Renal Function in Children Undergoing Cardiac Operations

Renal Function in Children Undergoing Cardiac Operations Eileen N. Ellis, M.D., Ben H. Brouhard, M.D., and Vincent R. Conti, M.D. ABSTRACT Because we sometimes observed large amounts of uric acid crystals in the urine of infants and children after open-heart operations and since renal insufficiency from any cause can be a serious complication of cardiac procedures, 8 acyanotic and 5 cyanotic children were studied prospectively by comparing several preoperative and postoperative measures of renal function. There were no significant differences between the acyanotic and cyanotic groups in terms of age, time on cardiopulmonary bypass, or other preoperative variables. Postoperatively, children in both groups had a wide range of free water clearances (CH,0), with some values in the range reported to be diagnostic of renal insufficiency in adults. Since none of these children had renal insufficiency by other criteria, CH,0 may not be as reliable an indicator of renal insufficiency in children. The major difference between the cyanotic and acyanotic groups was seen in postoperative serum uric acid levels (SuA); the mean S,, levels in the acyanotic and cyanotic groups were 5.3? 0.5 mg/dl ( c standard error of the mean) and 10.4? 1.7 mg/dl (range, 8.0 to 15.5 mg/dl), respectively. Since the hyperuricemia in the cyanotic children could not be related to increased exogenous administration or decreased renal excretion, it is probably caused by increased endogenous production and may be related to the resolution of the cyanotic state. Although severe renal impairment after openheart operations occurs infrequently today, this serious complication has in the past been reported in up to 30% of adult patients [l-31, with a mortality of 27 to 89% in patients developing moderate to severe renal insufficiency [l-51. Acute renal failure has also been noted to be a serious complication of cardiac operations in in- From the Departments of Pediatrics and Surgery, University of Texas Medical Branch, Galveston, TX. Accepted for publication Oct 3, 1982. Address reprint requests to Dr. Brouhard, Division of Pediatric Nephrology, University of Texas Medical Branch, Galveston, TX 77550. fants [6, 71 and may occur more frequently in this age group than in the adult population. In an attempt to predict those patients who are at risk for renal failure, some investigators have found abnormal free water clearance (CHLO) to be an early sign of renal insufficiency in adult patients [8-121. Other investigators have evaluated glomerular filtration rate, renal plasma flow, body water and muscle composition changes, and plasma electrolytes in children [13, 141 and in adults [15] undergoing cardiac operations. Though we have frequently observed large amounts of uric acid crystals in the urine of infants and children after open-heart procedures, no previous reports have discussed uric acid metabolism in patients undergoing cardiac operations. Because of our observations and since renal dysfunction is a serious potential complication of cardiac surgery, a prospective study was designed to investigate renal function preoperatively and postoperatively in children undergoing cardiac operations, with particular attention to renal tubular function and uric acid metabolism. Patients and Methods Clinical Data Children admitted consecutively to our institution for cardiac operations were identified by the cardiovascular surgery service and enlisted in the study after informed consent was obtained. The protocol was approved by the Institutional Review Board, University of Texas Medical Branch. Age, height, diagnosis, and medications were recorded. Preoperatively, blood was drawn from each child for measurement of levels of serum sodium, potassium, osmolality, uric acid, phosphorus, creatinine, and hematocrit. A timed six-hour urine collection was also obtained for measurement of levels of sodium, potassium, osmolality, uric acid, phosphorus, and creatinine. A cardiac operation was performed in each 167

