Li et al.

Journal of Cardiothoracic Surgery (2019) 14:217

https://doi.org/10.1186/s13019-019-1027-3

RESEARCH ARTICLE Open Access

Severe systemic inflammatory response

syndrome in patients following Total aortic
arch replacement with deep hypothermic
circulatory arrest
Jun Li1†, Lijing Yang1†, Guyan Wang2†, Yuefu Wang1*, Chunrong Wang1 and Sheng Shi1

Abstract
Background: This cohort study aims to retrospectively investigate the incidence of severe systemic inflammatory
response syndrome (sSIRS) in patients following total aortic arch replacement (TAR) under deep hypothermic
circulatory arrest (DHCA) with selective cerebral perfusion and its effect on clinical outcomes.
Methods: All patients who underwent TAR with DHCA were consecutively enrolled from January 2013 until
December 2015 at our institute. sSIRS was diagnosed between 12 and 48 h postoperatively if patients met all four
criteria of the SIRS definition.
Results: Of the 522 patients undergoing TAR with DHCA, 31.4% developed sSIRS. Patients aged under 60 yr were
characterized by a higher prevalence of sSIRS (OR = 2.93; 95% CI 2.01–4.28; P <0.001). Higher baseline serum creatinine
(OR = 1.61; 95% CI 1.18–2.20; P = 0.003), concomitant coronary disease (OR = 2.00; 95% CI 1.15–3.48; P = 0.015) and extended
cardiopulmonary time (OR = 1.63; 95% CI 1.23–2.18; P = 0.001) independently contributed to a greater likelihood of
postoperative sSIRS onset, while the preferred administration of ulinastatin (OR = 0.69; 95% CI 0.51–0.93; P = 0.015) and
dexmedetomidine (OR = 0.36; 95% CI 0.23–0.56; P < 0.001) attenuated it. Patients with sSIRS had a greater risk of developing
postoperative major adverse complications compared with the no sSIRS group [56.7%(93/164) vs 26.8% (96/358), P < 0.001].
sSIRS was found to be a significant risk factor for major adverse complications (OR, 4.52; 95% CI, 3.40–6.01; P < 0.001). A
significant difference was revealed in in-hospital death following TAR between the sSIRS group and the no-sSIRS group
[4.88% (8/164) vs 1.12% (4/358), P = 0.019]. The Kaplan-Meier curve indicated that the time to discharge from the intensive
care unit was significantly prolonged in the sSIRS group compared with patients without it (log-rank p < 0.001).
Conclusions: sSIRS occurs commonly in patients following TAR with DHCA. There is an inverse association between age
and sSIRS onset, whereby age over 60 yr can lower the risk of it. sSIRS development can increase the likelihood of major
postoperative major adverse events.
Keywords: Severe systemic inflammatory response syndrome, Total aortic arch replacement, Advancing age, Clinical
outcomes

* Correspondence: [email protected]
†
Jun Li, Lijing Yang and Guyan Wang contributed equally to this work.
1
Department of Anesthesiology, Fuwai Hospital, Chinese Academy of
Medical Sciences, Peking Union Medical College, National Center for
Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease,
Belishi road 167, Xicheng District, Beijing 100037, China
Full list of author information is available at the end of the article

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Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 2 of 11

