982
salivary glands work overtime producing drooling and a death rattle dying. The failing heart may become overloaded, redoubling the rattle and causing dyspnoea due to waterlogged lungs. Equally important is the nuisance of needles and tubes that make a cuddle almost impossible. Doctors may be reassured by the use of electrolytes, and such action might impress relatives that something is being done. But rehydration does no good. It is normal, and more comfortable, to die slightly dehydrated. Technological intervention in death is the antithesis of the hospice approach.
on
Hospice of the Marches, Tarrington, Hereford HR1 4HZ, UK
RICHARD LAMERTON
Inhibition of natural anti-inflammatory mechanism by &bgr;2-agonists SiR,—Dr Page’s hypothesis (March 23, p 717) that 0,,-agonists inhibit natural anti-inflammatory mechanisms is flawed. Mast cells release a wide range of pro-inflammatory mediators and their activation leads to immediate hypersensitivity reactions and inflammation in the lung and in the skin. Clinical doses of P,-agonists inhibit both the release of mediators and the consequences of their release in asthmatic patients. Human lung mast cells do synthesise and store heparin proteoglycan, the main purpose being to bind histamine, but less than 10% is released after IgE-mediated activation of mast cells1 (compared with more than 45% of histamine under the same conditions) and the small amount released remains granule-associated.2 The detection of "heparinlike material" in the plasma of allergic patients may therefore reflect release from other cells, such as endothelial cells. Even if heparin can be released in small quantities from mast cells, there is no evidence that such release can be inhibited by &bgr;2-agonists. Page ignores the probable consequences of the release of pro-inflammatory mediators from mast cells and focuses instead on evidence for the anti-inflammatory properties of heparin. Although these properties may be shown with very high concentrations of exogenous heparin, the limited extent of release means that an anti-inflammatory role for endogenous heparin is unlikely. For example, the contribution of heparin to the binding of eosinophil cationic proteins will be trivial compared with that of the vast excess of -macroglobulin3in plasma and bronchoalveolar lavage fluid. Cell damage induced directly by eosinophils or by major basic protein is not inhibited by heparin.4 Furthermore heparin exhibits pro-inflammatory activity, inducing the release of major basic protein from eosinophils, stabilising tryptase, enhancing kinin generation, potentiating IgE synthesis, and acting as a mitogen for
T-lymphocytes. Page’s contention that mast cell degranulation is a natural defence mechanism in asthma, and that to inhibit such a process with P-adrenoceptor agonists will lead to an inflammatory response is also open to question. Catecholamines are released in large amounts during an asthmatic attack, and there is evidence that adrenaline inhibits the release of mast cell mediators through activation of (32-receptors,§ and therefore, according to Page, should exacerbate airways inflammation. Taken to its logical conclusion, a (3-blocker would be expected to be a valuable adjunct to anti-asthma therapy: instead propranolol, which produces bronchoconstriction and increases airway hyperresponsiveness, is contraindicated in asthma. The hypothesis also assumes that mast cells play a key role in asthma. However, our proposal that the long-acting 0-adrenoceptor agonist salmeterol has anti-inflammatory properties is not only based on its ability to inhibit mast cell degranulation.6 Salmeterol limits the extent of eosinophil infiltration and accumulation in the lung in response to platelet-activating factor and antigen,and inhibits increased vascular permeability and plasma protein extravasation.8,9 By comparison, the reported effects of heparin are trivial. In clinical studies salmeterol has been found to inhibit the late response and bronchial hyperreactivity" after antigen challenge, and to reduce amounts of eosinophil cationic protein in bronchoalveolar lavage fluid." The anti-inflammatory profile of salmeterol therefore mimics that claimed by Page for heparin. There is no evidence that regular use of 0,-agonists leads to inflammation in the airways-indeed, one month of treatment with
salmeterol reduces mucosal swelling and airway inflammation in asthmatic patients." The clinical studies cited by Page as showing that P,-agonists are associated with increased risk of asthma death are largely based on experience with fenoterol, the &bgr;2-adrenoceptor, selectivity of which has recently been questioned. As pointed out in a series of letters to this journal (Jan 5, pp 43-46), such findings should therefore not be extrapolated to a class effect of &bgr;2-agonist drugs. Indeed, Grainger et ap2 have reported that the relative risk of asthma death is significantly lower (p < 001) in those asthmatics taking salbutamol. Extensive clinical trials with salmeterol have revealed a progressive improvement in morning and evening peak flow, increase in baseline lung function, and a reduction in nocturnal symptoms. Page’s pharmacological hypothesis is scientifically flawed and until there is better evidence, clinicians should err on the side of caution when interpreting such speculation in the context of treating patients with life-threatening disease.
