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POST-TRAUMATIC ACUTE RENAL FAILURE* ANDREW WHELTON, M.D. Associate Professor of Medicine Johns Hopkins University School of Medicine Baltimore, 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 trauma and subsequent acute renal failure had suffered extensive crushing injuries to various parts of their bodies, most particularly to the muscle mass of the limbs. Because of this pattern of injury, PTARF of the latter origin has also been known for many years as the crush syndrome. Investigations during World War II led to the description of PTARF, Korean War experience demonstrated a reduction of more than 90% in mortality from PTARF by the use of extracorporeal hemodialysis, and the Vietnam conflict documented that PTARF is a largely preventable form of acute renal failure.3-6 Information derived from military experience, clinical reviews of civilian trauma sequelae, and animal investigations now allow us to view the syndrome of PTARF more rationally from the standpoints of etiology, clinical management, and prognosis. ETIOLOGY As the name of the syndrome implies, patients with PTARF develop acute renal failure following an injury that has produced blood loss, prolonged hypotension, and often myoglobinuria. It is of fundamental importance for the clinician to remember that even though the etiology of PTARF is primarily related to the location and degree of trauma sustained by the patient, it is still necessary to consider the three etiologic *Presented as part of a Symposium on Diagnosis and Management of Abdominal and Thoracic Trauma sponsored by the New York Hospital-Cornell Medical Center and the New York Academy of Medicine in cooperation with Science & Medicine Publishing Co., Inc., under a grant from Pfizer Laboratories, 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-DIAGNOSTIC CATEGORIES IN ACUTE RENAL FAILURE
Prerenal (Irenal perfusion) Hypovolemia: multiple causes of acute blood and plasma loss Fluid anid electrolyte depletion: gastrointestinal loss, skin loss, segregated fluid accumulations Intravascular hemolysis: mismatched blood, intravenous hypotonic solutions Renal (intrinsic anatomic and vascular defects) Acute vasomotor nephropathy or acute tubular necrosis: secondary to prolonged Jrenal perfusion; myoglobinuria Acute primary and secondary glomerulopathies: acute poststreptococcal glomerulonephritis, acute lupus nephritis Nephrotoxins: heavy metals, many antibiotics, industrial solvents/chemicals Acute fulminant pyelonephritis Acute bilateral cortical necrosis Malignant' hypertension Postrenal (outflow obstruction) Calculi Blood clots Thmor Trauma Surgical accidents/sutures Ureteric edema Prostatic hypertrophy
categories-prerenal factors, intrinsic renal defects, and postrenal obstructive phenomena-that may complicate the clinical picture of any patient with PTARF (Table I). Injured patients most likely to develop acute renal failure are those who have the following: 1) A prolonged period of hypotension due to a delay of definitive medical and surgical care 2) Mismatched blood received as part of massive blood replacement therapy 3) Extensive muscle damage with resultant myoglobinemia and myoglobinuria 4) Third-degree burns of 20% or more of the body surface in association with the injury 5) Large bowel injury or necrosis with intra-abdominal abscess formation and systemic sepsis 6) Multisystem failure (hepatic, pulmonary, cardiac) following injury with late renal involvement Gunshot damage, stabbings, vehicular accidents, and crushing injuries Vol. 55, No. 2, February 1979
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of any nature all characteristically may lead to acute renal failure. We should also review the development of acute renal failure following rupture of an abdominal aneurysm or in the setting of postoperative hypovolemic shock. Pathophysiologically, the events that lead to acute renal failure are similar, 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 leads to "shutdown" of the kidney for two to five weeks, is not yet fully resolved. The tubular, vascular, and hormonal considerations that may be important are reviewed in detail elsewhere.7 INCIDENCE
The frequency with which PTARF is seen clinically has decreased dramatically during the past several years. This decrease reflects better understanding of the syndrome's pathophysiology and rapid and definitive management of trauma victims.3" Suffice it to say that among American military casualties during the early 1940s the incidence of PTARF was as much as one out of every three seriously injured soldiers; by the early 1950s the incidence was one in 200 in similarly injured military casualties; whereas by the mid to late 1960s the incidence in military casualties was computed as one in 600 or lower.' Clearly-, given the rapid availability of appropriate medical and surgical care, this syndrome is becoming quite rare.
However, considering the incidence of acute renal failure in connection with surgical repair of a ruptured abdominal aneurysm, we see many more such patients.8 This increase, of course, reflects improved intensive care and cardiovascular surgical techniques, as a result of which many elderly patients with acute rupture of an abdominal aneurysm now survive the initial insult and undergo vascular reparative surgery. The survival rate of these patients-those with postabdominal aneurysm rupture and acute renal failure-has also markedly improved in recent experience.8 DIAGNOSIS
At the initial examination of an injured patient with acute deterioration of renal function, the three major entities listed in Table I play an important role in the differential diagnosis. The first consideration is the patient's intravascular volume. If the patient is seen immediately after the Bull. N.Y. Acad. Med.
