Pharmacological Interventions for Cardiopulmonary Emergencies (Clinical Essentials) (Paramedic Care) Part 7


Patients without prior experience with diuretics may unpredictably experience a diuresis of large quantities of urine. The result can be severe hypovolemia, hypoperfusion, and frank shock. In those cases, gentle rehydration with intravenous solutions, such as Ringer’s lactate, can re-establish lost volume and restore the blood pressure.

Overly aggressive treatment of congestive heart failure, usually manifested by pulmonary edema, can also lead to even greater problems in the care of the patient over the long term. When confronted with a patient with pulmonary edema, Paramedics may be inclined to think that the patient is fluid overloaded. More accurately, these patients are fluid misplaced. That is, the blood is being sequestered in the venous circulation (venous pool) and is putting pressure on the failing heart to pump it forward. There are two treatment pathways to relieve this condition. First, the Paramedic can cause a diuresis which will in turn reduce the blood volume returning to the heart. Alternatively, the Paramedic can increase the venous pool’s capacitance, temporarily relieving the heart’s burden and allowing it to recover.

The classic diuretic for the treatment of acute pulmonary edema has been furosemide. Prompt treatment with furosemide will provide the patient with immediate relief of symptoms.117,118 This relief is due to the two-fold action of furosemide. Furosemide’s immediate effect is as a vasodilator. Within five minutes of administration, furosemide reduces the heart’s work by reducing the preload through vasodila-tion, increasing the venous pool capacitance. Following the vasodilatation, within 20 minutes of the onset of action furosemide causes diuresis. This diuresis removes fluid from the central circulation and reduces the heart’s work.

Patients in acute heart failure are not suffering from being fluid-overloaded. More correctly, the blood volume is improperly distributed, leading to an input-output mismatch. Vasodilator therapy may be more beneficial to the patient in the long run. More discussion about vasodilator therapy follows.

Potassium, an important cardiac electrolyte, is closely associated with sodium. As loop diuretics cause the excretion of sodium, they also cause a loss of potassium, earning them the label "potassium wasters." Serious potentially life-threatening cardiac dysrhythmias can follow the development of low serum potassium or hypokalemia. For this reason, potassium supplements are often co-prescribed to patients on loop diuretics. True toxicity from loop diuretics is rare. For example, patients have been given 2,000 mg of furosemide without toxic effect. This "high ceiling" makes these diuretics relatively safe to administer.

Osmotic Diuretics

Any substance with a large molecular weight which cannot pass through a semipermeable membrane will create an osmotic effect. The presence of formed elements and blood proteins, such as albumin, in the bloodstream creates an osmotic effect. This effect, called colloidal osmotic pressure (COP), occurs because these large molecules cannot pass through the blood vessel walls.

Similarly, when chemicals with a large molecular weight (i.e., heavy molecules) pass into the filtrate via the fenestrated membranes within the kidney (a very forgiving membrane that is 100 to 400 times more permeable than ordinary capillaries) and travel to the loop of Henle to encounter a semiper-meable membrane, they are entrapped. However, these heavy molecules continue to create an osmotic effect and thus draw fluids into the filtrate.

Examples of heavy molecules that are effective osmotic diuretics include mannitol (a complex sugar) and urea. Osmotic diuretics are used to reduce edema in special cases; for example, mannitol is used to treat increased intracranial pressure secondary to cerebral edema. Osmotic diuretics are also used to prevent kidney failure by forcing a continuous diuresis.

Caution must be exercised whenever osmotic diuretics are administered. Overly aggressive treatment can result in hypo-volemia (leading to hypoperfusion and shock), hypokalemia (leading to ventricular dysrhythmias), and hyponatremia (leading to seizures).

Distal Tubule Diuretics

The thiazides were one of the first diuretics used in medical therapeutics for the treatment of heart failure. As sulfonamide derivatives, the thiazides also work like carbonic anhydrase inhibitors. However, they work in the distal tubule instead of the proximal tubule.

Thiazides inhibit the reabsorption of sodium and therefore increase the excretion of sodium in the urine. The urine, now hyperosmolar, collects more water as it passes through the tubules. Thiazides also increase the excretion of potassium along with the sodium.

