Background The adult respiratory distress syndrome is characterizedby pulmonary hypertension and right-to-left shunting of venousblood. We investigated whether inhaling nitric oxide gas wouldcause selective vasodilation of ventilated lung regions, therebyreducing pulmonary hypertension and improving gas exchange.
Methods Nine of 10 consecutive patients with severe adult respiratorydistress syndrome inhaled nitric oxide in two concentrationsfor 40 minutes each. Hemodynamic variables, gas exchange, andventilation-perfusion distributions were measured by means ofmultiple inert-gas-elimination techniques during nitric oxideinhalation; the results were compared with those obtained duringintravenous infusion of prostacyclin. Seven patients were treatedwith continuous inhalation of nitric oxide in a concentrationof 5 to 20 parts per million (ppm) for 3 to 53 days.
Results Inhalation of nitric oxide in a concentration of 18ppm reduced the mean (±SE) pulmonary-artery pressurefrom 37 ±3 mm Hg to 30 ±2 mm Hg (P = 0.008) anddecreased intrapulmonary shunting from 36 ±5 percentto 31 ±5 percent (P = 0.028). The ratio of the partialpressure of arterial oxygen to the fraction of inspired oxygen(PaO2/FiO2), an index of the efficiency of arterial oxygenation,increased during nitric oxide administration from 152 ±15mm Hg to 199 ±23 mm Hg (P = 0.008), although the meanarterial pressure and cardiac output were unchanged. Infusionof prostacyclin reduced pulmonary-artery pressure but increasedintrapulmonary shunting and reduced the PaO2/FiO2 and systemicarterial pressure. Continuous nitric oxide inhalation consistentlylowered the pulmonary-artery pressure and augmented the PaO2/FiO2for 3 to 53 days.
Conclusions Inhalation of nitric oxide by patients with severeadult respiratory distress syndrome reduces the pulmonary-arterypressure and increases arterial oxygenation by improving thematching of ventilation with perfusion, without producing systemicvasodilation. Randomized, blinded trials will be required todetermine whether inhaled nitric oxide will improve outcome.
The adult respiratory distress syndrome (ARDS) is characterizedby intrapulmonary shunting that results in arterial hypoxemia,1and by acute pulmonary arterial hypertension due to vasoconstrictionand widespread occlusion of the pulmonary microvasculature2,3.Pulmonary arterial hypertension contributes to pulmonary edema4and can cause right ventricular dysfunction5. Reducing the abnormallyelevated pulmonary vascular resistance by infusing vasodilatorslowers pulmonary-artery pressure as well as the effective pulmonary-capillarypressure,6,7,8,9 thereby improving right ventricular function5,10and possibly promoting the resolution of pulmonary edema6. However,the dose of a vasodilator agent is limited by concomitant dilationof the systemic vasculature, leading to systemic arterial hypotension,right ventricular ischemia, and consequent heart failure7,8,9,11.In addition, intravenously infused vasodilators produce diffusedilation of the pulmonary vasculature that increases blood flowto areas of intrapulmonary shunting. This mismatch between ventilationand perfusion usually further reduces the already compromisedpartial pressure of arterial oxygen (PaO2)7,8,9,12,13.
Inhalation of nitric oxide gas in a concentration of 5 to 80parts per million (ppm) dilated the pulmonary circulation ofconscious, spontaneously breathing lambs in which acute vasoconstrictionhad been induced either by giving them an infusion of a stablethromboxane-endoperoxide analogue or by having them breathea hypoxic gas mixture14. In patients with primary pulmonaryhypertension, inhaling nitric oxide in a concentration of 40ppm produced pulmonary vasodilation equivalent to that producedby prostacyclin15. Nitric oxide is synthesized by the vascularendothelium from the terminal guanidino nitrogen atom of theamino acid L-arginine16 and acts as a natural local vasodilator.It relaxes muscular arteries and veins by activating guanylatecyclase and increasing cyclic guanosine 3',5'-monophosphate17,18.Since nitric oxide binds rapidly to hemoglobin with a high affinityand is thereby inactivated,19,20,21 inhalation of the gas cannotdilate the systemic circulation. Thus, the vasodilatory effectof nitric oxide should be limited to the ventilated regionsof the lung when it is given by inhalation. In contrast to intravenouslyadministered vasodilators, inhaled nitric oxide should selectivelyimprove the perfusion of ventilated regions, thus reducing intrapulmonaryshunting and improving arterial oxygenation.
