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1.  Cardiac troponin I levels in canine pyometra 
Myocardial injury may contribute to unexpected deaths due to pyometra. To detect myocardial damage, measurement of cardiac troponin I (cTnI) is currently the most sensitive and specific method. The aims of the present study were to evaluate presence of myocardial damage in canine pyometra by analysis of cTnI, to explore whether myocardial injury was associated with systemic inflammatory response syndrome (SIRS) and to evaluate whether other clinical or laboratory parameters were associated with cTnI increase.
Preoperative plasma levels of cTnI were investigated in 58 female dogs with pyometra and 9 controls. The value of physical examination findings, haematological, serum biochemical and pro-inflammatory (CRP and TNF-α) parameters as possible predictors of increased cTnI levels was also evaluated.
Seven dogs with pyometra (12%) and one control dog (11%) had increased levels of cTnI. In the pyometra group, the levels ranged between 0.3–0.9 μg l-1 and in the control dog the level was 0.3 μg l-1. The cTnI levels did not differ significantly between the two groups. No cardiac abnormalities were evident on preoperative physical examinations. Four of the pyometra patients died within two weeks of surgery, of which two were examined post mortem. In one of these cases (later diagnosed with myocarditis and disseminated bacterial infection) the cTnI levels increased from 0.9 μg l-1 preoperatively to 180 μg l-1 the following day when also heart arrhythmia was also detected. The other patient had cTnI levels of 0.7 μg l-1 with no detectable heart pathology post mortem. CTnI increase was not associated with presence of SIRS. There was a trend for the association of cTnI increase with increased mortality. No preoperative physical examination findings and few but unspecific laboratory parameters were associated with increased cTnI levels.
Increased cTnI levels were observed in 12% of the dogs with pyometra. The proportions of dogs with cTnI increase did not differ significantly in the pyometra group compared with the control group. CTnI increase was not associated with presence of SIRS. A trend for association of cTnI increase and mortality was observed. Preoperative physical examination findings and included laboratory parameters were poor predictors of increased cTnI levels.
PMCID: PMC1839102  PMID: 17328800
2.  Biomarkers for Severity of Neonatal Hypoxic-Ischemic Encephalopathy and Outcomes in Newborns Receiving Hypothermia Therapy 
The Journal of pediatrics  2013;164(3):468-74.e1.
To evaluate serum neuronal and inflammatory biomarkers to determine whether measurements of umbilical cords at birth can stratify severity of hypoxic-ischemic encephalopathy (HIE), whether serial measurements differ with hypothermia-rewarming, and whether biomarkers correlate with neurological outcomes.
Study design
This is a prospective cohort of inborn term newborns with varying degrees of HIE by neurological assessment. Neuronal glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and inflammatory cytokines were measured in serum from umbilical artery at 6–24, 48, 72, and 78 hours of age. Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales) were performed at 15–18 months.
Twenty neonates had moderate (n = 17) or severe (n = 3) HIE and received hypothermia; 7 had mild HIE and were not cooled. At birth, serum GFAP and ubiquitin carboxyl-terminal hydrolase L1 increased with the severity of HIE (P < .001), and serial GFAP remained elevated in neonates with moderate to severe HIE. Interleukin (IL)-6, IL-8, and vascular endothelial growth factor were greater at 6–24 hours in moderate to severe vs mild HIE (P < .05). The serial values were unaffected by hypothermia-rewarming. Elevated GFAP, IL-1, IL-6, IL-8, tumor necrosis factor, interferon, and vascular endothelial growth factor at 6–24 hours were associated with abnormal neurological outcomes.
The severity of the hypoxic-ischemic injury can be stratified at birth because elevated neuronal biomarkers in cord serum correlated with severity of HIE and outcomes.
PMCID: PMC4006934  PMID: 24332821
3.  Cardiac output, pulmonary artery pressure, and patent ductus arteriosus during therapeutic cooling after global hypoxia-ischaemia 
Objective: To assess by Doppler echocardiography the effects of 24 hours of whole body mild hypothermia compared with normothermia on cardiac output (CO), pulmonary artery pressure (PAP), and the presence of a persistent ductus arteriosus (PDA) after a global hypoxic-ischaemic insult in unsedated newborn animals.
Design: Thirty five pigs (mean (SD) age 26.6 (12.1) hours and weight 1.6 (0.3) kg) were anaesthetised with halothane, mechanically ventilated, and subjected to a 45 minute global hypoxic-ischaemic insult. At the end of hypoxia, halothane was stopped; the pigs were randomised to either normathermia (39°C) or hypothermia (35°C) for 24 hours. Rewarming was carried out for 24–30 hours followed by 42 hours of normothermia. Unanaesthetised pigs were examined with a VingMed CFM 750 ultrasound scanner before and 3, 24, 30, and 48 hours after the hypoxic-ischaemic insult. Aortic valve diameter, forward peak flow velocities across the four valves, and the occurrence of a PDA were measured. Tricuspid regurgitation (TR) velocity was used to estimate the PAP. Stroke volume was calculated from the aortic flow.
Results: Twelve animals (seven normothermic, five hypothermic) had a PDA on one or more examinations, which showed no association with cooling or severity of insult. There were no differences in stroke volume or TR velocity between the hypothermic and normothermic animals at any time point after the insult. CO was, however, 45% lower at the end of cooling in the subgroup of hypothermic pigs that had received a severe insult compared with the pigs with mild and moderate insults. CO and TR velocity were transiently increased three hours after the insult: 0.38 (0.08) v 0.42 (0.08) litres/min/kg (p = 0.007) for CO; 3.0 (0.42) v 3.4 (0.43) m/s (p < 0.0001) for TR velocity (values are mean (SD)).
