key: cord-0855602-4koygc79
authors: Ethgen, Oliver; Goldstein, Jacques; Harenski, Kai; Mekontso Dessap, Armand; Morimont, Philippe; Quintel, Michael; Combes, Alain
title: A preliminary cost-effectiveness analysis of lung protective ventilation with extra corporeal carbon dioxide removal (ECCO(2)R) in the management of acute respiratory distress syndrome (ARDS)
date: 2021-02-02
journal: J Crit Care
DOI: 10.1016/j.jcrc.2021.01.014
sha: 95365dace8febfaa6ef35542b52866753f130cd1
doc_id: 855602
cord_uid: 4koygc79

BACKGROUND: Mechanical ventilation (MV) is the cornerstone in the management of the acute respiratory distress syndrome (ARDS). Recent research suggests that decreasing the intensity of MV using lung protective ventilation (LPV) with lower tidal volume (Vt) and driving pressure (∆P) could improve survival. Extra-corporal CO(2) removal (ECCO(2)R) precisely enables LPV by allowing lower Vt, ∆P and mechanical power while maintaining PaCO(2) within a physiologic range. This study evaluates the potential cost-effectiveness of ECCO(2)R-enabled LPV in France. METHODS: We modelled the distribution over time of ventilated ARDS patients across 3 health-states (alive & ventilated, alive & weaned from ventilation, dead). We compared the outcomes of 3 strategies: MV (no ECCO(2)R), LPV (ECCO(2)R when PaCO(2) > 55 mmHg) and Ultra-LPV (ECCO(2)R for all). Patients characteristics, ventilation settings, survival and lengths of stay were derived from a large ARDS epidemiology study. Survival benefits associated with lower ∆P were taken from the analysis of more than 3000 patients enrolled in 9 randomized trials. Health outcomes were expressed in quality-adjusted life years (QALYs). Incremental cost-effectiveness ratios (ICERs) were computed with both Day 60 cost and Lifetime cost. RESULTS: Both LPV and ULPV as enabled by ECCO2R provided favorable results at Day 60 as compared to MV. Survival rates were increased with the protective strategies, notably with ULPV that provided even more manifest benefits as compared to MV. LPV and ULPV produced +0.162 and + 0.627 incremental QALYs as compared to MV, respectively. LPV and ULPV costs were augmented because of their survival benefits. Nonetheless, ICERs of LPV and ULPV vs. MV were all well below the €50,000 threshold. ULPV also presented with favorable ICERs as compared to LPV (i.e. less than €25,000/QALY). CONCLUSIONS: ECCO(2)R-enabled LPV strategies might provide cost-effective survival benefit. Additional data from interventional and observational studies are needed to support this preliminary model-based analysis.

A preliminary cost-effectiveness analysis of lung protective ventilation with extra corporeal carbon dioxide removal (ECCO 2 R) in the management of acute respiratory distress syndrome (ARDS) with high in-hospital mortality: 35% to 40% of ARDS patients die within the ICU or the hospital, respectively [1] . Beside the risk of in-hospital mortality, ARDS causes long-term functional disability and impaired quality of life [3, 4] .

Mechanical ventilation (MV) is a cornerstone in the management of ARDS. Significant progress has been achieved in the ventilatory management of ARDS patients since the landmark ARDS Network trial [5] in which lowering the tidal volume (Vt) to 6 mL/kg of predicted body weight improved survival. However, a growing body of evidence is suggesting that ultra-lung protective ventilation (ultra-LPV) with even lower Vt, lower plateau pressure (Pplat) and thus, lower driving pressure (ΔP), could further improve survival of ARDS patients [5] [6] [7] [8] [9] . Driving pressure (ΔP) has indeed been shown to be inversely related to survival in ARDS based on an analysis of more than 3000 patients from 9 clinical trials [7] .

However, Vt reduction may induce hypercapnia and its related complications [10] [11] [12] [13] . Extra Corporeal Carbon Dioxide Removal (ECCO 2 R) in association with mechanical ventilation may enable ultra-LPV by allowing lower Vt and ΔP while maintaining PaCO 2 within a physiologic range [14] .

Recent studies have demonstrated the feasibility of ultra-LPV as enabled by low-flow ECCO 2 R in moderate ARDS [15] [16] [17] [18] [19] [20] [21] [22] . The aim of this study was to evaluate the potential cost-effectiveness of ECCO 2 Renabled ultra-LPV in the setting of the French health-care system.

