- Email: [email protected]
Conventional insemination versus intracytoplasmic sperm injection
CORRESPONDENCE
3
4
5
Klang G. Measurments and studies of the fluorescence of the human lens in vivo. Acta Ophthalmol Scand 1948 (suppl 31). Van Best JA, Tjin A Tsoi EWSJ, Boot JP, Oosterhuis JA. In vivo assessment of lens transmission for blue-green light by autofluorescence measurement. Ophthalmic Res 1985; 17: 90–95. Brückner R, Batschelet E, Hugenschmidt F. The Basel longitudinal study on aging (1955-1978). Doc Ophthal 1987; 64: 235–310.
Conventional insemination versus intracytoplasmic sperm injection Sir—Siladitya Bhattacharya and colleagues (June 30, p 2075)1 report a randomised trial of the efficacy of conventional insemination and intracytoplasmic sperm injection (ICSI). They compare the techniques in nonmale-factor infertility couples, in which the female partner is younger than 37 years, for benefit in fertilisation, embryonic implantation, or overall pregnancy outcome. They conclude that ICSI leads to poorer implantation and pregnancy rates, and increased laboratory time, and that ICSI is, therefore, justified only for severe malefactor infertility. We appreciate the difficulty with doing such a randomised multicentre trial, and recognise the usefulness of such an approach, but we think Bhattacharya and colleagues’ ultimate message is a backward step for assisted reproduction. We reviewed 16 months of data retrospectively from our in-vitro fertilisation (IVF) programme to compare outcomes in all couples, including severe male-factor infertility couples in which the woman was younger than 37 years. More cycles of conventional insemination were undertaken than Conventional ICSI Mean maternal age (years)
35
Oocyte procedures Oocyte retrievals 605 (58%) Proportion mature 71% oocytes fertilised Embryo transfer 590 (98%) procedures Total embryos 1420 transferred Continuing and 50% delivered pregnancies Embryonic implantation Day 3 transfer 24% Blastocyst transfer 51%* Overall 32%
35
437 (42%) 74% 433 (99%) 1143 48%
25% 43%* 30%
*p<0·05.
Comparison of data for conventional insemination and ICSI in women younger than 37 years
THE LANCET • Vol 358 • November 10, 2001
ICSI procedures (58% of 1043 cases). Maternal age and the fertilisation rate of mature eggs were similar in the two groups. ICSI was done because of low oocyte numbers (<6) or for couples who had previously failed or had poor outcomes with conventional fertilisation. Fertilisation rates in the two groups seem to be higher than those achieved by Bhattacharya and colleagues. They had an apparently high rate of failure for embryo transfer after oocyte retrieval: in the conventional insemination group only 159 (86%) of 186 of collections made it to transfer, and only 159 (84%) of 189 in their ICSI group. Our rates were 98% and 99%, respectively. Pregnancy outcomes did not seem to differ in our data, nor did overall implantation rates defined as the number of fetal heart beats as a function of the number of embryos transferred. If the implantation rates are taken into account relative to whether embryo transfer was done on day 3 of development or at the blastocyst stage (day 5 or 6), the ICSI embryo implantation rate seems to be significantly poorer after extended culture than after transfer on day 3. We have no clear explanation for such a result, but will continue to monitor to see whether it is due merely to the nonrandomised comparison. We concede that ICSI can be more time-consuming and potentially incur greater cost for IVF couples. We believe, however, that ICSI generates more accurate information about oocyte quality and maturity on the day of retrieval, and enables maximum normal fertilisation outcomes. We suggest that unless the technique is practised in an optimum way by maintenance of a benign environment through careful control of temperature, pH, and osmolarity, and with no disruption of the oocyte spindle,2 embryonic viability may be lessened despite normal fertilisation. Therefore, we think the lower rate of fertilisation and poorer oocyte retrieval/embryo transfer ratio in Bhattacharya and colleagues’ study show that ICSI was not done in an optimum way and that the validity of their conclusion is reduced that ICSI should be used only for severe male-factor infertility. *Michael Tucker, Jim Graham, Taer Han, Robert Stillman, Michael Levy Shady Grove Fertility Reproductive Science Center, 15001 Shady Grove Road, Suite 400, Rockville, MD 20850, USA (e-mail: [email protected]) 1
Bhattacharya S, Hamilton MPR, Shaaban M, et al. Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial. Lancet 2001; 357: 2075–79.
