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Diuretic use in critical care
Diuretic Usein Critical Care ROBERT G. NARINS, MD, and PAULINE CHUSID, MD
mia are reviewed, and the rational use of loop diuretii and hypertonic saline is outlined. The 3 loopactive agents inhibit calcium reabsorption in the thiik ascending limb of Henle’s loop and therefore have proved useful in treating hypercalcemia. A practical approach to the diurettc-saline treatment of severe hypercalcemia ts outlined. The katiuretic effect of loop diuretics can be used to advantage in patients with acute or chronic hyperkalemia. A guide to such therapy is described.
Diuretics have found wide application in crkical care medicine. The use of mannitol and loop diuretics in a variety of Me-threatening disorders is reviewed. The combined venodllatory and natrluretic effects of bumetankte, furosemide and ethacrynic acid relieve congestive symptoms in pulmonary edema. Although c ommonly administered to prevent development of acute tubular necrosis or in varying stages of evolving disease, few data are available to demonstrate the efficacy of mannltol or loop diuretics. An approach to the dtguric patient with acute tubular necrosis is described. The dangers of hyponatre-
(Am J Cardiol 1966;57:26A-32A)
T
he usefulness of “loop-active” diuretics (bumetanide, furosemide and ethacrynic acid) in critically ill patients derives from their blockade of electrolyte transport in the medullary and cortical thick ascending limb of Henle’s loop. Venodilatation is their only extrarenal action that has been found of clinical utility. The application of these agents to desperate clinical settings forms the basis of this review. After briefly establishing the biochemical and physiologic principles underlying the action of these agents, their use in specific clinical settings will be described.
competitors, transport of loop-active agents into the tubular lumen is impeded, causing the plasma levels of bound and free diuretic to increase. Increasing glomerular filtration soon replaces the decreasing tubular secretion as the major route for nephronal entry.3 In the presence of probenecid, furosemide’s duration of action is prolonged, due to its slower tubular entry.3 The thick ascending limb is the only clinically significant renal site of action of these diuretics.* Recent studies indicate that these agents inhibit a sodium, potassium, chloride cotransport system in the urinary plasma membrane of thick ascending limb epithelia.4 Thus, this site normally mediates reabsorption of 1 mEq of sodium, 1 mEq of potassium and 2 mEq of chloride. Back diffusion of some cation without anion generates the normal lumen-positive electrical potential in the thick ascending limb. This positive luminal charge allows for the passive reabsorption of calcium. The thick ascending limb may also actively reabsorb calcium.5 The important physiologic and pathologic consequences of inhibiting this cotransporter are discussed next. Natriuresis and extracellular fluid (ECF) volume contraction: Inhibition of the thick ascending limb sodium reabsorption causes delivery to more distal tubular sites of an amount of sodium that acutely overwhelms the distal reabsorptive capacity. Resulting loss of sodium with water causes contraction of ECF volume. Under controlled conditions, loop-active diuretics can effect loss of 20 to 30% of the glomerular filtrate. Thus, they may cause enormous salt and water losses. As the ECF volume shrinks, a series of counter-
RenalEffects of Loop-ActiveDiuretics Pharmacologic and physiologic principles: These agents inhibit electrolyte transport by acting at the luminal surface of the epithelial cells of the thick ascending limb. Extensive albumin-binding markedly retards their glomerular filtration, making the luminal entry vitally dependent on proximal tubular secreti0n.l These organic anions are actively transported from peritubular capillary blood into the urine by a generic organic anion transporter, located in the proximal convoluted tubule. Additional substrates for the transporter include lactate, urate, ketone anions and such drugs as probenecid, penicillin and various cephalosporin antibiotics.2 Thus, in the presence of these From the Temple Univdrsity Health Sciences Center, Philadelphia, Pennsylvania. Address for reprints: Robert G. Narins, MD, Renal Section, Temple University Health Sciences Center, 3401 North Broad Street, Philadelphia, Pennsylvania 19140. 26A
January
24. 1986
vailing hormonal, neurologic, hemodynamic and physical intrarenal changes are provoked that stimulate sodium and water reabsorption at tubular sites proximal and distal to the locus of diuretic action.4.6 These offsetting events eventually limit the continuing effectiveness of the diuretic. Addition of proximally (aminophylline) or distally (thiazides) active agents will reestablish the diuresis. The urinary sodium concentration during loop blockade is almost always less than that in serum; in other words, the diuretics induce urinary loss of dilute solutions of sodium. Failure to drink or otherwise receive water will therefore result in hypernatremia. Conversely, ingestion of more electrolyte-free water than can be excreted during diuretic therapy results in water retention and hyponatremia. Altered renal water metabolism: The thick ascending limb is always “waterproof”! The reabsorption of sodium chloride and potassium chloride without water at once renders the luminal filtrate dilute and the medullary interstitium concentrated. In the absence of antidiuretic hormone, the continued removal of solute without its solvent (i.e., water] allows for excretion of potentially large quantities of electrolyte-free water. Thus, large ingestions of water are easily excreted. It follows that loop-active diuretics impair the generation and excretion of solute-free water, and thereby sensitize treated subjects exposed to excessive amounts of water to hyponatremia. Antidiuretic hormone stimulates sodium chloride reabsorption by the thick ascending limb7 and mediates osmotic communication between the dilute fluid in the distal nephron and the more hypertonic medullary interstitium. In the presence of antidiuretic hormone, electrolyte-free water enters the medulla, causing excretion of highly concentrated urine. The medullary hypertonicity is created by the local retention of electrolyte reabsorbed from the thick ascending limb. Because the free-water reabsorption ultimately depends on solute transported in the thick ascending limb, it follows that loop-active agents must also impair the renal concentrating capacity. Thus, maximal dilution and maximal concentration by kidneys exposed to these drugs becomes impaired. However, the excretion of large volumes of the submaximally dilute urine induced by these agents is used advantageously when it is crucial to rid the body of free water (see below). Kaliuresis: Renal potassium wasting is an intrinsic effect of all 3 loop-active diuretics. In addition to inhibiting its reabsorption in the thick ascending limb, distal potassium secretion is also stimulated by these agents. Diuretic-induced increases in distal sodium and water dilute luminal potassium concentration, thereby creating a cell-to-lumen concentration gradient that favors enhanced secretion. The associated ECF volume contraction ensures that abundant amounts of aldosterone will be available to stimulate distal potassium secretion further. The resulting loss of potassium may be an unwanted effect to be guarded against or replenished, or it can be a wanted effect, as when loop-agents are used in treating certain hyperkalemic states. Calcium excretion: Bumetanide, furosemide and ethacrynic acid all inhibit calcium reabsorption in the
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thick ascending limb, causing hypercalciuria. Inhibition of salt transport reduces or nullifies the normal positive luminal potential (as just discussed], thereby inhibiting passive calcium reabsorption. While longterm use of these diuretics does not seem to deplete body stores of calcium,2 acute high-dose therapy, coupled with replacement of excreted salt and water, effects striking hypercalciuria and reduces dangerously elevated serum levels. These agents have an important role in treating hypercalcemic states.
Venodilatation Although incompletely understood, it is clear that loop-active agents rapidly increase venous capacitance with sequestration of a significant fraction of the blood volume in this low pressure locus.* This “internal phlebotomy” in response to parenterally administered loop agents strikingly lowers pulmonary capillary wedge pressure (PCWP) within 15 minutes. This effect preceeds any diuresis and is equally demonstrable in anephric patients or animals.
Use of Loop-ActiveAgentsin EmergentSettings Acute pulmonary edema: Loop-active diuretics rapidly improve congestive symptoms by abruptly lowering cardiac preload. Within minutes of parenteral administration, venous capacitance first increases followed by the onset of brisk natriuresis. The reduced PCWP initially reflects the venodilatation and then the progressive loss of ECF volume. Frank-Starling curves demonstrating the dependence of cardiac output on the left ventricular enddiastolic pressure (LVEDP] are shown in Figure 1. The LVEDP progressively increases in the failing heart,
+++ +o
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-----
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--L~-~-~~:~~~
_____ DiuretiC
-
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+,#g
k3 12
Congestion
LVEDP mmlig
FIGURE 1. An illustration of Starling’s law of the heart. There Is normally a dependence of cardiac output (CO) on left ventricular end-diastolic pressure (LVEDP). The normal relatlon Is shown at the top, the relatlon in severe congestive heart failure Is shown at the bottom. Digitalis (point B) shifts tha curve towards the normal relation by virtue of its inotroplc actlon on the myocardlum. Dluretits (point C) do not shift the curve but rather decrease congestive symptoms owing to a decrease in plasma volume and LVEDP. Peripheral vasodilators such as nltroprusslde reduce the aflerload to the myocardium to simultaneously Increase CO and decrease congestlon In the pulmonary circuit. Reproduced wlth permlsslon from Churchill Livingstone.’
