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Acute renal failure requiring hemodialysis
Acute renal failure requiring hemodialysis JOSEPH H. HOLMES, M.D. E. STEWART TAYLOR, M.D. Denver, Colorado
S r N c E a significant per cent of patients treated by means of extracorporeal dialysis for acute renal failure represent complications of pregnancy or gynecological surgery, it is worthwhile to study the origin, course, and treatment of acute renal insufficiency as seen in a unit where patients of this type are received for treatment. In 1953, the University of Colorado Medical Center developed a unit for the treatment of subjects with acute renal insufficiency. For many years this unit operated the only artificial kidney in a wide geographic area covering several states. During the past nine years, 128 patients have been treated by use of the artificial kidney for various forms of acute renal failure. Twentysix or 20 per cent of the group had recently been pregnant or had had gynecological surgery. This is a report on the management of these 26 patients, and a discussion of the physiology and pathology of acute renal failure as encountered in our specialty of obstetrics and gynecology.
cur as a result of bacterial toxins, mismatched transfusion blood, hypovolemic shock secondary to acute blood loss, abruptio placentae, or severe electrolyte disturbance. Various substances used for the production of abortion, such as soap, may produce intravascular hemolysis, shock, and renal failure. Nephrotoxic agents as mercury, potassium chlorate, carbon tetrachloride, and sulfonamides may also cause acute renal insufficiency. The work of Smith, 1 Oliver, 2 • 3 Bull," Ober, 5 and others has explained the physiology and pathology of acute renal failure in a most understandable fashion. Amphibian6• 7 and mammalian kidneys8 react to acute blood loss and hypoxia by spasm of renal arterioles and reduced oxygen consumption, while capillaries elsewhere in the body dilate. Experiments of Lauson and associates9 have demonstrated that shock in man is associated with a markedly reduced renal blood flow and a reduced glomerular filtration rate. These physiological changes are better understood in the light of Oliver's 2 microdissection studies of nephron units obtained from patients dying in different states of acute renal insufficiency. His studies are interesting because they were performed on the kidneys of individuals whose deaths occurred from known circulatory or nephrotoxic insults. He also reported experiments on dogs which demonstrated the effects of acute circulatory disturbance or toxic agents on the kidneys. Oliver and his group showed that in acute renal failure associated with shock, hemorrhage, crushing injuries, and
Physiology and pathology
Renal ischemia and hemolysis are the usual causes of acute renal insufficiency in obstetrical and gynecologic patients. These may oc-
From the Department of Internal Medicine and the Department of Obstetrics and Gynecology, University of Colorado School of Medicine. Presented by E. Stewart Taylor at the E. E. Poole Lecture, Thirty-second Annual Meeting of the Royal College of Physicians and Surgeons of Canada, Edmonton, Alberta, Jan. 17, 1963.
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body burns, kidney tubular rhexis occurred in a random fashion throughout different nephrons, and at random points in the same nephron. Whether the injury took place after shock from trauma, blood loss, dehydration, or bacterial intoxication, the pathological end results in the kidneys seemed to be the same. In contrast, bichloride of mercury, sulfonamides, potassium chlorate, carbon tetrachloride, and certain other agents produced specific injury to the proximal convoluted tubules. Random tubular rhexis may also occur in this situation as a consequence of the associated vascular collapse and electrolyte disturbances. Tubular structures are capable of regeneration in about two weeks if the tubular basement membrane has not been disrupted. Studies of individual nephrons of patients dying of acute renal failure have revealed varying severities of injury and varying states of repair. If the basement membrane of a tubule is destroyed as part of the original insult, that tubule or group of tubules cannot regenerate. Recovery of the patient depends on the healing of the nephrons, which have not been subjected to total disruption of the basement membrane, and the return to function of nephrons that have escaped injury. Parenchymal edema from the original insult may prevent some essentially normal nephrons from functioning for a few days. The mechanism of acute tubular necrosis from incompatible infusion of blood is not clearly understood. Oliver2 has indicated that intravascular hemolysis with deposition of acid heme in kidney tubules is not the cause of the tubular necrosis since he could rarely demonstrate heme deposits in the proximal tubules. The heme casts were found almost entirely in the ascending limb of the distal tubules and increased in number in the distal convoluted tubules and collecting ducts. Intravascular hemolysis alone in the human subject or in the dog does not cause acute tubal necrosisY· 11 Renal failure probably occurs only when severe hypotension is part of the reaction to the incompatible blood or when the subject has been previously sensitized by incompatible blood. If previous sen-
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sttization exists, prolonged oliguria has been attributed to an allergic reaction in kidney efferent arterioles which results in major tubular damage secondary to arteriolar spasm and necrosis. McKay's 12 • ' ' experiments demonstrated the mechanism responsible for anuria in pregnant patients with sepsis. He reported several instances in which patients who were pregnant had acute renal insufficiency, hypotensive shock, and death associated with sepsis. The autopsy findings suggested a Shwartzman-like reaction with demonstrated tissue necrosis in many vital organs including kidneys, adrenals, pituitary, and liver. His experiments and those of Wong'' demonstrated that the pregnant animal is more sensitive to bacterial toxins than the nonpregnant. During pregnancy, kidney damage and dysfunction may occur in association with infections caused by enterobacillary organisms, streptococci, staphylococci, and W elchii bacilli. Eclampsia and pre-eclampsia, if uncomplicated by previous vascular or renal diseast>, do not in themselves lead to tubular necrosis. The anuria or oliguria sometimes seen as part of the eclamptogenic syndrome is not associated with tubular rhexis of the kidney. The observed urinary suppression is the result of a temporary humoral effect and urinary flow becomes re-established soon after delivery. If acute tubular necrosis complicates the postpartum period of a patient who has had pre-eclampsia or eclampsia, it must be presumed to be secondary to prolonged hypotension, incompatible blood transfusion reaction, sepsis, or a co-existing vascular lesion of the kidney. Necrotic lesions in the kidney may complicate abruptio placentae disease. Sheehan and Moore, 11' in their study of renal lesions occurring in patients with concealed accidental hemorrhage of the placenta, found lesions varying from bilateral cortical necrosis to focal minor lesions of tubules. All renal lesions studied resulted from ischemia which was produced by spasm of some part of the cortical arterial tree. The type of lesion in the kidney depended on the duration and the site of vascular spasm.
