Jeffrey W. Skimming

Nitric oxide inhalation in infants with respiratory distress syndrome

OBJECTIVE This study was designed to test the hypothesis that nitric oxide inhalation increases systemic arterial blood oxygen tension of prematurely delivered infants with respiratory distress syndrome. METHODS Nitric oxide was administered to 23 preterm infants with a diagnosis of respiratory distress syndrome. The infants were randomly assigned to receive either 5 or 20 ppm of nitric oxide and were studied between 24 and 168 hours after delivery. The treatment period for each infant lasted 15 minutes and was preceded by and followed by a 15-minute control period. We evaluated all outcome variables by using two-way repeated measures analysis of variance; p values less than 0.01 were considered significant. RESULTS Nitric oxide inhalation caused significant increases in the following: arterial blood oxygen tension, directly measured arterial oxyhemoglobin saturation, and transcutaneously measured arterial oxyhemoglobin saturation. No differences between the effects of the two nitric oxide concentrations were detected, nor were residual effects detected 15 minutes after either dose of nitric oxide was discontinued. CONCLUSIONS Inhalation of both 5 and 20 ppm nitric oxide causes concentration-independent increases in the blood oxygen tensions of preterm infants with respiratory distress syndrome. We speculate that nitric oxide inhalation may be a useful adjunctive therapy for these patients.

Sodium pyruvate is better than sodium chloride as a resuscitation solution in a rodent model of profound hemorrhagic shock

Pyruvate is an energy substrate that has both inotropic and antioxidant properties. In this study, we tested the hypothesis that survivorship would be better after resuscitation with 1.7% sodium pyruvate than 0.9% sodium chloride in a profound hemorrhagic shock model. The study was performed in a blinded manner. Rats were randomly assigned into two groups (ten in each group), a sodium chloride resuscitation group and a sodium pyruvate resuscitation group. After a 60-min shock period, we infused 80 ml/kg of a resuscitation solution. We continuously monitored mean arterial pressure and heart rate for 50 min after resuscitation. We recognized death by the disappearance of blood pressure pulsation and precordial movement. We performed a comparison of survivorship at 50 min post resuscitation using a Z-test of proportions. Nine (90%) of the animals that received sodium pyruvate were living 50 min after resuscitation, whereas only three (30%) of the animals that received sodium chloride survived to the same time point. We conclude that sodium pyruvate is better than sodium chloride as a resuscitation solution in a model of profound hemorrhagic shock.

Hypothermia induces interleukin-10 and attenuates injury in the lungs of endotoxemic rats

&NA; We recently reported that hypothermia protects against intrapulmonary nitric oxide overproduction and nitric oxide‐mediated lung injury in endotoxemic rats. Few studies have been performed to investigate whether hypothermia reduces inflammation by affecting favorable changes in chemokine and pro‐and anti‐inflammatory cytokine profiles. In this study, we tested the hypothesis that hypothermia decreases concentrations of growth‐related oncogene/cytokine‐induced neutrophil chemoattractant‐1 (GRO/CINC‐1), interleukin (IL)‐1&bgr;, IL‐6, and myeloperoxidase and increases concentration of IL‐10 in the lungs endotoxemic rats. Twelve rats were anesthetized and randomized to treatment with either hypothermia (T = 18‐24°C; n = 6) or normothermia (T = 36‐38°C, n = 6). Endotoxin (15 mg/kg of Escherichia coli lipopolysaccharide) was administered intravascularly and lung tissue was harvested 150 min later. Three additional rats were sham instrumented and maintained as normothermic but not given endotoxin. Hematoxylin & eosin staining was performed for qualitative inspection of tissues. Quantitative analyses of lung homogenates were performed using enzyme‐linked immunosorbent assays for IL‐1&bgr;, IL‐6, IL‐10, and GRO/CINC‐1. Myeloperoxidase concentrations were determined using a colorimetric assay. Hypothermia attenuated the induction of intrapulmonary IL‐1&bgr; (P < 0.05), IL‐6 (P < 0.05), GRO/CINC‐1 (P < 0.05), and myeloperoxidase (P < 0.05) caused by endotoxin. Inspection of the lungs revealed that hypothermia similarly attenuated histological signs of injury, such as interstitial edema and neutrophil accumulation. Hypothermia increased the intrapulmonary concentration of IL‐10 more than 3‐fold over that measured in the normothermia (endotoxinexposed) group (P < 0.05). Hypothermia inhibits neutrophil recruitment in the lungs of endotoxemic rats in part by decreasing proinflammatory cytokine expression. Additionally, hypothermia induces intrapulmonary IL‐10 expression. Further studies are needed to investigate whether IL‐10 mediates the anti‐inflammatory effects of hypothermia.

