PROTOCOL FOR HUMAN EXPOSURE TO OPIOIDS AND CONCENTRATED MEDETOMIDINE USED IN FIELD APPLICATIONS.

Wildlife professionals routinely use potent sedatives and anesthetics when chemically immobilizing wildlife and zoo species in remote environments. Accidental exposure to these prescription veterinary drugs is rare but could be rapidly fatal. Commonly used agents include opioids and α2 adrenoreceptor agonists. These drugs can be reversed with specific antagonists; however, they are often not approved for human use. The protocol created here can be used by wildlife health professionals in a field setting with basic human emergency medical response training in coordination with local Emergency Medical Services (EMS). Key components include, building local relationships between EMS and wildlife professionals, focused EMS training, administering opioid and α2 adrenergic antagonists off label, and local evacuation procedures. This framework could allow wildlife management agencies or zoos to mitigate the risk of human exposures to these commonly used drugs, significantly improving occupational safety in an otherwise high-risk environment.

Microsimulation of financial impact of demand surge on hospitals: the H1N1 influenza pandemic of fall 2009.

OBJECTIVE: Microsimulation was used to assess the financial impact on hospitals of a surge in influenza admissions in advance of the H1N1 pandemic in the fall of 2009. The goal was to estimate net income and losses (nationally, and by hospital type) of a response of filling unused hospital bed capacity proportionately and postponing elective admissions (a "passive" supply response). METHODS: Epidemiologic assumptions were combined with assumptions from other literature (e.g., staff absenteeism, profitability by payer class), Census data on age groups by region, and baseline hospital utilization data. Hospital discharge records were available from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS). Hospital bed capacity and staffing were measured with the American Hospital Association's (AHA) Annual Survey. RESULTS: Nationwide, in a scenario of relatively severe epidemiologic assumptions, we estimated aggregate net income of $119 million for about 1 million additional influenza-related admissions, and a net loss of $37 million for 52,000 postponed elective admissions. IMPLICATIONS: Aggregate and distributional results did not suggest that a policy of promising additional financial compensation to hospitals in anticipation of the surge in flu cases was necessary. The analysis identified needs for better information of several types to improve simulations of hospital behavior and impacts during demand surges.

National trends in emergency department occupancy, 2001 to 2008: effect of inpatient admissions versus emergency department practice intensity.

STUDY OBJECTIVE: We evaluate recent trends in emergency department (ED) crowding and its potential causes by analyzing ED occupancy, a proxy measure for ED crowding. METHODS: We analyzed data from the annual National Hospital Ambulatory Medical Care Surveys from 2001 to 2008. The surveys abstract patient records from a national sample of hospital EDs to generate nationally representative estimates of visits. We used time of ED arrival and length of ED visit to calculate mean and hourly ED occupancy. RESULTS: During the 8-year study period, the number of ED visits increased by 1.9% per year (95% confidence interval 1.2% to 2.5%), a rate 60% faster than population growth. Mean occupancy increased even more rapidly, at 3.1% per year (95% confidence interval 2.3% to 3.8%), or 27% during the 8 study years. Among potential factors associated with crowding, the use of advanced imaging increased most, by 140%. But advanced imaging had a smaller effect on the occupancy trend than other more common throughput factors, such as the use of intravenous fluids and blood tests, the performance of any clinical procedure, and the mention of 2 or more medications. Of patient characteristics, Medicare payer status and the age group 45 to 64 years accounted for small disproportionate increases in occupancy. CONCLUSION: Despite repeated calls for action, ED crowding is getting worse. Sociodemographic changes account for some of the increase, but practice intensity is the principal factor driving increasing occupancy levels. Although hospital admission generated longer ED stays than any other factor, it did not influence the steep trend in occupancy.

Mechanical ventilators in US acute care hospitals.

OBJECTIVE: The supply and distribution of mechanical ventilation capacity is of profound importance for planning for severe public health emergencies. However, the capability of US health systems to provide mechanical ventilation for children and adults remains poorly quantified. The objective of this study was to determine the quantity of adult and pediatric mechanical ventilators at US acute care hospitals. METHODS: A total of 5,752 US acute care hospitals included in the 2007 American Hospital Association database were surveyed. We measured the quantities of mechanical ventilators and their features. RESULTS: Responding to the survey were 4305 (74.8%) hospitals, which accounted for 83.8% of US intensive care unit beds. Of the 52,118 full-feature mechanical ventilators owned by respondent hospitals, 24,204 (46.4%) are pediatric/neonatal capable. Accounting for nonrespondents, we estimate that there are 62,188 full-feature mechanical ventilators owned by US acute care hospitals. The median number of full-feature mechanical ventilators per 100,000 population for individual states is 19.7 (interquartile ratio 17.2-23.1), ranging from 11.9 to 77.6. The median number of pediatric-capable device full-feature mechanical ventilators per 100,000 population younger than 14 years old is 52.3 (interquartile ratio 43.1-63.9) and the range across states is 22.1 to 206.2. In addition, respondent hospitals reported owning 82,755 ventilators other than full-feature mechanical ventilators; we estimate that there are 98,738 devices other than full-feature ventilators at all of the US acute care hospitals. CONCLUSIONS: The number of mechanical ventilators per US population exceeds those reported by other developed countries, but there is wide variation across states in the population-adjusted supply. There are considerably more pediatric-capable ventilators than there are for adults only on a population-adjusted basis.

