CONTINUOUS MONITORING OF BLOOD GLUCOSE CONCENTRATION DURING OPEN-HEART SURGERY

Br.jf. Anaesth. (1985), 57, 595-601

CONTINUOUS MONITORING OF BLOOD GLUCOSE CONCENTRATION DURING OPEN-HEART SURGERY c. K. MCKNIGHT, M. ELLIOTT, D. T. PEARSON, K. G. M. M. ALBERTI

Intermittent sampling has formed the basis of previously published reports on the changes in blood glucose concentration during open-heart surgery, and many workers have demonstrated marked alterations in glucose concentration under these circumstances (Moffitt et al., 1970, 1971; Allison, 1971; MacDonald et al., 1975; Yokota et al., 1977; Brandt etal., 1978; Landymore, Murphy and Kinley, 1981; Walsh et al., 1981). However, recent work from groups studying the management of diabetes during open-heart surgery has suggested that intermittent sampling, even of the frequency suggested by Yokota and colleagues (1977), may fail to reveal the true magnitude, rapidity or even occurrence of some of the changes in blood glucose concentration (Kuntschen, Galletti and Hahn, 1981; Elliott et al., 1984). It is not known whether similar changes occur in non-diabetic patients undergoing openheart surgery. To determine this, we have compared intermittent with continuous monitoring of blood glucose concentration in 12 non-diabetic adult patients undergoing open-heart surgery.

SUMMARY Continuous monitoring of blood glucose concentration was compared with frequent intermittent sampling in 12 non-diabetic adult patients undergoing open-heart surgery with cardiopulmonary by-pass using priming fluids free of glucose. Continuous monitoring revealed several changes which were not detected on intermittent sampling. Blood glucose concentration decreased by 2 mmol litre'1 ±0.5 (SEM) (P < 0.01) immediately on the institution of CPB, and increased during the succeeding minutes. Rewarming from hypothermic by-pass was associated with a 3 (± 0.5)-mmol litre'1 increase in blood glucose concentration (P < 0.01). Commencement of infusions of sympathomimetic agents resulted in a similar increase.

was obtained from the patients. The programme of the investigation was approved by the Newcastle Health Authority Ethical Committee. The following categories of patient were excluded from the study: PATIENTS AND METHODS (i) Patients with known ischaemic heart disease. Patients, anaesthesia and cardiopulmonary bypass (ii) Patients taking (3-adrenoceptor blocking agents, Twelve adult patients undergoing elective open- (iii) Patients with known endocrine or metabolic disheart surgery for valvular disease, and taken sequen- orders, or an abnormal oral glucose tolerance test on tially from the waiting list of one cardiac surgeon admission. (M.P.H.), were studied. Written, informed consent (iv) Patients with known hepatic or renal disease. To study the changes in blood glucose concentraCHARLES K. M C K N I G H T , * M.B., CH.B., F.F.A.R.C.S.; MARTIN tion which occurred during open-heart surgery and ELLIOTT, M.D., F.R.C.S.; D E R E K T. PEARSON, F.R.C.P., cardiopulmonary by-pass, it was felt that a pump F.F.A.R.C.S.; MICHAEL P. HOLDEN, M.B., F.R.C.S.; Department of prime free from glucose should be used, since gluCardiothoracic Anaesthesia and Surgery, Freeman Hospital, cose-containing primes result in large increases in Newcastle upon Tyne NE7 7DN. K. GEORGE M. M. ALBERTI, F.R.C.P.; Department of Clinical Biochemistry and Metabolic blood glucose concentration which might mask lesMedicine, University of Newcastle upon Tyne, Royal Victoria ser variations attributable to the technique itself (ElInfirmary, Newcastle upon Tyne NE1 4LP. liott, 1983). Two such non-glucose primes are in use •Present address: Newcastle General Hospital, Westgate in the United Kingdom (all U.K. centres having Road, Newcastle upon Tyne.

