Hemorragia variceal: terapia con drogas vasoactivas ¿siempre o en casos seleccionados? / Variceal hemorrhage: pharmacological therapy: always or in selected cases only?

One of the most relevant complications of portal hypertension in cirrhosis is the development of gastroesophageal varices. They are present in 50 percent of patients with cirrhosis at the diagnosis. The risk of bleeding depends on the degree of portal hypertension and the severity of liver disease. Variceal hemorrhage is the most common lethal complication of cirrhosis. In the last decades there had been numerous clinical trials involving different treatment options for variceal bleeding (pharmacological, endoscopic and surgery) trying to establish the best treatment strategy. Since the rise in portal pressure is the cause of variceal rupture, therapies that can decrease portal pressure have a theoretical rationale for their use. Endoscopic treatment, although effective, has no effect on portal pressure. Vasoactive agents (vasopressin and its analogue terlipressin, somatostatin and its analogue octreotide) cause splanchnic vasoconstriction and decrease portal pressure. Pharmacological treatments have the advantage that they can be easily administered, and started as soon as the diagnosis of variceal bleeding is suspected. This makes pharmacological treatment especially attractive for centers that have no chance of emergency endoscopy. At this moment there is sufficient evidence to recommend combined treatment with vasoactive drugs and endoscopy for the control of variceal hemorrhage.

Una de las principales complicaciones de los pacientes cirróticos con hipertensión portal es el desarrollo de várices gastroesofágicas. Éstas están presentes al momento del diagnóstico en alrededor de 50 por ciento de los pacientes con cirrosis. La hemorragia variceal es la complicación letal más frecuente en los pacientes cirróticos. En las últimas décadas se han realizado múltiples esfuerzos para lograr definir la mejor combinación de técnicas (endoscópicas, farmacológicas y quirúrgicas) para disminuir la morbimortalidad asociada a la hemorragia variceal. Dado que la causa de la ruptura de las várices es un aumento de la presión portal, todas las medidas que logren disminuirla son medidas racionales para lograr detener la hemorragia. El tratamiento endoscópico, si bien efectivo, no afecta la fisiopatología de la hemorragia variceal. Las drogas vasoconstrictoras (vasopresina y su derivado terlipresina o somatostatina y su derivado octreotide) actúan a nivel de la circulación esplácnica, disminuyendo el flujo sanguíneo. El tratamiento farmacológico tiene la ventaja de ser fácilmente administrado, incluso antes de realizar una endoscopia, toda vez que se sospecha una hemorragia variceal, lo que hace particularmente atractivo su uso en centros en que no se cuenta con endoscopia de urgencia. Actualmente, existe suficiente evidencia para recomendar el uso de estos fármacos como terapia adicional a la endoscopia ante la sospecha de una hemorragia variceal.

Effects of terlipressin and naloxone compared with epinephrine in a rat model of asphyxia-induced cardiac arrest

OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine. .

A eficácia da terlipressina versus adrenalina na ressuscitação cardiopulmonar em suínos / The efficacy of terlipressin versus adrenaline in swine cardiopulmonary resuscitation / La eficacia de la terlipresina versus adrenalina en la resucitación cardiopulmonar en cerdos

