Proactive Management of Intraoperative Hypotension Reduces Biomarkers of Organ Injury and Oxidative Stress during Elective Non-Cardiac Surgery: A Pilot Randomized Controlled Trial

Background: Intraoperative hypotension is associated with increased postoperative morbidity and mortality. Methods: We randomly assigned patients undergoing major general surgery to early warning system (EWS) and hemodynamic algorithm (intervention group, n = 20) or standard care (n = 20). The primary outcome was the difference in hypotension (defined as mean arterial pressure < 65 mmHg) and as secondary outcome surrogate markers of organ injury and oxidative stress. Results: The median number of hypotensive episodes was lower in the intervention group (−5.0 (95% CI: −9.0, −0.5); p < 0.001), with lower time spent in hypotension (−12.8 min (95% CI: −38.0, −2.3 min); p = 0.048), correspondent to −4.8% of total surgery time (95% CI: −12.7, 0.01%; p = 0.048).The median time-weighted average of hypotension was 0.12 mmHg (0.35) in the intervention group and 0.37 mmHg (1.11) in the control group, with a median difference of −0.25 mmHg (95% CI: −0.85, −0.01; p = 0.025). Neutrophil Gelatinase-Associated Lipocalin (NGAL) correlated with time-weighted average of hypotension (R = 0.32; p = 0.038) and S100B with number of hypotensive episodes, absolute time of hypotension, relative time of hypotension and time-weighted average of hypotension (p < 0.001 for all). The intervention group showed lower Neuronal Specific Enolase (NSE) and higher reduced glutathione when compared to the control group. Conclusions: The use of an EWS coupled with a hemodynamic algorithm resulted in reduced intraoperative hypotension, reduced NSE and oxidative stress.

Historical Asbestos Measurements in Denmark—A National Database

Objectives: Due to the long lag-time for health outcomes, historical asbestos exposure measurements are valuable to support assessments of associated occupational health effects, and also to assess time trends and effects of preventive measures. Methods: Different sources of stored data were collated, assessed and refined to create a harmonized database on historical asbestos fibre concentrations measured in specific work tasks and different industries. The final database contains 9236 asbestos measurements from Danish workplaces collected from 1971 to 1997. Results: The geometric mean of asbestos concentrations in different occupations and tasks ranged from 0.003 to 35 fibres cm−3. Highest concentrations were registered during handling of asbestos products in the construction services during the period 1981–1997. Although all the measured asbestos exposures without the use of respiratory equipment by the worker in the period of 1971–1997 exceeded the current 8-h time-weighted average exposure limit of 0.1 fibres cm−3, the majority of samples collected in the earlier period of 1971 to 1980 did not exceed the exposure limit of 2 fibres cm−3, which was in place at the time. All exposure data obtained from 1980 and onwards were found to be one seventh of the mean fibre concentrations in the previous measurement period. The impact of time shows a clear exponentially decreasing trend-line. Conclusions: Despite limitations in coverage of different occupations and tasks associated with the inventoried historical asbestos measurements, the data are helpful to identify specific work scenarios within an industry, where relatively high asbestos exposure levels may still occur or have occurred from 1971 to 1997.

Average corticosteroid dose and risk for HBV reactivation and hepatitis flare in patients with resolved hepatitis B infection

