Richard I. Hall

The systemic inflammatory response to cardiopulmonary bypass: pathophysiological, therapeutic, and pharmacological considerations.

C ardiac surgery and cardiopulmonary bypass (CPB) activate a systemic inflammatory response characterized clinically by alterations in cardiovascular and pulmonary function. Significant morbidity is rare (approximately l%-2% of cases), but when severe acute lung injury occurs, mortality is high (50%-70%) (1). H owever, most patients undergoing CPB experience some degree of organ dysfunction as a result of activation of the inflammatory response. The purpose of this review is to examine the recent developments in our understanding of the pathophysiological mechanisms responsible for this response, the treatment modalities that have been used to ameliorate it, and the possible implications of these findings for the conduct of anesthesia for cardiac surgery.

Antiplatelet drugs: a review of their pharmacology and management in the perioperative period.

In the normal course of the delivery of care, anesthesiologists encounter many patients who are receiving drugs that affect platelet function as a fundamental part of primary and secondary management of atherosclerotic thrombotic disease. There are several antiplatelet drugs available for use in clinical practice and several under investigation. Aspirin and clopidogrel (alone and in combination) have been the most studied and have the most favorable risk-benefit profiles of drugs currently available. Prasugrel was recently approved for patients with acute coronary syndrome undergoing percutaneous interventions. Other drugs such as dipyridamole and cilostazol have not been as extensively investigated. There are several newer investigational drugs such as cangrelor and ticagrelor, but whether they confer significant additional benefits remains to be established. Management of patients who are receiving antiplatelet drugs during the perioperative period requires an understanding of the underlying pathology and rationale for their administration, pharmacology and pharmacokinetics, and drug interactions. Furthermore, the risk and benefit assessment of discontinuing or continuing these drugs should be made bearing in mind the proposed surgery and its inherent risk for bleeding complications as well as decisions relating to appropriate use of general or some form of regional anesthesia. In general, the safest approach to prevent thrombosis seems to be continuation of these drugs throughout the perioperative period except where concerns about perioperative bleeding outweigh those associated with the development of thrombotic occlusion. Knowledge of the pharmacodynamics and pharmacokinetics of antiplatelet drugs may allow practitioners to anticipate difficulties associated with drug withdrawal and administration in the perioperative period including the potential for drug interactions.

The enflurane sparing effect of sufentanil in dogs.

There is a ceiling to the reduction of enflurane MAC by fentanyl in the dog. Sufentanil (SUF), a more potent narcotic, may be more efficacious in reducing enflurane MAC. To test this hypothesis, 25 mongrel dogs were studied in three groups. Group 1 (n = 8) received SUF in progressively increasing infusion rates from 0.005 μg · kg-1 · min-1 to a maximum of 1.215 μg · kg-1 · min-1. MAC was determined at stable SUF concentrations in plasma [SUF] during each infusion rate. Group 2 (n = 10) received SUF at a dose rate (0.007 μg · kg-1 · min-1) designed to produce approximately 35% MAC reduction, and MAC determinations were made at regular intervals over a mean infusion time of 7.6 ± 0.43 h (mean ± SEM). Group 3 (n = 7) received 1.215 μg · kg-1 · min-1 and were studied as in group 2 over an infusion time of 6.7 ± 0.42 h. In group 1, the highest infusion rate (1.215 μg · kg-1 · min-1) produced [SUF] = 48 ng/nil and reduced MAC by 71 ± 6%. This was not statistically different from the reduction which occurred at [SUF] = 0.92 ng/ml (57 ± 7%; infusion rate 0.015 μg · kg-1 · min-1; P = 0.21). In group 2, the degree of MAC reduction achieved by stable [SUF] (0.54 ± 0.08 ng/ml) declined over time (MAC reduction at start = 34 ± 2% versus 18 ± 4.0% at the end of the infusion; P = 0.001), suggesting the development of tolerance. In group 3 (1.215 μg · kg-1 · min-1), there was no statistically significant difference demonstrated between the degree of MAC reduction at the beginning versus the end of the infusion. The maximum reduction achieved by an infusion of 1.215 μg · kg-1 · min-1 (group 3) for nearly 7 h did not differ from that achieved with a series of progressively increasing infusion rates up to 1.215 μg · kg-1 · min-1 (group 1—70.5% reduction at [SUF] = 48 versus group 3—78% at 41 ng/ml). The authors conclude that there was a ceiling of approximately 70% reduction of enflurane MAC by SUF in the dog. This reduction was independent of the dose-rate at which it was achieved. At plasma concentrations below those producing a maximum reduction of MAC, acute tolerance was evident.

