Should Insulin be added to Parenteral Nutrition?

Jay M Mirtallo

ESPEN Congress Gothenburg 2011

Educational Session - Pharmaceutical session (in collaboration with ASPEN)

Should Insulin be added to Parenteral Nutrition?

Jay M Mirtallo, MS, RPh, BCNSP, FASHP Associate Professor of Clinical Pharmacy The Ohio State University, College of Pharmacy Pharmacy Practice and Administration Division President, The American Society for Parenteral and Enteral Nutrition

Insulin Indications for PN

Manage hyperglycemia

Protein accretion (anabolism)

Anti-inflammatory activity

Insulin in PN: Outline

Indication: Manage Hyperglycemia

Frequency of hyperglycemia in PN patients

Association of adverse outcomes with hyperglycemia in PN patients

Variables associated with poor glucose control in PN patients

Issues with insulin in PN

Criteria for adding medications to PN

PN: Frequency of Hyperglycemia Reference Criteria N (%) Comment NSS

Dodds et al. NCP 2001

@ least 1 value > 200 mg/dl

762 (28)

Only 2 pts developed symptoms complication

Yes

Weinsier et *al. JPEN 1982

> 300 mg/dl after at least 48 hrs of PN

47 (47) No symptoms observed

Dextrose based PN

Yes but not used, guidelines, flow sheets, order sets in place

ChrisAnderson* et al JPEN 1996

As per Weinsier 23 (22)

(41)

(39)

No effect of NSS in prospective trial

-Non NSS

-NSS

Use of 3 in 1 (TNA)

Yes, consult with recommendations only(64% compliance), substantial staff education

Rosmarin et al, NCP 1995

> 200 mg/dl 0 (0)

5 (7)

18 (43)

-Dext infusion < 4

-Dext infusion 4-5

-Dext infusion >5

No risk factors present

Yes, dextrose based diet

Pleva et al, NCP 2009

>200 mg/dl

>150 mg/dl

22 (44)

45 (90)

Resulted in 1.4 events per patient course

Risk factors: diab, pancreatitis, Steroids

Yes, pharmacist management

*Same institution

PN and Hyperglycemia: Adverse Outcomes

Relation between blood glucose levels and outcomes

Myocardial infarction

Stroke

Cardiothoracic surgery

Critical illness

General hospitalized patients

Cheung NW et al Diabetes Care 2005; 28: 2367-2371

PN and Hyperglycemia: Adverse Outcomes

Risk of any complication 1.58 (p <0.01)

Infection

Septicemia

Acute renal failure

Cardiac complications

Death

Quartile analysis

Risk level increased at high quartile vs low quartile group

OR of 4.3 for complication, 10.9 for death

Cheung NW et al Diabetes Care 2005; 28: 2367-2371

Severity of Hyperglycemia

Stronger predictor of adverse outcomes than history of diabetes

Majority of PN patients who become hyperglycemic are not diabetic

Excluded from Rosmarin study

12% of Pleva study population

27% of Wah Cheung study population

Evidence that hyperglycemia in itself is harmful.

Cheung NW et al Diabetes Care 2005; 28: 2367-2371

47

112

129

158

401

0

50

100

150

200

250

300

350

400

450

0 435 869 1304 1738

Quartile Values for Patient Population

Blo

od

glu

co

se

, m

g/d

l

Mirtallo PN Pleva et al Nutr Clin Pract 2009; 24:626-634

Variables Associated with PN Hyperglycemia

Caloric dose

Type of calorie provided

„Hidden‟ Sources of CHO

Target glucose range

Impact of controlling glucose to this range

Responsibility for glucose management

Use of sliding scale insulin

FEAR of hypoglycemia

Variables Associated with PN Hyperglycemia

No one method known to be effective in achieving target glucose

Lack of consensus for insulin use Long-acting insulin Sliding scale insulin Insulin drip Insulin in PN Any combination of the above

Practice varies widely among patient populations, disciplines and individual clinicians

Overall, management of hyperglycemia is most important Interdisciplinary nutrition care

Experience and skill of staff managing PN View as a process

Insulin in PN

Criteria for medications added to PN

Stable and compatible

Evidence supports clinical value of medication administered in PN

Frequency of dosage adjustment no more than every 24 hours

Insulin is associated with frequent harmful events in PN

Mirtallo et al. JPEN 28 (suppl) S39-S70, 2004

Management of Hyperglycemia: Alternative to Insulin-Hypocaloric PN

Reference Criteria Comment

Choban PS et al Am J Clin Nutr 1997

Hypocaloric 75 Cal:g nitrogen

Normal 150 Cal: g nitrogen

2 g Pro/kg IBW/d

Obese patients

12 pts received insulin (11/12 diabetic)

Less insulin days in NIDDM hypocaloric group

McCowen KC et al Crit Care Med 2000

Study: 1000 kcal, 70 g pro

Control: 25 kcal/kg, 1.5 g/kg pro

No difference in

Frequency of hyperglycemia – non diabetics

insulin use

Average glucose

worse nitrogen balance in hypocaloric group

Ahrens CL et al Crit Care Med 2005

Low Cal: 20 NPC/kg/d

Standard Cal: 30 NPC/kg/d

Excluded underweight/morbid obese

Used sliding scale insulin

Insulin in PN if >50% values > 200

Fewer hyperglycemic events and lower severity

Mean glucose lower (118 vs 172)

