Internal Memo Fresenius Medical CareNorth AmericaCorporate HeadquartersMedical Department

To: FMC Medical Directors 95 Hayden AvenueLexington, MA 02420-9192

From: J. Michael Lazarus, M.D. & the Bicarbonate Committee(Julie Brennan, Catherine Dubinsky, Paul Genoa, Maureen Herget,Chinu Jani, Nancy Lew, Norma Ofsthun, Dave Updyke, Scott Walker)

Phone: (781) 402-9000 Ext. 2215Fax: (781) 402-9582

Date: December 7, 2000 e-mail: michael.lazarus.md@fmc-na.com

Re: Bicarbonate Dialysate and Low Serum BicarbonateLevels

We recently corresponded with you concerning the problem of acidosis and our findings thatthere was no affect of shipment of blood specimens by either air or ground transportation onserum C02 levels. Further review of FMCNA data indicated that many facilities have anunacceptable number of patients with pre-dialysis bicarbonate levels below 18 mmol/l. Itappears that in many cases, physicians have ignored this finding, assuming it to be a “laboratoryerror”. Let me again assure you that, for the most part, the finding of low pre-dialysisbicarbonate levels is not related to laboratory error or transportation of blood specimens. It maywell be related to errors in the collection of blood samples by facility staff, but more importantly,may be related to an inadequate dialysate bicarbonate prescription.

Since low pre-dialysis bicarbonate levels seem to be a greater problem than we expected, wefurther evaluated laboratory results along with dialysate bicarbonate orders. Findings aresummarized in the following pages.

Internal MemoPage: 2

Date: 12/07/2000

Figure 1 demonstrates the distribution of pre-dialysis bicarbonate levels in 47,529 FMCNApatients who were so tested at Spectra East in July of 2000.

Distribution of Patient Pre-Dialysis Bicarbonate Levels in July 2000

0

1,000

2,000

3,000

4,000

5,000

6,000

4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 42

Pre-Dialysis Serum Bicarbonate Concentration (mmol/L)

Num

ber o

f Pat

ient

s

N=47,529

Figure 1.

Normal PredialysisRange

The shaded box outlines the “normal range” of pre-dialysis bicarbonate levels as determined byexperts in the field (see references). The K/DOQI recommendation for pre-dialysis plasmabicarbonate levels is 22 mmol/l or greater. Approximately 58% of patients are below therecommended level of 22 mmol/l.

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Date: 12/07/2000

Figure 2 shows the distribution broken out by hemodialysis and peritoneal dialysis patients.

Distribution of HD Patient and PD Patient Pre-Dialysis Bicarbonate Levels in July 2000

0%

2%

4%

6%

8%

10%

12%

14%

4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42

Pre-Dialysis Serum Bicarbonate Concentration (mmol/L)

Per

cent

of P

atie

nts

All HD (N=43,716)All PD (N=3,301)

Figure 2.

Normal Predialysis Range

It has been previously reported that PD patients have higher bicarbonate levels than HDpatients, which we reconfirm. The lactate level for PD fluids in our PD program is either 35 or 40meq/L depending on calcium and magnesium content.

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Date: 12/07/2000

Figure 3 shows the distribution of the percentages of HD patients in facilities with pre-dialysisplasma bicarbonates below 22 mmol/l.

Distribution of Percentages of Hemodialysis Patients in Facilities with Low Pre-Dialysis Plasma Bicarbonate Levels

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00%

% of Patients with Pre-Dialysis Plasma Bicarbonate < 22 mEq/L

Per

cent

of F

acili

ties

N=897 facilitiesJuly, 2000

Figure 3.

From this figure, you can see that 66% of facilities had 50% or greater of patients with a pre-dialysis serum bicarbonate level < 22 mmol/l and 93% of facilities had 25% or greater ofpatients with a pre-dialysis serum bicarbonate level < 22 mmol/l. All of the facilities use SpectraEast and supposedly employ the same blood collection technique. Thus, we believe thesedifferences are facility specific.

These findings led us to study a sample of 58 facilities to assess possible factors in low pre-dialysis serum bicarbonate levels. We selected 14 “high C02” facilities – each with mean pre-dialysis serum bicarbonate level 22 mmol/l and above, 20 “medium C02” facilities – each with amean pre-dialysis serum bicarbonate level between 18 and 22 mmol/l, and 24 “low C02”

Internal MemoPage: 5

Date: 12/07/2000

facilities – each with a mean pre-dialysis serum bicarbonate level < 18 mmol/l. We determinedthe total buffer (i.e., both bicarbonate and acetate) provided in the dialysate for the hemodialysispatients in each of those 3 groups. We subsequently studied a subset of these facilities asecond time to determine the post-dialysis serum bicarbonate value. The results of this studyare shown in Table I.

