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BACKGROUND: The development of lactic acidemia (LA) in septic shock (SS) is associated with an ominous prognosis. We previously showed that the mechanism of LA in SS may relate to impaired hepatic uptake of lactate, but the mechanism was not clear. Uptake of lactate by the liver occurs by a membrane-associated, pH-dependent, antiport system known as the monocarboxylate transporter. In the hepatocyte, lactate can then be metabolized by oxidative phosphorylation or converted to glucose in the cytosol. In the present study, we examined (1) whether hepatic mitochondrial dysfunction accounted for decreased uptake of lactate in a canine model of Pseudomonas aeruginosa SS, (2) whether norepinephrine (NE) treatment by increasing mean arterial pressure (MAP) could improve mitochondrial dysfunction and LA in this model, and (3) whether gentisic acid sodium salt (GSS), a novel phenolic compound, was superior to NE in these effects. METHODS: In anesthetized/ventilated dogs, we infused the bacteria over ~10 h and measured hemodynamics in various treatment groups (see below). We then euthanized the animal and isolated the hepatic mitochondria. We measured hepatic mitochondrial oxygen consumption rates using the novel Seahorse XF24 analyzer under conditions that included: basal respiration, after the addition of adenosine- diphosphate to produce coupled respiration, and after the addition of a protonophore to produce maximal respiration. RESULTS: We found that in the septic control group, mean arterial pressure decreased over the course of the study, and that mitochondrial dysfunction developed in which there was a reduction in maximal respiration. Whereas both NE and GSS treatments reversed the reduction in mean arterial pressure and increased maximal respiration to similar extents in respective groups, only in the GSS group was there a reduction in LA. CONCLUSIONS: Hepatic mitochondrial dysfunction occurs in SS, but does not appear to be required for the development of LA in SS, since NE improved mitochondrial dysfunction without reversing LA. GSS, a phenolic compound restored mean arterial pressure, mitochondrial dysfunction, and LA in SS. This reduction in LA may be independent of its effect on improving hepatic mitochondrial function.

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In septic shock (SS), dysfunction of many organ systems develops during the course of the illness, although the mechanisms are not clear. In earlier studies, we reported that lysozyme-c (Lzm-S), a protein that is released from leukocytes and macrophages, was a mediator of the myocardial depression and vasodilation that develop in a canine model of Pseudomonas aeruginosa SS. Whereas both of these effects of Lzm-S are dependent on its ability to intrinsically generate hydrogen peroxide, we subsequently showed that Lzm-S can also deposit within the vascular smooth muscle layer of the systemic arteries in this model. In the present study, we extend our previous findings. We used a canine carotid artery organ bath preparation to study the time course and dose dependence of Lzm-S deposition within the vascular smooth muscle layer. We used a human aortic vascular smooth muscle cell preparation to determine whether Lzm-S can persistently inhibit contraction in this preparation. We also used a canine P. aeruginosa model to determine whether Lzm-S deposition might occur in other organs such as the kidney, liver, and small intestine. The results showed that, in the carotid artery organ bath preparation, Lzm-S deposition occurred within minutes of instillation and there was a dose-response effect. In the human aortic vascular smooth muscle cell preparation, Lzm-S inhibited contraction during a 4-day period. In the in vivo model, Lzm-S accumulated in the kidney and the superior mesenteric artery. In a canine renal epithelial preparation, we further showed that Lzm-S can be taken up by the renal tubules to activate inflammatory pathways. We conclude that Lzm-S can deposit in the systemic vasculature and kidneys in SS, where this deposition could lead to acute organ dysfunction.

