CE Article: Can IV Nitro Help CHF With Acute Pulmonary Edema?

Objectives

Upon completion of this course, students will be able to:

• Examine the evidence supporting bolus IV nitroglycerin use in APE; 
• Describe an effective and safe administration protocol for NTG; 
• Consider the potential impact of bolus NTG treatment in the face of COVID-19.

Before discussing the use of bolus IV nitroglycerin in decompensated congestive heart failure patients, we should address the overall approach to CHF education. There is a wide variability of emergent patient presentations with congestive heart failure—so much so that the term itself is likely too broad to be useful when teaching EMS providers. Further delineation into three specific CHF categories provides a more specific framework and allows an obvious entry point to introduce bolus dose IV nitroglycerin (NTG) treatment. 

The first and least emergent category of CHF exacerbation is chronic volume overload. These patients progress in a subacute manner over days to weeks with complaints of dyspnea on exertion, orthopnea (often described using the number of pillows needed to prop the patient up at night while sleeping), and paroxysmal nocturnal dyspnea. The classic chronic volume overload patient will often have pulmonary rales, jugular venous distention (JVD), and pitting pedal edema on physical exam. They may be hypertensive, but they will not be in acute respiratory distress with accompanying sympathetic surge. The chronic volume overload patient may complain of weight gain, but they will speak normally without distress. 

In contrast, when the patient’s dyspnea develops acutely and severely over minutes to hours with accompanying malignant hypertension, this points to the diagnosis of decompensated CHF with acute pulmonary edema (APE). This is also often referred to as sympathetic crashing acute pulmonary edema (SCAPE). No matter the terminology, the key to recognizing these patients is the severity with rapid onset. An APE patient will be obviously tachypneic and often tachycardic and hypoxic as well. Rales, JVD, and pedal edema may also be present on exam, but they are not required to make the diagnosis. 

Finally, the third main category of decompensated CHF is cardiogenic shock, noted by marked hypotension and poor perfusion, often with altered mental status and hypoxia as well. The most common cause of cardiogenic shock is myocardial infarction.

Treating Decompensated CHF With APE

Teaching the above CHF exacerbation framework, which includes decompensated CHF with APE, allows a physiologic approach to treating this group of critically ill patients. This vicious cycle often starts with acute, severe hypertension, resulting in increased systemic vascular resistance, which causes worsened cardiac pump function. This leads to drastic increases in both preload and afterload, but this overload is not necessarily due to increased total body volume. In fact, approximately half of patients with decompensated CHF with APE are actually euvolemic.¹ The topic of furosemide (Lasix) often is broached when discussing the treatment of CHF. The high prevalence of euvolemia explains why acute diuresis can be potentially harmful in APE, leading to hypotension and acute kidney injury when given without knowing the patient’s true volume status.  

So why do these patients have pulmonary edema if they are euvolemic? This is a result of their severe hypertension and increased vascular resistance, which leads to rapid volume shifting into the pulmonary interstitial space. The ideal treatment to counteract this volume shift is an agent that quickly reduces both preload and afterload. At classic 0.4-mg sublingual doses, nitroglycerin does reduce preload but has little effect on afterload. Furthermore, APE patients also are often tachypneic, requiring noninvasive positive-pressure ventilation. Combined, these factors lead to dry oral mucus membranes, which decreases the rate of sublingual drug absorption. Only when used in higher doses (1 mg-plus) does NTG also reduce afterload.² Therefore, bolus dose IV NTG is an ideal agent for treating APE patients.

The initial Israeli prehospital studies using IV bolus isosorbide dinitrate for APE were encouraging.^3,4 However, furosemide was used in combination with nitrates, and the mobile intensive care units used for treatment contained physicians to aid in patient screening. Additional positive U.S. emergency department research using bolus NTG has shown decreases in intubation rates, ICU admission rates, and hospital lengths of stay when using IV bolus NTG in APE patients.^5,6 This combined body of evidence led to the development and release of an EMS protocol for ground paramedic use of IV bolus NTG in APE at the Montgomery County Hospital District (MCHD) EMS service in Conroe, Tex. 