JUSTIFICATIVA E OBJETIVOS: O objetivo deste estudo foi avaliar a eficácia da terlipressina (TP) versus adrenalina (ADR) em aumentar a pressão de perfusão coronariana (PPC) e o retorno da circulação espontânea (RCE) na RCP em suínos. MÉTODOS: Sob anestesia cetamina/tiopental, induziu-se fibrilação ventricular em 44 porcos fêmeas imaturos, permanecendo não assistida por 10 min, seguidos de 2 min de RCP-manual (100 compressões/10 ventilações/min com ar). Os animais foram então alocados em quatro grupos, recebendo: 1) ADR (45 µg.kg-1); 2) salina-placebo (10 mL); 3) TP (20 µg.kg-1); 4) TP (20 µg.kg-1) + ADR (45 µg.kg-1). Desfibrilação foi realizada 2 min após, observando-se os animais sobreviventes por um período de 30 min. ECG, PA sistêmica, PAD e PetCO2 foram monitorados continuamente. RESULTADOS: A TP não diferiu do placebo quanto aos efeitos na PPC, com baixas taxas de RCE em ambos os grupos (1/11 vs.2/11; p = NS). A ADR aumentou a PPC de 13 ± 12 para 54 ± 15 mmHg (p < 0,0001), efeito similar a TP + ADR (de 21 ± 10 para 45 ± 13 mmHg; p < 0,0001), com altas taxas de RCE/sobreviventes em ambos os grupos (10/11 vs.9/11, respectivamente). Entre os sobreviventes, maior PAM foi observada no grupo TP + ADR vs.ADR (105 ± 19 mmHg vs.76 ± 21 mmHg; p = 0,0157). CONCLUSÕES: ADR e TP + ADR foram efetivas para aumentar a PPC/RCE neste modelo experimental, mas a TP, isolada, não foi diferente do placebo. Contudo, nos animais sobreviventes do grupo TP + ADR observou-se maior estabilidade hemodinâmica após a RCE, sugerindo que a TP possa ser uma medicação útil no manuseio da hipotensão pós-RCP.

BACKGROUND AND OBJECTIVES: The objective of the present study was to evaluate the efficacy of terlipressin (TP) vs.adrenaline (ADR) in increasing coronary perfusion pressure (CPP) and return of spontaneous circulation (ROSC) in swine CPR. METHODS: Under anesthesia with ketamine/thiopental, ventricular fibrillation was induced in 44 female immature pigs, remaining unassisted for 10 minutes, followed by 2 minutes of manual CPR (100 compression/10 ventilations/min with air). Animals were, then, divided into four groups: 1) ADR (45 µg.kg-1); 2) saline-placebo (10 mL); 3) TP 20 µg.kg-1); and TP (20 µg.kg-1) + ADR (45 µg.kg-1). Defibrillation was performed after 2 minutes, observing surviving animals for a 30-minute period. Electrocardiogram, systemic BP, DBP, and PetCO2 were monitored continuously. RESULTS: Terlipressin did not differ from placebo regarding the effects on CPP, with low rates of ROSC in both groups (1/11 vs.2/11; p = NS). Adrenaline increased CPP from 13 ± 12 to 54 ± 15 mmHg (p < 0.0001), similar effect to TP + ADR (from 21 ± 10 to 45 ± 13 mmHg; p < 0.0001), with high rates of ROSC/survivors in both groups (10/11 vs.9/11, respectively). Among survivors, greater MAP was observed in the TP + ADR group vs.ADR (105 ± 19 mmHg vs.76 ± 21 mmHg; p = 0.0157) groups. CONCLUSIONS: Adrenaline and TP + ADR were effective on maintaining CPP/ROSC in this experimental model, but isolated TP did not differ from placebo. However, in surviving animals in the TP + ADR group, greater hemodynamic stability was observed after ROSC, suggesting that TP can be a useful medication in the management of post-CPR hypotension.

