Prediction of Outcome of Sepsis at Surgical ICU: A Prospective Multi-Center Prospective Study
Ahmed M Salem1*, Ahmed E Salem2 and Adel F Al Kholy3
1Department of Anesthesiology & ICU, Faculty of Medicine, Benha University, Egypt
2Department of Anesthesiology & ICU, Faculty of Medicine, Tanta University, Egypt
3Department of Medical Biochemistry, Faculty of Medicine, Benha University, Egypt
Submission: February 01, 2019; Published: March 27, 2019
*Corresponding author: Ahmed M Salem, Department of Anesthesiology & ICU, Faculty of Medicine, Benha University, Egypt
How to cite this article: Ahmed M Salem, Ahmed E Salem, Adel F Al Kholy. Prediction of Outcome of Sepsis at Surgical ICU: A Prospective Multi-Center
Prospective Study. J Anest & Inten Care Med. 2019; 8(4): 555743. DOI: 10.19080/JAICM.2019.08.555743
Objectives: To evaluate predictability of at ICU-admission levels of C-reactive protein (CRP), procalcitonin (PCT), interleukin (IL)-6 and co-peptin (Cp) for outcome of patients underwent major surgical resections, admitted to surgical ICU and developed sepsis during ICU stay.
Patients & Methods: 192 patients developed mild-moderate and 63 patients developed severe sepsis 24-hr after ICU admission. On appearance of early clinical sepsis manifestations, blood samples were obtained for ELISA estimation of studied parameters. Study outcome was defined as the 28-day mortality rate (28-MR) and the best predictor for it.
Results: 28-MR was 22% and was significantly higher among severe sepsis patients. Severe sepsis patients and non-survivors were significantly older, had higher APACHE II and SOFA scores and serum levels of Cp, IL-6, PCT and CRP than patients had mild-moderate sepsis and survivors, respectively. High serum Cp level was the highly significant independent predictor for both sepsis severity and mortality, while serum PCT was significant predictor for sepsis severity. Serum Cp levels at cutoff points of ≥55.2ng/ml and ≥94.6ng/ml could predict progressively increasing hazard of development of severe sepsis and mortality, respectively.
Conclusion: Elevated serum Cp could fulfill the requirements for ideal early biomarker for diagnosis and prognosis of sepsis patients especially at the assumed cutoff points. Estimation of serum Cp and PCT in conjunction with clinical scoring could complementary act to approach highest diagnostic and prognostic yield.
Arginine vasopressin (AVP) is a 9-amino acid peptide synthesized by magnocellular neurons of the hypothalamus . The released VAP is then stored in posterior pituitary gland  to be released following different stimuli especially change in plasma osmolality and hypovolemia  and various stressors such as hypoxia, acidosis, severe infections and different types of shock . Reliable measurement of AVP is hindered by several factors; its short half-life in serum, its instability in withdrawn blood samples and over 90% of AVP is tightly bound to platelets . Copeptin (Cp), a 39-aminoacid glycopeptide, is the COOH-terminal portion of the precursor pre-pro-vasopressin termed CTproAVP . Activation of the AVP system stimulates Cp secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP . Therefore, Cp directly reflects AVP concentration and can be used as a surrogate biomarker of AVP secretion .
The prevalence of sepsis continues to increase, and the sepsis total mortality is growing due to increased morbidity, so sepsis
should be considered as an emergency . The Third International Consensus Definitions Task Force defined sepsis as a life-threatening organ dysfunction due to dysregulated host response to infection , so its early recognition remains a fundamental challenge in clinical practice . However, the performance of sepsis clinical criteria and scores is unknown .
These data indicated the need for an early marker for effects of sepsis that may endanger patient’s life. Thus, this study tried to evaluate the predictability of at ICU-admission levels of C-reactive protein (CRP), procalcitonin (PCT) and interleukin (IL)-6 as primary phase reactant and Cp for outcome of patients underwent major surgical resections, admitted to ICU for cardiopulmonary support and developed infectious complications during ICU stay.
