Journal of Applied Physiology
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J Appl Physiol 84: 107-115, 1998;
8750-7587/98 $5.00
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Cardiopulmonary effects of inhaled nitric oxide in normal dogs and during E. coli pneumonia and sepsis

Zenaide M. N. Quezado, Charles Natanson, Waheedullah Karzai, Robert L. Danner, Cezar A. Koev, Yvonne Fitz, Donald P. Dolan, Steven Richmond, Steven M. Banks, Laura Wilson, and Peter Q. Eichacker

Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Quezado, Zenaide M. N., Charles Natanson, Waheedullah Karzai, Robert L. Danner, Cezar A. Koev, Yvonne Fitz, Donald P. Dolan, Steven Richmond, Steven M. Banks, Laura Wilson, and Peter Q. Eichacker. Cardiopulmonary effects of inhaled nitric oxide in normal dogs and during E. coli pneumonia and sepsis. J. Appl. Physiol. 84(1): 107-115, 1998.---We investigated the effect of inhaled nitric oxide (NO) at increasing fractional inspired O2 concentrations (FIO2) on hemodynamic and pulmonary function during Escherichia coli pneumonia. Thirty-eight conscious, spontaneously breathing, tracheotomized 2-yr-old beagles had intrabronchial inoculation with either 0.75 or 1.5 × 1010 colony-forming units/kg of E. coli 0111:B4 (infected) or 0.9% saline (noninfected) in one or four pulmonary lobes. We found that neither the severity nor distribution (lobar vs. diffuse) of bacterial pneumonia altered the effects of NO. However, in infected animals, with increasing FIO2 (0.08, 0.21, 0.50, and 0.85), NO (80 parts/million) progressively increased arterial PO2 [-0.3 ± 0.6, 3 ± 1, 13 ± 4, 10 ± 9 (mean ± SE) Torr, respectively] and decreased the mean arterial-alveolar O2 gradient (0.5 ± 0.3, 4 ± 2, -8 ± 7, -10 ± 9 Torr, respectively). In contrast, in noninfected animals, the effect of NO was significantly different and opposite; NO progressively decreased mean PO2 with increasing FIO2 (2 ± 1, -5 ± 3, -2 ± 3, and -12 ± 5 Torr, respectively; P < 0.05 compared with infected animals) and increased mean arterial-alveolar O2 gradient (0.3 ± 0.04, 2 ± 2, 1 ± 3, 11 ± 5 Torr; P < 0.05 compared with infected animals). In normal and infected animals alike, only at FIO2 <= 0.21 did NO significantly lower mean pulmonary artery pressure, pulmonary artery occlusion pressure, and pulmonary vascular resistance index (all P < 0.01). However, inhaled NO had no significant effect on increases in mean pulmonay artery pressure associated with bacterial pneumonia. Thus, during bacterial pneumonia, inhaled NO had only modest effects on oxygenation dependent on high FIO2 and did not affect sepsis-induced pulmonary hypertension. These data do not support a role for inhaled NO in bacterial pneumonia. Further studies are necessary to determine whether, in combination with ventilatory support, NO may have more pronounced effects.

Escherichia coli; hypoxemia; fractional inspired oxygen; pulmonary artery pressure

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

HYPOXEMIA AND PULMONARY hypertension contribute to the morbidity and mortality of patients with pneumonia and acute lung injury (50, 63). Hypoxemia during such injury results in large part from mismatching of perfusion and ventilation (23, 24, 63). In addition, abnormalities of hypoxic pulmonary vasoconstriction, the normal physiological response that diverts blood flow from poorly to well-ventilated lung regions, may contribute to hypoxemia (7, 24, 27-29, 45, 59).

Inhaled nitric oxide (NO), a potent pulmonary vasodilator, has been studied as adjuvant therapy for acute lung injury (4, 5, 11, 21, 50). Because inhaled NO only produces pulmonary vasodilation in well-ventilated lung regions, it can potentially improve matching of ventilation and perfusion (4, 5, 11, 21, 50). When inhaled NO reaches the pulmonary vasculature, it is thought to be rapidly bound to and inactivated by hemoglobin, which in turn precludes systemic effects (31, 46, 62). Therefore, in contrast to systemic vasodilators previously used to treat pulmonary hypertension (20, 39, 44, 52), inhaled NO may selectively dilate the pulmonary vasculature without producing systemic vasodilation (5, 11, 21, 46, 50).