To test this hypothesis we first compared the effects of inhalednitric oxide with those of an intravenously infused vasodilator,prostacyclin. We then treated the patients with inhalation ofnitric oxide for up to 53 days.
Methods
This investigation was approved by the institutional ethicscommittee. Informed consent was obtained from each patient'sfamily.
Patients
We studied 10 consecutive patients without a history of previouslung disease who had severe ARDS when referred to our hospital.Their clinical characteristics recorded immediately before inhalationof nitric oxide are shown in Table 1, including their ARDS-severityscores determined according to the technique of Murray et al.22(range, 3.2 to 4). The pulmonary occlusion pressure (pulmonary-capillarywedge pressure) ranged from 8 to 18 mm Hg. Acute renal failurerequiring hemodialysis or hemofiltration was present in sixpatients,23 and liver dysfunction in five23. All patients receivedmechanical ventilation in the pressure-controlled mode withthe application of positive end-expiratory pressure (10 to 15cm of water) (Servo 900C ventilator, Siemens Elema, Lund, Sweden).The inhalation of nitric oxide was begun 3 to 10 days afteradmission and before any signs of recovery. At that time, thepatients had undergone ventilation for 14 to 41 days, and sixof them were treated with venovenous extracorporeal membraneoxygenation at flow rates of 2 to 3 liters per minute as previouslydescribed,24 because of a persistent pulmonary venous admixture(QVA/QT) of more than 45 percent that was associated with severearterial hypoxemia.
Table 1. Clinical Characteristics of the Patients.
The patients were sedated and relaxed. The use of cardiotonicor vasoactive drugs was avoided during studies of gas exchange.
Measurements
Routine clinical monitoring of the patients included a thermodilutionpulmonary-artery catheter and a thermistor femoral-artery catheter(Baxter Healthcare, Irvine, Calif.). The mean systemic arterialpressure, pulmonary arterial pressure, right atrial pressure,and pulmonary occlusion pressure were measured with disposabletransducers (Abbott Laboratories, Chicago) and a monitoringsystem (Hewlett-Packard Model 66 S, Boblingen, Germany). Thezero reference level for the supine position was the midaxilla;the vascular pressures were the average of values taken at end-expirationfrom three successive respiratory cycles. Cardiac output wasmeasured with thermodilution techniques and expressed as themean of the values recorded after each of four injections ofsaline (10 ml at 1 degrees to 5 °C)25. The systemic andpulmonary vascular resistances were calculated according tostandard formulas. Measurements of extravascular lung water(Lung Water Computer 9310, Edwards Laboratories, Irvine, Calif.)were obtained daily with a double-indicator dilution technique26.
Arterial and mixed-venous-blood concentrations were measuredwith standard blood-gas electrodes (ABL 300, Radiometer, Copenhagen,Denmark), and the total hemoglobin concentration, hemoglobinoxygen saturation, and methemoglobin levels with spectrophotometry(OSM 3 Hemoximeter, Radiometer). Samples of inspired gas wereobtained from the inspiratory tubing; samples of expired gaswere drawn into a heated flow-through mixing box. The ratioof the partial pressure of arterial oxygen to the fraction ofinspired oxygen (PaO2/FiO2) was used as an index of arterialoxygenation because inspiratory admixture of nitrogen, the carriergas for nitric oxide, reduced the concentration of inspiredoxygen. Concentrations of arterial, mixed venous, and capillaryoxygen were calculated, and the QVA/QT was derived from thestandard shunt equation, with the concentration of oxygen inthe alveolar gas (FiO2) set at 0.90 to 0.98.
We compared the effects of inhaled nitric oxide with those ofinfused prostacyclin, using the multiple inert-gas-eliminationtechnique27,28. This technique characterizes pulmonary gas exchangeby analyzing the exchange of inert gases across the blood-gasbarrier. In brief, a solution of 5 percent glucose in waterwas equilibrated with a mixture of six inert gases (sulfur hexafluoride,ethane, cyclopropane, halothane, diethyl ether, and acetone)and infused continuously into a peripheral vein, beginning 30minutes before blood sampling. Samples of arterial and mixedvenous blood and mixed expired gas were collected during severalrespiratory cycles and analyzed by gas chromatography (Sichromat1, Siemens, Cologne, Germany). Retention (the ratio of the concentrationin arterial blood to that in mixed venous blood) and excretion(the ratio of the concentration in expired gas to that in mixedvenous blood) were calculated for each gas. Ventilation-perfusion(VA/Q) distributions were estimated from the retention-partitionand excretion-partition coefficients by means of a computerprogram with a 50-compartment model of ventilation and bloodflow, to estimate ventilation-perfusion ratios in the lungs27.The extent of intrapulmonary shunting (QS/QT) was derived fromthe sulfur hexafluoride measurements and was defined as thefraction of total blood flow perfusing unventilated lung units(VA/Q ratio <0.005). Low VA/Q, which indicates poor ventilation,was defined as the fraction of total blood flow perfusing areaswith VA/Q ratios of 0.005 to 0.10 (normal VA/Q ratios rangefrom 0.1 to 10). The fraction of gas entering unperfused lungunits was defined as the inert-gas dead space. LogSDQ, an indexof VA/Q inequality, was defined as the square root of the valuefor the second moment of the blood-flow distribution.
