Pulmonary effects of furosemide in preterm infants with lung disease

Pulmonary effects of furosemide in preterm infants with lung disease Twenty preterm infants recovering from respiratory distress syndrome at I week of age were randomized in this study either to a control or a treatment group. Those treated received a single daily dose of furosemide (1 mg/kg) intravenously. Pulmonary compliance was observed to improve significantly at two hours in the treated group, as compared with that in the controls. The calculated alveolar-arterial oxygen gradient was noted to decrease two hours after furosemide and to remain decreased over the four-day period in the treated group. This improvement in lung function was not secondary to diuresis in the infants treated with furosemide. We conclude that furosemide may have a direct pulmonary effect and improve lung function acutely as well as with chronic administration.

(J PEDIATR102:758, 1983)

Zeba D. Najak, M.B., Ch.B., Eva M. Harris, M.D., Anthony Lazzara, Jr., M.D., and Albert W. Pruitt, M.D. A t l a n t a , Ga.

THE UNDERSTANDING of lung fluid dynamics in newborn infants is based on work conducted in experimental animals, specifically in lambs? -5 The normal newborn animal lung has a higher transvascular fluid filtration rate than does the adult lung, and this rate is increased in a hypoxic state and during mechanical ventilation. In human infants, these mechanisms also appear to be operative, as indicated at autopsy by the presence of pulmonary interstitial edema when the infant has required ambient oxygen and prolonged mechanical ventilation. 6'7 The microscopic findings are characteristic of the exudative phase of bronchopulmonary dysplasia, which occurs postnatally between three and ten days in the lungs of preterm infants recovering from respiratory distress syndrome. 6 In lambs 2'4 and in dogs I treated with furosemide, the drug decreases pulmonary transvascular fluid filtration by a nondiuretic effect. It probably acts on the pulmonary vasculature, altering pulmonary blood flow. To date, there is very little information about the specific pulmonary effect of furosemide in human neonatal chronic lung disease, although the 'drug is used in infants with such From the Division of Neonatal/Perinatal Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30335. Reprint requests." Zeba D. Najak, M.B., Ch.B., Neonatal Unit, Shallowford Community Hospital, 4575 N. Shallowford Rd., Atlanta, GA 30338.

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The Journal of P E D I A T R I C S

disease? The only suggestion of any effect in infants with bronchopulmonary dysplasia was reported by Sniderman et al. 9 The effect in acute respiratory distress syndrome is questionable.~~ ~t The main purpose of this study was to evaluate alteration of pulmonary function after administration of furosemide in premature infants with respiratory distress syndrome and who were in the recovery phase. MATERIALS

AND METHODS

Preterm infants recovering from respiratory distress syndrome were eligible for this study on the seventh postnatal day if they had sustained oxygen need (FIO2 > 0.30) for the preceding 24 hours or if they continued to require ventilatory assistance. After parental consent was obtained, the patients were randomized to either the treatment or the control group. The 10" treated patients received furosemide 1 m g / k g Iv daily for four consecutive days. The control group of 10 patients received no diuretic, but otherwise were treated in a similar manner. The majority of patients were enrolled in the study on the seventh postnatal day; one entered on the sixth postnatal day, and another as late as the tenth postnatal day. The *Although 12 patients were randomized to the treated group, two did not have typical respiratory distress syndrome: one was thought to have Wilson-Mikity syndrome, and one had pneumonitis. Hence, these pharmacokinctic data are reported,~2but pulmonary function data have not been included.

