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Clinical implications of postnatal alterations in body water distribution
Seminars in Neonatology (2003) 8, 301–306
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
Review article
Clinical implications of postnatal alterations in body water distribution Neena Modi * a
Faculty of Medicine, Imperial College of Science, Technology and Medicine, Chelsea and Westminster Hospital, London, UK b Hammersmith and Queen Charlotte's Hospitals, Du Cane Road, London, W12 0NN, UK
KEYWORDS Infant; Newborn; Body water distribution; Extracellular fluid volume; Sodium and water balance
Summary Substantial alterations take place in the quantity and distribution of body water compartments after birth. Clinical management must be tailored to the pace of postnatal adaptation, and the neonatal physician must be aware of these alterations in order to promote both normal physiological change and growth. © 2003 Published by Elsevier Ltd.
Body water compartments The newborn baby is largely water. Total body water comprises approximately 75% of body weight at full term and about 80–85% in babies between 26 and 31 weeks' gestation.1 Given this, it is easy to understand why the maintenance of water and electrolyte homeostasis in neonates is so important and so easily perturbed. The size of the extracellular compartment decreases steadily throughout life, from around 65% of body weight at 26 weeks' gestation, to 40% at term and 20% by the age of 10 years.1 Of particular relevance to the neonatal pediatrician is the fact that a more abrupt contraction occurring shortly after birth is superimposed on this gradual reduction.2–7 During this period, there is isotonic fluid loss, largely from the interstitial * Faculty of Medicine, Imperial College, 4th Floor, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel.: +44-20-8237-5102; fax: +44-20-8746-8887 E-mail address: [email protected] (N. Modi).
compartment, this being clinically evidenced by postnatal weight loss.
Postnatal adaptation How is this response to the start of life in a gaseous environment brought about? In healthy babies, the loss of extracellular fluid occurs rapidly, but this is delayed in babies with respiratory distress syndrome.8 Observations that are now considered classical, of the natural history of respiratory distress syndrome prior to the use of antenatal steroids and postnatally administered exogenous surfactant, provided the first clues. In these infants, it was well recognized that the onset of improvement in respiratory function was marked by a diuresis. An abrupt increase in urinary output was a reassuring sign to clinicians because it meant that the baby was on the road to recovery. This observation suggested that the onset of extracellular fluid loss was closely related to cardiopulmonary adaptation. Several studies now suggest that the contraction of the extracellular compartment is triggered by
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atrial natriuretic peptide. Atrial natriuretic peptide is a natriuretic hormone produced within the cells of the myocardium, the release of which is stimulated by stretch of the atrial wall. When pulmonary vascular resistance falls as an adaptation to birth,9–12 pulmonary blood flow increases and left atrial venous return increases, stimulating the release of atrial natriuretic peptide. In addition, the intravascular compartment may be expanded acutely after birth by a variable placental transfusion and by the reabsorption of lung liquid. As the diuresis/natriuresis occurs only as a consequence of the fall in pulmonary vascular resistance—hence the close temporal relationship with improving respiratory function—it is not surprising that attempts to improve the course of respiratory distress syndrome with the use of furosemide have been unsuccessful.13
Sodium balance Sodium is the principal electrolyte of extracellular fluid. If extracellular fluid is lost, this means that there is a loss of sodium and water. The postnatal isotonic loss of extracellular fluid in the first days after birth must imply that net water and sodium balance is negative during this period. This has been demonstrated in careful observational studies of newborn infants. If neonates are given an increased intake of sodium in the first days after birth, there is an increase in sodium excretion6,14,15 until contraction of the extracellular compartment occurs. Sodium balance then becomes positive, commensurate with the need for growth. Preterm babies do, however, have a limited, albeit variable, capacity to excrete a sodium load so that, despite increasing excretion in response to an increase in intake, they are at risk of sodium retention.9,16 If the intake of water is limited at the same time, these babies readily become hypernatremic. This was demonstrated in a study by Shaffer and Meade6 in which babies between 25 and 31 weeks of gestation were randomized to receive a sodium intake of 3 or 1 mmol/kg/day. The intake of water was restricted to 75 ml/kg/day on the first day, increasing by 10 ml/kg/day until day 5. In the former group, 50% became hypernatremic, compared with 20% in the latter. If a more liberal intake of water accompanies the intake of sodium, extracellular tonicity is maintained but the extracellular compartment expands. This is shown by weight gain at a time when weight loss is to be expected. In the majority of babies, this cumulative positive balance is subsequently
N. Modi
lost, so that the normal postnatal change in body water distribution occurs but is delayed.9
