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Renal function in respiratory distress syndrome
May 1976
TheJournalofPEDIATRICS
845
Renal function in respiratory distress syndrome Renal function was assessed in 20 newborn infants with idiopathic respiratory distress syndrome and compared to that o f lO neonates without respiratory distress or renal disease, lnulin and P A H clearances were markedly depressed in neonates with R D S as compared to controls (5.9 4- 0.6 vs 9.3 4- 0.8 m l / m i n / m ~ [p < 0.01] and 13.5 +_ 2.0 vs 23.2 4- 1.2 m l / m i n / m 2 [t7 < 0.01], respectively). The impairment o f inulin and PA H clearances correlated with the severity o f the pulmonary disease. Improvement o f the respiratory distress was followed by a progressive rise o f inulin and PA H clearances toward normal values. Intravenous administration o f hypertonic mannitol in three patients resulted'in an immediate increase in urine flow and inulin and P A H clearances. It is concluded that a state o f acute, reversible, renal insufficiency can occur in the acute phase of idiopathic respiratory distress syndrome.
J.-P. Guignard,* A. Torrado, S. M. Mazouni, and E. Gautier, Lausanne,
PULMONARY
Switzerland
AND CARDIOVASCULAR
ASPECTS of
the respiratory distress syndrome have been extensively studied during the past decade. Pulmonary a s well as peripheral hypoperfusion have been demonstrated?. 2 Because oliguria is a common feature in this disease, one could assume that hypoperfusion also involves the kidney. This hypothesis is suggested by some ~- 4 but not by all studies? The purpose of this study was to define renal function in newborn infants presenting with the respiratory distress syndrome, and to compare it to that of neonates without renal disease. A better knowledge of this aspect of RDS could be of some importance in the clinical management of these babies. PATIENTS
AND METHODS
Renal function was evaluated in 20 neonates with RDS and compared to that of 10 control newborn infants. Gestational age was assessed according to Dubowitz and associates) The diagnoses in 10 control neonates without respiratory distress were: prematurity in eight, intrauterine growth retardation in one, and hyperbilirubinemia in one. Informed parental consent was obtained From the Division o f Nephrology, Department o f Pediatrics, Centre Hospitalier Universitaire Vaudois. Supported by the Fonds National Suisse de la Recherche Scientifique, Grant No 3. 749. 72. *Reprint address: Service de Pbdiatrie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
before the study which had been approved by an ad hoc research committee. 7 The group of affected patients included 20 newborn infants with typical clinical as well as radiologic signs of RDS. Severity of RDS was judged on radiographs by an independant observer and classified as grade 1 or 2, as described by Prod'hom and associates? Grade 1 is characterized by fine reticulogranular opacities, associated or not with an air bronchogram due to the air-filled bronchial tree. Grade 2 presents with opaque lung fields in which the borders of the heart and position
See related articles, pp. 851 and 856.
I
Abbreviations used RDS: respiratory distress syndrome PAH: para-aminohippurate FIoy: oxygen concentration in inspired air Pao: oxygen pressure in arterial blood
of the diaphragm are no longer clearly seen. Intermittent positive pressure ventilation was used in eight out of 14 grade 1 RDS patients, and in all six grade 2 RDS patients. Neonates breathing asynchronously with the respirator were given repeat intravenous injections of diazepam (4 mg/4 hr). Oxygen therapy was needed by all pati,ents. Oxygen concentration in inspired air (FIo~) was adjusted in order to raise Pao2 to 50 mm Hg. Pao~ values expressed
Vol. 88, No. 5, pp. 845-850
84 6
Guignard et al.
The Journal of Pediatrics May 1976
Table I. S u m m a r y of data in 10 control infants and in 20 newborn infants with RDS
Gestational age (wk)
Birth weight (gm)
Patients Control (N = 10) Mean Range SE RDS-type 1 (N = 14) Mean Range SE RDS type 2 (N = 6) Mean Range SE
Administered bicarbonate (mEq)
Flo z
Pao 2
(%)
(mm Hg)
20.9
86.2 78-100 3.5 54.3 46-60
1,796 1,200-2,600 129
33.5 29-37 0.8
1,900 1,100-2,550 111
32.3 29-36 0.6
6.2 0-18
77.5 40-100
1.6
6.8
1,751 1,020-2,500 202
32.3 28-39 1.5
6.5 0-15 2.4
90 60-100 6.8
1.3
56.2 38-76 6.4
RDS--Type 1, RDS Type 2: severity of RDS, classifiedin grades 1 and 2, as described by Prod'horn and associates.8 Fio2 = oxygen concentration in the inspired air. Pao~ = oxygen pressure in arterial blood.
Table II. Clearance data in 10 control newborn infants
Age at time of clearance (hO
Hematocrit
(%)
Pcrea (mg/ dl)
(ml/min/m 2)
CpAH (ml/min/m 2)
(~
46.9 29-72 4.9
48.6 41-61 2.2
22.6 14-37 2.1
9.3 6.0-14.8 0.8
23.2 15.0-27.7 1.2
40.6 23.0-58.0 3.3
Mean Range SE
Pu~o~= plasma urea concentration; C,n = inulin clearance; CpAII
=
FF
para-aminohippurate clearance; FF = filtration fraction.