JUSTIFICATIVA Y OBJETIVOS: El objetivo de este estudio fue evaluar la eficacia de la terlipresina (TP) versus adrenalina (ADR) en aumentar la presión de perfusión coronaria (PPC) y el retorno de la circulación espontánea (RCE) en la RCP en cerdos. MÉTODOS: Bajo la anestesia ketamina/tiopental, se indujo la fibrilación ventricular en 44 cerdos hembras no adultos, permaneciendo no asistida por 10 min, seguidos de 2 min de RCP-manual (100 compresiones/10 ventilaciones/min con aire). Los animales se ubicaron entonces en cuatro grupos, recibiendo: 1) ADR (45 µg.kg-1); 2) salina-placebo (10 mL); 3) TP (20 µg.kg-1); 4) TP (20 µg.kg-1) + ADR (45 µg.kg-1). La desfibrilación fue realizada 2 min después, haciendo el seguimiento de los animales sobrevivientes por un período de 30 min. ECG, PA sistémica, PAD y PetCO2 fueron monitorizados continuamente. RESULTADOS: La TP no fue diferente del placebo en cuanto a los efectos en la PPC, con bajas tasas de RCE en ambos grupos (1/11 vs.2/11; p = NS). La ADR aumentó la PPC de 13 ± 12 para 54 ± 15 mmHg (p < 0,0001), efecto similar a TP + ADR (de 21 ± 10 para 45 ± 13 mmHg; p < 0,0001), con altas tasas de RCE/supervivientes en ambos grupos (10/11 vs.9/11, respectivamente). Entre los supervivientes, se observó una mayor PAM en el grupo TP + ADR vs.ADR (105 ± 19 mmHg vs.76 ± 21 mmHg; p = 0,0157). CONCLUSIONES: La ADR y TP + ADR fueron efectivas para aumentar la PPC/RCE en este modelo experimental, pero la TP aislada, no fue diferente del placebo. Sin embargo, en los animales supervivientes del grupo TP + ADR, vimos una mayor estabilidad hemodinámica después de la RCE, lo que nos indica que la TP puede ser una medicación útil en el manejo de la hipotensión post-RCP.

Efeitos hemodinâmicos e metabólicos da terlipressina ou naloxona na ressuscitação cardiopulmonar: estudo experimental, randomizado e controlado / Hemodynamic and metabolic effects of terlipressin or naloxone in cardiopulmonary resuscitation: an experimental, randomized and controlled trial

Introdução: O prognóstico da parada cardiorrespiratória (PCR) em ritmo não chocável (assistolia/atividade elétrica sem pulso) é ruim e não melhorou significativamente nas últimas décadas. Embora a epinefrina seja o vasopressor recomendado, há evidências de que ela eleva o consumo de oxigênio, reduz a pressão de perfusão subendocárdica, causa grave disfunção miocárdica e piora a microcirculação cerebral durante a ressuscitação cardiopulmonar. Vasopressina foi muito estudada nos últimos anos e não se mostrou superior à epinefrina. Naloxona e terlipressina têm sido cogitadas como potenciais vasopressores no tratamento da PCR, entretanto há poucos estudos publicados e os resultados são controversos e inconclusivos. Objetivos: Avaliar os efeitos hemodinâmicos e metabólicos da terlipressina ou naloxona na PCR induzida por hipóxia e compará-las com o tratamento-padrão (epinefrina ou vasopressina). Métodos: Estudo experimental, randomizado, cego e controlado. Ratos Wistar adultos, machos, foram anestesiados, submetidos a traqueostomia e ventilados mecanicamente. A PCR foi induzida por obstrução da traqueia e mantida por 3,5 minutos. Em seguida, os animais foram ressuscitados de forma padronizada e randomizados em um dos grupos: placebo (n = 7), vasopressina (n = 7), epinefrina (n = 7), naloxona (n = 7) ou terlipressina (n = 21). Variáveis hemodinâmicas foram monitorizadas durante todo o experimento (via cateter intra-arterial e intraventricular) e mensuradas na base, no 10o (T10), 20o (T20), 30o (T30), 45o (T45) e 60o (T60) minutos pós-PCR. Amostras de sangue arterial foram coletadas para gasometria, hemoglobina, bioquímica e lactato em quatro momentos [base, 11o (T11), 31o (T31), e 59o (T59) minutos pós-PCR]. Resultados: Os grupos foram homogêneos e não houve diferença significativa entre eles nas variáveis de base...

