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Catecholamine and blood pressure levels in paralysed preterm ventilated infants
Early Humon Development, 16 (1988) 219-224 Elsevier Scientific Publishers Ireland Ltd.
219
EHD 00847
Catecholamine and blood pressure levels in paralysed preterm ventilated infants Anne Greenough” Jenny Pool” and H. Lagercrantzb aWmrtment of Child Health, King’s College Hospital, Denmark Hill, London,
SE5 8RX U.K. and bDeportmentof Poediotrics,KorolinskoHospitol, KorolinskoInstitutet,Stockholm, Sweden Accepted for publication 1 March 1987
Summary The effect of pancuronium administration on catecholamine levels and blood pressure was investigated. Noradrenaline levels prior to paralysis amongst infants fighting the ventilator were high, but were significantly reduced following treatment with pancuronium. There was no significant change in either blood pressure or adrenaline levels. Increasing peak inspiratory pressure (approx. 4 cmH,O) immediately prior to paralysis effectively prevented the hypoventilation previously associated with the administration of the first dose of pancuronium. noradrenaline;
adrenaline; pancuronium;
preterm infants; artificial ventilation
Introduction Preterm infants deteriorate with excessive handling, even routine care procedures can be associated with both transient disturbance of oxygenation [14] and abrupt changes in blood pressure [19]. The latter may contribute to abnormal cerebral perfusion and intracerebral haemorrhage [ 191. Increased sympathoadrenal activity could act as a mediator of such a response, as it has been demonstrated that catecholamine levels are significantly elevated following physiotherapy, suction [lo] and even special care nursing [ 121. Although variability of cerebral blood flow in mechanically ventilated infants can be reduced by paralysis, and in one study this resulted in a significant reduction in cerebral haemorrhage [17], the initiation of paralysis may result in a transient 0 1988 Elsevier Scientific Publishers Ireland Ltd. 0378-3782/88/$03.50 Published and Printed in Ireland
220
deterioration in the infant’s condition [1,6,7]. Hypoventilation is common [1,6,7] following the first dose of a paralysing agent, necessitating an increase in ventilator pressures to restore adequate oxygenation [7]. In animal studies such hypoxia also may lead to an increase in catecholamine levels [3] The aim of the present study was to investigate the effectiveness of increasing ventilator settings immediately prior to paralysis to try and prevent both the transient hypoxia [ 1,6,7] and the increase in catecholamine and blood pressure levels [2] previously associated with the administration of the first dose of pancuronium.
Patients Eleven infants (7 males) mean gestational age 30.3 weeks (range 26-34 weeks) and mean birth weight 1266 g (range 696-1944 gms) were studied. All the infants were less than 48 hours of age and ventilated for the respiratory distress syndrome (RDS) using Sechrist ventilators. The study was approved by the Hospital Ethical Committee.
Methods Infants were selected for paralysis if they were confirmed by respiratory monitoring [7] to be actively expiring against positive pressure inflation. Pancuronium (100 pg/kg) was only given when the infant was in a stable condition, with arterial blood gases within the accepted therapeutic range. Immediately prior to paralysis peak pressures were increased by approx. 4 cmH,O. This was the increase in pressure predicted by our previous results [7] which might prevent hypoventilation following the first dose of paralysis. Blood pressure (BP) was recorded from the umbilical arterial catheter sited for clinical purposes. BP was checked 5 min prior to, 15 min and 30 min post paralysis (BP was calculated as the average of recordings over a 60-s period). An arterial blood sample was taken via the catheter 5 min prior to (before the ‘compensatory’ increase in ventilator settings) and 20 min after paralysis for determination of Pao,, Pace, and pH and catecholamine analysis. One millilitre of blood was collected in chilled tubes containing preservative and then immediately centrifuged. The plasma was removed and stored at - 70°C. Catecholamine levels (noradrenaline and adrenaline) were determined by high performance cation exchange liquid chromatography with electro-chemical detection [ 111. The sensitivity of the assay was 0.1 nmol/l .
Statistical analysis The results before and after paralysis were compared and assessed for statistical significance using the Wilcoxon rank sum test.
