Clinical Division of Intensive Care Medicine, UZ Leuven, Leuven, Belgium; and.
Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Am J Respir Crit Care Med. 2024 Mar 1;209(5):497-506. doi: 10.1164/rccm.202309-1696SO.
This article tells the story of our long search for the answer to one question: Is stress hyperglycemia in critically ill patients adaptive or maladaptive? Our earlier work had suggested the lack of hepatic insulin effect and hyperglycemia as jointly predicting poor outcome. Therefore, we hypothesized that insulin infusion to reach normoglycemia, tight glucose control, improves outcome. In three randomized controlled trials (RCTs), we found morbidity and mortality benefit with tight glucose control. Moving from the bed to the bench, we attributed benefits to the prevention of glucose toxicity in cells taking up glucose in an insulin-independent, glucose concentration gradient-dependent manner, counteracted rather than synergized by insulin. Several subsequent RCTs did not confirm benefit, and the large Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation, or "NICE-SUGAR," trial found increased mortality with tight glucose control associated with severe hypoglycemia. Our subsequent clinical and mechanistic research revealed that early use of parenteral nutrition, the context of our initial RCTs, had been a confounder. Early parenteral nutrition (early-PN) aggravated hyperglycemia, suppressed vital cell damage removal, and hampered recovery. Therefore, in our next and largest "TGC-fast" RCT, we retested our hypothesis, without the use of early-PN and with a computer algorithm for tight glucose control that avoided severe hypoglycemia. In this trial, tight glucose control prevented kidney and liver damage, though with much smaller effect sizes than in our initial RCTs without affecting mortality. Our quest ends with the strong recommendation to omit early-PN for patients in the ICU, as this reduces need of blood glucose control and allows cellular housekeeping systems to play evolutionary selected roles in the recovery process. Once again, less is more in critical care.
危重病患者的应激性高血糖是适应性的还是适应性不良的？我们早期的工作表明，缺乏肝胰岛素效应和高血糖共同预测不良预后。因此，我们假设胰岛素输注以达到正常血糖、严格血糖控制可以改善预后。在三项随机对照试验（RCT）中，我们发现严格血糖控制可降低发病率和死亡率。从床边到实验室，我们将获益归因于预防葡萄糖毒性，葡萄糖毒性是指细胞以胰岛素非依赖性、葡萄糖浓度梯度依赖性方式摄取葡萄糖，从而拮抗而不是协同胰岛素。随后的几项 RCT 并没有证实获益，而大型的强化血糖控制评估中的血糖正常化使用血糖算法调节试验（或“NICE-SUGAR”试验）发现，严格血糖控制与严重低血糖相关，死亡率增加。我们随后的临床和机制研究揭示，早期肠外营养的使用（我们最初 RCT 的背景）是一个混杂因素。早期肠外营养（早期-PN）加重高血糖，抑制重要细胞损伤清除，并阻碍恢复。因此，在我们的下一个也是最大的“TGC-fast” RCT 中，我们重新检验了我们的假设，没有使用早期-PN，并且使用了严格血糖控制的计算机算法，以避免严重低血糖。在这项试验中，严格的血糖控制可以预防肾和肝损伤，尽管效果比我们最初的 RCT 小，而不会影响死亡率。我们的探索以强烈建议取消 ICU 患者的早期-PN 结束，因为这减少了血糖控制的需求，并允许细胞管家系统在恢复过程中发挥进化选择的作用。在危重病护理中，再次证明少即是多。
