Erik Zimmermann-Nielsen

Improving quality of care in peptic ulcer bleeding: nationwide cohort study of 13,498 consecutive patients in the Danish Clinical Register of Emergency Surgery.

OBJECTIVES:The treatment of peptic ulcer bleeding (PUB) is complex, and mortality remains high. We present results from a nationwide initiative to monitor and improve the quality of care (QOC) in PUB.METHODS:All Danish hospitals treating PUB patients between 2004 and 2011 prospectively registered demographic, clinical, and prognostic data. QOC was evaluated using eight process and outcome indicators, including time to initial endoscopy, hemostasis obtainment, proportion undergoing surgery, rebleeding risks, and 30-day mortality.RESULTS:A total of 13,498 PUB patients (median age 74 years) were included, of which one-quarter were in-hospital bleeders. Preadmission use of anticoagulants, multiple coexisting diseases, and the American Society of Anesthesiologists scores increased between 2004 and 2011. Considerable improvements were observed for most QOC indicators over time. Endoscopic treatment was successful with primary hemostasis achieved in more patients (94% in 2010–2011 vs. 89% in 2004–2006, relative risk (RR) 1.06 (95% confidence intervals 1.04–1.08)), endoscopy delay for hemodynamically unstable patients decreased during this period (43% vs. 34% had endoscopy within 6 h, RR 1.33 (1.10–1.61)), and fewer patients underwent open surgery (4% vs. 6%, RR 0.72 (0.59–0.87)). After controlling for time changes in prognostic factors, rebleeding rates improved (13% vs. 18%, adjusted RR 0.77 (0.66–0.91)). Crude 30-day mortality was unchanged (11% vs. 11%), whereas adjusted mortality decreased nonsignificantly over time (adjusted RR 0.89 (0.78–1.00)).CONCLUSIONS:QOC in PUB has improved substantially in Denmark, but the 30-day mortality remains high. Future initiatives to improve outcomes may include earlier endoscopy, having fully trained endoscopists on call, and increased focus on managing coexisting disease.

Complement activation in plasma before and after Infliximab treatment in Crohn disease

Background: Crohn disease is characterized by up‐regulated intestinal inflammation mainly caused by increased tumour necrosis factor alpha (TNF‐α) levels. However, the complement system (C) may also have a role in maintaining inflammation. Methods: Plasma from 26 patients with Crohn disease complicated by fistulizing ano‐rectal disease was collected before and after three Infliximab infusions (5 mg kg −1 ). Results: Before treatment, the C3‐activation capacities (C3‐AC) in plasma from patients with Crohn disease were comparable with values obtained from healthy controls. The classical C pathway‐mediated C3‐AC, mannan‐binding lectin C4‐AC, leucocyte count, C‐reactive protein concentration and Crohn Disease Activity Index decreased significantly 8 weeks after the first infusion of Infliximab (P < 0.04, Wilcoxon test). Conclusions: Before treatment, all three C pathways were within the normal range in plasma from patients with Crohn disease; the decrease observed in the classical pathway‐mediated C3‐AC after treatment with Infliximab reflects a general down‐regulation in immune activation.

Quality‐of‐care initiative in patients treated surgically for perforated peptic ulcer

Mortality and morbidity are considerable after treatment for perforated peptic ulcer (PPU). Since 2003, a Danish nationwide quality‐of‐care (QOC) improvement initiative has focused on reducing preoperative delay, and improving perioperative monitoring and care for patients with PPU. The present study reports the results of this initiative.

Risk factors in patients surgically treated for peptic ulcer perforation.

Objective. The overall mortality for patients undergoing surgery for perforated peptic ulcer has increased despite improvements in perioperative monitoring and treatment. The objective of this study was to identify and describe perioperative risk factors in order to identify ways of optimizing the treatment and to improve the outcome of patients with perforated peptic ulcer. Material and methods. Three hundred and ninety-eight patients undergoing emergency surgery in four university hospitals in Denmark were included in the study. Information regarding the pre-, intra- and postoperative phases were recorded retrospectively from medical records. Data were analysed using multiple logistic regression analysis. The primary end-point was 30-day mortality. Results. The 30-day mortality rate was 27%. The following variables were independently associated with death within 30 days of surgery: ASA (American Society of Anaesthesiologists) class, age, shock upon admission, preoperative metabolic acidosis, elevated concentration of creatinine upon admission, subnormal concentration of albumin upon admission and insufficient postoperative nutrition. Conclusions. Thus, preoperative metabolic acidosis, renal insufficiency upon admission and insufficient postoperative nutrition have been added to the list of independent risk factors for death within 30 days of surgery in patients with peptic ulcer perforation. Finding that shock upon admission, reduced albumin blood levels upon admission, renal insufficiency upon admission and preoperative metabolic acidosis are independently related to 30-day mortality could indicate that patients with peptic ulcer perforation are septic upon admission, and thus might benefit from a perioperative care protocol with early source control and early goal-directed therapy according to The Surviving Sepsis Campaign. This hypothesis should be addressed in future studies.

Complement activation mediated by mannan-binding lectin in plasma from healthy individuals and from patients with SLE, Crohn's disease and colorectal cancer. Suppressed activation by SLE plasma.