There was no significant change in blood pressure at either 15 (mean, 45/30; range, 33/20 to 80/62) or 30 min (mean, 46/31, range, 33/22 to 81/58) compared to pre-paralysis recordings (mean, 48/30; range, 30/21 to 83/61).
221
80
70
60
xl
10
0 FRE
POST ADRENALIN
FRE
FQSl
KRADREk4LlN
Fig. 1. Noradrenaline and adrenaline levels before and after paralysis (adrenaline was detected only in 8 infants). Individual infant’s results are shown by linked data points. One infant had extremely high levels of adrenaline (315 nmol/l pre-paralysis and 100 nmol/l post-paralysis) these results are not expressed on the figure.
222
Peak inspiratory pressure was increased from mean 23 cmH,O (range, 14-40) to 27 cmH,O (range, 20-43). Comparison of arterial blood gases immediately before the increase in peak inspiratory pressure pre-paralysis and 20 min after paralysis did not detect a significant change in pH or Pace,. Although in all infants arterial oxygenation rose post-paralysis; mean Pao, pre-paralysis 51 mmHg (range, 40-65 mmHg) to post-paralysis mean Pao, 64 mmHg (range, 41-90 mmHg), this increase was small and did not reach statistical significance (Wilcoxon rank sum test). Adrenaline was detected in 8 infants only, and there was no consistent change in adrenaline levels following the administration of pancuronium (see Fig. 1). The mean pre-paralysis noradrenaline level was 21.5 nmol/l (range, 3.3-78.9 nmol/l), this was significantly greater than the mean post-paralysis level 10.2 nmol/l (range, 1.7-29.9 nmol/l), P< 0.05 (see Fig. 1).
Discussion The noradrenaline levels seen in this study prior to paralysis are high compared to those reported previously in infants of similar postnatal and gestational ages [ 10,121. Indeed four of the infants had extremely high levels of noradrenaline (> 20 nmol/l), this suggests that ‘fighting the ventilator’ is a potent stimulator of sympathoadrenal activity. Following paralysis there was a significant reduction in noradrenaline levels. This was not related to any acute change in blood pressure, confirming the lack of effect of paralysing agents on blood pressure seen both in animal studies [4] and in infants suffering from a variety of diagnoses; hyaline membrane disease, meconium aspiration, pneumonia [18]. In two previous studies, however, one in infants [2] and the other in adults anaesthetised with halothane [15] an increase in both blood pressure and catecholamines the administration of occurred following pancuronium. It is possible that the discrepancies in the results from the present study and those earlier [2,15] may be explained by the differences in the maturity of the population studied, as certainly both the degree of and response to sympathoadrenal activity is affected by gestation [8]. Catecholamine levels are known to be affected by changes in blood gas tension, both carbon dioxide levels [5] and hypoxia [3]. In the present study the change in catecholamine level cannot be attributed to this cause, as there was no significant change in carbon dioxide levels and although arterial oxygenation improved following paralysis the infants were not hypoxic prior to treatment. A possible explanation for our results, may be a direct inhibitory effect of pancuronium on catecholamine release in immature infants. This could be either by blocking nicotinic receptors in the adrenal medulla or an action on higher centres, similar to that proposed for phenobarbitone anaesthesia which reduces noradrenaline levels by a differential effect on cortical and hypothalmic levels governing selective secretion [ 131. The reduction in catecholamine levels demonstrated in the present study following paralysis in these very immature infants may explain previous association
223
