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J A Carcillo

Publications and source records attributed to J A Carcillo.

54 records · Page 3Linked to original sources
PubMed1996

CYP2D6 mRNA expression in circulating peripheral blood mononuclear cells correlates with in vivo debrisoquine hydroxylase activity in extensive metabolizers.

Extensive metabolizers of drugs which are oxidized by cytochrome P450s show wide interindividual variability in drug metabolism. Elucidation of the relationship between specific P450 isozyme mRNA expression and variability in metabolism of specific drugs could improve understanding of the molecular mechanism involved. In this study, a novel non-radiometric reverse transcription polymerase chain reaction based assay was used to quantify CYP2D6 mRNA levels in peripheral blood mononuclear cells in twelve human volunteers who were phenotyped as extensive metabolizers of debrisoquine. We report a significant correlation (r=0.724, p= 0.008) between CYP2D6 mRNA levels in circulating peripheral blood mononuclear cells and the in vivo debrisoquine recovery ratio. This suggests that interindividual variability in extensive metabolizers could be related, in part, to differences in gene expression. Circulating peripheral blood mononuclear cells can provide an accessible ex vivo measure of this phenomenon.

Actins↗
PubMed1996

Treatment with the type IV phosphodiesterase inhibitor Ro 20-1724 protects renal and mesenteric blood flow in endotoxemic rats treated with norepinephrine.

We recently reported that pretreatment with the type IV phosphodiesterase inhibitor Ro 20-1724 attenuates the development of endotoxin-induced acute renal failure in rats. Norepinephrine is an important therapeutic agent in human endotoxemia, but its efficacy is limited by its deleterious side effect of potent renal and mesenteric vasoconstriction. In this study we examined whether posttreatment with Ro 20-1724 after endotoxin infusion 1) attenuates increased renal vascular resistance and the development of acute renal failure in the absence and presence of norepinephrine infusion, 2) improves mesenteric blood flow in the presence of norepinephrine and 3) improves survival rates in the absence and presence of norepinephrine infusion. Forty-eight rats were anesthetized and instrumented, and eight 20-min clearance periods were performed. Endotoxin (20 mg/kg i.v.) was administered after the first period, and a constant-rate i.v. infusion of either Ro 20-1724 (10 micrograms/kg/min) or vehicle was initiated after period 3, in the absence and presence of norepinephrine infusion (1 microgram/kg/ min, begun after period 4). Urinary cAMP excretion in the Ro 20-1724-treated groups was 2- to 3-fold (P < .001) higher, compared with the vehicle-treated groups. Ro 20-1724 markedly attenuated endotoxin-induced (P < .01) increases in renal vascular resistance and attenuated norepinephrine-induced (P < .05) increases in renal vascular resistance in rats pretreated with endotoxin. Moreover, Ro 20-1724 reduced endotoxin-induced decreases in renal blood flow (P < .05) and glomerular filtration rate (P < .01) in the absence and presence of norepinephrine. In animals pretreated with endotoxin, Ro 20-1724 attenuated norepinephrine-induced increases in mesenteric vascular resistance (P = .054) and decreases in mesenteric blood flow (P < .01). Ro 20-1724 also improved survival rates for endotoxin-treated rats, whether or not the rats were administered norepinephrine (P < .01). Type IV-specific phosphodiesterase inhibitors warrant further study as selective therapeutic agents that protect against endotoxin/vasopressor-induced renal and mesenteric ischemia and death.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1996

Injured erythrocytes release adenosine deaminase into the circulation.

The purpose of this study was to test the hypothesis that circulating red blood cells (RBCs) release adenosine deaminase (ADA) when injured. This hypothesis was evaluated in rats using dimethyl sulfoxide (DMSO) to damage RBCs. Boluses and infusions of DMSO caused a reduction in urinary adenosine and a concomitant hemoglobinuria, and the ability of DMSO to reduce urinary adenosine was blocked by pretreatment with the ADA inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine. Infusions of DMSO also significantly enhanced ADA activity in urine and plasma. Dimethylsulfone, an analog of DMSO that does not affect RBCs, did not cause hemoglobinuria and did not affect urinary adenosine. High concentrations of DMSO did not affect adenosine metabolism in rat kidneys perfused without RBCs, and DMSO did not decrease urinary adenosine in rats rendered severely anemic (hematocrit < 15%) by replacing whole blood with plasma. However, DMSO did decrease urinary adenosine in rats without a spleen, a major source of adenosine deaminase apart from circulating RBCs. DMSO reduced renal interstitial levels of adenosine and attenuated bradycardic responses to exogenous adenosine, and these effects were prevented by erythro-9-(2-hydroxy-3-nonyl)adenine. These results indicate that circulating damaged RBCs release significant amounts of ADA, a process that may predispose to vasoocclusive events.

