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Fluid and Electrolyte Homeostasis in the Neonate. Istvan Seri MD PhD USC Division of Neonatal Medicine Women’s and Children’s Hospital LAC/USC Medical Center and Children Hospital Los Angeles Keck School of Medicine University of Southern California Los Angeles, CA.

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slide1

Fluid and Electrolyte Homeostasis in the Neonate

Istvan Seri MD PhD

USC Division of Neonatal Medicine

Women’s and Children’s Hospital

LAC/USC Medical Center and

Children Hospital Los Angeles

Keck School of Medicine

University of Southern California

Los Angeles, CA

slide2

Total Body Water (TBW) Content and Fluid Distribution between Intracellular (ICF) and Extracellular (ECF) Fluid Compartments in Humans from the First Trimester until 9 Months of Age

%

100

90

80

70

60

50

40 30

20

10

0

Body Water Content (%)

FETUS NEWBORN

Age (months)

slide8

Electrolyte Composition of Fluid Compartments

Electrolyte Composition of Fluid Compartments

slide9

Filtration and reabsorption of fluid along the capillary under physiologic conditions

Movement of fluid across the capillary is determined by the direction of the net driving pressure [(PC-PT) – (P-T)] and the permeability characteristics of the capillary wall

slide10

Postnatal changes in body weight, extracellular fluid volume and sodium balance

Body weight - expressed in % of birth weight

Extracellular Fluid Volume - estimated by the bromide dilution method

Sodium Balance - calculated as the difference between sodium intake and urinary sodium excretion

Shaffer and Weismann; Clin Perinatol 19:233, 1992

slide11

Changes in Fluid Compartments in the Immediate Perinatal Period (1)

Changes in Fluid Compartments at Onset of Labor:

• decrease in the production of fetal lung fluid

• 20% increase in fetal blood pressure

Changes in Fluid Compartments During Labor and Delivery:

• 14% decrease in circulating blood volume

• 25% reduction in plasma volume

• placental transfusion induces a variable increase in circulating blood volume

Increased Interstitial Fluid Compartment

slide12

Changes in Fluid Compartments in the Immediate Perinatal Period (2)

Mechanisms Mediating Transcapillary Loss of Plasma Volume

  • Increase in fetal blood pressure enhances transcapillary distribution of fluid (and protein)
  • Mild hypoxia during labor and delivery increases transcapillary leak

Hormonal Regulation of Transcapillary Loss of Plasma Volume

  • Norepinephrine, vasopressin, renin-angiotensin, cortisol (vasoconstriction)
  • Bradykinin, prostaglandins, atrial natriuretic peptide (vasodilation)
slide13

Changes in Fluid Compartments in the Immediate Perinatal Period (3)

Neonatal Weight Loss

  • Term infants lose 5-10% of their birth weight during first week of life
  • Preterm infants lose 10-15% of their birth weight during the first two weeks of life

Fluid Compartments Involved in Neonatal Weight Loss

  • Perinatally expanded extracellular (interstitial) fluid compartment
  • Intracellular fluid compartment (prolactin?)
slide14

Regulation of the Extracellular Fluid Compartment

Extracellular fluid compartment is primarily regulated by total body sodium content

slide15

Increased Risk of Chronic Lung Disease in Preterm Neonates with Increased Fluid Intake (1)

Retrospective Studies

  • Excessive hydration increases risk of CLD

Brown et al 1978, J Pediatr; Tooley 1979, J Pediatr

  • Excessive hydration does not increase risk of CLD

Spar et al 1980; Am J Dis Child

  • Increased total, crystalloid and colloid fluid administration during the first 24 hours of life results in

1) a weight gain over the first 4 days

2) a higher incidence of a hemodynamically significant PDA

3) a higher incidence of CLD

Van Marter et al 1990, J Pediatr

slide16

Increased Risk of Chronic Lung Disease in Preterm Neonates with Increased Fluid Intake (2)

Prospective Studies (1)

Bell et al (New Engl J Med 1980, 302:598)

a) “Low-volume group” (n=85) received fluid supplementation to meet estimated requirements, while the “high-volume group” (n=85) received fluid intake in a mean excess of 47 mL/kg/day.

b) Fluid intake was followed from day #3 to day #30.

