- Email: [email protected]
Neonatal purpura fulminans associated with homozygous protein S deficiency
61
Benzodiazepine withdrawal
Respondents were asked, recognising there are not enough organs to go around and that difficult choices must be made in deciding who will get them, how strongly they agreed or conscious.
SIR,- The objections raised by Mr Elcock (Dec 9, p 1402) to Dr Clark’s method of benzodiazepine withdrawal are met by formulation of the drug in a freely mobile preserved base. The patient is issued with two clearly labelled bottles-one containing the drug and the other a preserved diluent. Such a system has been validated for stability beyond 90 days. The bottles are labelled and an accompanying information sheet gives the calculated drug concentration. My company offers a free service to clinicians for checking the amount of active drug in any doubtful cases. The withdrawal pack is available under the special dispensing provisions on FP10 prescriptions in the normal way (two
disagreed with the statements shown in the table: PUBLIC OPINION ON SELECTION OF TRANSPLANT RECIPIENTS
charges being levied). Patient involvement in dose adjustment may be judged a positive aspect of withdrawal therapy, and therefore such participation under clearly defined circumstances should be encouraged. Penn Pharmaceuticals,
Penn, High Wycombe HP10 8LN, UK
Drug economics
in
R. S.
JONES
developing countries
SIR,-Dr Lexchin (Sept 16, p 678) claims that our method of determining drug prices in developing countries contains the "fatal flaw" of reliance on the provision of non-essential drugs to achieve cost recovery. In fact, our method does not depend solely on non-essential drugs to recover costs but uses the twin factors of drug cost and necessity to direct cross-subsidisation. To ensure that all drugs are affordable, the price of expensive medications is lowered below cost, while the prices of less expensive ones are raised. And, to encourage appropriate drug use, we lower the price of essential drugs and raise the price of those less essential. Although Lexchin rightly notes that our Indonesian simulation did subsidise essential drugs through mark-ups on non-essential drugs (which are widely consumed in the country), the method does not depend on this subsidy; if drugs were not cross-subsidised on the basis of necessity, the model is designed to allow cost recovery by reliance on the cost factor alone. It is important to keep the basic concept in mind: in any health care environment some drugs are more costly and/or more essential from a public health perspective than are others. Our analysis and experience from several countries suggest that substantial cost can be achieved while preserving public health objectives by subsidy of the most costly and highly essential drugs through larger margins on less costly, less essential drugs. University College Annex, Oxford 0X2 6XL, UK
JENNIE I. LITVACK DONALD S. SHEPARD JONATHAN D. QUICK
Misuse of an organ SIR,-Your note on liver transplantation in alcoholics (Nov 11, p 1170) makes several points: (1) liver transplantation in alcoholics can be accomplished successfully; (2) the threat of death seems sufficient to "sober" alcoholics; (3) the availability of donor livers in the UK is not a difficulty; and (4) if there was a shortage in supply "... any priority given to people with what could be seen as a self-inflicted disease is likely to spark fierce public debate". On the basis of public opinion poll data we have collected in the US, we believe that your fourth point is debatable.1-3 In the US donor livers are scarce. The number of people on the United Network for Organ Sharing (UNOS) waiting list increased from 453 in June, 1988, to 761 in September, 1989. In 1988 there were 1680 liver transplants done. Even so most patients with end-stage liver disease will die awaiting a transplant. In January, 1987, in cooperation with the Gallup Organisation, conducted a nationally representative public opinion poll for UNOS about organ donation, procurement, and distribution. We found little evidence that people would strongly object to the transplantation of individuals who are not especially health we
Clearly, although the public seems inclined to distinguish among people by their personal characteristics or lifestyle, there is little evidence of consensus exclusion of anyone who, it could be argued, has directly contributed to his own demise. We conclude that, in the absence of data, it is inappropriate to talk about public opinion based on personal beliefs and prejudices, even when these are well intended. Health and Population Research Center, Battelle Human Affairs Research Center, Seattle, Washington 98103, USA
ROGER W. EVANS DIANE L. MANNINEN
1. Evans RW, Manninen DL. US public opinion concerning the procurement and distribution of donor organs. Transplant Proc 1988; 20: 781-85. 2. Evans RW. Public perception and the realities of organ transplantation. Michigan Hosp
1987; 23: 13-18. 3. Evans RW, Manninen DL. Public opinion concerning organ donation, procurement, and distribution: results of a national probability sample survey. Seattle, WA: Battelle Human Affairs Research Centers, 1988.
