Bioelectrical impedance phase angle in septic patients admitted to intensive care units.

OBJECTIVE: To calculate the values of the phase angle of septic patients using bioelectrical impedance analysis, correlate the values with clinical and biochemical variables, and compare them to reference values.
METHODS: Cohort study conducted with 50 septic patients aged ≥ 18 years old, admitted to intensive care units, and assessed according to prognostic indexes (APACHE II and SOFA), clinical progression (mortality, severity of sepsis, length of stay in intensive care unit), biochemical parameters (albumin and C-reactive protein), and the phase angle.
RESULTS: The average age of the sample was 65.6 ± 16.5 years. Most patients were male (58%) and suffering from septic shock (60%). The average APACHE II and SOFA scores were 22.98 ± 7.1 and 7.5 ± 3.4, respectively. The patients who survived stayed nine days on average (five to 13) in the intensive care unit, and the mortality rate was 30%. The average value of the phase angle was 5.4 ± 2.6° in the total sample and was smaller among the females compared with the males (p=0.01). The phase angle measures did not exhibit an association with the severity of the sepsis, mortality, gender, and age or correlate with the length of hospitalization or the biochemical parameters. The participants' phase angle values adjusted per gender and age were 1.1 to 1.9 times lower compared with the values for a normal population.
CONCLUSION: The average value of the phase angle of septic patients was lower compared with the reference values for a healthy population. The phase angle measures did not exhibit association with the clinical and biochemical variables, which might be explained by the sample homogeneity.

INTRODUCTION

Sepsis is a complex disease and is characterized by a systemic inflammatory response triggered by infection.( It is the most common cause of admission to and death in intensive care units (ICUs).( Several studies have demonstrated that the incidence of sepsis has increased in Brazil, with only a small decrease in mortality, and this incidence is higher than in other countries.( When associated with multiple organ failure, the sepsis mortality rate is often high, as are the hospital costs. Thus, the diagnosis and management of sepsis is an important challenge for healthcare professionals.(

The use of prognostic indices in critical patients facilitates the assessment of the severity and prognosis of the disease and the adequate monitoring of its clinical progress. Sequential Organ Failure Assessment (SOFA)( and Acute Physiology and Chronic Health Evaluation II (APACHE II)( are indices used to estimate the morbidity and mortality risk in inpatients. High scores correlate directly with a poorer clinical prognosis, particularly in critical patients.(

Bioelectrical impedance analysis (BIA) is a widely used method to assess body composition and nutritional status.( Because BIA is non-invasive and practical (it can be performed at bedside), it is used in both healthy and ill individuals.( BIA is based on the measurement of the total body resistance to the injection of a low-amplitude (800 mA) and high-frequency (50 kHz) electric current, which facilitates quantifying parameters such as impedance, resistance (R), reactance (Xc), and phase angle (PA).(

PA is calculated from the ratio between various R and Xc measurements (PA=arc tangent Xc/R) and affords a direct measure of cell stability while indicating the water distribution across the intra- and extracellular spaces. PA is considered to be an indicator of membrane integrity and body cell mass (BCM).(

In addition, PA has been used as a prognostic indicator and a predictor of survival under certain clinical conditions.( According to several studies, low PA values in critical patients correlate with poorer disease progress and higher mortality.( Different from the other parameters used to assess body composition measured by BIA, PA is considered to be valid when the hydration status varies.(

Therefore, the present study sought to assess PA calculated from BIA in patients diagnosed with sepsis and admitted to ICU, evaluate PA's association with the patients' length of hospitalization, mortality, clinical scores, and biochemical parameters, and compare the PA values with reference values.

METHODS

The present study was a cohort study that assessed patients admitted to three ICUs of the Hospital de Clínicas de Porto Alegre (HCPA). The data were collected from May to August 2012. Patients aged ≥18 years, diagnosed with sepsis upon ICU admission, and expected to be hospitalized for at least 72 hours were included, whereas patients for whom BIA could not be performed (pacemaker users, amputees, or patients with skin infections) were excluded. The International Sepsis Definitions Conference consensus was used to establish the sepsis diagnosis. (

The sociodemographic (age and gender), clinical (baseline disease; APACHE II and SOFA scores; clinical progression, i.e., the mortality and severity of the sepsis; and the length of ICU stay), and biochemical (serum albumin and C-reactive protein - CRP) data were collected from the clinical records. The albumin levels were measured within the first 48 hours of ICU admission. CRP was measured twice: on admission and three to five days after the first measurement. All of the patients were followed from ICU admission to their discharge, death, or day 28 of the study.

