James R. Miner

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication

RATIONALE We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. OBJECTIVES We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. METHODS We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. MEASUREMENTS AND MAIN RESULTS Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). CONCLUSIONS Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

Presentation, time to antibiotics, and mortality of patients with bacterial meningitis at an urban county medical center

Our objective was to analyze the presentation, time to antibiotics, treatment, and mortality of patients with bacterial meningitis at a large urban county hospital over a 10-year period. A retrospective chart review of all patients with the diagnosis of bacterial meningitis was done. Information concerning presentation, etiologic organisms, treatment (including time to antibiotics), and outcomes were collected and analyzed. There were 165 charts reviewed with 171 total cases of bacterial meningitis. For adults with community-acquired meningitis, the mortality rate was 14%, for children it was 1.6%. Seventy-six percent of patients received antibiotics in the Emergency Department (ED) with a mean time to antibiotics of 1:08 h +/- 13 min. The rest received them as inpatients with a mean time to antibiotics of 6 +/- 9 h. The mortality rate for patients with community-acquired disease who received an Emergency Department antibiotic was 7.9%; for patients who received their antibiotics as inpatients the mortality rate was 29%. Our results indicate that the mortality rates from bacterial meningitis at our institution are lower than previously published results. Furthermore, our study supports the concept that the early administration of antibiotics in the ED may reduce mortality and may be an explanation of the lower mortality rates seen here.

Impact of Physician and Patient Gender on Pain Management in the Emergency Department—A Multicenter Study

OBJECTIVE Pain is a complex experience influenced by factors such as age, race, and ethnicity. We conducted a multicenter study to better understand emergency department (ED) pain management practices and examined the influence of patient and provider gender on analgesic administration. DESIGN Prospective, multicenter, observational study. SETTING Consecutive patients, >or=8-years-old, presenting with complaints of moderate to severe pain (pain numerical rating scale [NRS] > 3) at 16 U.S. and three Canadian hospitals. OUTCOMES MEASURES Receipt of any ED analgesic, receipt of opioids, and adequate pain relief in the ED. RESULTS Eight hundred forty-two patients participated including 56% women. Baseline pain scores were similar in both genders. Analgesic administration rates were not significantly different for female and male patients (63% vs 57%, P = 0.08), although females presenting with severe pain (NRS >or=8) were more likely to receive analgesics (74% vs 64%, P = 0.02). Female physicians were more likely to administer analgesics than male physicians (66% vs 57%, P = 0.009). In logistic regression models, predictors of ED analgesic administration were male physician (odds ratio [OR] = 0.7), arrival pain (OR = 1.3), number of pain assessments (OR = 1.83), and charted follow-up plans (OR = 2.16). With regard to opioid administration, female physicians were more likely to prescribe opioids to females (P = 0.006) while male physicians were more likely to prescribe to males (P = 0.05). In logistic regression models, predictors of opioids administration included male patient gender (OR = 0.58), male patient-physician interaction (OR = 2.58), arrival pain score (OR = 1.28), average pain score (OR = 1.10), and number of pain assessments (OR = 1.5). Pain relief was not impacted by gender. CONCLUSION Provider gender as opposed to patient gender appears to influence pain management decisions in the ED.

Randomized Clinical Trial of Propofol Versus Ketamine for Procedural Sedation in the Emergency Department