Web-based self-triage of influenza-like illness during the 2009 H1N1 influenza pandemic.

The sudden emergence of 2009 H1N1 influenza in the spring of that year sparked a surge in visits to emergency departments in New York City and other communities. A larger, second wave of cases was anticipated the following autumn. To reduce a potential surge of health system utilization without denying needed care, we enlisted the input of experts from medicine, public health, nursing, information technology, and other disciplines to design, test, and deploy clinical algorithms to help minimally trained health care workers and laypeople make informed decisions about care-seeking for influenza-like illness. The product of this collaboration, named Strategy for Off-Site Rapid Triage (SORT) was disseminated in 2 forms. Static algorithms, posted on the Centers for Disease Control and Prevention's Web site, offered guidance to clinicians and telephone call centers on how to manage adults and children with influenza-like illness. In addition, 2 interactive Web sites, http://www.Flu.gov and http://www.H1N1ResponseCenter.com, were created to help adults self-assess their condition and make an informed decision about their need for treatment. Although SORT was anchored in a previously validated clinical decision rule, incorporated the input of expert clinicians, and was subject to small-scale formative evaluations during rapid standup, prospective evaluation is lacking. If its utility and safety are confirmed, SORT may prove to be a useful tool to blunt health system surge and rapidly collect epidemiologic data on future disease outbreaks.

Implications of the Emergency Medical Treatment and Labor Act (EMTALA) during public health emergencies and on alternate sites of care.

Hospitals throughout the country are using innovative strategies to accommodate the surge of patients brought on by the novel H1N1 virus. One strategy has been to help decompress the amount of patients seeking care within emergency departments by using alternate sites of care, such as tents, parking lots, and community centers as triage, staging, and screening areas. As at any other time an individual presents on hospital property, hospitals and providers must be mindful of the requirements of the Emergency Medical Treatment and Labor Act. In this article we review the act and its implications during public health emergencies, with a particular focus on its implications on alternative sites of care.

The effects of decreasing low-molecular weight hemoglobin components of hemoglobin-based oxygen carriers in swine with hemorrhagic shock.

BACKGROUND: Some hemoglobin-based oxygen carriers (HBOCs) improve outcome in animal models of hemorrhagic shock (HS) in comparison with standard asanguinous resuscitation fluids. Nevertheless, concern about intrinsic vasoactivity, linked in part to low-molecular weight (MW) hemoglobin (Hb), has slowed HBOC development. We assessed the impact of decreasing the low-MW Hb component of bovine HBOC on vasoactivity in severe HS. METHODS: Anesthetized invasively monitored swine were hemorrhaged 55% blood volume and resuscitated with bovine HBOC containing 31% (31 TD [HBOC-301]), 2% (2 TD [HBOC-201]), or 0.4% (0.4 TD) low-MW Hb. Pigs received four 10 mL/kg infusions over 60 minutes, hospital arrival was simulated at 75 minutes, organ blood flow (BF) was evaluated by microsphere injection, and monitoring was continued for 4 hours followed by complete necrotic evaluation. RESULTS: There were few differences between 2 TD and 0.4 TD. Thirty-one TD pigs had higher systemic and pulmonary blood pressure (BP), systemic vascular resistance index, and pulmonary artery wedge pressure, compared with 2 TD or 0.4 TD (p < 0.01); however, pigs in all groups had at least mildly elevated BP. Transcutaneous tissue oxygenation, base excess, and mixed venous oxygen saturation were similar across groups; lactate and methemoglobin were highest with 0.4 TD (p < 0.03). There were no group differences in BF. Over time, myocardial BF increased and hepatic BF decreased in all groups (for 31 TD, p < 0.05); renal BF was unchanged in all groups. There were no group differences in heart, lung, or liver histopathology, and survival. CONCLUSIONS: Although purification from 31% to 2% low-MW Hb content significantly decreased vasoactive responses, further purification to 0.4% had no additional clinically measurable effects in severe HS. If further diminution in HBOC vasoactivity is desired for use in HS, additional technical approaches may be required.