We simulated and compared the health outcomes and healthcare costs of 3 different mechanical ventilation strategies for patients diagnosed with moderate ARDS (defined as a PaO 2 /FiO 2 ratio comprised between 100 and 200 mmHg) in the ICU. The 3 ventilation strategies considered were: (1) . MV with Vt ≈ 7-8 mL/kg PBW and Pplat ≈ 20-30 cm H 2 O as conventional approach or standard of care that was reported in the LUNG-SAFE study [1] ; (2) . LPV with Vt ≈ 6 mL/kg PBW and Pplat ≈ 20 - 

The analysis was performed over a Day 60 and a lifetime horizon from a French hospital and healthcare perspectives. Only direct healthcare costs were thus considered.

We designed in MS Excel a partitioned survival time model whereby survival curves were extrapolated and areas under those curves were used to estimate the distribution over time of patients across mutually exclusive health states. The 3 mutually exclusive health states that were defined to describe the experience of mechanically ventilated ARDS patients were: Alive and ventilated (AV), alive and nonventilated, i.e. successfully weaned from ventilation (AnV) and dead (D). The proportion of patients in the AV state was obtained by combining overall survival time and ventilation duration. The proportion of patients in the AnV state was then determined by the difference between the proportion of patient alive minus the proportion of those in the AV state. Multiple episodes of ventilation were not considered given the absence of data to inform such transition. A 6-h cycle was used until Day 60 and a yearly cycle afterwards. The 6-h cycle was applied until Day 60 to better capture the sometimes-rapid evolution of patients during their ICU stays. Health outcomes and healthcare costs were thus accumulated cyclically by health states as the cohort of patients was distributed through the different health states over time. The model schematic is depicted on Fig. 1. 

Baseline patients' characteristics and ventilation settings, ventilation duration, ICU and hospital lengths of stay (LoS) were all derived from the LUNG SAFE study [1] . This study was a large observational and prospective cohort study carried out from a sample of 459 ICUs from 50 countries. In total, the study reported data from 2377 ARDS patients [1] . Baseline patients' characteristics and ventilation settings are shown in Table 1 . For LPV, the positive end-expiratory pressure (PEEP) was assumed to be the same as for MV. For ULPV, PEEP was increased up to 12-13 cm H 2 O for moderate ARDS to prevent atelectasis and derecruitment with ECCO 2 R, further inducing a reduction of ΔP.

The survival curve needed for the partitioned survival model was extrapolated using a Weibull regression from the Day 28 survival rate for moderate ARDS reported in the LUNG SAFE study (65%) and an assumed Day 60 survival rate of 60%, observing that survival tends to plateau from Day 30 [25, 26] . Survival benefits associated with lower ΔP were taken from the analysis of more than 3000 patients enrolled in 9 randomized trials [7] . This analysis showed that ΔP was the ventilation parameter most strongly associated with survival. The relationship between ΔP and the multivariable relative risk of death in the hospital was extrapolated using a second-order polynomial equation. The extrapolated survival curve and relationships between ΔP and risk of death are shown on Fig. 2 .

The probability of remaining on ventilation was extrapolated from the median and the inter-quartile ranges ventilation duration reported in the LUNG SAFE study using a Weibull regression (Fig. 2) . Average ICU and hospital LoS distinguishing between survivors and those who died at hospital were approximated from the median and the interquartile ranges reported in the LUNG SAFE study using the approximation methods proposed by Wan et al. [27] . It should be noted that ARDS survivors in the LUNG SAFE study consistently reported longer LoS.

The potential shortening of ventilation duration with ECCO 2 R (% with successful weaning from ventilation at Day 30) was inferred from a prospective randomized study of lower tidal volume strategy (≈ 3 mL/kg) combined with ECCO 2 R vs. "conventional" MV [16] . Considering that ECCO 2 R could be run with a renal replacement platform, ECCO 2 R complications in the model included major bleeding (MB) and catheter-related bloodstream infection (CRBI). The respective frequencies of these complications were taken from a large clinical study on renal replacement therapy in the ICU [28] . This assumption that MB and CRBI frequencies were nearly like those of renal replacement therapy can be justified by the fact that smaller catheter sizes are used as compared to full-blown extra-corporeal membrane oxygenation (ECMO).

