Glucose Control in The ICU
Glucose Control in The ICU
Glucose Control in The ICU
populations suitable for rhythm monitoring, the 6. Svendsen JH, Diederichsen SZ, Højberg S, et al. Implantable
loop recorder detection of atrial fibrillation to prevent stroke
threshold characteristics of AHREs that lead to (the LOOP study): a randomised controlled trial. Lancet 2021;
thrombus formation, and the specific atrial 398:1507-16.
tachyarrhythmias that occur during an AHRE 7. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS
Focused Update of the 2014 AHA/ACC/HRS guideline for the
that could justify anticoagulation. However, the management of patients with atrial fibrillation: a report of the
device-detected AHREs that occurred in this American College of Cardiology/American Heart Association
trial do not adequately infer a definitive diagno Task Force on Clinical Practice Guidelines and the Heart
Rhythm Society. J Am Coll Cardiol 2019;74:104-32.
sis of paroxysmal atrial fibrillation for all pa 8. Davidson KW, Barry MJ, Mangione CM, et al. Screening for
tients or a subsequent risk of stroke. atrial fibrillation: US Preventive Services Task Force recommen
Disclosure forms provided by the authors are available with dation statement. JAMA 2022;327:360-7.
the full text of this editorial at NEJM.org. 9. Kirchhof P, Toennis T, Goette A, et al. Anticoagulation with
edoxaban in patients with atrial high-rate episodes. N Engl J Med
From the Division of Cardiovascular Medicine, Brigham and 2023;389:1167-79
Women’s Hospital, and the Division of Cardiovascular Medi- 10. Perez MV, Mahaffey KW, Hedlin H, et al. Large-scale assess
cine, Harvard Medical School — both in Boston. ment of a smartwatch to identify atrial fibrillation. N Engl J Med
1. Camm AJ, Simantirakis E, Goette A, et al. Atrial high-rate 2019;381:1909-17.
episodes and stroke prevention. Europace 2017;19:169-79. 11. Campion EW, Jarcho JA. Watched by Apple. N Engl J Med
2. Özge Mert G, Kepez A, Uğur Mert K, Görenek B. What to do 2019;381:1964-5.
with device-detected atrial high-rate episodes: summary of the 12. Jensen MT, Treskes RW, Caiani EG, et al. ESC working group
evidences. Pacing Clin Electrophysiol 2022;45:250-61. on e-cardiology position paper: use of commercially available
3. Toennis T, Bertaglia E, Brandes A, et al. The influence of wearable technology for heart rate and activity tracking in pri
atrial high-rate episodes on stroke and cardiovascular death: an mary and secondary cardiovascular prevention-in collaboration
update. Europace 2023;25(7):euad166. with the European Heart Rhythm Association, European Asso
4. Van Gelder IC, Healey JS, Crijns HJGM, et al. Duration of ciation of Preventive Cardiology, Association of Cardiovascular
device-detected subclinical atrial fibrillation and occurrence of Nursing and Allied Professionals, Patient Forum, and the Digital
stroke in ASSERT. Eur Heart J 2017;38:1339-44. Health Committee. Eur Heart J Digit Health 2021;2:49-59.
5. Glotzer TV, Daoud EG, Wyse DG, et al. The relationship be
DOI: 10.1056/NEJMe2309444
tween daily atrial tachyarrhythmia burden from implantable
Copyright © 2023 Massachusetts Medical Society.
device diagnostics and stroke risk: the TRENDS study. Circ Ar
rhythm Electrophysiol 2009;2:474-80.
