Hypermetabolism and Coronavirus Disease 2019.

BACKGROUND: Hypermetabolism has been described in stress states such as trauma, sepsis, acute respiratory distress syndrome, and severe burn injuries. We hypothesize that patients with Coronavirus disease 2019 (COVID-19) may develop a hypermetabolic state, which may be a major contributing factor to the extraordinary ventilatory and oxygenation demands in patients with COVID-19.
METHOD: Resting energy expenditure (REE), carbon dioxide production (VCO2 ), and oxygen consumption (VO2 ) were measured by indirect calorimetry on 7 critically ill patients with COVID-19.
RESULTS: The median measured REE was 4044 kcal/d, which was 235.7% ± 51.7% of predicted. The median VCO2 was 452 mL/min (range, 295-582 mL/min), and the median VO2 was 585 mL/min (range, 416-798 mL/min).
CONCLUSION: Critically ill patients with COVID-19 are in an extreme hypermetabolic state. This may explain the high failure rates for mechanical ventilation for these patients and highlights the potential need for increased nutrition requirements for such patients.

Clinical Relevancy Statement

We describe our findings that critically ill patients with COVID‐19 are in an extreme hypermetabolic state, with extraordinary oxygen consumption and carbon dioxide production. This may explain the high failure rates for mechanical ventilation for patients with severe COVID‐19, may help direct nutrition requirements for such patients, and may also suggest targets for therapeutic interventions that have not been explored to date.

Introduction

Many patients with Coronavirus disease 2019 (COVID‐19) remain hypoxic and hypercarbic despite being on maximal ventilator settings. A dissociation between the degree of lung injury and the severity of hypoxia and hypercapnia has been observed in patients with COVID‐19. This suggests that the severity of acute respiratory failure of patients with COVID‐19 may not be solely attributable to pulmonary compromise. As acute respiratory distress syndrome (ARDS) is associated with production of pro‐inflammatory cytokines and induction of a hypermetabolic state, we hypothesize that patients with COVID‐19 may develop a hypermetabolic state, which may be a major contributing factor to the extraordinary ventilatory and oxygenation demands in patients with COVID‐19.

Methods and Results

This retrospective case series included 7 adults with confirmed COVID‐19 requiring mechanical ventilation, with continued hypercapnia and/or hypoxia. Resting energy expenditure (REE) was predicted using the Penn State equation and measured using CCM Express indirect calorimeter (MGC Diagnostics, St Paul, MN). All patients were on a fraction of inspired oxygen ≤ 60% and did not require renal replacement therapy and/or thoracostomy tubes to ensure the accuracy of the indirect calorimetry measurements.

All patients were on intravenous sedation infusions. Median age was 62 years (range, 55–74 years), 5 (71.4%) patients were male, and median length of intubation was 19 days (range, 3–39 days). Median pCO2 and pO2 were 60 mmHg (range, 53–72 mmHg) and 75 mmHg (range, 61–95 mmHg), respectively. Indirect calorimetry results are shown in Table 1. The median measured REE was 4044 kcal/day, which was 235.7% ± 51.7% of predicted. The median carbon dioxide production (VCO2) was 452 mL/min (range, 295–582 mL/min), and the median oxygen consumption (VO2) was 585 mL/min (range, 416–798 mL/min). Levels of inflammatory markers are shown in Table 2. There were no strong positive correlations between C‐reactive protein and D‐Dimer to both measured REE and measured REE/predicted REE (Pearson correlation coefficient < 0.5).

Table 1

Indirect Calorimetry Results

Patient #	Age	Body mass index	Measured REE (kcal/d)	Predicted REE (kcal/d)	VCO2 (mL/min)	VO2 (mL/min)
1	62	26.6	5186	1733	582	750
2	74	24.6	2845	1296	303	416
3	70	37.5	3052	1865	295	455
4	57	28.1	4044	2108	452	585
5	57	27.4	3952	1955	468	565
6	69	25.1	4282	1617	401	642
7	55	25.2	5414	1753	555	798

REE, resting energy expenditure.

Table 2

Inflammatory Markers

Patient #	Hospital day (#)	Measured REE (kcal/d)	Measured REE/predicted REE (% predicted)	C‐reactive protein (mg/dL)	D‐Dimer (ng/mL)
1	8	5186	299	7.11	13,862
2	8	2845	219	0.5	2894
3	22	3052	164	13.36	1160
4	23	4044	192	3.94	980
5	30	3952	202	13.38	2019
6	32	4282	265	14.5	560
7	55	5414	309	12.6	1393

REE, resting energy expenditure.

Discussion

This case series demonstrates the significant metabolic demands of critically ill patients with COVID‐19. Hypermetabolism has been described in stress states, such as trauma, sepsis, ARDS, and severe burn injuries. , However, the measured REE seen in our case series of patients with COVID‐19 far exceeds that described for other disease states. , The profoundly increased VO2 and VCO2 seen in our patient cohort, as a result of their hypermetabolism, may help explain the high failure rates for mechanical ventilation for patients with severe COVID‐19. Some of these patients may be considered for extracorporeal membrane oxygenator support (ECMO); however, the VO2 and VCO2 in all 7 patients in our cohort would have exceeded the O2 and CO2 transfer capacity of typical adult oxygenators used in ECMO circuits.

These observations may suggest the need for increased feeding beyond the 15–20 kilocalories per kilogram of actual body weight per day that is currently recommend for critically ill patients with COVID‐19. Although patients with ARDS have energy expenditures that are ∼30% above REE, we found most patients with COVID‐19 have energy expenditures of >200% of REE. Adequate nutrition support is vital for preservation of respiratory muscle function, promotion of immune response to infection, and mitigation of oxidative cellular injury. However, given the extraordinarily high REE seen in patients with COVID‐19, purely using REE measurements as the targeted goal for nutrition calories in these patients may result in overfeeding and increased CO2 production. We are currently involved in studies looking at the ideal target calories relative to the REE measured from indirect calorimetry in critically ill patients with COVID‐19.

In addition to having implications for the management of nutrition support in patients with COVID‐19, our observations of extreme hypermetabolism in critically ill patients with COVID‐19 suggest possible targets for therapeutic interventions that have not been explored to date. We are currently embarking on interventional studies aiming to decrease the metabolic demand of patients with COVID‐19 and reconfiguring ECMO circuits to meet the increased need for gas exchange.

Statement of Authorship

P. Yu, H. Cassiere, S. DeRosa, K. Bocchieri, and A. Hartman contributed to the conception and design of the research; P. Yu, S. DeRosa, and S. Yar contributed to the acquisition of the data; P. Yu, H. Cassiere, S. DeRosa, K. Bocchieri, and A. Hartman contributed to the interpretation of the data; P. Yu drafted the manuscript. All authors critically revised the manuscript, agree to be fully accountable for enduring the integrity and accuracy of the work, and read and approved the final manuscript