ICONIC study-conservative versus conventional oxygenation targets in intensive care patients: study protocol for a randomized clinical trial.

BACKGROUND: Oxygen therapy is a widely used intervention in acutely ill patients in the intensive care unit (ICU). It is established that not only hypoxia, but also prolonged hyperoxia is associated with poor patient-centered outcomes. Nevertheless, a fundamental knowledge gap remains regarding optimal oxygenation for critically ill patients. In this randomized clinical trial, we aim to compare ventilation that uses conservative oxygenation targets with ventilation that uses conventional oxygen targets with respect to mortality in ICU patients. METHODS: The "ConservatIve versus CONventional oxygenation targets in Intensive Care patients" trial (ICONIC) is an investigator-initiated, international, multicenter, randomized clinical two-arm trial in ventilated adult ICU patients. The ICONIC trial will run in multiple ICUs in The Netherlands and Italy to enroll 1512 ventilated patients. ICU patients with an expected mechanical ventilation time of more than 24 h are randomized to a ventilation strategy that uses conservative (PaO2 55-80 mmHg (7.3-10.7 kPa)) or conventional (PaO2 110-150 mmHg (14.7-20 kPa)) oxygenation targets. The primary endpoint is 28-day mortality. Secondary endpoints are ventilator-free days at day 28, ICU mortality, in-hospital mortality, 90-day mortality, ICU- and hospital length of stay, ischemic events, quality of life, and patient opinion of research and consent in the emergency setting. DISCUSSION: The ICONIC trial is expected to provide evidence on the effects of conservative versus conventional oxygenation targets in the ICU population. This study may guide targeted oxygen therapy in the future. TRIAL REGISTRATION: Trialregister.nl NTR7376 . Registered on 20 July, 2018.

Attitudes of Dutch intensive care unit clinicians towards oxygen therapy.

BACKGROUND: Over the last decade, there has been an increasing awareness for the potential harm of the administration of too much oxygen. We aimed to describe self-reported attitudes towards oxygen therapy by clinicians from a large representative sample of intensive care units (ICUs) in the Netherlands. METHODS: In April 2019, 36 ICUs in the Netherlands were approached and asked to send out a questionnaire (59 questions) to their nursing and medical staff (ICU clinicians) eliciting self-reported behaviour and attitudes towards oxygen therapy in general and in specific ICU case scenarios. RESULTS: In total, 1361 ICU clinicians (71% nurses, 24% physicians) from 28 ICUs returned the questionnaire. Of responding ICU clinicians, 64% considered oxygen-induced lung injury to be a major concern. The majority of respondents considered a partial pressure of oxygen (PaO2) of 6-10 kPa (45-75 mmHg) and an arterial saturation (SaO2) of 85-90% as acceptable for 15 minutes, and a PaO2 7-10 kPa (53-75 mmHg) and SaO2 90-95% as acceptable for 24-48 hours in an acute respiratory distress syndrome (ARDS) patient. In most case scenarios, respondents reported not to change the fraction of inspired oxygen (FiO2) if SaO2 was 90-95% or PaO2 was 12 kPa (90 mmHg). CONCLUSION: A representative sample of ICU clinicians from the Netherlands were concerned about oxygen-induced lung injury, and reported that they preferred PaO2 and SaO2 targets in the lower physiological range and would adjust ventilation settings accordingly.

Systemic infection and microglia activation: a prospective postmortem study in sepsis patients.

BACKGROUND: Systemic infection is associated with long-term cognitive deficits and functional decline. In this study we hypothesized that severe systemic inflammation leads to a neuroinflammatory response that is characterized by microglial activation, and that these effects might be more pronounced in patients using medication with anticholinergic side-effects. METHODS: Based on the results of a pilot study in 8 patients, we assessed the number of MHC-II and CD-68 positive cells by immunohistochemistry and compared the number of microglia in specific brain regions of 16 well-characterized patients with septic shock and 15 controls. RESULTS: In the pilot study, patients with sepsis tended to have higher density of MHC-II and CD-68 positive microglia in the basal ganglia (putamen, caudate nucleus and globus pallidus) and of MHC-II positive microglia in the hippocampus. In the validation study, patients with sepsis had a significantly higher number of CD-68 positive cells in hippocampus (1.5 fold; p = 0.012), putamen (2.2 fold; p = 0.008) and cerebellum (2.5 fold; p = 0.011) than control patients. The density of MHC-II positive microglia was similar between sepsis and control groups. There was no consistent correlation between microglia counts and anti-cholinergic activity drugs score. CONCLUSION: In patients who die during septic shock, severe systemic inflammation is accompanied by localized and strong upregulation of CD-68 positive microglia, but not of MHC-II positive microglia. We identified regional differences in the brain with increased microglial activation in putamen, hippocampus and cerebellum.

