Internal Memo Fresenius Medical CareNorth AmericaCorporate HeadquartersMedical Department

To: FMC Medical Directors, DoNs, Administrators(Route to Technical Staff)

95 Hayden AvenueLexington, MA 02420-9192

From: J. Michael Lazarus, M.D.Phone: (781) 402-9000 Ext. 2215Fax: (781) 402-9582

Date: March 23, 2001 e-mail: michael.lazarus.md@fmc-na.com

Re: Delivered Bicarbonate and Total Buffer with Fresenius2008H and 2008K Dialysis Machines

There apparently is confusion regarding bicarbonate delivery and the labeling on bicarbonateand acid concentrate products. An understanding of the chemistry of the dialysate process ishelpful in clarifying this issue. At the machine level, one subtracts the acetic acid concentration(shown as acetate on the label of the acid concentrate) from the bicarbonate concentration(shown as bicarbonate on the label of the bicarbonate concentrate) to determine the bicarbonateto be delivered to the patient. However, at the patient level, the sodium acetate concentration isadded to this bicarbonate level to determine the total buffer which results. This is becauseacetate is metabolically converted to bicarbonate in the body.

An example of the reaction which occurs in the dialysis delivery machine (using 9000 seriesbicarbonate and 9000 series liquid acid) is shown below and in Figure 1.

4HAc + 39NaHC03 → 4NaAc + 35NaHC03 + 4H2C03 → 4NaAc + 35NaHC03 + 4H20 + 4C02 ↑

Three streams (water, acid concentrate, and bicarbonate concentrate) are mixed together in thedialysis delivery machine. Labels of the concentrate utilized in this example are shown inAppendix 1 and Appendix 2. Because a near physiologic pH is required, it is necessary tobuffer the bicarbonate with a small amount of weak acid – acetic acid (HAc). When the threestreams are mixed together, the acetic acid reacts with the sodium bicarbonate to form carbonicacid which subsequently forms carbon dioxide (which escapes to the air) and water. [Illustratedin the left side of Figure 1]. Note on the NaturaLyte Bicarbonate 9000 label, the amount ofbicarbonate is shown as 39 mEq/L, but as explained on the label of the NaturaLyte AcidConcentrate which accompanies it, the final ionic concentration is a net bicarbonate of 35mEq/L. This phenomena occurs in all four concentrate families, but differs with varying amountsof acetic acid and bicarbonate. Thus, by the strictest definition, bicarbonate delivered to thepatient is the total bicarbonate that enters the machine proportioning system less the acetic acidfrom the acid concentrate.

Internal MemoPage: 2

Date: 03/23/2001

An additional variation occurs in the example in Figure 2 using 9000 series bicarbonate and1000 series Granuflo.

4HAc•NaAc + 39NaHC03 → 8NaAc + 35NaHC03 + 4H2C03 → 8NaAc + 35NaHC03 + 4H20 + 4C02↑

The concentrate labels for this reaction are shown in Appendix 1 and Appendix 3. For numerousreasons, we believe it is desirable to provide a dry dialysate product. Acetic acid is a liquid.Therefore, the powdered form – diacetic acid – has been used as the weak acid in Granuflo.Chemically, diacetic acid is half acetic acid and half sodium acetate. When Granuflo is used, anadvantage accrues in that there is a greater amount of acetate available to be metabolicallyconverted to bicarbonate in the body.

Manufacturers∗ label the contents of their concentrate, both before and after dilution. However,this is somewhat simplistic and perhaps confusing since the concentrate can be diluted over awide range of ratios to yield different sodium and bicarbonate levels (from 25 to 40 mEq/L) in thefinal dialysate as prescribed by the physician. Both the 2008H and 2008K machines can utilizevarious acid concentrates (within one "family" only) to deliver different concentrations of thecations (K, Ca, Mg) and dextrose. Each family of acid concentrate has a mating bicarbonateconcentrate.

The facility technical staff should have previously calibrated and entered into the dialysismachine's memory the concentrate family (35X or 6000 series, 45X or 4000 series, 36.83X or9000 series, or Granuflo) and the specific composition of the minor cations and dextrose foreach of the various acid concentrates used in the facility. The operator is forced into the "VerifyConcentrate" screen after each power up of the machine before being allowed into the dialysismode. It is important that the staff verify that the concentrate entering the delivery machine is thesame as the specific concentrate on the screen. The operator must then select the prescribedNa and bicarbonate concentration as well as K, Ca, Mg and dextrose before pressing the "set"key on the 2008H to begin dialysis. The delivery machine calculates and delivers the properamount of each concentrate. Note that the bicarbonate setting on the 2008H and 2008Kscreens is the bicarbonate concentration after reaction with the acetic acid.

Although the concentrate labels may indicate that the patient is to receive a certain sodium,potassium, calcium, magnesium and bicarbonate it is very important to understand that the

∗ I have only information on Fresenius Medical Care concentrates and 2008H and 2008K dialysis machines. The2008D’s and 2008E’s are similar to the 2008H’s and 2008K’s with regard to the dynamics but do not have thescreens. I assume that Baxter, Althin and Cobe delivery machines have mechanisms for control of bicarbonatesimilar to that of the 2008H and 2008K. The principles are the same for all delivery machines.

Internal MemoPage: 3

Date: 03/23/2001

settings on the delivery machine screen may and often do alter these proportions. If the contentof potassium, calcium, and magnesium are altered, the bicarbonate and sodium will be affectedin an inverse fashion. In other words, if one raises the bicarbonate (for instance from 32 to 38)the potassium, calcium and magnesium will all decrease by small amounts. If one reduces thebicarbonate, these three cations increase by small amounts (see Appendix #4). Thus, thephysician must decide if he/she is willing to accept mild alterations in potassium, calcium andmagnesium to obtain a certain bicarbonate. It is my belief that many facility staff set thepotassium and calcium levels without knowledge of the affect on the bicarbonate and, in fact, inmany cases the delivered bicarbonate is lower than what the physician believes he has ordered.

