Impacto del componente hiperclorémico de la acidosis metabólica en el estado de hidratación y en el tratamiento de la cetoacidosis diabética / Impact of the hyperchloremic component of metabolic acidosis on the patient's hydration status and the treatment of diabetic ketoacidosis

Introducción. La cetoacidosis diabética (CAD) se caracteriza por acidosis metabólica (AM) con anión restante (AR) elevado, aunque, ocasionalmente, puede presentar hipercloremia. Se postuló que la presencia de hipercloremia inicial podría reflejar un mejor estado de hidratación; sin embargo, su prevalencia y su impacto en el tratamiento de la CAD se desconoce. Objetivos. Determinar la prevalencia de AM con componente hiperclorémico previo al inicio del tratamiento y evaluar si su presencia se asocia con mejor estado de hidratación y con menor tiempo de salida de la CAD, en comparación con los pacientes con AR elevado exclusivo. Pacientes y métodos. Se agruparon los pacientes internados con CAD (período entre enero de 2014 y junio de 2016) según presentaran, al ingresar, AM con AR elevado exclusivo o con hipercloremia y se compararon sus variables clínicas, de laboratorio y la respuesta al tratamiento. Resultados. Se incluyeron 40 pacientes -amp;#91;17 varones, mediana de edad: 14,5 años (2,4-18)-amp;#93;, 22 con AM con componente hiperclorémico (prevalencia de 55%) y 18 con AR elevado exclusivo. La presencia de hipercloremia no se asoció con mejor estado de hidratación (porcentaje de déficit de peso en ambos grupos: 4,9%; p= 0,81) ni con una respuesta terapéutica más rápida (con componente hiperclorémico: 9,5 horas; con AR elevado exclusivo: 11 horas; p= 0,64). Conclusiones. En niños con CAD, la prevalencia de AM con componente hiperclorémico fue del 55% y no se asoció con un mejor estado de hidratación ni con una salida más temprana de la descompensación metabólica.

Introduction. Diabetic ketoacidosis (DKA) is characterized by metabolic acidosis (MA) with a high anion gap (AG), although, occasionally, it can present with hyperchloremia. It has been postulated that the early presence of hyperchloremia could reflect a better hydration status; however, its prevalence and impact on DKA treatment remain unknown. Objectives. To determine the prevalence of the hyperchloremic component in MA prior to treatment and to assess whether it is associated with a better hydration status and a shorter recovery time from DKA compared to patients with high AG only. Patients and Methods. Patients hospitalized with DKA (between January 2014 and June 2016) were grouped according to whether they were admitted with MA with high AG only. or with hyperchloremia, and clinical and laboratory outcome measures and response to treatment were compared. Results. Forty patients (17 males, median age: 14.5 years -amp;#91;2.4-18-amp;#93;) were included; 22 with hyperchloremic metabolic acidosis (prevalence of 55%) and 18 with metabolic acidosis with high AG only. The presence of hyperchloremia was not associated with a better hydration status (weight loss percentage in both groups: 4.9%; p= 0.81) nor with a faster treatment response (MA with a hyperchloremic component: 9.5 hours; MA with high AG only: 11 hours; p= 0.64). Conclusions. The prevalence of MA with a hyperchloremic component among children with DKA was 55% and was not associated with a better hydration status nor with a faster recovery from the metabolic decompensation.

Acute but not chronic metabolic acidosis potentiates the acetylcholine-induced reduction in blood pressure: an endothelium-dependent effect