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event that caused the acute intravascular depletion, it may be possible to arrest the pathophysiologic series of events at a prerenal or renal profusional level. The time between injury, intravascular depletion, hypotension, and development of organic acute renal failure is variable. It depends upon the extent of injury, the degree of intravascular depletion, and the patient's premorbid physical status. Generally, the time interval is from one to several hours, which means that appropriate reconstitution of the patient's intravascular volume will serve as both a diagnostic procedure and a therapeutic maneuver because if the patient is still in the prerenal phase of acute renal failure, he may well respond to volume expansion and normalization of blood pressure by a return of normal renal function. On the other hand, if the patient's blood pressure and intravascular volume have returned to normal but renal function continues to deteriorate, one is dealing with organic renal failure or the syndrome of PTARF. In essence, we have moved from the prerenal forms of failure to an intrinsic renal defect (Table I). Postrenal considerations listed in Table I should also be reviewed because in injuries involving the abdomen, pelvis, or both, one must carefully assess the anatomic integrity of the renal outflow tract. Compression injuries or direct trauma to the ureters or bladder may present as PTARF. Appropriate urological evaluation leads to correct diagnosis and, 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 status 2) Evaluation of serum electrolytes, with particular attention to potassium and bicarbonate levels 3) Blood-chemistry determinations, with particular attention to blood urea nitrogen and serum creatinine 4) Institution of an hourly intake and output fluid-flow chart 5) Urinalysis to determine the presence of protein, glucose, or other chemical abnormalities with microscopic evaluation for the presence of cellular elements or cast formations 6) Determinations of urine osmolality and sodium and potassium concentrations (osmolality > 300 to 400 mOsm. per liter and urine sodium > 20 mEq. per liter are highly suggestive of predominant prerenal factors because these data reflect good tubular function) 7) Daily body weight chart Vol. 55, No. 2, February 1979
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Such other investigations as quantitative renal function tests of glomerular filtration rate, renal sonography, renal isotopic scanning evaluation, or arteriographic procedures can be utilized depending on the individual case need. MANAGEMENT
Once acute renal failure has developed, following any of the many forms of injury and blood loss already reviewed, the patient requires continuous intensive medical and surgical care for several days or weeks. No effort should be spared because this form of renal failure is fully reversible. Obviously, in some individuals the nature and the extent of injury and the multisystem complications involved in their immediate management are such that these patients do not survive long enough to permit return of renal function. Standard medical and surgical management techniques and common sense are the most important ingredients in the management of patients with acute renal failure. These principles are directed toward the following: 1) Reversing the abnormalities that have led to acute renal failure 2) Maintaining the patient through a two- to five-week period of acute renal failure 3) 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 immediate management step in PTARF. As already noted, a vast majority of trauma victims who may initially show minor evidences of renal impairment-as manifested by slight elevation of their serum creatinine or transient diminution of their urinary output-will, nonetheless, respond well to restoration of their intravascular volume. On rare occasions, however, a patient will develop acute renal failure despite reconstitution of intravascular volume and despite return to normal pulse and blood pressure. These patients may have shown poor urinary output shortly after the time of trauma, or their previously normal urinary output may decrease steadily (designated as high-output failure). In either case, the ensuing period of renal failure may last from two to five weeks. Extracorporeal hemodialysis and peritoneal dialysis. Acute renal failure following trauma tends to be a more catabolic form of acute renal failure Bull. N.Y. Acad. Med.
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than is seen in most other circumstances.3'9-' Usually, the degree of catabolism is of sufficient magnitude that extracorporeal hemodialysis is more effective than peritoneal dialysis. Once the development of PTARF is apparent, it is possible to anticipate that the patient will need intensive hemodialysis for at least three or four weeks. In general, we recommend dialysis every second day for four- to six-hour periods. Clinical follow-up and blood-chemistry determinations will dictate any necessary changes in such a regimen. If there is any doubt about the time to begin dialysis, it is always wiser to err on the side of early dialysis. Although urea is not the key factor in induction of the uremic syndrome, blood urea nitrogen provides a yardstick to the accumulation of other end products of nitrogen metabolism that should have been excreted by the kidneys. Any combination of blood urea nitrogen greater than 100 mg./dl. and increasing, serum creatinine between 5 and 10 mg./dl. and increasing, or even mild impairment of renal function with evidence of hyperkalemia may be the signal to begin hemodialysis. Between dialyses, the blood urea nitrogen should preferably be kept below 100 mg./dl. Strong evidence suggests that the more "physiologically" the patient is maintained by hemodialysis, the better the function of all body systems, the more effective the rate of wound healing, and the greater the resistance to complicating infections. After fluid and blood replacement, correction of electrolyte abnormalities, and initiation of hemodialysis, day-to-day decisions about managing the patient's hydrational status should be based on physical examination, including meticulous determinations of daily weights, review of fluid intake and output flow charts, and evaluation of roentgenograms of the lungs. Other variables that require careful monitoring are arterial blood pressure and central venous pressure. In an afebrile patient, 500 to 700 ml. of fluid must be given daily to replace insensible fluid losses. Other fluid losses that occur by urinary output and nasogastric suction will require appropriate replacement. If the patient has suffered bowel injury, it will be necessary to estimate the amount of fluid loss through bowel fistulas and to replace these losses. Control of infection. All patients with acute renal failure have increased susceptibility to infection. 13,4 In the PTARF group of patients infection may often be a complication at the site of injury, most particularly if the large bowel has been injured. Invariably, antibiotic selection will be directed toward covering Gram-negative, Gram-positive, and anaerobic organisms. In realistic terms, this means that the physician should carefully Vol. 55, No. 2, February 1979
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consider the clinical effectiveness, the systemic toxicity profile, and the safety in renal failure of the antibiotic to be selected. The aminoglycosides, the penicillins, the cephalosporins, chloramphenicol, clindamycin, and doxycycline are all likely agents for use in renal failure. Aminoglycosides, such as gentamicin, tobramycin, or amikacin, are very effective against Gram-negative organisms typically encountered in patients with acute renal failure. The latter antibiotics have well-known toxic side effects upon the ear, kidney, and neuromuscular functions.'4-'7 Because serum therapeutic and toxic levels are not widely separated, aminoglycoside antibiotics must be administered with great care in patients with renal failure. Serum drug monitoring is of particular importance. Many dosage guide tables are available'4" 8 and should be used in association with serum drug monitoring. If an antibiotic must be selected early in the management of PTARF before the organisms in blood and tissue cultures have been identified, the choice will almost certainly be an aminoglycoside combined with another antibiotic active against Gram-positive and anaerobic organisms. The most frequent choices for the second agent are chloramphenicol, clindamycin, or doxycycline. Overall, doxycycline is the least toxic of the latter three. Chloramphenicol may very rarely cause hypersensitivity aplastic anemia but with renal failure may frequently produce a dose-related form of reversible marrow suppression. Clindamycin may occasionally cause pseudomembranous colitis. Because chloramphenicol and clindamycin are metabolized by the liver, they can be given to patients with acute renal failure in the same dosage as to patients with normal kidneys. This will not totally prevent their toxic side effects. Doxycycline is the only tetracycline that can be safely used in patients with acute renal failure. In such patients its toxicity is similar to that in patients with normal renal function. In contradistinction, such older tetracyclines as chlortetracycline, oxytetracycline, or tetracycline hydrochloride and the new tetracycline minocycline all accumulate during renal failure and produce catabolic effects that increase the patient's prerenal azotemia.'9 That doxycycline, a new member of the tetracycline class of antibiotics, does not accumulate in renal failure may, at first, seem somewhat surprising. However, recent metabolic studies from our laboratories have identified a nonhepatic, nonrenal, "alternate" gastrointestinal pathway of excretion for this compound.20 Our human studies have also identified that removal of the drug by hemodialysis is not of clinical significance. Therefore, doxycycline appears to be unique among the tetracyclines; when renal Bull. N.Y. Acad. Med.
