Fluid volume kinetics of dilutional hyponatremia; a shock syndrome revisited.

OBJECTIVE: To evaluate whether the pathophysiology of shock syndromes can be better understood by comparing central hemodynamics with kinetic data on fluid and electrolyte shifts. METHODS: We studied the dilutional hyponatremic shock that developed in response to overhydration with electrolyte-free irrigating fluid - the so-called 'transurethral resection syndrome' - by comparing cardiac output, arterial pressures, and volume kinetic parameters in 17 pigs that were administered 150 ml/kg of either 1.5% glycine or 5% mannitol by intravenous infusion over 90 minutes. RESULTS: Natriuresis appeared to be the key factor promoting hypovolemic hypotension 15-20 minutes after fluid administration ended. Excessive sodium excretion, due to osmotic diuresis caused by the irrigant solutes, was associated with high estimates of the elimination rate constant (k10) and low or negative estimates of the rate constant describing re-distribution of fluid to the plasma after translocation to the interstitium (k21). These characteristics indicated a high urinary flow rate and the development of peripheral edema at the expense of plasma volume and were correlated with reductions in cardiac output. The same general effects of natriuresis were observed for both irrigating solutions, although the volume of infused 1.5% glycine had a higher tendency to enter the intracellular fluid space. CONCLUSION: Comparisons between hemodynamics and fluid turnover showed a likely sequence of events that led to hypovolemia despite intravenous administration of large amounts of fluid.

Fluid volume kinetics of dilutional hyponatremia; a shock syndrome revisited

OBJECTIVE: To evaluate whether the pathophysiology of shock syndromes can be better understood by comparing central hemodynamics with kinetic data on fluid and electrolyte shifts. METHODS: We studied the dilutional hyponatremic shock that developed in response to overhydration with electrolyte-free irrigating fluid - the so-called ‘transurethral resection syndrome' - by comparing cardiac output, arterial pressures, and volume kinetic parameters in 17 pigs that were administered 150 ml/kg of either 1.5% glycine or 5% mannitol by intravenous infusion over 90 minutes. RESULTS: Natriuresis appeared to be the key factor promoting hypovolemic hypotension 15-20 minutes after fluid administration ended. Excessive sodium excretion, due to osmotic diuresis caused by the irrigant solutes, was associated with high estimates of the elimination rate constant (k10) and low or negative estimates of the rate constant describing re-distribution of fluid to the plasma after translocation to the interstitium (k21). These characteristics indicated a high urinary flow rate and the development of peripheral edema at the expense of plasma volume and were correlated with reductions in cardiac output. The same general effects of natriuresis were observed for both irrigating solutions, although the volume of infused 1.5% glycine had a higher tendency to enter the intracellular fluid space. CONCLUSION: Comparisons between hemodynamics and fluid turnover showed a likely sequence of events that led to hypovolemia despite intravenous administration of large amounts of fluid. .

Hemodynamic effects of mannitol infusion in patients with acute intracerebral hemorrhage.

PURPOSE: To evaluate hemodynamic effects of mannitol infusion in patients with acute intracerebral hemorrhage. METHODS: Thirty patients with acute intracerebral hemorrhage were enrolled. Transcranial doppler was used to detect variables of bilateral middle cerebral arteria (MCA) including mean velocity (Vm) and pulsitility index (PI) before and after 125 ml and 250 ml mannitol infusion (0, 30, 60, 90, 120, 180, 240 min). RESULTS: When 125 ml or 250 ml mannitol was infused in patients with acute intracerebral hemorrhage, Vm of bilateral MCA elevated, and reached the top at 30 min, and then decreased. PI decreased in the affected MCA (250 ml) and in the unaffected MCA (125 ml and 250 ml). CONCLUSION: Mannitol infusion in patients with acute intracerebral hemorrhage can improve cerebral blood flow in bilateral hemispheres and decrease intracranial pressure in the hemorrhagic hemisphere (250 ml) and in the nonhemorrhagic hemisphere (125 ml and 250 ml).