The APACHE II( and SOFA( scores were only applied on admission. Thus, delta SOFA was not included as a variable, i.e., the emergence or progression of organ dysfunctions was not assessed. The serum albumin and CRP measurements were performed using the bromocresol green colorimetric method and turbidimetry, respectively.

To calculate PA within the first 48 hours after ICU admission, the BIA device Biodynamics 450, version 5.1 (Biodynamics® Corp., Seattle, WA, USA) and Resting Tab ECG electrodes (Conmed® Corp., Utica, NY, USA) were used. Through the injection of low-frequency and high-voltage alternating current (800 mA and 50 kHz), this BIA device measures the following body parameters: R, Xc, PA, the cell, extracellular, lean, and fat masses, the body mass index (BMI), the basal metabolic rate (BMR), total body water, and intra- and extracellular water. The measurements were performed with the patients lying down with the legs and arms parallel to the body and positioned far from the trunk. The electrodes were placed on standard locations (the dorsal surface of the right wrist, the third metacarpal bone, the anterior surface of the right ankle between the bone prominences, and the dorsal surface of the third metatarsal bone).( All of the procedures were performed by trained staff.

The patient's weight and height were measured using an Eleve (Eleve Dymat E3 - Phoenix Mecano Company) or a bed scale and a Luft Ruler, respectively.(

To compare the PA values, the reference values described by Barbosa-Silva et al. for healthy US adults were used.(

All of the protocols to avoid infection during the handling of patients were followed with particular care to ensure patient safety. Thus, rubber gloves and disposable masks and aprons were used, and the body surfaces on which the electrodes were placed were cleansed with 70% ethanol before and after application.

The present study complied with the ethical principles for research on human beings established by the National Health Council (Conselho Nacional de Saúde - CNS) 196/96, protocol no. 110,663, and was approved by the HCPA Ethics Committee. All of the participants (or their legal guardians) signed a free and informed consent form.

Statistical analysis

Calculations based on the average PA values of surviving (5.6±2.2) and non-surviving (2.5±1.1)( septic patients in ICU resulted in a minimum sample size of 35 participants for an expected mortality of 20%,( a power of 90%, and a significance level of 0.05%.

The Kolmogorov-Smirnov test was used to investigate the normality of the variable distributions. The categorical variables were expressed as absolute or relative frequencies, and the continuous variables as a mean and standard deviation or a median and interquartile range, as appropriate. The chi-square test was used to investigate the association between the categorical variables, Student's t-test to compare means, the Mann-Whitney test for independent variables with non-normal distribution, the Wilcoxon test for repeated non-parametric measures, and the Spearman or Pearson's correlation coefficient to investigate the correlation of the parametric variables. The data were analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 18.0 (SPSS Inc., Chicago, IL), and the results were considered to be significant when p≤0.05.

RESULTS

Of 80 patients admitted to the HCPA Service of Intensive Care Medicine with sepsis during the study period, 22 were considered as losses. In 17 of these cases, the informed consent form was not signed within the first 48 hours (because it was impossible or a legal representative was absent), and five patients refused to participate. Six patients died before BIA could be performed, and thus did not meet the inclusion criteria. Two patients wore pacemakers. Therefore, the sample consisted of 50 participants (62% of the potential sample) of whom 29 were male (58%). The average age was 65.6 ± 16.5 years (Table 1).

Table 1

Sample characterization

Characterization		Results
		N = 50
	Gender
	Male	29 (58)
	Female	21 (42)
Age (years)		65.6±16.5
Profile
	Clinical	32 (64)
	Surgical	18 (36)
Sepsis severity
	Sepsis + severe sepsis	20 (40)
	Septic shock	30 (60)
Sepsis origin
	Respiratory	25 (50)
	Abdominal	11 (22)
	Urinary	8 (16)
	Other	6 (12)
SOFA (score)		7.5±3.4
APACHE II (score)		22.98±7.1
PAº		5.4±2.6
	Women	4.1±1.3*
	Men	5.4±1.9
PAº category
	≤5	29 (58)
	>5	21 (42)
Resistance Ω		333.0±104.3
Reactance Ω		28.0 (18.7 - 37.4)
CVVH		16 (32)
Albumin (g/dL)		2.5±0.4
CRP (mg/dL)
	1st assessment	164.3 (98.5 - 271.8)**
	2nd assessment	99.8 (51.8 - 167.7)
Length of ICU stay (days)		9.0 (5 - 13)
Mortality in ICU		15 (30)

