Markku Salmenperä

Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting

Background Alpha2 ‐Adrenergic agonists decrease sympathetic tone with ensuing attenuation of neuroendocrine and hemodynamic responses to anesthesia and surgery. The effects of dexmedetomidine, a highly specific alpha2 ‐adrenergic agonist, on these responses have not been reported in patients undergoing coronary artery bypass grafting. Methods Eighty patients scheduled for elective coronary artery bypass grafting received, in a double‐blind manner, either a saline placebo or a dexmedetomidine infusion, initially 50 ng [center dot] kg‐1 [center dot] min‐1 for 30 min before induction of anesthesia with fentanyl, and then 7 ng [center dot] kg‐1 [center dot] min‐1 until the end of surgery. Filling pressures, blood pressure, and heart rate were controlled by intravenous fluid and by supplemental anesthetics and vasoactive drugs. Results Compared with placebo, dexmedetomidine decreased plasma norepinephrine concentrations by 90%, attenuated the increase of blood pressure during anesthesia (3 vs. 24 mmHg) and surgery (2 vs. 14 mmHg), but increased slightly the need for intravenous fluid challenge (29 vs. 20 patients) and induced more hypotension during cardiopulmonary bypass (9 vs. 0 patients). Dexmedetomidine decreased the incidence of intraoperative (2 vs. 13 patients) and postoperative (5 vs. 16 patients) tachycardia. Dexmedetomidine also decreased the need for additional doses of fentanyl (3.1 vs. 5.4), the increments of enflurane (4.4 vs. 5.6), the need for beta blockers (3 vs. 11 patients), and the incidence of fentanyl‐induced muscle rigidity (15 vs. 33 patients) and postoperative shivering (13 vs. 23 patients). Conclusions Intraoperative intravenous infusion of dexmedetomidine to patients undergoing coronary artery revascularization decreased intraoperative sympathetic tone and attenuated hyperdynamic responses to anesthesia and surgery but increased the propensity toward hypotension.

Levosimendan : molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan

The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.

Anesthetic potency of remifentanil in dogs

Background Remifentanil is an opioid that is rapidly inactivated by esterases in blood and tissues. This study examined the anesthetic potency and efficacy of remifentanil in terms of its reduction of enflurane minimum alveolar concentration (MAC) in dogs. Methods Twenty-five dogs were anesthetized with enflurane. One group received incremental infusion rates of remifentanil from 0.055 to 5.5 micro gram *symbol* kg sup -1 *symbol* min sup -1. A second group received constant rate infusions of remifentanil of 1.0 micro gram *symbol* kg sup -1 *symbol* min sup -1 for 6-8 h. Enflurane MAC was measured before, hourly during remifentanil infusion, and at the end of the experiment after naloxone administration. A third group received alternating infusions of 0.5 and 1.0 micro gram *symbol* kg sup -1 *symbol* min sup -1 with MAC determinations made 30 min after each change in the infusion rate. Heart rate, mean arterial pressure, and remifentanil blood concentrations were measured during MAC determinations. Results Enflurane MAC was reduced up to a maximum of 63.0+/- 10.4% (mean+/-SD) in a dose-dependent manner by remifentanil infusion. The dose producing a 50% reduction in the enflurane MAC was calculated as 0.72 micro gram *symbol* kg sup -1 *symbol* min sup -1 and the corresponding blood concentration was calculated as 9.2 ng/ml. Enflurane MAC reduction remained stable during continuous, constant rate infusions for periods of 6-8 h without any signs of tolerance. Recovery of enflurane MAC to baseline occurred in 30 min (earliest measurement) after stopping the remifentanil infusion. Conclusions Remifentanil is equally efficacious and about half as potent as fentanyl, judging from the blood concentrations causing equivalent reductions in enflurane MAC in the dog. The characteristics of MAC reduction are similar to those of other opioids, including the ceiling effect. Recovery from remifentanil anesthesia is much more rapid than for any other opioid studied to date, especially after continuous infusions maintained for 6 or more h.

Hydroxyethyl Starch as a Priming Solution for Cardiopulmonary Bypass Impairs Hemostasis After Cardiac Surgery

We investigated the influence of hydroxyethyl starch (HES) as a priming solution for the cardiopulmonary bypass (CPB) circuit on postoperative hemostasis in 45 patients undergoing elective coronary artery bypass grafting. In a randomized sequence, 20 mL/kg of low-molecular-weight HES (HES 120; molecular weight 120,000 daltons), high-molecular-weight HES (HES 400; molecular weight 400,000 daltons), or 4% human albumin (ALB) was used as the main component of the CPB priming solution. The thromboelastographic values indicating the speed of solid clot formation (&agr;-angle) and the strength of the fibrin clot (maximum amplitude and shear elastic modulus) were decreased up to 2 h after CPB in both HES groups. Four hours after the operation, blood loss through the chest tubes had increased in the HES groups: HES 120, mean 804 mL (range, 330–1390 mL); HES 400, mean 1008 mL (range, 505–1955 mL); and ALB, mean 681 mL (range, 295–1500 mL) (P < 0.05 between the HES 400 and ALB groups). We conclude that HES solutions, when given in doses of 20 mL/kg in connection with the CPB prime, compromise hemostasis after cardiac surgery. This effect appears related to formation of a less stable thrombus compared with that formed in the presence of ALB.

