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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 4  |  Page : 177-183

Relation of left ventricular function and serum interleukin level to mortality in septic patients


1 Department of Critical Care Medicine, Cairo University, Cairo, Egypt
2 Critical Care Medicine, Manchester Royal Infirmary, University of Manchester, United Kingdom

Date of Submission08-Mar-2016
Date of Acceptance26-Mar-2017
Date of Web Publication11-Oct-2017

Correspondence Address:
Abdou M Azab
Critical Care Departement, Kasr Elini Old Medical School, Postal code 11562
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/roaic.roaic_79_16

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  Abstract 

Introduction
Left ventricular systolic dysfunction and elevated serum interleukins (ILs) are common in septic patients. However, whether left ventricular diastolic dysfunction is related to mortality in septic patients is a matter of debate.
Aim
The aim of the study was to assess the effect of myocardial systolic and diastolic functions on mortality in cases of sepsis and to predict an inflammatory marker that could be clearly linked to mortality in sepsis.
Patients and methods
Twenty patients were prospectively studied, with measurement of the following on admission and on day 7: left ventricular end-diastolic volume, left ventricular end-systolic volume, left ventricular ejection fraction% (echocardiography), mitral annulus S-velocity, Ed/t, and serum levels of ILs (IL-1α, IL-1β, IL-6, and IL-10). Mortality on day 28 was the study endpoint.
Results
Twenty patients with sepsis and septic shock were studied (45% were male and 55% were female; mean age 52±17 years). The patients were divided into group I (survivors, 55%) and group II (nonsurvivors, 45%). Regarding echocardiography there was no significant difference between the two groups in end-diastolic volume, end-systolic volume, or ejection fraction% (112.3±51 vs. 94.5±30, 43.8±30 vs. 29.4±22, and 61.5±12 vs.71.2±11; P=0.4, 0.1, and 0.08, respectively) on admission or on day 7 (114.6±21 vs. 99.8±65, 43.8±30 vs. 29.4±22, 61.7±12 vs. 59.6±17; P=0.1, 0.2, and 0.7, respectively), whereas Ed/t data on admission showed statistically significant short Ed/t in group II (103.5±28) compared with group I (127.2±25) (P=0.04). However, on day 7 the difference was not significant (115.3±41 vs. 119±48, P=0.8). The mitral annulus S-velocity did not show significant difference either on admission (10.7±5 vs. 9.9±2, P=0.9) or on day 7 (8.6±4 vs. 10.7±4, P=0.1). Regarding the levels of ILs, there was no difference between group I and group II in terms of admission IL-1α (33.7±48 vs. 27.1±21, P=0.7), IL-1β (74±55 vs. 54.5±32, P=0.7), IL-6 (235.1±357 vs. 234.2±355, P=0.9), or IL-10 (110.7±121 vs. 135.3±241, P=0.9) or in terms of day 7 IL-1α (41.6±76 vs. 208.2±410, P=0.8), IL-1β (154.1±255 vs. 39.3±15, P=0.06), or IL-10 (87.2±230 vs. 189.6±335, P=0.9). However, on day 7 IL-6 showed a significantly high level in group II (294.8±385) versus group I (68.9±110) (P=0.05).
Conclusion
Systolic function did not predict prognosis. However, diastolic dysfunction in the form of Ed/t predicted poor prognosis. The higher IL-6 level on day 7 was a good predictor of mortality.

Keywords: diastolic dysfunction, left ventricular function, systolic function


How to cite this article:
Soliman M, Azab AM, El Hossainy RM, Nirmalan M, Nagi HK. Relation of left ventricular function and serum interleukin level to mortality in septic patients. Res Opin Anesth Intensive Care 2017;4:177-83

How to cite this URL:
Soliman M, Azab AM, El Hossainy RM, Nirmalan M, Nagi HK. Relation of left ventricular function and serum interleukin level to mortality in septic patients. Res Opin Anesth Intensive Care [serial online] 2017 [cited 2020 Jun 4];4:177-83. Available from: http://www.roaic.eg.net/text.asp?2017/4/4/177/216453


  Introduction Top


Sepsis is a leading cause of death in critically ill patients despite the use of modern antibiotics and resuscitation therapies [1]. Sepsis is responsible for 10% of all ICU admissions [2]. The incidence of sepsis is expected to increase because of a higher incidence of severe sepsis in older patients, an increased number of people living with chronic diseases, and therapies aiming to suppress the native immune system [2].

