Characterization of the Glucocorticoid Receptor in Children Undergoing Cardiac Surgery.

OBJECTIVES: Postoperative administration of corticosteroids is common practice for managing catecholamine refractory low cardiac output syndrome. Since corticosteroid activity is dependent on the glucocorticoid receptor, we sought to characterize glucocorticoid receptor levels in children undergoing cardiac surgery and examined the association between glucocorticoid receptor levels and cardiovascular dysfunction. DESIGN: Prospective observational cohort study. SETTING: Large, tertiary pediatric cardiac center. SUBJECTS: Children undergoing corrective or palliative cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A prospective observational cohort study was conducted in 83 children with congenital heart disease. Total glucocorticoid receptor levels were measured in the peripheral WBCs using flow cytometry. In addition, blood samples were collected for total cortisol levels. The primary outcome studied was the time to being inotrope free. An increase in glucocorticoid receptor level from postoperative day 1 to postoperative day 3 was associated with a longer time to being inotrope free (hazard ratio, 0.49 [0.29-0.81]; p = 0.01) in the univariate analysis. This association remained significant after adjusting for age, weight, cardiopulmonary bypass time, cross clamp time, Risk Adjustment for Congenital Heart Surgery-1 score, and postoperative steroid use (hazard ratio, 0.53 [0.29-0.99]; p = 0.05). Postoperative day 3 glucocorticoid receptor level showed a trend to have longer time to being inotrope free (hazard ratio, 0.66 [0.42-1.02]; p = 0.0.06). The cortisol levels minimally increased during the study duration and did not correlate with glucocorticoid receptor levels. CONCLUSIONS: Increasing glucocorticoid receptor levels in peripheral WBCs of children undergoing cardiac surgery are associated with a longer time to being inotrope free. Cortisol levels minimally increased during the study duration. These results suggest that exposure to high-dose perioperative corticosteroids may suppress the hypothalamic-pituitary-adrenal axis leading to increase in glucocorticoid receptor levels in response to a low cortisol environment. Further studies are required to better delineate the interplay between glucocorticoid receptor levels, cortisol levels, corticosteroid exposure, and postoperative inotropic requirements.

Central Venous to Arterial CO2 Difference After Cardiac Surgery in Infants and Neonates.

OBJECTIVES: Venous to arterial CO2 difference correlates with cardiac output in critically ill adults, but its utility in pediatric patients is unclear. We sought to correlate venous to arterial CO2 difference with other cardiac output surrogates (arteriovenous oxygen saturation difference, central venous oxygen saturation, and lactate) and investigate its capacity to predict poor outcomes associated with low cardiac output (low cardiac output syndrome) in infants after cardiac surgery with cardiopulmonary bypass. DESIGN: Retrospective chart review. Poor outcome was defined as any inotrope score greater than 15; death, cardiac arrest, extracorporeal membrane oxygenation; and unplanned surgical reintervention. SETTING: Pediatric cardiovascular ICU. PATIENTS: One hundred thirty-nine infants less than 90 days who underwent cardiopulmonary bypass, from October 2012 to May 2015. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Two hundred ninety-six arterial and venous blood gas pairs from admission (n = 139), 6 (n = 62), 12 (n = 73), and 24 hours (n = 22) were included in analysis. For all pairs, venous to arterial CO2 difference was moderately correlated with arteriovenous oxygen saturation difference (R = 0.53; p < 0.01) and central venous oxygen saturation (R = -0.43; p < 0.01), but not lactate. At admission, venous to arterial CO2 difference was also moderately correlated with central venous oxygen saturation (R = -0.40; p < 0.01) and arteriovenous oxygen saturation difference (R = 0.55; p < 0.01), but not lactate. Thirty-four of 139 neonates (24.5%) had poor outcome. Median admission venous to arterial CO2 difference was 5.9 mm Hg (3.8-9.2 mm Hg). Patients with poor outcome had median admission venous to arterial CO2 difference 8.3 (5.6-14.9) versus 5.4 mm Hg (3.0-8.4 mm Hg) in those without poor outcome. Venous to arterial CO2 difference (area under the curve = 0.69; p < 0.01), serum lactate (area under the curve = 0.64; p = 0.02), and central venous oxygen saturation (area under the curve = 0.74; p < 0.01) were predictive of poor outcome. After controlling for covariates, admission venous to arterial CO2 difference remained significantly associated with poor outcome (odds ratio, 1.3; 95% CI, 1.1-1.45), including independent association with mortality (odds ratio, 1.2; 95% CI, 1.07-1.31). CONCLUSIONS: Venous to arterial CO2 difference is correlated with important surrogates of cardiac output, and is associated with poor outcome and mortality related to low cardiac output syndrome after cardiac surgery in infants. Prospective validation of these findings, including confirmation that venous to arterial CO2 difference can identify low cardiac output syndrome in real time, is warranted.

