- Email: [email protected]
Is harmonic imaging now fundamental?
COMMENTARY
scanning. Such selection would target thrombolysis at patients with clot to lyse and with potentially salvageable brain, and would prevent such therapy for those who cannot benefit but can still have an ICH. NINDS, ECASS I, and ECASS II did not screen patients by angiography or perfusion-diffusion scanning. A trial of 2400 patients in total would have a nominal power of 80% to find a clinically worthwhile absolute benefit of 6%. Since ECASS II suggested that giving alteplase within 6 h instead of 3 h did not increase hazard, this future trial should use a 6 h time window, thereby potentially benefiting far more patients. Patients with moderately severe stroke should predominate in the study, and the alteplase should be given intravenously at 0·9 mg/kg as in NINDS and ECASS II. Former debates about thrombolysis in acute ischaemic stroke have been about the relative merits of streptokinase and alteplase. A typical view is that streptokinase is dangerous since the three medium-sized “phase III” studies assessing it all showed an increased hazard related to intracranial bleeding.4-6 However, streptokinase has not been compared directly with alteplase, and the efficacy trials of streptokinase were not preceded by dose-ranging studies (unlike those of alteplase) so that the dose used, 1·5 MU, may have been excessive. Additionally, aspirin was used to varying degrees with streptokinase, whereas it was withheld for at least 24 h in NINDS and ECASS II. The Cochrane systematic review of thrombolysis provides tantalising, but indirect, evidence that aspirin may increase the risk of ICH in the presence of alteplase/streptokinase.3 Hence, streptokinase has been inadequately tested to date. However, much more development work (eg, doseranging studies) will have to be done to take streptokinase on, so there seems little further point doing so when a single large trial of alteplase should answer once and for all whether thrombolysis should be routinely used. Another issue to be sorted out in any trial of thrombolysis is how to manage hypertension during the acute phase of stroke. Both NINDS and ECASS II controlled hypertension before and during administration of alteplase,1,7 although there is no scientific basis for intervention,8 which has been challenged ethically.9 Further information on the management of hypertension in ECASS II is required. Finally, it is vital that doctors are trained in the interpretation of computed tomographic scans (as part of any training programme in stroke medicine,10 and as occurred in ECASS II), to minimise the risk that thrombolysis will be prescribed inaappropirately. I have received fees and expenses from Boehringer Ingelheim, which manufactures alteplase. I also act as consultant to other companies with an interest in acute stroke.
Philip Bath Division of Stroke Medicine, University of Nottingham, University Hospital, Nottingham NG7 2UH, UK 1
2
3
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group . Tissue plasminogen activator for acute stroke. N Engl J Med 1995; 333: 1581–87. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with tissue plasminogen activator for acute hemispheric stroke; the European Cooperative Acute Stroke Trial (ECASS). JAMA 1995; 274: 1017–25. Wardlaw J,Yamaguchi T, del Zoppo G. Thrombolytic therapy versus control in acute ischaemic stroke. In: The Cochrane Library, Issue 4, Oxford: Update Software, 1998.
THE LANCET • Vol 352 • October 17, 1998
4
Multicentre Acute Stroke Trial-Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346: 1509–14. 5 The Multicenter Acute Stroke Trial - Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335: 145–50. 6 Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996; 276: 995–96. 7 Brott T, Lu M, Kothari R, et al. Hypertension and its treatment in the NINDS rt-PA stroke trial. Stroke 1998; 29: 1504–09. 8 Bath FJ, Bath PMW. What is the correct management of blood pressure in acute stroke? The Blood pressure in Acute Stroke Collaboration. Cerebrovasc Dis 1997; 7: 205–13. 9 Slyter H. Ethical challenges in stroke research. Stroke 1998; 29: 1725–29. 10 Bath PMW, Lees KR, Dennis MS, et al. Should stroke medicine be a separate sub-specialty of medicine with its own training? BMJ 1997; 315: 1167–68.
