Legal and ethical implications of defining an optimum means of achieving unconsciousness in assisted dying.

A decision by a society to sanction assisted dying in any form should logically go hand-in-hand with defining the acceptable method(s). Assisted dying is legal in several countries and we have reviewed the methods commonly used, contrasting these with an analysis of capital punishment in the USA. We expected that, since a common humane aim is to achieve unconsciousness at the point of death, which then occurs rapidly without pain or distress, there might be a single technique being used. However, the considerable heterogeneity in methods suggests that an optimum method of achieving unconsciousness remains undefined. In voluntary assisted dying (in some US states and European countries), the common method to induce unconsciousness appears to be self-administered barbiturate ingestion, with death resulting slowly from asphyxia due to cardiorespiratory depression. Physician-administered injections (a combination of general anaesthetic and neuromuscular blockade) are an option in Dutch guidelines. Hypoxic methods involving helium rebreathing have also been reported. The method of capital punishment (USA) resembles the Dutch injection technique, but specific drugs, doses and monitoring employed vary. However, for all these forms of assisted dying, there appears to be a relatively high incidence of vomiting (up to 10%), prolongation of death (up to 7 days), and re-awakening from coma (up to 4%), constituting failure of unconsciousness. This raises a concern that some deaths may be inhumane, and we have used lessons from the most recent studies of accidental awareness during anaesthesia to describe an optimal means that could better achieve unconsciousness. We found that the very act of defining an 'optimum' itself has important implications for ethics and the law.

IL-4 mediated by HSV vector suppresses morphine withdrawal response and decreases TNFα, NR2B, and pC/EBPß in the periaqueductal gray in rats.

Chronic opiates induce the development of physical dependence. Opioid physical dependence characterized by withdrawal symptoms, may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. Elucidation of the mechanisms involved in physical dependence is crucial to developing more effective treatment strategies for opioid dependence. Chronic morphine induces production of proinflammatory cytokines in regional-specific sites of the brain. Interleukin-4 (IL-4) is a prototypical anti-inflammatory cytokine that globally suppresses proinflammatory cytokines. Here, we used recombinant herpes simplex virus vector S4IL4 that encode mouse il4 gene to evaluate the therapeutic potential of IL-4 in naloxone-precipitation morphine withdrawal (MW). One week after microinjection of the vector S4IL4 into the PAG LacZ or mouse IL-4 immunoreactivity in the vlPAG was visualized. ELISA assay showed that vector S4IL4 into the PAG induced the expression of IL-4. S4IL4 blunted the morphine withdrawal syndrome. S4IL4 suppressed the upregulated TNFα, NR2B and pC/EBPß in the PAG induced by MW. These results show that inhibition of proinflammatory factor in the PAG suppressed MW. This study may provide a novel therapeutic approach to morphine physical withdrawal symptoms.

HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a.

Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may have an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of the isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that (1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, (2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, (3) HSV vectors expressing GAD67 reversed the lowered GABA-IR expression and (4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain.

HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity.

Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite extensive research, the detailed neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. In this study, we investigated the role of proinflammatory molecules, tumor necrosis factor-α (TNFα), CXCR4 and stromal-derived factor-1 α (SDF1α), in the L4/5 dorsal root ganglia (DRG) and the spinal dorsal horn in HIV gp120 protein-mediated neuropathic pain. Our results showed that the application of HIV gp120 to the sciatic nerve induced upregulation of TNFα, CXCR4 and SDF1α in both the DRG and the lumbar spinal dorsal horn. Non-replicating herpes simplex virus (HSV) vector encoding the p55TNFSR gene and producing a TNF-soluble receptor (TNFSR) to block bioactivity of TNFα reversed mechanical allodynia. Intrathecal AMD3100 (CXCR4 antagonist) increased mechanical threshold. The HSV vectors expressing p55TNFSR reversed upregulation of TNFα, CXCR4 and SDF1α induced by gp120 in the DRG and the spinal dorsal horn. These studies suggest that proinflammatory TNFα to the CXCR4/SDF1 pathway has an important role in the HIV-related neuropathic pain state and that blocking the proinflammatory cytokines or chemokines is able to reduce neuropathic pain. This work provides a novel gene therapy proof-of-concept for HIV-associated neuropathic pain.

