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CLONIDINE POISONING IN CHILDREN
1266 PLATELET AGGREGATION IN VIVO BY THERAPEUTIC ULTRASOUND is being used more and more by and sports coaches to alleviate the effects of soft-tissue injury. Despite its beneficial effects, little is known about how it works or about possible complications.
SIR,-Ultrasonic therapy
physiotherapists
Human platelets are very susceptible to damage by hydrodynamic shear stresses.’-’ This type of stress may be produced by therapeutic ultrasound.4 Ultrasound at therapeutic in-
tensities accelerates the recalcification-time of human plateletrich plasma in vitro.s Other in-vitro experiments have shown that ultrasound induces human platelets to undergo the release reaction (as detected by the appearance in plasma of the platelet-specific protein &bgr;-thromboglobulinl and induces spon-
platelet aggregation.7 platelets are activated to a similar extent in vivo during exposure of tissues to therapeutic ultrasound then platelet taneous
If
aggregates may be formed in the circulation, and such aggregates might subsequently impact in the microcirculation of the irradiated tissue or in the lungs. We have looked for platelet microemboli within the microcirculation of mammalian subcutaneous tissues (the depilated pinna of a guineapig). The animal was given a general anaesthetic, and its external ear was subjected to ultrasonic irradiation from a therapeutic apparatus (Rank, Stanley, Cox ’Sonacell Multiphon’). The transducer was located over the central arteries of the pinna, and a tube containing degassed castor oil was placed behind the tissue to absorb the emerging ultrasound. All interfaces in the path of the ultrasonic beam were
1. Glover, G. J., McIntire, L. V., Res. 1977, 10, 11. 2. Williams, A. R., Sykes, S. M.,
1976, 2, 11. 3. Hung, T. C., Hochmuth,
R.
Brown, C. H., Natelson,
liberally coated with coupling cream. The tissues were sub. jected to sonication for 2 min at 0.75 and 3.0 MHz at a meter intensity of 1 W /cm2. Tissue was taken from upper and lower regions of the pinna immediately after sonication and prepared for electron microscopy by immersion fixation in 5% glutaraldehyde and 1% osmium tetroxide in buffered solutions, and stained with lead citrate and uranyl acetate. Control and test sections were prepared from six guineapigs of the DunkinHartley strain. Platelet aggregates of the type seen in the figure were found in the sonicated tissue. The platelets show pseudopod formation (see arrow) which is an early stage in the formation of a platelet mass (one platelet, marked DP, is degranulated). No aggregates were found in sections from non-sonicated tissue. Positive findings were seen in tissues whose vessels had been sonicated at frequencies of 3.0 MHz continuous wave and 0 73 MHz pulsed 1/1 (2 ms on, 2 ms off). These are within the range used to treat soft-tissue injuries. Although almost 2000 vessels from irradiated animals were examined, this corresponds to only 0.000015% of the tissue volume of a guineapig’s ear. Therefore, the detection of platelet aggregates within such small samples suggests that large numbers of similar aggregates may be distributed throughout the remaining irradiated tissue. Thus, in-vivo platelet aggrega. tion may be a common reaction to therapeutic ultrasound. of damaged vessels in the microcirculation by platelet aggregates may be one way in which therapeutic ultrasound diminishes the effect of soft-tissue injuries. Departments of Anatomy and Medical Biophysics, A. P. ZAROD University of Manchester, Manchester M 13 9PT A. R. WILLIAMS
only
Blockage
E. A. Thrombos.
O’Brien, W. B., Jr. Ultrasound Med. Biol.
M., Joist, J. H., Sutera, S. P., Trans. Am. Soc.
artif. intern. Organs., 1976, 22, 4. Nyborg, W. L., Physical Acoustics; vol. IIB. New York, 1965. Williams, A. R., O’Brien, W. D., Jr. Ultrasound Med. Biol. 1976, 2, 113. Williams, A. R., Chater, B., Allen, K., Sherwood, M. Paper read at a meeting of the Biocoustics Group, held in Dundee, in 1976. 7. Chater, B., Williams, A. R. Unpublished. 5. 6.