Hemodynamic effects of mannitol infusion in patients with acute intracerebral hemorrhage

PURPOSE: To evaluate hemodynamic effects of mannitol infusion in patients with acute intracerebral hemorrhage. METHODS: Thirty patients with acute intracerebral hemorrhage were enrolled. Transcranial doppler was used to detect variables of bilateral middle cerebral arteria (MCA) including mean velocity (Vm) and pulsitility index (PI) before and after125ml and 250ml mannitol infusion (0, 30, 60, 90, 120, 180, 240 min). RESULTS: When 125ml or 250ml mannitol was infused in patients with acute intracerebral hemorrhage, Vm of bilateral MCA elevated, and reached the top at 30min, and then decreased. PI decreased in the affected MCA (250ml) and in the unaffected MCA (125ml and 250ml). CONCLUSION: Mannitol infusion in patients with acute intracerebral hemorrhage can improve cerebral blood flow in bilateral hemispheres and decrease intracranial pressure in the hemorrhagic hemisphere (250ml) and in the nonhemorrhagic hemisphere (125ml and 250ml).

Inhaled mannitol in patients with cystic fibrosis: A randomised open-label dose response trial.

BACKGROUND: Cystic fibrosis (CF) is characterised by impaired mucociliary clearance (MCC), chronic inflammation and infection, and progressively deteriorating lung function. Inhaled mannitol (Bronchitol) has been shown to increase MCC and cough clearance and FEV(1) in CF patients, contributing to better lung hygiene and consequently a slower decline in lung function. This study was designed to determine the dose relationship of mannitol treatment and improvement in FEV(1) and FVC as well as safety. METHODS: This was a randomised, open-label, crossover, dose response study. Following a 2-week treatment with mannitol 400mg b.i.d., 48 CF patients with a mean (SD) FEV(1) % predicted of 64 (13.2), received a further 3 treatments with 40mg, 120mg or 240mg b.i.d. for 2weeks each, in random order. RESULTS: The study demonstrated a dose dependent increase in FEV(1) and FVC. The 400mg dose showed the greatest improvement and the 40mg dose had no discernible effect. The mean percent change in FEV(1) was -1.57%, 3.61%, 3.87% and 8.75% respectively for the 40mg, 120mg, 240mg and 400mg treatments. There was a statistically significant change in FEV(1) for 400mg compared to 40mg (p<0.0001) but the difference with 120mg and 240mg did not reach significance. The mean % change in FVC was -0.90, 1.74, 3.07 and 8.14, for the 40mg, 120mg, 240mg and 400mg treatment arms, with p=0.0001, p=0.0037 and p=0.0304 respectively when compared to 400mg. The highest tested dose of 400mg had a similar safety profile to the other doses tested. The change in FEV(1) and FVC by dose in the paediatric age group (<18years) was similar to the results in the adult population. CONCLUSION: Based on these results the 400mg b.i.d. dose has been further studied in phase III trials.

[Usefulness of sublingual isosorbide to assess the reversibility of pulmonary hypertension in cardiac transplant candidates]. / Utilidad de isosorbide sublingual en la reversibilidad de la hipertensión pulmonar reactiva, en pacientes candidatos a trasplante cardíaco.

