Pharmacokinetics of sevoflurane elimination from respiratory gas and blood after coronary artery bypass grafting surgery.

PURPOSE: Sevoflurane, with a relative low blood-gas partition coefficient, is an ideal anesthetic to achieve rapid offset and recovery from general anesthesia. This study will determine the profiles of four concentration-time curves to characterize the pharmacokinetics of sevoflurane elimination. METHODS: Eight patients (aged 54-76 years) undergoing coronary arterial bypass grafting surgery were enrolled in this study. At the end of surgery, anesthetic gas and blood were sampled 20 min before and after stopping sevoflurane administration, with prior maintenance of a fixed 5% inspired sevoflurane (CIsev) in 6 L/min oxygen flow for 60 min before the cessation of sevoflurane administration for the subsequent 20 min elimination. An infrared analyzer was used to determine both CIsev and end-tidal sevoflurane (CEsev). The sevoflurane concentrations in the internal jugular-bulb (Jsev), arterial (Asev) and pulmonary arterial blood (PAsev) were analyzed by gas chromatography, and cardiac output was measured using an Opti-Q pulmonary artery catheter. RESULTS: A bi-exponential decay function was the best fit for the CEsev,Jsev, Asev, and PAsev time curves. There were two distinct components, the initial 5-min fast or distribution phase and the subsequent 15-min slow or elimination phase. Before cessation of the sevoflurane supplement, the step-down concentration of sevoflurane was listed in the following order: CIsev > CEsev > Asev ≧ Jsev > PAsev. During the elimination phase, the fastest decay occurred in CEsev, followed by Jsev, Asev and PAsev. Therefore, a reverse step-down pattern was observed (PAsev > Asev ≧ Jsev > CEsev) after 20 min. The ratio of Asev to CEsev was 89% at baseline before stopping sevoflurane administration, but the ratio of Asev to CEsev increased to 128% at the twentieth min of the sevoflurane elimination phase. CONCLUSIONS: During elimination, the initial washout of sevoflurane from the functional residual capacity of the lungs was reflected in the fast component of the CEsev, Jsev, Asev, and PAsev time curves. In contrast, the slow component was dominated by the tangible effects of the physiological membrane barriers, such as the alveoli-pulmonary capillary and blood-brain barriers.

Pharmacokinetics of isoflurane in human blood.

Investigation of isoflurane washout from the human body and brain provides more precise information about elimination in anesthesia. The elimination pattern of isoflurane remains poorly quantified, and therefore this study tried to clarify the pharmacokinetic pattern of isoflurane elimination. Sixteen patients (aged 48-78 years), undergoing coronary arterial bypass grafting surgery were enrolled in this study. Sixty minutes prior to the end of surgery, we kept a fixed 2% inspired isoflurane in 6,000 ml min(-1) oxygen flow. Isoflurane supplement was then discontinued to study the 20-min isoflurane elimination. An infrared analyzer was used to determine both inspired isoflurane and end-tidal isoflurane. The isoflurane concentration in the internal jugular bulb blood, arterial blood and pulmonary arterial blood were analyzed by gas chromatography. Biexponential decay function was the best fitted for the end-tidal isoflurane- and arterial blood isoflurane-time curves. There were two distinct components, including initial 5-min fast component and the next 15-min slow component. Monoexponential decay function was the best fitted for the pulmonary arterial blood- and jugular bulb blood-time curves. During elimination, the initial washout of isoflurane from functional residual capacity of lungs is reflected in the fast component of the isoflurane concentration time curves. The later slow component is dominated by the tangible manifestation of physiological membrane barriers, including the existence of alveoli-pulmonary capillary, blood-brain barriers.

Closed-circuit isoflurane-based anesthesia provides better fast-tracking anesthesia than fentanyl/propofol-based anesthesia for off-pump coronary artery bypass graft surgery.

