Perioperative Glucose Management
An Evolving Standard of Care
Objectives
• Harmful effects of hyperglycemia
• Beneficial effects of insulin + glycemic control
• Observational studies
• Interventional studies
• Protocol implementation
Surgery
• Stress + fasting associated with surgery leads to
relative insulin deficiency
– ↑ insulin resistance
– ↓ insulin secretion
• Insulin deficiency leads to hyperglycemia + excess
circulating free fatty acids
Gandhi GY et al. Mayo Clin Proc 2008;83:418-30
Surgical stress
• Degree of hyperglycemia depends on severity +
extent of tissue trauma; anesthesia factors
• Elective intraperitoneal surgery +nondiabetics:
↑ 126-180 mg/dL (7-10 mmol/L)
• Cardiac surgery: impressive disturbance of
glucose homeostasis.
– > 270 mg/dL (15 mmol/L) in nondiabetics
– > 360 mg/dL (20 mmol/L) in diabetics
Schricker + Carvalho. J CTVA 2005;19:684-8
Surgical stress + hyperglycemia
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Typical metabolic + endocrine alterations
↑ glucose production
↓ glucose utilization
↑ renal absorption of filtered glucose
↓ insulin activity
Cardiac surgery: pancreatic hypoperfusion, excess
glucose in prime + cardioplegia, hypothermia
Schricker + Carvalho J CTVA 2005. Smith et al: JCTVA 2005;19:201-8
Immune system + hyperglycemia
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Impaired microvascular response
Adhesion + transmigration of leucocytes
Complement cascade
Cytokine network
Chemokine formation
Chemotaxis, phagocytosis
Generation of reactive O2 species
Neutrophil apoptosis
Turina M. CCM 2005;33:1624
Beneficial effects of glycemic control
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Protects hepatocytic mitochondria
Improved PMN neutrophil function
Better bactericidal + opsonic activity
Partial correction of abnormal serum lipids
Counteracts catabolism of critical illness
↑ endothelial function + myocardial protection
↓ inflammation + apoptosis
Brindley et al. CJA 2006;53:947-9
Beneficial effects of insulin
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Stimulates glucose uptake + lipogenesis
Inhibits lipolysis, proteolysis +glycogenolysis
Multiple nonmetablic effects:
↓ levels circulating adhesion molecule + E-selectin
↓ circulating NO levels by suppressing inducible
nitric oxide synthetase gene expression
• Protects vascular endothelium from injury
• Prevents organ system dysfunction
Schricker J CTVA 2005. Langouche et al. J Clin Invest 2005.
Insulin infusion + glycemic control
• Avoids sustained cellular glucose overload +
toxicity in many cell types
• ↓ likelihood for vital organ dysfunction
• Prevents damage to mitochondrion
• Blunts stress response to CPB
Van den Berghe Ann Int Med 2007;146;307-8
Albacker et al. Ann Thorac Surg 2008;86:20-7
Observational studies
• Relationship of hyperglycemia + adverse
outcomes well investigated
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Neurologic illness, trauma
Myocardial infarction
Burns
Cardiac surgery
Critical care
Kidney transplant donors
Gandhi et al Mayo Clin Proc 2008;83:418-30.
Blasi-Ibanez et al. Anesthesiology 2009;110:333
Interventional studies
• DCCT + EDIC 1993+ 2003; UKPDS 1998 + 2008
↓ complications + mortality in diabetics
• DIGAMI 2: ↓ mortality in diabetics w AMI
[Eur Heart J 2005]
• Leuven trial 2001: 34% ↓ mortality + 40-50% ↓ in
important co-morbidities
[NEJM 2001, postop surgical pts]
• Krinsley: 29% ↓ mortality + ↓ renal insufficiency
[Mayo Clin Proc 2004, postop ICU]
Cardiac Surgery + Intraop Insulin
• Furnary et al: ↓ mortality + deep sternal
wound infections in diabetics [Ann Thor Surg
1999 + J TCVS 2003]
• Lazar et al: ↓ infection, Afib, ischemia,
inotropes, LOS, mortality in diabetics
[Circulation 2004]
Portland Diabetic Project
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23,619 cardiac surgery pts, 1987-2005
5510 had diabetes, 40% on insulin
1987-92: subcut regular insulin, target 150-200
1992-05: continuous regular insulin, target ↓ over
time, currently 70-110 in ICU
• 3-BG= average value of all glucose measures on
each of 3 days: POD 0, 1, 2 [24-72 measures]
• Current 3- BG = 121 mg/dl
Furnary AP. Endocrine Practice 2006;12[Supp 3]:22-6.
