Introduction
Copeptin, the C-terminal part of the arginine vasopressin precursor peptide, is associated with the severity and outcome of critical illness, and therefore, has been proposed as a prognostic marker in acute illness
Materials and methods
Study population
Between July 2008 and March 2010, all patients with aneurysmal SAH confirmed by computerized tomography (CT) angiography with or without digital subtraction angiography who were admitted to Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University were evaluated in the study. Inclusion criteria were clinical history of SAH within the last 24 hrs before admission and the treatment by surgery or coiling within the 48 hrs after admission. Exclusion criteria were less than 18 years of age, existing previous head trauma, neurological diseases including ischemic or hemorrhagic stroke, use of antiplatelet or anticoagulant medication, and presence of other prior systemic diseases including uremia, liver cirrhosis, malignancy, chronic heart or lung disease, diabetes mellitus and hypertension.
A control group consisted of 150 healthy sex and age-matched subjects with normal results on brain magnetic resonance imaging and without vascular risk factors.
Written informed consent to participate in the study was obtained from the subjects or their relatives. This protocol was approved by the Ethics Committee of The Second Affiliated Hospital, School of Medicine, Zhejiang University before implementation.
Clinical and radiological assessment
On arrival to the emergency department, a detailed history of vascular risk factors, concomitant medication, Glasgow Coma Scale (GCS) score, body temperature, heart rate, respiratory rate and blood pressure were taken. At admission, clinical severity was assessed using the World Federation of Neurological Surgeons (WFNS) score
Patient management
The type of treatment (surgery or coiling) was decided according to both location and size of the aneurysm by the neurosurgeon and the neuroradiologist. All patients received intravenous Nimodipine at a dose of 2 mg/h from admission until at least day 14, except during periods of uncontrolled increased intracranial pressure during which intravenous Nimodipine was discontinued. Seizures were systematically prevented by Sodium Valproate (200 mg × 3, per os). After surgery or coiling, those patients who had delayed ischemic neurological deficit or cerebrovasospasm were managed with 'triple H' therapy (hypertension with a mean arterial pressure goal greater than 100 mm Hg, hypervolemia and hemodilution with a goal hematocrit of 30) through 12 days after hemorrhage. An external ventricular drain was inserted in case of hydrocephalus on CT and in patients with a high WFNS grade (WFNS score of 3-5). Increased intracranial pressure was treated by cerebrospinal fluid drainage, mechanical ventilation, reinforcement of sedation, and, rarely, moderate hypothermia. CT was performed whenever clinical deterioration occurred to search for secondary complications such as hydrocephalus or ischemia.
Clinical onset of cerebral vasospasm was defined as the acute onset of a focal neurologic deficit or a change in the GCS score of 2 or more points. All suspected cases of cerebral vasospasms were confirmed by CT angiography and were then taken to the interventional radiology suite for cerebral angiography. Each vasospasm episode was treated with intra-arterial administration of Nimodipine as recently described. This therapy was repeated if necessary. Balloon Angioplasty was used as a second-line therapy when Nimodipine was judged insufficient. Computed tomography ischemia was referred to as delayed ischemia attributed to vasospasm.
Determination of copeptin in plasma
The informed consents were obtained from study population or family members in all cases before the blood were collected. In the control group, venous blood was drawn at study entry. In the SAH patients, venous blood was drawn on admission. The blood samples were immediately placed into sterile EDTA test tubes and centrifuged at 1500 g for 20 minutes at 4°C to collect plasma. Plasma was stored at -70°C until assayed. The concentration of copeptin in plasma was analyzed by enzyme-linked immunosorbent assay (ELISA) using commercial kits (Cusabio biotech co. ltd, Wuhan, Hubei Province, China) in accordance with the manufactures' instructions. Intra-assay and inter-assay coefficients of variation were 4.2% and 6.8%. The blood samples were run in duplicate. Researchers running ELISAs were blinded to all patient details.
