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Effect of pump prime on acidosis, strong-ion-difference and unmeasured ions during cardiopulmonary bypass.

Changes in acid-base balance, particularly metabolic acidosis, are common in cardiac surgery with cardiopulmonary bypass (CPB) (1,2). The mechanisms for such metabolic acidosis however, remain controversial. Those who use bicarbonate centred approaches to acid-base (patho)physiology conclude that dilution of bicarbonate is the underlying mechanism for acid-base changes following large volume infusion during CPB (3,4). Using the Stewart approach to acid-base physiology (5) and fluid therapy (6), our group (1,7), and Himpe et al (8) and Morgan et al (9), concluded that bypass associated metabolic acidosis may instead depend on the electrolytes and colloids in the CPB prime. One limitation of these studies was that CPB primes included constituents that are not measured in routine clinical chemistry; either colloids such as gelatin (1,8) or smaller organic molecules such as gluconate and acetate (7,9). This limited the quantitative acid-base balance analysis possible with the Stewart approach (10), because of the relatively large effects of unmeasured ions from the CPB prime solutions. Further, there is limited data on the changes in acid-base variables during the first 30 minutes of CPB (7-9).

The underlying mechanisms of acid-base changes associated with CPB might be easier to quantify using CPB primes that contain only electrolytes and anions routinely measured in clinical chemistry. We hypothesised that a CPB prime with lactate and chloride would be associated with less metabolic acidosis than a prime with only chloride, because of a difference in the measured strong-ion-difference. To test this hypothesis, we conducted a randomised, double-blinded trial of two different CPB primes: one containing 152 mmol/l of chloride and another containing 109 mmol/l of chloride and 29 mmol/l of lactate.

MATERIALS AND METHODS

The Austin Health Human Research and Ethics Committee approved this study and all patients gave written informed consent. We estimated that we would need 10 patients in each group, a total sample size of 20 patients, to have a power of 0.8 to detect a 2 mmol/l difference in base-excess between the two solutions. This is in line with the detection of a base-excess difference in other studies (7-9). All patients underwent elective primary coronary revascularisation. Exclusion criteria included age less than 18 years or greater than 75 years, creatinine concentration greater than 150 [micro]mol/l, diabetes mellitus, anaemia (haemoglobin level <100 g/l), preexisting acid-base abnormalities (pH or base-excess outside the reference range) and extremes in weight (body weight <50 kg or >100 kg).

Patients were randomly assigned to one of two groups (Table 1) by hospital pharmacy staff using a random number allocation system with permuted blocks. One group received a pump prime of 1500 ml with all anions as chloride: chloride-only solution (Ringer's Injection solution, not Lactated Ringer's, Baxter, Sydney, NSW). The other group received a pump prime of 1500 ml with anions as lactate and chloride: lactated solution (Hartmann's solution, Baxter, Sydney, NSW) (Table 1). Patients, surgeons, anaesthetists and medical perfusionists were blinded to treatment allocation.

Cardiopulmonary bypass was performed using a membrane oxygenator (Sorin Monolyth; Biomedica, Mirandola, Italy). The pump rate was set at 2.4 l.[m.sup.-2].[min-sup.-1] and body temperature was kept at 32 to 34[degrees]C. Blood sampling was performed at six time points: baseline immediately prior to bypass (BL), and then two (C2), five (C5), 15 (C15) and 30 minutes (C30) after achieving full flows on CPB. A standard cardioplegia was used for all patients, minimizing differentiating effects of exogenous ions given by this route.

All clinical chemistry was measured and interpreted at 37[degrees]C. Serum sodium, chloride, potassium, magnesium, ionised calcium, phosphate, albumin and lactate were measured at each of these sample points. Using arterial blood, pH and carbon dioxide tension were measured. Analysis of blood gases and measurement of sodium, potassium, ionised calcium, chloride and lactate was performed on an ABL 30 Blood Gas Analyzer (Radiometer, Copenhagen, Denmark). The machine calculated the bicarbonate concentration (not standard bicarbonate) using the Henderson-Hasselbalch equation (11); the carbon dioxide solubility coefficient used was 0.0307 and the apparent overall dissociation constant for carbonic acid was 6.105. Standard base excess was calculated using a complex Radiometer specific algorithm giving similar results to the Van Slyke equation (12). All other variables were measured on a Hitachi 747 Analyzer (Boehringer Manheim, Indianapolis, IN, USA).

