Higher caloric intake through enteral nutrition is associated with lower hospital mortality rates in patients with candidemia and shock in Taiwan
Article information
Abstract
Background
Candidemia is associated with markedly high intensive care unit (ICU) mortality rates. Although the Impact of Early Enteral vs. Parenteral Nutrition on Mortality in Patients Requiring Mechanical Ventilation and Catecholamines (NUTRIREA-2) trial indicated that early enteral nutrition (EN) did not reduce 28-day mortality rates among critically ill patients with shock, the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend avoiding EN in cases of uncontrolled shock. Whether increased caloric intake from EN positively impacts clinical outcomes in patients with candidemia and shock remains unclear.
Methods
We retrospectively collected data from a tertiary medical center between January 2015 and December 2018. We enrolled patients who developed shock within the first 7 days following ICU admission and received a diagnosis of candidemia during their ICU stay. Patients with an ICU stay shorter than 48 hours were excluded.
Results
The study included 106 patients, among whom the hospital mortality rate was 77.4% (82 patients). The median age of the patients was 71 years, and the median Acute Physiology and Chronic Health Evaluation II score was 29. The Cox regression model revealed that a higher 7-day average caloric intake through EN (hazard ratio, 0.61; 95% CI, 0.44–0.83) was significantly associated with lower hospital mortality rates. Our findings suggest EN as the preferred feeding route for critically ill patients with shock.
Conclusions
Increased caloric intake through EN may be associated with lower hospital mortality rates in patients with candidemia and shock.
INTRODUCTION
Candida species, commonly found as commensal yeasts in various bodily locations such as the mouth, throat, gums, vagina, and skin, typically coexist in humans without inducing disease [1]. Invasive candidiasis denotes severe infection instigated by Candida species and can affect diverse anatomical sites such as the bloodstream, heart, brain, eyes, or bones [2]. Among critically ill patients, invasive candidiasis is the most prevalent invasive fungal infection [3], with an estimated global incidence of around 700,000 cases annually [4].
Intensive care unit (ICU) admission is a major risk factor for candidiasis [5,6]. Moreover, candidemia is a severe condition involving the presence of Candida species in the bloodstream. Candidemia has been associated with high mortality rates. In a retrospective study by Charles et al., which included 51 candidemia patients from both surgical and medical ICUs, the overall mortality was 60.8% [7]. Another study, conducted by Schroeder et al. [8], enrolled 391 candidemia patients from a mixed surgical and medical ICU. The 28-day mortality rate in their study was 47%, which increased to 60% after 180 days [8]. Risk factors for candidemia in critically ill patients include liver cirrhosis history, septic shock, a high Candida score, and prolonged ICU stay [8]. Studies have demonstrated that prompt removal of contaminated central venous catheters and early initiation of antifungal therapy can reduce mortality associated with candidemia [9-11].
In general, enteral nutrition (EN) is the preferred route for caloric intake in critically ill patients, except those with overt shock [12,13]. However, the Impact of Early Enteral vs. Parenteral Nutrition on Mortality in Patients Requiring Mechanical Ventilation and Catecholamines (NUTRIREA-2) trial revealed that EN did not reduce hospital mortality in patients with shock compared with full nutrition by parenteral nutrition (PN) in the first 7 days after enrollment; moreover, patients who received EN had more frequent gastrointestinal complications [14]. Nevertheless, other studies have reported that total PN without enteral feeding was associated with an increased risk of candidemia [15,16]. One possible explanation for this increased risk is Candida colonization in the gastrointestinal tract [1]. Candida species usually reside in the human gastrointestinal tract as commensal organisms [2]. However, if there is a disruption in the intestinal barrier, these organisms can enter the bloodstream, potentially causing systemic infections [2,17].
Gut barrier dysfunction and the impact of fasting have been observed in animal models, with fasting associated with an increased risk of candidemia [18]. Patel et al. [19] reported that early trophic EN without extra PN use was linked to reduced Candida colonization in patients with septic shock. Despite these findings, the ideal quantity of EN for patients with candidemia and shock remains uncertain. Therefore, this study was conducted to explore whether augmenting caloric intake via EN could decrease hospital mortality rates in patients with candidemia and shock.
