Acute renal failure following cardiac surgery

Acute renal failure following cardiac surgery In a prospective 6 month study of 204 patients requiring cardiac operations, five (2.5 percent) developed acute renal failure (ARF) and five (2.5 percent) had documented renal dysfunction (RD). Preoperative left ventricular dysfunction and prolonged cardiopulmonary bypass (CPR) were important predictors of subsequent RDIARF; CPR pressure per se was not. Physiological and clinical studies in 51 selected patients studied over an 18 month period documented the effectiveness of low flow, low pressure CPR in preserving postoperative renal function. Twenty-two patients with nonazotemic postoperative courses demonstrated moderate depression of cardiac function while the glomerular filtration rate (GFR) was normal (98 ± 30 mi. Imin. 11.73 M.2) within 24 hours of operation. Seventeen high risk patients developed ARF (65 percent mortality rate) and 12 experienced severe RD without ARF (17 percent mortality). Eleven patients with ARF and JJ with RD were studied in the early postoperative period; at this time. all 22 patients demonstrated RD with equivalent severe depression of cardiac and renal function. Superposition offurther hemodynamic or toxic insults upon ischemic kidneys was usually necessary for ARF to occur.

Mark Hilberman, M.D.,* Bryan D. Myers, M.B., Ch.B., M.R.C.P.,** Brian J. Carrie, M.B., Ch.B., M.R.C.P.,** Geraldine Derby, R.N.,*** Rex L. Jamison, M.D.,** and Edward B. Stinson, M.D.,*** Stanford, Calif.

Acute renal failure (ARF) persists as a major postoperative complication following cardiac surgery and carries a grave prognosis. 1-3 The causes of this condition are several; however, primacy is usually attributed either to postoperative cardiac dysfunction'"? or to events that occur during cardiopulmonary bypass (CPB).I. 2. 6-10 Maintenance of high blood flow and near normal mean arterial pressure (MAP) during CPB is said to be important for the maintenance of renal function. 1-3. 9. 10 However, low flow, low pressure CPB is employed at our institution. This technique was developed to minimize the risk of tubing and connector failure during CPB, to minimize trauma to blood comFrom the Departments of Anesthesia, Medicine and Cardiovascular Surgery, Stanford University Medical Center, Stanford, Calif. All work was done at Stanford University Medical Center, Stanford, California. Supported in part by a grant from the National Institutes of Health, HL 21210, and by donations from Arnar-Stone Laboratories and Merck, Sharp and Dohrne, Inc. Received for publication Oct. 30, 1978. Accepted for publication Jan. 17, 1979. Address for reprints: Mark Hilberman, M.D., Department of Anesthesia, Stanford University School of Medicine, Stanford, Calif. 94305. *Department of Anesthesia. Dr. Hilberman is a Mellin Foundation Fellow. **Division of Nephrology, Department of Medicine. ***Department of Cardiovascular Surgery.

880

ponents, and to minimize bronchial collateral flow to the left ventricle (L V).11, 12 To understand postoperative ARF in our patients required additional information. We performed a prospective study to determine the incidence of ARF in our population, and the relationship of potential preoperative risk factors and operative management (particularly CPB) to the development of ARF. In addition, we performed detailed postoperative physiological studies in selected patients to quantify the immediate effects of low flow, low pressure CPB upon renal function and to clarify the relationship between depressed cardiac function and depressed renal function. Finally, we analyzed clinical data to detect important clinical events antecedent to the development of ARF. Methods and patients A. Anesthetic and CPR management. During induction and prior to CPB, patients were infused with 1 to 3 L. of lactated Ringer's solution. With the patient breathing pure oxygen, anesthesia was induced and subsequently maintained with diazepam (0.3 to 0.5 mg.lKg.), morphine sulfate (I to 2 mg.lKg.), and pancuronium bromide (0.1 to 0.2 mg.lKg.). Barbiturates were used occasionally as supplemental or alternate sedatives to diazepam. Sodium nitroprusside, chlorpromazine, or inhalation anesthetics were used to control hypertension.

0022-5223/79/060880+09$00.90/0 © 1979 The C. V. Mosby Co.

Volume 77 Number 6 June, 1979

CPB was achieved through a median sternotomy incision (with rare exceptions) with the use of a nonpulsatile system. The roller pump-bubble oxygenator system* was primed with 2 L. of lactated Ringer's solution, to which calcium, bicarbonate, and heparin were added. Heparinized blood was added to maintain the hematocrit value during CPB between 20 and 25 percent. Mannitol, 12.5 Gm., was added at the beginning of CPB and hourly thereafter. Moderate systemic hypothermia (30 to 32° C.) was usual during the first half of CPB. Myocardial preservation was achieved during aortic cross-clamping by topical hypothermia with 4° C. saline. The heart was fibrillated electrically. CPB flow was maintained between 30 and 50 ml./Kg. Occasionally, ephedrine or phenylephrine was used to increase an unusually low MAP (below 30 torr), whereas pressures above 65 torr were lowered with vasodilators or further sedation. At the end of CPB, the contents of the pump oxygenator were returned to the patient and transfusions of whole blood were given to maintain high-normal ventricular filling pressures.

