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1.  Quality of Pharmaceutical Care in Surgical Patients 
PLoS ONE  2014;9(7):e101573.
Surgical patients are at risk for preventable adverse drug events (ADEs) during hospitalization. Usually, preventable ADEs are measured as an outcome parameter of quality of pharmaceutical care. However, process measures such as QIs are more efficient to assess the quality of care and provide more information about potential quality improvements.
To assess the quality of pharmaceutical care of medication-related processes in surgical wards with quality indicators, in order to detect targets for quality improvements.
For this observational cohort study, quality indicators were composed, validated, tested, and applied on a surgical cohort. Three surgical wards of an academic hospital in the Netherlands (Academic Medical Centre, Amsterdam) participated. Consecutive elective surgical patients with a hospital stay longer than 48 hours were included from April until June 2009. To assess the quality of pharmaceutical care, the set of quality indicators was applied to 252 medical records of surgical patients.
Thirty-four quality indicators were composed and tested on acceptability and content- and face-validity. The selected 28 candidate quality indicators were tested for feasibility and ‘sensitivity to change’. This resulted in a final set of 27 quality indicators, of which inter-rater agreements were calculated (kappa 0.92 for eligibility, 0.74 for pass-rate). The quality of pharmaceutical care was assessed in 252 surgical patients. Nearly half of the surgical patients passed the quality indicators for pharmaceutical care (overall pass rate 49.8%). Improvements should be predominantly targeted to medication care related processes in surgical patients with gastro-intestinal problems (domain pass rate 29.4%).
This quality indicator set can be used to measure quality of pharmaceutical care and detect targets for quality improvements. With these results medication safety in surgical patients can be enhanced.
PMCID: PMC4090008  PMID: 25006676
2.  Association Analysis of Genetic Variants in the Myosin IXB Gene in Acute Pancreatitis 
PLoS ONE  2013;8(12):e85870.
Impairment of the mucosal barrier plays an important role in the pathophysiology of acute pancreatitis. The myosin IXB (MYO9B) gene and the two tight-junction adaptor genes, PARD3 and MAGI2, have been linked to gastrointestinal permeability. Common variants of these genes are associated with celiac disease and inflammatory bowel disease, two other conditions in which intestinal permeability plays a role. We investigated genetic variation in MYO9B, PARD3 and MAGI2 for association with acute pancreatitis.
Five single nucleotide polymorphisms (SNPs) in MYO9B, two SNPs in PARD3, and three SNPs in MAGI2 were studied in a Dutch cohort of 387 patients with acute pancreatitis and over 800 controls, and in a German cohort of 235 patients and 250 controls.
Association to MYO9B and PARD3 was observed in the Dutch cohort, but only one SNP in MYO9B and one in MAGI2 showed association in the German cohort (p < 0.05). Joint analysis of the combined cohorts showed that, after correcting for multiple testing, only two SNPs in MYO9B remained associated (rs7259292, p = 0.0031, odds ratio (OR) 1.94, 95% confidence interval (95% CI) 1.35-2.78; rs1545620, p = 0.0006, OR 1.33, 95% CI 1.16-1.53). SNP rs1545620 is a non-synonymous SNP previously suspected to impact on ulcerative colitis. None of the SNPs showed association to disease severity or etiology.
Variants in MYO9B may be involved in acute pancreatitis, but we found no evidence for involvement of PARD3 or MAGI2.
PMCID: PMC3875581  PMID: 24386489
3.  Transluminal endoscopic step-up approach versus minimally invasive surgical step-up approach in patients with infected necrotising pancreatitis (TENSION trial): design and rationale of a randomised controlled multicenter trial [ISRCTN09186711] 
BMC Gastroenterology  2013;13:161.
Infected necrotising pancreatitis is a potentially lethal disease that nearly always requires intervention. Traditionally, primary open necrosectomy has been the treatment of choice. In recent years, the surgical step-up approach, consisting of percutaneous catheter drainage followed, if necessary, by (minimally invasive) surgical necrosectomy has become the standard of care. A promising minimally invasive alternative is the endoscopic transluminal step-up approach. This approach consists of endoscopic transluminal drainage followed, if necessary, by endoscopic transluminal necrosectomy. We hypothesise that the less invasive endoscopic step-up approach is superior to the surgical step-up approach in terms of clinical and economic outcomes.
The TENSION trial is a randomised controlled, parallel-group superiority multicenter trial. Patients with (suspected) infected necrotising pancreatitis with an indication for intervention and in whom both treatment modalities are deemed possible, will be randomised to either an endoscopic transluminal or a surgical step-up approach. During a 4 year study period, 98 patients will be enrolled from 24 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of death and major complications within 6 months following randomisation. Secondary endpoints include complications such as pancreaticocutaneous fistula, exocrine or endocrine pancreatic insufficiency, need for additional radiological, endoscopic or surgical intervention, the need for necrosectomy after drainage, the number of (re-)interventions, quality of life, and total direct and indirect costs.
The TENSION trial will answer the question whether an endoscopic step-up approach reduces the combined primary endpoint of death and major complications, as well as hospital stay and related costs compared with a surgical step-up approach in patients with infected necrotising pancreatitis.