c) In the “high-volume group”, there was a higher incidence of hemodynamically significant PDA as well as NEC (16 vs 3). However, the incidence of CLD was not different between the two groups.

slide17

Increased Risk of Chronic Lung Disease in Preterm Neonates with Increased Fluid Intake (3)

Prospective Studies (1)

Bell et al (New Engl J Med 1980, 302:598)

Problem with the study design :

Fluid intake was not controlled during the most critical first 3 days of life.

slide18

Increased Risk of Chronic Lung Disease in Preterm Neonates with Increased Fluid Intake (4)

Prospective Studies (2)

Lorenz et al (J Pediatr 1982, 101:423)

a) 88 preterm neonates with a birthweight range of 750-1500 g were randomized into 2 groups during the first 5 days of life

b) “Group 1” (n=44) patients were allowed to loose 1-2% body weight per day (maximum weight loss 8-10%), while in “Group 2” (n=44), 3-5% daily weight-loss was allowed (maximum weight loss 13-15%)

c) Cummulative fluid intake in “Group 2” during the study period was 220 mL/kg less than in “Group 1”, yet patients in “Group 2” patients lost weight only 41 g/kg more than patients in “Group 1”.

d)No difference in the incidence of hemodynamically significant PDA, CLD, NEC, dehydration, renal failure and neonatal mortality

slide19

Increased Risk of Chronic Lung Disease in Preterm Neonates with Increased Fluid Intake (5)

Prospective Studies (2)

Lorenz et al (J Pediatr 1982, 101:423)

Problem with the study design :

CLD was defined as ventilator- or oxygen-requirement at >14 days of life and fluid intake was not controlled after the first 5 days of life.

slide20

Increased Risk of Chronic Lung Disease in Preterm Neonates with Increased Fluid Intake (6)

Prospective Studies (3)

Tammela and Koivisto (Acta Pediatrica 1992, 81:207)

  • Fluid restriction group. Fifty (50) preterm neonates (BW <1750) received 50-60-70-80-90-100-120 mL/kg/d fluid during the first week and 150 mL/kg/d fluid during the ensuing 3 weeks of life with 145 kcal/kg/d caloric intake during weeks 2-4 weeks.
  • Control Group. Fifty (50) preterm neonates (BW <1750 g) received 80-100-120 mL/kg/d fluid intake during the first 3 days, 150 mL/kg/ during the rest of the first week and 200 mL/kg/d during the next 3 weeks with 145 kcal/kg/d caloric intake during weeks 2-4 weeks
slide21

Increased Risk of Chronic Lung Disease in Preterm Neonates with Increased Fluid Intake (7)

Prospective Studies (3)

Tammela and Koivisto (Acta Pediatrica 1992, 81:207)

  • There was no difference in the incidence of hypotension, hypoglycemia, hemodynamically significant PDA, duration of assisted ventilation, CLD and body weight at the end of the study.
  • However,
    • Incidence of air-leak and number of patients who died (1 vs 6) was less in the “fluid restriction group”
    • The number of survivors without BPD (27 vs 15 at 4 weeks of age; 28 vs 14 at term) was more in the “fluid restriction group”.
slide22

N-Acetyl-L-Cysteine (NAC) Does Not Prevent BPD In Preterm Neonates

N = 194N = 197

Role of glutathione as an antioxidant:

Cosubstrate in peroxidase reactions and direct scavenger of reactive oxygen species.

Synthesis of glutathione is not limited by the activity of g-glutamylcysteine synthetase in preterm infants, but rather by the availability of cysteine.

Hypothesis: NAC administration may increase antioxydant defenses and decrease the incidence and/or severity of CLD.

