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POST-TRAUMATIC ACUTE RENALFAILURE*

ANDREW WHELTON, M.D.Associate Professor of Medicine

Johns Hopkins University School of MedicineBaltimore, Maryland

THE clinical syndrome of post-traumatic acute renal failure (PTARF)was first clearly recognized as a disastrous complication of physical

trauma sustained by civilian and military casualties during World War II. 1,2

Many of the first patients described as having the association of traumaand subsequent acute renal failure had suffered extensive crushing injuriesto various parts of their bodies, most particularly to the muscle mass of thelimbs. Because of this pattern of injury, PTARF of the latter origin has alsobeen known for many years as the crush syndrome. Investigationsduring World War II led to the description of PTARF, Korean Warexperience demonstrated a reduction of more than 90% in mortality fromPTARF by the use of extracorporeal hemodialysis, and the Vietnamconflict documented that PTARF is a largely preventable form of acuterenal failure.3-6

Information derived from military experience, clinical reviews of civil-ian trauma sequelae, and animal investigations now allow us to view thesyndrome of PTARF more rationally from the standpoints of etiology,clinical management, and prognosis.

ETIOLOGY

As the name of the syndrome implies, patients with PTARF developacute renal failure following an injury that has produced blood loss,prolonged hypotension, and often myoglobinuria. It is of fundamentalimportance for the clinician to remember that even though the etiology ofPTARF is primarily related to the location and degree of trauma sustainedby the patient, it is still necessary to consider the three etiologic

*Presented as part of a Symposium on Diagnosis and Management of Abdominal and ThoracicTrauma sponsored by the New York Hospital-Cornell Medical Center and the New York Academy ofMedicine in cooperation with Science & Medicine Publishing Co., Inc., under a grant from PfizerLaboratories, New York, N.Y., and held at the Cornell Medical Center on October 28, 1978.

Address for reprint requests: Department of Medicine, Johns Hopkins Hospital, Baltimore, Md.21205

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TABLE I. ETIOLOGIC-DIAGNOSTICCATEGORIES IN ACUTE RENAL FAILURE

Prerenal (Irenal perfusion)Hypovolemia: multiple causes of acute blood and plasma lossFluid anid electrolyte depletion: gastrointestinal loss, skin loss, segregated fluid accumu-

lationsIntravascular hemolysis: mismatched blood, intravenous hypotonic solutions

Renal (intrinsic anatomic and vascular defects)Acute vasomotor nephropathy or acute tubular necrosis: secondary to prolonged Jrenal

perfusion; myoglobinuriaAcute primary and secondary glomerulopathies: acute poststreptococcal glomerulone-

phritis, acute lupus nephritisNephrotoxins: heavy metals, many antibiotics, industrial solvents/chemicalsAcute fulminant pyelonephritisAcute bilateral cortical necrosisMalignant' hypertension

Postrenal (outflow obstruction)CalculiBlood clotsThmorTraumaSurgical accidents/suturesUreteric edemaProstatic hypertrophy

categories-prerenal factors, intrinsic renal defects, and postrenal ob-structive phenomena-that may complicate the clinical picture of anypatient with PTARF (Table I).

Injured patients most likely to develop acute renal failure are those whohave the following:

1) A prolonged period of hypotension due to a delay of definitive medicaland surgical care

2) Mismatched blood received as part of massive blood replacementtherapy

3) Extensive muscle damage with resultant myoglobinemia and myo-globinuria

4) Third-degree burns of 20% or more of the body surface in associa-tion with the injury

5) Large bowel injury or necrosis with intra-abdominal abscess forma-tion and systemic sepsis

6) Multisystem failure (hepatic, pulmonary, cardiac) following injurywith late renal involvementGunshot damage, stabbings, vehicular accidents, and crushing injuries

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of any nature all characteristically may lead to acute renal failure. Weshould also review the development of acute renal failure following ruptureof an abdominal aneurysm or in the setting of postoperative hypovolemicshock. Pathophysiologically, the events that lead to acute renal failure aresimilar, in part, to those already noted for PTARF.From the glomerular and tubular functional point of view, the exact

nature of the pathophysiologic sequence of events in PTARF, which leadsto "shutdown" of the kidney for two to five weeks, is not yet fullyresolved. The tubular, vascular, and hormonal considerations that may beimportant are reviewed in detail elsewhere.7

