1323
19. Iwase M, Sotobata I, Yokota M, et al. Evaluation by pulsed doppler echocardiography of the atrial contribution to left ventricular filling in patients with DDD pacemakers. Am J Cardiol 1986; 58: 104-09. 20. Janosik DL, Pearson AC, Buckingham TA, Labovitz AJ, Redd RM. The hemodynamic benefit of differential atrioventricular delay intervals for sensed and paced atrial events during physiologic pacing. J Am Coll Cardiol 1989; 14: 499-507. 21. Spirito P, Maron BJ, Bonow RO, Epstein SE. Occurrence and significance of progressive left ventricular wall thinning and relative cavity dilatation in hypertrophic cardiomyopathy. Am J Cardiol 1987;
59: 123-29.
22. Askenazi J, Alexander JH, Koenigsberg DI, Belic N, Lesch M. Alteration of left ventricular performance by left bundle branch block simulated with atrio-ventricular sequential pacing. Am J Cardiol 1984; 53: 99-104. 23. Cannon RO, Schenke WH, Maron BJ, et al. Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 1987; 10: 53-62. 24. Zile MR, Blaustein AS, Shimizu G, Gaasch WH. Right ventricular pacing reduces the rate of left ventricular relaxation and filling. J Am Coll Cardiol 1987; 10: 702-09.
SHORT REPORT Abnormalities of surfactant in children with recurrent cyanotic
episodes
The mechanism of recurrent cyanotic episodes in infants and children is not known, but a deficiency of surfactant is a possible cause. We have measured the amount of surfactant collected by bronchoalveolar lavage from two children with recurrent cyanotic episodes and from two controls with anatomical airway obstructions. We also assessed the physical properties of the surfactant by changing the surface area (A) of a monolayer and measuring its surface tension (&ggr;). The cases had lower amounts of surfactant extracted, which could explain some of the abnormalities of the &ggr;/A loops. However, the finding that the cases had reversed loops (ie, the surface tension is higher during monolayer compression than during expansion) shows that there is also a qualitative abnormality. These features suggest a possible diagnostic test if not a mechanism for this disorder.
The mechanism of recurrent cyanotic episodes and occasional death in infants and children remains obscure.
Although prolonged expiratory apnoea is characteristic, its reported occurrence despite continued airflowl suggests that the hypoxaemia results from some abnormality of the distal air spaces. Reduced lung compliance is common; it could account for atelectasis and redistribution of blood flow, and it may be due to a deficiency of surfactant. 2,3 Consistent with the sudden onset of cyanotic episodes, surfactant has the capacity to change the mechanical properties of lung tissue very rapidly.4 We have studied surfactant obtained by bronchoalveolar lavage from two children with recurrent cyanotic episodes. The first child was a caucasian boy aged 6 years. Since the age of 4 months he had had about forty episodes of croup (barking cough, stridor, hoarse voice, and agitation), most associated with cyanosis. The episodes were precipitated by cold drinks, swimming, and upper respiratory tract infections, but some occurred in sleep. They all settled spontaneously, and did not require intubation; there was no loss of consciousness. The child also had unrelated breath-
holding attacks, in which he cried out, made stuttering inspiratory efforts, and became cyanosed; once the attack finished with a general convulsion. These episodes were precipitated by stress and did not occur during sleep; they were rare after age 4 years. Examination showed no abnormalities; Cl esterase, calcium phosphate, a barium study, flow-volume loops, and laryngoscopy/ bronchoscopy gave normal results. Surfactant was obtained by bronchoalveolar lavage. A disorder of respiratory control was diagnosed. The child is stable on treatment with inhaled budesonide and access to nebulised adrenaline/oxygen. The second child was a 10-month-old caucasian boy. At birth (36 weeks’ gestation) the baby had severe upper-airway obstruction that required endotracheal intubation but no anatomical or dynamic cause was found. After extubation, there were futher episodes of acute and severe upper-airway obstruction and cyanosis. A tracheostomy tube did not stop the episodes. Intermittent positive pressure ventilation (IPPV) with 100% oxygen did not result in immediate improvement; application of positive end-expiratory pressure before IPPV was more successful. Repeated endoscopy and neurological, cardiological, and metabolic investigations, including perfusion scanning for arteriovenous malformation, were unhelpful. Chest radiographs showed a high diaphragm and there were intermittent changes consistent with collapse of bronchopulmonary segments and pulmonary oedema. A presumptive diagnosis of prolonged expiratory apnoea was made. Bronchoalveolar lavage through a deeply placed suction catheter was undertaken on three occasions at least 2 months apart. He was managed as a long-term inpatient with oxygen, clonidine, and nutritional support until he was found in respiratory arrest. He was resuscitated but had signs of severe hypoxic ischaemic
