Clark R. Andersen

Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans.

Screw Fixation Compared with Suture-Button Fixation of Isolated Lisfranc Ligament Injuries

BACKGROUND A cannulated screw is currently used to reduce and stabilize diastasis at the Lisfranc joint. The screw requires removal and may break in situ. A suture button does not have these disadvantages, but it is not known if it can provide stability similar to that provided by a cannulated screw or an intact Lisfranc ligament. The objective of the present study was to compare the stability provided by a suture button with that provided by a screw when used to stabilize the diastasis associated with Lisfranc ligament injury. METHODS Fourteen fresh-frozen, paired cadaveric feet were dissected to expose the dorsal region. A registration marker triad consisting of three screws was fixed to the first cuneiform and the second metatarsal. A digitizer was utilized to record the three-dimensional positions of the registration markers and their displacement in test conditions before and after cutting of the Lisfranc ligament and after stabilization of the joint with either a suture button or a cannulated screw. The first and second cuneiforms and their metatarsals were removed, and the ligament attachment sites were digitized. Displacement at the Lisfranc ligament and the three-dimensional positions of the bones were determined. RESULTS Loading with the Lisfranc ligament cut resulted in displacement that was significantly different from that after screw fixation (p = 0.0001), with a difference between means of 1.2 mm. Likewise, loading with the Lisfranc ligament cut resulted in a displacement that was significantly different from that after suture-button fixation (p = 0.0008), with a difference between means of 1.00 mm. No significant difference in displacement was found between specimens fixed with the suture button and those fixed with the screw. CONCLUSIONS Suture-button fixation can provide stability similar to that provided by screw fixation in cadaver specimens after isolated transection of the Lisfranc ligament.

Propranolol attenuates hemorrhage and accelerates wound healing in severely burned adults

IntroductionPropranolol, a nonselective β-blocker, exerts an indirect effect on the vasculature by leaving α-adrenergic receptors unopposed, resulting in peripheral vasoconstriction. We have previously shown that propranolol diminishes peripheral blood following burn injury by increasing vascular resistance. The purpose of this study was to investigate whether wound healing and perioperative hemodynamics are affected by propranolol administration in severely burned adults.MethodsSixty-nine adult patients with burns covering ≥30% of the total body surface area (TBSA) were enrolled in this IRB-approved study. Patients received standard burn care with (n = 35) or without (control, n = 34) propranolol. Propranolol was administered within 48 hours of burns and given throughout hospital discharge to decrease heart rate by approximately 20% from admission levels. Wound healing was determined by comparing the time between grafting procedures. Blood loss was determined by comparing pre- and postoperative hematocrit while factoring in operative graft area. Data were collected between first admission and first discharge.ResultsDemographics, burn size, and mortality were comparable in the control and propranolol groups. Patients in the propranolol group received an average propranolol dose of 3.3 ± 3.0 mg/kg/day. Daily average heart rate over the first 30 days was significantly lower in the propranolol group (P <0.05). The average number of days between skin grafting procedures was also lower in propranolol patients (10 ± 5 days) than in control patients (17 ± 12 days; P = 0.02), indicative of a faster donor site healing time in the propranolol group. Packed red blood cell infusion was similar between groups (control 5.3 ± 5.4 units vs. propranolol 4.4 ± 3.1 units, P = 0.89). Propranolol was associated with a 5 to 7% improvement in perioperative hematocrit during grafting procedures of 4,000 to 16,000 cm2 compared to control (P = 0.002).ConclusionsAdministration of propranolol during the acute hospitalization period diminishes blood loss during skin grafting procedures and markedly improves wound healing in severely burned adults. As burn patients require serial surgical interventions for motor and cosmetic repair, restricting blood loss during operative intervention is optimal.

