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Intravenous essential L-amino acids and hypertonic dextrose in patients with acute renal failure
SCI ENTI FIC PAPERS
Intravenous Essential L-Amino Acids and Hypertonic Dextrose in Patients with Acute Renal Failure Effects on Serum Potassium, Phosphate, and Magnesium Ronald M. Abel, MD, Boston, Massachusetts William M. Abbott, MD, Boston, Massachusetts Josef E. Fischer, MD, Boston, Massachusetts The development of acute renal insufficiency in the recently postoperative patient adds additional stress to the hypercatabolic state in a patient already in negative nitrogen balance [I]. if, under such circumstances, the patient is unable to ingest adequate nutriment, the problem is compounded. Not only is the protein-sparing effect of calories unavailable and the excretion of nitrogenous products impaired, but also the breakdown of lean body tissue mass may become accelerated. The use of parenteral nutrition technics for patients in acute renal failure was advocated by Lee, Sharpstone, and Arnes [2], who administered casein hydrolysates and a lipid emulsion to patients unable to eat. Dudrick and his co-workers [3,4] utilized the Giordano-Giovannetti [5,6] principle, modified for intravenous use, in several patients with acute and chronic renal failure, with beneficial effects. More recently, we have confirmed and extended these observations, suggesting that under certain circumstances, dialysis may be completely avoidable, even in acute renal insufficiency [7,8]. These findings appear to substantiate the earlier observations of Giordano [5] and Giovannetti and Maggiore [6] that urea nitrogen could be reutilized for the biosynthesis of protein, resulting in decreased frequency of dialysis and positive nutritional benefits. The present study applies these previous observations to an additional group of patients treated with From the General Surgical Services, Department of Surgery, Harvard Medical School, and the Massachusetts General Hospital, Boston, Massachusetts. This work was supported in part by General Research Support Grant FR-05486-08. and by a gift to the Department of Surgery, Massachusetts General Hospital, from McGaw Laboratories, Glendale, California. Reprint requests should be addressed to Dr Abel, General Surgical Services, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.
632
an intravenous solution containing eight essential L-amino acids and hypertonic dextrose. During the course of this therapy in seventeen patients with acute renal failure, consistent decreases in serum potassium, phosphate, and magnesium levels were noted. These effects, which were unanticipated, resulted in salutory clinical side effects. This report will examine in detail these electrolyte shifts. Material and Methods Patient Selection. Patients were initially considered for intravenous treatment with essential L-amino acids primarily because of inadequate oral intake in the presence of acute renal failure. The seventeen patients (Table I) treated over a six month period included fifteen with episodes of postoperative acute renal failure, one patient (number 17) with acute renal failure secondary to hypotension during massive bleeding from the esophageal varices, and two medical patients with acute renal insufficiency associated with hepatic failure (numbers 15 and 16). The presence of active sepsis or diabetes mellitus, or the presence of prosthetic materials in the cardiovascular system (nine patients) did not contraindicate the use of this therapy which required long-term superior vena cava cannulation. Solution Preparation and Administration. Fresh solutions were mixed daily in the Pharmacy Manufacturing Branch of the Massachusetts General Hospital under a laminar-flow air hood using aseptic technics. Each unit of solution (Table II) contained 250 ml of a 5.25 per cent solution of eight L-amino acids* in sterile water to which was added 500 ml of 70 per cent dextrose in water. Vitamins were derived from a commercial preparation (MVI),? to which additional ascorbic acid and vitamin K1
*Kindly provided as FreAmine-E@ by Robert W. Nicora, Medical Affairs Division, McGaw Laboratories, Glendale, California.
tlJSVPharmaceutica1
Corporation, Tuckahoe, New York.
The American
Journal
of Surgery
Parenteral
TABLE I
Patient
Nutrition
in Acute
Renal
Failure
Data on Seventeen Patients with Acute Renal Failure
Age
1. 2. 3.
74 70 77
4. 5. 6.
79 78 62
7.
70
a. 9.
61 40
10.
23
11.
74
12.
78
13. 14.
57 44
15. 16. 17.
76 53 44
Operation
Diagnosis
(yr)
graft graft
Acute tubular necrosis Acute tubular necrosis Acute tubular necrosis
Aortoiliac graft Aortoiliac graft Aortoiliac graft; re-exploration for retroperitoneal hemorrhage; coronary artery bypass grafts; left ventricular aneurysmectomy
Acute tubular necrosis Acute tubular necrosis Acute tubular necrosis
Coronary
Acute tubular necrosis
Ruptured abdominal aortic aneurysm Ruptured abdominal aortic aneurysm Aortoiliac occlusive disease; acute myocardial infarction on 15th postoperative day Acute aortoiliac thrombosis Ruptured abdominal aortic aneurysm Ruptured abdominal aortic aneurysm
Aneurysmectomy, Aneurysmectomy, Aortoiliac graft
Coronary artery disease; left ventricular aneurysm Coronary artery disease Rheumatic heart disease; mitral stenosis and insufficiency; bleeding gastritis; Serratia septicemia Subacute glomerulonephritis “Giant” gastric ulcer; femoral thrombophlebitis Intestinal obstruction; small bowel infarction lschemic colitis: nutritional cirrhosis Nutritional cirrhosis; bleeding esophageal varices Postnecrotic cirrhosis Acute alcoholic, hepatitis Postnecrotic cirrhosis; bleeding esophageal varices
aortoiliac aortoiliac
artery bypass graft
Coronary artery bypass graft Mitral valve replacement; total gastrectomy
Acute tubular necrosis Acute tubular necrosis
Bilateral nephrectomy; transplantation Subtotal gastrectomy;
Acute tubular necrosis
renal femoral vein ligation
Small bowel resection Colectomy; drainage of abdominal abscesses Splenorenal shunt: re-exploration for intra-abdominal hemorrhage None None Splenorenal shunt
