Brandon H. Tieu

Coagulopathy: Its Pathophysiology and Treatment in the Injured Patient

Hemorrhage continues to be one of the leading causes of death following trauma. Trauma patients are susceptible to the early development of coagulopathy and the most severely injured patients are coagulopathic on hospital admission. Hypothermia, acidosis, and dilution from standard resuscitation can worsen the presenting coagulopathy and perpetuate bleeding. Early identification of coagulopathy is dependent on clinical awareness and point of care laboratory values. Routinely used laboratory coagulation parameters fail to adequately describe this state. Thrombelastography is a test that can be done at the bedside and uses whole blood to provide a functional evaluation of coagulation. Rapid diagnosis of coagulopathy, followed by prevention or correction of hypothermia and acidosis should be a priority during the initial evaluation and resuscitation. Judicious use of resuscitation fluids and early replacement of coagulation factors will help prevent iatrogenic hemodilution. This review covers the pathophysiology as well as the clinical and laboratory diagnosis of coagulopathy. Prevention and treatment strategies are discussed, including early transfusion of coagulation factors during massive transfusion and the use of recombinant factor VIIa. Damage control resuscitation is briefly discussed, and it involves the combination of hypotensive resuscitation and hemostatic resuscitation. Finally, a description of the use of fresh whole blood in the military setting is included. Its use has been proven to be safe and beneficial in this setting and warrants further investigation as an adjunct to the management of civilian trauma patients.

Reproducibility of an Animal Model Simulating Complex Combat-Related Injury in a Multiple-Institution Format

We developed a complex combat-relevant model of abdominal and extremity trauma, hemorrhagic shock, hypothermia, and acidosis. We then simulated injury, preoperative, and operative phases. We hypothesized that this model is reproducible and useful for randomized multicenter preclinical trials. Yorkshire swine were anesthetized, intubated, and instrumented. They then underwent femur fracture, 60% total blood volume hemorrhage, a 30-min shock period, induced hypothermia to 33°C, and hemorrhage volume replacement with 3:1 isotonic sodium chloride solution (NS) at each of three centers. Hemodynamic parameters were measured continuously. Thromboelastography, arterial blood gas, and laboratory values were collected at baseline, after the shock period, and after NS replacement. Thirty-seven animals were used for model development. Eight (21%) died before completion of the study period. Twenty-nine survivors were included in the analysis. MAP (±SEM) after the shock period was 32 ± 2 mmHg and was similar between centers (P = 0.4). Mean pH, base deficit, and lactate levels were 7.29 ± 0.02, 8.20 ± 0.65 mmol/L, and 5.29 ± 0.44 mmol/L, respectively, after NS replacement. These were similar between centers (P > 0.05). Prothrombin time values increased significantly over time at all centers, reflecting a progressive coagulopathy (P < 0.02). Thromboelastography maximum amplitude values were similar among centers (P > 0.05) and demonstrated progressively weakened platelet interaction over time (P < 0.03). Hematocrit was similar after controlled hemorrhage (P = 0.15) and dilution (P = 0.9). The pH, lactate, base deficit, and coagulation tests reflect a severely injured state. A complex porcine model of polytrauma and shock canbe used for multi-institutional study with excellent reproducibility. A consistent severe injury profile was achieved, afterwhich experimental interventions can be applied. This is the first report of a reproducible multicenter trauma and resuscitation-related animal model.

A novel highly porous silica and chitosan-based hemostatic dressing is superior to HemCon and gauze sponges.