Administration of Nitric Oxide
During the inspiratory cycle, the nebulizer of the ventilatorreleased nitric oxide from a tank of nitrogen with a nitricoxide concentration of 400 or 800 ppm (AGA, Bottrop, Germany).The resulting bolus of nitric oxide in nitrogen represented2 to 4 percent of inspired volume. The level of nitric oxidewas measured by chemiluminescence (CLD 700 AL, Tecan AG, Munich,Germany).
Short-Term Inhalation of Nitric Oxide as Compared with Prostacyclin Infusion
Nine consecutive patients (Table 1, Patients 1 through 9) inhalednitric oxide in a concentration of 18 ppm and then in a concentrationof 36 ppm, before or after they received an intravenous infusionof prostacyclin at a rate of 4 ng per kilogram of body weightper minute (Wellcome Laboratories, London). Systemic and pulmonaryhemodynamic variables and VA/Q distributions were measured before,during, and after each vasodilator was administered. To excludethe effects of sequential administration of vasodilators, thesequence of administration was randomized: in five patientsthe sequence was base-line study I, nitric oxide at 18 ppm,nitric oxide at 36 ppm, base-line study II, prostacyclin, andbase-line study III; in four other patients, the sequence wasbase-line study I, prostacyclin, base-line study II, nitricoxide at 18 ppm, nitric oxide at 36 ppm, and base-line studyIII. Each step in each sequence lasted approximately 40 minutes,and measurements were performed toward the end of each period,when hemodynamic function was stable.
Prolonged Inhalation of Nitric Oxide
Seven patients (Patients 4 through 10) were treated with prolongedinhalation of nitric oxide at 5 to 20 ppm, begun when the PaO2/FiO2was below 150 mm Hg. The administration of nitric oxide wasdiscontinued daily for 30 minutes, with the ventilator settingskept constant and the FiO2 set at 0.90 to 0.98, to determinethe effect of withdrawal and resumption of treatment on hemodynamicfunction, blood gas pressures, and QVA/QT. Extravascular lungwater was measured daily if the arterial thermistor remainedin place or until the measurements decreased to levels slightlyabove normal (5.7 ±1.2 g per kilogram)26. Treatment withnitric oxide was terminated after weaning from extracorporealmembrane oxygenation was successful and when the PaO2/FiO2 roseabove 250 mm Hg during daily tests without the inhalation ofnitric oxide.
Statistical Analysis
Values are expressed as means ±SE. Treatment effectsare reported as the difference between the mean of the base-linevalues (before and after treatment) and the value during theintervention. If a difference between base-line values was significant,the value recorded during the intervention was compared separatelywith the base-line values determined before and after the intervention.In addition, the effect of nitric oxide at 18 ppm was comparedwith its effect at 36 ppm, and the effects of both concentrationsof nitric oxide were compared with the effects of prostacyclininfusion.
The Wilcoxon test for paired samples was used to compare valuesrecorded during treatment with those recorded at base line fora single treatment and to compare differences between treatmentvalues and base-line values for the two treatments29. All testsof significance were two-tailed. A P value below 0.05 was assumedto indicate significance. No adjustment was made for comparisonsat multiple time points.