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Signs and symptoms Recognition of acute renal insufficiency is not difficult because the cardinal sign is oliguria or anuria. The syndrome usually occurs in a patient who was in good health until the insulting episode. The subject with severe bilateral cortical necrosis of the kidney, secondary to sepsis or as a complication of abruptio placentae, usually has rapid development of anuria or oliguria. Those patients who have acute septic abortion, prolonged hypotension, or an incompatible blood transfusion may have a profound reduction of urinary flow within a few hours with progressive diminution of urinary volume to less than 50 mi. a day by the second or third day. Anuria is not the rule; oliguria is more usual. Hemoglobinuria will be present if intravascular hemolysis occurs secondary to incompatible blood or sepsis. The oliguria of tubular necrosis will persist for a few days up to several weeks and is followed by the diuretic phase which is indicative of renal recovery. The early diuretic phase is characterized by a gradual increase of urine, ranging from 200 to 400 mi. each day. Once a volume of 2,000 mg. is reached, further increases may be large even to 6 or 7 thousand mi. of urine daily. If the oliguria lasts longer than three weeks, the prognosis is poor and irreversible kidney damage should be suspected. Recently, however, we have witnessed recovery from acute tubular necrosis after two months of oliguria. Recent development of a polytetrafluoroethylene catheter arteriovenous shunt system has made it possible to perform repeated hemodialyses easily, and thus manage successfully those cases in which tubular healing requires a prolonged time period. 16 Death results when body fluids, blood chemistry, or infection are not properly controlled. Frequent causes of death are cardiac failure, pulmonary edema, hyperkalemia, acidosis, pneumonia, or pancreatitis. Methods of management and indications for dialysis The management of patients with acute oliguria, because of the different therapeutic problems involved, is arbitrarily divided into
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111
three phases: ( 1) initial or early, (2) oliguric, and ( 3) diuretic. In the initial phase, therapeutic management is directed to correction of any precipitating factors and to assessment of the degree of renal damage. If renal failure is precipitated as a complication of sepsis, antibiotic treatment should be given. Streptomycin, chloramphenicol, and erythromycin are recommended until specific organism sensitivity has been determined. These drugs are best given intravenously, and approximately 2 Gm. of each should be administered during the first 24 hour period. Because of impaired renal excretion of antibiotics, subsequent dosage should be limited to 50 to 75 per cent of the usual daily maintenance requirement. Particular care should be taken with streptomycin, since its serum half life in uremic patients is 2 to 5 days as compared to 4 to 6 hours in the normal person. Serious complications can take place from overdosage of antibiotics; for example, in uremic patients the tetracyclines can cause a rapid rise in blood urea nitrogen, 17 and nitrofurantoin can cause a severe acidosis. 18 Overdosage with antibiotics can be successfully treated by hemodialysis. Hypotension should be treated vigorously with blood or plasma expanders, and in many instances urinary excretion may improve with such therapy. Pressor amines should be used only as a temporary measure or when correction of the hypovolemia fails to restore blood pressure. In any individual with anuria, ureteral catheterization should be performed to rule out obstructive causes. With hemoglobinuria secondary to transfusion reaction or septicemia, immediate alkalinization with sodium lactate or bicarbonate solutions may prevent further damage to the kidney. Recent work has indicated that immediate induction of osmotic diuresis by injection of 20 per cent mannitol solution may prevent renal damage and onset of tubular necrosisY In patients with overdosage of sulfa drugs, immediate removal by hemodialysis may prevent serious renal damage.
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and to control of sepsis or other complications. Early ambulation is suggested. Electrolyte therapy is determined by the analyses of the 24 hour urinary excretion of water and electrolytes, and the precise replacement of these losses. Hemodialysis. Hemodialysis should be used to supplement conservative therapy whenever the patient's condition deteriorates, as evidenced by persistent nausea and vomiting, overhydration, lethargy, disorientation, coma, or convulsions. Chemical indications for hemodialysis include a rising potassium level to above 6.5 mEq. per liter, the presence of electrocardiographic changes indicative of hyperkalemia, a blood urea nitrogen level above 150 mg. per cent, or a co" combining power below 12 mEq. per liter. More recently, a policy of earlier and more frequent dialysis has been adopted by ourselves and by other dialysis groups. This has made management easier since the patients have felt better, have been more able to cooperate in their own care, and sepsis has been less of a problem. Before 1958, 33 per cent of the deaths caused by acute tubular necrosis in our hospital occurred during the diuretic phase. Therefore, whenever definite indications exist, even though diuresis has ~tarted, dialysis is performed. All hemodialyses are performed with the Kolff twin-coil unit. 21 An arteriovenous shunt catheter is inserted into the radial artery and a forearm vein, blood is taken from the artery, passed through the coil unit, and returned to the patient through the venous catheter at a rate of approximately 300 mi. a minute. Its solute composition is adjusted to correct the chemical abnormalities of the patient's serum. Dialysis is performed, while the subject is resting on a scale. Frequent weighings permit precise adjustment of body fluid content. 22 In order to eliminate the hazards of bleeding, heparin is used regionally.23 This is accomplished by adding heparin as the blood enters the coil unit and neutralizing it with heradimethrine bromide as it is returned to the patient. In this way the clotting time of the patient can be kept below 10 minutes (Lee-White), while that
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113
in the coil ranges from 20 to 40 minutes. Antithrombin inhibitors, a common cause of bleeding in uremia, are successfully removed by dialysis. Therefore, uremic bleeding diathesis is no longer considered a contraindication for dialysis. The usual dialysis lasts 6 to 8 hours. Clinical material
Obstetrical and gynecological patients referred to the kidney unit of the Colorado General Hospital for hemodialysis because of acute renal failure may be grouped in the following categories: Incompatible blood transfusion Abdominal hysterectomy Ectopic pregnancy Hydatidiform mole Postpartum pyelitis Hypovolemic shock (rom acute blood loss Abdominal hysterectomy Sepsis Abortion Hepatitis in pregnancy Pyelitis in pregnancy Hydatidiform mole Chronic nephritis Recently pregnant Total
( 11) 8 1 1 I
( 5) 5 (8)
5 I
1 1 (2) 2 26
Transfusion reactions. Acute tubular necrosis developed in 11 patients as a consequence of a transfusion reaction (Table I). In many of these, hypotension was the indication for transfusion. Eight had had elective abdominal or vaginal hysterectomy. Of the remaining 3, 1 had a suspected ectopic pregnancy, another had a hydatidiform mole, while the third had postpartum pye· litis. The surgical patients received multiple transfusions because of blood loss associated with the operations. The other 3 were given single transfusions because of secondary anemia. Four patients died of complicating sepsis; 2 of these deaths occurred in the diuretic phase. The mortality rate in this group was 44 per cent. Hypovolemic shock from acute blood loss. There were 5 patients with acute tubular necrosis where the precipitating factor was hypovolemic shock, secondary to blood loss (Table II). All had abdominal hysterectomy, though 1 patient had an emergency operation
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because of a ruptured uterus. The hypovolemic shock was finally treated by compatible whole blood, but oliguria appeared 2 to 3 days later, and all patients required one
September I, 196:1 J. Obst. & Gynec.
to three dialyses. Two in this group died. sepsis was the cause of death in both; 1 died during the diuretic phase. There was a 40 per cent mortality rate in this group.
Table I. Transfusion reactions Predialysis blood chemistry
Patient No. Age Operation 17 None
Preoperative diagnosis Postpartum urinary infection
Abdominal Myomas hysterectomy
Nonprotein nitrogen or blood co, urea K. Days of nitrogen Creatinine (mEq. (mEq. Dialyses oliguria (mg.%) (mg.%) /L.) /L.)
--
I
Result
22
248*
20.0
8.5
14.1
5
Died 22 days after transfusion; oliguria and complications of uremta
8
200*
16.5
8.0
J 1.9
3
Died in diuretic phase from sepsis 22 days after admission; tubular rhexis
19
162*
10.5
5.8
15.0
2
Alive and well
16
186*
16.2
5.5
13.7
Alive and well
2
41
3
43 Vaginal hysterectomy and repair
4
37 Abdominal Pelvic inflammatory hysterdisease ectomy
5
35 Abdominal Myomas hysterectomy
6
106
6.0
4.7
23.5
Died of acute peritonitis
6
30 Abdominal Pelvic inflammatory hysterdisease ectomy
6
202
16.5
4.7
11.7
Died of sepsis 5 days after admission
7
25 Curettage
Hydatidiform mole
10
!94
18.8
4.7
20.1
Alive and well
8
46 Abdominal Dysfunctional uterine hysterbleeding ectomy
2
295
14.3
3.0
19.4
Alive and well
9
35 Abdominal Dysfunctional uterine hysterbleeding ectomy
3
127
9.1
5.3
16.6
Pelvic relaxation
10
39 Vaginal hysterectomy
Pelvic relaxation
13
238
17.0
3.6
13.8
11
24 None
Ectopic pregnancy
11
226
13.5
7,3
!1.8
*Nonprotein nitrogen.
