Modified indirect calorimetry for patients on venoarterial extracorporeal membrane oxygenation: a pilot feasibility study

Background/Objectives Traditional indirect calorimetry is unable to capture complete gas exchange in patients receiving venoarterial extracorporeal membrane oxygenation (VA ECMO). We aimed to determine the feasibility of using a modified indirect calorimetry protocol in patients receiving VA ECMO, report measured energy expenditure (EE) and compare EE to control critically ill patients. Subjects/Methods Mechanically ventilated adult patients receiving VA ECMO were included. EE was measured within 72 h of VA ECMO commencement (timepoint one [T1]) and on approximately day seven of Intensive Care Unit (ICU) admission (timepoint two [T2]). Traditional indirect calorimetry via the ventilator was combined with calculations of oxygen consumption and carbon dioxide production derived from pre- and post-ECMO membrane blood gas analyses. Completion of ≥60% EE measurements was deemed feasible. Measured EE was compared between T1 and T2 and to control patients not receiving VA ECMO. Data is presented as n(%) and median[interquartile range (IQR)]. Results Twenty-one patients were recruited; 16(76%) male, aged 55[42–64] years. The protocol was feasible to complete at T1 (14(67%)) but not at T2 (7(33%)) due to predominantly ECMO decannulation, extubation or death. EE was 1454[1213–1860] at T1 and 1657[1570–2074] kcal/d at T2 (P = 0.043). In patients receiving VA ECMO versus controls, EE was 1577[1434–1801] versus 2092[1609–2272] kcal/d, respectively (P = 0.056). Conclusion Modified indirect calorimetry is feasible early in admission to ICU but is not possible in all patients receiving VA ECMO, especially later in admission. EE increases during the first week of ICU admission but may be lower than EE in control critically ill patients.


INTRODUCTION
Extracorporeal membrane oxygenation (ECMO) is a specialised organ support for critically ill patients with severe respiratory and/ or cardiac failure.Deoxygenated blood is passed through an external gas exchange system before being returned to the circulation [1].Extracorporeal membrane oxygenation can be described as either venoarterial (VA) or venovenous (VV), depending on the site where oxygenated blood is returned [1].Previously, it was presumed that ECMO may increase energy expenditure (EE) and protein catabolism, in part due to the associated inflammatory response [2][3][4][5].The mode of ECMO may also alter important clinical factors related to metabolism during critical illness.In VV ECMO, a recent study reported a decrease in inflammation and in a second, measured EE was comparable to matched critically ill patients not receiving VV ECMO [6,7].Conversely, very little is known regarding EE during VA ECMO which is indicated in an entirely different patient cohort with cardiogenic shock, where part of the cardiac work is relieved by the mechanical pump [8].
Predictive equations are the most common method of determining EE in critical illness but are known to significantly under-or overestimate requirements compared to measured EE using indirect calorimetry [9].Accurate determination of EE is important in patients receiving ECMO who typically have higher illness severity and longer hospital admissions, making them more vulnerable to under-and overfeeding over the course of ICU admission [3,10].Indirect calorimetry is the current reference method for determining measured EE in critically ill patients by measuring volumes of inspired oxygen (VO 2 ) and expired carbon dioxide (VCO 2 ) [11].Until recently, indirect calorimetry had not been used in patients receiving ECMO due to the gas exchange occurring at the extracorporeal membrane that is not captured by traditional indirect calorimetry [4].A novel method of measuring EE has been proposed in patients receiving VV ECMO and has been reported to be feasible, using traditional indirect calorimetry in combination with the calculation of VO 2 and VCO 2 from preand post-ECMO membrane blood gas analyses [6].However, this method has not been applied in patients receiving VA ECMO where EE may differ.
The primary objective of our study was to assess the feasibility of measuring EE in patients receiving VA ECMO using a modified indirect calorimetry protocol.Secondary objectives were to report measured EE in patients receiving VA ECMO and to compare values with predictive equation estimates and to control critically ill patients not receiving ECMO.

