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Background The goal of this study is to determine the clinical value of multiplex polymerase chain reaction (PCR) study for enhancing pathogen detection in patients with suspected septicemia after trauma, emergency, and burn surgery. PCR-based pathogen detection quickly reveals occult bloodstream infections in these high-risk patients and may accelerate the initiation of targeted antimicrobial therapy. Methods We conducted a prospective observational study comparing results for 30 trauma and emergency surgery patients to 20 burn patients. Whole-blood samples collected with routine blood cultures (BCs) were tested using a new multiplex, PCR-based, pathogen detection system. PCR results were compared to culture data. Results PCR detected rapidly more pathogens than culture methods. Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Multiple Organ Dysfunction (MODS) scores were greater in PCR-positive versus PCR-negative trauma and emergency surgery patients (P ≤ .033). Negative PCR results (odds ratio, 0.194; 95% confidence interval, 0.045–0.840; P = .028) acted as an independent predictor of survival for the combined surgical patient population. Conclusion PCR detected the presence of pathogens more frequently than blood culture. These PCR results were reported faster than blood culture results. Severity scores were significantly greater in PCR-positive trauma and emergency surgery patients. The lack of pathogen DNA as determined by PCR served as a significant predictor of survival in the combined patient population. PCR testing independent of traditional prompts for culturing may have clinical value in burn patients. These results warrant further investigation through interventional trials.

Death from cocaine intoxication results from one or more of the multiple mechanisms including seizures, cardiovascular collapse, or apnea. In the free-moving rat model, continuous seizures are a major cause of death. To study other mechanisms of death unrelated to seizures in this model, we suppressed lethal seizures with diazepam (DZP) and investigated the effect of several pharmacological agents. Rats were pretreated with vehicle alone, diazepam 5 mg/kg alone, or a combination of DZP plus either nifedipine (NIFD) 2 mg/kg, propranolol (PROP) 10 mg/kg, or prazosin (PRAZ) 5 mg/kg. Five minutes after pretreatment, all animals received cocaine 100 mg/kg. Each test group consisted of 15 animals and all agents were given IP. Two animals in each group had cortical electrodes implanted. Animals that received vehicle followed by cocaine had 100% incidence of seizures and death. Those rats that received DZP alone followed by cocaine had no seizures and 53% death. Rats that received DZP plus NIFD or DZP plus PROP had suppression of seizures but no significant change in the incidence of death. The group that received DZP and PRAZ followed by cocaine had no seizures and 13% incidence of death (p0.001). Electroencephalogram recordings showed cortical electrical spike activity or spike-and-wave afterdischarges in all animals clinically observed to have seizures. In the absence of clinical seizure activity, no significant cortical spike activity was noted. It is concluded that animals protected from seizures with diazepam can still have nonseizure deaths after high-dose cocaine. The incidence of death in these animals is not reduced with nifedipine or propranolol pretreatment but is reduced with prazosin pretreatment.

The anticonvulsant properties of F-721(3-diethylamino-2,2-dimethylpropyl 5[p-trifluoromethylphenyl]-2furoate hydrochloride) were investigated in a battery of in vivo and in vitro anticonvulsant model systems. After intraperitoneal (ip) administration in mice, F-721 was effective in nontoxic doses against maximal electroshock (MES), subcutaneous picrotoxin clonic, intracerebroventricular (icv) N- methyl- d -aspartate (NMDA) tonic, icv NMDA clonic and icv quisqualic acid tonic seizures (ED50s: 11.1, 28.4, 1.76, 3.4, and 4.4 mg/kg, respectively). F-721 exhibited only partial activity against clonic seizures induced in the subcutaneous Metrazol and subcutaneous bicuculline test in mice and was inactive in this species against tonic seizures induced in the subcutaneous strychnine test. F-721 was effective against MES seizures following oral administration to mice (ED50: 31.3 mg/kg) and only partially effective by this route against clonic seizures induced by subcutaneous Metrazol. In rats, F-721 was a potent anticonvulsant in the maximal electroshock model following oral administration (ED50: 9.9 mg/kg). F-721 was also effective against corneal-kindled and amygdaloid-kindled seizures in rats. F-721 suppressed stage 5 seizures in corneal-kindled rats with an ED50 of 15 mg/kg, ip. In addition, it also decreased the afterdischarge duration and behavioral seizure stage in amygdaloid-kindled rats at doses that did not cause sedation or ataxia. At 40 mg/kg, F-721 reduced afterdischarge duration by 83.2% and reduced the seizure severity score to 1.7. The ED50 for 50% reduction of afterdischarge duration was 16.3 mg/kg, ip. In cultured mouse spinal cord neurons, F-721 suppressed sustained repetitive firing in response to a depolarizing current with a median inhibitory concentration (IC50) of 1.9 μM. F-721 had no effect on adenosine uptake γ-aminobutyric acid or NMDA receptor binding. Comparative data from previous studies with clinically established antiepileptic agents reveal that F-721's profile of activity most closely resembles that of phenytoin and carbamazepine. However, F-721 was notably more efficacious in suppressing amygdaloid-kindled seizures in rats and was a more potent antagonist of icv NMDA clonic seizures. Our studies indicate that F-721 is a potent, orally active anticonvulsant with a favorable margin of safety. The profile of anticonvulsant activity of F-721 suggests potential utility in the management of generalized tonic-clonic, simple and complex partial seizures.

