key: cord-1018196-a1xjhfyn authors: Viana, Marina V.; Pantet, Olivier; Charrière, Mélanie; Favre, Doris; Piquilloud, Lise; Schneider, Antoine G.; Hurni, Claire‐Anne; Berger, Mette M. title: Specific nutrition and metabolic characteristics of critically ill patients with persistent COVID‐19 date: 2022-02-16 journal: JPEN J Parenter Enteral Nutr DOI: 10.1002/jpen.2334 sha: 88712001a464bdb1e649f56d04fa541063492f24 doc_id: 1018196 cord_uid: a1xjhfyn BACKGROUND: Little is known about metabolic and nutrition characteristics of patients with coronavirus disease 2019 (COVID‐19) and persistent critical illness. We aimed to compare those characteristics in patients with PCI and COVID‐19 and patients without COVID‐19 infection (non‐CO)—primarily, their energy balance. METHODS: This is a prospective observational study including two consecutive cohorts, defined as needing intubation for >10 days. We collected demographic data, severity scores, nutrition variables, length of stay, and mortality. RESULTS: Altogether, 104 patients (52 per group) were included (59 ± 14 years old [mean ± SD], 75% men) between July 2019 and May 2020. SAPSII, Nutrition Risk Screening (NRS) score, proportion of obese patients, duration of intubation (18.2 ± 11.7 days), and mortality rates were similar. Patients with COVID‐19 (vs non‐CO) had lower SOFA scores (P = 0.013) and more frequently needed prone position (P < 0.0001) and neuromuscular blockade (P < 0.0001): lengths of ICU (P = 0.03) and hospital stays were shorter (P < 0.0001). Prescribed energy targets were below those of the ICU protocol. The energy balance of patients with COVID‐19 was significantly more negative after day 10. Enteral nutrition (EN) started earlier (P < 0.0001). During the first 10 days, COVID‐19 patients received more lipid (propofol sedation) and less protein. Higher admission C‐reactive protein (P = 0.002) decreased faster (P < 0.001). Whereas intestinal function was characterized by constipation in both groups during the first 10 days, diarrhea was less common in patients with COVID‐19 thereafter. CONCLUSION: Compared with non‐CO patients, COVID‐19 patients were not more obese, had lower SOFA scores, and were fed more rapidly with EN, because of a more normal gastrointestinal function possibly due to fewer non–respiratory organ failures: their energy balances were more negative after the first 10 days. Propofol sedation reduced protein delivery. recommendations to patients with COVID-19. [2] [3] [4] However, objective data remain limited. Some authors reported unexpected and unprecedented challenges to achieve adequate nutrition with the gastrointestinal (GI) tract's limited tolerance of EN, possibly related to the need for heavy sedation and neuromuscular blockades. 5, 6 The lack of prospective data was emphasized in the scoping review conducted by the American Society for Parenteral and Enteral Nutrition (ASPEN), which summarized the numerous unresolved questions regarding the specificities of the patients with COVID- 19. 7 From a metabolic point of view, the strongly inflammatory COVID-19 disease and its treatment, with heavy sedation and frequent prone position, are indeed likely to modify energy needs, GI function, and response to treatment. Two recent studies finally provided guidance about energy targets by using indirect calorimetry (IC)-measured energy expenditure. 8, 9 They show that energy expenditure neither was as elevated as previously hypothesized 3 nor was depressed. But other aspects of metabolism have not yet been described. The risk of acute malnutrition, assessed by the Nutrition Risk Screening (NRS) score, seems elevated according to a cohort including 413 critically ill patients from Wuhan: there, the proportion of patients with high NRS scores (≥5) was surprisingly high, which was associated with significantly higher mortality. 10 This high score was attributable to strongly reduced feeding during the days preceding the admission, because of coughing and fever. Observational studies show that about 5% of ICU patients will develop persistent critical illness (PCI), consuming up to 32.8% of total ICU bed-days. 11 Also, these patients have a greater risk of death and disproportionately consume vast health resources compared with patients without PCI. 11 All these features are extremely important for bedside decision-making and prognostication, especially during a pandemic, during which resources are limited. It has been reported that critically ill patients with COVID-19 frequently have a prolonged ICU stay. 12, 13 However, to our knowledge, no study has compared persitent critically ill patients with and without COVID-19. As the pandemic still rages worldwide, it is time to draw lessons from the first wave and develop practical orientation. Patients with COVID-19 constitute a rather homogeneous population characterized by a predominant respiratory failure with comorbidities mainly linked to a metabolic syndrome. In the Lausanne ICU, many patients with COVID-19 fulfilled the previously defined criteria for PCI, with prolonged ICU admissions. As our ICU had developed a program for general patients with PCI, 14 the present study aimed at prospectively collecting metabolism-and nutrition-related variables of patients with COVID-19 to compare them with the non-CO patients in an attempt to identify specific problems related to their management, with an emphasis on energy balance. This prospective observational study includes two consecutive cohorts of patients with PCI who were on mechanical ventilation, as well as a retrospective analysis of the data. It was conducted with the approval of the Commission cantonale d'éthique de la recherche sur l'être humain (CER 2018-02018 and CER-2020-01453) in the mul- Inclusion criteria were age >18 years, enrollment in the ICU's PCI program for the pre-COVID-19 period, and >10 days of invasive mechanical ventilation for both cohorts. 