Description of the Public Safety Medical Response and Patient Encounters Within and During the Indianapolis (USA) Spring 2020 Civil Unrest.

OBJECTIVE: This study describes the local Emergency Medical Services (EMS) response and patient encounters corresponding to the civil unrest occurring over a four-day period in Spring 2020 in Indianapolis, Indiana (USA). METHODS: This study describes the non-conventional EMS response to civil unrest. The study included patients encountered by EMS in the area of the civil unrest occurring in Indianapolis, Indiana from May 29 through June 1, 2020. The area of civil unrest defined by Indianapolis Metropolitan Police Department covered 15 blocks by 12 blocks (roughly 4.0 square miles) and included central Indianapolis. The study analyzed records and collected demographics, scene times, interventions, dispositions, EMS clinician narratives, transport destinations, and hospital course with outcomes from receiving hospitals for patients extracted from the area of civil unrest by EMS. RESULTS: Twenty-nine patients were included with ages ranging from two to sixty-eight years. In total, EMS transported 72.4% (21 of 29) of the patients, with the remainder declining transport. Ballistic injuries from gun violence accounted for 10.3% (3 of 29) of injuries. Two additional fatalities from penetrating trauma occurred among patients without EMS contact within and during the civil unrest. Conditions not involving trauma occurred in 37.9% (11 of 29). Among transported patients, 33.3% (7 of 21) were admitted to the hospital and there was one fatality. CONCLUSIONS: While most EMS transports did not result in hospitalization, it is important to note that the majority of EMS calls did result in a transport. There was a substantial amount of non-traumatic patient encounters. Trauma in many of the encounters was relatively severe, and the findings imply the need for rapid extraction methods from dangerous areas to facilitate timely in-hospital stabilization.

Prehospital lung ultrasound in acute heart failure: Impact on diagnosis and treatment.

OBJECTIVE: Patients with acute heart failure (AHF) are commonly misdiagnosed and undertreated in the prehospital setting. These delays in diagnosis and treatment have a direct negative impact on patient outcomes. The goal of this study was to determine the diagnostic accuracy of paramedics with and without the use of lung ultrasound (LUS) for the diagnosis of AHF in patients with dyspnea in the prehospital setting. Secondarily, we assessed LUS impact on rate of and time to initiation of HF therapies. METHODS: This was a prospective interventional study on a consecutive sample of patients transported to the hospital by one emergency medical services agency. Adult patients (>18 years) with a chief complaint of dyspnea were included. LUS was performed by trained paramedics and was defined as positive for AHF if both anterior-superior lung zones had greater than or equal to three B-lines or bilateral B-lines were visualized on a four-view protocol. Paramedic diagnosis was compared to hospital discharge diagnosis which served as the criterion standard. RESULTS: Of the 264 included patients, 94 (35%) had a final diagnosis of AHF. Forty total patients had a LUS performed; 17 of these patients had a final diagnosis of AHF. Sensitivity and specificity for AHF by paramedics were 23% (95% confidence interval [CI] 0.14-0.34) and 97% (95% CI 0.92-0.99) without LUS and 71% (95% CI 0.44-0.88) and 96% (95% CI 0.76-0.99) with the use of LUS. In the 94 patients with AHF, 14% (11/77) received HF therapy prehospital without the use of LUS and 53% (9/17) with the use of LUS. LUS improved frequency of treatment by 39%. Median time to treatment was 21 min with LUS and 169 min without. CONCLUSIONS: LUS improved paramedic sensitivity and accuracy for diagnosing AHF in the prehospital setting. LUS use led to higher rates of prehospital HF therapy initiation and significantly decreased time to treatment.

Assessment of Gender Bias During Paramedic-Physician Handoffs.

