Marinus J. Wiezer

The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitisA and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitisB in perforated diverticulitis (NTR2037)

BackgroundRecently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy.The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis).Methods/DesignIn this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmanns procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmanns procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90%) in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs.DiscussionThe Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy for both purulent and faecal generalised peritonitis.Trial registrationNederlands Trial Register NTR2037

Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy.

BACKGROUND Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of the arginine-nitric oxide pathway. It is conceivable that its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase, which is highly expressed in the liver. In rats, we showed a high net hepatic uptake of ADMA. Therefore, we aimed to confirm the role of the liver in humans and hypothesized elevated ADMA levels after major liver resection by a reduction of functional liver mass and injury to the remnant liver. METHODS Patients undergoing a major hepatic resection (HEP, n = 17) or major abdominal surgery (MAS, n = 12) were included and followed in time. In addition, ADMA levels were measured in 4 patients having severe hepatic failure after a liver resection. Plasma ADMA concentration was measured by high-performance liquid chromatography. RESULTS Preoperatively and on days 1, 3, and 5, plasma levels of ADMA were higher in HEP patients when compared with MAS patients. In HEP patients with prolonged (>7 days) hepatic injury, ADMA levels were especially elevated. On the first postoperative day, ADMA significantly correlated to bilirubin concentration (r = .528, p < .05) as a marker of postoperative hepatic function. Besides, in patients with severe hepatic failure, ADMA levels were highly elevated. CONCLUSIONS In the present study, evidence was found for the role of the liver in the elimination of ADMA in humans. Increased levels of ADMA occur in the postoperative course after a major hepatic resection, especially when liver function is severely impaired. Further studies need to assess the role of ADMA in the development of complications after liver surgery.

The effect of mild endotoxemia during low arginine plasma levels on organ blood flow in rats.

OBJECTIVE Arginine is the sole precursor in the generation of the vasodilating agent nitric oxide. Arginine plasma levels are low in situations associated with endotoxemia such as major trauma, sepsis, and experimental obstructive jaundice. The aim of the study was to evaluate hemodynamics at low arginine plasma levels during a low-grade endotoxemia. DESIGN Randomized, placebo-controlled animal laboratory investigation. SUBJECTS Male Wistar rats (n = 29), anesthetized. INTERVENTIONS Rats were randomly assigned to receive (at t = 0 mins) an intravenous infusion of 1.5 mL of 0.9% NaCl (SAL, n = 12) or 1.5 mL of an arginase (3200 IU) solution (ASE, n = 17) over a 20-min period. After the SAL or ASE infusion, rats were randomly assigned to receive an intravenous endotoxin (lipopolysaccharide [LPS], 150 microg/kg in 1.0 mL of 0.9% NaCl; ASE/LPS, n = 10 and SAL/LPS, n = 6) challenge or a control infusion (1.0 mL of 0.9% NaCl; ASE/SAL, n = 7 and SAL/SAL, n = 6) at t = 30 mins. MEASUREMENTS AND MAIN RESULTS Organ blood flow was measured at t = 270 mins, using radiolabeled microspheres. At this time point, arginine plasma levels were lower in the ASE-treated rats (ASE/SAL vs. SAL/SAL and ASE/LPS vs. SAL/LPS, both p < .005, respectively). Cardiac output, mean arterial pressure, and therefore total peripheral resistance were similar for all groups. In the LPS-treated animals (SAL/LPS and ASE/LPS), cardiac output was maintained by a higher heart rate compensating the lower stroke volume. Organ blood flow to the small intestine and splanchnic blood flow was lower in the ASE/LPS-treated rats (both p < .05 when compared with other groups). Total liver blood flow was similar for all groups; the lower splanchnic blood flow was compensated for by a higher hepatic arterial blood flow. CONCLUSION The present study shows that low arginine plasma levels do not influence organ blood flow, whereas, during a low-grade endotoxemia, low arginine plasma levels result in reduced blood flow to the small intestine.

Bactericidal/Permeability-Increasing Protein Preserves Leukocyte Functions After Major Liver Resection