Inhaled NO has been shown to decrease pulmonary hypertension associated with a number of stimuli, including hypoxia, thromboxane analogs, and heparin-protamine treatment (8, 12, 14, 47, 48). However, with acute lung injury, in humans and animals, the effects of inhaled NO on pulmonary hypertension and arterial oxygenation have been variable (3-5, 11, 12, 36-38, 40, 49-51, 53, 54) and in certain settings detrimental (1). Therefore, it is possible that the effects of inhaled NO may vary depending on several factors, such as the etiology, stage, and severity of the underlying lung injury and the presence of other therapies.

We have developed a canine model of gram-negative pneumonia that simulates many of the cardiopulmonary changes occurring in patients with this condition. We hypothesized that the selective pulmonary vasodilation associated with inhaled NO would reduce pulmonary arterial hypertension and improve oxygenation in this canine model. By altering inspired O2 concentrations, we also investigated whether hypoxic pulmonary vasoconstriction was still present during gram-negative pneumonia and, if present, how NO might alter it.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Study design and experimental subjects. Thirty-eight 2-yr-old purpose-bred beagles weighing 10-12 kg had permanent tracheostomies placed as previously described (9). Baseline evaluations were performed 7 days later. Using local anesthesia, we placed femoral and pulmonary arterial catheters (35). Awake animals were then studied while breathing eight different gas mixtures for 10 min each. Four fractional inspired O2 (FIO2) doses were tested (0.08, 0.21, 0.50, and 0.85) in both the presence [80 parts/million (ppm)] and absence (0 ppm) of NO. During the last 5 min of each 10-min inhalation period, a complete cardiopulmonary evaluation (see Cardiopulmonary measurements) was performed. After completion of this study, all intravascular catheters were removed. Seven days later (day 0), animals were challenged intrabronchially with Escherichia coli 0111:B4 (infected) or 0.9% saline (noninfected) administered in a lobar or diffuse distribution (see Intrabronchial inoculation). Studies identical to those at baseline were repeated 24, 48, and 504 h after intrabronchial inoculation (day E0). These time points were selected because pilot and other prior studies indicated that mortality was maximal during the first 48 h after inoculation and that by 504 h cardiopulmonary function in surviving septic animals had returned to preseptic baseline values (13).

Three animals were studied each day: one animal with lobar pneumonia, one animal with diffuse pneumonia, and one noninfected animal. For 5 days, all animals received ceftriaxone (100 mg · kg-1 · day-1) Ringer solution (50 ml/kg) at 6 and 12 h on day 0, in addition to a 20 ml/kg bolus followed by a 10 ml/kg continuous infusion that was administered during cardiopulmonary studies at baseline, 24, 48, and 504 h.

Intrabronchial inoculation. On day 0, using topical anesthesia (20 ml of 1% lidocaine), we introduced a bronchoscope (BF type 1T2OD; Olympus, Lake Success, NY) into the tracheal stoma. The right and left caudal and cranial lobe bronchi were identified, and a balloon-tipped pulmonary artery catheter was introduced through the injectate port of the bronchoscope. The balloon was then inflated, and an 8-ml aliquot of 0.9% saline or E. coli 0111:B4 was injected. Animals randomized to lobar pneumonia were inoculated with the total E. coli dose in one lobe and 0.9% saline in the other three lobes. Animals randomized to have diffuse pneumonia were given one-fourth of the total dose of E. coli in each of four lobes. Those randomized to be noninfected were given an equivalent amount of 0.9% saline in all four lobes. To study the effects of inhaled NO in nonlethal vs. lethal pneumonia, 9 animals were inoculated with 0.75 × 1010 colony-forming units (CFU)/kg body weight (5 lobar and 4 diffuse), and 16 animals were inoculated with 1.5 × 1010 CFU/kg body weight of E. coli 0111:B4 (50% lethal dose; n = 8 lobar and 8 diffuse animals).