Objective Gender bias against female physicians has been frequently demonstrated and associated with negative feelings toward their careers. Gender bias has also been demonstrated in prehospital clinical care. However, potential gender bias during paramedic-physician handoffs has not been studied. This study aimed to identify gender bias during interactions between prehospital personnel and emergency physicians at the time of patient handoff. Methods An observational study was conducted at an urban academic emergency department. Observers were trained to record information from paramedic-physician handoffs but were blind to the nature of the study. The primary outcome was to whom paramedics initially directed the focus of their handoff report based on physician gender, with secondary outcomes of to whom paramedics directed most of their report and whether they asked about further questions based on physician gender. Results There were 784 observed handoffs. There was no significant association between the gender of the physician and which physician received first attention (χ2 {1, N = 782} = 0.9736, p = 0.3238) or majority attention (χ2 {1, N = 780} = 1.9414, p = 0.1635). Paramedics were more likely to ask questions to male attendings than female attendings (χ2 {1, N = 784} = 4.4319, p = 0.0353). Conclusion We identified limited differences in communication based on gender between paramedics and physicians during emergency department patient handoffs.

Descriptive analysis of emergency medical services 72-hour repeat patient encounters in a single, Urban Agency.

INTRODUCTION: Emergency department unscheduled return visits within 72-h of discharge, called a "bounceback", have been used as a metric of quality of care. We hypothesize that specific demographics and dispositions may be associated with Emergency Medical Services (EMS) 72-h bouncebacks. METHODS: For all patient encounters within one calendar year from a large, urban EMS agency, we recorded demographics (name, date of birth, race, gender), primary impression, disposition, and vital signs for EMS encounters. A bounceback was defined as a patient, identified by matching first name, last name and date of birth, with more than one EMS encounter within 72 h. We performed descriptive statistics for patients that did and did not have a subsequent bounceback using median (interquartile range) and Wilcoxon Rank Sum test for age and frequency (percent) and chi square test for gender, race and run disposition. For patients with a bounceback, we describe the frequency and percentage of EMS professional primary impressions on initial encounter. RESULTS: 98,043 encounters from January 1, 2021 to December 31, 2021, were analyzed. The median age was 50 years (IQR 32-65); 49.4% (46,147) were female and 50.7% (47,376) were White patients. 3951 encounters had a subsequent bounceback, and compared to those without bouncebacks, they were more often male patients (58.7% versus 50.2%, p < 0.001) and more commonly not transported (22.3% versus 15.5%, p < 0.001). A multivariable logistic regression model estimated the odds of bounceback were lower for females [OR 0.64 (95% CI 0.61-0.68)], Asian and Latino patients compared to White patients [OR 0.33 (95% CI 0.21-0.53) and 0.42 (95% CI 0.34-0.51)], respectively, no significant difference for Black patients compared to White patients, and higher for non-transported patients [OR 1.25 (95% CI 1.16-1.34)]. The The most common EMS primary impression for initial and subsequent encounters was mental health [576 (14.7%) and 944 (17.0%), respectively]. For subsequent encounters, the primary impression was cardiac arrest or death in 67 (1.2%) of cases. CONCLUSION: Bouncebacks were common in this single year study of a high-volume urban EMS agency. Male and non-transported patients most often experienced bouncebacks. The most common primary impression for encounters with bounceback was mental health related. Out-of-hospital cardiac arrest occurred in 1 % of bounceback cases. Further study is necessary to understand the effect on patient-centered outcomes.

Mass Casualty Incident Involving Rapid Acting Insulin.

We report on an unusual prehospital incident involving the inadvertent administration of short-acting insulin among a group of high school students. Sixteen students iatrogenically received 10 units of insulin lispro intradermally instead of tuberculin purified protein derivative (PPD), resulting in several students experiencing symptomatic hypoglycemia. A mass casualty incident was declared and the local poison center consulted. An incident command system, with the support of on-scene EMS physicians, was established to track, treat, and transport the involved patients.

Safety of an Alternative Care Protocol for EMS Non-Transport in the COVID-19 Pandemic.

