Fluid and electrolyte management in preterm infants with patent ductus arteriosus

Abstract

Optimal fluid management of preterm babies with suspected or confirmed diagnosis of patent ductus arteriosus (PDA) is frequently challenging for neonatal care physician because of paucity of clinical trials. There is wide variation in practice across neonatal units, resulting in significant impact on outcomes in Extremely Low Birth Weight (ELBW) babies with hemodynamically significant PDA. A delicate balance is required in fluid management to reduce mortality and morbidity in this population. The purpose of this review is to lay out the current understanding about fluid and electrolyte management in ELBW babies with hemodynamically significant PDA and highlight areas for future research.

Keywords

Diuretics electrolytes fluid management patent ductus arteriosus preterm neonates

1 Introduction

Fluid balance in the first days to weeks of life is recognized as an important factor that influences neonatal morbidity [1, 2]. This is particularly more significant in ELBW babies owing to their precarious homeostasis [3]. Fluid restriction in these babies has been recommended as this allows for a negative fluid balance in the first few days of life based on the fact that increased fluid intake is associated with increased risk for morbidities, including bronchopulmonary dysplasia (BPD) and PDA [1 , 4–14]. Increasingly, fluid restriction is becoming a common practice in ELBW babies across many neonatal intensive care unit (NICU), but it is a practice that differs widely among individual physician staff and NICU at large, resulting in a large variation in the amount of fluid administered to these babies. This variation in practice has emerged as a result of differences in individual perception regarding the risk of fluid administration in ELBW babies, arbitrary policies on the timing and duration of fluid restriction in most units and lack of consensus in the use of birth weight versus current weight to calculate fluid administration during the first few weeks of life [3]. Furthermore, fluid management of preterm infants who have suspected or confirmed patent ductus arteriosus (PDA) can be challenging due to inconclusive and conflicting evidence. One major challenge of fluid restriction is maintaining adequate nutrition. In a growing infant, long-term fluid restriction limits the number of calories and minerals that can be given. Providing adequate calories and minerals with fluid restriction requires use of highly concentrated formulas which may increase the risk of feeding intolerance. Alternatively, it requires the use of parenteral alimentation which is associated with increased incidence of line associated infection [15]. Therefore, it is paramount for clinicians to understand the influence of fluid and electrolyte on cardiovascular changes resultant from PDA.

2 Methods

A detailed search of the electronic databases such as Cochrane Central Register of Controlled Trials, Ovid Medline, Pubmed, Embase, clinicaltrials.gov were performed by the authors to an end point of 2020 using the keywords “fluid management” “electrolytes”, “preterm”, “patent ductus arteriosus” and “diuretics”. A manual search of the abstract published from the Society of Pediatric Research (SPR) and the European Society of Pediatric Research (ESPR) for the period of 1975 to 2019 were also performed. Only studies included in preterm babies were included. Based on the levels of evidence and grades of recommendations developed by Shekelle et al (Table 1), the available credibility of the fluid and electrolyte management procedures have been summarized [16].

Table 1
Level of evidence and Grades of recommendations

Level of evidence

1A Evidence from meta-analysis of randomized controlled trials

1B Evidence from at least one randomized controlled trial

2A Evidence from at least one controlled study without randomization

2B Evidence from at least one other type of quasi-experimental study

3 Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies

4 Evidence from expert committee reports or opinions or clinical experience of respected authorities, or both

Grades of Recommendations

A Directly based on Level I evidence

B Directly based on Level II evidence or extrapolated recommendations from Level I evidence

C Directly based on Level III evidence or extrapolated recommendations from Level I or II evidence

D Directly based on Level IV evidence or extrapolated recommendations from Level I, II, or III evidence

Data from reference [16].

2.1 Pathophysiology of PDA

Physiologic consequences of PDA depend on ductal size and the pulmonary vascular resistance (PVR). In the absence of an intracardiac/extracardiac shunts, the pulmonary to systemic flow ratio (Qp: Qs) is around 1 with a range of 0.8–1.2 [17]. The right ventricular output is reflective of the systemic circulation whereas the left ventricular output is reflective of the pulmonary circulation. The level at which the shunting occurs impacts the cardiac outputs. The shunt across the atrial septum influences the right ventricular output while that across the PDA influences the left ventricular output [17].

As illustrated in Fig. 1, in case of hemodynamically significant PDA, the pulmonary blood flow (Qp) increases due to the amount of blood that is shunting from the descending aorta into the pulmonary artery through PDA resulting in pulmonary over circulation. The shunting away of blood from the descending aorta leads to decrease in the systemic blood flow (Qs), causing ductal steal phenomenon. This results in an increase in Qp:Qs ratio which manifests as increasing respiratory support, intraventricular hemorrhage (IVH), renal insufficiency, systemic hypotension and feeding intolerance [17, 18].

