Publication History

Journal Article, Academic Journal

• Martinez-Ruiz, MD, R.; Montero-Huerta, MD, P.; Hromi, J.; Head, MD, C. A. - "Inhaled Nitric Oxide Improves Survival Rates during Hypoxia in a Sickle Cell (SAD) Mouse Model" (Refereed) - Anesthesiology - 2001 - v. 94, no. 6, pp. 1113-1118 [View publication] [Show/Hide Abstract]
  Abstract: Background: The hallmark of sickle cell disease (SCD) is erythrocyte sickling during deoxygenation of the abnormal hemoglobin S (HbS). When HbS is deoxygenated, it aggregates into polymers, resulting in distortion of the erythrocyte structure, producing microvascular thrombosis and ischemia. The transgenic SAD mouse produces three types of human hemoglobin: S, Antilles, and D-Punjab (HbSAD) and provides an animal model for SCD. We studied the effects of nitric oxide (NO) breathing at various doses and time regimens in the presence of severe hypoxia (6% oxygen) using the SAD mouse model. Methods: Age- and sex-matched control and SAD mice were exposed to 6% oxygen breathing in an environmental chamber and assessed for survival up to 1 h. Animals received different inhaled NO concentrations before and/or during hypoxia. Blood was obtained to evaluate the oxyhemoglobin dissociation curve and measure methemoglobinemia. Results: Pretreatment by breathing NO at 20 ppm by volume in air for 30 min, and continuing to breathe 20 ppm NO during hypoxia resulted in improvement in survival rates in the SAD mouse (75%, n = 8) as compared with control SAD mice (11%, n = 9;P < 0.001). Pretreatment alone or breathing lower doses of NO were not protective. Changes in HbSAD oxygen affinity were not detected with NO breathing, and methemoglobin levels were low in all surviving mice. Conclusions: Breathing NO produced a rapid, protective effect to severe hypoxic stress in SAD mice. There appears to be a required loading period between NO breathing and its beneficial effect during hypoxic stress, possibly because of the total amount of NO delivered to SAD hemoglobin, blood cell components, and endothelium. NO breathing may be beneficial as a therapeutic intervention in SCD.
  
• Ichinose, MD, F.; Hromi, J.; Raveh, MD, Y.; Jones, PhD, R.; Krim, PhD, L.; Clark, BsC, M. W.; Winkler, PhD, J. D.; Bloch, MD, K. D.; Zapol, MD, W. M. - "Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension" (Refereed) - Critical Care Medicine - 2001 - v. 29, no. 5, pp. 1000-1005 [View publication] [Show/Hide Abstract]
  Abstract: Objective: To determine whether inhalation of aerosolized sildenafil with and without inhaled nitric oxide (NO) causes selective pulmonary vasodilation in a sheep model of pulmonary hypertension. Design: A controlled laboratory study in instrumented, awake, spontaneously breathing lambs. Setting: Animal research laboratory affiliated with a university hospital. Subject: Twenty Suffolk lambs. Interventions: Lambs were instrumented with a carotid artery catheter, a pulmonary artery catheter, and a tracheostomy tube and studied awake. After baseline measurements, pulmonary hypertension was induced by the continuous infusion of U46619, a thromboxane A2 analog. After breathing three concentrations of inhaled NO (2, 5, and 20 ppm), lambs were divided into two groups. Group 1 (n = 7) breathed aerosols containing 1, 10, and 30 mg of sildenafil alone, and group 2 (n = 4) simultaneously breathed NO (2 and 5 ppm) and aerosols containing 10 mg of sildenafil. Hemodynamic measurements were obtained before and at the end of each drug administration. Venous admixture was calculated, and plasma cyclic guanosine monophosphate and sildenafil concentrations were measured. Measurements and Main Results : Aerosols containing 10 mg and 30 mg of sildenafil selectively decreased the pulmonary artery pressure by 21% ?? 3% and 26% ?? 3%, respectively (p < .05 vs. baseline pulmonary hypertension). When 10 mg of sildenafil was inhaled while simultaneously breathing 2 ppm and 5 ppm NO, the pulmonary artery pressure decreased by 35% ?? 3% and 43% ?? 2% (p < .05 vs. baseline pulmonary hypertension). Inhaled sildenafil did not impair systemic oxygenation, increase right-to-left intrapulmonary shunting, or impair the ability of inhaled NO to reduce right-to-left shunting. Conclusions: Nebulized sildenafil is a selective pulmonary vasodilator that can potentiate the pulmonary vasodilating effects of inhaled NO.
  