PMCID: PMC4222267  PMID: 24274589
Acute pancreatitis; Necrotising; Treatment; Drainage; Trial; Endoscopy; Minimally invasive; Surgery; Necrosectomy; Pancreas
4.  Occurrence and preventability of adverse drug events in surgical patients: a systematic review of literature 
Adverse drug events (ADEs) are a considerable cause of inhospital morbidity and mortality. Patient flow differs substantially for surgical and nonsurgical patients: surgical patients are subjected to multiple medication changes related to surgical intervention or postoperative care. The objective of this study is to systematically review the occurrence and nature of ADEs in surgical patients. Also, a comparison with nonsurgical patients was made.
A search was conducted in Embase and Medline identifying studies that reported observational data on the occurrence and nature of ADEs in surgical hospitalised adult patients. If sufficient data were available, the occurrence of (preventable) ADEs was compared between surgical and nonsurgical patients.
Six studies fulfilled the inclusion criteria. The occurrence of ADEs in surgical patients ranged from 2.0 to 27.7 per 100 admissions, from 4.7 to 8.9 per 1,000 patient days, or involved 8.9% of the patients. Proportions of preventable ADEs in surgical patients were 18% and 54%, described in two studies. A head-to-head comparison of surgical patients and nonsurgical patients was possible for five of six studies. The occurrence of ADEs in nonsurgical patients was significantly higher than in surgical patients in three studies.
ADEs are a relevant problem in surgical patients and nonsurgical patients, with a high proportion of preventable ADEs. The occurrence of ADEs appears to be higher in nonsurgical patients than in surgical patients. However, studies lack details on the differences in nature of ADEs between hospital populations. To improve medication safety this knowledge is essential.
PMCID: PMC3852674  PMID: 24074346
Adverse drug events; Occurrence; Preventability; Nature; Surgical patient; Nonsurgical patient
5.  A decision rule to aid selection of patients with abdominal sepsis requiring a relaparotomy 
BMC Surgery  2013;13:28.
Accurate and timely identification of patients in need of a relaparotomy is challenging since there are no readily available strongholds. The aim of this study is to develop a prediction model to aid the decision-making process in whom to perform a relaparotomy.
Data from a randomized trial comparing surgical strategies for relaparotomy were used. Variables were selected based on previous reports and common clinical sense and screened in a univariable regression analysis to identify those associated with the need for relaparotomy. Variables with the strongest association were considered for the prediction model which was constructed after backward elimination in a multivariable regression analysis. The discriminatory capacity of the model was expressed with the area under the curve (AUC). A cut-off analysis was performed to illustrate the consequences in clinical practice.
One hundred and eighty-two patients were included; 46 were considered cases requiring a relaparotomy. A prediction model was build containing 6 variables. This final model had an AUC of 0.80 indicating good discriminatory capacity. However, acceptable sensitivity would require a low threshold for relaparotomy leading to an unacceptable rate of negative relaparotomies (63%). Therefore, the prediction model was incorporated in a decision rule were the interval until re-assessment and the use of Computed Tomography are related to the outcome of the model.
To construct a prediction model that will provide a definite answer whether or not to perform a relaparotomy seems a utopia. However, our prediction model can be used to stratify patients on their underlying risk and could guide further monitoring of patients with abdominal sepsis in order to identify patients with suspected ongoing peritonitis in a timely fashion.
PMCID: PMC3750491  PMID: 23870702
Secondary peritonitis; Abdominal sepsis; Relaparotomy; On-demand; Prediction model; Decision rule
6.  Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial 
BMC Gastroenterology  2013;13:49.
In current practice, patients with chronic pancreatitis undergo surgical intervention in a late stage of the disease, when conservative treatment and endoscopic interventions have failed. Recent evidence suggests that surgical intervention early on in the disease benefits patients in terms of better pain control and preservation of pancreatic function. Therefore, we designed a randomized controlled trial to evaluate the benefits, risks and costs of early surgical intervention compared to the current stepwise practice for chronic pancreatitis.
The ESCAPE trial is a randomized controlled, parallel, superiority multicenter trial. Patients with chronic pancreatitis, a dilated pancreatic duct (≥ 5 mm) and moderate pain and/or frequent flare-ups will be registered and followed monthly as potential candidates for the trial. When a registered patient meets the randomization criteria (i.e. need for opioid analgesics) the patient will be randomized to either early surgical intervention (group A) or optimal current step-up practice (group B). An expert panel of chronic pancreatitis specialists will oversee the assessment of eligibility and ensure that allocation to either treatment arm is possible. Patients in group A will undergo pancreaticojejunostomy or a Frey-procedure in case of an enlarged pancreatic head (≥ 4 cm). Patients in group B will undergo a step-up practice of optimal medical treatment, if needed followed by endoscopic interventions, and if needed followed by surgery, according to predefined criteria. Primary outcome is pain assessed with the Izbicki pain score during a follow-up of 18 months. Secondary outcomes include complications, mortality, total direct and indirect costs, quality of life, pancreatic insufficiency, alternative pain scales, length of hospital admission, number of interventions and pancreatitis flare-ups. For the sample size calculation we defined a minimal clinically relevant difference in the primary endpoint as a difference of at least 15 points on the Izbicki pain score during follow-up. To detect this difference a total of 88 patients will be randomized (alpha 0.05, power 90%, drop-out 10%).
The ESCAPE trial will investigate whether early surgery in chronic pancreatitis is beneficial in terms of pain relief, pancreatic function and quality of life, compared with current step-up practice.
