Target-controlled infusion of rocuronium in infants, children, and adults: a comparison of the pharmacokinetic and pharmacodynamic relationship.

UNLABELLED: Target-controlled infusion (TCI) of rocuronium can be used to maintain a stable blood concentration (Cp). At steady-state, the pharmacokinetics (PK) are compensated for by TCI, and a stable effect can be observed. The theoretical Cp may represent effect-site concentration (EC). We used the EC-effect relationship to study pharmacodynamics (PD) in infants, children, and adults. After giving their written, informed consent, 14 infants, 23 children, and 21 adults scheduled for elective surgical procedures received 3 to 6 ascending Cp targets of TCI rocuronium according to PD data. Just before each increase of TCI, venous blood samples were taken to measure Cp. Neuromuscular block was evaluated acceleromyographically. Individual effect data and measured Cp were fitted to the Hill equation. Maximum block during TCI targets-1000, 1300, and 1600 ng/mL-was smaller in children in comparison with infants and adults. The concentration in the effect compartment associated with a 50% drug effect (EC(50)) was significantly smaller in infants (mean [SD]) (652 [215] ng/mL) than in adults (954 [276] ng/mL) and was the largest in children (1200 [295] ng/mL). Calculated mean EC(90) values were 1705, 2230, and 2035 ng/mL, respectively, in infants, children, and adults. TCI rocuronium established steady-state PK/PD at different TCI targets and allowed us to define PK/PD relationships in a standardized way. Steady-state TCI rocuronium revealed the most potency of rocuronium in infants and the least in children. IMPLICATIONS: Target-controlled infusion (TCI) of rocuronium in infants, children, and adults was used to analyze the pharmacokinetic/pharmacodynamic relationship. Steady-state TCI rocuronium revealed the most potency of rocuronium in infants and the least in children.

Target controlled infusion of rocuronium: analysis of effect data to select a pharmacokinetic model.

BACKGROUND: We aimed to evaluate whether area under the curve (AUC) analysis of pharmacodynamic data can be used to compare pharmacokinetic models taken from the literature, during a target controlled infusion (TCI) of rocuronium. METHODS: Seventy-two patients scheduled for orthopaedic surgery received a TCI of rocuronium (Stanpump) based on one of four pharmacokinetic models: those described by Szenohradszky, Alvarez-Gomez, Wierda, and Cooper. The resulting theoretical plasma concentration versus time curve was calculated for all patients based on all four pharmacokinetic models. Predicted effect versus time curves were calculated following the pharmacokinetic-pharmacodynamic link model (Sheiner and colleagues). Neuromuscular block was evaluated acceleromyographically. The difference between the area under the observed effect (AUC(OE)) and predicted effect (AUC(PE)) versus time curves was used for comparison. RESULTS: AUC(PE )differed significantly from AUC(OE) in the Szenohradszky and Alvarez-Gomez models, both with the reference link-pharmacodynamic data and with altered link-pharmacodynamic variables. AUC(PE )and AUC(OE) were comparable for the Wierda and Cooper models. The mean AUC(OE) was 25.1 (SD 11.9)% block x h. AUC(PE)-AUC(OE) was significantly larger in the Szenohradszky model when compared with all other pharmacokinetic models. This difference remained when link or pharmacodynamic variables were modified. The smallest AUC(PE)-AUC(OE) difference was found with the Wierda model. CONCLUSION: It was possible to use AUC analysis for identification of the pharmacokinetic model that best predicted the pharmacodynamic characteristics of our patients.

Oxygen transport and myocardial function after the administration of albumin 5%, hydroxyethylstarch 6% and succinylated gelatine 4% to rabbits.

BACKGROUND AND OBJECTIVE: The effects of administering albumin 5%, hydroxyethylstarch 6% and succinylated gelatine 4% on oxygen transport and left ventricular function were prospectively investigated in different experimental conditions: baseline, fluid load, after 10 min of myocardial ischaemia and after reperfusion. METHODS: Twenty-seven rabbits received at random one of three colloids in escalating boluses over 10-15 min to achieve left ventricular end-diastolic pressures (LVEDP) between 8 and 10mmHg. A branch of the left anterior descending coronary artery was then temporarily occluded by a ligature and released after 10 min. Myocardial function was assessed using left ventricular pressure recordings and dimension data obtained from ultrasound crystals inserted onto the ventricular wall. Blood was sampled for the determination of oxygen delivery and consumption, the oxygen extraction ratio, acid-base status, and glucose and lactate concentrations. RESULTS: Administration of the colloids similarly increased oxygen delivery and improved left ventricular function in all groups. Peak rate of pressure development (dP/dt(max)) and oxygen delivery were reduced during ischaemia and reperfusion. The decrease in dP/dt(max) was more pronounced in the hydroxyethylstarch group. CONCLUSIONS: Administration of albumin 5%, hydroxyethylstarch 6% and succinylated gelatine 4% had similar effects on oxygen delivery and myocardial function. After ischaemia and during reperfusion, the decrease in myocardial function was most pronounced with hydroxyethylstarch 6%.

