RESUMEN

Trimethoprim-sulfamethoxazole (TMP-SMX) is the primary therapeutic option for Pneumocystis jirovecii pneumonia (PCP). Gastrointestinal symptoms and cutaneous rash are common side effects, with hyperkalemia being uncommon in patients without kidney dysfunction, and myelotoxicity being even rarer. We present the case of a male patient with hypertension and a recent diagnosis of non-Hodgkin lymphoma, undergoing rituximab treatment for two months. He was admitted to the intensive care unit due to dyspnea, tachypnea, and pleuritic pain, requiring mechanical ventilation. Chest computed tomography showed bilateral and multilobed ground-glass opacities, compromising more than 80% of the lung parenchyma. Pulmonary tuberculosis and COVID-19 were ruled out. An angiotomography and Doppler ultrasound revealed an extensive pulmonary thrombus and deep venous thrombosis. Empiric treatment with TMP-SMX for PCP was initiated, but within four days, the patient experienced metabolic acidosis and severe hyperkalemia, necessitating hemodialysis. He also presented with progressive pancytopenia and critical levels of leukopenia and thrombocytopenia. The hypothesis of TMP-SMX-induced myelotoxicity was suspected. Considering the unavailability of an alternative treatment, it was opted to continue TMP-SMX and initiate a granulocyte-colony-stimulating factor. However, the patient maintained medullary deterioration, becoming refractory to the transfusion of blood derivates. On the 17th day of treatment, a clinical decision was made to suspend TMP-SMX, leading to improvements within 48 hours in marrow and kidney functions, metabolic acidosis, and hyperkalemia. Despite all efforts, the patient died after 35 days of hospitalization due to hospital-acquired infections. This case highlights the importance of clinicians recognizing potential myelotoxicity with TMP-SMX and promptly discontinuing the drug if necessary.

Asunto(s)

Acidosis , Hiperpotasemia , Pneumocystis carinii , Neumonía por Pneumocystis , Humanos , Masculino , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Neumonía por Pneumocystis/tratamiento farmacológico , Neumonía por Pneumocystis/inducido químicamente , Hiperpotasemia/inducido químicamente , Hiperpotasemia/complicaciones , Hiperpotasemia/tratamiento farmacológico , Acidosis/inducido químicamente , Acidosis/complicaciones , Acidosis/tratamiento farmacológico , Riñón , Estudios Retrospectivos

RESUMEN

Severe metabolic acidosis is defined by a pH < 7.2 with HCO3− < 8 mE- q/L in plasma. Its best treatment is to correct the underlying cause. However, acidemia produces multiple complications such as resistance to the action of catecholamines, pulmonary vasoconstriction, impaired cardiovascular function, hyperkalemia, immunological dysregulation, respiratory muscle fatigue, neurological impairment, cellular dysfunction, and finally, it contributes to multisystemic failure. Intravenous NaHCO3 buffers severe acidemia, preventing the associated damage and gains time while the causal disease is corrected. Its indication requires a risk-benefit assessment, considering its complications. These are hypernatremia, hypokalemia, ionic hypocalcemia, rebound alkalosis, and intracellular acidosis. For this reason, therapy must be "adapted" and administered judiciously. The patient will require monitoring with serial evaluation of the internal environment, especially arterial blood gases, plasma electrolytes, and ionized calcium. Isotonic solutions should be preferred instead of hypertonic bicarbonate. The development of hypernatremia must be prevented, calcium must be provided for hypocalcemia to improve cardiovascular function. Furthermore, in mechanically ventilated patients, a respiratory response similar to the one that would develop physiologically, must be established to be able to extract excess CO2 and thus avoid intracellular acidosis. It is possible to estimate the bicarbonate deficit, speed, and volume of its infusion. However, the calculations are only for reference. More important is to start intravenous NaHCO3 when needed, administer it judiciously, manage its side effects, and continue it to a safe goal. In this review we address all the necessary elements to consider in the administration of intravenous NaHCO3, highlighting why it is the best buffer for the management of severe metabolic acidosis.

Asunto(s)

Humanos , Acidosis/tratamiento farmacológico , Bicarbonato de Sodio/administración & dosificación , Bicarbonato de Sodio/efectos adversos , Índice de Severidad de la Enfermedad , Medición de Riesgo , Administración Intravenosa

RESUMEN

Severe metabolic acidosis is defined by a pH < 7.2 with HCO3- < 8 mE- q/L in plasma. Its best treatment is to correct the underlying cause. However, acidemia produces multiple complications such as resistance to the action of catecholamines, pulmonary vasoconstriction, impaired cardiovascular function, hyperkalemia, immunological dysregulation, respiratory muscle fatigue, neurological impairment, cellular dysfunction, and finally, it contributes to multisystemic failure. Intravenous NaHCO3 buffers severe acidemia, preventing the associated damage and gains time while the causal disease is corrected. Its indication requires a risk-benefit assessment, considering its complications. These are hypernatremia, hypokalemia, ionic hypocalcemia, rebound alkalosis, and intracellular acidosis. For this reason, therapy must be "adapted" and administered judiciously. The patient will require monitoring with serial evaluation of the internal environment, especially arterial blood gases, plasma electrolytes, and ionized calcium. Isotonic solutions should be preferred instead of hypertonic bicarbonate. The development of hypernatremia must be prevented, calcium must be provided for hypocalcemia to improve cardiovascular function. Furthermore, in mechanically ventilated patients, a respiratory response similar to the one that would develop physiologically, must be established to be able to extract excess CO2 and thus avoid intracellular acidosis. It is possible to estimate the bicarbonate deficit, speed, and volume of its infusion. However, the calculations are only for reference. More important is to start intravenous NaHCO3 when needed, administer it judiciously, manage its side effects, and continue it to a safe goal. In this review we address all the necessary elements to consider in the administration of intravenous NaHCO3, highlighting why it is the best buffer for the management of severe metabolic acidosis.