Paired-pulse facilitation was studied at the perforant path-granule cell synapses in the dentate gyrus of urethane-anesthetized rats. Extracellular field potentials comprising excitatory postsynaptic potentials (EPSPs) and population spikes (PSs) were used to compare facilitation of both responses at interpulse intervals between 10 and 1000 ms. In this model system EPSPs, produced at stimulus intensities well below the PS threshold, exhibited paired-pulse facilitation (PPF) at intervals less than 40 ms. Between 40 and 100 ms both responses were of equal size and from 200 to 1000 ms the second response exhibited paired-pulse depression (PPD). With higher stimulus intensities, PSs exhibited early (10–30 ms) and late (400–1000 ms) PPD and intermediate interval (40–200 ms) PPF. The enhanced PS amplitude during facilitation was accompanied by a modest decrease in EPSP slope and increase in PS latencies to onset and to peak. If PS amplitude was increased to the same extent by simply increasing stimulus intensity, an increase in EPSP slope and decrease in PS latencies to onset and peak were observed. Current source-density analysis revealed that the current sink generated by synaptic activation of granule cell dendrites was indistinguishable between control and facilitated responses up to the onset of the PS. However, the facilitated response exhibited a marked increase in the duration and amplitude of current flowing into the dendrites during the late phase of the EPSP. PPF of the PS was attenuated or blocked by the administration of the known NMDA receptor-ion channel blockers, MK-801, dextromethorphan and ketamine. The depressant effects of these pharmacological agents on facilitation shared the same time course as facilitation itself, peaking at 60 ms and lasting approximately 200 ms. These data suggest that facilitation in this situation is due to postsynaptic rather than presynaptic modulations, and is based upon an increase in the NMDA-mediated component of the evoked response. No increase in transmitter release, per se, could be demonstrated.

Background: Recurrent intake of 4 g/day or more of acetaminophen has been associated with elevation of serum alanine aminotransferase (ALT) levels in 30–40% of the exposed population and may result in hepatotoxicity. Objective: To describe the frequency that patients are prescribed acetaminophen doses that exceed 4 g/day across a large population. Methods: Using California's Medicaid (MediCal) fee-for-service population, pharmacy claims including over-the-counter (OTC) medications were examined for prescriptions that could result in acetaminophen doses of 4 g/day or more. The period studied, October 2004 through September 2005, was before the Part D pharmacy benefit was available to dually eligible Medicare patients when all prescriptions were covered by the MediCal claims process. Results: During the pre-Part D evaluation period, approximately 3.27 million beneficiaries were enrolled in the fee-for-service MediCal program. A total of 192,716 (5.9%) were potentially exposed to at least 1 day of 4 g/day or more of acetaminophen. Of those, 769 patients were potentially exposed to at least 1 day of 16 g/day or more. A total of 2664 beneficiaries were dispensed prescriptions and OTC products that, if taken as directed, would have resulted in more than 100 days of acetaminophen doses of 4 g/day or more during the study year. Conclusions: Despite electronic systems designed to warn dispensing pharmacists of duplications of drug class and cumulative excessive doses, potentially toxic amounts of acetaminophen are commonly prescribed and dispensed to this population. Better systems, increased awareness, and education of patients, prescribers, and pharmacists are needed to reduce this potential toxic exposure.

Chronic bronchitis (CB) is a critical component of chronic obstructive pulmonary disease (COPD). Emphysema, reversible airway disease and bronchiectasis also contribute to COPD. Elderly patients are at increased risk for COPD and its components - emphysema, CB and bronchiectasis. In addition, older patients are at increased risk for resistant organisms during episodes of acute exacerbation of CB (AECB). These organisms include the more common bacteria implicated in AECB, such as Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae, and less common nonenteric, Gram-negative organisms such as Pseudomonas aeruginosa. Risk-stratified antibiotic treatment guidelines for AECB appear to be useful, although they have not been prospectively validated for the general CB population, and especially not in the elderly CB population. Many of the AECB treatment guidelines that are stratified based on risk factors have recommended that the oral respiratory fluoroquinolone antibiotics (gemifloxacin, levofloxacin and moxifloxacin) play a second-line but pivotal role, particularly in patients who have failed initial antibiotic treatment for simple CB or as initial treatment for complicated CB.

The rate of sudden unexpected death in epilepsy (SUDEP) approaches 9 per 1,000 patient-years in patients with refractory epilepsy. Respiratory causes are implicated in SUDEP. We reported that ictal hypoxemia occurs in one-third of seizures in localization-related epilepsy. We now report on respiratory changes in the ictal/postictal period including changes in end-tidal CO₂ (ETCO₂) that correlate directly with alveolar CO(2) , allowing a precise evaluation of seizure-related respiratory disturbances.One hundred eighty-seven seizures were recorded in 33 patients with localization-related epilepsy, with or without secondarily generalized convulsions, undergoing video-electroencephalography (EEG) telemetry with recording of respiratory data.The ictal/postictal ETCO₂ increase from baseline was 14 ± 11 mm Hg (11, -1 to 50) [mean ± standard deviation (SD) (median, range)]. ETCO₂ peak was at or above 50 mm Hg with 35 of 94 seizures, 60 mm Hg with 15, and 70 mm Hg with five seizures. Eleven of the 33 patients had seizures with ETCO₂ elevation above 50 mm Hg. The duration of ictal/postictal ETCO(2) increase above baseline was 424 ± 807 s (154, 4 to 6225). The duration of ictal apnea was 49 ± 46 s (31, 6-222); most ictal apneic events were central. Oxygen desaturation to 60% or less occurred with 10 seizures, including five that did not progress to generalized convulsions. Respiratory rate and amplitude increased postictally. The peak ictal ETCO₂ change and duration of change were not associated with apnea duration or seizure duration. Peak ETCO₂ change was significantly associated with contralateral seizure spread.Severe and prolonged increases in ETCO₂ occur with seizures. Postictally, respiratory effort is not impaired. Ictally triggered ventilation-perfusion inequality from pulmonary shunting or transient neurogenic pulmonary edema may account for these findings.

Epidemiological data shows low dietary magnesium(Mg) may be related to incidence and progression of asthma.To determine if long term(6.5 month) treatment with oral Mg would improve asthma control and increase serum measures of Mg status in men and women with mild-to-moderate asthma.55 males and females aged 21 to 55 years with mild to moderate asthma according to the 2002 National Heart, Lung, and Blood Institute(NHLBI) and Asthma Education and Prevention Program(NAEPP) guidelines and who used only beta-agonists or inhaled corticosteroids(ICS) as asthma medications were enrolled.Subjects were randomly assigned to consume 340 mg(170 mg twice a day) of Mg or a placebo for 6.5 months.Multiple measures of Mg status including serum, erythrocyte, urine, dietary, ionized and IV Mg were measured.markers of asthma control were: methacholine challenge test(MCCT) and pulmonary function test(PFT) results. Subjective validated questionnaires on asthma quality of life(AQLQ) and control(ACQ) were completed by participants. Markers of inflammation, including c-reactive protein(CRP) and exhaled nitric oxide(eNO) were determined.The concentration of methacholine required to cause a 20% drop in forced expiratory volume in in minute(FEV(1)) increased significantly from baseline to month 6 within the Mg group. Peak expiratory flow rate(PEFR) showed a 5.8% predicted improvement over time(P = 0.03) in those consuming the Mg. There was significant improvement in AQLQ mean score units(P0.01) and in overall ACQ score only in the Mg group(P = 0.05) after 6.5 months of supplementation. Despite these improvements, there were no significant changes in any of the markers of Mg status.Adults who received oral Mg supplements showed improvement in objective measures of bronchial reactivity to methacholine and PEFR and in subjective measures of asthma control and quality of life.

