Title: Diabetes overview
1Diabetes overview
Tom Archer, MD, MBA UCSD Anesthesia
2Diabetic 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.
3Do we?
- Proceed immediately and manage hyperglycemia on
the fly? - Delay to later on the same day?
- Delay to another day?
4Other questions
- What is our blood glucose cut-off that makes us
delay surgery? - Should we insist on other tests or evaluations
before proceeding?
5Would you proceed with the case
immediately?UTHSCSA faculty response
6Your blood glucose cut-off, above which you
would not immediately proceed with case. UTHSCSA
faculty response
7Other 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.
8My 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.
9Dangers 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!
10Enormous 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
11Obesity
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
12Hyperglycemia 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
13Inflammation as a cause of disease has entered
the popular imagination. Diet (macronutrients)
is rightly perceived as a factor in causing
inflammation.
14So, 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
15Insulin 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!
16Insulin 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.
17European Journal of Endocrinology 150
97104 European Journal of Endocrinology 150
97104 Bo Ahren and Giovanni Pacini
18(No Transcript)
19The 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
20The 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.
21Hgb A1c vs. Microvascular Disease and Myocardial
Infarction in type II DM.
UKPDS 35. BMJ 2000 321 405-12
22DIGAMI 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
23Admission 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)
24Q 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!
25Intensive 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
26Trauma 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.
27Cardiac 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.
28Tight 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
-
29Increasing mean intraoperative blood glucose is
associated with increasing morbidity in cardiac
surgery Gandhi GY 2005
30Furnary 2003
- Best results with average post-CABG glucose lt 150
mg . - Insulin infusion needed until POD 3
31Changing practice downward trend over time in
average post- CABG glucose. Furnary 2002
32Pre-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.
33So 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.
34Paying (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
35Hyperglycemia 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
36Hyperglycemia damages (activates) the
endothelium.
- Hyperglycemia causes inflammation.
Reinhart K 2002, Dandona P 2005 J Clin Invest,
Dandona P 2003 Curr Drug Targets
37(No Transcript)
38Hyperglycemia, 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
39HG damages mitochondria
- HG causes excessive entry of electrons (as NADH)
into mitochondrial electron transport chain. - Excess electrons create reactive oxygen species,
which damage mitochondria.
40HG 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.
41Cooper ME 2004
42Advanced Glycation Endproducts(AGE)
- Stiffen tissues, ? Causing?
- Atherosclerosis
- Diastolic dysfunction
- Stiff joints
Cooper ME 2004
43Can 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
44Endothelial 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
45How 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
46Back 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?
47Critical 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.
48For 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
49Hyperglycemia 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
50For 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
51So, 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.
52What 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
53In summary
- Both HG and serious illness activate
endothelium, causing inflammation,
vasoconstriction, coagulation and fibrosis.
54In 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.
55In 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.
56 57References (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
58References (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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- 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.
59References (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,
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