Acute Decompensated Heart Failure

Warm and wet just sounds weird to me. Not only does it allow the mind to drift to undesirable places, it also isn’t reflective of real practice. Whenever I open a pharmacy based text or review article regarding acute decompensated heart failure (ADHF), the first section invariably begins to discuss the Forrester Classification.[1] While it’s a useful visual learning tool, the routine dropping of Swan-Ganz catheters is no more. And who knew Frank Starling is two people! (Frank-Starling) In reality, the acute management of ADHF during the first 2-4 hours in the emergency department is guided based on clinical history, bedside imaging, some laboratory values and the patient’s clinical status. It IS possible to treat ADHF without knowing PCWP, and cardiac index.

While we will use clinical vignettes to frame the drug therapy for ADHF, these are just generalizations. The pharmacotherapy of ADHF is a delicate balance. In one respect, the drugs most feverishly requested relieve symptoms yet can worsen physiology. Furthermore, the drugs that support mortality benefits in long term management, can be detrimental in the acute phase. Couple this with the various pathophysiologic models, it is difficult to make broad generalizations about drug therapy. This chapter focuses on general concepts of ADHF pharmacotherapy in the ED.

Diuresis, Dilation, Inotropy


A 62 year old male was brought in to the ED by EMS for shortness of breath. The patient has been dyspneic for days but today got suddenly worse and called 911. In the ED, he’s now on BiPAP, with an O2 of 88%, heart rate of 108 bpm, blood pressure of 160/110 mmHg and is afebrile. Bedside ultrasound also shows B-lines, IVC congestion. The ED physician is asking for “80 of Lasix.”

Loop diuretics are one of the core components to ADHF management in the ED. These agents act on the Na-K-2CL symporter in the ascending loop of henle, inhibiting the reabsorption of sodium, potassium, and chloride.[2] The resulting diuretic action helps to resolve volume overload and pulmonary congestion. While furosemide is the most commonly used agent in this class, there is no proven benefit over bumetanide.[3,4]

The role of loop diuretics in ADHF is not necessarily limited to the obvious effect of diuresis. Relief of vascular congestion is one action, but loop diuretics also act by acutely increasing systemic venous capacitance and decreasing left ventricular filling pressure via vasodilation.[2] This mechanism is in fact what IV bolus administration of loop diuretics are doing in the ED. The production of prostaglandins that are responsible for improvement in renal perfusion, are thought to mediate these beneficial effects on the heart.[3,4] This action is an important distinction since it can help explain how loop diuretics fit into ADHF management. Conversely, points to the horrifying effects of NSAIDs across the spectrum of heart failure.

A closer examination of the evidence and current understanding of the pathophysiology of heart failure sheds light on the importance of this mechanistic distinction. The rationale for careful consideration of loop diuretics in ADHF starts with understanding that although diuretic therapy improves heart failure symptoms, it does not improve mortality.[5,6] The precise explanation for this is not fully elucidated. However, leading theories point towards the acute diuretic action of these drugs and the effects on the neurohormonal pathophysiology in heart failure.[7-9] Thus, the neurohormonal heart failure model warrants a brief overview.

The current understanding of the pathophysiology of heart failure is based around the neurohormonal model.[1,3,4] As a failing heart struggles to perfuse vital organs numerous physiologic events take place to attempt to augment this action. Perfusion is maintained through activation of the neurohormonal system, consisting of renin-angiotensin-aldosterone system (RAAS) activation, sympathetic nervous system (SNS) activation, increased arginine-vasopressin (AVP) activity, endothelin secretion, and increased immune cell signaling. Increased plasma volume, coupled with impaired venous capacitance increases preload and afterload with corresponding increases in cardiac filling pressures and congestion of pulmonary vasculature.[10-14] The resulting decrease in cardiac output further impairs perfusion to vital organs, leading to further activation of neurohormonal responses. Ultimately, the attempts to maintain perfusion to the heart and other organs results in further insult and progression of the disease.