Variations of Capitate Morphology in the Wrist

PURPOSE This anatomical study details and categorizes variations in capitate morphology and associated structures in the human cadaveric wrist. METHODS We dissected 107 cadaveric wrists. Capitate morphology, the presence of capitate and hamate ridges, the lunate types, and the width of the medial hamate facet of type II lunates and 4th carpometacarpal joint types were recorded. RESULTS Three types of capitate were identified. The flat type (69/107, or 65%) was characterized by a horizontally oriented (radio-ulnar) lunate-capitate articulation and a longitudinally oriented (proximal-distal) scaphoid-capitate articulation. The flat type was associated with type I lunates or type II lunates with a smaller facet. The spherical type (23/107, or 22%) was associated with a concave articulation formed by the scaphoid and lunate articulations, with an indistinct border between the scaphoid and lunate facets. The width of the medial hamate facet of type II lunates in wrists with a spherical-type capitate was <or=4 mm. The V-shaped type (15/107, or 14%) was characterized by separate lunate and scaphoid facets that converge, forming a V-shape. All the V-shaped capitates had a type II lunate with a large facet. CONCLUSIONS A relationship was found between the 3 capitate types and both the lunate types and the width of the medial hamate facet of the type II lunates. Further study is warranted to determine if these differences in capitate morphology influence the development or progression of various wrist pathologic conditions, such as Kienböcks disease and post-traumatic arthritis associated with scapholunate dissociation and scaphoid nonunion, and the outcome of certain surgical procedures, such as a proximal row carpectomy.

Intramural Purkinje Cell Network of Sheep Ventricles as the Terminal Pathway of Conduction System

To identify the anatomical basis for cardiac electrical signal conduction, particularly seeking the intramural terminals of conduction pathway within the ventricles, sheep hearts were examined compared with human hearts utilizing the characteristic morphology of Purkinje cells as a histological marker. In 15 sheep and five human autopsies of noncardiac death, prevalence of Purkinje or Purkinje‐type cells were histologically examined in the atrioventricular node, its distal conduction pathway, the interventricular septum, and the right‐ and left‐ventricular free walls. Myocardial tissue cleavages were examined in the transmural sections (along cardiac base‐to‐apex axis) obtained from the septum and ventricular free walls. Serial histological sections through virtually the entirety of the septum in selected sheep were used as the basis of a three‐dimensional reconstruction of the conduction pathway, particularly of the intramural Purkinje cell network. Purkinje cells were found within the mural myocardium of sheep ventricles whereas no intramural Purkinje‐type cell was detected within the human ventricles. In the sheep septum, every intramural Purkinje cell composed a three‐dimensional network throughout the mural myocardium, which proximally connected to the subendocardial extension of the bundle branches and distally formed an occasional junction with ordinary working myocytes. The Purkinje‐cell network may participate in the ventricular excitation as the terminal conduction pathway. Individual connections among the Purkinje cells contain the links of through‐wall orientation which would benefit the signal conduction crossing the architectural barriers by cleavages in sheep hearts. The myocardial architectural changes found in diseased hearts could disrupt the network links including those with transmural orientation. Anat Rec, 2009.

Impact of Stress-Induced Diabetes on Outcomes in Severely Burned Children

BACKGROUND Post-burn hyperglycemia leads to graft failure, multiple organ failure, and death. A hyperinsulinemic-euglycemic clamp is used to keep serum glucose between 60 and 110 mg/dL. Because of frequent hypoglycemic episodes, a less-stringent sliding scale insulin protocol is used to maintain serum glucose levels between 80 and 160 mg/dL after elevations >180 mg/dL. STUDY DESIGN We randomized pediatric patients with massive burns into 2 groups, patients receiving sliding scale insulin to lower blood glucose levels (n = 145) and those receiving no insulin (n = 98), to determine the differences in morbidity and mortality. Patients 0 to 18 years old with burns covering ≥ 30% of the total body surface area and not randomized to receive anabolic agents were included in this study. End points included glucose levels, infections, resting energy expenditure, lean body mass, bone mineral content, fat mass, muscle strength, and serum inflammatory cytokines, hormones, and liver enzymes. RESULTS Maximal glucose levels occurred within 6 days of burn injury. Blood glucose levels were age dependent, with older children requiring more insulin (p < 0.05). Daily maximum and daily minimum, but not 6 am, glucose levels were significantly different based on treatment group (p < 0.05). Insulin significantly increased resting energy expenditure and improved bone mineral content (p < 0.05). Each additional wound infection increased incidence of hyperglycemia (p = 0.004). There was no mortality in patients not receiving insulin, only in patients who received insulin (p < 0.004). Muscle strength was increased in patients receiving insulin (p < 0.05). CONCLUSIONS Burn-induced hyperglycemia develops in a subset of severely burned children. Length of stay was reduced in the no insulin group, and there were no deaths in this group. Administration of insulin positively impacted bone mineral content and muscle strength, but increased resting energy expenditure, hypoglycemic episodes, and mortality. New glucose-lowering strategies might be needed.