Conclusions: The introduction of mild hypothermia while the pigs were unsedated did not affect the incidence of PDA nor did it lead to any changes in MABP or PAP. Stroke volume was also unaffected by temperature, but hypothermic piglets subjected to a severe hypoxic-ischaemic insult had reduced CO because the heart rate was lower. Global hypoxia-ischaemia leads to similar transient increases in CO and estimated PAP in unsedated normothermic and hypothermic pigs. There were no signs of metabolic compromise in any subgroup, suggesting that 24 hours of mild hypothermia had no adverse cardiovascular effect.
PMCID: PMC2291510  PMID: 12719397
4.  Hepatic Dysfunction in Asphyxiated Neonates: Prospective Case-Controlled Study 
This study was performed to determine the occurrence of hypoxic hepatitis in full-term neonates after perinatal asphyxia and to correlate between the rise in enzymes and severity of asphyxia with Apgar score and hypoxic ischemic encephalopathy (HIE) grading of the neonates.
This prospective case-controlled study was conducted in a tertiary-level hospital in India for a period of 12 months. The study group A comprised 70 newborns suffering from birth asphyxia, while 30 healthy neonates were included in group B (control). All biochemical parameters of liver function, ie, serum alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein, serum albumin, bilirubin (total and direct), and international normalized ratio (INR), were measured on postnatal days 1, 3, and 10 in both study and control groups.
In group A, 22.8% newborns had severe (Apgar score 0–3), 47.1% had moderate (Apgar score 4–5), and 30% had mild (Apgar score 6–7) birth asphyxia at five minutes. In all, 14.28% babies were in HIE stage I, 25.73% babies were in HIE stage II, and 11.42% babies were in HIE stage III. The rest of the newborns, 48.57%, were normal. The prevalence of liver function impairment was seen in 42.85% of asphyxiated neonates. On day 1, ALT, AST, ALP, LDH, PT, and INR were significantly higher, and total protein and serum albumin were significantly lower in group A than in group B. However, ALT and AST correlated well with increasing severity of HIE score. On day 3, there was a rising trend observed in the concentration of mean LDH as HIE staging of neonates progressed from stage 0 to stage III, and among various HIE stages, the difference in LDH was statistically significant.
We concluded that AST, ALT at 24 hours, and LDH at 72 hours of animation can be a utilitarian diagnostic tool to differentiate asphyxiated neonates from non-asphyxiated neonates and to discover the severity of perinatal asphyxia because of easy accessibility and feasibility of tests. The outcomes of this survey would be useful for physicians who receive neonates for whom birth details are not easily documented as most of the time the referred newborn infants lack asphyxia history either because the attendants do not know clearly the whole birth history or it was an unattended delivery, or the referring health-care professional has not been observant because of legal threats. The neurological assessment also becomes difficult and inconclusive as ventilator treatment, sedative drugs, and anticonvulsant therapy would produce an evaluation of severity of hypoxic ischemic brain disease and neurological insult difficult.
PMCID: PMC4294631
birth asphyxia; hypoxic ischemic encephalopathy; hepatic dysfunction
5.  Differential Effects of Phosphorylation of Regions of Troponin I in Modifying Cooperative Activation of Cardiac Thin Filaments 
Ischemia and heart failure are associated with protein kinase C (PKC) dependent phosphorylation of cardiac troponin I (cTnI). We investigated the effect of phosphorylation of cTnI PKC sites S43, S45 and T144 under normal (pH 7.0) and acidic (pH 6.5) conditions on tension in skinned fiber bundles from mouse heart. To mimic the PKC-phosphorylation, we exchanged troponin (cTn) in these fiber bundles with cTn complex containing either cTnI-(S43E/S45E) or cTnI-(T144E). We determined how pseudo-phosphorylation and acidic pH affect activation of thin filaments by strongly bound crossbridges by use of n-ethyl maleimide (NEM-S1) to mimic rigor. We hypothesized that PKC-phosphorylation of cTnI amplifies the effect of ischemic/hypoxic conditions to depress myofilament force and Ca2+ -responsiveness by reducing the ability of rigor crossbridge to activate force. Pseudo-phosphorylation of cTnI at S43/S45 exacerbated the effect of acidic pH to induce a rightward shift in the Ca2+ -tension relation. Under acidic conditions, fibers regulated by cTnI-(S43E/S45E) demonstrated a significant reduction in the ability of NEM-S1 to recruit cycling crossbridges, when compared to controls regulated by cTnI. Similar effects of pseudo-phosphorylation of cTnI-(T144) occurred, but to a lesser extent that those of pseudo-phosphorylation of S43/S45. We conclude that under acidic conditions PKC-phosphorylation of cTnI residues at S43/S45 and at T144 is likely to have differential, but significant effects in depressing the ability of both Ca2+ and rigor crossbridges to activate force generation. Although these effects of PKC dependent phosphorylation may be maladaptive in heart failure, they may also spare ATP consumption and be cardioprotective in ischemia.
PMCID: PMC2716429  PMID: 19426736
Protein Kinase C (PKC); ischemia; acidosis; crossbridges
6.  Impact of therapeutic hypothermia on MRI diffusion changes in neonatal encephalopathy 
Neurology  2012;78(18):1420-1427.