were added. The resultant solution (“Renal Failure IV Diet”) contained a concentration of essential amino acids greater than the “safe” levels suggested by Rose et al [9]. The low total fluid volume made possible by high solution concentration allowed administration of at least a single unit daily to even anuric patients. Because of the solution’s hyperosmolarity (approximately 2,100 mOsm/L), direct superior vena cava infusion was required. All soluTABLE II
Renal Diagnosis
Acute tubular necrosis Acute tubular necrosis “Hepatorenal
syndrome”
“Hepatorenal
syndrome”
“Hepatorenal syndrome” “Hepatorenal syndrome” Acute focal glomerulonephritis
tions were administered at constant infusion rates by gravity via a subclavian or internal jugular venous catheter whose tip resided in the superior vena cava. Clinical management of the infusion and catheter care have previously been described [ 7,8]. Studies. Weights, accurate intake and output records, vital signs, blood counts, serum electrolytes, and renal function were recorded daily on all patients. At least
Composition of Massachusetts General Hospital “Renal Failure IV Diet” Water (750 ml)
L-Amino acids L-lsoleucine L-Leucine L-Lysine HCI L-Methionine L-Phenylalanine L-Threonine L-Tryptophan L-Valine Total Glucose
Volume 123, June 1972
Amount
1.4 2.2 2.0 2.2 2.2 1.0 0.5 1.6
(gm)
Vitamins
Amount
A B, (Thiamine HCI) Bz (Riboflavin) Bs (Pyridoxine HCI) Niacinamide Panthenol C (Ascorbic acid) D (Ergocalciferol) E (dl-a tocopheryl acetate) K1 (Aquamephytone)
5000 USP units 25 mg 5mg 7.5 mg 50 mg 12.5 mg 1.5 mg 500 USP units 2.5 IU 5mg
13.1 350
633
Abel, Abbott, and Fischer
twice weekly twenty-four hour urine collections enabled determinations of nitrogen and electrolyte balances, but because of the difficulties in determining the total body nitrogen in the presence of renal failure, nitrogen “balances”per se were not calculated. Management. Initial infusion rate in all patients was 30 ml/hour (approximately one unit per twenty-four hours) and was increased to a maximum of 100 ml/hour, depending upon glucose and fluid tolerance. Treatment was continued until it ‘was judged that the patient had sufficiently recovered from renal failure and could tolerate a normal diet (either orally or parenterally with protein hydrolysates). Daily measurements of serum osmolarity and blood glucose guided the actual flow rate administration and the need for exogenous insulin therapy. In patients requiring insulin administration (those with diabetes mellitus, pancreatitis, and the like), crystalline zinc insulin (20 units/L) was placed directly into the bottles containing the amino acid mixture.* Traditional modes of therapy for patients in renal failure were continued during the course of treatment. These included fluid restriction, prophylaxis against gastrointestinal bleeding, peritoneal or hemodialysis, ion-exchange resins for control of threatening hyperkalemia, buffering agents to treat severe metabolic acidosis, and electrolyte replacement for measured serum deficiencies. Results Survival. Of the seven patients (41 per cent) who survived the episodes of acute renal failure, two were initially oliguric (urinary volume of less than 600 ml/24 hours), and both required intermittent peritoneal dialysis. Four of the five nonoliguric survivors were managed without either peritoneal or hemodialysis. Since there was not a parallel series of similar patients treated without essential amino acid therapy, these data cannot be interpreted as representing a significant over-all influence upon the natural course of acute renal failure. Adverse Effects and Complications. Although long-term venous catheterization was employed in all patients, no instances of catheter-related sepsis occurred, although one patient (number 9) was known to have Serratia marcescens endocarditis prior to the institution of treatment. There were no technical complications related to subclavian or internal jugular venipuncture in any patient. Significant hyperglycemia of 910 mg/lOO ml and 520 mg/ 100 ml occurred in patients number 12 and 13, respectively, during the course of infusion of the hypertonic solution, but both responded to a decrease in the infusion rate and intravenous insulin administra*Determination of insulin effect in these bottles by radioimmunoassay technics confirmed less than 2 per cent 20~s of activity in vitro over a forty-eight hourperiod.
634
51oerzerk%
Mnmimf t
Dpt,.aflO”
POST-OPERATIVE
DAYS
Figure 1. Laboratory data obtained from a seventy year o/d man (number 2) affer the development of nonofiguric acute tubular necrosis which occurred in the ear/y postoperative period after abdominal aortic aneurysmectomy. The decrease in serum magnesium occurred durfng a period of worsening renal function. Despite stable function by the thirty-fifth postoperative day, institution of casein hydrolysate was accompanied by a recurrent rise in the Mood urea nitrogen level.
tion. The signs of hypertonic nonketotic dehydration and coma did not occur. Metabolic acidosis was noted in approximately half of the patients, but it was uncertain whether this was related to the renal insufficiency or the therapy. Nutritional Effects. Subjective clinical improvement in the nutritional status of all patients was observed, consisting of improved wound healing after early wound separation (two patients), and maintenance of body weight in the absence of peripheral edema or hyponatremia in four patients with prolonged postoperative adynamic ileus. Effects on Blood Urea Nitrogen. Although the rate of rise of blood urea nitrogen appeared to be slowed in most patients, the absence of suitable controls precluded statistical confirmation of these observations. In the majority of patients with daily urinary outputs of greater than 600 ml, however, a decrease followed by a stabilization of the blood urea nitrogen was observed. (Figure 1.) This stabilization often resulted in a lower blood urea nitrogenlcreatinine ratio than that normally predicted by the creatinine clearance determinations. In patients with marked oliguria, however, although the blood urea nitrogen continued to rise, the daily increment was less than that anticipated. (Figure 2.) Since all patients were treated by dialysis at blood urea nitrogen levels exceeding 150 to 175 mg/lOO ml, there are no data to suggest the limit of this blood urea nitrogenstabilizing effect.