Hospitals with briefer than average lengths of stays for common surgical procedures do not have greater odds of either re-admission or use of short-term care facilities.

We considered whether senior hospital managers and department chairs need to be concerned that small reductions in average hospital length of stay (LOS) may be associated with greater rates of re-admission, use of home health care, and/or transfers to short-term care facilities. The 2013 United States Nationwide Readmissions Database was used to study surgical Diagnosis Related Groups (DRG) with 1) national median LOS ≥3 days and 2) ≥10 hospitals in the database that each had ≥100 discharges for the DRG. Dependent variables were considered individually: 1) re-admission within 30 days of discharge, 2) discharge disposition to home health care, and/or 3) discharge disposition of transfer to short-term care facility (i.e., inpatient rehabilitation hospital or skilled nursing facility). While controlling for DRG, each one-day decrease in hospital median LOS was associated with an odds of re-admission nationwide of 0.95 (95% confidence interval [CI] 0.92-0.99; P=0.012), odds of disposition upon discharge being home care of 0.95 (95% CI 0.83-1.10; P=0.64), and odds of transfer to short-term care facility of 0.68 (95% CI 0.54-0.85; P=0.0008). Results were insensitive to the addition of patient-specific data. In the USA, patients at hospitals with briefer median LOS across multiple common surgical procedures did not have a greater risk for either hospital re-admission within 30 days of discharge or transfer to an inpatient rehabilitation hospital or a skilled nursing facility. The generalisable implication is that, across many surgical procedures, DRG-based financial incentives to shorten hospital stays seem not to influence post-acute care decisions.

Comparison of systemic oxygen delivery and uptake with NIR spectroscopy of brain during normovolemic hemodilution in the rabbit.

Incremental hyperoxic normovolemic hemodilution was utilized to progressively decrease oxygen delivery (DO2) in anesthetized rabbits. At decreasing DO2, we compared systemic responses related to the adequacy of DO2, i.e. mixed venous oxygen saturation (SvO2), oxygen consumption (VO2), and arterial lactate concentrations, to near infrared spectroscopy (NIRS) of the brain, a regional measure of intracellular oxygen availability. We sought concomitantly to define critical SvO2 and DO2, beyond which whole body VO2 begins to decline and arterial lactate concentrations increase. NIR Spectroscopy provided the means to test the hypothesis that systemic indicators of inadequate DO2 would not accurately reflect the oxygenation of a critical organ such as the brain. In thirteen rabbits anesthetized with fentanyl, paralyzed and artificially ventilated at an FIO2 of 0.60, hemodilution produced an early decrease in mixed venous oxygen saturation. When mixed venous oxygen saturation decreased below approximately 50%, arterial lactate concentrations began to increase significantly. Further decreases in oxygen delivery precipitated a decline in systemic VO2. Finally, NIRS revealed an increase in the reduction level of brain cytochrome a,a3 after systemic parameters of oxygen delivery had been altered. Analysis of the data indicated that falling SvO2 predicted inadequate DO2 to tissue during early hemodilution under narcotic/relaxant anesthesia and that the brain showed evidence of intracellular hypoxia only after systemic parameters such as SvO2 were affected markedly.

Using Medicare multiples results in disproportionate reimbursement for anesthesiologists compared to other physicians.

Multispecialty groups and insurer fee schedules computed as a multiple of the Medicare reimbursement rate have resulted in a severely low reimbursement rate for anesthesia compared to other specialties. The authors suggest that anesthesiologists negotiate for a discount from the usual and customary fee equal to what the other specialties have been asked to bear.

Anesthetic care of a patient with an intracranial hemorrhage after thrombolytic therapy.

Thrombolytic therapy is being used with increasing frequency to treat acute myocardial infarction (MI). It is important for both the general and cardiac anesthesiologist to understand the effects of thrombolysis on hemostasis and myocardial function, since these patients can present for emergent surgery in the cardiac or general operating theater. The authors report a case of a patient who developed an intracranial hemorrhage following thrombolytic therapy that required emergency surgical intervention.

