Jan Willem Haveman

The central role of monocytes in the pathogenesis of sepsis: consequences for immunomonitoring and treatment

Despite important advances in critical care medicine during the last two decades, the mortality rate of sepsis has remained high, probably because the pathogenesis of sepsis is still incompletely understood. Recent studies have shown that sepsis is a bimodal entity. The first phase is characterized by the systemic release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-8, and by activation of the complement and coagulation cascades. In the second phase, anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta), IL-10 and prostaglandin E2 (PGE2) may be released in an effort to counteract ongoing inflammation. Depending whether the pro- or anti-inflammatory response predominates, sepsis results in a systemic inflammatory response syndrome (SIRS), or a compensatory anti-inflammatory response syndrome (CARS). So far, most efforts to intervene in the immunopathogenesis of sepsis have been directed at the pro-inflammatory response. None of these interventions has been shown to improve the prognosis of sepsis, possibly because many patients were already in a state in which anti-inflammatory responses dominated. Recently, it has been shown that decreased expression of HLA-DR on monocytes in patients with sepsis constitutes a marker for CARS. We suggest that HLA-DR expression on monocytes might constitute a useful indicator of the immunological status of the individual patient with sepsis and a guide for treatment. Patients with CARS, as manifested by low HLA-DR expression, might benefit from immunostimulants, while patients with SIRS and normal or high monocyte HLA-DR expression should receive treatment directed to interfere with pro-inflammatory pathways.

Results of streamlined regional ambulance transport and subsequent treatment of acute abdominal aortic aneurysms

Objective: To describe the triage of patients operated for non-ruptured and ruptured abdominal aortic aneurysms (AAAs) before the endovascular era. Design: Retrospective single-centre cohort study. Methods: All patients treated for an acute AAA between 1998 and 2001 and admitted to our hospital were evaluated in the emergency department for urgent AAA surgery. All time intervals, from the telephone call from the patient to the ambulance department, to the arrival of the patient in the operating theatre, were analysed. Intraoperative, hospital and 1-year survival were determined. Results: 160 patients with an acute AAA were transported to our hospital. Mean (SD) age was 71 (8) years, and 138 (86%) were men. 34 (21%) of these patients had symptomatic, non-ruptured AAA (sAAA) and 126 patients had ruptured AAA (rAAA). All patients with sAAA and 98% of patients with rAAA were operated upon. For the patients with rAAA, median time from telephone call to arrival at the hospital was 43 min (interquartile range 33–53 min) and median time from arrival at the hospital to arrival at the operating room was 25 min (interquartile range 11–50 min). Intraoperative mortality was 0% for sAAA and 11% for rAAA (p = 0.042), and hospital mortality was 12% and 33%, respectively (p = 0.014). Conclusions: A multidisciplinary unified strategy resulted in a rapid throughput of patients with acute AAA. Rapid transport, diagnosis and surgery resulted in favourable hospital mortality. Despite the fact that nearly all the patients were operated upon, survival was favourable compared with published data.

HLA-DR expression on monocytes and systemic inflammation in patients with ruptured abdominal aortic aneurysms

IntroductionMortality from ruptured abdominal aortic aneurysms (RAAA) remains high. Severe systemic inflammation, leading to multi-organ failure, often occurs in these patients. In this study we describe the level of HLA-DR expression in a consecutive group of patients following surgery for RAAA and compare results between survivors and non-survivors. A similar comparison is made for IL-6 and IL-10 levels and Sequential Organ Failure Assessment (SOFA) scores.MethodsThis is a prospective observational study. Patients with RAAA were prospectively analysed. Blood samples were collected on days 1, 3, 5, 7, 10 and 14. The fraction of CD-14 positive monocytes expressing HLA-DR was measured by flow-cytometry. IL-6 and IL-10 levels were measured by ELISA.ResultsThe study included 30 patients with a median age of 70 years, of which 27 (90%) were men. Six patients died from multiple organ failure, all other patients survived. The SOFA scores were significantly higher in non-survivors on days 1 through 14. HLA-DR expression on monocytes was significantly lower on days 3, 5, 7, 10 and 14 in non-survivors. IL-6 and IL-10 levels were significantly higher in non-survivors on day 1 and days 1 and 3, respectively.ConclusionHLA-DR expression on monocytes was decreased, especially in non-survivors. All patients with RAAA displayed a severe inflammatory and anti-inflammatory response with an increased production of IL-6 and IL-10. Poor outcome is associated with high levels of IL-6 and IL-10 and a high SOFA score in the first three days after surgery, while low levels of HLA-DR expression are observed from day three after RAAA repair.

Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial

BACKGROUND Infected necrotising pancreatitis is a potentially lethal disease and an indication for invasive intervention. The surgical step-up approach is the standard treatment. A promising alternative is the endoscopic step-up approach. We compared both approaches to see whether the endoscopic step-up approach was superior to the surgical step-up approach in terms of clinical and economic outcomes. METHODS In this multicentre, randomised, superiority trial, we recruited adult patients with infected necrotising pancreatitis and an indication for invasive intervention from 19 hospitals in the Netherlands. Patients were randomly assigned to either the endoscopic or the surgical step-up approach. The endoscopic approach consisted of endoscopic ultrasound-guided transluminal drainage followed, if necessary, by endoscopic necrosectomy. The surgical approach consisted of percutaneous catheter drainage followed, if necessary, by video-assisted retroperitoneal debridement. The primary endpoint was a composite of major complications or death during 6-month follow-up. Analyses were by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN09186711. FINDINGS Between Sept 20, 2011, and Jan 29, 2015, we screened 418 patients with pancreatic or extrapancreatic necrosis, of which 98 patients were enrolled and randomly assigned to the endoscopic step-up approach (n=51) or the surgical step-up approach (n=47). The primary endpoint occurred in 22 (43%) of 51 patients in the endoscopy group and in 21 (45%) of 47 patients in the surgery group (risk ratio [RR] 0·97, 95% CI 0·62-1·51; p=0·88). Mortality did not differ between groups (nine [18%] patients in the endoscopy group vs six [13%] patients in the surgery group; RR 1·38, 95% CI 0·53-3·59, p=0·50), nor did any of the major complications included in the primary endpoint. INTERPRETATION In patients with infected necrotising pancreatitis, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing major complications or death. The rate of pancreatic fistulas and length of hospital stay were lower in the endoscopy group. The outcome of this trial will probably result in a shift to the endoscopic step-up approach as treatment preference. FUNDING The Dutch Digestive Disease Foundation, Fonds NutsOhra, and the Netherlands Organization for Health Research and Development.

Adequate debridement and drainage of the mediastinum using open thoracotomy or video-assisted thoracoscopic surgery for Boerhaave’s syndrome

BackgroundBoerhaave’s syndrome has a high mortality rate (14–40%). Surgical treatment varies from a minimal approach consisting of adequate debridement with drainage of the mediastinum and pleural cavity to esophageal resection. This study compared the results between a previously preferred open minimal approach and a video-assisted thoracoscopic surgery (VATS) procedure currently considered the method of choice.MethodsIn this study, 12 consecutive patients treated with a historical nonresectional drainage approach (1985–2001) were compared with 12 consecutive patients treated prospectively after the introduction of VATS during the period 2002–2009. Baseline characteristics were equally distributed between the two groups.ResultsIn the prospective group, 2 of the 12 patients had the VATS procedure converted to an open thoracotomy, and 2 additional patients were treated by open surgery. In the prospective group, 8 patients experienced postoperative complications compared with all 12 patients in the historical control group. Four patients (17%), two in each group, underwent reoperation. Six patients, three in each group, were readmitted to the hospital. The overall in-hospital mortality was 8% (1 patient in each group), which compares favorably with other reports (7–27%) based on drainage alone.ConclusionsAdequate surgical debridement with drainage of the mediastinum and pleural cavity resulted in a low mortality rate. The results for VATS in this relatively small series were comparable with those for an open thoracotomy.

Cost-effectiveness of intestinal transplantation for adult patients with intestinal failure: a simulation study

BACKGROUND Home parenteral nutrition (HPN) and intestinal transplantation (ITx) are the 2 treatment options for irreversible intestinal failure (IF). OBJECTIVE This study simulated the disease course of irreversible IF and both of these treatments--HPN and ITx--to estimate the cost-effectiveness of ITx. DESIGN We simulated IF treatment in adults as a discrete event model with variables derived from the Dutch Registry of Intestinal Failure and Intestinal Transplantation, the Intestinal Transplant Registry, hospital records, the literature, and expert opinions. Simulated patients were enrolled at a rate of 40/mo for 10 y. The maximum follow-up was 40 y. Survival was simulated as a probabilistic function. ITx was offered to 10% of patients with <12 mo of remaining life expectancy with HPN if they did not undergo ITx. Costs were calculated according to Dutch guidelines, with discounting. We evaluated the cost-effectiveness of ITx by comparing models conducted with and without ITx and by calculating the cost difference per life-year gained [incremental cost-effectiveness ratio (ICER)]. RESULTS The average survival was 14.6 y without ITx and 14.9 y with ITx. HPN costs were €13,276 for treatment introduction, followed by €77,652 annually. The costs of ITx were ∼€73,000 during the first year and then €13,000 annually. The ICER was €19,529 per life-year gained. CONCLUSION Our simulations show that ITx slightly improves survival of patients with IF in comparison with HPN at an additional cost of €19,529 per life-year gained.

