Prof. Mridul M. Panditrao tries to explain the pros and cons about the good strategy, whcih became controversial and almost obsolete. He also tries to tract the whole aspect of the phenomenon and reviews/ RCTs/ Strict (Tight) Glycemic control (SGC/TGC), as it is called, was and still is a good strategy. It can be defined as maintenance of the blood glucose level in the range of 80-110 mg /dl. with help of dose variable and intensive insulin therapy (IIT). Since its introduction, there have been conflicting reports of its efficacy and complications. This resulted in slow but steady neglect of this very good idea leading to its almost complete demise. An effort has been made in this review, to impartially analyze all the available evidence and try to find the reasons for the negative publicity which led to the neglect or worse still, the wrong use of this protocol. Some suggestions for fair and proper implementation of the strategy are put forward. etc/

1. Strict Glycemic Control in
Critically Ill Patients:
The Demise of another Good Strategy???

2. Dr. Mridul M. Panditrao
CONSULTANT
Department of Anesthesiology
& Intensive Care
Rand Memorial Hospital
Freeport, Grand Bahama
Commonwealth of The Bahamas

3. INTRODUCTION
Problems of Hyperglycemia in ICU patients
One of the most important causes of
morbidity and mortality
In itself maybe one of the major causes of
hospital admissions
Both for medical as well as surgical reasons
Most common reason of maximum number of
hospital days (20% of all hospital days out of
about 14 million hospital days)

4. INTRODUCTION
Etio-pathogenesis of Hyperglycemia
 Multiple mechanisms of initiation
 Absolute accompaniment with sepsis
 Found even in non-diabetic patients
 Once started progresses relentlessly
 Basic 2 mechanisms
 Gluconeogenesis
 glycogenolysis

5. INTRODUCTION
Causes of hyperglcemia
Increase in Hepatic Gluconeogenesis:
Due to Increased levels of
 Glucagon (Hill, 1991)
 Cortisol (Khani, 2001)
 Growth hormone
 Cytokines IL-1 (Flores, 1990), IL-6, TNF

6. INTRODUCTION
Causes of hyperglcemia
Increase in Hepatic Glycogenolysis
Due to Increased levels of
 Adrenaline
 Noradrenaline (Watt, 2001)
 Cytokines IL-1, IL-6, TNF (Sakurai, 1996)

7. INTRODUCTION
Major physiological factors of hyperglycemia
leading to increased morbidity and mortality
 Neutrophil dysfunctions such as impaired
chemotaxis, phagocytosis, adherence, etc.
 Compliment inhibition
 Glucose stimulating the process of
inflammation as well as acting as a rich
culture medium (glucose rich edema fluid)
Collier B, Dossett L, May A et al. Glucose control and inflammatory response. Nutrition in Clinical Practice
(2008)23;1:3-15

8. INTRODUCTION
 The high risk for bacterial infection be it while
having major intervention like surgery or
anesthesia
 minor procedures like catheter placements and
intravenous access, especially central lines
 Impaired tissue and organ perfusion.
 Delayed wound healing
 Multi-organ dysfunction syndrme
The proportions of these problems are simply
mind-boggling !

10. Regime for TDD of Insulin

11. Subcutaneous insulin regime

12. Insulin for enteral feeding

13. Sliding Scale insulin protocol

14. Management of Diabetes
Mellitus in Surgical Patients

15. Management of Diabetes
Mellitus in Surgical Patients

16. I.V. Infusion to Bolus

17. Strict (Tight) Glycemic Control
• “SGC/TGC “ as it is called, was and still is a
good strategy.
• All started with a very interesting, path-
breaking study by Van den Burghe et al
• Since its introduction, there have been
conflicting reports of its efficacy and
complications.
• This resulted in slow & steady neglect of a
very good idea leading to its near-total
demise.
Van den Berghe G, Woulters P, Weekers F, et al. Intensive Insulin Therapy in Critically ill patients.
N.Eng.J. Med 2001,345(19): 1359-67.

18. Definition
Maintenance of the Blood Glucose level
in the range of 80-110 mg /dl. with help
of Dose Variable and Intensive Insulin
Therapy (IIT)

19. Greet Van den Burghe et’ al’
• In twelve months period, in Surgical ICU
• In the patients enrolled in the study (N=1548)
• With intensive insulin therapy (IIT) when the
blood glucose levels were maintained < 110 mg/
dl
 The conventional group had 1.74 times more mortality
 IIT patients had 34% reduction in mortality,
 46% reduction in sepsis,
 41% reduction in dialysis,
 50% reduction in the blood transfusion
 44% reduction in polyneuropathy.