INCIDENCE

The frequency with which PTARF is seen clinically has decreaseddramatically during the past several years. This decrease reflects betterunderstanding of the syndrome's pathophysiology and rapid and definitivemanagement of trauma victims.3" Suffice it to say that among Americanmilitary casualties during the early 1940s the incidence of PTARF was asmuch as one out of every three seriously injured soldiers; by the early1950s the incidence was one in 200 in similarly injured military casualties;whereas by the mid to late 1960s the incidence in military casualties wascomputed as one in 600 or lower.' Clearly-, given the rapid availability ofappropriate medical and surgical care, this syndrome is becoming quiterare.

However, considering the incidence of acute renal failure in connectionwith surgical repair of a ruptured abdominal aneurysm, we see many moresuch patients.8 This increase, of course, reflects improved intensive careand cardiovascular surgical techniques, as a result of which many elderlypatients with acute rupture of an abdominal aneurysm now survive theinitial insult and undergo vascular reparative surgery. The survival rate ofthese patients-those with postabdominal aneurysm rupture and acute renalfailure-has also markedly improved in recent experience.8

DIAGNOSIS

At the initial examination of an injured patient with acute deteriorationof renal function, the three major entities listed in Table I play an impor-tant role in the differential diagnosis. The first consideration is the pa-tient's intravascular volume. If the patient is seen immediately after the

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event that caused the acute intravascular depletion, it may be possible toarrest the pathophysiologic series of events at a prerenal or renal profu-sional level. The time between injury, intravascular depletion, hypoten-sion, and development of organic acute renal failure is variable. It dependsupon the extent of injury, the degree of intravascular depletion, and thepatient's premorbid physical status. Generally, the time interval is fromone to several hours, which means that appropriate reconstitution of thepatient's intravascular volume will serve as both a diagnostic procedureand a therapeutic maneuver because if the patient is still in the prerenalphase of acute renal failure, he may well respond to volume expansion andnormalization of blood pressure by a return of normal renal function. Onthe other hand, if the patient's blood pressure and intravascular volumehave returned to normal but renal function continues to deteriorate, one isdealing with organic renal failure or the syndrome of PTARF. In essence,we have moved from the prerenal forms of failure to an intrinsic renaldefect (Table I). Postrenal considerations listed in Table I should also bereviewed because in injuries involving the abdomen, pelvis, or both, onemust carefully assess the anatomic integrity of the renal outflow tract.Compression injuries or direct trauma to the ureters or bladder may presentas PTARF. Appropriate urological evaluation leads to correct diagnosisand, hence, to the appropriate management.The immediate renal functional assessment of an injured patient, a bum

victim, or a patient with a ruptured aneurysm would include the following:1) Physical examination, with particular emphasis on the patient's

fluid-volume status2) Evaluation of serum electrolytes, with particular attention to potas-

sium and bicarbonate levels3) Blood-chemistry determinations, with particular attention to blood

urea nitrogen and serum creatinine4) Institution of an hourly intake and output fluid-flow chart5) Urinalysis to determine the presence of protein, glucose, or other

chemical abnormalities with microscopic evaluation for the presence ofcellular elements or cast formations

6) Determinations of urine osmolality and sodium and potassium con-centrations (osmolality > 300 to 400 mOsm. per liter and urine sodium > 20mEq. per liter are highly suggestive of predominant prerenal factors becausethese data reflect good tubular function)

7) Daily body weight chart

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Such other investigations as quantitative renal function tests of glomeru-lar filtration rate, renal sonography, renal isotopic scanning evaluation, orarteriographic procedures can be utilized depending on the individual caseneed.

MANAGEMENT

Once acute renal failure has developed, following any of the manyforms of injury and blood loss already reviewed, the patient requirescontinuous intensive medical and surgical care for several days or weeks.No effort should be spared because this form of renal failure is fullyreversible. Obviously, in some individuals the nature and the extent ofinjury and the multisystem complications involved in their immediatemanagement are such that these patients do not survive long enough topermit return of renal function.