Asunto(s)

Acidosis , Bicarbonato de Sodio , Humanos , Acidosis/tratamiento farmacológico , Bicarbonato de Sodio/administración & dosificación , Bicarbonato de Sodio/efectos adversos , Administración Intravenosa , Medición de Riesgo , Índice de Severidad de la Enfermedad

RESUMEN

Feedlot cattle is submitted to a diet rich in energy and reduced in fibres that induces the sub-acute ruminal acidosis (SARA) with its lesions and clinical signs. Recent studies have demonstrated some amelioration of this condition by the use of isoquinolone alkaloids found in Macleaya cordata (Papaveraceae) such as Sanguinarine and Chelerythrine. These compounds have demonstrated antimicrobial, antiinflammatory and immune-modulatory effects in both humans and animals The aim on this study, using histopathology and a score system, was to evaluate the differences between a non-treated and a treated group feed with these alkaloids, present in trade preparation Sangrovit-RS® as a source of sanguinarine (SG), chelerythrine (CH) and protropine (PA) standardized to 0.15% w/w SG, using feedlot cattle under a high-grain diet as an inflammatory model for gastrointestinal system. The samples of forestomachs were evaluated and graded using scores ranging from zero (0) to three (3) obtained at light-microscopic fields of 400X. Parameters such as inflammation, hydropic degeneration, hyperkeratosis, and vesicle formation were accessed in the different layers of the tissues, considering the severity and dispersion of the microscopic lesions. The soft tissues such as the abomasum, small intestine, cecum and colon had their total amount of inflammatory cells counted at light-microscopic fields of 200X. The rumen of the SG-CH-PRO-treated group showed a significant reduction in the epithelial hydropic degeneration scores (p ≤ 0.001) and lamina propria inflammation (p ≤ 0.001).The reticulum had a similar reduction in scores of epithelial (p ≤ 0.002) and stratum corneum hydropic degeneration (p ≤ 0.001), hyperkeratosis (p ≤ 0.002) and inflammation in lamina propria (p ≤ 0.001) and epithelium (p ≤ 0.002). The omasum had no significant differences. All non-keratinized tissues, except for ileum, had a significant decrease (p ≤ 0.001) in the total counting of inflammatory cells. In this trial, the feedlot cattle feed with high grain diet and treated with isoquinolone alkaloids expressed lesions that indicate ameliorations and worsening's. Ameliorating effects of the alkaloids were better demonstrated in tissues with reduced or no corneal layer in the mucosa and in the absence of a lipopolysaccharides rich acidic environment reinforcing the notion of the topic action, the dependence of the media pH and the time of exposure modulating the pharmacological mechanisms of these alkaloids. The observed cytolytic (oncolysis) effect in epithelial forestomachs cells under low pH values, worsening the osmotic status, should be considered before clinical applications.(AU)

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As dietas para bovinos confinados possuem alta quantidade de alimentos energéticos com menor quantidade de alimentos volumosos (fibras), favorecendo a indução de acidose ruminal subaguda com formação de lesões gastrointestinais e sintomas clínicos deletérios. Recentes trabalhos têm demonstrado alguma amenização desta condição pelo uso de alcaloides isoquinolínicos encontrados na Macleaya cordata (Papaveraceae) tais como a sanguinarina e a cheleretrina, os quais tem demonstrado efeitos anti-inflamatórios, antimicrobianos e imuno modulatórios em humanos e animais. O objetivo deste estudo foi, através da histopatologia e de um sistema de escores, avaliar as diferenças entre um grupo não tratado e um grupo tratado com alcaloides isoquinolínicos, presentes na formulação Sangrovit RS® como fonte de sanguinarina (SG), chelerethrina (CH) and protropina (PA) padronizadas em 0,15 % w/w SG, usando bovinos em confinamento recebendo uma dieta rica em grãos como modelo inflamatório para o sistema gastrointestinal. Amostras dos pré-estômagos foram avaliadas por escores variando de zero a três, obtidos por microscopia de luz em diferentes campos em aumentos de 400X. Inflamação, degeneração hidrópica, hiperqueratose e formação de vesículas foram avaliadas nas diferentes camadas dos pré-estômagos tendo em vista a intensidade e a extensão das lesões. Tecidos não queratinizados como abomaso e intestino delgado, ceco e cólon tiveram seu total de células inflamatórias contadas por microscopia de luz em diferentes campos com aumentos de 200X. No rumem do grupo tratado houve uma redução significante no número de campos contendo degeneração hidrópica epitelial (p ≤ 0,001) e inflamação de lâmina própria (p ≤ 0,001). O retículo teve uma redução similar nos escores scores de degeneração hidrópica epitelial (p ≤ 0.002), degeneração hidrópica no estrato córneo (p ≤ 0.001), hiperqueratose (p ≤ 0.002) e inflamação na lamina própria (p ≤ 0.001) e inflamação epitelial (p ≤ 0.002). Não foram encontradas diferenças significantes no omaso. Todos os tecidos não queratinizados, exceto pelo íleo, tiveram uma redução significativa (p ≤ 0.001) no total de células inflamatórias. Neste experimento, bovinos em confinamento recebendo dieta rica em grãos e tratados com alcaloides isoquinolínicos tiveram lesões que tiveram melhoras e pioras. Os efeitos de melhora foram melhor demonstrados em tecidos sem camada córnea e na ausência de um meio ácido rico em lipopolisacarídeos, reforçando a noção da ação tópica, da dependência do pH do meio e do tempo de exposição modulando os mecanismos farmacológicos destes alcalóides. O efeito citolítico (oncólise) sobre células epiteliais de pré-estômagos em baixos valores de pH, piorando o estado osmótico das células, deveria ser considerado antes das aplicações clínicas.(AU)

Asunto(s)