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failure complicates clinical management decisions, or indeed when the renal functional status is not known, and if a tetracycline is indicated for systemic infection, doxycycline is the drug of choice. In the context of PTARF, doxycycline would be very useful for combined anaerobe and Gram-positive coverage. Nutritional care. Patients with acute renal failure require adequate caloric intake, even if they are physiologically normal in body weight or even obese. Although such patients have enough body calories to burn up, all efforts should be made to keep them from becoming catabolic. Breakdown of body tissues involves breakdown of proteins and the liberation of sulfate and phosphate anions. In these patients the latter anions represent the equivalent of adding sulfuric acid or phosphoric acid to the extracellular fluids. Obviously, immediate buffering of these strong acids is necessary. The buffered sulfate or phosphate anions can only be excreted by the kidney or by hemodialysis. If they accumulate, they lead to progressive acidosis. 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 40 gm. of protein per day to make up for the breakdown of endogenous protein, the remainder being carbohydrates and fats (nonprotein calories). Most patients with acute renal failure can be fed orally, but extensive abdominal injury may require that feeding be intravenous (total parenteral nutrition or hyperalimentation). In patients with PTARF, where acute renal failure is likely to last a long time and where shock has occurred, it is wise to move rapidly to hyperalimentation. Commercially available solutions for hyperalimentation contain a mixture of essential and nonessential amino acids. The amount of protein given as amino acids varies with the patient's condition, e.g., as much as 80 gm. of protein daily, accompanied by carbohydrate as dextrose, may be given to patients with rapid tissue breakdown. Hyperalimentation must be administered into a vein in which blood flows rapidly so that both venotomy and meticulous care of the catheter obligated to this use are required. The rate of hyperalimentation may affect the frequency and duration of hemodialysis because some of the amino acids administered contain sulfate radicals, which can be eliminated only by hemodialysis. Hyperkalemia. The principal warning sign of hyperkalemia-the appearance of tall, peaked T waves on the electrocardiogram-should elicit Vol. 55, No. 2, February 1979
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TABLE II. MANAGEMENT OF HYPERKALEMIA
Stabilization of the excitability of cardiac muscle Infuse 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 cell NaHCO: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 in exchange 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 of insulin. 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. Avoid ion-exchange resin in any patient with bowel trauma or other bowel complications. Extracorporeal hemodialysis or peritoneal dialysis for removal of potassium. Repeat dialysis as necessary.
immediate attention. Hyperkalemia will lead to acute cardiac arrhythmias and can be fatal. In general, a value of 7 mEq. per liter is dangerous, and levels of 10 to 12 mEq. per liter are usually fatal. Relative change in the ratio between intracellular and extracellular potassium causes changes in polarization of the cardiac muscle membrane. The resultant hyperexcitability of the muscle predisposes to the development of arrhythmias. Table II identifies a sequence of management steps for most patients with hyperkalemia. The initial steps represent what might be designated as a minuteto-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 from two to five weeks, the PTARF or postabdominal aneurysm-rupture, renalfailure patient enters a recovery or a diuretic phase of the syndrome. Progressively increasing urinary volumes will be produced. Dramatic and rapid diuresis is quite rare, and one can usually expect to see urinary volumes increase from a daily figure of approximately 400 ml. to perhaps a 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 a fixed 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 recovery phase of renal function. Increases in glomerular filtration rate and redevelopment of adequate electrolyte transport in the tubule continue for several days. In fact, maximal urinary concentrating ability may take as much as three months or more for full recovery, but clinically the patient should be ready for discharge from the hospital long before maximal return of renal function is noted. PROGNOSIS It is reasonable to state that if the PTARF patient can be kept alive during the period of acute renal failure by the management already reviewed, then the individual's kidney function will return to, or approximate, preshutdown levels. The exception to this rule is the very rare case of acute cortical necrosis, which is almost uniformly seen in renal failure complicating the third trimester of pregnancy. With acute cortical necrosis, glomeruli become necrotic and cannot regain normal function. Elderly patients with acute renal failure and pre-existing vascular disease of the kidney, such as arteriolonephrosclerosis, may recover renal function only to the level of 50% to 75% of preshutdown function. All patients with PTARF require aggressive management because invariably one cannot predict their clinical outcome. It is realistic, however, to acknowledge that even in the best of circumstances of modem intensivecare management, 45% to 65% of severely injured patients who have also developed acute renal failure die despite our best efforts.:3i69-12,21-23; These are patients with multisystem failure, massive infectious complications, and nutritional defects; those presenting such a clinical picture by no means die from kidney failure alone. A more encouraging finding emerges from our recent experience with acute renal failure complicating abdominal aneurysm rupture. Several reports 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., a mortality rate of 83%. However, our most recent clinical experience with 11 consecutive patients saw eight survive with recovery of renal function, i.e., a mortality rate of only 27%.8 We emphasize that this improved prognosis simply reflects maximum-effort intensive-care management together with prompt and vigorous dialysis. The outlook for this subset of acute renal failure patients clearly improves.