Standard medical and surgical management techniques and commonsense are the most important ingredients in the management of patientswith acute renal failure. These principles are directed toward the follow-ing:

1) Reversing the abnormalities that have led to acute renal failure2) Maintaining the patient through a two- to five-week period of acute

renal failure3) Eliminating intercurrent problems (e.g., infection)A few specific management features deserve separate emphasis.Fluid replacement and restoration of electrolyte balance. Appropriate

replacement of blood losses, fluids, and electrolytes is the first immediatemanagement step in PTARF. As already noted, a vast majority of traumavictims who may initially show minor evidences of renal impairment-asmanifested by slight elevation of their serum creatinine or transient dim-inution of their urinary output-will, nonetheless, respond well to resto-ration of their intravascular volume. On rare occasions, however, a patientwill develop acute renal failure despite reconstitution of intravascularvolume and despite return to normal pulse and blood pressure. Thesepatients may have shown poor urinary output shortly after the time oftrauma, or their previously normal urinary output may decrease steadily(designated as high-output failure). In either case, the ensuing period ofrenal failure may last from two to five weeks.

Extracorporeal hemodialysis and peritoneal dialysis. Acute renal failurefollowing trauma tends to be a more catabolic form of acute renal failure

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l~~~~~~CT EA ALR 5

than is seen in most other circumstances.3'9-' Usually, the degree ofcatabolism is of sufficient magnitude that extracorporeal hemodialysis ismore effective than peritoneal dialysis. Once the development of PTARFis apparent, it is possible to anticipate that the patient will need intensivehemodialysis for at least three or four weeks. In general, we recommenddialysis every second day for four- to six-hour periods. Clinical follow-upand blood-chemistry determinations will dictate any necessary changes insuch a regimen. If there is any doubt about the time to begin dialysis, it isalways wiser to err on the side of early dialysis. Although urea is not thekey factor in induction of the uremic syndrome, blood urea nitrogenprovides a yardstick to the accumulation of other end products of nitrogenmetabolism that should have been excreted by the kidneys. Any combina-tion of blood urea nitrogen greater than 100 mg./dl. and increasing, serumcreatinine between 5 and 10 mg./dl. and increasing, or even mild impair-ment of renal function with evidence of hyperkalemia may be thesignal to begin hemodialysis. Between dialyses, the blood urea nitrogenshould preferably be kept below 100 mg./dl. Strong evidence suggests thatthe more "physiologically" the patient is maintained by hemodialysis, thebetter the function of all body systems, the more effective the rate ofwound healing, and the greater the resistance to complicating infections.

After fluid and blood replacement, correction of electrolyte abnor-malities, and initiation of hemodialysis, day-to-day decisions about manag-ing the patient's hydrational status should be based on physical examina-tion, including meticulous determinations of daily weights, review of fluidintake and output flow charts, and evaluation of roentgenograms of thelungs. Other variables that require careful monitoring are arterial bloodpressure and central venous pressure. In an afebrile patient, 500 to 700 ml.of fluid must be given daily to replace insensible fluid losses. Other fluidlosses that occur by urinary output and nasogastric suction will requireappropriate replacement. If the patient has suffered bowel injury, it will benecessary to estimate the amount of fluid loss through bowel fistulas and toreplace these losses.

Control of infection. All patients with acute renal failure have increasedsusceptibility to infection. 13,4 In the PTARF group of patients infectionmay often be a complication at the site of injury, most particularly if thelarge bowel has been injured. Invariably, antibiotic selection will bedirected toward covering Gram-negative, Gram-positive, and anaerobicorganisms. In realistic terms, this means that the physician should carefully

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consider the clinical effectiveness, the systemic toxicity profile, and thesafety in renal failure of the antibiotic to be selected. The aminoglyco-sides, the penicillins, the cephalosporins, chloramphenicol, clindamycin,and doxycycline are all likely agents for use in renal failure. Ami-noglycosides, such as gentamicin, tobramycin, or amikacin, are very effec-tive against Gram-negative organisms typically encountered in patientswith acute renal failure. The latter antibiotics have well-known toxic sideeffects upon the ear, kidney, and neuromuscular functions.'4-'7 Becauseserum therapeutic and toxic levels are not widely separated, ami-noglycoside antibiotics must be administered with great care in patientswith renal failure. Serum drug monitoring is of particular importance.Many dosage guide tables are available'4"8 and should be used in associa-tion with serum drug monitoring.