Animales , Acidosis/tratamiento farmacológico , Bovinos , Alcaloides/efectos adversos , Gastroenteritis/tratamiento farmacológico , Tracto Gastrointestinal/lesiones

RESUMEN

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de betaína. en pacientes con homocistinuria aislada (HCT) o en combinación a acidosis metilmalónica (AMM). Así, la médica endocrinóloga pediatra y genetista. La homocistinuria (HST) es un desorden del metabolismo caracterizado por niveles elevados del aminoácido homocisteína. Existen diferentes tipos de HST que se caracterizan por la acumulación anormal de homocisteína y sus metabolitos en sangre y orina : 1) HST provocada por defectos en el metabolismo intracelular de la cobalamina con la presencia de diferentes grupos de complementación (cblA-J); 2) HST clásica: defecto de la enzima cistationina B-sintetasa (CBS), y 3) defecto en la enzima metiltetrahidrofolato que convierte el 5-10-metil-tetrahidrofolato en 5-metil-tetrahidrofolato en el proceso de remetilación de la homocisteína. Las HST puede presentarse de forma aislada o en combinación con otras manifestaciones clínicas, como la acidemia metilmalónica (AMM). La betaína es un pequeño aminoácido con absorción rápida a nivel del íleo. Este aminoácido puede ser producido de manera endógena a partir de la oxidación de la colina en el organismo, principalmente en el hígado y riñones. La betaína cumple una función muy importante en la HST ya que es un donador de grupos metilo en la reacción enzimática de la enzima betaína-homocisteína-metiltransferasa que convierte (a través de la re-metilación) homocisteína a metionina. METODOLOGIA: Se realizó una búsqueda de literatura científica en relación a la eficacia y seguridad del uso de betaína anhidra en pacientes con homocistinuria aislada (HCT) o en combinación de acidosis metilmalónica (AMM). Se dio preferencia a guías de práctica clínica, revisiones sistemáticas con o sin meta-análisis y ensayos clínicos aleatorizados. Asimismo, se consideró extraer información con una estrategia de "bola de nieve" mediante la revisión de las referencias bibliográficas de las guías de práctica clínica, revisiones sistemáticas, estudios primarios, estudios descriptivos y revisiones narrativas seleccionadas, relevantes a la pregunta PICO a evaluar. La búsqueda de la literatura se realizó en las bases de datos The National Library of Medicine (Pubmed), y Cochrane Library. Asimismo, se buscó información en los metabuscadores Epistemonikos, y Translating Research into Practice (TRIPDATABASE). Específicamente, la búsqueda de guías de prácticas clínicas se realizó en las páginas de internet de la National Institute for Health and Care Excellence (NICE); y The National Guideline of Clearinghouse (NGC), el repositorio creado por la Agencia para la Investigación en Salud y Calidad (AHRQ). Finalmente, se hizo una búsqueda en la página de registro de ensayos clínicos www.clinicaltrials.gov, para identificar estudios primarios en elaboración o que no hayan sido publicados aún. RESULTADOS: Se realizó la búsqueda bibliográfica y de evidencia científica que sustente el uso de betaína en pacientes pediátricos con homocistinuria (HCT) aislada o en combinación con academia metilmalónica (AMM). Luego de revisar un total de 265 referencias, un total de 12 artículos fueron revisados a texto completo de los cuales sólo dos referencias fueron finalmente seleccionadas para ser analizadas, al ser las únicas que respondían a nuestra pregunta PICO en evaluación. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se presenta la evidencia recabada sobre el uso de betaína anhidra en pacientes pediátricos con homocistinuria (HST) aislada o en combinación con acidosis metilmalónica (AMM). La evidencia encontrada que evalúa el uso de la betaína en pacientes pediátricos con HST es escasa. Se ha identificado evidencia proveniente de un estudio observacional y una revisión sistemática de reportes y series de casos. El reporte de casos muestra que una dosis de 3g/día de betaína anhidra se reduce los niveles AMM y HST luego de cinco meses de suplementación, además, mejoran los indicadores de percentiles de peso, longitud y perímetro cefálico. La agrupación de resultados de varios reportes y series de casos en la revisión sistemática mostró que la suplementación de betaína anhidra tiene un efecto beneficioso en el desarrollo psicomotor y el aumento de la sobrevida. La calidad de evidencia de los estudios incluidos es baja. Si bien la betaína anhidra ha mostrado tener efectos beneficiosos en el tratamiento de la HST, es importante tener en cuenta que el tratamiento de las HST está conformado por la combinación de varios suplementos incluyendo a la cobalamina, ácido fólico, carnitina, entre otros. Por esta razón, no es posible atribuir los resultados de los estudios a los efectos de la betaína anhidra de manera individual, por lo que estos deben ser tomados con precaución para la toma de decisiones sobre la mejor estrategia terapéutica a utilizar. Adicionalmente, los estudios incluidos presentan ciertas limitaciones metodológicas debido a que se incluyen dentro del análisis descriptivo a estudios observacionales de tipo reporte de caso o serie de caso. No obstante, en las enfermedades innatas del metabolismo, como es el caso de la HST, los pacientes presentan características clínicas muy similares entre sí, el tratamiento indicado es parecido para todos los pacientes, y el cegamiento de los evaluadores no influye en los desenlaces clínicos, por lo que se podría subvaluar la severidad de estas limitaciones. En base a aspectos teóricos, en ninguna de las causas de la HST el mecanismo de acción de la betaína anhidra ayuda de manera directa a solucionar el defecto existente. Sin embargo, la suplementación de betaína tiene como objetivo saturar a la célula y potenciar la reacción enzimática de la enzima metionina sintetasa para convertir la homocisteína en metionina, y así reducir la HST. Además, no existen otras alternativas terapéuticas específicas para la disminución de la HST, por lo que el tratamiento con betaína podría ser una terapia efectiva para esta enfermedad. Los expertos en pediatría reportan que el uso de betaína, en conjunto con otras terapias como la dieta hipoproteica y la suplementación de cobalamina, carnitina y ácido fólico, es el mejor método terapéutico a emplear en pacientes en pacientes con HST aislada o en combinación con AMM, con el objetivo de prevenir complicaciones tromboembólicas y, secundarias a estas, la aparición de diversas complicaciones neurológicas, cardiacas, retraso en el crecimiento y desarrollo cognitivo, síndrome urémico hemolítico, postración, microangiopatía trombótica con capacidad de generar necrosis a nivel de los tejidos, entre otras. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI, aprueba el uso de betaína anhidra en pacientes con HST aislada o en combinación con AMM, según las condiciones establecidas en el Anexo 01. El presente Dictamen Preliminar tiene una vigencia de dos años a partir de la fecha de publicación.

