Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study.

BACKGROUND: High-sensitivity cardiac troponin I (hs-cTnI) assays have been developed that quantify lower cTnI concentrations with better precision versus earlier generation assays. hs-cTnI assays allow improved clinical utility for diagnosis and risk stratification in patients presenting to the emergency department with suspected acute myocardial infarction. We describe the High-Sensitivity Cardiac Troponin I Assays in the United States (HIGH-US) study design used to conduct studies for characterizing the analytical and clinical performance of hs-cTnI assays, as required by the US Food and Drug Administration for a 510(k) clearance application. This study was non-interventional and therefore it was not registered at clinicaltrials.gov. METHODS: We conducted analytic studies utilizing Clinical and Laboratory Standards Institute guidance that included limit of blank, limit of detection, limit of quantitation, linearity, within-run and between run imprecision and reproducibility as well as potential interferences and high dose hook effect. A sample set collected from healthy females and males was used to determine the overall and sex-specific cTnI 99th percentile upper reference limits (URL). The total coefficient of variation at the female 99th percentile URL and a universally available American Association for Clinical Chemistry sample set (AACC Universal Sample Bank) from healthy females and males was used to examine high-sensitivity (hs) performance of the cTnI assays. Clinical diagnosis of enrolled subjects was adjudicated by expert cardiologists and emergency medicine physicians. Assessment of temporal diagnostic accuracy including sensitivity, specificity, positive predictive value, and negative predictive value were determined at presentation and collection times thereafter. The prognostic performance at one-year after presentation to the emergency department was also performed. This design is appropriate to describe analytical characterization and clinical performance, and allows for acute myocardial infarction diagnosis and risk assessment.

Ninety-minute exclusion of acute myocardial infarction by use of quantitative point-of-care testing of myoglobin and troponin I.

BACKGROUND: Diagnostic strategies with ECG and serum cardiac markers have been used to rule out acute myocardial infarction in 6 to 12 hours. The present study evaluated whether a multimarker strategy that used point-of-care measurement of myoglobin, creatine kinase (CK)-MB, and troponin I could exclude acute myocardial infarction in

Characterization of cerebral energetics and brain pH by 31P spectroscopy after graded canine cardiac arrest and bypass reperfusion.

Recovery of cerebral energy metabolism is used to indicate CNS viability after ischemia. This study utilized 31P nuclear magnetic resonance (NMR) spectroscopy to measure cerebral energy state and intracellular pH in dogs subjected to 8, 12, or 16 min of cardiac arrest and reperfusion using cardiopulmonary bypass. Spectra were obtained throughout ischemia and initial reperfusion and repeated at 30 and 144 h post ischemia. Neurologic deficit scoring was performed at 12 and 24 h post insult and then daily. High-energy phosphates were depleted by the end of all ischemic intervals. Recovery occurred within 60 min of reperfusion and persisted with no differences in the rate of return between groups (p greater than 0.05). Brain pH (pHb) decreased by the end of ischemia in all groups (p less than 0.0001). Neither the pHb nadir nor its recovery differed between groups (p greater than 0.05). Although longterm neurologic outcome differed between groups, the spectra were similar. Assessment of cerebral energy state using 31P NMR spectroscopy does not appear to be a sensitive indicator of neurologic outcome after global ischemia in dogs. Return of high-energy phosphates may be a necessary but not sufficient condition for cerebral recovery after ischemia. The return of high-energy phosphates after a 16-min cardiac arrest, however, indicates a potential for neurological recovery.

Cerebral lactate uptake during cardiopulmonary resuscitation in humans.

Animal studies have shown cerebral lactate uptake under conditions of anoxia and ischemia. Cerebral lactate uptake in humans during cardiopulmonary resuscitation (CPR) has not been previously reported in the literature. Forty-five patients receiving CPR underwent simultaneous sampling through jugular venous bulb, right atrial, and central aortic catheterization. The mean net cerebral lactate uptake (central aortic minus jugular venous bulb) was 0.76 +/- 1.86 and 0.80 +/- 2.03 mM on initial measurement and 10 min later, respectively. Both measurements were statistically significant (p = 0.01) compared to normal controls who have net cerebral output of lactate of -0.18 +/- 0.1 mM. Seventy-one percent of all patients had a cerebral uptake on initial sampling and this gradient persisted upon sampling 10 min later in 68% of the remaining 40 patients who did not have a return of spontaneous circulation. Among multiple variables measured, patients who exhibited a cerebral lactate uptake were 13.2 years younger (p = 0.004), received an additional 7.6 min of CPR (p = 0.05), and had a mean arterial lactate concentration of 4.8 mM higher (p = 0.005) than the nonuptake group. The pathophysiologic explanation of cerebral lactate uptake during CPR is multifactorial and includes utilization and/or diffusion.