AIM: Our primary goal was to evaluate safety of a new emergency medical services (EMS) protocol directing non-transport of low-acuity patients during the COVID-19 pandemic. METHODS: We performed a retrospective cohort analysis of all patients in Marion County, Indiana, from March 23, 2020 to May 25, 2020 for whom a novel non-transport protocol was used by EMS for patients with low-acuity COVID-19 symptoms. We assessed paramedic compliance with the protocol to determine numbers and types of deviations. We further reviewed a statewide health information exchange database to identify any patients with emergency department (ED) visits, hospital admissions, or death within 30 days of the EMS non-transport. For ED and hospital visits, we collected ED or admission diagnoses to determine if the etiologies were COVID-related. RESULTS: Between March 24, 2020 and May 25, 2020, 222 patients were documented as "Treated, Released (per protocol)." The protocol was correctly applied 144 times (64.8%). The other 78 times, although the EMS clinicians documented use of the protocol, it was not actually used (e.g., another protocol such as "no medical emergency" was used). Of the 144 patients for whom the protocol was used, in 55 cases (38.2%), the clinicians documented patient factors that should have contraindicated use of the protocol (e.g., chest pain, past medical history of asthma). The protocol was applied 5 times (3.5%) in pediatric patients. Two patients were admitted to the hospital within 72 hours of incorrect application of the protocol; both were for COVID-related complaints. Two patients were admitted to the hospital within 72 hours of correct protocol use; one was for a COVID-related complaint. CONCLUSION: In this case series, paramedics demonstrated large deviations from the novel non-transport protocol. Several patients were admitted to the hospital within 72 hours of non-transport both when the protocol was used correctly, and when it was used incorrectly.

Patient Demographics Are Associated with Differences in Prehospital Pain Management among Trauma Patients.

OBJECTIVE: Disparities have been observed in the treatment of pain in emergency department patients. However, few studies have evaluated such disparities in emergency medical services (EMS). We describe pain medication administration for trauma indications in an urban EMS system and how it varies with patient demographics. METHODS: We performed a retrospective review of the electronic medical records of adult patients transported for isolated trauma (without accompanying medical complaint) from 1/1/18 to 6/30/2020 by a third service EMS agency in a major United States metropolitan area. We performed descriptive statistics on epidemiology, type of pain medications administered, and pain scores. Kruskall-Wallis and chi-square or Fisher's exact tests were used to compare continuous and categorical variables, respectively. We constructed a logistic regression model to estimate the odds of nontreatment of pain by age, race, sex, transport interval, pain score, and Glasgow Coma Scale (GCS) score for patients with pain scores of at least four on a one to ten scale, the threshold for pain treatment per the EMS protocol. RESULTS: Of 32,463 EMS patients with traumatic injuries included in the analysis, 40% (12,881/32,463) were African American, 50% (16,284/32,463) were female, the median age was 27 years (IQR 45-64), and the median initial pain score was 5 (IQR 2-8). Fifteen percent (4,989/32,463) received any analgesic. Initial pain scores were significantly higher for African American and female patients. African American patients were less likely to receive analgesia compared to White and Hispanic patients (19% versus 25% and 23%, respectively, p < 0.0001). Adjusting for age, pain score, transport interval, and GCS, African American compared to White, and female compared to male patients were less likely to be treated for pain, OR 1.59 (95% CI 1.47-1.72) and OR 1.20 (95% CI 1.11-1.28), respectively. CONCLUSION: Among patients with isolated traumatic injuries treated in a single, urban EMS system, African American and female patients were less likely to receive analgesia than White or male patients. Analgesics were given to a small percentage of patients who were eligible for treatment by protocol, and intravenous opioids were used in the vast majority patients who received treatment.

A novel emergency medical services protocol to improve treatment time for large vessel occlusion strokes.