ObjectivesCorticosteroids remain the mainstay of treatment for rheumatic diseases but can cause hepatitis B virus (HBV) reactivation in patients with resolved HBV infection. Risk assessment and stratification are needed to guide the management of these patients before corticosteroid therapy.MethodsWe prospectively enrolled patients with negative hepatitis B surface antigen positive Anti-hepatitis B core status with or without corticosteroid use and determined corticosteroid exposure by calculating cumulative dose and time-weighted average daily dose of prednisone. The primary outcome was the time to a composite of HBV reactivation, hepatitis flare or severe hepatitis.ResultsAmong 1303 participants, the median of cumulative dose and time-weighted average dose of prednisone used in this cohort was 3000 mg (IQR: 300–6750 mg) and 15 mg/day (IQR: 10–20 mg/day), respectively. In multivariable analyses, cumulative dose showed inverted V-shaped relationship with primary events, which peaked at a cumulative dose of 1506 mg (HR: 3.72; 95% CI, 1.96 to 7.08). Quartiles of time-weighted average dose were independently associated with a monotonic increase in event risk (HR per quartile increase: 2.15; 95% CI, 1.56 to 2.98), reaching an HR of 49.48 (95% CI, 6.24 to 392.48) in the top quartile. The incidence of primary outcome was 16.67 per 100 person-years in the top quartile of time-weighted average dose (Q4>20 mg/day). Other quartiles all had an incidence of primary outcome less than 10 per 100 person-years.ConclusionPatients with time-weighted average prednisone dose greater than 20 mg/day would be classified as the high risk for HBV reactivation or hepatitis flare. Prophylactic Anti-HBV therapy may be needed for these high-risk patients.Trial registration numberChiCTR1900023955.

The impact of relative hypotension on acute kidney injury progression after cardiac surgery: a multicenter retrospective cohort study

Background Cardiac surgery is performed worldwide, and acute kidney injury (AKI) following cardiac surgery is a risk factor for mortality. However, the optimal blood pressure target to prevent AKI after cardiac surgery remains unclear. We aimed to investigate whether relative hypotension and other hemodynamic parameters after cardiac surgery are associated with subsequent AKI progression. Methods We retrospectively enrolled adult patients admitted to 14 intensive care units after elective cardiac surgery between January and December 2018. We defined mean perfusion pressure (MPP) as the difference between mean arterial pressure (MAP) and central venous pressure (CVP). The main exposure variables were time-weighted-average MPP-deficit (i.e., the percentage difference between preoperative and postoperative MPP) and time spent with MPP-deficit > 20% within the first 24 h. We defined other pressure-related hemodynamic parameters during the initial 24 h as exploratory exposure variables. The primary outcome was AKI progression, defined as one or more AKI stages using Kidney Disease: Improving Global Outcomes’ creatinine and urine output criteria between 24 and 72 h. We used multivariable logistic regression analyses to assess the association between the exposure variables and AKI progression. Results Among the 746 patients enrolled, the median time-weighted-average MPP-deficit was 20% [interquartile range (IQR): 10–27%], and the median duration with MPP-deficit > 20% was 12 h (IQR: 3–20 h). One-hundred-and-twenty patients (16.1%) experienced AKI progression. In the multivariable analyses, time-weighted-average MPP-deficit or time spent with MPP-deficit > 20% was not associated with AKI progression [odds ratio (OR): 1.01, 95% confidence interval (95% CI): 0.99–1.03]. Likewise, time spent with MPP-deficit > 20% was not associated with AKI progression (OR: 1.01, 95% CI 0.99–1.04). Among exploratory exposure variables, time-weighted-average CVP, time-weighted-average MPP, and time spent with MPP < 60 mmHg were associated with AKI progression (OR: 1.12, 95% CI 1.05–1.20; OR: 0.97, 95% CI 0.94–0.99; OR: 1.03, 95% CI 1.00–1.06, respectively). Conclusions Although higher CVP and lower MPP were associated with AKI progression, relative hypotension was not associated with AKI progression in patients after cardiac surgery. However, these findings were based on exploratory investigation, and further studies for validating them are required. Trial Registration UMIN-CTR, https://www.umin.ac.jp/ctr/index-j.htm, UMIN000037074.