in Table I and IV are the m e a n minimal values measured before the study. Usual therapeutic measures were continued unchanged throughout the clearance studies. All neonates were infused with 10% glucose solution at a rate of 70 m l / k g / d a y . Repeat bolus injections of 1M N a H C O 3 were administered to RDS patients, whenever blood p H and base excess decreased below 7.25 and - 8 mEq/1, respectively. Seventeen R D S patients received various amounts of sodium bicarbonate (range 1.5 to 18 mEq) during the hours or days preceding the study. Fourteen out of 20 RDS patients made a complete recovery after the acute phase of the respiratory distress. The remaining six had a fatal outcome; death occurred 24 hours to seven days after the clearance study. Death was secondary to ventricular hemorrhage in all cases. In two of the deceased patients, R D S had been associated with the presence of perinatal asphyxia. EXPERIMENTAL
Gin
PROTOCOL
Clearances studies were performed in the morning and lasted from four to six hours. All studies but two were performed during the first 72 hours of life (Tables II and
III). A peripheral vein was used for infusion. Priming doses of 10% inulin and 20% para-amino-hippuric acid were given to obtain plasma concentrations of 30 and 2 mg/dl, respectively. Inulin and PAH were then infused in 10% glucose in order to maintain stable plasma concentrations. Infusion rate was 0.1 m l / m i n , using a Braun constant infusion p u m p (Braun, Melsungen). Blood samples (0.5 ml) were withdrawn at the midpoint of urine collection periods, either from an arterial umbilical catheter (Argyl No. 3 or 5, Sherwood Med. Indust. Inc.) or from a peripheral vein (Butterfly 25 infusion set, Abbott Laboratories). Urine was collected from a ~bladder catheter (Argyl No. 5) inserted under sterile conditions. Urine collection periods lasted for approximately 30 minutes in the control infants and 50 minutes in the sick infants. Emptiness of the bladder was assured by flushing the catheter with air at the end of each collection period. There were four or five urine collection periods in each study. The clearance values expressed in Tables II and III are the m e a n values observed during these four to five collection periods. In three R D S patients mannitol infusion was administered at the end of the
Volume 88 Number 5
Renal function in R D S
847
Table III. Clearance data in 20 newborn infants with RDS Age at time of clearance (hO RDS type 1 (N = 14) Mean Range SE RDS-type 2 (N = 6) Mean Range SE
Hematocrit
C~,A. (ml/min/m ~)
FF (%)
6.7 3.1-12.5 0.8
15.8 3.9-29.1 2.5
55.5 14.1-127.0 8.8
4.2 2.8-6.9 0.6
8.0 2.4-15.6 2.0
67.5 43.4-117.7 11.3
(%)
Purea
Gin
(mg / dl)
(ml/min/m ~)
44.6 17-120 6.9
44.9 36-55 1.1
47.2 28-86 4.1
44.3 20-80 8.8
45.7 40-55 2.6
54.0 17-100 13.9
Pur,~ = plasma urea concentration; C[, = inulin clearance; C,^~ = para-aminohippurate clearance; FF = filtration fraction.
clearance study: 10 ml of 20% mannitol were infused during a 30-minute period. Urine was collected during and in the 30 minutes following infusion. The clearance values observed during and immediately after mannitol were averaged and considered as representative o f the mannitol effect. At the end of the study the bladder was rinsed with a 0.5% nitrofurantoin solution (Furadantine, Boehringer Mannheim). Bacteriologic cultures were performed before and at the end of each clearance study, and repeated afterward: they were negative in all cases. ANALYTICAL
METHODS
Blood acid-base values were measured at 38 ~ C with a Radiometer blood gas analyser (Radiometer, Copenhagen), using the Astrup technique and the SiggaardAndersen nomogram2, 1 0 Arterial blood Pao2 was measured with an IL model 127 electrode (Instrumentation Laboratory, Lexington). Blood urea was measured with an AutoAnalyser adaptation of the diacetylmonoxime method. Inulin and PAH were determined in blood and urine by the method of Heyrovsky 11 and Bratton and Marshall, 12 respectively. Hematocrit values were estimated by a standard capillary method using heparinized blood samples. Calculation of regression and correlation coefficients were performed according to standard statistical methods, la Values are expressed as m e a n _+ SEM. RESULTS Gestational ages and birth weights of normal and R D S patients are listed in Table I. They were comparable in the two groups. Individual data of the 10 infants without R D S are shown in Table I. Oxygen was never administered to these babies; the Pao2 values were within normal limits at the time of the study in all of them. This group was compared to 20 infants with RDS. Data of the sick patients are summarized in Table I. PaO2 was significantly depressed in this group. Despite administration of
Table IV. Comparison of clearance data in control newborn infants and those with moderate (type 1) or severe (type 2) R D S
Control C~n* CpAK* Pao2t
9.3 _+ 0.8 23.2 --+ 2.1 90.7 _+ 3.1
P'
RDS Type 1
0.05 6.7 + 0.8 0.05 15.8 _+ 2.5 0.001 54.3 _+ 1.3
P"
RDS type 2
0.001 4.2 _+ 0.6 0.001 8.0 + 2.0 0.001 56.2 _+ 6.4
c~n = Inulin clearance; CpAII = para-aminohippurate clearance. P' = Significanceof difference between controls and RDS-type 1. P" = Significanceof difference between controls and RDS type 2. *ml/min/m 2. tmm Hg.
oxygen in various concentrations, 17 out of 20 patients had a Pao~ of less than 60 m m Hg. Fourteen required artificial ventilation, which was continued unchanged during the clearance study. Data concerning age at the time of the clearance study, hematocrit, plasma urea, inulin and PAH clearances, and filtration fraction for each groups are listed in Tables II and III. M e a n age at the time o f the clearance study was comparable in the two groups. Hematocrit values were also similar. Blood urea concentration was significantly higher in R D S patients when compared to that in the controls ( P < 0.01). This difference could be partly related to the increased tissue catabolism presumably present in infants with RDS, and partly to a depressed glomerular filtration rate. There was indeed a significant depression of inulin and PAH clearances in R D S patients (Tables I1 to IV). Because of a more important fall in PAH clearance, the filtration fraction was significantly elevated in R D S infants. When severity of respiratory distress was considered according to strict radiographic criteria? the lowest values for inulin as well as for PAH clearances were observed in
848
Guignard et al.
The Journal of Pediatrics May 1976
~0-
30e"
2o-
10"
' '
|
2
"
i
iX
2b 2?