CLONIDINE POISONING IN CHILDREN a boy aged 3 years 8 months weigh16 and his sister aged 2 years 6 months weighing 15 kg, ing kg who had shared 20-25 tablets of clonidine 25 g (’Dixarit’) 3 h before being sent to hospital. The girl was drowsy, unsteady, and pale with peripheral vasoconstriction; pupils were constricted, and her conscious level fluctuated. Systolic blood-pressure 105 mm Hg, pulserate 100/min with episodes of bradycardia to 60-70/min while active, and respiration 18/min. Tendon retiexes and bowel sounds normal. Atropine 200 g was given intravenously when the pulse-rate persisted at 68/min and within 3 min the pulserate rose to above 100/min. After half an hour the pupils dilated. Stomach washout produced a large quantity of tablet debris. Over the next 18 h her conscious level fluctuated between arousal with confusion, and depression. During the depressed episodes she would respond only to shouting and an increase in pallor was accompanied by constriction of the pupils, shallow respirations and a sinus bradycardia (lowest rate 68/min). Four further doses of atropine were given intravenously on separate occasions when monitoring revealed a pulse-rate, persisting over 15 min, of 70-80/min. Over the first 8 h the child had four seizures, lasting about 10 s in which her eyes rolled, she became limp, her expression was blank, and there were clonic movements of her jaw. A blood-glucose during one of these fits was normal ; blood-pressure recordings each quarter hour were normal, and there was no hypothermia. The brother had similar but less severe signs of poisoning and had no seizures. The duration of the signs of poisoning was compatible with the 12-18 h halt-life of this drug. Clonidine has complex actions; peripherally it alters responsiveness of arterioles to vasoactive substances and by central action it produces hypotension, bradycardia, and a tall in cardiac output. It also has a chlorpromazine like action with sedation and hypothermia.
SIR,-We have treated
-
Platelet aggregate within vessel lumen after exposure to therapeutic ultrasound.
(About
x
3500)
1267 The 3-year-old patient reported by Pai and Lipsitz’ ingested up to ten times more of the drug. However, neither their patient nor ours became hypotensive. The bradycardia was not symptomatic and may not have required treatment. However,
response to atropine was rapid. Clonidine is being used increasingly in both childhood and adult migraine. It is also used in adults for hypertension and menopausal flushing. Trials of its efficacy in recurrent abdominal-pain syndrome of childhood are under way. However, experience with its use in children is still limited. Our observations indicate that dosages in young children should be careiully evaluated and that vasoconstriction and bradycardia rather than hypotension may be the first signs of overdosage. R. MACFAUL Cambridge Military Hospital, Aldershot, Hants GU11 2AN G. MILLER
Denticator Company, San Francisco) from a large cardboard container. 11 (85%) of 13 children with cyanotic congenital heart-disease spontaneously chose black or purple lollipops, while 24 (73%) of 33 children with either no shunt (8 children) or left-to-right shunt (25 children) chose light-coloured lolliA small number pops (pink, red, orange, or yellow) (p<0001). of children changed their preference from dark to light coloured lollipops after corrective surgery for cyanotic congenital heart-disease. This procedure could be used by primary-care physicians in children old enough to choose a lollipop, thereby avoiding unnecessary referrals to a cardiologist. It might also be used to follow-up patients with tetralogy of Fallot, thereby avoiding multiple cardiac catheterisations which are otherwise necessary to establish the direction of shunting as the disease progresses. This studv
was
suocorted in
Dart
bv the Meridian Natant Societv.
RHESUS-MONKEY PANCREAS FOR MEASURING ISLET-CELL ANTIBODIES
SIR,-Pancreatic islet-cell antibodies (I.C.A.) have been demonstrated in the serum of many patients at the onset of insulin-requiring diabetes mellitus by the technique of indirect immunofluorescence on human pancreas.2 I.C.A. also occur in persons with autoimmune polyendocrine disorders, with or without overt diabetes.3,4 We have been studying the frequency of I.C.A. in our local population of juvenile diabetics, and the relation between I.C.A. and other indices of the disease. Because of difficulties in obtaining fresh human pancreas, we investigated the cross-reactivity of I.C.A. on animal pancreases. Although there are reports2.3 of partial cross-reactivity on rodent pancreas (rat, mouse, guineapig), we have found no published data for other species. We tested 8 sera that were I.C.A. positive on human pancreas, and for rat, mouse, guineapig, sheep, and pig pancreas (serum dilution 1/2) the islets did not fluoresce significantly above background, the fluorescence pattern varying in a manner characteristic for each species. Islets fluoresced brightly on rabbit pancreas for those sera that were I.C.A. positive on human pancreas: however, in a "blind" experiment including i.c.A.-negative sera (10 diabetic, 10 nondiabetic), 70% of these were scored positive at 1/2 and 1/6 dilution of sera. Rhesus-monkey pancreas, however, proved a very convenient alternative to human pancreas. Non-specific background fluorescence was low. All 11 sera which were positive on human pancreas were also positive on monkey pancreas, and with a similar titre. Sera which were negative on human pancreas (15 diabetic, 18 non-diabetic) were also scored negative on monkey pancreas in blind experiments: the islets, although architecturally distinguishable, had only an orange-red autofluorescence. All sera tested (positive and negative) had a similar low fluorescence on monkey liver. Department of Pædiatrics, School of Medicine,
University of Auckland, Auckland 3, New Zealand
Childrens Orthopedic Hospital and Medical Center, and University of Washington, Seattle, Washington 98105, U.S.A.