Adenosine↗
PubMed1995

Increased serum nitrite and nitrate concentrations in children with the sepsis syndrome.

OBJECTIVES: To measure total serum nitrite and nitrate concentrations in children with the sepsis syndrome as an indicator of endogenous nitric oxide production. To determine if there is an association between total serum nitrite and nitrate concentrations and vascular responsiveness to norepinephrine. DESIGN: A prospective, clinical study. SETTING: Tertiary, multidisciplinary, pediatric intensive care unit. PATIENTS: Thirty-one children with the sepsis syndrome, 18 of whom were also hypotensive. Sixteen critically ill children without signs of the sepsis syndrome served as controls. INTERVENTIONS: Blood samples were obtained from indwelling catheters. The norepinephrine dose to reach the age appropriate, 50th percentile mean arterial blood pressure was determined in patients receiving norepinephrine. MEASUREMENTS AND MAIN RESULTS: Total serum nitrite and nitrate concentrations were measured on the first three days after the recognition of the sepsis syndrome. Patients with the sepsis syndrome had increased mean total serum nitrite and nitrate concentrations (day 1, 118 +/- 93 microM; day 2, 112 +/- 94 microM; day 3, 112 +/- 93 microM) vs. controls (43 +/- 24 microM, p < .05) on all 3 days. When sepsis syndrome patients were separated into nonhypotensive and hypotensive groups, only the patients with hypotension had increased concentrations vs. controls on all three days (p < .05). Sepsis syndrome patients with hypotension also had higher total serum nitrite and nitrate concentrations (145 +/- 97 microM) than sepsis syndrome patients without hypotension (82 +/- 76 microM, p < .05) on day 1. In five patients receiving norepinephrine infusions, increased total serum nitrite and nitrate concentrations were associated with higher norepinephrine requirements to maintain an age-appropriate, 50th percentile mean arterial blood pressure on each of the three study days (day 1, rs = 0.821, p < .05; day 2, rs = 0.900, p < .05; day 3, rs = 0.872, p < .05). CONCLUSIONS: Children with the sepsis syndrome, particularly those patients with hypotension, have increased total serum nitrite and nitrate concentrations that likely reflect increased endogenous production of nitric oxide. Vascular hyporesponsiveness to norepinephrine during the sepsis syndrome may be, in part, a nitric oxide-mediated process.

Adolescent↗
PubMed1995

Plasma bactericidal/permeability-increasing protein concentrations in critically ill children with the sepsis syndrome.

Bactericidal/permeability-increasing protein (BPI) is a neutrophil azurophilic granule component that is bactericidal towards Gram-negative bacteria and inhibits lipopolysaccharide-mediated inflammatory responses. We conducted a prospective study to measure plasma BPI concentrations in 36 critically ill children with and without the sepsis syndrome. Plasma BPI concentrations ranged from 0.5 to 452 ng/ml. Patients with the sepsis syndrome had higher median plasma BPI concentrations than critically ill controls (5.1 vs. 1.8 ng/ml, P = 0.006). Patients with organ system failure had higher median plasma BPI concentrations than those with no organ system failure (4.5 vs. 1.3 ng/ml, P = 0.001). Plasma BPI concentrations were positively associated with pediatric risk of mortality score (P = 0.03, rs = 0.4). These data provide the first clinical insights regarding the role of endogenous BPI production in critically ill children and suggest that BPI may play an important role in host defenses.

Anti-Bacterial Agents↗
PubMed1995

Norepinephrine induces expression of c-fos mRNA through the alpha-adrenoceptor in rat aortic rings.