Indications for thiazides, such as hydrochlorothiazide, include relief from mild to moderate heart failure as well as the treatment of mild to moderate hypertension. Thiazides are often preferred as a treatment for hypertension because they are inexpensive (a benefit for patients on a fixed income), easy to administer, and have fewer side effects than other diuretics.

Thiazides are also potassium wasters and have the same precautions as other potassium wasters. Potassium depletion can, for example, predispose a patient to a number of dysrhythmias.

Potassium-Sparing Diuretics

Potassium-sparing diuretics are particularly attractive for use in patients who are sensitive to hypokalemia (e.g., patients on digitalis) or patients who require a diuretic therapy but who cannot tolerate potassium supplements. Unfortunately, potassium-sparing diuretics, as a class, are weak diuretics. To improve their efficiency, as well as maintain the advantage of preserving potassium, they are often given in combination with the thiazides.

Several agents (e.g., amiloride and triamterene) work indirectly in the distal tubule, while spironolactone works by blocking the effects of aldosterone in the distal tubule. As a result of these two actions, sodium and water are excreted and potassium is retained.

Spironolactone, as an aldosterone-antagonist, also has a secondary use in the treatment of hyperaldosteronism, an adrenal disease.

Vasodilator Therapy

Certain vasodilators work on the same mechanism as nitrates, thereby creating a direct vasodilation in the blood vessels. Since a larger portion of blood and blood vessels is on the venous side of the central circulation, the venous side is more affected. This causes a drop in the venous pressure and therefore the amount of preload the heart receives.

Alternatively, other vasodilators create relaxation of the muscle within the vessel walls, resulting in dilation. Since arteries and arterioles have more muscle than veins and venules, these medications have a more pronounced effect on the arterial side of the central circulation. Arterial vasodila-tion directly translates to lowered diastolic pressure, reduced peripheral vascular resistance, and a reduction in cardiac afterload.119

Afterload Reduction

The arteriole beds are largely controlled by the alpha receptors of the sympathetic nervous system. Alpha-receptor antagonists prevent vasoconstriction and the resulting increases in peripheral vascular resistance (afterload) that occur as a result of vasoconstriction. An example of an alpha-blocker is hydralazine, a current and commonly used alpha-blocker.

The difficulty with using alpha-blockers lies in the sympathetic nervous system’s response to the decrease in diastolic pressure. The baroreceptors reflexively stimulate the sympathetic nervous system to increase the blood pressure. This is achieved via peripheral vasoconstriction, now inhibited by the alpha-blockers, and tachycardia. This tachycardia can tax the already overtaxed heart and induce ischemia. To prevent this reflexive tachycardia, a beta-blocker is often given in combination with the alpha-blocker in an effort to balance the effects of each.

Other arterioles affecting antihypertensives work directly upon the smooth muscles in the arteriole walls. These agents, usually administered intravenously, are very effective in reducing peripheral vascular resistance (the diastolic blood pressure) and reduce the heart’s work.

Unfortunately, the same issue exists for these agents (e.g., diazoxide) as did for the alpha-blockers. Again, beta-blockers are occasionally co-prescribed to balance the effects of each.

Preload Reduction

In the not too distant past, Paramedics used a device called a "rotating tourniquet" to mechanically sequester blood in the periphery. That technique, though fraught with complications, was effective in reducing preload. Today, medications are used to obtain a similar effect.

Nitrates are potent vasodilators, and their main impact is on the venous circulation. Dilating the venous circulation, nitrates increase the "pooling" of blood in the venous circulation and reduce the preload returning to the heart. In essence, nitrates create an "internal phlebotomy" by withholding blood from the central circulation.

A number of long-acting nitrates have been developed for this purpose. Perhaps the earliest long-acting nitrates were oral preparations, such as isosorbide. Isosorbide now comes in extended release capsules, chewable tablets, and sublingual tablets.

To further extend the vasodilator effects, nitrates are also available in transdermal systems. These "patch" systems contain nitrate in a gel-like "reservoir." After the gel melts, the drug passes through the skin and then is absorbed, by passive diffusion, into the bloodstream. There are a number of patch systems on the market and each works in a slightly different manner.