Neonatal purpura fulminans associated with homozygous protein S deficiency SIR,-Neonatal purpura fulminans is known to be associated with
homozygous protein C (PC) deficiency" but has not been seen with severe protein S (PS) deficiency. A Thai baby girl who was small for gestational age at birth presented at age 10 days with progressive purpura and necrotic skin lesions of the left thigh, lower abdomen, and scalp. Partial response to whole blood transfusion, antibiotics, and heparinisation was seen. The family history was negative for thrombosis. At age 3 months, she was referred to Siriraj Hospital, Bangkok, and had dark blue necrotic skin lesions on top of the old scar at thigh, abdomen, and scalp. Routine haematological investigation showed evidence of disseminated intravascular coagulation (DIC). The daily dose of cryoprecipitate transfusion resulted in a striking response with healing of the necrotic skin lesions. During admission, she proved to have endophthalmitis and was blind. These changes were suggestive of retinal vessel thrombosis in utero. Tests for intrauterine infection were negative. A search for the cause of the thrombosis was done during her full recovery at 6 and 7 months old, after withholding of cryoprecipitate for 72 hours. 7,8 Blood samples from the patient and her parents were sent to the University of Colorado School of Medicine for measurement of natural protease inhibitors (table). At age 3, 6, and 7 months PS (both total and free form) was not detectable, despite normal C4b binding protein. The parent’s plasma had moderately low PS concentrations and normal PC. The low PC concentrations in the infant at 3 and 7 months were attributable to DIC. When she was in full recovery at 6 months, PC was normal. Antithrombin III and plasminogen concentrations were also normal. On the basis of these results, homozygous PS
62
BLOOD PROTEIN CAND PROTEIN S MEASUREMENTS IN INFANT AND PARENTS
have led
to self-immunisation, accounting for the raised LPS antibody concentrations. Part of the benefit of severe physical training might therefore be
the induction of LPS antibodies which could reduce any endotoxaemia caused by physical heat stress, as you suggest. It remains to be seen whether the "doping" of an athlete with parenteral administration of anti-LPS IgG leads to his improved performance in a medium to long-distance race or in a soccer game on a warm day. If so, miners, pilots, soldiers, and possibly racehorses, might also benefit. -Normai
range (/m!)
in aamts snown m
parentneses
deficiency diagnosed. The thrombosis can be controlled by oral warfarin and cyroprecipitate transfusion every other day. daily To our knowledge this report is the first of homozygous PS deficiency associated with neonatal purpura fulminans. The treatment seems to be life-long replacement therapy, and fresh frozen plasma is planned to replace cryoprecipitate when the patient grows older. PS concentrate, the ideal treatment for this baby, is not yet available in Thailand. was
Department of Paediatrics, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA
CHULARATANA MAHASANDANA VINAI SUVATTE RICHARD A. MARLAR MARILYN J. MANCO-JOHNSON LINDA J. JACOBSON WILLIAM E. HATHAWAY
HE, Katz J, Marble R, Griffin JH. Inherited protein C deficiency and coumarin responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; ii: 1165-68. 2. Seligsohn U, Berger A, Abend M, et al. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med 1984; 310: 559-62. 3. Marciniak E, Wilson HD, Marlar RA. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood 1985; 65: 15-20. 4. Yuen P, Cheung A, Lin HJ, et al. Purpura fulminans in a Chinese boy with congenital protein C deficiency. Pediatrics 1986; 77: 670-76. 5. Manco-Johnson MJ, Marlar RA, Jacobson LJ, Hays T, Warady BA. Severe protein C deficiency in newborn infants. J Pediatr 1988; 113: 359-63. 6. Marlar RA, Montgomery RR, Broekmans AW. Diagnosis and treatment of homozygous protein C deficiency. J Pediatr 1989; 114: 528-34. 7 Comp PC, Nixon RR, Cooper R, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-88. 8. Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504. 1. Branson
