effects of target temperature management on the outcome of septic patients with...

Research ArticleEffects of Target Temperature Management on the Outcome ofSeptic Patients with Fever

Ye Gao,1 Jianjun Zhu,2 Chenyu Yin,1 Jianliang Zhu,2 Tao Zhu,1 and Lijun Liu2

1 Intensive Care Unit, Taicang Affiliated Hospital of Soochow University, Taicang 215400, China2Intensive Care Unit, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China

Correspondence should be addressed to Lijun Liu; [email protected]

Received 8 August 2017; Accepted 8 October 2017; Published 12 November 2017

Academic Editor: Hideo Inaba

Copyright © 2017 Ye Gao et al. This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives. To investigate the effects of target temperature management on hemodynamic changes, inflammatory and immunefactors, and clinical outcomes of sepsis patients with fever. Methods. Patients diagnosed with sepsis with a core temperature of≥39∘C were randomly divided into two groups: a low-temperature group (LT group: 36.5∘C–38∘C) and a high-temperature group(HT group: 38.5∘C–39.5∘C). A target core temperature was achieved within 6 hrs posttreatment and maintained for 24 hrs. Then,the hemodynamic changes, inflammatory and immune factors, and clinical outcomes were evaluated. Results. Compared with theHT group, C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and tumor necrosis factor-𝛼 (TNF-𝛼) showed asignificant decrease in the LT group (𝑃 < 0.05). In contrast, IL-4 and IL-10 were higher in the LT group than in the HT group(𝑃 < 0.05). The CD4-T lymphocyte (CD4+), CD8-T lymphocyte (CD8+), and monocytic human leukocyte antigen-DR (mHLA-DR) in the LT group were higher than in the HT group (𝑃 < 0.05).The ICU stay and the anti-infection treatment costs were higherin the LT group (𝑃 < 0.05). Conclusion. Low-temperature management of patients resulted in a low level of proinflammatorycytokines. Excessive temperature control in sepsis patients with fever may be harmful.

1. Introduction

Sepsis remains a significant healthcare issue that may triggerhigh mortality and expensive healthcare cost [1]. It mayprogress into severe sepsis, septic shock, or even multi-ple organ dysfunction syndrome (MODS) if no treatmentoptions are available immediately after diagnosis [2]. Nowa-days, the mortality and prevalence of sepsis are on risealthough extensive efforts have been made to better under-stand its pathogenesis [3].

Hyperthermia (>38∘C) and hypothermia (<36∘C) are themajor clinical manifestations for patients with sepsis. In aprevious study, Young et al. reported that elevated peaktemperature in the first 24 hrs in the ICU was associatedwith decreased in-hospital mortality in critically ill patientswith infection [4]. However, hyperthermia may contributeto tissue and organ damage, which finally results in poorprognosis. For example, Laupland et al. reported that patientswith a temperature of ≥39.5∘C showed a higher incidence of

arrhythmia, tachycardia, severe brain injury, and even mor-tality comparedwith their counterparts with a temperature of<39.5∘C [5]. Similarly, hypothermia may also induce deterio-ration of infection and coagulation disorder and even deathas it may inhibit the migration of white blood cells and affectphagocytosis [6]. In septic rats, hypothermia may increasethe prevalence of complications after infection comparedwith the mild hypothermia in septic rats [7]. Additionally,Yang et al. showed that controlling fever to a lower range of36.0∘C–37.5∘C may induce harmful effects in patients withrefractory septic shockwith elevation of white blood cells andneutrophils, which implied the decreased capacity of anti-infectionwhen compared to controllingwithin a higher rangeof 37.5∘C–38.3∘C [8]. In experimental sepsis rats, postcondi-tioning hypothermia was associated with increased survivalduration during experimental sepsis [9]. Moreover, in aclinicalmulticenter randomized controlled trial, fever controlusing external cooling was considered to be safe and could

HindawiBioMed Research InternationalVolume 2017, Article ID 3906032, 10 pageshttps://doi.org/10.1155/2017/3906032

https://doi.org/10.1155/2017/3906032

2 BioMed Research International

decrease the vasopressor requirements and early mortality inseptic shock fever patients requiring vasopressors [10].