2
Alive and well
Alive and well
3
Died 20 days after admission from in diuretic
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Table II. Hypovolemic shock from acute blood loss Predialvsi< blood chemistrv J
Patient No. Age OPeration
Preoperative diagnosis
J
Nonprotein nitrogen or blot»d co, K. urea Days of nitrogen Creatinine (mEq. (mEq. Dialyses oliguria (mg.%) (mg.%) /L.J /L.J
12
35 Abdominal Pelvic inflammatory hysterectomy disease
16
260*
22
6.3
17.0
13
49 Abdominal Adenomyosis hysterectomy
17
197*
19
6.3
13.0
14
45 Abdominal Rupture of the hysteruterus ectomy
8.4
12.3
15
37 Abdominal Endometriosis
5
250
Rewlt Died 9 days later of sepsis
3
Died in diuretic phase of sepsis 19 days after admission Alive and well
p
198*
19.5
7.8
9.5
2
Alive and well
15
164
16.3
3.5
16.6
2
Alive and well
hysterectomy 16
39 Abdominal Dead fetus hysterectomy
*Nonprotein nitrogen.
Sepsis in pregnancy. There were 8 patients who had sepsis complicating abortion or the immediate postpartum period (Table III). Seven had dialysis, but one patient (No. 18) died before dialysis could be performed. There were two deaths (Nos. 17 and 18), one was caused by an E. coli septicemia, while the other had a Clostridium welchii toxemia secondary to an abortion. The patient who had the E. coli infection was in the immediate postpartum period and hypotensive shock developed. The autopsy revealed cellular necrosis of the renal tubules, liver, anterior pituitary, and adrenal cortex. The organisms involved in the patients with septic abortion who survived tubular necrosis were Clostridium welchii in 2, E. coli in 1, and alpha hemolytic streptococcus in 1. In one patient (No. 23) postpartum renal insufficiency developed as a complication of viral hepatitis. The mortality rate for the pregnancy sepsis group was 25 per cent. Chronic nephritis and pregnancy. There were two subjects with chronic nephritis
whose renal failure occurred in relation to pregnancy, thus presenting a problem in differential diagnosis (Table IV). One (~1o. 25) had chronic glomerular nephritis which was first diagnosed in late pregnancy. Delivery was normal, and several months later the patient died of progressive uremia and pulmonary edema. Hemodialysis was used in a hope of gaining a temporary remission. The other patient (No. 26) had a recent pregnancy and recurrent episodes of postpartum hemorrhage requiring several transfusions. This led to some initial confusion as to the cause of the renal failure. She died of progressive uremia and pulmonary edema approximately 5 months after delivery, and the kidney lesion at autopsy was diagnosed as chronic glomerulonephritis. Mortality rate of acute tubular necrosis. The total mortality rate among the 24 patients with acute tubular necrosis was 38 per cent. Durin?; the first four years of the dialysis unit, there were 7 subjects with acute tubular necrosis who required hemodialysis
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Table III. Sepsis Predialysis blood chemistry ·--·----
Patient No. Age
Preoperative diagnosis
Nonprotein nitrogen or co, blood urea K. Days of nitrogen Creatinine (mEq. (mEq. (mg.%) /L.) /L.) Dialyses oli~uria (mg.%) ll.O
19.9
Result D1ed 8 days later; necrosis of tu buies, adrenals, liver, and anterior pituitary; E. coli in unne
17
31 Immediate postpartum hypotension, E. coli infection
7
157*
Ill
40 Septic abortion, Cl. welchii
2
144
8.0
5.4
10.8
0
Died of kidney tubular necrosis and pulmonary edema
19
25 Septic abortion, Cl. welchii
9
162
12.8
3.9
10.7
2
Alive and well
20
41 Septic abortion, E. coli
10
212
21.0
6.1
8.2
Alive and well
21
26 Septic abortion, alpha hemolytic streptococcus
9
111
9.8
2.8
33.3
Alive and well
'"-
'"
116
6.0
4.0
15.2
Alive and well
"" "'"'
00
.JU
Septic abortion, Cl. welchii
23
20 Immediate postpartum hepatitis, nausea, and vomiting
10
90
4.9
6.0
22.3
2
Alive and well
24
18 Hydatidiform mole, Cl. welchii
II
230
9.2
6.3
13.5
3
Alive and well
4
Nonprotein nitrogen.
and 5 ( 71 per cent) died. In the past four years, 17 had dialysis performed and 4 died (24 per cent). Residual kidney function. Surviving patients were free of residual kidney disease, as evidenced by the usual clinical and laboratory examinations. Special problems. The following clinical histories illustrate some problems of management. The definition of oliguria that we have used is a volume of urine less than 400 mi. in a 24 hour period, but tubular necrosis may produce uremia when the urinary excretion is in excess of this amount. For example, one patient (No. 9) had 3 days' urinary volume less than 400 mi., yet required two dialyses. Another subject (No. 8) had only two days' urine excretion below 400 mi., but required
a hemodialysis and had a predialysis blood urea nitrogen of 295 mg. per cent. One patient (No. 14) is particularly interesting in that conservative management appeared to be successful until the diuretic phase. At this juncture, the patient suddenly became critically ill with progressive lethargy and coma. She was transferred to Denver and on admission the serum potassium was found to be 8.4 mEq. per liter and the blood urea nitrogen was 250 mg. per cent, even though the daily urine volume at that time was 3,000 mi. The patient's electrocardiogram showed marked spreading of the QRS complex secondary to potassium intoxication. Immediate hemodialysis reduced the serum potassium to normal and corrected the abnormal electrocardiographic tracing
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Table IV. Chronic nephritis Predialvsis blood chemistrv
-
Patient No. Age
Nonprotein nitrogen or blood urea co, K. Days of nitrogen Creatinine (mEq. (mEq. oliguria (m/!. o/o) (mg. o/o) /L.) /L.) Dialysis
Preoperative dial!nosis
25
26
Chronic glomerulonephritis in pregnancy
26
21
Delivery 2 months before; delayed postpartum hemorrhage
15
120*
93
4.8
Result
6.0
10.6
Died of pulmonary edema 10 months after delivery
6.4
20.1
Died of glomerulonephritis 5 months after delivery
'*Nonprotein nitrogen.
Table V. Blood chemistry changes in 2 typical patients after hemodialysis
Blood sample
Blood urea nitrogen or nonprotein nitrogen (mg. %)
Creatinine (mg. o/o)
K. (mEq./L.)
Pre dialysis
198
19.5
7.8
J.<,
/,J
"' "
3.6 3.5
13.8 26.3
Patient No. 15
n __
U~l.Ulei.ty~t~
c:o uu
Predialysis Postdialysis
238 42
.1
10
.~....J:_l
___ :_
within 2 hours. Only one hemodialysis was required. Chemical abnormalities. The blood levels of urea nitrogen or nonprotein nitrogen, creatinine, potassium, and the C0 2 combining power for each patient are given in Tables I, II, III, and IV. The rr1ost significant changes to be noted in the predialysis blood chemistry values are that the blood urea nitrogen levels were above 150 mg. per cent in all but 5 of the 26 subjects in this group. The highest blood urea nitrogen level was 295 mg. per cent. The serum potassium levels were above 6.5 mEq. per liter in only 6 patients. Six others had potassium values between 6 and 6.5. In the remaining patients, hyperkalemia was not a problem. Changes in blood chemistries following dialysis are presented for 2 typical patients (Nos. 10 and 15) in Table V, and show the degree of correction of serum abnormalities that can be obtained by a 5 to 8 hour hemodialysis.
""
17.0 5.5
., .,
co,
(mEq./L.) 9.5
41 . .;.
Table VI lists some of the complications which were considered indications for hemodialysis. Proper conservative management might have prevented the overhydration and electrolyte imbalance. The incidence of convulsions and coma is an effective argument for early and frequent dialysis. Autopsy findings. The following microscopic sections are from autopsies performed on 3 of our patients with acute tubular necrosis. The first section (Fig. 1) is from the kidney of one subject (No. 2) who died in the diuretic phase after 22 days of illness. Table VI. Indications for hemodialysis Progressive lethargy Coma Mental deterioration Convulsions Severe nausea and vomiting Overhydration Electrolyte imbalance Blood urea nitrogen over 180 mg. per cent Serum K. above~ 6 mEq./L. - CO, 12 or below
14 4 5 4 3 4 4 14 11 8
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Fig. 1. Kidney of patient (No. 2) who died in the diure:ic phase of sepsis in the twenty-second day of illness. The tubular necrosis is extreme, and there is considerable aimless regeneration of tubular epithelium. The tubular necrosis was secondary to a transfusion reaction.
