Influence of Blood Glucose Level on Acid-Base Balance Kyoung-Min Lee, M.D

대한중환자의학회지：제 24 권 제 1 호 ■ 원저■ Vol. 24, No. 1, April, 2009

Influence of Blood Glucose Level on Acid-Base Balance Kyoung-Min Lee, M.D.

Department of Anesthesiology and Critical Care Medicine, Konkuk University Hospital, Seoul, Korea

Background: This study was performed to evaluate whether blood glucose concentrations have a significant influence on acid-base balance. Methods: We studied 157 adult patients who underwent intra-abdominal operations under general anesthesia. Postoperative blood samples were withdrawn from radial artery and blood glucose concentrations, gas values, and chemistry values were measured. All patients were divided into three groups according to the postoperative blood glucose level. The group 1 contained the patients who had postoperative blood glucose level lower than 126 mg/dl, the group 2, the patients with glucose level higher than 126 mg/dl, lower than 180 mg/dl, and the group 3, the patients with glucose level higher than 180 mg/dl. Results: Metabolic acidosis rate was significantly higher in group 3 than in group 1, group 2 and arterial blood ＋ pH was significantly lower in group 3 than that in group 1, group 2. Regression analysis showed that [H ] was correlated with blood glucose level. Strong ion difference (SID) was significantly lower in group 3 than group 1

and PaCO2 level was significantly lower in group 2 and group 3 than that in group 1. In regression analysis, there ＋ was a negative correlation between blood glucose concentration and SID. [H ] had a negative correlation with SID

and PaCO2 was correlated with SID. Conclusions: These findings suggest that blood glucose level affects acid-base balance and a disturbance in SID is accompanied with respiratory compensation.

Key Words: acid-base balance, blood glucose concentration, metabolic acidosis, respiratory compensation, strong ion difference.

INTRODUCTION glycemia has been known to increase the susceptibility to infections and decrease in neutrophil phagocytic activity.11,12) Hyperglycemia with insulin resistance are common in crit- By the way, since glucose is largely restricted to ex- ically ill patients and are associated with poor prognosis.1-4) tracellular fluid, an increase in its concentration moves water Van den Berghe et al.5) recently demonstrated that controlling out of cells, causing dilution of extracellular substance,13) blood glucose levels by intensive insulin therapy dramatically which might affect strong ion difference (SID). According to decreased mortality and morbidity in critically ill patients of the Stewart’s physicochemical analysis of acid-base status, SID surgical intensive care unit, even though didn’t show the re- is one of independent variables determining acid-base ba- duced mortality in patients of medical intensive care unit.6) lance.14) We therefore hypothesized that blood glucose level Glucose has been shown to be a powerful pro-inflammatory would affect SID and acid-base balance. mediator and increase reactive oxygen species generation by polymorphonuclear leukocytes and mononuclear cells.7,8) Glu- MATERIALS AND METHODS cose also has been shown to exert prothrombotic effects and reduce endothelial nitric oxide levels, causing abnormal vas- The institutional review board approved this research. We cular reactivity and organ perfusion.9,10) In addition, hyper- studied 157 adult patients who underwent intra-abdominal operations under general anesthesia. Patients with preoperatively ex- Received on February 27, 2009, Accepted on April 10, 2009 Correspondence to: Kyoung-Min Lee, Department of Anesthesiology and isting cardiac, hepatic, or renal dysfunction were excluded. In Critical Care Medicine, Konkuk University Hospital, 4-12, type of surgical procedures, there were 82 gastric, 41 color- Hwayang-dong, Gwangjin-gu, Seoul 143-729, Korea ectal, and 34 hepatobiliary operations (Table 1). Tel: 82-2-2030-5443, Fax: 82-2-2030-5449 E-mail: [email protected] Anesthesia was induced in all patients by thiopental (4−5 17 18 대한중환자의학회지：제 24 권 제 1 호 2009

