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FIRST IN A SERIES SPONSORED BY
Continuous Glucose Monitoring in the ICU:
Meeting a Critical Unmet Need
Aiming to Achieve Better Glucose
Management Practices
Inpatient glucose control has become an important standard of
care for limiting hospital morbidity and mortality, however, good
glucose control is difficult to achieve.
Today, the importance of inpatient glycemic management –
especially among the critically ill – is well appreciated, whether
in patients undergoing cardiac surgery, neurosurgery, post
myocardial infarction or other critical illness. Studies have shown
reduced morbidity and mortality in those whose glucose has
been controlled to less than 10 mmol/L, (180 mg/dL).1-8 However,
ongoing surveillance and clinical studies have shown that good
glycemic control is difficult to achieve, and remains elusive for
most hospital settings.9, 10
Multi-disciplinary teams supporting development and
imple­mentation of evidence-supported protocols have
become the new standard as institutions work to improve
glucose control within the critical care setting. These protocols
and procedures can vary among hospitals, between nursing
units within hospitals, and even between managing clinicians.9
And, importantly, the one consensus among societies across
specialties regarding glycemic management appears to be
that there is no consensus on what the standard glucose
target should be.
Glucose Control Improves Outcomes
Much of the research demonstrating the benefit of glucose
control has come from notable European institutions.11-13 While
the range of sophistication of these programs, protocols and
procedures varies from paper-based instructions to highly
complex computer algorithms, the evidence suggests that
improved outcomes can be achieved:
Reduced morbidity
• At 12 months, with a total of 1548 patients enrolled, the insulin
therapy protocol used in Leuven I, helped reduce bloodstream
infections by 46%, acute renal failure requiring dialysis or
hemofiltration by 41%, the median number of red-cell transfusions
by 50%, and critical-illness polyneuropathy by 44%.12
Reduced mortality
• The intensive insulin therapy in the Leuven I trial reduced mortality
during intensive care from 8.0% with conventional treatment to 4.6%,
with the greatest reduction in mortality involving deaths due to
multiple organ failure with a proven septic focus. Overall in-hospital
mortality was reduced by 34%.12
Prior to the Leuven trials, hyperglycemia was considered
common during critical illness.14 This stress hyperglycemia was
deemed a beneficial, adaptive response to provide energy
substrate to those organs such as brain, cardiac and renal cells
that rely on glucose during the hypermetabolic stress state.14
While it seems clear that the findings from the Leuven trials
created a paradigm shift with respect to glucose management
in the ICU, there is still a great deal of ground to cover to reach
the optimal methods for safe glucose control in critically ill
patients. Additionally, the initial enthusiasm for tight glucose
Morbidity and Mortality Reduction
60
50
40
41%
44%
46%
50%
34%
30
20
10
0
Mortality
Acute
Renal Failure
Polyneuropathy
Bloodstream
Red cell
Infections Transfustions
Van den Berghe et al., N Engl J Med. 2001; 345:1359-67
control that followed the first Leuven trial has been tempered
by the less favorable findings of the NICE-SUGAR study.15
As the pendulum swings back towards less intensive glucose
management practices, the conversation continues to intensify
in an effort to drive to a consensus. A recent publication from
several of the NICE-SUGAR investigators concludes that the
available clinical trial data does not support widespread
adoption of intensive glucose control in critically ill patients,
but neither does it support ignoring glucose control.16
In spite of measurable progress, much of the initial promise
of tight glycemic control has not been realized,15-18 leaving a
significant unmet need in the critically ill population. Questions
about ideal glucose target ranges and current practice
limitations go unresolved, inhibiting the evolution of glucose
management in the ICU.
What is the ideal blood glucose target range? Is there an
absolute target or is controlling variability more important?
• Prior to the paradigm shift in glucose management in 2001, most
intensivists allowed blood glucose levels to remain high, unless the
levels exceeded 11 to 12 mmol/L, (200 to 215 mg/dL). However,
the Leuven trials showed the merits of keeping patients in a
normoglycemic range of 4.4 to 6.2 mmol/L (80 to 110 mg/dL).12
• In 2007, international recommendations for glucose control in adult,
non-diabetic critically ill patients were developed by the European
Society of Cardiology (ESC) and the European Association for the
Study of Diabetes (EASD)19 and more recently by French Society of
Anesthesia and Intensive Care which validated experts from other
societies within the European Union13 stating “A glucose target
of less than 10 mmol/L is strongly suggested, using intravenous
insulin following a standard protocol [...]. Definition of the severe
hypoglycemia threshold of 2.2 mmol/L is recommended,
regardless of the clinical signs.”