We examined whether norepinephrine at pharmacologically relevant doses induces increased expression of c-fos mRNA in rat aortic rings. c-fos mRNA was expressed at norepinephrine concentrations known to cause minimum and maximum contraction of rat aorta in vitro. At the concentration known to cause maximum contraction, norepinephrine produced a marked and sustained increase of c-fos mRNA expression. Induction of c-fos was blocked completely by the alpha 1-adrenergic antagonist prazosin, partially by the alpha 2-adrenergic antagonist yohimbine, and not at all by the beta-adrenergic antagonist propranolol. A prazosin inhibition curve showed that 1 nmol/L prazosin inhibited 10 micromol/L norepinephrine induced c-fos expression by 40%. At the pharmacologic dose known to cause maximum contraction, norepinephrine induces c-fos mRNA expression through the alpha-adrenoceptor in rat aortic rings.

Adrenergic alpha-Antagonists↗
PubMed1995

Improved maternal and child health care access in a rural community.

Few studies have measured the extent to which expansion of health services for pregnant women and children in poor rural communities improves access to care and health status. This paper describes an underserved rural community in which health care initiatives increased access to comprehensive care. Over a three-year period, use of preventive services increased, whereas emergency room visits and hospitalizations at the community hospital decreased. Low birthweight, risk of congenital syphilis and childhood tuberculosis, and child mortality all decreased. Provision of comprehensive services was met with increased use of preventive health care and improved health outcomes in this rural community.

Child↗
PubMed1991

Role of early fluid resuscitation in pediatric septic shock.

OBJECTIVE: To examine the association of the volume of fluid administered at 1 and 6 hours after presentation, with survival and the occurrence of the adult respiratory distress syndrome, cardiogenic pulmonary edema, and persistent hypovolemia during the resuscitation of children with septic shock. SETTING AND PATIENTS: All pediatric patients with septic shock presenting to the emergency department over a 6-year period and having a pulmonary artery catheter inserted by 6 hours after presentation were identified. METHODS: Patients were analyzed together and in three groups based on fluid volume in the first hour: group 1, less than 20 mL/kg; group 2, 20 to 40 mL/kg; and group 3, more than 40 mL/kg. Adult respiratory distress syndrome was diagnosed by the presence of alveolar infiltrates, hypoxemia, and a pulmonary capillary wedge pressure of 15 mm Hg or less. Cardiogenic pulmonary edema was diagnosed similarly, except the pulmonary capillary wedge pressure was greater than 15 mm Hg. Hypovolemia was diagnosed by the presence of oliguria, hypotension, and a pulmonary capillary wedge pressure of 8 mm Hg or less 6 hours after presentation. RESULTS: We identified 34 patients (median age, 13.5 months). At 1 and 6 hours, respectively, group 1 (n = 14) received 11 +/- 6 and 71 +/- 29 mL/kg (mean +/- SD) of fluid; group 2 received 32 +/- 5 and 108 +/- 54 mL/kg of fluid; and group 3 received 69 +/- 19 and 117 +/- 29 mL/kg of fluid. Survival in group 3 (eight of nine patients) was significantly better than in group 1 (six of 14 patients) or group 2 (four of 11 patients). Adult respiratory distress syndrome developed in 11 patients (32%) and cardiogenic pulmonary edema developed in five patients (15%). Having adult respiratory distress syndrome was associated with increased mortality, but adult respiratory distress syndrome was not increased in any group. Similarly, cardiogenic pulmonary edema was not associated with the fluid volume received or with decreased survival. Hypovolemia occurred in six patients in group 1 and two patients in group 2; all eight subsequently died. CONCLUSION: Rapid fluid resuscitation in excess of 40 mL/kg in the first hour following emergency department presentation was associated with improved survival, decreased occurrence of persistent hypovolemia, and no increase in the risk of cardiogenic pulmonary edema or adult respiratory distress syndrome in this group of pediatric patients with septic shock.

Adolescent↗
PubMed1991

Awake porcine model of intraperitoneal sepsis and altered oxygen utilization.

