A Reminder of Methylene Blue's Effectiveness in Treating Vasoplegic Syndrome after On-Pump Cardiac Surgery

The inflammatory response induced by cardiopulmonary bypass decreases vascular tone, which in turn can lead to vasoplegic syndrome. Indeed the hypotension consequent to on-pump cardiac surgery often necessitates vasopressor and intravenous fluid support. Methylene blue counteracts vasoplegic syndrome by inhibiting the formation of nitric oxide.We report the use of methylene blue in a 75-year-old man who developed vasoplegic syndrome after cardiac surgery. After the administration of methylene blue, his hypotension improved to the extent that he could be weaned from vasopressors. The use of methylene blue should be considered in patients who develop hypotension refractory to standard treatment after cardiac surgery.     

Spilled Gallstones: the Source of an Enigma

Spillage of gallstones may occur in the course of laparoscopic cholecystectomy. The incidence of this mishap and its consequences are variable. Ignored by many surgeons, stone spillage may be the source of significant morbidity many years after surgery. In this report, we describe the clinical course of a patient who presented with upper abdominal pain and swelling. The past history was positive for laparoscopic cholecystectomy 15 years earlier. After excision, the swelling was found to be a pseudocyst formed around spilled gallstones during a previous cholecystectomy. Apart from postoperative wound infection, the patient recovered well and remains so. Here, we discuss the problem and provide suggestions for spillage prevention and stone retrieval once spillage occurs.     

Cellular dyscohesion in fine-needle aspiration of breast carcinoma. Prognostic indicator for axillary lymph node metastases?

The role of fine-needle aspiration (FNA) in the diagnosis of breast carcinoma is established. We evaluated whether the degree of cellular dyscohesion and the nuclear grade in FNA material of breast carcinomas are reliable prognostic predictors for ipsilateral axillary lymph node metastasis. FNA specimens from 98 women with infiltrating ductal and infiltrating lobular carcinomas were evaluated by 2 observers for degree of cellular dyscohesion and nuclear grade. Follow-up specimens from lumpectomy and/or mastectomy with axillary dissection were available for each patient. By univariate analysis, degree of cellular dyscohesion and nuclear grade were not predictive of axillary lymph node metastasis regardless of tumor size. High histologic grade, size greater than 2 cm, and patient age younger than 52 years were significant predictors of metastasis. By multivariate analysis, size greater than 2 cm and age younger than 52 years were statistically significant for lymph node metastasis. In contrast with a published study, the results of the present study fail to show cellular dyscohesion in FNA specimens as predictive of lymph node metastasis; however, the scoring method for determining the degree of cellular dyscohesion is reproducible between 2 independent observers.     

Survival Outcomes for Metaplastic Breast Cancer Differ by Histologic Subtype

Background

Metaplastic breast carcinoma (MBC) is a rare, aggressive subtype of breast cancer associated with poorer overall survival than other triple-negative breast cancers. This study sought to compare survival outcomes among histologic subtypes of MBC with those of non-metaplastic triple-negative breast cancer.

Methods

Clinicopathologic and treatment data for all patients with non-metastatic, pure MBC undergoing surgery from 1995 to 2017 and for a large cohort of patients with other types of triple-negative breast cancer during that period were collected from an institutional database. The MBC tumors were classified as having squamous, spindle, heterologous mesenchymal, or mixed histology. Survival outcomes were compared using the Kaplan-Meier method.

Results

Of 132 MBC patients, those with heterologous mesenchymal MBC (n?=?45) had the best 5-year overall and breast cancer-specific survival (BCSS, 88%; 95% confidence interval [CI], 0.78–0.99), whereas those with squamous MBC had the worst survival (BCSS, 56%; 95% CI, 0.32–0.79). Overall survival, BCSS, and recurrence-free survival were worse for the patients with MBC than for the patients who had non-MBC triple-negative breast cancer, with a clinicopathologically adjusted recurrence hazard ratio of 2.4 (95% CI, 1.6–3.3; p?<?0.001). Of the 10 MBC patients who received neoadjuvant chemotherapy, 4 progressed while receiving treatment, and 3 had no response.

Conclusions

Metaplastic breast carcinoma is associated with worse survival than other triple-negative breast cancers. The heterologous mesenchymal subtype is associated with the best survival, whereas the squamous subtype is associated with the worst survival. These data call for research to identify therapies tailored to MBC’s unique biology.

