Pathophysiological stress responsefollowing surgery & ERAS

Olle Ljungqvist MD PhDProfessor of Surgery Örebro University & Karolinska Intitutet Stockholm Sweden

Chairman ERAS Society

ERAS UK conference 2013

Birmingham November 8 2013

Recovery After SurgeryWhat are we trying to achieve?

Patient back to preoperative function

• Normal gastrointestinal function

– Normal food intake

– Bowel movement

• Pain control

• Mobility

• No complication

The Metabolic Stress Response to

Surgery and Trauma

Philosophy

ERAS philosophy: The Patients journey

PreopSurgery

Anesthesia

Recovery

Ward

Audit compliance & outcomes

Home

H

D

U

C

l

i

n

i

c

Audit compliance and outcomePatients journey

ERAS

Epidural

Anaesthesia

Prevention

of ileus/

prokinetics

CHO - loading/

no fasting

Early

mobilisation

Peri-op fluid

management

DVT

prophylaxis

Pre-op councelling

Short acting anestetics

No - premed

No bowel prep

Perioperative

Nutrition

Body heating devises

Oral analgesics/

NSAID’s

Incisions

No NG tubes

Early removal

of catheters/drains

Fearon et al, Clin Nutr 2005

ERASSecuring modern care

Surgeon:

No bowel prep

Food after surgery

No drains

Early removal u-catheter

No iv fluids, no lines

Early discharge

All evidence based!

Anesthetist:

Carbohydrates no fasting

No premedication

Thoracic Epidural Anesthesia (open)

Balanced fluids

Vasopressors

No or short actingopioids

ERAS team approach

• Surgeon

• Anesthestist

• HDU specialist

• Ward nurses

• Anesthesia nurses

• Physiotherapist

• Dietitian

• Management

Team work:

• Training

• Implementing

• Planning

• Auditing

• Updating

• Reporting

• Research

ERAS works!

ERAS Meta analys

ERAS: shorter length of stay by 2.5 days

Varadhan et al, Clin Nutr 2010

ERAS Meta analys

ERAS: Reduce complications by 50%

Varadhan et al, Clin Nutr 2010

How does ERAS work?

Mechanisms

3 new guidelines 2012

ERAS

Epidural

Anaesthesia

Prevention

of ileus/

prokinetics

CHO - loading/

no fasting

Early

mobilisation

Peri-op fluid

management

DVT

prophylaxis

Pre-op councelling

Remifentanyl

No - premed

No bowel prep

Perioperative

Nutrition

Bairhugger

Oral analgesics/

NSAID’s

Incisions

No NG tubes

Early removal

of catheters/drains

Fearon et a al 2005, Lassen et al Arch Surg 2009

How does ERAS work?

Mechanisms

Insulin

Insulin & Recovery

Insulin: main anabolic hormone involved in• All parts of metabolism

– Glucose control– Fat metabolism– Protein

• Regulator of return of key functions• Central to development of complications• Affected by many perioperative treatments

Insulin & Recovery

Insulin: main anabolic hormone involved in• All parts of metabolism

– Glucose control– Fat metabolism– Protein

• Regulator of return of key functions• Central to development of complications• Affected by many perioperative treatments

• Insulin resistance: a key for understanding and enhancing recovery

Postoperative Insulin resistance

Defintion:

Below normal metabolic effect of insulin

• Glucose uptake

• Reduction in glucose production

• Lipolysis

• Protein breakdown / balance

Insulin sensitivity falls with the magnitude of surgery

Adopted from Thorell et al: Curr Opin Clin Nutr Metab Care 1999

-80

-70

-60

-50

-40

-30

-20

-10

0

Lap chol Open hernia Open chol Open colorectal

Reduction in Insulin Sensitivity (%)

Post

op

/ P

reo

pM

-val

ue

x 1

00

(%

)

P < 0.001, ANOVAn = 6-13

MoreInsulin

Resistance

Preop level

Independent factors predicting length of stay

• Type of surgery

• Perioperative blood loss

• Postoperative insulin resistance

R2 = 0.71, p < 0.01

Thorell et al: Curr Opin Clin Nutr Metab Care 1999

Muscle

Fat

Liver

Kidney

Blood cells

Endothel

Storage

Neural tissue

Insulin regulatedConcentration regulated

Fat

[B-Glucose]

