Manipulation of oxygen radical-scavenging capacity in mice alters host sensitivity to tumor necrosis factor toxicity but does not interfere with its antitumor efficacy.

The role of oxygen free radicals in the toxicity and antitumor effect of tumor necrosis factor was investigated in vivo. Treatment of non-tumor-bearing mice and mice bearing methylcholanthrene-induced sarcomas with bovine CuZn superoxide dismutase or recombinant human CuZn superoxide dismutase afforded significant protection to these mice from a subsequent challenge with recombinant human tumor necrosis factor (rhTNF). Pretreatment with superoxide dismutase increased survival rates, at 48 h after rhTNF injection, in non-tumor-bearing mice from 22 to 65% and in tumor-bearing mice from 25 to 79%. Protection from rhTNF toxicity was not associated with any reduction in the therapeutic efficacy of rhTNF against methylcholanthrene-induced sarcomas in either s.c. or visceral sites (e.g., cure rates in mice bearing s.c. tumors which were treated with rhTNF without or with superoxide dismutase pretreatment were 18 and 39%, respectively). Furthermore, the administration of L-buthionine-S,R-sulfoximine, an inhibitor of glutathione synthesis, to mice bearing s.c. tumors resulted in increased rhTNF toxicity but no improvement in therapeutic efficacy. Tumor necrosis factor toxicity is mediated by the release of oxygen free radicals, probably from activated neutrophils, but its antitumor effect in methylcholanthrene-induced sarcomas is not dependent on their generation.

Routine chest radiographs in pediatric intensive care: a prospective study.

The clinical value of routine chest radiographs was prospectively evaluated in a pediatric intensive care unit. Physicians were asked to predict findings of clinical impact in 353 routine morning chest radiographs performed in 101 patients after examining the patients. In 81 instances (23%), the clinical impact of the chest radiographs was incorrectly predicted and significant alterations in management would have potentially been missed had the chest radiographs not been available. These 81 chest radiographs included 72 unpredicted radiographic changes of clinical significance, and nine chest radiographs in which a significant radiographic change was incorrectly predicted. Thirty five (43.2%) of these 81 chest radiographs had unpredicted pulmonary findings and 46 (56.8%) showed unpredicted appliance malpositions. Incorrect predictions were significantly associated with radiographs from patients who were younger, intubated, mechanically ventilated, and had indwelling central venous catheters. Level of training of the predicting physicians did not affect prediction accuracy. In analysis of 43 routine postintubation chest radiographs and 39 routine postcentral venous catheter placement chest radiographs, appliance malpositions were disclosed in 34.9% and 43.6%, respectively. Routine daily and post-appliance placement chest radiographs have significant clinical value in the pediatric intensive care unit.

Effect of sodium arsenite on iNOS expression and vascular hyporeactivity associated with cecal ligation and puncture in the rat.

Induction of the heat shock response protects animals from either endotoxemia or peritonitis. In endotoxemia, heat shock protein (HSP) induction is associated with reversal of vascular hyporeactivity and inhibition of iNOS expression. Recent studies suggest differences in the inflammatory mechanisms during endotoxemia and peritonitis animal models and their response to therapeutic interventions. We therefore studied the effect of the HSP inducer sodium arsenite (SA) on vascular reactivity and iNOS expression in rats undergoing cecal ligation and puncture (CLP). CLP resulted in suppression of the pressor effect of norepinephrine (NE) in vivo (measured by changes in blood pressure in response to NE boluses) and ex vivo (changes in contraction force in isolated mesenteric arteries in response to NE concentrations), and in the expression of iNOS protein. Pretreatment of the rats with SA resulted in reversal of CLP-induced vascular hyporeactivity in vivo and ex vivo, and inhibition of iNOS expression after 22 h. SA pretreatment improved 7-day survival after CLP from 18.2% to 70% (P < 0.005). Glucocorticoid receptor inhibition did not affect the effect of HSP induction on iNOS expression. The similarity of the effect of HSP on vascular reactivity and iNOS expression in two distinct sepsis models suggests that this effect may be clinically important and that a causative relationship between HSP induction, iNOS inhibition, and reversal of vascular reactivity is likely.