The utility level during a patient stay in the ICU was set at 0.13 [29] . In case of ventilation during the ICU stay, we assumed the utility would be lower to some extent and assumed a level of 0.10. The utility level during hospitalization was set at 0.60 [30] . Regarding health utility evolution over lifetime for ARDS survivors once discharged from hospital, we interpolated the published French population norms based on the EQ-5D index [31] . The interpolation was done continuously over the 18-100 years of age range using a slightly decreasing utility as function of age. The impact of ARDS was then estimated from a quality of life study in ARDS. The study reported a 31.8% reduction at 1-year from age-and sex-matched reference values in EQ-5D score for ARDS survivors under the age of 65 years [32] . We assumed this impact would last over the entire remaining lifetime of ARDS survivors (Fig. 2 ).

Healthcare costs were expressed in € 2018 and included costs of ECCO 2 R implementation and complications, ICU and hospital costs for the Day 60 horizon. Whenever possible, costs were documented from published literature or official sources. Both daily costs for an ICU stay (inclusive of MV cost) and a hospital stay (general wards) were taken from the official inpatient 2018 tariffs of 2 large French hospitals [33, 34] . For ECCO 2 R, as a kit allows for 72 h on ECCO 2 R, we stipulated that 2 kits would be necessary and set the cost of a kit at €3000. In absence of reliable data, we assumed the cost of an ECCO 2 R complication (i.e. MB or CRBI) at €10,000. Additionally, we assumed that a complication would incur 2 extra days in the ICU. All costing assumptions were done conservatively. For the lifetime horizon, we assigned a yearly cost to each surviving patient using the healthcare cost per capita in France [35] . As data were available over the 2009-2015-time frame, the yearly healthcare cost per capita was linearly trended until 2018.

Health outcomes, LoS and healthcare costs were simulated and averaged for a cohort of 1000 moderate ARDS patients. Health outcomes were expressed in terms of Day 60 survival, Life Day Gained (LDG) and Quality-adjusted Life-Days (QALDs) for the Day 60 horizon and in Life Year (LY) gained and Quality-adjusted Life-Years (QALYs) gained for the lifetime horizon. Incremental cost-effectiveness ratios (ICERs) expressed as incremental cost-per-LY gained and incremental cost-per-QALY gained were computed to compare the 3 ventilations strategies. All ICERs were computed using both the Day 60 cost and the lifetime cost. Both health outcomes and cost were discounted at 4% per annum, as recommended by the French health technology assessment agency [36] . Deterministic one-way sensitivity analyses were carried by varying all model parameters individually within their 95%CI bounds when available or within a ± 20% range, alternatively. Results were presented using Tornado diagrams as appropriate. A probabilistic sensitivity analysis was also performed to appraise the multivariate uncertainty in the model. Utilities and proportions were simulated with a Beta distribution. Costs were simulated with a Gamma distribution. The risk ratio for successful weaning at Day 30 with ECCO 2 R was simulated with a Log-Normal distribution. All other parameters were simulated with a Normal distribution. All inputs data and their respective variations and probabilistic distributions used for the sensitivity analyses are summarized in Table 1 . Results were presented as scatter plots of pairwise strategies comparisons and costeffectiveness effectiveness acceptability curves (CEAC) against maximum willingness-to-pay (WTP) thresholds for a QALY ranging from € 0 to €100,000.

Base case results are presented on Table 2 . Both LPV and ULPV as enabled by ECCO 2 R provided favorable results for all Day 60 health outcomes as compared to conventional MV. Survival rates were increased with the protective strategies, notably with ULPV that provided even more manifest benefits as compared to MV. Consequently, LoS were slightly increased with the protective strategies reflecting the greater proportion of survivors. Day 60 costs were increased with LPV and ULPV due to the cost of ECCO 2 R per se and, to a lesser extent, to the management of its potential complications and to the somewhat longer LoS that LPV and ULPV entailed due to extended survival. Using Day 60 survival and cost only, the incremental cost per additional life saved were €57,024 for LPV vs. MV, €82,314 for ULPV vs. MV and €104,963 for ULPV vs. LPV, respectively.