While the diuresis induced by loop diuretics reduces plasma volume, it also stimulates renin secretion, RAAS activation and the subsequent detrimental effects therein.[6,7] Not to mention, the excess volume was being used to maintain a patch-work state of perfusion to the heart, kidneys, lung and brain. So abrupt removal of this volume can lead to hypoperfusion and potentially ischemia.[8,9]  Furthermore, if the volume eliminated through diuresis is not replaced, the risk of acute kidney injury and a cardiorenal syndrome is increased. This vicious cycle has been called the “recurring cycle of decompensation.”[8] So as it turns out, the very drugs we are deploying to resolve volume overload can untowardly cause intravascular volume depletion, increasing the activation of the SNS, RAAS of the neuroendocrine system with resulting detrimental consequences. This physiologic rationale should not be used as justification for omitting loop diuretics. However, it should raise caution, and adjustments of expectations and therapeutic goals.[14]

There exists yet another consideration, that some ADHF patients may infact be intravascularly volume depleted. As we know, cardiogenic pulmonary edema is a result of high pulmonary capillary hydrostatic pressures that force plasma ultrafiltrate into the pulmonary interstitium.[rosens] In patients with ADHF from a myocardial infarction or rapid increases in vascular resistance/afterload, plasma volume may actually be contracted. So in this setting, attempts at further reducing ‘volume’ with diuresis, or even vasodilation, would be met with worsening ADHF. These patients often require IV fluid bolus administered in delicate aliquots to maintain cardiac output.

After careful consideration, loop diuretics may be administered to improve symptoms of ADHF. Determination of the dose involves investigation into whether the patient is currently taking a loop diuretic prior to admission. If a patient is taking a loop diuretic, the total daily dose should be administered as an IV bolus.[3] Otherwise, a reasonable starting dose of furosemide is 40 mg. Whether an IV bolus or continuous infusion strategy is selected, the guidelines do not make a preference. The DOSE study backs this up, in that there is no difference in continuous vs intermittent bolus and high vs normal dosing of furosemide.[15]  

Bottom line: Loop diuretics have a place in ADHF, just not what you think. Dilation is a key effect and diuresis is a double edge sword.

  • Furosemide
    • Dose: 40-160 mg IV (usually take the patients total daily dose and administer IV)
  • Bumetanide
    • Dose: 0.5-4 mg IV (usually take the patients total daily dose and administer IV)
  • IV onset 5-15 minutes for vasodilation, 20-30 for diuresis
  • PO bioavailability in ADHF is poor, so IV is preferred

Expanded diuresis:

High dose loop diuretic, addition of thiazide/metolazone for diuretic resistanc

The 62 year old ADHF patient received furosemide 80 mg IV push, but after 15 minutes, is still not improving- oxygen saturation sill below 90% on BiPAP, tachycardic and hypertensive in the 160’s. The nurse at the bedside suggests 1 mg bolus of nitroglycerin.


Vasodilators play another key role in ADHF by optimizing perfusion and cardiac functioning. Nitroglycerin, the primary vasodilator for ADHF, is actually a prodrug.[18-20] Nitroglycerin has three nitrooxy moieties that liberate nitric oxide (NO) after bioactivation. This NO then goes on to activate soluble guanylyl cyclase which forms cGMP. cGMP then activates protein kinase G which reduces intracellular calcium by and enhancing reuptake of calcium into the sarcoplasmic reticulum, and moves calcium to the extracellular compartment. This reduction in intracellular calcium causes smooth muscle relaxation since the ability of myosin light chain kinase to phosphorylate myosin is impaired.