Introduction secondary to prolonged mechanical ventilation treat-

Postoperative systemic inflammatory response syndrome ment and other infections. Finally, 24 patients were ex-
(SIRS), discussed in some specific cardiovascular interven- cluded, and valuable data on the population of 522
tions such as transcatheter or open aortic valve repair [1–3], subjects were collected. Of these, 496 were all operated
has received limited attention yet. Nevertheless, studies on on for acute type A dissection, 26 for aneurysms and 60
the prevalence of inflammatory responses following open for Marfan syndrome.
total aortic replacement (TAR) using 4-branch graft are
lacking. Inflammation following TAR can be incurred by op- Clinical definitions
erative trauma, blood exposed to cardiopulmonary bypass SIRS was diagnosed on the basis of the existing American
(CPB), infection and hypothermia, although the combination College of Chest Physicians/Society of Critical Care Medi-
of TAR and DHCA to treat aortic pathology with selective cine Consensus Conference if patients met at least two of
cerebral perfusion is technically preferable. the following: (1) white blood cell count <4 or > 12 (109
SIRS, a whole-body inflammation, has remained a /L); (2) heart rate > 90 bpm or partial pressure of arterial
primary clinical problem to be addressed despite sig- carbon dioxide (PaCO2) < 32 mmHg; (3) temperature > 38
nificant improvement of strategies in diagnostics and or < 36 °C; (4) respiratory rate > 20 per minute [10]. The
therapy. As SIRS progresses, the incidence of morbid- application of sSIRS was used if all four criteria were met.
ity, such as multi-organ failure and even mortality, In our study, sSIRS was observed within 12–48 postopera-
will increase in cardiac [4, 5] and noncardiac settings tive hours after intensive care unit (ICU) admission from
[6, 7]. The inflammatory response has detrimental ef- the operating room. No evaluation of the occurrence of
fects on cardiac function, and it arouses respiratory any criteria related to the first 12 h following repair was
problems, hemostasis dysfunction, and kidney or liver carried out, which aimed to avoid spurious findings pro-
injury. However, SIRS as a consequence of multiple duced by numerous inotropes, diuretic drugs and various
coexisting factors has been controversial due to its fluid inputs achieved immediately in the postoperative set-
high prevalence but low specificity for infection [8]. It ting. Finally, patients in our cohort were divided into the
is currently recognized that severe SIRS (sSIRS) is a sSIRS group and the no-sSIRS group.
more practical term for inflammation and has high Emergent treatment at our institute was defined as
accuracy to predict prognosis [2, 9]. surgery within 24 h of admission to the hospital. All pa-
We hypothesize that sSIRS following TAR with DHCA tients routinely received both patient-controlled anal-
appears often because of the complex and risky surgical gesia and continuous body rewarming during their
procedure and contact with CPB. This retrospective treatment in the ICU. Prolonged ICU length was de-
study carried out at our institute is intended to explore fined as a stay of greater than 7 days. The assessment of
the incidence, independent predictors, and clinical out- renal failure before and after TAR was based on stage
comes of sSIRS in patients following TAR with DHCA. III in the Kidney Disease: Improving Global Outcomes
(KDIGO) criteria. Hemodialysis at our institute was
Methods used to attenuate every renal failure case intraopera-
This cohort study was approved by the Ethics Commit- tively. In our study, hemoglobin less than 10 g/dL was
tees of Fuwai Hospital. Informed consent from the par- perceived as moderate-severe anemia [11]. Patients’
ticipants was waived for the retrospective nature. All body mass index (BMI) was obtained with the following
details of design, conception and conduct are listed in equation: weight (kg)/height2 (m2); accordingly, patients
the following parts. were classified as underweight (BMI < 18.5 kg/m2), nor-
mal weight (BMI 18.5–24.9 kg/m2), overweight (BMI
Study population 25.0–29.9 kg/m2), obese (BMI 30.0–39.9 kg/m2), and
There were a total of 546 charts of patients enrolled morbidity obese (≥ 40 kg/m2) [12]. The glucose level
consecutively, who underwent TAR with DHCA from measured prior to repair was categorized as follows:
January 2013 to December 2015. The perioperative in- ≤140, 141–170, 171–200 and > 200 mg/dl, and patients
formation was obtained from digital medical records at with glucose >200 mg/dl were diagnosed with severe
our center. Participants meeting one of the following hyperglycemia [13].
were excluded: a) mechanical ventilation support before
surgery; b) infection prior to surgery; c) death during Endpoint definition
surgery or the first 48 h postoperatively; d) precocious The primary endpoint after aortic replacement was the
postoperative infection within the first 5 days; and e) major adverse events, that is, a composite defined as ex-
record with incomplete data. The purpose of these periencing one of the following: in-hospital mortality,
exclusion criteria was to eliminate known causes of renal failure, pulmonary infection, reintubation, tracheot-
inflammation with a deflagration process, especially omy, arrhythmia, stroke, paraplegia, and gastrointestinal
Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 3 of 11