Inhalation challenges. The order of the eight inhalation challenges for each animal was randomly determined at baseline, and this order was repeated on all subsequent study days. Briefly, the animals had a cuffed tracheostomy tube placed. The tube was then connected to a nonrebreathing gas system consisting of a 5-liter mixing chamber, a 5-liter reservoir bag, and a one-way valve to separate inspired from expired gas. By using volumetric calibrated flowmeters, varying quantities of O2, nitrogen, and NO were delivered through the gas system to produce gas mixtures with four FIO2 doses (0.08, 0.21, 0.50, and 0.85), each administered with or without NO (80 or 0 ppm). Inhaled NO concentration was continuously monitored and maintained constant throughout the duration of each inhalation challenge by using chemiluminescence analysis (model 14A; Thermo Environmental Instruments, Franklin, MA). The efficiency of the chemiluminescence analyzer was measured by a generator of NOx (model 100B; Thermo Environmental Instruments); the efficiency was found to be 98%. NO, mixed with pure nitrogen, was supplied at a concentration of 800 ppm from a tank that contained only 3.2 ppm of other nitrogen oxides such as NO2 (Air Products and Chemicals, Allentown, PA). After cardiopulmonary variables were measured, all animals were disconnected from the circuit and allowed to breath room air.

Cardiopulmonary measurements. Femoral arterial and thermodilution pulmonary arterial catheters were used to measure, at each NO and FIO2 concentration studied, heart rate (HR), mean arterial pressure (MAP, in mmHg), central venous pressure, mean pulmonary artery pressure (MPAP, in mmHg), pulmonary artery occlusion pressure (Ppao, in mmHg), and cardiac output (in ml/min). Hemodynamic data were indexed to body weight in kilograms. Cardiac index (CI), stroke volume index (SVI), left ventricular stroke work index, systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI; in dyn · s · cm-5 · kg-1), O2 delivery index, and alveolar-arterial O2 gradient (A-aDO2, in Torr) were calculated by using standard formulas. At baseline and at 48 and 504 h after completing all inhalation challenges, left ventricular ejection fraction (LVEF) was measured by radionuclide-gated blood pool scanning as previously described (35).

Laboratory measurements. Routine chemistries, complete blood counts, quantitative blood and sputum cultures, and endotoxin levels were obtained on each study day by using previously described techniques (35). In addition, complete blood counts were obtained at 1, 2, and 3 h on day 0. Furthermore, at each FIO2 and NO concentration studied, arterial and mixed-venous partial pressures of O2 (PaO2 and a-vPO2, respectively, in Torr), arterial partial pressure of CO2 (PaCO2, in Torr), and methemoglobin concentration were measured by using a blood-gas analyzer (model 288, Radiometer, Medfield, MA). Blood lactate (in mM) was determined by using a glucose-lactate analyzer (YSI model 2300 STAT; Yellow Springs Instrument, Yellow Springs, OH). Anterior-posterior and lateral chest radiographs were also obtained on each study day before beginning inhalation studies (model SPG 5125; CGR Medical, Baltimore, MD). Chest radiographs and the severity of infiltrates were analyzed by a veterinarian radiologist unaware of the treatment group to which each animal belonged. The right and left cranial and caudal lobes, as well as the right middle and accessory lobes, were graded as to the level of opacification on a scale of 1 (normal) to 4 (severe).

Animal care. The protocol for this investigation was approved by the Animal Care and Use Committee of the Clinical Center of the National Institutes of Health. Throughout the studies, all efforts were undertaken to minimize animal pain and suffering.

Statistical methods. Hemodynamic and laboratory parameters were analyzed by using an analysis of variance (ANOVA; Ref. 52). The analyses were performed in stages. At baseline, to examine the effects of FIO2 and inhaled NO before infection, a five-way ANOVA with FIO2 dose (0.08, 0.21, 0.50, and 0.85), inhaled NO dose (0 and 80 ppm), group (control, diffuse, and lobar), dose of E. coli, and dog (nested within group and dose of E. coli) was performed. All higher order interactions, except those including dog, were included in the model. All interactions that include dog were used as the error term. When interaction terms were nonsignificant, data were pooled over these terms to increase the power of analysis. When FIO2, NO, or FIO2-NO interactions are reported, all higher order interactions involving these terms were not significant.