If an antibiotic must be selected early in the management of PTARFbefore the organisms in blood and tissue cultures have been identified, thechoice will almost certainly be an aminoglycoside combined with anotherantibiotic active against Gram-positive and anaerobic organisms. The mostfrequent choices for the second agent are chloramphenicol, clindamycin, ordoxycycline. Overall, doxycycline is the least toxic of the latter three.Chloramphenicol may very rarely cause hypersensitivity aplastic anemia butwith renal failure may frequently produce a dose-related form of reversiblemarrow suppression. Clindamycin may occasionally cause pseudomembra-nous colitis. Because chloramphenicol and clindamycin are metabolized by theliver, they can be given to patients with acute renal failure in the same dosageas to patients with normal kidneys. This will not totally prevent their toxicside effects. Doxycycline is the only tetracycline that can be safely used inpatients with acute renal failure. In such patients its toxicity is similar to that inpatients with normal renal function. In contradistinction, such older tetracy-clines as chlortetracycline, oxytetracycline, or tetracycline hydrochloride andthe new tetracycline minocycline all accumulate during renal failure andproduce catabolic effects that increase the patient's prerenal azotemia.'9 Thatdoxycycline, a new member of the tetracycline class of antibiotics, does notaccumulate in renal failure may, at first, seem somewhat surprising. How-ever, recent metabolic studies from our laboratories have identified anonhepatic, nonrenal, "alternate" gastrointestinal pathway of excretionfor this compound.20 Our human studies have also identified that removalof the drug by hemodialysis is not of clinical significance. Therefore,doxycycline appears to be unique among the tetracyclines; when renal

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failure complicates clinical management decisions, or indeed when therenal functional status is not known, and if a tetracycline is indicated forsystemic infection, doxycycline is the drug of choice. In the context ofPTARF, doxycycline would be very useful for combined anaerobe andGram-positive coverage.

Nutritional care. Patients with acute renal failure require adequatecaloric intake, even if they are physiologically normal in body weight oreven obese. Although such patients have enough body calories to burn up,all efforts should be made to keep them from becoming catabolic. Break-down of body tissues involves breakdown of proteins and the liberation ofsulfate and phosphate anions. In these patients the latter anions representthe equivalent of adding sulfuric acid or phosphoric acid to the extracellu-lar fluids. Obviously, immediate buffering of these strong acids is neces-sary. The buffered sulfate or phosphate anions can only be excreted by thekidney or by hemodialysis. If they accumulate, they lead to progressiveacidosis.A certain amount of carbohydrate in the diet spares protein breakdown,

viz., at least 400 to 500 kcal. per day, given intravenously if necessary.Ideally, one should give 2,000 to 3,000 kcal. per day, including 30 to 40gm. of protein per day to make up for the breakdown of endogenousprotein, the remainder being carbohydrates and fats (nonprotein calories).Most patients with acute renal failure can be fed orally, but extensiveabdominal injury may require that feeding be intravenous (total parenteralnutrition or hyperalimentation). In patients with PTARF, where acuterenal failure is likely to last a long time and where shock has occurred, it iswise to move rapidly to hyperalimentation. Commercially available solu-tions for hyperalimentation contain a mixture of essential and nonessentialamino acids. The amount of protein given as amino acids varies with thepatient's condition, e.g., as much as 80 gm. of protein daily, accompaniedby carbohydrate as dextrose, may be given to patients with rapid tissuebreakdown. Hyperalimentation must be administered into a vein in whichblood flows rapidly so that both venotomy and meticulous care of thecatheter obligated to this use are required. The rate of hyperalimentationmay affect the frequency and duration of hemodialysis because some of theamino acids administered contain sulfate radicals, which can be eliminatedonly by hemodialysis.