http://www.providence.org/protocoldownload
Portland Diabetic Project, results
• ↓ risk of death by 60%, mainly pump failure + afib
(4.4% vs 1.1%)
• Annual CABG mortality < nondiabetics
• ↓ risk of deep sternal wound infection by 77%
(2% to 0.6%)
• Other effects: ↓ transfusion, afib, inotropes,
infections, LOS
Furnary AP, Wu YX. Endocrine Practice 2006;12 (Supp 3) :22-6
Boston GIK Study
• 149 diabetic pts, CABG
• Randomized to GIK vs std therapy
• GIK started before anesthesia induction +
continued until 12 hr postop.
• GIK: insulin 4.8 u/hr+ dextrose 1.5 g/h + KCL 2.4
mEq//h. Target: 125-200.
• Std therapy: sliding scale subcut insulin if > 250
Lazar et al. Circulation 2004;109:1497-1502
Boston GIK Study, results
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↓ glucose:
↓ afib:
↓ LOS
↓ infections:
Other: postop:
Other: 2yrs:
138 vs 260 [12 hr postop]
17 vs 42%
6.5 vs 9.2 days
0 vs 13 pts [pneumonia, wound]
↑ CI, ↓ pacing, ↓ inotropes
improved outcome, ↓ ischemia,
↓ wound infections
Lazar et al. Circulation 2004;109:1497-1502
Mayo Intraop Cardiac Surgery Study
• 400 pts: 20% diabetics, Hg A1C 7%
• Randomized to intraop intensive vs std therapy
• Intensive:
– Insulin started > if 100 mg/dl. Target 80-100
• Std therapy:
– sliding scale IV insulin 200-250, or IV insulin if > 250
• Postop:
– Both groups had intensive IV insulin, target 80-100
Gandhi GY et al. Ann Intern Med 2007;146:233-43
Mayo Intraop Cardiac Surgery Study
• ↓ glucose after CPB: 123 vs 148 [19 u insulin]
• ↓ glucose ICU arrival: 114 vs 157
• All pts normoglycemic afterwards by protocol
design (103-104 mg/dl, 72-73 u insulin/ 24 h)
• No difference in 1o or 2o outcomes:
– death, sternal wound infection, cardiac arrest,
arrhythmias, ARF, > 24h intubation, LOS
• More deaths + strokes in treatment gp
(4 vs 0, P =0.06; 8 vs 1, P = 0.02)
Gandhi GY et al. Ann Intern Med 2007;146:233-43
Neurosurgical Patients
• RCT 483 adult pts admitted to neuro ICU postop
[20% head trauma]: IIT, target gluc 80-110, vs
control (gluc < 200). Excluded pts w diabetes
• LOS shorter + infection rate lower with IIT
• More hypoglycemic (gluc < 50) episodes in IIT
• 94% of IIT gp had hypoglycemic episodes
• No difference in mortality + Glasgow outcome
scale between gps
Bilotta et al. Anesthesiology 2009;110:611
Rethinking Glucose Control
• Tight glucose control did not prevent CV deaths +
macrovascular complications in type 2 diabetes
– ADVANCE
– VADT
– ACCORD
• Tight glucose control leads to hypoglycemia
– VISEP
– Glucontrol
ADA 2008: 68th Annual Scientific Sessions
Meta-analysis of IIT
• 29 RCTs, 8432 pts
• No mortality difference
– Tightness of control
– Surgical, medical, med/surg
• ↓ sepsis (10.9 vs 13.4%)
• ↑ hypoglycemia (< 40 mg/dL, 13.7 vs 2.5%)
Wiener et al. JAMA. 2008;300(8):933-944
Consensus recommendations
Pt Population:
[In-patients]
General medical +
surgical pts*
Target glucose
Rationale
1 mmol/L = 18 mg/dL
↓ mortality, LOS,
infection
Cardiac surgery*
Fasting 90-126
Random < 200
< 150
Critically ill**
< 150
↓ mortality,
morbidity, LOS
Acute Neuro
disorders***
80-140
Lack of data
