Acta neurol. scandinav. 57, 239-247, 1978 Department of Neonatology, Rigshospitalet, Copenhagen, Denmark
Decreased cerebral blood flow after administration of sodium bicarbonate in the distressed newborn infant HANSC . Lou. NIELSA. LASSEN AND BENTFRIIS-HANSEN In the course of our studies on cerebral blood flow in newborn infants, we have observed a striking depressing effect of sodium bicarbonate infusion on cerebral blood flow which in some cases may severely aggravate cerebral ischemia. We measured cerebral blood flow before and after the treatment with 1 to 8 meqs of sodium bicarbonate in seven distressed newborn infants. The 133 Xe clearance techni,que was used. The results showed in six of the seven cases a decrease in cerebral blood flow, which in most cases was reduced to 14 to 22 m1/100 g/min, which is about half the value prior to the bicarbonate infusion. In one case an extreme reduction occurred: cerebral blood flow was reduced to 3 m1/100g/min, well below the level compatible with tissue survival. The results are discussed with regard to the optimal treatment of the acidotic newborn.
Hypoxic brain damage is a frsquent autopsy finding in infants who have died during the first month of life (Schwartz 1971). In experimental studies of asphyxiated fetal sheep we have shown that hypotensive asphyxia is accompanied by pronounced cerebral ischaemia. As asphyxiated newborn infants often are hypotensive a few hours after birth, we have recently carried out an investigation to substantiate whether this hypotension was in fact accompanied by ischaemia or not. The results showed clearly, as would be expected from the animal studies, that the hypotensive distressed newborn actually had very low values of cerebral blood flow (Lou et al. 1977). Thus, cerebral ischaemia constitutes a crucial complication to hypoxia in the hypotensive distressed newborn. Cerebral hypoxia-ischaemia is in many cases complicated by fatal intraventricular haemorrhage which is now of growing importance as a cause of death in small, premature infants (Harcke et al. 1972). It is well known that these bleedings usually originate in the germinal layer over the caudate nucleus, and it has recently been shown that they are due to rupture of the capillaries in that structure (Humbleton & Wigglesworth 1976). From the retrospective studies of Wigglesworth et al. (1976) it appears that there has been an increase in the incidence of fatal intra-ventricular
240 haemorrhage from 1958 to the period 1966-1973 in infants with a birt weight of less than 1500 g, and the authors suspect that this increase migl be due to increased use of large doses of sodium bicarbonate. But, it is ver difficult to establish a causal relationship in a retrospective study, and othc workers are at variance with this interpretation (Anderson et al. 1976). The possible effects of bicarbonate administration now so widely use( controversial as it might be, deserve careful consideration. Speculations hav hitherto centered on the possible deleterious effects of an increased osmoti load due t o sodium bicarbonate administration (Simmonds et al. 1974, Volp 1974, Baum 1975, Robertson 1974). This hypothesis suffers from the fac that no clear relationship between hypercusmolality and hypernatricemia ha been established (Thomas 1976). However, we have been able to observe a depressing effect of scrdiun bicarbonate infusion on cerebral blood flow which seems to alter the perspec tive considerably, as it points to an aggravation of hypoxic ischaemic braii injury after sodium bicarbonate administration. Table 1. Main clinical data
Patient
GN GN GN GN GN GN GN
345 346 390 404 484 485 540
Sex iF)
iw (F) (M) iM) ( M)
04)
Birth weight (g) 3755 2720 2000 1880 1050 1190 1180
Weeks of gestation 34 34 35 35 29 29 29
Apgar scores
9/1 min 10/5 rnin 9/1 rnin 9/5 rnin 6/1 min 10/5 rnin 3/1 min 7/5 rnin 6/1 min 6/5 rnin 611 rnin 615 rnin 6/1 rnin 8/5 rnin
Ventilator therapy
+ -
+ + + -
MATERIAL AND METHODS
Patient group Seven newborn infants were studied. The main clinical data are summarized in Table 1. All infants except G N 345 and 346 were moderately asphyxiated at birth, and all developed varying degrees of respiratory distress after birth with acidosis (pH 7.117.23). This situation required sodium bicarbonate administration in order t o achieve a partial compensation of the acidosis according to the general policy of the department until now.