hemorrhage. Other clinical outcomes included time free variables, whereas the chi-square test or Fisher’s exact test
from mechanical ventilation, and duration of ICU and was used for categorical variables. Predictive factors for
postoperative in-hospital length of stay. sSIRS were identified with multivariable logistic analysis
after collecting baseline characteristics, preoperative bio-
Arch replacement technique marker level and perioperative information. A logistic re-
All patients in our study underwent TAR with DHCA, gression model was used to examine the association
which was performed with right axillary and femoral between sSIRS and major adverse events. All variables
artery cannulation for CPB, antegrade selective cere- with a P-level < 0.2 on univariable analysis were entered
bral perfusion, and the DHCA technique at 20 °C. This into multivariable logistic models. The Kaplan-Meier
procedure involved implantation of a frozen elephant method was used to estimate the association between se-
trunk, total arch replacement with a 4-branched vas- vere SIRS and the ICU length of stay. SPSS for Windows
cular graft (Vascutek Terumo, Tokyo, Japan; 28–30 release 25.0 (SPSS, Inc., Chicago, IL, USA) was used for all
mm in diameter), a particular sequence for aortic re- statistical calculations. GraghPad Prism 7.0a was used for
construction (i.e., proximal descending aorta, then left the Kaplan-Meier curve.
carotid artery, ascending aorta, left subclavian artery,
and finally innominate artery), early rewarming and Results
then reperfusion after distal anastomosis to lessen Patient characteristics
cerebral and coronary ischemia. The duration of se- A total of 522 patients who underwent TAR with DHCA
lective cerebral perfusion referred to the interval be- were included in our cohort. The age was 46.7 ± 11.2
tween the initiation of hypothermic circulatory arrest years (range, 19–83 years). The age distribution was
and completion of left carotid anastomosis, which was depicted in Fig. 1. The weight in this cohort was 74.4 ±
longer than the duration of DHCA itself. In this 14.1 kg, and the BMI was 25.4 ± 4.9 kg/m2. There were
period, lower body perfusion was arrested to implant 382 (73.1%) males included, and 9.0% had a history of
the stented graft (MicroPort Medical Co, Ltd., Shang- previous cardiac surgery. The number of patients diag-
hai, China; 26–32 mm in diameter) and suture the nosed with aortic dissection was up to 95.0% (496/522).
proximal descending anastomosis. In all the patient charts, the duration of operation, CPB,
aortic cross clamp and DHCA were 378.9 ± 88.4 min,
Myocardial protection 177.7 ± 50.8 min, 97.3 ± 26.3 min and 21.3 ± 7.0 min, re-
Blood cardioplegia was used to protect the myocardium spectively. In addition, following aortic replacement, the
in our routine work. Hypothermic techniques combined time of weaning from mechanical ventilation was 20.0 h
with ice sprinkled on the surface of the heart were used (14.0–45.0 h), and the ICU length of stay was 3.0 days
to achieve the goal of myocardial protection. However, (2.0–5.0 days).
in the surgical process, CPB (S5 roller pump 150, Sorin
Group, Munich, Germany) was implemented with tubes Prevalence of sSIRS
not coated; at our institute, coated tube systems were The proportion of patients diagnosed with sSIRS was
provided to patients in need of extracorporeal mem- 31.4% (164/522) within 12–48 h, after they were trans-
brane oxygenation. ferred into the ICU from the operating room.
The comparisons of patients’ baseline characteristics
Intraoperative management between groups were shown in Table 1. The number of
All patients in our center received vasodilator as a rou- patients aged 60 yr or more was significantly greater in
tine practice before operation to control systolic pres- the no-sSIRS group than that in the sSIRS group [14.3%
sure under 120 mmHg. In addition, methylprednisolone, (51/358) vs 6.7% (11/164), P = 0.013]. Compared with
an anti-inflammatory agent, was prophylactically admin- the no-sSIRS cohort, patients who developed sSIRS after
istered during the surgical procedure. The use of dexme- TAR had a lower body weight (P = 0.017), higher base-
detomidine or ulinastatin was determined by the present line hemoglobin level (P = 0.004) and higher baseline
anesthesiologists and their individual preference towards serum creatinine level (P = 0.027).
intraoperative management. Peri-operative information was listed in Table 2. There
was no significant difference between groups in the type
Statistical analysis of concomitant operation, amount of transfusion or the
Continuous data were presented as mean and standard usage of inotropic drugs during surgical repair. The dur-
deviation (M ± SD) or median and interquartile range ation of CPB was significantly longer in the sSIRS group
(IQR). Categorical data were presented as count and per- [174.0 min (153.3–211.5 min) vs 166.0 min (142.5–197.0
centage (n, %). For comparisons between cohorts, the t min), P = 0.003]. The number of patients administered
test or the Mann-Whitney U test was used for continuous dexmedetomidine following anesthesia induction was
Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 4 of 11

