Chelation with DTPA

Variations of this blog have been previously written, but it is worth repeating, as it is central to

management of GDD. The following is the protocol that we generally use. I will also provide rationale for this protocol and suggest reasonable modifications, and when to use them.

This protocol we have published in our article on DTPA chelation published in Investigative Radiology, but often perform in a simplified fashion. We administer Ca-DTPA on

day 1, and Zn-DTPA on day 2. An iv is started with 20 - 22 gauge iv cath and hang a 1 L bag of normal saline. The 5 ml ampule of DTPA we inject as two 2.5 ml injections, each as a 1 min bolus pushes into the iv line We space the split dose approximately 50- 80 minutes apart while the iv is running. We have the patient initially sitting upright for about 30-40 minutes, and then reclining for the second half.

The reason why we have used the iv push (bolus injection) of contrast, rather than diluting the quantity of DTPA (the entire 5 ml) into 1 Litre of solution is to replicate how the GBCA was administered to begin with: as a bolus injection and not an iv drip. We have used this bas

ed on earlier work first described with iodine contrast in the early 1980s and then later with GBCAs around 1990, bolus injection forces contrast agents into the tissues at higher concentration than drip infusion, which has allowed better visualization of lesions in organs on imaging studies. Therefore our opinion is, that with the dynamic injection of GBCA contrast agent typically administered at a rate of 2.5 ml/min, contrast is forced into interstitial tissues at higher concentration in a short time interval, and has thus likely deposited this way. So in effect we want the chelator, DTPA, to chase down/ follow the same pathway as the Gd now deposited into interstitial tissues. Our opinion, again using the contrast agent experience, drip infusion does not result in that high a concentration of DTPA into interstitial tissues, so may not capture as much agent. That is our explanation for bolus injection.

The reason why we start by having the patient sitting is again to follow where the Gd seems to be most accumulated - in the lower arms and legs, so we initially want the DTPA to pool in those locations to capture Gd. We then have the subject lie supine to facilitate the rechelated Gd-DTPA to be removed from veins in the legs and lower arms and excreted by the kidneys. We have used empirical reasoning for this.

We also based our approach of iv push administration technique of Ca-DTPA on the first day and Zn-DTPA on the second day to follow the protocol of the manufacturer for radioactive metals. It makes physiologic sense, Ca-DTPA is a better chelator for a range of metals and cations, and picks up more Gd (and other metals, including Zn) on the first day. Zn-DTPA is more selective for exogenous heavy metals and is more specific for Gd, so on the second day, the chelation process continues with more selective uptake of Gd, which we believe may also pick up Gd loosened but not

removed by Ca-DTPA on day 1. At the same time replenishing Zn, that had been removed on the first day. Measuring electrolytes should probably not be done until about 1 week after chelation as after the first few days following Zn-DTPA, the Zn appears frighteningly high, but will decrease over the course of a few days.

Splitting the dose into two equal volumes we have done to create essentially two chelation procedures into one day. In part, this acknowledges that with iv administrations one wants to minimize the number of completely separate sessions, for patient pain considerations (repeat iv sticks), and to diminish the number of sessions performed because most patients have travelled from a distance. . We space the bolus injections 60- 80 minutes apart, as the half life for Gd-DTPA (which we have created) in the body, is 90 minutes. We want to minimize the interaction of newly administered DTPA with rechelated Gd-DTPA, to minimize the possibility of new chelator removing Gd from recreated chelate.

The most important adverse reaction is the Flare reaction, which has been reported as occurring in 30-50% of patients, but actually occurs inn 100% of patients. The presence of a Flare to Ca-DTPA (Ca-DTPA because it is the most effective chelator- this reflects the effectiveness of the chelator and not a property of Ca-DTPA) is the most definitive clinical test verifying the patient has GDD, and is generally most intense for atleast the first 3 chelation sessions. We have described the Flare reaction in earlier blogs. It typically becomes most noticeable on day 3 (1 day following Zn-DTPA), and diminish by day 7. In the great majority it has already developed within 24 hrs, and may also be observed at the time of chelation. It is most likely to be severe if GDD is of recent onset (GBCA injection. within 3 months). We consider that dampening of the immune response is essentially always important concurrent with chelation.

Patients can leave the facility shortly after chelation.

Patients probably require atleast 5 chelation sessions (that is 5 of the paired administrations of Ca- and Zn-DTPA). Generally we prefer a 3-4 week spacing between sessions, as empirically it allows more time for the patient's metabolites to return to normal/ homeostasis - although shorter 1 week spacing is fine. We always aim to be on the cautious side as it is early in the clinical use of the agent, and we want to minimize potential problems with the chelation process. Prior blogs have described judging the spacing between sessions - patient response and Flare severity guides this.

With the first chelation we test 24 hr urine (pre- and after the first day with Ca-DTPA) to see what amount of Gd is being removed. It should be at least 4 times the amount of Gd in 24 hr urine than pre-treatment, to reflect that chelation is having an important and beneficial effect. We space the next 24 hr urine pre- and post till at 5- session intervals (5th, 10th chelation session) as a cost and patient convenience measure, and more frequent testing does not impact how I manage the patient.

Regarding concurrent use of supplements, it may be wise to stop supplements at least 2 days before and 3 days after chelation. We do not want ingredients of the supplements (eg: Manganese, Magnesium) to be picked up by the chelator DTPA, in place of Gd. Why infusions of cations like Magnesium around the time of chelation reduces Flare, is because Magnesium is being picked up instead of Gd, as we have previously written.

This above describes the standard protocol. Of course this is not the only method that works and variations may be reasonable to use. For example if calcium overload is present in a patient, a solely Zn-DTPA protocol would be appropriate, which also could be considered when more targeted and less aggressive Gd removal is favored.

Lower dose chelations, especially for the first session could be considered, however this would mean that relatively expensive chelate would have to be discarded. This is because standard practice with iv medications is that once the package/ampule is opened the iv agent must be used within a certain time frame. There would be guidelines for this, and virtually all guidelines call for discarding agent after 1 day (basically 12 hours), but often within 2-4 hours. So until we learn more, I am hesitant to recommend to all patients that they discard 2 ml of the 5mls they have paid for (which is not cheap) without based on definitive evidence that this is important. An added problem is that we would be discarding agent that could be binding to more Gd in their body, and removing it. Dilution of the chelator into the 1 Litre or 500 ml iv bag can also be performed, and the agent administered as a drip. It may result in less Flare but may also result in less removal of Gd. This is not determined as yet. Other manufacturers of DTPA have described the iv drip technique with their agent.

With now considerable experience, we favor the approach of using the standard method we have developed for DTPA administration and couple with an immune reaction dampening strategy the latter administered as a 7-9 day envelope around chelation.

Richard Semelka, MD