Richard J. Levy

Mitochondrial dysfunction and resuscitation in sepsis.

Sepsis is among the most common causes of death in patients in intensive care units in North America and Europe. In the United States, it accounts for upwards of 250,000 deaths each year. Investigations into the pathobiology of sepsis have most recently focused on common cellular and subcellular processes. One possibility would be a defect in the production of energy, which translates to an abnormality in the production of adenosine triphosphate and therefore in the function of mitochondria. This article presents a clear role for mitochondrial dysfunction in the pathogenesis and pathophysiology of sepsis. What is less clear is the teleology underlying this response. Prolonged mitochondrial dysfunction and impaired biogenesis clearly are detrimental. However, early inhibition of mitochondrial function may be adaptive.

PEDIATRIC AIRWAY ISSUES

Airway management in the pediatric patient requires an understanding and knowledge of the differences and characteristics unique to the child and infant. New and exciting techniques are currently being explored and developed for management of the pediatric airway. Technology in the area of imaging has allowed clinicians to better visualize the airway and aberrations of it. Presently, there are many different modes and routes of ventilation and oxygenation that are being applied to the pediatric patient for different disease states. Work continues to probe for methods and ways that will allow us to take care of infants and children better and to provide the safest and most effective means of delivering that care. No doubt, there will be more advances and exciting ideas to come that lead to better management of the pediatric airway.

Specialized Delivery Room Planning for Fetuses With Critical Congenital Heart Disease

Improvements in fetal echocardiography have increased recognition of fetuses with congenital heart disease (CHD) that require specialized delivery room (DR) care. In this study, care protocols for these low-volume and high-risk deliveries were created. Elements included (1) diagnosis-specific DR care plans and algorithms, (2) a multidisciplinary team with expertise, (3) simulation, (4) checklists, and (5) debriefing. The purpose of this study was to assess the accuracy of fetal echocardiography to predict the need for specialized DR care and determine the effectiveness of the care protocols for the treatment of patients with critical CHD. Fetal and postnatal medical records and echocardiograms of fetuses with CHD assigned to an advanced level of care were reviewed. Safety and outcome variables were analyzed to determine care plan and algorithm efficacy. Thirty-four fetuses were identified: 12 delivered at Childrens National Medical Center and 22 at the adult hospital. Diagnoses included hypoplastic left heart syndrome, aortic stenosis, d-transposition of the great arteries, tetralogy of Fallot with absent pulmonary valve, complex pulmonary atresia, arrhythmias, ectopia cordis, and conjoined twins. Delivery at Childrens National Medical Center was associated with a shorter time to specialty care or intervention. Measures of physiologic stability and survival were similar. Need for specialized care was predicted in 84% of deliveries. For hypoplastic left heart syndrome, intervention was predicted in 10 of 11 deliveries and for d-transposition of the great arteries in 10 of 12 deliveries. Care algorithms addressed most DR events. Of the unanticipated events, none were unrecoverable. DR survival was 100%, and survival to discharge was 83%. In conclusion, fetal echocardiography predicted the need for specialized DR care in fetuses with critical CHD. Algorithm-driven protocols enable planning such that maternal and infant risk is minimized and outcomes are good.

Critical heart disease in the neonate: Presentation and outcome at a tertiary care center

Objective: To define the modes of presentation, incidence of major organ dysfunction, predictors of hospital mortality, and adverse outcomes in neonates with critical heart disease admitted to a tertiary care center. Design: Retrospective chart review. Setting: A tertiary care pediatric cardiac intensive care unit and neonatal intensive care unit. Patients: The medical records for all neonates (≤30 days of age) with heart disease admitted to the cardiac intensive care unit or neonatal intensive care unit between October 1, 2002, and September 30, 2003, were reviewed. Interventions: None. Measurements and Main Results: A total of 190 neonates met inclusion criteria during this 1-yr period, of which 146 (77%) had at least one surgical procedure. Single ventricle heart disease was present in 42%. The most common mode of presentation was following a prenatal diagnosis (53%), followed by diagnosis in the newborn nursery (38%) and diagnosis after newborn hospital discharge (8%). The most common presenting findings in the newborn nursery were isolated murmur (38%) or cyanosis (32%), while circulatory collapse (38%) was the most common presentation after discharge. For the entire study cohort, 13% had a known genetic syndrome, 23% had a major noncardiac congenital anomaly, and 16% weighed <2.5 kg. The hospital mortality for the entire cohort was 7.4%. Risk factors associated with an increased risk of hospital mortality included younger age at admission, higher number of cardiopulmonary bypass runs, and need for postoperative cardiopulmonary resuscitation. Total hospital length of stay was >1 month in 17% of neonates. Conclusions: In patients with complex congenital heart disease, including nearly half with single ventricle heart disease, neonatal hospital mortality was 7%. These patients have a high frequency of multiple congenital anomalies, genetic syndromes, low birth weight, and prolonged length of stay.

