Early Nutritional Supplementation in Non-critically Ill Patients Hospitalized for the 2019 Novel Coronavirus

Disease (COVID-19): Rationale and Feasibility of a Shared Pragmatic Protocol

Riccardo CaccialanzaUOC Dietetica e Nutrizione Clinica

Fondazione IRCCS Policlinico

San Matteo

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• Changes in intestinal barrier

• Reduction in glomerular filtration

• Alterations in cardiac function

• Altered drug pharmacokinetics

• Delayed wound healing

• Increased surgical complications

• Increased treatment toxicity

• Impaired immunity

• Increase in length of hospital stay

• Increased hospital readmissions

• Increased mortality

• Increased treatment costs

• Impaired quality of life and functional status

Malnutrition/Cachexia: Consequences

Butterworth CE Jr. Nutrition Today 1974;9:4–8.

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It is based on the observation that most patients present at admission with severe inflammation and anorexia leading

to the drastic reduction of food intake, and that a substantial percentage develops respiratory failure requiring

non-invasive ventilation or even continuous positive airway pressure.

Early Nutritional Supplementation in Non-critically Ill Patients Hospitalized for the 2019 Novel

Coronavirus Disease (COVID-19): Rationale and Feasibility of a Shared Pragmatic Protocol

Riccardo Caccialanza, M.D.; Alessandro Laviano, M.D, Ph.D.; Federica Lobascio, M.D; Elisabetta Montagna RD; Raffaele Bruno, M.D.; Serena Ludovisi, M.D.;

Angelo Guido Corsico, M.D., Ph.D.; Antonio Di Sabatino, M.D.; Mirko Belliato, M.D.; Monica Calvi Pharm.D.; Isabella Iacona, Pharm.D.; Giuseppina Grugnetti, R.N.;

Elisa Bonadeo, M.D.; Alba Muzzi, M.D.; Emanuele Cereda, M.D., Ph.D.

We are aware that our straight approach may be debatable. However, in order to cope with the current emergency

crisis, its aim is to promptly and pragmatically implement nutritional care in COVID-19 patients, which would risk to be

overlooked in spite of being potentially beneficial to clinical outcomes and effective in preventing the consequences

of malnutrition in this patient population.

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Simplified nutritional risk screening§ Yes No

1 Is BMI <22 kg/m2?

2 Did the patient loose weight in the last 3 months?

3 Did the patient reduce food intake or is expected to reduce it in the next few days?

§If any answer is «Yes», start supplementation (between or straight after meals) with high-protein, high-calorie oral nutritional supplements (ONS; 2-3 bottles [125/200 ml each] providing 600-900 kcal and 35-55 grams of proteins).

*Use referred or estimated values if scales are not available or cannot be used due to hygienical reasons.

**Albumin, transferrin, prealbumin, glucose, kidney (creatinine and blood urea nitrogen) and liver (cholinesterase, aspartate amino-transferase, alanine amino-transferase, gamma glutamyl transferase) function, electrolytes (Na, K, Cl, Ca, P, Mg), triglyceride, folic acid, vitamina B12, 25-hydroxyvitamin D, C-reactive protein.

***Recommended dietary allowance.

Start Systematic Supplementation With:

• Whey proteins 20 g/day (in one or two occasions, preferably during meals)

• Daily infusion of RDA*** tailored multivitamin, multimineral and trace elements solutions (eg, in 100/250 mL of physiological saline solution)

• Cholecalciferol - 50.000 UI or 25.000 UI/week if 25-hydroxyvitamin D is <20 ng/mL or ≥20 <30 ng/mL, respectively.

If patients don’t tolerate ONS (ie, less than 2 bottles/day are consumed for 2 consecutive days) or respiratory conditions worsen, contact the Clinical Nutrition and Dietetics Unit for the prescription of parenteral nutrition or start it implementing strict biochemical monitoring**

DURING THE HOSPITAL STAY

Monitor food/supplements intake with the aid of local healthcare professionals.