OBJECTIVES The objective was to compare the occurrence of respiratory depression, adverse events, and recovery duration of propofol versus ketamine for use in procedural sedation in the emergency department (ED). METHODS This was a randomized nonblinded prospective clinical trial of adult patients undergoing procedural sedation for painful procedures in the ED. Patients with pain before the procedure were treated with intravenous (IV) morphine sulfate until their pain was adequately treated at least 20 minutes before starting the procedure. Patients were randomized to receive either propofol 1 mg/kg IV followed by 0.5 mg/kg every 3 minutes as needed or ketamine 1.0 mg/kg IV followed by 0.5 mg/kg every 3 minutes as needed. Doses, vital signs, nasal end-tidal CO(2) (ETCO(2)), and pulse oximetry were recorded. Subclinical respiratory depression was defined as a change in ETCO(2) of >10 mm Hg, an oxygen saturation of <92% at any time, or an absent ETCO(2) waveform at any time. Clinical interventions related to respiratory depression were noted during the procedure, including the addition of or increase in the flow rate of supplemental oxygen, the use of a bag-valve mask apparatus, airway repositioning, or stimulation to induce breathing. After the procedure, patients were asked if they experienced pain during the procedure and had recall of the procedure. Physicians were asked to describe any adverse events or the occurrence of recovery agitation. RESULTS One-hundred patients were enrolled; 97 underwent sedation and were included in the analysis. Fifty patients received propofol and 47 received ketamine. Subclinical respiratory depression was seen in 20 of 50 patients in the propofol group and 30 of 47 patients in the ketamine group (p = 0.019, effect size 22.8%; 95% CI = 4.0% to 43.6%). Clinical interventions related to respiratory depression were used in 26 of 50 propofol patients and 19 of 47 ketamine patients (p = 0.253, effect size = -13.7%; 95% CI = -33.8% to 6.4%). The median times of the procedures were 11 minutes (range = 4 to 33 minutes) for the ketamine group versus 10 minutes (range = 5 to 33 minutes) for the propofol group (p = 0.256). The median time to return to baseline mental status after the procedure was completed was 14 minutes (range = 2 to 47 minutes) for the ketamine group and 5 minutes (range = 1 to 32 minutes) for the propofol group (p < 0.001). Pain during the procedure was reported by 3 of 50 patients in the propofol group and 1 of 47 patients in the ketamine group (effect size = -3.9%, 95% confidence interval [CI] = -11.9 to 4.1). Recall of some part of the procedure was reported by 4 of 50 patients in the propofol group and 6 of 47 patients in the ketamine group (effect size = 4.8%, 95% CI = -7.6% to 17.1%). Forty-eight of 50 procedures were successful in the propofol group and 43 of 47 in the ketamine group (p = 0.357, effect size = 0.3%; 95% CI = -7.8% to 8.4%). Recovery agitation was reported in 4 of 50 in the propofol group and 17 of 47 in the ketamine group (effect size = 28.2%, 95% CI = 12.4% to 43.9%). CONCLUSIONS This study detected a higher rate of subclinical respiratory depression in patients in the ketamine group than the propofol group. There was no difference in the rate of clinical interventions related to respiratory depression, pain, or recall of the procedure between the groups. Recovery agitation was seen more frequently in patients receiving ketamine than in those receiving propofol. The time to regain baseline mental status was longer in the ketamine group than the propofol group. This study suggests that the use of either ketamine or propofol is safe and effective for procedural sedation in the ED.

Human cardiovascular effects of a new generation conducted electrical weapon

OBJECTIVES The conducted electrical weapon (CEW) is used by law enforcement to control potentially violent people. Much of the research in CEW safety has focused on the TASER X26, which uses a single deployment cartridge. New Generation CEW (NGCEW) technology has been developed that uses a different circuit and multiple cartridges that can be simultaneously deployed. The objective of this study is to examine the cardiovascular effects of the NGCEW in different deployment possibilities. METHODS This was a prospective study of human subjects during NGCEW training courses. Subjects received a NGCEW probe deployment to the frontal torso in 1 of 3 configurations: 2, 3,or 4 embedded probes and then underwent a 10-s exposure. Before and after vital signs, electrocardiograms (ECGs), and serum troponin I values were obtained. Real-time echocardiography was utilized before, during and after the exposure to evaluate heart rate and rhythm. RESULTS Initially, a 1st version NGCEW (NGCEWv1) that was in the final stages of manufacturer verification was used at the training courses. It had not been publicly released. During a NGCEWv1 exposure with 2 probes, there was an apparent brief episode of cardiac capture. Testing was halted and the manufacturer was notified. The device was redesigned and the study continued when a redesigned, 2nd version (NGCEWv2) was used. The NGCEW1 was studied in 8 subjects. The NGCEWv2 was studied in 45 subjects with no evidence of cardiac capture. There were no important post-exposure vital sign, troponin I or ECG changes found in any volunteers. CONCLUSIONS An apparent brief myocardial capture event occurred with the NGCEWv1. This device was not released and was redesigned. The NGCEWv2 appears to exhibit a reasonable degree of cardiac safety with frontal torso exposures and multiple probe combination configurations.