• In 2009, the US societies ADA and AACE established glycemic target
ranges in response to the NICE SUGAR trial of 7.8 to 10.2 mmol/L,
(140mg/dL to 180 mg/dL).20 Recent publications are in broad
agreement with the ADA recommendations for targeting glucose
concentration, generally between 140 and 180 mg/dL (8-10 mmol/L)
once insulin is started.16,21
Although these ranges minimize risk of severe hypoglycemia
[as defined by blood glucose less than or equal to 2.2 mmol/L
(40 mg/dL)], advocates of tighter glycemic control are concerned
that the benefits of glycemic control as established by the
Leuven I and Leuven II studies will no longer be realized.11
Additionally, with all of the discussion around ideal target ranges,
there is growing research and interest into the effects of glycemic
variability (GV) on patient outcomes. One study concluded that GV
was strongly related to increasing mortality in a heterogeneous
population of critically ill patients and that patients in the lowest
quartile of GV had shorter lengths of stay.22
How much does typical frequency of testing (q1-q4 hrs)
limit the ability to detect and/or
avoid hypoglycemia and
Blood Glucose Measurements (2 hour protocol)
dangerous excursions?
• Hypoglycemia is strongly
independently associated with
increased mortality and increased
intensive care unit length of
stay16, 23-25 and close monitoring
Target Range for Blood Glucose Level
of glucose blood levels is strongly
recommended for the early
detection of severe hypoglycemia.13
0
2
4
6
8
10
Time (hours)
• Some guidelines even recommend
BG testing ranging from every 30
minutes to 2 hours for patients receiving IV insulin infusions.20
• Researchers employing continuous glucose monitoring (CGM) technology
have demonstrated the ability to identify hypoglycemic events that were
otherwise missed with standard glucose monitoring, and detected
hypoglycemic excursions hours before the patient exhibits symptoms
alerting healthcare providers to the event.26
• Additionally, studies using real time CGM devices have shown reduced
rates of hypoglycemic episodes because the ability to monitor trends
enables clinicians to detect lower glucose levels and reverse them before
dangerous levels are reached.27, 28
A consensus for these questions and others will be addressed with
ongoing scientific investigation. However, a fundamental underlying
limitation remains in the method by which glucose is most commonly
measured and the resulting impact on protocol administration, safety
and efficacy. Protocols requiring hourly (or less frequent) blood glucose
measurements are leaving gaps of time and data between measures
and may be insufficient to realize the full benefits of glycemic
management.12 This is specifically a concern in the prevention of
hypoglycemia, since recent studies have shown that even mild
hypoglycemia, BG less than 3.9 mmol/L (BG < 70 mg/dL) is
independently associated with increased risk of mortality.23
Unmet Needs = New Opportunities
Continuous glucose monitoring technology represents a significant
step toward realizing the promised, but as yet unrealized benefits of
glycemic control among the critically ill.
The evolution of glycemic management has reached a stage where
new technology, such as inpatient CGM tools, are necessary to
optimize glucose management and ultimately clinical and
economic outcomes.9, 29, 30
Continuous Glucose Measurements
Continuous glucose monitoring
can reveal the trend of a glucose
Unnoticed
excursions
excursion from a normal and
stable glucose level to an
impending, unstable and
abnormal level. With this
information, clinicians can be
Predictive alarms could help to reduce
number and severity of hypoglycemic events
proactive rather than reactive
0
2
4
6
8
10
in adjusting insulin dosing and
Time (hours)
limit iatrogenic glucose
variability resulting from insulin
dosing adjustments. CGM devices also provide the opportunity to
assess glycemic variability and may lead to a greater understanding
of variability data within individual patients and across
heterogeneous populations.22, 31, 32
What is needed is new, commercially supported technology that
enables greater visibility into glucose levels without a proportionate
increase in nursing burden, patient inconvenience or costs.
Evolution toward Continuous Glucose
Monitoring in the ICU
The current body of knowledge on this topic leads to one conclusion;
that glucose management in the ICU is far from optimal. As we move
towards creating better solutions, real time CGM offers the possibility
of performing clinical trials without increased rates of hypoglycemia
because CGM not only detects excursions but helps investigators
prevent them.24
A commercial CGM solution designed to monitor critically ill patients
in the ICU has the potential to provide the necessary visibility into
glycemic variability while supporting more predictive (versus
reactive) glycemic management. This new tool should enable
clinicians to monitor glucose in a timely way, and manage glucose
levels to a target without increasing the risk of dangerous
hypoglycemic events.
Ultimately, use of CGM technology could be instrumental in driving
the evolution of safe and effective glucose management protocols
that will support more consistent glycemic management standards
within ICU’s and across institutions.
Works Cited:
1. The NICE-SUGAR Study Investigators, Intensive versus Conventional Glucose Control in Critically Ill Patients. N Engl J Med. 2009 Mar 26;360(13):1283-1297. Epub 2009 Mar 24. NICE-SUGAR online abstract at http://ajrccm.atsjournals.org/cgi/data/172/11/1358/
DC1/1 2. Furnary AP, Cheek DB, Holmes SC et al. Achieving tight glycemic control in the operating room: lessons learned from 12 years in the trenches of a paradigm shift in anesthetic care. Semin Thorac Cardiovasc Surg. 2006; 18: 339–345. 3. Moyer MT.