Is harmonic imaging now fundamental? See page 1264 In the past 10 years, there has been striking growth in the applications of echocardiography in adult and paediatric medicine. Doppler techniques, including colour flow mapping, permit the diagnosis and quantification of all types of valvular heart disease, in many instances obviating the need for invasive studies. Transoesophageal echocardiography has rapidly been established as the technique of choice for the diagnosis of acute aortic dissections and the planning of surgical repair of the mitral valve, and it is increasingly being used in the search for cardiac sources of emboli and in the stratification of embolic risk in patients undergoing elective cardioversion for atrial fibrillation. Advances in digital technology have permitted widespread use of echocardiography as an alternative to stress testing with nuclear perfusion imaging, both for the diagnosis of coronary artery disease and for the assessment of myocardial viability. Although the recent advances in ultrasound technology have expanded the indications for echocardiography to more esoteric diagnoses, the commonest reason for this investigation in adults is to get an answer to a fundamental question: “what is the ejection fraction?”1 Information on left-ventricular function is essential to the clinician who is caring for patients with symptoms thought to reflect cardiac disease, or patients with a clinical diagnosis of heart failure. In these instances, the estimation of ejection fraction with reasonable accuracy and reproducibility is key to proper therapy (eg, with inhibitors of angiotensin-converting enzyme).2 The assessment of systolic function by echocardiography depends on adequate visualisation of most, if not all, of the walls of the left ventricle. Despite the best efforts of experienced sonographers and the availability of highquality, state-of-the-art equipment, the images are, at times, technically inadequate for this purpose. Age, obesity, chronic lung disease, and recent thoracic surgery increase the likelihood of technically inadequate images. In today’s Lancet, Kenneth Caidahl and co-workers describe their investigation with a technical advance, harmonic imaging, which promises to reduce the frequency of inadequate echocardiographic studies in clinical practice. Harmonic imaging developed as a means of potentiating the effects of ultrasound contrast agents, and the term refers to the fact that the ultrasound received back by the imaging transducer is a multiple, or harmonic, of the ultrasound emitted. By properly filtering the returning signal, harmonic imaging greatly increases the signal-to-noise ratio of the received signal.3 1239
COMMENTARY
There are two types of harmonic imaging—harmonic imaging with contrast agents and tissue harmonic imaging.3 Various ultrasound contrast agents (“microbubbles”) have been used to enhance images of the left ventricle or myocardium, but until recently these agents had to be injected directly into the left ventricle or coronary arteries, which limited their applicability to the catheterisation laboratory or operating theatre. Now there are commercially available agents (and others are in development) that can be passed through the pulmonary circulation, so opacification of the left-ventricular cavity is obtainable with a peripheral intravenous injection.4 Contrast harmonic imaging exploits the resonance characteristics of microbubbles when these bubbles are exposed to an acoustic field, thus improving the ability to detect contrast-containing structures while suppressing the reception of echoes from non-contrast-containing structures. This technique has enabled investigators to observe blood flow within intramyocardial arteries, and improved the cavity enhancement provided by contrast injection with standard, “fundamental” imaging.4 Tissue harmonic imaging uses the fact that harmonic energy is generated as ultrasound passes through tissue. An ultrasound machine equipped for harmonic imaging can selectively display images created with harmonic energy and suppress many artefacts that bedevil conventional, fundamental images. How useful is tissue harmonic imaging? To study this issue, Caidahl and colleagues assessed a group of patients with ischaemic heart disease and a group with systemic sclerosis, a disorder that affects the myocardium and endocardium. All patients underwent fundamental and tissue harmonic imaging, with equipment that is now commercially available. On a variety of measures— some technical and related to gray-scale imaging, some related to the frequency of “unacceptable images”—tissue harmonic imaging provided incremental value compared with fundamental imaging. Importantly, it improved the reproducibility of measurement of the ejection fraction. Do the data presented live up to the researchers’ characterisation of harmonic imaging as a “landmark" advance in echocardiography? An important (and as yet unanswered) question is whether harmonic imaging improves outcome in clinical practice. For example, does tissue harmonic imaging lead to fewer suboptimum images, and thus reduce the number of additional tests? Despite this caveat, Caidahl and colleagues are probably correct in believing that harmonic imaging is an important technical advance that will influence clinical practice. Experience with harmonic imaging in Massachussetts is that the technique helps substantially with suboptimum images, in indirect proportion to the quality of the fundamental images—those studies with the worst fundamental images seem to gain the most from the application of tissue harmonic imaging.3 It goes without saying that experience with this technique is important; harmonic imaging tends to “enhance” both myocardial and valvular tissue and at first glance normal valves may seem abnormally thickened. Importantly, however, the interface between the endocardium and the ventricular cavity is almost always enhanced, thus enabling better assessment of wall motion and whether there is likelihood of ischaemic heart disease. For that reason, when possible (not all echocardiographic machines in use are equipped with the appropriate hardware and software), tissue harmonic imaging is used 1240
whenever fundamental imaging is suboptimum. It is likely that harmonic imaging, alone or in combination with contrast agents, will become a routine part of echocardiography (and stress echocardiography), especially in patients who present technical challenges.
