HPV Vaccine: Politics Obscure Potential Benefits
To the Editor: I read with interest the Drug Update on the quadrivalent human papillomavirus (HPV) vaccine (March 2007). The article only briefly mentions the controversy that this vaccine has engendered. The discussion in several states to mandate HPV vaccination for all 11- to 12-year-old schoolgirls obscures the potential for this vaccine.

Mandatory vaccination programs eliminated smallpox, and international efforts have polio on the ropes. In clinical trials, the quadrivalent HPV vaccine was 95% protective against cervical cancer caused by the strains it contains and 100% effective against HPV strains 16 and 18.¹ HPV strains 16 and 18 are said to account for 70% of all cases of cervical cancer. Why, then, would anyone balk at such an effective vaccine against cervical cancer?

The answer is sex. Unlike polio or chickenpox, HPV infection is not transmitted by casual contact. HPV infection is most often transmitted through sexual intercourse. In addition, not every woman infected with HPV will develop cervical cancer.

Protecting our young girls and women with such a vaccine does not promote the behavior that leads to transmission. The discussion should focus on the health of our children. The moral discussion of the behavior that leads to HPV infection rests with the parents in the home, not with state governments.

Should every girl receive this vaccine? Yes. Should it be required to attend school? No.

Stephen R. Boden, MD
Chief, Pediatric Element
Bitburg Annex, Germany, United States Air Force

1. Centers for Disease Control and Prevention. Human papilloma virus. In: Atkinson W, Hamborsky J, McIntyre L, et al, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 10th ed. Washington, DC: Public Health Foundation; 2007:283-294.

Acute Pulmonary Edema: Emergency versus Inpatient Treatment
To the Editor: Thank you for the timely review of acute pulmonary edema PE (February 2007).¹ This illness unites healthcare professionals across the acute care spectrum. For physicians in an emergency medicine residency program, the delivery of effective first-line treatment modalities is of prime importance. Although the management of this disease involves input from different specialties, the article by Dr Barreiro and colleagues underscores an apparent disconnect between emergency and inpatient treatment strategies.

With respect to the patient presenting to the emergency department (ED) with cardiogenic PE, recent research suggests a shift away from the long-standing paradigm of forced diuresis. Patients with PE are not uniformly fluid overloaded, and as many as 40% may actually be intravascularly depleted.² It therefore follows that the hypoperfused kidney will be less responsive to intravenous (IV) diuretics. Furosemide almost never results in "instant diuresis," as suggested in the article.¹ Cardiologists and emergency physicians alike acknowledge that the diuretic response can take up to 2 hours in decompensated patients.³ Effective emergency treatment emphasizes preload reduction. Aggressive nitrate administration is the rule, and patients with severe PE can receive as much as their blood pressure will tolerate.

Maryland's statewide prehospital protocols have recently been updated to reflect this management shift. The routine use of furosemide is discouraged, and treatment priorities involve high-dose sublingual nitroglycerin, noninvasive ventilation, and consideration of an IV angiotensin-converting-enzyme inhibitor. Little research exists to support the routine use of morphine sulfate. Although patients in severe respiratory distress have good reasons to require anxiolysis, morphine is associated with undesirable side effects and potential respiratory depression. A recent study demonstrated that patients who received IV morphine were more likely to require care in the intensive care unit in addition to endotracheal intubation.⁴ The idea of morphine being associated with demonstrable "central" preload reduction has not been borne out in the emergency medicine literature.

The patient presenting to the ED with acute cardiogenic PE represents significant diagnostic and therapeutic challenges. Although diuresis can play a pivotal role in long-term treatment, ED care revolves around the reduction of preload. A targeted strategy that incorporates the liberal use of nitrates and noninvasive ventilation results in better patient outcomes.

Clearly, there is not a "one-strategy-fits-all" approach to the patient in extremis. Some patients will require diuretics, and some will not tolerate aggressive nitroglycerin. Our treatment decisions should be individualized and should incorporate a thorough understanding of disease mechanisms. The reflexive, first-line use of IV diuretics should be discouraged in favor of proven and aggressive preload reduction.