Performance improvement measures in achieving glycemic control in the acute brain injury population. J Neurosci Nurs. 2009; 41:72-82. 4. Kosiborod M, Rathore SS, Inzucchi SE et al. Admission glucose and mortality in elderly patients hospitalized with acute
myocardial infarction: implications for patients with and without recognized diabetes. Circulation. 2005; 111: 3078–3086. 5. Kosiborod M, Inzucchi SE, Krumholz HM et al. Glucose normalization and outcomes in patients with acute myocardial infarction.
Arch Intern Med. 2009; 169: 438–446. 6. Deedwania P, Kosiborod M, Barrett E et al. Hyperglycemia and acute coronary syndrome: a scientific statement from the American heart association diabetes committee of the council on nutrition, physical activity, and
metabolism. Circulation. 2008; 117: 1610–1619. 7. Sinnaeve PR, Steg PG, Fox KA et al. Association of elevated fasting glucose with increased short-term and 6-month mortality in st-segment elevation and non-st-segment elevation acute coronary syndromes:
the global registry of acute coronary events. Arch Intern Med. 2009; 169: 402–409. 8. Bagshaw SM, Egi M, George C, et al. Early blood glucose control and mortality in critically ill patients in Australia. Crit Care Med. 2009; 37:463-470. 9. Cook CB, Elias B, Kongable
G, et al. Diabetes and hyperglycemia quality improvement efforts in hospitals in the United States: current status, practice variation and barriers to implementation. Endocr Pract. 2010; 16:219-230. 10. Swanson CM, Potter DJ, Kongable G, Cook CB, et al.
An update on inpatient glycemic control in US hospitals. Endocr Pract. 2012; DOI:10.4158/EP11042.OR. 11. Mesotten, G. Van den Berghe, G. Clinical benefits of tight glycaemic control: focus on the intensive care unit. Best Pract Res Clin Anaesthesiol. 2009;
23: 421–429. 12. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Eng J Med. 2001; 345:1359-1367. 13. Ichai C, Preiser JC, et al. International recommendations for glucose control in adult non-diabetic critically
ill patients. Critical Care. 2010; 14:R166. 14. Mizock BA. Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med. 1995; 98:75–84. 15. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in
critically ill patients. N Eng J Med. 2009; 360:1283-1297. 16. Egi M, Finfer S, Bellomo R. Glycemic control in the ICU. Chest. 2011; 140: 212-220. 17. Weiner RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: A meta-analyses.
JAMA. 2008; 300:933-944. 18. Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and mortality among critically ill patients: a metaanalysis including NICE-SUGAR Study data. Canadian Medical Anesthesia Journal. 2009; 180:821-827. 19. The
Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD), Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. Eur
Heart J. 2007; 28:88-136. 20. Moghissi E, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists/American Diabetes Association consensus statement on inpatient glycemic control. Endocr Pract. 2009; 15:353-369. 21. Kavanagh
B, McCowen K, Glycemic control in the ICU. N Eng J Med. 2010; 363:2540-2546. 22. Krinsley J, Glycemic Variability: A strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008. 36:3008-3013. 23. Krinsley JS, Schultz MJ, Spronk PE
et al., Mild hypoglycemia is strongly associated with increased intensive care unit length of stay. Ann Intensive Care. 2011; 1:49 24. Egi M , Bellomo R , Stachowski E , et al. Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc . 2010; 85:217-224.
25. Hermanides J, Bosman RJ, Vriesendorp TM. Hypoglycemia is associated with intensive care unit mortality. Crit Care Med. 2010; 38:1430-1434. 26. Ryan MT, Savarese VW, Hipszer B, Dizdarevic I, Joseph M, Shively N, Joseph JI. Continuous glucose
monitor shows potential for early hypoglycemia detection in hospitalized patients. Diabetes Technol Ther. 2009; 11:745-747. 27. Holzinger I, Warszawska J, Kitzberger R, et al., Real time continuous glucose monitoring in critically ill patients: A prospective,
randomized trial. Diabetes Care. 2010; 33:467-472. 28. Brunner R, Kitzberger, R, Miehsler W, et al., Accuracy and reliability of a subcutaneous continuous glucose-monitoring system in critically ill patients. Crit Care Med. 2011; 39:1-6. 29. Miller M, Skladany
MJ, Ludwig CR, and Guthermann JS. Convergence of continuous glucose monitoring and in-hospital tight glycemic control: closing the gap between caregivers and industry. J Diabetes Sci Technol. 2007: 903-906. 30. Joseph J, Hipszer B, Mraovic B, et
al. Clinical need for continuous glucose monitoring in the hospital. J Diabetes Sci Technol. 2009; 3: 1309-1318. 31. Egi M, Bellomo R, Reade MC. Is reducing variability of blood glucose the real but hidden target of intensive insulin therapy? Critical Care.
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