Trandolapril reduced insulin consumption of nondiabetic hypertensive critically ill patients
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Trandolapril reduced insulin consumption of nondiabetic hypertensive critically ill patients(pdf)
1 Trakya University,Medical Faculty,Department of Anaesthesiology and Reanimation
2 Trakya University,Medical Faculty,Department of Biostatistic
3 Trakya University,Medical Faculty,Department of Urology
Correspondence to Dilek Memi�瘙塂,Department of Anaesthesiology,Trakya University Medical Faculty,Edirne 22030,Turkey
Fax:0090 284 235 80 96，Email: dilmemis@mynet.com
[Abstract] Objective We compared the effect of a nondihydropyridine calcium channel blocker(verapamil) and angiotensin converting enzyme inhibitor(trandolapril) in patients with nondiabetic and hypertensive in critically ill patients. Methods Arterial hypertension was defined as an untreated systolic blood pressure of 130 mm Hg or more or a diastolic blood pressure of 85 mm Hg or more or as the need for antihypertensive therapy to attain a systolic or diastolic blood pressure under these levels. Eligible subjects were randomly assigned to receive one of the study treatments:the nondihydroprydine calciumchannel blocker verapamil 240 mg per day (Group Ⅰ,n=15),the angiotensin converting enzyme inhibitor trandolapril 2 mg per day (Group Ⅱ,n=15). During ICU stay daily data collection included the administration of insulin to control blood glucose concentration(100~110 mg/dl). Total daily insulin dose recorded per day for ten days. Results Mean arterial pressure and glucose levels 10 days values in group Ⅰ and Ⅱ were significantly lower in group Ⅰ and Ⅱ baseline values (P<0.001). The groups were similar in baseline insulin requirement,1st,2nd,3rd,and 4th days (P>005),while group Ⅰ when compared with groups Ⅱ at 5th,and 6th days (P<005),7th,8th,9th,and 10th days (P<0001) insulin requirement were found to be significantly high (P<005). Conclusions We found that,trandolapril decreases insulin requirement in nondiabetic,hypertensive critically ill patients.The results of ongoing and future clinical trials should help to answer whether recent experimental findings on the antidiabetic potential of certain angiotensin converting enzyme inhibitors will ultimately prove relevant to clinical practice.
[Key words] trandolapril; verapamil; insulin requirement;nondiabetic hypertensive;critically ill patients
INTRODUCTION
Several recent studies have demonstrated that the development of hyperglycemia is an important risk factor in terms of mortality and morbidity of critically ill patients. A metaanalysis of myocardial infarction revealed an association between stress hyperglycemia and increased risk of inhospital mortality and congestive heart failure or cardiogenic shock[1]. Elevated glucose levels also predicted increased mortality and length of ICU and hospital stay of trauma patients and were associated with infectious morbidity[2]. Retrospective analysis of a heterogeneous population of critically ill patients showed that even a modest degree of hyperglycemia was associated with substantially increased hospital mortality[3]. A study of the occurrence of hyperglycemia among critically ill children with widely varying pathologic conditions showed a correlation with higher inhospital mortality and longer length of stay[4]. A landmark prospective,randomized,controlled study on a large group of patients admitted to the ICU predominantly after extensive surgery revealed major clinical
benefits of intensive insulin therapy in critically ill patients [5]. Insulin was administered to the patients in the intensive insulin therapy group to maintain blood glucose levels between 80 and 110 mg/dl and resulted in mean blood glucose levels of 90 to 100 mg/dl (normoglycemia),without the risk of hypoglycemiainduced adverse events. Maintain safe levels of glycemia after massive insulin overdose. Indeed,several factors can influence the kinetics and magnitude of hypoglycemia in this situation,such as prolonged absorption of insulin if a large dose is injected,due to a "depot effect",variations in local blood flow,impaired renal function and,in diabetic patients,local lipodystrophy if the injection site has been used previously as well as circulating antibodies against insulin [6].
In vitro experiments and studies in animals and in humans have suggested a possible relationship between the reninangiotensin system and the pathogenesis of insulin resistance. For example,recent studies have suggested that angiotensin Ⅱ (AII) may promote impaired glucose metabolism through its effects on insulin signaling pathways,tissue blood flow,oxidative stress,sympathetic activity and adipogenesis [7~14]. Thus,pharmacologic interruption of the reninangiotensin system (RAS) with angiotensinconverting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) might improve glucose metabolism by interfering with AII generation or AII receptor activation.
