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The vasopressin response to severe birth asphyxia
Early Human Development, 22 ( 1990) 119- 129 Elsevier Scientific Publishers Ireland Ltd.
119
EHD 01057
The vasopressin response to severe birth asphyxia Albert0 Smith”, Prem Prakasha, Jennifer Nesbittb and Neil McIntosh” Departments of “Child Health and %hemical Pathology, St George’s Hospital and Medical School, London SW170QT(U.K.) Accepted for publication 24 February 1990
Summary
Serial measurements of urinary arginine vasopressin (AVP) were made in six severely birth asphyxiated newborn infants. In five infants serial plasma concentrations were also evaluated. There was a strong negative correlation between plasma AVP and plasma osmolality in these infants (r = - 0.52, P = 0.0012). In neither the individual babies nor the group as a whole was there a significant correlation between plasma AVP and the urinary excretion of AVP even if the latter was standardised for creatinine content. Normal development at follow up was only observed in two asphyxiated infants who had consistently low urinary arginine vasopressin levels in the first days of life. Infants with consistently high urinary vasopressin concentrations either died or were severely abnormal in their subsequent development. birth asphyxia; vasopressin (arginine vasopressin); osmolality; syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Introduction
Hoppenstein et al. in 1968 [l] and others since [2--61 showed high cord plasma AVP concentrations in infants delivered vaginally compared with infants delivered by operative means. The levels have been shown to be lowest in infants delivered by elective caesarean section with intermediate levels in caesarean sections performed
Correspondence to: Professor N. McIntosh, Department of Child Life and Health, 17 Hatton Place, Edinburgh EH9 IUW, U.K. 0378-3782/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland
120
after the onset of labour. It has been suggested that the stress and hypoxia of a normal vaginal delivery causes these high cord values and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been associated with severe birth asphyxia [7]. There are few reports of serial measurements of plasma AVP after delivery [8,9]. One of these and also the available cross sectional data [5] suggest that plasma levels quickly become unmeasurable. Only McIntosh and Smith [9] using a very sensitive cytochemical assay have shown subsequent peaks in a group of mainly preterm babies. Recent data has suggested that the problems of plasma sampling were made unnecessary by the close relationship of urinary AVP excretion to the plasma concentration [ 10,111. We have evaluated serial postnatal urinary collections in six severely birth asphyxiated infants in five of whom we have serial plasma concentrations during part of the urinary collections. The study aimed to: 1. Review the vasopressin response to the severest degree of birth asphyxia (cardiac arrest at the time of birth). 2. Compare the plasma and urinary vasopressin response in a situation where renal damage might be expected, 3. Evaluate the developmental outcome with reference to the vasopressin response. Patients and Methods The detail of the six infants and the degree of asphyxia are shown in Table I. The surviving infants have all been followed in a baby follow up clinic for 2-4 years. On arrival at St George’s Hospital Neonatal Unit (range OS-56 h), serial fourhourly urine collections were made using the method of Liu and Anderson [12]. Because of the difficulty of always ensuring that the urine collections were complete, we elected to express the urine excretions with reference to concentrations of urinary creatinine. In five infants who had arterial catheters present for continuous blood pressure evaluation and blood gas analysis additional blood was taken (1 ml) up to three times daily for the measurement of plasma AVP, creatinine and osmolality. The heparinised blood was immediately separated by centrifugation at 10 000 x g for 1 min in a microfuge and the plasma was frozen in liquid nitrogen and stored at - 70 ‘C until measured. Plasma was extracted on C8 reverse phase chromatography columns (Jones Chromatography) that gave a recovery of 87 + 5% (mean + S.D., N = 12). Urine samples were measured both unextracted and after C8 extraction. The correlation was very close (r = 0.98, P < 0.0001). The extracted results were used in Fig. 1. Urine and plasma measurements were made in triplicate or duplicate by radioimmunoassay using an in-house method 1131. The interassay coefficients of variation using low and high quality controls were 15% and 6%, respectively. Plasma and urine osmolality were measured using vapour pressure osmometry (TM Wescor) and creatinine by the routine clinical laboratory. The study was sanctioned by the Hospital Medical Ethical Committee.
39 37 32
39 35 33
Needed IPPV > 15 min
1 2 3
4 5 6
I.D.
B. wt.
of inappropriate
“Syndrome
3 4 5 6
yes yes yes yes yes yes
out out in in
in in
Inborn/ outborn
yes yes yes
yes no
no
hormone
yes yes yes yes yes yes secretion.
Kept ventilated thereafter
Clinical foetal distress before delivery
antidiuretic
3200 2850 1960
4660 2580 1600
(9)
1 2
after birth
Gest. weeks
details.
Patient
I.D.
I
TABLE
yes yes yes
yes yes no
15 min 25 min 90 min 30 min ? ?