End point
Participants were followed up until death or completion of one year after SAH. Their primary outcome was death (at 1 year or in-hospital) and their secondary outcomes were vasospasm and functional outcome at 1 year. The functional outcome was defined by Glasgow outcome scale (GOS) score. GOS was defined as follows: 1 = death; 2 = persistent vegetative state; 3 = severe disability; 4 = moderate disability; and 5 = good recovery
Statistical analysis
Statistical analysis was performed with SPSS 10.0 (SPSS Inc., Chicago, IL, USA) and MedCalc 9.6.4.0. (MedCalc Software, Mariakerke, Belgium). The normality of data distribution was assessed by the Kolmogorovor-Smirnov test or Shapiro-Wilk test. All values are expressed as mean ± standard deviation or counts (percentage) unless otherwise specified. Comparisons were made by using (1) chi-square test or Fisher exact test for categorical data, (2) unpaired Student
Results
Study population characteristics
During the recruitment period, 347 patients were admitted with an initial diagnosis of aneurysmal SAH, 312 (89.9%) patients fulfilled the inclusion criteria, and adequate data on admission and follow-up were available for 303 individuals (87.3%) who were finally included in the analysis (Figure
Graph documenting patients' entry into the study from screening
Graph documenting patients' entry into the study from screening.
The characteristics for 303 patients
Characteristics
Sex (male/female)
131/172
Age (y)
43.9 ± 12.4
World Federation of Neurological Surgeons score on admission
2.3 ± 1.2
Modified Fisher score on admission
2.7 ± 1.0
Aneurysmal location
Posterior communication artery
83 (27.4%)
Internal carotid artery
43 (14.2%)
Anterior communication artery
66 (21.8%)
Middle cerebral artery
45(14.9%)
Anterior cerebral artery
35 (11.6%)
Posterior cerebral artery
23 (7.6%)
Vertebral artery
8 (2.6%)
Surgery
186 (61.4%)
Aneurysmal size (mm)
7.2 ± 4.9
Rebleeding
16 (5.3%)
Acute hydrocephalus
90 (29.7%)
Intracerebral hemorrhage
39 (12.9%)
Intraventricular hemorrhage
72 (23.8%)
External ventricular drain
109 (36.0%)
Angiographic vasospasm
131 (43.2%)
Computed tomography ischemia
50 (16.5%)
Admission time (hr)
4.7 ± 3.6
Plasma-sampling time (hr)
6.7 ± 4.4
Seizure
44 (14.5%)
Plasma C-reactive protein level (mg/L)
7.1 ± 2.7
plasma D-dimer level (mg/L)
2.1 ± 0.9
Plasma copeptin level (pmol/L)
21.2 ± 9.0
Numerical variables were presented as mean ± standard deviation. Categorical variables were expressed as counts (percentage).
The change in plasma copeptin level on admission in patients with SAH
After SAH, plasma copeptin level on admission in patients was statistically significantly higher than that in healthy controls (21.2 ± 9.0 pmol/L vs. 6.4 ± 1.8 pmol/L;
Graph showing the change of plasma copeptin concentration in the patients with aneurysmal subarachnoid hemorrhage
Graph showing the change of plasma copeptin concentration in the patients with aneurysmal subarachnoid hemorrhage. Data are expressed as mean ± standard deviation.