2X
postnatal age days Fig. ]. Follow-up studies of inulin clearance in two neonates with respiratory distress syndrome. The shaded area shows the 95% confidence limits of the regression line observed in normal infants. 7
the most severe cases, i.e. in infants with grade 2 RDS (Table IV). There was no statistical difference in Pao2 of infants with mild (grade 1) and severe (grade 2) cases. A follow-up of renal function was possible in two patients (Fig. 1). Disappearance of the respiratory distress was associated with an improvement in the glo.merular filtration rate. A normal glomerular filtration rate for age was observed at 20 and 25 days of life, respectively. A similar improvement also occurred in the PAH clearances. The response to hypertonic mannitol was investigated in three RDS patients. A striking increase in urine flow and in inulin and PAH clearances was observed immediately after mannitol administration (Fig. 2). DISCUSSION Impairment of renal function in RDS has been suggested by previous observations of edema, oliguria,~ and renal acidification defects during the course of the disease.4. 14 This supposition is confirmed by the demonstration of a marked decrease in inulin and PAH clearances in newborn infants with RDS as compared t o control neonates without renal or cardiorespiratory disease. Patients in our study were compared to neonates of similar gestational age and body weight. Fluid administration was similar in all infants, except for the administration of sodium bicarbonate in the RDS group. Plasma pH and bicarbonate concentrations were maintained at normal or near-normal levels in RDS patients. Acidosis as a cause of compromise of renal function can therefore be
excluded, and comparison of the two groups thus seems valid. Our observations showed that idiopathic respiratory distress syndrome was accompanied by a marked decrease in glomerular filtration rate. This impairment was most evident in the most severe cases. Our results Contrast with those reported by Siegel and associates? From endogenous creatinine clearance studies in newborn infants with RDS, these authors concluded that renal function was normal during the acute phase of the disease. The discrepancies between Siegel and associates' results and our observations have been discussed elsewhere. 1~' They could be related to differences in the severity of the disease in the patients studied, or to differences in the methods used to assess renal function. The PAH clearance was also markedly decreased in RDS patients. The interpretation of differences in PAH clearances between control and sick neonates is more difficult, however. Extraction of PAH is low in newborn infants, TM and PAH clearance thus does not reflect true renal blood flow at this age. The significant decrease in PAH, as well as in inulin clearance observed in RDS patients co~uld indicate a state of renal hypoperfusion in RDS, as observed in other areas? ,2 The decrease in PAH clearance could also reflect a decrease in the extraction of PAH, owing to a tubular transport defect and/or to a shift of intrarenal blood flow to deep areas. 17 Such a redistribution of renal blood flow has been observed in some forms of acute renal failure. The pathophysiology of the impairment in renal func-
Volume 88 Number 5
Renal function in R D S
V
Cin
ml/rn[n per m2 2..0-
ml/min per m2 20-
10
1.0-
C PAH ml/min per m2
// e
!
!
/
849
~0
--0
I
Fig, 2. Effect of hypertonic mannitol on the renal function of three neonates with respiratory distress syndrome. C, Mean individual values observed in the three clearance periods preceding administration of mannitol. M, Mean individual values observed during and 30 min after administration of mannitol. V, Urine flow. Cin, Inulin clearance. CeAH, Paraaminohippurate clearance.
tion observed in RDS is difficult to define; several factors could be involved. In a previous paper 4 we have shown a significant correlation between Pao2 and urine output in hypoxemic infants: severe hypoxemia was accompanied by oliguria. The same observation has been made in human volunteers during acute hypoxemia? 6 In the present study, both Pao~ and renal clearances were depressed in RDS patients. Hypoxemia could thus possibly mediate the fall in inulin and PAH clearances observed in RDS, as observed in hypoxemic puppies. 19 Within the RDS group, however, Pao~ was the same in patients with a moderate or a severe impairment of renal function. This suggests that factors other than Pao~ must play a role in the impairment of renal function during the respiratory distress syndrome. The severity of RDS was graded by chest radiography in two categories ~ initiating mechanical ventilation. The degree of impairment in renal function appeared to correlate with the severity of the pulmonary disease. The significance of this correlation remains to be clarified. Systemic hypotension2~should also be considered as a possible cause for the decrease in renal function observed in RDS; when present, it could depress glomerular perfusion pressure below a critical threshold for adequate filtration. Although a significant decrease in blood pressure cannot be excluded in some of our patients, hypotension is unlikely to have played a major role in all of the sick infants. Blood pressure was within normal limits in seven of them in which it was measured. A normal blood pressure has also been reported recently in neonates with
RDS. 2~Preliminary studies from this laboratory, however, suggest that systolic blood pressure can be slightly decreased in RDS, and, if so, might contribute to the observed decrease in glomerular filtration rate. Other ',perenal" factors, such as a decrease in blood volume or in red cell volume as recently observed in RDS patients~l. 22 could also play a role in the pathogenesis of the renal insufficiency. It should be mentioned, however, that most earlier studies have reported normal blood volumes in infants with RDSY ~. ~ It is possible that iatrogenic factors contributed to the oliguria of the RDS patients. In infant primates, intermittent positive pressure ventilation, as used in this study, decreased cardiac output and renal blood flow, and increased renal vascular resistance. It also induced a redistribution of intrarenal blood ftow2 ~ Whether this effect applies to the human newborn infant and particularly to the infant with RDS is unknown. There is also the possibility that intravenous administration of diazepam, used to control out of phase respiration by the infant on the ventilator, could depress renal functionY6 Several features suggest that the renal insufficiency observed in RDS is "prerenal," i.e., functional rather than secondary to parenchymal damage: (1) The rapid reversibility of the renal condition favors this hypothesis. In all patients surviving the acute phase of the disease, a normalization of blood urea was observed. Subsequent improvement of renal function was demonstrated in two patients in whom normal inulin and PAH clearances were
850
Guignard et al.