Prolonged TASER use on exhausted humans does not worsen markers of acidosis

OBJECTIVE There are safety concerns about TASER conducted electrical weapon (CEW) use on humans, and there have been media reports of adverse human outcomes after CEW exposure. Conducted electrical weapons are often used on physically exhausted subjects. A single CEW application of a CEW is generally accepted to be 5 seconds of exposure. Some exposures in reality involve more than 5 seconds. We sought to determine if a prolonged (15 seconds) CEW exposure on exhausted humans caused acidosis, hyperkalemia, serum lactate change, or troponin change. METHODS This was a prospective study of generally healthy human volunteers. Medical histories and baseline serum values were obtained, and several of the volunteers did have acute or chronic medical problems. Subjects underwent an exercise protocol until subjective exhaustion. Exhaustion was defined by the volunteer no longer being able to perform the exercise at a given pace. Blood was drawn immediately (defined as within 20 seconds) after exercise and was immediately followed by a 15-second CEW exposure. Blood was drawn immediately after exposure and again at 16 to 24 hours after exposure. Blood was analyzed for pH, pco(2), potassium, lactate, and troponin. Data were compared using Wilcoxon signed rank tests. RESULTS There were 38 subjects enrolled with an average age of 39 years. The following health conditions were reported among the volunteers: hypertension (2), gastritis/reflux (2), active respiratory tract infections (3), asthma (2), chronic muscular pain conditions (4), pituitary adenoma (1) and glaucoma (1). Sixteen volunteers reported use of prescription medication at the time of their participation. The median initial pH of 7.38 (interquartile range [IQR], 7.35-7.40) decreased to 7.23 (IQR, 7.19-7.31) immediately after exercise. Immediately after exposure, median pH was 7.22 (IQR, 7.18-7.25). It was 7.39 (IQR, 7.37-7.43) at 24 hours. The pCO2 increased from 46.3 (IQR, 43.0-54.5) to 57.4 (IQR, 49.9-67.7) immediately after exercise, decreased to 51.3 (IQR, 44.4-65.0) immediately after exposure, and was 46.3 (IQR, 42.7-51.7) at 24 hours. Lactate increased from a median of 1.65 (IQR, 1.14-2.55) to 8.39 (IQR, 6.98-11.66) immediately after exercise, increased to 9.85 (IQR, 7.70-12.87) immediately after exposure, and was 1.02 (IQR, 0.91-1.57) at 24 hours. Serum potassium increased from 3.9 (IQR, 3.8-4.4) to 4.2 (IQR, 4.0-4.9) immediately after exercise, decreased to 3.8 (IQR, 3.7-4.4) immediately after exposure, and was 4.1 (IQR, 3.9-4.6) at 24 hours. No troponin elevations were detected. CONCLUSION Prolonged CEW application on exhausted humans was not associated with worsening change in pH or troponin. Decreases in pCO2 and potassium and a small increase in lactate were found. Worsening acidosis theories due to CEW use in this population are not supported by these data.

Acidosis and catecholamine evaluation following simulated law enforcement "use of force" encounters.

