The Impact of Fluid Therapy Strategies on Nonoliguric Hyperkalemia in Extremely Low Birth Weight Infants

Original Article

Neonatal Med 2013 November;21(1):28-37 http://dx.doi.org/10.5385/nm.2014.21.1.28 pISSN 2287-9412 . eISSN 2287-9803

Min Young Kim, M.D., Eun Jae Chang, M.D., Young Hye Kim, M.D.*, Woo Jung Jang, M.D., Hye Jung Cho, M.D., Ji Sung Lee, M.D.†, and Dong Woo Son, M.D. Departments of Pediatrics, Obstetrics and Gynecology†, Graduate School of Medicine, Gachon University, Incheon, Korea Department of Anesthesiology*, Incheon Saint Mary’s Hospital, The Catholic University of Korea, Incheon, Korea

ABSTRACT Received: 20 August 2013 Revised: 24 September 2013 Purpose: The aim of this study was to characterize the changes in the incidence and Accepted: 9 October 2013 clinical characteristics of nonoliguric hyperkalemia (NOHK), together with plasma Correspondence to: potassium levels, according to the fluid therapy strategies for extremely low birth Dong Woo Son, M.D. weight infants (ELBWIs) during the first few days of life. Department of Pediatrics, Graduate School of Medicine, Methods: This retrospective study enrolled ELBWIs. We analyzed the occurrence Gachon University, of NOHK, plasma potassium levels, other biochemical data, and fluid balances 21 Namdongdaero-77th St., according to historically controlled strategies such as conventional limited-volume Namdong-gu, Incheon 405-760, supply and low-dose calcium supplementation (P1), increased-volume supply and Korea high-dose calcium supplementation (P2), and early aggressive nutrition (EAN) and Tel: +82-1577-2299 high-dose calcium supplementation (P3). Fax: +82-32-460-3224 Results: The incidence of NOHK and the plasma potassium levels in P2 (127 E-mail: [email protected] ELBWIs) were not different from those in P1 (39 ELBWIs). However, arrhythmia and fatality significantly decreased in P2 compared to those in P1. In P3 (68 ELBWIs), the incidence of NOHK after 24 h and the plasma potassium levels after 36 h of life were significantly reduced compared to those in P1 and P2. Neither arrhythmia nor fatality developed in P3. Conclusion: EAN combined with high-dose calcium supplementation could be a potential strategy for the prevention of NOHK along with consequent arrhythmia and fatality in ELBWIs.

Copyright(c) Amino acids, Calcium/therapeutic use, Hyperkalemia, Infant/ex Key Words: By Korean Society of Neonatology. tremely low birth weight, Nitrogen, Phosphorus/blood, Potassium/blood All right reserved. This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License INTRODUCTION (http://creativecommons.org/licenses/ by-nc/3.0), which permits unrestricted Nonoliguric hyperkalemia (NOHK), which develops frequently in very premature infants non-commercial use, distribution, and during the first 72 h after birth, has been known for more than 30 years1-4). However, NOHK reproduction in any medium, provided the original work is properly cited. Neonatal Med 2014 February;21(1):28-37 http://dx.doi.org/10.5385/nm.2014.21.1.28 29