Secondary polycythemia does not increase the risk of perioperative hemorrhagic or thrombotic complications.

STUDY OBJECTIVE: To determine the effects of secondary polycythemia on perioperative hemorrhagic and thrombotic complications. DESIGN: Retrospective chart review. SETTING: Surgical patients at a university-affiliated Veterans Administration Hospital. PATIENTS: One hundred patients with a diagnosis of chronic obstructive pulmonary disease and a preoperative hemoglobin concentration (Hb) greater than 16 g/dl and 100 age-, sex-, operation-, and ASA physical status-matched control patients without secondary polycythemia having operations during January to June 1988. MEASUREMENTS AND MAIN RESULTS: Anesthetic and perioperative records were retrospectively analyzed for excessive bleeding and transfusion requirements. Charts also were retrospectively analyzed for the presence of hemorrhagic and thrombotic complications for 30 days following surgery. The secondary polycythemic patients were compared with the matched control group and did not have a higher frequency of these complications. Red blood cell transfusion requirements for patients with secondary polycythemia were less than that for the matched controls (p less than 0.005). There was no statistical difference for transfusions of other types of blood products such as platelets and fresh frozen plasma (FFP). CONCLUSION: Secondary polycythemia does not impart any added perioperative risk.

Relying solely on historical surgical times to estimate accurately future surgical times is unlikely to reduce the average length of time cases finish late.

STUDY OBJECTIVE: To determine whether using only previous cases' surgical times for predicting accurately surgical times of future cases is likely to reduce the average length of time cases finish late (after their scheduled finish times). DESIGN: Computer simulation. MEASUREMENTS AND MAIN RESULTS: Data from an operating room (OR) information system for two surgical suites were analyzed. For each case performed in fiscal year 1996, we searched backward for 1 year and counted the number of previous cases that were the same type of procedure performed by the same surgeon. Then, for each suite, surgical times were fitted to a statistical model estimating the effect of the type of procedure and who the surgeon was on surgical time. The estimated "variance components" were used in Monte-Carlo computer simulations to evaluate whether a hypothetical increase in the number of previous cases available to estimate the next case's surgical time would improve scheduling accuracy. Predictions of how long newly scheduled cases should take were impaired because 36.5% +/- 0.4% (mean +/- SE) of cases at a tertiary surgical suite and 28.6% +/- 0.7% of cases at an ambulatory surgery center did not have any cases in the previous year with the same procedure type and surgeon. Computer simulation was used to generate additional hypothetical cases. Using this data, even having many previous cases on which to base predictions of future surgical times would only decrease the average length of time that cases finish late by a few minutes. CONCLUSION: An OR manager considering using only historical surgical times to estimate future surgical times should first investigate, using data from their own surgical suite, what percentage of cases do not have historical data. Even if there are sufficient historical data to estimate future surgical times accurately, relying solely on historical times is probably an ineffective strategy to have future cases finish on time.

Myocardial ischemia correlates with reduced fibrinolytic activity following peripheral vascular surgery.

STUDY OBJECTIVES: To evaluate the relationship between perioperative ischemia and serial concentrations of D-dimer, which is a sensitive and specific marker of fibrinolytic activity. Myocardial ischemia and infarction are well-recognized complications of peripheral vascular surgery. We hypothesized that patients at increased risk of perioperative myocardial ischemia might be identified preoperatively by abnormal hemostatic indices. DESIGN: Prospective clinical outcomes study. SETTING: A 1,124-bed tertiary care medical center. PATIENTS: 42 ASA physical status II, III, and IV patients undergoing peripheral vascular surgery. INTERVENTIONS: Serial D-dimer concentrations were measured preoperatively, and at 24 and 72 hours postoperatively. Continuous 12-lead ST-segment monitoring (Mortara Instrument, Inc., Milwaukee, WI) was performed with the acquisition of a 12-lead ECG every 20 seconds for 72 hours. MEASUREMENTS AND MAIN RESULTS: D-dimer measurements were performed in duplicate using the Dimer Gold assay (American Diagnostica, Greenwich CT). Ischemic episodes, as defined by continuous 12-lead ST-segment monitoring, occurred in 49% of patients. There were no demographic differences between ischemic and nonischemic groups. Although baseline D-dimer concentrations were not statistically significantly different between groups, patients experiencing perioperative myocardial ischemia generated significantly less D-dimer during the perioperative period (p = 0. 014). CONCLUSIONS: PATIENTS with an impaired fibrinolytic response, as defined by reduced generation of D-dimer, experienced an increased incidence of perioperative myocardial ischemia.

