Emergency Subglottic Airway Training and Assessment of Skills Retention of Attending Anesthesiologists With Simulation Mastery-Based Learning.

BACKGROUND: Although included within the American Society of Anesthesiologists difficult airway algorithm, the use of "invasive airway access" is rarely needed clinically. In conjunction with highly associated morbidity and liability risks, it is a challenge for the average anesthesiologist to develop and maintain competency. The advancement of high-fidelity simulators allows for practice of rarely encountered clinical scenarios, specifically those requiring invasive subglottic airway techniques. METHODS: Sixty board-certified academic anesthesiologists were enrolled and trained in dyads in a simulation-based, mastery-based learning (MBL) course directed at 2 emergency airway subglottic techniques: transtracheal jet ventilation (TTJV) and bougie cricothyrotomy (BC). Performance metrics included: pretest, posttest, specific skill step error tracking, and 15-month period retest. All were pretested and trained once on the Melker cricothyrotomy (MC) kit. All pretest assessment, training, posttesting, and 15-month retesting were performed by a single expert clinical and educational airway management faculty member. RESULTS: Initial testing showed a success rate of 14.8% for TTJV, 19.7% for BC, and 25% for MC. After mastery-based practice, all anesthesiologists achieved successful invasive airway placement with TTJV, BC, and MC. Repeated performance of each skill improved speed with zero safety breaches. BC was noted to be the fastest performed technique. Fifteen months later, retesting showed that 80.4% and 82.6% performed successful airway securement for TTJV and BC, respectively. For safety, average placement time and costs, MC was discarded after initial training results. CONCLUSIONS: We discovered that only ~20% of practicing anesthesiologists were able to successfully place an invasive airway in a simulated life or death clinical setting. Using mobile simulation (training performed in department conference room) during a 2.5-hour session using mastery-based training pedagogy, we increased our success rate of invasive airway placement to 100%, while also increasing the successful speed to ventilation (TTJV, 32 seconds average; BC, 29 seconds average). Finally, we determined that there was a 15-month 80% retention rate of the airway skills learned, indicating that skills last at least a year before retraining is required using this training methodology.

Observational study of anaesthesia workflow to evaluate physical workspace design and layout.

BACKGROUND: The safety and efficiency of anaesthesia care depend on the design of the physical workspace. However, little is known about the influence that workspace design has on the ability to perform complex operating theatre (OT) work. The aim of this study was to observe the relationship between task switching and physical layout, and then use the data collected to design and assess different anaesthesia workspace layouts. METHODS: In this observational study, six videos of anaesthesia providers were analysed from a single centre in the United States. A task analysis of workflow during the maintenance phase of anaesthesia was performed by categorising tasks. The data supported evaluations of alternative workspace designs. RESULTS: An anaesthesia provider's time was occupied primarily by three tasks: patient (mean: 30.0% of total maintenance duration), electronic medical record (26.6%), and visual display tasks (18.6%). The mean time between task switches was 6.39 s. With the current workspace layout, the anaesthesia provider was centred toward the patient for approximately half of the maintenance duration. Evaluating the alternative layout designs showed how equipment arrangements could improve task switching and increase the provider's focus towards the patient and visual displays. CONCLUSIONS: Our study showed that current operating theatre layouts do not fit work demands. We report a simple method that facilitates a quick layout design assessment and showed that the anaesthesia workspace can be improved to better suit workflow and patient care. Overall, this arrangement could reduce anaesthesia workload while improving task flow efficiency and potentially the safety of care.

Effects of Combining a Brief Cognitive Intervention with Transcranial Direct Current Stimulation on Pain Tolerance: A Randomized Controlled Pilot Study.