Myocardial protection during minimally invasive cardiac surgery through right mini-thoracotomy.

BACKGROUND: Myocardial damage is an independent predictor of adverse outcome following cardiac surgery and myocardial protection is one of the key factors to achieve successful outcomes. Cardioplegia with Custodiol is currently the most used cardioplegia during minimally invasive cardiac surgery (MICS). Different randomized controlled trials compared blood and Custodiol cardioplegia in the context of traditional cardiac surgery. No data are available for MICS. AIM: The aim of this study was to compare the efficacy of cold blood versus Custodiol cardioplegia during MICS. METHOD: We retrospectively evaluated 90 patients undergoing MICS through a right mini-thoracotomy in a three-year period. Myocardial protection was performed using cold blood (44 patients, CBC group) or Custodiol (46 patients, Custodiol group) cardioplegia, based on surgeon preference and complexity of surgery. RESULTS: The primary outcomes were post-operative cardiac troponin I (cTnI) and creatine kinase MB (CKMB) serum release and the incidence of Low Cardiac Output Syndrome (LCOS). Aortic cross-clamp and cardiopulmonary bypass times were higher in the Custodiol group. No difference was observed in myocardial injury enzyme release (peak cTnI value was 18±46 ng/ml in CBC and 21±37 ng/ml in Custodiol; p=0.245). No differences were observed for mortality, LCOS, atrial or ventricular arrhythmias onset, transfusions, mechanical ventilation time duration, intensive care unit and total hospital stay. CONCLUSIONS: Custodiol and cold blood cardioplegic solutions seem to assure similar myocardial protection in patients undergoing cardiac surgery through a right mini-thoracotomy approach.

Clinical utility of B-type natriuretic peptide (NP) in pediatric cardiac surgery--a systematic review.

BACKGROUND: NP is a biomarker that has been used in the diagnosis, management, and prognostication of a number of cardiovascular disorders in the pediatric population. The physiological role of this hormone is to allow the myocardium to adapt to stress or strain imposed by a volume and/or pressure load. OBJECTIVE: The aim of this study was to determine the utility of preoperative and postoperative NP to predict outcome in pediatric patients undergoing cardiac surgery for structural congenital heart disease. METHOD: We conducted a systematic review by searching three electronic databases using the search terms 'paediatric' or 'pediatric' and 'B-type natriuretic peptide'. Twenty peer-reviewed papers were included in the study. RESULTS: Preoperative NP levels were associated with the severity of cardiac failure in several studies. Preoperative NPs also correlated with early postoperative outcome measures such as duration of cardiopulmonary bypass, duration of mechanical ventilation, presence of low cardiac output syndrome, length of stay in the intensive care unit and in one study, death. Early (within 24 h) postoperative NPs showed a stronger correlation than preoperative NPs to early postoperative adverse events. CONCLUSION: NPs provide a simple, noninvasive and complementary tool to echocardiography that can be used to assist clinicians in the assessment and management of pediatric patients with congenital heart disease in the perioperative period.

Low cardiac output stimulates vasopressin release in patients with stage d heart failure.