We have characterized an awake swine model of septic shock. Hemodynamic, serum chemistry, and oxygen metabolism parameters were compared between eight septic and five sham animals. Eight male Yucatan miniature swine, weighing 20-28 kg, were anesthetized and catheters were placed in the pulmonary artery, external jugular, and the carotid artery. On day 2, 1.1-4.0 x 10(10) cfu Escherichia coli/kg were administered via an intraperitoneal catheter. Hemodynamic parameters were monitored hourly for 6 hours in awake animals. The animals were then placed back into the animal holding facility for clinical observation until the 24 hour post infusion measurements were taken. Septic animals were initially hypodynamic, with a decrease in cardiac index (CI) from a baseline value of 152.8 +/- 24.8 to 87.9 +/- 17.8 ml/kg/min (P less than .05) and an increased systemic vascular resistance index (SVRI) from a control value of 48.1 +/- 9.5 to 65.0 +/- 16.7 dynes*sec*cm-5/kg. At 24 hours post infusion, the animals were hyperdynamic with the CI increased to 211.0 +/- 27.2 ml/kg/min (P less than .05) and a decreased SVRI to 30.64 +/- 3.9 dynes*sec*cm-5/kg (P less than .05). Oxygen utilization (VO2) increased during sepsis from 6.6 +/- 0.8 to 8.1 +/- 0.8 ml/kg/min at 6 hours (P less than .05) and remained elevated at 24 hours at 7.7 +/- 0.4 (P less than .05). Increased oxygen consumption was attained with an increase in oxygen extraction (O2 ext) from 0.34 +/- 0.03 to 0.56 +/- 0.07 (P less than .05) during the first 6 hours of sepsis. At 24 hours, increased oxygen utilization was maintained by high oxygen delivery state. Significant alterations in serum chemistries in conjunction with post mortem evidence of multiple organ system failure were observed. Mortality on or before 4 days post infusion was 50% and positive blood cultures were obtained in 38% of the animals studied. This awake swine model serves as an excellent model to study metabolic pathophysiology and the treatment of septic shock.

Animals↗
PubMed1989

Sequential physiologic interactions in pediatric cardiogenic and septic shock.

We report that the pediatric cardiogenic shock and septic shock populations show similar hemodynamic and oxygen utilization physiologic relationships during aggressive intensive care therapy. We examined the mathematical relationships between vascular tone and flow, and oxygen utilization and oxygen delivery (DO2) in the early and middle stages of cardiogenic and septic shock. The fitted curves between cardiac index and systemic vascular resistance, and oxygen consumption (VO2) and DO2 were clinically and statistically similar in both shock populations. We found no evidence for decreased oxygen extraction in sepsis as compared to the cardiogenic shock population. In addition, it appears that the major determinant of VO2 in these populations is DO2, not oxygen extraction. We suggest that patients with cardiogenic or septic shock can be treated according to similar physiologic principles.

Child, Preschool↗
PubMed1989

Norepinephrine-induced phosphorylation of a 25 kd phosphoprotein in rat aorta is altered in intraperitoneal sepsis.

An attenuation of the contractile response to norepinephrine (NE) has been previously demonstrated in rat aorta during intraperitoneal sepsis and endotoxemia. In this study, we determined whether NE-induced protein phosphorylation is altered in septic rat aorta as compared to control rat aorta. We found that the NE-induced phosphorylation of a 25 kd phosphoprotein was decreased. NE increased phosphorylation of the 25 kd band by 54% (P less than .01) in the control aorta but only 12% (not significant) in the septic aorta. Pyrophosphate gel purification of phosphorylated myosin showed that this 25 kd band was not related to the myosin-phosphorylated (P) light chain. Two-dimensional polyacrylamide gel electrophoresis analysis revealed that this 25 kd band represents two proteins with distinct isoelectric points of 6.5 and 6.2. These results further document that intrinsic alterations occur in the NE-mediated signal transduction system in rat aorta during sepsis and that such alterations could contribute to depressed aortic contractility.

Animals↗
PubMed1988

Alterations in bidirectional transmembrane calcium flux occur without changes in protein kinase C levels in rat aorta during sepsis.