Metabolic acidosis has profound effects on vascular tone. This study investigated the in vivo effects of acute metabolic acidosis (AMA) and chronic metabolic acidosis (CMA) on hemodynamic parameters and endothelial function. CMA was induced by ad libitum intake of 1% NH4Cl for 7 days, and AMA was induced by a 3-h infusion of 6 M NH4Cl (1 mL/kg, diluted 1:10). Phenylephrine (Phe) and acetylcholine (Ach) dose-response curves were performed by venous infusion with simultaneous venous and arterial blood pressure monitoring. Plasma nitrite/nitrate (NOx) was measured by chemiluminescence. The CMA group had a blood pH of 7.15±0.03, which was associated with reduced bicarbonate (13.8±0.98 mmol/L) and no change in the partial pressure of arterial carbon dioxide (PaCO2). The AMA group had a pH of 7.20±0.01, which was associated with decreases in bicarbonate (10.8±0.54 mmol/L) and PaCO2 (47.8±2.54 to 23.2±0.74 mmHg) and accompanied by hyperventilation. Phe or ACh infusion did not affect arterial or venous blood pressure in the CMA group. However, the ACh infusion decreased the arterial blood pressure (ΔBP: -28.0±2.35 mm Hg [AMA] to -4.5±2.89 mmHg [control]) in the AMA group. Plasma NOx was normal after CMA but increased after AMA (25.3±0.88 to 31.3±0.54 μM). These results indicate that AMA, but not CMA, potentiated the Ach-induced decrease in blood pressure and led to an increase in plasma NOx, reinforcing the effect of pH imbalance on vascular tone and blood pressure control.

Relação cerebroplacentária e acidemia ao nascimento em gestações com insuficiência placentária detectada antes da 34ª semana de gestação / Cerebroplacental ratio and acidemia to the birth in placental insufficiency detected before 34th week's gestation

OBJETIVO: avaliar a hipótese de que a relação cerebroplacentária (RCP) fetal relaciona-se com acidemia no nascimento, em gestações complicadas pela insuficiência placentária detectada antes da 34ª semana de gestação. MÉTODOS: trata-se de coorte prospectiva de 55 pacientes entre a 26ª e a 34ª semanas de gestação, com diagnóstico de insuficiência placentária caracterizada pelo Doppler de artéria umbilical alterado (índice de pulsatilidade >p95). Para cada paciente foi realizada avaliação da vitalidade fetal pela doplervelocimetria de artéria umbilical, artéria cerebral média e ducto venoso, e pelo perfil biofísico fetal. Foi calculada a RCP pela razão entre os valores do índice de pulsatilidade da artéria umbilical e da artéria cerebral média, bem como o cálculo de seu z-score (número de desvios padrão que se afasta da média para a idade gestacional). A acidemia no nascimento foi caracterizada quando pH<7,2. RESULTADOS: das 55 pacientes, 29 (52,7 por cento) apresentaram acidemia no nascimento. O grupo com acidemia, comparado ao grupo com pH>7,2, apresentou associação significativa com os valores da RCP (mediana 0,47 versus 0,58; p=0,009), índice de pulsatilidade da artéria umbilical (mediana 2,45 versus 1,93; p=0,003), índice de pulsatilidade para veias (IPV) do ducto venoso (mediana 1,08 versus 0,85; p=0,034) e perfil biofísico fetal suspeito ou alterado (37 versus 8 por cento; p=0,031). A análise da RCP pelo seu z-score demonstrou tendência de maior afastamento negativo da média, mas sem atingir valor significativo (p=0,08). Foi constatada correlação significativa entre o pH no nascimento e a RCP (r=0,45; p<0,01), o z-score da RCP (r=0,27; p<0,05) e o IPV do ducto venoso (r=-0,35 p<0,01). CONCLUSÃO: A RCP associa-se à presença de acidemia no nascimento nas gestações com insuficiência placentária antes da 34ª semana, e esse parâmetro pode configurar potencial fator para avaliação da gravidade do comprometimento fetal.

