Enterocytes, tight junctions, and the mucus layer in the gut play an important role in acting as barrier against pathogens (1). In septic patients, splanchnic hypoperfusion followed by reperfusion is involved in damage to these barrier components (2). Furthermore, the inflammatory response in sepsis is also implicated to play an important role in the pathophysiology of intestinal injury through suppression of gut cell proliferation and apoptosis of gut epithelium (1). Intestinal injury may lead to impaired gut barrier function, which may result in translocation of bacteria and toxins from the intestinal lumen to the mesenteric lymph and systemic circulation. Subsequently, this bacterial translocation may amplify the systemic inflammatory response and contribute to multiple organ failure and death (3, 4). As such, the gut is considered as “the motor” of systemic inflammation in sepsis. We hypothesize that enterocyte damage plays a key role in this process and thereby contributes to aggravation of the inflammatory response in sepsis.
Several factors may contribute to enterocyte damage itself. First, previous work has shown that catecholamines may exert additional detrimental effects on mesenteric blood flow in sepsis (5, 6), thereby possibly contributing to enterocyte damage. Second, patients who require norepinephrine therapy to maintain adequate blood pressure at ICU admission seem to have more enterocyte damage than those who do not, suggesting that low blood pressure contributes to enterocyte injury as well (7). However, the relationship between catecholamine administration, low blood pressure, and enterocyte damage remains to be determined. Intestinal fatty acid-binding protein (I-FABP) is a protein exclusively expressed by enterocytes, which is released into the circulation upon enterocyte injury. I-FABP has previously been identified as a marker for the early diagnosis of intestinal damage (8–11). Furthermore, increased I-FABP concentrations are also observed in ICU patients suffering from shock and are associated with poor prognosis (3, 12, 13).
The aim of the present study was 2-fold: we determined which factors contribute to enterocyte damage in septic shock patients, by investigating the relationship between catecholamine use, hemodynamic status, the inflammatory response, and enterocyte damage, and we investigated the relationship between I-FABP levels and subsequent plasma concentrations of inflammatory cytokines to assess whether enterocyte damage is associated with a sustained or amplified systemic inflammatory response.
We performed a prospective observational cohort study in a convenience sample of 129 adult patients with newly developed septic shock admitted to the ICU between the March 2012 and the June 2015. We included patients with septic shock defined as refractory hypotension that requires norepinephrine administration less than 24 h after ICU admission. (14, 15) Patients without an arterial line were excluded. In addition, we performed a sensitivity analysis of our results using the new sepsis-3 criteria (16). Exclusion criteria were chronic bowel disease, immune suppression, and documented chronic renal disease (serum creatinine concentration >150 μmol/L). The study was carried out in the Netherlands in accordance with the applicable rules concerning the review of research ethics committees and informed consent. All patients or legal representatives were informed about the study details and could refuse to participate.
Lithium heparin- and ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood was sampled at ICU admission (day 1) and at days 3, 5, 7, 9, 14, 21, and 28. Blood was centrifuged at 1,600 g at 4oC for 10 min, after which plasma was stored at −80oC until further analysis.
Patient characteristics, mean arterial pressure (MAP), norepinephrine infusion rate (μg/kg/min), lactate and creatinine levels, heart rate, focus of sepsis, Acute Physiology and Chronic Health Evaluation (APACHE II) scores, and need for mechanical ventilation and CVVH were obtained from the electronical patient file. For each patient who died or was discharged from the ICU within 5 days, missing I-FABP values were imputed by replacing them with the last-observation-carried-forward method (n = 2 for missing I-FABP levels at day 3 only, n = 29 for missing I-FABP levels at day 5 only, and n = 25 for missing I-FABP levels at both days 3 and 5). We hypothesized that an increase or decrease in norepinephrine infusion rate between the 1st and 3rd day of ICU admission might influence I-FABP levels to the largest extent. Patients who died during ICU admission and for whom no norepinephrine infusion rate data were available on day 3 were counted as having an increase in norepinephrine infusion rate (n = 15). Patients who were discharged from the ICU within 5 days and for whom no norepinephrine infusion rate data were available on day 3 were regarded as having a decrease in norepinephrine infusion rate (n = 10).
