Discussion:
Acute cardiogenic pulmonary edema is a life-threatening condition requiring immediate treatment. Usual treatment such as intravenous diuretic therapy will take time to reduce congestion and rarely will prevent intubation in severe pulmonary edema with severe hypoxia on maximal oxygen therapy or BIPAP. Morphine administration can be helpful but by suppressing respiratory drive it can worsen respiratory failure and hypoxia. It is also not a very strong pre- and afterload reducer and has rarely prevented intubation. Any agents that can rapidly and safely reduce pre- and afterload is ideal for this situation. Nitroglycerin is an ideal drug in this setting. Sublingual nitroglycerin theoretically could be used for this purpose but a tablet of 0.2 which equals to 200 micrograms of nitro is a very low dose. In patients with severe pulmonary edema, at least up to 800-5000 micrograms of nitro boluses are required to be rapidly effective. This would translate to about 4-20 nitroglycerin sublingual tablets with each treatments. This will make giving sublingual nitro impractical and will make nursing personnel very resistant to providing these high doses. Furthermore, due to dry mouth related to hyperventilation, sublingual nitro will take much longer time to resolve. Bussmann et al (1) successfully gave up 0.8 to 2.4 mg of nitroglycerin sublingually at intervals of 5 to 10 minutes as proof of concept that rapid nitro administration can avoid intubation in acute heart failure. However, superiority of buccal nitro ointment regarding pharmacodynamic and ease of use in comparison to sublingual nitroglycerin will be discussed later. High-doses of IV nitroglycerin have been effective in patients with acute pulmonary edema (2-4). Bosc et al. used up to 3 milligrams (3000 microgram) IV successfully in such a patient (2) Stemple et al. (3) described 4 patients with severe cardiogenic pulmonary edema that were started mostly with 400 microgram IV nitro per minute with rapid up titration to 800 micrograms per minutes. Using their protocol, they could avoid intubation in all 4 of their patients. High dose IV nitroglycerin has been also successful in a pre-hospital setting (4). However, it is important to notice that ordering and mixing IV nitroglycerin by a pharmacist will take time and again pharmacists and nursing personnel will be very reluctant to follow physicians’ orders to start very high doses of IV nitroglycerin due to unfamiliarity with such a high dosing.
Nitro ointment, commonly called nitropaste, is widely available with excellent rapid resorption and pharmacodynamics if it is administrated buccally. Buccal administration of nitro ointment has been shown to be superior compared to other nitroglycerin agents in patients with angina (5-8) In patients with chronic congestive heart failure buccal administration of nitroglycerin ointment has also been shown to be superior to other forms of nitroglycerines with rapid onset, longer duration of drug effect and superior hemodynamic response (9-16 ). Abrams (12) studied a variety of nitroglycerin formulations, including sublingual, buccal, oral tablets, capsules, topical creams, ointments, patches, tapes, and inhalable sprays. As it can be seen in Table 2, buccal nitroglycerin ointment was superior in comparison to other forms. It had rapid onset of effect within 2 minutes with a long sustained effect ranging from 30-300 minutes making it an ideal formulation for rapid administration of high doses.
Nitroglycerin ointment contains approximately 15 mg of nitroglycerin per one inch of paste that can rapidly absorbed by buccal application simulating intravenous nitroglycerin administration. Giving a quarter of an inch (the tip of index finger, figure 1) of buccal nitroglycerin ointment, (if SBP >120 but <140) about 3-4 mg (3000-4000 microgram) of nitroglycerin can be given rapidly with each administration. By administrating half inch (half of the distal phalanx of the index finger, figure 1) of buccal nitroglycerin ointment (for SBP >140) 6-7 mg (6000-7 000 microgram) can be given rapidly that can induce quick pre- and afterload reduction thus dramatically reducing pulmonary congestion. An important part of this treatment is the presence of adequate blood pressure. This is the reason that this type of treatment should not be initiated in patients with cardiogenic shock or marginal SBP <120 mmHg. Therefore, SBP has to be rechecked every minute before each buccal administration to make sure SBP remained above 120 mmHg before next buccal nitroglycerin administration.
In the setting of acute pulmonary edema without cardiogenic shock, there are case reports and case series that have demonstrated the effectiveness and safety of buccal nitroglycerin application (17-19) including repeated very high initial doses of one inch (equal to 15,000 microgram) of nitroglycerin treatment without causing hypotension (19). Unfortunately, this very effective treatment of patients with acute hypoxic pulmonary edema without cardiogenic shock is barely utilized as the medical communities are not aware of this lifesaving treatment. Every time I have used this method, every single medical staff including nurses, residents, fellows, and cardiology attendings were unaware of this treatment and were surprised about its usage and effectiveness. Our case series is the largest reported case series in this regard showing very effective and safe use of buccal nitroglycerin ointment. Due to ease of use, safety, and efficacy, the use of buccal nitroglycerin ointment should be encouraged and be the standard of care in patients presenting with severe cardiogenic hypoxic pulmonary edema without cardiogenic shock in order to avoid imminent intubation and mechanical ventilation. Based on our patients and reported cases in the literature, a treatment protocol and algorithm are developed for the prevention of intubation in these patients that can be seen in Figure 2.