To date, there are still some disputes on temperaturecontrol for septic patients with fever. In this study, we aimto identify the temperature range that may benefit septicpatients after target temperature management.

2. Materials and Methods

2.1. Patients. Septic patients with a core temperature of≥39.0∘C admitted to the ICU of the Second Affiliated Hos-pital of Soochow University and Taicang Affiliated Hospitalof Soochow University from June 2015 to July 2016 wereincluded in this study. Sepsis was diagnosed according to theSepsis-3.0 diagnostic standards as previously described [11].The inclusion criteria were as follows: (i) those diagnosedwith sepsis according to the 3.0 standard, (ii) those aged18–85 yrs, (iii) those with an expected ICU stay of at least48 hrs, and (iv) those with a core temperature of ≥39.0∘C.These patients also comprised those with septic shock. If theymet the inclusion criteria, they were included immediately.Otherwise, antishock therapy should be performed accordingto the guidelines, and then they were included until theymet the inclusion criteria. All the exclusion criteria were asfollows: (i) those that received defervescence drugs (e.g., non-steroidal anti-inflammatory drug, NSAID) and/or intravas-cular cooling; (ii) those with severe cardiac diseases such asobstructive myocardiopathy, myocardial infarction, and ven-tricular regional wall motion abnormalities; (iii) those thatreceived agents inhibiting the inflammatory mediators (e.g.,glucocorticosteroid or ulinastatin); (iv) those with refractoryshock [12] as previously described; (v) those that are preg-nant; (vi) those with nervous system diseases that may affectthe thermoregulatory center, such as cerebral hemorrhage,craniocerebral trauma, intracranial infection, and new cere-bral infarction; (vii) those that received renal replacementtherapy; and (viii) those who terminated the treatment.All patients signed an informed consent form. The studyprotocols were approved by the Ethical Committee of the Sec-ond Affiliated Hospital of Soochow University and TaicangAffiliated Hospital of Soochow University.

2.2. Grouping. Patients diagnosed with sepsis with a coretemperature of ≥39∘C were randomly divided into twogroups: a group achieving a “low-temperature” range (LTgroup: 36.5∘C–38∘C) and a group achieving a “high-temperature” range (HT group: 38.5∘C–39.5∘C) by physicalmethods including a water-flow cooling blanket and icepacks. A target core temperature was achieved within 6 hrsposttreatment and maintained for 24 hrs. All the monitoringof core temperature was performed through rectal or bloodtemperature methods as previously described [13].

2.3. Treatment. The patients were managed according to theguidelines for bundle therapy for sepsis and septic shockas previously described [14]. The major treatment optionsincluded fluid resuscitation, vasoactive agents, anti-infectivetherapy, and other supportive therapies such as analgesics,sedative therapy, respiratory support, blood sugar control,

prevention of deep vein thrombosis, nutritional support, andstress ulcer management.

2.4. Data Collection. The data collected included age, sex,admission diagnosis, infection sites, ICU stay, duration andmethods of temperature management, Acute Physiology andChronic Health Evaluation II (APACHE II) score, SequentialOrgan Failure Assessment (SOFA) score, drugs for analgesiaand sedative therapy, way of ventilation, and temperaturemonitoring methods.

2.5. Vital Signs and Laboratory Index. The vital signs, cir-culating monitor indices, routine blood test, bleeding time,coagulation time, infection indices, immune inflammatoryfactors, blood gas analysis, and blood sugar were determinedbefore temperature management, as well as 12 hrs and 24 hrsafter temperature management.

2.6. Hemodynamics and the Use of Vasoactive Agent. Thehemodynamics of the patients were monitored using thePICCO system as previously described [15]. The vasoactiveagent used for the subjects was noradrenalin, pumped inthrough a central venous catheter.