MATERIALS AND METHODS
Study Design and Patient Enrollment
This retrospective cohort study was conducted in the surgical and medical ICU of Taichung Veterans General Hospital between January 2015 and December 2018. The study was approved by the Institutional Review Board Taichung Veterans General Hospital (No. CE19376A). The study enrolled patients who experienced shock within the first 7 days following ICU admission, received a candidemia diagnosis during their ICU stay, and experienced respiratory failure necessitating ventilator support. We excluded patients aged less than 18 years and those with an ICU stay less than 48 hours. Informed consent was waived by the IRB due to the retrospective study design, and all data extracted from medical charts were de-identified. Shock was defined as blood pressure and tissue perfusion prompting any of several vasoactive drugs administered via central venous catheter. The vasoactive drugs used included adrenaline, dobutamine, dopamine, or noradrenaline. Invasive candidiasis refers to severe infections caused by Candida species, which can affect various anatomical sites such as the bloodstream, heart, brain, eyes, or bones [2]. Candidemia was defined as the presence of Candida species in the blood.
The EN protocol used for all participants followed a standardized regimen across the study ICUs. This protocol was based on a modified version of the Enhanced Protein-Energy Provision via the Enteral Route Feeding (PEPuP) protocol, employing a volume-based feeding approach [20,21]. EN was initiated on day 1 and gradually increased to the target rate by day 2. The daily energy requirement was estimated using a simple weight-based equation (25 kcal/kg/day). A semi-elemental EN formula was used initially, along with prophylactic intravenous metoclopramide (10 mg every 8 hours) to enhance digestion. If gastric residual volumes (GRVs) exceeded 250 ml in two consecutive measurements, erythromycin (250 mg every 12 hours) was introduced. The GRV threshold was set at 250 ml, and continuous pump feeding was employed.
Data Collection
We collected data on basic demographics, including age, sex, body weight, comorbidities, Sequential Organ Failure Assessment (SOFA) score, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. Nutritional risk was evaluated using the Modified Nutrition Risk in the Critically Ill (mNUTRIC) score, comprising age, APACHE II score, SOFA score, number of comorbidities, and days of hospitalization before ICU admission. A score ≥5 indicated a high nutritional risk, while a score <5 indicated a low nutritional risk [22,23]. We calculated the average caloric intake during the initial 7 days accounting for both EN and PN. The caloric calculation for EN was determined by summing the total daily volume of EN and its caloric density per milliliter. In contrast, the caloric calculation for PN encompassed the total caloric contributions from PN solutions, propofol, and intravenous dextrose. For patients with fewer than 7 days of stay in the ICU, caloric intake data were calculated based on the actual duration of their stay. The decision to implement non-EN status was made by the clinical physician.
Outcome Measurement
The study assessed various outcomes, including hospital mortality, duration of hospital stay, length of ICU stay, and duration of mechanical ventilation.
Statistical Analysis
Data were analyzed using SPSS statistical software version 22.0 (IBM Corp.). Either the Student t-test or the Wilcoxon rank-sum test was used to compare continuous variables between the study groups. The chi-square test or Fisher exact test was used to compare categorical variables between the study groups. Cox regression analysis was used to assess factors associated with mortality, and hazard ratios (HRs) along with 95% CIs were derived to demonstrate the strength of the associations. The variables selected for inclusion in the multiple regression model were those with a P-value <0.05 in the univariate analysis. Additionally, we assessed multicollinearity by examining the variance inflation factor (VIF) for each variable included in the model. All variables passed the VIF examination, indicating that multicollinearity was not a concern and that each variable is independent of the others. All tests were two-sided, and a P-value <0.05 was considered statistically significant. We added a time-dependent variable to test the model, and the P-value was non-significant (P=0.492). The Harrell's C-index for the final model in our study was 0.69.