BACKGROUND: Depressed hemodynamics stimulates arginine vasopressin (AVP) release, but the relationship between plasma AVP levels (P-AVP) and cardiac parameters, especially in patients with stage D heart failure (HF) receiving guideline-directed medical therapy, has not examined. METHODS AND RESULTS: Data including P-AVP were obtained from 162 in-hospital patients with stage D HF and from 80 patients receiving ventricular assist device (VAD, n=46) or heart transplantation (HTx, n=34) at 3 months after surgery. In the HF group, considerably high P-AVP (5.9±6.1 pg/ml) negatively correlated with serum sodium concentration (S-Na, 135.3±5.8 mEq/L, r=-0.548 [P<0.01]) and cardiac index (CI, 2.2±0.5 L·min(-1)·m(-2), r=-0.458 [P<0.01]). After VAD/HTx treatment, improvement in the CI (2.7±0.5 L·min(-1)·m(-2)[P<0.01] vs. HF) was accompanied by normalization of serum sodium concentration (S-Na; 138.2±2.0 mEq/L [P<0.01] vs. HF) and suppressed release of AVP (1.7±3.4 pg/ml [P<0.01] vs. HF). P-AVP positively correlated with only S-Na (r=0.454 [P<0.01]), whereas no correlation was observed with CI after VAD/HTx treatment. P-AVP ≥5.3 pg/ml well predicted poor 2-year survival in HF group (60% [P<0.01] vs. 90%). CONCLUSIONS: Low cardiac output stimulates AVP release via a non-osmotic process that results in hyponatremia and poor prognosis in patients with stage D HF. After sufficient recovery of cardiac output by cardiac replacement therapy, AVP release is suppressed and is mainly regulated by serum osmolality.

Natriuretic peptides in heart failure with preserved ejection fraction.

Timely diagnosis, early introduction of appropriate treatment, accurate risk stratification, and optimal titration of therapy are all key to the management of acute and chronic heart failure (HF). Plasma concentrations of the cardiac natriuretic peptides (NPs) are valuable aids in each of these elements of care. However, most data are derived from cohorts with undifferentiated HF or HF with reduced ejection fraction (HFREF), and the performance and best application of NPs in HF with preserved ejection fraction (HFPEF) is less certain. This review outlines the evidence for use of NPs in the evaluation and management of HFPEF.

Change in regional (somatic) near-infrared spectroscopy is not a useful indicator of clinically detectable low cardiac output in children after surgery for congenital heart defects.

OBJECTIVE: Near-infrared spectroscopy correlation with low cardiac output has not been validated. Our objective was to determine role of splanchnic and/or renal oxygenation monitoring using near-infrared spectroscopy for detection of low cardiac output in children after surgery for congenital heart defects. DESIGN: Prospective observational study. SETTING: Pediatric intensive care unit of a tertiary care teaching hospital. PATIENTS: Children admitted to the pediatric intensive care unit after surgery for congenital heart defects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We hypothesized that splanchnic and/or renal hypoxemia detected by near-infrared spectroscopy is a marker of low cardiac output after pediatric cardiac surgery. Patients admitted after cardiac surgery to the pediatric intensive care unit over a 10-month period underwent serial splanchnic and renal near-infrared spectroscopy measurements until extubation. Baseline near-infrared spectroscopy values were recorded in the first postoperative hour. A near-infrared spectroscopy event was a priori defined as ≥20% drop in splanchnic and/or renal oxygen saturation from baseline during any hour of the study. Low cardiac output was defined as metabolic acidosis (pH <7.25, lactate >2 mmol/L, or base excess ≤-5), oliguria (urine output <1 mL/kg/hr), or escalation of inotropic support. Receiver operating characteristic analysis was performed using near-infrared spectroscopy event as a diagnostic test for low cardiac output. Twenty children were enrolled: median age was 5 months; median Risk Adjustment for Congenital Heart Surgery category was 3 (1-6); median bypass and cross-clamp times were 120 mins (45-300 mins) and 88 mins (17-157 mins), respectively. Thirty-one episodes of low cardiac output and 273 near-infrared spectroscopy events were observed in 17 patients. The sensitivity and specificity of a near-infrared spectroscopy event as an indicator of low cardiac output were 48% (30%-66%) and 67% (64%-70%), respectively. On receiver operating characteristic analysis, neither splanchnic nor renal near-infrared spectroscopy event had a significant area under the curve for prediction of low cardiac output (area under the curve: splanchnic 0.45 [95% confidence interval 0.30-0.60], renal 0.51 [95% confidence interval 0.37-0.65]). CONCLUSIONS: Splanchnic and/or renal hypoxemia as detected by near-infrared spectroscopy may not be an accurate indicator of low cardiac output after surgery for congenital heart defects.

[Veno-arterial difference of carbon dioxide as a predictor of low cardiac output in an experimental pediatric model]. / Diferencia veno-arterial de dióxido de carbono como predictor de gasto cardiaco disminuido en modelo pediátrico experimental.