B. Data coUection. Prospective data. During a 6 month period, January through June, 1977, 204 consecutive patients underwent open cardiac operations on one cardiovascular surgical service at Stanford University Hospital. These patients form the prospective risk factor group. Two patients had chronic renal failure and were excluded from the study. Preoperative data included clinical history, laboratory values, and results of cardiac catheterization. Systolic contractile motion was semiquantitatively graded from the preoperative left ventriculogram (right anterior oblique projection); normal inward motion was scored 0, and mild, moderate, or severe impairment of inward motion was scored I, 2, or 3, respectively. The sum of the anterior, apical, and inferior segment scores was the L V dysfunction score (0 to 9). During CPB the MAP was recorded every 5 minutes, whereas the CPB flow and the patient's temperature were recorded every 15 minutes. Postoperative data included serum blood urea nitrogen (BUN), creatinine, complications, and outcome. Detailed physiological and clinical data. During an 18 month period beginning in January, 1977, 51 patients from two cardiovascular surgical services were selected for detailed study. From the available population of over 1,200 cardiac operations performed in adults, 43 patients were selected for study on the basis of an estimated high risk for postoperative renal

Renal failure after cardiac surgery

dysfunction/acute renal failure (RD/ARF). Eight patients were selected for elective postoperative studies to ensure normal postoperative data. Initial criteria for high risk were based upon the available literature and included advanced age and preoperative LV dysfunction or RD. These criteria failed to predict postoperative RD/ ARF reliably; presumably, they neither estimated the repairability of the cardiac lesion nor allowed for technical difficulties encountered during the procedure. Therefore, the surgeon's decision to employ an intra-aortic balloon pump (lABP) for hemodynamic support following CPB became our primary criterion for patient selection. In addition, patients with poor postoperative cardiac performance of RD/ ARF were studied. Informed consent was obtained from all patients selected for study prior to operation. Patients who had IABP placement on an emergency basis or who demonstrated severe postoperative cardiac dysfunction or RD/ARF were studied without consent because of the relevance of the data to their management. The study protocols and consent procedures were approved by the Committee on the Use of Human Subjects in Research at Stanford. Physiological measurements were performed serially, and 42 of the 51 patients were studied within 24 hours of operation. Measurements were obtained during periods of relative hemodynamic stability; diuretic administration in the prior 6 hour period, hyperoncotic volume expansion, and changes in infusion rates of vasoactive drugs were avoided. Cardiac output determinations were performed in duplicate with indocyanine green as the indicator and a Waters* cuvette densitometer (D-400) and cardiac output computer (CO-4). Pulmonary artery and pulmonary capillary wedge pressures were measured through the quadruple-lumen Swan-Ganz thermodilution cathetert; in some patients left atrial and pulmonary artery catheters were placed at operation. Heart rate and MAP were measured by the Hewlett-Packardt bedside monitors. The following calculations were used: CI (L./min.lM.2) =

;S~

(I)

where CI = cardiac index, CO = cardiac output, and BSA = body surface area; SWI (Gm.-M.lM. 2)

=

~~

x (MAP - LAP) x 0.0 I36 (2)

where SWI = stroke work index, LAP = left atrial, *Waters Instrument Corporation, Rochester, Mich.

*Roller pump, Pempco, Inc., Cleveland, Ohio; bubble oxygenator, William Harvey Research Corp.• Santa Ana. Calif.

88 1

tEdwards Laboratories. Inc., Santa Ana, Calif. :j:Hewlett-Packard, Palo Alto, Calif.

The Journal of Thoracic and Cardiovascular Surgery

882 Hilberman et al.

pulmonary capillary wedge (PCW), or pulmonary artery diastolic pressure. Standard techniques for measuring glomerular filtration rate (GFR, clearance of inulin) and effective renal plasma flow (ERPF, clearance of para-aminohippurate [PAH]) were employed.P' P A bolus injection of PAH and inulin was followed by a sustaining infusion to achieve stable plasma concentrations of approximately I and 10 mg.zdl., respectively. Three 20 minute urine collections were performed. The bladder was completely emptied at the start and end of each collection period by flushing 60 to 120 m!. of air from a sterile syringe into the bladder through the Foley catheter and then allowing complete gravity drainage of residual urine. Blood samples were obtained at the beginning and end of each collection period. The following calculations were used: Cx

=

. Ux x V Px

(3)

-

where C = clearance; U = urine concentration; P = average plasma concentration for the collection period; V = urine flow in milliliters per minute; and x = marker being employed. A time-weighted average clearance value was calculated. Then average clearance values were normalized and expressed as milliliters per minute per 1.73 M. 2. The fractional excretion of sodium (FENa) was calculated as a guide to tubular sodium handling and an index of ARF.18-20 FENa (%)

= C Na

c,

X

100

=

UNa X Pin U in X PNa

X

100

(4)