PURPOSE: to evaluate the hypothesis that the fetal cerebroplacental ratio (CPR) is related to acidemia at birth in pregnancies complicated by placental insufficiency detected before 34 weeks of gestation. METHODS: this is a prospective cohort study of 55 patients between 26 and 34 weeks of gestation with a diagnosis of placental insufficiency characterized by abnormal umbilical artery Doppler (pulsatility index>95p). Fetal assessment was performed for each patient by dopplervelocimetry of the umbilical artery, middle cerebral artery and ductus venosus, and by the fetal biophysical profile. CPR was calculated using the ratio between middle cerebral artery pulsatility index and umbilical artery pulsatility index, and the z-score was obtained (number of standard deviations of the mean value at each gestational age). Acidemia at birth was characterized when pH<7.2. RESULTS: of 55 patients, 29 (52.7 percent) presented acidemia at birth. In the group of fetal acidemia, when compared with the group with pH>7.2, a significant association was observed with CPR values (median 0.47 versus 0.58; p=0.009), pulsatility index of the umbilical artery (median 2.45 versus 1.93; p=0.003), ductus venosus pulsatility index for veins (PIV) (median 1.08 versus 0.85; p=0.034) and suspected or abnormal fetal biophysical profile (37 versus 8 percent; p=0.031). CPR analysis by z-score showed a negative tendency, but was not statistically significant (p=0.080). Significant correlations were found between pH at birth and CPR (r=0.45; p<0.01), z-score of CPR (r=0.27; p<0.05) and ductus venosus PIV (r=-0.35 p<0.01). CONCLUSION: CPR is associated with the presence of acidemia at birth in pregnancies with placental insufficiency detected before 34 weeks of gestation and this parameter could potentially represent a factor for assessing the severity of fetal involvement.

Acidosis hiperclorémica: mito y realidad / Hyperchloremic acidosis

La acidosis metabólica es una alteración ácido-base frecuentemente observada en pacientes críticos. Aunque en situaciones extremas este desorden en sí mismo es amenazante para la vida, la presencia de una acidosis metabólica leve no siempre es nociva y puede ser un reflejo de la adaptación fisiológica del organismo a la injuria aguda. Diferentes autores han documentado el desarrollo de acidosis metabólica hiperclorémica asociada al aporte de grandes cantidades de solución salina 0,9 por ciento. Algunos consideran que se trata de una condición benigna y autolimitada, mientras otros sostienen que la acidosis hiperclorémica puede deteriorar la perfusión renal y esplácnica, sin embargo su relevancia clínica real es aún incierta. En un afán de evitar la aparición de acidosis hiperclorémica y sus potenciales efectos adversos, se han desarrollado cristaloides y coloides en formulaciones modificadas para que se asemejen más a la composición del plasma. En este artículo de revisión analizaremo slos mecanismos de producción de la acidosis metabólica hiperclorémica en base al abordaje físico-químico de Stewart; la evidencia existente sobre el impacto de este trastorno sobre las variables de desenlace de los pacientes críticos, y el rol clínico de las nuevas “soluciones balanceadas”.

Metabolic acidosis is an acid-base alteration frequently observed in critically ill patients. Even in extreme situations this disorder in itself is life threatening, the presence of a mild metabolic acidosis is not always harmful and may be the result of physiological adaptation of the organism to acute injury. Several authors have documented the development of hyperchloremic metabolic acidosis associated with the infusion of large amounts of 0.9 percent normal saline. Some consider this to be a benign and transient, while others argue that hyperchloremic acidosis can impair renal and splanchnic perfusion, but her real clinical relevance remains uncertain. In an effort to prevent the development of hyperchloremic acidosis and its potential adverse effects have been development formulations of crystalloid and colloid modified to more closely resemble the composition of the plasma. In this review article will discuss the mechanism of production of hyperchloremic metabolic acidosis by the physicochemical approach Stewart, the existing evidence on the impact of this disorder on the outcome variables in critically ill patients, and clinical role of new “balanced solutions”.

Effects of acid-base imbalance on vascular reactivity

Acid-base homeostasis maintains systemic arterial pH within a narrow range. Whereas the normal range of pH for clinical laboratories is 7.35-7.45, in vivo pH is maintained within a much narrower range. In clinical and experimental settings, blood pH can vary in response to respiratory or renal impairment. This altered pH promotes changes in vascular smooth muscle tone with impact on circulation and blood pressure control. Changes in pH can be divided into those occurring in the extracellular space (pHo) and those occurring within the intracellular space (pHi), although, extracellular and intracellular compartments influence each other. Consistent with the multiple events involved in the changes in tone produced by altered pHo, including type of vascular bed, several factors and mechanisms, in addition to hydrogen ion concentration, have been suggested to be involved. The scientific literature has many reports concerning acid-base balance and endothelium function, but these concepts are not clear about acid-base disorders and their relations with the three known mechanisms of endothelium-dependent vascular reactivity: nitric oxide (NO/cGMP-dependent), prostacyclin (PGI2/cAMP-dependent) and hyperpolarization. During the last decades, many studies have been published and have given rise to confronting data on acid-base disorder and endothelial function. Therefore, the main proposal of this review is to provide a critical analysis of the state of art and incentivate researchers to develop more studies about these issues.