Effect of diltiazem on midazolam and alfentanil disposition in patients undergoing coronary artery bypass grafting.

Background Midazolam and alfentanil are desirable anesthetic adjuncts for cardiac anesthesia. They are metabolized by cytochrome P450 3A (CYP3A) enzymes. These isozymes are inhibited by concurrent medications, including the calcium channel antagonist diltiazem, which may have an effect on recovery from anesthesia. Methods Thirty patients having coronary artery bypass grafting were randomly assigned to receive either diltiazem (60 mg orally 2 h before induction of anesthesia and an infusion of 0.1 mg [centered dot] kg sup -1 [centered dot] h sup -1 started at induction and continued for 23 h) or placebo in a double-blind study. Anesthesia was induced with 0.1 mg/kg midazolam, 50 micro gram/kg alfentanil, and 20 to 80 mg propofol and maintained with infusions of 1 micro gram [centered dot] kg sup -1 [centered dot] min sup -1 of both midazolam and alfentanil supplemented with isoflurane. Plasma midazolam and alfentanil concentrations and areas under the plasma concentration-time curves were determined. The terminal half-life and the time for the drug plasma level to decrease 50% after cessation of the infusion (t50) were calculated for midazolam and alfentanil. Separation from mechanical ventilation and tracheal extubation were performed according to the study protocol. Results Diltiazem increased the mean concentration-time curves (from end of anesthesia until 23 h) of midazolam by 24% (P < 0.05) and that of alfentanil by 40% (P < 0.05). The mean half-life of midazolam was 43% (P < 0.05) and that of alfentanil was 50% (P < 0.05) longer in patients receiving diltiazem. The mean t50 of alfentanil was 40% longer (P <0.05) in patients receiving diltiazem, but the change in the mean t50 of midazolam (25%) was not statistically significant. In patients receiving diltiazem, tracheal extubation was performed on average 2.5 h later (P = 0.054) than in those receiving placebo. Conclusions Diltiazem slows elimination of midazolam and alfentanil and may delay tracheal extubation after large doses of these anesthetic adjuncts. CYP3A-mediated drug interactions should be considered as confounders when recovery from anesthesia with midazolam and alfentanil infusions is assessed.

Cardiopulmonary Bypass With Heparin-Coated Circuits and Reduced Systemic Anticoagulation

BACKGROUND The improved biocompatibility of the cardiopulmonary bypass circuits made possible by the use of surface-immobilized heparin may allow for a reduction in the amount of heparin administered systemically. This study was performed to elucidate the effects of cardiopulmonary bypass using heparin-coated circuits and reduced heparinization on hemostatic variables and clinical outcome. METHODS Thirty patients scheduled to undergo myocardial revascularization were randomized to have either a heparin-coated or an uncoated cardiopulmonary bypass circuit. Anticoagulation was induced with heparin (100 IU/kg in the coated group and 300 IU/kg in the uncoated group) and the activated clotting time was kept over 200 and 480 seconds in the coated and uncoated groups, respectively. RESULTS The postoperative overnight loss of hemoglobin through the drains was lower in the heparin-coated group (43.6 g; range, 18.5-69.0 g) than in the uncoated group (73.0 g; range, 32.2-137.7 g) (p = 0.0015). Plasma concentrations of prothrombin fragment 1 + 2 and D-dimer were significantly more elevated after cardiopulmonary bypass in the coated group than they were in the uncoated group. Two patients in the coated group had a stroke postoperatively. CONCLUSIONS The reduction in systemic heparinization was associated with thrombin formation, which may predispose to intravascular and cardiopulmonary bypass circuit clotting. Therefore, generous systemic heparinization may still be prudent despite the improved biocompatibility offered by heparin-coated surface.

N-acetylcysteine for the prevention of kidney injury in abdominal aortic surgery: a randomized, double-blind, placebo-controlled trial.