Table 1. Demographic Data Table 2. Comparison of Postoperative Variables between Groups

Group 1 Group 2 Group 3 Group 1 Group 2 Group 3 (n = 32) (n = 97) (n = 28) Number of patients 32 97 28 Age (yr) 62.1 ± 10.6 60.9 ± 12.65 57.2 ± 11.8 Glucose level (mg/dl) 116.5 ± 8.4 149.9 ± 14.8* 219.0 ± 31.9† † Gender (M/F) 25/7* 52/45 16/12 Metabolic acidosis, 13 (41.9) 54 (57.4) 23 (85.2) Body weight (kg) 59.2 ± 10.7 55.8 ± 10.1 57.3 ± 7.7 n (%) Diabetes mellitus (−/＋) 30/2 85/12 18/10* Arterial blood pH 7.36 ± 0.05 7.37 ± 0.06 7.33 ± 0.07‡

Type of surgery PaCO2 (mmHg) 42.2 ± 5.9 38.0 ± 5.0* 36.2 ± 4.3* Gastroduodenal 20 47 15 SID (mEq/L) 36.1 ± 3.0 35.3 ± 2.7 34.0 ± 3.6§ Colorectal 9 29 3 Na＋ (mEq/L) 137.9 ± 2.6 138.1 ± 3.0 137.6 ± 3.4 ＋ Hepatobiliary 3 21 10 K (mEq/L) 3.9 ± 0.4 4.0 ± 0.4 4.1 ± 0.5 − Cl (mEq/L) 105.6 ± 4.3 106.7 ± 4.2 107.7 ± 5.6 *p ＜ 0.05 by Chi-square test. Albumin (g/dl) 3.01 ± 0.44 3.00 ± 0.44 2.84 ± 0.39 Protein (g/dl) 5.05 ± 0.67 5.11 ± 0.73 4.94 ± 0.72 [Atot] (mEq/L) 12.1 ± 1.6 12.3 ± 1.7 11.9 ± 2.0 mg/kg) and maintained with sevoflurane (1.8−3.5 vol%) or BEua (mEq/L) 0.6 ± 3.3 0.3 ± 2.8 −1.8 ± 4.3† isoflurane (1.0−2.3 vol%) in a mixture of nitrous oxide 50% SID: strong ion difference; [Atot]: total weak acids concentration; in oxygen. Neuromuscular relaxation was induced by an intra- BEua: base excess by unmeasured anions; *p ＜ 0.01 vs group 1; venous injection of vecuronium (0.1−0.2 mg/kg) and main- †p ＜ 0.01 vs group 1, 2; ‡p ＜ 0.05 vs group 1, 2; §p ＜ 0.05 tained by continuous infusion of 0.04−0.06 mg/kg/h. vs group 1. Following endotracheal intubation, ventilation of the lungs was controlled by tidal volume of 8−10 ml/kg and respiratory rate of 12 breaths/min. We used isotonic solutions (lactated titative acid-base studies of Stewart show that three in- Ringer’s solution, normal saline) for intraoperative fluid dependent variables determine the hydrogen ion and the bicar- ＋＋ management. We measured blood glucose level every 2 hrs bonate concentrations: the SID calculated as [Na ] ＋ [K ] − − during operation and intravenous infusion of regular insulin [Cl ], PCO2, and the concentration of weak acids in which the (unit/ml in normal saline) started in two patients (group 3) major contributor is albumin.14) Fencl and Leith16) and Gilfix et 17) when the blood glucose level increased higher than 200 mg/dl. al. developed equations to correct the base excess (BE) for At the end of surgery, patients were extubated following antag- changes in sodium, chloride, and albumin: onism of residual neuromuscular block with pyridostigmine (0.2 ＋＋ mg/kg) and glycopyrrolate (0.004 mg/kg). Free water effect (A) = 0.3 ([Na] − 140) (Na in Postoperative blood samples were withdrawn from radial ar- mmol/L) − − ＋ − tery and blood glucose and gas values were measured (348 Corrected chloride [Cl c] = [Cl] × 140/[Na ] (Cl in pH/Blood Gas Analyzer, Bayer Diagnostics LTD, Indianapolis, mmol/L) − IN, USA). Blood chemistry values also were measured Chloride effect (B) = 102 − [Cl c] (Olympus AU400, Olympus Optical Co. LTD, Tokyo, Japan). Albumin effect (C) = (0.148 × pH − 0.818) (42 − We divided the patients into three groups according to the [albumin]) (albumin in g/L) immediate postoperative blood glucose level. The group 1 (n = BEua = measured BE − (A ＋ B ＋ C) (in mmol/L) 32) contained the patients who had postoperative glucose level lower than 126 mg/dl. The group 2 (n = 97) contained the Data are presented as mean ± SD. Chi-square test and patients with postoperative glucose level between 126 and 180 ANOVA with Student-Newman-Keuls multiple comparison test mg/dl and the group 3 (n = 28) contained the patients with were used to assess differences between the groups. glucose level higher than 180 mg/dl. Correlations between the postoperative blood glucose level and Metabolic acidosis was defined as arterial blood bicarbonate other continuous variables were studied using linear regression ＋ concentration less than 22 mEq/L and SID was defined as [Na ] analysis. Data analysis was performed with SPSS version 12.0 ＋ − ＋ [K ] − [Cl ]. Total weak acids concentration ([Atot]) was (SPSS Inc., Chicago, IL, USA) and p value less than 0.05 defined as multiplication of the plasma protein content (g/L) was considered statistically significant. by 0.24.15) We calculated base excess by unmeasured anions (BEua) based on the Stewart principle in all groups. The quan- Kyoung-Min Lee：Influence of Glucose Level on Acid-Base 19