2
Wang WH, Meng L, Hackett RJ, Odenbourg R, Keefe DL. The spindle observation and its relationship with fertilization after intracytoplasmic sperm injection in living human oocytes. Fertil Steril 2001; 75: 348–53.
Authors’ reply Sir—Our results led us to conclude that ICSI offers no advantage over conventional IVF in non-male factor infertility. We are sorry and surprised to learn that Michael Tucker and colleagues feel that this finding was a backward step for assisted reproduction. Assisted reproduction has always been technologically driven rather than evidence-based and has traditionally relied heavily on uncontrolled and anecdotal data.1 Tucker and colleagues present a retrospective analysis of their clinic database to show that ICSI is better than conventional insemination. We believe no firm conclusions can be drawn from these non-randomised data from dissimilar groups of couples. Additionally, any comparison with our results should take into account the differing sample populations, methods of embryo transfer, and data analysis, including calculation of fertilisation and pregnancy rates, in the two studies. Our fertilisation rates, which seem to be lower, were calculated by use of the number of normally fertilised embryos as the numerator, and the number of oocytes collected (not mature oocytes) as the denominator. Our high rate of failure to attain embryo transfer does not necessarily show poor fertilisation or poor embryo cleavage; there are various reasons, including poor ovarian stimulation leading to failure to collect oocytes at egg recovery and elective cryopreservation of all embryos to avoid the risk of ovarian hyperstimulation syndrome. Furthermore, we feel that our pragmatic multicentre approach improves the external validity of our results. We are disturbed by the suggestion that ICSI may not have been done in an optimum way. Data published annually by the Human Fertilisation and Embryology Authority suggest that ICSI success rates at our participating centres are in line with the UK national average.2 We are impressed by the high pregnancy rate in the two groups studied by Tucker and colleagues. We agree that ICSI generates more accurate information about oocyte quality and maturity on the day of retrieval, but remain uncertain about how this information enables maximum normal fertilisation. Certainly, their data do not seem to favour ICSI over IVF in terms of implantation or pregnancy rates.
1645
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
We believe that randomised controlled trials and systematic reviews remain the gold standards for judging the benefits of treatments.3 The outcome of our trial for ICSI in non-male-factor infertility is in agreement with the only systematic review on this subject.4 As for Tucker and colleagues’ arguments, it is difficult to imagine how the results of their observational study or their unjustified misgivings about how well we did ICSI can challenge the validity of our message. *Siladitya Bhattacharya, Mark Hamilton Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen AB25 2ZD, UK 1
2
3
4
Vandekerckhove P, O’Donovan PA, Lilford RJ, Harada TW. Infertility treatment: from cookery to science: the epidemiology of randomised controlled trials. Br J Obstet Gynaecol 1993; 100: 1005–36. The patients’ guide to IVF clinics. London: Human Fertilisation and Embryology Authority, 2000. Barton S. Which clinical studies provide the best evidence? The best TCY still trumps over the best observational study. BMJ 2000; 321: 255–56. van Rumste MME, Evers JLH, Farquhar CM, Blake DA. Intra-cytoplasmic sperm injection versus partial zona dissection, subzonal insemination and conventional techniques for oocyte insemination during in vitro fertilisation (Cochrane Review). In: The Cochrane Library. Issue 2. Oxford: Update Software, 2001.