In this prospective, randomized, placebo-controlled, double-blind trial we studied the effects of IV N-acetylcysteine for prevention of renal injury in patients undergoing abdominal aortic surgery. Seventy patients without previously documented renal dysfunction were randomly allocated to receive either N-acetylcysteine (150 mg/kg mixed in 250 mL of 5% dextrose infused in 20 min, followed by an infusion of 150 mg/kg in 250 mL of 5% dextrose over 24 h) or placebo. The infusion was started after the induction of anesthesia. The primary outcome measure was renal injury as measured by the increases in urinary N-acetyl-β-d-glucosaminidase (NAG)/creatinine ratio (indicator of renal tubular injury) and urinary albumin/creatinine ratio (indicator of glomerular injury). Renal function was assessed by measuring plasma creatinine and serum cystatin C concentrations. The urinary NAG/creatinine ratio increased significantly from baseline to before crossclamp and remained increased on day 5 in both groups. The urinary albumin/creatinine ratio increased significantly from baseline to 6 h after declamping in the N-acetylcysteine group. However, the changes in the NAG/creatinine ratio and the albumin/creatinine ratio were not significantly different between the two groups. Plasma creatinine and serum cystatin C values remained unchanged during the study period in both groups. In conclusion, N-acetylcysteine did not offer any significant protection from renal injury during elective aortic operation in patients with normal preoperative renal function, and some degree of tubular injury seems to occur before aortic crossclamp.

Anesthetic and Hemodynamic Interactions of Dexmedetomidine and Fentanyl in Dogs

Background:Anesthetic doses of dexmedetomidine (DMED), a highly selective α2agonist, are not well tolerated hemodynamically. The combination of an opioid with DMED might reduce the dosage requirements for each drug and thereby allow the same anesthetic depth to be achieved with lesser degrees of their individual side effects. Methods:Dogs were anesthetized with enflurane. One group (n = 5) received intravenous doses of DMED from 0.1 to 10 μg/kg. Two other groups of five dogs each received fentanyl 15 μg/kg plus 0.05 μg · kg-1·min-1 or fentanyl 45 μg/kg plus 0.2 μg· kg-1· min-1. Thereafter, they received DMED doses of 0.03-3 μg/kg. After the effects of the last DMED dose were measured, atipamezole 0.3 mg/kg was infused intravenously and all measurements were repeated. Then, naloxone (1 mg/kg) was injected intravenously and a final set of measurements obtained. Anesthetic effects were assessed by determining enflurane minimum alveolar concentration (MAC). Hemodynamics and plasma fentanyl concentrations were measured at each determination of MAC. Results:DMED and fentanyl individually produced dose-related reductions of enflurane MAC. During the lower rate infusion of fentanyl (plasma fentanyl concentration 1.0 ± 0.3 ng/ml), DMED reduced enflurane MAC more than could be attributed to a simple additive interaction. During the higher rate infusion of fentanyl (plasma fentanyl concentration 4.4 ± 0.7 ng/ml), DMED reduced enflurane MAC to greater degrees than were achievable by fentanyl alone. DMED caused a dosedependent increase in arterial pressure concomitantly with a decrease in cardiac output, and these changes were not modified by fentanyl. The bradycardia following DMED was augmented by fentanyl. Conclusions:There was a positive interaction, additive or synergistic, between DMED and fentanyl with respect to their enflurane-sparing effects. The interaction allowed the same depth of anesthesia to be achieved by lower doses of all three drugs, potentially limiting the intensity of their individual side effects. However, the presence of fentanyl increased the degree of bradycardia induced by DMED.

Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion

In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan.

Renal effects of dexmedetomidine during coronary artery bypass surgery: a randomized placebo-controlled study

BackgroundDexmedetomidine, an alpha2-adrenoceptor agonist, has been evaluated as an adjunct to anesthesia and for the delivery of sedation and perioperative hemodynamic stability. It provokes dose-dependent and centrally-mediated sympatholysis. Coronary artery bypass grafting (CABG) with extracorporeal circulation is a stressful procedure increasing sympathetic nervous system activity which could attenuate renal function due the interrelation of sympathetic nervous system, hemodynamics and renal function. We tested the hypothesis that dexmetomidine would improve kidney function in patients undergoing elective CABG during the first two postoperative days.MethodsThis was a double-blind, randomized, parallel-group study. Patients with normal renal function and scheduled for elective CABG were randomized to placebo or to infusion of dexmedetomidine to achieve a pseudo steady-state plasma concentration of 0.60 ng/ml. The infusion was started after anesthesia induction and continued until 4 h after surgery. The primary endpoint was creatinine clearance. Other variables included urinary creatinine and output, fractional sodium and potassium excretion, urinary potassium, sodium and glucose, serum and urinary osmolality and plasma catecholamine concentrations. The data were analyzed with repeated-measures ANOVA or Cochran-Mantel-Haenszel test.ResultsSixty-six of 87 randomized patients were evaluable for analysis. No significant between-group differences were recorded for any indices of renal function except for a mean 74% increase in urinary output with dexmedetomidine in the first 4 h after insertion of a urinary catheter (p < 0.001). Confidence interval examination revealed that the sample size was large enough for the no-difference statement for creatinine clearance.ConclusionsUse of intravenous dexmedetomidine did not alter renal function in this cohort of relatively low-risk elective CABG patients but was associated with an increase in urinary output.This study was carried out in 1994-1997 and was thus not registered.