Strict Glycemic Control in Critically Ill Patients:

The Demise of another Good Strategy???

Dr. Mridul M. PanditraoCONSULTANT

Department of Anesthesiology & Intensive Care

Rand Memorial HospitalFreeport, Grand Bahama

Commonwealth of The Bahamas

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 reasonsMost common reason of maximum number

of hospital days (20% of all hospital days out of about 14 million hospital days)

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

Gluconeogenesisglycogenolysis

INTRODUCTION

Causes of hyperglcemiaIncrease in Hepatic

Gluconeogenesis: Due to Increased levels of

Glucagon (Hill, 1991) Cortisol (Khani, 2001) Growth hormone Cytokines IL-1 (Flores, 1990), IL-6,

TNF

INTRODUCTION

Causes of hyperglcemiaIncrease in Hepatic Glycogenolysis

Due to Increased levels of Adrenaline Noradrenaline (Watt, 2001) Cytokines IL-1, IL-6, TNF (Sakurai,

1996)

INTRODUCTIONMajor 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

INTRODUCTIONThe 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 healingMulti-organ dysfunction syndrme

The proportions of these problems are simply mind-boggling !

Regime for TDD of Insulin

Subcutaneous insulin regime

Insulin for enteral feeding

Sliding Scale insulin protocol

Management of Diabetes Mellitus in Surgical Patients

Management of Diabetes Mellitus in Surgical Patients

I.V. Infusion to Bolus

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.

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)

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/ dlThe 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.

Building EvidenceThis 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.

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.

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

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

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

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

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

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.

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.

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.

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

Final Straw that broke camel’s..

Absolutely no difference, in both groupsin the length of the ICU stay of 6 dayshospital 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.

Outcome

• Total chaos• Initial confabulation• Later dilemma• Final complete indifference and

avoidance/neglect of SGC/TGC

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!!!!!!

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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) protocolChase 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

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.

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.

Thank

You!