Quantitative physicochemical analysis of the results was performed using Stewart's quantitative biophysical methods as modified by Figge to take into the effects of weak acids (13). This method involves first calculating the measured strong-ion-difference (measured SID):

measured SID, mEq/l

=[[Na.sup.+]]+[[K. sup.+]]+[[Mg.sup.2+]]+[Ca.sup.2+]]-[[Cl.sup.-]]-[[lactate.sup.-]]

This equation, however, does not take into account the role of weak acids (carbon dioxide, albumin, phosphate) in the balance of electrical charges in plasma water. This is expressed through the calculation of the effective anion concentrations for bicarbonate, albumin and phosphate. The anion concentrations for albumin and phosphate were calculated using Figge's formulae (11):

albumin anions, mEq/l

=[albumin] x (0.123 x pH-0.631)

phosphate anions, mEq/l

=[phosphate] x (0.309 x pH-0.469)

The net unmeasured ions (14), also known as the strong-ion-gap, are equal to the sum of the cations minus the sum of the anions (10):

net unmeasured ions

=[[Na.sup.+]]+ [[K.sup.+]]+[[Mg.sup.2+]]+[[Ca.sup.2+]]-[[Cl.sup.-]] -[[Lactate.sup.-]][bicarbonate]-[albumin ions]-[phosphate ions]

The measured strong-ion-difference and net unmeasured ions were calculated for each individual patient.

Statistical analysis

We used repeated measures analysis of variance (ANOVA), to compare the pH, [PCO.sub.2], chloride, lactate, bicarbonate, base-excess, measured strong-ion-difference and net unmeasured ions (strong-ion-gap) between the chloride-only and lactated groups (15). We tested for the effects of treatment (fluid allocation), time and interaction between treatment and time to determine if the two groups behaved differently across time. The calculated time point P values were corrected for multiple testing using the Bonferroni approach (16). We used GraphPad Prism Version 4 software (GraphPad Software, San Diego, CA, USA). A P value less than 0.05 was considered statistically significant. One data point for one of the 10 patients was missing from the chloride-only group at 30 minutes after starting bypass time point. To allow the repeated measures ANOVA, this single missing point was filled with the baseline value for each of the base-excess, measured strong-ion-difference and net unmeasured ions.

RESULTS

The patients in the chloride-only (Ringer's Injection) and the lactated (Hartmann's solution) groups were similar at baseline before CPB (Table 2). Both groups had marked decreases in measured strong-ion-difference from baseline (Figure 1A) within the first two minutes of bypass. These changes trended back towards baseline across the time of the study. The measured strong-ion-difference in the two groups was almost the same (Figure 1A), P=0.88. Both groups had large decreases in standard base-excess from baseline after two minutes (C2) of bypass (Figure 1B). Comparing between the groups, the lactated group had less acidosis with significantly greater standard base-excess (P=0.04). The greatest difference in base-excess was at five minutes after starting CPB (C5) when the mean base excess in the lactated group was -0.9 mmol/l compared with -2.8 mmol/l (difference 1.9 mmol/l; 95% confidence interval: 0.1 to 3.7 mmol/l, P <0.05) in the chloride-only group. When the difference in standard base-excess between the groups was greatest at C5, the mean measured strong-ion-difference in the lactated group was 35.5 mmol/l compared to 35.7 mEq/l in the chloride-only group, difference -0.2 mEq/l; (95% confidence interval: -2.7 to 2.4 mEq/l; P >0.05).

[FIGURE 1 OMITTED]

The changes in pH in the first two minutes were less marked than changes in standard base-excess after starting bypass (Figure 2A). Comparing between the groups across the 30 minutes of the study, the pH was significantly more acidic in the chloride-only group (P=0.03, Figure 2A). The other two variables in the Henderson-Hasselbalch equation, partial pressure of carbon dioxide ([PCO.sub.2]) and bicarbonate, had marked decreases in the first two minutes but there were no statistical differences between the fluid groups, P=0.16 and P=0.13 (Figures 2B and 2C).