2.7. Evaluation of Outcomes. The outcomes evaluated in thestudy included ICU stay, anti-infection cost, and 28-daysurvival rate.

2.8. Statistical Analysis. PASWStatistics 18 software was usedfor the data analysis. Measurement data that are normallydistributed were presented as mean ± standard deviation,while those not normally distributed were presented asmedian (interquartile). Student’s 𝑡-test or Mann–Whitney 𝑈test was used for intergroup comparison. Enumeration datawere compared using chi-square test. R-Project software andBionom.test were used to estimate the 95%CI of patients’ pro-portion with a 50% decrease of the vasoactive agent. Prop.testwas utilized to compare the difference. Kaplan-Meiermethodwas used to calculate the 28-day survival. Log-rank test wasused for the intergroup comparison.𝑃 < 0.05was consideredto be statistically significant.

3. Results

3.1. Patient Characteristics. In total, 63 patients (males: 48,females: 15, mean age: 58.54±16.82 yrs) were included in thisstudy, amongwhom 31 patients were assigned to the LT groupand 32 patients were assigned to the HT group. No statisticaldifferences were noticed in the sex, age, diseases, APACHEII and SOFA scores, infection source, pathogen, and compli-cations between the two groups (𝑃 > 0.05, Table 1). Duringthe 24 hrs of the temperature management, no incidenceof severe cardiac arrhythmia or pressure sores was noticedin each group. Eight cases showed shivering, which wasmitigated after sedative therapy.

3.2. Changes of Temperature and Hemodynamics at Each TimePoint. Before temperature control, no statistical differenceswere noticed in the core temperature, heart rate,mean arterial

BioMed Research International 3

Table 1: Clinical characteristics at baseline.

Variable Low-temperature group(𝑛 = 31)

High-temperature group(𝑛 = 32)

𝑇 or 𝜒2 or Mann–Whitney𝑈 value 𝑃 value

Age (yr) 56.90 ± 14.75 60.13 ± 18.70 0.758 0.452Gender (male/female) 23/8 25/7 0.134 0.714Complication (cases) 1.417 0.702

Hypertension 12 9Diabetes 5 7COPD 4 3Old cerebral infarction 7 10

APACHE II score 22 (20∼30) 24 (21∼31) 399.00 0.538SOFA score 9 (7∼13) 9 (6∼13) 491.50 0.950Classification of diseases (cases) 0.176 0.674

Medical diseases 20 18Surgical diseases 11 14

Infective site 2.816 0.412Lung 19 24Abdominal cavity 9 7Urinary passage 1 1Catheter relevance 2 0

Infectious pathogens 0.718 0.949Gram-positive bacteria 5 6Gram-negative bacteria 15 13Fungal infection 2 2

Mixed infection 6 6Others 3 5Number of mechanical ventilationinstances (rate) 11 (35.5%) 13 (40.6%) 1.417 0.702

Accuracy of anti-infective therapy 1.171 0.557Yes 24 25No 4 2Uncertainty 3 5

APACHE II score: Acute Physiology and Chronic Health Evaluation II score; SOFA score: Sequential Organ Failure Assessment score.

pressure (MAP), central venous pressure (CVP), stroke vol-ume (SV), cardiac output (CO), global end-diastolic volume(GEDV), and systemic vascular resistance index (SVRI) (𝑃 >0.05, Figure 1). Within 24 hrs after temperature control, thecore temperature, heart rate, SV, andCO in the LT groupwerestatistically lower than those of the HT group (𝑃 < 0.05). Incontrast, no statistical differences were noticed in the MAP,CVP, GEDV, and SVRI between the LT group and the HTgroup (𝑃 > 0.05).

3.3. Changes of Lactic Acid in Each Time Point of TemperatureControl. No statistical differences were identified in lacticacid in both groups before temperature control (𝑃 > 0.05).About 12 hrs and 24 hrs after temperature control, the lacticacid in the LT group was significantly higher than that in theHT group (𝑃 < 0.05, Table 2).

