To investigate the effects of N omega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, on hemodynamics, gas exchange and oxygen transport in an ovine model of hyperdynamic ...sepsis.
Prospective, nonrandomized, controlled study, with repeated measurements.
University research laboratory.
Twenty healthy adult sheep (weighing 20 to 45 kg) were divided into two groups of 12 treated sheep and eight control sheep and studied.
Twenty awake, chronically instrumented sheep received a continuous infusion of endotoxin (10 ng/kg/min) over 48 hrs. Twenty-four hours after the start of the endotoxin infusion, 12 sheep (treatment group) received a bolus of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (25 mg/kg), while the other eight animals (control group) received the carrier (0.9% NaCl).
Twenty-four hours after the start of the endotoxin infusion, both groups exhibited a hyperdynamic state with increased cardiac indices, decreased systemic vascular resistance indices, impaired oxygenation, and increased pulmonary shunt fractions. In both groups, oxygen delivery was significantly increased, while oxygen consumption remained virtually unchanged, resulting in a decreased oxygen extraction ratio. In the control group, the significant alterations in systemic hemodynamics, lung function and oxygen transport persisted for the remainder of the study. Administration of N omega-nitro-L-arginine methyl ester normalized cardiac index and systemic vascular resistance index, increased mean arterial blood pressure, and decreased heart rate. Although oxygen delivery significantly decreased after administration of N omega-nitro-L-arginine methyl ester, oxygen consumption did not change, resulting in a normalization of oxygen extraction ratio. Despite a significant reduction of pulmonary shunt fraction, oxygenation did not improve. Pulmonary arterial pressure and pulmonary vascular resistance index showed a peak 2 hrs after administration of the nitric oxide synthesis inhibitor and then tended to decrease. In contrast, the effects of N omega-nitro-L-arginine methyl ester on the systemic circulation persisted for the remainder of the study.
The data support the assumption that augmented nitric oxide production is a major cause of the hemodynamic alterations seen in hyperdynamic endotoxemia. Administration of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester normalized the endotoxin-induced hyperdynamic state, but did not impair oxygen consumption, indicating adequate tissue perfusion of metabolically active organs. Inhibition of nitric oxide synthesis may be a therapeutic option in the treatment of hyperdynamic septic patients when conventional therapy fails to maintain a minimum of cardiovascular performance.
Inhalation injury represents an ongoing threat to patients with thermal injury. The magnitude of the disease severity is related to the multilevel insult to the pulmonary system. Asphyxiants present ...in inhaled smoke can compromise oxygen delivery, resulting in cell death. Also, early changes in the microcirculation of the lung parenchyma, related to polymorphonuclear cell activation and oxygen free radical production, are responsible for early pulmonary edema. Perhaps the most significant pathologic change caused by smoke inhalation is loss of the respiratory epithelium and the formation of tracheobronchial casts. The recent application of high-frequency flow interruption ventilation and intrapulmonary percussive ventilation has made the largest impact on improved survival in patients suffering from smoke inhalation.
To evaluate the hypothesis that heparin administration increases cardiac output and improves oxygenation in experimental hyperdynamic sepsis in sheep.
Prospective trial.
Laboratory at a large ...university-affiliated medical center.
A total of 14 sheep weighing 28 to 44 kg.
All 14 chronically instrumented sheep received a continuous infusion of Escherichia coli endotoxin (10 ng/kg/min) over 24 hrs. Seven sheep received a fixed bolus of beef lung heparin (5000 units) every 4 hrs intravenously. The other seven sheep served as controls.
The heparinized animals showed a triphasic cardiovascular response. Cardiac index increased (p < .05), and systemic vascular resistance index decreased (p < .05) at 2 hrs after the start of the endotoxin infusion (early phase, 0 to 2 hrs). Both variables returned to approximately baseline levels at 4 hrs (second period, 2 to 4 hrs). A hyperdynamic state (in terms of an increased cardiac index), a decreased systemic vascular resistance index, and a decreased mean arterial pressure (MAP) (p < .05 for all) was observed in the third phase (8 to 24 hrs). In the control group, cardiac index, systemic vascular resistance index, and MAP showed no changes in the first period, but a slight decrease in cardiac index and a slight increase in systemic vascular resistance index in the second period. The onset of the hyperdynamic state was less pronounced in the control group and cardiac index was lower (p < .05); likewise, systemic vascular resistance index was increased (p < .05) when compared with heparinized animals. Both groups developed pulmonary hypertension during the endotoxin infusion. The gas exchange in the heparin group was significantly impaired in the first and second periods, but returned to baseline levels in the hyperdynamic phase, whereas the oxygenation of the nonheparinized animals showed only minor changes in the first and second phases, but deteriorated significantly during the third phase of endotoxemia.
In this experimental model of hyperdynamic sepsis, heparin significantly influenced the cardiopulmonary performance. Heparin preserved gas exchange and increased cardiac output but lowered systemic vascular resistance and MAP in the hyperdynamic state.
Emergency operative intervention has been one of the cornerstones of the care of the injured patient. Over the past several years, nonoperative management has increasing been recommended for the care ...of selected blunt abdominal solid organ injuries. The purpose of this study was to utilize a large statewide, population-based data set to perform a time-series analysis of the practice of physicians caring for blunt solid organ injury of the abdomen. The study was designed to assess the changing frequency and the outcomes of operative and nonoperative treatments for blunt hepatic and splenic injuries.