In a number of circumstances (e.g., a change in dialysate family), the dialysis delivery machinewill default the bicarbonate setting to that of the concentrate. It is important that, with eachindividual dialysis, the staff verify the concentrate setting of each of the elements of theconcentrate. If facility staff do not properly set the bicarbonate level with each dialysis(understanding that this will create some minor changes in the potassium, calcium andmagnesium) the delivered bicarbonate will not be as prescribed. Because of the complexity ofthese relationships Clinical Services and Technical Services will shortly distribute underseparate cover the proper procedure for setting sodium and bicarbonate and how this mayaffect the potassium, calcium, magnesium or vice versa and how to properly enter thisinformation into Proton.

Once dialysate contacts and interacts with the patient’s blood, acetate is metabolically convertedto bicarbonate. (Illustrated in the right side of Figures 1 and 2). Thus, the total buffer is the sumof the acetate and bicarbonate. Therefore, one must add the delivered acetate to the deliveredbicarbonate to appreciate the total buffer which the patient is receiving.

In summary:

1. The amount of bicarbonate delivered to the patient is determined by the bicarbonatesetting on the dialysis delivery machine, not necessarily the bicarbonate concentration onthe label.

2. Setting the bicarbonate level must be carried out prior to initiation of each dialysis. If not,the bicarbonate delivered will be the same as on the previous dialysis or in the casewhere the concentrate family has changed, the bicarbonate value will default to that of theconcentrate. Also be aware that changing the potassium, calcium, magnesium levels willaffect the bicarbonate and sodium levels.

Internal MemoPage: 4

Date: 03/23/2001

3. The bicarbonate and acetate delivered must be added to determine the total bufferprovided to the patient.

4. The physician and the facility staff must take the following steps prior to dialysis:

a. Select and provide an appropriate acid and bicarbonate concentrate.

b. Select (physician) and appropriately set (facility staff) the sodium and bicarbonatealong with the potassium, calcium and magnesium to be delivered to each patientbefore each dialysis. Recall that increasing or decreasing the potassium, calcium,and magnesium will affect the delivery of bicarbonate and vice versa.

c. Observe and monitor the patient’s serum bicarbonate level to determine that theprescribed dialysate bicarbonate is actually being delivered and is appropriate forthat particular patient. If not, the physician should establish a new bicarbonateprescription and the staff should readjust the bicarbonate setting as is appropriate,with consideration of the affect on potassium, calcium, and magnesium.

d. It is my recommendation that physicians review the “Verify Concentrate” screenwith the technical and nursing staff to witness how the bicarbonate level is alteredby changing the potassium, calcium, and magnesium levels and vice versa. Thephysician must make a decision whether the small changes in those cations areacceptable to deliver the bicarbonate he or she desires.

JML/kr

Attachments

Delivered Bicarbonate and Total Buffer with Fresenius 2008H & 2008K Dialysis Machines Medical Director Memorandum

Distribution List

Tom AmitranoPaul Balter, M.D.Jose Diaz-Buxo, M.D.Mark CostanzoEd CoxKathy CrockerPeter Crooks, M.D.Craig DawsonProf. Jutta Passlick-DeetjenLinda DonaldCatherine DubinskyDeb HarveyMaureen HergetDoug KottRon KuerbitzGordon Lang, M.D.Nathan Levin, M.D.Ben LippsJohn MarkusJudy MihokDwight MorganColeman Mosley, M.D.Bill NumbersNorma OfsthunRice PowellChris PriccoMohsen ReihanyBrooks RogersJeff Sands, M.D.Gary ScherChristian SchlaeperKathleen SmithDonna St. PierreDavid UpdykeScott WalkerJeff WeixJerry WoodsPaul Zabetakis, M.D.Business Unit Compliance OfficersBusiness Unit VPs of QualityClinical Quality Managers (8) – c/o Gisele KayDSD Regional ManagersDSD Regional Quality ManagersDSD Regional Technical ManagersDSD Regional Vice Presidents

Acid ConcentrateLiquid

4.0 Acetate(as HAc)

Bicarb ConcentrateLiquid

39 NaHC03

H20

Dialysis Setting of"35 Bicarb"

Dialysis Setting of"39 Bicarb"

Dialysis Setting of"32 Bicarb"

35 Bicarb+

4 NaAc

39 total buffer

39 Bicarb+

4 NaAc

43 total buffer

32 Bicarb+

4 NaAc

36 total buffer

o o o

o o o

o o o

Figure 1Example: 9000 Series Bicarb with 9000 Series Liquid Acid

4 NaAc35 NaHC03

4 H2C03

Text4 NaAc

35 NaHC034 H204 C02

Dialysis Delivery Machine

Figure 2Example: 9000 Series Bicarbonate with 1000 Series Granuflo

Acid ConcentrateGranuflo

8.0 Acetate(as 4HAc + 4NaAc)

Bicarb Concentrate

39 NaHC03

H20

Dialysis Setting of"35 Bicarb"

Dialysis Setting of"39 Bicarb"

Dialysis Setting of"32 Bicarb"

35 mg Bicarb+

8 NaAc

43 mg total bufferdelivered

39 mg Bicarb+

8 NaAc

47 mg total bufferdelivered

32 mg Bicarb+

8 NaAc

40 mg total bufferdelivered

o o o

o o o

o o o

8 NaAc35 NaHC03

4 H2C03

Text8 NaAc

35 NaHC034 H204 C02

Dialysis Delivery Machine