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TABLE Tubular
A SYMPOSIUM:
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High-Risk Necrosis
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That
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Commonly
Spawn
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Acute
Extensive cardiovascular surgery Surgery on jaundiced patients Massive trauma Sepsis Nephrotoxins: aminoglycosides, amphotericin B, cis-platinum Radiocontrast agents
which simultaneously sustains cardiac output adequate to tissue needsbut eventually resultsin congestive symptoms. By diminishing preload, diuretics reduce LVDEP, thereby improving symptomsbut at the potential expenseof reducing cardiac output.Of interestis the recent observation9that cardiac output actually did not fall despitesubstantialdiuresis and reduction in PCWP in several well-studied patients with congestiveheart failure. The authors argued that the diininished congestivesymptomseffectedreductionin sympathetic outflow which, in turn, diminished afterload. The offsetting effects of reduced preload and afterload diminished dyspnea and sustained tissue perfusion. While diuretic therapy plays a key role in treating congestivesymptoms, it must be remembered that in some patients, induced reductions in cardiac output may result in a hypoperfusionsyndrome.Thus, diuretic therapy is best coupled with other agentsthat increaseinyocardial contractility [e.g,,digitalis, sympathomimetic agents)and reduce myocardial workload (vasodilators). Therapy with thesepotent diuretics rendersthe distal nephron awashwith ample sodium and water and striking kaliuresis can be initiated. Thtis, potassium supplements or use of potassium-sparing diuretics +st be considered.Potassiumdepletion reducesrenal clearanceof digoxin, increasesbinding to the myocardium and dangerouslysensitizes the heart to the toxic, effects of digitalis-l0 Diuretic adnhinistration in acute tubular necrosis: Suddensuppressionof renal function (acuterenal failure] may result from a rapidly reversible reduction of renal perfusion (prerenal acuterenal failure], obstruction of urinary outflow from an otherwisenormal kidney (postrenalacute renal failure) or an acute lesion intrinsic to the renal parenchyma(intrarenal acuterenal failure). Prerenal acute renal failure, due to reduced effective arterial blood volume causedby ECF loss or congestiveheart failure, is usually recognized without difficulty and usually quite responsiveto therapy. Postrenalacute renal failure generally occursin well-defined clinical settingsand is easily identified with standardtests.Intrinsic renal acute renal failure may result from severelesions of ihe glomeruli, interstitium, renal vasculature or from “acute tubular necrosis”. Acute glomerulonephritis, acute interstitial nephritis and acute vasculitic syndromes are readily diagnosedby history, physical and standardblood and urinary chemical analyses.l1 By far, the most common
causeof intrinsic renal acuterenal failure in hospitalized patients is acutetubular necrosis.The morbidity and the mortality associatedwith this usually transient, functional renal failure are high and over the years have not been effectively reduced.Becauseoliguria has.beenan important and characteristicaccompaniment of many casesof acute tubular necrosis,it was natural to use diuretics in its therapy. Indeed,the observation that nonoliguric forms of acute tubular necrosis have a better outlook than do the oliguric forms suggestedto many that diuretic-induced increasesin urinary volume may improve prognosis. Although the pathogenesisof acutetubular necrosis has not been clearly defined, contributing factors include tiasomotor changesthat reduce glomerular filtration, epithelial cell damageleading to tubular obstruction from shedmaterial and rents in the nephron causingleakageof glomerular filtrate into the interstitium.12Loop-activediuretics exert a number of effects on the kidney that could theoretically neutralize certain of the factors that induce acute tubular necrosis. Furosemide and man&to1 increase renal blood flow13s14 and also increase the flow of glomerular filtrate along the tubule, helping to dislodge collections of occluding debris. While there are ample theoretical grounds for anticipating a salutaryresult from diuretic administration in acute tubular necrosis,little evidence can be marshalled to prove their effectiveness? Loop-active agentshave been used prophylactically to prevent acute tubular necrosisin high-risk settings,to reverse early or establishedacute tubular necrosisor to convert oliguric acute tubular necrosisto the nonoliguric form [urine volume >5OOml/day). As recently summarized,l5 the use of diuretics and saline repletion or the use of volume reexpansion alone in high-risk clinical settings(Table I) seemsto reduce the incidence of acute tubular necrosis.Jaundiced patients undergoing elective surgery suffer a lower incidence of postoperativereduction in glomerular filtration rate if they receivedmannitol perioperatively.16s17 Similarly, prophylaxis with mannitol may prevent acute tubular necrosis in patients receiving suchnephrotoxinsascis-platinum,l* amphotericin-Big. and radiocontrastdyes.20,21 In prophylaxis, saline expansion,loop-active diuretics or mannitol seem to be equally effective in reducing the risk of acutetubular necrosisin patientsundergoingcardiovascularsurgery or suffering niassivetrauma. Initiation of diuresiswith 50ml of 25% mannitol(12.5g] and maintenanceof the diuresis with an infusion of mannitol has been useful in thesehigh-risk settings.Similar diureseswith appropriatedosesof loop-activediuretics may well be equally helpful in preventing acutetubular necrosis.It is imperative that excretedurine be replacedqualitatively and quantitatively, lest volume contraction develop. Early acute tubular necrosis is thought to be that stage of diseasewherein appropriate therapy could prevent establishment of the full-blown syndrome. Proponentsarguethat use of diuretics at this incipient stagecould be life-saving, whereas others argue that 5%
January
TABLE
II
Symptoms
Serum Sodium (mEq/liter)
24, 1988
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of Hyponatremia
Symptoms
120-125
Nausea Malaise
115-120
Lethargy Headache stupor Seizures
<115
Coma
Hypovolemia Diminished brain perfusion exacerbates symptoms
this early stageis simply prerenal acute renal failure misdiagnosedas acute tubular necrosis. Our present inability to separatethese2 syndromeshasblurred the interpretation of published reports. Even if “early acute tubular necrosis” representsa narrow window of therapeuticopportunity, a salutaryresponseto diuretics by some patients may simply identify thosewith mild diseaseswho would have donewell evenwithout suchtherapy.Carefully designedprospectivetrials are sorely needed to clarify whether diuretics have an important role in this setting. Establishedoliguric acutetubular necrosismay be converted to the nonoliguric form if a large enough doseof diuretic is administered.Again, in the absence of controlled studies, the responseto diuretics may only unmask mild casesof acutetubular necrosis.Use of loop-active agentsincreasesurine volume in a significant number of patients,which at a minimum lessensthe risk of volume overloadfrom parenteralfluids used to administer needed antibiotics and nutrition. This easeof fluid therapy notwithstanding,published studies remain inconclusive regarding the benefits of diuretic therapy in established acute tubular necrosis.15Despite inducing diuresis, there is no proof that morbidity or mortality is lessened. Becausepublished studiesare in conflict regarding efficacy,it remainspossiblethat diureticsafford significantbenefitto somepatients.Becauseloop-activediuretics and mannitol areminimally toxic drugs,we administer them in establishedacutetubularnecrosis.In support of this unprovenapproach,we arguethat thesedesperately ill patientscan potentially benefitfrom evensmall advantages.Accordinglynormovolemicoliguric patients with establishedacutetubularnecrosisaregiven50ml of 25% mannitol every30minutesfor 2 administrations.If diuresis(urinevolume >40 ml/hr) is not provoked,“crescendodoses”of loop-activeagentsareused.For example, an initial intravenousinfusion of 2-mg bumetanide is given;if ineffective,it is followed by a doubleor quadruple doseat 30-minuteintervals (4,8 and then 10 mg). Repeateddosesare given to sustainthe diuresis.Correspondingdosesof furosemideor ethacrynicacid may be used. Hypotonic hyponatremia: The signsand symptoms of this disorder include progressivelethargy and som-
Hypervolemia Tissue perfusion may also be impaired by associated heart, liver or kidney disease
nolence,which give rise to disorientation, and culminate in seizures,coma and death. It follows that the prime danger of hypotonic hyponatremia is cerebral cell swelling. In acute hyponatremia, the concentration of themajor ECFsolute,sodium,is reduced,rendering ECF more hypotonicthan intracellular fluid. Since cell membranesarefreely permeableto waterand since watermovesfrom areasof low to areasof high osmolality, ECFwater redistributesto theintracellularspace.The life-threateningconsequencesof the resulting cerebral edemaare well known (Table II]. In chronic hypotonic hyponatremic states, the brain, unlike peripheral tissues,can eventually reduce its intracellular solutecontent.This solute lossreduces intracellular fluid osmotic pressurewithout requiring the acquisition of water.z Thus, transcellular osmolality is equalized without the pernicious requirement of cell swelling. It follows, therefore, that patients with acutehyponatremiaare more likely to be symptomatic at any given serum sodium concentration.The therapeutic approachto symptomatic patientsis directed by the stateof the ECF volume and the adequacyof their renal function. Hyponatremia may be subclassifiedin terms of ECF volumez3(Fig. 21. Hypovolemic hypotonic hyponatremia: Replacement of renal or extrarenal lossesof salt and water with dilute fluid results in hyponatremia. The initial loss of ECF elicits the characteristicfindings of hypovolemia: i.e., tachycardia,hypotension [with postural accentuation),diminished skin turgor and dry mucosae. Hypovolemia provokes release of antidiuretic hormone, aldosteroneand catecholamines,the effects of which, when coupled with intrinsic renal adaptations to volume contraction,limit urinary dilution. Administered solute-free water is retained, causinghyponatremia. Reexpansion of the ECF with normal saline suppressesthe forces abetting renal water retention and therebyallows the kidney to excretewater and retain salt and sonormalize the volume and composition of the ECF and intracellular fluid. Diuretics are obviously inappropriate to the patient’s needs in this setting. lsovolemic hypotonic hyponatremia:The disorders causingthis pathophysiologicstate (Fig. 2) also cause primary water retention. Becausetwo-thirds of re-