Paramedics often use nitroglycerin paste for the same effect. A ribbon of paste, measured in one-half inch increments, is placed on an impervious paper and placed against the patient’s skin. The selection of a site for the paste’s placement is important. The paste should be applied to a hairless area, usually on the upper anterior chest, where it is clearly visible. Avoid placing the patch below the knees or elbows. Circulation is frequently poor in these areas and absorption less predictable.

Alternative placement sites include the shoulder or the inside of the upper arm. Some Paramedics will loosely encircle the limb with a plastic wrap to prevent liquefied nitroglyc-erin paste from dripping.

In every case, it is important to report where the paste was applied when patient care is transferred. Nitroglycerin can induce significant hypotension, in which case the first action should be to remove the paste. Failure to notify other providers of the presence of nitroglycerin paste can lead to inappropriate treatment of the hypotension.

Nitroprusside is an effective intravenous vasodilator that has a greater impact on the venous circulation (preload) than on the arterial circulation (afterload), making it attractive for the treatment of acute heart failure, especially heart failure secondary to valvular regurgitation. Nitroprusside is also used to treat acute hypertensive crisis, an abnormal and potentially life-threatening elevation of blood pressure.

Chemically, nitroprusside contains five cyanide groups bound to nitric acid, the active ingredient in nitroglycerin, within its structure. When the nitric acid breaks off and causes vasodilation, the cyanide remains. The free cyanide is then metabolized into thiosulfate by the liver and excreted harmlessly.

When the level of cyanide exceeds the liver’s capacity to detoxify it, then cyanide poisoning can occur. Fortunately, the half-life of nitroprusside is 2.7 days. Cyanide levels can be tested daily to ensure that the patient remains symptom-free.

Nitroprusside infusions are easily identified because the solution container must be protected from light. Therefore, the IV bag is always covered with aluminum foil or another similarly opaque material.

Nitroprusside infusions must be very carefully titrated, typically to the patient’s blood pressure, starting at 0.3 micrograms per kilogram of patient’s weight per minute (mcg/kg/ min). Therefore, nitroprusside infusions are typically placed on an infusion pump.

Cardiac Glycosides

Digitalis is the quintessential cardiac glycoside. One of the few plants that make a steroid similar to animal steroids, digitalis is processed from the foxglove plant. Used for hundreds of years as the "housewife’s recipe" for swelling and edema, digitalis did not enter into modern pharmacy until 1876.120 The story is told of a patient who went to Dr. William Withering, a Scottish physician, with "dropsy" (congestive heart failure) and was diagnosed as incurable. The patient then went to a gypsy who treated him with a secret herbal remedy and he recovered. Intrigued, Dr. Withering sought out the gypsy and bartered for the remedy. The key ingredient in the concoction was the purple foxglove, digitalis purpurea (L).

Digitalis had long been known for its toxicity, having been used by the Romans as rat poison and in medieval "trials by ordeal." However, it was not thought to have many medicinal uses. Dr. Withering made his fortune on the "discovery" of the medicinal uses of digitalis after he recounted its benefits in a treatise entitled, "An Account of Foxglove." In that treatise, he strongly advised that the effects of digitalis on the patient be closely monitored and that it was imperative to individualize the dose and schedule. No wiser words could have been offered as digitalis toxicity is a common impediment to the drug’s use.20

Mechanism of Action

Digitalis has two unique therapeutic benefits: a slowing of the cardiac conduction, resulting in increased ventricular filling, and increased strength of contraction without the use of additional oxygen. Together, these effects culminate in an overall decrease in the heart’s work. This is a desirable situation for the compromised myocardium, as it allows for more efficient functioning.

Digitalis acts by binding to and disabling (blocking) Na+/ K+ ATPase, the enzyme that breaks down ATP to release its energy. Without ATP breakdown there is no energy to power the Na+/K+ pump during repolarization. The accumulation of intracellular sodium, which results from the failure of the sodium-potassium pump, leads to an ionic imbalance. Calcium is then exchanged to help maintain that balance.

The slowed depolarization prolongs the cardiac cycle (a negative chronotropic and negative dromotropic effect), leading to reduced heart rate. This maximizes the diastolic potential of Starling’s Law, as the slowed heart has more time for ventricular and coronary artery filling.

The heart is further slowed when digitalis inhibits the calcium-sensitive AV node from passing the action potential down the bundle branches to the ventricles. This slowing of AV node conduction can be observed by a lengthening of the PR interval.

