Intravenous Cefazolin Achieves Sustained High Interstitial Concentrations in Open Lower Extremity Fractures.

BACKGROUND: Infection remains a serious clinical concern in patients with open fractures, despite timely antibiotic administration and surgical debridement. Soft tissue and periosteal stripping may alter local tissue homeostasis and antibiotic pharmacokinetics in the injured limb. The tissue (interstitial) concentration of intravenously administered antibiotics at an open fracture site has not been characterized using direct sampling techniques. QUESTION/PURPOSE: We performed this study to evaluate the concentration and pharmacokinetics of intravenously delivered cefazolin at an open fracture site after surgical debridement. METHODS: Twelve patients with an open fracture distal to the knee who presented at a regional Level I trauma center were approached for enrollment in this nonrandomized, observational study. Of the 12 patients, eight adults (one female, seven male) with a median age of 32 years (range 23 to 51 years) were enrolled and underwent successful sample collection for analysis. Three patients had incomplete datasets because of equipment malfunction and one elected not to participate. Seven patients had open tibia fractures, and one patient had an open fibula fracture associated with a closed tibia fracture. There were six Gustilo-Anderson Type II injuries and two Type IIIA injuries. Empiric antibiotics were administered in the prehospital setting or in the emergency department according to institutional protocol. When patients were taken to the operating room, a 2-g intravenous dose of cefazolin was administered. After surgical debridement, fracture stabilization, and wound closure, a microdialysis catheter was placed transdermally into the injury zone (within 5 cm of the fracture site) and a second catheter was placed in the contralateral uninjured (control) limb. Additional doses of cefazolin were administered every 8 hours postoperatively. Baseline and periodic interstitial fluid and whole blood (plasma) samples were collected in the operating room and at prespecified times for 24 hours postoperatively. Free cefazolin in the interstitial fluid and plasma samples were analyzed by ultra-high-performance liquid chromatography using C 18 column separation with quadrupole time-of-flight mass spectrometry detection. Data from the second postoperative dose of cefazolin were used to characterize pharmacokinetic parameters through a noncompartmental analysis using time-concentration curves of free cefazolin and assuming first-order elimination. For pharmacodynamic analyses, the modal cefazolin minimum inhibitory concentration (MIC) of Staphylococcus aureus (1 µg/mL) was used. RESULTS: With the samples available, no difference was observed in the median free cefazolin exposure over 24 hours ( f area under the curve [AUC] 0→24hrs ) between injured limbs (352 µg∙hr/mL [IQR 284 to 594 µg∙hr/mL]) and uninjured limbs (341 µg∙hr/mL [IQR 263 to 438 µg∙hr/mL]; p = 0.64). The median time to achieve the maximum concentration of free cefazolin ( f T max ) for injured limbs was delayed (2.7 hours [IQR 2.2 to 3.1 hours]) compared with control limbs (1.7 hours [IQR 1.2 to 2.0 hours]; p = 0.046). The time to the maximum concentration for plasma was not different from that of control limbs (p = 0.08). The time the cefazolin concentration was above the modal S. aureus MIC (T > MIC) in the injured and control limbs over 24 hours was 100% (IQR 100% to 100%) and 100% (IQR 97% to 100%), respectively. CONCLUSION: These preliminary findings suggest that current prophylactic cefazolin dosing regimens result in successful antibiotic delivery to the traumatized limb in moderately severe open fractures. Although cefazolin delivery to open-fracture wound beds was delayed compared with healthy tissues, the cefazolin concentration was sustained above the European Union Committee Antimicrobial Susceptibility Testing modal MIC for S. aureus , demonstrating a high likelihood of a prophylactic antimicrobial environment at an open fracture site with this empiric antimicrobial regimen. Importantly, patients in this analysis had Gustilo-Anderson Types II and IIIA injuries. Further research with a larger patient cohort is needed to determine whether antibiotic delivery to traumatized soft tissues in patients with higher-grade open fractures (Gustilo-Anderson Types IIIB and IIIC) demonstrates similar pharmacokinetic characteristics. LEVEL OF EVIDENCE: Level II, therapeutic study.

The Difficult Airway Redefined.

There is no all-encompassing or universally accepted definition of the difficult airway, and it has traditionally been approached as a problem chiefly rooted in anesthesiology. However, with airway obstruction reported as the second leading cause of mortality on the battlefield and first-pass success (FPS) rates for out-of-hospital endotracheal intubation (ETI) as low as 46.4%, the need to better understand the difficult airway in the context of the prehospital setting is clear. In this review, we seek to redefine the concept of the "difficult airway" so that future research can target solutions better tailored for prehospital, and more specifically, combat casualty care. Contrasting the most common definitions, which narrow the scope of practice to physicians and a handful of interventions, we propose that the difficult airway is simply one that cannot be quickly obtained. This implies that it is a situation arrived at through a multitude of factors, namely the Patient, Operator, Setting, and Technology (POST), but also more importantly, the interplay between these elements. Using this amended definition and approach to the difficult to manage airway, we outline a target-specific approach to new research questions rooted in this system-based approach to better address the difficult airway in the prehospital and combat casualty care settings.

Indices of complement activation and coagulation changes in trauma patients.

Objectives: Early complementopathy and coagulopathy are shown often after trauma. However, the prevalence of any interplay between complement cascade (ComC) and coagulation cascade (CoaC) after trauma remains unclear. This study intended to explore whether complement-coagulation crosstalk exists, which may provide a reliable guide to clinical implications in trauma patients. Methods: This single-center cohort study of trauma patients enrolled 100 patients along with 20 healthy volunteers. Blood samples from patients were collected at admission, 45, 90, 135 minutes, and 18 hours after admission. Demographic characteristics were recorded, blood levels of ComC and CoaC factors, and inflammatory cytokines were measured by ELISA, clot-based assays, or luminex multiplex assay, and partial thromboplastin (PT) and partial thromboplastin time (PTT) were assessed using a Behring blood coagulation system. Results: Compared with the healthy controls, plasma levels of complement factors (C5b-9 and Bb) and 11 tested inflammatory cytokines increased in moderately and severely injured patients as early as 45 minutes after admission and sustained higher levels up to 18 hours after admission. C5b-9 correlated positively to patients' hospital stay. In parallel, the consumption of coagulation factors I, II, X, and XIII was shown throughout the first 18 hours after admission in moderately and severely injured patients, whereas PT, PTT, D-dimer, factor VII, and factor VIII values significantly increased from the admission to 135 minutes in moderately and severely injured patients. Along with an inverse correlation between plasma Bb, factors I and II, a positive correlation between C5b-9, Bb, D-dimer, PT, and PTT was evident. Conclusions: This study demonstrates trauma-induced early activation of plasma cascades including ComC, CoaC, and fibrinolytic cascade, and their correlation between plasma cascades in severe trauma patients. Our study suggests that the simultaneous modulation of plasma cascades might benefit clinical outcomes for trauma patients. Level of evidence: Prospective study, level III.