M. JOHNSON Department of Peripheral Pharmacology, Glaxo Group Research Ltd, Ware SG12 0DP, UK
R. A. COLEMAN S. SANJAR C. J. VARDEY C. J. WHELAN
Department of Respiratory Medicine, Glaxo Group Research Ltd, Greenford
M. M.
JENKINS
RL, Fox CC, Lichtenstein LM, Austen KF. Identification of chondroitin sulfate E proteoglycans and heparin proteoglycans in the secretory granule of human lung mast cells. Proc Natl Acad Sci USA 1988; 85: 2284-87. 2. Yurt RW, Leid RW, Spragg J, Austen KF. Immunologic release of heparin from purified rat peritoneal mast cells. J Immunol 1977; 118: 1201-07. 3. Peterson CGB, Venge P. Interaction and complex formation between the eosinophil cationic protein and &agr;2-macroglobulin. Biochem J 1987; 245: 781-87. 4. Frigas E, Loegering BS, Gleich GJ. Cytotoxic effects of the guinea-pig eosinophil major basic protein on the tracheal epithelium. Lab Invest 1980; 42: 35-43. 5. Butchers PR, Skidmore IF, Vardey CJ, Wheeldon A. Characterisation of the receptor mediating the anti-anaphylactic effects of &bgr;-adrenoceptor agonists in human lung tissue in vitro. Br J Pharmacol 1980; 71: 663-67. 6. Butchers PR, Cousins SA, Vardey CJ. Salmeterol: a potent and long-acting inhibitor of the release of inflammatory and spasmogenic mediators from human lung. Br J Pharmacol 1987; 92: 745P. 7. Whelan CJ, Johnson M. The anti-inflammatory effects of inhaled salmeterol in guinea-pig lung. BrJ Pharmacol 1990; 101: 528P. 8. Johnson M. The pharmacology of salmeterol. Lung 1990; 168: 115-19. 9. Whelan CJ, Johnson M. Salmeterol, but not salbutamol has anti-inflammatory activity in guinea-pig skin. Br J Pharmacol 1991; 102: 95P (abstr). 10. Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST. Protection against allergen-induced asthma by salmeterol. Lancet 1990; 336: 1338-41. 11. Dahl R, Pedersen B. The influence of inhaled salmeterol on bronchial inflammation:a bronchoalveolar lavage study in patients with bronchial asthma. Eur Resp J 1990; 10: S795. 12. Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study. Thorax 1991; 46: 105-11. 1. Stevens
&bgr;2-agonists and
New Zealand asthma
mortality SIR,-Dr Taylor and Professor Sears (Feb 16, p 426) continue to ignore the substantial pharmacological differences between fenoterol and other 0,-agonists and fail to provide appropriate references for their claims to the contrary. For example, we have already drawn their attention to work by Trembath et al,l who showed that regular fenoterol, but not terbutaline, reduced baseline airway calibre in patients with asthma. More importantly, it should be pointed out that their findings mainly relate to the New Zealand cluster of asthma deaths in that they provide one possible mechanism by which fenoterol increases the risk of death. Keating et al2 have shown that the switch to regular use of &bgr;2-agonists aerosols (in general), and the corresponding rise in sales, happened in 1979, whereas the sudden upsurge in deaths in young asthmatics began in 1976. Sears himself, when referring to a possible role of a class-effect of &bgr;2-agonists in the New Zealand deaths, has stated that "the temporal relationship between increased sales and deaths does not suggest a direct causal relationship".’ Thus, although it is possible that regular inhaled &bgr;2-agonist treatment contributes to the gradual increase in asthma morbidity and mortality that has taken place in many countries since the late 1970s, this conclusion
