Strict Glucose Control in the Critically Ill – Not Such a Bad Thing to do
Two large randomized trials showed that strict glucose control (SGC)
aiming at normoglycaemia (blood glucose concentrations (BGC) between
80–110 mg/dl) benefits surgical and medical intensive care unit
(ICU)–patients [1,2]. These favorable effects were confirmed in a cohort
study [3] and a meta-analysis [4]. SGC is presently recommended standard
of care for the critically ill by several groups, including the Joint
Commission on Accreditation of Healthcare Organization (www.jcaho.org),
the Institute for Healthcare Improvement (www.ihi.org) and the Volunteer
Hospital Organization (www.vha.com). In addition, SGC is promoted as part
of a care bundle for septic patients by the American Thoracic Society
(www.thoracic.org) and experts in the field [5]. Finally, SGC is, to some
extent, a benchmark for the quality of ICU-care [6]. Despite all these
recommendations, GCS is far from being implemented [7-10].
Opinion pieces in the literature have raised concern about the benefit of
SGC for critically ill patients. The relatively high mortality among
patients in the control group in one of the abovementioned studies[1], the
frequent administration of parenteral calories, not common in all ICUs –
but in accordance with existing guidelines, the single-centre design, and
the fact that investigators could not be blinded lead to criticism [6,11].
While awaiting the results of two multi-centre trials (the GLUControl
trial [12] and the NICE-SUGAR trial [13]), different recommendations are
made by experts: some argue that although the evidence for SGC does not
yet support grade A-recommendation, it does appear to be stronger than
that for continuing a policy of tolerating hyperglycaemia [11]. Others
suggest to target BGC <_150 mg="mg" dl="dl" _6.="_6." in="in" your="your" journal="journal" an="an" editorial="editorial" comment="comment" by="by" dr.="dr." watkinson="watkinson" _14="_14" raised="raised" several="several" arguments="arguments" against="against" sgc="sgc" which="which" we="we" do="do" not="not" totally="totally" agree="agree" with.="with." p="p"/>First, concluding that the second trial by van den Berghe [2] showed no
benefit is incorrect. The first (surgical) study had shown that at least 3
days of IIT are needed to reduce hospital mortality [1]. Based on this
information the second (medical) study was statistically powered for
mortality effect among patients treated at least a third day. As
hypothesized, a 10% absolute mortality reduction was observed in this
predetermined target group together with a 3% lower mortality in the
intention-to-treat group. Mortality in the intention-to-treat group was,
in fact, significantly reduced (OR 0.77 (95%CI 0.60-0.99); P = 0.04) when
correcting for pre-existing risk factors.
Second, the German SepNet study was stopped early for safety reasons, as
in 12% of patients hypoglycaemia occurred [15]. This study, however, does
not provide information on efficacy, as it was under-powered for a
mortality effect, and morbidity was not reported. In addition, the CREATE-
ECLA trial does not serve as an indirect evidence against SGC [16] as in
this study, GIK caused higher instead of lower blood glucose levels in the
intervention group. The lack of glucose control is in fact the explanation
for the negative results of certain GIK trials [17].
Third, the suggestion that SGC may be harmful is speculative. The most
feared consequence of hypoglycemia is potential irreversible neurological
damage. But how low does the hypoglycaemia need to be, and for how long,
for this to occur [18]? Repeated episodes of insulin-induced hypoglycaemic
coma for periods ranging from ¾ – 3 hours for the treatment of opiate
addiction and schizophrenia has been found to have minimal long-term
effects and a mortality of less than 1% [19]. In addition, long-term
follow-up of patients with diabetes mellitus randomized in a large
prospective trial of SGC failed to detect any association between the
frequency of severe hypoglycaemia and cognitive decline [20]. Only subtle,
reversible impairments of attention could be detected in non-diabetic
patients undergoing dynamic pituitary function assessment using
hypoglycaemic stress with BGC of 29 mg/dl [21]. Finally, in 2 years of SGC
Mackinzie recorded 128 instances of hypoglycaemia (blood glucose
concentration <40 mg/dl) out of 29,733 measurements (median value of
33 mg/dl (IQR 25 – 36 mg/dl) – median duration of 18.2 minutes [8.4 – 37.5
minutes]) [22]. Their incidence of hypoglycaemia decreased significantly
with time. The risk of a patient suffering prolonged severe hypoglycaemia
was concluded to be small and the risk of this resulting in significant
neurological damage even smaller.
