Statistical analysis of joint short-term and long-term survival in resuscitation research

Objective: To develop statistical tools that utilize combined initial survival data and post-resuscitation survival data to test the null hypothesis that true, population-wide outcomes following experimental CPR interventions are not different from control. Method: A new test statistic, d2, for evaluating Type 1 error is derived from a bivariate, two-dimensional analysis of categorical initial resuscitation and post-resuscitation survival data, which are statistically independent because they are obtained during non-overlapping periods of time. The d2 test statistic, which is distributed as a chi-squared distribution, is derived from first principles and validated using Monte Carlo methods of computer simulation for thousands of clinical trials. Results: Under the null hypothesis, the normalized difference in the proportions of patients surviving the initial resuscitation period and the normalized difference in the proportions of such short-term survivors that also survive the post-resuscitation period are jointly distributed in a two-dimensional space as a bivariate standard normal distribution, against which observed intervention and control outcomes can be compared in a test of statistical significance. Typically this two-dimensional approach has greater statistical power to detect true differences, compared to conventional one-dimensional tests. Smaller group sizes (Ns) are usually required to reach statistical significance when both initial survival and post-resuscitation survival are considered together. Such two-dimensional analysis is easily extended to meta-analysis of multiple trials. Conclusions: A straightforward, easy-to-use bivariate test for Type I errors in statistical inference can be done for resuscitation studies reporting both short-term and long-term survival data. Acceptance of such two-dimensional tests of the null hypothesis, as proposed by Hallstrom, can save time, money, effort, and disappointment in the difficult and sometimes frustrating field of resuscitation researc

Circulatory Adjuncts: Newer Methods of Cardiopulmonary Resuscitation

Current standard CPR only provides about one fifth of normal forward blood flow and only about one quarter of the blood flow that is theoretically possible with advanced external techniques. Two such techniques are now approved as optional alternatives in resuscitation guidelines. This chapter reviews modern understanding of the physiology of blood flow during CPR and practical aspects of utilizing more advanced resuscitation methods. When properly performed these methods produce statistically significant increases in survival

Quantitative prediction of body surface potentials from myocardial action potentials using a summed dipole model

This paper demonstrates quantitatively, using streamlined mathematics, how the transmembrane ionic currents in individual cardiac muscle cells act to produce the body surface potentials of the electrocardiogram (ECG). From fundamental principles of electrostatics, anatomy, and physiology, one can characterize the strength of apparent dipoles along a wavefront of depolarization in a local volume of myocardium. Net transmembrane flow of ionic current in actively depolarizing or repolarizing tissue induces extracellular current flow, which sets up a field of electrical potential that resembles that of a dipole. The local dipole strength depends upon the tissue cross section, the tissue resistivity, the resting membrane potential, the membrane capacitance, the volume fraction of intracellular fluid, the time rate of change of the action potential, and the cell radius. There are no unknown, free parameters. There are no arbitrary scale factors. Body surface potentials are a function of the summed local dipole strengths, directions, and distances from the measuring point. Calculations of body surface potentials can be made for the scenarios of depolarization (QRS complex), repolarization (T wave) and localized acute injury (ST segment shifts) and agree well with experimentally measured potentials. This simplified predictive dipole theory provides a solution to the forward problem of electrocardiography that explains from a physiological perspective how the collective depolarization and repolarization of individual cardiac muscle cells create body surface potentials in health and disease

Biomechanics of Retinal Venous Pulsations as Indicators of Intracranial Pressure

The origin of retinal venous pulsations remains an open problem in physiology and medicine; so too, their exact relationship to intracranial pressure. This study takes a mathematical modeling approach to explore details of blood flow through the eye to reveal the mechanism of pulsations. The intravaginal, intraneural, and intraocular segments of the retinal arteries and veins are modeled as connected resistive-capacitive segments. The analysis incorporates two critical mechanical properties of these small blood vessels, not heretofore studied, which become significant under conditions of negative transmural pressures: (1) dramatically reduced compliance during flattening and (2) cross-sectional shape change as internal volume decreases. Intraocular pressure acting on these veins close to the optic disc normally creates fluctuating negative transmural pressure. The observed long diameters of these venous segments become wider during diastole as they empty and flatten and narrower during systole as they refill with blood. Such visible pulsations occur only in models that include nonlinear compliance and constant-perimeter flattening. Further, the pulsations disappear when raised intracranial pressure, raised cavernous sinus pressure, or reduced arteriolar resistance elevates internal pressure in all retinal veins above the level of intraocular pressure. In this case transmural venous pressures are always positive, cross sectional shapes are circular, and compliance is greatly reduced. Then visible retinal venous pulsations disappear. Scenarios are suggested under which intracranial pressure can be estimated quantitatively from physical examination of retinal venous pulsations, if intraocular pressure is also measured

