Umbilical Cord Blood Gas Pairs with Near-Identical Results: Probability of Arterial or Venous Source.

OBJECTIVE: In studies of concomitant arterial-venous umbilical cord blood gases (CAV-UBGs), approximately 10% of technically valid samples have very similar pH and/or pCO2 values and were probably drawn from the same type of blood vessel. Without a way to objectively determine the source in these cases, it has been argued that most of these same-source CAV-UBGs are venous because the vein is larger and more easily sampled than the artery. This study aimed to calculate the probability of an arterial (ProbAS) or venous source (ProbVS) of same-source CAV-UBGs in the clinically and medicolegally important pH range of 6.70 to 7.25 using a statistical predictive model based on the cord blood gas values. STUDY DESIGN: Starting with a dataset of 56,703 CAV-UBGs, the ProbAS, ProbVS, and respective 95% confidence intervals (CIs) were calculated for the 241 sample pairs with near-identical pH, pCO2, and pO2 values and a pH of 6.70 to 7.25. Using a previously validated generalized additive model, the source was categorized as: Probable Arterial or Highly Probable Arterial if the ProbAS and CIs were >0.5 or >0.8, respectively; Probable Venous or Highly Probable Venous if the ProbVS and CIs were >0.5 or >0.8, respectively; or Indeterminant if the CIs encompassed ProbAS/VS = 0.5. RESULTS: A total of 39% of the same-source CAV-UBGs were Probable Arterial, 56% were Probable Venous, and 5% were Indeterminant. However, considering samples with a pH ≤7.19, 80% were Probable Arterial and 16% were Probable Venous. Considering the Highly Probable categories, the more acidemic specimens were 9 times more likely to be arterial than venous. Similarly, CAV-UBGs with pCO2 > 8.2 kPa (62 mm Hg) or pO2 ≤ 1.9 kPa (14 mm Hg) were more likely to be in the arterial rather than the venous categories. CONCLUSION: Same-source CAV-UBGs in the more acidemic, hypercarbic, or hypoxemic ranges are more likely to be arterial than venous. KEY POINTS: · Umbilical cord arterial/venous gases (CAV-UBGs) with similar values are thought to be mainly venous.. · A validated statistical model was used to predict the probability an arterial or venous source.. · CAV-UBGs with very similar values and pH > 7.19 are likely venous; however, those with pH ≤ 7.19 and/or pCO2 > 8.2 kPa and/or pO2 ≤1.9 kPa are more likely arterial..

Non-linearity in lipase assays: A multicentric comparison on different analysers.

OBJECTIVES: Non-linearity in lipase assays and the ensuing gaps in results distribution have been described on Roche analysers, but have yet to be studied on other analysers. DESIGN AND METHODS: Eighteen lithium-heparinized plasma pools of lipase activities decreasing from 1700 to <4 U/L were prepared for multicentric evaluation on several analysers. Non-linearity was modelled as the difference between the polynomial regression of lipase activities depending on relative dilutions over the primary measuring range, and the linear regression of the same variables above the manufacturer's limit of linearity (MLL). Gaps in lipase distribution resulting from non-linearity were graphically evidenced through histograms. Upper limits of gaps were calculated, which are lipase activities where non-linearity biases no longer impact the diluted lipase results. RESULTS: MLLs and lipase (U/L) calculated at MLL (%biases versus MLL) were respectively: 1200 and 1124 (-6.3%) on the Architect C16000 (Abbott); 300 and 248 (-17.3%) on the Cobas c503 (Roche); 1500 and 1458 (-2.8%) on the Dimension Vista (Siemens); and 700 and 659 (-5.9%) on the Atellica CH930 (Siemens). Using Sentinel Lipase reagents on Abbott analysers, these measurements were respectively: 300 and 294 (-2.0%) on the Architect C16000, and 300 and 298 (-0.7%) on the Alinity. Setting Randox Lipase reagents on the Alinity, MLL and lipase at MLL were 953 and 776 (-18.6%), respectively. CONCLUSIONS: Considering the desirable (±14.2 %) and optimal (±7.1 %) allowable total error for lipase (EFLM/EuBIVAS), biases at manufacturer's limit of linearity were acceptable, except for Roche Cobas c503 method and Randox method on Abbott Alinity.