Inulin and PAH were determined by AutoAnalyzer methods.": 22 Osmolality was measured with a Fiske* Osmometer. Sodium and potassium were determined with an IL t flame photometer. Detailed clinical data were abstracted from the medical record and encoded on daily summary sheets. Periods of hypotension, oliguria, cardiac arrhythmias, and cardiac arrests were recorded for duration and severity. Further operative procedures; daily respirator and IABP usage; fluid intake and output; daily weight; antibiotic, diuretic, and vasoactive drug usage; daily serum BUN, creatinine, sodium, and potassium values; endogenous 2 hour creatinine clearances; and all positive cultures were also recorded. These data were reviewed carefully in conjunction with the physiological *Fiske Associates, Oxbridge, Mass. tInstrumentation Laboratories, Inc., Lexington, Mass.

data to categorize individual patients and identify potentially significant interrelationships; a summary of this review was written for each patient. C. Definitions. In patients who did not have detailed studies, acute renal failure (ARF) was defined by the requirement for peritoneal dialysis or hemodialysis or by the development of anuria prior to death. When detailed individual data were available, criteria for ARF included severe azotemia (maximum postoperative BUN over 70 mg.Zdl.), isosthenuria (a urinary: plasma osmolality ratio of I), and increased fractional excretion of sodium (FENa over I percent in the absence of induced or spontaneous diuresesj'": 19 in association with depression of the GFR below 30 ml./min./1.73 M. 2. The diagnosis of renal dysfunction (RD) required: moderate azotemia (postoperative BUN 30 to 70 mg./dl.) or inulin or creatinine clearance values below 50 ml./min.!1.73 M. 2. With severe depression of these clearance values « 30 ml./ min. / I. 73 M.2), evidence of avid sodium retention (FENa < I percent) was required to diagnose RD. Patients whose indices of renal function remained superior to the criteria just defined were designated control subjects in the prospective analysis and normal subjects in the detailed analysis of physiological and clinical data. D. Data analysis. Prospective data. These data were analyzed by means of the Statistical Package for the Social Sciences (SPSS).23 The study population was dichotomized into two groups, control subjects and RD/ ARF, as previously defined. A two-tailed t test with separate variance estimates was used to test the significance of the differences observed; p < 0.05 defined statistical significance. Detailed physiological and clinical data. A set of APL24. 25 programs was implemented to manage the large volume of data. Four data entry/analysis programs were developed: I. Basic patient description: This included demographic and operative data and a summary of apparent temporal relationships and critical events in the hospital course. 2. Cardiac function data: Indices of cardiac function were derived from primary measurements of pressure and flow. 3. Renal function data: Clearance values, urine-toplasma concentration ratios, and urinary excretion values for each 20 minute clearance period were calculated from plasma and urine values for inulin, PAH, creatinine, sodium, plasma, and osmolality.

Volume 77 Number 6 June, 1979

Renal failure after cardiac surgery

883

Table I. Risk factors antecedent to ARF following cardiac surgery Eighteen-month study period

Six-month control period J: Normal controls

Number Age (yr.) History prior cardiac surgery (%) Active bacterial endocarditis (%) Admission blood urea nitrogen (mg.ldl.) Coronary artery surgery onl y (%) Preoperative cardiac status: Pulmonary capillary wedge pressure (torr) Left ventricular end-diastolic pressure (torr) Cardiac index (L./min.lM2) Left ventricular dysfunction score (0-9) Cardiopulmonary bvpass data: Flow (ml./Kg./min.> Mean arterial pressure (torr) Low mean arterial pressure (torr) Duration (min.) Aortic cross-clamp time (min.) Deaths (%)

194 57 ± 12 7 0.6 19 ± 8 52

I

2: RDIARF

3: All patients with RDIARF

10 62 ± 20 20 29 34 ± 23 20*

32 64 ± 13* 31* 26* 32 ± 20 6*

16 ± 9 16 ± 7 2.5 ± 0.7 1.5 ± 2.3

25 24 2.4 4.9

42 ± 7 49 ± 7 35 ± 19 110 ± 40 60 ± 22 0.6

54 49 33 156 73

± 5*

± 9 ± 0.9

± 4* ± 6* ± 8 ± 7 ± 46*

± 37

60*

25 19 2.25 5.7 50 50 34 159 75

± 10* ± 9

± 0.8 ± 3.4* ± 7* ± 8 ± 7 ± 62*

± 31 50*

Legend: Selected data related

10 the development and outcome of renal dysfunctionlacute renal failure (RDI ARF) are presented. These data illustrate important risk factor and cardiopulmonary bypass variables and are shown as mean ± standard deviation, except when expressed as percentages. Columns 1 and 2 contain data from the 6 month control period; column I summarizes data from 194 patients who did not have renal failure or documented RD, and column 2 summarizes data from the five patients who developed ARF and five additional patients from the control period who had detailed studies indicating severe RD (Group 2 in Table II). Column 3 presents data from 32 RD/ARF patients studied over an 18 month period. For details and analysis see text. *Data significantly different from controls in column I (p < 0.05).

