- Email: [email protected]
Cell death in myocardial infarction
CORRESPONDENCE
Jurkovich GJ, Mock CN. Systematic review of published evidence regarding trauma system effectiveness. J Trauma 1999; 47 (suppl): 25–33.
Sir—We congratulate F Lecky and colleagues1 for their analysis of the UK trauma network database and for the years of hard work and commitment involved in this project. We have contributed data to this project since its inception, and have never doubted the importance of this organisation, although we have been critical of some of the methods and conclusions drawn.2–4 The researchers used a logistic-regression model to adjust for differences in age and injury severity score but it would have been more reassuring to see the extent of the differences in case mix stated in the paper. TRISS methods are sensitive to case mix. Paradoxically, in the UK there is a higher mortality rate in lessseverely than more-severely injured elderly patients because of the effects of concurrent illness. There is no evidence that the researchers adjusted for case mix in other outcome measures, such as proportion of patients seen by senior staff. Data quality is also a major difficulty, often because of underresourced data collection systems at individual hospital level. However, even with these limitations, this system is one of the few examples of a robust audit system that can be used to compare performance of hospitals and systems over time. This system was set up even before audit became the buzz word of the early 1990s and clinical governance became fashionable. It is, however, unfortunate that we can no longer participate in sending data to Manchester. Our district health authority has withdrawn financial support. Perhaps more importantly, our trauma audit research post is very likely to change as the priorities for new audits emerge. We suspect that we are not alone in this dilemma, since we note the lower numbers of cases being submitted in the last 2 years of the series. The UK trauma audit has successfully provided a detailed comparative audit system but it takes years of hard work to see any results. If clinical governance is to be effective, audit systems such as UK Trauma Audit and Research Network are pivotal in monitoring performance. Such detailed audit does require extra resources, but these resources are miniscule compared with the cost of trauma to the National Health Service and society. We are thankful for the support that we have received over the past 10 years, which has allowed us to contribute to this system, but are sorry
THE LANCET • Vol 356 • October 21, 2000
that our continuity of data entry is now lost. *J Wardrope, S Cross Accident and Emergency Department, Northern General Hospital, Sheffield S5 7AU, UK (e-mail: [email protected]) 1
2
3 4
Lecky F, Woodford M, Yates DM. Trends in trauma care in England and Wales 1989–97. Lancet 2000; 355: 1771–75. Wardrope J, Cross SF, Fothergill DJ. One years experience of major trauma outcome study methodology. BMJ 1990; 301: 156–59. Wardrope J. UK major trauma outcome study. BMJ 1993; 305: 1016. Wardrope J, Walker L. The association between the seniority of accident and emergency doctor and outcome following trauma. J Accid Emerg Med 1999; 16: 449.
Author’s reply Sir—Anne-Maree Kelly and Jon Nicholl disagree with my interpretation of F Lecky and colleagues’ data.1 In reading their criticism, however, I find we are in general agreement: improvement in care of the seriously ill patient improves care of trauma patients. Trauma patients are usually seriously ill, and the benefits of trauma-centre care have been most apparent in the seriously injured. The administrative constructs of US trauma centres have not been adopted in England and Wales, but the improvements in care cited were, in fact, brought about by implementation of trauma centres and trauma systems. Education, formation of trauma response teams, benchmarking and monitoring, quality assurance programmes with corrective action authority, reliable call schedules, and the availability of skilled (senior) physicians are all essential components of trauma centres. Triage of trauma patients to dedicated trauma centres, and monitoring and benchmarking of regional performance criteria are hallmarks of trauma systems. A valid criticism of Lecky and colleagues’ report is that the results of their study, and nearly all other traumasystem analyses, do not adjust for general trends in health care that are not trauma related or disease specific. This type of analysis is difficult since it requires comparison of a large cohort of patients who have similar injuries and comorbidities, cared for in one region with an intact trauma system compared with another region with no trauma system, but with otherwise identical health-care capabilities. Alternatively, Nathens and colleagues2 compared mortality rates before and after trauma-system implementation, with adjustment for general trends in mortality. They used a cross-sectional time-series analysis of motor-vehicle crash mortality in the
USA, comparing mortality before and after trauma-system implementation in various states, taking into account changes in traffic safety laws and secular trends in crash mortality. They did assume that general (non-trauma centre) health-care improves in parallel with states with trauma systems, but showed convincingly that trauma systems reduce crash mortality which is consistent with the findings of Lecky and colleagues. Although the administration of trauma care is clearly different between the USA and England and Wales, the principle components of trauma centres and trauma systems are largely the same. As noted by J Wardrope and S Cross, funding for trauma registry and qualityassurance programmes is frequently in jeopardy. In the USA, the governing authority for trauma-centre designation has made such funding a mandatory responsibility of the participating hospital. The benefits of a reliable and accurate registry are many3 and essential for comparison of outcomes of trauma centres with benchmark norms. Gregory J Jurkovich University of Washington, Harborview Medical Center, Seattle, WA, USA (e-mail: [email protected]) 1
2
3
Lecky F, Woodford M, Yates DW. Trends in trauma care in England and Wales 1989–97. Lancet 2000; 355: 1771–75. Nathens AB, Jurkovich GJ, Cummings P, Rivara FP, Maier RV. The effect of organized systems of trauma care on motor vehicle crash mortality. JAMA 2000; 283: 1990–94. Jurkovich GJ, Mock CM. Systematic review of trauma system effectiveness based on registry comparisons: Skamania Symposium 1998. J Trauma (Suppl): 47: 46–55.