Time regular respiration
Abnormal CTG. Birth 1 3 3 0 7 6
0 1 2 0 1 2
yes
yes no
yes yes no
yes yes yes yes yes yes
Hypotonia
5 min
1 min
Cerebral oedema
APGARS
4 6 7 1 7 9
yes yes
yes -
-
Hypertonia
10 min 6.89 7.12 6.98 6.12 6.71 7.03
1st pH
yes
yes yes yes yes yes
Fits
yes
no no no no no
SIADH’
(16) (30) (120) (40) (60) (2)
(Time taken, min after birth)
122
Results Renal function
The renal function over the first seven days of life is shown in Table II. Urine flow rates are less than those accepted with normal renal function [14] in infants 2 (day 3), 3 (day 3), 4 (day 3), 5 (day 3, 5 and 6) and 6 (day 4) - only complete 24-h urine collections are included. Infants 4, 5 and 6 all show a polyuric phase with a fixed osmolality and specific gravity following a period of oliguria. Plasma creatinines of 174 (infant l), 461 (infant 4), 390 (infant 5) I.tmol/l and a plasma urea of 16.5 (infant 6) mmol/l are all greater than the accepted normal range suggesting that glomerular function is significantly impaired [ 14,151 but in infant 1 the coincident creatinine clearance of 2.6 ml/min implies only minimal injury [16]. The creatinine clearances of infants 3, 4 and 5 are all persistently less than 1 ml/ min indicating significant renal failure [16] and in infants 4 and 5 they remain 1.0 ml/min for the first 6 days of life. Infants 1 and 2 both show clearances of more than 1 throughout. Concurrent urine and plasma osmolalities and AVP concentrations and excretions are shown in Table III. Three infants had evidence of a concentration defect on the basis of low urinary osmolality at a time of high plasma osmolality (infants 1, 2, 4; Table III). The normal postnatal diuresis, usually seen between 26 and 34 hours of age [17,18], is only seen within this time in infants 1 and 2. The diuresis in infants 3, 4 and 5 occurred on day 4 and in infant 6 it occurred on day 7. Plasma A VP
The plasma AVP levels of the five infants are shown in Fig. 1 with time after birth. The levels in the different babies are very variable as are the levels in the individual babies at different times. All infants at some time had at least one high plasma AVP level but these were not necessarily immediately after birth. There was a significant negative correlation between the plasma AVP and the plasma osmolality(r = - 0.52, P = 0.0012) in the group as a whole but in individual babies significance was not demonstrated. There was no correlation between the plasma AVP concentration and the osmolality of the urine (r = 0.007, P = 0.7) or between plasma and urine osmolality (r = 0.02, P = 0.89). Urinary A VP
Four-hourly excretions of AVP were related to excretions of creatinine as renal damage was thought to be likely in all infants. The four-hourly AVP excretions in pmol/mmol creatinine were very variable from baby to baby (Fig. l), with values from 1 pmol/mmol creatinine in babies 1 and 2 (never rising above 5 in these infants), to levels of many hundreds pmol/mmol creatinine in babies 5 and 6. In infants 3 and 4 the levels were intermediate but frequently above 5 pmol/mmol creatinine and the excretion was prolonged. The correlation between plasma AVP concentration and the concurrent urinary content was significant in only 1 infant (r-values for the 6 babies respectively = - 0.27, + 0.06, - , +0.04, - 0.27,
6
2
(0.2)IC 0.6 196 (0.5) (0.02)lC 4.1 1.7
? ?
‘I
1.1 1.5 NM (0.6)IC 2.0 NM ? ? ? ? ?
1
Urine vol (ml/kg/h) Urinary creatinine (mmol/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) Urinary creatinine (mmol/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) Urinary creatinine (mmol/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) Urinary creatinine (mmol/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) , Urinary creatinine (mmoJ/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) Urinary creatinine (mmoV1) Plasma urea (mmol/I)
Day 1
Baby 1.7 1.7 153 2.1 1.4 2.0 130 1.3 1.5 1.1 143 0.4 (O.l)IC 0.6 226 (0.02) (0.6)IC 1.1 230 (0.2) (O.l)lC 0.5 6.5
Day 2 (1.3)IC 3.3 174 2.6 1.9 1.7 NM 1.6 1.6 134 0.7 1.8 0.7 269 0.3 1.8 1.8 286 0.8 (0.3)lC 1.2 7.9
Day 3
3.0 NM IC 1.2 67 4.5 0.8 143 1.0 2.7 0.7 390 0.4 2.7 1.8 386 0.9 0.7 2.5 7.2
IC
Day 4
0.8 120 1.4 2.8 0.9 460 0.4 1.6 2.5 390 0.7 0.34 3.9 9.1
5.5
Day 5
5.2 0.8 96 1.7 3.6 1.0 461 0.6 1.2 3.2 NM IC 0.5 16.5
Day 6
4.3 1.2 351 1.0 1.7 0.7 15
3.0 1.1 NM -
Day I
Urine volumes, plasma and urinary creatinines and creatinine clearance in the six infants during the first week of life. NM, not measured; IC, incomplete (if leakage only small, the value is given in brackets).
TABLE II
u OSMO u AVP cont.
pl AVP pl OSMO u AVP excr . u OSMO u AVP cont. pl AVP pl OSMO u AVP excr. u OSMO u AVP cont. pl AVP pl OSMO u AVP excr. u OSMO u AVP cont. pl AVP pl OSMO u AVP excr. u OSMO u AVP cont. pl AVP pl OSMO u AVP excr . u OSMO u AVP cont. pl AVP pl OSMO u AVP excr .
IC200 325 165 20 263
438
307 IC560 320 58 3 268
9.3 317 IC2900 326 280 17 213
7.8 321 IC5oOo 336 248 8 265 IC2430
308
394 250
5065 365 39
260 320 5 2.6 308 IC20 304 13
88 290 8
721 305
2
0.8 298 120 225 1.3 0.7 296 134 232 1.7
0.5 293 3 298 1 0.5 298 240 304 3.3
0.6 300 6 236 1 0.5 311 11 417 4.4
7
a.m.
p.m.
a.m.
p.m.
a.m.
Day 3
Day 2
Day 1
pl AVP, pmol/mmol creatinine (mean of samples in 12- or 24-h period. pl OSMO, mosm/kg (mean of samples in 12- or 24-h period. u AVP excr.. fmol excreted/l2 or 24 h. u OSMO, mosm/kg (mean of specimens in 12- or 24-h period. u AVP cont., pmol/mmol creatinine (mean of samples in 12-or 24-h period. IC, incomplete collection.
Baby
3300 342 40 49 232 IC6OOO
298
612 292 8
IC36 250 0.7
13.5 315 3 223 1 1
p.m.