One-year mortality prediction
Forty-two patients (13.9%) died from SAH in one year. Higher plasma copeptin level was associated with one-year mortality, as well as other variables shown in the Table
The factors associated with one-year mortality
Non-survivals
(
Survival
(
Sex (male/female)
18/24
113/148
0.958
Age (y)
45.4 ± 13.4
43.6 ± 12.2
0.389
WFNS score on admission
4.0 ± 0.7
2.1 ± 1.0
<0.001
Modified Fisher score on admission
4.2 ± 0.6
2.5 ± 0.8
<0.001
Aneurysmal location
0.614
Posterior communication artery
8 (19.0%)
75 (28.7%)
Internal carotid artery
6 (14.3%)
37(14.2%)
Anterior communication artery
9 (21.4%)
57 (21.8%)
Middle cerebral artery
7 (16.7%)
38 (14.6%)
Anterior cerebral artery
6 (14.3%)
29 (11.1%)
Posterior cerebral artery
4 (9.5%)
19 (7.3%)
Vertebral artery
2 (4.8%)
6 (2.3%)
Surgery
21 (50.0%)
165 (63.2%)
0.102
Aneurysmal size (mm)
11.1 ± 5.3
6.6 ± 4.5
<0.001
Rebleeding
10 (23.8%)
6 (2.3%)
<0.001
Acute hydrocephalus
25 (59.5%)
65 (24.9%)
0.001
Intracerebral hemorrhage
19 (45.2%)
20 (7.7%)
<0.001
Intraventricular hemorrhage
37 (88.1%)
35 (13.4%)
<0.001
External ventricular drain
38 (90.5%)
71 (27.2%)
<0.001
Angiographic vasospasm
38 (90.5%)
93 (35.6%)
<0.001
Computed tomography ischemia
18 (42.9%)
32 (12.3%)
<0.001
Admission time (hr)
5.5 ± 4.4
4.6 ± 3.5
0.128
Seizure
9 (21.4%)
35 (13.4%)
0.171
Plasma C-reactive protein level (mg/L)
8.7 ± 3.3
6.9 ± 2.6
<0.001
plasma D-dimer level (mg/L)
2.4 ± 1.0
2.0 ± 1.0
0.015
Plasma copeptin level (pmol/L)
31.4 ± 8.3
19.5 ± 8.0
<0.001
Numerical variables were presented as mean ± standard deviation. Categorical variables were expressed as counts (percentage). Numerical variables were analyzed by Mann-Whitney U-test or unpaired Student
Multivariate analysis of factors predicting the one-year mortality among 303 patients
Odds ratio
95% confidence interval
WFNS score on admission
7.530
1.351~20.642
0.002
Modified Fisher score on admission
9.181
2.236~22.297
0.006
Aneurysmal size (mm)
1.182
0.914~1.324
0.361
Rebleeding
4.243
0.624~26.748
0.311
Acute hydrocephalus
1.249
0.230~25.387
0.401
Intracerebral hemorrhage
1.235
0.642~6.891
0.183
Intraventricular hemorrhage
3.822
0.893~11.402
0.064
External ventricular drain
1.105
0.611~4.008
0.397
Angiographic vasospasm
2.164
0.912~6.217
0.132
Computed tomography ischemia
1.472
0.881~5.438
0.271
Plasma C-reactive protein level (mg/L)
1.104
0.861~1.945
0.401
plasma D-dimer level (mg/L)
0.941
0.573~1.908
0.781
Plasma copeptin level (pmol/L)
2.307
1.324~6.974
0.004
The relation of copeptin to the mortality was assessed in a logistic-regression model. WFNS indicates World Federation of Neurological Surgeons.
A receiver operating characteristic curve showed that plasma copeptin level on admission predicted one-year mortality of patients statistically significantly (Figure
Graph showing receiver operating characteristic curve analysis of plasma copeptin level for one-year mortality (3A), in-hospital mortality (3B), cerebrovasospasm (3C) and one-year poor functional outcome (3D)
Graph showing receiver operating characteristic curve analysis of plasma copeptin level for one-year mortality (3A), in-hospital mortality (3B), cerebrovasospasm (3C) and one-year poor functional outcome (3D).
Receiver operating characteristic curve analysis of factors predicting the one-year mortality among 303 patients
Copeptin
WFNS score
Modified Fisher score
Criterion
>20.5 pmol/L
>3
>3
Area under curve
0.868
0.920
0.927
95% confidence interval
0.824 ~ 0.904
0.884 ~ 0.948
0.892~0.954
Sensitivity
92.9
78.6
88.1
95% confidence interval
80.5 ~98.4
63.2 ~89.7
74.4 ~96.0
Specificity
70.1
90.4
86.6
95% confidence interval
64.2 ~ 75.6
86.2~93.7
81.8~90.5
Odds ratio
29.949
34.613
47.743
95% confidence interval
8.998~99.796
14.876~80.563
17.579~129.667
+ likelihood ratio
3.11
8.20
6.57
95% confidence interval
2.8 ~3.5
7.0~ 9.7
5.8 ~7.4
- likelihood ratio
0.10
0.24
0.14
95% confidence interval
0.03~ 0.3
0.1 ~0.5
0.06 ~0.3
Reference
0.197
0.155
WFNS indicates World Federation of Neurological Surgeons.
