Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment.

BACKGROUND: Cyclooxygenase-2-specific anti-inflammatory drugs (coxibs) and nonspecific nonsteroidal anti-inflammatory drugs have been shown to inhibit experimental fracture-healing. The present study tested the hypothesis that these effects are reversible after short-term treatment. METHODS: With use of a standard model of fracture-healing, identical ED50 dosages of either a nonsteroidal anti-inflammatory drug (ketorolac), a coxib (valdecoxib), or vehicle (control) were orally administered to rats for either seven or twenty-one days and fracture-healing was assessed with biomechanical, histological, and biochemical analyses. RESULTS: When healing was assessed at twenty-one days, the seven-day treatment produced only a trend for a higher rate of nonunion in valdecoxib and ketorolac-treated animals as compared with controls. No differences were observed at thirty-five days. The twenty-one-day treatment produced significantly more nonunions in valdecoxib-treated animals as compared with either ketorolac-treated or control animals (p < 0.05), but these differences disappeared by thirty-five days. The dose-specific inhibition of these drugs on prostaglandin E2 levels and the reversibility of the effects after drug withdrawal were assessed in fracture calluses and showed that ketorolac treatment led to twofold to threefold lower levels of prostaglandin E2 than did valdecoxib. Withdrawal of either drug after six days led to a twofold rebound in these levels by fourteen days. Histological analysis showed delayed remodeling of calcified cartilage and reduced bone formation in association with valdecoxib treatment. CONCLUSIONS: Cyclooxygenase-2-specific drugs inhibit fracture-healing more than nonspecific nonsteroidal anti-inflammatory drugs, and the magnitude of the effect is related to the duration of treatment. However, after the discontinuation of treatment, prostaglandin E2 levels are gradually restored and the regain of strength returns to levels similar to control.

Mechanics of avian fibrous periosteum: tensile and adhesion properties during growth.

We report the results of direct mechanical tests of the fibrous periosteum from the tibiotarsi of white leghorn chicks at 4, 6, 8, 9, 10, 11, 12, and 14 weeks of age using a newly developed sample isolation technique. Additionally, this technique allows the determination of the apparent in vivo load on the fibrous periosteum. The periosteum has a highly nonlinear stress-strain relationship at all ages. For loading below the in vivo level, the periosteum is pliant and mean tensile modulus is 3.35 MPa (+/- 1.84 SD, n = 75). For loading above the in vivo level, tensile stiffness is nearly two orders of magnitude greater. In the region of high stiffness, mean modulus is 229.5 MPa (+/- 89.6, n = 72). In vivo, the periosteum is loaded at the transition between these two stiffness regions. We interpret this as indicating that, in vivo, the collagen fibers of the periosteum are aligned, but subject to minimal loading. Stress levels in the periosteum corresponding to in vivo conditions indicate modest loading, and mean apparent in vivo stress levels are 0.92 MPa (+/- 0.37 SD, n = 67). A second technique demonstrated that the adhesion of the periosteum in the diaphyseal region (1-6 weeks of age) is minimal, but is substantial in the metaphyseal region. The metaphyseal adhesion will affect the transmission of load between the physes. These studies suggest that growth of the fibrous periosteum follows the longitudinal growth of the bone, rather than the periosteum having a direct mechanical influence on growth plate activity. Comparison of tensile properties over the course of growth indicates a substantial increase in periosteal stiffness in the early portion of the growth period, which reaches a maximum at approximately 9 weeks posthatching. There is also a marked decline in periosteal stiffness as growth rate declines in the latest stages of growth (14 weeks). This suggests that the basic properties of periosteal collagen may undergo a transition during the course of this tissue's brief functional lifetime; that is, during long bone growth.

A multi-institutional study of factors associated with fetal death in injured pregnant patients.

HYPOTHESIS: Factors associated with fetal death in injured pregnant patients are related to increasing injury severity and abnormal maternal physiologic profile. DESIGN: A multi-institutional retrospective study of 13 level I and level II trauma centers from 1992 to 1996. MAIN OUTCOME MEASURE: Fetal survival. RESULTS: Of 27,715 female admissions, there were 372 injured pregnant patients (1.3%); 84% had blunt injuries and 16% had penetrating injuries. There were 14 maternal deaths (3.8%) and 35 fetal deaths (9.4%). The population suffering fetal death had higher injury severity scores (P<.001), lower Glascow Coma Scale scores (P<.001), and lower admitting maternal pH (P = .002). Most women who lost their fetus arrived in shock (P = .005) or had a fetal heart rate of less than 110 beats/min at some time during their hospitalization (P<.001). An Injury Severity Score greater than 25 was associated with a 50% incidence of fetal death. Placental abruption was the most frequent complication, occurring in 3.5% of patients and associated with 54% mortality. Cardiotrophic monitoring to detect potentially threatening fetal heart rates was performed on only 61% of pregnant women in their third trimester. Of these patients, 7 had abnormalities on cardiotrophic monitoring and underwent successful cesarean delivery. CONCLUSIONS: Fetal death was more likely with greater severity of injury. Cardiotrophic monitoring is underused in injured pregnant patients in their third trimester even after admission to major trauma centers. Increased use of cardiotrophic monitoring may decrease the mortality caused by placental abruption.