To examine the effects of E. coli challenges, changes from baseline on hemodynamic and laboratory parameters were computed. These changes were computed for each dog and each dose of FIO2 and NO, on both days 1 and 2 postclot implantation. We performed a six-way ANOVA by using all factors above plus the aditional factor of day of the study. In addition, the factor for group was decomposed into two independent factors: one for infected-noninfected and the other for the type of infection. Similar to the analyses performed on baseline data, the reporting of significant effects implies that the higher order interactions that include the reported term are all nonsignificant. Multiple comparisons associated with FIO2 effects were controlled by using a Tukey test.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Comparison of pulmonary and systemic hemodynamic variables at baseline. At baseline, there were no significant [P = not significant (NS)] differences in pulmonary or systemic hemodynamic variables among study groups (Tables 1 and 2), except that all animals (both those designated to be noninfected controls or infected animals) from the low-dose bacteria experiments (E. coli dose of 0.75 × 1010 CFU) at FIO2 0.85 had higher PaO2 (470 ± 5 vs. 434 ± 5 Torr, mean ± SE) and lower A-aDO2 (95 ± 4 vs. 129 ± 5 Torr), compared with all animals from the high-dose bacteria experiments (E. coli dose of 1.5 × 1010 CFU) (both P = 0.0001). Inhaled NO had similar (P = NS) effects on all pulmonary and systemic hemodynamic variables measured in all groups at baseline (Tables 1 and 2).

                              
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  		Table 1.   Pulmonary hemodynamic and gas exchange variables measured 7 days before intrabronchial inoculation during inhalation of 4 different FIO2 levels with and without NO

                              
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  		Table 2.   Systemic hemodynamic and left ventricular variables measured 7 days before intrabronchial inoculation during inhalation of 4 different FIO2 levels with and without NO

Clinical manifestations of pneumonia and survival. After intrabronchial E. coli challenges, all infected animals had signs of pneumonia, including lethargy, tachypnea, and production of purulent sputum. After intrabronchial saline challenges, all noninfected animals appeared healthy throughout.

All animals receiving 0.75 × 1010 CFU E. coli intrabronchially survived to 21 days. Five of eight animals receiving 1.5 × 1010 CFU E. coli in one pulmonary lobe and four of eight receiving this dose equally divided among four pulmonary lobes died (Fig. 1).


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  		Fig. 1.   Survival after intrabronchial inoculation of Escherichia coli (15 × 1010 colony-forming units) in only 1 lobe (lobar pneumonia; n = 8 dogs) or divided in 4 lobes (diffuse pneumonia; n = 8 dogs), or saline (controls; n = 8 dogs).

Pulmonary and systemic hemodynamic effects of pneumonia. Animals with diffuse and lobar E. coli challenges had similar pulmonary and systemic hemodynamic measurements at all FIO2 doses studied with or without inhaled NO. Therefore we averaged over this variable to increase our ability to find significant effects (Tables 1-4, Fig. 2). Unless specified, animals with either lobar or diffuse E. coli pneumonia are referred to as infected animals.

                              
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  		Table 3.   Pulmonary hemodynamic variables measured on days 1 and 2 after intrabronchial inoculation during inhalation of 4 FIO2 levels with and without NO

From baseline to day 2, infected animals had significantly greater decreases in mean LVEF compared with noninfected animals (-0.17 ± 0.09 vs. -0.06 ± 0.05, P = 0.0001). Infected animals, from baseline to days 1 and 2 alike, had significant increases in mean MPAP (P = 0.0005), Ppao (P = 0.01), PVRI (P = 0.0014), and A-aDO2 (P = 0.0001); significant decreases in mean PaO2 (P = 0.0001), MAP (P = 0.0002), CI (P = 0.02, data not shown), SVI (P = 0.002, data not shown), and left ventricular stroke work index (P = 0.0001, data not shown); and no significant changes in mean lactate, HR, and SVRI (P = NS) compared with noninfected animals.