I-FABP and inflammatory cytokine determinations
For analysis of I-FABP in lithium heparin plasma, enzyme-linked immunosorbent assay (ELISA) kits from Hycult Biotech (Uden, The Netherlands) were used. Plasma concentrations of tumor necrosis factor (TNF)-α, interferon (IFN)-y, interleukin (IL)-1β, IL-6, IL-8, IL-1 receptor antagonist (RA), and IL-10 were measured batchwise in EDTA plasma using a simultaneous Luminex assay (Milliplex, Billerica, Calif).
Distribution of data was determined using Kolmogorov–Smirnov tests. Continuous data in tables are presented as median [interquartile range], whereas numbers and percentages are given for dichotomous data. Continuous variables were analyzed using Mann–Whitney U test or Kruskal–Wallis tests followed by Dunn post-hoc tests. Dichotomous data were analyzed using Fisher exact test. Spearman correlation analysis was used. For each patient who died or was discharged from the ICU within 5 days, missing I-FABP values were imputed up to day 5 by replacing them with the last-observation-carried-forward method (n = 2 for missing I-FABP levels at day 3 only, n = 29 for missing I-FABP levels at day 5 only, and n = 25 for missing I-FABP levels at both days 3 and 5). Area under curve (AUC; reflecting total release) I-FABP levels over the first 5 days were calculated. Receiver-operating characteristic (ROC) curve analysis was performed to calculate the optimal cutoff value of I-FABP levels for the prediction of 28-day mortality.
We hypothesized that an increase or decrease in norepinephrine infusion rate between the 1st and 3rd day of ICU admission influences I-FABP levels to the largest extent. Patients who died during ICU admission and for whom no norepinephrine infusion rate data were available on day 3 were designated as having an increase in norepinephrine infusion rate (n = 15). Patients who were discharged from the ICU within 5 days and for whom no norepinephrine infusion rate data were available on day 3 were regarded as having a decrease in norepinephrine infusion rate (n = 10). Crude logistic regression was used to evaluate associations between several factors that we hypothesized to be related with mortality (I-FABP, APACHE II score, creatinine, lactate and bilirubin at admission, age and sex) and 28-mortality. Factors that were significantly associated with 28-mortality in the crude analysis were evaluated using multiple logistic regression. A similar approach, but using linear regression, was used to assess the associations between several factors that we hypothesized to be related with enterocyte damage (an increase in norepinephrine infusion rate between days 1 and 3, APACHE II score, an increase in MAP between days 1 and 3, and mean creatinine level between days 1 and 5) and enterocyte damage (reflected as AUC I-FABP levels over the first 5 days of ICU admission and I-FABP levels at the 5th day of ICU admission). A P < 0.05 was considered to be statistically significant. Statistical analysis was performed using GraphPad Prism 5 software (GraphPad Software, La Jolla, Calif) and IBM SPSS statistics 22 (IBM, Armonk, NY).
A total of 729 patients were prospectively evaluated for inclusion in the study. A total of 355 patients were eligible, 172 were excluded because they were not included in the study within 24 h after ICU admission, 10 were excluded because the patient or legal representatives declined to participate in the study, 21 died before inclusion, and 23 patients were excluded because no research staff was available or the patient already participated in another trial (Fig. 1).
The median age of the patients was 67 years [56–74]. Per septic shock definition, all patients received norepinephrine with a median infusion rate of 0.2 [0.1–0.5] μg/kg/min on day 1 of ICU admission. Apart from norepinephrine, 8 (6%) patients received dobutamine, 5 (4%) received vasopressin, and 10 (8%) received milrinone. The demographic characteristics of the patients are described in Table 1.
