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Biomedical subjects

S L Beal

Publications and source records attributed to S L Beal.

At least 19 recordsLinked to original sources
PubMed1991

A simulation study comparing designs for dose ranging.

Only with knowledge of the (prior) distribution of dose-response parameters in a population, can one determine both the initial dose of a drug for chronic administration to an individual (such as the dose producing a fixed degree of response in a fixed proportion of the population) and an appropriate subsequent (adjusted) dose (such as the dose yielding a desirable response according to the posterior parameter distribution, given an observed response to an initial dose). The currently FDA-sanctioned design for a dose-ranging study, the parallel-dose design, assigns just one of several doses to each patient. It does not provide good information on the distribution of individual dose-response parameters. A cross-over design assigns several dose levels to each patient. It therefore can provide better information, but does not resemble clinical practice. Consequently, study participants must be restricted to patients who can tolerate such non-therapeutic drug exposure, posing problems in extrapolation of study results to other types of patients. A titration or dose-escalation design begins all patients on placebo and, except for those patients assigned to a placebo-only group, escalates the dose for a patient at preset intervals only when clinical response at lower doses is inadequate. It both exposes patients to several dose levels and resembles good clinical practice, allowing study of a representative patient sample. We report here the simulation results of parameter estimation for the three designs when the data arise from complex and realistic dose-response models and/or with certain complications in study execution. The dose-escalation design clearly performs better overall than the parallel-dose design for the models considered here, and generally, just a little worse than the cross-over design. These results support the conclusion that for dose ranging, depending on the demands of the clinical situation, one should use either the cross-over or the dose-escalation design.

Algorithms↗
PubMed1991

Mean time parameters for generalized physiological flow models (semihomogeneous linear systems).

This note gives expressions for recirculation mean time parameters of the disposition kinetics of particles in a semihomogeneous stationary linear system. In such a system each compartment may have an arbitrary single-pass disposition function, rather than a known parametric (usually monoexponential) one. Such systems provide a generalization of physiological flow models. Given observations of arterial blood concentrations and tissue amounts, and making the additional assumptions that (i) the fraction of total blood flow exiting each tissue that goes to each other tissue is constant and known, and (ii) the fraction of drug entering each tissue that is eliminated to the outside is constant and known, the input to each tissue can be known, and therefore both its total blood flow and its single-pass disposition function can be estimated. Recirculation mean time parameters can be computed from these estimates. Application to real thiopental data is presented as an example.

Mathematical Computing↗
PubMed1991

Maxillofacial trauma: a potentially fatal injury.

Trauma remains one of the fastest growing causes of death in the United States, especially within the young adult population. Injuries to both the soft tissue and bony skeleton of the face constitute a high percentage of all traumatic admissions that pass through many emergency rooms. Because maxillofacial injuries are often dramatic, they can easily divert attention away from other medical priorities. In spite of numerous significant advances, the management of maxillofacial trauma remains a challenging problem for all reconstructive surgeons. From reading the literature, it can be assumed that maxillofacial trauma is rarely life threatening or an immediate cause of death, unless associated with airway compromise. We present our experience with 6 illustrative patients who either succumbed to complications or had life-threatening exsanguination secondary to isolated facial trauma.

Adult↗
PubMed1990

Fatal hepatic hemorrhage: an unresolved problem in the management of complex liver injuries.

The operative records of 683 patients who required an exploratory laparotomy for trauma with the findings of a liver injury were reviewed. Of the 683 patients 18% (121) sustained severe liver injuries with difficult to control hemorrhage, and 82% of the deaths, in this group of severe liver injuries, were due to exsanguination. A critical analysis of the specific surgical techniques used for hemostasis was undertaken. Hepatotomy with subsequent direct vascular and/or biliary duct repair or ligation was used in 44% of the cases and was successful 87% of the time. Hepatic resection was employed in 10% of the cases with a 50% mortality. Liver packs were used in 29% of the cases which included 14 hepatic vein and six retrohepatic vena caval injuries and five extensive bilobar parenchymal disruptions. The survival rate for this group of patients was 86%. Vascular isolation of the liver was used 8.3% of the cases and was successful 40% of the time. An algorithm for the successful surgical control of hemorrhage from severe liver injuries including indications and contra-indications of specific surgical techniques is presented.

Adolescent↗
PubMed1989

Successful atrial caval shunting in the management of retrohepatic venous injuries.

Over a 3-year period, 519 patients underwent laparotomy for liver injuries. Nine (2 percent) required insertion of an atrial caval catheter to control hemorrhage from perihepatic venous injuries. In three cases, the shunt arrested the hemorrhage, allowing successful surgical repair of the venous injuries. From a careful analysis of our experience, we have identified common errors made in shunt placement, developed a modified atrial caval catheter, and have simplified the surgical technique for insertion.

Adolescent↗
PubMed1989

Rapid venous access using saphenous vein cutdown at the ankle.

