Timing of onset of gastrointestinal bleeding in the ICU: Protocol for a preplanned observational study.

BACKGROUND: Critically ill patients are at risk of gastrointestinal bleeding, but clinically important gastrointestinal bleeding is rare. The majority of intensive care unit (ICU) patients receive stress ulcer prophylaxis (SUP), despite uncertainty concerning the balance between benefit and harm. For approximately half of ICU patients with gastrointestinal bleeding, onset is early, ie within the first two days of the ICU stay. The aetiology of gastrointestinal bleeding and consequently the balance between benefit and harm of SUP may differ between patients with early vs late gastrointestinal bleeding. METHODS: This is a protocol and statistical analysis plan for a preplanned exploratory substudy of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) randomized clinical trial, comparing intravenous pantoprazole (40 mg once daily) with placebo in 3350 acutely ill adult ICU patients. We will describe baseline characteristics and assess the time to onset of the first clinically important episode of GI bleeding accounting for survival status and allocation to SUP or placebo. In addition, we will describe differences in therapeutic and diagnostic procedures used in patients with clinically important gastrointestinal bleeding according to early vs late bleeding and 90-day vital status. CONCLUSIONS: The study outlined in this protocol will provide detailed information on patient characteristics and the timing of onset of gastrointestinal bleeding in the patients enrolled in the SUP-ICU trial. This may provide additional knowledge and incentives for future studies on which patients benefit from SUP.

pRotective vEntilation with veno-venouS lung assisT in respiratory failure: A protocol for a multicentre randomised controlled trial of extracorporeal carbon dioxide removal in patients with acute hypoxaemic respiratory failure.

One of the few interventions to demonstrate improved outcomes for acute hypoxaemic respiratory failure is reducing tidal volumes when using mechanical ventilation, often termed lung protective ventilation. Veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R) can facilitate reducing tidal volumes. pRotective vEntilation with veno-venouS lung assisT (REST) is a randomised, allocation concealed, controlled, open, multicentre pragmatic trial to determine the clinical and cost-effectiveness of lower tidal volume mechanical ventilation facilitated by vv-ECCO2R in patients with acute hypoxaemic respiratory failure. Patients requiring intubation and mechanical ventilation for acute hypoxaemic respiratory failure will be randomly allocated to receive either vv-ECCO2R and lower tidal volume mechanical ventilation or standard care with stratification by recruitment centre. There is a need for a large randomised controlled trial to establish whether vv-ECCO2R in acute hypoxaemic respiratory failure can allow the use of a more protective lung ventilation strategy and is associated with improved patient outcomes.

Stress ulcer prophylaxis in the intensive care unit trial: detailed statistical analysis plan.

BACKGROUND: In this statistical analysis plan, we aim to provide details of the pre-defined statistical analyses of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. The aim of the SUP-ICU trial is to assess benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the intensive care unit (ICU). METHODS: The SUP-ICU trial is an investigator-initiated, international, multicentre, randomised, blinded, parallel-group trial of intravenously pantoprazole 40 mg once daily vs. placebo in 3350 acutely ill adult ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support, serious adverse reactions, 1-year mortality, and a health economic analysis. Two formal interim analyses will be performed. The statistical analyses will be conducted according to the outlined pre-defined statistical analysis plan. The primary analysis will be a logistic regression analysis adjusted for stratification variables comparing the two intervention groups in the intention-to-treat population. In a secondary analysis, we will additionally adjust the primary outcome for potential random differences in baseline characteristics. The conclusion will be based on the intention-to-treat population. CONCLUSION: Stress ulcer prophylaxis is standard of care in ICUs worldwide, but has never been tested in large high-quality randomised placebo-controlled trials. The SUP-ICU trial will provide important high-quality data on the balance between the benefits and harms of stress ulcer prophylaxis in adult critically ill patients.

Anxiety and depression among out-of-hospital cardiac arrest survivors.

AIM: Survivors of out-of-hospital cardiac arrest (OHCA) may experience psychological distress but the actual prevalence is unknown. The aim of this study was to investigate anxiety and depression within a large cohort of OHCA-survivors. METHODS: OHCA-survivors randomized to targeted temperature of 33 °C or 36 °C within the Target Temperature Management trial (TTM-trial) attended a follow-up after 6 months that included the questionnaire Hospital Anxiety and Depression Scale (HADS). A control group with ST-elevation myocardial infarction (STEMI) completed the same follow-up. Correlations to variables assumed to be associated with anxiety and depression in OHCA-survivors were tested. RESULTS: At follow-up 278 OHCA-survivors and 119 STEMI-controls completed the HADS where 24% of OHCA-survivors (28% in 33 °C group/22% in 36 °C group, p=0.83) and 19% of the STEMI-controls reported symptoms of anxiety (OR 1.32; 95% CI (0.78-2.25), p=0.30). Depressive symptoms were reported by 13% of OHCA-survivors (equal in both intervention groups, p=0.96) and 8% of STEMI-controls (OR 1.76; 95% CI (0.82-3.79), p=0.15). Anxiety and depression among OHCA-survivors correlated to Health-Related Quality-of-Life, and subjectively reported cognitive deterioration by patient or observer. In addition, depression was associated with a poor neurological outcome. CONCLUSION: One fourth of OHCA-survivors reported symptoms of anxiety and/or depression at 6 months which was similar to STEMI-controls and previous normative data. Subjective cognitive problems were associated with an increased risk for psychological distress. Since psychological distress affects long-term prognosis of cardiac patients in general it should be addressed during follow-up of survivors with OHCA due to a cardiac cause. ClinicalTrials.gov NCT01020916/NCT01946932.