BACKGROUND: In recent years, low-dose fentanyl combined with short-acting hypnotic drug has been thought to be better than traditional high-dose fentanyl in cardiac anesthesia. On the other hand, the practice of closed-circuit inhaled anesthesia offers many advantages, including hemodynamic stability, maintenance of adequate anesthesia depth and early recovery. This study sought to evaluate the effect of closed-circuit isoflurane-based anesthesia (CIA) and fentanyl/propofol-based anesthesia (FPA) on off-pump coronary artery bypass graft (OPCABG) surgery. METHODS: Fifty patients scheduled for elective OPCABG surgery were enrolled and randomly assigned to receive either CIA (n = 25) or FPA (n = 25). In the CIA group, anesthesia was induced with fentanyl 2 microg/kg and midazolam 0.05 mg/kg, followed by 2% isoflurane in oxygen (oxygen flow rate = 3 L/min) via mask ventilation for 30 min. Pancuronium 0.1-0.15 mg/kg was given thereafter to facilitate endotracheal intubation. Anesthesia was maintained by isoflurane in a minimal oxygen flow of 300 mL/min, with the vaporizer adjusted to deliver 3%-5% concentration. In the FPA group, anesthesia was induced with fentanyl 10-15 microg/kg and midazolam 0.05 mg/kg; and pancuronium 0.1-0.15mg/kg was used for endotracheal intubation. Anesthesia was maintained by propofol 2-6 mg/kg/hr and fentanyl 1-2 microg/kg/hr, and an incremental bolus of i.v. propofol 20 mg was given if the patient's mean blood pressure (MBP) exceeded 85 mmHg. An inotropic agent was given if the patient's MBP dropped below 65 mmHg or if the patient experienced a decrease in MBP greater than 20% of the preinduction value. The time of extubation, length of stay in the intensive care unit, and inotropic requirements were recorded. RESULTS: The patients in the CIA group were extubated earlier than those in the FPA group (281.3 +/- 32.5 min versus 311.3 +/- 38.5 min, respectively; P < 0.05), although there was no statistical difference in the length of stay in the intensive care unit (29.6 +/- 4.8 hr versus 30.1 +/- 7.6 hr, respectively; P = 0.4). The use of inotropic agent in the CIA group was less than in the FPA group (16% vs. 56%, P < 0.01). Dopamine requirement was less in the CIA group than in the FPA group (0.8 +/- 0.3 vs. 3.7 +/- 0.4 microg/kg/min, respectively; P < 0.01). CONCLUSIONS: These results suggest that CIA, as compared with FPA, provides a significant reduction in the time to extubation after OPCABG surgery with less use of inotropic agents.

Cellular mechanisms responsible for the inotropic action of insulin on failing human myocardium.

BACKGROUND: An increase in intracellular calcium transients is responsible for the positive inotropic effect of insulin on human myocardium, but the mechanisms involved in this increase in [Ca2+]i remain unclear. METHODS: We studied isolated trabeculae or cardiomyocytes from end-stage failing hearts of 38 patients undergoing heart transplantation. The effect of insulin on isometric twitch force (37 degrees C, 0.5 Hz) and L-type Ca2+ current (whole-cell voltage clamp) was assessed. RESULTS: Crystalline insulin increased the contractile force in a dose-dependent manner (0.01 to 10 micromol/liter), with a maximum increase of 45 +/- 8% (p < 0.05) at 1 micromol/liter. It also increased L-type Ca2+ peak current density by 26 +/- 6% (p < 0.05). This insulin-mediated positive inotropic effect was unchanged in the presence of propranolol (1 micromol/liter). Positive inotropy was partially independent of glucose. L-type Ca2+ channel blockade (diltiazem, 5 micromol/liter), and sarcoplasmic reticulum (SR) Ca2+-release channel blockade (ryanodine, 0.1 micromol/liter) did not affect the inotropic response to insulin. However, blockade of SR Ca2+-ATPase (cyclopiazonic acid, 10 micromol/liter), inhibition of Na+-H+ exchange (HOE642, 10 micromol/liter), and inhibition of Na+-Ca2+ exchange (SEA0400, 1 micromol/liter) partially prevented the inotropic response to insulin. CONCLUSIONS: Positive inotropy of insulin was not related to catecholamine release and subsequent stimulation of beta-adrenergic receptor, but it may enhance the activity of SR Ca2+-ATPase and trans-sarcolemmal Ca2+ entry, mainly via reverse-mode Na+-Ca2+ exchange and insulin-mediated activation of Na+-H+ exchange. We hypothesize that these changes in [Ca2+]i might be secondary to the activation of reverse-mode Na+-Ca2+ exchange, presumably via elevated intracellular Na+ concentration.