Predictors of short-term and long-term mortality in critically ill patients admitted to the intensive care unit following allogeneic stem cell transplantation.

Historically, the mortality of patients admitted to the ICU after allogeneic stem cell transplantation (alloSCT) is high. Advancements in transplantation procedures, infectious monitoring and supportive care may have improved the outcome. This study aimed to determine short-term and long-term mortality after ICU admission of patients after alloSCT and to identify prognostic clinical and transplantation-related determinants present at ICU admission for long-term outcome. A multicenter cohort study was performed to determine 30-day and 1-year mortality within 2 years following alloSCT. A total of 251 patients were included. The 30-day and 1-year mortality was 55% and 80%, respectively. Platelet count <25 × 109/L (OR: 2.26, CI: 1.02-5.01) and serum bilirubin >19 µmol/L (OR: 2.47 CI: 1.08-5.65) at admission, other donor than a HLA-matched-related or HLA-matched-unrelated donor (OR: 4.59, CI: 1.49-14.1) and vasoactive medication within 24 h (OR: 2.35, CI: 1.28-4.31) were associated with increased 30-day mortality. Other donor than a HLA-matched-related or HLA-matched-unrelated donor (OR: 1.9, CI: 1.13-3.19), serum bilirubin >77 (OR: 2.05, CI: 1.28-3.30) and vasoactive medication within 24 h (OR: 1.65, CI: 1.12-2.43) were associated with increased 1-year mortality. Neutropenia was associated with decreased 30-day and 1-year mortality (OR: 0.29, CI: 0.14-0.59 and OR: 0.70, CI: 0.48-0.98). Myeloablative conditioning and T cell-depleted transplantation were not associated with increased mortality.

The management of critically ill patients with haematological malignancies.

The management of critically ill patients with haematological malignancy (HM) still shows inter- and intra-regional differences. Our objective in this updated review was to address the evidence supporting the potential treatment options, based on multidisciplinary processes, of critically ill patients with HM. A stepwise approach to the critical care pathway of this patient population from the triage to ICU admission to ICU discharge was chosen to emphasise certain key findings. Our main focus relied on significant issues of decision-making in daily clinical routine. The plethora of studies shifted the pragmatic treatment policy into an evidence-based approach. The transfer of a patient with HM from the haematology ward to the ICU and vice versa should be based on a well-defined clinical care process in which the haematologists and intensivists are in close collaboration and direct communication. A protocolised clinical approach to treat a critically ill patient with HM seems helpful to optimise patient-oriented care and patient safety.

Organ Donation After Euthanasia in the Netherlands: A Case Report.

In 2014, there was still a shortage of available organs for transplantation, and 1044 patients were waiting for an organ in the Netherlands. Maximizing the pool of organ donors is part of the solution. In 2001, the Dutch Termination of Life on Request and Assisted Suicide Act was adopted, legalizing euthanasia under strict conditions. In 2010, 3136 reports were made of euthanasia and assisted suicide; in 2014, 5306 reports were made. Among them were patients with a desire to donate their organs after their deaths. Although a potential source of donor organs, only a few cases of organ donation after active euthanasia have been described. Since 2012, 16 combinations of these procedures have been performed in the Netherlands. The literature mentions 16 Belgian cases between 2005 and 2013. This limited number can be the result of lack of knowledge about this subject among healthcare professionals or because of practical, ethical, and/or legal considerations. Performing this combination has possible advantages, both in number as well as in transplantation outcomes. By describing a recent case in our center, we will try to outline the state of the art in the Netherlands and disseminate knowledge about the possibilities and limitations of organ donation after active euthanasia.