The effects of the pericardium on length-dependent regulation of left ventricular function in coronary artery surgery patients.

OBJECTIVE: To analyze the effects of the pericardium on the length-dependent regulation of myocardial function in coronary artery surgery patients. DESIGN: Prospective. SETTING: University hospital. PARTICIPANTS: Patients scheduled for elective coronary artery surgery. INTERVENTIONS: In 10 patients, a combined micromanometer transducer conductance catheter was inserted into the left ventricle for measurement of left ventricular pressures and volumes. MEASUREMENTS AND MAIN RESULTS: Consecutive data were obtained during a progressive increase in left ventricular pressures and volumes obtained by leg elevation in closed chest-closed pericardium and open chest-open pericardium conditions. Pericardiotomy did not alter baseline left ventricular hemodynamics. The effects of leg elevation were different, however. In closed chest-closed pericardium conditions, stroke volume and stroke work remained unchanged, whereas these parameters increased in open chest-open pericardium conditions. This increase was related to the increase in end-diastolic volume that was observed in open chest-open pericardium conditions and not in closed chest-closed pericardium conditions. CONCLUSIONS: In coronary artery surgery patients, pericardiotomy does not alter baseline left ventricular function. When cardiac load is increased by leg elevation, however, use of the Frank-Starling mechanism is enhanced in open chest-open pericardium conditions.

Postoperative analgesia with i.v. patient-controlled morphine: effect of adding ketamine.

We have studied the effect of adding ketamine to i.v. morphine patient-controlled analgesia (PCA) for the treatment of pain after laparotomy. Thirty patients were allocated randomly to receive PCA with saline or ketamine in a double-blind, randomized study. Analgesia was started in the recovery room when visual analogue scale (VAS) scores were > 4. A bolus dose of morphine 3 mg was given to all the patients followed by i.v. PCA. Simultaneously, an infusion of ketamine 2.5 micrograms kg-1 min-1 or saline was started. Pain scores, morphine consumption and side effects were noted for up to 48 h after the start of PCA. VAS scores decreased significantly with time (P = 0.0001) and were similar (P = 0.3083) in both groups. Cumulative morphine consumption at 48 h was significantly lower in the ketamine group (28 mg) than in the control group (54 mg) (P = 0.0003). Nausea was less frequent in the ketamine group (P = 0.03).

Effects of calcium on left ventricular function early after cardiopulmonary bypass.

OBJECTIVES: Evaluation of the effects of intravenous CaCl2 on systolic and diastolic function early after separation from cardiopulmonary bypass (CPB) DESIGN: Prospective study SETTING: University hospital PARTICIPANTS: Twenty patients scheduled for elective coronary artery surgery INTERVENTIONS: Left ventricular (LV) pressures were measured with fluid-filled catheters. Data were digitally recorded during pressure elevation induced by tilt-up of the legs. Transgastric short-axis echocardiographic views of the LV were simultaneously recorded on videotape. Measurements were obtained before the start of CPB, 10 minutes after termination of CPB, after intravenous administration of CaCl2, 5 mg/kg, and 10 minutes later. MEASUREMENTS AND MAIN RESULTS: Systolic function was evaluated with the slope (Ees, mmHg/mL) of the systolic pressure-volume relation. Diastolic function was evaluated with the chamber stiffness constant (Kc, mmHg/mL) of the diastolic pressure-volume relation. CaCl2 increased Ees from 2.62 +/- 0.46 to 5.58 +/- 0.61 (mean +/- SD), but induced diastolic dysfunction with an increase in Kc from 0.011 +/- 0.006 to 0.019 +/- 0.007. These changes were transient and had disappeared within 10 minutes after administration of CaCl2. CONCLUSIONS: CaCl2 early after CPB transiently improved systolic function at the expense of an increase in ventricular stiffness, suggesting temporary diastolic dysfunction.