Fig. 1

Illustration of PDA flow and its hemodynamic significance. Illustrates the shunting of blood from the Aorta to LPA branch of pulmonary artery which returns blood back to the lung increasing pulmonary blood flow (Qp) and decreasing systemic blood flow (Qs). The blood from the lung re-enters the left side of the heart causing dilatation of LA and LV. At the level of PDA, the blood is shunted again from Aorta through the PDA to LPA causing a vicious circle of shunting blood away from the systemic circulation. LA = left atrium, LV = left ventricle, RA = right atrium, RV = right ventricle, Qp = Pulmonary blood flow, Qs = Systemic blood flow, LPA = Left Pulmonary Artery, RPA = Right Pulmonary Artery, PDA-patent ductus arteriosus.

2.2 Fluid requirements in preterm babies

Total fluid requirement includes the fluid requirement for growth, the maintenance requirement to replace measured sensible losses (urine, stool) and insensible water loss (IWL). The total body water composition is very high in ELBW babies as shown in Table 2 [19, 20]. During the first postnatal week, there is loss of excess extracellular water content, which results in 10% to 15% weight loss in preterm babies. In addition to mandatory water loss by the kidneys and gastro-intestinal system (termed as sensible loss), additional water losses occur due to evaporation from the skin and respiratory tract which are not measurable in clinical sense. This water loss is termed as insensible water loss (IWL, Table 2) [19, 20]. ELBW babies commonly have delayed postnatal diuresis compared to their term counterparts. The indiscriminate administration of sodium and water, particularly before establishment of postnatal diuresis, leads to expansion of extracellular fluid (ECF) which has an adverse effect on outcomes, particularly in ELBW babies. High fluid intake and weight gain/absence of appropriate weight loss within the first 10 days of life in ELBW babies has been associated with BPD [21, 22]. Serum sodium is a great marker for assessing hydration in these infants. Maintaining serum sodium between 135–145 mmol/l by titrating maintenance fluid and incubator humidity is the primary goal during the first few postnatal days [1 , 23–27]. AWAKEN study has demonstrated that a positive peak in the fluid balance during the first week of life to be independently associated with mechanical ventilation on day 7 of life in preterm babies. [28]. With the achievement of postnatal diuresis, maintenance fluids can be increased based on the serum sodium trends and adequate weight loss of 1–2% per day.

Table 2
Total body water, Extracellular fluid (ECF) volume and Insensible water loss (IWL) at birth based on gestational age and birth weight

Gestational age (weeks) Body Weight, BW (grams) Total Body water (% BW) ECF volume (% BW) IWL on Day 1of life (ml/kg/day)

23–27 500–1000 85–90 60–70 60–80

28–32 1000–2000 80–85 50–60 40–60

36–40 > 2500 70–75 ∼40 ∼20

Gestational age (weeks)	Body Weight, BW (grams)	Total Body water (% BW)	ECF volume (% BW)	IWL on Day 1of life (ml/kg/day)
23–27	500–1000	85–90	60–70	60–80
28–32	1000–2000	80–85	50–60	40–60
36–40	> 2500	70–75	∼40	∼20

Data from reference [19], [20], ECF- Extracellular fluid, IWL- Insensible water loss, BW-birth weight.

Earlier studies have shown that fluid volumes between 96 and 200 mL/kg/day are tolerated after third day of life, serving as lower and upper limits for total fluid intake [29]. The lower range is favorable in minimizing the risk of preterm morbidity such as bronchopulmonary dysplasia and patent ductus arteriosus. It is possible that the presence of a significant left to right shunt across the PDA along with retention of ECF leads to higher pulmonary interstitial fluid content which decreases the lung compliance and increases ventilator needs. The latter can result in lung endothelial damage thereby increasing the risk for BPD [30]. The European Society of Pediatric Gastroenterology (ESPGAN), considers 135 mL/kg/day as the minimum fluid volume for to promote growth with 200 mL/kg/day as a reasonable upper limit. An optimal range of calorie intake for healthy growing preterm babies in the context of an adequate protein intake is 110 to 135 kcal/kg/day [31]. This intake promotes normal rates of growth at 15–20 g/kg/ day in the first 4 weeks of life for which fluid administration of 150–180 ml/kg/ day is required [31].