Asunto(s)

Humanos , Acidosis/tratamiento farmacológico , Homocistinuria/tratamiento farmacológico , Betaína/uso terapéutico , Eficacia , Análisis Costo-Beneficio

RESUMEN

REASONS FOR PERFORMING STUDY: Treatment of metabolic acidosis using sodium bicarbonate solutions is safe when blood gas analysis is available. The evidence that solutions containing metabolisable buffers can be used as an alternative for treatment of metabolic acidosis in horses is of practical interest. OBJECTIVES: To investigate the safety and efficacy of a polyionic solution containing 84 mEq/l of lactate (L84) for the correction of induced hyperchloraemic metabolic acidosis. STUDY DESIGN: Non-randomised crossover design. METHODS: Five healthy, adult, crossbred horses were used. A solution containing 100 mmol/l of HCl was infused intravenously (100 ml/kg bwt) for 5 h to induce metabolic acidosis. Metabolic acidosis was induced in each horse twice, with a minimum 15-day interval after recovery from the first induction: the first time no treatment was administered (control group) and the second time horses were treated with an intravenous infusion of L84 solution, 100 ml/kg bwt for 5 h, beginning 3 h after the end of HCl infusion. Venous blood samples were taken at 0, 2.5, 5, 8, 10.5, 13, 24 and 48 h; and urine at 0, 5, 8 and 13 h. Laboratory data included pH (blood and urine), PCO2 , HCO3- , base excess, total plasma protein concentration, l-lactate, Na+ , K+ , Cl- , strong ion difference (SID4 ), anion gap, change in plasma volume and fractional excretions of Na+ , K+ and Cl- . Effects of time and treatment were tested by 2-way repeated measures ANOVA. RESULTS: Severe hyperchloraemic metabolic acidosis was induced. In the untreated horses, correction of the imbalance occurred gradually, and mild acidosis was still present at 48 h. In horses treated with the L84 solution, acidosis was corrected by the end of the infusion. There were no adverse effects with the administration of the L84 solution. CONCLUSIONS: A polyionic solution containing 84 mEq/l of lactate effectively corrected induced metabolic acidosis in horses within 5 h.

Asunto(s)

Acidosis/veterinaria , Electrólitos/farmacología , Enfermedades de los Caballos/inducido químicamente , Ácido Clorhídrico/toxicidad , Ácido Láctico/uso terapéutico , Desequilibrio Ácido-Base , Acidosis/inducido químicamente , Acidosis/tratamiento farmacológico , Animales , Estudios Cruzados , Electrólitos/administración & dosificación , Femenino , Enfermedades de los Caballos/tratamiento farmacológico , Caballos , Inyecciones Intravenosas , Ácido Láctico/administración & dosificación , Masculino

RESUMEN

BACKGROUND: Being born preterm implies comorbidities, among them the risk of intraventricular hemorrhage (IVH). The use of sodium bicarbonate has been linked to the presence of IVH. The main purpose of this study was to determine if the infusion of sodium bicarbonate during the first 24 hours increases the risk of IVH in preterm infants. METHODS: Our study is a cohort; we analyzed the files of 160 patients and divided them into two groups: one in which sodium bicarbonate was not used and another in which it was; this latter group was subdivided into two considering if the use was therapeutic of prophylactic. RESULTS: In our total group of patients 10 % presented IVH; had a mean weight of 1500 g and 31 weeks of gestational age. The incidence of IVH was identical between both groups, although patients in which bicarbonate was used were more premature, unstable, and in worse clinical conditions. CONCLUSIONS: Our data indicate the need of large scale studies to determine if the clinical benefits of the use of sodium bicarbonate outweigh the risk of IVH.

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Introducción: nacer prematuro conlleva riesgos, como la posibilidad de sufrir hemorragia intraventricular. El 90 % de los casos se presenta dentro de los primeros 4 a 7 días; Se ha relacionado el uso de bicarbonato de sodio con su aparición. El propósito de este estudio fue determinar si el uso de bicarbonato en infusión continua, en las primeras 24 horas, aumenta el riesgo de hemorragia intraventricular. Métodos: cohorte retrospectiva, se revisaron 160 expedientes formándose 2 grupos: uno sin y otro con uso de bicarbonato. Posteriormente, el grupo con uso se dividió en dos: uso terapéutico y profiláctico. Resultados: Del total de los prematuros, 10 % presentaron hemorragia intraventricular, tenían un peso promedio de 1,500 g y una edad gestacional promedio de 31 semanas. La incidencia fue idéntica entre los grupos, aunque en el grupo con bicarbonato había pacientes más prematuros, y clínicamente más inestables. Se realizó una regresión logística donde se observó asociación entre la incidencia de hemorragia intraventricular y el peso al nacimiento (OR de 0.99); así como en el caso del uso de bicarbonato de sodio con una OR 1.22. Conclusiones: Nuestros datos indican la necesidad de evaluación sistemática del uso de bicarbonato, con el fin de determinar si los beneficios sobrepasan el riesgo de hemorragia intraventricular.