cannot
be drawn from Sears’
study of
983
fenoterol, and this general increase (if it exists) does
not seem to
for the sudden upsurge in asthma deaths in New Zealand that began when fenoterol was introduced in 1976. account
CARL BURGESS
Department of Medicine, Wellington School of Medicine,
JULIAN CRANE NEIL PEARCE RICHARD BEASLEY
PO Box 7343, Wellington, New Zealand
1. Trembath PW, Greenacre JK, Anderson M, et al. Comparison of four weeks’ treatment with fenoterol and terbutaline aerosols in adult asthmatics. J Allergy Clin Immunol 1979; 63: 395-400. 2. Keating G, Mitchell EA, Jackson R, et al. Trends in sales of drugs for asthma in New Zealand, Australia, and the United Kingdom, 1975-81. Br Med J 1984; 289: 348-51. 3. Sears MR, Beaglehole R. Ashtma mortality: a review of recent experience in New Zealand. J Allergy Clin Immunol 1987; 80: 319-25.
Fat embolism after
lipid emulsion infusion
SIR,-Dr Estebe and Dr Malledant (March 16,
p
673) report
postoperative fat embolism (day 20) linked to rapid infusion of 500 H soybean oil lipid solution (’Intralipid’). They do not fully describe the details of their case or explain the reasons for the very high rate of infusion. We would put the case into perspective, in view of current knowledge of the safety and tolerance of intralipid. The recommended rate of infusion is 500 ml intralipid 20% over not less than 5 h, and of intralipid 10% over not less than 3 h. Precautions in the use of intralipid should be taken when fat metabolism may be disturbed, and in renal insufficiency, hepatic insufficiency, uncompensated diabetes, metabolic disorders, and sepsis. In patients with such conditions and in longlasting administration, fat elimination should be checked daily by a simple test. Fat overload can occur within 24 h, the symptoms of which include fever, thrombocytopenia, jaundice, and internal haemorrhage. Estebe and Malledant cite two papers in support of fat embolism complication of lipid emulsion. In one of these Goulon et all referred to an emulsion of cotton seed oil and soybean phospholipids as an emulsifier, but this is not relevant to intralipid, a soybean preparation developed much earlier, with egg-yolk phospholipids as the emulsifying agent. Intralipid was the first non-toxic fat emulsion. In the second report, Horisberger described a 32-year-old woman receiving fat 2-5 g/kg daily. Pulmonary symptoms featured more prominently in this patient, although the concluding statement suggests that the event was "probably provoked by intravascular aggregation of cellular elements rather than by fat embolism". Although precautions in the use of fat emulsions should be borne in mind, over sixty million infusions of intralipid have been given, with a very low rate of adverse events. Intralipid is a valuable source of energy and essential fatty acids in patients needing parenteral nutrition. as a
Kabi Pharmacia,
Knowlhill, Milton Keynes MK5 8PH, UK
M. McCRACKEN
1. Goulon M, Barois A, Grosbuis 2
S, Schortgen G. Embolie Graisseuse après perfusions répétées d’émulsions lipidiques. Nouv Presse Méd 1974; 3: 13-18. Honsberger B. Schwere pulmonale and cerebrale Zirkulationsstorungen nach hoch dosierter parenteraler Zufuhr einer Fettemulsion. Ein Fall einer aussegewohnlichen terapeutischen Komplikation. Schweiz Med Wschr 1966; 96: 1065-69.