DARRELL SALK STANLEY STAMM ELLIOT VICHINSKY RONALD LEMIRE MARLENE KROPP
REDUCTION OF SERUM-PROLACTIN AFTER SUBCUTANEOUS SALMON CALCITONIN al.’ have reviewed the many hypothalamic regulate prolactin release. We have found that a non-hypothalamic factor, calcitonin, is associated with striking decreases in circulating prolactin. For reasons discussed elsewhere2we have compared the effects of calcitonin and placebo, on mood, behaviour, and neurochemical findings in nine psychotic inpatients of various ages, sexes, and diagnoses. Synthetic salmon calcitonin and placebo injections of identi-
SIR,-Zacur
et
influences which
1. 2.
Zacur, H. A., Foster, G. V., Tyson, J. E. Lancet, 1976, i, 410. Carman, J. S., Post, R. M., Goodwin, F. K., Bunney, W. E. Biol. Psychiat. 1977, 12, 5.
JEANETTE R. CROSSLEY BETH D. LENDRUM R. B. ELLIOTT
NON-INVASIVE DIAGNOSIS OF CONGENITAL HEART-DISEASE a pilot study of children with congenital heart-dishave explored a non-invasive procedure for verifying the direction of haemodynamic shunting. We could differentiate between cyanotic and acyanotic heart-disease in approximately three-quarters of the children studied. Patients chosen at random from a psediatric cardiology clinic were offered a mixture of coloured lollipops (sugarless,
SIR,-In
ease we
1. Pai, G. S., Lipsitz, D. J. Pediatrics, 1976, 58, 749. 2. Lendrum, R., Walker, G., Gamble, D. R. Lancet, 1975, i, 880. 3. Bottazzo, G. F., Florin-Christensen, A., Doniach, D. ibid. 1974, ii, 1279. 4. MacCuish, A. C., Barnes, E. W., Irvine, W. J., Duncan, L. J. P. ibid. p. 1529.
Decrease in
serum-prolactin in patients given calcitonin.
SIR,-Ultrasonic therapy
physiotherapists
Human platelets are very susceptible to damage by hydrodynamic shear stresses.’-’ This type of stress may be produced by therapeutic ultrasound.4 Ultrasound at therapeutic in-
tensities accelerates the recalcification-time of human plateletrich plasma in vitro.s Other in-vitro experiments have shown that ultrasound induces human platelets to undergo the release reaction (as detected by the appearance in plasma of the platelet-specific protein &bgr;-thromboglobulinl and induces spon-
platelet aggregation.7 platelets are activated to a similar extent in vivo during exposure of tissues to therapeutic ultrasound then platelet taneous
If
aggregates may be formed in the circulation, and such aggregates might subsequently impact in the microcirculation of the irradiated tissue or in the lungs. We have looked for platelet microemboli within the microcirculation of mammalian subcutaneous tissues (the depilated pinna of a guineapig). The animal was given a general anaesthetic, and its external ear was subjected to ultrasonic irradiation from a therapeutic apparatus (Rank, Stanley, Cox ’Sonacell Multiphon’). The transducer was located over the central arteries of the pinna, and a tube containing degassed castor oil was placed behind the tissue to absorb the emerging ultrasound. All interfaces in the path of the ultrasonic beam were
1. Glover, G. J., McIntire, L. V., Res. 1977, 10, 11. 2. Williams, A. R., Sykes, S. M.,
1976, 2, 11. 3. Hung, T. C., Hochmuth,
R.