Cell death in myocardial infarction Sir—Leo Hofstra and colleagues (July 15, p 209)1 showed that increased uptake of Technetium-99m-labelled annexin-V is present in the infarct area of patients with acute myocardial infarction treated with primary or rescue angioplasty. They suggest that this increased uptake reflects binding to cardiomyocytes that have surfaceexpressed phosphatidylserine, and, therefore, activation of cell death (apoptosis). However, phosphatidylserine exposure also occurs on activated platelets and 99Tc annexin V was seen to bind to activated platelets in an animal model of acute leftatrial thrombi.2 Since platelets are clearly activated in acute myocardial infarction, and since downstream embolisation of these platelets is frequent,3 the uptake of this tracer might have reflected
1439
For personal use only. Not to be reproduced without permission of The Lancet.
CORRESPONDENCE
the presence of activated platelets trapped in the microcirculation of the infarct zone and not apoptotic cardiomyocytes. This could explain why the uptake of 99Tc annexin V was noted in the whole infarct region, not only at its borders (where it would have been expected in accordance with human necropsy findings after thrombolysis). Furthermore, we did an experimental study with I-123-labelled annexin V in four Franco-Anglaise dogs, in which myocardial infarction was created by 1·5 h balloon occlusion of the proximal left circumflex artery, followed by reperfusion.4 In this model, activated platelets play only a minor part in the process of myocardial injury. The presence of myocardial infarction after the occlusion was documented by a perfusion defect in the circumflex region on 99Tc sestamibi images. No significant uptake of 123I annexin V could, however, be documented in the infarct zone on early (3 h) and late (24 h) images obtained after intravenous injection 3 weeks after myocardial infarction. Since we have shown that 123I annexin V binds to apoptotic cells in vitro,5 this is a further argument against the presence of large numbers of apoptotic cardiomyocytes 3 weeks after myocardial infarction treated with reperfusion. We believe, therefore, that Hofstra and co-workers’ results should be interpreted cautiously. Further experimental studies are needed before this tracer can be presented as a marker of apoptosis in patients with acute myocardial infarction. *Johan De Sutter, Christophe Lahorte, Yves Taeymans, Rudi Dierckx, Guido Slegers Departments of *Cardiology and Nuclear Medicine, Ghent University Hospital, 9000 Ghent, Belgium, and Department of Radiopharmacy, University of Ghent, Ghent (e-mail: [email protected])
1
2
3
4
5
Hofstra L, Liem IH, Dumont EA, et al. Visualisation of cell death in vivo in patients with acute myocardial infarctions. Lancet 2000; 356: 209–12. Stratton JR, Dewhurst TA, Kasina S, et al. Selective uptake of radiolabelled annexin V on acute porcine left atrial thrombi. Circulation 1995; 92: 3113–21. Topol EJ, Yadav JS. Recognition of the importance of embolisation in atherosclerotic vascular disease. Circulation 2000; 101: 570–80. Lahorte C, De Sutter J, Van de Wiele C, et al. Evaluation of 123I-labelled annexin V in normal and infarcted myocardium in dogs. Nucl Med Comm 1999; 20: 948 (abstr). Lahorte C, Dumont F, Slegers G, et al. Synthesis and in vitro stability of 123I-labelled annexin V: a potential agent for SPECT imaging of apoptotic cells. J Labelled Cpd Radiopharm 2000; 43: 739–51.