2.3 Fluid management in PDA

2.3.1 Fluid management in prevention of PDA

Excessive fluid administration as well as high sodium supplementation prevents ECF volume contraction and this in turn can result in a symptomatic PDA [1, 32]. A retrospective study in 2008 by Stephens et al demonstrated that high fluid intake greater than 170 ml/kg/day in the first week of life was associated with significantly higher rates of PDA as shown in Table 3 [3] (level 2b). Bell and Acarregui completed a Cochrane systematic review in 2014 comprising of 5 RCTs to determine the effects of fluid restriction on neonatal morbidity including PDA [33] (level 1a). They demonstrated that restricted parenteral fluid was associated with decreased incidence of PDA (Fig. 2) and a trend towards decreasing BPD and IVH. Although, there was a higher incidence of weight loss and an increased risk of dehydration associated with this restricted strategy, the long-term impact of this strategy is however currently unknown. The 5 studies included in the systematic review (Table 4) had limitations with regards to differing timing, fluid volumes, and restriction durations. This lack of homogeneity has led to confusion about when, how much, and how long fluids should be restricted. The majority of those studies were conducted in the early 1980s and 1990s, and therefore this practice remains untested in the modern era. The ELBW population was also under represented, leading to difficulty generalizing to the most problematic PDA population [33].

More recently, the retrospective study of fluid management in 200 VLBW neonates born less than 1250 grams by Levinson and colleagues in 2018 did not support early fluid restriction in VLBW neonates for the purposes of a protective effect with regard to PDA requiring medical and/or surgical treatment [34] (level 2b). But the study was limited by its single center retrospective methodology and only assessed fluid management with the first 24 hours of life potentially restricting generalizability of its results [34]. With inconclusive and conflicting evidences for fluid restriction, a judicious and individualized approach to fluid restriction at the same time meeting the preterm infant’s physiological needs is therefore recommended. Allowing for minimal positive fluid balance and a weight loss of 1–2% per day for the first 7–10 days of life should facilitate basic physiologic needs and possibly reduce the risk of symptomatic PDA [35].

Table 3
Prevalence of PDA in babies receiving different cut off of fluids within the first 1 week of life

Day of life Cut off fluid intake, ml/kg/day PDA rate for fluid intake < cut off, % PDA rate for fluid intake > cut off, % p-value

Day 1 146 8% 25% 0.016

Day 2 172 7% 33% 0.001

Day 3 179 7% 40% 0.001

Day 4 189 9% 15% 0.411

Day 5 190 9% 19% 0.133

Day 6 181 8% 24% 0.023

Day 7 171 8% 29% 0.002

Week 1 170 7% 35% 0.001

Day of life	Cut off fluid intake, ml/kg/day	PDA rate for fluid intake < cut off, %	PDA rate for fluid intake > cut off, %	p-value
Day 1	146	8%	25%	0.016
Day 2	172	7%	33%	0.001
Day 3	179	7%	40%	0.001
Day 4	189	9%	15%	0.411
Day 5	190	9%	19%	0.133
Day 6	181	8%	24%	0.023
Day 7	171	8%	29%	0.002
Week 1	170	7%	35%	0.001

Data from reference [3], PDA- patent ductus arteriosus.

Fig. 2

Restricted Vs liberal water intake and incidence of PDA. Data from reference [33], PDA- patent ductus arteriosus.

Table 4

Characteristics of the 5RCTs included in the Cochrane review 2014

Study, n	Mean GA/weight	Study period	Liberal Volume	Restricted volume
Bell 1980, n = 170	31 weeks	3–30 days	169 ml/kg/day	122 ml/kg/day
	751–2000 g
Kavvadia 2000, n = 168	< 1500 g		1–7 days	20–40 ml/kg/day lower than liberal group
Lorenz 1982, n = 88	29 weeks	1–5 days	80–140 ml/kg/day	65–80 ml/kg/day
	750–1500 g
Tammela 1992, n = 97	31 weeks	1–28 days	50 ml/kg/day@ day1	80 ml/kg/day@ day1
	< 1751 g		Increase by 10 ml/kg/day till day7	100 ml/kg/day@ day2
			150 ml/kg/day thereafter	120 ml/kg/day@ day3
				150 ml/kg/day@ day4–7
				200 ml/kg/day thereafter
Von Stockhausen 1980, n = 56	34 weeks	1–3 days	60 ml/kg/day	150 ml/kg/day

Data from reference [33], RCT- randomized control trial, GA- gestational age.