[Confusion and abnormal liver enzyme levels: problems with diagnosing hepatic encephalopathy]. / Verwardheid en afwijkende leveruitslagen: de lastige diagnose 'hepatische encefalopathie'.

3 patients with liver failure developed hepatic encephalopathy. 2 patients, men aged 60 and 72 years, had chronic liver disease and presented with episodes of confusion. They recovered after being treated with lactulose. The third patient, a 37-year-old woman, became comatose shortly after the onset of acute liver failure due to acute autoimmune hepatitis. She died before a suitable donor liver became available. Hepatic encephalopathy is a syndrome of potential reversible neurological symptoms. Especially in the early stages of the condition, hepatic encephalopathy can be difficult to diagnose. Patients may present with mild cognitive impairment or episodes characterized by neurological symptoms. Hepatic encephalopathy is a clinical diagnosis. The pathophysiologic mechanism is only partly understood but toxicity of ammonia on the central nervous system seems to be of major importance. Raised ammonia concentrations or EEG findings consistent with metabolic encephalopathy may support but are not essential to the diagnosis. Episodes of hepatic encephalopathy are often elicited by an underlying disease such as infection or gastro-intestinal bleeding. It is important to recognize hepatic encephalopathy in its early stages because adequate treatment of the condition and any underlying disease reduces morbidity and mortality.

Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats.

BACKGROUND: Sepsis and endotoxemia are associated with concurrent activation of inflammation and the hemostatic mechanism, which both contribute to organ dysfunction and death. Electrical vagus nerve stimulation (VNS) has been found to inhibit tumor necrosis factor (TNF)-alpha release during endotoxemia in rodents. OBJECTIVE: To determine the effect of VNS on activation of coagulation and fibrinolysis. METHODS: Rats received a sublethal i.v. dose of lipopolysaccharide (LPS) after electrical VNS or sham stimulation. Activation of coagulation and fibrinolysis, as well as cytokine release, was measured before LPS injection and 2, 4 and 6 h thereafter. RESULTS: LPS induced activation of the coagulation system (increases in the plasma concentrations of thrombin-antithrombin complexes and D-dimer, and a decrease in antithrombin) and biphasic changes in the fibrinolytic system [early rises of plasminogen activator activity and tissue-type plasminogen activator, followed by a delayed increase in plasminogen activator inhibitor type 1 (PAI-1)]. VNS strongly inhibited all LPS-induced procoagulant responses and more modestly attenuated the fibrinolytic response. In addition, VNS attenuated the LPS-induced increases in plasma and splenic concentrations of the proinflammatory cytokines TNF-alpha and interleukin-6 (IL-6), while not influencing the release of the anti-inflammatory cytokine IL-10. CONCLUSION: These data illustrate a thus far unrecognized effect of VNS and suggest that the cholinergic anti-inflammatory pathway not only impacts on inflammation but also on the coagulant-anticoagulant balance.

[Rhabdomyolysis in a bodybuilder using steroids]. / Rabdomyolyse bij een bodybuilder na gebruik van diverse dopingmiddelen.

A 34-year-old bodybuilder presented at the emergency room with fever, vomiting and muscle cramps that had started during a bodybuilding session. Several days before he started training he had used tablets and intramuscular injections containing the anabolic steroids: dehydro-chloro-methyltestosterone, boldenone and trenbolone. In addition, he had taken clenbuterol tablets, liothyronine tablets and subcutaneous injections of phosphatidylcholine. Laboratory investigations revealed massive rhabdomyolysis. The patient was treated with intravenous fluid replacement and sodium bicarbonate to alkalinize the urine. He recovered quickly and his renal function remained unaffected. 'Doping' among amateur athletes in the Netherlands occurs frequently. Apart from long term side-effects, doping can also cause acute health problems. Therefore it is important to ask about doping use during history taking in amateur athletes.

Self-expanding metal stents in benign biliary strictures due to chronic pancreatitis.