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F u r o s e m i d e in lung disease

Table II. Baseline comparison of lung function

Table I. Clinical data

Tracheal intubation Mild respiratory distress syndrome Severe respiratory distress syndrome Pulmonary interstitial emphysema Gestational age (wk) Mean Range Birth weight (gin) Mean Range Age when studied days postnatal) Fluid intake over four study days (ml/kg/day) Mean Range Urine output (mean) (ml/kg/6 hr) Day 1 Day4 Sodium excretion (mean) (mEq/kg/6 hr) Sodium intake (mean) (mEq/kg/24 hr)

759

Control group (n = 10)

Treated group (n = 10)

6 3

8 3

7

7

1

2

30 • 2.9 27 to 36

29 • 1.4 26 to 31

1271 + 553 840 to 2360 6 to 11

1019 _+ 269 740 to 1700 7 to 13

153 97 to 243

147 86 to 280

21 • 4 21 _+ 6 1.12

27 _+ 9 28 • 7 1.98

5.5

4.1

Control group

Treated group

A-aDO2 (mm Hg) (mean _+ SD)

184 • 146

207 • 58

Compliance (ml/cm/kg) (mean _+ SD) Pco2 (ram Hg) (mean _+ SD) FIO2 (mean _+ SD)

1.4 + 0.7

0.95 • 0.5

46 _+ 1I

45 • 7

t

P= (U e P = =

two groups were comparable (TabIe I). All had normal hydration, blood pressure, and oxygenation during the study. None was in cardiac failure or had renal disease or a clinically significant patent ductus arteriosus. The shunt through the patent ductus arteriosus was estimated by echocardiography; if the ratio of left atrium to aorta was
0.6 test, 0.15) 0.14

P = 0.8

0.4 _+ 0.22 0.43 _+ 0.09 P = 0.7

a face mask. Although cuffed endotracheal tubes were not used, leakage of air was minimal as established by auscultation and by the equal inspiratory and exhaled tidal volumes. If these volumes differed, the exhaled volume was used. Compliance was computed at points of no flow in all subjects (ventilated and spontaneously breathing). In mechanically ventilated infants this closely approximated the dynamic compliance, and in spontaneously breathing infants the dynamic compliance was documented. Other pulmonary function assessments included alveolar-arterial oxygen gradient (A-aDO2) calculated two hours after a furosemide dose and over the 72-hour study period. The partial pressure of alveolar oxygen was calculated using the concentration of inspired oxygen and arterial CO2 tension (Paco2), assuming that the alveolar Pco2 equals the arterial Pco2. Arterial oxygen tension was measured in the aorta (through an umbilical catheter) or in a peripheral artery and was used to calculate A-aDO2 gradient. The changes in arterial Pco2 were compared two hours after a furosemide dose and after four days of repeated daily therapy. Similarly, any changes in ambient oxygen requirements were recorded for each patient over the study period. Clinical testing included daily measurements of serum electrolyte values and weight, continuous blood pressure monitoring, and urine output for six hours with analysis of its sodium content. STATISTICAL

ANALYSIS

The furosemide and control groups were compared using either t test or Mann-Whitney U test. ~3 Comparisons of changes before vs after furosemide were accomplished using the paired t tests? 3 Differences were reported as significant if P = 0.059 RESULTS The patients in the two study groups had equally poor lung function; i.e., the baseline values for A-a DO2, Paco2, and FIO2 were similar in the control and treated groups (Table II). No significant systemic effect of furosemide was seen in

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Najak et al.

The Journal of Pediatrics May 1983

5040% COMPLIANCE CHANGE (mean)

!

302010-

Baseline

0

I 2 HOUR (mean) 2 0 FLUID INTAKE 1 0 ml/kg

'

1 "

m

010-

I

m

2 HOUR (mean) URINE OUTPUT ml/kg 20-

0

i 2Hr DAY 1

I2Hr

I0

DAY 2

1o

12 Hr DAY 3

I

U lO

'2Hr DAY 4

I

Fig. 1. Top, Mean percentage compliance change observed at two hours after furosemide dose. Solid baseline is daily pretreatment compliance for study subjects. Bottom, Concomitant fluid changes during two hours in treated group. Hatched bar, mean intake; solid bar, urine output. Observations also recorded for four study days.