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tained water enters cells, the signs of hypervolemia (i.e., edema] are not usually clinically apparent. Depending on the rapidity with which water has been retained, patients may develop the neuropathic signs of their disorderedchemical state.Predisposingconditions usually cause absolute or relative increasesin circulating antidiuretic hormone levels. It thereby follows that neutralization of antidiuretic hormone action would effect a water diuresis and prove to be the most efficient and rational therapy. Currently available inhibitors of antidiuretic hormone effects are unfortunately too slow in their onsetof action to be useful in emergencysituations.Experimental inhibitors of antidiuretic hormone’s renal action, which are soon to be released,offer great promise in treating this electrolyte disorder.24 In the absenceof rapidly actinginhibitors of antidiuretic hormone, loop diuretics have been used as imperfectstimulators of water excretion.In fact, relatively large dosesof these agentscause urine excretion that is approximately one-half normal in electrolyte concentration (Fig. 3). One can conceptualize such urine as composedof 2 virtual volumes, one portion containing all the urinary electrolyte distributed in the precisevolume required to make this electrolyte solution isotonic with plasma. Thus, this electrolyte-containing portion would be 300mOsm/liter. The other portion consistsof any remaining electrolyte-freevolume, which would, of course,be free water. Replacement of each milliequivalent of excreted electrolyte, but in small volumes of water, causesnet loss of body water and thereby acts to normalize serum sodium concentration,
LOW i
l3OTONlC HYPONATREMIA
For example, administration of 1 to 3 mg/hour of bumetanide could causethe hourly excretionof 1 liter of urine containing 50 mEq of sodium chloride (100 mosm of solute)and 20 mEq of potassiumchloride (40 mosm of solute).This urine could be viewed as 500ml of isotonic solution (140mosmA.5 liter correspondsto the isotonic concentrationof 280mosm/liter) and 500 ml of free water. Replacementof only 500ml of isotonic electrolyte solution would create a 500ml negative free-water balance,causingthe serumsodiumconcentration to increase.If anotherdoseof diuretic effected the sameurinary response,and againonly the isotonic componentwere replaced, another5110ml of electrolyte-free water would be shed,and a cummulative loss of 1,000ml of free water would accrue. It should be noted that return of the same number of shed milliequivalents of electrolyte in a lesser volume would allow for greaterwater loss. For example, return of the 70mEq of NaCl excretedin 1 liter of urine (140mOsm] in 140ml (i.e.,as saline)would causenet lossof 860 ml of electrolyte-free water (1,000ml excreted, only 140ml returned).Little more is gainedby returning the electrolyteas sodium chloride solution.This therapy leaves total body sodium content unchangedbecausethe absolutenumber of milliequivalents of excretedsalt arereturnedbut in a lesservolume of water. Patients so treated lose free water and their serum sodium concentrationincreases.The way to approach such patients follows.25 Indications for loop diuretics and 3% saline:Symptomatic patients with isovolemic, hypotonic hyponatremia (Fig. 2),23whosekidneys are responsiveto loop active agents, are the prime candidates for this 3%
5%
HYPERTONIC HYPONCITREMIA
FIGURE 2. IllagnostIc approach to hyponatremia. This algorithm describes a stepwlse cllnlcel and chemlcel approach to patients with hyponatremia. See reler8nc8 23 for a detailed dlscusslon of the approach to hyponatremla. Arrows indicate dIreCtiOn of change; Iso = Isotonlq V = varlable. Reproduced’ wlth permfsslon from Am J Med.2’
I. HYPERGLYCEMIA Z.~T&7$ON&C INFUSIONS
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January
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therapy. Hypovolemic patients require only saline, and hypervolemic (edematous) patients require specific therapy of their underlying illnesses (i.e., heart or liver failure or nephrotic syndrome]. Because diuretics effect loss of both isotonic fluid (sodium chloride excreted at the same concentration as in plasma) and electrolyte-free water, edematous patients with adequate effective arterial blood volume (i.e., normal blood pressure, pulse and apparent tissue perfusion) need only receive diuretics. Concomitant loss of isotonic urine and free water will simultaneously shrink the ECF and increase the serum sodium concentration. Goal of loop diuretics and saline therapy: Much controversy surrounds the rate at which normonatremia should be achieved.22J6 Reasonable arguments can be advanced in favor of either a conservative, slow increase in sodium concentration or for a more rapid rise. We are most impressed with evidence supporting a 2 mEq/liter/hr increase in serum sodium concentration, to values of 120 to 130 mEq/liter. Data in support of this position are derived from retrospective and prospective human studies and from experimental animals.22J6 Calculation of how much free water to remove: Assume that a previously healthy 70-kg man with a total body water of 42 liters (60% body weight) and a previously normal serum sodium concentration (140 mEq/liter) sustains postoperative iatrogenic isovolemic hypotonic hyponatremia. He is symptomatic (Table II], and it is decided to return his serum sodium concentration to 120 mEq/liter from 110 mEq/liter over 5 hours. His apparent premorbid total body sodium content (total body water [42 liter] X 140 mEq/liter = 5,880 mEq) is assumed to be unchanged. In what volume of water must these 5,880 mEq now be distributed to yield a concentration of 110 mEq/liter? The new volume must be 5,880 mEq + 110 mEq/liter (i.e., 53.45 liters]; 11.45 liters of water was retained (53.4 42 liters]. To lower the serum sodium concentration to 120 mEq/liter (5,880 mEq + 120 mEq/liter equals 49 liters), 7 liters of water must be retained. It follows that in order to raise the serum sodium concentration from 110 mEq/liter to 120 mEq/liter, approximately 5 liters of electrolyte-free water must be excreted, or 1 liter/hr must be lost to accomplish this in 5 hours. This calculation should be considered nothing more than a gross estimate. As therapy proceeds, frequent measurements of serum electrolytes must be made and rates of diuresis and infusion can be readjusted to achieve the desired goal. It must also be emphasized that if the patient shows striking improvement during the course of treatment, the rate of diuresis can and should be slowed. While rapid correction of hyponatremia can at times be lifesaving, there are dangers inherent in this treatment, and one must apply it most cautiously. Technique of loop diuretic and saline therapy: This treatment should be carried out in an intensive care unit where urine collections, infusion rates and vital signs can be closely followed. The object is to ensure that minimal change in total body sodium occurs as water is being removed. A parenteral dose of diuretic is chosen and repeated often enough to effect excre-
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tion of 500 to 1,000 ml/hr of urine. Initial diuretic doses could be as follows: bumetanide, 2 to 3 mg, furosemide, 80 to 100 mg and ethacrynic acid, 50 to 100 mg. After 30 minutes, a urine sample is analyzed for sodium and potassium. One may assume initially that 70 mEq/liter of electrolyte is being excreted and therefore administer 3% saline (0.5 mEq/ml] such that 70 mEq of sodium chloride will be infused in 1 hour. Thus, excretion of 1,000 ml of 70 mEq/liter electrolyte will be matched with the return of 140 ml of 3% saline (70 mEq sodium chloride). Net loss of 860 ml of water will result. Infusion rates can be adjusted as indicated by laboratory evaluation of urinary electrolyte excretion and the observed rate of increase in serum sodium concentration. Potassium is usually excreted as 10 to 20 mEq/liter and must, of course, be replenished. Diuretic and normal saline therapy of hypercalcemia: While the differential diagnosis of hypercalcemia encompasses a long list of etiologies, life-threatening causes of severe hypercalcemia (>13 to 14 mg%) are few, and malignancy looms high on the listsz7 In most circumstances, hypercalcemia results from the combined effects of resorption of bone coupled with reduced renal excretion of calcium. The relative or absolute hypocalciuria reflects reductions in glomerular filtration rate, hypovolemia or the presence of a circulating substance that stimulates tubular calcium reabsorption (parathyroid hormone). Severe hypercalcemia causes glomerular afferent arteriolar constriction and deposition of calcium salts in the kidney;28 both events reduce the glomerular filtration rate and thereby calcium filtration and excretion. Renal tubular calcium reabsorption is largely coupled with that of sodium and, in addition, hypercalcemia seems to inhibit sodium reabsorption. Thus, a vicious cycle often develops. Hypercalcemia causes natriuresis and consequent hypovolemia, and the latter reduces the glomerular filtration rate and stimulates proximal sodium and calcium reabsorption, thereby reducing calcium excretion and worsening the hypercalcemia. Many if not most patients with severe hypercalcemia are volume contracted upon hospitalization,27 making volume reexpansion with normal saline the
CONCEPl=UALlZATlON OF OSMOLAR AND FREE WATER CLEARANCE
ISOTONIC
FIGURE 3. The hypotonic (150 water fractions. volume of urine tion as plasma the remaining dilute urine can
URINE
HYPOTONIC
URINE
virtual components of hypotonlc urine. One liter of mOsm) urine is conceptualized as isotonic and freeThe osmoiar clearance (Cosm) is viewed as the required to dliute all solute to the same concentra(i.e., isobdcity). fhe free-water clearance (CH,) is solute-free urine. Thus, the components of 1 liter of be viewed of as 500 ml of Cosm and 500 ml of CH20.
