Novel Strategies to Promote ICU Recovery Via Personalized Exercise, Nutrition and Anabolic Interventions

Synopsis

Survivors of critical illness experience significant morbidity, reduced physiological reserve, and long-term complications that negatively impact quality of life. Although rehabilitative treatments are beneficial during early recovery, there is limited evidence regarding effective multi-modal rehabilitation, nutrition, and anabolic nutrient/agent strategies for improving long-term outcomes. This review discusses novel personalized rehabilitation, nutrition, and anabolic nutrient/agent (I.e. creatine, HMB, testosterone) approaches that allow for precise exercise and nutrition prescription and have potential to improve patient care, address continued medical needs, and optimize long-term recovery. Continued research is needed to further evaluate effectiveness and implementation of these strategies throughout the continuum of care.

Introduction

More than 5 million patients are admitted to the intensive care unit (ICU) in the United States every year,¹ and as a result of improved treatments and care, more than 85% will survive hospitalization.² Despite low in-hospital mortality, ICU survivors face many challenges including significant morbidity, reduced physiological reserve, and long-term complications that negatively impact health and quality of life.^3,4 Critical illness combined with intensive treatments and prolonged bed rest also accelerates losses in muscle mass, cardiorespiratory fitness, and physical function.^5–7 ICU-acquired weakness is experienced by approximately 40% of critical care patients,⁸ with a higher incidence among those experiencing sepsis, multiple organ failure, or greater exposure to mechanical ventilation.⁹ Post-ICU functional capacity is also significantly impaired, reaching 56% of predicted norms,⁶ and often fails to recover over time.¹⁰ Impairments can continue to worsen as 54% of survivors report further decline in neuropsychological or physical function.¹¹ Physical, cognitive, and mental health deficits, collectively known as post-intensive care syndrome (PICS),¹² can persist years after hospitalization,¹¹ negatively impacting long-term recovery, rehospitalization risk,¹³ and survival.¹⁴ As a result, there has been an urgent call for an increased focus on clinical trials investigating recovery from critical illness.

One of the major pillars involved in critical illness recovery is the prevention of PICS.¹² Introduction of early mobilization and nutrition support within the first few days of ICU admission are recommended strategies for preventing and treating PICS and promoting initial recovery.^15–20 Several systematic reviews and meta-analyses support early mobilization, including walking intubated ICU patients, to reduce the incidence of ICU-acquired weakness, shorten hospital stays, and promote short-term strength and physical function benefits^21–24. However, results are mixed regarding the positive impacts of early rehabilitation on long-term outcomes and recovery.^22,24,25 For example, some studies have reported benefits on post-discharge physical function^26,27 while others report no effect,^22,24 and findings related to long-term outcomes, including rehospitalization and survival, vary among studies.^26,28–31 Differing results may be confounded by differences in intervention frequency, intensity, duration, and dosage, timing and type of outcome assessments, and heterogeneity in the control group characteristics.^23,32,33 This highlights the complexity of designing and implementing effective rehabilitation strategies to optimize long-term recovery. Nevertheless, current evidence supports the use of early ICU rehabilitation for short-term benefits, but also highlights the need for high-quality research and evidence-based approaches throughout the continuum of care that focus on improving long-term outcomes.

