Early versus Late Parenteral Nutrition in

Critically Ill Adults

Joy A. Awoniyi, PharmD. CandidateFlorida Agricultural and Mechanical UniversityAugust 2, 2011

Surgery Elective RotationPreceptor: Dr. Lisa Joseph

N Engl J Med 2011Authors: Casaer MP, Mesotten D, Hermans G, et. al.

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

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).”

Objectives

EPaNIC StudyEarly 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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

Statistical Analysis

Variable Test UsedData 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

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

Results

Death

in IC

U

Death

In H

ospita

l

Death

With

in 9

0 Day

s

Nutrit

ion-

relate

d Com

plicat

ions

0.0%4.0%8.0%

12.0%16.0%20.0%

6.1%10.4% 11.2%

18.2%

6.3%

10.9% 11.2%

18.8%Safety Outcomes

LateEarly

Results

Discharged Alive in 8 days

69.0%

70.0%

71.0%

72.0%

73.0%

74.0%

75.0%

76.0% 75.2%

71.7%

p = 0.007

LateEarly

Hypoglycemia dur-ing intervention

0.0%

1.0%

2.0%

3.0%

4.0%3.5%

1.9%

p = 0.001

Statistically Significant Safety Outcomes

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 OutcomeDuration 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

ResultsKaplan-Meier Estimates

Proportion Discharged from ICU Proportion discharged alive from ICU

ResultsKaplan-Meier Estimates

Discharged from Hospital Discharged Alive from Hospital

Results

Any (p

=0.

008)

Airway

or L

ung

(p=0.

009)

Blood

stre

am (p

= 0

.05)

Wou

nd (p

=0.

006)

Urinar

y Tr

act (

p=0.

28)

0.0%5.0%

10.0%15.0%20.0%25.0%30.0%

Secondary Outcome – New Infections

Late

Early

Results

Max CRP (mg/L)140

150

160

170

180

190

200

Secondary Outcome - Inflammation

LateEarly

More pronounced acute inflammatory response in the late Initiation group (p<0.001)

Results

Median Duration of Selected Secondary Outcomes

048

1216

LateEarly

Tim

e (

days)

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

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

Results

€ 16,000

€ 16,500

€ 17,000

€ 17,500

€ 18,000

€ 18,500

16,863

17,973

Mean Total Incre-mental Health Care

CostP =0.04

LateEarly

• 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

ResultsSubgroup Analysis

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

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 ”

Journal Critique

Title and Abstract

Strong

• Title reflective of study and objectives

• Abstract well organized

Weak

• Results regarding acute inflammation and hypoglycemia not addressed in abstract

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

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

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

Conclusions

Strong

• Supported by the collected data

• Study limitations addressed

Weak

• Late-initiation group short-comings not addressed• Hypoglycemia

• Hyperbulirubinemia

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

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.