Gerard Aurigemma Department of Medicine, University of Massachusetts, Worcester, MA 01655, USA 1
2 3 4
Krumholz HM, Douglas PS, Goldman L, Waksmonski C. Clinical utility of transthoracic two-dimensional and Doppler echocardiography. J Am Coll Cardiol 1994; 24: 125–31. Poole-Wilson P. Prediction of heart failure —an art aided by technology. N Engl J Med 1997; 336:: 1381-82. Thomas JD, Rubin DN. Tissue harmonic imaging. Why does it work? J Am Soc Echocardiogr 1998; 11: 803–08. Grayburn PA, Weiss JL, Hack TC, et al. Phase III multicenter trial comparing the efficacy of 2% dodecafluropentane emulsion (Echogen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiogram. J Am Coll Cardiol 1998; 32: 230–36.
New strategies for prevention and treatment of noise-induced hearing loss New developments that provide the basis for strategies for the prevention of noise-induced hearing loss will soon be tested in clinical trials. If effective, these strategies will have enormous impact for the 600 million or more people who work in potentially hazardous noisy places; 25–30 million of these people are in Europe and a similar number are in the USA.1 Environmental and leisure-activity noise is increasingly contributing to acquired hearing loss, and the probability of such impairment increases if noise exposure is combined with other factors such as chemicals, extreme temperatures, and vibration. There are indications that, when combined with exposure to ototoxic chemicals, even noise levels within current exposure limits can result in hearing loss.2 Excessive exposure to noise damages the sensitive cochlear structures through direct mechanical damage or through metabolic overload due to overstimulation. Direct shearing forces damage the outer hair cells of the organ of Corti in the cochlea and the delicate displacement-detecting stereocilia that are the weakest link in the transduction of sonic information to the cochlea. Outer hair cells provide biomechanical feedback to enhance cochlear sensitivity and frequency selectivity, whereas the inner hair cells relay signals to the brain via the VIIIth cranial nerve. For mechanical damage, repair is unlikely, but there is some potential for pharmacological strategies to counter or reverse metabolic effects. Pathological changes can be observed in the nucleus and cytoplasmic structures. Furthermore, membrane alterations lead to changes in ionic composition and herniation of cell contents. Vascular changes in the stria vascularis and the spiral ligament have also been reported. No direct relation between pathophysiological changes and function has yet been defined. Thresholds may be normal despite substantial loss of outer and inner hair cells and cannot be predicted accurately on the basis of the extent of hair-cell loss; nor can pathological changes be predicted from threshold. However, noise characteristically causes a notch in auditory sensitivity in the region of 2–8 kHz, with reduction in the dynamic range of hearing and with impairment of the ability to enhance selectively the detection of a specific frequency of signal. There may also be pitch distortion, speech impairment, and tinnitus. Since molecular alterations
THE LANCET • Vol 352 • October 17, 1998