• Goddon, MD, S.; Fujino, MD, Y.; Hromi, J.; Kacmarek, PhD, RRT, R. M. - "Optimal Mean Airway Pressure during High-frequency Oscillation: Predicted by the Pressure-Volume Curve" (Refereed) - Anesthesiology - 2001 - v. 94, no. 5, pp. 862-869 [View publication] [Show/Hide Abstract]
  Abstract: Background: A number of groups have recommended setting positive end-expiratory pressure during conventional mechanical ventilation in adults at 2 cm H2O above the lower corner pressure (PCL) of the inspiratory pressure-volume (P-V) curve of the respiratory system. No equivalent recommendations for the setting of the mean airway pressure (Paw) during high-frequency oscillation (HFO) exist. The authors questioned if the Paw resulting in the best oxygenation without hemodynamic compromise during HFO is related to the static P-V curve in a large animal model of acute respiratory distress syndrome. Methods: Saline lung lavage was performed in seven sheep (28 ?? 5 kg, mean ?? SD) until the arterial oxygen partial pressure/fraction of inspired oxygen ratio decreased to 85 ?? 27 mmHg at a positive end-expiratory pressure of 5 cm H2O (initial injury). The PCL (20 ?? 1 cm H2O) on the inflation limb and the point of maximum curvature change (PMC; 26 ?? 1 cm H2O) on the deflation limb of the static P-V curve were determined. The sheep were subjected to four 1-h cycles of HFO at different levels of Paw (PCL + 2, + 6, + 10, + 14 cm H2O), applied in random order. Each cycle was preceded by a recruitment maneuver at a sustained Paw of 50 cm H2O for 60 s. Results: High-frequency oscillation with a Paw of 6 cm H2O above PCL (PCL + 6) resulted in a significant improvement in oxygenation (P < 0.01 vs. initial injury). No further improvement in oxygenation was observed with higher Paw, but cardiac output decreased, pulmonary vascular resistance increased, and oxygen delivery decreased at Paw greater than PCL + 6. The PMC on the deflation limb of the P-V curve was equal to the PCL + 6 (r = 0.77, P < 0.05). Conclusion: In this model of acute respiratory distress syndrome, optimal Paw during HFO is equal to PCL + 6, which correlates with the PMC.
  
• Steudel, W.; Kirmse, M.; Weimann, J.; Ullrich, R.; Hromi, J.; Zapol, W. M. - "Exhaled Nitric Oxide Production by Nitric Oxide Synthase-deficient Mice " (Refereed) - Respiratory and Critical Care Medicine - 2000 - v. 162, no. 4, pp. 1262-1267 [View publication] [Show/Hide Abstract]
  Abstract: Nitric oxide (NO) is produced in the nasal cavities, airways, and lungs and is exhaled by normal animals and humans. Although increased exhaled NO concentrations in airway inflammation have been associated with increased airway expression of nitric oxide synthase 2 (NOS 2), it is uncertain which NOS isoform is responsible for baseline levels of exhaled NO. We therefore studied wild-type mice and mice with a congenital deficiency of NOS 1, NOS 2, or NOS 3. By studying a closed chamber in which the exhaled gas of a group of mice was collected, gaseous NO production rates were measured. Wild-type mice exhaled 362 ?? 35 ?? 1015 mol g1 min1 NO (mean ?? SE, n = 16 groups of five mice), NOS 1-deficient mice exhaled 592 ?? 74 ?? 1015 mol g1 min1 NO (n = 15 groups, p < 0.05 versus wild-type and NOS 2-deficient mice), NOS 2-deficient mice 330 ?? 74 ?? 1015 mol g1 min1 NO (n = 14 groups) and NOS 3-deficient mice 766 ?? 101 ?? 1015 mol g1 min1 NO (n = 16 groups, p < 0.001 versus wild-type and NOS 2-deficient mice). Pharmacological NOS inhibition with L-NAME decreased (p < 0.05) the exhaled NO production rate of wild-type and NOS 3-deficient but not of NOS 2-deficient mice. L-Arginine administration increased exhaled NO production rate in all but NOS 2-deficient mice. Absence of NOS 1 or 3 is associated with increased murine exhaled NO production rates. Since NOS 2-deficient mice were the only genotype to lack substrate- and inhibitor-regulated changes of NO exhalation, we suggest that NOS 2 is an important isoform contributing to exhaled NO exhalation in healthy mice.
  