Sepsis is a common illness of intensive care unit patients that carries a high morbidity, mortality, and increases hospital cost. Although mortality from sepsis remains high when compared with other critical illnesses, it has declined over the last few decades due to several adjunctive therapies and focused care programs or guidelines. Many interventions, such as early appropriate antibiotic therapy and lung protective, low tidal volume ventilation are commonplace and carry little controversy in their benefit. However, other therapies still have an unclear benefit and remain controversial. This article discusses the controversial roles of intensive insulin therapy, corticosteroids, and activated protein C in the treatment of sepsis.

Increasing doses of the injectable anesthetics etomidate, Saffan, thiopental, ketamine, and xylazine and the vehicles saline and propylene glycol were administered to urethane-anesthetized rats. Their effects in vivo on perforant pathway-evoked field excitatory post-synaptic potentials and population spikes in the hippocampal dentate gyrus were determined. The primary purpose was to ascertain whether these compounds affect hippocampal excitability in a manner consistent with their proposed mechanisms of action. Compared with their respective vehicles, thiopental, etomidate, and xylazine reduced the amplitude of population spikes to single perforant pathway stimulation by 20-30% at the highest doses tested. Xylazine also increased the latency to onset of the population spike. No other effects were observed. Using paired pulse paradigms, it was determined that etomidate produced a dramatic, prolonged reduction in granule cell excitability at interpulse intervals of 10-100 ms. The magnitude of the effect was dose related and was reversible with the discontinuance of administration of the drug. Similar changes occurred with Saffan (althesin) and thiopental. Ketamine produced a small but significant depression in granule cell excitability during intervals of 10-200 ms. Xylazine had no effect. These data corroborate the importance of a prolongation of gamma-aminobutyric acid A-mediated inhibition to the mechanism of actions of etomidate, thiopental, and Saffan at relevant exposure concentrations in vivo.

To determine if respiratory depression is an important mechanism of cocaine-induced death in conscious rats.Male Sprague-Dawley rats weighing between 200 and 300 g and fitted with cortical electrodes were pretreated intraperitoneally with either saline (vehicle), MK-801, or valproic acid for 30 minutes before challenge with 70 mg/kg IP cocaine followed by spontaneous breathing or mechanical ventilation after acute tracheostomy. Behavior, seizures, death, EEGs, and ECGs were observed and measured.In group 1, animals received saline followed by cocaine. The incidence rates of seizures and death were 92% and 83%, respectively. Group 2 received saline followed by cocaine and then were ventilated mechanically through an acute tracheostomy after respiratory arrest (late mechanical ventilation). This group experienced seizures in 100% and death in 67% of animals. Group 3 also received saline followed by cocaine but were ventilated mechanically immediately after the first seizures (early mechanical ventilation). They had experienced seizures in 100% and death in 30%, the latter being significantly (P less than .025) reduced compared with group 1. In group 4, an anticonvulsant (1 mg/kg MK-801) was given before cocaine challenge, resulting in seizures in 10% (P less than .002 compared with group 1) and death in 90%. Group 5 received MK-801 followed by cocaine and then were ventilated mechanically after respiratory arrest (late mechanical ventilation). They experienced seizures in 20% (P less than .002 compared with group 1), and no animals in this group died (P less than .002 compared with group 1 or 4). Group 6 received an anticonvulsant (400 mg/kg valproic acid), followed by cocaine. This resulted in seizures in 20% (P less than .002 compared with group 1) and death in 90%. Group 7 received valproic acid followed by cocaine and then were ventilated mechanically (late mechanical ventilation). They experienced seizures in 30% (P less than .002 compared with group 1), and all animals survived (P less than .002 compared with group 1 or 6).Early mechanical ventilation reduces cocaine toxicity. Control of seizure activity with specific anticonvulsants allows delayed mechanical ventilation to protect against cocaine toxicity. This suggests that respiratory depression in conjunction with seizure activity plays a major role in the mechanisms of cocaine-induced death in this model.

Study objective: To determine the seroprevalence rates of hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV-I/II) and to compare these rates with the HIV-1 seroprevalence rate in a sample of injured patients admitted through ten California emergency departments. Design: Prospective blinded testing for serologic markers for HBV, HTLV-I/II, and HIV-1 on routinely collected blood samples. Setting: Ten California hospitals were chosen to reflect geographic and demographic diversity. Type of participants: All injured adult patients who were admitted to a participating hospital through the ED during consecutive three-month periods from June through November 1989. Measurements: Serum samples were tested for HIV-1 antibody, HTLV-I/II antibody, and hepatitis B surface antigen (HBsAg) using standard methods. Mann-Whitney U tests, χ 2 tests for independence, sign tests, χ 2 tests for goodness of fit, and logistic regression were used as appropriate. Results: Seroprevalence rates were as follows: HBV, 2.6% (57 of 2,209); HTLV-I/II, 2.0% (46 of 2,262); and HIV-1, 1.4% (31 of 2,264). Conclusion: The seroprevalence rate of HBV was slightly higher than that of HIV-1 in this sample of injured patients. Mortality estimates suggest, however, that HBV and HIV-1 pose roughly similar risks to emergency personnel, although the risk of HBV infection can be markedly reduced by vaccination. The data from this and other studies suggest that the ED incidence of HTLV-I/II in United States is low. The relative health risks to emergency personnel from HTLV-I/II appear to be minimal at this time.