The MCHD Experience

MCHD employs approximately 250 advanced life support providers and more than 1,000 emergency medical technicians in 13 first responder organizations. The service area covers 1,100 square miles and encompasses more than 70,000 annual calls for service. Prior to the protocol implementation, all paramedics underwent an initial mandatory two-hour training that included a review of nitroglycerin pharmacology, focused didactic instruction on the pathophysiology and clinical findings of acute decompensated CHF with APE, and specifics of the treatment protocol. 

The training sessions occurred approximately one month prior to protocol deployment. This knowledge was then reinforced by two podcasts, produced in house, that were available and promoted for the duration of the study period. Providers demonstrated an understanding of acute decompensated CHF and the treatment protocol through both written and psychomotor examinations at the conclusion of the training. We sourced nitroglycerin at the 100 mcg/mL concentration for less than $20 a bottle. 

The EMS protocol used in this study is shown in Figure 1. Paramedics initially identified CHF with APE within their clinical management scope and then had the option to administer sublingual nitroglycerin (0.4-mg tablets) while IV or intraosseous access was being obtained. Following this they slowly administered an initial dose of 1 mg IV nitroglycerin (10 mL of 100 mcg/mL) and repeated it in five minutes if the systolic blood pressure remained greater than 160 mmHg. A maximum total dose of 2 mg of IV nitroglycerin was allowed within this protocol. Noninvasive positive-pressure ventilation (NIPPV) was also available and encouraged but not required. Paramedics were taught to consider bolus IV NTG and NIPPV as a duo when treating APE, and nearly 90% of study patients indeed received both.

After protocol implementation, we collected data in an effort to answer three questions: 

1. Is bolus dose IV NTG safe in the prehospital setting? 
2. Is bolus dose IV NTG effective in reducing blood pressure in APE patients? 
3. Can paramedics correctly identify decompensated CHF with APE?

During the one-year MCHD study period, 48 patients were treated with bolus dose IV NTG.⁷ This cohort was indeed critically ill, with a quarter being intubated within six hours of ED arrival (8% EMS, 17% ED). Patients treated had a median initial EMS SBP of 211.0 mmHg (190–229.5). The median SBP five minutes post EMS IV NTG administration was 177.0 mmHg (155–199), and the median initial emergency department SBP was 181.5 mmHg. Of the patients treated, 41 of 48 (85%) had an improvement in SBP, and 45/48 (94%) had improved oxygen saturation following nitroglycerin administration. 

One patient did experience hypotension, which resolved without treatment during EMS transport, following a 1-mg dose of nitroglycerin. The blood pressure in this patient dropped from 203/88 to 71/38 and improved to 105/73 in four minutes without additional treatment. The patient was normotensive upon ED arrival and had no syncope, chest pain, or other complaints. The hospital echocardiogram was also reviewed, and the patient did not have aortic stenosis. Erectile dysfunction medications were not involved, as this patient was female. There were no other reported adverse events during transport. 

Based on hospital EMR review, 45 of 48 (94%) of the patients treated with IV bolus nitroglycerin were found to have CHF with APE during their ED stay. Two were diagnosed with pneumonia, and the third with COPD. 

The 2% rate of hypotension observed following treatment with bolus IV NTG is consistent with that seen in prior studies. A 16% reduction in SBP was noted in patients treated with bolus IV NTG, which is well within accepted parameters for blood pressure control in the setting of hypertensive emergency. More than 90% of all patients treated with IV nitroglycerin were correctly identified by paramedics as decompensated CHF with APE based on the final ED diagnosis. 

In conclusion, MCHD use of bolus IV NTG has indeed been safe and effective in treating decompensated CHF with APE. Additionally, MCHD paramedics were able to accurately diagnose decompensated CHF with APE in the prehospital setting. Larger studies are needed to further confirm safety and investigate the effects of bolus IV NTG on patient morbidity and mortality. 