168 The Annals of Thoracic Surgery Vol 36 No 2 August 1983 child using cardiopulmonary bypass with a bubble oxygenator at a flow rate of 2.2 to 2.8 liters per minute per square meter of body surface area along with systemic hypothermia and ischemic cardiac arrest with cold cardioplegic solution. Time on bypass and plasma hemoglobin levels before and after bypass were noted. During the night after the surgical procedure, each child received 500 mum2 of 5% dextrose in water with 10 meq of potassium chloride per square meter of body surface area. On the first and second postoperative days, each child received 750 ml/m2/24 hours of 5% dextrose in water with 10 meq of KC1 per square meter of body surface area every 24 hours. On the first postoperative day, inulin and paraaminohippurate clearances were performed by standard clearance techniques [16]. Sodium, potassium, osmolality, phosphorus, uric acid, and creatinine levels were measured for each of the blood and urine specimens obtained during the clearance study. Hematocrit on the first postoperative day was also recorded. Additionally, serial six-hour urine specimens were collected from 4 of the children throughout the second postoperative day; uric acid was measured in each of these specimens. Measurement Techniques Urine and serum creatinine levels were measured by the Beckman Creatinine Analyzer 11. Urine and serum sodium and potassium levels were measured by a flame photometer with lithium as an internal standard. Serum and urine osmolality levels were measured by freezing point depression on the Precision Osmette A Osmometer (Precision Systems, Waltham, MA). Urine and serum phosphorus levels were measured by the Hycel phosphorus test (Hycel, Inc., Houston, TX). Serum and urine uric acid levels were measured by the Stanbio phospholithotungstic acid test (Stanbio Laboratory, Inc., San Antonio, TX). Calcu la t ions Clearances of creatinine (Ccr), inulin (C,J, paraaminohippurate (C,,,), and uric acid (C,,), as well as osmolar clearance (C,,,), were all calculated using this standard formula: Clearance = U, x V/S, where U, is urine concentration of the substance, V is urine volume in milliliters per minute, and S, is serum concentration. Each clearance calculation was corrected for body surface area and expressed as milliliters per minute per square meter of body surface area. The fractional excretions of sodium (FEN,), potassium (FEK), and uric acid (FE,,) were calculated in the following manner: where x is Na, K, or UA. Free water clearance (CHZO) was calculated by the following formula: and expressed as milliliters per minute. Results Thirteen patients were studied; 8 had acyanotic lesions while 5 were cyanotic. The mean age of the acyanotic children was 5.9 * 1.1 years (standard error of the mean), which was not significantly different from the mean age of 5.6? 1.7 years in the cyanotic group. The age and diagnosis of each child are shown in Table 1. Time on cardiopulmonary bypass was similar in both groups, with a mean of 103 f 18 minutes in the acyanotic group and 141 k 17 minutes in the cyanotic group. There were no significant differences between the cyanotic and acyanotic groups in preoperative values for serum creatinine, sodium, potassium, uric acid, phosphorus, osmolality, plasma hemoglobin, Ccr, Cosm, CH,O, FEN^, FEK, FEU, C, and urinary levels of uric acid or phosphorus. Mean preoperative and postoperative values for all patients are listed in Table 2. Significant differences between preoperative and postoperative values were noted for plasma hemoglobin, serum phosphorus, S, C,,, FEK, urinary levels of uric acid, and urinary levels of phosphorus. Postoperative free water clearance in all patients showed wide variation, with a range of + 28.4 to - 13.2 mumin. When the acyanotic and cyanotic groups were compared, the major difference noted was in S, values; the mean postoperative level was 5.3 t