Nicardipine reverses vasoactivity associated with University of Wisconsin solution in the rat peripheral circulation.

BACKGROUND: The rapid uniform delivery of University of Wisconsin solution (UW) to the microcirculation may be compromised by its vasoactivity. METHODS: In 2 different rodent models, we tested whether UW-mediated vasoconstriction could be reversed with nicardipine. RESULTS: In the perfused, splanchnic circulation, intravascular control solutions (lactated Ringers [LR], Hextend [HEX], histidine-tryptophan-ketoglutarate [HTK]) or UW (± nicardipine) evoked pressure changes in 3 protocols (series 1; n = 35). In the cremaster muscle, topical control solutions or UW (± nicardipine) evoked vascular responses measured by video microscopy in 4 protocols (series 2; n = 47). In series 1A, 37°C UW increased perfusion pressure, but there was no change caused by LR, HEX, or HTK. In series 1B, 4°C UW caused a similar, albeit transient, increase. In series 1C, nicardipine reversed 37°C UW-mediated vasoconstriction in a dose-related manner. In series 2A, UW caused a 30%-59% constriction that varied with arteriolar branching order. In series 2B, the recovery from UW-induced vasoconstriction varied with duration of exposure, but nicardipine fully reversed residual vasoconstriction. In series 2C, cold and warm UW were equipotent, near maximal, vasoconstrictors. In series 2D, UW potentiated no-reflow. CONCLUSION: UW causes a potent temperature-independent vasoconstriction by a calcium-mediated mechanism and this effect can be mitigated with nicardipine.

The business of perioperative medicine.

Medical centers should insist that their top officials have a firm grasp of contemporary business principles, use that skill set, and run the medical business like any other. This business imperative does not exclude a conscious decision to measure success by the amount of articles published or charity care given rather than the amount of profits. Physician leaders should insist that while they care for patients, someone cares for the business.

Anesthesia for carotid endarterectomy.

Patients presenting for carotid endarterectomy provide anesthesiologists with many challenges. These include optimization of cerebrovascular hemodynamics and oxygen balance, as well as minimizing myocardial risk. Fiscal pressures have encouraged the development of clinical pathways in many centers, with a remarkable trend towards decreased intensive care unit utilization and length of hospital stay. Anesthetic and surgical practices vary widely, but outcomes in these high-risk patients are usually excellent despite these differences. The potential for expanded indications for carotid endarterectomy and development of percutaneous treatment for carotid stenosis will provide neurovascular anesthesiologists with additional incentives to refine the anesthetic management of these patients.

Carbon dioxide embolism during laparoscopic cholecystectomy.

We present a 38-year-old woman with cholelithiasis having laparoscopic cholecystectomy. After two attempts of abdominal insufflation using CO2 and a Verres needle, the patient had symptoms consistent with a venous gas embolism. The patient was treated quickly and recovered without sequelae. Surgery was continued, and inspection of the liver showed two Verres needle puncture wounds.

Anesthesia information management systems as a cost containment tool.

Anesthesia information management systems (AIMS) have uses that extend far beyond automatic anesthesia record-keeping. After initial experience with the development of monitoring technology, the Department of Anesthesiology at Duke University Medical Center, Durham, North Carolina, began the installation of the Arkive anesthesia information management system in 1987. The system was installed hospital-wide in 1992. AIMS played an integral role in determining the cost of pharmaceutical agents used during an anesthetic procedure. Clinicians targeted areas of high cost in which anesthetic practice could be modified. Establishment of an educational program followed by the institution of practice guidelines allowed for an annualized savings of more than $900,000 on drug costs with no effect on the quality of care provided. Future generations of AIMS need to be more fully integrated into hospital information management systems.