scanning. Such selection would target thrombolysis at patients with clot to lyse and with potentially salvageable brain, and would prevent such therapy for those who cannot benefit but can still have an ICH. NINDS, ECASS I, and ECASS II did not screen patients by angiography or perfusion-diffusion scanning. A trial of 2400 patients in total would have a nominal power of 80% to find a clinically worthwhile absolute benefit of 6%. Since ECASS II suggested that giving alteplase within 6 h instead of 3 h did not increase hazard, this future trial should use a 6 h time window, thereby potentially benefiting far more patients. Patients with moderately severe stroke should predominate in the study, and the alteplase should be given intravenously at 0·9 mg/kg as in NINDS and ECASS II. Former debates about thrombolysis in acute ischaemic stroke have been about the relative merits of streptokinase and alteplase. A typical view is that streptokinase is dangerous since the three medium-sized “phase III” studies assessing it all showed an increased hazard related to intracranial bleeding.4-6 However, streptokinase has not been compared directly with alteplase, and the efficacy trials of streptokinase were not preceded by dose-ranging studies (unlike those of alteplase) so that the dose used, 1·5 MU, may have been excessive. Additionally, aspirin was used to varying degrees with streptokinase, whereas it was withheld for at least 24 h in NINDS and ECASS II. The Cochrane systematic review of thrombolysis provides tantalising, but indirect, evidence that aspirin may increase the risk of ICH in the presence of alteplase/streptokinase.3 Hence, streptokinase has been inadequately tested to date. However, much more development work (eg, doseranging studies) will have to be done to take streptokinase on, so there seems little further point doing so when a single large trial of alteplase should answer once and for all whether thrombolysis should be routinely used. Another issue to be sorted out in any trial of thrombolysis is how to manage hypertension during the acute phase of stroke. Both NINDS and ECASS II controlled hypertension before and during administration of alteplase,1,7 although there is no scientific basis for intervention,8 which has been challenged ethically.9 Further information on the management of hypertension in ECASS II is required. Finally, it is vital that doctors are trained in the interpretation of computed tomographic scans (as part of any training programme in stroke medicine,10 and as occurred in ECASS II), to minimise the risk that thrombolysis will be prescribed inaappropirately. I have received fees and expenses from Boehringer Ingelheim, which manufactures alteplase. I also act as consultant to other companies with an interest in acute stroke.
Philip Bath Division of Stroke Medicine, University of Nottingham, University Hospital, Nottingham NG7 2UH, UK 1
2
3
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group . Tissue plasminogen activator for acute stroke. N Engl J Med 1995; 333: 1581–87. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with tissue plasminogen activator for acute hemispheric stroke; the European Cooperative Acute Stroke Trial (ECASS). JAMA 1995; 274: 1017–25. Wardlaw J,Yamaguchi T, del Zoppo G. Thrombolytic therapy versus control in acute ischaemic stroke. In: The Cochrane Library, Issue 4, Oxford: Update Software, 1998.
THE LANCET • Vol 352 • October 17, 1998
4
Multicentre Acute Stroke Trial-Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346: 1509–14. 5 The Multicenter Acute Stroke Trial - Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335: 145–50. 6 Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996; 276: 995–96. 7 Brott T, Lu M, Kothari R, et al. Hypertension and its treatment in the NINDS rt-PA stroke trial. Stroke 1998; 29: 1504–09. 8 Bath FJ, Bath PMW. What is the correct management of blood pressure in acute stroke? The Blood pressure in Acute Stroke Collaboration. Cerebrovasc Dis 1997; 7: 205–13. 9 Slyter H. Ethical challenges in stroke research. Stroke 1998; 29: 1725–29. 10 Bath PMW, Lees KR, Dennis MS, et al. Should stroke medicine be a separate sub-specialty of medicine with its own training? BMJ 1997; 315: 1167–68.