The American
Journal of Surgery
Parenteral
Poto.ssium. Clinically significant hyperkalemia did not develop in any patient during the course of treatment despite the absence of any urinary output in many patients. Indeed, positive potassium balances associated with decreases in serum concentrations were noted in all patients. This hypokalemic effect was observed within the first eight hours of infusion. In patient number 3 (Figure 3) “malignant” hyperkalemia developed after an acute myocardial infarction with ventricular fibrillation, requiring ion-exchange resins per rectum every two hours. Although his hourly urine volume did not increase during the first twenty-four hours after the infusion of “Renal Failure IV Diet” at 50 ml per hour, the serum potassium decreased from 5.8 to 3.7 mEq/L during a time that ion-exchange resins were no longer administered. The mean maximal decrease in serum potassium in seventeen patients was statistically significant. (Table III.) Hyperkalemia was not an indication for dialysis in any of the nine patients who required it. Serum potassium was controlled for eight days in one anuric patient in whom potassium levels remained below 4.4 mEq/L, and potassium supplement was eventually required. He did receive peritoneal dialysis, however, on the ninth postoperative day because of a blood urea nitrogen level of 200 mg/lOO ml. (Figure 4.) Phosph.ate. Consistent decreases in serum phosphate occurred in all patients in association with therapy, despite no immediate improvement in the level of renal function. The immediate post-treatment phosphate level in fifteen patients was 2.2 f 1.7 mg/lOO ml (Table III) and in twelve of seventeen patients, the lowest value recorded prior to replaceESSENTIAL L-AMINO ACID SOLUTION (ml124h)
,000 ‘cm
o
Figure 2. Stabilization of blood urea nitrogen level in a seventy-eight year old man (number 12) with ofiguric acute tubular necrosis after septic shock trom small bowel infarction. DesjVte no improvement in renal function, peritoneal dialysis was avoided until the seventh day.
Volume 123, June 1972
Nutrition
in Acute Renal Failure
ESSENTIAL L-AYI ACID soLuTloN
Figure 3. Immediate decrease in serum potassium levels observed in a seventy-seven year old man (number 3) after postoperative cardiac arrest and renal failure. Potassium replacement was indicated within forly-eight hours.
ment with inorganic phosphate was below normal (that is, less than 3.0 mg/lOO ml). Extremely low levels of serum phosphate were even noted in eight patients with marked oliguria. (Figure 5.) Although serum calcium levels appeared to increase slightly (Figure 5) in association with the decreases noted in serum phosphate, these changes were neither consistent nor statistically significant. In five nonoliguric patients, phosphate excretion studies confirmed low urinary clearances, thereby eliminating a phosphaturic effect of the amino acid infusion as the mechanism of this hypophosphatemic effect. The addition of potassium phosphate (10 to 60 mflq/L) directly to the study solution was necessary in twelve patients in whom extremely low serum potassium levels had developed. Magnesium. Although decreases in serum magnesium occurred in nine of ten patients in whom data were complete, these changes were not as marked as those for phosphate and potassium. (Table III.) In one patient in whom the serum magnesium rose slightly within the normal range over eleven days of therapy (from 1.4 to 1.8 mEq/L), magnesium-containing antacids were being constantly administered. The magnesium-lowering effect was noted within the first forty-eight hours of treatment in most instances. (Figure 1.) The highest magnesium value recorded in any patient was 2.5 mEq/L (two patients, both re-
635
Abel, Abbott, and Fischer
URINE (ml/24h)
VOL
‘O” 0
ANEURYSMECTOMY
Figure 4. Control of serum potassium m@thinthe normal range without ion exchange resins or dialysis in a seventy-eight year old man (number 5) after ruptured ab dominal aortic aneurysm for eight days, at which time dia/ysis was instituted for controt of azotemia.
ceiving oral magnesium), and no neurologic or cardiac complications attributable to magnesium toxicity were observed. Comments
Acute renal failure in the postoperative period is a life-threatening complication. This often occurs in the setting of prolonged starvation due to inadequate alimentary tract function (by postoperative ileus, nausea and vomiting of uremia, and the like). Furthermore, the ionic imbalances associated with accelerated catabolism and inadequate excretion of wastes add to the difficulties of clinical management. The release of potassium, phosphate, magnesium, and other substances from the intracellular to the intravascular space is often responsible for the development of life-threatening metabolic, neuromuscular, and cardiotoxic side effects. The present group of patients is of interest because the addition of the modified program of total parenteral nutrition to a standard acute renal failure regimen resulted in improvement not only of the nutritional, but also of the metabolic status of a heterogeneous group of critically ill patients. The need for intracellular potassium during active anabolism was described by Moore [I] and was confirmed experimentally by Cannon, Frazier, and Hughes [IO]. Early experiences with intravenous alimentation by Dudrick et al [ll] suggested a high potassium requirement for patients receiving solutions containing protein hydrolysates with hypertonic dex-
636
trose. Conversely, the liberation of intracellular potassium which may occur during states of low cardiac output, after general anesthesia and surgery or associated with gluconeogenesis and protein breakdown during renal failure, is often associated with the development of dangerously high levels of serum potassium. The cardiotoxic effect of hyperkalemia is a common cause of death during the early period after the onset of acute renal failure [I]. The hypokalemic effect of “Renal Failure IV Diet” was the most consistent ionic shift observed in any patient. Although the transmembrane glucose-insulin-potassium effects may explain acute decreases in serum values, the prolonged effect associated with positive potassium balances (Figures 3 and 4) is probably due to incorporation of potassium ion into cellular components during an induced anabolic state. The fate of the “disappearing” phosphate can also only be conjectured. The known requirements for intracellular phosphate during oxidative metabolism and synthesis of membrane phospholipids and other intracellular components may explain the decreases observed in serum phosphate levels in the presence of positive balances. The clinical significance of maintaining normal or subnormal levels of serum phosphate during renal failure, however, remains uncertain. The usual toxicity associated with hypermagnesemia in patients in acute renal failure consists of the development of hypotension, nausea, vomiting, 4000
ESSENTIAL L-AMINO ACID SOLUTION (ml/24h)
800 600 400 2oo 0
SERUM PHOSPHATE (mg/10Dmll
URINE VOLUME (ml /24hl
200
DA YS
Figure 5. Marked decreases in serum phosphate observed in a seventy-nine year old man after aortoiliac grafting and development of acute renal failure.
