So wrote Henry W Gray as part of a dramatic personalised introduction to his excellent review ‘The Natural History of Venous Thromboembolism: Impact on Ventilation/Perfusion Scan Reporting’ published in Seminars in Nuclear Medicine vol XXXII, 159-172, 2002. Further illustration of the importance of an urgent correct diagnosis and therapy is given by Frank Broderick in a personal review for this site of a 47 year Physician practise.

The Diagnostic Difficulty of Pulmonary Embolism

Pulmonary Embolism (PE) is currently listed as the third highest cause of death in hospitalised patients in the USA. A national survey published back in 1975, as summarised in the diagram below adapted from that survey, is still being quoted in support of the need to take care in ensuring the correct diagnosis is made. It is generally agreed that a clinical differential diagnosis is only accurate in about 60+% of cases, underlining the critical importance of a high quality, rapid, safe and easily performed screening test.

These statistics emerged at about the same time as the ventilation/perfusion (V/Q) procedure was evolving in Nuclear Medicine departments as a diagnostic tool for PE. Macro-aggregated albumin (MAA) labelled with 99mTc was from the very start recognised as the ideal perfusion agent. But there arose a plethora of ventilation agents, all of which were considerably inferior in terms of providing a true congruent image of airways distribution, to the MAA perfusion under routine clinical conditions. As a consequence, publication of numerous ‘algorithms’ for reporting the V/Q images left many referring Clinicians feeling they were not much better off than trusting in their own clinical judgement for a diagnosis.

PIOPED. Then along came the publication of the results of PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis JAMA 1990: 263;2753-2759)a major USA-based multi-centre clinical trial that for the first time set out to put some quantitation into the V/Q image result data against the ‘gold standard’ of pulmonary angiography. There were subsequent publications reinterpreting the data, and ultimately a “PIOPED II” in 2002 (Seminars in Nuclear Medicine volXXXII; 173-182; Gottschalk A et al.). In a sense PIOPED II reflected the anomalous position the USA Nuclear Medicine fraternity had found itself in for not having access to high quality ventilation agents, and the concomitant imaging techniques, largely because of regulatory inhibitions.
They were still locked in to >30 year old technique of single view planar images with 133Xe, or at best, 8 view planar DTPA aerosol studies as the ventilation (V) component of a V/Q study to be compared with the latest X-ray tomographic technology (MDCT). Meanwhile, in all other countries where advanced Nuclear Medicine is practised, very high quality tomographic V/Q is now demonstrated, through numerous peer reviewed publications (listed chronologically on this site) to, at worst, be equal in specificity and sensitivity to MDCT without the excessive radiation dose, or hazard from injecting x-ray contrast materials.
Indeed, at the 2005 European Nuclear Medicine Congress in Istanbul, at an invited presentation, Professor Carl Schümichen from Rostock in Germany noted "In the individual patient, both occlusive and non-occlusive emboli are present, otherwise a high sensitivity of scintigraphy could not be achieved. In a patient-by-patient analysis (PE yes or no), V/Q scanning is superior to multislice CT and sensitivity of scintigraphy is increased even more by SPECT." The full abstract of his talk can be found here.Howarth and his colleagues recently published an authoritative report demonstrating that a V/Q mismatch of >0.5 segment, if necessary summed in both lungs is indicative of PE. Over a total of 924 patients followed up for three months, this simplified unambiguous reporting criterion returned <5% indeterminate rate, bringing a much needed diagnostic certainty to light. An abstract of the report is here.
Much needed objectivity has now been brought to the SPECT story in a major report from Australia’s most experienced respiratory imaging group. By measuring V/Q ratios they have been able to demonstrate a high diagnostic accuracy in patients with suspected PE. Their objective analysis has the potential to reduce the number of non diagnostic scan results, and may be useful for quantifying V/Q mismatch in other pulmonary disorders. (Biblio ref# 236).

Respiratory Physiology. An attempt to try and measure the ability of various radio-gases and aerosols, including Technegas, to correlate with FEV1 data in 20 patients with COPD has been reported (Magnant J, et al. J aerosol Med 2006;19:148-159). Unfortunately, the basic methodology is flawed in that the techniques for inhaling each agent is different, leading to anomalous conclusions for both Kr-81m and Technegas .

Technegas was the name coined in November 1984 to describe what we now know to be a specialised sub-set of nano-encapsulated carbon composites. Technegas, as produced in a purpose-built apparatus for lung ventilation work, consists of hexagonal flat crystals of Technetium metal cocooned in multiple layers of graphite sheets completely isolating the metal from the external environment. Each particle is from 5-30nm in cross-section and 3nm thick, and is suspended in an argon carrier gas as a consequence of its production. The discovery of Technegas was the outcome of an eight years search for the "ideal" diagnostic ventilation agent to complement Technetium-labelled macro-aggregated albumin (MAA) in the combination V/Q radionuclide diagnostic examination for the differential diagnosis of pulmonary embolism or blood clots in the lung.Details of the History of the development of Technegas are located on a separate page.|
A commercial apparatus was developed in conjunction with a small engineering firm in Sydney, Australia, and the first machines sold locally in 1986. Now about 1000 machines are in use in 43 countries where about 200,000 diagnostic examinations are performed each year. It is estimated from sales of consumables that 2,000,000 patients will have been studied with Technegas by October 2007 without a single report of adverse events attributable to the test itself logged by Regulatory authorities anywhere. A modified production technique to improve particle size uniformity and yield is available in a second generation machine and known as "Technegas Plus".