Progress in improving patient outcomes and advancing therapeutics in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) is hampered by phenotypic heterogeneity and variable responsiveness to clinical interventions that are not fully explained by currently held disease paradigms for COPD and IPF. Although these chronic lung diseases differ in their geoepidemiology and immunopathogenesis, emerging evidence suggest that organ-specific autoimmunity may underlie subphenotypes of COPD and IPF. In particular, the links to tobacco smoking, diet, gender, and environment are explored in this review. We also highlight potential mechanisms that could guide future investigations in both laboratory and clinical settings. A paradigm shift is needed in how we think about COPD and IPF, based on geoepidemiology and a broader understanding of disease pathogenesis that may ultimately lead to new therapies and improved patient outcomes.

Study objectives: To measure the HIV seroprevalence of injured emergency department patients in a number of California hospitals and to examine the relationship between ED seroprevalence and local AIDS incidence. Design: Prospective blinded testing for HIV-1 antibody was performed on routinely collected blood samples. Setting: Ten California hospitals; group 1 included three hospitals from counties of high AIDS incidence (more than 40 cases per 100,000 population), group 2 included three hospitals from counties of intermediate AIDS incidence (20 to 40 cases per 100,000 population); and group 3 included four hospitals from counties of low AIDS incidence (less than 20 cases per 100,000 population). Type of participants: Eligible patients were all adult trauma victims admitted to a participating hospital through the ED during a consecutive three-month period occurring between June and November 1989. Measurements: HIV-1 antibody testing was done using enzyme immunoassay confirmed by immunofluorescence assay. Equivocal results were confirmed by Western blot. Mann-Whitney U test, χ 2 test, and multiple logistic regression were used where appropriate. Results: There were 2,264 patients with adequate blood samples for serologic testing. The seroprevalence rates for hospitals in groups 1, 2, and 3 were significantly different ( χ 2 = 8.44, P = .02): Group 1, 2.5% (19 of 756; 95% confidence interval [CI], 1.5% to 3.9%); group 2, 0.9% (10 of 1,078; CI, 0.5% to 1.7%); and group 3, 0.5% (two of 430; CI, 0.06% to 1.7%). Conclusion: This study suggests that local AIDS incidence rates do not necessarily predict the seroprevalence rates of injured patients who are admitted through local EDs.

Urethane-anesthetized rats were used to study the mechanism of cocaine-induced death. Continuous recording of the changes in five physiological parameters, including respiratory rate (RR), electroencephalogram (EEG), blood pressure (BP), electrocardiogram (ECG), and body temperature (BT), were conducted after intraperitoneal (IP) administration of a single dose of cocaine HCl (70 mg/kg). In the control group (normothermic with core body temperature 37.7 +/- 0.1 degree C and spontaneously breathing), the death rate was 88% (15/17), and the average time to respiratory arrest was 12.99 +/- 1.40 min (mean +/- SEM). The first set of experiments investigated the contribution of hypothermia to cocaine-induced death. The hypothermic group (core body temperature 33.9 +/- 0.3 degrees C and spontaneously breathing) had a death rate of 81.5% (22/27), and an average time to respiratory arrest of 16.70 +/- 1.24 min, which was significantly (p les than 0.05) prolonged. A substantial decrease in respiratory rate was seen in normothermic group, while all the other measured parameters remained relatively stable until respiratory arrest. Sequential arterial blood gas data in this group showed a decrease in PaO2 from 116.0 +/- 5.7 mmHg to 57.7 +/- 4.6 mmHg, an increase in PaCO2 from 27.7 +/- 2.2 mmHg to 42.7 +/- 3.0 mmHg, and a decrease in pH from 7.467 +/- 0.039 to 7.357 +/- 0.003. To confirm that respiratory depression was an important mechanism of cocaine-induced death in this model, ten normothermic rats underwent mechanical ventilation, and all survived cocaine exposure. This study points to the important role of respiratory depression as a cause of cocaine-induced death.

The term biologic pharmaceutical agents is used to define compounds that are naturally occurring physiologic substances or synthetic variations of naturally occurring subs.ances that have been adapted to therapeutic uses. This article reviews the pharmacologic mechanisms, actions, toxicity, and drug interactions of a number of examples from this important group of therapeutic agents.

Activation of dentate gyrus granule cells leads to a period of depressed excitability mediated primarily by recurrent inhibition. This response can be increased in intensity and duration by drugs that enhance GABAA-mediated inhibition including GABA uptake blockers (SKF100330A), benzodiazepines (diazepam), and barbiturates (pentobarbital). It can be attenuated or abolished by administration of the GABAA antagonists picrotoxin and bicuculline. Type II pyrethroids, such as deltamethrin, produce effects in vitro which lead one to expect that they would decrease GABA-mediated inhibition. However, administration of deltamethrin to animals intensifies the inhibitory consequences of granule cell activation by many fold. To determine the role of GABAA-mediated mechanisms in the action of deltamethrin, we have looked at its antagonism by bicuculline and picrotoxin. Neither GABAA antagonist reduced the duration of the inhibition produced by deltamethrin. The only effect observed was a small but significant reduction in intensity of inhibition during the period of 10–40 msec after activation of the granule cells. For comparative purposes we have also examined the antagonism produced by bicuculline and picrotoxin on agents known to enhance GABAA-mediated inhibition. These antagonists were quite effective in antagonizing the enhancement of inhibition produced by diazepam a and SKF 100330A. Bicuculline was also effective in antagonizing pentobarbital while picrotoxin was not. These results suggest that the prolongation of inhibition produced by deltamethrin in dentate granule cells does not result simply from an extension of GABAA-mediated inhibition, but rather derives from a different source.