Predicting in-hospital mortality during cardiopulmonary resuscitation.

On the average, 10-15% of patients who undergo cardiopulmonary resuscitation (CPR) following a cardiopulmonary arrest in the hospital environment will survive to be discharged. The purpose of this study was to determine objective factors influencing patient outcome after CPR to determine who should be resuscitated and when to end CPR efforts. The records of 266 patients who underwent in-hospital CPR over a 3-year period were retrospectively analyzed with regard to age, gender, co-morbid conditions, setting of arrest, duration of resuscitation, initial pH and PO2 during resuscitation, and outcome of resuscitative efforts. Twenty-four (9%) patients survived to be discharged from hospital. Eighty-seven (33%) patients arrested in the intensive care unit, 77 (29%) on the ward, 91 (34%) in the emergency room, six (2%) in the cardiac catheterization laboratory and five (2%) in the operating room. There was no significant difference in survival based on location of arrest. Factors associated with a poor prognosis included age greater than 60, co-morbid disease (i.e. pneumonia, sepsis, renal failure, heart disease, etc.), an initial PO2 < 50 mmHg and CPR efforts extending beyond 10 min. Based on this data, guidelines regarding initiation and termination of CPR should be instituted in light of poor outcome in patients over 60 years of age with co-morbid conditions, specifically after 10 min of CPR.

The futility of chest roentgenograms following routine central venous line changes.

OBJECTIVE: To demonstrate chest roentgenograms after central venous line changes over a guidewire delay the use of the central lines and increases charges with no change of morbidity or the rate of complication. METHODS: Retrospective study using the Surgical Intensive Care database followed by a nonrandomized, prospective study of central venous line changes. The total time from the catheter change until chest radiograph confirmation and an analysis of charges was done. RESULTS: The retrospective study of 1,201 central line changes demonstrated no pneumothorax and two central lines malpositioned. The prospective study of 100 patients demonstrated no pneumothorax and one catheter malpositioned. The average time from completion of the central line change until the radiographic confirmation was 60.2 minutes. The charge for the chest x-ray film was $156. CONCLUSIONS: The combined studies composed of 1,301 patients demonstrated no pneumothorax and three malpositioned catheters. This study demonstrates that radiographic confirmation of central venous line placement after routine line change is of no benefit as the malpositioned catheters caused no morbidity, produces significant delays and increases medical charges to the patient. Extrapolation predicts an annual reduction of $46,800 in the Vanderbilt Surgical Intensive Care Unit.

Hypothermia, coagulopathy, and acidosis.

The management of patients requiring a damage control approach taxes the abilities of the best equipped trauma center. These patients present with severe metabolic abnormalities, most notably characterized by a deadly triad of hypothermia, coagulopathy, and acidosis. Using volumetric, oxymetric pulmonary artery catheters, hypothermia and any ongoing cardiovascular abnormalities can be identified quickly and treatment can be monitored. External, forced air rewarming is a valuable technique in treating the patient with hypothermia, as are more invasive modalities, including body cavity lavage. Although there is no shotgun approach to blood component transfusion therapy, the coagulopathy shown by these patients has a time course that is more rapid than stat laboratories can presently keep up with. Given the fulminant nature of this coagulopathy, the authors feel justified in empirically initiating platelet and plasma or cryoprecipitate transfusion on identification of visible coagulopathy. The willingness of trauma surgeons to push the envelope in treating these most severely afflicted patients has allowed patients who once would have certainly died to lead meaningful lives.

The role of osteocytes in bone regulation: mineral homeostasis versus mechanoreception.