Regarding lifetime cost-effectiveness outcomes, MV yielded 7.393 LYs and 2.595 QALYs. In comparison, LPV and ULPV produced 8.204 (+0.811) and 9.110 (+1.716) LYs, respectively. This resulted in higher QALYs gains as compared to MV, with 2.711 (+0.176) and 3.203 (+0.609) QALYs for LPV and ULPV, respectively. LPV and ULPV lifetime costs were also augmented because of their survival benefits. ICERs of LPV and ULPV vs. MV were all well below the €50,000 WTP threshold. The greatest ICER was for LPV vs. MV with lifetime cost and QALY (+€27,772/QALY) and the lowest ICER was for LPV vs. MV with Day 60 cost and LY (+€4407/LY). ULPV also presented with favorable ICERs as compared to LPV in both cost scenarios (less than €25,000/QALY). Fig. 3 displays the pairwise scatter plots obtained from the multiway probabilistic sensitivity analyses. ULPV consistently shown greater costs and health benefits as compared to MV or LPV. Difference was less marked for LPV vs. MV. Fig. 4 shows the CEAC for each strategy, indicating the probabilities that a strategy is costeffective for a range of maximum WTP thresholds. ULPV becomes the strategy with the highest probability of cost-effectiveness as from a WTP of ≈ €22,500 per QALY. Fig. 5 shows the Tornado diagrams from the one-way deterministic sensitivity analyses on the ICERs comparing ULPV vs. LPV. Regardless the outcome measure used, LY or QALY, ICERs variations was within a ± 20% range only. The most influential parameter on both ICERs was the number of ECCO 2 R kits used in moderate ARDS.

We designed a partitioned survival model over patients' lifetime to assess the value of LPV and ULPV strategies as enabled by the addition of ECCO 2 R in the management of ARDS. Our findings suggest that in moderate ARDS LPV and ULPV represents cost-effective ventilation strategies when compared to the conventional MV approach. The decrease of ΔP with LPV and ULPV would indeed provide survival benefit and shorten ventilation duration. All of this would be achieved by maintaining patient's PaCO2 within physiologic ranges and thus minimizing the risk of hypercapnia and its related complications [12] .

Increased survival is nonetheless associated with longer LoS and causes somewhat higher costs, but our analysis suggests that the incremental survival benefit seems worth the incremental cost with ICERs remaining within acceptable ranges. The potential economic benefit of protective ventilation could be furthered in future research by broadening the perspective of the analysis. Indeed, typical patients are in the range of 60 years of age and still belong to the economically active population. Better preservation of life when ARDS occurs has more than surely the potential to generate broader economic returns. In our analysis, both the protective (i.e. Vt ≈ 6 mL/kg PBW to keep Pplat between 20 and 30 cm H 2 O + ECCO 2 R if PaCO 2 > 55 mmHg) and the ultra-protective (i.e. Vt ≈ 3-4 mL/kg PBW to keep Pplat between 20 and 25 cm H 2 O + ECCO 2 R) ventilation strategies were defined on the basis of recent feasibility studies and experts consensus, and were not based on clinical evidence supporting their use. Admittedly, optimal ventilation strategies with ECCO 2 R are still a matter of intense research and the definition of such strategies should be cautiously treated. To our knowledge, this study is the first that has intended to estimate the cost-effectiveness of both LPV and ULPV strategies. Our results add an economic perspective to the use of ECCO 2 R and complement the results of clinical studies that have demonstrated both the feasibility and the clinical value of the use of ECCO 2 R in the management of ARDS [15] [16] [17] [18] [19] 21] . Cooke et al. also reported that LPV was a highly costeffective ventilation strategy [37] . Based on a decision-analytic model, the authors showed that a hypothetical intervention aimed at improving LPV adherence at the ICU level would generate 0.62 additional QALYs (4.83 QALYs for LPV vs. 4.21 QALYs for non-LPV care) with an ICER of $11,690/QALY gained (expressed in $2008). Few other studies have assessed the cost-effectiveness of MV vs. non-MV but did not necessarily intend to document the cost-effectiveness of more recent and highly protective strategies as enabled by ECCO 2 R [2, 38] .

Many parameters of our model were informed by sound evidence. The LUNG SAFE study, a large international study reporting a wealth of information from 2377 ARDS patients, was used to document baseline characteristics, MV ventilation settings and corresponding LoS and survival outcomes [1] . However, it should be kept in mind there are limitations regarding the use of the LUNG SAFE study to define the MV comparator in our analysis. In LUNG SAFE, plateau pressure was not monitored in 60% of ventilated ARDS and a sizeable proportion of patients had a plateau pressure above 30 cm H 2 O. The risk is thus that our analysis may overestimate the effect size of the benefit associated to ECCO 2 R.