Preclinical Studies of Abdominal Counterpulsation in CPR

Abdominal counterpulsation added to standard cardiopulmonary resuscitation improves blood flow in animal models when compared to chest compressions alone. Similar effects can be demonstrated in analog and digital computer models of the circulation. The technique generates both central aortic and central venous pressure pulses, and successful application of the method depends on maximizing the former and minimizing the latter. Proper technique is important in order to generate the largest possible arteriovenous pressure difference

Choosing inclusion criteria that minimize the time and cost of clinical trials

AIM: To present statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria. METHODS: We consider a two treatment, dichotomous outcome trial that includes a proportion of patients who are strong responders to the tested intervention. Patients are screened for inclusion using an arbitrary number of test results that are combined into an aggregate suitability score. The screening score is regarded as a diagnostic test for the responsive phenotype, having a specific cutoff value for inclusion and a particular sensitivity and specificity. The cutoff is a measure of stringency of inclusion criteria. Total cost is modeled as a function of the cutoff value, number of patients screened, the number of patients included, the case occurrence rate, response probabilities for control and experimental treatments, and the trial duration required to produce a statistically significant result with a specified power. Regression methods are developed to estimate relevant model parameters from pilot data in an adaptive trial design. RESULTS: The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist between 5.6 and 6.1 on a representative 10-point scale of exclusiveness. Potential cost savings for typical trial scenarios range in millions of dollars. As the response rate for controls approaches 50%, the proper choice of inclusion criteria can mean the difference between a successful trial and a failed trial. CONCLUSION: Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of Type II errors

Generalized Fractals for Computer Generated Art: Preliminary Results

This paper explores new types of fractals created by iteration of the functions xn+1 = f1(xn, yn) and yn+1 = f2(xn, yn) in a general plane, rather than in the complex plane. Iteration of such functions generates orbits with novel fractal patterns. Especially interesting are N-th order polynomials, raised to a positive or negative integer power, p. Such functions create novel fractal patterns, including budding, spiked, striped, dragon head, and bat-like forms. The present faculty working paper shows how to create a rich variety of complex and fascinating fractals using this generalized approach, which is accessible to students with high school level skills in mathematics and coding

Relative effectiveness of interposed abdominal compression CPR: sensitivity analysis and recommended compression rates

Interposed abdominal compression (IAC)-CPR incorporates alternating chest and abdominal compressions to generate enhanced artificial circulation during cardiac arrest. The technique has been generally successful in improving blood flow and survival compared to standard CPR; however some questions remain. Objective: To determine why does IAC-CPR produce more apparent benefit in some subjects than in others? and what is the proper compression rate, given that there are actually two compressions (chest and abdomen) in each cycle? Method: Computer models provide a means to search for subtle effects in complex systems. The present study employs a validated 12-compartment mathematical model of the human circulation to explore the effects upon systemic perfusion pressure of changes in 35 different variables, including vascular resistances, vascular compliances, and rescuer technique. CPR with and without IAC was modeled. Results and conclusions: Computed results show that the effect of 100 mmHg abdominal compressions on systemic perfusion pressure is relatively constant (about 16 mmHg augmentation). However, the effect of chest compression depends strongly upon chest compression frequency and technique. When chest compression is less effective, as is often true in adults, the addition of IAC produces relatively dramatic augmentation (e.g. from 24 to 40 mmHg). When chest compression is more effective, the apparent augmentation with IAC is relatively less (e.g. from 60 yo 76 mmHg). The optimal frequency for uninterrupted IAC-CPR is near 50 complete cycles per minute with very little change in efficacy over the range of 20 to 100 cycles/min. In theory, the modest increase in systemic perfusion pressure produced by IAC can make up in part for poor or ineffective chest compressions in CPR. IAC appears relatively less effective in circumstances when chest pump output is high

Drug Induced Changes in Ventricular Defibrillation Threshold

Abstract not availabl