Clinical implications The management of sodium and water balance during the period of postnatal adaptation is governed by principles that differ from those governing management afterwards. Early fluid management, during the period of postnatal adaptation, should permit an isotonic contraction of the extracellular compartment and a brief period of negative sodium and water balance. The baby with respiratory distress syndrome may be regarded as a model of delayed postnatal maturation in whom the postnatal diuresis is delayed, and who is at great risk of persisting expansion of the extracellular compartment. In contrast, in the healthy preterm baby, postnatal cardiopulmonary adaptation occurs over the same rapid timescale as in a full-term baby. Providing routine sodium supplements in parenteral fluid without any consideration of the phase of postnatal adaptation may promote the retention of extracellular fluid, including pulmonary interstitial fluid. In newborn infants with respiratory distress, routine sodium supplementation in parenteral fluid should be avoided until the physiological postnatal diuresis/natriuresis has occurred.8,9 If this point cannot be determined, supplementation should be deferred until postnatal weight loss has occurred.3,7,17 There is no ‘correct’ figure for postnatal weight loss as hydration at birth is variable18 and birthweight does not accurately predict extracellular water volume.5 Although antenatal glucocorticoid therapy induces the maturation of sodium excretion and confers partial protection against the adverse consequences of early sodium administration, the early administration of ‘maintenance’ sodium to infants admitted to neonatal intensive care units remains unnecessary and adversely affects respiratory outcome even in babies who received antenatal steroids. Costarino et al.16 first provided some justification for this tailored approach to the introduction of parenteral sodium in a blind trial comparing sodium restriction in the first 5 days after birth with sodium supplementation at 3–4 mmol/kg/day immediately after birth. Water was prescribed independently. Extracellular volume was not measured in this study, nor were the babies weighed, but sodium balance was positive in the sodium-supplemented group on the first day after birth, and this group had a significantly higher incidence of bronchopulmonary dysplasia. More
Postnatal alterations in body water distribution
recently, Hartnoll et al.19 randomized infants born at 25–30 weeks' gestation to receive a sodium intake of 4 mmol/kg/day from the first day after birth or when a weight loss of 6% had occurred. Extracellular fluid volume was measured at birth and on day 14. A significant reduction in extracellular fluid volume was observed in the group who received the delayed intake of sodium, in contrast to the early-intake group, in whom no reduction was seen. By the end of the first week, 35% of babies in the delayed-supplemented group, compared with 8.7% of the early-supplemented group, no longer required supplemental oxygen. At 28 days after birth, 82% of the early-supplemented group but only 60% of the late-supplemented group had a continuing requirement for additional oxygen. There was no difference between the groups in the rate of reduction of pulmonary artery pressure,20 suggesting that the poorer respiratory outcome in the group receiving the earlier sodium intake was influenced by persistent expansion of the extracellular compartment and delayed clearance of pulmonary interstitial fluid. Early postnatal weight loss reflects both the loss of body water and the loss or gain of body solids. As nutritional support for sick, preterm babies improves, it is likely that early postnatal weight loss will be diminished, although body water will still be lost to the same extent. This was shown in a study comparing healthy preterm babies with a group with respiratory distress syndrome during the first week after birth. Both groups lost an identical amount of body water—10% of the total body water content at birth. The healthy babies, however, lost a maximum of 5.9% of their birthweight, in contrast to 8.6% in the respiratory distress group. This was because although both groups gained in body solids during the period of weight loss, the healthy babies, who received a higher energy intake, gained solids to a significantly greater extent.17
Excessive fluid intake Why do neonatal pediatricians remain concerned about so-called ‘excessive’ fluid intake? Associations have been described between high fluid intake and an increased risk of symptomatic patent ductus arteriosus,21,22 necrotizing enterocolitis23 and bronchopulmonary dysplasia.16,24–27 In the former condition, an expanded intravascular compartment might exacerbate left-to-right shunting, and in the latter conditions, interstitial oedema has been implicated in pathogenesis. An increased quantity of interstitial lung water will increase the amount of ventilatory support required and poten-
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tiate pulmonary barotrauma. Of relevance is the fact that sodium intake was not controlled in these studies, so increased ‘fluid’ meant an increased intake of both sodium and water. There is good evidence that extracellular water overload increases the risks and severity of respiratory illness in the newborn,19,28–31 and weight gain in the first days after birth in babies with respiratory distress syndrome is associated with an increased risk of developing chronic lung disease.25 Taken together, the evidence suggests that it is the inappropriate early intake of sodium and resulting expansion of the extracellular compartment, rather than an excessive intake of fluid, that is responsible for the increase in morbidity. Tang et al.17 compared healthy preterm babies with a group with respiratory distress syndrome. Although the latter group received the same volume of fluid as the healthy babies, there was no difference between the groups in the amount of body water lost by the end of the first week. In addition, there was no relationship between the volume of fluid administered and total body water lost.
