In a Dutch IDDM population, including 69 patients with (incipient) diabetic nephropathy, the T-allele of the AGT-M235T polymorphism is associated with an elevated UAE and diabetic retinopathy and the CC-genotype of the AT1-A1166C polymorphism is associated with hypertension. A previously described interaction between the AGT-M235T and the ACE-ID polymorphisms could not be confirmed. Since the number of nephropathic patients in this study is small, these conclusions must be interpreted with caution.

Positive end-expiratory pressure (PEEP) is routinely applied in mechanically ventilated patients to improve gas exchange and respiratory mechanics by increasing end-expiratory lung volume (EELV). In a recent experimental study in rats, we demonstrated that prolonged application of PEEP causes diaphragm remodeling, especially longitudinal muscle fiber atrophy. This is of potential clinical importance, as the acute withdrawal of PEEP during ventilator weaning decreases EELV and thereby stretches the adapted, longitudinally atrophied diaphragm fibers to excessive sarcomere lengths, having a detrimental effect on force generation. Whether this series of events occurs in the human diaphragm is unknown. In the current study we investigated if short-term application of PEEP affects diaphragm geometry and function, which are prerequisites for the development of longitudinal atrophy. Nineteen healthy volunteers were non-invasively ventilated with PEEP levels of 2, 5, 10 and 15 cmH2O. Magnetic resonance imaging was performed to investigate PEEP-induced changes in diaphragm geometry. Subjects were instrumented with nasogastric catheters to measure diaphragm neuromechanical efficiency (i.e., diaphragm pressure normalized to its electrical activity) during tidal breathing with different PEEP levels. We found that increasing PEEP from 2 to 15 cmH2O resulted in a caudal diaphragm displacement (19 [14-26] mm, P<0.001), muscle shortening in the zones of apposition (20.6% anterior and 32.7% posterior, P<0.001), increase in diaphragm thickness (36.4 [0.9-44.1] %, P<0.001) and reduction in neuromechanical efficiency (48 [37.6-56.6] %, P<0.001). These findings demonstrate that conditions required to develop longitudinal atrophy in the human diaphragm are present with the application of PEEP.

Background Monitoring and controlling lung stress and diaphragm effort has been hypothesized to limit lung injury and diaphragm injury. The occluded inspiratory airway pressure (Pocc) and the airway occlusion pressure at 100ms (P0.1) have been used as non-invasive methods to assess lung stress and respiratory muscle effort, but comparative performance of these measures and their correlation to diaphragm effort is unknown. We hypothesized that Pocc and P0.1 correlate to diaphragm effort and lung stress, and would have strong discriminative performance in identifying extremes of lung stress and diaphragm effort. Methods Secondary analysis of two studies. Transdiaphragmatic pressure (ΔPdi) and transpulmonary pressure (ΔPL) were obtained with double-balloon nasogastric catheters in critically ill patients (n = 38). Pocc and P0.1 were measured every 1-3 hours. Correlations between Pocc and P0.1 with ΔPL and ΔPdi were computed from patients from the first cohort. Accuracy of Pocc and P0.1 to identify patients with extremes of lung stress (ΔPL&gt;20cmH2O) and diaphragm effort (ΔPdi &lt;3cmH2O and &gt;12cmH2O) in the preceding hour was assessed with area under receiver-operator characteristic curves (AUROC). Cut-offs were validated in patients from the second cohort (n = 13). Results Pocc and P0.1 correlate with ΔPL (r2=0.62 and 0.51, respectively) and ΔPdi (r2 = 0.53 and 0.22, respectively). AUROC to detect high lung stress is 0.90 (0.86–0.94) for Pocc and 0.88 (0.84-0.92) for P0.1. AUROC to detect low diaphragm effort is 0.97 (0.87–1.00) for Pocc and 0.93 (0.81–0.99) for P0.1. AUROC to detect high diaphragm effort is 0.86 (0.81–0.91) for Pocc and 0.73 (0.66-0.79) for P0.1. Performance was similar in the external dataset. Conclusions Pocc and P0.1 correlate with lung stress and diaphragm effort in the preceding hour. Diagnostic performance of Pocc and P0.1 to detect extremes in these parameters is reasonable to excellent. Pocc is more accurate in detecting high diaphragm effort.

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Background High-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. The aim of this study is to investigate whether short-term treatment with a supplementary or very high-dose intravenous vitamin C reduces organ failure in post-cardiac arrest patients. Methods This is a double-blind, multi-center, randomized placebo-controlled trial conducted in 7 intensive care units (ICUs) in The Netherlands. A total of 270 patients with cardiac arrest and return of spontaneous circulation will be randomly assigned to three groups of 90 patients (1:1:1 ratio, stratified by site and age). Patients will intravenously receive a placebo, a supplementation dose of 3 g of vitamin C or a pharmacological dose of 10 g of vitamin C per day for 96 h. The primary endpoint is organ failure at 96 h as measured by the Resuscitation-Sequential Organ Failure Assessment (R-SOFA) score at 96 h minus the baseline score (delta R-SOFA). Secondary endpoints are a neurological outcome, mortality, length of ICU and hospital stay, myocardial injury, vasopressor support, lung injury score, ventilator-free days, renal function, ICU-acquired weakness, delirium, oxidative stress parameters, and plasma vitamin C concentrations. Discussion Vitamin C supplementation is safe and preclinical studies have shown beneficial effects of high-dose IV vitamin C in cardiac arrest models. This is the first RCT to assess the clinical effect of intravenous vitamin C on organ dysfunction in critically ill patients after cardiac arrest. Trial registration ClinicalTrials.gov NCT03509662. Registered on April 26, 2018. https://clinicaltrials.gov/ct2/show/NCT03509662European Clinical Trials Database (EudraCT): 2017-004318-25. Registered on June 8, 2018. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004318-25/NL