Publications by authors named "Erkki Kentala"

11 Publications

  • Page 1 of 1

Sleep apnoea is associated with major cardiac events in peripheral arterial disease.

Eur Respir J 2014 Jun 20;43(6):1652-60. Epub 2014 Feb 20.

Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku

Obstructive sleep apnoea (OSA) is associated with atherosclerosis and cardiovascular events. Peripheral arterial disease (PAD) represents severe atherosclerosis with a high mortality after vascular surgery. The role of OSA in the prognosis of these patients is not yet established. 84 patients (aged 67 ± 9 years) scheduled for sub-inguinal surgical revascularisation were enrolled for preoperative polysomnography. The threshold for significant OSA was an apnoea/hypopnoea index ≥ 20 events·h(-1). Major adverse cardiovascular and cerebrovascular events (MACCE), including cardiac death, myocardial infarction, coronary revascularisation, angina pectoris requiring hospitalisation and stroke, were used as a combined end-point. During follow-up (median 52 months), 17 out of 39 patients with and six out of 45 patients without significant OSA suffered MACCE. In the multivariate Cox regression, the primary predictors of MACCE were significant OSA (hazard ratio (HR) 5.1 (95% CI 1.9-13.9); p=0.001) and pre-existing coronary artery disease (HR 4.4 (95% CI 1.8-10.6); p=0.001). Other significant predictors were a ≥ 4 year history of PAD (HR 3.8 (95% CI 1.3-11.5); p=0.02) and decreasing high-density lipoprotein/total cholesterol ratio (HR 0.95 per percentage (95% CI 0.90-1.00); p=0.048). OSA is associated with poor long-term outcome in patients with PAD following revascularisation. OSA might have an important role in the pathogenesis of cardiovascular morbidity and mortality in these patients.
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http://dx.doi.org/10.1183/09031936.00130913DOI Listing
June 2014

Unrecognised obstructive sleep apnoea is common in severe peripheral arterial disease.

Eur Respir J 2013 Mar 14;41(3):616-20. Epub 2012 Jun 14.

Dept of Internal Medicine,Turku University Hospital, Turku, Finland.

Patients needing surgery for peripheral arterial disease (PAD) represent a severe form of atherosclerosis with an overall 5-yr mortality of 30% after revascularisation. The aetiology for poor post-operative clinical outcome in these high-risk patients is not fully established. Obstructive sleep apnoea (OSA) is associated with atherosclerosis and is an independent risk factor for fatal and nonfatal cardiac events. Here, we determine the prevalence of undiagnosed OSA in a homogenous group of PAD patients undergoing subinguinal surgical revascularisation. 82 consecutive patients (mean age 67±9 yrs, 52 males) with sinus rhythm and without congestive heart failure or previously diagnosed OSA were enrolled for pre-operative polysomnography and echocardiography. OSA was present in 70 (85%) patients (95% CI 75-93%), of whom 24 (34%) had severe OSA. OSA was mostly asymptomatic, and age- and sex-adjusted multivariate regression analysis showed no relation to obesity, metabolic syndrome or any manifestation of atherosclerosis, other than PAD. Left ventricular ejection fraction (p = 0.002) and high-density lipoprotein/total cholesterol ratio (p = 0.03) were the only independent predictors for the severity of OSA. Thus, prevalence of OSA is unexpectedly high in patients with PAD and is not related to classical risk factors of sleep apnoea.
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http://dx.doi.org/10.1183/09031936.00227611DOI Listing
March 2013

Pharmacokinetics of prolonged infusion of high-dose dexmedetomidine in critically ill patients.

Crit Care 2011 26;15(5):R257. Epub 2011 Oct 26.

Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, PO Box 52, FI-20521 Turku, Finland.

Introduction: Only limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.

Methods: Thirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.

Results: The following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.

Conclusions: The results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.

Trial Registration: ClinicalTrials.gov: NCT00747721.
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http://dx.doi.org/10.1186/cc10518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334808PMC
August 2012

Highly variable pharmacokinetics of dexmedetomidine during intensive care: a case report.

J Med Case Rep 2010 Feb 25;4:73. Epub 2010 Feb 25.

Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, FIN-20521, Turku, Finland.

Introduction: Dexmedetomidine is a selective and potent alpha2-adrenoceptor agonist licensed for use in the sedation of patients initially ventilated in intensive care units at a maximum dose rate of 0.7 mug/kg/h administered for up to 24 hours. Higher dose rates and longer infusion periods are sometimes required to achieve sufficient sedation. There are some previous reports on the use of long-term moderate to high-dose infusions of dexmedetomidine in patients in intensive care units, but none of these accounts have cited dexmedetomidine plasma concentrations.