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IN DIURETIC
THERAPY
initial treatment of choice. Serum calcium will commonly fall to values below 12 to 13 mg% with such treatment. For thosepatientswithout ECF volume contraction and thoseresistantto simple reexpansion,the addition of loop-activediureticsto the regimen may provehelpfu1.2gAs noted previously, the loop diuretics inhibit calcium reabsorptionin the thick ascendinglimb, and resulting hypercalciuria will help to further lower the serum calcium concentration.Unless excretedsodium is replaced, the ensuing hypovolemia will stimulate proximal calcium reabsorption,thereby diminishing the calciuric effect of the diuretics. Once normal ECF expansionhas beenestablished, loop-active diuretics may be administered intravenously every 1 to 2 hours at the following doses:bumetanide, 2 to 3 mg, furosemide, 80 to 100mg and ethacrynic acid, 50 to 100mg. This diuretic therapy will result in urine volumes of 500 to 1,000ml/hr and excretion of 90to 120 mEq/liter of sodium, 10to 20 mEq/ liter of potassiumand loss of approximately 80 mg/hr of calcium.2gSerum calcium can be expectedto fall by approximately 3 mg% over 4 to 8 hours.29Published reportsdo not clearly indicate.what fraction of the fall in serum calcium concentrationis.due to the diuretic or how much is due to rehydration alone. Potassiumand free-water lossesmust be repleted, and care must be taken to prevent either overdiuresis or sodium overload with its potential for congestive heart failure. For reasonspreviously noted, heart failure or overdiuresis would cause hypercalcemia to recur. Hyperkalemia: Life-threatening degreesof hyperkalemia are best treatedby simultaneously neutralizing the toxic effect of potassiumon the heart, stimulating its intracellular translocation and ridding the cation from the body. Infusions of calcium and hypertonic sodium reduce the cardiotoxic effects of potassium while glucose,insulin and bicarbonatereduce its serum concentrationby increasingcellular uptake.Sodium polystyrenesulfonate (Kayexalatee)reducesthe body content of potassiumby binding the cation in the intestine, Loop-active diuretics may also have a role in this setting by enhancing renal potassium excretion, Volume overloaded,severelyhyperkalemic patients may benefit from hourly dosesof intravenousbumetanide (2to 3 mg/hr), furosemide(40to 80mg/hr] or ethacrynic acid (50to 100mg/hr). Free-water losseswould, of course,have to be replenished. As previously noted, excretion of urine one-half normal in electrolyte concentration can be viewed as an equal mixture of isotonic solution (lossof which simply shrinks the ECF) and electrolyte-freewater [lossof which would lead to hypernatremia). Thus, to effect isotonic volume loss without causing hypernatremia, each milliliter of urine should be replaced with a 0.5 ml of free water (i.e., dextrose solution). Each liter of urine excreted will contain 10 to 20 mEq of potassium.It should also be rememberedthat eachmilliequivalent of potassium removed by Kayexalateecausesreturn of 1 to 2 mEq of sodium, i.e., the exchangeresin yields 1 to 2 mEq of
sodium for eachmilliequivalent of potassiumit binds. The concomitantuseof loop-activeagentswill prevent development of sodium overload in this setting.
References 1. Grantham JJ, Chonko AM. The physiologic basis and clinical use of diuretics. In: Brenner BM, Stein JH, eds. Sodium and Water Homeostasis. New York: Churchill Livingstone, 1978:178-211. 2. Grantham JJ, Irish JM. Organic acid transport and fluid excretion in the pars recta (PST) of the proximal tubule. Exerpta Medica Int. Congress Series No. 422:1977;83-90. 3. Chennavasin P, Seiwell R, Brater DC, Liang WMM. Pharmacodynamic analysis of the furosemide-probenecid interaction in man. Kidney Int 1979;16:187-196. 4. Chonko AM, Grantham ]J. Treatment of edema states. In: Maxwell MH, Kleeman CR, Narins RG, eds. Clinical Disorders of Fluid and Electrolyte Metabolism. New York: McGraw-HiII, in press. 5. Marx SJ, Bourdeau JE. Calcium metabolism. In: Ref 4. 6. Reineck HJ, Stein JH. Sodium metabolism. In: Ref 4. 7. Hall DA, Varney DM. Effect of vasopressin on electrical potential difference and chloride tmnsport in mouse medullary thick ascending limbs of Henle’s loop. J CIin Invest 1980;68:792-802. 8. Dikshit K, Vyden JK, Forrester JS, Chattejee K, Prakash R, Swan HJC. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N EngI J Med 1973;228: 1087-1090. 9. Wilson JR, Reichek N, Dunkman WB, Goldberg S. Effect of diuresis on the performance of the failing Ieft ventricIe in man. Am J Med 1981;70:234239. 10. Steiness E. Diuretics, digitalis and arrhythmias. Acta Med Stand 1981; 209:suppI 647:75-78. 11. Rudnick MR, Bastl CP, Elfinbein IB, Narins RG. The differential diagnosis of acute renal failure. In: Brenner BM, Lazarus JM, eds. Acute Renal Failure. Philadelphia: WB Saunders, 1983:176-222. 12. Schrier RW, Gardenswartz MH, Burke TJ. Acute renal failure: pathogenesis, diagnosis and treatment. In: Hamburger J. Crosnier 1. Grfinfeld JP, Maxwell MN, eds. Advances in Nephrology. Vol. II. Chicago: Year Book Medical Publishers. 1982:213-240. 13. Birtch’AG, Zekheim RM, Jones LJ, Barger AC. Redistribution of renal blood flow produced by furosemide and ethocrynic acid. Circ Res 1967; 21:869-878. 14. Johnston
PA, Bernard DB. Perrin NS, Levinsky NG. Prostaglandins mediate the vosodilatory effect of mannitol in the hypoperfused rat kidney. 1 CIin Invest 1981;68:127-138. 15. Levinsky NG, Bernard DB, Johnston PA. Mannitol and loop diuretics in acute renal failure. In: Ref 11:712-722. 16. Untura A. Incidence and nrouhvlaxis of acute wstonerative renal failure in obstructive jaundice. Rev Meh Chir Sot Med ‘Nat iAS 1979;83:247-254. 17. Dawson JL. Post-operative renal function in obstructive jaundice. Effect of a mannitol diuresis. Br Med J 1965;1:82-85. 18. Hayes DM, Cvitkovic E, Golbey RB, Scheiner E, Helson L. Krakoff I. High dose cisplatinum diammine dichloride. Amelioration of renal toxicity by monnitol diuresis. Cancer 1977;39:1372-1376. 19.Olivero JJ. Lozano-Mendez J, Ghafary EM, et al. Mitigation ofamphoteritin B nephrotoxicity by mannitol. Br Med J 1975:1:550-554. 20. Anto HR, Chou SY. Porush JG. Shapiro WB. Mannitol prevention of acute renal failure associated with infusion intravenous pyelography [abstr). Clin Res 1979;27:407A. 21. Old CW, Lehrner LM. Prevention of radiocontrast induced acute renal failure with mannitol (letter). Lancet 1980;2:885. 22. Dubois GD, Arieff AI. Treatment of hyponatremia: the case for rapid correction. In: Narins RG, ed. Controversies in Nephrology and Hypertension New York: Churchill Livingstone, 1984:393-408. 23. Narins RG, Jones ER, Stom MC, Rudnick MR, Bast) CP. Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis. Am 1 Med i982;72:498-519.
24. Schrier RW. Treatment of hyponatremia (editorioI). N Engl J Med 1985:17:1121. 25. Hantman D, Rossier B, Zohlman R, Schrier RW. Rapid correction of byponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: an alternative to hypertonic saline. Ann Intern Med 1973;78: 870-878. 26. Norenberg MD. Treatment of hyponatremia: the case for o more conservative approach. In: Ref 22393-408. 27. Mundy CR, Martin TJ. The hypercalcemia of malignancy: pathogenesis and management. Metabolism 1982:31:1247-1277. 28. Benabe JE. Martinez-Maldinado M. Hypercalcemic nephropathy. Arch Intern Med 1976:138:777-789, 29. Suki WN, Yiu’m-JJ, Minden MV. Saller-Herbert C. Eknoyan G, MartinezMaldinado M. Acute treatment of hypercalcemia with furosemide. N Engl J Med 1970;283:836-840.
mia are reviewed, and the rational use of loop diuretii and hypertonic saline is outlined. The 3 loopactive agents inhibit calcium reabsorption in the thiik ascending limb of Henle’s loop and therefore have proved useful in treating hypercalcemia. A practical approach to the diurettc-saline treatment of severe hypercalcemia ts outlined. The katiuretic effect of loop diuretics can be used to advantage in patients with acute or chronic hyperkalemia. A guide to such therapy is described.