Randomized, controlled trials aiming for near- organizations worldwide and resulted in recom
normal glycemic targets (80 to 110 mg per deci mendations for intensive glucose control in
liter [4.4 to 6.1 mmol per liter]) in critically ill critically ill patients in the ICU.
patients have shown conflicting data regarding Subsequently, several multicenter, random
the benefits of intensive glycemic control (Ta ized, controlled trials and meta-analyses consis
ble 1). In 2001, Van den Berghe et al. reported a tently showed that intensive glycemic control
dramatic 42% lower mortality among patients in was not associated with benefits but was asso
the surgical intensive care unit (ICU) in whom ciated with unacceptably high rates of hypogly
the blood glucose level had been adjusted to 80 cemia.4-9 Moreover, in 2009, the NICE-SUGAR
to 110 mg per deciliter than among those who (Normoglycemia in Intensive Care Evaluation–
had received conventional treatment that was Survival Using Glucose Algorithm Regulation)
initiated when glucose levels exceeded 215 mg randomized, controlled trial,8 which had a prag
per deciliter (11.9 mmol per liter), with a target matic design, showed that a tight glucose target
of 180 to 200 mg per deciliter (10.0 to 11.1 mmol (81 to 108 mg per deciliter [4.5 to 6.0 mmol per
per liter).2 In 2006, with the same glucose tar liter]) was associated with a higher incidence of
gets, the same investigators reported no signifi marked hypoglycemia (≤40 mg per deciliter
cant mortality benefit from intensive glucose [2.2 mmol per liter]) and higher mortality at 90
control in the medical ICU, except in patients days than a moderate glucose target (≤180 mg
receiving critical care for 3 or more days.3 These per deciliter [≤10.0 mmol per liter]). Several hy
studies received the attention of professional potheses have been proposed to explain the con
nejm.org
Preiser et al.,7 ICU 1101 80–110 140–180 Death in ICU 15.3 17.2 Odds ratio, 1.10 NS
Editorials
* To convert values for glucose to millimoles per liter, multiply by 0.05551. CI denotes confidence interval, ICU intensive care unit, MICU medical ICU, NICE-SUGAR Normoglycemia in
Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation, NS not significant, SICU surgical ICU, and VISEP Efficacy of Volume Substitution and Insulin Therapy in Severe
Sepsis.
† Data are from Inzucchi and Siegel.1
‡ In the GLUCO-CABG trial (Randomized Controlled Trial of Intensive versus Conservative Glucose Control in Patients Undergoing Coronary Artery Bypass Graft Surgery), the primary
outcome was a composite of hospital complications including death, wound infection, pneumonia, bacteremia, respiratory failure, acute kidney injury, or major cardiovascular events.
1235
The n e w e ng l a n d j o u r na l of m e dic i n e
trast in outcome effects between more recent ous studies indicate that normalization of glu
trials and the original single-center studies re cose levels does not alter in-ICU, in-hospital, or
ported by Van den Berghe et al.2,3 In the earlier postdischarge mortality or length of ICU stay.
studies, patients received medical nutrition with Furthermore, avoidance of hypoglycemia is criti
intravenous glucose, parenteral nutrition, enteral cally important in the ICU because it has been
feeding, or combined feeding within 24 hours associated with poor outcomes. Clinical trials
after ICU admission, an uncommon practice have shown fewer hypoglycemic events with the
that has not been followed in other trials. use of computer-based insulin-infusion algo
In this issue of the Journal, Gunst et al.10 report rithms than with traditional “paper” form algo
the results of a multicenter, randomized trial rithms.9 Finally, we have evidence against the
involving 9230 patients in medical and surgical use of early parenteral nutrition because it may
ICUs, 4622 of whom were assigned to liberal result in hyperglycemia, an increased need for
glucose control (with insulin initiated only when insulin therapy, and an increased risk of compli
the blood-glucose level was >215 mg per deci cations.
liter [11.9 mmol per liter]) and 4608 of whom Despite a century of insulin use in clinical
were assigned to tight glucose control targeting practice, the ideal blood-glucose target in criti
a glucose level between 80 and 110 mg per deci cally ill patients remains unclear. Conclusive
liter. In contrast to the previous studies from the evidence from observational and randomized,
same institution,2,3 the present trial was conduct controlled trials indicates that hyperglycemia is
ed in 11 ICUs at two university hospitals and one associated with adverse clinical outcomes both
district hospital in Belgium, parenteral nutrition in patients with and those without diabetes.
