Our intensive care research group has previously published systematic reviews and meta-analyses of clinical trials demonstrating that mortality is significantly reduced, if critically ill patients are provided EN within 24 hours of ICU admission or injury compared with standard care, where standard care is defined as any form of nutritional support commenced later than 24 hours from ICU admission or injury.6
In order to assess the full financial impact of the delivery of early EN during critical illness, this current project updates these meta-analyses to include assessments of the major measures of health care resource consumption: ICU length of stay, duration of invasive mechanical ventilation, and duration of hospital stay.
Type of economic evaluation
In the context of a significant reduction in mortality attributable to early EN, established by published meta-analyses of clinical trials (odds ratio = 0.34, 95% confidence interval [CI] 0.14 to 0.85, P
= 0.02, I2
a cost-effectiveness analysis (CEA) was undertaken.
Major measures of resource consumption demonstrating marginal differences between the competing treatment alternatives (early EN versus standard care) were eligible for inclusion in the economic analysis and were combined with costs obtained from the published literature, using a stochastic model with a large-scale Monte Carlo simulation, conducted to estimate the total cost differences and 95% CI.
Perspective and time horizon
This CEA was conducted from the perspective of the US acute care hospital system. The time horizon of the analysis was the period from study enrolment (ICU admission) until acute care hospital discharge.
Discounting/indexing of costs
The US Department of Labor Consumer Price Index (CPI) for Medical Consumers was used to index published US costs to 2012 US funds, based on the specific index rate reported for each year.9
In addition, a sensitivity analysis was conducted using a conservative index rate of 4.0%.10
All costs reported in this manuscript were indexed to 2012 US funds, using the CPI, unless explicitly reported otherwise.
Costs of acute care whilst in the ICU
Cost distributions for acute care whilst admitted to an ICU were obtained from the published literature. Dasta et al11
reported the mean daily costs of care from the perspective of the acute care hospital, for patients admitted to an ICU, using an administrative database composed of 51,009 ICU patients from 253 geographically diverse hospitals across the USA. This database, maintained by NDCHealth, contains patient charges recorded by operational billing systems and is regularly audited for accuracy.11
Costs were estimated using hospital-specific cost-to-charge ratios. Hospitals contributing to this study are considered to be representative of the larger US hospital population with regards to geographic location, bed number, and teaching status.
Dasta et al11
found costs to be significantly higher for the first 2 days of ICU admission compared with subsequent days, with significant differences also existing between the major patient groups (medical patient, surgical patient, and trauma patient) and between patients who received invasive mechanical ventilation during their ICU stay compared with patients who did not receive mechanical ventilation. presents the relevant cost distribution matrix abstracted from the publication by Dasta et al.11
Matrix of the distributions of daily costs of care whilst admitted to the intensive care unit
Costs of 1 day of enteral nutrition
The costs for the delivery of 1 day of EN to a critically ill patient were established from review of the published literature. A systematic review conducted by Pritchard et al8
reported a wide variation in costs, ranging from £7 per day of EN (1994 UK pounds) to charges of US$46 per day for pediatric ICU patients (1996 US dollars). This review made specific comments on the poor quality of most studies reporting daily costs of EN and noted that older studies reporting costs may not be relevant due to recent reductions in the purchase price of EN.8
A more recent study by Strickland et al,12
which was not included in the review by Pritchard et al,8
documented the total costs (purchase costs, supplies used for delivery, and professionals’ time) of providing EN to critically ill patients in the US market.12
This single-centre study reported the total costs of providing a 7-day postoperative EN course to a medical ICU or trauma patient was US$245 (2012 US dollars), or US$35 per day.
To allow for inherent variability between hospitals, and to ensure a conservative overcosting of EN, we inflated these costs by 50% and assumed a wide standard deviation (SD), in keeping with the SD of other reported medical costs (see ) used in this simulation. The daily cost of EN used in our stochastic model was US$52.50 per day, with an SD of US$52.50.