Effect of varying FIO2 (0.08, 0.21, 0.50, and 0.85) on the pulmonary and systemic hemodynamic effects of pneumonia. At all FIO2 doses studied on days 1 and 2 alike, infected animals had higher mean Ppao and lower MAP compared with noninfected animals (Fig. 2, Tables 3 and 4). However, this difference was significantly greater at FIO2 0.08 (for both parameters P < 0.0008) compared with other FIO2 doses. Furthermore, infected animals at all FIO2 doses studied on days 1 and 2 alike had lower PaO2 and higher A-aDO2 compared with noninfected animals, and this difference was progressively and significantly greater with increasing FIO2 doses (0.08 <=  0.21 <=  0.50 <=  0.85; for both parameters, P = 0.0001). On days 1 and 2, at FIO2 >= 0.21, mean HR was higher in infected compared with noninfected animals, whereas at FIO2 <0.21 it was lower in infected compared with noninfected animals (P = 0.0001). Finally, infected animals challenged with low-dose E. coli (0.75 × 1010 CFU), at FIO2 <= 0.21, compared with FIO2 >0.21, had on days 1 and 2 alike greater increases in mean PVRI compared with noninfected animals (data not shown; P = 0.01).

On days 1 and 2, infected animals, similarly at all FIO2 doses studied, had higher mean MPAP (P = 0.0001), PVRI (P = 0.02), and arterial lactate (P = 0.008) but lower SVRI (P = 0.09) compared with noninfected animals. Furthermore, on days 1 and 2 alike at FIO2 <= 0.21, infected animals and noninfected animals had higher MPAP (P = 0.0001), PVRI (P = 0.02), and arterial lactate levels (P = 0.0001) than at FIO2 doses >0.21.

Effect of inhaled NO (80 ppm) at varying FIO2 on the pulmonary and systemic hemodynamic effects of pneumonia. On days 1 and 2 alike, in infected animals, with increasing FIO2 doses (0.08-0.85), NO produced progressively greater increases in mean PaO2 and decreases in mean A-aDO2 and MAP, whereas in noninfected animals, the effects of NO were significantly different and opposite (all P < 0.05), such that NO produced progressively greater decreases in mean PaO2 and increases in mean A-aDO2 and MAP (Figs. 3 and 4). In infected animals on days 1 and 2 alike, with increasing FIO2 doses (0.08-0.85), NO produced no significant (P = NS) changes in mean HR, whereas in noninfected animals, the response was significantly different (all P < 0.05) such that NO produced progressive increases in HR.

In infected and noninfected animals alike on days 1 and 2, inhaled NO at FIO2 doses of 0.08 and 0.21, but not at FIO2 doses of 0.50 and 0.85, significantly decreased MPAP (P = 0.05; Fig. 5). In addition, at FIO2 <0.21, in infected animals and noninfected animals alike, inhaled NO significantly decreased mean Ppao and PVRI (all P < 0.001). At FIO2 0.85, in infected animals and noninfected animals alike, inhaled NO significantly increased mean arterial lactate (P = 0.03).

On days 1 and 2, in infected and noninfected animals alike, at all FIO2 doses studied, NO significantly decreased mean SVRI (-1.13 ± 0.46 dyn · s · cm-5 · kg-1; P < 0.014). Finally, on days 1 and 2, there were no significant effects of NO at any FIO2 studied on methemoglobin levels (P = NS; data not shown).

                              
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  		Table 4.   Systemic hemodynamics and left ventricular variables measured on days 1 and 2 after intrabronchial inoculation during inhalation of 4 FIO2 levels with and without NO


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  		Fig. 2.   Values (means ± SE) of arterial PO2 (PaO2; A) and alvolar-arterial O2 gradient (A-aDO2; B) during inhalation of 4 different fractions of inspired O2 (FIO2) doses (0.08, 0.21, 0.50, and 0.85) in absence of NO. Data are average of values measured 24 and 48 h after intrabronchial inoculation with E. coli (infected animals; solid bars) or saline (noninfected controls; open bars). Overall, compared with noninfected controls, infected animals had lower PaO2 (P = 0.0014) and higher A-aDO2 (P = 0.0001).


