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Objective: Patients with severe acute pancreatitis were excluded from major trials of human recombinant activated protein C (Xigris) because of concern about pancreatic haemorrhage although these individuals have an intense systemic inflammatory response that may benefit from treatment. The object of this study was to provide initial safety data evaluating Xigris in severe acute pancreatitis., Design: Prospective clinical trial recruiting between November 2009 and October 2011. Patients received human recombinant activated protein C (Xigris) for 24 h by intravenous infusion (24 μg/kg/h) in addition to standard clinical care. A matched historical control group treated within the same hospital unit were used to compare outcomes. Of 166 consecutive admitted patients, 43 met the screening criteria for severe acute pancreatitis and 19 were recruited, all contributing to the analyses., Results: Compared to historical controls, there were fewer bleeding events in the Xigris group although the finding did not reach significance (Xigris 0% vs. Control 21%, p = 0.13), similarly further intervention appeared less frequent (11% vs. 47%, p = 0.07) in the treatment group. Length of stay was shorter for patients receiving Xigris (19 vs. 41 days, p = 0.03) as was inotrope use (5% vs. 32%, p = 0.02); mortality and incidence of infections in both groups were similar. Biomarker protein C increased while IL-6 decreased following infusion., Conclusions: A 24-hr infusion of Xigris appears safe when used in patients with severe acute pancreatitis., Trial Registration: Eudract Number 2007-003635-23., (Copyright © 2015 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.)

Background: Failure to comply with clinical protocols and failure of communication to ensure delivery of the most appropriate timely clinical responses to patients whose conditions are acutely deteriorating have been shown to be significant causative factors associated with inhospital adverse events., Objective: To determine whether automated clinical alerts increase compliance with an Early Warning Score (EWS) protocol and improve patient outcomes., Methods: We performed a historically controlled study of bedside electronic capture of observations and automated clinical alerts. The primary outcome measure was hospital length of stay (LOS); secondary outcome measures were compliance with the EWS protocol, cardiac arrest incidence, critical care utilisation and hospital mortality., Results: Between baseline and intervention, 1481 consecutive patients were recruited generating 13 668 observation sets. There was a reduction in hospital LOS between the baseline and alert phase (9.7 days v 6.9 days, P < 0.001). EWS accuracy improved from 81% to 100% with electronic calculation. Clinical attendance to patients with EWS 3, 4 or 5 increased from 29% at baseline to 78% with automated alerts (P < 0.001). For patients with an EWS > 5, clinical attendance increased from 67% at baseline to 96% with automatic alerts (P < 0.001)., Conclusions: Electronic recording of patient observations linked to a computer system that calculates patient risk and then issues automatic graded alerts can improve clinical attendance to unstable general medical ward patients.

Objectives: This study investigated the effects of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) on gut barrier function in critically ill surgical patients., Methods: A prospective observational cohort study on patients with severe acute pancreatitis or abdominal sepsis admitted to an intensive care or high-dependency unit. Intra-abdominal pressure (IAP) and plasma levels of immunoglobulin G (IgG) and IgM antiendotoxin core antibodies (EndoCAb) and procalcitonin (ProCT) were measured serially., Results: Among 32 recruited patients, 24 (75%) and 8 patients (25%) developed IAH and ACS, respectively. The state of ACS was associated with significant reductions in plasma IgG EndoCAb (P = 0.015) and IgM EndoCAb (P = 0.016) and higher concentrations of plasma ProCT (P = 0.056) compared with absence of ACS. Resolution of IAH and ACS was associated with significant recovery of plasma IgG EndoCAb (P = 0.003 and P = 0.009, respectively) and IgM EndoCAb (P = 0.002 and P = 0.003, respectively) and reduction in plasma ProCT concentration (P = 0.049 and P = 0.019, respectively). Negative correlations were observed between IAP and plasma IgG EndoCAb (P = 0.003) and IgM EndoCAb (P = 0.002)., Conclusions: Intra-abdominal hypertension and ACS are associated with significantly higher endotoxin exposure and ProCT concentrations, suggestive of gut barrier dysfunction. Resolution of IAH and ACS is associated with evidence for recovery of gut barrier function.

