Background: Sepsis continues to cause significant morbidity and mortality despite technological advancements in medical management. While sepsis is defined as organ dysfunction owing to the dysregulated host response to infection, our understanding of the dysregulation of the host response remains incomplete. Summary: Many metabolic derangements that occur during sepsis, including those associated with anorexia, hyperglycemia, and proteolysis, have largely been considered maladaptive. Supportive medical and nutritional interventions targeted at correcting these metabolic derangements have not led to improved outcomes, suggesting a reappraisal of our approach to metabolism and nutrition in critically ill septic patients is needed. Key Messages: Explanations of the lack of efficacy of these clinical interventions may include targeting the wrong metric or patient population, or the possibility that some of these metabolic changes could be protective. In this mini-review, we propose a paradigm shift that is needed in metabolism and nutrition management in sepsis.

Despite the availability of broad-spectrum antibiotics and life-supporting technologies, sepsis remains a major cause of morbidity and mortality. While the most recent clinical consensus defines sepsis as organ dysfunction owing to the dysregulated host response to infection [1], it is unclear whether many metabolic derangements associated with sepsis, including metabolic changes associated with poor appetite, hyperglycemia, and proteolysis, are truly dysregulated and pathologic. Many clinical interventions to correct these presumed metabolic derangements have not improved outcomes. The failure to improve outcomes raises questions about our current approach to managing metabolism and nutrition in septic patients.

An effective host response requires both disease resistance and tolerance. Disease resistance includes pathogen recognition and clearance, while tolerance encompasses the activation of pathways that limit tissue damage resulting from the inflammatory response [2]. In fact, disease tolerance pathways could include metabolic and physiologic responses to promote tissue protection and organismal survival. Certain metabolic derangements observed in sepsis could reflect disease tolerance pathways, and our attempts to correct the metabolic derangements could inadvertently interfere with these protective pathways. This mini-review will briefly examine whether we should re-consider how we approach nutrition and metabolism in septic patients.

Over the last decade, there has been a deeper understanding of the biochemical and immune changes that occur in sepsis. There is the initial hyperinflammatory phase, which manifests as hemodynamic changes such as fever, shock, and the ensuing multiorgan dysfunction, and hypermetabolism, including anorexia, hyperglycemia, and proteolysis. This phase is followed by immunosuppression which is thought to be driven by an impaired immune system [3]. The current management of sepsis focuses on early recognition, hemodynamic resuscitation, source control, and organ support. However, effective management strategies to approach inflammation, metabolism, glycemic control, and nutritional targets remain unsettled. Thus, there is a need for a better understanding of how metabolic changes contribute to sepsis in general and specifically to the manifestation of each phase.

Not only does sepsis differ from other critical illnesses, but there is also apparent heterogeneity in the morbidity and mortality of sepsis. This is understood to be driven by the hyperinflammatory response, which, in turn, is affected by multiple factors such as age, comorbidities, nutritional status, and the extent of the infection, including type, pathogen load, and virulence [3]. Studies have attempted to classify patients into subphenotypes categorized by protein biomarkers or mRNA transcriptional patterns, which are associated with differences in morbidity and mortality outcomes [4]. In preclinical work, we have shown heterogeneity in metabolic responses when comparing viral and bacterial infections, where early feeding improved survival in viral infections, while feeding increased mortality in bacterial infections [5]. Thus, interpreting negative results from clinical trials with heterogeneous critically ill cohorts can mask important subphenotypes.

Energy metabolism during sepsis continues to be incompletely understood. While we are yet to fully delineate the role and regulation of energy expenditure during sepsis, clinically, we do not systematically or accurately measure energy expenditure at the bedside. While major guidelines recommend indirect calorimetry, it is not widely available, and thus, highly inaccurate equations are still standard practice. These equations that estimate energy expenditure also cannot account for changes in metabolism during the disease course. While we assume critically ill patients are hypercatabolic, patients can exhibit hypocatabolism depending on the type, stage, and severity of their illness [6, 7]. As a result, many patients could be either overfed or underfed.

Many recent clinical studies of nutrition in the ICU focused on total calories. However, whether the quantity and timing of specific calories could modify the outcomes in critical illness is unknown. Prior studies have shown that septic patients have suppressed glucose oxidation and increased fatty acid oxidation (FAO) [8]. Is this metabolic pattern pathologic, or potentially a beneficial defense mechanism? Our preclinical studies suggest that glucose metabolism is detrimental in bacterial sepsis, while fasting metabolism is protective [5]. Activation of FAO is a central component of fasting metabolism. Importantly, a large body of evidence from preclinical studies shows that enhancing FAO prevents septic organ damage, while inhibition exacerbates septic tissue injury [9]. This suggests that FAO could be the preferred metabolic program during sepsis. Given this possibility, a re-evaluation of the NICE-Sugar trial [10] is needed. While patients in the intensive glycemic control arm had more hypoglycemic events, the presumed cause of increased mortality, they also received more insulin and glucose. The increased glucose and insulin administration would lead to increased glucose oxidation and inhibition of FAO. This raises the possibility that insulin and its downstream metabolic consequences of shutting down protective metabolic pathways, but not glycemic control per se, could be driving mortality.