Effect of tyrosine kinase inhibition on sepsis-induced vascular hyporesponsiveness, inos mrna expression and NF-kappaB nuclear translocation in rats.

The dependence of the critical steps in the sepsis cascade on the transcription factor NF-kappaB andation to nitric oxide (NO) production are controversial. Tyrosine kinase (TK) is involved in several of the steps, and TK inhibitors (TKI) inhibit lipopolysaccharide (LPS)-induced vascular hyporesponsiveness in septic animals. We studied the relationship of TK inhibition, hemodynamics, vascular contraction, iNOS mRNA expression and NF-kappaB translocation in anesthetized endotoxic rats. The TKI AG556 (2.5 mg/kg i.p.), given 1 h before i.v. endotoxin (LPS) resulted in attenuation of early (<60 min) and late (60-120 min) hypotension, improved contraction of mesenteric arteries to norepinephrine 4 h after LPS, and attenuated tissue iNOS mRNA expression. LPS-induced NF-kappaB translocation was unaffected. The observed dissociation between NF-kappaB translocation and the salutary effect of TKI in vivo and ex vivo and its effect on iNOS mRNA expression suggest that although NF-kappaB may be involved in the sepsis cascade, it may not be essential for some of the molecular and vascular consequences of septic shock.

Noninvasive positive-pressure ventilation facilitates tracheal extubation after laryngotracheal reconstruction in children.

Tracheal extubation after laryngotracheal reconstruction in children may be complicated by postoperative tracheal edema and pulmonary dysfunction. The replacement of a tracheal tube in this situation may exacerbate the existing injury to the tracheal mucosa, complicating subsequent attempts at tracheal extubation. We present two cases where noninvasive positive-pressure ventilation was employed to treat partial airway obstruction and respiratory failure in two children following laryngotracheal reconstruction. Noninvasive positive-pressure ventilation served as a bridge between mechanical ventilation via a tracheal tube and spontaneous breathing, providing airway stenting and ventilatory support while tracheal edema and pulmonary dysfunction were resolved. Under appropriate conditions, noninvasive positive-pressure ventilation may be useful in the management of these patients.

Misplacement of a femoral venous catheter into the ascending lumbar vein: repositioning using ultrasonographic guidance.

A 5-week-old infant with congenital chylothorax required long-term intravenous access for parenteral nutrition. Cannulation of the inferior vena cava via the left femoral vein was attempted, but the catheter was misplaced into the left ascending lumbar vein. Catheter removal is advised when such malposition is identified. We were able successfully to redirect the catheter into the inferior vena cava using ultrasonographic guidance. This procedure has not been described previously in children. We propose that repositioning of incorrectly placed vascular catheters can be achieved using ultrasound guidance at the bedside.

Initial postoperative serum lactate levels predict survival in children after open heart surgery.