Objective: To examine clinical outcome in a consecutive cohort of patients undergoing open necrosectomy for postinflammatory necrosis., Background Information: The last decade has witnessed major developments in the surgical management of pancreatic necrosis. Minimally invasive approaches have become established. However, there are limited data from contemporary open necrosectomy, in particular where multidisciplinary care and aggressive interventional radiology are used. This report provides data on outcome from open necrosectomy in a tertiary referral Hepatobiliary unit over the last decade., Methods: During the period January 1, 2000 to July 31, 2008, 1535 patients were admitted with a final discharge code of acute pancreatitis. Twenty-eight (1.8%) of all admissions underwent open surgical necrosectomy. Twenty-four (86%) were tertiary referral patients., Results: The median APACHE II score on admission was 10.5 (5-26). Median logistic organ dysfunction score on admission was 3 (0-10). Median LODS score after surgery was 2 (0-8). Twenty patients (71%) underwent radiologically guided drainage of collections before surgery. Thirty-day mortality occurred in 2 (7%), 4 further deaths occurred in patients after discharge from intensive care resulting in a total of 6 (22%) episode-related deaths., Conclusions: Modern open necrosectomy can be performed without the procedure-related deterioration in organ dysfunction associated with major debridement. Multidisciplinary care with an emphasis on aggressive radiologic intervention before and after surgery results in acceptable outcomes in this cohort of critically ill patients. Newer laparoscopic techniques must demonstrate similar outcomes in the setting of stage-matched severity before wider acceptance.

Introduction: To evaluate the impact of recent evidence-based treatments for severe sepsis in routine clinical care requires an understanding of the underlying epidemiology, particularly with regard to trends over time. We interrogated a high quality clinical database to examine trends in the incidence and mortality of severe sepsis over a nine-year period., Methods: Admissions with severe sepsis occurring at any time within 24 hours of admission to critical care were identified to an established methodology using raw physiological data from the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database, containing data from 343,860 admissions to 172 adult, general critical care units in England, Wales and Northern Ireland between December 1995 and January 2005. Generalised linear models were used to assess changes in the incidence, case mix, outcomes and activity of these admissions., Results: In total, 92,672 admissions (27.0%) were identified as having severe sepsis in the first 24 hours following admission. The percentage of admissions with severe sepsis during the first 24 hours rose from 23.5% in 1996 to 28.7% in 2004. This represents an increase from an estimated 18,500 to 31,000 admissions to all 240 adult, general critical care units in England, Wales and Northern Ireland. Hospital mortality for admissions with severe sepsis decreased from 48.3% in 1996 to 44.7% in 2004, but the total number of deaths increased from an estimated 9,000 to 14,000. The treated incidence of severe sepsis per 100,000 population rose from 46 in 1996 to 66 in 2003, with the associated number of hospital deaths per 100,000 population rising from 23 to 30., Conclusion: The population incidence of critical care admission with severe sepsis during the first 24 hours and associated hospital deaths are increasing. These baseline data provide essential information to those wishing to evaluate the introduction of the Surviving Sepsis Campaign care bundles in UK hospitals.

Background: To observe outcome in a cohort of patients with severe acute pancreatitis receiving multiple anti-oxidant therapy., Methods: An observational study was carried out in 46 consecutive patients with acute pancreatitis fulfilling current Atlanta consensus criteria for severe disease. All patients received multiple anti-oxidant therapy based on intravenous selenium, N-acetylcysteine and ascorbic acid plus beta-carotene and alpha-tocopherol delivered via nasogastric tube. Principal outcomes were the effect of anti-oxidant supplementation on anti-oxidant levels, morbidity and mortality in patients on anti-oxidant therapy, case-control analysis of observed survival compared to predicted survival derived from logistic organ dysfunction score (LODS), logistic regression analysis of factors influencing outcome and side effect profile of anti-oxidant therapy., Results: Paired baseline and post-supplementation data were available for 25 patients and revealed that anti-oxidant supplementation restored vitamin C (P = 0.003) and selenium (P = 0.028) toward normal. In univariate survival analysis, patient survival to discharge was best predicted by admission APACHE-II score with relative risk of death increasing 12.6% for each unit increase (95% CI 6.0% to 19.6%). The mean LODS calculated on admission to hospital was 3.7 (standard error of the mean 4.1) giving a predicted mortality for the cohort of 21%. The observed in-hospital mortality was 43%., Conclusions: Case-control analyses do not appear to demonstrate any benefit from the multiple anti-oxidant combination of selenium, N-acetylcysteine and ascorbic acid in severe acute pancreatitis.