Water excretion In contrast to the limited ability to excrete a sodium load, the ability of the preterm neonate to excrete a water load is less likely to lead to clinical difficulty. Preterm babies are able to achieve minimal urine osmolalities similar to those of adults, and diluting ability is unlikely to limit water excretion. The peak urine flow of mature infants given a water load is the same as that of adults when expressed per unit body water.32 Coulthard and Hey33 showed that healthy preterm babies were able to adjust their water excretion appropriately from the second day after birth when their daily intake was varied between 95 and 200 ml/kg, the sodium intake remaining constant. The fractional excretion of water increased from a mean of 7.4 to 13.1% of the filtered volume with the higher intake. A similarly high fractional excretion of water in adults would result in a daily urine volume of over 20 l. Water excretion is largely regulated by antidiuretic hormone (ADH), arginine vasopressin. ADH release is stimulated by a rise in osmolality and also by baroreceptors located in the heart and great vessels. ADH has two principal actions. It increases the permeability of the renal collecting ducts and thereby the reabsorption of water, and it is a potent vasoconstrictor, contributing to the maintenance of blood pressure. The pressor effect of ADH appears to be one of the mediators through
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which central arterial blood pressure is maintained, and both hypovolemia and hypotension will result in a rise in circulating ADH.34 Under experimental conditions, a rise in ADH occurs when intravascular volume falls by about 10%.34 A raised circulating ADH concentration and hyponatremia are common in acutely ill infants and suggest that baroreceptordriven ADH release is responsible for impaired water excretion in this situation. Gerigk et al.35 found that although plasma osmolality was lower in acutely ill infants and children in a large, prospective study, compared with controls, both ADH and plasma renin activity were raised, indicating activation of the renin–angiotensin–aldosterone system. The intravenous infusion of isotonic saline resulted in a better reduction in ADH and plasma renin activity than was seen with hypotonic saline and oral fluid. This suggested that ADH was appropriately elevated as a consequence of a reduced intravascular volume. The recognition of an inadequate intravascular volume can be difficult, and it has been shown that only a third of acutely ill infants and children show overt signs of dehydration.35 Newborn babies are at particular risk of intravascular volume depletion.36 Immediate cord clamping may result in as much as a 50% reduction in blood volume when compared with late clamping.37 Neonates admitted to intensive care are also vulnerable to the effects of frequent blood sampling. As the normal range for blood pressure in the newborn is wide, and blood pressure correlates poorly with blood volume,38,39 blood pressure measurements cannot be relied upon to detect hypovolemia. Other methods of assessment of the adequacy of the circulating volume using central venous pressure monitoring,40 capillary refill time, Doppler echocardiographic assessment of cardiac output41 (see also the chapter by N. Evans in the volume) and core–peripheral temperature difference—which correlates with circulating arginine vasopressin level14—should be utilized. Postoperatively, a low serum sodium concentration is usually the result of unrecognized intravascular volume depletion with ADH-driven water retention and the continuing provision of salt-poor fluid, and not due to the syndrome of inappropriate ADH secretion (SIADH). True SIADH is rare in neonatal intensive care, and the diagnosis should be made only when the criteria originally laid down by Bartter and Schwartz42 have been fulfilled. In SIADH, hyponatremia occurs with normovolemia, normal blood pressure, normal renal, cardiac and thyroid function and continuing sodium excretion. The appropriate management of postoperative
N. Modi
fluid balance includes the relative restriction of salt-poor fluid and the adequate use of saltcontaining fluid.43 Normal saline rather than colloid is now considered to be the preferred fluid.44 Once water retention and hyponatremia have occurred, water restriction is necessary to correct the hyponatremia safely.
The growing infant Growth is of paramount importance in the newborn baby. Once the phase of immediate postnatal adaptation is over, the management of fluid and electrolyte balance must be tailored to the demands of growth. Sodium is a permissive factor for growth, deficiency of which inhibits DNA synthesis in the most immature cells.45 Chronic limitation of sodium intake is associated not only with extracellular volume contraction and poor weight gain, but also with poor skeletal and tissue growth46–49 and adverse neurodevelopmental outcome.47 Human milk provides a daily sodium intake of about 1 mmol/kg body weight, which is sufficient for normal growth if retained. The full-term baby is able to do so virtually completely as a result of both renal tubular and intestinal reabsorption. Extremely immature babies, however, require a sodium intake of at least 4 mmol/kg/day, or more if being treated with xanthines or other diuretics, in order to ensure the retention of 1 mmol/kg/day.48 In babies below 32 weeks' gestation, a sodium intake of at least 4 mmol/kg/day should be commenced once postnatal weight loss is underway.
Sodium depletion If preterm babies are fed unsupplemented or unfortified breast milk, chronic sodium depletion will be revealed in the first instance by poor weight gain. The serum sodium level will remain within normal limits until there is a profound depletion of the extracellular compartment. The effect of progressive depletion in humans was well demonstrated in experiments conducted by McCance in the 1930s. In adult human volunteers in whom progressive salt depletion was induced by a salt-free diet and vigorous sweating50 and in whom water intake was unrestricted, whole-body sodium depletion was initially accompanied by rapid weight loss and isotonic contraction of the extracellular compartment. As the maintenance of intravascular volume and blood pressure overrides the defence of tonicity, with increasing depletion affecting the intravascular compartment, baroreceptor-stimulated, ADH-induced water reabsorption slowed down the rate of weight loss but
Postnatal alterations in body water distribution
serum sodium and osmolality fell. As a fall in serum sodium is a late sign, sodium depletion will be missed unless careful attention is paid to whether or not an infant is gaining weight at an appropriate rate. Sodium supplementation at 4 mmol/kg/day should continue until around 32–34 weeks' postmenstrual age, by which time maturation of sodium conservation should have occurred.51,52 It is not known whether supplementation to this extent beyond this time is harmful and increases the risk of later hypertension.