The objective of this work was to determine the impact of therapeutic hypothermia (TH) on the magnitude and time course of mean diffusivity (MD) changes following hypoxic-ischemic encephalopathy (HIE) in newborns.
Cerebral MRI scans of infants undergoing whole body TH for HIE from 2007 to 2010 were retrospectively reviewed. The data were analyzed identically to a control group of newborns with HIE previously published, prior to the development of TH. Anatomic injury was defined on T1- and T2-weighted (“late”) MRI obtained after the fifth day of life. Since MD values vary regionally, the ratios of MD values for injured and normal tissue were calculated for areas of injury. Normal values were obtained from corresponding brain regions of 12 infants undergoing TH who had no injury on MRI studies.
Twenty-three of 59 infants who underwent TH and MRI displayed cerebral injury on late MRI and were included in the study. MD ratios were decreased in all injured infants within the first 7 days of life. The return of MD to normal (pseudonormalization) occurred after the tenth day as compared to 6–8 days in the control group. Infants with severest injury demonstrated greater reduction in MD, but no difference in time to pseudonormalization.
TH slows the evolution of diffusion abnormalities on MRI following HIE in term infants.
PMCID: PMC3345786  PMID: 22517107
7.  Changes in the PQRST Intervals and Heart Rate Variability Associated with Rewarming in Two Newborns Undergoing Hypothermia Therapy 
Neonatology  2009;96(2):93-95.
Little is known about the effects of hypothermia therapy and subsequent rewarming on the PQRST intervals and heart rate variability (HRV) in term newborns with hypoxic-ischemic encephalopathy (HIE).
This study describes the changes in the PQRST intervals and HRV during rewarming to normal core body temperature of 2 newborns with HIE after hypothermia therapy.
Within 6 h after birth, 2 newborns with HIE were cooled to a core body temperature of 33.5°C for 72 h using a cooling blanket, followed by gradual rewarming (0.5°C per hour) until the body temperature reached 36.5°C. Custom instrumentation recorded the electrocardiogram from the leads used for clinical monitoring of vital signs. Generalized linear mixed models were calculated to estimate temperature-related changes in PQRST intervals and HRV.
For every 1°C increase in body temperature, the heart rate increased by 9.2 bpm (95% CI 6.8–11.6), the QTc interval decreased by 21.6 ms (95% CI 17.3–25.9), and low and high frequency HRV decreased by 0.480 dB (95% CI 0.052–0.907) and 0.938 dB (95% CI 0.460–1.416), respectively.
Hypothermia-induced changes in the electrocardiogram should be monitored carefully in future studies.
PMCID: PMC2957844  PMID: 19252411
Hypoxic-ischemic encephalopathy; Hypothermia therapy; Electrocardiogram; QT interval; Heart rate variability
8.  Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study 
BMC Pediatrics  2012;12:45.
In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180–185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.
Multicenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.
On basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references.
Trial registration
PMCID: PMC3358232  PMID: 22515424
Perinatal asphyxia, Therapeutic hypothermia; Pharmacokinetic research; Drug monitoring; Evidence based; Drug dosing; Guideline
9.  Hypocarbia and Adverse Outcome in Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of pediatrics  2010;158(5):752-758.e1.
To evaluate the association between early hypocarbia and 18-22 month outcome among neonates with hypoxic-ischemic encephalopathy (HIE).
Study design
Data from the NICHD NRN randomized controlled trial of whole body hypothermia for neonatal HIE were used for this secondary observational study. Infants (n=204) had multiple blood gases recorded from birth-12h of study intervention (hypothermia vs. intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18-22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO2 and cumulative exposure to PCO2 <35 mmHg. The relationship between cumulative PCO2 <35 mmHg (calculated as the difference between 35mmHg and the sampled PCO2 multiplied by the duration of time spent <35 mmHg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), time to spontaneous respiration and ventilator days; results were expressed as OR and 95% confidence intervals. Alternative models of CO2 concentration were explored to account for fluctuations in CO2.
Both minimum PCO2 and cumulative PCO2 <35mmHg were associated with poor outcome (P<0.05). Moreover, death/disability increased with greater cumulative exposure to PCO2 <35mmHg.
Hypocarbia is associated with poor outcome following HIE.
PMCID: PMC3229432  PMID: 21146184
hypocarbia; hypoxic ischemic encephalopathy; whole body hypothermia; outcome; neurodevelopmental impairment
10.  Cardiac isoenzymes in healthy Holstein calves and calves with experimentally induced endotoxemia 
This paper describes a controlled study designed to establish normal values for cardiac troponins I and T (cTnI and cTnT) and CK-MB mass in healthy newborn Holstein calves, and to compare values for cTnI, cTnT, CK-MB and total creatine kinase (CK) with age-matched calves experiencing experimentally induced endotoxemia. Nineteen healthy Holstein bull calves, 48 to 72 h of age were used. Baseline cTnI, cTnT, CK-MB and total CK measurements were obtained from control (n = 9) and experimental (n = 10) calves. Controls then received physiological saline and experimental calves received endotoxin (O55:B5 Escherichia coli LPS) intravenously after which cardiac biomarkers and total CK were measured at 3 h, 6 h, 12 h, and 24 h post-initiation of infusion. Measured values were analyzed and compared using analysis of variance (ANOVA) by repeated measure design, with statistical significance set at P < 0.05. The cardiac biomarker cTnT was not detected in any calf at any time point, and CK-MB was only detected in 5 of 95 samples. The cTnI was significantly increased compared to baseline and controls, 3 h post lipopolysaccharide (LPS) infusion. Total CK was significantly increased in LPS administered calves at 18 and 24 h post infusion. The mean, standard deviation, and range for cTnI in healthy controls were 0.023 ng/mL (s = 0.01), and 0.01 to 0.05 ng/mL, respectively. In conclusion, LPS administration was associated with rapid and significant increases in cTnI but CK-MB and cTnT were not detected in the plasma of healthy calves. Total CK values increased significantly following LPS administration. Biochemical evidence of myocardial injury occurs within 3 h following LPS administration to neonatal Holstein calves.