Sedation for Critically Ill or Injured Adults in the Intensive Care Unit

As most critically ill or injured patients will require some degree of sedation, the goal of this paper was to comprehensively review the literature associated with use of sedative agents in the intensive care unit (ICU). The first and selected latter portions of this article present a narrative overview of the shifting paradigm in ICU sedation practices, indications for uninterrupted or prolonged ICU sedation, and the pharmacology of sedative agents. In the second portion, we conducted a structured, although not entirely systematic, review of the available evidence associated with use of alternative sedative agents in critically ill or injured adults. Data sources for this review were derived by searching OVID MEDLINE and PubMed from their first available date until May 2012 for relevant randomized controlled trials (RCTs), systematic reviews and/or meta-analyses and economic evaluations.Advances in the technology of mechanical ventilation have permitted clinicians to limit the use of sedation among the critically ill through daily sedative interruptions or other means. These practices have been reported to result in improved mortality, a decreased length of ICU and hospital stay and a lower risk of drug-associated delirium. However, in some cases, prolonged or uninterrupted sedation may still be indicated, such as when patients develop intracranial hypertension following traumatic brain injury. The pharmacokinetics of sedative agents have clinical importance and may be altered by critical illness or injury, co-morbid conditions and/or drug-drug interactions. Although use of validated sedation scales to monitor depth of sedation is likely to reduce adverse events, they have no utility for patients receiving neuromuscular receptor blocking agents. Depth of sedation monitoring devices such as the Bispectral Index (BIS©) also have limitations.Among existing RCTs, no sedative agent has been reported to improve the risk of mortality among the critically ill or injured. Moreover, although propofol may be associated with a shorter time to tracheal extubation and recovery from sedation than midazolam, the risk of hypertriglyceridaemia and hypotension is higher with propofol. Despite dexmedetomidine being linked with a lower risk of drug-associated delirium than alternative sedative agents, this drug increases risk of bradycardia and hypotension. Among adults with severe traumatic brain injury, there are insufficient data to suggest that any single sedative agent decreases the risk of subsequent poor neurological outcomes or mortality. The lack of examination of confounders, including the type of healthcare system in which the investigation was conducted, is a major limitation of existing pharmacoeconomic analyses, which likely limits generalizability of their results.

Less than additive antinociceptive interaction between midazolam and fentanyl in enflurane-anesthetized dogs

The anesthetic interactions of midazolam and fentanyl were determined in terms of enflurane MAC reduction in dogs. In part 1, 8 animals received an intravenous (iv) loading dose of fentanyl followed by a constant infusion at 0.05 micrograms.kg-1.min-1 to produce a stable enflurane MAC reduction of approximately 20%. Midazolam was then administered in a series of three incremental loading doses and infusions (2.4, 9.6, and 28.8 micrograms.kg-1.min-1 previously determined to produce enflurane MAC reductions of approximately 30, 45, and 60%, respectively. Enflurane MAC was determined for each infusion. Then fentanyl was discontinued; naloxone 1 mg/kg was administered; and enflurane MAC was determined. In part 2, six dogs received a loading dose and a continuous infusion of fentanyl (0.2 micrograms.kg-1.min-1) designed to produce a stable enflurane MAC reduction of approximately 40%. A series of two incremental loading doses and infusions of midazolam (2.4 and 28.8 micrograms.kg-1.min-1) were added, and MAC determinations were repeated at each infusion rate. Then midazolam was discontinued; flumazenil (RO 15-1788) 1.5 mg/kg was administered; and enflurane MAC was determined. The fentanyl concentrations in plasma remained stable at 1.0 +/- 0.3 ng/ml (mean +/- standard deviation [SD], part 1) and 3.1 +/- 0.5 ng/ml (part 2) throughout the study and, in the absence of midazolam, reduced enflurane MAC by 28 +/- 11 and 44 +/- 5%, respectively. The addition of midazolam produced significant further reductions in enflurane MAC, but the reductions were less than those predicted on the basis of an additive interaction. Naloxone returned enflurane MAC reduction to that expected for midazolam alone (part 1).(ABSTRACT TRUNCATED AT 250 WORDS)