4. Study description: This included data on drug administration, hemodynamic stability during the study period, and the duration of the study period. An APL summary program integrated these data elements and produced a two-page summary of the hospital course, including selected, normalized physiological data. From these summaries the patient groupings were developed and physiological data were selected for further analysis. These data were then averaged by group, and the data were compared by Student's t test for unpaired data. Variables rendered uninterpretable by therapy were deleted when indicated (e.g., FENa values> I percent following prior diuretic administration).

Results A. Prospective incidence data and risk factor analysis. The data from the 6 month prospective study are summarized in columns I and 2 of Table I. One hundred ninety-four patients were designated as control subjects since they did not demonstrate postoperative RD or ARF (column I). Five patients (2.5 percent) had ARF and five (2.5 percent) had RD. The data from these 10 cases are presented in column 2. To avoid

basing our risk factor analysis on too small a population, we added all 29 RD/ ARF patients studied over the 18 month period to three patients from the prospective 6 month period who lacked detailed studies. These form the population of 32 patients with RD/ ARF presented in column 3 and compared to the control subjects. Significant differences from the control population included greater age (64 ± 13 versus 57 ± 12 years), higher incidence of prior cardiac surgery (31 versus 7 percent), higher incidence of active bacterial endocarditis (26 versus I percent), higher preoperative BUN (32 ± 20 versus 19 ± 8 mg.Zdl.), and a lower incidence of coronary artery bypass grafting (CABG) as the sole cardiac operation (6 versus 52 percent). The preoperative pulmonary capillary wedge pressure was significantly higher in the RD/ARF patients, but the left ventricular end-diastolic pressure and the cardiac index were only slightly different. The LV dysfunction scores were significantly higher in the RD/ARF patients (5.7 ± 3.4 versus 1.5 ± 2.3). In the RD/ ARF group the average values for CBP flow were higher (50 ± 7 versus 42 ± 7 ml./Kg.J min.), but the values for average CPB MAP (50 ± 8 versus 49 ± 7 torr) and low CPB MAP (34 ± 7 versus

The Journal of

884 Hilberman et al.

Thoracic and Cardiovascular Surgery

Table II. Hemodynamic and renal function within 24 hours of cardiac surgery

Group

No.

Operation

I (Normals)

22

2 (RD)

12

3 (ARF)

17

8 MVR, with CABG (2) 2 AVR and CABG 8 CABG, with IHSS (I) 4 LVA and CABG, reop (I) 6 MVR, with reop (2), CABG (2), TAN (I) 2 reop AVR, with CABG (I) 4 LVA, with CABG (2), AVR (I), MVR (I) 5 MVR, with reop (2), TAN (2), CABG (I) 3 AVR with CABG (I) I AVR, MVR, TAN 4 LVA, with CABG (3) 4 complex cardiac reconstructions

Age (yr.)

CPB duration (min.)

Postop stay 12 ± 6 days; I death (5%)

58 ± 10

124 ± 44

18 ± 6

10/12

Postop stay 25 ± 15 days; 2 deaths (17%)

59 ± 16

135 ± 44

28 ± 20

15/17

Postop stay 32 ± 22 days; II deaths (65%)

64 ± 9

168 ± 77*

32 ± 20*

IABP

4/22

Outcome

Adm. BUN (mg. /dl.)

Maximum postop. BUN (mg./dl.)

21 ± 6

42 ± 18*

III :t 30*

Legend: Summary of data from 51 patients who had one or more detailed physiological studies performed in the postoperative period. Group I consists of 22 patients who had normal postoperative renal function; 20 had detailed physiological studies performed within 24 hours of operation. Group 2 consists of 12 patients who exhibited renal dysfunction following operation; II had detailed physiological studies performed within 24 hours of operation. Group 3 consists of 17 patients who developed acute renal failure; II had detailed physiological studies performed within 24 hours of operation. The physiological data represent average values obtained from measurements made within 24 hours of operation. Data are expressed as mean ± standard deviation where relevant. For details see text. Abbreviations: IABP, Intra-aortic balloon pump. CPB, Cardiopulmonary bypass. BUN, Blood urea nitrogen. MAP, Mean arterial pressure. PCWP, Pulmonary capillary wedge pressure. CI, Cardiac index. SWI, Stroke work index. GFR, Glomerular filtration rate, measured by the clearance of inulin. ERPF, Effective renal plasma flow, measured by the clearance of para-aminohippurate. FENa, Fractional excretion of sodium. M YR, Mitral valve replacement. CABG, Coronary artery bypass grafting. AYR, Aortic valve replacement. IHSS, Idiopathic hypertrophic subaortic stenosis (resection of). LVA, Left ventricular aneurysmectomy. TAN, Tricuspid valvular annuloplasty. Reop, A second or subsequent cardiac operation. *p < 0.05 in comparison to normal subjects (Group I).

to.i > P > 0.05.