Trial registration
PMCID: PMC3610165  PMID: 23506415
Chronic pancreatitis; Pain; Surgical management; Surgery; Endoscopic treatment; Endoscopy; ERCP; Opioid; Pancreaticojejunostomy; Frey procedure
7.  Pancreatitis of biliary origin, optimal timing of cholecystectomy (PONCHO trial): study protocol for a randomized controlled trial 
Trials  2012;13:225.
After an initial attack of biliary pancreatitis, cholecystectomy minimizes the risk of recurrent biliary pancreatitis and other gallstone-related complications. Guidelines advocate performing cholecystectomy within 2 to 4 weeks after discharge for mild biliary pancreatitis. During this waiting period, the patient is at risk of recurrent biliary events. In current clinical practice, surgeons usually postpone cholecystectomy for 6 weeks due to a perceived risk of a more difficult dissection in the early days following pancreatitis and for logistical reasons. We hypothesize that early laparoscopic cholecystectomy minimizes the risk of recurrent biliary pancreatitis or other complications of gallstone disease in patients with mild biliary pancreatitis without increasing the difficulty of dissection and the surgical complication rate compared with interval laparoscopic cholecystectomy.
PONCHO is a randomized controlled, parallel-group, assessor-blinded, superiority multicenter trial. Patients are randomly allocated to undergo early laparoscopic cholecystectomy, within 72 hours after randomization, or interval laparoscopic cholecystectomy, 25 to 30 days after randomization. During a 30-month period, 266 patients will be enrolled from 18 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite endpoint of mortality and acute re-admissions for biliary events (that is, recurrent biliary pancreatitis, acute cholecystitis, symptomatic/obstructive choledocholithiasis requiring endoscopic retrograde cholangiopancreaticography including cholangitis (with/without endoscopic sphincterotomy), and uncomplicated biliary colics) occurring within 6 months following randomization. Secondary endpoints include the individual endpoints of the composite endpoint, surgical and other complications, technical difficulty of cholecystectomy and costs.
The PONCHO trial is designed to show that early laparoscopic cholecystectomy (within 72 hours) reduces the combined endpoint of mortality and re-admissions for biliary events as compared with interval laparoscopic cholecystectomy (between 25 and 30 days) after recovery of a first episode of mild biliary pancreatitis.
Trial registration
Current Controlled Trials: ISRCTN72764151
PMCID: PMC3517749  PMID: 23181667
Acute pancreatitis; Gallstones; Trial; Common bile duct; Cholecystitis; Endoscopic retrograde cholangiopancreaticography; Surgery; Cholecystectomy; Timing; Mortality
8.  Plain abdominal radiography in acute abdominal pain; past, present, and future 
Several studies have demonstrated that a diagnosis based solely on a patient’s medical history, physical examination, and laboratory tests is not reliable enough, despite the fact that these aspects are essential parts of the workup of a patient presenting with acute abdominal pain. Traditionally, imaging workup starts with abdominal radiography. However, numerous studies have demonstrated low sensitivity and accuracy for plain abdominal radiography in the evaluation of acute abdominal pain as well as various specific diseases such as perforated viscus, bowel obstruction, ingested foreign body, and ureteral stones. Computed tomography, and in particular computed tomography after negative ultrasonography, provides a better workup than plain abdominal radiography alone. The benefits of computed tomography lie in decision-making for management, planning of a surgical strategy, and possibly even avoidance of negative laparotomies. Based on abundant available evidence, major advances in diagnostic imaging, and changes in the management of certain diseases, we can conclude that there is no place for plain abdominal radiography in the workup of adult patients with acute abdominal pain presenting in the emergency department in current practice.
PMCID: PMC3396109  PMID: 22807640
abdominal x-ray; acute abdomen; acute abdominal pain; emergency department; diagnostic imaging; abdominal radiography
9.  A Checklist to Improve Patient Safety in Interventional Radiology 
To develop a specific RADiological Patient Safety System (RADPASS) checklist for interventional radiology and to assess the effect of this checklist on health care processes of radiological interventions.
Materials and Methods
On the basis of available literature and expert opinion, a prototype checklist was developed. The checklist was adapted on the basis of observation of daily practice in a tertiary referral centre and evaluation by users. To assess the effect of RADPASS, in a series of radiological interventions, all deviations from optimal care were registered before and after implementation of the checklist. In addition, the checklist and its use were evaluated by interviewing all users.
The RADPASS checklist has two parts: A (Planning and Preparation) and B (Procedure). The latter part comprises checks just before starting a procedure (B1) and checks concerning the postprocedural care immediately after completion of the procedure (B2). Two cohorts of, respectively, 94 and 101 radiological interventions were observed; the mean percentage of deviations of the optimal process per intervention decreased from 24 % before implementation to 5 % after implementation (p < 0.001). Postponements and cancellations of interventions decreased from 10 % before implementation to 0 % after implementation. Most users agreed that the checklist was user-friendly and increased patient safety awareness and efficiency.
The first validated patient safety checklist for interventional radiology was developed. The use of the RADPASS checklist reduced deviations from the optimal process by three quarters and was associated with less procedure postponements.
PMCID: PMC3595473  PMID: 22562482
Checklist; Interventional radiology; Patient safety
10.  Failure of available scoring systems to predict ongoing infection in patients with abdominal sepsis after their initial emergency laparotomy 
BMC Surgery  2011;11:38.
