Transcript Perioperative Management of Insulin Resistance and Diabetes

Alfred Martello, MD
Medical Director
The Ohio Anesthesia Group
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No Commercial endorsements
I’m not really smart enough to give this lecture.
It’s really complicated stuff.
I’ll try to keep it simple.
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Define scope of the problem
Pathophysiology of insulin resistance and diabetes
(VERY) brief review of metabolic syndrome
Medications used for treatment of diabetes
Perioperative Hyperglycemia
Preoperative Evaluation
Intraoperative management
Same day surgery
 Inpatient surgery
 Reliability of glucose measurements
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Diabetes is a group of metabolic diseases
characterized by hyperglycemia resulting from
defects in insulin secretion, insulin action, or
both.
According to the ADA, a fasting plasma
glucose of >= 126 mg/dl, or a HGB A1c > 6.5%
is diagnostic of Diabetes
FPG of 100 to 125 are considered “pre-diabetic”
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12.9% of the adult population of the United
States have diabetes.
Approximately 40% of these individuals are
unaware of their diagnosis.
An additional 26% of the population has
impaired fasting glucose.
80% of the cases of diabetes in the US and
Europe are Type 2.
5 to 10% are type 1 and the rest are of other
etiologies.
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Normal function involves the appropriate
secretion of insulin binding to its receptors
producing the appropriate response.
Increased levels of glucose in plasma trigger the
release of insulin from the B-cells from the islet
cells of the pancreas.
There is a basal level of insulin secretion that
rapidly increases with the ingestion of food.
Other factors involved in the secretion of insulin
include pancreatic and intestinal hormones,
growth factors, nitric oxide, amino acids,
catecholamines, cyclic AMP, and vagal
stimulation.
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Once Insulin is released, it binds its receptors.
These receptors are located on both cells that
are involved in insulin metabolism as well a
many other cells such as endothelium,
lymphocytes, monocytes, macrophages, an
others.
The binding to the receptor will lead to a
cascade of reactions via phosphorylation
pathways.
These pathways will lead to metabolic or
proliferative events.
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Metabolic Effects of Insulin
Promotes glucose uptake by translocation of Glucose
transporter protein 4 to the surface of the cell.
 Promotes glycogen synthesis
 Promotes transcription of genes involved in fasting,
feed, nitric oxide production, lipogenesis and protein
synthesis.
 Net effect is to increase uptake of glucose into the
peripheral tissues, especially skeletal muscle, thereby
decreasing the circulating level of glucose. The
endogenous production of glucose is inhibited.
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The non metabolic effects of insulin are
mediated through a different pathway.
These include suppression of pro-inflammatory
transcription factors decreasing the expression
of inflammatory mediators.
Augmentation of nitric oxide production leads
to vasodilatation and inhibits platelet
aggregation.
Insulin also has other antifibrinolytic and
antithrombotic effects.
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Type 1 Diabetes is cause by the lack of
production of insulin.
Accounts for a minority of cases of diabetes in
the United states.
Usually diagnosed in patients less than 30
years old.
This type of diabetes requires the
administration of insulin to prevent
ketoacidosis
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Type 2 Diabetes is characterized by relative
insulin resistance, which is defined as a
decrease biologic effect for any given
concentration of insulin.
Will initially lead to increased insulin
production.
Eventually the B-cells of the pancreas “burn
out” leading to the need for insulin
supplementation.
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Characterize by varying degrees of insulin
resistance, central obesity, atherogenic lipid
profile, and hypertension.
May affect up to 20-25% of the general population.
Patients with metabolic syndrome are at a greater
risk for development of Coronary Artery Disease
and major adverse cardiac events.
The risk is elevated relative to any individual of
the above risk factors because they are clustered.
Table 1
Metabolic Syndrome and Insulin
Resistance: Perioperative Considerations
Bagry, Hema S.; Raghavendran,
Sreekrishna; Carli, Franco
Anesthesiology. 108(3):506-523, March
2008.
doi: 10.1097/ALN.0b013e3181649314
Table 1. Definitions of Metabolic Syndrome
Copyright © 2012 Anesthesiology. Published by Lippincott Williams & Wilkins.
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Hyperglycemia is a common response to
metabolic stress and illness.
This stress induces a reversible acceleration of
the progression of insulin resistance.
The magnitude of this response may be related
to the duration and invasiveness of surgery, as
well as blood loss.
Anesthesia, Surgical insult, and metabolic
stress all lead to hyperglycemia.
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Surgical stress leads to the release of counter
regulatory hormones cortisol, glucagon,
epinephrine and growth hormone, leading to
gluconeogenesis and glycogenolysis.