SUBJECTS AND METHODS
A single-centre prospective observational study was conducted at The Alfred Intensive Care Unit (ICU) in Melbourne, Australia between 20 August 2019 and 8 September 2021.The Alfred ICU is a quaternary referral centre providing regional services for ECMO.The study was prospectively registered on the Australian New Zealand Clinical Trials Registry (ACTRN12619000760178).Ethics approval was granted from the Alfred Hospital Ethics Committee (project number: 76/19) with informed consent obtained from the medical treatment decision maker.Ethics approval included permission to access a database of indirect calorimetry measurements completed as part of standard practice in the ICU for the comparison of measured EE to control patients not receiving ECMO.

ELIGIBILITY CRITERIA
Patients were considered for inclusion within 72 h of commencement of VA ECMO according to the following criteria:

Commenced on VA ECMO for any reason;
• Expected to require mechanical ventilation for at least 48 h from initiation of ECMO; • Expected to remain in the ICU and on ECMO for at least 48 h.

Exclusion criteria
• Patients with a poor prognosis where death was imminent in the subsequent 24 h; • Where participation in the study was not in the interest of the patient in the opinion of the treating physician.

MEASURED ENERGY EXPENDITURE
Measurements of EE were attempted at two timepoints; within 72 h of ECMO commencement (timepoint one [T1]) and on day seven of ICU admission (timepoint two [T2]).If day seven measurements were scheduled on a day of low staff availability (e.g., a weekend), EE measurements were completed prior to and as close to day seven as possible.Energy expenditure was measured as described by Wollersheim et al. in three steps (Fig. 1) [6].ECMO blood flow, fresh gas flow and ventilator settings were not changed 20 min prior to and during measurement of EE.
Step (1) Indirect calorimetry Indirect calorimetry was conducted by trained staff for a minimum of 30 min with the Quark RMR (COSMED, Italy) device while patients were receiving VA ECMO support and were mechanically ventilated.Technical exclusions to measurement included fraction of inspired oxygen (FiO 2 ) > 60%, positive endexpiratory pressure (PEEP) > 12 cmH 2 O and known leaks in the ventilator circuit.
Step (2) blood gas measurements pre-and post-the ECMO membrane Pre-and post-oxygenator arterial blood gases were collected within 30 min of indirect calorimetry measurement.Samples were collected by an ECMO trained nurse or ECMO credentialed physician from the ECMO pre-and post-oxygenator port.Using a mathematical model published by Dash and Bassingthwaighte, available at www.physiome.org,(model 0149) [12], the O 2 and CO 2 content pre-and post-the ECMO membrane were determined using MATLAB version R2019b, Mathworks.In two patients with a low CO 2 exchange at the oxygenator where the mathematical model generated small negative values of CO 2 uptake, these values were recorded as zero for physiological plausibility.
Step (3) Calculation of EE Values of VO 2 and VCO 2 from indirect calorimetry and blood gas measurement were totalled and EE was calculated using the Weir equation [13].

RESULTS
Over the recruitment period, 21 patients receiving VA ECMO support were included (Fig. 2).The study was stopped prior to meeting the target sample size due to difficulties with recruitment related to the COVID-19 pandemic.All patients were included for the analysis of feasibility while 16 patients had indirect calorimetry measurements for the analysis of measured EE (Fig. 2).Patient demographics are presented in Table 1.

FEASIBILITY OF COMPLETING ENERGY EXPENDITURE MEASUREMENTS
In total, 21 EE measurements were conducted during the study period.Energy expenditure was measured in 14 of the 21 patients (67%) at T1 on ICU day 1 [1,2].Reasons for non-completion are outlined in Fig. 3, with contraindications to indirect calorimetry the most common reason.Energy expenditure was measured in 7 of the 21 patients (33%) at T2 on ICU day 5 [5,6], with the most common reason for test non-completion being ECMO decannulation (Fig. 3).