encephalopathy. Bronchial washings were obtained from two male control infants (8 and 10 months) with tracheostomies for severe upper-airway obstruction (Pierre-Robin syndrome in one, lymph-haemangioma of the epiglottis in one). Samples were obtained from unanaesthetised children. We did not attempt to confirm typical bronchoalveolar wash cytology, since all liquid retrieved was used in the surfactant evaluation. Surfactant was extracted from the lavage fluid with chloroform within 1 min of collection and stored in ice; later it was evaporated to dryness and redissolved in hexane/ethanol for deposition as a monolayer on the saline pool of a Langmuir trough. A standard procedures was used for the physical evaluation whereby the surface area (A) of the monolayer was cycled over a ratio of 5/1 while its surface tension (y) was measured by the Wilhelmy method. The amount of surfactant in the lavage fluid was measured by thin-layer chromatography (TLC)6 and total solvent-extractable
phosphorus.7 The figure shows representative results for a patient and a control. In the first cycle the surfactant from the patients had higher surface tension at all surface areas than that of the control children and the "loops" were much narrower. Less surfactant was removed from the patients (by TLC and total solvent-extractable phosphorus), and this deficiency in the quantity could account for the differences in the y/A loops.
1324
points on the alveolar surface to alternate microconcave and microconvex with a corresponding change in the direction for shifting fluid by surface tension forces. The expanding monolayer (convex) effects a return of any excess alveolar fluid to the deeper structures; return of fluid would not occur for surfactant with the properties of that from our two patients. A deficiency in quantity of surfactant results in pulmonary oedema, reduced compliance, and atelectasis, all of which can induce shunt and ventilation-perfusion inequality. These changes are characteristic of the respiratory distress syndrome, caused by a deficiency in surfactant,10 and are common in premature infants at high risk of recurrent apnoeic episodes. In vivo, the thermodynamics of anticlockwise y/A cycles are complex in their beneficial implications to the work of breathing.8 In addition, the abnormal y/A profile seen in the figure would cause the dominating surface tension force to keep the mechanoreceptors in the bronchioles fully stretched during
capillaries
cause
between
expiration (monolayer compression); thus signals would be sent to the brainstem indicating that the lung was still fully inflated and there would be no inspiratory drive at end-expiration. The abnormal physical properties of the surfactant from these children suggest a possible diagnostic test if not a mechanism for this disorder.
REFERENCES 1. Southall DP, Samuels with severe arterial
Representative diagrams of y/A loops
for
patients and
controls. < - - =tracing as A is being decreased (monolayer compression); as A is returning to maximum (monolayer expansion). ->-=tracing Results were similar for both patients. -
-
However, the deficiency could not explain the finding that
y/A loop
is reversed in the patients in all five cycles (figure). In the controls, the loop is clockwise-ie, for a given surface area, the surface tension is lower during compression of the monolayer than during expansion. The anticlockwise loops of the patients indicate a qualitative abnormality as well as a quantitative deficiency of their surfactant. The abnormalities of surfactant were found in both children despite the difference in their ages and the fact that they were both well at the time of sampling; moreover, the abnormalities persisted for at least 4 months in patient 2. However, the physical properties of surfactant should be stable after hypoxic stress even though cellular cycling and availability of surfactant may be altered by the effect of hypoxia on type II cell processing. Reverse cycles have been reported previously after repeated cycling of surfactantg but the fact that the surface tension is higher during monolayer compression than at the corresponding point of expansion is likely to produce alveolar oedema by the "oilcan" phenomenon.9 This is a mechanism whereby red cells bulging through alveolar the
2.