347 7ooo 344 24 25 215 1c12ooo 476 300
160 245 1.25 4 295 184 250 7
310 IC130 154 1
140 313 1
Day 4
420 262 3 2.5 312 IC185 230 3 3 332 3162 337 14 21 228 IC3ooo 493 50
IC2 164 1.4
IC5 271 1
0.5
Day 5
610 200 7 341 1800 280 6 20 800 212 2
IC2OO 348 5
330 IC530 300 4.5 3 309 400 298 3
IC20 416 4
Day 7
periods.
677 250 4
0.7 272 ICI 215 1
Day 6
Plasma and urine osmolalities and AVP concentrations and excretions. Over the first 3 days 12-h periods are considered and from Day 4-7,24-h
TABLE III
F?.
LOG PLASMA AVP pmol/l O----O
? t
. I
!
?
=I
~w!v=J~
www~d
- dAV
3Nlklr-l
00-1
126
+ 0.89) in whom the correlation was very close. The values on individual days are shown in Table III. Outcome No infant had a pulmonary air leak and none had ultrasound or clinical evidence of intracranial haemorrhage. Case 4 died in the second week of life when ventilatory support was withdrawn for severe hypoxic-ischaemic encephalopathy. Three infants developed a severe spastic quadriplegia and microcephaly and one of these (case 3) died at six months of age with a developmental age of less than six weeks. Cases 1 and 2 are normal at 3 and 3.5 years. Discussion
The plasma AVP concentrations and the urinary AVP excretions need to be evaluated with reference to renal function in these infants who had been subjected to severe asphyxia. There is some evidence that in aduhs plasma AVP concentrations are slightly elevated in renal failure due to reduced excretion of the hormone [ 191but the AVP levels in our infants are orders of magnitude higher than were described. All infants show some evidence of renal damage; this is minor in infants 1 and 2, moderate to severe in infant 3 and very severe in infants 4,5 and 6. The normal urine flow rate is more than 1 ml/kg body weight/h in the first 24 h and more than 2 ml/ kg body weight/h after this time [14] with the diuresis usually occurring between 26 and 34 h [17,18]. The creatinine clearances of infants 3, 4 and 5 are all persistently less than the normal reference range [16] indicating glomerular failure and the high plasma urea and low urine production rate in infant 6 we also believe indicates significant renal failure. Only infants 1 and 2 consistently have relatively normal plasma creatinine [15] and creatinine clearances greater than 1 indicating relatively undamaged glomerular function but both of them (and infant 5) had evidence of tubular damage being unable to concentrate their urine in the presence of a high plasma osmolality. High umbilical cord AVP levels have been shown after vaginal delivery and have been postulated as being caused by hypoxic stress during labour [2,4]. Polin confirmed the high levels but found no correlation with umbilical pH and therefore postulated that the secretion of vasopressin might be the cause of labour [3]. Stark et al. [20] have clearly shown that experimental hypoxia in the chronic sheep preparation leads to massive plasma AVP response lasting for about two hours after the acute insult (F102 = 0.1 for 30 min or acute cord compression). Over this two-hour period the amniotic fluid concentation peaked and remained high for at least 24 h. Although it is unusual for hypoxia to be an isolated problem, careful experiments by Forsling and Ullmann have shown that the AVP release is due to this stimulus 1231. No infant in this study showed evidence of hypovolaemia and all had adequate blood pressures. High plasma osmolalities were seen in infants 1, 2, 4 and 5 (Table III) and this may have been the stimulus for AVP secretion in infants 1,4 and 5. It is worth stating that clinically, none of these infants were even mildly dehydrated and we do not know what caused this additional circulating osmolar stress. Infant 6 had
127
the classical features of SIADH. Our data would suggest that the poor urine outputs (Table II) were more likely due to degrees of renal failure than to AVP because of the paired and sequential relationships of the plasma and urinary osmolalities. Hyponatraemia following birth asphyxia was first shown by Khare [21] and was postulated to be due to fluid retention as a consequence of vasopressin release. Kaplan and Feigin [7] described two cases of innappropriate secretion of antidiuretic hormone associated with hypoxic-ischaemic encephalopathy where the AVP levels were high on the second and third days of life. There have been few serial measurements of plasma AVP but Speer et al. [8] found high plasma levels in thirteen asphyxiated infants in the first two days of life falling to normal on the third day. The six infants reported here all showed both evidence of severe birth asphyxia as evidenced by an absent heart beat at birth and very poor Apgar scores and also a severe acidosis after birth. All the infants went on to show severe hypoxic-ischaemic encephalopathy with hypotonia and fits. Despite this, the first plasma level in infant 1 was low at 14 h and the first and only recorded high value was at 46 h. Three other infants had high plasma AVP levels in the first 24 h which rapidly fell in case 2 but were maintained in cases 5 and 6. Case 4 was transferred from another hospital at 48 h of age: the plasma AVP level was low on arrival but a peak of 6 pm0111 occurred at 72 h of age which was not associated with hypotension, hypovolaemia or a high serum osmolality. Infants 3, 4 and 5 had evidence of severe renal failure but despite this had very variable plasma AVP levels. We would postulate that it is unlikely, therefore, that these concentrations are solely related to poor vasopressin excretion. Because of the difficulties of measuring plasma AVP in small and sick infants, Rees et al. [I l] suggested measuring serial urine excretions of AVP to evaluate posterior pituitary function in the newborn. They showed a significant positive correlation between plasma and urinary levels overall but their data also showed some infants where there was marked discrepancy of these