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In septic shock (SS), cardiovascular collapse is caused by the release of inflammatory mediators. We previously found that lysozyme-c (Lzm-S), released from leukocytes, contributed to systemic vasodilation in a canine model of SS. We then delineated the pathway by which this occurs in a canine carotid artery organ bath preparation (CAP). We showed that Lzm-S could intrinsically generate hydrogen peroxide (H(2)O(2)) and that H(2)O(2) subsequently reacted with endogenous catalase to form compound I, an oxidized form of catalase. In turn, compound I led to an increase in cyclic guanosine 3',5'-monophosphate to produce vasodilation. However, it was not clear from previous studies whether it is necessary for Lzm-S to bind to the vasculature to cause vasodilation or, alternatively, whether the generation of H(2)O(2) by Lzm-S in the surrounding medium is all that is required. We examined this question in the present study in which we used multiple preparations. In a partitioned CAP, we found that when we added Lzm-S to a partitioned space in which a semipermeable membrane prevented diffusion of Lzm-S to the carotid artery tissue, vasodilation still occurred because of diffusion of H(2)O(2). On the other hand, we found that Lzm-S could accumulate within the vascular smooth muscle layer (VSML) after 7 h of SS in a canine model. We also determined that when Lzm-S was located in close proximity to vascular smooth muscle cells, it could generate H(2)O(2) to produce lengthening in a human cell culture preparation. We conclude that there are two mechanisms by which Lzm-S can cause vasodilation in SS. In one instance, H(2)O(2) generated by Lzm-S in plasma diffuses to the VSML to cause vasodilation. In a second mechanism, Lzm-S directly binds to the VSML, where it generates H(2)O(2) to produce vasodilation.

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INTERVENTIONS: Vasopressor therapy is required in septic shock to maintain tissue perfusion in the face of hypotension. Unfortunately, there are significant side effects of current vasopressors, and newer agents need to be developed. We recently discovered that ethyl gallate, a nonflavonoid phenolic antioxidant found in food substances, could reverse low mean arterial pressure found in an experimental model of septic shock due to inhibition of hydrogen peroxide signaling. In the present study, we compared the hemodynamic and biochemical effects of ethyl gallate vs. those of the commonly used vasopressor, norepinephrine, in a bacteremic canine model of Pseudomonas aeruginosa sepsis in two protocols. MEASUREMENTS AND MAIN RESULTS: We performed these studies in anesthetized and mechanically ventilated dogs. In the early treatment protocol, we infused P. aeruginosa until mean arterial pressure first decreased to ∼60 mm Hg (about 2-3 hrs), after which we stopped the infusion and randomly administered ethyl gallate or norepinephrine in respective groups. In the late treatment protocol, we administered ethyl gallate or norepinephrine after a sustained ∼5-hr decrease in mean arterial pressure to 60 mm Hg and continued the infusion for the duration of the experiment. We followed parameters for over 10 hrs after the initiation of P. aeruginosa in both groups. We measured stroke work, urine output, serum creatinine, among other parameters, and used serum troponin T as an index of myocardial injury. We found that in both protocols, ethyl gallate and norepinephrine improved mean arterial pressure and stroke work to similar extents over the duration of the study. Particularly in the late treatment protocol, ethyl gallate resulted in a lower heart rate, a lower troponin T, and a greater urine output as compared with norepinephrine (p < .05). CONCLUSIONS: These results suggest that phenolic antioxidants, such as ethyl gallate, that inhibit hydrogen peroxide signaling, may represent an alternative class of vasopressors for use in septic shock.

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Although hydrogen peroxide (H2O2) is a well-described reactive oxygen species that is known for its cytotoxic effects and associated tissue injury, H2O2 has recently been established as an important signaling molecule. We previously demonstrated that lysozyme (Lzm-S), a mediator of sepsis that is released from leukocytes, could produce vasodilation in a phenylephrine-constricted carotid artery preparation by H2O2 signaling. We found that Lzm-S could intrinsically generate H2O2 and that this generation activated H2O2-dependent pathways. In the present study, we used this carotid artery preparation as a bioassay to define those antioxidants that could inhibit Lzm-S's vasodilatory effect. We then determined whether this antioxidant could reverse the hypotension that developed in an Escherichia coli bacteremic model. Of the many antioxidants tested, we found that ethyl gallate (EG), a nonflavonoid phenolic compound, was favorable in inhibiting Lzm-S-induced vasodilation. In our E. coli model, we found that EG reversed the hypotension that developed in this model and attenuated end-organ dysfunction. By fluorometric H2O2 assay and electrochemical probe techniques, we showed that EG could scavenge H2O2 and that it could reduce H2O2 production in model systems. These results show that EG, an antioxidant that was found to scavenge H2O2 in vitro, was able to attenuate cardiovascular dysfunction in a canine in vivo preparation. Antioxidants such as EG may be useful in the treatment of hemodynamic deterioration in septic shock.

