Journal of Perinatology (2009) 29, 444–447 r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32 www.nature.com/jp ORIGINAL ARTICLE Albumin versus normal saline for dehydrated term infants with metabolic acidosis due to acute diarrhea

JJ Han, HE Yim, JH Lee, YK Kim, GY Jang, BM Choi, KH Yoo and YS Hong Department of Pediatrics, College of Medicine, Korea University, Seoul, Republic of Korea

histidine residues with a pKa of approximately 7.4; it shows a Objective: To compare the efficacy of albumin to normal saline (NS) for buffering effect in the acid-base balance and influences the pH.1 initial hydration therapy for dehydrated term infants with severe metabolic Although there is a dispute concerning the efficacy of albumin acidosis due to acute diarrhea. infusion for neonatal metabolic acidosis, albumin infusion to Study Design: We randomized 33 infants presenting with moderate-to- improve pH and/or base deficits in acidotic infants may be 2–6 severe dehydration and metabolic acidosis (pH <7.25 or base excess (BE) clinically useful. However, to date there are no randomized <À15) into two groups, an albumin group (n ¼ 15) and a NS group studies assessing the efficacy of albumin infusion for the treatment (n ¼ 18). For initial hydration treatment, the albumin group received 5% of neonatal metabolic acidosis; in addition, there are no studies on albumin (10 ml kgÀ1), whereas the NS group received NS (10 ml kgÀ1). its efficacy when combined with sodium bicarbonate. Therefore, the aim of our study was to compare the efficacy of Result: After 3 h of treatment, both groups improved. However, the albumin to NS for initial hydration therapy in dehydrated term magnitude of improvement in the pH, BE and HCOÀ levels were not 3 infants with moderate and severe metabolic acidosis, especially with different in comparisons between these two groups. In addition, there were regard to buffering effects. no differences either in the body weight and weight gain 4 days after treatment or in the length of hospital stay. Methods Conclusion: Albumin was not more effective than NS for initial Infants admitted to Ansan Hospital, Korea University Medical Center, hydration treatment of dehydrated term infants with metabolic acidosis who developed moderate-to-severe dehydration with metabolic acidosis, due to acute diarrhea. due to acute watery diarrhea within the first month of life, were Journal of Perinatology (2009) 29, 444–447; doi:10.1038/jp.2008.244; eligible for this study. Patients were enrolled between September 2002 published online 22 January 2009 and December 2003. The study protocol was approved by the local Keywords: albumin; dehydration; metabolic acidosis; neonate research ethics committee at Ansan Hospital, and written parental informed consent was obtained in all cases. The information collected on all of the participating neonates included age, initial birth weight, body weight, complete blood count, electrolytes, blood urea nitrogen, Introduction creatinine, protein, albumin and blood gas analysis, as well as physical findings such as a dry tongue or lips, depressed fontanel, sunken eyes, Although sodium bicarbonate is the most widely used buffer for the decreased urination and decreased activity. treatment of metabolic acidosis, hypovolemic infants with severe Initially, 78 neonates who had symptoms or signs of metabolic acidosis may require intravascular fluid administration as dehydration were eligible for a diagnosis of moderate-to-severe supplemental fluid management to correct their dehydration. dehydration.7 Among them, 33 were included because their initial Therefore, neonates with severe dehydration and metabolic acidosis pH was below 7.25 or their initial base excess (BE) was below À15. require acute intervention to ensure adequate tissue perfusion as well Neonates without metabolic acidosis were excluded. All neonates as correction of metabolic acidosis. Normal saline (NS) is frequently were born full term and were healthy at the time of delivery. used for volume expansion during the neonatal period; however, NS After randomization, 5% albumin (10 ml kgÀ1) and NS has no known buffering capacity. As a serum protein, albumin has (10 ml kgÀ1) were administrated to infants in the albumin group Correspondence: Professor BM Choi, Department of Pediatrics, College of Medicine, Korea (n ¼ 15) and in the NS group (n ¼ 18) as open label initial University, Ansan Hospital, no. 516, Gojan-Dong, Danwon-Gu, Ansan-City, Kyungki-Do hydration therapy. All patients were treated in accordance with our 425-707, Korea. standard treatment protocol that included sodium bicarbonate E-mail: [email protected] Received 24 October 2007; revised 19 July 2008; accepted 20 July 2008; published online supplements (0.3 Â weight (Kg) Â BE Â 1/2), maintenance fluid À1 À1 À1 22 January 2009 (5% dextrose/NaCl 20 mEq l at a rate 4 ml kg h ) and Albumin versus NS for neonatal metabolic acidosis JJ Han et al 445 potassium supplements (if the plasma potassium level was recommended as first-line therapy because of many associated <3.0 mEq lÀ1). problems such as the potential risk of infection, hypersensitivity At 3 h after initial hydration, arterial blood gas analysis was reactions, fluid overload, capillary leakage and high costs. However, performed as a measure of the short-term effects of the 5% the absence of albumin-related mortality has been documented