Dr. Watkinson is surprised that a simple change in blood glucose
management reduces mortality more than other far more costly and complex
interventions. Does he suggest cheap strategies could not possibly be
beneficial? The impacts of lower tidal volumes in patients with acute lung
injury [23], early goal directed therapy [24], steroids for refractory
shock [25] and selective decontamination of the digestive tract [26] do
suggest otherwise.
Awaiting results from ongoing multi-centre trials, current evidence
supports SGC in ICU-patients.
Marcus J Schultz, Annick ANM Royakkers, Peter E Spronk, Alexander
Wilmer and Greet van den Berghe
References
1. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F,
Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive
insulin therapy in the critically ill patients. N Engl J Med 2001:345:1359
-1367.
2. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ,
Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin
therapy in the medical ICU. N Engl J Med 2006:354:449-461.
3. Krinsley JS. Effect of an intensive glucose management protocol on
the mortality of critically ill adult patients. Mayo Clin Proc 2004:79:992
-1000.
4. Pittas AG, Siegel RD, Lau J. Insulin Therapy and In-Hospital
Mortality in Critically Ill Patients: Systematic Review and Meta-analysis
of Randomized Controlled Trials. JPEN J Parenter Enteral Nutr 2006:30:164-
172.
5. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J,
Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL,
Vincent JL, Levy MM. Surviving Sepsis Campaign guidelines for management
of severe sepsis and septic shock. Crit Care Med 2004:32:858-873.
6. Malhotra A. Intensive insulin in intensive care. N Engl J Med
2006:354:516-518.
7. McMullin J, Brozek J, Jaeschke R, Hamielec C, Dhingra V, Rocker G,
Freitag A, Gibson J, Cook D. Glycemic control in the ICU: a multicenter
survey. Intensive Care Med 2004:30:798-803.
8. Mackenzie I, Ingle S, Zaidi S, Buczaski S. Tight glycaemic
control: a survey of intensive care practice in large English hospitals.
Intensive Care Med 2005:31:1136.
9. Schultz MJ, Spronk PE, Moeniralam HS. Tight glycaemic control: a
survey of intensive care practice in the Netherlands. Intensive Care Med
2006:32:618-619.
10. Mitchell I, Finfer S, Bellomo R, Higlett T. Management of blood
glucose in the critically ill in Australia and New Zealand: a practice
survey and inception cohort study. Intensive Care Med 2006:
11. Angus DC, Abraham E. Intensive insulin therapy in critical
illness. Am J Respir Crit Care Med 2005:172:1358-1359.
12. National Institute of Health. Glucoontrol study: comparing the
effects of two glucose control regimens by insulin in intensive care unit
patients. http://clinicaltrials.gov/show/NCT00107601 [accessed May 2006].
13. Current controlled trials. A multi-centre, open label, randomised
cotrolled trial of two target ranges for glycemic control in intensive
care unit patients. http://controlled-
trials.com/isrctn/trial/ISRCTN04968275/0/04968275.htm [accessed may 2006].
14.Watkinson P, Barber VS, Young JD. Strict glucose control in the
critically ill. Bmj 2006:332:865-866.
15. Brunkhorst FM, Kuhnt E, Engel C, Meier-Hellmann A, Raggaler M,
Quintel M, Weiler N, Grundling M, Oppert M, Deufel T. Intensive insulin in
patients with severe sepsis and septic shock is associated with an
increased rate of hypoglycemia -results from a randomized multicenter
study (VISEP). Infection 2005:33:19-20.
16. Mehta SR, Yusuf S, Diaz R, Zhu J, Pais P, Xavier D, Paolasso E,
Ahmed R, Xie C, Kazmi K, Tai J, Orlandini A, Pogue J, Liu L. Effect of
glucose-insulin-potassium infusion on mortality in patients with acute ST-
segment elevation myocardial infarction: the CREATE-ECLA randomized
controlled trial. Jama 2005:293:437-446.