OBJECTIVES Law enforcement authorities are often charged with controlling resisting suspects. These encounters sometimes result in the sudden and unexpected death of the suspect. Drug intoxication, excited delirium syndrome, or excessive uses of force are factors that are often blamed, but sometimes the mechanism of these deaths is not fully understood. It is possible that worsening acidosis or excessive catecholamine release play a part. The objective of this study was to determine the effect on markers of acidosis and catecholamines of various tasks intended to simulate common arrest-related situations. METHODS Subjects were assigned to one of five task groups: 1) a 150-meter sprint and wall hurdle (simulated flight from arrest); 2) 45 seconds of striking a heavy bag (simulated physical resistance); 3) a 10-second TASER X26 electronic control device exposure; 4) a fleeing and resistance exercise involving a law enforcement dog (K-9); or 5) an oleoresin capsicum (OC) exposure to the face and neck. Baseline serum pH, lactate, potassium, troponin I, catecholamines, and creatine kinase (CK) were evaluated. Serum catecholamines, pH, lactate, and potassium were sampled immediately after the task and every 2 minutes for 10 minutes posttask. Vital signs were repeated immediately after the task. Serum CK and troponin I were evaluated again at 24 hours posttask. RESULTS Sixty-six subjects were enrolled; four did not complete their assigned task. One subject lost the intravenous (IV) access after completing the task and did not have data collected, and one subject only received a 5-second TASER device exposure and was excluded from the study, leaving 12 subjects in each task group. The greatest changes in acidosis markers occurred in the sprint and heavy bag groups. Catecholamines increased the most in the heavy bag group and the sprint group and increased to a lesser degree in the TASER, OC, and K-9 groups. Only the sprint group showed an increase in CK at 24 hours. There were no elevations in troponin I in any group, nor any clinically important changes in potassium. CONCLUSIONS The simulations of physical resistance and fleeing on foot led to the greatest changes in markers of acidosis and catecholamines. These changes may be contributing or causal mechanisms in sudden custodial arrest-related deaths (ARDs). This initial work may have implications in guiding applications of force for law enforcement authorities (LEAs) when apprehending resisting subjects.

Randomized Clinical Trial of Propofol With and Without Alfentanil for Deep Procedural Sedation in the Emergency Department

OBJECTIVES The objectives were to compare the efficacy, occurrence of adverse events, and recovery duration of propofol with and without alfentanil for use in procedural sedation in the emergency department (ED). METHODS This was a randomized nonblinded prospective trial of adult patients undergoing procedural sedation for painful procedures in the ED. Patients with pain before the procedure were given intravenous (IV) morphine sulfate until their pain was adequately treated at least 20 minutes before starting the procedure. Patients received 1 mg/kg propofol either with or without a supplemental dose of 10 mug/kg alfentanil for deep procedural sedation. Doses, vital signs, nasal end-tidal CO(2) (ETCO(2)), pulse oximetry, and bispectral electroencephalographic (EEG) analysis scores were recorded. Subclinical respiratory depression was defined as a change in ETCO(2) of >10 mmHg, an oxygen saturation of <92% at any time, or an absent ETCO(2) waveform at any time. Clinical events related to respiratory depression were noted during the procedure, including the addition of or increase in the flow rate of supplemental oxygen, the use of a bag-valve mask apparatus, airway repositioning, or stimulation to induce breathing. After the procedure, patients were asked if they experienced pain during the procedure or had recall of the procedure. RESULTS A total of 150 patients were enrolled; 146 underwent sedation and were included in the analysis. Seventy-four patients received propofol, and 71 received propofol with alfentanil. No clinically significant complications were noted. Subclinical respiratory depression was seen in 24/74 patients in the propofol group and 30/71 patients in the propofol/alfentanil group (effect size = 9.8%, 95% CI = -5.8% to 25.5%). Clinical signs of respiratory depression included an increase in supplemental oxygen use in 25 of the 74 propofol patients and 31 of the 71 propofol/alfentanil patients (effect size 9.9%, 95% CI = -5.9% to 25.7%), the use of bag-valve mask apparatus in seven patients in the propofol group and 12 in the propofol/alfentanil group (effect size = 5.6%, 95% CI = -3.5% to 18.4%), airway repositioning in 13 propofol patients and 20 propofol/alfentanil patients (effect size = 10.6%, 95% CI = -3.0% to 24.2%), and stimulation to induce breathing in 11 propofol patients and 20 propofol/alfentanil patients (effect size = 13.3%, 95% CI = 0.1% to 26.5%). The total time of the procedure was longer for the alfentanil/propofol group (median = 11 minutes, range = 5-22 minutes) than for the propofol group (median = 9 minutes, range = 1 to 43 minutes; effect size = 1.93 minutes, 95% CI = 0.73 to 2.58, p = 0.02). Pain during the procedure was reported by 10 of the 74 patients in the propofol group and 7 of the 71 patients in the propofol/alfentanil group (effect size = 4.5%, 95% CI = -6.8% to 14.1%). Recall of some part of the procedure was reported by 12 patients in the propofol group and 9 in the propofol/alfentanil group (effect size = 3.5%, 95% CI = -7.9% to 15.0%). All procedures were successfully completed. CONCLUSIONS The use of supplemental alfentanil with propofol for procedural sedation did not result in a difference in reported pain or recall immediately after the procedure. There was an increase in the proportion of patients who required stimulation to induce respiration during the procedure in patients who received propofol with supplemental alfentanil. The addition of supplemental opioid to procedural sedation with propofol does not appear beneficial.