Case Presentation: We describe the case of a 42-year-old Caucasian woman with severe hemorrhagic pancreatitis following laparoscopic cholecystectomy who received dexmedetomidine for 24 consecutive days at a maximum dose rate of 1.9 mug/kg/h. Samples for the measurement of dexmedetomidine concentrations in her plasma were drawn at intervals of eight hours. On average, the observed plasma concentrations were well in accordance with previous knowledge on the pharmacokinetics of dexmedetomidine. There was, however, marked variability in the concentration of dexmedetomidine in her plasma despite a stable infusion rate.

Conclusion: The pharmacokinetics of dexmedetomidine appears to be highly variable during intensive care.
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http://dx.doi.org/10.1186/1752-1947-4-73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848065PMC
February 2010

Effects of low and high plasma concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy male subjects.

Anesthesiology 2006 Nov;105(5):902-10; quiz 1069-70

Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Itäinen Pitkäkatu 4B, FI-20520 Turku, Finland.

Background: Dexmedetomidine, a selective alpha2-adrenoceptor agonist, has counteracting effects on the cardiovascular system. It mediates sympatholysis by activating alpha2 adrenoceptors in the central and peripheral nervous system, and vasoconstriction and vasorelaxation by activating postsynaptic alpha2 adrenoceptors in blood vessels. The goal of this study was to determine the effects of therapeutic and high concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy subjects.

Methods: The authors studied 12 healthy young men. Myocardial blood flow (assessed with positron emission tomography), myocardial function (by echocardiography), and hemodynamic data were collected before and during low (measured mean plasma concentration, 0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine.

Results: The low concentration of dexmedetomidine reduced myocardial perfusion (mean difference, -27% from baseline [95% confidence interval, -31 to -23%], P < 0.001) in parallel with a reduction in myocardial oxygen demand (estimated by the rate-pressure product (-23% [-28 to -18%], P < 0.001). The high dexmedetomidine plasma concentration did not further attenuate myocardial perfusion (-3% [-12 to +6%] from low dexmedetomidine, P > 0.05; -29% [-39 to -18%] from baseline, P < 0.001) or statistically significantly affect the rate-pressure product (+5% [0 to +10%], P > 0.05). Systolic myocardial function was attenuated by sympatholysis during the low infusion rate and was further attenuated by a combination of the sustained sympatholysis and increased afterload during the high infusion rate.

Conclusions: In healthy subjects, plasma concentrations of dexmedetomidine that significantly exceed the recommended therapeutic level do not seriously attenuate myocardial perfusion below the level that is observed with usual therapeutic concentrations and do not induce evident myocardial ischemia.
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http://dx.doi.org/10.1097/00000542-200611000-00010DOI Listing
November 2006

Cardiomyocyte apoptosis and duration of aortic clamping in pig model of open heart surgery.

Eur J Cardiothorac Surg 2006 Sep 20;30(3):480-4. Epub 2006 Jul 20.

Research Centre of Applied and Preventive Cardiovascular Medicine, Turku University, FIN-20520 Turku, Finland.

Objective: Apoptotic cardiomyocyte death is induced during open heart surgery, but its determinants are poorly understood. Prolonged aortic clamping time is associated with adverse clinical outcomes. The purpose of this study was to determine whether occurrence of cardiomyocyte apoptosis is related to the duration of aortic clamping in experimental pig model of cardiac surgery with cardiopulmonary bypass.

Methods: The pigs (mean weight 29 +/- 1 kg) were randomly divided to undergo cardioplegic arrest for 60 (n = 4) or 90 (n = 4) min followed by reperfusion period of 120 min. Control group (n = 5) was connected to cardiopulmonary bypass for 120 min without cardioplegic arrest. Cardiomyocyte apoptosis was detected (TUNEL assay and immunohistochemical staining of active caspase-3) in left ventricular tissue samples obtained before ischemia and after the ischemia-reperfusion period.

Results: Apoptotic cardiomyocytes were found in all samples obtained after cardioplegic arrest and cardiopulmonary bypass alone with the TUNEL assay. The amount of apoptosis after the 120 min of cardiopulmonary bypass alone in the control group was 0.006 +/- 0.001%. Compared with this, cardiomyocyte apoptosis was increased after cardioplegic arrest. After 60 min of aortic cross-clamp the amount of apoptosis was 0.019 +/- 0.004% (p = 0.031). After 90 min of aortic cross-clamp the amount was 0.042 +/- 0.005% (p < 0.001) being significantly higher than after 60 min (p = 0.001). Aortic cross-clamp of 90 min also resulted in a detectable increase in caspase-3 activation when compared with controls.