17. Malmberg K, Ryden L, Wedel H, Birkeland K, Bootsma A, Dickstein
K, Efendic S, Fisher M, Hamsten A, Herlitz J, Hildebrandt P, MacLeod K,
Laakso M, Torp-Pedersen C, Waldenstrom A. Intense metabolic control by
means of insulin in patients with diabetes mellitus and acute myocardial
infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J
2005:26:650-661.
18. Mackenzie I, Ingle S, Zaidi S, Buczaski S. Hypoglycaemia? So
what! Intensive Care Med 2006:in press.
19. Sargant W, Slater E. Physical methods of treatment in psychiatry.
In: Livingstone, Edinburgh 1944: pp 171.
20. Austin EJ, Deary IJ. Effects of repeated hypoglycemia on
cognitive function: a psychometrically validated reanalysis of the
Diabetes Control and Complications Trial data. Diabetes Care 1999:22:1273-
1277.
21. Osorio I, Arafah BM, Mayor C, Troster AI. Plasma glucose alone
does not predict neurologic dysfunction in hypoglycemic nondiabetic
subjects. Ann Emerg Med 1999:33:291-298.
22. Mackenzie I, Ingle S, Zaidi S, Buczaski S. Hypoglycaemia? So
what! Intensive Care Med 2006:32:620-621.
23. Ventilation with lower tidal volumes as compared with traditional
tidal volumes for acute lung injury and the acute respiratory distress
syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med
2000:342:1301-1308.
24. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B,
Peterson E, Tomlanovich M. Early goal-directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 2001:345:1368-1377.
25. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B,
Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P,
Bellissant E. Effect of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic shock. JAMA
2002:288:862-871.
26. de Jonge E, Schultz MJ, Spanjaard L, Bossuyt PM, Vroom MB,
Dankert J, Kesecioglu J. Effects of selective decontamination of digestive
tract on mortality and acquisition of resistant bacteria in intensive
care: a randomised controlled trial. Lancet 2003:362:1011-1016.
Competing interests:
None declared
Competing interests:
No competing interests
16 June 2006
Marcus J Schultz
Internist-intensivist - Research Coordinator
Annick A.N.M. Royakkers, Peter E Spronk, Alexander Wilmer and Greet van den Berghe
Dept of Intensive Care, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Rapid Response:
Strict Glucose Control in the Critically Ill – Not Such a Bad Thing to do
Two large randomized trials showed that strict glucose control (SGC)
aiming at normoglycaemia (blood glucose concentrations (BGC) between
80–110 mg/dl) benefits surgical and medical intensive care unit
(ICU)–patients [1,2]. These favorable effects were confirmed in a cohort
study [3] and a meta-analysis [4]. SGC is presently recommended standard
of care for the critically ill by several groups, including the Joint
Commission on Accreditation of Healthcare Organization (www.jcaho.org),
the Institute for Healthcare Improvement (www.ihi.org) and the Volunteer
Hospital Organization (www.vha.com). In addition, SGC is promoted as part
of a care bundle for septic patients by the American Thoracic Society
(www.thoracic.org) and experts in the field [5]. Finally, SGC is, to some
extent, a benchmark for the quality of ICU-care [6]. Despite all these
recommendations, GCS is far from being implemented [7-10].
Opinion pieces in the literature have raised concern about the benefit of
SGC for critically ill patients. The relatively high mortality among
patients in the control group in one of the abovementioned studies[1], the
frequent administration of parenteral calories, not common in all ICUs –
but in accordance with existing guidelines, the single-centre design, and
the fact that investigators could not be blinded lead to criticism [6,11].
While awaiting the results of two multi-centre trials (the GLUControl
trial [12] and the NICE-SUGAR trial [13]), different recommendations are
made by experts: some argue that although the evidence for SGC does not
yet support grade A-recommendation, it does appear to be stronger than
that for continuing a policy of tolerating hyperglycaemia [11]. Others
suggest to target BGC <_150 mg="mg" dl="dl" _6.="_6." in="in" your="your" journal="journal" an="an" editorial="editorial" comment="comment" by="by" dr.="dr." watkinson="watkinson" _14="_14" raised="raised" several="several" arguments="arguments" against="against" sgc="sgc" which="which" we="we" do="do" not="not" totally="totally" agree="agree" with.="with." p="p"/>First, concluding that the second trial by van den Berghe [2] showed no
benefit is incorrect. The first (surgical) study had shown that at least 3
days of IIT are needed to reduce hospital mortality [1]. Based on this
information the second (medical) study was statistically powered for
mortality effect among patients treated at least a third day. As
hypothesized, a 10% absolute mortality reduction was observed in this
predetermined target group together with a 3% lower mortality in the
intention-to-treat group. Mortality in the intention-to-treat group was,
in fact, significantly reduced (OR 0.77 (95%CI 0.60-0.99); P = 0.04) when
correcting for pre-existing risk factors.
