Diabetes overview

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Diabetes overview
Tom Archer, MD, MBA UCSD Anesthesia
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Diabetic outpatient case

• Healthy 48 y.o. diabetic for hernia repair /
  GA.
• Elective, but patient has made plans.
• Pt. stopped his metformin 48 hours before
  surgery, per instructions, and finger stick blood
  sugar 357.
• Surgeon wants to proceed with minor procedure in
  a healthy patient.

3
Do we?

• Proceed immediately and manage hyperglycemia on
  the fly?
• Delay to later on the same day?
• Delay to another day?

4
Other questions

• What is our blood glucose cut-off that makes us
  delay surgery?
• Should we insist on other tests or evaluations
  before proceeding?

5
Would you proceed with the case
immediately?UTHSCSA faculty response
6
Your blood glucose cut-off, above which you
would not immediately proceed with case. UTHSCSA
faculty response
7
Other considerations

• Evaluate for dehydration and acidosis.
• Get EKG, Chem 7, ABG or urine for glucose /
  ketones.
• Worry about infection and wound healing.
• Worry about DKA, MI, stroke, hypotension.

8
My perspective

• Evidence-based safety, above all.
• No UNNECESSARY delays or cancellations.
• We have to JUSTIFY delays or cancellations.
• Safety does NOT more tests and delays.

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Dangers of hyperglycemia

• Long term dangers in asymptomatic patients.
• Short term dangers in sick patients.
• No studies of short term dangers of HG in healthy
  patients!

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Enormous dangers of hyperglycemia in pregnant
patients!

• HG alters DNA transcription, causing
• Diabetic embryopathy-- birth defects.
• Diabetic fetopathy macrosomia and organ
  immaturity for gestational age (e.g. lung).
• Placental vascular disease (IUGR, chronic
  malnutrition / hypoxia)
• Non-specific inflammation, vasoconstriction,
  coagulation and fibrosis.
• Decreased neutrophil / monocyte function.
• Neonatal hypoglycemia

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Obesity
Type II DM in 2006
Inflammation
Genetic predisposition
Insulin resistance
Hyperglycemia
Atherosclerosis Nephropathy Retinopathy Neuropathy
Immune dysfunction Poor wound healing
Decreased insulin output
Pancreatic beta cell damage
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Hyperglycemia cries wolf to the innate immune
system activating it when it is not needed and
weakening its capacity to respond to a real
infection.
portland.indymedia.org accessed on Google images
13
Inflammation as a cause of disease has entered
the popular imagination. Diet (macronutrients)
is rightly perceived as a factor in causing
inflammation.
14
So, food kills! Calorie restricted mice live 30
longer than normally fed mice.
Calorie restricted mice http//www.lef.org/magazin
e/mag2006/images/jan2006_cover_lef_04.jpg
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Insulin is a ANABOLIC hormone

• Causes glucose uptake into muscle and liver,
  amino acid uptake into muscle and free fatty acid
  (FFA) uptake into adipose tissue.
• Insulin affects gene transcription, allowing
  tissue growth and translocation of GLUT4
  transport protein to the cell membrane.
• Insulin is NOT just about blood glucose control!

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Insulin enables three distinct stages of glucose
utilization

• Microvascular functionwithout insulin,
  microvasculature (capillaries and precapillary
  sphincters) do not supply blood appropriately to
  muscle cells.
• Uptake of glucose into muscle cell requires GLUT4
  transport protein, made in response to insulin.
• Phosphorylation of glucose to glucose-6-phosphate
  by hexokinase inside the mitochondrion, a
  limiting step of glucose utilization.

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European Journal of Endocrinology 150
97104 European Journal of Endocrinology 150
97104 Bo Ahren and Giovanni Pacini
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(No Transcript)
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The hyperbolic function in diabetes
Obese non-diabetic (insulin resistance, but
compensated)
B
Pancreatic output of insulin
Thin non-diabetic
C
Obese, diabetic (no longer compensated)
A
Peripheral tissue sensitivity to insulin
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The Diabetes Control and Complications Trial

• Definitive, landmark 1993 study. 1441 patients
  with type I DM followed for 9 years.
• 35-70 reduction in retinopathy, neuropathy and
  nephropathy with intensive blood glucose control.

