The association between time to antibiotics and relevant clinical outcomes in emergency department patients with various stages of sepsis: a prospective multi-center study.

INTRODUCTION: In early sepsis stages, optimal treatment could contribute to prevention of progression to severe sepsis. Therefore, we investigated if there was an association between time to antibiotics and relevant clinical outcomes in hospitalized emergency department (ED) patients with mild to severe sepsis stages. METHODS: This is a prospective multicenter study in three Dutch EDs. Patients were stratified into three categories of illness severity, as assessed by the predisposition, infection, response, and organ failure (PIRO) score: PIRO score 1 to 7, 8 to 14 and >14 points, reflected low, intermediate, and high illness severity, respectively. Consecutive hospitalized ED patients with a suspected infection who were treated with intravenous antibiotics were eligible to participate in the study. The primary outcome measure was the number of surviving days outside the hospital at day 28 which was used as an inverse measure of hospital length of stay (LOS). The secondary outcome measure was 28-day mortality, taking into account the time to mortality. Multivariable Cox regression analysis was used to estimate the association between time to antibiotics and the primary and secondary outcome measures corrected for confounders, including appropriateness of antibiotics and initial ED resuscitation, in three categories of illness severity. RESULTS: Of the 1,168 included patients, 112 died (10%), while 85% and 95% received antibiotics within three and six hours, respectively. No association between time to antibiotics and surviving days outside the hospital or mortality was found. Only in PIRO group 1 to 7 was delayed administration of antibiotics (>3 hours) associated with an increase in surviving days outside the hospital at day 28 (hazard ratio: 1.46, 95% confidence interval: 1.05 to 2.02 after correction for potential confounders). CONCLUSIONS: In ED patients with mild to severe sepsis who received antibiotics within six hours after ED presentation, a reduction in time to antibiotics was not found to be associated with an improvement in relevant clinical outcomes.

Early resuscitation with fresh frozen plasma for traumatic brain injury combined with hemorrhagic shock improves neurologic recovery.

BACKGROUND: We have shown that early administration of fresh frozen plasma (FFP) reduces the size of brain lesions 6 hours after injury in a large animal model of traumatic brain injury (TBI) and hemorrhagic shock (HS). To examine long-term outcomes, we hypothesized that early treatment with FFP would result in faster neurologic recovery and better long-term outcomes in a combined TBI and HS model. STUDY DESIGN: Anesthetized Yorkshire swine underwent combined TBI and volume-controlled hemorrhage (40% blood volume). After 2 hours of shock, animals were randomized (n = 5/group) to normal saline (3× shed blood) or FFP (1× shed blood) treatment. A neurologic severity score was assessed for 30 days. Magnetic resonance imaging of the brain was performed at days 3, 10, and 24. Cognitive function was tested by training animals to retrieve food from color-coded boxes. RESULTS: Neurologic impairment was lower and speed of recovery was considerably faster in the FFP-treated animals. There was a trend toward a smaller lesion size in FFP-treated animal at days 3 and 10, but this did not reach statistical significance. Both groups reached baseline performance on the cognitive testing; however, FFP-treated animals were able to participate, on average, 8 days earlier due to quicker recovery. CONCLUSIONS: This is the first study to demonstrate the beneficial effects of FFP treatment in a long-term survival model of combined TBI and HS. Our data show that early treatment with FFP substantially attenuates the degree of neurologic impairment, improves the rate of recovery, and preserves the cognitive functions.

Hypothermia and valproic acid activate prosurvival pathways after hemorrhage.

BACKGROUND: Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C-37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA (n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot. RESULTS: Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia (P < 0.05). Levels of the prosurvival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia + VPA groups (P < 0.005). The downstream prosurvival protein phospho-GSK-3ß was significantly higher in the sham, hypo, and combined treatment groups compared with that in normothermia groups with or without VPA (P < 0.05). Levels of the prosurvival ß-catenin were significantly higher in the combined treatment group relative to normothermia (P < 0.01). CONCLUSIONS: This is the first in vivo study to demonstrate that combined treatment with VPA and hypo offers better cytoprotection than these treatments given independently.

Development of a novel neuroprotective strategy: combined treatment with hypothermia and valproic acid improves survival in hypoxic hippocampal cells.

