Harm-Jan de Grooth

Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens

Background: Early high‐dose IV vitamin C is being investigated as adjuvant therapy in patients who are critically ill, but the optimal dose and infusion method are unclear. The primary aim of this study was to describe the dose‐plasma concentration relationship and safety of four different dosing regimens. Methods: This was a four‐group randomized pharmacokinetic trial. Patients who were critically ill with multiple organ dysfunction were randomized to receive 2 or 10 g/d vitamin C as a twice daily bolus infusion or continuous infusion for 48 h. End points were plasma vitamin C concentrations during 96 h, 12‐h urine excretion of vitamin C, and oxalate excretion and base excess. A population pharmacokinetic model was developed using NONMEM. Results: Twenty patients were included. A two‐compartment pharmacokinetic model with creatinine clearance and weight as independent covariates described all four regimens best. With 2 g/d bolus, plasma vitamin C concentrations at 1 h were 29 to 50 mg/L and trough concentrations were 5.6 to 16 mg/L. With 2 g/d continuous, steady‐state concentrations were 7 to 37 mg/L at 48 h. With 10 g/d bolus, 1‐h concentrations were 186 to 244 mg/L and trough concentrations were 14 to 55 mg/L. With 10 g/d continuous, steady‐state concentrations were 40 to 295 mg/L at 48 h. Oxalate excretion and base excess were increased in the 10 g/d dose. Forty‐eight hours after discontinuation, plasma concentrations declined to hypovitaminosis levels in 15% of patients. Conclusions: The 2 g/d dose was associated with normal plasma concentrations, and the 10 g/d dose was associated with supranormal plasma concentrations, increased oxalate excretion, and metabolic alkalosis. Sustained therapy is needed to prevent hypovitaminosis. Trial Registry: ClinicalTrials.gov; No.: NCT02455180; URL: www.clinicaltrials.gov

Vitamin C Pharmacokinetics in Patients Who Are Critically Ill: A Randomized Trial of Four IV Regimens

Background: Early high‐dose IV vitamin C is being investigated as adjuvant therapy in patients who are critically ill, but the optimal dose and infusion method are unclear. The primary aim of this study was to describe the dose‐plasma concentration relationship and safety of four different dosing regimens. Methods: This was a four‐group randomized pharmacokinetic trial. Patients who were critically ill with multiple organ dysfunction were randomized to receive 2 or 10 g/d vitamin C as a twice daily bolus infusion or continuous infusion for 48 h. End points were plasma vitamin C concentrations during 96 h, 12‐h urine excretion of vitamin C, and oxalate excretion and base excess. A population pharmacokinetic model was developed using NONMEM. Results: Twenty patients were included. A two‐compartment pharmacokinetic model with creatinine clearance and weight as independent covariates described all four regimens best. With 2 g/d bolus, plasma vitamin C concentrations at 1 h were 29 to 50 mg/L and trough concentrations were 5.6 to 16 mg/L. With 2 g/d continuous, steady‐state concentrations were 7 to 37 mg/L at 48 h. With 10 g/d bolus, 1‐h concentrations were 186 to 244 mg/L and trough concentrations were 14 to 55 mg/L. With 10 g/d continuous, steady‐state concentrations were 40 to 295 mg/L at 48 h. Oxalate excretion and base excess were increased in the 10 g/d dose. Forty‐eight hours after discontinuation, plasma concentrations declined to hypovitaminosis levels in 15% of patients. Conclusions: The 2 g/d dose was associated with normal plasma concentrations, and the 10 g/d dose was associated with supranormal plasma concentrations, increased oxalate excretion, and metabolic alkalosis. Sustained therapy is needed to prevent hypovitaminosis. Trial Registry: ClinicalTrials.gov; No.: NCT02455180; URL: www.clinicaltrials.gov

Should we rely on trials with disease- rather than patient-oriented endpoints?

Introduction Should I change practice on the basis of this study [1]? Which primary endpoint should I choose to compute the sample size of my trial [2, 3]? Answering these questions requires a critical appraisal of study endpoints by both researchers and clinicians. In this report, we analyze the use of disease-oriented endpoints (such as organ dysfunction scores) in intensive care (IC) trials, and we briefly review the pitfalls of extrapolating disease-oriented endpoints to real patient benefit.