Introduction: The prognosis of cardiac arrest (CA) with nonshockable rhythm (asystole/pulseless electrical activity) is poor and not improved significantly in recent decades. Epinephrine is the most commonly used vasopressor, although there is evidence that its use correlates with myocardial dysfunction and worsens the cerebral microcirculation. Vasopressin has been widely studied in recent years and was not superior to epinephrine. Naloxone and terlipressin have been considered as potential vasopressors in the treatment of CA, however, there are few published studies and the results are controversial and inconclusive. Objectives: To evaluate the hemodynamic and metabolic effects of terlipressin or naloxone in CA induced by hypoxia and compare with standard treatment with epinephrine or vasopressin. Methods: Experimental, randomized, blinded and controlled trial. Adult male Wistar rats were anesthetized, the proximal trachea was surgically exposed, and a 14-gauge cannula was inserted 10 mm into the trachea to the larynx. They were mechanically ventilated and monitored. The CA was induced by tracheal obstruction and maintained for 3.5 minutes. Subsequently, the animals were resuscitated using standard maneuvers and randomized to one of groups: placebo (n=7), vasopressin (n=7), epinephrine (n=7), naloxone (n=7) or terlipressin (n=21). Hemodynamic variables were monitored throughout the study (intra-arterial and intra-ventricular catheter) and measured at baseline, in the 10th (T10), 20th (T20), 30th (T30), 45th (T45) and 60th (T60) minute post-cardiac arrest. Arterial blood samples were collected for hemoglobin, biochemistry, blood gases and lactate at four moments: baseline, 11th (T11), 31st (T31) and 59th (T59) minute post-cardiac arrest. Results: The groups were homogenous and there were no significant differences among them regarding the baseline variables. The return of spontaneous circulation (ROSC) occurred in 57% of the animals (4 of 7) in the placebo...

Poor outcomes with treatment of hepatorenal syndrome type 1 with splancnic vasoconstrictors and albumin: report of seven cases and review of the literature / Resultados adversos com o emprego de vasoconstritores esplâncnicos e albumina para tratamento da síndrome hepatorrenal do tipo 1: relato de sete casos e revisão da literatura

CONTEXT: Treatment of hepatorenal syndrome type 1 (HRS-1) with splancnic vasoconstrictors and high-dose albumin has been associated with reversal of renal failure in approximately 60 percent to 80 percent of the cases in pilot or uncontrolled studies. OBJECTIVE: To evaluate the results of treatment of HRS-1 with terlipressin and high-dose albumin. METHODS: All patients with HRS-1 that underwent treatment with terlipressin and high-dose albumin at our unit were retrospectively reviewed. Outcomes including reversal of renal failure and death were recorded and compared to baseline clinical and laboratory parameters. RESULTS: Seven subjects (median age 64 [47-69] years, 5 males) with median Child-Pugh and MELD scores of 12 [10-15] and 22 [17-38], respectively, hospitalized with decompensated chronic liver disease secondary to tense ascitis and infections, who exhibited criteria for HRS-1, were submitted to therapy with terlipressin and high-dose albumin according to a predefined standard protocol. Baseline creatinine levels were 2.9 [2.3-4.0] mg/mL. None of the patients achieved reversal of HRS-1 and five subjects died on-treatment due to sudden-death (n = 1), multiple organ dysfunction associated with end-stage liver failure (n = 2) and sepsis (n = 2). CONCLUSIONS: Treatment of HRS-1 with terlipressin and high-dose albumin was not associated with reversal of renal failure, but most of the treated subjects had severe end-stage liver disease with high MELD scores as well as high baseline creatinine values, parameters previously associated with bad outcomes.

