Finally, what else in terms acid-base / electrolyte problems contributed to by therapy with citrate itself?

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Problems associated with citrate administration
What is specific to citrate? You can have hypocalcemia, citrate gap, alkalemia, and some other issues here.

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Some commonly available citrate formulations, citrate blood levels, and basics of citrate metabolism
Just to reorient you, the citric formulations which are available on the market range from a 4 percent trisodium citrate, which is 0.14 molar, to a hypertonic citrate, which is 1.6 mol/L, to the ACD solution, which is used to anticoagulate stored plasma, and which is a mixture of citrate and citric acid.

Normal citrate blood levels are about 0.05 mmol/L. To prolong an ACT, you need about 4 to 6 mmol, and for blood storage, about 12 to 15 mmol/L.

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Citrate transport during CRRT
Citrate chelates calcium across the filter. In the ultrafiltrate, you have citrate and ionized calcium appearing. However, you deliver a fair amount of citrate across to the blood stream. That is shown here. This is a citrate transfer across the filter. Notice the post-filter citrate levels are still fairly high. That is what is contributing to the base load.

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Citrate metabolism
Citrate is metabolized such that each mole of citrate will give you 3 moles of bicarbonate. If you use a citric acid and citrate combination, there are 2 moles of net bicarbonate generated for each mole of the citrate / citric acid combination (3 from citrate, none from citric acid).

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Anticoagulation with citrate
Some of the data I am going to show you is from our analysis from a randomized study. These are my colleagues, whom I would like to acknowledge.

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Anticoagulation in CRRT Study: Patient distribution
We analyzed all of our citrate experience, which was over a five-year period, and these are the number of patients who were treated. This is the distribution of how they were treated across these parameters.

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Distribution of anticoagulants used by CRRT duration
We had over 18,000 hours of experience with citrate in that group; about 5,000 hours of heparin; and 2,500 hours of saline experience. The next few slides will reflect these three comparisons across these groups.

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Anticoagulation in CRRT Study: Hypernatremia
Here is the incidence of hypernatremia in the first 10 days of the procedure. The green is saline; the blue is heparin; the white is citrate. You can notice that actually the percentage of patients getting hypernatremic were greater in the patients who got no anticoagulation, just got saline. So despite the fact that using a hypertonic citrate solution, you are more likely to get hypernatremic if you are just using a saline flush for your anticoagulation.

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Anticoagulation in CRRT Study: Hypocalcemia
If you look at the ionized calciums of less than 1, it is more common in the first day or so when you are trying to fine-tune how much citrate is being given or how much calcium is being given to replace this. As you go further along in the course, this becomes a very minuscule incidence.

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Anticoagulation in CRRT Study: Alkalemia
In terms of alkalemia, as defined here with a pH of more than 7.45--see the percentage is pretty similar to some extent in the saline and the heparin categories. You have an 8 to 10 percent incidence for alkalemia across the board. Superimposed upon that, in the earlier part of our studies, we were seeing a fair amount of alkalemia. Now our incidence is down to about 2 percent or less, just because we have learned how much citrate to utilize and which are the high-risk populations.

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Source: Meier-Kriesche HU et al, Am J Kidney Dis. 1999 Apr;33(4):e8.

Hypocalcemica and citrate gap with CRRT
This is another example, and this is actually from Dr. DuBose's hospital, published in The American Journal of Kidney Disease, where they were using citrate anticoagulation to treat a patient.

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Source: Meier-Kriesche HU et al, Am J Kidney Dis. 1999 Apr;33(4):e8.

This graphically represents what they found. You can have patients who when you are giving citrate all of a sudden you find that their ionized calciums are persistently low. And since you have a protocol to replace the ionized calcium, you find you keep giving more calcium. You keep giving more calcium, but your ionized calcium continues to be low.

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Source: Meier-Kriesche HU et al, Am J Kidney Dis. 1999 Apr;33(4):e8.

What you end up finding is that you actually have raised the total calcium because all the extra calcium you gave is being complexed to citrate and produces an anion gap, which once you start removing the amount of citrate from the blood, will gradually correct. The reason is not that you are delivering more citrate; the reason is the patient is getting more citrate from exogenous products which are likely from blood.

