Bias flow does not affect ventilation during high-frequency oscillatory ventilation in a pediatric animal model of acute lung injury.

OBJECTIVE: During high-frequency oscillatory ventilation, bias flow is the continuous flow of gas responsible for replenishing oxygen and removing CO(2) from the patient circuit. Bias flow is usually set at 20 L/min, but many patients require neuromuscular blockade at this flow rate. The need for neuromuscular blockade may be eliminated by increasing the bias flow rate, but CO(2) retention is a potential concern. We hypothesize that in a swine model of acute lung injury, increased bias flow rates will not affect CO(2) elimination. DESIGN: Prospective, randomized, experimental study. SETTING: Research laboratory at a university medical center. SUBJECTS: Sixteen juvenile swine. INTERVENTIONS: Sixteen juvenile swine (12-16.5 kg) were studied using a saline lavage model of acute lung injury. During high-frequency oscillatory ventilation, each animal was ventilated with bias flows of 10, 20, 30, and 40 L/min in random sequence. For ten animals, power was set at a constant level to maintain PaCO(2) 50-60 mm Hg, and amplitude was allowed to vary. For the remaining six animals, amplitude was kept constant to maintain PaCO(2) within the same range, while power was adjusted as needed with changes in bias flow. Linear regression was used for data analysis. MEASUREMENTS AND MAIN RESULTS: Median overall PaCO(2) was 53 mm Hg (range: 31-81 mm Hg). Controlling for both power and amplitude, there was no statistically significant change in PaCO(2) as bias flow varied from 10 to 40 L/min. CONCLUSIONS: Changes in bias flow during high-frequency oscillatory ventilation did not affect ventilation. Further clinical investigation is ongoing in infants and children with acute lung injury being managed with high-frequency oscillatory ventilation to assess the impact of alterations of bias flow on gas exchange, cardiopulmonary parameters, sedation requirements, and other clinical outcomes.

Development of universal antidotes to control aptamer activity.

With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo. The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may be a particularly safe class of therapeutics.

Complement factor 1 inhibitor improves cardiopulmonary function in neonatal cardiopulmonary bypass.

BACKGROUND: The inflammatory insult associated with cardiopulmonary bypass (CPB) continues to result in morbidity for neonates undergoing complex repair of congenital cardiac defects. Complement and contact activation are important mediating processes involved in this injury. Complement factor 1 esterase inhibitor (C1-inh), a natural inhibitor of complement, kallikrein, and coagulation pathways, may be decreased in children undergoing cardiac operations requiring CPB. We tested the hypothesis that C1-inh supplementation will ameliorate the cardiac and pulmonary dysfunction in a model of neonatal CPB. METHODS: Fifty-two neonatal pigs were randomly assigned to receive 0 IU (n = 22), 500 IU (n = 15), 1,000 IU (n = 8), or 1,500 IU (n = 7) of C1-inh. Doses were delivered 5 minutes before starting 90 minutes of normothermic CPB. Pulmonary and cardiovascular measures were taken before and 5, 30, and 60 minutes after CPB. RESULTS: Five animals did not survive CPB. The C1-inh concentration post-CPB increased monotonically with increasing dose (p < 0.001). Weight gain was significantly less in the 1,500 IU group (0.24 +/- 0.10 kg versus 0.38 +/- 0.09 kg, p = 0.001). Dynamic compliance increased with C1-inh dose from 0 to 500 IU by 23% +/- 4% (p < 0.001), but the increase leveled off at the higher doses. Alveolar-arterial O2 gradient decreased with C1-inh dose (p = 0.009). Time derivative of left ventricular pressure (dP/dt(max)) increased significantly with increasing dose (p = 0.016). At the highest dose of C1-inh, the time constant of isovolumic relaxation was increased (p = 0.018). CONCLUSIONS: The C1-inh supplementation results in improved pulmonary and systolic cardiac function in a model of neonatal CPB. The negative effect on diastolic function requires further investigation.

A novel inhaled organic nitrate that affects pulmonary vascular tone in a piglet model of hypoxia-induced pulmonary hypertension.

Persistent pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance after birth leading to right-to-left shunting and systemic arterial hypoxemia. Inhaled nitric oxide (NO) is effective in reducing the need for extracorporeal membrane oxygenation, but it has potential toxicities, especially in an oxygen-rich environment. A number of other NO-based molecules have been given by inhalation, but their structure-function relationships have not been established. Recent studies have raised the idea that toxic and beneficial properties can be separated. We synthesized a novel organic nitrate [ethyl nitrate (ENO2)], tested it in vitro, and administered it to hypoxic piglets. ENO2 lowered pulmonary artery pressure and raised the Po2 in arterial blood but did not alter systemic vascular resistance or methemoglobin levels. In addition, we tested the effect of ENO2 in the presence of the thiol glutathione, both in vivo and in vitro, and found its action to be enhanced. Although ENO2 is less potent than inhaled NO on a dose-equivalency basis, pretreatment of hypoxic animals with glutathione, which may be depleted in injured lungs, led to a markedly enhanced effect (largely mitigating the difference in potency). These results suggest that ENO2 may hold promise as a safe alternative to NO, particularly in hypoxemic conditions characterized by thiol depletion.

Antidote-mediated control of an anticoagulant aptamer in vivo.