MEASURED ENERGY EXPENDITURE
Coronary bypass graft 2 Sepsis with shock, other than urinary Other respiratory diseases related to the inability to complete indirect calorimetry measurements due to contraindications (e.g.PEEP and FiO 2 levels above manufacturer specifications) and on day five were due to ECMO decannulation, extubation or death.Measurements of EE were not attempted following ECMO decannulation in our study which should be considered when interpreting feasibility results.Similar findings were reported by Wollersheim et al.where EE was measured in 20 of 24 patients within two days of ECMO commencement and 8 of 24 patients directly before and after VV ECMO decannulation [6].
Measurements of EE were lower on day one compared to day five of ICU admission likely reflecting the Ebb phase of the metabolic response to critical illness, which is marked by decreases in core temperature, basal metabolic rate and cardiac output in the first 24-48 h of ICU admission [16].Values for EE were lower than predicted by the unit dietitian using the Schofield equation multiplied by stress factor at both timepoints.Conversely, the weight based 25 kcal/kg/d equation overestimated EE on day one but was comparable to values on day five of ICU admission.This is an interesting finding as predictive equations have been shown to be more prone to underestimation, rather than overestimation, of EE in general ICU populations [9,17].Further, EE was also lower than control critically ill patients not receiving ECMO support, albeit this difference did not reach statistical significance.
Previously, it was speculated that use of ECMO was associated with increased inflammation and subsequent hypermetabolism [5].Recent studies have reported decreases in inflammation following commencement of VV ECMO and EE comparable to other critically ill subpopulations [6,7].Although using different methods, our findings are comparable to De Waele et al.where indirect calorimetry was used to measure EE at both the ventilator and at the ECMO membrane oxygenator.In this study, a median EE of 1334 kcal/d equivalent to 21 kcal/kg/d was reported in seven patients receiving VV (n = 3) and VA ECMO (n = 4) [15].In contrast, Wollersheim et al reported a higher median EE of 2013 kcal/d in 20 patients with acute respiratory distress syndrome receiving VV ECMO [6] and Ong et al. reported a mean EE of 29 ± 6 kcal/kg/d in seven patients treated with VV ECMO when not prescribed paralytic agents [18].However, the latter study determined EE at one timepoint using blood gas measurements pre-and post-the ECMO membrane and mathematical equations to calculate VO 2 and VCO 2 , without completion of indirect calorimetry [18].Reasons for the higher EE observed by Wollersheim et al. and Ong et al. may be due to the type of ECMO (VA versus VV) and admission diagnosis (predominantly cardiogenic shock in our study versus acute respiratory distress syndrome in Wollersheim et al.).The use of VA ECMO provides both respiratory and haemodynamic support, replacing the function of the heart and lungs, which may be associated with lower EE.This relief of cardiac work may similarly explain why EE was lower in patients receiving VA ECMO compared to control critically ill patients in our study.While severity of illness was comparable between groups, data was not collected on the use of sedatives, paralytic agents, vasopressors or analgesics at the time of measurement, which may have also contributed to differences in EE.

Strengths and limitations
This study was registered a priori and provides the largest dataset of measured EE in patients receiving VA ECMO, which is particularly important for centres that are not able to perform indirect calorimetry but care for critically ill patients receiving ECMO.The assessment of EE was hampered by research staff  unavailability during the COVID 19 pandemic and this is a limitation.The sample size single-centre design should be considered when interpreting generalisability of findings.However, it does approximate the size of other similar studies and combined, all studies provide valuable information.Data for control patients was sourced from a database of indirect calorimetry measurements where temperature at the time of EE measurement was not routinely collected.The model by Dash and Bassingthwaighte is mathematically sound and has been validated but not in the context of an extracorporeal oxygenator.Small margins of measurement errors of pre-and post-the oxygenator gas may occur; it is unknown how this compares to volumetric gas measurements.Ideally new methods would be validated prior to use to ensure accuracy; however, validation of methods involving metabolism are technically difficult in the acute setting [19].