Diuretics have found wide application in crkical care medicine. The use of mannitol and loop diuretics in a variety of Me-threatening disorders is reviewed. The combined venodllatory and natrluretic effects of bumetankte, furosemide and ethacrynic acid relieve congestive symptoms in pulmonary edema. Although c ommonly administered to prevent development of acute tubular necrosis or in varying stages of evolving disease, few data are available to demonstrate the efficacy of mannltol or loop diuretics. An approach to the dtguric patient with acute tubular necrosis is described. The dangers of hyponatre-
(Am J Cardiol 1966;57:26A-32A)
T
he usefulness of “loop-active” diuretics (bumetanide, furosemide and ethacrynic acid) in critically ill patients derives from their blockade of electrolyte transport in the medullary and cortical thick ascending limb of Henle’s loop. Venodilatation is their only extrarenal action that has been found of clinical utility. The application of these agents to desperate clinical settings forms the basis of this review. After briefly establishing the biochemical and physiologic principles underlying the action of these agents, their use in specific clinical settings will be described.
competitors, transport of loop-active agents into the tubular lumen is impeded, causing the plasma levels of bound and free diuretic to increase. Increasing glomerular filtration soon replaces the decreasing tubular secretion as the major route for nephronal entry.3 In the presence of probenecid, furosemide’s duration of action is prolonged, due to its slower tubular entry.3 The thick ascending limb is the only clinically significant renal site of action of these diuretics.* Recent studies indicate that these agents inhibit a sodium, potassium, chloride cotransport system in the urinary plasma membrane of thick ascending limb epithelia.4 Thus, this site normally mediates reabsorption of 1 mEq of sodium, 1 mEq of potassium and 2 mEq of chloride. Back diffusion of some cation without anion generates the normal lumen-positive electrical potential in the thick ascending limb. This positive luminal charge allows for the passive reabsorption of calcium. The thick ascending limb may also actively reabsorb calcium.5 The important physiologic and pathologic consequences of inhibiting this cotransporter are discussed next. Natriuresis and extracellular fluid (ECF) volume contraction: Inhibition of the thick ascending limb sodium reabsorption causes delivery to more distal tubular sites of an amount of sodium that acutely overwhelms the distal reabsorptive capacity. Resulting loss of sodium with water causes contraction of ECF volume. Under controlled conditions, loop-active diuretics can effect loss of 20 to 30% of the glomerular filtrate. Thus, they may cause enormous salt and water losses. As the ECF volume shrinks, a series of counter-
RenalEffects of Loop-ActiveDiuretics Pharmacologic and physiologic principles: These agents inhibit electrolyte transport by acting at the luminal surface of the epithelial cells of the thick ascending limb. Extensive albumin-binding markedly retards their glomerular filtration, making the luminal entry vitally dependent on proximal tubular secreti0n.l These organic anions are actively transported from peritubular capillary blood into the urine by a generic organic anion transporter, located in the proximal convoluted tubule. Additional substrates for the transporter include lactate, urate, ketone anions and such drugs as probenecid, penicillin and various cephalosporin antibiotics.2 Thus, in the presence of these From the Temple Univdrsity Health Sciences Center, Philadelphia, Pennsylvania. Address for reprints: Robert G. Narins, MD, Renal Section, Temple University Health Sciences Center, 3401 North Broad Street, Philadelphia, Pennsylvania 19140. 26A
January
24. 1986
vailing hormonal, neurologic, hemodynamic and physical intrarenal changes are provoked that stimulate sodium and water reabsorption at tubular sites proximal and distal to the locus of diuretic action.4.6 These offsetting events eventually limit the continuing effectiveness of the diuretic. Addition of proximally (aminophylline) or distally (thiazides) active agents will reestablish the diuresis. The urinary sodium concentration during loop blockade is almost always less than that in serum; in other words, the diuretics induce urinary loss of dilute solutions of sodium. Failure to drink or otherwise receive water will therefore result in hypernatremia. Conversely, ingestion of more electrolyte-free water than can be excreted during diuretic therapy results in water retention and hyponatremia. Altered renal water metabolism: The thick ascending limb is always “waterproof”! The reabsorption of sodium chloride and potassium chloride without water at once renders the luminal filtrate dilute and the medullary interstitium concentrated. In the absence of antidiuretic hormone, the continued removal of solute without its solvent (i.e., water] allows for excretion of potentially large quantities of electrolyte-free water. Thus, large ingestions of water are easily excreted. It follows that loop-active diuretics impair the generation and excretion of solute-free water, and thereby sensitize treated subjects exposed to excessive amounts of water to hyponatremia. Antidiuretic hormone stimulates sodium chloride reabsorption by the thick ascending limb7 and mediates osmotic communication between the dilute fluid in the distal nephron and the more hypertonic medullary interstitium. In the presence of antidiuretic hormone, electrolyte-free water enters the medulla, causing excretion of highly concentrated urine. The medullary hypertonicity is created by the local retention of electrolyte reabsorbed from the thick ascending limb. Because the free-water reabsorption ultimately depends on solute transported in the thick ascending limb, it follows that loop-active agents must also impair the renal concentrating capacity. Thus, maximal dilution and maximal concentration by kidneys exposed to these drugs becomes impaired. However, the excretion of large volumes of the submaximally dilute urine induced by these agents is used advantageously when it is crucial to rid the body of free water (see below). Kaliuresis: Renal potassium wasting is an intrinsic effect of all 3 loop-active diuretics. In addition to inhibiting its reabsorption in the thick ascending limb, distal potassium secretion is also stimulated by these agents. Diuretic-induced increases in distal sodium and water dilute luminal potassium concentration, thereby creating a cell-to-lumen concentration gradient that favors enhanced secretion. The associated ECF volume contraction ensures that abundant amounts of aldosterone will be available to stimulate distal potassium secretion further. The resulting loss of potassium may be an unwanted effect to be guarded against or replenished, or it can be a wanted effect, as when loop-agents are used in treating certain hyperkalemic states. Calcium excretion: Bumetanide, furosemide and ethacrynic acid all inhibit calcium reabsorption in the
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thick ascending limb, causing hypercalciuria. Inhibition of salt transport reduces or nullifies the normal positive luminal potential (as just discussed], thereby inhibiting passive calcium reabsorption. While longterm use of these diuretics does not seem to deplete body stores of calcium,2 acute high-dose therapy, coupled with replacement of excreted salt and water, effects striking hypercalciuria and reduces dangerously elevated serum levels. These agents have an important role in treating hypercalcemic states.
Venodilatation Although incompletely understood, it is clear that loop-active agents rapidly increase venous capacitance with sequestration of a significant fraction of the blood volume in this low pressure locus.* This “internal phlebotomy” in response to parenterally administered loop agents strikingly lowers pulmonary capillary wedge pressure (PCWP) within 15 minutes. This effect preceeds any diuresis and is equally demonstrable in anephric patients or animals.
Use of Loop-ActiveAgentsin EmergentSettings Acute pulmonary edema: Loop-active diuretics rapidly improve congestive symptoms by abruptly lowering cardiac preload. Within minutes of parenteral administration, venous capacitance first increases followed by the onset of brisk natriuresis. The reduced PCWP initially reflects the venodilatation and then the progressive loss of ECF volume. Frank-Starling curves demonstrating the dependence of cardiac output on the left ventricular enddiastolic pressure (LVEDP] are shown in Figure 1. The LVEDP progressively increases in the failing heart,
+++ +o
I1 II II I I i-B’ b “k-+
------
--__-
-----
0. 8. ‘G+ *
--L~-~-~~:~~~
_____ DiuretiC
-
@A
+,#g
k3 12
Congestion
LVEDP mmlig
FIGURE 1. An illustration of Starling’s law of the heart. There Is normally a dependence of cardiac output (CO) on left ventricular end-diastolic pressure (LVEDP). The normal relatlon Is shown at the top, the relatlon in severe congestive heart failure Is shown at the bottom. Digitalis (point B) shifts tha curve towards the normal relation by virtue of its inotroplc actlon on the myocardlum. Dluretits (point C) do not shift the curve but rather decrease congestive symptoms owing to a decrease in plasma volume and LVEDP. Peripheral vasodilators such as nltroprusslde reduce the aflerload to the myocardium to simultaneously Increase CO and decrease congestlon In the pulmonary circuit. Reproduced wlth permlsslon from Churchill Livingstone.’