The study protocol was approved by the Local Ethical Committees
and the nearest relative of patients signed written fully
informed consents according to the declaration of Helsinki. All
patients developed sepsis within the 1st 24-hr of ICU admission
are eligible for evaluation. Exclusion criteria included development
of sepsis prior to ICU admission, maintenance on immune
depressant therapy for any indication, severe hemorrhagic shock,
tissue hypoperfusion diagnosed if Systolic Blood Pressure (SBP)
was ≤90mmHg, Urinary Output (UOP) <0.5ml/kg/min for >2h,
increased Heart Rate (HR) by ≥10% from baseline, skin mottling
and/or hyperlactatemia (>2mmol/L) , pregnancy, children
and adulthoods younger than 18 years and patients who were not
expected to survive were also excluded from the study.
Collected at enrollment data included demographic characteristics,
including age, sex, Body Mass Index (BMI) data, acute
physiology and chronic health evaluation II score (APACHE II)
, global hemodynamic parameters, arterial and central venous
blood gas analysis and pH were obtained simultaneously. Impact
of disease on body organs was evaluated using the Sequential Organ
Failure Assessment (SOFA) scores  at time of insertion of
the central venous catheter.
Sepsis was diagnosed depending on the presence of at least
two of the four Systemic Inflammatory Response Syndrome (SIRS)
criteria’s and fulfilled the requirements for either severe sepsis or
septic shock as documented by Yussof et al. . Patients were
managed according to the Surviving Sepsis Campaign guidelines
 with hemodynamic support aiming to achieve the following:
Central Venous Pressure (CVP) of 8-12mmHg; Mean Arterial Pressure
(MAP) >65mmHg and UOP >0.5ml/kg of body weight.
At time of appearance of early clinical manifestations of sepsis,
5ml blood sample was withdrawn under complete aseptic
conditions, allowed to clot and then centrifuged at 3000rpm for
10 minutes to separate serum that was collected in sterile Eppindorff
tube and stores at -80oC till be assayed. Blood samples were
collected and numbered by an assistant who was blinded about
Serum levels of CRP, PCT, IL-6 and Cp were measured using
enzyme linked immunosorbent assay (ELISA) kits according to
the manufacturer’s instructions and were read using a 96 well microplate
ELISA reader (Dynatech. MR 7000)
a. Human CRP was measured with the Enzyme Linked Immunoassay
(ELISA) kit () by quantitative sandwich enzyme
immunoassay technique .
b. Human PCT was measured with the Enzyme Linked Immunoassay
(ELISA) kit () by quantitative sandwich enzyme
immunoassay technique .
c. Human IL-6 was measured with the Enzyme Linked Immunoassay
(ELISA) kit (catalogue no. IL631-k01, Eagle Biosciences,
Inc., USA) by quantitative sandwich enzyme immunoassay
d. Human Cp was measured with the Enzyme Linked Immuno
Assay (ELISA) kit () by quantitative sandwich enzyme
immunoassay technique .
Review of literature showed that the overall MR of surgical
patients not requiring ICU admission is 18.2%  and among
those admitted to ICU is 28.7  to defined the predictability of
estimated parameters for MR among surgical patients admitted to
ICU and developed sepsis and to get study power of 80% with α
value of 0.05 and β value of 0.2, sample size was calculated to be
Obtained data were presented as mean±SD, numbers and
percentages. Data were analyzed using One-way ANOVA Test.
Possible relationships were investigated using Pearson linear regression
analysis. Sensitivity & specificity of estimated parameters
as predictors for 28-MR were evaluated using the Receiver
Operating Characteristic (ROC) curve analysis judged by the Area
Under Curve (AUC) that was compared versus null hypothesis
that AUC=0.5. Kaplan-Meier regression analysis was used to determine
a cutoff point for serum Cp above which 28-MR increases.
Statistical analysis was conducted using the IBM SPSS (Version 23,
2015) for Windows statistical package. P value <0.05 was considered
Throughout 5-year case collection period 287 cases of those
admitted to surgical ICU were eligible for evaluation. Unfortunately,
15 patients required emergency 2nd look surgery for causes
other than sepsis and were excluded from the study and 17 patients
were excluded for not fulfilling the study inclusion criteria;
thus 255 patients were enrolled in the study. During ICU stay, 63
patients developed severe sepsis (24.7%); twenty of them were
progressed to septic shock, while 192 patients had mild-moderate
sepsis (Figure 1).