of paralysis with a reduction in abnormal fluctuations in cerebral blood flow [ 171. Thus selective paralysis may be successful in reducing the incidence of intraventricular haemorrhages [9] both by an effect on cerebral blood flow [ 171 and via the significant decrease in peneumothoraces [7]. The adoption of the policy outlined in the present report, that is increasing peak inspiratory pressure immediately prior to the first dose of paralysis, can effectively ensure even the initial transient disturbance in oxygenation associated with this beneficial treatment [1,7] is effectively eliminated. Acknowledgements Sister Jenny Pool is supported by Children Nationwide Medical Research Fund; we thank Mrs. Angela McPherson for secretarial assistance. References 1 2
3 4
5 6
I
8 9 10
11
12 13
Bourgeois, J., Berthier, J.G., Cottancin, G., Millan, J.J. and Bethenod, M. (1982): Dangers de la curarisation an cours de la ventilation artificielle chez le nouveaune. Pediatrie, 37, 101-l 12. Cabal, L.A., Siassi, B., Artal, R., Gonzalez, F., Hodgman, J. and Plajstek C. (1985): Cardiovascular and catecholamine changes after administration of pancuronium in distressed neonates. Pediatrics 75,284-287. Comline, R.S., Silver, I.A. and Silver, M. (1965): Factors responsible for the stimulation of the adrenal medulla during asphyxia in the fetal lamb. J. Physiol., 178,21 l-234. Driscoll, D.J., Fukushige, J.G., Hartley, C., Lewis, R.M. and Entman, M.L. (1982): Haemodynamic effects of pancuronium bromide in chronically instrumented dogs. Crit. Care Med., 10,41-43. Gertel, M., Fox, G.S., Rabon. F.L. et al. (1972): The cardiovascular effects of pancuronium bromide during halothane anaesthesia. Can. Anaesth. Sot. J., 19,599-604. Faxelius, G., Swenson, S.A. and Hagerman, L. (1981): Hypoxaemia following the use of pancuronium in a mechanically ventilated infant with meconium aspiration. In: Intensive Care of the Newborn. pp. 85-87. Editors: L. Stan, B. Salle and B. Friis-Hansen, Vol. III, Masson, New York. Greenough, A., Wood, S., Morley, C.J. and Davis, J.A. (1984): Pancuronium prevents pneumothoraces in ventilated premature babies who actively expire against positive pressure inflation. Lancet, i, l-4 Greenough, A., Lagercrantz, H., Pool, J. and Dahlin, 1. (1987): Plasma catecholamine levels in preterm infants. Acta Paediatr. Stand., 76, 54-59. Greenough, A., Wood, S., Morley, S.J. and Davis, J.A. (1984): One year’s experience of selectively paralysing ventilated babies to prevent pneumothoraces. Biol Neonate, 45, 150. Greisen, G., Frederiksen, S., Hertel, J. and Christensen, N.J. (1985): Catecholamine response to chest physiotherapy and endotracheal suctioning in preterm infants. Acta Paediatr. Stand., 74, 525-529. Hjemdahl, P., Daleskog, M. and Kahan, T. (1979): Determination of plasma catecholamines by high performance liquid chromatography with electrochemical detection. Comparison with a radioenzymatic method. Life Sci., 25, 131-138. Lagercrantz, H., Nilsson, E., Redham, I. and Hjemdahl, P. (1986): Plasma catecholamines following nursing procedures in a neonatal ward. Early Hum. Dev., 14,61-65. Lagercrantz, H. (1983): The development and functional role of the sympathoadrenal system in the newborn. In: Intensive Care of the Newborn. pp. 67-75. Editors: L. Stern, H. Bard and B. FriisHansen. Vol. IV, Masson, New York,
224 14 15 16 17 18 19
Long, J.G. Philip, A.G.S. and Lucey, J.F. (1980): Excessive handling as a cause of hypoxaemia. Pediatrics, 65,203-207. Nana. A., Canada, E. and Domokos, M. (1973): Blood catecholamine changes after pancuronium. Acta Anaesth. Stand., 17,83-87 Perlman, J.M., McMenamin, J.B. and Volpe, J.J. (1983): Fluctuating cerebra) blood flow velocity in respiratory distress syndrome. New Engl. J. Med., 309.204-209. Perlman, J.M. and Volpe, J.J. (1982): Cerebral blood flow velocity in relation to intraventricular haemorrhage in the premature newborn infant. J. Pediatr., 100,956-959. Runkle, B. and Bancalari, E. (1984): Acute cardiopulmonary effects of pancuronium bromide in mechanically ventilated infants. J. Pediatr., 104,614-617. Wimberley, P.D., Lon, H.C., Pedersen, H., Kejl, M., Lassen, N.A. and Friss-Hansen, B. (1982): Hypertensive peaks in the pathogenesis of intraventricular haemorrhage in the newborn. Acta Paediatr. Stand., 71,537-542.
