Catabolic response to surgery Flashcards
What are the causes of hyperglycemia and structural body protein loss in response to surgery?
o Increased glucose production
o Decreased peripheral glucose utilization
o Increased rate of muscle protein breakdown
o Increased rate of amino acid oxidation
What are the two key features to the surgical catabolic response?
Hyperglycemia and protein breakdown
In which types of surgeries is glycemia the highest?
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
What is the proportion of non-diabetic patients showing high BG before elective surgery?
What about diabetic patients?
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!
Why is insulin not working well during surgery?
• 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
Define insulin resistance
Any condition whereby a normal blood concentration of insulin produces a subnormal biological response.
Which 2 different scenarios can lead to insulin resistance?
- Lack of insulin sensitivity
2. Lack of insulin responsiveness
Define insulin sensitivity
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
Define insulin responsiveness
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
Name 3 metabolic effects of insulin
o Hypoglycemic
o Protein anabolic
o Anti-lipolytic
Name 5 non-metabolic effects of insulin
o Anti-inflammatory o Anti-aggregatory o Vasodilatory o Positive inotropic (increases strength of muscular contraction) o Neuroprotective?
Describe the relationship between surgery and insulin sensitivity
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
Name 3 ways to measure insulin resistance
- Fasting circulating concentrations glucose/insulin (HOMA – Homeostasis model assessment index)
- Glucose tolerance tests oral/intravenous
- Clamps (Normoglycemic hyperinsulinemic clamps) (gold standard)
Explain how the hyperinsulinemic normoglycemic clamp works.
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
Define diabetes mellitus and name the diagnostic criteria.
DM: Metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion, action or both.
- Fasting BG >= 7.0 mmol/L
- Casual glucose >= 11.1 mmol/L + symptoms (polyuria, polydipsia, unexplained wt loss)
- Random or 2h-post OGTT (75g PO) >= 11.1 mmol/L
What is the relationship between acute hyperglycemia and mortality in surgical/critically ill patients?
FBG higher than 7 mmol/L is associated with an 18-fold increase in hospital mortality
What are the risks associated with hyperglycemia in diabetic and non-diabetic surgical patients?
- 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
Explain the association between peri-operative insulin sensitivity and post-operative complications and LOS.
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
Explain how preoperative glycemic control affects IS during surgery and complications.
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
Name 3 associations with high HgbA1C that predict post-op complications after cardiac and major colorectal surgery.
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)
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?
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)
Explain the Leuven study, its results and limitations
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
What did a 2013 meta-analysis show following the leuven study?
no other studies could reproduce the results from Leuven
• BG control had no significant benefit on mortality
• No impact on infectious complications
Based on recent studies, what did the recommendations (2013) state about peri-operative glycemic control?
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
Explain the NICE sugar study, its results and limitations
- 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
Explain the VISEP study, its results and limitations
- 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)
Explain why there might be an increase in surgical risk associated with tight BG control
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”
Name the 4 principles of diabetes therapy
- Monitoring
- Nutrition
- Physical activity
- Drugs
Name the limitations of glucometers to measure BG
• 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
How does anesthesia affect glycemic response?
It attenuates glycemic response
How is neuraxial anesthesia also called, and how does it work to attenuate glycemic response?
AKA epidural analgesia
o Neuraxial anesthesia attenuates glycemic response through an inhibition of cortisol plasma levels; endocrine response is blocked
Name one side effect of high dose opioids and name 2 examples.
respiratory depression
o Morphine, fentanyl
What are advantages of using a clamp for peri-operative insulin?
Maintain normoglycemia (4-6) with low risk of hypos, gives an idea of the pt’s IS
What are the positive effects of insulin on surgical patients?
o Anti-inflammatory (dec cytokines)
o Positive inotropic (strengthens heart contractions)
o Cardioprotective (dec myocardial trauma)
What did a clinical trial show on glucose + insulin + normoglycemia therapy (GIN)?
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
In the GIN study in Montreal and Cleveland, why was the significant effect seen in Montreal but not Cleveland?
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).
What is the impact of diabetes on protein loss?
- 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
Name 3 impacts of mild protein (LBM) losses (10-15%) on surgery patients.
o Immunosuppression (increased infection rates) o Delayed wound healing o Respiratory muscle weakness (fatigue) --> Complicates weaning from ventilator, prolongs post-op immobilization
Name 2 hormonal anti-catabolic therapies
o Insulin
Studied in mainly critically ill patients
o Growth hormone
Improves protein economy, but is associated with increased mortality
Name 2 pharmacological anti-catabolic therapies
o Glutamine Essential AA Decreases protein losses Not commercially available o Beta-blocker Studied in mainly critically ill patients
Name 3 problems associated with peri-operative nutrition.
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
How does pain decrease insulin sensitivity?
o Increases cortisol
o Increases epinephrine
o Increases glucagon
Explain the limitations of urinary nitrogen as a marker for protein intake.
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
Which method can we use to assess protein metabolism?
Stable isotope tracers: [1-13C] leucine and [2H5] phenylalanine
Assesses:
o Protein breakdown
o Protein oxidation
o Protein synthesis
Name 3 static measurements of muscle mass.
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
Name 3 dynamic measurements of physical fitness
a. Six-minute walk test (6MWT)
b. Hand grip strength
c. Cardiopulmonary exercise testing (CPET)
Why was pre-op fasting first implemented? What is it? and What effect does it have on surgical patients?
- 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
What is the effect of oral ingestion of a drink with 50g dextrose up to 2h before surgery?
- Decreased IR
- Attenuated hyperglycemic response to surgery
- Decreased length of stay
- Decreased N/V
- Better muscle strength
What are the problems with nutrition studies that were not done with Dr Shricker’s studies?
- Optimization of pain control (epidural analgesia)
- Pre-operative assessment of the patient’s catabolic state (stable isotope tracer techniques)
- Individualized nutrition support (indirect calorimetry during study period)
- Avoidance of pre-op fasting
Is it possible to provoke anabolism during surgery with hypocaloric nutrition? What aspects must be met for this to happen?
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
How does the anabolic response compare in malnourished vs healthy patients?
More catabolic the patients before surgery = greater anabolic response when patients are fed. T2DM patients are typically more catabolic during surgery than non-diabetics
How does insulin sensitivity relate to the capacity of a patient to mount an anabolic response to surgery?
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)