Less is known regarding post-discharge rehabilitation, nutrition interventions, and anabolic nutrients/agents, and optimal strategies have yet to be determined. For example, results from previous studies investigating post-ICU rehabilitation programs are inconsistent, with many showing little to no effects on physical health, function, or health-related quality of life.^10,25,34,35 Despite insufficient evidence specific to rehabilitation interventions, findings from several studies support the feasibility and benefit of critical care transition and recovery programs for reducing ICU readmission and optimizing recovery.^13,36,37 However, patients face many barriers to post-ICU care including functional and cognitive impairments, limited ability to attend clinical visits, lack of knowledge regarding the importance of follow-up care, and lack of availability of coordinated post-ICU rehabilitation programs.³⁷ Furthermore, critical illness survivors are a heterogeneous population with varying pathophysiology, symptoms, and impairments.³⁸ Therefore, a one-size-fits-all approach to rehabilitation, nutrition, and anabolic nutrients/agents is not likely to be ideal for reducing ICU-related deficits and improving long-term outcomes. This warrants the need for personalized rehabilitation, nutrition, and anabolic nutrient/agent strategies that address patients’ continued and changing medical needs. Furthermore, combining physical rehabilitation with personalized nutrition and anabolic strategies may further reduce ICU-related impairments and enhance recovery.³⁹ This review aims to discuss novel personalized multi-modal rehabilitation approaches that can potentially improve patient care and promote long-term recovery. We will also address current recommendations and new approaches to optimize patients’ nutritional status and promote anabolism/muscle mass preservation and recovery throughout the critical illness care continuum.

Rehabilitation Strategies

Multi-domain Rehabilitation Interventions

The implementation of multi-domain rehabilitation interventions that target several physical function domains may be an effective novel strategy to comprehensively address the numerous impairments experienced by critical illness survivors. Multi-domain exercise interventions have been found to improve strength and physical function to a greater extent than single-domain programs in frail older adults.^40,41 Although the efficacy of this type of intervention has not been fully explored within the critical care realm, the previous REHAB-HF trial with older heart failure patients,^42–44 a population with broad physical impairments as those surviving critical illness, provides a very successful model warranting further exploration. This study implemented a 12-week progressive, individualized rehabilitation program that transitioned from the hospital to an outpatient setting and targeted domains for endurance, strength, mobility, and balance. Results demonstrated high retention (82%) and session adherence (67%). The program led to significantly improved performance on the Short Physical Performance Battery and clinically important changes in six-minute walk distance and quality of life in the intervention group^42,43. Importantly, there was a dose-response effect such that higher session adherence associated improved patient-centered and clinical event outcomes.⁴⁵

Recent evidence in patients with COVID-19 offers additional insight. For example, a single-arm post-ICU study in older adults with post-COVID-19 functional impairment reported improved functional capacity, balance, and ability to perform activities of daily living following a 4-week in-hospital, exercise program with strength, cardiovascular, balance, and gait components.⁴⁶ Another single-arm 7-week multi-component exercise study in COVID-19 patients discharged from the hospital or ICU similarly reported increased aerobic capacity, health status, and dyspnea-related disability following the intervention.⁴⁷ A two-year follow-up revealed that 86% of patients continued to exercise, and their health status increased.⁴⁷ Although these recent findings support the potential benefit of post-ICU multi-domain rehabilitation approaches, neither one had a control group for comparison, thus limiting the strength of the evidence. Additional studies, including large randomized controlled trials, are needed to test the feasibility, efficacy, and implementation of multi-domain interventions in survivors of critical illness. One study of interest is an NIH-funded randomized clinical trial in patients surviving COVID-19 hospitalization (REMM-HIIT-COVID-19; clinicaltrials.gov/ct2/show/NCT04664101) that utilizes a multi-domain, progressive intervention consisting of high-intensity interval training (HIIT) guided by post-hospital cardiopulmonary exercise testing (CPET) and exercises targeting strength, mobility, and balance. This study is currently underway and in the recruitment phase; results will provide valuable insight that may be further translated to the critical care setting.

