This paper will concentrate on the pharmacokinetics and pharmacodynamics of thiopental. As applied here, pharmacokinetics is the study of the concentration of thiopental as a function of time in tissues (particularly brain), while pharmacodynamics is the study of the effects of thiopental (particularly the production of unconsciousness and impairment of the heart’s ability to circulate blood). By using generally accepted computer modeling techniques, and considering the wealth of published studies on the pharmacology of thiopental, we can prepare predictions of such relevant parameters as the onset (how long it takes for the inmate to become unconscious) and duration (how long the inmate would remain unconscious) of the pharmacological effects of thiopental.

BACKGROUND: Safety climate is often measured via surveys to identify appropriate patient safety interventions. The introduction of an insurance premium incentive for simulation-based anesthesia crisis resource management (CRM) training motivated our naturalistic experiment to compare the safety climates of several departments and to assess the impact of the training. METHODS: We administered a 59-item survey to anesthesia providers in six academic anesthesia programs (Phase 1). Faculty in four of the programs subsequently participated in a CRM program using simulation. The survey was readministered 3 yr later (Phase 2). Factor analysis was used to create scales regarding common safety themes. Positive safety climate (% of respondents with positive safety attitudes) was computed for the scales to indicate the safety climate levels. RESULTS: The usable response rate was 44% (309/708) and 38% (293/772) in Phases 1 and 2 respectively. There was wide variation in response rates among hospitals and providers. Eight scales were identified. There were significantly different climate scores among hospitals but no difference between the trained and untrained cohorts. The positive safety climate scores varied from 6% to 94% on specific survey questions. Faculty and residents had significantly different perceptions of the degree to which residents are debriefed about their difficult clinical situations. CONCLUSIONS: Safety climate indicators can vary substantially among anesthesia practice groups. Scale scores and responses to specific questions can suggest practices for improvement. Overall safety climate is probably not a good criterion for assessing the impact of simulation-based CRM training. Training alone was insufficient to alter engrained behaviors in the absence of further reinforcing actions.

As of this writing, anesthesiologists have been living with the “black box” warning (or the “boxed warning” in FDA parlance) for droperidol for over two years. The response by clinicians and institutions has ranged from little change in practice (as in my own institution) to complete removal from the formulary. Clinicians who have described in letters to the editor or public lectures abandoning droperidol usually give as the reason their concerns about the liability of continuing to use a drug with a boxed warning. In addition, these writers and speakers (including myself) have castigated the FDA for taking too drastic an action without adequate supporting data. It is clear to me that, although the FDA was successful in informing anesthesiologists about the change in the droperidol label, including the boxed warning, they were quite unsuccessful in explaining why they took the action they did. For example, it was not until November 18, 2003 that the FDA held a meeting with anesthesiologists to discuss droperidol safety. At this meeting of the Anesthetic and Life Support Drugs Advisory Committee, one of the Human Drug Advisory Committees within the Center for Drug Evaluation and Research, the attendees were charged by the FDA with recommending what was currently known about the safety of droperidol and what studies should be done to remedy the gaps in knowledge. The minutes and transcript of this meeting are major sources for this article.

In December 2001, the United States Food and Drug Administration (FDA) added a "black box" warning to the labeling for droperidol stating that all doses, even those typically used for postoperative nausea and vomiting, were potentially associated with malignant ventricular dysrhythmias, including torsade de pointes. The 19 cases in which droperidol doses less than 10 mg were allegedly associated with such dysrhythmias are reviewed in detail. Confounding issues present in a majority of the cases make it difficult to incriminate droperidol as the likely cause of the reported adverse events.

STUDY OBJECTIVE: To compare the frequency and duration of postoperative nausea and vomiting (PONV) following total intravenous anesthesia (TIVA) with propofol and either remifentanil or alfentanil in outpatients undergoing arthroscopic surgery of the extremities. DESIGN: Randomized, third-party blinded study. SETTING: University medical center. PATIENTS: 100 ASA physical status I and II patients scheduled for arthroscopic surgery of the knee or shoulder. INTERVENTIONS: The anesthesia regimen consisted of a bolus followed by continuous infusion of propofol (2 mg/kg followed by 120 microg/kg/min) and the opioid (remifentanil 0.5 microg/kg followed by 0.1 microg/kg/min or alfentanil 10 microg/kg followed by 0.25 microg/kg/min). Patients breathed 100% oxygen spontaneously through a Laryngeal Mask Airway (or an endotracheal tube when medically indicated). Opioids were titrated to maintain blood pressure and heart rate within 20% of baseline and a respiratory rate of 10 to 16 breaths/min. Propofol was titrated downward as low as possible without permitting patient movement. MEASUREMENTS: Nausea was determined by an 11-point categorical scale and was recorded before surgery and multiple time points thereafter. The times of emetic episodes were recorded. Treatment of PONV was at the discretion of the postanesthesia care unit (PACU) nurses who were blinded to the identity of the opioid used. MAIN RESULTS: Nausea scores were 0 at all time points in over 70% of the patients in each group. None of the 100 patients vomited while in the hospital, and only one patient required antiemetic therapy. CONCLUSION: When propofol-based TIVA is used for arthroscopic surgery, short-acting opioids do not significantly affect the risk of PONV.

BACKGROUND: A new pulmonary drug delivery system produces aerosols from disposable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intravenous morphine. METHODS: Fifteen healthy volunteers were enrolled. Two subjects were administered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 mg over 3 min by intravenous infusion. Thirteen subjects were given twice the above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration and at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after administration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge. Pharmacokinetic and pharmacodynamic analyses were performed simultaneously using mixed-effect models. RESULTS: The pharmacokinetic data after intravenous administration were described by a three-exponent decay model preceded by a lag time. The pharmacokinetic model for administration by inhalation consisted of the three-exponent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the total bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the half-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P < 0.01). The pharmacodynamic parameter ke0 was approximately 0.003 min-1. CONCLUSIONS: The onset and duration of the effects of morphine are similar after intravenous administration or inhalation via this new pulmonary drug delivery system. Morphine bioavailability after such administration is 59% of the dose loaded into the dosage form.