Ann Thorac Surg 2000;69:224-227
© 2000 The Society of Thoracic Surgeons
Original Articles
Sodium nitroprusside mitigates oleic acid-induced acute lung injury
Jeffrey S. Young, MDa,
Constanze S. Rayhrer, MDb,
Timothy D. Edmisten, MDb,
Gerald A. Cephas, MDa,
Curtis G. Tribble, MDa,
Irving L. Kron, MDa
a Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA
b Roanoke Memorial Hospital, Roanoke, Virginia, USA
Address reprint requests to Dr Young, Trauma Center, Department of Surgery, University of Virginia Health System, PO Box 10005, Charlottesville, VA 22906-0005
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Abstract
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Background. Acute lung injury (ALI) is associated with pulmonary hypertension, intrapulmonary shunting, and increased microvascular permeability, leading to altered oxygenation capacity. Oleic acid (OA) creates a significant ALI that physiologically mimics human adult respiratory distress syndrome (ARDS). It has been hypothesized that pulmonary vasodilatation may improve ALI. Studies in our laboratory using this model and nitric oxide (NO) have shown that NO inhalation is detrimental and worsens the effects of OA. We studied the effect of pretreatment with a potent vasodilator, sodium nitroprusside (SNP), on ALI induced by OA in an isolated lung model. We hypothesized that pretreatment with SNP will worsen pulmonary hypertension and oxygenation in OA-induced ALI, similar to the effects seen with inhaled NO in this model.
Methods. Rabbit heart lung blocks were isolated, flushed in vivo, harvested, immediately perfused with whole blood, and ventilated with 50% oxygen. Pulmonary artery pressure was determined every 15 seconds for 90 minutes of perfusion. Oxygenation was determined by blood gas analysis of pulmonary venous effluent at 0, 20, 40, 60, and 90 minutes after initiation of OA infusion. Four groups were studied: saline control (SC), oleic acid control (OAC; 20-minute infusion of 50% OA/ethanol into pulmonary circulation), SNP control (NPC; 10 µg/kg/min SNP infused without subsequent OA infusion), and SNP treatment (NPRx); 10 µg/kg/min SNP infused before OA/ethanol. Pulmonary artery pressure (PAP), oxygenation (arterio-venous oxygen difference [AVO2], compliance (CPL), and wet/dry lung weight were determined.
Results. No significant differences were found between the NPRx group and SC. Pretreatment with SNP eliminated the detrimental effects of OA infusion.
Conclusions. Contrary to our hypothesis, pretreatment with SNP eliminates the decrease in oxygenation and increase in lung weight, and ameliorates pulmonary hypertension in our isolated lung model of OA-induced ALI.
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Introduction
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Adult respiratory distress syndrome (ARDS) is a significant clinical problem in critical care medicine. Oleic acid (OA) infusion provides an experimental model that closely mimics the pulmonary hypertension, decrease in oxygenation, increase in extravascular lung water and lung weight, and decrease in compliance (CPL) seen in human acute lung injury (ALI) and after ischemia/reperfusion [1–3]. Previous studies in our laboratory and others have demonstrated beneficial effects of thromboxane receptor antagonism [1] before and after instillation of OA, and a deleterious effect of pretreatment with inhaled nitric oxide (NO) [3, 4]. Because NO has been shown by other investigators to have other than pure vasodilatory effects [5, 6], we wished to test the effects of a pure vasodilator, sodium nitroprusside (SNP), in our isolated OA injury model. Our isolated lung model allows us to perform these experiments without the combined effects of OA on other organ systems. It was our hypothesis that pretreatment with SNP in our current model should have similar effects to those of our previous experiments with inhaled NO, namely, that vasodilatation should enhance the effects of OA by allowing it to enter areas of the lung that would be protected by vasoconstriction, worsening pulmonary hypertension, oxygenation, and CPL, while increasing lung weight.
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Material and methods
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Our experimental protocol was approved by the University of Virginia’s Institutional Animal Care and Use Committee. All animals were cared for in accordance with Committee guidelines, as well as those set forth by the National Institutes of Health.