progress, as we note in the report. We also disagree with Adinolfi and Sherlock’s numbers. An abnormality rate of 2–3% might be correct for women with raised maternal age, but many referrals throughout the UK are for women identified as having increased risk after serum screening or those pregnancies with abnormalities on ultrasonography. In the UK, the overall chromosome abnormality rate in prenatal samples is 7%.3 Workers have shown that 75–95% of clinically relevant chromosome abnormalities are detected by QF-PCR.4,5 We quote 80% as a conservative approximation based on those studies, and we believe that value gives a more realistic assessment of the usefulness of QF-PCR than the numbers quoted by Adinolfi and Sherlock. Adinolfi and Sherlock correctly state that other centres in the UK and the rest of Europe are using the test diagnostically. Only one other centre, however—a private laboratory—in the UK currently offers this service. Kathy Mann, *Caroline Mackie Ogilvie Genetics Centre, Guy’s and St Thomas’ Hospital Trust, London SE1 9RT, UK (e-mail: [email protected]) 1
2
Prenatal detection of chromosome disorders Sir—Although we welcome the support of Matteo Adinolfi and Jon Sherlock, given in their Sept 29 commentary,1 for the work we describe in our report on a rapid aneuploidy diagnostic service in the UK (Sept 29, p 1057),2 there are some errors in the commentary that need correction. Adinolfi and Sherlock state that we had false-positive and false-negative results in the period when setting up the test. However, we had no false-positive or false-negative results at any time during our work. They state also, in their final paragraph, that we are suggesting that full karyotype analysis should be done in addition to quantitative fluorescence (QF) PCR because of our concern over false-positive or falsenegative results with this method. This is not the case; full karyotype analysis detects chromosome abnormalities not detected by QF-PCR. We therefore suggest that karyotype analysis should be continued for all pregnancies at least until a full audit of pregnancy outcomes in cases referred for raised serum screening or raised maternal age has been done. Such an audit is currently in
1646
3
4
5
Adinolfi M, Sherlock J. Prenatal detection of chromosome disorders by QF-PCR. Lancet 2001; 358: 1030–31. Mann K, Fox SP, Abbs SJ, et al. Development and implementation of a new rapid aneuploidy diagnostic service within the UK National Health Service and implications for the future of prenatal diagnosis. Lancet 2001; 358: 1057–61. NEQAS: national external quality assessment scheme in clinical cytogenetics, annual report, 2000. Levett LJ, Liddle S, Meredith R. A largescale evaluation of amnio-PCR for the rapid prenatal diagnosis of fetal trisomy. Ultrasound Obstet Gynecol 2001; 17: 115–18. Lewin P, Kleinfinger P, Bazin A, Mossafa H, Szpiro-Tapia S. Defining the efficiency of fluorescence in situ hybridization on uncultured amniocytes on a retrospective cohort of 27 407 prenatal diagnoses. Prenat Diagn 2000; 20: 1–6.
Authors’ reply Sir—We mentioned in our commentary that the rate of numerical chromosome abnormalities that can be detected by QF-PCR in pregnant women older than 36 years is around 2–3%; this value excludes women at high risk because of previous biochemical or ultrasonography tests. Of course, if many pregnant women at risk are included, the incidence increases.1 Kathy Mann and Caroline Olgivie claim that the other workers have shown that 75–95% of relevant chromosomal abnormalities are detected by QF-PCR, but they quote
one study in which fluorescent in situ hybridisation (FISH) was used. If the QF-PCR test is correctly applied, in the absence of false-negative results, all numerical disorders affecting chromosomes 21, 18, 13, X, and Y should be correctly detected. This is the experience of many genetic centres in Europe that provide service for local hospitals at a fee, as does the Genetic Centre at Guy’s and Thomas’ Hospital, London. *Matteo Adinolfi, Jon Sherlock *Galton Laboratory, Department of Genetics and Biometry, and Department of Obstetrics and Gynaecology, University College London, London NW1 2HE, UK 1
Pertl B, Kopp S, Kroisel PM, et al. Quantitative fluorescent PCR for the rapid prenatal detection of common aneuploidies and fetal sex. Am J Obstet Gynecol 1997; 177: 899–906.
Flash pulmonary oedema: think of coronary artery disease first Sir—Fiona Walker and colleagues (Aug 18, p 556)1 report a case of recurrent pulmonary oedema secondary to renalartery stenosis, and remind us that flash pulmonary oedema can suggest a renovascular substrate. Their report led me to reflect on an impression I have formed over the years that although this cause of pulmonary oedema is well recognised (although rarely sought) by generalists, that of painless myocardial ischaemia without infarction, which can be thought of as angina equivalent in this context,2 is little known outside cardiology circles. The disorder is, however, probably a more important cause of unheralded pulmonary oedema than renovascular disease. Patients exhibiting this phenomenon are generally elderly and have severe coronary artery disease, typically with one occluded vessel and a severely stenosed coronary artery supplying collateral flow.2 Suddenly reduced flow in the collateral vessel, or increased myocardial oxygen demand, might, therefore, produce a large area of reversibly ischaemic myocardium, causing transient left-ventricular dysfunction, raised left-ventricular enddiastolic pressure, and acute pulmonary oedema.2 Only a minority of myocardial ischaemic episodes cause chest pain, and, given that left-ventricular dysfunction arises before electrocardiographic changes and pain during these episodes, it is not surprising that this process can be entirely painless. The proportion of all cases of pulmonary oedema accounted for by
THE LANCET • Vol 358 • November 10, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
3
4
5
Klang G. Measurments and studies of the fluorescence of the human lens in vivo. Acta Ophthalmol Scand 1948 (suppl 31). Van Best JA, Tjin A Tsoi EWSJ, Boot JP, Oosterhuis JA. In vivo assessment of lens transmission for blue-green light by autofluorescence measurement. Ophthalmic Res 1985; 17: 90–95. Brückner R, Batschelet E, Hugenschmidt F. The Basel longitudinal study on aging (1955-1978). Doc Ophthal 1987; 64: 235–310.