Endotoxins in heatstroke SIR,-Indirect evidence supports your suggestion (Nov 4, p 1137) that inducing high levels of antibodies to lipopolysaccharide (LPS) is beneficial in the treatment of heat stress. 81 % of competitors in an ultramarathon (89-5 km) who collapsed along the way or were carried to the medical tent at the finishing line, had raised plasma LPS concentrations (including two in the reported lethal range). They also had high indices of nausea/vomiting/diarrhoeasymptoms produced by LPS-and they needed hours to days to recover. The remaining 19% with LPS in the normal range had far fewer and less severe episodes of nausea, vomiting, and diarrhoea, and they recovered within minutes to an hour or two. Those with low concentrations of plasma LPS had high levels of "natural" LPS IgG antibodies and vice versa. In the group of runners who managed to finish the race before collapsing, those with the lowest LPS and highest anti-LPS IgG concentrations performed betterie, they finished sooner. Racehorses, too, showed rises in LPS at the end of a stakes race .2 In a triathlon, athletes who trained the hardest (most miles jogged, bicycled, or swum) during the two weeks before the contest had the highest levels of natural anti-LPS IgG at the start of the race and lowest LPS concentrations at the end.3 Prolonged severe exercise may lead to periods of hypoxia, intestinal ischaemia, and raised body temperature. Short periods of expeirmental hypoxia,4 intestinal ischaemia,s or body temperature of 41-42°C6 led to the entry of large quantities of LPS into the circulation. This LPS may
Department of Physiology, University of Natal Medical School, Durban, South Africa
STEPHEN L. GAFFIN
JG, Gaffin SL, Wells MT, et al. Endotoxaemia in exhausted runners following a long distance race. S Afr Med J 1988; 73: 533-36. 2. Baker B, Gaffin SL, Wells MT, Brock-Utne JG. Endotoxaemia in race horses following exertion. J S Afr Vet Assoc 1988; 59: 63-66. 3. Bosenberg AT, Brock-Utne JG, Wells MTB, et al. Strenuous exercise causes systematic endotoxaemia. J Appl Physiol 1988; 65: 106-08. 4. Gaffin SL, Brock-Utne JG, Zanotti A, Wells MTB. Hypoxia induced endotoxemia in primates. Aviat Space Environ Med 1986; 57: 1044-49. 5. Gathiram P, Wells MT, Raidoo D, et al. Changes in plasma lipopolysaccharide concentrations in portal venous and systemic arterial blood during intestinal ischemia in primates. Circ Shock 1989; 27: 103-09. 6. Gathiram P, Wells MT, Raidoo D, et al. Portal and systemic plasma lipopolysaccharide concentrations in heat-stressed primates. Circ Shock 1988; 25: 1. Brock-Utne
223-30.
Human insulin and
hypoglycaemia
SIR,-Dr Egger and Dr Teuscher (Nov 25, p 1268) report that the introduction of human insulin in the Canton of Berne, Switzerland, caused a huge increase in admissions for severe hypoglycaemia to eight public hospitals during 1984-87. They attributed these cases of hypoglycaemia to a reduced awareness of hypoglycaemia, which may be partly caused by differences in counterregulatory responses to human and porcine insulin.1 The rise in the number of admissions seems to correlate quite well with the introduction of human insulin, but may also have been caused by other factors such as lowering of the mean HbA, value in the Canton of Berne in the pursuit of normoglycaemia, which may itself be responsible for the lowering of hypoglycaemia awareness2 In the Netherlands no rise in the number of admissions for severe hypoglycaemia has been reported. On the contrary, the information centre on hospital admissions recorded a decrease in the number of admissions for severe hypoglycaemia during 1983-88, the period when the market share of human insulin increased from 4-1% to 82.1%
These data conflict with those of Egger and Teuscher. The main reason for this discrepancy might be the fact that our data are less likely than theirs to be affected by factors such as changes in blood glucose control since they are derived from data for the whole country, including university centres and non-specialist clinics. Although there may be a difference in the effects of human porcine insulin on the counterregulatory response to hypoglycaemia, there is still no evidence for a causal relation between the use of human insulin and the risk of severe
hypoglycaemia. Polyclinic Inwendige Geneeskunde, Academisch Ziekenhuis, Free University, 1081 HV Amsterdam, Netherlands 1. Heine RJ, Van der Heyden
R. J. HEINE E. A.
VAN DER
VEEN
EAP, Van der Veen EA. Responses to human and porcine insulin in healthy subjects. Lancet 1989; ii: 946-48. 2. Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effects of intensive insulin therapy on glycaemic thresholds for counterregulatory hormone release. Diabetes 1988; 37: 901-07.