Objective: Cognitive behavioral therapy has been shown to be effective for treating chronic pain, and a growing literature shows the potential analgesic effects of minimally invasive brain stimulation. However, few studies have systematically investigated the potential benefits associated with combining approaches. The goal of this pilot laboratory study was to investigate the combination of a brief cognitive restructuring intervention and transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex in affecting pain tolerance. Design: Randomized, double-blind, placebo-controlled laboratory pilot. Setting: Medical University of South Carolina. Subjects: A total of 79 healthy adult volunteers. Methods: Subjects were randomized into one of six groups: 1) anodal tDCS plus a brief cognitive intervention (BCI); 2) anodal tDCS plus pain education; 3) cathodal tDCS plus BCI; 4) cathodal tDCS plus pain education; 5) sham tDCS plus BCI; and 6) sham tDCS plus pain education. Participants underwent thermal pain tolerance testing pre- and postintervention using the Method of Limits. Results: A significant main effect for time (pre-post intervention) was found, as well as for baseline thermal pain tolerance (covariate) in the model. A significant time × group interaction effect was found on thermal pain tolerance. Each of the five groups that received at least one active intervention outperformed the group receiving sham tDCS and pain education only (i.e., control group), with the exception of the anodal tDCS + education-only group. Cathodal tDCS combined with the BCI produced the largest analgesic effect. Conclusions: Combining cathodal tDCS with BCI yielded the largest analgesic effect of all the conditions tested. Future research might find stronger interactive effects of combined tDCS and a cognitive intervention with larger doses of each intervention. Because this controlled laboratory pilot employed an acute pain analogue and the cognitive intervention did not authentically represent cognitive behavioral therapy per se, the implications of the findings on chronic pain management remain unclear.

Developing a 3D Gestural Interface for Anesthesia-Related Human-Computer Interaction Tasks Using Both Experts and Novices.

OBJECTIVE: The purpose of this research was to compare gesture-function mappings for experts and novices using a 3D, vision-based, gestural input system when exposed to the same context of anesthesia tasks in the operating room (OR). BACKGROUND: 3D, vision-based, gestural input systems can serve as a natural way to interact with computers and are potentially useful in sterile environments (e.g., ORs) to limit the spread of bacteria. Anesthesia providers' hands have been linked to bacterial transfer in the OR, but a gestural input system for anesthetic tasks has not been investigated. METHODS: A repeated-measures study was conducted with two cohorts: anesthesia providers (i.e., experts) ( N = 16) and students (i.e., novices) ( N = 30). Participants chose gestures for 10 anesthetic functions across three blocks to determine intuitive gesture-function mappings. Reaction time was collected as a complementary measure for understanding the mappings. RESULTS: The two gesture-function mapping sets showed some similarities and differences. The gesture mappings of the anesthesia providers showed a relationship to physical components in the anesthesia environment that were not seen in the students' gestures. The students also exhibited evidence related to longer reaction times compared to the anesthesia providers. CONCLUSION: Domain expertise is influential when creating gesture-function mappings. However, both experts and novices should be able to use a gesture system intuitively, so development methods need to be refined for considering the needs of different user groups. APPLICATION: The development of a touchless interface for perioperative anesthesia may reduce bacterial contamination and eventually offer a reduced risk of infection to patients.

Realizing improved patient care through human-centered operating room design: a human factors methodology for observing flow disruptions in the cardiothoracic operating room.

BACKGROUND: Human factors engineering has allowed a systematic approach to the evaluation of adverse events in a multitude of high-stake industries. This study sought to develop an initial methodology for identifying and classifying flow disruptions in the cardiac operating room (OR). METHODS: Two industrial engineers with expertise in human factors workflow disruptions observed 10 cardiac operations from the moment the patient entered the OR to the time they left for the intensive care unit. Each disruption was fully documented on an architectural layout of the OR suite and time-stamped during each phase of surgery (preoperative [before incision], operative [incision to skin closure], and postoperative [skin closure until the patient leaves the OR]) to synchronize flow disruptions between the two observers. These disruptions were then categorized. RESULTS: The two observers made a total of 1,158 observations. After the elimination of duplicate observations, a total of 1,080 observations remained to be analyzed. These disruptions were distributed into six categories such as communication, usability, physical layout, environmental hazards, general interruptions, and equipment failures. They were further organized into 33 subcategories. The most common disruptions were related to OR layout and design (33%). CONCLUSIONS: By using the detailed architectural diagrams, the authors were able to clearly demonstrate for the first time the unique role that OR design and equipment layout has on the generation of physical layout flow disruptions. Most importantly, the authors have developed a robust taxonomy to describe the flow disruptions encountered in a cardiac OR, which can be used for future research and patient safety improvements.