Asunto(s)

Acidosis/tratamiento farmacológico , Hemorragia Cerebral/inducido químicamente , Enfermedades del Prematuro/inducido químicamente , Bicarbonato de Sodio/efectos adversos , Acidosis/prevención & control , Hemorragia Cerebral/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/tratamiento farmacológico , Enfermedades del Prematuro/epidemiología , Infusiones Intravenosas , Masculino , Estudios Retrospectivos , Bicarbonato de Sodio/uso terapéutico , Resultado del Tratamiento

RESUMEN

OBJECTIVES: This study was designed to investigate the activation of the unfolded protein response (UPR) in tumor associated endothelial cells (TECs) and its association with chemoresistance during acidic pH stress. MATERIALS AND METHODS: Endothelial cells from human oral squamous cell carcinomas (OSCC) were excised by laser capture microdissection (LCM) followed by analysis of UPR markers (Grp78, ATF4 and CHOP) using quantitative PCR. Grp78 expression was also determined by immunostaining. Acidic stress was induced in primary human dermal microvascular endothelial cells (HDMECs) by treatment with conditioned medium (CM) from tumor cells grown under hypoxic conditions or by adjusting medium pH to 6.4 or 7.0 using lactic acid or hydrochloric acid (HCl). HDMEC resistance to the anti-angiogenic drug Sunitinib was assessed with SRB assay. RESULTS: UPR markers, Grp78, ATF4 and CHOP were significantly upregulated in TECs from OSCC compared to HDMECs. HDMECs cultured in acidic CM (pH 6.0-6.4) showed increased expression of the UPR markers. However, severe acidosis led to marked cell death in HDMECs. Alternatively, HDMECs were able to adapt when exposed to chronic acidosis at pH 7.0 for 7 days, with concomittant increase in Grp78 expression. Chronic acidosis also confers drug resistance to HDMECs against Sunitinib. Knockdown of Grp78 using shRNA resensitizes HDMECs to drug treatment. CONCLUSIONS: UPR induction in ECs under acidic pH conditions is related to chemoresistance and may contribute to therapeutic failures in response to chemotherapy. Targeting Grp78, the key component of the UPR pathway, may provide a promising approach to overcome ECs resistance in cancer therapy.

Asunto(s)

Acidosis/patología , Dermis/patología , Resistencia a Antineoplásicos , Endotelio Vascular/patología , Proteínas de Choque Térmico/metabolismo , Neoplasias de la Boca/patología , Respuesta de Proteína Desplegada/efectos de los fármacos , Acidosis/tratamiento farmacológico , Acidosis/metabolismo , Inhibidores de la Angiogénesis/farmacología , Apoptosis , Western Blotting , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Ciclo Celular , Proliferación Celular , Células Cultivadas , Dermis/efectos de los fármacos , Dermis/metabolismo , Chaperón BiP del Retículo Endoplásmico , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Técnica del Anticuerpo Fluorescente , Proteínas de Choque Térmico/genética , Humanos , Concentración de Iones de Hidrógeno , Técnicas para Inmunoenzimas , Captura por Microdisección con Láser , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

We examined the isolated and combined effects of beta-alanine (BA) and sodium bicarbonate (SB) on high-intensity intermittent upper-body performance in judo and jiu-jitsu competitors. 37 athletes were assigned to one of four groups: (1) placebo (PL)+PL; (2) BA+PL; (3) PL+SB or (4) BA+SB. BA or dextrose (placebo) (6.4 g day⁻¹) was ingested for 4 weeks and 500 mg kg⁻¹ BM of SB or calcium carbonate (placebo) was ingested for 7 days during the 4th week. Before and after 4 weeks of supplementation, the athletes completed four 30-s upper-body Wingate tests, separated by 3 min. Blood lactate was determined at rest, immediately after and 5 min after the 4th exercise bout, with perceived exertion reported immediately after the 4th bout. BA and SB alone increased the total work done in +7 and 8 %, respectively. The co-ingestion resulted in an additive effect (+14 %, p < 0.05 vs. BA and SB alone). BA alone significantly improved mean power in the 2nd and 3rd bouts and tended to improve the 4th bout. SB alone significantly improved mean power in the 4th bout and tended to improve in the 2nd and 3rd bouts. BA+SB enhanced mean power in all four bouts. PL+PL did not elicit any alteration on mean and peak power. Post-exercise blood lactate increased with all treatments except with PL+PL. Only BA+SB resulted in lower ratings of perceived exertion (p = 0.05). Chronic BA and SB supplementation alone equally enhanced high-intensity intermittent upper-body performance in well-trained athletes. Combined BA and SB promoted a clear additive ergogenic effect.

Asunto(s)

Acidosis/prevención & control , Rendimiento Atlético , Carbonato de Calcio/farmacología , Artes Marciales , Fatiga Muscular/efectos de los fármacos , Bicarbonato de Sodio/farmacología , beta-Alanina/farmacología , Acidosis/tratamiento farmacológico , Acidosis/metabolismo , Adulto , Atletas , Carbonato de Calcio/administración & dosificación , Carbonato de Calcio/efectos adversos , Suplementos Dietéticos , Método Doble Ciego , Prueba de Esfuerzo , Humanos , Ácido Láctico/sangre , Masculino , Destreza Motora/efectos de los fármacos , Tono Muscular/efectos de los fármacos , Tono Muscular/fisiología , Esfuerzo Físico , Bicarbonato de Sodio/administración & dosificación , Bicarbonato de Sodio/efectos adversos , Extremidad Superior/fisiología , Adulto Joven , beta-Alanina/administración & dosificación , beta-Alanina/efectos adversos

Asunto(s)

Acidosis/tratamiento farmacológico , Recien Nacido Prematuro , Bicarbonato de Sodio/uso terapéutico , Humanos , Recién Nacido , Infusiones Intravenosas