Nondihydropyridine calcium channel blocker (verapamil) improves the tolerance for oral glucose in patients with type 2 diabetes and appears to have no additive hypoglycaemic effect to sulfonylurea [15]. Studies in rats suggest that verapamil inhibits the effect of glucagon stimulation at the hepatocyte level [16].
There is no evidence that nondihydropyridine calcium channel blocker and angiotensin converting enzyme inhibitor effect of impair glucose tolerance nondiabetic and mildtomoderate hypertension. We compared the effect of a nondihydropyridine calcium channel blocker and angiotensin converting enzyme inhibitor in patients with nondiabetic and mildtomoderate hypertension in critically ill patients.
MATERIAL AND METHODS
The Regional Committee on Medical Research Ethics approved the study. Written informed consent was obtained from the patients wherever possible,or from the next of kin. All consecutive admissions to participating ICUs during between 1 March 2004 and 1 May 2006 were included in the study. We enrolled subjects who were 40 years of age or older,serum creatinine concentration of no more than 1.5 mg per deciliter. In this instance only data from the first ICU admission were included,nondiabetic and hypertensive patients but who were not taking antihypertensive drug before. Demographic,clinical and physiological data were prospectively collected,and entered into a computerized database. Demographic information age,gender,duration of ICU stay and outcome were recorded. Physiology scores were calculated for the first 24 hours after ICU admission. Patients under 18 years of age whose stay in the ICU was less than 24 hours,presence or absence of preexisting diabetes mellitus and its management,patients transferred from another ICU were not included.
APACHE Ⅱ score were employed to determine the initial severity of illness. The APACHE Ⅱ score were calculated for each patient using data from the first 24 hours of admission. Patients were followed until death or discharge from ICU. Patients received a loading dose of 0.2 mg/kg midazolam iv over 10 min followed by a maintenance 0.1~0.5 mg/kg/h infusion. Alfentanil was infused at 0.25~1.0 mg/kg/min if analgesia was required. Patients were ventilated mechanically with oxygenenriched air to attain acceptable blood gases. All patients had arterial catheters (arterial line kit:Abbott,monitoring kit transpac 8”,Sligo,Ireland) and central venous catheters via subclavian (Braun,Certofix trio V 720 7F×8”,Melsungen,Germany) in place. Nasogastric tube was placed and its correct location in the gastric lumen confirmed radiologically. All patients were placed on continuous infusion of enteral tube feeding. The enteral feed was delivered by a pump device and 25 to 30 kcal/kg/day (Biosorb,Nutricia,Netherland) as the caloric requirement.
Arterial hypertension was defined as an untreated systolic blood pressure of 130 mm Hg or more or a diastolic blood pressure of 85 mm Hg or more or as the need for antihypertensive therapy to attain a systolic or diastolic blood pressure under these levels [17]. Eligible subjects were randomly assigned to receive one of the study treatments: the nondihydroprydine calciumchannel blocker verapamil (Isoptin SR,240 mg,Abotte) 240 mg per day (Group Ⅰ,n=15),the ACE inhibitor trandolapril (TARKA,2 mg trandolapril,Abotte) 2 mg per day (Group Ⅱ,n=15).
The target blood pressure was 120/80 mm Hg [17]. Additional antihypertensive drugs were allowed,to achieve the target blood pressure,in the following steps: step 1,hydrochlorothiazide or furosemide; step 2,doxazosin,prozosin,methyldopa,or betablockers; and step 3,minoxidil or longacting dihydropyridine calciumchannel blockers. The use of potassiumsparing diuretics,inhibitors of the reninangiotensin system,and nondihydropyridine calciumchannel blockers different from the study drugs was not allowed.
During ICU stay daily data collection included the administration of intravenous insulin to control blood glucose concentration (100~110 mg/dl). Blood glucose concentration was measured every three hours. Total daily insulin dose recorded per day for ten days.