1440
Hereditary angioedema and normal C1-inhibitor activity in women Sir—Konrad Bork and colleagues’ findings (July 15, p 213)1 on hereditary angioedema (HAE) motivated them to introduce a new variant of HAE (type III). We care for six unrelated families with HAE in Austria, and wish to criticise three points. First, although it seems unnecessary to await an attack of angioedema to obtain a diagnostic sample, assessment of C1-inhibitor activity and C4 concentrations during an attack in all 36, and not only four, of the Bork and colleagues’ female patients might have substantiated their conclusions. In our experience, gained over 10 years in female and male patients, C1-inhibitor activity can sometimes be normal or near normal in symptom-free periods, as Bork and colleagues show, but is substantially lowered during an attack. Moreover, even male HAE patients with normal C4 values in symptom-free periods have been described.2 Second, in the four women reported to have had episodes of acute laryngeal oedema, treatment with 1000 U C1-inhibitor concentrate was ineffective. Bork and colleagues classified this finding as an essential feature of the newly postulated variant of HAE, but the result might be more due to an underdosed therapeutic regimen than a pathogenetic concept.2 The manufacturer of C1-esterase inhibitor S-TIM 3 human haemoderivate (Immuno, Vienna, Austria) recommends a dose of 1000–1500 U during an acute attack, to be repeated if ineffective (total ⭐3000 U). Moreover, one patient in Bork and colleagues’ study became symptom-free under treatment with danazol, whereas this androgen was ineffective in another (in a daily dose of 200 mg). This finding allows no speculation on the pathogenesis, because androgen therapy shows a dissociation of clinical response from concentrations of C1-inhibitor and C4.3 Last, the proposed term HAE III is awkwardly chosen, since N K Day and R A Good identified and named a variant of HAE as HAE III more than 10 years ago.4 That type is characterised by an albumin-bound C1-inhibitor protein without functional activity, which can be differentiated from the C1-inhibitor protein of HAE II by electrophoresis. It seems more suitable, therefore, for
Bork and colleagues to name the type of angioedema they describe as HAE IV. *Birger Kränke, Wolfgang Salmhofer, Werner Aberer Department of Dermatology, University of Graz, A-8036 Graz, Austria (e-mail: [email protected]) 1
2
3
4
Bork K, Barnstedt S-E, Koch P, Traupe H. Hereditary angioedema with normal C1inhibitor activity in women. Lancet 2000; 356: 213–17. Visentin DE, Yang WH, Karsh J. C1-esterase inhibitor transfusions in patients with hereditary angioedema. Ann Allergy Asthma Immunol 1998; 80: 457–61. Warin AP, Greaves MW, Gatecliff M, et al. Treatment of hereditary angioedema by low-dose attenuated androgens: dissociation of clinical response from levels of C1 esterase inhibitor and C4. Br J Dermatol 1980; 103: 405–09. Day NK, Good RA. Inherited and acquired deiciencies of C1 esterase inhibitor in man. In: Rother K, Till GO, eds. The complement system. Heidelberg: Springer, 1988.
Authors’ reply Sir—In nearly all patients with HAE due to C1-inhibitor deficiency (HAE type I and II) C1-inhibitor plasma activity is low during the oedema attacks and in the symptom-free period. Very few patients have normal C1-inhibitor activity in plasma between oedema attacks and lowered activity only during attacks. Such a pattern is exceptional and concerns only a few individual patients, but never all family members affected by HAE. By contrast, we consistently found normal C1-inhibitor concentrations and activity in up to seven affected family members. We measured C1-inhibitor during ten oedema episodes in four patients and found normal C1inhibitor concentration and activity. We have had the opportunity to measure C1-inhibitor activity in a further six attacks in four other patients and obtained the same results. We believe that 1000 U C1-inhibitor concentrate is not underdosed in laryngeal oedema. We have treated 193 episodes of life-threatening laryngeal oedema with C1-inhibitor concentrate in 18 patients.2 In 48 episodes only 500 U were needed, and in the other 145 laryngeal oedemas 1000 U were necessary. No patient needed more than 1000 U. All patients survived and no patient needed intubation or tracheostomy. In HAE type II, or variant forms, a normal and a mutated allele of the structural gene is present. HAE II includes two phenotypes; in one a functionally inactive C1-inhibitor protein circulates in normal concentrations and the normal protein
THE LANCET • Vol 356 • October 21, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Jurkovich GJ, Mock CN. Systematic review of published evidence regarding trauma system effectiveness. J Trauma 1999; 47 (suppl): 25–33.
