Segar J L, Robillard J E, Johnson K J, Bell E F, Chemtob S
Department of Pediatrics, University of Iowa, Iowa City.
J Pediatr. 1992 Jun;120(6):966-73. doi: 10.1016/s0022-3476(05)81972-9.
A decreased response to the loop diuretic furosemide develops within a few doses in young infants. We tested the hypothesis that the use of the thiazide-like diuretic metolazone, in combination with furosemide, would inhibit water and electrolyte reabsorption and overcome pharmacologic tolerance to furosemide alone. Infants with bronchopulmonary dysplasia of similar gestational and postnatal ages were randomly assigned to one of three groups. Group 1 (n = 6) received furosemide (1 mg/kg per dose) intravenously every 24 hours for a total of five doses. Group 2 (n = 8) received the same treatment as group 1, but in addition metolazone (0.2 mg/kg per dose) was given enterally with doses 3 and 4 of furosemide. Group 3 (n = 8) received metolazone (0.2 mg/kg per dose) enterally every 24 hours for five doses. Urine was collected before the first diuretic dose and throughout the study for determination of the urine flow rate; urinary excretion of sodium, chloride, and potassium; and creatinine clearance. Urinary flow rate and urinary sodium and chloride excretion increased after the first dose in all groups. In the infants treated with either furosemide or metolazone, urinary flow rate and urinary and chloride excretion returned to baseline values after the last three doses. In contrast, when furosemide was administered with metolazone, urinary flow rate and urinary excretion of sodium, chloride, and potassium were greater than the values for baseline and for the previous dose, as well as for the corresponding doses of furosemide in group 1 and metolazone in group 3. Tolerance to furosemide (group 1) and metolazone (group 3) appeared to be explained by compensatory increased sodium and chloride reabsorption without changes in creatinine clearance. We conclude that the administration of metolazone with furosemide enhances diuresis, natriuresis, and chloruresis and overcomes the rapid development of tolerance to furosemide in infants with bronchopulmonary dysplasia by blocking the compensatory increase in renal sodium and chloride absorption.
在小婴儿中，连续几次使用袢利尿剂呋塞米后，机体对其反应会减弱。我们检验了这样一个假设：使用噻嗪类利尿剂美托拉宗联合呋塞米，会抑制水和电解质的重吸收，并克服单独使用呋塞米时产生的药物耐受性。将孕周和出生后年龄相近的支气管肺发育不良婴儿随机分为三组。第1组（n = 6）每24小时静脉注射呋塞米（每剂1 mg/kg），共注射五剂。第2组（n = 8）接受与第1组相同的治疗，但在第3剂和第4剂呋塞米给药时，额外经肠道给予美托拉宗（每剂0.2 mg/kg）。第3组（n = 8）每24小时经肠道给予美托拉宗（每剂0.2 mg/kg），共五剂。在首次给予利尿剂之前以及整个研究过程中收集尿液，以测定尿流率、尿钠、氯和钾的排泄量以及肌酐清除率。所有组在首次给药后尿流率以及尿钠和氯排泄量均增加。单独接受呋塞米或美托拉宗治疗的婴儿，在最后三剂给药后，尿流率以及尿和氯排泄量恢复至基线值。相比之下，当呋塞米与美托拉宗联合使用时，尿流率以及尿钠、氯和钾排泄量均高于基线值、前一剂的值，也高于第1组中呋塞米相应剂量的值以及第3组中美托拉宗相应剂量的值。对呋塞米（第1组）和美托拉宗（第3组）的耐受性似乎是由钠和氯重吸收的代偿性增加所解释的，而肌酐清除率并无变化。我们得出结论，美托拉宗与呋塞米联合使用可增强利尿、利钠和利氯作用，并通过阻断肾脏钠和氯吸收的代偿性增加，克服支气管肺发育不良婴儿对呋塞米耐受性的快速发展。