the treated patients when the four-day change in weight, serum sodium concentration, and mean systemic arterial pressure were compared with those Of the control group. There was no difference between the groups in mean six-hour urine output (Table I). The range of fluid intake over 24 hours was large for both control and treated patients. Although fluid intake and output were recorded over the six-hour study period, the two-hour fluid balance was evaluated for correlation with compliance changes observed at two hours after furosemide administration. Urine output in excess of intake did not occur on any treatment day (Figs. 1 and 2). Although it appears that the least lung compliance change was noted concomitant with the highest intake-output ratio, this was not statistically verified. In the subgroup of four mechanically ventilated patients, the change in compliance was studied over six hours after a furosemide dose (Fig. 2). There was improvement in compliance after two hours, which persisted for four hours after a dose and then returned to baseline by six hours. Although improvement in compliance was also noted at four hours, the two-hour values were recorded in all patients for practical reasons, this being avoidance of respirator changes over the minimum time. In the 10 patients treated over four days, there were 39 total observations of compliance two hours after a furosemide dose. Furosemide treatment resulted in improved compliance on 27 of the 39 occasions (Fig. I). In comparison, the control patients showed no spontaneous change

over two hours; no improvement occurred on any of the 30 occasions (P < 0.01). In contrast to the marked immediate effect, no sustained improvement in compliance was observed over the 72 hours of the study period (Fig. 3). There was no improvement in peak compliance (measured two hours after a dose) or in the daily pretreatment compliance with chronic therapy. On most occasions, there was a reduction in A-aDO2 gradients two hours after furosemide administration (Table III). (A negative difference in A-aDO2 gradients two hours after furosemide indicated improvement.) The mean of the gradient changes was significant when the treated group was compared with the control value (P = 0.004). To evaluate sustained effect, the mean A-aDO~ gradients over the 72-hour study period was examined. In the treated group, in which each patient was his own control, the change in mean A-aDO2 gradient over 72 hours was significant using a paired t test (P < 0.01). This 72-hour change in A-aDO2 gradient was calculated for each of the 10 patients by subtracting the pretreatment values of the initial treatment day from pretreatment A-aDO2 on the fourth treatment day. Assigning zero value to the baseline A-aDO2 (mean pretreatment A-aDO~ value for day 1), the daily A-aDO2 changes were negative for both control and treated groups. Yet the 72 hour difference in A-aDO2 (subtract day 1 value from day 4 value) was significantly greater for the treated group (Fig. 4). We interpreted the Paco2 changes observed at two hours in the treated group as indicating improved ventilation

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Furosemide in tung disease

761

55 50

5

40

0

0

Meen%CL Chsnge

UJ

30

Z

,( "," 2 O o

10 S

4 -10 i 0

i 1

i 2

i 3

i 4

i 5

i e

Fluid Intake Mean Urine Output

HOUR

ml/kg/hr

5

jii i iiiii i i i i Jii i ii!iiii i i ii!i!i iiiIiiiiiii i iiiiiiiiiii ii iiiiii i iiiiiii m,k~;.r

10~

Fig. 2. Compliance change over six hours after a single furosemide dose (1 mg/kg Iv) in subgroup of mechanically ventilated patients. Numbers at each point indicate observations made at that time. Mean values are plotted. Bars indicate l SD Corresponding mean fluid intake and output are displayed during each hour.

( P = 0.03), as compared with the control group. O f the 39 measurements in the treated group, improvement was recorded in 22, whereas in the controls, improvement occurred in 10 of the 38 measurements. However, there was no evidence of cumulative improvement over the four days. Changes in a m b i e n t oxygen r e q u i r e m e n t were not significant between the two groups, either two hours after a dose or over the entire study period. T h e two-hour serum Concentration of furosemide and the two-hour values of A-aDO2 gradient and compliance were statistically assessed for correlation using the paired t test. T h e r e was no significant association between them. DISCUSSION Furosemide has been shown to affect fluid dynamics in the lung. 1.24 This effect has been used therapeutically in adults with pulmonary edema of various causes. 14~6 Our data show that the m a x i m u m effect of furosemide on lung compliance occurred two hours after the dose, persisted at four hours, but did not last until six hours. N o corresponding sustained effect was noted. This p u l m o n a r y effect did not parallel the plasma concentration of furosemide. Drugs exhibit a dose-effect relationship, and we had expected to see an association between the serum furosemide concen-