Risk factors for death from sepsis include underlying illness, increased age, and multisystem organ failure [1],[2],[3].

Because sepsis is associated with widespread injury to the vascular endothelium, multiple organ failure, including cardiac failure, acute respiratory distress syndrome, acute kidney injury, and coagulation disorder and as the cardiovascular system plays a key homeostatic role, sepsis-induced myocardial depression is usually associated with increased morbidity and mortality [4].

Although sepsis-induced myocardial depression has not yet been clearly defined, it is known to involve both the left and right sides of the heart, and is thus global or systemic [5]. It may also be systolic or diastolic or both [6]. Sepsis-induced cardiac dysfunction has been shown to occur very early in sepsis, including in the hyperdynamic phase of septic shock, and the underlying pathogenesis may be related to mitochondrial dysfunction, as well as to levels of nitric oxide, complements, and cytokines [7]. However, the pathogenesis of this condition (septic myocardial depression) is so complex that there is no single effective treatment for it. Therefore, additional studies are necessary to improve our understanding of the disease, develop reliable diagnostic procedures, as well as develop effective therapeutic interventions for this disorder [8].

Identification of septic patients with a higher mortality risk is extremely important. Therefore, additional studies are necessary to improve our understanding of myocardial dysfunction in sepsis and develop reliable diagnostic procedures and effective therapeutic interventions for this disorder [9].


  Aim Top


The aim of the study was to assess the effect of myocardial systolic and diastolic function on mortality in sepsis and to predict an inflammatory marker that could be clearly linked to mortality in sepsis.


  Patients and methods Top


Twenty consecutive patients with sepsis were enrolled in our study. The study protocol was approved by the institutional ethical committee and local review board. The patients met the criteria for sepsis and/or refractory circulatory failure and/or Multiple Organ Dysfunction Syndrome (MODS) as defined by the International Sepsis Consensus [10].

Sepsis was defined as at least two of the following conditions occurring within the context of infection: temperature above 38°C or below 36°C, heart rate above 90 beats/min, and white blood cell count above 12 000 or below 4000 cells/mm. Refractory circulatory failure was defined as persistent or growing metabolic acidosis despite adequate vasoactive support over an observation period of 6–12 h.

Only patients with pre-existing cardiomyopathies, valvular heart disease, and poor echocardiographic window were excluded from the study.

After obtaining written consent from the patient or his (or her) family, full history, complete clinical examination, routine laboratory investigations as well as any additional laboratory or imaging modality needed to identify the source of sepsis were performed. Each patient was subjected to the following:
  1. Peripheral venous samples were collected on admission and on day 7 for measurement of interleukin-1α (IL-1α), IL-1β, IL-6, IL-10, and tumor necrosis factor-α (TNF-α) using the enzyme-linked immunosorbent assay technique.

    Samples of 10 ml were collected in a dry plastic tube with a clot activator where they were left to clot for 20 min at 37°C and then centrifuged at 3000g for 15 min. Samples were stored in the Biology Laboratory in the Critical Care Department at −70°C in a fridge (Jouan VX-530 series 2; Jouan; Thermo Fisher Scientific, Waltham, MA, USA).