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Hgb A1c vs. Microvascular Disease and Myocardial
Infarction in type II DM.
UKPDS 35. BMJ 2000 321 405-12
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DIGAMI studyIntensive blood glucose control
after AMI lessens mortality.

• Pts. had suspected MI and BG gt 200 mg
• Both groups got thrombolysis, aspirin, beta
  blockers and ACE inhibitors as indicated.

Malmberg K DIGAMI study 1999
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Admission glucose predicts long term mortality
after AMI. Intensive insulin therapy (over
months) mitigates effect of admission blood
glucose on mortality.
234 297 mg
lt234 mg
gt 297 mg
(Malmberg K DIGAMI study 1999)
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Q How does glycemic control compare with other
post- AMI interventions?A Extremely well!

• Absolute reduction of death rate
• Thrombolysis 3.7
• Acute beta blockade 3.5
• Chronic beta blockade 9.3
• Long term simvastatin 10.4
• Aspirin 3.8 (CV events).
• DIGAMI blood glucose control 15 absolute
  reduction of death rate over 3.4 years!

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Intensive insulin therapy in critically ill
patients (Van den Berghe et. al. 2001)

• Conventional therapy Average BG 173.
• Intensive therapy Average BG 103.
• Intensive therapy decreased
• mortality (4.6 vs. 8)
• renal failure
• sepsis
• polyneuropathy
• prolonged mechanical ventilation
• red cell transfusions

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Trauma patients thresholds for damage from HG

• Yendamuri 2003 HG gt 135 mg / dL ? increased ICU
  LOS, infection and mortality.
• Laird 2004 HG gt 200 mg / dL ? increased
  mortality and infection.

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Cardiac surgery and hyperglycemia

• CPB damages endothelium (apart from its role in
  causing hyperglycemia).
• CPB and hypothermia cause extreme hyperglycemia
  which damages endothelium.
• CPB is a double insult for endothelium.

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Tight glycemic control in diabetic CABG patients
improves outcomes.Lazar 2004, Ouattara 2005

• Tight blood glucose control (target 125-200 mg )
  significantly reduced
• Atrial fibrillation
• Sternal and leg wound infections and pneumonia
• Time on ventilator
• Maximum weight gain (edema?)
• ICU stay duration
• Post-op hospital stay
• Recurrent ischemia
• Angina class
• Mortality in first two years

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Increasing mean intraoperative blood glucose is
associated with increasing morbidity in cardiac
surgery Gandhi GY 2005
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Furnary 2003

• Best results with average post-CABG glucose lt 150
  mg .
• Insulin infusion needed until POD 3

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Changing practice downward trend over time in
average post- CABG glucose. Furnary 2002
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Pre-op Hgb A1c gt 7 associated with increased
infections in surgical patientsDronge AS 2006

• 647 known diabetic VA patients for non-cardiac
  surgery.
• Infectious outcomes followed were pneumonia,
  wound infection, urinary tract infection or
  sepsis.
• Retrospective analysis and statistical
  association only no proven causation.

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So should we delay elective surgery if Hgb A1c gt
7?

• Discussion of this option at UTHSCSA. Be careful
  what you wish for.
• Be wary of setting unnecessarily stringent
  standards.
• You may get sued if you dont adhere to your
  standard and there is a problem.
• Its hard to abolish a standard, once set.

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Paying (and suing?) for glycemic control in
cardiac and general surgery?

• Will glycemic control soon be monitored and
  rewarded / punished by CMMS and other payers?
• perioperative maintenance of normoglycemia
  will become a valid performance measure for
  practicing surgical specialists.
• CMMS target in Turina study was 200 mg .
• 150 mg is better, say commenting surgeons.

Turina M 2006
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Hyperglycemia and the brain

• Cardiac arrest, stroke, neurotrauma and
  neurosurgery
• Both animal and human studies show that
  hyperglycemia during or after brain injury causes
  worse outcomes.