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OBJECTIVE: Capillary blood gas test has had ample use in the infantile population. In the adult population, the information is limited and controversial. The agreement between capillary-arterial gases seems to parallel the pH and the carbon dioxide pressure in different studied populations. In order to know the degree of agreement between these gases, we evaluate them at breathing room air and at 100% of oxygen fractions at 2,240 meters above sea level. METHODS: We obtained capillary-arterial blood gases simultaneously from subjects with stable cardiopulmonary disease in both conditions of inspired oxygen. Demographic, hemodynamic, diagnostic, and laboratory variables were gathered. STATISTICAL ANALYSIS: agreement was analyzed with the intraclass correlation coefficient and the Bland-Altman procedure. RESULTS: We studied 101 subjects, 48 men and 53 women, whose respective ages were 55 +/- 16 and 56 +/- 16. Mean systemic arterial pressure was 94.96 +/- 10.57 mmHg. Hemoglobin was 15.94 +/- 2.48 g/dl. The agreement between the variables with the inspired oxygen fractions, 21%, 100%, and the mean difference in parenthesis was respectively: potential hydrogen, 0.94 (0.0091), 0.94 (0.0039); oxygen pressure, 0.90 (2.94), 0.84 (74.99); carbon dioxide pressure, 0.97 (0.079), 0.97 (0.179); bicarbonate, 0.93 (-0.067), 0,96 (0.262); total dissolved carbon dioxide, 0.94 (-0.142), 0.93 (0.161); base excess: 0.94, (-0.125), 0.92 (0.235); oxygen saturation, 0.98 (0.764), 0.97(0.202). CONCLUSIONS: Capillary blood gas test could be a useful alternative to the arterial one, nevertheless, it is limited by its low agreement with the oxygen pressure in both oxygen inspired fractions.

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OBJECTIVE: Capillary blood gas test has had ample use in the infantile population. In the adult population, the information is limited and controversial. The agreement between capillary-arterial gases seems to parallel the pH and the carbon dioxide pressure in different studied populations. In order to know the degree of agreement between these gases, we evaluate them at breathing room air and at 100% of oxygen fractions at 2,240 meters above sea level. METHODS: We obtained capillary-arterial blood gases simultaneously from subjects with stable cardiopulmonary disease in both conditions of inspired oxygen. Demographic, hemodynamic, diagnostic, and laboratory variables were gathered. Statistical analysis: agreement was analyzed with the intraclass correlation coefficient and the Bland-Altman procedure. RESULTS: We studied 101 subjects, 48 men and 53 women, whose respective ages were 55 +/- 16 and 56 +/- 16. Mean systemic arterial pressure was 94.96 +/- 10.57 mmHg. Hemoglobin was 15.94 +/- 2.48 g/dl. The agreement between the variables with the inspired oxygen fractions, 21%, 100%, and the mean difference in parenthesis was respectively: potential hydrogen, 0.94 (0.0091), 0.94 (0.0039); oxygen pressure, 0.90 (2.94), 0.84 (74.99); carbon dioxide pressure, 0.97 (0.079), 0.97 (0.179); bicarbonate, 0.93 (-0.067), 0,96 (0.262); total dissolved carbon dioxide, 0.94 (-0.142), 0.93 (0.161); base excess: 0.94, (-0.125), 0.92 (0.235); oxygen saturation, 0.98 (0.764), 0.97(0.202). CONCLUSIONS: Capillary blood gas test could be a useful alternative to the arterial one, nevertheless, it is limited by its low agreement with the oxygen pressure in both oxygen inspired fractions.