Poison Control Centers (PCCs) have been shown to reduce health expenditures by reducing emergency department and clinic visits. The effect or association of PCC call frequency on acute hospitalization rates for poisonings has not been studied extensively.All nonfederal hospital discharges for acute poisoning principal diagnosis codes (960-979, 980-989, 9956X, 3030, and 005) in California between October 1999 and June 2002 were examined. Approximately 3.3% of the discharges had county/hospital information suppressed in the public-use database because of confidentiality criteria and were excluded from the analysis. U.S. Census Bureau population estimates for appropriate years by counties were also obtained. The 58 California counties were condensed to 48 counties and 3 "small-county" geographic groupings. Exposure calls by counties/groupings to the California Poison Control System(CPCS) for the same period were tabulated.In California, rates of hospital discharges for poisoning averaged 0.54/1000 person years with a range of 0.25/1000 person years (Central Counties) to 1.53/1000 person years (Del Norte County). Poison call rates averaged 8.5/1000 person years with a range of 4.9/1000 person years (Los Angeles County) to 19.6/1000 person years (Napa County). Poisoning discharges per 1000 person years positively correlated with PCC calls per 1000 person years (Spearman correlation 0.41, p = 0.0003). The average hospital length of stay (LOS) did not correlate with PCC call frequency or poisoning discharges per 1000 person years.The CPCS call frequency or county penetrance was not correlated with a reduction in the number of hospitalizations for poisoning nor was it associated with reduced average LOS in this study. Further study is needed to understand the etiology of the large differences in county rates of poisoning hospitalization and average LOS.

Background The use of self-expanding metallic stents (SEMAS) in the treatment benign airway obstruction is controversial. Methods To evaluate the safety and efficacy of SEMAS for this indication, we conducted a 10-year retrospective review at our tertiary medical centre. Results Using flexible bronchoscopy, 82 SEMAS (67% Ultraflex, 33% Wallstent) were placed in 35 patients with inoperable lesions, many with significant medical comorbidities (88%). 68% of stents were tracheal, and 83% of patients showed immediate symptomatic improvement. Reversible complications developed in 9% of patients within 24 hrs of stent placement. Late complications (>24 hrs) occurred in 77% of patients, of which 37% were clinically significant or required an interventional procedure. These were mainly due to stent migration (12.2%), fracture (19.5%), or obstructive granulomas (24.4%). The overall granuloma rate of 57% was higher at tracheal sites (59%) than bronchial ones (34%), but not significantly different between Ultraflex and Wallstents. Nevertheless, Wallstents were associated with higher rates of bleeding (5% vs. 30%, p = 0.005) and migration (7% vs. 26%, p = 0.026). Of 10 SEMAS removed using flexible bronchoscopy, only one was associated with incomplete removal of fractured stent wire. Median survival was 3.6 ± 2.7 years. Conclusion Ill patients with inoperable lesions may be considered for treatment with SEMAS.

We administered a 31-question multiple-choice examination to 496 physicians practicing in 13 medical facilities in the United States and Canada to assess their knowledge and understanding of the use of the pulmonary artery catheter and interpretation of data derived from it. The mean test score was 20.7 (67% correct), with an SD of 5.4 and a range of 6 to 31 (19% to 100%). Mean scores varied independently by training, frequency of use of pulmonary artery catheter data in patient treatment, frequency of inserting a pulmonary artery catheter, and whether the respondent's hospital was a primary medical school affiliate. Given the variability in physician understanding of the pulmonary artery catheter, we believe that credentialing policies should be reevaluated and that consideration should be given to restricting its use to individuals with documented competency.

The diagnosis of Pneumocystis carinii pneumonia (PCP) often requires bronchoscopy. In 82 consecutive human immunodeficiency virus (HIV)-positive patients suspected of having PCP, we passed a 14-F catheter into the trachea under local anesthesia without intubation, instilled saline solution, and then collected the secretions by aspiration. Bronchoscopy with collection of bronchial washings and performance of bronchoalveolar lavage (BAL) was then performed and the results were compared. The catheter results were identical with the results of BAL in 77 of 82 patients. This inexpensive technique may provide a reasonable early step in the diagnosis of PCP.

Agents which interact with alpha- or beta-adrenoceptors were evaluated for efficacy in preventing seizures and death from a lethal dose of cocaine. Rats were first pretreated with the test drug(s), then subjected to an intraperitoneal LD86 of cocaine (70 mg/kg). In this model, control vehicle-pretreated animals developed seizures within six minutes, followed by death within 10 minutes. Significant protection against death was afforded by pretreatment with clonidine (0.25 mg/kg), prazocin (5.0 to 20 mg/kg), propranolol (8.0 to 32 mg/kg), or labetalol (40 mg/kg). Surviving animals still experienced seizures as judged through behavior and EEG recordings. Phentolamine did not affect the incidence of seizures or death. Two nonadrenoceptor agents were also studied: hydralazine reduced the incidence of death and seizures at 5.0 and 10 mg/kg, but reserpine did not alter the incidence of death or seizures. A combination of prazocin and propranolol did not provide additional protection compared to single agents. We conclude that the pathogenesis of acute cocaine death is complex, and that this toxicity can be antagonized by agents having either central or peripheral effects.

The efficacy of diazepam, haloperidol, propranolol, and yohimbine in antagonizing the toxic manifestations of d-amphetamine were studied in rats. In the control group of animals given 75 mg/kg intraperitoneal (ip) d-amphetamine, 95% developed seizures, and 100% died in mean times of 12.6 ± 1.0 and 50.1 ± 5.9 minutes, respectively. Significant protection against d-amphetamine-induced death was afforded by pretreatment with haloperidol (1.0 to 20.0 mg/kg) or propranolol (20.0 to 30.0 mg/kg). Diazepam (5.0 to 10.0 mg/kg) significantly reduced the incidence of clinically overt seizures but offered no protection against death. Yohimbine (2.5 to 10.0 mg/kg) was ineffective in preventing either seizures or death. When haloperidol (1.0 mg/kg) was administered in combination with diazepam (2.0 mg/kg), the incidence of death was no different than if haloperidol were given alone. In combination, haloperidol (1.0 mg/kg) and propranolol (10.0 mg/kg) reduced death more than either agent alone. These data support a protective role of haloperidol or propranolol in the treatment of d-amphetamine intoxication and show no protection with diazepam or yoshimbine.