Blood pressure and randomly collected morning urine samples were evaluated at the time of randomization,at ten days after randomization. Blood glucose,serum potassium,sodium,urea,and creatinine levels were measured at baseline and ten days after. Urinary albumin excretion,and other laboratory values,including levels of serum cholesterol and triglycerides,were also measured at randomization and ten days after. Additional evaluations were performed within one week after any change in antihypertensive therapy and whenever deemed clinically appropriate.
Duration of mechanical ventilation was recorded. Survival was defined as being alive at ICU discharge.
Statistics
MannWhitney U test was used for comparison of the differences between groups toward the values. Data were expressed as mean±SD. A P value of <0.05 was considered significant.
RESULTS
Clinical and demographic characteristics of the patients were listed on Table 1. 15 of 30 patients received verapamil (group Ⅰ) and 15 received trandolapril (group Ⅱ). Five patiens had septic shock on admission [1 (6.5%) in the group Ⅰ and 2 (12.5%) trandolapril patients] and they died while hospitalised in the ICU. Baseline APACHE Ⅱ (19±7 and 21±4,group Ⅰ and Ⅱ,respectively) was similar (P>005) (Table 1). Infection was documented in all patients. The verapamil and trandolapril were well tolerated by all patients,and no adverse effects were noted.
Table 1 Baseline Characteristics of Patients
Note:n=15,Values are expresses as mean± SD,APACHE Ⅱ=The acute physiology and chronic health evaluation
Four patients in the verapamil group,and three patients in the trandolapril group received additional antihypertensive drugs (furosemide). During the study no inotropic agent was administered.
All nonsurvivors died while being mechanically ventilated. In the Ⅰ and Ⅱ groups,ventilation duration was 9±2 and 8±5 days,respectively (P>005). The ICU stay of groupⅠ treated survivors was not significantly different to that of the group Ⅱ survivors (11±5 vs 13±8 days) (P>005) (Table 1).
There was no significant difference between the groups with biochemical parameters (P>005). MAP 10 days values in group Ⅰ and Ⅱ were significantly lower in group Ⅰ and Ⅱ baseline values (Table 2).
Table 2 Baseline and 10th Day Biochemical and Hemodynamic Parameters
Note:n=15,Values are expresses as mean± SD，*P<0.001,10th day when compared with baseline values
Note:n=15,Values are expresses as mean± SD，
*P<0.05;**P<0.01 when compared group Ⅰ and Ⅱ
Glucose 10th day levels in group Ⅰ and Ⅱ were significantly lower in group Ⅰ and Ⅱ baseline values(Table 2). The groups were similar in baseline insulin requirement,1st,2nd,3rd,and 4th days (P>005),while group Ⅰ when compared with groups Ⅱ at 5th,and 6th days (P<005),7th,8th,9th,and 10th days (P<0001) insulin requirement were found to be significantly high (P<005).
DISCUSSION
In our study,we compared the effect of a nondihydropyridine calcium channel blocker and angiotensin converting enzyme inhibitor in patients with nondiabetic and mildto moderate hypertension in critically patients. We found that,trandolapril decreases insulin requirement in nondiabetic,hypertensive critically ill patients.
Hyperglycemia is a common finding in acutely ill patients and is associated with an adverse outcome [18,19,20]. It may worsen outcome through impairment of white cell function,greater susceptibility to infection [21],detrimental effects on the cardiovascular system [22] and multiorgan failure [23]. Intentional insulin overdose carries a mortality rate of approximately 25% and can lead to permanent hypoglycemiainduced neurologic complications [24]. One of the main goals of therapy is to avoid ongoing or recurrent hypoglycemia by the intravenous administration of glucose [24,25]. This strategy is made difficult by the erratic and often delayed absorption of subcutaneously injected insulin,the varying kinetics when different types of insulin are used and the increased likelihood of both immediate and recurrent hypoglycemia in nondiabetic,compared to diabetic patients [24,25]. Hence,exogenous glucose administration should be carefully titrated on closely monitored blood glucose levels.