Sir—We congratulate F Lecky and colleagues1 for their analysis of the UK trauma network database and for the years of hard work and commitment involved in this project. We have contributed data to this project since its inception, and have never doubted the importance of this organisation, although we have been critical of some of the methods and conclusions drawn.2–4 The researchers used a logistic-regression model to adjust for differences in age and injury severity score but it would have been more reassuring to see the extent of the differences in case mix stated in the paper. TRISS methods are sensitive to case mix. Paradoxically, in the UK there is a higher mortality rate in lessseverely than more-severely injured elderly patients because of the effects of concurrent illness. There is no evidence that the researchers adjusted for case mix in other outcome measures, such as proportion of patients seen by senior staff. Data quality is also a major difficulty, often because of underresourced data collection systems at individual hospital level. However, even with these limitations, this system is one of the few examples of a robust audit system that can be used to compare performance of hospitals and systems over time. This system was set up even before audit became the buzz word of the early 1990s and clinical governance became fashionable. It is, however, unfortunate that we can no longer participate in sending data to Manchester. Our district health authority has withdrawn financial support. Perhaps more importantly, our trauma audit research post is very likely to change as the priorities for new audits emerge. We suspect that we are not alone in this dilemma, since we note the lower numbers of cases being submitted in the last 2 years of the series. The UK trauma audit has successfully provided a detailed comparative audit system but it takes years of hard work to see any results. If clinical governance is to be effective, audit systems such as UK Trauma Audit and Research Network are pivotal in monitoring performance. Such detailed audit does require extra resources, but these resources are miniscule compared with the cost of trauma to the National Health Service and society. We are thankful for the support that we have received over the past 10 years, which has allowed us to contribute to this system, but are sorry
THE LANCET • Vol 356 • October 21, 2000
that our continuity of data entry is now lost. *J Wardrope, S Cross Accident and Emergency Department, Northern General Hospital, Sheffield S5 7AU, UK (e-mail: [email protected]) 1
2
3 4
Lecky F, Woodford M, Yates DM. Trends in trauma care in England and Wales 1989–97. Lancet 2000; 355: 1771–75. Wardrope J, Cross SF, Fothergill DJ. One years experience of major trauma outcome study methodology. BMJ 1990; 301: 156–59. Wardrope J. UK major trauma outcome study. BMJ 1993; 305: 1016. Wardrope J, Walker L. The association between the seniority of accident and emergency doctor and outcome following trauma. J Accid Emerg Med 1999; 16: 449.
Author’s reply Sir—Anne-Maree Kelly and Jon Nicholl disagree with my interpretation of F Lecky and colleagues’ data.1 In reading their criticism, however, I find we are in general agreement: improvement in care of the seriously ill patient improves care of trauma patients. Trauma patients are usually seriously ill, and the benefits of trauma-centre care have been most apparent in the seriously injured. The administrative constructs of US trauma centres have not been adopted in England and Wales, but the improvements in care cited were, in fact, brought about by implementation of trauma centres and trauma systems. Education, formation of trauma response teams, benchmarking and monitoring, quality assurance programmes with corrective action authority, reliable call schedules, and the availability of skilled (senior) physicians are all essential components of trauma centres. Triage of trauma patients to dedicated trauma centres, and monitoring and benchmarking of regional performance criteria are hallmarks of trauma systems. A valid criticism of Lecky and colleagues’ report is that the results of their study, and nearly all other traumasystem analyses, do not adjust for general trends in health care that are not trauma related or disease specific. This type of analysis is difficult since it requires comparison of a large cohort of patients who have similar injuries and comorbidities, cared for in one region with an intact trauma system compared with another region with no trauma system, but with otherwise identical health-care capabilities. Alternatively, Nathens and colleagues2 compared mortality rates before and after trauma-system implementation, with adjustment for general trends in mortality. They used a cross-sectional time-series analysis of motor-vehicle crash mortality in the
USA, comparing mortality before and after trauma-system implementation in various states, taking into account changes in traffic safety laws and secular trends in crash mortality. They did assume that general (non-trauma centre) health-care improves in parallel with states with trauma systems, but showed convincingly that trauma systems reduce crash mortality which is consistent with the findings of Lecky and colleagues. Although the administration of trauma care is clearly different between the USA and England and Wales, the principle components of trauma centres and trauma systems are largely the same. As noted by J Wardrope and S Cross, funding for trauma registry and qualityassurance programmes is frequently in jeopardy. In the USA, the governing authority for trauma-centre designation has made such funding a mandatory responsibility of the participating hospital. The benefits of a reliable and accurate registry are many3 and essential for comparison of outcomes of trauma centres with benchmark norms. Gregory J Jurkovich University of Washington, Harborview Medical Center, Seattle, WA, USA (e-mail: [email protected]) 1
2
3
Lecky F, Woodford M, Yates DW. Trends in trauma care in England and Wales 1989–97. Lancet 2000; 355: 1771–75. Nathens AB, Jurkovich GJ, Cummings P, Rivara FP, Maier RV. The effect of organized systems of trauma care on motor vehicle crash mortality. JAMA 2000; 283: 1990–94. Jurkovich GJ, Mock CM. Systematic review of trauma system effectiveness based on registry comparisons: Skamania Symposium 1998. J Trauma (Suppl): 47: 46–55.