MP, Talbert DG. Recurrent cyanotic episodes hypoxaemia and intrapulmonry shunting: a mechanism for sudden death. Arch Dis Child 1990; 65: 953-61. Southall DP, Johnson P, Salmons S, Talbert DG, Morley CJ, Miller J. Prolonged expiratory apnoea: a disorder resulting in episodes of severe arterial hypoxaemia in infants and young children. Lancet 1985; ii:
571-77. 3. Southall DP, Johnson P, Salmons S, et al. Lancet 1985; ii: 1125-26. 4. Goerke J, Gonzales J. Temperature
Prolonged expiratory apnoea.
dependence of dipalmitoyl phosphatidylcholine monolayer stability. J Appl Physiol Respir Environ Exercise Physiol 1981; 51: 1108-14. 5. Clements JA, Tierney DF. Alveolar instability associated with altered surface tension. In: Fenn WO, Rahn H, eds. Handbook of physiology: respiration, vol II. 1965: 1565-83. 6. Skipski U, Peterson RF, Sanders J, Barclay M. Thin layer chromatography of phospholipids using silica gel without calcium sulfate binder. J Lipid Res 1963; 4: 227-28. 7. Rouser G, Nelson GJ, Fleischer S, Simon G. Lipid composition of animal cell membranes, organelles and organ. In: Chapman D, ed. Biological membranes. London: Academic Press, 1968: 5-69. 8. Hills BA. A thermal surface phenomenon in the rabbit lung: possible basis for the conversion of heat into work. J Physiol 1988; 402: 463-71. 9. Hills BA. Rapidly alternating curvature ("oilcanning") as a mechanism preventing alveolar oedema. J Appl Physiol (in press). 10. Avery MA, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child 1959; 97: 517-23. ADDRESS: Mater Children’s Hospital, South Brisbane, Queensland (Prof B. A. Hills, ScD, I. B. Masters, FRACP, J. F. O’Duffy, FRACP) and Department of Physiology, University of New England, New South Wales, Australia (Prof B. A Hills) Correspondence to Dr I. B. Masters, Mater Children’s Hospital, Annerley Road, South Brisbane, 4101 Queensland, Australia.
19. Iwase M, Sotobata I, Yokota M, et al. Evaluation by pulsed doppler echocardiography of the atrial contribution to left ventricular filling in patients with DDD pacemakers. Am J Cardiol 1986; 58: 104-09. 20. Janosik DL, Pearson AC, Buckingham TA, Labovitz AJ, Redd RM. The hemodynamic benefit of differential atrioventricular delay intervals for sensed and paced atrial events during physiologic pacing. J Am Coll Cardiol 1989; 14: 499-507. 21. Spirito P, Maron BJ, Bonow RO, Epstein SE. Occurrence and significance of progressive left ventricular wall thinning and relative cavity dilatation in hypertrophic cardiomyopathy. Am J Cardiol 1987;
59: 123-29.
22. Askenazi J, Alexander JH, Koenigsberg DI, Belic N, Lesch M. Alteration of left ventricular performance by left bundle branch block simulated with atrio-ventricular sequential pacing. Am J Cardiol 1984; 53: 99-104. 23. Cannon RO, Schenke WH, Maron BJ, et al. Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 1987; 10: 53-62. 24. Zile MR, Blaustein AS, Shimizu G, Gaasch WH. Right ventricular pacing reduces the rate of left ventricular relaxation and filling. J Am Coll Cardiol 1987; 10: 702-09.
SHORT REPORT Abnormalities of surfactant in children with recurrent cyanotic
episodes
The mechanism of recurrent cyanotic episodes in infants and children is not known, but a deficiency of surfactant is a possible cause. We have measured the amount of surfactant collected by bronchoalveolar lavage from two children with recurrent cyanotic episodes and from two controls with anatomical airway obstructions. We also assessed the physical properties of the surfactant by changing the surface area (A) of a monolayer and measuring its surface tension (&ggr;). The cases had lower amounts of surfactant extracted, which could explain some of the abnormalities of the &ggr;/A loops. However, the finding that the cases had reversed loops (ie, the surface tension is higher during monolayer compression than during expansion) shows that there is also a qualitative abnormality. These features suggest a possible diagnostic test if not a mechanism for this disorder.