An evaluation of a noninvasive cardiac output measurement using partial carbon dioxide rebreathing in children

Cardiac output (CO) is an important hemodynamic measure that helps to guide the therapy of critically ill patients. Invasive CO assessment in infants and children is often avoided because of the inherent risks. A noninvasive CO monitor that uses partial rebreathing has been recently developed to determine CO via the Fick principle for carbon dioxide. There have been no clinical studies confirming its accuracy in pediatric patients. This is a prospective observational study of 37 children <12 yr of age who underwent cardiac catheterization. Under general anesthesia via an endotracheal tube without a leak, we made multiple CO measurements using thermodilution and compared them with noninvasively determined CO measurements. Paired measurements were analyzed for bias, precision, and correlation via Bland-Altman plot and linear regression. Noninvasive measurements showed a linear correlation with thermodilution CO assessment with an r value of 0.83 (P < 0.03). Bland-Altman analysis yielded a bias of −0.27 L/min and a precision ±1.49 L/min. Cardiac index measurements demonstrated a decreased r value of 0.67 (P = 0.15) and a bias of −0.18 L · min−1 · m−2 and precision of ±2.13 L · min−1 · m−2. Differences between partial rebreathing measurements and thermodilution measurements were largest in children with a body surface area of ≤0.6 m2 ventilated with tidal volumes <300 mL. Based on these findings, noninvasive CO measurement using partial rebreathing may be clinically acceptable in children with >0.6 m2 body surface area and >300 mL tidal volume.

Detection of Carbon Monoxide During Routine Anesthetics in Infants and Children

BACKGROUND: Carbon monoxide (CO) can be produced in the anesthesia circuit when inhaled anesthetics are degraded by dried carbon dioxide absorbent and exhaled CO can potentially be rebreathed during low-flow anesthesia. Exposure to low concentrations of CO (12.5 ppm) can cause neurotoxicity in the developing brain and may lead to neurodevelopmental impairment. In this study, we aimed to quantify the amount of CO present within a circle system breathing circuit during general endotracheal anesthesia in infants and children with fresh strong metal alkali carbon dioxide absorbent and define the variables associated with the levels detected. METHODS: Fifteen infants and children (aged 4 months to 8 years) undergoing mask induction followed by general endotracheal anesthesia were evaluated in this observational study. CO was measured in real time from the inspiratory limb of the anesthesia circuit every 5 minutes for 1 hour during general anesthesia. Carboxyhemoglobin (COHb) levels were measured at the 1-hour time point and compared with baseline. RESULTS: CO was detected in all patients older than 2 years (0–18 ppm, mean 3.7 ± 4.8 ppm) and rarely detected in patients younger than 2 years (0–2 ppm, mean 0.2 ± 0.6 ppm). Only the relationship between CO concentration and fresh gas flow to minute ventilation ratio (FGF:&OV0312;e) remained significant after adjustment in longitudinal regression analysis (P < 0.001). Although not powered to determine such a relationship, CO levels were weakly associated with the use of desflurane and female sex. There was no significant association between CO concentration and anesthetic concentration. Baseline COHb levels were higher in children younger than 2 years and decreased significantly at the 1-hour time point compared with baseline and children older than 2 years. However, COHb levels increased significantly from baseline in a predictable manner consistent with CO exposure in children older than 2 years. FGF:&OV0312;e correlated significantly with change in COHb using simple linear regression (r = 0.62; P < 0.02). CONCLUSIONS: CO was detected routinely during general anesthesia in infants and children when FGF:&OV0312;e was <1. Peak CO levels measured in the anesthesia breathing circuit were in the range thought to impair the developing brain. Further study is required to identify the source of CO detected (CO produced by degradation of volatile anesthetic versus rebreathing CO from endogenous sources or both). However, these findings suggest that avoidance of low-flow anesthesia will prevent rebreathing of exhaled CO, and use of carbon dioxide absorbents that lack strong metal hydroxide could limit inspired CO if detection was attributable to degradation of volatile anesthetic.

Subclinical Carbon Monoxide Limits Apoptosis in the Developing Brain After Isoflurane Exposure

BACKGROUND:Volatile anesthetics cause widespread apoptosis in the developing brain. Carbon monoxide (CO) has antiapoptotic properties, and exhaled endogenous CO is commonly rebreathed during low-flow anesthesia in infants and children, resulting in subclinical CO exposure. Thus, we aimed to determine whether CO could limit isoflurane-induced apoptosis in the developing brain. METHODS:Seven-day-old male CD-1 mouse pups underwent 1-hour exposure to 0 (air), 5, or 100 ppm CO in air with or without isoflurane (2%). We assessed carboxyhemoglobin levels, cytochrome c peroxidase activity, and cytochrome c release from forebrain mitochondria after exposure and quantified the number of activated caspase-3 positive cells and TUNEL positive nuclei in neocortex, hippocampus, and hypothalamus/thalamus. RESULTS:Carboxyhemoglobin levels approximated those expected in humans after a similar time-weighted CO exposure. Isoflurane significantly increased cytochrome c peroxidase activity, cytochrome c release, the number of activated caspase-3 cells, and TUNEL positive nuclei in the forebrain of air-exposed mice. CO, however, abrogated isoflurane-induced cytochrome c peroxidase activation and cytochrome c release from forebrain mitochondria and decreased the number of activated caspase-3 positive cells and TUNEL positive nuclei after simultaneous exposure with isoflurane. CONCLUSIONS:Taken together, the data indicate that CO can limit apoptosis after isoflurane exposure via inhibition of cytochrome c peroxidase depending on concentration. Although it is unknown whether CO directly inhibited isoflurane-induced apoptosis, it is possible that low-flow anesthesia designed to target rebreathing of specific concentrations of CO may be a desired strategy to develop in the future in an effort to prevent anesthesia-induced neurotoxicity in infants and children.