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Discussion DR. G. THOMAS SHIRES: Dr. Whelton, what is the role of mannitol and furosemide in preventing the onset of acute renal failure? DR. WHELTON: Dr. Kevin Barry and several other investigators at The Walter Reed Medical Center showed in the early 1960s that if one used mannitol to preinfuse patients who will undergo aneurysmal resection and continued this infusion intraoperatively, the incidence of post-operative acute renal failure could be decreased. Subsequently, Dr. Barry and associates did control studies, using simple saline solutions and other forms of volume-replacement therapy, and showed that these solutions were as good as mannitol in the preoperative and intraoperative approach to reducing acute renal failure associated with aortic aneurysm surgery. So, as our understanding of the pathophysiological changes leading to vasomotor nephropathy increased, we began to realize that mannitol did not really have any intrinsically special action on the kidney and that volumereplacement therapy was actually the most important thing. As to the use of furosemide, if a patient is still in the prerenal phase of acute renal failure, there certainly will be a responsiveness from the tubules; in particular, an increased urinary output can be expected as a result of the action of the diuretic upon the ascending limb of the loop of Henle. I believe that furosemide can be utilized as a simple and quick clinical monitoring device indicating to what extent a patient is responding to fluid therapy; but once a patient has established acute renal failure, this diuretic is not helpful. DR. PAUL C. PETERS: In the prerenal phase of acute renal failure, do diuretics play a role in the prevention of tubular cast formation? DR. WHELTON: There is no doubt that diuretics increase the volume flow rate per unit of time and would tend to mobilize casts, if already formed. During the 1950s and the 1960s it was believed that the presence of casts-whether myoglobin or hemoglobin casts or simply casts from sloughed renotubular epithelial cells-was an important factor in the pathogenesis of post-traumatic acute renal failure. However, subsequent micropuncture studies, investigating the pressure inside the lumen of the tubule proximal and distal to the cast, showed that the casts do not contribute in an obstructive mechanical nature to the pathogenesis of the acute renal failure. So, even though the loop diuretics may increase the flow 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 issue that 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 not a tubular toxin). In massive hemolysis with adequate intravascular volume we do not see acute renal failure from just hemoglobin and hemoglobinuria. But one can certainly produce acute renal failure by the infusion of myoglobin in the presence of a volume-expanded animal. QUESTION: Dr. Whelton, does the antidiuretic hormone (ADH) exert any significant effect on the development of postoperative oliguria or the development of renal failure in the adequately resuscitated patient? DR. WHELTON: In this clinical setting, the secretion of ADH would probably be mediated by factors such as postoperative pain and as a result of the use of narcotic agents used for the relief of pain. These are probably the most important clinical situations. Therefore, the patient may have the equivalent of a brief episode of ADH secretion. REFER ENCES 1. Bywaters, E. G. L. and Beall, D.: Crush failure in Vietnam: A milestone in proginjuries with impairment of renal funcress. Conn. Med. 38:7, 1974. tion. Br. Med. J. 1:427, 1941. 7. Gabow, P. A., Anderson, R. J., and 2. Board for the Study of the Severely Schrier, R. W.: Acute renal failure. Wounded: The Physiologic Effects of Cardiovasc. Med. 2:1161, 1977. Wounds. In:Mediterranean Theater of 8. Sapir, D. G., Dandy, W. E., Jr., WhelOperations. Washington, D.C., Office ton, A., and Cooke, C. R.: Acute renal of the Surgeon General, Department of failure following ruptured abdominal the Army, 1952, p. 376. aneurysms: An improved clinical prog3. Whelton, A. and Donadio, J. V., Jr.: nosis. Crit. Care Med. In press. Post-traumatic acute renal failure in 9. Teschan, P. E., Post, R. S., Smith, L. Vietnam: A comparison with the Korean H., Jr., et al.: Post-traumatic renal inWar experience. Johns Hopkins Med. J. sufficiency in military casualties: I. Clinical characteristics. Am. J. Med. 18:172, 124:95, 1969. 4. Donadio, J. V., Jr. and Whelton, A.: 1955. Operation of a renal center in a combat 10. Smith, L. H., Jr., Post, R. S., Teschan, P. E., et al.: Post-traumatic renal insufzone. Milit. Med. 133:833, 1968. 5. Whelton, A.: Post-traumatic Acute ficiency in military casualties: II. ManRenal Failure in Vietnam Combat Inagement, use of an artificial kidney, juries; Incidence, Morbidity and Morprognosis. Am. J. Med. 18:187, 1955. tality. In: Proceedings; Conference on 11. London, R. E. and Burton, J. R.: PostAcute Renal Failure, Friedman, E. A. traumatic renal failure in military perand Eliahou, H. E., editors. Brooklyn, sonnel in Southeast Asia. Am. J. Med. N.Y., Downstate Medical Center, 53:137, 1972. 1973, p. 125. 12. Conger, J. D.: A controlled evaluation 6. Whelton, A.: Post-traumatic acute renal of prophylactic dialysis in post-traumatic
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acute renal failure. J. Trauma 15:1056, 1975. Montgomerie, J. Z., Kalmanson, G. M., and Guze, L. B.: Renal failure and infection. Medicine (Baltimore) 47:1, 1968. Whelton, A.: Antibacterial chemotherapy in renal insufficiency: A review. Antibiot. Chemother. 18:1, 1974. Whelton, A., Carter, G. G., Craig, T. J., et al.: Comparison of the intrarenal disposition of tobramycin and gentamicin: Therapeutic and toxicologic answers. J. Antimicrob. Chemother. (Suppl. A)4:13, 1978. Brummett, R. E., Fox, K. E., Bendrick, T. W., and Himes, D. L.: Ototoxicity of tobramycin, gentamicin, amikacin, and sisomicin in the guinea pig. J. Antimicrob. Chemother. (Suppl. A) 4:73,1978. Appel, G. B. and Neu, H. C.: The nephrotoxicity of antimicrobial agents (three parts). N. Engl. J. Med. 296:663, 1977. Bennett, W. M., Singer, I., Golper, T.,
19.
20.
21.
22.
23.
et al.: Guidelines for therapy in renal failure. Ann. Intern. Med. 86:754, 1977. Whelton, A.: Tetracyclines in renal insufficiency: Resolution of a therapeutic dilemma. Bull. N.Y. Acad. Med. 54:233, 1978. Whelton, A., Schach von Wittenau, M., Twomey, T. M., et al.: Doxycycline pharmacokinetics in the absence of renal function. Kidney Int. 5:365, 1974. Kleinknecht, D., Jungers, P., Chanard, J., et al.: Uremic and non-uremic complications in acute renal failure: Evaluation of early and frequent dialysis on prognosis. Kidney Int. 1: 190, 1972. Scott, R. B., Cameron, J. S., Ogg, C. S., and Bewick, M.: Why the persistently high mortality in acute renal failure? Lancet 2:75, 1972. Champion, H., Sacco, W., Long, W., et al.: Indications for early haemodialysis in multiple trauma. Lancet 1:1125, 1974.
