Ingvar Syk

Postoperative fever, bowel ischaemia and cytokine response to abdominal aortic aneurysm repair — a comparison between endovascular and open surgery

OBJECTIVES To study bowel ischaemia in transfemorally placed endoluminal grafting (TPEG) for abdominal aortic aneurysms, and any relation to cytokine response or postoperative fever. DESIGN Prospective not randomised. University hospital setting. MATERIAL Fourteen cases of conventional surgery and 23 cases of endovascular technique for infrarenal abdominal aortic aneurysm repair. METHODS Tonometry was used for sigmoid colon pH, and ELISAs for serum IL-6. RESULTS Mucosal pH in the sigmoid colon fell significantly during clamping and reperfusion in both groups. Lowest measured sigmoid colon pH was 7.10 in the open group, compared to 7.22 in the TPEG group (p < 0.05). The IL-6 levels in serum peaked after 4 h of reperfusion; 249 pg/ml in the open group, compared to 89 pg/ml in the TPEG group (p < 0.05). High levels of IL-6 in the postoperative period and persisting low sigmoidal pH were associated with serious complications. Postoperative temperature did not differ significantly between the groups, and no significant correlation could be found with sigmoid colon pH or IL-6 levels. CONCLUSIONS The less pronounced perioperative bowel ischaemia in TPEG patients indicates an advantage of the TPEG technique. Splanchnic ischaemia was not related to postoperative fever, nor the IL-6 or TNF response.

Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial

BACKGROUND Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. METHODS In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 × 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4-8 weeks (short-course radiotherapy with delay) or 25 × 2 Gy radiation dose with surgery after 4-8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1·7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov, number NCT00904813. FINDINGS Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33·4 months (range 18·2-62·2) in the short-course radiotherapy group and 19·3 months (8·5-39·5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33·3 months (range 17·8-114·3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1·44 [95% CI 0·41-5·11]; long-course radiotherapy with delay 2·24 [0·71-7·10]; p=0·48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (<1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 [50%] of 129 patients in the short-course radiotherapy group; 48 [38%] of 128 patients in the short-course radiotherapy with delay group; 50 [39%] of 128 patients in the long-course radiotherapy with delay group; odds ratio [OR] vs short-course radiotherapy: short-course radiotherapy with delay 0·59 [95% CI 0·36-0·97], long-course radiotherapy with delay 0·63 [0·38-1·04], p=0·075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 [53%] of 355 vs 188 [41%] of 357; OR 0·61 [95% CI 0·45-0·83] p=0·001). INTERPRETATION Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery. FUNDING Swedish Research Council, Swedish Cancer Society, Stockholm Cancer Society, and the Regional Agreement on Medical Training and Clinical Research in Stockholm.

Pro-inflammatory role of neutrophil extracellular traps in abdominal sepsis.

Excessive neutrophil activation is a major component in septic lung injury. Neutrophil-derived DNA may form extracellular traps in response to bacterial invasions. The aim of the present study was to investigate the potential role of neutrophil extracellular traps (NETs) in septic lung injury. Male C57BL/6 mice were treated with recombinant human (rh)DNAse (5 mg/kg) after cecal ligation and puncture (CLP). Extracellular DNA was stained by Sytox green, and NET formation was quantified by confocal microscopy and cell-free DNA in plasma, peritoneal cavity, and lung. Blood, peritoneal fluid, and lung tissue were harvested for analysis of neutrophil infiltration, NET levels, tissue injury, as well as CXC chemokine and cytokine formation. We observed that CLP caused increased formation of NETs in plasma, peritoneal cavity, and lung. Administration of rhDNAse not only eliminated NET formation in plasma, peritoneal cavity, and bronchoalveolar space but also reduced lung edema and tissue damage 24 h after CLP induction. Moreover, treatment with rhDNAse decreased CLP-induced formation of CXC chemokines, IL-6, and high-mobility group box 1 (HMGB1) in plasma, as well as CXC chemokines and IL-6 in the lung. In vitro, we found that neutrophil-derived NETs had the capacity to stimulate secretion of CXCL2, TNF-α, and HMGB1 from alveolar macrophages. Taken together, our findings show that NETs regulate pulmonary infiltration of neutrophils and tissue injury via formation of proinflammatory compounds in abdominal sepsis. Thus we conclude that NETs exert a proinflammatory role in septic lung injury.

Population-based data from the Swedish Colon Cancer Registry

Evaluating the external validity of clinical trials requires knowledge not only of the study population but also of a relevant reference population. The main aim of this study was to present data from a large, contemporary, population‐based cohort of patients with colonic cancer.

Survival after Operations for Ischaemic Bowel Disease

OBJECTIVE To find out what factors influence the outcome of operations for ischaemic bowel disease. DESIGN Retrospective study. SETTING University hospital, Sweden. MAIN OUTCOME MEASURES Morbidity and mortality. SUBJECTS 74 patients, mean age 75 years (range 40-98), operated on for acute bowel ischaemia between 1987 and 1996. RESULTS A total of 75 emergency operations were done, including 42 bowel-resections, one percutaneous transluminal angioplasty, and one thrombectomy. Thirty-one patients had exploration alone because of extensive gangrene. These explorations were performed in 11 of 14 (79%) patients aged >84 years; 18 of 40 (45%) patients aged 71-84 years and 2 of 21 (9%) patients aged <71 years, (p < 0.001). Of the 14 patients over 84 years old only one survived more than 30 days, compared with 12 of 40 (30%) aged 71-84 years, and 17 of 21 (81%) younger than 71 years (p < 0.001). Operation within 6 hours of admission resulted in significantly better survival compared with operations done after more than 6 hours delay (p = 0.04). CONCLUSIONS Advanced age was a strong risk factor for death after operation for ischaemic bowel disease, and there was a higher incidence of unresectable gangrene. Delay in surgical intervention was associated with increasing mortality.