Hemodynamic Responses to Crystalloid and Colloid Fluid Boluses during Noncardiac Surgery

Background Colloids are thought to sustain blood pressure and cardiac index better than crystalloids. However, the relative effects of intraoperative hydroxyethyl starch and crystalloid administration on the cardiac index and blood pressure remain unclear. This study therefore tested in this subanalysis of a previously published large randomized trial the hypothesis that intraoperative goal-directed colloid administration increases the cardiac index more than goal-directed crystalloid administration. Further, the effects of crystalloid and colloid boluses on blood pressure were evaluated. Methods This planned subanalysis of a previous trial analyzed data from 973 patients, of whom 480 were randomized to colloids and 493 were randomized to crystalloids. Fluid administration was guided by esophageal Doppler. The primary outcome was the time-weighted average cardiac index during surgery between the colloid and crystalloid group. The secondary outcomes were the cardiac index just after bolus administration, time elapsed between boluses, and the average real variability during surgery. The study recorded cardiac index, corrected flow time, and blood pressure at 10-min intervals, as well as before and after each bolus. Results Time-weighted average of cardiac index over the duration of anesthesia was only slightly greater in patients given colloid than crystalloid, with the difference being just 0.20 l · min–1 · m–2 (95% CI, 0.11 to 0.29; P &lt; 0.001). However, the hazard for needing additional boluses was lower after colloid administration (hazard ratio [95% CI], 0.60 [0.55 to 0.66]; P &lt; 0.001) in a frailty time-to-event model accounting for within-subject correlation. The median [quartiles] number of boluses per patient was 4 [2, 6] for colloids and 6 [3, 8] for crystalloids, with a median difference (95% CI) of –1.5 (–2 to –1; P &lt; 0.001). The average real mean arterial pressure variability did not differ significantly between the groups (difference in means [95% CI] of –0.03 (–0.07 to 0.02) mmHg, P = 0.229). Conclusions There were not clinically meaningful differences in the cardiac index or mean pressure variability in patients given goal-directed colloid and crystalloids. As might be expected from longer intravascular dwell time, the interval between boluses was longer with colloids. However, on a case basis, the number of boluses differed only slightly. Colloids do not appear to provide substantial hemodynamic benefit. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Performance of Hypotension Prediction Index for Prevention of Hypotension and Results on Biomarkers of Organ Injury and Oxidative Stress During Elective Non-Cardiac Surgery: A Randomized Controlled Trial

Background: Intraoperative hypotension is associated with increased postoperative morbidity and mortality. We tested whether the clinical application of an early warning system (EWS) in combination with an algorithm for hemodynamic management reduces the occurrence of intraoperative hypotension as well as decrease the degree of organ injury and oxidative stress. Methods: We randomly assigned patients undergoing major general surgery EWS and hemodynamic algorithm (intervention group, n=20) or standard care (n=20). The primary outcome was the difference in hypotension (defined as mean arterial pressure<65mmHg) evaluated as episodes, time and time-weighted average of hypotension. As secondary outcome we assessed surrogate markers of organ injury (neuron specific enolase -NSE), S100B protein, high-sensitive troponin, neutrophil gelatinase-associated lipocalin -NGAL) and oxidative stress (reduced glutathione). Results: The median number of hypotensive episodes was lower in the intervention group [-5.0 (95%CI:-9.0,-0.5);P<0.005], with lower time spent in hypotension [-12.8 minutes (95%CI:-38.0,-2.3 min);P<0.001], correspondent to -4.8% of total surgery time (95%CI: -12.7,0.01%; P<0.05). The median time-weighted average of hypotension was 0.12 mmHg (0.35) in the intervention group and 0.37 mmHg (1.11) in the control group, with a median difference of -0.25 mmHg (95%CI:-0.85, -0.01;P<0.05). NGAL was correlated with time-weighted average of hypotension (R=0.32;P<0.05) and S100B with all primary outcomes investigated (all P<0.001). The intervention group had lower NSE and higher reduced glutathione when compared to the control group. Conclusions: The use of an EWS coupled with an hemodynamic algorithm resulted in reduced intraoperative hypotension. This finding was coupled with a reduction of biomarkers of brain injury and oxidative stress.Trial Registration number and date: “Correlation Between Circulating Biomarkers of Organ Damage and Intraoperative Hypotension Management”, NCT03527758, registered on May 17, 2018.https://www.clinicaltrials.gov/ct2/show/NCT03527758?term=NCT03527758&draw=2&rank=1

