Catabolic response to surgery

Question 1

What are the causes of hyperglycemia and structural body protein loss in response to surgery?

Answer 1

o Increased glucose production
o Decreased peripheral glucose utilization
o Increased rate of muscle protein breakdown
o Increased rate of amino acid oxidation

Question 2

What are the two key features to the surgical catabolic response?

Answer 2

Hyperglycemia and protein breakdown

Question 3

In which types of surgeries is glycemia the highest?

Answer 3

The hyperglycemic response to surgery has been shown to depend on the severity of surgical tissue trauma.
Worst glycemia during surgery is in open heart surgery –> ~12mmol/L; frequently exceeding the renal threshold of glucose excretion of 10mmol/L

Question 4

What is the proportion of non-diabetic patients showing high BG before elective surgery?
What about diabetic patients?

Answer 4

Non-diabetic:
20% between 6.1 and 6.9
7% >= 7mmol/L
Diabetic: 
Only 11% have normal BG before elective surgery, 60% are between 6.1 and 9.9 and 29% are over 10mmol/L!

Question 5

Why is insulin not working well during surgery?

Answer 5

• Increased cortisol, glucagon and catecholamines, cytokines (IL-6 particularly)
o All of those decrease glucose uptake and increase glucose production
o All are “counterregulatory” because they counteract the metabolic effects of insulin –> state of insulin resistance

Question 6

Define insulin resistance

Answer 6

Any condition whereby a normal blood concentration of insulin produces a subnormal biological response.

Question 7

Which 2 different scenarios can lead to insulin resistance?

Answer 7

1. Lack of insulin sensitivity

2. Lack of insulin responsiveness

Question 8

Define insulin sensitivity

Answer 8

Insulin concentration required to achieve a half maximal biological response.
o Decreased insulin sensitivity characterized by a rightward shift in the insulin dose response curve
o More insulin is needed to achieve a biological response
o Use this term when normal BG can be achieved at one point

Question 9

Define insulin responsiveness

Answer 9

Maximal effect that can be obtained from insulin
o Decreased insulin responsiveness characterized by a reduction in height of the curve
o Even high amounts of insulin will not reach normal biological response
o Use this term if you never reach normal BG no matter the amount of insulin used

Question 10

Name 3 metabolic effects of insulin

Answer 10

o Hypoglycemic
o Protein anabolic
o Anti-lipolytic

Question 11

Name 5 non-metabolic effects of insulin

Answer 11

o	Anti-inflammatory
o	Anti-aggregatory
o	Vasodilatory
o	Positive inotropic (increases strength of muscular contraction)
o	Neuroprotective?

Question 12

Describe the relationship between surgery and insulin sensitivity

Answer 12

Relationship between degree of insulin resistance and magnitude of surgical stress
• Bed rest by itself has an effect on IS
• IS deteriorates quickly after abdominal surgery and remains low for at least 5 days post-op!
• IS after colorectal surgery decreased to 70% and to almost 50% after open cholecystectomy

Question 13

Name 3 ways to measure insulin resistance

Answer 13

1. Fasting circulating concentrations glucose/insulin (HOMA – Homeostasis model assessment index)
2. Glucose tolerance tests oral/intravenous
3. Clamps (Normoglycemic hyperinsulinemic clamps) (gold standard)

Question 14

Explain how the hyperinsulinemic normoglycemic clamp works.

Answer 14

o Constant insulin infusion to induces hyperinsulinemia
o Variable glucose infusion to to maintain normoglycemia
o Endogenous hepatic glucose production and renal glucose production suppressed
o More glucose infused = more insulin sensitivity

Question 15

Define diabetes mellitus and name the diagnostic criteria.

Answer 15

DM: Metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion, action or both.

1. Fasting BG >= 7.0 mmol/L
2. Casual glucose >= 11.1 mmol/L + symptoms (polyuria, polydipsia, unexplained wt loss)
3. Random or 2h-post OGTT (75g PO) >= 11.1 mmol/L

Question 16

What is the relationship between acute hyperglycemia and mortality in surgical/critically ill patients?