in albumin or NS therapy. If there was a sustained metabolic acidosis the medical literature.8–10 In addition, there is a lack of evidence (pH <7.25 or BE <À15), additional infusion with sodium that albumin is associated with significant side effects such as bicarbonate was carried out. In addition, if patients did not urinate infection.11 The fact that some data in the literature have not during the 3 h after initial hydration, an additional infusion with shown increased mortality with albumin administration does not the same fluids as in initial hydration therapy (10 ml kgÀ1,5% support its use, particularly in neonates with dehydration. albumin or NS) was performed. Studies have shown that NS was as effective as 5% albumin for Body weight and weight gain 4 days after treatment, as well as the treatment of hypotensive preterm neonates during the first the length of hospital stay, were evaluated as long-term outcomes. postnatal days; the albumin-treated infants, however, had a At all times, usual feeding was allowed and oral rehydration decreased ability to appropriately lose weight after treatment.12,13 solutions were administered during the rehydration and Recently, however, Lynch et al.14 reported that preterm infants with maintenance phases, except that severe vomiting made patients hypotension are more likely to respond favorably and to decrease intolerant of oral feeding. Patients who were tolerant toward oral subsequent use of dopamine after albumin bolus infusion rehydration solutions were offered 100 ml kgÀ1 of the oral compared with NS. rehydration solution over 6 h. Ongoing losses due to vomiting and In the case of respiratory disease, albumin has not been shown diarrhea were replaced with an additional 5 and 10 ml kgÀ1 of oral to alter the duration of assisted ventilation and oxygen rehydration solution for each vomiting and diarrhea, respectively. dependency.15 By contrast, the infusion of colloidal fluid during the Pre- and post treatment values were compared using the paired perinatal period in premature infants of median gestational age 27 t-test. Comparisons between the two treatment groups were weeks has been related to an increased duration of oxygen performed by Student’s t-test, Fisher’s exact test and w2 test. dependency and abnormal neurodevelopmental outcomes.16,17 In addition, albumin potentially causes deterioration of the protein leak syndrome of prematurity and lung function by deactivation of Results the surfactant in alveolar spaces.18–20 We found no significant statistical differences between the two There are a few studies on the effects of albumin administration groups in initial body weight at birth, body weight at admission, in neonates with metabolic acidosis. Some studies have shown an electrolytes, blood urea nitrogen, creatinine, total serum protein, increment of pH after albumin infusion. In one study, the albumin levels and the number of hypotensive neonates (Table 1). administration of 4.5% albumin to ventilated, normotensive, very The results of the initial blood gas analysis showed moderate and low birth weight infants with metabolic acidosis (pH <7.25) severe metabolic acidosis and no significant difference between the resulted in an immediate significant increase in pH and a BE 6 h albumin and NS groups. post-infusion.2 However, this study had no control group and the À At 3 h after initial hydration, the pH, BE and HCO3 in both results therefore have limited value. Another study reported that groups were significantly increased compared with the pretreatment albumin significantly increased pH compared with pretreatment values. However, there was no statistically significant difference in values; however, bicarbonate was significantly more effective than À 4 the magnitude of the improvements in the pH, BE and HCO3 levels albumin. Although there was no improvement of pH, Dimitriou between the two groups (Table 2). In addition, there was no et al.3 reported that the infusion of albumin improved the base statistically significant difference in the frequency of sodium deficit in hypotensive, very premature infants. bicarbonate therapy and bolus hydration therapy (albumin or NS) Prior to beginning our study, we predicted that albumin would between the two groups (Table 3). Furthermore, there was no be more effective than NS for correction of dehydration and significant difference in body weight and ratio (%) of weight gain acidosis in neonates. However, our results showed that albumin by the fourth day of treatment as well as in the length of hospital was not more effective than NS. There was no significant difference stay in comparisons between the albumin group (3097±343 g, between the two groups after a comparison of the variables À 5.08±6.33% and 8.13±3.23 day) and the NS group associated with the short-term effects (pH, BE and HCO3 ) and the (3050±397 g, 5.67±5.73% and 9.36±4.16 day). long-term effects (body weight and weight gain 4 days after treatment and the length of hospital stay). We could not study the pure effects of albumin and NS on acidosis because sodium Discussion bicarbonate was required in all infants to treat severe metabolic Traditionally, albumin has been widely used in many different acidosis; however, albumin was not more effective than NS given clinical situations in neonatology. Currently, albumin is not that all infants received sodium bicarbonate.