Benzodiazepine withdrawal
Respondents were asked, recognising there are not enough organs to go around and that difficult choices must be made in deciding who will get them, how strongly they agreed or conscious.
SIR,- The objections raised by Mr Elcock (Dec 9, p 1402) to Dr Clark’s method of benzodiazepine withdrawal are met by formulation of the drug in a freely mobile preserved base. The patient is issued with two clearly labelled bottles-one containing the drug and the other a preserved diluent. Such a system has been validated for stability beyond 90 days. The bottles are labelled and an accompanying information sheet gives the calculated drug concentration. My company offers a free service to clinicians for checking the amount of active drug in any doubtful cases. The withdrawal pack is available under the special dispensing provisions on FP10 prescriptions in the normal way (two
disagreed with the statements shown in the table: PUBLIC OPINION ON SELECTION OF TRANSPLANT RECIPIENTS
charges being levied). Patient involvement in dose adjustment may be judged a positive aspect of withdrawal therapy, and therefore such participation under clearly defined circumstances should be encouraged. Penn Pharmaceuticals,
Penn, High Wycombe HP10 8LN, UK
Drug economics
in
R. S.
JONES
developing countries
SIR,-Dr Lexchin (Sept 16, p 678) claims that our method of determining drug prices in developing countries contains the "fatal flaw" of reliance on the provision of non-essential drugs to achieve cost recovery. In fact, our method does not depend solely on non-essential drugs to recover costs but uses the twin factors of drug cost and necessity to direct cross-subsidisation. To ensure that all drugs are affordable, the price of expensive medications is lowered below cost, while the prices of less expensive ones are raised. And, to encourage appropriate drug use, we lower the price of essential drugs and raise the price of those less essential. Although Lexchin rightly notes that our Indonesian simulation did subsidise essential drugs through mark-ups on non-essential drugs (which are widely consumed in the country), the method does not depend on this subsidy; if drugs were not cross-subsidised on the basis of necessity, the model is designed to allow cost recovery by reliance on the cost factor alone. It is important to keep the basic concept in mind: in any health care environment some drugs are more costly and/or more essential from a public health perspective than are others. Our analysis and experience from several countries suggest that substantial cost can be achieved while preserving public health objectives by subsidy of the most costly and highly essential drugs through larger margins on less costly, less essential drugs. University College Annex, Oxford 0X2 6XL, UK
JENNIE I. LITVACK DONALD S. SHEPARD JONATHAN D. QUICK
Misuse of an organ SIR,-Your note on liver transplantation in alcoholics (Nov 11, p 1170) makes several points: (1) liver transplantation in alcoholics can be accomplished successfully; (2) the threat of death seems sufficient to "sober" alcoholics; (3) the availability of donor livers in the UK is not a difficulty; and (4) if there was a shortage in supply "... any priority given to people with what could be seen as a self-inflicted disease is likely to spark fierce public debate". On the basis of public opinion poll data we have collected in the US, we believe that your fourth point is debatable.1-3 In the US donor livers are scarce. The number of people on the United Network for Organ Sharing (UNOS) waiting list increased from 453 in June, 1988, to 761 in September, 1989. In 1988 there were 1680 liver transplants done. Even so most patients with end-stage liver disease will die awaiting a transplant. In January, 1987, in cooperation with the Gallup Organisation, conducted a nationally representative public opinion poll for UNOS about organ donation, procurement, and distribution. We found little evidence that people would strongly object to the transplantation of individuals who are not especially health we
Clearly, although the public seems inclined to distinguish among people by their personal characteristics or lifestyle, there is little evidence of consensus exclusion of anyone who, it could be argued, has directly contributed to his own demise. We conclude that, in the absence of data, it is inappropriate to talk about public opinion based on personal beliefs and prejudices, even when these are well intended. Health and Population Research Center, Battelle Human Affairs Research Center, Seattle, Washington 98103, USA
ROGER W. EVANS DIANE L. MANNINEN
1. Evans RW, Manninen DL. US public opinion concerning the procurement and distribution of donor organs. Transplant Proc 1988; 20: 781-85. 2. Evans RW. Public perception and the realities of organ transplantation. Michigan Hosp
1987; 23: 13-18. 3. Evans RW, Manninen DL. Public opinion concerning organ donation, procurement, and distribution: results of a national probability sample survey. Seattle, WA: Battelle Human Affairs Research Centers, 1988.