Conclusions The clinical management of the newborn baby should be tailored to the pace of postnatal adaptation. The importance of facilitating normal physiological alterations in the perinatal period cannot be overemphasized. It is normal for newborn babies to lose extracellular fluid immediately after birth, with a commensurate loss of sodium and water. The demands of growth then call for an intake of sodium sufficient to contend with the reduced ability of the extremely preterm infant to retain sodium. Impaired water excretion and resulting hypo-osmolality and hyponatremia are not uncommon in neonatal intensive care situations when an inadequate intravascular volume goes unrecognized.
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References 1. Friis Hansen B. Water distribution in the fetus and newborn infant. Acta Paediatr Scand 1983;305(Suppl):7–11. 2. Bauer K, Versmold H. Postnatal weight loss in preterm neonates less than 1500 g is isotonic dehydration of the extracellular volume. Acta Paediatr Scand 1989;360(Suppl): 37–42. 3. Bauer K, Bovermann G, Roithmaier A et al. Body composition, nutrition and fluid balance during the first two weeks of life in preterm neonates weighing less than 1500 g. J Pediatr 1991;118:615–20. 4. Heimler R, Doumas BT, Jendrzejczak BM et al. Relationship between nutrition, weight change and fluid compartments in preterm infants during the first week of life. J Pediatr 1993;122:110–4. 5. Shaffer SG, Bradt SK, Hall RT. Postnatal changes in total body water and extracellular volume in the preterm infant with respiratory distress syndrome. J Pediatr 1986; 109:509–14. 6. Shaffer SG, Meade VM. Sodium balance and extracellular volume regulation in very low birth weight infants. J Pediatr 1989;115:285–90. 7. Singhi SC, Sood V, Bhakoo NK et al. Composition of postnatal weight loss and subsequent weight gain in preterm infants. Indian J Med Res 1995;101:157–62. 8. Modi N, Hutton JL. The influence of postnatal respiratory adaptation on sodium handling in preterm neonates. Early Hum Dev 1990;21:11–20. 9. Be ´tre ´mieux P, Modi N, Hartnoll G et al. Longitudinal changes in extracellular fluid volume, sodium excretion and atrial
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natriuretic peptide, in preterm neonates with hyaline membrane disease. Early Hum Dev 1995;41:221–2. Kojima T, Hirata Y, Fukuda Y et al. Plasma atrial natriuretic peptide and spontaneous diuresis in sick neonates. Arch Dis Child 1987;62:667–70. Rozycki JH, Baumgart S. Atrial natriuretic factor and postnatal diuresis in respiratory distress syndrome. Arch Dis Child 1991;66:43–7. Tulassay T, Seri I, Rascher W. Atrial natriuretic peptide and extracellular volume control after birth. Acta Paediatr Scand 1987;76:444–6. Aranda JV, Chemtob S, Laudignon N et al. Furosemide and vitamin E: two problem drugs in neonatology. Pediatr Clin N Am 1986;33:583–602. Lambert HJ, Coulthard MG, Palmer JM et al. Control of sodium and water balance in the preterm neonate. Pediatr Nephrol 1990;4:C53. Rees L, Shaw JCL, Brook CDG et al. Hyponatraemia in the first week of life. II. Sodium and water balance. Arch Dis Child 1984;59:423–9. Costarino AT, Gruskay JA, Corcoran L et al. Sodium restriction versus daily maintenance replacement in very low birth weight premature neonates: a randomised, blind therapeutic trial. J Pediatr 1992;120:99–106. Tang W, Ridout D, Modi N. Influence of respiratory distress syndrome on body composition after preterm birth. Arch Dis Child 1997;77:F28–31. Tang W, Modi N, Clark P. Dilution kinetics of H218O for the measurement of total body water in preterm babies in the first week after birth. Arch Dis Child 1994;69:28–31. Hartnoll G, Be ´tre ´mieux P, Modi N. Randomised controlled trial of postnatal sodium supplementation on body composition in 25–30 week gestation infants. Arch Dis Child Fetal Neonatal Ed 2000;82:F24–8. Hartnoll G, Modi N, Be ´tre ´mieux P. Randomised controlled trial of postnatal sodium supplementation in 25–30 week gestational age infants: effects on cardiopulmonary adaptation. Arch Dis Child Fetal Neonatal Ed 2001;85: F29–32. Bell EF, Warburton D, Stonestreet B et al. Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. N Engl J Med 1980;302:598–604. Stevenson JG. Fluid administration in the association of patent ductus arteriosus complicating respiratory distress syndrome. J Pediatr 1977;90:257–61. Bell EF, Warburton D, Stonestreet B et al. High volume fluid intake predisposes premature infants to necrotising enterocolitis. Lancet 1979;ii:90. Brown ER, Stark A, Sosneko I et al. Bronchopulmonary dysplasia: possible relationship to pulmonary oedema. J Pediatr 1978;92:982–4. Van Marter LJ, Leviton A, Allred EN et al. Hydration during the first days of life and the risk of bronchopulmonary dysplasia in low birth weight infants. J Pediatr 1990;116: 942–9. Kavvadia V, Greenough A, Dimitriou G et al. Randomised trial of fluid restriction in ventilated very low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2000;83:F91–6. Tammela OK, Koivisto ME. Fluid restriction for preventing bronchopulmonary dysplasia? Reduced fluid intake during the first weeks of life improves the outcome of low-birth-weight infants. Acta Paediatr 1992;81:207–12. Mohan P, Rojas J, Davidson KK et al. Pulmonary air leak associated with neonatal hyponatraemia in premature infants. J Pediatr 1984;105:153–7.