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AND M. P. HOLDEN

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596

TABLE I. Clinical details of the patients studied (mean values±SEM where applicable). AV = Aortic valve replacement; MV = mitral valve replacement; DV = double valve replacement Prime Plasmalyte 148 Hartmann's Solution (group 2) (group 1) Number

6

6

Age (yr)

59.8±3.3

Sex

2M,4F

4M,2F

Height (m)

1.59±O.O2

1.71±0.02

Weight (kg)

60.1+1.1 2

Surface area (m ) Operation

1.63±0.02 MV,MV,MV MV,AV,DV

56±1.7

67±4.6 1.77±0.07 MV,AV,MV MV,MV,MV

T A B L E II. Composition (mmol litre ') of the by-pass pump priming fluid used in each group

Na+ K+ Ca 2+ Mg 2 +

cr Lactate Acetate

Group 1 Hartmann's Solution

Group 2 Plasmalyte 148

131 5 2 — Ill 29 —

140 5 5 1.5 80 — 27

Clinical details of the patients are given in table I, and details of the two primingfluidsin table II. The anaesthetic technique was as follows: premedication consisted of papaveretum 11.75 mg m"2 and hyoscine 0.25 mg m~2 i.m. 1 h before surgery. Anaes-

thesia was induced with thiopentone 120 mg m 2, droperidol 11.75 mg m"2 and phenoperidine 2.4 mg m~2 i.v., and neuromuscular blockade produced by pancuronium 4.7 mg m~2. Anaesthesia was maintained with nitrous oxide in oxygen plus intermittent injections of phenoperidine. Further pancuronium was added as required to permit intermittent positive pressure ventilation. The perfusion technique was standardized: cardiopulmonary by-pass was conducted at 28 °C (veno-arterial cooling) at a flow of 2.4 litre m'2 min 1 , maintained at all temperatures. A Travenol membrane oxygenator was used in each patient, and pulsatile flow was utilized. Pulsatile flow was generated using a Stockert (Stockert Instrumente, Miinchen, F.R.G.) pulsatile roller-pump system set to deliver for 50% of the cycle at 90 beat min"1 whenever the left ventricle was not ejecting blood to the aorta. The prime volume of the system was 2.5 litre. No glucose-containing fluids were infused or used toflushthe pressure monitoring systems. All the operations were performed by the same surgeon (M.P.H.). Cardioplegic arrest was achieved using a modified Kirklin solution at 4 °C and all excised valves were replaced with Ionescu-Shiley bovine xenografts. Blood glucose sampling

The Biostator (Miles Laboratories Ltd, Stoke Poges, England) glucose-controlled insulin infusion system, shown in diagram form in figure 1, was used to estimate the blood glucose concentration continuously. From an indwelling double-lumen peripheral venous cannula, a small amount of blood (2 ml h"1) was withdrawn continuously and, after dilution, passed across a glucose sensor (glucose oxidase membrane and polarographic electrode). The blood glucose concentration was relayed to a computer, allowing display and recording of the data. IntermitPatient

Analyser pump module

Glucose analyser

I Computer

nsulin Dextrose

Display recorder

Infusion module

FIG. 1. Block diagram of the Biostator glucose-controlled insulin infusion system. The monitoring ability only was used in this study.

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been questioned): Hartmann's solution and Plasmalyte 148 (Travenol). Since Hartmann's solution contains lactate 29 mmol litre"1, and lactate, at least in diabetic patients, has been shown to be gluconeogenic when infused during surgery (Thomas and Alberti, 1978), it was felt that the glucose concentrations should be monitored in association with the use of both primes. Thus, the 12 patients were randomly allocated to one of two groups: Group 1: Six patients undergoing cardiopulmonary by-pass with a pump prime of Hartmann's solution. Group 2: Six patients undergoing cardiopulmonary by-pass with a Plasmalyte 148 pump prime.

MONITORING OF BLOOD GLUCOSE CONCENTRATION tent sampling of venous blood was carried out according to the sampling regimen shown in table III. Samples were drawn into fluorinated tubes and analysed using a sensitive fluorimetric assay. Statistics Student's t test, paired and unpaired, was used to evaluate the significance of differences within and between groups, respectively. Results are expressed as mean ± SEM.

