Archives of Disease in Childhood 1993; 69: 87-91

CURRENT TOPIC

Sodium intake and preterm babies

Neena Modi

How much sodium do preterm babies needand when should sodium supplementationstart? Sodium is required to maintain extra-cellular tonicity and positive sodium balance isa prerequisite of growth. However, for mostpreterm babies, growth is unlikely during thefirst days after birth, as overall nutritionalintake is limited. The primary aim of nutri-tional management, during this time, shouldbe to provide an energy intake sufficient tominimise tissue breakdown. Total energyexpenditure in stable, non-growing pretermbabies in the first few days after birth varieswidely around 84-168 kJ (20-40 kcal)Ikglday. lMany infants do not even receive such aminimum intake in this time.

In addition, during the first days after birth,several adaptive processes must take place ifthe newborn baby is to negotiate successfullythe transition from the intrauterine environ-ment. Failure of adaptation of the cardio-pulmonary system is the commonest cause ofperinatal death. Less attention has been paid tothe adaptive changes that occur in body waterdistribution, though failure of, or delay in,achieving this aspect of postnatal adaptation isalso a cause of significant morbidity.2-7

Department ofPaediatrics andNeonatal Medicine,Royal PostgraduateMedicine School, DuCane Road, LondonW12 ONNCorrespondence to:Dr Modi.

Postnatal alterations in body waterWhat are the normal changes in body waterdistribution after birth and how do they occur?After birth, a contraction of the extracellularcompartnent takes place due to loss of inter-stitial fluid8-12 and accounts, at least in part,for early postnatal weight loss. A contraction inthe percentage of total body weight that isextracellular water takes place steadilythroughout life. Extracellular water decreasesfrom around 65% at 28 weeks' gestation to40% at term and 20% by the age of 10 years.13Superimposed on this gradual change withtime, there is a more abrupt contraction in theextracellular compartment that occurs shortlyafter birth. This change appears to be closelyinterrelated with cardiopulmonary adaptation.Several studies now suggest that the postnatalnatriuresis/diuresis and extracellular volumecontraction is triggered by a surge in atrialnatriuretic peptide release brought about byincreased atrial stretch as pulmonary vascularresistance falls. 1418 The intravascular com-partment may also be acutely expanded duringbirth because of reabsorption of lung liquidand a variable placental transfusion. It hasbeen suggested that there is movement of

water from the intracellular to the extracellularcompartment immediately after birth, thoughthe evidence for this is not conclusive as thestudy in question drew conclusions from crosssectional data from dehydrated subjects.'9

If isotonic contraction of the extracellularcompartment is to occur, net water and sodiumbalance in the first days after birth must benegative and should be regarded as physiologi-cal. That early negative sodium balance isphysiological is borne out by the observationthat, in healthy newborn babies, an increase inearly sodium intake leads to an increase insodium excretion.122021 However all pretermbabies have a limited (but variable) capacity toexcrete a sodium load so that, despite increas-ing excretion in response to an increase inintake, sodium retention readily occurs.222Shaffer and Meade studied sodium balance andextracellular volume regulation in a group ofbabies between 25-31 weeks' gestation in thefirst 10 days after birth.12 In the group given asodium intake of 3 mmol/kg/day, 50% becamehypernatraemic, as did 20% in the group given1 mmol/kg/day. In this study, water intakebegan at 75 ml/kg/day on the first day, increas-ing by 10 ml/kg/day until day 5. Ifa more liberalwater intake is allowed in conjunction withsodium intake, extracellular tonicity is main-tained by expansion of the extracellular com-partnent. This is a common occurrence inneonatal intensive care units; many babies gainweight in the first days after birth, when nutri-tional intake is clearly insufficient to sustaingrowth and have a positive sodium balance witha normal serum sodium concentration.22 23 Inthe majority of babies this cumulative positivebalance is subsequently lost; in other words, thenormal postnatal changes in body water dis-tribution occur, but are delayed.22 The wellrecognised diuresis that accompanies improv-ing respiratory function in babies with respira-tory distress syndrome is in fact a natriuresisI4and is an example of delayed postnatal adapta-tion. Costarino et al confirmed some of theseobservations in a blind trial comparing sodiumrestriction in the first five days after birth withsodium supplementation of 3-4 mmol/kg/dayfrom birth.2 Water intake was administeredindependently. Unfortunately extracellularvolume was not measured in this study, norwere the babies weighed. However, sodiumbalance was positive in the sodium supple-mented group on the first day after birth andthis group had a significantly higher incidenceof bronchopulmonary dysplasia.