parameters. Our data on these severely asphyxiated infants show no correlation between plasma and urine concentrations of AVP in 4 out of the 5 infants who had both plasma and urinary levels measured. This may be related to the degree of coincident renal failure. Although we were able to demonstrate a significant negative correlation between plasma AVP and plasma osmolality taking all the values in the 5 infants - a possible indication of SIADH and a relationship not shown by Rees et al. [5] we were not able to demonstrate a significant correlation - positive or negative in any individual baby. Like Rees et al., we were unable to demonstrate a relationship between plasma AVP and urine osmolality and would thus agree that the kidney at least following asphyxia does not respond to high vasopressin concentrations although one infant - No. 6, Table III - did show classical clinical features of the syndrome of antidiuretic hormone release. Our inability to demonstrate a relationship between plasma and urine osmolality (r = 0.03, P = 0.8) may also reflect the extent of the renal damage. Wiriyathian et al. 1241found high urinary AVP levels in 13 asphyxiated preterm infants in the first day of life falling on the second day, but remaining higher than normal for at least four days after birth. We could find no trend in urinary AVP levels in the first few days of life. Case 1 showed a measurable urinary AVP concentration on only one occasion and case 2 never exceeded 5 pmol/mmol creatinine. Both
128
of these infants are normal at follow up. The asphyxia in case 1 although severe (leading to birth without a recordable heart beat) was short in duration arising because of shoulder dystocia. Resuscitation was prompt but there was still a significant acidosis and subsequently the signs of hypoxic-ischaemic encephalopathy and there was also a high plasma creatinine although urine production rate and creatinine clearances were in acceptable ranges. In case 2 the cord was compressed during cord prolapse. In this instance there was recorded fetal distress and an absent heart beat at birth again leading to severe acidosis. Despite prompt resuscitation spontaneous respiration did not occur until 25 min after birth. There was again a severe acidosis and the signs afterwards of encephalopathy. The other infants all had much higher urinary AVP concentrations and for prolonged periods. These four infants were severely and irreparably damaged. We wonder whether the excretion of AVP in the urine for long periods after birth may be associated with a perinatal problem sufficient to cause lasting damage. Although Rees et al. [22] reported preterm infants with high urinary levels, they give no detail of the follow up. Acknowledgements We would like to thank nursing and medical staff of the Neonatal Unit at St George’s Hospital for their dedicated care of the infants; Birthright for funding AS. during the study; Miss Elaine Forbes for help with the manuscript and Miss Lesley Skeates and Apple Mac for help with the graphics. References 1 2 3 4
11 12
Hoppenstein, J.M., Miltenberger, F.W. and Moran, W.H. (1968): The increase in blood levels of vasopressin in infants during birth and surgical procedures. Surg. Gynecol. Obstet. 127,966-974. Chard, R., Hudson, C.N., Edwards, C.R.W. and Boyd, N.R.H. (1971): Release of oxytocin and vasopressin by the human foetus during labour. Nature, 234,352-354. Polin, R.A., Husain, M.K., James. L.S. and Frantz, A.G. (1977): High vasopressin concentrations in human umbilical cord blood - lack of correlation with stress. J. Perinatal. Med. 5, 114-. De Vane, G.W. and Porter, J.C. (1980) An apparent stress-induced release of arginine vasopressin by humanneonates. J. Clin. Endocrinol. Metab., 51, 1412-1416. Rees, L., Forsling, M.L. and Brook, C.G.D. (1980): Vasopressin concentrations in the neonatal period. Clin. Endocrinol. 12(4), 357-362. Czernichow, P., Pattin, A. (1978): La vasopressine chez le nouveau-ne: taux plasmatiques dans le sang du cordon et chez la mere. Anal. Endocrinol. (Paris), 39,225-226. Speer, M.E., Gorman, W.A., Kaplan, S.L. and Rudolph, A.J. (1984): Elevation of plasma concentrations of arginine vasopressin following perinatal asphyxia. Acta Paediatr. Stand., 73,610-614. McIntosh, N. and Smith, A. (1985): Serial management of plasma arginine vasopressin in the newborn. Arch. Dis. Child., 60, 1031-1035. Stern, P. and La Rochelle. F.T. Similar relationship between plasma and urinary vasopressin in the newborn. Hormone Res., 17, 134-140. Rees, L., Brook, C.G.D. and Forsling, M.L. (1983): Continuous urine collection in the study of vasopressin in the newborn. Hormone Res., 17,134-140. Liu, H.-Y. and Anderson, G.J. (1967): A method for long-term quantitative and fractional urine collection. J. Pediatr., 70,276-279. Smith, A. and McIntosh, N. (1985): A new radioimmunoassay for AVP in unextracted human urine. Biochem. Sot. Trans. 14.782-783.
129
13 14 15 16 17 18
Stark, RI., Daniel, S.S., Husain, M.K. et al. (1984): Vasopressin concentration in amniotic fluid as an index of fetal hypoxia: mechanism of release in sheep. Pediatr. Res., 18,552-558. Khare. S.K. (1977): Neurohypophyseal dysfunction following perinatal asphyxia. J. Pediatr., 90, 628-629. Kaplan, S.L. and Feigin. R.D. (1978): Inappropriate secretion of antidiuretic hormone complicating neonatal hypoxic-ischemic encephalopathy. J. Pediatr., 92,431-433. Rees, L., Shaw. J.C.L., Brook, C.G.D. and Forsling, M.L. (1984): Hyponatraemiain the first week of life in preterm infants: Part II sodium and water balance. Arch. Dis. Child. 59,423-429. Forsling, M.L. and Ullmann, E.A. (1976): Non-osmotic stimulation of vasopressin release. Neurohypophysis. Int. Conf., Key Biscayne, FL, 128-135. Wiriyathian, S., Rosenfeld, C.R., Arant, B.S., Porter, J.C., Faucher. D.J. and Engle, W.D. Urinary arginine vasopressin: pattern of excretion in the neonatal period. Pediatr. Res., 20, 103-108.