Treatment with different antihypertensive agents reduces cardiovascular morbidity and mortality [26]. There has been concern over adverse effects of thiazide diuretics and β blockers,since both agents decrease insulin sensitivity and impair glucose tolerance [27,28]. The influence on glycemic control might be even more pronounced by combinations of these agents. Calcium channel blockers and angiotensin converting enzyme inhibitors are considered to lack these undesirable effects on glucose tolerance [29]. Angiotensin converting enzyme inhibitors potentially improve insulin sensitivity [30,31]. However,there are no controlled clinical studies over several months comparing glycemic control in large groups of hypertensive diabetic patients after treatment with combinations of diuretics plus β blockers and calcium channel blockers plus angiotensin converting enzyme inhibitors.
Previous reports of effects of ACE inhibition on insulin and glucose metabolism have generated much speculation regarding potential mechanisms,including inhibition of angiotensin Ⅱ formation (which may have glycogenolytic and gluconeogenic properties)[31],inhibition of bradykinin degradation [32],vasodilatation of insulinsensitive tissues [33],decrease in circulating catecholamines [34],or a combination of one or more of these. In contrast,many trials have reported no effect of ACE inhibition on insulin sensitivity [35~38] but,like the “positive” trials,few of these “negative” studies have been entirely satisfactory in terms of methodology.
Laboratory and clinical studies have suggested that angiotensin II may adversely affect glucose metabolism via a number of mechanisms,including impairment of insulinsignaling pathways,increased oxidative stress,and decreased tissue blood flow [39]. Inhibition of the RAS might thus be expected to reduce insulin resistance and improve glucose metabolism. Pharmacologic interruption of the RAS with ACE inhibitors or ARBs might improve glucose metabolism by interfering with AII generation or AII receptor activation. However,recent studies suggest that the antidiabetic effects of ACE inhibitors may not only be mediated via inhibition of the RAS,but also through activation of bradykinin and nitric oxide pathways and glucose transporter [4] (GLUT 4) [39]). ARBs may also exert effects on bradykinin and nitric oxide pathways,but evidence supporting a role for these effects in the antidiabetic properties of ARBs is less compelling than that for ACE inhibitors. These ARBs appear to be bifunctional molecules capable of activating the nuclear peroxisome proliferatoractivated receptor (PPAR)-γ in addition to blocking the angiotensin Ⅱ type 1 receptor.
Verapamil has previously been found to inhibit insulin release from pancreatic betacells in laboratory animals. Verapamil improves the tolerance for oral glucose in patients with type 2 diabetes and appears to have no additive hypoglycemic effect to sulfonylurea [15]. Studies in rats suggest that verapamil inhibits the effect of glucagon stimulation at the hepatocyte level [16]. Absolute or relative hyperglycemia often prevails in patients with type 2 diabetes,so it is conceivable that verapamil blocks the effect such glucagon predominance and thereby reduces the glucose ingestion in type 2 diabetic patients. Alada [40] demonstrated that effects of verapamil on nicotineinduced hyperglycemia were studied in fasted,anesthetized male rats. He found that verapamil had no significant effect on the basal blood glucose levels at any dose used. In our study,we found that,verapamil did not decrease insulin requirement in nondiabetic,hypertensive critically ill patients.
CONCLUSION
We found that,trandolapril decreases insulin requirement in nondiabetic,hypertensive critically ill patients. Because of the limited number of patients in our study and the short period of observation,our findings need to be confirmed by larger clinical trials of trandolapril. The results of ongoing and future clinical trials should help to answer whether recent experimental findings on the antidiabetic potential of certain ACE inhibitors will ultimately prove relevant to clinical practice.
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18. Umpierrez GE,Isaacs SD,Bazargan N,et al. Hyperglycemia: an independent marker of inhospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol MeTable,2002,87:978-982.
19. Mizock BA. Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med,1995,98: 75-107.
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21. McMahon MM,Bistrian BR. Host defenses and susceptibility to infection inpatients with diabetes mellitus. Infect Dis Clin North Am,1995,9: 1-9.
22. Preiser JC,Devos P,Van den Berghe G. Tight control of glycaemia in critically ill patients. Cur Opin Clin Nutr Metab Care,2002,5: 533-537.
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31. Kneer NM,Lardy HA. Regulation of gluconeogenesis by norepinephrine,vasopressin and angiotensin II: a comparative study in the absence and presence of extracellular calcium. Arch Biochem Biophys,1983,225:187-195.