Answer 16

FBG higher than 7 mmol/L is associated with an 18-fold increase in hospital mortality

Question 17

What are the risks associated with hyperglycemia in diabetic and non-diabetic surgical patients?

Answer 17

• In diabetic patients, each 1mmol/L increase in BG post-op (over 6.1 mmol/L) is associated with a 17% increase in adverse outcomes
• In non-diabetic patients, every 1.1 mmol/L increase in mean intraop BG (during open heart surgery) was associated with a 30% increase in adverse outcomes (death, renal and pulmonary complications)
• In diabetic patients, the risk of mediastinitis increases more than 2-fold for every 50mg/dL (2.8 mmol/L) increase in BG
• Strong and independent relationship between the quality of periop glycemic control and mediastinitis

Question 18

Explain the association between peri-operative insulin sensitivity and post-operative complications and LOS.

Answer 18

Independent on the presence of DM, each 20% decrease in IS during surgery increased odds ratio (OR) for death, heart failure, stroke and dialysis increased (no statistical significance)
• Negative correlation between post-op insulin sensitivity and LOS after abdominal procedures

Question 19

Explain how preoperative glycemic control affects IS during surgery and complications.

Answer 19

There is a negative correlation between HbA1C (indicative of preop BG control) and insulin sensitivity during surgery (r=0.53)
Increase in major complications and minor infections with an increased HbA1C (>6.5%) in diabetics

Question 20

Name 3 associations with high HgbA1C that predict post-op complications after cardiac and major colorectal surgery.

Answer 20

HbA1C > 7%
o 2.8x risk of cardiac ischemia
o 2.1x increased Troponin T
o 5.3x increased risk of cardiac death or MI (in 30 days)

Question 21

What two changes performed in diabetic patients undergoing open-heart surgery aided to better glycemic control perioperatively? What did this lead to in terms of complications?

Answer 21

o 1995: Subcutaneous basal insulin was replaced by continuous IV insulin in OR, ICU and floor
o 2001: Set upper blood glucose target = 8.3 mmol/L

This led to a gradual decrease in mortality AND a reduction in the incidence of sternal wound infections from 2% to 0.3% (= to incidence in non-diabetic patients)

Question 22

Explain the Leuven study, its results and limitations

Answer 22

Critically ill patients were randomized to tight (4.4-6.1 mmol/L) or conventional (< 11.1 mmol/L) glucose control in the ICU. Insulin was started on patient’s ICU admission for 24h until normoglycemia
Tight glycemic control group had:
o Decreased ICU mortality (almost 50% difference with other group)
o Decreased sepsis
o Decreased renal failure
o Early mortality within the first 5 days of ICU was not affected
Limitations: Results not reproduced in other studies

Question 23

What did a 2013 meta-analysis show following the leuven study?

Answer 23

no other studies could reproduce the results from Leuven
• BG control had no significant benefit on mortality
• No impact on infectious complications

Question 24

Based on recent studies, what did the recommendations (2013) state about peri-operative glycemic control?

Answer 24

we recommend that hyperglycemia (>10.0 mmol/L) be avoided in all critically ill patients and we recommend a blood glucose target of around 8.0 mmol/L, rather than a more stringent target range of 4.4 to 6.1 mmol/L or a more liberal range of 10.0 to 11.1 mmol/L.
• Current literature does not seem to support the concept of tight BG control around 4.4 to 6.1

Question 25

Explain the NICE sugar study, its results and limitations

Answer 25

* Pts were assigned to either normal glycemia or BG < 10 mmol/L (however normal glycemia was not quite achieved in the normal glycemia group) * Normal group was actually related to increased 90-d mortality (and similar rate for renal failure) Limitations • Normoglycemia not accomplished • Hypocaloric PN feeding (inadequate) • High Steroid use in therapy group