The American
Journal of Surgery
Parenteral
TABLE III ~_~
in Acute
Renal
Failure
Mean Serum Electrolyte Changes in Patients Receiving Essential L-Amino Acids and Hypertonic Dextrose
Ion Potassium Magnesium Phosphate * T t 0
Nutrition
Number of Patients* ~____ 17 10 12
f Pretreatment? 4.8 f 0.7 2.3 f 0.9 5.3 f 2.5
Post-treatmentt 3.5 f 0.8 1.7 f 0.5 2.2 f 1.7
Number in whom values were obtained before and after treatment. Level immediately prior to infusion. Lowest level which occurred during course of treatment prior to replacement Using Student’s t test for paired data, with a two-tailed p value.
malaise, central nervous system depression, and electrocardiographic manifestations of myocardial depression [16]. The cardiotoxic effects of hypermagnesemia are often synergistic with hyperkalemia and hypocalcemia, both of which may occur simultaneously in acute renal failure. Randall et al [12] also observed serious manifestations of hypermagnesemia in patients receiving large doses of magnesium-containing antacids. The current group of patients was conspicious in that none developed major cardiac conduction defects, which may result from either magnesium or potassium excess, or calcium deficienCY. Measurement of total urinary magnesium excretion in several of the patients confirmed that, as in the case of phosphate and potassium, the lowering of serum magnesium levels was not secondary to augmented urinary excretion. The fate of magnesium ions is also presumed to be due to intracellular deposition during an induced anabolic state. Magnesium has been observed to be an important activator of many enzyme systems critical to cellular metabolism, including its requirement for hydrolysis and transfer of phosphate groups (for example, adenosine triphosphate) and for protein and nucleotide metabolism [13-151. These processes require a shift of magnesium across the cell membrane from the intravascular space, and a marked correlation is noted to exist between the intracellular concentrations of magnesium and potassium [IS]. Although isotopic labeling may be the only direct means of supporting these hypotheses, it seems reasonable to assume that the use of a high caloric source with substrates for intracellular protein synthesis (that is, essential amino acids) may result in a decrease in serum concentration of these substances. Preliminary results from our laboratory of quantitative blood and urine amino acid determinations in a group of similar patients suggest that the administration of essential amino acids is not attended by increased urinary ex-
Volume 123, June 1972
Difference Standard Error
1.3 f 0.8 0.7 f 0.5 3.0 f 1.9
Significance Level § p X.001 <.OOl X.001
or dialysis therapy.
cretion or retention in the blood [17]. This lends still additional support to the hypothesis of induction of intracellular deposition of protein as the mechanism of the nitrogen and ionic shifts. Summary An intravenous diet of essential L-amino acids with a high carbohydrate source was administered to seventeen critically ill patients in acute renal failure. No serious untoward side effects associated with therapy occurred in any patient. Positive nutritional effects including weight gain and improved wound healing were attended by a blood urea nitrogen-stabilizing effect. Unanticipated salutary metabolic effects also occurred, consisting of lower serum concentrations of magnesium, phosphate, and potassium. An hypothesis to explain the presumed ionic shifts intracellularly is discussed. References 1. Moore FD: Metabolic Care of the Surgical Patient. Philadelphia, Saunders, 1959. 2. Lee HA, Sharpstone P, Arnes A: Parenteral nutrition in renal failure. Postgrad Med J 43: 61, 1967. 3. Wilmore DW, Dudrick SJ: Treatment of acute renal failure with intravenous essential L-amino acids. Arch Surg 99: 669,1969. 4. Dudrick SJ, Steiger E, Long JM: Renal failure in surgical patients. Treatment with intravenous essential amino acids and hypertonic dextrose. Surgery 66: 160,197O. 5. Giordano C: Use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J Lab C/in Med 62: 231, 1963. 6. Giovannetti S, Maggiore Q: A low-nitrogen diet with proteins of high biological value for severe chronic uremia. Lancet 1: 1000. 1964. 7. Abel RM, Abbott WM, Fischer JE: Acute renal failure. Treatment without dialysis by total parenteral nutrition. Arch surg 103: 513, 1971. 6. Abbott WM. Abel RM. Fischer JE: Treatment of acute renal insufficiency after aortoiliac surgery. Arch Surg 103: 590, 1971. 9. Rose WC, Wixom RJ, Lockhart HD, Lambert GF: The amino acid requirements of man. XV. The valine requirement,
637
Abel,
10. 11.
12.
13.
630
Abbott,
and Fischer
summary and final observations. J Biol Chem 217: 987. 1955. Cannon PR, Frazier LE, Hughes RH: Influence of potassium on tissue protein synthesis. Metabolism 1: 49, 1952. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE: Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Surgery 169: 974, 1969. Randall RE, Cohen MD, Spray CC, Rossmeise EC: Hypermagnesemia in renal failure: etiology and toxic manifestations. Ann Intern Med 61: 73, 1964. Dove WF, Davidsen N: Catabolic effects on denaturation of
DNA. J Molec Biol5: 467, 1962. 14. Brenner S, Jacob F, Meselson M: Unstable intermediate carrying information from genes to ribosomes for Iprotein synthesis. Nature 190: 576, 1961. 15. Hougland MD, Stephenson ML, Scott JE, Hecht LI, Zandinle PC: Soluble ribonucleic acid intermediates in protein synthesis. J Biol Chem 231: 24, 1958. 16. Wacker WEC, Parisi AF: Magnesium metabolism. New Eng J Med278: 658,712,772, 1968. 17. Abel RM, Shih VE, Abbott WM. Fischer JE: Fate of intravenous essential L-amino acids to patients in acute renal failure. (In preparation.)
