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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.  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
6.  Effects of xenon and hypothermia on cerebrovascular pressure reactivity in newborn global hypoxic–ischemic pig model 
Autoregulation of cerebral perfusion is impaired in hypoxic–ischemic encephalopathy. We investigated whether cerebrovascular pressure reactivity (PRx), an element of cerebral autoregulation that is calculated as a moving correlation coefficient between averages of intracranial and mean arterial blood pressure (MABP) with values between −1 and +1, is impaired during and after a hypoxic–ischemic insult (HI) in newborn pigs. Associations between end-tidal CO2, seizures, neuropathology, and PRx were investigated. The effect of hypothermia (HT) and Xenon (Xe) on PRx was studied. Pigs were randomized to Sham, and after HI to normothermia (NT), HT, Xe or xenon hypothermia (XeHT). We defined PRx >0.2 as peak and negative PRx as preserved. Neuropathology scores after 72 hours of survival was grouped as ‘severe' or ‘mild.' Secondary PRx peak during recovery, predictive of severe neuropathology and associated with insult severity (P=0.05), was delayed in HT (11.5 hours) than in NT (6.5 hours) groups. Seizures were associated with impaired PRx in NT pigs (P=0.0002), but not in the HT/XeHT pigs. PRx was preserved during normocapnia and impaired during hypocapnia. Xenon abolished the secondary PRx peak, increased (mean (95% confidence interval (CI)) MABP (6.5 (3.8, 9.4) mm Hg) and cerebral perfusion pressure (5.9 (2.9, 8.9) mm Hg) and preserved the PRx (regression coefficient, −0.098 (95% CI (−0.18, −0.01)), independent of the insult severity.
PMCID: PMC3824173  PMID: 23899927
cerebrovascular pressure reactivity; hypothermia; hypoxia–ischemia; newborn; pig; xenon
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  Neonatal Neurobehavioral Abnormalities and MRI Brain Injury in Encephalopathic Newborns Treated With Hypothermia 
Early human development  2013;89(9):733-737.
Neonatal Encephalopathy (NE) is a prominent cause of infant mortality and neurodevelopmental disability. Hypothermia is an effective neuroprotective therapy for newborns with encephalopathy. Post-hypothermia functional-anatomical correlation between neonatal neurobehavioral abnormalities and brain injury findings on MRI in encephalopathic newborns has not been previously described.
To evaluate the relationship between neonatal neurobehavioral abnormalities and brain injury on magnetic resonance imaging (MRI) in encephalopathic newborns treated with therapeutic hypothermia.
Study Design
Neonates with hypoxic ischemic encephalopathy (HIE) referred for therapeutic hypothermia were prospectively enrolled in this observational study. Neurobehavioral functioning was assessed with the NICU Network Neurobehavioral Scale (NNNS) performed at target age 14 days. Brain injury was assessed by MRI at target age 7–10 days. NNNS scores were compared between infants with and without severe MRI injury.
Subjects & Outcome Measures
Sixty-eight term newborns (62% males) with moderate to severe encephalopathy underwent MRI at median 8 days (range 5–16) and NNNS at median 12 days of life (range 5–20). Fifteen (22%) had severe injury on MRI.
Overall Total Motor Abnormality Score and individual summary scores for Nonoptimal Reflexes and Asymmetry were higher, while Total NNNS Z-score across cognitive/behavioral domains was lower (reflecting poorer performance) in infants with compared to those without severe MRI injury (p<0.05).
Neonatal neurobehavioral abnormalities identified by the NNNS are associated with MRI brain injury in encephalopathic newborns post-hypothermia. The NNNS can provide an early functional assessment of structural brain injury in newborns, which may guide rehabilitative therapies in infants after perinatal brain injury.
PMCID: PMC3780358  PMID: 23787090
18.  Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics 
Pediatrics  2012;130(4):683-691.
To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L).
In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses.
Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen.
Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.
PMCID: PMC3457622  PMID: 23008465
neonatal encephalopathy; asphyxia; hypoxia-ischemia; neuroprotection
19.  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
20.  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
21.  Hypothermia and Postconditioning after Cardiopulmonary Resuscitation Reduce Cardiac Dysfunction by Modulating Inflammation, Apoptosis and Remodeling 
PLoS ONE  2009;4(10):e7588.
Mild therapeutic hypothermia following cardiac arrest is neuroprotective, but its effect on myocardial dysfunction that is a critical issue following resuscitation is not clear. This study sought to examine whether hypothermia and the combination of hypothermia and pharmacological postconditioning are cardioprotective in a model of cardiopulmonary resuscitation following acute myocardial ischemia.
Methodology/Principal Findings
Thirty pigs (28–34 kg) were subjected to cardiac arrest following left anterior descending coronary artery ischemia. After 7 minutes of ventricular fibrillation and 2 minutes of basic life support, advanced cardiac life support was started according to the current AHA guidelines. After successful return of spontaneous circulation (n = 21), coronary perfusion was reestablished after 60 minutes of occlusion, and animals were randomized to either normothermia at 38°C, hypothermia at 33°C or hypothermia at 33°C combined with sevoflurane (each group n = 7) for 24 hours. The effects on cardiac damage especially on inflammation, apoptosis, and remodeling were studied using cellular and molecular approaches. Five animals were sham operated. Animals treated with hypothermia had lower troponin T levels (p<0.01), reduced infarct size (34±7 versus 57±12%; p<0.05) and improved left ventricular function compared to normothermia (p<0.05). Hypothermia was associated with a reduction in: (i) immune cell infiltration, (ii) apoptosis, (iii) IL-1β and IL-6 mRNA up-regulation, and (iv) IL-1β protein expression (p<0.05). Moreover, decreased matrix metalloproteinase-9 activity was detected in the ischemic myocardium after treatment with mild hypothermia. Sevoflurane conferred additional protective effects although statistic significance was not reached.
Hypothermia reduced myocardial damage and dysfunction after cardiopulmonary resuscitation possible via a reduced rate of apoptosis and pro-inflammatory cytokine expression.
PMCID: PMC2764338  PMID: 19855846
22.  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
23.  Hypothermia for hypoxic–ischemic encephalopathy 
Moderate to severe hypoxic–ischemic injury in newborn infants, manifested as encephalopathy immediately or within hours after birth, is associated with a high risk of either death or a lifetime with disability. In recent multicenter clinical trials, hypothermia initiated within the first 6 postnatal hours has emerged as a therapy that reduces the risk of death or impairment among infants with hypoxic–ischemic encephalopathy. Prior to hypothermia, no therapies directly targeting neonatal encephalopathy secondary to hypoxic–ischemic injury had convincing evidence of efficacy. Hypothermia therapy is now becoming increasingly available at tertiary centers. Despite the deserved enthusiasm for hypothermia, obstetric and neonatology caregivers, as well as society at large, must be reminded that in the clinical trials more than 40% of cooled infants died or survived with impairment. Although hypothermia is an evidence-based therapy, additional discoveries are needed to further improve outcome after HIE. In this article, we briefly present the epidemiology of neonatal encephalopathy due to hypoxic–ischemic injury, describe the rationale for the use of hypothermia therapy for hypoxic–ischemic encephalopathy, and present results of the clinical trials that have demonstrated the efficacy of hypothermia. We also present findings noted during and after these trials that will guide care and direct research for this devastating problem.
PMCID: PMC2897079  PMID: 20625441
HIE; hyperthermia; hypothermia; hypoxic–ischemic encephalopathy; neonate; perinatal asphyxia
24.  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
25.  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

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