20A
TABLE Tubular
A SYMPOSIUM:
I
High-Risk Necrosis
CURRENT
Settings
TRENDS
That
IN DIURETIC
Commonly
Spawn
THERAPY
Acute
Extensive cardiovascular surgery Surgery on jaundiced patients Massive trauma Sepsis Nephrotoxins: aminoglycosides, amphotericin B, cis-platinum Radiocontrast agents
which simultaneously sustains cardiac output adequate to tissue needsbut eventually resultsin congestive symptoms. By diminishing preload, diuretics reduce LVDEP, thereby improving symptomsbut at the potential expenseof reducing cardiac output.Of interestis the recent observation9that cardiac output actually did not fall despitesubstantialdiuresis and reduction in PCWP in several well-studied patients with congestiveheart failure. The authors argued that the diininished congestivesymptomseffectedreductionin sympathetic outflow which, in turn, diminished afterload. The offsetting effects of reduced preload and afterload diminished dyspnea and sustained tissue perfusion. While diuretic therapy plays a key role in treating congestivesymptoms, it must be remembered that in some patients, induced reductions in cardiac output may result in a hypoperfusionsyndrome.Thus, diuretic therapy is best coupled with other agentsthat increaseinyocardial contractility [e.g,,digitalis, sympathomimetic agents)and reduce myocardial workload (vasodilators). Therapy with thesepotent diuretics rendersthe distal nephron awashwith ample sodium and water and striking kaliuresis can be initiated. Thtis, potassium supplements or use of potassium-sparing diuretics +st be considered.Potassiumdepletion reducesrenal clearanceof digoxin, increasesbinding to the myocardium and dangerouslysensitizes the heart to the toxic, effects of digitalis-l0 Diuretic adnhinistration in acute tubular necrosis: Suddensuppressionof renal function (acuterenal failure] may result from a rapidly reversible reduction of renal perfusion (prerenal acuterenal failure], obstruction of urinary outflow from an otherwisenormal kidney (postrenalacute renal failure) or an acute lesion intrinsic to the renal parenchyma(intrarenal acuterenal failure). Prerenal acute renal failure, due to reduced effective arterial blood volume causedby ECF loss or congestiveheart failure, is usually recognized without difficulty and usually quite responsiveto therapy. Postrenalacute renal failure generally occursin well-defined clinical settingsand is easily identified with standardtests.Intrinsic renal acute renal failure may result from severelesions of ihe glomeruli, interstitium, renal vasculature or from “acute tubular necrosis”. Acute glomerulonephritis, acute interstitial nephritis and acute vasculitic syndromes are readily diagnosedby history, physical and standardblood and urinary chemical analyses.l1 By far, the most common
causeof intrinsic renal acuterenal failure in hospitalized patients is acutetubular necrosis.The morbidity and the mortality associatedwith this usually transient, functional renal failure are high and over the years have not been effectively reduced.Becauseoliguria has.beenan important and characteristicaccompaniment of many casesof acute tubular necrosis,it was natural to use diuretics in its therapy. Indeed,the observation that nonoliguric forms of acute tubular necrosis have a better outlook than do the oliguric forms suggestedto many that diuretic-induced increasesin urinary volume may improve prognosis. Although the pathogenesisof acutetubular necrosis has not been clearly defined, contributing factors include tiasomotor changesthat reduce glomerular filtration, epithelial cell damageleading to tubular obstruction from shedmaterial and rents in the nephron causingleakageof glomerular filtrate into the interstitium.12Loop-activediuretics exert a number of effects on the kidney that could theoretically neutralize certain of the factors that induce acute tubular necrosis. Furosemide and man&to1 increase renal blood flow13s14 and also increase the flow of glomerular filtrate along the tubule, helping to dislodge collections of occluding debris. While there are ample theoretical grounds for anticipating a salutaryresult from diuretic administration in acute tubular necrosis,little evidence can be marshalled to prove their effectiveness? Loop-active agentshave been used prophylactically to prevent acute tubular necrosisin high-risk settings,to reverse early or establishedacute tubular necrosisor to convert oliguric acute tubular necrosisto the nonoliguric form [urine volume >5OOml/day). As recently summarized,l5 the use of diuretics and saline repletion or the use of volume reexpansion alone in high-risk clinical settings(Table I) seemsto reduce the incidence of acute tubular necrosis.Jaundiced patients undergoing elective surgery suffer a lower incidence of postoperativereduction in glomerular filtration rate if they receivedmannitol perioperatively.16s17 Similarly, prophylaxis with mannitol may prevent acute tubular necrosis in patients receiving suchnephrotoxinsascis-platinum,l* amphotericin-Big. and radiocontrastdyes.20,21 In prophylaxis, saline expansion,loop-active diuretics or mannitol seem to be equally effective in reducing the risk of acutetubular necrosisin patientsundergoingcardiovascularsurgery or suffering niassivetrauma. Initiation of diuresiswith 50ml of 25% mannitol(12.5g] and maintenanceof the diuresis with an infusion of mannitol has been useful in thesehigh-risk settings.Similar diureseswith appropriatedosesof loop-activediuretics may well be equally helpful in preventing acutetubular necrosis.It is imperative that excretedurine be replacedqualitatively and quantitatively, lest volume contraction develop. Early acute tubular necrosis is thought to be that stage of diseasewherein appropriate therapy could prevent establishment of the full-blown syndrome. Proponentsarguethat use of diuretics at this incipient stagecould be life-saving, whereas others argue that 5%
January
TABLE
II
Symptoms
Serum Sodium (mEq/liter)
24, 1988
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of Hyponatremia
Symptoms
120-125
Nausea Malaise
115-120
Lethargy Headache stupor Seizures
<115
Coma
Hypovolemia Diminished brain perfusion exacerbates symptoms
this early stageis simply prerenal acute renal failure misdiagnosedas acute tubular necrosis. Our present inability to separatethese2 syndromeshasblurred the interpretation of published reports. Even if “early acute tubular necrosis” representsa narrow window of therapeuticopportunity, a salutaryresponseto diuretics by some patients may simply identify thosewith mild diseaseswho would have donewell evenwithout suchtherapy.Carefully designedprospectivetrials are sorely needed to clarify whether diuretics have an important role in this setting. Establishedoliguric acutetubular necrosismay be converted to the nonoliguric form if a large enough doseof diuretic is administered.Again, in the absence of controlled studies, the responseto diuretics may only unmask mild casesof acutetubular necrosis.Use of loop-active agentsincreasesurine volume in a significant number of patients,which at a minimum lessensthe risk of volume overloadfrom parenteralfluids used to administer needed antibiotics and nutrition. This easeof fluid therapy notwithstanding,published studies remain inconclusive regarding the benefits of diuretic therapy in established acute tubular necrosis.15Despite inducing diuresis, there is no proof that morbidity or mortality is lessened. Becausepublished studiesare in conflict regarding efficacy,it remainspossiblethat diureticsafford significantbenefitto somepatients.Becauseloop-activediuretics and mannitol areminimally toxic drugs,we administer them in establishedacutetubularnecrosis.In support of this unprovenapproach,we arguethat thesedesperately ill patientscan potentially benefitfrom evensmall advantages.Accordinglynormovolemicoliguric patients with establishedacutetubularnecrosisaregiven50ml of 25% mannitol every30minutesfor 2 administrations.If diuresis(urinevolume >40 ml/hr) is not provoked,“crescendodoses”of loop-activeagentsareused.For example, an initial intravenousinfusion of 2-mg bumetanide is given;if ineffective,it is followed by a doubleor quadruple doseat 30-minuteintervals (4,8 and then 10 mg). Repeateddosesare given to sustainthe diuresis.Correspondingdosesof furosemideor ethacrynicacid may be used. Hypotonic hyponatremia: The signsand symptoms of this disorder include progressivelethargy and som-
Hypervolemia Tissue perfusion may also be impaired by associated heart, liver or kidney disease
nolence,which give rise to disorientation, and culminate in seizures,coma and death. It follows that the prime danger of hypotonic hyponatremia is cerebral cell swelling. In acute hyponatremia, the concentration of themajor ECFsolute,sodium,is reduced,rendering ECF more hypotonicthan intracellular fluid. Since cell membranesarefreely permeableto waterand since watermovesfrom areasof low to areasof high osmolality, ECFwater redistributesto theintracellularspace.The life-threateningconsequencesof the resulting cerebral edemaare well known (Table II]. In chronic hypotonic hyponatremic states, the brain, unlike peripheral tissues,can eventually reduce its intracellular solutecontent.This solute lossreduces intracellular fluid osmotic pressurewithout requiring the acquisition of water.z Thus, transcellular osmolality is equalized without the pernicious requirement of cell swelling. It follows, therefore, that patients with acutehyponatremiaare more likely to be symptomatic at any given serum sodium concentration.The therapeutic approachto symptomatic patientsis directed by the stateof the ECF volume and the adequacyof their renal function. Hyponatremia may be subclassifiedin terms of ECF volumez3(Fig. 21. Hypovolemic hypotonic hyponatremia: Replacement of renal or extrarenal lossesof salt and water with dilute fluid results in hyponatremia. The initial loss of ECF elicits the characteristicfindings of hypovolemia: i.e., tachycardia,hypotension [with postural accentuation),diminished skin turgor and dry mucosae. Hypovolemia provokes release of antidiuretic hormone, aldosteroneand catecholamines,the effects of which, when coupled with intrinsic renal adaptations to volume contraction,limit urinary dilution. Administered solute-free water is retained, causinghyponatremia. Reexpansion of the ECF with normal saline suppressesthe forces abetting renal water retention and therebyallows the kidney to excretewater and retain salt and sonormalize the volume and composition of the ECF and intracellular fluid. Diuretics are obviously inappropriate to the patient’s needs in this setting. lsovolemic hypotonic hyponatremia:The disorders causingthis pathophysiologicstate (Fig. 2) also cause primary water retention. Becausetwo-thirds of re-