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Developmental changes in sodiumtransportHow are the age dependent alterations in theregulation of sodium balance brought about?Immediately after birth there is a net stimulusto excrete sodium, followed later by a netstimulus to retain sodium as the demands ofgrowth become paramount. In preterm babiesboth abilities are limited. The low glomerularfiltration rate24 is not a limiting factor forsodium excretion. Circulating levels of natri-uretic agents are variable and are influenced bythe stage of cardiopulmonary adaptation.'6The renin-angiotensin-aldosterone systemcannot be fully inhibited in preterm babiesduring intravascular volume expansion, furtherlimiting sodium excretory capacity.25 26 Thehypothesis that natriuresis may be induced byredistribution of blood flow to nephrons thatare more immature and therefore more saltlosing, remains unproved.26 The role of pro-lactin27 and the kinins28 in the regulation ofperinatal body water distribution in unclear.Of most importance appears to be that bothsodium transporting and regulating systemsundergo postnatal maturation in a complexand exquisitely controlled manner.

Sodium transportersSodium, potassium (Na+,K+)-ATPase is theenzyme responsible for active sodium transportin all eukaryotic cells. It is a transmembraneprotein, made up of two subunits, that main-tains electrochemical sodium and potassiumgradients across the cell membrane. The largerof the subunits, the a subunit, contains anintracellular ATP binding site and a phospho-rylation site and extracellular binding sites forvarious hormones and drugs. There are manyforms of Na+,K+-ATPase, each encoded byspecific groups ofNa+,K+-ATPase genes.

In renal tubular cells Na+,K+-ATPasecreates an electrochemical gradient that is theenergy source for the cotransport, involvingspecific transporter proteins, of sodium ionsand glucose and sodium ions and amino acidsand the countertransport of sodium andhydrogen ions. These transporters are alsotransmembrane proteins. There is a postnatal,maturational increase in abundance ofNa+,K+-ATPase and other transporter pro-teins.29 This postnatal increase is accompaniedby an increase in Na+,K+-ATPase mRNA.303'There are tissue specific differences in the timescale of such maturational changes.3'

RegulatorsSodium balance is subject to both long andshort term regulation. Changes in the abun-dance of sodium transporters are responsiblefor long term regulation. Glucocorticoids, forexample, lead to an increased abundance ofNa+,K+-ATPase and chronic incubation ofrenal tubular cells in an acid medium, to anincrease in the protein responsible for thecountertransport of sodium and hydrogenions. Short term regulation of sodium balanceis brought about by increases or decreases

in the activity of sodium transporters.Downregulatory factors, which cause natri-uresis, include atrial natriuretic peptide,dopamine, and diuretics. Noradrenaline is anupregulatory factor, which results in sodiumretention. Dopamine inhibits and noradrena-line stimulates, Na+,K+-ATPase activity. Therenal tubular sodium/hydrogen ion exchangeris amiloride sensitive.

Regulatory factors exert their effects via acascade of intracellular messengers. Theseintracellular signal systems also undergo post-natal maturation. End organ responsivenessincreases with postnatal maturation of cellularsignal systems,3'-33 and evidence of this atmolecular3l and cellular32 levels, now substan-tiates clinical observations.33 Atrial natriureticpeptide stimulates membrane bound guanylatecyclase, which leads to an increase in the intra-cellular second messenger, cyclic guanosinemonophosphate (cGMP), generated fromendogenous guanosine triphosphate. cGMPinteracts with specific protein kinases which inturn catalyse the phosphorylation of severalprotein substrates and finally leads to a biologi-cal effect such as inhibition of sodium re-absorption. Each step in such a cascade issubject to developmental regulation. In a studyof preterm babies, the ratio of cGMP to atrialnatriuretic peptide was found to increaseexponentially in the first three days after birth,then reaching a plateau. The ratio of sodiumexcretion to cGMP continued to increase overthe 10 days of the study.33 This suggests apostnatal increase in the atrial natriureticpeptide/cGMP/sodium excretion cascade andthus an increasing postnatal ability to excretesodium.