Patient-Centered Individually Personalized Rehabilitation

Many of the aforementioned multi-domain studies also utilized novel strategies for individually personalizing the intervention to match the exercise prescription to each patient’s needs. Personalized and tailored interventions can be characterized by 1) rehabilitation protocols where exercise frequency, intensity, duration, and/or volume are prescribed based on each patient’s individual and unique characteristics, exercise capacity, and functional needs; and 2) gradual progression that corresponds to adaptation and improvement. For example, the REMM-HIIT-COVID-19 trial (clinicaltrials.gov/ct2/show/NCT04664101) personalizes the intervention to participants by utilizing CPET-testing to calculate individualized target heart rates for HIIT and prescribing strength, mobility, and balance exercises based on pre-determined levels that correspond to each patient’s functional assessment scores. Our team has developed a simple step-test-based CPET modality using a simple Bluetooth-based CPET mask that can be conducted at the hospital bedside or in any clinical setting without needing a large bike or CPET device. (See Figure 1) Given the heterogeneity in critical illness survivors’ characteristics, disease status, comorbidities, and impairments, personalized rehabilitation protocols must align the intervention with patient needs, address limitations and impairments, promote progressive improvements, and prioritize patient goals and preferences. This is supported by a recent machine learning study that defined four different ICU patient groups based on clinical characteristics and demonstrated that the most effective rehabilitation strategies for increasing the likelihood of discharge to home differed between groups.⁴⁸ Furthermore, personalized exercise is perceived by patients as an essential component of successful rehabilitation programs. For example, patients participating in the REVIVE trial, which consisted of a 6-week post-ICU intervention, reported that the tailored exercise program was an important facilitator related to perceived benefit.⁴⁹ Patients participating in ICU recovery programs also highlighted the importance of programs focused on helping them set and meet their own personal care goals, which they deemed important for developing intrinsic motivation and self-efficacy.¹³

Figure 1:

Novel cardiopulmonary exercise testing (CPET) via step test that can be utilized in hospital rooms and clinic settings. Utilizes Bluetooth-linked CPET mask and provides VO2peak measures. (Mask: Vo2Master Pro, VO2 Master Health Sensors Inc. BC, Canada)

Finally, interventions that integrate personalized strategies to promote exercise adherence and address barriers to rehabilitation are needed. Few studies have focused on interventions that specifically target ICU survivors’ barriers to rehabilitation, and a recent review in older adults with multi-morbidities suggested that interventions are not addressing important patient priorities and barriers to participation.⁵⁰ Therefore, current evidence supports the use and value of individually personalized rehabilitation interventions for survivors of critical illness; however, future studies are needed to expand current evidence to develop approaches that address specific facilitators and barriers to rehabilitation and explore approaches that optimize benefits based on specific patient and disease-related characteristics.

Remotely Delivered and Monitored Rehabilitation

Successfully transitioning care from the inpatient to outpatient setting poses many challenges related to resource allocation, patient communication and support, accessibility of clinics and rehabilitation services, and poor patient attendance.^37,51 Telemedicine has become more popular in recent years and has the potential to address many of these challenges. Although remotely delivered rehabilitation protocols have not been fully explored in survivors of critical illness, evidence from other patient populations demonstrates that they are feasible, cost-efficient, effective for improving symptoms and outcomes, and produce comparable results to in-person programs.^52–57 A recent review on ICU follow-up care interventions also highlighted better recruitment, delivery rates, and retention for programs that did not require in-person attendance.⁵⁸ Technology such as video-conferencing and wearable devices also enhance intervention delivery, enabling personalized high-touch instruction, goal setting, behavior change support (i.e. alerts, feedback, and reminders), and continuous remote monitoring of health outcomes and exercise adherence.^59,60 The aforementioned REMM-HIIT-COVID-19 trial of post-COVID-19 rehabilitation provides all subjects with an Apple Watch and iPhone to monitor heart rate training, measure activity, and allow for personalized video coaching by a remote physical therapist or physiologist with each exercise session. Future research should identify best practices for remote rehabilitation delivery in the outpatient setting to optimize benefits and minimize barriers in critical illness survivors.