Intermittent sampling The results of blood glucose estimations obtained by intermittent sampling are shown in figure 2. There were no significant differences between groups 1 and 2 at any stage. Thus, these results may be conveniently described together. There were no significant changes in blood glucose concentration before, or on institution of, cardiopulmonary by-pass. Blood glucose concentrations increased steadily from 5.6 ± 0.4 mmol

litre 1 5 min after the institution of by-pass to 10 ± 0.6 mmol litre"1 5 min before the end of by-pass. There were no significant changes in blood glucose concentration on the cessation of by-pass, nor were there any significant decreases until the morning of the first day after operation when the mean glucose values were 8.4 ± 0.7. mmol litre"1. Continuous sampling Because of a variable time-base, the data obtained from continuous monitoring do not lend themselves to cumulative graphical presentation. Thus, figures 3 and 4 are representative Biostator records from two patients. When analysed in relation to perioperative events rather than to time, no significant differences in blood glucose concentration could be demonstrated between the two groups at any stage. Following skin incision and before cardiopulmonary by-pass, there was a steady increase in blood glucose concentration of 1.3 ± 0.3 mmol litre"1 (P < 0.01). The institution of cardiopulmonary bypass was associated with an abrupt decrease in blood glucose concentration of 2 ± 0 . 5 mmol litre"1 as the patient's blood was diluted by the prime. This was

TABLE III. Regimen for intermittent sampling of venous blood Sample No.

Day

Time of event

1 2

1 Day before operation

08.00h 18.00h

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Day of operation

08.00h 5 min After induction of anaesthesia 5 min After skin incision 5 min After heparin 5 min After onset of CPB 15 min 30 min 60 min 5 min Before end of CPB 5 min After protamine lh After operation 2h 4h 6h 8h

18 19 20

1 Day after operation

08.00h 12.00h 18.00h

21 22

2 Days after operation

08.00h 18.00h

23 24

3 Days after operation

08.00h 18.00h

25 26

4 Days after operation

08.00h 18.00h

27

7 Days after operation

08.00h

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RESULTS

597

BRITISH JOURNAL OF ANAESTHESIA

598

.

2

3

4

5

6

7

8

9

10 11 12 13 14 15 16 17 18 19 20 21 22 23 2a, 25

26 27

Sample No.

FIG. 2. Blood glucose concentrations in both groups as estimated by intermittent sampling.

10

$

•D

8 m

5

CPB HS prime

FIG. 3. Continuously monitored blood glucose concentration in a patient from group 1 (Hartmann's Solution prime) (HS prime). CPB = pulsatile CPB (28 °C); R = rewarming. 10 r

.2

FIG. 4. Continuously monitored blood glucose concentration in a patient from group 2 (Plasmalyte 148 prime) (P prime). CPB = pulsatile CPB (28 °C); R = rewarming.

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1

. Plasmalyte 148 Hartmann's sol.

MONITORING OF BLOOD GLUCOSE CONCENTRATION

5

10

8

I m •a

5

FIG. 5. Continuously monitored blood glucose concentration showing the effect of an infusion of dopamine. CPB = pulsatile CPB (28 °C); HS prime = Hartmann's Solution prime.

FIG. 6. Continuously monitored blood glucose concentration showing the effect of an infusion of isoprenaline. CPB = pulsatile CPB (28 °C); P prime = Plasmalyte 148 prime.

