Society of Cardiovascular Anesthesiologists

Drug and Innovation Review

Alternatives to inhaled NO

E. Andrew Ochroch, MD
John G. Augostides, MD
Department of Anesthesia
University of Pennsylvania

Endothelial derived relaxant factor was identified in 1980[1] and was later identified as nitric oxide (NO). NO was first used therapeutically in the early 1990s in the treatment of pulmonary hypertension (PHTN) and adult respiratory distress syndrome (ARDS). NO has the desired properties of decreasing PHTN, unloading the right ventricle and not significantly affecting mean arterial pressure (MAP), and its utilization in the perioperative period has grown.[2-4] Unfortunately, the system for monitoring and delivering NO is specialized and the cost of NO is significant. Consequently, alternative treatments that are as safe and effective and less expensive have been sought. This review will focus on inhalational delivery of agents that attempt to replace NO in clinical care. A more thorough review of this topic is by Lowson et al.[5]

Nitric oxide synthetase produces NO from oxygen and the amino acid l-arginine.[6] Inhalational l-arginine has been explored as a vehicle for increasing targeted NO production. [7, 8] Although l-arginine increased NO production significantly more that saline, NO was only increased to 15 parts per billion. This is roughly 1/4000 of the usual therapeutic dose of NO, so no effect on pulmonary pressure was tested. Inhaled l-arginine's role was further restricted by the finding of significant bronchoconstriction.[7, 8]

Sodium nitroprusside (SNP) will spontaneously release NO at physiologic pH. Its role as an inhalational treatment has not been thoroughly examined. In sheep, concentrations of SNP < 10-2M produced significant reductions in PHTN from hypoxia. Pulmonary vascular resistance (PVR) fell 42% with minimal effect on MAP. This selectivity was lost at higher concentrations.[9] Similar results were seen in piglets where PHTN was induced with hypoxia or group B streptococci infusion. Pulmonary artery pressure (PAP) was decreased 8.4% and PVR decreased by 25%.[10] No effect on MAP was seen, and this effect was maintained through 1 hour of treatment. SNP has been used in one trial of hypoxic infants where 0.25mg/ml aerosol of SNP was delivered for 97 to 157 hours. Nine out of 10 infants responded with improvements in oxygenation, and MAP response was variable.[11] Clearly much more clinical work is needed to determine the true efficacy and safety of SNP.

Prostaglandin I2 (PGI2 , Prostacycline) is produced by tissue isomerases at the end of a long chain of enzymatic processes that begins with cyclooxygenase acting upon arachidonic acid.[12] In plasma, it has a very short half-life.[12] PGI2 has a long history of successful intravenous use in pulmonary hypertension.[13-15] Although it causes the release of NO, its main effect of vasodilatation is the result of producing adenosine-3,5-cyclic monophosphate which relaxes endovascular smooth muscle.[12, 15] There have been many trials of inhaled PGI2.[16-32] Essentially, these studies show that inhaled PGI2 in a dose of 15 - 50 ng . kg-1 . min-1 is usually as effective as NO from 5 - 100 ppm.(Table 1) These trials have been in primary pulmonary hypertension,[23, 27, 32] post transplant,[21, 25, 26] cardiac surgery,[17, 28, 33] and septic shock/ARDS.[18, 28, 30] Depending on the cause of the pulmonary hypertension, both therapies decreased PAP by 6% - 9%, PVR by 35% - 50%, decreased right ventricular work and oxygen demand, improved arterial oxygenation, all with minimal effect on MAP. In some studies, the two treatments had additive effects.[24] Phosphodiesterase inhibitors, which augment adenosine-3,5-cyclic monophosphate levels by inhibiting their destruction, augment the effect of inhaled PGI2.[33, 34] In contrast to NO, delivery of PGI2 is simple: the drug is diluted in a glycine buffer delivered to the Y piece in the ventilatory circuit by an infusion pump. [35]

There is a real and theoretical toxicity associated with PGI2 use. The common side effects seen with intravenous use (headache, jaw pain, flushing and diarrhea) have not been reported with inhaled use.[13, 36] The potential for left ventricular overload from increase forward flow from the right ventricle has been reported, but most of these patients will be under high acuity monitoring, and the decision to support the LV with inotropes or decrease PGI2 can be quickly made. Similarly, interruptions of PGI2 delivery can cause rebound PHTN, but this should be discovered by properly trained staff. While intravenous PGI2 profoundly inhibits platelet aggregation,[37] there has been no increased perioperative bleeding with inhaled use, even after cardiopulmonary bypass.[13] Consequently due to its relatively low cost, ease of use, safety and efficacy, PGI2 has gained widespread use.

Iloprost is a stable cabacyclin derivative of PGI2.[38] Its main advantage is its significantly longer duration of action which allows for intermittent treatment.[38] It has mostly been examined for treatment of PHTN outside of the operating room.[36, 37, 39-41] In these situations, doses of 15 mg - 20 mg produced decreases in PVR of 25% - 40% with a duration of up to 75 minutes. The maximum decrease in PVR was similar to NO and PG+I2. Iloprost is not currently available in the United States.

References

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