BACKGROUND: Cardiac output (CO) measurement is not a standard of care for critically ill children, but it can be estimated by indirect methods such as veno-arterial pCO2 difference (ΔVACO2). AIM: To determine the correlation between CO and ΔVACO2 and evaluate the usefulness of ΔVACO2 in the diagnosis of low CO in an experimental pediatric model. MATERIALS AND METHODS: Thirty piglets weighing 4.8 ± 0.35 kg were anesthetized and monitored with transpulmonary thermodilution. Lung injury was induced with tracheal instillation of Tween 20®. Serial measurements of central venous and arterial blood gases, as well as CO, were obtained at baseline, 1, 2 and 4 h after lung injury induction. Low cardiac output (LCO) was defined as CO lower than 2.5 Llminlm². RESULTS: There was an inverse correlation between CO and ΔVACO2 (r = -0.36, p < 0.01). ΔVACO2 was 14 ± 8 mmHg in LCO state and 8 ± 6 mmHg when this condition was not present (p < 0.01). Area under the receiver operating characteristic (ROC) curves of ΔVACO2 and LCO state was 0.78 (0.68-0.86). The best cut-point was 8.9 mmHg to determine LCO with a sensibility 0.78, specificity 0.7, positive predictive value 0.27 and negative predictive value 0.96. CONCLUSIONS: In this model there was an inverse correlation between ΔVACO2 and CO. The best cutoff value to discard LCO was ΔVACO2 of 8.9 mmHg, indicating that under this value the presence of LCO is very unlikely.

Myocardial protection during aortic surgery: comparison between Bretschneider-HTK and cold blood cardioplegia.

The ideal cardioplegic strategy in thoracic aorta operations requiring long cardiopulmonary bypass and cross-clamp time has not been established. Suboptimal myocardial protection may lead to myocardial damage and possible post-operative complications. We evaluate post-operative cardiac Troponin I (cTnI) release, low cardiac output syndrome (LCOS) and mortality, using a cold crystalloid single-dose intracellular or cold blood multidose cardioplegia in 112 elective or emergent thoracic aorta operation patients. Fifty-four patients (HTK group) received Custodiol® cardioplegic solution and 58 received cold blood cardioplegia (CB group). Cross-clamp time, cardiopulmonary bypass (CPB) time and cTnI peak release were similar in both groups. No differences were found for atrial and ventricular arrhythmias, inotropic support, LCOS and in-hospital mortality. Two-way ANOVA analysis revealed an interactive effect on cTnI peak (p=0.012) of cardioplegic solution type across the cross-clamp time quintile. In the fifth quintile, cross-clamp time patient (>160 min) cTnI peak value was higher in CB patients (p=0.044). HTK and CB cardioplegic solutions assure similar myocardial protection in patients undergoing thoracic aorta operations. In long cross-clamp times, the lower post-operative cTnI release detected using HTK may be indicative of a better myocardial protection in these extreme conditions.

[Low cardiac output syndrome score to evaluate postoperative cardiac surgery patients in a pediatric intensive care unit]. / Çocuk yogun bakim ünitesinde kardiyak cerrahi sonrasi hastalarin degerlendirilmesinde kullanilan düsük kardiyak debi sendromu skorlamasi.

OBJECTIVE: There is no clear consensus regarding the definition of low cardiac output syndrome (LCOS) or the follow-up of this patient group. Given this lack of a clinical definition, the aim of this study was to use a LCOS score (LCOSs) similar to the low cardiac output score previously presented in the literature and evaluate the relationship between a high LCOSs and poor clinical outcome. METHODS: A total of 54 patients were prospectively evaluated after cardiac surgery. The LCOSs was used to evaluate the deve-lopment of low cardiac output. Each parameter was scored as 1 point. The score was calculated every hour for 24 hours postoperatively and the highest score was recorded as the peak score (pLOCSs). The LOCSs at the time of admission to the pediatric intensive care unit, at the 4th, 8th, and 16th hour were recorded and a cumulative score (cLOCSs) score was calculated. RESULTS: The mean age of the patients was 49.40±53.15 months and 24.07% had LOCS. In the group with LCOS, the cLOCSs, vasoactive-inotropic score (VIS), lactate mean, aortic clamp time, and the total cardiopulmonary bypass time were significantly higher. In this study, a significant and positive correlation was found between the cLOCSs and pLOCSs and the length of hospital stay, length of stay in the pediatric intensive care unit, VIS, lactate mean, and aortic clamp duration. CONCLUSION: The objective of this study was to draw attention to the potential use of a common language in the care of critical pediatric patients undergoing cardiac surgery with a previously defined scoring method that includes parameters indicating poor perfusion in the patient.