Question 26

Explain the VISEP study, its results and limitations

Answer 26

* Same as NICE-sugar patient population strictly septic * Normoglycemia could not be achieved in the treatment group * No outcome benefit * Two-by-two factorial trial design (4 groups total, 2 received different insulin therapies) Limitations: • Hypocaloric parenteral feeding (1200 kcal, 50g protein) • 60% of patients received high-dose steroid therapy • Underpowered (study terminated early d/t hypoglycemia)

Question 27

Explain why there might be an increase in surgical risk associated with tight BG control

Answer 27

Rate of hypoglycemia in previous studies ranged from 6 to 29% --> The potential benefits of normal glycemia may have been offset by the adverse effects of hypoglycemia! “BG < 7mmol/L is associated with a measurable increase in the odds of survival, if hypoglycemia is avoided”

Question 28

Name the 4 principles of diabetes therapy

Answer 28

* Monitoring * Nutrition * Physical activity * Drugs

Question 29

Name the limitations of glucometers to measure BG

Answer 29

• Anemia has a sig impact on accuracy • Glucometers might not give a right value for people with kidney failure on peritoneal dialysis o Some of the solutions used for this type of dialysis contain icodextrin dialysate o Maltose in there is absorbed in the system and reacts with enzyme glucose dehydrogenase, which is being used by some glucometers, causing falsely elevated BG values

Question 30

How does anesthesia affect glycemic response?

Answer 30

It attenuates glycemic response

Question 31

How is neuraxial anesthesia also called, and how does it work to attenuate glycemic response?

Answer 31

AKA epidural analgesia o Neuraxial anesthesia attenuates glycemic response through an inhibition of cortisol plasma levels; endocrine response is blocked

Question 32

Name one side effect of high dose opioids and name 2 examples.

Answer 32

respiratory depression | o Morphine, fentanyl

Question 33

What are advantages of using a clamp for peri-operative insulin?

Answer 33

Maintain normoglycemia (4-6) with low risk of hypos, gives an idea of the pt’s IS

Question 34

What are the positive effects of insulin on surgical patients?

Answer 34

o Anti-inflammatory (dec cytokines) o Positive inotropic (strengthens heart contractions) o Cardioprotective (dec myocardial trauma)

Question 35

What did a clinical trial show on glucose + insulin + normoglycemia therapy (GIN)?

Answer 35

o Composite outcome: Death, balloon pump (myocardial failure), renal failure, severe infection (pneumonia, septic shock), stroke. o Study was terminated d/t significant outcome benefit

Question 36

In the GIN study in Montreal and Cleveland, why was the significant effect seen in Montreal but not Cleveland?

Answer 36

 In Cleveland, the control group had an incidence of complications of 8.3%  In Montreal, control group had higher incidence, 12.9%  The fact that they’ve already done the best care to reduce complication gives a limit to reduce complications, its harder to reduce more than that, hence why there could be a limited effect of the intervention in this center.  Cleveland clinic uses glucose-containing cardioplegia solution to paralyze the heart during sx. Significant amount is used; so their BG control was not as good as in Montreal (avg 6.8 vs 5.0).

Question 37

What is the impact of diabetes on protein loss?

Answer 37

* Protein catabolism is aggravated in the presence of DM | * T2DM patients have an almost 50% greater protein loss in elective colorectal cancer surgery compared to non-diabetics

Question 38

Name 3 impacts of mild protein (LBM) losses (10-15%) on surgery patients.

Answer 38

``` o Immunosuppression (increased infection rates) o Delayed wound healing o Respiratory muscle weakness (fatigue) --> Complicates weaning from ventilator, prolongs post-op immobilization ```

Question 39

Name 2 hormonal anti-catabolic therapies

Answer 39

o Insulin  Studied in mainly critically ill patients o Growth hormone  Improves protein economy, but is associated with increased mortality

Question 40

Name 2 pharmacological anti-catabolic therapies

Answer 40

``` o Glutamine  Essential AA  Decreases protein losses  Not commercially available o Beta-blocker  Studied in mainly critically ill patients ```

Question 41

Name 3 problems associated with peri-operative nutrition.