PMCID: PMC2442679  PMID: 18783025
11.  Restoration of cardiopulmonary function with 21% versus 100% oxygen after hypoxaemia in newborn pigs 
Objective: To assess the consequences of hypoxaemia and resuscitation with room air versus 100% O2 on cardiac troponin I (cTnI), cardiac output (CO), and pulmonary artery pressure (PAP) in newborn pigs.
Design: Twenty anaesthetised pigs (12–36 hours; 1.7–2.7 kg) were subjected to hypoxaemia by ventilation with 8% O2. When mean arterial blood pressure fell to 15 mm Hg, or arterial base excess was ⩽ –20 mmol/l, resuscitation was performed with 21% (n = 10) or 100% (n = 10) O2 for 30 minutes, then ventilation with 21% O2 for 120 minutes. Blood was analysed for cTnI. Ultrasound examinations of CO and PAP (estimated from tricuspid regurgitation velocity (TR-Vmax)) were performed at baseline, during hypoxia, and at the start of and during reoxygenation.
Results: cTnI increased from baseline to the end point (p<0.001), confirming a serious myocardial injury, with no differences between the 21% and 100% O2 group (p = 0.12). TR-Vmax increased during the insult and returned towards baseline values during reoxygenation, with no differences between the groups (p = 0.11) or between cTnI concentrations (p = 0.31). An inverse relation was found between increasing age and TR-Vmax during hypoxaemia (p = 0.034). CO per kg body weight increased during the early phase of hypoxaemia (p<0.001), then decreased. Changes in CO per kg were mainly due to changes in heart rate, with no differences between the groups during reoxygenation (p = 0.298).
Conclusion: Hypoxaemia affects the myocardium and PAP. During this limited period of observation, reoxygenation with 100% O2 showed no benefits compared with 21% O2 in normalising myocardial function and PAP. The important issue may be resuscitation and reoxygenation without hyperoxygenation.
PMCID: PMC1721882  PMID: 15846013
12.  An Inhibitor of the δPKC Interaction with the d Subunit of F1Fo ATP Synthase Reduces Cardiac Troponin I Release from Ischemic Rat Hearts: Utility of a Novel Ammonium Sulfate Precipitation Technique 
PLoS ONE  2013;8(8):e70580.
We have previously reported protection against hypoxic injury by a cell-permeable, mitochondrially-targeted δPKC-d subunit of F1Fo ATPase (dF1Fo) interaction inhibitor [NH2-YGRKKRRQRRRMLA TRALSLIGKRAISTSVCAGRKLALKTIDWVSFDYKDDDDK-COOH] in neonatal cardiac myo-cytes. In the present work we demonstrate the partitioning of this peptide to the inner membrane and matrix of mitochondria when it is perfused into isolated rat hearts. We also used ammonium sulfate ((NH4)2SO4) and chloroform/methanol precipitation of heart effluents to demonstrate reduced card-iac troponin I (cTnI) release from ischemic rat hearts perfused with this inhibitor. 50% (NH4)2SO4 saturation of perfusates collected from Langendorff rat heart preparations optimally precipitated cTnI, allowing its detection in Western blots. In hearts receiving 20 min of ischemia followed by 30, or 60 min of reperfusion, the Mean±S.E. (n = 5) percentage of maximal cTnI release was 30±7 and 60±17, respectively, with additional cTnI release occurring after 150 min of reperfusion. Perfusion of hearts with the δPKC-dF1Fo interaction inhibitor, prior to 20 min of ischemia and 60–150 min of reperfusion, reduced cTnI release by 80%. Additionally, we found that when soybean trypsin inhibitor (SBTI), was added to rat heart effluents, it could also be precipitated using (NH4)2SO4 and detected in western blots. This provided a convenient method for normalizing protein recoveries between groups. Our results support the further development of the δPKC-dF1Fo inhibitor as a potential therapeutic for combating cardiac ischemic injury. In addition, we have developed an improved method for the detection of cTnI release from perfused rat hearts.
PMCID: PMC3731279  PMID: 23936451
13.  Circulating miRNAs reflect early myocardial injury and recovery after heart transplantation 
MicroRNAs (miRNAs) are short, single-stranded and non-coding RNAs, freely circulating in human plasma and correlating with vary pathologies. In this study, we monitored early myocardial injury and recovery after heart transplantation by detecting levels of circulating muscle-specific miR-133a, miR-133b and miR-208a.
7 consecutive patients underwent heart transplantation in Fuwai hospital and 14 healthy controls were included in our study. Peripheral vein blood was drawn from patients on the day just after transplantation (day 0), the 1st, 2nd, 3rd, 7th and 14th day after transplantation respectively. Serum from peripheral blood was obtained for cardiac troponin I (cTnI) measurement. Plasma was centrifuged from peripheral blood for measuring miR-133a, miR-133b and miR-208a by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The plasma concentration of miRNAs were calculated by absolute quantification method. The sensitivity and specificity of circulating miRNAs were revealed by receiver operating characteristic curve (ROC) analysis. Correlations between miRNAs and cTnI / perioperative parameters were analyzed.