Journal of Perinatology Albumin versus NS for neonatal metabolic acidosis JJ Han et al 446

Table 1 Clinical characteristics of the albumin group and the normal saline group

Albumin group (n ¼ 15) Normal saline group (n ¼ 18)P-value

Initial body weight (g) 3316±344 3324±463 NS Body weight at admission (g) 2957±364 2989±446 NS Weight loss (%) 10.7±7.1 9.9±7.8 NS Age (day) 9.7±4.1 10.6±2.6 NS Blood urea nitrogen (mg per 100 ml) 17.0±11.8 24.8±26.4 NS Creatinine (mg per 100 ml) 0.7±0.3 1.0±0.9 NS Protein (g per 100 ml) 7.3±0.9 7.0±0.6 NS Albumin (g per 100 ml) 3.9±0.4 3.8±0.3 NS Hypotensive infants (n, %) 4 (26.7%) 6 (33.3%) NS

Abbreviation: NS, nonsignificant. Values are expressed as mean±s.d. or number (%).

À Table 2 Changes in pH, base excess and HCO3 before and after the infusion of albumin or normal saline with sodium bicarbonate

À1 À À1 pH Base excess (mmol l ) HCO3 (mmol l )

Before After 3 h Change P-valuea Before After 3 h Change P-valuea Before After 3 h Change P-valuea

Albumin group 7.15±0.11 7.30±0.08 0.16±0.14 <0.001 À22.0±4.6 À17.8±3.2 4.2±3.1 <0.001 6.9±4.0 8.5±3.0 1.6±2.8 <0.05 Normal saline group 7.14±0.12 7.31±0.08 0.16±0.13 <0.001 À22.0±5.5 À15.9±4.2 6.1±3.6 <0.001 7.0±4.1 10.4±3.4 3.4±2.9 <0.001 P-valueb NS NS NS NS NS NS NS NS NS

Abbreviation: NS, nonsignificant. Value are expressed as mean±s.d. aBefore vs After 3 h. bAlbumin group vs normal saline group.

Table 3 Continuing acidosis and anuria at 3 h after initial hydration therapy

Albumin group (n ¼ 15) Normal saline group (n ¼ 18)P-value

Continuing acidosisa (n, %) 12 (80.0%) 11 (61.1%) NS Frequency of sodium bicarbonate therapy 2.1±0.8 1.9±1.1 NS Continuing anuriab (n, %) 9 (60.0%) 9 (50.0%) NS Frequency of bolus hydration therapy 1.6±0.5 1.6±0.7 NS

Abbreviation: NS, nonsignificant. Values are expressed as mean±s.d. or number (%). aNeonates who continued acidosis at 3 h after initial hydration therapy. bNeonates who continued anuria at 3 h after initial hydration therapy.

Maitland et al.21 reported a randomized trial of volume and better than saline for correcting acidosis by providing increased expansion with albumin and NS in children with severe malaria. bicarbonate.22 Their patients had a moderate-to-severe acidosis and dehydration; The results of our study showed that albumin was not there was no significant difference in the resolution of acidosis in more effective than NS for initial hydration treatment of comparisons between the two groups. Their results were consistent dehydrated term infants accompanied by metabolic acidosis with our study findings. with respect to short-term and long-term prognostic variables. Recent studies have shown that polyelectrolyte solutions may Therefore, infusion with albumin for the treatment of dehydrated offer a more effective approach. A comparison between NS and neonates with metabolic acidosis does not appear to be indicated. polyelectrolyte solutions for fluid resuscitation, in severely Further studies are needed to evaluate the safety and efficacy dehydrated infants with acute diarrhea, has shown that the of crystalloid fluid for treatment of severe dehydration with polyelectrolyte solution was as effective as NS for volume expansion metabolic acidosis.