Longitudinal high-sensitivity C-reactive protein and long-term cardiovascular outcomes in optimally-treated patients with high-risk vascular disease

Background High-sensitivity C-reactive protein (hsCRP) predicts major cardiovascular events (MACE) in patients with chronic atherosclerotic cardiovascular disease. The relationship between serial longitudinal hsCRP assessment and long-term MACE has not been explored. Purpose We tested the hypothesis that longitudinal follow-up hsCRP levels (repeated measures over time) would associate with 30-month MACE (cardiovascular death, myocardial infarction, cerebrovascular accident, coronary revascularization or hospitalization for unstable angina) rates. Methods We performed a post-hoc analysis of the ACCELERATE trial of optimally-treated patients with high-risk vascular disease and evaluated data from patients with available baseline and at least one follow-up hsCRP level measured at 3, 12, and 24 months. Those with a MACE event occurring before 3 months were omitted. Using multivariable Cox proportional hazard models, we determined the association of longitudinal follow-up hsCRP levels with MACE, its components, and all-cause mortality at 30-months, adjusting for age, race, sex, region, smoking status, body mass index, diabetes, baseline hsCRP, low density lipoprotein-cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, statin use, and treatment group. Results Among 8,563 patients, mean age was 64.6±9.3 years and 22.2% were women. Median baseline hsCRP was 1.49 (0.74, 3.3) mg/L. Median time-weighted average follow-up hsCRP was 1.80 (0.88, 3.9) mg/L and mean time-weighted average follow-up LDL-C was 71.7±28.0 mg/dL. At 30 months, there was a significant stepwise relationship between cumulative MACE and increasing tertiles of last prior hsCRP value before an event or censoring (KM estimates for tertiles 1–3, respectively: 8.9 vs. 12.4 vs. 15.6%, p&lt;0.001). In multivariable analysis, higher longitudinal follow-up hsCRP levels were independently associated with MACE [HR (95% CI) per SD: 1.19 (1.10, 1.29), p&lt;0.001], all-cause death [1.66 (1.48, 1.86), p&lt;0.001], cardiovascular death [1.39 (1.19, 1.62), p&lt;0.001], myocardial infarction [1.28 (1.12, 1.46), p&lt;0.001], stroke [1.32 (1.08, 1.62), p=0.007], and coronary revascularization [1.12 (1.01, 1.24), p=0.03], but not with hospitalization for unstable angina [0.94 (0.77, 1.14), p=0.51]. Longitudinal follow-up hsCRP was significantly associated with MACE in patients with baseline hsCRP &lt;2mg/L [1.16 (1.04, 1.30), p=0.008] and ≥2mg/L [1.25 (1.12, 1.40), p&lt;0.001]. Conclusions In the setting of established medical therapies, longitudinal follow-up hsCRP is significantly associated with an increased risk of long-term MACE, myocardial infarction, stroke, cardiovascular mortality, coronary revascularization, and all-cause death. Longitudinal follow-up hsCRP may thus represent a novel marker of residual cardiovascular risk, supporting further work exploring the potential diagnostic and therapeutic implications of these findings. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Iryna Dykun was supported by the German Research Foundation

The Association Between Exposure to Low Magnesium Blood Levels After Renal Transplantation and Cardiovascular Morbidity and Mortality