three women in whom DES exposure probably caused hyperprolactinaemia after birth. In the first patient menarche was followed by irregular menses. At age 20 she had a clear-cell carcinoma of the vagina and secondary amenorrhoea and hyperprolactinaemia (prolacnn [PRL] 1200 mU/1; normal < 300). She was also mentally retarded and grossly obese. The second patient was oligophrenic. Epilepsy developed coincidentally with menarche. At age 21 she had hyperprolactinaemia (PRL 50 µg/1; normal 22) with galactorrhoea. On computed tomographic (CT) scanning the sella was slightly enlarged and partly empty. The third patient had secondary amenorrhoea, galactorrhoea, and hyperprolactinaemia (PRL 500 µg/1) after withdrawal from 10 years’ use of oral contraceptives. On CT scan the sella was enlarged and the floor eroded. Pregnancy was induced by bromocriptine. During pregnancy PRL concentrations were twice as high as is normal in pregnancy. Toxaemia developed and she gave birth by caesarean section to a son with a large omphalocele. Although three patients do not prove causality I propose that exposure to DES may lead to a disturbance of PRL secretion. In the three patients, hyperprolactinaemia was identified on the basis of lactotroph hyperplasia and/or (micro) prolactinoma. My observations also suggest that DES exposure may impair brain development. I believe that endocrine and neurological investigation of DES-exposed offspring is warranted.
prenatal
Departments of Endocrinology and Academic Medical Centre, 1105 AZ Amsterdam, Netherlands
Psychiatry,
J. ASSIES
1. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med
1971, 284: 878-81. 2. Vessey MP, Fairweather DVI, Norman-Smith B, Buckley J. A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers and their offspring. Br J Obstet Gynecol 1983; 90: 1007-17. 3. Wu CH, Mangan CE, Burtnett M, Mikhail G. Plasma hormones in DES-exposed females. Obstet Gynecol 1980; 55: 157-62. 4. Menczer J, Dilitzky M, Ben-Baruch G, Modan M. Primary infertility in women exposed to diethylstilboestrol in utero. BrJ Obstet Gynecol 1986; 93: 503-07. 5. Ehrhardt AA, Meyer-Bahlburg HFL, Rosen LR, et al. The development of gender-related behaviour in females following prenatal exposure to diethylstilbestrol (DES). Hormones Behav 1989; 23: 526-41.
Epidemic tuberculosis in north Lebanon SIR,- The long civil war in Lebanon has caused poverty and severely disrupted health services. Evidence now suggests these conditions have led to an epidemic of tuberculosis.l Between 1980 and 1984 skin-test surveys of children in the districts of Akkar and Zgharta2,3pointed to a low exposure both to tubercle bacilli and to other environmental mycobacteria, and clinical accounts indicated only isolated instances of the disease.’ A chest clinic in Tripoli, reporting 25-35 cases per year in the early 1980s, records 325 cases in 1989, and over 400 in 1990 (figure). About 80% of cases are among adults and 20% among children. Drugs are scarce, most patients remain untreated, and very few children have received BCG vaccination. In October, 1990, a survey of 432 schoolchildren was done in some villages of Akkar that were studied earlier. There have been significant increases in tuberculin positivity rates:
Hyperprolactinaemia in diethylstilboestrol-exposed women SIR,- The
use
of the
synthetic oestrogen diethylstilboestrol
(DES) in women during pregnancy has been associated with cancer and developmental abnormalities in the lower urogenital tract in behaviour and even cause psychiatric disease (depression, anxiety).2,3 Although the frequency of menstrual irregularity and primary infertility among DES-exposed women is significantly higher than in the general population, surprisingly little systemic
There was no evidence of an increase in tuberculin positivity over the years of the earlier study, so the change has happened since 1984. There is a pressing need for a BCG vaccination programme for all children in the region. The development of an infrastructure to report cases of tuberculosis, to make short-course chemotherapy available, and to provide follow-up is also a priority. Security difficulties continue to restrict the work of government and non-government organisations in developing basic primary health
evaluation of their endocrine system has been done.4,5 I report
care.