BACKGROUND: Therapeutic hypothermia and histone deacetylase inhibitors, such as valproic acid (VPA), independently have been shown to have neuroprotective properties in models of cerebral ischemic and traumatic brain injury. However, the depth of hypothermia and the dose of VPA needed to achieve the desired result are logistically challenging. It remains unknown whether these two promising strategies can be combined to yield synergistic results. We designed an experiment to answer this question by subjecting hippocampal-derived HT22 cells to severe hypoxia in vitro. METHODS: Mouse hippocampal HT22 cells were exposed to 200 µM cobalt chloride (CoCl(2)), which created hypoxic conditions in vitro. Cells were incubated for 6 or 30 hours under the following conditions: (1) Dulbecco's Modified Eagle Medium; (2) 200 µM CoCl(2); (3) 200 µM CoCl(2) plus 1 mmol/L VPA; (4) 200 µM CoCl(2) plus 32°C hypothermia; and (5) 200 µM CoCl(2) plus both 1 mmol/L VPA and 32°C hypothermia. Cellular viability was evaluated by (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) and lactate dehydrogenase release assays at 30 hours after treatment. Levels of acetylated histone H3, hypoxia-inducible factor-1α, phospho-GSK-3ß, ß-catenin, and high-mobility group box-1 were measured by Western blotting. RESULTS: High levels of acetylated histone H3 were detected in the VPA-treated cells. The release of lactate dehydrogenase was greatly suppressed after the combined hypothermia + VPA treatment (0.269 ± 0.003) versus VPA (0.836 ± 0.026) or hypothermia (0.451 ± 0.005) treatments alone (n = 3, P = .0001). (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay showed that the number of viable cells was increased by 17.6 % when VPA and hypothermia were used in combination (n = 5, P = .0001). Hypoxia-inducible factor-1α and phospho-GSK-3ß expression were synergistically affected by the combination treatment, whereas high-mobility group box-1 was increased by VPA treatment, and inhibited by the hypothermia. CONCLUSION: This is the first study to demonstrate that the neuroprotective effects of VPA and hypothermia are synergistic. This novel approach can be used to develop more effective therapies for the prevention of neuronal death.

Treatment with a histone deacetylase inhibitor, valproic acid, is associated with increased platelet activation in a large animal model of traumatic brain injury and hemorrhagic shock.

BACKGROUND: We have previously shown that resuscitation with fresh frozen plasma (FFP) in a large animal model of traumatic brain injury (TBI) and hemorrhagic shock (HS) decreases the size of the brain lesion, and that addition of a histone deacetylase inhibitor, valproic acid (VPA), provides synergistic benefits. In this study, we hypothesized that VPA administration would be associated with a conservation of platelet function as measured by increased platelet activation after resuscitation. MATERIALS AND METHODS: Ten swine (42-50 kg) were subjected to TBI and HS (40% blood loss). Animals were left in shock for 2 h before resuscitation with either FFP or FFP+VPA (300 mg/kg). Serum levels of platelet activation markers transforming growth factor beta, CD40 L, P-selectin, and platelet endothelial cell adhesion molecule (PECAM) 1 were measured at baseline, postresuscitation, and after a 6-h observation period. Platelet activation markers were also measured in the brain whole cell lysates and immunohistochemistry. RESULTS: Circulating P-selectin levels were significantly higher in the FFP+VPA group compared with the FFP alone group (70.85±4.70 versus 48.44±7.28 ng/mL; P<0.01). Likewise, immunohistochemistry data showed elevated P-selectin in the VPA treatment group (22.30±10.39% versus 8.125±3.94%, P<0.01). Serum sCD40L levels were also higher in the FFP+VPA group (3.21±0.124 versus 2.38±0.124 ng/mL; P<0.01), as was brain sCD40L levels (1.41±0.15 versus 1.22±0.12 ng/mL; P=0.05). Circulating transforming growth factor beta levels were elevated in the FFP+VPA group, but this did not reach statistical significance (11.20±1.46 versus 8.09±1.41 ng/mL; P=0.17). Brain platelet endothelial cell adhesion molecule 1 levels were significantly lower in the FFP+VPA group compared with the FFP group (5.22±2.00 pg/mL versus 7.99±1.13 pg/mL; P=0.03). CONCLUSIONS: In this clinically relevant large animal model of combined TBI+HS, the addition of VPA to FFP resuscitation results in an early upregulation of platelet activation in the circulation and the brain. The previously observed neuroprotective effects of VPA may be due to a conservation of platelet function as measured by a higher platelet activation response after resuscitation.

Comparison of elbow contracture release in elbows with and without heterotopic ossification restricting motion.