Is harmonic imaging now fundamental? See page 1264 In the past 10 years, there has been striking growth in the applications of echocardiography in adult and paediatric medicine. Doppler techniques, including colour flow mapping, permit the diagnosis and quantification of all types of valvular heart disease, in many instances obviating the need for invasive studies. Transoesophageal echocardiography has rapidly been established as the technique of choice for the diagnosis of acute aortic dissections and the planning of surgical repair of the mitral valve, and it is increasingly being used in the search for cardiac sources of emboli and in the stratification of embolic risk in patients undergoing elective cardioversion for atrial fibrillation. Advances in digital technology have permitted widespread use of echocardiography as an alternative to stress testing with nuclear perfusion imaging, both for the diagnosis of coronary artery disease and for the assessment of myocardial viability. Although the recent advances in ultrasound technology have expanded the indications for echocardiography to more esoteric diagnoses, the commonest reason for this investigation in adults is to get an answer to a fundamental question: “what is the ejection fraction?”1 Information on left-ventricular function is essential to the clinician who is caring for patients with symptoms thought to reflect cardiac disease, or patients with a clinical diagnosis of heart failure. In these instances, the estimation of ejection fraction with reasonable accuracy and reproducibility is key to proper therapy (eg, with inhibitors of angiotensin-converting enzyme).2 The assessment of systolic function by echocardiography depends on adequate visualisation of most, if not all, of the walls of the left ventricle. Despite the best efforts of experienced sonographers and the availability of highquality, state-of-the-art equipment, the images are, at times, technically inadequate for this purpose. Age, obesity, chronic lung disease, and recent thoracic surgery increase the likelihood of technically inadequate images. In today’s Lancet, Kenneth Caidahl and co-workers describe their investigation with a technical advance, harmonic imaging, which promises to reduce the frequency of inadequate echocardiographic studies in clinical practice. Harmonic imaging developed as a means of potentiating the effects of ultrasound contrast agents, and the term refers to the fact that the ultrasound received back by the imaging transducer is a multiple, or harmonic, of the ultrasound emitted. By properly filtering the returning signal, harmonic imaging greatly increases the signal-to-noise ratio of the received signal.3 1239
COMMENTARY
There are two types of harmonic imaging—harmonic imaging with contrast agents and tissue harmonic imaging.3 Various ultrasound contrast agents (“microbubbles”) have been used to enhance images of the left ventricle or myocardium, but until recently these agents had to be injected directly into the left ventricle or coronary arteries, which limited their applicability to the catheterisation laboratory or operating theatre. Now there are commercially available agents (and others are in development) that can be passed through the pulmonary circulation, so opacification of the left-ventricular cavity is obtainable with a peripheral intravenous injection.4 Contrast harmonic imaging exploits the resonance characteristics of microbubbles when these bubbles are exposed to an acoustic field, thus improving the ability to detect contrast-containing structures while suppressing the reception of echoes from non-contrast-containing structures. This technique has enabled investigators to observe blood flow within intramyocardial arteries, and improved the cavity enhancement provided by contrast injection with standard, “fundamental” imaging.4 Tissue harmonic imaging uses the fact that harmonic energy is generated as ultrasound passes through tissue. An ultrasound machine equipped for harmonic imaging can selectively display images created with harmonic energy and suppress many artefacts that bedevil conventional, fundamental images. How useful is tissue harmonic imaging? To study this issue, Caidahl and colleagues assessed a group of patients with ischaemic heart disease and a group with systemic sclerosis, a disorder that affects the myocardium and endocardium. All patients underwent fundamental and tissue harmonic imaging, with equipment that is now commercially available. On a variety of measures— some technical and related to gray-scale imaging, some related to the frequency of “unacceptable images”—tissue harmonic imaging provided incremental value compared with fundamental imaging. Importantly, it improved the reproducibility of measurement of the ejection fraction. Do the data presented live up to the researchers’ characterisation of harmonic imaging as a “landmark" advance in echocardiography? An important (and as yet unanswered) question is whether harmonic imaging improves outcome in clinical practice. For example, does tissue harmonic imaging lead to fewer suboptimum images, and thus reduce the number of additional tests? Despite this caveat, Caidahl and colleagues are probably correct in believing that harmonic imaging is an important technical advance that will influence clinical practice. Experience with harmonic imaging in Massachussetts is that the technique helps substantially with suboptimum images, in indirect proportion to the quality of the fundamental images—those studies with the worst fundamental images seem to gain the most from the application of tissue harmonic imaging.3 It goes without saying that experience with this technique is important; harmonic imaging tends to “enhance” both myocardial and valvular tissue and at first glance normal valves may seem abnormally thickened. Importantly, however, the interface between the endocardium and the ventricular cavity is almost always enhanced, thus enabling better assessment of wall motion and whether there is likelihood of ischaemic heart disease. For that reason, when possible (not all echocardiographic machines in use are equipped with the appropriate hardware and software), tissue harmonic imaging is used 1240
whenever fundamental imaging is suboptimum. It is likely that harmonic imaging, alone or in combination with contrast agents, will become a routine part of echocardiography (and stress echocardiography), especially in patients who present technical challenges.