Glucose uptake

Muscle

Fat

Liver

Kidney

Blood cells

EndothelNeural tissue

Insulin regulatedConcentration regulated

Glucose uptake- meal

Fat

Liver

Kidney

Blood cells

Endothel

Storage

Neural tissue

Insulin regulatedConcentration regulated

[B-Glucose]

Glucose uptake- stress

Fat

Liver

Kidney

Blood cells

Endothel

Neural tissue

Insulin regulated

Concentration regulated

[Glucose]Muscle

Driving forces for hyperglycemiaafter surgery

Postop

Hyperglycemia +

Insulin sensitivity -

Glucose production +

Peripheral glucose uptake -

GLUT4 translocation -

Glycogen formation -

Adopted from Ljungqvist et al, Clin Nutr 2001

Postop Type 2 DM

Hyperglycemia + +

Insulin sensitivity - -

Glucose production + +

Peripheral glucose uptake - -

GLUT4 translocation - -

Glycogen formation - -

Adopted from Ljungqvist et al, Clin Nutr 2001

Driving forces for hyperglycemiaafter surgery similar to diabetes

Normalizing insulin action normalizes metabolism

Insulin infusion to normalize:

• Blood glucose

Also controlled:

• FFA

• Urea excretion

• Substrate utilization after major surgery

Insulin resistance the key to catabolism

Brandi LS et al: Clin Sci 1990

Glucose uptake- stress

Fat

Liver

Kidney

Blood cells

Endothel

Neural tissue

Insulin regulated

Concentration regulated

[Glucose]Muscle

Too little

Too much

Insulin resistance muscle

• Reduced glucose uptake

• Reduced glycogen storage

• Increased protein catabolism

Insulin resistance muscle

• Reduced glucose uptake

• Reduced glycogen storage

• Increased protein catabolism

Lean body massLean body mass

Muscle functionMuscle function

MobilisationMobilisation

Energy supplyEnergy supply

Impaired Recovery

Postop (days) Tissues/cells

Muscle weakness muscle

Infections leukocytes

Cardiovascular blood vessels

Renal failure kidney

Polyneuropathy nerve tissue

Glucose uptake- stress

Fat

Liver

Kidney

Blood cells

Endothel

Neural tissue

Insulin regulated

Concentration regulated

[Glucose]Muscle

Too little

Too much

Complications

Postop (days) Tissues/cells

Infections leukocytes

Cardiovascular blood vessels

Renal failure kidney

Polyneuropathy nerve tissue

Muscle weakness muscle

Why these organs/cells?

Tissues unprotected to glucose uptake:

• Uncontrolled inflow of glucose• No storage• Overflow of glycolysis• ROS production• Block of glycolysis & Krebs cycle• Altered gene expression• Enhanced inflammatory response• Vicious circle

Vicious circle

ROS production

Enhanced inflammation Insulin resistance

Hyperglycemia

Stress of surgery

Stress hormones Cytokines

Insulin important for wound healing

• 6 patients studied twice, >40% burn injury

• Placebo – randomised - cross over design

• Hyperinsulinemia

– 400-900 microunits/ml for 7 days or placebo

• Glucose infusion to normoglycemia

• Donor-site healing time reduced

– from 6.5 to 4.7 days, p < 0.05

EJ Pierre et al, J Trauma 1998

Glucose levels in ERAS& outcomes after surgery

• 120 Consecutive patients

• Colorectal surgery

• No history of diabetes

• Preop HbA1c – above or below 6.1

• 26% pathologically high (≥ 6.1 mM)

• Glucose 5 times daily postop

• CRP and complications (30 day follow up)