Background: Serum magnesium levels are associated with cardiovascular disease and all-cause mortality in the general population and chronic kidney disease patients, but the association between serum magnesium levels and cardiovascular risk after kidney transplantation is not established. We sought to evaluate whether exposure to low serum magnesium levels after renal transplantation is related to cardiovascular morbidity and mortality.Methods: We conducted a single center retrospective study that included all transplanted patients who had a functioning graft for at least 6 months after transplantation between January 2001 and December 2013. We calculated exposure to magnesium using time weighted average for serum magnesium levels, using all values available during the follow-up. Several statistical methods were used, including liner regression analysis, χ2 test, and multivariate Cox proportional hazard model.Results: Four hundred ninety-eight patients were included. Median follow-up was 5.26 years. High time weighted average of serum magnesium was associated with a hazard ratio of 1.94 for all-cause mortality and major cardiovascular outcome compared to low levels (95% CI 1.18–3.19, p = 0.009). The high quartile of time weighted average of serum magnesium was associated with death censored major cardiovascular outcome (hazard ratio 2.13, 95% CI 1.17–3.86, p = 0.013) in multivariate analysis.Conclusions: Exposure to low serum magnesium levels in renal transplant recipients was associated with a lower risk for all-cause mortality and major cardiovascular outcome. These findings contrast the higher risk found in the general population.

Comparative Evaluation of the Polar Organic Chemical Integrative Sampler (POCIS) in Two Types of Validation Systems

<p>Polar organic chemical integrative sampler (POCIS) devices have been suggested for monitoring contaminant fluctuations in aquatic environments, resulting from chemical leak accidents. However, the response of the POCIS device in the emergency condition in natural water remains unclear. The response of the POCIS device to contaminant fluctuation was investigated using a simplified chamber test with tap water and a channel test with natural water in the present study. The fluctuation in the chamber and the channel replicated the condition of river water under a chemical leak scenario (maximum concentration: 1–10 μg L^–1, half-life: 1 d). The target chemicals were neonicotinoid pesticides (dinotefuran, clothianidin, thiamethoxam, imidacloprid, acetamiprid, and thiacloprid) and bisphenol A. The ratio of the POCIS measured value to the time-weighted average value of grab samplings (POCIS/TWA) for the channel test (temperature: 15 °C, flow velocity: 15 cm s^–1) ranged from 61% (clothianidin) to 133% (thiacloprid). The results indicated that the POCIS device could be effectively used as a monitoring device in an aquatic environment under the chemical leak scenario. In addition, the differences in the POCIS/TWA ratios obtained from the chamber test and the channel test were in the range of –50 to 50%, except for a few data points. Thus, the simplified chamber test could be used as a validation system to evaluate the POCIS device at a low cost.</p>

Comparative Evaluation of the Polar Organic Chemical Integrative Sampler (POCIS) in Two Types of Validation Systems

<p>Polar organic chemical integrative sampler (POCIS) devices have been suggested for monitoring contaminant fluctuations in aquatic environments, resulting from chemical leak accidents. However, the response of the POCIS device in the emergency condition in natural water remains unclear. The response of the POCIS device to contaminant fluctuation was investigated using a simplified chamber test with tap water and a channel test with natural water in the present study. The fluctuation in the chamber and the channel replicated the condition of river water under a chemical leak scenario (maximum concentration: 1–10 μg L^–1, half-life: 1 d). The target chemicals were neonicotinoid pesticides (dinotefuran, clothianidin, thiamethoxam, imidacloprid, acetamiprid, and thiacloprid) and bisphenol A. The ratio of the POCIS measured value to the time-weighted average value of grab samplings (POCIS/TWA) for the channel test (temperature: 15 °C, flow velocity: 15 cm s^–1) ranged from 61% (clothianidin) to 133% (thiacloprid). The results indicated that the POCIS device could be effectively used as a monitoring device in an aquatic environment under the chemical leak scenario. In addition, the differences in the POCIS/TWA ratios obtained from the chamber test and the channel test were in the range of –50 to 50%, except for a few data points. Thus, the simplified chamber test could be used as a validation system to evaluate the POCIS device at a low cost.</p>