Glucose uptake into skeletal muscle is
decreases
Inhalational anesthetics depress glucose
stimulated insulin release.
Decrease levels of activity
Iatrogenic from steroids, enteral and parenteral
nutrition, hypothermia and alpha 2-agonists.
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Leads to decreased immune function.
Leads to endothelial dysfunction.
Leads to hypercoagulability.
Leads to increased inflammatory response
Leads to delayed wound healing.
Leads to susceptibility to infection.
Leads to end organ dysfunction.
Perioperative Glycemic Control: An
Evidence-based Review
Lipshutz, Angela K. M.; Gropper,
Michael A.
Anesthesiology. 110(2):408-421,
February 2009.
doi: 10.1097/ALN.0b013e3181948a80
Fig. 1. Pathophysiology of
hyperglycemia. Anesthesia, metabolic
stress, and critical illness lead to
metabolic derangements, resulting in
hyperglycemia. Hyperglycemia is
associated with increased
inflammation, susceptibility to
infection, and organ dysfunction.
Copyright © 2012 Anesthesiology. Published by Lippincott Williams & Wilkins.
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Development of acute hyperglycemia in patients
without diabetes portends a poorer prognosis than
in those patients with diabetes.
If hyperglycemia leads to all of these detrimental
effects, it would seem logical to try to obtain tight
glycemic control in the perioperative period.
Most of studies for perioperative glucose control
performed in Cardiac Surgery, and has shown a
morbidity and mortality benefit.
The occurrence of hyperglycemia in the
perioperative period peaks on post op day one,
and can persist for up to 5 days.
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We can alter our anesthetic technique to
mitigate perioperative hyperglycemia, but this
modulation of the stress response is limited to
the intraoperative period.
Therefore we need to do more than alter our
anesthetic technique.
The question is How much is too much? How
much is enough?
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Can be divided into insulin, oral
hypoglycemics, and injectable pharmacologic
analogues of GI hormones.
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Rapid Acting: Insulin Lispro and Aspart
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Short Acting: Regular insulin
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Produced by recombinant DNA technology
Used for IV infusions as the rapid acting insulin offer
no advantage in this application.
Intermediate: NPH
Long Acting: Ultralente, Glargine (Lantus) and
Insulin Detemir (Levimir)
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Provides stable baseline insulin levels, minimal peak
effect.
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Sulfonureas: Glyburide, Glipizide,
Tolazamide, Tolbutamide, Chlorpropramide.
Increase Insulin secretion
 May lead to an increase in appetite and weight gain.
 Once thought to increase cardiovascular risk, but
were shown to slightly decrease cardiovascular risk
by the United Kingdom Prospective Diabetes study.
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Biguanide:
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Metformin (Glucophage)
Acts to decrease hepatic glucose output
Improves insulin sensitivity
Does not cause weight gain
May be taken up to the day of surgery.
Decreases the incidence of MI and all cause mortality
as a monotherapy.
Hypoglycemia is rare as a monotherapy.
Concern about lactic acidosis is overstated.
 Incidence is 3 cases per 100,000 patient years
 Risk is increased with IV dye and Renal disease.
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Thiazolinediones : (TZD) Rosiglitazone,
Poiglitazone
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Enhance insulin sensitivity by increasing the efficiency of
glucose transporters.
May cause hypoglycemia in combination with other
drugs.
May cause weight gain and edema
Improved endothelial function, and has modest
antihypertensive effects.
Rosiglitazone may have adverse cardiovascular effects.
ADA issued guidelines against the use of Rosiglitazone in
treatment of type 2 DM.
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Exenatide:(Byetta)
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Incretin mimetic, analogue of peptide hormone
GLP-1.
Enhances insulin exocytosis from B-cells in a glucose
dependent manner.
Induces insulin biosynthesis
Promotes B-cell proliferation
Inhibits Glucagon secretion from A-cells
Decreases appetite and induces weight loss
Slows gastric emptying
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Sitagliptin:
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(Januvia)
Enhances insulin secretion and decreases glucagon
secretion through inhibition of DPP-IV, the enzyme
that breaks down GLP-1
Does not affect gastric emptying
Given twice daily injection
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Preoperative Evaluation
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Type of Diabetes
Medications
Incidence of hypoglycemia and level of glucose
when symptoms occur.
Long term glucose control.
How hypoglycemia is manifested.
Degree of surgical trauma
Inpatient or outpatient status
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Therapeutic Goals:
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Maintenance of adequate blood glucose control
Avoidance of hypoglycemia.
Avoidance of complications due to co morbidities
This is accomplished by:
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Minimizing the disruption of the patients
antidiabetic therapy.