Umbilical cord blood gases: probability of arterial or venous source in acidemia.

OBJECTIVES: Umbilical cord blood gases (UBG) may be a critical element in the assessment of a depressed newborn infant but in some cases the arterial or venous UBG source is uncertain making clinical and/or medical-legal interpretation difficult. Objective: to estimate the probability of an arterial (ProbAS) or venous (ProbVS) UBG source depending on blood gas parameters in acidemic cases. METHODS: A total of 56,703 pairs of concomitant arterial and venous (CAV) UBG results assayed over an 8.8-year period were analyzed. Specimen pairs with preanalytical issues, duplicate source, or physiologically out-of-range or uninterpretable results were excluded. The 3,579 CAV-UBGs with an arterial and venous pH 6.70 to 7.25 were analyzed. Generalized additive model (gam)-based binomial logistic regressions were used to determine the ProbAS and ProbVS according to the blood gas parameters. RESULTS: The relative differences between arterial and venous medians were: pO2 ‒47%, pCO2 22%, pH -11%, and BD 4%. Below a median of 2.4 kPa, the lower the pO2, the higher the ProbAS. Above this value, the higher the pO2, the lower the ProbAS. An Excel worksheet is provided to calculate ProbAS and ProbVS from the regression model for different combinations of pH, pCO2, and pO2 values. Considering ProbAS and ProbVS above a cutoff 0.8, the model correctly identified the source in 56% of cases while 41% were indeterminant and 3% were erroneous. CONCLUSIONS: The probability of an arterial or venous source of an umbilical blood gas can be estimated based on the pH, pCO2, and pO2 in most acidemic specimens.

Absolute Versus Relative Changes in Cardiac Troponin T: Corresponding Cutoffs Based on Quantile Generalized Additive Models (QGAM).

BACKGROUND: The diagnosis of myocardial injury/infarction (MI) mainly relies on relative changes in cardiac troponin. However, absolute change cutoffs provide greater diagnostic sensitivity. We determined the absolute changes in high-sensitive cardiac troponin T concentrations (absΔhs-cTnT) corresponding to the main relative cutoffs (relΔhs-cTnT), using a quantile generalized additive model (qgam). METHODS: Plasma Δhs-cTnT from patients selected with a time variation of 1 to 6 hours were collected over a 6-year period. The absΔhs-cTnT-to-relΔhs-cTnT relationship was fitted using qgam, after ordered quantile-based normalization (OQN) to reduce the influence of extreme values. RESULTS: The qgam regression curve was nonlinear. Classifying patients (n = 9,753) above the recommended relΔhs-cTnT and predicted absΔhs-cTnT cutoffs as positive, the MI diagnosis rates were similar, and more reliable using the OQN-transformed data-based qgam, as compared to the untransformed data-based one. CONCLUSIONS: Through an optimized qgam-based approach accounting for heavy-tailed distributions, absolute Δhs-cTnT are provided for the corresponding relative Δhs-cTnT cutoffs.

Relationships between renal function variations and relative changes in cardiac troponin T concentrations based on quantile generalized additive models (qgam).

OBJECTIVES: The relationship between high-sensitive cardiac troponin T concentration (hs-cTnT) and renal markers levels is known. However, the extent to which their variations are associated remains to be explored. Objective: model the relationship between relative changes in hs-cTnT (Δhs-cTnT) and variations in creatinine (Δcre) or estimated glomerular filtration rate (ΔeGFR), using a quantile generalized additive model (qgam). METHODS: Concomitant plasma Δhs-cTnT and Δcre from patients aged 18-100 years, selected with a time variation (Δtime) of 3 h-7 days, were collected over a 5.8-year period. Relationships between Δhs-cTnT and covariates Δcre (A) or ΔeGFR (B), including age, Δtime, hour of blood sampling (HSB) and covariates interactions were fitted using qgam. RESULTS: On the whole (n=106567), Δhs-cTnT was mainly associated with Δcre, in a positive and nonlinear way (-21, -6, +5, +20, +55% for -50, -20, +20, +50, +100%, respectively), but to a lesser extent with age (min -9%, max +2%), Δtime (min -4%, max +8%), and HSB (min -5%, max +7%). Δhs-cTnT was negatively associated with ΔeGFR (+46, +7, -5, -11, -20% for -50, -20, +20, +50, +100%, respectively). Classifying Δhs-cTnT as consistent or not with myocardial injury based on recommendations, an interpretation of Δhs-cTnT adjusted for model A or B led to statistically significant but small diagnostic discrepancies (<2%), as compared to an interpretation based on Δhs-cTnT only. CONCLUSIONS: From a laboratory and statistical standpoint, considering renal function variations when interpreting relative changes in cardiac troponin T has a minor impact on the diagnosis rate of myocardial injury.