169 Ellis, Brouhard, and Conti Renal Function in Children Undergoing Cardiac Operations Table 1. Age and Diagnosis of Children Included in the Study (N = 13) ACYANOTIC PATIENTS 3 3 5 5 5 6 7 13 CYANOTIC PATIENTS Complete AV canal with pulmonary artery banding Atrial septal defect VSD Mitral valve insufficiency following complete AV canal repair VSD with pulmonary artery banding TOF Prosthetic mitral valve stenosis and tricuspid valve incompetence Aortic and mitral valve insufficiency 2 TOF 4 TOF and peripheral pulmonic stenosis 5 TOF with Blalock-Taussig shunt 5 Tricuspid atresia with Blalock-Taussig shunt 12 Pulmonarv atresia and VSD AV = atrioventricular; VSD = ventricular septal defect; TOF = tetralogy of Fallot. 0.5 mg/dl in the acyanotic group and 10.4 2 1.7 mg/dl in the cyanotic group (Table 3). The range of postoperative levels was from 2.8 to 7.6 mg/dl in the acyanotic group and from 8.0 to 15.5 mg/dl in the cyanotic group. In the cyanotic children, all preoperative S,, values were within the normal range while all postoperative values were greater than the normal range [17, 181 (Fig 1). In 4 of the cyanotic children, serial urinary uric acid excretion (in milligrams per hour) was also measured (Fig 2). Uric acid excretion was greatest on the first postoperative day (during the clearance studies) and then progressively diminished. Visible, pink uric acid crystals were deposited on the tubing of the urinary catheters of 3 of the 5 cyanotic children on the first postoperative day. Hematocrit values in the cyanotic children markedly decreased from a mean of 55.7 k 1.9% preoperatively to a mean of 38.8 k 2.9% postoperatively. There was no correlation between preoperative hematocrit and postoperative S,, values. Comment This study investigated renal function variables preoperatively and postoperatively in cyanotic and acyanotic children undergoing cardiac operations. Although renal insufficiency did not develop to any degree in any of these children, certain changes in renal function were demonstrated postoperatively. Free water clearance has been recommended as an early indicator of renal insufficiency in postoperative adult patients, with a value of -20 mllhr (-0.33 mll min) or greater indicating renal dysfunction [8-121. Even though several of the children in both of our groups demonstrate CH,O values more positive than -20 mlhr, none had renal insufficiency. Thus, it appears that CH,O values reported to be diagnostic of renal failure in adults are not applicable to children. Perhaps if CH,O values in both adults and children were corrected for surface area they might be comparable, but these data are not available from the reported adult values. The cyanotic and acyanotic children in this study were quite comparable; there were no significant differences in age, time on cardiopulmonary bypass, or in the renal function variables studied preoperatively. Postoperatively, the two groups also showed similar changes: increases in plasma hemoglobin, C,,, FEK, uric acid excretion, and urinary phosphorus excretion, and a decrease in serum phosphorus. Although postoperative serum phosphorus decreased significantly in all patients, values remained in the normal range. The observed decrease may be accounted for by increased phosphaturia. Hyperphosphaturia can, in turn, be related to the saline loading and consequent increase in extracellular volume that occur during cardiopulmonary bypass [ 191. Increased uric acid excretion was noted in all patients as well; the mechanism for this increase and the hyperphosphaturia may be similar [19]. The only significant difference between the cyanotic and acyanotic groups was in postoperative SuA. All children had normal S,, values preoperatively. All but 1 child in the acyanotic group had normal values postoperatively, and this child's S,, level was only slightly above the

170 The Annals of Thoracic Surgery Vol 36 No 2 August 1983 Table 2. Measurement of Renal Function in 23 Children Undergoing Cardiac Operations" Variable Preop. Postop. Plasma hemoglobin Serum sodium (meq/l) Serum potassium (meq/l) Serum creatinine (mgw Serum osmolality (mosm/l) 5.9? 1.9b 139 t 1 4.3 t 0.1 0.5 t 0.1 298 t 3 28.0? 4.3b 137 t 1 4.3? 0.2 0.5 t 0 298 t 6 Serum phosphorus Serum uric acid 5.3 t 0.4b 4.2 & 0.4' 3.7 t 0.2b 7.3 t 1.0' Creatinine clearance 57.7 t 10.2 84.6 t 8.2 Inulin clearance... 64.1 t 5.0 "Values shown are mean 2 standard error of the mean. bsignificance: p < 0.005. 'Significance: p < 0.05. dsignificance: p < 0.02. 'Significance: p < 0.001. PAH = paraaminohippurate. Variable Preop. Postop. PAH clearance Osmolar clearance (ml/min) Free water clearance (ml/min) Uric acid clearance Fractional excretion of sodium (%) Fractional excretion of potassium (%) Fractional excretion of uric acid (%) Urinary uric acid (mgm Urinary phosphorus... 