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.