Effect of Low-Normal vs High-Normal Oxygenation Targets on Organ Dysfunction in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Hyperoxemia may increase organ dysfunction in critically ill patients, but optimal oxygenation targets are unknown. Objective: To determine whether a low-normal Pao2 target compared with a high-normal target reduces organ dysfunction in critically ill patients with systemic inflammatory response syndrome (SIRS). Design, Setting, and Participants: Multicenter randomized clinical trial in 4 intensive care units in the Netherlands. Enrollment was from February 2015 to October 2018, with end of follow-up to January 2019, and included adult patients admitted with 2 or more SIRS criteria and expected stay of longer than 48 hours. A total of 9925 patients were screened for eligibility, of whom 574 fulfilled the enrollment criteria and were randomized. Interventions: Target Pao2 ranges were 8 to 12 kPa (low-normal, n = 205) and 14 to 18 kPa (high-normal, n = 195). An inspired oxygen fraction greater than 0.60 was applied only when clinically indicated. Main Outcomes and Measures: Primary end point was SOFARANK, a ranked outcome of nonrespiratory organ failure quantified by the nonrespiratory components of the Sequential Organ Failure Assessment (SOFA) score, summed over the first 14 study days. Participants were ranked from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). Secondary end points were duration of mechanical ventilation, in-hospital mortality, and hypoxemic measurements. Results: Among the 574 patients who were randomized, 400 (70%) were enrolled within 24 hours (median age, 68 years; 140 women [35%]), all of whom completed the trial. The median Pao2 difference between the groups was -1.93 kPa (95% CI, -2.12 to -1.74; P < .001). The median SOFARANK score was -35 points in the low-normal Pao2 group vs -40 in the high-normal Pao2 group (median difference, 10 [95% CI, 0 to 21]; P = .06). There was no significant difference in median duration of mechanical ventilation (3.4 vs 3.1 days; median difference, -0.15 [95% CI, -0.88 to 0.47]; P = .59) and in-hospital mortality (32% vs 31%; odds ratio, 1.04 [95% CI, 0.67 to 1.63]; P = .91). Mild hypoxemic measurements occurred more often in the low-normal group (1.9% vs 1.2%; median difference, 0.73 [95% CI, 0.30 to 1.20]; P < .001). Acute kidney failure developed in 20 patients (10%) in the low-normal Pao2 group and 21 patients (11%) in the high-normal Pao2 group, and acute myocardial infarction in 6 patients (2.9%) in the low-normal Pao2 group and 7 patients (3.6%) in the high-normal Pao2 group. Conclusions and Relevance: Among critically ill patients with 2 or more SIRS criteria, treatment with a low-normal Pao2 target compared with a high-normal Pao2 target did not result in a statistically significant reduction in organ dysfunction. However, the study may have had limited power to detect a smaller treatment effect than was hypothesized. Trial Registration: ClinicalTrials.gov Identifier: NCT02321072.

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

OBJECTIVE: 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. METHODS: Fifteen healthy volunteers breathed increasing oxygen fractions for 10 minutes to reach arterial oxygen tensions of baseline (breathing air), 20, 40, 60 kPa, and max kPa (breathing oxygen). Systemic hemodynamics were measured continuously by the volume-clamp method. At the end of each period, the sublingual microcirculation was assessed by SDF. RESULTS: Systemic DO2 was unchanged throughout the study (Pslope  = .8). PVD decreased in a sigmoidal fashion (max -15% while breathing oxygen, SD18, Pslope  = .001). CI decreased linearly (max -10%, SD10, Pslope  < .001) due to a reduction in HR (max -10%, SD7, Pslope  = .009). There were no changes in stroke volume or MAP. Most changes became apparent above an arterial oxygen tension of 20 kPa. CONCLUSIONS: In healthy volunteers, supraphysiological arterial oxygen tensions have no effect on systemic DO2 . Sublingual microcirculatory PVD decreased in a dose-dependent fashion. All hemodynamic changes appear negligible up to an arterial oxygen tension of 20 kPa.

