Perioperative Glucose Management

1
Perioperative Glucose Management
An Evolving Standard of Care

• Charles E. Smith, MD, FRCPC
• Professor, Case Western Reserve University
• Director, Cardiothoracic and Trauma Anesthesia
• MetroHealth Medical Center
• Cleveland, OH

2
Objectives

• Harmful effects of hyperglycemia
• Beneficial effects of insulin glycemic control
• Observational studies
• Interventional studies
• Protocol implementation

3
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 200883418-30
4
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.
• gt 270 mg/dL (15 mmol/L) in nondiabetics
• gt 360 mg/dL (20 mmol/L) in diabetics

Schricker Carvalho. J CTVA 200519684-8
5
Surgical stress hyperglycemia

• 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 200519201-8
6
Immune system hyperglycemia

• 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 2005331624
7
Beneficial effects of glycemic control

• 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 200653947-9
8
Beneficial effects of insulin

• 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.
9
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 2007146307-8 Albacker
et al. Ann Thorac Surg 20088620-7
10
Observational studies

• Relationship of hyperglycemia adverse outcomes
  well investigated
• Neurologic illness, trauma
• Myocardial infarction
• Burns
• Cardiac surgery
• Critical care
• Kidney transplant donors

Gandhi et al Mayo Clin Proc 200883418-30.
Blasi-Ibanez et al. Anesthesiology 2009110333
11
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

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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

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Portland Diabetic Project

• 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 200612Supp
322-6. http//www.providence.org/protocoldownloa
d
14
Portland Diabetic Project, results

• ? risk of death by 60, mainly pump failure
  afib (4.4 vs 1.1)
• Annual CABG mortality lt 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 200612
(Supp 3) 22-6
15
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 gt
  250

Lazar et al. Circulation 20041091497-1502
16
Boston GIK Study, results

• ? glucose 138 vs 260 12 hr postop
• ? afib 17 vs 42
• ? LOS 6.5 vs 9.2 days
• ? infections 0 vs 13 pts pneumonia, wound
• Other postop ? CI, ? pacing, ? inotropes
• Other 2yrs improved outcome, ? ischemia,
  ? wound infections

Lazar et al. Circulation 20041091497-1502
17
Mayo Intraop Cardiac Surgery Study

• 400 pts 20 diabetics, Hg A1C 7
• Randomized to intraop intensive vs std therapy
• Intensive
• Insulin started gt if 100 mg/dl. Target 80-100
• Std therapy
• sliding scale IV insulin 200-250, or IV insulin
  if gt 250
• Postop
• Both groups had intensive IV insulin, target
  80-100

Gandhi GY et al. Ann Intern Med 2007146233-43
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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, gt 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 2007146233-43
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Neurosurgical Patients

• RCT 483 adult pts admitted to neuro ICU postop
  20 head trauma IIT, target gluc 80-110, vs
  control (gluc lt 200). Excluded pts w diabetes
• LOS shorter infection rate lower with IIT
• More hypoglycemic (gluc lt 50) episodes in IIT
• 94 of IIT gp had hypoglycemic episodes
• No difference in mortality Glasgow outcome
  scale between gps

Bilotta et al. Anesthesiology 2009110611
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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
21
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 (lt 40 mg/dL, 13.7 vs 2.5)

Wiener et al. JAMA. 2008300(8)933-944
22
Consensus recommendations
Pt Population In-patients Target glucose 1 mmol/L 18 mg/dL Rationale
General medical surgical pts Fasting 90-126 Random lt 200 ? mortality, LOS, infection
Cardiac surgery lt 150 ? mortality sternal wound inf
Critically ill lt 150 ? mortality, morbidity, LOS
Acute Neuro disorders 80-140 Lack of data
ADA. SCCM. AHA. Loh-Trivedi Rothenberg,
2008
23
Protocol Implementation

• Periop glycemic control depends on
• nature of surgery
• severity of illness, age
• sensitivity to insulin
• modality used to achieve glycemic control
• body temp, caloric intake, infection
• Preop diabetes treatment

24
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
25
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
26
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
27
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 2003261902-12
28
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 2003261902-12
29
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

30
Glycemic control future directions

• Glucose regulated insulin replacement via
  pancreatic islet transplant (diabetics)
• Bio-engineered artificial ß-cell (diabetics)
• Closed loop insulin replacement systems
• 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
31
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