In many systems, patients with large vessel occlusion (LVO) strokes experience delays in transport to thrombectomy-capable centers. This pilot study examined use of a novel emergency medical services (EMS) protocol to expedite transfer of patients with LVOs to a comprehensive stroke center (CSC). From October 1, 2020 to February 22, 2021, Indianapolis EMS piloted a protocol, in which paramedics, after transporting a patient with a possible stroke remained at the patient's bedside until released by the emergency department or neurology physician. In patients with possible LVO, EMS providers remained at the bedside until the clinical assessment and CT angiography (CTA) were complete. If indicated, the paramedics at bedside transferred the patient, via the same ambulance, to a nearby thrombectomy-capable CSC with which an automatic transfer agreement had been arranged. This five-month mixed methods study included case-control assessment of use of the protocol, number of transfers, safety during transport, and time saved in transfer compared to emergent transfers via conventional interfacility transfer agencies. In qualitative analysis EMS providers, and ED physicians and neurologists at both sending and receiving institutions, completed e-mail surveys on the process, and offered suggestions for process improvement. Responses were coded with an inductive content analysis approach. The protocol was used 42 times during the study period; four patients were found to have LVOs and were transferred to the CSC. There were no adverse events. Median time from decision-to-transfer to arrival at the CSC was 27.5 minutes (IQR 24.5-29.0), compared to 314.5 minutes (IQR 204.0-459.3) for acute non-stroke transfers during the same period. Major themes of provider impressions included: incomplete awareness of the protocol, smooth process, challenges when a stroke alert was activated after EMS left the hospital, greater involvement of EMS in patient care, and comments on communication and efficiency. This pilot study demonstrated the feasibility, safety, and efficiency of a novel approach to expedite endovascular therapy for patients with LVOs.

Increased weight in patients with time-sensitive diagnosis is associated with longer prehospital on-scene times.

BACKGROUND: Obesity is a growing epidemic associated with higher rates of metabolic disease, heart disease and all-cause mortality. Heavier patients may require more advanced resources and specialized equipment. We hypothesize that increasing patient weight will be associated with longer prehospital on-scene times. METHODS: We reviewed electronic patient care records for patients transported by two urban 9-1-1 emergency medical services (EMS) agencies. We collected age, sex, estimated patient weight, vital signs (systolic blood pressure, heart rate, pulse oximetry), provider impression, method of moving patient to ambulance, and on-scene times. We selected patients with time-sensitive diagnoses of stroke, ST-segment elevation myocardial infarction (STEMI), and trauma and compared on-scene times for patients who weighed above or below 300 pounds. We performed descriptive statistics, Mann-Whitney U tests for continuous variables and Chi-square tests for discrete variables. We constructed a generalized linear model to determine the effect of patient weight adjusted for covariates. RESULTS: For a three-year period (May 1, 2018 to April 30, 2021) 48,203 patients were transported with an EMS impression of stroke, ST-segment elevation myocardial infarction (STEMI), and trauma. 23,654 (49.1%) patients were female, and the median age was 52 (IQR 34-68) years. The median weight was 175.0 (IQR 150.0-205.0) pounds. Patients above a dichotomous weight categorization of 300 pounds experienced a longer median scene time with any time-sensitive diagnosis (12.6 versus 11.9 min p < 0.001), STEMI (16.0 versus 13.1 min, p = 0.014) and blunt trauma (12.6 versus 11.9 min, p < 0.001)). They were more likely to be hypoxic (p < 0.001) and more likely to experience cardiac arrest (p < 0.001). They were less likely to walk to the ambulance (22.1% versus 32.2%, p < 0.001). CONCLUSION: Patient weight above 300 pounds was associated with significantly longer on-scene time. These patients were more likely to be hypoxic, sustain a cardiac arrest, and less likely to walk to the ambulance.

Out-of-hospital cardiac arrest volumes and characteristics during the COVID-19 pandemic.

