Leaders in Pharmaceutical Business Intelligence (LPBI) Group

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Department of Anesthesiology, Rigshospitalet, University of Copenhagen, Anestheisa, Juliane Marie Centre, Copenhagen, 2100, Denmark.

Abstract

Discussion

NO is naturally produced in the body by the enzyme NO synthase, which converts L-arginine to L-citrulline and NO in the presence of oxygen and certain cofactors. Both constitutive and inducible forms of NO synthase are present in endothelium and various other tissues.^39–,⁴¹ NO has several important physiological roles, including involvement in smooth muscle relaxation, neurotransmission, host defense responses, and platelet function. NO produced by the vascular endothelium causes local vasodilatation, thereby regulating vasomotor tone. Circulating NO is present in only picomolar amounts and is rapidly inactivated by reaction with hemoglobin. Because of this short circulating half-life (3–5 seconds), inhalation of subtoxic levels of NO causes vasodilatation of the pulmonary vasculature with little or no systemic vasodilatation. Therapeutic administration of NO by inhalation thus provides a means of selectively lowering pulmonary arterial blood pressure, potentially improving hemodynamic status and gas exchange.^{11–13,15,17,18,23}

Inhaled NO has been widely studied in adults with pulmonary hypertension and acute lung injury, and it is currently approved by the Food and Drug Administration for treatment of hypoxic respiratory failure in neonates with pulmonary hypertension. Three potential hazards associated with inhaled NO therapy are recognized:

(1) direct pulmonary toxic effects of NO,

(2) pulmonary toxic effects due to NO₂ produced by oxidation of NO, and

(3) development of methemoglobinemia.

Studies of exposure to toxic levels of NO and NO₂ in various species indicated that high concentrations of these gases can be lethal. Pulmonary edema, hypoxemia, acidosis, and hypotension developed in dogs exposed to 0.5% to 2% NO or NO₂, and most animals died within 7 to 50 minutes of exposure.⁴² In rats, inhaled NO₂ concentrations of 127 ppm were lethal within 30 minutes in 50% of animals (LC₅₀).⁴³ The LC₅₀ in primates exposed to NO₂ for 30 to 60 minutes is 100 to 200 ppm.⁴³ Methemoglobinemia is detectable by measurement of blood levels of methemoglobin and is manifested clinically as cyanosis and hypoxia. Methemoglobinemia developed in animals exposed to high concentrations of NO or NO₂, although not uniformly. In one instance, a methemoglobin level of 1.00 developed in a dog exposed to 2% NO for 50 minutes.⁴²

In humans, NO at 10 to 20 ppm can cause irritation of the eyes and nose, 25 ppm can be irritating to the respiratory tract and cause chest pain, 50 ppm can cause pulmonary edema, and 100 ppm can be fatal.^1,4

Legally permissible exposure limits for NO and NO₂ have been issued by the Occupational Safety and Health Administration. For NO, this threshold is 25 ppm (30 mg/m³), averaged over an 8-hour work shift.¹⁰ This value corresponds to the threshold limit value promulgated by the American Conference of Governmental Industrial Hygienists.² Adherence to this limit is thought to provide adequate protection against methemoglobinemia and other toxic effects. Concentrations of 100 ppm and higher (30-minute mean) are deemed to be an immediate threat to life and health by the National Institute for Occupational Safety and Health.⁴⁴ The Occupational Safety and Health Administration ceiling limit for NO₂ is 1 ppm (1.8 mg/m³), and this limit is not to be exceeded at any time during the work shift.¹⁰ The threshold limit for TWA concentration of NO₂ issued by the American Conference of Governmental Industrial Hygienists is 3 ppm,² and the National Institute for Occupational Safety and Health requires that NO₂exposures not exceed 1 ppm.^10,44

These threshold values are thought to represent maximum concentrations to which nearly all workers can be exposed on a regular basis without adverse effects. Nevertheless, evidence suggests that lower levels of exposure can have deleterious effects. For example, irreversible emphysematous changes to the lungs occurred in beagles exposed to 0.6 ppm NO₂ for 16 h/d for 68 months and then to clean air for 32 to 36 months.⁴⁵ In a study of exposure of humans to NO at 1.0 ppm, small but significant increases in airway resistance occurred in half the subjects.⁴⁶ Similarly, inhalation of NO₂ at 0.7 to 2 ppm for 10 minutes increased airflow resistance in healthy subjects.¹ Exposure to NO₂ at 2.3 ppm for 5 hours reportedly altered alveolar permeability in humans.⁴⁷ Brief exposure to NO₂ levels as low as 0.4 ppm may augment the response to challenge with specific allergens, and exposure to 0.1 to 0.5 ppm may affect pulmonary function in patients with asthma or chronic obstructive lung disease.^1,5,7,48,49