Periods of sensitivityIn an elegant series of experiments, Celsi andothers have shown age dependent differencesin the ability of glucocorticoids to induceNa',K+-ATPase.30 In rats, betamethasonewill increase Na+,K+-ATPase mRNA in thekidney during infancy, but not during fetallife, nor in adults. In contrast, lung tissueNa+,K+-ATPase is maximally induced byglucocorticoids during the perinatal period.The inference is that glucocorticoids interactwith other transcriptional factors, expressed inan age dependent fashion, to activate thegenes for Na+,K+-ATPase so that differenttissues have different periods of sensitivityto glucocorticoid regulation. In the future,the therapeutic activation of transcriptionalfactors determining tissue maturation may bepossible. Conversely, a note of caution mustbe sounded, as activation of transcriptionalfactors during periods of sensitivity may leadto 'imprinting', an example of which may bethe recent evidence that antenatal exposure tocorticosteroids increases the risks of laterhypertension.34

WaterNeonatal paediatricians have long beenconcerned about 'excessive' fluid intake.

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Sodium intake and preterm babies

Associations have been described between highfluid intakes and increased risk of symptomaticpatent ductus arteriosus, necrotising entero-colitis, and bronchopulmonary dysplasia.2-7 Inthe former condition an expanded intravascu-lar compartment might exacerbate left to rightshunting and in the latter conditions, intersti-tial oedema has been implicated in pathogene-sis. Regrettably, these studies have, withoutexception, failed to standardise sodium intake,so that increased 'fluid' has meant an increasedintake ofboth sodium and water. In contrast tothe reduced but rapidly altering sodium excre-tory capacity, preterm babies have less of areduced ability to excrete water and this is tosome extent compensated for by high insens-ible water losses. Coulthard and Hey haveshown that stable, preterm babies are able totolerate intakes of 200 ml/kg from the third dayafter birth, sodium intake remaining con-stant.35 They calculated that healthy pretermbabies can achieve a urine flow rate of up to7 ml/kg/hour. Leake et al found a group ofbabies between 28-34 weeks' gestation toincrease urine flow rate to a mean of 12ml/kg/hour during acute increases in infusionrate to 250 ml/kg/day.36The capacity to excrete a water load may

however be impaired in sick neonates by highcirculating levels of the antidiuretic hormone,arginine vasopressin. Babies born after fetal dis-tress or after difficult delivery have higher circu-lating arginine vasopressin concentrations thanthose born uneventfully.37 Rees et al haveshown peaks of arginine vasopressin occurringduring acute clinical events such as thedevelopment of a pneumothorax and cite thisas evidence for the frequent occurrence of in-appropriate antidiuretic hormone secretion inpreterm neonates.38 However, the secretion ofantidiuretic hormone can only be said to be'inappropriate' if it occurs in the absence ofosmotic or volume stimuli. Effective hypo-volaemia probably occurs more frequently thanis recognised in neonates receiving intensivecare and in the postoperative period.39 Moreattention should be paid to assessment of thecirculation using invasive arterial blood pres-sure and central venous pressure monitoring40and non-invasively, core-peripheral tempera-ture gradient, aiming to maintain this below1-1 5°C. The latter parameter is an extremelyuseful index of volume depletion as shown byits strong correlation with circulating argininevasopressin.21 Failure to provide adequatevolume support in the form of salt containingsolutions, preferably colloid, will lead to anappropnate stimulus to arginine vasopressinrelease, water retention, and hyponatraemia.Once this has occurred water restriction will benecessary to correct the hyponatraemia safely.