Funding opportunities in knowledge translation: review of the AHRQ's "Translating Research into Practice" initiatives, competing funding agencies, and strategies for success.

The Agency for Healthcare Research and Quality actively funds and conducts research to improve health care for all Americans. This article is intended to provide a brief overview of Agency for Healthcare Research and Quality activities in knowledge translation and to accompany the presentation given on May 15, 2007, to the Academic Emergency Medicine Consensus Conference, "Knowledge Translation in Emergency Medicine: Establishing a Research Agenda and Guide Map for Evidence Uptake."

Resuscitation following severe, controlled hemorrhage associated with a 24 h delay to surgical intervention in swine using a hemoglobin based oxygen carrier as an oxygen bridge to definitive care.

OBJECTIVES: To test our hypothesis that the hemoglobin based oxygen carrier HBOC-201 would have similar or superior efficacy to 6% hetastarch (HEX) as a pre-hospital 'bridging' fluid for hemorrhagic shock when delay to definitive medical care is prolonged to 24h. METHODS: Twenty-four pigs were anesthetized, instrumented, given a soft tissue injury, and bled 55% estimated blood volume. Pigs were randomized to receive HBOC-201, HEX, or no resuscitation fluids (NON). At 4h post-injury, surgical sites were repaired and pigs were recovered from anesthesia. Animals were non-invasively monitored, administered blood for anemia or saline for hypotension at 24 and 48h, and monitored for 72h. RESULTS: Survival to 72h was 87.5% (7/8) in HBOC-201 and HEX pigs compared to 25% (2/8) in NON pigs (p=0.01). Increased mean arterial pressure was observed in the HBOC-201 group (p<0.0001). Cardiac index was highest in HEX pigs (overall p<0.001, HBOC-201 versus HEX p=0.002). Transcutaneous tissue oxygenation was higher with HBOC-201 (overall p=0.04, HBOC-201 versus HEX p<0.01). HBOC-201 and HEX pigs had comparable heart rates, pulmonary pressures, pre-hospital fluid requirements, venous O(2) saturation, base deficit, and lactic acid. Hemoglobin was decreased with HEX (overall p<0.0001, HBOC-201 versus HEX p<0.0002). At 24h, 14.3% (1/7) HBOC-201 pigs required blood transfusions versus 100% HEX (7/7) and NON (2/2) pigs (p>0.001). CONCLUSIONS: HBOC-201 restored hemodynamics, maintained tissue oxygenation, and decreased blood transfusions in comparison to HEX in severe controlled HS with 24h delay to simulated hospital care. These results support the potential use of HBOC-201 as a bridging resuscitation fluid for HS.

C5-blocking antibody reduces fluid requirements and improves responsiveness to fluid infusion in hemorrhagic shock managed with hypotensive resuscitation.

Hypotensive resuscitation strategies and inhibition of complement may both be of benefit in hemorrhagic shock. We asked if C5-blocking antibody (anti-C5) could diminish the amount of fluid required and improve responsiveness to resuscitation from hemorrhage. Awake, male Sprague-Dawley rats underwent controlled hemorrhage followed by prolonged (3 h) hypotensive resuscitation with lactated Ringer's or Hextend, with or without anti-C5. Anti-C5 treatment led to an estimated 62.3 and 58.5% reduction in the volume of Hextend and lactated Ringer's, respectively. In the subgroup of animals with a positive mean arterial pressure (MAP) response to fluid infusion following prolonged hypotension, anti-C5 treatment led to an estimated 4.7- and 4.1-fold increase in mean arterial pressure response per unit Hextend and lactated Ringer's infused, respectively. We observed no significant postresuscitation metabolic differences between the anti-C5 groups and controls. Whether anti-C5 could serve as a volume-sparing adjunct that improves responsiveness to fluid administration in humans deserves further study.

Vasoactivity of bovine polymerized hemoglobin (HBOC-201) in swine with traumatic hemorrhagic shock with and without brain injury.