I-FABP levels and norepinephrine infusion rates during ICU admission
Plasma I-FABP levels did not significantly change during ICU admission (Fig. 2A). This was also the case when we performed this analysis in subgroups of patients with a complete follow-up of 7, 14, 21, and 28 days. No differences in I-FABP levels in patients with abdominal sepsis compared with other sites of infection were found (data not shown). Norepinephrine infusion rates significantly decreased from the 3rd day of ICU admission onward (Fig. 2B).
Relation between I-FABP levels and mortality
A total of 31 patients (24%) died within 28 days after ICU admission. Because a relevant proportion of patients were either discharged or deceased after day 5 (resulting in missing I-FABP values), we restricted our primary association analyses to data obtained on days 1, 3, and 5. I-FABP levels at admission as well as AUC (reflecting total release) I-FABP levels over the first 5 days were significantly higher in nonsurvivors than survivors (Fig. 3). ROC curves were constructed for I-FABP levels at admission to assess the cutoff point that best predicted 28-day mortality. This analysis yielded a cutoff point of 994 pg/mL (sensitivity 58%, specificity 78%, positive likelihood ratio 2.6, negative likelihood ratio 0.4, AUROC 0.70, P < 0.001). Multiple logistic regression analysis including I-FABP levels, APACHE II score, creatinine, lactate and bilirubin at admission, and age and sex showed that only APACHE II score and I-FABP concentration more than 994 pg/mL were independently associated with28-day mortality (Table 2).
Factors contributing to I-FABP levels
Because I-FABP levels, reflecting enterocyte damage, were associated with mortality, we set out to determine which factors contribute to this enterocyte damage. In patients in whom norepinephrine infusion rate increased between days 1 and 3, AUC plasma I-FABP levels over the first 5 days and I-FABP levels at the 5th day of admission were significantly higher than those in whom norepinephrine infusion rate decreased (2,760 [1,257–4,937] vs. 1,009 [556–2,198] pg/mL/day, P < 0.001 and 1,444 pg/mL vs. 419 pg/mL, P < 0.010, respectively). Besides an increase in norepinephrine infusion rate, a decrease in MAP between days 1 and 3 was also associated with higher AUC plasma I-FABP levels (1,509 [834–3,080] vs. 1,159 [517–2,371] pg/mL/day, P = 0.045), but not with I-FABP levels at the 5th day of admission (552 [213–1,286] vs. 483 [201–1,254] pg/mL, P = 0.725). Furthermore, crude regression analysis also revealed a relationship of both APACHE II score and average creatinine levels between days 1 and 5, and AUC I-FABP levels (Table 3), the latter suggestive of renal dysfunction contributing to impaired I-FABP clearance. However, multiple linear regression analysis demonstrated that only an increase in norepinephrine infusion rate and APACHE II score were independently associated with AUC plasma I-FABP levels, with the highest regression coefficient (β) observed for the increase in norepinephrine infusion rate (Table 3). Accordingly, crude regression analysis revealed that only an increase in norepinephrine infusion rate was significantly associated with I-FABP levels at the 5th day of admission (Table 3). The relationship between increase in norepinephrine infusion rate, decrease in MAP, and AUC plasma I-FABP levels is visualized in Figure 4.
Plasma concentrations of inflammatory cytokines and their relationship with I-FABP levels
Plasma concentrations of IFN-y and IL-1β were below the detection limit in virtually all patients and showed no kinetics (data not shown). Concentrations of all other cytokines measured were highest at ICU admission, both in the group with I-FABP levels above and below the median I-FABP level at admission (544 pg/mL) (Fig. 5). At the 3rd or 5th day of admission, cytokine concentrations were significantly decreased compared with the levels observed at the first day of admission (Fig. 5). No differences in the kinetics of cytokine concentrations between the groups of patients with I-FABP levels above or below 544 pg/mL at admission were apparent. This suggests that more extensive enterocyte damage at admission does not contribute to a more sustained or pronounced systemic inflammatory response during ICU stay. To further explore whether enterocyte damage is associated with the systemic cytokine response, we assessed the relationship between I-FABP levels at admission and peak cytokine levels, which revealed only weak correlations for two cytokines (IL-10: r = 0.20, P = 0.02, IL1RA: r = 0.21, P = 0.02).