To examine commonly used scoring systems, designed to predict overall outcome in critically ill patients, for their ability to select patients with an abdominal sepsis that have ongoing infection needing relaparotomy.
Data from a RCT comparing two surgical strategies was used. The study population consisted of 221 patients at risk for ongoing abdominal infection. The following scoring systems were evaluated with logistic regression analysis for their ability to select patients requiring a relaparotomy: APACHE-II score, SAPS-II, Mannheim Peritonitis Index (MPI), MODS, SOFA score, and the acute part of the APACHE-II score (APS).
The proportion of patients requiring a relaparotomy was 32% (71/221). Only 2 scores had a discriminatory ability in identifying patients with ongoing infection needing relaparotomy above chance: the APS on day 1 (AUC 0.61; 95%CI 0.52-0.69) and the SOFA score on day 2 (AUC 0.60; 95%CI 0.52-0.69). However, to correctly identify 90% of all patients needing a relaparotomy would require such a low cut-off value that around 80% of all patients identified by these scoring systems would have negative findings at relaparotomy.
None of the widely-used scoring systems to predict overall outcome in critically ill patients are of clinical value for the identification of patients with ongoing infection needing relaparotomy. There is a need to develop more specific tools to assist physicians in their daily monitoring and selection of these patients after the initial emergency laparotomy.
Trial registration number
PMCID: PMC3268736  PMID: 22196238
11.  A systematic review of high-fibre dietary therapy in diverticular disease 
The exact pathogenesis of diverticular disease of the sigmoid colon is not well established. However, the hypothesis that a low-fibre diet may result in diverticulosis and a high-fibre diet will prevent symptoms or complications of diverticular disease is widely accepted. The aim of this review is to assess whether a high-fibre diet can improve symptoms and/or prevent complications of diverticular disease of the sigmoid colon and/or prevent recurrent diverticulitis after a primary episode.
Clinical studies were eligible for inclusion if they assessed the treatment of diverticular disease or the prevention of recurrent diverticulitis with a high-fibre diet. The following exclusion criteria were used for study selection: studies without comparison of the patient group with a control group.
No studies concerning prevention of recurrent diverticulitis with a high-fibre diet met our inclusion criteria. Three randomised controlled trials (RCT) and one case–control study were included in this systematic review. One RCT of moderate quality showed no difference in the primary endpoints. A second RCT of moderate quality and the case–control study found a significant difference in favour of a high-fibre diet in the treatment of symptomatic diverticular disease. The third RCT of moderate quality found a significant difference in favour of methylcellulose (fibre supplement). This study also showed a placebo effect.
High-quality evidence for a high-fibre diet in the treatment of diverticular disease is lacking, and most recommendations are based on inconsistent level 2 and mostly level 3 evidence. Nevertheless, high-fibre diet is still recommended in several guidelines.
PMCID: PMC3308000  PMID: 21922199
High-fibre dietary therapy; Diverticular disease; Sigmoid colon
12.  Activation of factor VII-activating protease in human inflammation: a sensor for cell death 
Critical Care  2011;15(2):R110.
Cell death is a central event in the pathogenesis of sepsis and is reflected by circulating nucleosomes. Circulating nucleosomes were suggested to play an important role in inflammation and were demonstrated to correlate with severity and outcome in sepsis patients. We recently showed that plasma can release nucleosomes from late apoptotic cells. Factor VII-activating protease (FSAP) was identified to be the plasma serine protease responsible for nucleosome release. The aim of this study was to investigate FSAP activation in patients suffering from various inflammatory diseases of increasing severity.
We developed ELISAs to measure FSAP-C1-inhibitor and FSAP-α2-antiplasmin complexes in plasma. FSAP-inhibitor complexes were measured in the plasma of 20 adult patients undergoing transhiatal esophagectomy, 32 adult patients suffering from severe sepsis and 8 from septic shock and 38 children suffering from meningococcal sepsis.
We demonstrate plasma FSAP to be activated upon contact with apoptotic and necrotic cells by an assay detecting complexes between FSAP and its target serpins α2-antiplasmin and C1-inhibitor, respectively. By means of that assay we demonstrate FSAP activation in post-surgery patients, patients suffering from severe sepsis, septic shock and meningococcal sepsis. Levels of FSAP-inhibitor complexes correlate with nucleosome levels and correlate with severity and mortality in these patients.
These results suggest FSAP activation to be a sensor for cell death in the circulation and that FSAP activation in sepsis might be involved in nucleosome release, thereby contributing to lethality.
PMCID: PMC3219388  PMID: 21466697
13.  Pancreatitis, very early compared with normal start of enteral feeding (PYTHON trial): design and rationale of a randomised controlled multicenter trial 
Trials  2011;12:73.
In predicted severe acute pancreatitis, infections have a negative effect on clinical outcome. A start of enteral nutrition (EN) within 24 hours of onset may reduce the number of infections as compared to the current practice of starting an oral diet and EN if necessary at 3-4 days after admission.
The PYTHON trial is a randomised controlled, parallel-group, superiority multicenter trial. Patients with predicted severe acute pancreatitis (Imrie-score ≥ 3 or APACHE-II score ≥ 8 or CRP > 150 mg/L) will be randomised to EN within 24 hours or an oral diet and EN if necessary, after 72 hours after hospital admission.