2.3.2 Fluid management in the presence of HS-PDA

The practice of fluid restriction for symptomatic PDA is derived from the conservative management strategy applied to infant with congenital heart disease who have evidence of pulmonary over circulation or congestive heart failure. Quasi-randomized trial by Reller et al in VLBW infants demonstrated that more severe degrees of fluid restriction (13% –15% weight loss vs 8% –10%) had no bearing on the development of hsPDA in VLBW infants [36] (level 1b). But increasing concerns have arisen on excessive fluid restriction compromising regional blood flow particularly to the gut and the brain as well as effect on the growth of the preterm infants. De Buyst et al showed through his prospective observational study in 2012 of 18 ELBW newborns that fluid restriction to 100–120 mL/kg/d in the setting of HS-PDA led to decreased blood flow in both the superior vena cava and the superior mesenteric artery without any beneficial hemodynamic effects on PDA size or respiratory parameters [37] (level 2b). Additionally, retrospective study by Hansson et al in 2019 showed that energy and protein intake was diminished in prematurely born infants with hsPDA when fluid was restricted after diagnosis. This may have contributed to their lower postnatal growth due to the concurrent calorie restriction [38].

The evidence for fluid restriction with HS-PDA lacks well controlled studies and the existing studies were limited by its size and shorter period of follow-up. With this inconclusive evidences, optimal fluid therapy should be titrated to balance growth and caloric needs and avoid additional compromise of systemic perfusion in the setting of HS-PDA. Functional echocardiographic assessment of pulmonary and systemic blood flow status along with clinical and biochemical parameters could guide fluid management in the setting of HS-PDA as illustrated in Fig. 3 (adopted with some modification from Mosalli, et al, NeoReviews Vol.11 No.9 September 2010) [35].

Fig. 3

Fluid management in the presence of a hemodynamically significant patent ductus arteriosus (HS-PDA). α- Indices of pulmonary over circulation: LVO (mL/kg/min) > 300, La: Ao≥1.5, Pulmonary vein d wave velocity (m/s) > 0.3, LPA diastolic velocity (m/s) > 0.2, Mitral valve E: A > 1, IVRT (ms)< 40. β - Flow direction in one of the following post-ductal arteries: Absent or Reversed End diastolic flow in Abdominal aorta, Celiac trunk, Superior Mesenteric Artery or Middle Cerebral Artery. Data from reference [35, 55]. HS-PDA- hemodynamically significant patent ductus arteriosus, iT- inspiratory time, NEC-necrotizing enterocolitis, PaCO2- partial pressure of carbon dioxide, PDA-patent ductus arteriosus, PEEP- Peak End Expiratory Pressure, PVR- Pulmonary vascular resistance, Qp- Pulmonary blood flow, Qs- systemic blood flow, UO- urine output.

2.3.3 Fluid management during PDA pharmacotherapy

Ductal patency is maintained by circulating prostaglandin levels. Pharmacologic treatments are available to induce constriction of a PDA using Indomethacin and ibuprofen which are nonselective cyclooxygenase inhibitors that prevents the conversion of arachidonic acid to prostaglandins. Being nonselective, both indomethacin and ibuprofen exerts vasoconstrictive effects on other regional blood vessels especially renal vasculature resulting in decreased urine output. This could result in fluid retention leading to pulmonary edema causing escalation of respiratory support and development of BPD secondary to lung trauma [21, 22]. Due to lack of controlled studies to guide fluid therapy during PDA treatment, clinical vigilance is paramount. Careful monitoring of fluid intake and output with the aim of maintaining minimal positive balance and voidance of the therapeutic agent when urine output is less than 1 ml/kg/hr should help guide fluid management during PDA pharmacotherapy.

2.3.4 Beyond first one month of life

To date, no studies exist that have looked at the impact of fluid restriction in the setting of PDA beyond 1 month of life. Currently the fluid management strategies in preterm infants after 1 month of life has been extrapolated from studies done in their counterpart under one month of life. Therefore, caution should be executed when chronically fluid restricting these infants. Diligent nutritional assessment using weight trends, clinical assessment of regional perfusion and nutritional blood parameters would be the way forward until further trial results are available to enlighten us on the appropriate long-term fluid management strategies when a hemodynamically significant PDA is in question.

2.4 PDA and electrolyte management

Magnesium and calcium play a vital role in the maintenance of intrinsic vascular tone. Magnesium influences intracellular calcium mobilization within the vascular smooth muscles and endothelial cells as well as promotes PGI production. Both of these mechanisms may contribute to the maintenance of the ductal patency [39]. One prospective study demonstrated a significant relationship between infants with a delayed closure of the ductus arteriosus born before 32 gestational weeks of age and elevated serum magnesium concentration at birth [39] (level 2b). There was also increased incidence of symptomatic PDA that was dose dependent among infants with antenatal MgSO₄ exposure compared with unexposed infants (67 vs 60%, respectively; P < 0.01) [40 –43] (level 2a). But this effect seems to be short as it only reduced the response to postnatal indomethacin prophylaxis without influencing the symptomatic treatment later on [42, 44]. On the contrary, the randomized study conducted by Paradisis [45] (level 1b) and group in 2011, did not find significant difference in treatment of PDA between groups exposed to antenatal MgSO₄ in comparison to those unexposed (38% versus 28%). The discrepancies between results may be due to the small sample size with a relatively high range of gestational age seen in these studies.