RESUMEN

BACKGROUND/AIMS: This study aimed to identify the signaling pathway for the proposed link between phosphodiesterase-5A (PDE5A) inhibition and decreased cardiac Na(+)/H(+) exchanger (NHE-1) activity. METHODS: NHE-1 activity was assessed in rat isolated papillary muscles by the Na(+)-dependent initial pH(i) recovery from a sustained acidosis (ammonium prepulse). ERK1/2, p90RSK and NHE-1 phosphorylation state during acidosis was determined. RESULTS: PDE5A inhibition (1 µmol/L sildenafil, SIL) did not modify basal pH(i) but significantly blunted pH(i) recovery after sustained acidosis. Although preventing ERK1/2- p90RSK signaling pathway (10 µmol/L U0126) mimicked SIL effect, SIL did not blunt the acidosis-mediated increase in kinases activation. SIL+U0126 did not show additive effect on NHE-1 activity. Then, we hypothesized that SIL could be activating phophasatases (PP1 and/or PP2A) to directly dephosphorylate NHE-1 despite preserved ERK1/2-p90RSK activation. Non-specific phosphatases inhibition (1 µmol/L okadaic acid) canceled SIL effect on pH(i) recovery from acidosis. Same result was observed by inhibiting PP2A either with a lower dose of okadaic acid (1 nmol/L) or, more specifically, with 100 µmol/L endothall. Consistently, NHE-1 phosphorylation at Ser703 increased after acidosis, SIL prevented this effect and PP2A inhibition (endothall) reverted SIL effect. CONCLUSION: We suggest that PDE5A inhibitors decrease NHE-1 phosphorylation and activity through a mechanism that involves PP2A activation.

Asunto(s)

Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Proteína Fosfatasa 1/fisiología , Proteína Fosfatasa 2/fisiología , Intercambiadores de Sodio-Hidrógeno/metabolismo , Acidosis/tratamiento farmacológico , Animales , Butadienos/farmacología , Ácidos Dicarboxílicos/farmacología , Concentración de Iones de Hidrógeno , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Nitrilos/farmacología , Ácido Ocadaico/farmacología , Músculos Papilares/efectos de los fármacos , Músculos Papilares/metabolismo , Fosforilación , Piperazinas/farmacología , Proteína Fosfatasa 1/antagonistas & inhibidores , Proteína Fosfatasa 1/metabolismo , Proteína Fosfatasa 2/antagonistas & inhibidores , Proteína Fosfatasa 2/metabolismo , Purinas/farmacología , Ratas , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Citrato de Sildenafil , Sulfonas/farmacología

RESUMEN

Sepsis is the systemic inflammatory response syndrome secondary to a local infection, and severe sepsis and septic shock are the more devastating scenarios of this disease. In the last decade, considerable achievements were obtained in sepsis knowledge, and an international campaign was developed to improve the treatment of this condition. However, sepsis is still one of the most important causes of death in intensive care units. The early stages of sepsis are characterized by a variety of hemodynamic derangements that induce a systemic imbalance between tissue oxygen supply and demand, leading to global tissue hypoxia. This dysfunction, which may occur in patients presenting normal vital signs, can be accompanied by a significant increase in both morbidity and mortality. The early identification of high-risk sepsis patients through tissue perfusion markers such as lactate and venous oxygen saturation is crucial for prompt initiation of therapeutic support, which includes early goal-directed therapy as necessary. The purpose of this article was to review the most commonly used hemodynamic and perfusion parameters for hemodynamic optimization in sepsis, emphasizing the physiological background for their use and the studies that demonstrated their effectiveness as goals of volemic resuscitation.

Asunto(s)

Hemodinámica , Resucitación/métodos , Sepsis/terapia , Choque/terapia , Acidosis/tratamiento farmacológico , Acidosis/etiología , Animales , Biomarcadores , Presión Sanguínea , Gasto Cardíaco , Diagnóstico Precoz , Humanos , Hipoxia/sangre , Hipoxia/etiología , Hipoxia/prevención & control , Lactatos/sangre , Oxígeno/sangre , Riesgo , Sepsis/sangre , Sepsis/fisiopatología , Choque/etiología , Choque/fisiopatología , Venas

RESUMEN

The short-term outcomes of sodium bicarbonate therapy in preterm infants were investigated by retrospective analysis of 165 of 984 infants who received sodium bicarbonate. The infants treated with sodium bicarbonate were more immature and had greater severity of illness and more adverse outcomes. Sodium bicarbonate therapy did not improve the blood pH.

Asunto(s)

Acidosis/tratamiento farmacológico , Acidosis/metabolismo , Concentración de Iones de Hidrógeno/efectos de los fármacos , Bicarbonato de Sodio/farmacología , Enfermedad Crónica , Humanos , Recién Nacido , Recien Nacido Prematuro , Infusiones Intravenosas , Índice de Severidad de la Enfermedad , Bicarbonato de Sodio/administración & dosificación