Not only do we have a poor understanding of and an inability to measure substrate preferences, we are also unable to measure the capacity for substrate utilization in sepsis. One example is how we approach proteolysis and negative nitrogen balance in sepsis. We presume that higher dietary protein intake would be sufficient to counter poor outcomes associated with negative nitrogen balance. However, randomized controlled trials have not shown benefit [11, 12]. The assumption that patients can utilize administered dietary protein is a major limitation. Patients who remain inflamed will likely have minimal capacity for dietary protein utilization. Moreover, due to the inability to measure the capacity for dietary protein utilization, we are unable to identify patients who would definitively benefit from high protein feeding versus those in whom high dietary protein administration is, at best, not beneficial and, at worst, harmful.

There is a clear need for future research. We have limited tools for measuring substrate preferences and the capacity for substrate utilization in sepsis. We need a better understanding of metabolic pathways in sepsis, how to measure them, and what biomarkers mean. Sepsis is a complex, highly dynamic condition that requires attention to the differences in disease phases and temporal changes. Metabolic and nutritional needs will also differ among critical illnesses of different etiologies and, most likely among septic patients with different infectious sources.

While we wait for future research to shed light on changes to our clinical management, practical approaches can be implemented in our management of septic patients. The first is to know what we are feeding our patients, both intentionally with enteral or parenteral feeds and also with dextrose-containing intravenous solutions. Total dextrose exposures from intravenous medications and fluids as well as carbohydrates from enteral feeds are not often considered in the day-to-day management of critically ill patients and could have significant relevance, especially in patients with bacterial sepsis. One alternative approach in managing insulin resistance and hyperglycemia in sepsis is to limit glucose and carbohydrate exposure, thereby limiting obligate insulin requirements. As there is emerging evidence of potential insulin toxicity in sepsis independent of glycemic control and hypoglycemia [13], a glycemic control approach that can limit insulin exposures could be of benefit. This approach would then prevent downstream effects of excess insulin signaling, such as inhibiting FAO. The second is to consider potential harm. While extra protein could be merely wasted as ureagenesis [14], there could be potential harm in giving excess dietary protein. The recently published data from the EFFORT randomized controlled trial further suggest that not only does high protein feeding not improve mortality, it may also be harmful in certain subgroups, such as patients with significant organ dysfunction, including acute kidney injury [12]. Urea diuresis, for which excess dietary protein is a known risk factor, is a common cause of hypernatremia, a known cause of increased mortality among critically ill patients [15].

Some metabolic derangements observed in sepsis could be important components of host defense mechanisms that promote disease tolerance. Therefore, it is crucial that we take further steps to differentiate maladaptive from protective metabolic pathways as well as unravel the mechanisms and regulation of protective metabolic pathways in sepsis. There is a need to develop ways of measuring substrate preference and the capacity for utilization. Further studies are needed to define how metabolism differs during various phases of sepsis and how metabolism in sepsis differs from other critical illnesses. A critical appraisal of our current clinical approach in the management of metabolism in critical illness urges the need to consider alternative approaches and more research (summarized in Table 1). A fundamental understanding of the metabolic determinants of tissue protection and survival in sepsis will be essential to further developing and improving medical management that may reduce morbidity and mortality.

Table 1.

Reappraisal of the current clinical approach to metabolism and nutrition in critical illness

Current clinical approachAlternative approach
Caloric supplementation Energy requirements are estimated with inaccurate equations Measurement of energy requirements throughout course of illness 
No adjustment based on substrate preferences or capacity for utilization Determine substrate preferences (fatty acid vs. glucose oxidation) and develop methods to determine capacity for substrate utilization 
Glycemic control Conservative correction of hyperglycemia with insulin to avoid hypoglycemia Decrease carbohydrate exposures to decrease obligate insulin requirement to avoid the negative effects of excess insulin signaling 
Management of negative nitrogen balance High-protein feeding to decrease negative nitrogen balance Consider the extent of concurrent inflammation (inability to utilize dietary protein) 
Determine capacity for protein utilization to identify patients and time points at which dietary protein can be efficiently utilized for protein synthesis 
Current clinical approachAlternative approach
Caloric supplementation Energy requirements are estimated with inaccurate equations Measurement of energy requirements throughout course of illness 
No adjustment based on substrate preferences or capacity for utilization Determine substrate preferences (fatty acid vs. glucose oxidation) and develop methods to determine capacity for substrate utilization 
Glycemic control Conservative correction of hyperglycemia with insulin to avoid hypoglycemia Decrease carbohydrate exposures to decrease obligate insulin requirement to avoid the negative effects of excess insulin signaling 
Management of negative nitrogen balance High-protein feeding to decrease negative nitrogen balance Consider the extent of concurrent inflammation (inability to utilize dietary protein) 
Determine capacity for protein utilization to identify patients and time points at which dietary protein can be efficiently utilized for protein synthesis 

The authors have no conflicts of interest to disclose.

This work was supported by the National Institutes of Health Grant R35GM137984 to S.C.H.

Kristina Collins and Sarah Huen both wrote and edited this manuscript and approved the final version.

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