The tubular necrosis is extreme, and there is considerable aimless regeneration of tubular epithelium. This patient's tubular necrosis was secondary to a transfusion reaction. The second kidney section (Fig. 2 ) is from the autopsy of a patient (No. 17 ) who died of necrotic lesions of the liver, anterior pituitary, and adrenal gland. This individual had hypotensive shock from postpartum sepsis, received one dialysis, and died 8 days later. The convoluted and collecting tubules show swelling, atrophy, and necrosis. The last patient (No. 13 ) died in the diuretic phase on the nineteenth day, and had superimposed sepsis. The acute tubular necrosis was caused by hypovolemic shock. This
woman had three dialyses. The microscopic section (Fig. 3) shows that the tubules are dilated and lined by deeply stained small cells. Tubular cells are occasionally absent or partially fragmented. Comment
Incompatible blood transfusions were the contributing cause of 42 per cent of the acute renal failure problems in this series. These accidents are preventable and chargeable to human error. They emphasize one of the constant dangers of blood transfusions. A single transfusion was ordered for each of 3 patients, and we can question the indications for or the value of a single blood trans-
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Fig. 2. Kidney of patient (No. 17) who d:ed with necrotic lesions of the liver, anterior p1tmtary, adrenal gland, and kidney tubules. The convoluted and collecting tubules show swelling, atrophy, and necrosis. This patient had hypotensive shock from postpartum sepsis, received one dialysis, and died 8 days later.
fusion. The others received multiple transfusions to combat hypovolemic shock which occurred during surgery. Often the emergency call for blood adds to the confusion and error in typing or administration. If a patient has a normal blood volume before surgery, or has been properly prepared for surgery by treatment of any existent anemia, blood transfusions should not be a requirement. Most elective gynecological surgery can be performed without the aid of blood transfusions except for the prolonged radical cancer procedures. When hypovolemic shock is encountered, however, it should be treated by properly matched blood replacement. In patients with a normal preopera-
tive hematocrit, plasma may be used successfully to combat hypovolemic shock until properly checked cross-matched blood can be obtained. There is some danger in using vasopressor agents for treatment of hypovolemic shock instead of blood, since the vasopressors promote renal ischemia. Acute renal insufficiency is not a common complication of septic abortion. In a series of 201 patients admitted to our service with septic abortion over a 2 year period, only 6 (3 per cent) had renal insufficiency. 24 The alerting signs and symptoms of septic abortion with acute renal insufficiency are persistent hypotension (out of proportion to blood loss), oliguria, hematuria, jaundice, or
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Fig. 3. Kidney of patient {No. 13) who died in the diuretic phase on the nineteenth day, and had superimposed sepsis. Acute tubular necrosis was caused by hypovolemic shock. Tubular cells are occasionally absent or partially fragmented . Some recovery of tubules is evident.
ecchymosis. Hypotension and oliguria sometimes seen with septic abortion may or may not be associated with acute tubular necrosis. If the urinary specific gravity remains 1.018 or greater, the oliguria is probably secondary to hypotension or dehydration. Correction of the hypotension with vasopressors, treatment with antibiotics, and evacuation of the infected products of conception wiil often result in a good urine excretion. When an adequate urine volume is not obtained after appropriate therapy, the patient should be considered to have acute tubular necrosis. We have noted that intravenous oxytocin preparations may produce an oliguria in the
pregnant or postpartum patient for as long as 24 hours after the discontinuation of the oxytocin infusion. Under these circumstances the urinary specific gravity remains 1.018 or greater, and the oliguria is self-limiting. After establishing the diagnosis of acute tubular necrosis, arrangements should be made for early transfer of the patient to a hemodialysis center. Transfer is recommended under the following circumstances: 1. Continued oliguria that does not respond to adequate fluid and blood replacement. 2. Progressive rise in blood urea nitrogen or in serum potassium, or a fall m C0 2 combining power.
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3. Electrocardiographic evidence of hyperkalemia. 4. Severe nausea and vomiting. 5. Lethargy, mental deterioration, coma, or convulsions. 6. Overhydration, particularly with associated cardiac failure. A lower mortality rate (24 per cent) in the past four years might be attributed to a number of improvements in management of these patients that have become standard practice in the kidney unit. These practices include: ( 1) early recognition of acute tubular necrosis by the attending physician, and early transfer of patients to a center equipped for their care; (2) the earlier and more frequent use of hemodialysis; (3) improved dialysis techniques and the training of a more proficient dialysis team; (4) the use of heparin regionally which has eliminated most of the bleeding complications during and after dialysis; and ( 5) better control of antibiotic and drug therapy in the oliguric patient. Summary
Twenty-six patients with acute renal insufficiency originating in gynecological or obstetrical patients have been treated with hemodialysis by the kidney unit of the University of Colorado Medical Center. In 11 of the 26 patients, acute renal failure developed as a result of incompatible blood transfusions. Ten of the individuals were referred to our hospital from the surround-
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ing geographic area. Five more patients were referred to us with acute renal failure secondary to hypovolemic shock that occurred during elective surgery. In another 8 patients, oliguria developed because of sepsis associated with abortion or the postpartum period. Two of the patients who died of oliguria had chronic renal disease that antedated the uremia. The physiology, pathology, principles of management of acute renal failure, and the results of hemodialysis therapy were given. The mortality rate among these 26 patients was 42 per cent, a rate approximating the 50 per cent mortality cited in the literature. The mortality rate in patients with acute tubular necrosis during the past four years was 24 per cent, and this improvement has been attributed to earlier transfer to the dialysis unit, more frequent dialysis, and improved dialysis techniques. Conclusions
1. Blood transfusion reactions, sepsis, and hypovolemic shock were the primary causes of acute renal insufficiency in obstetrical and gynecological patients referred to this unit. 2. Many of the complications leading to acute tubular necrosis in this series were preventable. 3. A reduced mortality can be achieved in patients with acute tubular necrosis by proper conservative management, early transfer to a dialysis center, the appropriate and frequent use of dialysis, and proper control of sepsis.
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1. Smith, H. W.: The Kidney, New York, 1951,
2. 3. 4.
5. 6.
7.
Oxford University Press, chap. 24. Oliver, ]., MacDowell, M., and Tracy, A.: J. Clin. Invest. 30: 1307, 1951. Oliver, J.: Am. J. Med. 15: 535, 1953. Bull, G. M., Joekes, A. M., and Lowe, K. G.: Clin. Sc. 9: 379, 1950. Ober, W. E., Reid, D. E., Romney, S. L., and Merrill, J. P.: Am. J. Med. 21: 781, 1956. Tamura, K., Miyamura, K., Nishina, T., and Nagasawa, H.: Studies in the Excretion of Urine. I. The Glomerular Circulation in the Living Frog's Kidney, Jap. J. M. Sc., Trans. 4, Pharmacology 1: 211, 1927. Beck, L. V., Kempton, R. T., and Richards, A. N.: Am. J. Physiol. 122: 676, 1938.
8. Dole, V. P., et a!.: Am. J. Physiol. 145: 337, 1946. 9. Lauson, H. D., Bradley, S. E., and Cournand, A.: J. Clin. Invest. 23: 381, 1944. 10. Blackburn, C. R. B., Hensley, W. J., Grant, D. K., and Wright, F. B.: J. Clin. Invest. 33: 825, 1954. 11. Mason, A. D., and Mueller, C. B.: Science 116: 526, 1952. 12. McKay, D. G., Jewett, J. F., and Reid, D. E.: AM. J. 0BST. & GYNEC. 78: 546, 1959. 13. McKay, D. G.: Obst. & Gynec. 20: 446, 1962. 14. Wong, T.: AM. J. 0BST. & GYNEC. 84: 786, 1962. 15. Sheehan, H. L., and Moore, H. C.: Renal
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Cortical Necrosis and the Kidney of Concealed Accidental Hemorrhage, Springfield, Ill.. 1953. Charles C Thomas. Publisher. o. 174. . . . . 16. Quinton, W., Dillard, D., and Scribner, B. H.: Tr. Am. Soc. Artif. Int. Organs 6: 104, 1960. 17. Sh!ls, M. E.: Ann. Int. Med. 56: 698, 1962. 18. Holmes, ]. H.: Acidosis Associated with Administration of Furadantin. (In preparation.) 19. Barry, K. G., and Malloy, ]. P.: ]. A. M. A. 179: 510, 1962. 20. Holmes, J. H., Crandall, ]. I., Dwyer, W. C.,
Am.