BACKGROUND: Continuous infusion of short life vasodilators are employed to test reversibility of pulmonary hypertension in cardiac transplant candidates. Sublingual isosorbide administration has not been described in the literature and it might be a simpler alternative. AIM: To evaluate sublingual isosorbide administration as a test of reversibility of pulmonary hypertension in heart failure. PATIENTS AND METHODS: Prospective evaluation of patients referred for cardiac transplant evaluation. Patients underwent right catheterization for hemodynamic measurements at baseline and after repeated doses of 5 mg sublingual isosorbide every 5 minutes until observing a decrease in pulmonary vascular resistance decrease or symptomatic hypotension. RESULTS: Twenty one patients, 18 men, age 49+/-15 years, were studied. Fourteen (66%) were transplanted. The mean sublingual isosorbide dose was 15+/-5 mg. After isosorbide administration, there was a significant decrease in mean arterial pressure (80+/-8.5 to 71+/-6.6 mmHg, p <0.0001), mean pulmonary artery pressure (38+/-11 to 26+/-7.8 mmHg, p <0.0001), systemic vascular resistance (1540+/-376 to 1277+/-332 dyn*s/cm5 p <0.001), pulmonary vascular resistance (3.5+/-2.2 to 2,5+/-1.6 Wood Units, p <0.05) and transpulmonary gradient (13+/-7 a 10+/-4 mmHg, p <0.004). The cardiac output increased from 3.96+/-0.7 to 4.38+/-0.9 L/min, p=0.05. The relation between pulmonary and systemic vascular resistance before and after isosorbide was 0.17 and 0.15, respectively (p=0.04). One transplanted patient with partial reversibility of pulmonary hypertension developed acute right heart failure. CONCLUSIONS: Sublingual isosorbide administration is useful and well tolerated to evaluate the reversibility of pulmonary hypertension prior cardiac transplant.

Utilidad de isosorbide sublingual en la reversibilidad de la hipertensión pulmonar reactiva, en pacientes candidatos a trasplante cardíaco / Usefulness of sublingual isosorbide to assess the reversibility of pulmonary hypertension in cardiac transplant candidates

Background: Continuous infusion of short life vasodilators are employed to test reversibility of pulmonary hypertension in cardiac transplant candidates. Sublingual isosorbide administration has not been described in the literature and it might be a simpler alternative. Aim: To evaluate sublingual isosorbide administration as a test of reversibility of pulmonary hypertension in heart failure. Patients and Methods: Prospective evaluation of patients referred for cardiac transplant evaluation. Patients underwent right catheterization for hemodynamic measurements at baseline and after repeated doses of 5 mg sublingual isosorbide every 5 minutes until observing a decrease in pulmonary vascular resistance decrease or symptomatic hypotension. Results: Twenty one patients, 18 men, age 49±15 years, were studied. Fourteen (66%) were transplanted. The mean sublingual isosorbide dose was 15±5 mg. After isosorbide administration, there was a significant decrease in mean arterial pressure (80±8.5 to 71±6.6 mmHg, p <0.0001), mean pulmonary artery pressure (38±11 to 26±7.8 mmHg, p <0.0001), systemic vascular resistance (1540±376 to 1277±332 dyn*s/cm5 p <0.001), pulmonary vascular resistance (3.5±2.2 to 2,5±1.6 Wood Units, p <0.05) and transpulmonary gradient (13±7 a 10±4 mmHg, p <0.004). The cardiac output increased from 3.96±0.7 to 4.38±0.9 L/min, p=0.05. The relation between pulmonary and systemic vascular resistance before and after isosorbide was 0.17 and 0.15, respectively (p=0.04). One transplanted patient with partial reversibility of pulmonary hypertension developed acute right heart failure. Conclusions: Sublingual isosorbide administration is useful and well tolerated to evaluate the reversibility of pulmonary hypertension prior cardiac transplant.

Successful use of the new high-dose mannitol treatment in patients with Glasgow Coma Scale scores of 3 and bilateral abnormal pupillary widening: a randomized trial.