BACKGROUND: We previously reported that bovine polymerized hemoglobin (HBOC- 201) improved outcome in swine with hemorrhagic shock (HS) with and without traumatic brain injury (TBI). Herein, we add analyses of blood pressure (BP) responses, associated physiologic data, and HS fluid infusion guidelines. METHODS: HBOC-201 versus standard fluid resuscitation was compared in four anesthetized invasively monitored swine models: moderate controlled HS, severe controlled HS, severe uncontrolled HS (liver injury), and severe uncontrolled HS/TBI (liver/parietal brain injuries). Pigs received fluid for hypotension and tachycardia, and were followed up to 6 (HS alone) or 72 hours (HS/TBI). The change in mean arterial pressure (DeltaMAP) response severity was stratified and analyzed based on infusion number and HS severity, using Student's t and Fisher's exact tests. RESULTS: HBOC-201 vasoactivity resulted in higher MAP in all studies. Among HBOC-201 pigs, DeltaMAP responses were significant for the first two infusions and inversely related to HS severity. Among controls, DeltaMAP responses remained significant through the fourth infusion in controlled HS models, and through the first in severe uncontrolled HS/TBI; none were significant in severe uncontrolled HS. DeltaMAP was higher with HBOC-201 through the first infusion in moderate controlled HS, the fifth in severe uncontrolled HS, and the second in severe uncontrolled HS/TBI; there were no group differences in severe controlled HS. No severe MAP responses occurred. Higher DeltaMAP severity did not impact outcome. Hypotension satisfied fluid reinfusion criteria less consistently than tachycardia. Overall, HBOC-201 improved physiologic parameters and survival without causing hypoperfusion; in severe HS, perfusion improved. CONCLUSIONS: In swine with HS +/- TBI, HBOC-201 had mild to moderate vasoactivity, resulting in significant DeltaMAP responses mainly after initial infusions, no severe/adverse responses, and improved outcome. Our data suggest that use of physiologic parameters (e.g., tachycardia), in addition to hypotension to guide fluid reinfusion during HS resuscitation with HBOC-201, will minimize hypoperfusion risk and maximize potential benefit.

Bovine polymerized hemoglobin versus Hextend resuscitation in a swine model of severe controlled hemorrhagic shock with delay to definitive care.

To compare the efficacy of low-volume resuscitation with bovine polymerized hemoglobin (HBOC-201) versus hetastarch (HEX) in an intermediate severity combat-relevant hemorrhagic shock swine model with a simulated delay to hospital care. Twenty-four anesthetized pigs were hemorrhaged 55% estimated blood volume in conjunction with a 5-min rectus abdominus crush. At 20 min, pigs were resuscitated with 10 mL/kg of HBOC-201 or HEX or nothing (NON); resuscitated pigs received additional infusions (5 mL/kg) at 30, 60, 120, or 180 min if hypotension or tachycardia persisted. Pigs were monitored for a 4-h "prehospital" period. At 4-h, hospital arrival was simulated: surgical sites were repaired, blood, or saline provided, and pigs were recovered from anesthesia. Pigs were monitored for 72 h and then killed for histological evaluation. One hundred percent (8/8) of HBOC-201-, 75% (6/8) of HEX-, and 25% (2/8) of NON-resuscitated pigs survived to 72 h (P = 0.007 overall, HBOC vs. HEX P > 0.05). Mean arterial pressure and mean pulmonary arterial pressure were highest in the HBOC-201 group (P < 0.001), and HR was lowest (P < 0.001). HBOC-201- and HEX-resuscitated pigs had comparable cardiac index and prehospital fluid requirements. HBOC-201 pigs had higher transcutaneous tissue oxygen tension, P < 0.001) and lower urine output (P < 0.001). At simulated hospital arrival, no HBOC-201 pigs required additional fluids or blood transfusion. In contrast, 100% of HEX pigs required blood transfusions (P < 0.01). In this swine model of controlled hemorrhage with low-volume resuscitation and delayed definitive care, HBOC-201 pigs had improved hemodynamics, transcutaneous tissue oxygen tension, and transfusion avoidance compared with HEX.

Brisk production of nitric oxide and associated formation of S-nitrosothiols in early hemorrhage.

The results of previous inhibitor studies suggest that there is some increase in nitric oxide (NO) production from constitutive NO synthase in early hemorrhage (H), but the magnitude of NO production early after H has not been previously assessed. It is generally believed that only modest production rates are possible from the constitutively expressed NO synthases. To study this, anesthetized male Sprague-Dawley rats were subjected to 90 min of isobaric (40 mmHg) H. During this period of time, the dynamics of accumulation of NO intermediates in the arterial blood was assessed using electron paramagnetic resonance spectroscopy, chemiluminescence, fluorescence imaging, and mass spectrometry. Electron paramagnetic resonance-detectable NO adducts were also measured with spin traps in blood plasma and red blood cells. H led to an increase in the concentration of hemoglobin-NO from 0.9 +/- 0.2 to 4.8 +/- 0.7 microM. This accumulation was attenuated by a nonselective inhibitor of NO synthase, NG-nitro-L-argininemethyl ester (L-NAME), but not by NG-nitro-D-argininemethyl ester (D-NAME) or 1400W. Administration of L-NAME (but not 1400W or D-NAME) during H produced a short-term increase in mean arterial pressure ( approximately 90%). In H, the level of N oxides in red blood cells increased sevenfold. S-nitrosylation of plasma proteins was revealed with "biotin switch" techniques. The results provide compelling evidence that there is brisk production of NO in early H. The results indicate that the initial compensatory response to H is more complicated than previously realized, and it involves an orchestrated balance between intense vasoconstrictor and vasodilatory components.

