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© 1999 International Anesthesia Research Society
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Abstract |
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Inhaled nitric oxide (NO) has been used to treat pulmonary hypertension. Experimental studies have suggested therapeutic effects of NO after pulmonary microembolism. We evaluated the protective effects of NO in dogs during a pulmonary air embolism (PAE). NO (3 ppm) was administered to six anesthetized mongrel dogs (NO group) but not to the seven dogs in the control group. After 20 min, each dog received a venous air injection of 2.5 mL/kg. Hemodynamic evaluation was performed, and blood samples were drawn for blood gas analysis before and after NO inhalation and 5–60 min after the PAE. Both arterial blood pressure and cardiac output were decreased in the control group for >15 min after PAE, whereas NO-treated animals showed only transient hypotension. NO attenuated the pulmonary hypertension after PAE, as demonstrated by small (P < 0.05) increases in pulmonary artery pressure and pulmonary vascular resistance index in NO-treated animals (90% and 135%, respectively) compared with the controls (196% and 282%, respectively). These hemodynamic effects of NO were associated with higher mixed venous O2 tensions and saturations in the NO group compared with the controls. We conclude that small-dose NO (3 ppm) attenuated the hemodynamic changes induced by PAE in dogs. This protective effect of NO on hemodynamics is not accompanied by improvement in pulmonary oxygenation in this setting.
Implications: In this study, we evaluated the protective effects of inhaled nitric oxide in a pulmonary air embolism setting. Nitric oxide attenuated the hemodynamic changes induced by pulmonary air embolism without improving pulmonary oxygenation.
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Introduction |
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Pulmonary air embolism (PAE) is a serious complication that may occur during neurosurgery and other therapeutic interventions. A mortality rate of 73% for the 93 cases reported in the literature (1) indicates that the early detection and treatment of this condition is of utmost importance. Recent studies have focused on the sensitivity of the monitors used to detect PAE and on the effectiveness of certain therapeutic approaches for treating or preventing the occurrence of this condition (2–4). Although an early diagnosis may limit the extent of this complication, therapy may be ineffective in acute massive PAE. Because certain endogenous mediators may be released during PAE and can contribute to the pulmonary hypertension (5), pharmacological blockade of the pulmonary vasoconstriction has been suggested as an approach to PAE therapy (3).
Inhaled nitric oxide (NO) is used to treat pulmonary hypertension and in experimental models of lung injury (6–8). The selective pulmonary vasodilation caused by NO is attributable to its rapid diffusion across the capillary membrane and to its inactivation by hemoglobin in the pulmonary vascular lumen (9). These observations have suggested the possibility of administering NO to patients suffering from lung diseases characterized by pulmonary hypertension and hypoxemia, such as acute respiratory distress syndrome or pulmonary hypertension in newborns, and in patients undergoing cardiothoracic surgery (10–13). Even very low concentrations (60–250 ppb) of inhaled NO may have beneficial effects in some patients with acute respiratory distress syndrome (12). NO-induced redistribution of blood flow from nonventilated to ventilated areas of the lung decreases intrapulmonary shunting and improves arterial oxygenation (10).
Some experimental studies (6–8) have demonstrated that inhaled NO can have positive effects on hemodynamics after acute pulmonary microembolism, which thus suggests possible useful therapeutic effects of NO in this setting. In addition, one case report has described a patient with acute pulmonary embolism whose hypoxemia and pulmonary hypertension were improved by NO (14). In contrast, inhaled NO worsened the gas exchange in another patient with massive embolism (15).
Because the effects of inhaled NO during PAE have not previously been investigated, we examined the protective effects of NO inhalation in dogs subjected to an acute massive PAE.