their female and male offspring.’ Early exposure of the fetus to oestrogen can also determine subsequent temperament and
salivary glands work overtime producing drooling and a death rattle dying. The failing heart may become overloaded, redoubling the rattle and causing dyspnoea due to waterlogged lungs. Equally important is the nuisance of needles and tubes that make a cuddle almost impossible. Doctors may be reassured by the use of electrolytes, and such action might impress relatives that something is being done. But rehydration does no good. It is normal, and more comfortable, to die slightly dehydrated. Technological intervention in death is the antithesis of the hospice approach.
on
Hospice of the Marches, Tarrington, Hereford HR1 4HZ, UK
RICHARD LAMERTON
Inhibition of natural anti-inflammatory mechanism by &bgr;2-agonists SiR,—Dr Page’s hypothesis (March 23, p 717) that 0,,-agonists inhibit natural anti-inflammatory mechanisms is flawed. Mast cells release a wide range of pro-inflammatory mediators and their activation leads to immediate hypersensitivity reactions and inflammation in the lung and in the skin. Clinical doses of P,-agonists inhibit both the release of mediators and the consequences of their release in asthmatic patients. Human lung mast cells do synthesise and store heparin proteoglycan, the main purpose being to bind histamine, but less than 10% is released after IgE-mediated activation of mast cells1 (compared with more than 45% of histamine under the same conditions) and the small amount released remains granule-associated.2 The detection of "heparinlike material" in the plasma of allergic patients may therefore reflect release from other cells, such as endothelial cells. Even if heparin can be released in small quantities from mast cells, there is no evidence that such release can be inhibited by &bgr;2-agonists. Page ignores the probable consequences of the release of pro-inflammatory mediators from mast cells and focuses instead on evidence for the anti-inflammatory properties of heparin. Although these properties may be shown with very high concentrations of exogenous heparin, the limited extent of release means that an anti-inflammatory role for endogenous heparin is unlikely. For example, the contribution of heparin to the binding of eosinophil cationic proteins will be trivial compared with that of the vast excess of -macroglobulin3in plasma and bronchoalveolar lavage fluid. Cell damage induced directly by eosinophils or by major basic protein is not inhibited by heparin.4 Furthermore heparin exhibits pro-inflammatory activity, inducing the release of major basic protein from eosinophils, stabilising tryptase, enhancing kinin generation, potentiating IgE synthesis, and acting as a mitogen for
T-lymphocytes. Page’s contention that mast cell degranulation is a natural defence mechanism in asthma, and that to inhibit such a process with P-adrenoceptor agonists will lead to an inflammatory response is also open to question. Catecholamines are released in large amounts during an asthmatic attack, and there is evidence that adrenaline inhibits the release of mast cell mediators through activation of (32-receptors,§ and therefore, according to Page, should exacerbate airways inflammation. Taken to its logical conclusion, a (3-blocker would be expected to be a valuable adjunct to anti-asthma therapy: instead propranolol, which produces bronchoconstriction and increases airway hyperresponsiveness, is contraindicated in asthma. The hypothesis also assumes that mast cells play a key role in asthma. However, our proposal that the long-acting 0-adrenoceptor agonist salmeterol has anti-inflammatory properties is not only based on its ability to inhibit mast cell degranulation.6 Salmeterol limits the extent of eosinophil infiltration and accumulation in the lung in response to platelet-activating factor and antigen,and inhibits increased vascular permeability and plasma protein extravasation.8,9 By comparison, the reported effects of heparin are trivial. In clinical studies salmeterol has been found to inhibit the late response and bronchial hyperreactivity" after antigen challenge, and to reduce amounts of eosinophil cationic protein in bronchoalveolar lavage fluid." The anti-inflammatory profile of salmeterol therefore mimics that claimed by Page for heparin. There is no evidence that regular use of 0,-agonists leads to inflammation in the airways-indeed, one month of treatment with
salmeterol reduces mucosal swelling and airway inflammation in asthmatic patients." The clinical studies cited by Page as showing that P,-agonists are associated with increased risk of asthma death are largely based on experience with fenoterol, the &bgr;2-adrenoceptor, selectivity of which has recently been questioned. As pointed out in a series of letters to this journal (Jan 5, pp 43-46), such findings should therefore not be extrapolated to a class effect of &bgr;2-agonist drugs. Indeed, Grainger et ap2 have reported that the relative risk of asthma death is significantly lower (p < 001) in those asthmatics taking salbutamol. Extensive clinical trials with salmeterol have revealed a progressive improvement in morning and evening peak flow, increase in baseline lung function, and a reduction in nocturnal symptoms. Page’s pharmacological hypothesis is scientifically flawed and until there is better evidence, clinicians should err on the side of caution when interpreting such speculation in the context of treating patients with life-threatening disease.
