| Abstract|| |
Acute catastrophic pulmonary vasoconstriction frequently leads to cardiovascular collapse. Rapid and selective pulmonary vasodilation is desired in order to restore haemodynamic stability. This pilot study examined the effectiveness of inhaled amyl nitrite as a selective pulmonary vasodilator. Nine adult swine were anaesthetized. Acute pulmonary hypertension with haemodynamic collapse was induced with a bolus administration of a thromboxane analogue, U46619. Six animals then received a capsule of amyl nitrite. The administration of inhaled amyl nitrite decreased mean pulmonary artery pressure from 42±3 to 22±3 mmHg at five minutes (p<0.05), with a concomitant increase in cardiac output and mean arterial pressure. Pulmonary vascular resistance decreased from 4889±1338 to 380±195 dyne. sec. cm -5 (by 92% from the maximal pulmonary hypertension change), with significant improvement in systemic haemodynamics. During acute thromboxane-mediated pulmonary hypertension with cardiovascular collapse, prompt administration of inhaled amyl nitrite was effective in restoring pulmonary and systemic haemodynamics within five minutes.
Keywords: Amyl nitrite, Pulmonary hypertension, Cor-pulmonale
|How to cite this article:|
Muehlschlegel JD, Lobato EB, Kirby DS, Arnaoutakis G, Sidi A. Inhaled amyl nitrite effectively reverses acute catastrophic thromboxane-mediated pulmonary hypertension in pigs. Ann Card Anaesth 2007;10:113-20
|How to cite this URL:|
Muehlschlegel JD, Lobato EB, Kirby DS, Arnaoutakis G, Sidi A. Inhaled amyl nitrite effectively reverses acute catastrophic thromboxane-mediated pulmonary hypertension in pigs. Ann Card Anaesth [serial online] 2007 [cited 2020 Apr 9];10:113-20. Available from: http://www.annals.in/text.asp?2007/10/2/113/37936
Acute catastrophic pulmonary vasoconstriction leading to acute cor-pulmonale can occur after various clinical conditions such as protamine administration,  massive amniotic fluid,  or pulmonary embolus,  or as a result of ischaemiareperfusion injury following repair of congenital heart defects. , Although the stimulus for pulmonary vasoconstriction may be short-lived, it frequently leads to acute right ventricular failure and haemodynamic collapse, with high morbidity and mortality.
The main treatment goal, besides supportive therapy for right and left ventricular function, is to achieve prompt and selective pulmonary relaxation. Due to the unexpected nature of acute catastrophic vasoconstriction, the ideal drug would be one that is immediately available, easy to administer, and rapid in onset, with pulmonary selectivity. Pulmonary vasorelaxation can be achieved by the increased production of pulmonary smooth muscle cGMP and cAMP, or by preventing its breakdown with phosphodiesterase type V (cyclic GMP) or type III (cAMP) inhibition. 
The presently available intravenous nitrosovasodilators increase cGMP but lack selectivity. Inhaled nitric oxide is rapid and selective, but may not be immediately available in some clinical circumstances. Recent data suggest that inhaled nitroglycerin and sodium nitroprusside may be effective pulmonary vasodilators with relative selectivity, but the results have been inconsistent. , The predominant pathway for inactivation of these cyclic nucleotides in the pulmonary vasculature is via phosphodiesterase enzymes type III (PDEIII) like milrinone, and type V (PDEV) like sildenafil. ,
Inhaled amyl nitrite is the oldest nitrovasodilator available for clinical use.  For many years, inhaled amyl nitrite was a popular antianginal agent due to its ease of administration, rapid onset, and established safety record.  Amyl nitrite fell out of favour worldwide as an antianginal drug, due to the production of longer-acting nitrates, which were also easier to administer. Today, it is rarely used, because nitroglycerin tablets are more convenient, less expensive, and less likely to be attended by unpleasant symptoms.  Nevertheless, it is still available and presently used in cardiology as a pulmonary vasodilator,  as well as an antidote for cyanide toxicity. Anaesthesiologists have had considerable experience with inhaled amyl nitrite in the past for smooth muscle uterine relaxation during caesarean delivery, with little or no risk to the mother or foetus in perinatology for the last decade.  Inhaled amyl nitrite has also been utilized in the evaluation of cardiac murmurs since it decreases systemic vascular resistance (SVR).  In addition, anaesthesiologists have used inhaled amyl nitrite to induce rapid, smooth muscle uterine relaxation in obstetric patients. 
Traditionally, the use of inhaled amyl nitrite is associated with systemic vasodilatation. However, to our knowledge, there is no data in the literature on the haemodynamic effects of inhaled amyl nitrite in the presence of acute pulmonary hypertension. Since inhaled amyl nitrite is more readily available, fast-acting, and easy to administer, we postulate that it may behave as a potent selective pulmonary vasodilator in cases of acute catastrophic pulmonary vasoconstriction.
