The Obesity Paradox in the Trauma Patient: Normal May not Be Better.

OBJECTIVE: The obesity paradox is the association of increased survival for overweight and obese patients compared to normal and underweight patients, despite an increased risk of morbidity. The obesity paradox has been demonstrated in many disease states but has yet to be studied in trauma. The objective of this study is to elucidate the presence of the obesity paradox in trauma patients by evaluating the association between BMI and outcomes. METHODS: Using the 2014-2015 National Trauma Database (NTDB), adults were categorized by WHO BMI category. Logistic regression was used to assess the odds of mortality associated with each category, adjusting for statistically significant covariables. Length of stay (LOS), ICU LOS and ventilator days were also analyzed, adjusting for statistically significant covariables. RESULTS: A total of 415,807 patients were identified. Underweight patients had increased odds of mortality (OR 1.378, p < 0.001 95% CI 1.252-1.514), while being overweight had a protective effect (OR 0.916, p = 0.002 95% CI 0.867-0.968). Class I obesity was not associated with increased mortality compared to normal weight (OR 1.013, p = 0.707 95% CI 0.946-1.085). Class II and Class III obesity were associated with increased mortality risk (Class II OR 1.178, p = 0.001 95% CI 1.069-1.299; Class III OR 1.515, p < 0.001 95% CI 1.368-1.677). Hospital and ICU LOS increased with each successive increase in BMI category above normal weight. Obesity was associated with increased ventilator days; Class I obese patients had a 22% increase in ventilator days (IRR 1.217 95% CI 1.171-1.263), and Class III obese patients had a 54% increase (IRR 1.536 95% CI 1.450-1.627). CONCLUSION: The obesity paradox exists in trauma patients. Further investigation is needed to elucidate what specific phenotypic aspects confer this benefit and how these can enhance patient care. LEVEL OF EVIDENCE: Level III, prognostic study.

An in vivo demonstration of efficacy and acute safety of burst wave lithotripsy using a porcine model.

Burst wave lithotripsy (BWL) is a new non-invasive method for stone comminution using bursts of sub-megahertz ultrasound. A porcine model of urolithiasis and techniques to implement BWL treatment has been developed to evaluate its effectiveness and acute safety. Six human calcium oxalate monohydrate stones (6-7 mm) were hydrated, weighed, and surgically implanted into the kidneys of three pigs. Transcutaneous stone treatments were performed with a BWL transducer coupled to the skin via an external water bath. Stone targeting and treatment monitoring were performed with a co-aligned ultrasound imaging probe. Treatment exposures were applied in three 10-minute intervals for each stone. If sustained cavitation in the parenchyma was observed by ultrasound imaging feedback, treatment was paused and the pressure amplitude was decreased for the remaining time. Peak negative focal pressures between 6.5 and 7 MPa were applied for all treatments. After treatment, stone fragments were removed from the kidneys. At least 50% of each stone was reduced to <2 mm fragments. 100% of four stones were reduced to <4 mm fragments. Magnetic resonance imaging showed minimal injury to the functional renal volume. This study demonstrated that BWL could be used to effectively fragment kidney stones with minimal injury.

Weak correlations between local density and dynamics near the glass transition.

We perform experiments on two different dense colloidal suspensions with confocal microscopy to probe the relationship between local structure and dynamics near the glass transition. We calculate the Voronoi volume for our particles and show that this quantity is not a universal probe of glassy structure for all colloidal suspensions. We correlate the Voronoi volume to displacement and find that these quantities are only weakly correlated. We observe qualitatively similar results in a simulation of a polymer melt. These results suggest that the Voronoi volume does not predict dynamical behavior in experimental colloidal suspensions; a purely structural approach based on local single particle volume likely cannot describe the colloidal glass transition.

Animal model of portal hypertension with observations regarding the relationship between portal flow and pressure.