In-hospital mortality prediction
Thirty-two patients (10.6%) died from SAH in the hospital. Higher plasma copeptin level was associated with in-hospital mortality, as well as other variables shown in the Table
The factors associated with in-hospital mortality
Non-survivals
(
Survival
(
Sex (male/female)
12/20
119/152
0.489
Age (y)
45.4 ± 12.9
43.7 ± 12.3
0.469
WFNS score on admission
3.9 ± 0.7
2.2 ± 1.1
<0.001
Modified Fisher score on admission
4.3 ± 0.6
2.6 ± 0.8
<0.001
Aneurysmal location
0.599
Posterior communication artery
5 (15.6%)
78 (28.8%)
Internal carotid artery
6 (18.8%)
37(13.7%)
Anterior communication artery
8 (25.0%)
58 (21.4%)
Middle cerebral artery
4 (12.5%)
41 (15.1%)
Anterior cerebral artery
4 (12.5%)
31 (11.4%)
Posterior cerebral artery
3 (9.4%)
20 (7.4%)
Vertebral artery
2 (6.3%)
6 (2.2%)
Surgery
17 (53.1%)
169 (62.4%)
0.310
Aneurysmal size (mm)
11.9 ± 5.1
6.7 ± 4.5
<0.001
Rebleeding
6 (18.8%)
10 (3.7%)
<0.001
Acute hydrocephalus
19 (59.4%)
71 (26.2%)
<0.001
Intracerebral hemorrhage
15 (46.9%)
24 (8.9%)
<0.001
Intraventricular hemorrhage
31 (96.9%)
41 (15.1%)
<0.001
External ventricular drain
30 (93.8%)
79 (29.2%)
<0.001
Angiographic vasospasm
30 (93.8%)
101 (37.3%)
<0.001
Computed tomography ischemia
16 (50.0%)
34 (12.6%)
<0.001
Admission time (hr)
5.4 ± 4.2
4.6 ± 3.6
0.276
Seizure
7 (21.9%)
37 (13.7%)
0.212
Plasma C-reactive protein level (mg/L)
9.0 ± 3.2
6.9 ± 2.6
<0.001
plasma D-dimer level (mg/L)
2.4 ± 1.1
2.0 ± 1.0
0.045
Plasma copeptin level (pmol/L)
31.8 ± 8.5
19.9 ± 8.2
<0.001
Numerical variables were presented as mean ± standard deviation. Categorical variables were expressed as counts (percentage). Numerical variables were analyzed by Mann-Whitney U-test or unpaired Student
Multivariate analysis of factors predicting the in-hospital mortality among 303 patients
Odds ratio
95% confidence interval
WFNS score on admission
4.973
1.497~13.137
0.003
Modified Fisher score on admission
5.982
2.469~17.149
0.001
Aneurysmal size (mm)
1.218
0.909~1.423
0.103
Rebleeding
1.483
0.882~5.492
0.163
Acute hydrocephalus
1.097
0.711~4.483
0.242
Intracerebral hemorrhage
1.479
0.703~5.176
0.207
Intraventricular hemorrhage
3.94
0.816~9.407
0.096
External ventricular drain
2.009
0.518~5.36
0.148
Angiographic vasospasm
2.930
0.918~7.998
0.091
Computed tomography ischemia
1.482
0.683~5.004
0.315
Plasma C-reactive protein level (mg/L)
1.455
0.673~2.947
0.482
plasma D-dimer level (mg/L)
0.915
0.587~2.936
0.367
Plasma copeptin level (pmol/L)
2.515
1.399~8.229
0.002
The relation of copeptin to the mortality was assessed in a logistic-regression model. WFNS indicates World Federation of Neurological Surgeons.