BACKGROUND Hemostatic dressings have become increasingly popular as the optimal initial treatment for severe hemorrhage. The purpose of this study was to compare the hemostatic properties of a novel highly porous silica and chitosan-based dressing (TraumaStat) to HemCon, and gauze dressing in a severe groin injury model in swine. METHODS Thirty swine were blindly randomized to receive TraumaStat, HemCon, or standard gauze dressing for hemostatic control. A complex groin injury involving complete transaction of the femoral artery and vein was made. After 30 seconds of uncontrolled hemorrhage, the randomized dressing was applied and pressure was held for 5 minutes. Fluid resuscitation was initiated to achieve and maintain the baseline mean arterial pressure and the wound was inspected for bleeding. Failure of hemostasis was defined as pooling of blood outside of the wound. Animals were then monitored for 120 minutes and surviving animals were euthanized. RESULTS Blood loss before treatment was similar between groups (p > 0.1). TraumaStat had one failure, compared with five for gauze, and eight for HemCon (p = 0.005, TraumaStat vs. HemCon). TraumaStat significantly reduced median blood loss when compared with both HemCon and gauze (117 vs. 774 and 268 mL respectively, p < 0.05). At study conclusion, TraumaStat animals had a greater median hematocrit than both HemCon (24 vs. 19, p = 0.033), and gauze (24 vs. 19, p = 0.049) animals. Median volume of fluid resuscitation and mortality were not different between groups (p > 0.1). CONCLUSIONS TraumaStat was superior to HemCon and gauze dressings in controlling bleeding from a severe groin injury. TraumaStat may be a better hemostatic dressing for control of active hemorrhage than current standards of care.

Effect of high product ratio massive transfusion on mortality in blunt and penetrating trauma patients.

BACKGROUND Recent data suggest that massively transfused patients have lower mortality rates when high ratios (>1:2) of plasma or platelets to red blood cells (RBCs) are used. Blunt and penetrating trauma patients have different injury patterns and may respond differently to resuscitation. This study was performed to determine whether mortality after high product ratio massive transfusion is different in blunt and penetrating trauma patients. METHODS Patients receiving 10 or more units of RBCs in the first 24 hours after admission to one of 23 Level I trauma centers were analyzed. Baseline physiologic and biochemical data were obtained. Univariate and logistic regression analyses were performed. Adjusted mortality in patients receiving high (≥ 1:2) and low (<1:2) ratios of plasma or platelets to RBCs was calculated for blunt and penetrating trauma patients. RESULTS The cohort contained 703 patients. Blunt injury patients receiving a high ratio of plasma or platelets to RBCs had lower 24-hour mortality (22% vs. 31% for plasma, p = 0.007; 20% vs. 30% for platelets, p = 0.032), but there was no difference in 30-day mortality (40% vs. 44% for plasma, p = 0.085; 37% vs. 44% for platelets, p = 0.063). Patients with penetrating injuries receiving a high plasma:RBC ratio had lower 24-hour mortality (21% vs. 37%, p = 0.005) and 30-day mortality (29% vs. 45%, p = 0.005). High platelet:RBC ratios did not affect mortality in penetrating patients. CONCLUSION Use of high plasma:RBC ratios during massive transfusion may benefit penetrating trauma patients to a greater degree than blunt trauma patients. High platelet:RBC ratios did not benefit either group.

Neoadjuvant Therapy for Resectable Non–Small Cell Lung Cancer with Mediastinal Lymph Node Involvement

The optimal treatment for stage IIIA (N2) NSCLC remains controversial. Numerous studies with induction chemotherapy or chemoradiotherapy show that both approaches in the neoadjuvant setting are feasible. Outcomes following induction therapy have been associated with mediastinal nodal response, with residual mediastinal involvement a negative predictor of survival. Appropriate selection of patients to undergo resection following induction therapy is critical. Lobectomy may be safely performed following induction therapy while pneumonectomy may carry a high and possibly unacceptable rate of perioperative mortality. Combined modality therapy has increased the overall survival of patients with stage III NSCLC. Future trials looking at different induction regimens with or without radiotherapy and with or without surgery may help identify the ideal treatment for this heterogeneous disease stage. The SAKK-16/00 study is an ongoing phase III European trial randomizing patients with stage IIIA NSCLC to receive neoadjuvant chemotherapy with three cycles of docetaxel and cisplatin followed by radiation and then surgical resection, or to chemotherapy with the same regimen followed by surgery alone. Other ongoing trials include investigations of novel chemotherapeutic combinations, such as cisplatin with pemetrexed, in the phase II setting. The RTOG 0229 phase II study is evaluating neoadjuvant paclitaxel and carboplatin concurrently with radiation therapy, followed by surgery and consolidation chemotherapy with paclitaxel and carboplatin for stage III NSCLC. The combination of neoadjuvant docetaxel, carboplatin, and radiation therapy followed by surgical resection for stage III NSCLC is also currently being investigated in a phase II trial. The future of treatment for stage III NSCLC may lie in the outcome of trials investigating molecularly targeted agents, such as EGFR inhibitors, anti-angiogenic agents, or multitargeted agents. Optimal incorporation into the multimodality approach required of locally advanced N2 NSCLC will require careful investigation. The results from these trials are eagerly awaited.