Conclusions: The occurrence of cardiomyocyte apoptosis increases with prolonged aortic clamping time during open heart surgery.
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http://dx.doi.org/10.1016/j.ejcts.2006.06.003DOI Listing
September 2006

Estimation of cardiac output in a pharmacological trial using a simple method based on arterial blood pressure signal waveform: a comparison with pulmonary thermodilution and echocardiographic methods.

Eur J Clin Pharmacol 2006 Jun 29;62(6):401-7. Epub 2006 Mar 29.

Turku PET Centre, Turku University Central Hospital, Turku, Finland.

Objective: Cardiac output (CO) has traditionally been measured using invasive techniques, which involve an element of risk. Thus, a reliable less-invasive method for determining CO would be very valuable for research use. We tested whether simple analysis of the arterial pulse waveform, not requiring large-vessel catheterisation or expensive equipment, could provide an estimate of CO that is accurate enough for pharmacological studies.

Methods: We measured CO in 11 healthy male subjects who received low and high doses of dexmedetomidine (alpha2-adrenoceptor agonist), using pulse contour analysis, echocardiography and pulmonary thermodilution techniques.

Results: At baseline, these methods gave the following mean (SD) values of CO: 6.18 (1.59), 5.22 (1.35) and 7.03 (1.54) l/min, respectively. High-dose dexmedetomidine reduced CO to 4.50 (0.68), 3.65 (0.65) and 4.80 (0.89) l/min, corresponding to -25 (14) %, -28 (12) % and -30 (14) % reductions from baseline, respectively. The pulse contour method described these dexmedetomidine-induced changes in CO very similarly to the thermodilution and echocardiographic methods. The limits of agreement [bias (2SD)] were 0.55 (2.55) and -0.10 (2.04) l/min, respectively.

Conclusion: The minimally invasive pulse contour analysis technique might be suitable for pharmacological studies for the detection of major drug-induced reductions in CO.
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http://dx.doi.org/10.1007/s00228-006-0115-1DOI Listing
June 2006

Long-term alterations of heart rate dynamics after coronary artery bypass graft surgery.

Anesth Analg 2006 Apr;102(4):1026-31

Department of Anesthesiology and Intensive Care, Turku University Hospital, Turku, Finland.

We tested the hypothesis that there may be long-term alterations in overall heart rate (HR) variability and in fractal HR behavior after coronary artery bypass graft (CABG) surgery. Reduced HR variability predicts morbidity in various patient populations. Continuous 24-h electrocardiograph recordings were performed in 25 elective CABG surgery patients 1 wk before the operation and 6 wk and 6 mo after. Seventeen of the patients also had recordings 12 mo after CABG. Time and frequency domain measures of HR variability were assessed, along with measurement of short-term fractal scaling exponent (alpha1), approximate entropy, and power-law relationship of relative risk interval variability (beta-slope). The high, low, very low, and ultra low frequency powers decreased significantly after the operation and remained at a significantly decreased level 6 wk and 6 and 12 mo after the operation than before (P = 0.01, P < 0.001, P < 0.001, and P < 0.001 for overall difference between the time points, respectively). The fractal scaling exponent alpha1 was at significantly more decreased 6 wk after (P < 0.05) CABG than before surgery but recovered to the preoperative level 6 mo after the operation. Long-term fractal organization (beta-slope) remained stable, but the overall complexity (approximate entropy) decreased toward more predictable HR dynamics during the study period (P < 0.01 after 1 yr). The predictive value of temporary and persistent long-term changes of the HR dynamics after CABG surgery for long-term outcome is not clear.
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http://dx.doi.org/10.1213/01.ane.0000198674.90500.59DOI Listing
April 2006

Cardiomyocyte apoptosis after antegrade and retrograde cardioplegia.

Ann Thorac Surg 2005 Dec;80(6):2229-34

Department of Cardiothoracic Surgery, Turku University Central Hospital, Turku, Finland.

Background: Retrograde cardioplegia alone is often used in aortic valve and aortic root surgery. Due to the differences in venous anatomy between the right and the left side of the heart, retrograde cardioplegia is associated with incomplete protection of the right side. Since some apoptotic cardiomyocyte death is inevitable during an open heart surgery, we compared the extent of cardiomyocyte apoptosis in the left and right ventricles after antegrade and retrograde cardioplegia in a pig ischemia-reperfusion model.

Methods: Pigs (n = 16, mean weight 30 kg) were openly assigned into the groups of antegrade and retrograde cardioplegia. After aortic cross-clamping, 500 mL of cold crystalloid (modified St Thomas) cardioplegia was administered into the ascending aorta or the coronary sinus. Aortic cross-clamp time was 30 minutes. Cardiomyocyte apoptosis was measured using the terminal transferase mediated ddUTP nick end-labeling (TUNEL) assay and immunohistochemical (IHC) staining for active caspase-3 in myocardial biopsies obtained before ischemia and after 90 minutes of reperfusion.