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UNLABELLED: Different congenital or acquired diseases increase the right ventricular systolic pressure. The elevation is achieved by pulmonary artery banding with linen tape or hydraulic devices. We introduce a new hydraulic device to be used in experimental subjects of less than 15 kilograms. METHODS: An experimental laboratory phase was conducted. In this phase, the hydraulic devices were tested against pressures as high as 80 mm Hg; later on the hydraulic devices were placed on the dogs' main pulmonary artery; the right ventricular systolic pressure, pulmonary artery pressure, and their differences were obtained. The values are expressed in average +/- standard deviation. RESULTS: The average weight of the dogs was 12.6 +/- 2.2 kg. The average diameter found in the main pulmonary artery was 12.4 +/- 1.4 mm and 27.5 +/- 1.6 mm length. Right ventricular systolic pressure of basal condition to maximum pressure obtained was 25.5 +/- 1.9 mm Hg vs 50.3 +/- 6.9 mm Hg, p < 0.0001; pulmonary artery pressures under the same conditions were 24.7 +/- 2 mm Hg vs 21.5 +/- 6.9 mm Hg, p < 0.043; and the differences between them were 0.8 +/- 1.4 mm Hg vs 28.8 +/- 4.2 mm Hg, p < 0.0001, developed by the hydraulic device respectively. CONCLUSIONS: The hydraulic device allows attaining a controlled acute increase in right ventricular systolic pressure.

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Right ventricular hypertension (RVH) is an entity that could be expected in various cardiopulmonary diseases. Mechanical obstruction to the right ventricle outflow tract is a cause of RVH. We present the case of a 69 year-old male with a history of hepatocarcinoma previously treated. The developed RVH due to mechanical obstruction secondary to metastatic infiltration of the right ventricle. The clinical syndrome was characterized by systemic venous hypertension. Non-invasive studies, such as electrocardiogram and computed tomography scan limited the metastasis to the right ventricle; the diagnosis was confirmed by cardio-angiography and endocardial biopsy. The studies did not demonstrate neoplastic activity at any other level.

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Diversas enfermedades congénitas o adquiridas incrementan la presión sistólica del ventrículo derecho. Este incremento se ha realizado con el bandaje del tronco arterial pulmonar con cintas de lino o dispositivos hidráulicos. Presentamos un nuevo dispositivo hidráulico para ser usado en sujetos experimentales menores a 15 kilogramos. Material y métodos: Se realizó una fase experimental de laboratorio donde los dispositivos hidráulicos fueron probados contra presiones hasta de 80 mm Hg; posteriormente se colocaron en el tronco de la arteria pulmonar de perros donde se les determinó la presión sistólica del ventrículo derecho, la de la arteria pulmonar y el gradiente de ambos. Los valores se expresaron en medias ± desviación estándar. Resultados: El peso de los perros fue 12.6 ± 2.2 kilogramos. El diámetro del tronco de la arteria pulmonar encontrado en los perros fue de 12.4 ± 1.4 mm y 27.5 ± 1.6 mm de largo. Las presiones sistólicas ventriculares derechas en condición basal y de máxima elevación fueron: 25.5 ± 1.9 mm Hg vs 50.3 ± 6.9 mm Hg, p < 0.0001; las presiones sistólicas de la arteria pulmonar para estas mismas condiciones fueron: 24.7 ± 2 mm Hg vs 21.5 ± 6.9 mm Hg, p < 0.043; y el respectivo gradiente de ambas para estas presiones fueron: 0.8 ± 1.4 mm Hg vs 28.8 ± 4.2 mm Hg, p < 0.0001. Conclusiones: El DH permite el incremento agudo controlado de la presión sistólica del ventrículo derecho.