20. Building Evidence
This was followed by few encouraging
studies by
• Lazar et al.
• Juvela et al.
• Krinsley et al.
Which were supporting the use of IIT or
strict or tight control of glucose improving
the outcomes.
• Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glycemic control in diabetic coronary artery bypass graft patients improves
perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004; 109: 1497–1502.
• Juvela S, Siironen J, Kuhmonen J. Hyperglycemia, excess weight, and history of hypertension as risk factors for poor outcome and
cerebral infarction after aneurysmal subarachnoid hemorrhage J of Neurosurgery 2005;102(6 ) :998-1003
• Krinsley JS et al. Effect of an intensive glucose management protocol on the mortality of criticall illadult patients. Mayo Clinics
Proceedings 2004; 79: 992-1000.

21. Beginning of Conflict
• Then Van den Burghe et al. came back again in 2006,
• “IIT and understanding it’s impact in medical ICU
patients”
• Could not convincingly prove significant reduction in,
in-hospital mortality
• 40% in conventional treatment vs. 37.7% in IIT group,
(p=0.33)
• The saving grace was
• significant reduction in morbidity by prevention of new kidney
injury
• earlier ventilator weaning
• so logically earlier ICU and hospital discharge.
This led to serious introspection, debates & further trials.
Van den Berghe G, Woulters P, Hermans G, et al. Intensive Insulin Therapy in the medical ICU. N.Eng.J. Med 2006,354(5): 449-61.

22. Building up of Conflict
• The plethora of evidence : very conflicting
/argumentive from both perspectives
• A study done on 10000 patients in a level I,
Intensive Care unit
• Extending for over four years
• Goal was: monitoring of the outcome--
Mainly the mortality both in ICU as well as
the hospital.
• Plaut D. A Review of Tight Glycemic Control : ADVANCE for Administrators of laboratory;21.6:42 http://laboratory-
manager.advanceweb.com/Archives/Article-Archives/A-Review-of-Tight-Glycemic-Control.aspx: posted on June 5, 2012,
accessed10/10/2012

23. Building up of Conflict
Authors used 3 glycemic control protocols
i. No control protocol (no glucose
limits)
ii. Target glucose of 80-130 mg per dl.
iii. Standard (tight glucose control) of 80-
110 mg per dl.
• Treggiari MV, Karir V, Yanez ND et al. Intensive Insulin Therapy and mortality in critically ill patients. Crit Care 2008,
12(1): R29

24. Building up of Conflict
The results were striking.
• In all the 3 groups, the use of insulin was
increased by 9%, 25%, and 42% respectively
• But contradictory to the previous thinking,
there was overall higher mortality in group
iii. (Odds Ratio 1.15)
• Especially in patients with ICU stay of 3 or
lesser days
• As would be expected nearly 4 times
increase in the incidence of hypoglycemia
from group i through ii to iii

25. Crescendo of Conflict
Study in a trauma center, retrospective
2000 adults with 2 protocols
i. Pre-TGC (80-200 mg per dl)
ii. Post TGC (80-110 mg per dl)
• Eriksson EA, Christianson DA, Venderkolk WE et al. Tight Blood Glucose Control in trauma patients: who really
benefits? J. Emerg. Trauma, Shock; 4(3): 359-364

26. Crescendo of Conflict
• The most important finding was that the
mortality was significantly higher in Pre
TGC period (21.5%)
• As compared to that of post TGC period
(14.7%)
• Hospital stay was much lesser in Post
TGC

27. Crescendo of Conflict
• To put to rest all these controversies, NIH
funded a study from 2003-2008
• It appeared that TGC had 25% higher
mortality
• The study was voluntarily discontinued
• Welch HG. Schwartz LM, Woloshin S. Over diagnosed, making people sick in the pursuit of health. Publishers:
Beacon Press, Massachusetts, c 2011.

28. Final Straw that broke camel’s..
NICE-SUGAR study (Normoglycemia in Intensive Care
Evaluation-Survival Using Glucose Algorithm Regulation
study)
• Published in 2009,
• 38 tertiary hospitals and 4 community hospitals,
• 6030 patient evaluable in the period of 5 years
(December 2004-November 2008)
• Again the groups were Intensive vs. Conventional;
i.e. 81 to 108 mg per dl vs. <180 mg per dl glucose levels
were the targets
• The patients were randomized but not blinded
• The mean age was 60 years with equal distribution by
gender and Apache II scoring of 21 in each group.
• NICE-SUGAR Study: Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Intensive versus conventional glucose
control in critically ill patients.N Engl J Med 2009, 360:1283-1297.