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POST-TRAUMATIC ACUTE RENAL FAILURE* ANDREW WHELTON, M.D. Associate Professor of Medicine Johns Hopkins University School of Medicine Baltimore, 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 trauma and subsequent acute renal failure had suffered extensive crushing injuries to various parts of their bodies, most particularly to the muscle mass of the limbs. Because of this pattern of injury, PTARF of the latter origin has also been known for many years as the crush syndrome. Investigations during World War II led to the description of PTARF, Korean War experience demonstrated a reduction of more than 90% in mortality from PTARF by the use of extracorporeal hemodialysis, and the Vietnam conflict documented that PTARF is a largely preventable form of acute renal failure.3-6 Information derived from military experience, clinical reviews of civilian trauma sequelae, and animal investigations now allow us to view the syndrome of PTARF more rationally from the standpoints of etiology, clinical management, and prognosis. ETIOLOGY As the name of the syndrome implies, patients with PTARF develop acute renal failure following an injury that has produced blood loss, prolonged hypotension, and often myoglobinuria. It is of fundamental importance for the clinician to remember that even though the etiology of PTARF is primarily related to the location and degree of trauma sustained by the patient, it is still necessary to consider the three etiologic *Presented as part of a Symposium on Diagnosis and Management of Abdominal and Thoracic Trauma sponsored by the New York Hospital-Cornell Medical Center and the New York Academy of Medicine in cooperation with Science & Medicine Publishing Co., Inc., under a grant from Pfizer Laboratories, 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-DIAGNOSTIC CATEGORIES IN ACUTE RENAL FAILURE
Prerenal (Irenal perfusion) Hypovolemia: multiple causes of acute blood and plasma loss Fluid anid electrolyte depletion: gastrointestinal loss, skin loss, segregated fluid accumulations Intravascular hemolysis: mismatched blood, intravenous hypotonic solutions Renal (intrinsic anatomic and vascular defects) Acute vasomotor nephropathy or acute tubular necrosis: secondary to prolonged Jrenal perfusion; myoglobinuria Acute primary and secondary glomerulopathies: acute poststreptococcal glomerulonephritis, acute lupus nephritis Nephrotoxins: heavy metals, many antibiotics, industrial solvents/chemicals Acute fulminant pyelonephritis Acute bilateral cortical necrosis Malignant' hypertension Postrenal (outflow obstruction) Calculi Blood clots Thmor Trauma Surgical accidents/sutures Ureteric edema Prostatic hypertrophy
categories-prerenal factors, intrinsic renal defects, and postrenal obstructive phenomena-that may complicate the clinical picture of any patient with PTARF (Table I). Injured patients most likely to develop acute renal failure are those who have the following: 1) A prolonged period of hypotension due to a delay of definitive medical and surgical care 2) Mismatched blood received as part of massive blood replacement therapy 3) Extensive muscle damage with resultant myoglobinemia and myoglobinuria 4) Third-degree burns of 20% or more of the body surface in association with the injury 5) Large bowel injury or necrosis with intra-abdominal abscess formation and systemic sepsis 6) Multisystem failure (hepatic, pulmonary, cardiac) following injury with late renal involvement Gunshot damage, stabbings, vehicular accidents, and crushing injuries Vol. 55, No. 2, February 1979
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of any nature all characteristically may lead to acute renal failure. We should also review the development of acute renal failure following rupture of an abdominal aneurysm or in the setting of postoperative hypovolemic shock. Pathophysiologically, the events that lead to acute renal failure are similar, 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 leads to "shutdown" of the kidney for two to five weeks, is not yet fully resolved. The tubular, vascular, and hormonal considerations that may be important are reviewed in detail elsewhere.7 INCIDENCE
The frequency with which PTARF is seen clinically has decreased dramatically during the past several years. This decrease reflects better understanding of the syndrome's pathophysiology and rapid and definitive management of trauma victims.3" Suffice it to say that among American military casualties during the early 1940s the incidence of PTARF was as much as one out of every three seriously injured soldiers; by the early 1950s the incidence was one in 200 in similarly injured military casualties; whereas by the mid to late 1960s the incidence in military casualties was computed as one in 600 or lower.' Clearly-, given the rapid availability of appropriate medical and surgical care, this syndrome is becoming quite rare.
However, considering the incidence of acute renal failure in connection with surgical repair of a ruptured abdominal aneurysm, we see many more such patients.8 This increase, of course, reflects improved intensive care and cardiovascular surgical techniques, as a result of which many elderly patients with acute rupture of an abdominal aneurysm now survive the initial insult and undergo vascular reparative surgery. The survival rate of these patients-those with postabdominal aneurysm rupture and acute renal failure-has also markedly improved in recent experience.8 DIAGNOSIS
At the initial examination of an injured patient with acute deterioration of renal function, the three major entities listed in Table I play an important role in the differential diagnosis. The first consideration is the patient's intravascular volume. If the patient is seen immediately after the Bull. N.Y. Acad. Med.
