Drug delivery system to improve the perioperative administration of intravenous drugs: computer assisted continuous infusion (CACI)
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Biomedical subjects
Publications and source records attributed to J G Reves.
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Systemic venous oxygen saturation is clinically used as an indicator of a satisfactory oxygen supply demand balance on cardiopulmonary bypass (CBP). Cerebral desaturation has been associated with postoperative cognitive dysfunction and has an incidence of 17% to 23% on bypass. We tested the hypothesis that systemic venous saturation did not correlate with jugular bulb venous saturation. Blood was drawn from the radial artery, jugular bulb catheter, and venous return line for determination of pH, oxygen tension and saturation, and carbon dioxide tension at four times during bypass: warm 1 (following initiation of CPB); cold 1 (stable hypothermia); cold 2 (hypothermia prior to rewarm); and warm 2 (nasopharyngeal temperature 36 degrees C to 37 degrees C). Correlations of jugular bulb and systemic venous saturation at cold 1 were r = 0.29, r2 = 0.08, and p = 0.0005, and at warm 2 were r = 0.22, r2 = 0.05, and p = 0.007. We conclude that systemic saturation is a poor indicator of cerebral saturation. The poor association of jugular and systemic pump venous saturations underscores our inability to evaluate adequacy of cerebral perfusion. Jugular saturation is lower than pump venous return blood, especially at times of lower oxygen delivery, thus either continuous invasive or noninvasive evaluation of cerebral oxygenation is required to evaluate the adequacy of cerebral perfusion.
The present longitudinal study was designed to determine the prevalence of depression in male and female patients undergoing cardiac surgery, and to examine what factors are associated with depression before and after surgery. One day prior to surgery (T1), and one day prior to discharge from the hospital (T2), 141 patients completed a psychometric test battery including the Center for Epidemiological Studies Depression Scale (CES-D), the State-Trait Anxiety Inventory (STAI), and the Perceived Social Support Scale (PSSS). Data were also collected on 13 physiological measures. Forty-seven per cent of patients were depressed (defined as a score of 16 or above on the CES-D) at T1. Scores on the CES-D significantly increased from T1 (M = 15) to T2 (M = 20), with 61 per cent of patients classified as depressed at T2. Factors associated with depression at T1 were female gender, higher state anxiety, and less social support. Depressed patients at T2 were characterized by higher scores on the STAI at T2 and higher scores on the CES-D at T1. The prevalence of depression in cardiac surgery patients, particularly women, may be underrecognized and warrants increased attention.
Acadesine (5-amino-4-imidazole carboxamide riboside) is a purine nucleoside analog that has been shown in animals to reduce myocardial ischemic injury by selectively increasing the availability of adenosine in ischemic tissues. Because patients undergoing coronary artery bypass graft (CABG) surgery are especially vulnerable to developing myocardial ischemia, we investigated whether perioperative use of this adenosine-regulating drug with potential anti-ischemic properties could modify the incidence and severity of perioperative myocardial ischemia. The goals of this study were to evaluate safety and the effects of acadesine on myocardial ischemia, left ventricular function, and, secondarily, on adverse clinical outcomes (myocardial infarction, heart failure, life-threatening dysrhythmias, and death) in patients undergoing CABG surgery. One hundred sixteen patients were randomized to receive one of three continuous intravenous dosing regimens (placebo [control] or one of two doses of acadesine [high- and low-dose infusion]) in double-blind fashion intraoperatively and in the early postoperative period (total infusion time was 7 h). Multidose cold crystalloid cardioplegia (each containing either acadesine or placebo) was used for myocardial protection. All were monitored for potentially drug-related adverse events and the presence of myocardial ischemia was assessed by continuous Holter electrocardiography (ECG) and transesophageal echocardiography (TEE). All patients received standardized anesthetic, surgical, and hemodynamic management during the intraoperative period. All research data (ECG, TEE, outcome data) were evaluated at the coordinating center (San Francisco) in blinded fashion to ensure that uniform data analysis criteria were employed. The administration of acadesine was safe: mild increases in plasma uric acid (a metabolite of acadesine) occurred only in patients