Brown, C. H., Natelson,
liberally coated with coupling cream. The tissues were sub. jected to sonication for 2 min at 0.75 and 3.0 MHz at a meter intensity of 1 W /cm2. Tissue was taken from upper and lower regions of the pinna immediately after sonication and prepared for electron microscopy by immersion fixation in 5% glutaraldehyde and 1% osmium tetroxide in buffered solutions, and stained with lead citrate and uranyl acetate. Control and test sections were prepared from six guineapigs of the DunkinHartley strain. Platelet aggregates of the type seen in the figure were found in the sonicated tissue. The platelets show pseudopod formation (see arrow) which is an early stage in the formation of a platelet mass (one platelet, marked DP, is degranulated). No aggregates were found in sections from non-sonicated tissue. Positive findings were seen in tissues whose vessels had been sonicated at frequencies of 3.0 MHz continuous wave and 0 73 MHz pulsed 1/1 (2 ms on, 2 ms off). These are within the range used to treat soft-tissue injuries. Although almost 2000 vessels from irradiated animals were examined, this corresponds to only 0.000015% of the tissue volume of a guineapig’s ear. Therefore, the detection of platelet aggregates within such small samples suggests that large numbers of similar aggregates may be distributed throughout the remaining irradiated tissue. Thus, in-vivo platelet aggrega. tion may be a common reaction to therapeutic ultrasound. of damaged vessels in the microcirculation by platelet aggregates may be one way in which therapeutic ultrasound diminishes the effect of soft-tissue injuries. Departments of Anatomy and Medical Biophysics, A. P. ZAROD University of Manchester, Manchester M 13 9PT A. R. WILLIAMS
only
Blockage
E. A. Thrombos.
O’Brien, W. B., Jr. Ultrasound Med. Biol.
M., Joist, J. H., Sutera, S. P., Trans. Am. Soc.
artif. intern. Organs., 1976, 22, 4. Nyborg, W. L., Physical Acoustics; vol. IIB. New York, 1965. Williams, A. R., O’Brien, W. D., Jr. Ultrasound Med. Biol. 1976, 2, 113. Williams, A. R., Chater, B., Allen, K., Sherwood, M. Paper read at a meeting of the Biocoustics Group, held in Dundee, in 1976. 7. Chater, B., Williams, A. R. Unpublished. 5. 6.
CLONIDINE POISONING IN CHILDREN a boy aged 3 years 8 months weigh16 and his sister aged 2 years 6 months weighing 15 kg, ing kg who had shared 20-25 tablets of clonidine 25 g (’Dixarit’) 3 h before being sent to hospital. The girl was drowsy, unsteady, and pale with peripheral vasoconstriction; pupils were constricted, and her conscious level fluctuated. Systolic blood-pressure 105 mm Hg, pulserate 100/min with episodes of bradycardia to 60-70/min while active, and respiration 18/min. Tendon retiexes and bowel sounds normal. Atropine 200 g was given intravenously when the pulse-rate persisted at 68/min and within 3 min the pulserate rose to above 100/min. After half an hour the pupils dilated. Stomach washout produced a large quantity of tablet debris. Over the next 18 h her conscious level fluctuated between arousal with confusion, and depression. During the depressed episodes she would respond only to shouting and an increase in pallor was accompanied by constriction of the pupils, shallow respirations and a sinus bradycardia (lowest rate 68/min). Four further doses of atropine were given intravenously on separate occasions when monitoring revealed a pulse-rate, persisting over 15 min, of 70-80/min. Over the first 8 h the child had four seizures, lasting about 10 s in which her eyes rolled, she became limp, her expression was blank, and there were clonic movements of her jaw. A blood-glucose during one of these fits was normal ; blood-pressure recordings each quarter hour were normal, and there was no hypothermia. The brother had similar but less severe signs of poisoning and had no seizures. The duration of the signs of poisoning was compatible with the 12-18 h halt-life of this drug. Clonidine has complex actions; peripherally it alters responsiveness of arterioles to vasoactive substances and by central action it produces hypotension, bradycardia, and a tall in cardiac output. It also has a chlorpromazine like action with sedation and hypothermia.
SIR,-We have treated
-
Platelet aggregate within vessel lumen after exposure to therapeutic ultrasound.
(About
x
3500)
1267 The 3-year-old patient reported by Pai and Lipsitz’ ingested up to ten times more of the drug. However, neither their patient nor ours became hypotensive. The bradycardia was not symptomatic and may not have required treatment. However,
response to atropine was rapid. Clonidine is being used increasingly in both childhood and adult migraine. It is also used in adults for hypertension and menopausal flushing. Trials of its efficacy in recurrent abdominal-pain syndrome of childhood are under way. However, experience with its use in children is still limited. Our observations indicate that dosages in young children should be careiully evaluated and that vasoconstriction and bradycardia rather than hypotension may be the first signs of overdosage. R. MACFAUL Cambridge Military Hospital, Aldershot, Hants GU11 2AN G. MILLER
Denticator Company, San Francisco) from a large cardboard container. 11 (85%) of 13 children with cyanotic congenital heart-disease spontaneously chose black or purple lollipops, while 24 (73%) of 33 children with either no shunt (8 children) or left-to-right shunt (25 children) chose light-coloured lolliA small number pops (pink, red, orange, or yellow) (p<0001). of children changed their preference from dark to light coloured lollipops after corrective surgery for cyanotic congenital heart-disease. This procedure could be used by primary-care physicians in children old enough to choose a lollipop, thereby avoiding unnecessary referrals to a cardiologist. It might also be used to follow-up patients with tetralogy of Fallot, thereby avoiding multiple cardiac catheterisations which are otherwise necessary to establish the direction of shunting as the disease progresses. This studv
was
suocorted in
Dart
bv the Meridian Natant Societv.