Cell death in myocardial infarction Sir—Leo Hofstra and colleagues (July 15, p 209)1 showed that increased uptake of Technetium-99m-labelled annexin-V is present in the infarct area of patients with acute myocardial infarction treated with primary or rescue angioplasty. They suggest that this increased uptake reflects binding to cardiomyocytes that have surfaceexpressed phosphatidylserine, and, therefore, activation of cell death (apoptosis). However, phosphatidylserine exposure also occurs on activated platelets and 99Tc annexin V was seen to bind to activated platelets in an animal model of acute leftatrial thrombi.2 Since platelets are clearly activated in acute myocardial infarction, and since downstream embolisation of these platelets is frequent,3 the uptake of this tracer might have reflected
1439
For personal use only. Not to be reproduced without permission of The Lancet.
CORRESPONDENCE
the presence of activated platelets trapped in the microcirculation of the infarct zone and not apoptotic cardiomyocytes. This could explain why the uptake of 99Tc annexin V was noted in the whole infarct region, not only at its borders (where it would have been expected in accordance with human necropsy findings after thrombolysis). Furthermore, we did an experimental study with I-123-labelled annexin V in four Franco-Anglaise dogs, in which myocardial infarction was created by 1·5 h balloon occlusion of the proximal left circumflex artery, followed by reperfusion.4 In this model, activated platelets play only a minor part in the process of myocardial injury. The presence of myocardial infarction after the occlusion was documented by a perfusion defect in the circumflex region on 99Tc sestamibi images. No significant uptake of 123I annexin V could, however, be documented in the infarct zone on early (3 h) and late (24 h) images obtained after intravenous injection 3 weeks after myocardial infarction. Since we have shown that 123I annexin V binds to apoptotic cells in vitro,5 this is a further argument against the presence of large numbers of apoptotic cardiomyocytes 3 weeks after myocardial infarction treated with reperfusion. We believe, therefore, that Hofstra and co-workers’ results should be interpreted cautiously. Further experimental studies are needed before this tracer can be presented as a marker of apoptosis in patients with acute myocardial infarction. *Johan De Sutter, Christophe Lahorte, Yves Taeymans, Rudi Dierckx, Guido Slegers Departments of *Cardiology and Nuclear Medicine, Ghent University Hospital, 9000 Ghent, Belgium, and Department of Radiopharmacy, University of Ghent, Ghent (e-mail: [email protected])
1
2
3
4
5
Hofstra L, Liem IH, Dumont EA, et al. Visualisation of cell death in vivo in patients with acute myocardial infarctions. Lancet 2000; 356: 209–12. Stratton JR, Dewhurst TA, Kasina S, et al. Selective uptake of radiolabelled annexin V on acute porcine left atrial thrombi. Circulation 1995; 92: 3113–21. Topol EJ, Yadav JS. Recognition of the importance of embolisation in atherosclerotic vascular disease. Circulation 2000; 101: 570–80. Lahorte C, De Sutter J, Van de Wiele C, et al. Evaluation of 123I-labelled annexin V in normal and infarcted myocardium in dogs. Nucl Med Comm 1999; 20: 948 (abstr). Lahorte C, Dumont F, Slegers G, et al. Synthesis and in vitro stability of 123I-labelled annexin V: a potential agent for SPECT imaging of apoptotic cells. J Labelled Cpd Radiopharm 2000; 43: 739–51.