Gerard Aurigemma Department of Medicine, University of Massachusetts, Worcester, MA 01655, USA 1
2 3 4
Krumholz HM, Douglas PS, Goldman L, Waksmonski C. Clinical utility of transthoracic two-dimensional and Doppler echocardiography. J Am Coll Cardiol 1994; 24: 125–31. Poole-Wilson P. Prediction of heart failure —an art aided by technology. N Engl J Med 1997; 336:: 1381-82. Thomas JD, Rubin DN. Tissue harmonic imaging. Why does it work? J Am Soc Echocardiogr 1998; 11: 803–08. Grayburn PA, Weiss JL, Hack TC, et al. Phase III multicenter trial comparing the efficacy of 2% dodecafluropentane emulsion (Echogen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiogram. J Am Coll Cardiol 1998; 32: 230–36.
New strategies for prevention and treatment of noise-induced hearing loss New developments that provide the basis for strategies for the prevention of noise-induced hearing loss will soon be tested in clinical trials. If effective, these strategies will have enormous impact for the 600 million or more people who work in potentially hazardous noisy places; 25–30 million of these people are in Europe and a similar number are in the USA.1 Environmental and leisure-activity noise is increasingly contributing to acquired hearing loss, and the probability of such impairment increases if noise exposure is combined with other factors such as chemicals, extreme temperatures, and vibration. There are indications that, when combined with exposure to ototoxic chemicals, even noise levels within current exposure limits can result in hearing loss.2 Excessive exposure to noise damages the sensitive cochlear structures through direct mechanical damage or through metabolic overload due to overstimulation. Direct shearing forces damage the outer hair cells of the organ of Corti in the cochlea and the delicate displacement-detecting stereocilia that are the weakest link in the transduction of sonic information to the cochlea. Outer hair cells provide biomechanical feedback to enhance cochlear sensitivity and frequency selectivity, whereas the inner hair cells relay signals to the brain via the VIIIth cranial nerve. For mechanical damage, repair is unlikely, but there is some potential for pharmacological strategies to counter or reverse metabolic effects. Pathological changes can be observed in the nucleus and cytoplasmic structures. Furthermore, membrane alterations lead to changes in ionic composition and herniation of cell contents. Vascular changes in the stria vascularis and the spiral ligament have also been reported. No direct relation between pathophysiological changes and function has yet been defined. Thresholds may be normal despite substantial loss of outer and inner hair cells and cannot be predicted accurately on the basis of the extent of hair-cell loss; nor can pathological changes be predicted from threshold. However, noise characteristically causes a notch in auditory sensitivity in the region of 2–8 kHz, with reduction in the dynamic range of hearing and with impairment of the ability to enhance selectively the detection of a specific frequency of signal. There may also be pitch distortion, speech impairment, and tinnitus. Since molecular alterations
THE LANCET • Vol 352 • October 17, 1998