Percutaneous transcatheter occlusion of coronary artery fistulas using detachable balloons

Three pediatric patients underwent successful transcatheter coronary artery fistula occlusion using the Debrun system. This latex balloon system offers several advantages over other occlusion systems. First, the balloon delivery and release is controlled. Second, “test occlusions” can be performed that allow simultaneous balloon inflation, coronary cineangiography, and electrocardiographic monitoring. Third, because the balloons are flow-directed, they are easily positioned in properly chosen locations. Finally, the balloons can be constructed to suit the size of the fistula. In this study, two patients received only one balloon; in the other patient two balloons were placed in the same fistula. All fistulas drained into either the right atrium or ventricle and were successfully occluded. After a follow-up period of up to 3 years, no local or systemic reactions to the balloons were recognized. We conclude that detachable balloon occlusion of coronary artery fistulas is a safe, effective alternative to surgical ligation in selected pediatric patients.

Intravascular infusion of acid promotes intrapulmonary inducible nitric oxide synthase activity and impairs blood oxygenation in rats.

ObjectiveTo test the hypothesis that intravascular acid infusion promotes intrapulmonary nitric oxide formation by promoting inducible nitric oxide synthase (iNOS) and inhibiting endothelial nitric oxide synthase (eNOS) expression in rats. DesignProspective, placebo controlled, randomized laboratory study. SettingUniversity laboratory. SubjectsTwelve male Sprague-Dawley rats weighing 317 ± 30 g served as study subjects. All animals were anesthetized, paralyzed, and mechanically ventilated throughout the experiment. InterventionsThe animals were randomized to receive either 0.1 N hydrochloric acid or 0.9% saline intravenously. The infusions were initially given at a rate of 11 mL/kg/hr for 15 mins and then at a rate of 0.95 mL/kg/hr for the remainder of the experiment. Exhaled nitric oxide concentrations and hemodynamic measurements were monitored throughout the experiment. Lung tissues were harvested for Western blot analysis and immunostaining 4 hrs after starting the intravascular infusion. Measurement and Main ResultsAt the end of the experiment, we found more than a four-fold higher concentration of exhaled nitric oxide in the acid-treated animals than in the saline-treated animals (p < .001). Western blot analysis revealed that the acid infusion increased intrapulmonary iNOS concentrations (p < .001), yet it decreased intrapulmonary eNOS concentrations (p = .009). Acid-related lung injury manifested as a decrease in blood oxygen tensions (p = .045) and as an increase in lung homogenate interleukin-6 concentrations (p = .003). ConclusionsOur results reveal that hydrochloric acid infusion stimulates intrapulmonary nitric oxide formation at least in part by promoting the expression of iNOS. Our findings suggest that correcting acidosis should attenuate iNOS formation. Our data also support the idea that metabolic acidosis itself can lead to impaired intrapulmonary gas exchange and increased expression of pro-inflammatory cytokines such as interleukin-6. Whether the induction of intrapulmonary nitric oxide formation mediates or simply indicates lung injury warrants further investigation.

Nitric oxide inhalation increases alveolar gas exchange by decreasing deadspace volume.

Objective To test the hypothesis that nitric oxide inhalation facilitates CO2 elimination by decreasing alveolar deadspace in an ovine model of acute lung injury. Design Prospective, placebo-controlled, randomized, crossover model. Setting University research laboratory. Subjects Eleven mixed-breed adult sheep. Interventions To induce acute lung injury, hydrochloric acid was instilled into the tracheas of paralyzed sheep receiving controlled mechanical ventilation. Each sheep breathed 0 ppm, 5 ppm, and 20 ppm nitric oxide in random order. Measurements and Main Results Estimates of alveolar deadspace volumes and arterial-to-end tidal CO2 partial pressure differences were used as indicators of CO2 elimination efficiency. At a constant minute ventilation, nitric oxide inhalation caused dose-independent decreases in Paco2 (p < .05), alveolar deadspace (p < .01), and arterial-to-end tidal CO2 partial pressure differences (p < .01). We found that estimates of arterial-to-end tidal CO2 partial pressure differences may be used to predict alveolar deadspace volume (r2 = .86, p < .05). Conclusions Estimates of arterial-to-end tidal CO2 partial pressure differences are reliable indicators of alveolar deadspace. Both values decreased during nitric oxide inhalation in our model of acutely injured lungs. This finding supports the idea that nitric oxide inhalation facilitates CO2 elimination in acutely injured lungs. Future studies are needed to determine whether nitric oxide therapy can be used to reduce the work of breathing in selected patients with cardiopulmonary disorders.