p ＜ 0.05) than group 1 (36.1 ± 3.0 mEq/L) and PaCO2 level RESULTS was significantly lower in group 2 (38.0 ± 5.0 mmHg, p ＜ 0.01) and group 3 (36.2 ± 4.3 mmHg, p ＜ 0.01) than that in The groups did not differ in terms of age, body weight, or group 1 (42.2 ± 5.9 mmHg). In regression analysis, there was type of surgery. Postoperative blood glucose concentrations a negative correlation between blood glucose concentration and ＋ (155.4 ± 37.2 mg/dl) were approximately 42% higher than pre- SID (r = −0.260, p ＜ 0.01, Fig. 2). [H ] had a negative operative values (109.3 ± 33.2 mg/dl). correlation with SID (r = 0.478, p ＜ 0.01, Fig. 3) and PaCO2 Metabolic acidosis rate was significantly higher in group 3 was correlated with SID (r = 0.221, p ＜ 0.01, Fig. 4). (85.2%, p ＜ 0.01, Table 2) than in group 1 (41.9%) and In protein concentration, the group 3 showed the lowest val- group 2 (57.4%) and arterial blood pH was significantly lower ue (4.94 ± 0.72 g/dl) compared with group 1 (5.05 ± 0.67 in group 3 (7.33 ± 0.07, p ＜ 0.05) than that in group 1 g/dl) and group 2 (5.11 ± 0.73 g/dl), even though not statisti- (7.36 ± 0.05) and 2 (7.37 ± 0.06). Regression analysis showed cally significant (Table 2). In regression analysis, there was an ＋ − that [H ] was correlated with blood glucose level (r = 0.265, inverse correlation between protein concentration and [Cl ] (r p ＜ 0.01, Fig. 1). = −0.236, p ＜ 0.01, Fig. 5) and a strong negative correla- − SID was significantly lower in group 3 (34.0 ± 3.6 mEq/L, tion was observed between [Cl ] and SID (r = −0.755, p ＜

＋ Fig. 1. Relationship between blood glucose level and [H＋]. There was Fig. 3. Relationship between strong ion difference (SID) and [H ]. ＋ a correlation between blood glucose level and [H＋]. There was a negative correlation between SID and [H ].