At ‘normal’ doses (less than 200 mcg/min), nitroglycerin predominantly acts as a vasodilator. In this dose range, nitroglycerin improves pulmonary congestion symptoms by reducing preload and improving venous capacitance.[20] At higher doses (more than 200 mcg/min), nitroglycerin acts as an arterial dilator, reducing afterload and increasing cardiac output. As a means of rapidly achieving arterial, and pulmonary arterial dilation, large bolus doses of nitroglycerin have been evaluated in the ED.[21,22] As of now, there are no adequate evaluations to say whether high dose nitroglycerin is any better than normal (adequate normal dosing, not 5 mcg/min and walking away).

Nitroglycerin is one of the vasodilators in patients who are not hypotensive (SBP > 100 mmHg), and are still experiencing ADHF symptoms (dyspnea) after diuretic therapy.[3] Alternate therapies include nitroprusside and nesiritide. Similar to diuretics, however, vasodilators have not consistently shown benefits in mortality.[23] As adjuncts to diuretic therapy, vasodilators improve symptoms, blood pressure, intubation rates, and mortality in heart failure, however, these data include long acting nitrates, in addition to short acting vasodilator nitrates.[24-26] Considering their place in therapy and level of evidence, the AHA rightfully places a IIb recommendation on the use of nitrate vasodilators.[3]

Nitroglycerin comes in a plethora of dosage forms. For ADHF, the more commonly used preparations are the IV dosage form and paste. If a patient doesn’t have IV access, nitroglycerin paste could be used. However, caution should be taken since if the patient’s blood pressure drops, or are highly dependent on venous return, getting IV access and subsequent fluid/norepinephrine/epinephrine would be extremely challenging. I highly caution this application since, as described above, nitroglycerin is not a mortality benefiting intervention. With that said, if paste is selected, it’s useful to have an idea of how much it roughly converts to in IV dose. The application of 1.0 inches of paste converts to approximately 10-40 mcg/min, correspondingly, 2.0 inches converts to 60-100 mcg/min. For more on this, see this Classic EM PharmD post.

Although recommended alongside nitroglycerin as first line vasodilators in the guidelines, nesiritide and nitroprusside are not commonly used in the ED to manage ADHF, and for good reason. Nesiritide, a recombinant form of BNP, was at one point ubiquitously used in the ED for management of ADHF. Acting as exogenously administered BNP, nesiritide produced both arterial and venous dilation, and improvements in ADHF symptoms. However, a combination of controversial and conflicting literature, no proven benefit over nitroglycerin, no mortality benefit, and a much much higher cost, the use of nesiritide has faded to the fringes of heart failure.[27-32] Save for critical drug shortages, that is.

Nitroprusside is one of the few structures I can draw. Namely since it’s an iron bound to 5x CN moieties and one NO. In order to liberate the NO, nitroprusside reacts with oxyhemoglobin to produce methemoglobin and cyanide.[18] So although it is a NO donor, arterial and venous dilator, it has the consequence of exposing the patient to cyanide. While low doses, for short periods of time, nitroprusside isn’t necessarily hazardous since most patients have the ability to detoxify cyanide to the much less toxic thiocyanate. The cumbersome safety concerns with nitroprusside restrict its use to refractory cases.

Bottom line:

Nitroglycerin can help improve ADHF symptoms in conjunction with diuretics. At best, it can reduce the need for intubation and potentially serves a benefit in mortality. Nesiritide may be an alternative, but cost and safety are considerations. Nitroprusside best be reserved for highly selected cases.

Expanded dilation:

  • I can’t believe low-dose dopamine is still a recommendation[3,32,33 ]
  • Textbooks talk extensively about ‘vaptans.’ A) No role in the ED, B) stop working when they’re stopped, C) significant drug interactions, ADRs and contraindications.
  • IV enalaprilat – interesting, but effects better applied over long term
  • Coronary steal is an old pimping question with nitroprusside. Know for pharmacy trivia

A 72 year old female with history of CHF and recently discharged from this hospital 2 weeks ago for an ADHF episode. She arrives to the ED via EMS on CPAP for shortness of breath at home for 3 days. In the ED, she is cold, poor capillary refill, hypoxic, tachycardic (110s) and hypotensive 80 mmHg SBP. A peripheral 20 gauge IV in the right forearm is the only access currently.