Nutrition Strategies

Protein Guidelines

Optimal protein delivery is essential for recovery from critical illness as it improves outcomes, supports immune function, and attenuates muscle mass loss.⁶¹ For example, it has been previously suggested that there is a 1% reduction in mortality for every gram of daily ingested protein.⁶² For patients in the ICU at high nutritional risk or diagnosed with severe malnutrition, enteral or parenteral nutrition should be initiated once the patient is stabilized with the goal of 1.2– 2.0 gm/kg/day.^61,63 Guidelines from the European Society for Clinical Nutrition and Metabolism (ESPEN) state the target of 1.3 gm of protein/kg/day, with a minimum of 1.2 gm/kg/day, increased in a stepwise approach following the period of critical illness.^20,64,65

For optimal recovery, protein delivery may change over the course of the ICU stay and throughout recovery. For example, a previous study reported increased mortality for protein doses > 1.2 g/kg/d for ICU days 1–3, with lower mortality for patients provided high protein (>1.2 gm/kg/day) intake after day 4. Consistently low protein throughout ICU stay (<0.8gm/kg of protein per day) showed the highest mortality.⁶⁶ The authors suggest that protein should be limited to <0.8gm/kg per day for the first 3 days of ICU admission and then gradually increased to ≥1.2 gm/kg of protein per day by or after the 6^th day.⁶⁶ In the post-ICU phase, the protein delivery goal is 1.5–2.0 gm of protein/kg/day, and following hospital discharge, protein needs may need to be increased to 2.0–2.5 gm/kg/day.^64,66

Oral nutrition supplements are imperative to patients meeting protein goals in both the ICU and post-ICU setting.⁶⁴ When patients are discharged from the hospital and recovering at home, protein needs remain elevated, although there is currently no consensus on the amount of protein recommended, especially in the long-term recovery phases.⁶⁵ Increased protein consumption and exercise can stimulate muscle protein synthesis⁶⁴, and thus is important for promoting recovery and mitigating further loss in muscle mass, strength, and function. There is limited research on energy and protein needs while undergoing rehabilitation, but indirect calorimetry can help provide more precise measurements.⁶⁵

Nutrition Support Starting in the ICU

Early Enteral and Parenteral Nutrition.

International clinical guidelines recommend early (within 48 hours of ICU admission) initiation of enteral nutrition (EN) for improved patient outcomes, including fewer infectious complications.^19,20,67,68 In cases where enteral feeding is contraindicated, parenteral nutrition (PN) is recommended and can be used as early as EN with no increased risk of infection in the setting of glycemic control and eucaloric feeding.^67,69,70

Supplemental Parenteral Nutrition.

Although improvements have been made in the last decade or so at many centers throughout the world, nutritional adequacy has historically still been low in ICUs. One multicenter study of 2,946 ICU mechanically ventilated patients showed an average intake of only 59% of prescribed calories via tube feeding for the first 12 days in the ICU.⁷¹ Many times, the inadequacies come from interruptions in the tube feeding, such as pauses for procedures and, in some cases, being held for multiple hours each day.⁷² Because of this, piqued interest in supplemental parenteral nutrition (SPN) has resulted in recent trials showing that SPN improves energy intake and reduces nosocomial infections, with no increase in hospital mortality or length of stay.^73–75 Thus, we suggest SPN should become routine worldwide for patients not at >70% of nutrition goal for protein and calorie delivery at 72 h post-ICU admission.

Oral Intake.

In patients who no longer require nutrition support in the form of tube feeding or PN, oral intake has also been shown to be inadequate in the critically ill. In a study evaluating 19 patients over the course of 125 days after they were weaned from mechanical ventilation, oral intake only met 71% of predicted energy needs and 46% of predicted protein needs.⁷⁶ Average calorie delivery has been shown to be ~700 kcal/day post-ICU, which is far insufficient to promote recovery.⁷⁷

Perioperative Oral Nutrition Supplements.