OBJECT: The authors evaluated long-term clinical outcomes in selected acutely comatose patients with severe diffuse brain swelling and recent clinical signs of impending brain death who received a novel high-dose mannitol treatment compared with those who received conventional-dose mannitol in the emergency room. METHODS: Forty-four adult patients with traumatic, nonmissile-inflicted, acute, severe diffuse brain swelling were prospectively and randomly evaluated. All patients were selected based on the presence of recent clinical signs of impending brain death on the first emergency room evaluation. These signs included bilateral abnormal pupillary widening and lack of motor responses to painful stimulation (Glasgow Coma Scale score of 3). The study group (23 patients) received ultra-early and fast intravenous high-dose mannitol treatment (approximately 1.4 g/kg), whereas the control group (21 patients) received half that dose (approximately 0.7 g/kg). Ultra-early improvement of bilateral abnormal pupillary widening was significantly more frequent in the high-dose mannitol group than in the conventional-dose group (p < 0.02). High-dose mannitol treatment in the emergency room was also associated with significantly better 6-month clinical outcomes (p < 0.02); the best rate of favorable outcomes was 43.5%, compared with only 9.5% in the conventional-dose mannitol group. The two groups of patients were well matched with respect to all emergency room and head computerized tomography findings, as well as the timing of initial mannitol treatment (approximately 80-90 minutes after the first evaluation at the scene of the injury). Comparative evaluation of bilateral pupillary widening between the scene of the injury and the emergency room showed no significant differences between groups, whereas mannitol dose dependence was statistically significant (p < 0.05), insofar as early pupillary improvement in the emergency room was concerned. CONCLUSIONS: Ultra-early high-dose mannitol administration in the emergency room is the first known treatment strategy significantly to reverse recent clinical signs of impending brain death, and also to contribute directly to improved long-term clinical outcomes for these patients who have previously been considered unsalvageable.

Effects of mannitol on the acute lung injury induced by oleic acid in rats.

Our purpose was to evaluate the pulmonary effects of mannitol infusion in a rat model of acute lung injury induced by oleic acid (OA) to compare the effects of mannitol to those of another diuretic, furosemide (FUR), and to assess if mannitol effects remained after correction of the volume depletion induced by this agent. Acute lung injury was induced in Wistar rats by intravenous administration of 100 mg/kg of OA. Mannitol (1 mL of a 20% solution) was infused either 15 min before or 2 h after OA infusion. FUR was infused intravenously in a dose (1 mg/kg) that induced a similar amount of diuresis compared to mannitol. We also studied rats that received NaCl 0.9% infusion to correct for volume losses induced by mannitol. The severity of the acute lung injury was evaluated by morphometric studies of the lungs 4 h after OA infusion. The amount of intraalveolar fluid accumulation and the intensity of alveolar distention and collapse were evaluated. Mannitol infusion either 15 min before or 2 h after OA administration resulted in a significant decrease in the amount of intraalveolar edema and alveolar distention and collapse (P < 0.001). FUR administration before OA infusion had an effect similar to mannitol. We did not observe any significant effect of mannitol when the rats received saline infusion to correct for diuresis induced by mannitol. We conclude that mannitol decreases the severity of pulmonary injury induced by OA in rats. This effect is mainly due to its diuretic properties.

Isosorbide aerosol: an option for the treatment of hypertensive crises.

In this study the authors assessed the effectiveness and safety of isosorbide dinitrate aerosol administered through the oral mucosa in 30 adult patients who presented with a hypertensive crisis (mean arterial pressure > 130 mm Hg and evidence of target organ damage). The patients were given a first dose of 1.25 mg of aerosol when they were admitted to the hospital; a second dose was administered 15 minutes later if the mean arterial pressure had not decreased by > 15%. An electrocardiogram (ECG) was obtained for every patient immediately prior to and 30 minutes after administration of the medication. Nine patients (30%) had a good response with one dose, whereas 21 patients (70%) required a second dose. All 30 patients had a significant reduction of the arterial blood pressure (187+/-13 / 121+/-6.6 to 153+/-15.3 / 92.3+/-7.6 mm Hg; p<0.005) as well as of the mean arterial pressure (136.6+/-8 to 109.5+/-7 mm Hg; p<0.005) in a period of 30 minutes. No adverse effects, rebound hypertension, or severe hypotension were observed. These figures remained under control for 6 hours. Two of the patients had angina pectoris at admission and their ECG showed subepicardial ischemia, both of which disappeared with the medication. A second ECG appeared normal. A reduction of 14% in heart rate was obtained (95+/-15 to 82+/-14 beats per minute; p<0.005). These observations suggest that isosorbide dinitrate aerosol is an effective and safe alternative for the treatment of patients with hypertensive crises.