15 Exclusion criteria were admission for major burns >20% body surface, traumatic brain injury, and refusal to participate. score, 16 with emphasis on preadmission nutrition intake (NRS-"A" for "alimentation"); time to feeding initiation; feeding route; bowel activity; energy, protein, and glucose intakes; energy balance; and frequency and timing of IC. Furthermore, requirement for continuous renal replacement therapy (CRRT), prone position, neuromuscular blockade (cisatracurium or rocuronium), duration of mechanical ventilation and ICU stay, and mortality (ICU and 90 days) were recorded. Laboratory variables were recorded during the first 30 days: blood creatinine, urea, triglycerides, and prealbumin (routine weekly value). The ICU's standard operating procedures (SOPs) are based on the ESPEN guidelines 17 and were not modified during the study period. Briefly, EN is recommended as the preferential route, to be initiated within the first 48-72 h, after hemodynamic stabilization. Gastric EN is started at a rate of 10-20 ml/h, depending on patient size and hemodynamic stability (never at full target, by ESPEN recommendation 17 For the IC protocol, the Q-NRG (Cosmed, Italy) gas analyzer device is connected to the ventilator circuit next to the endotracheal tube, and the second analyzer is connected to the ventilator port after the filter. IC measurement is considered possible as soon as a steady-state condition is reached, defined as a coefficient of variation of VO 2 and VCO 2 ≤5% for 5 min: the measure is continued for 10-15 min. 19 The Q-NRG device is calibrated once monthly according to manufacturer instructions. Two dietitians shared one supervisory position throughout the study period. Before the pandemic, they were physically attending the nurse morning report during weekdays. During the COVID-19 phase, both dietitians were working remotely and did not realize IC studies: early morning meetings were replaced by daily phone calls and emails to nurses. The potential number of patients to supervise at a distance increased from 35 to 76. Energy balance was calculated by computer daily as the difference between total energy delivery and prescribed value. Cumulative energy balances were the sum of daily balances. SOPs recommend an energy target of 20 kcal/kg in the first week, to be increased in the absence of IC to 25 kcal/kg thereafter. The increase was frequently not done in patients with COVID-19, and targets remained at the initial level: the targets and balances were recalculated after day 10 and called "per protocol." Feeding solutions were the same in both periods (Table S1): pharmacy-compounded PN was available for individual cases. Whatever the feeding route, an intravenous "stress micronutrient profile" was administered during the first 6 days (local ICU SOP): thiamin 100 mg, vitamin C 500 mg, zinc 5 mg, one vial multi-trace element (Addaven; Fresenius Kabi), and one vial multivitamin (Cernevit; Baxter). Daily protein, lipid, and glucose delivery was extracted from the EMR. Median protein delivery per kilogram of BW or IBW was calculated: a cumulative protein deficit of −300 g by day 20 was considered a critical cutoff. 20 Stools were defined as absent (>4 days: constipation), normal, diarrhea (more than three stools per day), fluid (response to enema), gas, or melena (black liquid stools). SOPs recommend measuring GRVs every 12 h (more in case of high volumes): values ≥50 ml were recorded, and any value ≥500 ml/24 h was considered abnormal (number of days was recorded). Recommended JOURNAL OF PARENTERAL AND ENTERAL NUTRITION | 3 prokinetics are metoclopramide (3 × 10-20 mg/day), followed by erythromycin (500 mg/day for 48 h). There was no sample size calculation: consecutive non-CO patient enrollment stopped with the first COVID-19 wave, and patients were compared with the next consecutive patients with COVID-19 who fulfilled the inclusion criterion of >10 days of invasive mechanical ventilation. According to their distribution (the Shapiro-Wilk test used for normality), data are reported as mean ± SD or median (IQR). Data analysis is limited to the first 30 days of the ICU stay. Two phases of the stay were considered: the first 10 days (days 1-10) and days 11-30, with the first corresponding to the minimal duration of mechanical ventilation and to the previously observed inflexion of high variability in nutrition delivery. 