Early work on the role of osteocytes in bone regulation suggested that the primary function of these cells was osteolysis. This lytic function was not precisely defined but included mineral homeostasis and at least the initiation of matrix remodeling, if not a primary role in remodeling. This paper is an attempt to promote the concept of osteocytic osteolysis as a method of systemic mineral homeostasis and to separate it from bone remodeling. Although recent investigations have pointed to mechanotransduction as a primary function of osteocytes, resulting in a general abandonment of the osteocytic osteolysis concept, the corpus of evidence suggests that osteocytes likely have a multipurpose role in the biology of bone. The osteocyte network represents an enormous surface area over which the cells interface with the surrounding matrix, useful for both strain detection and matrix mineral access. Osteocytes have been found to possess receptors for PTH, a known regulator of mineral ion homeostasis. Cultured osteocytes placed on dentin slices demonstrated no capacity to pit the dentin, but they were not treated with a regulating factor such as PTH, nor does mineral homeostasis require substantial bone volume removal. Scaling relationships suggest that osteocyte density is inversely proportional to body mass, R(2) = 0.86, and thus directly proportional to metabolic rate. Thus, species with higher metabolic rates (and therefore a greater demand for immediate access to minerals) have more osteocytes per bone volume. Finally, osteocytes express molecules typically associated with nerve cells and which are involved with glutamate neurotransmission. By this system, almost instantaneous messages may be transmitted throughout the network, an important feature in cells whose homeostatic function would be utilized on a scale of seconds, rather than hours or days. Experimental procedures for determining the role of the osteocyte in mineral homeostasis would require calcium mobilization from the bone matrix on a relatively immediate time scale. The experimental procedure would then be coupled with a high resolution histomorphometric analysis of lacunar radiographic area and mineral density. Added to this would be an in vitro study of mineral activation capacity via cultured osteocytes treated with PTH. Osteocytic osteolysis would be confirmed by an increase in the demineralized volume of osteocytic lacunae and the identification of a chemical mechanism by which osteocytes can readily access the mineral portion of their immediate bone matrix. It should also be true that a reverse capacity exists by which osteocytes can remineralize their immediate matrix utilizing alkaline phosphatase for example, a chemical which they, like osteoblasts, are known to generate. It is thus proposed that osteocytes are both mechanoreceptors and systemic mineral homeostasis regulators.

Immediate angioplasty for acute myocardial infarction: a community hospital's experience.

This study describes prospective outcome data from 100 consecutive patients presenting with acute myocardial infarction and treated with immediate angioplasty in a community hospital setting. Successful angioplasty was achieved in 86% of patients with a mean reperfusion time of 77.5 minutes. Only 4 patients did not survive initial hospitalization; three of these initially presented with cardiogenic shock. The survival rate in noncardiogenic shock patients was 98.9%. Four patients underwent repeat angioplasty of the infarct-related artery and 6 patients were referred for coronary artery bypass surgery during initial hospitalization. During the 6 month follow-up, nine patients required repeat hospitalization. Seven of these patients presented with recurrent ischemia; four underwent repeat angioplasty and 3 coronary artery bypass surgery. There were no subsequent deaths or reinfarctions during the 6 month follow-up. The angioplasty success rate and clinical outcomes in this study compare favorably to previous trials performed in select interventional centers and suggest that immediate angioplasty can be the preferred reperfusion therapy in a community hospital setting.

Hypothermia: impact on the trauma victim.

Secondary hypothermia may present the clinician with an extraordinary set of challenging problems. Rapid rewarming using both passive and active techniques is essential to correct the many reversible changes associated with hypothermia. Despite aggressive management, secondary hypothermia continues to exact a large toll in terms of the mortality of trauma victims.

Computer-assisted screw insertion into the first sacral vertebra using a three-dimensional image intensifier: results of a controlled experimental investigation.

Currently there are few data available regarding the application and efficacy of computer-assisted procedures in the sacral spine. In order to optimize and standardize this procedure, a controlled experimental investigation has been performed. The aim of the study is to systematically assess the efficacy of a novel three-dimensional image intensifier used for navigated transiliac screw insertion into the first sacral vertebra. Screws were inserted iliosacrally into the first sacral vertebra of preserved human cadaver specimens. The instrument navigated procedure was performed with the "Siremobil Iso-C(3D) " (Siemens Medical Solutions) and the "Navigation System" by Stryker. The accuracy and quality of the imaging procedure as well as the fluoroscopic exposure times were measured. These results were compared to three control groups (CT-based navigation, C-arm navigation, and fluoroscopic guidance). In each group a total amount of 20 screws was implanted. Screw position was postoperatively assessed by Iso-C(3D) or CT-scan. The navigated procedure using the Iso-C(3D) provided good feasibility characteristics without requiring a specific matching process. It revealed the shortest procedure time of all navigated procedures and significantly decreased fluoroscopic time compared to C-arm navigation and fluoroscopic guidance. Furthermore, Iso-C(3D) navigation showed no screw malposition and was in this regard superior to C-arm navigated and fluoroscopic guided procedures. The quality of imaging was sufficient for accurate placement, but did not share the high-resolution level of CT-based navigation. These findings indicate that application of the Iso-C(3D) for navigated transiliac screw insertion into S1 can be recommended as a feasible and safe technique, enabling the surgeon to reduce procedure and fluoroscopic time. Further progress in improving the quality of the Iso-C(3D) image should be attempted.