Similar to cTnI, miR-133a, miR-133b and miR-208a all showed dynamic changes from high to low levels early after operation. The Sensitivity and specificity of miRNAs were: miR-133a (85.7%,100%), miR-208a (100%,100%), and miR-133b (90%,100%). Correlations between miRNAs and cTnI were statistically significant (p < 0.05), especially for miR-133b (R2 = 0.813, p < 0.001). MiR-133b from Day 0-Day 2 (r > 0.98, p < 0.01), and cTnI from Day 1- Day 3 (r > 0.86, p < 0.05) had strong correlations with bypass time, particularly parallel bypass time. Obviously, miR-133b had a better correlation than cTnI. Circulating miR-133b correlated well with parameters of heart function such as central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and inotrope support, while cTnI only correlated with 3 of the 4 parameters mentioned above. MiR-133b also had strong correlations with ventilation time (r > 0.99, p < 0.001) and length of ICU stay (r > 0.92, p < 0.05), both of which reflected the recovery after operation. The correlation coefficients of miR-133b were also higher than that of cTnI.
The dynamic change in circulating muscle-specific miRNAs, especially miR-133b can reflect early myocardial injury after heart transplantation. And miR-133b may have advantages over cTnI in forecasting graft dysfunction and recovery of patients after operation.
PMCID: PMC3716980  PMID: 23816326
Circulating miRNAs; Myocardial injury; Ischemia-reperfusion injury; Heart surgery; Heart transplantation
14.  Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of Pediatrics  2011;160(4):567-572.e3.
To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.
Study design
Stage of encephalopathy was evaluated at <6 hr of age, during study intervention and at discharge among 204 participants in the NICHD Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.
Moderate and severe HIE occurred at <6 hrs of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hrs of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hrs increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at < 6hrs for death/disability.
On serial neurological examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurological exam at discharge was associated with a greater risk of death or disability.
PMCID: PMC3299861  PMID: 22050871
Neurological examinations; neonates; clinical biomarker; death; disability
15.  Cerebrovascular autoregulation and neurologic injury in neonatal hypoxic-ischemic encephalopathy 
Pediatric research  2013;74(5):525-535.
Neonates with hypoxic-ischemic encephalopathy (HIE) are at risk of cerebral blood flow dysregulation. Our objective was to describe the relationship between autoregulation and neurologic injury in HIE.
Neonates with HIE had autoregulation monitoring with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The 5-mmHg range of mean arterial blood pressure (MAP) with best vasoreactivity (MAPOPT) was identified. The percentage of time spent with MAP below MAPOPT and deviation in MAP from MAPOPT were measured. Neonates received brain MRIs 3–7 days after treatment. MRIs were coded as no, mild, or moderate/severe injury in five regions.
HVx identified MAPOPT in 79% (19/24), 77% (17/22), and 86% (18/21) of neonates during hypothermia, rewarming, and normothermia, respectively. Neonates with moderate/severe injury in paracentral gyri, white matter, basal ganglia, and thalamus spent a greater proportion of time with MAP below MAPOPT during rewarming than neonates with no or mild injury. Neonates with moderate/severe injury in paracentral gyri, basal ganglia, and thalamus had greater MAP deviation below MAPOPT during rewarming than neonates without injury.
Maintaining MAP within or above MAPOPT may reduce the risk of neurologic injuries in neonatal HIE.
PMCID: PMC3954983  PMID: 23942555
16.  Effects of Hypoxic-Ischemic Encephalopathy and Whole-Body Hypothermia on Neonatal Auditory Function: A Pilot Study 
American journal of perinatology  2008;25(7):435-441.
We assessed the effects of hypoxic-ischemic encephalopathy (HIE) and whole-body hypothermia therapy on auditory brain stem evoked responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We performed serial assessments of ABRs and DPOAEs in newborns with moderate or severe HIE, randomized to hypothermia (n = 4) or usual care (n = 5). Participants were five boys and four girls with mean gestational age (standard deviation) of 38.9 (1.8) weeks. During the first week of life, peripheral auditory function, as measured by the DPOAEs, was disrupted in all nine subjects. ABRs were delayed but central transmission was intact, suggesting a peripheral rather than a central neural insult. By 3 weeks of age, peripheral auditory function normalized. Hypothermia temporarily prolonged the ABR, more so for waves generated higher in the brain stem but the effects reversed quickly on rewarming. Neonatal audiometric testing is feasible, noninvasive, and capable of enhancing our understanding of the effects of HIE and hypothermia on auditory function.