Fig. 1 Age distribution of patients undergoing TAR, compared between the whole cohort, the no-sSIRS group and the sSIRS group. The age was
46.7 ± 11.2 years (range, 19–83 years). TAR, total arch replacement; sSIRS, systemic inflammatory response syndrome

found to be significantly lower in the sSIRS group There were 8 deaths (4.8%) in the sSIRS group and 4 (1.1%)
[85.3% (140/164) vs 93.3% (334/358), P = 0.004]. in patients without sSIRS, which was a significant difference
(P = 0.019). With logistic regression adjusting for related-
Clinical predictors of sSIRS covariates, sSIRS still had a 4.5-fold increased risk of occur-
The risk factors associated with sSIRS onset with multi- rence of any major adverse event following TAR (OR, 4.52;
variable logistic regression were shown in Table 3. After 95% CI, 3.40–6.01; P < 0.001). Age greater than 60 yr (OR,
adjusting for covariates, including sex, age (< 60, ≥ 60 yr), 1.81; 95% CI, 1.32–2.48; P < 0.001), severe hyperglycemia
BMI (< 18.5, 18.5–24.9, 25.0–29.9, 30.0–39.9, ≥ 40 kg/m2), (OR, 3.48; 95% CI, 1.35–8.97; P = 0.01), dialysis to treat
hyperlipidemia, glucose (≤140, 141–170, 171–200 and > renal failure prior to surgery (OR, 2.21; 95% CI, 1.05–4.68;
200 mg/dl), moderate-severe anemia, serum creatinine, P = 0.038), emergent status (OR, 1.52; 95% CI, 1.17–1.98;
smoking, COPD, cerebral infarction, dialysis prior to sur- P = 0.002) and duration of CPB longer than 200 min (OR,
gery, hypertension, dissection, coronary disease, cardiac 2.83; 95% CI, 2.12–3.77; P < 0.001) were also independently
surgery history, aortic regurgitation, left ventricular ejec- associated with major adverse events, as seen in Table 5.
tion fraction, CPB duration (< 200, ≥ 200 min), and the
usage of ulinastatin or dexmedetomidine, we demon-
Other in-hospital outcomes
strated that patients younger than 60 yr had a nearly 3-
Patients with sSIRS were characterized by longer mechan-
fold higher likelihood of developing sSIRS (OR = 2.93; 95%
ical ventilation duration (P < 0.001), ICU length of stay
CI 2.01–4.28; P < 0.001). Higher baseline serum creatinine
(P < 0.001) and postoperative hospital stay (P < 0.001).
level prior to surgery contributed to sSIRS development
The percentage of patients experiencing prolonged ICU
(OR = 1.61; 95% CI 1.18–2.20; P = 0.003). The increased
duration in the sSIRS group (> 7 d) was significantly
risk for sSIRS was 2-fold if patients had concomitant cor-
greater than that in the no-sSIRS group [36.0% (59/164)
onary artery disease (OR = 2.00; 95% CI 1.15–3.48; P =
vs 9.8% (35/358), P < 0.001]. The Kaplan-Meier curve indi-
0.015). Extended duration of CPB, that is, more than 200
cating the time to the discharge from the ICU was
min, was also a risk factor for sSIRS (OR = 1.63; 95% CI
depicted in Fig. 2. The median time to discharge from the
1.23–2.18; P = 0.001). However, the intravenous adminis-
ICU was 5.0 days (95% CI 4.2–5.8 days) in the sSIRS group
tration of ulinastatin (OR = 0.69; 95% CI 0.51–0.93; P =
and 3.0 days (95% CI 2.8–3.2 days) in the no-sSIRS group,
0.015) or dexmedetomidine (OR = 0.36; 95% CI 0.23–0.56;
log-rank P < 0.001.
P < 0.001) lowered the risk of sSIRS.

Clinical outcomes associated with sSIRS Discussion

In-hospital outcomes were listed in Table 4. To the best of our knowledge, this is the first study to
investigate the prevalence of severe inflammation follow-
Major adverse events ing TAR with DHCA. The incidence of sSIRS was 31.4%
The proportion of major adverse events was significantly following TAR regardless of routine methylprednisolone
greater in patients suffering sSIRS compared with the no- prophylaxis, which obviously contributed to the postop-
sSIRS cohort [56.7% (93/164) vs 26.8% (96/358), P < 0.001]. erative development of major adverse events.
Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 5 of 11