RESULTS
This study enrolled 106 patients (Figure 1), with an overall hospital mortality rate of 77.4% (82 of 106 patients). The median age was 71 years, with a median APACHE II score of 29 and a day 1 SOFA score of 10. The average body mass index (BMI) was 22.5 kg/m2. Most patients (63.2%) were recruited from the medical ICU. The median caloric intake of EN and PN in the first 7 days of ICU admission was 18.2 kcal/kg/day. The median mNUTRIC score was 6, with 91 patients (85.8%) classified as high nutrition risk (Table 1). The day 1 SOFA score was significantly higher in the non-survivor group compared to the survivor group. Additionally, the median caloric intake from enteral and parenteral nutrition (EN+PN) during the first 7 days was significantly higher in the survivor group than in the non-survivor group (1,391 kcal vs. 1,011 kcal, P=0.047).
Patient recruitment and study flow.
Patients’ demographic characteristics, clinical outcomes, and energy intakes between survivor and non-survivor groups
Regarding outcome measurements, the duration of hospital stay and mechanical ventilation were significantly shorter in the non-survivor group compared to the survivor group (Table 1). The non-EN and EN groups differed primarily with respect to the 7-day median caloric intake through EN or PN. Nevertheless, the groups had similar total caloric intake rates (Table 2). In the univariate analysis using the Cox regression model, the results indicated that both the 7-day average caloric intake via EN (HR, 0.75; 95% CI, 0.57–0.98) and the 7-day average caloric intake via PN (HR, 0.47; 95% CI, 0.26–0.86) were associated with reduced hospital mortality rates. However, when we included multiple factors in the Cox regression model, the 7-day average caloric intake through EN was linked to lower hospital mortality (HR, 0.61; 95% CI, 0.44–0.83), while ICU stay was associated with higher hospital mortality (HR, 2.24; 95% CI, 1.18–4.23) after adjusting for age, sex, SOFA score, and 7-day average caloric intake via PN (Table 3).
Energy intake between non-EN before candidemia and EN before candidemia groups
Adjusted hazard ratio of hospital mortality
DISCUSSION
Our findings suggest that increased caloric intake through EN may be associated with lower hospital mortality rates in patients with candidemia and shock. Higher caloric intake through EN is significantly linked to a reduced risk of hospital mortality (HR, 0.61; 95% CI, 0.44–0.83). These findings indicate that increasing EN for these patients could lead to improved outcomes. Candida species are widely recognized as commensal organisms residing in the human gastrointestinal lumen [2]. However, Candida species from this gastrointestinal source can lead to systemic infections in critically ill patients, patients undergoing abdominal surgery, and immunocompromised patients [2,24]. A possible reason for this phenomenon is that disruption of the intestinal barrier can allow Candida species to enter the bloodstream or other parts of the body, causing systemic infections [2,17].
During episodes of circulatory shock, reduced splanchnic blood supply can lead to impaired oxygen delivery to the villous tips, predisposing patients to hypoperfusion [25]. Additionally, systemic inflammation can disrupt tight junctions, further compromising the intestinal barrier [26,27]. Such critical conditions can accelerate microbial invasion of the intestinal wall and activate virulence factors [28,29]. EN can help maintain the integrity of the mucus layer and defense mechanisms against pathogens [30,31]. Accordingly, fasting before a confirmed candidemia diagnosis could impair the integrity of the intestinal mucosa and potentially exacerbate clinical outcomes. Our results are consistent with these insights, demonstrating that a higher caloric intake through EN may reduce hospital mortality rate for patients with circulatory shock and candidemia.
Clinical studies have provided conflicting findings regarding the benefits of fasting or EN in critically ill patients [32]. For example, a previous study reported that fasting in the early phase of a critical illness was associated with potential benefits such as improving autophagy, enhancing ketogenesis, and providing cell-protective effects [32]. However, recent randomized controlled trials (RCTs) investigating the effects of early caloric supplementation through PN in critically ill patients have not confirmed these benefits [33]. Specifically, the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients trial and its preplanned sub-studies have demonstrated that early caloric supplementation through PN did not prevent muscle atrophy and did prolong the duration of renal replacement therapy [34,35]. Similarly, other RCTs have reported that additional amino acid supplementation through PN appeared to be detrimental to renal recovery [36,37].