PMCID: PMC2586420  PMID: 18720323
Hypoxia-ischemia; hypothermia; auditory evoked potentials; otoacoustic emissions
17.  Evaluation of Innotrac Aio! Second-Generation Cardiac Troponin I Assay: The Main Characteristics for Routine Clinical Use 
The availability of a simple, sensitive, and rapid test using whole blood to facilitate processing and to reduce the turnaround time could improve the management of patients presenting with chest pain. The aim of this study was an evaluation of the Innotrac Aio! second-generation cardiac troponin I (cTnI) assay. The Innotrac Aio! second-generation cTnI assay was compared with the Abbott AxSYM first-generation cTnI, Beckman Access AccuTnI, and Innotrac Aio! first-generation cTnI assays. We studied serum samples from 15 patients with positive rheumatoid factor but with no indication of myocardial infarction (MI). Additionally, the stability of the sample with different matrices and the influence of hemodialysis on the cTnI concentration were evaluated. Within-assay CVs were 3.2%–10.9%, and between-assay precision ranged from 4.0% to 17.2% for cTnI. The functional sensitivity (CV = 20 %) and the concentration giving CV of 10% were approximated to be 0.02 and 0.04, respectively. The assay was found to be linear within the tested range of 0.063–111.6 μ g/L. The correlations between the second-generation Innotrac Aio!, Access, and AxSYM cTnI assays were good (r coefficients 0.947–0.966), but involved differences in the measured concentrations, and the biases were highest with cTnI at low concentrations. The second-generation Innotrac Aio! cTnI assay was found to be superior to the first-generation assay with regard to precision in the low concentration range. The stability of the cTnI level was best in the serum, lithium-heparin plasma, and lithium-heparin whole blood samples (n = 10 , decrease < 10 % in 24 hours at +20°C and at +4°C. There was no remarkable influence of hemodialysis on the cTnI release. False-positive cTnI values occurred in the presence of very high rheumatoid factor values, that is, over 3000 U/L. The 99th percentile of the apparently healthy reference group was ≤ 0.03   μ g/L. The results demonstrate the very good analytical performance of the second-generation Innotrac Aio! cTnI assay.
PMCID: PMC1903460  PMID: 17671616
18.  The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy 
PLoS ONE  2012;7(12):e50520.
Hypoxic ischaemic encephalopathy (HIE) in newborns can cause significant long-term neurological disability. The insult is a complex injury characterised by energy failure and disruption of cellular homeostasis, leading to mitochondrial damage. The importance of individual metabolic pathways, and their interaction in the disease process is not fully understood. The aim of this study was to describe and quantify the metabolomic profile of umbilical cord blood samples in a carefully defined population of full-term infants with HIE.
Methods and Findings
The injury severity was defined using both the modified Sarnat score and continuous multichannel electroencephalogram. Using these classification systems, our population was divided into those with confirmed HIE (n = 31), asphyxiated infants without encephalopathy (n = 40) and matched controls (n = 71). All had umbilical cord blood drawn and biobanked at −80°C within 3 hours of delivery. A combined direct injection and LC-MS/MS assay (AbsolutIDQ p180 kit, Biocrates Life Sciences AG, Innsbruck, Austria) was used for the metabolomic analyses of the samples. Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). 9 of these metabolites were only significantly altered between neonates with Hypoxic ischaemic encephalopathy and matched controls, while 14 were significantly altered in both study groups. Multivariate Discriminant Analysis models developed showed clear multifactorial metabolite associations with both asphyxia and HIE. A logistic regression model using 5 metabolites clearly delineates severity of asphyxia and classifies HIE infants with AUC = 0.92. These data describe wide-spread disruption to not only energy pathways, but also nitrogen and lipid metabolism in both asphyxia and HIE.
This study shows that a multi-platform targeted approach to metabolomic analyses using accurately phenotyped and meticulously biobanked samples provides insight into the pathogenesis of perinatal asphyxia. It highlights the potential for metabolomic technology to develop a diagnostic test for HIE.
PMCID: PMC3515614  PMID: 23227182
19.  Cardioprotective effect of sevoflurane in patients with coronary artery disease undergoing vascular surgery 
Saudi Journal of Anaesthesia  2012;6(2):125-130.
The present study was conducted to evaluate the cardioprotective effect of sevoflurane compared with propofol in patients with coronary artery disease (CAD) undergoing peripheral vascular surgery; and to address the question whether a volatile anesthetic might improve cardiac outcome in these patients.
One hundred twenty-six patients scheduled for elective peripheral vascular surgery were prospectively randomized to receive either sevoflurane inhalation anesthesia or total intravenous anesthesia. ST-segment monitoring was performed continuously during intra- and post-operative 48 h periods. The number of ischemic events and the cumulative duration of ischemia in each patient were recorded. Blood was sampled in all patients for the determination of cTnI. Samples were obtained before the induction of anesthesia, on admission to the ICU, and at 6, 12, 24, and 48 h after admission to the intensive care unit (ICU). Patients were followed-up during their hospital stay for any adverse cardiac events.
The incidence of ischemia were comparable among the groups [16 (25%) patients in sevoflurane group vs 24 (39%) patients in propofol group; P=0.126]. Duration, cumulative duration, and magnitude of ST-segment depression of ischemic events in each patient were significantly less in sevoflurane group (P=0.008, 0.048, 0.038, respectively). cTnI levels of the overall population were significantly less in sevoflurane group vs propofol group (P values <0.0001) from 6 h postoperative and onward. Meanwhile, cTnI levels at 6, 12, 24, and 48 h after admission to the ICU in patients who presented with ischemic electrocardiographic (ECG) changes were significantly lower in sevoflurane group than in the propofol group (P<0.0001, <0.0001, <0.0001, 0.0003). None of the patients presented with unstable angina, myocardial infarction, congestive heart failure, or serious arrhythmia either during ICU or hospital stay.
Patients with CAD receiving sevoflurane for peripheral vascular surgery had significantly lower release of cardiac troponin I at 6 h postoperatively and lasting for 48 h than patients receiving propofol for the same procedure with significant decrease in duration, cumulative duration of ischemic events, and degree of ST depression in each patient.