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Citrate gap: Features
So the key features of this complication, what we have termed the citrate gap, is an increased total calcium, decreased ionized calcium, increased total to ionized calcium ratio, you have an increased anion gap, alkalemia may occur. So this is one of the conditions where you have a high anion gap in the presence of a pH which is alkalemic. Citrate levels are high, and the bicarbonate levels increase as the anion gap resolves.

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Citrate gap: Predisposing factors
The predisposing factors are impaired hepatic function, high citrate flow rate and a low blood flow rate, a large amount of blood products, and a low ultrafiltration rate or pre-existing alkalosis.

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Citrate content of blood products
I can't overemphasize this: If you notice here, for each one bag of FFP, which is a standard volume of 200, you have about 14 mEq of citrate per bag. In contrast, a liter of the solution we use has about 10 mEq/L. So over the course of a day if a patient is receiving 5 units of FFP, you have already greatly exceeded what you would give them in terms of citrate. So if you have a combination here, it is the blood products which will contribute to this.

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Citrate gap vs. duration of CRRT
When we looked at citrate gap across our population here, you can see it tends to develop somewhere downstream, again reflecting that over time you have some accumulated citrate. But if you separate out the patients who got the FFP in this, the incidence is actually very low.

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Citrate gap: management
So how do you manage a citrate gap kind of situation or alkalemia? The main thing is to reduce citrate delivery. Look at the blood flow products and the citrate flow rate, change the thresholds for citrate and calcium replacement, or in the worst cases, stop citrate anticoagulation.

In the previous years to treat alkalemia we were using hydrochloric acid to correct the alkalemia. However, we have not used that now for over six years. You can easy get away with alkalemia correction by simply changing the dialysate flow rates to 2 liters/hour. You will increase the clearance of citrate across the filter.

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A final area to think about is hypothermia.

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Case example of hypothermia with CRRT
This is exemplified by this patient. He is a 48-year old male. He had a C7 fracture. He was quadriplegic following a diving accident. He was febrile without an identified source and had septic hemodynamic parameters on pressors. He became oligoanuric. We started him on CVVHDF. But here is when he starts at 40.4 as his temperature at the start of CRRT. About 24 hours later, his temperature was down to 36.

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Effect of hypothermia on oxygen consumption
We measured his oxygen consumption, and you can see it is dramatically reduced, and his energy requirements were dramatically reduced. If you look at this in terms of comparing him to his previous 24 hours, his first 24 hours off CRRT and then again the second 24 hours off CRRT, his oxygen consumption goes up. You can see his energy requirements also go up, and his temperature comes back up. This happens because when you are using the fluids, either substitution fluid or dialysate, if they are not warm, you are actually causing core temperature cooling.

So two caveats occurred there. You should use a blood warmer. You should use a temperature warmer to try to heat the fluids before they are given. But second is recognize that you may not see the same temperature profiles as you would in a person who is off CRRT. So the recognition of that fact should trigger off an investigation if you find someone is spiked even a little bit on CRRT because that means that they are trying to mount a response which would otherwise be masked by the procedure itself.

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Source: Matamis D et al, Intensive Care Med. 1994 Jul;20(6):431-6.

Hypothermia: Effect of substitution fluid flow rate
This has been also shown previously by Dr. Matamis in Greece looking at the relationship with the ultrafiltration rate. The more you ultrafilter, the more substitution fluid you will need. That means the more rapidly you are delivering it. As a consequence, you are more likely to have decrease in your temperature as you go along.

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Iatrogenic acid-base / electrolyte problems
The last set of problems that occur are purely iatrogenic, as exemplified by what I showed you. We order something, but it is not done, or it is inappropriately ordered. There are three categories. An inappropriate prescription: That means that you don't recognize that you are going to need to replace base and you don't prescribe it appropriately. Or there is no adjustment for the dextrose absorption. These are just two examples of this.

Errors in formulation are really something you need to consider. If you are concocting your own solutions, recognize that it is important that the pharmacy does it and you have some idea of what is going on. If you do bedside mixing, it is prone to error because the nurses are already rushed, you don't know where things are, and we have seen patients... I have heard of and I know of patients who have actually died because the potassium mixed in the bag was 10-fold greater than it should have been, resulting in profound hyperkalemia and death. So you can see that happen.

Another thing to recognize is some people are starting to use the dialysate bicarbonate. You make a batch of dialysate from your dialysate solution, and then you let it sit and use that because it is cost effective. Well, the problem there is you have a significant precipitation of calcium in the dialysate because of this. There is a very good poster at this meeting, which was yesterday, demonstrating that aspect of it.