    All samples were collected and analysis was done by the laboratory team in our unit.
  2. Bedside echocardiography was performed using Philips ATL HDI 5000 (Philips). The examination was done on admission and on day 7 with measurement of the following: left ventricular end-diastolic and end-systolic volumes, with calculation of left ventricular ejection fraction% (LVEF%) (LVEF%<45% was considered abnormal), early diastolic filling velocity (E), late diastolic filling velocity (A) with calculation of E/A ratio, and grading of diastolic function (I–IV). Pulsed-wave tissue-Doppler was applied to the septal mitral annulus with measurement of systolic and diastolic velocities (S, E’, A’) and E’ deceleration time. Ratios of E’/A’ and E/E’ were also calculated.
  3. Morbidity and mortality on day 28 in the ICU were targeted as the study endpoint.


Statistical analysis

Data were coded and entered using the Statistical Package fir Social Sciences (SPSS, version 15; it is a Statistical Program). Data were summarized using mean and SD for quantitative variables and percentage for quantitative variables. Comparison between groups was done using the χ2-test for qualitative variables and the independent-samples t-test for normally distributed quantitative variables. Quantitative variables not normally distributed were compared using the nonparametric Mann–Whitney test and Wilcoxon’s signed-rank test. P-values less than 0.05 were considered statistically significant.


  Results Top


The study included 20 consecutive septic patients admitted to the Critical Care Department, Cairo University.

Our results are discussed under two sections:
  1. Baseline characteristics.
  2. Comparison between survivors and nonsurvivors.


Baseline characteristics

[Table 1] summarizes the baseline characteristics of the study group.
Table 1 Baseline characteristics

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Mortality rate was 45% (nine patients).

Both groups were compared with respect to the following:
  1. Baseline characteristics.
  2. Serum levels of inflammatory markers.
  3. Echocardiographic data.


[Table 2] summarizes the baseline characteristics between survivors and nonsurvivors.
Table 2 Baseline characteristics between survivors and nonsurvivors

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Serum levels of inflammatory markers

Nonsurvivors had statistically higher TNF-α on day 0 (P=0.04) and higher IL-6 on day 7. None of the other markers showed any relation to mortality ([Table 3] and [Figure 1])
Table 3 Serum level of the measured inflammatory markers

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Figure 1 Interleukin-6 (IL-60) and tumor necrosis factor-α (TNF-α) in survivors and nonsurvivors. *P-value is significant

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Echocardiographic data

Left ventricular volume and systolic function

Despite higher left ventricular end-diastolic volume in survivors than in nonsurvivors, the difference was not statistically significant either on admission or on day 7 (P=0.4 and 0.1, respectively). There was no significant difference between survivors and nonsurvivors regarding left ventricular end-systolic volume or LVEF% on admission or on day 7 ([Table 4]).
Table 4 Left ventricular volumes and ejection fraction% between survivors and nonsurvivors

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Left ventricular diastolic dysfunction

The only two patients with normal diastolic function during sepsis died.

Types I and III diastolic dysfunction (DD) were the most common types seen in the study group, with an incidence of 60 and 30%, respectively. Sixty-four percent of survivors had type I DD versus 56% of nonsurvivors, whereas 36% of survivors had type III DD versus 22% of nonsurvivors ([Table 5]).
Table 5 Types of diastolic left ventricular function

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E-deceleration time did not show statistically significant difference between survivors and nonsurvivors on admission and on day 7.

Tissue Doppler echocardiography

Ed/t was significantly shorter in nonsurvivors than in survivors on admission (P=0.04). However, on day 7, there was no statistical difference (P=0.8) ([Figure 2]).
Figure 2 Ed/t in survivors and nonsurvivors. *P-value is significant

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E/E’ ratio and S-velocity did not show statistically significant difference between survivors and nonsurvivors on admission or on day 7 ([Table 6]).
Table 6 Tissue Doppler parameters between survivors and nonsurvivors

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  Discussion Top


Sepsis is a leading cause of death in critically ill patients despite the use of modern antibiotics and resuscitation therapies [1]. Early diagnosis and stratification of the severity of sepsis is very important, increasing the possibility of starting timely and specific treatment [11],[12].

Biomarkers can have an important place in this process because they can indicate the presence or absence or severity of sepsis, and can differentiate bacterial from viral and fungal infection, and systemic sepsis from local infection [13].