British Thoracic Society community acquired pneumonia guideline and the NICE pneumonia guideline: how they fit together.

The British Thoracic Society (BTS) guideline for the management of adults with community acquired pneumonia (CAP) published in 2009 was compared with the 2014 National Institute for Health and Care Excellence (NICE) Pneumonia Guideline. Of the 36 BTS recommendations that overlapped with NICE recommendations, no major differences were found in 31, including those covering key aspects of CAP management: timeliness of diagnosis and treatment, severity assessment and empirical antibiotic choice. Of the five BTS recommendations where major differences with NICE were identified, one related to antibiotic duration in low and moderate severity CAP, two to the timing of review of patients and two to legionella urinary antigen testing.

British Thoracic Society community acquired pneumonia guideline and the NICE pneumonia guideline: how they fit together.

The British Thoracic Society (BTS) guideline for the management of adults with community acquired pneumonia (CAP) published in 2009 was compared with the 2014 National Institute for Health and Care Excellence (NICE) Pneumonia Guideline. Of the 36 BTS recommendations that overlapped with NICE recommendations, no major differences were found in 31, including those covering key aspects of CAP management: timeliness of diagnosis and treatment, severity assessment and empirical antibiotic choice. Of the five BTS recommendations where major differences with NICE were identified, one related to antibiotic duration in low and moderate severity CAP, two to the timing of review of patients and two to legionella urinary antigen testing.

Stress ulcer prophylaxis in the intensive care unit: an international survey of 97 units in 11 countries.

BACKGROUND: Stress ulcer prophylaxis (SUP) may decrease the incidence of gastrointestinal bleeding in patients in the intensive care unit (ICU), but the risk of infection may be increased. In this study, we aimed to describe SUP practices in adult ICUs. We hypothesised that patient selection for SUP varies both within and between countries. METHODS: Adult ICUs were invited to participate in the survey. We registered country, type of hospital, type and size of ICU, preferred SUP agent, presence of local guideline, reported indications for SUP, criteria for discontinuing SUP, and concerns about adverse effects. Fisher's exact test was used to assess differences between groups. RESULTS: Ninety-seven adult ICUs in 11 countries participated (eight European). All but one ICU used SUP, and 64% (62/97) reported having a guideline for the use of SUP. Proton pump inhibitors were the most common SUP agent, used in 66% of ICUs (64/97), and H2-receptor antagonists were used 31% (30/97) of the units. Twenty-three different indications for SUP were reported, the most frequent being mechanical ventilation. All patients were prescribed SUP in 26% (25/97) of the ICUs. Adequate enteral feeding was the most frequent reason for discontinuing SUP, but 19% (18/97) continued SUP upon ICU discharge. The majority expressed concern about nosocomial pneumonia and Clostridium difficile infection with the use of SUP. CONCLUSIONS: In this international survey, most participating ICUs reported using SUP, primarily proton pump inhibitors, but many did not have a guideline; indications varied considerably and concern existed about infectious complications.

The effect of serum matrix and gender on cortisol measurement by commonly used immunoassays.

BACKGROUND: Considerable intermethod bias has been observed between cortisol immunoassays, with some also displaying a gender difference. Cortisol immunoassay performance is affected by serum matrix effects such as changes in steroid binding proteins and presence of interfering steroids which can be altered in various clinical settings. This study investigates cortisol immunoassay bias in pregnancy, renal failure and intensive care patients. METHODS: Serum remaining after routine analysis from pregnant patients, patients on the intensive care unit and patients with renal failure were obtained prior to disposal and used to create 20 anonymous samples per group. A male and female serum pool was prepared and spiked with cortisol. Samples were aliquoted and distributed to four hospitals for cortisol analysis by immunoassays from four different manufacturers. Cortisol was also measured by an isotope dilution-gas chromatography-mass spectrometry method for comparison of assay bias. RESULTS: Differences in cortisol immunoassay bias were observed across the different patient groups. A negative bias compared to pooled serum samples was observed for pregnancy serum, whilst a more positive bias was seen in renal failure and intensive care patients. Variation in bias was greatest in renal failure with the Roche E170 the most affected and the Abbott architect the least (interquartile ranges 44% and 14%, respectively). CONCLUSIONS: Cortisol immunoassay bias may be affected by gender and differences in serum matrix from patients with various clinical conditions. Users of cortisol assays should be aware of differing matrix effects on their assay and the relevance of these for the interpretation of clinical results.