was withheld in both groups during the first Therefore, clinicians should continue to manage
week, and the investigators used the LOGIC- blood-glucose levels in order to avoid the ex
Insulin computer algorithm to guide insulin tremes of hyperglycemia, which have acute ad
infusion. verse effects with respect to inflammation and
The length of time that ICU care was needed oxidative stress, neutrophil function, renal func
(the primary outcome) did not differ significantly tion, and hemodynamics.
between the two trial groups (hazard ratio for On the basis of evidence from previous ran
earlier discharge alive with tight glucose control, domized, controlled trials, the American Diabe
1.00; 95% confidence interval [CI], 0.96 to 1.04), tes Association recommends initiation of insulin
despite effective glycemic separation between for the treatment of persistent hyperglycemia
the groups with respect to the median absolute (blood-glucose level >180 mg per deciliter), with
difference of −28 mg per deciliter (95% CI, −29 a targeted glucose range of 140 mg per deciliter
to −27) in overall daily blood glucose levels. (7.8 mmol per liter) to 180 mg per deciliter for
Mortality within 90 days after randomization most critically ill patients.11 More stringent
(the safety outcome) was 10.1% among patients goals, such as a glucose level of 100 to 180 mg
in the liberal-control group and 10.5% among per deciliter (5.6 to 10.0 mmol per liter), may be
those in the tight-control group. The incidence appropriate as long as they can be achieved
of severe hypoglycemia was low (0.7% in the without clinically significant hypoglycemia.
liberal-control group and 1.0% in the tight-con Disclosure forms provided by the author are available with the
trol group). Among other secondary outcomes full text of this editorial at NEJM.org.
(not controlled for multiplicity), there were no From Emory University, Atlanta.
major differences in the time to discharge alive
1. Inzucchi SE, Siegel MD. Glucose control in the ICU — how
from the hospital, use of respiratory support, or tight is too tight? N Engl J Med 2009;360:1346-9.
in-hospital mortality, but markers of liver and 2. Van den Berghe G, Wouters P, Weekers F, et al. Intensive
kidney injury were less common with tight glu insulin therapy in critically ill patients. N Engl J Med 2001;345:
1359-67.
cose control than with liberal glucose control. 3. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive in
The results of this new trial help to settle and sulin therapy in the medical ICU. N Engl J Med 2006;354:449-61.
contextualize the long-term controversy about the 4. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin
therapy and pentastarch resuscitation in severe sepsis. N Engl J
safety and efficacy of intensive glucose control Med 2008;358:125-39.
in the ICU. These new results and those of previ 5. De La Rosa GdelC, Donado JH, Restrepo AH, et al. Strict
glycaemic control in patients hospitalised in a mixed medical 9. Umpierrez G, Cardona S, Pasquel F, et al. Randomized con
and surgical intensive care unit: a randomised clinical trial. Crit trolled trial of intensive versus conservative glucose control in
Care 2008;12(5):R120. patients undergoing coronary artery bypass graft surgery:
6. Arabi YM, Dabbagh OC, Tamim HM, et al. Intensive versus GLUCO-CABG trial. Diabetes Care 2015;38:1665-72.
conventional insulin therapy: a randomized controlled trial in 10. Gunst J, Debaveye Y, Güiza F, et al. Tight blood-glucose con
medical and surgical critically ill patients. Crit Care Med 2008; trol without early parenteral nutrition in the ICU. N Engl J Med
36:3190-7. 2023;389:1180-90.
7. Preiser JC, Devos P, Ruiz-Santana S, et al. A prospective ran 11. ElSayed NA, Aleppo G, Aroda VR, et al. 16. Diabetes care in
domised multi-centre controlled trial on tight glucose control by the hospital: standards of care in diabetes — 2023. Diabetes
intensive insulin therapy in adult intensive care units: the Glu Care 2023;46:Suppl:S267-S278.
control study. Intensive Care Med 2009;35:1738-48.
8. NICE-SUGAR Study Investigators. Intensive versus conven DOI: 10.1056/NEJMe2309442
tional glucose control in critically ill patients. N Engl J Med Copyright © 2023 Massachusetts Medical Society.
2009;360:1283-97.