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33. Junichi K,Shigehiro K,Kiyishi T,et al. Effects of captopril on glucose concentration: possible role of augmented postprandial forearm blood flow. Diabetes Care,1991,13:1109-1111.
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38. Allemann Y,Baumann S,Jost M,et al. Insulin sensitivity in normotensive subjects during angiotensin converting enzyme inhibition with fosinopril. Eur J Clin 1992; Pharmacol. 42: 275-280.
39. Kurtz TW,Pravenec M. Antidiabetic mechanisms of angiotensinconverting enzyme inhibitors and angiotensin II receptor antagonists: beyond the reninangiotensin system. J Hypertens,2004,22: 2253-2261.
40. Alada AR.Effects of calcium channel blockers on nicotineinduced hyperglycemia in the rat. Afr J Med Med Sci,2001,30: 57-59.
(Editor Jaque)(Dilek Memis1,Sevtap Hekim)
1 Trakya University,Medical Faculty,Department of Anaesthesiology and Reanimation
2 Trakya University,Medical Faculty,Department of Biostatistic
3 Trakya University,Medical Faculty,Department of Urology
Correspondence to Dilek Memi�瘙塂,Department of Anaesthesiology,Trakya University Medical Faculty,Edirne 22030,Turkey
Fax:0090 284 235 80 96，Email: dilmemis@mynet.com
[Abstract] Objective We compared the effect of a nondihydropyridine calcium channel blocker(verapamil) and angiotensin converting enzyme inhibitor(trandolapril) in patients with nondiabetic and hypertensive in critically ill patients. Methods Arterial hypertension was defined as an untreated systolic blood pressure of 130 mm Hg or more or a diastolic blood pressure of 85 mm Hg or more or as the need for antihypertensive therapy to attain a systolic or diastolic blood pressure under these levels. Eligible subjects were randomly assigned to receive one of the study treatments:the nondihydroprydine calciumchannel blocker verapamil 240 mg per day (Group Ⅰ,n=15),the angiotensin converting enzyme inhibitor trandolapril 2 mg per day (Group Ⅱ,n=15). During ICU stay daily data collection included the administration of insulin to control blood glucose concentration(100~110 mg/dl). Total daily insulin dose recorded per day for ten days. Results Mean arterial pressure and glucose levels 10 days values in group Ⅰ and Ⅱ were significantly lower in group Ⅰ and Ⅱ baseline values (P<0.001). The groups were similar in baseline insulin requirement,1st,2nd,3rd,and 4th days (P>005),while group Ⅰ when compared with groups Ⅱ at 5th,and 6th days (P<005),7th,8th,9th,and 10th days (P<0001) insulin requirement were found to be significantly high (P<005). Conclusions We found that,trandolapril decreases insulin requirement in nondiabetic,hypertensive critically ill patients.The results of ongoing and future clinical trials should help to answer whether recent experimental findings on the antidiabetic potential of certain angiotensin converting enzyme inhibitors will ultimately prove relevant to clinical practice.
[Key words] trandolapril; verapamil; insulin requirement;nondiabetic hypertensive;critically ill patients
INTRODUCTION
Several recent studies have demonstrated that the development of hyperglycemia is an important risk factor in terms of mortality and morbidity of critically ill patients. A metaanalysis of myocardial infarction revealed an association between stress hyperglycemia and increased risk of inhospital mortality and congestive heart failure or cardiogenic shock[1]. Elevated glucose levels also predicted increased mortality and length of ICU and hospital stay of trauma patients and were associated with infectious morbidity[2]. Retrospective analysis of a heterogeneous population of critically ill patients showed that even a modest degree of hyperglycemia was associated with substantially increased hospital mortality[3]. A study of the occurrence of hyperglycemia among critically ill children with widely varying pathologic conditions showed a correlation with higher inhospital mortality and longer length of stay[4]. A landmark prospective,randomized,controlled study on a large group of patients admitted to the ICU predominantly after extensive surgery revealed major clinical
benefits of intensive insulin therapy in critically ill patients [5]. Insulin was administered to the patients in the intensive insulin therapy group to maintain blood glucose levels between 80 and 110 mg/dl and resulted in mean blood glucose levels of 90 to 100 mg/dl (normoglycemia),without the risk of hypoglycemiainduced adverse events. Maintain safe levels of glycemia after massive insulin overdose. Indeed,several factors can influence the kinetics and magnitude of hypoglycemia in this situation,such as prolonged absorption of insulin if a large dose is injected,due to a "depot effect",variations in local blood flow,impaired renal function and,in diabetic patients,local lipodystrophy if the injection site has been used previously as well as circulating antibodies against insulin [6].