Randomized trial of 392 ELBW neonates (500-999 g)Dose of NAC = 16-32 mg/kg/day X 6 days

Ahola et al. J Pediatr, 143:713; 2003

slide23

Crystalloid vs Colloid Administration for Volume Resuscitation and Pharmacologic Support (1)

  • In adults, intravascular volume increases only by 25-40% of the volume bolus when isotonic saline is used, while albumin is preferentially retained in the intravascular compartment (Ernest et al 1999 Crit Care Med, 27:46).
  • In sick preterm infants (So et al 1999 ADC 76:F43; Oca et al 2003 J Perinatol; 23:473) and adults with impaired capillary integrity (Pockaj et al 1994 J Immonother, 15:22), crystalloids and colloids appear to be equally effective in the initial treatment of hypotension.
  • However, unlike isotonic saline, albumin may induce a fluid shift from the intracellular compartment (Ernest et al 1999 Crit Care Med, 27:46). This shift could be especially harmful in the immature brain.
  • Finally, there is a renewed debate over the possible association of the use of albumin with increased mortality in hypotensive patients (Nadel et al 1998 ACD, 79:384).
slide24

Crystalloid vs Colloid Administration for Volume Resuscitation and Pharmacologic Support (2)

Randomized Controlled Trial of Colloid and Crystalloid Infusions in Hypotensive Preterm Infants

5% Albumin (n=32)  59% required pressor support

Normal Saline (n=31) 58% required pressor support

Mean Blood Pressure (mm Hg)

MAP x FiO2 (cm H2O)

Mean Blood Pressure (mm Hg)

MAP x FiO2 (cm H2O)

2 8 24 48

2 8 24 48

Time (hours)

Time (hours)

So et al, Arch Dis Child; 1997

slide25

Crystalloid vs Colloid Administration for Volume Resuscitation and Pharmacologic Support (3)

Randomized Controlled Trial of Colloid vs Crystalloid Infusions in Hypotensive Neonates

Preterm Neonates Term Neonates

^

*

Blood Pressure

*

^

Oca et al, J Perinatol; 23:473; 2003

slide26

Crystalloid vs Colloid Administration for Volume Resuscitation and Pharmacologic Support (4)

  • Based on the available information, it is reasonable to suggest that, unless evidence of intravascular volume loss or hypoalbuminemia is present, volume support in hypotensive preterm infants should be provided in the form of 10-20 mL/kg of isotonic saline administered over 15-30 minutes.

Seri 2001 Semin Perinatol; 6:85

  • If ineffective, this single volume bolus should be followed by the early initiation of pharmacological cardiovascular support with dopamine titrated to the lowest effective dose

Seri et al 1984 Eur J Pediatr, 142:3; Padbury 1986 J Pediatr, 110:293; Gill et al 1993 ACD, 69:284; Seri 1993 Ped Res, 34:742; Seri 1995 J Pediatr, 126:333

slide27

Crystalloid vs Colloid Administration for Volume Resuscitation and Pharmacologic Support (5)

  • However, if evidence of myocardial dysfunction and/or peripheral vasoconstriction is present, dobutamine (with or without low-dose dopamine) should be considered.

Kluckow and Evans 2000 ACD, 82:F182; Seri 2001 Semin Perinatol, 6:85; Osborn et al 2002 J Pediatr, 140:183

  • In ELBW neonates during the first day of life when a unique form of compensated shock commonly occurs (normotension with decreased non-vital organ perfusion which includes hypoperfusion of the cerebral cortex), the use of low-dose milrinone is being evaluated.

Kluckow, Osborb and Evans Pediatr Res 2004

slide28

Postnatal Water and Electrolyte Losses

  • Sensible Fluid Losses:
    • Urine
    • Stool
  • Insensible Fluid Losses:
    • Skin
    • Respiratory tract
slide29

Sensible Fluid Losses

  • Urine:
  • Preterm infants at 26-30 weeks: 1.6 and 5.4 ml/kg/h during the first and third day of life, respectively
  • Preterm infants at 30-34 weeks: 3.75 and 6.25 ml/kg/h during the first and third day of life, respectively

Stool:

  • Preterm infants: 7 ml/kg/day
  • Term infants: 10 ml/kg/day
slide30

Factors Influencing Sensible Fluid Losses

  • Urine Output:
  • Renal blood flow and glomerular filtration rate
  • Maturity of tubular functions

Stool Output:

  • Maturity of gut motility and mucosal functions
  • Type of feeding: breast milk vs formula
slide31

Insensible Fluid Losses

  • Skin:
  • Transepidermal water loss of a 24-week AGA infant is 10 to 15 times higher than that of a term neonate during the first day of life.
  • Although the difference in transepidermal water loss diminishes with age, it is still twice as high in a former 24-week AGA infant compared to that of a former term neonate on the 28th day of life.