Cerebral blood flow (CBF) measurements In distressed infants as these included in the present investigation, it is the routine of our department of intensive neonatal care to introduce a thin polyethylene umbilical artery catheter to monitor acid-base status and other metabolic paramenters.
24 1 In order to measure CBF before and after sodium bicarbonate administration, the catheter was originaIly introduced so far as to reach a position with the tip placed in the innominate or left common carotid artery, or at the origin of one of these arteries. The introduction was done blindly, but with radiological verification of the position. A total of 0.5 mCi of 133 Xe dissolved in 1 ml of physiological saline was injected continuously during 5-10 sec through the catheter and CBF was calculated from the ,,initial slope" (15 sec after starting the injection of 133 Xe) of the semilogarithmically depicted clearance curve obtained by a 22 m KJ Scintillation detector (Olesen et al. 1971). The detector was placed in the ipsilateral fronto-temporal region as previously described (Lou et al. 1977). By placing the detector in this region the contribution of extracerebral tissue (skin and scull) to the eluation curve was considered to be minimal. The recirculation of 133 Xe was, as in adult studies, presumed to be insignificant, as none oh the infants studied showed signs of right-to-left shunt. After the initial CBF measurement a second measurement before bicarbonate administration was carried out 30 min later in two cases. In one (GN 404) as a control, in another (GN 484) because a significant drop in arterial blood pressure had occurred. 10-20 min after measurement of CBF. 1-8 meqs of sodium bicarbonate from a mixed 0.5 M sodium bicarbonate and 0.14 M glucose solution were slowly infused through the catheter with a speed of 0.5 meq/min. By using such a low injection speed the increase in osmolality in the carotid arterial blood was estimated to be about 1-3 % or comparable to that of the more rapid intravenous injection generally used (Thomas 1976). In one case, however, sodium bicarbonate was infused through a peripheral vein (GN 404). 5 min after termination of the infusion the last CBF measurement was made according to the procedure described above. Systolic blood pressure was monitored regularly throughout the procedure by means of the doppler ultrasound technique (Roche arteriosondeB) and pH and gas status were monitored by means of the ABL-X apparatus (Radiometerm). After termination of the examination the arterial catheter was withdrawn to its usual position in the descending thoracic aorta. In the cases where critically low values of cerebral blood flow were found, the oxygen administration was increased in an attempt to ensure adequate oxygen supply t o the brain in spite of compromised CBF (see discussion) and in some cases repeated small transfusions were given in order to increase the capacity for oxygen transport (Emerson et al. 1977). The effects of sodium bicarbonate infusion on osmotic pressure and on plasma sodium concentration were not systematically studied, but plasma sodium concentration was determined 6-12 h later in each case. The values ranged from 122 to 155 M/1 (mean 144 MA). Thus, no excessive values were found. Neurological assessment Patient G N 345: At the neurological examination on admission she appeared normal for her gestational age: normal consciousness, slightly weak primitive reflexes (moro, rooting, sucking and grasping), moderate hypotonia and slightly poor spontaneous movements. Brain stem reflexes were normal. After the bicarbonate injection a moderate deterioration had taken place: consciousness and spontaneous movements wede definitely subnormal, she was more hypotonic. The moro reflex was weaker, and the other primitive reflexes could no longer be elicited.
During the following days her consciousness and reflexes improved, but she became jittery. (Cerebrospinal fluid, blood culture, Ca'+, plasma glucose and Mg" were normal). She had to be tube-fed for many days, but eventually recovered. Patient G N 346: H e appeared neurologically normal before and after the infusion of bicarbonate. The later course was uneventful. Patient G N 390: Neurologically she was normal at the time of the first CBF measurement. After the bicarbonate injection she was generally hypotonic with weak neonatal reflexes. A couple of hours after the bicarbohate infusion she developed severe and prolonged apnoeic spells with cyanosis, but eventually she recovered. Patient G N 404: At the time of the first CBF measurement he showed signs of moderately depressed cerebral function. H e was generally hypotonic, with weak neonatal reflexes and impaired consciousness and sparse spontaneous movements. After the bicarbonate infusion it was noted that he became more flaccid and primitive reflexes were impossible t o elicit. Spontaneous movements were rare and the pupils were contracted and unresponsive. One week later he died with clinical signs of sepsis. Gram-negative rods were cultured from the blood. Patient G N 484 Twin A : Consciousness was moderately depressad, spontaneous movements moderately active and the moro and grasp reflexes were weak but could be elicited, whereas other neonatal reflexes could not. However, after the decrease in blood pressure with concomitant acidosis and subsequent bicarbonate treatment he deteriorated. He became comatose almost without spontaneous movements, and without primi-
1 min
Figure I . Clearance curve of 133 X e . The tip of the cutheter for injection was located in rhe innominate artery. The scintillation detector was placed in the ipsilateral temporofrontal region. (Patient G N 345). CBF was calculated to be 33 mU100 g/min.