Given the prevalence of poor oral intake (PO), the prescription of oral nutrition supplements (ONS) is vital to helping patients achieve adequate calories, protein, and micronutrients to aid in recovery from their illness. A study on the use of early ONS in the postoperative period in colorectal surgery patients showed fewer infectious complications, ICU admissions, and gastrointestinal complications, along with reduced rates of pneumonia.⁷⁸ More studies are needed on using ONS in critical illness and post-ICU recovery, but it appears to be one simple solution to the problem of poor nutritional intake during recovery after the ICU.

Nutrition Care in Post-ICU Hospitalization

The importance of adequate nutrition does not lessen once the patient is discharged from the ICU. Instead, nutritional adequacy should follow a patient well beyond the ICU, and unfortunately, many patients continue with poor nutritional intake during their post-ICU hospitalization.

Oral Intake.

A cohort study published in 2018 assessed the oral intake adequacy of hospitalized patients post-critical illness during a one-month period.⁷⁹ Out of 79 patients assessed, 62% were identified with inadequate oral intake (an average of less than 2/3 meal intake). This study group also showed that in the patients with inadequate oral intake, only 32% were offered an ONS.⁷⁹ A 2019 study evaluated patients’ energy and protein intake after discharge from the ICU.⁸⁰ Among 32 patients evaluated, a median intake of 1238 kcals and 60 gm of protein from all sources was found, translating to 79% [41–108%] of predicted energy needs and 73% [44–98%] of predicted protein needs. The authors found wide ranges in nutrition intake, with median daily deficits in the post-ICU hospitalization period of −442 [−1323 to 186] kcals/day for energy and −30 [−69 to −1] gm/d for protein. Another study evaluated oral intake three months after ICU discharge and found that reductions in appetite, oral intake, and body weight were prevalent, and ICU survivors consumed fewer calories compared to healthy controls (ICU survivors: 1876±708 vs. healthy controls 2291±834 kcal; p = 0.025).⁸¹ Therefore, future work should focus on strategies and interventions to support oral intake adequacy in hospitalized patients recovering from critical illness.

Nutrition Strategies for Post-hospital Discharge

There is also an increased interest in post-hospital discharge nutrition, including the use of oral nutrition supplements (ONS), during recovery at home. A recent systematic review and meta-analysis of 14 studies, including 2480 participants who underwent gastrointestinal surgery, showed that patients who received ONS for at least two weeks after hospital discharge had improved outcomes, including reduced postoperative weight loss, increased serum albumin, and increased hemoglobin.⁸² Another randomized clinical trial studying malnourished, older hospitalized patients showed that patients who received a high protein-HMB oral nutrition supplement during hospitalization and 90 days post-discharge had significantly lower 90-day mortality compared to placebo.⁸³ The number needed to treat to prevent a single death was 20.3 (95% CI 10.9 to 121.4) in this key trial. One study group investigated nutrition intake up to one year following critical illness: In 206 patients studied at 1-month, 3-month, and 12-month post-discharge, both calorie and protein intake was below target goals at all time points (defined as 25 kcal/kg/day and 1.3 g protein/kg/day, respectively).⁸⁴ Further studies, particularly randomized controlled trials, are needed to elucidate the benefits of ONS in post-critically ill patients.

Individually Personalized Nutrition Using Indirect Calorimetry

With the use of indirect calorimetry (IC), we are better able to provide patients with measured nutrition accurately. IC is a method that measures VO₂ and VCO₂, which are used to calculate resting energy expenditure.⁸⁵ In the critical care setting, it can be difficult to estimate a patient’s energy needs based on the degree of critical illness, thus highlighting the importance of objective assessment of resting energy expenditure (REE). IC can benefit patients who are complex and have changing metabolic needs, including inflammation, increased energy needs, and insulin resistance in the critical care setting.^64,85 Utilizing results from IC testing and providing 70% of REE improved patient outcomes compared to feeding > 100% of REE, which was associated with longer ICU days and length of time on the ventilator.⁶² Feeding < 70% of REE was also associated with increased mortality. In addition, IC-directed nutrition recommendations have been found to provide higher amounts of protein and total calories compared to predictive energy equations, and clinical trials and multiple meta-analysis papers have shown significant reductions in mortality when IC-guided nutrition targets are utilized.^86–90 In summary, recent ICU nutrition guidelines suggest targeted energy delivery be started at ~10–15 kcal/kg or <70% of measured-IC REE at ICU admission whether EN/PN is used and be advanced to goal as patient stabilizes.^20,63