During a 3-year period, 208 patients will be enrolled from 20 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of mortality or infections (bacteraemia, infected pancreatic or peripancreatic necrosis, pneumonia) during hospital stay or within 6 months following randomisation. Secondary endpoints include other major morbidity (e.g. new onset organ failure, need for intervention), intolerance of enteral feeding and total costs from a societal perspective.
The PYTHON trial is designed to show that a very early (< 24 h) start of EN reduces the combined endpoint of mortality or infections as compared to the current practice of an oral diet and EN if necessary at around 72 hours after admission for predicted severe acute pancreatitis.
Trial Registration
PMCID: PMC3068962  PMID: 21392395
14.  Cost-effectiveness of ward-based pharmacy care in surgical patients: protocol of the SUREPILL (Surgery & Pharmacy In Liaison) study 
Preventable adverse drug events (pADEs) are widely known to be a health care issue for hospitalized patients. Surgical patients are especially at risk, but prevention of pADEs in this population is not demonstrated before. Ward-based pharmacy interventions seem effective in reducing pADEs in medical patients. The cost-effectiveness of these preventive efforts still needs to be assessed in a comparative study of high methodological standard and also in the surgical population. For these aims the SUREPILL (Surgery & Pharmacy in Liaison) study is initiated.
A multi-centre controlled trial, with randomisation at ward-level and preceding baseline assessments is designed. Patients admitted to the surgical study wards for elective surgery with an expected length of stay of more than 48 hours will be included. Patients admitted to the intervention ward, will receive ward-based pharmacy care from the clinical pharmacy team, i.e. pharmacy practitioners and hospital pharmacists. This ward-based pharmacy intervention includes medication reconciliation in consultation with the patient at admission, daily medication review with face-to-face contact with the ward doctor, and patient counselling at discharge. Patients admitted in the control ward, will receive standard pharmaceutical care.
The primary clinical outcome measure is the number of pADEs per 100 elective admissions. These pADEs will be measured by systematic patient record evaluation using a trigger tool. Patient records positive for a trigger will be evaluated on causality, severity and preventability by an independent expert panel. In addition, an economic evaluation will be performed from a societal perspective with the costs per preventable ADE as the primary economic outcome. Other outcomes of this study are: severity of pADEs, number of patients with pADEs per total number of admissions, direct (non-)medical costs and indirect non-medical costs, extra costs per prevented ADE, number and type of pharmacy interventions, length of hospital stay, complications registered in a national complication registration system for surgery, number of readmissions within three months after initial admission (follow-up), quality of life and number of non-institutionalized days during follow-up.
This study will assess the cost-effectiveness of ward-based pharmacy care on preventable adverse drug events in surgical patients from a societal perspective, using a comparative study design.
Trial registration
Netherlands Trial Register (NTR): NTR2258
PMCID: PMC3059300  PMID: 21385352
15.  A comparison of the Accuracy of Ultrasound and Computed Tomography in common diagnoses causing acute abdominal pain 
European Radiology  2011;21(7):1535-1545.
Head-to-head comparison of ultrasound and CT accuracy in common diagnoses causing acute abdominal pain.
Materials and methods
Consecutive patients with abdominal pain for >2 h and <5 days referred for imaging underwent both US and CT by different radiologists/radiological residents. An expert panel assigned a final diagnosis. Ultrasound and CT sensitivity and predictive values were calculated for frequent final diagnoses. Effect of patient characteristics and observer experience on ultrasound sensitivity was studied.
Frequent final diagnoses in the 1,021 patients (mean age 47; 55% female) were appendicitis (284; 28%), diverticulitis (118; 12%) and cholecystitis (52; 5%). The sensitivity of CT in detecting appendicitis and diverticulitis was significantly higher than that of ultrasound: 94% versus 76% (p < 0.01) and 81% versus 61% (p = 0.048), respectively. For cholecystitis, the sensitivity of both was 73% (p = 1.00). Positive predictive values did not differ significantly between ultrasound and CT for these conditions. Ultrasound sensitivity in detecting appendicitis and diverticulitis was not significantly negatively affected by patient characteristics or reader experience.
CT misses fewer cases than ultrasound, but both ultrasound and CT can reliably detect common diagnoses causing acute abdominal pain. Ultrasound sensitivity was largely not influenced by patient characteristics and reader experience.
PMCID: PMC3101356  PMID: 21365197
Acute abdominal pain; Computed tomography; Ultrasound; Appendicitis; Emergency Department
16.  Optimizing imaging in suspected appendicitis (OPTIMAP-study): A multicenter diagnostic accuracy study of MRI in patients with suspected acute appendicitis. Study Protocol 
In patients with clinically suspected appendicitis, imaging is needed to substantiate the clinical diagnosis. Imaging accuracy of ultrasonography (US) is suboptimal, while the most accurate technique (CT) is associated with cancer related deaths through exposure to ionizing radiation. MRI is a potential replacement, without associated ionizing radiation and no need for contrast medium administration. If MRI is proven to be sufficiently accurate, it could be introduced in the diagnostic pathway of patients with suspected appendicitis, increasing diagnostic accuracy and improving clinical outcomes, without the risk of radiation induced cancer or iodinated contrast medium-related drawbacks. The multicenter OPTIMAP study was designed to estimate the diagnostic accuracy of MRI in patients with suspected acute appendicitis in the general population.