A depression in aortic contractility has been previously demonstrated in rat intraperitoneal sepsis and during endotoxemia. In this study, we determined whether the mobilization of extracellular calcium (using 45Ca) and the release of intracellular calcium are altered in septic rat aorta when compared to sham-operated controls. The concentration of protein kinase C was also determined by using [3H] phorbol-12,13-dibutyrate (PDBu). We found that calcium influx was unaltered under basal conditions but that the ability of norepinephrine (NE) to augment influx was significantly depressed (P less than .05; [control vs. septic, 572 +/- 54 [SE] vs. 428 +/- 30 mumol Ca2+/kg dry wt. aorta]). Calcium influx stimulated by high K+ was unchanged in aortae between control and septic animals. In the presence of NE, calcium efflux (an indirect measurement of intracellular calcium release) was significantly diminished (P less than .001) in aortae from septic rats. The concentration of aortic protein kinase C as assessed by PDBu binding sites was unaltered in septic rats when compared with controls. In conclusion, we found that during sepsis alpha 1-adrenergic receptor activation of both calcium influx and efflux by NE is decreased; these alterations could be related to the depressed aortic contractility observed in sepsis.

Animals↗
PubMed1988

Alterations in rat aortic alpha 1-adrenoceptors and alpha 1-adrenergic stimulated phosphoinositide hydrolysis in intraperitoneal sepsis.

We investigated the alterations of rat aortic alpha 1-adrenoceptors and alpha 1-adrenergic stimulated phosphoinositide (PI) metabolism in intraperitoneal sepsis. An analysis of [125I]-hydroxyethylaminotetralone (HEAT) binding to alpha 1-adrenoceptors on rat aortic membranes revealed decreased numbers of receptors without changes in affinity. The maximum number of binding sites decreased from 349 +/- 35 fmol/mg to 146 +/- 16 fmol/mg (P less than 0.05 vs. control). PI metabolism was similarly attenuated in aortae from septic rats. The norepinephrine-stimulated hydrolysis of [32P]-phosphatidylinositol-4,5-bisphosphate was significantly decreased in aortae from septic rats as was the alpha 1-adrenoceptor stimulated accumulation of [3H]-inositol monophosphate. Finally, the basal labeling of [32P]-phosphatidylinositol-4,5-bisphosphate but not of [32P]-phosphatidylinositol or [32P]-phosphatidic acid was significantly diminished. These results imply that signal transduction induced by alpha 1-adrenoceptor agonists in rat aorta is significantly altered in intraperitoneal sepsis. These findings may help define the mechanisms of depressed aortic contractility in models of sepsis and endotoxic shock.

Animals↗
PubMedDate not supplied

Cardiac failure in hemolytic uremic syndrome and rescue with extracorporeal life support.

Extrarenal involvement manifesting in the cardiovascular system is a rare but potentially fatal complication of hemolytic uremic syndrome (HUS). Current treatment is aimed at cardiovascular supportive measures while awaiting organ recovery. However, there are cases in which this recovery never occurs, and patients succumb secondary to heart failure. We report two cases of severe cardiac failure in children in the acute phase of HUS and the use of extracorporeal membrane oxygenation (ECMO) to support one patient to cardiac recovery. Clinicians should be aware of this potentially life-threatening cardiac involvement and should consider the use of ECMO for potentially salvageable children with HUS.

Child, Preschool↗
PubMedDate not supplied

Liposomal atp or NAD+ protects human endothelial cells from energy failure in a cell culture model of sepsis.

Sepsis depletes intracellular stores of ATP and NAD+, leading to cellular energy failure. Liposome encapsulation improves intracellular delivery of bulky, charged molecules and substrates susceptible to extracellular enzyme degradation. We hypothesized that treatments with liposome encapsulated ATP or NAD+ would protect human endothelial cells exposed to endotoxin (LPS) and interferon-gamma (IFN-gamma) from energy failure. Liposomal ATP and NAD+ were prepared by a modification of the thin film method. Human endothelial cells were exposed to LPS 50 microg/ml and IFN-gamma 50 ng/ml for 72 hours, and liposomal ATP and NAD+ treatments were dosed at 0 and 24 hours. Energy state was determined by rate of mitochondrial respiration as measured by WST-1 assay. Mitochondrial respiration significantly decreased to 57% +/- 3 of control in LPS/IFN-gamma exposed cells after 72 hours. Liposomal ATP (200 microM) and NAD+ (100 microM) completely reversed this respiratory depression while empty liposomes, free ATP (200 microM). and free NAD+ (100 microM) did not. These results support the hypothesis that treatments with liposome encapsulated ATP or NAD+ protect human endothelial cells from energy failure in a cell culture model of sepsis and potentially may provide a novel therapy for use in clinical sepsis.

Adenosine Triphosphate↗