Hydroxyethyl starch inhibits neutrophil adhesion and transendothelial migration.

A resuscitation strategy that significantly alters the state of neutrophil (PMN) activation may impact organ function and survivability after shock. Various resuscitative fluids have been shown to elicit a severe immune activation and an upregulation of cellular injury markers, whereas other fluids have been shown to be protective. Recent studies have demonstrated that hydroxyethyl starch (HES), an artificial colloid, may exert significant anti-inflammatory effects, whereas conflicting studies with the same substance have shown an increase in PMN activation. Successful manipulation of the early immune events associated with hemorrhage and resuscitation will require a better understanding of the possible pro- or anti-inflammatory effects of resuscitation fluids. Our study investigated the effect of HES directly on PMN and cultured vascular endothelial cells in vitro. The effect of HES on PMN surface expression of CD11b and L-selectin was measured by flow cytometry. PMN activation response to HES was measured using a shape-change assay in response to formyl-methionyl-leucyl-phenylalanine (f-MLP). The effect of HES on endothelial cell surface expression of E-selectin, P-selectin, vascular cell adhesion molecule-1(VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) was evaluated by enzyme-linked immunoabsorbant assay. PMN rolling, adhesion, and migration events were measured using direct microscopy under conditions simulating microvascular flow. PMN surface expression of CD11b and L-selectin in whole blood samples and isolated PMNs were unaffected by exposure to HES. HES had no effect on the normal f-MLP dose-dependent increase in PMN activation. In the absence of IL-1 stimulation, there was a small but statistically significant (P < 0.05) increase in ICAM-1 after exposure to HES. After stimulation with IL-1 (10 U/mL), HES had no effect on the expression of P-selectin, E-selectin, ICAM-1, or VCAM-1. Under simulated microvascular flow conditions in vitro, HES significantly diminished the PMN tethering rate (P < 0.05) and the transendothelial migration rate (P < 0.05) in a dose-dependent manner. HES significantly alters the function of the PMN at the interface of the PMN responding to activated endothelium. The effect occurs, surprisingly, without a coincident effect on the state of PMN activation or a significant change in the surface expression of the adhesion molecules responsible for PMN-endothelial interaction.

Choice of fluid influences outcome in prolonged hypotensive resuscitation after hemorrhage in awake rats.

Hypotensive resuscitation (Hypo) has been considered an alternate resuscitation strategy in clinical settings that prevent the application of standard Advanced Trauma Life Support care. However, validation of this approach when used for prolonged periods of time remains to be demonstrated. The purpose of this study was to evaluate prolonged Hypo as an alternative to standard resuscitation using various currently available resuscitative fluids. Unanesthetized, male Sprague-Dawley rats underwent computer-controlled hemorrhagic shock and resuscitation. There were six experimental groups; nonhemorrhage (NH), nonresuscitated control (C), Hypo with lactated Ringer's (HypoLR), Hypo with Hextend, 6% hydroxyethyl starch in a balanced salt solution (HEX), Hypo with PolyHeme, a polymerized hemoglobin solution (HBOC), or standard resuscitation with LR (StandLR). Animals were bled over 15 min to a mean arterial blood pressure (MAP) of 40 mmHg where the blood pressure (BP) was held for 30 min. Hypo groups were resuscitated to 60 mmHg for 4 h followed by further resuscitation to 80 mmHg. StandLR rats were resuscitated to 80 mmHg immediately after the hemorrhage period. Animals were monitored until death or they were sacrifice at 24 h. Prolonged Hypo with HEX or LR resulted in a trend toward improved 24-h survival compared with C (71%, 65%, and 48%, respectively), and performed at least as well as StandLR (58% survival). HEX required significantly less intravenous fluid (0.7x total estimated blood volume [EBV]) compared with HypoLR (1.9x EBV) and StandLR (3.2x EBV) (P < 0.05). Although HBOC required the smallest fluid volume (0.4x EBV), survival was no better than C and it resulted in the most significant acidosis. These results support the decision to use Hextend for Hypo, a strategy currently being applied on the battlefield.