     

Surface Modification of Poly(lactide-co-glycolide) Nanospheres by Biodegradable Poly(lactide)-Poly(ethylene glycol) Copolymers

The modification of surface properties of biodegradable poly(lactide-co-glycolide) (PLGA) and model polystyrene nanospheres by poly(lactide)-poly(ethlene glycol) (PLA:PEG) copolymers has been assessed using a range of in vitro characterization methods followed by in vivo studies of the nanospheres biodistribution after intravenous injection into rats. Coating polymers with PLA:PEG ratio of 2:5 and 3:4 (PEG chains of 5000 and 2000 Da, respectively) were studied. The results reveal the formation of a PLA: PEG coating layer on the particle surface resulting in an increase in the surface hydrophilicity and decrease in the surface charge of the nanospheres. The effects of addition of electrolyte and changes in pH on stability of the nanosphere dispersions confirm that uncoated particles are electrostatically stabilized, while in the presence of the copolymers, steric repulsions are responsible for the stability. The PLA:PEG coating also prevented albumin adsorption onto the colloid surface. The evidence that this effect was observed for the PLA:PEG 3:4 coated nanospheres may indicate that a poly(ethylene glycol) chain of 2000 Da can provide an effective repulsive barrier to albumin adsorption. The in vivo results reveal that coating of PLGA nanospheres with PLA:PEG copolymers can alter the biodistribution in comparison to uncoated PLGA nanospheres. Coating of the model polystyrene nanospheres with PLA:PEG copolymers resulted in an initial high circulation level, but after 3 hours the organ deposition data showed values similar to uncoated polystyrene spheres. The difference in the biological behaviour of coated PLGA and polystyrene nanospheres may suggest a different stability of the adsorbed layers on these two systems. A similar biodistribution pattern of PLA:PEG 3:4 to PEG 2:5 coated particles may indicate that poly(ethylene glycol) chains in the range of 2000 to 5000 can produce a comparable effect on in vivo behaviour.     

Hepatic blood flow and oxygen consumption after burn and sepsis

BACKGROUND: Alteration in the hepatic circulation after burn and in sepsis seems to be an essential component in the development of multiple organ failure. METHODS: Female pigs (n = 12, 20-25 kg) were instrumented with ultrasonic flow probes on the portal vein and the common hepatic artery. Catheters were inserted in the superior mesenteric and left hepatic veins. After 5 days, all animals were anesthetized and six of them received 40% total body surface area third-degree burn. A total of 100 microg/kg Escherichia coli LPS was intravenously administered at 18 hours after burn. All animals were studied for 42 hours. RESULTS: Thermal injury resulted in a 48% decrease in hepatic arterial blood flow despite maintenance of normal cardiac output, resulting in a fall in hepatic oxygen delivery rate. Portal venous blood flow showed a 32% increase at 4 hours after burn. Post-LPS portal blood flow was significantly reduced for a period of 8 hours (51% of baseline (bl), p < 0.05 analysis of variance [ANOVA]). The hepatic arterial blood supply was also significantly reduced (12-67% of bl, p < 0.05 ANOVA) during the first 4 hours after LPS, indicating loss of the hepatic arterial response. The following 12 hours, a hepatic reperfusion phase was observed with an elevation of the hepatic arterial blood flow to 152% of bl (p < 0.05 ANOVA). Postburn endotoxemia resulted in a significant decrease of hepatic oxygen delivery (88%) and hepatic oxygen consumption (79%). Although the burn injury did not affect the portal venous pressure, postburn endotoxemia caused a significant portal hypertension during a period of 8 hours (225% of bl, p < 0.05 ANOVA). CONCLUSION: Postburn sepsis amplifies the selective vasconstrictive impact of thermal injury on hepatic arterial blood flow, yielding a pronounced ischemia/ reperfusion injury, associated with a critical reduction of hepatic oxygen delivery and consumption. A postburn septic challenge induces portal hypertension, which may account for previously documented gut barrier dysfunction.     

Trauma- and sepsis-induced hepatic ischemia and reperfusion injury: role of angiotensin II