Clinical assessmentURINARY SODIUM CONCENTRATIONThe fraction of filtered sodium excreted(FeNa) and urinary sodium concentration risetransiently during the postnatal natriuresis andthen fall with postnatal age. Values for babiesbetween 25-34 weeks' gestation in the first

weeks after birth are around 5%/o and 90 mmol/lrespectively.22 'Spot' urinary sodium concen-trations bear no relationship to daily sodiumbalance22 and are of little use in determiningthe cause of hyponatraemia. A low urinarysodium concentration may be dilutionalbecause of water excess or indicative of avidsodium retention. A high urinary sodium con-centration in the presence of hyponatraemiamay be due to inappropriate antidiuretichormone secretion, to expansion of the extra-cellular compartment as in heart failure, todiuretic treatment or to true renal salt wastage.It is not uncommon for chronic sodium deple-tion to coexist with extracellular volumeexpansion as in the baby with cor pulmonalesecondary to bronchopulmonary dysplasia whohas also been on long term diuretic treatment.Fractional sodium excretion is often used inthe evaluation of the oliguric infant. A valuebelow 2.5% is said to be suggestive of prerenaloliguria and the urgent need for volumereplacement whereas a high FeNa suggestsestablished renal failure and the equally urgentneed for restriction of fluid intake. Unfor-tunately, an FeNa greater than 2-5% has poorsensitivity to distinguish intrinsic renal failurein the preterm baby.4'

SERUM SODIUM CONCENTRATIONWater balance, before the postnatal diuresis/natriuresis, is best assessed by the change inserum sodium concentration. A decrease inserum sodium suggests positive water balanceand excessive water intake; a rise in serumsodium suggests negative water balance andpossibly insufficient water intake. After the firstfew days after birth the serum sodium concen-tration may reflect either water or sodiumbalance.

URINE FLOW RATEIt is generally held that a urine output less than1 ml/kg/hour is suggestive of impaired renalfunction. This is because in the presence of arenal solute load of 15 mosm/kg/day and anapproximate maximum urinary concentrationof 500-700 mosm/kg water, solute retentionwould occur if urine flow rate were less than1 ml/kg/hour. Extremely immature infantshave considerably smaller solute loads on thefirst day after birth, and in these infants it maybe more appropriate to regard a urine flow rateof less than 0 5 ml/kg/hour on day 1 and1 ml/kg/hour thereafter, as abnormal. It hasbeen estimated that the most immaturepreterm infants might achieve a maximumurine flow rate of around 7 ml/kg/hour.35 Asneonates do not empty their bladders com-pletely on voiding and as 7% fail to void duringthe first 24 hours of life external urine col-lections of short duration may be inaccurate.

URINE OSMOLALITYWell, preterm infants are able to achieve aminimum urine osmolality of around 45mosm/kg and infants with respiratory distress

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syndrome around 90 mosm/kg.24 Maximumosmolality is of the order of 800 mosm/kgthough higher values exceeding 1000 mosm/kgare occasionally seen. Urine osmolality that liesbetween 200-400 mosm/kg usually suggeststhat fluid intake is satisfactory. However, asimmature babies in the first days after birthmay have even more limited concentratingabilities, these infants may become dehydratedwhile continuing to pass urine of low osmolal-ity. Specific gravity is often measured in placeof osmolality as it can easily be performed onthe ward. The presence of glucose or protein(both often found in samples from sick pretermbabies) will however falsely increase thespecific gravity. In addition the relationshipbetween specific gravity, as measured with arefractometer, and osmolality, differs betweenthe newborn and older children so that inthe newborn an osmolality of 400 mosm/kgis indicative of a specific gravity between1020-1030.42.

WEIGHTIsotonic expansion of the extracellular com-partment can, and frequently does, occur inthe preterm neonate. This will be missed ifchanges in body weight are not considered inconjunction with serum electrolytes. Poorgrowth, in the face of an adequate energyintake, may reflect chronic sodium depletionand this may occur with a normal or lownormal serum sodium concentration.

