Background: One goal of wound healing research is to discover agents to accelerate healing. Regulatory agencies have suggested stringent criteria to determine efficacy, that of 100% wound closure. Data analysis at a single point such as 100% closure does not provide detailed information about agent effectiveness over the entire span of healing. Hypothesis: Wound healing trajectories can provide such information and can be used to demonstrate utility as alternative end points for wound healing trials. Design: Data from 160 patients in 11 clinical trials of diabetic foot ulcers conducted at 2 centers were evaluated. Wound healing trajectories were constructed for patients whose wounds healed (100% closure) and those whose did not (Ͻ100% closure) over a 20-week period. The percentage of patients achieving total healing vs time of treatment was plotted and divided into patients receiving a test agent or placebo. Results: The healing trajectories were almost identical for patients achieving complete healing at the 2 centers, as were the trajectories for patients with less than 100% closure. However, the trajectories of patients achieving total healing were significantly different from those not achieving 100% closure. Fifty-two percent of all patients achieved 100% healing by 20 weeks; 61% of patients receiving an experimental agent had total healing compared with 39% of placebo-treated patients. Linear regression suggested that all patients would achieve total healing by 37 weeks. Conclusions: Since wound healing trajectories for diabetic foot ulcers treated at 2 centers so closely mimic one another, trajectories might be useful efficacy end points, and used to compare significant points along a continuum rather than a single static end point. Shifting of the wound healing trajectory from an impaired to a more ideal course may be consideredwhendeterminingefficacyofnewwoundtreatments.
Rodent models of chronic intermittent hypoxia (IH) are commonly used to investigate the pathophysiological sequelae that result from hypoxic exposure in patients experiencing obstructive sleep apnea (OSA). Despite the widespread use of IH models, little attention has been paid to carefully defining the degree of oxyhemoglobin desaturation that occurs during each hypoxic period. Therefore, we developed a rapid blood sampling technique to determine the arterial blood gas changes that occur in conscious unrestrained mice during a single IH event and hypothesized that the arterial Po(2) (Pa(O(2))) at the nadir level of the inspired oxygen profile causes oxyhemoglobin saturation to fall to between 80% and 90%. Mice were exposed to 120-180 cycles of IH at a rate of 60 cycles/h, and arterial blood samples were withdrawn (<3 s) at baseline and at 10-s time intervals over the course of a single IH cycle. The IH regimen caused a decline in the fraction of inspired oxygen from room air levels to a transient nadir of 6.0 +/- 0.2% over the 30-s hypoxic period. The Pa(O(2)) and arterial oxyhemoglobin saturation reached a nadir of 47 +/- 2 mmHg and 85 +/- 2% at 30 s, respectively. Arterial Pco(2) decreased to a nadir of 26 +/- 2 mmHg at 30 s, associated with a rise in arterial pH to 7.46 +/- 0.2. We conclude that the magnitude of oxyhemoglobin desaturation that is induced in our murine model of IH is consistent with the degree of hypoxic stress that occurs in moderate to severe clinical OSA.
Outcome measures of venous ulcer healing are not uniformly accepted. Stringent criteria of 100% closure fail to provide information of healing over the entire span of repair. Wound-healing trajectories (plot of percentage of wound closure versus time of wound treatment) were constructed for 232 patients treated in eight clinical trials at two independent wound care/research centres. Trajectories were constructed for ulcers that totally healed (100% closure) and those that did not (<100% closure) over a 20-week period. Kaplan-Meier survival plots determined the percentage of patients achieving total healing versus time of treatment. The wound-healing trajectories were almost identical for patients achieving complete ulcer healing, as were the trajectories for patients with less than 100% closure. The trajectories for the ulcers healing completely were significantly different from those with <100% closure. Only 60% of all patients achieved 100% closure by 20 weeks. Using linear regression, it was predicted that it would take 31 weeks for all patients to achieve total healing. Total healing is an inadequate outcome measure for healing of venous stasis ulcers. Clinical trials using this measure would require excessive time periods. As wound-healing trajectories for patients treated at two centres mimic one another, shifting the wound-healing trajectory from one of impaired healing to one of a more ideal healing course may be considered a better outcome measure for determining healing of venous stasis ulcers.
Objectives The mechanisms by which correcting hyperglycemia with exogenous insulin improves mortality and morbidity in critically ill patients remain unclear. We designed this study to test the hypothesis that relative endogenous insulin deficiency is associated with adverse outcomes in critical illness related to hyperglycemia. Design Prospective controlled animal study. Setting University research laboratory. Subjects Male C57BL/6J mice, 8–12 wks old. Interventions Spontaneously breathing mice were instrumented with chronic indwelling arterial and venous catheters. After a postoperative recovery period, endotoxemia was initiated with intra-arterial lipopolysaccharide (1 mg/kg) in the presence of dextrose infusion (100 μL/hr). Insulin secretion was blocked with diazoxide (2.5–30 mg/kg/day). Mice were monitored continuously for 48 hrs with blood sampled serially for blood glucose and plasma insulin determinations. Measurements and Main Results In both saline- and glucose-infused mice, lipopolysaccharide administration induced transient hemodynamic instability without significant impact on mortality. In the saline-infused group, lipopolysaccharide administration caused a transient reduction in blood glucose and in circulating insulin. However, in glucose-infused mice, lipopolysaccharide induced a large and unexpected increase in circulating insulin without significant alteration in blood glucose. Blockade of insulin secretion in response to lipopolysaccharide in the presence of exogenous glucose precipitated marked hyperglycemia and resulted in >90% mortality. In a subanalysis of animals matched for the degree of hyperglycemia, nonsurvivors had markedly lower insulin levels compared with survivors (3.5 ± 0.8 ng/dL vs. 9.3 ± 1.4 ng/dL; p < .004). Conclusions Endogenous insulin deficiency in the face of hyperglycemia is associated with mortality in a mouse model of lipopolysaccharide-induced critical illness.
Acute septic thrombophlebitis of the internal jugular vein (IJV), better known as Lemierre syndrome, is a rare entity which poses several challenges in management. Treatment involves prompt use of intravenous antibiotics over a prolonged period of time, typically 6–8 weeks. The use of anticoagulation is controversial, but indicated for some. We describe the first reported case of Lemierre syndrome associated with a hypercoagulable state in an adult. We propose that all patients with Lemierre syndrome should be evaluated for hypercoagulable states and that the indications for anticoagulation in Lemierre syndrome are (1) propagation or nonresolution of IJV thrombus despite antibiotics and (2) identification of a hypercoagulable state, as in our case.
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