Purpose: Colonic ischemia after aortic surgery is associated with increased mortality and morbidity rates. This study was conducted as a single-center side arm to a multicenter, randomized, placebo-controlled study to evaluate the effect of dopexamine hydrochloride on its incidence., Methods: Thirty patients, mean age 65.1 years (range, 46-84), undergoing elective infrarenal aortic surgery were entered. Preoperative hemodynamic and respiratory parameters were optimized. Patients were then randomly assigned to receive a perioperative infusion of dopexamine at 2 microg/kg per minute (n = 12) or 0.9% saline placebo (n = 18). All patients underwent colonoscopy and biopsy preoperatively and 1 week postoperatively. Specimens were assessed for evidence of mucosal ischemia, presence of mast cell tryptase, myeloperoxidase activity, and both the inducible and endothelial isoforms of nitric oxide synthase., Results: There was no significant difference in perioperative fluid and blood requirements or hemodynamic and respiratory parameters between the two groups. However, there was significantly less evidence of mucosal ischemic changes in dopexamine-treated patients (n = 1) compared with placebo (n = 8) (P =.049). Furthermore, when preoperative biopsies were compared with those performed 1 week postoperatively, nine (50%) patients in the placebo group and two (16.7%) in the dopexamine group scored worse. Although there was no significant difference in inflammatory markers between the two groups, both mast cell tryptase and myeloperoxidase expression were increased in patients with histologic evidence of ischemia (P <.05). Furthermore, inducible nitric oxide synthase staining within the vascular (P =.001) and lamina propria (P <.05) components of the mucosa was also significantly greater., Conclusion: A perioperative dopexamine infusion affords significant histologic protection to colonic mucosa after aortic surgery.

Objective: To evaluate the effect of dopexamine on the incidence of acute inflammation in the stomach/duodenum in patients undergoing abdominal surgery > or =1.5 hrs with a minimum of one high-risk criterion., Design: Prospective, randomized, double-blind, placebo-controlled study. This study was conducted as a side arm to a multicenter, multinational study., Setting: University hospital in an adult intensive care unit., Patients: Thirty-eight patients., Interventions: Patients were stabilized with fluid, blood products, and supplementary oxygen to achieve predetermined goals: cardiac index > 2.5 L/min/m2, mean arterial blood pressure of 70 mm Hg, pulmonary arterial occlusion pressure of 10 mm Hg, hemoglobin of 100 g/L, and arterial saturation of 94%. After stabilization, the study drug (either placebo [group A], dopexamine 0.5 microg/kg/min [group B], or dopexamine 2.0 microg/kg/min [group C]) was commenced. The study drug infusion was started 2 to 12 hrs before surgery and infused for 24 hrs after surgery. Estimation of upper gut blood flow was assessed using a gastric tonometer, and gastroscopy with biopsy was performed before surgery (after induction of anesthesia) and 72 hrs after surgery. Comparisons were made between endoscopic findings and histologic proof of acute inflammatory changes. In addition, biopsies were assessed for the presence in the mucosa of mast cells, myeloperoxidase activity, and inducible nitric oxide synthase., Measurements and Main Results: Intramucosal pH decreased significantly with time in all three groups (p < .001), reaching the lowest point at the end of surgery. There was no difference among the groups. Endoscopy visualized acute inflammatory changes in 58.3% of group A patients, 46.2% of group B patients, and 53.90% of group C patients after hemodynamic optimization. At 72 hrs, dopexamine-treated patients compared with placebo-treated patients had a significantly lower incidence of gastric and duodenal acute inflammatory changes, as defined by myeloperoxidase activity (37.5% in groups B and C vs. 86% in group A; p < .05)., Conclusion: Dopexamine in doses of 0.5 and 2.0 microg/kg/min affords significant histologic protection to the upper gastrointestinal tract mucosa 72 hrs after operation in high-risk surgical patients undergoing abdominal surgery.