Effects of hyperoxia on vascular tone in animal models: systematic review and meta-analysis.

BACKGROUND: Arterial hyperoxia may induce vasoconstriction and reduce cardiac output, which is particularly undesirable in patients who already have compromised perfusion of vital organs. Due to the inaccessibility of vital organs in humans, vasoconstrictive effects of hyperoxia have primarily been studied in animal models. However, the results of these studies vary substantially. Here, we investigate the variation in magnitude of the hyperoxia effect among studies and explore possible sources of heterogeneity, such as vascular region and animal species. METHOD: Pubmed and Embase were searched for eligible studies up to November 2017. In vivo and ex vivo animal studies reporting on vascular tone changes induced by local or systemic normobaric hyperoxia were included. Experiments with co-interventions (e.g. disease or endothelium removal) or studies focusing on lung, brain or fetal vasculature or the ductus arteriosus were not included. We extracted data pertaining to species, vascular region, blood vessel characteristics and method of hyperoxia induction. Overall effect sizes were estimated with a standardized mean difference (SMD) random effects model. RESULTS: We identified a total of 60 studies, which reported data on 67 in vivo and 18 ex vivo experiments. In the in vivo studies, hyperoxia caused vasoconstriction with an SMD of - 1.42 (95% CI - 1.65 to - 1.19). Ex vivo, the overall effect size was SMD - 0.56 (95% CI - 1.09 to - 0.03). Between-study heterogeneity (I2) was high for in vivo (72%, 95% CI 62 to 85%) and ex vivo studies (86%, 95% CI 78 to 98%). In vivo, in comparison to the overall effect size, hyperoxic vasoconstriction was less pronounced in the intestines and skin (P = 0.03) but enhanced in the cremaster muscle region (P < 0.001). Increased constriction was seen in vessels 15-25 µm in diameter. Hyperoxic constriction appeared to be directly proportional to oxygen concentration. For ex vivo studies, heterogeneity could not be explained with subgroup analysis. CONCLUSION: The effect of hyperoxia on vascular tone is substantially higher in vivo than ex vivo. The magnitude of the constriction is most pronounced in vessels ~ 15-25 µm in diameter and is proportional to the level of hyperoxia. Relatively increased constriction was seen in muscle vasculature, while reduced constriction was seen in the skin and intestines.

Hemodynamic effects of acute hyperoxia: systematic review and meta-analysis.

BACKGROUND: In clinical practice, oxygen is generally administered to patients with the intention of increasing oxygen delivery. Supplemental oxygen may, however, cause arterial hyperoxia, which is associated with hemodynamic alterations. We performed a systematic review and meta-analysis of the literature to determine the effect of hyperoxia on central hemodynamics and oxygen delivery in healthy volunteers and cardiovascular-compromised patients. METHODS: PubMed and EMBASE were searched up to March 2017. Studies with adult humans investigating changes in central hemodynamics or oxygen delivery induced by acute normobaric hyperoxia were included. Studies focusing on lung, retinal, or brain parameters were not included. We extracted subject and oxygen exposure characteristics, indexed and unindexed values for heart rate, stroke volume, cardiac output, mean arterial pressure (MAP), systemic vascular resistance, and oxygen delivery during normoxia and hyperoxia. For quantitative synthesis of the data, a random-effects ratio of means (RoM) model was used. RESULTS: We identified 33 studies with 42 datasets. Study categories included healthy volunteers (n = 22 datasets), patients with coronary artery disease (CAD; n = 6), heart failure (HF; n = 6), coronary artery bypass graft (CABG; n = 3) and sepsis (n = 5). Hyperoxia (arterial oxygen tension of 234-617 mmHg) reduced cardiac output (CO) by 10-15% in both healthy volunteers (-10.2%, 95% confidence interval (CI) -12.9% to -7.3%) and CAD (-9.6%, 95% CI -12.3% to -6.9%) or HF patients (-15.2%, 95% CI -21.7% to -8.2%). No significant changes in cardiac output were seen in CABG or septic patients (-3%). Systemic vascular resistance increased remarkably in patients with heart failure (24.6%, 95% CI 19.3% to 30.1%). In healthy volunteers, and those with CAD and CABG, the effect was smaller (11-16%) and was virtually absent in patients with sepsis (4.3%, 95% CI -3.2% to 12.3%). No notable effect on MAP was found in any group (2-3%). Oxygen delivery was not altered by hyperoxia. Considerable heterogeneity existed between study results, likely due to methodological differences. CONCLUSIONS: Hyperoxia may considerably decrease cardiac output and increase systemic vascular resistance, but effects differ between patient categories. Heart failure patients were the most sensitive while no hemodynamic effects were seen in septic patients. There is currently no evidence supporting the notion that oxygen supplementation increases oxygen delivery.