RHESUS-MONKEY PANCREAS FOR MEASURING ISLET-CELL ANTIBODIES
SIR,-Pancreatic islet-cell antibodies (I.C.A.) have been demonstrated in the serum of many patients at the onset of insulin-requiring diabetes mellitus by the technique of indirect immunofluorescence on human pancreas.2 I.C.A. also occur in persons with autoimmune polyendocrine disorders, with or without overt diabetes.3,4 We have been studying the frequency of I.C.A. in our local population of juvenile diabetics, and the relation between I.C.A. and other indices of the disease. Because of difficulties in obtaining fresh human pancreas, we investigated the cross-reactivity of I.C.A. on animal pancreases. Although there are reports2.3 of partial cross-reactivity on rodent pancreas (rat, mouse, guineapig), we have found no published data for other species. We tested 8 sera that were I.C.A. positive on human pancreas, and for rat, mouse, guineapig, sheep, and pig pancreas (serum dilution 1/2) the islets did not fluoresce significantly above background, the fluorescence pattern varying in a manner characteristic for each species. Islets fluoresced brightly on rabbit pancreas for those sera that were I.C.A. positive on human pancreas: however, in a "blind" experiment including i.c.A.-negative sera (10 diabetic, 10 nondiabetic), 70% of these were scored positive at 1/2 and 1/6 dilution of sera. Rhesus-monkey pancreas, however, proved a very convenient alternative to human pancreas. Non-specific background fluorescence was low. All 11 sera which were positive on human pancreas were also positive on monkey pancreas, and with a similar titre. Sera which were negative on human pancreas (15 diabetic, 18 non-diabetic) were also scored negative on monkey pancreas in blind experiments: the islets, although architecturally distinguishable, had only an orange-red autofluorescence. All sera tested (positive and negative) had a similar low fluorescence on monkey liver. Department of Pædiatrics, School of Medicine,
University of Auckland, Auckland 3, New Zealand
Childrens Orthopedic Hospital and Medical Center, and University of Washington, Seattle, Washington 98105, U.S.A.
DARRELL SALK STANLEY STAMM ELLIOT VICHINSKY RONALD LEMIRE MARLENE KROPP
REDUCTION OF SERUM-PROLACTIN AFTER SUBCUTANEOUS SALMON CALCITONIN al.’ have reviewed the many hypothalamic regulate prolactin release. We have found that a non-hypothalamic factor, calcitonin, is associated with striking decreases in circulating prolactin. For reasons discussed elsewhere2we have compared the effects of calcitonin and placebo, on mood, behaviour, and neurochemical findings in nine psychotic inpatients of various ages, sexes, and diagnoses. Synthetic salmon calcitonin and placebo injections of identi-
SIR,-Zacur
et
influences which
1. 2.
Zacur, H. A., Foster, G. V., Tyson, J. E. Lancet, 1976, i, 410. Carman, J. S., Post, R. M., Goodwin, F. K., Bunney, W. E. Biol. Psychiat. 1977, 12, 5.
JEANETTE R. CROSSLEY BETH D. LENDRUM R. B. ELLIOTT
NON-INVASIVE DIAGNOSIS OF CONGENITAL HEART-DISEASE a pilot study of children with congenital heart-dishave explored a non-invasive procedure for verifying the direction of haemodynamic shunting. We could differentiate between cyanotic and acyanotic heart-disease in approximately three-quarters of the children studied. Patients chosen at random from a psediatric cardiology clinic were offered a mixture of coloured lollipops (sugarless,
SIR,-In
ease we
1. Pai, G. S., Lipsitz, D. J. Pediatrics, 1976, 58, 749. 2. Lendrum, R., Walker, G., Gamble, D. R. Lancet, 1975, i, 880. 3. Bottazzo, G. F., Florin-Christensen, A., Doniach, D. ibid. 1974, ii, 1279. 4. MacCuish, A. C., Barnes, E. W., Irvine, W. J., Duncan, L. J. P. ibid. p. 1529.
Decrease in
serum-prolactin in patients given calcitonin.