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event that caused the acute intravascular depletion, it may be possible to arrest the pathophysiologic series of events at a prerenal or renal profusional level. The time between injury, intravascular depletion, hypotension, and development of organic acute renal failure is variable. It depends upon the extent of injury, the degree of intravascular depletion, and the patient's premorbid physical status. Generally, the time interval is from one to several hours, which means that appropriate reconstitution of the patient's intravascular volume will serve as both a diagnostic procedure and a therapeutic maneuver because if the patient is still in the prerenal phase of acute renal failure, he may well respond to volume expansion and normalization of blood pressure by a return of normal renal function. On the other hand, if the patient's blood pressure and intravascular volume have returned to normal but renal function continues to deteriorate, one is dealing with organic renal failure or the syndrome of PTARF. In essence, we have moved from the prerenal forms of failure to an intrinsic renal defect (Table I). Postrenal considerations listed in Table I should also be reviewed because in injuries involving the abdomen, pelvis, or both, one must carefully assess the anatomic integrity of the renal outflow tract. Compression injuries or direct trauma to the ureters or bladder may present as PTARF. Appropriate urological evaluation leads to correct diagnosis and, 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 status 2) Evaluation of serum electrolytes, with particular attention to potassium and bicarbonate levels 3) Blood-chemistry determinations, with particular attention to blood urea nitrogen and serum creatinine 4) Institution of an hourly intake and output fluid-flow chart 5) Urinalysis to determine the presence of protein, glucose, or other chemical abnormalities with microscopic evaluation for the presence of cellular elements or cast formations 6) Determinations of urine osmolality and sodium and potassium concentrations (osmolality > 300 to 400 mOsm. per liter and urine sodium > 20 mEq. per liter are highly suggestive of predominant prerenal factors because these data reflect good tubular function) 7) Daily body weight chart Vol. 55, No. 2, February 1979
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Such other investigations as quantitative renal function tests of glomerular filtration rate, renal sonography, renal isotopic scanning evaluation, or arteriographic procedures can be utilized depending on the individual case need. MANAGEMENT
Once acute renal failure has developed, following any of the many forms of injury and blood loss already reviewed, the patient requires continuous intensive medical and surgical care for several days or weeks. No effort should be spared because this form of renal failure is fully reversible. Obviously, in some individuals the nature and the extent of injury and the multisystem complications involved in their immediate management are such that these patients do not survive long enough to permit return of renal function. Standard medical and surgical management techniques and common sense are the most important ingredients in the management of patients with acute renal failure. These principles are directed toward the following: 1) Reversing the abnormalities that have led to acute renal failure 2) Maintaining the patient through a two- to five-week period of acute renal failure 3) 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 immediate management step in PTARF. As already noted, a vast majority of trauma victims who may initially show minor evidences of renal impairment-as manifested by slight elevation of their serum creatinine or transient diminution of their urinary output-will, nonetheless, respond well to restoration of their intravascular volume. On rare occasions, however, a patient will develop acute renal failure despite reconstitution of intravascular volume and despite return to normal pulse and blood pressure. These patients may have shown poor urinary output shortly after the time of trauma, or their previously normal urinary output may decrease steadily (designated as high-output failure). In either case, the ensuing period of renal failure may last from two to five weeks. Extracorporeal hemodialysis and peritoneal dialysis. Acute renal failure following trauma tends to be a more catabolic form of acute renal failure Bull. N.Y. Acad. Med.
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than is seen in most other circumstances.3'9-' Usually, the degree of catabolism is of sufficient magnitude that extracorporeal hemodialysis is more effective than peritoneal dialysis. Once the development of PTARF is apparent, it is possible to anticipate that the patient will need intensive hemodialysis for at least three or four weeks. In general, we recommend dialysis every second day for four- to six-hour periods. Clinical follow-up and blood-chemistry determinations will dictate any necessary changes in such a regimen. If there is any doubt about the time to begin dialysis, it is always wiser to err on the side of early dialysis. Although urea is not the key factor in induction of the uremic syndrome, blood urea nitrogen provides a yardstick to the accumulation of other end products of nitrogen metabolism that should have been excreted by the kidneys. Any combination of blood urea nitrogen greater than 100 mg./dl. and increasing, serum creatinine between 5 and 10 mg./dl. and increasing, or even mild impairment of renal function with evidence of hyperkalemia may be the signal to begin hemodialysis. Between dialyses, the blood urea nitrogen should preferably be kept below 100 mg./dl. Strong evidence suggests that the more "physiologically" the patient is maintained by hemodialysis, the better the function of all body systems, the more effective the rate of wound healing, and the greater the resistance to complicating infections. After fluid and blood replacement, correction of electrolyte abnormalities, and initiation of hemodialysis, day-to-day decisions about managing the patient's hydrational status should be based on physical examination, including meticulous determinations of daily weights, review of fluid intake and output flow charts, and evaluation of roentgenograms of the lungs. Other variables that require careful monitoring are arterial blood pressure and central venous pressure. In an afebrile patient, 500 to 700 ml. of fluid must be given daily to replace insensible fluid losses. Other fluid losses that occur by urinary output and nasogastric suction will require appropriate replacement. If the patient has suffered bowel injury, it will be necessary to estimate the amount of fluid loss through bowel fistulas and to replace these losses. Control of infection. All patients with acute renal failure have increased susceptibility to infection. 13,4 In the PTARF group of patients infection may often be a complication at the site of injury, most particularly if the large bowel has been injured. Invariably, antibiotic selection will be directed toward covering Gram-negative, Gram-positive, and anaerobic organisms. In realistic terms, this means that the physician should carefully Vol. 55, No. 2, February 1979
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consider the clinical effectiveness, the systemic toxicity profile, and the safety in renal failure of the antibiotic to be selected. The aminoglycosides, the penicillins, the cephalosporins, chloramphenicol, clindamycin, and doxycycline are all likely agents for use in renal failure. Aminoglycosides, such as gentamicin, tobramycin, or amikacin, are very effective against Gram-negative organisms typically encountered in patients with acute renal failure. The latter antibiotics have well-known toxic side effects upon the ear, kidney, and neuromuscular functions.'4-'7 Because serum therapeutic and toxic levels are not widely separated, aminoglycoside antibiotics must be administered with great care in patients with renal failure. Serum drug monitoring is of particular importance. Many dosage guide tables are available'4" 8 and should be used in association with serum drug monitoring. If an antibiotic must be selected early in the management of PTARF before the organisms in blood and tissue cultures have been identified, the choice will almost certainly be an aminoglycoside combined with another antibiotic active against Gram-positive and anaerobic organisms. The most frequent choices for the second agent are chloramphenicol, clindamycin, or doxycycline. Overall, doxycycline is the least toxic of the latter three. Chloramphenicol may very rarely cause hypersensitivity aplastic anemia but with renal failure may frequently produce a dose-related form of reversible marrow suppression. Clindamycin may occasionally cause pseudomembranous colitis. Because chloramphenicol and clindamycin are metabolized by the liver, they can be given to patients with acute renal failure in the same dosage as to patients with normal kidneys. This will not totally prevent their toxic side effects. Doxycycline is the only tetracycline that can be safely used in patients with acute renal failure. In such patients its toxicity is similar to that in patients with normal renal function. In contradistinction, such older tetracyclines as chlortetracycline, oxytetracycline, or tetracycline hydrochloride and the new tetracycline minocycline all accumulate during renal failure and produce catabolic effects that increase the patient's prerenal azotemia.'9 That doxycycline, a new member of the tetracycline class of antibiotics, does not accumulate in renal failure may, at first, seem somewhat surprising. However, recent metabolic studies from our laboratories have identified a nonhepatic, nonrenal, "alternate" gastrointestinal pathway of excretion for this compound.20 Our human studies have also identified that removal of the drug by hemodialysis is not of clinical significance. Therefore, doxycycline appears to be unique among the tetracyclines; when renal Bull. N.Y. Acad. Med.