[FIGURE 2 OMITTED]

The lactated group had a significantly greater lactate throughout the first 30 minutes of bypass (Figure 3A). At C2 the mean lactate was 4.9 mmol/l, which was 3.9 mmol/l greater than the chloride-only group (95% confidence interval: 3.1 to 4.8 mmol/l greater, P <0.001). Albumin, the major weak acid in plasma, changed with time but did not differ between the fluids (Figure 3B). The concentration of net unmeasured ions (strong-ion-gap) was lower in the lactated group, P=0.01 (Figure 3C).

DISCUSSION

We undertook a blinded, randomised trial comparing the acid-base effects during the first 30 minutes of cardiopulmonary bypass of two 1500 ml primes with different anions: one with chloride anions only (chloride-only group, Ringer's Injection) and the other with both chloride and lactate (lactated group, Hartmann's solution). We proposed that the lactated prime would be associated with less metabolic acidosis due to differences in the measured-strong-ion-difference. Contrary to our hypothesis, we found no difference in the measured strong-ion-difference between the fluid groups. We did find however, less acidosis as expected (greater standard base-excess) in the lactated group.

Previously our group (7) reported that a CPB prime with Plasmalyte solution (Baxter, Sydney, NSW) containing acetate and gluconate was associated with greater resolution of metabolic acidosis by the end of bypass than a chloride and gelatin-based CPB prime. The analysis was complicated by unmeasured ions in both primes (7), unlike the current study. In the previous study (7), the primary difference was in the measured strong-ion-difference. Further, unlike the current study, in the previous study (7) two minutes after initiating bypass, the decrease in base-excess was similar for the two primes. Himpe et al (8) conducted a randomised trial with CPB primes containing gelatin with either chloride or chloride and lactate. Himpe et al concluded that lactate containing solutions were associated with less acidosis after bypass, consistent with our findings in this study (7). Their quantitative analysis (8) was limited by both primes containing gelatin, an unmeasured weak acid (1), in differing amounts. Further, their two principal analysis points were before and after CPB (8) which did not allow them to examine early acid-base changes during CPB. They did however, conclude that the principal difference between the groups was in the measured strong-ion-difference following clearance of plasma lactate (8).

The question arises as to why, in this study, we did not find that the measured strong-ion-difference differed between the groups as we (7) and Himpe (8) found previously. One explanation is that we included lactate in the measured strong-ion-difference calculation while the previous studies (7,8) did not. Until recently, lactate was not included in the measured strong-ion-difference (13) calculation because lactate was not routinely measured in clinical chemistry. Because lactate is now routinely available from blood gas reports, it can and should be included in the measured strong-ion-difference (17). Another possibility is that we studied the first 30 minutes of bypass. Clearing lactate and increasing the measured strong-ion-difference would be expected to be alkalinising (18). However, the extent of the alkalosis in the first half hour of bypass is uncertain. Another possibility is that this is a false negative study (15). While the mean difference was 0.2 mEq/l, the 95% confidence interval for the measured strong-ion-difference five minutes after starting bypass was -2.7 mEq/l to 2.4 mEq/l, which includes the difference in base-excess of 1.9 mmol/l. Therefore our sample size appeared to be too small to adequately answer this question. There is also another possibility given the marked decrease in bicarbonate within two minutes of CPB and that bicarbonate did not significantly differ between the groups: we cannot exclude the possibility the bicarbonate centred approach is correct and the acid-base effects of CPB are due to bicarbonate dilution (3,4).

[FIGURE 3 OMITTED]

In the Stewart approach, the independent factors for non-respiratory changes in acid-base status are the strong-ion-difference and total weak acids (19). To address questions about acid-base disorders using the Stewart approach we are dependent on the available clinical chemistry (19,20). If the measured strong-ion-difference did not differ between the fluid groups, other alternative explanations included differences in the total weak acids and differences in the net unmeasured ions (strong-ion-gap) (14). The net unmeasured ions may consist of both strong ions and weak acids (10,13). From our results the weak acids did not appear to differ while the unmeasured ions did. Therefore an alternative explanation could lie with differences in unmeasured ions with the different bypass primes.