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4) in

ft

599

600

Catecholamines are known to stimulate glycogenolysis and hepatic gluconeogenesis (De Fronzo, Sherwin and Felig, 1980). Thus, it is to be expected that there would be an increase in the release of glucose from the liver. In addition, the peripheral utilization of glucose is decreased greatly at these body temperatures (Black, Van Devanter and Cohn, 1976; Stoner et al., 1980), and this would account for the increase in blood glucose concentration observed during the first hour of by-pass. The changes in blood glucose concentration noted during rewarming are of interest also. During the rewarming phase, there may be changes in the blood concentrations of various hormones which are known to have profound effects on glucose metabolism. Thus, the concentrations of adrenaline and noradrenaline have been shown to increase considerably during the return to normothermia (Stanley et al., 1980; Landymore, Murphy and Kinley, 1981). This additional increase in catecholamine concentrations is likely to increase further the rates of hepatic and renal medulla glycogenolysis and gluconeogenesis, resulting in increased glucose release. In addition, the serum cortisol concentration increases during cardiopulmonary by-pass (Walsh et al., 1981) and die increased concentration has a synergistic effect with catecholamines on DISCUSSION gluconeogenesis (De Fronzo, Sherwin and Felig, Previous reports using intermittent sampling of 1980). A direct stimulatory effect of increasing blood contain results similar to those obtained with temperature on the enzyme systems involved in gluintermittent sampling in this study, when similar cose production cannot be ruled out. primes were used. However, our comparison of conIt is surprising that the increase in blood glucose tinuous with intermittent sampling has shown that concentration associated with rewarming occurs at a intermittent sampling failed to reveal several sigtime when serum insulin concentrations have been nificant changes in blood glucose concentration. The decrease in blood glucose concentration on shown to increase markedly. Insulin secretion is commencement of cardiopulmonary by-pass and the decreased during hypothermic cardiopulmonary byincreases associated with rewarming and the infu- pass, but increases rapidly during rewarming (Allision of sympathomimetic agents were not detected son, 1971; Elliott, 1983). The relationship between the time course of the action of insulin on glucose by intermittent sampling. uptake and utilization, and that attributable to The decrease in blood glucose concentration (of endocrine stimulation of glucose production during 2 mmol litre"1) with the onset of cardiopulmonary rewarming has not been established by us. by-pass may be explained by dilution of the patient's circulating blood volume with the glucose-free The increases in blood glucose concentration pump prime. Some subsequent redistribution must observed during the infusions of sympathomimetic occur as the prime equilibrates with the extracellu- agents are presumably the result of direct stimultion lar fluid. Thereafter, the steady increase in blood of glycogenolysis and gluconeogenesis, and of the glucose concentration observed during the first hour indirect effect of increasing insulin resistance. The of hypothermic cardiopulmonary by-pass merits increases in blood glucose concentration observed consideration. High concentrations of during die infusions of blood almost certainly catecholamines, particularly noradrenaline, are resulted from the glucose content of the transfusion. known to occur during hypothermic by-pass C-P-D blood contains from 7 to 22 mmol litre"1 of (Landymore et al., 1979; Stanley et al., 1980). glucose (mean 19 mmol litre"1). Further clarifica-

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followed by an increase to 9 ± 0.8 mmol litre ' during the first hour of hypothermic by-pass. During rewarming, a much more rapid increase in blood glucose concentration was observed in all patients. This increase of 3 ± 0.5 mmol litre"1 was not demonstrated by intermittent sampling. Thereafter, the blood glucose concentrations decreased to a mean of 9.5 + 0.8 mmol litre"1, which had not varied significantly by 4 h into the postoperative period, when continuous monitoring was discontinued. Figures 5 and 6 demonstrate the effects on blood glucose concentration of the infusion of sympathomimetic agents. Four of the 12 patients required inotropic support at some stage in the period after operation. This was associated, in each case, with an increase in blood glucose concentration with a mean value of 2.5 + 0.4 mmol litre"1 which was sustained for the duration of the infusion —although the infusions were of fairly short duration (1.5-2.5 h). It should be noted that a variable and unpredictable increase in blood glucose concentration was observed during the rapid infusion of Citrate—Phosphate-Dextrose blood in those patients who received it, the increase being related to the glucose content of the transfused blood.

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MONITORING OF BLOOD GLUCOSE CONCENTRATION

ACKNOWLEDGEMENTS

C. K. McK. was supported by a grant from the Newcastle Health Authority Scientific and Research Committee. Support was also received from the Lesley Scott Memorial Fund (now the Children's Heart Unit Fund). REFERENCES

Allison, S. P. (1971). Changes in insulin secretion during openheart surgery. Br.J. Anaeslh., 43, 138. Black, P. R., Van Devanter, S., and Cohn, L. H. (1976). Effects of hypothermia on systemic and organ system metabolism and function.,7. Surg. Res., 20, 49. Brandt, M. R., Korskin, J., Prange-Hansen, A., Hummer, L., Nistrop-Madsen, S., Rygg, I., and Kehlet, H. (1978). Influence ot morphine anaesthesia on the endocrine-metabolic response to open-heart surgery. Acta Anaesthesiol. Scand., 22, 400. De Fronzo, R. A., Sherwin, R. S., and Felig, P. (1980). Synergistic interactions of counterregulatory hormones: a mechanism for stress hyperglycaemia. Acta Chir. Scand. (Suppl), 498, 33.

