Introduction
Sepsis is an important public health and critical care problem worldwide. Despite a significant progress in understanding the mechanisms underlying sepsis, mortality in these patients is still high, and sepsis per se is the main cause of adverse outcomes in intensive care units (ICU) [1-3]. In this regard, searching for prognostic criteria of unfavorable course of disease is an actual scientific problem.
Body temperature is an obligatory physiological constant, and its maintaining within a certain range is essential for adequate functioning of human organs and systems. Even small deviations in body temperature can lead to significant metabolic changes [4]. Temperature imbalances are common in patients with systemic inflammation and often accompany sepsis and septic shock. Hyperthermia (central body temperature > 38°C) is due to the effect of pyrogens. It is a generally recognized manifestation of infectious diseases [5]. However, some observational studies revealed hypothermia (body temperature < 36 °C) in 35% of patients with sepsis [6].
It is known that unintentional hypothermia can be complicated by dysfunction of cardiovascular system, central nervous system, blood coagulation system and other ones [7, 8]. Hypothermia in patients with sepsis may be associated with immune suppression, hypodynamic shock and some other manifestations. Nevertheless, the effect of temperature imbalances on the course and outcomes of sepsis is still a matter of debate [9–11].
The causes of hypothermic reaction in patients with sepsis also raise certain questions. Analysis of cytokines as main mediators of hyperthermia showed that suppression of pro-inflammatory reaction following sepsis is not always accompanied by body temperature decrease [12, 13]. Importantly, damage to endothelial glycocalyx may be essential in hypothermia following sepsis. Indeed, this event contributes to vascular tone decrease, leads to heat loss and prevents the body's ability to regulate central temperature [13, 14].
The objective was to assess the relationship of body temperature disorders with organ dysfunction and outcomes in patients with sepsis.
Material and methods
A single-center retrospective study enrolled data of 353 ICU patients admitted to the Volosevich Clinical Hospital between 2018 and 2020. Inclusion criterion was signs of sepsis upon admission to ICU according to Sepsis-3 definition, i.e. focal infection combined with organ dysfunction (SOFA score increase by more than 2 points compared to baseline values). We collected biometric data, indicators of clinical severity and severity of organ dysfunction, including diagnosis, surgical intervention before admission to ICU, ICU-stay, mortality, SOFA score upon admission, special methods of treatment (mechanical ventilation, inotropic / vasopressor support), body temperature, hemodynamic parameters and laboratory data (pH, serum glucose, lactate, hemoglobin, bilirubin, creatinine, white blood cell count, platelet count, international normalized ratio (INR)).
We analyzed data upon admission to ICU, 12 and 24 hours later. Additionally, blood sampling and evaluation of endothelial glycocalyx (EG) components were carried out in 21 patients (heparan sulfate proteoglycan (HSPG) and syndecan 1 (S1)). EG components were assessed by using of enzyme immunoassay (ELISA Kit for HSPG, SDC 1, USA). Data were recorded at the beginning of the study, after 2 and 24 hours.
Statistical analysis was performed using the SPSS software package version 21.0 (SPSS Inc., USA). Data distribution normality was tested using the Shapiro–Wilk test. Data are presented as mean and standard deviation or median (25th-75th percentile) depending on distribution. Statistical analysis was performed using parametric and non-parametric tests (Student's t-test and Mann-Whitney test). The χ2 test was used to analyze qualitative features. Repeated measure data were assessed by variance analysis for repeated measures followed by contrast test or Friedman's test depending on distribution. Spearman's correlation analysis with rho coefficient was used to identify data correlation. For all tests, p<0.05 was considered significant.
Results
A total of 6304 ICU cards were analyzed. The study included 353 ones with sepsis who accounted for 5.6% of all ICU patients. Demographic data, mean age and length of ICU-stay are presented in Table 1.
Table 1. Characteristics of patients with sepsis
|
Variable |
Patients (n=353) |
|
Male, n (%) |
191 (54.1) |
|
Female, n (%) |
162 (45.9) |
|
ICU-stay, days |
3 (2—6) |
|
Overall mortality, n (%) |
150 (42.5) |
|
Cause of sepsis, n (%) |
|
|
Pulmonary infection |
115 (32.6) |
|
Abdominal infection |
141 (39.9) |
|
Urological infection |
40 (11.3) |
|
Skin and soft tissue infection |
27 (7.6) |
|
Vascular infections |
15 (4.2) |
|
CNS infections |
9 (2.5) |
|
Other infections |
5 (1.7) |
Note. CNS — central nervous system; ICU — intensive care unit.
When ranking by temperature, we found that 82 (23.2%) patients admitted with hypothermia (<36°C), 254 (72.0%) patients with normal/subfebrile body temperature (36-38°C) and 17 (4.8%) patients with febrile temperature (over 38°C). Among all ICU patients, 173 (49%) ones admitted after previous surgery. Surgery was performed in 52 (63%) patients with hypothermia. There were 30 (37%) therapeutic patients with hypothermia.