Performance of liver biomarkers, in patients at risk of nonalcoholic steato-hepatitis, according to presence of type-2 diabetes.

OBJECTIVE: There is a controversy about the performance of blood tests for the diagnostic of metabolic liver disease in patients with type-2-diabetes in comparison with patients without type-2-diabetes. These indirect comparisons assumed that the gold-standard is binary, whereas fibrosis stages, steatosis and nonalcoholic-steato-hepatitis (NASH) grades use an ordinal scale. The primary aim was to compare the diagnostic performances of FibroTest in type-2-diabetes vs. controls matched on gender, age, fibrosis stages and obesity, and taking into account the spectrum effect by Obuchowski measure. METHODS: Data were retrospectively compared among patients prospectively included, with simultaneous biopsy and blindly assessed FibroTest, SteatoTest-2 and NashTest-2. The secondary aim was to construct an index (SpectrumF3F4-Index) to predict an adjusted-area under the receiver operating curve (AUROC) for F3F4 diagnosis from the prevalences of fibrosis stages, permitting to reduce the spectrum effect when performances of FibroTest, transient elastography and magnetic resonance elastography are indirectly compared. RESULTS: In 505 patients at risk of NASH, the Obuchowski measures [95% confidence interval (CI)] of FibroTest, SteatoTest-2 and NashTest-2 were all equivalent in 136 type-2-diabetes cases vs. 369 matched controls: 0.871 (0.837-0.905), vs. 0.880 (0.879-0.881), 0.835 (0.797-0.873) vs. 0.806 (0.780-0.832) and 0.829 (0.793-0.865) vs. 0.855 (0.829-0.869), respectively. Standard-AUROCs (95% CI) were 0.932 (0.898-0.965), 0.872 (0.837-0.907) and 0.834 (0.699-0.969) and reduced after adjustment by SpectrumF3F4-Index to 0.794 (0.749-0.838), 0.767 (0.750-0.783) and 0.773 (0.725-0.822) for transient, magnetic resonance elastography and FibroTest, respectively. CONCLUSIONS: When compared by Obuchowski measures, the performances of tests were not different in patients with T2-diabetes vs. patients without T2-diabetes. When individual data are not available, adjusted-AUROCs reduced the spectrum effect.

Non-linearity and gaps in results distribution over successive Roche Lipase method applications: improvement but persistence.

Non-linearity within the primary measurement range of a lipase assay (<300 U/L) has been shown on Cobas® Roche analyzers, causing gaps in results distribution between 300 and 400 U/L. Since, new lipase method applications (LMAs) have been used. The purpose is to retrospectively evaluate their impact on relative frequencies of lipase results (RFLs).Plasma lipase results from two hospital laboratories, assayed over 7.2 years, were collected. Over this period, three successive LMAs, characterized by automated repeat-on-dilution (1/11, 1/2, or 1/10), were applied for lipase results >300 U/L: LMA1 and LMA2 on the Modular®P800, Cobas®c501 and Cobas®C701 analyzers, and LMA3 on the Cobas®C701. RFLs were determined, linearity tests were performed, and inter-agreements between lipase results corrected and uncorrected for nonlinear biases were assessed, using 180 U/L as a decisional cut-off for acute pancreatitis.Overall, RFL gaps narrowed from LMA1 (300 to ∼380 U/L) to LMA3 (300 to ∼330 U/L). For a lipase activity fixed at 300 U/L, non-linearity biases were determined at -11.2% on the Modular®P800 (LMA1), -20.8% on the Cobas®c501 (LMA1), and -3.5% (LMA2) and -2.2% (LM3) on the Cobas®C701. Diagnostically, a maximum of 0.48% lipase results were misclassified as negative (LMA1 on the Cobas®c501), and a minimum of 0.01% misclassified as negative (LMA3 on the Cobas®C701). In conclusion, successive Roche lipase method applications improved linearity within the primary measurement range. While persisting, gaps in lipase results distribution narrowed with the evolution of the methods, with a minor impact in terms of diagnostic of acute pancreatitis.