A receiver operating characteristic curve showed that plasma copeptin level on admission predicted in-hospital mortality of patients statistically significantly (Figure
Receiver operating characteristic curve analysis of factors predicting the in-hospital mortality among 303 patients
Copeptin
WFNS score
Modified Fisher score
Criterion
>28.7 pmol/L
>3
>3
Area under curve
0.868
0.893
0.922
95% confidence interval
0.825 ~0.904
0.853 ~ 0.926
0.886~0.950
Sensitivity
78.1
75.0
90.6
95% confidence interval
60.0 ~90.7
56.6 ~88.5
75.0 ~97.9
Specificity
89.7
87.5
84.1
95% confidence interval
85.4 ~ 93.0
82.9~91.2
79.2~88.3
Odds ratio
29.798
20.911
51.254
95% confidence interval
11.847~74.946
8.698~50.270
14.944~105.792
+ likelihood ratio
7.56
5.98
5.71
95% confidence interval
6.3 ~9.1
4.9~ 7.3
5.1 ~6.5
- likelihood ratio
0.24
0.29
0.11
95% confidence interval
0.1~ 0.5
0.1 ~0.6
0.04 ~0.3
Reference
0.613
0.246
WFNS indicates World Federation of Neurological Surgeons.
Cerebrovasospasm prediction
One hundred and thirty-one (43.2%) suffered from cerebrovasospasm in the hospital. Higher plasma copeptin level was associated with cerebrovasospasm, as well as other variables shown in the Table
The factors associated with cerebrovasospasm
Vasospasm
(
Non-vasospasm
(
Sex (male/female)
61/70
70/102
0.307
Age (y)
43.8 ± 12.2
43.9 ± 12.5
0.973
WFNS score on admission
3.2 ± 1.1
1.7 ± 0.9
<0.001
Modified Fisher score on admission
3.5 ± 1.0
2.2 ± 0.6
<0.001
Aneurysmal location
0.813
Posterior communication artery
33 (25.2%)
50 (29.1%)
Internal carotid artery
20 (15.3%)
23(13.4%)
Anterior communication artery
29 (22.1%)
37 (21.5%)
Middle cerebral artery
22 (16.8%)
23 (13.4%)
Anterior cerebral artery
16 (12.2%)
19 (11.0%)
Posterior cerebral artery
7 (5.3%)
16 (9.3%)
Vertebral artery
4 (3.1%)
4 (2.3%)
Surgery
86 (65.5%)
100 (58.1%)
0.183
Aneurysmal size (mm)
9.1 ± 5.7
5.8 ± 3.5
<0.001
Rebleeding
10 (7.6%)
6 (3.5%)
0.110
Acute hydrocephalus
71 (54.2%)
19 (11.0%)
<0.001
Intracerebral hemorrhage
26 (19.9%)
13(7.6%)
0.002
Intraventricular hemorrhage
52 (39.7%)
20 (11.6%)
<0.001
External ventricular drain
90 (68.7%)
19 (11.0%)
<0.001
Admission time (hr)
4.5 ± 3.4
4.9 ± 3.8
0.342
Seizure
17 (13.0%)
27 (15.7%)
0.505
Systolic arterial pressure (mmHg)
134.2 ± 23.6
128.7 ± 21.2
0.033
Diastolic arterial pressure (mmHg)
81.1 ± 15.1
77.5 ± 13.8
0.031
Mean arterial pressure (mmHg)
98.8 ± 16.1
94.6 ± 15.3
0.020
Plasma C-reactive protein level (mg/L)
7.9 ± 3.0
6.6 ± 2.4
<0.001
plasma D-dimer level (mg/L)
2.2 ± 1.1
1.9 ± 0.9
0.011
Plasma copeptin level (pmol/L)
25.0 ± 8.4
18.3 ± 8.3
<0.001
Numerical variables were presented as mean ± standard deviation. Categorical variables were expressed as counts (percentage). Numerical variables were analyzed by Mann-Whitney U-test or unpaired Student
Multivariate analysis of factors predicting the cerebrovasospasm among 303 patients
Odds ratio
95% confidence interval
WFNS score on admission
3.988
1.248~8.909
0.005
Modified Fisher score on admission
4.692
1.627~15.726
0.001
Aneurysmal size (mm)
1.104
0.998~1.247
0.061
Acute hydrocephalus
1.548
0.932~4.877
0.078
Intracerebral hemorrhage
1.709
0.437~5.174
0.514
Intraventricular hemorrhage
2.472
0.911~6.972
0.060
External ventricular drain
1.615
0.604~6.183
0.176
Systolic arterial pressure (mmHg)
1.012
0.989~1.214
0.612
Diastolic arterial pressure (mmHg)
1.003
0.972~1.044
0.622
Mean arterial pressure (mmHg)
1.005
0.901~1.103
0.583
Plasma C-reactive protein level (mg/L)
0.893
0.713~1.082
0.204
plasma D-dimer level (mg/L)
0.829
0.519~1.327
0.595
Plasma copeptin level (pmol/L)
1.292
1.149~1.605
0.025
The relation of copeptin to the mortality was assessed in a logistic-regression model. WFNS indicates World Federation of Neurological Surgeons.