In this prospective meta-analysis, we have evaluated the effect of epidural analgesia with ropivacaine for pain in labour on neonatal outcome and mode of delivery compared with bupivacaine. In six randomized, double-blind studies, 403 labouring women, primigravidae and multiparae, received epidural analgesia with ropivacaine or bupivacaine 2.5 mg ml-1. The drugs were administered as intermittent boluses in four studies and by continuous infusion in two. Apgar scores, neurological and adaptive capacity scores (NACS), degree of motor block and mode of delivery were recorded. The studies were designed prospectively to fit meta-analysis of the pooled results. Results showed similar pain relief and consumption of the two drugs. In the vaginally delivered neonates, NACS scores were approximately equal for both groups at 2 h, but at 24 h there were fewer infants with NACS less than 35 in the ropivacaine compared with the bupivacaine group (2.8% vs 7.6%; P < 0.05). Spontaneous vaginal deliveries occurred more frequently overall with ropivacaine than with bupivacaine (58% vs 49%; P < 0.05) and instrumental deliveries (forceps and vacuum extraction) less frequently (27% vs 40%; P < 0.01), while the frequency of Caesarean section was similar between groups. The intensity of motor block was lower with ropivacaine. There were no significant differences in adverse events.

We report on five patients in whom long-term sedation with isoflurane for up to 7 days was used successfully. Serum inorganic fluoride concentrations were measured daily. The concentrations ranged from 12 mmol l-1 to 29 mmol l-1. These were well below the described renal toxic level of 50 mmol l-1. There was no deterioration in renal function attributable to the use of isoflurane.

Ropivacaine is a new aminoamide local anaesthetic. Compared with bupivacaine, ropivacaine possesses a higher threshold for systemic toxicity and a high selectivity for sensory fibres. We have compared prospectively these two agents in a concentration of 0.25% for extradural analgesia in labour. A total of 104 parturients requesting extradural analgesia were randomized to receive either ropivacaine or bupivacaine. The women in the bupivacaine group required more top-up doses to maintain analgesia (median 3.0 vs 2.0) (P < 0.05). The onset of sensory block, quality of analgesia, ultimate level of maximum sensory block and maternal satisfaction were similar in both groups. The incidence, intensity and duration of motor block were slightly but not significantly less in the ropivacaine group. The ropivacaine group had a higher incidence of spontaneous vaginal delivery (70.59% vs 52.00%). There was no significant difference in neonatal outcome as assessed by Apgar scores, umbilical acid-base status and neurological and adaptive capacity score at 2 and 24 h after delivery. We conclude that ropivacaine and bupivacaine in a concentration of 0.25% produced comparable analgesia for pain relief of labour with no detectable adverse effect on the neonate.

Objective: To assess the requirement for propofol to provide sedation in critically ill patients in established renal failure during the commencement of haemodiafiltration., Design: Prospective clinical study., Setting: ICU, University Hospital., Patients: 10 adult patients. All were mechanically ventilated, had acute oliguric renal failure which necessitated continuous veno-venous haemodiafiltration and were receiving a continuous intravenous infusion of propofol for sedation. Sedation was assessed using a scoring system., Intervention: Veno-venous haemodiafiltration., Measurements and Results: Connection of the extracorporeal circuit produced a reduction in plasma propofol concentration in 7 out of 9 patients (one sample misplaced) with subsequent awakening in 3 of these 7 patients. The commencement of haemodiafiltration itself did not significantly influence the requirement for propofol (8 out of 10 patients)., Conclusion: Haemodiafiltration does not substantially influence the requirement for propofol but the initial introduction of the extracorporeal circuit will reduce plasma concentrations in the majority of patients. This may be due to haemodilution alone or absorption of plasma albumin (with propofol) onto the membrane.