↓ mortality +
sternal wound inf
*ADA. **SCCM. ***AHA. Loh-Trivedi + Rothenberg, 2008
Protocol Implementation
• Periop glycemic control depends on:
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nature of surgery
severity of illness, age
sensitivity to insulin
modality used to achieve glycemic control
body temp, caloric intake, infection
Preop diabetes + treatment
Protocol Implementation, cont’
• Interaction between glucose metabolism + surgical
trauma + CPB is complex
• Optimal intraop glycemic control cannot be
achieved by occasional measurements of glucose
+ reactive adjustments of insulin infusion
Schricker + Carvalho. J CTVA 2005
Cardiac surgery + intraop glycemic control
• Hyperinsulinemic, normoglycemic clamp
• Infuse insulin at constant rate
• Infuse dextrose to clamp blood glucose at a
specific level
Carvalho et al. Anesth Analg 2004
Smith et al. J CTVA 2005
Van Wezel at al. J Clin Endocrinol Metab 2006
Cardiac surgery + intraop glycemic control
• IV insulin
• IV GIK
• Sliding scale insulin
• Adjust rate + dose based on glucose levels
Furnary et al. Ann Thorac Surg 1999 + J TCVS 2003
Lazar et al. Circulation 2004
Gandhi et al. Ann Int Med 2007
Iatrogenic hypoglycemia
• Brain cannot synthesize glucose or store more
than a few min supply as glycogen
• Brain is critically dependent on continuous supply
of glucose from circulation
• Signs + symptoms masked by anesthesia:
– anxiety, palpitations, tremor, sweating, hunger,
paresthesias, cognitive dysfct, seizures, coma,
brain damage
Cryer et al. Diabetes Care 2003;26:1902-12
Glycemic thresholds
• 72-108 mg/dL (4.0-6.0 mmol/L) :
– normal range
• ~ 65-70 mg/dL (3.6-3.9 mmol/L):
– neuroendocrine response (↑ glucagon + epinephrine)
• ~ 50-55 mg/dL (2.8-3.0 mmol/L):
– neurologic symptoms, cognitive impairment
• Thresholds may be shifted in poorly controlled
diabetics
Cryer et al. Diabetes Care 2003;26:1902-12
My Perspective
• Current treatment does not provide plasma
glucose-regulated insulin replacement or secretion
• Pharmacokinetics of insulin are imperfect
– Time course of short acting analogues measured in hrs
– Time course of endogenous insulin in nondiabetics
measured in min
• Iatrogenic hypoglycemia can be minimized but not
eliminated if goal of treatment is near- euglycemia
Glycemic control: future directions
• Glucose – regulated insulin replacement via
pancreatic islet transplant (diabetics)
• Bio-engineered artificial β-cell (diabetics)
• Closed loop insulin replacement systems:
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reliable glucose sensor necessary
CGMS gold: measures subcut glucose q 10 s
CGMS guardian: measures interstitial glucose q 5min
CSII: continuous subcut insulin infusion
IV-intraperitoneal systems
Cryer et al. Diabetes Care 2003. Ferrari. Curr Opin Anaesthesiol 2008
Summary
• Glycemic control of benefit in pts with
diabetes, + in nondiabetic critically ill patients
• Optimal periop glycemic control will carry risk
of iatrogenic hypoglycemia
• Periop control can be achieved in most pts
through coordinated protocols, but ideal
glucose level not known