JOURNAL OF THE
ROYAL MEDICAL SERVICES

Official Publication for the Jordanian Royal Medical Services


Clinical Usefulness Of C-Reactive Protein Versus Shock Index In Predicting Mortality In Septic Critically Ill Patients Who Are Taking Nor-epinephrine


Laith Abdul Salam Obeidat MD*, Basel Al-Rawashdah MD**, “Moh’d Nour” Bani Younes Ph***, Osama Atoom MD****, Mohammad Ali Zreqat MD*****, Salem Alsalman



ABSTRACT


Objective: C-reactive protein (CRP) and shock index (SI) have been previously shown to identify high risk septic shock patients.Our objective was to compare the ability of SI and CRP to predict the primary outcome of overall 28-day mortality, and the secondary outcomes of early mortality (≤ 14 days), late mortality (>14 days) in septic critically ill patients who are taking norepinephrine as a vasopressor.


Methods:  We performed a retrospective analysis of patientsadmitted to our adult ICU between April 2017 and Sep 2018 who were meet the inclusion criteria. Independent T-test, Mann Whitney U test, and χ2 test were used to express all patient variables.A receiver operating char­acteristic (ROC) curve followed by sensitivity analysis was generated to determine the predictive performances, and the optimal cut-off values for CRP and SI. The binary logistic regression model was used to generate CRP and SI predictive equations and correlation plots for early, late, and overall 28-day ICU mortality.


Results : A total of 163 critically ill patients were finally included in this study. The mean overall age was 58.37±9.96 years, and 112 subjects (68.71%) were male. The early, late, and overall 28-day ICU mortality rate were9.82%, 29.45%, and 39.82%, respectively. SI and CRP were significantly higher in non-survivors (1.29±0.17 bpm/mmHg and 43.09±19.28 mg/dl, p<0.05) than in survivors (1.12±0.03 bpm/mmHg, and 28.38±14.38 mg/dl).


Conclusion: SI is an effective, no-cost bedside modality, which is a realistic, reliable, and discriminative prognosticator with high sensitivity, specificity, performance, and accuracy when compared with CRP.


Key words: C-reactive protein, Shock index, Critically ill patients, Norepinephrine.


JRMS December 2019;26(3):12-27/DOI: 10.12816/0054814 



Introduction 

Sepsis is a complex syndrome caused by the body’s systemic response to an infection with a major cause of high treatment cost, single or multiple organ dysfunction, morbidity, and mortality [1]. The importance of having reliable, cost effective, and easily attainable clinical prognostic indicators that would help to predictand differentiate the mortality risk of these critically ill patientsis invaluable within an Intensive Care Unit (ICU). C-reactive protein (CRP) is a useful positive acute-phase reactant marker that can predict morbidity and mortality among critically ill patients. However,the results of CRP and other severity indices of sepsis may not be immediately available upon request [2], potentially delaying effective dynamic risk stratification and goal directed management in these unstable studied cohort. Also, Shock index (SI), defined as heart rate (HR) over systolic blood pressure (SBP)is a readily and affordable attained comprehensive parameter that combines two physiological variables (HR and SBP) into a single ratio that has previously been shown to stratify and served as an early warning indicator of high risk haemorrhagic shock from various aetiologies when compared to other conventional vital signs [3-8].From previous studies, SI has never been compared with CRP for its value in predicting early mortality (≤ 14 days), late mortality (> 14 days), and overall 28-day mortality among septic critically ill patients who are taking nor-epinephrine. Our objective was to compare the mortality risk stratifying ability of SI and CRP regarding the primary outcome of overall 28-day mortality, and the secondary outcomes of early and late mortality and ICU length of stay.


Methods

Study design and setting

This was a single-centreobservational retrospective study conducted in the department of adult ICU of King Hussein Medical Centre (KHMC) at Royal Medical Services (RMS) in Jordan. This study was approved by our Institutional Review Board (IRB), and a requirement for consent was waived owing to its retrospective design. This study included a cohort of critically ill patients admitted to our adult ICU via the emergency department (ED) or via other hospital wards with any medicalor surgical problems. Flow chart of critically ill patient’s selection and data collection process is fully illustrated in (Figure1).