A pilot functional MRI study of the effects of prefrontal rTMS on pain perception.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has been shown to effectively treat depression, and its potential value in pain management is emphasized by recent studies. Transcranial magnetic stimulation (TMS)-evoked activity in the prefrontal cortex may be associated with corticolimbic inhibitory circuits capable of decreasing pain perception. The present exploratory pilot study used functional magnetic resonance imaging (fMRI) to examine the effects of left prefrontal rTMS on brain activity and pain perception. DESIGN AND INTERVENTION: Twenty-three healthy adults with no history of depression or chronic pain underwent an 8-minute thermal pain protocol with fMRI before and after a single rTMS session. Participants received 15 minutes of either real (N = 12) or sham (N = 11) 10 Hz rTMS over the left prefrontal cortex (110% of resting motor threshold; 5 seconds on, 10 seconds off). RESULTS: TMS was associated with a 13.30% decrease in pain ratings, while sham was associated with an 8.61% decrease (P = 0.04). TMS was uniquely associated with increased activity in the posterior cingulate gyrus, precuneous, right superior frontal gyrus, right insula, and bilateral postcentral gyrus. Activity in the right superior prefrontal gyrus was negatively correlated with pain ratings (r = -0.65, P = 0.02) in the real TMS group. CONCLUSIONS: Findings suggest that prefrontal rTMS may be capable of activating inhibitory circuits involved with pain reduction.

Comparing User Perceptions of Surgical Environments: Simulations in a High-Fidelity Physical Mock-Up Versus a Postoccupancy Evaluation.

OBJECTIVE: The purpose of this study was to compare perceptions and behaviors of end users participating in simulations in a high-fidelity physical mock-up of an operating room (OR) prototype with the perceptions and behaviors of end users in the built out ORs postoccupancy. BACKGROUND: Simulation-based evaluations of high-fidelity physical mock-ups of proposed layouts are increasingly being conducted during the facility design process to understand impacts on workflow and potential adverse patient safety outcomes. Nevertheless, it is unclear to what extent user experiences in these simulated healthcare spaces are similar to those in built and occupied healthcare environments. METHODS: Using interviews, surveys, and observations, this study compared user evaluations in a high-fidelity physical mock-up of an OR with user evaluations of the built and occupied OR postoccupancy. Workflow disruptions were also analyzed using video recordings for a simulated pediatric surgery and five pediatric surgeries in the actual OR. RESULTS: This study found that user perceptions and behavior in the two types of environments were mostly similar with regard to perceived support for the location of surgeon workstation, perceived space and task performance, perceived access to storage locations, boom setup, and OR cleanability. Participant's ratings differed for supportiveness of the mobile Circulating Nurse (CN) workstation, maneuvering booms, and environmental disruptions. CONCLUSION: Simulation-based evaluations are extremely beneficial during the design process and can provide valuable input to design teams as well as clinical teams about workflow and safety issues that allow design issues to be addressed before construction.

Feasibility, safety, and effectiveness of transcranial direct current stimulation for decreasing post-ERCP pain: a randomized, sham-controlled, pilot study.