Biphasic extrathoracic pressure CPR. A human pilot study.

HYPOTHESIS: Alternating intrathoracic pressure by means of a chest cuirass can cause perfusion and ventilation equal to or better than standard cardiopulmonary resuscitation (CPR) for humans in cardiac arrest. DESIGN: Nonrandomized, nonblinded, crossover pilot study. SETTING: Large urban emergency department. SUBJECTS: Five adult normothermic, nontraumatic, out-of-hospital cardiac arrest patients unresponsive to standard advanced cardiac life support. METHOD: Right atrial and aortic catheters were inserted for pressure measurement and blood gas analysis while the patient was receiving standard CPR by a pneumatic compression device (Thumper). The Thumper was then replaced by a chest cuirass (Hayek Oscillator). Pressure and blood gas measurements were then repeated. RESULTS: The coronary perfusion pressure increased from -1.2 +/- 8.6 mm Hg to 6.2 +/- 6.9 mm Hg for a mean change of 7.4 +/- 3.1 mm Hg (p = 0.006). The compression phase gradient increased 10.0 +/- 21.9 mm Hg (p = 0.364). The venous to arterial PCO2 gradient decreased 44.5 +/- 32.3 mm Hg (p = 0.070). The oxygen extraction ratio increased 1.6 +/- 9.4 percent (p = 0.761). The mean arterial PO2 and PCO2 changed from 252 to 240 mm Hg (p = 0.836) and from 53 to 66 (p = 0.172) mm Hg, respectively. CONCLUSION: The Hayek Oscillator chest cuirass produced a significant improvement in the coronary perfusion pressure. There was a trend for improved systemic perfusion as indicated by an improved compression phase gradient and venous to arterial PCO2 gradient, although this was not supported by the lack of improvement in the oxygen extraction ratio. The cuirass also adequately oxygenates and ventilates unassisted by positive pressure ventilation.

Aortic pressure during human cardiac arrest. Identification of pseudo-electromechanical dissociation.

We measured aortic pressure during clinically apparent cardiac electromechanical dissociation (EMD). Patients with pulse pressures were designated as having pseudo-EMD; those without, as having true EMD. Of the 200 patients studied, 54 presented with EMD, and 40 others developed it during resuscitation. Of the 94 with EMD, 39 were found to have pseudo-EMD. We compared the two types of EMD for electrocardiographic duration, return of palpable pulses, and response to standard- and high-dose epinephrine. The mean resting aortic pressure was 18 +/- 11 mm Hg in patients with true EMD and 28 +/- 11 mm Hg in those with pseudo-EMD. The mean pulse pressure in patients with pseudo-EMD was 6.3 +/- 3.5 mm Hg. Patients with pseudo-EMD had a higher proportion of witnessed arrests, higher PaO2, and lower PaCO2 than patients with true EMD. Patients with pseudo-EMD had shorter QR and QRS durations than patients with true EMD. They had a better response to standard- and high-dose epinephrine than patients with true EMD. Many patients diagnosed clinically to be in EMD have mechanical cardiac activity; this should be considered when interpreting the results of cardiac arrest research.

Venous hyperoxia after cardiac arrest. Characterization of a defect in systemic oxygen utilization.