There are over 200 predicative energy equations published, which have variable accuracy compared to IC, with accuracy ranging from 40–75%.^63,91 Patients’ acute and chronic conditions can influence metabolic demands that shift throughout a patient’s hospital admission.⁸⁵ There is no estimated equation that is more accurate than IC.⁶³ IC remains the gold standard for determining a patient’s energy needs, especially in the critical care setting.^63,65 Regular IC measurements can provide a greater understanding of metabolic changes during critical illness to guide the dietitian’s recommendations.⁸⁶ The International Multicentric Study Group for Indirect Calorimetry (ICALIC) developed and assessed an indirect calorimetry device, Q-NRG^®, that requires significantly less time than most other IC devices currently used, highlighting recent developments for incorporating IC into routine clinical care.^85,92 In addition, McClave et al.⁹³ reported that a 5-minute steady state reflected 24-hour total energy expenditure for mechanically ventilated patients, further supporting the use and feasibility of IC in the clinical setting. Point-of-care testing in the ICU must move towards implementing IC measures to optimize patient outcomes and personalize nutrition delivery.⁸⁶ European/American guidelines advocate IC to measure EE^20,63 In addition to IC, bedside devices are also available to measure and assess body composition to optimize individualized nutrition delivery.

A recent study that evaluated IC measurements in comparison to estimated equations in the ICU and ward setting reported a significant increase in REE compared to the mean REE within the ICU.⁹⁴ The importance and use of an activity factor in the clinical setting was not discussed, but would be an area for future research. Once a patient is in a step-down level of care, feeding at 100% of their REE (or greater (up to 1.3 × REE) based on rehabilitation activities) is recommended.⁶⁴ There is little research published in the post-hospital phase of care that provides recommendations for utilizing IC measurements in the outpatient setting and would provide a greater understanding to assist patients recovering from a hospitalization. See summary of personalized nutrition care pathway in Figure 2.

Figure 2:

Personalized IC-guided ICU nutrition algorithm. Please note suggested IC measurement days are meant as a guideline to ensure consistent IC-measurements over ICU and hospital stay. IC should optimally be performed 2 times per week in ICU or when a significant clinical change in patient status has occurred. EN, enteral nutrition; IC, indirect calorimetry; ICU, intensive care unit; PN, parenteral nutrition (adapted from Wischmeyer et al.¹²²)

Role of Anabolic Nutrients and Anabolic Agents

Anabolic nutrients are a mainstay for amateur and professional athletes. These are quite potentially relevant to recovering ICU patients due to their ability to increase muscle mass, reduce muscle loss, and improve strength and function. These include creatine, β-hydroxy-β-methylbutyrate (HMB) and leucine.

Creatine

Creatine’s mechanism of benefit is via increased phosphocreatine within cell, which increases ATP production essential for muscle protein synthesis. Recent reviews demonstrate creatine supplementation shows potential benefits in a range of illness and injury states.⁹⁵ Creatine is safe for long-term use in a range of populations in multiple studies.⁹⁶ A recent meta-analysis of 33 RCTs in 1076 older adults with chronic disease showed creatine supplementation improves physical function via sit to stand test, improves upper body muscle strength, handgrip strength and lean muscle tissue.⁹⁷ Given safety and effectiveness, it seems reasonable to consider the use of creatine in recovering post-ICU patients at a dose of 5 gm/day. It is also urgent that high-quality prospective RCTs utilizing creatine to improve physical function, and potentially cognition in post-ICU patients are conducted.