Ketamine-based Total Intravenous Anesthesia Versus Isoflurane Anesthesia in a Swine Model of Hemorrhagic Shock

BACKGROUND Inhalational anesthetics can cause profound hemodynamic effects including decreases in systemic vascular resistance and cardiac inotropy. Although widely used in uncontrolled hemorrhagic shock (UHS), their consequences compared with other anesthetic regimens are not well-studied. Ketamine-based total intravenous anesthesia (TIVA) may produce less profound cardiovascular depression, and has been used during elective surgery but rarely during traumatic shock. The purpose of this study was to compare the effects of isoflurane (ISO) and TIVA regimens in a swine grade V liver injury model. We hypothesized that TIVA would result in less hypotension and dysfunctional inflammation than ISO. METHODS Twenty swine were randomized blindly to receive either 1% to 3% ISO, or intravenous ketamine, midazolam, and buprenorphine for maintenance anesthesia. Six animals acted as controls. After sedation and intubation, randomized anesthesia was initiated and monitored by an independent animal technician. Invasive lines were placed followed by celiotomy and splenectomy. Baseline mean arterial pressure (MAP) was documented and a grade V liver injury created. After 30 minutes of UHS, animals were resuscitated with 8 mL of Ringers lactate per milliliter blood loss at 165 mL/min. MAP and tissue oxygen saturation (StO2) were continuously recorded. The animals were sacrificed 120 minutes after injury and lung tissue was harvested. Serum cytokines (interleukin-6 [IL-6], IL-8, and tumor necrosis factor-alpha [TNF-alpha]) were quantified with enzyme-linked immunosorbent assay. Lung cytokine mRNA levels were quantified with real time reverse transcriptase polymerase chain reaction. RESULTS Animal weight, liver injury pattern, and blood loss were similar (p > 0.1). The ISO group had a lower MAP at baseline (p = 0.02), at injury (p = 0.004), and study completion (p = 0.001). After resuscitation, MAP decreased in the ISO group but remained stable in the TIVA group. StO2 was significantly higher in the TIVA group immediately after injury (p = 0.004), but similar between groups throughout the remainder of the study. Animals who received TIVA trended toward higher levels of lactate and lower pH throughout the study, reaching significance at 30 minutes postinjury (p = 0.037 and 0.043). Inflammatory cytokine (IL-6, IL-8, and TNF-alpha) production did not differ between groups, however TNF-alpha mRNA production was significantly lower in the TIVA group (p = 0.04). CONCLUSION Although a TIVA regimen produced less pronounced hypotension in a swine model of UHS than did ISO, end-organ perfusion with TIVA appeared to be equivalent or inferior to ISO. In circumstances of limited resources, such as those experienced by forward Army surgical teams, a ketamine-based TIVA regimen may be an option for use in UHS.

Specific abbreviated injury scale values are responsible for the underestimation of mortality in penetrating trauma patients by the injury severity score.

BACKGROUND The Injury Severity Score (ISS) is widely used as a method for rating severity of injury. The ISS is the sum of the squares of the three worst Abbreviated Injury Scale (AIS) values from three body regions. Patients with penetrating injuries tend to have higher mortality rates for a given ISS than patients with blunt injuries. This is thought to be secondary to the increased prevalence of multiple severe injuries in the same body region in patients with penetrating injuries, which the ISS does not account for. We hypothesized that the mechanism-based difference in mortality could be attributed to certain ISS ranges and specific AIS values by body region. METHODS Outcome and injury scoring data were obtained from transfused patients admitted to 23 Level I trauma centers. ISS values were grouped into categories, and a logistic regression model was created. Mortality for each ISS category was determined and compared with the ISS 1 to 15 group. An interaction term was added to evaluate the effect of mechanism. Additional logistic regression models were created to examine each AIS category individually. RESULTS There were 2,292 patients in the cohort. An overall interaction between ISS and mechanism was observed (p = 0.049). Mortality rates between blunt and penetrating patients with an ISS between 25 and 40 were significantly different (23.6 vs. 36.1%; p = 0.022). Within this range, the magnitude of the difference in mortality was far higher for penetrating patients with head injuries (75% vs. 37% for blunt) than truncal injuries (26% vs. 17% for blunt). Penetrating trauma patients with an AIS head of 4 or 5, AIS abdomen of 3, or AIS extremity of 3 all had adjusted mortality rates higher than blunt trauma patients with those values. CONCLUSION Significant differences in mortality between blunt and penetrating trauma patients exist at certain ISS and AIS category values. The mortality difference is greatest for head injured patients.