Myocardial dysfunction may contribute to the hemodynamic instability that accompanies sepsis and may result in circulatory failure. However, the relation between DD and sepsis mortality is conflicting [14].

In our study we aimed to evaluate the relation of some of the inflammatory markers and cardiac function to mortality in septic patients. ICU mortality was the study endpoint.

We found that higher TNF-α on day 0 and IL-6 on day 7 were associated with increased mortality. The presence of shorter E’d/t and the absence of diastolic function were related to increased mortality in sepsis. None of the other parameters were related to mortality.

Regarding inflammatory mediators, our results partially agreed with Sabelnikovs et al. [15], who enrolled 103 consecutive intensive care unit patients with sepsis in a prospective case–control study. Nonsurvivors had significantly higher concentrations of TNF-α, IL-6, and IL-10 during the first 24 h. However, in our study, nonsurvivors had higher IL-6 on day 7 with no difference in IL-10 on mortality.

This could be explained by the result of Moscovitz et al. [16], who enrolled a total of 100 patients admitted through the emergency department with signs of infection and a presumptive diagnosis of bacteremia. They aimed to determine the predictive value of plasma IL-6 and TNF-α measurements in assessing bacteremia and subsequent morbidity and mortality rates in emergency department patients. Only plasma IL-6 concentrations predicted bacteremia (P=0.006) and death from infection (P=0.009). Plasma TNF concentrations predicted mortality from all causes (P=0.009). It appears that the increase in plasma IL-6 concentration is both delayed and sustained in comparison with other cytokines and is therefore more easily detectable than, for example, TNF-α, which shows peak activity early but vanishes within hours after induction [16].

Our result regarding IL-6 was similar to that of Oda et al. [17]. They enrolled 40 consecutive ICU patients with systemic inflammatory response syndrome (SIRS)/sepsis. This study was conducted to investigate whether sequential measurement of blood IL-6 levels using chemiluminescent enzyme immunoassay would be useful for the management of patients with SIRS/sepsis. The blood IL-6 levels were elevated in SIRS/sepsis patients and were extremely high in patients with septic shock. There was no significant difference in blood IL-6 level on admission between survivors (n=27) and nonsurvivors (n=13). However, the mean blood IL-6 level during ICU stay was significantly higher in nonsurvivors (P<0.05) [17].

Miguel-Bayarria et al. [18] selected 81 patients in whom the underlying etiology was an infection and who met the criteria for sepsis. Comparison of survivors versus deceased patients showed significant differences in Acute Physiology and Chronic Health Evaluation (Apache-II) score, IL-6, and lactate (P<0.001) upon admission and after 3 and 7 days. In the multivariate analysis with mortality as the dependent variable, IL-6 proved significant on day 3 (odds ratio=2.6).

In our study, IL-10 level did not show any significant difference between survivors and nonsurvivors. Kellum et al. [19] included 1423 patients from the emergency department. They measured the cytokine level of IL-10 on day 1 in severely septic and nonseptic patients. Concentrations of IL-10 were also lower than those observed for IL-6, with more noticeable decay over the first 2 days. A very high proportion of participants had normal concentrations (64% of survivors and 42% of nonsurvivors had normal levels throughout), but higher levels were associated with survivors with severe sepsis compared with survivors without severe sepsis (P<0.001) and nonsurvivors (P<0.001), and with nonsurvivors with sepsis versus survivors with sepsis (P=0.002) [19].

The study by Cesur et al. [20] partially agreed with our results. They enrolled 46 adults with sepsis and 55 healthy adults as the control group to investigate the correlation between prognosis of disease and several factors including TNF-α, CRP, and IL-10 levels. They found that of initial serum IL-10 level and TNF-α and CRP levels on the 3rd day of treatment and the 5th day of treatment, only serum TNF-α level was higher in nonsurviving than in surviving septic patients.