In a limited number of studies, the association of hypocalcemia with PDA has been shown [46]. Cakir et al in 2019, through a large retrospective study demonstrated lower levels ionized calcium and higher levels of potassium in hsPDA suggesting its possible significance with ductal patency [47] (level 2b). Consequently, there may be other unknown etiological factors, such as iCa^2 +, K⁺, and Mg⁺ levels, which predispose to PDA, besides proven mechanisms. Although the effects of these electrolytes on vascular smooth muscle tone might be a plausible explanation. But randomized control trial is needed in the modern era looking at the association of serum electrolytes and PDA persistence. Until then electrolyte determinations and trending them to normal ranges should be aimed during the postnatal course of preterm babies.

2.5 Diuretics in PDA

Diuretic medications are often used as a conservative management strategy in order to alleviate pulmonary edema and left-heart volume overload secondary to PDA shunt [48].

Furosemide is the diuretic most used and studied in newborn infants. It is a loop diuretic and is known to stimulate renal synthesis of prostaglandin E2 which is a powerful dilator of the ductus arteriosus [49, 50]. This may inhibit ductal closure which was first observed in 1983 in a randomized control trial that compared furosemide to chlorothiazide in premature infants with respiratory distress syndrome and PDA. The study found significantly higher incidence of PDA in the frusemide group than in the chlorothiazide group [49]. Cochrane systematic review by Stewart in 2011 and Brion and Soll in 2008 cautioned routine prescription of furosemide to any preterm infant with respiratory distress [51, 52] (level 1a). Increased risk of development of renal tubular calcifications, acute kidney injury especially in conjunction with non-steroidal anti-inflammatory drugs and risk of ototoxicity warrants caution in its use in this population [53].

While Lee et al. 2010 did not show any difference in PDA closure rate in his RCT involving < 34 weeks comparing furosemide (1 mg/kg) to placebo administration after indomethacin treatment for PDA [53] (level 1b). Findings from a large contemporary cohort of hospitalized VLBW infants through Pediatrix Medical Group Clinical Data warehouse 2018, also did not show an increased odds of PDA treatment following furosemide exposure despite cautious interpretation [54] (level 2a). This database included 43,576 VLBW infants and therefore being one of its biggest strength. Currently available data are contradictory and therefore further studies are needed to assess benefits versus hazards of diuretics systematically.

3 Conclusion

Large fluid intake has been associated with increased risk of PDA and bronchopulmonary dysplasia in the overall population of preterm infants. Furthermore, fluid restriction limits calorie and protein intake thereby retarding growth and therefore poor trade off to control symptoms of PDA at the expense of adequate nutrition. As such routine restriction of fluid in the scenario of PDA cannot be recommended (Grade A recommendation). Careful attention to fluid balance is therefore recommended as preventive strategy of PDA. The most prudent prescription of fluid intake in premature infants would seem to be a careful individualized restriction of water intake so that physiological needs are met without allowing significant dehydration and closely following serum electrolytes (Grade B recommendation). This practice could be expected to decrease the risks of patent ductus arteriosus without significantly increasing the risk of adverse consequences. Routine fluid restriction in the setting of HS-PDA and while on PDA treatment is also not recommended (Grade A recommendation). While the benefits of diuretics are still at large, its use should be reserved when there is concomitant clinical and echocardiographic evidence of pulmonary edema or heart failure.

Footnotes

Acknowledgments

None.

Disclosure statements

The authors have no financial or other disclosure or disclaimer to declare.

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Level of evidence
1A	Evidence from meta-analysis of randomized controlled trials
1B	Evidence from at least one randomized controlled trial
2A	Evidence from at least one controlled study without randomization
2B	Evidence from at least one other type of quasi-experimental study
3	Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies
4	Evidence from expert committee reports or opinions or clinical experience of respected authorities, or both
Grades of Recommendations
A	Directly based on Level I evidence
B	Directly based on Level II evidence or extrapolated recommendations from Level I evidence
C	Directly based on Level III evidence or extrapolated recommendations from Level I or II evidence
D	Directly based on Level IV evidence or extrapolated recommendations from Level I, II, or III evidence