Results
Nitric Oxide as Compared with Prostacyclin
The inhalation of nitric oxide usually produced a prompt reductionin the pulmonary-artery pressure and a concomitant increasein the PaO2/FiO2 (Figure 1). The hemodynamic responses to inhalationof nitric oxide and infusion of prostacyclin are summarizedin Table 2. During inhalation of nitric oxide at 18 ppm, pulmonary-arterypressure decreased by 6 ±1 mm Hg from base line (P =0.008). There was no significant difference between the effectsof the two concentrations of nitric oxide on pulmonary-arterypressure. Intravenous prostacyclin infusions reduced the pulmonary-arterypressure by 6 ±2 mm Hg (P = 0.011). The mean systemicarterial pressure remained constant during inhalation of nitricoxide but decreased by 6 ±2 mm Hg (P = 0.018) duringinfusion of prostacyclin. Cardiac output remained unchangedfrom base-line values during inhalation of nitric oxide butincreased by 1.3 ±0.4 liters per minute when prostacyclinwas infused (P = 0.015). Pulmonary vascular resistance decreasedduring inhalation of nitric oxide at 18 ppm, by 71 ±17dyn • sec • cm-5 (P = 0.008), and did not change furtherduring the inhalation of the gas at 36 ppm; during prostacyclininfusion, it decreased by 102 ±30 dyn • sec •cm-5 (P = 0.011). Systemic vascular resistance was not alteredby inhalation of nitric oxide but decreased during prostacyclininfusion by 152 ±34 dyn • sec • cm-5 (P = 0.002).The heart rate, central venous pressure, and pulmonary occlusionpressure did not change during the administration of eithervasodilator. The values for all variables shown in Table 2 returnedto base line after the end of treatment with each vasodilator,with the exception of the pulmonary vascular resistance aftercessation of nitric oxide treatment.
Figure 1. Mean Pulmonary-Artery Pressure (PAP), Arterial Oxygenation Efficiency (PaO2/FiO2), and Intrapulmonary Shunting (QS/QT) in Nine Patients with ARDS during Inhalation of Nitric Oxide.
Solid symbols represent patients treated with extracorporeal membrane oxygenation.
Table 2. Hemodynamic Responses of Nine Patients to Short-Term Nitric Oxide Inhalation and Prostacyclin Infusion (4 ng per Kilogram per Minute).
Data on pulmonary gas exchange are shown in Figure 1 and Table 3.With inhalation of nitric oxide at 18 ppm, the PaO2/FiO2increased by 51 ±11 mm Hg (P = 0.008) and the QVA/QTdecreased by 6 ±1 percent (P = 0.008); nitric oxide at36 ppm did not cause further changes in these variables. Incontrast to inhalation of nitric oxide, prostacyclin infusiondecreased the PaO2/FiO2 by 26 ±7 mm Hg (P = 0.005) andincreased the QVA/QT by 8 ±2 percent (P = 0.011). Thepartial pressure of arterial carbon dioxide decreased by 2 ±1mm Hg only during the inhalation of nitric oxide at 36 ppm (P= 0.038). The partial pressure of oxygen in mixed venous bloodincreased by 2 ±0.3 mm Hg only during the inhalationof nitric oxide at 18 ppm (P = 0.008). Arterial pH values didnot differ throughout the study.
Table 3. Data on Blood Gas Exchange and Inert-Gas Elimination in Nine Patients during Short-Term Nitric Oxide Inhalation and Prostacyclin Infusion (4 ng per Kilogram per Minute).
The results of the inert-gas studies are shown in Table 3. Inhalationof nitric oxide at 18 ppm decreased the QS/QT by 3 ±1percent (P = 0.028); there was no further change during inhalationof 36 ppm. The fraction of blood flowing to lung regions withnormal VA/Q ratios increased by 5 ±1 percent (P = 0.011)during inhalation of nitric oxide at 18 ppm and was unchangedduring inhalation of the gas at 36 ppm. A prostacyclin infusion,however, had the opposite effect on both measurements. The QS/QTwas increased by 9 ±2 percent (P = 0.012), and bloodflow to lung regions with normal VA/Q ratios decreased by 9±2 percent (P = 0.012). Inhalation of nitric oxide at18 ppm was associated with a trend of decreasing logSDQ (P =0.051) that became significant during the inhalation of 36 ppm(P = 0.011). Infusion of prostacyclin was associated with atrend of increasing logSDQ, which rose by 0.1 ±0.01;this trend was not significant (P = 0.093). Blood flow to lungregions with low VA/Q ratios was reduced by 2 ±1 percentonly during the inhalation of nitric oxide at 36 ppm (P = 0.028).The inert-gas dead space did not change throughout the entirestudy. The delivered tidal volume at constant inspiratory andend-expiratory pressure did not change during inhalation ofnitric oxide or infusion of prostacyclin.