New Zealand White rabbits were anesthetized with intramuscular injections of xylazine (5 mg/kg) and ketamine (50 mg/kg). After anesthesia, blood was obtained from systematically heparinized (500 U/kg iv) donor rabbits via right ventricle cannulation. This blood was diluted with normal saline to an hematocrit between 25% and 30%. Study rabbits weighing between 3 and 3.5 kg received tracheostomies after administration of vecuronium. Rabbits were ventilated with a small animal ventilator (Kent Scientific, Litchfield, CT) to a respiratory rate of 20 bpm and tidal volume of 10 cc/kg. Inspired oxygen concentrations of 50% were maintained throughout the experiment.
After tracheostomy, a midline thoracotomy was performed. Animals were systematically heparinized. After isolation and ligation of the two superior vena cavae and single inferior vena cava, the pulmonary artery was cannulated via the right heart. A 6°C normal saline flush was then administered through the PA catheter (total volume 40 cc/kg). Outflow control was obtained by placing dual catheters through the left ventricle to the left atrium. Thymectomy was then performed. The lung/heart block was removed from the chest and placed ex vivo into our continuous blood perfusion circuit. Lungs were allowed to stabilize after the initiation of perfusion for 2 to 4 minutes before measurements were begun. Lungs with evidence of air leak were excluded from the study. Blood was circulated through the circuit at 60 cc/min with a Masterflex (Cole-Parmer Instruments, Vernon Hills, IL) roller pump (Barrant Company, Barrington, IL) (Fig 1).
OA injury was induced with 0.4 cc of 50% solution of OA and 95% ethanol infused over 20 min directly into the perfusion circuit (oleic acid control [OAC] group). Control groups received an equal amount of normal saline delivered similarly (saline control [SC] group). A second group of animals was treated similarly with OA to create injury, and animals were treated intravenously with SNP (10 µg/kg/min) (SNP treatment (NPRx) group). Administration also began before injury and was continued throughout the study. SNP was reconstituted within 3 days of first use and protected from light exposure during use and storage. An SNP control group (NPC) received only saline and SNP during the study period.
Measurement of pulmonary artery pressure (PAP) and pulmonary resistance were made at intervals of 15 seconds. Calculations of lung edema were made from sections of lower lobes and recorded as wet/dry weight ratios. The oxygenation capacity of each lung was calculated by measuring arterial blood gasses of delivered fresh venous whole blood from a reservoir before and after perfusion through the lung at 20-minute intervals for 1 hour. Sections of lower lobes were preserved in formalin for histologic examination.
Data analysis of PAP, CPL, pulmonary vascular resistance (PVR), and AVO2 was performed using analysis of variance (ANOVA) and repeated measures ANOVA. Wet/dry weight ratios were calculated from portions of lower lobes from each animal. Resulting values are reported as the mean ± standard error of the mean (SEM). A p value less than 0.05 was considered significant.
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Results
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A total of 32 lung heart blocks were analyzed. The mean ± SEM of each parameter at 90 minutes of perfusion was compared.
Pulmonary artery pressures
At 90 minutes of study, PAP in the NPC (26.3 ± 2.9), SC (31.2 ± 1.2), and NPRx (27.5 ± 1.6) groups was significantly less than OA (38.9 ± 3.6) (p < 0.05). There were no significant differences in PAP between the SC, NPC, and NPRx groups (Fig 2).
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Fig 2. Pulmonary artery pressure at 90 minutes after OA, saline, or SNP infusion. (* p < 0.05 versus SC, NPC, and NPRx Groups.)
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Pulmonary vascular resistance
At 90 minutes, PVR in the OA group (43,808 ± 5,600) was significantly higher than in the SC, NPC, and NPRx groups (Fig 3).
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Fig 3. Pulmonary vascular resistance at 90 minutes after OA, saline, or SNP infusion. (* p < 0.05 versus SC, NPC, and NPRx Groups.)
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Dynamic airway compliance
CPL was significantly lower in the OA group than in the SC and NPC groups. There was no significant difference in CPL between the OA group and the NPRx group (Fig 4).
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Fig 4. Dynamic airway compliance at 90 minutes after infusion of OA, saline, or SNP. (* p < 0.05 versus SC and NPC Groups.)