Results: Apoptotic cardiomyocytes were significantly increased after ischemia-reperfusion as shown by both the TUNEL assay and caspase-3 activation. In the right ventricle, retrograde cardioplegia was associated with a 3.4-fold higher amount (TUNEL assay) of apoptotic cardiomyocytes as compared with antegrade cardioplegia (0.107% vs 0.032%, p < 0.05). A similar difference was also found in the left ventricle, although at a lower level (0.027% vs 0.012%, p < 0.05).

Conclusions: Increased apoptotic death of cardiomyocytes after retrograde cardioplegia as compared with the antegrade procedure implicates that retrograde cardioplegia alone provides inferior cardioprotection against irreversible ischemia-reperfusion injury both in the right and the left ventricle.
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http://dx.doi.org/10.1016/j.athoracsur.2005.05.057DOI Listing
December 2005

The breakdown of fractal heart rate dynamics predicts prolonged postoperative myocardial ischemia.

Anesth Analg 2004 May;98(5):1239-44, table of contents

Department of Anesthesiology and Intensive Care, Turku University Hospital, Turku, Finland.

Unlabelled: Patients with myocardial ischemia after noncardiac surgery have a three- to ninefold increased risk of adverse cardiac events. In this study we tested the hypothesis that altered preoperative heart rate variability (HRV) predicts postoperative prolonged myocardial ischemia (>10 min) in elderly surgical patients. Thirty-two patients, age 60 yr or older, admitted to hospital for surgical repair of a traumatic hip fracture with preoperative night and daytime Holter recordings were included. Holter monitoring was initiated at arrival at hospital and continued until the third postoperative morning. Conventional HRV measures along with analysis of short-term fractal scaling exponent (alpha(1)) of RR intervals were assessed for night (from 2 AM to 5 AM) and day (7 AM to 12 AM) periods in each patient. Preoperative alpha(1) was significantly lower (i.e., increased randomness in HRV) during the nighttime compared with daytime (mean +/- SEM; 0.92 +/- 0.08 versus 1.03 +/- 0.06; P = 0.002) in patients with postoperative myocardial ischemia. Patients without ischemia had no such difference. In stepwise multivariate logistic regression analysis, increased preoperative night-day difference of alpha(1) was the only independent predictor of postoperative prolonged ischemia. The odds ratio for an increase of 0.16 U in night-day difference of alpha(1) (corresponding to interquartile range) was 7.7 (95% confidence interval, 1.9-51.4; P = 0.0018). Breakdown of fractal-like heart rate dynamics is predictive for postoperative prolonged myocardial ischemia in elderly patients having emergency surgery for traumatic hip fracture.

Implications: Night and daytime Holter recordings before surgical repair of traumatic hip fracture were analyzed with linear and nonlinear heart rate variability methods. Preoperatively increased randomness in heart rate variability was predictive for postoperative, silent prolonged myocardial ischemia. Prolonged myocardial ischemia increases the risk for adverse cardiac events.
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May 2004

Relation of heart rate dynamics to the occurrence of myocardial ischemia after coronary artery bypass grafting.

Am J Cardiol 2002 May;89(10):1176-81

Department of Anesthesiology, Turku University Hospital, Turku, Finland.

Postoperative myocardial ischemia is a common finding after coronary artery bypass grafting (CABG) and is associated with an adverse short-term clinical outcome. The reasons and pathophysiologic background for the occurrence of ischemia after CABG are not well established. We tested the hypothesis that altered heart rate (HR) behavior precedes the onset of myocardial ischemic episodes in patients after CABG. Time-domain HR variability measurements, along with analysis of Poincaré plots and fractal scaling analysis were assessed in 40 CABG patients from 48-hour postoperative Holter recordings. Twenty patients experienced 195 ischemic episodes during the postoperative course. In the univariate analysis of HR variability measurements of the first postoperative day (POD), the increased ratio between the short-term (SD1) and long-term (SD2) HR variability analyzed from the Poincaré plot and the decreased short- and intermediate-term fractal scaling exponents alpha(1) and alpha(2) were significantly associated with ischemia during the study period (p <0.01, p <0.05, and p <0.05, respectively). In the multivariate model, the increased SD1/SD2 ratio of the first POD was the most powerful independent predictor of all possible confounding variables for the occurrence of postoperative ischemia (corresponding to a change of 0.15 U; odds ratio 2.2 and 95% confidence interval 1.2 to 5.7; p <0.01). Altered HR dynamics have been associated with myocardial ischemic episodes in patients after CABG, suggesting that the autonomic nervous system has an important role in the pathogenesis of myocardial ischemia in the postoperative phase of CABG.
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http://dx.doi.org/10.1016/s0002-9149(02)02300-7DOI Listing
May 2002