35 ± 19 torr) were similar. Most striking was the significantly longer average duration of CPB observed in the RD/ ARF population (159 ± 62 versus 110 ± 40 minutes). Urine flow during CPB usually fell to zero initially and then increased; average urine flow was not different between the groups (I. 3 ± I. 2 versus 1.4 ± 0.9 ml./min.). The average rectal temperature for all 204 patients during CPB was 33.8 ± 1.3° C. and was not statistically different between the groups. Finally, the in-hospital mortality rate was 50 percent in the 32 RD/ARF patients, in contrast to a rate below 1 percent in the control group. B. Detailed physiological data. The 51 patients studied in detail were classified into three groups (Table II). Twenty-two patients with nonazotemic postoperative courses, including the eight patients studied electively (Group I-normal subjects); 12 patients who exhibited RD (Group 2); and 17 patients who had ARF (Group 3). Only physiological measurements performed within 24 hours of operation were averaged in Table II. Four of the 22 normal subjects required IABP support in the postoperative period, and none had active

endocarditis. The average postoperative stay was 12 ± 6 days. One death (4.5 percent) occurred due to erosion of the LV by a mitral valve prosthesis. Fourteen of these 22 patients were selected for study on the basis of an estimated high risk for developing postoperative ARF. Nonetheless, age (58 ± 10 years), CPB MAP (49 ± 6 torr), preoperative BUN (18 ± 6 mg./ dl.), and the maximum postoperative BUN (21 ± 6 mg.rdl.) were all similar to their respective values in the control patients (column 1, Table I). The percentage of patients undergoing CABG only (36 percent) was less than the percentage of control subjects and the duration of CPB (124 ± 44 minutes) was longer, but these differences were not statistically significant. Twenty had physiological studies performed within 24 hours of operation; the average MAP at the time of study was 82 ± 9 torr, pulmonary capillary wedge pressure was 18 ± 4 torr, cardiac index was 2.6 ± 0.5 L. /M. 2, and stroke work index was 23 ± 8 Gm.-M./M2. On an age-adjusted basis, the mean GFR 26( P 99) was within normal limits, 98 ± 30 ml./ min.! I. 73 M.2, despite a 30 percent depression of ERPF 26(P 98) to 382 ± 94 ml./min./1.73 M. 2. As a re-

Volume 77 Number 6 June, 1979

Renal failure after cardiac surgery

885

Results offirst postop. studies performed within 24 hr. of operation CI (L./

MAP (torr)

min.LMs?

SW/(Gm.M./M.2

GRF (ml./ min/J.73 M.2)

ERPF (ml./ min/J.73 M. 2)

Filtration fraction

FENa (%)

82 ± 9

18 ± 4

2.6 ± 0.5

23 ± 8

98 ± 30

382 ± 94

0.28 ± 0.07

0.48 ± 0.7

77 ± 8

20 ± 5

2.1 ± 0.6*

17 ± 7*

45 ± 21*

162 ± 89*

0.32 ± 0.17

0.35 ± 0.3

75 ± 7t

28 ± 8*

2.2 ± 0.6t

15 ± 6*

36 ± 25*

128 ± 76*

0.29 ± O.ll

0.61 ± 0.8

suit, the filtration was elevated to 0.29 ± 0.06 (normal approximately 0.20 26( P 90). FENa was 0.48 ± 0.7 percent, indicating sodium retention consistent with poor cardiac function and the postoperative state. In the 12 patients who evidenced RD, the operations were more complex than in the normal subjects and 10 patients required IABP support. The average hospitalization was longer than in Group 1,25 ± 15 days, and two patients died (17 percent). Four were treated with aminoglycoside antibiotics. The age (59 ± 16 years), average duration of CPB (135 ± 44 minutes), and average CPB MAP (52 ± 8 torr) were similar in Groups I and 2; but the average BUN on admission was higher in Group 2 (29 ± 20 mg.Zdl.). Eleven of the 12 had physiological studies performed within 24 hours of operation. In comparison to values in Group I patients, average MAP (77 ± 8 torr) and pulmonary capillary wedge pressure (20 ± 5 torr) were not statistically different, but cardiac index (2.1 ± 0.6 L./min./M. 2) and stroke work index (17 ± 7 Gm.-M./M.2) were significantly more depressed. This depression of cardiac performance was associated with marked depression of GFR (45 ± 21 ml./min./1.73 M. 2) and ERPF (162 ± 89 ml./min.l1.73 M.2). The filtration fraction remained elevated (0.32 ± 0.17) and the FENa remained below 1 percent. Those 17 patients who hadARF underwent still more complex operations. Fifteen required IABP support, the average postoperative stay was 32 ± 22 days, and II patients died (65 percent). Three patients had preoperative sepsis and nine had postoperative sepsis.