S100B Serum Elevation Predicts In-Hospital Mortality After Brain Arteriovenous Malformation Rupture.

Background and Purpose- S100B protein serum elevation has been associated with poor prognosis in neurologically ill patients. The purpose of this study is to determine whether elevation of S100B is associated with increased in-hospital mortality after brain arteriovenous malformation rupture. Methods- This is a retrospective study of patients admitted for brain arteriovenous malformation rupture. The study population was divided into derivation and validation cohorts. Univariate followed by multivariate logistic regression was used to determine whether elevation of S100B serum levels above 0.5 µg/L during the first 48 hours after admission (S100Bmax48) was associated with in-hospital mortality. Results- Two hundred and three ruptures met inclusion criteria. Twenty-three led to in-hospital mortality (11%). Mean S100Bmax48 was 0.49±0.62 µg/L. In the derivation cohort (n=101 ruptures), multivariate analysis found Glasgow coma scale score ≤8 (odds ratio, 21; 95% CI, 2-216; 0.001) and an S100Bmax48>0.5 µg/L (odds ratio, 19; 95% CI, 2-188; P=0.001) to be associated with in-hospital mortality. When applied to the validation cohort (n=102 ruptures), the same model found only S100Bmax48>0.5 µg/L (odds ratio, 8; 95% CI, 1.5-44; P=0.01) to be associated with in-hospital mortality. Conclusions- Elevated S100B protein serum level is strongly associated with in-hospital mortality after brain arteriovenous malformation rupture.

Reference percentiles for paired arterial and venous umbilical cord blood gases: An indirect nonparametric approach.

BACKGROUND: Reference intervals for arterial and venous umbilical cord blood gas (UCBG) parameters are scarce, are mainly focused on pH, pO2, pCO2 and base deficit, and are usually assessed using parametric tests, despite a generally skewed data distribution. Here, the purpose is to determine reference percentiles for nine parameters of concomitant arterial and venous UCBG (CAV-UCBG) from neonates at birth, using nonparametric tests. METHODS: Results of CAV-UCBG, assayed over a 4.5-year period, were extracted from a hospital laboratory database for pH, pCO2, pO2, oxygen saturation, concentration of total oxygen, total carbon dioxide, hydrogen carbonate, total haemoglobin, and acid-base excess. Exclusion criteria were: a venous-arterial pH difference <0.02, an arterial-venous pCO2 <0.7 kPa, and a venous pCO2 <2.9 kPa. Nonparametric bivariate kernel density estimations were used for the selection of plots within the 95% percentile surface of the pCO2-to-pH relationship (NBKDE-95P). Outliers from skewed data were removed using an adjusted-Tukey method, and percentiles were calculated according to the CLSI EP28-A3 nonparametric method. RESULTS: Overall, 31% (5033/16164) of CAV-UCBG were discarded using the three exclusion criteria. Then, 6% (670/11131) of CAV-UCBG were excluded from the NBKDE-95P, and 0.1 to 3.5% outliers were subsequently removed. Depending on the parameter, the 2.5th and 97.5th percentiles from the whole group were similar or slightly narrower compared to reference intervals from other studies, while those from female and male neonates did not differ substantially. CONCLUSIONS: Using an indirect nonparametric approach, this study proposes new percentiles for parameters from concomitant arterial and venous umbilical cord blood gases.

Sample management for clinical biochemistry assays: Are serum and plasma interchangeable specimens?

