Mulla Hussain, Lawson Graham, Peek Giles J, Firmin R K, Upton David R
University Hospitals of Leicester-De Montfort University, England.
ASAIO J. 2003 Jan-Feb;49(1):41-7. doi: 10.1097/00002480-200301000-00007.
Drug disposition is affected during extracorporeal membrane oxygenation (ECMO). This study investigates the dose-concentration relationship of midazolam in neonates requiring ECMO during continuous infusion into the circuit (extracorporeally; n = 10) and intravenously (n = 10). Data on hourly doses and sedation scores were collected for 120 hours. Plasma concentrations were analyzed at times 0, 2, 4, 6, 12, 18, and 24, and every 12 hours thereafter. Both groups were clinically similar. Mean (standard deviation) dose for all patients was 250 (185) microg/kg/h, four times greater than previously reported. Doses administered in the first 24 hours were significantly greater extracorporeally [361 (300)] compared with intravenous [258 (190) microg/kg/h, p < 0.001]. Mean (standard deviation) plasma concentrations in all patients at 24, 48, and 72 hours were 1.4 (0.9), 1.8 (1.2), and 2.6 (1.8) microg/ml, respectively. Satisfactory sedation levels were achieved in all patients. Comparison of the actual observed with predicted (simulated) midazolam concentrations suggested significant attenuation of plasma levels during the first 24 hours of ECMO. However, at 48 hours, observed concentrations exceeded those predicted, suggesting accumulation. We conclude that in the first 24 hours of ECMO, because of an expanded circulating volume and sequestration by the circuit, significantly more midazolam is required to achieve adequate sedation. Subsequently, and because of circuit saturation, maintenance doses should be reduced.
体外膜肺氧合（ECMO）期间药物处置会受到影响。本研究调查了咪达唑仑在需要ECMO的新生儿中，经体外回路持续输注（体外；n = 10）和静脉输注（n = 10）时的剂量-浓度关系。收集了120小时的每小时剂量和镇静评分数据。在0、2、4、6、12、18和24小时以及此后每12小时分析血浆浓度。两组在临床上相似。所有患者的平均（标准差）剂量为250（185）μg/kg/h，是先前报道的四倍。与静脉输注[258（190）μg/kg/h，p < 0.001]相比，前24小时体外给药剂量[361（300）]显著更高。所有患者在24、48和72小时的平均（标准差）血浆浓度分别为1.4（0.9）、1.8（1.2）和2.6（1.8）μg/ml。所有患者均达到了满意的镇静水平。实际观察到的与预测（模拟）的咪达唑仑浓度比较表明，在ECMO的前24小时血浆水平显著衰减。然而，在48小时时，观察到的浓度超过了预测值，表明有蓄积。我们得出结论，在ECMO的前24小时，由于循环容量扩大和回路中的隔离作用，需要显著更多的咪达唑仑才能达到充分镇静。随后，由于回路饱和，维持剂量应减少。
