Showing papers by "Warren M. Zapol published in 2015"

Pulmonary fibrosis in severe acute respiratory failure.

Abstract: Diffuse interstitial fibrosis often follows severe acute lung injury of diverse causes. Total lung collagen (g per m2 of body surface area) was determined in 12 patients who died at various times after severe acute respiratory failure (ARF). The total collagen content of each lung was calculated from the mean concentration of collagen (hydroxyproline × 7.23) in numerous tissue samples taken from one to 3 lobes and the total weight of the lung. These results were compared to those obtained with 9 normal lungs. In 2 patients who succumbed during the first 10 days of ARF, total lung collagen was within the normal range, whereas it was abnormally high in patients who survived for longer periods (12 to 29 days). Morphologic evidence of fibrosis correlated with chemical results in the patients with ARF. After three to 4 weeks of ARF, the lungs of all patients had severe and diffuse interstitial fibrosis as evidenced by histologic assessment; in these lungs, the total collagen content was increased two- to 3-fol...

Platelet Consumption and Sequestration in Severe Acute Respiratory Failure1–3

Abstract: To evaluate alterations in platelet kinetics and organ sequestration patterns during acute lung injury, we studied the fate of autologous radiolabeled platelets in 15 patients with severe acute respiratory failure (ARF) of diverse etiology. Thrombocytopenia (< 100,000 platelets/μl) occurred in 10 patients. Platelet lifespan was reduced (2.30 ± 0.39 days; mean ± SEM) compared with normal volunteers (6.29 ± 0.69; p < 0.01). Platelet turnover rate during ARF (251,000 ± 90,000 platelets/μl · day) was twice normal and never below the normal range. Platelet sequestration, determined by surface scintillation counting, occurred in the lungs, liver, and spleen. Although our measurements in patients with severe ARF did not determine whether platelets cause or exacerbate acute lung disease, the increased platelet consumption and pulmonary sequestration we detected suggests that platelets are directly involved in the pathophysiology of acute lung injury.

Producing nitric oxide by pulsed electrical discharge in air for portable inhalation therapy

Abstract: Inhalation of nitric oxide (NO) produces selective pulmonary vasodilation and is an effective therapy for treating pulmonary hypertension in adults and children. In the United States, the average cost of 5 days of inhaled NO for persistent pulmonary hypertension of the newborn is about $14,000. NO therapy involves gas cylinders and distribution, a complex delivery device, gas monitoring and calibration equipment, and a trained respiratory therapy staff. The objective of this study was to develop a lightweight, portable device to serve as a simple and economical method of producing pure NO from air for bedside or portable use. Two NO generators were designed and tested: an offline NO generator and an inline NO generator placed directly within the inspiratory line. Both generators use pulsed electrical discharges to produce therapeutic range NO (5 to 80 parts per million) at gas flow rates of 0.5 to 5 liters/min. NO was produced from air, as well as gas mixtures containing up to 90% O2 and 10% N2. Potentially toxic gases produced in the plasma, including nitrogen dioxide (NO2) and ozone (O3), were removed using a calcium hydroxide scavenger. An iridium spark electrode produced the lowest ratio of NO2/NO. In lambs with acute pulmonary hypertension, breathing electrically generated NO produced pulmonary vasodilation and reduced pulmonary arterial pressure and pulmonary vascular resistance index. In conclusion, electrical plasma NO generation produces therapeutic levels of NO from air. After scavenging to remove NO2 and O3 and filtration to remove particles, electrically produced NO can provide safe and effective treatment of pulmonary hypertension.

Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial.

Abstract: Background. Children with cerebral malaria (CM) have high rates of mortality and neurologic sequelae. Nitric oxide (NO) metabolite levels in plasma and urine are reduced in CM. Methods. This randomized trial assessed the efficacy of inhaled NO versus nitrogen (N2) as an adjunctive treatment for CM patients receiving intravenous artesunate. We hypothesized that patients treated with NO would have a greater increase of the malaria biomarker, plasma angiopoietin-1 (Ang-1) after 48 hours of treatment. Results. Ninety-two children with CM were randomized to receive either inhaled 80 part per million NO or N2 for 48 or more hours. Plasma Ang-1 levels increased in both treatment groups, but there was no difference between the groups at 48 hours (P = not significant [NS]). Plasma Ang-2 and cytokine levels (tumor necrosis factor-α, interferon-γ, interleukin [IL]-1β, IL-6, IL-10, and monocyte chemoattractant protein-1) decreased between inclusion and 48 hours in both treatment groups, but there was no difference between the groups (P = NS). Nitric oxide metabolite levels-blood methemoglobin and plasma nitrate-increased in patients treated with NO (both P < .05). Seven patients in the N2 group and 4 patients in the NO group died. Five patients in the N2 group and 6 in the NO group had neurological sequelae at hospital discharge. Conclusions. Breathing NO as an adjunctive treatment for CM for a minimum of 48 hours was safe, increased blood methemoglobin and plasma nitrate levels, but did not result in a greater increase of plasma Ang-1 levels at 48 hours.

Pulmonary Phototherapy for Treating Carbon Monoxide Poisoning.