A receiver operating characteristic curve showed that plasma copeptin level on admission predicted cerebrovasospasm of patients statistically significantly (Figure
Receiver operating characteristic curve analysis of factors predicting the cerebrovasospasm among 303 patients
Copeptin
WFNS score
Modified Fisher score
Criterion
>23.4 pmol/L
>2
>2
Area under curve
0.792
0.879
0.874
95% confidence interval
0.742 ~0.836
0.837 ~ 0.913
0.831~0.909
Sensitivity
69.2
80.9
84.7
95% confidence interval
60.8 ~77.4
73.1 ~87.3
77.4 ~90.4
Specificity
84.9
79.7
76.7
95% confidence interval
78.6 ~ 89.9
72.9~85.4
69.4~82.2
Odds ratio
7.783
9.488
7.814
95% confidence interval
4.617~13.121
5.597~16.085
4.663~13.096
+ likelihood ratio
4.60
3.98
3.64
95% confidence interval
4.0 ~5.2
3.6~ 4.4
3.3 ~4.1
- likelihood ratio
0.36
0.24
0.20
95% confidence interval
0.2~ 0.6
0.2 ~0.4
0.1 ~0.3
Reference
0.002
0.006
WFNS indicates World Federation of Neurological Surgeons.
Poor neurologic function prediction
Ninety patients (29.7%) suffered from poor neurologic outcome (GOS 1-3) in one year. Higher plasma copeptin level was associated with one-year poor neurologic outcome, as well as other variables shown in the Table
The factors associated with one-year function outcome
GOS 1-3
(
GOS 4-5
(
Sex (male/female)
42/48
89/124
0.433
Age (y)
44.7 ± 11.3
43.5 ± 12.8
0.422
WFNS score on admission
3.6 ± 0.7
1.8 ± 0.9
<0.001
Modified Fisher score on admission
3.8 ± 0.8
2.3 ± 0.7
<0.001
Aneurysmal location
0.291
Posterior communication artery
24 (26.7%)
59 (27.7%)
Internal carotid artery
13 (14.4%)
30(14.1%)
Anterior communication artery
17 (18.9%)
49 (23.0%)
Middle cerebral artery
14 (15.6%)
31 (14.6%)
Anterior cerebral artery
7 (7.8%)
28 (13.1%)
Posterior cerebral artery
11 (12.2%)
12 (5.6%)
Vertebral artery
4 (4.4%)
4 (1.9%)
Surgery
54 (60.0%)
132 (62.0%)
0.747
Aneurysmal size (mm)
10.4 ± 5.8
5.9 ± 3.7
<0.001
Rebleeding
10 (11.1%)
6 (2.8%)
0.003
Acute hydrocephalus
47 (52.2%)
43 (20.2%)
<0.001
Intracerebral hemorrhage
20 (22.2%)
19 (8.9%)
0.002
Intraventricular hemorrhage
59(65.6%)
12 (5.6%)
<0.001
External ventricular drain
66 (73.3%)
43 (20.2%)
<0.001
Angiographic vasospasm
71 (78.9%)
60 (28.2%)
<0.001
Computed tomography ischemia
28 (31.1%)
22 (10.3%)
<0.001
Admission time (hr)
4.5 ± 3.5
4.8 ± 3.7
0.577
Seizure
19 (21.1%)
25 (11.7%)
0.085
Plasma C-reactive protein level (mg/L)
8.2 ± 3.2
6.7 ± 2.4
<0.001
plasma D-dimer level (mg/L)
2.4 ± 1.2
1.9 ± 0.9
<0.001
Plasma copeptin level (pmol/L)
29.3 ± 9.0
17.8 ± 6.4
<0.001
Numerical variables were presented as mean ± standard deviation. Categorical variables were expressed as counts (percentage). Numerical variables were analyzed by Mann-Whitney U-test or unpaired Student
Multivariate analysis of factors predicting one-year poor functional outcome among 303 patients
Odds ratio
95% confidence interval
WFNS score on admission
4.930
1.997~13.438
0.005
Modified Fisher score on admission
5.743
2.502~16.307
0.001
Aneurysmal size (mm)
1.129
0.782~1.337
0.137
Rebleeding
1.219
0.841~9.090
0.103
Acute hydrocephalus
1.132
0.730~8.004
0.218
Intracerebral hemorrhage
2.670
0.470~14.003
0.314
Intraventricular hemorrhage
2.404
0.817~12.337
0.087
External ventricular drain
1.316
0.718~4.796
0.316
Angiographic vasospasm