Injured adults can usually be treated adequately with peripheral intravenous lines. However, in hypotensive patients, alternative techniques such as venous cutdown may be necessary. There are no adult studies that document the success rate or time required to complete this procedure in the emergent situation. During a 1-year period, 73 cutdowns were attempted on 56 patients. Sixty-two of these attempts resulted in venous cannulation with a free flow of fluid (84.9%). The average time required for placement was 4.9 minutes. First-year residents had a significantly lower success rate (70%) than emergency department staff (89%) or second- through fifth-year surgical residents (94%). One patient who lived developed a local cellulitis. There were no other complications. In the hands of an experienced operator, saphenous vein cutdown at the ankle is a reliable method of rapidly gaining venous access in the adult patient. There are few immediate or late complications if the catheter is removed within 24 hours.

Adult↗
PubMed1989

Study designs for dose-ranging.

Premarketing dose-ranging studies of a drug are done to establish a reasonable initial dose. According to the current procedure sanctioned by the Food and Drug Administration, each patient is given one of several possible doses, including placebo, after an initial placebo run-in period. Data analysis is based on a model in which the mean response at each dose is independent of the magnitude of the dose. The initial dose is the lowest dose tested that has a response that is statistically significantly greater than the response after placebo administration. We suggest that the present conceptual approach to, and standard study design and analysis for, dose-ranging studies be changed. We believe one must begin with a parametric model for patient-specific dose-response curves. Knowledge of the distribution of these curves in a population provides a basis for choice of an initial dose (e.g., the dose that achieves a given response in a given fraction of patients) and, after observation of response to an initial dose, for choice of an incremental dose for a specific patient (by use of Bayes rule). The current parallel-dose design can provide only poor information about the distribution of dose-response curves, biased estimates of the typical curve, and little information on interpatient variability. Crossover studies provide better information. In studies in which a parametric patient-specific dose-response model is used, a dose-escalation design provides no less information than a crossover design, and it has ethical advantages that allow a more representative patient group and clinical setting to be studied.

Analysis of Variance↗
PubMed1989

Semiparametric approach to pharmacokinetic-pharmacodynamic data.

A semiparametric model for analysis of pharmacokinetic (PK) and pharmacodynamic (PD) data arising from non-steady-state experiments is presented. The model describes time lag between drug concentration in a sampling compartment, e.g., venous blood (Cv), and drug effect (E). If drug concentration at the effect site (Ce) equilibrates with arterial blood concentration (Ca) slower than with Cv, a non-steady-state experiment yields E vs. Cv data describing a counterclockwise hysteresis loop. If Ce equilibrates with Ca faster than with Cv, clockwise hysteresis is observed. To model hysteresis, a parametric model is proposed linking (unobserved) Ca to Cv with elimination rate constant kappa ov and also linking Ca to Ce with elimination rate constant kappa oe. When kappa oe is greater than (or less than) kappa ov clockwise (or counterclockwise) hysteresis occurs. Given kappa oe and kappa ov, numerical (constrained) deconvolution is used to obtain the disposition function of the arterial compartment (Ha), and convolution is used to calculate Ce given Ha. The values of kappa oe and kappa ov are chosen to collapse the hysteresis loops to single curves representing the Ce-E (steady-state) concentration-response curve. Simulations, and an application to real data, are reported.

Humans↗
PubMed1989

Traumatic hemipelvectomy: a catastrophic injury.

Traumatic hemipelvectomy is a catastrophic injury resulting from violent blunt shearing forces which cause massive skin, bone, and soft-tissue destruction. The initial extent of the injury as well as the complexity of the consequent problems is staggering. As such it constitutes one of the major challenges seen by trauma surgeons. Patients surviving traumatic hemipelvectomy are rare. We found a total of 36 cases reported in this century. The University of California at Davis General Surgery Trauma Service admitted 9,369 major trauma victims from June 1985 to May 1988. During this 3-year period eight patients sustained a traumatic hemipelvectomy, of whom three survived. Given the complexity, yet rarity, of this injury, a review of the world literature was undertaken to compile collective experiences to aid surgeons in the management of this injury.

Adolescent↗
PubMed1989

Sample size determination for confidence intervals on the population mean and on the difference between two population means.

Sample size determination is usually based on the premise that a hypothesis test is to be used. A confidence interval can sometimes serve better than a hypothesis test. In this paper a method is presented for sample size determination based on the premise that a confidence interval for a simple mean, or for the difference between two means, with normally distributed data is to be used. For this purpose, a concept of power relevant to confidence intervals is given. Some useful tables giving required sample size using this method are also presented.

Biometry↗
PubMed1988

Blunt diaphragm rupture. A morbid injury.

A review of our past year's trauma experience revealed that we admitted an average of three patients per month with blunt diaphragm rupture, a total of 39 ruptures in 37 patients. Twenty patients (54%) presented to the emergency room in shock. Thirty patients (81%) required urgent airway intervention. All but one patient had associated injuries. Diaphragm rupture is difficult to diagnose; it was not initially recognized in 69% of cases. Chest roentgenogram was often nondiagnostic. Peritoneal lavage gave false-negative results. We ultimately failed to diagnose diaphragm rupture in only three cases. We attributed our low incidence of missed injury to an aggressive approach in the severely injured patient population, where exploratory laparotomy is a routine part of the complete evaluation. One third of the ruptures were on the right side. The complication rate was 82%, excluding a mortality rate of 40.5%. High morbidity and mortality were related primarily to associated injuries.