243 tive neonatal reflexes. Blood pressure continued t o fall during the next few days, but then circulation and neurollogical status improved somewhat. Patient G N 485 Twin B: He was markedly hypotonic, with impaired consciousness and sparse spontaneous movements. Primitive neonatal reflexes were unelicitable. Brain stem reflexes were present. H e was clinically unchanged after the bicarbonate infusion. A few days later, the situation was complicated by a pneumothorax, and eventually he died. Patient G N 485 Twin B: He was markedly hypotonic, with impaired consciousness and infusion.
RESULTS
The results of the repeated CBF measurements in the seven infants are shown in Table 2. CBF approaches or reaches normal values of adults (33 to 64 mV100 g/ min) at arterial systolic blood pressures of 60 to 65 mm Hg (GN 345, 346, and 484). It is seen that CBF is low (22 to 30 m1/100 g/min) in the infants with lower arterial blood pressure: 40-50 mm Hg (patients GN 390, 404, 484, 485, and 540). In all cases, except GN 485 who only received 1 meq, infusion of sodium bicarbonate induced a dramatic decrease in the cerebral blood flow, in most cases to about half the original value.
Figure 2. Clearunce curve 45 min later, 5 min after termination of slow intra-urterial infusion of 7 meqs of HCO-,. (Patient G N 345). CBF is reduced to 16 ml/IOOg/min (See table).
98 76 76 157 74 58
45 45 45 65 40 40 40
3 3 !/2
4
8 8 Y2 9
7
G N 404 (1) - (2) 5 meqs HCO-,
G N 484 (1) - (2) 2 meqs HCO-,
G N 485
+ 1meq HCO-,
GN 540
+ 1meq HCO-,
+
+
45
70
73
40
3
3 ‘/z
157
45
7 Y2
201
93 70
50 50
4 4 Vi
+
G N 390 5 meqs HCO-,
88
100
60 60
161
60
3%
3
98
PO, (mmHg)
60
Syst. BP (mmHg)
+8 meqs HCO-,
G N 346
3%
3
GN 345
f 7 meqs HCO-,
Age (hours)
Patient
7.25
7.22
44 45
7.32
7.23
43 37
-8 -16 -8
7.29 7.11 7.23
38 44 46
- 7
-10
-7
-10
-13 -14 - 8
-13 -7
7.22 7.25
-9
7.19 - 3
+ 2
7.38
7.26
-6
Base Excess (BE)
7.21
pH
7.21 7.21 7.32
39 33 34
35 48
58
53
48
59
PCO, (mmHg) BE
3
3
8
6
6
6
6
Table 2. CBF measurements before and after sodium bicarbonate infusion
17
28
26
26
64 30 20
22 24 14
24 3
22
44
16
33
CBF (m1/100g/ min)
-39 %
0%
-33 %
-42 %
-87 %
-50 %
-52 %
a CBF
P
P
245 This decrease could not readily be attributed to other factors as changes in gas tensions and blood pressure did not show a consistent pattern. IN GN 484 and 346 CBF reached levels of 20-26 m1/100 g/min. This is near the point where electrical function may become affected in experimental cerebral ischemia in the baboon (Asrrup et al. 1977). GN 346 and 540 did not show any clinical signs of neurological dysfunction before or after the treatment. As mentioned earlier GN 484 deteriorated in association with a marked drop in blood pressure and CBF, and the development or treatment of acidosis. The reduced CBF concomitant with a drop in blood pressure is in complete agreement with the previous observation of the association of low CBF with low arterial blood pressure in the distressed newborn (Lou er al. 1977). In two cases (GN 345 and 404) the CBF was reduced to values at the limit of complete electrical failure (Astrup er al. 1977) (around 15 m1/100 g/min), and in one case (GN 390) the flow was reduced to an extremely low value of 3 m1/100 g/min. This value is in the range that results in complete electrical failure and potassium release (Astrup et al. 1977), as well as in cell death if sustained (Jones et al. 1977). GN 345, 390, and 404 all showed some signs of neurological deterioration which might be associated with the bicarbonate infusion and with the measured decrease of rCBF. DISCUSSION