The Enflurane-sparing Effect of Alfentanil in Dogs

Some investigators believe that the dog is less sensitive than are humans to the anesthetic/analgesic actions of opioids. The alfentanil plasma concentration [ALF] vs anesthetic effect relationship has been determined for humans undergoing surgery. This study was designed to determine the [ALF] vs anesthetic relationship for alfentanil in the enflurane-anesthetized dog and thereby to provide data by which the [ALF] vs anesthetic effect relationships in the dog and in humans could be compared. Mongrel dogs (n = 10) were anesthetized with enflurane, and enflurane MAC (EMAC) was determined in each dog. After this, each dog received at least three incremental infusions of alfentanil using infusion rates of 0.625, 1.6, 8, 32, or 80 μg·kg−1·min−1. EMAC and [ALF] were determined during each infusion rate. There was a linear increase in [ALF] produced by incremental infusions of alfentanil (r = 0.999). Administration of alfentanil produced a dose-dependent reduction of EMAC up to a maximum of 72.5 ± 3.7% (mean ± sem) at 32 μg·kg−1·min−1 ([ALF] = 960 ± 86 ng/ml); a ceiling effect was evident. The degree of EMAC reduction (69%) produced by an infusion rate of 8 μg·kg−1·min−1 ([ALF] = 223 ± 13 ng/ml) was not statistically different from the EMAC reductions produced by infusion rates of 32 (73% reduction at [ALF] = 960 ± 86 ng/ml) or 80μg·kg−1·min−1 (70% reduction at [ALF] = 2613 ± 247 ng/ml) (P > 0.05). The relative potency of alfentanil was one-seventh to one-tenth that of fentanyl studied under identical conditions. The [ALF] producing maximal EMAC reduction in the enflurane anesthetized dog in response to a tail-clamp stimulus (223 ng/ml) was similar to the [ALF] required to provide adequate anesthesia of patients for skin incision in the presence of nitrous oxide (mean plasma concentration required to prevent response to skin incision, 279 ± 20 ng/ml; 95% confidence interval, 238–320 ng/ml). It is concluded that alfentanil, in common with other μ-receptor agonists, is capable of reducing enflurane MAC by only 70% in dogs. The anesthetic efficacy of alfentanil in humans and in the dog appears to be similar.

The Anesthetic Efficacy of Midazolam in the Enflurane-anesthetized Dog

This study determined the anesthetic efficacy of midazolam (MID) in terms of its ability to reduce enflurane MAC (EMAC). Control EMAC was determined by the tail-clamp method in 15 mongrel dogs. Each animal then received at least three incremental infusion rates of MID from among the following: 0.48, 2.4, 9,6, 19.2, 28.8, 48, or 151.2 μg · kg−1 · min−1. MAC was determined during each infusion rate following a 1-h observation period, during which time MID concentration in plasma ([MID]) stabilized. [MID] was measured every 15 min beginning 45 min from the start of each new infusion rate. There was a linear relationship between MID infusion rates and the resulting [MID] (r = 0.995). In the range of [MID] from 14 to 14,118 ng/ml, there was a linear relationship between the log [MID] and the percent EMAC reduction. The slope of the line was very shallow, and the [MID] required to reduce EMAC by more than 50% exceeded the [MID] likely to be employed clinically in humans (750 ng/ml). Also, the 73 ± 4% (mean ± SEM) EMAC reduction produced by [MID] = 9,763 ± 1213 ng/ml was not significantly greater than the 60 ± 3% EMAC reduction achieved by [MID] = 1,464 ± 293 ng/ml, a finding which suggests a ceiling effect to the anesthetic efficacy of midazolam. The authors conclude that, within the dose range of MID likely to be employed in humans, MID produced a concentration-dependent reduction of enflurane MAC in the dog. In doses above those likely to be employed clinically, a ceiling effect to the anesthetic efficacy of MID may become evident.