Insulin Availability from PN

Range: 10-95%

Composition of PN

Lipids, trace elements, vitamins

Final concentration of insulin

Assay for insulin

Laboratory simulation of clinical practice

Adequate monitoring of patient clinical response

Seres DS; NCP 1990;5: 111-116

Evidence Supporting Insulin Use

Diabetic Patients

Pre hospital insulin dose Reduced daily dextrose dose to start

100 g – Type 1 150 g – Type 2

Accept modest hyperglycemia to avoid hypoglycemia Sliding scale insulin: glucose > 250

Mean glucose around 200 mg/dl No hypoglycemic episodes

Insulin in PN Significant calories from enteral nutrition or tube feeding

Insulin separate from PN

Source of dextrose determines route of insulin Dialysis

Hongsermeier T et al. JPEN 17:16-19, 1993

Evidence Supporting Insulin Use: Insulin protocol

NSS: primarily pharmacist Capillary Blood glucose (CBG) every 6 hrs Criteria: glucose > 140 mg/dl

Insulin dose per g Carbohydrate (CHO) PN induced hyperglycemia

1 U/20 g CHO Diabetes/glucocorticoids

CBG <11.1 mmol/L (200 mg/dl) 1 U/10 g CHO + 0.15 U/kg/d

CBC > 11.1 mmol/L 1 U/5 g CHO + 0.25 U/kg/d

2/3 insulin dose in PN, 1/3 separate as long-acting insulin

Jakoby MG et al. JPEN @

http://pen.sagepub.com/content/early/2011/08/06/0148607111415628

Evidence Supporting Insulin Use: Insulin protocol

Mean CBG < in protocol group by 21 mg/dl

Higher CBG in diabetic group but better control with protocol

Hypoglycemia (CBG < 80)

more frequent in protocol group (3 vs 1%)

No episodes of severe hypoglycemia (CBG < 40)

Jakoby MG et al. JPEN @

http://pen.sagepub.com/content/early/2011/08/06/0148607111415628

Evidence Supporting Insulin Use: Computer-assisted, Critically Ill

Nurse centered computerized decision support for insulin administration “step-up” rule

Graded increases in amount of PN administered For glucose < 10 mmol/L (180 mg/dl)

End-point: achieve full PN at 24 hours along with glucose control during introduction period Goal: 25 kcal/kg/d, max = 2500 kcal

Use of insulin drip Desired caloric intake achieved within 24 hr Glucose levels

6.6 (119 mg/dl) to 7.6 (137 mg/dl) mmol/L (ave – 7.4 (133))

Insulin drip rate of 1.1-2.0 U/h

Hoekstra M et al. JPEN 34: 549-553. 2010

Should Insulin be Added to PN? It depends

Critically ill: separate insulin infusion (drip)

Significant calories from enteral or tube feeding: separate insulin as sliding scale or long-acting Minimize „Hidden‟ sources of glucose

Others: definitely use insulin in PN Evidence that better than using sliding scale insulin

Reasonable glucose control with minimal hypoglycemia

Consider insulin dose per gram of carbohydrate in PN Adjust dose daily with sliding scale insulin

2/3 previous days insulin dose

Systems Issues

Establish target glucose

Interdisciplinary involvement

Assign responsibility for glucose control

Provide algorithm or protocol to follow

Evaluate success in achieving target glucose values

A.S.P.E.N. Guideline

Insulin use in PN should be done in a consistent manner according to a method that healthcare personnel have adequate knowledge

Mirtallo et al. JPEN 28 (suppl) S39-S70, 2004

Algorithm – Steps 1 and 2

Does the patient have risk factors*

for hyperglycemia during PN?

Risk Factors*

Diabetes

Pre-existing hyperglycemia (> 150)

Pancreatitis

Corticosteroids

Octreotide

Routine Glucose Monitoring

Monitor 5 AM blood glucose daily

Order Accuchecks Q6H

Target Serum Glucose

Continuous infusion: 100-150 mg/dL

Cyclic: 100-200 mg/dL

Step 1: Risk Assessment

Order Accuchecks Q6H with sliding scale insulin

Start sliding scale at 150 mg/dL and correct with 2-4 units

for every 50 mg/dL above 150

YesNo

Does patient have >2 blood

glucose >150 mg/dL in 24 hr?

No

Yes

Step 2: Minimize glucose from other sources

Maintenance IV

with dextrose

Medications

prepared in

dextrose

Oral diet Tube feeding

Is the patient hyperglycemic while on

sliding scale insulin?

If yes, then minimize...

Glucose Algorithm – Step 3

Step 3: Adding insulin into PN

What is the patient’s glucose level

prior to initiation?