Eligible for this study are consecutive patients presenting with clinically suspected appendicitis at the emergency department in six centers. All patients will undergo imaging according to the Dutch guideline for acute appendicitis: initial ultrasonography in all and subsequent CT whenever US does not confirm acute appendicitis. Then MRI is performed in all patients, but the results are not used for patient management. A final diagnosis assigned by an expert panel, based on all available information including 3-months follow-up, except MRI findings, is used as the reference standard in estimating accuracy. We will calculate the sensitivity, specificity, predictive values and inter-observer agreement of MRI, and aim to include 230 patients. Patient acceptance and total imaging costs will also be evaluated.
If MRI is found to be sufficiently accurate, it could replace CT in some or all patients. This will limit or obviate the ionizing radiation exposure associated risk of cancer induction and contrast medium induced nephropathy with CT, preventing the burden and the direct and indirect costs associated with treatment. Based on the high intrinsic contrast resolution of MRI, one might envision higher accuracy rates for MRI than for CT. If so, MRI could further decrease the number of unnecessary appendectomies and the number of missed appendicitis cases.
Trial registration
PMCID: PMC2978143  PMID: 20961412
17.  A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial) 
BMC Surgery  2010;10:23.
Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects.
A randomized multicenter pragmatic clinical trial comparing two treatment strategies for uncomplicated acute diverticulitis. I) A conservative strategy with antibiotics: hospital admission, supportive measures and at least 48 hours of intravenous antibiotics which subsequently are switched to oral, if tolerated (for a total duration of antibiotic treatment of 10 days). II) A liberal strategy without antibiotics: admission only if needed on clinical grounds, supportive measures only. Patients are eligible for inclusion if they have a diagnosis of acute uncomplicated diverticulitis as demonstrated by radiological imaging. Only patients with stages 1a and 1b according to Hinchey's classification or "mild" diverticulitis according to the Ambrosetti criteria are included. The primary endpoint is time-to-full recovery within a 6-month follow-up period. Full recovery is defined as being discharged from the hospital, with a return to pre-illness activities, and VAS score below 4 without the use of daily pain medication. Secondary endpoints are proportion of patients who develop complicated diverticulitis requiring surgery or non-surgical intervention, morbidity, costs, health-related quality of life, readmission rate and acute diverticulitis recurrence rate. In a non-inferiority design 264 patients are needed in each study arm to detect a difference in time-to-full recovery of 5 days or more with a power of 85% and a confidence level of 95%. With an estimated one percent of patients lost to follow up, a total of 533 patients will be included.
A clinically relevant difference of more than 5 days in time-to-full recovery between the two treatment strategies is not expected. The liberal strategy without antibiotics and without the strict requirement for hospital admission is anticipated to be more a more cost-effective approach.
Trial registration
Trial registration number: NCT01111253
PMCID: PMC2919453  PMID: 20646266
18.  Costs of relaparotomy on-demand versus planned relaparotomy in patients with severe peritonitis: an economic evaluation within a randomized controlled trial 
Critical Care  2010;14(3):R97.
Results of the first randomized trial comparing on-demand versus planned-relaparotomy strategy in patients with severe peritonitis (RELAP trial) indicated no clear differences in primary outcomes. We now report the full economic evaluation for this trial, including detailed methods, nonmedical costs, further differentiated cost calculations, and robustness of different assumptions in sensitivity analyses.
An economic evaluation was conducted from a societal perspective alongside a randomized controlled trial in 229 patients with severe secondary peritonitis and an acute physiology and chronic health evaluation (APACHE)-II score ≥11 from two academic and five regional teaching hospitals in the Netherlands. After the index laparotomy, patients were randomly allocated to an on-demand or a planned-relaparotomy strategy. Primary resource-utilization data were used to estimate mean total costs per patient during the index admission and after discharge until 1 year after the index operation. Overall differences in costs between the on-demand relaparotomy strategy and the planned strategy, as well as relative differences across several clinical subgroups, were evaluated.
Costs were substantially lower in the on-demand group (mean, €65,768 versus €83,450 per patient in the planned group; mean absolute difference, €17,682; 95% CI, €5,062 to €29,004). Relative differences in mean total costs per patient (approximately 21%) were robust to various alternative assumptions. Planned relaparotomy consistently generated more costs across the whole range of different courses of disease (quick recovery and few resources used on one end of the spectrum; slow recovery and many resources used on the other end). This difference in costs between the two surgical strategies also did not vary significantly across several clinical subgroups.
The reduction in societal costs renders the on-demand strategy a more-efficient relaparotomy strategy in patients with severe peritonitis. These differences were found across the full range of healthcare resources as well as across patients with different courses of disease.
Trial Registration
PMCID: PMC2911734  PMID: 20507557
19.  The SURgical PAtient Safety System (SURPASS) checklist optimizes timing of antibiotic prophylaxis 
Surgical site infection (SSI) is an adverse event in which a close relation between process of care and outcome has been demonstrated: administration of antibiotic prophylaxis decreases the risk of SSI. In our tertiary referral centre, a SURgical PAtient Safety System (SURPASS) checklist was developed and implemented. This multidisciplinary checklist covers the entire surgical pathway and includes, among other items, administration of antibiotic prophylaxis before induction of anaesthesia. The aim of this study was to determine the effect of SURPASS implementation on timing of antibiotic prophylaxis.
A retrospective analysis was performed on two cohorts of patients: one cohort of surgical patients that underwent surgery before implementation of the checklist and a comparable cohort after implementation. The interval between administration of antibiotic prophylaxis and incision was compared between the two cohorts.