remains a threat to the lives of extremely low birth weight in few days of life. fants (ELBWIs), and is a great challenge to neonatologists5). Hyperkalemia can cause cardiac arrhythmias, changes on cranial ultrasonographic findings such as intracerebral hemorrhage and MATERIALS AND METHODS periventricular leukomalacia, and sudden death6). To prevent these serious complications of NOHK, effective therapeutic or 1. Patients preventive modalities for hyperkalemia should be provided. This was a retrospective review of ELBWIs who were born and Therapeutic interventions are conventionally aimed at hospitalized at a tertiary university hospital between September redistributing serum potassium (sodium bicarbonate or insulin 2004 and July 2013. Infants with oliguria (urine output ＜1 mL · kg-1 and glucose injection), increasing the elimination of potassium · h-1), with early mortality (died within 6 h after birth), or with major from the body (diuretics or ion exchange resins, exchange congenital anomalies were excluded. transfusion, peritoneal dialysis, salbutamol, or albuterol), or counteracting potential arrhythmias from hyperkalemia 2. Fluid therapy strategies according to study periods (calcium). A systematic review on these interventions for NOHK Period 1 (P1): For the ELBWIs who were hospitalized between was not able to draw definitive conclusion on the effectiveness of September 2004 and February 2007, the fluid therapy strategy each intervention, but suggested that the combination of insulin consisted of electrolyte-free 10% dextrose-water solution (D10W) and glucose is preferred to treatment with rectal cation-resin for and ≤ 4 mL · kg-1 · day-1 of 10% calcium gluconate (low-dose hyperkalemia in preterm infants7). However, the combination calcium) during the first 3 days. D10W was started at 60 mL · of insulin and glucose may cause hypoglycemia8), and rectal kg-1 · day-1 on the first DOL, and increased by 10 mL · kg-1 · day-1 cation-resin may cause colonic necrosis and impaction with daily up to100 mL · kg-1 · day-1 on the fifth DOL. Fluid intake was perforation9,10). increased by 20–30 mL · kg-1 · day-1 when hypernatremia appeared. Calcium is actively transported across the placenta to the fetus Catecholamines were added when required. Electrolytes such as during the last trimester11). Preterm infants born early in this period sodium, potassium, and phosphate were added to the fluids after commonly experience hypocalcemia, especially during the first 3 DOL. After the third DOL, when the infant’s electrolytes and 24-48 h of life when NOHK frequently occurs. Supplementation blood chemical measurements were stabilized, total parenteral of calcium to preterm infants after birth may provide their nutrition (TPN) was started. The amino acid content of TPN was calcium requirements and decrease the arrhythmogenic effect increased from 1 to 3 g · kg-1 · day-1 for 3 days. Lipid was started at of NOHK by stabilizing the cell membranes. Very little research 1 g · kg-1 · day-1. We initiated enteral feeding at 10 mL · kg-1 · day-1 of has been performed on the effects of calcium supplementation breast milk or formula milk for premature infants by the second or for NOHK12,13). For years, we have provided high-dose calcium third DOL. We increased the enteral feeding by 10 mL · kg-1 · day-1 supplementation to very premature infants during the first few for 3 days and then by 20 mL · kg-1 · day-1 thereafter when tolerable. days of life (DOLs) to meet their requirements, control potassium The final amount of fluid intake was 130 mL · kg-1 · day-1 with the levels, and overcome the arrhythmogenic effect of NOHK13). combination of intravenous intake and enteral feeding, and 160 Early aggressive nutrition (EAN), such as providing nutrients mL · kg-1 · day-1 with enteral feeding alone. consisting of an amino acid intake of 2-2.5 g · kg-1 · day-1 and glucose Period 2 (P2): For ELBWIs born and hospitalized between March infusion of 4-6 mg · kg-1 · min-1 on the first DOL, is now commonly 2007 and August 2011, the fluid therapy strategy was changed to prescribed in many neonatal intensive care units (NICUs) to provide 10 mL · kg-1 · day-1 of 10% calcium gluconate during the first achieve improved growth in very premature infants14). We have 3 days (high-dose calcium)13). To keep the ionized calcium (iCa) also adopted EAN in our NICU and we have found that EAN is level at about 1.5 mmol/L, the calcium dosage was adjusted. D10W associated with some changes in blood potassium levels in very was started at 60 mL · kg-1 · day-1 on the first DOL, and increased by premature infants. 10 mL · kg-1 · day-1 every 12 h up to 100 mL · kg-1 · day-1 on the third The aim of this study was to clarify the changes in potassium DOL. Strategies for TPN, enteral feeding, and the intake goal were levels and the clinical characteristics of NOHK according to the the same as in period 1. When the serum phosphorus level was ＜4 different fluid therapy strategies applied to ELBWIs during the first mg/dL, phosphate supplementation at 1-2 mEq · kg-1 · day-1 was Min Young Kim, et al. 30 Impact of Fluid Strategies on NOHK in ELBWI