observed 20 and 25 days after the onset of the disease. (2) Pathologic studies of all deceased patients (unpublished observations) failed to demonstrate any significant renal lesion. (3) The response to mannitol infusion als0 favors this hypothesis; a striking increase in urine flow, and in inulin and P A H clearances was observed, as it is in acute prerenal failure. TM 2s This effect of mannitol might be explained by the specific osmotic effect on the renal tubule and vascular cells, ~'~ a n d / o r by the expansion o f bot h plasma and extracellular volume. On the basis of our observations, we conclude that a state of acute, reversible renal insufficiency can occur during the acute phase of the idiopathic respiratory distress syndrome, and that this possibility should be kept in mind in the m a n a g e m e n t of affected infants. We are indebted to Prof. L. S. Prod'horn for his support and encouragement. We thank Bernadette Filloux, Julie Lavoie, Marinette Maillard, Muriel Croisier, Anne-Marie Zogg, and Jacqueline Pelet for valuable technical assistance, and Drs. DaCuhna, Micheli, and Lemos for the clinical care of the patients. REFERENCES
1. Celander O: Blood flow in the foot and calf of the newborn. A plethysmographic study, Acta Paediatr (Upps) 49:488, 1960. 2. Rudolph AM, Drorbaugh JE, Auld PAM, Rudolph AJ, Nadas AS, Smith CA, and Hubbel JP: Studies on the circulation in the neonatal period. The circulation in the respiratory distress syndrome, Pediatrics 27:551, 1961. 3. Cort RL: Renal function in the respiratory distress syndrome, Acta Paediatr Scand 51:313, 1962. 4. Torrado A, Guignard JP, and Gautier E : Hypoxemia and renal function in newborns with respiratory distress syndrome (RDS), Helv Paediatr Acta 29:399, 1974. 5. Siegel SR, Fisher DA,'and Oh W: Renal function and serum aldosterone levels in infants with respiratory distress syndrome, J PEDIATR83:854, 1973. 6. Dubowitz LM, Dubowitz V, and Goldberg C: Clinical assessment of gestafional age in the newborn infant, J PEDIATR77:1, 1970. 7. Guignard JP, Torrado A, DaCuhna O, and Gautier E; Glomerular filtration rate in the first three weeks of life, J PEDIATR 87:268, 1975. 8. Prod'horn LS, Choffat JM, Frenck N, Mazouni M, Relier JP, and Torrado A: Care of the seriously ill neonate with hyaline membrane disease and with sepsis (sclerema neonatorum), Pediatrics 53:170, 1974. 9. Astrup P, Jorgensen K, Siggaard-Andersen OS, and Engel K: The acid-base metabolism. A new approach, Lancet 1:1035, 1960. 10. Siggaard-Andersen O: The acid-base status of the blood, Scand J Clin Invest 15 (Suppl 70):1, 1963.
The Journal of Pediatrics May 1976
11. Heyrovsky A: A new method for the determination of inulin in plasma and urine, Clin Chim Acta 1:470, 1956. 12. Bratton AC, and Marshall EK: A new coupling component for sulfanilamide determination, J Biol Chem 128:537, 1939. 13. Snedecor GW: Statistical methods applied to experiments in agriculture and biology, Ames, 1956, Iowa State University Press. 14. Allen AC, and Usher R: Renal acid excretion in infants with the respiratory distress syndrome, Pediatr Res 5:345, 1971. 15. Torrado A, and Guignard JP: Renal failure in respiratory distress syndrome (RDS), J PEDIATR85:443, 1974. 16. Calcagno PL, and Rubin MI: Renal extraction of paraaminohippurate in infants and children, J Clin Invest 42:1632, 1963. 17. Pitts RF: Physiology of the kidney and body fluids, ed 2, Chicago, 1968, Year Book Medical Publishers, Inc, p 145. 18. Granberg PO: Effect of acute hypoxia on renal hemodynamics and water diuresis in man, Scand J Clin Lab Invest 14 (Suppl 63):1, 1962. 19. Winterborn MH, Primack WA, Edelmann CM Jr, and Spitzer A: Effect of hypoxia on renal function in puppies, Pediatr Res 9:381, 1975 (abstr.). 20. Neligan GA~ Oxon DM, and Smith CA: The blood pressure of newborn infants in asphyxial states and hyaline membrane disease, Pediatrics 26:735, 1960. 21. Brown EG, Krouskop RW, and Sweet AY: Low blood volume with normal systemic blood pressure in infants With hyaline membrane disease (HMD), Pediatr Res 8:444, 1974 (abstr.). 22. Usher RH, Saigal S, O'Neil A, Surainder Y, and Chua L-B: Estimation of red blood cell volume in premature infants with and without respiratory distress syndrome, Biol Neonate 26:241, 1975. 23. Inall JA, Bluhm MM, Keer MM, Douglas TA, Hope GS, and Hutchison JH: Blood volume and hematocrit studies in respiratory distress syndrome of the newborn, Arch Dis Child 40:480, 1965. 24. Cassady G" Plasma volume studies in low birth weight infants, Pediatrics 38:1020, 1966. 25. Moore ES, Galvez MB, Paton JB, Fisher DE, and Behrman RE: Effects of positive pressure ventilation on intrarenal blood flow in infant primates, Pediatr Res 8:792, 1974. 26. Guignard JP, Filloux B, Lavoie J, and Torrado A: Effect of intravenous diazepam on renal function, Clin Pharm Ther 18:401, 1975. 27. Morris CR, Alexander EA, Bruns F J, and Levinsky NG: Restoration and maintenance of glomerular filtration by mannitol during hypoperfusion of the kidney, J Clin Invest 51:1555, 1972. 28. Peters G, and Brunner H: Mannitol diuresis in hemorrhagic hypotension, Am J Physiol 204:555, 1963. 29. Flores J, Di Bona DR, Beck CH, and Leaf A: The role of cell swelling in ischemic renal damage and the protective effect of hypertonic solute, J Clin Invest 51:118, 1972.