Moderate hyperoxic versus near-physiological oxygen targets during and after coronary artery bypass surgery: a randomised controlled trial.

BACKGROUND: The safety of perioperative hyperoxia is currently unclear. Previous studies in patients undergoing coronary artery bypass surgery suggest reduced myocardial damage when avoiding extreme perioperative hyperoxia (>400 mmHg). In this study we investigated whether an oxygenation strategy from moderate hyperoxia to a near-physiological oxygen tension reduces myocardial damage and improves haemodynamics, organ dysfunction and oxidative stress. METHODS: This was a single-blind, single-centre, open-label, randomised controlled trial in patients undergoing elective coronary artery bypass surgery. Fifty patients were randomised to a partial pressure of oxygen in arterial blood (PaO2) target of 200-220 mmHg during cardiopulmonary bypass and 130-150 mmHg during intensive care unit (ICU) admission (control group) versus lower targets of 130-150 mmHg during cardiopulmonary bypass and 80-100 mmHg at the ICU (conservative group). Primary outcome was myocardial injury (CK-MB and Troponin-T) at ICU admission and 2, 6 and 12 hours thereafter. RESULTS: Weighted PaO2 during cardiopulmonary bypass was 220 mmHg (interquartile range (IQR) 211-233) vs. 157 (151-162) in the control and conservative group, respectively (P < 0.0001). During ICU admission, weighted PaO2 was 107 mmHg (86-141) vs. 90 (84-98) (P = 0.03), respectively. Area under the curve of CK-MB was median 23.5 µg/L/h (IQR 18.4-28.1) vs. 21.5 (15.8-26.6) (P = 0.35) and 0.30 µg/L/h (0.25-0.44) vs. 0.39 (0.24-0.43) (P = 0.81) for Troponin-T. Cardiac index, systemic vascular resistance index, creatinine, lactate and F2-isoprostane levels were not different between groups. CONCLUSIONS: Compared to moderate hyperoxia, a near-physiological oxygen strategy does not reduce myocardial damage in patients undergoing coronary artery bypass surgery. Conservative oxygen administration was not associated with increased lactate levels or hypoxic events. TRIAL REGISTRATION: Netherlands Trial Registry NTR4375, registered on 30 January 2014.

NT-proBNP in cardiopulmonary resuscitated patients treated with mild therapeutic hypothermia is not independently associated with mortality: a retrospective observational study.