The mechanical behaviour of a novel mammalian intervertebral joint.

The mechanics of mammalian intervertebral joints are complicated by the viscoelastic nature of the connective tissues joining vertebrae, and by multiple vertebral articulations and complex morphologies. Further, interspecific variation in these structures can greatly compound their functional variation between species, making comparative mechanical analyses even more difficult. Despite these sources of variation however, mammalian intervertebral joints universally exhibit a creep relaxation behaviour based on the viscoelastic nature of the soft tissue joint. We have evaluated, in 6 degrees of freedom, the mechanical signature of a novel mammalian lumbar intervertebral joint found in the Scutisorex spine, and compared it with a more typical mammalian joint in the Rattus (rat) lumbar spine. Scutisorex, the hero shrew, is an East African species of shrew with what is likely the most highly modified vertebral morphology in the entire history of mammals. Thus we decided to evaluate the mechanical behaviour of the intervertebral joint of this species, comparing it with a more representative mammal species in Rattus. We built a custom, 6 degrees of freedom, intervertebral joint transducer and a combined axial moment and load application system in order to quantify and compare the complex mechanical behaviour of these joints. Our results suggest that the Scutisorex joint is 5 times more resilient to simple axial torsion per body mass unit than Rattus, and that the complex load (combined axial compression and torsion) mechanical signature of Scutisorex is probably novel among all mammalian intervertebral joints. Under significant but physiological axial compression the Scutisorex intervertebral joint demonstrates no creep relaxation behaviour, simulating the mechanical behaviour of a rigid construct rather than a viscoelastic joint. The purpose of this rigid intervertebral joint in the ecology of Scutisorex remains unknown.

Sarcoidosis manifesting as acute appendicitis: report of a case.

PURPOSE: This report presents a patient who developed signs and symptoms of acute appendicitis because of sarcoid involvement of the appendix. METHODS: This is a retrospective case review with review of the English language literature. RESULTS: The patient underwent appendectomy for suspected acute appendicitis. Histologically the appendix had no signs of acute inflammation but did have noncaseating granulomas. The patient's abdominal pain resolved following appendectomy, and she has had no further similar pain in the two years since the operation. CONCLUSION: Patients with sarcoidosis may develop signs and symptoms of acute appendicitis without inflammation. Operative exploration should not be delayed in equivocal cases of right lower quadrant abdominal pain in patients with sarcoidosis.

Needle thoracostomy may not be indicated in the trauma patient.

OBJECTIVE: The aim of this study was to evaluate the usefulness of needle thoracostomy catheter (NTC) placement in trauma. METHODS: A consecutive case series was conducted from November 1996 to September 1997. All patients admitted to a level I trauma centre who had NTCs placed prior to arrival in the Emergency Department were included. No patients were excluded or omitted. During the course of the study 2801 patients were admitted to our trauma centre. Nineteen patients (0.68%) had NTCs placed prior to arrival in the emergency department. RESULTS: Twenty-five needle thoracostomies were performed in 19 patients. This group represented 0.68% of the trauma admissions. Four patients were found to have evidence of a pneumothorax with an air leak (28%). The NTC failed to decompress the chest in one of two patients who had physiologic evidence of a tension pneumothorax. Eleven patients (58%) were endotracheally intubated prior to NTC. CONCLUSIONS: This study suggests that field NTC placements are often ineffective and may be over-used. Further study on the usefulness of NTC is required.

Oxidative stress as a precursor to the irreversible hepatocellular injury caused by hyperthermia.

