Table 1 Personalized Nutrition in Critical Care: Practical Practice Recommendations, Current Guideline Recommendations, and Future Research Priorities

1

Personalizing when to start nutrition?

While EN is the preferred route of early nutrition delivery, new data highlight isocaloric doses of PN can be given safely without increased risk vs. EN, such that when EN is not feasible, provision of early PN over the short term is effective and results in similar outcomes. Key message is early high-dose feeding should be avoided until the patient is stabilized early in ICU stay

Trophic EN may prove to exert non-nutritional benefits on microbiome, gut barrier function, vagal nerve signaling, and mesenteric lymph toxicity

ASPEN 2021—Although EN is preferred, either PN or EN is acceptable as the primary early feeding modality in the first week of critical illness. EN and PN may be considered equivalent in terms of risk and outcome benefits

ESPEN 2019—If oral intake is not possible, early EN (within 48 h) in adult ICU patients should be performed/initiated rather than delaying EN

ASPEN/SCCM 2016—We recommend nutrition care in the form of early EN be initiated within 24–48 h in the ICU patient unable to maintain volitional intake

Research/development of new “ready-to-feed” indicators or markers to assist understanding when is most optimal to initiate nutrition delivery

Research on optimal timing to start nutrition based on non-nutritional benefits of EN, even trophic EN, on microbiome/dysbiosis, gut barrier function, vagal nerve signaling, and mesenteric lymph toxicity

—SendHOME Trial: Personalized Targeted Nutrition Via StructurEd Nutrition Delivery Pathway to Improve Recovery of Physical Function in Trauma (RCT)—(starting 7/2023)—Duke University—Funded by Department of Defense

2

Personalizing how much to feed: Role of Indirect Calorimetry?

IC measurement is gold standard measurement of EE

IC measurements of EE are recommended by current ESPEN/ASPEN guidelines after stabilization of patient post-ICU admission (after day 2–3) to attempt to prevent over-/underfeeding. The evolution of IC technology has made utilization of IC targets more practical for centers worldwide to consider in clinical practice

In acutely ill patients, early endogenous glucose production cannot be suppressed by providing nutrition. In such case, matching the energy target with measured EE could lead to overfeeding

In well-nourished mechanically ventilated patients admitted to ICU on high doses of vasopressors (doses of > 0.2 ug/kg/min norepinephrine), lower energy doses (5–10 kcal/kg/d and < 0.4 g/kg/d of protein) can be considered to be delivered until day 7 or until patient is extubated and weaning off of vasopressors

Predictive equations need to be used in early acute phase (up to day 3) and can be used patients when IC cannot be utilized

If IC is used: Delivery below EE target (~ 70%) during early phase (day 3 to ~ day 7) is suggested—to be increased gradually to match EE later in stay as patient recovers. As patient recovers and starts physical therapy, the addition of an activity factor to REE may be needed and can be considered

In general, predictive equations are inaccurate and often lead to over and underfeeding. However, in patients not able to have energy needs measured via IC or where IC is not available—predictive equations need to be used (i.e., Penn State in ventilated patients)

ASPEN 2021—We suggest feeding between 12–25 kcal/kg (i.e., the range of mean energy intakes examined) in the first 7–10 days of ICU stay

ESPEN 2019—To avoid overfeeding, early full EN and PN shall not be used in critically ill patients but shall be prescribed within three to seven days

—EE should be measured by IC where available

—If IC is used, isocaloric nutrition rather than hypocaloric nutrition can be progressively implemented after the early phase of acute illness

—Hypocaloric nutrition (not exceeding 70% of EE) should be administered in the early phase of acute illness

—After day 3, energy delivery can be increased up to 80–100% of measured EE

—If predictive equations are used to estimate the energy need, hypocaloric nutrition (below 70% estimated needs) should be preferred over isocaloric nutrition for first week of ICU stay

ASPEN/SCCM 2016—Suggest IC be used to determine energy requirements in absence of variables that affect accuracy of measurement

Trials utilizing IC-guided nutrition delivery to generate evidence to better define energy needs in different populations and demonstrate further evidence of clinical outcome benefits of personalization of nutrition delivery via IC, especially after acute phase of critical illness and in post-ICU recovery period

Study of utility of RQ measurements to determine response to nutrition interventions and recovery from ICU

—SendHOMETrial (RCT)—(starting 7/2023)—Duke University—Funded by Department of Defense

3

Personalizing Protein Delivery: How much and timing?

