Journal Club and article review presented at the Miami VA during my Pharmacy Surgery Elective Rotation.

1. Early versus Late
Parenteral Nutrition in
Critically Ill Adults
Joy A. Awoniyi, PharmD. Candidate
Florida Agricultural and Mechanical University
August 2, 2011
Surgery Elective Rotation
Preceptor: Dr. Lisa Joseph
N Engl J Med 2011
Authors: Casaer MP, Mesotten D, Hermans G, et. al.

2. Background
• Parenteral Nutrition provides caloric requirements when
other routes of administration are not possible
• Short Bowel Syndrome
• Bowel Obstruction
• Chron’s Disease
• Ulcerative Colitis
• Starvation or underfeeding in intensive care unit patients
is associated with increased morbidity and mortality
• 20-40% of critically ill patients show evidence of protein-
energy malnutrition
• Optimal timing for the initiation of parenteral nutrition in
critical care is a major area of uncertainty

3. Guideline Differences
European Society of
Enteral and Parenteral
Nutrition. 2009
“All patients who are not
expected to be on normal
nutrition within 3 days
should receive parenteral
nutrition within 24 to 48
hours if enteral nutrition is
contraindicated or if they
cannot tolerate enteral
nutrition.”
Society of Critical Care
Medicine and American
Society of Parenteral and
Enteral Nutrition. 2009
“Use of parenteral nutrition
should be reserved and
initiated only after the first
7 days of hospitalization
(when EN is not
available).”

4. Objectives
EPaNIC Study
Early Parenteral Nutrition Completing Enteral
Nutrition in Adult Critically Ill Patients
• To compare the effect of late initiation of parenteral
nutrition with early initiation on rates of death and
complications in adults in the ICU who are at risk but not
chronically malnourished
• To investigate whether preventing a caloric deficit
during critical illness by providing PN early in disease
course would reduce the rate of complication or
whether withholding PN for 1 week would be clinically
superior

5. Methods
Study Design
• Prospective
• Randomized
• Controlled
• Parallel-group
• Multi-centered
Study Population
• 4640 Underwent
Randomization
• 2313 – Early Initiation
• 2328 – Late Initiation
• Patients stratified
according to diagnostic
categories
• Subjects were not
blinded

6. Methods
Inclusion Criteria
• Score of 3 or more on
the Nutritional Risk
Screening
• 18 years or older
• BMI of at least 17
Exclusion Criteria
• Short-bowel syndrome
• Home ventilation
• Pregnant or Lactating
• Enrollment in another
trial
• Readmission to the ICU

7. Baseline Characteristics
• Well matched between groups (Table 1)
• Sex, Age, Weight, BMI
• Disease States: Diabetes Mellitus, Dialysis-dependent
Kidney Failure, Cancer, Nutritional Risk Screening Score
• Emergency Admission
• Severity of Illness by APACHE II Scoring
• Scale of 0 to 71
• Sepsis diagnosed by the ACCP Society of Critical Care
Medicine Criteria
• Score calculated by trained experts

8. Study Procedure
All Patients
• Enteral Nutrition if unable to eat by Day 2
• Twice daily increase in infusion rate
• Prokinetic agents
• Duodenal feeding tubes
• Parenteral administration early in the ICU stay to
avoid micronutrient depletion on re-feeding
• Trace elements
• Minerals
• Vitamins

9. Study Procedure
Early Initiation Group
• Day 1: 20% IV Glucose Solution
• Target total daily energy intake of 400 kcal
• Day 2: 20% IV Glucose Solution
• Target total daily energy intake of 800 kcal
• Day 3: Initiation of PN
• Target: 100% of caloric goal (EN and PN)
• Maximum caloric goal for all patients: 2880 kcal per
day.

10. Study Procedure
Late Initiation Group
• Day 1-7: 5% Glucose solution in a volume equal
to parenteral nutrition
• Day 8: Parenteral nutrition administration if
enteral nutrition proved insufficient

11. Study Procedure
Administration and Monitoring
• Patient-data-management system used to calculate
daily volumes of EN and PN for each patient
• After discharge from the ICU, nutritional management
at the discretion of attending physicians
• Continuous Insulin infusion
• Glucose goal: 80-110 mg/dL
• Blood Gas analyzer to monitor ABG every 1-4hours

12. Data Collection
• Intensive care treatments and procedures
• New bacterial or fungal infections
• Chemical Analysis Results
• Blood
• Urine
• Hematologic Studies
• Inflammation markers
• Total Energy Intake by EN and PN