Evaluation of tissue saturation as a noninvasive measure of mixed venous saturation in children

Background: Mixed venous saturation (S&OV0456;o2) is an important measurement that helps guide the care of critically ill patients. Invasive S&OV0456;o2 assessment in infants and children is often avoided because of the inherent risks. A noninvasive tissue saturation (Sto2) monitor has recently been developed that uses near-infrared spectroscopy to measure oxyhemoglobin saturation in muscle. In adult and animal studies, Sto2 correlated with oxygen delivery and S&OV0456;o2. There has been no evaluation in pediatric patients. Objective: To evaluate tissue saturation as a noninvasive measure of mixed venous saturation in children. Design: A prospective observational study. Setting: Catheterization laboratory in a tertiary care children’s medical center. Patients: We studied 98 children (49 without intracardiac mixing and 49 with intracardiac mixing) ≤12 yrs of age who underwent cardiac catheterization. Under general anesthesia, we compared Sto2 measured over the deltoid muscle with superior vena cava saturation in both groups and Sto2 with pulmonary artery saturation in patients without intracardiac mixing. Paired measurements were analyzed for bias, precision, and correlation via Bland-Altman plot and linear regression. Results: No meaningful correlation was found between Sto2 and superior vena cava saturation or pulmonary artery saturation. Bland-Altman analyses of Sto2 with superior vena cava saturation yielded bias values of -6.67 ± 37.33% in patients with intracardiac mixing and −0.82 ± 41.31% in patients without mixing. Bland-Altman analysis of Sto2 with pulmonary artery saturation yielded a bias of 3.61 ± 41.32% in patients without mixing. Differences between noninvasive and invasive measurements were greatest in smaller children. Conclusion: Noninvasive tissue saturation over the deltoid does not correlate with S&OV0456;o2 in children. It is possible that more precise probe spacing, coupled with optimal muscle-mass location, could result in more accurate measures in future investigations.

Chronic Hypoxemia Increases Ventricular Brain Natriuretic Peptide Precursors in Neonatal Swine

BACKGROUNDnCirculating levels of atrial natriuretic peptide and brain natriuretic peptide (BNP) are elevated in patients with cyanotic congenital heart disease and associated with the severity of ventricular dysfunction. We evaluated the effect of chronic hypoxemia on left ventricle pro-atrial natriuretic peptide and pro-BNP, the cytoplasmic precursors of the plasma hormones.nnnMETHODSnForty newborn piglets were randomized to placement of a pulmonary artery to left atrium shunt to create hypoxemia or sham thoracotomy. Animals were studied at 1 or 2 weeks after the procedure (four groups, n = 10 per group). Arterial oxygen tension and hematocrit were obtained. Left ventricular shortening fraction was measured by echocardiography. Left ventricular tissue was harvested and cytoplasm was extracted. Pro-BNP levels were determined by Western blot analysis. Pro-atrial natriuretic peptide levels were determined using enzyme-linked immunosorbent assay.nnnRESULTSnSignificant differences among treatment groups were observed for arterial oxygen tension (p < 0.001) and hematocrit (p < 0.001). Pairwise comparisons indicated lower arterial oxygen tension and higher hematocrit for hypoxemic piglets compared with control piglets at 1 and 2 weeks. Left ventricular shortening fraction was not decreased in the hypoxemic animals at any time (p = 0.638). Left ventricular pro-atrial natriuretic peptide decreased in hypoxemic piglets (p = 0.029), whereas left ventricular pro-BNP increased in hypoxemic piglets at 2 weeks (p = 0.002).nnnCONCLUSIONSnChronic hypoxemia alone, even in the absence of cardiac dysfunction, is sufficient to increase ventricular levels of pro-BNP. This finding may have implications for the interpretation of BNP levels in the clinical management of patients with cyanotic congenital heart disease.

Pentalogy of Cantrell with a Single-Ventricle Cardiac Defect: Collaborative Management of a Complex Disease

We present a case of ectopia cordis with a complex single-ventricle congenital heart defect in association with pentalogy of Cantrell. Management by a skilled multidisciplinary team was critical for patient survival. Early fetal diagnosis and the use of advanced imaging techniques allowed adequate time for planning and identified critical anatomic details. Preserving the heart’s natural covering, performing cardiac surgery without cardiopulmonary bypass, and using catheter intervention decreased the risk to the patient. Complete coverage of the defect was achieved using skin generated with tissue expanders. This case illustrates the importance of collaboration when caring for infants with critical, high-risk disease and highlights the increased potential for survival with complex ectopia cordis in the current medical era.