Hemodynamic parameters and laboratory data depending on baseline body temperature are presented in Table 2. Vasopressor support and low mean arterial pressure (MAP) were more common in patients with hypothermia upon admission to ICU and after 24 hours compared to patients with normal and elevated body temperature. Moreover, hypothermia was followed by more severe acidosis. Correlation analysis revealed the relationship between body temperature and pH upon admission to ICU (rho =0.304, p<0.001). There were no significant between-group differences in SOFA scores, serum glucose, bilirubin, creatinine, platelet count and INR.
Table 2. Characteristics of patients depending on body temperature
|
Variable |
Hypothermia |
Normal/febrile temperature |
p-value |
|
Body temperature upon admission, °C |
35.6 (35.0—35.7) |
36.5 (36.1—37.0) |
<0.001 |
|
Vasopressor support, n (%) |
57 (70.4) |
156 (57.6) |
0.039 |
|
MAP upon admission, mm Hg |
77 (60—90) |
82 (67—98) |
0.023 |
|
MAP after 12 hours, mm Hg |
78 (70—88) |
81 (72—90) |
0.177 |
|
MAP after 24 hours, mm Hg |
77 (70—90) |
83 (73—93) |
0.03 |
|
pH upon admission |
7.21 (7.12—7.34) |
7.34 (7.23—7.41) |
<0.001 |
|
Lactate upon admission, mmol/l |
4.0 (1.7—8.4) |
3.1 (1.7—6.4) |
0.19 |
|
WBC count upon admission, × 109/L |
12.7 (6.7—20.4) |
13.0 (7.8—19.7) |
0.54 |
|
Mortality, n (%) |
39 (48) |
111 (40) |
0.445 |
Note. MAP — mean arterial pressure. WBC — white blood cell.
Subgroup of therapeutic patients
Hemodynamic parameters and laboratory data of therapeutic patients depending on baseline body temperature are presented in Table 3. Patients with hypothermia upon admission to ICU and no need for surgery had lower MAP, more severe metabolic lactic acidosis, INR increase and lower serum glucose. Moreover, therapeutic patients with hypothermia following sepsis were characterized by higher mortality rate (53.3% compared to 31.5% in patients with normal and febrile body temperature).
Table 3. Characteristics of therapeutic patients with sepsis depending on body temperature
|
Variable |
Hypothermia |
Normal/febrile temperature |
p-value |
|
Body temperature upon admission, °C |
35.5 (35.0—35.7) |
36.7 (36.3—37.3) |
<0.001 |
|
Vasopressor support, n (%) |
20 (66.7) |
69 (47.63) |
0.041 |
|
MAP upon admission, mm Hg |
65 (54—89) |
82 (70—98) |
0.022 |
|
MAP after 12 hours, mm Hg |
76 (70—83) |
83 (70—91) |
0.079 |
|
MAP after 24 hours, mm Hg |
75 (65—79) |
83 (70—91) |
0.012 |
|
pH upon admission |
7.23 (7.11—7.4) |
7.35 (7.233—7.43) |
0.017 |
|
Lactate in 12 hours after admission, mmol/l |
2.7 (1.8—5.9) |
2.4 (1.5—4.1) |
0.03 |
|
INR in 24 hours after admission |
1.7 (1.3—2.2) |
1.3 (1.1—1.6) |
0.03 |
|
Serum glucose in 24 hours after admission, mmol/l |
6.6 (4.6—10.3) |
7.8 (6.2—10.3) |
0.023 |
|
Mortality, n (%) |
16 (53.3) |
46 (31.5) |
0.023 |
Note. MAP — mean arterial pressure; INR — international normalized ratio.
There were no between-group differences in SOFA score, WBC and platelet count, serum bilirubin and creatinine levels. Correlation analysis of therapeutic patients revealed a relationship between body temperature and pH upon admission to ICU (rho=0.328, p<0.001), as well as between body temperature and MAP (rho=0.231, p<0.002).
Indicators of endothelial glycocalyx components
Parameters of EG components were analyzed in 8 patients with hypothermia and 13 patients with normothermia/febrile temperature. Concentrations of S1 and HSPG within 2 hours are presented in Table 4. It is noteworthy that patients with hypothermia had higher serum S1 at all stages of the study compared to those with normal or febrile body temperature. At the same time, we found increment of serum S1 by 20% within 2 hours of ICU-stay in patients with hypothermia (p<0.001). After 24 hours, serum S1 concentrations were similar to baseline values in patients with hypothermia. There were no significant between-group differences in HSPG concentration.