To investigate possible effects of systemic inflammation on enterocyte damage, we explored correlations between peak cytokine concentrations on the one hand and AUC plasma I-FABP levels and I-FABP levels at the 5th day after admission on the other hand. These analyses revealed no significant correlations as well (data not shown).
Subgroup analysis of patients with septic shock according to the SEPSIS-3 criteria
The inclusion of our patients took place before the new sepsis definition (SEPSIS-3) was published. (16) To investigate whether our findings are still valid taking the new criteria into account, we repeated the analyses on the subset of patients that fulfilled the new criteria for septic shock (vasopressor requirement to maintain an MAP of 65 mmHg or greater and serum lactate level greater than 2 mmol/L in the absence of hypovolemia). This subgroup consisted of 68 out of the original group of 129 patients. Forty-seven patients had lactate levels below 2 mmol/L at admission and in 14 patients lactate levels were not measured. Although the patients in this subgroup exhibited higher creatinine levels, a higher heart rate and required more norepinephrine at ICU admission compared with the group who fulfilled the initial septic shock criteria (17) (Supplemental Table 1, http://links.lww.com/SHK/A623), no differences in factors contributing to 28-day mortality and I-FABP levels were found compared with the initial analyses (Supplemental Tables 2 and 3, respectively, http://links.lww.com/SHK/A623). Also, no correlations between I-FABP at day 1 and cytokine levels were found in this subgroup. Lastly, except for a weak correlation between peak IL-10 levels and AUC I-FABP levels (r = 0.24, P = 0.047), no relationships between peak cytokine levels and AUC I-FABP levels or I-FABP levels at day 5 were found.
The present study demonstrates that increasing norepinephrine infusion rates early during ICU admission is independently associated with more pronounced enterocyte damage. We did not find a signal that the initial cytokine levels relate to enterocyte damage or that increased I-FABP levels were related to a more sustained or pronounced inflammatory response in this group of patients.
The association found between I-FABP levels and mortality is in line with previous work, underlining the importance of intestinal integrity in critically ill patients (12, 18). The difference in cutoff point for 28-day mortality between our study (994 pg/mL) and the study of Piton (355 pg/mL) (12) may be explained by a difference in case mix. We only included patients with septic shock, whereas Piton et al. also included patients with metabolic failure, intoxications, neurological disease, and hemorrhagic shock. Until now, it was unknown which factors contribute to the observed enterocyte damage. Although previous work suggested that vasopressor treatment may play an important role in the normalization of I-FABP levels after ICU admission (3), other data showed that catecholamines may cause splanchnic hypoperfusion (5, 6), or changes in intestinal microcirculatory flow (19), suggesting that vasopressor treatment also exerts detrimental effects. Our finding that increasing norepinephrine infusion rate independently contributes to I-FABP levels indeed strongly suggest that, apart from the severity of sepsis itself, norepinephrine directly contributes to enterocyte damage. On the contrary, we show that I-FABP levels do not change significantly over time, but norepinephrine infusion rate significantly decreases after the first day of ICU admission, suggesting that norepinephrine infusion rate is not related to enterocyte damage. However, a decrease in norepinephrine infusion rate does not necessarily affect I-FABP levels immediately. It could be possible that patients in whom the norepinephrine infusion rate was decreased were discharged from the ICU before the next I-FABP level was determined. This may explain why the significant decrease in norepinephrine dose during the first days of ICU admission does not parallel a decrease in I-FABP levels. So although norepinephrine infusion for hemodynamic support is one of the most basic and accepted interventions in the treatment of septic shock (20), and may have beneficial effects to other organs, such as the kidneys (21, 22), it also has deleterious effects.