119
EHD 01057
The vasopressin response to severe birth asphyxia Albert0 Smith”, Prem Prakasha, Jennifer Nesbittb and Neil McIntosh” Departments of “Child Health and %hemical Pathology, St George’s Hospital and Medical School, London SW170QT(U.K.) Accepted for publication 24 February 1990
Summary
Serial measurements of urinary arginine vasopressin (AVP) were made in six severely birth asphyxiated newborn infants. In five infants serial plasma concentrations were also evaluated. There was a strong negative correlation between plasma AVP and plasma osmolality in these infants (r = - 0.52, P = 0.0012). In neither the individual babies nor the group as a whole was there a significant correlation between plasma AVP and the urinary excretion of AVP even if the latter was standardised for creatinine content. Normal development at follow up was only observed in two asphyxiated infants who had consistently low urinary arginine vasopressin levels in the first days of life. Infants with consistently high urinary vasopressin concentrations either died or were severely abnormal in their subsequent development. birth asphyxia; vasopressin (arginine vasopressin); osmolality; syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Introduction
Hoppenstein et al. in 1968 [l] and others since [2--61 showed high cord plasma AVP concentrations in infants delivered vaginally compared with infants delivered by operative means. The levels have been shown to be lowest in infants delivered by elective caesarean section with intermediate levels in caesarean sections performed
Correspondence to: Professor N. McIntosh, Department of Child Life and Health, 17 Hatton Place, Edinburgh EH9 IUW, U.K. 0378-3782/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland
120
after the onset of labour. It has been suggested that the stress and hypoxia of a normal vaginal delivery causes these high cord values and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been associated with severe birth asphyxia [7]. There are few reports of serial measurements of plasma AVP after delivery [8,9]. One of these and also the available cross sectional data [5] suggest that plasma levels quickly become unmeasurable. Only McIntosh and Smith [9] using a very sensitive cytochemical assay have shown subsequent peaks in a group of mainly preterm babies. Recent data has suggested that the problems of plasma sampling were made unnecessary by the close relationship of urinary AVP excretion to the plasma concentration [ 10,111. We have evaluated serial postnatal urinary collections in six severely birth asphyxiated infants in five of whom we have serial plasma concentrations during part of the urinary collections. The study aimed to: 1. Review the vasopressin response to the severest degree of birth asphyxia (cardiac arrest at the time of birth). 2. Compare the plasma and urinary vasopressin response in a situation where renal damage might be expected, 3. Evaluate the developmental outcome with reference to the vasopressin response. Patients and Methods The detail of the six infants and the degree of asphyxia are shown in Table I. The surviving infants have all been followed in a baby follow up clinic for 2-4 years. On arrival at St George’s Hospital Neonatal Unit (range OS-56 h), serial fourhourly urine collections were made using the method of Liu and Anderson [12]. Because of the difficulty of always ensuring that the urine collections were complete, we elected to express the urine excretions with reference to concentrations of urinary creatinine. In five infants who had arterial catheters present for continuous blood pressure evaluation and blood gas analysis additional blood was taken (1 ml) up to three times daily for the measurement of plasma AVP, creatinine and osmolality. The heparinised blood was immediately separated by centrifugation at 10 000 x g for 1 min in a microfuge and the plasma was frozen in liquid nitrogen and stored at - 70 ‘C until measured. Plasma was extracted on C8 reverse phase chromatography columns (Jones Chromatography) that gave a recovery of 87 + 5% (mean + S.D., N = 12). Urine samples were measured both unextracted and after C8 extraction. The correlation was very close (r = 0.98, P < 0.0001). The extracted results were used in Fig. 1. Urine and plasma measurements were made in triplicate or duplicate by radioimmunoassay using an in-house method 1131. The interassay coefficients of variation using low and high quality controls were 15% and 6%, respectively. Plasma and urine osmolality were measured using vapour pressure osmometry (TM Wescor) and creatinine by the routine clinical laboratory. The study was sanctioned by the Hospital Medical Ethical Committee.
39 37 32
39 35 33
Needed IPPV > 15 min
1 2 3
4 5 6
I.D.
B. wt.
of inappropriate
“Syndrome
3 4 5 6
yes yes yes yes yes yes
out out in in
in in
Inborn/ outborn
yes yes yes
yes no
no
hormone
yes yes yes yes yes yes secretion.
Kept ventilated thereafter
Clinical foetal distress before delivery
antidiuretic
3200 2850 1960
4660 2580 1600
(9)
1 2
after birth
Gest. weeks
details.
Patient
I.D.
I
TABLE
yes yes yes
yes yes no
15 min 25 min 90 min 30 min ? ?