Prolonged Inhalation of Nitric Oxide
Nitric oxide (5 to 20 ppm) was inhaled by seven patients for3 to 53 days (Table 1 and Figure 2). The mean ARDS-severityscore of these seven patients just before long-term inhalationof nitric oxide was 3.6 (range, 2.75 to 4)22. During brief dailyinterruptions of nitric oxide treatment, pulmonary-artery pressureand QVA/QT were consistently increased and the PaO2/FiO2 wasconsistently decreased. Representative changes during the firstsix days of nitric oxide treatment are shown in Figure 2. Valuesfor extravascular lung water showed a declining trend (P>0.05).Methemoglobin levels, measured daily, always remained below1.3 percent.
Figure 2. Hemodynamic Function and Gas Exchange before, during, and after Brief Interruptions (Arrows) of Nitric Oxide Inhalation (Bars) during the First Six Days of Treatment in Seven Patients with ARDS.
Values are means ±SE (solid symbols); also shown (open symbols) are the means ±SE of the individual differences between the values for the effect of treatment and the means of the values determined before and after interruption of nitric oxide therapy. The standard errors for the treatment effects were small, indicating that the effects of withdrawal of nitric oxide were clear and precisely estimated. Each asterisk denotes a significant difference from the means of the values determined before and after interruption of nitric oxide therapy.
Discussion
In 1987, nitric oxide was reported to be an important endothelium-derivedrelaxing factor30,31. Although inhaling high concentrationsof nitric oxide can be lethal because it causes severe acutepulmonary edema and methemoglobinemia,32 there is little evidenceof toxicity when the concentration is below 50 ppm. Animalshave breathed the gas in concentrations of 10 to 40 ppm forsix days to six months without evidence of such toxicity33,34.The Occupational Safety and Health Administration has set theeight-hour maximal working-exposure level for nitric oxide at25 ppm35.
Frostell et al. demonstrated that inhaling nitric oxide in aconcentration of 5 to 80 ppm reversed hypoxic pulmonary vasoconstrictionwithout affecting systemic hemodynamic function in conscioussheep14 and volunteers with induced hypoxia36. Fratacci et al.reported that inhalation of nitric oxide prevented thromboxane-inducedpulmonary hypertension during the heparin-protamine reactionin lambs37. Recently, Dupuy et al. demonstrated in anesthetizedguinea pigs that inhaling nitric oxide at 5 to 300 ppm reversedmethacholine-induced bronchoconstriction38.
In our patients with ARDS, inhaled nitric oxide decreased intrapulmonaryshunting and improved arterial oxygenation while reducing thepulmonary-artery pressure. Our inert-gas analyses revealed thatthis beneficial effect was due to a redistribution of pulmonaryblood flow away from nonventilated regions of the lungs andtoward ventilated regions, thereby improving the matching ofventilation and perfusion. Inhaled nitric oxide can decreasethe regional pulmonary vascular resistance of ventilated lungareas, decreasing intrapulmonary shunting and selectively reducingthe pulmonary-artery pressure without causing systemic vasodilation.
An increased pulmonary-artery pressure due to pulmonary vasoconstrictionand vascular obstruction is a hallmark of severe ARDS2,9. Pulmonary-arteryhypertension promotes the accumulation of extravascular lungwater4 by increasing the microvascular filtration pressure39.Pulmonary hypertension can cause right ventricular dysfunction,reducing the right ventricular ejection fraction and cardiacoutput5. Intravenous infusion of nitroprusside reduces pulmonary-arterypressure and the accumulation of extravascular lung water inexperimental pulmonary edema6,40. Reducing the pulmonary-arterypressure may improve right-sided cardiac performance5,10.
The clinical use of intravenously infused vasodilators to treatARDS is limited because vasodilators reduce systemic arterialpressure. Intravenously infused vasodilators can markedly increaseintrapulmonary shunting, leading to a severely reduced PaO2,7,8,9,12,13as we demonstrated with prostacyclin (Table 3).
We observed a consistent reduction in pulmonary hypertensionand improvement in arterial oxygenation in patients with severeARDS who inhaled low concentrations of nitric oxide. This isboth surprising and therapeutically important. Although inhalingnitric oxide did not reduce the pulmonary-artery pressure toa normal level, probably because vascular occlusion or compressionhad occurred, it did lower pulmonary-artery pressure to thelevel achieved by infusing prostacyclin, and to the extent achievedby infusing nitroprusside in other patients with ARDS9. Unlikeintravenously infused vasodilators, inhaled nitric oxide doesnot reduce systemic arterial pressure. We believe that thisis because inhalation allowed nitric oxide to target and dilatelung vessels; thereafter, nitric oxide was inactivated rapidlyby combination with hemoglobin in red cells and by oxidation19,20,21.Methemoglobin levels remained low because nitric oxide was reducedby methemoglobin reductase in red cells41.