The American Journal of Surgery
Intravenous Essential L-Amino Acids and Hypertonic Dextrose in Patients with Acute Renal Failure Effects on Serum Potassium, Phosphate, and Magnesium Ronald M. Abel, MD, Boston, Massachusetts William M. Abbott, MD, Boston, Massachusetts Josef E. Fischer, MD, Boston, Massachusetts The development of acute renal insufficiency in the recently postoperative patient adds additional stress to the hypercatabolic state in a patient already in negative nitrogen balance [I]. if, under such circumstances, the patient is unable to ingest adequate nutriment, the problem is compounded. Not only is the protein-sparing effect of calories unavailable and the excretion of nitrogenous products impaired, but also the breakdown of lean body tissue mass may become accelerated. The use of parenteral nutrition technics for patients in acute renal failure was advocated by Lee, Sharpstone, and Arnes [2], who administered casein hydrolysates and a lipid emulsion to patients unable to eat. Dudrick and his co-workers [3,4] utilized the Giordano-Giovannetti [5,6] principle, modified for intravenous use, in several patients with acute and chronic renal failure, with beneficial effects. More recently, we have confirmed and extended these observations, suggesting that under certain circumstances, dialysis may be completely avoidable, even in acute renal insufficiency [7,8]. These findings appear to substantiate the earlier observations of Giordano [5] and Giovannetti and Maggiore [6] that urea nitrogen could be reutilized for the biosynthesis of protein, resulting in decreased frequency of dialysis and positive nutritional benefits. The present study applies these previous observations to an additional group of patients treated with From the General Surgical Services, Department of Surgery, Harvard Medical School, and the Massachusetts General Hospital, Boston, Massachusetts. This work was supported in part by General Research Support Grant FR-05486-08. and by a gift to the Department of Surgery, Massachusetts General Hospital, from McGaw Laboratories, Glendale, California. Reprint requests should be addressed to Dr Abel, General Surgical Services, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.
632
an intravenous solution containing eight essential L-amino acids and hypertonic dextrose. During the course of this therapy in seventeen patients with acute renal failure, consistent decreases in serum potassium, phosphate, and magnesium levels were noted. These effects, which were unanticipated, resulted in salutory clinical side effects. This report will examine in detail these electrolyte shifts. Material and Methods Patient Selection. Patients were initially considered for intravenous treatment with essential L-amino acids primarily because of inadequate oral intake in the presence of acute renal failure. The seventeen patients (Table I) treated over a six month period included fifteen with episodes of postoperative acute renal failure, one patient (number 17) with acute renal failure secondary to hypotension during massive bleeding from the esophageal varices, and two medical patients with acute renal insufficiency associated with hepatic failure (numbers 15 and 16). The presence of active sepsis or diabetes mellitus, or the presence of prosthetic materials in the cardiovascular system (nine patients) did not contraindicate the use of this therapy which required long-term superior vena cava cannulation. Solution Preparation and Administration. Fresh solutions were mixed daily in the Pharmacy Manufacturing Branch of the Massachusetts General Hospital under a laminar-flow air hood using aseptic technics. Each unit of solution (Table II) contained 250 ml of a 5.25 per cent solution of eight L-amino acids* in sterile water to which was added 500 ml of 70 per cent dextrose in water. Vitamins were derived from a commercial preparation (MVI),? to which additional ascorbic acid and vitamin K1
*Kindly provided as FreAmine-E@ by Robert W. Nicora, Medical Affairs Division, McGaw Laboratories, Glendale, California.
tlJSVPharmaceutica1
Corporation, Tuckahoe, New York.
The American
Journal
of Surgery
Parenteral
TABLE I
Patient
Nutrition
in Acute
Renal
Failure
Data on Seventeen Patients with Acute Renal Failure
Age
1. 2. 3.
74 70 77
4. 5. 6.
79 78 62
7.
70
a. 9.
61 40
10.
23
11.
74
12.
78
13. 14.
57 44
15. 16. 17.
76 53 44
Operation
Diagnosis
(yr)
graft graft
Acute tubular necrosis Acute tubular necrosis Acute tubular necrosis
Aortoiliac graft Aortoiliac graft Aortoiliac graft; re-exploration for retroperitoneal hemorrhage; coronary artery bypass grafts; left ventricular aneurysmectomy
Acute tubular necrosis Acute tubular necrosis Acute tubular necrosis
Coronary
Acute tubular necrosis
Ruptured abdominal aortic aneurysm Ruptured abdominal aortic aneurysm Aortoiliac occlusive disease; acute myocardial infarction on 15th postoperative day Acute aortoiliac thrombosis Ruptured abdominal aortic aneurysm Ruptured abdominal aortic aneurysm
Aneurysmectomy, Aneurysmectomy, Aortoiliac graft
Coronary artery disease; left ventricular aneurysm Coronary artery disease Rheumatic heart disease; mitral stenosis and insufficiency; bleeding gastritis; Serratia septicemia Subacute glomerulonephritis “Giant” gastric ulcer; femoral thrombophlebitis Intestinal obstruction; small bowel infarction lschemic colitis: nutritional cirrhosis Nutritional cirrhosis; bleeding esophageal varices Postnecrotic cirrhosis Acute alcoholic, hepatitis Postnecrotic cirrhosis; bleeding esophageal varices
aortoiliac aortoiliac
artery bypass graft
Coronary artery bypass graft Mitral valve replacement; total gastrectomy
Acute tubular necrosis Acute tubular necrosis
Bilateral nephrectomy; transplantation Subtotal gastrectomy;
Acute tubular necrosis
renal femoral vein ligation
Small bowel resection Colectomy; drainage of abdominal abscesses Splenorenal shunt: re-exploration for intra-abdominal hemorrhage None None Splenorenal shunt