IMPLICATIONS OF DEVELOPMENTAL CHANGES

Weight loss in preterm babies in the first daysafter birth is associated with a reduced mor-bidity from symptomatic patent ductusarteriosus,57 necrotising enterocolitis4 andbronchopulmonary dysplasia.236 Earlymanagement should permit an isotonic contrac-tion of the extracellular compartment. In orderto allow the reduction in extracellular fluidvolume which is the basis for weight loss, theprimary necessity is to avoid an early intake ofsodium. Early water intake should be sufficientto maintain glomerular filtration to allow theexcretion of the relatively small renal soluteload43 and to maintain tonicity in the face ofhigh, but rapidly changing, transepidermallosses.44 A reasonable 'best guess' of the volumeat which to start is therefore 30-60ml/kg/day plus estimated insensible water loss.Subsequently, the appropriate volume of intakewil be determined by the nutritional content ofthe fluid used. Early physiological weight lossshould be of the order of 7% of birth weight,89but this is only an approximation as hydration atbirth is variable and birth weight does not corre-late closely with extracellular water volume.'0The principles of management of sodium

balance during the period of postnatal adapta-tion should be clearly distinguished from thosepertaining subsequently. An early intake ofsodium is unnecessary and possibly harmful andtherefore should be avoided or at leastminimised until the physiological postnataldiuresis/natriuresis.14 If this point is indeter-

minate, supplementation should be deferreduntil a steady weight loss of at least 7%/o of birthweight has occurred. Once the phase of imme-diate postnatal adaptation is over, growthbecomes of paramount importance. Chroniclimitation of sodium intake is associated withpoor growth29 45-47 and adverse neurodevelop-mental outcome. There is increasing evidencethat sodium is a permissive factor forgrowth.48 Sodium deficiency inhibits DNAsynthesis in the most immature cells.48 Renalsalt wasting is common in babies below 32weeks' gestation and is due to impaired reab-sorption at both proximal and distal tubule.Intestinal absorption is also limited.49 Rapidpostnatal maturation occurs by an increase inNa',K+-ATPase29 and by increasing respon-siveness of distal tubule to aldosterone.50 51 It ispossible that in sick babies persistent expansionof the extracellular space may be another causeof continued sodium loss. Sodium should beprovided in an amount sufficient to allow theretention of 1 mmol/kg/day necessary forgrowth. For most preterm babies this will bearound 4-5 mmol/kg/day29 but may be higher inthe most immature infants. For babies of lessthan 32 weeks' gestation sodium supplementa-tion of this order should continue for around2-4 weeks by which time postnatal maturationof sodium conservation should have occurred.4652A high sodium intake beyond this point is notnecessary but whether it is harmful, for examplein relation to the subsequent development ofhypertension, is unknown.

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3 Brown ER, Stark A, Sosneko I, Lawson EF, Avery ME.Bronchopulmonary dysplasia: possible relationship topulmonary oedema.Jf Pediatr 1978; 92: 982-4.

4 Bell EF, Warburton D, Stonestreet B, Oh W. High volumefluid intake predisposes premature infants to necrotisingenterocolitis. Lancet 1979; ii: 90.

5 Bell EF, Warburton D, Stonestreet B, Oh W. Effect of fluidadministration on the development of symptomatic duc-tus arteriosis and congestive heart failure in prematureinfants. NEnglJMed 1980; 302: 598-604.

6 Van Marter U,Leviton A, Allred EN, Pagano M, KubanKC. Hydration during the first days of life and the risk ofbronchopulmonary dysplasia in low birth weight infants.JPediatr 1990; 116: 942-9.

7 Stevenson JG. Fluid administration in the association ofpatent ductus arteriosus complicating respiratory distresssyndrome. JPediatr 1977; 90: 257-61.

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9 Bauer K, Versmold H. Postnatal weight loss in pretermneonates less than 1500 g is isotonic dehydration of theextracellular volume. Acta Paediatr Scand 1989; 360(suppl): 37-42.

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