Capes SE 2001, Jeremitsky E 2005, Wass CT 1996
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Hyperglycemia damages (activates) the
endothelium.

• Hyperglycemia causes inflammation.

Reinhart K 2002, Dandona P 2005 J Clin Invest,
Dandona P 2003 Curr Drug Targets
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Hyperglycemia, sepsis and pre-eclampsia all
activate (damage) endothelium, white cells and
platelets, leading to white cell adhesion and
infiltration, thrombosis and edema (inflammation).
WBC
WBC
Hyperglycemia, sepsis or pre-eclampsia
Platelet
Platelets
Protein (edema)
Archer TL 2006 unpublished
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HG damages mitochondria

• HG causes excessive entry of electrons (as NADH)
  into mitochondrial electron transport chain.
• Excess electrons create reactive oxygen species,
  which damage mitochondria.

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HG produces advanced glycation end-products (AGE)

• Mechanically cross link and stiffen collagen and
  elastin fibers, decreasing tissue elasticity
  (e.g. arteries).
• Activate AGE receptors on macrophages to produce
  inflammatory mediators.

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Cooper ME 2004
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Advanced Glycation Endproducts(AGE)

• Stiffen tissues, ? Causing?
• Atherosclerosis
• Diastolic dysfunction
• Stiff joints

Cooper ME 2004
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Can we reverse AGE?

• Alagebrium chloride is in phase II trials breaks
  AGE cross-links and restores vascular
  flexibility.
• Pimagedine appears to block cross-link formation.
• Reversal / prevention of atherosclerosis,
  systolic hypertension and diastolic dysfunction?

Cooper ME 2004
44
Endothelial cells send molecular signals to
surrounding smooth muscle
Insulin makes endothelium produce
Glucose makes endothelium produce
vasodilatory signals (NO, prostacyclin)
Vessel lumen
vasoconstrictive signals (thromboxane, endothelin)
Archer TL 2006 unpublished, Idea from Dandona P
2004
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How rapidly can endothelial activation occur?

• Evidence from 300 cal of oral glucose vs. 300 cal
  of vodka.
• Oral glucose increases inflammatory markers
  within 2 hours.
• Equal calories as ethanol do not.
• Is this relevant to our outpatient scenario? We
  dont know.

Dhindsa S 2004
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Back to the outpatient case

• Why is blood glucose 357 so bad in ICU patient,
  yet well-tolerated in many ambulatory patients?
• Should we delay the case, since blood glucose in
  critically ill patients appears to be
  increasingly dangerous above the 150 mg range?
• Or should we proceed, since no one has shown that
  short-term hyperglycemia harms asymptomatic
  patients?

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Critical illness and hyperglycemia work
synergistically to damage endothelium.

• The significance of a blood glucose level depends
  on what else is going on with the patients
  endothelium.
• In other words, we have to look at a given blood
  sugar value in context.

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For any given blood glucose value, end organ
damage will depend on degree of non-hyperglycemic
endothelial damage.
Zone of severe end-organ damage
Non-hyperglycemic endothelial damage (sepsis,
etc.)
Zone of
Zone of
moderate end-
limited
organ damage
end-organ
damage
Zone of no end-organ damage
Blood glucose
Archer TL 2006 unpublished
49
Hyperglycemia may cause different degrees of
end-organ damage, depending on the degree of
pre-existing endothelial damage.
Patient B
Zone of severe end-organ damage
Non-hyperglycemic endothelial damage (sepsis,
etc.)
Zone of
Zone of
moderate end-
limited
organ damage
end-organ
damage
Zone of no end-organ damage
Patient A
Blood glucose
Archer TL 2006 unpublished
50
For any degree of non-hyperglycemic endothelial
damage, end organ damage will depend on level of
hyperglycemia.
Zone of severe end-organ damage
Non-hyperglycemic endothelial damage (sepsis,
etc.)
Zone of
Zone of
moderate end-
limited
organ damage
end-organ
damage
Zone of no end-organ damage
Blood glucose
Archer TL 2006 unpublished
51
So, what do we do with our outpatient with blood
glucose 357?