219
EHD 00847
Catecholamine and blood pressure levels in paralysed preterm ventilated infants Anne Greenough” Jenny Pool” and H. Lagercrantzb aWmrtment of Child Health, King’s College Hospital, Denmark Hill, London,
SE5 8RX U.K. and bDeportmentof Poediotrics,KorolinskoHospitol, KorolinskoInstitutet,Stockholm, Sweden Accepted for publication 1 March 1987
Summary The effect of pancuronium administration on catecholamine levels and blood pressure was investigated. Noradrenaline levels prior to paralysis amongst infants fighting the ventilator were high, but were significantly reduced following treatment with pancuronium. There was no significant change in either blood pressure or adrenaline levels. Increasing peak inspiratory pressure (approx. 4 cmH,O) immediately prior to paralysis effectively prevented the hypoventilation previously associated with the administration of the first dose of pancuronium. noradrenaline;
adrenaline; pancuronium;
preterm infants; artificial ventilation
Introduction Preterm infants deteriorate with excessive handling, even routine care procedures can be associated with both transient disturbance of oxygenation [14] and abrupt changes in blood pressure [19]. The latter may contribute to abnormal cerebral perfusion and intracerebral haemorrhage [ 191. Increased sympathoadrenal activity could act as a mediator of such a response, as it has been demonstrated that catecholamine levels are significantly elevated following physiotherapy, suction [lo] and even special care nursing [ 121. Although variability of cerebral blood flow in mechanically ventilated infants can be reduced by paralysis, and in one study this resulted in a significant reduction in cerebral haemorrhage [17], the initiation of paralysis may result in a transient 0 1988 Elsevier Scientific Publishers Ireland Ltd. 0378-3782/88/$03.50 Published and Printed in Ireland
220
deterioration in the infant’s condition [1,6,7]. Hypoventilation is common [1,6,7] following the first dose of a paralysing agent, necessitating an increase in ventilator pressures to restore adequate oxygenation [7]. In animal studies such hypoxia also may lead to an increase in catecholamine levels [3] The aim of the present study was to investigate the effectiveness of increasing ventilator settings immediately prior to paralysis to try and prevent both the transient hypoxia [ 1,6,7] and the increase in catecholamine and blood pressure levels [2] previously associated with the administration of the first dose of pancuronium.
Patients Eleven infants (7 males) mean gestational age 30.3 weeks (range 26-34 weeks) and mean birth weight 1266 g (range 696-1944 gms) were studied. All the infants were less than 48 hours of age and ventilated for the respiratory distress syndrome (RDS) using Sechrist ventilators. The study was approved by the Hospital Ethical Committee.
Methods Infants were selected for paralysis if they were confirmed by respiratory monitoring [7] to be actively expiring against positive pressure inflation. Pancuronium (100 pg/kg) was only given when the infant was in a stable condition, with arterial blood gases within the accepted therapeutic range. Immediately prior to paralysis peak pressures were increased by approx. 4 cmH,O. This was the increase in pressure predicted by our previous results [7] which might prevent hypoventilation following the first dose of paralysis. Blood pressure (BP) was recorded from the umbilical arterial catheter sited for clinical purposes. BP was checked 5 min prior to, 15 min and 30 min post paralysis (BP was calculated as the average of recordings over a 60-s period). An arterial blood sample was taken via the catheter 5 min prior to (before the ‘compensatory’ increase in ventilator settings) and 20 min after paralysis for determination of Pao,, Pace, and pH and catecholamine analysis. One millilitre of blood was collected in chilled tubes containing preservative and then immediately centrifuged. The plasma was removed and stored at - 70°C. Catecholamine levels (noradrenaline and adrenaline) were determined by high performance cation exchange liquid chromatography with electro-chemical detection [ 111. The sensitivity of the assay was 0.1 nmol/l .
Statistical analysis The results before and after paralysis were compared and assessed for statistical significance using the Wilcoxon rank sum test.
