Ypsilantis Petros, Politou Maria, Mikroulis Dimitrios, Pitiakoudis Michail, Lambropoulou Maria, Tsigalou Christina, Didilis Vasilios, Bougioukas Georgios, Papadopoulos Nikolaos, Manolas Constantinos, Simopoulos Constantinos
Laboratory of Experimental Surgery and Surgical Research, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
Anesth Analg. 2007 Jul;105(1):155-66. doi: 10.1213/01.ane.0000265544.44948.0b.
Prolonged administration of propofol at large doses has been implicated in propofol infusion syndrome in intensive care unit patients. In this study we investigated organ toxicity and mortality of propofol sedation at large doses in prolonged mechanically ventilated rabbits and determined the role of propofol's lipid vehicle.
Eighteen healthy male rabbits were endotracheally intubated and sedated with propofol 2% (Group P), sevoflurane (Group S) or sevoflurane while receiving Intralipid 10% (Group SI). Sedation lasted 48 h or until death (Group P) or the maximum surviving period of Group P (Groups S and SI). The initial propofol infusion rate (20 mg x kg(-1) x h(-1)) or sevoflurane concentration (1.5%) was adjusted, if needed, to maintain a standard level of sedation. Blood biochemical analysis was performed in serial blood samples and histologic examination in the heart, lungs, liver, gallbladder, kidneys, urinary bladder, and quadriceps femoris muscle at autopsy.
The mortality rate was 100% (surviving period, 26-38 h) for Group P, whereas 0% for Groups S and SI. The initial propofol infusion rate had to be increased up to 65.7 +/- 4.6 mg x kg(-1) x h(-1) and sevoflurane concentration up to 4%. Serum liver function indices, lipids and creatine kinase were significantly increased (P < 0.05) in Groups P and SI and lactate was increased only in Group P, whereas amylase was increased in all groups. In Group P, histologic examination revealed myocarditis, pulmonary edema with interstitial pneumonia, hepatitis, steatosis, and focal liver necrosis, cholangitis, gallbladder necrosis, acute tubular necrosis of the kidneys, focal loss of the urinary bladder epithelium, and rhabdomyolysis of skeletal muscles; in Group S, low-grade bronchitis and incipient inflammation of the liver and the kidneys; and in Group SI, low-grade bronchitis, liver steatosis and hepatitis, and incipient inflammation of the gallbladder, kidneys, and urinary bladder.
Continuous infusion of 2% propofol at large doses for the sedation of rabbits undergoing prolonged mechanical ventilation induced fatal multiorgan dysfunction syndrome similar to the propofol infusion syndrome seen in humans. Our novel findings including lung, liver, gallbladder, and urinary bladder injury were also noted. The role of propofol's lipid vehicle in the manifestation of the syndrome was minor. Sevoflurane proved to be a safe alternative medication for prolonged sedation.
在重症监护病房患者中，大剂量长时间输注丙泊酚与丙泊酚输注综合征有关。在本研究中，我们调查了长时间机械通气兔大剂量丙泊酚镇静的器官毒性和死亡率，并确定了丙泊酚脂质载体的作用。
18只健康雄性兔经气管插管，分别用2%丙泊酚（P组）、七氟醚（S组）或七氟醚联合10%脂肪乳剂（SI组）进行镇静。镇静持续48小时或直至死亡（P组）或P组的最长存活时间（S组和SI组）。必要时调整初始丙泊酚输注速率（20mg·kg⁻¹·h⁻¹）或七氟醚浓度（1.5%）以维持标准镇静水平。在连续采集的血样中进行血液生化分析，并在尸检时对心脏、肺、肝、胆囊、肾、膀胱和股四头肌进行组织学检查。
P组死亡率为100%（存活时间为26 - 38小时），而S组和SI组为0%。P组初始丙泊酚输注速率不得不增至65.7±4.6mg·kg⁻¹·h⁻¹，七氟醚浓度增至4%。P组和SI组血清肝功能指标、脂质和肌酸激酶显著升高（P<0.05），乳酸仅在P组升高，而淀粉酶在所有组均升高。P组组织学检查显示心肌炎、伴有间质性肺炎的肺水肿、肝炎、脂肪变性和局灶性肝坏死、胆管炎、胆囊坏死、肾急性肾小管坏死、膀胱上皮局灶性缺失以及骨骼肌横纹肌溶解；S组为轻度支气管炎以及肝和肾的早期炎症；SI组为轻度支气管炎、肝脂肪变性和肝炎以及胆囊、肾和膀胱的早期炎症。
对长时间机械通气的兔进行镇静时，持续大剂量输注2%丙泊酚会诱发致命的多器官功能障碍综合征，类似于人类所见的丙泊酚输注综合征。我们还发现了包括肺、肝、胆囊和膀胱损伤等新的结果。丙泊酚脂质载体在该综合征表现中的作用较小。七氟醚被证明是长时间镇静的安全替代药物。