Fig. 2. Relationship between blood glucose level and strong ion

difference (SID). A negative correlation was observed between Fig. 4. Relationship between strong ion difference (SID) and PaCO2.

blood glucose level and SID. A correlation was observed between SID and PaCO2. 20 대한중환자의학회지：제 24 권 제 1 호 2009

Fig. 5. Relationship between protein concentration and [Cl−]. There Fig. 6. Relationship between [Cl−] and strong ion difference (SID). was a negative correlation between protein concentration and A strong negative correlation was observed between [Cl−] and [Cl−]. SID.

0.01, Fig. 6). BEua was significantly lower in group 3 (−1.8 istic of nonpermeant proteins in the plasma space will attract ± 4.3 mEq/L, p ＜ 0.01) than group 1 (0.6 ± 3.3 mEq/L) and positively charged ions and repel negatively charged ions. As a 2 (0.3 ± 2.8 mEq/L). There was no significant difference in result, the diffusible cation concentration is higher in the com- [Atot] between the groups (Table 2). partment containing nondiffusible, anionic proteins, whereas diffusible anion concentration is lower in the protein-contain DISCUSSION compartment.20,21) Therefore, decrease of protein concentration will repel positively charged ions and attract negatively charged Metabolic acidosis correlates with increased mortality even in ions. In our study, the group 3 showed the lowest protein con- the absence of increased lactate levels and is a reliable pre- centration compared with other groups and there was a weak but dictor of patient’s outcome.18) In this study, blood glucose lev- significant negative correlation between plasma protein concen- − − el was associated with development of metabolic acidosis. tration and [Cl ]. The [Cl ] was strongly inversely correlated Since glucose is largely restricted to extracellular fluid, an in- with the SID. These findings suggest that hyperglycemia may re- crease in its concentration moves water out of cells, causing sult in decrease of plasma protein concentration and increase of − dilution of extracellular substance. In group 3 of this study, [Cl ], which develop decrease of SID and metabolic acidosis. ＋ the postoperative glucose level (219.0 ± 31.9 mg/dl) increased In terms of [Na ], the glucose concentration was not asso- ＋ average 102.5 mg/dl from the preoperative level (128.2 ± 52.3 ciated with [Na ] in this study, even though it was expected mg/dl), which was accounted for 5.7 mOsm/kg increase of that change of glucose levels should have resulted in change ＋＋ plasma osmolality and should have moved water out of cells. of [Na ]. However, [Na ] does not vary appreciably as long If plasma was diluted with water moved out of cells from as osmoregulation is intact. For example, hypercapnia and as- ＋＋ the change of osmolality, [Na ] should have decreased. Katz19) sociated increase in [H ] are compensated for by a decrease − ＋ reported that there was an expected decrease of 1.6 mEq per in [Cl ] and increased SID, not increase in [Na ].22,23) liter in serum sodium for each 100 mg per 100 ml increment By the way, in our study SID had a significant weak corre- ＋ in serum glucose. However, in this study the [Na ] was not lation with PaCO2 and there was no significant correlation be- associated with the blood glucose concentration and even the tween protein concentration and PaCO2. These results indicate increase of blood glucose level was related with the increase that there is a controlled respiratory compensation in response − of [Cl ], which could account for the decrease of SID. to primary disturbances in the SID. Reduction in SID increases ＋ We may explain these findings from the point of view of [H ] and stimulate breathing, leading to a decrease in PCO2. Gibbs-Donnan effect or Gibbs-Donnan equilibrium. Proteins are The effectiveness of this response is dependent on the ven- substances with large molecular weight and therefore do not tilatory capacity, the effectiveness of pulmonary gas exchange, cross the capillary membrane easily. Negative charge character- and the integrity of ventilatory control reflexes and the fall in Kyoung-Min Lee：Influence of Glucose Level on Acid-Base 21

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