306 29. Rojas J, Mohan P, Davidson KK. Increased extracellular water volume associated with hyponatraemia at birth in premature infants. J Pediatr 1984;105:158–61. 30. Singhi SC, Chookang E. Maternal fluid overload during labour, transplacental hyponatraemia and risk of transient neonatal tachpnoea in term infants. Arch Dis Child 1984; 59:1155–8. 31. Singhi SC, Chookang E, Hall JS et al. Iatrogenic neonatal and maternal hyponatraemia following oxytocin and aqueous glucose infusion during labour. Br J Obstet Gynaecol 1985; 92:356–63. 32. McCance RA, Naylor NJB, Widdowson EM. The response of infants to a large dose of water. Arch Dis Child 1954; 29:104–9. 33. Coulthard MG, Hey EN. Effect of varying water intake on renal function in healthy preterm babies. Arch Dis Child 1985;60:614–20. 34. Dunn FL, Brennan TJ, Neelson AE et al. The role of blood osmolality and volume in regulating vasopressin secretion by the rat. J Clin Invest 1976;52:3212–9. 35. Gerigk M, Gnehm HE, Rascher W. Arginine vasopressin and renin in acutely ill children: implications for fluid therapy. Acta Paediatr 1996;85:550–3. 36. Wardrop CA, Holland BM. The roles and vital importance of placental blood to the newborn infant. J Perinatal Med 1995;23:139–43. 37. Linderkamp O, Nelle M, Kraus M et al. The effects of early and late cord clamping on blood viscosity and other haemorheological parameters in full term neonates. Acta Paediatr 1992;81:745–50. 38. Barr PA, Bailey PE, Sumners J et al. Relation between arterial blood pressure and blood volume and effect of infused albumin in sick preterm infants. Pediatrics 1977; 60:282–9. 39. Bauer K, Linderkamp O, Versmold HT. Systolic blood pressure and blood volume in preterm infants. Arch Dis Child 1993;69:521–2.
N. Modi 40. Skinner JR, Milligan DWA, Hunter S et al. Central venous pressure in the ventilated neonate. Arch Dis Child 1992; 67:374–7. 41. Pladys P, Be ´tre ´mieux P, Lefrancois C et al. Apport de l'echocardiographie Doppler dans l'evaluation des effets de l'expansion vole ´mique chez le nouveau-ne ´. Arch Pediatr 1994;1:470–6. 42. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1967;42: 790–806. 43. Judd BA, Haycock GB, Dalton N et al. Hyponatraemia in premature babies and following surgery in older children. Acta Paediatr Scand 1987;76:385–93. 44. So KW, Fok TF, Ng PC et al. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child 1997;76:F43–6. 45. Ostlund EV, Eklof AC, Aperia A. Salt deficient diet and early weaning inhibit DNA synthesis in immature rat proximal tubular cells. Pediatr Nephrol 1993;7:41–4. 46. Chance GW, Radde IC, Willis DM et al. Postnatal growth of infants of <1.3 kg birth weight; effects of metabolic acidosis, of caloric intake and of calcium, sodium and phosphate supplementation. J Pediatr 1977;91:787–93. 47. Haycock GB. The influence of sodium on growth in infancy. Pediatr Nephrol 1993;7:871–5. 48. Haycock GB, Aperia A. Salt and the newborn kidney. Pediatr Nephrol 1991;5:65–70. 49. Wassner SJ. The effect of sodium repletion on growth and protein turnover in sodium depleted rats. Pediatr Nephrol 1991;5:501–4. 50. McCance RA. Experimental sodium chloride deficiency in man. Proc R Soc Lond (Biol) 1936;119:245–68. 51. Roy RN, Chance GW, Radde IC et al. Late hyponatraemia in very low birthweight infants (<1.3 kg). Pediatr Res 1976; 10:526–31. 52. Al-Dahhan J, Haycock GB, Nichol B et al. Sodium homeostasis in term and preterm neonates. III. Effect of salt supplementation. Arch Dis Child 1984;59:945–50.
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
Review article
Clinical implications of postnatal alterations in body water distribution Neena Modi * a
Faculty of Medicine, Imperial College of Science, Technology and Medicine, Chelsea and Westminster Hospital, London, UK b Hammersmith and Queen Charlotte's Hospitals, Du Cane Road, London, W12 0NN, UK
KEYWORDS Infant; Newborn; Body water distribution; Extracellular fluid volume; Sodium and water balance
Summary Substantial alterations take place in the quantity and distribution of body water compartments after birth. Clinical management must be tailored to the pace of postnatal adaptation, and the neonatal physician must be aware of these alterations in order to promote both normal physiological change and growth. © 2003 Published by Elsevier Ltd.