Conventional insemination versus intracytoplasmic sperm injection Sir—Siladitya Bhattacharya and colleagues (June 30, p 2075)1 report a randomised trial of the efficacy of conventional insemination and intracytoplasmic sperm injection (ICSI). They compare the techniques in nonmale-factor infertility couples, in which the female partner is younger than 37 years, for benefit in fertilisation, embryonic implantation, or overall pregnancy outcome. They conclude that ICSI leads to poorer implantation and pregnancy rates, and increased laboratory time, and that ICSI is, therefore, justified only for severe malefactor infertility. We appreciate the difficulty with doing such a randomised multicentre trial, and recognise the usefulness of such an approach, but we think Bhattacharya and colleagues’ ultimate message is a backward step for assisted reproduction. We reviewed 16 months of data retrospectively from our in-vitro fertilisation (IVF) programme to compare outcomes in all couples, including severe male-factor infertility couples in which the woman was younger than 37 years. More cycles of conventional insemination were undertaken than Conventional ICSI Mean maternal age (years)
35
Oocyte procedures Oocyte retrievals 605 (58%) Proportion mature 71% oocytes fertilised Embryo transfer 590 (98%) procedures Total embryos 1420 transferred Continuing and 50% delivered pregnancies Embryonic implantation Day 3 transfer 24% Blastocyst transfer 51%* Overall 32%
35
437 (42%) 74% 433 (99%) 1143 48%
25% 43%* 30%
*p<0·05.
Comparison of data for conventional insemination and ICSI in women younger than 37 years
THE LANCET • Vol 358 • November 10, 2001
ICSI procedures (58% of 1043 cases). Maternal age and the fertilisation rate of mature eggs were similar in the two groups. ICSI was done because of low oocyte numbers (<6) or for couples who had previously failed or had poor outcomes with conventional fertilisation. Fertilisation rates in the two groups seem to be higher than those achieved by Bhattacharya and colleagues. They had an apparently high rate of failure for embryo transfer after oocyte retrieval: in the conventional insemination group only 159 (86%) of 186 of collections made it to transfer, and only 159 (84%) of 189 in their ICSI group. Our rates were 98% and 99%, respectively. Pregnancy outcomes did not seem to differ in our data, nor did overall implantation rates defined as the number of fetal heart beats as a function of the number of embryos transferred. If the implantation rates are taken into account relative to whether embryo transfer was done on day 3 of development or at the blastocyst stage (day 5 or 6), the ICSI embryo implantation rate seems to be significantly poorer after extended culture than after transfer on day 3. We have no clear explanation for such a result, but will continue to monitor to see whether it is due merely to the nonrandomised comparison. We concede that ICSI can be more time-consuming and potentially incur greater cost for IVF couples. We believe, however, that ICSI generates more accurate information about oocyte quality and maturity on the day of retrieval, and enables maximum normal fertilisation outcomes. We suggest that unless the technique is practised in an optimum way by maintenance of a benign environment through careful control of temperature, pH, and osmolarity, and with no disruption of the oocyte spindle,2 embryonic viability may be lessened despite normal fertilisation. Therefore, we think the lower rate of fertilisation and poorer oocyte retrieval/embryo transfer ratio in Bhattacharya and colleagues’ study show that ICSI was not done in an optimum way and that the validity of their conclusion is reduced that ICSI should be used only for severe male-factor infertility. *Michael Tucker, Jim Graham, Taer Han, Robert Stillman, Michael Levy Shady Grove Fertility Reproductive Science Center, 15001 Shady Grove Road, Suite 400, Rockville, MD 20850, USA (e-mail: [email protected]) 1
Bhattacharya S, Hamilton MPR, Shaaban M, et al. Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial. Lancet 2001; 357: 2075–79.