Clinical implications and future research
The clinical implications of our work are that measured EE may be lower in patients receiving VA ECMO early in ICU admission than initially hypothesised, a finding that is supported by other work [15].Clinicians should be aware of the possibility of overestimation of EE with predictive equations early in illness.However, standard care delivery of nutrition often only approximates 50-60% of prescribed volumes in critical illness and this should also be a consideration to prevent the profound under provision of nutrition in a patient group which is likely to have prolonged ICU and hospital admissions [10,20,21].This reinforces the importance of indirect calorimetry to enable tailored nutrition provision and align management with best practice guidelines.Future work should explore the accuracy of the present method and other techniques of measuring gas exchange at the oxygenator to continue to test the practicability of using indirect calorimetry to measure temporal changes in EE.Differences in ECMO support modality and underlying diagnoses in these severely ill patient groups may exist and need to be explored on a larger scale.
In conclusion, it is feasible to use a modified indirect calorimetry protocol to measure EE in patients receiving VA ECMO early in ICU admission, but this may not be possible in all patients, especially later in admission.Energy expenditure may be lower in critically ill patients receiving VA ECMO compared to other critically ill populations and predictive estimates may be more prone to overestimation of EE.

Fig. 2
Fig. 2 Flow chart of participant recruitment.*n = 5 had measurements at both timepoints.EE energy expenditure.

Fig. 3
Fig. 3 Feasibility of completing energy expenditure measurements in patients receiving VA ECMO.*n = 5 had measurements at both timepoints.ECMO extracorporeal membrane oxygenation, FiO 2 fraction of inspired oxygen, IC indirect calorimetry, ICC intercostal catheter, PEEP positive end-expiratory pressure.

Fig. 4
Fig. 4 Measured versus Estimated EE.Comparison of measured versus estimated EE using the Schofield and 25 kcal/kg/d predictive equations in kcal/d.
Overview of the modified indirect calorimetry protocol used to measure EE during VA ECMO.ECMO extracorporeal membrane oxygenation, EE energy expenditure, VCO 2 carbon dioxide production, VO 2 oxygen consumption.
[6,14,15]AND NUTRITION DATA COLLECTIONAdmission and discharge data collected included: Acute Physiology and Chronic Health Evaluation (APACHE) III diagnosis code, APACHE II and III scores, ICU and hospital length of stay and in-hospital mortality.Patients received standard nutrition therapy as per evidence-based feeding protocols used in the unit, with EE estimated by dietitians using the Schofield equation multiplied by a clinically relevant stress factor as per standard practice at The Alfred Hospital.Weight, height, estimated EE and protein requirements were collected from the dietitian notes in the electronic medical record.An adjusted weight was used to calculate requirements in patients classified as overweight or obese.Common practice within the unit is to use a body mass index of 25 kg/m 2 + 25% excess weight.Estimated EE using the weight-based predictive equation 25 kcal/kg/d, which is commonly recommended and used in the ICU, was also calculated by investigators[6,14,15].Secondary 1. Feasibility of measuring EE at T2. 2. Difference between EE at T1 and T2.3.Difference between measured and predicted (Schofield and 25 kcal/kg/d) EE at T1 and T2. 4. Difference between measured EE in patients receiving VA ECMO versus control critically ill patients not receiving ECMO.STATISTICAL ANALYSESThe aim was to recruit a convenience sample of 30 mechanically ventilated patients receiving VA ECMO.All data are presented using medians [interquartile range (IQR)].In the absence of previously published data, feasibility was defined as completion of ≥60% EE measurements at each timepoint.Measured EE was compared between T1 and T2 and to predictive equation estimates using the Wilcoxon signed-rank test.Comparisons between patients receiving VA ECMO and control critically ill patients not receiving ECMO were made using the Mann-Whitney U test for continuous variables and the Chi-Square Test for categorical variables.All analyses were performed using IBM® SPSS®, Version 28 (Armonk, NY: IBM Corp) and a p-value of <0.05 was considered statistically significant.

Table 1 .
Demographic and clinical data for all patients receiving VA ECMO (n = 21) and those included in energy expenditure analysis (n = 16).

Table 2 .
Contribution of pulmonary indirect calorimetry and ECMO to total EE (n = 21).
Continuous variables are reported as median [IQR].EE energy expenditure, ECMO extracorporeal membrane oxygenation.