Significant understaging is seen in clinically staged T2N0 esophageal cancer patients undergoing esophagectomy

This study aimed to determine the impact of preoperative staging on the treatment of clinical T2N0 (cT2N0) esophageal cancer patients undergoing esophagectomy. We reviewed a retrospective cohort of 27 patients treated at a single institution between 1999 and 2011. Clinical staging was performed with computed tomography, positron emission tomography, and endoscopic ultrasound. Patients were separated into two groups: neoadjuvant therapy followed by surgery (NEOSURG) and surgery alone (SURG). There were 11 patients (41%) in the NEOSURG group and 16 patients (59%) in the SURG group. In the NEOSURG group, three of 11 patients (27%) had a pathological complete response and eight (73%) were partial or nonresponders after neoadjuvant therapy. In the SURG group, nine of 16 patients (56%) were understaged, 6 (38%) were overstaged, and 1 (6%) was correctly staged. In the entire cohort, despite being clinically node negative, 14 of 27 patients (52%) had node-positive disease (5/11 [45%] in the NEOSURG group, and 9/16 [56%] in the SURG group). Overall survival rate was not statistically significant between the two groups (P = 0.96). Many cT2N0 patients are clinically understaged and show no preoperative evidence of node-positive disease. Consequently, neoadjuvant therapy may have a beneficial role in treatment.

Specialty Matters in the Treatment of Lung Cancer

The effect of surgeon volume, hospital volume, and surgeon specialty on operative outcomes has been reported in numerous studies. Short-term and long-term outcome comparisons for pulmonary resection for lung cancer have been performed between general surgeons (GS), cardiothoracic surgeons (CTS), and general thoracic surgeons (TS), using large administrative and inpatient databases. In the United States, general surgeons perform more pulmonary resection than thoracic surgeons. Studies have found that in cases involving thoracic surgeons, there is a lower operative mortality and morbidity, improved long-term survival, better adherence to established practice standards, and a lower cost compared with cases involving general surgeons. Some specific processes of care that account for these improved economic, operative, and oncological outcomes have been identified. Others are not yet specifically known and associated with specialization in thoracic surgery.

“Even if I Don’t Remember, I Feel Better”. A Qualitative Study of Patients with Early-Stage Non–Small Cell Lung Cancer Undergoing Stereotactic Body Radiotherapy or Surgery

RATIONALE While surgical resection is recommended for most patients with early stage lung cancer according to the National Comprehensive Cancer Network guidelines, stereotactic body radiotherapy is increasingly being used. Provider-patient communication regarding the risks and benefits of each approach may be a modifiable factor leading to improved patient-centered outcomes. OBJECTIVES To qualitatively describe the experiences of patients undergoing either surgery or stereotactic body radiotherapy for early stage non-small cell lung cancer. METHODS We qualitatively evaluated and used content analysis to describe the experiences of 13 patients with early clinical stage non-small cell lung cancer before undergoing treatment in three health care systems in the Pacific Northwest, with a focus on knowledge obtained, communication, and feelings of distress. MEASUREMENTS AND MAIN RESULTS Although most participants reported rarely having been told about other options for treatment and could not readily recall many details about specific risks of recommended treatment, they were satisfied with their care. The patients paradoxically described clinicians as displaying caring and empathy despite not explicitly addressing their concerns and worries. We found that the communication domains that underlie shared decision making occurred infrequently, but that participants were still pleased with their role in the decision-making process. We did not find substantially different themes based on where the participant received care or the treatment selected. CONCLUSIONS Patients were satisfied with all aspects of their care, despite reporting little knowledge about risks or other treatment options, no direct elicitation of worries from providers, and a lack of shared decision making. While the development of effective communication strategies to address these gaps is warranted, their effect on patient-centered outcomes, such as distress and decisional conflict, is unclear.