2
Wang WH, Meng L, Hackett RJ, Odenbourg R, Keefe DL. The spindle observation and its relationship with fertilization after intracytoplasmic sperm injection in living human oocytes. Fertil Steril 2001; 75: 348–53.
Authors’ reply Sir—Our results led us to conclude that ICSI offers no advantage over conventional IVF in non-male factor infertility. We are sorry and surprised to learn that Michael Tucker and colleagues feel that this finding was a backward step for assisted reproduction. Assisted reproduction has always been technologically driven rather than evidence-based and has traditionally relied heavily on uncontrolled and anecdotal data.1 Tucker and colleagues present a retrospective analysis of their clinic database to show that ICSI is better than conventional insemination. We believe no firm conclusions can be drawn from these non-randomised data from dissimilar groups of couples. Additionally, any comparison with our results should take into account the differing sample populations, methods of embryo transfer, and data analysis, including calculation of fertilisation and pregnancy rates, in the two studies. Our fertilisation rates, which seem to be lower, were calculated by use of the number of normally fertilised embryos as the numerator, and the number of oocytes collected (not mature oocytes) as the denominator. Our high rate of failure to attain embryo transfer does not necessarily show poor fertilisation or poor embryo cleavage; there are various reasons, including poor ovarian stimulation leading to failure to collect oocytes at egg recovery and elective cryopreservation of all embryos to avoid the risk of ovarian hyperstimulation syndrome. Furthermore, we feel that our pragmatic multicentre approach improves the external validity of our results. We are disturbed by the suggestion that ICSI may not have been done in an optimum way. Data published annually by the Human Fertilisation and Embryology Authority suggest that ICSI success rates at our participating centres are in line with the UK national average.2 We are impressed by the high pregnancy rate in the two groups studied by Tucker and colleagues. We agree that ICSI generates more accurate information about oocyte quality and maturity on the day of retrieval, but remain uncertain about how this information enables maximum normal fertilisation. Certainly, their data do not seem to favour ICSI over IVF in terms of implantation or pregnancy rates.
1645
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
We believe that randomised controlled trials and systematic reviews remain the gold standards for judging the benefits of treatments.3 The outcome of our trial for ICSI in non-male-factor infertility is in agreement with the only systematic review on this subject.4 As for Tucker and colleagues’ arguments, it is difficult to imagine how the results of their observational study or their unjustified misgivings about how well we did ICSI can challenge the validity of our message. *Siladitya Bhattacharya, Mark Hamilton Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen AB25 2ZD, UK 1
2
3
4
Vandekerckhove P, O’Donovan PA, Lilford RJ, Harada TW. Infertility treatment: from cookery to science: the epidemiology of randomised controlled trials. Br J Obstet Gynaecol 1993; 100: 1005–36. The patients’ guide to IVF clinics. London: Human Fertilisation and Embryology Authority, 2000. Barton S. Which clinical studies provide the best evidence? The best TCY still trumps over the best observational study. BMJ 2000; 321: 255–56. van Rumste MME, Evers JLH, Farquhar CM, Blake DA. Intra-cytoplasmic sperm injection versus partial zona dissection, subzonal insemination and conventional techniques for oocyte insemination during in vitro fertilisation (Cochrane Review). In: The Cochrane Library. Issue 2. Oxford: Update Software, 2001.
