The Five Horsemen of GDD Flare Apocalypse, and strategies to manage.
These are the 5 Horsemen of the GDD Flare Apocalypse: initial deposition, stationary presence, removal, redistribution, re-equilibration.
Below they are listed and strategies to manage them.
Management: health care workers and patients must recognize GDD when it first arises after a GBCA injection. The principle treatment for GDD, as for most toxic exposures, is to never get another GBCA agent again. If GDD is recognized when it first occurs, often subtle findings with the first injection (unfortunately all too often, of many subsequent injections) and no more GBCA given ever again, the majority of sufferers will recover , to a considerable extent, on their own. Once it gets beyond the first injection, then advanced treatment is almost always necessary.
Management: two components: 1) removal of the toxin (obvious common sense)> chelation, 2) management of the host reaction to both presence and removal phases. Almost always the first step must be done, most often in combination with the second step. Occasionally the second step alone will suffice (most often with mild cases and just 1 GBCA injection). Stationary presence may progressively get worse, remain stable, or gradually diminish some with time. At present it is not possible to predict in advance which of these pathways GDD will follow in a particular person. Stationary presence does not mean there is no motion of Gd: there is always micromotion (which can be the source of intense Flare) and constant minuscule elimination of Gd from body reservoirs.
Management: there are two basic strategies to decrease Flare with removal: 1) manage the host response by immune system dampening, and 2) decrease the amount of chelator employed, and both. We have developed our Frame strategy to manage the host immune reaction, but a number of strategies may work. Until recently we have tried to avoid reducing the amount of chelator used., primarily because the agent is only manufactured in a 5 ml vial, and we have not wanted to throw away agent (that the patient has paid for), and since they generally have travelled from some distance, most individuals prefer to undergo fewer than more chelation sessions, hence want to have removed more than less Gd. Lesser amount of agent means more total sessions of chelation required. Some individuals may experience such severe Flares, even with immune dampening, that we have gone more often to 1 day Zn-DTPA only approaches, and even 1/2 dose Zn-DTPA, and generally still use Frame. Other approaches have been used, such as simultaneous administration of Mg iv. Administering another metal/cation lessens Flare because the Mg has competed with Gd for removal, so less Gd removed as explanation for less Flare. A more logical strategy would be simply to use less chelator. One can still supplement with Mg 2-3 days after chelation. This makes more sense.
Removal Flare generally arises right after the injection of the chelator, but can occur up to 3 days later.
Management: straightforward obvious approach: use the most stable chelator available. At present this is DTPA. In time the most stable available may be HOPO. Redistribution is the picking up of Gd, and shortly after re-releasing it, before the Gd -chelator molecule is eliminated in urine. This is what can happen: Gd pickup up in skin, re-released and travels to brain. This is also a very easy Flare to avoid.
Redistribution Flare arises right after injection.
Re-equilibration (le Chateliere's principle).
Management: Empirically we have employed a 3 week interval between chelation sessions, primarily for two reasons: 1. allows individuals to fly here, fly back home, and work or spend family time, and then return, and to hit the Goldilocks spot of enough time to allow some re-equilibration to occur, as a means to facilitate bone Gd removal, but not too much time that re-equilibration Flare has become too severe. We have not really explored as yet the concept about very short term interval between chelation sessions, even daily, to avoid re-equilibration Flare altogether?
There may be some important problems with too short intervals, which include: 1) no re-equilibration, therefore delayed removal from bone, 2) disturbing the electrolyte balance- and this may then be the actual circumstance where authority figures claim chelation can be dangerous, 3) requirement to pay close attention to serum values of native metals and cations to supplement them if too much removal has occurred with insufficient time to rebalance, 4) with so many daily needle sticks it may make sense to put in a central port, and I have wanted to avoid this - because of concern of complications from an indwelling iv line, highest on the list: thrombosis and embolization from the port line, and infection of the indwelling port. As it is directly situated in the vascular system, rapid dissemination of infection is facilitated. So these are the considerations that have caused me to not chelate more frequently than weekly. But I am looking into this subject, perhaps every other day Zn-DTPA.
Re-equilibration Flare arises after approximately 1 week, becomes prominent at week 4-5, plateaus for 2-3 months, and may start to diminish after that period. Repeat chelations ofcourse eliminate/reduce this Flare.
If the toxic exposure is a radioactive metal such as plutonium, I would absolutely do daily chelation, and probably with the stronger removal agent Ca-DTPA - from a risk-benefit analysis.
Richard Semelka, MD