Introduction

Diaphragm dysfunction, atrophy, and weakness in the intensive care units (ICUs) have long plagued the immobile, chronically ill, catabolic patients who represent ICU-acquired weakness (ICUAW) [1•, 2, 3]. Severe sepsis stands as one of the main culprits for promoting ICUAW, which interestingly is also the main culprit of persistent immunosuppression, inflammation, catabolism syndrome (PICS) [4,5,6,7]. What is typically observed in patients with ICUAW as a response to illness is synonymous with the response PICS patients have to sustained catabolism. Using ICUAW as a surrogate for whole body muscle catabolism with wasting, especially in those patients with prolonged mechanical ventilation, we can see how this patient population ends up with diaphragm dysfunction, atrophy, and weakness leading to respiratory insufficiency.

Following severe sepsis, there are simultaneous pro-inflammation (called SIRS) and anti-inflammation (called CARS) systemic responses. In some cases, SIRS becomes overwhelming and can lead to early multiple organ failure (MOF) and even death. Fortunately, modern ICU care is directed at early detection and prevention of this trajectory’s fatal expression. If severe sepsis patients do not die of early MOF, there are two alternatives: Either their aberrant immunology rapidly recovers (i.e., achieves homeostasis) or its dysfunction persists and they enter chronic critical illness (CCI) (defined as >14 days in ICU with organ dysfunction). These CCI patients experience ongoing immunosuppression (e.g., lymphopenia) and inflammation (e.g., neutrophilia) that is associated with a persistent acute-phase response (e.g., high CRPs) with ongoing protein catabolism (Fig. 1). It is within this arena that intensivists witness the significant lean muscle mass of ICUAW, diaphragm dysfunction, and ongoing catabolism [8••].

Fig. 1
figure 1

Used with permission from the Wolters Kluwer Health

Full size image

Even despite aggressive nutritional intervention, there is a tremendous loss of lean body mass and proportional decrease in functional status (including respiratory dysfunction from diaphragm atrophy) and poor wound healing. An estimated 30 to 50% of these CCI patients progress into PICS. Clinically, PICS patients suffer from recurrent nosocomial infections and poor wound healing, develop decubitus ulcers and ICUAW, and typically have prolonged mechanical ventilation leading to diaphragm atrophy. These patients typically undergo tracheostomy for respiratory insufficiency and are discharged to long-term acute care (LTAC) facilities where they experience sepsis recidivism requiring re-hospitalization, failure to rehabilitate, and an indolent death [9].

PICS and ICU-Acquired Weakness

The loss of lean body mass in patients with prolonged ICU stays is dramatic. In a classic study, Graham Hill and colleagues performed serial body composition by bioimpedance studies in critically injured patients over 25 days in the ICU. They demonstrated that despite optimal nutritional support, there was an obligatory 16% loss of lean body mass and that excessive administration of substrates was converted into fat. This tremendous loss of lean body mass was recently confirmed by Puthucheary et al. who performed serial ultrasound of the rectus femoris over the first 10 days of ICU stay and demonstrated a 20% decrease in cross-sectional area (CSA) and that a subset of MOF patients lost 30%. Interestingly, at 7 days, protein synthesis was variably increased, but continual breakdown led to negative protein balance despite all patients being fed. Muscle biopsies looking at intracellular regulators of protein homeostasis revealed decreased anabolic and increased catabolic signaling [10]. These studies indicate that simply giving macronutrients is not going to reverse the loss of lean body mass and that interventions are needed to promote anabolism.

Despite best efforts, persistent inflammation increasing metabolic demand, protein catabolism, and disuse atrophy (immobilization of ICU patients) promotes ICUAW. A better understanding of possible intervention could potentially help both patient populations: those with ICUAW and those with PICS. It should be made clear in this manuscript that the authors are not suggesting that all ICUAW patients have PICS, but it is certain that all PICS patients have some varying degree of ICUAW.

PICS and Diaphragm Dysfunction

It has long been accepted that prolonged mechanical ventilation causes diaphragm atrophy, weakness, and ventilator-induced diaphragm dysfunction (VIDD), which can lead to a multitude of poor outcomes including extubation failure, tracheostomy, and pneumonia and even increases mortality [11,12,13]. Irrespective of the etiology for prolonged mechanical ventilation, patients typically have varying degrees of ICUAW. In an elaborate study by Jung et al., diaphragm function was assessed in 185 patients mechanically ventilated for >48 h. Diaphragm function was assessed by magnetic stimulation of the phrenic nerve while observing change in endotracheal pressure. Of the 185 patients, 40 were diagnosed with ICUAW (based on a Medical Research Council Score <48) and 80% had diaphragm dysfunction defined by an endotracheal pressure change of less than 11 cmH2O. They concluded that diaphragm dysfunction correlates with ICUAW [13].