Data were obtained from the state hospital discharge data base, which tracks information on all hospitalized patients from each of the 157 hospitals in the state of North Carolina. All trauma patients who had sustained injury to a solid abdominal organ (kidney, liver, or spleen) were selected for initial analysis.
During the 5 years of the study, 210,256 trauma patients were admitted to the state's hospitals (42,051 +/- 7802 per year). The frequency of nonoperative interventions for hepatic and splenic injuries increased over the period studied. The frequency of nonoperative management of hepatic injuries increased from 55% in 1988 to 79% in 1992 in patients with hepatic injuries and from 34% to 46% in patients with splenic injuries. The rate of nonoperative management of hepatic injuries increased from 54% to 64% in nontrauma centers compared with an increase from 56% to 74% in trauma centers (p = 0.01). In patients with splenic injuries, the rate of nonoperative management increased from 35% to 44% in nontrauma centers compared with an increase from 33% to 49% in trauma centers (p < 0.05). The rate of nonoperative management was associated with the organ injury severity, ranging from 90% for minor injuries to 19%-40% for severe injuries. Finally, in an attempt to compare blood use in operatively and nonoperatively treated patients, the total charges for blood were compared in the two groups. When compared, based on organ injury severity, the total blood used, as measured by charges, was lower for nonoperatively treated patients.
This large, statewide, population-based time-series analysis shows that the management of blunt injury of solid abdominal organs has changed over time. The incidence of nonoperative management for both hepatic and splenic injuries has increased. The study indicates that the rates of nonoperative management vary in relation to the severity of the organ injury. The rates increase in nonoperative management were greater in trauma centers than in nontrauma centers. These findings are consistent with the hypothesis that this newer approach to the care of blunt injury of solid abdominal organs is being led by the state's trauma centers.
The Baxter formula is commonly used to calculate fluid requirements. Baxter reported that 12% of patients would require more than 4.3 mL/kg per percentage of total body surface area (%TBSA). We ...anecdotally observed that we frequently exceeded the predictions of the formula, and we wondered if this was unique to our practice. We studied our last 11 burn-related resuscitations and collected fluid resuscitation data from US burn centers. Twenty-eight centers were queried, and 6 centers shared data. We were therefore able to study the resuscitation data of 50 adult patients. For 29 patients (58%), 4.3 mL/kg/%TBSA was exceeded compared with the 12% reported by Baxter. These findings suggest that in actual practice, fluid volumes administered are larger than the Baxter formula predicts. This survey does not explain why. Possible reasons for the larger fluid volumes are as follows: (1) the sample is not representative; (2) the formula is used improperly; (3) burns have changed and require more fluids; (4) burn care has changed.
Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and ...chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.
Treatment of metastatic pancreatic neuroendocrine tumors (pancNETs), particularly grade 2 (G2) and grade 3 (G3), often presents a dilemma in choosing from multiple similarly efficacious therapies. ...Data on targeted therapies for these tumor types is limited, and this report presents BRAF-targeted therapy as a therapeutic option for metastatic pancNET G3.
This is a case report of a patient with G3 pancNET metastatic to the liver, lung, lymph node, and scalp (soft tissue) treated with dabrafenib/trametinib (D/T) in the presence of a BRAF V600E mutation detected in tumor tissue.
This patient has demonstrated an ongoing partial response to therapy at all involved sites for nearly 15 months with minimal side effects attributable to D/T.
Dabrafenib/trametinib therapy for BRAF-mutated metastatic pancNETs provides a novel treatment option and, especially in the G3 setting, should be considered a first-line option. Tumor testing for actionable mutations should be undertaken at the time of diagnosis and/or progression to identify novel therapeutic avenues in these rare tumors.
Robotic-assisted bronchoscopy has recently emerged as an alternative to electromagnetic navigational bronchoscopy for the evaluation of peripheral pulmonary lesions. While robotic-assisted ...bronchoscopy is proposed to have several advantages, such as an easier learning curve, it is unclear if it has comparable diagnostic utility as electromagnetic navigational bronchoscopy.
Robotic versus Electromagnetic bronchoscopy for pulmonary LesIon AssessmeNT (RELIANT) is an investigator-initiated, single-center, open label, noninferiority, cluster randomized controlled trial conducted in two operating rooms at Vanderbilt University Medical Center. Each operating room (OR) is assigned to either robotic-assisted or electromagnetic navigational bronchoscopy each morning, with each OR day considered one cluster. All patients undergoing diagnostic bronchoscopy for evaluation of a peripheral pulmonary lesion in one of the two operating rooms are eligible. Schedulers, patients, and proceduralists are blinded to daily group allocations until randomization is revealed for each operating room each morning. The primary endpoint is the diagnostic yield defined as the proportion of cases yielding lesional tissue. Secondary and safety endpoints include procedure duration and procedural complications. Enrolment began on March 6, 2023, and will continue until 202 clusters have been accrued, with expected enrolment of approximately 400 patients by the time of completion in March of 2024.
RELIANT is a pragmatic randomized controlled trial that will compare the diagnostic yield of the two most commonly used bronchoscopic approaches for sampling peripheral pulmonary lesions. This will be the first known cluster randomized pragmatic trial in the interventional pulmonology field and the first randomized controlled trial of robotic-assisted bronchoscopy.
ClinicalTrials.gov registration (NCT05705544) on January 30, 2023.
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