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  		Fig. 3.   Increases or decreases (Delta ; means ± SE) in PaO2 (A) and A-aDO2 (B) produced by inhaled NO [80 parts/million (ppm)] with 4 different FIO2 doses (0.08, 0.21, 0.50, and 0.85) after intrabronchial inoculation with E. coli (infected animals; solid bars) or saline (noninfected controls; open bars). In infected animals, with increasing FIO2 (0.08-0.85), NO produced progressively greater increases in mean PaO2 and decreases in mean A-aDO2, whereas, in noninfected animals, the effects of NO were significantly different and opposite (all P < 0.05) such that NO produced progressively greater decreases in mean PaO2 and increases in mean A-aDO2.


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  		Fig. 4.   Increases or decreases (means ± SE) in mean arterial pressure (Delta MAP; A), heart rate (Delta HR; B), and arterial lactate (Delta Lactate; C) produced by inhaled NO (80 ppm) with 4 different FIO2 doses (0.08, 0.21, 0.50, and 0.85) after intrabronchial inoculation with E. coli (infected animals; solid bars) or saline (noninfected controls; open bars). In infected animals, with increasing FIO2 doses (0.08-0.85), NO produced progressively greater decreases in MAP, whereas in noninfected animals, the effects of NO were significantly different and opposite (all P < 0.05), producing progressively greater increases in MAP. In infected animals, with increasing FIO2 doses (0.08 to 0.85), NO produced no significant (P = NS) changes on mean HR, whereas in noninfected animals, the response was significantly different (all P < 0.05) such that NO produced progressive increases in HR. At FIO2 0.85, in infected animals and noninfected animals alike, inhaled NO significantly increased mean arterial lactate (P = 0.03).


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  		Fig. 5.   Increases or decreases (means ± SE) in mean pulmonary arterial pressure (Delta MPAP; A), pressure at pulmonary airway opening (Delta Ppao; B), and pulmonary vascular resistance index (Delta PVRI; C) produced by inhaled NO (80 ppm) with 4 different FIO2 doses (0.08, 0.21, 0.50, and 0.85) after intrabronchial inoculation with E. coli (infected animals; solid bars) or saline (noninfected controls; open bars). In infected and noninfected animals, inhaled NO at FIO2 doses of 0.08 and 0.21 but not at FIO2 doses of 0.50 and 0.85, significantly decreased MPAP (P = 0.05). At FIO2 <0.21, in infected animals and noninfected animals alike, inhaled NO significantly decreased mean Ppao and PVRI (all P < 0.001).

Endotoxemia, microbiology, radiology, blood counts, and routine chemistry. Infected animals vs. noninfected animals had higher mean endotoxin levels at 6 h (5 ± 3 vs. 0.05 ± 0.03 EU/ml) and at 24 h (4 ± 2 vs. 0 EU/ml) (P = 0.008). Infected animals vs. noninfected animals also had greater numbers of E. coli in sputum cultures at 24 h (0.44 ± 0.12 vs. 0.10 ± 0.10 colonies per plate) and at 48 h (0.32 ± 0.10 vs. 0.10 ± 0.10 colonies per plate; both P = 0.02). Infected animals had significantly more severe (P < 0.05) pulmonary infiltration in the right cranial, right caudal, right middle, and left caudal lobes on chest radiograph (data not shown). In addition, on chest radiograph, animals with diffuse pneumonia had more severe infiltration in the left cranial lobe compared with lobar pneumonia animals and noninfected animals (P < 0.05). For the first 24 h, infected animals had lower white blood cell numbers and, for the first 48 h, had lower platelet counts compared with noninfected animals (both P = 0.0001; data not shown). In addition, after intrabronchial inoculation, infected animals compared with noninfected animals had greater increases in triglycerides, bilirubin, hemoglobin, and hematocrit as well as greater decreases in albumin and calcium (all P < 0.05, data not shown).

Recovery. When infected and noninfected survivors were compared 10 days after intrabronchial inoculation, the effects of varying FIO2 dose and inhaling NO on all pulmonary and systemic hemodynamic variables were similar to those at baseline, except that on day 10, infected animals had lower lactate levels at all FIO2 doses compared with noninfected animals (data not shown, P = 0.007).