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Statistical analysis

All patient continuous variables were expressed as mean± standard deviation by using the independent samples T-test while categorical and ordinal variables were expressed as numbers with percentages by using the χ2 test or as median (interquartile range) by using the Mann-Whitney U test, respectively. Analysis values were compared for the two tested groups (survivors vs. non-survivors) and the non-survival group was further analysed after being divided into 2 subgroups, early (≤14 days) and late (>14 days) mortality. Univariate analysis was conducted first followed by multivariate logistic regression for the most possible affected patient’s variables associated with ICU mortality. A receiver operating char­acteristic (ROC) curve followed by sensitivity analysis wasused to determine the area under the ROC curves (AUROCs), predictive performances, and the optimal cut-off values for CRP and SI. Youden indices, sensitivities, specificities, positive and negative predictive val­ues, and accuracy indices were also calculated. The binary logistic regression model was used to generate CRP and SI predictive equations and correlation plots for early, late, and overall 28-day ICU mortality. Statisticalanalyses were performed using IBM SPSS ver. 25 (IBM Corp., Armonk, NY, USA) and P-values ≤0.05 were considered sta­tistically significant.

  

Results

Characteristics of the subjects

The mean overall age was 58.37±9.96 years, and 112 subjects (68.71%) were male. The overall 28-day ICU mortality rate was 39.26% (64 patients); in16 patients (9.82%), this was early mortality and in 48 patients (29.45%) it was late mortality. Demographics, admission co-morbidities and class, anthropometrics, and follow-up comparison data of the study’s critically ill patients are fully summarised in (Table I) and (Table II) , respectively.

 

Table I: Demographics and anthropometrics comparison of study’s critically ill patients.

 

 

 

 

Variables

 

 

 

Total

(n=163)

 

 

 

Survivors

(n=99 )

Non-survivors

 (n=64)

 

 

 

 

P-Value

Early Mortality

(≤14 days)

 (n=16)

Late Mortality (>14 days)

(n=48)

Age (Yrs)

58.37±9.96

58.55±9.948

58.09±10.053

0.92

NS

62.31±11.12

56.69±9.38

Gender

Male

112 (68.71%)

67 (67.68%)

45 (70.31%)

0.79

NS

11 (68.75%)

34 (70.83%)

Female

51 (31.29%)

32 (32.32%)

19 (29.69%)

5 (31.25%)

14 (29.17%)

Day(s) Pre-ICU admission (day(s))

4.27±3.91

2.23±1.06

7.42±4.57

0.00

S

13.31±5.89

5.46±1.10

ICU Stay day(s)

12.40±4.79

9.23±1.06

17.30±4.14

0.00

S

10.56±1.97

19.54±1.10

Hospital Stay day(s)

16.67±6.81

11.46±2.12

24.72±1.98

0.00

S

23.87±3.93

25.00±0.00

Number of comorbidities

0, 1

74 (45.39%)

52 (52.53%)

22 (34.38%)

0.03

NS

3 (18.75%)

19 (39.58%)

2 , 3, 4+

89 (54.60%))

47 (47.47%)

42 (65.63%)

 13 (81.25%)

29 (60.42%)

Admission class

Medical

105 (64.42%)

50 (50.51%)

55 (85.94%)

0.00

S

14 (87.5%)

41 (85.42%)

Surgical

58 (35.58%)

49 (49.49%)

9 (14.06%)

2 (12.5%)

7 (14.58%)

BW1(Kg)

74.17±10.24

74.63±10.06

73.45±10.56

0.61

NS

69.44±9.34

74.79±10.69

BMI1 (Kg/m²)

25.92±4.00

26.19±3.85

25.50±4.22

0.31

NS

24.11±4.28

25.97±4.14

28-day ICU Survival

99 (60.74%)

28-day ICU Mortality

Overall Mortality

64 (39.26%)

Early Mortality (≤14 days)

16 (9.82%)

Late Mortality (>14 days)

48 (29.45%)

Values are presented as mean±standard deviation or number (%).