There was no significant change in blood pressure at either 15 (mean, 45/30; range, 33/20 to 80/62) or 30 min (mean, 46/31, range, 33/22 to 81/58) compared to pre-paralysis recordings (mean, 48/30; range, 30/21 to 83/61).
221
80
70
60
xl
10
0 FRE
POST ADRENALIN
FRE
FQSl
KRADREk4LlN
Fig. 1. Noradrenaline and adrenaline levels before and after paralysis (adrenaline was detected only in 8 infants). Individual infant’s results are shown by linked data points. One infant had extremely high levels of adrenaline (315 nmol/l pre-paralysis and 100 nmol/l post-paralysis) these results are not expressed on the figure.
222
Peak inspiratory pressure was increased from mean 23 cmH,O (range, 14-40) to 27 cmH,O (range, 20-43). Comparison of arterial blood gases immediately before the increase in peak inspiratory pressure pre-paralysis and 20 min after paralysis did not detect a significant change in pH or Pace,. Although in all infants arterial oxygenation rose post-paralysis; mean Pao, pre-paralysis 51 mmHg (range, 40-65 mmHg) to post-paralysis mean Pao, 64 mmHg (range, 41-90 mmHg), this increase was small and did not reach statistical significance (Wilcoxon rank sum test). Adrenaline was detected in 8 infants only, and there was no consistent change in adrenaline levels following the administration of pancuronium (see Fig. 1). The mean pre-paralysis noradrenaline level was 21.5 nmol/l (range, 3.3-78.9 nmol/l), this was significantly greater than the mean post-paralysis level 10.2 nmol/l (range, 1.7-29.9 nmol/l), P< 0.05 (see Fig. 1).
Discussion The noradrenaline levels seen in this study prior to paralysis are high compared to those reported previously in infants of similar postnatal and gestational ages [ 10,121. Indeed four of the infants had extremely high levels of noradrenaline (> 20 nmol/l), this suggests that ‘fighting the ventilator’ is a potent stimulator of sympathoadrenal activity. Following paralysis there was a significant reduction in noradrenaline levels. This was not related to any acute change in blood pressure, confirming the lack of effect of paralysing agents on blood pressure seen both in animal studies [4] and in infants suffering from a variety of diagnoses; hyaline membrane disease, meconium aspiration, pneumonia [18]. In two previous studies, however, one in infants [2] and the other in adults anaesthetised with halothane [15] an increase in both blood pressure and catecholamines the administration of occurred following pancuronium. It is possible that the discrepancies in the results from the present study and those earlier [2,15] may be explained by the differences in the maturity of the population studied, as certainly both the degree of and response to sympathoadrenal activity is affected by gestation [8]. Catecholamine levels are known to be affected by changes in blood gas tension, both carbon dioxide levels [5] and hypoxia [3]. In the present study the change in catecholamine level cannot be attributed to this cause, as there was no significant change in carbon dioxide levels and although arterial oxygenation improved following paralysis the infants were not hypoxic prior to treatment. A possible explanation for our results, may be a direct inhibitory effect of pancuronium on catecholamine release in immature infants. This could be either by blocking nicotinic receptors in the adrenal medulla or an action on higher centres, similar to that proposed for phenobarbitone anaesthesia which reduces noradrenaline levels by a differential effect on cortical and hypothalmic levels governing selective secretion [ 131. The reduction in catecholamine levels demonstrated in the present study following paralysis in these very immature infants may explain previous association
223
