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Time in Range: A Fourth Domain in Glycemic Control or a Glucose Variability Alternative?

      To the Editor:
      The outcome of glucose control in critically ill patients has received significant attention. Krinsley
      • Krinsley J.S.
      Glycemic control in the critically ill—3 domains and diabetic status means one size does not fit all.
      has stated that hyperglycemia, hypoglycemia, and high glucose variability (GV) are the 3 domains that are independently associated with high mortality in critically ill patients. Moving away from tight to safe glucose control provides an optimum goal.
      • van Hooijdonk R.T.
      • Mesotten D.
      • Krinsley J.S.
      • Schultz M.J.
      Sweet spot: glucose control in the intensive care unit.
      The interest in measuring GV has been raised after multiple studies demonstrated its association with mortality in intensive care units (ICUs).
      • Krinsley J.S.
      Glycemic control in the critically ill—3 domains and diabetic status means one size does not fit all.
      • Kovatchev B.P.
      • Otto E.
      • Cox D.
      • Gonder-Frederick L.
      • Clarke W.
      Evaluation of a new measure of blood glucose variability in diabetes.
      Multiple approaches had to be used to measure GV, including average daily risk range
      • Kovatchev B.P.
      • Otto E.
      • Cox D.
      • Gonder-Frederick L.
      • Clarke W.
      Evaluation of a new measure of blood glucose variability in diabetes.
      ; however, these measures seem to be too sophisticated to be implemented in each ICU. Time in range (TIR), defined as a measure of time where the blood glucose remains within the proposed target range, has been investigated by Omar et al.
      • Omar A.S.
      • Salama A.
      • Allam M.
      • Elgohary Y.
      • Mohammed S.
      • Tuli A.K.
      • et al.
      Association of time in blood glucose range with outcomes following cardiac surgery.
      Our group found it to be a simple parameter that could be measured without specific requirements; therefore, it could be simply applied in any ICU. We
      • Omar A.S.
      • Salama A.
      • Allam M.
      • Elgohary Y.
      • Mohammed S.
      • Tuli A.K.
      • et al.
      Association of time in blood glucose range with outcomes following cardiac surgery.
      calculated the whole time of insulin infusion (A) and the time being within the proposed target range (B) during insulin infusion, and expressed TIR as TIR = (B/A) × 100. We found that patients with more than 80% TIR, whether or not they had diabetes, had better outcomes than those with less than 80% TIR, as determined by wound infection, lengths of ventilation, and ICU stay. In addition, they were not subject to frequent hypoglycemic events.
      • Omar A.S.
      • Salama A.
      • Allam M.
      • Elgohary Y.
      • Mohammed S.
      • Tuli A.K.
      • et al.
      Association of time in blood glucose range with outcomes following cardiac surgery.
      Interestingly, Krinsley and Preiser
      • Krinsley J.S.
      • Preiser J.C.
      Time in blood glucose range 70-140 mg/dL >80% is strongly associated with increased survival in non-diabetic critically ill adults.
      followed the same technique in stratifying mortality in critically ill patients without diabetes in a retrospective descriptive study. The authors concluded that survival in critically ill patients without diabetes is strongly associated with a TIR 70 to 140 mg/dL value of more than 80%, independent of the ICU length of stay and severity of the individual's illness.
      • Krinsley J.S.
      • Preiser J.C.
      Time in blood glucose range 70-140 mg/dL >80% is strongly associated with increased survival in non-diabetic critically ill adults.
      Individualized algorithms for patients with and without diabetes, as mentioned by Tafelski et al,
      • Tafelski S.
      • Spies C.
      • Nachtigall I.
      Look at the patient—in sugar and infection.
      could replace published working guidelines. Therefore, management of blood glucose in the ICU by a single target looks unnecessarily restrictive. The clinical settings could mandate a target to fit, as in cardiac surgery where 6.0 to 8.1 mmol/L seems to be an acceptable goal.
      • Omar A.S.
      • Salama A.
      • Allam M.
      • Elgohary Y.
      • Mohammed S.
      • Tuli A.K.
      • et al.
      Association of time in blood glucose range with outcomes following cardiac surgery.
      In the view of the reports relating the TIR value to mortality and morbidity in those with and without diabetes, TIR value emerges. In addition to its simplicity, TIR could provide a possible alternative to GV measurements. Even if TIR and GV are mathematically and conceptually linked, they are not interchangeable. Research in ICU glucose control could move a step forward considering the proper intervention in intensive insulin therapy.

      References

        • Krinsley J.S.
        Glycemic control in the critically ill—3 domains and diabetic status means one size does not fit all.
        Crit Care. 2013; 17: 131
        • van Hooijdonk R.T.
        • Mesotten D.
        • Krinsley J.S.
        • Schultz M.J.
        Sweet spot: glucose control in the intensive care unit.
        Semin Respir Crit Care Med. 2016; 37: 57-67
        • Kovatchev B.P.
        • Otto E.
        • Cox D.
        • Gonder-Frederick L.
        • Clarke W.
        Evaluation of a new measure of blood glucose variability in diabetes.
        Diabetes Care. 2006; 29: 2433-2438
        • Omar A.S.
        • Salama A.
        • Allam M.
        • Elgohary Y.
        • Mohammed S.
        • Tuli A.K.
        • et al.
        Association of time in blood glucose range with outcomes following cardiac surgery.
        BMC Anesthesiol. 2015; 15: 14
        • Krinsley J.S.
        • Preiser J.C.
        Time in blood glucose range 70-140 mg/dL >80% is strongly associated with increased survival in non-diabetic critically ill adults.
        Crit Care. 2015; 19: 179
        • Tafelski S.
        • Spies C.
        • Nachtigall I.
        Look at the patient—in sugar and infection.
        Crit Care. 2015; 19: 454