receiving high doses (mean increase 1.6 +/- 0.2 mg/dL) and were without clinical sequelae. Before drug administration in the preoperative period (baseline), the incidence and severity of ECG ischemia did not differ among the three groups (placebo = 18%; low-dose = 14%; high-dose = 14%). During prebypass, the incidence of ECG ischemia was similar in all three groups (0%, 3%, 3%, respectively). The incidence of TEE ischemia was numerically lower in the two acadesine groups (high-dose = 6%, low-dose = 15%) than in the control group (19%), but this was not statistically significant (P = 0.22). During postbypass, the incidence of ECG ischemia was 11% in the high-dose group, 22% in the low-dose group, and 18% in the control group (P = 0.42), and TEE ischemia was similar in incidence in all groups (placebo = 29%; low dose = 27%; high-dose = 24%) (P = 0.86).(ABSTRACT TRUNCATED AT 400 WORDS)
Acute isovolemic hemodilution is used increasingly to avoid the potentially serious side effects of homologous blood transfusions. Cardiovascular physiology during hemodilution is characterized by a marked increase in cardiac output and organ blood flow to compensate for the decrease in arterial oxygen-carrying capacity. During advanced hemodilution an increased oxygen extraction is also observed, such that oxygen consumption generally is maintained even during advanced hemodilution. The increase in cardiac output is related mainly to a decrease in blood viscosity and an enhanced sympathetic tone resulting in stimulation of the heart. The magnitude and the mechanisms involved in the increase depend upon species, state of awareness (awake versus anesthetized), type of anesthesia, type of exchange solution, and condition of the heart prior to hemodilution. Recent laboratory findings, as well as clinical practice in cardiac surgery, suggest that moderate hemodilution to hematocrit values of approximately 25% is well tolerated in single vessel coronary artery disease which should thus not be regarded as an absolute contraindication for moderate hemodilution. An integral concept to minimize homologous blood transfusions consists of preoperative autologous blood donation, preoperative isovolemic hemodilution, meticulous (asanguineous) surgical technique, and acceptance of minimum hemoglobin levels during the entire hospitalization. The incidence of homologous blood transfusions will be reduced using acute isovolemic hemodilution. This incidence will be further reduced once hemoglobin solutions become clinically available for specific indications. At present, research activities are concentrated on defining the critical level of hemodilution in various pathologic conditions and to investigate pharmacology and physiology of the new hemoglobin solutions. Finally, several chemically modified hemoglobin-based oxygen-carrying solutions devoid of renal toxicity will be available in the future. The cardiovascular physiology and pharmacology of these hemoglobin solutions have been studied. Cardiac output is generally constant and oxygen extraction is increased to maintain oxygen consumption during hemodilution with hemoglobin solutions. In most studies, some vasoconstriction was observed also, which might result from interaction of the hemoglobin molecule with the EDRF/NO system. However, with enhanced purification, chemical modification or microencapsulation of the hemoglobin molecule, vasoconstriction can be limited.
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We sought to determine the actual cost to Duke University Medical Center of a perioperative red blood cell transfusion. A recent audit at Duke University Medical Center determined the base average direct and indirect hospital costs for providing a unit of red blood cells. The Transfusion Service's base cost for providing an allogeneic unit of red blood cells was $113.58. To obtain the actual hospital cost of transfusing a unit of red blood cells in the perioperative period, associated costs were calculated and added to the Transfusion Service's base cost. These associated costs included compatibility tests on multiple units per each unit transfused in the perioperative period, performing ABO and Rh typing and antibody screening on samples from patients who were not subsequently transfused, compatibility tests on units not issued, handling costs of units issued but not used, physically administering the blood, and the cost of the recipient contracting an infectious disease or developing a transfusion reaction. These associated costs increased the cost of transfusing an allogeneic unit of red blood cells in the perioperative period to $151.20. Perhaps the techniques described in the study can be used to quantify cost/benefit ratios associated with future changes in transfusion practice.