0.64 t 0.13-0.26 2 0.09 5.5 t 1.3d 0.8 t 0.2 10.0 t 1.6' 11.8 t 3.2 10.3 t 2.2' 10.2 t 2.1' 459 t 61 3.12 t 1.17-0.80 t 0.90 10.3 f l.zd 1.4 t 0.3 20.8 t 4.2' 10.4 t 1.7 29.1 t 4.9' 52.6 t 8.8' (mg/hr) Table 3. Measurement of Renal Function in Acyanotic and Cyanotic Children Undergoing Cardiac Operations" Acyanotic Cyanotic (N = 8) (N = 5) Variable Preop. Postop. Preop. Postop. Serum uric acid 4.5 t 0.5 5.3 t 0.5 3.9 t 0.7b 10.4 t 1.7b Serum phosphorus 5.4 t 0.6' 3.7 t 0.2' 5.2 t 0.2d 3.9 * 0.6d (mgidl) Fractional excretion 9.1 t 0.8 12.3? 2.2 16.5 t 8.9 8.6 t 2.2 of uric acid (%) Uric acid clearance 5.5 t 1.7' 10.4 t 2.0' 5.6 t 2.5 7.7 t 1.8 Urinary uric acid 7.5 t 2.1' 23.8 t 5.8' 16.2 t 3.8 37.78 t 8.0 (mg/hr) Urinary phosphorus 10.7 t 2.9' 56.1 t 12.6f 9.5 * 3.4 46.5 +- 11.9 (mg/hr) Hematocrit (%)...... 55.7 t 1.9 38.8 t 2.9 "Values shown are mean 2 standard error of the mean. bsignificance: p < 0.02. 'Significance: p < 0.05. dsignificance: p < 0.1. 'significance: p < 0.01. %ignificance: p < 0.005.

171 Ellis, Brouhard, and Conti Renal Function in Children Undergoing Cardiac Operations 160 1 1401 0 1. - - Pre-operative 60-50 - i Post -operative Fig 1. Preoperative and postoperative serum uric acid (SUA) values in cyanotic patients. Adult normal range is considered to be 2.5 to 7.0 mgldl in our laboratory. Normal values for children have been reported to be 2.6 to 4.4 mgldl[17] and 4.0? 1.5 mgldl (standard deviation) 1181. 6 hrs 6 hrs 6 hrs Post-op POD1 POD2 study 6 hrs 6 hrs Fig 2. Urinary uric acid (UUA) excretion in cyanotic patients. (POD = postoperative day.) normal range. In contrast, all the cyanotic children had elevated S,, values postoperatively. Serial urinary uric acid values in these children demonstrate a sharp rise in uric acid excretion early,in the first postoperative day subsiding toward preoperative values later that same day. The cause of this marked rise in S,, levels following cardiac operations in cyanotic children is not fully known. Hyperuricemia in indi- viduals without inherited enzyme deficiencies can result from several mechanisms, including increased exogenous administration, increased endogenous production, and decreased renal excretion [19]. Woolliscroft and co-workers [20] have estimated that in an adult a rise of only 2.5 mg/dl per day in S, level could be accounted for by changes in excretion of uric acid. None of the cyanotic children developed even mild renal dysfunction, and the rise in S, level was certainly greater than 2.5 mg/dl per day in each child. Additionally, renal function was similar in both the cyanotic and acyanotic groups, but hyperuricemia developed only in the cyanotic children. Thus, changes in renal function cannot account for the increase in s,, level in the cyanotic children. Similarly, none of the cyanotic or acyanotic children received an increased exogenous load of uric acid preoperatively or on the day of operation. Clearly, the hyperuricemia in the cyanotic children must result from increased endogenous production, which, in turn, appears to be related to the resolution of the cyanotic state. Hyperuricemia, or gout, or both conditions have been reported in patients with polycythemia Vera and other myeloproliferative disorders; overproduction of uric acid has been stated to be the cause [21]. At least one adult has also been reported to have gout secondary to the polycythemia associated with congenital heart disease [21]. Hyperuricemia and occasional gout have also been reported in sickle cell anemia and are thought to be related to increased erythropoiesis [22, 231. Thus, the hyperuricemia seen after resolution of the cyanotic state in children with cyanotic congenital heart disease may be related to preoperative polycythemia followed postoperatively by improved oxygenation and the breakdown of unneeded erythrocyte precursors. Despite the fact that the cause is uncertain, the hyperuricemia seen postoperatively in cyanotic patients may result in urate deposits in the kidneys and consequently could cause acute renal insufficiency and contribute to morbidity and mortality following cardiac operations. Thus, although we did not observe any compromise in renal function in our patients, it may be important during the postoperative course to

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