Marginal difference in days of enteral nutrition between early enteral nutrition patients and standard care
A multicentre survey of international nutrition practices reviewing 2,946 patients admitted to 158 ICUs from 20 countries reported the mean time from ICU admission to starting EN was 46 hours, with the worst performing hospital waiting in excess of 149.1 hours, mean time, to commence EN.13
To ensure conservative overcosting of the number of extra days of EN support provided by starting EN within 24 hours of ICU admission, the worst performing hospital case was used. The stochastic model therefore assumes that early EN patients received an additional mean of 6.21 days (SD = 6.21 days) of EN compared with standard care patients.
Measures of acute care hospital resource consumption
By meta-analysis, the net impact of providing early EN was assessed on major measures of resource consumption (ICU stay, duration of invasive mechanical ventilation, and hospital stay). Only measures demonstrating marginal differences between the competing alternatives (P-value < 0.10) were considered for inclusion in the stochastic model.
Structure of the stochastic cost model and large-scale Monte Carlo simulation
Costs of care were estimated using a stochastic model based on the sum of daily cost components, modeled using the gamma distribution with mean μ and shape α, where
For example, the total costs of acute care for a group of ten trauma patients who received mechanical ventilation and consumed 115 days of care in an ICU (ten patients × average stay of 11.5 days) and 70 days of EN would be estimated as the sum of four randomly generated gamma-distributed cost components: ten day-1 ICU costs at G(US$15,625, US$11,955) each day plus ten day-2 ICU costs at G(US$7,414, US$6,683) each day plus 95 day-3 ICU costs at G(US$5,880, US$5,750) each day plus 70 EN costs at G(US$52.50, US$52.50) each day, where G(mean, SD). Daily costs for each major patient type abstracted from Dasta et al11
are reported in .
For each of the 1,000 simulated patients (500 early EN versus 500 standard care) in the stochastic model, measures of resource consumption and costs were estimated for N = 1,000,000 episodes of care, to generate stable estimates of costs and confidence intervals. The CEA was based on the net differences in costs between the 1,000,000 simulated patient groups.
All simulations were conducted using SAS® version 9.2 (SAS Institute, Cary, NC, USA). Meta-analyses were conducted using RevMan 5.2 (The Nordic Cochrane Centre, Copenhagen, Denmark).
Calculation of the mean costs and 95% confidence intervals
The mean cost difference of acute care between the competing alternatives (early EN versus standard care), along with 95% CIs, were obtained using the percentile method. As opposed to bootstrapping, which requires resampling and typically uses fewer trials (N = 1,000), the percentile method does not require correction for bias when applied to large-scale simulations, which typically use more trials (N > 250,000) with no resampling.14
Four sensitivity analyses were planned in advance of conducting the primary CEA, and one additional sensitivity analysis was undertaken in response to peer review:
- The primary CEA analysis was rerun using lognormal distributional assumptions for cost data, instead of gamma distributional assumptions.
- The primary CEA analysis was rerun using a conservative discount of 4% per annum, instead of discounting according to the CPI.
- The primary CEA analysis was rerun for each major patient type (eg, 100% medical, 100% surgical, 100% trauma), instead of using a mixed distribution of patients.
- The primary CEA analysis was rerun using published daily costs of ICU care and study intervention costs for the European market, instead of published US costs. Based on a microcosting study conducted in the Netherlands, the average total costs of 1 ventilated-ICU day has been reported as a mean €2,349 with SD €2,206 and for an unventilated-ICU day as mean €1,835 with SD €1688,15,16 indexed to 2012 Euros, using the European Central Bank Harmonised Index of Consumer Prices, Overall Index.17
The European costs for 1 day of EN were set to a mean €39.30 with SD €39.30, converted from the estimated US costs used in the primary CEA, at the rate of 1 USD = 0.748597 EUR (mid-market rates, June 13, 2013 at 2:22 am coordinated universal time [UTC]).
- An additional sensitivity analysis was undertaken assuming zero marginal differences between the treatment alternatives with regards to the major measures of hospital resource consumption. The primary CEA analysis was rerun assuming zero impact on ICU length of stay and mechanical ventilation. The incremental cost-effectiveness ratio, and its 95% CI, was calculated using the percentile method.