29. Final Straw that broke camel’s..
The outcome majors were:
• 90-day mortality
• Duration of mechanical ventilation
• renal replacement therapy,
• Length of stay in ICU/hospital & cause of
death.
• 28-day all-cause mortality,
• incidence of organ system failure,
• transfusion requirements
• new positive blood cultures.

30. Final Straw that broke camel’s..
Results were very revealing:
• Mortality at 90 days was 27.5% in IIT group
vs. 24.9% in conventional group (CT)
(Odds Ratio- O.R. 1.14, p=0.02)
• Mortality at 28 days was 22.3% in IIT group
vs. 20.8% in CT ( O.R. 1.09, p=0.17)
• Location of death in ICU
65.9% in IIT vs. 66.3% in CT
In-hospital 26.9% IIT vs. 26.2% CT

31. Final Straw that broke camel’s..
Absolutely no difference, in both groups
in the length of the ICU stay of 6 days
hospital stay of 17 days
on-ventilator stay of 6.6 days in both the
groups
hypoglycemia (glucose levels<40 mg per dl)
was found in 6.8% patients in IIT as
compared to 0.5% in CT ,(O.R.) of 14.7.

32. Outcome
• Total chaos
• Initial confabulation
• Later dilemma
• Final complete indifference and
avoidance/neglect of SGC/TGC

33. WHAT WENT WRONG?
• In their overenthusiasm to implement
the IIT/ SGC/TGC, the Researchers
and clinicians went overboard with
their own half-baked protocols,
without enough planning and giving
consideration to the available
infrastructure!!!!!!

34. Aftermath, review & analysis!
A very interesting review tries to answer few
very important and pertinent queries like:
• How safe is the IIT, with various Glycemic
targets from risk of hypoglycemia?
• How tightly blood glucose must be
controlled for this approach to be effective?
• What role does the accuracy of blood
glucose measurement play in affecting the
study of this method?
 Klonoff DC. Intensive insulin therapy in critically ill hospitalized patients; making it safe and effective. J. Diabeteco Sci.
Tecnol 2011; 5(3): 755-67.

35. Aftermath, review & analysis!
One has to understand basic flaw that can creep in
while designing of SGC/TGC:
• Targets/ goals, risks and benefits TGC protocol
(IIT), might be different.
• With the standardization/accuracy of blood
glucose monitoring, the risk of overdosing of
insulin & hypo/hyperglycemia will be reduced
• The various methods of glucose measurement
– Handheld devices (POCT),
– Paper or plastic sticks which use a drop of blood
– Blood gas analyzers/other analyzers in the central
labs),
The values of these methods have inherent fallacies/
variations.

36. Aftermath, review & analysis!
• Accordingly it has been documented
that
Fasting Blood Glucose levels in the venous
sample are :
 5 -10% lower than in arterial sample,
 may be up to 15% lower than in capillary
sample.

37. Factors which can be considered as
confounding
• Accuracy and reproducibility of results
• User Expertise
• Types of devices
• Anemia causes false evaluation of glucose
levels
• Anemia is one of the commonest findings in
critically ill patients
• As already mentioned, arterial, plasma,
serum, capillary, venous samples give
different results.

38. Et’ tu Insulin?
Which insulin to be given:
The onsets, peaks & duration of various
preparations varies :
Regular: 30-60 min, 2-4 hrs. 6-10 hrs
NPH/Lente 1-2 hrs 4-8 hrs 10-20 hrs.
Lispro/Aspat 5-15 min. 1-2 hrs 4-6 hrs
Glargine/ lantus 1-2 hrs Flat 20-24 hrs.