ADHF may progress, or initially present in a state where cardiac output is sufficiently low that results in end-organ dysfunction. While ADHF in any severity is fundamentally end-organ dysfunction, the distinction of cardiogenic shock (the presence of hypotension, pulmonary edema, and peripheral hypoperfusion) eliminates conventional ADHF approaches of diuretics and dilation. In order to achieve the therapeutic goal of reestablishing cardiac output sufficient to perfuse vital tissue, inotropic therapy is needed. The term inotropic is imprecise and the superior method of categorizing these agents is the following: inotrope, inoDILATOR, inoPRESSOR, vasoPRESSOR. This is an important distinction since by the old nomenclature, an inotrope includes drugs like dopamine, dobutamine, milrinone, isoproterenol, and norepinephrine. However, at normal therapeutic dosing, dobutamine and milrinone improve cardiac contractility and rate, and have no net effect on vascular resistance. Norepinephrine and dopamine, increase both heart contractility, rate and vasoconstrict, while isoproterenol improves contractility, rate and vasodilates. For ADHF selecting the appropriate inotrope, inoDILATOR or inoPRESSOR is critical. Strict vasopressors include phenylephrine, vasopressin and angiotensin-II.

As the case above describes, it is very difficult do determine which inodilator or inopressor is appropriate in ADHF. Invasive monitoring is almost never available, and modern techniques of point of care ultrasound are not routine practice in all emergency departments (such as community hospitals). Therefore, selection of appropriate cardiac drug support is challenging and has to be guided empirically. InoPressor therapy is a logical method to improve contractility and perfusion since these patients may be hypotensive. However, given that many ADHF-shock patients have low cardiac output but increased peripheral vasoconstriction. Further efforts of vasoconstriction would only worsen afterload, thereby decreasing cardiac output, increasing tissue oxygen demand. Ultimately this can precipitate further ischemia and arrhythmias. Balancing these risks, inopressor and inodilator therapy should only be continued for the shortest time necessary. Most literature points towards increasing mortality with the use of inodilator therapy.[3] However, it is still debated as to whether this is an independent predictor/cause of increase mortality, or rather, patients at already higher risk of mortality require inopressor and inodilator more often.

As it stands in the AHA guidelines, inodilator therapy is reserved for patients who exhibit signs of end-organ dysfunction (cardiogenic shock) or as a bridge to some other definitive care (for example, heart transplant).[3] The agents the AHA guidelines are referring to include the inodilators dobutamine and milrinone, and the inopressor dopamine. What’s missing from the guidelines is guidance on norepinephrine. A different, and more comprehensive approach to management of cardiogenic shock is outlines in the ACC/AHA guidelines for STEMI.[34] These guidelines offer guidance on the selection of inodilator vs inopressor as a function of systolic blood pressure.

SBP 70 to 100 mm Hg without signs of shock
Dobutamine or milrinone is preferred in patients without shock since they may contractility without increasing afterload. As you’ll recall, blood pressure is the product of cardiac output and systemic vascular resistance, by increasing the cardiac output with an inodilator which should not impact SVR at normal doses will lead to a net improvement in perfusion. The act of increasing vascular resistance with a vasopressor or inopressor here would worsen afterload and potentially decrease cardiac output.[34]

DOBUtamine, a beta-1 agonist is the preferred agent.[3] As a racemic mixture, dobutamine exhibits some dose-dependent characteristics. At normal therapeutic dosing (2-20 mcg/kg/min), the (+) enantiomer’s effects of beta-1 and beta-2 agonism predominate. At escalating doses (>20 mcg/kg/min), the (-) enantiomers alpha-1 agonist effects at high doses, becoming an inopressor. This increase in SVR and afterload becomes counterproductive to the goals of therapy in ADHF.[18, 35] Patients with concomitant use of beta-blockers may have blunted or unpredictable responses to dobutamine.