Second, the German SepNet study was stopped early for safety reasons, as
in 12% of patients hypoglycaemia occurred [15]. This study, however, does
not provide information on efficacy, as it was under-powered for a
mortality effect, and morbidity was not reported. In addition, the CREATE-
ECLA trial does not serve as an indirect evidence against SGC [16] as in
this study, GIK caused higher instead of lower blood glucose levels in the
intervention group. The lack of glucose control is in fact the explanation
for the negative results of certain GIK trials [17].
Third, the suggestion that SGC may be harmful is speculative. The most
feared consequence of hypoglycemia is potential irreversible neurological
damage. But how low does the hypoglycaemia need to be, and for how long,
for this to occur [18]? Repeated episodes of insulin-induced hypoglycaemic
coma for periods ranging from ¾ – 3 hours for the treatment of opiate
addiction and schizophrenia has been found to have minimal long-term
effects and a mortality of less than 1% [19]. In addition, long-term
follow-up of patients with diabetes mellitus randomized in a large
prospective trial of SGC failed to detect any association between the
frequency of severe hypoglycaemia and cognitive decline [20]. Only subtle,
reversible impairments of attention could be detected in non-diabetic
patients undergoing dynamic pituitary function assessment using
hypoglycaemic stress with BGC of 29 mg/dl [21]. Finally, in 2 years of SGC
Mackinzie recorded 128 instances of hypoglycaemia (blood glucose
concentration <40 mg/dl) out of 29,733 measurements (median value of
33 mg/dl (IQR 25 – 36 mg/dl) – median duration of 18.2 minutes [8.4 – 37.5
minutes]) [22]. Their incidence of hypoglycaemia decreased significantly
with time. The risk of a patient suffering prolonged severe hypoglycaemia
was concluded to be small and the risk of this resulting in significant
neurological damage even smaller.
Dr. Watkinson is surprised that a simple change in blood glucose
management reduces mortality more than other far more costly and complex
interventions. Does he suggest cheap strategies could not possibly be
beneficial? The impacts of lower tidal volumes in patients with acute lung
injury [23], early goal directed therapy [24], steroids for refractory
shock [25] and selective decontamination of the digestive tract [26] do
suggest otherwise.
Awaiting results from ongoing multi-centre trials, current evidence
supports SGC in ICU-patients.
Marcus J Schultz, Annick ANM Royakkers, Peter E Spronk, Alexander
Wilmer and Greet van den Berghe
References
1. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F,
Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive
insulin therapy in the critically ill patients. N Engl J Med 2001:345:1359
-1367.
2. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ,
Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin
therapy in the medical ICU. N Engl J Med 2006:354:449-461.
3. Krinsley JS. Effect of an intensive glucose management protocol on
the mortality of critically ill adult patients. Mayo Clin Proc 2004:79:992
-1000.
4. Pittas AG, Siegel RD, Lau J. Insulin Therapy and In-Hospital
Mortality in Critically Ill Patients: Systematic Review and Meta-analysis
of Randomized Controlled Trials. JPEN J Parenter Enteral Nutr 2006:30:164-
172.
5. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J,
Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL,
Vincent JL, Levy MM. Surviving Sepsis Campaign guidelines for management
of severe sepsis and septic shock. Crit Care Med 2004:32:858-873.
6. Malhotra A. Intensive insulin in intensive care. N Engl J Med
2006:354:516-518.
7. McMullin J, Brozek J, Jaeschke R, Hamielec C, Dhingra V, Rocker G,
Freitag A, Gibson J, Cook D. Glycemic control in the ICU: a multicenter
survey. Intensive Care Med 2004:30:798-803.