We did not find a relation between a decrease in MAP and I-FABP levels, suggesting that restoring systemic blood pressure does not prevent aggravation of enterocyte damage in this limited range of blood pressure. Naturally, this does not exclude that lower blood pressure may result in intestinal hypoperfusion and enterocyte damage. Our finding is in line with earlier work in septic shock patients where no significant decrease of urinary I-FABP levels was found despite improvement of hemodynamic parameters (23). A possible explanation for this finding is that global hemodynamic parameters do not represent local intestinal mucosal perfusion (24).
Although it has been argued that cytokines (especially TNF-α) may play an important role in the process of intestinal injury (1, 25, 26), we did not find a relationship between cytokine and I-FABP levels. These results suggest that cytokines do not play an important role in the development of enterocyte damage. Similarly, no increases in I-FABP levels were found during experimental human endotoxemia, a model of systemic inflammation in vivo in which high levels of circulating cytokines are present (approximately 4–20-fold higher than in our patient cohort) (27, 28). Interestingly, enhanced intestinal permeability has been demonstrated in the same model (27). Possibly, inflammatory cytokines do not directly cause damage to enterocytes but only to other parts of the gut barrier, such as tight junctions or the mucus layer (1, 13, 29).
The mechanism by which intestinal damage contributes to increased mortality remains to be elucidated. It has been hypothesized that intestinal damage may lead to translocation of bacteria and/or endotoxin to the lymph and systemic circulation, which amplifies systemic inflammation, ultimately resulting in organ injury (1, 25). However, we did not find relationships between I-FABP levels at ICU admission and concentrations of inflammatory cytokines in the following days. As a consequence, we conclude that enterocyte damage does not sustain or amplify the inflammatory response in our patient group. Importantly, I-FABP relates to enterocyte damage and not to, for example, tight junctions patency or functional enterocyte mass. Therefore, our observations do not exclude the possibility that damage to other parts of the intestinal epithelium, such as tight junctions or the mucus layer (13), results in impairment of gut barrier function and thereby may amplify the systemic immune response. This theory is supported by the results of earlier animal work, in which alterations in intestinal permeability caused by destruction of tight junctions were associated with increases in inflammatory cytokine levels in a model of critical illness (30). In addition, a reduction in functional enterocyte mass, exemplified by low levels of citrulline (a biomarker of the functional enterocyte mass), was previously found to be associated with bacterial translocation in critically ill patients (13).
Our study has several limitations. First, as it concerns an observational study, cause and effect cannot be deduced. Although an increase in the norepinephrine infusion rate emerged as an independent predictor of more pronounced enterocyte damage, we cannot exclude the possibility of residual confounding. Second, we used I-FABP as a proxy for enterocyte damage. However, we did not confirm this using other markers/techniques, such as histology or another form of direct detection of enterocyte damage.
Third, we did not perform measurements of mesenteric hemodynamics or collect microcirculatory data. This would have been of value, as these can aid in elucidation of the mechanisms behind the effects of norepinephrine on enterocyte damage. Fourth, we only determined a limited number of cytokines, which cannot provide a full characterization of the systemic inflammatory response. Finally, septic shock was not defined according to the most recent criteria (vasopressor requirement to maintain an MAP of ≥65 mmHg and serum lactate level >2 mmol/L in the absence of hypovolemia) (16). However, this does not seem to have influenced our results because our sensitivity analysis demonstrated similar results when we restricted our analysis to patients that fulfilled the new criteria.
In conclusion, our results suggest that norepinephrine may directly contribute to enterocyte damage. Furthermore, enterocyte injury is not associated with increased circulating cytokine concentrations. This finding argues against the notion that enterocyte damage results in bacterial/toxin translocation leading to persistent systemic inflammation.
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Catecholamines; cytokine response; gut; I-FABP; sepsis
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