3.4. Comparison of Vasoactive Agent Utilization. At the base-line level, 23 cases received noradrenalin in the LT group

and 25 cases received noradrenalin in the HT group, whichshowed no statistical differences compared with the HTgroup (74.2% versus 78.1%, 𝑃 = 0.714). Nevertheless, about24 hrs after temperature control, the proportion of patientswith noradrenalin decrease of 50% compared to the baselinein the HT group was statistically higher than that of the LTgroup (𝑃 < 0.01, Figure 2).

3.5. Comparison of Inflammatory and Immune Indices. At thebaseline level, no statistical differences were noticed in thewhite blood cell (WBC) count, C-reactive protein (CRP), andprocalcitonin (PCT) in both the low-temperature and thehigh-temperature groups (𝑃 > 0.05). In contrast, about 24 hrsafter temperature control, theWBC, CRP, and PCT in the HTgroupwere statistically higher than in the LT group (𝑃 < 0.05,Table 3).

No statistical differences were identified in IL-6 andTNF-𝛼 in both groups before the temperature control (𝑃 > 0.05),whereas IL-6 andTNF-𝛼 in the LT group showed a significant


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Table 2: Levels of lactic acid (mmol/L) at different time points in the two groups.

Time (h) LT group (𝑛 = 31) HT group (𝑛 = 32) Mann–Whitney 𝑈 value 𝑃 value0 1.20 (1.10∼1.60) 1.15 (0.83∼2.30) 495.00 0.98912 1.75 (1.20∼2.43) 1.20 (0.70∼1.95) 349.50 0.04324 1.80 (1.18∼2.50) 1.05 (0.90∼1.90) 341.50 0.033

Table 3: Changes of WBC, CRP, and PCT at different time points of temperature management.

Time (h) LT group (𝑛 = 31) HT group (𝑛 = 32) Mann–Whitney 𝑈 value P value

WBC (109/L) 0 15.70 (12.30∼26.52) 17.25 (10.80∼27.37) 479.00 0.98324 10.57 (6.39∼14.10) 13.90 (9.60∼23.08) 331.00 0.023

CRP (mg/L) 0 161.51 (81.15∼276.51) 164.60 (85.68∼205.71) 467.00 0.85524 89.92 (43.08∼144.03) 137.95 (76.05∼181.34) 327.00 0.031

PCT (𝜇g/L) 0 4.73 (2.07∼9.46) 5.42 (1.69∼7.51) 473.50 0.75724 2.65 (0.70∼5.65) 5.38 (2.36∼12.11) 341.50 0.034

Table 4: Changes of proinflammatory factors at different time points of temperature management.

Time (h) LT group (𝑛 = 31) HT group (𝑛 = 32) Mann–Whitney 𝑈 value 𝑃 value

IL-6 (pg/ml)0 40.40 (13.68∼105.01) 37.19 (15.16∼108.76) 491.00 0.94512 20.19 (17.34∼49.04) 43.57 (21.33∼114.65) 361.00 0.04524 17.54 (13.11∼98.01) 38.40 (29.08∼161.54) 182.00 0.010

Time (h) LT group (𝑛 = 31) HT group (𝑛 = 32) 𝑇 value 𝑃 value

TNF-𝛼 (pg/ml)0 2.45 ± 2.33 2.20 ± 1.96 0.450 0.65412 1.56 ± 0.65 2.11 ± 0.80 2.950 0.00524 1.66 ± 0.96 2.46 ± 1.26 2.837 0.006

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decrease compared with these of the HT group at 12 hrs and24 hrs after temperature control (𝑃 < 0.05, Table 4).