AIM: The COVID-19 pandemic has significantly impacted Emergency Medical Services (EMS) operations throughout the country. Some studies described variation in total volume of out-of-hospital cardiac arrests (OHCA) during the pandemic. We aimed to describe the changes in volume and characteristics of OHCA patients and resuscitations in one urban EMS system. METHODS: We performed a retrospective cohort analysis of all recorded atraumatic OHCA in Marion County, Indiana, from January 1, 2019 to June 30, 2019 and from January 1, 2020 to June 30, 2020. We described patient, arrest, EMS response, and survival characteristics. We performed paired and unpaired t-tests to evaluate the changes in those characteristics during COVID-19 as compared to the prior year. Data were matched by month to control for seasonal variation. RESULTS: The total number of arrests increased from 884 in 2019 to 1034 in 2020 (p = 0.016). Comparing 2019 to 2020, there was little difference in age [median 62 (IQR 59-73) and 60 (IQR 47-72), p = 0.086], gender (38.5% and 39.8% female, p = 0.7466, witness to arrest (44.3% and 39.6%, p = 0.092), bystander AED use (10.1% and 11.4% p = 0.379), bystander CPR (48.7% and 51.4%, p = 0.242). Patients with a shockable initial rhythm (19.2% and 15.4%, p = 0.044) both decreased in 2020, and response time increased by 18 s [6.0 min (IQR 4.5-7.7) and 6.3 min (IQR 4.7-8.0), p = 0.008]. 47.7% and 54.8% (p = 0.001) of OHCA patients died in the field, 19.7% and 19.3% (p = 0.809) died in the Emergency Department, 21.8% and 18.5% (p = 0.044) died in the hospital, 10.8% and 7.4% (p = 0.012) were discharged from the hospital, and 9.3% and 5.9% (p = 0.005) were discharged with Cerebral Performance Category score ≤ 2. CONCLUSION: Total OHCA increased during the COVID-19 pandemic when compared with the prior year. Although patient characteristics were similar, initial shockable rhythm, and proportion of patients who died in the hospital decreased during the pandemic. Further investigation will explore etiologies of those findings.

Limited data to support improved outcomes after community paramedicine intervention: A systematic review.

BACKGROUND: Community paramedicine (CP) leverages trained emergency medical services personnel outside of emergency response as an innovative model of health care delivery. Often used to bridge local gaps in healthcare delivery, the CP model has existed for decades. Recently, the number of programs has increased. However, the level of robust data to support this model is less well known. OBJECTIVE: To describe the evidence supporting community paramedicine practice. DATA SOURCES: OVID, PubMed, SCOPUS, EMBASE, Google Scholar-WorldCat, OpenGrey. STUDY APPRAISAL AND SYNTHESIS METHODS: Three people independently reviewed each abstract and subsequently eligible manuscript using prespecified criteria. A narrative synthesis of the findings from the included studies, structured around the type of intervention, target population characteristics, type of outcome and intervention content is presented. RESULTS: A total of 1098 titles/abstracts were identified. Of these 21 manuscripts met our eligibility criteria for full manuscript review. After full manuscript review, only 6 ultimately met all eligibility criteria. Given the heterogeneity of study design and outcomes, we report a description of each study. Overall, this review suggests CP is effective at reducing acute care utilization. LIMITATIONS: The small number of available manuscripts, combined with the lack of robust study designs (only one randomized controlled trial) limits our findings. CONCLUSIONS: Initial studies suggest benefits of the CP model; however, notable evidence gaps remain.

Comparison between emergency department and inpatient nurses' perceptions of boarding of admitted patients.

INTRODUCTION: The boarding of admitted patients in the emergency department (ED) is a major cause of crowding and access block. One solution is boarding admitted patients in inpatient ward (W) hallways. This study queried and compared ED and W nurses' opinions toward ED and W boarding. It also assessed their preferred boarding location if they were patients. METHODS: A survey administered to a convenience sample of ED and W nurses was performed in a 631-bed academic medical center (30,000 admissions/year) with a 68-bed ED (70,000 visits/ year). We identified nurses as ED or W, and if W, whether they had previously worked in the ED. The nurses were asked if there were any circumstances where admitted patients should be boarded in ED or W hallways. They were also asked their preferred location if they were admitted as a patient. Six clinical scenarios were then presented, and the nurses' opinions on boarding based on each scenario were queried. RESULTS: Ninety nurses completed the survey, with a response rate of 60%; 35 (39%) were current ED nurses (cED), 40 (44%) had previously worked in the ED (pED). For all nurses surveyed 46 (52%) believed admitted patients should board in the ED. Overall, 52 (58%) were opposed to W boarding, with 20% of cED versus 83% of current W (cW) nurses (P < 0.0001), and 28% of pED versus 85% of nurses never having worked in the ED (nED) were opposed (P < 0.001). If admitted as patients themselves, 43 (54%) of all nurses preferred W boarding, with 82% of cED versus 33% of cW nurses (P < 0.0001) and 74% of pED versus 34% nED nurses (P = 0.0007). The most commonly cited reasons for opposition to hallway boarding were lack of monitoring and patient privacy. For the 6 clinical scenarios, significant differences in opinion regarding W boarding existed in all but 2 cases: a patient with stable chronic obstructive pulmonary disease but requiring oxygen, and an intubated, unstable sepsis patient. CONCLUSION: Inpatient nurses and those who have never worked in the ED are more opposed to inpatient boarding than ED nurses and nurses who have worked previously in the ED. Primary nursing concerns about boarding are lack of monitoring and privacy in hallway beds. Nurses admitted as patients seemed to prefer not being boarded where they work. ED and inpatient nurses seemed to agree that unstable or potentially unstable patients should remain in the ED but disagreed on where more stable patients should board.