administered with TPN. as PDA that required pharmacological treatment and showed Period 3 (P3): From September 2011, we started EAN consisting the following signs on echocardiography: systolic/diastolic flow of dextrose and 2.0 g · kg-1 · day-1 of amino acids. The increment of velocity ratio of the left pulmonary artery (LPA) of ≥0.3; diastolic fluid intake was the same as that for P2. High-dose calcium was flow velocity of the LPA ≥0.3 m/sec and left atrium/aorta ratio started from the first few hours of life, and controlled to maintain ＞1.3; diastolic flow interruption of the celiac artery or anterior iCa levels at about 1.5 mmol/L for the first 3 days. Policies for TPN, cerebral artery owing to ductal steal. Cardiac arrhythmia was enteral feeding, phosphorus supplementation, and the intake goal defined as widening of QRS complex on electrocardiogram, remained unchanged. bradycardia with heart rate ＜60/min, supraventricular/ The combination of insulin and glucose infusion was used ventricular tachycardia, or ventricular fibrillation that appeared when plasma potassium levels exceeded 8.0 mEq/L, or when the with hyperkalemia. attending neonatologist decided to administer this combination to ELBWIs whose potassium levels were increasing rapidly, 5. Statistical analysis or when there were changes in the rhythm and waves on the The study population was divided into 3 groups according to the electrocardiogram. Although bolus injection of calcium (1 mL · kg-1 study periods (P1, P2, and P3). Clinical characteristics including I/ · dose-1 of 10% calcium gluconate) was used during P1 when the O and serial laboratory data were compared between the 3 groups. potassium levels of infants exceeded 7.0 mEq/L, it was never given All statistical analyses were performed using MedCalc version 12.7 during P2 and P3 because of the well-maintained plasma iCa level. (MedCalc software, Ostend, Belgium). Comparisons of means between the 3 groups were performed using one-way analysis of 3. Data collection variance (ANOVA). Comparisons of ordinal data between the 3 This study was approved by the clinical research ethics com groups were performed using the Kruskal-Wallis test. Data were mittee of our university hospital. We collected clinical data summarized as mean±standard deviation or median (range). including birth weight, gestational age, sex, mortality, 1-min and Significance was set atP ＜0.05. 5-min Apgar scores, mode of delivery, use of antenatal steroids, patent ductus arteriosus (PDA), 24 h fluid intakes and outputs (I/ O), and data related to NOHK such as cardiac arrhythmia and use RESULTS of insulin and glucose. We did not measure the body weights of ELBWIs during the first week when the infants were in an acute 1. Patients' characteristics unstable clinical condition. A total of 258 ELBWIs were reviewed during the study period. All ELBWIs were tested for the levels of plasma potassium and During P1, 2 ELBWIs with oliguria and 1 ELBWI with VATER iCa every 6-8 h during the first 7 DOL through capillary blood syndrome were excluded. We also exclude 12 ELBWIs with oliguria gas and electrolyte analysis with Critical Care Xpress (Nova and 6 with early mortality during P2, and 3 with early mortality Biomedical Corporation, Waltham, MA, USA). Data from samples during P3. A total of 234 ELBWIs were enrolled in the analyses. The with hemolysis were discarded. Levels of phosphorus, alkaline numbers of ELBWIs enrolled in P1, P2, and P3 were 39, 127, and 68, phosphatase, blood urea nitrogen (BUN), and serum creatinine respectively. (sCr) were obtained through routine blood tests or when required The clinical characteristics of the 3 groups are shown in Table by using a central laboratory chemistry analyzer (Chemistry 1. No differences were found in the gestational age, 1-min and Analyzer 7600-110; Hitachi Ltd., Tokyo, Japan). 5-min Apgar scores, sex ratio, frequency of small for gestational age, and incidence of hsPDA among the 3 groups. Antenatal 4. Definitions steroids injections were more frequent (P=0.0013) for the mothers NOHK was defined as a plasma potassium level of ≥7 mEq/L of ELBWIs in P2 (60%) and P3 (60%) compared with those in P1 during the first 72 h of life with a urine output of ≥1 mL · kg-1 · h-1. (28%). Hypercalcemia was defined as a plasma iCa level of ≥1.6 mmol/ L, and hypophosphatemia as a serum phosphorus level of ≤2.5 2. Characteristics related to NOHK according to the study mg/dL. Hemodynamically significant PDA (hsPDA) was defined periods Neonatal Med 2014 February;21(1):28-37 http://dx.doi.org/10.5385/nm.2014.21.1.28 31

The occurrence of NOHK during the first 24 h was not different calcium supplementation in P2 and P3 compared with P1; third, between the 3 groups (Table 1). The occurrence of NOHK in to administer ≥2.0 g · kg-1 · day-1 of amino acids from the first few P3 on the second DOL was 18%, which was significantly lower hours of life in P3. The fluid intake of ELBWIs in each study period (P=0.0027) than that in P1 (44%) and P2 (40%). On the third DOL, during the first 7 DOL showed that significantly more volume of NOHK occurred much less frequently in P3 (7%) than in P1 (26%, fluid was given in P2 and P3 than in P1, although no difference P=0.0018). The combination of insulin and glucose injection was was observed on the first DOL between the 3 periods (Figure used for the management of NOHK less frequently in P2 than in P1 1A). On the fourth DOL, intake fluid volume was higher in P3 (18% vs. 44% of all hyperkalemic episodes during the first 3 DOL,P than in P2. ELBWIs in P2 and P3 had greater urine output than ＜0.0001). The incidence of cardiac arrhythmia was significantly those in P1 on the first DOL (P1, 40.1±21.2 mL · kg-1 · day-1; P2, lower in P2 than in P1 (5% vs. 14%, P=0.02). No episode of cardiac 56.9±25.5 mL · kg-1 · day-1; P3, 57.4±18.3 mL · kg-1 · day-1) (Figure arrhythmia was observed, and the combination of insulin and 1B). ELBWIs in P1 had a higher urine output on the third DOL glucose was never administered in P3. Five cases of mortality (13%) compared to that for ELBWIs in P2 and P3 (P1, 111.9±41.9 mL · from NOHK occurred in P1, whereas no mortality from NOHK kg-1 · day-1; P2, 87.9±30.1 mL · kg-1 · day-1; P3, 76.4±24.8 mL · kg-1 · occurred in P2 and P3. Hypercalcemia from bolus or continuous day-1). The difference in 24 h I/O during the first 7 DOLs showed infusion of calcium gluconate developed in 56%, 41%, and 41% of a more negative balance in P1 than in P2 and P3 for each of the 7 ELBWIs in P1, P2, and P3, respectively. days. On the third and fourth DOLs, infants in P3 showed a more positive balance compared with that in infants in P2. 3. Changes in fluid balances according to study periods Our strategies for fluid therapy during each study period can 4. Changes in electrolytes and chemistry findings accord be summarized as follows: first, to provide increased fluid intake ing to study periods in P2 and P3 compared with P1; second, to provide higher-dose

