The Impact of Dysglycemia and Glycemic Variability on Targeted Temperature Management*

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Two previous randomized clinical trials found that lowering body temperature from 32°C to 34°C for 12 to 24 hours in patients who remained unconscious after being resuscitated from cardiac arrest (of presumed cardiac cause, with an initial shockable rhythm) showed a significant improvement in survival and neurologic function of survivors compared with standard treatment (1, 2).
The term targeted temperature management (TTM) or temperature control is now preferred over the previous term therapeutic hypothermia (3).
Early initiation of TTM is critical and should neither delay nor interfere with an early invasive approach. During the decade after the original reports of TTM efficacy in postcardiac arrest patients, clinical cohort studies signaled that the combination of early coronary angiography and TTM might provide the best outcomes in the resuscitated, but unconscious, critically ill population (4).
Although several unanswered questions remain before abandoning therapeutic hypothermia in patients after cardiac arrest, Nielsen et al (5) recently confirmed that fever should be avoided in resuscitated patients. They concluded that their trial [The Target Temperature Management 33°C versus 36°C after Out-of-Hospital Cardiac Arrest (TTM) trial] does not provide evidence that targeting a body temperature of 33°C confess any benefit for unconscious patients admitted to the hospital after out-of-hospital cardiac arrest, as compared with targeting a body temperature of 36°C. Importantly, patients in both arms of this trial had their temperature well controlled, so that fever was prevented in both groups.
Stress-induced hyperglycemia occurs in over 75% of the patients admitted to an ICU, irrespective of a previous diagnosis of diabetes (6). The first large randomized clinical trial (Leuven I) (6) demonstrated that providing tight glycemic control (the practice of maintaining blood glucose (BG) levels between 80 and 110 mg/dL using intensive IV insulin) to a cohort of predominantly surgical patients admitted to ICUs compared with conventional glucose control (BG level, < 200 mg/dL) results in one life saved for every 29 patients treated. Consequently, BG control became tighter in many ICUs worldwide. However, the initial enthusiasm ceased as their results could not be reproduced.
Subsequently, the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation trial, the largest multinational randomized clinical trial to examine tight glycemic control in the broadest cohort of medical and surgical ICU patients, demonstrated that tight glycemic control increased the risk of developing severe hypoglycemia and 90-day mortality (7). With these data in mind, tight glycemic control can no longer be the rationale for critically ill patients.
Nowadays, consensus status that hyperglycemia in critically ill patients should be monitored and treated, with recent guidelines recommendation to target an upper BG level less than or equal to 180 mg/dL rather than an upper target BG level less than or equal to 110 mg/dL (Society of Critical Care Medicine and the European Society of Intensive Care Medicine) (8) or between 140 and 180 mg/dL (American Diabetes Association) (9).
With patients undergoing therapeutic hypothermia after cardiac arrest, Cueni-Villoz et al (10) identify a group at special risk for high glycemic variability (GV). Insulin resistance and reduced glucose consumption due to hypothermia, as well as a pronounced endogenous stress response and need for catecholamines after cardiac arrest, render this cohort prone to alterations in glucose homeostasis. Hypoglycemia was more frequent when variability was high (with a BG variability ≥ 5 mmol/L), compared with low BG variability less than 5 mmol/L (15% vs 2%; p < 0.001) (10). For such trials, it will be important to use consistent measures for GV.
To explain the discrepancy between the data of Leuven I (6) and those of the following trials, the focus on research switched from absolute glucose levels to GV.
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