Time regular respiration
Abnormal CTG. Birth 1 3 3 0 7 6
0 1 2 0 1 2
yes
yes no
yes yes no
yes yes yes yes yes yes
Hypotonia
5 min
1 min
Cerebral oedema
APGARS
4 6 7 1 7 9
yes yes
yes -
-
Hypertonia
10 min 6.89 7.12 6.98 6.12 6.71 7.03
1st pH
yes
yes yes yes yes yes
Fits
yes
no no no no no
SIADH’
(16) (30) (120) (40) (60) (2)
(Time taken, min after birth)
122
Results Renal function
The renal function over the first seven days of life is shown in Table II. Urine flow rates are less than those accepted with normal renal function [14] in infants 2 (day 3), 3 (day 3), 4 (day 3), 5 (day 3, 5 and 6) and 6 (day 4) - only complete 24-h urine collections are included. Infants 4, 5 and 6 all show a polyuric phase with a fixed osmolality and specific gravity following a period of oliguria. Plasma creatinines of 174 (infant l), 461 (infant 4), 390 (infant 5) I.tmol/l and a plasma urea of 16.5 (infant 6) mmol/l are all greater than the accepted normal range suggesting that glomerular function is significantly impaired [ 14,151 but in infant 1 the coincident creatinine clearance of 2.6 ml/min implies only minimal injury [16]. The creatinine clearances of infants 3, 4 and 5 are all persistently less than 1 ml/ min indicating significant renal failure [16] and in infants 4 and 5 they remain 1.0 ml/min for the first 6 days of life. Infants 1 and 2 both show clearances of more than 1 throughout. Concurrent urine and plasma osmolalities and AVP concentrations and excretions are shown in Table III. Three infants had evidence of a concentration defect on the basis of low urinary osmolality at a time of high plasma osmolality (infants 1, 2, 4; Table III). The normal postnatal diuresis, usually seen between 26 and 34 hours of age [17,18], is only seen within this time in infants 1 and 2. The diuresis in infants 3, 4 and 5 occurred on day 4 and in infant 6 it occurred on day 7. Plasma A VP
The plasma AVP levels of the five infants are shown in Fig. 1 with time after birth. The levels in the different babies are very variable as are the levels in the individual babies at different times. All infants at some time had at least one high plasma AVP level but these were not necessarily immediately after birth. There was a significant negative correlation between the plasma AVP and the plasma osmolality(r = - 0.52, P = 0.0012) in the group as a whole but in individual babies significance was not demonstrated. There was no correlation between the plasma AVP concentration and the osmolality of the urine (r = 0.007, P = 0.7) or between plasma and urine osmolality (r = 0.02, P = 0.89). Urinary A VP
Four-hourly excretions of AVP were related to excretions of creatinine as renal damage was thought to be likely in all infants. The four-hourly AVP excretions in pmol/mmol creatinine were very variable from baby to baby (Fig. l), with values from 1 pmol/mmol creatinine in babies 1 and 2 (never rising above 5 in these infants), to levels of many hundreds pmol/mmol creatinine in babies 5 and 6. In infants 3 and 4 the levels were intermediate but frequently above 5 pmol/mmol creatinine and the excretion was prolonged. The correlation between plasma AVP concentration and the concurrent urinary content was significant in only 1 infant (r-values for the 6 babies respectively = - 0.27, + 0.06, - , +0.04, - 0.27,
6
2
(0.2)IC 0.6 196 (0.5) (0.02)lC 4.1 1.7
? ?
‘I
1.1 1.5 NM (0.6)IC 2.0 NM ? ? ? ? ?
1
Urine vol (ml/kg/h) Urinary creatinine (mmol/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) Urinary creatinine (mmol/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) Urinary creatinine (mmol/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) Urinary creatinine (mmol/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) , Urinary creatinine (mmoJ/l) Mean plasma creatinine (mmol/l) Creatinine clearance Urine vol (ml/kg/h) Urinary creatinine (mmoV1) Plasma urea (mmol/I)
Day 1
Baby 1.7 1.7 153 2.1 1.4 2.0 130 1.3 1.5 1.1 143 0.4 (O.l)IC 0.6 226 (0.02) (0.6)IC 1.1 230 (0.2) (O.l)lC 0.5 6.5
Day 2 (1.3)IC 3.3 174 2.6 1.9 1.7 NM 1.6 1.6 134 0.7 1.8 0.7 269 0.3 1.8 1.8 286 0.8 (0.3)lC 1.2 7.9
Day 3
3.0 NM IC 1.2 67 4.5 0.8 143 1.0 2.7 0.7 390 0.4 2.7 1.8 386 0.9 0.7 2.5 7.2
IC
Day 4
0.8 120 1.4 2.8 0.9 460 0.4 1.6 2.5 390 0.7 0.34 3.9 9.1
5.5
Day 5
5.2 0.8 96 1.7 3.6 1.0 461 0.6 1.2 3.2 NM IC 0.5 16.5
Day 6
4.3 1.2 351 1.0 1.7 0.7 15
3.0 1.1 NM -
Day I
Urine volumes, plasma and urinary creatinines and creatinine clearance in the six infants during the first week of life. NM, not measured; IC, incomplete (if leakage only small, the value is given in brackets).
TABLE II
u OSMO u AVP cont.
pl AVP pl OSMO u AVP excr . u OSMO u AVP cont. pl AVP pl OSMO u AVP excr. u OSMO u AVP cont. pl AVP pl OSMO u AVP excr. u OSMO u AVP cont. pl AVP pl OSMO u AVP excr. u OSMO u AVP cont. pl AVP pl OSMO u AVP excr . u OSMO u AVP cont. pl AVP pl OSMO u AVP excr .
IC200 325 165 20 263
438
307 IC560 320 58 3 268
9.3 317 IC2900 326 280 17 213
7.8 321 IC5oOo 336 248 8 265 IC2430
308
394 250
5065 365 39
260 320 5 2.6 308 IC20 304 13
88 290 8
721 305
2
0.8 298 120 225 1.3 0.7 296 134 232 1.7
0.5 293 3 298 1 0.5 298 240 304 3.3
0.6 300 6 236 1 0.5 311 11 417 4.4
7
a.m.
p.m.
a.m.
p.m.
a.m.
Day 3
Day 2
Day 1
pl AVP, pmol/mmol creatinine (mean of samples in 12- or 24-h period. pl OSMO, mosm/kg (mean of samples in 12- or 24-h period. u AVP excr.. fmol excreted/l2 or 24 h. u OSMO, mosm/kg (mean of specimens in 12- or 24-h period. u AVP cont., pmol/mmol creatinine (mean of samples in 12-or 24-h period. IC, incomplete collection.
Baby
3300 342 40 49 232 IC6OOO
298
612 292 8
IC36 250 0.7
13.5 315 3 223 1 1
p.m.