Table 1. Characteristics of Infants According to the Time Period P1 (n=39) P2 (n=127) P3 (n=68) Clinical characteristics Gestational weeks, median (range) 26 (22-33) 26 (22-31) 26 (22-33) Birth weight (g), median (range) 840 (530-990) 830 (420-990) 785 (320-990) Sex (male), n (%) 18 (46) 62 (49) 40 (59) 1-min Apgar score, median (range) 4 (1-8) 5 (0-9) 4 (1-8) 5-min Apgar score, median (range) 7 (4-9) 7 (1-10) 8 (3-10) Caesarian section, n (%) 24 (62) 82 (65) 44 (65) Small for date, n (%) 6 (15) 16 (13) 6 (9) Death, n (%) 13 (33) 28 (22) 18 (26) Antenatal steroid, n (%) 11 (28) 76 (60)* 41 (60)* HsPDA, n (%) 18 (46) 48 (38) 37 (54) Hypercalcemia, n (%) 22 (56) 52 (41) 28 (41) Nonoliguric hyperkalemia On the first day, n (%) 16 (41) 71 (56) 31 (46) On the second day, n (%) 17 (44) 51 (40) 12 (18)* On the third day, n (%) 10 (26) 17 (13) 5 (7)* Death, n (%) 5 (13) 0 (0)* 0 (0)* Total hyperkalemic episodes, n 70 260 89 Insulin and glucose infusion, n (%) 31 (44) 46 (18)* 0 (0)* Arrhythmia, n (%) 10 (14) 13 (5)* 0 (0)* *P<0.05 Abbreviation: HsPDA, hemodynamically significant patent ductus arteriosus. Min Young Kim, et al. 32 Impact of Fluid Strategies on NOHK in ELBWI

Plasma potassium levels during the first 30 h were not different in P2 and P3 (P1, 0.95±0.25 mmol/L; P2, 1.05±0.14 mmol/L; between the 3 study periods (Figure 2). From 36 h of life, plasma P3, 1.08±0.13 mmol/L). At 12 h of life, the iCa levels of P2 and P3 potassium levels in P3 became significantly lower compared increased significantly from their at-birth level (1.10±0.15 and to those in P1 and P2 (P1, 6.5±1.1 mEq/L; P2, 6.4±1.3 mEq/L; 1.12±0.14 mmol/L). The mean iCa levels in P2 and P3 were at their P3, 5.6±1.2 mEq/L). The plasma potassium levels in P1 started peak (1.30±0.25 and 1.36±0.18 mmol/L) at 72 h of life. The iCa to decrease from 72 h of life. In contrast, the potassium levels in levels in all 3 periods converged to 1.2 mmol/L from 108 h of life P2 remained higher compared to those in P3. At 84 h of life, the (Figure 3A). Serum phosphorus levels in each group were similar plasma potassium level in P1 (4.7±1.0 mEq/L) was significantly at birth (P1, 6.2±1.4 mg/dL; P2, 5.8±1.1 mg/dL; P3, 5.9±1.0 mg/ lower compared to that in P2 (5.3±1.0 mEq/L, P=0.0185), and dL). Serum phosphorus levels in P2 and P3 reached their lowest not different from that in P3 (4.7±0.9 mEq/L). At 120 h of life, the point at the fifth day of life (P2, 3.3±1.1 mg/dL; P3, 2.6±0.7 mg/ plasma potassium levels of P1, P2, and P3 were not different from dL). The decrement was steeper in P3 than in P2, and a significant each other (P1, 5.0±0.9 mEq/L; P2, 5.4±0.7 mEq/L; P3, 5.4±1.0 decrease from the at-birth phosphorus levels was noted on the first mEq/L). DOL in P3 and on the second DOL in P2. During the first 5 DOLs, The plasma iCa level at birth was significantly lower in P1 than the serum phosphorus levels in the 3 periods were significantly different from one another. From the sixth DOL, the serum phosphorus levels converged to ＞4 mg/dL in all 3 periods (Figure 3B). BUN levels at birth were not different in the 3 periods (P1, 9.3±5.3 mg/dL; P2, 8.7±6.8 mg/dL; P3, 10.0±5.3 mg/dL). BUN levels rapidly increased on the first DOL in the 3 periods. BUN levels were significantly higher in P3 than in P1 and P2 from the first DOL (P1, 21.1±8.6 mg/dL; P2, 23.8±7.9 mg/dL; P3, 32.8±14.3 mg/dL)