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Arteriovenous oxygen gradient
A 30-mL venous blood challenge was administered during reperfusion from a separate, noncirculating, venous blood reservoir. Single-pass pulmonary venous blood gas analysis could be carried out on aspirated samples immediately after reperfusion of the lungs. The oxygenation gradient was then determined by subtracting the oxygen tension of the venous reservoir from the oxygen tension of the blood returning from the pulmonary venous catheter. The oxygen gradient was significantly lower in the OA group when compared with all other groups at 90 minutes (Fig 5).
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Fig 5. Arterial-venous oxygen gradient at 90 minutes after OA, saline, or SNP infusion. (* p < 0.05 versus SC, NPC, and NPRx Groups.)
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Wet/dry ratios were significantly greater in the OA group when compared with all other groups (p < 0.01) (Fig 6).
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Comment
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SNP has been found by other investigators to have varied effects on PVR after hypoxia and endotoxin infusion [7, 8]. SNP is known to be a potent donor of NO in the vasculature and causes smooth muscle relaxation by an endothelial-independent, cyclic guanosine monophosphate-dependent mechanism [8]. Our isolated rabbit lung model provides a method to examine the effects of different agents on PVR, PAP, CPL, and oxygenation dynamically in isolation from other organ interactions. In our previous studies [1–3], we have examined the effects of different treatments on OA-induced ALI. Our most recent study used inhaled NO in OA-induced ALI and found a detrimental effect on lung function and pulmonary hemodynamics [3]. We hypothesized that this effect could be explained by vasodilation of the pulmonary circulation by NO with subsequent increased delivery of OA into areas of the lung that would have been protected by hypoxic vasoconstriction. Thus, we wished to examine the effect of a pure vasodilator, SNP, on this form of lung injury. Foulke and associates [9] found no beneficial effect of SNP on transvascular fluid flux or microvascular protein permeability after Escherichia coli endotoxin lung injury in sheep. In their study, SNP infusion was begun after endotoxin infusion, while in this experiment, SNP was given before OA. SNP has also been shown in our laboratory to ameliorate lung reperfusion injury in the isolated rabbit lung model [10] and in other models [11, 12]. In our study, SNP had a profound salutary effect on pulmonary hemodynamics, oxygenation, and lung edema. Because SNP acts as a NO donor in the pulmonary circulation, the effects on PAP and PVR were not unexpected. Other investigators have found that SNP is more effective than inhaled NO in inducing pulmonary vascular relaxation after a variety of insults [13]. However, our results indicate that SNP improves both oxygenation and edema. This could be explained by a more potent effect than inhaled NO on PVR and pulmonary artery hypertension, leading to a decrease in transvascular fluid filtration. Essentially, SNP may be acting as a more potent vasodilator in the pulmonary circulation than NO in this model. Thus, there may be more profound effects on shunting between areas of the lung with significant alveolar damage and those areas that are functioning well. We feel that these effects are more related to changes in pulmonary physiology than other reported mechanisms of NO and SNP. However, without more detailed knowledge of intrapulmonary blood flow, further speculation on the exact mechanisms involved is difficult.
We feel that pretreatment with SNP in this experiment caused a significant decrease in pulmonary hypertension caused by OA infusion, thus leading to a decrease in hydrostatic pressure in the pulmonary vasculature with subsequent improvement in oxygenation and wet/dry weight ratios. Thus, the beneficial effect of SNP, as opposed to the detrimental effect of NO, may be solely physiologic, and related to the superior ability of SNP to dilate the pulmonary vasculature. A direct salutary effect of SNP on the effect of OA on membrane permeability can also be implicated from this study. Bouchier-Hayes and associates [14] found that SNP significantly reduced leukocyte sequestration, pulmonary congestion, and microvascular protein leakage from interleukin-2. The mechanism of this effect is thought to result from the ability of SNP to donate NO. NO inhibits neutrophil superoxide anion synthesis and adherence to endothelial cells.