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Intrabronchial E. coli challenge in canines produced pulmonary infiltrates, purulent sputum, hypoxemia, pulmonary arterial hypertension, cardiovascular dysfunction, and death. In noninfected and infected animals with increasing FIO2 doses, inhaled NO modestly altered oxygenation. In animals with pneumonia, inhaled NO progressively decreased A-aDO2 and increased PO2 with increasing FIO2 doses, whereas in noninfected animals, inhaled NO increased A-aDO2 and decreased PaO2. Under hypoxic and normoxic conditions in both noninfected and infected animals, inhaled NO decreased pulmonary arterial pressures, but had no significant effect on increases in pulmonary arterial pressures related to sepsis alone. Lastly, inhaled 80 ppm NO had modest effects on systemic pressures, HR, and arterial lactate levels. When noninfected and infected animals were compared, these effects were significantly different and opposite.

The NO-related changes in oxygenation that were seen in canines with gram-negative pneumonia are consistent with clinical studies of acute respiratory distress syndrome, showing that inhaled NO may improve oxygenation without observable changes in pulmonary arterial pressures (15). It has been postulated that the increased oxygenation with NO in this setting results from redistribution of blood flow rather than from reductions in global pulmonary pressures with enhancement of total pulmonary perfusion. The small improvements we observed in oxygenation with NO were unexpectedly dependent on a high FIO2 dose. These changes may reflect a direct effect of high FIO2 doses on the measurement of PaO2 and A-aDO2. It is also possible, however, that the effects of inhaled NO are augmented by increasing O2 concentration (10). In vitro studies evaluating alterations in the activity of guanylate cyclase, the primary receptor for NO, suggest a mechanism by which O2 could produce this effect. In these studies, carbon monoxide and hydrogen peroxide, both of which could increase with hyperoxia, facilitate the activity of guanylate cyclase (34, 57). Therefore, during hyperoxia, the effects of NO on guanylate cyclase might be augmented by either of these molecules. Many studies in humans and animals with lung injury report improvements in oxygenation with NO in subjects administered increased FIO2 doses (8, 15, 37, 41, 43, 50, 53, 54, 60, 61). Our data suggest that these changes may be less pronounced if the effects of NO on oxygenation were examined at lower FIO2 doses. Of note, our findings suggest that exogenous NO may minimally but significantly antagonize mechanisms maintaining optimal ventilation and perfusion matching in the normal lung.

Gram-negative pneumonia with sepsis, which our model was designed to simulate, is associated with increases in both PVR resistance and pulmonary arterial pressures. Mechanisms for these increases may be related to endothelial injury, with a subsequent fall in endogenous vasodilators such as NO, or to a reduction in the responsiveness of the endothelium to such media-tors. In endotoxemic dogs without pneumonia, treatment with NO synthase inhibitors demonstrated that NO was critically important in maintaining a low level of pulmonary vascular tone (6). Conversely, in dogs with pneumonia, administration of inhaled NO in a dose sufficient to reduce increases in pulmonary pressures related to hypoxia had no significant effect on increases in pulmonary pressures related to gram-negative pneumonia. These findings suggest that insufficient production of or responsiveness to NO is not the sole or predominant mechanism for the increases in pulmonary artery pressures observed during pneumonia. Other mechanisms, such as obstruction to blood flow by intravascular cellular elements or excessive production of endogenous vasoconstrictors may also play important roles in some types of lung injury (33).

Our findings differ from other models of lung injury such as challenges with endotoxin, oleic acid, thromboxane analogs, and saline lavage in which inhaled NO reduced pulmonary arterial hypertension (12, 14, 22, 37, 38, 41, 51, 53, 60, 61). It is important to note, however, that our model and study design were directed at assessing the effects of NO during the later stages of lung injury associated with intrapulmonary infection. In contrast to our model, the effects of NO in other models cited were assessed immediately or shortly after administration of challenge. Insufficient production of or unresponsiveness to NO may have a role in early pulmonary arterial hypertension with these types of acute lung injury, but not necessarily over the full time course of all forms of lung injury.