Figure 2. Serial changes in plasma potassium levels. From 36 B h of life, plasma potassium levels in P3 became significantly Figure 1. (A) The fluid intake of extremely low birth weight lower compared to those in P1 and P2. The plasma potassium infants (ELBWIs) in each study period during the first 7 days of level in P1 started to decrease from 72 h of life. In contrast, the life showed that a significantly greater volume was given in P2 potassium level in P2 remained higher compared to those in and P3 than in P1. (B) Urine outputs from ELBWIs in P2 and P3. The markers represent the means. For clear visualization, P3 were greater compared to those in P1 on the first day of life. error bars for standard deviation have been omitted (*significant ELBWIs in P1 had a higher urine output on the third day of life difference between P3 vs. P1 and P2; †significant difference compared to those in P2 and P3 (* P＜0.05). between P2 and P3; ‡ significant difference between P1 and P2). Neonatal Med 2014 February;21(1):28-37 http://dx.doi.org/10.5385/nm.2014.21.1.28 33

until the sixth DOL. The level of sCr at birth differed between the of NOHK or potassium levels, but may have decreased the 3 periods (P1, 0.7±0.2 mg/dL; P2, 0.4±0.3 mg/dL; P3, 0.2±0.2 mg/ development of arrhythmia and death due to NOHK. In addition, dL). The sCr levels in P1 were higher compared to those in P2 and EAN decreased the incidence of NOHK after 24 h of life and the P3 until the eighth DOL. plasma potassium levels after 36 h of life. This is the first report that compares the effect of 3 fluid therapy strategies on NOHK. During the early period (P1), our fluid therapy strategy was DISCUSSION a conventional limited-volume supply with low-dose calcium supplementation (≤4 mL · kg-1 · day-1 of 10% calcium gluconate). This study showed that increased fluid supply along with a The incidence of NOHK was ＞40% during the first and second high-dose calcium supply did not influence either the occurrence DOLs and 26% on the third DOL in ELBWIs. The incidence of NOHK has been reported to be 30% to 50% in very low birth weight infants15), and the reported incidences in ELBWIs in the Republic of Korea were 31%16) and 26.7%5), which were comparable to our incidences in P1. Despite multiple bolus injections of calcium and the combination of glucose and insulin injection (44% of total hyperkalemic episodes), the mortality from NOHK was 13%. We did not use rectal cation-resin because it is not effective and could cause damage to the intestine of extremely premature infants9). A systematic review summarized that the combination of insulin and glucose is the preferred method for the management of NOHK7). In our clinical experience, however, this treatment frequently causes glucose derangement and is often ineffective. Cardiac arrhythmia was reported to occur in 60% of infants with NOHK6). Arrhythmia A developed in 13% of hyperkalemic episodes during P1. The incidence was comparable to that in a recent report from Korea5). Subsequently, however, cardiac arrhythmia decreased and then disappeared with the high-dose calcium supplementation during P2 and P3 in this study. The difference in the fluid therapy strategy in P1 and P2 was that the volume of fluid intake was increased and high-dose calcium was used. The incidences of NOHK in P2 during the first 3 DOLs was not different from that in P1. The plasma potassium level during the first 72 h in P1 and P2 was the same. Two studies have reported that calcium supplementation decreased the potassium level prophylactically12), and that the effect was dose-related13). We did not find an effect of calcium in reducing the potassium B level. No research has been performed to show the effect of higher Figure 3. (A) The plasma ionized calcium level at birth was lower in P1 than in P2 and P3. At 12 h of life, the ionized calcium volume intake on NOHK. In this study, the difference in volume levels in P2 and P3 increased significantly from the level at birth. intake between P1 and P2 did not seem to have any influence on The ionized calcium level reached a peak at 72 h in P2 and P3. NOHK. (B) Serum phosphorus levels in each group were similar at birth. Serum phosphorus level decreased significantly on the first day Antenatal steroids are known to be effective in protecting in P3 and on the second day in P2. Serum phosphorus levels ELBWIs from hyperkalemia by increasing the activity of Na+/ reached their lowest point on the fifth day of life in P2 and P3. K+-ATPase15). In this study, the proportion of mothers receiving (*P<0.05; †significant decrement from the level at birth in P3; ‡ significant decrement from the level at birth in P2). antenatal steroid injections in P3 was higher than that in P1. Min Young Kim, et al. 34 Impact of Fluid Strategies on NOHK in ELBWI