SOFA - Sequential Organ Failure Assessment; APACHE II - Acute Physiology and Chronic Health Evaluation II; PA - phase angle; CVVH - continuous venovenous hemodialysis; CRP -C-reactive protein; ICU - intensive care unit. Data expressed as number (%), mean ± standard deviation, or median (25%-75%). * p=0.015 between both genders (Student's t-test); ** p<0.001 between the first and second assessments (Wilcoxon test).

Regarding the inpatient profiles, most participants (64%) were clinical (non-surgical). Most (60%) were suffering from septic shock on admission, whereby the respiratory system was the most frequent source of the primary infection. The average APACHE II score was 22.98±7.1, and SOFA was 7.5±3.4. The average PA was 5.4±2.6º), lower among the females (p=0.01), and lower than ≤5º in more than 50% of the sample (Table 1).

The median ICU stay length of the survivors was nine days. A total of 15 (30%) patients died (Table 1).

The average PA values did not differ between the patients with sepsis or severe sepsis compared with the patients with septic shock (4.5±14º and 5.0±1.9º; p=0.36; Student's t-test). Figure 1 depicts the PA value as a function of the severity of sepsis. PA was not associated with the severity of sepsis, the inpatient's profile, mortality, gender, or age (Table 2).

Figure 1

Boxplot of the phase angle in patients according to the severity of sepsis. PA - phase angle. Sepsis and severe sepsis, N=20; septic shock, N=30.

Table 2

Clinical variables, age, mortality and phase angle in septic patients

Variables			PAº		p value
			≤5 (N = 29)	>5 (N = 21)
Sepsis
	Sepsis + severe sepsis		12 (60)	8 (40)	0.81
	Septic shock		17 (56.7)	13 (43.3)
Profile
	Clinical		16 (50)	16 (50)	0.12
	Surgical		13 (72.2)	5 (27.8)
Death
	Yes		9 (60)	6 (40)	0.76
	No		20 (64.5)	11 (35.5)
Age
	<60 years		9 (60)	6 (40)	0.85
	≥60 years		20 (57.1)	15 (42.9)
Gender
	Male
		<60 years	3 (60)	2 (40)	0.92
		≥60 years	10 (62.5)	6 (37.5)
	Female
		<60 years	6 (60)	4 (40)	0.70
		≥60 years	10 (52.6)	9 (47.4)

PA - phase angle. Results expressed as number (%).

The PA did not correlate with the APACHE II and SOFA scores, hospitalization length, or biochemical parameters (Table 3). When these parameters were analyzed according to the categories PA≤5 and >5º, the following values were found: averages of 22.7±7.3 and 23.2±7.1 (p=0.82) in APACHE II, 7.1±3.4 and 8±3.5 (p=0.35) in SOFA, 2.4±0.4 and 2.6±0.4 (p=0.45) in the albumin level; medians of 222.5 (106.5 - 323.9) and 134.2 (76.4 - 219) in CRP1 (p=0.13); and 8 (5.0 - 13) and 10 (7.0 - 12) days in the length of hospitalization (p=0.23) (according to Student's t or Mann-Whitney tests).

Table 3

Prognostic scores, biochemical parameters, length of hospitalization, and phase angle in septic patients

Variables	Coefficient of correlation (r)	p value
APACHE II*	-0.005	0.97
SOFA*	0.210	0.16
CRP1**	-0.264	0.09
Albumin*	0.229	0.25
Length of ICU stay**	0.059	0.75
Resistance*	-0.188	0.21
Reactance**	0.714	<0.001

APACHE II - Acute Physiology and Chronic Health Evaluation II; SOFA - Sequential Organ Failure Assessment; CRP - C-reactive protein. * Pearson's coefficient of correlation; ** Spearman's coefficient of correlation.