Overt circulatory shock is recognized as a contraindication for EN [13,38]. The NUTRIREA-2 trial found that EN in patients with shock was associated with a higher rate of gastrointestinal complication compared with PN; similarly, the NUTRIREA-3 trial demonstrated that increasing the amount of EN in shock patients was associated with a higher incidence of gastrointestinal complication compared to those receiving lower amounts of EN. Despite these findings, neither study observed significant differences in mortality rate between the groups [14,39]. The Augmented Versus Routine Approach to Giving Energy (TARGET) trial also revealed that most patients receiving EN along with vasopressors did not have higher 90-day mortality rates compared with patients receiving other interventions [40]. Furthermore, Patel et al. [19] conducted a small phase 3 pilot study involving ventilated patients with septic shock. The study enrolled 31 patients, with 15 randomized to receive early trophic EN and 16 receiving no EN. Interestingly, the candida isolation rate was significantly lower in the early EN group compared to the no EN group. This suggests that early EN may potentially reduce the candida load and decrease the likelihood of candida isolation; this finding is consistent with our findings. Our study underscores the potential benefit of a higher caloric intake through EN in reducing hospital mortality rates among patients with candidemia and shock. The aforementioned large RCTs have not demonstrated superiority of EN over PN in critically ill patients; nevertheless, the benefit of a higher caloric intake through EN in our patients with candidemia might be attributed to its potential in reducing the pathogen burden, ultimately leading to improved outcomes.
To achieve the target amount of enteral feeding in critically ill patients, various barriers must be overcome [41]. ASPEN guidelines recommend feeding protocols to optimize EN in these patients, which has been shown to increase caloric intake [21,42]. However, achieving predicted caloric intake remains challenging, as demonstrated in previous clinical trials. For instance, in the PermiT study by Arabi et al. [43], the permissive underfeeding group received only 46% of calculated caloric requirements (compared to the recommended range of 40 to 60%), while the standard enteral feeding group received 71% of calculated caloric requirements (compared to the recommended range of 70 to 100%). In the TARGET trial, which investigated the impact of an energy-dense formula versus routine EN in critically ill patients, the overall caloric intake in the 1.0-kcal group was 17.4 kcal/kg/day [40]. Even in well-designed RCT trials, real caloric intake often falls below expectations. In our study, the median actual caloric intake reached 18.2 kcal/kg/day. Although achieving full or even 70% of estimated caloric intake remains challenging, our findings align with the ASPEN guideline recommendation of 12–25 kcal/kg/day.
The PermiT study and TARGET study failed to demonstrate beneficial effects of increased calorie intake on patient outcomes [40,43]. However, there were notable differences in disease severity among patients in those studies. In the PermiT study, the APACHE II score was 21, with an average patient age of 51 years, and 55%–57% of shock patients required vasopressors. In the TARGET study, the APACHE II score was 22, with an average patient age of 57 years, and 63% of shock patients required vasopressors. In contrast, our study had an APACHE II score of 29, a median age of 71 years, and 100% of shock patients required vasopressors. Additionally, 42.3% of patients in the PermiT trial were at high nutritional risk, compared to 85.8% in our study. These findings indicate a higher disease severity in our study compared to both the PermiT and TARGET studies. Furthermore, a larger proportion of patients in our study was classified as high nutritional risk compared to that in the PermiT trial. Several retrospective studies suggest that higher caloric intake may be associated with lower mortality in patients at high nutritional risk, which might partially explain our study results [42,44,45].