IntraoperatIve MotIve For perForMIng a LaparoscopIc appendectoMy on a postoperatIve HIstoLogIcaL proven norMaL appendIx

Background: Diagnostic laparoscopy is the ultimate tool to evaluate the appendix. However, the intraoperative evaluation of the appendix is difficult, as the negative appendectomy rate remains 12%–18%. The aim of this study is to analyze the intraoperative motive for performing a laparoscopic appendectomy of an appendix that was proven to be noninflamed after histological examination. Methods: In 2008 and 2009, in five hospitals, operation reports of all negative laparoscopic appendectomies were retrospectively analyzed in order to assess the intraoperative motive for removing the appendix. Results: A total of 1,465 appendectomies were analyzed with an overall negative appendectomy rate of 9% (132/1,465). In 57% (841/1,465), a laparoscopic appendectomy was performed, with 9% (n = 75) negative appendectomies. In 51% of the negative appendectomies, the visual assessment of the appendix was decisive in performing the appendectomy. In 33%, the surgeon was in doubt whether the appendix was inflamed or normal. In 4%, the surgeon was aware he removed a healthy appendix, and in 9%, an appendectomy was performed for different reasons. Conclusion: In more than half of the microscopic healthy appendices, the surgeon was convinced of the diagnosis appendicitis during surgery. Intraoperative laparoscopic assessment of the appendix can be difficult.

Effectiveness of treatment for octogenarians with acute abdominal aortic aneurysm

OBJECTIVE To investigate whether advanced age may be a reason to refrain from treatment in patients with an acute abdominal aortic aneurysm (AAAA). METHODS This was a retrospective cohort study that took place in a tertiary care university hospital with a 45-bed intensive care unit. Two hundred seventy-one patients with manifest AAAA, admitted and treated between January 2000 and February 2008, were included. Six patients died during operation and were included in the final analysis to ensure an intention-to-treat protocol, resulting in 234 men and 37 women with a mean age of 72 ± 7.8 years (range, 54-88 years). Forty-six patients (17%) were 80 years or older. Interventions involved open or endovascular AAAA repair. RESULTS Mean follow-up was 33 ± 30.4 months (including early deaths). Mean hospital length of stay was 16.9 ± 20 days for patients younger than 80 and 13 ± 16.7 days for patients older than 80 years of age. Kaplan-Meier survival analysis revealed a significantly better survival for the younger patients (P < .05). Stratification based on urgency or type of treatment did not change the difference. Two-year actuarial survival was 70% for patients younger than 80 and 52% for those older than 80. At 5-year follow-up, these figures were 62% and 29%, respectively. Mean survival in patients older than 80 was 39.8 ± 6.8 months versus 64.5 ± 3.0 months in those younger than 80. CONCLUSIONS For octogenarians, our liberal strategy of treating patients with AAAA was associated with satisfactory short- and long-term outcome, with no difference with regard to disease- or procedure-related morbidity between the younger and older group. Assuming an integrated system for managing AAAA is in place, advanced age is not a reason to deny patients surgery.

Surgical management and autologous intestinal reconstruction in short bowel syndrome

Short bowel syndrome (SBS) is a serious condition with considerable morbidity and mortality. When treatment with parenteral nutrition fails and life-threatening complications occur, autologous intestinal reconstruction (AIR) should be considered before intestinal transplantation (ITx). Single or combined ITx should be reserved for patients with severe liver disease and as last resort in the treatment of SBS. Longitudinal intestinal lengthening and tailoring (LILT) has proven its value in AIR, but its availability depends on the expertise of the surgeons. Serial transverse enteroplasty (STEP) has similar success rates as LILT and fewer patients progress to ITx. STEP is also applicable at small bowel dilatation in ultra-short bowel syndrome. The scope may be widened when duodenal dilatation can be treated as well. Spiral intestinal lengthening and tailoring (SILT) is a promising alternative. More research is needed to confirm these findings. Therefore we suggest an international data registry for all intestinal lengthening procedures.

Proactive Versus Standard Percutaneous Catheter Drainage for Infected Necrotizing Pancreatitis

Objectives Percutaneous catheter drainage (PCD) is often the first invasive treatment step for infected necrotizing pancreatitis. A proactive PCD strategy, including frequent and early drain revising and upsizing, may reduce the need for surgical necrosectomy and could improve outcomes, but data are lacking. Methods Necrotizing pancreatitis patients were identified from in-hospital databases (2004–2014). Patients with primary PCD for infected necrotizing pancreatitis were included. Outcomes of patients from 1 center using a proactive PCD strategy were compared with 3 standard strategy centers. Results In total, 369 (25.9%) of 1427 patients received a diagnosis of necrotizing pancreatitis, and 117 (31.7%) of 369 patients underwent primary PCD for infected necrosis: 42 in the proactive group versus 75 in the standard group. Patients in the proactive group had more drain-related procedures (median, 3; interquartile range [IQR], 2–4; versus 2; IQR, 1–2; P < 0.001) and larger final drain sizes (median, 16F; IQR, 14F–20F; versus 14F; IQR, 12F–14F; P < 0.001). Fewer patients underwent additional necrosectomy in the proactive group, 12 (28.6%) versus 39 (52.0%) (adjusted odds ratio, 0.349; 95% confidence interval, 0.137–0.889; P = 0.027), with similar hospital stay and mortality. Conclusions A proactive PCD strategy is associated with reduced need for necrosectomy in infected necrotizing pancreatitis, compared with standard PCD, with similar clinical outcomes.