Like dobutamine, milrinone increases cAMP although it does so via phosphodiesterase-3 inhibition rather than adrenergic stimulation.  It’s inodilator effects are similar to dobutamine, but is not first line due to a higher propensity to decrease vascular resistance and cause hypotension. This decrease in vascular resistance extends to the pulmonary vasculature, making milrinone preferable in certain patient populations, such as those with pulmonary hypertension.[36]

Milrinone is often utilized as an outpatient bridge-strategy and knowledge of it and how to convert outpatient infusions to inpatient formulations is important. However, milrinone may have a unique role in patients on high dose beta-blockers since it can bypass beta-blockade to exert its inodilatory effects. [37,38]  The normal dosing of milrinone includes a loading dose (25-75 mcg/kg) followed by a continuous infusion between 0.375 to 0.75 mcg/kg/min. The loading dose is often omitted due to risk of excessive hypotension. Furthermore, medication accumulation in renal failure patients, ultimately leads to limited clinical use of this drug is limited.

SBP < 100 mm Hg with shock

DOPAmine when systolic blood pressure is between 70 and 100 mmHg with signs of shock.[34]
NOREPInephrine when systolic is less than 70 mm Hg with signs of shock.[34]

If shock is present, inoPRESSORs are the agents of choice. Inopressors will improve contractility as well as vascular resistance. This benefit is weighted against the higher risk of worsening myocardial ischemia and causing arrhythmias. The two inopressors recommended are dopamine and norepinephrine.

Dopamine is an indirect (effectively a prodrug) catecholamine through interaction with different receptors with escalating doses. As is almost ubiquitously thought, the receptor activity of dopamine changes depending on the given dose; D1 agonist 0-3 mcg/kg/min, beta agonist 3-10 mcg/kg/min and alpha agonist activity > 10 mcg/kg/min. However, patients do not predictably respond in this manner since there these effects have significant (10 to 75 fold) interpatient variability.[39] Should dopamine be selected, it’s wise to start with these dosing concepts, but the dose should be titrated to the desired clinical end point, rather than adhering to dose ranges. Furthermore, low dose or “renal dose” dopamine is targeted towards D1 receptor activation, activating adenylyl cyclase via Gs and increase cAMP in neurons and vascular smooth muscle. Although associated with increased mortality, it’s somehow making a comeback in the ADHF population.[33]

Norepinephrine, a balanced alpha-1 and beta-1 agonist, should be selected for patients with cardiogenic shock with SBP less than 70.[34] When compared with dopamine, NOREPinephrine is associated with trends toward improved mortality and lower risk of arrhythmogenesis, specifically in cardiogenic shock populations.[40] Norepinephrine is similarly preferred to epinephrine for cardiogenic shock due to myocardial infarction.[41]

Norepinephrine should be started at 0.1 mcg/kg/min, but titrated rapidly to achieve desired endpoint. The concern often arises of starting norepinephrine in a peripheral IV line, due to a perceived higher risk of extravasation compared to a central IV. While in general, this is true, peripheral norepinephrine is acceptable if there is reliable access in the forearm (not antecubital fossa or the hand) and limited to 4 hours or less.[42] By this time, one would hope that central access could be secured.

Bottom line

Inotropes/pressor/dilators are important agents for cardiogenic shock. While it would be nice to have invasive monitoring in ADHF in the ED, it isn’t always available, and not practical in the hyperacute setting. Thoughtful consideration of both the pharmacology and physiologic implications coupled with advanced monitoring to be able to change doses or strategies on a dime is a sound approach.

Expanded inotrope:

  • Weight based vs non-weight based norepinephrine and epinephrine dosing
  • Renal dose dopamine?
  • Digoxin…
  • Unavailable agents – levosimendan


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