Seven patients were treated with aminoglycoside antibiotics. Age (63 ± 10 years), admission BUN (34 ± 21 mg.Zdl.), maximum postoperative BUN (101 ± 35 mg./dl.), and the duration of CPB (167 ± 47 minutes) were significantly greater than in Group I. The average CPB MAP (48 ± 8 torr) was not different. Eleven had physiological studies performed within 24 hours of operation. In comparison to values in Group I patients, the average MAP (75 ± 7 torr), pulmonary capillary wedge pressure (28 ± 8 torr), cardiac index (2.2 ± 0.6 L./min.lM.2), stroke work index (15 ± 6 Gm.-M.lM. 2), GFR (36 ± 25 ml./ min./1.73 M. 2), and ERPF (128 ± 76 ml./min./1.73 M. 2) all reflect significant depression of cardiac and renal function. That FENa remained below I percent suggests persistence of normal tubular function in the early postoperative period. The pulmonary capillary wedge pressure, maximum postoperative BUN, and death rate were the only variables that were significantly different when patients with ARF (Group 3) were compared with patients with RD (Group 2). C. Clinical analysis. Detailed correlation of physiological and clinical data in the 17 Group 3 patients lead to the definition of four groups of patients in whom: (A) ARF developed in the immediate preoperative or operative period; (B) ARF resulted from a progressive low cardiac output syndrome; (C) ARF followed withdrawal of mechanical or pharmacological circulatory support; and (D) ARF developed secondary to discrete hypotensive insult(s). Group 3-A (jour patients, one survivor). One sep-

The Journal of Thoracic and Cardiovascular Surgery

886 Hilberman et al.

tuagenarian, who had severe cardiac distress and RD, became anuric following preoperative angiography. The other three had preoperative septicemia. One of these patients had a cardiac arrest preoperatively and ARF ensured. In another RD developed following preoperative streptomycin therapy, and ARF followed a 51,4 hour CPB (this patient also had had ARF following a previous cardiac operation). The fourth patient was moribund and in ARF at the time of operation but demonstrated a dramatic recovery beginning on postoperative day 4. Group 3-B (three patients, no survivors). All three evidenced an unrelenting low cardiac output syndrome postoperati vely. In one, autops y demonstrated that an acute aortic dissection from the site of IABP insertion had occluded the renal arteries and complicated already established RD associated with extremely depressed cardiac function (cardiac index = 1.7 L./min./M. 2, stroke work index = 7 Gm.-M./M. 2). In the second patient, 3 hours of CPB and prophylactic gentamicin therapy probably added to the effects of extreme cardiac depression to cause ARF (cardiac index = 1.7 L./min./M. 2 and stroke work index = 9 Gm.-M./ M.2). In the third patient a sustained low output state, following an extensive left ventricular aneurysmectomy, was the evident proximate cause of ARF (cardiac index = 1.2 L./min./M.2 and stroke work index = 8.5 Gm.-M./M. 2 on the sixth postoperative day). Group 3-C (seven patients, three survivors). These seven patients appeared to progress to ARF following withdrawal of circulatory support. ARF developed on postoperative days I, 4, 6, 6, 7, 8, and I I. Two patients had low GFR's and progressive azotemia; they initially were categorized in Group 3-B. In both, however, a GFR previously stable in the range of 20 to 30 ml./min./ 1.73 M. 2 decreased an additional 30 to 50 percent following IABP removal, at which time the FENa also rose (initial FENa's less than 0.2 percent, increased to over 2 percent). One patient had mildly depressed renal function until withdrawal of IABP support, at which time ARF developed. One patient evidenced a drop in GFR to 17 ml./min./ 1.73 M. 2 on postoperative day 2, at which time the FENa was 0.05 percent. This patient's MAP was increased by the addition of an epinephrine infusion at 22 ng./Kg./min., and over the next 3 days the GFR increased steadily to 50 ml./min./1.73 M. 2. A cardiac arrest occurred after removal of IABP, and ARF developed over the subsequent 48 hours. Another patient had septicemia and gentamicin therapy superimposed on withdrawal of circulatory support, with subsequent development of ARF. Still another patient in whom ARF developed

following withdrawal of IABP support recovered from the initial episode of ARF but demonstrated a secondary depression of renal function concurrent with gentamicin administration. One patient with preoperative RD and severe LV failure, underwent an uncomplicated operation, but ARF followed early withdrawal (postoperative day I) of inotropic support. Group 3-D (three patients, two survivors). These three patients had major hypotensive crises prior to the development of ARF. One patient sustained hypotension and oliguria for several hours prior to diagnosis and treatment of a silent hemorrhage into the left pleural space. This episode, late in postoperative day 2, was followed by ARF. The second patient had dehiscence of the ventriculotomy suture line following left ventricular aneurysmectomy. After resuscitation and repair, the patient appeared to have adequate renal function (GFR 64 ml./min./ 1.73 M. 2 and FENa 0.09 percent). Over the next 2 days ARF developed in association with continued depression of hemodynamic status and high-dose epinephrine infusions. This episode of ARF resolved, but secondary and tertiary depressions of renal function followed gentamicin administration and recurrent sepsis, respectively. The last patient had recurrent bleeding, with two periods of hypovolemia and oliguria, after aortic and mitral valve replacement, tricuspid valvular annuloplasty, and reconstruction of the aortic root. The prolonged surgical procedure and two hypotensive insults seem sufficient to explain the subsequent ARF.

