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1.  Preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE): study protocol for a randomized controlled trial 
Trials  2015;16:389.
Preventive nebulization of mucolytic agents and bronchodilating drugs is a strategy aimed at the prevention of sputum plugging, and therefore atelectasis and pneumonia, in intubated and ventilated intensive care unit (ICU) patients. The present trial aims to compare a strategy using the preventive nebulization of acetylcysteine and salbutamol with nebulization on indication in intubated and ventilated ICU patients.
The preventive nebulization of mucolytic agents and bronchodilating drugs in invasively ventilated intensive care unit patients (NEBULAE) trial is a national multicenter open-label, two-armed, randomized controlled non-inferiority trial in the Netherlands. Nine hundred and fifty intubated and ventilated ICU patients with an anticipated duration of invasive ventilation of more than 24 hours will be randomly assigned to receive either a strategy consisting of preventive nebulization of acetylcysteine and salbutamol or a strategy consisting of nebulization of acetylcysteine and/or salbutamol on indication. The primary endpoint is the number of ventilator-free days and surviving on day 28. Secondary endpoints include ICU and hospital length of stay, ICU and hospital mortality, the occurrence of predefined pulmonary complications (acute respiratory distress syndrome, pneumonia, large atelectasis and pneumothorax), and the occurrence of predefined side effects of the intervention. Related healthcare costs will be estimated in a cost-benefit and budget-impact analysis.
The NEBULAE trial is the first randomized controlled trial powered to investigate whether preventive nebulization of acetylcysteine and salbutamol shortens the duration of ventilation in critically ill patients.
Trial registration
NCT02159196, registered on 6 June 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0865-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4557315  PMID: 26329352
Mechanical ventilation; Nebulization; Intensive care unit; Critical care; Aerosol therapy; Mucolytic agents; Bronchodilators; Acetylcysteine; Salbutamol
2.  The Development of a Clinical Screening Instrument For Tumour Predisposition Syndromes In Childhood Cancer Patients 
Identification of tumour predisposition syndromes in patients who have cancer in childhood is paramount for optimal care. A screening instrument that can help to identify such patients will facilitate physicians caring for children with cancer. The complete screening instrument should consist of a standardized series of pictures and a screening form for manifestations not visible in the pictures. Here we describe the development of such a screening form based on an international two-stage Delphi process and an initial validation of the complete instrument.
Patients and Methods
We identified manifestations that may contribute to the diagnosis of a tumour predisposition syndrome through the Winter-Baraitser Dysmorphology Database and the textbook “Gorlin's Syndromes of the Head and Neck”. In a two-round Delphi process, eight international content-experts scored the contribution of each of these manifestations. We performed a clinical validation of the instrument in a selected cohort of ten paediatric cancer patients from another centre.
In total, 49 manifestations were found to contribute to the diagnosis of a tumour predisposition syndrome and were included in the screening form. The pilot validation study showed that patients suspect for having a tumour predisposition syndrome were recognized. Excellent correlation for indication for referral of a patient between the screening instrument and the reference standard (personal evaluation by an experienced clinical geneticist) was found.).
The Delphi process performed by international specialists with a function as opinion leaders in their field of expertise has led to a screening form and instrument with which those childhood cancer patients can be identified who may have a tumour predisposition syndrome and thus have an indication to be referred for further genetic analysis.
PMCID: PMC4277698  PMID: 23855994
Paediatric oncology; childhood cancer; screening instrument; tumour predisposition syndromes; Delphi process; questionnaires
3.  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
4.  Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study 
BMJ : British Medical Journal  2006;332(7554):1355.
Objective To compare the effectiveness of discontinuing treatment with amoxicillin after three days or eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment.
Design Randomised, double blind, placebo controlled non-inferiority trial.
Setting Nine secondary and tertiary care hospitals in the Netherlands.
Participants Adults with mild to moderate-severe community acquired pneumonia (pneumonia severity index score ≤ 110).
Interventions Patients who had substantially improved after three days' treatment with intravenous amoxicillin were randomly assigned to oral amoxicillin (n = 63) or placebo (n = 56) three times daily for five days.
Main outcome measures The primary outcome measure was the clinical success rate at day 10. Secondary outcome measures were the clinical success rate at day 28, symptom resolution, radiological success rates at days 10 and 28, and adverse events.
Results Baseline characteristics were comparable, with the exception of symptom severity, which was worse in the three day treatment group. In the three day and eight day treatment groups the clinical success rate at day 10 was 93% for both (difference 0.1%, 95% confidence interval - 9% to 10%) and at day 28 was 90% compared with 88% (difference 2.0%, - 9% to 15%). Both groups had similar resolution of symptoms. Radiological success rates were 86% compared with 83% at day 10 (difference 3%, - 10% to 16%) and 86% compared with 79% at day 28 (difference 6%, - 7% to 20%). Six patients (11%) in the placebo group and 13 patients (21%) in the active treatment group reported adverse events (P = 0.1).