347 7ooo 344 24 25 215 1c12ooo 476 300
160 245 1.25 4 295 184 250 7
310 IC130 154 1
140 313 1
Day 4
420 262 3 2.5 312 IC185 230 3 3 332 3162 337 14 21 228 IC3ooo 493 50
IC2 164 1.4
IC5 271 1
0.5
Day 5
610 200 7 341 1800 280 6 20 800 212 2
IC2OO 348 5
330 IC530 300 4.5 3 309 400 298 3
IC20 416 4
Day 7
periods.
677 250 4
0.7 272 ICI 215 1
Day 6
Plasma and urine osmolalities and AVP concentrations and excretions. Over the first 3 days 12-h periods are considered and from Day 4-7,24-h
TABLE III
F?.
LOG PLASMA AVP pmol/l O----O
? t
. I
!
?
=I
~w!v=J~
www~d
- dAV
3Nlklr-l
00-1
126
+ 0.89) in whom the correlation was very close. The values on individual days are shown in Table III. Outcome No infant had a pulmonary air leak and none had ultrasound or clinical evidence of intracranial haemorrhage. Case 4 died in the second week of life when ventilatory support was withdrawn for severe hypoxic-ischaemic encephalopathy. Three infants developed a severe spastic quadriplegia and microcephaly and one of these (case 3) died at six months of age with a developmental age of less than six weeks. Cases 1 and 2 are normal at 3 and 3.5 years. Discussion
The plasma AVP concentrations and the urinary AVP excretions need to be evaluated with reference to renal function in these infants who had been subjected to severe asphyxia. There is some evidence that in aduhs plasma AVP concentrations are slightly elevated in renal failure due to reduced excretion of the hormone [ 191but the AVP levels in our infants are orders of magnitude higher than were described. All infants show some evidence of renal damage; this is minor in infants 1 and 2, moderate to severe in infant 3 and very severe in infants 4,5 and 6. The normal urine flow rate is more than 1 ml/kg body weight/h in the first 24 h and more than 2 ml/ kg body weight/h after this time [14] with the diuresis usually occurring between 26 and 34 h [17,18]. The creatinine clearances of infants 3, 4 and 5 are all persistently less than the normal reference range [16] indicating glomerular failure and the high plasma urea and low urine production rate in infant 6 we also believe indicates significant renal failure. Only infants 1 and 2 consistently have relatively normal plasma creatinine [15] and creatinine clearances greater than 1 indicating relatively undamaged glomerular function but both of them (and infant 5) had evidence of tubular damage being unable to concentrate their urine in the presence of a high plasma osmolality. High umbilical cord AVP levels have been shown after vaginal delivery and have been postulated as being caused by hypoxic stress during labour [2,4]. Polin confirmed the high levels but found no correlation with umbilical pH and therefore postulated that the secretion of vasopressin might be the cause of labour [3]. Stark et al. [20] have clearly shown that experimental hypoxia in the chronic sheep preparation leads to massive plasma AVP response lasting for about two hours after the acute insult (F102 = 0.1 for 30 min or acute cord compression). Over this two-hour period the amniotic fluid concentation peaked and remained high for at least 24 h. Although it is unusual for hypoxia to be an isolated problem, careful experiments by Forsling and Ullmann have shown that the AVP release is due to this stimulus 1231. No infant in this study showed evidence of hypovolaemia and all had adequate blood pressures. High plasma osmolalities were seen in infants 1, 2, 4 and 5 (Table III) and this may have been the stimulus for AVP secretion in infants 1,4 and 5. It is worth stating that clinically, none of these infants were even mildly dehydrated and we do not know what caused this additional circulating osmolar stress. Infant 6 had
127
the classical features of SIADH. Our data would suggest that the poor urine outputs (Table II) were more likely due to degrees of renal failure than to AVP because of the paired and sequential relationships of the plasma and urinary osmolalities. Hyponatraemia following birth asphyxia was first shown by Khare [21] and was postulated to be due to fluid retention as a consequence of vasopressin release. Kaplan and Feigin [7] described two cases of innappropriate secretion of antidiuretic hormone associated with hypoxic-ischaemic encephalopathy where the AVP levels were high on the second and third days of life. There have been few serial measurements of plasma AVP but Speer et al. [8] found high plasma levels in thirteen asphyxiated infants in the first two days of life falling to normal on the third day. The six infants reported here all showed both evidence of severe birth asphyxia as evidenced by an absent heart beat at birth and very poor Apgar scores and also a severe acidosis after birth. All the infants went on to show severe hypoxic-ischaemic encephalopathy with hypotonia and fits. Despite this, the first plasma level in infant 1 was low at 14 h and the first and only recorded high value was at 46 h. Three other infants had high plasma AVP levels in the first 24 h which rapidly fell in case 2 but were maintained in cases 5 and 6. Case 4 was transferred from another hospital at 48 h of age: the plasma AVP level was low on arrival but a peak of 6 pm0111 occurred at 72 h of age which was not associated with hypotension, hypovolaemia or a high serum osmolality. Infants 3, 4 and 5 had evidence of severe renal failure but despite this had very variable plasma AVP levels. We would postulate that it is unlikely, therefore, that these concentrations are solely related to poor vasopressin excretion. Because of the difficulties of measuring plasma AVP in small and sick infants, Rees et al. [I l] suggested measuring serial urine excretions of AVP to evaluate posterior pituitary function in the newborn. They showed a significant positive correlation between plasma and urinary levels overall but their data also showed some infants where there was marked discrepancy of these parameters. Our data on