coronary artery bypass surgery ( cabg ) is the most common heart surgery . in the united states , 515,000 patients undergo coronary artery bypass surgery ( cabg ) each year ; about 28% of them have diabetes . hyperglycemia ( blood glucose over 200 mg / dl ) is common in patients in a poor clinical condition . this causes more infection , ischemic events , renal and neurological complications , and higher mortality . the main mechanism of increased blood glucose in this condition is insulin resistance ( ir ) ; therefore , insulin is considered to be the main drug for treatment of hyperglycemia . however , insulin accelerates the transfer of potassium and magnesium into the cells that may lead to hypokalemia and hypomagnesia . in addition , due to insulin resistance and insulin induced hypoglycemia , the use of products such as metformin , which does not cause hypoglycemia , is recommended for blood glucose control in patients with insulin resistance . it is a dimethyl biguanide oral anti - hyperglycemic drug that reduces overall mortality in type 2 diabetes . metformin reduces gluconeogenesis and glycogenolysis , and increases sensitivity of insulin receptors through multiple mechanisms . metformin has different mechanisms of action from other anti - hyperglycemic drugs and does not lead to a severe drop in the blood glucose level of diabetic patients . between the years 1985 to 2001 , 66 cases of metformin - associated lactic acidosis ( mala ) were reported by the fda and 48 cases by the australian adverse drug reactions advisory committee ( adrac ) . mala is a fatal metabolic condition that limits metformin use in patients in poor clinical condition . these restrictions considerably reduce the number of patients who could benefit from this advantageous drug . however , salpeter et al . have estimated the incidence of lactic acidosis in type 2 diabetic metformin users to be less than non - metformin users ( 0.0043% vs 0.0054% ) . this clinical trial was performed to determine whether metformin can create lactic acidosis in type 2 diabetic patients after cabg surgery . whereas previous studies have taken a descriptive or retrospective approach with different times/ dose of metformin , to our knowledge , this is the first clinical trial studying the effect of metformin administration in such patients . in this double blind randomized clinical trial , 200 type 2 diabetic patients were studied following cabg surgery in the open heart icu of the mazandaran heart center . approval from the ethics committee of mazandaran university of medical sciences and informed consent from patients were obtained . patients were randomly and simultaneously assigned to 2 groups ; 100 patients received insulin and 100 received insulin - metformin . inclusion criteria were : age between 35 to 75 years , type 2 diabetes , non - emergency cabg surgery , the use of cardiopulmonary pump during the operation and hemodynamic stability ( map > 60 , lack of dangerous dysrhythmia and heart rate between 50 to 100 ) . we excluded patients with any kind of liver disorder ( sgpt and sgot more than 75 ) , renal dysfunction ( serum creatinine more than 1.5 mg / dl in 2 consecutive tests ) , heart failure ( ejection fraction ratio less than 30% ) , and the use of any contrast or history of angiography within two days before the operation . medication would be interrupted and patients would leave the study if at any time during the study the following events were recorded : serum lactate level more than 45 mg / dl ( 5 mmol / l ) or had values which increased more than 18 mg / dl ( 2 mmol / l ) compared to previous levels , ph less than 7.25 or serum base excess ( be ) of less than -6 mmol / l , mean arterial oxygen pressure less than 60 mmhg in two consecutive arterial blood gas ( abg ) tests , potassium drops of less than 3 meq / l , nausea and vomiting , use of metformin metabolism inhibitors such as amiodarone and cimetidine , use of high - dose inotrope drugs more than 3 h after extubation and need for reoperation for any reason . insulin group : regular insulin infusion based on the center protocol with 2 placebo tablets ( sari pharmaceutical laboratory , iran ) every 12 h. insulin - metformin group : regular insulin infusion based on the center protocol with 2 metformin tablets 500 mg ( aria , iran ) every 12 h. metformin or placebo were prescribed 3 h after extubation by oral administration and in the absence of oral tolerance through a nasogastric tube . all oral anti - hyperglycemic drugs were discontinued two days before the surgery in all patients and subsequent blood glucose levels were controlled with insulin . there was no difference in onset of intervention or patient diet before and after surgery between the 2 groups ( diabetic and cardio diet based on hospital routine ) . patients were placed in treatment protocols for 60 h during which blood glucose , lactate , ph and be were measured every 2 h and creatinine was measured daily . the study was divided into 5 stages and the mean 12 h period values were calculated . blood