21. 22. 23. 24.
September I, 1963 J, Obst. & Gym~c-
and Short, W. F.: Tr. Am. Soc. Artif. Int. Organs 6: 152, 1960. Holmes, J. H., eta!.: J. Urol. 80: 102, 1958. Holmes, J. H., and Nakamoto, S.: Tr. Am. Soc. Artif. Int. Organs 5: 58, 1959. Nakamoto, S., and Holmes, ]. H.: Tr. Am. Soc. Artif. Int. Organs 4: 36, 1958. Woodard, D. E.: Obst. & Gynec. 19: 642, 1962. 4200 East 9th Ave. Denver 20, Colorado
S r N c E a significant per cent of patients treated by means of extracorporeal dialysis for acute renal failure represent complications of pregnancy or gynecological surgery, it is worthwhile to study the origin, course, and treatment of acute renal insufficiency as seen in a unit where patients of this type are received for treatment. In 1953, the University of Colorado Medical Center developed a unit for the treatment of subjects with acute renal insufficiency. For many years this unit operated the only artificial kidney in a wide geographic area covering several states. During the past nine years, 128 patients have been treated by use of the artificial kidney for various forms of acute renal failure. Twentysix or 20 per cent of the group had recently been pregnant or had had gynecological surgery. This is a report on the management of these 26 patients, and a discussion of the physiology and pathology of acute renal failure as encountered in our specialty of obstetrics and gynecology.
cur as a result of bacterial toxins, mismatched transfusion blood, hypovolemic shock secondary to acute blood loss, abruptio placentae, or severe electrolyte disturbance. Various substances used for the production of abortion, such as soap, may produce intravascular hemolysis, shock, and renal failure. Nephrotoxic agents as mercury, potassium chlorate, carbon tetrachloride, and sulfonamides may also cause acute renal insufficiency. The work of Smith, 1 Oliver, 2 • 3 Bull," Ober, 5 and others has explained the physiology and pathology of acute renal failure in a most understandable fashion. Amphibian6• 7 and mammalian kidneys8 react to acute blood loss and hypoxia by spasm of renal arterioles and reduced oxygen consumption, while capillaries elsewhere in the body dilate. Experiments of Lauson and associates9 have demonstrated that shock in man is associated with a markedly reduced renal blood flow and a reduced glomerular filtration rate. These physiological changes are better understood in the light of Oliver's 2 microdissection studies of nephron units obtained from patients dying in different states of acute renal insufficiency. His studies are interesting because they were performed on the kidneys of individuals whose deaths occurred from known circulatory or nephrotoxic insults. He also reported experiments on dogs which demonstrated the effects of acute circulatory disturbance or toxic agents on the kidneys. Oliver and his group showed that in acute renal failure associated with shock, hemorrhage, crushing injuries, and
Physiology and pathology
Renal ischemia and hemolysis are the usual causes of acute renal insufficiency in obstetrical and gynecologic patients. These may oc-
From the Department of Internal Medicine and the Department of Obstetrics and Gynecology, University of Colorado School of Medicine. Presented by E. Stewart Taylor at the E. E. Poole Lecture, Thirty-second Annual Meeting of the Royal College of Physicians and Surgeons of Canada, Edmonton, Alberta, Jan. 17, 1963.
109
110
Holmes and Taylor
body burns, kidney tubular rhexis occurred in a random fashion throughout different nephrons, and at random points in the same nephron. Whether the injury took place after shock from trauma, blood loss, dehydration, or bacterial intoxication, the pathological end results in the kidneys seemed to be the same. In contrast, bichloride of mercury, sulfonamides, potassium chlorate, carbon tetrachloride, and certain other agents produced specific injury to the proximal convoluted tubules. Random tubular rhexis may also occur in this situation as a consequence of the associated vascular collapse and electrolyte disturbances. Tubular structures are capable of regeneration in about two weeks if the tubular basement membrane has not been disrupted. Studies of individual nephrons of patients dying of acute renal failure have revealed varying severities of injury and varying states of repair. If the basement membrane of a tubule is destroyed as part of the original insult, that tubule or group of tubules cannot regenerate. Recovery of the patient depends on the healing of the nephrons, which have not been subjected to total disruption of the basement membrane, and the return to function of nephrons that have escaped injury. Parenchymal edema from the original insult may prevent some essentially normal nephrons from functioning for a few days. The mechanism of acute tubular necrosis from incompatible infusion of blood is not clearly understood. Oliver2 has indicated that intravascular hemolysis with deposition of acid heme in kidney tubules is not the cause of the tubular necrosis since he could rarely demonstrate heme deposits in the proximal tubules. The heme casts were found almost entirely in the ascending limb of the distal tubules and increased in number in the distal convoluted tubules and collecting ducts. Intravascular hemolysis alone in the human subject or in the dog does not cause acute tubal necrosisY· 11 Renal failure probably occurs only when severe hypotension is part of the reaction to the incompatible blood or when the subject has been previously sensitized by incompatible blood. If previous sen-
Am,
September I, 1963 J, Obst. & Gynec.
sttization exists, prolonged oliguria has been attributed to an allergic reaction in kidney efferent arterioles which results in major tubular damage secondary to arteriolar spasm and necrosis. McKay's 12 • ' ' experiments demonstrated the mechanism responsible for anuria in pregnant patients with sepsis. He reported several instances in which patients who were pregnant had acute renal insufficiency, hypotensive shock, and death associated with sepsis. The autopsy findings suggested a Shwartzman-like reaction with demonstrated tissue necrosis in many vital organs including kidneys, adrenals, pituitary, and liver. His experiments and those of Wong'' demonstrated that the pregnant animal is more sensitive to bacterial toxins than the nonpregnant. During pregnancy, kidney damage and dysfunction may occur in association with infections caused by enterobacillary organisms, streptococci, staphylococci, and W elchii bacilli. Eclampsia and pre-eclampsia, if uncomplicated by previous vascular or renal diseast>, do not in themselves lead to tubular necrosis. The anuria or oliguria sometimes seen as part of the eclamptogenic syndrome is not associated with tubular rhexis of the kidney. The observed urinary suppression is the result of a temporary humoral effect and urinary flow becomes re-established soon after delivery. If acute tubular necrosis complicates the postpartum period of a patient who has had pre-eclampsia or eclampsia, it must be presumed to be secondary to prolonged hypotension, incompatible blood transfusion reaction, sepsis, or a co-existing vascular lesion of the kidney. Necrotic lesions in the kidney may complicate abruptio placentae disease. Sheehan and Moore, 11' in their study of renal lesions occurring in patients with concealed accidental hemorrhage of the placenta, found lesions varying from bilateral cortical necrosis to focal minor lesions of tubules. All renal lesions studied resulted from ischemia which was produced by spasm of some part of the cortical arterial tree. The type of lesion in the kidney depended on the duration and the site of vascular spasm.