Limited information is available on occupational exposure to NO in the healthcare setting. Using stationary chemiluminescence monitoring, Mourgeon et al⁵⁰ determined ambient concentrations of NO and NO₂ in the main corridor of an ICU. They found that mean ambient NO concentrations within the ICU were 0.237 ppm (SD 0.147 ppm) during the therapeutic use of inhaled NO at 5 ppm or less in 1 or more patients and 0.289 ppm (SD 0.147 ppm) during times when inhaled NO therapy was not used. The institution where this study⁵⁰ was performed is located on a main street in Paris, and Mourgeon et al concluded that the ICU corridor values were entirely dependent on prevailing outdoor concentrations. Markhorst et al⁵¹ examined ambient levels of NO and NO₂ in well-ventilated and poorly ventilated pediatric ICU rooms in which administration of inhaled NO at 20 ppm was simulated. As in the study by Mourgeon et al, sampling was done from a stationary position (in the study by Markhorst et al, 65 cm from the high-frequency oscillator used) at a height of 150 cm. During the simulation, maximum NO and NO₂levels were 0.462 and 0.064 ppm, respectively. Phillips et al⁵² used occupational hygiene techniques similar to those we used to examine exposure levels in medical personnel during administration of inhaled NO to 6 patients in a pediatric ICU. In all instances, TWA concentrations were less than the limits of detection for the assay used. The patients’ sizes and minute volumes were not specified, although 3 of the patients were classified as neonatal.

We examined the occupational exposure of ICU nurses to NO during NO therapy at delivery levels of 5 and 20 ppm in adult patients with acute respiratory distress syndrome. The maximum TWA exposures in our study were 0.45 ppm for NO and 0.28 ppm for NO₂, well below the legally permissible exposure limits mandated by the Occupational Safety and Health Administration, and the involved nurses reported no respiratory or other signs or symptoms. The maximum outdoor background concentrations of NO and NO₂ in our county during the periods of study ranged from 0.006 to 0.030 ppm for NO and 0.018 to 0.090 ppm for NO₂. For comparison, the primary national ambient air quality standard issued by the Environmental Protection Agency is 0.053 ppm (100 μg/m³), calculated as an annual arithmetic mean.⁵³ We did not assess methemoglobin levels in the nurses; however, methemoglobinemia did not develop in the treated patients. Marked methemoglobinemia is uncommon in patients treated with inhaled NO at concentrations similar to those used in our study.^{11,12,15,16,18,23}

In the simulation study of Markhorst et al,⁵¹ ambient NO concentrations were measured at distances of 15 to 200 cm from a high-frequency oscillator, yielding levels ranging from 1.2 to 0.4 ppm. Our measurements yielded similar results (see Figure⇑); however, in our study, NO levels at the ventilator exhaust port were nearly 10 times higher (9.2 ppm) than those 15 cm away (1.0 ppm). NO concentrations decreased rapidly; the mean was about 0.030 ppm in the area between 0.6 m from the ventilator and 0.6 m outside the patient’s room. For comparison, in homes with gas cooking stoves, ambient NOx levels of 0.025 to 0.075 ppm are typical.⁹

A number of factors determine the concentrations of NO and NO₂ to which personnel are exposed during the therapeutic use of inhaled NO. These include the concentration of NO delivered to the patient, the patient’s minute volume, room size, room ventilation, and whether special ventilator exhaust routing or chemical scavenging devices are used. Baseline ambient levels of NO and NO₂ depend on outdoor environmental factors such as proximity to motor vehicle traffic or heavy industry, climate, wind, and sky clarity.⁵⁰Depending on the mode of administration, the actual concentration of NO delivered to a patient can fluctuate from the intended level. Continuous delivery during the entire respiratory cycle can produce more atmospheric contamination than does sequential administration limited to the inspiratory phase.⁵⁴ The amount of NO₂ formed during NO therapy varies according to the concentrations of oxygen and NO delivered, the time the 2 gases remain in contact, total gas flow, and minute volume.⁵⁵ Thus, higher fractions of inspired oxygen will lead to increased formation of NO₂ during inhaled NO therapy.

Because of differences in minute volume, therapeutic administration of inhaled NO to adult patients will result in substantially greater release of NO than will administration to infants or children. For example, to achieve a delivered NO concentration of 20 ppm, the required flow from a 1000-ppm NO source varies from 20 mL/min for a minute volume of 1 L/min to more than 200 mL/min for a minute volume of 11 L/min¹⁹ (our patients’ minute volumes exceeded 11 L/min). Simultaneous treatment of multiple patients in the same room or unit might increase exposure levels. The time spent by healthcare providers in the patient’s room and their average exposure distance from the ventilator exhaust port are also important factors. Room ventilation is clearly a factor. Ventilation in our negative-pressure isolation rooms exceeded that mandated by the Centers for Disease Control and Prevention (ie, ≥6 air changes per hour for existing rooms and ≥12 air changes per hour where possible and in new hospital construction).⁵⁶ Our study design did not allow analysis of the effects of any of these factors; however, the methods we used provide data for real-world examples of ICU nurses caring for typical adult patients receiving inhaled NO. These techniques also constitute the standard method for evaluations of occupational exposure to toxic gases. Studies in which these methods are used, but involving larger samples of nurses and patients in various settings, would allow better definition of variance and the effects that factors such as room ventilation have on exposure to ambient NO and NO₂.

In summary, we found that inhaled NO therapy at doses up to 20 ppm does not appear to pose a risk of excessive occupational exposure to NO or NO₂ to healthcare workers during the routine delivery of critical care nursing in typical adult ICU settings. These findings lend support to the occupational safety of this therapeutic modality.