Gamma-aminobutyric acid type A receptor ß3 subunit forebrain-specific knockout mice are resistant to the amnestic effect of isoflurane.

BACKGROUND: ß3 containing γ-aminobutyric acid type A receptors (GABA(A)-Rs) mediate behavioral end points of IV anesthetics such as immobility and hypnosis. A knockout mouse with targeted forebrain deletion of the ß3 subunit of the GABA(A)-R shows reduced sensitivity to the hypnotic effect of etomidate, as measured by the loss of righting reflex. The end points of amnesia and immobility produced by an inhaled anesthetic have yet to be evaluated in this conditional knockout. METHODS: We assessed forebrain selective ß3 conditional knockout mice and their littermate controls for conditional fear to evaluate amnesia and MAC, the minimum alveolar concentration of inhaled anesthetic necessary to produce immobility in response to noxious stimulation, to assess immobility. Suppression of conditional fear was assessed for etomidate and isoflurane, and MAC was assessed for isoflurane. RESULTS: Etomidate equally suppressed conditional fear for both genotypes. The knockout showed resistance to the suppression of conditional fear produced by isoflurane in comparison with control littermates. Controls and knockouts did not differ in isoflurane MAC values. CONCLUSIONS: These results suggest that ß3 containing GABA(A)-Rs in the forebrain contribute to hippocampal-dependent memory suppressed by isoflurane, but not etomidate.

Conserved role of unc-79 in ethanol responses in lightweight mutant mice.

The mechanisms by which ethanol and inhaled anesthetics influence the nervous system are poorly understood. Here we describe the positional cloning and characterization of a new mouse mutation isolated in an N-ethyl-N-nitrosourea (ENU) forward mutagenesis screen for animals with enhanced locomotor activity. This allele, Lightweight (Lwt), disrupts the homolog of the Caenorhabditis elegans (C. elegans) unc-79 gene. While Lwt/Lwt homozygotes are perinatal lethal, Lightweight heterozygotes are dramatically hypersensitive to acute ethanol exposure. Experiments in C. elegans demonstrate a conserved hypersensitivity to ethanol in unc-79 mutants and extend this observation to the related unc-80 mutant and nca-1;nca-2 double mutants. Lightweight heterozygotes also exhibit an altered response to the anesthetic isoflurane, reminiscent of unc-79 invertebrate mutant phenotypes. Consistent with our initial mapping results, Lightweight heterozygotes are mildly hyperactive when exposed to a novel environment and are smaller than wild-type animals. In addition, Lightweight heterozygotes exhibit increased food consumption yet have a leaner body composition. Interestingly, Lightweight heterozygotes voluntarily consume more ethanol than wild-type littermates. The acute hypersensitivity to and increased voluntary consumption of ethanol observed in Lightweight heterozygous mice in combination with the observed hypersensitivity to ethanol in C. elegans unc-79, unc-80, and nca-1;nca-2 double mutants suggests a novel conserved pathway that might influence alcohol-related behaviors in humans.

Inhaled anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats.

