Nebulized nitroglycerin in the emergency department
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NEBULIZED NITROGLYCERIN
Inhaled pulmonary vasodilators have been a common management option for patients with pulmonary hypertension. Massive pulmonary embolisms (PE) have a similar pathophysiology in which the abrupt increase in pulmonary artery pressure results in right ventricular (RV) failure and hemodynamic collapse. Decreasing pulmonary artery pressure decreases RV afterload and improves RV function. Preventing RV failure is critical in the management of such patients as they can rapidly decompensate. Although the effects are typically short-lived, pulmonary vasodilators are a useful adjunct for the temporization of RV function and can be utilized as a bridge to definitive interventions. Depending on the resources of the emergency department (ED), it may be difficult to utilize typical pulmonary vasodilators such as nitric oxide (NO) and epoprostenol within a reasonable timeframe to benefit a crashing patient. Nitric oxide, although it is becoming more common, is simply not available in the average ED. Epoprostenol requires complicated assembly that is limited to respiratory therapists, which has significant logistical limitations when resuscitating a hyperacute critically ill patient. A reasonable and effective alternative is nebulized nitroglycerin.
MECHANISM OF ACTION
Nitroglycerin is metabolized into NO. NO leads to an increase in cyclic guanosine monophosphate (GMP) in vascular smooth muscles and ultimately results in vasodilation. Nebulized nitroglycerin largely remains in the pulmonary vasculature and has strong local pulmonary effects without systemic side effects such as hypotension. Therefore, nitroglycerin is essentially liquid NO and has the same effect when it is nebulized into an inhaled form.
INDICATIONS
Nebulized nitroglycerin can provide benefits for a variety of patient presentations, including crashing pulmonary embolism, acutely decompensating pulmonary hypertension and profound refractory hypoxemia (Table 1). These patients have similar pathophysiology, which can be simplified to RV failure secondary to increased afterload in the pulmonary vasculature. Pulmonary vasodilation reduces the RV afterload and improves RV function. In addition, inhaled pulmonary vasodilators tend to be distributed to the well-ventilated alveoli, thus directing blood preferentially toward better ventilated areas and improving ventilation-perfusion mismatch [1].
Summary of the indications, pathophysiology, dose, and effect of nebulized nitroglycerin
As mentioned above, other departments may not have access to NO, and it may be unrealistic to assemble an epoprostenol circuit in a timely manner. However, all emergency departments should have nitroglycerin and a nebulizer readily available.
Although there are no randomized controlled trials comparing patient outcomes with and without nebulized nitroglycerin, there are small studies and case reports suggesting that nebulized nitroglycerin is effective in decreasing pulmonary pressure without impacting systemic hemodynamics.
For example, Yurtseven et al. [2] studied 100 stable patients with history of chronic pulmonary hypertension who were intubated after mitral valve surgery and found that a dose of 20 μg/kg of nebulized nitroglycerin caused a 43% decrease in pulmonary vascular resistance with no change in systemic vascular resistance.
Another study conducted by Mandal et al. [3] studied 40 stable patients with chronic pulmonary hypertension following cardiac surgery who received 2.5 μg/kg/min of nebulized nitroglycerin for 10 minutes and found a 40% decrease in pulmonary vascular resistance without affecting the systemic vascular resistance.
Kline et al. [4] studied the effects of NO in the management of intermediate risk PE regarding improvement of echocardiographic abnormalities such as RV hypokinesis and dilation, which was accomplished 29% more often versus the control group who received oxygen as a placebo (in addition to standard anticoagulation therapy). Although this is a smaller study that does not directly investigate nebulized nitroglycerin, it suggests that NO (nitroglycerin’s metabolite) can aid in the recovery of RV function.
DOSING AND LIMITATIONS
For a critically ill or crashing patient, the dose of nitroglycerin is 5 mg nebulized over 20 to 30 minutes and repeated as necessary [1]. The main limitation is the volume of medication that will fit in the nebulizer, which is 3 to 5 mL. Some formulations of nitroglycerin have a 1 mg/mL concentration, which achieves the desired dosage of 5 mg. The studies mentioned above utilize lower doses such as 20 μg/kg or 2.5 μg/kg/min and demonstrate a statistically significant reduction in pulmonary vascular resistance [2,3]. Therefore, even if your department does not carry the 1 mg/mL concentration, it is reasonable to nebulize 3 to 5 mL of the dilute nitroglycerin (200 or 400 μg/mL) and repeat dosing as needed. The duration of action of nebulized nitroglycerin is approximately 20 to 30 minutes. Finally, inhaled nitroglycerin should be used with extreme caution in those with profound left ventricular failure, as the decrease in pulmonary vascular resistance results in an increase in left ventricular preload. This may worsen cardiogenic pulmonary edema.
CONCLUSION
Patients with massive PE, decompensated pulmonary hypertension, and refractory hypoxemia are at high risk for deterioration from RV failure and hemodynamic collapse. Nebulized nitroglycerin can be a valuable therapeutic adjunct and therapeutic bridge that aims to reduce RV afterload, improve RV function, and promote recovery. This management approach has a practical advantage versus other pulmonary vasodilators since it is readily available in most EDs and can be promptly administered, as opposed to NO and epoprostenol, respectively. Although most of the supporting literature is extrapolated from the pulmonary hypertension and/or the NO literature, there is enough research to suggest a benefit without significant harm. Large randomized controlled trials are still necessary to demonstrate whether there is a difference in clinical outcomes when comparing nebulized nitroglycerin versus standard therapy alone.
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CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
FUNDING
None.
AUTHOR CONTRIBUTIONS
Conceptualization: all authors; Investigation: all authors; Visualization: NAU; Writing–original draft: NAU; Writing–review & editing: all authors. All authors read and approved the final manuscript.
References
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Capsule Summary
What is already known
In patients with massive and submassive pulmonary embolism, hemodynamic instability starts with elevation in pulmonary artery pressures which leads to right ventricular failure, then left ventricular failure, and then hemodynamic collapse. Inhaled pulmonary vasodilators are mentioned in the literature but infrequently utilized due to lack of availability and/or logistical challenges.
What is new in the current study
Nebulized nitroglycerin is a safe and effective way to decrease right ventricular after load and aid in right ventricular recovery. Through small studies we can extrapolate data that suggests this may be a useful adjunct when treating crashing pulmonary embolisms or pulmonary hypertension patients.