glucose , lactate , ph and be were measured by advanced blood gas machine gem 3000 ( instrumentation laboratory , ma , usa ) using future pulse medical company cartridge . this was a double blind study and none of the patients , physicians , nurses or laboratory staff was aware of the type of treatment received . blood glucose level , ph and be were assessed as secondary outcomes . in this study , after controlling the normal distribution of numerical variables by the kolmogorov - smirnov test , an independent student 's t - test was calculated to compare the two groups . to compare changes in multiple measurements in each group and to analyze group interaction , a repeated measurement anova test was used . in all statistical tests , two hundred patients were entered in this clinical trial ; 100 patients in the insulin group and 100 patients in the insulin - metformin group ( using an equal randomized allocation ) . ten patients were excluded during the project and data from 190 patients were analyzed ( figure 1 ) . forty - six of 96 patients ( 52.1% ) among the insulin group and 50 of 94 patients ( 46.8% ) among the insulin - metformin group were men but the difference was not statistically significant ( p>0.05 ) . also there was no statistically significant difference in the basic and clinical characteristics between the 2 groups ( table 1 ) . table 1pre - operative patient characteristics.insulin group ( n=96)insulin - metformin group ( n=94)p ( t - test)mean95% cimean95% ciage ( y)60.559.2 to 61.859.858.3 to 61.20.435weight ( kg)66.464.4 to 68.467.865.7 to 70.00.350height ( m)1.621.60 to 1.641.631.61 to 1.650.367body mass index ( kg / m)25.324.6 to 26.125.424.6 to 26.30.844mean arterial pressure ( mm / hg)71.370.0 to 72.573.371.5 to 75.20.072ejection fraction ( % ) 46.544.7 to 48.247.145.6 to 48.50.585intubation time ( hr)5.475.33 to 5.625.325.18 to 5.460.150lactate ( mg / dl)23.425.5 to 21.423.025.0 to 21.10.793ph7.3537.359 to 7.3467.3577.364 to 7.3500.392base excess ( mmol / l)3.683.48 to -3.893.613.40 to 3.810.606serum creatinine0.890.93 to 0.850.920.95 to 0.870.426potassium ( meq / l)4.324.38 to 4.264.374.42 to 4.320.235 lactic acidosis was not observed in either of the study arms . in patients receiving insulin , at baseline the serum lactate level was 23.410.1 ( mg / dl ) , while at the end of study , it reached 18.95.9 ( a 19% reduction ) . similarly , an approximately 19% reduction in serum lactate level was seen in the metformin group ( figure 2 ) . figure 2changes in blood lactate level ( mean and sem ) of patients in insulin and insulin - metformin groups during the study . changes in blood lactate level ( mean and sem ) of patients in insulin and insulin - metformin groups during the study . changes in ph and be were similar in both groups with no statistically significant difference ( f(1 , 187)=0.286 ; p=0.853 for ph and f(1 , 187)=0.159 ; p=0.932 ) for be ( figure 3 ) . figure 3changes in ph level of blood and the amount of base excess ( mean and sem ) of patients in insulin and insulin - metformin groups during the study . changes in ph level of blood and the amount of base excess ( mean and sem ) of patients in insulin and insulin - metformin groups during the study . average consumed bicarbonate during the study was 6.77 meq ( 95%ci : 4.07 to 9.470 ) in the insulin group and 6.91meq ( 95%ci : 3.97 to 9.86 ) in the insulin - metformin group . there was no significant difference between the 2 groups ( t= 0.072 ; p=0.943 ) . no significant difference was observed in the number of high blood lactate events ( between 3045 mg / dl ) during the study in the insulin group and the insulin - metformin group ( =0.850 ; p=0.467 ) ( figure 4 ) . figure 4high blood lactate ( between 30 and 45 mg / dl ) separately in studied groups . high blood lactate ( between 30 and 45 mg / dl ) separately in studied groups . however , the reduction observed in the insulin - metformin group was more than the insulin group and this difference was statistically significant ( f(1 , 187 ) = 9.873 ; p<0.001 ) . the study findings showed that use of metformin ( 1,000 mg / bd ) together with insulin in type 2 diabetic icu patients after cabg surgery did not cause lactic acidosis . blood lactate levels in both groups gradually decreased during the study , but we observed no significant difference between the 2 groups . there was no significant difference in blood ph between the 2 groups during the study period and mean blood ph in patients were in the normal range ( 7.357.45 ) . some cases of lactic acidosis caused by metformin were reported by preiser and vincet , lustik et al . , that led to stricter limits in the use of metformin in type 2 diabetic patients . however , lalau and race and kamber have stated that lactic acidosis can not be directly attributed to metformin use . their rationale was that many patients who developed lactic acidosis while taking metformin were those who suffered from underlying problems such as heart failure , kidney and liver diseases , and diabetes , which are known as risk factors of