IL-4 and IL-10 in both groups showed no statistical dif-ferences at the baseline levels (𝑃 > 0.05). Compared with thebaseline level, IL-4 in the LT group showed a gradual increaseat 12 hrs and 24 hrs after temperature control. Meanwhile,IL-10 reached the peak level at 12 hrs, followed by a gradual

decrease at 24 hrs. In the HT group, both IL-4 and IL-10 showed a trend of decrease. Statistical differences werenoticed in IL-4 and IL-10 between the two groups at 12 hrsand 24 hrs after temperature control (𝑃 < 0.05, Table 5).

At the baseline level, the lymphocyte subpopulation(CD4+ andCD8+) andmonocytic human leukocyte antigen-DR (mHLA-DR) showed no statistical differences in bothgroups (𝑃 > 0.05). The lymphocyte subpopulation (CD4+and CD8+) and mHLA-DR in the LT group showed agradual increase after temperature control comparedwith thebaseline level (𝑃 < 0.05). In the HT group, the lymphocytesubpopulation (CD4+ and CD8+) showed no significantdifference compared to the baseline level (𝑃 > 0.05). For theexpression of mHLA-DR, a significant increase was noticedin the LT group compared to the control group, while that ofthe HT group showed a significant decrease compared withthe baseline level (𝑃 < 0.05, Figure 3).

3.6. Comparison of ICU Stay and Anti-InfectionTherapy Cost.Compared with the HT group, the ICU stay in the LT groupshowed a significant increase. Similarly, the anti-infectiontherapy cost in the LT group showed a significant increasecompared with that of HT group (𝑃 < 0.05, Figure 4).

3.7. Comparison of 28-Day Survival Analysis. The 28-daysurvival rate in the LT group was 71.0%, while that in the


Table 5: Changes of anti-inflammatory factors at different time points of temperature management.

Time (h) LT group (𝑛 = 31) HT group (𝑛 = 32) 𝑇 value 𝑃 value

IL-4 (pg/ml)0 3.64 ± 0.64 3.63 ± 0.62 0.044 0.96512 4.56 ± 1.27 3.56 ± 0.80 3.753 0.00024 4.90 ± 0.95 3.46 ± 0.65 3.906 0.000

Time (h) LT group (𝑛 = 31) HT group (𝑛 = 32) Mann–Whitney 𝑈 value 𝑃 value

IL-10 (pg/ml)0 8.91 (6.14∼45.94) 7.75 (5.32∼21.75) 449.00 0.30512 10.03 (5.91∼25.34) 6.96 (4.45∼8.91) 325.50 0.00924 8.80 (5.47∼15.82) 5.54 (3.98∼6.83) 292.00 0.047

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HT group was 81.3%. Using log-rank analysis, no statisticaldifferences were noticed in the 28-day survival rates betweenthe two groups (𝑃 = 0.298, Figure 5).

4. Discussion

Fever is an adaptive physiological response to infection andis an important clinical sign in patients with sepsis. In the

ICU, more than 90% of sepsis patients have fever [16], whichis also considered an independent risk factor for death [5,17]. As an effective strategy for organ protective therapy,body temperature management has been widely used in thetreatment of fever [18]. Previous clinical studies reportedthat body temperature management may affect the survivalof patients with sepsis [19, 20]. For instance, Peres Botaet al. [6] found that patients with septic shock combined


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Figure 5:The prognosis and 28-day survival rate analysis in the twogroups.

with hypothermia showed the highest mortality. Meanwhile,patients with natural hypothermia showed a higher risk ofdeath compared with those with fever [21]. However, thereis still a lack of convincing evidence about how patients withsepsis and fever may benefit from temperature management.