Management of Aneurysm Sac Hygroma

Purpose: To document the management strategies and outcome of patients diagnosed with sac hygroma following open or endovascular abdominal aortic aneurysm (AAA) repair. Methods: Seven men (median 68 years, range 43–79) with previous open (n=3) or endovascular (n=4) AAA repairs and increasing aneurysm diameters documented on spiral computed tomography (CT) were diagnosed with sac hygroma based on the lack of a demonstrable endoleak on CT imaging; the presence of a gelatinous, clear fluid in the sac; and a nonpulsatile sac pressure that was about one third of the systemic blood pressure. The patients were followed at regular intervals with spiral CT and percutaneous CT-guided translumbar intrasac pressure measurements. Surgical interventions were performed for sac diameter increase >5 mm or expansion-related pain. Blood samples and fluid aspirated from the sac were analyzed to detect activation of the coagulation and fibrinolytic systems. Results: Over a median 21.5-month follow-up, open fenestration with resection of the aneurysm wall or open tight wrapping of the wall around the graft in 4 patients did not prevent hygroma reoccurrence, nor did repeated punctures with aspiration of fluid in the other 3 patients. Aneurysm diameters remained unchanged during the observation period. Conclusions: Only symptomatic hygromas need be treated, but the treatment of choice remains to be established, since puncture, fenestration, or resection of the sac do not seem to be adequate.

Platelet shedding of CD40L is regulated by matrix metalloproteinase-9 in abdominal sepsis.

Platelet‐derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase (MMP)‐9 might cleave surface‐expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis.

Epidemiology and Prognostic Factors in Acute Superior Mesenteric Artery Occlusion.

BackgroundReports on trends in incidence and mortality of acute superior mesenteric artery (SMA) occlusion and evaluation of prognostic factors in recent years are lacking.MethodsPatients with acute SMA occlusion were identified through the in-patient and autopsy registry between 1970 and 1982 (n = 270), 1987 to 1996 (n = 135), and 2000 and 2006 (n = 100) in Malmö, Sweden.ResultsThe overall incidence rate decreased from 8.6 to 5.4/100,000 person years and the autopsy rate from 87% to 25% over time. A higher serum creatinine level was associated with a lower probability of undergoing multi-detector row computed tomography with intravenous contrast (MDCTiv) (p = 0.006). Not performing a MDCTiv (odds ratio 4.0; 95% confidence interval [1.0–16.0]) remained as independent prognostic factor for in-hospital mortality. General and vascular surgeons collaborated in 25 out of 61 patients that underwent an intervention, of which 21 (84%) (p < 0.001) survived.ConclusionsA close collaboration between radiologists and general and vascular surgeons seems to be most important to lower the mortality in patients with acute SMA occlusion.

Impact of MDCT with intravenous contrast on the survival in patients with acute superior mesenteric artery occlusion.

Acute thromboembolic occlusion in the superior mesenteric artery (SMA) is a condition with high mortality and morbidity. Multi-detector computerised tomography with intravenous contrast enhancement (MDCTiv) may improve diagnostic accuracy and survival. Patients with acute SMA occlusion were identified between 2004 and 2008 at Malmö University Hospital, Sweden. Medical records were analysed. Each MDCTiv was re-evaluated. A total of 67 patients were identified with SMA occlusion, of which 36 were examined with MDCTiv and ten with plain MDCT without intravenous contrast. In all, 24 (67%) of the 36 patients were correctly diagnosed by MDCTiv at first evaluation. Clinical suspicion of intestinal ischemia followed by a distinct inquiry for intestinal ischemia was associated with trend for a higher rate of correct radiological diagnosis, 18 of 23 (78%), at first evaluation (0.06) but without affecting in-hospital survival (p = 0.27). At re-evaluation, SMA occlusion was found in all cases with MDCTiv, whereas intestinal findings were present in half. In-hospital mortality rate was 42% for patients who underwent MDCTiv, which was significantly lower compared to 90% for the ten patients examined with plain MDCT (p = 0.007) and 71% for patients not examined with MDCTiv or plain MDCT (p = 0.031). Patients that underwent plain MDCT had higher levels of creatinine compared to those examined with MDCTiv (p = 0.005). Patients who underwent intestinal revascularisation, endovascular or open, had higher survival rate (p = 0.001). Examination with MDCTiv in patients with acute SMA occlusion was associated with survival benefit. Hence, MDCTiv seems to be the method of choice in the workup phase. Radiologists should routinely describe the mesenteric vessels in patients with acute abdomen even when the diagnosis is not asked for. Patients with high creatinine levels are at risk to be examined without intravenous contrast, and survival in these patients is poor.

Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis

ObjectivePlatelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.MethodsWild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to determine expression of Mac-1 on neutrophils and CD40L on platelets. Intravital fluorescence microscopy was used to analyze leukocyte–endothelial cell interactions in the pulmonary microcirculation.ResultsThe MMP inhibitor reduced sepsis-induced release of CD40L and maintained normal levels of CD40L on platelets. Inhibition of MMP decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration in the lung. Intravital fluorescence microscopy revealed that the MMP inhibitor attenuated leukocyte adhesion in venules whereas capillary trapping of leukocytes was not affected by MMP inhibition.ConclusionsWe describe a novel role of metalloproteinases in regulating platelet-dependent activation and infiltration of neutrophils in septic lung injury which might be related to controlling CD40L shedding from platelets. We conclude that targeting metalloproteinases may be a useful strategy for limiting acute lung injury in abdominal sepsis.