Benjamin Lawner, DO, EMT-P
Resident, Emergency Medicine
University of Maryland Medical System
Amal Mattu, MD, FAAEM
Director, Emergency Medicine Residency Program
University of Maryland School of Medicine

1. Barreiro T, Vijayakumar A, Gemmel D, et al. Pulmonary edema: a clinical overview. Resident & Staff Physician. 2007;53(2):27-34.
2. Mattu A, Martinez JP, Kelly BS. Modern management of cardiogenic pulmonary edema. Emerg Med Clin North Am. 2005;23:1105-1125.
3. Rogers RL, Feller ED, Gottlieb SS. Acute congestive heart failure in the emergency department. Cardiol Clin. 2006;24:115-123, vii.
4. Sacchetti A, Ramoska E, Moakes ME, et al. Effect of ED management on ICU use in acute pulmonary edema. Am J Emerg Med. 1999;17:571-574.

The Authors' Reply: We thank Drs Lawner and Mattu for their comments. Acute cardiogenic pulmonary edema (PE) is prevalent in the emergency department (ED), and when secondary to heart failure (HF) it is the main reason for hospital admissions in the United States.¹ In-hospital and long-term mortality from HF remains high,² but because PE presents as a spectrum of symptoms, the diagnosis is difficult in patients rife with comorbidities. The rate of misdiagnosis in the ED is as high as 12%³ to 20%⁴; misdiagnosis may increase morbidity and mortality.

HF is dichotomized into systolic and diastolic dysfunction, characterized as (1) an inability to pump (systolic HF) or (2) an inability to fill the pump (diastolic HF). This knowledge is rarely obtainable in the ED; imprecise treatments have detrimental effects.

In researching our article, we found a paucity of literature on the ED treatment of acute decompensated HF. However, we would agree that the HF syndrome may result in a decrease in renal blood flow and a decrease in sodium excretion, with an expansion of extracellular fluid volume. Approaches to medical therapy include reduction of pulmonary venous return (preload reduction); reduction of systemic vascular resistance (afterload reduction); and inotropic support, if needed. Preload reduction decreases pulmonary capillary hydrostatic pressure and reduces fluid transudation into the pulmonary interstitium and alveoli. Afterload reduction increases cardiac output and improves renal perfusion, which allow for diuresis in the patient with fluid overload. Patients with severe left ventricular dysfunction or acute valvular disorders may present with hypotension. These patients and preload-dependent patients do not tolerate medications that reduce preload. Therefore, the third goal of treatment is to provide inotropic support to maintain adequate blood pressure. Management of chronic HF would include medications or dietary changes that reduce fluid or sodium retention, medications that improve ventricular function, and those that reduce cardiac workload.⁵

We agree that in acute PE, improving hemodynamics by lowering cardiac filling pressures while relieving vasoconstriction improves dyspnea. Controversy exists about the best agent, and few studies are well-designed. Use of intravenous (IV) vasodilators to treat acute HF and PE makes sound physiologic sense. Nitroglycerin has been the vasodilator of choice, acting to lower preload by increasing venous capacitance.⁶

The use of angiotensin-converting-enzyme (ACE) inhibitors to treat decompensated HF is controversial among cardiologists and emergency physicians,⁷ and the literature is anecdotal. One pilot study showed that sublingual captopril improved hemodynamics in 24 patients with acute cardiogenic PE,⁸ yet no clear conclusions were reached. A small study of 48 patients looked at the effects of adding ACE inhibitors to usual therapy with oxygen, nitrates, morphine, and diuretics for acute PE; the addition of ACE inhibitors produced more rapid clinical improvement than standard treatment.⁹ Early administration of IV enalapril was effective and well-tolerated in patients with decompensated HF.¹⁰ In addition to limited power in the studies, ACE inhibitor use can cause renal dysfunction in volume-depleted patients. Large randomized studies are lacking.

Our hospital actively participated in the Acute Decompensated Heart Failure National Registry (ADHERE). This registry, a multicenter database of patients with HF discharged from hospitals,¹¹ reported that 81% of patients received diuretics and that patients who received therapy with vasodilators (eg, nesiritide, nitroglycerin, nitroprusside) in the ED had a 3.1-day mean decrease in-hospital length of stay. In ADHERE, only 10% of patients did not receive any IV diuretics at any point during their hospitalization.

