Investigations of New Therapies in Septic Shock

感染性休克和相关感染后遗症（例如多器官系统衰竭）是重症监护病房最常见的死亡原因。脓毒症导致的死亡可能发生在以前健康的个体、所有年龄段以及各种常见的临床环境中。一些常见的诱发因素是早产儿、先前健康的患有获得性感染（例如脑膜炎、肺炎、上呼吸道感染）的儿童、患有外伤或癌症的青少年或年轻人，以及患有肺炎或胆囊疾病的老年患者。患有感染性休克的儿童或成人中有一半死于该综合征。因此，败血性休克影响幼儿和老年人（甚至那些没有诱发疾病的人），是一种常见且重要的临床问题，死亡率很高，给社会带来巨大的经济负担。令人惊讶的是，人们对这种疾病感染的病理生理学（生物体毒力因子和毒素）以及与宿主反应相关的因素（影响和调节炎症反应的内源性分子）知之甚少。因此，通过治愈感染并中断这些生物体和宿主介质的作用，可以成功治疗败血性休克综合征，从而降低发病率和死亡率。使用专门饲养的比格犬，感染性休克的犬模型已成功提供有关人类疾病的病理生理学和治疗的信息。这种急性和慢性感染模型模拟了感染性休克儿童和成人中常见的病程和心血管变化。先前使用该模型的实验已经确定了特定细菌（革兰氏阳性和革兰氏阴性）、细菌毒素（内毒素）和宿主介质在产生感染性休克中的作用。因此，犬类模型在模拟人类疾病和指导人类治疗方面取得了巨大成功。有几种疗法正在研究中，可能对人类感染性休克有效。犬模型模拟了患有感染性休克的儿童和成年人的心血管变化，非常适合这些新疗法的临床前试验。犬模型允许进行适当的对照试验来评估治疗机制和治疗的副作用；这在人类研究中并不总是可能的。我们正在或将要评估以下犬模型感染性休克疗法：超氧化物歧化酶、酪氨酸激酶抑制剂、内毒素前体、缓激肽拮抗剂、丹曲林、可溶性肿瘤坏死因子受体、白细胞上 CD-18 受体抗体；布洛芬;人肿瘤坏死因子受体、粒细胞刺激因子抗体；血小板活化因子抗体；蛋白C抗体；连续动静脉血液滤过；高密度脂蛋白；血小板活化因子抑制剂。

Septic shock and related sequelae of infection (e.g., multiple organ system failure) are the most common cause of death in intensive care units. Deaths due to sepsis can occur in previously healthy individuals, in all age groups, and in a variety of common clinical settings. Some common predisposing conditions are premature neonates, previously healthy children with acquired infections (e.g., meningitis, pneumonia, upper respiratory infections), teenagers or young adults with trauma or cancer, and elderly patients with pneumonia or gall bladder disease. Half of all children or adults who acquire this septic shock die from the syndrome. Thus septic shock, which affects young children and the elderly alike (even those without predisposing illness), is a common and important clinical problem with substantial mortality and produces an great financial burden on society. Surprisingly little is known about the pathophysiology of this disease infection (organism virulence factors and toxins) and factors related to the host response (endogenous molecules that affect and modulate the inflammatory response). Thus successful treatment of the septic shock syndrome which reduces morbidity and mortality will result from curing the infection and interrupting the effects of these organism and host mediators. Using purpose bred beagles, the canine model of septic shock has successfully provided information on the pathophysiology and treatment of human disease. This model of acute and chronic infection simulates the course and cardiovascular changes seen routinely in children and adults with septic shock. Prior experiments using the model have established the role of specific bacteria (gram positive and gram negative), bacterial toxins (endotoxin), and host mediators to produce septic shock. Thus, the canine model has been highly successful in simulating the human disease and guiding therapy for humans. There are several therapies under investigation that might be effective in human septic shock. The canine model, which simulates the cardiovascular changes seen in children and adult humans with septic shock is ideally suited for pre-clinical trials of these new therapies. The canine model allows properly controlled trials to evaluate therapeutic mechanisms and adverse effects of therapies; that is not always possible in human studies. We are evaluating or will evaluate the following therapies for septic shock in the canine model: superoxide dismutase, Tyrosine kinase inhibitors, endotoxin precursors, bradykinin antagonists, dantrolene, soluble tumor necrosis factor receptor, antibodies to CD-18 receptors on white blood cells; ibuprofen; antibody to human tumor necrosis factor receptor, granulocyte stimulating factor; antibodies to platelet activating factor; antibodies to protein C; continuous arteriovenous hemofiltration; high-density lipoproteins; platelet activating-factor inhibitor.