[Efficacy of isosorbide in aerosol form in the management of hypertensive crisis in severe preeclampsia]. / Eficacia del isosorbide en aerosol en el manejo de la crisis hipertensiva de la preeclampsia severa.

In this assay, we evaluated the utility of isosorbide given by a sprayer in the management of hypertensive crisis of severe preeclampsia. 36 pregnant women with severe preeclampsia received fluid therapy and were randomly dividend in two groups of 18 patients each. Group A, received isosorbide in spray 1.25 mg when admitted and a second dose 10 minutes after if mean arterial blood pressure decreased less than 15%. and group B, in whom 4 g of magnesium sulphate was infused in one hour and then 1 g each hour for a maximum of five hours. In all patients blood pressure, proteinuria, fetal and maternal heart rate and Apgar score at minute and five minutes were obtained. In Group A 13 patients had a significative blood pressure reduction with one application and 5 needed a second one (p < 0.002). fetal (p < 0.005), and maternal (p < 0.005) heart rate also had a significative reduction. Whereas three patients in Group B did not respond and the rest had a poor blood pressure control (p > 0.05) with no changes in fetal and maternal heart rate. No patient developed eclampsia. When compared both groups, there were a significative difference for blood pressure (p < 0.005), fetal heart rate (p < 0.002), maternal heart rate (p < 0.05) and Apgar at minute (p < 0.01) in isosorbide's group. Our data suggest that isosorbide given by a sprayer is effective and safer in the management of the hypertensive crisis of severe preeclampsia.

Eficacia del isosorbide en aerosol en el manejo de la crisis hipertensiva de la preeclampsia severa / Efficancy of isosorbide in aerosol in the management of hypertensive crisis of severe preeclampsia

En un estudio clínico aleatorizado se evaluaron 36 pacientes con preclampsia severa divididos en dos grupos de 18 pacientes c/u. Grupo A: Recibieron 1.25 mg de isosorbide en aerosol oral al ingreso, repitiéndose la dosis a los 10 minutos si la reducción en la presión arterial media fue < 15 por ciento, Grupo B: Recibieron sulfato de magnesio en infusión continua intravenosa, 4 g la primera hora y después un gramo por hora durante cinco horas. En ambos grupos se administró terapia con líquidos parenterales y se vigiló con monitor la presión arterial desde el ingreso, se determinó frecuencia cardiaca materna (FCM), fetal (FCF) y proteinuria antes y después del fármaco, así como el Apgar del producto al minuto y a los cinco minutos. El grupo A presentó disminución significativa de la presión arterial (p<0.0002), FCM (p<0.005), FCF (p<0.05), 13 pacientes con una aplicación y cinco con dos. En el grupo B tres pacientes no respondieron, y el resto tuvo un mal control de la presión arterial (p>0.05), sin cambios en FCM. FCM y proteinuria. En ningún caso hubo progresión a eclampsia. Al comparar ambos grupos entre sí, hubo una diferencia significativa para la presión arterial (<0.005), FCM (p<0.05), FCF (p<0.002) y Apgar al minuto (p<0.01) en el grupo con isosorbide. Los datos sugieren que el isosorbide es eficaz y seguro en el manejo de la preeclampsia severa

Manitol- fundamentos para sua utilizaçäo / Mannitol- reasons for its utilization

O diurético osmótico manitol é uma droga amplamente utilizada em neurociruriga e neurologia a fim de diminuir a pressäo intracraniana e melhorar a microcirculaçäo cerebral. As teorias sobre seu mecanismo de açäo säo revisadas: gradiente osmótico pela barreira hematoencefálica, auto-regulaçäo vascular e neutralizaçäo dos radicais livres do oxigênio. Sua posologia é empírica, segunda a experiência própria de cada autor. O conhecimento dos critérios básicos para o uso do manitol e de sua reposiçäo hidreletrolítica é fundamental para a manutençäo da osmolaridade sérica em valores terapêuticos