M. JOHNSON Department of Peripheral Pharmacology, Glaxo Group Research Ltd, Ware SG12 0DP, UK
R. A. COLEMAN S. SANJAR C. J. VARDEY C. J. WHELAN
Department of Respiratory Medicine, Glaxo Group Research Ltd, Greenford
M. M.
JENKINS
RL, Fox CC, Lichtenstein LM, Austen KF. Identification of chondroitin sulfate E proteoglycans and heparin proteoglycans in the secretory granule of human lung mast cells. Proc Natl Acad Sci USA 1988; 85: 2284-87. 2. Yurt RW, Leid RW, Spragg J, Austen KF. Immunologic release of heparin from purified rat peritoneal mast cells. J Immunol 1977; 118: 1201-07. 3. Peterson CGB, Venge P. Interaction and complex formation between the eosinophil cationic protein and &agr;2-macroglobulin. Biochem J 1987; 245: 781-87. 4. Frigas E, Loegering BS, Gleich GJ. Cytotoxic effects of the guinea-pig eosinophil major basic protein on the tracheal epithelium. Lab Invest 1980; 42: 35-43. 5. Butchers PR, Skidmore IF, Vardey CJ, Wheeldon A. Characterisation of the receptor mediating the anti-anaphylactic effects of &bgr;-adrenoceptor agonists in human lung tissue in vitro. Br J Pharmacol 1980; 71: 663-67. 6. Butchers PR, Cousins SA, Vardey CJ. Salmeterol: a potent and long-acting inhibitor of the release of inflammatory and spasmogenic mediators from human lung. Br J Pharmacol 1987; 92: 745P. 7. Whelan CJ, Johnson M. The anti-inflammatory effects of inhaled salmeterol in guinea-pig lung. BrJ Pharmacol 1990; 101: 528P. 8. Johnson M. The pharmacology of salmeterol. Lung 1990; 168: 115-19. 9. Whelan CJ, Johnson M. Salmeterol, but not salbutamol has anti-inflammatory activity in guinea-pig skin. Br J Pharmacol 1991; 102: 95P (abstr). 10. Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST. Protection against allergen-induced asthma by salmeterol. Lancet 1990; 336: 1338-41. 11. Dahl R, Pedersen B. The influence of inhaled salmeterol on bronchial inflammation:a bronchoalveolar lavage study in patients with bronchial asthma. Eur Resp J 1990; 10: S795. 12. Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study. Thorax 1991; 46: 105-11. 1. Stevens
&bgr;2-agonists and
New Zealand asthma
mortality SIR,-Dr Taylor and Professor Sears (Feb 16, p 426) continue to ignore the substantial pharmacological differences between fenoterol and other 0,-agonists and fail to provide appropriate references for their claims to the contrary. For example, we have already drawn their attention to work by Trembath et al,l who showed that regular fenoterol, but not terbutaline, reduced baseline airway calibre in patients with asthma. More importantly, it should be pointed out that their findings mainly relate to the New Zealand cluster of asthma deaths in that they provide one possible mechanism by which fenoterol increases the risk of death. Keating et al2 have shown that the switch to regular use of &bgr;2-agonists aerosols (in general), and the corresponding rise in sales, happened in 1979, whereas the sudden upsurge in deaths in young asthmatics began in 1976. Sears himself, when referring to a possible role of a class-effect of &bgr;2-agonists in the New Zealand deaths, has stated that "the temporal relationship between increased sales and deaths does not suggest a direct causal relationship".’ Thus, although it is possible that regular inhaled &bgr;2-agonist treatment contributes to the gradual increase in asthma morbidity and mortality that has taken place in many countries since the late 1970s, this conclusion