An average core temperature of more than 38.3∘C isdefined as fever in sepsis, while a core temperature of morethan 39.5∘C is defined as hyperpyrexia [22]. Fever in sepsiscould lead to an increased heart rate and elevation of oxygendemand, while decreased body temperature could reduce theoxygen consumption and energy requirements of the tissues.In our study, patients with hypothermia showed a decreasedheart rate and SV, which then led to a decrease of cardiac out-put directly, thereby reducing tissue perfusion and increasing

the risk of poor prognosis. Our study also showed that thelevels of blood lactic acid in patients with high temperaturewere lower than those in patientswith lower temperature aftertemperature management for 24 hours. This indicated thathigher CO and higher oxygen delivery in patients with hightemperature caused increased levels of tissue perfusion andpromoted the aerobic activity and function recovery of tissuesand organs, which finally contributed to the prognosis. Suet al. [23] showed that, in a sheep peritonitis sepsis model,the sheep in the fever group had higher oxygenation index,lower lactic acid level, and longer survival time comparedwith the sheep in other groups.The normal body temperatureof sheep was in the range of 38.0∘C–39.0∘C. Therefore, thetemperature of >39.0∘C was not considered as high fever, butmoderate fever. These studies suggested that patients withhigh temperature may have a better prognosis by means oftargeted temperature management.

In addition, in order to investigate whether the dose ofvasoactive agent (noradrenaline) could be reduced throughtarget temperature management in sepsis patients with fever,the use of vasoactive agent in the two groups was analyzed inour study. Our results showed that there was no significantdifference for the proportion of patients in the use ofvasoactive agent in the two groups before temperature man-agement. However, the proportion of patients in whom thedose of vasoactive agent decreased 50% baseline levels aftertemperature management for 24 h was significantly higherin the high-temperature group than in the low-temperaturegroup, whichmay be related to higher CO and higher oxygendelivery that cause the easy correction of shock (lower levelof lactic acid) in patients with high temperature. However,in a clinical multicenter randomized controlled study, thedose of vasoactive agent was reduced 2 times in septic shockpatients with fever after targeted temperature management(36.5∘C–37.0∘C) for 48 hours, and the 14-day mortality wassignificantly lower [10]. The reasons for this contradictory


result may be associated with temperature management timeand duration and clinical heterogeneity of sepsis patients.Therefore, the relationship between the use of vasoactivedrugs and the targeted temperature management in sepsispatients with fever should be further explored.

When sepsis occurs, a network is established between theendogenous inflammatory mediators including vasoactivesubstances, cytokines, chemokines, oxygen radicals, acutephase reactants, bioactive lipid, plasma enzyme systemproducts, and fibrinolytic pathways. In cases of networkimbalance, widespread damage of various systems and organswas induced. Proinflammatory factors such as IL-1, IL-6, and TNF-𝛼 could aggravate tissue injury, while anti-inflammatory factors such as IL-4, IL-10, and transforminggrowth factor-beta (TGF-𝛽) could inhibit the inflammatoryreaction. The destruction of the dynamic balance betweenproinflammatory factors and anti-inflammatory factors maybe an important mechanism for the development of sepsis. Insome experiments, fever could improve the endotoxin effects,and temperature management would affect the changes ofinflammation mediators in sepsis. An animal experimentshowed that, compared with the normal temperature group(36∘C–38∘C), the rats injected with endotoxin had reducedmortality, decreased proinflammatory factors such as IL-6and TNF-𝛼, and decreased NO in the mild-to-moderate low-temperature (34∘C-35∘C, 30∘C-31∘C) group [24]. Leon et al.[25] found that lowering body temperature could reducethe release of certain inflammatory mediators (IL-6 andTNF-𝛼) and extent of oxidative response and improve thesurvival rate in septic rats. Huet et al. [26] revealed thathypothermia (32∘C) could significantly reduce the mortalityof rats with endotoxemia, which may be associated with anincreased protective effect of the anti-inflammatory factorIL-10. In this study, a decrease of WBC, CRP, PCT, andproinflammatory factors (IL-6 and TNF-𝛼) and an increaseof anti-inflammatory factors (IL-4 and IL-10) were noticedin the low-temperature group after 24 hours of temperaturemanagement, while these indexes had little changes in thehigh-temperature group after 24 hours of temperature man-agement. This indicated proper reduction of body tempera-ture to 36.0∘C–38.5∘C; the endotoxin induced body excessiveinflammatory reaction was inhibited, and the survival rate ofpatients increased. For these reasons, the reduction of bodytemperature may be related to the decrease of metabolismand energy demands of inflammatory cells, the reduction ofproinflammatory cytokines (IL-6 and TNF-𝛼) release, andthe increase of the anti-inflammatory cytokines (IL-4 and IL-10) contents.