We used the relationship between ΔP and risk of hospital mortality demonstrated by Amato et al. from 3562 ARDS patients enrolled in nine randomized trials [7] . Of interest, The LUNG SAFE investigators also noticed an inverse relationship between ΔP and the risk of hospital death. They reported for instance that patients with a ΔP greater than 14 cm H 2 O on day 1 of ARDS had a higher risk of hospital mortality [1] . Moreover, the prediction of ΔP reduction as enabled by ECCO 2 R using alveolar dead space fraction and respiratory system compliance may allow increased mortality benefit, and reduced sample size and screening size requirements to enrich future clinical trials of ECCO 2 R for ULPV in ARDS [39, 40] .

Nonetheless, our approach hypothesized that very low Vt as enabled by ECCO 2 R prospectively could achieve similar outcomes to that retrospectively observed in studies among ARDS patients with variable ΔP, including studies that did not employ ECCO 2 R. While ΔP is an important predictor of death in ARDS, it remains uncertain whether ventilator strategies that attempt to minimize this parameter will achieve better outcomes than traditional MV. This should be kept in mind in the interpretation of our analysis to modern ventilation practice and further emphasizes the need for interventional and observational studies with that regard.

We had difficulties to identify reliable and published sources for some of the cost estimates. In our analysis, protective ventilation followed the approach protocolized in the SUPERNOVA study [21] . As there are multiple ways to deliver ECCO 2 R, we assumed low flow veno-venous ECCO 2 R vascular access, as integrated on a continuous renal replacement therapy device. In this condition, we assumed that 2 ECCO 2 R kits would be necessary, whose cost was hypothesized at €3000 per kit. It should be kept in mind that alternative ways of delivering ECCO 2 R could lead to other cost estimate. We also did not account for the potential costs of clotting as well as manpower and training that might be needed for the implementation and supervision of ECCO 2 R.

However, this limitation on cost estimates must be nuanced as we have used a rather conservative approach to compute ICU and hospital costs. By applying a fix cost per day spend in the ICU and the hospital, ARDS survivors who tend to have longer LoS as suggested by the LUNG SAFE study were attributed a greater overall cost in our analysis. Some studies conducted in various ICU patients' population have evidenced that this is not necessarily the case. Even if ICU survivors tend to have longer ICU LoS, their overall ICU cost could be lower [41] . This is at least partly explained by the fact that their cost per day in the ICU gradually declines during their stay [42] [43] [44] .

Moreover, as a main limit of our analysis, we had to rely on relatively sparse evidence for what appeared as a key parameter of the model: the impact that ECCO 2 R could have on the potential shortening of ventilation duration. We have used the results from the prospective randomized Xtravent-study suggesting that ARDS patients with a PaO 2 /FiO 2 ratio below 150 mmHg and receiving ECCO 2 R were 2.1 times more likely at Day 30 to be successfully weaned from ventilation as compared to controls [16] to inform this parameter. Though this study demonstrated an effect as a ratio of 2.1, we have conservatively used this value as the best-case assumption. In the absence of any other information, the lower or worst-case was set at 1.1 (nearly no effect) and the base case value at 1.6 (median point). Finally, this parameter did not emerge in the deterministic sensitivity analyses as so impactful on the ICERs, which remained below the €30,000 threshold in the worst case (Fig. 5) . Therefore, cost-effectiveness of ECCO 2 R was still granted even with very minimal effect on the shortening of ventilation duration.

This observation stresses the interest of modeling. First, to overcome the lack of direct information by combining multiple sources of data and assumptions. Second, to guide eventual future research. In effect, it should be kept in mind that our model is a preliminary approach whose findings need to be completed as more data become available on ECCO 2 R. We have identified the potential effect of adding ECCO 2 R on the reduction of ventilation duration as a main source of uncertainty. It is thus advisable that the design of future interventional or observational studies pay attention to proper collection of ventilation duration data with or without ECCO 2 R-enabled LPV or ULPV.

Our analysis suggests that ECCO 2 R-enabled LPV and ULPV strategies might provide cost-effective survival benefit in moderate ARDS. Additional data from interventional and observational studies are needed to support this preliminary model-based analysis.

OE, AMD, PM, MQ and AC have received reimbursements and consulting fees from Baxter in the conduct of the study and the preparation of the manuscript. JG and KH are employees of Baxter and own stocks or shares of the company.

This study was funded by Baxter. The sponsor had no influence on the design of the model and the choice of sources to feed it.

Authors are grateful to Dilip Makhija and Stephen Russel for their valuable inputs at the study inception.

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