John C. Wain

Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction.

BackgroundWe examined the effects of inhalation of 5-80 ppm nitric oxide (NO) gas on the normal and acutely constricted pulmonary circulation in awake lambs. Methods and ResultsSpontaneous breathing of nitric oxide (an endothelium-derived relaxing factor) at 40 ppm or more reversed acute pulmonary vasoconstriction within 3 minutes either because of infusion of the stable thromboxane endoperoxide analogue U46619 or because of pulmonary hypertension due to breathing a hypoxic gas mixture. Systemic vasodilation did not occur. Pulmonary vasodilation by NO inhalation was produced during infusion of U46619 for periods of 1 hour without observing evidence of short-term tolerance. Pulmonary hypertension resumed within 3-6 minutes of ceasing NO inhalation. In the normal lamb, the pulmonary vascular resistance, systemic vascular resistance, cardiac output, left atrial and central venous pressures were unaltered by NO inhalation. ConclusionBreathing 80 ppm NO for 3 hours did not increase either methemoglobin or extravascular lung water levels or modify lung histology compared with those in control lambs. (Circulation 1991;83:2038—2047)

Inhaled Nitric Oxide A Selective Pulmonary Vasodilator of Heparin-Protamine Vasoconstriction in Sheep

Nitric oxide (NO) has recently been discovered to be an important endothelium-derived relaxing factor and produces profound relaxation of vascular smooth muscle. To learn if NO could be a potent and selective pulmonary vasodilator, NO was inhaled by 16 awake lambs in an attempt to reduce the increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) induced by either the infusion of an exogenous pulmonary vasoconstrictor (the thromboxane analog U46619) or the endogenous release of thromboxane that occurs during the neutralization of heparin anticoagulation by protamine sulfate. Inhaling greater than or equal to 40 ppm of NO during a continuous U46619 infusion returned the PAP to a normal value, without affecting systemic blood pressure or vascular resistance. Pretreatment with the cyclooxygenase inhibitor indomethacin before infusing U46619 did not reduce the pulmonary vasodilatory effect of inhaled NO, and we conclude that the dilatory effect of NO on the lungs circulation is independent of cyclooxygenase products such as prostacyclin. Continuously inhaling NO at 180 ppm did not significantly reduce the mean peak thromboxane B2 concentration at 1 min after protamine injection; however, the mean values of pulmonary hypertension and vasoconstriction at 1 min were markedly reduced below the levels in untreated heparin-protamine reactions. Breathing NO at lower concentrations (40-80 ppm) did not decrease the mean peak PAP and PVR at 1 min after protamine but decreased the PAP and PVR values at 2, 3, and 5 min below those of control heparin-protamine reactions. Intravenous infusion of nitroprusside completely prevented the transient increase of PAP and PVR during the heparin-protamine reaction; however, marked concomitant systemic vasodilation occurred. Inhaled NO is a selective pulmonary vasodilator that can prevent thromboxane-induced pulmonary hypertension during the heparin-protamine reaction in lambs and can do so without causing systemic vasodilation.

Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb.

We determined whether inhaling low levels of nitric oxide (NO) gas could selectively reverse hypoxic pulmonary vasoconstriction in the near-term newborn lamb and whether vasodilation would be attenuated by respiratory acidosis. To examine the mechanism of air and NO-induced pulmonary vasodilation soon after birth, we measured plasma and lung cGMP levels in the newly ventilated fetal lamb. Breathing at FIO2 0.10 nearly doubled the pulmonary vascular resistance index in newborn lambs and decreased pulmonary blood flow primarily by reducing left-to-right blood flow through the ductus arteriosus. Inhaling 20 ppm NO at FIO2 0.10 completely reversed hypoxic pulmonary vasoconstriction within minutes. Maximum pulmonary vasodilation occurred during inhalation of > or = 80 ppm NO. Breathing 8% CO2 at FIO2 0.10 elevated the pulmonary vascular resistance index to a level similar to breathing at FIO2 0.10 without added CO2. Respiratory acidosis did not attenuate pulmonary vasodilation by inhaled NO. In none of our studies did inhaling NO produce systemic hypotension or elevate methemoglobin levels. Four minutes after initiating ventilation with air in the fetal lamb lung, cGMP concentration nearly doubled without changing preductal plasma cGMP concentration. Ventilation with 80 ppm NO at FIO2 0.21 increased both lung and preductal plasma cGMP concentration threefold. Our data suggest that inhaled NO gas is a rapid and potent selective vasodilator of the newborn pulmonary circulation with an elevated vascular tone due to hypoxia and respiratory acidosis that acts by increasing lung cGMP concentration.