Acid-base disarrangement and gastric intramucosal acidosis predict outcome from major trauma / Desarranjo ácido-base e acidose gástrica intramucosal predizem desfecho de trauma grave

INTRODUCTION: This prospective non-interventional study intended to assess the prognostic value of gastric intramucosal acidosis in patients with severe trauma admitted to a medical/surgical ICU. METHODS: Gastric tonometer catheters were introduced to measure air PCO2 level (Tonocap device) in forty consecutive critically ill trauma patients. Gastric intramucosal pH, air PCO2 gradient, lactate and acid-base parameters were measured at admission and at 6, 12 and 24 h thereafter. RESULTS: The median age, mean APACHE II and SOFA scores were higher in nonsurvivors than in survivors (p<0.05). There were significant differences in the PCO2 gradient between survivors and nonsurvivors at 12 and 24 hours (10±7 vs. 24±19 mmHg, 13±16 vs. 29±25 mmHg; p<0.05). Gastric intramucosal pH values were lower in nonsurvivors than in survivors, on admission and after 12 or 24 hours (p<0.05). Arterial pH and bicarbonate were lower, lactate concentration higher, and base excess more negative in nonsurvivors. Prediction of outcome (mortality and MODS) at 24 hours of ICU assessed by their ROC curves was similar (p=NS). At 24 hours, air PCO2 gradient > 18 mmHg carried a relative risk of 4.6 for death, slightly higher than a HCO3 <20 mEq/L (RR=4.29) or base excess of <-2 mmol/L (RR=3.65). CONCLUSION: Bicarbonate, base deficit, lactate, gastric intramucosal pH and PCO2 gradient discriminate survivors from nonsurvivors of major trauma. A critical air PCO2 gradient carried the greatest relative risk for death at 24 hours of ICU. Inadequate regional blood flow as detected by a critical PCO2 gradient seems to contribute to morbidity and mortality of severe trauma patients.

INTRODUÇÃO: O objetivo deste estudo prospectivo, não-intervencionista, foi avaliar o valor prognóstico da acidose gástrica intramucosal em pacientes com trauma grave admitidos numa UTI. MÉTODOS: Cateteres tonométricos gástricos foram introduzidos para medir o nível de PCO2 aéreo em 40 pacientes traumatizados. O pH gástrico intramucosal, o gradiente de PCO2 aéreo, o lactato e os parâmetros ácido-base foram medidos na admissão e 6, 12 e 24 h após a admissão. RESULTADOS: A idade mediana, o APACHE II e os escores SOFA médios foram maiores nos não-sobreviventes que nos sobreviventes (p<0.05). Não houve diferenças significativas para o gradiente de PCO2 entre sobreviventes e não-sobreviventes após 12 e 24 horas (10±7 vs. 24±19 mmHg, 13±16 vs. 29±25 mmHg; P<0.05). Os valores de pH gástrico intramucosal foram menores nos não-sobreviventes que nos sobreviventes na admissão e após 12 ou 24 horas (P<0.05). O pH arterial e o bicarbonato foram menores, a concentração de lactato maior, o excesso de base mais negativo nos não-sobreviventes. Predição do desfecho (mortalidade e FMOS) nas 24 horas de UTI acessada pelas curvas ROC foi similar (p=NS). Nas 24 horas, um gradiente de PCO2 aéreo >18 mmHg acarretou um risco relativo de 4.6 para óbito, um pouco maior que um HCO3 <20 mEq/L (RR=4.29) ou um excesso de base <-2 mmol/L (RR=3.65). CONCLUSÃO: Bicarbonato, déficit de base, lactato, pH gástrico intramucosal e o gradiente de PCO2 discriminaram os sobreviventes dos não-sobreviventes de trauma. Um gradiente crítico de PCO2 aéreo acarretou o maior risco relativo para óbito após 24 horas de UTI. Fluxo sangüíneo regional inadequado detectado por um gradiente crítico de PCO2 parece contribuir para a morbidade e mortalidade de pacientes traumatizados graves.