Table 1 Comparisons of patient characteristics

Characteristics Overall (n = 522) sSIRS (n = 164) No-sSIRS (n = 358) P value
Baseline
Male 382 (73.1) 129 (78.6) 253 (70.6) 0.056
Age (years) 46.7 ± 11.2 45.7 ± 10.3 47.2 ± 11.6 0.145
≥ 60 72 (13.8) 14 (8.5) 58 (16.2) 0.018
Weight (kg) 74.4 ± 14.1 76.6 ± 16.4 73.4 ± 12.9 0.017
BMI (kg/m2) 25.4 ± 4.9 26.1 ± 4.2 25.4 ± 5.8 0.001
Underweight (< 18.5) 20 (3.8) 6 (3.7) 14 (3.9) 0.126
Normal weight (18.5–24.9) 200 (38.3) 63 (38.4) 167 (46.6)
Overweight (25.0–29.9) 215 (41.2) 71 (43.3) 144 (40.2)
Obese (30.0–39.9) 53 (10.2) 21 (12.8) 32 (8.9)
Morbidly obese (≥ 40) 4 (0.8) 3 (1.8) 1 (0.3)
Preoperative comorbidities
Hypertension 365 (69.9) 115 (70.1) 250 (69.8) 0.947
Diabetes mellitus 11 (2.1) 6 (3.6) 5 (1.4) 0.180
Smoking 294 (56.3) 63 (38.4) 131 (36.5) 0.689
Dialysis for renal failure 14 (2.6) 4 (2.4) 10 (2.7) 1.000
Coronary artery disease 23 (4.4) 9 (5.4) 14 (3.9) 0.415
Moderate-severe anemia 20 (3.8) 5 (3.1) 15 (4.2) 0.528
Marfan syndrome 60 (11.4) 20 (12.1) 40 (11.1) 0.734
Aortic dissection 496 (95.1) 154 (93.9) 342 (95.5) 0.073
Aortic aneurysm 26 (4.9) 10 (6.1) 16 (4.5) 0.065
Previous cardiac surgery 47 (9.0) 15 (9.1) 32 (8.9) 0.939
Emergent operation 290 (55.5) 90 (54.8) 200 (55.8) 0.833
Laboratory values
Hemoglobin (g/dL) 133.3 ± 17.9 136.7 ± 17.6 131.8 ± 17.9 0.004
Serum creatinine (mg/dL) 93.2 ± 36.1 98.4 ± 36.7 90.9 ± 35.5 0.027
Glucose (mmol/l) 6.8 ± 1.6 7.0 ± 1.7 6.8 ± 1.6 0.184
White blood cell count (109/L) 7.2 ± 2.1 7.3 ± 2.2 7.1 ± 2.1 0.235
Echocardiography
LVEF (%) 59.7 ± 5.5 59.3 ± 6.3 59.9 ± 5.1 0.295
Aortic regurgitation 205 (39.2) 66 (40.2) 139 (38.8) 0.758
Normally distributed continuous data are presented as mean ± SD and categorical data are presented as n (%). sSIRS Severe systematic inflammatory response
syndrome, BMI Body mass index, LVEF Left ventricular ejection fraction

The inflammatory response after cardiac surgery has transcatheter aortic valve replacement; sSIRS itself was
been widely recognized [4, 14, 15]; however, few studies also strongly associated with a greater risk of six-month
have focused on its occurrence following repair of aortic mortality. It is the conception of severe SIRS rather than
pathology, especially its severity. SIRS, defined when the conventional SIRS criteria that is more appropriate to
patient met two or more criteria, is seen in 96.2% of pa- depict the relationship between the inflammatory re-
tients after cardiac surgery, without any discriminatory sponse and its clinical outcomes.
value for predicting clinical outcomes [6]. A previous The patients undergoing arch repair for aortic path-
study carried out among patients undergoing elective ab- ology had an average age of 40 yr at our institute, youn-
dominal aneurysm repair demonstrated that SIRS devel- ger than those of other investigations, where patients
opment was as high as 89% [16]. Recently, Lindman and aged 53.9 to 70.1 yr [17–21]. The incidence of emergent
colleagues [2] introduced the application of severe SIRS, status was as greater, at 55.8%, than in previous settings.
which developed in 11% of patients undergoing surgical At two institutes in Japan, the emergency rates were
aortic valve replacement but 6% of patients treated with 26.1% [17] and 25.1% [18], respectively, according to
Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 6 of 11