In conclusion, we have found that SNP infusion improves pulmonary hypertension, oxygenation, CPL, and lung edema in OA-induced ALI. The mechanisms of the beneficial effect of SNP in this model may include both its vasodilatory properties, and its inhibition of superoxide anion synthesis. While SNP has not, thus far, been proven to be beneficial in ARDS treatment, our findings may offer insight into other benefits of SNP treatment. Because clinical use of these substances has not been extensively studied, condemnation of its potential use in all cases is unwarranted at this time. The protean manifestations of ARDS in patients with sepsis, heart failure, trauma, and burns make it very likely that a single physiologic treatment is unlikely to be effective in all cases. However, we can conceive of clinical situations where potent dilation of the pulmonary vasculature with attendant decreases in right ventricular afterload, as well as the redirection of pulmonary shunts, may provide added benefit in the treatment of severe respiratory failure. Its ability to scavenge free radicals, and to inhibit leukocyte sequestration, may also make it a useful adjunct in the treatment of ARDS. The salutary effects of SNP in the early treatment of ARDS require further study.
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References
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Thies S.D., Corbin R.S., Goff C.D., et al. Thromboxane receptor blockade improves oxygenation in an experimental model of acute lung injury. Ann Thorac Surg 1996;61:1453-1457.[Abstract/Free Full Text]
-
Goff C.D., Corbin R.S., Theiss S.D., et al. Postinjury thromboxane receptor blockade ameliorates acute lung injury. Ann Thorac Surg 1997;64:826-829.[Abstract/Free Full Text]
-
Rayhrer C.S., Edmisten T.D., Cephas G.A., Tribble C.G., Kron I.L., Young J.S. Nitric oxide potentiates acute lung injury in an isolated rabbit lung model. Ann Thorac Surg 1998;65:935-938.[Abstract/Free Full Text]
-
Eppinger M.J., Ward P.A., Jones M.L., Bolling S.F., Deeb G.M. Disparate effects of nitric oxide on lung ischemia-reperfusion injury. Ann Thorac Surg 1995;60:1169-1176.[Abstract/Free Full Text]
-
Rossetti M., Guenard H., Gabinski C. Effects of nitric oxide inhalation on pulmonary serial vascular resistances in ARDS. Am J Respir Crit Care Med 1996;154:1375-1381.[Abstract]
-
Chollet-Martin S., Gatecel C., Kermarrec N., Gougerot-Pocidalo M.A., Payen D.M. Alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation. Am J Respir Crit Care Med 1996;153:985-990.[Abstract]
-
Sheridan B.C., McIntyre R.C., Agrafojo J., Meldrum D.R., Meng X., Fullerton D.A. Neutrophil depletion attenuates endotoxin-induced dysfunction of cGMP-mediated pulmonary vasorelaxation. Am J Physiol 1996;271:L820-L828.[Abstract/Free Full Text]
-
McIntyre R.C., Jr, Banerjee A., Hahn A.R., Agrafojo J., Fullerton D.A. Selective inhibition of cyclic adenosine monophosphate-mediated pulmonary vasodilation by acute hypoxia. Surgery 1995;117:314-318.[Medline]
-
Foulke G.E., Fisher C.J., Jr, Demling R.H. Effect of nitroprusside on pulmonary hypertension and lung fluid balance after E coli endotoxin. Crit Care Med 1982;10:427-431.[Medline]
-
King R.C., Binns O.A., Kanithanon R.C., et al. Low-dose sodium nitroprusside reduces pulmonary reperfusion injury. Ann Thorac Surg 1997;63:1398-1404.[Abstract/Free Full Text]
-
Yamashita M., Schmid R.A., Ando K., Cooper J.D., Patterson G.A. Nitroprusside ameliorates lung allograft reperfusion injury. Ann Thorac Surg 1996;62:791-797.[Abstract/Free Full Text]
-
Abdih H., Kelly C.J., Bouchier-Hayes D., et al. Nitric oxide (endothelium-derived relaxing factor) attenuates revascularization-induced lung injury. J Surg Res 1994;57:39-43.[Medline]
-
Roos C.M., Rich G.F., Uncles D.R., Daugherty M.O., Frank D.U. Sites of vasodilation by inhaled nitric oxide vs. sodium nitroprusside in endothelin-constricted isolated rat lungs. J Appl Physiol 1994;77:51-57.[Abstract/Free Full Text]
-
Bouchier-Hayes D., Abdih H., Kelly C.J., et al. Nitric oxide attenuates interleukin 2-induced lung injury. Br J Surg 1997;84:540-542.[Medline]
Accepted for publication June 7, 1999.
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Abstract
Introduction