Studies in animal models and human patients have shown that the massive production of proinflammatory cytokines such as TNF-α, IL-1, and IL-6 is a hallmark of sepsis and of particular importance in the pathophysiology of disease [18],[19],[20],[21]. However, evidence on their relation to mortality is conflicting and treatment directed against TNF-α and IL-1 lacked success in clinical practice [22],[23],[24],[25].

Among many potential reasons, it was reported that circulating levels of ‘early’ cytokines like TNF-α and IL-1 return to almost baseline levels within the first few hours of progression of disease [26]. Thus, specific inhibition of ‘early’ cytokines may provide only a narrow window for clinical intervention. Moreover, the elevation of their circulating levels may be downregulated even before the diagnosis of sepsis is made [27], indicating that early diagnosis of sepsis is crucial for the outcome. The role of cytokines in sepsis was elegantly reviewed by Schulte et al. [28].

In our study echocardiography was performed on admission and on day 7. We had only 2 patients with normal diastolic function who died early in the study. In our study only shorter Ed/t on day 0 was related to mortality in sepsis.

The studies on left ventricular dysfunction and mortality are controversial.

Landesberg et al. [6] stated that ‘DD is common and is a major predictor of mortality in severe sepsis and septic shock’. A sizeable number of patients (262) were enrolled in this study to allow for a powerful statistical analysis (univariate and multivariate regression analyses) and a comprehensive collection of echocardiographic data. DD has been evaluated in accordance with recent guidelines [29]. Ninety-five patients died in the hospital and the reduced mitral annular e’-wave was the strongest predictor of mortality, even after adjusting for the other independent predictors of mortality (Apache-II score, low urine output, low left ventricular stroke volume index, and the lowest oxygen saturation). Patients with systolic dysfunction (SD) only (LVEF%<50%), DD only (e’-wave<8 cm/s), or combined SD and DD had higher mortality than those with no diastolic or SD [6].

However, the study by Pulido et al. [30] found that myocardial dysfunction in patients with severe sepsis and septic shock has a wide spectrum but is not associated with increased 30-day or 1-year mortality.

They prospectively studied 106 patients with severe sepsis or septic shock by transthoracic echocardiography within 24 h of admission to the intensive care unit: 37% had left ventricular DD, 27% had left ventricular SD, and right ventricular dysfunction was present in 31%. Several patients had a combination of SD and DD, as well as right and left ventricular dysfunction. There was no difference in mortality between patients with normal myocardial function and those with left, right, or any ventricular dysfunction [30].

Sanfilippo et al. [14] performed a systematic review on the effects of DD using tissue Doppler criteria according to the recent recommendations on mortality in septic patients using the longest reported follow-up. The association between SD and mortality according to the results reported by the retrieved studies was the secondary endpoint.

They included seven studies in their meta-analysis of 636 septic patients; 48% of them were found to have DD and a significant association was found between DD and mortality [Relative Risk (RR)=1.82, 95% confidence interval=1.12–2.97, P=0.02]. This finding remained valid in a further analysis that included an older study reporting DD without Tissue Doppler Imaging (TDI) criteria. Five studies reported data on SD for a total of 581 patients, 29.6% of them with SD. No association was found between SD and mortality (RR=0.93, 95% confidence interval=0.62–1.39, P=0.73). Looking at subgroups, there was a trend toward higher mortality comparing isolated DD or combined SD–DD versus normal heart function (P=0.10 and 0.05, respectively) [14].

Limitations

  1. Only a small number of patients were included.
  2. Despite the publication of diagnostic guidelines by the American Society of Echocardiography in 2009 for standardized data interpretation, normal cutoff values for each parameter are still required in relation to age, sex, racial origin, and associated pathologies.



  Conclusion Top


  1. Higher TNF-α on admission, higher IL-6 on day 7, and a shorter E'd/t on admission were related to mortality in sepsis.
  2. DD should be considered a variant of myocardial dysfunction in sepsis and should be evaluated in each patient, given that a sizable proportion of these patients have preserved systolic function.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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