Yrs: Years.

Kg: Kilogram.

m: Meter.

BW1: Actual body weight at admission.

BMI1: Body mass index at admission.

 

ICU: Intensive care unit.

S: Significant (P-Value <0.05).

NS: Non-significant (P-Value >0.05).

n: Number of study’s critically ill patients.

 

 

 

 

Table II: Follow-up data comparison of study’s critically ill patients.

 

 

Variables

Total

(n=163)

Survivors

(n=99 )

Non-survivors

 (n=64)

P-Value

Early Mortality

(≤14 days)

 (n=16)

Late Mortality

 (>14 days) (n=48)

Norepinephrine Rate (mcg/min)

9.53±1.79

9.27±1.68

9.94±1.89

0.72

NS

9.94±2.49

9.94±1.67

GCS (3-15)

12 (12-13)

12 (12-13)

12 (12-13)

0.34

NS

12 (12-13)

12 (12-13)

Child-Pugh Score( 5-15)

6 (6-8)

6 (6-8)

6 (6-7)

0.09

NS

6 (6-7)

6 (6-7)

ALB 1 (g/dl)

2.75±0.32

2.63±0.20

2.94±0.39

0.00

S

3.28±0.46

2.82±0.28

Human Albumin Dose (g/day)

16.99±5.11

18.89±3.16

14.06±6.09

0.00

S

9.38±6.80

15.63±5.01

ALB (g/dl)

2.61±0.13

2.64±0.12

2.57±0.13

0.44

NS

2.55±0.11

2.57±0.14

CRP (mg/dl)

34.16±17.93

28.38±14.38

43.09±19.28

0.01

S

50.55±21.88

40.61±17.89

SBP (mmHg)

99.19±5.70

102.29±2.19

94.39±6.14

0.00

S

86.44±7.04

97.04±2.44

DBP (mmHg)

49.19±5.70

52.29±2.19

44.39±6.14

0.00

S

36.44±7.04

47.04±2.44

MAP (mmHg)

65.87±5.72

68.95±2.27

61.11±6.18

0.00

S

53.13±7.00

63.77±2.56

HR (bpm)

117.16±4.67

114.76±1.19

120.88±5.55

0.00

S

128.06±7.15

118.48±1.20

SI (bpm/mmHg)

1.19±0.14

1.12±0.03

1.29±0.17

0.00

S

1.49±0.23

1.22±0.04

TC (Cal/day)

1327.32±261.96

1357.56±270.23

1280.54±243.32

0.58

NS

1181.86±269.47

1313.43±227.52

PD (g/100Cal/day)

3.64±0.63

3.72±0.74

3.50±0.36

0.00

S

3.46±0.42

3.52±0.35

Values are presented as mean ± standard deviation, median (range), or number (%).

n: Number of study’s critically ill patients.

bpm: beat per minute.

mcg: microgram.

min: minute.

1: At admission.

S: Significant (P-Value <0.05).

NS: Non-significant (P-Value >0.05).

MAP: Mean arterial pressure.

HR: Heart rate.

SBP: Systolic blood pressure.

DBP: Diastolic blood pressure.

Cal: Kcal.

TC: Total calories.

PD: Protein density.

SI: Shock index.

CRP:C-reactive protein.

GCS: Glasgow coma scale.

ALB: Albumin level.