Neonatal purpura fulminans associated with homozygous protein S deficiency SIR,-Neonatal purpura fulminans is known to be associated with
homozygous protein C (PC) deficiency" but has not been seen with severe protein S (PS) deficiency. A Thai baby girl who was small for gestational age at birth presented at age 10 days with progressive purpura and necrotic skin lesions of the left thigh, lower abdomen, and scalp. Partial response to whole blood transfusion, antibiotics, and heparinisation was seen. The family history was negative for thrombosis. At age 3 months, she was referred to Siriraj Hospital, Bangkok, and had dark blue necrotic skin lesions on top of the old scar at thigh, abdomen, and scalp. Routine haematological investigation showed evidence of disseminated intravascular coagulation (DIC). The daily dose of cryoprecipitate transfusion resulted in a striking response with healing of the necrotic skin lesions. During admission, she proved to have endophthalmitis and was blind. These changes were suggestive of retinal vessel thrombosis in utero. Tests for intrauterine infection were negative. A search for the cause of the thrombosis was done during her full recovery at 6 and 7 months old, after withholding of cryoprecipitate for 72 hours. 7,8 Blood samples from the patient and her parents were sent to the University of Colorado School of Medicine for measurement of natural protease inhibitors (table). At age 3, 6, and 7 months PS (both total and free form) was not detectable, despite normal C4b binding protein. The parent’s plasma had moderately low PS concentrations and normal PC. The low PC concentrations in the infant at 3 and 7 months were attributable to DIC. When she was in full recovery at 6 months, PC was normal. Antithrombin III and plasminogen concentrations were also normal. On the basis of these results, homozygous PS
62
BLOOD PROTEIN CAND PROTEIN S MEASUREMENTS IN INFANT AND PARENTS
have led
to self-immunisation, accounting for the raised LPS antibody concentrations. Part of the benefit of severe physical training might therefore be
the induction of LPS antibodies which could reduce any endotoxaemia caused by physical heat stress, as you suggest. It remains to be seen whether the "doping" of an athlete with parenteral administration of anti-LPS IgG leads to his improved performance in a medium to long-distance race or in a soccer game on a warm day. If so, miners, pilots, soldiers, and possibly racehorses, might also benefit. -Normai
range (/m!)
in aamts snown m
parentneses
deficiency diagnosed. The thrombosis can be controlled by oral warfarin and cyroprecipitate transfusion every other day. daily To our knowledge this report is the first of homozygous PS deficiency associated with neonatal purpura fulminans. The treatment seems to be life-long replacement therapy, and fresh frozen plasma is planned to replace cryoprecipitate when the patient grows older. PS concentrate, the ideal treatment for this baby, is not yet available in Thailand. was
Department of Paediatrics, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA
CHULARATANA MAHASANDANA VINAI SUVATTE RICHARD A. MARLAR MARILYN J. MANCO-JOHNSON LINDA J. JACOBSON WILLIAM E. HATHAWAY
HE, Katz J, Marble R, Griffin JH. Inherited protein C deficiency and coumarin responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; ii: 1165-68. 2. Seligsohn U, Berger A, Abend M, et al. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med 1984; 310: 559-62. 3. Marciniak E, Wilson HD, Marlar RA. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood 1985; 65: 15-20. 4. Yuen P, Cheung A, Lin HJ, et al. Purpura fulminans in a Chinese boy with congenital protein C deficiency. Pediatrics 1986; 77: 670-76. 5. Manco-Johnson MJ, Marlar RA, Jacobson LJ, Hays T, Warady BA. Severe protein C deficiency in newborn infants. J Pediatr 1988; 113: 359-63. 6. Marlar RA, Montgomery RR, Broekmans AW. Diagnosis and treatment of homozygous protein C deficiency. J Pediatr 1989; 114: 528-34. 7 Comp PC, Nixon RR, Cooper R, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-88. 8. Comp PC, Doray D, Patton D, Esmon CT. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986; 67: 504. 1. Branson