We have developed a method for quantitating mannan‐binding lectin (MBL)‐induced activation of the complement system (MBL‐C4‐AC) in human plasma. This method and an assay for MBL concentration were applied to plasma samples from healthy individuals and patients with systemic lupus erythematosus (SLE), Crohns disease (CD) and colorectal cancer (CRC). The MBL concentration was measured by an enzyme‐linked immunosorbent assay (ELISA) using monoclonal anti‐MBL‐antibodies and MBL‐C4‐AC by an ELISA using solid‐phase mannan, incubating with plasma samples and quantitating the complement (C) activation by the use of antibodies against the C split‐products C4b/C4c. The MBL concentration was nonsignificantly elevated in plasma from SLE‐patients, whereas MBL‐C4‐AC was suppressed ( P < 0.04). There was no correlation between MBL concentration and MBL‐C4‐AC in plasma from SLE‐patients. In contrast, a significant correlation was found between the MBL concentration and MBL‐C4‐AC in plasma from healthy individuals. The C4 concentration was significantly reduced ( P < 0.002) in plasma from the SLE patients and showed a significant correlation to MBL‐C4‐AC. The MBL‐C4‐AC assay was highly effective in discriminating the SLE patients from the other patient groups and healthy individuals.

Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis

BackgroundUlcerative colitis (UC) and Crohns disease (CD) are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C) activation. Our aim was to evaluate possible associations between C activation capacity and prednisolone treatment.MethodsPlasma from patients with exacerbations of UC (n = 18) or CD (n = 18) were collected before and during high dose prednisolone treatment (1 mg/kg body weight) and tapering. Friedmans two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were usedResultsBefore treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p < 0.02), and in mannan binding lectin (MBL)-concentration and MBL-C4-activation capacity (AC) values compared to UC patients (p < 0.02). Before treatment, plasma from UC patients showed significant elevations only in the classical pathway-mediated C3-AC compared to values obtained from healthy controls (p < 0.01). After treatment was initiated, significant reductions, which persisted during follow-up, were observed in the classical pathway-mediated C3-AC and MBL-C4-AC in plasma from CD patients (p < 0.05).ConclusionOur findings indicate that C activation capacity is up-regulated significantly in plasma from CD patients. The decreases observed after prednisolone treatment reflect a general down-regulation in immune activation.

ELISA for evaluating the incorporation of plasma derived complement split-products C3b/iC3b into solid-phase immune complexes

An ELISA that measures plasma derived complement (C) split-products C3b/iC3b deposited on solid-phase immune complexes during C activation is described. Plates are coated with BSA, anti-BSA and plasma is added. Deposited C3b/iC3b is then detected by biotinylated anti-C3c-antibodies, avidin-alkaline phosphatase and para-nitrophenylphosphate. A novel feature is that the assay measures residual C activation capacity rather than in vivo generated C activation products. The assay was applied to plasma from 250 healthy blood donors. No difference in activation capacity of either the alternative (AP) or classical pathway (CP) with regard to age or gender was demonstrated. The total coefficient of variation was <5.7%. The ELISA procedure was compared to a standard hemolytic complement CH(50) assay using plasma from 23 out-patients with systemic lupus erythematosus (SLE). There was a weak correlation between the two assays for both C pathways, but neither the ELISA nor the CH(50) assay showed any correlation with the diagnostic ACR-criteria for SLE. However, the capacity of the CP was significantly reduced in SLE out-patients compared to healthy blood donors (P<0.0001).

Activation capacity of the alternative and classic complement pathways in patients operated on for colorectal cancer.

AbstractPURPOSE: Tumor cells may suppress activation of the host’s complement system, and the functional state of the complement system may be a prognostic marker of outcome in patients with malignancies. Serial plasma samples from patients undergoing intended curative surgery for colorectal cancer were analyzed for complement factor C3 activation capacity. METHODS: Samples were collected from 91 patients with colorectal cancer and 13 with benign colorectal diseases before surgery and 1, 2, and 7 days after surgery, between 8 and 13 days after surgery, and 3, 6, 12, 18, 24, 36, 48, and 60 months after surgery. The samples were analyzed with an enzyme-linked immunosorbent assay that measured C3 activation capacity by the alternative and classic complement pathways. Cancer patients were compared according to Dukes stage, type of surgery performed, transfusion of blood, development of infection, venous thromboembolism, and cancer recurrence. RESULTS: Plasma samples obtained from cancer patients before surgery showed C3 activation capacities corresponding to those of samples from patients with benign disease. For both patient groups, C3 activation capacity decreased after surgery and normalized within seven days. Significant differences in C3 activation capacities were observed between cancer patients that were related to Dukes stage and in patients with and without buffy coat-depleted red cells suspended in saline, adenine, glucose, and mannitol transfusion, infectious events, and deep venous thromboembolism. Measurement of C3 activation capacity was of predictive value in patients who developed infection. CONCLUSION: Serial measurements of C3 activation capacity in plasma from patients who had undergone surgery for colorectal cancer revealed significant differences related to Dukes staging after surgery and to the development of infections but not to cancer recurrence.

Perioperative functional activity of the alternative pathway of complement in patients with colonic cancer

OBJECTIVE To investigate the functional capacity of the alternative pathway of complement in patients with cancer of the colon before, during, and after operation. DESIGN Prospective study. SETTING One university and two district hospitals, Denmark. SUBJECTS 28 patients having elective or emergency operations for colonic cancer. INTERVENTIONS Measurements of C3b fixing capacity of the alternative complement pathway in serum before, during, and after operation. MAIN OUTCOME MEASUREMENTS The functional capacity of the alternative pathway of complement, and changes during operation. RESULTS The functional capacity of the alternative pathway in patients with cancer of the colon was above normal (p < 0.0001 for both men and women), and the capacity remained unchanged during operation despite dilution of serum peroperatively. CONCLUSION The alternative pathway seems to be the only immunological variable that has so far been shown to have increased functional capacity in patients with cancer, and that remains unaltered (mean value) during operation. The importance of retaining normal function of the alternative complement pathway in the prevention of postoperative infective complications and recurrence of cancer has not yet been elucidated.