JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (30) Citing Articles via Google Scholar Google Scholar Articles by Tanus-Santos, J. E. Articles by de Nucci, G. Search for Related Content PubMed PubMed Citation Articles by Tanus-Santos, J. E. Articles by de Nucci, G.

---

CARDIOVASCULAR ANESTHESIA

Small-Dose Inhaled Nitric Oxide Attenuates Hemodynamic Changes After Pulmonary Air Embolism in Dogs

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, São Paulo, Brazil

Address correspondence and reprint requests to Jose Eduardo Tanus-Santos, MD, PhD, Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, PO Box 6111, 13081-970 Campinas, São Paulo, Brazil. Address e-mail to tanus{at}turing.unicamp.br

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
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.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
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.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
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.

	Results

Top Abstract Introduction Methods Results Discussion References

 
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).

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), heart rate (HR), and central venous pressure (CVP) at baseline (BL); after 10 (B10) and 20 min of NO inhalation (B20); and 5 (5E), 10 (10E), 15 (15E), 30 (30E), and 60 (60E) min after pulmonary air embolism in the NO group () and in the control group (). Values are mean ± SEM. *P < 0.05 versus BL. #P < 0.05 NO group versus control group.

View larger version (19K): [in this window] [in a new window]   Figure 2. Cardiac index (CI), pulmonary vascular resistance index (PVRI), and systemic vascular resistance index (SVRI) at baseline (BL); after 10 (B10) and 20 min of NO inhalation (B20); and 5 (5E), 10 (10E), 15 (15E), 30 (30E), and 60 (60E) min after pulmonary air embolism in the NO group () and in the control group (). Values are mean ± SEM. *P < 0.05 versus BL. #P < 0.05 NO group versus control group.

	Discussion

Top Abstract Introduction Methods Results Discussion References

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.

	Footnotes

 
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.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Ericsson JA, Gottlieb JD, Sweet RB. Closed chest cardiac massage in the treatment of air embolism. Engl J Med 1964;270:1353–4.
2. Mehlhorn U, Burke EJ, Butler BD, et al. Body position does not affect the hemodynamic response to venous air embolism in dogs. Anesth Analg 1994;79:734–9.[Abstract/Free Full Text]
3. Geissler HJ, Allen SJ, Mehlhorn U, et al. Effect of body repositioning after venous air embolism : an echocardiographic study. Anesthesiology 1997;86:710–7.[Web of Science][Medline]
4. Wilson MM, Curley FJ. Gas embolism. Part I. Venous gas emboli. J Intensive Care Med 1996;11:182–204.
5. Barnes PJ, Liu SF. Regulation of pulmonary vascular tone. Pharmacol Rev 1995;47:87–131.[Web of Science][Medline]
6. Bottiger BW, Motsch J, Dorsam J, et al. Inhaled nitric oxide selectively decreases pulmonary artery pressure and pulmonary vascular resistance following acute massive pulmonary microembolism in piglets. Chest 1996;110:1041–7.[Abstract/Free Full Text]
7. Mélot C, Vermuelen F, Maggiorini M, et al. Site of pulmonary vasodilation by inhaled nitric oxide in microembolic lung injury. Respir Crit Care Med 1997;156:75–85.[Abstract/Free Full Text]
8. Gries A, Böttiger BW, Dörsam J, et al. Inhaled nitric oxide inhibits platelet aggregation after pulmonary embolism in pigs. Anesthesiology 1997;86:387–93.[Web of Science][Medline]
9. Rich GF, Roos CM, Anderson SM, et al. Inhaled nitric oxide : dose response and the effect of blood in the isolated rat lung. J Appl Physiol 1993;75:1278–84.[Abstract/Free Full Text]
10. Rossaint R, Falke KJ, Lopez F, et al. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328:399–405.[Abstract/Free Full Text]
11. Rich GF, Lowson SM, Johns RA, et al. Inhaled nitric oxide selectively decreases pulmonary vascular resistance without impairing oxygenation during one-lung ventilation in patients undergoing cardiac surgery. Anesthesiology 1994;80:57–62.[Web of Science][Medline]
12. Zapol WM, Falke KJ, Roissant R. Inhaled nitric oxide for the adult respiratory distress syndrome. J Med 1993;329:206–7.
13. Lönnqvist PA. Inhaled nitric oxide in newborn and paediatric patients with pulmonary hypertension and moderate to severe impaired oxygenation : effects of doses of 3–100 parts per million. Care Med 1997;23:773–9.
14. Estagnasié P, Le Bourdellès G, Mier L, et al. Use of inhaled nitric oxide to treat reverse flow through a patent foramen ovale during pulmonary embolism. Ann Intern Med 1994;120:757–9.[Free Full Text]
15. Tulleken JE, Zijlstra JG, Evers K, Werf TJ. Oxygen desaturation after treatment with inhaled nitric oxide for obstructive shock due to massive pulmonary embolism. Chest 1997;112:296–7.[Free Full Text]
16. Berglund E, Josephson S. Pulmonary air embolization in the dog : hemodynamic changes on repeated embolizations. Invest 1970;26:97–103.
17. Adornato DC, Gildenberg PL, Ferrario CM, et al. Pathophysiology of intravenous air embolism in dogs. Anesthesiology 1978;49:120–7.[Web of Science][Medline]
18. Marshall BM. Air embolus in neurosurgical anaesthesia : its diagnosis and treatment. Can Anaesth Soc J 1965;12:255–61.
19. Ghignone M, Girling L, Prewitt RM. Volume expansion versus norepinephrine in treatment of a low cardiac output complicating an acute increase in right ventricular afterload in dogs. Anesthesiology 1984;60:132–5.[Web of Science][Medline]
20. Sergysels R, Jasper N, Delaunois L, et al. Effect of ventilation with different gas mixtures on experimental lung air embolism. Respir Physiol 1978;34:329–43.[Web of Science][Medline]
21. Josephson S. Pulmonary air embolization in the dog : evidence and location of pulmonary vasoconstriction. Lab Invest 1970;26:113–23.
22. Josephson S, Ovenfors CO. Experimental pulmonary air embolism : angiographic study in dogs. Invest Radiol 1970;5:220–31.[Web of Science][Medline]
23. Presson RG, Kirk KR, Haselby KA, et al. Fate of air emboli in the pulmonary circulation. J Appl Physiol 1989;67:1898–902.[Abstract/Free Full Text]
24. Hall JE, Hofman WF, Ehrhart IC. Venous occlusion pressure and vascular permeability in the lung after air embolization. J Appl Physiol 1988;65:34–40.[Abstract/Free Full Text]
25. Rimar S, Gillis CN. Site of vasodilation by nitric oxide in the perfused lung. Physiol 1995;78:1745–9.
26. Lindeborg DM, Kavanagh BP, Meurs KV, Pearl RG. Inhaled nitric oxide does not alter the longitudinal distribution of pulmonary vascular resistance. J Appl Physiol 1995;78:341–8.[Abstract/Free Full Text]
27. Warren BA, Philp RB, Inwood MJ. The ultrastructural morphology of air embolism : platelet adhesion to the interface and endothelial damage. Exp Pathol 1973;54:163–72.
28. Rengasamy A, Johns RA. Regulation of nitric oxide synthesis by nitric oxide. Mol Pharmacol 1993;44:124–8.[Abstract]
29. Frostell C, Fratacci MD, Wain JC, et al. Inhaled nitric oxide : a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038–47.[Abstract/Free Full Text]
30. Chang HK, Delaunois L, Boileau R, Martin RR. Redistribution of pulmonary blood flow during experimental air embolism. J Appl Physiol 1981;51:211–7.[Abstract/Free Full Text]