Table I

First Study Pre / Post Study

#Facilities

#Patients

AveragePredialysis

SerumBicarbonate

Level

Average TotalDialysate Buffer

(Bicarb & Acetate)

#Facilities

#Patients

AveragePredialysis

SerumBicarbonate

Level

AveragePredialysis

SerumBicarbonate

Level

Average TotalDialysate Buffer

(Bicarb & Acetate)

HighGroup

14 2740 24.5 mmol/l 43.2 mmol/l 5 274 24.4 mmol/l 31.0 mmol/l 42.2 mmol/l

MediumGroup

20 4761 20.6 mmol/l 38.9 mmol/l 5 301 21.9 mmol/l 28.9 mmol/l 39.0 mmol/l

LowGroup

24 4105 17.4 mmol/l 36.3 mmol/l 4 145 19.8 mmol/l 23.8 mmol/l 35.9 mmol/l

The weighted average bicarbonate in the “high” group was 24.5, the average in the “middle”group was 20.6, and the average in the “low” group was 17.4. Values were very similar onrepeat testing in 14 facilities some several weeks later. The post-dialysis weighted averageswere 31.0, 28.9, and 23.8, respectively. We then examined these findings in relation to the totalbuffer provided in the dialysate. In the “high” group, the weighted average total buffer provided indialysate was 43.2 mmol/l, in the “middle” group – 38.9 mmol/l, and in the “low” group – 36.3mmol/l. Dialysate bicarbonate was similar in the first and second studies.

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Date: 12/07/2000

Figure 4 shows a plot of the facility mean pre-dialysis serum bicarbonate levels vs. the totaldialysate buffer. In general, it appears that one must order a total dialysate buffer of 38 to 40mmol/l to obtain a mean facility serum bicarbonate level of 22 mmol/l.

Facility Mean Pre-Dialysis Bicarbonate vs. Total Dialysate Buffer

y = 0.778x - 9.6217R2 = 0.591

16

18

20

22

24

26

28

34 36 38 40 42 44 46

Total Dialysate Buffer (mmol/L)

Fac

ility

Mea

n P

re-D

ialy

sis

Ser

um B

icar

bona

te (

mm

ol/L

)

Figure 4.

To obtain a clearer understanding of how to obtain total dialysate buffer, Table II illustrates thetotal dialysate buffer obtained from various dialysate series with different dialysis machinebicarbonate settings.

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Date: 12/07/2000

Table II

Examples to Obtain Indicated Total Buffer

9000 Series (Liquid) 9000 SeriesGranuFlo

6000 SeriesGranuFlo 6000 Series (Liquid) 4000 Series (Liquid)

BicarbSetting

Acetate BicarbSetting

Acetate BicarbSetting

Acetate BicarbSetting

Acetate BicarbSetting

Acetate TotalBuffer

39 4 35 8 37 6 40 3 39 4 43

36 4 32 8 34 6 37 3 36 4 40

34 4 30 8 32 6 35 3 34 4 38

32 4 28 8 30 6 33 3 32 4 36

You must consider that the buffer activity from acetate in the acid solution contributes to the totalbuffer – particularly in the GranuFlo dialysate.

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Date: 12/07/2000

Figure 5 shows the distribution of dialysate bicarbonate prescribed in all patients’ most recenthemodialysis order as of June 30, 2000 (57,191 patients).

Figure 5. Distribution of Dialysate Bicarbonate Prescribed in each Patient's Most Recent HD Orders as of 6/30/00

0.48%

16.42%

1.50% 0.73%

51.81%

1.00% 0.78% 0.23% 1.17% 0.75%

25.1%

0.0%0%

10%

20%

30%

40%

50%

60%

70%

80%

<=31 32 33 34 35 36 37 38 39 40 41 >41

Bicarbonate Concentration (mmol/L), rounded to nearest integer

Per

cent

of P

atie

nts

Approximately, 16% of patients received a dialysate bicarbonate of ~ 32 mmol/l, 52% receiveda bicarbonate dialysate of ~ 35 mmol/l, and 25% received a bicarbonate dialysate of ~ 39mmol/l. This reflects the distribution of facility-wide dialysate orders, since most physiciansorder the same dialysate bicarbonate for most patients in the facility. Further search revealedthat 63% of facilities currently use the 9000 Series, 34% utilize the 6000 Series, and 2% utilizethe 4000 series. Twenty-nine (29) facilities are currently using GranuFlo with either the 6000 or9000 Series. Because of the increased acetate in the acid portion of GranuFlo powder (whichis metabolized to bicarbonate), significantly higher base is delivered.