BACKGROUND: Emerging evidence shows that transcranial direct current stimulation (tDCS), a minimally invasive brain stimulation technique, has analgesic effects in chronic pain patients and in healthy volunteers with experimental pain. No studies have examined the analgesic effects of tDCS immediately after surgical/endoscopic procedures. Endoscopy investigating abdominal pain, especially ERCP, can cause significant postprocedural pain. OBJECTIVE: To test the feasibility, efficacy, and safety of tDCS on post-ERCP pain and analgesia use. DESIGN: Randomized, sham-controlled, pilot study. SETTING: Tertiary-care medical center. PATIENTS: This study involved 21 patients who were hospitalized overnight for ERCP for unexplained right upper quadrant pain. INTERVENTION: Twenty minutes of real 2.0 mA tDCS or sham (anode over left prefrontal cortex; cathode over gut-representation of right sensory cortex) immediately after ERCP. MAIN OUTCOME MEASUREMENTS: Pain (visual analogue scale, McGill pain questionnaire, brief pain inventory), patient-controlled analgesia use, adverse events. RESULTS: Real tDCS was associated with 22% less total hydromorphone use, versus sham. The slope of the cumulative patient-controlled analgesia usage curve was significantly steeper in the sham tDCS group (F [2,13] = 15.96; P = .0003). Real tDCS patients reported significantly less pain interference with sleep (t [17] = 3.70; P = .002) and less throbbing pain (t [16] = 2.37; P = .03). Visual analogue scale pain and mood scores (4 hours post-ERCP) suggested a nonsignificant advantage for real tDCS, despite less hydromorphone use. Side effects of tDCS were limited to mild, self-limited tingling, itching, and stinging under electrodes. LIMITATIONS: Small sample size, variability in chronic pain, and chronic opioid use. CONCLUSION: In this pilot study, tDCS appears to be safe, has minimal side effects, and may reduce postprocedural analgesia requirements and subjective pain ratings. Future studies appear warranted.

Continuous localized monitoring of plasmin activity identifies differential and regional effects of the serine protease inhibitor aprotinin: relevance to antifibrinolytic therapy.

BACKGROUND: Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis after cardiac surgery. However, aprotinin was empirically dosed, and although the pharmacological target was the inhibition of plasmin activity (PLact), this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical empirical aprotinin dosing would impart differential and regional effects on PLact. METHODS/RESULTS: Pigs (30 kg) were instrumented with microdialysis probes to continuously measure PLact in myocardial, kidney, and skeletal muscle compartments (deltoid) and then randomized to high-dose aprotinin administration (2 mKIU load/0.5 mKIU/hr infusion; n = 7), low-dose aprotinin administration (1 mKIU load/0.250 mKIU/hr infusion; n = 6). PLact was compared with time-matched vehicle (n = 4), and PLact was also measured in plasma by an in vitro fluorogenic method. Aprotinin suppressed PLact in the myocardium and kidney at both high and low doses, indicative that both doses exceeded a minimal concentration necessary for PLact inhibition. However, differential effects of aprotinin on PLact were observed in the skeletal muscle, indicative of different compartmentalization of aprotinin. CONCLUSIONS: Using a large animal model and a continuous method to monitor regional PLact, these unique results demonstrated that an empirical aprotinin dosing protocol causes maximal and rapid suppression in the myocardium and kidney and in turn would likely increase the probability of off-target effects and adverse events. Furthermore, this proof of principle study demonstrated that continuous monitoring of determinants of fibrinolysis might provide a novel approach for managing fibrinolytic therapy.

Plasma profiling determinants of matrix homeostasis in paediatric dilated cardiomyopathy.