Body water compartments The newborn baby is largely water. Total body water comprises approximately 75% of body weight at full term and about 80–85% in babies between 26 and 31 weeks' gestation.1 Given this, it is easy to understand why the maintenance of water and electrolyte homeostasis in neonates is so important and so easily perturbed. The size of the extracellular compartment decreases steadily throughout life, from around 65% of body weight at 26 weeks' gestation, to 40% at term and 20% by the age of 10 years.1 Of particular relevance to the neonatal pediatrician is the fact that a more abrupt contraction occurring shortly after birth is superimposed on this gradual reduction.2–7 During this period, there is isotonic fluid loss, largely from the interstitial * Faculty of Medicine, Imperial College, 4th Floor, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel.: +44-20-8237-5102; fax: +44-20-8746-8887 E-mail address: [email protected] (N. Modi).
compartment, this being clinically evidenced by postnatal weight loss.
Postnatal adaptation How is this response to the start of life in a gaseous environment brought about? In healthy babies, the loss of extracellular fluid occurs rapidly, but this is delayed in babies with respiratory distress syndrome.8 Observations that are now considered classical, of the natural history of respiratory distress syndrome prior to the use of antenatal steroids and postnatally administered exogenous surfactant, provided the first clues. In these infants, it was well recognized that the onset of improvement in respiratory function was marked by a diuresis. An abrupt increase in urinary output was a reassuring sign to clinicians because it meant that the baby was on the road to recovery. This observation suggested that the onset of extracellular fluid loss was closely related to cardiopulmonary adaptation. Several studies now suggest that the contraction of the extracellular compartment is triggered by
1084-2756/03/$ - see front matter © 2003 Published by Elsevier Ltd. doi:10.1016/S1084-2756(03)00043-5
302
atrial natriuretic peptide. Atrial natriuretic peptide is a natriuretic hormone produced within the cells of the myocardium, the release of which is stimulated by stretch of the atrial wall. When pulmonary vascular resistance falls as an adaptation to birth,9–12 pulmonary blood flow increases and left atrial venous return increases, stimulating the release of atrial natriuretic peptide. In addition, the intravascular compartment may be expanded acutely after birth by a variable placental transfusion and by the reabsorption of lung liquid. As the diuresis/natriuresis occurs only as a consequence of the fall in pulmonary vascular resistance—hence the close temporal relationship with improving respiratory function—it is not surprising that attempts to improve the course of respiratory distress syndrome with the use of furosemide have been unsuccessful.13
Sodium balance Sodium is the principal electrolyte of extracellular fluid. If extracellular fluid is lost, this means that there is a loss of sodium and water. The postnatal isotonic loss of extracellular fluid in the first days after birth must imply that net water and sodium balance is negative during this period. This has been demonstrated in careful observational studies of newborn infants. If neonates are given an increased intake of sodium in the first days after birth, there is an increase in sodium excretion6,14,15 until contraction of the extracellular compartment occurs. Sodium balance then becomes positive, commensurate with the need for growth. Preterm babies do, however, have a limited, albeit variable, capacity to excrete a sodium load so that, despite increasing excretion in response to an increase in intake, they are at risk of sodium retention.9,16 If the intake of water is limited at the same time, these babies readily become hypernatremic. This was demonstrated in a study by Shaffer and Meade6 in which babies between 25 and 31 weeks of gestation were randomized to receive a sodium intake of 3 or 1 mmol/kg/day. The intake of water was restricted to 75 ml/kg/day on the first day, increasing by 10 ml/kg/day until day 5. In the former group, 50% became hypernatremic, compared with 20% in the latter. If a more liberal intake of water accompanies the intake of sodium, extracellular tonicity is maintained but the extracellular compartment expands. This is shown by weight gain at a time when weight loss is to be expected. In the majority of babies, this cumulative positive balance is subsequently
N. Modi
lost, so that the normal postnatal change in body water distribution occurs but is delayed.9