OBJECTIVE: To evaluate the relationship between postoperative serum lactate levels and outcome in children undergoing open heart surgery. DESIGN: Prospective, noninterventional study. SETTING: Pediatric intensive care unit (PICU) of a university hospital. PATIENTS: 41 nonconsecutive children who had had cardiopulmonary bypass for repair of congenital heart disease. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Serum lactate levels were measured on admission to the PICU immediately after open heart surgery. Lactate levels were correlated with bypass and cross clamp times, estimated intraoperative blood loss, lowest temperature on bypass, admission Pediatric Risk of Mortality score, anion gap, and measures of postoperative morbidity. Mean lactate levels on admission to the PICU were 6.86 +/- 0.79 mmol/l for nonsurvivors (n = 7) and 2.38 +/- 0.13 mmol/l for survivors (n = 34) (p < 0.0001), and 4.87 +/- 0.7 mmol/l and 2.35 +/- 0.19 mmol/l, for patients with (n = 11) and without (n = 30) multiple organ system failure, respectively (p < 0.0001). Admission lactate levels correlated with all measurements of postoperative morbidity. A serum lactate level of greater than 4.2 mmol/l had a positive predictive value of 100% and a negative predictive value of 97% for postoperative death. CONCLUSIONS: Initial postoperative serum lactate levels after pediatric open heart surgery may be predictive of outcome. Lactate levels are also higher in patients who go on to develop multiple organ system failure. Elevated postoperative lactate levels may reflect intraoperative tissue hypoperfusion, and measures aimed at increasing oxygen delivery, with normalization of lactate, may improve patient outcome.

Interleukin-6 levels in serum and lung lavage fluid of children undergoing open heart surgery correlate with postoperative morbidity.

OBJECTIVE: To evaluate the relationship of perioperative levels of interleukin 6 (IL-6) in serum and bronchoalveolar fluid with morbidity and mortality in children undergoing cardiopulmonary bypass (CPB). DESIGN: Prospective, noninterventional study. SETTING: Operating room and pediatric intensive care unit (PICU) of a university hospital. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: IL-6 levels were measured in serum and lung lavage fluid obtained before, during, and after CPB using the B9.9 bioassay. Alveolar epithelial lining fluid (AELF) volume was calculated using the urea correction method. Mean intraoperative AELF IL-6 levels increased fourfold compared to preoperative levels, and mean serum IL-6 levels increased fivefold after CPB. Mean intraoperative AELF IL-6 levels correlated with intraoperative blood transfusion (r2 = 0.18; p = 0.049) and duration of inotropic support (r2 = 0.29; p = 0.009), mechanical ventilation (r2 = 0.24; p = 0.019), and PICU stay (r2 = 0.29; p = 0.008). Mean serum IL-6 levels 2 h after CPB correlated with intraoperative blood transfusion (r2 = 0.3;p = 0.007), and with Pediatric Risk of Mortality score on postoperative day 3 (r2 = 0.24; p = 0.022), and were higher in patients with massive fluid retention (p = 0.014) and in nonsurvivors (p = 0.003). CONCLUSIONS: Serum and alveolar IL-6 levels increase after CPB, and correlate with postoperative morbidity. Serum IL-6 levels also correlate with mortality. They may be useful in assessing the severity of the systemic inflammatory response after CPB.

Endogenous neuropeptide Y mediates vasoconstriction during endotoxic and hemorrhagic shock.

Neuropeptide Y (1-36), NPY, is a sympathetic vasoconstrictor whose activities in blood vessels is determined by the presence of vasoconstrictive Y1 receptors and the enzyme dipeptidyl peptidase IV (DPPIV), which converts NPY to non-vasoconstrictive peptides. While the role of the NPY system has been established during cold water stress, its role in hypotensive conditions has not; yet, exogenous NPY improves hemodynamics and survival in rats with endotoxic shock. We used a new selective non-peptidergic Y1 receptor antagonist, BIBP-3226, to determine the role of the endogenous NPY/Y1 system in endotoxic shock (induced by i.v. injection of 10 mg/kg of Escherichia coli lipopolysaccharide 0127:B8, LPS) and hemorrhagic shock (bleeding of 15 ml/kg over 1.5 min). Conscious rats received a bolus of BIBP-3226 or the vehicle 5 min before endotoxin challenge or induction of hemorrhage, followed by continuous infusion. Mean arterial pressure (MAP) at 5 min after LPS administration dropped in the control group by 15%, compared to 36% in the BIBP-3226-treated group (p < 0.01). Similarly, the hemorrhage-induced drop in MAP in the control group was 32% at 5 min, compared to 53% in the BIBP-treated rats (p < 0.01). Plasma NPY levels were unchanged in the endotoxic shock group, but were significantly elevated in the hemorrhagic shock group. BIBP-3226 pretreatment abrogated the increased plasma NPY levels after hemorrhagic shock. Endogenous NPY contributes to blood pressure recovery during endotoxic and hemorrhagic shock.