were added. The resultant solution (“Renal Failure IV Diet”) contained a concentration of essential amino acids greater than the “safe” levels suggested by Rose et al [9]. The low total fluid volume made possible by high solution concentration allowed administration of at least a single unit daily to even anuric patients. Because of the solution’s hyperosmolarity (approximately 2,100 mOsm/L), direct superior vena cava infusion was required. All soluTABLE II
Renal Diagnosis
Acute tubular necrosis Acute tubular necrosis “Hepatorenal
syndrome”
“Hepatorenal
syndrome”
“Hepatorenal syndrome” “Hepatorenal syndrome” Acute focal glomerulonephritis
tions were administered at constant infusion rates by gravity via a subclavian or internal jugular venous catheter whose tip resided in the superior vena cava. Clinical management of the infusion and catheter care have previously been described [ 7,8]. Studies. Weights, accurate intake and output records, vital signs, blood counts, serum electrolytes, and renal function were recorded daily on all patients. At least
Composition of Massachusetts General Hospital “Renal Failure IV Diet” Water (750 ml)
L-Amino acids L-lsoleucine L-Leucine L-Lysine HCI L-Methionine L-Phenylalanine L-Threonine L-Tryptophan L-Valine Total Glucose
Volume 123, June 1972
Amount
1.4 2.2 2.0 2.2 2.2 1.0 0.5 1.6
(gm)
Vitamins
Amount
A B, (Thiamine HCI) Bz (Riboflavin) Bs (Pyridoxine HCI) Niacinamide Panthenol C (Ascorbic acid) D (Ergocalciferol) E (dl-a tocopheryl acetate) K1 (Aquamephytone)
5000 USP units 25 mg 5mg 7.5 mg 50 mg 12.5 mg 1.5 mg 500 USP units 2.5 IU 5mg
13.1 350
633
Abel, Abbott, and Fischer
twice weekly twenty-four hour urine collections enabled determinations of nitrogen and electrolyte balances, but because of the difficulties in determining the total body nitrogen in the presence of renal failure, nitrogen “balances”per se were not calculated. Management. Initial infusion rate in all patients was 30 ml/hour (approximately one unit per twenty-four hours) and was increased to a maximum of 100 ml/hour, depending upon glucose and fluid tolerance. Treatment was continued until it ‘was judged that the patient had sufficiently recovered from renal failure and could tolerate a normal diet (either orally or parenterally with protein hydrolysates). Daily measurements of serum osmolarity and blood glucose guided the actual flow rate administration and the need for exogenous insulin therapy. In patients requiring insulin administration (those with diabetes mellitus, pancreatitis, and the like), crystalline zinc insulin (20 units/L) was placed directly into the bottles containing the amino acid mixture.* Traditional modes of therapy for patients in renal failure were continued during the course of treatment. These included fluid restriction, prophylaxis against gastrointestinal bleeding, peritoneal or hemodialysis, ion-exchange resins for control of threatening hyperkalemia, buffering agents to treat severe metabolic acidosis, and electrolyte replacement for measured serum deficiencies. Results Survival. Of the seven patients (41 per cent) who survived the episodes of acute renal failure, two were initially oliguric (urinary volume of less than 600 ml/24 hours), and both required intermittent peritoneal dialysis. Four of the five nonoliguric survivors were managed without either peritoneal or hemodialysis. Since there was not a parallel series of similar patients treated without essential amino acid therapy, these data cannot be interpreted as representing a significant over-all influence upon the natural course of acute renal failure. Adverse Effects and Complications. Although long-term venous catheterization was employed in all patients, no instances of catheter-related sepsis occurred, although one patient (number 9) was known to have Serratia marcescens endocarditis prior to the institution of treatment. There were no technical complications related to subclavian or internal jugular venipuncture in any patient. Significant hyperglycemia of 910 mg/lOO ml and 520 mg/ 100 ml occurred in patients number 12 and 13, respectively, during the course of infusion of the hypertonic solution, but both responded to a decrease in the infusion rate and intravenous insulin administra*Determination of insulin effect in these bottles by radioimmunoassay technics confirmed less than 2 per cent 20~s of activity in vitro over a forty-eight hourperiod.
634
51oerzerk%
Mnmimf t
Dpt,.aflO”
POST-OPERATIVE
DAYS
Figure 1. Laboratory data obtained from a seventy year o/d man (number 2) affer the development of nonofiguric acute tubular necrosis which occurred in the ear/y postoperative period after abdominal aortic aneurysmectomy. The decrease in serum magnesium occurred durfng a period of worsening renal function. Despite stable function by the thirty-fifth postoperative day, institution of casein hydrolysate was accompanied by a recurrent rise in the Mood urea nitrogen level.
tion. The signs of hypertonic nonketotic dehydration and coma did not occur. Metabolic acidosis was noted in approximately half of the patients, but it was uncertain whether this was related to the renal insufficiency or the therapy. Nutritional Effects. Subjective clinical improvement in the nutritional status of all patients was observed, consisting of improved wound healing after early wound separation (two patients), and maintenance of body weight in the absence of peripheral edema or hyponatremia in four patients with prolonged postoperative adynamic ileus. Effects on Blood Urea Nitrogen. Although the rate of rise of blood urea nitrogen appeared to be slowed in most patients, the absence of suitable controls precluded statistical confirmation of these observations. In the majority of patients with daily urinary outputs of greater than 600 ml, however, a decrease followed by a stabilization of the blood urea nitrogen was observed. (Figure 1.) This stabilization often resulted in a lower blood urea nitrogenlcreatinine ratio than that normally predicted by the creatinine clearance determinations. In patients with marked oliguria, however, although the blood urea nitrogen continued to rise, the daily increment was less than that anticipated. (Figure 2.) Since all patients were treated by dialysis at blood urea nitrogen levels exceeding 150 to 175 mg/lOO ml, there are no data to suggest the limit of this blood urea nitrogenstabilizing effect.