A sex-balanced rodent model for evaluating phosphine inhalation toxicity.

Exposure to phosphine (PH3 ), a common grain fumigant, is characterized by diverse nonspecific symptoms and a high mortality rate. Although PH3 poisoning is thought to target oxidative respiration, the exact mechanism of action remains largely unknown, resulting in limited treatment options. In our study, the effects of PH3 on female rats were assessed to elucidate potential sex-specific differences and obtain a more comprehensive understanding of PH3 toxicity. Lethality, physiology, and behavior were evaluated in female rats exposed to gaseous PH3 (13,200-26,400 ppm × min), and results were compared with corresponding findings in male rats. Median lethal concentration-time (LCt50 ) and time of death (tTOD ) did not differ significantly between the sexes. Cardiopulmonary changes induced by PH3 were also of comparable magnitude, although temporally, respiratory responses occurred earlier and cardiovascular variations manifested later in female rats. Behavioral observations corroborated physiological findings and indicated a response to hypoxic conditions and low cardiac output. Together, these results provided insights on the toxic mechanisms of PH3 , in particular, its potential interference with oxygen transport and circulation.

Does pre-eclampsia influence fetal cardiovascular function in early-onset intrauterine growth restriction?

OBJECTIVES: Increasing evidence shows that intrauterine growth restriction (IUGR) is associated with fetal cardiac dysfunction. Most studies group IUGR with and without pre-eclampsia (PE) altogether. Our objective was to evaluate whether the association with PE has any impact on cardiac function in IUGR fetuses METHODS: Thirty-one normotensive IUGR cases and 31 IUGR cases with pre-eclampsia (PE + IUGR) below 34 weeks of gestation were included. IUGR was defined as a birth weight below the 10(th) centile together with an umbilical artery pulsatility index above 2 SD. Fetal cardiac function was assessed by measuring ductus venosus pulsatility index, modified myocardial performance index, aortic isthmus blood flow, E/A ratios and cardiac output. The presence of fetal cardiac dysfunction was also assessed by measuring cord blood B-type natriuretic peptide (BNP) levels collected at birth. Echocardiographic data were compared with those in 80 term appropriate-for-gestational age (AGA) fetuses from normotensive mothers. Cord blood BNP levels were compared with those in 40 AGA cases that delivered preterm. RESULTS: All IUGR cases (with or without PE) showed echocardiographic and biochemical signs of cardiac dysfunction compared with AGA cases. However, no differences were observed between IUGR and PE + IUGR cases either in echocardiographic or in biochemical parameters. IUGR cases with or without PE had similar perinatal results. CONCLUSIONS: IUGR fetuses showed echocardiographic and biochemical signs of cardiac dysfunction. Pre-eclampsia per se does not influence cardiac function in IUGR fetuses.

Tezosentan normalizes hepatomesenteric perfusion in a porcine model of cardiac tamponade.

BACKGROUND: To investigate endothelin-1 (ET-1)-dependent hepatic and mesenteric vasoconstriction, and oxygen and lactate fluxes in an acute, fixed low cardiac output (CO) state. METHODS: Sixteen anesthetized, mechanically ventilated pigs were studied. Cardiac tamponade was established to reduce portal venous blood flow (Q(PV)) to 2/3 of the baseline value. CO, hepatic artery blood flow (Q(HA)), Q(PV), hepatic laser-Doppler flow (LDF), hepatic venous and portal pressure, and hepatic and mesenteric oxygen and lactate fluxes were measured. Hepatic arterial (R(HA)), portal (R(HP)) and mesenteric (R(mes)) vascular resistances were calculated. The combined ET(A)-ET(B) receptor antagonist tezosentan (RO 61-0612) or normal saline vehicle was infused in the low CO state. Measurements were made at baseline, after 30, 60, 90 min of tamponade, and 30, 60, 90 min following the infusion of tesozentan at 1 mg/kg/h. RESULTS: Tamponade decreased CO, Q(PV), Q(HA), LDF, hepatic and mesenteric oxygen delivery, while hepatic and mesenteric oxygen extraction and lactate release increased. R(HA), R(HP) and R(mes) all increased. Ninety minutes after tesozentan, Q(PV), LDF and hepatic and mesenteric oxygen delivery and extraction increased approaching baseline values, but no effect was seen on CO or Q(HA). Hepatic and mesenteric handling of lactate converted to extraction. R(HA), R(HP) and R(mes) returned to baseline values. No changes were observed in these variables among control animals not receiving tesozentan. CONCLUSION: In a porcine model of acute splanchnic hypoperfusion, unselective ET-1 blockade restored hepatomesenteric perfusion and reversed lactate metabolism. These observations might be relevant when considering liver protection in low CO states.