OBJECTIVE: Dilated cardiomyopathy is an important cause of cardiac failure in both children and adults, but is more progressive in children. In adult dilated cardiomyopathy, left ventricular remodelling is associated with changes in the plasma levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases. Plasma matrix metalloproteinases and tissue inhibitors of metalloproteinase changes in paediatric dilated cardiomyopathy have not been examined. This study developed a low blood volume, high-sensitivity assay to test the hypothesis that unique and differential plasma matrix metalloproteinases and tissue inhibitors of metalloproteinase profile exist in patients with paediatric dilated cardiomyopathy. METHODS/RESULTS: A systemic blood sample (1 millilitre) was obtained from seven children aged 8 plus or minus 7 years with dilated cardiomyopathy and 26 age-matched normal volunteers. Using a high-throughput multiplex suspension immunoassay, plasma levels were quantified for collagenases (matrix metalloproteinase-8), gelatinases (matrix metalloproteinase-2 and -9), lysins (matrix metalloproteinase-3 and -7), and tissue inhibitor of metalloproteinases-1, -2, and -4. The matrix metalloproteinase to tissue inhibitors of metalloproteinases ratios were also calculated. The plasma matrix metalloproteinase-2, -7, -8, and -9 levels were increased by greater than twofold in patients with dilated cardiomyopathy than normal patients (with p less than 0.05). Patients with dilated cardiomyopathy also had significantly higher tissue inhibitors of metalloproteinases-1 and -4 (298% and 230%; with p less than 0.05). CONCLUSIONS: These unique findings show that a specific plasma matrix metalloproteinase/tissue inhibitor of metalloproteinase profile occurs in paediatric dilated cardiomyopathy when compared to the cases of normal children. These distinct differences in the determinants of myocardial matrix structure and function may contribute to the natural history of dilated cardiomyopathy in children and may provide a novel biomarker platform in paediatric dilated cardiomyopathy.

Proactive Evaluation of an Operating Room Prototype: A Simulation-Based Modeling Approach.

OBJECTIVES: There is a pressing need to improve safety and efficiency in the operating room (OR). Postsurgical adverse events, such as surgical site infections and surgical flow disruption, occur at a significant rate in industrial countries where a considerable portion of such complications result in death. The aim of the study was to identify an ideal room design that improves the flow of staff members using risk and safety performance measures. METHODS: Operating room designs were compared by using computer simulation modeling to analyze traffic flow inside an OR. The study was conducted in two phases. A historical data set was first created based on surgical flow data obtained from 23 video observations of actual surgical procedures. A detailed simulation-based model was then developed. RESULTS: As room size increases, staff members have more available space to maneuver in the room, resulting in more distance walked but far fewer undesirable contacts. An angled table orientation is preferred with the circulating nurse workstation at the foot of the OR table, as it provides more space for staff to move across the room without increasing the number of contacts. Furthermore, when the nurse workstation is near the wall, staff members experience fewer undesirable contacts. CONCLUSIONS: Simulation modeling was used to assess the impact of OR layout alternatives on three performance metrics, and the medium-sized OR prototype performs well across the metrics. Future research will consider the relative influence of several factors on traffic-based safety and efficiency performance metrics, resulting in a more predictive simulation design model.

Temporally and regionally disparate differences in plasmin activity by tranexamic acid.

BACKGROUND: A major complication associated with cardiac surgery is excessive and prolonged bleeding in the perioperative period. Improving coagulation by inhibiting fibrinolysis, primarily through inhibition of plasmin activity (PLact) with antifibrinolytics such as tranexamic acid (TXA), has been a pharmacological mainstay in cardiac surgical patients. Despite its almost ubiquitous use, the temporal and regional modulation of PLact profiles by TXA remains unexplored. Accordingly, we developed a fluorogenic-microdialysis system to measure in vivo dynamic changes in PLact after TXA administration in a large animal model. METHODS: Pigs (25-35 kg) were randomly assigned to receive TXA (30 mg/kg, diluted into 50 mL normal saline; n = 9) or vehicle (50 mL normal saline; n = 7). Microdialysis probes were placed in the liver, myocardium, kidney, and quadriceps muscle compartments. The microdialysate infusion contained a validated plasmin-specific fluorogenic peptide. The fluorescence emission (standard fluorogenic units [SFU]) of the interstitial fluid collected from the microdialysis probes, which directly reflects PLact, was determined at steady-state baseline and 30, 60, 90, and 120 min after TXA/vehicle infusion. Plasma PLact was determined at the same time points using the same fluorogenic substrate approach. RESULTS: TXA reduced plasma PLact at 30 min after infusion by >110 SFU compared with vehicle values (P < 0.05). Specifically, there was a decrease in liver PLact at 90 and 120 min after TXA infusion of >150 SFU (P < 0.05) and 175 SFU (P < 0.05), respectively. The decrease in liver PLact occurred 60 min after the maximal decrease in plasma PLact. In contrast, kidney, heart, and quadriceps PLact transiently increased followed by an overall decrease at 120 min. CONCLUSIONS: Using a large animal model and in vivo microdialysis measurements of PLact, the unique findings from this study were 2-fold. First, TXA induced temporally distinct PLact profiles within the plasma and selected interstitial compartments. Second, TXA caused region-specific changes in PLact profiles. These temporal and regional differences in the effects of TXA may have important therapeutic considerations when managing fibrinolysis in the perioperative period.