The purpose of our pilot study was to examine the effects of inhaled amyl nitrite on pulmonary and systemic haemodynamics in a porcine model of acute thromboxane-mediated pulmonary vasoconstriction.
| Methods|| |
The protocol was approved by the University of Florida Institutional Animal Care and Use Committee. Animals were handled in accordance with guidelines established by the National Institutes of Health (NIH publication 85-23, revised 1985).
Nine domestic swine weighing 50 to 55 kg were premedicated with intramuscular ketamine (usual pig dose of 35 mg/kg ,, ) and anaesthetized with 1.1% end-tidal isoflurane in 100% oxygen. A tracheostomy was then performed, and the animals were mechanically ventilated at 12 breaths per minute, with tidal volume of 12 mL/kg to maintain an end-tidal carbon dioxide 2 between 32 and 36 mm Hg. Anaesthesia and mechanical ventilation were maintained with the use of a Narkomed 4 anaesthesia machine (North American Drager, Telford, PA). Pancuronium (0.2 mg/kg/h) was utilized for muscle relaxation during the surgical preparation. A 7 French (Fr) pressure-tipped, flotation pulmonary artery catheter (Millar Instruments Inc, Houston, TX) was inserted via the right internal jugular vein into the main pulmonary artery through an 8 Fr Cordis introducer (Arrow International, Reading, PA). A 7 Fr triple lumen, central venous catheter was placed through the left internal jugular vein. The left carotid artery was exposed, and a 5 Fr micromanometer-tipped catheter (Millar Instruments Inc, Houston, TX) was placed and advanced into the ascending aorta for continuous arterial pressure monitoring. A median sternotomy was then performed, and the heart was placed in a pericardial cradle. Cardiac output was measured with a 10 mm perivascular ultrasound probe (Transonic Systems Inc., Ithaca, NY) placed in the main pulmonary artery. , All transducers were connected to a biomedical amplifier (Grass model 7D, Grass Instruments Co, Quincy, MA). The signals were digitized and continuously recorded at 200 Hz on a personal computer for later analysis (Sonometrics Corp, London, Ontario, Canada).
Maintenance of intravascular volume was accomplished with lactated Ringer's solution administered by continuous infusion through a peripheral vein at a rate of 10 mL/kg/h. Anaesthetic maintenance was achieved with normothermia (pulmonary artery temperature of 37°C) and maintained by the application of a warming blanket and heating lamps. All animals were allowed to stabilize for one hour following the surgical preparation prior to data collection
| Haemodynamic Measurements|| |
Haemodynamic measurements included systemic arterial pressure, pulmonary artery pressure, central venous pressure, pulmonary artery occlusion pressure, and pulmonary flow (cardiac output). Pulmonary and systemic vascular resistances were calculated using standard formulae (PVR=MPAP-PAOP/CO and SVR =MAP-CVP/CO; where PVR=pulmonary vascular resistance, MPAP=mean pulmonary artery pressure, PAOP=pulmonary artery occlusion pressure, CO=cardiac output; SVR=systemic vascular resistance, MAP=mean arterial pressure; CVP=central venous pressure). The mean pressures were derived by the calculation: mean pressure= (systolic-diastolic difference) 1/3 + (diastolic pressure).
| Drug Preparation and Administration|| |
Before the study, 1 mg of the thromboxane A2 analogue, U46619 (Biomol Inc., St Louis, MO), was diluted in 20 mL of lactated Ringer's solution, making it a solution of 50 µg/mL. Amyl nitrite is contained within a capsule that holds 0.3 mL of the drug, which vaporizes upon being broken immediately prior to use.
After baseline measurements, acute pulmonary hypertension and haemodynamic collapse were induced with the rapid administration of the thromboxane analog, U46619, at a rate of approximately 50 µg (approximately 1 µg/kg) every 10 seconds to rapidly achieve at least a twofold elevation in MPAP. This was accomplished with a mean dose of 5 µg/kg over 60 seconds (= 250 µg/min for 50 kg pig). The first three animals were considered the control group and were not treated in order to observe the effects of the rapid administration of U46619 (Group 1; n=3). The next six pigs were put into the treatment group (Group 2, n=6).
Group 2 received one capsule of amyl nitrite within 60 seconds of achieving acute pulmonary hypertension. Inhaled amyl nitrite was delivered via a standard nebulizer with an oxygen flow of 5 L/min, attached to the inspiratory limb of the breathing circuit. The use of a nebulizer apparatus ensured a uniform and continuous mode of administration. Data were monitored continuously and collected at baseline, during initial acute pulmonary hypertension, and at one, two, and five minutes after the administration of inhaled amyl nitrite, while PAOP was measured continuously throughout the experiment. The pigs were observed for 30 more minutes without any complications.
| Statistical Analysis|| |
Values were expressed as mean (standard error). A two-way analysis of variance (ANOVA) was utilized, followed by a Student Newman-Keuls test for multiple comparisons. A P<0.05 was considered significant.
| Results|| |
Baseline haemodynamics were similar between the two groups [Table 1]. Acute pulmonary hypertension with concomitant cardiovascular collapse was achieved in all animals [Table 2].