β-hydroxy-β-methylbutyrate

β-hydroxy-β-methylbutyrate (HMB) is a leucine metabolite that stimulates muscle protein synthesis and inhibits muscle protein breakdown via effects on the mTOR pathway; HMB also inhibits inflammation, which may lead to increased muscle catabolism. HMB is a widely studied supplement for trained/untrained athletes.⁹⁸ Many studies have looked at the effects of HMB on recovering patients post-injury and illness. One example was a study of hip fracture patients, which showed improved wound healing and a significant increase in mobile patients at the end of the study period when HMB was utilized.⁹⁹ A recent systematic review in 15 RCTs of 2137 patients by Bear et al.¹⁰⁰ reported improved muscle mass and strength in a range of clinical populations (not in ICU) at risk of muscle wasting. Two recent ICU studies reported no difference in muscle loss, as measured by ultrasound or CT,^101,102 but the possible duration of intervention was likely too short for benefit.^103,104 Finally, as muscle loss due to bedrest is a major contributor to ICU-acquired weakness and PICS, HMB has been shown to markedly reduce or almost eliminate bedrest-related muscle loss in a group of elderly subjects in a well-done study by Deutz et al.¹⁰⁵ HMB also shows great promise to improve muscle mass and reduce muscle loss in the ICU and post-ICU setting; more studies of HMB in the ICU and post-ICU setting in illness and injury are urgently needed, looking at functional outcomes such as the 6-minute walk test.

Testosterone and Anabolic Steroids

In addition to the catabolic effects of critical illness and inadequate ICU nutrition delivery, a majority (~95%) of ICU patients demonstrate severe testosterone deficiency quite early in their ICU stay.¹⁰⁶ Persistent hypotestosteronemia (Low-T) in acute illness is known to impair recovery/rehabilitation, and low-T at hospital admission is known to significantly increase hospital mortality and overall lifetime risk of cardiac events.^106–109 Further, in ICU patients, low-T levels correlate with time on the ventilator, ICU LOS, disease severity, and survival.^106,109 The benefits of testosterone/oxandrolone combined with exercise on clinical outcomes and physical function have been demonstrated in a range of illnesses.^110–112 In burn injury, a range of trials show the benefits of oxandrolone (OX),¹¹³ and oxandrolone is a common standard of care in many burn centers worldwide.¹⁰⁹ Systematic reviews of OX treatment demonstrate significant benefits in burn injury, which include increased lean body mass, improved donor-site healing, reduced weight loss, and reduced LOS without increased risk of liver dysfunction, infection, or hyperglycemia.¹¹⁴ Historically, concerns for testosterone replacement therapy (TRT) being associated with increased cardiovascular/stroke-related events and prostate cancer have been completely dispelled by three large studies.^115–117 The recent TRAVERSE trial, a large RCT published in the New England Journal of Medicine,¹¹⁷ showed in men with low-T levels and preexisting or a high risk of cardiovascular disease, TRT with transdermal testosterone showed no increased risk of cardiovascular events or prostate cancer over ~3 years of follow-up. Further, 2 large recent studies demonstrate that subjects with low-T levels, in fact, have a significant reduction in all-cause cardiovascular events and stroke risk with TRT compared to untreated low-T patients.¹¹⁵ Low-T levels persist into the post-ICU period, with 96% of patients being T-deficient post-ICU.¹¹⁸ Further, research is urgently needed on testosterone repletion to targets of 500–600 ng/dl in men and perhaps lower target levels in women (note there is a large NIH trial of TRT in women post-hip fracture ongoing¹¹⁹) as there are no current studies for interventions with testosterone agents in non-burn post-ICU settings.