 

 

 Mortality was significantly higher in medical than surgical critically ill patients. Baseline pre-ICU admission days and number of co-morbidities were also significantly higher in non-survivors than survivors. There were insignificant differences between the two groups regarding average child-Pugh score, average Glasgow coma scale (GSC), and average norepinephrine infusion rate. Despite baseline albumin levels (ALB1)being significantly higher in non-survivors (2.94±0.39 g/dl)than survivors (2.63±0.20 g/dl), survivors had significantly higher average administered human albumin dosesand average protein density (PD) inputs (18.89±3.16 g/day and 3.72±0.74 g/100 Cal, respectively)than non-survivors (14.06±6.09 g/day and3.50±0.36 g/100 Cal). SI, HR, and CRP were significantly higher in non-survivors (1.29±0.17 bpm/mmHg, 120.88±5.55 bpm, and 43.09±19.28 mg/dl, respectively) than in survivors (1.12±0.03 bpm/mmHg, 114.76±1.19 bpm, and 28.38±14.38 mg/dl). In contrast, all haemodynamic parameters of SBP, diastolic blood pressure (DBP), and mean arterial pressure (MAP) had significantly higher values in survivors (102.29±2.19 mmHg, 52.29±2.19 mmHg, and 68.95±2.27 mmHg, respectively) than in non-survivors (94.39±6.14 mmHg, 44.39±6.14 mmHg, and 61.11±6.18 mmHg, respectively). SI and CRP were significantly higher in early non-survivors (1.49±0.23 bpm/mmHg and 50.55±21.88 mg/dl, respectively) than in late non-survivors (1.22±0.04 bpm/mmHg and 40.61±17.89 mg/dl, respectively).

Logistic regression analysis

In the univariate analyses, child-Pugh score, CRP, SBP, DBP, MAP, and SI showed statistically significant associations with early (OR, 0.07, 0.47,0.45, 0.45, 0.45, and 5.0*1028, respectively), late (OR, 0.31,0.87,0.91, 0.91, 0.92, and 11.25, respectively), and overall 28-day ICU mortality (OR, 0.17, 0.78, 0.42, 0.42, 0.45, and 1.6*1038, respectively),while total calorie (TC) inputs and HR showed only statistically significant associations with early mortality (OR, 0.99) and late mortality (OR, 1.08), respectively. Average albumin levels (ALB) during the first week of ICU admission showed astatistically significant association with both early (OR, 248.65) and overall 28-day ICU mortality (OR, 47.06). After adjusting for these variables, only SI still showed a statistically significant association with early, late, and overall 28-day ICU mortality,while CRP still showed statistically significant association with only overall 28-day ICU mortality. The odd ratios (ORs) of early, late, and all-cause 28-day ICU mortality events are shown in (Table III).

 

 

Table III: ORs for early, late, and all-cause in-ICU mortality events

 

Variable

Univariate

Multivariate

OR

95% CI

P-value

OR

95% CI

P-value

Age

 (Yrs)

Overall 28-day mortality

0.99

0.96-1.03

0.78 (NS)

----

-----

-----

Early mortality (≤ 14 days)

1.05

0.99-1.10

0.09 (NS)

----

-----

-----

Late Mortality (> 14 days)

0.98

0.94-1.01

0.17 (NS)

----

-----

-----

Gender

(Male)

Overall 28-day mortality

1.13

0.57-2.24

0.72 (NS)

----

-----

-----

Early mortality (≤ 14 days)

1.00

0.33-3.05

0.99 (NS)

----

-----

-----

Late Mortality (> 14 days)

1.15

0.55-2.40

0.71 (NS)

----

-----

-----

BMI

(Kg/m²)

Overall 28-day mortality

0.96

0.84-1.04

0.28 (NS)

----

-----

-----

Early mortality (≤ 14 days)

0.88

0.76-1.01

0.06 (NS)

----

-----

-----

Late Mortality (> 14 days)

1.00

0.92-1.09

0.92 (NS)

----

-----

-----

Child-Pugh score (5-15)

Overall 28-day mortality

0.17

0.06-0.45

0.00 (S)

----

-----

-----

Early mortality (≤ 14 days)

0.07

0.01-0.68

0.02 (S)

----

-----

-----

Late Mortality (> 14 days)

0.31

0.12-0.82

0.02 (S)

----

-----

-----

PD

(g/100 Cal/day)

Overall 28-day mortality

0.52

0.28-0.97

0.52 (NS)

----

-----

-----

Early mortality (≤ 14 days)

0.503

0.16-1.63

0.25 (NS)

----

-----

-----

Late Mortality (> 14 days)