Laboratory Tests: Blood Gases, Anion Gap, and Strong Ion Gap

Abstract Blood gas measurements provide the intensivist with diagnostic information on many organ systems. The anion gap (AG) and the strong ion gap (SIG) exploit the principle of electroneutrality to quantify the net balance of unmeasured ions in plasma. The AG should be corrected for abnormalities in plasma albumin and phosphate concentrations. The AG and SIG can be used to narrow the differential diagnosis of acid-base disorders, and an increased corrected AG or SIG is diagnostic of a metabolic acidosis (i.e., an acidifying process) irrespective of plasma pH or bicarbonate. The SIG is often perceived as more complex but frequently yields more precise results in critically ill patients. In addition, the strong ion model can be used to guide fluid management because it acknowledges that electrolyte changes are causal mechanisms of acid-base disorders.

Hyperoxia does not affect oxygen delivery in healthy volunteers while causing a decrease in sublingual perfusion

To determine the human dose‐response relationship between a stepwise increase in arterial oxygen tension and its associated changes in DO2 and sublingual microcirculatory perfusion.

Positive outcomes, mortality rates, and publication bias in septic shock trials

Dear Editor, Decades of septic shock research have not produced new therapies specifically targeting the dysregulated host response [1], and promising results were not replicated in larger studies [2]. We previously described a large variation in the control-group mortality rates of septic shock trials [3], but we did not investigate trial outcomes. The aim of the present study was to explore the influence of between-trial mortality variations on trial results. We performed a systematic search of randomized controlled trials with septic shock patients published between 2006 and 2018, described in detail elsewhere [3]. For the present study we classified trials as “positive” if the primary endpoint (as defined by the authors) was in favor of the intervention group with p < 0.05. We used linear models and logistic regression to compare controland intervention-group 28-day mortality between positive and negative trials. To control for differences in mean baseline severity of illness between trials, we used a combination of baseline mean SOFA score, mean serum creatinine, and the proportion of mechanically ventilated patients (details in the Electronic Supplementary Material (ESM) and [3]). We also calculated the mortality odds ratio of each trial (intervention ÷ control group) and used linear mixed-effects regression to test for associations with mortality in the control and intervention groups. Publication bias was investigated with a funnel plot and Egger’s test for asymmetry.

Focus on focus: lack of coherence between systemic and microvascular indices of oedema formation

BACKGROUND Fluid therapy remains a cornerstone of therapy in shock states. However, fluid overloading ultimately results in oedema formation which is related to excess morbidity and mortality. Handheld microscopes are now frequently used to study the sublingual microcirculation. As a corollary, these devices measure focal distance, or surface to capillary distance. Physiologically, this could represent a microvascular index of oedema formation and could have the potential to guide fluid therapy. This potential tool should be investigated, especially given the frequently reported lack of coherence between systemic and microvascular parameters in the critically ill. Therefore, we set out to assess the correlation between microvascular focal distance and systemic indices of oedema formation, specifically fluid balance and weight gain. METHODS Following ex vivo testing of focal distance measurement reliability, we conducted a prospective observational cohort study in patients admitted to the intensive care unit of our university teaching hospital. We determined surface to capillary distance using sidestream dark field (SDF) and incident dark field (IDF) imaging by assessing the focal distance point or object distance range at which a sharp recording could be made. Measurements were performed in post-cardiac surgery patients and in patients following emergency admission at two time points separated by at least several hours. Data on fluid balance, weight and weight gain were collected simultaneously. RESULTS Sixty patients were included. The focal setting, focus point for SDF and the object distance range for IDF did not differ significantly between time points. Focus was not correlated with difference in fluid balance or weight gain. CONCLUSIONS There is a lack of coherence between surface to capillary distance as determined by SDF or IDF imaging and fluid balance or weight gain. Thus, focal distance as a microvascular index of oedema formation cannot currently be used as a proxy for systemic indices of oedema formation. However, given the lack of coherence, further research should determine whether focal distance may provide better guidance for fluid therapy than traditional markers of overzealous fluid administration. RESULTS Sixty patients were included. Focal setting, focus point for SDF and an object distance range for IDF did not differ significantly between time points. Focus was not correlated with difference in fluid balance or weight gain. CONCLUSIONS There is a lack of coherence between surface to capillary distance as determined by SDF or IDF imaging and fluid balance or weight gain. Thus, focal distance as a microvascular index of edema formation cannot currently be used as a proxy for systemic indices of edema formation. However, given the lack of coherence, further research should determine whether focal distance may provide better guidance for fluid therapy than traditional markers of overzealous fluid administration.

Intravenous furosemide in decompensated heart failure: do not protocolize dosing but the desired effect!

No abstract