BACKGROUND: In spite of the introduction of mild therapeutic hypothermia (MTH), mortality rates remain high in patients with return of spontaneous circulation (ROSC) after cardiac arrest (CA). To date, no accurate and independent biomarker to predict survival in these patients exists. B-type natriuretic peptide (BNP) was found to provide both prognostic and diagnostic value in various cardiovascular diseases, including survival to hospital discharge in patients with ROSC. However, the biologically inactive counterpart of BNP, NT-proBNP, was found to be a more stable and accurate analyte. The current retrospective observational study investigates the value of NT-proBNP to predict 28-day mortality in post-CA patients treated with MTH, as well as the dynamics of NT-proBNP during MTH. METHODS: NT-proBNP levels were measured in post-CA patients cooled via cold intravenous saline infusion and water-circulating body wraps (Medi-Therm®, Gaymar). Plasma samples were obtained before cooling was started, at the start and end of the maintenance phase and at the end of rewarming. RESULTS: 250 patients, admitted between 2009 and 2013, had NT-proBNP levels measured on ICU admission and were included for the evaluation of NT-proBNP as a prognostic marker. In the 28 days following ICU admission, 114 patients died (46%). Non-survivors had significantly higher NT-proBNP (median 1448 ng/l, IQR 366-4623 vs median 567 ng/1, IQR 148-1899; P < 0.001) levels on ICU admission. Unadjusted odds ratios for 28-day mortality were 1.7 (95% CI 0.8-3.5), 1.6 (0.8-3.3) and 3.6 (1.7-7.5) for increasing quartiles of NT-proBNP as compared to the lowest quartile. Adjusted odds ratios were 1.1 (95% CI 0.5-2.5), 1.1 (0.5-2.5) and 1.6 (0.7-3.8), respectively. A cut-off value of 834 ng/l achieved a sensitivity of 58% and a specificity of 58% to predict 28-day mortality. Of 113 patients, NT-proBNP values of each MTH phase were available and grouped in decreased or increased levels in time. Both decreases and increases of NT-proBNP values were observed during the MTH phases, but presence of either was not associated with outcome. CONCLUSIONS: High NT-proBNP plasma concentrations on ICU admission are associated with high 28-day mortality in post-CA patients treated with MTH in a univariate analysis, but not in a multivariate analysis. Increases or decreases of NT-proBNP levels during MTH appear unrelated to 28 day mortality.

Routine Lupus Anticoagulant Sensitive aPTT Testing Can Prevent Unnecessary LA Testing.

Even though routine screening of the general hospital population is discouraged, medical laboratories may use a "lupus sensitive" activated partial thromboplastin time test (aPTT) with phospholipid concentrations that are susceptible to inhibition by lupus anticoagulant (LA), to screen for the presence of LA. If deemed necessary, follow-up testing according to ISTH guidelines may be performed. However, LA testing is a laborious and time-consuming effort that is often not readily available due to a lack of automation and/or temporary unavailability of experienced staff. In contrast, the aPTT is a fully automated test that is available 24/7 in almost all medical laboratories and is easily interpreted with the use of reference ranges. In addition to clinical signs, the result of an LA sensitive aPTT may thus be used to lower the suspicion of the presence of LA and reduce costly follow-up testing. In this study, we show that a normal LA sensitive aPTT result may be safely used to refrain from LA testing in the absence of strong clinical suspicion.

Rapid screening of critically ill patients for low plasma vitamin C concentrations using a point-of-care oxidation-reduction potential measurement.

BACKGROUND: Hypovitaminosis C and vitamin C deficiency are common in critically ill patients and associated with organ dysfunction. Low vitamin C status often goes unnoticed because determination is challenging. The static oxidation reduction potential (sORP) reflects the amount of oxidative stress in the blood and is a potential suitable surrogate marker for vitamin C. sORP can be measured rapidly using the RedoxSYS system, a point-of-care device. This study aims to validate a model that estimates plasma vitamin C concentration and to determine the diagnostic accuracy of sORP to discriminate between decreased and higher plasma vitamin C concentrations. METHODS: Plasma vitamin C concentrations and sORP were measured in a mixed intensive care (IC) population. Our model estimating vitamin C from sORP was validated by assessing its accuracy in two datasets. Receiver operating characteristic (ROC) curves with areas under the curve (AUC) were constructed to show the diagnostic accuracy of sORP to identify and rule out hypovitaminosis C and vitamin C deficiency. Different cut-off values are provided. RESULTS: Plasma vitamin C concentration and sORP were measured in 117 samples in dataset 1 and 43 samples in dataset 2. Bias and precision (SD) were 1.3 ± 10.0 µmol/L and 3.9 ± 10.1 µmol/L in dataset 1 and 2, respectively. In patients with low plasma vitamin C concentrations, bias and precision were - 2.6 ± 5.1 µmol/L and - 1.1 ± 5.4 µmol in dataset 1 (n = 40) and 2 (n = 20), respectively. Optimal sORP cut-off values to differentiate hypovitaminosis C and vitamin C deficiency from higher plasma concentrations were found at 114.6 mV (AUC 0.91) and 124.7 mV (AUC 0.93), respectively. CONCLUSION: sORP accurately estimates low plasma vitamin C concentrations and can be used to screen for hypovitaminosis C and vitamin C deficiency in critically ill patients. A validated model and multiple sORP cut-off values are presented for subgroup analysis in clinical trials or usage in clinical practice.