8. Mackenzie I, Ingle S, Zaidi S, Buczaski S. Tight glycaemic
control: a survey of intensive care practice in large English hospitals.
Intensive Care Med 2005:31:1136.
9. Schultz MJ, Spronk PE, Moeniralam HS. Tight glycaemic control: a
survey of intensive care practice in the Netherlands. Intensive Care Med
2006:32:618-619.
10. Mitchell I, Finfer S, Bellomo R, Higlett T. Management of blood
glucose in the critically ill in Australia and New Zealand: a practice
survey and inception cohort study. Intensive Care Med 2006:
11. Angus DC, Abraham E. Intensive insulin therapy in critical
illness. Am J Respir Crit Care Med 2005:172:1358-1359.
12. National Institute of Health. Glucoontrol study: comparing the
effects of two glucose control regimens by insulin in intensive care unit
patients. http://clinicaltrials.gov/show/NCT00107601 [accessed May 2006].
13. Current controlled trials. A multi-centre, open label, randomised
cotrolled trial of two target ranges for glycemic control in intensive
care unit patients. http://controlled-
trials.com/isrctn/trial/ISRCTN04968275/0/04968275.htm [accessed may 2006].
14.Watkinson P, Barber VS, Young JD. Strict glucose control in the
critically ill. Bmj 2006:332:865-866.
15. Brunkhorst FM, Kuhnt E, Engel C, Meier-Hellmann A, Raggaler M,
Quintel M, Weiler N, Grundling M, Oppert M, Deufel T. Intensive insulin in
patients with severe sepsis and septic shock is associated with an
increased rate of hypoglycemia -results from a randomized multicenter
study (VISEP). Infection 2005:33:19-20.
16. Mehta SR, Yusuf S, Diaz R, Zhu J, Pais P, Xavier D, Paolasso E,
Ahmed R, Xie C, Kazmi K, Tai J, Orlandini A, Pogue J, Liu L. Effect of
glucose-insulin-potassium infusion on mortality in patients with acute ST-
segment elevation myocardial infarction: the CREATE-ECLA randomized
controlled trial. Jama 2005:293:437-446.
17. Malmberg K, Ryden L, Wedel H, Birkeland K, Bootsma A, Dickstein
K, Efendic S, Fisher M, Hamsten A, Herlitz J, Hildebrandt P, MacLeod K,
Laakso M, Torp-Pedersen C, Waldenstrom A. Intense metabolic control by
means of insulin in patients with diabetes mellitus and acute myocardial
infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J
2005:26:650-661.
18. Mackenzie I, Ingle S, Zaidi S, Buczaski S. Hypoglycaemia? So
what! Intensive Care Med 2006:in press.
19. Sargant W, Slater E. Physical methods of treatment in psychiatry.
In: Livingstone, Edinburgh 1944: pp 171.
20. Austin EJ, Deary IJ. Effects of repeated hypoglycemia on
cognitive function: a psychometrically validated reanalysis of the
Diabetes Control and Complications Trial data. Diabetes Care 1999:22:1273-
1277.
21. Osorio I, Arafah BM, Mayor C, Troster AI. Plasma glucose alone
does not predict neurologic dysfunction in hypoglycemic nondiabetic
subjects. Ann Emerg Med 1999:33:291-298.
22. Mackenzie I, Ingle S, Zaidi S, Buczaski S. Hypoglycaemia? So
what! Intensive Care Med 2006:32:620-621.
23. Ventilation with lower tidal volumes as compared with traditional
tidal volumes for acute lung injury and the acute respiratory distress
syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med
2000:342:1301-1308.
24. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B,
Peterson E, Tomlanovich M. Early goal-directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 2001:345:1368-1377.
25. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B,
Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P,
Bellissant E. Effect of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic shock. JAMA
2002:288:862-871.
26. de Jonge E, Schultz MJ, Spanjaard L, Bossuyt PM, Vroom MB,
Dankert J, Kesecioglu J. Effects of selective decontamination of digestive
tract on mortality and acquisition of resistant bacteria in intensive
care: a randomised controlled trial. Lancet 2003:362:1011-1016.
Competing interests:
None declared
Competing interests: No competing interests