The effect of SCH 23390, a dopamine-one (D1) antagonist, in preventing acute toxicity induced by lethal doses of cocaine, d-amphetamine, and methamphetamine was studied in the rat. Animals were first pretreated with SCH 23390 (0.0, 0.5, 1.0, and 2.5 mg/kg, i.p.) and then were challenged with cocaine (70 mg/kg, i.p., an LD85), d-amphetamine (75 mg/kg, i.p., an LD95), and methamphetamine (100 mg/kg, i.p., an LD90). SCH 23390 did not alter the incidence of stimulant-induced seizures compared to the vehicle controls. Significant protection against cocaine-induced death was afforded only by the lowest dose of SCH 23390 tested. Significant protection against d-amphetamine-induced death was provided by all doses, with a dose dependent effect noted so that the incidence decreased from 95% for vehicle to 30% (p less than or equal to 0.01) with 2.5 mg/kg SCH 23390 pretreatment. No statistically significant reduction in the incidence of methamphetamine-induced death was seen with SCH 23390 pretreatment. The ability of SCH 23390 to protect against d-amphetamine, but apparently not against methamphetamine-induced death, suggests that different mechanisms of toxicity may exist between these drugs at high doses.

Ryanodine receptor isoforms are expressed in both excitable and nonexcitable tissues where they form microsomal Ca2+ release channels broadly involved in shaping cellular signaling. In this report, we provide a detailed structure-activity relationship (SAR) for polychlorinated biphenyl (PCB) congeners and metabolites necessary for enhancing ryanodine receptor type 1 (RyR1) activity using [3H]ryanodine ([3H]Ry) binding analysis. The 2,3,6-Cl PCB configuration is most important for optimal recognition by the RyR1 complex and/or critical for sensitizing its activation. Para substitution(s) diminishes the activity with para-chloro having a higher potency than the corresponding para-hydroxy derivative. The addition of a more bulky para-methyl-sulfonyl group eliminates the activity toward RyR1, supporting the importance of the para positions in binding RyR1. The requirement for an intact major T cell immunophilin FKBP12-RyR1 complex was observed with each of 12 active PCB congeners indicating a common mechanism requiring an immunophilin-regulated Ca2+ release channel. An excellent correlation between the relative potencies for doubling [3H]Ry binding and the corresponding initial rates of PCB-induced Ca2+ efflux indicates that [3H]Ry binding analysis provides a measure of dysregulation of microsomal Ca2+ transport. The SAR for activating RyR1 is consistent with those previously reported in several in vivo and in vitro studies, suggesting that a common mechanism may contribute to the toxicity of noncoplanar PCBs. A practical application of the receptor-based screen developed here with RyR1 is that it provides a quantitative SAR that may be useful in predicting biological activity and risk of mixtures containing noncoplanar PCB congeners that have low or a lack of aryl hydrocarbon receptor activity.

BACKGROUND: Tramadol is a unique analgesic that has been associated with seizures on overdose. OBJECTIVE: To determine the toxic effects associated with tramadol exposure. METHODS: A retrospective chart review of tramadol exposures reported to a multisite, state-wide poison control system over a 2.5-year period was performed. RESULTS: A total of 602 cases were retrieved; 190 had sufficient data for study evaluation. Cases with coingestants or unknown outcomes were eliminated. Of the 190 remaining cases, 55% were females. Acute ingestions represented 90.0%, chronic ingestions 7.9%, and acute on chronic 2.1% of the overdoses. Ages of the patients ranged from 9 months to 80 years. Suicide attempts represented the largest group of exposures. Main symptoms included central nervous system (CNS) depression (27.4%), nausea and vomiting (21.1%), tachycardia (17.4%), and seizures (13.7%). Dosage ranged from a taste amount to 5000 mg. The smallest amount of tramadol associated with seizure was 200 mg, and 84.6% of seizures occurred within 6 hours of time of ingestion. Logistic regression analysis showed an association between seizures and tramadol use in males, chronic use, suicide attempts, intentional abuse or misuse, and tachycardia (HR >100 beats/min). No effect was seen in 36.3% of patients, minor effects in 43.7%, moderate effects in 19.5%, and major effects in 0.5%. Symptoms resolved within 24 hours in 96.7% of the 121 patients who had symptoms. Naloxone improved CNS depression in 7 of 8 patients in whom a response was documented. CONCLUSIONS: Tramadol overdoses frequently cause CNS depression, nausea/vomiting, tachycardia, and seizures. Symptoms generally resolve within 24 hours. Accidental ingestions in children were well tolerated, primarily causing sedation.

The use of recreational drugs of abuse continues to expand without limitations to national boundaries, social status, race, or education. Beyond the prevalence of illicit drug use and dependence, their contribution to the global burden of disease and death are large and troubling. All medical providers should be aware of the evolving drugs of abuse and their medical and social consequences. In addition to heroin and stimulants such as cocaine and methamphetamine, new designer stimulants called "bath salts" and cannabinoids called "spice," along with the abuse of prescription drugs and volatile substances, are now widely recognized problems in many societies. The wide variety and continuingly expanding clinical manifestations of toxicity of recreational drugs of abuse is not widely appreciated by clinicians. This edition attempts to summarize six major classes of drugs of abuse and their clinical effects with special emphasis on their immunological and respiratory effects.

To investigate regional variations in public awareness and utilization of the services of Poison Control Centers (PCC) before and after an intervention.This study examines call rates of different California regions based on the final five regional PCCs prior to the consolidation of these services under a single statewide California Poison Control System (CPCS) and interventions to increase utilization. Awareness surveys were performed before and after a media campaign that was directed primarily to the Los Angeles basin and to a lesser extent other high Hispanic concentration areas. Focus groups were also utilized to better define specific areas of poison knowledge and awareness of CPCS services.Large differences in regional California call rates were seen, with the Los Angeles basin showing the lowest utilization of CPCS services compared with the rest of California. Significant seasonal variation in utilization was also found, with the highest average call rates observed in August and the lowest in February. Focus groups demonstrated that urban awareness of PCC was lower than suburban awareness, particularly in monolingual Hispanic households. An improvement was seen after the institution of a media education campaign that included use of Spanish language material and radio spots. Similar increases in call rates were also seen in Fresno county category, with a higher percentage of Hispanic population that was not as aggressively targeted by the awareness campaign.Significant regional variations in CPCS call rates were found and an increased awareness and utilization was seen in the Los Angeles basin after a directed media campaign compared with most areas of California. Further efforts to increase CPCS utilization in the Los Angeles region, primarily among urban monolingual Hispanics, are needed.