Dose dependent effect of aprotinin on rate of clot formation.

Forty-eight patients scheduled for elective cardiac surgery were randomly assigned to receive aprotinin in the following doses: 0.2 mg kg-1 (group A), 0.7 mg kg-1 (group B), 1 mg kg-1 (group C) and 1.4 mg kg-1 (group D). Clot formation was analysed by thromboelastography immediately after induction of anaesthesia and again 30 min after administration of aprotinin. Rate of clot formation was assessed using R (reaction time = rate of initial fibrin formation), K (clot formation time = rate of fibrin build-up and cross linking) and angle of clot formation (denoting speed at which solid clot forms). Strength of the clot was assessed by maximal amplitude of clot formation (MA) and % lysis after 30 and 60 min. Significant reduction of R and K times and increase in angle of clot formation was observed in groups A and B. This effect was not apparent in the other groups. In group D, an increase in R time was noted. These findings indicate a dose-dependent effect of aprotinin on rate of clot formation with an earlier clot formation at low doses.

Efficacy and safety of aprotinin in aortocoronary bypass and valve replacement operations: a placebo-controlled randomized double-blind study.

To assess the efficacy and safety of the use of a high-dose regimen of aprotinin in routine cardiac operations, a placebo-controlled randomized double-blind study was conducted in 93 adult patients undergoing cardiopulmonary bypass. Aprotinin-treated patients (group A, n = 46) received 2 x 10(5) Kallikrein Inactivating Units (KIU) of aprotinin before incision, 2 x 10(6) KIU in the priming solution and 5 x 10(5) KIU/h during CPB. Control patients (group B, n = 47) received the same volume of normal saline. Mean postoperative blood loss in ml after six hours and in total until removal of thoracic drains decreased significantly from 752 and 1933 in controls, to 358 and 1051 in treated patients (p < 0.001). Mean total transfusion needs were 2.6 (A) and 4.8 (B) units per patient. Adverse events were evenly distributed between both groups and could not be attributed to aprotinin use. We, therefore, recommend the use of a high-dose regimen of aprotinin for routine cardiac operations despite its cost.

Onset of segmental relaxation dysfunction with decreased myocardial tissue perfusion: modulation by propofol.

OBJECTIVES: To estimate myocardial oxygen needs by studying the effects of reduced coronary blood flow on segmental myocardial function. To study the tolerance of limited oxygen supply to a myocardial segment during propofol administration. DESIGN: A prospective experimental study. SETTING: An experimental animal laboratory in a university. PARTICIPANTS: Eighteen adult dogs, weighing 20 to 35 kg. INTERVENTIONS: Open thorax open pericardium experiments were performed under standard anesthetic conditions. Segment length gauges were placed subendocardially in an anteroapical and in a basal segment. Flow to the anteroapical segment was reduced by tightening a micrometer-controlled snare placed around the second diagonal coronary artery. Left ventricular pressure-length signals allowed for identification of onset of relaxation dysfunction. Myocardial tissue flow at onset of relaxation dysfunction was defined as critical flow. Tracer microspheres were used to measure subepicardial, midwall, and subendocardial flow at critical flow. MEASUREMENTS AND MAIN RESULTS: Stability of the model and reproducibility of critical flow were studied in a first series of six dogs with the hearts paced at 110 beats/min. Hemodynamics, left ventricular, and segmental myocardial function during critical flow were stable. Subendocardial critical flow was identical with each flow reduction (45% +/- 5, 44% +/- 8, and 43% +/- 5 of baseline myocardial tissue flow). In a second series of six dogs, critical flow was measured at pacing rates 100 beats/min, 150 beats/min, and 100 beats/min with propranolol, 0.1 mg/kg, pretreatment. Critical flows were 38% +/- 5, 55% +/- 6, and 17% +/- 2 of baseline, respectively (p < 0.05). In a third series of six dogs, critical flow was measured during sufentanil, 0.6 microgram/kg/min, and increasing doses of propofol (P0: 0.0 mg/kg/h, P4: 4.0 mg/kg/h and P8: 8.0 mg/kg/h). Heart rate was kept constant at 110 beats/min. When compared with P0, hemodynamic and left ventricular contraction parameters were stable at P4 but were decreased at P8. At P0, critical flow was: 0.63 +/- 0.14, at P4: 0.34 +/- 0.09, and at P8: 0.25 +/- 0.07 mL/min/g (p < 0.05). CONCLUSION: Critical myocardial tissue flow was reproducible and sensitive for altered myocardial oxygen needs. The negative inotropic properties of P decreased myocardial oxygen needs during unchanged hemodynamic and left ventricular contraction parameters. A higher P dose depressed left ventricular function.