The constrained economic context leads laboratories to centralize their routine analyses on high-throughput platforms, to which blood collection tubes are sent from peripheral sampling sites that are sometimes distantly located. Providing biochemistry results as quickly as possible implies to consolidate the maximum number of tests on a minimum number of blood collection tubes, mainly serum tubes and/or tubes with anticoagulants. However, depending on the parameters and their pre-analytical conditions, the type of matrix - serum or plasma - may have a significant impact on results, which is often unknown or underestimated in clinical practice. Importantly, the matrix-related effects may be a limit to the consolidation of analyses on a single tube, and thus must be known by laboratory professionals. The purpose of the present critical review is to put forward the main differences between using serum and plasma samples on clinical biochemistry analyses, in order to sensitize laboratory managers to the need for standardization. To enrich the debate, we also provide an additional comparison of serum and plasma concentrations for approximately 30 biochemistry parameters. Properties, advantages, and disadvantages of serum and plasma are discussed from a pre-analytical standpoint - before, during, and after centrifugation - with an emphasis on the importance of temperature, delay, and transport conditions. Then, differences in results between these matrices are addressed for many classes of biochemistry markers, particularly proteins, enzymes, electrolytes, lipids, circulating nucleic acids, metabolomics markers, and therapeutic drugs. Finally, important key-points are proposed to help others choose the best sample matrix and guarantee quality of clinical biochemistry assays. Moreover, awareness of the implications of using serum and plasma samples on various parameters assayed in the laboratory is an important requirement to ensure reliable results and improve patient care.

Wide-range CRP versus high-sensitivity CRP on Roche analyzers: focus on low-grade inflammation ranges and high-sensitivity cardiac troponin T levels.

Wide-range C-reactive protein (wr-CRP) has been proposed as an economical alternative to high-sensitivity C-reactive protein (hs-CRP) for the evaluation of low-grade inflammation-associated cardiovascular risk (LGI-CVR). Concomitant values of serum hs-CRP and plasma wr-CRP ≤5 mg/L, and high-sensitivity cardiac troponin T (hs-cTnT), all assayed on Roche Diagnostics analyzers over a 1.8-year period, were extracted from a hospital laboratory database. Hs-CRP and wr-CRP values were compared (Bland-Altman method; Deming's correlation), then separately classified into low (<1 mg/L), moderate (1-3 mg/L) and high (>3 mg/L) LGI-CVR ranges for agreement test (κ), assessed before and after Deming's regression-based adjustment of wr-CRP (Adj-wr-CRP). Wr-CRP and hs-CRP values were strongly correlated, with linearity, whether below 5 mg/L (n = 744; τ = 0.933; p < .001) or below 1 mg/L (n = 283; τ = 0.823; p < .001). Overall, wr-CRP values were lower than hs-CRP (mean bias: -0.11 ± 0.17 mg/L). Agreement was good, with 8.1% of wr-CRP values misclassified compared to hs-CRP (κ: 0.874), and weakly improved after regression-based adjustment (7.7% reclassified values; κ: 0.881). Lowering the Adj-wr-CRP cutoff of the moderate LGI-CVR subrange from 1.0 to 0.9 mg/L resulted in an almost perfect agreement (3.2% reclassified data; κ: 0.950). Hs-cTnT concentration was positively associated with hs-CRP, wr-CRP, and Adj-wr-CRP (p < .001). Within each LGI-CVR subrange, hs-cTnT medians were similar regardless of the hs-CRP, wr-CRP or Adj-wr-CRP used for risk classification. Based on hs-cTnT, this study supports the use of wr-CRP as a low-cost alternative to hs-CRP for cardiovascular risk evaluation.

N-terminal pro-brain natriuretic peptide: a potential follow-up biomarker of mandibular advancement device efficacy on cardiac function in obstructive sleep apnea.