Euglycemic (for diabetic patients)

Insulin dose: 0.1 units per gram of

dextrose in formula

(i.e. 15 units insulin per 150 grams/L

dextrose)

If glucose > 200 mg/dL

Start PN at 100 grams/L dextrose

Insulin dose: 0.1 units per gram of

dextrose in formula

(i.e. 10 units insulin per 100 grams/L

dextrose)

Serum glucose > 300 mg/dL

PN contraindicated

Normalize serum glucose prior to

starting PN

Hyperglycemic

If glucose is 150-200 mg/dL

Insulin dose: 0.1-0.2 units per gram of

dextrose in formula

(i.e. 15-30 units insulin per 150 grams/

L dextrose)

Glucose Algorithm – Step 4 Step 4: Insulin monitoring

Monitor Q6H Accuchecks

Is the patient’s blood glucose within

goal range?

Continue current insulin regimen

Adjust insulin in PN by adding 75% of

insulin dose used via sliding scale in

previous 24 hours

Increase PN to goal rate

When glucose is controlled at 40 mL/hr

Monitor Q6H Accuchecks

Is glucose within range?

Monitor Q6H Accuchecks

Is glucose within range?

Monitor Q6H Accuchecks

Is glucose within range?

Increase PN to goal rate

When glucose is controlled at 40 mL/hr

Yes No

Yes

No

Yes

No

Yes

Adjust insulin in PN by adding 75% of

insulin dose used via sliding scale in

previous 24 hours

No

Glucose Algorithm - Notes

PN may be cycled if glucose is controlled on continuous PN while at goal rate

Taper insulin in PN when glucose < 100 mg/dL for 3 of 4 Accuchecks in a 24-hr period

Insulin limit in PN is 60 units/L.

If patient needs more insulin, then discontinue insulin in PN and begin insulin drip.

Summary

The use of insulin in PN is a controversial topic Primary indication: hyperglycemia

associated with PN

Original issues with bioavailability from PN

Little evidence evaluating outcomes of insulin use in PN

Considerable variability in types of patients and PN practices

Conclusion

Evidence and clinical practice suggests insulin is clinically effective in PN when dosage adjustments are suitable on a daily basis

References

Shizgal HM, Posner B. Insulin and the efficacy of total parenteral nutrition. Am J Clin Nutr 50:1355-63, 1989.

Cheung NW, Zaccaria C, Napier B, Fletcher JP. Hyperglycemia is associated with adverse outcomes in patients receiving total parenteral nutrition. Diabetes Care 28:2367-2371, 2005

Dodds ES, Murray JD, Trexler KM, Grant JP. Metabolic occrurences in total parenteral nutrition patients managed by a nutrition support team. Nutr Clin Pract 16:78-84, 2001

Weinsier RL, Bacon J, Butterworth CE. Central venous alimentation: a prospective study of the frequency of metabolic abnormalities among medical and surgical patients. J Parenter Enter Nutr 6: 421-425, 1982

ChrisAnderson D, Heimburger DC, Morgan SL et al. Metabolic complications of total parenteral nutrition: effects of a nutrition support service. J Parenter Enter Nutr 20:206-210, 1996

Rosmarin DK, Wardlaw GM, Mirtallo J. Hyperglycemia associated with high, continuous infusion rates of total parenteral nutrition. Nutr Clin Pract 11:151-156, 1996

Pleva M, Mirtallo JM, Steinberg SM. Hyperglycemic events in non-intensive care unit patients receiving parenteral nutrition. Nutr Clin Pract 24: 626-634, 2009

Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. J Parenteral Enter Nutr 28 (suppl):S39-S70, 2004

Choban PS, Burge JC, Scales D, Flancbaum L. Hypoenergetic nutrition support in hospitalized obese patients: a simplified method for clinical application. Am J Clin Nutr 66:546-550, 1997

McCowen KC, Friel C, Sternberg J, et al. Hypocaloric total parenteral nutrition: effectiveness in prevention of hyperglycemia and infectious complications – a randomized clinical trial. Crit Care Med 28:3606-3611, 2000

Ahrens CL, Barietta JF, Kanji S et al. Effect of low-calorie parenteral nutrition on the incidence and severity of hyperglycemia in surgical patients: a randomized, controlled trial. Crit Care Med 33:2507-2512, 2005\

Seres DS, Insulin adsorption to parenteral infusion systems: case report and review of the literature. Nutr Clin Pract 5:111-117, 1990

McMahon MM. Management of parenteral nutrition in acutely ill patients with hyperglycemia. Nutr Clin Pract 19:120-128, 2004

Hongsermeier T, Bistrian BR. Evaluation of a practical technique for determining insulin requirements in diabetic patients receiving total parenteral nutrition. J Parenter Enter Nutr 17:16-19, 1993

Jacoby MG, Nannapaneni N. An insulin protocol for management of hyperglycemia in patients receiving parenteral nutrition is superior to ad hoc management. J Parenter Enter Nutr accessed August 17, 2011. avaialble at: http://pen.sagepub.com/content/early/2011/08/06/0148607111415628

Hoekstra M, Schoorl MA, Iwan CC, et al. Computer-assisted glucose regulation during rapid step-wise increases of parenteral nutrition in critically ill patients: a prood of concept study. J Parenter Enter Nutr 34:549-553, 2010