CONTEXTO: O tratamento da síndrome hepatorrenal do tipo 1 (SHR-1) com vasoconstritores esplâncnicos e albumina intravenosa tem se associado, em relatos de caso e estudos piloto não-controlados, à reversão da insuficiência renal em 60 por cento-80 por cento dos pacientes tratados. OBJETIVO: Avaliar os resultados do tratamento da SHR-1 com terlipressina e albumina. MÉTODOS: Foram avaliados, retrospectivamente, todos os pacientes hospitalizados com o diagnóstico de SHR-1 que se submeteram a tratamento com terlipressina associada à albumina em altas doses. As frequências de reversão de insuficiência renal e óbito foram comparados com parâmetros clínicos e laboratoriais pré-tratamento. RESULTADOS: Sete pacientes (5 homens, idade mediana 64 [47-69] anos) com mediana de pontuação Child-Pugh e MELD respectivamente de 12 [10-15] e 22 [17-38], admitidos na unidade de terapia intensiva por desconforto respiratório secundário à ascite tensa ou por infecções, que apresentaram critérios para SHR-1 e eligibilidade para o transplante de fígado foram submetidos a tratamento com terlipressina e albumina, de acordo com protocolo pré-definido. Níveis de creatinina prévios ao tratamento foram de 2.9 [2.3-4.0] mg/mL. Nenhum paciente apresentou reversão da SHR-1 e cinco faleceram por morte súbita (n = 1), disfunção de múltiplos órgãos associada a falência hepática (n = 2) e sepse (n = 2), a maioria antes de completar o tratamento. CONCLUSÕES: O tratamento da SHR-1 com terlipressina e albumina, em altas doses, não foi associado à reversão da insuficiência renal em nenhum dos pacientes tratados, mas a maioria dos pacientes apresentava doença hepática em fase avançada, com altos valores de MELD, e níveis elevados de creatinina pré-tratamento, parâmetros previamente associados com pior resposta e prognóstico mais reservado.

Hyperkalemia accompanies hemorrhagic shock and correlates with mortality

OBJECTIVE: This study was designed to evaluate the effects of terlipressin versus fluid resuscitation with normal saline, hypertonic saline or hypertonic-hyperoncotic hydroxyethyl starch, on hemodynamics, metabolics, blood loss and short-term survival in hemorrhagic shock. METHOD: Twenty-nine pigs were subjected to severe liver injury and treated 30 min later with either: (1) 2 mg terlipressin in a bolus, (2) placebo-treated controls, (3) 4 mL/kg 7.5% hypertonic NaCl, (4) 4 mL/kg 7.2% hypertonic-hyperoncotic hydroxyethyl starch 200/0.5, or (5) normal saline at three times lost blood volume. RESULTS: The overall mortality rate was 69%. Blood loss was significantly higher in the hypertonic-hyperoncotic hydroxyethyl starch and normal saline groups than in the terlipressin, hypertonic NaCl and placebo-treated controls groups (p<0.005). Hyperkalemia (K>5 mmol/L) before any treatment occurred in 66% of the patients (80% among non-survivors vs. 22% among survivors, p=0.019). Post-resuscitation hyperkalemia occurred in 86.66% of non-survivors vs. 0% of survivors (p<0.001). Hyperkalemia was the first sign of an unsuccessful outcome for the usual resuscitative procedure and was not related to arterial acidemia. Successfully resuscitated animals showed a significant decrease in serum potassium levels relative to the baseline value. CONCLUSION: Hyperkalemia accompanies hemorrhagic shock and, in addition to providing an early sign of the acute ischemic insult severity, may be responsible for cardiac arrest related to hemorrhagic shock.

Treatment of active gastroesophageal variceal bleeding with terlipressin or hemostatic ballon in patients with cirrhosis. A randomized controlled trial