Therefore, a decreased occurrence of NOHK and lowered plasma is mainly due to a shift of potassium from the intracellular to the potassium levels in P3 might be due to the effect of antenatal extracellular space associated with a decrease in the erythrocyte steroid injections. However, the incidence of NOHK and plasma Na+/K+-ATPase activity19-21). It is thought that this impairment potassium levels in P1 and P2 was the same, even though the could be caused at birth by disruption of the placental uptake of proportion of mothers receiving antenatal steroid injections in P2 active amino acids and that it could be limited by early amino was higher than that in P1. Conversely, the incidence of NOHK and acid supply17). Furthermore, it was suggested that when a patient plasma potassium levels in P3 was lower than that in P2, while P2 becomes anabolic, a considerable shift of potassium into the and P3 had the same proportions of mothers receiving antenatal intracellular space occurs22). However, another study reported no steroid injections. These findings suggest that EAN had the effect of difference in the degree of the negative nitrogen balance between reducing the potassium level. 2 groups of ELBWIs with and without NOHK23). In this regard, the The frequency of using the glucose and insulin combination was effectiveness of nutritional interventions for the prevention of significantly less during P2 than during P1, although the incidence NOHK warrants randomized controlled trials. of NOHK was similar in both periods. Cardiac arrhythmia became Infants with NOHK are known to have high levels of serum less frequent, and no fatality from NOHK was observed in P2. phosphorus24,25). We did not address this in the present study. We The frequencies of episodes of hypercalcemia in P1, P2, and P3 did find, however, that the serum phosphorus levels decreased were not different because the bolus injection of calcium for the soon after birth in P2 and P3. High-dose calcium supplementation treatment of NOHK in P1 sometimes caused a brief episode of could promote a decrease in phosphorus levels. Moreover, the hypercalcemia (＞2.0 mEq/L). As we controlled the infusion decrement of serum phosphorus in P3 was steeper, and the nadir rate of 10% calcium gluconate to maintain iCa levels at about was lower than that in P2. We started administration of lipid, which 1.5 mmol/L (in about 30% of cases, we decreased the infusion is high in phosphorus, after the third DOL so that the intake of rate by half at 60 h of life), we seldom noted hypercalcemia of phosphorus would be inadequate during the first 3 days. However, ≥1.8 mEq/L in P2 and P3. Furthermore, we could not find any the intake of phosphorus was also inadequate in P1 when the clinical problem caused by high-dose calcium such as abnormal decrement of phosphorus occurred at the third DOL. Another electrocardiogram, increased urine output, change in blood possible explanation is that the nutrition could lead to usage and pressure, or nephrocalcinosis during hospital days. One study intake of phosphate at the cellular level22,26). As phosphate is mainly on high-dose calcium supplementation in ELBWIs reported the an intracellular anion, the increased cellular phosphate may have absence of complications induced by hypercalcemia13). caused a shift of potassium or magnesium into the cells. Hence, The fluid therapy strategy in P3 was EAN and high-dose calcium decreased serum phosphorus levels would be associated with supplementation. The incidence of NOHK at the second and third decreased potassium levels22). In addition, it has been suggested DOLs in P3 was decreased significantly compared with that in P1 that a hypokalemic effect on renal tubular function might result and P2. The appearance of the trend curves of P3 for changes in in excessive loss of phosphate through the urine27). Although this plasma potassium level after birth was similar to those of P1 and seems unlikely in ELBWIs whose renal tubular function and Na+/ P2, but the levels were different. The plasma potassium level in K+-ATPase activity are immature, there must be some relation P3 was low from 12 h of life, and became significantly lower than between phosphorus levels and potassium levels. This relation that in P1 and P2 at 36 h of life and thereafter until 112 h of life. The of decreased phosphorus level with decreased potassium level same phenomenon was reported in 2 other studies. In one study, requires further study. which compared the electrolyte balance according to amino acid BUN levels at birth were not different between the 3 periods. intake, high amino acid intake (＞2 g · kg-1 · day-1) was found to BUN levels increased soon after birth, and the levels in P3 reduce the incidence of NOKH17). The other study compared the were higher compared to those in the other 2 periods. The in impact on electrolyte balance of batch-produced standardized creased BUN level in P3 represents the effect of early amino parenteral nutrition (SPN) and individualized parenteral nutrition acid administration28). The concentration of sCr at birth was (IPN) where the amino acid content of SPN was higher than that significantly higher, and the iCa level at birth was significantly of IPN. The authors reported that NOHK was less frequent in the lower in P1 than in P2. Hyperkalemic infants are known to have SPN group than in the IPN group18). The pathophysiology of NOHK significantly higher sCr, serum phosphorus and urea, and lower Neonatal Med 2014 February;21(1):28-37 http://dx.doi.org/10.5385/nm.2014.21.1.28 35