cannot
be drawn from Sears’
study of
983
fenoterol, and this general increase (if it exists) does
not seem to
for the sudden upsurge in asthma deaths in New Zealand that began when fenoterol was introduced in 1976. account
CARL BURGESS
Department of Medicine, Wellington School of Medicine,
JULIAN CRANE NEIL PEARCE RICHARD BEASLEY
PO Box 7343, Wellington, New Zealand
1. Trembath PW, Greenacre JK, Anderson M, et al. Comparison of four weeks’ treatment with fenoterol and terbutaline aerosols in adult asthmatics. J Allergy Clin Immunol 1979; 63: 395-400. 2. Keating G, Mitchell EA, Jackson R, et al. Trends in sales of drugs for asthma in New Zealand, Australia, and the United Kingdom, 1975-81. Br Med J 1984; 289: 348-51. 3. Sears MR, Beaglehole R. Ashtma mortality: a review of recent experience in New Zealand. J Allergy Clin Immunol 1987; 80: 319-25.
Fat embolism after
lipid emulsion infusion
SIR,-Dr Estebe and Dr Malledant (March 16,
p
673) report
postoperative fat embolism (day 20) linked to rapid infusion of 500 H soybean oil lipid solution (’Intralipid’). They do not fully describe the details of their case or explain the reasons for the very high rate of infusion. We would put the case into perspective, in view of current knowledge of the safety and tolerance of intralipid. The recommended rate of infusion is 500 ml intralipid 20% over not less than 5 h, and of intralipid 10% over not less than 3 h. Precautions in the use of intralipid should be taken when fat metabolism may be disturbed, and in renal insufficiency, hepatic insufficiency, uncompensated diabetes, metabolic disorders, and sepsis. In patients with such conditions and in longlasting administration, fat elimination should be checked daily by a simple test. Fat overload can occur within 24 h, the symptoms of which include fever, thrombocytopenia, jaundice, and internal haemorrhage. Estebe and Malledant cite two papers in support of fat embolism complication of lipid emulsion. In one of these Goulon et all referred to an emulsion of cotton seed oil and soybean phospholipids as an emulsifier, but this is not relevant to intralipid, a soybean preparation developed much earlier, with egg-yolk phospholipids as the emulsifying agent. Intralipid was the first non-toxic fat emulsion. In the second report, Horisberger described a 32-year-old woman receiving fat 2-5 g/kg daily. Pulmonary symptoms featured more prominently in this patient, although the concluding statement suggests that the event was "probably provoked by intravascular aggregation of cellular elements rather than by fat embolism". Although precautions in the use of fat emulsions should be borne in mind, over sixty million infusions of intralipid have been given, with a very low rate of adverse events. Intralipid is a valuable source of energy and essential fatty acids in patients needing parenteral nutrition. as a
Kabi Pharmacia,
Knowlhill, Milton Keynes MK5 8PH, UK
M. McCRACKEN
1. Goulon M, Barois A, Grosbuis 2
S, Schortgen G. Embolie Graisseuse après perfusions répétées d’émulsions lipidiques. Nouv Presse Méd 1974; 3: 13-18. Honsberger B. Schwere pulmonale and cerebrale Zirkulationsstorungen nach hoch dosierter parenteraler Zufuhr einer Fettemulsion. Ein Fall einer aussegewohnlichen terapeutischen Komplikation. Schweiz Med Wschr 1966; 96: 1065-69.