Volume 87 Numbe1l
Signs and symptoms Recognition of acute renal insufficiency is not difficult because the cardinal sign is oliguria or anuria. The syndrome usually occurs in a patient who was in good health until the insulting episode. The subject with severe bilateral cortical necrosis of the kidney, secondary to sepsis or as a complication of abruptio placentae, usually has rapid development of anuria or oliguria. Those patients who have acute septic abortion, prolonged hypotension, or an incompatible blood transfusion may have a profound reduction of urinary flow within a few hours with progressive diminution of urinary volume to less than 50 mi. a day by the second or third day. Anuria is not the rule; oliguria is more usual. Hemoglobinuria will be present if intravascular hemolysis occurs secondary to incompatible blood or sepsis. The oliguria of tubular necrosis will persist for a few days up to several weeks and is followed by the diuretic phase which is indicative of renal recovery. The early diuretic phase is characterized by a gradual increase of urine, ranging from 200 to 400 mi. each day. Once a volume of 2,000 mg. is reached, further increases may be large even to 6 or 7 thousand mi. of urine daily. If the oliguria lasts longer than three weeks, the prognosis is poor and irreversible kidney damage should be suspected. Recently, however, we have witnessed recovery from acute tubular necrosis after two months of oliguria. Recent development of a polytetrafluoroethylene catheter arteriovenous shunt system has made it possible to perform repeated hemodialyses easily, and thus manage successfully those cases in which tubular healing requires a prolonged time period. 16 Death results when body fluids, blood chemistry, or infection are not properly controlled. Frequent causes of death are cardiac failure, pulmonary edema, hyperkalemia, acidosis, pneumonia, or pancreatitis. Methods of management and indications for dialysis The management of patients with acute oliguria, because of the different therapeutic problems involved, is arbitrarily divided into
Hemodialysis m renal failure
111
three phases: ( 1) initial or early, (2) oliguric, and ( 3) diuretic. In the initial phase, therapeutic management is directed to correction of any precipitating factors and to assessment of the degree of renal damage. If renal failure is precipitated as a complication of sepsis, antibiotic treatment should be given. Streptomycin, chloramphenicol, and erythromycin are recommended until specific organism sensitivity has been determined. These drugs are best given intravenously, and approximately 2 Gm. of each should be administered during the first 24 hour period. Because of impaired renal excretion of antibiotics, subsequent dosage should be limited to 50 to 75 per cent of the usual daily maintenance requirement. Particular care should be taken with streptomycin, since its serum half life in uremic patients is 2 to 5 days as compared to 4 to 6 hours in the normal person. Serious complications can take place from overdosage of antibiotics; for example, in uremic patients the tetracyclines can cause a rapid rise in blood urea nitrogen, 17 and nitrofurantoin can cause a severe acidosis. 18 Overdosage with antibiotics can be successfully treated by hemodialysis. Hypotension should be treated vigorously with blood or plasma expanders, and in many instances urinary excretion may improve with such therapy. Pressor amines should be used only as a temporary measure or when correction of the hypovolemia fails to restore blood pressure. In any individual with anuria, ureteral catheterization should be performed to rule out obstructive causes. With hemoglobinuria secondary to transfusion reaction or septicemia, immediate alkalinization with sodium lactate or bicarbonate solutions may prevent further damage to the kidney. Recent work has indicated that immediate induction of osmotic diuresis by injection of 20 per cent mannitol solution may prevent renal damage and onset of tubular necrosisY In patients with overdosage of sulfa drugs, immediate removal by hemodialysis may prevent serious renal damage.
Volume 87 Number I
and to control of sepsis or other complications. Early ambulation is suggested. Electrolyte therapy is determined by the analyses of the 24 hour urinary excretion of water and electrolytes, and the precise replacement of these losses. Hemodialysis. Hemodialysis should be used to supplement conservative therapy whenever the patient's condition deteriorates, as evidenced by persistent nausea and vomiting, overhydration, lethargy, disorientation, coma, or convulsions. Chemical indications for hemodialysis include a rising potassium level to above 6.5 mEq. per liter, the presence of electrocardiographic changes indicative of hyperkalemia, a blood urea nitrogen level above 150 mg. per cent, or a co" combining power below 12 mEq. per liter. More recently, a policy of earlier and more frequent dialysis has been adopted by ourselves and by other dialysis groups. This has made management easier since the patients have felt better, have been more able to cooperate in their own care, and sepsis has been less of a problem. Before 1958, 33 per cent of the deaths caused by acute tubular necrosis in our hospital occurred during the diuretic phase. Therefore, whenever definite indications exist, even though diuresis has ~tarted, dialysis is performed. All hemodialyses are performed with the Kolff twin-coil unit. 21 An arteriovenous shunt catheter is inserted into the radial artery and a forearm vein, blood is taken from the artery, passed through the coil unit, and returned to the patient through the venous catheter at a rate of approximately 300 mi. a minute. Its solute composition is adjusted to correct the chemical abnormalities of the patient's serum. Dialysis is performed, while the subject is resting on a scale. Frequent weighings permit precise adjustment of body fluid content. 22 In order to eliminate the hazards of bleeding, heparin is used regionally.23 This is accomplished by adding heparin as the blood enters the coil unit and neutralizing it with heradimethrine bromide as it is returned to the patient. In this way the clotting time of the patient can be kept below 10 minutes (Lee-White), while that
Hemodialysis
1n
renal failure
113
in the coil ranges from 20 to 40 minutes. Antithrombin inhibitors, a common cause of bleeding in uremia, are successfully removed by dialysis. Therefore, uremic bleeding diathesis is no longer considered a contraindication for dialysis. The usual dialysis lasts 6 to 8 hours. Clinical material
Obstetrical and gynecological patients referred to the kidney unit of the Colorado General Hospital for hemodialysis because of acute renal failure may be grouped in the following categories: Incompatible blood transfusion Abdominal hysterectomy Ectopic pregnancy Hydatidiform mole Postpartum pyelitis Hypovolemic shock (rom acute blood loss Abdominal hysterectomy Sepsis Abortion Hepatitis in pregnancy Pyelitis in pregnancy Hydatidiform mole Chronic nephritis Recently pregnant Total
( 11) 8 1 1 I
( 5) 5 (8)
5 I
1 1 (2) 2 26
Transfusion reactions. Acute tubular necrosis developed in 11 patients as a consequence of a transfusion reaction (Table I). In many of these, hypotension was the indication for transfusion. Eight had had elective abdominal or vaginal hysterectomy. Of the remaining 3, 1 had a suspected ectopic pregnancy, another had a hydatidiform mole, while the third had postpartum pye· litis. The surgical patients received multiple transfusions because of blood loss associated with the operations. The other 3 were given single transfusions because of secondary anemia. Four patients died of complicating sepsis; 2 of these deaths occurred in the diuretic phase. The mortality rate in this group was 44 per cent. Hypovolemic shock from acute blood loss. There were 5 patients with acute tubular necrosis where the precipitating factor was hypovolemic shock, secondary to blood loss (Table II). All had abdominal hysterectomy, though 1 patient had an emergency operation
114
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because of a ruptured uterus. The hypovolemic shock was finally treated by compatible whole blood, but oliguria appeared 2 to 3 days later, and all patients required one
September I, 196:1 J. Obst. & Gynec.
to three dialyses. Two in this group died. sepsis was the cause of death in both; 1 died during the diuretic phase. There was a 40 per cent mortality rate in this group.
Table I. Transfusion reactions Predialysis blood chemistry
Patient No. Age Operation 17 None
Preoperative diagnosis Postpartum urinary infection
Abdominal Myomas hysterectomy
Nonprotein nitrogen or blood co, urea K. Days of nitrogen Creatinine (mEq. (mEq. Dialyses oliguria (mg.%) (mg.%) /L.) /L.)
