Comparison of models to explain the association of postnatal age with carboxyhemoglobin levels.

<p>Comparison of models to explain the association of postnatal age with carboxyhemoglobin levels.</p

Determinants of Carboxyhemoglobin Levels and Relationship with Sepsis in a Retrospective Cohort of Preterm Neonates

<div><p>Carboxyhemoglobin levels in blood reflect endogenous carbon monoxide production and are often measured during routine blood gas analysis. Endogenous carbon monoxide production has been reported to be increased during sepsis, but carboxyhemoglobin levels have not been thoroughly evaluated as a biomarker of sepsis. We sought to determine whether carboxyhemoglobin levels were elevated during sepsis in a high risk population of premature neonates. We conducted a retrospective cohort study of 30 infants in two neonatal intensive care units using electronic medical and laboratory records. The majority of infants were extremely premature and extremely low birth weight, and 25 had at least one episode of sepsis. We collected all carboxyhemoglobin measurements during their in-patient stay and examined the relationship between carboxyhemoglobin and a variety of clinical and laboratory parameters, in addition to the presence or absence of sepsis, using linear mixed-effect models. We found that postnatal age had the most significant effect on carboxyhemoglobin levels, and other significant associations were identified with gestational age, hemoglobin concentration, oxyhemoglobin saturation, and blood pH. Accounting for these covariates, there was no significant relationship between the onset of sepsis and carboxyhemoglobin levels. Our results show that carboxyhemoglobin is unlikely to be a clinically useful biomarker of sepsis in premature infants, and raise a note of caution about factors which may confound the use of carbon monoxide as a clinical biomarker for other disease processes such as hemolysis.</p></div

Linear mixed-effects model to describe the effect of variables on COHb levels in the absence of sepsis.

<p>Linear mixed-effects model to describe the effect of variables on COHb levels in the absence of sepsis.</p

Characteristics of study subjects.

<p>Characteristics of study subjects.</p

Linear mixed-effects model to describe the effect of variables on COHb levels including data at the onset of sepsis.

<p>Linear mixed-effects model to describe the effect of variables on COHb levels including data at the onset of sepsis.</p

Multiple linear regression analysis of the relationships between ADMA and arginine and hemoglobin, HRP2, sVCAM, or lactate.

<p>ADMA, Arg, HRP2, and sVCAM were natural log-transformed. Lactate was square root-transformed. ADMA and arginine were explanatory variables in four separate linear models predicting hemoglobin, HRP2, sVCAM, or Lactate.</p><p>Multiple linear regression analysis of the relationships between ADMA and arginine and hemoglobin, HRP2, sVCAM, or lactate.</p

The ADMA/arginine ratio is acutely elevated in African children with severe malaria.

<p>ADMA and arginine concentrations were measured in plasma samples collected at the time of presentation (Day 0) and at follow-up visits 28 days later (Day 28) in children with WHO-defined uncomplicated malaria or severe malaria. Healthy Gambian children served as a reference group. Wilcoxon test was used for pair-wise comparison of admission and day 28 mesurements within individuals (47 paired observations from patients with severe malaria; 65 paired observations from patients with uncomplicated malaria). Mann-Whitney test was used to compare patients with severe malaria (n = 81) versus uncomplicated malaria (n = 75) and to compare patients with uncomplicated malaria versus healthy children (n = 31). Each horizontal line depicts the group median. **** p < 0.0001; ns p > 0.05.</p

DDAH regulates NO synthesis via ADMA metabolism.

<p>Protein arginine methyltransferases (PRMTs) methylate arginine (Arg) residues on proteins to form asymmetric dimethylarginine (ADMA). Proteolysis releases free ADMA that inhibits nitric oxide synthase (NOS). Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes free ADMA to citrulline (Cit) that can be recycled to arginine. Inactivation of DDAH leads to accumulation of ADMA, inhibition of endothelial NO synthesis, and endothelial dysfunction.</p

Baseline clinical characteristics of the study population.

<p>Values are presented as median [interquartile range]. ADMA: asymmetric dimethylarginine, sVCAM: soluble vascular cell adhesion molecule, PfHRP2: <i>P</i>. <i>falciparum</i> histidine-rich protein 2.</p><p>^a p < 0.001 compared to healthy Gambian children by Mann-Whitney test.</p><p>^b p < 0.001 compared to uncomplicated malaria by Mann-Whitney test.</p><p>Baseline clinical characteristics of the study population.</p

Correlation of ADMA with biomarkers of anemia, hemolysis, parasite biomass, endothelial activity, and tissue perfusion among children with severe malaria.

<p>ADMA, Arg, ADMA/Arg, HRP2 and sVCAM were natural log-transformed. Hemoglobin was normally distributed and was not transformed. Lactate was square root-transformed. Haptoglobin could not be transformed to a normally distributed variable. All correlations were calculated using Pearson’s method, except for correlations with haptoglobin which were calculated using Spearman’s method. A plot of each correlation is presented in the supplement (<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005119#ppat.1005119.s005" target="_blank">S3 Fig</a>).</p><p>Correlation of ADMA with biomarkers of anemia, hemolysis, parasite biomass, endothelial activity, and tissue perfusion among children with severe malaria.</p