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Methods |
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All procedures were approved by our animal care committee. The animals were handled according to the guiding principles published by the National Institutes of Health and the Council of the American Physiology Society. Thirteen mongrel dogs (11.7 ± 0.7 kg) of either sex were anesthetized with sodium pentobarbital (30 mg/kg IV) and tracheally intubated, and their lungs were mechanically ventilated with room air using a volume-cycled respirator. The tidal volume was 15 mL/kg, and the respiratory rate was adjusted to maintain a baseline physiologic arterial carbon dioxide tension. Anesthesia was maintained with an infusion of pentobarbital (6–10 mg · kg-1 · h-1). Fluid-filled catheters were placed into the left femoral artery and right femoral vein for mean arterial pressure (MAP) monitoring via a pressure transducer and fluid administration, respectively. A 7F balloon-tipped Swan-Ganz thermodilution catheter was placed into the pulmonary artery via the left femoral vein, and its correct location was confirmed by detection of the typical pressure wave of this artery. The catheter was connected to a pressure transducer to allow the monitoring of mean pulmonary artery pressure (MPAP), central venous pressure (CVP), and pulmonary capillary wedge pressure. The transducers were zeroed at the level of the right heart and recalibrated before each set of measurements. Cardiac output was determined in triplicate by injecting 10 mL of saline, and the results recorded on a computerized system. The heart rate (HR) was measured using a surface electrocardiogram (lead I). Blood samples were drawn from the pulmonary artery and the femoral artery at predetermined times for blood gas analysis. PaO2, SaO2, PaCO2, mixed venous oxygen tension (PvO2), mixed venous O2 saturation (SvO2), arterial blood pH, and hemoglobin were determined using a blood gas analyzer (Stat Profile 5 Analyzer; Biomedical, Waltham, MA).
After at least 20 min of stabilization, a baseline (BL) hemodynamic evaluation was performed, and continuous inhalation of NO (3 ppm) was initiated in the NO group (n = 6). NO was not administered in the control group (n = 7). The hemodynamic data were again recorded 10 (B10) and 20 (B20) min after BL. Thereafter, each dog received 2.5 mL of air/kg body weight at a rate of 5 mL/s into the right femoral vein, followed by a 10-mL saline flush. Hemodynamic variables were measured 5 (5E), 10 (10E), 15 (15E), 30 (30E), and 60 min (60E) after the air embolism. The cardiac index (CI), systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI) were calculated by using standard formulae. Arterial and mixed venous blood samples were drawn at BL, B20, 5E, 10E, 15E, 30E, and 60E.
NO was obtained as a mixture of 93 ppm NO in pure nitrogen (Oxygen, São Paulo, Brazil). Using a special flowmeter, NO was administered into the inspiratory limb of the respiratory circuit close to the endotracheal tube. The flow of NO was adjusted to obtain a constant concentration of 3 ppm. Inspiratory and expiratory concentrations of NO and nitrogen dioxide (NO2) were analyzed continuously at the proximal end of the endotracheal tube using a Bedfont electrochemical NO/NO2 analyzer (Bedfont Scientific Ltd., Kent, UK). NO2 concentrations remained <0.3 ppm throughout the experiments. This method of NO administration and monitoring does, however, present some limitations. Because the NO flow into the inspiratory limb of the respiratory circuit was continuous, the true delivered concentrations may have reached levels >3 ppm because of the intermittent flow volume ventilation.
All the results are given as means ± SEM. Analysis of changes from BL values and comparisons of the data between groups were performed using one-way and two-way analysis of variance for repeated measures, respectively, followed by the Dunnett multiple comparisons test. P < 0.05 was considered the minimal level of statistical significance.
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Results |
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Of the seven dogs in the control group, three died before 5E, whereas only one of the six dogs in the NO group died (P = 0.6 by Fisher's exact test).
PAE clearly decreased MAP in the control group for >15 min after PAE, whereas NO-treated animals showed only transient hypotension seen only at 5E (Fig. 1). MPAP and PVRI increased to higher levels in the control group at 5E and 10E compared with the NO group. These variables returned to baseline 15–60 min after PAE in both groups. CI was decreased for >15 min after PAE in the control group, whereas CI was unchanged in NO-treated animals, with significantly higher values than the controls at 10E, 15E, and 30E (Fig. 2). HR, CVP, and SVRI presented comparable changes in both groups during the experiments. After 20 min of NO inhalation, there was no significant difference in any hemodynamic variable in either group of animals (Figs. 1 and 2).
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) and in the control group (
). Values are mean ± SEM. *P < 0.05 versus BL. #P < 0.05 NO group versus control group.
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No hemodilution was evident from the repetitive saline injections, as revealed by the sustained hemoglobin levels throughout the study period. NO inhalation did not change any of these variables. PaO2 and SaO2 remained decreased for at least 15 min after PAE in the control group, whereas NO-treated animals showed lower values only at 5E and 10E (Table 1). The PvO2 and SvO2 levels were similar to the corresponding arterial values, except that the PvO2 and SvO2 values were significantly higher in the NO group than in the control group 15–60 min after PAE.