Hyperkalemia. The principal warning sign of hyperkalemia-the appear-ance of tall, peaked T waves on the electrocardiogram-should elicit

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TABLE II. MANAGEMENT OF HYPERKALEMIA

Stabilization of the excitability of cardiac muscleInfuse calcium salts, such as 10% calcium gluconate; three vials or 30 ml. for adults over

10- to 20-minute period.Monitor for bradycardia; if it develops, discontinue calcium infusion.Do not mix calcium-containing solutions and sodium bicarbonate solutions because

calcium salts will precipitate out of solution.Measures to drive K+ back into cellNaHCO:g to correct acidosis. Usually 1.5 to 2 mEq./kg. body weight over 20- to

60-minute period, depending on cardiac status of patient. Hydrogen ion moves out of cell inexchange for potassium moving into cell.

Glucose and insulin intravenously. Usually 50 gm. hypertonic glucose (20% or 50%solution) associated with 15 units of insulin, i.e., 3 to 4 gm. of glucose require one unit ofinsulin.Definitive corrective measures

Ion-exchange resin; sodium polystyrene sulfonate (Kayexalate) 25% in 25% sorbitol.Give 50 ml. orally every four hours as tolerated or 100 ml. as a retention enema. Avoidion-exchange resin in any patient with bowel trauma or other bowel complications.

Extracorporeal hemodialysis or peritoneal dialysis for removal of potassium. Repeatdialysis as necessary.

immediate attention. Hyperkalemia will lead to acute cardiac arrhythmiasand can be fatal. In general, a value of 7 mEq. per liter is dangerous, andlevels of 10 to 12 mEq. per liter are usually fatal. Relative change in theratio between intracellular and extracellular potassium causes changes inpolarization of the cardiac muscle membrane. The resultant hyperexcita-bility of the muscle predisposes to the development of arrhythmias. TableII identifies a sequence of management steps for most patients with hyper-kalemia. The initial steps represent what might be designated as a minute-to-minute approach to hyperkalemia; then follows an hour-to-hour, more

definitive series of management steps.Diuretic phase of PTARF and aftercare. Following a finite period of

dialysis, which will vary from patient to patient but frequently ranges fromtwo to five weeks, the PTARF or postabdominal aneurysm-rupture, renal-failure patient enters a recovery or a diuretic phase of the syndrome.Progressively increasing urinary volumes will be produced. Dramatic andrapid diuresis is quite rare, and one can usually expect to see urinaryvolumes increase from a daily figure of approximately 400 ml. to perhapsa daily volume of 4,000 ml. during a 10-day to two-week diuretic period.During this time the urinary sodium concentration is characteristically in afixed range of about 60 to 80 mEq. per liter. This means that careful

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electrolyte and fluid-replacement therapy must continue during this recov-ery phase of renal function. Increases in glomerular filtration rate andredevelopment of adequate electrolyte transport in the tubule continue forseveral days. In fact, maximal urinary concentrating ability may take asmuch as three months or more for full recovery, but clinically the patientshould be ready for discharge from the hospital long before maximal returnof renal function is noted.

PROGNOSIS

It is reasonable to state that if the PTARF patient can be kept aliveduring the period of acute renal failure by the management already re-viewed, then the individual's kidney function will return to, or approxi-mate, preshutdown levels. The exception to this rule is the very rare caseof acute cortical necrosis, which is almost uniformly seen in renal failurecomplicating the third trimester of pregnancy. With acute cortical necrosis,glomeruli become necrotic and cannot regain normal function. Elderlypatients with acute renal failure and pre-existing vascular disease of thekidney, such as arteriolonephrosclerosis, may recover renal function onlyto the level of 50% to 75% of preshutdown function.