This study demonstrates that as a muscle group, the diaphragm is certainly not spared when patients acquire muscle weakness in the ICU. Traditionally, many think of ICUAW afflicting voluntary muscles and the weakness associated with inability to ambulate, but ICUAW spares no muscle group and can have lasting implications on health care cost and recovery. In fact, Hermans et al. published that the cost for this patient population is typically 30.5% higher than a propensity-matched cohort [14]. Various hypotheses have been proposed to why ICUAW occurs: disuse atrophy, protein catabolism, cytokine milieu, decreased nerve stimulation, or a combination of these factors. It is not surprising that cross talk occurs between aggravating factors for ICUAW, VIDD, and PICS, including malnutrition, chronic electrolyte imbalance, hyperglycemia, corticosteroids, muscle relaxants, sepsis, and compromised cardiac function [15, 16].

The PICS patients represent an ongoing catabolic state with tremendous metabolic demand associated with inflammation; the observation seen by Jung et al. should be applied to PICS patients as they have all been critically ill with varying degrees of ICUAW. Despite best efforts in nutritional support, the PICS patient continues to have a net negative protein balance correlating with ICUAW and associated diaphragm dysfunction. De Jonghe demonstrated an association between respiratory weakness and limb weakness [17]. ICU patients that have difficulty ambulating after critical illness would have ICUAW. If the same patient with ICUAW continues to be critically ill for 14 days, they would have CCI and may fall into the realm of a PICS patient if there is laboratory evidence of ongoing inflammation, immunosuppression, and catabolism (i.e., elevated CRP, low pre-albumin or visceral proteins, and reduced lymphocyte count). With the information provided by Jung and De Jonghe, intensivists should be more diligent towards rehabilitating the pulmonary muscle, as well. These patients should receive physical therapy directed at strengthening both limb muscles and pulmonary muscles and optimizing supplemental nutrition where appropriate, for example increasing protein calories (perhaps an argument for immunomodulatory, immune-enhancing formulas).

PICS and Nutritional Supplementation

After reviewing the literature, several possible therapies became apparent to overcome some of the immunosuppression, inflammation, and catabolism. For the sake of brevity, there are three supplements should be discussed to bring awareness to possible new practices. These supplements decrease the persistent inflammation (specialized pro-resolving mediators), restore immune competence (arginine), and help rebuild lean muscle and combat catabolism (leucine).

Specialized pro-resolving mediators (SPMs) are a purified fish oil that promote resolution of the aberrant inflammatory cascade and could potentially prevent patients with chronic critical illness from progressing to the chronic PICS phenotype [5, 18]. Serhan et al. discovered that SPMs have the ability to decrease inflammation by cessation of leukocyte infiltration and activation and “pro-resolve” inflammation through enhanced macrophage clearance of debris, bacteria, and apoptotic cells [18, 19].

Arginine is an interesting substrate that could help reverse some of the immunosuppression associated with sepsis. It is well established that arginine depletion occurs with increased states of stress [20]. Arginine is structurally part of the zeta chain on T cell receptor (TCR), and arginine deficiency has been shown to render T cells incompetent [21,22,23,24,25,26,27,28]. By supplementing arginine, studies have shown improved T cell function, proliferation, and maturation to better fight infections [28,29,30,31,32,33,34].

Leucine is an amino acid that can stimulate the mammalian target of rapamycin (mTOR) pathway to increase protein synthesis and inhibit proteosomal protein breakdown. Leucine stimulates multiple enzymes that ultimately increase either mRNA to produce anabolism (protein synthesis). Through leucine supplementation and mTOR signaling, a PICS patient ought to reduce catabolism and enter an anabolic state to regain muscle mass, increase the possibility of rehab, and regain baseline function/independence once discharged from the ICU.

These three supplements provide interesting possibilities in treating an ever-growing MOF phenotype: PICS. The implications may not be limited with PICS. Further research is warranted to determine whether these supplements have a therapeutic role in treating ICUAW and diaphragm dysfunction, atrophy, and weakness.

Conclusions

Patients with diaphragm dysfunction, ICUAW, and even PICS suffer poor, long-term consequences; typically use tremendous hospital resources; and can be a lofty burden on health care cost. By bringing awareness to an increasingly more prevalent phenotype, PICS, we see that ICUAW and diaphragm dysfunction lie along a spectrum. If the disability lasts long enough, these patients could progress to PICS, which ultimately has a worse prognosis. There is an overwhelming need for more concrete research to combat diaphragm dysfunction, ICUAW, and PICS. Future clinical trials will hopefully elucidate if the three supplements discussed above truly have a positive impact on patient care.