Inhalation of nitric oxide decreased the QVA/QT and the QS/QT,thereby improving arterial oxygenation. Our analysis of VA/Qdistributions demonstrated that the increase in PaO2 duringinhalation of nitric oxide was due to a redistribution of bloodflow away from regions with low VA/Q ratios and toward regionswith normal ratios, thus decreasing the inequality in VA/Q amongregions. This redistribution of pulmonary blood flow duringnitric oxide inhalation occurred without any important variationin the two major determinants of intrapulmonary shunting: cardiacoutput did not change, and the partial pressure of oxygen inmixed venous blood increased only during inhalation of nitricoxide at 18 ppm.42,43,44 Therefore, we believe that the redistributionof pulmonary flow was due to a reversal of regional vasoconstrictionin ventilated lung, supporting the hypothesis that nitric oxideselectively dilates blood vessels in ventilated lung regions.During inhalation of nitric oxide, we noted no change in thetidal volume delivered by constant inspiratory airway pressures.Thus, these effects of nitric oxide were probably not producedby bronchodilation. In contrast to inhaled nitric oxide, prostacyclinincreased the QVA/QT and the QS/QT, thereby reducing the PaO2by increasing the fraction of blood flowing to nonventilatedlung regions and thus enhancing VA/Q mismatching. Our data didnot determine whether the inhalation of nitric oxide is preferableto intravenous prostacyclin as therapy for ARDS, since the effectsof prostacyclin on hemodynamic function and gas exchange weremeasured for only brief periods.
Long-term inhalation of nitric oxide, for 3 to 53 days, didnot cause tachyphylaxis: prolonged inhalation remained effectivein reducing pulmonary-artery hypertension and improving oxygenexchange. The increase of approximately 15 percent in the base-lineQVA/QT and pulmonary-artery pressure during the brief dailyperiods when inhalation of nitric oxide was discontinued wassimilar at both the beginning and the end of the study. Addingnitric oxide to the inhaled gas allowed us to reduce the FiO2by about 15 percent. This minimizes exposure to high concentrationsof inhaled oxygen and may reduce its pulmonary toxicity45,46.Since we have treated only a small group of patients with ARDS,we are uncertain whether nitric oxide therapy will improve thesurvival rate. Nevertheless, six of seven patients admittedwith high ARDS-severity scores survived and were dischargedfrom the hospital. This preliminary and uncontrolled study inpatients with a high expected mortality rate is encouraging,but the findings must be confirmed by a prospective controlledtrial to determine whether nitric oxide can improve the outcomein patients with ARDS. Future studies should evaluate any potentialsystemic effects of nitric oxide, such as interference withendogenous production of nitric oxide, platelet function,47or leukocyte adhesion48.
Supported by a grant (Fa 139/1-3/2-3) from the Deutsche Forschungsgemeinschaftand a grant (HL-42397) from the National Heart, Lung, and BloodInstitute.
We are indebted to R. Monhaupt, G. Merker, O. Weber, and R.Simon for technical assistance; to Dr. A. Zaslavsky (HarvardUniversity Department of Statistics) and W. Steudel for statisticaladvice; to the nurses and staff of the intensive care unit (UniversitatsklinikumRudolf Virchow/Wedding, Freie Universitat Berlin) for theirdevoted care of our patients; and to Christine Heidelmeyer andMargaret Flynn for assistance in the preparation of the manuscript.
Source Information
From the Klinik fur Anaesthesiologie und operative Intensivmedizin, Universitatsklinikum Rudolf Virchow, Freie Universitat Berlin, Berlin (R.R., K.J.F., F.L., K.S., U.P.), and the Department of Anaesthesia, Harvard Medical School at Massachusetts General Hospital, Boston (W.M.Z.). The Massachusetts General Hospital has filed for a patent (pending) on the respiratory uses of nitric oxide.
Address reprint requests to Dr. Falke at Klinik fur Anaesthesiologie und operative Intensivmedizin, Universitatsklinikum Rudolf Virchow/Wedding, Freie Universitat Berlin, Augustenburger Platz 1, 1000 Berlin 65, Germany.
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