ObjectiveTo analyze postoperative leukocyte functions in patients undergoing hemihepatectomy, and to assess the effect of treatment with the endotoxin-neutralizing agent bactericidal/permeability-increasing protein (rBPI21). Summary Background DataExtensive liver resection is associated with a high incidence of infectious complications. Because elimination of pathogenic microorganisms occurs mainly by leukocytes, this increased rate of infections is most likely due to an impaired function of these cells. Endotoxin, translocated from the gut into the systemic circulation as a result of increased gut permeability and reduced hepatic clearance function after major liver resection, may play an important role in the impairment of posthepatectomy leukocyte function. MethodsTo investigate whether hemihepatectomy results in impaired leukocyte functions and to determine the role of endotoxin in this process, leukocyte oxidative burst and leukocyte antigen expression were studied in three groups of patients: patients undergoing a hemihepatectomy and receiving rBPI21 treatment, patients undergoing hemihepatectomy and receiving placebo, and as an extra control group patients undergoing other major abdominal surgeries. Blood samples were collected before surgery, 2 hours after surgery, and at days 1, 2, 5, and 7. Phorbol myristate acetate-stimulated oxidative burst was measured using dihydrorhodamine, and leukocyte surface expression of the antigens CD11b, CD16, and CD14 was investigated by indirect immunofluorescence. Both oxidative burst and membrane surface expression were quantified by flow cytometry. An indication of the antiendotoxin effect of rBPI21 treatment was provided by assessment of plasma lipopolysaccharide binding protein (LBP) levels by enzyme-linked immunosorbent assay. ResultsThe oxidative burst in the hemihepatectomized patients receiving placebo and the controls increased 2 hours after surgery, whereas it decreased in the rBPI21-treated patients, resulting in significant differences between the groups. On day 1, neutrophil CD11b expression and monocyte CD14 expression in the rBPI21-treated patients and controls were significantly lower than in the placebo group. At 2 hours, CD16 expression in the placebo-treated patients was significantly higher than in the rBPI21-treated patients and controls. On day 5 and day 7, plasma LBP levels were significantly higher in the placebo-treated patients compared with the rBPI21-treated patients. ConclusionsThe results of this study show that patients undergoing major liver resection have an increased activation of leukocytes compared with those undergoing other major abdominal surgery. This enhanced activation may contribute to the increased risk of infection in these patients. Administration of the endotoxin-neutralizing agent rBPI21 to hemihepatectomy patients was shown to reduce plasma LBP levels, to preserve leukocyte functions partially, and to reduce leukocyte activation to the level of other, nonhepatic abdominal surgery.

Coagulopathy following major liver resection: the effect of rBPI21 and the role of decreased synthesis of regulating proteins by the liver.

This prospective study investigated the role of reduced hepatic synthesis of regulating proteins in coagulopathy after partial hepatectomy (PH) compared with major abdominal surgery (MAS) without involvement of the liver. Furthermore, we studied the effect of rBPI21, an endotoxin-neutralizing agent, on coagulopathy after PH was studied. Compared with MAS, PH resulted in significantly elevated levels of thrombin-antithrombin-III and plasmin-alpha2-antiplasmin complexes. Levels of antithrombin-3, alpha2-antiplasmin, fibrinogen, plasminogen, alpha2-macroglobulin (alpha2-M), and C1-inhibitor remained lower following PH. Treatment with rBPI21 led to significantly lower levels of tissue-type plasminogen activator (t-PA). Post-operative disseminated intravascular coagulation (DIC) was associated with significantly higher bilirubin and t-PA plasma levels and significantly lower levels of alpha2-M. This study indicates that PH induced hepatic failure results in decreased synthesis of hepatic regulating plasma proteins and subsequent activation of coagulation and fibrinolysis. Prevention of t-PA release by rBPI21 may have important clinical implications. Decreased availability of alpha2-M may be a factor in post-operative DIC.

High plasma levels of arginine and liver arginase in Kupffer-cell-depleted rats after partial hepatectomy.

Abstract Background/Aims: The remnant liver after partial hepatectomy releases arginase into the plasma, which is a reliable indicator of hepatocellular damage. Little information is available on how this release affects arginine plasma levels. We hypothesized that Kupffer cells after partial hepatectomy may prevent further hepatocellular damage, contributing to lower arginase release. The aim of the study was to evaluate the role of Kupffer cells in plasma arginase activity and arginine plasma levels after partial hepatectomy. Methods: Wag/Rij rats ( n =72, 250–275 g) were randomly assigned to receive 1 ml liposome-encapsulated dichloromethylene-diphosphonate in order to eliminate Kupffer cells (DMDP, n =24), 1 ml liposome encapsulated-phosphate buffered saline (PBS, n =24) or 1 ml NaCl 0.9% (NaCl, n =24) intravenously. Forty-eight hours later, all rats had a two-third liver resection. Rats were killed at 0, 24, 48 and 96 h after partial hepatectomy. Results: Arginase plasma activity was higher in the DMDP-treated group compared to NaCl and PBS (both p p p p p Conclusion: The study showed that Kupffer cell depletion results in a higher arginase release from the remnant liver after partial hepatectomy, indicating a hepatocellular protective function of Kupffer cells. Despite this arginase release, arginine plasma levels were increased after partial hepatectomy.

Pharmacokinetics of a recombinant amino terminal fragment of bactericidal/permeability increasing protein (rBPI21) after liver surgery in rats and humans.