progress, as we note in the report. We also disagree with Adinolfi and Sherlock’s numbers. An abnormality rate of 2–3% might be correct for women with raised maternal age, but many referrals throughout the UK are for women identified as having increased risk after serum screening or those pregnancies with abnormalities on ultrasonography. In the UK, the overall chromosome abnormality rate in prenatal samples is 7%.3 Workers have shown that 75–95% of clinically relevant chromosome abnormalities are detected by QF-PCR.4,5 We quote 80% as a conservative approximation based on those studies, and we believe that value gives a more realistic assessment of the usefulness of QF-PCR than the numbers quoted by Adinolfi and Sherlock. Adinolfi and Sherlock correctly state that other centres in the UK and the rest of Europe are using the test diagnostically. Only one other centre, however—a private laboratory—in the UK currently offers this service. Kathy Mann, *Caroline Mackie Ogilvie Genetics Centre, Guy’s and St Thomas’ Hospital Trust, London SE1 9RT, UK (e-mail: [email protected]) 1
2
Prenatal detection of chromosome disorders Sir—Although we welcome the support of Matteo Adinolfi and Jon Sherlock, given in their Sept 29 commentary,1 for the work we describe in our report on a rapid aneuploidy diagnostic service in the UK (Sept 29, p 1057),2 there are some errors in the commentary that need correction. Adinolfi and Sherlock state that we had false-positive and false-negative results in the period when setting up the test. However, we had no false-positive or false-negative results at any time during our work. They state also, in their final paragraph, that we are suggesting that full karyotype analysis should be done in addition to quantitative fluorescence (QF) PCR because of our concern over false-positive or falsenegative results with this method. This is not the case; full karyotype analysis detects chromosome abnormalities not detected by QF-PCR. We therefore suggest that karyotype analysis should be continued for all pregnancies at least until a full audit of pregnancy outcomes in cases referred for raised serum screening or raised maternal age has been done. Such an audit is currently in
1646
3
4
5
Adinolfi M, Sherlock J. Prenatal detection of chromosome disorders by QF-PCR. Lancet 2001; 358: 1030–31. Mann K, Fox SP, Abbs SJ, et al. Development and implementation of a new rapid aneuploidy diagnostic service within the UK National Health Service and implications for the future of prenatal diagnosis. Lancet 2001; 358: 1057–61. NEQAS: national external quality assessment scheme in clinical cytogenetics, annual report, 2000. Levett LJ, Liddle S, Meredith R. A largescale evaluation of amnio-PCR for the rapid prenatal diagnosis of fetal trisomy. Ultrasound Obstet Gynecol 2001; 17: 115–18. Lewin P, Kleinfinger P, Bazin A, Mossafa H, Szpiro-Tapia S. Defining the efficiency of fluorescence in situ hybridization on uncultured amniocytes on a retrospective cohort of 27 407 prenatal diagnoses. Prenat Diagn 2000; 20: 1–6.
Authors’ reply Sir—We mentioned in our commentary that the rate of numerical chromosome abnormalities that can be detected by QF-PCR in pregnant women older than 36 years is around 2–3%; this value excludes women at high risk because of previous biochemical or ultrasonography tests. Of course, if many pregnant women at risk are included, the incidence increases.1 Kathy Mann and Caroline Olgivie claim that the other workers have shown that 75–95% of relevant chromosomal abnormalities are detected by QF-PCR, but they quote
one study in which fluorescent in situ hybridisation (FISH) was used. If the QF-PCR test is correctly applied, in the absence of false-negative results, all numerical disorders affecting chromosomes 21, 18, 13, X, and Y should be correctly detected. This is the experience of many genetic centres in Europe that provide service for local hospitals at a fee, as does the Genetic Centre at Guy’s and Thomas’ Hospital, London. *Matteo Adinolfi, Jon Sherlock *Galton Laboratory, Department of Genetics and Biometry, and Department of Obstetrics and Gynaecology, University College London, London NW1 2HE, UK 1
Pertl B, Kopp S, Kroisel PM, et al. Quantitative fluorescent PCR for the rapid prenatal detection of common aneuploidies and fetal sex. Am J Obstet Gynecol 1997; 177: 899–906.
Flash pulmonary oedema: think of coronary artery disease first Sir—Fiona Walker and colleagues (Aug 18, p 556)1 report a case of recurrent pulmonary oedema secondary to renalartery stenosis, and remind us that flash pulmonary oedema can suggest a renovascular substrate. Their report led me to reflect on an impression I have formed over the years that although this cause of pulmonary oedema is well recognised (although rarely sought) by generalists, that of painless myocardial ischaemia without infarction, which can be thought of as angina equivalent in this context,2 is little known outside cardiology circles. The disorder is, however, probably a more important cause of unheralded pulmonary oedema than renovascular disease. Patients exhibiting this phenomenon are generally elderly and have severe coronary artery disease, typically with one occluded vessel and a severely stenosed coronary artery supplying collateral flow.2 Suddenly reduced flow in the collateral vessel, or increased myocardial oxygen demand, might, therefore, produce a large area of reversibly ischaemic myocardium, causing transient left-ventricular dysfunction, raised left-ventricular enddiastolic pressure, and acute pulmonary oedema.2 Only a minority of myocardial ischaemic episodes cause chest pain, and, given that left-ventricular dysfunction arises before electrocardiographic changes and pain during these episodes, it is not surprising that this process can be entirely painless. The proportion of all cases of pulmonary oedema accounted for by
THE LANCET • Vol 358 • November 10, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.