Low-dose (e.g., ≤ 0.8 g/kg/day) protein delivery can be considered during the early acute phase (up to day 3)—to be progressively increased > 1.2 g/kg/d later. Higher doses of protein should be avoided in unstable patients (i.e., in shock on higher doses of vasopressors)

In well-nourished mechanically ventilated patients admitted to ICU in shock on high doses of vasopressors (doses of norepi. ≥ 0.2 ug/kg/min) < 0.4 g/kg/d of protein can be considered to be delivered until patient is stabilized and weaning off of vasopressors

Higher doses of protein (> 1.2 g/kg/d) should potentially be avoided in patients presenting with acute kidney injury (stage 1–3) (not or CRRT) and high SOFA score (≥ 9)

ASPEN 2021—Given limited new data continue to utilize 2016 ASPEN/SCCM guideline suggestion for 1.2–2.0 g/kg/day

ESPEN 2019—During critical illness, 1.3 g/kg protein per day can be delivered progressively

Studies of role of bedside techniques such as BIA, muscle ultrasound and new validated biomarkers can facilitate nutritional protein therapy individualization. (i.e., use of BIA or other muscle measures to base protein delivery on lean mass as opposed to total body weight)

Development of markers of protein utilization and incorporation into muscle and progression/resolution of anabolic resistance

Urea/creatinine to monitor catabolism and intervention response

—NEXIS trial: Nutrition and Exercise in Critical Illness Trial (NEXIS Trial): a protocol of a multicentered, randomized controlled trial of combined cycle ergometry and amino acid supplementation commenced early during critical illness (multicenter RCT)

(Ongoing)-NIH funded NCT#: 03021902 Protocol Publication: https://bmjopen.bmj.com/content/9/7/e027893

—TARGET Protein: The effect of augmented administration of enteral protein to critically ill adults on clinical outcomes: A cluster randomized, cross-sectional double crossover, registry-embedded, pragmatic clinical trial (Cluster randomized RCT) (Ongoing 3000/4000 enrolled)

Link: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621001484831

—PRotEin Provision in Critical IllneSs (PRECISe) (Randomized multicenter trial) NCT# 04633421

4

Personalization of PN Timing and Delivery?

If EN is not able to be started early PN may be started safely w/o increased risk and results in similar outcomes. Early high-dose PN feeding should be avoided until the patient is stabilized during ICU stay

EE measurements targets should be made with IC which may assist with determining PN energy dose (when possible). Below EE (~ 70%) should be considered during the early phase (4–7 days)

Energy delivery to be increased to match EE later in stay

ASPEN 2021—In adult critically ill patients, we recommend that either PN or EN is acceptable as the primary early feeding modality in the first week of critical illness. EN and PN may be considered equivalent in terms of risk and outcome benefits

ESPEN 2019—In case of contraindications to oral and EN, PN should be implemented within three to seven days

Early and progressive PN can be provided instead of no nutrition in case of contraindications for EN in severely malnourished patients

Studies on role of IC guidance to personalize PN and SPN delivery and potentially improve clinical and long-term functional outcomes in ICU patients

Studies of role of early PN and SPN use on post-ICU functional outcomes and MM/function

—INTENT Trial: Intensive Nutrition Therapy comparEd to usual care iN criTically ill adults (INTENT): a phase II randomized controlled trial (Phase II multicenter RCT) (completed)—ANZICS group: NCT#: 03292237

Protocol Publication: https://bmjopen.bmj.com/content/12/3/e050153

—SendHome Trial (RCT)—(starting 7/2023)—Duke University—Funded by Department of Defense

5

Personalization of Feeding and Fasting Periods?

Recent evidence suggests that the lack of early full feeding in large RCTs may be explained by the delivery mode of artificial nutrition. Switching from continuous nutrition to intermittent nutrition, hence alternating feeding and fasting intervals may be superior, although confirmatory RCT evidence is needed

In case of GI dysfunction impairing the tolerance of full-volume isocaloric EN, fluid restriction or transitioning to oral nutrition using an intermittent-feeding schedule (e.g., overnight) can be considered safely given recent data (ref. 69–70)

ESPEN 2019—Continuous rather than bolus EN should be used

ASPEN/SCCM 2016—Based on expert consensus, we suggest for high-risk patients or those shown to be intolerant to bolus gastric EN, EN delivery be switched to continuous infusion

Further studies should investigate how efficacy and safety of intermittent feeding/fasting can be monitored. The ideal feeding/fasting regimen (if any) also remains to be determined

Studies of Ketogenic substrates such as ketones in ICU

Outcomes assessing muscle mass/function and post-ICU functional and quality of life outcomes should be key endpoints in these studies

—Alternative Substrates in the Critically Ill Subject (Randomized Controlled Pilot trial) (ASICS) (Recruitment completed)

NCT#: NCT04101071

—Effect of Continuous Versus Cyclic Daytime Enteral Nutrition on Circadian Rhythms in Critical Illness (CIRCLES) (Randomized controlled trial) (Not yet recruiting) NCT#: 05795881

6

Personalizing Monitoring of Nutrition Delivery?

It is critical ICU clinicians are aware on a daily basis of delivered energy/protein and what percentage of personalized goal nutrition targets this delivered amount represents

New computerized nutrition monitoring systems and full-automated ICU nutrition platforms are now widely available

No specific recommendations

Studies of integrated nutrition delivery platforms and nutrition delivery monitors to assess effect on clinical and functional outcomes

7

Personalizing Monitoring and Repletion of Micronutrient Deficiencies?