Venoarterial PCO2 difference: a marker of postoperative cardiac output in children with congenital heart disease.

OBJECTIVE: To determine the relationship between venoarterial carbon dioxide gradient (DeltapCO2) and central venous oxygen saturation (ScvO2) in children after cardiac surgery. STUDY DESIGN: A cohort study. PLACE AND DURATION OF STUDY: The Paediatric cardiac intensive care unit of the Aga Khan University Hospital, Karachi, from June 2006 to May 2007. METHODOLOGY: All children admitted in the paediatric cardiac intensive care after complete repair of congenital heart defect using cardiopulmonary bypass were included in the study. Simultaneous arterial and central venous blood gas samples were obtained from a catheter placed in the artery (either radial or femoral) and superior vena cava respectively. Linear regression analysis was performed between ScvO2 and DeltapCO2. RESULTS: Fifty seven children aged from 5 days to 14 years were included and 272-paired simultaneous arterial and central venous samples were analyzed. Mean venous pCO2 was 47.82+/-9.03 mmHg and mean arterial pCO2 was 40.50+/-9.06 mmHg. One hundred seventy four samples had ScvO2 > 70% with mean DeltapCO2 of 5.44+/-2.55 mmHg and 98 samples had ScvO2 < 70% with mean DeltapCO2 of 9.07+/-3.90 mmHg. With ScvO2 < 70%, 77 samples had DeltapCO2 of > 6 mmHg while only 21 samples had DeltapCO2 of < 6 mmHg (p < 0.001). On the contrary with ScvO2 > 70%, 71 samples had DeltapCO2 of > 6 mmHg and 103 samples had DeltapCO2 of < 6 mmHg. Coefficient of correlation (R2) between 0.340 was ScvO2 and DeltapCO2. CONCLUSION: Elevated DeltapCO2 is practical and can be utilized as a useful adjunct to low ScvO2 in the assessment of low cardiac output syndrome in children after cardiac surgery.

Evaluation of the vasoactive-inotropic score, mid-regional pro-adrenomedullin and cardiac troponin I as predictors of low cardiac output syndrome in children after congenital heart disease surgery.

OBJECTIVE: To determine the predictive value of the inotropic score (IS) and vasoactive-inotropic score (VIS) in low cardiac output syndrome (LCOS) in children after congenital heart disease surgery involving cardiopulmonary bypass (CPB), and to establish whether mid-regional pro-adrenomedullin (MR-proADM) and cardiac troponin I (cTn-I), associated to the IS and VIS scores, increases the predictive capacity in LCOS. DESIGN: A prospective observational study was carried out. SETTING: A Paediatric Intensive Care Unit. PATIENTS: A total of 117children with congenital heart disease underwent CPB. Patients were divided into two groups: LCOS and non-LCOS. INTERVENTIONS: The clinical and analytical data were recorded at 2, 12, 24 and 48h post-CPB. Logistic regression was used to develop a risk prediction model using LCOS as dependent variable. MAIN OUTCOME MEASURES: LCOS, IS, VIS, MR-proADM, cTn-I, age, sex, CPB time, PIM-2, Aristotle score. RESULTS: While statistical significance was not recorded for IS in the multivariate analysis, VIS was seen to be independently associated to LCOS. On the other hand, VIS>15.5 at 2h post-CPB, adjusted for age and CPB timepoints, showed high specificity (92.87%; 95%CI: 86.75-98.96) and increased negative predictive value (75.59%, 95%CI: 71.1-88.08) for the diagnosis of LCOS at 48h post-CPB. The predictive power for LCOS did not increase when VIS was combined with cTn-I >14ng/ml at 2h and MR-proADM >1.5nmol/l at 24h post-CPB. CONCLUSIONS: The VIS score at 2h post-CPB was identified as an independent early predictor of LCOS. This predictive value was not increased when associated with LCOS cardiac biomarkers. The VIS score was more useful than IS post-CPB in making early therapeutic decisions in clinical practice post-CPB.

Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery.

BACKGROUND AND OBJECTIVE: Milrinone is used for the prevention of low cardiac output syndrome in pediatric patients after cardiac surgery. Milrinone is mainly eliminated by the kidneys; however, there is limited information on milrinone pharmacokinetics in infants who have acute kidney injury (AKI). The aim of this study was to develop a milrinone population pharmacokinetic model in neonates and infants with or without AKI. The developed milrinone pharmacokinetic model was utilized for a Monte Carlo simulation analysis to identify age-appropriate dosing regimens in neonates and infants. METHODS: Population pharmacokinetic analysis was performed with a total of 1088 serum milrinone concentrations obtained from 92 infants as part of a prospective clinical study in neonates and infants following cardiac surgery (ClinicalTrials.gov identifier NCT01966237). AKI stages were determined based on the Kidney Injury Improving Global Outcomes (KDIGO) Clinical Practice Guideline within the first three postoperative days. RESULTS: A two-compartment model was found to adequately describe the pharmacokinetic data. Allometrically scaled body weight, AKI stages, and maturation function were identified as significant predictors of milrinone clearance. The proposed dosing regimens for milrinone continuous infusions were determined based on a target concentration attainment of simulated steady-state concentration and covered three age groups across 0-12 months of age for each AKI stage. CONCLUSION: This study provides a milrinone population pharmacokinetic model in neonates and infants and captures the developmental changes in clearance. Age-appropriate dosing regimens were determined based on the simulation analysis with the developed pharmacokinetic model. The findings will facilitate model-informed precision dosing of milrinone in infants with or without AKI.

Risk stratification in neonates and infants submitted to cardiac surgery with cardiopulmonary bypass: a multimarker approach combining inflammatory mediators, N-terminal pro-B-type natriuretic peptide and troponin I.

Low cardiac output syndrome (LCOS) is a common problem following cardiac surgery with cardiopulmonary bypass (CPB) in neonates and infants, and its early recognition remains a challenging task. We aimed to test whether a multimarker approach combining inflammatory and cardiac markers provides complementary information for prediction of LCOS and death in children submitted to cardiac surgery with CPB. Forty-six children younger than 18 months with congenital heart defects were prospectively enrolled. No intervention was made. Blood samples were collected pre-operatively, during CPB and post-operatively (PO) for measurement of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Clinical data and outcome variables were recorded. Logistic regression was used to identify predictors of LCOS and death. Multivariate logistic regression identified pre-operative NT-proBNP and IL-8 4h PO as independent predictors of LCOS, while cTnI 4h PO and CPB length were independent predictors of death. The use of inflammatory and cardiac markers in combination improved sensitivity, negative predictive value and accuracy of the models. In conclusion, the combined assessment of inflammatory and cardiac biochemical markers can be useful for identifying young children at increased risk for LCOS and death after heart surgery with CPB.

Tissue inhibitor of metalloproteinases levels in patients with chronic heart failure: an independent predictor of mortality.

BACKGROUND: Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in cardiac remodelling. The prognostic utility of TIMP is unknown in chronic heart failure (CHF). AIMS: We investigated the association of plasma levels of soluble MMP-9 and TIMP-1 with clinical, laboratory and echocardiographic parameters and estimated their prognostic value in the prediction of all-cause death. METHODS: MMP-9, TIMP-1, tumour necrosis factor-alpha, and amino-terminal pro-brain natriuretic peptide were measured in 249 consecutively enrolled CHF patients and 74 healthy individuals. RESULTS: After adjustment for age, sex and creatinine, levels of TIMP-1 (1640 vs. 735 ng/ml, P<0.001) but not MMP-9 were elevated in CHF patients compared to controls. During a median follow-up period of 2.5 years, 66 patients (27%) died. In multivariable Cox regression models TIMP-1 but not MMP-9 emerged as an independent predictor of all-cause death (hazard ratio per tertile, 3.5; 95% confidence interval [CI], 2.2-5.1). In addition to the full set of univariately predictive clinical and serological markers, information on TIMP-1 significantly increased the area under the receiver operating characteristic curve from 0.77 (95% CI, 0.71-0.84) to 0.87 (95% CI, 0.82-0.92). CONCLUSION: In stable CHF patients, TIMP-1 but not MMP-9 is of independent and incremental value regarding the prediction of all-cause death.