Table 4. Changes of endothelial glycocalyx components in hypothermic and normothermic/febrile patients with sepsis
|
Variable |
Hypothermia |
Normal/febrile temperature |
p-value |
|
S1 upon admission, ng/ml |
2.55 (1.15—3.29) |
0.91 (0.70—1.88) |
0.010 |
|
S1 in 2 hours after admission, ng/ml |
3.06 (1.75—7.01) |
0.94 (0.57—1.31) |
0.003 |
|
S1 in 24 hours after admission, ng/ml |
2.23 (1.44—2.95) |
0.74 (0.46—0.95) |
0.003 |
|
HSPG upon admission, ng/ml |
2.94 (2.17—5.16) |
2.56 (1.48—7.42) |
0.800 |
|
HSPG in 2 hours after admission, ng/ml |
3.26 (1.93—7.59) |
3.00 (1.79—5.62) |
0.657 |
|
HSPG in 24 hours after admission, ng/ml |
2.15 (1.70—4.13) |
1.58 (1.40—6.95) |
0.711 |
Note. S1 — syndecan-1; HSPG — heparan sulfate proteoglycan.
Discussion
According to our data, hypothermia in ICU patients with sepsis is accompanied by more severe hemodynamic disorders and acidosis. Moreover, hypothermia is associated with impaired tissue perfusion and coagulation abnormalities, as well as unfavorable outcomes in therapeutic patients. Patients with hypothermia had certain concomitant syndromes, mainly due to pulmonary, abdominal and urological infections, which could affect the course and outcomes of disease. Other authors reported similar results [10, 15–17].
The majority of patients (95.2%) admitted to ICU with normal body temperature or hypothermia. Considering that 49% of patients admitted after surgery, we can assume that some patients developed unintentional hypothermia due to insufficient intraoperative temperature control. According to literature data, intraoperative body temperature control is still an important problem requiring changes in approaches to thermometry and treatment of hypothermia in ICU patients with a wider use of hardware monitoring, including nasopharyngeal and esophageal sensors, as well as devices for warming in perioperative period [18, 19].
Lower body temperature in patients with sepsis was associated with more severe arterial hypotension. These changes were accompanied by metabolic acidosis that is confirmed by direct correlation between body temperature and pH upon admission to ICU. More common hemodynamic disturbances in patients with hypothermia required inotropic/vasopressor support that is consistent with the results obtained by other authors [15, 18, 19]. At the same time, mortality was similar in both groups.
Hypothermia may be unintentional in postoperative patients [20]. Therefore, we additionally analyzed therapeutic patients with sepsis. Analyzing hemodynamic parameters and laboratory data upon admission to ICU in these patients, we found a direct correlation between severity of hypothermia and arterial hypotension. In addition, hypothermia associated with non-surgical sepsis was accompanied by significant metabolic disturbances including lactic acidosis and higher INR. These disorders characterize severity of organ dysfunction that indicates the need for more comprehensive approach to treatment of these patients in addition to maintaining normothermia [10, 20]. It is noteworthy that we observed a lower severity of hyperglycemia in therapeutic patients with hypothermia and sepsis. This phenomenon can be explained by adrenal insufficiency. The last one is common in patients with sepsis and septic shock and accompanied by hypotension, hypoglycemia, electrolyte disorders and hypothermia [21, 22].
Mortality rate in therapeutic patients with sepsis and hypothermia is 53.3% that is similar to previous data [23–25]. This value significantly exceeds mortality rate in patients with normal and febrile body temperature. This is consistent with the data of experimental studies, which also showed that fever associated with infectious diseases can be a sign of physiological reaction. Indeed, fever increases the effectiveness of antibiotics and improves function of immune cells via suppression of replication of bacteria and viruses [26]. These data indicate the need for timely screening for organ dysfunction and early personalized therapy in patients with hypothermia and sepsis.
Endotheliopathy is the key mechanism of sepsis-associated multiple organ failure. We found that hypothermia was accompanied by higher level of S1 at all stages of the study. Wiewel M.A. et al. [13] also reported the relationship between hypothermia and characteristics of glycocalyx components in patients with sepsis. The authors emphasized that hypothermia following infectious process is associated with release of endothelial damage marker (fractalkine). Probably, endothelial damage and vasodilation are among the factors disrupting thermoregulation in sepsis and leading to hypothermia. Nevertheless, additional prospective studies are required to assess the role of endothelium in temperature imbalance in patients with sepsis.
Conclusion
Hypothermia upon admission to intensive care unit can be a predictor of unfavorable course of disease and outcomes in patients with sepsis. This is especially true for therapeutic patients. Hypothermia following sepsis is accompanied by more severe shock and acidosis, as well as endotheliopathy and coagulopathy. Further studies of functional role of endothelial glycocalyx in hypothermia are needed.
The authors declare no conflicts of interest.