Compared with the PA values of the healthy population adjusted per age and gender, the median values of the participants were lower, corresponding to 67.7% (P25=59.9%; P75=83.7%) of the reference values.(

DISCUSSION

The identification of prognostic factors for septic patients is important for the clinical management of the disease. PA has been recently investigated as a prognostic instrument to assess the cell membrane function under different clinical conditions.( The average PA values were lower in those studies compared with the healthy population (from 4 to 10º as a function of age and gender).( Low PA values correlate with reduced cell integrity and lean mass and increased morbidity and mortality.( In patients with liver cirrhosis, PA ≤5.4º correlated with higher mortality compared with patients with higher PA values.( Several studies found PA to be a strong prognostic indicator and an important tool to assess the clinical signs and monitor the progress of the disease in patients who were either undergoing peritoneal dialysis, were HIV-positive, or had colon or pancreatic cancer.( One study assessed patients with breast, head and neck cancer, among others, and found that PA behaved as an independent predictor of mortality in the patients on chemotherapy, with an average of 5.12±0.89º.(

Among the few studies that assessed septic patients, one study, which compared patients with and without sepsis, corroborated the use of PA as a prognostic indicator.( The PA values in that study were similar to those found by Miranda, who reported an average of 5.6±2.2º in the patients with sepsis who survived compared with 2.5±1.1º in the non-survivors.( In the present study, 60% of the patients who died exhibited PA ≤5º, which agrees with all of the reports in the literature.

However, the analysis of PA relative to the various investigated variables exhibited no association with the severity of sepsis, the inpatient's profile, mortality, gender, or age. This lack of association might result from the sample's homogeneity. Different from the present study, in which most of the sample was in a state of septic shock, the sample in a study that found an association between PA and the previously mentioned variables exhibited a regular distribution of the various degrees of sepsis severity. In addition, that study performed sequential assessments of the variable.( However, although most of the participants in the present study were clinical (64%), the surgical patients exhibited the highest percentages of PA≤5, which agrees with the findings of other studies conducted on septic, polytrauma and emergency surgery patients.(

The correlation between PA and variables such as gender, age, ethnicity, and the indicators of body composition was investigated by Barbosa-Silva et al.( In the present study, the PA values were approximately 32% lower for both genders and all of the age groups compared with the reference values for the US healthy population.( Miranda performed the same comparison and also found lower PA values among the patients with sepsis.(

In the present study, the average PA was 5.4±2.6º and lower among the females (4.1±1.3º), which is similar to what has been found in other studies(. Lower values are expected among women in healthy populations because the PA increases together with the muscle mass and the BCM.(

In this context, PA tends to decrease with age as a function of the reduction of muscle mass and the influence of the alterations in the ratio of intra and extracellular water associated with aging.( Additionally, studies conducted on ill individuals, including patients with sepsis( and undergoing dialysis(, found a negative correlation between age and PA, i.e., the latter decreases with age. That relationship was not found in the present study. Because the patients in a critical state also exhibit a loss of muscle mass and alterations in the water distribution between the intra- and extracellular compartments,( this lack of a relationship might have resulted from the severity of the patients' condition, given that 60% exhibited septic shock, and the average APACHE II and SOFA scores were 22.98±7.1 and 7.5±3.4, respectively.

High APACHE II and SOFA scores are associated with an increased risk of morbidity and mortality and longer hospitalization periods, particularly for critical patients.( In addition, an inverse correlation was found between the PA values and the clinical indices in patients with sepsis (higher severity scores, longer hospitalization periods, and lower PA values).( In critical patients, high CRP and low serum albumin levels are considered to be prognostic markers and tools to assess the progress of disease. Low albumin levels correlate with the PA in certain clinical conditions, such as sepsis and pancreatic cancer, whereby the degree of correlation varies from very weak to moderate.( In the present study, the serum albumin and CRP levels did not correlate with PA, which did not correlate with APACHE II, SOFA, and the length of hospitalization indices. The Xc correlated positively with PA as expected because it is an indicator of BCM. Such association surpasses the morphological assessment of the cell membrane as a measure of cell function.(

Regarding this study's limitations, the sample homogeneity (more than half of the patients were suffering from septic shock) must be mentioned. Other limitations include the significant losses observed, the lack of PA reference values for the Brazilian population, which compelled the use of the values established for a US healthy population, and the small number of studies conducted on critical patients, which hindered comparative analysis.

Further studies are required with larger and more diversified samples with respect to the severity of disease to enable a more accurate assessment of PA's prognostic ability in patients with sepsis.

CONCLUSION

The average PA value was lower in septic patients compared with the reference values for a healthy population and not associated with the clinical and biochemical variables most likely because of sample homogeneity.