The mechanism of recurrent cyanotic episodes and occasional death in infants and children remains obscure.
Although prolonged expiratory apnoea is characteristic, its reported occurrence despite continued airflowl suggests that the hypoxaemia results from some abnormality of the distal air spaces. Reduced lung compliance is common; it could account for atelectasis and redistribution of blood flow, and it may be due to a deficiency of surfactant. 2,3 Consistent with the sudden onset of cyanotic episodes, surfactant has the capacity to change the mechanical properties of lung tissue very rapidly.4 We have studied surfactant obtained by bronchoalveolar lavage from two children with recurrent cyanotic episodes. The first child was a caucasian boy aged 6 years. Since the age of 4 months he had had about forty episodes of croup (barking cough, stridor, hoarse voice, and agitation), most associated with cyanosis. The episodes were precipitated by cold drinks, swimming, and upper respiratory tract infections, but some occurred in sleep. They all settled spontaneously, and did not require intubation; there was no loss of consciousness. The child also had unrelated breath-
holding attacks, in which he cried out, made stuttering inspiratory efforts, and became cyanosed; once the attack finished with a general convulsion. These episodes were precipitated by stress and did not occur during sleep; they were rare after age 4 years. Examination showed no abnormalities; Cl esterase, calcium phosphate, a barium study, flow-volume loops, and laryngoscopy/ bronchoscopy gave normal results. Surfactant was obtained by bronchoalveolar lavage. A disorder of respiratory control was diagnosed. The child is stable on treatment with inhaled budesonide and access to nebulised adrenaline/oxygen. The second child was a 10-month-old caucasian boy. At birth (36 weeks’ gestation) the baby had severe upper-airway obstruction that required endotracheal intubation but no anatomical or dynamic cause was found. After extubation, there were futher episodes of acute and severe upper-airway obstruction and cyanosis. A tracheostomy tube did not stop the episodes. Intermittent positive pressure ventilation (IPPV) with 100% oxygen did not result in immediate improvement; application of positive end-expiratory pressure before IPPV was more successful. Repeated endoscopy and neurological, cardiological, and metabolic investigations, including perfusion scanning for arteriovenous malformation, were unhelpful. Chest radiographs showed a high diaphragm and there were intermittent changes consistent with collapse of bronchopulmonary segments and pulmonary oedema. A presumptive diagnosis of prolonged expiratory apnoea was made. Bronchoalveolar lavage through a deeply placed suction catheter was undertaken on three occasions at least 2 months apart. He was managed as a long-term inpatient with oxygen, clonidine, and nutritional support until he was found in respiratory arrest. He was resuscitated but had signs of severe hypoxic ischaemic
encephalopathy. Bronchial washings were obtained from two male control infants (8 and 10 months) with tracheostomies for severe upper-airway obstruction (Pierre-Robin syndrome in one, lymph-haemangioma of the epiglottis in one). Samples were obtained from unanaesthetised children. We did not attempt to confirm typical bronchoalveolar wash cytology, since all liquid retrieved was used in the surfactant evaluation. Surfactant was extracted from the lavage fluid with chloroform within 1 min of collection and stored in ice; later it was evaporated to dryness and redissolved in hexane/ethanol for deposition as a monolayer on the saline pool of a Langmuir trough. A standard procedures was used for the physical evaluation whereby the surface area (A) of the monolayer was cycled over a ratio of 5/1 while its surface tension (y) was measured by the Wilhelmy method. The amount of surfactant in the lavage fluid was measured by thin-layer chromatography (TLC)6 and total solvent-extractable
phosphorus.7 The figure shows representative results for a patient and a control. In the first cycle the surfactant from the patients had higher surface tension at all surface areas than that of the control children and the "loops" were much narrower. Less surfactant was removed from the patients (by TLC and total solvent-extractable phosphorus), and this deficiency in the quantity could account for the differences in the y/A loops.