Image fusion and subtraction. Multi-slice computed tomographic angiography (CTA), an x-ray imaging modalitiy has displaced V/Q imaging for PE in some centers. But with the availability of Technegas tomographic ventilation to complement the perfusion studies and the use of the “quotient” software concept, there is increasing recognition that the “indeterminate” rate for V/Q is no worse than CTA. Ease of patient compliance alone puts the V/Q Nuclear Medicine modality well in front. Ultimately, it seems to come down to proper recognition that PE demands an urgent and correct diagnosis and treatment.

Pertechnegas, a derivative product, is now finding an application in diagnosing pathology specifically involving the permeability of the alveolar-capillary membrane. Papers which demonstrate applications of this agent are cited in the Pertechnegas bibliography and there are currently 38 citations in this page.
Careful experimental observations of TLC strips by the late Rod Browitt (see tribute) from our lab in 1995 identified what he termed a “Third Species” lying somewhere between Pertechnegas and Technegas. Based on how it arises, we hypothesized that it represents an insoluble oxide of Technetium, but no additional developmental work has been done on it.Nemmar et al in a paper in Circulation (Bibl ref # 199) may have incidentally discovered the 3rd Species in a clinical study. But Nicholas Mills and his colleagues from Edinburgh in the UK have just published a comprehensive report on 10 volunteers (Mills NL, Amin N, Robinson SD et al.,"Do inhaled carbon nanoparticles translocate directly into the circulation in humans?" Am J Respir Crit Care Med 2006; 173: 426-431) that clearly demonstrates no movement of Technegas into the systemic circulation, a finding that concurs with data we collected as part of the regulatory requirements in 1986. The abstract of this important paper is here.
The Swedish Karolinska group has also published a second paper reaffirming Mills findings (Biblio # 235) and further emphasising that the particles are retained in the lungs at least for the measurable lifetime of the radionuclide (~24h).

ThromboTrace® is the name given to a product formed by electrostatically suspending Technegas particles in aqueous solutions using a device developed by one of our research group Rod Browitt, and termed a Precipitron. The entire activity of the Technegas generator can be transferred to 1mL of injectable liquid such as 5% glucose in a few minutes, autoclaved and on iv injection it has been shown to locate actively developing DVT in humans and experimental PE in rabbits. Details of the preliminary phase 1 clinical trial of this agent were presented at the WFNMB meeting in Berlin in 1998 (bibl. Ref. # 144).
The United States patent office has now granted (December 20, 2005) a patent to the ANU (#6,977,068) for ThromboTrace under the title "Method for detection of fibrin clots",acknowledging the extensive research work by our small team over many years. The priority date was set as July 24, 1997 and the full published patent description contains much of the data and images acquired in our laboratory at the School.

Technecoat™ has now been developed by a British Company, Pharmaceutical Profiles as a product that simply labels dispersable drugs with Technegas to trace the lung distribution and retention of the drugs on inhalation. It looks like being a useful tool in refining parameters relating to lung deposition of different drug formulations. A paper on the work is logged as Bibl Ref #202.

Analysis of the effects of smoking low tar cigarettes using Technegas.   Progress on this study from the Menzies Research Institute in Tasmania may be found on their web site www.menzies.utas.edu.au  

Environmental applications for Technegas are being developed by the Swedish national Air Pollution and Health Effects Program (SNAP). Further details can be found on their web site.

A Screening test for Pulmonary Embolism?
That so many different “tests” for PE are extant after all these years of new and better medical diagnostic procedures, is proof enough that no universally recognised screening test exists; and that a final diagnosis is arrived at via various pathways, depending on clinical experience and technology availability inter alia.
Ideally any screening test should be non-invasive, or trivially so, for example a venous blood sample and applicable for all patients. But the more serious the consequences of a missed diagnosis will to a large extent raise the threshold of invasiveness tolerated for that diagnosis to be made. Hence the tendency to ignore ‘hidden’ invasiveness like radiation burden, by using computerised tomography pulmonary angiograms (CTPA) for seeking to differentiate PE.
The greatest single factor leading to this trend amounts to a perception that higher resolution is better because it will lead to more definitive diagnoses of smaller lesions. And coupled with that, is the lack of current high quality literature defining a practical threshold lesion size equally met by other less invasive technologies such as V/Q. The first report of a threshold lesion size of ≥ 0.5 segment by Howarth and his colleagues(1), was established through outcome studies on 924 patients who had V/Q as their primary investigation. It will hopefully stimulate replication and validation and should lead eventually to a sensible re-appraisal of the importance of this less invasive and more universally applicable technology for PE diagnosis.

Breath-hold transverse slice at level of hilum.
Note penetrations of the main bronchi.