ABSTRACT Major liver resections are associated with considerable morbidity and mortality. Gut-derived bacteria and bacterial endotoxin (LPS) are considered to play a central role in the pathophysiology of these complications. Like human BPI, rBPl21 binds to LPS from Gram-negative bacteria. By binding and clearing of LPS, rBPI21 can inhibit a number of endotoxin-induced humoral and cellular responses. Because of this capacity, rBPI21 could partially compensate for the loss of hepatic mononuclear phagocytic system function after liver resection. However, the liver is also thought to be an important organ for the clearance of BPI, and reduction of liver mass could result in a decreased clearance and exceedingly high plasma levels of rBPI21. In this study we therefore investigated the pharmacokinetics of rBPI21 in rats and in patients undergoing a major liver resection. Rats were administered an intravenous (i.v.) bolus of rBPI21 after undergoing a 60% or 80% hepatectomy (with sham-operated controls). Patients undergoing a hemihepatectomy and healthy volunteers received rBPI21 or placebo by continuous i.v. infusion for 48 h. Plasma concentrations were measured by sandwich ELISA. In rats, 60% hepatectomy did not consistently change the clearance of rBPI21, whereas 80% hepatectomy decreased the clearance of rBPI21 severalfold. In hemihepatectomized patients, the clearance of rBPI21 after major hepatectomy was also slower, when compared with healthy volunteers, but this difference had disappeared within 24 h. Our data indicate that the administration of rBPI21 in patients undergoing liver resection is well tolerated and does not result in exceedingly high plasma levels. Additional studies on the efficacy of rBPI21 in the prevention of complications after hepatectomy are needed.

Elective Resection for Ongoing Diverticular Disease Significantly Improves Quality of Life

Background: Although the risks of elective resection for diverticular disease are well studied, studies on subjective improvement are scarce. This study aims to investigate subjective improvement. Methods: All patients who underwent elective resection for recurring or persisting complaints after an episode of diverticulitis were identified from an in-hospital database. Patients with at least 1 year of follow-up were sent visual analogue scales (VAS) to grade their quality of life (QoL) and the degree of discomfort caused by abdominal pain, abnormal defecation and fatigue before and after resection. Results: One hundred and five patients responded to the questionnaire (response rate 76.6%). The median follow-up was 33 (15-53) months. Elective resection improved general QoL (median VAS improvement 40) and reduced discomfort caused by abdominal pain (median VAS improvement 60) in up to 89.3 and 87.5% of patients, respectively. The effects of elective resection are less profound for discomfort caused by abnormal defecation (77.1%, median VAS improvement 33) and fatigue (75.2%, median VAS improvement 30). Conclusion: Elective resection of the sigmoid for persisting or recurring symptoms after an episode of diverticulitis improves general QoL and discomfort caused by abdominal pain, abnormal defecation and fatigue in the vast majority of patients.

Cytoreductive surgery and HIPEC offers similar outcomes in patients with rectal peritoneal metastases compared to colon cancer patients: a matched case control study

The effect of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with rectal peritoneal metastases (PM) is unclear. This case‐control study aims to assess the results of cytoreduction and HIPEC in patients with rectal PM compared to colon PM patients.

Pilot-study on the feasibility of sentinel node navigation surgery in combination with thoracolaparoscopic lymphadenectomy without esophagectomy in early esophageal adenocarcinoma patients

High-risk submucosal esophageal adenocarcinomas might be treated curatively by means of radical endoscopic resection, followed by thoracolaparoscopic lymphadenectomy without concomitant esophagectomy. A preclinical study has shown the feasibility and safety of this approach; however, no studies are performed in a clinical setting. In addition, sentinel node navigation surgery could be valuable in tailoring the extent of the lymphadenectomy. This study aimed to evaluate the feasibility and safety of thoracolaparoscopic lymphadenectomy without esophagectomy (phase I) and sentinel node navigation surgery (phase II) in patients with early esophageal adenocarcinoma. Patients with T1N0M0 early esophageal adenocarcinoma scheduled for esophagectomy without neoadjuvant therapy were included. Phase I: Two-field, esophagus preserving, thoracolaparoscopic lymphadenectomy was performed, followed by esophagectomy in the same session. Primary outcome parameters were the number of lymph nodes resected, and number of retained lymph nodes in the esophagectomy specimen. Phase II: A radioactive tracer was injected endoscopically the day before surgery. Static imaging was performed 15 and 120 minutes after injection. The day of surgery, sentinel node navigation surgery followed by esophagectomy was performed. Primary outcome parameters were the percentage of patients with a detectable sentinel node, and the concordance between static imaging and probe-based detection of sentinel node. Phase I: Five patients were included, and a median of 30 (IQR: 25-46) lymph nodes was resected. A median of 6 (IQR: 2-9) retained lymph nodes was found in the esophagectomy specimen. No acute adverse events occurred, but near the end of lymphadenectomy esophageal discoloration was observed, possibly indicating ischemia. Phase II: In all five included patients sentinel nodes could be visualized and resected, at a median of 3 (IQR: 2-5) locations. There was a high concordance between imaging and probe-based detection of sentinel nodes. In conclusion, sentinel node navigation surgery followed by lymphadenectomy without concomitant esophagectomy seems feasible in patients with high-risk submucosal early esophageal adenocarcinoma. More evidence is however needed before applying this technique in clinical practice.