Answer 41

Problem 1: In order to achieve a positive protein balance (anabolism), we need to administer large quantities of energy and amino acids. Only hyperalimentation is capable of inducing anabolism. - Iso and hypocaloric concepts may slow down protein loss but does not result in protein gain Problem 2: All glucose-based feeding concepts almost inevitably cause hyperglycemia - A large number of drugs, including antibiotics, vasopressin, nitroglycerin, are administered with D5W solutions. We unintentionally infuse dextrose at this rate during sx Problem 3: Hyper- and iso-caloric solutions require central venous access - Due to the hyperosmolarity - Central venous catheters bother patients and can cause serious complications o Infections increases by 10%, d/t bacterial contamination of the catheter

Question 42

How does pain decrease insulin sensitivity?

Answer 42

o Increases cortisol o Increases epinephrine o Increases glucagon

Question 43

Explain the limitations of urinary nitrogen as a marker for protein intake.

Answer 43

o There are significant non-urinary N losses (wound, stools) o 24-hour urine collection is needed o Urinary N measurements are incomplete (NH3, uric acid); typically only urea nitrogen is measured out of practicality o One assumes normal kidney and liver function

Question 44

Which method can we use to assess protein metabolism?

Answer 44

Stable isotope tracers: [1-13C] leucine and [2H5] phenylalanine Assesses: o Protein breakdown o Protein oxidation o Protein synthesis

Question 45

Name 3 static measurements of muscle mass.

Answer 45

Dual Energy X-ray Absorptiometry (DEXA) i. Expensive, not portable Point-of-care ultrasound (POCUS) i. Can be used to measure muscle diameter, typically in the thigh ii. Inexpensive and portable, but no international consensus of this methodology, high variability between devices and observers ``` Computed tomography (CT) i. Muscle thickness ```

Question 46

Name 3 dynamic measurements of physical fitness

Answer 46

a. Six-minute walk test (6MWT) b. Hand grip strength c. Cardiopulmonary exercise testing (CPET)

Question 47

Why was pre-op fasting first implemented? What is it? and What effect does it have on surgical patients?

Answer 47

- To avoid aspiration during sx - Minimum duration of fasting preop used to be: o 8 hours after a meal that includes meat, fried or fatty foods o 6 hours after a light meal like toast and clear fluid - Preop fast decreases body’s IS by 40%, and glucose administration before surgery maintains IS

Question 48

What is the effect of oral ingestion of a drink with 50g dextrose up to 2h before surgery?

Answer 48

- Decreased IR - Attenuated hyperglycemic response to surgery - Decreased length of stay - Decreased N/V - Better muscle strength

Question 49

What are the problems with nutrition studies that were not done with Dr Shricker's studies?

Answer 49

1. Optimization of pain control (epidural analgesia) 2. Pre-operative assessment of the patient’s catabolic state (stable isotope tracer techniques) 3. Individualized nutrition support (indirect calorimetry during study period) 4. Avoidance of pre-op fasting

Question 50

Is it possible to provoke anabolism during surgery with hypocaloric nutrition? What aspects must be met for this to happen?

Answer 50

Yes, but: - Need to feed patients preop (not only during surgery) i.e. start IV 24h before surgery - Glucose is needed in ADDITION to AAs: Data shows that when comparing a group getting AA only to a group getting glucose as well as AAs, the group getting only AA did not have a good protein balance. Remained significantly negative. - Maintaining normoglycemia with insulin! I+N has an anti-catabolic effect, but does not reach anabolism. I+N+AA --> ANABOLISM Enhancing AA quantity does not enhance anabolism but promotes the energetic waste of proteins

Question 51

How does the anabolic response compare in malnourished vs healthy patients?

Answer 51

More catabolic the patients before surgery = greater anabolic response when patients are fed. T2DM patients are typically more catabolic during surgery than non-diabetics

Question 52

How does insulin sensitivity relate to the capacity of a patient to mount an anabolic response to surgery?

Answer 52

T2DM patients are typically more catabolic during surgery than non-diabetics. Only patients who came to the OR with normal IS were able to mount an anabolic response to surgery. --> Explore efforts to improve IS before surgery in diabetic patients (lifestyle, others)