Unlike any Radiology procedure, the Nuclear Medicine patient’s dose is committed at injection (or inhalation) of the radiotracer. Resolution for a given detector and processing system approaches the limiting value as the counts rise and in practice is a trade-off between tolerable imaging time linked in turn to patient or organ movement. This transverse slice from one of our research group in the mid 1990’s at about the level of the hilum, shows what is technically achievable with a volunteer, performing 64 breath-hold manoeuvres and imaged on a 30 year old single head GE Camera.
Radiological imaging, by contrast, demands more photons passing through the body in order to deliver better resolution. Hence the now oft-expressed concern particularly about breast dose in multi-slice CTPA.(2)
But if a lesion size threshold of clinical importance as described by Howarth (1) can be validated, then the need for spatial resolution beyond the limits of gamma cameras vanishes and V/Q can return to its rightful place as the pre-eminent screening test for PE, eliminating both the higher radiation burden and the significant number of patients (~15%) who cannot be imaged for reason of hazard from contrast injection or complete inability to breath-hold.
Mammography is a standard screening test for breast cancer delivering a non-trivial radiation burden, and it is instructive to compare as Parker did (2), for example, the dose received from that test with a CTPA. He finds that CTPA delivers a minimum of 20mGy breast dose compared with 3mGy for mammography. A combined V/Q procedure using 37MBq of Technegas followed by 150MBq of MAA delivers only 1.4mGy, or about half the mammography dose to the female breasts.

How significant is size for PE?
In principle, any PE reflects a dissecting thrombus somewhere in the venous circulation, and some have argued that inconsequential minor PE’s could arise routinely in the course of the body’s vascular maintenance activity. But what really does constitute that all-important warning ‘flag’ bringing the patient in and leading to anti-coagulant therapy? Howarth’s report (1) has given a sound basis from which to work, and its important to recognise that the 0.5 segment threshold is a cumulative figure that can be made up of multiple smaller elements. As noted in “Harper’s Biochemistry”(3), the initial clot formed in the complex cascade of thrombus production is rather weak, held together only by the non-covalent association of fibrin monomers. Only later do the covalent cross-links form, yielding a more stable fibrin clot. It may well be these fresh clots that further fragment in their turbulent passage through the right heart giving rise to the multiple small emboli often seen peripherally and accompanied most frequently by chest pain symptoms.
Recently at the world Federation meeting in Seoul, Korea, Härkönen (4), and his group from Finland have demonstrated that 14 of 43 cases (32%) who were CT negative demonstrated PE on V/Q SPECT. They were made up of 6 patients with a cumulative defect size equivalent of 1 segment, 4 with 1.5 segments and 4 with 2 segments equivalent defect volumes. These would all clearly qualify within the Howarth criterion of ≥ 0.5 segment minimum.
It is to be hoped that more work will be reported on this important point of size threshold as it has significant ramifications both in terms of immediate diagnosis for the patients together with the radiation insult necessary to make the diagnosis.

(1) Howarth DM, Booker JA, Voutris DD. Diagnosis of pulmonary embolus using ventilation/perfusion lung scintigraphy: more than 0.5 segment of ventilation/perfusion mismatch is sufficient. Int Med J 2006: 36; 281-288

(2) Parker MS, Hui FK, et al. Female breast radiation exposure during CT pulmonary angiography. AJR 2005;185:1228-1233.

(3) Murray RK, Granner DK et al (Eds). Harper’s Biochemistry 1993: 23rd ed; p681, Publ. Prentice-Hall.

(4)Härkönen RA et al. Detection of pulmonary embolism by ventilation/perfusion SPECT in cases where helical CT was non diagnostic. Poster, WFNMB 2006 Seoul, Korea.

Bibliography
A scientific and clinical bibliography of currently 236 publications attests to the perceived value of the agent. It is particularly encouraging to read of new reports of experimental work in sheep (ref# 213) indicating how useful Technegas is in monitoring lung physiological parameters. Increasing use of SPECT imaging techniques is finally being reflected by more positive reports in comparison with alternative x-ray based imaging.Quantitative regional lung data (ref# 214) and identification of PE with severe co-existing pneumonia (#216) are published, as well as the use of Technegas SPECT in detecting chronic rejection following lung transplantation (#217). A set of early SPECT abstracts from the bibliography is reproduced here.

A “Universal” radiotracer. The outcome of ongoing research at the Browitt Nanoparticle research Laboratory here at the ANU has identified several exciting future applications for the Technegas technology involving the graphitic cocooning of many other nuclides as well as Technetium, and leading towards the realisation of a "universal" radio-tracer. This tracer, to the external environment, can be manipulated as a structured carbon cluster, while within the graphitic cage of each particle lies a nano-crystal of any one of a range of radioactive metals.
Please browse through the topics presented by the headings in blue and underlined, including some lung images very kindly provided by users whose identities are listed with the images they have supplied. This site is maintained to serve the academic community. Any comments, criticisms, suggested additions to this site, may be directed to: bill.burch@anu.edu.au

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Content updated: December 2007
Content: Bill Burch
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