TheJournalofPEDIATRICS
845
Renal function in respiratory distress syndrome Renal function was assessed in 20 newborn infants with idiopathic respiratory distress syndrome and compared to that o f lO neonates without respiratory distress or renal disease, lnulin and P A H clearances were markedly depressed in neonates with R D S as compared to controls (5.9 4- 0.6 vs 9.3 4- 0.8 m l / m i n / m ~ [p < 0.01] and 13.5 +_ 2.0 vs 23.2 4- 1.2 m l / m i n / m 2 [t7 < 0.01], respectively). The impairment o f inulin and PA H clearances correlated with the severity o f the pulmonary disease. Improvement o f the respiratory distress was followed by a progressive rise o f inulin and PA H clearances toward normal values. Intravenous administration o f hypertonic mannitol in three patients resulted'in an immediate increase in urine flow and inulin and P A H clearances. It is concluded that a state o f acute, reversible, renal insufficiency can occur in the acute phase of idiopathic respiratory distress syndrome.
J.-P. Guignard,* A. Torrado, S. M. Mazouni, and E. Gautier, Lausanne,
PULMONARY
Switzerland
AND CARDIOVASCULAR
ASPECTS of
the respiratory distress syndrome have been extensively studied during the past decade. Pulmonary a s well as peripheral hypoperfusion have been demonstrated?. 2 Because oliguria is a common feature in this disease, one could assume that hypoperfusion also involves the kidney. This hypothesis is suggested by some ~- 4 but not by all studies? The purpose of this study was to define renal function in newborn infants presenting with the respiratory distress syndrome, and to compare it to that of neonates without renal disease. A better knowledge of this aspect of RDS could be of some importance in the clinical management of these babies. PATIENTS
AND METHODS
Renal function was evaluated in 20 neonates with RDS and compared to that of 10 control newborn infants. Gestational age was assessed according to Dubowitz and associates) The diagnoses in 10 control neonates without respiratory distress were: prematurity in eight, intrauterine growth retardation in one, and hyperbilirubinemia in one. Informed parental consent was obtained From the Division o f Nephrology, Department o f Pediatrics, Centre Hospitalier Universitaire Vaudois. Supported by the Fonds National Suisse de la Recherche Scientifique, Grant No 3. 749. 72. *Reprint address: Service de Pbdiatrie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
before the study which had been approved by an ad hoc research committee. 7 The group of affected patients included 20 newborn infants with typical clinical as well as radiologic signs of RDS. Severity of RDS was judged on radiographs by an independant observer and classified as grade 1 or 2, as described by Prod'hom and associates? Grade 1 is characterized by fine reticulogranular opacities, associated or not with an air bronchogram due to the air-filled bronchial tree. Grade 2 presents with opaque lung fields in which the borders of the heart and position
See related articles, pp. 851 and 856.
I
Abbreviations used RDS: respiratory distress syndrome PAH: para-aminohippurate FIoy: oxygen concentration in inspired air Pao: oxygen pressure in arterial blood
of the diaphragm are no longer clearly seen. Intermittent positive pressure ventilation was used in eight out of 14 grade 1 RDS patients, and in all six grade 2 RDS patients. Neonates breathing asynchronously with the respirator were given repeat intravenous injections of diazepam (4 mg/4 hr). Oxygen therapy was needed by all pati,ents. Oxygen concentration in inspired air (FIo~) was adjusted in order to raise Pao2 to 50 mm Hg. Pao~ values expressed
Vol. 88, No. 5, pp. 845-850
84 6
Guignard et al.
The Journal of Pediatrics May 1976
Table I. S u m m a r y of data in 10 control infants and in 20 newborn infants with RDS
Gestational age (wk)
Birth weight (gm)
Patients Control (N = 10) Mean Range SE RDS-type 1 (N = 14) Mean Range SE RDS type 2 (N = 6) Mean Range SE
Administered bicarbonate (mEq)
Flo z
Pao 2
(%)
(mm Hg)
20.9
86.2 78-100 3.5 54.3 46-60
1,796 1,200-2,600 129
33.5 29-37 0.8
1,900 1,100-2,550 111
32.3 29-36 0.6
6.2 0-18
77.5 40-100
1.6
6.8
1,751 1,020-2,500 202
32.3 28-39 1.5
6.5 0-15 2.4
90 60-100 6.8
1.3
56.2 38-76 6.4
RDS--Type 1, RDS Type 2: severity of RDS, classifiedin grades 1 and 2, as described by Prod'horn and associates.8 Fio2 = oxygen concentration in the inspired air. Pao~ = oxygen pressure in arterial blood.
Table II. Clearance data in 10 control newborn infants
Age at time of clearance (hO
Hematocrit
(%)
Pcrea (mg/ dl)
(ml/min/m 2)
CpAH (ml/min/m 2)
(~
46.9 29-72 4.9
48.6 41-61 2.2
22.6 14-37 2.1
9.3 6.0-14.8 0.8
23.2 15.0-27.7 1.2
40.6 23.0-58.0 3.3
Mean Range SE
Pu~o~= plasma urea concentration; C,n = inulin clearance; CpAII
=
FF
para-aminohippurate clearance; FF = filtration fraction.