The importance of the Thr17 residue of phospholamban as a phosphorylation site under physiological and pathological conditions

The sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) is under the control of an SR protein named phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a, whereas phosphorylation of PLN at either the Ser16 site by PKA or the Thr17 site by CaMKII reverses this inhibition, thus increasing SERCA2a activity and the rate of Ca2+ uptake by the SR. This leads to an increase in the velocity of relaxation, SR Ca2+ load and myocardial contractility. In the intact heart, ß-adrenoceptor stimulation results in phosphorylation of PLN at both Ser16 and Thr17 residues. Phosphorylation of the Thr17 residue requires both stimulation of the CaMKII signaling pathways and inhibition of PP1, the major phosphatase that dephosphorylates PLN. These two prerequisites appear to be fulfilled by ß-adrenoceptor stimulation, which as a result of PKA activation, triggers the activation of CaMKII by increasing intracellular Ca2+, and inhibits PP1. Several pathological situations such as ischemia-reperfusion injury or hypercapnic acidosis provide the required conditions for the phosphorylation of the Thr17 residue of PLN, independently of the increase in PKA activity, i.e., increased intracellular Ca2+ and acidosis-induced phosphatase inhibition. Our results indicated that PLN was phosphorylated at Thr17 at the onset of reflow and immediately after hypercapnia was established, and that this phosphorylation contributes to the mechanical recovery after both the ischemic and acidic insults. Studies on transgenic mice with Thr17 mutated to Ala (PLN-T17A) are consistent with these results. Thus, phosphorylation of the Thr17 residue of PLN probably participates in a protective mechanism that favors Ca2+ handling and limits intracellular Ca2+ overload in pathological situations.

Dopplervelocimetria do ducto venoso na predicão da acidemia fetal / Ductus venosus Doppler velocimetry to predict acidemia at birth in pregnancies with placental insufficiency

OBJETIVOS: Investigar a possibilidade da predicão da acidemia no nascimento mediante dopplervelocimetria do ducto venoso e definir qual o melhor parâmetro e seus pontos de corte nessa predicão em gestacões com insuficiência placentária. MÉTODOS: Trata-se de estudo transversal e prospectivo que analisou 47 gestacões únicas com insuficiência placentária e idade gestacional superior a 26 semanas, realizado no Hospital São Paulo (UNIFESP) e na Maternidade-Escola Assis Chateaubriand (UFC). A insuficiência placentária foi diagnosticada quando o índice de pulsatilidade da artéria umbilical encontrava-se acima do percentil 95 para a idade gestacional estimada. Fetos com anomalias estruturais ou cromossômicas foram excluídos. O doppler foi realizado a menos de 24 horas do parto. A amostra de sangue da artéria umbilical foi coletada imediatamente após o nascimento para análise da gasometria. Diagnosticou-se acidemia quando o pH encontrava-se abaixo de 7,20 na ausência de trabalho de parto e abaixo de 7,15 quando parto vaginal. Foram consideradas patológicas as acidemias metabólicas ou mistas. Construiu-se curva ROC para as velocidades S, D e A e para o IPV e as relacões S/A e (S-A)/S do DV (variáveis independentes) e acidemia (variável dependente). O teste de MacNemar foi utilizado para comparar os parâmetros entre si. RESULTADOS: As velocidades absolutas S, D e A mostraram ser pobres preditoras da acidemia no nascimento. O IPV mostrou ser bom preditor de acidemia (área sob a curva ROC 0,79, p=0,003). As relacões S/A e (S-A)/S também mostraram ser boas preditoras da acidemia (área sob a curva ROC 0,818, p=0,001). Os pontos de corte calculados foram: IPV = 0,76, S/A = 2,67 e (S-A)/S = 0,63. CONCLUSÕES: Os índices ângulo-independentes do doppler do DV mostraram excelente correlacão com acidemia no nascimento nesta populacão. Não houve diferenca estatisticamene significativa entre estes parâmetros.