Estimating Vitamin C Status in Critically Ill Patients with a Novel Point-of-Care Oxidation-Reduction Potential Measurement.

Vitamin C deficiency is common in critically ill patients. Vitamin C, the most important antioxidant, is likely consumed during oxidative stress and deficiency is associated with organ dysfunction and mortality. Assessment of vitamin C status may be important to identify patients who might benefit from vitamin C administration. Up to now, vitamin C concentrations are not available in daily clinical practice. Recently, a point-of-care device has been developed that measures the static oxidation-reduction potential (sORP), reflecting oxidative stress, and antioxidant capacity (AOC). The aim of this study was to determine whether plasma vitamin C concentrations were associated with plasma sORP and AOC. Plasma vitamin C concentration, sORP and AOC were measured in three groups: healthy volunteers, critically ill patients, and critically ill patients receiving 2- or 10-g vitamin C infusion. Its association was analyzed using regression models and by assessment of concordance. We measured 211 samples obtained from 103 subjects. Vitamin C concentrations were negatively associated with sORP (R2 = 0.816) and positively associated with AOC (R2 = 0.842). A high concordance of 94-100% was found between vitamin C concentration and sORP/AOC. Thus, plasma vitamin C concentrations are strongly associated with plasma sORP and AOC, as measured with a novel point-of-care device. Therefore, measuring sORP and AOC at the bedside has the potential to identify and monitor patients with oxidative stress and vitamin C deficiency.

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.

The effects of hyperoxia on microvascular endothelial cell proliferation and production of vaso-active substances.

BACKGROUND: Hyperoxia, an arterial oxygen pressure of more than 100 mmHg or 13% O2, frequently occurs in hospitalized patients due to administration of supplemental oxygen. Increasing evidence suggests that hyperoxia induces vasoconstriction in the systemic (micro)circulation, potentially affecting organ perfusion. This study addresses effects of hyperoxia on viability, proliferative capacity, and on pathways affecting vascular tone in cultured human microvascular endothelial cells (hMVEC). METHODS: hMVEC of the systemic circulation were exposed to graded oxygen fractions of 20, 30, 50, and 95% O2 for 8, 24, and 72 h. These fractions correspond to 152, 228, 380, and 722 mmHg, respectively. Cell proliferation and viability was measured via a proliferation assay, peroxynitrite formation via anti-nitrotyrosine levels, endothelial nitric oxide synthase (eNOS), and endothelin-1 (ET-1) levels via q-PCR and western blot analysis. RESULTS: Exposing hMVEC to 50 and 95% O2 for more than 24 h impaired cell viability and proliferation. Hyperoxia did not significantly affect nitrotyrosine levels, nor eNOS mRNA and protein levels, regardless of the exposure time or oxygen concentration used. Phosphorylation of eNOS at the serine 1177 (S1177) residue and ET-1 mRNA levels were also not significantly affected. CONCLUSIONS: Exposure of isolated human microvascular endothelial cells to marked hyperoxia for more than 24 h decreases cell viability and proliferation. Our results do not support a role of eNOS mRNA and protein or ET-1 mRNA in the potential vasoconstrictive effects of hyperoxia on isolated hMVEC.