Heat-induced hepatotoxicity accompanying hyperthermic liver perfusion was studied in the isolated, haemoglobin-free perfused rat liver. Trypan blue uptake, a sensitive indicator of cell death, was used to examine the relationship between the efflux of oxidized glutathione (oxidative stress), the appearance of cytosolic enzymes in the perfusate and cell death. Livers were perfused at 37, 42, 42.5 and 43 degrees C. The efflux of total glutathione (GSH) and oxidized glutathione (GSSG) increased with time and temperature. Differences between temperature groups were significant for both parameters for 37 versus 42, 42.5 and 43 degrees C (p less than 0.05). Temperature-related differences in GSH levels appeared at 15 min for 37 versus 42 degrees C and in GSSG levels at 30 min for 37 versus 42 and 42.5 degrees C. Biliary excretion of total GSH increased from 72 nmol at 37 degrees C to 144 nmol at 42 degrees C, 160 nmol at 42.5 degrees C and 124 nmol at 43 degrees C, which was significant for 37 versus 42 and 42.5 degrees C (p less than 0.05). The release of allantoin into the perfusate, a measure of purine catabolism and flux through xanthine oxidase, was increased at 42, 42.5 and 43 degrees C compared to 37 degrees C (p less than 0.05). Liver injury was assessed by measuring the release of asportate aminotransferase (AST) and lactate dehydrogenase (LDH) and uptake of trypan blue after perfusion at each temperature. There was a pronounced release of LDH and AST into the perfusate after 60 min of perfusion at 42, 42.5 and 43 degrees C, the levels of which were significantly different from the 37 degrees C mean level. There was no uptake of trypan blue after 60 min perfusion at 37 degrees C. Perfusion at 42, 42.5 and 43 degrees C resulted in the uptake of trypan blue in the pericentral areas, but the dye uptake was significant (p less than 0.05) compared to 37 degrees C at 42.5 and 43 degrees C only. These data show that heat-induced pericentral cell death is minimal after 60 min at 42-43 degrees C, and that the biochemical process which occurred during this period suggest 'oxidative stress' as a causative factor in hyperthermic hepatotoxicity. In addition, this liver toxicity is probably related to xanthine oxidase activity or the depletion of GSH as the initiating event which leads to lipid peroxidation and cellular damage.

The dynamics of flight-initiating jumps in the common vampire bat Desmodus rotundus.

Desmodus rotundus, the common vampire bat (Phyllostomidae: Desmodontinae), exhibits complex and variable terrestrial movements that include flight-initiating vertical jumps. This ability is unique among bats and is related to their unusual feeding behavior. As a consequence of this behavior, the wing is expected to have design features that allow both powered flight and the generation of violent jumps. In this study, high-speed cine images were synchronized with ground reaction force recordings to evaluate the dynamics of jumping behavior in D. rotundus and to explore the functional characteristics of a wing operating under competing mechanical constraints. The pectoral limbs are responsible for generating upward thrust during the jump. The hindlimbs stabilize and orient the body over the pectoral limbs. The thumbs (pollices) stabilize the pectoral limb and contribute to extending the time over which vertical force is exerted. Peak vertical force can reach 9.5 times body weight in approximately 30 ms. Mean impulse is 0.0580+/-0.007 N s (mean +/- s.d., N=12), which accelerates the animal to a mean take-off velocity of 2.38+/-0.24 m s-1. A model of the muscular activity during jumping is described that accounts for the characteristic force output shown by these animals during flight-initiating jumps.

Anterior ischemic optic neuropathy: a complication after systemic inflammatory response syndrome.

BACKGROUND: Patients are surviving previously fatal injuries. Unique morbidities are occurring in these survivors. Anterior ischemic optic neuropathy represents a previously unrecognized cause of blindness in the trauma victim. We hypothesize that this phenomenon is caused by unique characteristics of optic edema/ pressure or decreased blood flow associated with massive resuscitation. METHODS: Between November of 1991 and August of 1998, there were 18,199 admissions to our trauma center. Of this group, 350 patients required massive volume resuscitation (>20 liters infused over first 24 hours). Patients having closed head injuries, facial fractures or direct orbital trauma were excluded from study. The following variables were studied: demographics, injury severity (Injury Severity Score, highest lactate, worst base deficit, and lowest pH) crystalloid and transfusion requirements, ventilator requirements (PEEP) RESULTS: Of the 350 patients with massive resuscitation, 9 patients were diagnosed with anterior ischemic optic neuropathy (2.6%). Of these, seven patients required celiotomy (78%). Six of the seven celiotomy patients had damage control celiotomies and abdominal compartment syndrome (86%). One patient had a repair of a subclavian artery; one had a complex acetabular repair. Blindness was unilateral in five patients and bilateral in four. All nine patients had evidence of global hypoperfusion, systemic inflammatory response, massive resuscitation, and high ventilatory support; one patient required cardiopulmonary resuscitation. CONCLUSION: Prone positioning is known to be associated with an increased intraocular pressure. We postulate that the combination of massive resuscitation and prone positioning will increase the incidence of anterior ischemic optic neuropathy. As such, we recommend that prone positioning for adult respiratory distress syndrome be reserved for only those patients at risk of death.