The American
Journal of Surgery
Parenteral
Poto.ssium. Clinically significant hyperkalemia did not develop in any patient during the course of treatment despite the absence of any urinary output in many patients. Indeed, positive potassium balances associated with decreases in serum concentrations were noted in all patients. This hypokalemic effect was observed within the first eight hours of infusion. In patient number 3 (Figure 3) “malignant” hyperkalemia developed after an acute myocardial infarction with ventricular fibrillation, requiring ion-exchange resins per rectum every two hours. Although his hourly urine volume did not increase during the first twenty-four hours after the infusion of “Renal Failure IV Diet” at 50 ml per hour, the serum potassium decreased from 5.8 to 3.7 mEq/L during a time that ion-exchange resins were no longer administered. The mean maximal decrease in serum potassium in seventeen patients was statistically significant. (Table III.) Hyperkalemia was not an indication for dialysis in any of the nine patients who required it. Serum potassium was controlled for eight days in one anuric patient in whom potassium levels remained below 4.4 mEq/L, and potassium supplement was eventually required. He did receive peritoneal dialysis, however, on the ninth postoperative day because of a blood urea nitrogen level of 200 mg/lOO ml. (Figure 4.) Phosph.ate. Consistent decreases in serum phosphate occurred in all patients in association with therapy, despite no immediate improvement in the level of renal function. The immediate post-treatment phosphate level in fifteen patients was 2.2 f 1.7 mg/lOO ml (Table III) and in twelve of seventeen patients, the lowest value recorded prior to replaceESSENTIAL L-AMINO ACID SOLUTION (ml124h)
,000 ‘cm
o
Figure 2. Stabilization of blood urea nitrogen level in a seventy-eight year old man (number 12) with ofiguric acute tubular necrosis after septic shock trom small bowel infarction. DesjVte no improvement in renal function, peritoneal dialysis was avoided until the seventh day.
Volume 123, June 1972
Nutrition
in Acute Renal Failure
ESSENTIAL L-AYI ACID soLuTloN
Figure 3. Immediate decrease in serum potassium levels observed in a seventy-seven year old man (number 3) after postoperative cardiac arrest and renal failure. Potassium replacement was indicated within forly-eight hours.
ment with inorganic phosphate was below normal (that is, less than 3.0 mg/lOO ml). Extremely low levels of serum phosphate were even noted in eight patients with marked oliguria. (Figure 5.) Although serum calcium levels appeared to increase slightly (Figure 5) in association with the decreases noted in serum phosphate, these changes were neither consistent nor statistically significant. In five nonoliguric patients, phosphate excretion studies confirmed low urinary clearances, thereby eliminating a phosphaturic effect of the amino acid infusion as the mechanism of this hypophosphatemic effect. The addition of potassium phosphate (10 to 60 mflq/L) directly to the study solution was necessary in twelve patients in whom extremely low serum potassium levels had developed. Magnesium. Although decreases in serum magnesium occurred in nine of ten patients in whom data were complete, these changes were not as marked as those for phosphate and potassium. (Table III.) In one patient in whom the serum magnesium rose slightly within the normal range over eleven days of therapy (from 1.4 to 1.8 mEq/L), magnesium-containing antacids were being constantly administered. The magnesium-lowering effect was noted within the first forty-eight hours of treatment in most instances. (Figure 1.) The highest magnesium value recorded in any patient was 2.5 mEq/L (two patients, both re-
635
Abel, Abbott, and Fischer
URINE (ml/24h)
VOL
‘O” 0
ANEURYSMECTOMY
Figure 4. Control of serum potassium m@thinthe normal range without ion exchange resins or dialysis in a seventy-eight year old man (number 5) after ruptured ab dominal aortic aneurysm for eight days, at which time dia/ysis was instituted for controt of azotemia.
ceiving oral magnesium), and no neurologic or cardiac complications attributable to magnesium toxicity were observed. Comments
Acute renal failure in the postoperative period is a life-threatening complication. This often occurs in the setting of prolonged starvation due to inadequate alimentary tract function (by postoperative ileus, nausea and vomiting of uremia, and the like). Furthermore, the ionic imbalances associated with accelerated catabolism and inadequate excretion of wastes add to the difficulties of clinical management. The release of potassium, phosphate, magnesium, and other substances from the intracellular to the intravascular space is often responsible for the development of life-threatening metabolic, neuromuscular, and cardiotoxic side effects. The present group of patients is of interest because the addition of the modified program of total parenteral nutrition to a standard acute renal failure regimen resulted in improvement not only of the nutritional, but also of the metabolic status of a heterogeneous group of critically ill patients. The need for intracellular potassium during active anabolism was described by Moore [I] and was confirmed experimentally by Cannon, Frazier, and Hughes [IO]. Early experiences with intravenous alimentation by Dudrick et al [ll] suggested a high potassium requirement for patients receiving solutions containing protein hydrolysates with hypertonic dex-
636
trose. Conversely, the liberation of intracellular potassium which may occur during states of low cardiac output, after general anesthesia and surgery or associated with gluconeogenesis and protein breakdown during renal failure, is often associated with the development of dangerously high levels of serum potassium. The cardiotoxic effect of hyperkalemia is a common cause of death during the early period after the onset of acute renal failure [I]. The hypokalemic effect of “Renal Failure IV Diet” was the most consistent ionic shift observed in any patient. Although the transmembrane glucose-insulin-potassium effects may explain acute decreases in serum values, the prolonged effect associated with positive potassium balances (Figures 3 and 4) is probably due to incorporation of potassium ion into cellular components during an induced anabolic state. The fate of the “disappearing” phosphate can also only be conjectured. The known requirements for intracellular phosphate during oxidative metabolism and synthesis of membrane phospholipids and other intracellular components may explain the decreases observed in serum phosphate levels in the presence of positive balances. The clinical significance of maintaining normal or subnormal levels of serum phosphate during renal failure, however, remains uncertain. The usual toxicity associated with hypermagnesemia in patients in acute renal failure consists of the development of hypotension, nausea, vomiting, 4000
ESSENTIAL L-AMINO ACID SOLUTION (ml/24h)
800 600 400 2oo 0
SERUM PHOSPHATE (mg/10Dmll
URINE VOLUME (ml /24hl
200
DA YS
Figure 5. Marked decreases in serum phosphate observed in a seventy-nine year old man after aortoiliac grafting and development of acute renal failure.