We have begun to monitor final dialysate bicarbonate levels in facilities on a regular basis. In thepast, we have not measured the dialysate bicarbonate level. In the most recent monitoringperiod, 363 machines were monitored and delivered dialysate bicarbonate levels within 2 mmol/lof the prescribed level. I encourage you to review the random sampling of dialysate bicarbonatelevels being carried out in your facility.

Internal MemoPage: 9

Date: 12/07/2000

I have provided a copy of this memo along with 4 reference articles and the K/DOQI Guidelineson the FMCNA Intranet*. It is clear that acidosis has a serious negative impact on nutrition andbone disease as well as mortality. It seems prudent, therefore, that physicians strive to achievea pre-dialysis bicarbonate level at or slightly above 22 mmol/l in individual dialysis patients.

I urge you to review each individual patients’ bicarbonate levels in your facility and your overallfacility distribution. If patients in your facility have low mean serum bicarbonate levels, or thereare a high percentage of patients below 22 mmol/l, I recommend you review and monitor bloodcollection techniques with the facility staff. If a significant percentage of patients consistentlyexhibit serum bicarbonate levels below 22 mmol/l, we suggest you consider increasing thedialysate bicarbonate level or patients should receive base (NaHC03) orally to achieve theselevels. It appears that, except in the case of GranuFlo, the dialysis machine bicarbonate settingsshould be 35 mmol/l or higher since below that prescription, very low serum bicarbonate levelsoccur in a high percentage of patients. Depending on the concentrate type, it may be necessaryto set the machine dialysate bicarbonate as high as 40 mmol/l for some patients. In patientswho have normal to high pre-dialysis levels, or in whom you have concern for the affects of highpost-dialysis levels which may be adversely affect a co-morbid condition, individual dialysatebicarbonate levels should be prescribed. I would appreciate your comments or suggestionsregarding the treatment of acidosis.

*Go to the FMCNA Intranet site (http://home.fmcna.com/ ), type in your User ID and Password. On navigationbar, click on the red “Services” tab. Under “Clinical Library/Medical Directors Information”, click on“Medical Director’s Memos” and then click on the above titled memo. You can print out the articles if sodesired.

JML/kr

xc: See Distribution List

Internal MemoPage: 10

Date: 12/07/2000

References

Articles Posted on FMCNA Intranet:

1. Gennari FJ: Acid-base balance in dialysis patients. Semin Dial 13(4):235-239, 2000.

2. Chauveau P, Fouque D, Combe C, Laville M, Canaud B, Azar R, Cano N, Aparicio M,Leverve X, and the French Study Group for Nutrition in Dialysis: Acidosis and nutritionalstatus in hemodialyzed patients. Semin Dial 13(4):241-246, 2000.

3. Kraut JA: Disturbances of acid-base balance and bone disease in end-stage renaldisease. Semin Dial 13(4):261-266, 2000.

4. Grassmann A, Uhlenbusch-Körwer I, Bonnie-Schorn E, Vienken J: Composition andManagement of Hemodialysis Fluids (Good Dialysis Practice; Vol. 2). Lengerich; Berlin;Riga; Rom; Wien; Zagreb: Pabst, 2000. p 51, pp 60-99.

5. K/DOQI Nutrition in Chronic Renal Failure. Am J Kidney Dis 35(6) Suppl 2(June):S38-S39, 2000. (Text unavailable)

6. K/DOQI Nutrition in Chronic Renal Failure. Am J Kidney Dis 35(6) Suppl 2(June):S107-S108, 2000. (Text unavailable)

Bicarbonate Dialysate and Low Serum Bicarbonate Levels Medical Director Memorandum

Distribution List

Tom AmitranoJose Diaz-Buxo, M.D.Mark CostanzoKathy CrockerCraig DawsonProf. Jutta Passlick-DeetjenLinda DonaldAnn EckertDeb HarveyDoug KottRon KuerbitzGordon Lang, M.D.Nathan Levin, M.D.Ben LippsJohn MarkusDwight MorganColeman Mosley, M.D.Bill NumbersBrian O’ConnellMichael PerryAlexis PorrasRice PowellChris PriccoMohsen ReihanyJoe RumaJeff Sands, M.D.Gary ScherHeinz SchmidtKathleen SmithDonna St. PierreJeff WeixGail WickHock Yeoh, M.D.Business Unit Compliance OfficersBusiness Unit VPs of QualityClinical Quality Managers (6) – c/o Gisele KayDSD Regional ManagersDSD Regional Quality ManagersDSD Regional Vice Presidents