• Fujino, Y.; Goddon, S.; Chiche, J.; Hromi, J.; Kacmarek, R. M. - "Partial Liquid Ventilation Ventilates Better than Gas Ventilation " (Refereed) - Respiratory and Critical Care Medicine - 2000 - v. 162, no. 2, pp. 650-657 [View publication] [Show/Hide Abstract]
  Abstract: Respiratory Care Department Laboratory and the Department of Anesthesia, Massachusetts General Hospital and Harvard Medical School, Boston, Massuchusetts Partial liquid ventilation (PLV) improves oxygenation in several models of lung injury. However, PLV has only been compared with conventional gas ventilation (GV) with low PEEP. Both PLV and GV can markedly improve oxygenation when PEEP is set above the lower corner pressure (Plc) on the inspiratory pressure-volume (P-V) curve of the total respiratory system. We questioned if the use of PEEP set above the Plc during PLV and GV would result in similar gas exchange. Lung injury was induced in 12 sheep by saline lavage before randomization to PLV (n = 6) or GV (n = 6). Animals in the PLV group were filled with perflubron (22 ml/kg) until a meniscus at the teeth was observed. Both groups were then ventilated with pressure control (FIO2, 1.0; rate, 20/min; I:E, 1:1) and PEEP (1 cm H2O above the Plc on the inspiratory P-V curve). Peak inspiratory pressure (PIP) was limited to 35 cm H2O. Animals were ventilated for 5 h and then killed for histologic examinations. All 12 animals survived the 5-h ventilation period. After increasing PEEP above Plc, PaO2 increased significantly (p < 0.01) in both the GV and the PLV groups, but it did not differ significantly between groups (p = 0.86) at any time during the experiment. PaCO2 and VD/VT in GV increased markedly throughout the experiment after increasing PEEP (p < 0.001), but there was no significant change in PaCO2 in PLV (p = 0.13). Mean arterial blood pressure, mean pulmonary artery pressure, pulmonary artery occlusion pressure, and central venous pressure, increased and SVR decreased in GV (p < 0.05). The extent and the severity of lung injury in the dependent regions was greater in the GV group (p < 0.05). Both PLV and GV improved oxygenation, but PLV resulted in better ventilation than GV while preserving lung structure when PEEP was set 1 cm H2O above the Plc and PIP limited to 35 cm H2O.
  
• Weimann, MD, J.; Ullrich, MD, R.; Hromi, J.; Fujino, MD, Y.; Clark, BsC, M. W.; Bloch, MD, K. D.; Zapol, MD, W. M. - "Sildenafil Is a Pulmonary Vasodilator in Awake Lambs with Acute Pulmonary Hypertension" (Refereed) - Anesthesiology - 2000 - v. 92, no. 6, pp. 1702-1712 [View publication] [Show/Hide Abstract]
  Abstract: Background: Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction. Methods: In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6). Results: Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation. Conclusions: Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.
  
• Kirmse, M.; Fujino, Y.; Hromi, J.; Mang, H.; Hess, D.; Kacmarek, R. M. - "Pressure-release Tracheal Gas Insufflation Reduces Airway Pressures in Lung-injured Sheep Maintaining Eucapnia " (Refereed) - American Journal of Respiratory and Critical Care Medicine - 1999 - v. 160, no. 5, pp. 1462-1467 [View publication] [Show/Hide Abstract]
  Abstract: Respiratory Care Department Laboratory and the Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts Although tracheal gas insufflation (TGI) has proved to be a useful adjunct to mechanical ventilation, end-inspiratory as well as end-expiratory pressures may increase. We investigated the ability of continuous-flow TGI to maintain eucapnia while reducing airway pressure (Paw) and tidal volume (VT). Seven sheep (36 ?? 2 kg) were ventilated using the Dr??ger Evita 4 in the pressure control plus mode where flow is released via the expiratory valve to maintain constant inspiratory pressure. To avoid TGI-generated positive end-expiratory pressure (PEEP), a prototype reverse flow TGI tube was used. Two TGI flows (5 and 10 L/min) were investigated pre- and postsaline lavage-induced lung injury. Inspiratory pressures and VT were significantly reduced as TGI flow increased. At 10 L/min TGI flow the carinal pressures (Pcar) and VT were reduced pre- and postinjury by 15% and 20%, and by 28% and 34%, respectively. Tidal volume to dead space ratio (VD/VT) decreased preinjury from 0.49 ?? 0.1 to 0.18 ?? 0.2 and postinjury from 0.62 ?? 0.1 to 0.33 ?? 0.1 at a TGI flow of 10 L/min. The combination of the reverse flow TGI tube and a ventilator with an inspiratory pressure relief mechanism kept set end-inspiratory and end-expiratory pressures constant. This TGI system effectively reduced set Paw and VT while maintaining eucapnia. Kirmse M, Fujino Y, Hromi J, Mang H, Hess D, Kacmarek RM. Pressure-release tracheal gas insufflation reduces airway pressures in lung-injured sheep maintaining eucapnia.