39. HOW TO OVERCOME?
The Leuven IIT trials were successful and effective because:
• The SGC was applied by the insulin infusion via central
venous line and administered using very precise syringe
infusion pumps
• Subtle dose adjustments, made by ICU nurses, using
guidelines to keep blood glucose to lower normal limit (81-
110 mg per dl)
• ’High level of intuitive decision making’
• The blood glucose level measurement in arterial blood was
carried out at strict time interval points using accurate blood
gas analyzers.
• The measurements were carried out at an intermediate time
interval points if required.
• Patients were always in a non-fasting state at all times.
•Schultz MJ et al http://www.ihe-online.com/feature-articles/strict-or-loose-glycemic-control-in-critically-ill-patients-conflicting-evidence/trackback/1/accessed on 10/10/2012
•Arabi YM, Dabbagh OC, Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients.Crit Care Med 2008, 36:3190-3197.
•De la Rosa GD, Donado JH, Restrepo AH et al: Strict glycemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomized clinical trial.Crit care 2008; 12: R120
•Brunkhorst FM, Engel C, Bloos F. et al Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 125- 139
•Preiser JC et al. Intensive care Med 2009; 35 (10): 1738 -48
•Preiser JC, Devos P, A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study.
Intensive Care Med 2009, 35:1738-1748.
•Van den Berghe G, Schetz M, Vlasselaers D, et al. Clinical review: Intensive insulin therapy in critically ill patients: NICE-SUGAR or Leuven blood glucose target?
J ClinEndocrinolMetab 2009, 94:3163-3170.

40. HOW TO OVERCOME?
Judging, on the basis of these observations - The
later date trials, reports and assessments----- glaring
fallacies are:
 Instead of syringe infusion pumps, volumetric
infusion pumps were used.
 Level of knowledge, training about guidelines and
involvement of the ICU nurses is disputed.
 In addition the decision making, training was related
to only prevention and correction of hypoglycemia.
 Fallacies of blood glucose level measurements played
a major factor
- Use of capillary blood samples as an indicator of
glycemic control is inferior
- So are the assessment of the glucose levels in the
absence of accurate glucose analyzers.

41. HOW TO OVERCOME?
Last but not the least(rather most important
key factor in the success of Leuven trials):
The pure, simple plan and high level of
intuitive decision making
 skill and motivation on the part of ICU
nurses
 actual absence of highly explicit rules
required in closed loop, paper-based &
computer-based decision support systems
required in sliding scales.

42. HOW TO OVERCOME?
• This discussion about what went, goes and will
go wrong can go on endlessly,
• Especially when discussing improperly and
inadequately designed and executed randomized
trials involving SGC/TGC.
• One has to, without an iota of doubt, accept that
hyperglycemia is deleterious to the critically ill
• There is adequate evidence that lowering of
blood glucose levels have the potential to
prevent injury in already compromised organs in
the patients.
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.
Finney SJ, Zekveld C, Elia A, Evans TW: Glucose control and mortality in critically ill patients. JAMA 2003, 290:2041-2047.
Krinsley JS: Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo ClinProc 2003, 78:1471-1478.
Falciglia M, Freyberg RW, Almenoff PL, et al. Hyperglycemia-related mortality in critically ill patients varies with admission diagnosis. Crit Care Med 2009, 37:3001-3009.

43. Take Home Message!
So while planning your own strategies to
achieve these targets, one has to keep in mind:
– Perfect planning of design of your protocols!
– Precise methodology to achieve optimal target
levels of blood glucose.
– Critical check of methods and equipment used
to measure and control the glucose.
– Try to extrapolate all the available evidence
from various RCTs to your own circumstances
and infrastructure.
•Chase JG, Shaw G, Le Compte A. et al. Implementation and evaluation of SPRINT protocol for Tight Glycemic control in Critically ill patients: A clinical practice change Critical care 2008; 12: R 49

44. Take Home Message!
Evolving newer strategies/protocol of
maintaining Good Glycemic Control (GGC):
• Continuous variable rate of intravenous insulin
drip especially in:
 Patients undergoing major surgery
 Remaining NPO for prolonged duration
 Patients with Myocardial infarction,
 Diabetic keto-acidosis or
 Patients on chronic steroid administration.
• SPRINT (Specialized Regulative Insulin
Nutrition Table) protocol
Chase JG, Shaw G, Le Compte A. et al. Implementation and evaluation of SPRINT protocol for Tight Glycemic control in Critically ill
patients: A clinical practice change Critical care 2008; 12: R 49

45. CONCLUSION
• Hyperglycemia in hospitalized, especially
critically ill patients is undoubtedly
harmful
• Adequate glycemic control has been proven
to be beneficial by multiple SGC, TGC
trials carried out by various workers
• Some confounding evidence of supposed
deleterious effects of SGC/TGC has caused
lot of confabulations and dilemmas leading
to near-total demise of a good therapeutic
strategy.

46. CONCLUSION
• One has to be very circumspect
• Have clear understanding of your own
infrastructural and logistical short-
comings while planning and
implementing SGC/TGC protocols
• It would be prudent to do thorough stock
checking and defining our own target
limits of SGC/TGC before embarking on
this promising but tricky journey.