Endotoxins in heatstroke SIR,-Indirect evidence supports your suggestion (Nov 4, p 1137) that inducing high levels of antibodies to lipopolysaccharide (LPS) is beneficial in the treatment of heat stress. 81 % of competitors in an ultramarathon (89-5 km) who collapsed along the way or were carried to the medical tent at the finishing line, had raised plasma LPS concentrations (including two in the reported lethal range). They also had high indices of nausea/vomiting/diarrhoeasymptoms produced by LPS-and they needed hours to days to recover. The remaining 19% with LPS in the normal range had far fewer and less severe episodes of nausea, vomiting, and diarrhoea, and they recovered within minutes to an hour or two. Those with low concentrations of plasma LPS had high levels of "natural" LPS IgG antibodies and vice versa. In the group of runners who managed to finish the race before collapsing, those with the lowest LPS and highest anti-LPS IgG concentrations performed betterie, they finished sooner. Racehorses, too, showed rises in LPS at the end of a stakes race .2 In a triathlon, athletes who trained the hardest (most miles jogged, bicycled, or swum) during the two weeks before the contest had the highest levels of natural anti-LPS IgG at the start of the race and lowest LPS concentrations at the end.3 Prolonged severe exercise may lead to periods of hypoxia, intestinal ischaemia, and raised body temperature. Short periods of expeirmental hypoxia,4 intestinal ischaemia,s or body temperature of 41-42°C6 led to the entry of large quantities of LPS into the circulation. This LPS may
Department of Physiology, University of Natal Medical School, Durban, South Africa
STEPHEN L. GAFFIN
JG, Gaffin SL, Wells MT, et al. Endotoxaemia in exhausted runners following a long distance race. S Afr Med J 1988; 73: 533-36. 2. Baker B, Gaffin SL, Wells MT, Brock-Utne JG. Endotoxaemia in race horses following exertion. J S Afr Vet Assoc 1988; 59: 63-66. 3. Bosenberg AT, Brock-Utne JG, Wells MTB, et al. Strenuous exercise causes systematic endotoxaemia. J Appl Physiol 1988; 65: 106-08. 4. Gaffin SL, Brock-Utne JG, Zanotti A, Wells MTB. Hypoxia induced endotoxemia in primates. Aviat Space Environ Med 1986; 57: 1044-49. 5. Gathiram P, Wells MT, Raidoo D, et al. Changes in plasma lipopolysaccharide concentrations in portal venous and systemic arterial blood during intestinal ischemia in primates. Circ Shock 1989; 27: 103-09. 6. Gathiram P, Wells MT, Raidoo D, et al. Portal and systemic plasma lipopolysaccharide concentrations in heat-stressed primates. Circ Shock 1988; 25: 1. Brock-Utne
223-30.
Human insulin and
hypoglycaemia
SIR,-Dr Egger and Dr Teuscher (Nov 25, p 1268) report that the introduction of human insulin in the Canton of Berne, Switzerland, caused a huge increase in admissions for severe hypoglycaemia to eight public hospitals during 1984-87. They attributed these cases of hypoglycaemia to a reduced awareness of hypoglycaemia, which may be partly caused by differences in counterregulatory responses to human and porcine insulin.1 The rise in the number of admissions seems to correlate quite well with the introduction of human insulin, but may also have been caused by other factors such as lowering of the mean HbA, value in the Canton of Berne in the pursuit of normoglycaemia, which may itself be responsible for the lowering of hypoglycaemia awareness2 In the Netherlands no rise in the number of admissions for severe hypoglycaemia has been reported. On the contrary, the information centre on hospital admissions recorded a decrease in the number of admissions for severe hypoglycaemia during 1983-88, the period when the market share of human insulin increased from 4-1% to 82.1%
These data conflict with those of Egger and Teuscher. The main reason for this discrepancy might be the fact that our data are less likely than theirs to be affected by factors such as changes in blood glucose control since they are derived from data for the whole country, including university centres and non-specialist clinics. Although there may be a difference in the effects of human porcine insulin on the counterregulatory response to hypoglycaemia, there is still no evidence for a causal relation between the use of human insulin and the risk of severe
hypoglycaemia. Polyclinic Inwendige Geneeskunde, Academisch Ziekenhuis, Free University, 1081 HV Amsterdam, Netherlands 1. Heine RJ, Van der Heyden
R. J. HEINE E. A.
VAN DER
VEEN
EAP, Van der Veen EA. Responses to human and porcine insulin in healthy subjects. Lancet 1989; ii: 946-48. 2. Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effects of intensive insulin therapy on glycaemic thresholds for counterregulatory hormone release. Diabetes 1988; 37: 901-07.