Abstract: Rationale: Carbon monoxide (CO) exposure is a leading cause of poison-related mortality. CO binds to Hb, forming carboxyhemoglobin (COHb), and produces tissue damage. Treatment of CO poisoning requires rapid removal of CO and restoration of oxygen delivery. Visible light is known to effectively dissociate CO from Hb, with a single photon dissociating one CO molecule.Objectives: To determine whether illumination of the lungs of CO-poisoned mice causes dissociation of COHb from blood transiting the lungs, releasing CO into alveoli and thereby enhancing the rate of CO elimination.Methods: We developed a model of CO poisoning in anesthetized and mechanically ventilated mice to assess the effects of direct lung illumination (phototherapy) on the CO elimination rate. Light at wavelengths between 532 and 690 nm was tested. The effect of lung phototherapy administered during CO poisoning was also studied. To avoid a thoracotomy, we assessed the effect of lung phototherapy delivered to murine lungs via an optical ...

Pulmonary hypertension after prolonged hypoxic exposure in mice with a congenital deficiency of Cyp2j.

Abstract: Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to the regulation of pulmonary vascular tone and hypoxic pulmonary vasoconstriction. We investigated whether the attenuated acute vasoconstrictor response to hypoxic exposure of Cyp2j(-/-) mice would protect these mice against the pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia. Cyp2j(-/-) and Cyp2j(+/+) male and female mice continuously breathed an inspired oxygen fraction of 0.21 (normoxia) or 0.10 (hypoxia) in a normobaric chamber for 6 weeks. We assessed hemoglobin (Hb) concentrations, right ventricular (RV) systolic pressure (RVSP), and transthoracic echocardiographic parameters (pulmonary acceleration time [PAT] and RV wall thickness). Pulmonary Cyp2c29, Cyp2c38, and sEH mRNA levels were measured in Cyp2j(-/-) and Cyp2j(+/+) male mice. At baseline, Cyp2j(-/-) and Cyp2j(+/+) mice had similar Hb levels and RVSP while breathing air. After 6 weeks of hypoxia, circulating Hb concentrations increased but did not differ between Cyp2j(-/-) and Cyp2j(+/+) mice. Chronic hypoxia increased RVSP in Cyp2j(-/-) and Cyp2j(+/+) mice of either gender. Exposure to chronic hypoxia decreased PAT and increased RV wall thickness in both genotypes and genders to a similar extent. Prolonged exposure to hypoxia produced similar levels of RV hypertrophy in both genotypes of either gender. Pulmonary Cyp2c29, Cyp2c38, and sEH mRNA levels did not differ between Cyp2j(-/-) and Cyp2j(+/+) male mice after breathing at normoxia or hypoxia for 6 weeks. These results suggest that murine Cyp2j deficiency does not attenuate the development of murine pulmonary vascular remodeling and hypertension associated with prolonged exposure to hypoxia in mice of both genders.

"Treating Lungs": The Scientific Contributions of Dr. Theodor Kolobow.

Abstract: We are fortunate to live in an age in which biomedical technology has provided us with unprecedented ability to supplant the functions of organs and support the physiologic processes of the human body. Ingenious doctors, physiologists, and engineers helped create these advances with new and innovative ideas. One of these pioneers was Dr. Theodor Kolobow. He is best known for one of his earliest inventions, the spiral coil membrane lung. His contributions to medical innovation, however, are diverse, as he also contributed to advances in hemodialysis, improvements in extracorporeal life support technology/circuit components, and through his laboratory experiments helped shape our current understanding of cardiopulmonary pathophysiology. In retrospect, much of Kolobow's work was unified by the theme of preventing iatrogenic lung injury caused by mechanical ventilation. This tenet became more obvious as his later studies progressed to developing techniques and devices intended to limit ventilator pressures, and prevent bacterial colonization of the lungs. Although he formally retired from his research endeavors in 2009, the impact of his contributions remains prominent in our everyday use of techniques and equipment that he either originated or helped to develop.

Heteroaryl disulfide compounds as allosteric effectors for increasing the oxygen-binding affinity of hemoglobin

Abstract: This invention relates to compounds of Formula I: (Formula I), and pharmaceutically acceptable salt thereof, which are allosteric effectors that increase the oxygen-being affinity of hemoglobin, which are useful in the treatment of sickle cell disease, high altitude tissue hypoxia, and other conditions.

Bisamide compounds as allosteric effectors for reducing the oxygen-binding affinity of hemoglobin

Abstract: This invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, which are allosteric effectors that reduce the oxygen-binding affinity of hemoglobin, which can enhance the efficacy of radiation therapy for cancer and which are useful for the treatment of ischemia and other conditions.

Inhaled Nitric Oxide: an sGC-dependent IOP lowering agent

Abstract: Background The nitric oxide (NO)-soluble guanylate cyclase (sGC)cyclic guanosine 3’5’-monophosphate (cGMP) pathway regulates intraocular pressure (IOP). Preclinical and clincial studies have demonstrated the ability of NO-donor compounds to lower IOP (e.g. VESNEO). The use of inhaled NO gas (iNO), a specific pulmonary but not systemic vasodilator, is an approved therapy for pulmonary hypertension and is under development as a treatment for other cardiovascular diseases (e.g. for myocardial ischemia, the NOMI trial). We hypothesized that breathing NO lowers IOP in an sGC-dependent manner.