Elliott M. J. (1983). Some aspects of the metabolic response to open-heart surgery. M.D. Thesis, University of Newcastle upon Tyne. Gill, G. V., Home, P. D., Noy, G. A., Holden, M. P., and Alberti, K. G. M. M. (1984). A comparison of two regimes for the management of diabetes during open-heart surgery. Anesthesiology, (In press). Kuntschen, P., Galletti, P. M., and Hahn, C. (1981). Blood glucose control by closed loop insulin delivery during coronary artery by-pass surgery. Trans. Am. Soc. Artif. Intern. Organs, 27,241. Landymore, R. W., Murphy, D. A., and Kinley, E. (1981). Does pulsatile flow improve glucose tolerance during extra-corporeal circulation?^. Cardiovasc. Surg., 22, 239. Parrott,J.C.,Moffitt,E. A., Longley, W. I., and Qirbi, A. A. (1979). Does pulsatile flow infuence the incidence of post-operative hypertension? Ann. Thorac. Surg., 28, 261. MacDonald, R. G., Buckler, J. M. H., Deverall, P. B., Watson, D. A., and Ballint, M. (1975). Growth hormone and blood glucose concentraions during cardiopulmonary by-pass. Br. J. Anaesth., 47, 7\1. Moffitt, E. A., Rosevear, J. W., Molnar, G. D.,andMcGoon, D. C. (1970). Myocardial metabolism in open-heart surgery. Correlation with insulin response. J. Thorac. Cardiovasc. Surg., 59,691. Sessler, A. D., Molnar, G. D., and McGoon, D. C. (1971). Normothermia versus hypothermia for whole-body perfusion. Effects on myocardial and body metabolism. Anesth. Analg., 50, 505. Stanley, T. H., Herman, L., Green, O., and Robertson, D. (1980). Plasma cathecholamine and cortisol responses to fentanyl—oxygen anesthesia for coronary artery operations. Anesthesiology, 53, 250. Stoner, H. B., Frayn, K. N., Little, R. A., Threlfall, C. J., Yates, D. W., Barton, R. N . , and Heath, D. F. (1980). Metabolic aspects of hypothermia in the elderly. Clin. Sci., 59, 19. Thomas, D. J., and Alberti, K. G. (1978). Effects of Hartmann's Solution during surgery in patients with maturity-onset diabetes. Br.J. Anaesth., 50, 185. Walsh, E. S., Paterson, J. L., O'Riordan, J. B. A., and Hall, G. M. (1981). Effect of high-dose fentanyl anaesthesia on the metabolic and endocrine response to cardiac surgery. Br. J. Anaesth., 53,1155. Yokota, H., Kawashima, Y., Takao, T., Hashimoto, S., and Manabe, H. (1977). Carbohydrate and lipid metabolism in open-heart surgery. J . Thorac. Cardiovasc. Surg., 73, 543.

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tion of these glucosefluxeswould require catheterization or turnover studies. We did not observe a gluconeogenic effect of the lactate primes in these non-diabetic patients undergoing open-heart surgery with hypothermic bypass, there being no differences in the blood glucose concentrations between the groups at any stage. However, the patient population and intraoperative management were quite different from those reported by Thomas and Alberti (1978), who demonstrated a gluconeogenic effect of lactate infusions in diabetic patients undergoing surgery. Apart from the obvious pathophysiological interest of these results, the consequent increase in understanding of blood glucose homeostasis during open-heart surgery is of importance in clinical management. This will be particularly true of the patient with diabetes. Indeed, both we (Elliott et al., 1984) and others (Kuntschen, Galletti and Hahn, 1981) have observed similar changes in diabetic patients undergoing open-heart surgery using the Biostator blood glucose control. It is clear from this study that the continuous monitoring of blood glucose yields considerably more information than intermittent sampling during open-heart surgery; rapid changes in glucose homeostasis occur, and continuous monitoring is ideally suited for the study of glucose metabolism in this situation. The technique may prove to be a valuable tool in the further assessment of per- and postoperative glucose dynamics in such patients, as, for example, when different pump priming fluids are used, or when different perfusion techniques are utilized.

601