lactic acidosis . duncan et al . showed that type 2 diabetic patients treated with metformin would not develop more severe acidosis . also long - term intubation , infection and overall morbidity in the metformin group were significantly less than the non - metformin group . in the duncan et al . study , serum lactate level was measured only in patients with primary diseases , while the exact dose and the last dose of metformin were not clear and metformin was continued up to cardiac surgery . importantly , the present study showed that the use of insulin along with high - dose metformin , even immediately after cardiac surgery , does not create acidosis , but improves blood glucose control in these patients . our results in a larger number of patients confirmed the study by mojtahedzadeh et al . which showed no significant relationship between plasma level of metformin , blood lactate and ph . also blood ph was in the normal range and no ph less than 7.3 was seen . we showed that the use of 1,000 mg metformin twice daily plus insulin does not cause lactic acidosis in type 2 diabetic patients , while there was no difference in the amount of bicarbonate prescribed to each of the 2 groups . importantly , no lactic acidosis occurred following high - dose metformin in patients undergoing cabg with cardiopulmonary pump who have a higher potential risk of lactic acidosis . ansari showed that taking metformin with insulin in icu patients did not cause acidosis , which is consistent with the results of this study . therefore , based on the current published data and results of the present study , it seem that metformin administration in postoperative or critically injured patients is not absolutely contraindicated , but rather beneficial , particularly if selected for those patients with satisfactory hepatic , renal and cardiac function , and as long as these parameters are appropriately monitored . lactic acidosis due to metformin is easily preventable by avoiding dehydration , especially in concomitant nephrotoxic drug use . this study showed that high - dose metformin along with appropriate monitoring of renal and liver function not only protects against but also reduces microvascular complications and deaths from cardiovascular disease , even after coronary artery surgery in type 2 diabetic patients . during the present study , after frequent monitoring of the patients in the icu , a patient was excluded due to a creatinine level higher than 1.5 ( unit ) on 2 consecutive tests . on the other hand , blood glucose level in the metformin - insulin group this result suggests the positive effect of metformin in the control of blood glucose in type 2 diabetic patients undergoing cabg surgery , which is probably due to the metformin effect on the insulin resistance of these patients . use of metformin in type 2 diabetic icu patients after cabg surgery is associated with better glucose control without theoccurrence of lactic acidosis . consequently , it is a safe and effective drug and , so , a good choice for controlling blood glucose in order to reduce the complications and improve survival in these patients .
metformin is a dimethyl biguanide oral anti - hyperglycemic agent . 
 lactic acidosis due to metformin is a fatal metabolic condition that limits its use in patients in poor clinical condition , consequently reducing the number of patients who benefit from this medication . in a double blind randomized clinical trial 
 , we investigated 200 type 2 diabetic patients after coronary artery bypass surgery in the open heart icu of the mazandaran heart center , and randomly assigned them to equal intervention and control groups . 
 the intervention group received regular insulin infusion along with 2 metformin 500 mg tablets every twelve hours , while the control group received only intravenous insulin with 2 placebo tablets every twelve hours . 
 lactate level , ph , base excess , blood glucose and serum creatinine were measured over five 12 h periods , with data averaged for each period . 
 the primary outcome in this study was high lactate levels . 
 comparison between the 2 groups was made by independent student s t - test . to compare changes in multiple measures in each group and analysis of group interaction , 
 a repeated measurement anova test was used.there was no significant difference between the 2 groups regarding ph , base excess , or bicarbonate intake ( p>0.05 ) . 
 no patient showed lactic acidosis in either group . 
 lactate levels were 23.0 vs 23.4 in the insulin - metformin and insulin only groups when the study was started , respectively . at the end of the study , 
 those levels were 18.7 vs 18.9 , respectively . 
 in addition , the anova repeated measurement test did not show a significant difference in terms of changes in the amount of lactate level between the 2 groups during the five measurement tests of the study period ( p>0.05).high - dose metformin ( 1,000 mg twice daily with insulin ) does not cause lactic acidosis in type 2 diabetic patients after coronary artery bypass surgery .