in Table I and IV are the m e a n minimal values measured before the study. Usual therapeutic measures were continued unchanged throughout the clearance studies. All neonates were infused with 10% glucose solution at a rate of 70 m l / k g / d a y . Repeat bolus injections of 1M N a H C O 3 were administered to RDS patients, whenever blood p H and base excess decreased below 7.25 and - 8 mEq/1, respectively. Seventeen R D S patients received various amounts of sodium bicarbonate (range 1.5 to 18 mEq) during the hours or days preceding the study. Fourteen out of 20 RDS patients made a complete recovery after the acute phase of the respiratory distress. The remaining six had a fatal outcome; death occurred 24 hours to seven days after the clearance study. Death was secondary to ventricular hemorrhage in all cases. In two of the deceased patients, R D S had been associated with the presence of perinatal asphyxia. EXPERIMENTAL
Gin
PROTOCOL
Clearances studies were performed in the morning and lasted from four to six hours. All studies but two were performed during the first 72 hours of life (Tables II and
III). A peripheral vein was used for infusion. Priming doses of 10% inulin and 20% para-amino-hippuric acid were given to obtain plasma concentrations of 30 and 2 mg/dl, respectively. Inulin and PAH were then infused in 10% glucose in order to maintain stable plasma concentrations. Infusion rate was 0.1 m l / m i n , using a Braun constant infusion p u m p (Braun, Melsungen). Blood samples (0.5 ml) were withdrawn at the midpoint of urine collection periods, either from an arterial umbilical catheter (Argyl No. 3 or 5, Sherwood Med. Indust. Inc.) or from a peripheral vein (Butterfly 25 infusion set, Abbott Laboratories). Urine was collected from a ~bladder catheter (Argyl No. 5) inserted under sterile conditions. Urine collection periods lasted for approximately 30 minutes in the control infants and 50 minutes in the sick infants. Emptiness of the bladder was assured by flushing the catheter with air at the end of each collection period. There were four or five urine collection periods in each study. The clearance values expressed in Tables II and III are the m e a n values observed during these four to five collection periods. In three R D S patients mannitol infusion was administered at the end of the
Volume 88 Number 5
Renal function in R D S
847
Table III. Clearance data in 20 newborn infants with RDS Age at time of clearance (hO RDS type 1 (N = 14) Mean Range SE RDS-type 2 (N = 6) Mean Range SE
Hematocrit
C~,A. (ml/min/m ~)
FF (%)
6.7 3.1-12.5 0.8
15.8 3.9-29.1 2.5
55.5 14.1-127.0 8.8
4.2 2.8-6.9 0.6
8.0 2.4-15.6 2.0
67.5 43.4-117.7 11.3
(%)
Purea
Gin
(mg / dl)
(ml/min/m ~)
44.6 17-120 6.9
44.9 36-55 1.1
47.2 28-86 4.1
44.3 20-80 8.8
45.7 40-55 2.6
54.0 17-100 13.9
Pur,~ = plasma urea concentration; C[, = inulin clearance; C,^~ = para-aminohippurate clearance; FF = filtration fraction.
clearance study: 10 ml of 20% mannitol were infused during a 30-minute period. Urine was collected during and in the 30 minutes following infusion. The clearance values observed during and immediately after mannitol were averaged and considered as representative o f the mannitol effect. At the end of the study the bladder was rinsed with a 0.5% nitrofurantoin solution (Furadantine, Boehringer Mannheim). Bacteriologic cultures were performed before and at the end of each clearance study, and repeated afterward: they were negative in all cases. ANALYTICAL
METHODS
Blood acid-base values were measured at 38 ~ C with a Radiometer blood gas analyser (Radiometer, Copenhagen), using the Astrup technique and the SiggaardAndersen nomogram2, 1 0 Arterial blood Pao2 was measured with an IL model 127 electrode (Instrumentation Laboratory, Lexington). Blood urea was measured with an AutoAnalyser adaptation of the diacetylmonoxime method. Inulin and PAH were determined in blood and urine by the method of Heyrovsky 11 and Bratton and Marshall, 12 respectively. Hematocrit values were estimated by a standard capillary method using heparinized blood samples. Calculation of regression and correlation coefficients were performed according to standard statistical methods, la Values are expressed as m e a n _+ SEM. RESULTS Gestational ages and birth weights of normal and R D S patients are listed in Table I. They were comparable in the two groups. Individual data of the 10 infants without R D S are shown in Table I. Oxygen was never administered to these babies; the Pao2 values were within normal limits at the time of the study in all of them. This group was compared to 20 infants with RDS. Data of the sick patients are summarized in Table I. PaO2 was significantly depressed in this group. Despite administration of
Table IV. Comparison of clearance data in control newborn infants and those with moderate (type 1) or severe (type 2) R D S
Control C~n* CpAK* Pao2t
9.3 _+ 0.8 23.2 --+ 2.1 90.7 _+ 3.1
P'
RDS Type 1
0.05 6.7 + 0.8 0.05 15.8 _+ 2.5 0.001 54.3 _+ 1.3
P"
RDS type 2
0.001 4.2 _+ 0.6 0.001 8.0 + 2.0 0.001 56.2 _+ 6.4
c~n = Inulin clearance; CpAII = para-aminohippurate clearance. P' = Significanceof difference between controls and RDS-type 1. P" = Significanceof difference between controls and RDS type 2. *ml/min/m 2. tmm Hg.
oxygen in various concentrations, 17 out of 20 patients had a Pao~ of less than 60 m m Hg. Fourteen required artificial ventilation, which was continued unchanged during the clearance study. Data concerning age at the time of the clearance study, hematocrit, plasma urea, inulin and PAH clearances, and filtration fraction for each groups are listed in Tables II and III. M e a n age at the time o f the clearance study was comparable in the two groups. Hematocrit values were also similar. Blood urea concentration was significantly higher in R D S patients when compared to that in the controls ( P < 0.01). This difference could be partly related to the increased tissue catabolism presumably present in infants with RDS, and partly to a depressed glomerular filtration rate. There was indeed a significant depression of inulin and PAH clearances in R D S patients (Tables I1 to IV). Because of a more important fall in PAH clearance, the filtration fraction was significantly elevated in R D S infants. When severity of respiratory distress was considered according to strict radiographic criteria? the lowest values for inulin as well as for PAH clearances were observed in
848
Guignard et al.
The Journal of Pediatrics May 1976
~0-
30e"
2o-
10"
' '
|
2
"
i
iX
2b 2?