Table 2 Peri-operative information between groups

Variables sSIRS (n = 164) No-sSIRS (n = 358) P value
Surgical data
Concomitant procedures
Bentall 44 (26.8) 93 (25.9) 0.543
CABG 11 (6.3) 22 (6.1) 0.782
CABG + Bentall 5 (3.0) 9 (2.5) 0.214
Operative Variables
Operation time (minutes) 376.0 (320.3–448.8) 360.0 (316.0–420.8) 0.213
CPB time (minutes) 174.0 (153.3–211.5) 166.0 (142.5–197.0) 0.003
≤ 180 90 (54.88) 224 (62.57) 0.143
181–240 55 (33.54) 108 (30.17)
> 240 19 (11.59) 26 (7.26)
Aortic cross clamp time (minutes) 96.5 (83.3–113.5) 93.0 (79.0–107.3) 0.015
DHCA time (minutes) 21.0 (17.0–25.0) 21.0 (16.0–25.0) 0.288
Lowest temperature (°C) 20.9 ± 3.3 19.5 ± 1.7 0.356
Transfusion
Red blood cell (u) 2.8 ± 1.2 2.9 ± 1.3 0.857
Fresh frozen plasma (ml) 321 (0–800) 309 (0–1000) 0.638
Platelet (u) 1.7 ± 0.5 1.7 ± 0.6 0.976
Intra-operative inotropic drugs
Epinephrine 15 (9.2) 31 (8.6) 0.253
Norepinephrine 146 (89.1) 321 (89.6) 0.932
Intra-operative medications
Ulinastatin 116 (70.7) 273 (76.2) 0.179
Dexmedetomidine 140 (85.3) 334 (93.3) 0.004
Normally distributed continuous data are presented as mean ± SD, whereas non-normal data as median (interquartile range). Categorical data are presented as n
(%). sSIRS Severe systematic inflammatory systematic syndrome, CABG Coronary artery bypass grafting, CPB Cardiopulmonary bypass, DHCA Deep hypothermic
cardiac arrest

recent publications in the field of TAR using a 4- evidence that the risk of SIRS at any time within 24 h after
branched graft. The definition of an emergent procedure cardiac surgery is uniquely attenuated in patients aged 72
at our institution was within 24 h prior to surgery, while yr or older [4]. It is hypothesized that the phenotypic and
the precise time was not given in those two single-center genomic variation and patients’ susceptibility had good
experiences. perioperative predictability of the individual inclination to
In this study, we demonstrated the clear association of develop inflammatory syndromes. Systematic inflamma-
age with sSIRS development. Our logistic regression tory responses were also not intensive and diminished in
showed that advancing age was correlated with a lower patients aged over 80 yr who had community-acquired
risk of sSIRS in patients following TAR with DHCA. pneumonia and reduced levels of C-reactive protein and
Elderly individuals presented delayed initiative and even cytokines after admission [26]. A precise scheme for anti-
poor maintenance with regard to the immune system after inflammation should be put into practice in our clinical
encountering inflammatory stressors [22]. It is a fact that settings, although the patients’ age varies greatly. The
age-related immunosenescence, consisting of dysregula- therapeutic approach, such as intraoperative dexametha-
tion of immune cells (such as incompetency to generate sone, gave no benefit to patients aged over 80 yr undergo-
pro-inflammatory cytokines and compromising capacity ing cardiac repair [27].
of phagocytizing) and reduced level of C-reactive protein This study showed that either dexmedetomidine or
upon interleukin-6 stimulation is a common scenario in ulinastatin could diminish the likelihood of postoperative
elderly patients [23–25]. This kind of nonintensive inflam- development of sSIRS. Dexmedetomidine, a highly se-
mation reaction uniquely linked to advancing age has lective α2-adrenergic agonist and universal option for
strong evidence in clinical work. There was striking sedation, has been revealed to be effective in reducing
Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 7 of 11

Table 3 Risk factors associated with postoperative sSIRS

Variables Univariable analysis Multivariable analysis
OR 95% CI P OR 95% CI P
Male 1.56 1.17–2.09 0.003
Age (years)
<60 1.37 1.06–1.76 0.015 2.93 2.01–4.28 < 0.001
≥ 60 1
BMI (kg/m2)
Underweight (< 18.5) 0.22 0.05–1.02 0.054
Normal weight (18.5–24.9) 0.23 0.06–0.83 0.024
Overweight (25.0–29.9) 0.33 0.09–1.17 0.086
Obese (30.0–39.9) 0.39 0.10–1.46 0.161
Morbidly obese (≥ 40) 1 0.011
Hyperlipidemia 1.18 0.90–1.56 0.231
Glucose (mmol/l)
(≤ 140) 1.61 0.53–4.87 0.397
(141–170) 2.21 0.72–6.83 0.168
(171–200) 1.58 0.45–5.50 0.473
(> 200) 1 0.161
Moderate-severe anemia 1.51 0.80–2.84 0.200
Serum creatinine 1.66 1.23–2.24 0.001 1.61 1.18–2.20 0.003
Smoking 1.02 0.79–1.33 0.868
COPD 1.62 0.54–4.93 0.392
Cerebral infarction 0.77 0.47–1.28 0.320
Dialysis prior to surgery 1.24 0.55–2.79 0.609
Hypertension 0.98 0.73–1.32 0.915
Dissection 1.15 0.64–2.04 0.647
Coronary disease 0.69 0.42–1.14 0.151 2.00 1.15–3.48 0.015
Cardiac surgery history 0.78 0.67–1.70 0.784
Aortic regurgitation 0.99 0.76–1.28 0.920
LVEF 0.98 0.96–1.01 0.118
CPB (minutes)
< 200 1
≥ 200 1.59 1.21–2.09 0.001 1.63 1.23–2.18 0.001
Ulinastatin 0.63 0.48–0.83 0.001 0.69 0.51–0.93 0.015
Dexmedetomidine 0.36 0.24–0.54 <0.001 0.36 0.23–0.56 < 0.001
sSIRS Severe systematic inflammatory systematic syndrome, OR Odds ration, CI Confidential interval, BMI Body mass index, COPD Chronic obstructive pulmonary
disease, LVEF Left ventricular ejection fraction, CPB Cardiopulmonary disease

