MEDdesign

Risks and A Better Solution for Cylinder-Free Nitric Oxide Delivery

By Henry Szymanski
October 31, 2019


• Categories: 04-Product Design & Development, 05-Quality/Regulatory, Market Access, MEDdesign

Inhaled nitric oxide (NO) used in the treatment of persistent pulmonary hypertension of newborns have long been delivered in hospitals by diluting high concentrations of NO supplied in high-pressure gas cylinders. These cylinders when full are pressurized to approximately 2000 psi and contain approximately 2,239 liters of NO at concentrations of 400 ppm or 800 ppm. The cylinders are of significant size and weight, measuring 18.4 cm in diameter and 83.6 cm in height at a weight of 20 kg. In practice, two NO gas cylinders are usually secured to the back of a wheeled delivery device cart. During inhaled NO treatment the delivery device cart with the cylinders are placed at the bedside in an intensive care unit. The space around the patient bedside is typically crowded, shared with other essential clinical equipment and monitors, making direct access to the system and cylinders challenging. The use of high concentration NO gas supplied in these heavy high-pressure gas cylinders pose multiple risks to patient and the healthcare workers responsible for managing the NO delivery devices in the intensive care environment.

A recent study presented in poster form at the International Society for Aerosols in Medicine Congress in May 2019 analyzed the various risks associated with cylinder-based NO delivery systems.¹ The investigators identified and analyzed risks to both the patient and the healthcare worker, ranking the probability, severity and hazard classification. In terms of the risk to the patient, typically a newborn, potential exposure to nitrogen dioxide and an undetected change in the fraction of inspired oxygen (FiO2) were the most common risks identified. First, NO in presence of oxygen quickly converts to nitrogen dioxide. Nitrogen dioxide is toxic to tissues at low concentrations, with a short-term exposure limit of 5 ppm Second, the action of adding or changing the NO gas flow to the breathing circuit impacts the delivered FiO2. In terms of risks to the healthcare worker, physical injury associated with the weight and size of the cylinders and exposure to nitrogen dioxide were identified as the highest risk factors to healthcare workers.

Study authors used standardized risk assessment tools (ISO 14971: 2007, Annex D) to analyze the risks. Their results indicate patient exposure to nitrogen dioxide posted serious risk to these newborns at all stages of treatment when utilizing the cylinder-based delivery system, including system set up, delay in therapy initiation, pre- and post- manual resuscitation, and when changing cylinders. Study findings also indicate that the risk of an undetected decrease in FiO2 was determined to be of serious nature upon initiation of NO therapy and when NO concentrations to the patient were increased. Additionally, the risk of undetected change in FiO2 was found to be of a critical nature when NO concentrations were decreased. The risk of exposure to nitrogen dioxide was considered to be of relative probability (“occasional”), while the likelihood of an undetected change FiO2 was more remote, although no less real.

From the perspective of healthcare workers, the exposure to nitrogen dioxide was considered most likely to occur in the case of cylinder leaks. Damaged gas supply lines and damage to the gas cylinder regulator were other possible scenarios for exposure of the healthcare worker to nitrogen dioxide. Certainly, the health risk associated with exposure to nitrogen dioxide was found to be lower than that of risk to the patient, but in the case of regulator and cylinder valve-stem damage, it was considered serious due to the large volume of nitric oxide under high pressure in the cylinders. The most serious risk identified was that of physical injury associated with the handling of the heavy compressed gas cylinders.

Currently there is a cylinder-free system in development that uses plasma arc technology to generate a controlled concentration of nitric oxide gas over a wide range of gas flows. The system, which is for investigational use only, has been designed to provide on-demand NO generation from a room air and will operate in the same fashion as current cylinder-based nitric oxide delivery systems for use with mechanical ventilators. Consistent with current cylinder-based systems, the user-set NO concentration is accurately delivered over the same clinically relevant ventilator flows and pressures. Nitric oxide gas is supplied as a non-hypoxic mixture with room air as the carrier gas, preventing hypoxic gas delivery and decreasing the effects on ventilator-set FiO2. More importantly, on-demand NO generation eliminates the need for all NO reservoirs in the system. This eliminates the potential build-up of toxic nitrogen dioxide in the reservoir and negates the need to purge the system of NO2 prior to starting treatment or during the change of gas cylinders both can delay or interrupt NO delivery to the patient. Cylinder changes are also eliminated, instead a small NO2 filter, weighing approximately 50 g, is changed with every 12 hours of NO delivery. The NO2 filters can be stored in a drawer on or near the delivery device. The filter change takes less than 10 seconds. These characteristics are projected to have a significant impact on the risk profile for both patient and healthcare workers.

By applying the same risk analysis to the on-demand system the investigators found that nitrogen dioxide exposure was negligible to the patient at all stages of use, setup, pause in therapy, pre- and post-manual resuscitation, and during required NO2 filter changes. The results also showed the occurrence of undetected FiO2 changes at initiation of therapy were reduced to “improbable”. The risk of undetected changes in FiO2 during adjustment in NO concentrations up or down received a marginal severity score using the on-demand NO device. Findings pertaining to the healthcare worker showed that the likelihood and potential severity of all risk opportunities, including potential leak and damage to the regulator, cylinder stem, and supply line were extremely unlikely and risk score was negligible. The most dramatic finding was the change in probability and severity of physical injury associated with the changing of cylinders. The occurrence of such injuries was deemed extremely unlikely and severity of any such injury was consistently negligible no matter the stage of use, or likely body part to sustain injury.

The use of inhaled NO in persistent pulmonary hypertension is an integral part of intensive care therapy, but the risks associated with high NO concentration (400–800 ppm) supplied in high pressure cylinders have long been significant enough to warrant the need to examine new options. This new, on-demand NO technology provides significant safety improvements to both patient and healthcare provider. The manner of NO delivery with lower risk of changes to delivered FiO2, and the elimination of heavy, high-pressure gas cylinders bring significant improvements to a well-established therapeutic modality in neonatal intensive care. The company is currently working toward an FDA PMA submission, and believes that this technology advancement will significantly enhance patient care for these newborn patients.

Reference

1. Rimkus, M., Bathe, D., Montgomery, F. On-Demand Nitric Oxide for Ventilator-Based Nitric Oxide Inhalation: A Risk-Reduction Perspective. Abstracts of International Society for Aerosols in Medicine e.V. 22nd ISAM Congress, May 24, 2019. https://doi.org/10.1089/jamp.2019.ab02.abstracts