Protocol for Early Nutritional Supplementation in Non-critically Ill COVID-19 Patients AT ADMISSION

Record:

• Body weight and height*

• Relevant biochemical parameters**

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Cholecalciferol

50.000 UI/week if 25-OH vitamin D <20 ng/mL

25.000 UI/week if 25-OH vitamin D ≥20 <30 ng/mL

McPherson RA, et al. Curr Opin Clin Nutr Metab Care. 2011;14:562‐568; Rondanelli M, et al. Nutrition. 2020;72:110667; Teixeira FJ, et al. PharmacolRes. 2019;144:245-256; Cereda E, et al. Cancer Med. 2019; 8:6923-6932; Cross ML, et al. British J Nutr. 2000;84:S81‐S89; Ng TB, et al. Appl Microbiol Biotechnol. 2015;99:6997-7008; Olsen MF, et al. BMJ. 2014;348:g3187.

Systematic supplementation with:

Whey proteins 20 g/day (in one or two occasions, preferably

during meals)

• Anabolic and antioxidant properties + high digestibility

• Potential clinical benefits in cancer cachexia

• Immunomodulatory properties

• Potential antiviral activity

• Improved immune recovery in patients with HIV during ART

Daily e.v. infusion of RDA tailored multivitamin,

multimineral and trace elements solutions (eg, in 100/250 mL of

physiological saline solution)

• Anti-oxidant properties

• Specific vitamin and micronutrient deficits harmful during viral infections

• Approach is not precise (not available single nutrient dosage)

• May be beneficial with very limited risk of harm secondary to overdosing

Liu M, et al. Microbes Infect. 2017; 19:580-586; Beck MA. J Am Coll Nutr. 2001;20:384S-388S; Camini FC, et al. Arch Virol. 2017;162:907-917; Weger-Lucarelli J, et al. PLoS Pathog. 2019;15:e1008089; Evans P, et al. Br J Nutr. 2001;85:S67-74; Gupta S, et al. Cells. 2019;8(6); Beck MA. Nutr Rev. 1998;56:S140-6; Meyer M, et al. Am J Physiol Lung Cell Mol Physiol. 2015;308:L1189-201; Li Z, et al. Arch Virol. 2017;162:603-610; Baum MK, et al. JAMA. 2013;310:2154-63; Levett-Jones T. J Assoc Nurses AIDS Care. 2017;28:984-986; Tasca KI, et al. Oxid Med Cell Longev. 2017;2017:9834803; Isanaka S, et al. JAMA. 2012;308:1535-44; McGill JL, et al. Sci Rep. 2019;9:15157; Lee H, et al. Sci Rep. 2016;6:25835.

• Restoration to normal values in infected patients may improve immunologic recovery, reduce levels of inflammation and increase immunity against pathogens

Beard JA, et al. J Clin Virol. 2011;50:194-200; Teymoori-Rad M, et al. Rev Med Virol. 2019;29:e2032; Jiménez-Sousa MÁ, et al. Front Immunol. 2018;9:458; Havers F, et al. J Infect Dis. 2014;210:244-53; Gruber-Bzura BM. Int J Mol Sci. 2018;19. pii:E2419.

At Admission

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§Referred or estimated weight & height values if scales are not available or cannot be used due to hygienical reasons.

*Albumin, transferrin, prealbumin, glucose, kidney (creatinine and blood urea nitrogen) and liver (cholinesterase, aspartate amino-transferase, alanine amino-transferase, gamma glutamyl transferase) function, electrolytes (Na, K, Cl, Ca, P, Mg), triglyceride, folic acid, vitamina B12, 25-hydroxyvitamin D, C-reactive protein.

Norman K, et al. Clin Nutr. 2008;27:5-15; Schuetz P, et al. Lancet. 2019;393:2312-2321; Gomes F, et al. Clin Nutr. 2018;37:336-353.

If any answer is «Yes»:

Start supplementation (between or straight after meals) with high-protein, high-calorie ONS (2-3 bottles [125/200 ml each] 600-900 kcal /35-55 g proteins)

Relevant biochemical parameters collected*

At Admission

Simplified nutritional risk screening§ Yes No

1 Is BMI§ <22 kg/m2?

2 Did the patient loose weight in the last 3 months?

3 Did the patient reduce food intake or is expected to reduce it in the next few days?

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Monitor food/ONS intake with the aid of local healthcare professional (as available…)

If patients don’t tolerate ONS (ie, less than 2 bottles/day are consumed for 2 consecutive days) or respiratory conditions worsen, contact the Clinical Nutrition and Dietetics Unit for the prescription

of parenteral nutrition or start it implementing strict biochemical monitoring

• NGT may result in air leakage and compromise the effectiveness of NIV or CPAP

• Special NIV masks with a port for NGT may be hardly available

• Positive pressure ventilation through a face mask may also result in gastric distention, further compromising the respiratory conditions