30A
A SYMPOSIUM:
CURRENT
TRENDS
IN DIURETIC
THERAPY
tained water enters cells, the signs of hypervolemia (i.e., edema] are not usually clinically apparent. Depending on the rapidity with which water has been retained, patients may develop the neuropathic signs of their disorderedchemical state.Predisposingconditions usually cause absolute or relative increasesin circulating antidiuretic hormone levels. It thereby follows that neutralization of antidiuretic hormone action would effect a water diuresis and prove to be the most efficient and rational therapy. Currently available inhibitors of antidiuretic hormone effects are unfortunately too slow in their onsetof action to be useful in emergencysituations.Experimental inhibitors of antidiuretic hormone’s renal action, which are soon to be released,offer great promise in treating this electrolyte disorder.24 In the absenceof rapidly actinginhibitors of antidiuretic hormone, loop diuretics have been used as imperfectstimulators of water excretion.In fact, relatively large dosesof these agentscause urine excretion that is approximately one-half normal in electrolyte concentration (Fig. 3). One can conceptualize such urine as composedof 2 virtual volumes, one portion containing all the urinary electrolyte distributed in the precisevolume required to make this electrolyte solution isotonic with plasma. Thus, this electrolyte-containing portion would be 300mOsm/liter. The other portion consistsof any remaining electrolyte-freevolume, which would, of course,be free water. Replacement of each milliequivalent of excreted electrolyte, but in small volumes of water, causesnet loss of body water and thereby acts to normalize serum sodium concentration,
LOW i
l3OTONlC HYPONATREMIA
For example, administration of 1 to 3 mg/hour of bumetanide could causethe hourly excretionof 1 liter of urine containing 50 mEq of sodium chloride (100 mosm of solute)and 20 mEq of potassiumchloride (40 mosm of solute).This urine could be viewed as 500ml of isotonic solution (140mosmA.5 liter correspondsto the isotonic concentrationof 280mosm/liter) and 500 ml of free water. Replacementof only 500ml of isotonic electrolyte solution would create a 500ml negative free-water balance,causingthe serumsodiumconcentration to increase.If anotherdoseof diuretic effected the sameurinary response,and againonly the isotonic componentwere replaced, another5110ml of electrolyte-free water would be shed,and a cummulative loss of 1,000ml of free water would accrue. It should be noted that return of the same number of shed milliequivalents of electrolyte in a lesser volume would allow for greaterwater loss. For example, return of the 70mEq of NaCl excretedin 1 liter of urine (140mOsm] in 140ml (i.e.,as saline)would causenet lossof 860 ml of electrolyte-free water (1,000ml excreted, only 140ml returned).Little more is gainedby returning the electrolyteas sodium chloride solution.This therapy leaves total body sodium content unchangedbecausethe absolutenumber of milliequivalents of excretedsalt arereturnedbut in a lesservolume of water. Patients so treated lose free water and their serum sodium concentrationincreases.The way to approach such patients follows.25 Indications for loop diuretics and 3% saline:Symptomatic patients with isovolemic, hypotonic hyponatremia (Fig. 2),23whosekidneys are responsiveto loop active agents, are the prime candidates for this 3%
5%
HYPERTONIC HYPONCITREMIA
FIGURE 2. IllagnostIc approach to hyponatremia. This algorithm describes a stepwlse cllnlcel and chemlcel approach to patients with hyponatremia. See reler8nc8 23 for a detailed dlscusslon of the approach to hyponatremla. Arrows indicate dIreCtiOn of change; Iso = Isotonlq V = varlable. Reproduced’ wlth permfsslon from Am J Med.2’
I. HYPERGLYCEMIA Z.~T&7$ON&C INFUSIONS
NORMAL POOR
SKIN
HYPOVOLEMIC HYPOTONIC HYPONATREMIA
HYPONATREMIA
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UNIC ACID
I. 01 LbSSES 2. SKIN LDSSES
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URINARY 6iaia I. CHF
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January
24, 1988
therapy. Hypovolemic patients require only saline, and hypervolemic (edematous) patients require specific therapy of their underlying illnesses (i.e., heart or liver failure or nephrotic syndrome]. Because diuretics effect loss of both isotonic fluid (sodium chloride excreted at the same concentration as in plasma) and electrolyte-free water, edematous patients with adequate effective arterial blood volume (i.e., normal blood pressure, pulse and apparent tissue perfusion) need only receive diuretics. Concomitant loss of isotonic urine and free water will simultaneously shrink the ECF and increase the serum sodium concentration. Goal of loop diuretics and saline therapy: Much controversy surrounds the rate at which normonatremia should be achieved.22J6 Reasonable arguments can be advanced in favor of either a conservative, slow increase in sodium concentration or for a more rapid rise. We are most impressed with evidence supporting a 2 mEq/liter/hr increase in serum sodium concentration, to values of 120 to 130 mEq/liter. Data in support of this position are derived from retrospective and prospective human studies and from experimental animals.22J6 Calculation of how much free water to remove: Assume that a previously healthy 70-kg man with a total body water of 42 liters (60% body weight) and a previously normal serum sodium concentration (140 mEq/liter) sustains postoperative iatrogenic isovolemic hypotonic hyponatremia. He is symptomatic (Table II], and it is decided to return his serum sodium concentration to 120 mEq/liter from 110 mEq/liter over 5 hours. His apparent premorbid total body sodium content (total body water [42 liter] X 140 mEq/liter = 5,880 mEq) is assumed to be unchanged. In what volume of water must these 5,880 mEq now be distributed to yield a concentration of 110 mEq/liter? The new volume must be 5,880 mEq + 110 mEq/liter (i.e., 53.45 liters]; 11.45 liters of water was retained (53.4 42 liters]. To lower the serum sodium concentration to 120 mEq/liter (5,880 mEq + 120 mEq/liter equals 49 liters), 7 liters of water must be retained. It follows that in order to raise the serum sodium concentration from 110 mEq/liter to 120 mEq/liter, approximately 5 liters of electrolyte-free water must be excreted, or 1 liter/hr must be lost to accomplish this in 5 hours. This calculation should be considered nothing more than a gross estimate. As therapy proceeds, frequent measurements of serum electrolytes must be made and rates of diuresis and infusion can be readjusted to achieve the desired goal. It must also be emphasized that if the patient shows striking improvement during the course of treatment, the rate of diuresis can and should be slowed. While rapid correction of hyponatremia can at times be lifesaving, there are dangers inherent in this treatment, and one must apply it most cautiously. Technique of loop diuretic and saline therapy: This treatment should be carried out in an intensive care unit where urine collections, infusion rates and vital signs can be closely followed. The object is to ensure that minimal change in total body sodium occurs as water is being removed. A parenteral dose of diuretic is chosen and repeated often enough to effect excre-
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tion of 500 to 1,000 ml/hr of urine. Initial diuretic doses could be as follows: bumetanide, 2 to 3 mg, furosemide, 80 to 100 mg and ethacrynic acid, 50 to 100 mg. After 30 minutes, a urine sample is analyzed for sodium and potassium. One may assume initially that 70 mEq/liter of electrolyte is being excreted and therefore administer 3% saline (0.5 mEq/ml] such that 70 mEq of sodium chloride will be infused in 1 hour. Thus, excretion of 1,000 ml of 70 mEq/liter electrolyte will be matched with the return of 140 ml of 3% saline (70 mEq sodium chloride). Net loss of 860 ml of water will result. Infusion rates can be adjusted as indicated by laboratory evaluation of urinary electrolyte excretion and the observed rate of increase in serum sodium concentration. Potassium is usually excreted as 10 to 20 mEq/liter and must, of course, be replenished. Diuretic and normal saline therapy of hypercalcemia: While the differential diagnosis of hypercalcemia encompasses a long list of etiologies, life-threatening causes of severe hypercalcemia (>13 to 14 mg%) are few, and malignancy looms high on the listsz7 In most circumstances, hypercalcemia results from the combined effects of resorption of bone coupled with reduced renal excretion of calcium. The relative or absolute hypocalciuria reflects reductions in glomerular filtration rate, hypovolemia or the presence of a circulating substance that stimulates tubular calcium reabsorption (parathyroid hormone). Severe hypercalcemia causes glomerular afferent arteriolar constriction and deposition of calcium salts in the kidney;28 both events reduce the glomerular filtration rate and thereby calcium filtration and excretion. Renal tubular calcium reabsorption is largely coupled with that of sodium and, in addition, hypercalcemia seems to inhibit sodium reabsorption. Thus, a vicious cycle often develops. Hypercalcemia causes natriuresis and consequent hypovolemia, and the latter reduces the glomerular filtration rate and stimulates proximal sodium and calcium reabsorption, thereby reducing calcium excretion and worsening the hypercalcemia. Many if not most patients with severe hypercalcemia are volume contracted upon hospitalization,27 making volume reexpansion with normal saline the
CONCEPl=UALlZATlON OF OSMOLAR AND FREE WATER CLEARANCE
ISOTONIC
FIGURE 3. The hypotonic (150 water fractions. volume of urine tion as plasma the remaining dilute urine can
URINE
HYPOTONIC
URINE
virtual components of hypotonlc urine. One liter of mOsm) urine is conceptualized as isotonic and freeThe osmoiar clearance (Cosm) is viewed as the required to dliute all solute to the same concentra(i.e., isobdcity). fhe free-water clearance (CH,) is solute-free urine. Thus, the components of 1 liter of be viewed of as 500 ml of Cosm and 500 ml of CH20.