BACKGROUND: Supranormal mixed venous oxygen saturation (mixed venous hyperoxia), although reported, has never been characterized in humans resuscitated from cardiac arrest (postarrest cardiogenic shock). By contrast, cardiogenic shock without cardiopulmonary arrest (primary cardiogenic shock) is accompanied by mixed venous hypoxia under similar conditions of low oxygen delivery (DO2). The appearance of mixed venous hyperoxia indicates an excessive supply relative to demand in perfused tissue or cellular impairment of oxygen utilization, ie, low systemic oxygen consumption (VO2). Failure to improve VO2 has been associated with a poor outcome in other shock states. STUDY OBJECTIVE: This study evaluates the clinical significance of mixed venous hyperoxia and its implications for impaired systemic oxygen utilization. The oxygen transport patterns in surviving and nonsurviving cardiac arrest patients are compared for their prognostic and therapeutic implications. STUDY DESIGN: Consecutive, nonrandomized series. SETTING: Large urban emergency department (ED). PARTICIPANTS: Adult normothermic, nontraumatic out-of-hospital cardiac arrest patients presenting to the ED who develop a return of spontaneous circulation (ROSC). INTERVENTIONS: On arrival to the ED, a fiberoptic catheter was placed in the central venous position for continuous central venous oxygen saturation monitoring (ScvO2). A proximal aortic catheter was placed via the femoral artery for blood pressure monitoring. Upon ROSC, the fiberoptic catheter was advanced to the pulmonary artery. Mean arterial pressure (MAP), cardiac index (CI), VO2, DO2, systemic oxygen extraction ratio (OER), and systemic vascular resistance index (SVRI-dynes.s/cm5.m2) were measured immediately and every 30 min. The duration of cardiac arrest (DCA) in minutes and amount of epinephrine (milligrams) administered during ACLS was recorded. MEASUREMENTS AND RESULTS: Twenty-three patients were entered into the study. Survivors (living more than 24 h) and nonsurvivors (living less than 24 h) were compared. CONCLUSIONS: These findings indicate an impairment of systemic oxygen utilization in postarrest cardiogenic shock patients. In spite of a lower DO2 than survivors, the OER in nonsurvivors remained lower than expected. Venous hyperoxia is a clinical manifestation of this derangement. Epinephrine dose may have a causal relationship. The inability to attain a VO2 of greater than 90 ml/min.m2 after the first 6 h of aggressive therapy was associated with a 100 percent mortality in 24 h.

Emergency department cardiopulmonary bypass in the treatment of human cardiac arrest.

OBJECTIVE: To study the use of emergency department (ED) femoro-femoral cardiopulmonary bypass (CPB) in the resuscitation of medical cardiac arrest patients. DESIGN: Prospective, uncontrolled trial. SETTING: Urban academic ED staffed with board-certified emergency physicians (EPs). PARTICIPANTS: Ten patients with medical cardiac arrest unresponsive to standard therapy. INTERVENTIONS: Femoro-femoral CPB instituted by EPs. RESULTS: The time of cardiac arrest prior to CPB (mean+/-SD) was 32.0+/-13.6 min. The cardiac output while on CPB was 4.09+/-1.03 L/min with an average of 229+/-111 min on bypass. All 10 patients had resumption of spontaneous cardiac activity while on CPB. Seven of these were weaned from CPB with intrinsic spontaneous circulation. Of these, six patients were transferred from the ED to the operating room for cannula removal and vessel repair while the other patient died in the ED soon after discontinuing CPB. Mean survival was 47.8+/-44.7 h in the six patients leaving the ED. Although these patients had successful hemodynamic resuscitation, there were no long-term survivors. CONCLUSION: CPB instituted by EPs is feasible and effective for the hemodynamic resuscitation of cardiac arrest patients unresponsive to advanced cardiac life support therapy. Future efforts need to focus on improving long-term outcome.

The effect of cardiopulmonary bypass resuscitation on cardiac arrest induced lactic acidosis in dogs.