RATIONALE AND OBJECTIVES: The feasibility of producing acute portal hypertension in a porcine model was evaluated to test the relationship between portosystemic shunt flow and portal pressure. METHODS: Percutaneous transhepatic cannulation of the portal vein and cutdown of a systemic vein was accomplished in anesthetized pigs. The portal system was subsequently embolized with polyvinyl alcohol (Ivalon) particles. Portosystemic shunting was performed with the assistance of a centrifugal pump. RESULTS: Portal hypertension could be routinely produced, and portosystemic shunting was successfully studied in three of four animals. Linear changes in shunt flow led to exponential pressure changes. CONCLUSIONS: This animal model provides a representation of acute portal hypertension that provides useful data regarding the compliance of the portal system and illustrates the pressure/flow relationship.

Hepatic contrast-enhancing properties of manganese-mesoporphyrin and manganese-TPPS4. A comparative magnetic resonance imaging study in rats.

OBJECTIVES: Manganese (III) mesoporphyrin (Mn-mesoporphyrin), a synthetic and stable complex, was investigated for its hepatic magnetic resonance imaging (MRI) properties and compared with manganese tetrakis-(4 sulfonatophenyl) porphyrin (Mn-TPPS4). METHODS: Liver abscesses (n = 10) and tumors (n = 14) were induced in rats. These rats then underwent MRI at 2.0 T. Animals received one of the two contrast agents, and measurement of lesion enhancement was performed. RESULTS: At an intravenous dose of 0.035 mmol/kg, Mn-mesoporphyrin caused significant enhancement of normal liver parenchyma and increased the lesion-to-liver contrast in both the models of heptic liver abscess and metastatic liver disease. Mn-TTPS4 at an intravenous dose of 0.04 mmol/kg typically enhanced both lesion and normal liver parenchyma and therefore did not improve the lesion-to-liver contrast. CONCLUSIONS: The hepatotrophic properties of Mn-mesoporphyrin indicate its potential as an intravenous contrast agent for liver imaging.

Organ ablation by fluid emboli. An experimental study comparing two solidifying liquids.

Embolization for ablation of organs and tumor infarction requires uniform permanent occlusion of the distal vasculature. This is best accomplished through the use of solidifying liquids. The study on 15 dogs reported here compares the degree of peripheral vascular embolization and its relation to tissue infarction both acutely and chronically following embolization of the renal arteries with two solidifying liquids, a low viscosity silicone and the occlusion gel Ethibloc. Silicone produced quite uniform distal distribution including 50 to 80% (mean 66%) of renal glomeruli, whereas Ethibloc occluded more proximally and reached only 10 to 50% (mean 22%) of all glomeruli. After three months complete cortical infarction of all nine kidneys embolized with silicone was found, whereas two of the three kidneys embolized with Ethibloc retained nests of viable glomeruli. Balloon occlusion of the entire renal artery inflow during embolization prevented distal venous emboli whereas partial inflow occlusion allowed systemic venous embolization. It is concluded that due to its more uniform distal penetration low viscosity silicone is a more suitable embolization agent than Ethibloc for organ ablation. Total arterial inflow occlusion during embolization effectively prevents systemic venous embolization.

A reproducible canine model of nonocclusive mesenteric ischemia.

A technique for producing a reliable, clinically applicable, and highly reproducible canine model of nonocclusive mesenteric ischemia was developed. Following left thoracotomy in 10 dogs, a 1 mm diameter soft polyethylene tube was inserted into the pericardial space via a small puncture site. This tube was sealed in place with cyanoacrylate tissue adhesive. A solution of 10% Dextran 40 in saline was infused into the pericardial space until a 50% reduction (as monitored by electromagnetic flowmeter) in superior mesenteric artery flow (SMAQ) was obtained. Without additional intrapericardial infusion of the Dextran solution, SMAQ was reduced 51 +/- 4% to 54 +/- 3% of control values during a 60 minute post-tamponade observation period. During the same time. Cardiac output was depressed between 40 +/- 8% and 54 +/- 3%, and right atrial pressure remained elevated between 164 +/- 15% and 171 +/- 15%. Systemic arterial pressure initially dropped 28 +/- 5% but compensated to within 11 +/- 5% of pre-tamponade level at 60 minutes. The stability of this model is well suited for evaluating new experimental diagnostic and therapeutic procedures.

Gallstone susceptibility to in vitro fragmentation by a 480-nm pulsed dye laser. Correlation with computed tomography characteristics.