13. Data Collection
• Therapy Interruptions
• Feeding Related Complications
• Functional Status before discharge
• Direct Health Care costs
• Patient invoices
• Analyzed from healthcare payer perspective
• Government and patient costs
• Vital Status 90 days after randomization

14. Outcome Measures
Primary Endpoint
• Duration of
dependency on
intensive care
• Number of ICU days
• Time to discharge from the
ICU
• Defined as time patients
were ready for ICU
discharge, to avoid bias
Safety Endpoints
• Vital Status
• Proportion alive at ICU
discharge in 8 days or less
• Rates of ICU and Hospital
deaths
• Rates of survival up to 90
days
• Rates of complications
and hypoglycemia

15. Outcome Measures
• Number of patients with new infections
• Infection site
• Duration of Antibiotic Therapy
• Inflammation (C-reactive Protein max)
• Time to final weaning from mechanical ventilatory
support
• Duration of hospital stay and time to discharge
• Functional status
• Distance walked in 6 minutes
• Proportion of patients independent in all ADLs
Secondary Endpoints

16. Outcome Measures
• Rate of acute renal injury
• RIFLE Criteria (Risk, Injury, Failure, Loss, End-stage)
• Doubling of the SrCr level from admission
• Proportion of patients requiring renal
replacement therapy
• Duration of the therapy in the ICU
• Need for and duration of pharmacologic or
mechanical hemodynamic support
Secondary Endpoints

17. Outcome Measures
• Proportion of patients presenting with liver
dysfunction
• Total Bilirubin >3mg/dL
• GGT >79.5Units/L
• Alkaline phosphatase >405 Units/L
• ALT >123
• AST>114
• Incremental Healthcare costs from randomization
to discharge
Secondary Endpoints

18. Statistical Analysis
• Sample size
• Ability to detect a between-group change of 1 day
in the ICU stay
• Power at least 80%
• Ability to detect a change of 3% in the rate of
death
• Power of at least 70%
• Intention-to-treat Analysis
• Two-sided p value of less than 0.05 to indicate
statistical significance
• Use of JMP Software for analysis

19. Statistical Analysis
Variable Test Used
Data Comparison • Chi-squared Test
• Student’s T-Test
• Non-parametric testing
• Median Test
• Wilcoxon Rank-sum Test
• Mann-Whitney U Test
Healthcare Costs • Student T Tests
Time-To Event • Analysis: Kaplan Meier Methods
• Effect Size: Cox-proportional Hazards

20. Results
• Insulin Requirements to reach target
• Late: 31 IU (Interquartile 19-48)
• Early: 58 IU (Interquartile 40-85)
• Glucose Level
• Late: 102 ± 14 mg/dL
• Early: 107 ± 18 mg/dL
• P <0.001
Study Intervention

21. Results
6.1%
10.4%
11.2%
18.2%
6.3%
10.9% 11.2%
18.8%
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
14.0%
16.0%
18.0%
20.0%
Death in ICU Death In
Hospital
Death Within 90
Days
Nutrition-related
Complications
Safety Outcomes
Late
Early

22. Results
75.2%
71.7%
69.0%
70.0%
71.0%
72.0%
73.0%
74.0%
75.0%
76.0%
Discharged Alive in
8 days
p = 0.007
Late
Early
3.5%
1.9%
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
3.5%
4.0%
Hypoglycemia
during intervention
p = 0.001
Statistically Significant Safety
Outcomes

23. Results
Median days
• Late – 3 (2-7)
• Early – 4 (7-9)
• P = 0.02
Duration greater than 3
days
• Late – 48%
• Early – 51.3%
• P= 0.02
Primary Outcome
Duration of dependency on Intensive Unit care
Hazard Ratio for time To
discharge from the ICU
• 1.06
• 95% CI between 1.00
and 1.13
• P= 0.04

24. Results
Kaplan-Meier Estimates
Proportion Discharged from ICU Proportion discharged alive from ICU

25. Results
Kaplan-Meier Estimates
Discharged from Hospital Discharged Alive from Hospital

26. Results
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
Secondary Outcome – New Infections
Late
Early

27. Results
140
150
160
170
180
190
200
Max CRP (mg/L)
Secondary Outcome - Inflammation
Late
Early
More pronounced acute inflammatory response in
the late Initiation group (p<0.001)