Patient safety and treatment outcome could be improved if physicians could rapidly control the activity of therapeutic agents in their patients. Antidote control is the safest way to regulate drug activity, because unlike rapidly clearing drugs, control of the drug activity is independent of underlying patient physiology and co-morbidities. Until recently, however, there was no general method to discover antidote-controlled drugs. Here we demonstrate that the activity and side effects of a specific class of drugs, called aptamers, can be controlled by matched antidotes in vivo. The drug, an anticoagulant aptamer, systemically induces anticoagulation in pigs and inhibits thrombosis in murine models. The antidote rapidly reverses anticoagulation engendered by the drug, and prevents drug-induced bleeding in surgically challenged animals. These results demonstrate that rationally designed drug-antidote pairs can be generated to provide control over drug activities in animals.

Inhaled nitric oxide results in deteriorating hemodynamics when administered during cardiopulmonary bypass in neonatal swine.

OBJECTIVE: To evaluate if inhaled nitric oxide (iNO) has a lung-protective effect when it is delivered during the ischemic phase of neonatal cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized, controlled study. SETTING: Surgical research laboratory in a university hospital. SUBJECTS: Thirty-five neonatal swine. INTERVENTIONS: One-week-old swine (2.1-3.4 kg) were exposed to cool, low-flow CPB bypass designed to mimic the bypass used during neonatal congenital heart repair. Animals were randomized to four groups: a) CPB without exposure to iNO (n = 9); b) iNO delivery only during CPB with discontinuation of iNO at the start of reperfusion (n = 7); c) iNO delivery both during CPB and during the 90-min post-CPB observation period (n = 7); and d) iNO delivery only after separation from CPB (n = 7). Each animal was placed on nonpulsatile CPB and cooled to a nasopharyngeal temperature of 18 degrees C (64 degrees F). Low-flow CPB (35 mL.kg(-1).min(-1)) was instituted for 90 mins. The blood flow then was returned to 100 mL.kg(-1).min(-1), and the animals were warmed to 36 degrees C (96.8 degrees F) before separation from CPB. Animals were followed 90 mins post-CPB. Lung tissue was harvested and evaluated for myeloperoxidase activity, wet/dry weight, and lung pathology. Five animals underwent sham protocol, receiving instrumentation but not exposure to CPB or iNO. MEASUREMENTS AND MAIN RESULTS: We measured pulmonary vascular resistance, right ventricular output, and pulmonary artery pressure in all animals at 30, 60, and 90 mins following separation from CPB. Study animals that received iNO during the ischemic period of CPB were not protected against CPB-induced lung injury. Those animals treated with iNO both during and after CPB trended worse than those receiving iNO only after CPB. Inhaled nitric oxide delivered only after separation from CPB improved the hemodynamic variables compared with all other groups. Differences in lung wet/dry weight, myeloperoxidase, and pathology were not significantly different among groups. CONCLUSIONS: The delivery of iNO during the ischemic period of CPB does not protect against CPB-induced lung injury in a neonatal piglet CPB model. Delivery of iNO during this phase of CPB may, in fact, worsen the post-CPB hemodynamic condition. Inhaled nitric oxide should be used with caution during periods of low pulmonary blood flow CPB. Inhaled nitric oxide remains effective for reducing pulmonary vascular resistance after CPB.

Heliox does not affect gas exchange during high-frequency oscillatory ventilation if tidal volume is held constant.

OBJECTIVE: To compare gas exchange with heliox and oxygen-enriched air during high-frequency oscillatory ventilation, while controlling for tidal volume, in a pediatric swine model of acute lung injury. We hypothesized that when tidal volume delivery is held constant, heliox does not alter gas exchange. DESIGN: Randomized, crossover trial. SETTING: University animal research laboratory. SUBJECTS: Ten swine (4.4-5.4 kg). INTERVENTIONS: Acute lung injury (A-a gradient of >300 mm Hg) was created using repeated saline lavage during conventional mechanical ventilation. The animals were then administered high-frequency oscillatory ventilation and ventilated with 60% oxygen/40% helium and 60% oxygen/40% nitrogen in a randomized, crossover trial. When changing gas mixtures within each animal, mean airway pressure (Paw = 16.8 +/- 0.3 cm H(2)O) and frequency (10 Hz) were held constant. Oscillation amplitude (DeltaP) was adjusted to maintain constant tidal volume delivery as measured by respiratory inductive plethysmography. Next, the animals were ventilated with 40% oxygen/60% helium and 40% oxygen/60% nitrogen in a randomized crossover trial, again controlling for tidal volume. MEASUREMENTS AND MAIN RESULTS: Gas exchange was assessed by arterial blood gas analysis after ventilation with each gas mixture. We demonstrated no significant difference in Paco(2) or Pao(2) between the heliox and oxygen-enriched air with either the 40% or 60% oxygen mixtures. The oscillation amplitude required to achieve the same tidal volume delivery was significantly less with heliox. CONCLUSIONS: We conclude that if tidal volume delivery is maintained constant, heliox does not alter gas exchange when compared with oxygen-enriched air. However, to achieve the same tidal volume delivery, a lower oscillation amplitude is required with heliox. The clinical benefit of heliox administration during high-frequency oscillatory ventilation has yet to be determined. Possible advantages of heliox include improved ventilation of larger patients when approaching the power limitations of the Sensormedics 3100A oscillator and a potential reduction in the oscillation amplitude delivered to the more proximal gas exchange units.