cytokine release associated with the nuclear factor kappa surgery with CPB could attenuate postoperative typical
B activation inhibition mechanism in cardiac surgery inflammatory biomarker release, such as interleukin,
with CPB [28, 29]. However, whether dexmedetomidine tumor necrosis factor-α, and other cytokines [30–32].
is of prophylactic benefit in a population with sSIRS has Consequently, the organ-protective property of ulinasta-
been obscure, and more clinical trials are imperative in tin has been reported, primarily in correlation with at-
the future. Ulinastatin, extracted from humane urine, tenuating acute kidney injury, pulmonary compromise
acts as a unique anti-inflammatory agent with a mechan- and hemodynamic instability [30, 33].
ism that includes the inhibition of neutrophil elastase Patients diagnosed with sSIRS were found to have a
and of various other proteases. Clinical trials have pro- greater likelihood of suffering any adverse complications
vided robust evidence that its administration in cardiac after the TAR procedure. In-hospital outcomes were not
Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 8 of 11

Table 4 In-hospital outcomes after TAA with DHCA

Variables sSIRS (n = 164) No-sSIRS (n = 358) P value
Major adverse events 93 (56.7) 96 (26.8) < 0.001
In-hospital mortality 8 (4.8) 4 (1.1) 0.019
Renal failure 33 (20.1) 28 (7.8) < 0.001
Pulmonary infection 67 (40.8) 71 (19.8) < 0.001
Re-intubation 16 (9.7) 10 (2.7) 0.001
Tracheotomy 11 (6.7) 2 (0.5) < 0.001
Arrhythmia 32 (19.5) 26 (7.2) < 0.001
Stroke 6 (3.6) 5 (1.4) 0.180
Paraplegia 9 (5.4) 9 (2.5) 0.084
Gastrointestinal hemorrhage 10 (6.1) 7 (1.9) 0.013
Re-thoracotomy for bleeding 8 (4.8) 11 (3.0) 0.307
Mechanical ventilation time (hours) 82.6 (23.2, 235.4) 37.4 (13.0, 102.3) < 0.001
Intensive care unit length of stay (days) 7.0 (3.0, 10.0) 3.0 (1.0, 7.0) < 0.001
Length of hospital stay (days) 14 (7.0, 24.0) 12.0 (6.0, 19.0) < 0.001
TAA Total arch replacement, DHCA Deep hypothermic cardiac arrest, sSIRS Severe systematic inflammatory systematic response

Table 5 Multivariable logistic regression for major adverse events following arch replacement
Variables Univariable analysis Multivariable analysis
OR 95% CI P OR 95% CI P
Male 0.94 0.73–1.22 0.650
Age (years)
< 60 1
≥ 60 1.31 0.99–1.75 0.058 1.81 1.32–2.48 < 0.001
BMI (kg/m2)
Underweight (< 18.5) 0.50 0.11–2.30 0.374
Normal weight (18.5–24.9) 0.96 0.27–3.45 0.952
Overweight (25.0–29.9) 1.09 0.30–3.93 0.892
Obese (30.0–39.9) 0.94 0.25–3.53 0.930
Morbidly obese (≥ 40) 1 0.447
Severe hyperglycemia 2.29 0.93–5.65 0.092 3.48 1.35–8.97 0.010
Dissection 0.55 0.30–1.01 0.053
Hypertension history 1.48 1.11–1.97 0.007
Preoperative renal failure 1.86 0.91–3.81 0.090 2.21 1.05–4.68 0.038
Coronary artery disease 2.05 1.25–3.34 0.004
Emergent operation 1.31 1.03–1.66 0.029 1.52 1.17–1.98 0.002
CPB (minutes)
< 200 1
≥ 200 2.81 2.15–3.67 < 0.001 2.83 2.12–3.77 < 0.001
sSIRS 4.01 3.11–5.30 < 0.001 4.52 3.40–6.01 < 0.001
OR Odds ratio, CI Confidence interval, BMI Body mass index, CPB Cardiopulmonary bypass, sSIRS Severe systematic inflammatory systematic response.
Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 9 of 11