Circulating neuropeptide Y in humans: relation to changes in catecholamine levels and changes in hemodynamics.

Neuropeptide-Y (NPY) is a sympathetic cotransmitter, which causes vasoconstriction, decreases coronary blood flow and decreases cardiac output. Circulating immunoreactive NPY (ir-NPY) levels increase with exercise, in patients admitted to the coronary care unit, and during thoracic surgery, and may play a role in postoperative hemodynamics. We studied changes in ir-NPY, epinephrine (E) and norepinephrine (NE) arterial plasma levels, and their correlation to simultaneous hemodynamic measurements at 8 perioperative time points in 13 patients undergoing open heart surgery. Changes in circulating ir-NPY negatively correlated with changes in systemic vascular resistance index (SVRI), mean arterial pressure (MAP) and mean pulmonary arterial pressure (MPAP) (P < 0.05), suggesting that the hemodynamic changes were the cause of the changes in ir-NPY levels, inducing overflow of NPY into the circulation via sympathetic activation. Changes in NE and E levels positively correlated with changes in heart rate (HR), SVRI and MPAP. Changes in E levels also positively correlated with changes in stroke volume index (SVI), central venous pressure (CVP) and cardiac index (CI). NE levels correlated well with E levels, but catecholamine levels did not correlate with ir-NPY levels. These results suggest, that the elevation in circulating NPY levels previously noted in patients with heart failure and acute myocardial infarction may reflect changes in NPY overflow and/or clearance secondary to increased sympathetic activity and to hemodynamic changes.

Control of a Serratia marcescens outbreak in a maternity hospital.

During the period between October 1984 and January 1985, an outbreak of Serratia marcescens took place in the Serlin Maternity Hospital in Tel-Aviv. Four major and six minor infections were noted in newborn and preterm infants. An additional group of 24 neonates were asymptomatic carriers of S. marcescens. Extensive control measures were undertaken, including closing the SCBU to further admissions and the opening of a new SCBU. Other measures included maintaining babies in cohort groups, strict handwashing, and use of gloves and gowns. There was also intensified encouragement of breast feeding and thorough cleansing and disinfection of the SCBU and nurseries. After 3 months, the outbreak was controlled. No identified source for the outbreak was detected. We feel that the extensive measures employed were responsible for controlling the outbreak within a relatively short time.

Effect of neuropeptide Y on endotoxin-induced suppression of the response to various agonists in conscious rats.

Hypotension during endotoxic shock is related to reduced vascular responsiveness to vasoconstrictors. Neuropeptide Y (NPY) is known to potentiate the pressor response to some agonists, and NPY infusion has been shown to improve hemodynamics and survival in endotoxemic rats. We therefore studied the effect of NPY infusion on the suppressed pressor effect of norepinephrine (NE), angiotensin II (AII), vasopressin (VP), and endothelin (ET) in conscious endotoxemic rats. Chronically cannulated conscious rats were infused with a non-hypotensive dose of endotoxin (LPS, 10 micrograms/10 microliters/min) throughout the experiment. Infusion of NPY, 40 pmol/10 microliters/min was started 15 minutes before the LPS infusion, and continued for 65 minutes. Five minutes after the termination of NPY infusion, increasing agonist doses were administered i.v. to construct dose-response curves. Each experiment included one control group where saline replaced LPS, and one control group where saline replaced NPY. LPS infusion caused suppression of the pressor responses to all four agonists, as expressed by ED50 and by decreased pressor response to the individual agonist doses. In addition, LPS infusion altered the bradycardic response to AII and ET. NPY infusion prior to the administration of NE, AII and VP resulted in partial reversal of the LPS-induced suppressed responsiveness to these agonists. NPY infusion had no effect on the response to ET in either control or endotoxemic rats. Partial reversal of the suppressed responsiveness to the three agonists by NPY infusion may contribute to the observed NPY-induced improvement of blood pressure and survival rate during endotoxic shock.