Respiratory Tract:

  • Term infants: 4.9 mg/kg/min at an ambient air temperature of 32.5°C and 50% ambient humidity

Hammarlund et al; A Paed Scand 72:721, 1983; Sedin; Current Topics in Neonatology; WB Saunders Co, p 50, 1995

slide32

Mean Insensible Water Loss Through the Skin in AGA Infants in a Relative Ambient Humidity of 50%

Transepidermal Water Loss

(mL/kg/day)

Postnatal Age (days)

Hammarlund et al; A Paed Scand 72:721, 1983; Sedin; Current Topics in Neonatology; WB Saunders Co, p 50, 1995

slide33

Transepidermal Water Loss during the First Week of Life in Infants Born at 25-27 Weeks

mL/day

Relative Ambient Humidity

Relative Ambient

Humidity

Day of Life

Hammarlund et al; A Paed Scand 72:721, 1983; Sedin; Current Topics in Neonatology; WB Saunders Co, p 50, 1995

slide34

Transepidermal Water Loss in Relation to Gestational Age at Birth and During the First Month of Life in AGA Infants

Postnatal Age (days)

Transepidermal Water Loss

(g/m2/h)

Postnatal Age (days)

Gestational Age (weeks)

Hammarlund et al; A Paed Scand 72:721, 1983; Sedin; Current Topics in Neonatology; WB Saunders Co, p 50, 1995

slide35

Factors Influencing Insensible Fluid Losses (1)

  • Transepidermal Water Loss
  • Gestational age
  • Postnatal age
  • Intrauterine growth retardation
  • Intrauterine stress (steroids)
  • Prenatal steroid administration
  • Total body surface area
  • Ambient temperature
  • Ambient humidity
  • Type of heat source
  • Activity
  • Phototherapy
slide36

Factors Influencing Insensible Fluid Losses (2)

  • Water Loss from the Respiratory Tract
  • Temperature of inspired air
  • Humidity of inspired air
  • Respiratory rate
  • Tidal volume
  • Ability of the nose to dehumidify and cool
  • Expiratory air
slide37

Daily Electrolyte Requirements in the Newborn

  • Sodium Balance: 2-3 mEq/kg/day

Sick preterm infants may not need sodium supplementation during the first 3-4 days of life

  • Potassium Balance: 1-2 mEq/kg/day

Sick extremely preterm infants may develop non-oliguric hyperkalemia during the first days of life

  • Calcium Balance: 8-180 mg/1.73 m2/day

Degree of prematurity, postnatal age, severity of disease, sodium intake, and type of feeding significantly influence calcium balance

  • Phosphorus Balance: 22-217 mg/1.73 m2/day

Degree of prematurity, postnatal age, severity of disease, sodium intake, and the type of feeding significantly influence phosphorus balance

slide38

Neonatal Acid Base Balance (1)

  • Acid Production:
  • Protein is essential for growth and development
  • Metabolism of sulfur containing amino acids (AAs) leads to H+ production
  • Hydroxyapatite formation for bone mineralization leads to acid production
  • The growing neonate must excrete 2-3 mEq of acid per kg per day

Bicarbonate losses:

  • In urine and stool (developmentally regulated immaturity of renal and intestinal functions)

If renal acidification and/or bicarbonate generation are impaired (immaturity, illness, renal disorders), metabolic acidosis develops and results in inappropriate growth

Quigley and Baum Seminars in Perinatol; 28:97; 2004

slide39

Neonatal Acid Base Balance (2)

1. Aniongap Acidosis:

Production of acids (protein metabolism, tissue hypoperfusion resulting in lactate production, metabolic diseases)

2. Non-aniongap acidosis:

Loss of bicarbonate (renal, intestinal losses or iatrogenic hyperchloremia)

Seri et al: Fluid, Electrolyte and Acid-base Management in the Neonate; Avery Textbook of Diseases of the Newborn, WB Saunders Co, 2004

slide40

Anion gap and non-anion gap metabolic acidosis in the newborn

Seri et al: Fluid, Electrolyte and Acid-base Management in the Neonate; Avery Textbook of Diseases of the Newborn, WB Saunders Co, 2004

slide41

Use of Diuretics in Neonates

Renal Effects of

Furosemide in the Neonate

slide42

Diuretics in Neonates

Furosemide (1)

Diuretic Effect:

Primary mechanism of action is the inhibition of the Na, K, 2 Cl co-transporter in the thick ascending limb of the loop of Henle;

Activation of renal PG synthesis is important ( RBF, GFR, renin secretion)

Directly related to the renal tubular drug concentration and thus depends on GFR;

Increased water, sodium, potassium, chloride, calcium, magnesium, and phosphate excretion.