Gastroesophageal variceal bleeding due to portal hypertension should be treated by endoscopic sclerotherapy. This procedure, however, has some limitations. It has been established that vasoactive drugs are effective for controlling active variceal bleeding. We report the results of a randomized contolled trial comparing terlipressin to hemostatic tube (Linton-Michel tube) for the treatment of bleeding gastroesophageal varices in cirrhotic patients. Thirty-seven cirrhotic patients with a total of 40 episodes of gastroesophageal variceal bleeding were included in this trial. Patients were randomly assigned to intravenous terlipressin or Linton-Michel tube (LM tube), for 24 h. During this period, hemostasis was defined as obtaining of hemodynamic and hematocrit stabilization and/or absence of hematemesis or melena. Bleeding recurrence was assessed during a 1-month period after treatment. Twenty bleeding episodes were treated with terlipressin (Group I) and 20 with LM tube (group II). Both groups of patients were similar in age, sex distribution, etiology of cirrhosis and degree of hepatic insufficiency. Bleeding was controlled in 70 percent of patients from Group I and in 95 percent from Group II (p<0.05) during treatment. Bleeding recurred in 14 percent of patients in Group I vs. 36 percent in Group II 1 week following the treatment (p>0.05) and in 16.6 percent in Group I vs. 83.3 percent in Group II 1 month after treatment (p<0.05). Mortality rate was similar in both groups 1 month after treatment. In conclusion, hemostatic tubes were superior to terlipressin for the control of active gastroesophageal variceal bleeding within the first 24 h. Complications and bleeding recurrence were more frequent in patients treated by hemostatic tube within a period of 1 month after treatment. Mortality rate was similar in both groups of patients

Diabetes insipidus em paciente com síndrome de Sheehan: relato de um caso / Diabetes insipidus in Sheehan's syndrome: case report

Os autores descrevem o caso de uma paciente de 44 anos com hipopituitarismo, diagnosticado 18 meses após o parto (Síndrome de Sheehan), Desde o início do quadro a paciente apresentava poliúria e polidipsia. Na prova de restriçäo hídrica, a osmolaridade máxima urinária foi de 400 m0sm, com aumento para 560 m0sm, após a administraçäo de lisina-vasopressina, confirmando o dianóstico de diabetes insipidus parcial. A terapêutica com hidroclortiazida promoveu regressäo dos sintomas

Niveis sericos de hormonio de crescimento na sindrome de Hunter / Serum growth hormone levels in Hunter's syndrome

Os niveis sericos de hormonio de crescimento (GH) foram estudados em tres irmaos com sindrome de Hunter (Mucopolissacaridose tipo II). A dinamica da secrecao do GH foi analisada por meio de testes com insulina (0,05 UI/Kg, i.v.), glicose (1,75 g/Kg, v.o.), lisina vasopressina (LPV) (5 ou 10 UI, i.m.) e L-Dopa (500 mg, v.o.). Os niveis basais de GH durante os quatro testes eram elevados (X = 14,2 ng/ml) nos tres casos. As respostas do GH ao estimulo com insulina e LPV mostraram tendencia a apresentar uma correlacao direta com a idade dos casos analisados, sendo maiores no paciente mais velho. Ao contrario dos dois outros casos, no teste com L-Dopa o paciente mais velho nao mostrou elevacao de niveis de GH. Apos administracao de glicose, os niveis de GH se deprimiram, como esperado nos tres casos. Como valores basais de cortisol e prolactina eram usualmente normais durante estes testes, nao se valorizou a hipotese de que o stress fosse o unico causador dos valores basais elevados de GH. Para tentar melhor esclarecer estes achados, dosaram-se os niveis de GH sob condicoes basais de 20-20 min., durante 120 min.; nos tres casos as medias destes valores de GH eram normais nos casos 1 e 3, enquanto tendiam a se elevar no caso 2. Valores da somatomedina-C eram normais-baixos nos tres casos...

Atrial natriuretic factors (ANF) and antidiuretic agents

Se demuesta que, en ratas anestesiadas y perfundidas con solución isotónica de glucosa, la administracíon i.v. previa de lisil-vasopresina, en dosis de 0.1 a 10 m, no inhibe la respuesta diurética y salurética del FNA (2.5 ug); en cambio, la dosis de 50 mU, que produce una elevación transitoria, pero acentuada de la presión arterial, intensifica el efecto del FNA. La pepsanurina obtenida de la hidrólisis de globulinas de 20 ml de plasma humano, administrada i.p., 40 a 60 m antes de la administración i.v. de FNA, produce una significativa inhibición de la respuesta diurética natriurética