Esmolol hydrochloride was administered by constant-rate continuous infusion to 10 patients undergoing hypothermic cardiopulmonary bypass for coronary artery revascularization surgery. After a suitable loading dose, the esmolol infusion was started approximately 30 minutes before bypass and was stopped 10 minutes after termination of bypass. Esmolol concentrations were measured in arterial and venous blood samples collected before and after bypass and in samples taken from the inflow and outflow ports of the membrane oxygenator during bypass. Blood esmolol concentrations increased during hypothermia in a manner that correlated significantly and inversely with temperature. All patients were separated from the extracorporeal circulation without difficulty, and the average arterial esmolol concentration was slightly below the prebypass concentration within minutes of discontinuing bypass. Esmolol disappeared from the blood rapidly on terminating the infusion. There was no difference between esmolol concentrations measured simultaneously from the inflow and outflow ports of the membrane oxygenator during bypass, but radial arterial esmolol concentrations before and after bypass were on average about sevenfold higher than forearm venous esmolol concentrations during the esmolol infusion. The results of this study lead to two important conclusions: (1) in vivo clearance of esmolol demonstrates acute temperature dependence and (2) esmolol is removed irreversibly as it passes through the microcirculation of the hand, making measurement of peripheral esmolol concentrations markedly dependent on sampling site (arterial versus venous).
The effects of reduced pump flow rate (PFR) on cerebral blood flow, cerebral oxygen consumption (CMRO2), oxygen extraction, cerebral vascular resistance, and total body vascular resistance were examined in 27 pediatric patients during hypothermic cardiopulmonary bypass (hCPB). During steady state hCPB the extracorporeal flows were randomly adjusted to a conventional PFR and a reduced PFR for each patient. The reduced pump flow rates were dictated by surgical needs. Cerebral blood flow measured using Xenon 133 clearance, and CMRO2 and oxygen extraction were calculated. Our results demonstrated that cerebral blood flow and CMRO2 are unchanged if pump flow rates are reduced by 35% to 45% of conventional PFRs at moderate and deep hypothermic temperatures. Reductions in PFR of 45%-70% from conventional PFRs affect the brain differently during either moderate or deep hCPB. At moderate hCPB (26 degrees to 29 degrees C), reductions in PFRs of 45% to 70% resulted in a significant decrease in cerebral blood flow and CMRO2, whereas oxygen extraction increased in a compensatory manner. During deep hCPB (18 degrees to 22 degrees C), PFR reductions of 45% to 70% of conventional PFR significantly reduced cerebral blood flow and CMRO2 but did not increase oxygen extraction, suggesting that at deep hypothermic temperatures, cerebral blood flow and CMRO2 exceed cerebral metabolic needs. Cerebral vascular resistance increased significantly with decreasing temperature but was not affected by pump flow reductions. We have derived indices for minimal acceptable low-flow cardiopulmonary bypass based on the known effects of temperature on cerebral metabolism and have speculated on its utility based on our limited data and a literature review.