The increased calcium also produces more excitation-coupling of actin and myosin in the ventricle’s myocardial fibers and a stronger contraction of the now overfilled ventricle. This improvement in the strength of contraction, a positive inotropic effect, is done without consuming additional oxygen.

Electrocardiographically, the digitalis effect can be seen by the prolonged PR interval, the shortened QT interval, and an inverted T wave, the impact of altered repolarization opposite of the major QRS forces (Figure 30-11).


In the past, a common cause of congestive heart failure was the loss of atrial kick, which contributes approximately 25% of the cardiac output. It also accompanied new onset atrial fibrillation.121 In this situation, digitalis slows the racing heart, which was trying to compensate for the ventricular filling pressure lost to atrial fibrillation. Slowing the heart rate allowed for more ventricular filling and thus led to an augmented cardiac output. The positive inotropic effect of digitalis can further improve cardiac output to levels that are tolerable for the patient. It should be noted that digitalis does not convert atrial fibrillation back into normal sinus rhythm, but instead merely slows the ventricular response.

Currently, digitalis has been replaced with better Class II and III agents, which slow the heart without the serious side effects and dangers of digitalis toxicity, some of which will be explained shortly. In many cases of atrial fibrillation, the etiology is identified and eliminated (if possible), sometimes by radio ablation therapy in the electrophysiology lab of a cardiac care center.

Digitalis may still have a therapeutic advantage in treating congestive heart failure from other causes. No other single chemotherapeutic agent has the same dual actions—negative chronotropy and positive inotropy—as digitalis.


A new-onset atrial fibrillation may mask the tell-tale ECG signs of Wolff-Parkinson-White (WPW) syndrome. Digitalis mistakenly administered in those cases allows uninhibited conduction over the bypass tract, as the AV node conduction is slowed by the digitalis. The resulting antegrade conduction over the bypass tract, in concert with normal conduction down the intra-atrial pathways, can contribute to circus movement and high rate tachycardia, which may eventually deteriorate into ventricular tachycardia/fibrillation.

The digitalis effect demonstrated on ECG.

Figure 30-11 The digitalis effect demonstrated on ECG.

Digitalis also has a relative contraindication during heart block. The impact of digitalis upon the calcium-sensitive AV node can further slow conduction through the AV node and aggravate a pre-existing heart block, causing profound brady-cardia and hypotension.

Digitalis Toxicity

Digitalis has a narrow therapeutic range. As a result, the incidence of toxicity is fairly high, so much so that between 10% and 20% of nursing home patients receiving digitalis will develop digitalis toxicity during the course of treatment. The early identification and treatment of digitalis toxicity will help to decrease the estimated 34% moderate to severe morbidity associated with digitalis toxicity.

Several conditions contribute to the problem of digitalis toxicity. For one, digitalis is primarily excreted via the kidneys. Therefore, any change in kidney function, such as can occur with heart failure, can cause an increase in digitalis to toxic levels.122

Digitalis also affects the sodium-potassium pump. Ordinary doses of digitalis administered to a patient with hypokalemia can result in toxicity. This toxicity is not a true toxicity, but rather a pseudo-toxicity (the relative imbalance between the regular dose and the desired therapeutic effect, which is exaggerated by the hypokalemia). This pseudo-toxicity is sometimes occasioned by the concurrent use of the potassium-wasting diuretic furosemide.

The mechanism of cardiotoxicity relates to the intra-cellular calcium overload, which results from high levels of digitalis. This increased calcium load has a two-fold effect. First, it increases spontaneous afterdepolarizations in the myocardium. These afterdepolarizations create ectopic beats, including junctional and ventricular extrasystoles. Unabated, the heightened reactivity of the myocardium can lead to junc-tional tachycardia and ventricular tachycardia/flutter.

Concurrent calcium buildup within the AV node depresses the AV node, causing bradycardia, as low as "35 beats in a minute."120 It can even create a complete AV block. This ECG manifestation, AV blocks of varying degrees, is seen in 30% to 40% of patients with digitalis toxicity.

Extreme digitalis-induced AV dissociation sets the stage for a rare but potentially lethal phenomenon called "bidirectional tachycardia." Bidirectional tachycardia is the result of concurrent atrial and junctional/ventricular tachycardia with a complete heart block at the AV node.

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