The extracellular pH is a main factor controlling cerebral b l d flow. According to evidence reviewed by Lassen (1968), a decrease in the bicarbonate concentration in the cerebral extracellular fluid around the arterioles will result in vasodilatation at a normal pCO,, and, conversely, an increase in the bicarbonate concentration will induce vasoconstriction. The fact that p C 0 ~ induced changes in cerebral extracellular pH readily influences the CBF in normal conditioas whereas changes in plasma bicarbonate at constant pCO2 do not, is probably related to the fact that CO, readily crosses the endothelid membrane whereas H and HCOa- cannot freely cross the intact blood-brain barrier. It has been demonstrated, however, that hypercapnia, o'r, in particular, damage to the blood-brain barrier induced by acute hypertension in cats, results in an increased reactivity of the cerebral blood flow to changes in the plasma bicarbonate concentration at constant pC0, (Pannier et al. 1974, Pannier & Leusen 1975). The CBF was lowered to about half the normal value after intravenous infusion of about 18 ml 0.23 M Na2C03 per kg in cats with damage to the blood-brain barrier. Recently we have shown that the blood-brain barrier is severely damaged in prolonged partial asphyxia in the near-term fetal sheep. Thus, the blood-brain barrier can be assumed to be more permeable in the asphyxiated infant, and this probably explains
246 the rapid and marked effect of bicarbonate infusion on the CBF seen in our cases. The demonstration of a depressing effect of bicarbonate infusion on the CBF in the distressed infant has important clinical consequences. The high CBF seen in normotensive experimental asphyxia (Lou et al. 1977) must be regarded as a homeostatic mechanism counteracting the effects of hypoxemia and ensuring sufficient oxygen supply to the brain (Johansson & Siesjo 1974). In hypotension, as is frequently seen a few hours after birth, particularly in babies with perinatal asphyxia, cerebral blood flow is markedly reduced (Lou et al. 1977). Presumably this is due to failure of the arterioles to dilate further as a response to hypotension, as they already are maximally dilated because af tissue acidosis and hypoxia. In the present series it has been demonstrated that sodium bicarbonate infusion in the distressed infant with low CBF is able to reduce CBF even further to attain values below the critical levels of retained function or even jeopardizing the viability of the neurons (Astrup et al. 1977, Jones et al. 1977). This effect is probably due to penetration of bicarbonate from the plasma to the cerebral extracellular fluid with resulting perivascular alkalosis and vasoconstriction. If hypoxemia is present the situation may become even more serious, and extensive hypoxic-ischemic brain injury can be expected to occur if this situation is maintained. The increased tissue hypoxia is likely to postpone restoration of autoregulation and thus to increase the risk of capillary germinal bleedings (Lou et al. 1977). It is our opinion that infusion of sodium bicarbonate should be avoided if at all possible in hypotensive postnatal distress. This condition should primarily be treated by sufficient oxygen and glucose supply and by other methods to support cerebral metabolism and cardiovascular function. In addition, therapy aiming at reducing oxygen demands, in particular prevention of seizures, should be employed. In the case of asphyxia at birth with marked metabolic acidosis, a glucose infusion should be given. A partial correction of the acidosis by bicarbonate infusion may be necessary in order to prevent a depression of the cardiovascular function during the following hours. But it must be stressed that this correction should take place during the first minutes after birth when the blood pressure, and hence the cerebral blood flow, is still high (Modanlou et al. 1974), and the procedure should be accompanied by adequate oxygen supply to compensate for a decrease in CBF.
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Hans C . Lou Department of Neonatology Rigshospitalet Blegdamsvej 9 2100 Copenhagen @ Denmark