Conclusions Discontinuing amoxicillin treatment after three days is not inferior to discontinuing it after eight days in adults admitted to hospital with mild to moderate-severe community acquired pneumonia who substantially improved after an initial three days' treatment.
PMCID: PMC1479094  PMID: 16763247
5.  Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials 
BMJ : British Medical Journal  2005;330(7503):1297.
Objective To determine the cost utility of medical co-prescription of heroin compared with methadone maintenance treatment for chronic, treatment resistant heroin addicts.
Design Cost utility analysis of two pooled open label randomised controlled trials.
Setting Methadone maintenance programmes in six cities in the Netherlands.
Participants 430 heroin addicts.
Interventions Inhalable or injectable heroin prescribed over 12 months. Methadone (maximum 150 mg a day) plus heroin (maximum 1000 mg a day) compared with methadone alone (maximum 150 mg a day). Psychosocial treatment was offered throughout.
Main outcome measures One year costs estimated from a societal perspective. Quality adjusted life years (QALYs) based on responses to the EuroQol EQ-5D at baseline and during the treatment period.
Results Co-prescription of heroin was associated with 0.058 more QALYs per patient per year (95% confidence interval 0.016 to 0.099) and a mean saving of €12 793 (£8793, $16 122) (€1083 to €25 229) per patient per year. The higher programme costs (€16 222; lower 95% confidence limit €15 084) were compensated for by lower costs of law enforcement (- €4129; upper 95% confidence limit - €486) and damage to victims of crime (- €25 374; upper 95% confidence limit - €16 625). The results were robust for the use of national EQ-5D tariffs and for the exclusion of the initial implementation costs of heroin treatment. Completion of treatment is essential; having participated in any abstinence treatment in the past is not.
Conclusions Co-prescription of heroin is cost effective compared with treatment with methadone alone for chronic, treatment resistant heroin addicts.
PMCID: PMC558200  PMID: 15933353
6.  Continuous Postoperative Pericardial Flushing: A Pilot Study on Safety, Feasibility, and Effect on Blood Loss 
EBioMedicine  2015;2(9):1217-1223.
Prolonged or excessive blood loss is a common complication after cardiac surgery. Blood remnants and clots, remaining in the pericardial space in spite of chest tube drainage, induce high fibrinolytic activity that may contribute to bleeding complications. Continuous postoperative pericardial flushing (CPPF) with an irrigation solution may reduce blood loss by preventing the accumulation of clots. In this pilot study, the safety and feasibility of CPPF were evaluated and the effect on blood loss and other related complications was investigated.
Between November 2011 and April 2012 twenty-one adult patients undergoing surgery for congenital heart disease (CHD) received CPPF from sternal closure up to 12 h postoperative. With an inflow Redivac drain that was inserted through one of the chest tube incision holes, an irrigation solution (NaCl 0.9% at 38 °C) was delivered to the pericardial cavity using a volume controlled flushing system. Safety aspects, feasibility issues and complications were registered. The mean actual blood loss in the CPPF group was compared to the mean of a retrospective group (n = 126).
CPPF was successfully completed in 20 (95.2%) patients, and no method related complications were observed. Feasibility was good in this experimental setting. Patients receiving CPPF showed a 30% (P = 0.038) decrease in mean actual blood loss 12 h postoperatively.
CPPF after cardiac surgery was found to be safe and feasible in this experimental setting. The clinically relevant effect on blood loss needs to be confirmed in a randomized clinical trial.
Graphical abstract
•This pilot study shows safety and feasibility of continuous postoperative pericardial flushing (CPPF) in experimental setting;•CPPF improves chest tube patency and postoperative drainage;•CPPF may reduce postoperative bleeding complications after cardiac surgery.
Continuous postoperative pericardial flushing (CPPF) has specifically been designed to promote the evacuation of contaminated blood and clots out of the pericardial cavity in order to reduce postoperative blood loss and other bleeding complications. To our knowledge, there is no literature available on techniques similar to CPPF after cardiac surgery. Current state of the art techniques to reduce blood loss after cardiac surgery all have different targets and/or time of action. Regardless of their effects, the use of CPPF is an additional improvement to the current state of the art. We report that CPPF is safe and feasible in the experimental setting that was used and that CPPF may reduce postoperative blood loss and bleeding complications. The 30% reduction of blood loss that we found in this pilot study needs to be confirmed in a randomized clinical trial.
PMCID: PMC4587997  PMID: 26501121
Continuous postoperative pericardial flushing; Therapeutic irrigation [mesh]; Pericardial cavity; Cardiac surgical procedures [mesh]; Thoracic surgery [mesh]; Postoperative hemorrhage [mesh]; Cardiac tamponade [mesh]; Chest tubes [mesh]

Results 1-6 (6)