Journal of Perinatology Albumin versus NS for neonatal metabolic acidosis JJ Han et al 447

Acknowledgments 10 von Hoegen I, Waller C. Safety of human albumin based on spontaneously reported serious adverse events. Crit Care Med 2001; 29: 994–996. This study was supported by a Korea University Grant and by the Hin Moe 11 Jardine LA, Jenkins-Manning S, Davies MW. Albumin infusion for low serum albumin (Dr Hyun-Gum Lee) Research Foundation. We thank the physicians and nursing in preterm newborn infants. Cochrane Database Syst Rev 2004; 3: CD004208. staff working in the neonatal intensive care unit and the pediatric general ward of 12 Oca MJ, Nelson M, Donn SM. Randomized trial of normal saline versus 5% albumin for Korea University Ansan Hospital for their enthusiastic support and cooperation. the treatment of neonatal hypotension. J Perinatol 2003; 23: 473–476. 13 So KW, Fok TF, Ng PC, Wong WW, Cheung KL. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child Fetal Neonatal Ed 1997; References 76: F43–F46. 14 Lynch SK, Mullett MD, Graeber JE, Polak MJ. A comparison of albumin-bolus therapy 1 Doweiko JP, Nompleggi DJ. Role of albumin in human physiology and versus normal saline-bolus therapy for hypotension in neonates. J Perinatol 2008; 28: pathophysiology. JPEN J Parenter Enteral Nutr 1991; 15: 207–211. 29–33. 2 Belgaumkar A, Greenough A, Kavvadia V, Dimitriou G. Metabolic acidosis: response to 15 Greenough A, Emery E, Hird MF, Gamsu HR. Randomised controlled trial of albumin albumin infusion. Eur J Pediatr 1998; 157: 520–521. infusion in ill preterm infants. Eur J Pediatr 1993; 152: 157–159. 3 Dimitriou G, Greenough A, Mantagos J, Skinner S. Metabolic acidosis, core-peripheral 16 Kavvadia V, Greenough A, Dimitriou G, Hooper R. Randomised trial of fluid restriction temperature difference and blood pressure response to albumin infusion in in ventilated very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2000; 83: hypotensive, very premature infants. J Perinat Med 2001; 29: 442–445. F91–F96. 4 Dixon H, Hawkins K, Stephenson T. Comparison of albumin versus 17 Greenough A, Cheeseman P, Kavvadia V, Dimitriou G, Morton M. Colloid infusion in bicarbonate treatment for neonatal metabolic acidosis. Eur J Pediatr 1999; 158: the perinatal period and abnormal neurodevelopmental outcome in very low birth 414–415. weight infants. Eur J Pediatr 2002; 161: 319–323. 5 Lawn CJ, Weir FJ, McGuire W. Base administration or fluid bolus for preventing 18 Jobe A, Jacobs H, Ikegami M, Berry D. Lung protein leaks in ventilated lambs: effects of morbidity and mortality in preterm infants with metabolic acidosis. Cochrane gestational age. J Appl Physiol 1985; 58: 1246–1251. Database Syst Rev 2005; 2: CD003215. 19 Nitta K, Kobayashi T. Impairment of surfactant activity and ventilation by proteins in 6 Narchi H. Is an intravenous fluid bolus of albumin or normal saline beneficial in the lung edema fluid. Respir Physiol 1994; 95: 43–51. treatment of metabolic acidosis in a normovolaemic newborn? Arch Dis Child 2004; 20 Seeger W, Gunther A, Walmrath HD, Grimminger F, Lasch HG. Alveolar surfactant and 89: 884–885. adult respiratory distress syndrome. Pathogenetic role and therapeutic prospects. Clin 7 Kliegman RM, Behrman RE, Jenson HB, Stanton BF. Nelson textbook of pediatrics. Investig 1993; 71: 177–190. WB Saunders CO: Philadelphia, 2007, pp 313. 21 Maitland K, Pamba A, English M, Peshu N, Marsh K, Newton C et al. Randomized trial 8 Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A of volume expansion with albumin or saline in children with severe malaria: meta-analysis of randomized, controlled trials. Ann Intern Med 2001; 135: preliminary evidence of albumin benefit. Clin Infect Dis 2005; 40: 538–545. 149–164. 22 Juca CA, Rey LC, Martins CV. Comparison between normal saline and a polyelectrolyte 9 Vincent JL, Wilkes MM, Navickis RJ. Safety of human albuminFserious adverse events solution for fluid resuscitation in severely dehydrated infants with acute diarrhoea. Ann reported worldwide in 1998–2000. Br J Anaesth 2003; 91: 625–630. Trop Paediatr 2005; 25: 253–260.

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