Table III. C h a n g e in A-aDO2 at two hours after furosemide

Treated group

Control group pairs 1

0

2

0

3 4 5 6 7 8 9 10

14 33 -27 1 -1 54 4 18

0 0 6

0 0 0

-0 3

23 6 -38 10 15 25 2

-2 1 -13 -4 0 11 14

-12 -10 23 7 -6 7 5

D;y

D~y

D~y DaY4

0 -33 -ll 2 -2 -39 11 15 -11 36

-15 -23 -17 8 -10 9 -2 -22 -21 -18

0 -34 -3 13 -1 2 -9 -12 -8 -11

31 -3 -20 -18 0 28 -21 37 19 -2

P = 0.004 (comparing enUre treated group vs control group). Negative number represents improvement in lung function.

tration and pulmonary function. Perhaps this was not observed here because the range of drug concentrations was not wide enough. A n o t h e r very significant effect (P = 0.004) observed during our study was the decrease in A-aDO2 gradient two hours after a dose of furosemide. T h e most r e m a r k a b l e

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The Journal of Pediatrics May 1983

1.3 CL (ml/cm/kg) 1.0q 0.5 Fluid I nta ke (ml/kg)

70 60 50 40 30 010

Urine Output (ml/kg)

2O 3O 4O 5O 60 7O 0

I

0

2

4 6 hours

t 'r I 8 10' 2

Study Day 1

I I I l I I I I 4 6 8 1 0 / / 2 4 6 8 hours hours

Study Day 2

110

Study Day 3

ff

I , 2 4 6

t

1

i

8

10

_

hours

Study Day 4

Fig. 3. Top, Daily compliance (CL) and changes in compliance at two and six hours after furosemide (1 mg/kg Iv) in a representative preterm infant. Bottom, corresponding fluid intake and output during the six hours, every day, in this patient.

A

r t~

E

+30T

A----A Control g r o u p

/

-{-20- I-

=

/

(DZ ZE

< 7 -E

O . c_ 9

D

= Treated group

+10 t O0 ' , . ~ . , ~ , ~ .. .. ~ ......

9......

Baseline (Pretreatment D I Value)

9

-20-30' -40 -

I

-50

~ Day 1 F

I Day 2

tF

I Day3

tF

Day4

tF

Fig. 4. Changes in A-aDO2 in treated and control groups over four days. F, injection of furosemide. These A-aDO2 changes are based on mean pretreatment observations every day of l0 treated patients. To obtain 72-hour change in A-aDO2, substract day 1 values from day 4 values.

aspect was the cumulative effect of daily therapy over the 72-hour study period. The A-aDO2 gradient is a measure of intrapulmonary shunt (in the absence of cardiac disease or a patent ductus arteriosus), so our observations indicate an acute and sustained decrease in this shunt in the patients given furosemide. The transpulmonary pressure remained constant, so the improvement in lung compliance was related entirely to increased tidal volume. In mechanically ventilated patients, improved tidal volume could result from

decreased extravascular lung water as well as diminished pulmonary blood volume. In premature newborn infants recovering from respiratory distress syndrome, excess in lung water or edema of the pulmonary interstitium has been verified pathologically ~6 Various mechanisms could contribute to this edema, including altered lymphatic vessels obstructing lung lymph flow, ~7 increased transvascular fluid filtration in the lung, ventilator therapy, ~8'~9 or oxygen toxicity. 6 Whatever the underlying pathophysiologic findings, the agent that