Immune dysfunction in the critically ill infant and child.

Factors contributing to the high prevalence of immunodeficiency in the PICU population include conditions that lead to frequent requirement of intensive care, suppression of immunity secondary to an acute insult, and iatrogenic measures. The immunodeficiency observed in the critically ill correlates well with their susceptibility to infection and explains the high prevalence of nosocomial sepsis in the PICU--a major cause of morbidity and mortality in critically ill children. Dysactivation of the immune system during an acute insult, with the subsequent release of humoral mediators from activated immune cells, leads to tissue injury and may be involved in the pathogenesis of ARDS, DIC, capillary leak syndrome, and to the development of multiple organ system failure. Suggested approaches to correct the immunodeficiency in the critically ill include reconstitutional immunotherapy, mediator-inhibiting drugs, and mediator removal by plasma exchange. Intensivists should be aware of the phenomenon of immunodeficiency in the critically ill, be accordingly aggressive in diagnosing and treating infections, and avoid, as much as possible, measures that further suppress immunity.

The use of a mobile computed tomography scanner in the pediatric intensive care unit to evaluate airway stenting and lung volumes with varying levels of positive end-expiratory pressure.

OBJECTIVE: Presentation of a case report describing the use of a mobile computed tomography (CT) scanner in the pediatric intensive care unit (PICU) to radiographically evaluate tracheobronchial stenting and lung volumes while using different levels of positive end-expiratory pressure (PEEP) and positioning in a critically ill infant. DESIGN: Case report of a single patient. SETTING: Pediatric intensive care unit in a University Hospital. PATIENT: A 6-month-old premature infant with bronchopulmonary dysplasia, tracheobronchomalacia, and progressive respiratory failure. INTERVENTIONS: CT scans of the chest were performed by using a mobile CT scanner in the PICU. Serial CT scans were performed at PEEP levels of 5, 10, 15, and 20 cm H(2)O in both the supine and prone position. Scheduled medical care and standard monitoring were continued during the course of the CT scans. MEASUREMENTS AND MAIN RESULTS: Identical anatomic levels demonstrating the trachea, bronchi, and lung parenchyma were compared while different levels of PEEP and supine or prone positioning were used. From these comparisons, the level of PEEP in which lung volumes were optimized was radiographically determined. No significant changes in large airway caliber were observed. There was no difference noted between prone and supine positioning. CT scans were completed with minimal disruption to the patient's care. CONCLUSIONS: Mobile CT scanners can be used in the PICU for the diagnostic evaluation of critically ill children. This option allows for the continuation of medical therapies and monitoring in the intensive care setting while avoiding the potential complications of transporting a critically ill child to the radiology department. The use of mobile CT scanners may disrupt PICU routine and is more expensive than use of fixed CT scanners. Mobile CT scanners may be useful in radiographically determining the optimal level of PEEP in infants with tracheobronchomalacia and bronchopulmonary dysplasia.

Incidental discovery of asplenia syndrome, with situs inversus and a normal heart by radionuclide biliary imaging. A case report.

Tc-99m biliary imaging was performed on a 34-year-old woman who was being investigated for suspected cholelithiasis. A left-sided liver was detected. On subsequent radionuclide imaging, partial visceral situs inversus and asplenia were demonstrated. Extensive roentgenographic investigation, ECG, echocardiogram, and laparotomy confirmed the radionuclide findings. Asplenia syndrome may exist without cardiovascular abnormalities and thus be undiscovered. Radionuclide imaging is important in the diagnosis of this syndrome.