All patients with PTARF require aggressive management because in-variably one cannot predict their clinical outcome. It is realistic, however,to acknowledge that even in the best of circumstances of modem intensive-care management, 45% to 65% of severely injured patients who have alsodeveloped acute renal failure die despite our best efforts.:3i69-12,21-23; Theseare patients with multisystem failure, massive infectious complications,and nutritional defects; those presenting such a clinical picture by nomeans die from kidney failure alone.A more encouraging finding emerges from our recent experience with

acute renal failure complicating abdominal aneurysm rupture. Several re-ports up to the 1970s emphasized the dismal prognosis for these patients.Pooling such data,8 one finds that only 12 of 89 patients survive, i.e., amortality rate of 83%. However, our most recent clinical experience with11 consecutive patients saw eight survive with recovery of renal function,i.e., a mortality rate of only 27%.8 We emphasize that this improvedprognosis simply reflects maximum-effort intensive-care management to-gether with prompt and vigorous dialysis. The outlook for this subset ofacute renal failure patients clearly improves.

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Discussion

DR. G. THOMAS SHIRES: Dr. Whelton, what is the role of mannitol andfurosemide in preventing the onset of acute renal failure?

DR. WHELTON: Dr. Kevin Barry and several other investigators at TheWalter Reed Medical Center showed in the early 1960s that if one usedmannitol to preinfuse patients who will undergo aneurysmal resection andcontinued this infusion intraoperatively, the incidence of post-operativeacute renal failure could be decreased. Subsequently, Dr. Barry and asso-ciates did control studies, using simple saline solutions and other forms ofvolume-replacement therapy, and showed that these solutions were as goodas mannitol in the preoperative and intraoperative approach to reducingacute renal failure associated with aortic aneurysm surgery. So, as ourunderstanding of the pathophysiological changes leading to vasomotornephropathy increased, we began to realize that mannitol did not reallyhave any intrinsically special action on the kidney and that volume-replacement therapy was actually the most important thing.

As to the use of furosemide, if a patient is still in the prerenal phase ofacute renal failure, there certainly will be a responsiveness from thetubules; in particular, an increased urinary output can be expected as aresult of the action of the diuretic upon the ascending limb of the loop ofHenle. I believe that furosemide can be utilized as a simple and quickclinical monitoring device indicating to what extent a patient is respondingto fluid therapy; but once a patient has established acute renal failure, thisdiuretic is not helpful.

DR. PAUL C. PETERS: In the prerenal phase of acute renal failure, dodiuretics play a role in the prevention of tubular cast formation?

DR. WHELTON: There is no doubt that diuretics increase the volumeflow rate per unit of time and would tend to mobilize casts, if alreadyformed. During the 1950s and the 1960s it was believed that the presenceof casts-whether myoglobin or hemoglobin casts or simply casts fromsloughed renotubular epithelial cells-was an important factor in thepathogenesis of post-traumatic acute renal failure. However, subsequentmicropuncture studies, investigating the pressure inside the lumen of thetubule proximal and distal to the cast, showed that the casts do notcontribute in an obstructive mechanical nature to the pathogenesis of theacute renal failure. So, even though the loop diuretics may increase theflow rate and the mobilization of the casts, I am not really convinced that

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they can pathophysiologically change the progress of events. This is an issuethat is still the focus of ongoing investigation.

DR. PETERS: Do the casts have any role as direct toxins to the tubule?DR. WHELTON: There is some suggestive evidence from animal models

that myoglobin is a tubular toxin, as opposed to hemoglobin (which is nota tubular toxin). In massive hemolysis with adequate intravascular volumewe do not see acute renal failure from just hemoglobin and hemoglo-binuria. But one can certainly produce acute renal failure by the infusionof myoglobin in the presence of a volume-expanded animal.

QUESTION: Dr. Whelton, does the antidiuretic hormone (ADH) exertany significant effect on the development of postoperative oliguria or thedevelopment of renal failure in the adequately resuscitated patient?

DR. WHELTON: In this clinical setting, the secretion of ADH wouldprobably be mediated by factors such as postoperative pain and as a resultof the use of narcotic agents used for the relief of pain. These are probablythe most important clinical situations. Therefore, the patient may have theequivalent of a brief episode of ADH secretion.

REFER ENCES

1. Bywaters, E. G. L. and Beall, D.: Crushinjuries with impairment of renal func-tion. Br. Med. J. 1:427, 1941.

2. Board for the Study of the SeverelyWounded: The Physiologic Effects ofWounds. In:Mediterranean Theater ofOperations. Washington, D.C., Officeof the Surgeon General, Department ofthe Army, 1952, p. 376.