The object of this investigation was to determine gallstone susceptibility to laser lithotripsy and to discover whether this susceptibility is related to the computed tomography (CT) appearance of gallstones. Gallstones collected from surgery were scanned by CT and classified as homogeneously dense (greater than 90 Hounsfield units [HU]), homogeneously faint (30-60 HU), or rimmed. Sixty stones were subjected to laser energy at 20, 40, 60, 80, or 100 mJ. Fracture and fragmentation (all particles less than 2 mm) were assessed in relation to the energy level setting and number of laser pulses delivered. The authors found that a 480-nm, flashlamp-pumped pulsed dye laser can fragment completely all the types of human gallstones that were tested, although there is significant variability in gallstone susceptibility to laser lithotripsy. This susceptibility varies with CT appearance: dense stones require fewer pulses and lower energies for fracture and fragmentation, compared to faint or rimmed stones. The authors anticipate that CT characterization of gallstones may be a clinically useful screening tool before laser lithotripsy.

Pharmaceutical properties, biodistribution, and imaging characteristics of manganese-mesoporphyrin. A potential hepatobiliary contrast agent for magnetic resonance imaging.

OBJECTIVES: Manganese (III) mesoporphyrin (Mn-mesoporphyrin) was investigated for its pharmaceutical properties and magnetic resonance imaging characteristics as a potential hepatobiliary contrast agent. METHODS: Solubility, partition coefficient, plasma binding, proton relaxation enhancement, biodistribution, biliary excretion, liver extraction ratio, and liver enhancement were measured in various in-vitro and in-vivo systems. RESULTS: Mn-mesoporphyrin was soluble and stable at moderate alkaline pH in phosphate buffer. The octanol/water coefficient was 25.98, and the compound was highly protein bound. R1 for water and plasma were 1.94 and 2.35 L/mmol sec, respectively. R1 in liver was calculated to be 15.72 L/mmol sec. Biodistribution studies in rats and mice confirmed hepatotrophic properties and biliary excretion was 65% over 24 hours. First pass liver uptake was 15%. Magnetic resonance imaging studies showed persistent liver enhancement at 0.05 mmol/kg. CONCLUSION: Mn-mesoporphyrin is a lipophilic compound that shows potential as a hepatobiliary magnetic resonance contrast agent.

A simple method to measure mesenteric arteriovenous shunt flow during arteriography.

A quantitative method for external detection of mesenteric arteriovenous shunts was developed. 99mTc-Human Serum Albumin Microspheres (15--30 microns) were injected into the superior mesenteric artery of dogs through an angiographic catheter, followed by external scintillation counting of the liver activity, which represented the shunted spheres. Thereafter, 99mTc-sulfur colloid was injected identically and the liver activity counted again. The liver net count after sulfur colloid represented a 100% shunt, when a correction factor for the actual liver uptake was applied. The a shunt rate was calculated. Eleven animal studies were performed and shunt rates similar to previous in vitro determinations were obtained. This method is suitable for clinical investigation and can conveniently be applied to mesenteric arteriography.

Normalization of intraoperative parathyroid hormone does not predict normal postoperative parathyroid hormone levels.

BACKGROUND: Intraoperative intact parathyroid hormone (iPTH) is being used to confirm complete excision of hyperfunctioning parathyroid tissue. It is uncertain whether normalization of intraoperative iPTH levels accurately predicts long-term postoperative iPTH values. METHODS: Fifty-two consecutive patients with primary or secondary hyperparathyroidism underwent parathyroidectomy with measurement of intraoperative iPTH. Ten patients were excluded due to incomplete laboratory follow-up. Follow-up serum calcium and iPTH levels were measured at 1- and 3-month intervals. RESULTS: Before operation, the mean serum iPTH level was 249 pg/mL (SD=208) and mean serum calcium level was 11.4 +/- 0.9 mg/dL (+/- SD). In all but 4 patients, final intraoperative iPTH levels normalized to less than 67 +/- 41 pg/mL (mean, 35 pg/mL). One week after operation, serum calcium levels had returned to normal (mean, 9.4 +/- 1.1 pg/mL), which directly correlated with the final intraoperative serum iPTH values (Pearson correlation, r = -.434; P <.01). By 1 month, all but 2 patients were normocalcemic (mean, 9.4 +/- 0.9 pg/mL) with a mean iPTH level of 74.8 +/- 82 pg/mL. There was no correlation between final intraoperative and postoperative serum iPTH values (r =.099; P <.533). Both patients with persistent hypercalcemia at 1 month had appropriate intraoperative decreases in iPTH values. CONCLUSIONS: Intraoperative serum iPTH levels significantly correlate with postoperative serum calcium levels but not with postoperative serum iPTH levels. There was a 4.8% failure rate in the correction of postoperative serum calcium levels and a 29% failure rate in the normalization of postoperative serum iPTH levels.