Continuous infusion of intravenous anesthetics can be achieved either by a manually controlled infusion (MCI) pump, or by a computer-assisted continuous infusion (CACI) pharmacokinetic model-driven infusion system. Randomized double-blind comparisons of the two infusion systems for general anesthesia were performed in 24 patients undergoing coronary artery bypass grafting. Patients were allocated to receive continuous infusions of midazolam and fentanyl by either a MCI device or CACI. Midazolam and fentanyl infusions were independently titrated to maintain hemodynamic stability, defined as mean arterial pressure (MAP) and heart rate (HR) within 20% of baseline values. As directed by the study design, comparable hemodynamic control was achieved in both groups. Mean plasma fentanyl concentrations measured at specific timepoints were similar between groups. The plasma midazolam level for induction was 196 +/- 139 ng/mL in the CACI group and 300 +/- 128 ng/mL in the MCI group, and the fentanyl level was similar in both groups, 6.7 +/- 1.9 ng/mL in CACI and 6.3 +/- 4.6 ng/mL in the MCI group. The drug levels were lower (P < or = .05) for midazolam during maintenance of anesthesia and similar for fentanyl during the maintenance of anesthesia. In the MCI group, the average duration of anesthesia was 246.5 +/- 35.0 minutes, with a mean total fentanyl dose of 30.27 +/- 11.14 micrograms/kg. In the CACI group, the average duration of anesthesia was 230.8 +/- 44.1 minutes, with a mean total fentanyl dose of 34.61 +/- 5.40 micrograms/kg (P > 0.05 for comparisons between groups for duration of anesthesia and total fentanyl dose).(ABSTRACT TRUNCATED AT 250 WORDS)
Having examined the options for adjuvant drug use during cardiac anesthesia, it becomes increasingly apparent that midazolam is "the drug" of choice and that supplementation with an opioid is an ideal adjuvant. In the hands of experienced cardiac anesthesiologists, the majority of the drugs discussed could provide adequate anesthesia with outcomes that would be difficult to distinguish, with the exception of awakening and time to extubation. Regardless of the inability to differentiate overall outcome, when comparing ease of providing complete "balanced" anesthesia, minimal cost increase, ease of use, hemodynamic stability, reliability of amnesia and ability to decrease narcotic requirement and allow early extubation, midazolam is a clear winner. Given as a continuous infusion or a bolus, potent opioids such as alfentanil, fentanyl or sufentanil enhance the amnestic and hypnotic effect of midazolam, decreasing the required dose. In addition, the combination of midazolam and narcotics decreases the catecholamine response that either one alone would produce. This removes the necessity of marked narcotic overdose required when narcotics alone are used. The result of this anesthetic combination is a technique that can be used in the majority of cardiac patients regardless of their ventricular performance, allowing options for earlier awakening, earlier extubation and decreased ICU stay. The goal of complete "balanced" anesthesia is best achieved with continuous infusions of midazolam and opioids. Accepting recall of intraoperative events as a necessary evil is unacceptable in the stable cardiac surgery patient.(ABSTRACT TRUNCATED AT 250 WORDS)
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Although much has been learned about cerebral physiology during CPB in the past decade, the role of alterations in CBF and CMRO2 during CPB and the unfortunately common occurrence of neuropsychologic injury still is understood incompletely. It is apparent that during CPB temperature, anesthetic depth, CMRO2, and PaCO2 are the major factors that effect CBF. The systemic pressure, pump flow, and flow character (pulsatile versus nonpulsatile) have little influence on CBF within the bounds of usual clinical practice. Although cerebral autoregulation is characteristically preserved during CPB, untreated hypertension, profound hypothermia, pH-stat blood gas management, diabetes, and certain neurologic disorders may impair this important link between cerebral blood flow nutrient supply and metabolic demand (Figure 5). During stable moderate hypothermic CPB with alpha-stat management of arterial blood gases, hypothermia is the most important factor altering cerebral metabolic parameters. Autoregulation is intact and CBF follows cerebral metabolism. Despite wide variations in perfusion flow and systemic arterial pressure, CBF is unchanged. Populations of patients have been identified with altered cerebral autoregulation. To what degree the impairment of cerebral autoregulation contributes to postoperative neuropsychologic dysfunction is unknown. It must be emphasized that not the absolute level of CBF, but the appropriateness of oxygen delivery to demand is paramount. However, the assumption that the control of cerebral oxygen and nutrient supply and demand will prevent neurologic injury during CPB is simplistic. A better understanding of CBF, CMRO2, autoregulation and mechanism(s) of cerebral injury during CPB has lead to a scientific basis for many of the decisions made regarding extracorporeal perfusion.