3. Whelton, A. and Donadio, J. V., Jr.:Post-traumatic acute renal failure inVietnam: A comparison with the KoreanWar experience. Johns Hopkins Med. J.124:95, 1969.

4. Donadio, J. V., Jr. and Whelton, A.:Operation of a renal center in a combatzone. Milit. Med. 133:833, 1968.

5. Whelton, A.: Post-traumatic AcuteRenal Failure in Vietnam Combat In-juries; Incidence, Morbidity and Mor-tality. In: Proceedings; Conference onAcute Renal Failure, Friedman, E. A.and Eliahou, H. E., editors. Brooklyn,N.Y., Downstate Medical Center,1973, p. 125.

6. Whelton, A.: Post-traumatic acute renal

failure in Vietnam: A milestone in prog-ress. Conn. Med. 38:7, 1974.

7. Gabow, P. A., Anderson, R. J., andSchrier, R. W.: Acute renal failure.Cardiovasc. Med. 2:1161, 1977.

8. Sapir, D. G., Dandy, W. E., Jr., Whel-ton, A., and Cooke, C. R.: Acute renalfailure following ruptured abdominalaneurysms: An improved clinical prog-nosis. Crit. Care Med. In press.

9. Teschan, P. E., Post, R. S., Smith, L.H., Jr., et al.: Post-traumatic renal in-sufficiency in military casualties: I. Clin-ical characteristics. Am. J. Med. 18:172,1955.

10. Smith, L. H., Jr., Post, R. S., Teschan,P. E., et al.: Post-traumatic renal insuf-ficiency in military casualties: II. Man-agement, use of an artificial kidney,prognosis. Am. J. Med. 18:187, 1955.

11. London, R. E. and Burton, J. R.: Post-traumatic renal failure in military per-sonnel in Southeast Asia. Am. J. Med.53:137, 1972.

12. Conger, J. D.: A controlled evaluationof prophylactic dialysis in post-traumatic

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acute renal failure. J. Trauma 15:1056,1975.

13. Montgomerie, J. Z., Kalmanson, G.M., and Guze, L. B.: Renal failure andinfection. Medicine (Baltimore) 47:1,1968.

14. Whelton, A.: Antibacterial chemo-therapy in renal insufficiency: A review.Antibiot. Chemother. 18:1, 1974.

15. Whelton, A., Carter, G. G., Craig, T.J., et al.: Comparison of the intrarenaldisposition of tobramycin and gentami-cin: Therapeutic and toxicologic an-swers. J. Antimicrob. Chemother.(Suppl. A)4:13, 1978.

16. Brummett, R. E., Fox, K. E., Bendrick,T. W., and Himes, D. L.: Ototoxicity oftobramycin, gentamicin, amikacin, andsisomicin in the guinea pig. J. Antimi-crob. Chemother. (Suppl. A) 4:73,1978.

17. Appel, G. B. and Neu, H. C.: The neph-rotoxicity of antimicrobial agents (threeparts). N. Engl. J. Med. 296:663, 1977.

18. Bennett, W. M., Singer, I., Golper, T.,

et al.: Guidelines for therapy in renalfailure. Ann. Intern. Med. 86:754,1977.

19. Whelton, A.: Tetracyclines in renal in-sufficiency: Resolution of a therapeuticdilemma. Bull. N.Y. Acad. Med.54:233, 1978.

20. Whelton, A., Schach von Wittenau, M.,Twomey, T. M., et al.: Doxycyclinepharmacokinetics in the absence of renalfunction. Kidney Int. 5:365, 1974.

21. Kleinknecht, D., Jungers, P., Chanard,J., et al.: Uremic and non-uremic com-plications in acute renal failure: Evalua-tion of early and frequent dialysis onprognosis. Kidney Int. 1: 190, 1972.

22. Scott, R. B., Cameron, J. S., Ogg, C.S., and Bewick, M.: Why the persis-tently high mortality in acute renal fail-ure? Lancet 2:75, 1972.

23. Champion, H., Sacco, W., Long, W., etal.: Indications for early haemodialysisin multiple trauma. Lancet 1:1125,1974.

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