Women who present with pulmonary hypertension during gestation have traditionally been persuaded to terminate their pregnancy. Historically, the mortality associated with this group is very high. Certain patients with a secondary cause of pulmonary hypertension are believed to share similar pathophysiology with primary pulmonary hypertension patients. Recently, new treatments have become available that have slowed disease progression. We present the successful treatment of two patients who presented during late gestation with moderate pulmonary hypertension. Both patients were managed with intravenous vasodilators and anticoagulants without complication. Each patient successfully delivered a healthy child via spontaneous vaginal delivery. The review of the historical management of similar patients including new insights into the etiology of pulmonary arterial hypertension is also included. It highlights the complexity involved in managing such patients and the requirement of a multidisiplinary team approach.

This article aims to review all relevant genetic polymorphism studies that may contribute to the pathogenesis of sepsis with emphasis on polymorphisms of the innate immunity, pro- and anti-inflammatory cytokines, and coagulation mediators.Published articles reporting on studies of associations between genetic polymorphisms, sepsis, septic shock, and other relevant infectious disease models.Research into the pathogenesis of sepsis has led to the development of many potential therapeutic strategies. Several therapeutic agents and treatment modalities have been shown to decrease mortality rates in large, prospective, and randomized clinical trials. However, although these advances have resulted in improved survival for certain patient populations, the overall mortality rate for septic patients remains high. With the rapid development of molecular and genetic techniques, substantial interests have developed in using genomic information to define disease-mediating genetic variants in sepsis. Combined with microarray technology, it is anticipated in the near future that one will be able to tailor drug selection and dosage and predict outcome by correlating genetic profile with disease presentation. Numerous genetic association studies in sepsis have already been reported and more are likely to be published.Although studies examined in this review are of small heterogeneous populations, the identification of strong associations between certain genetic polymorphisms and increased mortality rate or susceptibility to severe sepsis is intriguing and supports further research using this approach. The establishment of these associations does not equal causation, and further research is required in both genetic and molecular aspect of sepsis.

The effective palliation of endobronchial malignancies often involves the use of multiple modalities including surgery, external beam radiation, chemotherapy, or a variety of interventional bronchoscopic techniques. The authors discuss in detail recent advances in interventional bronchoscopy that enhance local tumor control. An integrated and individualized approach to the use of these complementary modalities can provide rapid palliation and may improve survival in a subset of patients.

As part of the Monoclonal Anti-TNF: A Randomized Controlled Sepsis (MONARCS) trial, which enrolled patients with suspected sepsis, we sought to determine whether adequate antibiotic therapy was associated with a decreased mortality rate. The study enrolled 2634 patients, 91% of whom received adequate antibiotic therapy. The mortality rate among patients given adequate antibiotic treatment was 33%, versus 43% among patients given inadequate treatment (P

Objective: To evaluate in Gram-negative sepsis patients the human monoclonal immunoglobulin M antibody (MAB-T88) directed at the enterobacterial common antigen which is a specific surface antigen closely linked to lipopolysaccharide and shared by all members of the Enterobacteriaceae family of Gram-negative bacteria. Design: Prospective, randomized, double-blinded, placebocontrolled, multicenter trial. Setting: Thirty-three academic medical centers in the United States. Patients: Patients were entered with a clinical diagnosis of sepsis, the presence of either shock or multiple organ dysfunction, and presumptive evidence for Gram-negative infection. Interventions: Patients received a single intravenous infusion, over 30 mins, of either 300 mg of MAB-T88 formulated in albumin, or placebo (albumin). Measurements and Main Results: The primary analysis group was prospectively identified as those patients with documented evidence of an infection with bacteria of the family Enterobacteriaceae at any site. The primary end point was survival within the first 28 days. A total of 826 patients were enrolled with 55% (n 455) in the primary analysis group. There were no significant differences between the intervention and control primary analysis group study groups for sites of infection, severity of illness, underlying medical conditions, adequacy of antibiotic or surgical treatment, or other baseline variables except for a higher frequency of chronic renal failure in the MAB-T88 group (4.4% vs. 1.3%, p .051). The average Acute Physiology and Chronic Health Evaluation II scores were 26.8 8.6 (mean SD) in the MAB-T88-treated group and 26.5 8.3 in the placebo-treated group (p .72). There was no significant difference between MAB-T88- and placebo-treated groups during the first 28-day all-cause mortality in the primary analysis group (34.2% vs. 30.8%, p .44) or in all 826 patients enrolled (37.0% vs. 34.0%, p .36). On subset analysis, the use of MAB-T88 was not associated with significant mortality trends. More adverse events were seen with the use of MAB-T88 in the bacteremic enterobacterial common antigen group (p < .05). Conclusions: Use of the human monoclonal antibody, MABT88, did not improve the mortality in patients with presumed Gram-negative sepsis or in those patients with proven enterobacterial common antigen infections. No subset trends were identified that would support further investigation of this agent in sepsis. (Crit Care Med 2003; 31:419 ‐427)

Asthma is a syndrome which is seen by physicians in nearly every specialty and affects millions of people throughout the world. Although the geoepidemiology with respect to prevalence and incidence of asthma does vary, even under the most mild of circumstance, asthma is among the leading causes of school absenteeism, work loss, and physician visits. In the past, it was considered primarily a disorder of childhood. Hence, the adage that children outgrow their asthma. We now realize that children really only outgrow their pediatrician and the genetic predisposition to asthma and bronchial hyperactivity persists throughout life. This issue is devoted to key papers that focus on important clinical problems in allergies and asthma. This issue is dedicated to helping the many sufferers of asthma with the hope that this topic will eventually become a medical anachronism.

Medication adherence among patients with chronic diseases, such as COPD, may be suboptimal, and many factors contribute to this poor adherence. One major factor is the frequency of medication dosing. Once-daily dosing has been shown to be an important variable in medication adherence in chronic diseases, such as COPD. New inhalers that only require once-daily dosing are becoming more widely available. Combination once-daily inhalers that combine any two of the following three agents are now available: 1) a long-acting muscarinic antagonist; 2) a long acting beta2 agonist; and 3) an inhaled corticosteroid. A new once-daily inhaler with both a long-acting muscarinic antagonist, umeclidinium bromide, and a long acting beta2 agonist, vilanterol trifenatate, is now available worldwide for COPD treatment. It provides COPD patients convenience, efficacy, and a very favorable adverse-effects profile. Additional once-daily combination inhalers are available or will soon be available for COPD patients worldwide. The use of once-daily combination inhalers will likely become the standard maintenance management approach in the treatment of COPD because they improve medication adherence.