Our study has several limitations. It was a single centre study of 20 patients and was confined to elective coronary artery bypass surgery; therefore limiting the generalisability of our findings to other types of surgery and other institutions. Further, because it is the clinical practice at our hospital, we used the same volume of CPB fluid in patients of differing size. While the chloride-only and lactated solution groups were similar, differing body size led to considerable variation within the groups, which will have affected the required sample size required for adequate power.

This study also has several strengths. First, both solutions contained only electrolytes that are routinely measured in clinical chemistry. Therefore none of the unmeasured ions were directly from the solutions. Second, we measured plasma chemistry after two minutes of bypass and then during the first half hour of bypass. This sampling allowed us to compare the effects of the two primes during redistribution and early clearance phases.

The clinical importance of this study is that we found that the prime of CPB can produce rapid changes in a patient's acid-base status. We conclude that acid-base changes with CPB primes of chloride-only or lactated solutions did not differ in the measured strong-ion-difference if lactate is included in the calculation of the measured strong-ion-difference. There appear, however, to be differences in standard base-excess. By using a lactated solution, patients had less acidosis with a standard base-excess about 2 mmol/l higher than with a chloride-only solution. We think this is clinically relevant when considering how to maintain physiological homeostasis (4,9). We suggest future studies, using solutions with only constituents measured in clinical chemistry, to examine other possible mechanisms for differences in base-excess, including unmeasured ions.

ACKNOWLEDGEMENT

Funded by a Research Grant, Australian and New Zealand College of Anaesthetists; and Anaesthesia Research Fund, Austin Health.

REFERENCES

(1.) Hayhoe M, Bellomo R, Liu G, McNicol L, Buxton B. The aetiology and pathogenesis of cardiopulmonary bypass-associated metabolic acidosis using polygeline pump prime. Intensive Care Med 1999; 25:680-685.

(2.) Lilley A. The selection of priming fluids for cardiopulmonary bypass in the Uk and Ireland. Perfusion 2002; 17:315-319.

(3.) Mathes DD. Is chloride or dilution of bicarbonate the cause of metabolic acidosis from fluid administration? Anesthesiology 2001; 95:809; author reply 81.

(4.) Neligan PJ, Deutschman CS. Perioperative acid-base balance. In Miller's Anesthesia, 6th Edition. Miller R, ed. Philadelphia, Elsevier, 2005. p. 1599-1615.

(5.) Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983; 61:1444-1461.

(6.) Morgan TJ. The meaning of acid-base abnormalities in the intensive care unit: part III--effects of fluid administration. Crit Care 2005; 9:204-211.

(7.) Liskaser FJ, Bellomo R, Hayhoe M, Story D, Poustie S, Smith B et al. Role of pump prime in the etiology and pathogenesis of cardiopulmonary bypass-associated acidosis. Anesthesiology 2000; 93:1170-1173.

(8.) Himpe D, Neels H, De Hert S, Van Cauwelaert P. Adding lactate to the prime solution during hypothermic cardiopulmonary bypass: a quantitative acid-base analysis. Br J Anaesth 2003; 90:440-445.

(9.) Morgan TJ, Power G, Venkatesh B, Jones MA. Acid-base effects of a bicarbonate-balanced priming fluid during cardiopulmonary bypass: comparison with Plasma-Lyte 148. A randomised single-blinded study. Anaesth Intensive Care 2008; 36:822-829.

(10.) kellum JA, kramer DJ, Pinsky MR. Strong ion gap: a methodology for exploring unexplained anions. J Crit Care 1995; 10:51-55.

(11.) Burnett RW, Noonan DC. Calculations and correction factors used in determination of blood pH and blood gases. Clin Chem 1974; 20:1499-1506.

(12.) kofstad J. Base excess: a historical review--has the calculation of base excess been more standardised the last 20 years? Clin Chim Acta 2001; 307:193-195.