BACKGROUND AND STUDY AIMS: In selected patients with chronic pancreatitis in whom conventional plastic stenting fails and in whom surgery is contraindicated or declined, insertion of a biliary self-expanding metal stent (SEMS) may be a valuable treatment option. PATIENTS AND METHODS: Between 1994 and 1999, 13 patients with chronic pancreatitis received SEMS for benign biliary strictures (four women and nine men; mean age 56). The indications for SEMS placement were: contraindication to surgery (n = 10), presumed inoperable pancreatic carcinoma (n = 1), concomitant unresectable lung cancer (n = 1), and declined surgery (n = 1). The success of treatment was defined as adequate biliary drainage due to SEMS therapy. RESULTS: The mean follow-up period was 50 months (range 6 days - 86 months). Nine patients (69 %) were successfully treated with SEMS therapy: a patent first SEMS (n = 5); a patent second SEMS inserted through the first SEMS (n = 3); and one patent SEMS after balloon cleaning. SEMS treatment was not successful in four patients (due to stent migration in one case and occlusion in three ). The mean patency period of the SEMS was 60 months (95 % CI, 43 months - 77 months). At 33 months, the probability of adequate biliary drainage with SEMS therapy was 75 %. CONCLUSIONS: SEMS therapy was safe and provided successful and prolonged biliary drainage in a selected group of patients with benign biliary strictures due to chronic pancreatitis in whom surgical intervention was not possible or desirable.

Acute pancreatitis in peritoneal dialysis and haemodialysis: risk, clinical course, outcome, and possible aetiology.

BACKGROUND: It has been suggested that the incidence of acute pancreatitis in patients with end stage renal failure is increased. AIMS: To assess the risk of acute pancreatitis in patients on long term peritoneal dialysis and long term haemodialysis compared with the general population, to evaluate its clinical course and outcome, and to identify possible aetiological factors. PATIENTS: All patients who were maintained on long term peritoneal dialysis and/or haemodialysis (total dialysis time more than six weeks) from January 1989 to March 1998 in a large general hospital in The Netherlands. METHODS: Retrospective cohort study. Standardised ratios (as an approximate relative risk) between the incidence of acute pancreatitis in haemodialysis or peritoneal dialysis and the general population were calculated. Possible risk factors were identified. Patients with and without acute pancreatitis were compared. RESULTS: In 269 patients on haemodialysis (total of 614 person years), one patient developed an attack of acute pancreatitis. Patients on haemodialysis did not show an increased risk for acute pancreatitis compared with the general population (standardised ratio 11; 95% confidence interval (CI) 0.275 to 60.5). In 128 patients on peritoneal dialysis (total of 241 person years), seven patients had nine attacks of acute pancreatitis. Patients on peritoneal dialysis had a significantly and highly increased risk for acute pancreatitis (standardised ratio 249; 95% CI 114 to 473). Mortality in this series of nine attacks was 11%. No single aetiological risk factor could be identified. CONCLUSIONS: The risk of acute pancreatitis in patients on long term peritoneal dialysis is significantly and highly increased compared with the general population. The underlying causal mechanisms remain to be elucidated.

Insertion of mini-IS605 and deletion of adjacent sequences in the nitroreductase (rdxA) gene cause metronidazole resistance in Helicobacter pylori NCTC11637.

We found that NCTC11637, the type strain of Helicobacter pylori, the causative agent of peptic ulcer disease and an early risk factor for gastric cancer, is metronidazole resistant. DNA transformation, PCR-based restriction analysis, and DNA sequencing collectively showed that the metronidazole resistance of this strain was due to mutation in rdxA (gene HP0954 in the full genome sequence of H. pylori 26695) and that resistance did not depend on mutation in any of the other genes that had previously been suggested: catalase (katA), ferredoxin (fdx), flavodoxin (fldA), pyruvate:flavodoxin oxidoreductase (porgammadeltaalphabeta), RecA (recA), or superoxide dismutase (sodB). This is in accord with another recent study that attributed metronidazole resistance to point mutations in rdxA. However, the mechanism of rdxA inactivation that we found in NCTC11637 is itself also novel: insertion of mini-IS605, one of the endogenous transposable elements of H. pylori, and deletion of adjacent DNA sequences including 462 bp of the 851-bp-long rdxA gene.