of paralysis with a reduction in abnormal fluctuations in cerebral blood flow [ 171. Thus selective paralysis may be successful in reducing the incidence of intraventricular haemorrhages [9] both by an effect on cerebral blood flow [ 171 and via the significant decrease in peneumothoraces [7]. The adoption of the policy outlined in the present report, that is increasing peak inspiratory pressure immediately prior to the first dose of paralysis, can effectively ensure even the initial transient disturbance in oxygenation associated with this beneficial treatment [1,7] is effectively eliminated. Acknowledgements Sister Jenny Pool is supported by Children Nationwide Medical Research Fund; we thank Mrs. Angela McPherson for secretarial assistance. References 1 2
3 4
5 6
I
8 9 10
11
12 13
Bourgeois, J., Berthier, J.G., Cottancin, G., Millan, J.J. and Bethenod, M. (1982): Dangers de la curarisation an cours de la ventilation artificielle chez le nouveaune. Pediatrie, 37, 101-l 12. Cabal, L.A., Siassi, B., Artal, R., Gonzalez, F., Hodgman, J. and Plajstek C. (1985): Cardiovascular and catecholamine changes after administration of pancuronium in distressed neonates. Pediatrics 75,284-287. Comline, R.S., Silver, I.A. and Silver, M. (1965): Factors responsible for the stimulation of the adrenal medulla during asphyxia in the fetal lamb. J. Physiol., 178,21 l-234. Driscoll, D.J., Fukushige, J.G., Hartley, C., Lewis, R.M. and Entman, M.L. (1982): Haemodynamic effects of pancuronium bromide in chronically instrumented dogs. Crit. Care Med., 10,41-43. Gertel, M., Fox, G.S., Rabon. F.L. et al. (1972): The cardiovascular effects of pancuronium bromide during halothane anaesthesia. Can. Anaesth. Sot. J., 19,599-604. Faxelius, G., Swenson, S.A. and Hagerman, L. (1981): Hypoxaemia following the use of pancuronium in a mechanically ventilated infant with meconium aspiration. In: Intensive Care of the Newborn. pp. 85-87. Editors: L. Stan, B. Salle and B. Friis-Hansen, Vol. III, Masson, New York. Greenough, A., Wood, S., Morley, C.J. and Davis, J.A. (1984): Pancuronium prevents pneumothoraces in ventilated premature babies who actively expire against positive pressure inflation. Lancet, i, l-4 Greenough, A., Lagercrantz, H., Pool, J. and Dahlin, 1. (1987): Plasma catecholamine levels in preterm infants. Acta Paediatr. Stand., 76, 54-59. Greenough, A., Wood, S., Morley, S.J. and Davis, J.A. (1984): One year’s experience of selectively paralysing ventilated babies to prevent pneumothoraces. Biol Neonate, 45, 150. Greisen, G., Frederiksen, S., Hertel, J. and Christensen, N.J. (1985): Catecholamine response to chest physiotherapy and endotracheal suctioning in preterm infants. Acta Paediatr. Stand., 74, 525-529. Hjemdahl, P., Daleskog, M. and Kahan, T. (1979): Determination of plasma catecholamines by high performance liquid chromatography with electrochemical detection. Comparison with a radioenzymatic method. Life Sci., 25, 131-138. Lagercrantz, H., Nilsson, E., Redham, I. and Hjemdahl, P. (1986): Plasma catecholamines following nursing procedures in a neonatal ward. Early Hum. Dev., 14,61-65. Lagercrantz, H. (1983): The development and functional role of the sympathoadrenal system in the newborn. In: Intensive Care of the Newborn. pp. 67-75. Editors: L. Stern, H. Bard and B. FriisHansen. Vol. IV, Masson, New York,
224 14 15 16 17 18 19
Long, J.G. Philip, A.G.S. and Lucey, J.F. (1980): Excessive handling as a cause of hypoxaemia. Pediatrics, 65,203-207. Nana. A., Canada, E. and Domokos, M. (1973): Blood catecholamine changes after pancuronium. Acta Anaesth. Stand., 17,83-87 Perlman, J.M., McMenamin, J.B. and Volpe, J.J. (1983): Fluctuating cerebra) blood flow velocity in respiratory distress syndrome. New Engl. J. Med., 309.204-209. Perlman, J.M. and Volpe, J.J. (1982): Cerebral blood flow velocity in relation to intraventricular haemorrhage in the premature newborn infant. J. Pediatr., 100,956-959. Runkle, B. and Bancalari, E. (1984): Acute cardiopulmonary effects of pancuronium bromide in mechanically ventilated infants. J. Pediatr., 104,614-617. Wimberley, P.D., Lon, H.C., Pedersen, H., Kejl, M., Lassen, N.A. and Friss-Hansen, B. (1982): Hypertensive peaks in the pathogenesis of intraventricular haemorrhage in the newborn. Acta Paediatr. Stand., 71,537-542.