Congenital coronary artery fistula suggesting a "steal phenomenon" in a neonate.

SummaryThe case of a neonate reported herein demonstrates a congenital fistula between the left circumflex coronary artery and the right ventricle. Intraoperative stress to the patients heart suggested a coronary “steal phenomenon.”

Resuscitation of hemorrhagic shock attenuates intrapulmonary nitric oxide formation

Hemorrhagic shock has been shown to upregulate intrapulmonary inducible nitric oxide (NO) synthase (iNOS) expression. Increased intrapulmonary iNOS expression is reflected by increases in concentrations of NO in the airways. The purpose of this study was to examine the effects of resuscitation on this induction of intrapulmonary NO formation caused by hemorrhage. Eighteen rats were randomized to one of three groups. One group of rats was simply sham-instrumented and monitored. Two other groups experienced hemorrhagic shock (mean systemic blood pressure of 40-45 mmHg) for 60 min. In one of the hemorrhagic shock groups, resuscitation was performed by re-infusing the shed blood and supplementing it with normal saline. Compared with sham-instrumented rats, those exposed to hemorrhagic shock without subsequent resuscitation exhibited a 10-fold increase in exhaled NO concentrations. Additionally, concentrations of both intrapulmonary iNOS protein and mRNA increased. Resuscitation attenuated the hemorrhage-induced upregulation of exhaled NO, iNOS protein and iNOS mRNA. This data suggests that resuscitation attenuates the hemorrhagic shock-induced formation of intrapulmonary NO by downregulating iNOS transcription. We believe that exhaled NO concentrations provide a useful, non-invasive method of monitoring the intrapulmonary inflammatory sequelae of hemorrhagic shock.

Effects of zaprinast and dissolved nitric oxide on the pulmonary circulation of fetal sheep

This study was designed to determine indirectly if the changes in ovine fetal pulmonary vascular tone caused by i.v. injections of nitric oxide-containing solutions are mediated by cGMP. We first characterized the dose-response relationship of bolus intrapulmonary injections of zaprinast (a cGMP-selective phosphodiesterase inhibitor) and nitric oxide solutions. Injections of nitric oxide solutions as well as zaprinast solutions resulted in dose-dependent decreases in pulmonary arterial pressure that were greater than reductions in systemic arterial pressure. We also evaluated the effects of simultaneous infusions of zaprinast and U46619 (a thromboxane mimetic) on the response to bolus injections of 1.0 μg of acetylcholine, 100 ng of endothelin-1, and 10.0 μL of ethanol saturated with nitric oxide. Zaprinast was infused at a rate of 1.5 mg/min, and the concentration of U46619 was titrated to raise mean left pulmonary arterial pressure (LPAP) to the steady state level that was present before infusing zaprinast. All bolus injections reduced left pulmonary arterial pressure more than they reduced mean systemic arterial pressure. However, neither the response magnitudes nor the response durations were affected by simultaneous infusions of zaprinast and U46619. We therefore suggest that modulation of fetal pulmonary vascular tone by endogenously produced nitric oxide may involve mechanisms other than raising smooth muscle cytoplasmic cGMP concentrations.

Renal transcription of high‐affinity type‐2 cationic amino acid transporter is up‐regulated in LPS‐stimulated rodents

Objective:  Sepsis stimulates renal nitric oxide (NO) biosynthesis through up‐regulation of inducible NO synthase (iNOS) expression. Type‐2 cationic amino acid transporter (CAT‐2) mediation of trans‐membrane L‐arginine (L‐Arg) transportation has been identified as one of the crucial regulatory mechanisms involved in the formation of NO by iNOS. We had previously shown that CAT‐2B, a high‐affinity alternative‐spliced transcript of the CAT‐2, is involved in induced NO biosynthesis by iNOS (Nitric Oxide, 2002). In this present study, we sought to assess the effects of sepsis on the expression of CAT‐2B in lipopolysaccharide (LPS)‐stimulated rat kidney.