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failure complicates clinical management decisions, or indeed when the renal functional status is not known, and if a tetracycline is indicated for systemic infection, doxycycline is the drug of choice. In the context of PTARF, doxycycline would be very useful for combined anaerobe and Gram-positive coverage. Nutritional care. Patients with acute renal failure require adequate caloric intake, even if they are physiologically normal in body weight or even obese. Although such patients have enough body calories to burn up, all efforts should be made to keep them from becoming catabolic. Breakdown of body tissues involves breakdown of proteins and the liberation of sulfate and phosphate anions. In these patients the latter anions represent the equivalent of adding sulfuric acid or phosphoric acid to the extracellular fluids. Obviously, immediate buffering of these strong acids is necessary. The buffered sulfate or phosphate anions can only be excreted by the kidney or by hemodialysis. If they accumulate, they lead to progressive acidosis. 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 40 gm. of protein per day to make up for the breakdown of endogenous protein, the remainder being carbohydrates and fats (nonprotein calories). Most patients with acute renal failure can be fed orally, but extensive abdominal injury may require that feeding be intravenous (total parenteral nutrition or hyperalimentation). In patients with PTARF, where acute renal failure is likely to last a long time and where shock has occurred, it is wise to move rapidly to hyperalimentation. Commercially available solutions for hyperalimentation contain a mixture of essential and nonessential amino acids. The amount of protein given as amino acids varies with the patient's condition, e.g., as much as 80 gm. of protein daily, accompanied by carbohydrate as dextrose, may be given to patients with rapid tissue breakdown. Hyperalimentation must be administered into a vein in which blood flows rapidly so that both venotomy and meticulous care of the catheter obligated to this use are required. The rate of hyperalimentation may affect the frequency and duration of hemodialysis because some of the amino acids administered contain sulfate radicals, which can be eliminated only by hemodialysis. Hyperkalemia. The principal warning sign of hyperkalemia-the appearance of tall, peaked T waves on the electrocardiogram-should elicit Vol. 55, No. 2, February 1979
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TABLE II. MANAGEMENT OF HYPERKALEMIA
Stabilization of the excitability of cardiac muscle Infuse 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 cell NaHCO: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 in exchange 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 of insulin. 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. Avoid ion-exchange resin in any patient with bowel trauma or other bowel complications. Extracorporeal hemodialysis or peritoneal dialysis for removal of potassium. Repeat dialysis as necessary.
immediate attention. Hyperkalemia will lead to acute cardiac arrhythmias and can be fatal. In general, a value of 7 mEq. per liter is dangerous, and levels of 10 to 12 mEq. per liter are usually fatal. Relative change in the ratio between intracellular and extracellular potassium causes changes in polarization of the cardiac muscle membrane. The resultant hyperexcitability of the muscle predisposes to the development of arrhythmias. Table II identifies a sequence of management steps for most patients with hyperkalemia. The initial steps represent what might be designated as a minuteto-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 from two to five weeks, the PTARF or postabdominal aneurysm-rupture, renalfailure patient enters a recovery or a diuretic phase of the syndrome. Progressively increasing urinary volumes will be produced. Dramatic and rapid diuresis is quite rare, and one can usually expect to see urinary volumes increase from a daily figure of approximately 400 ml. to perhaps a 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 a fixed 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 recovery phase of renal function. Increases in glomerular filtration rate and redevelopment of adequate electrolyte transport in the tubule continue for several days. In fact, maximal urinary concentrating ability may take as much as three months or more for full recovery, but clinically the patient should be ready for discharge from the hospital long before maximal return of renal function is noted. PROGNOSIS It is reasonable to state that if the PTARF patient can be kept alive during the period of acute renal failure by the management already reviewed, then the individual's kidney function will return to, or approximate, preshutdown levels. The exception to this rule is the very rare case of acute cortical necrosis, which is almost uniformly seen in renal failure complicating the third trimester of pregnancy. With acute cortical necrosis, glomeruli become necrotic and cannot regain normal function. Elderly patients with acute renal failure and pre-existing vascular disease of the kidney, such as arteriolonephrosclerosis, may recover renal function only to the level of 50% to 75% of preshutdown function. All patients with PTARF require aggressive management because invariably one cannot predict their clinical outcome. It is realistic, however, to acknowledge that even in the best of circumstances of modem intensivecare management, 45% to 65% of severely injured patients who have also developed acute renal failure die despite our best efforts.:3i69-12,21-23; These are patients with multisystem failure, massive infectious complications, and nutritional defects; those presenting such a clinical picture by no means die from kidney failure alone. A more encouraging finding emerges from our recent experience with acute renal failure complicating abdominal aneurysm rupture. Several reports 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., a mortality rate of 83%. However, our most recent clinical experience with 11 consecutive patients saw eight survive with recovery of renal function, i.e., a mortality rate of only 27%.8 We emphasize that this improved prognosis simply reflects maximum-effort intensive-care management together with prompt and vigorous dialysis. The outlook for this subset of acute renal failure patients clearly improves.