2X
postnatal age days Fig. ]. Follow-up studies of inulin clearance in two neonates with respiratory distress syndrome. The shaded area shows the 95% confidence limits of the regression line observed in normal infants. 7
the most severe cases, i.e. in infants with grade 2 RDS (Table IV). There was no statistical difference in Pao2 of infants with mild (grade 1) and severe (grade 2) cases. A follow-up of renal function was possible in two patients (Fig. 1). Disappearance of the respiratory distress was associated with an improvement in the glo.merular filtration rate. A normal glomerular filtration rate for age was observed at 20 and 25 days of life, respectively. A similar improvement also occurred in the PAH clearances. The response to hypertonic mannitol was investigated in three RDS patients. A striking increase in urine flow and in inulin and PAH clearances was observed immediately after mannitol administration (Fig. 2). DISCUSSION Impairment of renal function in RDS has been suggested by previous observations of edema, oliguria,~ and renal acidification defects during the course of the disease.4. 14 This supposition is confirmed by the demonstration of a marked decrease in inulin and PAH clearances in newborn infants with RDS as compared t o control neonates without renal or cardiorespiratory disease. Patients in our study were compared to neonates of similar gestational age and body weight. Fluid administration was similar in all infants, except for the administration of sodium bicarbonate in the RDS group. Plasma pH and bicarbonate concentrations were maintained at normal or near-normal levels in RDS patients. Acidosis as a cause of compromise of renal function can therefore be
excluded, and comparison of the two groups thus seems valid. Our observations showed that idiopathic respiratory distress syndrome was accompanied by a marked decrease in glomerular filtration rate. This impairment was most evident in the most severe cases. Our results Contrast with those reported by Siegel and associates? From endogenous creatinine clearance studies in newborn infants with RDS, these authors concluded that renal function was normal during the acute phase of the disease. The discrepancies between Siegel and associates' results and our observations have been discussed elsewhere. 1~' They could be related to differences in the severity of the disease in the patients studied, or to differences in the methods used to assess renal function. The PAH clearance was also markedly decreased in RDS patients. The interpretation of differences in PAH clearances between control and sick neonates is more difficult, however. Extraction of PAH is low in newborn infants, TM and PAH clearance thus does not reflect true renal blood flow at this age. The significant decrease in PAH, as well as in inulin clearance observed in RDS patients co~uld indicate a state of renal hypoperfusion in RDS, as observed in other areas? ,2 The decrease in PAH clearance could also reflect a decrease in the extraction of PAH, owing to a tubular transport defect and/or to a shift of intrarenal blood flow to deep areas. 17 Such a redistribution of renal blood flow has been observed in some forms of acute renal failure. The pathophysiology of the impairment in renal func-
Volume 88 Number 5
Renal function in R D S
V
Cin
ml/rn[n per m2 2..0-
ml/min per m2 20-
10
1.0-
C PAH ml/min per m2
// e
!
!
/
849
~0
--0
I
Fig, 2. Effect of hypertonic mannitol on the renal function of three neonates with respiratory distress syndrome. C, Mean individual values observed in the three clearance periods preceding administration of mannitol. M, Mean individual values observed during and 30 min after administration of mannitol. V, Urine flow. Cin, Inulin clearance. CeAH, Paraaminohippurate clearance.
tion observed in RDS is difficult to define; several factors could be involved. In a previous paper 4 we have shown a significant correlation between Pao2 and urine output in hypoxemic infants: severe hypoxemia was accompanied by oliguria. The same observation has been made in human volunteers during acute hypoxemia? 6 In the present study, both Pao~ and renal clearances were depressed in RDS patients. Hypoxemia could thus possibly mediate the fall in inulin and PAH clearances observed in RDS, as observed in hypoxemic puppies. 19 Within the RDS group, however, Pao~ was the same in patients with a moderate or a severe impairment of renal function. This suggests that factors other than Pao~ must play a role in the impairment of renal function during the respiratory distress syndrome. The severity of RDS was graded by chest radiography in two categories ~ initiating mechanical ventilation. The degree of impairment in renal function appeared to correlate with the severity of the pulmonary disease. The significance of this correlation remains to be clarified. Systemic hypotension2~should also be considered as a possible cause for the decrease in renal function observed in RDS; when present, it could depress glomerular perfusion pressure below a critical threshold for adequate filtration. Although a significant decrease in blood pressure cannot be excluded in some of our patients, hypotension is unlikely to have played a major role in all of the sick infants. Blood pressure was within normal limits in seven of them in which it was measured. A normal blood pressure has also been reported recently in neonates with
RDS. 2~Preliminary studies from this laboratory, however, suggest that systolic blood pressure can be slightly decreased in RDS, and, if so, might contribute to the observed decrease in glomerular filtration rate. Other ',perenal" factors, such as a decrease in blood volume or in red cell volume as recently observed in RDS patients~l. 22 could also play a role in the pathogenesis of the renal insufficiency. It should be mentioned, however, that most earlier studies have reported normal blood volumes in infants with RDSY ~. ~ It is possible that iatrogenic factors contributed to the oliguria of the RDS patients. In infant primates, intermittent positive pressure ventilation, as used in this study, decreased cardiac output and renal blood flow, and increased renal vascular resistance. It also induced a redistribution of intrarenal blood ftow2 ~ Whether this effect applies to the human newborn infant and particularly to the infant with RDS is unknown. There is also the possibility that intravenous administration of diazepam, used to control out of phase respiration by the infant on the ventilator, could depress renal functionY6 Several features suggest that the renal insufficiency observed in RDS is "prerenal," i.e., functional rather than secondary to parenchymal damage: (1) The rapid reversibility of the renal condition favors this hypothesis. In all patients surviving the acute phase of the disease, a normalization of blood urea was observed. Subsequent improvement of renal function was demonstrated in two patients in whom normal inulin and PAH clearances were
850
Guignard et al.