A total of 772 surgical procedures were included. More than half of procedures were gastro-intestinal; others were vascular, trauma and hernia repair procedures. After implementation, the checklist was used in 81.4% of procedures. The interval between administration of antibiotic prophylaxis and incision increased from 23.9 minutes before implementation of SURPASS to 29.9 minutes after implementation (p = 0.047). In procedures where the checklist was used, the interval increased to 32.9 minutes (p = 0.004). The proportion of patients that did not receive antibiotics until after the incision decreased significantly.
The use of the SURPASS checklist leads to better compliance with regard to the timing of antibiotic prophylaxis administration.
PMCID: PMC2867812  PMID: 20388204
20.  Mannose-Binding Lectin Deficiency Facilitates Abdominal Candida Infections in Patients with Secondary Peritonitis▿  
Mannose-binding lectin (MBL) deficiency due to variations in the MBL gene is associated with increased susceptibility to infections. In this study, the association between MBL deficiency and the occurrence of abdominal yeast infection (AYI) in peritonitis patients was examined. Eighty-eight patients with secondary peritonitis requiring emergency laparotomy were included. MBL genotype (wild type [WT] versus patients with variant genotypes), MBL plasma concentrations, and Candida risk factors were examined in patients with and those without AYI (positive abdominal yeast cultures during [re]laparotomy). A variant MBL genotype was found in 53% of patients with AYI and 38% of those without AYI (P = 0.18). A significantly higher proportion of variant patients had an AYI during early peritonitis (during first laparotomy) than WT patients (39% versus 16%, respectively; P = 0.012). Patients with AYI had lower MBL levels than did patients without AYI (0.16 μg/ml [0.0 to 0.65 μg/ml] versus 0.65 μg/ml (0.19 to 1.95 μg/ml); P = 0.007). Intensity of colonization (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.0 to 1.1), MBL plasma concentrations of <0.5 μg/ml (OR, 4.5; 95% CI, 1.2 to 16.3), and numbers of relaparotomies (OR, 1.7; 95% CI, 1.0 to 2.8) were independently associated with AYI. In summary, deficient MBL plasma levels were independently associated with the development of AYI in patients with secondary peritonitis and seemed to facilitate early infection.
PMCID: PMC2223851  PMID: 17978009
21.  Factors associated with posttraumatic stress symptoms in a prospective cohort of patients after abdominal sepsis: a nomogram 
Intensive Care Medicine  2008;34(4):664-674.
To determine to what extent patients who have survived abdominal sepsis suffer from symptoms of posttraumatic stress disorder (PTSD) and depression, and to identify potential risk factors for PTSD symptoms.
Design and setting
PTSD and depression symptoms were measured using the Impact of Events Scale–Revised (IES-R), the Post-Traumatic Symptom Scale 10 (PTSS-10) and the Beck Depression Inventory II (BDI-II).
Patients and participants
A total of 135 peritonitis patients were eligible for this study, of whom 107 (80%) patients completed the questionnaire. The median APACHE-II score was 14 (range 12–16), and 89% were admitted to the ICU.
Measurements and results
The proportion of patients with “moderate” PTSD symptom scores was 28% (95% CI 20–37), whilst 10% (95% CI 6–17) of patients had “high” PTSD symptom scores. Only 5% (95% CI 2–12) of the patients expressed severe depression symptoms. Factors associated with increased PTSD symptoms in a multivariate ordinal regression model were younger age (0.74 per 10 years older, p = 0.082), length of ICU stay (OR = 1.4 per doubling of duration, p = 0.003) and having some (OR = 4.9, p = 0.06) or many (OR = 55.5, p < 0.001) traumatic memories of the ICU or hospital stay.
As many as 38% of patients after abdominal sepsis report elevated levels of PTSD symptoms on at least one of the questionnaires. Our nomogram may assist in identifying patients at increased risk for developing symptoms of PTSD.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-007-0941-3) contains supplementary material, which is available to authorized users.
PMCID: PMC2271079  PMID: 18197398
Peritonitis; Sepsis; Posttraumatic stress disorder; PTSD; Depression; Intensive care; IES-R; PTSS-10; BDI-II
22.  Single-drug therapy or selective decontamination of the digestive tract as antifungal prophylaxis in critically ill patients: a systematic review 
Critical Care  2007;11(6):R126.
The objective of this study was to determine and compare the effectiveness of different prophylactic antifungal therapies in critically ill patients on the incidence of yeast colonisation, infection, candidemia, and hospital mortality.
A systematic review was conducted of prospective trials including adult non-neutropenic patients, comparing single-drug antifungal prophylaxis (SAP) or selective decontamination of the digestive tract (SDD) with controls and with each other.
Thirty-three studies were included (11 SAP and 22 SDD; 5,529 patients). Compared with control groups, both SAP and SDD reduced the incidence of yeast colonisation (SAP: odds ratio [OR] 0.38, 95% confidence interval [CI] 0.20 to 0.70; SDD: OR 0.12, 95% CI 0.05 to 0.29) and infection (SAP: OR 0.54, 95% CI 0.39 to 0.75; SDD: OR 0.29, 95% CI 0.18 to 0.45). Treatment effects were significantly larger in SDD trials than in SAP trials. The incidence of candidemia was reduced by SAP (OR 0.32, 95% CI 0.12 to 0.82) but not by SDD (OR 0.59, 95% CI 0.25 to 1.40). In-hospital mortality was reduced predominantly by SDD (OR 0.73, 95% CI 0.59 to 0.93, numbers needed to treat 15; SAP: OR 0.80, 95% CI 0.64 to 1.00). Effectiveness of prophylaxis reduced with an increased proportion of included surgical patients.