Different congenital or acquired diseases increase the right ventricular systolic pressure. The elevation is achieved by pulmonary artery banding with linen tape or hydraulic devices. We introduce a new hydraulic device to be used in experimental subjects of less than 15 kilograms. Methods: An experimental laboratory phase was conducted. In this phase, the hydraulic devices were tested against pressures as high as 80 mm Hg; later on the hydraulic devices were placed on the dogs' main pulmonary artery; the right ventricular systolic pressure, pulmonary artery pressure, and their differences were obtained. The values are expressed in average ± standard deviation. Results: The average weight of the dogs was 12.6 ± 2.2 kg. The average diameter found in the main pulmonary artery was 12.4 ± 1.4 mm and 27.5 ± 1.6 mm length. Right ventricular systolic pressure of basal condition to maximum pressure obtained was 25.5 ± 1.9 mm Hg vs 50.3 ± 6.9 mm Hg, p < 0.0001; pulmonary artery pressures under the same conditions were 24.7 ± 2 mm Hg vs 21.5 ± 6.9 mm Hg, p < 0.043; and the differences between them were 0.8 ± 1.4 mm Hg vs 28.8 ± 4.2 mm Hg, p < 0.0001, developed by the hydraulic device respectively. Conclusions: The hydraulic device allows attaining a controlled acute increase in right ventricular systolic pressure.

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La hipertensión ventricular derecha es una entidad esperada en enfermedades cardiopulmonares. La obstrucción mecánica del tracto de salida del ventrículo derecho es una de ellas. Presentamos el caso clínico de un paciente masculino de 69 años de edad con historia de hepatocarcinoma previamente tratado, quien presentó hipertensión ventricular derecha por obstrucción metastásica única al ventrículo derecho. El comportamiento clínico es de un síndrome de hipertensión venosa sistémica. Los estudios no invasivos, como el ecocardiograma y la tomografía axial computarizada la delimitaron. No se demostró actividad neoplásica o metástasis en otros órganos. La neoformación intra-ventricular derecha fue corroborada mediante cardio-angiografía y la biopsia tumoral confirmó el diagnóstico.

Right ventricular hypertension (RVH) is an entity that could be expected in various cardiopulmonary diseases. Mechanical obstruction to the right ventricle outflow tract is a cause of RVH. We present the case of a 69 year-old male with a history of hepatocarcinoma previously treated. The developed RVH due to mechanical obstruction secondary to metastatic infiltration of the right ventricle. The clinical syndrome was characterized by systemic venous hypertension. Non-invasive studies, such as electrocardiogram and computed tomography scan limited the metastasis to the right ventricle; the diagnosis was confirmed by cardio-angiography and endocardial biopsy. The studies did not demonstrate neoplastic activity at any other level. (Arch Cardiol Mex 2005; 75: 170-177).

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La embolia grasa describe la presencia de grasa en la circulación sanguínea, asociado o no al desarrollo de un síndrome clínico identificable por sus signos y síntomas. Puede ser secundaria a traumatismos, cirugía ortopédica, causas no traumáticas y al uso de sustancias y procedimientos con fines estéticos. Presentamos el caso clínico de una mujer que desarrolló el síndrome de embolia grasa después de la inyección de una sustancia oleosa en ambos glúteos, con fines estéticos. Hubo manifestaciones clínicas del aparato respiratorio, del sistema nervioso central y hematológicos. El diagnóstico fue establecido por los criterios clínicos de Gurd y Lindeque. La paciente presentó el síndrome de dificultad respiratoria del adulto por lo que requirió de ventilación mecánica. La evolución fue hacia la mejoría, y egresó del hospital con recuperación completa de sus funciones, que ha mantenido durante un año.

The term fat embolism refers to the presence of fat droplets in the circulation; patients can be asymptomatic or present with a full blown clinical syndrome. Fat embolism can develop after trauma, orthopedic surgery and cosmetic procedures. We present the case of a 15-year-old female that developed the fat embolism syndrome after a single intra-muscular injection in each buttock of an oily substance, for cosmetic reasons. The clinical picture was associated with respiratory failure, neurological impairment and blood abnormalities. The diagnosis was established according to the Gurd and Lindeque criteria. The patient developed the acute respiratory distress syndrome and required mechanical ventilation. The patient had a complete recovery and is without any sequelae after a one-year follow up.