RESUMEN

OBJECTIVES: To critically discuss the treatment of metabolic acidosis and the main mechanisms of disease associated with this disorder; and to describe controversial aspects related to the risks and benefits of using sodium bicarbonate and other therapies. SOURCES: Review of PubMed/MEDLINE, LILACS and Cochrane Library databases for articles published between 1996 and 2006 using the following keywords: metabolic acidosis, lactic acidosis, ketoacidosis, diabetic ketoacidosis, cardiopulmonary resuscitation, sodium bicarbonate, treatment. Classical publications concerning the topic were also reviewed. The most recent and representative were selected, with emphasis on consensus statements and guidelines. SUMMARY OF THE FINDINGS: There is no evidence of benefits resulting from the use of sodium bicarbonate for the hemodynamic status, clinical outcome, morbidity and mortality in high anion gap metabolic acidosis associated with lactic acidosis, diabetic ketoacidosis and cardiopulmonary resuscitation. Therefore, the routine use of sodium bicarbonate is not indicated. Potential side effects must be taken into consideration. Treating the underlying disease is essential to reverse the process. The efficacy of other alternative therapies has not been demonstrated in large-scale studies. CONCLUSIONS: Despite the known effects of acidemia on the organism in critical situations, a protective role of acidemia in hypoxic cells and the risk of alkalemia secondary to drug interventions are being considered. There is consensus regarding the advantages of alkali and sodium bicarbonate therapy in cases with normal anion gap; however, in the presence of high anion gap acidosis, especially lactic acidosis, diabetic acidosis and cardiopulmonary resuscitation, the use of sodium bicarbonate is not beneficial and has potential adverse effects, limiting its indication. The only points of agreement in the literature refer to the early treatment of the underlying disease and the mechanisms generating metabolic acidemia. Other promising treatment alternatives have been proposed; however, the side effects and absence of controlled studies with pediatric populations translate into lack of evidence to support the routine use of such treatments.

Asunto(s)

Acidosis/tratamiento farmacológico , Bicarbonato de Sodio/uso terapéutico , Acidosis/etiología , Acidosis Láctica/tratamiento farmacológico , Reanimación Cardiopulmonar/efectos adversos , Niño , Cetoacidosis Diabética/tratamiento farmacológico , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Bicarbonato de Sodio/efectos adversos

RESUMEN

OBJETIVO: Apresentar uma revisão atualizada e crítica sobre os mecanismos das principais patologias associadas e o tratamento da acidose metabólica, discutindo aspectos controversos quanto aos benefícios e riscos da utilização do bicarbonato de sódio e outras formas de terapia. FONTES DOS DADOS: Revisão da literatura publicada, obtida através de busca eletrônica com as palavras-chave acidose metabólica, acidose láctica, cetoacidose diabética, ressuscitação cardiopulmonar, bicarbonato de sódio e terapêutica nas bases de dados PubMed/MEDLINE, LILACS e Cochrane Library, entre 1996 e 2006, além de publicações clássicas referentes ao tema, sendo selecionadas as mais atuais e representativas, buscando-se consensos e diretrizes. SíNTESE DOS DADOS: A utilização de bicarbonato de sódio não demonstra benefícios no quadro hemodinâmico, evolução clínica, morbidade e mortalidade nos quadros de acidose metabólica de anion gap elevado, relacionados à acidose láctica, cetoacidose diabética e ressuscitação cardiorrespiratória. Assim, a sua utilização rotineira não é indicada. Devem ser considerados os potenciais efeitos colaterais. O tratamento da doença de base é fundamental para reversão do processo. Outras terapias alternativas não demonstram efetividade comprovada em grande escala. CONCLUSÕES: Apesar dos efeitos conhecidos da acidemia em situações críticas no organismo, discute-se o papel protetor da acidemia nas células sob hipoxemia e os riscos da alcalemia secundária à intervenção medicamentosa. Existe consenso na reposição de álcalis e bicarbonato de sódio nos casos de acidose de anion gap normal; entretanto, nos casos de acidose de anion gap elevado, particularmente na acidose láctica, cetoacidose diabética e na ressuscitação cardiorrespiratória, o uso de bicarbonato de sódio não demonstra benefícios, além dos potenciais efeitos adversos, o que torna restrita sua indicação. Apesar da controvérsia, o único ponto concordante refere-se à abordagem...

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OBJECTIVES: To critically discuss the treatment of metabolic acidosis and the main mechanisms of disease associated with this disorder; and to describe controversial aspects related to the risks and benefits of using sodium bicarbonate and other therapies. SOURCES: Review of PubMed/MEDLINE, LILACS and Cochrane Library databases for articles published between 1996 and 2006 using the following keywords: metabolic acidosis, lactic acidosis, ketoacidosis, diabetic ketoacidosis, cardiopulmonary resuscitation, sodium bicarbonate, treatment. Classical publications concerning the topic were also reviewed. The most recent and representative were selected, with emphasis on consensus statements and guidelines. SUMMARY OF THE FINDINGS: There is no evidence of benefits resulting from the use of sodium bicarbonate for the hemodynamic status, clinical outcome, morbidity and mortality in high anion gap metabolic acidosis associated with lactic acidosis, diabetic ketoacidosis and cardiopulmonary resuscitation. Therefore, the routine use of sodium bicarbonate is not indicated. Potential side effects must be taken into consideration. Treating the underlying disease is essential to reverse the process. The efficacy of other alternative therapies has not been demonstrated in large-scale studies. CONCLUSIONS: Despite the known effects of acidemia on the organism in critical situations, a protective role of acidemia in hypoxic cells and the risk of alkalemia secondary to drug interventions are being considered. There is consensus regarding the advantages of alkali and sodium bicarbonate therapy in cases with normal anion gap; however, in the presence of high anion gap acidosis, especially lactic acidosis, diabetic acidosis and cardiopulmonary resuscitation, the use of sodium bicarbonate is not beneficial and has potential adverse effects, limiting its indication. The only points of agreement in the literature refer to the early treatment of the underlying disease...

Asunto(s)

Niño , Humanos , Acidosis/tratamiento farmacológico , Bicarbonato de Sodio/uso terapéutico , Acidosis Láctica/tratamiento farmacológico , Acidosis/etiología , Reanimación Cardiopulmonar/efectos adversos , Cetoacidosis Diabética/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Bicarbonato de Sodio/efectos adversos

RESUMEN

A 32-year old male, with a history of depression and previous suicide attempts, was brought to hospital comatose after ingestion of brake fluid. He developed severe metabolic acidosis with an increased anion gap, hypotension, seizures and mild renal impairment. He required intensive care treatment for ventilatory and inotropic support. The clinical features, diagnosis and treatment of this unusual poison are discussed.