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Discussion |
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This is the first study to evaluate the possible benefits of inhaled NO in a PAE setting. Our results suggest that NO can attenuate the hemodynamic changes in a PAE model.
Experimentally, increasing amounts of air cause proportionally greater hemodynamic changes and gas exchange impairments (16). When death occurs, it is usually as a result of cardiac failure and shock caused by massive obstruction of the right ventricle and the pulmonary vascular bed (4,17,18). Ischemia may supervene and be exacerbated by the decrease in MAP and CI (19). In our study, the responses to PAE in the control group were similar to those reported by others (2,3,17,20,21). The explanation for the increase in MPAP is more complicated because the increase in PVRI is not caused solely by the obstruction of vessels (17). General arteriolar constriction has been demonstrated and has been explained either by a neurogenic reflex or by the release of vasoactive factors (5). In the present study, inhaled NO attenuated the pulmonary hypertension after PAE, as demonstrated by the lower increases in MPAP and PVRI in NO-treated animals (90% and 135%, respectively) compared with the controls (196% and 282%, respectively).
During PAE, air bubbles are propelled into the pulmonary circulation and are broken down into smaller bubbles that obstruct small pulmonary vessels (21,22). Their disappearance from the pulmonary vascular bed is attributed mainly to gas diffusion into the alveoli (4,23). Histological and functional data indicate that air emboli lodge principally in the arterial segments of the pulmonary vasculature and are eliminated exclusively from that site, except for occasional, very small (<5 µm) bubbles that flow into the capillary network (21,23,24). Thus, a possible explanation for our findings is that the PAE-induced increases in MPAP and PVRI were attenuated by the direct effects of inhaled NO in the pulmonary arterioles, which were obstructed by air bubbles. In accordance with this hypothesis, inhaled NO has been demonstrated to affect primarily the arterial component of the pulmonary circulation (25), although it can cause vasodilation in any part of the pulmonary circulation (7,26).
Similar to our findings, previous studies have shown that NO significantly improves hemodynamic conditions in animal models of pulmonary embolism (6,8). Although the pathophysiological mechanisms associated with microsphere embolism may differ from those associated with PAE, there may be some similarities between them, mainly through the involvement of platelets and possible vasoconstrictor products in the pulmonary hypertension seen after embolism. This suggestion is supported by the observation that platelets and fibrin may accumulate around air bubbles (4,27) after air embolism. Thus, in addition to its direct relaxing vascular properties in lowering PVRI, inhaled NO may have attenuated platelet aggregation around air bubbles. In a setting of PAE, we found beneficial effects of inhaled NO (3 ppm) that were very similar to those previously described after the inhalation of NO (40 ppm) during microsphere macroembolism in animals (6–8)—namely, a significant decrease in MPAP and PVRI with no improvement in PaO2. Because the potential toxicity of NO increases with the dose administered and because NO may regulate its own synthesis by product inhibition (28), we chose a low NO concentration (3 ppm) for our experiment. Furthermore, previous studies have reported clinical effects of NO even at very low concentrations (13,29). Two previous studies (2,3) reported that the greatest changes in hemodynamic variables occur 5 min after an identical IV bolus of air; because the effects of inhaled NO take approximately 3 min to occur (29), we chose to administer inhaled NO before the induction of PAE to be sure that NO would act during the PAE challenge.
Inhaled NO may have affected the redistribution of pulmonary blood flow after PAE, thereby influencing blood oxygenation. After PAE, blood perfusion is shifted toward the dependent areas of the lung (30). Because PAE decreased the SvO2 in control but not in NO-treated animals, and because there were no differences in SaO2 between the two groups, it seems reasonable that pulmonary blood oxygenation was more effective in the controls than in the NO-treated animals. Inhaled NO may have diverted the blood flow to nonobstructed pulmonary vessels, thereby decreasing the ventilation-perfusion ratio in these pulmonary areas.
In conclusion, we found that inhalation of 3 ppm NO can attenuate hemodynamic changes after PAE in dogs. This effect was associated with a lack of improvement in pulmonary oxygenation by inhaled NO in this setting.
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Footnotes |
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JET-S received a fellowship from FAPESEP, São Paulo, Brazil.
Abstract presented at the 72nd meeting of the International Anesthesia Research Society Clinical and Scientific Congress, Orlando, FL.
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