Onset and Duration on Action:

30-60 minutes, peaks within 1-3 hours and dissipates during 6 hours. Duration is variably prolonged in preterm neonates.

Clearance:

Adults: Proximal tubular organic acid transport system and hepatic biotransformation

Preterm neonates: Excreted unchanged in urine (renal immaturity); thus depends on GFR

slide43

Diuretics in Neonates

Furosemide (2)

1. Administration

A. Bolus:

- 1-2 mg/kg/dose iv Q12-24 hours (oral dosage is usually higher due to poor bio-availability)

- Maximum dose: 16 mg/kg/day for neonates on ECMO

B. Continuous Infusion:

- 0.01-0.05 mg/kg/hour, titrate dosage to desired clinical effect

- Continuous infusion has several advantages over bolus administration including

+ decreased dosage requirements

+ decreased adverse effects

+ improved diuretic response

2. Tolerance: Decreased effectiveness over time primarily due to activation of compensatory homeostatic mechanisms and changes in tubular electrolyte concentration.

- Combination of furosemide with a thiazide diuretic

- Administration via continuous infusion

slide44

Diuretics in Neonates

Furosemide (3)

Indications

- Fluid retention without evidence for decreased effective circulating blood volume (hypotension)

- Congestive heart failure (congenital heart disease with left-to-right shunting; left outflow tract obstruction to decrease afterload; cardiomyopathy)

- Acute renal insufficiency

- Chronic lung disease: Recent metaanalysis concluded that chronic administration of Lasix cannot be recommended in preterm neonates with CLD due to the lack of appropriately designed and powered clinical trials looking at outcome measures other than changes in pulmonary physiology (Cochrane Database; 2000). Theoretical benefits:

+ Decreases total body sodium and thus extracellular volume

+ Direct inhibition of the upregulated pulmonary Na-K-2 Cl co-transporter

- In an attempt to decrease cerebrospinal fluid production in certain cases of obstructive hydrocephalus (in combination with acetazolamide)

slide45

Diuretics in Neonates

Furosemide (4)

Side Effects:

- Hyponatremia, hypokalemia, hypochloremia, volume contraction

- Growth failure due to contraction alkalosis

- Enhanced urinary calcium losses (nephrocalcinosis; nephrolithiasis)

- Secondary hyperparathyroidism

- Osteopenia, bone fractures

- Ototoxicity:

+ concurrent aminoglycoside administration may increase the risk of ototoxicity

+ slow infusion decreases the risk of ototoxicity

- Displacement of bilirubin from albumin binding

slide46

Diuretics in Neonates

Furosemide (5)

Electrolyte Losses:

- Sodium and chloride losses are readily reflected in the electrolyte panel

- The potentially severe decrease in total body potassium usually goes undetected (2% of the total body potassium is outside the cells)

- The excess chloride loss results in bicarbonate retention and metabolic alkalosis

- Due to the decrease in the intracellular potassium concentration, renal hydrogen wasting occurs resulting in worsening metabolic alkalosis

- In neonates with CLD, the metabolic alkalosis may go undetected as CO2 is being retained by the patient to compensate for the metabolic alkalosis. The increase in CO2 may inappropriately trigger an increase in ventilatory support and a vicious cycle may develop: the respiratory compensation (CO2 retention) is being treated instead of addressing the primary acid-base derangement (metabolic alkalosis).

slide47

Diuretics in Neonates

Furosemide (6)

Replacement of Electrolyte Losses:

- Potassium chloride supplementation should be initiated early (3-8 mEq/Kg/day)

- If seCl remains < 95 mEq/L, low-dose NaCl (1-3 mEq/kg/day) and/or arginine chloride (2-4 mEq/kg/day) supplementation should be considered

- If hypokalemia persists or is suspected, addition of spironolactone may be considered since if total body potassium remains low, the hypochloremia cannot be corrected even with excessive NaCl and arginine chloride supplementation. However, when spironolactone is added, seK must be monitored very closely due to enhanced renal K retention and K supplementation should be adjusted accordingly.