In Group 2, when U46619 (5 µg/kg) was administered, MPAP increased from 18(2) mm Hg to 41(2) mm Hg (P<0.05), with concomitant reductions in mean arterial pressure from 75(3) mm Hg to 47(11) mm Hg (P<0.05) and cardiac output [2.9(0.3) L/min to 0.6(0.1) L/min; P<0.05)] [Figure 1]. The PVR rose more than tenfold, to more than 4000 dyne. sec. cm -5 while CO fell to about one fifth.
The administration of inhaled amyl nitrite decreased MPAP by 25% at one minute, 39% at two minutes, and 78% at five minutes for the respective time periods (P<0.05 for the respective time periods), with simultaneous improvement in CO and mean arterial pressure [Table 2] and [Figure 1]. Additionally, PVR decreased from 4889(1338) to 243(305), 512(169), and 380(195) dyne.sec.cm -5 (by 75%, 89%, and 92% from the maximal pulmonary hypertension change, respectively) [Figure 2]. SVR changed by 42%, 53%, and 44%, respectively, with return of systemic haemodynamics close to baseline [Figure 2].
The three animals in the control group, which were not treated with amyl nitrite, progressed to complete cardiovascular collapse: two pigs expired after one minute, and the third expired after three minutes. Thus, N=3 for the control group at one minute, N=1 at two minutes, and N=0 at 3 minutes. Due to the precipitous decrease in CO, the calculated PVR continued to increase. The PVR and SVR could no longer be calculated in the one minute control group due to the severe decrease in CO and MAP and increase in CVP. Upon averaging the three animals, this would have led to negative numbers. [Figure 3] shows severe dilatation of the pulmonary artery and right ventricle following the administration of U46619 with the displacement of the left ventricle.
Upon visualization, the right ventricle was severely dilated before the heart went into an agonal rhythm and then asystole.
| Discussion|| |
The main finding in this pilot study was that the administration of inhaled amyl nitrite during acute severe pulmonary hypertension was associated with immediate and effective pulmonary vasodilatation and significant haemodynamic improvement.
In this animal model, a bolus intravenous administration of U46619 led to acute corpulmonale. One dose of inhaled amyl nitrite produced rapid and dramatic improvement in pulmonary and systemic haemodynamics. This effect was evident within seconds and peaked within five minutes, to decrease PVR by 92% from the maximal pulmonary hypertension change. All animals in the control group expired within three minutes, whereas all animals who received inhaled amyl nitrite survived without showing signs of rebound hypertension. This finding of a catastrophic and lethal response without the suggested treatment led us to limit our control group to three animals.
Our goal was to create a model of non-survivable acute pulmonary vasoconstriction. The dose of the thromboxane analogue we used is fatal in large doses, as was shown in comparable studies in guinea-pigs and rats. , Due to the catastrophic pulmonary hypertension caused by the agent and its known lethal properties, we limited our control group to three animals in a non-randomized fashion despite the statistical problem such a small sample group can create. The main role of the control group was to demonstrate that, in large doses, the thromboxane analogue is uniformly fatal, and that amyl nitrite can reverse this catastrophic event. In a previous study by Yalcin, the thromboxane-mediated effect has a peak at 3 to 5 minutes and lasts around 15 minutes in haemorrhaged hypotensive rats.  Therefore, we observed all animals in the treatment group for 30 more minutes after data collection was completed without any further change in haemodynamics.
Although we demonstrated pulmonary selectivity with amyl nitrite, that selectivity is not absolute, and there are systemic effects, as our data demonstrated (SVR decreased by 42%). However, the SVR changes could be directly related to the calculated SVR (which is CO-dependent) due to the changes in CO, which improved threefold [Table 2].
The CO changes are also responsible for the calculated changes in SVR and PVR and the differences between the two groups, according to those calculated values. The CO deteriorated with pulmonary hypertension to low values (<1 L/min) in both groups. However, the difference in deterioration to 0.6 L/min (amyl nitrite group) or 1.0 L/min (control group) was calculated as a twoto three-fold difference in PVR (4889 and 2921, respectively) and SVR (3037 and 924, respectively) between the two groups.