Use of intraoperative parathyroid hormone measurement does not improve success of bilateral neck exploration for hyperparathyroidism.

HYPOTHESIS: Use of intraoperative measurement of intact parathyroid hormone (iPTH) to confirm complete excision of hyperfunctioning parathyroid tissue does not improve overall operative success rates. DESIGN: Case series of patients undergoing parathyroidectomy with or without intraoperative iPTH measurement. SETTING: University teaching hospital. PATIENTS AND INTERVENTIONS: Fifty patients undergoing parathyroidectomy before our institution of intraoperative iPTH sampling in March 1999 (group 1) were compared with 50 patients undergoing parathyroidectomy after this technique was adopted (group 2). Overall, 100 patients underwent operation between December 1996 and May 2000. Serum calcium and iPTH levels were measured at 1- and 3-month intervals. Intraoperative frozen sections and operative times were also analyzed. RESULTS: Mean preoperative calcium levels were 2.85 and 2.82 mmol/L (11.4 and 11.3 mg/dL) in groups 1 and 2, respectively. One-month postoperative calcium values were identical in both groups at 2.35 mmol/L (9.4 mg/dL) (group 1 SD = 0.18 [0.74], group 2 SD = 0.20 [0.82]). At 1 month, all but 1 patient in group 1 had normalized calcium values (2% failure rate), while 3 patients in group 2 (6%) remained hypercalcemic. All 3 patients in group 2 had intraoperative iPTH levels that returned to normal. There was a significant difference in the number of intraoperative frozen sections between groups, with a mean (SD) of 3.4 (1.7) in group 1 and 2.0 (1.6) in group 2 (P<.01). There was no significant difference in operative times between groups. CONCLUSIONS: Use of intraoperative iPTH sampling did not significantly affect the overall success of parathyroidectomy, as determined by postoperative normocalcemia. There was, however, a significant decrease in the number of frozen sections sent at operation.

A reservoir model for repeated CSF access in the rabbit.

A simple, reliable and inexpensive subcutaneously implanted reservoir-catheter system method was developed for repeated sterile access to the rabbit brain ventricular system. The system provides an avenue for the repeated intrathecal administration of drugs and for the withdrawal of cerebrospinal fluid (CSF). Reservoirs were subcutaneously implanted under the scalp and connected to tubing inserted into the cisterna magna or the lateral ventricle. The systems successfully functioned in 38 of 41 animals (12 with cisternal magna catheters and 29 with lateral ventricle catheters), for up to 12 weeks following implantation. Patency of the systems were documented with X-rays and radiopaque injected contrast medium.

MR assessment of radiation-induced blood-brain barrier permeability changes in rat glioma model.

PURPOSE: To assess the potential of a T1-weighted, gadolinium-enhanced MR technique for quantifying radiation-induced changes of blood-brain barrier permeability in a model of stereotactically implanted intracerebral gliomas in rats. METHODS: We calculated the gadolinium blood-to-tissue transport coefficient for gadopentetate dimeglumine from signal intensities in sequential MR images in nine control animals that were not irradiated and in five and three animals that had received 2500 cGy and 1500 cGy whole-brain irradiation, respectively, at 2 days before imaging. RESULTS: The average blood-to-tissue transport coefficient values were 9.76 mL.kg-1.min-1 in the control group, 23.41 mL.kg-1.min-1 in the 2500 cGy group, and 25.63 mL.kg-1.min-1 in the 1500-cGy group. Blood-to-tissue transport coefficients were significantly higher after irradiation, indicating increased radiation-induced blood-brain barrier permeability. Similar increased blood-brain barrier leakiness in brain tumors after high-dose irradiation has been shown by previous nuclear medicine studies using quantitative autoradiography. CONCLUSION: Contrast-enhanced dynamic MR of brain gliomas is a sensitive method to document radiation-induced blood-brain barrier breakdown. Quantitative gadolinium-enhanced MR may become a useful tool for the management of patients with brain tumors undergoing radiation therapy.