Objective: To compare the frequency of stress erosions and ulcers in critically ill adult patients treated with either sucralfate or placebo., Design: Prospective, randomized study., Setting: Intensive care unit in a university hospital., Patients: Twenty-six adult patients. All patients were mechanically ventilated and were at risk of developing stress ulceration., Interventions: Patients were randomized to receive either sucralfate (2 g every 8 hrs) (group 1) via the nasogastric tube (flushed with 10 mL of sterile water) or 20 mL of sterile water every 8 hrs (group 2) via the nasogastric tube., Measurements and Main Results: At the time of intensive care unit admission, the frequency of stress (acute) erosions (as assessed with the endoscope) was 21.7%. No ulcers were detected. By day 3, the frequency had increased to 37.5% in group 1 and 88.9% in group 2. Mucosal deterioration was more likely in the patients treated with placebo (water) (p < .05). In total, seven patients developed acute ulceration in group 2 compared with only one patient in group 1 (p < .05). The frequency of gastric colonization with aerobic Gram-negative bacilli was 25.6% in group 1 and 28.6% in group 2. Only one retrograde nosocomial pneumonia developed (group 1)., Conclusion: Based on our findings, we strongly recommend the adoption of sucralfate as opposed to no prophylaxis in the prevention of acute upper gastrointestinal ulceration.

An epidural catheter may be inserted with the patient either in the flexed left lateral or the sitting position. We have studied, non-invasively, the haemodynamic changes associated with these positions, using the thoracic bio-impedance method (BOMED NCCOM3 Monitor). Maternal arterial pressure and fetal heart rate were monitored simultaneously. Twenty healthy pregnant patients at term and 20 non-pregnant healthy controls, matched for age and height, were studied. The pregnant patients were scheduled for elective caesarean section and had singleton healthy fetuses. A significant reduction in stroke index (SI) occurred when the pregnant patients were repositioned from supine 15degrees wedged position to either flexed left lateral (P < 0.01) or sitting positions (P < 0.05). Similar reductions in SI with positioning were observed in the non-pregnant patients: flexed left lateral (P < 0.01); and sitting (P < 0.01). These changes in SI produced significant reductions in cardiac index (CI) in both groups. In the pregnant patients the CI was significantly lower in the flexed left lateral than in the sitting position (P < 0.01). Consequently maternal systolic blood pressure was lower in the flexed left lateral position (P < 0.01).

Eighty normal primigravidae received an extradural dose of 0.25% bupivacaine and were then allocated randomly to receive "top-ups" of 0.25% bupivacaine (group A) or an infusion of 0.125% bupivacaine (group B). Group B received supplementary top-ups if required. Group A required more top-ups (147 vs 80) (P < 0.01). No maternal advantage was demonstrated from each regimen. Fetal state was assessed by analysis of the cardiotocograph during labour and the condition of the fetus at delivery. Three different patterns of late deceleratory episodes were identified (grades 1-3). Total numbers of episodes per group were similar (group A, 71; group B, 69). More episodes in group A were related to top-ups (42/71 vs 18/69; P < 0.01) but the incidence of episodes after a top-up was similar (group A, 42/147 (28.6%); group B, 18/80 (22.5%)). In group A, 31/42 events (73.8%) were transient compared with 11/18 persistent episodes (61.1%) (> 10 min duration) in group B. However, the difference in the deceleratory patterns did not influence the condition of the fetuses at delivery.