The majority of micronutrient analysis should be initiated after 5–7 days in the ICU, i.e., in patients with risk factors for nutrient losses as follows: patients with active losses of biological fluids, especially continuous renal replacement therapy (CRRT)

CRRT is now understood to lead to significant losses and low plasma levels in multiple micronutrients and water-soluble vitamins in ~ 90% of patients within 5–7 days of CRRT initiation. Additionally, intestinal losses, major drains, and major burns lead to MN deficiencies

If repletion initiated, monitoring results is required within a ~ week. CRP should be utilized when trace element levels assessed

ESPEN Micronutrient Guideline: Adequate amounts of all essential trace elements and vitamins shall be supplied to all patients receiving medical nutrition from the beginning of the period of nutritional support

C-reactive protein should be determined at the same time as any micronutrient analysis to assist with interpretation

Trials of role of routine micronutrient supplements to prevent micronutrient deficiencies in patients at high risk of nutrient deficiencies (especially CRRT patients). Focus on clinical and long-term functional outcomes

—Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial (Randomized MultiCenter Trial) (Enrollment Completed):

NCT#: 03680274 Protocol Paper: Doi: https://doi.org/10.2196/36261

8

Personalizing Monitoring Of Catabolism And Muscle Mass And Effect Of Nutrition On Muscle Recovery?

Routine use of modalities such as muscle ultrasound, CT scan, and/or BIA monitoring to assess nutrition risk, effect of/response to nutrition delivery are widely used in ICU research and may become a future standard of care in clinical ICU care and clinical /translational ICU nutrition research to personalize nutrition care

GLIM Criteria 2018—Muscle mass is now a key malnutrition diagnostic criterion. Beginning to be required by insurers in USA for validation of malnutrition diagnosis

Trials examining modalities such as muscle ultrasound, CT scan, and/or BIA monitoring to assess nutrition risk, effect of/response to nutrition delivery, and accurate determination of nutrition needs (i.e., BIA or other measures of lean mass to more accurately determine protein dose)

Urea/creatinine to monitor catabolism and intervention response

9

Personalizing Use of Specialized Anabolic Nutrients?

HMB, creatine, and leucine may be promising at improving strength, MM, and lean mass given data in other clinical populations. More data in ICU populations are needed

No specific recommendations

Further studies of HMB, creatine, and leucine on muscle strength, MM, and lean mass given data in ICU populations are needed. Trials also should examine long-term functional outcomes

Urea/creatinine to monitor catabolism and intervention response

A study to investigate the effect of HMB on skeletal muscle wasting in early critical illness (HMB-ICU). NCT# 03464708

10

Personalizing Post-ICU Physical Function Recovery via Combination of Personalized Nutrition, Exercise, and Anabolic Pharmacologic Agents?

Post-ICU Personalized Nutrition: Continued use of indirect calorimetry, MM and energy states analysis can be considered post-ICU to personalize nutrition delivery in critical post-ICU recovery period. This is an area of significant research need

Post-ICU Personalized Exercise: The potential to guide and personalize post-ICU exercise with CPET testing and VO2 peak step testing is promising and is undergoing current research in clinical trials and deserves additional research effort

Post-ICU Anabolic Pharmacologic Agents: Data for oral oxandrolone are positive for clinical and functional outcome improvements in burns. A vast majority of ICU patients are severely testosterone deficient. More research in broader ICU populations is needed to determine who will optimally benefit from testosterone/oxandrolone treatment

ESPEN 2019—Physical activity may improve the beneficial effects of nutritional therapy

ASPEN/SCCM 2016—Based on expert consensus, we suggest that chronically critically ill patients (defined as those with persistent organ dysfunction requiring ICU LOS > 21.days) be managed with aggressive high-protein EN therapy and, when feasible, that a resistance exercise program be used

Studies examining use of IC, MM, and EE analysis in post-ICU setting to personalize nutrition delivery needed

Trials of personalized post-ICU exercise with CPET testing and VO2 peak step testing as well as monitoring of exercise at home via mobile technologies urgently needed

Studies of oxandrolone/testosterone agents as part of nutrition/exercise intervention in non-burn ICU patients and post-ICU patients needed. Endpoints should include long-term post-ICU functional and MM/function endpoints (i.e., 6 min walk test, muscle strength, QOL)

—REmotely Monitored, Mobile Health Supported Multidomain Rehabilitation Program With High Intensity Interval Training for COVID-19 (REMM-HIIT-CoV) (Multicenter RCT) (NIH Funded) (Currently enrolling)

NCT#: 05218083

—NEXIS trial (multicenter RCT)

(Ongoing)-NIH funded

NCT#: 03021902

Protocol Publication: https://bmjopen.bmj.com/content/9/7/e027893

—Personalized Nutrition Delivery to Improve Resilience in Older Adult Trauma Patients (SeND Home) (Randomized trial) (enrolling) NCT#: 05544162

—Optimised Nutritional Therapy and Early Physiotherapy in Long Term ICU Patients (NutriPhyT Trial) (NutriPhyT) (Randomized clinical trial) (Enrolling) NCT# NCT05865314