Identification of Inflammatory Mediators and Their Modulation by Strategies for the Management of the Systemic Inflammatory Response During Cardiac Surgery

b v THE SYSTEMIC INFLAMMATORY RESPONSE (manifested by pyrexia, leukocytosis, tachycardia, hypotension, issue fluid accumulation, and organ failure) is generated during ardiac surgery because of processes such as ischemia-reperfusion njury, gut ischemia, and contact activation of cells by the extraorporeal circuit (Fig 1).1-3 The release of inflammatory mediators, ncluding the proinflammatory cytokines interleukin (IL) 64 and umor necrosis factor (TNF),5,6 subsequent modulation f effects by various anti-inflammatory cytokines,7,8 and activation of monocytes/neutrophils/tissue macrophages ensues.1,2,9-12 Subsequently, endothelial cell activation occurs, ith the expression of adhesion molecules on the endothelial ell surface13,14 leading to the adhesion of white blood cells to the endothelium, diapedesis, and the release of intracellular granule contents causing further amplification of the inflammatory process.2,15 There are increased endothelial cell permeability and dysfunction of the microcirculation,16 coagulopahy,17-19 the generation of oxygen free radicals,20 and alterations in regulatory protein function21 including the function of transport proteins.22,23 Depending on the magnitude of the response, here may be alterations in immunologic function24,25 and tissue injury leading to organ failure and death.26-50 Despite the foreoing, although the inflammatory response has been measured n all patients undergoing cardiac surgery in which it has been xamined, there is tremendous variability in this response from ne patient to another, and it must be emphasized that the vast ajority of patients have an uncomplicated course, making the mpact of inflammation on the outcome uncertain. Many meiators have been identified as contributing to the inflammatory esponse, and a variety of approaches have been explored to meliorate it.51 However, a comprehensive compilation of inammatory mediators released during cardiac surgery and hose involved in intervention-driven therapies to ameliorate he inflammatory response and the development of subsequent rgan dysfunction has not been reviewed recently. This review xamines the identification of inflammatory mediators and the pproaches used to modify their effect on the development of he inflammatory response to cardiac surgery. It enlarges on the nformation provided in previous reviews of the topic.1,2,9,52-59

Economic evaluation of propofol for sedation of patients admitted to intensive care units.

Background The goal of the current study was to evaluate the economic impact of propofol as compared with midazolam for sedating patients in the intensive care unit (ICU). Methods A randomized, unblinded, multicenter pharmacoeconomic trial captured health resource utilization and outcome measurements associated with sedation and treatment of patients in four ICUs across Canada. Statistical analysis was performed to investigate the difference in sedation quality, ICU length of stay, and other health resources used. The authors compared the costs (1997 Canadian dollars) associated with the two treatments. Two types of sensitivity analyses were performed. Results Although overall sedation duration was similar, propofol patients spent more time at adequately sedated status (60.2%vs. 44%;P = 0.01) and were extubated faster (median extubation time, 2.5 vs. 7.1 h;P = 0.001). The ICU length of stay and health resource utilization did not differ. The total cost per patient, including drug cost and ICU stay cost, did not differ between groups (median,

The Use of Tegaserod in Critically ill Patients with Impaired Gastric Motility

5,718 for propofol vs.