This article has been cited by other articles:

				D. C. Souza-Costa, T. Zerbini, A. C. Palei, R. F. Gerlach, and J. E. Tanus-Santos L-arginine Attenuates Acute Pulmonary Embolism-Induced Increases in Lung Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 Chest, November 1, 2005; 128(5): 3705 - 3710. [Abstract] [Full Text] [PDF]

				C. A. Dias-Junior, D. C. Souza-Costa, T. Zerbini, J. B. T. da Rocha, R. F. Gerlach, and J. E. Tanus-Santos The Effect of Sildenafil on Pulmonary Embolism-Induced Oxidative Stress and Pulmonary Hypertension Anesth. Analg., July 1, 2005; 101(1): 115 - 120. [Abstract] [Full Text] [PDF]

				C. A. Dias-Junior, A. Martineau, P. Couture, and A. Denault Pharmacologic Therapy of Acute Pulmonary Embolism * Response Anesth. Analg., January 1, 2004; 98(1): 266 - 267. [Full Text] [PDF]

				J. E. Tanus-Santos Pharmacologic Therapy of Pulmonary Vasoconstriction in Acute Pulmonary Embolism Anesth. Analg., January 1, 2004; 98(1): 273 - 273. [Full Text] [PDF]

				G. Bushman Essentials of Nitric Oxide for the Pediatric (Cardiac) Anesthesiologist Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2001; 5(1): 79 - 90. [Abstract] [PDF]

				J. E. Tanus-Santos, H. Moreno Jr, K. Janata, I. Kurkciyan, and F. Sterz Treatment of Massive Pulmonary Embolism Arch Intern Med, February 12, 2001; 161(3): 481 - 482. [Full Text] [PDF]

				Y. M. Smulders Pathophysiology and treatment of haemodynamic instability in acute pulmonary embolism: the pivotal role of pulmonary vasoconstriction Cardiovasc Res, October 1, 2000; 48(1): 23 - 33. [Abstract] [Full Text] [PDF]

				J. E. Tanus-Santos, W. M. Gordo, A. Udelsmann, M. H. Cittadino, and H. Moreno Jr. Nonselective Endothelin-Receptor Antagonism Attenuates Hemodynamic Changes After Massive Pulmonary Air Embolism in Dogs Chest, July 1, 2000; 118(1): 175 - 179. [Abstract] [Full Text] [PDF]

				J. E. Tanus-Santos, W. M. Gordo, A. Udelsmann, and H. M. Junior The Hemodynamic Effects of Endothelin Receptor Antagonism During a Venous Air Infusion in Dogs Anesth. Analg., January 1, 2000; 90(1): 102 - 102. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (30) Citing Articles via Google Scholar Google Scholar Articles by Tanus-Santos, J. E. Articles by de Nucci, G. Search for Related Content PubMed PubMed Citation Articles by Tanus-Santos, J. E. Articles by de Nucci, G.

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999