High Tidal Volume Decreases Adult Respiratory Distress Syndrome, Atelectasis, and Ventilator Days Compared with Low Tidal Volume in Pediatric Burned Patients with Inhalation Injury

BACKGROUND Inhalation injury, which is among the causes of acute lung injury and acute respiratory distress syndrome (ARDS), continues to represent a significant source of mortality in burned patients. Inhalation injury often requires mechanical ventilation, but the ideal tidal volume strategy is not clearly defined in burned pediatric patients. The aim of this study was to determine the effects of low and high tidal volume on the number of ventilator days, ventilation pressures, and incidence of atelectasis, pneumonia, and ARDS in pediatric burned patients with inhalation injury within 1 year post burn injury. METHODS From 1986 to 2014, inhalation injury was diagnosed by bronchoscopy in pediatric burned patients (n = 932). Patients were divided into 3 groups: unventilated (n = 241), high tidal volume (HTV, 15 ± 3 mL/kg, n = 190), and low tidal volume (LTV, 9 ± 3 mL/kg, n = 501). RESULTS High tidal volume was associated with significantly decreased ventilator days (p < 0.005) and maximum positive end expiratory pressure (p < 0.0001) and significantly increased maximum peak inspiratory pressure (p < 0.02) and plateau pressure (p < 0.02) compared with those in patients with LTV. The incidence of atelectasis (p < 0.0001) and ARDS (p < 0.02) was significantly decreased with HTV compared with LTV. However, the incidence of pneumothorax was significantly increased in the HTV group compared with the LTV group (p < 0.03). CONCLUSIONS High tidal volume significantly decreases ventilator days and the incidence of both atelectasis and ARDS compared with low tidal volume in pediatric burned patients with inhalation injury. Therefore, the use of HTV may interrupt sequences leading to lung injury in our patient population.

A minimally disruptive model and three-dimensional evaluation of Lisfranc joint diastasis.

BACKGROUND There is no model that can reproduce the diastasis at the Lisfranc joint after isolated transection of the Lisfranc ligament. Prior models required extensive sectioning of ligaments in the midfoot and represent injuries that cause extensive tarsometatarsal fracture-dislocations. They do not represent a subset of injuries that cause subtle or limited disruption at the Lisfranc joint. The purpose of this study was to create a model with the minimum amount of ligamentous disruption and loading necessary to consistently observe diastasis at the Lisfranc joint. METHODS Fourteen fresh-frozen paired cadaver feet were dissected to expose the dorsum. Three screws were inserted into each first cuneiform and second metatarsal to create a pair of registration triads. A digitizer was utilized to record the three-dimensional positions of the screws and their displacement under loaded and unloaded conditions before and after the Lisfranc ligament was cut (intact and cut conditions). The first and second cuneiforms and their metatarsals were removed, and the attachment sites of the dorsal and the Lisfranc ligament were digitized. The three-dimensional positions of the bones and ligament displacement were determined. The significance of differences between conditions was tested with analysis of variance, and linear regression analysis was used to test the correlation between dorsal and plantar displacements. RESULTS There was a significant difference, of 1.3 mm, in the mean displacement between the cut loaded and intact loaded conditions (p < 0.0001). A modest correlation (r(2) = 0.60) was found between dorsal displacement and displacement at the site of the Lisfranc ligament, possibly attributable to rotations between the first cuneiform and second metatarsal. CONCLUSIONS Isolated sectioning of the Lisfranc ligament is sufficient to consistently create diastasis at the Lisfranc joint. Dorsal displacements between the first cuneiform and second metatarsal are a modest predictor of plantar displacements.