Antifungal prophylaxis (SAP or SDD) is effective in reducing yeast colonisation and infections across a range of critically ill patients. Indirect comparisons suggest that SDD is more effective in reducing yeast-related outcomes, except for candidemia.
PMCID: PMC2246222  PMID: 18067657
23.  Optimization of diagnostic imaging use in patients with acute abdominal pain (OPTIMA): Design and rationale 
The acute abdomen is a frequent entity at the Emergency Department (ED), which usually needs rapid and accurate diagnostic work-up. Diagnostic work-up with imaging can consist of plain X-ray, ultrasonography (US), computed tomography (CT) and even diagnostic laparoscopy. However, no evidence-based guidelines exist in current literature. The actual diagnostic work-up of a patient with acute abdominal pain presenting to the ED varies greatly between hospitals and physicians. The OPTIMA study was designed to provide the evidence base for constructing an optimal diagnostic imaging guideline for patients with acute abdominal pain at the ED.
Thousand consecutive patients with abdominal pain > 2 hours and < 5 days will be enrolled in this multicentre trial. After clinical history, physical and laboratory examination all patients will undergo a diagnostic imaging protocol, consisting of plain X-ray (upright chest and supine abdomen), US and CT. The reference standard will be a post hoc assignment of the final diagnosis by an expert panel. The focus of the analysis will be on the added value of the imaging modalities over history and clinical examination, relative to the incremental costs.
This study aims to provide the evidence base for the development of a diagnostic algorithm that can act as a guideline for ED physicians to evaluate patients with acute abdominal pain.
PMCID: PMC1976317  PMID: 17683592
24.  Health related quality of life six months following surgical treatment for secondary peritonitis – using the EQ-5D questionnaire 
To compare health related quality of life (HR-QoL) in patients surgically treated for secondary peritonitis to that of a healthy population. And to prospectively identify factors associated with poorer (lower) HR-QoL.
A prospective cohort of secondary peritonitis patients was mailed the EQ-5D and EQ-VAS 6-months following initial laparotomy.
Multicenter study in two academic and seven regional teaching hospitals.
130 of the 155 eligible patients (84%) responded to the HR-QoL questionnaires.
HR-QoL was significantly worse on all dimensions in peritonitis patients than in a healthy reference population. Peritonitis characteristics at initial presentation were not associated with HR-QoL at six months. A more complicated course of the disease leading to longer hospitalization times and patients with an enterostomy had a negative impact on the mobility (p = 0.02), self-care (p < 0.001) and daily activities: (p = 0.01). In a multivariate analysis for the EQ-VAS every doubling of hospital stay decreases the EQ-VAS by 3.8 points (p = 0.015). Morbidity during the six-month follow-up was not found to be predictive for the EQ-5D or EQ-VAS.
Six months following initial surgery, patients with secondary peritonitis report more problems in HR-QoL than a healthy reference population. Unfavorable disease characteristics at initial presentation were not predictive for poorer HR-QoL, but a more complicated course of the disease was most predictive of HR-QoL at 6 months.
PMCID: PMC1950493  PMID: 17601343
25.  Long-term prevalence of post-traumatic stress disorder symptoms in patients after secondary peritonitis 
Critical Care  2007;11(1):R30.
The aim of this study was to determine the long-term prevalence of post-traumatic stress disorder (PTSD) symptomology in patients following secondary peritonitis and to determine whether the prevalence of PTSD-related symptoms differed between patients admitted to the intensive care unit (ICU) and patients admitted only to the surgical ward.
A retrospective cohort of consecutive patients treated for secondary peritonitis was sent a postal survey containing a self-report questionnaire, namely the Post-traumatic Stress Syndrome 10-question inventory (PTSS-10). From a database of 278 patients undergoing surgery for secondary peritonitis between 1994 and 2000, 131 patients were long-term survivors (follow-up period at least four years) and were eligible for inclusion in our study, conducted at a tertiary referral hospital in Amsterdam, The Netherlands.
The response rate was 86%, yielding a cohort of 100 patients; 61% of these patients had been admitted to the ICU. PTSD-related symptoms were found in 24% (95% confidence interval 17% to 33%) of patients when a PTSS-10 score of 35 was chosen as the cutoff, whereas the prevalence of PTSD symptomology when borderline patients scoring 27 points or more were included was 38% (95% confidence interval 29% to 48%). In a multivariate analyses controlling for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, number of relaparotomies and length of hospital stay, the likelihood of ICU-admitted patients having PTSD symptomology was 4.3 times higher (95% confidence interval 1.11 to 16.5) than patients not admitted to the ICU, using a PTSS-10 score cutoff of 35 or greater. Older patients and males were less likely to report PTSD symptoms.
Nearly a quarter of patients receiving surgical treatment for secondary peritonitis developed PTSD symptoms. Patients admitted to the ICU were at significantly greater risk for having PTSD symptoms after adjusting for baseline differences, in particular age.
PMCID: PMC2151910  PMID: 17319937

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