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Un sujeto masculino de 32 años de edad, con una historia de depresión y previos intentos de suicidio, fue llevado en estado comatoso al hospital, luego de haber ingerido líquido de freno. El paciente desarrolló una acidosis metabólica severa con aumento del gap aniónico, hipertensión, convulsiones, e insuficiencia renal moderada. Requirió tratamiento mediante cuidados intensivos con apoyo ventilatorio e inotrópico. El trabajo analiza las características clínicas, el diagnóstico y el tratamiento de este envenenamiento inusual.

Asunto(s)

Humanos , Masculino , Adulto , Acidosis/inducido químicamente , Bicarbonato de Sodio/uso terapéutico , Glicol de Etileno/envenenamiento , Intento de Suicidio , Desequilibrio Hidroelectrolítico , Acidosis/tratamiento farmacológico , Equilibrio Ácido-Base

RESUMEN

The amount needed to change the concentration of a solute requires the knowledge of its volume of distribution in the solution. Electrolytes that do not participate in active metabolic reactions have a fixed volume of distribution that corresponds to the volume of water in which they solubilize. Bicarbonate infusion is used to correct hyperchloremic metabolic acidosis. Its volume of distribution (bicarbonate space) changes with its participation in the blood buffer systems. In other words, it is not a fixed physical volume, like that of other solutes. In this paper, we shall review experimental studies that supported evidence for this knowledge and analyze the basic hypothesis to explain the phenomena. Since we have not found clinical studies in children, we shall report our experience in a group of patients with metabolic acidosis treated with bicarbonate infusion in whom apparent bicarbonate space was measured and compared with data in adults from the literature. Guidelines for amount of bicarbonate needed to increase its concentration according to baseline bicarbonate concentration will be suggested.

Asunto(s)

Acidosis/tratamiento farmacológico , Acidosis/metabolismo , Modelos Biológicos , Bicarbonato de Sodio/administración & dosificación , Bicarbonato de Sodio/farmacocinética , Equilibrio Hidroelectrolítico/efectos de los fármacos , Niño , Preescolar , Medicina Basada en la Evidencia , Femenino , Humanos , Concentración de Iones de Hidrógeno , Inyecciones Intravenosas , Masculino , Distribución Tisular , Resultado del Tratamiento

RESUMEN

A 32-year old male, with a history of depression and previous suicide attempts, was brought to hospital comatose after ingestion of brake fluid. He developed severe metabolic acidosis with an increased anion gap, hypotension, seizures and mild renal impairment. He required intensive care treatment for ventilatory and inotropic support. The clinical features, diagnosis and treatment of this unusual poison are discussed.

Asunto(s)

Acidosis/inducido químicamente , Glicol de Etileno/envenenamiento , Bicarbonato de Sodio/uso terapéutico , Intento de Suicidio , Equilibrio Ácido-Base , Acidosis/tratamiento farmacológico , Adulto , Humanos , Masculino , Desequilibrio Hidroelectrolítico/inducido químicamente

RESUMEN

OBJECTIVE: The objective was to determine the long-term clinical outcome and the effects of treatment of patients with glutathione synthetase (GS) deficiency (n = 28). METHODS: The diagnosis was based on demonstration of a marked decrease in GS activity in erythrocytes or cultured fibroblasts in all patients and was supported by finding a decrease in erythrocyte or fibroblast glutathione, presence of 5-oxoprolinuria, or both. The treatment varied but usually included correction of acidosis and supplementation with vitamins C and/or E. RESULTS: Sixteen patients were severely affected with neurologic symptoms such as seizures and psychomotor retardation; 7 had died at the time of the study. None of the severely affected patients had been treated with both vitamins C and E from the neonatal period. No significant difference was found in GS activity between patients with or without neurologic symptoms or in erythrocyte or fibroblast glutathione levels. Five patients had recurrent bacterial infections. CONCLUSION: On the basis of clinical symptoms, patients with GS deficiency can be classified into 3 phenotypes: mild, moderate, and severe. Our results indicate that early supplementation with vitamins C and E may improve the long-term clinical outcome.

Asunto(s)

Glutatión Sintasa/deficiencia , Acidosis/tratamiento farmacológico , Adulto , Anemia Hemolítica/genética , Ácido Ascórbico/uso terapéutico , Niño , Preescolar , Eritrocitos/enzimología , Femenino , Fibroblastos/enzimología , Genes Recesivos , Glutatión Sintasa/genética , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Enfermedades del Sistema Nervioso/genética , Trastornos Psicomotores/genética , Factores de Tiempo , Vitamina E/uso terapéutico

RESUMEN

Objetivo. Evaluar la evolución de pacientes con acidosis metabólica tardía con el uso de bicarbonato por vía oral. Diseño. Estudio descriptivo observacional. Población. Siete recién nacidos de ambos sexos. Metodología. Se incluyeron todos los pacientes con detención de ganancia de peso, prematuros, de bajo peso a quienes se les diagnosticó acidosis metabólica tardía. Al diagnóstico se inició bicarbonato de sodio a 2 mEq/kg/día, dividido en siete tomas y se redujo el aporte protéico al 50 de la cantiad de proteína que estaba tomando, durante 48 horas. Los pacientes fueron controlados a través de gases arteriales y evolución clínica. Resultados. No hubo diferencia con relación al sexo. Ningún paciente menor de 14 días desarrolló acidosis metabólica tardía. El grupo más afectado fue el de niños con pesos entre 1001 y 1200 gramos y aquellos cuyo aporte protéico superó los 3 gms/kg/día. El 87 de los pacientes resolvió su acidosis después del tratamiento. Conclusiones. La acidosis metabólica tardía del prematuro puede resolverse utilizando bicarbonato por vía oral, sin ninguna complicación

Asunto(s)

Humanos , Masculino , Femenino , Recién Nacido , Acidosis/tratamiento farmacológico , Bicarbonatos/uso terapéutico , Recien Nacido Prematuro