• Discuss benefits of tight glucose control with
  patient and surgeon.
• Use the occasion as a teachable moment (Roizen)
  to stimulate patient toward better health.
• Be aware that surgeons themselves are starting to
  talk about BG 150-200 mg as a reasonable
  perioperative target for major surgery.

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What else should we do?

• Consider NOT stopping metformin-- to help keep
  blood glucose down.
• Evidence against perioperative metformin is weak
  to non-existent.

Misbin RI 2004, Holstein A 2005
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In summary

• Both HG and serious illness activate
  endothelium, causing inflammation,
  vasoconstriction, coagulation and fibrosis.

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In summary

• Long term HG increases CV disease, retinopathy,
  neuropathy and nephropathy in asymptomatic
  diabetics.
• Short term HG causes multiple and serious
  complications in sick patients-- in whom the
  endothelium is already compromised.

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In summary

• However, there is no evidence at present that
  short term hyperglycemia in an asymptomatic
  patient confers increased risk of surgical or
  anesthetic complications.
• Until such evidence is forthcoming, caution,
  clinical judgment and common sense must guide
  our practice.

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• The End

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References (1)

• Ahmed N. Diabetes Research Clinical Practice.
  67(1)3-21, 2005 Jan. Capes SE et al Stroke
  2001 322426-2432.
• Cooper ME American Journal of Hypertension
  20041731S-38S
• Coutinho M et al Diabetes Care 1999 22233-240.
• Dandona P Current Drug Targets 2003 4, 487-492.
• Dandona P et al Med Clin N Am 88 2004, 911-931
• Dandona P et al J Clin Invest 2005, 1152069-2072
• Dhindsa S et al Metabolism 2004 53 330-334.
• Diabetes Control and Complications Trial (DCCT)
  Research Group. New England Journal of Medicine
  September 30, 1993 Volume 329977-986. No 14.
• Dronge AS et al Arch Surg 2006 141375-380
• Finney SJ et al JAMA 2003 2902041-2047
• Freire AX et al Chest 2005 1283109-3116
• Furnary AP et al J Thorac Cardiovasc Surg 2003
  1251007-21
• Gandhi GY et al Mayo Clin Proc July 2005
  80(7)862-866

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References (2)

• Holstein A et al Diabetologia (2005)
  482454-2459.
• Jeremitsky E et al J Trauma 20055847-50.
• Khaw KT et al BMJ 20013221-6
• Krinsley JS et al Mayo Clin Proc
  200479(8)992-1000.
• Laird AM et al J Trauma 2004561058-1062
• Langouche L et al J of Clin Invest
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• Lazar HL et al Circulation 20041091497-1502
• Leiter LA et al AJH 200518121-128
• Malmberg K et al Circulation 1999992626-2632
• Misbin RI Diabetes Care Volume 2004
  27(7)1791-1793
• Ouattara A et al Anesthesiology 2005 V 103, No 4,
  pp. 687-694
• Reinhart K et al Crit Care Med 2002 30Suppl.
  S302-312
• Turina M et al Crit Care Med 2005 Vol.33, No. 7,
  pp.1624-1633.
• Turina M et al Annals of Surgery vol 243 number 6
  June 2006
• UKPDS Lancet 1998 352 854-865.

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References (3)

• Umpierrez GE et al J Clin Endocrinol Metab 2002
  87978-982.
• Viberti G New England Journal of Medicine Vol
  3321293-1294, May 11, 1995, Number 19.
• Van den Berghe G et al N Engl J Med
  20013451359-67
• Vanhorebeek I et al Lancet 200536553-59.
• Vanhorebeek I et al Curr Opin Crit Care 2005,
  11304-311
• Wass CT et al Mayo Clin Proc 1996 Vol
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• Yendamuri S et al J Trauma 20035533-38.
• Whitcomb BW Crit Care Med 2005 332772-2777