In vitro experiments and studies in animals and in humans have suggested a possible relationship between the reninangiotensin system and the pathogenesis of insulin resistance. For example,recent studies have suggested that angiotensin Ⅱ (AII) may promote impaired glucose metabolism through its effects on insulin signaling pathways,tissue blood flow,oxidative stress,sympathetic activity and adipogenesis [7~14]. Thus,pharmacologic interruption of the reninangiotensin system (RAS) with angiotensinconverting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) might improve glucose metabolism by interfering with AII generation or AII receptor activation.
Nondihydropyridine calcium channel blocker (verapamil) improves the tolerance for oral glucose in patients with type 2 diabetes and appears to have no additive hypoglycaemic effect to sulfonylurea [15]. Studies in rats suggest that verapamil inhibits the effect of glucagon stimulation at the hepatocyte level [16].
There is no evidence that nondihydropyridine calcium channel blocker and angiotensin converting enzyme inhibitor effect of impair glucose tolerance nondiabetic and mildtomoderate hypertension. We compared the effect of a nondihydropyridine calcium channel blocker and angiotensin converting enzyme inhibitor in patients with nondiabetic and mildtomoderate hypertension in critically ill patients.
MATERIAL AND METHODS
The Regional Committee on Medical Research Ethics approved the study. Written informed consent was obtained from the patients wherever possible,or from the next of kin. All consecutive admissions to participating ICUs during between 1 March 2004 and 1 May 2006 were included in the study. We enrolled subjects who were 40 years of age or older,serum creatinine concentration of no more than 1.5 mg per deciliter. In this instance only data from the first ICU admission were included,nondiabetic and hypertensive patients but who were not taking antihypertensive drug before. Demographic,clinical and physiological data were prospectively collected,and entered into a computerized database. Demographic information age,gender,duration of ICU stay and outcome were recorded. Physiology scores were calculated for the first 24 hours after ICU admission. Patients under 18 years of age whose stay in the ICU was less than 24 hours,presence or absence of preexisting diabetes mellitus and its management,patients transferred from another ICU were not included.
APACHE Ⅱ score were employed to determine the initial severity of illness. The APACHE Ⅱ score were calculated for each patient using data from the first 24 hours of admission. Patients were followed until death or discharge from ICU. Patients received a loading dose of 0.2 mg/kg midazolam iv over 10 min followed by a maintenance 0.1~0.5 mg/kg/h infusion. Alfentanil was infused at 0.25~1.0 mg/kg/min if analgesia was required. Patients were ventilated mechanically with oxygenenriched air to attain acceptable blood gases. All patients had arterial catheters (arterial line kit:Abbott,monitoring kit transpac 8”,Sligo,Ireland) and central venous catheters via subclavian (Braun,Certofix trio V 720 7F×8”,Melsungen,Germany) in place. Nasogastric tube was placed and its correct location in the gastric lumen confirmed radiologically. All patients were placed on continuous infusion of enteral tube feeding. The enteral feed was delivered by a pump device and 25 to 30 kcal/kg/day (Biosorb,Nutricia,Netherland) as the caloric requirement.
Arterial hypertension was defined as an untreated systolic blood pressure of 130 mm Hg or more or a diastolic blood pressure of 85 mm Hg or more or as the need for antihypertensive therapy to attain a systolic or diastolic blood pressure under these levels [17]. Eligible subjects were randomly assigned to receive one of the study treatments: the nondihydroprydine calciumchannel blocker verapamil (Isoptin SR,240 mg,Abotte) 240 mg per day (Group Ⅰ,n=15),the ACE inhibitor trandolapril (TARKA,2 mg trandolapril,Abotte) 2 mg per day (Group Ⅱ,n=15).