14 Comparisons between periods were conducted by using one-way and two-way analysis of variance being ventilated in a prone position for a median duration of 3 days (P < 0.0001). But the length of mechanical ventilation and of ICU and hospital stays did not differ, nor did ICU or hospital mortality ( Figure S1 ). Mortality was similarly significantly higher in both groups in patients with an NRS score >5 (P = 0.042). Sedation was mainly by propofol during the first 2 weeks in patients with COVID-19, resulting in significantly higher doses exceeding 5000 mg/day vs 1800 mg/day in non-CO patients (P < 0.0001) (Figure 2 ). The number of patients requiring paralysis via neuromuscular blockade during mechanical ventilation was significantly higher in the COVID-19 cohort ( Table 2 ; P = 0.0002), as was the duration of paralysis (P < 0.0001). Altogether, 2349 days were analyzed, evenly distributed among the periods (1035 days for the first 10-day period and 1314 days for days [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] . The time to feeding was significantly shorter in patients with Prescribed blood glucose targets were frequently tighter Intestinal function High GRVs occurred in both periods (Table 2) During the first 10 days, median urea/creatinine ratios were similar and, therafter, tended to be higher in the non-CO patients (days on CRRT excluded). To evaluate the nutrition risk, this study used the NRS, which is recommended by the ESPEN guidelines 17 : scores >5 have been shown to be associated with mortality in general ICU patients, 14 which was confirmed in the present study ( Figure S1B ). Moreover, as observed by colleagues from Wuhan, 10 the feeding part of the NRS score (food intake before admission) was modestly higher in the patients with COVID-19 (P = 0.088), resulting in a high risk of refeeding syndrome. Indeed, significantly lower phosphate values were observed in patients with COVID-19 during the first 48 h, requiring active treatment. 23 EN was started significantly earlier in the patients with COVID-19, who mostly suffered single organ failure: the rapid sequence "intubation → gastric tube insertion → control chest x-ray → proning → starting EN" only takes 3-5 h. This rapidity in execution proved to be successful for the first 10 days' feeding and possibly contributed to maintaining GI function. Very few patients needed prokinetics. It resulted in a significant reduction of days with fasting and a more rapid progression to the initially prescribed energy target, with PN and SPN being rarely required. The limited use of PN and SPN was further motivated by the lack of specific training of both nurses and doctors, as a substantial proportion came untrained to reinforce the ICU team. Because the use of PN and SPN is more complex, it will not be easily trusted under such crisis circumstances. The prevalence of GI problems reported in the literature is variable. In addition, mechanical ventilation while in the prone position with sedative and paralyzing drugs is also a risk factor of altered intestinal function. We were therefore expecting to observe more GI symptoms and diarrhea in these patients with severe COVID-19. Short-lived episodes of high GRV were found in a few cases in both groups, which is very reassuring regarding the safety of EN during prone sessions. Constipation predominated in non-CO patients and patients with COVID-19, being present in about 60% of patients during the first 10 days, whereas diarrhea occurred in 20.4% of patients in both groups. These positive findings regarding intestinal function contrast with worries that have been expressed in reviews. 24 Reported incidences of diarrhea vary between 2% and 50%. 25, 26 A study from Wuhan did not signal major GI problems. 27 A metanalysis including 23 published and 6 preprint studies showed that 12% of patients with COVID-19 were reported to manifest GI symptoms. 28 One study, using the paracetamol test, showed a 50% reduction of intestinal absorption. 29 The presence of GI symptoms has been associated with more frequent detection of RNA viruses in the stool 25 : the colonization of the GI mucous membrane is possibly causing the symptoms through alteration of the mucosal permeability. 30 In a cohort of 198 patients, Cereda et al signaled that difficult EN with large early energy deficits was associated with higher mortality. 31 A strict application of our SOPs might have favored a smoother clinical course. Serum prealbumin levels upon admission have been suggested to be an indicator of prognosis in a cohort of 408 patients with COVID-19: a cutoff of 0.15 g/L seems to indicate severity. 32 The majority of the patients with COVID-19 started with very low values ( Figure 5 )-significantly lower than those of the non-CO patientsthat reverted to within-normal values significantly faster vs non-CO patients, with resolution of inflammation. The changes were so rapid that we could not rely on serum prealbumin levels to estimate feeding adequacy as we usually do. 33 Considering the greater severity of illness in the non-CO patients, who suffered more multiorgan failure by SOFA, lower mortality rates might have been expected in the patients with COVID-19. But because of the limited number of patients and the heterogeneity of diagnoses in the non-CO group, comparison is hazardous. Moreover, the mortality of our selected COVID-19 cohort is much lower than that reported by others (25%-42%). 13 Other factors such as lower protein and higher fat intakes, as well as an absence of individual adaptation of the energy target, might have contributed to a suboptimal outcome, but this remains to be verified. 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We thank Prof Philippe Eckert (past head of the ICU and actual General Director of CHUV, Lausanne) for internal resources to support of the study and Mrs Tatiana Kelevina (ICU nurse, CHUV, Lausanne) for assistance with data extraction. Open access funding provided by Universite de Lausanne. None declared. The study was funded exclusively by internal service resources.