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A SYMPOSIUM:
CURRENT
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initial treatment of choice. Serum calcium will commonly fall to values below 12 to 13 mg% with such treatment. For thosepatientswithout ECF volume contraction and thoseresistantto simple reexpansion,the addition of loop-activediureticsto the regimen may provehelpfu1.2gAs noted previously, the loop diuretics inhibit calcium reabsorptionin the thick ascendinglimb, and resulting hypercalciuria will help to further lower the serum calcium concentration.Unless excretedsodium is replaced, the ensuing hypovolemia will stimulate proximal calcium reabsorption,thereby diminishing the calciuric effect of the diuretics. Once normal ECF expansionhas beenestablished, loop-active diuretics may be administered intravenously every 1 to 2 hours at the following doses:bumetanide, 2 to 3 mg, furosemide, 80 to 100mg and ethacrynic acid, 50 to 100mg. This diuretic therapy will result in urine volumes of 500 to 1,000ml/hr and excretion of 90to 120 mEq/liter of sodium, 10to 20 mEq/ liter of potassiumand loss of approximately 80 mg/hr of calcium.2gSerum calcium can be expectedto fall by approximately 3 mg% over 4 to 8 hours.29Published reportsdo not clearly indicate.what fraction of the fall in serum calcium concentrationis.due to the diuretic or how much is due to rehydration alone. Potassiumand free-water lossesmust be repleted, and care must be taken to prevent either overdiuresis or sodium overload with its potential for congestive heart failure. For reasonspreviously noted, heart failure or overdiuresis would cause hypercalcemia to recur. Hyperkalemia: Life-threatening degreesof hyperkalemia are best treatedby simultaneously neutralizing the toxic effect of potassiumon the heart, stimulating its intracellular translocation and ridding the cation from the body. Infusions of calcium and hypertonic sodium reduce the cardiotoxic effects of potassium while glucose,insulin and bicarbonatereduce its serum concentrationby increasingcellular uptake.Sodium polystyrenesulfonate (Kayexalatee)reducesthe body content of potassiumby binding the cation in the intestine, Loop-active diuretics may also have a role in this setting by enhancing renal potassium excretion, Volume overloaded,severelyhyperkalemic patients may benefit from hourly dosesof intravenousbumetanide (2to 3 mg/hr), furosemide(40to 80mg/hr] or ethacrynic acid (50to 100mg/hr). Free-water losseswould, of course,have to be replenished. As previously noted, excretion of urine one-half normal in electrolyte concentration can be viewed as an equal mixture of isotonic solution (lossof which simply shrinks the ECF) and electrolyte-freewater [lossof which would lead to hypernatremia). Thus, to effect isotonic volume loss without causing hypernatremia, each milliliter of urine should be replaced with a 0.5 ml of free water (i.e., dextrose solution). Each liter of urine excreted will contain 10 to 20 mEq of potassium.It should also be rememberedthat eachmilliequivalent of potassium removed by Kayexalateecausesreturn of 1 to 2 mEq of sodium, i.e., the exchangeresin yields 1 to 2 mEq of
sodium for eachmilliequivalent of potassiumit binds. The concomitantuseof loop-activeagentswill prevent development of sodium overload in this setting.
References 1. Grantham JJ, Chonko AM. The physiologic basis and clinical use of diuretics. In: Brenner BM, Stein JH, eds. Sodium and Water Homeostasis. New York: Churchill Livingstone, 1978:178-211. 2. Grantham JJ, Irish JM. Organic acid transport and fluid excretion in the pars recta (PST) of the proximal tubule. Exerpta Medica Int. Congress Series No. 422:1977;83-90. 3. Chennavasin P, Seiwell R, Brater DC, Liang WMM. Pharmacodynamic analysis of the furosemide-probenecid interaction in man. Kidney Int 1979;16:187-196. 4. Chonko AM, Grantham ]J. Treatment of edema states. In: Maxwell MH, Kleeman CR, Narins RG, eds. Clinical Disorders of Fluid and Electrolyte Metabolism. New York: McGraw-HiII, in press. 5. Marx SJ, Bourdeau JE. Calcium metabolism. In: Ref 4. 6. Reineck HJ, Stein JH. Sodium metabolism. In: Ref 4. 7. Hall DA, Varney DM. Effect of vasopressin on electrical potential difference and chloride tmnsport in mouse medullary thick ascending limbs of Henle’s loop. J CIin Invest 1980;68:792-802. 8. Dikshit K, Vyden JK, Forrester JS, Chattejee K, Prakash R, Swan HJC. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N EngI J Med 1973;228: 1087-1090. 9. Wilson JR, Reichek N, Dunkman WB, Goldberg S. Effect of diuresis on the performance of the failing Ieft ventricIe in man. Am J Med 1981;70:234239. 10. Steiness E. Diuretics, digitalis and arrhythmias. Acta Med Stand 1981; 209:suppI 647:75-78. 11. Rudnick MR, Bastl CP, Elfinbein IB, Narins RG. The differential diagnosis of acute renal failure. In: Brenner BM, Lazarus JM, eds. Acute Renal Failure. Philadelphia: WB Saunders, 1983:176-222. 12. Schrier RW, Gardenswartz MH, Burke TJ. Acute renal failure: pathogenesis, diagnosis and treatment. In: Hamburger J. Crosnier 1. Grfinfeld JP, Maxwell MN, eds. Advances in Nephrology. Vol. II. Chicago: Year Book Medical Publishers. 1982:213-240. 13. Birtch’AG, Zekheim RM, Jones LJ, Barger AC. Redistribution of renal blood flow produced by furosemide and ethocrynic acid. Circ Res 1967; 21:869-878. 14. Johnston
PA, Bernard DB. Perrin NS, Levinsky NG. Prostaglandins mediate the vosodilatory effect of mannitol in the hypoperfused rat kidney. 1 CIin Invest 1981;68:127-138. 15. Levinsky NG, Bernard DB, Johnston PA. Mannitol and loop diuretics in acute renal failure. In: Ref 11:712-722. 16. Untura A. Incidence and nrouhvlaxis of acute wstonerative renal failure in obstructive jaundice. Rev Meh Chir Sot Med ‘Nat iAS 1979;83:247-254. 17. Dawson JL. Post-operative renal function in obstructive jaundice. Effect of a mannitol diuresis. Br Med J 1965;1:82-85. 18. Hayes DM, Cvitkovic E, Golbey RB, Scheiner E, Helson L. Krakoff I. High dose cisplatinum diammine dichloride. Amelioration of renal toxicity by monnitol diuresis. Cancer 1977;39:1372-1376. 19.Olivero JJ. Lozano-Mendez J, Ghafary EM, et al. Mitigation ofamphoteritin B nephrotoxicity by mannitol. Br Med J 1975:1:550-554. 20. Anto HR, Chou SY. Porush JG. Shapiro WB. Mannitol prevention of acute renal failure associated with infusion intravenous pyelography [abstr). Clin Res 1979;27:407A. 21. Old CW, Lehrner LM. Prevention of radiocontrast induced acute renal failure with mannitol (letter). Lancet 1980;2:885. 22. Dubois GD, Arieff AI. Treatment of hyponatremia: the case for rapid correction. In: Narins RG, ed. Controversies in Nephrology and Hypertension New York: Churchill Livingstone, 1984:393-408. 23. Narins RG, Jones ER, Stom MC, Rudnick MR, Bast) CP. Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis. Am 1 Med i982;72:498-519.
24. Schrier RW. Treatment of hyponatremia (editorioI). N Engl J Med 1985:17:1121. 25. Hantman D, Rossier B, Zohlman R, Schrier RW. Rapid correction of byponatremia in the syndrome of inappropriate secretion of antidiuretic hormone: an alternative to hypertonic saline. Ann Intern Med 1973;78: 870-878. 26. Norenberg MD. Treatment of hyponatremia: the case for o more conservative approach. In: Ref 22393-408. 27. Mundy CR, Martin TJ. The hypercalcemia of malignancy: pathogenesis and management. Metabolism 1982:31:1247-1277. 28. Benabe JE. Martinez-Maldinado M. Hypercalcemic nephropathy. Arch Intern Med 1976:138:777-789, 29. Suki WN, Yiu’m-JJ, Minden MV. Saller-Herbert C. Eknoyan G, MartinezMaldinado M. Acute treatment of hypercalcemia with furosemide. N Engl J Med 1970;283:836-840.