Gustafsson et al, BJS 2009: 96; 1358-64

Gustafsson et al, BJS 2009: 96; 1358-64

Glucose after major elective surgery

N = 1201500 kcal/d

0

20

40

60

80

100

120

1

CR

P m

g/L

HbA1c < 6.1

HbA1c ≥ 6.1

*

* P< 0.05

CRP postop day 1

Gustafsson et al, BJS 2009: 96; 1358-64

HbA1c, Glucose controland postop complications

Gustafsson et al, BJS 2009: 96; 1358-64

0

5

10

15

20

25

30

35

40

45

50

Complications infections

HBA1c >6.1

HBA1c ≤6.1

OR 2.9P < 0.05

OR 2.3P=0.13

% o

f p

atie

nts

Postoperative insulin resistanceincrease the risk for complications

The ORs were adjusted for potential confounders

Complication OR for every decrease by1 mg/kg/min

(Insulin sensitivity)

P value

Death 2.33 (0.94-5.78) 0.067

Major complication 2.23 (1.30-3.85) 0.004

Severe infection 4.98 (1.48-16.8) 0.010

Minor infection 1.97 (1.27-3.06) 0.003

Sato et al, JCEM 2010; 95: 4338-44

273 patients open cardiac surgery, insulin sensitivity determined at the end of op

ERAS

EpiduralAnaesthesia

Preventionof ileus/

prokinetics

Preop CHO/no fasting

Early mobilisation

Peri-op fluidbalance

DVT prophylaxis

Pre-op councelling

Short acting anaesthetics

No - premed

No bowel prep

Early postoporal feeding

Maintaining body temperature

Oral analgesics/NSAID’s

Surgicaltechnique

No NG tubes

Early removalof catheters/drains

Fearon et al, Clin Nutr, 2005

ERAS

EpiduralAnaesthesia

Preventionof ileus/

prokinetics

Preop CHO/no fasting

Early mobilisation

Peri-op fluidbalance

DVT prophylaxis

Pre-op councelling

Short acting anaesthetics

No - premed

No bowel prep

Early postoporal feeding

Maintaining body temperature

Oral analgesics/NSAID’s

Surgicaltechnique

No NG tubes

Early removalof catheters/drains

Fearon et al, Clin Nutr, 2005

ERAS elements to reduce insulin resistance

Preoperative

• Preoperative carbohydrates

• Epidural anesthesia

Postoperative

• Pain control

• Early postop feeding

Preoperative CHO reducespostop insulin resistance

-60

-50

-40

-30

-20

-10

0

10

20

Cholecystectomy Colorectal Arthroplasty Arthroplasty

* * * *

*P < 0.05

Nygren et al: Curr Opin Clin Nutr Metab Care 2001

CHOControl

More resistance

Preoperative carbohydrates retains lean body mass (MAC)

Yuill et al, Clin Nutr 2005

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

CHO

Placebo

P <0.05

[cm]

0

1

2

3

4

5

6

Ure

a lo

sse

s (m

mo

l/kg

/d)

Preoperative carbohydrates reduces protein losses and improves muscle

strength

P<0.05

-16

-14

-12

-10

-8

-6

-4

-2

0

Po

sto

pe

rati

ve m

usc

le s

tre

ngt

h (

%)

ControlCHO

P<0.05

Mean (SEM)

Crowe, BJS 1984; Henriksen Acta Anaesth Scand 2003

Urea losses Muscle strength

EDA reduces postoperative insulin resistance

Uchida, Br J Surg 1988

-100

-50

0

50

100

150

200

250

300

350

Epinephrine Cortisol Insulin sensitivity

Po

sto

per

ativ

e c

han

ge (

%)

IV Opiates EDA *p<0.05**p<0.01

* * **

EDA + Preoperative CHO to control glucose during enteral feeding

Soop M et al, Br J Surg, 2004; *Harrison et al, JPEN 1997

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

Glu

co

se

(m

mo

l/l)

Day

complete

hypocaloric

Traditional*

No insulin required

Insulin sensitivity improved with pre op Carb, EDA + post op feed

From Thorell et al: Curr Opin Clin Nutr Metab Care 1999, Soop M et al, Br J Surg, 2004

-80

-70

-60

-50

-40

-30

-20

-10

0

Lap chol Open hernia Open chol Open colorectal

Post op change in Insulin Sensitivity (%)