Conclusion

Countering the deleterious effects associated with critical illness and addressing patients’ changing care priorities requires a multifaceted rehabilitation approach that focuses on patient-centered, personalized, multi-domain strategies that span the continuum of recovery (See Figure 3). Identifying novel physical rehabilitation strategies and optimizing nutritional and anabolic nutrient/agent approaches for targeting patients’ energy and protein needs are the first steps to promoting meaningful recovery. More research is needed to further develop, implement, and test these strategies, especially in the out-patient setting. In addition, future work should be directed towards interventions that combine physical rehabilitation, nutrition, and anabolic nutrients/agents to minimize ICU-related deficits, optimally build and recover muscle mass, and promote recovery following critical illness.^120,121

Figure 3:

Etiology & Personalized Treatment for Post-ICU Physical Disability. IC- Indirect Calorimetry

Key Points:

• Survivors of critical illness experience significant morbidity, reduced physiological reserve, and health complications that persist long into survivorship.

• Evidence is sparse regarding rehabilitation, nutrition, and anabolic agent/nutrient approaches, especially in the out-patient setting, that improve long-term outcomes and recovery.

• Promising novel strategies include multi-domain interventions, individually tailored exercise prescription, remote rehabilitation delivery, anabolic nutrients (I.e. creatine and HMB), and anabolic agents (I.e. testosterone).

• Individualized nutrition support should follow a patient well beyond the intensive care unit and include strategies to achieve adequate calories, protein, and micronutrient intake.

• More research is needed to further evaluate effectiveness and inform implementation of novel rehabilitation, nutrition, and anabolic nutrient/agent strategies throughout the continuum of care.

Clinics Care Points.

1. Survivors of critical illness are a heterogenous population with varying pathophysiology, symptoms, and impairments. Therefore, a one-size-fits-all approach to rehabilitation may not be ideal for reducing ICU-related deficits and improving long-term outcomes.

2. Although research is limited regarding the effectiveness of post-ICU interventions, current evidence supports the implementation of multi-domain interventions that include two or more components to comprehensively address numerous impairments experienced by critical illness survivors.

3. Current evidence suggests that rehabilitation programs should be prescribed via personalized methods where the exercise prescription is based on each patient’s individual and unique characteristics, exercise capacity, and functional needs. Strategies include using baseline functional assessments to inform exercise prescription, setting personalized target exercise heart rates based on newly affordable portable cardiopulmonary exercise testing, and gradual progression that corresponds to adaptation and improvement.

4. Although early enteral (EN) nutrition is preferred, Early Parenteral Nutrition (PN) and supplemental PN should be a standard of care if patients are not at enteral or oral nutrition goals within 72 hours of ICU admission as new data and ICU nutrition guidelines show enteral nutrition and parenteral nutrition are equally safe and efficacious and can be used interchangeably in the ICU setting.

5. Early and ongoing use of HMB (3 g/day) and creatine (5 g/day) has a strong and growing evidence base from multiple studies and meta-analysis for improving muscle mass, muscle function and outcomes in acute illness, chronic illness, and/or ICU patients. This should be continued in the post-ICU and post-hospital settings.

6. Indirect calorimetry should be utilized in ICU patients after day 3 to set accurate and personalized energy/calorie targets and needs to be repeated regularly throughout ICU stay and the post-ICU period.

7. The majority of ICU and post-ICU patients are testosterone deficient. Especially in male patients (and perhaps in females as well where more data is needed), new data on the safety and benefit of intramuscular or transdermal testosterone replacement therapy (TRT) show TRT in testosterone deficient individuals can be given safely and does not promote cardiac or prostate cancer risk, but instead may reduce cardiac (i.e. myocardial infarction) and stroke event rates and may be effective in improving muscle mass, muscle function, and quality of life as has been shown in burn injury settings, thus demanding further research in broad post-ICU settings.

8. High protein oral nutrition supplements (ONS) are essential in the ICU, post-ICU, and post-hospital setting and have been shown conclusively to improve clinical and functional outcomes in acutely ill patients.