PERIOPERATIVE MANAGEMENT OF INSULIN RESISTANCE AND DIABETES

Alfred Martello, MDMedical Director

The Ohio Anesthesia Group

Disclosures 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.

Objectives

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

Definition of the Problem

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”

Definition of the Problem

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.

Glucose Homeostasis

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.

Physiology

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.

Physiology

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.

Non Metabolic Effects of Insulin

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.

Pathophysiology

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

Pathophysiology

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.

Metabolic Syndrome

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

Table 1. Definitions of Metabolic Syndrome

Copyright © 2012 Anesthesiology. Published by Lippincott Williams & Wilkins. 15

Metabolic Syndrome and Insulin Resistance: Perioperative Considerations Bagry, Hema S.; Raghavendran, Sreekrishna; Carli, FrancoAnesthesiology. 108(3):506-523, March 2008.doi: 10.1097/ALN.0b013e3181649314

Effects of Acute Hyperglycemia

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.

Acute Hyperglycemia

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.

Acute Hyperglycemia

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.

Copyright © 2012 Anesthesiology. Published by Lippincott Williams & Wilkins.

Fig. 1

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.

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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

Hyperglycemia

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.

Hyperglycemia

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?

Therapeutic Agents for the Management of Diabetes

Can be divided into insulin, oral hypoglycemics, and injectable pharmacologic analogues of GI hormones.

Insulin Types

Rapid Acting: Insulin Lispro and Aspart Produced by recombinant DNA technology

Short Acting: Regular insulin 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) Provides stable baseline insulin levels,

minimal peak effect.

Oral Agents

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.

Oral Agents

Biguanide: 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.

Oral Agents

Thiazolinediones : (TZD) Rosiglitazone, Poiglitazone 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.

Non Insulin Injectables

Exenatide:(Byetta) 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

Non insulin injectables

Sitagliptin: (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

Perioperative Management

Preoperative Evaluation 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

Perioperative Management

Therapeutic Goals: Maintenance of adequate blood glucose

control Avoidance of hypoglycemia. Avoidance of complications due to co

morbidities

This is accomplished by: Minimizing the disruption of the patients

antidiabetic therapy. Frequent blood glucose monitoring Prompt resumption of oral intake post

operatively

Perioperative Management

Preoperative laboratory evaluation 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.

Medication Management Day of Outpatient Surgery

High quality evidence is lacking, so we rely on expert opinion. 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.

Medication Management Day of Surgery

Insulin therapy According to SAMBA guidelines for outpatients:

Basal insulin regimens should be maintained, as these 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

Medication ManagementDay of Inpatient Surgery

Preoperative Principles the same as outpatients. Intensive Insulin Regimens

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.

Medication Management

Intensive Insulin Therapy 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.

Medication Management

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.

Medication Management

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.

Medication Management

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.

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.

RABBIT 2

Findings 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.

Blood Glucose Measurement

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.

In The Future

A Novel Computerized Fading Memory Algorithm for Glycemic Control in Postoperative Surgical PatientsAnesthesia and Analgesia, Vol. 115, number 3 580-587

Conclusions

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.