Diaphragmatic shortening after thoracic surgery in humans. Effects of mechanical ventilation and thoracic epidural anesthesia.

BackgroundDiaphragmatic function is believed to be inhibited after thoracic surgery and may be improved by thoracic epidural anesthesia. MethodsDiaphragmatic function after a thoracotomy was monitored by implanting one pair of sonomicrometry crystals and two electromyogram (EMG) electrodes on the costal diaphragm of six patients undergoing an elective pulmonary resection. Crystals and EMG electrodes remained in place for 12–24 h. ResultsDuring mechanical ventilation, costal diaphragmatic length (as a percent of rest length; %LFRC)decreased passively as tidal volume (VT) Increased (%LFRC = 2.81 + 1.12 × 10-2 VT (ml), r = 0.99). During spontaneous ventilation, the costal shortening (2.1 ± 2.3 %LFRC) was less than during mechanical ventilation (7.9 ± 3.0 %LFRC, P < 0.05) at the same VT. Comparing spontaneous ventilation before and 30 min after thoracic epidural anesthesia, there were Increases of VT (390 ± 78 to 555 ± 75 ml), vital capacity (1.37 ± 0.16 to 1.68 ± 0.21 1), and esophageal (-8.5 ± 1.5 to −10.6 ± 1.7 cmH2O), gastric (-0.7 ± 0.8 to ±0.8 ± 0.8 cmH2O), and transdiaphragmatic (7.7 ± 1.5 to 11.5 ± 1.9 cmH2O) pressures, but diaphragmatic EMG and shortening fraction remained constant. In three of six patients, epidural anesthesia produced paradoxical segment lengthening upon inspiration. ConclusionsThoracotomy and pulmonary resection produce a marked reduction of active diaphragmatic shortening, which is not reversed by thoracic epidural anesthesia despite improvement of other indices of respiratory function.

Thoracic Epidural Anesthesia Increases Diaphragmatic Shortening after Thoracotomy in the Awake Lamb

BackgroundProlonged inhibition of diaphragmatic function occurs after thoracic and upper abdominal surgery. It was hypothesized that thoracic epidural anesthesia on the day after a thoracotomy could block inhibitory neural pathways and increase the shortening of costal and crural diaphragmatic segments. MethodsPairs of sonomicrometer crystals were implanted into the costal and crural regions of the diaphragm through a right lateral thoracotomy in 14 30-kg, 4–5-month-old lambs. One day after surgery, a thoracic epidural catheter was placed at the T8-T9 level. Regional diaphragmatic shortening normalized to end-expiratory length (%LFRC), was measured by sonomicrometry in these awake lambs. Changes in gastric (ΔPgas), esophageal (ΔPcs,), and transdiaphragmatic (ΔPdi) pressures were measured with transnasal balloon catheters. End-tidal carbon dioxide (FETCO2), costal and crural electromyogram (Edi), and tidal volume (VT) were measured. Inductance plethysmography was used in four lambs to assess relative contributions of the rib cage and abdomen to VT. Control values were obtained during quiet breathing and while rebreathing at up to 10% FETco2 To block thoracic dermatomes, 1% or 2% lidocaine was injected through the epidural catheter. Measurements were repeated after each lidocaine injection. ResultsThere was no change of resting length with 1% lidocaine; costal resting length increased by 22% with 2% lidocaine. After 2% lidocaine, costal %LFRC increased from control both during quiet breathing (8.7 ± 0.7 to 18.1 ± 1, x ± SEM%) and at FETCO2 10% (22.1 ± 2 to 33.7 ± 3%). VT during quiet breathing was unchanged after 1% lidocaine but increased from 235 ± 16 to 283 ± 28 ml after 2% lidocaine. At 10% FeTco2, ΔPdl was unchanged after 1% lidocaine and decreased from 36.5 ± 4.3 to 26.3 ± 4.9 cmH2O after 2% lidocaine. Regional ΔEdl, was unchanged with both 1% and 2% lidocaine at rest and during carbon dioxide rebreathing. Plethysmography in three lambs showed a reduction in rib cage contribution to tidal volume with 2% lidocaine during quiet breathing. ConclusionsImproved postoperative tidal volume and diaphragmatic shortening after thoracic epidural blockade may be due to changes of chest wall conformation and resting length and a shift of the workload of breathing from the rib cage to the diaphragm caused by intercostal muscle paralysis.