The North Memorial Experience

North Memorial Health Ambulance and Air Care (NMHA) operates approximately 125 ground ambulances and seven helicopters across Minnesota and western Wisconsin. We operate in EMT/paramedic, paramedic/paramedic, and paramedic/RN configurations across our service area and transport around 70,000 patients a year, including some 3,500 by air. Our protocol for management of acute pulmonary edema has historically included sublingual nitroglycerin and continuous positive airway pressure (CPAP). 

During ongoing audits of advanced airway management performance, we noted a significant number of patients with a diagnosis of APE were receiving advanced airway management in the field due to treatment failure under the existing APE protocol. We noted attempts at advanced airway management in this population were often complicated by copious airway secretions and labile vital signs that often ended with negative changes in hemodynamic stability. 

As a result we began to explore alternative treatment modalities for APE in hopes we could reduce the number of patients requiring advanced airway management. In doing so, we mirrored MCHD in discovering a body of literature from the 1970s through the present day that described both in-hospital and out-of-hospital experiences using large doses of intravenous nitrates to manage severe cases of APE. From this we generated a new protocol for the prehospital treatment of APE and began collecting data with the aim of answering several questions similar to those posed by the group at MCHD. 

Our training protocol consisted of online training modules with accompanying quizzes, as well as hands-on skills training at annual sessions. Similar to MCHD, this training focused on the pathophysiology of APE, pharmacodynamics of nitroglycerin, and proper method of administration. Because our service area includes geographically rural areas with transports that may exceed 60 minutes, our protocol was developed to include an intravenous infusion of nitroglycerin following stabilization with intravenous bolus nitroglycerin. Thus, our protocol developed as follows:  

Paramedics identified APE within their scope of training and existing protocols. Following the diagnosis, they administered 0.8 mg (800 mcg) SL NTG while obtaining vascular access. They applied CPAP concurrently. Doses of 0.4 mg SL NTG were subsequently administered every five minutes until vascular access was obtained. 

Following IV/IO access, they administered a bolus of 400 mcg NTG every two minutes while maintaining a systolic blood pressure of 120 mmHg or more. They could repeat the 400-mcg IV/IO bolus as needed without a maximum dose at the treating provider’s discretion until resolution of dyspnea or establishment of the NTG infusion. Providers were directed to initiate a NTG infusion if transport time was estimated to be 10 minutes or more. They initiated the infusion at 80 mcg/min and titrated it every five minutes to resolution of symptoms and/or SBP of 120 mmHg or more. 

Minnesota Results 

In seven months NMHA treated 44 patients with intravenous nitrates for APE. Approximately half were treated with IV bolus NTG alone; the remainder received at least one bolus in addition to a NTG infusion. Forty-one of the 44 patients in the cohort received at least one dose of SL NTG prior to IVB NTG. The median dose of IVB NTG was 400 mcg. For patients treated with a subsequent infusion, the median dose was 80 mcg/min., which was the initial starting dose for the protocol. 

For all patients the initial median blood pressure prior to IVB NTG was 191/113 mmHg. Five minutes after IVB NTG, the median was 160/94 mmHg, and by hospital arrival it was 152/90. This represents a 20% median reduction in systolic blood pressure, which is consistent with published guidelines for the management of acute heart failure. 

In our series one patient experienced a transient episode of hypotension that resolved three minutes later without intervention or adverse effects. In this series the median SpO₂ prior to IVB NTG was 88%; five minutes after IVB NTG, it was 92%, and by ED arrival it was 94%. CPAP was used in 38 of the 44 patients in the cohort. Several were unable to tolerate the mask, and several improved to such a degree with IVB NTG that CPAP was not required. None of the patients treated with IVB NTG required invasive airway management in the field, and there were no other documented adverse events. 

Our experience indicates prehospital use of IVB NTG safely lowers blood pressure and improves SpO₂ in patients with APE in the field. 

What Did We Learn?