serum calcium24). In P1 and P2, the incidence of NOHK and very low birth weight infants (VLBW) with non oliguric renal other clinical characteristics including 1-min and 5-min Apgar failure. Pediatr Res 1985;19:336A. scores were similar, except for the frequency of antenatal steroid 2) Gruskay J, Costarino AT, Polin RA, Baumgart S. Nonoliguric injections. It is unclear whether the difference in antenatal steroid hyperkalemia in the premature infant weighing less than 1000 grams. J Pediatr 1988;113:381-6. administration would induce a difference in sCr and iCa at birth. 3) Kilbride HW, Cater G, Warady BA. Early onset hyperkalemia The sCr levels in P1 remained high during the first 7 DOLs. As the in extremely low birth weight infants. J Perinatol 1988;8:211-4. fluid intake and the I/O balance in P1 and P2/P3 were different 4) Brion LP, Schwartz GJ, Campbell D, Fleischman AR. Early from one another, a more negative balance in P1 during the first 7 hyperkalaemia in very low birthweight infants in the absence DOLs may have caused the increased sCr in P1 during the first 7 of oliguria. Arch Dis Child 1989;64:270-2. days. 5) Kwak JR, Gwon M, Lee JH, Park MS, Kim SH. Non-oliguric We did not insert an umbilical artery catheter throughout the hyperkalemia in extremely low birth weight infants. Yonsei study. Dopamine infusion did not differ between the 3 periods Med J 2013;54:696-701. 6) Shortland D, Trounce JQ, Levene MI. Hyperkalaemia, cardiac (＜40% for each period, data not shown). About 25% of ELBWIs arrhythmias, and cerebral lesions in high risk neonates. Arch had a transfusion in each period (data not shown) during the Dis Child 1987;62:1139-43. first 3 days. Alkaline solutions such as sodium bicarbonate were 7) Vemgal P, Ohlsson A. Interventions for non-oliguric hyper infused in 12.8% of ELBWIs in P1, 15.7% in P2, and 14.7% in P3 kalaemia in preterm neonates. Cochrane Database Syst Rev during the first 3 days, according to our policy of alkaline infusion [serial online]. 2012;5:[CD005257]. Available from: URL: (pH ＜7.2 and base excess ≤ -15). The profiles of pH and base http://onlinelibrary.wiley.com/doi/10.1002/14651858. excess on capillary blood gas analysis during the first 3 days were CD005257.pub3/abstract;jsessionid=FC93D512AAF22297AD not different between the 3 periods. Body weight was not checked 5D72929A1C25B0.f04t01 during the first week or until the status of the ELBWIs became 8) Malone TA. Glucose and insulin versus cation-exchange resin for the treatment of hyperkalemia in very low birth weight stable. infants. J Pediatr 1991;118:121-3. The limitations of this study are as follows. First, this study 9) Grammatikopoulos T, Greenough A, Pallidis C, Davenport M. was retrospective in nature, had an unequal group size, and Benefits and risks of calcium resonium therapy in hyper used historically controlled groups. Randomized prospective kalaemic preterm infants. Acta Paediatr 2003;92:118-20. multicenter trials are needed to confirm our findings. Second, 10) Bennett LN, Myers TF, Lambert GH. Cecal perforation asso the study periods were long and distant from each other; thus, it ciated with sodium polystyrene sulfonate-sorbitol enemas in is possible that some uncontrolled hidden bias remained. Third, a 650 gram infant with hyperkalemia. Am J Perinatol 1996; we did not measure the body weight changes, serum sodium, 13:167-70. and laboratory findings in urine such as electrolytes, calcium, and 11) Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. phosphorus. With these data, more exact information on sodium, Endocr Rev 1997;18:832-72. potassium, calcium, and phosphorus balances could be obtained. 12) Iijima S, Uga N, Kawase Y, Tada H. Prophylactic calcium Fourth, we did not focus on the side effects of the strategies in this administration for hyperkalemia in extremely low birthweight study. Studies with long-term follow-up data will be needed. infants. Am J Perinatol 2005;22:211-6. In conclusion, we have shown that high-dose calcium supple 13) Enomoto M, Minami H, Takano T, Katayama Y, Lee YK. High- mentation is effective in decreasing the frequency of cardiac dose calcium reduces early-onset hyperkalemia in extremely arrhythmia as well as mortality from NOHK. Moreover, EAN preterm neonates. Pediatr Int 2012;54:918-22. ameliorates the occurrence of NOHK from the second DOL along 14) Parish A, Bhatia J. Early aggressive nutrition for the premature infant. Neonatology 2008;94:211-4. with decreasing the potassium level. This is a potential new strategy 15) Omar SA, DeCristofaro JD, Agarwal BI, LaGamma EF. Effect of for the prevention of NOHK in ELBWIs. prenatal steroids on potassium balance in extremely low birth weight neonates. Pediatrics 2000;106:561-7. REFERENCES 16) Shim JW, Ko SY, Kim SS, Kim MJ, Chang YS, Park WS. Non- oliguric hyperkalemia in extremely low birth weight infants. J 1) Brion L, Fleischman AR, Schwartz GJ. Hyperkalemia (HK) in Korean Soc Neonatol 2002;9:21-8. Min Young Kim, et al. 36 Impact of Fluid Strategies on NOHK in ELBWI