The dose of inhaled NO (80 ppm) used in this study was based in part on dose-response studies we had performed in normal animals breathing hypoxic O2 concentrations. These studies were consistent with other published studies showing that this dose of inhaled NO (80 ppm) would decrease pulmonary arterial pressures and PVR more than lower doses would (10, 53, 54, 57). It is possible, however, that with lung injury and hypoxemia related to pneumonia, lower doses of inhaled NO may have produced a more selective effect in well-ventilated lung regions and produced greater improvements in arterial oxygenation (13).

It is also important to note that our model evaluated the effects of inhaled NO in spontaneously breathing canines. Mechanical ventilation in such a model requires the use of additional drugs (e.g., sedatives and paralytics) that may have confounded the effects of NO in the setting of gram-negative pneumonia. However, many patients with gram-negative pneumonia and severe hypoxemia are supported with positive pressure mechanical ventilation and positive end-expiratory pressure. Application of inhaled NO with this mode of ventilation might have augmented its effects and resulted in greater increases in arterial oxygenation in our pneumonia model (41, 43).

Both infected and noninfected animals during inhalation of hypoxic gas mixtures had significant increases in pulmonary pressures that were reversible with NO. In contrast, other studies have shown that hypoxic pulmonary vasoconstriction is blunted or absent after intravenous endotoxin (19, 30, 59) or bacteria challenge (17, 18, 24, 33). These disparate results may relate to type of challenge (intrabronchial vs. intravenous), or the fact that measurements were made either earlier (within hours, Refs. 18 and 59) or later (7-10 days; Refs. 17 and 33) than those in our study. Nonetheless, our data suggest that hypoxic pulmonary vasoconstriction may be preserved in some cases of bacterial pneumonia, even when abnormalities of systemic hemodynamics are pronounced and/or death occurs.

During pneumonia, inhaled NO with increasing FIO2 doses modestly decreased blood pressure, but in noninfected animals it increased blood pressure and HR. Inhaled NO increased serum lactate in both noninfected and infected animals. Similarly, in all animals, inhaled NO also modestly decreased SVRI. Adverse effects of NO on blood pressure have been noted in a porcine model of oleic acid-induced lung injury (53). These data suggest that under some conditions inhaled NO may be able to alter systemic hemodynamics. In vitro and in vivo studies have shown that a biologically active form of NO can circulate in plasma while reversibly bound to serum proteins (S-nitrosylated protein) like albumin (16, 55, 56). If inhaled NO can enter this circulating pool of protein-bound NO, it might cause changes in systemic vasomotor tone (16, 55). Alterations of this mechanism by sepsis or by changing O2 concentrations may explain the differential effects we observed of NO with increasing FIO2 in infected and noninfected animals. The effect of inhaled NO on systemic hemodynamics, however, may also be dose dependent, as suggested by others (53). Therefore, reducing its concentration may limit its potential adverse hemodynamic effects.

In summary, intrabronchial E. coli inoculation in dogs resulted in pulmonary infiltration, purulent sputum, hypoxemia, changes in pulmonary and systemic hemodynamics, and death. In this model of pneumonia, inhaled NO reversed hypoxic pulmonary vasoconstriction, but had only modest effects on arterial oxygenation and did not affect increases in PVR related to pneumonia. Extrapolated clinically, these findings suggest that inhaled NO may have a limited therapeutic role in acute lung injury associated with gram-negative bacterial pneumonia. Further studies to evaluate the effects of lowered concentrations of inhaled NO in combination with mechanical ventilation and positive end-expiratory pressure may still be necessary to define a role for inhaled NO during gram-negative pneumonia.

    ACKNOWLEDGEMENTS

We thank Allen T. Hilton and Stephen Richmond for providing technical support during the study and Dr. Victoria Hampshire for giving veterinary care.

    FOOTNOTES

Preliminary data have been published in abstract form in Am. Rev. Respir. Dis. 147: 720, 1993; Crit. Care Med. 21, Suppl.: S210, 1993; and Am. J. Respir. Crit. Care Med. 149: A813, 1994.

Address for reprint requests: P. Q. Eichacker, Critical Care Medicine Dept., National Institutes of Health, Bldg. 10, Rm. 7D43, 9000 Rockville Pike, Bethesda, MD 20892.

Received 28 January 1997; accepted in final form 24 September 1997.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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