When comparing patients who do and do not receive IV diuretics, heterogenicity of groups is observed. Patients without diuretics had a shorter length of stay in the intensive care unit and in the hospital and had a lower mortality rate. Loop diuretics, (eg, furosemide) produce an initial increase in pulmonary capillary wedge pressure, mean arterial pressure, and systemic vascular resistance.¹² These data likely were the basis for the comment about the aggressive use of IV diuretics. In one article, an IV loop diuretic (eg, torsemide or furosemide) was stated to lower pulmonary artery wedge pressure by about 25%.¹³ In addition, the registry is not a randomized control trial.

A retrospective chart review suggested that morphine administered in the ED led to a high rate of intubation.¹⁴ Of the 2466 patient records with congestive heart failure or PE, only 181 were analyzed; 25% were dialysis-dependent chronic renal failure patients, and 15% had an emergency department diagnosis of rule out myocardial infarction. In this study, 51% required some form of respiratory support: 22% received bilevel positive airway pressure and 60 (33%) underwent endotracheal intubation, of which 45% were pre-hospital.¹⁴ The retrospective nature of this study and the inability to objectively compare the degree of respiratory distress between patients prevents causal statements that morphine leads to increased intubation.

In our article, we state that PE is a dynamic condition, and treatment should be directed at ensuring adequate oxygenation and maintaining hemodynamic stability while reducing myocardial stress. We write, "Morphine will lessen anxiety, decrease sympathetic outflow, and cause vasodilatation." And, "We caution its use in the presence of decreased sensorium and respiratory drive."

We admire the ED physician who treats this disease state. The ability to determine volume status is difficult. While the role of alpha- and beta-natriuretic peptides has helped in the differential diagnosis, Lawner and Mattu remind us that individual treatment, use of good clinical skills, and knowledge of physiologic differences between right and left HF require an astute physician. Emergency treatment of acute PE should be quickly initiated; vasodilators offer important benefits, but no treatment is perfect. A multi-team, multi-modality approach with individualized treatment is the best approach.

Timothy J. Barreiro, DO, FCCP
David J. Gemmel, PhD

1. Adams KF, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States. Am Heart J. 2005;149:209-216.
2. Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005;46:57-64.
3. Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol. 2001;37:379-385.
4. Peacock WF IV, Emerman CL. Emergency department management of patients with acute decompensated heart failure. Heart Fail Rev. 2004;9:187-193.
5. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. J Am Coll Cardiol. 2001;38:2101-2113.
6. Levy P, Compton S, Welch R, et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin. Ann Emerg Med. (2007 May 15. Online before print.)
7. Rogers RL, Feller ED, Gottlieb SS. Acute congestive heart failure in the emergency department. Cardiol Clin. 2006;24:115-123, vii.
8. Haude M, Steffen W, Erbel R, et al. Sublingual administration of captopril versus nitroglycerin in patients with severe congestive heart failure. Int J Cardiol. 1990;27:351-359.
9. Hamilton RJ, Carter WA, Gallagher EJ. Rapid improvement of acute pulmonary edema with sublingual captopril. Acad Emerg Med. 1996;3:205-212.
10. 1Annane D, Bellissant E, Pussard E, et al. Placebo-controlled, randomized, double-blind study of intravenous enalaprilat efficacy and safety in acute cardiogenic pulmonary edema. Circulation. 1996;94:1316-1324.
11. Fonarow GC. The Acute Decompensated Heart Failure National Registry (ADHERE). Rev Cardiovasc Med. 2003;4 (suppl 7):S21-S30.
12. Francis GS, Siegel RM, Goldsmith SR, et al. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Ann Intern Med. 1985;103:1-6.
13. Moser M. Diuretics in the prevention and treatment of congestive heart failure. Cardiovasc Drugs Ther. 1997;11(suppl 1):273-277.
14. Sacchetti A, Ramoska E, Moakes ME, et al. Effect of ED management on ICU use in acute pulmonary edema. Am J Emerg Med. 1999;17:571-574.