Airway catastrophes.

PURPOSE OF REVIEW: The article reviews the epidemiology of airway injuries, airway anatomy, techniques for airway management, helpful pharmacologic adjuncts and finally alternatives to airway manipulation. RECENT FINDINGS: Principles of airway management including the maintenance of spontaneous ventilation and careful and adequate preparation for an alternative plan will always be important. Advances in pharmacologic agents provide a safer, more controlled environment through which the patient's compromised airway can be controlled. Recent publications add to the evidence that alternative methods of oxygenation and ventilation such as cardiopulmonary bypass can be used successfully to treat patients with catastrophic airway injuries. SUMMARY: Trauma to the airway, either blunt or penetrating or iatrogenic, can result in significant patient morbidity and mortality. Although, relatively rare, if we practice long enough, each of us will encounter such a patient. The anesthesiologist must be familiar with airway anatomy and the location of injury for successful treatment. Along with airway injuries, associated injuries are common and often complicate definitive airway treatment. Modern anesthetic medications such as dexmedetomidine and proven techniques such as awake fiberoptic intubation can be used to safely treat these difficult patients. Alternative therapies such as cricothyroidotomy and cardiopulmonary bypass should be available if first-line therapies fail to secure an injured airway.

The Evaluation of Tactile Parameters and Display Prototype to Support Physiological Monitoring and Multitasking for Anesthesia Providers in the Operating Room.

Communicating physiological information via the tactile modality is shown as a promising means to address data overload faced by anesthesia providers. However, it is important to ensure that the tactile parameters which represent information are intuitive. There is currently no consensus on which tactile parameters should be used to present information within anesthesia. The two studies presented here evaluate: (a) a set of 24 tactile cues manipulating intensity, temporal, and spatial tactile parameters in a usability study and (b) a prototype tactile display based on the usability study's findings in a single and dual-task scenario. Findings of the usability study show intensity and temporal were rated most urgent and had the most potential to represent changes in physiological measures. This was confirmed in the follow up study as increases/decreases in intensity were shown to represent increases/decreases in a physiological measure and using different spatial locations to represent physiological measures resulted in greater than 95% response accuracy. Response times and accuracy were not adversely affected while performing a secondary task. The findings contribute to a better understanding of how to map tactile parameters to physiological information and demonstrate the effectiveness of end-user feedback in tactile display design to develop intuitive alerts.

A pilot study investigating the effects of fast left prefrontal rTMS on chronic neuropathic pain.

OBJECTIVE: Stimulating the human cortex using transcranial magnetic stimulation (TMS) temporarily reduces clinical and experimental pain; however, it is unclear which cortical targets are the most effective. The motor cortex has been a popular target for managing neuropathic pain, while the prefrontal cortex has been investigated for an array of nociceptive pain conditions. It is unclear whether the motor cortex is the only effective cortical target for managing neuropathic pain, and no published studies to date have investigated the effects of prefrontal stimulation on neuropathic pain. DESIGN: This preliminary pilot trial employed a sham-controlled, within-subject, crossover design to evaluate clinical pain as well as laboratory pain thresholds among four patients with chronic neuropathic pain. Each participant underwent three real and three sham 20-minute sessions of 10 Hz left prefrontal repetitive TMS. Daily pain diaries were collected for 3 weeks before and after each treatment phase along with a battery of self-report pain and mood questionnaires. RESULTS: Time-series analysis at the individual patient level indicated that real TMS was associated with significant improvements in average daily pain in 3 of the 4 participants. These effects were independent of changes in mood in two of the participants. At the group level, a decrease of 19% in daily pain on average, pain at its worst, and pain at its least was observed while controlling for changes in mood, activity level and sleep. The effects of real TMS were significantly greater than sham. Real TMS was associated with increases in thermal and mechanical pain thresholds, whereas sham was not. No statistically significant effects were observed across the questionnaire data. CONCLUSIONS: The prefrontal cortex may be an important TMS cortical target for managing certain types of pain, including certain neuropathic pain syndromes.