Comparison of central venous to mixed venous oxygen saturation in patients with low cardiac index and filling pressures after coronary artery surgery.

OBJECTIVE: To evaluate the correlation and agreement between mixed venous oxygen saturation (SvO(2)) and central venous oxygen saturation (ScvO(2)) in patients with low cardiac index and filling pressures after coronary artery surgery. DESIGN: Prospective observational study. SETTING: Tertiary care academic hospital. PARTICIPANTS: Sixty consecutive patients with a cardiac index <2 L/min/m(2) and a pulmonary artery occlusion pressure <12 mmHg after coronary artery surgery were included. INTERVENTIONS: Patients were monitored by a pulmonary artery catheter and a central venous catheter positioned in the superior vena cava. MEASUREMENTS AND RESULTS: SvO(2) and ScvO(2) were simultaneously measured before (T0) and after (T1) normalization of the cardiac index (>2.5 L/min/m(2)) by fluid therapy. Sixty pairs of measures were obtained at T0 and at T1. Bias between SvO(2) and ScvO(2) was -0.6% (T0) and -0.8% (T1). Limits of agreement were from -19.2% to 18% (T0) and from -15.6% to 14% (T1), and the correlation coefficient was 0.463 (T0) and 0.72 (T1). SvO(2) and ScvO(2) changes from T0 to T1 (DeltaSvO(2) and DeltaScvO(2)) were calculated. The bias between DeltaSvO(2) and DeltaScvO(2) was -0.25. Limits of agreement were from -20% to 19.5%, and the correlation coefficient was 0.6. CONCLUSIONS: In patients with low cardiac index and filling pressures after coronary artery surgery, ScvO(2) could not be used as a direct alternative for SvO(2). After fluid therapy and normalization of the cardiac index, differences between individual values remained large, and the disagreement between ScvO(2) and SvO(2) changes was significant.

Low cardiac output syndrome in the postoperative period of cardiac surgery. Profile, differences in clinical course and prognosis. The ESBAGA study. / Síndrome de bajo gasto cardiaco en el postoperatorio de cirugía cardiaca. Perfil, diferencias en evolución clínica y pronóstico. Estudio ESBAGA.

OBJECTIVES: An analysis is made of the clinical profile, evolution and differences in morbidity and mortality of low cardiac output syndrome (LCOS) in the postoperative period of cardiac surgery, according to the 3 diagnostic subgroups defined by the SEMICYUC Consensus 2012. DESIGN: A multicenter, prospective cohort study was carried out. SETTING: ICUs of Spanish hospitals with cardiac surgery. PATIENTS: A consecutive sample of 2,070 cardiac surgery patients was included, with the analysis of 137 patients with LCOS. INTERVENTIONS: No intervention was carried out. RESULTS: The mean patient age was 68.3±9.3 years (65.2% males), with a EuroSCORE II of 9.99±13. NYHA functional class III-IV (52.9%), left ventricular ejection fraction<35% (33.6%), AMI (31.9%), severe PHT (21.7%), critical preoperative condition (18.8%), prior cardiac surgery (18.1%), PTCA/stent placement (16.7%). According to subgroups, 46 patients fulfilled hemodynamic criteria of LCOS (group A), 50 clinical criteria (group B), and the rest (n=41) presented cardiogenic shock (group C). Significant differences were observed over the evolutive course between the subgroups in terms of time subjected to mechanical ventilation (114.4, 135.4 and 180.3min in groups A, B and C, respectively; P<.001), renal replacement requirements (11.4, 14.6 and 36.6%; P=.007), multiorgan failure (16.7, 13 and 47.5%), and mortality (13.6, 12.5 and 35.9%; P=.01). The mean maximum lactate concentration was higher in cardiogenic shock patients (P=.002). CONCLUSIONS: The clinical evolution of these patients leads to high morbidity and mortality. We found differences between the subgroups in terms of the postoperative clinical course and mortality.