Comparison of two different loading doses of milrinone for weaning from cardiopulmonary bypass.

OBJECTIVE: To compare the hemodynamic effects, pharmacokinetic profiles, and the need for vasoactive agents between a low (20 micrograms/kg during 15 minutes [group 1; n = 10]) and a high (40 micrograms/kg during 15 minutes [group 2; n = 10]) loading dose of milrinone. DESIGN: Prospective, randomized, double-blind. SETTING: University hospital. PARTICIPANTS: Twenty patients scheduled for elective coronary artery surgery. INTERVENTIONS: Weaning from CPB was achieved using a strict protocol. After atrioventricular pacing at 90 beats per minute and preload optimalization, a first weaning attempt was started with only calcium and nitroglycerin as support. If this attempt was unsuccessful (cardiac index < 2L/min/m2), CPB was reinitiated and weaning level 2 was prepared, consisting of inotropic support with milrinone. Patients received either the low (group 1) or the high (group 2) loading dose of milrinone. After the end of the loading dose, a continuous infusion of milrinone of 0.5 micrograms/kg/min was started in both groups. MEASUREMENTS AND MAIN RESULTS: Both groups were comparable regarding preoperative and intraoperative data. Hemodynamic data were comparable in both groups at each time of measurement (p = 0.941). The need for vasoactive medication (norepinephrine [NE]) in order to keep mean arterial pressure > or = 50 mm Hg was significantly higher in group 2 (p = 0.004). Need for NE during the loading infusion was 9.6 +/- 4.9 micrograms (mean +/- SEM) in group 1 and 41.6 +/- 7.6 micrograms in group 2 (p = 0.004). Need for NE during the immediate post-CPB period was also higher in group 2 (16.0 +/- 10.4 micrograms in group 1 and 232.5 +/- 82.8 micrograms in group 2 (p = 0.002)). Plasma clearance of milrinone after CPB was less in both groups than in healthy volunteers. However, clearance of milrinone was significantly higher in group 2 (p = 0.006), and consequently, half-life of milrinone was significantly less in group 2 (p = 0.007). CONCLUSIONS: The present results demonstrate that when milrinone is used during weaning from CPB, a loading dose of 20 micrograms/kg provided to similar hemodynamic support a loading dose of 40 micrograms/kg. The need for vasoconstrictive medication was significantly less in the group with the low loading dose.

Central-to-peripheral arterial pressure gradient during cardiopulmonary bypass: relation to pre- and intra-operative data and effects of vasoactive agents.

A significant central-to-peripheral arterial pressure gradient may exist during and after cardiopulmonary bypass (CPB). The etiology and mechanisms of this phenomenon remain controversial. We studied the pressure gradient between aorta, brachial artery and radial artery in 68 patients, scheduled for elective coronary artery bypass surgery. We evaluated whether choice of cardioprotection during CPB (use of cold cardioplegic solution or use of intermittent crossclamping under protection with lidoflazine), and choice of pulsatile or nonpulsatile flow during the course of CPB, affected the magnitude and duration of the systolic pressure gradient. We also studied whether central-to-peripheral pressure gradient was influenced by administration on CPB of different vasoactive drugs with different mode of action: sodium nitroprusside (direct action on the vessels), droperidol (alpha-adrenergic blocking action), ketanserin (5-hydroxytryptamine antagonist) and phenylephrine (selective alpha 1-agonist). It appeared that central-to-peripheral gradient occurred early during CPB and remained constant throughout the course of CPB. The gradient disappeared within 60 min after weaning from CPB. We found the main pressure gradient to occur between the brachial and the radial artery. There was no relation between magnitude of the gradient and sex, weight, length or age of the patient. There was also no relation between magnitude of the pressure gradient and type of cardioprotection, choice of pulsatile vs nonpulsatile flow on CPB and duration of CPB. We also found no relation between pressure gradients and changes in temperature, haematocrit and systemic vascular resistance. The pressure gradient was not affected by any of the vasoactive drugs.

Use of the right-sided precordial lead V4R in the detection of intraoperative myocardial ischemia.