Temperature-dependent ultrasound color flow Doppler imaging in the study of a VX2 tumor in rabbits: preliminary findings.

Neovascularity in a VX2 carcinoma in rabbit liver was detectable, using an ultrasonic color Doppler flow imager. Intraportal infusion of heated saline increased the fractional area of color flow Doppler signals by at least 5% and as much as 30%, within and surrounding the tumors of all six rabbits studied. The effect of the fluid load was an increase in fractional area of color flow Doppler signals by 5 to 20% and was determined by the measurements following infusion and return to baseline temperature. The largest increment in color Doppler signal was observed in peritumoral vessels (10-40%). In contrast, the fractional area of color-coded pixels within the tumor was only slightly higher or lower (5-10%) at the peak temperature than at the baseline measurements. The temperature within the tumors was as much as 1 degree lower than parenchymal tissue in all animals measured. This was presumably due to the portal vein blood supply to normal tissue and predominantly hepatic artery supply to the pathological tissue. High velocities and persistent bidirectional flow were observed within the tumors only at the peak temperatures (> 43.5 degrees C). This experiment suggests that thermal stress may enhance tumor detectability by color Doppler imaging. Further development of a quantitative analysis method for color Doppler studies is needed.

Intestinal absorption of Mn-mesoporphyrin in a small bowel sac system: effect of oleic acid.

RATIONALE AND OBJECTIVES: The authors investigated the effect of oleic acid (cis-9-octadecenoic acid) (OA), a lipidic carrier, on the intestinal absorption rate and T1 relaxation time of manganese (III) mesoporphyrin (Mn-mesoporphyrin), a prototype hepatobiliary contrast agent for magnetic resonance imaging. METHODS: Mn-mesoporphyrin was formulated with OA at various concentrations. Small bowel sacs were created in 36 rats and filled with complexed and free Mn-mesoporphyrin. Intestinal absorption of Mn-mesoporphyrin was measured with spectrophotometry at 364 nm. T1 relaxation times were measured in samples of Mn-mesoporphyrin solutions, bowel wall, liver, and bile. RESULTS: Absorption rates ranged from 4.2%/cm2/h to 13%/cm2/h. Absorption was greatest (13%/cm2/h) when a combination of 1 mmol/L Mn-mesoporphyrin and 26.5 mmol/L OA was used. The T1 of bile decreased from 2,480 to 248 msec (maximum decrease) in rats that received Mn-mesoporphyrin. CONCLUSION: Mn-mesoporphyrin is absorbed from the small bowel in both the lipid-associated and free form, resulting in substantial shortening of the T1 in bile.

Intravenous manganese-mesoporphyrin as a magnetic resonance imaging contrast agent: an experimental model using VX-2 carcinoma in rabbits.

RATIONALE AND OBJECTIVES: We investigated the potential of manganese (III) mesoporphyrin (Mn-mesoporphyrin) as a hepatobiliary contrast agent for magnetic resonance (MR) imaging in rabbits given VX-2 carcinoma liver implants. METHODS: Rabbits given VX-2 carcinoma liver implants (n = 8) were imaged before and after the intravenous (i.v.) administration of 0.04 mmol/kg Mn-mesoporphyrin. MR images were correlated with gross-specimen cross-sections. The distribution of Mn in various tissues following i.v. administration of 0.04 mmol/kg Mn-mesoporphyrin was determined using atomic absorption analysis. A standard panel of serum chemistries was followed over 7 days in six rabbits following this same dose of Mn-mesoporphyrin and compared with chemistries from two control rabbits. RESULTS: I.v. administration of 0.04 mmol/kg (25 mg/kg) Mn-mesoporphyrin resulted in improvement of tumor-to-liver contrast, with enhancement of normal liver (99.7 +/- 14.7%) and the gallbladder (442 +/- 116%), but not VX-2 tumor tissue (14.8 +/- 13.9%), (n = 8, p = .05). Analysis of tissue Mn levels 100 min after i.v. Mn-mesoporphyrin injection demonstrated preferential distribution of Mn to normal liver tissue (57.8 +/- 15.3 micrograms Mn/g) compared with VX-2 tumor (4.28 +/- 1.48 micrograms Mn/g). No significant change was found in the serum chemistries of six normal rabbits over a 7-day period after the i.v. administration of 0.04 mmol/kg Mn-mesoporphyrin. CONCLUSION: I.v. Mn-mesoporphyrin improved lesion-to-liver contrast because of preferential distribution of Mn-mesoporphyrin to normal liver parenchyma and bile.