Volume 102 Number 5

decreases transvascular hydraulic pressure gradient in the lung ~ would also minimize interstitial edema. The possible mechanisms whereby furosemide lowered p u l m o n a r y artery pressure include volume depletion following diuresis and increased venous capacitance resulting in reduced left ventricular filling pressure? 5 An additional effect attributed to furosemide is its action on lymph flow. A l t h o u g h Bland et al. 2 d e m o n s t r a t e d decreased lung flow in lambs, others 2~ have demonstrated an increase in lymph flow after furosemide administration. Because furosemide did not produce detectable volume depletion in our patients, ~2 we speculate t h a t the observed p u l m o n a r y changes resulted from an effect on lymph flow or pulmonary and systemic vascular capacitance changes. We thank George W. Brumley, M.D., for reviewing the manuscript, and all the personnel in the Neonatal Intensive Care Unit at Grady Memorial Hospital for their help. REFERENCES 1. All J, Chernicki W, Wood LDH: Effect of furosemide in canine low-pressure pulmonary edema. J Clin Invest 64:1494, 1979. 2. Bland TD, McMillan DD, Bressack MA: Decreased pulmonary transvascular fluid filtration in awake newborn lambs after intravenous furosemide. J Clin Invest. 62:601, 1978. 3. Bressack MA, Bland RA: Alveolar hypoxia increases lung fluid filtration in unanesthetized newborn lambs. Circ Res 46:111, 1980. 4. Demling RH, Will JA: The effect of furosemide on the pulmonary transvascular fluid filtration rate. Crit Care Med 6:317, 1978. 5. Staub N: Pulmonary edema. Physiol Rev 54:678, 1974. 6. Anderson WR, Strickland MB: Pulmonary complications of oxygen therapy in the neonate. Arch PathoI 91:506, 1971. 7. Taghizadeh A, Reynolds EOR: Pathogenesis of bronchopulmonary dys

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8. Moylan FMB, O'Connell KC, Todres ID, Shannon DC: Edema of the pulmonary interstitium in infants and children. Pediatrics 55:783, 1975. 9. Snidcrman S, Chung M, Roth R, Ballard R: Treatment of neonatal chronic lung disease with furosemide. Clin Res 26:201A, 1978 (abst). 10. Keith MH, Berman W, Friedman Z, Whitman V, Lee C, Maisel M J: Furosemide in hyaline membrane disease. Pediatrics 62:785, 1978. 11. Savage MO, Wilkinson AT, Baum JD, Roberton NRC: Furosemide in respiratory distress syndrome. Arch Dis Child 50:709, 1975. 12. Najak Z, Harris E, Pruitt A: Furosemide excretion and pharmacologic effect in premature newborns on chronic therapy. (Submitted for publication.) 13. Armitage P: 1971 Statistical methods in medical research. New York, 1972, John Wiley, pp 118-119. 14. Bhatia ML, Singh I, Manchanda SC, Khanna PK, Roy SB: Effect of furosemide on pulmonary blood volume. Br Med J 2:551, 1969. 15. Dikshit K, Vyden JK, Forrester JS, Chatterjee K, Prakash R, Swan HJC: Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N Engl J Med 288:1087, 1973. 16. Gandy G, Jacobson W, Gairdner D: Hyaline membrane. I. Cellular changes. Arch Dis Child 45:289, 1970. 17. Lauweryns JM, St. Claessens, Boussauw L: The pulmonary lymphatics in neonatal hyaline membrane disease. Pediatrics 41:917, 1968. 18. Gett PM, Sherwood J, Shepherd GF: Pulmonary edema associated with sodium retention during ventilator treatment. Br J Anesth 43:460, 1971. 19. Sladen A, Laver MB, Pontappidan H: Pulmonary complications and water retention in prolonged mechanical ventilation. N Engl J Med 179:48, 1968. 20. Stowe NT, Hook JB: Effect of furosemide on renal hilar lymph flow. Arch int Pharmacodyn Ther 224:299, 1976. 21. Szwed J J, Kelit SA, Hamberger R J: Effect of furosemide and chlorthiazide on the thoracic duct lymph flow in the dog. J Lab Clin Med 79:693, 1972.