Boerhaave's syndrome - rapidly evolving pleural effusion; a radiographic clue.

Boerhaave's syndrome is the rare and often fatal condition of spontaneous esophageal rupture. Meckler's triad of vomiting, pain and subcutaneous emphysema are characteristic features of Boerhaave's syndrome. When these symptoms are absent, diagnosis is frequently late and often occurs as the result of incidental investigation. This contributes to the observed high morbidity and mortality. Unless specifically considered in the differential diagnosis, this rare disease is frequently overlooked. The authors described the case of a patient in whom the diagnosis was made several days following presentation by observing that a large pleural effusion had evolved rapidly on chest radiographs. This uncommon radiological sign has relatively few causes and prompted a review of the history and diagnosis, followed by the initiation of additional investigations that confirmed Boerhaave's syndrome.

Bacteraemia following single-stage percutaneous dilatational tracheostomy.

OBJECTIVE: Surgical tracheostomy in critically ill adults has largely been replaced by physicians performing percutaneous dilatational tracheostomy (PDT) at the bedside. Complications associated with this technique include haemorrhage, wound infection, barotrauma, false passage, ruptured tracheal ring and bacteraemia. Prophylactic antibiotics are not generally used with this procedure, however the incidence of bacteraemia following PDT has not been extensively studied. DESIGN: Prospective observational study. SETTING: Adult intensive care unit of a university medical centre. METHODS: Peripheral venous blood cultures were obtained immediately before and after PDT in 118 consecutive patients. Surveillance cultures of potential respiratory pathogens were also recorded using routine non-directed broncholalveolar lavage. RESULTS: Forty-three female and 75 male patients underwent PDT. Fifty-seven patients (48.3%) were not receiving antibiotics on the day of PDT, whilst the remaining 61 individuals (51.7%) were on antibiotic therapy at the time of the procedure. Bacteraemia following PDT occurred in six out of 113 patients (5.3%), five of which occurred in patients not receiving antibiotics (9.2%). Unexpected bacteraemia (positive pre-and post PDT blood cultures) was identified in five patients, two of whom were on antibiotic therapy. CONCLUSION: The incidence of bacteraemia following a single stage PDT was similar to other manipulations of the aerodigestive tract such as intubation, insertion of an LMA or tooth brushing. We suggest that routine antibiotic prophylaxis is unnecessary for this procedure.

Elimination of the immunogenicity of therapeutic antibodies.

The immunogenicity of therapeutic Abs limits their long-term use. The processes of complementarity-determining region grafting, resurfacing, and hyperchimerization diminish mAb immunogenicity by reducing the number of foreign residues. However, this does not prevent anti-idiotypic and anti-allotypic responses following repeated administration of cell-binding Abs. Classical studies have demonstrated that monomeric human IgG is profoundly tolerogenic in a number of species. If cell-binding Abs could be converted into monomeric non-cell-binding tolerogens, then it should be possible to pretolerize patients to the therapeutic cell-binding form. We demonstrate that non-cell-binding minimal mutants of the anti-CD52 Ab CAMPATH-1H lose immunogenicity and can tolerize to the "wild-type" Ab in CD52-expressing transgenic mice. This finding could have utility in the long-term administration of therapeutic proteins to humans.

Linked suppression of skin graft rejection can operate through indirect recognition.

Adult mice can be rendered immunologically tolerant of allogeneic tissues if transplanted under cover of mAbs to CD4 and CD8. Tolerance generated in this manner is characterized by the presence of regulatory CD4+ T cells that can recruit naive T cells to become tolerant also through "infectious tolerance." Regulatory CD4+ T cells can also suppress rejection of third party transplant Ags provided they are expressed on the same graft as the tolerated Ags. This process of linked suppression can act across whole MHC barriers and represents a powerful mechanism with therapeutic potential. Tolerance can also be induced to reprocessed minor transplantation Ags presented through host APCs (indirect recognition). We here demonstrate that linked suppression can also be induced through the indirect pathway. This finding may be important in the development of transplantation tolerance in the clinic.

Neurological presentations of hypothyroidism: the importance of slow relaxing reflexes.

Neurological sequelae of hypothyroidism are well recognized and relatively common. Neurological symptoms occurring as a presenting feature of this illness are, however, uncommon. Here we report three patients who presented in such a way and in whom the diagnosis was only suspected because of slow relaxing reflexes.