The target blood pressure was 120/80 mm Hg [17]. Additional antihypertensive drugs were allowed,to achieve the target blood pressure,in the following steps: step 1,hydrochlorothiazide or furosemide; step 2,doxazosin,prozosin,methyldopa,or betablockers; and step 3,minoxidil or longacting dihydropyridine calciumchannel blockers. The use of potassiumsparing diuretics,inhibitors of the reninangiotensin system,and nondihydropyridine calciumchannel blockers different from the study drugs was not allowed.
During ICU stay daily data collection included the administration of intravenous insulin to control blood glucose concentration (100~110 mg/dl). Blood glucose concentration was measured every three hours. Total daily insulin dose recorded per day for ten days.
Blood pressure and randomly collected morning urine samples were evaluated at the time of randomization,at ten days after randomization. Blood glucose,serum potassium,sodium,urea,and creatinine levels were measured at baseline and ten days after. Urinary albumin excretion,and other laboratory values,including levels of serum cholesterol and triglycerides,were also measured at randomization and ten days after. Additional evaluations were performed within one week after any change in antihypertensive therapy and whenever deemed clinically appropriate.
Duration of mechanical ventilation was recorded. Survival was defined as being alive at ICU discharge.
Statistics
MannWhitney U test was used for comparison of the differences between groups toward the values. Data were expressed as mean±SD. A P value of <0.05 was considered significant.
RESULTS
Clinical and demographic characteristics of the patients were listed on Table 1. 15 of 30 patients received verapamil (group Ⅰ) and 15 received trandolapril (group Ⅱ). Five patiens had septic shock on admission [1 (6.5%) in the group Ⅰ and 2 (12.5%) trandolapril patients] and they died while hospitalised in the ICU. Baseline APACHE Ⅱ (19±7 and 21±4,group Ⅰ and Ⅱ,respectively) was similar (P>005) (Table 1). Infection was documented in all patients. The verapamil and trandolapril were well tolerated by all patients,and no adverse effects were noted.
Table 1 Baseline Characteristics of Patients
Note:n=15,Values are expresses as mean± SD,APACHE Ⅱ=The acute physiology and chronic health evaluation
Four patients in the verapamil group,and three patients in the trandolapril group received additional antihypertensive drugs (furosemide). During the study no inotropic agent was administered.
All nonsurvivors died while being mechanically ventilated. In the Ⅰ and Ⅱ groups,ventilation duration was 9±2 and 8±5 days,respectively (P>005). The ICU stay of groupⅠ treated survivors was not significantly different to that of the group Ⅱ survivors (11±5 vs 13±8 days) (P>005) (Table 1).
There was no significant difference between the groups with biochemical parameters (P>005). MAP 10 days values in group Ⅰ and Ⅱ were significantly lower in group Ⅰ and Ⅱ baseline values (Table 2).
Table 2 Baseline and 10th Day Biochemical and Hemodynamic Parameters
Note:n=15,Values are expresses as mean± SD，*P<0.001,10th day when compared with baseline values
Note:n=15,Values are expresses as mean± SD，
*P<0.05;**P<0.01 when compared group Ⅰ and Ⅱ
Glucose 10th day levels in group Ⅰ and Ⅱ were significantly lower in group Ⅰ and Ⅱ baseline values(Table 2). The groups were similar in baseline insulin requirement,1st,2nd,3rd,and 4th days (P>005),while group Ⅰ when compared with groups Ⅱ at 5th,and 6th days (P<005),7th,8th,9th,and 10th days (P<0001) insulin requirement were found to be significantly high (P<005).
DISCUSSION
In our study,we compared the effect of a nondihydropyridine calcium channel blocker and angiotensin converting enzyme inhibitor in patients with nondiabetic and mildto moderate hypertension in critically patients. We found that,trandolapril decreases insulin requirement in nondiabetic,hypertensive critically ill patients.