Clinical implications The management of sodium and water balance during the period of postnatal adaptation is governed by principles that differ from those governing management afterwards. Early fluid management, during the period of postnatal adaptation, should permit an isotonic contraction of the extracellular compartment and a brief period of negative sodium and water balance. The baby with respiratory distress syndrome may be regarded as a model of delayed postnatal maturation in whom the postnatal diuresis is delayed, and who is at great risk of persisting expansion of the extracellular compartment. In contrast, in the healthy preterm baby, postnatal cardiopulmonary adaptation occurs over the same rapid timescale as in a full-term baby. Providing routine sodium supplements in parenteral fluid without any consideration of the phase of postnatal adaptation may promote the retention of extracellular fluid, including pulmonary interstitial fluid. In newborn infants with respiratory distress, routine sodium supplementation in parenteral fluid should be avoided until the physiological postnatal diuresis/natriuresis has occurred.8,9 If this point cannot be determined, supplementation should be deferred until postnatal weight loss has occurred.3,7,17 There is no ‘correct’ figure for postnatal weight loss as hydration at birth is variable18 and birthweight does not accurately predict extracellular water volume.5 Although antenatal glucocorticoid therapy induces the maturation of sodium excretion and confers partial protection against the adverse consequences of early sodium administration, the early administration of ‘maintenance’ sodium to infants admitted to neonatal intensive care units remains unnecessary and adversely affects respiratory outcome even in babies who received antenatal steroids. Costarino et al.16 first provided some justification for this tailored approach to the introduction of parenteral sodium in a blind trial comparing sodium restriction in the first 5 days after birth with sodium supplementation at 3–4 mmol/kg/day immediately after birth. Water was prescribed independently. Extracellular volume was not measured in this study, nor were the babies weighed, but sodium balance was positive in the sodium-supplemented group on the first day after birth, and this group had a significantly higher incidence of bronchopulmonary dysplasia. More
Postnatal alterations in body water distribution
recently, Hartnoll et al.19 randomized infants born at 25–30 weeks' gestation to receive a sodium intake of 4 mmol/kg/day from the first day after birth or when a weight loss of 6% had occurred. Extracellular fluid volume was measured at birth and on day 14. A significant reduction in extracellular fluid volume was observed in the group who received the delayed intake of sodium, in contrast to the early-intake group, in whom no reduction was seen. By the end of the first week, 35% of babies in the delayed-supplemented group, compared with 8.7% of the early-supplemented group, no longer required supplemental oxygen. At 28 days after birth, 82% of the early-supplemented group but only 60% of the late-supplemented group had a continuing requirement for additional oxygen. There was no difference between the groups in the rate of reduction of pulmonary artery pressure,20 suggesting that the poorer respiratory outcome in the group receiving the earlier sodium intake was influenced by persistent expansion of the extracellular compartment and delayed clearance of pulmonary interstitial fluid. Early postnatal weight loss reflects both the loss of body water and the loss or gain of body solids. As nutritional support for sick, preterm babies improves, it is likely that early postnatal weight loss will be diminished, although body water will still be lost to the same extent. This was shown in a study comparing healthy preterm babies with a group with respiratory distress syndrome during the first week after birth. Both groups lost an identical amount of body water—10% of the total body water content at birth. The healthy babies, however, lost a maximum of 5.9% of their birthweight, in contrast to 8.6% in the respiratory distress group. This was because although both groups gained in body solids during the period of weight loss, the healthy babies, who received a higher energy intake, gained solids to a significantly greater extent.17
Excessive fluid intake Why do neonatal pediatricians remain concerned about so-called ‘excessive’ fluid intake? Associations have been described between high fluid intake and an increased risk of symptomatic patent ductus arteriosus,21,22 necrotizing enterocolitis23 and bronchopulmonary dysplasia.16,24–27 In the former condition, an expanded intravascular compartment might exacerbate left-to-right shunting, and in the latter conditions, interstitial oedema has been implicated in pathogenesis. An increased quantity of interstitial lung water will increase the amount of ventilatory support required and poten-
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tiate pulmonary barotrauma. Of relevance is the fact that sodium intake was not controlled in these studies, so increased ‘fluid’ meant an increased intake of both sodium and water. There is good evidence that extracellular water overload increases the risks and severity of respiratory illness in the newborn,19,28–31 and weight gain in the first days after birth in babies with respiratory distress syndrome is associated with an increased risk of developing chronic lung disease.25 Taken together, the evidence suggests that it is the inappropriate early intake of sodium and resulting expansion of the extracellular compartment, rather than an excessive intake of fluid, that is responsible for the increase in morbidity. Tang et al.17 compared healthy preterm babies with a group with respiratory distress syndrome. Although the latter group received the same volume of fluid as the healthy babies, there was no difference between the groups in the amount of body water lost by the end of the first week. In addition, there was no relationship between the volume of fluid administered and total body water lost.