Adolescent↗
PubMed1988

The risk of splenorrhaphy.

The main reason for splenorrhaphy is to prevent the occurrence of overwhelming postsplenectomy sepsis. This fear of postsplenectomy sepsis has led to an enthusiasm for splenic salvage to the extent that it may be felt that the injured spleen must be saved at all costs. However, if that is valid, the complications that result from splenic salvage must not exceed the risk incurred by loss of this organ. To assess this, 119 splenic injuries treated by splenorrhaphy were reviewed. These were major splenic injuries that were actively hemorrhaging at laparotomy and, therefore, required specific operative intervention for hemostasis. There were 14 complications in 11 patients (11.8%) directly attributed to the splenorrhaphy. In one patient, the repaired spleen rebled 17 days postoperatively, necessitating splenectomy. Ten patients had persistent or recurrent bleeding, requiring blood transfusions. Three of these underwent reexploration for additional hemostasis. Blood transfusion in association with splenorrhaphy has not previously been considered a complication. However, the literature clearly documents that the risk of blood transfusion heavily outweighs the risk of postsplenectomy sepsis. Therefore, if blood transfusion becomes a necessary adjunct for successful splenorrhaphy, then splenectomy without transfusion is the safer treatment.

Adolescent↗
PubMed1988

Esophageal perforation following external blunt trauma.

Esophageal perforation from external blunt trauma is an exceedingly rare injury. Since 1900, including our five cases, we found 96 reported cases. The most common cause was violent vehicular trauma. The cervical and upper thoracic esophagus was the site of perforation in 82%. In 78% of the cases, there were findings consistent with esophageal injury, but there was a delay in diagnosis in two thirds of these. The diagnostic difficulty was due to lack of a specific symptom complex for esophageal perforation. Often esophageal perforation was not suspected and the symptoms were attributed to the more common injuries, or the diagnostic workup was incomplete. There were 24 (38%) infectious complications directly related to the esophageal perforation. In 21 of these, there was a delay in diagnosis. There were five (9.4%) deaths due to sepsis from the esophageal perforation.

Accidents, Traffic↗
PubMed1987

Some clarifications regarding moments of residence times with pharmacokinetic models.

The stochastic formulation of linear kinetic models is elaborated in order to introduce some new concepts and help clarify the meaning and role of residence time moments. Certain conditional moments are introduced. Multicompartment and steady-state dosing within the stochastic context are considered. A general model-independent formula for steady state volume of distribution and a new concept of steady-state moments are presented. A technique for constructing a model of a given topology from its moments is also given.

Kinetics↗
PubMed1987

A note on confidence intervals with extended least squares parameter estimates.

It has previously been shown that the extended least squares (ELS) method for fitting pharmacokinetic models behaves better than other methods when there is possible heteroscedasticity (unequal error variance) in the data. Confidence intervals for pharmacokinetic parameters, at the target confidence level of 95%, computed in simulations with several pharmacokinetic and error variance models, using a theoretically reasonable approximation to the asymptotic covariance matrix of the ELS parameter estimator, are found to include the true parameter values considerably less than 95% of the time. Intervals with the ordinary least squares method perform better. Two adjustments to the ELS confidence intervals, taken together, result in better performance. These are: (i) apply a bias correction to the ELS estimate of variance, which results in wider confidence intervals, and (ii) use confidence intervals with a target level of 99% to obtain confidence intervals with actual level closer to 95%. Kineticists wishing to use the ELS method may wish to use these adjustments.

Kinetics↗
PubMed1987

Pulmonary microembolism: a cause of lung injury.

Microthrombi found in the pulmonary capillaries in patients dying with post-traumatic pulmonary insufficiency suggests that pulmonary microembolism (PME) may be etiologically important, but a temporal relationship has not been demonstrated. We used a modified Lim-Blaisdell model of PME to cause a severe ischemic soft tissue injury in dogs. The appearance of microaggregates (MA) in the venous circulation was measured using a laser optical scanning technique. The effect of MA on pulmonary physiologic and histologic parameters was measured and compared to control animals. In the ischemic soft tissue injury group, following restoration of local circulation, the platelet count dropped by 72% (P less than 0.00002), the number of MA increased by 800% (P less than 0.00002), the mean pulmonary artery pressure (PA) increased from 15.6 to 32 mm Hg (P less than 0.00002), and electron micrographs of lung obtained at 4 hr after ischemic insult revealed PM with severe lung injury that was consistent with a capillary membrane leak. The control group never demonstrated a significant change in platelets, MA, PA, or histologic lung injury. These findings imply that MA found in the pulmonary microcirculation are temporally related to the development of physiologic and anatomic lung abnormalities.

Animals↗
PubMed1987

Rupture of inferior thyroid artery aneurysm.

We report a case in which rupture of an aneurysm of the inferior thyroid artery caused respiratory arrest. The aneurysm was embolized successfully by an angiographic technique. Published reports of rupture of thyroid artery aneurysms are reviewed.

Aged↗