Hyperglycemia is a common finding in acutely ill patients and is associated with an adverse outcome [18,19,20]. It may worsen outcome through impairment of white cell function,greater susceptibility to infection [21],detrimental effects on the cardiovascular system [22] and multiorgan failure [23]. Intentional insulin overdose carries a mortality rate of approximately 25% and can lead to permanent hypoglycemiainduced neurologic complications [24]. One of the main goals of therapy is to avoid ongoing or recurrent hypoglycemia by the intravenous administration of glucose [24,25]. This strategy is made difficult by the erratic and often delayed absorption of subcutaneously injected insulin,the varying kinetics when different types of insulin are used and the increased likelihood of both immediate and recurrent hypoglycemia in nondiabetic,compared to diabetic patients [24,25]. Hence,exogenous glucose administration should be carefully titrated on closely monitored blood glucose levels.
Treatment with different antihypertensive agents reduces cardiovascular morbidity and mortality [26]. There has been concern over adverse effects of thiazide diuretics and β blockers,since both agents decrease insulin sensitivity and impair glucose tolerance [27,28]. The influence on glycemic control might be even more pronounced by combinations of these agents. Calcium channel blockers and angiotensin converting enzyme inhibitors are considered to lack these undesirable effects on glucose tolerance [29]. Angiotensin converting enzyme inhibitors potentially improve insulin sensitivity [30,31]. However,there are no controlled clinical studies over several months comparing glycemic control in large groups of hypertensive diabetic patients after treatment with combinations of diuretics plus β blockers and calcium channel blockers plus angiotensin converting enzyme inhibitors.
Previous reports of effects of ACE inhibition on insulin and glucose metabolism have generated much speculation regarding potential mechanisms,including inhibition of angiotensin Ⅱ formation (which may have glycogenolytic and gluconeogenic properties)[31],inhibition of bradykinin degradation [32],vasodilatation of insulinsensitive tissues [33],decrease in circulating catecholamines [34],or a combination of one or more of these. In contrast,many trials have reported no effect of ACE inhibition on insulin sensitivity [35~38] but,like the “positive” trials,few of these “negative” studies have been entirely satisfactory in terms of methodology.
Laboratory and clinical studies have suggested that angiotensin II may adversely affect glucose metabolism via a number of mechanisms,including impairment of insulinsignaling pathways,increased oxidative stress,and decreased tissue blood flow [39]. Inhibition of the RAS might thus be expected to reduce insulin resistance and improve glucose metabolism. Pharmacologic interruption of the RAS with ACE inhibitors or ARBs might improve glucose metabolism by interfering with AII generation or AII receptor activation. However,recent studies suggest that the antidiabetic effects of ACE inhibitors may not only be mediated via inhibition of the RAS,but also through activation of bradykinin and nitric oxide pathways and glucose transporter [4] (GLUT 4) [39]). ARBs may also exert effects on bradykinin and nitric oxide pathways,but evidence supporting a role for these effects in the antidiabetic properties of ARBs is less compelling than that for ACE inhibitors. These ARBs appear to be bifunctional molecules capable of activating the nuclear peroxisome proliferatoractivated receptor (PPAR)-γ in addition to blocking the angiotensin Ⅱ type 1 receptor.
Verapamil has previously been found to inhibit insulin release from pancreatic betacells in laboratory animals. Verapamil improves the tolerance for oral glucose in patients with type 2 diabetes and appears to have no additive hypoglycemic effect to sulfonylurea [15]. Studies in rats suggest that verapamil inhibits the effect of glucagon stimulation at the hepatocyte level [16]. Absolute or relative hyperglycemia often prevails in patients with type 2 diabetes,so it is conceivable that verapamil blocks the effect such glucagon predominance and thereby reduces the glucose ingestion in type 2 diabetic patients. Alada [40] demonstrated that effects of verapamil on nicotineinduced hyperglycemia were studied in fasted,anesthetized male rats. He found that verapamil had no significant effect on the basal blood glucose levels at any dose used. In our study,we found that,verapamil did not decrease insulin requirement in nondiabetic,hypertensive critically ill patients.
CONCLUSION
We found that,trandolapril decreases insulin requirement in nondiabetic,hypertensive critically ill patients. Because of the limited number of patients in our study and the short period of observation,our findings need to be confirmed by larger clinical trials of trandolapril. The results of ongoing and future clinical trials should help to answer whether recent experimental findings on the antidiabetic potential of certain ACE inhibitors will ultimately prove relevant to clinical practice.
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(Editor Jaque)(Dilek Memis1,Sevtap Hekim)