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Discussion DR. G. THOMAS SHIRES: Dr. Whelton, what is the role of mannitol and furosemide in preventing the onset of acute renal failure? DR. WHELTON: Dr. Kevin Barry and several other investigators at The Walter Reed Medical Center showed in the early 1960s that if one used mannitol to preinfuse patients who will undergo aneurysmal resection and continued this infusion intraoperatively, the incidence of post-operative acute renal failure could be decreased. Subsequently, Dr. Barry and associates did control studies, using simple saline solutions and other forms of volume-replacement therapy, and showed that these solutions were as good as mannitol in the preoperative and intraoperative approach to reducing acute renal failure associated with aortic aneurysm surgery. So, as our understanding of the pathophysiological changes leading to vasomotor nephropathy increased, we began to realize that mannitol did not really have any intrinsically special action on the kidney and that volumereplacement therapy was actually the most important thing. As to the use of furosemide, if a patient is still in the prerenal phase of acute renal failure, there certainly will be a responsiveness from the tubules; in particular, an increased urinary output can be expected as a result of the action of the diuretic upon the ascending limb of the loop of Henle. I believe that furosemide can be utilized as a simple and quick clinical monitoring device indicating to what extent a patient is responding to fluid therapy; but once a patient has established acute renal failure, this diuretic is not helpful. DR. PAUL C. PETERS: In the prerenal phase of acute renal failure, do diuretics play a role in the prevention of tubular cast formation? DR. WHELTON: There is no doubt that diuretics increase the volume flow rate per unit of time and would tend to mobilize casts, if already formed. During the 1950s and the 1960s it was believed that the presence of casts-whether myoglobin or hemoglobin casts or simply casts from sloughed renotubular epithelial cells-was an important factor in the pathogenesis of post-traumatic acute renal failure. However, subsequent micropuncture studies, investigating the pressure inside the lumen of the tubule proximal and distal to the cast, showed that the casts do not contribute in an obstructive mechanical nature to the pathogenesis of the acute renal failure. So, even though the loop diuretics may increase the flow 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 issue that 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 not a tubular toxin). In massive hemolysis with adequate intravascular volume we do not see acute renal failure from just hemoglobin and hemoglobinuria. But one can certainly produce acute renal failure by the infusion of myoglobin in the presence of a volume-expanded animal. QUESTION: Dr. Whelton, does the antidiuretic hormone (ADH) exert any significant effect on the development of postoperative oliguria or the development of renal failure in the adequately resuscitated patient? DR. WHELTON: In this clinical setting, the secretion of ADH would probably be mediated by factors such as postoperative pain and as a result of the use of narcotic agents used for the relief of pain. These are probably the most important clinical situations. Therefore, the patient may have the equivalent of a brief episode of ADH secretion. REFER ENCES 1. Bywaters, E. G. L. and Beall, D.: Crush failure in Vietnam: A milestone in proginjuries with impairment of renal funcress. Conn. Med. 38:7, 1974. tion. Br. Med. J. 1:427, 1941. 7. Gabow, P. A., Anderson, R. J., and 2. Board for the Study of the Severely Schrier, R. W.: Acute renal failure. Wounded: The Physiologic Effects of Cardiovasc. Med. 2:1161, 1977. Wounds. In:Mediterranean Theater of 8. Sapir, D. G., Dandy, W. E., Jr., WhelOperations. Washington, D.C., Office ton, A., and Cooke, C. R.: Acute renal of the Surgeon General, Department of failure following ruptured abdominal the Army, 1952, p. 376. aneurysms: An improved clinical prog3. Whelton, A. and Donadio, J. V., Jr.: nosis. Crit. Care Med. In press. Post-traumatic acute renal failure in 9. Teschan, P. E., Post, R. S., Smith, L. Vietnam: A comparison with the Korean H., Jr., et al.: Post-traumatic renal inWar experience. Johns Hopkins Med. J. sufficiency in military casualties: I. Clinical characteristics. Am. J. Med. 18:172, 124:95, 1969. 4. Donadio, J. V., Jr. and Whelton, A.: 1955. Operation of a renal center in a combat 10. Smith, L. H., Jr., Post, R. S., Teschan, P. E., et al.: Post-traumatic renal insufzone. Milit. Med. 133:833, 1968. 5. Whelton, A.: Post-traumatic Acute ficiency in military casualties: II. ManRenal Failure in Vietnam Combat Inagement, use of an artificial kidney, juries; Incidence, Morbidity and Morprognosis. Am. J. Med. 18:187, 1955. tality. In: Proceedings; Conference on 11. London, R. E. and Burton, J. R.: PostAcute Renal Failure, Friedman, E. A. traumatic renal failure in military perand Eliahou, H. E., editors. Brooklyn, sonnel in Southeast Asia. Am. J. Med. N.Y., Downstate Medical Center, 53:137, 1972. 1973, p. 125. 12. Conger, J. D.: A controlled evaluation 6. Whelton, A.: Post-traumatic acute renal of prophylactic dialysis in post-traumatic
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acute renal failure. J. Trauma 15:1056, 1975. Montgomerie, J. Z., Kalmanson, G. M., and Guze, L. B.: Renal failure and infection. Medicine (Baltimore) 47:1, 1968. Whelton, A.: Antibacterial chemotherapy in renal insufficiency: A review. Antibiot. Chemother. 18:1, 1974. Whelton, A., Carter, G. G., Craig, T. J., et al.: Comparison of the intrarenal disposition of tobramycin and gentamicin: Therapeutic and toxicologic answers. J. Antimicrob. Chemother. (Suppl. A)4:13, 1978. Brummett, R. E., Fox, K. E., Bendrick, T. W., and Himes, D. L.: Ototoxicity of tobramycin, gentamicin, amikacin, and sisomicin in the guinea pig. J. Antimicrob. Chemother. (Suppl. A) 4:73,1978. Appel, G. B. and Neu, H. C.: The nephrotoxicity of antimicrobial agents (three parts). N. Engl. J. Med. 296:663, 1977. Bennett, W. M., Singer, I., Golper, T.,
19.
20.
21.
22.
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et al.: Guidelines for therapy in renal failure. Ann. Intern. Med. 86:754, 1977. Whelton, A.: Tetracyclines in renal insufficiency: Resolution of a therapeutic dilemma. Bull. N.Y. Acad. Med. 54:233, 1978. Whelton, A., Schach von Wittenau, M., Twomey, T. M., et al.: Doxycycline pharmacokinetics in the absence of renal function. Kidney Int. 5:365, 1974. Kleinknecht, D., Jungers, P., Chanard, J., et al.: Uremic and non-uremic complications in acute renal failure: Evaluation of early and frequent dialysis on prognosis. Kidney Int. 1: 190, 1972. Scott, R. B., Cameron, J. S., Ogg, C. S., and Bewick, M.: Why the persistently high mortality in acute renal failure? Lancet 2:75, 1972. Champion, H., Sacco, W., Long, W., et al.: Indications for early haemodialysis in multiple trauma. Lancet 1:1125, 1974.
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