Objective: To compare the frequency of acute stress ulceration and secondary pneumonia caused by aerobic Gram-negative bacilli in ICU patients treated with either sucralfate or ranitidine., Design: Prospective, randomized study., Setting: ICU, university hospital., Patients: Sixty adult patients who were mechanically ventilated and at risk of developing stress ulceration., Intervention: The patients were randomized to receive either sucralfate (1 g every 6 hrs) via the nasogastric tube or iv ranitidine (50 mg every 6 hrs). If the gastric pH was less than 3.5 in the latter group, 30 mL of 0.3M sodium citrate was given via the nasogastric tube., Measurements and Main Results: On admission, the frequency rate of erosion/ulceration (assessed with the endoscope) was 13.5%. After 4 days, this rate had increased to 18% in sucralfate-treated patients and 36% in ranitidine-treated patients (NS). Mean gastric pH was more alkaline in the ranitidine-treated patients (5.50) compared with the sucralfate-treated patients (4.26) (p less than .01). This pH permitted a higher occurrence rate of gastric colonization by aerobic Gram-negative bacilli in ranitidine-treated patients (64.3%) compared with sucralfate-treated patients (23.8%) (p less than .01). Retrograde bacterial colonization from the stomach to oropharynx and trachea occurred more frequently in ranitidine-treated patients compared with sucralfate-treated patients. Ultimately, the occurrence rate of pneumonia was greater in the ranitidine-treated (35.7%) than in the sucralfate-treated patients (10.3%) (p less than .05)., Conclusion: Based on our findings, we recommend the adoption of sucralfate for routine prophylaxis against stress ulceration.

Serum concentrations of triglyceride, cholesterol and high density lipoprotein-cholesterol (HDL-cholesterol) were measured in an ICU patient after he had received a 10-day continuous infusion of propofol. No additional parenteral lipid was given in the 72 h prior to initial sampling, but a total of 71 of 10% intralipid had been administered over the remaining 7 days. The total cumulative dose of propofol was 66.1 g (range 0.7-6.4 mg kg-1 h-1). There was no visual appearance of lipaemia. Both the serum triglyceride and cholesterol concentrations increased (triglyceride level increased to 4 times normal whereas the cholesterol elevation was minimal). The HDL-cholesterol concentration decreased. At 72 h after discontinuing the infusion of propofol the triglyceride level remained elevated, the cholesterol concentration had returned to normal and the HDL-cholesterol concentration remained unchanged. The implications of hypertriglyceridaemia are discussed.

We have measured concentrations of atracurium and laudanosine in cerebrospinal fluid (CSF) and plasma in three intensive care patients receiving atracurium infusions of 22.5-106 h duration to maintain neuromuscular block. Two patients had suffered severe closed head injuries and the third patient had developed respiratory failure following the clipping of two intracranial aneurysms. The total dose of atracurium given was 14.3-136.6 mg kg-1; rate of infusion was 0.6-1.38 mg kg-1 h-1. Plasma concentrations of atracurium and laudanosine were 0.73-3.11 micrograms ml-1 and 0.48-8.65 micrograms ml-1, respectively; CSF concentration of laudanosine was 70-440 ng ml-1. No adverse effects attributable to these concentrations of laudanosine were observed.

Sixty children aged 6 wk to 10 yr were studied. The children were undergoing cardiopulmonary bypass (CPB) for correction of congenital heart defects. The aim of the study was to provide prophylaxis for stress-induced gastric ulceration by elevating the gastric pH to at least 3.5. Two infusion regimes of ranitidine were compared: 0.1 and 0.2 mg/kg.h. The period of study was from induction of anesthesia until the end of the first 24 h after surgery. Both regimes were effective. The 0.2-mg/kg.h infusion produced a significantly higher plasma concentration of ranitidine throughout the study period without any additional clinical benefit. Both regimes produced, within 3 h of cessation of CPB, a significant elevation in mean gastric pH to at least 5.3. This paper concludes that 0.1-mg/kg.h infusion of ranitidine is a safe and efficacious regime for the critically ill pediatric patient.

Concentrations of atracurium and laudanosine in cerebrospinal fluid (CSF) and plasma were assayed in nine patients receiving atracurium infusions of 111-251 min duration to maintain neuromuscular block during intracranial surgery. The total dose of atracurium was 1.57-2.60 mg kg-1 and the plasma concentration of atracurium was 1.27-5.44 micrograms ml-1. Concentrations of laudanosine in CSF and plasma increased during the infusion period, and after 125-140 min reached means of 202.5 ng ml-1 and 1448.7 ng ml-1, respectively. The highest recorded concentration of laudanosine in CSF was 570 ng ml-1, in one of two CSF samples found to contain atracurium. After operation, two patients had fits, but these were not thought to be related to laudanosine. It is concluded that during infusion of atracurium, laudanosine accumulates in both plasma and CSF.