28. Results
Median Duration of Selected Secondary Outcomes
0
2
4
6
8
10
12
14
16
18
Mechanical
Ventilation
(p=0.02)
Renal
Replacement
Therapy (p=0.008)
Hospital Stay
(p=0.004)
Time(days)
Late
Early

29. Results
Kidney Failure
• Percentage with Modified
RIFLE Category
• Late – 4.6%
• Early – 5.8%
• P = 0.06
• Percentage requiring Renal
Replacement therapy
• Late – 8.6%
• Early – 8.9%
• P= 0.77
Mechanical Ventilation
• Percentage of patients
requiring MV for >2days
• Late – 36.3%
• Early – 40.2%
• P = 0.006
• Hazard ratio for discharge
alive from hospital: 1.06
• 95% CI = 1.00-1.13

30. Results
Functional Status at Discharge
• Distance on 6 minute walk
test
• Late (624 pts) – 277 meters
• Early (603 pts) – 283 meters
• P = 0.57
• Percentage of patients
independent in all ADLs
• Late (1060 pts) – 73.5%
• Early (996 pts) – 75.5%
• P= 0.31
Hospital Stay
• Percentage in the hospital
for >15 days
• Late – 45.5%
• Early – 50.1%
• P = 0.001
• Hazards ratio for time to
discharge alive from the
hospital: 1.06
• 95% CI = 0.99 – 1.12

31. Results
16,863
17,973
€ 16,000
€ 16,500
€ 17,000
€ 17,500
€ 18,000
€ 18,500
Mean Total
Incremental Health
Care Cost
P =0.04
Late
Early
• Included in Total Cost
Calculation
• Cost billed to
government
• Costs billed to
patient
• From randomization
to discharge
• Values do not include
deduction of cost of PN
in the late-initiation
group

32. Results
Subgroup Analysis

33. Study Limitations
• No glutamine or immune-modulating
compounds
• Low protein-to-energy ratio due to
standardized, premixed parenteral nutrition
products
• Subjects and providers were aware of study
group assignments

34. Author’s Conclusions
“Early initiation of parenteral nutrition appears to
be inferior to the strategy of with-holding until
Day 8 while providing vitamins, trace elements,
and minerals. Late initiation was associated with
fewer infections, enhanced recovery, and lower
healthcare costs ”

35. Journal Critique

36. Title and Abstract
Strong
• Title reflective of study
and objectives
• Abstract well organized
Weak
• Results regarding acute
inflammation and
hypoglycemia not
addressed in abstract

37. Methods
Strong
• IRB Approved
• Appropriate Study
Duration
• Patients stratified
according to 16
diagnostic criteria
• 7 Participating ICUs
Weak
• Site locations?
• Trace elements, vitamins
and minerals given to
both groups

38. Outcomes and
Statistical Analysis
Strong
• IRB Approved
• Safety Outcomes
included
• Analysis by computer
software
• Sub-group analysis
performed
Weak
• Too many secondary
outcomes
• Intention-to-treat
analysis vs per-protocol

39. Results
Strong
• Establishes 1-day
difference in ICU stay
between groups
• Distinguishes results
between overall hospital
stay and ICU stay
• Graphs and charts
provided are helpful
Weak
• Article mentions few
results of the stated
secondary outcomes
• Reader must refer to
supplementary appendix

40. Conclusions
Strong
• Supported by the
collected data
• Study limitations
addressed
Weak
• Late-initiation group
short-comings not
addressed
• Hypoglycemia
• Hyperbulirubinemia

41. Overall Impression
Benefits of Late Initiation of TPN therapy
• Fewer ICU infections
• Shorter duration of mechanical ventilation
• Shorter course of renal-replacement therapy
• Shorter ICU and hospital stay
• Reduced Health care costs
Disadvantages of Late Initiation of TPN therapy
• Higher degree of acute inflammation
• Increase in hypoglycemic episodes

42. References
• Zeigler TR. “Parenteral Nutrition in the Critically Ill Patient”. N Eng J Med. 2009;361:1088-1097.
• Casaer MP, Dieter M, Hermans G, et. al. “Early versus Late Parenteral Nutrition in Critically Ill
Adults”. N Eng J Med. 2011;
• Singer P, Berger MM, Van den Berghe G, et al. “ESPEN guidelines on parenteral nutrition:
Intensive Care”. Clin Nutr 2009;28:387-400.
• Martindale RG, McClave SA ,Venek VW, et al. “Guidelines for the provision and assessment
of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine
and American Society for Parenteral and Enteral Nutrition: Executive summary”. Crit Care
Med, 2009;37:1757-61.