--
I
Result
22
248*
20.0
8.5
14.1
5
Died 22 days after transfusion; oliguria and complications of uremta
8
200*
16.5
8.0
J 1.9
3
Died in diuretic phase from sepsis 22 days after admission; tubular rhexis
19
162*
10.5
5.8
15.0
2
Alive and well
16
186*
16.2
5.5
13.7
Alive and well
2
41
3
43 Vaginal hysterectomy and repair
4
37 Abdominal Pelvic inflammatory hysterdisease ectomy
5
35 Abdominal Myomas hysterectomy
6
106
6.0
4.7
23.5
Died of acute peritonitis
6
30 Abdominal Pelvic inflammatory hysterdisease ectomy
6
202
16.5
4.7
11.7
Died of sepsis 5 days after admission
7
25 Curettage
Hydatidiform mole
10
!94
18.8
4.7
20.1
Alive and well
8
46 Abdominal Dysfunctional uterine hysterbleeding ectomy
2
295
14.3
3.0
19.4
Alive and well
9
35 Abdominal Dysfunctional uterine hysterbleeding ectomy
3
127
9.1
5.3
16.6
Pelvic relaxation
10
39 Vaginal hysterectomy
Pelvic relaxation
13
238
17.0
3.6
13.8
11
24 None
Ectopic pregnancy
11
226
13.5
7,3
!1.8
*Nonprotein nitrogen.
2
Alive and well
Alive and well
3
Died 20 days after admission from in diuretic
Hemodialysis in renal failure
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115
Table II. Hypovolemic shock from acute blood loss Predialvsi< blood chemistrv J
Patient No. Age OPeration
Preoperative diagnosis
J
Nonprotein nitrogen or blot»d co, K. urea Days of nitrogen Creatinine (mEq. (mEq. Dialyses oliguria (mg.%) (mg.%) /L.J /L.J
12
35 Abdominal Pelvic inflammatory hysterectomy disease
16
260*
22
6.3
17.0
13
49 Abdominal Adenomyosis hysterectomy
17
197*
19
6.3
13.0
14
45 Abdominal Rupture of the hysteruterus ectomy
8.4
12.3
15
37 Abdominal Endometriosis
5
250
Rewlt Died 9 days later of sepsis
3
Died in diuretic phase of sepsis 19 days after admission Alive and well
p
198*
19.5
7.8
9.5
2
Alive and well
15
164
16.3
3.5
16.6
2
Alive and well
hysterectomy 16
39 Abdominal Dead fetus hysterectomy
*Nonprotein nitrogen.
Sepsis in pregnancy. There were 8 patients who had sepsis complicating abortion or the immediate postpartum period (Table III). Seven had dialysis, but one patient (No. 18) died before dialysis could be performed. There were two deaths (Nos. 17 and 18), one was caused by an E. coli septicemia, while the other had a Clostridium welchii toxemia secondary to an abortion. The patient who had the E. coli infection was in the immediate postpartum period and hypotensive shock developed. The autopsy revealed cellular necrosis of the renal tubules, liver, anterior pituitary, and adrenal cortex. The organisms involved in the patients with septic abortion who survived tubular necrosis were Clostridium welchii in 2, E. coli in 1, and alpha hemolytic streptococcus in 1. In one patient (No. 23) postpartum renal insufficiency developed as a complication of viral hepatitis. The mortality rate for the pregnancy sepsis group was 25 per cent. Chronic nephritis and pregnancy. There were two subjects with chronic nephritis
whose renal failure occurred in relation to pregnancy, thus presenting a problem in differential diagnosis (Table IV). One (~1o. 25) had chronic glomerular nephritis which was first diagnosed in late pregnancy. Delivery was normal, and several months later the patient died of progressive uremia and pulmonary edema. Hemodialysis was used in a hope of gaining a temporary remission. The other patient (No. 26) had a recent pregnancy and recurrent episodes of postpartum hemorrhage requiring several transfusions. This led to some initial confusion as to the cause of the renal failure. She died of progressive uremia and pulmonary edema approximately 5 months after delivery, and the kidney lesion at autopsy was diagnosed as chronic glomerulonephritis. Mortality rate of acute tubular necrosis. The total mortality rate among the 24 patients with acute tubular necrosis was 38 per cent. Durin?; the first four years of the dialysis unit, there were 7 subjects with acute tubular necrosis who required hemodialysis
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Septembe1· 1, 1963 Am. J. Obst. & Gynec.
Table III. Sepsis Predialysis blood chemistry ·--·----
Patient No. Age
Preoperative diagnosis
Nonprotein nitrogen or co, blood urea K. Days of nitrogen Creatinine (mEq. (mEq. (mg.%) /L.) /L.) Dialyses oli~uria (mg.%) ll.O
19.9
Result D1ed 8 days later; necrosis of tu buies, adrenals, liver, and anterior pituitary; E. coli in unne
17
31 Immediate postpartum hypotension, E. coli infection
7
157*
Ill
40 Septic abortion, Cl. welchii
2
144
8.0
5.4
10.8
0
Died of kidney tubular necrosis and pulmonary edema
19
25 Septic abortion, Cl. welchii
9
162
12.8
3.9
10.7
2
Alive and well
20
41 Septic abortion, E. coli
10
212
21.0
6.1
8.2
Alive and well
21
26 Septic abortion, alpha hemolytic streptococcus
9
111
9.8
2.8
33.3
Alive and well
'"-
'"
116
6.0
4.0
15.2
Alive and well
"" "'"'
00
.JU
Septic abortion, Cl. welchii
23
20 Immediate postpartum hepatitis, nausea, and vomiting
10
90
4.9
6.0
22.3
2
Alive and well
24
18 Hydatidiform mole, Cl. welchii
II
230
9.2
6.3
13.5
3
Alive and well
4
Nonprotein nitrogen.
and 5 ( 71 per cent) died. In the past four years, 17 had dialysis performed and 4 died (24 per cent). Residual kidney function. Surviving patients were free of residual kidney disease, as evidenced by the usual clinical and laboratory examinations. Special problems. The following clinical histories illustrate some problems of management. The definition of oliguria that we have used is a volume of urine less than 400 mi. in a 24 hour period, but tubular necrosis may produce uremia when the urinary excretion is in excess of this amount. For example, one patient (No. 9) had 3 days' urinary volume less than 400 mi., yet required two dialyses. Another subject (No. 8) had only two days' urine excretion below 400 mi., but required
a hemodialysis and had a predialysis blood urea nitrogen of 295 mg. per cent. One patient (No. 14) is particularly interesting in that conservative management appeared to be successful until the diuretic phase. At this juncture, the patient suddenly became critically ill with progressive lethargy and coma. She was transferred to Denver and on admission the serum potassium was found to be 8.4 mEq. per liter and the blood urea nitrogen was 250 mg. per cent, even though the daily urine volume at that time was 3,000 mi. The patient's electrocardiogram showed marked spreading of the QRS complex secondary to potassium intoxication. Immediate hemodialysis reduced the serum potassium to normal and corrected the abnormal electrocardiographic tracing
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117
Table IV. Chronic nephritis Predialvsis blood chemistrv
-
Patient No. Age
Nonprotein nitrogen or blood urea co, K. Days of nitrogen Creatinine (mEq. (mEq. oliguria (m/!. o/o) (mg. o/o) /L.) /L.) Dialysis
Preoperative dial!nosis
25
26
Chronic glomerulonephritis in pregnancy
26
21
Delivery 2 months before; delayed postpartum hemorrhage
15
120*
93
4.8
Result
6.0
10.6
Died of pulmonary edema 10 months after delivery
6.4
20.1
Died of glomerulonephritis 5 months after delivery
'*Nonprotein nitrogen.
Table V. Blood chemistry changes in 2 typical patients after hemodialysis
Blood sample
Blood urea nitrogen or nonprotein nitrogen (mg. %)
Creatinine (mg. o/o)
K. (mEq./L.)
Pre dialysis
198
19.5
7.8
J.<,
/,J
"' "
3.6 3.5
13.8 26.3
Patient No. 15
n __
U~l.Ulei.ty~t~
c:o uu
Predialysis Postdialysis
238 42
.1
10
.~....J:_l
___ :_
within 2 hours. Only one hemodialysis was required. Chemical abnormalities. The blood levels of urea nitrogen or nonprotein nitrogen, creatinine, potassium, and the C0 2 combining power for each patient are given in Tables I, II, III, and IV. The rr1ost significant changes to be noted in the predialysis blood chemistry values are that the blood urea nitrogen levels were above 150 mg. per cent in all but 5 of the 26 subjects in this group. The highest blood urea nitrogen level was 295 mg. per cent. The serum potassium levels were above 6.5 mEq. per liter in only 6 patients. Six others had potassium values between 6 and 6.5. In the remaining patients, hyperkalemia was not a problem. Changes in blood chemistries following dialysis are presented for 2 typical patients (Nos. 10 and 15) in Table V, and show the degree of correction of serum abnormalities that can be obtained by a 5 to 8 hour hemodialysis.
