Department of Emergency Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX.
Medical Toxicology, San Antonio Military Medical Center, San Antonio, TX.
Ann Emerg Med. 2016 Feb;67(2):196-205.e3. doi: 10.1016/j.annemergmed.2015.05.028. Epub 2015 Jul 9.
Diphenhydramine is a moderately lipophilic antihistamine with sodium channel blockade properties. It is consumed recreationally for mild hallucinogenic and hypnotic effects and causes dysrhythmias, seizures, and death with overdose. Intravenous lipid emulsion is a novel agent used to treat lipophilic drug overdose. Two case reports describe clinical improvement with intravenous lipid emulsion after diphenhydramine toxicity, but no prospective studies have been reported. Our objective is to determine whether intravenous lipid emulsion improved hypotension compared with sodium bicarbonate for severe diphenhydramine toxicity in a model of critically ill swine.
Twenty-four swine weighing 45 to 55 kg were infused with diphenhydramine at 1 mg/kg per minute until the mean arterial pressure reached 60% of baseline. Subjects were randomized to receive intravenous lipid emulsion (bolus of 7 mL/kg and then 0.25 mL/kg per minute) or sodium bicarbonate (2 mEq/kg plus an equal volume of normal saline solution). We measured pulse rate, systolic blood pressure, mean arterial pressure, cardiac output, QRS interval, and serum diphenhydramine level. Twelve animals per group provided a power of 0.8 and α of .05 to detect a 50% difference in mean arterial pressure. We assessed differences between groups with a repeated-measures linear model (MIXED) and Kaplan-Meier estimation methods. We compared systolic blood pressure, mean arterial pressure, and cardiac output with repeated measures ANOVA.
Baseline weight, hemodynamic parameters, QRS interval, time to hypotension, and diphenhydramine dose required to achieve hypotension were similar between groups. After hypotension was reached, there was no overall difference between intravenous lipid emulsion and sodium bicarbonate groups for cardiac output or QRS intervals; however, there were transient differences in mean arterial pressure and systolic blood pressure, favoring intravenous lipid emulsion (difference: mean arterial pressure, sodium bicarbonate versus intravenous lipid emulsion -20.7 [95% confidence interval -31.6 to -9.8]; systolic blood pressure, sodium bicarbonate versus intravenous lipid emulsion -24.8 [95% confidence interval -37.6 to -12.1]). Time to death was similar. One intravenous lipid emulsion and 2 sodium bicarbonate pigs survived. End-of-study mean total serum diphenhydramine levels were similar. The mean lipid layer diphenhydramine level was 6.8 μg/mL (SD 3.1 μg/mL) and mean aqueous layer level 8.6 μg/mL (SD 5.5 μg/mL).
In our study of diphenhydramine-induced hypotensive swine, we found no difference in hypotension, QRS widening, or diphenhydramine levels in aqueous layers between intravenous lipid emulsion and sodium bicarbonate.
苯海拉明是一种中等亲脂性抗组胺药，具有钠通道阻滞作用。它被人们当作轻度致幻和催眠作用的消遣性药物来使用，过量使用会导致心律失常、癫痫发作和死亡。静脉内用脂肪乳剂是一种新型药物，用于治疗亲脂性药物过量。有两份病例报告描述了苯海拉明中毒后使用静脉内用脂肪乳剂后临床症状改善，但没有报告前瞻性研究。我们的目的是确定在重症猪模型中，与碳酸氢钠相比，静脉内用脂肪乳剂是否能改善严重苯海拉明中毒引起的低血压。
24 头体重 45 至 55 公斤的猪以 1 毫克/千克/分钟的速度输注苯海拉明，直到平均动脉压降至基线的 60%。将受试者随机分为静脉内用脂肪乳剂（7 毫升/千克的负荷量，然后是 0.25 毫升/千克/分钟）或碳酸氢钠（2 毫当量/千克，加等量生理盐水）。我们测量脉搏率、收缩压、平均动脉压、心输出量、QRS 间隔和血清苯海拉明水平。每组 12 只动物提供了 0.8 的功效和.05 的 α，以检测平均动脉压差异的 50%。我们使用重复测量线性模型（MIXED）和 Kaplan-Meier 估计方法评估组间差异。我们使用重复测量方差分析比较收缩压、平均动脉压和心输出量。
基线体重、血流动力学参数、QRS 间隔、达到低血压所需的时间以及达到低血压所需的苯海拉明剂量在两组之间相似。达到低血压后，静脉内用脂肪乳剂和碳酸氢钠组的心输出量或 QRS 间隔没有总体差异；然而，平均动脉压和收缩压有短暂差异，静脉内用脂肪乳剂有优势（差异：平均动脉压，碳酸氢钠与静脉内用脂肪乳剂-20.7 [95%置信区间-31.6 至-9.8]；收缩压，碳酸氢钠与静脉内用脂肪乳剂-24.8 [95%置信区间-37.6 至-12.1]）。死亡时间相似。1 只静脉内用脂肪乳剂和 2 只碳酸氢钠猪存活。研究结束时的总血清苯海拉明水平相似。平均总血清苯海拉明水平为 6.8μg/ml（标准差 3.1μg/ml），平均水相水平为 8.6μg/ml（标准差 5.5μg/ml）。
在我们的苯海拉明诱导的低血压猪研究中，我们没有发现静脉内用脂肪乳剂和碳酸氢钠在低血压、QRS 增宽或水相苯海拉明水平方面有差异。