17) Bonsante F, Iacobelli S, Chantegret C, Martin D, Gouyon JB. 23) Stefano JL, Norman ME. Nitrogen balance in extremely low The effect of parenteral nitrogen and energy intake on elec birth weight infants with nonoliguric hyperkalemia. J Pediatr trolyte balance in the preterm infant. Eur J Clin Nutr 2011;65: 1993;123:632-5. 1088-93. 24) Yaseen H. Nonoliguric hyperkalemia in neonates: a case- 18) Iacobelli S, Bonsante F, Vintéjoux A, Gouyon JB. Standardized controlled study. Am J Perinatol 2009;26:185-9. parenteral nutrition in preterm infants: early impact on fluid 25) Thayyil S, Kempley ST, Sinha A. Can early-onset nonoliguric and electrolyte balance. Neonatology 2010;98:84-90. hyperkalemia be predicted in extremely premature infants? 19) Stefano JL, Norman ME, Morales MC, Goplerud JM, Mishra Am J Perinatol 2008;25:129-33. OP, Delivoria-Papadopoulos M. Decreased erythrocyte 26) Ichikawa G, Watabe Y, Suzumura H, Sairenchi T, Muto T, Na+,K(+)-ATPase activity associated with cellular potassium Arisaka O. Hypophosphatemia in small for gestational age loss in extremely low birth weight infants with nonoliguric extremely low birth weight infants receiving parenteral hyperkalemia. J Pediatr 1993;122:276-84. nutrition in the first week after birth. J Pediatr Endocrinol 20) Sato K, Kondo T, Iwao H, Honda S, Ueda K. Internal potassium Metab 2012;25:317-21. shift in premature infants: cause of nonoliguric hyperkalemia. 27) Betro MG, Pain RW. Hypophosphataemia and hyperphos J Pediatr 1995;126:109-13. phataemia in a hospital population. Br Med J 1972;1:273-6. 21) Semama DS, Martin-Delgado M, Gouyon JB. [Metabolism of 28) Porcelli Jr PJ, Sisk PM. Increased parenteral amino acid potassium in preterm infants]. Arch Pediatr 2007;14:249-53. administration to extremely low-birth-weight infants during 22) Tovey SJ, Benton KG, Lee HA. Hypophosphataemia and early postnatal life. J Pediatr Gastroenterol Nutr 2002;34:174- phosphorus requirements during intravenous nutrition. 9. Postgrad Med J 1977;53:289-97. Neonatal Med 2014 February;21(1):28-37 http://dx.doi.org/10.5385/nm.2014.21.1.28 37

수액치료 전략이 초극소 저체중 출생아의 비핍뇨성 고칼륨혈증에 미치는 영향

가천대학교 의학전문대학원 소아과학교실, 산부인과학교실†, 인천성모병원 마취과학교실* 김민영・장은재・김영혜*・장우정・조혜정・이지성†・손동우

목적: 생후 첫 며칠 동안 초극소 저출생체중아들에게 적용하는 서로 다른 수액요법의 전략이 비핍뇨성 고칼륨혈증의 빈도, 칼륨의 농도 및 임상적 특성에 미치는 변화를 밝히는 것을 목적으로 연구를 시행하였다. 방법: 이 연구는 후향적 연구로 초극소 저출생체중아들을 대상으로 하였다. 세 가지 수액요법 전략, 즉 재래적인 수액 용량 제한과 저용량의 칼슘보충(P1), 증량된 수액공급과 고용량 칼슘보충(P2), 그리고 조기강화영양법과 고용량 칼슘보충(P3)을 각각 사용한 세 시기에서 비핍뇨성 고칼륨혈증의 빈도, 혈장 칼륨 농도, 기타 생화학 검사소견, 그리고 수분 균형 등을 분석하였다. 결과: 초극소 저출생체중아 127명이 포함된 P2의 비핍뇨성 고칼륨혈증 빈도와 혈장 칼륨 농도는 P1(39명)에서와 다르지 않았다. 그러나 P2에서는 P1에서보다 부정맥과 사망 예가 의미 있게 감소하였다. P3(68명)에서는 P1, P2와 비교하 여 생후 24시간과 그 이후의 비핍뇨성 고칼륨혈증의 빈도와 36시간과 그 이후의 혈장 칼륨 농도의 의미 있는 감소 를 보였다. 부정맥이나 사망의 발생은 없었다. 결론: 조기강화영양법과 병용하는 고용량 칼슘보충은 초극소 저출생체중아에서 비핍뇨성 고칼륨혈증과 이에 의한 부 정맥 및 사망 예방에 유력한 수액 전략이 될 수 있다.