In addition, our study also observed that there were nosignificant differences in the levels of lymphocytes subpopu-lations (CD4+ and CD8+) and mHLA-DR at the beginningof temperature management in the two groups. The levels oflymphocytes subpopulations (CD4+ and CD8+) andmHLA-DR were increased in the low-temperature group after 24hours of temperaturemanagement. No significant differenceswere noticed in the levels of CD4+ and CD8+ in the high-temperature group after 24 hours of temperature manage-ment, whereas mHLA-DR showed a decreased trend. Lym-phocytes are the main cells of the adaptive immune response,

which are involved in the innate immune response. Theyplay a vital role in the immune response against pathogenicmicroorganisms.There is a serious lack of important immunecells such as CD4+ T-cells, CD8+ T-cells, B-cells, dendriticcells, and mononuclear cells in sepsis. HLA-DR is a classMHC-II molecule in the immune index and plays an impor-tant role in the monocyte antigen presenting process. Theexpression level of mHLA-DR is the most commonly usedbiomarker in the evaluation of the immune status of sepsis,and its persistent low expression is the main feature ofimmunosuppression stage in sepsis patients [27]. Some stud-ies found that mHLA-DR could be used to assess the prog-nosis, and its persistent low expression (the positive rate wasbelow 20%–40%) is also an independent risk factor for septicshock and the incidence of nosocomial infection in ICUhospitalization patients [28, 29]. However, the lymphocytesubsets (CD4+ andCD8+) andmHLA-DRonly reflect part ofthe body’s immune function. The changes of immune statusin patients with sepsis are very complex and dynamic, andthe heterogeneity among patients is great; therefore, the useof these indicators for the assessment of the overall immunestatus needs to be discussed.

For the effects of temperature management on theoutcome of septic patients, we investigated the ICU stayand anti-infection therapy cost. After achieving a targettemperature, the ICU stay in the high-temperature groupwas comparatively lower than that in the low-temperaturegroup, together with the anti-infection therapy cost for theICU hospitalization. Meanwhile, the 28-day survival rate inthe high-temperature group was higher than that in the low-temperature group (81.3% versus 71.0%). Although no statis-tical differences were identified (𝑃 = 0.298), this indicatedthat septic patients in the high-temperature group showedbetter outcome and prognosis than those in the low-temperature group.

There are really some limitations in this study. Septicpatients were included in separate ICUs from two differenthospitals, which may trigger some differences for the pro-cedures except for temperature management. No subgroupanalysis was carried out in this study as the sample size wasnot large enough, which may affect the outcome to someextent. For the utilization of vasoactive agents, noradrenalinis the major agonist for the 𝛼 receptor, but it may affect thecardiac 𝛽1 receptor. However, in this study, we do not analyzethe effects of such agent on the heart rate and CO, whichmay cause differences in the results. For the analysis of 28-daysurvival rate, no statistical differences were noticed betweenthe two groups whichmay be related to the small sample size,duration of temperature management, and disease severity.

5. Conclusions

Low temperature results in a low level of proinflammatorycytokines in septic patients with fever, and the quantityof lymphocyte subsets becomes high. Meanwhile, the ICUstay in the high-temperature group was comparatively lowerthan that in the low-temperature group, together with theanti-infection therapy cost for the hospitalization. Excessivetemperature control may be harmful to septic patients.


Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper.

Authors’ Contributions

Ye Gao and Jianjun Zhu equally contributed to this work.

Acknowledgments

This study was supported by the Youth Science and Tech-nology Project in Science and Education of Suzhou City(no. KJXW2016059) and a grant from Suzhou Key MedicineProject Fund of China (no. SZXK201504).

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