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Errors in delivery
If the calcium solution, by chance, gets used as a dialysate or the citrate gets infused directly into the blood stream, you can have significant problems. Low citrate flow rates, similarly... people instead of using Dianeal have put just simply saline as a dialysate. You can see what kind of changes would occur there. Or interference--another whole area: Somebody changes your order. Excess bicarbonate is given exogenously or fluid imbalance. Not an uncommon situation where the therapy is going on for so long and you have the opportunity to have more problems.

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Prevention strategies
So how do you prevent this? The best way to prevent it is to have protocols. You should have standardized orders. You should label the solution. You should have random audits for solution concentrations. I can't emphasize more than that--you must have a team approach with trained caregivers. This is not a therapy you want to do lightly without having the experience or at least an infrastructure to deliver it appropriately.

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Advantages of written protocols
This is just an example of the kind of protocol we have. We have standardized order sheets. So all the physician has to really check off is what they are going to change here. There is no second guessing. Our entire colleagues do the same thing. That is what makes it somewhat easier to do. For example, it is the same example with respect in terms of the flow rates and how you are using the solutions. There is less opportunity for mistakes if you use that kind of system.

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Management of acid - base /electrolyte problems
An finally, the management. It boils down to early recognition based on the knowledge of the operational characteristics. You should modify the treatment to correct the disorder. Remember, CRRT techniques are flexible. There is nothing stopping you from changing the blood flow rate temporarily, changing the dialysate flow rate up, as long as you understand what you are going to expect to happen. Once you do that, it actually gives you maximum flexibility of dealing with most problems. And remember, time is to your advantage. It is not an intermittent procedure where you are trying to do it in three hours. You've got time on your side, so you can go slow and correct it appropriately. Finally, a specific intervention when it is required.

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Summary
So in summary, what I have tried to demonstrate for you is that CRRT techniques have a greater opportunity to result in complication. However, these are under-reported because you can't tell if they are because of CRRT or the underlying condition? But most complications can be anticipated and prevented. I think the key is attention to detail and standardization of techniques. They should reduce the prevalence and incidence of complications.

I would like to thank you all for your attention. Thank you.

References

1. Feriani M. Behaviour of acid-base control with different dialysis schedules. Nephrol Dial Transplant. 1998;13 Suppl 6:62-5. Review. No abstract available.

2. Kumar VA, Craig M, Depner TA, Yeun JY. Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit. Am J Kidney Dis. 2000 Aug;36(2):294-300.

3. Levraut J, Ciebiera JP, Jambou P, Ichai C, Labib Y, Grimaud D. ffect of continuous venovenous hemofiltration with dialysis on lactate clearance in critically ill patients. Crit Care Med. 1997 Jan;25(1):58-62.

4. Zimmerman D, Cotman P, Ting R, Karanicolas S, Tobe SW. Continuous veno-venous haemodialysis with a novel bicarbonate dialysis solution: prospective cross-over comparison with a lactate buffered solution. Nephrol Dial Transplant. 1999 Oct;14(10):2387-91.

5. Locatelli F, Pontoriero G, Di Filippo S. Electrolyte disorders and substitution fluid in continuous renal replacement therapy. Kidney Int Suppl. 1998 May;66:S151-5. Review.

6. Sigler MH, Teehan BP. Solute transport in continuous hemodialysis: a new treatment for acute renal failure. Kidney Int. 1987 Oct;32(4):562-71.

7. Monaghan R, Watters JM, Clancey SM, Moulton SB, Rabin EZ. Uptake of glucose during continuous arteriovenous hemofiltration. Crit Care Med. 1993 Aug;21(8):1159-63.

8. Meier-Kriesche HU, Finkel KW, Gitomer JJ, DuBose TD Jr. Unexpected severe hypocalcemia during continuous venovenous hemodialysis with regional citrate anticoagulation. Am J Kidney Dis. 1999 Apr;33(4):e8.

9. Matamis D, Tsagourias M, Koletsos K, Riggos D, Mavromatidis K, Sombolos K, Bursztein S. Influence of continuous haemofiltration-related hypothermia on haemodynamic variables and gas exchange in septic patients. Intensive Care Med. 1994 Jul;20(6):431-6.

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Topic Index  Chronic Renal Failure -- Continuous Renal Replacement Therapies