Discussion The results presented herein permit the following conclusions: low flow, low pressure CPB usually provides satisfactory preservation of renal function during operative procedures; severe depression of postoperative cardiac function with resultant renal ischemia is the critical common denominator present in patients in whom ARF develops; finally, the pathogenesis of ARF appears multifactorial, dependent upon superposition of additional renal insults upon ischemic kidneys. The average CPB MAP approximated 50 torr with a CPB flow of 42 ml./Kg./min. In the prospective study period, the mortality rate was low, 3.5 percent, and the incidence of ARF (2.5 percent) and RD (2.5 percent) in these patients is lower than that previously reported. 1-4. 6-9 If the two ARF patients who had anuria prior to death during the first 24 postoperative hours are excluded, the incidence of ARF would have been 1.5 percent. That the incidence of ARF in this relatively small patient sample is low reflects improving techniques. In a retrospective review of 1,962 patients who

Volume 77

Renal failure after cardiac surgery

Number 6 June, 1979

underwent heterograft valve replacement at our institutions between 1964 and 1976, the incidence of ARF was 3.4 percent and the mortality rate was 9 percent (unpublished data, available upon request). The most recent data we have seen in the literature include the retrospective review, by Bhat and associates, 1 of 528 patients operated upon during 1972. They excluded 23 patients with preoperative RD and 15 patients (2.8 percent) who died during the first 24 postoperative hours. Of the 490 remaining patients, 35 percent underwent CABG, 12 percent developed significant RD, 4.3 percent developed ARF, and 8.5 percent died. Able and associates! reported a prospective study of 538 patients having cardiac operations during 1974. Thirty-five early deaths were excluded (7 percent); of the remaining 503 patients, 40 percent underwent CABG, 3.4 percent developed significant RD, 3.6 percent developed ARF, and an additional 6.8 percent died. The recent reports by McLeish and co-workers'" (!.6 percent ARF, 9.6 percent mortality rate) and Krian" (5 percent ARF) are difficult to compare to our data because of the long duration of their reported experience and the marked differences in definitions and selection criteria. The conclusion that postoperative renal function is adequately preserved by our CPB technique is further supported by the measurements of renal function made in our normal subjects (Group I, Table II). As noted previously (Results, Section B), these normal subjects were similar to our control population, and hence to our over-all population. In prior studies, in apparently comparable patients, GFR 5 • 6. 17 was depressed to 65 mUmin.!!.73 M. 2, and ERPf5· 17 was depressed to approximately 220 to 300 mUmin./!.73 M. 2, compared to 98 ± 30 and 382 ± 94 mUmin.!!.73 M. 2, respectively, in our study. Many differences in operative and postoperative management preclude attributing the superior early postoperative renal function observed in our patients to low flow, low pressure CPB. Nevertheless, our data indicate that the emphasis upon maintenance of high CPB pressures and flows to preserve renal function'r" 9. 10 cannot be universally substantiated. The magnitude of preoperative LV dysfunction was a valuable predictor of postoperative RDI ARF. Presumably, depressed preoperative L V function presages depressed postoperative LV function, a critically important feature in the development of ARF. 2-6 Long CPB times are a risk factor emphasized by others': 2.6-9 and confirmed by our studies. We believe this reflects both a direct deleterious effect of prolonged nonpulsatile CPB and an association between complex, pro-

887

longed surgical procedures and depression of postoperative cardiac performance. The predictive importance of a history of prior cardiac surgery, active bacterial endocarditis, and the low incidence of only CABG in the RDI ARF patients probably reflect the latter association. The mortality rate in patients with ARF was 65 percent, a result not different from that previously reported. 1-4. 7. 9. 28 That 15 of these 17 patients had nonoliguric ARF indicates that postoperative nonoliguric ARF may be as lethal as oliguric ARF, in contrast to other somewhat more benign forms of nonoliguric ARF.29 Many of our ARF patients would not have survived even the immediate postoperative period a few years ago, because of the severity of their cardiac disease and the magnitude of complications. Thus the persistence of ARF with its attendant high mortality rate appears related to increasing severity of illness, as has been suggested previously by Stott and asso-

ciates." The striking similarity in early postoperative hemodynamic and renal function between RD patients and ARF patients (Table II) suggests that depressed hemodynamic function per se usually is not sufficient to cause progression of RD to ARF. The paramount importance of secondary insults, which usually occurred in idiosyncratic combinations, is further emphasized by the clinical data. Despite their early similarity, ARF patients had a 65 percent mortality rate, whereas RD patients had a 17 percent mortality rate. Therefore, an important route to reducing mortality rate lies in avoiding the progression from RD to ARF. The nature of the clinical events preceding ARF suggests this objective may be achievable, even in these extremely ill patients. We gratefully acknowledge the assistance of Mr. Ryan Yee and Mrs. Helen Golbetz , who performed the critical laboratory measurements. The risk factor data were collected by Ronald D. Kolkka, M.D., Raymond C. Stofer, D. V.M., and perfusionists Steve Baker, Eke Chang, Alan Fujihara, Bernice Gerbo, Louise Hogan, Karen Logan, Virginia Martorell , Mary Ann Overton, and Dave Rowland. We thank, too, Drs. N. E. Shumway and P. E. Oyer, who allowed us to study their patients. Robin Spencer, Betty Estes, Virginia Perondi , and Kathleen A. Orth provided invaluable assistance. REFERENCES Bhat JG, Gluck M, Lowenstein J, Baldwin DS: Renal failure after open heart surgery. Ann Intem Med 84:677682, 1976 2 Abel RM, Buckley MJ, Austen WG. Barnett GO, Beck CH Jr, Fischer JE: Etiology, incidence, and prognosis of renal failure following cardiac operations. J THORAC CARDIOVASC SURG 71:323-333, 1976