Post

op

/ P

reo

pM

-val

ue

x 1

00

(%

)

MoreInsulin

Resistance

Preop level

CHOEDAPostop

Feed

CHOEDAPostop

Feed

EDA vs. Iv opiates

Jorgensen Cochr Database Syst Rev 2004

Epidural - less paralysis

ERAS: oral intake development (mean

intake postop day 1-4)

Insulin sensitivityDay before surgery

Insu

lin s

en

sitv

ity

Bowel prepNo nutrition

Dinner, normal sleep

ERAS Care

Traditional care

Insulin sensitivityMorning of surgery

Insu

lin s

en

sitv

ity

Bowel prepNo nutrition

Dinner, normal sleep

Carbohydrate treatment

Overnight fasting

ERAS Care

Traditional care

Insulin sensitivityMorning of surgery

Insu

lin s

en

sitv

ity

Bowel prepNo nutrition

Dinner, normal sleep

Carbohydrate treatment

Overnight fasting

ERAS Care

Traditional care

Insulin sensitivityAnesthesia start

Insu

lin s

en

sitv

ity

Bowel prepNo nutrition

Dinner, normal sleep

Carbohydrate treatment

Overnight fasting

Thoracic Epidural

Preoperative sedation

ERAS Care

Traditional care

Insulin sensitivityReaction to surgery

Insu

lin s

en

sitv

ity

Bowel prepNo nutrition

Dinner, normal sleep

Carbohydrate treatment

Overnight fasting

Thoracic Epidural

Preoperative sedation

Surgery

Greater drop without Epidural

ERAS Care

Traditional care

Insulin sensitivityAfternoon of surgeryIn

sulin

se

nsi

tvit

y

Bowel prepNo nutrition

Dinner, normal sleep

Carbohydrate treatment

Overnight fasting

Thoracic Epidural

Preoperative sedation

Surgery

Immediate feeding & mobilisation

NPO iv low caloric fluids

ERAS Care

Traditional care

Insulin sensitivityDays after surgery

Insu

lin s

en

sitv

ity

Bowel prepNo nutrition

Dinner, normal sleep

Carbohydrate treatment

Overnight fasting

Thoracic Epidural

Preoperative sedation

Surgery

Immediate feeding & mobilisation

NPO iv low caloric fluids

Oral feeding & mobilisation

Slow return to feeding and mobilisation

Days - weeks

ERAS Care

Traditional care

Insulin sensitivity Days after surgery

Ins

uli

n s

en

sit

vit

y

Bowel prepNo nutrition

Dinner, normal sleep

Carbohydrate treatment

Overnight fasting

Thoracic Epidural

Preoperative sedation

Surgery

Immediate feeding & mobilisation

NPO iv low caloric fluids

Oral feeding & mobilisation

Slow return to feeding and mobilisation

Days - weeks

ERAS Care

Traditional care

Ljungqvist JPEN 2012

-80

-60

-40

-20

0

20

40

60

80

100

N losses N balance Energyexp

Glucose Insulin Insulinsens

Post

op

erat

ive

chan

ge (

%)

Traditional

Metabolic response to surgery intraditional perioperative care

-80

-60

-40

-20

0

20

40

60

80

100

N losses N balance Energyexp

Glucose Insulin Insulin

sens

Post

op

erat

ive

chan

ge (

%)

Traditional ERAS protocols

Metabolic response to surgery in traditional perioperative care vs. ERAS

protocols

Conclusions

• Minimizing metabolic stress is key to improved recovery

• Insulin resistance is central

• ERAS principles works in all major surgery

• Many ERAS components reduce metabolic stress

• Combining ERAS elements for best results

2013-11-12 63

• Valencia Spain

• April 23-26, 2014

• Multiprofessional

• Multi disciplinary

• Patient, Practice & Outcomes

• Henrik Kehlet Lecture:– Economics of ERAS / A Senagore

• ERAS Lecture:– Postoperative cognition / S Newman

• World leaders in ERAS

2nd World ERAS Congress