The adequacy of end organ blood flow following a cardiac arrest varies depending on the artificial reperfusion technique utilized and may critically affect patient outcome. Both oxygen consumption (VO2) and arterial lactate values have previously been used to assess tissue perfusion. Cardiopulmonary bypass resuscitation (CPB) is a reperfusion technique capable of providing near normal end organ blood flow. The purpose of this investigation was to study the effect of femoro-femoral veno-arterial CPB resuscitation compared to standard CPR on VO2 and arterial lactic acid values after a prolonged cardiac arrest. Ten mongrel dogs were electrically fibrillated and left in cardiopulmonary arrest without therapy for 12 min. Resuscitation was attempted according to a standardized protocol utilizing either CPB (n = 5) or standard external CPR (n = 5). Oxygen consumption values and arterial lactic acid samples were obtained at baseline, at timed intervals throughout resuscitation and after return of spontaneous circulation in successfully resuscitated dogs. Baseline hemodynamic and biochemical measurements were similar in both treatment groups (P greater than 0.05). Oxygen consumption (440 +/- 50 ml/min/M2) and mean arterial lactic acid values (7.44 +/- 2.25 mmol/l) were significantly higher at 1 min of resuscitation in CPB-treated dogs compared to dogs treated with CPR (60 +/- 10 ml/min/M2) (3.16 +/- 0.69 mmol/l) respectively (P less than 0.05). Mean arterial lactic acid values rose significantly at each sampling interval during CPR (P less than 0.05) but began to decrease after 5 min of resuscitation in the CPB animals and were not significantly different than baseline after 60 min of bypass (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of arterial and venous volume infusion on coronary perfusion pressures during canine CPR.

Intraarterial (IA) volume infusion has been reported to be more effective than intravenous (IV) infusion in treating cardiac arrest due to exsanguination. A rapid IA infusion was felt to raise intraaortic pressure and improve coronary perfusion pressure (CPP). The purpose of this study was to determine if IA or IV volume infusion could augment the effect of epinephrine on CPP during CPR in the canine model. Nineteen mongrel dogs with a mean weight of 26.3 +/- 4.2 kg were anesthetized and mechanically ventilated. Thoracic aortic (Ao), right atrial (RA) and pulmonary artery catheters were placed for hemodynamic monitoring. Additional Ao and central venous catheters were placed for volume infusion. Ventricular fibrillation was induced and Thumper CPR was begun after 5 min (t = 5). At t = 10, all dogs received 45 micrograms/kg IV epinephrine. Six animals received epinephrine alone (EPI). Five dogs received EPI plus a 500 cc bolus of normal saline over 3 min intravenously (EPI/IV). Another group (n = 8) received EPI plus the same fluid bolus through the aortic catheter (EPI/IA). Resuscitation was attempted at t = 18 using a standard protocol. There was a significant increase in CPP over baseline in all groups. The changes in CPP from baseline induced by EPI, EPI/IV and EPI/IA were 20.6 +/- 3.7, 22.8 +/- 4.2 and 22.2 +/- 2.4 mmHg, respectively. Volume loading did not augment the effect of therapeutic EPI dosing. By increasing both preload and afterload, volume administration may in fact be detrimental during CPR.

Acute bronchial asthma.

Advances in the understanding of the pathophysiology of acute asthma have been reflected in the changing patterns of present treatment and future research. Monitoring objectively the severity of the airway obstruction and its response to treatment will further make the care of the asthmatic patient a more rational event.

Procedures for respiratory function.

The emergency practitioner has a wide array of procedures in his armamentarium for the diagnosis of pulmonary dysfunction. The combination of blood gas analysis, spirometry, peak expiratory measurements, and trans-tissue monitors, coupled with clinical and radiographic findings, can offer a concise picture of pulmonary status. Further emergency medicine research in these areas will provide exciting methods of assessing and monitoring treatment responses for patients with pulmonary dysfunction.

Catheter aspiration for simple pneumothorax.

A prospective study was conducted in the emergency setting to determine the efficacy of treatment of simple pneumothorax by catheter aspiration. Patients who were successfully treated were discharged to home. Sixty-one patients with a total of 76 pneumothoraces were involved in the study. The overall success rate was 75.6%, with an 82% success rate for needle-induced, 75% for traumatic, and 45% for spontaneous pneumothorax. The duration of symptoms, the size of the pneumothorax, the patient's age, and a prior history of pneumothorax did not affect the outcome. The poorest results were noted with spontaneous pneumothoraces, as would be expected since a majority of these patients have preexistent lung disease. Catheter aspiration of simple pneumothorax offers a cost-effective approach to this clinical problem.

Hyperkalemia during human cardiopulmonary resuscitation: incidence and ramifications.