Despite the 2007 National Asthma Education and Prevention Program Expert Panel 3 guidelines for the treatment of uncontrolled asthma, many patients with poorly controlled asthma still continue to tax the health care system. Controlling asthma symptoms and preventing acute exacerbations have been the foundation of care. Using long-term controller treatments such as inhaled corticosteroids (ICS) and inhaled long-acting beta2-agonists (LABAs) is a common approach. While patient responses to recommended pharmacotherapy may vary, poor adherence to therapy also contributes to poor asthma control. A once-daily combination inhaler, such as fluticasone furoate, an ICS, in combination with vilanterol, a LABA, offers increased convenience and potential improved adherence, which should result in enhanced clinical outcomes and reduced exacerbations. The ICS/LABA combination inhaler of fluticasone furoate and vilanterol is currently approved in the United States for use in the maintenance of chronic obstructive pulmonary disease and to reduce exacerbations. This paper reviews the expanding literature on the efficacy of fluticasone furoate and vilanterol in treating asthma.

Hydroxychloroquine overdoses are rarely reported with 7 previous cases found in the English medical literature. We report a case and review the literature. A 16-year-old girl ingested a handful of hydroxychloroquine 200mg, 30 minutes before presentation and presented with tachycardia (heart rate 110 beats/min), hypotension (systolic blood pressure 63 mm Hg), central nervous system depression, conduction defects (QRS = 0.14 msec), and hypokalemia (K = 2.1 meq/L). She was treated with fluid boluses and dopamine, oxygen, and potassium supplementation. Toxicologic tests confirmed the presence of hydroxychloroquine. The patient's hypotension resolved within 4.5 hours, serum potassium stabilized in 24 hours, and tachycardia gradually decreased over 3 days. Although hydroxychloroquine overdoses are very rare, life-threatening hypotension, conduction problems, and hypokalemia can occur within 30 minutes of ingestion. Symptoms are similar to chloroquine and treatment must be implemented quickly and should be modeled after experience with chloroquine overdoses. Treatment modalities need further study, but current recommendations are: (1) diazepam for seizures and sedation; (2) early intubation and mechanical ventilation; (3) epinephrine for treatment of vasodilation and myocardial depression; (4) potassium replacement with close monitoring of levels; (5) charcoal for gastrointestinal decontamination if ingestion occurred within an hour; (6) high dose diazepam for life-threatening symptoms, until more information becomes available. No value was found for serum alkalinization or extracorporeal methods of drug removal.

Recreational drug use is an epidemic problem in the United States. Case reports of asthma exacerbations following recreational drug usage have increased significantly in the past decade. Cocaine and heroin abuses, in particular, are considered confounding variables in several reports of new onset asthma. Pulmonary function tests in patients who abuse recreational drugs do not consistently reveal an obstructive pattern suggestive of asthma. Tobacco use is associated with worsening asthma, however nicotine addiction is not. Habitual marijuana use, like tobacco use, can lead to a progressive decline in lung function. Drugs of abuse have not been proven to cause asthma, but they may exacerbate pre-existing asthma. The definitive treatment for patients with asthma and a drug abuse habit is abstinence. Physicians need to specifically question their patients about drug usage.

OBJECTIVE: To determine the effect of daily consultation by a team of hospital pharmacists on the accuracy and rapidity of optimizing warfarin therapy. DESIGN: Comparison of a historical control cohort with a prospective cohort matched for treatment indication. SETTING: A 400-bed university teaching hospital. PATIENTS: Sixty consecutive patients hospitalized in 1992 and starting warfarin for the first time, with anticoagulation therapy managed by physicians, were compared with 60 patients matched for warfarin indication hospitalized in 1995, but with anticoagulation therapy managed with pharmacy consultation. RESULTS: Pharmacist management of initial warfarin therapy resulted in a significant reduction in the length of hospitalization compared with physician dosing, from 9.5 ± 5.6 days to 6.8 ± 4.4 days (p = 0.009). The number of patients and patient-days with international normalized ratio (INR) values >3.5 were reduced by pharmacist dosing from 37 patients and 142 days to 16 patients and 29 days, respectively (p < 0.001). Similarly, the number of patients and patient-days with INR >6.0 were reduced from 20 patients and 50 days to two patients and six days, respectively (p < 0.001). There were six documented bleeding complications in 1992 compared with one in 1995 (p = 0.11). The mean INR at discharge was significantly lower in the pharmacy surveillance group, 2.6 ± 0.58, compared with the physician cohort, 3.3 ± 2.1 (p = 0.07). Readmissions after discharge due to bleeding or recurrent thrombosis were reduced from five (at 1 mo) and 10 (at 3 mo) to two and five readmissions, respectively, by pharmacist intervention (p = 0.43). The number of patients with concurrently prescribed drugs known to significantly interact with warfarin was significantly lower (6 vs. 13; p = 0.02) in the pharmacy surveillance group. CONCLUSIONS: Among patients starting warfarin for the first time, daily consultation by a pharmacist significantly decreased the length of hospital stay and the number of patients who received excessive anticoagulation therapy. These findings translate into improved quality of care and potentially significant cost savings.

Patients suffering from toxicological emergencies (TE) represent a small and previously unreported subset of aeromedical transport patients. We analyzed data from a large multicenter study of aeromedical transport patients to identify the percentage of patients transported for TE; we also assessed both severity of illness and requirements for care. Of 1,927 patient flights 32 (1.7%) were for TE. The TE patients had similar APACHE II scores compared to the remainder of the group (12 + 2 vs. 11 ± 0.2) and significantly lower TISS scores (20 ± 2.3 vs. 27 ± 0.4). An in-depth case review of 35 TE patients transported by our two flight programs was also undertaken. In 16 of 35 patients the flight team was judged to have added a significant therapeutic intervention. Three of 35 patients ultimately expired. Two of the three patients died of problems from instability during flight. The review revealed some important considerations for programs undertaking transport of such patients.