Effects of digoxin on regional diaphragm function after thoracotomy in awake sheep

The effects of digoxin on diaphragmatic contraction were studied in 12 sheep, within 6 days after a right thoracotomy, during the period of intense diaphragmatic inhibition. Diaphragmatic function was assessed by implanting sonomicrometry crystals and electromyographic (EMG) electrodes in both the costal and crural diaphragmatic regions. Awake sheep were studied before and after intravenous digoxin (0.04 mg/kg) during both quiet breathing (QB) and during CO2 rebreathing, until the fractional concentration of expired CO2 (FETCO2) reached 0.10. After digoxin infusion, during both QB and at FETCO2 of 0.10, esophageal and transdiaphragmatic pressures increased (P < 0.05). After digoxin infusion no changes were measured for end-expiratory resting length, shortening fraction, shortening velocity or EMG activity of either diaphragmatic segment or for respiratory frequency, ventilation, tidal volume and FETCO2. We conclude that intravenous digoxin given to awake sheep after a thoracotomy increases Pdi, but does not alter diaphragmatic shortening nor alter the level of diaphragmatic activation either during QB or at FETCO2 of 0.10.

Effects of Aminophylline on Regional Diaphragmatic Shortening after Thoracotomy in the Awake Lamb

Aminophylline has been reported to augment diaphragmatic contraction, although this remains a controversial finding. We studied the effect of aminophylline on regional diaphragmatic shortening, changes in transdiaphragmatic pressure (delta Pdi), and integrated regional electromyographic (EMG) activity of the diaphragm (Edi) after a right thoracotomy in nine lambs using sonomicrometry, esophageal and gastric balloons, and EMG. Sonomicrometer crystals and EMG leads were implanted into the costal and crural regions of the diaphragm through a right thoracotomy, and a tracheostomy was performed. The animals were studied while awake within 4 days after surgery. Fractional costal and crural diaphragmatic shortening was measured using the sonomicrometer; delta Pdi was calculated from esophageal and gastric pressures. Respiratory variables were measured through the tracheostomy. Data were collected during quiet breathing and during CO2 rebreathing. After control measurements, aminophylline (10 mg/kg) was administered intravenously, producing a serum concentration of 17.7 +/- 1.5 micrograms/ml. Aminophylline did not augment shortening, increase delta Pdi, or overcome postoperative diaphragmatic inhibition acutely in the awake sheep after a right lateral thoracotomy. A small decrease of end-tidal CO2, from 5.2% to 4.9%, was measured at rest during aminophylline infusion, but Edi was unchanged. Although during CO2 rebreathing diaphragmatic shortening increased, the addition of aminophylline did not further augment shortening. Our data in awake lambs suggest that aminophylline does not improve diaphragmatic contraction in the acute postoperative period.