""
17.0 5.5
., .,
co,
(mEq./L.) 9.5
41 . .;.
Table VI lists some of the complications which were considered indications for hemodialysis. Proper conservative management might have prevented the overhydration and electrolyte imbalance. The incidence of convulsions and coma is an effective argument for early and frequent dialysis. Autopsy findings. The following microscopic sections are from autopsies performed on 3 of our patients with acute tubular necrosis. The first section (Fig. 1) is from the kidney of one subject (No. 2) who died in the diuretic phase after 22 days of illness. Table VI. Indications for hemodialysis Progressive lethargy Coma Mental deterioration Convulsions Severe nausea and vomiting Overhydration Electrolyte imbalance Blood urea nitrogen over 180 mg. per cent Serum K. above~ 6 mEq./L. - CO, 12 or below
14 4 5 4 3 4 4 14 11 8
118
September I, 1963 Am. ]. Obst. & Gynec.
Holmes and Taylor
Fig. 1. Kidney of patient (No. 2) who died in the diure:ic phase of sepsis in the twenty-second day of illness. The tubular necrosis is extreme, and there is considerable aimless regeneration of tubular epithelium. The tubular necrosis was secondary to a transfusion reaction.
The tubular necrosis is extreme, and there is considerable aimless regeneration of tubular epithelium. This patient's tubular necrosis was secondary to a transfusion reaction. The second kidney section (Fig. 2 ) is from the autopsy of a patient (No. 17 ) who died of necrotic lesions of the liver, anterior pituitary, and adrenal gland. This individual had hypotensive shock from postpartum sepsis, received one dialysis, and died 8 days later. The convoluted and collecting tubules show swelling, atrophy, and necrosis. The last patient (No. 13 ) died in the diuretic phase on the nineteenth day, and had superimposed sepsis. The acute tubular necrosis was caused by hypovolemic shock. This
woman had three dialyses. The microscopic section (Fig. 3) shows that the tubules are dilated and lined by deeply stained small cells. Tubular cells are occasionally absent or partially fragmented. Comment
Incompatible blood transfusions were the contributing cause of 42 per cent of the acute renal failure problems in this series. These accidents are preventable and chargeable to human error. They emphasize one of the constant dangers of blood transfusions. A single transfusion was ordered for each of 3 patients, and we can question the indications for or the value of a single blood trans-
Volume 67 Number 1
Hemodialysis 1n renal failure
119
Fig. 2. Kidney of patient (No. 17) who d:ed with necrotic lesions of the liver, anterior p1tmtary, adrenal gland, and kidney tubules. The convoluted and collecting tubules show swelling, atrophy, and necrosis. This patient had hypotensive shock from postpartum sepsis, received one dialysis, and died 8 days later.
fusion. The others received multiple transfusions to combat hypovolemic shock which occurred during surgery. Often the emergency call for blood adds to the confusion and error in typing or administration. If a patient has a normal blood volume before surgery, or has been properly prepared for surgery by treatment of any existent anemia, blood transfusions should not be a requirement. Most elective gynecological surgery can be performed without the aid of blood transfusions except for the prolonged radical cancer procedures. When hypovolemic shock is encountered, however, it should be treated by properly matched blood replacement. In patients with a normal preopera-
tive hematocrit, plasma may be used successfully to combat hypovolemic shock until properly checked cross-matched blood can be obtained. There is some danger in using vasopressor agents for treatment of hypovolemic shock instead of blood, since the vasopressors promote renal ischemia. Acute renal insufficiency is not a common complication of septic abortion. In a series of 201 patients admitted to our service with septic abortion over a 2 year period, only 6 (3 per cent) had renal insufficiency. 24 The alerting signs and symptoms of septic abortion with acute renal insufficiency are persistent hypotension (out of proportion to blood loss), oliguria, hematuria, jaundice, or
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September I, 1963 J, Obst. & Gyncc.
Fig. 3. Kidney of patient {No. 13) who died in the diuretic phase on the nineteenth day, and had superimposed sepsis. Acute tubular necrosis was caused by hypovolemic shock. Tubular cells are occasionally absent or partially fragmented . Some recovery of tubules is evident.
ecchymosis. Hypotension and oliguria sometimes seen with septic abortion may or may not be associated with acute tubular necrosis. If the urinary specific gravity remains 1.018 or greater, the oliguria is probably secondary to hypotension or dehydration. Correction of the hypotension with vasopressors, treatment with antibiotics, and evacuation of the infected products of conception wiil often result in a good urine excretion. When an adequate urine volume is not obtained after appropriate therapy, the patient should be considered to have acute tubular necrosis. We have noted that intravenous oxytocin preparations may produce an oliguria in the
pregnant or postpartum patient for as long as 24 hours after the discontinuation of the oxytocin infusion. Under these circumstances the urinary specific gravity remains 1.018 or greater, and the oliguria is self-limiting. After establishing the diagnosis of acute tubular necrosis, arrangements should be made for early transfer of the patient to a hemodialysis center. Transfer is recommended under the following circumstances: 1. Continued oliguria that does not respond to adequate fluid and blood replacement. 2. Progressive rise in blood urea nitrogen or in serum potassium, or a fall m C0 2 combining power.
Volume 8i 1\umbet· I
3. Electrocardiographic evidence of hyperkalemia. 4. Severe nausea and vomiting. 5. Lethargy, mental deterioration, coma, or convulsions. 6. Overhydration, particularly with associated cardiac failure. A lower mortality rate (24 per cent) in the past four years might be attributed to a number of improvements in management of these patients that have become standard practice in the kidney unit. These practices include: ( 1) early recognition of acute tubular necrosis by the attending physician, and early transfer of patients to a center equipped for their care; (2) the earlier and more frequent use of hemodialysis; (3) improved dialysis techniques and the training of a more proficient dialysis team; (4) the use of heparin regionally which has eliminated most of the bleeding complications during and after dialysis; and ( 5) better control of antibiotic and drug therapy in the oliguric patient. Summary
Twenty-six patients with acute renal insufficiency originating in gynecological or obstetrical patients have been treated with hemodialysis by the kidney unit of the University of Colorado Medical Center. In 11 of the 26 patients, acute renal failure developed as a result of incompatible blood transfusions. Ten of the individuals were referred to our hospital from the surround-
Hemodialysis m renal failure
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ing geographic area. Five more patients were referred to us with acute renal failure secondary to hypovolemic shock that occurred during elective surgery. In another 8 patients, oliguria developed because of sepsis associated with abortion or the postpartum period. Two of the patients who died of oliguria had chronic renal disease that antedated the uremia. The physiology, pathology, principles of management of acute renal failure, and the results of hemodialysis therapy were given. The mortality rate among these 26 patients was 42 per cent, a rate approximating the 50 per cent mortality cited in the literature. The mortality rate in patients with acute tubular necrosis during the past four years was 24 per cent, and this improvement has been attributed to earlier transfer to the dialysis unit, more frequent dialysis, and improved dialysis techniques. Conclusions
1. Blood transfusion reactions, sepsis, and hypovolemic shock were the primary causes of acute renal insufficiency in obstetrical and gynecological patients referred to this unit. 2. Many of the complications leading to acute tubular necrosis in this series were preventable. 3. A reduced mortality can be achieved in patients with acute tubular necrosis by proper conservative management, early transfer to a dialysis center, the appropriate and frequent use of dialysis, and proper control of sepsis.
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