888 Hilberman et al.

The Journal of Thoracic and Cardiovascular Surgery

3 Krian A: Incidence, prevention and treatment of acute renal failure following cardiopulmonary bypass. Intemat Anesth C1in 14:87-101, 1976 4 Dobemak RD, Reiser MP, Lillehie CW: Acute renal failure after open-heart surgery utilizing extracorporeal circulation and total body perfusion. Analysis of 1000 patients. J THoRAc CARDIOVASC SURG 43:441-452, 1962 5 Mielke JE, Maher rr, Hunt JC, Kirklin JW: Renal performance in patients undergoing replacement of the aortic valve. Circulation 32:394-405, 1965 6 Porter GA, Kloster FE, Herr RJ, Starr A, Griswold HE. Kimsey J, Lenertz H: Relationship between alterations in renal hemodynamics during cardiopulmonary bypass and postoperative renal function. Circulation 39: 1005- 1021, 1966 7 Porter GA, Starr A: Management of postoperative renal failure following cardiovascular surgery. Surgery 65:390-398, 1968 8 Porter GA, Kloster FE, Herr RJ. Starr A, Griswold HE, Kimsey J: Renal complications associated with valve replacement surgery. J THoRAc CARDIOV ASC SURG 53: 145-152, 1967 9 Yeboah ED, Petrie A, Pead JL: Acute renal failure and open heart surgery. Br Med J 1:415-418, 1972 10 Senning A, Andres J, Bomstein P, Norberg B, Nadersen MN: Renal function during extracorporeal circulation at high and low flow rates. Experimental studies in dogs. Ann Surg 151:63-70, 1960 II Stofer RC: Technique for Extracorporeal Circulation, Springfield, 111., 1968, Charles C Thomas, Publisher 12 Reitz BA, Baumgartner WA, Stinson EB: Myocardial protection by topical hypothermia, Current Techniques in Extracorporeal Circulation, ed 2, MI lonescu, GH Woolner, eds. London, 1979, Butterworth & Co., Ltd. 13 Smith HW, Finkelstein N. Aliminosa L, Crawford B, Graber M: The renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man. J C1in Invest 24:388-404, 1945 14 Smith HW: Principles of Renal Physiology. New York, 1956, Oxford University Press 15 Renkin EM, Robinson RR: Glomerular filtration. N Engl J Med 290:785-792, 1974

16 Levinsky NG, Levy M: Clearance techniques, Handbook of Physiology, Vol 8, Renal Physiology. Chap 4. J Orloff, RW Berliner, eds., Washington, D. C., 1973, American Physiological Society, pp 103-118 17 Lundberg S: Renal function during anesthesia and openheart surgery in man. Acta Anaesth Scand (Suppl) 27:182, 1967 18 Espinel CH: The FEN a test. JAMA 236:579-581. 1976 19 Miller TR, Anderson RJ, Linas SL, Henrich WL. Berns AS, Gabow PA, Schrier RW: Urinary diagnostic indices in acute renal failure. Ann Intern Med 89:47-50, 1978 20 Bricker NS, Bourgoignie JJ, Weber H: The Renal Response to Progressive Nephron Loss, The Kidney, BM Brener, FC Rector Jr, eds., Philadelphia, 1976, W. B. Saunders Company, pp 703-736 21 Fjeldbo W, Stamey TA: Adapted method for determination of inulin in serum and urine with an AutoAnalyzer. J Lab C1in Med 72:353-358, 1968 22 Harvey RB, Brothers AJ: Renal extraction of paraaminohippurate and creatinine measured by continuous in vivo sampling of arterial and renal-vein blood. Ann NY Acad Sci 102:46-54, 1962 23 Nie NH, Hull CH, Jenkins JG. Steinbrenner K, Bent DH: SPSS-Statistical Package for the Social Sciences, New York, 1975, McGraw-Hili Book Company, Inc. 24 Iverson KE: A Programming Language. New York, 1962, John Wiley & Sons, Inc. 25 Gilman L, Rose AJ: APL. An Interactive Approach, New York, 1976, John Wiley & Sons, Inc. 26 Wesson LG: Physiology of the Human Kidney, New York, 1969, Grune & Stratton, Inc. 27 McLeish KR, Luft FC, Kleit SA: Factors affecting prognosis in acute renal failure following cardiac operations. Surg Gynecol Obstet 145:28-32, 1977 28 Stott RB, Ogg CS, Camerson JS, Bewick M: Why the persistently high mortality in acute renal failure. Lancet 2:75-79, 1972 29 Anderson RJ, Linas SL, Berns AS, Henrich WL, Miller TR, Gabow PA, Schrier RW: Nonoliguric acute renal failure. N Engl J Med 296: 1134-1138, 1977