Interrelationships between obstructive sleep apnea (OSA) and cardiovascular diseases are now recognized, but some underlying pathophysiological mechanisms remain controversial. Circulating cardiac biomarkers are diagnostic tools that can help understand them, in particular the N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of myocardial stretch, and a potential indicator of subclinical cardiac stress in OSA. Continuous positive airway pressure (CPAP), the first-line treatment of moderate to severe OSA, may be considered as uncomfortable, resulting in poor adherence, and reduced effectiveness. In this case, mandibular advancement devices (MAD) are an effective alternative therapy, more comfortable, and generally well accepted, with higher compliance. To date, few studies have compared the cardiovascular effects of CPAP and MAD. From recent literature reviews, it emerges that both therapies are effective in blood pressure reduction. However, the effects of MAD on other cardiovascular outcomes are conflicting, in particular as regards to its impact on circulating cardiac biomarkers. In a recent ancillary study from a randomized controlled trial, Recoquillon et al concluded that two months of MAD treatment had no effect on NT-proBNP plasma levels in patients with severe OSA. The present discussion analyses this result from a biological, statistical, and analytical standpoint, in light of results from other studies evaluating natriuretic peptides in MAD-treated OSA, with the aim to support further longitudinal studies designed with a high methodological quality.

Determination of age- and sex-specific 99th percentiles for high-sensitive troponin T from patients: an analytical imprecision- and partitioning-based approach.

BACKGROUND: Detection of acute myocardial infarction (AMI) is mainly based on a rise of cardiac troponin with at least one value above the 99th percentile upper reference limit (99th URL). However, circulating high-sensitive cardiac troponin T (hs-cTnT) concentrations depend on age, sex and renal function. Using an analytical imprecision-based approach, we aimed to determine age- and sex-specific hs-cTnT 99th URLs for patients without chronic kidney disease (CKD). METHODS: A 3.8-year retrospective analysis of a hospital laboratory database allowed the selection of adult patients with concomitant plasma hs-cTnT (<300 ng/L) and creatinine concentrations, both assayed twice within 72 h with at least 3 h between measurements. Absence of AMI was assumed when the variation between serial hs-cTnT values was below the adjusted-analytical change limit calculated according to the inverse polynomial regression of analytical imprecision. Specific URLs were determined using Clinical and Laboratory Standards Institute (CLSI) methods, and partitioning was tested using the proportion method, after adjustment for unequal prevalences. RESULTS: After outlier removal (men: 8.7%; women: 6.6%), 1414 men and 1082 women with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 were assumed as non-AMI. Partitioning into age groups of 18-50, 51-70 and 71-98 years, the hs-cTnT 99th URLs adjusted on French prevalence were 18, 33, 66 and 16, 30, 84 ng/L for men and women, respectively. Age-partitioning was clearly required. However, sex-partitioning was not justified for subjects aged 18-50 and 51-70 years for whom a common hs-cTnT 99th URLs of about 17 and 31 ng/L could be used. CONCLUSIONS: Based on a laboratory approach, this study supports the need for age-specific hs-cTnT 99th URLs.

Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study.

Hepatic encephalopathy (HE) influences short-term and long-term prognoses. Recently, glycerol phenylbutyrate (PB), that lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion, has shown that it was effective in preventing the occurrence of HE in RCT. The aim was to assess the benefits of sodium PB in cirrhotic patients admitted to ICU for overt HE, in terms of ammonia levels decrease, neurological improvement, and survival. Cirrhotic patients who presented with overt HE, ammonia levels >100 µmol/L, and did not display any contra-indication were included. Sodium PB was administered at 200 mg/kg/day. Control group included historical controls treated by standard therapy, matched for age, sex, MELD score, and severity of HE. Eighteen patients were included and treated with sodium PB (age: 59 [45-68], male gender: 15 [83%], Child-Pugh B: 8 [44%], Child-Pugh C: 10 [56%], and MELD score: 16 [13-23]). Ammonia levels significantly decreased in the PB as compared to the control group from inclusion to 12 h and from inclusion to 48 h (P = 0.0201 and P = 0.0230, respectively). The proportion of patients displaying neurological improvement was only higher in the PB-treated group as compared to controls at ICU discharge (15 [83%] vs. 9 [50%], P = 0.0339). ICU discharge survival was significantly higher in patients treated with PB (17 [94%] vs. 9 [50%], P = 0.0017). In cirrhotic patients with overt HE, sodium PB could be effective in reducing ammonia levels and might be effective in improving neurological status and ICU discharge survival. More extensive data, especially a RCT, are mandatory.