three women in whom DES exposure probably caused hyperprolactinaemia after birth. In the first patient menarche was followed by irregular menses. At age 20 she had a clear-cell carcinoma of the vagina and secondary amenorrhoea and hyperprolactinaemia (prolacnn [PRL] 1200 mU/1; normal < 300). She was also mentally retarded and grossly obese. The second patient was oligophrenic. Epilepsy developed coincidentally with menarche. At age 21 she had hyperprolactinaemia (PRL 50 µg/1; normal 22) with galactorrhoea. On computed tomographic (CT) scanning the sella was slightly enlarged and partly empty. The third patient had secondary amenorrhoea, galactorrhoea, and hyperprolactinaemia (PRL 500 µg/1) after withdrawal from 10 years’ use of oral contraceptives. On CT scan the sella was enlarged and the floor eroded. Pregnancy was induced by bromocriptine. During pregnancy PRL concentrations were twice as high as is normal in pregnancy. Toxaemia developed and she gave birth by caesarean section to a son with a large omphalocele. Although three patients do not prove causality I propose that exposure to DES may lead to a disturbance of PRL secretion. In the three patients, hyperprolactinaemia was identified on the basis of lactotroph hyperplasia and/or (micro) prolactinoma. My observations also suggest that DES exposure may impair brain development. I believe that endocrine and neurological investigation of DES-exposed offspring is warranted.
prenatal
Departments of Endocrinology and Academic Medical Centre, 1105 AZ Amsterdam, Netherlands
Psychiatry,
J. ASSIES
1. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med
1971, 284: 878-81. 2. Vessey MP, Fairweather DVI, Norman-Smith B, Buckley J. A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers and their offspring. Br J Obstet Gynecol 1983; 90: 1007-17. 3. Wu CH, Mangan CE, Burtnett M, Mikhail G. Plasma hormones in DES-exposed females. Obstet Gynecol 1980; 55: 157-62. 4. Menczer J, Dilitzky M, Ben-Baruch G, Modan M. Primary infertility in women exposed to diethylstilboestrol in utero. BrJ Obstet Gynecol 1986; 93: 503-07. 5. Ehrhardt AA, Meyer-Bahlburg HFL, Rosen LR, et al. The development of gender-related behaviour in females following prenatal exposure to diethylstilbestrol (DES). Hormones Behav 1989; 23: 526-41.
Epidemic tuberculosis in north Lebanon SIR,- The long civil war in Lebanon has caused poverty and severely disrupted health services. Evidence now suggests these conditions have led to an epidemic of tuberculosis.l Between 1980 and 1984 skin-test surveys of children in the districts of Akkar and Zgharta2,3pointed to a low exposure both to tubercle bacilli and to other environmental mycobacteria, and clinical accounts indicated only isolated instances of the disease.’ A chest clinic in Tripoli, reporting 25-35 cases per year in the early 1980s, records 325 cases in 1989, and over 400 in 1990 (figure). About 80% of cases are among adults and 20% among children. Drugs are scarce, most patients remain untreated, and very few children have received BCG vaccination. In October, 1990, a survey of 432 schoolchildren was done in some villages of Akkar that were studied earlier. There have been significant increases in tuberculin positivity rates:
Hyperprolactinaemia in diethylstilboestrol-exposed women SIR,- The
use
of the
synthetic oestrogen diethylstilboestrol
(DES) in women during pregnancy has been associated with cancer and developmental abnormalities in the lower urogenital tract in behaviour and even cause psychiatric disease (depression, anxiety).2,3 Although the frequency of menstrual irregularity and primary infertility among DES-exposed women is significantly higher than in the general population, surprisingly little systemic
There was no evidence of an increase in tuberculin positivity over the years of the earlier study, so the change has happened since 1984. There is a pressing need for a BCG vaccination programme for all children in the region. The development of an infrastructure to report cases of tuberculosis, to make short-course chemotherapy available, and to provide follow-up is also a priority. Security difficulties continue to restrict the work of government and non-government organisations in developing basic primary health
evaluation of their endocrine system has been done.4,5 I report
care.
their female and male offspring.’ Early exposure of the fetus to oestrogen can also determine subsequent temperament and