PMCID: PMC3385253  PMID: 22754437
Coronary artery disease; cardioprotective; sevoflurane; vascular surgery
20.  The One Year Incidence of Postoperative Myocardial Infarction in an Orthopedic Population 
HSS Journal  2007;4(1):76-80.
The diagnosis of a postoperative myocardial infarction (PMI) is important in the orthopedic population because these events can be associated with significant cardiac morbidity. Plasma troponin I (cTnI) analysis has markedly increased our ability to detect myocardial damage. Using cTnI analysis for evidence of a PMI, we prospectively assessed all of our patients for (1) the 1-year incidence of PMI, (2) the clinical consequences of a PMI in relation to the level of the cTnI release, and (3) 6-month follow-up for cardiac complications. During a 12-month period, patients at risk for perioperative myocardial ischemia were assessed for a PMI by serum cTnI levels and daily serial ECGs. Patients with cTnI levels above the reference level (≥0.4 ng/ml) were also assessed for new cardiac regional wall motion abnormalities with an echocardiogram and 6-month postdischarge adverse cardiac events. Of the 758 patients who were assessed for a PMI, 49 patients had detectable cTnI levels (≥0.4 ng/ml); the incidence of a PMI was 0.6% of all surgical cases and 6.5% of those patients were at risk for a cardiac event. A PMI was more common after hip arthroplasty than other orthopedic procedures. Twenty-three patients had a cTnI level >3.0 ng/ml, and 74% these patients (17/23) had anginal symptoms and/or ischemic ECG changes. Nine of these patients (9/23) had new postoperative echocardiographic changes, five (5/23) required emergency transfer to a cardiac care unit, and 10 (10/23) had postoperative cardiac complications. In contrast, 15 patients with levels of cTnI <3.0 ng/ml and without ischemic ECG changes and/or anginal symptoms had no postoperative cardiac complications. Fourteen patients (14/47) had cardiac complications 6 months after discharge, including four cardiac deaths, one fatal stroke, and four patients with unstable anginal episodes that required a change in medical management, and six patients required coronary revascularization. Orthopedic surgical patients with cTnI level <3 ng/ml and without symptoms or ECG changes suggestive of myocardial ischemia (15/49) may have different risks than those with higher-level cTn1.
PMCID: PMC2504276  PMID: 18751868
postoperative myocardial infarction; troponin levels
21.  Early identification of brain injury in infants with hypoxic ischemic encephalopathy at high risk for severe impairments: accuracy of MRI performed in the first days of life 
BMC Pediatrics  2014;14:177.
Despite therapeutic hypothermia 30-70% of newborns with moderate or severe hypoxic ischemic encephalopathy will die or survive with significant long-term impairments. Magnetic resonance imaging (MRI) in the first days of life is being used for early identification of these infants and end of life decisions are relying more and more on it. The purpose of this study was to evaluate how MRI performed around day 4 of life correlates with the ones obtained in the second week of life in infants with hypoxic-ischemic encephalopathy (HIE) treated with hypothermia.
Prospective observational cohort study between April 2009 and July 2011. Consecutive newborns with HIE evaluated for therapeutic hypothermia were included. Two sequential MR studies were performed: an •early’ study around the 4th day of life and a •late’ study during the second week of life. MRI were assessed and scored by two neuroradiologists who were blinded to the clinical condition of the infants.
Forty-eight MRI scans were obtained in the 40 newborns. Fifteen infants underwent two sequential MR scans. The localization, extension and severity of hypoxic-ischemic injury in early and late scans were highly correlated. Hypoxic-ischemic injury scores from conventional sequences (T1/T2) in the early MRI correlated with the scores of the late MRI (Spearman ρ = 0.940; p < .001) as did the scores between diffusion-weighted images in early scans and conventional images in late MR studies (Spearman ρ = 0.866; p < .001). There were no significant differences in MR images between the two sequential scans.
MRI in the first days of life may be a useful prognostic tool for clinicians and can help parents and neonatologist in medical decisions, as it highly depicts hypoxic-ischemic brain injury seen in scans performed around the second week of life.
PMCID: PMC4113122  PMID: 25005267
Hypoxic-ischemic encephalopathy; MRI; Newborn; Brain injury; Hypothermia; Sequential MR studies
22.  Adherence to Hypothermia Guidelines: A French Multicenter Study of Fullterm Neonates 
PLoS ONE  2013;8(12):e83742.
The objective of this study was to describe the French practice of hypothermia treatment (HT) in full-term newborns with hypoxic-ischemic encephalopathy (HIE) and to analyze the deviations from the guidelines of the French Society of Neonatology.
Materials and Methods
From May 2010 to March 2012 we recorded all cases of HIE treated by HT in a French national database. The population was divided into three groups, "optimal HT" (OHT), “late HT” (LHT) and “non-indicated” HT (NIHT), according to the guidelines.
Of the 311 newborns registered in the database and having HT, 65% were classified in the OHT group, 22% and 13% in the LHT and NIHT groups respectively. The severity of asphyxia and HIE were comparable between newborns with OHT and LHT, apart from EEG. HT was initiated at a mean time of 12 hours of life in the LHT group. An acute obstetrical event was more likely to be identified among newborns with LHT (46%), compared to OHT (34%) and NIHT (22%). There was a gradation in the rate of complications from the NIHT group (29%) to the LHT (38%) group and the OHT group (52%). Despite an insignificant difference in the rates of death or abnormal neurological examination at discharge, nearly 60% of newborns in the OHT group had an MRI showing abnormalities, compared to 44% and 49% in the LHT and NIHT groups respectively.