In a recent retrospective multicenter study conducted in Brazil from 2010 to 2018, 397 candidemia patients were enrolled. The average age was 64 years, and the 30-day mortality rate in critically ill patients was 65% [46]. In another multinational observational cohort study conducted in 2018, the overall 90-day mortality rate among 632 patients was 43%. ICU admission was identified as one of the independent predictors for mortality [47]. However, disease severity indicators such as the APACHE II score and hemodynamic status were not reported. Regarding studies on circulatory shock and candidemia, Bassetti et al. [48] conducted a multicenter study involving 216 patients and reported a 30-day mortality rate of 54%. They identified lower APACHE II scores, appropriate antifungal therapy, and source control as key factors associated with reduced mortality. In contrast, our single-center cohort study revealed a higher hospital mortality rate (77.4%). Moreover, Bassetti et al. [48] reported an average APACHE II score of 23, whereas our study revealed an average APACHE II score of 29. This difference in disease severity might explain the higher mortality rate in our study. Additionally, our study primarily focused on the routes and status of nutrition and did not include detailed data on the use of antibiotics. Microbial translocation warrants consideration in critically ill patients with circulatory shock. Although all patients in the present study had documented candidemia, determining the definitive luminal source or the potential of EN in reducing the pathogen burden was challenging.
Higher protein intake is essential for critically ill patients, but the optimal amount remains a topic of debate. ASPEN guidelines recommend 1.2–2.0 g/kg/day [42], while European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines suggest 1.3 g/kg/day [13]. A recent RCT by Reignier et al. [39] found that reducing caloric and protein intake in early-stage shock patients did not reduce 90-day mortality compared to normal intake levels. Heyland et al. conducted another RCT comparing high-dose protein (≥2.2 g/kg/day) to the usual dose (≤1.2 g/kg/day) intake in high-nutrition-risk patients. Intriguingly, higher protein doses not only failed to decrease 60-day mortality, but might have worsened outcomes for patients with acute kidney injury [49]. In our study, more than 85% of high-nutritional-risk patients had shock, raising questions about the role of protein intake. Unfortunately, our data lacked protein intake amounts due to the retrospective study design. Further well-designed studies are needed to explore this issue.
This study has several limitations that merit discussion. First, the retrospective design limited our ability to establish causal relationships, in contrast to prospective designs. Second, because the study findings were obtained from a single center, they may not be generalizable to other medical institutions or populations; hence, external validation is necessary. Third, owing to the limitations of retrospective data collection, accurate vasopressor dosages were not reported, introducing a potential confounding factor. Fourth, the study did not report protein consumption levels, which could serve as another confounding factor affecting clinical outcomes.
Despite the aforementioned limitations, our study has several strengths. First, the medical team successfully delivered >70% of the median energy target, demonstrating the team's effectiveness in overcoming the challenges associated with nutritional support. Second, we calculated nutritional risks for all patients, and we determined that more than 86% of the patients had a high nutritional risk; the medical team prescribed a higher rate of estimated caloric intake to meet the nutritional needs of these patients.
Our findings suggest that a higher caloric intake through EN might be associated with lower hospital mortality rates in patients with candidemia and circulatory shock. However, additional comprehensive prospective studies are warranted to validate our findings and address our study limitations.
KEY MESSAGES
▪ The study investigates the impact of early enteral nutrition (EN) on hospital mortality rates in critically ill patients with shock and candidemia given the mixed evidence on the benefits in such patients.
▪ A higher 7-day average caloric intake through EN was significantly associated with lower hospital mortality rates, with a hazard ratio of 0.61.
▪ Increased caloric intake through EN may be beneficial and may be considered the preferred feeding route for critically ill patients with shock and candidemia, potentially leading to lower mortality rates.
Notes
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
FUNDING
This study was supported by the Department of Medical Research of Taichung Veterans General Hospital (TCVGH-1124403C).
ACKNOWLEDGMENTS
None.
AUTHOR CONTRIBUTIONS
Conceptualization: CYW, TJW. Data curation: TJW, YCW. Formal analysis: CYW, TJW, CYH. Funding acquisition: CYW. Methodology: CYW, CYH. Project administration: CYW, TJW. Visualization: CYW. Writing – original draft: CYW. Writing – review & editing: CYW, TJW, YCW. All authors read and agreed to the published version of the manuscript.