• Receiving EN during NIV was associated with a significantly higher rate of airway complications and longer NIV duration

• There is currently no validated strategy to reduce the critical complications of EN among patients with NIV or CPAP

• Patients receiving ART, frequently present diarrhea that can contribute to treatment interruption

• Gastrointestinal symptoms are frequently reported by COVID-19, which may increase the risk of EN intolerance

Singer P, et al. Crit Care. 2018;22:27; Kogo M, et al. Respir Care. 2017;62:459-467; Kogo M, et al. Respir Care. 2017;62:1119-1120; Doig GS, et al. JAMA. 2013;309:2130-2138; Dikman AE, et al. Dig Dis Sci. 2015;60:2236-2245; Bezabih YM, et al. BMC Infect Dis. 2019;19:537; Pan L, et al. Am J Gastroenterol. 2020 [Epub ahead of print].

During the Hospital Stay

Why not enteral nutrition

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Results: One hundred eighteen patients (90.1%) completed the 7-day SPN support regimen and 102 of them (86.4%) were in advanced disease stage. SPN induced a significant improvement of phase angle (PhA, + 0.25 [95% CI 0.11, 0.39]; p=0.001), standardized phase angle (SPA, + 0.33 [95% CI 0.13, 0.53]; p=0.002), HG (+ 2.1 kg -95% CI 1.30, 2.81]; p<0.001), and PAB (+ 3.8 mg/dL [95% CI 2.1, 5.6]; p<0.001). In multivariable analysis, the effects on BIVA parameters were more pronounced in patients (N=90, 76.3%) in whom estimated protein and calorie requirements were both satisfied (adjusted difference: PhA, + 0.39 [95% CI 0.04, 0.73]; p=0.030; SPA, + 0.62 [95% CI 0.16, 1.09]; p=0.009).

No significant changes in hydration status were detected and no severe metabolic or other complications occurred.

Conclusions: Early 7-day SPN resulted in improved body composition, HG and PAB levels in hypophagic, and hospitalized cancer patients at nutritional risk in the absence of any relevant clinical complications. Further trials, aimed at verifying the efficacy of this early nutritional intervention on mid- and long-term primary clinical endpoints in specific cancer types, are warranted.

Which Parenteral Nutrition (Ideally…)

Males

Females

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• Limited accuracy of nutritional assessment and support due to weight and height measurement hard or even impossible to perform, like body composition assessment and calorimetry.

• Underfeeding very hard to avoid for several reasons: constantly increasing number of admitted patients; impossibility to assist patients during meals; monitoring of food intake extremely difficult, if feasible at all.

PN support may only partially fit the needs of pre-ICU COVID-19 patients due to:

• Central infusion lines not always available outside the ICU wards; elevated energy requirements (severe acute inflammatory response and average high patients’ BMI); cardiovascular and pulmonary compliance limit PN volume.

• Clinical Nutrition Units not widespread in Italian hospitals, thus specific competences in nutritional care not always available.

• Potentially problematic timely provision and availability of ONS, EN formulas, PN bags, infusion pumps.

Critical Issues and Perspectives

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Specific nutritional support issues:

• COVID-19 disease can suddenly require intensive care measures, including intubation EN

• EN tolerance (gastric distention, erosive gastritis)

• Supplemental PN

• Specific high protein-calorie, highly digestible enteral formulas enriched in anti-inflammatory or immunomodulatory nutrients

• Use of omega-3 fatty acids (anti-inflammatory/immunosuppressive properties)

• Clinical research focused on nutritional issues in COVID-19 patients is hard, if not impossible to perform.

Critical Issues and Perspectives (cont.)

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However, any effort should be done to try to guarantee adequate nutritional support to hospitalized patients, as it may be potentially beneficial to clinical outcomes and effective in reducing or preventing the deleterious consequences of malnutrition in this patient population.

Conclusions

Implementing prompt and

appropriate nutritional care in

COVID-19 disease management

is a hard challenge due to the

current dramatic emergency

circumstances.

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We are infinitively grateful to all the employees of the Fondazione IRCCS Policlinico San Matteo for their tremendous

and courageous efforts in struggling against the current tragic clinical and social COVID-19 emergency.

We are extremely grateful to all friends, medical nutrition industries and colleagues who will contribute to spread and share the challenge of implementing nutritional care in COVID-19 disease management.

Acknowledgments

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