Treatment of acute pulmonary hypertension with intravenous agents, such as beta adrenergic agonists, PDEIII inhibitors, or organic nitrates, is limited by the risk of systemic vasodilatation and hypotension. , Inhaled nitric oxide is traditionally utilized to achieve fast and selective pulmonary vasodilation with several limitations. ,, Similarly, oral sildenafil is relatively slow in onset, and the intravenous preparation is not available for routine clinical use.  Inhaled sodium nitroprusside and nitroglycerin have been used experimentally in animals and humans, again with similar limitation - hypotension. ,
Inhaled amyl nitrite was first used by Guthrie in 1859 and its antianginal use described by Lauder Brunton in 1867. , In the 1960s and 1970s, in addition to its antianginal use, inhaled amyl nitrite was utilized as a diagnostic tool in phonocardiography due to its safety record, ease of administration, and properties of afterload reduction. , Its use in inducing rapid, smooth muscle uterine relaxation has been described in several studies similar to nitroglycerin. , Due to the production of longer-acting nitrates, which were also easier to administer, inhaled amyl nitrite fell out of favour as an antianginal drug. Nevertheless, it is still available for use in cardiology and as an antidote for cyanide toxicity. Anaesthesiologists have had considerable experience with inhaled amyl nitrite in the past for smooth muscle uterine relaxation during caesarean delivery, with little or no risk to the mother or foetus. ,,,,,,,,,,,,,,,
Inhaled amyl nitrite is known to cause hypotension due to its vasodilating properties, although with relatively low frequency. ,, In this model, however, inhaled amyl nitrite produced significant pulmonary selectivity, thus allowing for an increase in CO and systemic blood pressure. The effects of inhaled amyl nitrite persisted beyond the half-life of U44619, which led to haemodynamic stabilization and survival of all animals. In contrast, every animal in the control group expired within minutes.
Organic nitrates (e.g. nitroglycerin, isosorbide dinitrate ) and organic nitrites (e.g. isoamyl nitrite) have similar chemical structures and a common mechanism of vascular relaxation (i.e. conversion to nitric oxide in vascular tissues and activation of guanylyl cyclase).  They are considered therapeutic substitutes for endogenous endothelialderived relaxing factor/nitric oxide.  Similar to organic nitrates (e.g. sodium nitroprusside, nitroglycerin), the organic nitrites are assumed to undergo vascular enzymatic activation to nitric oxide, thereby producing smooth muscle relaxation.  The advantage of inhaled over intravenous organic nitrates is the pulmonary selectivity due to the route of administration.
Inhaled amyl nitrite has the advantage of a very rapid onset. Earlier work by Mason, et al, showed the peak effect on forearm blood flow at 75 seconds.  Similar to other organic nitrates and nitrites, amyl nitrite can induce significant tachyphylaxis with repeated use. However, the use of inhaled amyl nitrite has limitations. It can be explosive; it needs to be stored at ambient temperatures, shielded from light; and it must be administered in a closed circuit to avoid operator exposure.
This study has several limitations that need to be addressed. We did not attempt to establish a dose-response curve or look at the long lasting effects of amyl nitrite or its metabolites. It was administered at a fixed dose, and the experiment was terminated less than an hour after the reversal of the catastrophic event. Additionally, thromboxane-mediated pulmonary vasoconstriction is only one model of pulmonary hypertension. We assume that the common pathway of nitric oxide release by inhaled amyl nitrite will react similarly in reducing pulmonary pressures in other models of pulmonary vasoconstriction. Multiple studies have shown direct involvement of throm boxane in acute pulmonary vasoconstriction. , Other experimental or physiological inflammatory mediators could possibly change the outcome. 
In clinical situations, even the slightest delay in instituting therapy may prove costly. The instantaneous recognition of the underlying problem in a clinical setting is not always possible; and even if the drug can be administered within seconds, the need for treatment must be recognized. As shown by the control group, irreversible cardiovascular collapse may occur over a span of only one to three minutes.
The delivery of inhaled amyl nitrite is simple and fast, yet, clinically, it is not possible to titrate the dose to a haemodynamic parameter or to determine the concentration given. The nebulizer or the reservoir bag will deliver a full dose. As in our study, this proves to be a very effective way to reverse an otherwise lethal injury. It is, therefore, an attractive option as an effective temporizing measure to reduce severe acute pulmonary hypertension until long term haemodynamic stabilization is achieved.
In conclusion, we demonstrated that, in an animal model of thromboxane-mediated, acute catastrophic pulmonary vasoconstriction, the prompt administration of inhaled amyl nitrite was effective in restoring pulmonary and systemic haemodynamics within minutes. This potentially new, therapeutic application warrants further study.
| Acknowledgements|| |
Support was provided solely from institutional and/or departmental funds. None of the authors have any conflicts of interest.
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Department of Anesthesiology, University of Florida College of Medicine, PO Box 100254, 1600 SW Archer Road, Gainesville, Florida 32610-0254.
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]