We compared 16 patients with post-traumatic heterotopic ossification (HO) restricting elbow motion (but not complete bony ankylosis) after elbow trauma with 21 patients with capsular contracture alone to test the hypothesis that HO is associated with diminished motion after release. Patients with burns or head injury were excluded. The preoperative flexion arc averaged 59 degrees in the HO cohort and 52 degrees in the capsular contracture cohort. The mean flexion arc after the index surgery improved by 54 degrees to a mean arc of 113 degrees in the HO cohort and by 35 degrees to a mean of 87 degrees in the capsular contracture cohort (P = .02). After all subsequent procedures (including procedures to address residual stiffness in 1 patient in the HO cohort and 4 patients in the capsular contracture cohort), the flexion arc averaged 116 degrees in the HO cohort and 98 degrees in the capsular contracture cohort (P = .19). Open release of post-traumatic elbow stiffness is more effective when HO hindering motion is removed than when there is capsular contracture alone.

Surgical treatment of intra-articular fractures of the distal part of the humerus. Functional outcome after twelve to thirty years.

BACKGROUND: The short-term results of open reduction and internal fixation of intra-articular distal humeral fractures are good to excellent in approximately 75% of patients, but the long-term results have been less well studied. This investigation addressed the long-term clinical and radiographic results of surgical treatment of intra-articular distal humeral fractures (AO Type C) as assessed with use of standardized outcome measures. METHODS: Thirty patients were evaluated at an average of nineteen years (range, twelve to thirty years) after open reduction and internal fixation of a fracture of the distal part of the humerus to assess the range of elbow motion and the functional outcome. Twenty patients had an olecranon osteotomy, and all had fixation with plates and/or screws and/or Kirschner wires. No ulnar nerve was transposed. RESULTS: Excluding one elbow salvaged with an arthrodesis and counted as a poor result, the average final flexion arc was 106 degrees and the average pronation-supination arc was 165 degrees. The average American Shoulder and Elbow Surgeons (ASES) score was 96 points, with an average satisfaction score of 8.8 points on a 0 to 10-point visual analog scale. The average Disabilities of the Arm, Shoulder and Hand (DASH) score was 7 points, and the average Mayo Elbow Performance Index (MEPI) score was 91 points. Including the patient with the arthrodesis, the final categorical ratings were nineteen excellent results, seven good results, one fair result, and three poor results. The presence of arthrosis did not appear to correlate with pain or predict disability or function. Subsequent procedures were performed in twelve patients (40%). CONCLUSIONS: The long-term results of open reduction and internal fixation of AO-Type-C fractures of the distal part of the humerus are similar to those reported in the short term, suggesting that the results are durable. Functional ratings and perceived disability were predicated more on pain than on functional impairment and did not correlate with radiographic signs of arthrosis.

Reference points for radial head prosthesis size.

PURPOSE: Metallic radial head implants are useful when the radial head cannot be repaired reliably and when either the elbow or the forearm is unstable. Problems arise when the radial head prosthesis is too thick, causing erosions of the capitellum and incongruity of the ulnohumeral joint. We used quantitative 3-dimensional computed tomography analysis to investigate the relative height of the radial head relative to the lateral edge and central ridge of the coronoid process as reference points for optimal insertion of a radial head prosthesis. METHODS: Seventeen computed tomography scans of the elbow were analyzed. The anatomic coronal plane of the forearm was determined using 3-dimensional images and a 2-dimensional image bisecting the articular surface of the radial head was created in this plane. The distance between the plane of the articular surface of the radial head and parallel planes at the most proximal aspect of the coronoid (the central ridge) and the lateral edge of the coronoid articular surface were measured. Negative values indicate the radial head is proximal to the coronoid. RESULTS: The average distance between the planes defined by the radial head articular surface and the coronoid central ridge was -0.8 mm. The average distance between the planes defined by the radial head articular surface and the lateral edge of the coronoid articular surface was -0.9 mm. CONCLUSIONS: Because the radial head was on average only 0.9 mm more proximal than the lateral edge of the coronoid process and because the key is to not overstuff the joint a useful general guideline would be to place the plane of the articular surface of the radial head even with or just slightly more proximal than the lateral edge of the coronoid articular surface. Considering the substantial variability of the normal height of the articular surface of the radial head with respect to that of the coronoid, preoperative radiographs of the opposite elbow may be useful to avoid overstuffing the elbow.