observed 20 and 25 days after the onset of the disease. (2) Pathologic studies of all deceased patients (unpublished observations) failed to demonstrate any significant renal lesion. (3) The response to mannitol infusion als0 favors this hypothesis; a striking increase in urine flow, and in inulin and P A H clearances was observed, as it is in acute prerenal failure. TM 2s This effect of mannitol might be explained by the specific osmotic effect on the renal tubule and vascular cells, ~'~ a n d / o r by the expansion o f bot h plasma and extracellular volume. On the basis of our observations, we conclude that a state of acute, reversible renal insufficiency can occur during the acute phase of the idiopathic respiratory distress syndrome, and that this possibility should be kept in mind in the m a n a g e m e n t of affected infants. We are indebted to Prof. L. S. Prod'horn for his support and encouragement. We thank Bernadette Filloux, Julie Lavoie, Marinette Maillard, Muriel Croisier, Anne-Marie Zogg, and Jacqueline Pelet for valuable technical assistance, and Drs. DaCuhna, Micheli, and Lemos for the clinical care of the patients. REFERENCES
1. Celander O: Blood flow in the foot and calf of the newborn. A plethysmographic study, Acta Paediatr (Upps) 49:488, 1960. 2. Rudolph AM, Drorbaugh JE, Auld PAM, Rudolph AJ, Nadas AS, Smith CA, and Hubbel JP: Studies on the circulation in the neonatal period. The circulation in the respiratory distress syndrome, Pediatrics 27:551, 1961. 3. Cort RL: Renal function in the respiratory distress syndrome, Acta Paediatr Scand 51:313, 1962. 4. Torrado A, Guignard JP, and Gautier E : Hypoxemia and renal function in newborns with respiratory distress syndrome (RDS), Helv Paediatr Acta 29:399, 1974. 5. Siegel SR, Fisher DA,'and Oh W: Renal function and serum aldosterone levels in infants with respiratory distress syndrome, J PEDIATR83:854, 1973. 6. Dubowitz LM, Dubowitz V, and Goldberg C: Clinical assessment of gestafional age in the newborn infant, J PEDIATR77:1, 1970. 7. Guignard JP, Torrado A, DaCuhna O, and Gautier E; Glomerular filtration rate in the first three weeks of life, J PEDIATR 87:268, 1975. 8. Prod'horn LS, Choffat JM, Frenck N, Mazouni M, Relier JP, and Torrado A: Care of the seriously ill neonate with hyaline membrane disease and with sepsis (sclerema neonatorum), Pediatrics 53:170, 1974. 9. Astrup P, Jorgensen K, Siggaard-Andersen OS, and Engel K: The acid-base metabolism. A new approach, Lancet 1:1035, 1960. 10. Siggaard-Andersen O: The acid-base status of the blood, Scand J Clin Invest 15 (Suppl 70):1, 1963.
The Journal of Pediatrics May 1976
11. Heyrovsky A: A new method for the determination of inulin in plasma and urine, Clin Chim Acta 1:470, 1956. 12. Bratton AC, and Marshall EK: A new coupling component for sulfanilamide determination, J Biol Chem 128:537, 1939. 13. Snedecor GW: Statistical methods applied to experiments in agriculture and biology, Ames, 1956, Iowa State University Press. 14. Allen AC, and Usher R: Renal acid excretion in infants with the respiratory distress syndrome, Pediatr Res 5:345, 1971. 15. Torrado A, and Guignard JP: Renal failure in respiratory distress syndrome (RDS), J PEDIATR85:443, 1974. 16. Calcagno PL, and Rubin MI: Renal extraction of paraaminohippurate in infants and children, J Clin Invest 42:1632, 1963. 17. Pitts RF: Physiology of the kidney and body fluids, ed 2, Chicago, 1968, Year Book Medical Publishers, Inc, p 145. 18. Granberg PO: Effect of acute hypoxia on renal hemodynamics and water diuresis in man, Scand J Clin Lab Invest 14 (Suppl 63):1, 1962. 19. Winterborn MH, Primack WA, Edelmann CM Jr, and Spitzer A: Effect of hypoxia on renal function in puppies, Pediatr Res 9:381, 1975 (abstr.). 20. Neligan GA~ Oxon DM, and Smith CA: The blood pressure of newborn infants in asphyxial states and hyaline membrane disease, Pediatrics 26:735, 1960. 21. Brown EG, Krouskop RW, and Sweet AY: Low blood volume with normal systemic blood pressure in infants With hyaline membrane disease (HMD), Pediatr Res 8:444, 1974 (abstr.). 22. Usher RH, Saigal S, O'Neil A, Surainder Y, and Chua L-B: Estimation of red blood cell volume in premature infants with and without respiratory distress syndrome, Biol Neonate 26:241, 1975. 23. Inall JA, Bluhm MM, Keer MM, Douglas TA, Hope GS, and Hutchison JH: Blood volume and hematocrit studies in respiratory distress syndrome of the newborn, Arch Dis Child 40:480, 1965. 24. Cassady G" Plasma volume studies in low birth weight infants, Pediatrics 38:1020, 1966. 25. Moore ES, Galvez MB, Paton JB, Fisher DE, and Behrman RE: Effects of positive pressure ventilation on intrarenal blood flow in infant primates, Pediatr Res 8:792, 1974. 26. Guignard JP, Filloux B, Lavoie J, and Torrado A: Effect of intravenous diazepam on renal function, Clin Pharm Ther 18:401, 1975. 27. Morris CR, Alexander EA, Bruns F J, and Levinsky NG: Restoration and maintenance of glomerular filtration by mannitol during hypoperfusion of the kidney, J Clin Invest 51:1555, 1972. 28. Peters G, and Brunner H: Mannitol diuresis in hemorrhagic hypotension, Am J Physiol 204:555, 1963. 29. Flores J, Di Bona DR, Beck CH, and Leaf A: The role of cell swelling in ischemic renal damage and the protective effect of hypertonic solute, J Clin Invest 51:118, 1972.