The conduct of the HT for HIE newborns is not consistent with French guidelines for 35% of newborns, 22% being explained by an excessive delay in the start of HT, 13% by the lack of adherence to the clinical indications. This first report illustrates the difficulties in implementing guidelines for HT and should argue for an optimization of perinatal care for HIE.
PMCID: PMC3877096  PMID: 24391817
23.  Physiologic and pharmacologic considerations for hypothermia therapy in neonates 
With mounting evidence that hypothermia is neuroprotective in newborns with hypoxic-ischemic encephalopathy (HIE), an increasing number of centers are offering this therapy. Hypothermia is associated with a wide range of physiologic changes affecting every organ system, and awareness of these effects is essential for optimum patient management. Lowering the core temperature also alters pharmacokinetic and pharmacodynamic properties of medications commonly used in asphyxiated neonates, necessitating close attention to drug efficacy and side effects. Rewarming introduces additional risks and challenges as the hypothermia-associated physiologic and pharmacologic changes are reversed. In this review we provide an organ system-based assessment of physiologic changes associated with hypothermia. We also summarize evidence from randomized controlled trials showing lack of serious adverse effects of moderate hypothermia therapy in term and near-term newborns with moderate-to-severe HIE. Finally, we review the effects of hypothermia on drug metabolism and clearance based on studies in animal models and human adults, and limited data from neonates.
PMCID: PMC3552186  PMID: 21183927
hypothermia; hypoxic-ischemic encephalopathy; neonate; pharmacologic effect; physiology effect; rewarming
24.  Concentrations of cardiac Troponin I before and after ovariohysterectomy in 46 female dogs with pyometra 
Canine pyometra is a common disease in countries where routine spaying of young dogs is not common practice. This disease is known to lead to systemic inflammation potentially affecting multiple organs in the body, including the heart. Cardiac-specific Troponin I (cTnI) is a sensitive marker of myocardial cell damage, which can result from ischemia, trauma, toxins or inflammation. Dogs with pyometra are also exposed to anaesthesia which can potentially result in myocardial cell damage. The aims of the study were 1) to evaluate the occurrence of myocardial cell damage as indicated by increased serum concentrations of cTnI in dogs with pyometra and relate these to presence of systemic inflammation and 2) to evaluate the change in cTnI-concentrations after anaesthesia and surgery.
Serum cTnI concentration was measured preoperatively and one day after surgery in 46 female dogs with pyometra and 15 female dogs that underwent surgery for other reasons (ovariohysterectomy and mammary tumours).
Forty-six female dogs of different breeds diagnosed with pyometra were included. The dogs had a median age of 8.5 years (IQR 7.5–10) and a median weight of 29 kg (IQR 9–32). Of the 46 dogs, 37 (80%) fulfilled the chosen criteria for systemic inflammatory response syndrome (SIRS) at inclusion. Thirteen (28%) of the dogs had increased cTnI concentrations (> 0.2 μg/l) before surgery and 18 (39%) had increased cTnI-concentrations the day after surgery. The cTnI concentrations in the 13 dogs with increased preoperative cTnI concentrations decreased in 8 dogs, increased in 4 dogs, and was unchanged in one dog. Seven dogs with nondetectable preoperative cTnI concentrations had increased postoperative concentrations. The only significant association between the studied laboratory or clinical variables (including SIRS) and cTnI concentration was preoperative percentage band neutrophils (PBN) and postoperative cTnI concentration (P = 0.016). In total, 20 dogs (43%) had increased pre- or postoperative cTnI concentrations. Seven dogs (15%) had pre-or postoperative concentrations of cTnI of 1.0 μg/l or higher.
Mild to moderate increases in cTnI appears to be common in dogs with pyometra before and after surgery, but the clinical importance of this finding is uncertain. None of the studied clinical variables were found to reliably predict increased preoperative cTnI concentrations. Because of the pre- and postoperative variation in cTnI concentrations, it was not possible to identify a negative effect of anaesthesia and surgery on myocardial cell integrity.
PMCID: PMC2546406  PMID: 18786242
25.  Cardiac troponin I but not cardiac troponin T adheres to polysulfone dialyser membranes in an in vitro haemodialysis model: explanation for lower serum cTnI concentrations following dialysis 
Open Heart  2014;1(1):e000108.
Elevated serum cardiac troponin T (cTnT) and I (cTnI) can occur in patients with chronic kidney disease. Differences in cTn concentrations between cTnT and cTnI have been reported but the mechanism of such discrepancy has not been investigated. This study investigates the clearance of cTn with the aid of an in vitro model of haemodialysis (HD).
Serum was obtained before and after a single session of dialysis from 53 patients receiving HD and assayed for cTnT and cTnI. An in vitro model of the dialysis process was used to investigate the mechanism of clearance of cTn during HD.
Serum cTnI was significantly lower (p=0.043) following a session of HD whereas cTnT concentrations were similar to those obtained before HD.
Using an in vitro model of dialysis, it was demonstrated that cTnI is not dialysed from the vascular compartment but adheres to the dialyser membrane.
The adherence of cTnI to the dialyser membrane is responsible for the observed decrease in serum cTnI following a session of dialysis. The adherence of cTnT or T-I-C complex to the dialyser membrane could not be demonstrated and supports the observation that pre-HD and post-HD serum concentrations of cTnT are similar.
PMCID: PMC4195923  PMID: 25332816
Troponin; CKD; Haemodialysis

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