Patients who developed severe sepsis were significantly older
and obese and had higher APACHE II and SOFA scores. Also,
at ICU admission MAP, CVP and UOP were significantly lower in
severe sepsis patients. Laboratory variables estimated at time of
development of sepsis were significantly higher in severe sepsis
patients than patients developed mild-moderate sepsis (Table 1).
During 28-days after appearance of sepsis manifestations, 56
patients died for sepsis-related mortality rate of 22%. Non-survivors
were 20 severe sepsis patients (31.7%) and 36 patients had
mild-moderate sepsis (18.8%) with significantly (p=0.031) higher
mortality rate among patients had severe sepsis. Non-survivors
were significantly older and had significantly higher APACHE II
and SOFA scores, significantly lower MAP, but significantly higher
serum levels of CRP, IL-6, PCT and CP than survivors. However,
non-survivors were non-significantly obese and had non-significantly
lower CVP and UOP than survivors (Table 2).
Regression analysis for at ICU admission patients’ data and
laboratory finding defined old age, high APACHE II score and high
serum levels of CRP, IL-6, PCT and Cp as the significant predictors
for possibility of development of severe sepsis. Verification of
these predictors using ROC curve analysis defined high serum Cp
level at time of appearance of sepsis manifestations as the highly
significant sensitive predictor for possibility of progress of sepsis
to severe sepsis, followed by high serum PCT, IL-6, old age, high
APACHE II score and high serum CRP, in descending order of significance
(Table 3, Figure 2).
For prediction of mortality among patients developed sepsis,
Regression analysis defined old age, high SOFA score and high
serum levels of CRP, IL-6, PCT and Cp as the significant negative
predictors for survival. Verification of these predictors using ROC
curve analysis defined high serum Cp level at time of appearance
of sepsis manifestations as the highly significant specific predictor
for mortality, followed by high serum IL-6, old age and high SOFA
score, in descending order of significance (Table 3, Figure 3).
Kaplan-Meier regression analysis for serum Cp levels of studied
patients defined median value at 55.2±4.33ng/ml (95% CI:
46.7-63.7) as cutoff point above which the hazard of development
of severe sepsis increased progressively (Figure 4) and at
94.6±1.07ng/ml (95% CI: 92.5-96.7) as cutoff point above which
the hazard of death increased progressively (Figure 5).
Throughout 5-year duration of study, 255 of patients admitted
to surgical ICU for varied indications developed sepsis 24-hr
after ICU admission; such observation goes in hand with Sakr et
al.  who reported an incidence of sepsis during the ICU stay of
11.4% and found sepsis was observed within 48 hours after ICU
admission in 50.9% while 49.1% developed ICU-acquired sepsis.
Out of the currently studied patients, 63 patients had severe sepsis
(24.7%), a figure which is better that that reported by Zhou et
al.  who found 37.3/100 ICU admissions were diagnosed with
severe sepsis or septic shock.
The current study reported a 28-day mortality rate (28-MR)
of 22% among these patients who developed sepsis during ICU
stay; in line with this figure Yoo et al.  and Badia et al. 
reported a 28-MR of 19 and 19.6%, respectively. However, the reported
28-MR was lower than the rates of 41.3%, 28.7% and 29%
which had been reported by Zhou et al. , Sakr et al.  &
Yokota et al., , respectively.
The currently reported percentage of non-survivors was significantly
higher among patients who had severe sepsis and septic
shock than patients who developed mild-moderate sepsis (31.7%
vs. 18.8%). Similarly, Heldens et al.  reported MR of 17% and
37% in patients diagnosed with sepsis and septic shock, respectively.