Although hypokalemia has been reported after cardiac arrest and successful resuscitation, experimental data indicate that potassium is released from cells during ischemia. The purpose of this investigation was to study serum potassium concentration ([K+]) during closed chest cardiopulmonary resuscitation (CC-CPR) in humans. Twenty-two patients presenting to the emergency department (ED) in cardiopulmonary arrest had simultaneous measurement of central venous and arterial [K+] and blood gases during CC-CPR utilizing current advanced cardiac life support protocols and a pneumatic chest compressor and ventilator. Mean arterial and central venous [K+] were 5.0 +/- 1.3 and 5.6 +/- 2.9 mEq/L, respectively, (p greater than .05) with 7 patients having [K+] of greater than 6 mEq/L. Significant hyperkalemia does occur in some patients during cardiac arrest and CC-CPR. Because poor tissue perfusion during CC-CPR impairs exchange between the interstitial and intravascular compartments, increases in interstitial [K+] would be expected to be even greater. Interstitial hyperkalemia may play a role in the genesis of wide complex electromechanical dissociation (EMD) seen after prolonged cardiac arrest. Since calcium has long been known to be beneficial in the treatment of hyperkalemia-induced dysrhythmias, the success of calcium chloride in treating wide complex EMD may be on the basis of this phenomenon.

Use of bretylium tosylate as prophylaxis and treatment in hypothermic ventricular fibrillation in the canine model.

We conducted a study to determine if bretylium tosylate (BT) is effective in the prophylaxis and treatment of hypothermic ventricular fibrillation (VF) in the setting of various maneuvers thought to induce this lethal arrhythmia. Twenty-two mongrel dogs were cooled to 24 C after being placed in a cold room. At 24 C, a double-blinded placebo or BT solution was infused. The dogs then were removed from the cold. They underwent the following sequential maneuvers: oral endotracheal extubation and intubation, central line and nasogastric tube placement, vigorous movement, and Swan-Ganz catheter insertion. If VF ensued, arterial blood gases were drawn, and BT was given only if refractory to countershock and epinephrine. Of the dogs that were given placebo, six of 11 (55%) fibrillated with manipulation, as compared with one of 11 (9%) dogs pretreated with BT (P = .067). Three of the 11 dogs that received BT fibrillated within minutes of its infusion. In the placebo dogs that fibrillated, four required BT and two defibrillated with countershock alone or with epinephrine prior to achieving stable rhythms.

Resuscitation of the critically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate.

To describe the simultaneous responses of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), heart rate (HR), shock index (SI = HR/SBP), central venous oxyhemoglobin saturation (ScvO2), and arterial blood lactate concentration (Lact) to resuscitation of critically ill patients in the emergency department (ED), an observational descriptive study was conducted in the ED of an urban teaching hospital. Thirty- six patients admitted from the ED to the medical intensive care unit were studied. Vital signs were measured immediately on arrival to the ED (phase 1). After initial resuscitation and stabilization, ie, HR between 50 and 120 beats/min and MAP between 70 and 110 mm Hg (phase 2), ScvO2 and Lact were measured and additional therapy was given in the ED to increase ScvO2 to > 65% and decrease Lact to < 2 mmol/L, if needed (phase 3). SBP, DBP, MAP, HR. SI, ScvO2, and Lact were measured. Initial resuscitation increased SBP from 103 +/- 39 to 118 +/- 29 mm Hg (P < .05) and MAP from 67 +/- 35 to 82 +/- 22 mm Hg (P < .05) but did not affect DBP (53 +/- 35 to 63 +/- 22 mm Hg, P = NS), HR (110 +/- 26 to 110 +/- 22 beats/min, P = NS) or SI (from 1.3 +/- 0.7 to 1.0 +/- 0.3, P =NS) from phase 1 to phase 2. ScvO2 remained < 65% and/or Lact > 2.0 mmol/L in 31 of 36 patients at phase 2, and additional therapy was required. Lact was decreased (from 4.6 +/- 3.8 to 2.6 +/- 2.5 mmol/L, P < .05) and ScvO2 was increased (from 52 +/- 18 to 65 +/- 13%, P < .05) without significant additional changes in SBP, DBP, MAP, HR, or SI at phase 3. The in-hospital mortality was 14% for this group of patients. It was concluded that additional therapy is required in the majority of critically ill patients to restore adequate systemic oxygenation after initial resuscitation and hemodynamic stabilization in the ED. Additional therapy to increase ScvO2 and decrease Lact may not produce substantial responses in SBP, DBP, MAP, HR, and SI. The measurement of ScvO2 and Lact can be utilized to guide this phase of additional therapy in the ED.