Fig. 2 The comparison of ICU length of stay with the Kaplan-Meier curve. The proportion of patients treated in the ICU following TAR was
significantly greater in the sSIRS group compared with patients without sSIRS (log-rank P < 0.001) after excluding 12 in-hospital deaths. sSIRS,
severe systematic inflammatory response syndrome; ICU, intensive care unit; TAR, total arch replacement. ICU, intensive care unit; TAR, total arch
replacement; sSIRS, systemic inflammatory response syndrome

promising in the sSIRS cohort: they had extended dur- new-set atrial fibrillation [34, 35]. Surgical techniques,
ation of weaning from mechanical ventilation, as well as including hypothermic circulatory arrest times, selective
prolonged duration of ICU length of stay and postopera- antegrade cerebral temperature [36, 37], unilateral or bi-
tive hospital stay. In a population with transcatheter aor- lateral cerebral perfusion [38] and treatment for distal
tic valve implantation, sSIRS has also raised the risk of aortic arch aneurysm [19], also significantly contribute
certain adverse events: mortality, stroke, infection, bleed- to stroke development. There is a classic view in clinics
ing, myocardial infarction and acute kidney injury [3]. It that coronary artery disease is an alternative to athero-
is implied that sSIRS also has predictive ability for the sclerosis, feasibly extending to the bloodstream and
length of stay after admission to the ICU [9]. maximizing the risk of thrombosis of the neurologic sys-
Undergoing an emergent procedure could have en- tem. Paraplegia, a serious complication of spinal injury,
hanced the chance of experiencing major adverse events can be primarily predicted by stented elephant trunk im-
in patients following TAR in our investigation. One of plantation. Extended stent graft implanted into the de-
the potential reasons would be that the population re- scending aorta could harm the intercostal arteries, and
quiring emergency treatment was indeed in an exacer- then collateral blood supplying to the spinal cord ex-
bated status prior to surgery and had greater risks to tremely deteriorates [20]. Therefore, cerebral spinal fluid
develop sequentially worse outcomes after the imple- drainage, and reduced hypothermic circulatory arrest to
mentation of total arch repair. However, another possi- 25 °C, and stent-graft lengths less than 10 cm are prac-
bility, which cannot be ruled out, is that preoperative tical techniques to prevent spinal cord injury [18, 20].
temporary treatments for patients were insufficient This study has several limitations. First, heterogeneity
within the limited duration under study, so that they did existed owning to its retrospective and single-centered na-
not reach an optimized status and then had a higher in- ture. Second, the identification of SIRS and even its sever-
cidence of major adverse events after discharge from the ity following TAR may not be accurate because it was
operating room. only judged by patients’ vital signs instead of strong evi-
No further analysis of neurological defects following dence from serial biomarkers measurements, including
TAR, such as stroke or paraplegia until hospital dis- serum C-reactive protein and interleukins. The number of
charge, was carried out in this cohort study owning to leukocytes and the ratio of lymphocytes/macrophages
their lower incidence (2.1, 3.4%, respectively). Previous cannot be obtained routinely, major contributors to the
investigations provided robust evidence that stroke pri- imperfection of this work. Third, it was proposed that
marily occurred in patients with concomitant coronary meeting three criteria of SIRS within 24 h after cardiac
artery bypass grafting, cerebrovascular defect history, or surgery or at least two criteria for 6 h would be more valid
Li et al. Journal of Cardiothoracic Surgery (2019) 14:217 Page 10 of 11

in predicting clinical outcomes [6]. However, the time for Competing interests
severe SIRS in our research was extended until 48 h post- The athors declare that they have no competing interests.

operatively. The validity of sSIRS for organ dysfunction, Author details

ICU length of stay and hospital stay should be explored 1
Department of Anesthesiology, Fuwai Hospital, Chinese Academy of
further. Forth, evidence of preoperative malperfusion can- Medical Sciences, Peking Union Medical College, National Center for
Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease,
not be obtained, which resulted in bias. Finally, all partici- Belishi road 167, Xicheng District, Beijing 100037, China. 2Department of
pants with aortic dissection undergoing repair had a Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing
history of acute status. Further investigations should be 100730, China.

aimed at elucidating the relationship between sSIRS onset Received: 14 June 2019 Accepted: 18 November 2019
and acute, subacute or chronic dissection pathology.

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