Water excretion In contrast to the limited ability to excrete a sodium load, the ability of the preterm neonate to excrete a water load is less likely to lead to clinical difficulty. Preterm babies are able to achieve minimal urine osmolalities similar to those of adults, and diluting ability is unlikely to limit water excretion. The peak urine flow of mature infants given a water load is the same as that of adults when expressed per unit body water.32 Coulthard and Hey33 showed that healthy preterm babies were able to adjust their water excretion appropriately from the second day after birth when their daily intake was varied between 95 and 200 ml/kg, the sodium intake remaining constant. The fractional excretion of water increased from a mean of 7.4 to 13.1% of the filtered volume with the higher intake. A similarly high fractional excretion of water in adults would result in a daily urine volume of over 20 l. Water excretion is largely regulated by antidiuretic hormone (ADH), arginine vasopressin. ADH release is stimulated by a rise in osmolality and also by baroreceptors located in the heart and great vessels. ADH has two principal actions. It increases the permeability of the renal collecting ducts and thereby the reabsorption of water, and it is a potent vasoconstrictor, contributing to the maintenance of blood pressure. The pressor effect of ADH appears to be one of the mediators through
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which central arterial blood pressure is maintained, and both hypovolemia and hypotension will result in a rise in circulating ADH.34 Under experimental conditions, a rise in ADH occurs when intravascular volume falls by about 10%.34 A raised circulating ADH concentration and hyponatremia are common in acutely ill infants and suggest that baroreceptordriven ADH release is responsible for impaired water excretion in this situation. Gerigk et al.35 found that although plasma osmolality was lower in acutely ill infants and children in a large, prospective study, compared with controls, both ADH and plasma renin activity were raised, indicating activation of the renin–angiotensin–aldosterone system. The intravenous infusion of isotonic saline resulted in a better reduction in ADH and plasma renin activity than was seen with hypotonic saline and oral fluid. This suggested that ADH was appropriately elevated as a consequence of a reduced intravascular volume. The recognition of an inadequate intravascular volume can be difficult, and it has been shown that only a third of acutely ill infants and children show overt signs of dehydration.35 Newborn babies are at particular risk of intravascular volume depletion.36 Immediate cord clamping may result in as much as a 50% reduction in blood volume when compared with late clamping.37 Neonates admitted to intensive care are also vulnerable to the effects of frequent blood sampling. As the normal range for blood pressure in the newborn is wide, and blood pressure correlates poorly with blood volume,38,39 blood pressure measurements cannot be relied upon to detect hypovolemia. Other methods of assessment of the adequacy of the circulating volume using central venous pressure monitoring,40 capillary refill time, Doppler echocardiographic assessment of cardiac output41 (see also the chapter by N. Evans in the volume) and core–peripheral temperature difference—which correlates with circulating arginine vasopressin level14—should be utilized. Postoperatively, a low serum sodium concentration is usually the result of unrecognized intravascular volume depletion with ADH-driven water retention and the continuing provision of salt-poor fluid, and not due to the syndrome of inappropriate ADH secretion (SIADH). True SIADH is rare in neonatal intensive care, and the diagnosis should be made only when the criteria originally laid down by Bartter and Schwartz42 have been fulfilled. In SIADH, hyponatremia occurs with normovolemia, normal blood pressure, normal renal, cardiac and thyroid function and continuing sodium excretion. The appropriate management of postoperative
N. Modi
fluid balance includes the relative restriction of salt-poor fluid and the adequate use of saltcontaining fluid.43 Normal saline rather than colloid is now considered to be the preferred fluid.44 Once water retention and hyponatremia have occurred, water restriction is necessary to correct the hyponatremia safely.
The growing infant Growth is of paramount importance in the newborn baby. Once the phase of immediate postnatal adaptation is over, the management of fluid and electrolyte balance must be tailored to the demands of growth. Sodium is a permissive factor for growth, deficiency of which inhibits DNA synthesis in the most immature cells.45 Chronic limitation of sodium intake is associated not only with extracellular volume contraction and poor weight gain, but also with poor skeletal and tissue growth46–49 and adverse neurodevelopmental outcome.47 Human milk provides a daily sodium intake of about 1 mmol/kg body weight, which is sufficient for normal growth if retained. The full-term baby is able to do so virtually completely as a result of both renal tubular and intestinal reabsorption. Extremely immature babies, however, require a sodium intake of at least 4 mmol/kg/day, or more if being treated with xanthines or other diuretics, in order to ensure the retention of 1 mmol/kg/day.48 In babies below 32 weeks' gestation, a sodium intake of at least 4 mmol/kg/day should be commenced once postnatal weight loss is underway.
Sodium depletion If preterm babies are fed unsupplemented or unfortified breast milk, chronic sodium depletion will be revealed in the first instance by poor weight gain. The serum sodium level will remain within normal limits until there is a profound depletion of the extracellular compartment. The effect of progressive depletion in humans was well demonstrated in experiments conducted by McCance in the 1930s. In adult human volunteers in whom progressive salt depletion was induced by a salt-free diet and vigorous sweating50 and in whom water intake was unrestricted, whole-body sodium depletion was initially accompanied by rapid weight loss and isotonic contraction of the extracellular compartment. As the maintenance of intravascular volume and blood pressure overrides the defence of tonicity, with increasing depletion affecting the intravascular compartment, baroreceptor-stimulated, ADH-induced water reabsorption slowed down the rate of weight loss but
Postnatal alterations in body water distribution
serum sodium and osmolality fell. As a fall in serum sodium is a late sign, sodium depletion will be missed unless careful attention is paid to whether or not an infant is gaining weight at an appropriate rate. Sodium supplementation at 4 mmol/kg/day should continue until around 32–34 weeks' postmenstrual age, by which time maturation of sodium conservation should have occurred.51,52 It is not known whether supplementation to this extent beyond this time is harmful and increases the risk of later hypertension.
Conclusions The clinical management of the newborn baby should be tailored to the pace of postnatal adaptation. The importance of facilitating normal physiological alterations in the perinatal period cannot be overemphasized. It is normal for newborn babies to lose extracellular fluid immediately after birth, with a commensurate loss of sodium and water. The demands of growth then call for an intake of sodium sufficient to contend with the reduced ability of the extremely preterm infant to retain sodium. Impaired water excretion and resulting hypo-osmolality and hyponatremia are not uncommon in neonatal intensive care situations when an inadequate intravascular volume goes unrecognized.
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