- Since extracellular volume (and thus the propensity to edema formation) is primarily determined by the total body sodium content, excessive sodium supplementation may defeat the purpose of diuretic administration

- Calcium, phosphorous and magnesium losses must also be replaced with appropriately fortified preterm formulas which provide fair-to-good supplementation of these macrominerals (and Vitamin D)

slide48

Diuretics in Neonates

Renal Effects of

Theophylline in the Neonate

slide49

Diuretics in Neonates

Theophylline

Patient population:

19 preterm neonates; gestational age 31.1 ±2.8 weeks; during postnatal first week

Results:

Increase in diuresis immediately after loading dose

Increased FeNa and FeK

Increase in urinary calcium and uric acid excretion

No effect on phosphorus excretion

The effects last up to 24 hours despite continuing maintenance therapy

No change in blood pressure, heart rate and creatinine clearance (direct tubular effects?)

Mazkereth et al; 1997 Am J Perinatol 14:45

slide50

Diuretics in Neonates

Renal Effects of

Thiazide Diuretics in the Neonate

slide51

Diuretics in Neonates

Combination of Distal Diuretics

Brion LP et al; Cochrane Database Systematic Reviews; 2002

- Effects of distal diuretics in preterm infant with CLD on ventilatory support, oxygen requirement and long-

term outcome

- Six randomized controlled studies with substantial heterogeneity were found

- In preterm infants >3 weeks of age, 4-week treatment with thiazide and spironolactone improved lung compliance and reduced the need for Lasix

- Thiazide and spironolactone administration decreased the risk of death and tended to facilitate extubation after 8 weeks in preterm infants without steroid, bronchodilators or theophylline treatment

- Little or no evidence to support any benefit of diuretic administration on need for ventilatory support, length of hospital stay or long-term outcome.

- There is no evidence that addition of spironolactone to thiazide or metolazone to Lasix improves outcome of preterm infants with CLD.

Conclusion:

- Acute and chronic administration of distal diuretics improves pulmonary mechanics

slide52

Diuretics in Neonates

Combination of Diuretics

Furosemide and Thiazide Diuretics:

- Attenuates the development of tolerance

- No clear evidence of attenuation of side effects of Lasix administration unless the dose can be decreased

Thiazide and Spironolactone:

- Chronic administration of this combination improved lung compliance and reduced the use of Lasix in preterm neonates with CLD (Brion, Cochrane Library, 2002)

Furosemide and Dopamine:

- May be synergistic (Tulassay and Seri 1986; Acta Paediatr Scand 75:420)

Methylxanthines and Dopamine:

- May be synergistic (Bell et al 1998; Int Care Med 24:1099)

slide53

Diuretics in Neonates

Renal Effects of

Dopamine in the Neonate

slide54

.

K+

K+

K+

K+

X

X

K+

K+

Na+

Na+

Na+

Na+

Na+

Na+

X

Na+

H+

X

K+

X

K+

Na+

Na+

Pi

X

K+

Na+

X

K+

Na+

Na+

CORTEX

K+

Na+

H2O

ADH

K+

Na+

Dopamine Inhibits:

Na+,K+-ATPase, Na+/H+ exchanger, Na+/Pi cotransporter,

ADH-sensitive H2O channel

Dopamine Increases: RBF, GFR

The net effect of dopamine:

 Na+, Pi , HCO-3, H2O excretion, concentrating capacitity

X

K+

Na+

MEDULLA

X

K+

H2O

ADH

Na+

renal effects of dopamine in the preterm neonate summary
Renal Effects of Dopamine in the Preterm NeonateSUMMARY

1. Renal hemodynamic effects of dopamine:

• Increases in total renal blood flow;

• Increases in renal medullary blood flow;

• Increases in glomerular filtration rate.

2. Direct renal tubular effects of dopamine:

• Increases in renal sodium, phosphorous, andfree water excretion and decreases concentrating capacity.