(13.) Figge J, Mydosh T, Fencl V. Serum proteins and acid-base equilibria: a follow-up. J Lab Clin Med 1992; 120:713-719.

(14.) Lloyd P. Strong ion gap or net unmeasured ions? Crit Care Resusc 2005; 7:64.

(15.) Myles PS, Gin T. Statistical methods for anaestheia and intensive care. Oxford, Butterworth-Heinemann, 2000; p. 80-81.

(16.) Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ 1995; 310:170.

(17.) Story DA, Morimatsu H, Bellomo R. Hyperchloremic acidosis in the critically ill: one of the strong-ion acidoses? Anesth Analg 2006; 103:144-148.

(18.) White SA, Goldhill DR. Is Hartmann's the solution? Anaesthesia 1997; 52:422-427.

(19.) kellum JA, Elbers PWG. Stewart's Textbook of Acid-Base, 2nd ed. Philadelphia. From Lulu.com 2009.

(20.) Fencl V, Jabor A, kazda A, Figge J. Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 2000; 162:2246-2251.

F. Liskaser *, D. A. Story ([dagger]), M. Hayhoe ([double dagger]), S. J. Poustie ([section]), M. J. Bailey**, R. Bellomo ([double dagger])

Departments of Anaesthesia and Intensive Care, Austin Health, Heidelberg, Victoria, Australia

* M.B., B.S., F.A.N.Z.C.A., Staff Anaesthetist, Department of Anaesthesia.

([dagger]) B.Med.Sci. (Hons.), M.B., B.S. (Hons.), M.D., F.A.N.Z.C.A., Head of Research, Department of Anaesthesia and Associate Professor, The University of Melbourne, Department of Surgery, Austin Health.

([double dagger]) M.B., B.S., F.A.N.Z.C.A., Staff Anaesthetist, The Northern Hospital, Epping.

([section]) B.N., Crit. Care Cert., M.P.H., Research Officer, Trials Group, Australian and New Zealand College of Anaesthetists.

** B.Sc.(Hons), M.Sc., Ph.D., Senior Statistical Consultant, ANZIC Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital.

([double dagger]) M.B., B.S., M.D., F.J.F.I.C.M., Director of Research, Department of Intensive Care.

Address for reprints: Associate Professor D. A. Story, Department of Anaesthesia, Austin Hospital, Studley Rd, Heidelberg, Vic. 3084.

Accepted for publication on March 10, 2009.
Table 1

Composition of pump primes

Strong ion Ringer's Injection Hartmann's (mEq/l)
 (mEq/l)

Sodium ([Na.sup.+]) 144 129
Chloride ([Cl.sup.-]) 152 109
Potassium ([K.sup.+]) 4 5-Jan
Calcium ([Ca.sup.2+]) 4 4
Lactate 0 29

Table 2

Baseline (pre-bypass) patient characteristics *

Characteristics Chloride-only Lactated P

Age, y 62.5 (48-74) 65.5 (53-73) 0.59
Weight, kg 76.5 (57-93) 78.5 (60-97) 0.70
Surface area, [m.sup.2] 1.88 (1.58-2.09) 1.89 (1.65-2.22) 0.47
Female/male, n 1/9 4/6 0.3
pH 7.40 (7.35-7.47) 7.43 (7.34-7.48) 0.34
PC[O.sub.2], mmHg 40.7 (31.2-47.1) 37.3 (32.3-42.7) 0.19
Base-excess, mmol/l 0.4 (-1.4-3.4) 0.5 (-2.5-1.7) 0.69
Measured SID, 41.1 (39.9-46.6) 41.1 (38.1-45.2) 0.55
mmol/l
Net unmeasured ions, 7.4 (2.9-9.7) 6.8 (5.0-8.5) 0.57
mEq/l
Albumin, g/l 31(19-36) 30 (28-33) 0.72

* Median (range).
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Author:Liskaser, F.; Story, D.A.; Hayhoe, M.; Poustie, S.J.; Bailey, M.J.; Bellomo, R.
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:8AUST
Date:Sep 1, 2009
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