This study evaluated the benefit of additional electrocardiographic monitoring of the right precordial lead V4R for detection of ST segment changes during elective coronary artery bypass surgery in 210 patients. ST segment analysis was performed for leads I, II, CB5, and V4R. ST segment changes were noted in 60 patients. Of these, 32 had combined left-sided and right-sided coronary artery disease (group A), and 28 had only left-sided coronary artery disease on coronary angiography (group B). Lead sensitivity was estimated assuming that all ST segment changes were true positive responses. Sensitivity using a single lead was greatest for lead CB5 in the two groups (76% in group A and 78% in group B). Sensitivity for lead I was low in both groups (34% in group A and 26% in group B). Sensitivity for lead II was 63% in group A and 52% in group B, and sensitivity for lead V4R was 71% in group A but only 37% in group B. Combination of leads V4R and CB5 increased sensitivity to 98% in group A. In group B, this lead combination had a sensitivity of 93%, but lead combinations I-CB5-V4R and II-CB5-V4R were more sensitive (97% and 100%, respectively). The monitoring of lead V4R allowed detection of 20% of ST segment changes in group A that would have passed undetected if only leads I, II, and CB5 were monitored. These results demonstrate the value of additional electrocardiographic monitoring of the right precordial lead V4R during coronary artery bypass grafting in patients with right-sided coronary artery disease.

Myocardial metabolism during anaesthesia with propofol--low dose fentanyl for coronary artery bypass surgery.

We have studied the haemodynamic and myocardial effects of propofol-fentanyl anaesthesia in 12 patients undergoing coronary artery bypass surgery during the pre-bypass period. The induction dose of propofol was 1.5 mg kg-1 and mean infusion rate during maintenance was 4.48 mg kg-1 h-1 (range 1.87-7.24 mg kg-1 h-1). The total dose of fentanyl was 30 micrograms kg-1. The haemodynamic changes indicated myocardial depression and peripheral vasodilatation. Coronary sinus flow and indicators of global myocardial perfusion (myocardial oxygen consumption, myocardial lactate extraction) did not change. Although not excluding regional myocardial ischaemia, these results show that propofol-fentanyl anaesthesia has no major adverse effects on cardiac function.

Influence of thiopental, etomidate, and propofol on regional myocardial function in the normal and acute ischemic heart segment in dogs.

The effects of 30-min infusions of thiopental (20, 30, 40, 50, 60, and 70 mg.kg-1.h-1), etomidate (2.4, 3.6, 7.2, 9.6, 12, and 14.4 mg.kg-1.h-1), and propofol (6, 9, 12, 15, 18, and 21 mg.kg-1.h-1) on regional hemodynamic variables in the normal and acute ischemic heart segment were studied in dogs using ultrasonic segment length gauges. The three agents were associated with a dose-dependent decrease in end-diastolic length, indicating a decrease in left ventricular filling. This effect was most pronounced for propofol. At the doses tested, etomidate did not significantly alter regional myocardial function. Thiopental, however, was associated with a dose-dependent decrease in systolic shortening, which was significantly greater in the ischemic segment. These findings confirm the hemodynamic stability seen with etomidate and show that thiopental depresses myocardial function more in the acute ischemic heart than in the normal heart. The decrease in systolic shortening associated with propofol was similar in the normal and in the acute ischemic heart segment.

Low-dose sufentanil-isoflurane anaesthesia for coronary artery surgery.

Haemodynamic changes and catecholamine responses were measured during anaesthesia with sufentanil (total dose 7 micrograms kg-1) supplemented with isoflurane in 14 patients undergoing coronary artery surgery. Isoflurane was used to control systolic arterial pressure, which was allowed to decrease to 100 mm Hg. Mean inspired isoflurane concentration was 0.22 (SD 0.19)% (induction), 0.34 (0.18)% (pre-bypass) and 0.22 (0.17)% (post-bypass). During cardiopulmonary bypass 0.22 (0.13)% isoflurane was administered to control mean perfusion pressure. During induction and the pre-bypass period, significant decreases in systolic and diastolic arterial pressure, systemic vascular resistance and left ventricular stroke work index (LVSWI) (P less than 0.01) were noted. The decrease in LVSWI with unchanged filling pressures indicated myocardial depression. Serum catecholamine concentrations remained at the pre-induction value until cardiopulmonary bypass, when a significant increase was noted. Tracheal intubation, sternotomy and sternal spread were not associated with hypertension or tachycardia. Clinical signs that could reflect myocardial ischaemia were not observed peroperatively. After operation, cardiac enzymes were within the normal clinical range and ECG was unchanged.