these severely asphyxiated infants show no correlation between plasma and urine concentrations of AVP in 4 out of the 5 infants who had both plasma and urinary levels measured. This may be related to the degree of coincident renal failure. Although we were able to demonstrate a significant negative correlation between plasma AVP and plasma osmolality taking all the values in the 5 infants - a possible indication of SIADH and a relationship not shown by Rees et al. [5] we were not able to demonstrate a significant correlation - positive or negative in any individual baby. Like Rees et al., we were unable to demonstrate a relationship between plasma AVP and urine osmolality and would thus agree that the kidney at least following asphyxia does not respond to high vasopressin concentrations although one infant - No. 6, Table III - did show classical clinical features of the syndrome of antidiuretic hormone release. Our inability to demonstrate a relationship between plasma and urine osmolality (r = 0.03, P = 0.8) may also reflect the extent of the renal damage. Wiriyathian et al. 1241found high urinary AVP levels in 13 asphyxiated preterm infants in the first day of life falling on the second day, but remaining higher than normal for at least four days after birth. We could find no trend in urinary AVP levels in the first few days of life. Case 1 showed a measurable urinary AVP concentration on only one occasion and case 2 never exceeded 5 pmol/mmol creatinine. Both
128
of these infants are normal at follow up. The asphyxia in case 1 although severe (leading to birth without a recordable heart beat) was short in duration arising because of shoulder dystocia. Resuscitation was prompt but there was still a significant acidosis and subsequently the signs of hypoxic-ischaemic encephalopathy and there was also a high plasma creatinine although urine production rate and creatinine clearances were in acceptable ranges. In case 2 the cord was compressed during cord prolapse. In this instance there was recorded fetal distress and an absent heart beat at birth again leading to severe acidosis. Despite prompt resuscitation spontaneous respiration did not occur until 25 min after birth. There was again a severe acidosis and the signs afterwards of encephalopathy. The other infants all had much higher urinary AVP concentrations and for prolonged periods. These four infants were severely and irreparably damaged. We wonder whether the excretion of AVP in the urine for long periods after birth may be associated with a perinatal problem sufficient to cause lasting damage. Although Rees et al. [22] reported preterm infants with high urinary levels, they give no detail of the follow up. Acknowledgements We would like to thank nursing and medical staff of the Neonatal Unit at St George’s Hospital for their dedicated care of the infants; Birthright for funding AS. during the study; Miss Elaine Forbes for help with the manuscript and Miss Lesley Skeates and Apple Mac for help with the graphics. References 1 2 3 4
11 12
Hoppenstein, J.M., Miltenberger, F.W. and Moran, W.H. (1968): The increase in blood levels of vasopressin in infants during birth and surgical procedures. Surg. Gynecol. Obstet. 127,966-974. Chard, R., Hudson, C.N., Edwards, C.R.W. and Boyd, N.R.H. (1971): Release of oxytocin and vasopressin by the human foetus during labour. Nature, 234,352-354. Polin, R.A., Husain, M.K., James. L.S. and Frantz, A.G. (1977): High vasopressin concentrations in human umbilical cord blood - lack of correlation with stress. J. Perinatal. Med. 5, 114-. De Vane, G.W. and Porter, J.C. (1980) An apparent stress-induced release of arginine vasopressin by humanneonates. J. Clin. Endocrinol. Metab., 51, 1412-1416. Rees, L., Forsling, M.L. and Brook, C.G.D. (1980): Vasopressin concentrations in the neonatal period. Clin. Endocrinol. 12(4), 357-362. Czernichow, P., Pattin, A. (1978): La vasopressine chez le nouveau-ne: taux plasmatiques dans le sang du cordon et chez la mere. Anal. Endocrinol. (Paris), 39,225-226. Speer, M.E., Gorman, W.A., Kaplan, S.L. and Rudolph, A.J. (1984): Elevation of plasma concentrations of arginine vasopressin following perinatal asphyxia. Acta Paediatr. Stand., 73,610-614. McIntosh, N. and Smith, A. (1985): Serial management of plasma arginine vasopressin in the newborn. Arch. Dis. Child., 60, 1031-1035. Stern, P. and La Rochelle. F.T. Similar relationship between plasma and urinary vasopressin in the newborn. Hormone Res., 17, 134-140. Rees, L., Brook, C.G.D. and Forsling, M.L. (1983): Continuous urine collection in the study of vasopressin in the newborn. Hormone Res., 17,134-140. Liu, H.-Y. and Anderson, G.J. (1967): A method for long-term quantitative and fractional urine collection. J. Pediatr., 70,276-279. Smith, A. and McIntosh, N. (1985): A new radioimmunoassay for AVP in unextracted human urine. Biochem. Sot. Trans. 14.782-783.
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13 14 15 16 17 18
Stark, RI., Daniel, S.S., Husain, M.K. et al. (1984): Vasopressin concentration in amniotic fluid as an index of fetal hypoxia: mechanism of release in sheep. Pediatr. Res., 18,552-558. Khare. S.K. (1977): Neurohypophyseal dysfunction following perinatal asphyxia. J. Pediatr., 90, 628-629. Kaplan, S.L. and Feigin. R.D. (1978): Inappropriate secretion of antidiuretic hormone complicating neonatal hypoxic-ischemic encephalopathy. J. Pediatr., 92,431-433. Rees, L., Shaw. J.C.L., Brook, C.G.D. and Forsling, M.L. (1984): Hyponatraemiain the first week of life in preterm infants: Part II sodium and water balance. Arch. Dis. Child. 59,423-429. Forsling, M.L. and Ullmann, E.A. (1976): Non-osmotic stimulation of vasopressin release. Neurohypophysis. Int. Conf., Key Biscayne, FL, 128-135. Wiriyathian, S., Rosenfeld, C.R., Arant, B.S., Porter, J.C., Faucher. D.J. and Engle, W.D. Urinary arginine vasopressin: pattern of excretion in the neonatal period. Pediatr. Res., 20, 103-108.