The history leading to the discovery of Technegas
Early Ventilation Agents: Professor George Taplin’s group at UCLA were instrumental in recognising the importance of V/Q imaging and promoting its use with both 133Xe (an inert radioactive gas and a by-product of the uranium fission process) and99mTc-based aerosols as the ventilation agents. Despite an extensive range of protocols developed over the years,133Xe is far from suitable as a ventilation imaging agent because of its high radiation dose and a gamma emission energy (81keV), too low for good spatial resolution. All the aerosol agents produced by one type of nebuliser or another, were highly inefficient in terms of time taken to administer a reasonable dose, and their lung penetration was often compromised by airways obstruction, leading to almost complete trapping in the central airways in the significant proportion of patients thus afflicted.
An invited lecture from (the now late) Professor George Taplin at the first Asia and Oceania Congress of Nuclear Medicine in Sydney, September 1976 'Lung imaging in pulmonary disease' in effect highlighted the mismatch between the quality of the perfusion agent and the different ventilation agents, and led to our search for a better ventilation tool that was truly congruent with its perfusion counterpart.
The Basic Anatomic hurdles: Evolution of land-based mammals over countless millennia is elegantly demonstrated in the structure and function of the human lung. At its core is a two cell thick membrane separating the outside air from our blood, and in the adult human, its surface area would cover about half the area of a tennis court. To ensure that only clean air, free from dust and other natural aerosols reaches this membrane, it has to navigate a tortuous pathway involving 23 bifurcations of pipes of decreasing diameter. Moreover, as the branching goes deeper the angle of the branch gets steeper, further encouraging inertial impaction of any particles at the junctions; and at each junction lies a lymphatic opening ready to swallow any foreign particle that does impact. To add further protection, the vapour in the bronchial tree beyond about the 3rd branch is supersaturated, ensuring rapid particle size growth, in a matter of milliseconds, where the particle is hydrophilic. Since a doubling of diameter leads to an 8-fold increase in momentum, this rapid particle growth enhances impaction at the bronchiolar junctions. Finally, there is a rapid clearing mechanism for inhaled particles that operates down to the 16th of the 23 branches of the bronchial tree, rhythmically washing impacted material up and out via the oesophagus. It is known as the muco-ciliary escalator, a neat demonstration of which is on a separate page on this site. As casts of lungs show, the overall shape and size is fully developed by the 12th branch, so that all the remaining branches are in-filled within that 3-D outline.
Form of efficiency curve for particle deposition in the lung (dp is particle diameter).
Aerosol Transport: The two basic mechanisms of particle transport in any gas are convection and diffusion, and these are independent parameters. Where the particles are small enough, they can remain suspended indefinitely in still air – all other things being equal. It was the realization that thousands of tons of lead were suspended as smog over major cities from vehicle exhaust in times gone by, that focused the research for a small form of Technetium particulate and which eventually became Technegas. In the lung, even under maximum breathing exertion, the airflow is laminar beyond about the 3rd division, and suspended particles, depending on size, will either be constrained by the dominant convective flow to remain in the stream until the flow ceases, or their momentum will override the ever increasing sharp branching of the bronchi, leading to impaction at the junctions. If the particles are small enough, they will remain in the lumen of the airway, all the way to the alveolus. A summary of this transport process is clearly portrayed in the classic graph by Friedlander. It is a ‘meta-analysis’ from multiple data sources demonstrating the fraction of an inhaled aerosol deposited in the lung as a function of particle size.
It is important to keep these basic details in mind when reviewing the claimed efficacy of various ventilation agents in Nuclear Medicine. One of the reasons Technegas was named thus, was to highlight the very real transport differences compared with conventional aerosols once inhaled. Unlike all other aerosols for imaging - and even therapeutic applications - however generated, Technegas is unique in being hydrophobic. It will not grow as it navigates its way into the depths of the lung, therefore it exhibits virtually no deposition in the conducting airways, except in very severe chronic obstructive airways disease (COPD). Indeed its intrinsic gas-like behaviour was validated by use of a “Penetration Index” (PI) which compared the distribution of the peripheral to central regions of each lung against the same regions ventilated with 133Xe gas. Crawford and his colleagues, back in 1990 found, after studying 12 male subjects with COPD, that “even in the presence of severe airways limitation, the radio-labelled tracer Technegas mimics the regional distribution of a real gas”. A more recent report comes from a group in Korea. It seems to be part of an academic thesis, and only a summary of the material is presented in English. But in essence, a group of 12 patients with various COPD pathologies were studied comparing Technegas with DTPA aerosol, quantifying the image quality with the PI. They concluded: “The average values of PI were 61.26% with 99mTc-DTPA aerosol and 69.20% with Technegas (p〉0.05). Using 99mTc-DTPA aerosol, COPD patients showed deposition in the central airways with poor visualization of the peripheral areas of the lungs. In Technegas studies these phenomena were less prominent, and the examination is well tolerated by patient and requires only a minimum of patient cooperation.”
Thus when an aerosol manufacturer claims a certain particle size using the standard aqueous ingredient DTPA, and that their aerosol is ‘superior in alveolar deposition’ the figure and the claim is effectively meaningless as it only refers to the size at generation, not after it reaches equilibrium with the super-saturated vapour in the bronchial tree only a little way up (down) the ‘trunk’. It is inconceivable that in patients with COPD, the PI for a DTPA aerosol would be anything like the value for Technegas. But it is the PI that really matters in terms of imaging the ventilation of all your patients. Even inhalation of a good quality insect spray loaded with DTPA will generate a reasonable looking image in healthy lungs!
It is not really necessary to quantify the comparison between ‘wet’ aerosols and Technegas via the PI. If you need to validate the point, a simple test can be done in the course of a regular study investigating PE, and will only require the informed consent of the patient. On a patient with known COPD, administer 0.5 the standard activity with Technegas and take a single PA view for double the imaging time, then administer the remaining dose with the aerosol, and re-image to acquire about double the total counts of image 1. Subtract the decay corrected original Technegas counts and compare the first and last images.
Friedlander SK. Smoke, Dust and Haze (fundamentals of aerosol behavior). Publ. Wiley 1977, p4.
Dolovich MB, Sanchis J, Rossman C, Newhouse MT. J Appl Physiol 1976: 40; 468-471.
Crawford ABH, Davison A, Amis TC, Engel LA. Eur Respir J 1990: 3;686-692.