MICA: Can interferon gamma prevent infection in critically ill patients at highest risk? A phase II randomised controlled trial.

住进重症监护病房(ICU)的患者在ICU期间极易发生新的感染。这些额外的感染增加了死亡风险，增加了在ICU度过的时间，并显著增加了医疗成本。在ICU给了太多的患者使用抗生素，部分原因是医生担心患者可能会出现新的感染。过度使用抗生素会导致出现对抗生素具有抗药性的“超级细菌”。由于所有这些原因，迫切需要新的方法来预防ICU中使用抗生素以外的其他治疗方法的感染。ICU中感染风险增加的部分原因是，导致患者病情危重的严重疾病首先会“震撼”免疫系统，使免疫细胞杀死细菌的能力降低。我们知道，一种名为干扰素伽马(IFNG)的药物可以恢复患者免疫细胞的良好功能。这项建议的目的是确定IFNG是否安全，以及它是否可以减少住进ICU的患者的抗生素使用和感染，这些患者发展为新感染的风险最大。我们知道，在ICU的两组患者中，新感染的风险特别高：(A)昏迷的患者，他们的呼吸通过连接到呼吸机的气管中的管子为他们进行呼吸；以及(B)需要机器来接管他们的肾功能和药物来维持正常血压的患者。我们还知道，一种名为mhla-DR的特定血液测试可以很好地指示免疫系统是否受到了惊吓--低mhla-DR与更高的感染风险和病情严重相关。我们在英国组建了一个横跨11个ICU的团队。上文(A)或(B)类病人将获邀请(透过其亲属)参与研究。如果获得同意，将进行MHLA-DR血液测试。如果这是低的，患者将继续进行研究，这是一项临床试验。患者将被随机分配到四组中的一组(患者和研究团队都不知道四种治疗中的哪一种)。每个患者在接下来的一周内接受一次皮下注射(皮下注射)，共三次。这两个组是1个。在所有3种情况下都使用安慰剂2。三种情况下均以标准剂量(100微克)注射。在所有3种情况下，IFNG都是标准剂量的一半(50微克)。IFNG的第一剂量是100微克，但接下来的两剂是安慰剂或IFNG 100微克，这分别取决于mhla-DR测试的高或低。在所有研究患者中，我们将记录他们接受的抗生素、在ICU度过的时间、他们是否出现新的感染、有多少人在30天后仍然活着、IFNG的任何潜在副作用以及mhla-DR测试。一旦168名患者(每组42名)进入研究，我们将暂停试验，统计学家将分析结果，看看IFNG组中哪一组需要的抗生素最少，同时保持安全。实际上，我们从3个IFNG组中“挑选出获胜者”，其他两个IFNG组不再有患者入院。然后我们恢复试验，只有安慰剂组和“获胜者”IFNG组各招募了42名患者。一旦他们有了，我们将评估抗生素的使用、死亡率、新感染、在ICU的住院时间和副作用是否显著少于安慰剂组，以及mhla-DR是否比安慰剂组升高更多。

Patients admitted to an intensive care unit (ICU) are extremely vulnerable to developing new infections during their time in the ICU. These additional infections add to the risk of death, increase the time spent in the ICU and significantly increase healthcare costs. Antibiotics are given to too many patients in the ICU, partly because doctors are fearful that patients may develop new infections. Overuse of antibiotics leads to the emergence of "superbugs" that are resistant to antibiotics. For all these reasons, there is a pressing need for new methods to prevent infection in the ICU using treatments other than antibiotics.Part of the heightened risk of infection in the ICU is because severe illnesses that cause patients to be critically ill in the first place "stun" the immune system, leaving immune cells less able to kill bugs. We know that a drug called interferon gamma (IFNg) can restore good function to patients' immune cells. The purpose of this proposal is to determine whether IFNg is safe, and whether it can reduce antibiotic use and infections, in patients admitted to the ICU who are at greatest risk of developing new infections. We know that the risk of new infections is particularly high in two groups of patients in the ICU (a) patients who are unconscious and whose breathing is being done for them through a tube in their windpipe, which is connected to a ventilator machine, and (b) patients who require a machine to take over their kidney function and drugs to maintain a normal blood pressure. We also know that a particular blood test, called mHLA-DR, gives a good indication of whether the immune system has been stunned - a low mHLA-DR is associated with higher risk of developing infection and doing badly. We have assembled a team across 11 ICUs in the UK. Patients in categories (a) or (b) in the paragraph above will be invited (through their relatives) to take part in the study. If consent is granted, a mHLA-DR blood test will be taken. If this is low, the patient will proceed into the study, which is a clinical trial. Patients will be allocated at random to one of four groups (neither the patient nor the research team will know which of the four treatments has been given). Each patient receives an injection under the skin (subcutaneously) once on 3 occasions over the next week. The groups are1. Placebo on all 3 occasions2. IFNg in the standard dose (100 microgrammes) on all 3 occasions3. IFNg at half the standard dose (50 microgrammes) on all 3 occasions4. IFNg where the first dose is 100 microgrammes, but the next 2 doses are either placebo or IFNg 100 microgrammes, depending on whether mHLA-DR tests are high or low, respectively.In all study patients we shall record the antibiotics they receive, the time spent in ICU, whether they develop new infections, how many are still alive at 30 days, any potential side effects of IFNg, and mHLA-DR tests. Once 168 patients (42 per group) have entered the study, we shall pause the trial, and a statistician will analyse the results to see which of the IFNg groups has required the least antibiotics, while remaining safe. Effectively we "pick the winner" from the 3 IFNg groups and no more patients are admitted to the other two IFNg groups. We then resume the trial with only the placebo group and the "winner" IFNg group recruiting another 42 patients each. Once they have, we shall assess whether antibiotic use, death, new infections, length of stay in the ICU, and side effects are significantly less in the "winner" IFNg group than in the placebo group, and whether mHLA-DR goes up more in the "winner" IFNg group.