1324
points on the alveolar surface to alternate microconcave and microconvex with a corresponding change in the direction for shifting fluid by surface tension forces. The expanding monolayer (convex) effects a return of any excess alveolar fluid to the deeper structures; return of fluid would not occur for surfactant with the properties of that from our two patients. A deficiency in quantity of surfactant results in pulmonary oedema, reduced compliance, and atelectasis, all of which can induce shunt and ventilation-perfusion inequality. These changes are characteristic of the respiratory distress syndrome, caused by a deficiency in surfactant,10 and are common in premature infants at high risk of recurrent apnoeic episodes. In vivo, the thermodynamics of anticlockwise y/A cycles are complex in their beneficial implications to the work of breathing.8 In addition, the abnormal y/A profile seen in the figure would cause the dominating surface tension force to keep the mechanoreceptors in the bronchioles fully stretched during
capillaries
cause
between
expiration (monolayer compression); thus signals would be sent to the brainstem indicating that the lung was still fully inflated and there would be no inspiratory drive at end-expiration. The abnormal physical properties of the surfactant from these children suggest a possible diagnostic test if not a mechanism for this disorder.
REFERENCES 1. Southall DP, Samuels with severe arterial
Representative diagrams of y/A loops
for
patients and
controls. < - - =tracing as A is being decreased (monolayer compression); as A is returning to maximum (monolayer expansion). ->-=tracing Results were similar for both patients. -
-
However, the deficiency could not explain the finding that
y/A loop
is reversed in the patients in all five cycles (figure). In the controls, the loop is clockwise-ie, for a given surface area, the surface tension is lower during compression of the monolayer than during expansion. The anticlockwise loops of the patients indicate a qualitative abnormality as well as a quantitative deficiency of their surfactant. The abnormalities of surfactant were found in both children despite the difference in their ages and the fact that they were both well at the time of sampling; moreover, the abnormalities persisted for at least 4 months in patient 2. However, the physical properties of surfactant should be stable after hypoxic stress even though cellular cycling and availability of surfactant may be altered by the effect of hypoxia on type II cell processing. Reverse cycles have been reported previously after repeated cycling of surfactantg but the fact that the surface tension is higher during monolayer compression than at the corresponding point of expansion is likely to produce alveolar oedema by the "oilcan" phenomenon.9 This is a mechanism whereby red cells bulging through alveolar the
2.
MP, Talbert DG. Recurrent cyanotic episodes hypoxaemia and intrapulmonry shunting: a mechanism for sudden death. Arch Dis Child 1990; 65: 953-61. Southall DP, Johnson P, Salmons S, Talbert DG, Morley CJ, Miller J. Prolonged expiratory apnoea: a disorder resulting in episodes of severe arterial hypoxaemia in infants and young children. Lancet 1985; ii:
571-77. 3. Southall DP, Johnson P, Salmons S, et al. Lancet 1985; ii: 1125-26. 4. Goerke J, Gonzales J. Temperature
Prolonged expiratory apnoea.
dependence of dipalmitoyl phosphatidylcholine monolayer stability. J Appl Physiol Respir Environ Exercise Physiol 1981; 51: 1108-14. 5. Clements JA, Tierney DF. Alveolar instability associated with altered surface tension. In: Fenn WO, Rahn H, eds. Handbook of physiology: respiration, vol II. 1965: 1565-83. 6. Skipski U, Peterson RF, Sanders J, Barclay M. Thin layer chromatography of phospholipids using silica gel without calcium sulfate binder. J Lipid Res 1963; 4: 227-28. 7. Rouser G, Nelson GJ, Fleischer S, Simon G. Lipid composition of animal cell membranes, organelles and organ. In: Chapman D, ed. Biological membranes. London: Academic Press, 1968: 5-69. 8. Hills BA. A thermal surface phenomenon in the rabbit lung: possible basis for the conversion of heat into work. J Physiol 1988; 402: 463-71. 9. Hills BA. Rapidly alternating curvature ("oilcanning") as a mechanism preventing alveolar oedema. J Appl Physiol (in press). 10. Avery MA, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child 1959; 97: 517-23. ADDRESS: Mater Children’s Hospital, South Brisbane, Queensland (Prof B. A. Hills, ScD, I. B. Masters, FRACP, J. F. O’Duffy, FRACP) and Department of Physiology, University of New England, New South Wales, Australia (Prof B. A Hills) Correspondence to Dr I. B. Masters, Mater Children’s Hospital, Annerley Road, South Brisbane, 4101 Queensland, Australia.
