Istvan Seri MD PhD USC Division of Neonatal Medicine Women’s and Children’s Hospital LAC/USC Medical Center and Childre

1. 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

2. 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)

3. Electrolyte Composition of Fluid Compartments:Cations

4. Electrolyte Composition of Fluid Compartments:Anions

5. Electrolyte Composition of Fluid Compartments:Cations (mEq/L) (mEq/L) (mEq/kg H2O)

6. Electrolyte Composition of Fluid Compartments:Anions (mEq/L) (mEq/L) (mEq/kg H2O)

7. Electrolyte Composition of Fluid Compartments mEq/L

8. Electrolyte Composition of Fluid Compartments Electrolyte Composition of Fluid Compartments

9. 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

10. 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

11. 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

12. 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)

13. 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?)

14. Regulation of the Extracellular Fluid Compartment Extracellular fluid compartment is primarily regulated by total body sodium content

15. 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

16. 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.

17. 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.

18. 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

19. 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.

20. 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

21. 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”.

22. 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

23. 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).

24. 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

25. 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

26. 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

27. 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

28. Postnatal Water and Electrolyte Losses • Sensible Fluid Losses: • Urine • Stool • Insensible Fluid Losses: • Skin • Respiratory tract

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. Use of Diuretics in Neonates Renal Effects of Furosemide in the Neonate

42. 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

43. 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

44. 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)

45. 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

46. 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).

47. 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)

48. Diuretics in Neonates Renal Effects of Theophylline in the Neonate

49. 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

50. Diuretics in Neonates Renal Effects of Thiazide Diuretics in the Neonate