BACKGROUND: We hypothesized that pairs of inhaled anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By "divergently," we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and gamma-aminobutyric acid type A, glycine, N-methyl-D-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-D-aspartic acid blocker MK-801 had divergent effects on the MACs of these anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that inhaled anesthetics act on a single site to produce immobility in the face of noxious stimulation.

Anesthetic properties of some fluorinated oxolanes and oxetanes.

BACKGROUND: The search for new potent inhaled anesthetics has slowed, in large part because of the excellence of the two most recent additions, desflurane and sevoflurane. Nonetheless, neither desflurane nor sevoflurane are ideal anesthetics, desflurane causing cardiorespiratory stimulation, and sevoflurane having a slower (albeit rapid) recovery from anesthesia. Sevoflurane also can produce convulsions and postoperative agitation. METHODS AND RESULTS: In the present report, we describe the physical and anesthetic properties of 31 cyclic ethers halogenated solely with fluorine. Although several produced anesthesia, none had solubilities that would make them better than sevoflurane. The remaining ethers were unstable or produced obvious central nervous system irritation, including convulsions. CONCLUSIONS: We find that none of these cyclic ethers appear to provide advantages over desflurane or sevoflurane.

Effect of isoflurane and other potent inhaled anesthetics on minimum alveolar concentration, learning, and the righting reflex in mice engineered to express alpha1 gamma-aminobutyric acid type A receptors unresponsive to isoflurane.

BACKGROUND: Enhancement of the function of gamma-aminobutyric acid type A receptors containing the alpha1 subunit may underlie a portion of inhaled anesthetic action. To test this, the authors created gene knock-in mice harboring mutations that render the receptors insensitive to isoflurane while preserving sensitivity to halothane. METHODS: The authors recorded miniature inhibitory synaptic currents in hippocampal neurons from hippocampal slices from knock-in and wild-type mice. They also determined the minimum alveolar concentration (MAC), and the concentration at which 50% of animals lost their righting reflexes and which suppressed pavlovian fear conditioning to tone and context in both genotypes. RESULTS: Miniature inhibitory postsynaptic currents decayed more rapidly in interneurons and CA1 pyramidal cells from the knock-in mice compared with wild-type animals. Isoflurane (0.5-1 MAC) prolonged the decay phase of miniature inhibitory postsynaptic currents in neurons of the wild-type mice, but this effect was significantly reduced in neurons from knock-in mice. Halothane (1 MAC) slowed the decay of miniature inhibitory postsynaptic current in both genotypes. The homozygous knock-in mice were more resistant than wild-type controls to loss of righting reflexes induced by isoflurane and enflurane, but not to halothane. The MAC for isoflurane, desflurane, and halothane did not differ between knock-in and wild-type mice. The knock-in mice and wild-type mice did not differ in their sensitivity to isoflurane for fear conditioning. CONCLUSIONS: gamma-Aminobutyric acid type A receptors containing the alpha1 subunit participate in the inhibition of the righting reflexes by isoflurane and enflurane. They are not, however, involved in the amnestic effect of isoflurane or immobilizing actions of inhaled agents.

Determination of the EC50 amnesic concentration of etomidate and its diffusion profile in brain tissue: implications for in vitro studies.

BACKGROUND: Etomidate is a widely used general anesthetic that has become a useful tool to investigate mechanisms of anesthetic action in vivo and in brain slices. However, the free aqueous concentration of etomidate that corresponds to amnesia in vivo and the diffusion profile of etomidate in brain slices are not known. METHODS: The authors assessed the effect of intraperitoneally injected etomidate on contextual fear conditioning in mice. Etomidate concentrations in brain tissue were obtained by high-performance liquid chromatography. Uptake studies in 400-microm-thick brain slices were used to calculate the diffusion and partition coefficients of etomidate. A diffusion model was used to calculate the expected concentration profile within a brain slice as a function of time and depth. The predicted rate of drug equilibration was compared with the onset of electrophysiologic effects on inhibitory circuit function in recordings from hippocampal brain slices. RESULTS: Etomidate impaired contextual fear conditioning with an ED50 dose of 11.0+/-0.1 mg after intraperitoneal injection, which corresponded to an EC50 brain concentration of 208+/-9 ng/g. The brain:artificial cerebrospinal fluid partition coefficient was 3.35, yielding an EC50,amnesia aqueous concentration of 0.25 microm. The diffusion coefficient was approximately 0.2x10 cm/s. The development of etomidate action in hippocampal brain slices was compatible with the concentration profile predicted by this diffusion coefficient. CONCLUSIONS: The free aqueous concentration of etomidate corresponding to amnesia, as defined by impaired contextual fear conditioning in mice, is 0.25 microM. Diffusion of etomidate into brain slices requires approximately an hour to reach 80% equilibration at a typical recording depth of 100 microm. This information will be useful in designing and interpreting in vitro studies using etomidate.

