in CE. DFGs were given at 4.2 g/kg, a consistent reduction in the pancreatic histopathology score and severity indices was observed in both CER-AP and TLCS-AP. In vitro, AE significantly reduced both apoptotic and necrotic cell death pathway activation, while CE increased TLCS-induced acinar cell necrosis. In vivo, AE at dose of 1.2 g/kg consistently reduced pancreatic histopathological scores and myeloperoxidase in the CER-AP that were associated with suppressed expression of pro-inflammatory meditator mRNAs and proteins. CE increased lung myeloperoxidase and failed to protect against CER-AP in all dosages. AE was demonstrated to be more effective than DFGs in reducing pancreatic histopathological scores and myeloperoxidase. CONCLUSIONS: AE from DFGs alleviated the severity of mouse AP models via an inhibition of pancreatic pro-inflammatory signalling pathways. Efficacy of AE on experimental AP was more potent than its original DFGs and DCQD monomers.

Improving Small Intestinal Motility in Experimental Acute Necrotising Pancreatitis by Modulating the CPI-17/MLCP Pathway Using Chaiqin Chengqi Decoction.

Protein kinase C-potentiated inhibitor protein of 17 kDa (CPI-17), a specific inhibitor of myosin light-chain phosphatase (MLCP) regulated by proinflammatory cytokines, is central for calcium sensitisation. We investigated the effects of chaiqin chengqi decoction (CQCQD) on the CPI-17/MLCP pathway in the small intestinal smooth muscle cells (SMCs) and strips (SMS) in an AP model. Necrotising AP was induced in rats by intraperitoneal injections (IPI) of L-ornithine (3.0 g/kg, pH 7.0; hourly × 2) at 1 hour apart; controls received saline. In treatment groups, carbachol (CCh; 60 µg/kg, IPI) or CQCQD (20 g/kg; 2-hourly × 3, intragastric) was administered. The necrotising AP model was associated with systemic inflammation (serum IL-1ß and TNF-α) and worsened jejunum histopathology and motility (serum vasoactive intestinal peptide and intestinal fatty acid-binding protein) as the disease progressed. There was decreased intracellular calcium concentration ([Ca2+]i) SMCs. Contractile function of isolated SMCs was reduced and associated with down-regulated expression of key mRNAs and proteins of the CPI-17/MLCP pathway as well as increased IL-1ß and TNF-α. CQCQD and CCh significantly reversed these changes and the disease severity. These data suggest that CQCQD can improve intestinal motility by modulating the CPI-17/MLCP pathway in small intestinal smooth muscle during AP.

Early Rapid Fluid Therapy Is Associated with Increased Rate of Noninvasive Positive-Pressure Ventilation in Hemoconcentrated Patients with Severe Acute Pancreatitis.

BACKGROUND/AIMS: Hematocrit is a widely used biomarker to guide early fluid therapy for patients with acute pancreatitis (AP), but there is controversy over whether early rapid fluid therapy (ERFT) should be used in hemoconcentrated patients. This study investigated the association of hematocrit and ERFT with clinical outcomes of patients with AP. METHODS: Data from prospectively maintained AP database and retrospectively collected fluid management details were stratified according to actual severity defined by revised Atlanta classification. Hemoconcentration and "early" were defined as hematocrit > 44% and the first 6 h of general ward admission, respectively, and "rapid" fluid rate was defined as ≥ 3 ml/kg/h. Patients were allocated into 4 groups for comparisons: group A, hematocrit ≤ 44% and fluid rate < 3 ml/kg/h; group B, hematocrit ≤ 44% and fluid rate ≥ 3 ml/kg/h; group C, hematocrit > 44% and fluid rate < 3 ml/kg/h; and group D, hematocrit > 44% and fluid rate ≥ 3 ml/kg/h. Primary outcome was rate of noninvasive positive-pressure ventilation (NPPV). RESULTS: A total of 912 consecutive AP patients were analyzed. ERFT has no impact on clinical outcomes of hemoconcentrated, non-severe or all non-hemoconcentrated AP patients. In hemoconcentrated patients with severe AP (SAP), ERFT was accompanied with increased risk of NPPV (odds ratio 5.96, 95% CI 1.57-22.6). Multivariate regression analyses confirmed ERFT and hemoconcentration were significantly and independently associated with persistent organ failure and mortality in patients with SAP. CONCLUSIONS: ERFT is associated with increased rate of NPPV in hemoconcentrated patients with SAP.

Is the failing heart out of fuel or a worn engine running rich? A study of mitochondria in old spontaneously hypertensive rats.

Hypertension now affects about 600 million people worldwide and is a leading cause of death in the Western world. The spontaneously hypertensive rat (SHR), provides a useful model to investigate hypertensive heart failure (HF). The SHR model replicates the clinical progression of hypertension in humans, wherein early development of hypertension is followed by a long stable period of compensated cardiac hypertrophy that slowly progresses to HF. Although the hypertensive failing heart generally shows increased substrate preference towards glucose and impaired mitochondrial function, the cause-and-effect relationship between these characteristics is incompletely understood. To explore these pathogenic processes, we compared cardiac mitochondrial proteomes of 20-month-old SHR and Wistar-Kyoto controls by iTRAQ-labelling combined with multidimensional LC/MS/MS. Of 137 high-scoring proteins identified, 79 differed between groups. Changes were apparent in several metabolic pathways, chaperone and antioxidant systems, and multiple subunits of the oxidative phosphorylation complexes were increased (complexes I, III and IV) or decreased (complexes II and V) in SHR heart mitochondria. Respiration assays on skinned fibres and isolated mitochondria showed markedly lower respiratory capacity on succinate. Enzyme activity assays often also showed mismatches between increased protein expression and activities suggesting elevated protein expression may be compensatory in the face of pathological stress.