Frequent blood glucose monitoring
Prompt resumption of oral intake post operatively
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Preoperative laboratory evaluation
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Depends upon the co morbidities and scope of
surgery.
For minor procedures, no evaluation should be
necessary other than a blood sugar on morning of
surgery.
For more extensive procedures, Preoperative
evaluation should include ECG, BMP, and A1C to
determine adequacy of long term blood glucose
management.
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High quality evidence is lacking, so we rely on
expert opinion.
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Oral Hypoglycemics may be taken up to the day
prior to surgery.
The risk of hypoglycemia with these medications is
low when taken as monotherapy
There is no evidence that Metformin is associated
with perioperative lactic acidosis, except for those
with renal dysfunction or those receiving contrast
agent.
The non-insulin injectables should be held on the
day of surgery.
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Insulin therapy
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According to SAMBA guidelines for outpatients:
 Basal insulin regimens should be maintained, as these
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rarely induce hypoglycemia.
Long acting insulin should be given in the usual dose
the night prior, and 75% of the dose the morning of
surgery.
Intermediate insulin should be administered at 75% of
dose the night prior and 50% of the dose the morning
of.
For combination insulin, use NPH instead, at 50-75% of
intermediate dose.
Hold Short and rapidly acting doses
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Preoperative Principles the same as outpatients.
Intensive Insulin Regimens
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Leuven protocols of early 2000’s showed that an effort to
normalize BG in critically ill patients (BG 80-110)
improved in-hospital mortality, and significantly
decreased morbidity.
These patients were in a surgical ICU, single center.
Could not reproduce these results in a multicenter,
medical ICU study.
Follow up studies in a medical ICU were stopped due to
severe hypoglycemia and worse outcome.
Leuven studies had very strict protocols for glucose
measurement, feeding and nursing protocols.
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Intensive Insulin Therapy
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Subgroup analysis showed benefit in patients that
stayed in the ICU for more than 3 days, with a
statistically insignificant trend towards increased
mortality if the ICU stay was less than 3 days.
The problem is that you cannot identify these
patients prospectively.
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NICE-SUGAR Study: Normoglycemia in
Intensive Care Evaluation and Survival using
Glucose Algorithm Regulation.
Multicenter, 6100 patients to be enrolled
 2 groups, IIT and Intermediate therapy( 140-180
mg/dl)
 Revealed that targeting a BG < 108 mg/dl provided
no further benefit than intermediate therapy. In fact
there was an increase in 90 day mortality attributable
to cardiovascular death.
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So…
Can we generalize ICU studies to the OR?
First, do no harm. The marginal benefit of tighter
insulin control does not seem worth the risk.
 For longer, more extensive inpatient surgeries, it is
reasonable to target an intermediate control of blood
glucose.
 Insulin infusions are better than intermittent SQ
injections for control in the operating room.
 The nursing staff must be competent in the ICU post
operatively to avoid complications of severe
hypoglycemia with insulin infusions.
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RABBIT 2 Surgery Trial (2011)
Prospective, randomized trial comparing SSI to
Basal-Bolus insulin regimen.
 RABBIT was for medical patients.
 RABBIT 2 was for general surgery patients
 Patients were not expected to be transferred to the
ICU post operatively.
 Basal insulin was Lantus, and the bolus insulin was
Apidra, (Glulisine), a rapidly acting insulin in the
same class as Insulin aspart and lispro.
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A: Glucose levels during basal-bolus and SSI treatment.
Umpierrez G E et al. Dia Care 2011;34:256-261
Copyright © 2011 American Diabetes Association, Inc.
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Findings
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Basal Bolus insulin regimen was superior to SSI in
achieving BG target values.
The incidence of complications was lower in the
basal-bolus arm
There were more cases of hypoglycemia in the
treatment arm than the control arm
There were more cases of severe hypoglycemia
BG<40 in the treatment arm.
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Point of Care capillary meters are less reliable
than central laboratory or onsite gas analyzers.
The allowable variation for POC meters versus
laboratory analyzers is +- 15% for BG < 100,
and +- 20% for BG > 100.
This variability makes management of
intraoperative glucose control difficult.
Sampling site: Arterial vs. Venous vs. capillary
Hemodynamic status of patient, sample
volume and anemia all affect precision of POC.
A Novel Computerized Fading Memory
Algorithm for Glycemic Control in
Postoperative Surgical Patients
Anesthesia and Analgesia, Vol. 115, number 3 580-587
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Physiology of glucose homeostasis is complex
We must try to understand the perioperative
implications of hyper and hypoglycemia
Hyperglycemia in the perioperative period is
bad. But…
Very tight control is not necessarily better.
At this point, Aristotle was right, try to achieve
a balance between the extremes.