Magnetic resonance imaging of the hepatobiliary system: intestinal absorption studies of manganese mesoporphyrin.

RATIONALE AND OBJECTIVES: We studied the intestinal absorption of manganese mesoporphyrin (Mn-mesoporphyrin), a potential oral hepatobiliary contrast agent. METHODS: Mn-mesoporphyrin was complexed with monoolein and taurocholate (mixed micelles). Portal venous delivery and biliary excretion were measured after intestinal administration in rats and rabbits, and the mechanism of intestinal transport was studied in a combined lymph-bile fistula model in rats. T1-weighted magnetic resonance (MR) images of the liver were obtained in rats and domestic pigs before and after gastric administration of Mn-mesoporphyrin in mixed micelles. RESULTS: A 2.2-fold increase of portal venous Mn concentration was found 90 min after intestinal administration of the complex. None was found in the lymph collected from the thoracic duct, indicating a transcellular transport mechanism through the intestinal mucosa with portal venous delivery. Mn-mesoporphyrin levels in bile peaked between 240 and 270 min after administration (200-fold increase). The greatest liver enhancement (20-90%) was measured 360 min after administration. CONCLUSION: The feasibility of intestinal delivery of Mn-mesoporphyrin, a lipophilic hepatobiliary contrast agent was demonstrated.

Effects of a nanoscopic filler on the structure and dynamics of a simulated polymer melt and the relationship to ultrathin films.

We perform molecular dynamics simulations of an idealized polymer melt surrounding a nanoscopic filler particle. We show that the glass transition temperature T(g) of the melt can be shifted to either higher or lower temperatures by tuning the interactions between polymer and filler. A gradual change of the polymer dynamics approaching the filler surface causes the change in the glass transition. We also find that polymers close to the surface tend to be elongated and flattened. Our findings show a strong similarity to those obtained for ultrathin polymer films.

Spatially correlated dynamics in a simulated glass-forming polymer melt: analysis of clustering phenomena.

In recent years, experimental and computational studies have demonstrated that the dynamics of glass-forming liquids are spatially heterogeneous, exhibiting regions of temporarily enhanced or diminished mobility. Here we present a detailed analysis of dynamical heterogeneity in a simulated "bead-spring" model of a low-molecular-weight polymer melt. We investigate the transient nature and size distribution of clusters of "mobile" chain segments (monomers) as the polymer melt is cooled toward its glass transition. We also explore the dependence of this clustering on the way in which the mobile subset is defined. We show that the mean cluster size is time dependent with a peak at intermediate time, and that the mean cluster size at the peak time grows with decreasing temperature T. We show that for each T a particular fraction of particles maximizes the mean cluster size at some characteristic time, and this fraction depends on T. The growing size of the clusters demonstrates the growing range of correlated motion, previously reported for this same system [C. Beneman et al. Nature (London) 399, 246 (1999)]. The distribution of cluster sizes approaches a power law near the mode-coupling temperature, similar to behavior reported for a simulated binary mixture and a dense colloidal suspension, but with a different exponent. We calculate the correlation length of the clusters, and show that it exhibits similar temperature- and time-dependent behavior as the mean cluster size, with a maximum at intermediate time. We show that the characteristic time of the maximum cluster size follows the scaling predicted by mode-coupling theory (MCT) for the beta time scale, revealing a possible connection between spatially heterogeneous dynamics and MCT.