FIVE-YEAR OUTCOMES AFTER LONG-TERM OXANDROLONE ADMINISTRATION IN SEVERELY BURNED CHILDREN: A RANDOMIZED CLINICAL TRIAL

ABSTRACT Administration of oxandrolone, a nonaromatizable testosterone analog, to children for 12 months following severe burn injury has been shown to improve height, increase bone mineral content (BMC), reduce cardiac work, and augment muscle strength. Surprisingly, the increase in BMC persists well beyond the period of oxandrolone administration. This study was undertaken to determine if administration of oxandrolone for 2 years yields greater effects on long-term BMC and bone mineral density (BMD). Patients between 0 and 18 years of age with ≥30% of total body surface area burned were consented to an IRB-approved protocol and randomized to receive either placebo (n = 84) or 0.1 mg/kg oxandrolone orally twice daily for 24 months (n = 35). Patients were followed prospectively from the time of admission until 5 years postburn in a single-center, intent-to-treat setting. Height, weight, BMC, and BMD were recorded annually through 5 years postinjury. The long-term administration of oxandrolone for 16 ± 1 months postburn (range, 12.1–25.2 months) significantly increased whole-body (WB) BMC (p < 0.02) and lumbar spine (LS) BMC (p < 0.05); these effects were significantly pronounced for a longer time in patients who were in growth spurt years (7–18 years). When adjusted for height, sex, and age, LS BMD was found to significantly increase with long-term oxandrolone administration (p < 0.0009). Fewer patients receiving oxandrolone exhibited LS BMD z scores below −2.0 as compared with controls, indicating a significantly reduced risk for future fracture with oxandrolone administration. Long-term oxandrolone patients had significantly greater height velocity than controls throughout the first 2-year postburn (p < 0.05). No adverse side effects were attributed to the long-term administration of oxandrolone. A comparison of the current patients receiving long-term oxandrolone to previously described patients receiving 12 months of oxandrolone revealed that long-term oxandrolone administration imparted significantly greater increases in WB-BMC, WB-BMD, and LS-BMD (p < 0.05). In conclusion, the administration of oxandrolone for up to 24 months to severely burned pediatric patients significantly improves WB BMC, LS BMC, LS BMD, and height velocity. The administration of long-term oxandrolone was more efficacious than administration for 12 months. Additionally, fewer patients in the oxandrolone cohort met the diagnostic criteria for pediatric osteoporosis, pointing to a reduced risk for future bone fracture. This study demonstrates that administering oxandrolone for up to 2 years following severe burn injury results in greater improvements in BMC, BMD, and height velocity.

Long-Term Skeletal Muscle Mitochondrial Dysfunction is Associated with Hypermetabolism in Severely Burned Children

The long-term impact of burn trauma on skeletal muscle bioenergetics remains unknown. Here, the authors determined respiratory capacity and function of skeletal muscle mitochondria in healthy individuals and in burn victims for up to 2 years postinjury. Biopsies were collected from the m. vastus lateralis of 16 healthy men (26 ± 4 years) and 69 children (8 ± 5 years) with burns encompassing ≥30% of their total BSA. Seventy-nine biopsies were collected from cohorts of burn victims at 2 weeks (n = 18), 6 months (n = 18), 12 months (n = 25), and 24 months (n = 18) postburn. Hypermetabolism was determined by the difference in predicted and measured metabolic rate. Mitochondrial respiration was determined in saponin-permeabilized myofiber bundles. Outcomes were modeled by analysis of variance, with differences in groups assessed by Tukey-adjusted contrasts. Burn patients were hypermetabolic for up to 2 years postinjury. Coupled mitochondrial respiration was lower at 2 weeks (17 [8] pmol/sec/mg; P < .001), 6 months (41 [30] pmol/sec/mg; P = .03), and 12 months (35 [14] pmol/sec/mg; P < .001) postburn compared with healthy controls (58 [13] pmol/sec/mg). Coupled respiration was greater at 6, 12, and 24 months postburn vs 2 weeks postburn (P < .001). Mitochondrial adenosine diphosphate and oligomycin sensitivity (measures of coupling control) were lower at all time-points postburn vs control (P < .05), but greater at 6, 12, and 24 months postburn vs 2 weeks postburn (P < .05). Muscle mitochondrial respiratory capacity remains significantly lower in burn victims for 1-year postinjury. Mitochondrial coupling control is diminished for up to 2 years postinjury in burn victims, resulting in greater mitochondrial thermogenesis. These quantitative and qualitative derangements in skeletal muscle bioenergetics likely contribute to the long-term pathophysiological stress response to burn trauma.