Echocardiographic evaluation of TASER X26 probe deployment into the chests of human volunteers

Several animal studies have shown that the TASER X26 (TASER International, Scottsdale, Ariz) conducted electrical weapon can electrically capture the myocardium when discharged on the thorax. These results have not been reproduced in human echocardiographic studies. A primary limitation of those human studies is that the TASER device was connected by taping the wires into conductive gel on the skin surface of the thorax. This study overcomes those limitations. In this study, a training instructor discharged a TASER X26 into the chests of 10 subjects from a distance of 7 ft so that a 5-second discharge could be administered through the probes as in field exposures. Limited echocardiography was performed before, during, and after discharge. In agreement with 2 prior studies by these authors, the TASER X26 did not electrically capture the human myocardium when used with probe deployment. These data are contrary to animal studies in which capture occurred.

The influence of triage systems and triage scores on timeliness of ED analgesic administration

OBJECTIVES The aim of the study was to examine the association between triage scoring systems and triage priority scores on time to initial emergency department (ED) analgesic administration. METHODS An observational, multicenter, prospective, cohort study was conducted at 20 US and Canadian EDs. Centers from the United States used the Emergency Severity Index triage system or 1 of 3 unvalidated triage systems. Canadian centers used the Canadian Triage and Acuity Scale. Patients aged 8 years or older who presented to the ED with a chief complaint of moderate to severe pain (>3 on a 10-point numerical rating scale) and who were ultimately discharged home were eligible for study enrollment. Triage score, triage system, pain rating on arrival, and time of initial analgesic administration were recorded. RESULTS Among 842 enrolled subjects, 506 (60%) received an analgesic while in the ED. Lower-acuity patients consistently waited longer for analgesics. On multivariate modeling, presenting pain intensity, total time spent in the ED, white ethnicity, and triage system were associated with time to initial analgesic administration. Emergency departments using the Canadian Triage and Acuity Scale triage system exhibited the lowest rates of analgesic use and displayed longer median times to initial analgesic administration. CONCLUSIONS Although there were some differences between triage systems, all sites and systems demonstrated unacceptably long times to analgesic provision. Many patients with moderate to severe pain received no analgesic during their ED stay. Future studies should examine whether ED overcrowding impacts timeliness of analgesic administration and identify specific strategies to improve pain management practices in this challenging environment.