HYPOTHESIS: We hypothesized that angiotensin II, a potent vasoconstrictor, is involved in the occurrence of hepatic ischemia after burn and sepsis, and that administration of angiotensin II antagonist DuP753 would ameliorate this process. DESIGN: Randomized animal study. SETTING: University laboratory, investigational intensive care unit, University of Texas Medical Branch, Galveston. MATERIALS: Female pigs (n = 18, weighing 20-25 kg). INTERVENTIONS: All animals were prepared with ultrasonic flow probes on the portal vein and the common hepatic artery. Catheters were inserted in the superior mesenteric and left hepatic veins. After 5 days all animals were anesthetized and 12 of them received 40% total body surface area third-degree burn. Escherichia coli lipopolysaccharide (100 microg/kg) was intravenously administered at 18 hours postburn DuP753 was administered intravenously in a dose of 1 microg/kg to 6 pigs immediately after the burn. All animals were studied for 42 hours. MAIN OUTCOME MEASURES: Systemic and hepatic hemodynamics were measured and blood samples were drawn for determinations of arterial, mixed venous, and portal blood gases at baseline and at 14 consecutive time points, starting 1 hour after the burn. RESULTS: Burn caused a 4.6-fold increase in hepatic arterial vascular resistance and a 49% decrease in hepatic arterial blood flow. Postburn administration of angiotensin II receptor blocker DuP753 yielded a significant improvement in the hepatic arterial hemodynamics (only 12% increase in hepatic arterial vascular resistance and 8% decrease in hepatic arterial blood flow, P<.05 vs nontreated group, analysis of variance [ANOVA]). Postlipopolysaccharide hepatic arterial blood flow was significantly reduced (12% of baseline, P<.05, ANOVA), in contrast to DuP753-treated animals (64% of baseline, P<.05 vs nontreated group, ANOVA). Postburn blocking of angiotensin II receptors yielded a significant improvement in postlipopolysaccharide portal venous blood flow (85% of baseline vs 48% of baseline in nontreated animals, P<.05, ANOVA ). Postburn endotoxemia resulted in a significant decrease of hepatic oxygen delivery (22% of baseline) and hepatic oxygen consumption (30% of baseline), while no marked changes were observed in the DuP753-treated group (P<.05 vs nontreated group, ANOVA). CONCLUSIONS: Angiotensin II seems to play a pivotal role in burn- and sepsis-induced hepatic ischemia and reperfusion injury. Blocking angiotensin II receptors by DuP753 seems to abrogate this adverse effect of thermal injuries and sepsis on hepatic perfusion and oxygenation.     

Angiotensin II inhibitor DuP753 attenuates burn- and endotoxin-induced gut ischemia, lipid peroxidation, mucosal permeability, and bacterial translocation

OBJECTIVE: To investigate the role of angiotensin II as a mediator of burn- and sepsis-induced gut ischemia and reperfusion injury and to determine whether treatment with the angiotensin II inhibitor DuP753 can attenuate mucosal injury and bacterial translocation in a burn/endotoxemia porcine model. SUMMARY BACKGROUND DATA: Thermal injuries and endotoxemia have been shown to induce ischemia and reperfusion injury to the intestine, leading to increased mucosal permeability and bacterial translocation. Angiotensin II, the production of which has been reported to increase after burn, is thought to be one of the primary mediators of postburn mesenteric vasoconstriction. METHODS: An ultrasonic flow probe was inserted into the superior mesenteric artery and a catheter into the superior mesenteric vein in 21 female pigs. After 5 days, all animals were anesthetized, and 14 received 40% total body surface area third-degree burn. DuP753 was administered intravenously at 1 microg/kg to seven pigs immediately after burn. Eighteen hours after burn, 100 microg/kg Escherichia coli lipopolysaccharide (LPS) was intravenously administered. Systemic and splanchnic hemodynamics were measured and blood samples were drawn for blood gas analysis. Plasma conjugated dienes (PCDs), an index of lipid peroxidation, were measured every 6 hours. Intestinal permeability was assessed every 6 hours by measuring the lactulose/mannitol excretion ratio. At the end of the study (42 hours), tissue samples were harvested for bacteriologic cultures. RESULTS: Burn caused a significant decrease in mesenteric blood flow, to approximately 58% of baseline. Postburn endotoxemia significantly reduced the blood flow in the superior mesenteric artery to 53% of baseline. Treatment with DuP753 prevented postburn vasoconstriction and subsequently abrogated the impact of postburn endotoxemia on blood flow in the superior mesenteric artery. Mesenteric oxygen supply was significantly reduced after burn and endotoxin to 60% and 51% of baseline levels, respectively. DuP753 administration significantly improved mesenteric oxygen supply after both insults. Burn- and LPS-induced mesenteric hypoxia, as indicated by decreased mesenteric oxygen consumption, was also ameliorated by DuP753 treatment. PCD levels were significantly elevated 8 hours after burn. LPS caused a higher and prolonged increase in PCD levels. Treatment with DuP753 significantly reduced PCD levels after burn and after LPS. Intestinal permeability, as assessed by the lactulose/mannitol ratio, showed 6-fold and 12-fold increases after thermal injury and LPS, respectively. In contrast, the lactulose/mannitol ratio was only doubled in DuP753-treated animals. Bacterial translocation was significantly increased after burn and endotoxin. The incidence of bacterial translocation in the DuP753-treated animals was similar to that in the sham group. CONCLUSIONS: Angiotensin II appears to play a pivotal role in the burn- and endotoxin-induced intestinal ischemia and reperfusion injury, with subsequent increases in permeability and bacterial translocation. Postburn administration of the angiotensin II receptor antagonist DuP753 significantly reduces the extent of these events.