Aprotinin modifies left ventricular contractility and cytokine release after ischemia-reperfusion in a dose-dependent manner in a murine model.

BACKGROUND: Periods of ischemia-reperfusion (I/R) during cardiac surgery are associated with transient left ventricular (LV) dysfunction and an inflammatory response. In this study, we examined the potential dose-dependent effects of aprotinin (APRO) on LV contractility and cytokine release in the setting of I/R. METHODS: An index of LV contractility, LV maximal elastance (E(max)), was measured at baseline, 30 min of ischemia, and 60 min of reperfusion by microtransducer volumetry. Mice were randomized as follows: (a) APRO 20,000 kallikrein-inhibiting units (KIU)/kg (n = 11); (b) APRO 4 x 10(4) KIU/kg (n = 10); (c) APRO 8 x 10(4) KIU/kg (n = 10); and (d) vehicle (saline; n = 10). APRO doses were calculated to reflect half, full, and twice the clinical Hammersmith dosing schedule. After I/R, plasma was collected for cytokine measurements. RESULTS: After I/R, E(max) decreased from the baseline value by more than 40% in the vehicle group as well as in the APRO 4 x 10(4) KIU/kg and APRO 8 x 10(4) KIU/kg groups (P < 0.05). However, E(max) returned to near baseline values in the APRO 2 x 10(4) KIU/kg group. Tumor necrosis factor (TNF) increased 10-fold after I/R, but it was reduced with higher APRO doses. CONCLUSIONS: This study demonstrated that a low dose of APRO provided protective effects on LV contractility, whereas higher doses suppressed TNF release. These unique findings suggest that there are distinct and independent mechanisms of action of APRO in the context of I/R.

Aprotinin exacerbates left ventricular dysfunction after ischemia/reperfusion in mice lacking tumor necrosis factor receptor I.

Aprotinin is a serine protease inhibitor with diverse biological effects; until recently, it was utilized in the context of ischemia/reperfusion (I/R). It has been hypothesized that a signaling pathway modulated by aprotinin in the context of I/R is the tumor necrosis factor-alpha receptor (TNFR) pathway. An intact mouse model of I/R (30 min ischemia and 60 min reperfusion) was used and left ventricular (LV) peak + maximal rate of left ventricular (LV) peak pressure (dP/dt) was measured in wild-type mice (WT, C57BL/6; n = 10), WT mice with aprotinin (4 mL/kg; n = 10), transgenic mice devoid of the TNFRI (TNFRI-null; n = 10), and TNFRI-null with aprotinin (n=10). Following I/R, LV peak + dP/dt decreased in both WT groups, but remained similar to baseline values in the TNFRI-null group. In contrast, aprotinin caused a marked reduction in LV peak + dP/dt in the TNFRI-null group following I/R. Soluble plasma TNF levels increased in the WT and TNFRI-null mice with I/R and was reduced with aprotinin. Soluble TNFRI and TNFRII levels, indicative of TNF activation, increased in the WT mice following I/R and remained elevated with aprotinin. Soluble TNFRII levels were increased in the TNFRI-null mice following I/R and remained elevated with aprotinin. The new and unique findings of this study were twofold. First, aprotinin failed to improve LV function after I/R despite a reduction in circulating TNF levels. Second, genetic ablation of TNFRI uncovered a negative inotropic effect of aprotinin. These findings demonstrate that complex biological pathways and interactions are affected with broad spectrum serine protease inhibition, which are relevant to myocardial function in the context of I/R.