In closing we would like to compare the MCHD and NHMA IV bolus NTG experiences and consider the potential impact of this treatment in the face of COVID-19. The intubation rate was much higher in the MCHD population (around 25% of patients intubated within six hours of ED arrival). This could have been because the patients in their study had a higher entry systolic blood pressure requirement, making them sicker at baseline. Also, the NHMA group included NTG drip use secondary to increased transport time length. This will be a service-specific decision made with resource use and geographic considerations at the forefront. 

There were also several significant similarities between the MCHD and NHMA patient groups. Most important, both studies showed a minimal incidence of hypotension (2%), which was clinically insignificant and self-resolved in both instances. Patients treated in the MCHD and NHMA studies showed systolic blood pressure reductions of 16% and 20% respectively. As both teams noted, this is clinically appropriate in the setting of hypertensive emergency/acute pulmonary edema. 

Finally, and most important in the age of COVID-19, multiple patients in both studies ended up not needing noninvasive positive-pressure ventilation after the administration of IV bolus NTG. With the current COVID-19 concerns surrounding NIPPV as an aerosol-generating procedure, IV bolus NTG is an intriguing potential treatment option for APE patients that may eliminate entirely the need for positive pressure. This may improve patient care along with decreasing potential viral exposure risk for prehospital providers. 

Obviously, larger, randomized studies are needed to confirm these results, but these experiences are hopefully a foundation for expanding the EMS use of IV bolus NTG in patients with decompensated acute pulmonary edema. 

References

1. Cotter G, Kaluski E, Moshkovitz Y, Milovanov O, Krakover R, Vered Z. Pulmonary edema: new insight on pathogenesis and treatment. Curr Opin Cardiol, 2001; 16: 159–63.

2. Kelly RP, Gibs HH, O’Rourke MF, Daley JE, Mang K, Morgen JJ, Avolid AP. Nitroglycerin has more favourable effects on left ventricular afterload than apparent from measurement of pressure in a peripheral artery. Eur Heart J, 1990; 11: 138–44.

3. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low- dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet, 1998; 351: 389–93.

4. Sharon A, Shpirer I, Kaluski E, et al. High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema. J Am Coll Cardiol, 2000; 36: 832–7.

5. Levy P, Compton S, Welch R, et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med, 2007; 50: 144–52.

6. Wilson SS, Kwiatkowski GM, Millis SR, Purakal JD, Mahajan AP, Levy PD. Use of nitroglycerin by bolus prevents intensive care unit admission in patients with acute hypertensive heart failure. Am J Emerg Med, 2017; 35: 126–31.

7.  Patrick C, Ward B, Anderson J, Rogers Keene K, Adams E, Cash RE, Panchal AR, Dickson R. Feasibility, Effectiveness and Safety of Prehospital Intravenous Bolus Dose Nitroglycerin in Patients with Acute Pulmonary Edema. Prehosp Emerg Care, 2020 Jan 27 [epub ahead of print].

Casey B. Patrick, MD, is assistant medical director for Montgomery County Hospital District EMS.

Brad Ward, EMT-P, is cardiac coordinator for Montgomery County Hospital District EMS in Conroe, Tex.

Jordan Anderson, BS, LP, CCP-C, is CEO of North Texas Regional EMS and former assistant chief-clinical at Montgomery County Hospital District EMS.

Kevin Crocker, LP,  is quality assurance coordinator for the Department of Clinical Services at Montgomery County Hospital District in Conroe, Tex.

Robert L. Dickson, MD, FAAEM, FACEP, FACEM, is EMS medical director at Montgomery County Hospital District EMS and an assistant professor of emergency medicine at Baylor College of Medicine in Houston. 

Michael C. Perlmutter, BA, FP-C, is a paramedic with North Memorial Health in St. Paul, Minn. 

Matthew Cohen, BA, EMT, is a student at the University of Minnesota School of Medicine.

Nathan S. Stratton, MEd, is a student at the University of Minnesota School of Medicine. 

Marc Conterato, MD, FACEP, FAEMS, is associate medical director for North Memorial Health Ambulance Service in Minnesota. 

Figure 1: MCHD protocol

Figure 2: North Memorial protocol