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“VTE [venous thrombo-embolism] is an uncompromising predator that can gnaw at the very strands of life itself.Yet it develops slowly, usually unseen and unheralded, to burst upon clinical consciousness with frightening rapidity”.
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. Large scale statistical data was last published in 1975 in Progess in Cardiovascular Diseases (Dalen JE and AlpertJS, vol 17:259-270) where the authors demonstrated graphically that of some 630,000 incidents of VTE per annum in the USA, 10% died from a pulmonary embolism (PE) within an hour of first symptoms. But most importantly, a further 22% died later following a misdiagnosis and no appropriate therapy, yet only 2% succumbed if the diagnosis was correct.
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.
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.

Respiratory Physiology. A recent 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.

A commercial apparatus was developed in conjunction with a small engineering firm in Sydney, Australia and more than 900 machines are now in use in 43 countries where about 200,000 diagnostic examinations are performed each year. It is estimated from sales of consumables that over 1.5 million patients have been studied with Technegas and no single report of adverse events attributable to the test itself have been logged by Regulatory authoritites.

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.

A derivative product, Pertechnegas, 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.

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.

Properties (click on hyperlinks to pages below)

Applications  (click on hyperlinks to pages below)

 

The outcome of a two year research program 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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Site published continuously since September 1996.

Content updated: September 2006
Content: Bill Burch
Layout Tim Senden
 

Bibliography

  • A scientific and clinical bibliography of currently 221 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.