Pharmacokinetics of isoflurane: uptake in the body.

We investigated the effect of the inspired isoflurane concentration (C(I)iso) on body uptake by comparing the isoflurane concentration in the pulmonary artery blood (PAiso) and that in the arterial blood (Aiso) in 16 patients undergoing coronary artery bypass grafting surgery during the 1st, hour of isoflurane anesthesia. The patients received standardized anesthetics consisting of fentanyl and thiopental and were then allocated to receive either 1% or 2% C(I)iso (n = 8 in each group). C(I)iso and end-tidal isoflurane concentration (C(E)iso) were measured by infrared analysis, and Aiso and PAiso were analyzed by gas chromatography. The cardiac output was measured by thermodilution by use of a pulmonary artery catheter. The body tissue could be represented by the gradient C(I)iso-C(E)iso or Aiso-PAiso over time, respectively. The 2% inspired isoflurane group had twice the gradients (either C(I)iso-C(E)iso or Aiso-PAiso) than the 1% inspired isoflurance group. Additionally, both C(I)iso-C(E)iso and Aiso-PAiso were nearly constant over the hour of the study. The inspired concentration-dependent and near-constant uptake of isoflurane over time has important implications which enable us to apply the uptake pattern of isoflurane to clinical practice.

Minimal low-flow isoflurane-based anesthesia benefits patients undergoing coronary revascularization via preventing hyperglycemia and maintaining metabolic homeostasis.

BACKGROUND: The objectives of this study were to determine whether minimal low-flow isoflurane-based anesthesia could be a feasible technique for patients undergoing coronary artery bypass graft surgery. It is hypothesized that isoflurane-based anesthesia facilitates an agreeable recovery from surgery is mediated through preventing hyperglycemia and metabolic disturbance associated with cardiopulmonary bypass. METHODS: 107 consecutive patients were randomly assigned to two groups, i.e., isoflurane-based anesthesia group (n = 54) and fentanyl-based anesthesia group (control group, n = 53). In isoflurane-based anesthesia group, patients received isoflurane from induction up till departure from operating room to intensive care unit (ICU). In the control group, fentanyl (66.4 +/- 3.2 micrograms/kg) and midazolam (320 +/- 20 micrograms/kg) were administered to anesthetize the patients during the operation. RESULTS: Patients with isoflurane-based anesthesia required less dopamine (0.6 +/- 0.2 vs. 4.2 +/- 0.4 micrograms/min) and dobutamine (0.4 +/- 0.2 vs. 4.1 +/- 0.5 micrograms/min); they could be extubated earlier (7.9 +/- 1.0 vs. 35.1 +/- 2.9 h), and had a shorter stay at ICU (2.2 +/- 0.2 vs. 4.8 +/- 0.4 days). In addition, occurrence of hyperglycemia (167 +/- 7.7 vs. 243 +/- 9.5 mg/dl) and bicarbonate requirement (128 +/- 7.0 vs. 313 +/- 22.0 mEq) were less in patients with isoflurane-based anesthesia as compared with those in fentanyl group. CONCLUSIONS: These results demonstrate that isoflurane, not fentanyl, benefits patients undergoing coronary artery bypass grafting surgery. This benefit perhaps is mediated through maintaining hemodynamic stability and metabolic homeostasis and preventing hyperglycemia.