Severe sepsis patients and non-survivors were significantly
older and had higher APACHE II and SOFA scores with significantly
lower MAP, CVP and UOP at time of ICU admission. Moreover,
statistical analyses defined high at admission APACHE II and SOFA
scores as predictors for possibility of developing severe sepsis
and/or mortality, respectively. Multiple recent studies assured
that among variables registered on day 1, APACHE II and SOFA
scores were independently associated with sepsis severity and
Moreover, severe sepsis patients and non-survivors showed
significantly higher serum levels of Cp, IL-6, PCT and CRP than
patients had mild-moderate sepsis and survivors, respectively.
Statistical analyses defined high serum Cp levels as the most the
highly significant independent predictor for both sepsis severity
and mortality, followed by high serum IL-6, while serum PCT was
significant predictor for severity of sepsis. All of the three markers
showed superior diagnostic validity than clinical data and scores.
In line with these data, Jiang et al.  found plasma Cp, CRP
and PCT concentrations were positively correlated with APACHE
II score in patients with sepsis, and reflected disease severity,
while Ameen et al.  reported that at admission serum Cp and
blood lactate levels are significant predictors for mortality of septic
patients. Also, Huang et al.  documented that APACHE II
scores and the levels of serum calprotectin and PCT on postoperative
day-1 were the variables significantly associated with sepsis
and its severity. Thereafter, Ríos-Toro et al.  found the absence
of risk factors for infection and decrease of PCT and IL-6 levels
from baseline to day-5 were variables associated to survival in the
univariate analysis. Recently, Qiu et al.  reported that serum
Hepcidin, PCT, IL-6, TNF-α, APACHE II, SOFA score and 28-MR all
showed an increasing trend with the increase in infection severity
in ICU patients. Also, Barre et al.  found both IL-6 and monocyte
chemotactic protein 1 levels had valuable prognostic discrimination
of 30-day and 6-months all-cause mortality compared to
PCT, CRP, SOFA and APACHE II score.
Regarding serum Cp, the obtained results go in hand with
Zhang et al. , who reported that high baseline Cp levels may
provide crucial information for risk stratification in a variety of
septic states and were independent predictors of septic shock and
28-MR with AUC of 0.856 and 0.826, respectively. Also, Battista et
al.  documented that Cp can distinguish cases of sepsis from
controls and between sepsis and septic shock patients, while PCT
could distinguish severe sepsis from septic shock patients.
Regression analysis showed that serum Cp levels at cutoff
points of ≥55.2ng/ml and ≥94.6ng/ml could predict progressively
increasing hazard of development of severe sepsis and mortality,
respectively. These findings point to the feasibility of reliance on
estimated serum Cp level at time of appearance of early manifestations
of sepsis to predict patients’ outcome. Similarly, Dabla et
al.  reported that Cp levels are altered in various physiological
and pathological conditions indicating its possible diagnostic and
prognostic roles in various clinical settings especially in critically
ill patients. In line with the validity of Cp cutoff point for diagnosis
and prediction of outcome of septic patients Battista et al. 
found patients with Cp concentrations higher >23.2pmol/L at-admission
presented higher 30-day mortality.
Recently, in 2018, Koch et al.  reported significantly elevated
plasma Cp levels in critically ill patients at ICU admission
than control levels, and were closely associated with disease severity
judged by APACHE-II score, correlated with biomarkers of
inflammation and tissue perfusion and could predict short-term
and long-term mortality, so concluded that Cp could be a promising
tool for prognostication and management of critically ill patients.
Development of sepsis after admission to surgical ICU is still
a problematic dilemma. Despite of the diagnostic validity of clinical
scores, it could not fulfill the best prognostic target for sepsis
patients. Early systemic release of primary-phase reactants could
be a diagnostic and prognostic tool for sepsis patients even prior
to establishment of diagnosis. Elevated serum co-peptin could
fulfill the requirements for ideal early biomarker for diagnosis
and prognosis of sepsis patients especially at the assumed cutoff
points. Combined estimation of serum co-peptin and procalcitonin
in conjunction with clinical scoring could complementary
act to approach highest diagnostic and prognostic yield. However,
wider scale studies are mandatory to assure the validity of the assumed
cutoff points for co-peptin.