1440
Hereditary angioedema and normal C1-inhibitor activity in women Sir—Konrad Bork and colleagues’ findings (July 15, p 213)1 on hereditary angioedema (HAE) motivated them to introduce a new variant of HAE (type III). We care for six unrelated families with HAE in Austria, and wish to criticise three points. First, although it seems unnecessary to await an attack of angioedema to obtain a diagnostic sample, assessment of C1-inhibitor activity and C4 concentrations during an attack in all 36, and not only four, of the Bork and colleagues’ female patients might have substantiated their conclusions. In our experience, gained over 10 years in female and male patients, C1-inhibitor activity can sometimes be normal or near normal in symptom-free periods, as Bork and colleagues show, but is substantially lowered during an attack. Moreover, even male HAE patients with normal C4 values in symptom-free periods have been described.2 Second, in the four women reported to have had episodes of acute laryngeal oedema, treatment with 1000 U C1-inhibitor concentrate was ineffective. Bork and colleagues classified this finding as an essential feature of the newly postulated variant of HAE, but the result might be more due to an underdosed therapeutic regimen than a pathogenetic concept.2 The manufacturer of C1-esterase inhibitor S-TIM 3 human haemoderivate (Immuno, Vienna, Austria) recommends a dose of 1000–1500 U during an acute attack, to be repeated if ineffective (total ⭐3000 U). Moreover, one patient in Bork and colleagues’ study became symptom-free under treatment with danazol, whereas this androgen was ineffective in another (in a daily dose of 200 mg). This finding allows no speculation on the pathogenesis, because androgen therapy shows a dissociation of clinical response from concentrations of C1-inhibitor and C4.3 Last, the proposed term HAE III is awkwardly chosen, since N K Day and R A Good identified and named a variant of HAE as HAE III more than 10 years ago.4 That type is characterised by an albumin-bound C1-inhibitor protein without functional activity, which can be differentiated from the C1-inhibitor protein of HAE II by electrophoresis. It seems more suitable, therefore, for
Bork and colleagues to name the type of angioedema they describe as HAE IV. *Birger Kränke, Wolfgang Salmhofer, Werner Aberer Department of Dermatology, University of Graz, A-8036 Graz, Austria (e-mail: [email protected]) 1
2
3
4
Bork K, Barnstedt S-E, Koch P, Traupe H. Hereditary angioedema with normal C1inhibitor activity in women. Lancet 2000; 356: 213–17. Visentin DE, Yang WH, Karsh J. C1-esterase inhibitor transfusions in patients with hereditary angioedema. Ann Allergy Asthma Immunol 1998; 80: 457–61. Warin AP, Greaves MW, Gatecliff M, et al. Treatment of hereditary angioedema by low-dose attenuated androgens: dissociation of clinical response from levels of C1 esterase inhibitor and C4. Br J Dermatol 1980; 103: 405–09. Day NK, Good RA. Inherited and acquired deiciencies of C1 esterase inhibitor in man. In: Rother K, Till GO, eds. The complement system. Heidelberg: Springer, 1988.
Authors’ reply Sir—In nearly all patients with HAE due to C1-inhibitor deficiency (HAE type I and II) C1-inhibitor plasma activity is low during the oedema attacks and in the symptom-free period. Very few patients have normal C1-inhibitor activity in plasma between oedema attacks and lowered activity only during attacks. Such a pattern is exceptional and concerns only a few individual patients, but never all family members affected by HAE. By contrast, we consistently found normal C1-inhibitor concentrations and activity in up to seven affected family members. We measured C1-inhibitor during ten oedema episodes in four patients and found normal C1inhibitor concentration and activity. We have had the opportunity to measure C1-inhibitor activity in a further six attacks in four other patients and obtained the same results. We believe that 1000 U C1-inhibitor concentrate is not underdosed in laryngeal oedema. We have treated 193 episodes of life-threatening laryngeal oedema with C1-inhibitor concentrate in 18 patients.2 In 48 episodes only 500 U were needed, and in the other 145 laryngeal oedemas 1000 U were necessary. No patient needed more than 1000 U. All patients survived and no patient needed intubation or tracheostomy. In HAE type II, or variant forms, a normal and a mutated allele of the structural gene is present. HAE II includes two phenotypes; in one a functionally inactive C1-inhibitor protein circulates in normal concentrations and the normal protein
THE LANCET • Vol 356 • October 21, 2000
For personal use only. Not to be reproduced without permission of The Lancet.