The American
Journal of Surgery
Parenteral
TABLE III ~_~
in Acute
Renal
Failure
Mean Serum Electrolyte Changes in Patients Receiving Essential L-Amino Acids and Hypertonic Dextrose
Ion Potassium Magnesium Phosphate * T t 0
Nutrition
Number of Patients* ~____ 17 10 12
f Pretreatment? 4.8 f 0.7 2.3 f 0.9 5.3 f 2.5
Post-treatmentt 3.5 f 0.8 1.7 f 0.5 2.2 f 1.7
Number in whom values were obtained before and after treatment. Level immediately prior to infusion. Lowest level which occurred during course of treatment prior to replacement Using Student’s t test for paired data, with a two-tailed p value.
malaise, central nervous system depression, and electrocardiographic manifestations of myocardial depression [16]. The cardiotoxic effects of hypermagnesemia are often synergistic with hyperkalemia and hypocalcemia, both of which may occur simultaneously in acute renal failure. Randall et al [12] also observed serious manifestations of hypermagnesemia in patients receiving large doses of magnesium-containing antacids. The current group of patients was conspicious in that none developed major cardiac conduction defects, which may result from either magnesium or potassium excess, or calcium deficienCY. Measurement of total urinary magnesium excretion in several of the patients confirmed that, as in the case of phosphate and potassium, the lowering of serum magnesium levels was not secondary to augmented urinary excretion. The fate of magnesium ions is also presumed to be due to intracellular deposition during an induced anabolic state. Magnesium has been observed to be an important activator of many enzyme systems critical to cellular metabolism, including its requirement for hydrolysis and transfer of phosphate groups (for example, adenosine triphosphate) and for protein and nucleotide metabolism [13-151. These processes require a shift of magnesium across the cell membrane from the intravascular space, and a marked correlation is noted to exist between the intracellular concentrations of magnesium and potassium [IS]. Although isotopic labeling may be the only direct means of supporting these hypotheses, it seems reasonable to assume that the use of a high caloric source with substrates for intracellular protein synthesis (that is, essential amino acids) may result in a decrease in serum concentration of these substances. Preliminary results from our laboratory of quantitative blood and urine amino acid determinations in a group of similar patients suggest that the administration of essential amino acids is not attended by increased urinary ex-
Volume 123, June 1972
Difference Standard Error
1.3 f 0.8 0.7 f 0.5 3.0 f 1.9
Significance Level § p X.001 <.OOl X.001
or dialysis therapy.
cretion or retention in the blood [17]. This lends still additional support to the hypothesis of induction of intracellular deposition of protein as the mechanism of the nitrogen and ionic shifts. Summary An intravenous diet of essential L-amino acids with a high carbohydrate source was administered to seventeen critically ill patients in acute renal failure. No serious untoward side effects associated with therapy occurred in any patient. Positive nutritional effects including weight gain and improved wound healing were attended by a blood urea nitrogen-stabilizing effect. Unanticipated salutary metabolic effects also occurred, consisting of lower serum concentrations of magnesium, phosphate, and potassium. An hypothesis to explain the presumed ionic shifts intracellularly is discussed. References 1. Moore FD: Metabolic Care of the Surgical Patient. Philadelphia, Saunders, 1959. 2. Lee HA, Sharpstone P, Arnes A: Parenteral nutrition in renal failure. Postgrad Med J 43: 61, 1967. 3. Wilmore DW, Dudrick SJ: Treatment of acute renal failure with intravenous essential L-amino acids. Arch Surg 99: 669,1969. 4. Dudrick SJ, Steiger E, Long JM: Renal failure in surgical patients. Treatment with intravenous essential amino acids and hypertonic dextrose. Surgery 66: 160,197O. 5. Giordano C: Use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J Lab C/in Med 62: 231, 1963. 6. Giovannetti S, Maggiore Q: A low-nitrogen diet with proteins of high biological value for severe chronic uremia. Lancet 1: 1000. 1964. 7. Abel RM, Abbott WM, Fischer JE: Acute renal failure. Treatment without dialysis by total parenteral nutrition. Arch surg 103: 513, 1971. 6. Abbott WM. Abel RM. Fischer JE: Treatment of acute renal insufficiency after aortoiliac surgery. Arch Surg 103: 590, 1971. 9. Rose WC, Wixom RJ, Lockhart HD, Lambert GF: The amino acid requirements of man. XV. The valine requirement,
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10. 11.
12.
13.
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and Fischer
summary and final observations. J Biol Chem 217: 987. 1955. Cannon PR, Frazier LE, Hughes RH: Influence of potassium on tissue protein synthesis. Metabolism 1: 49, 1952. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE: Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Surgery 169: 974, 1969. Randall RE, Cohen MD, Spray CC, Rossmeise EC: Hypermagnesemia in renal failure: etiology and toxic manifestations. Ann Intern Med 61: 73, 1964. Dove WF, Davidsen N: Catabolic effects on denaturation of
DNA. J Molec Biol5: 467, 1962. 14. Brenner S, Jacob F, Meselson M: Unstable intermediate carrying information from genes to ribosomes for Iprotein synthesis. Nature 190: 576, 1961. 15. Hougland MD, Stephenson ML, Scott JE, Hecht LI, Zandinle PC: Soluble ribonucleic acid intermediates in protein synthesis. J Biol Chem 231: 24, 1958. 16. Wacker WEC, Parisi AF: Magnesium metabolism. New Eng J Med278: 658,712,772, 1968. 17. Abel RM, Shih VE, Abbott WM. Fischer JE: Fate of intravenous essential L-amino acids to patients in acute renal failure. (In preparation.)
The American Journal of Surgery