Esvaziamento gástrico e acidose metabólica: II. estudo, num modelo experimental em ratos, da retençäo gástrica de uma soluçäo de bicarbonato de sódio / Gastric emptying and metabolic acidosis: II. study in an experimental model in rats, of the gastric retention of a sodium bicarbonate solution

O esvaziamento gástrico (EG) de 2ml/100g de peso do animal de uma soluçäo de bicarbonato de sódio 0,25 M, acrescida de fenol vermelho (6 mg/dl) foi estudado em ratos com acidose metabólica induzida por infusäo orogástrica prévia de volume igual de uma soluçäo de cloreto de amônio 0,5 M. Como grupos controles foram utilizados animais com infusäo prévia de 2ml/100g de peso do animal de soluçäo de cloreto de sódio 0,5M e de água. As retençöes (RG) foram avaliadas 6 horas após a infusäo das refeiçöes prévias nos tempos de 5, 10, 20 e 30 minutos. Os resultados mostrtam que as RG da soluçäo de bicarbonato de sódio nos animais com acidose metabólica foram significativamente menores que as apresentadas pelos animais com infusäo prévia de água (aos 20 minutos) e áquelas apresentadas pelos animais metabólica acelera o esvaziamento gástrico de uma soluçäo de bicarbonato de sódio, havendo evidências de que este fato ocorra devido a aumento de secreçäo de ácido pela mucosa gástrica

Tratamiento de la acidosis metabólica grave / Treatment of severe metabolic acidosis

Estudio de 18 lactantes con acidosis metabólica grave (pH sérico menor de siete) tratados con diálisis peritoneal. En cada paciente se determinó pH, EB (exceso de base) y HCO3 previos al procedimiento quirúrgico; posteriormente, control al quinto baño de diálisis y a las seis horas de evolución. En siete pacientes se determinó lactato sérico y líquido de diálisis. Se correlacionaron número de baños de diálisis y pH sérico; r=0.89 y p<0.01. Se demuestra diferencia significativa entre el inicio y la evolución a las seis horas para el pH,t=13.42 y p<0.001, EB con t=7.99 y p<0.001, y para HCO3, t=5.67 y p<0.001; lactado sérico de 23.2 mg%, lactado en líquido de diálisis promedio, de 23.23 mg%. No hubo complicaciones. Se considera que la acidosis metabólica grave es mortal o deja secuelas neurales irreversibles. Consideramos que todo pacientes con acidosis metabólica con pH menor de siete debe recibir el beneficio de la diálisis

Aumento del efecto depresor del verapamil en acidosis / Increase of the depressive effect of verapamil in acidosis

En aurículas aisladas de rata se estudió el efecto depresor de la respuesta cronotrópica por los bloqueadores de los canales lentos de calcio a pH 7.39 (grupo control) y pH 7.03 (grupo en acidosis). Se realizaron curvas concentración-respuesta con verapamil, nitrendipina y nifedipina, midiendo la frecuencia de despolarización espontánea luego de 20 minutos de exposición a cada concentración de la droga. Tanto el verapamil como las dihidropiridinas producen una depresión del automatismo sinusal, pero sólo el verapamil presentó un reforzamiento del efecto depresor en acidosis. El cambio en la frecuencia sinusal fue significativamente mayor en el grupo en acidosis que en el control, entre las dosis de 3 x 10**-9 y 10**-7 M. La acidosis aumenta el efecto depresor del verapamil sobre el cronotropismo de manera similar a lo descripto para su efecto sobre el inotropismo. Nuestros resultados sugieren un mecanismo sinérgico para la inhibición del canal de calcio por iones H+ y verapamil, pero no para iones H+ y dihidropiridinas