Do dopamine receptors mediate part of MAC?

BACKGROUND: Depletion of central nervous system catecholamines, including dopamine, can decrease MAC (the minimum alveolar concentration of an inhaled anesthetic required to suppress movement in response to a noxious stimulus in 50% of test subjects); release of central nervous system catecholamines, including dopamine, can increase MAC; and increased free dopamine concentrations in the striatum can decrease MAC. Such findings suggest that dopamine receptors might mediate part of the capacity of inhaled anesthetics to provide immobility in the face of noxious stimulation. METHODS: We measured the effect of blockade of D2 dopamine-mediated transmission with 0.3 mg/kg or 3.0 mg/kg droperidol on the MAC of cyclopropane, desflurane, halothane, isoflurane, or sevoflurane in rats, and the effect of 3.0 mg/kg droperidol on the dose or concentration of etomidate (an anesthetic known to act principally by enhancing the response of gamma-aminobutyric acid(A) receptors to gamma-aminobutyric acid) required to suppress movement in response to noxious stimulation. RESULTS: Blockade of D2 dopamine-mediated transmission with droperidol does not decrease the MAC of cyclopropane, desflurane, halothane, isoflurane, or sevoflurane or its equivalent for etomidate in rats. CONCLUSIONS: These data, plus data from studies by others about D1 dopamine receptors, indicate that dopamine receptors do not mediate the immobility produced by inhaled anesthetics.

Contrasting roles of the N-methyl-D-aspartate receptor in the production of immobilization by conventional and aromatic anesthetics.

We hypothesized that N-methyl-d-aspartate (NMDA) receptors mediate some or all of the capacity of inhaled anesthetics to prevent movement in the face of noxious stimulation, and that this capacity to prevent movement correlates directly with the in vitro capacity of such anesthetics to block the NMDA receptor. To test this hypothesis, we measured the effect of IV infusion of the NMDA blockers dizocilpine (MK-801) and (R)-4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP) to decrease the MAC (the minimum alveolar concentration of anesthetic that prevents movement in 50% of subjects given a noxious stimulation) of 8 conventional anesthetics (cyclopropane, desflurane, enflurane, halothane, isoflurane, nitrous oxide, sevoflurane, and xenon) and 8 aromatic compounds (benzene, fluorobenzene, o-difluorobenzene, p-difluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, pentafluorobenzene, and hexafluorobenzene) and, for comparison, etomidate. We postulated that MK-801 or CPP infusions would decrease MAC in inverse proportion to the in vitro capacity of these anesthetics to block the NMDA receptor. This notion proved correct for the aromatic inhaled anesthetics, but not for the conventional anesthetics. At the greatest infusion of MK-801 (32 microg x kg(-1) x min(-1)) the MACs of conventional anesthetics decreased by 59.4 +/- 3.4% (mean +/- sd) and at 8 microg x kg(-1) x min(-1) by 45.5 +/- 4.2%, a decrease not significantly different from a 51.4 +/- 19.0% decrease produced in the EC50 for etomidate, an anesthetic that acts solely by enhancing gamma-amino butyric acid (GABA) receptors. We conclude that some aromatic anesthetics may produce immobility in the face of noxious stimulation by blocking the action of glutamate on NMDA receptors but that conventional inhaled anesthetics do not.