1.174
0.790~3.931
0.113
Computed tomography ischemia
1.422
0.849~3.640
0.139
Plasma C-reactive protein level (mg/L)
1.019
0.827~1.213
0.709
plasma D-dimer level (mg/L)
1.182
0.762~1.899
0.418
Plasma copeptin level (pmol/L)
1.253
1.109~1.504
0.001
The relation of copeptin to the poor functional outcome was assessed in a logistic-regression model. WFNS indicates World Federation of Neurological Surgeons.
A receiver operating characteristic curve showed that plasma copeptin level on admission predicted one-year poor neurologic outcome of patients statistically significantly (Figure
Receiver operating characteristic curve analysis of factors predicting one-year poor functional outcome among 303 patients
Copeptin
WFNS score
Modified Fisher score
Criterion
>23.8 pmol/L
>2
>2
Area under curve
0.860
0.909
0.902
95% confidence interval
0.815~0.897
0.871~0.939
0.863~0.933
Sensitivity
82.2
96.7
95.6
95% confidence interval
72.7~89.5
90.6~99.3
89.0 ~98.7
Specificity
79.8
74.7
69.5
95% confidence interval
73.8~85.0
68.3 ~80.3
62.8~75.6
Odds ratio
18.284
85.228
48.941
95% confidence interval
9.684~34.522
25.912~280.325
17.237~139.015
+ likelihood ratio
4.07
3.81
3.13
95% confidence interval
3.6~4.6
3.5~4.2
2.8 ~3.5
- likelihood ratio
0.22
0.045
0.064
95% confidence interval
0.1~0.4
0.01 ~0.1
0.02 ~0.2
Reference
0.109
0.178
WFNS indicates World Federation of Neurological Surgeons.
Discussion
In this retrospective study, we aimed to investigate the plasma copeptin levels in the SAH patients, and therefore, presence of other prior systemic diseases including uremia, liver cirrhosis, malignancy, chronic heart or lung disease, diabetes mellitus and hypertension, that may be associated with plasma copeptin levels
Copeptin is co-synthesized with arginine vasopressin in the hypothalamus and is released into the portal circulation of the neurohypophysis. Arginine vasopressin contributes to the regulation of osmotic and cardiovascular homeostasis
Copeptin comes from the same precursor as mature arginine vasopressin, which is already well associated with hemodynamic changes and patient outcome. The measurement of mature arginine vasopressin, however, is subject to considerable challenges, and has therefore not reached clinical routine in the context of rapid measurements in the critically ill patients. Here, the stability and longer ex vivo half-life of copeptin is a practical advantage, which makes it easier to determine in the clinical laboratory. In this study, a receiver operating characteristic curve showed that plasma copeptin level on admission predicted poor functional outcome and mortality after 1 year, and in-hospital mortality of patients obviously. The area under curve of the copeptin concentration was similar to those of WFNS score and modified Fisher score for the prediction of these poor outcomes. In a combined logistic-regression model, copeptin improved the area under curve of WFNS score and modified Fisher score for the prediction of poor functional outcome after 1 year, but not for the prediction of mortality after 1 year or in-hospital mortality. Therefore, the determination of copeptin in the plasma of patients on admission provides the ability to distinguish between patients with good and bad outcome.
Cerebrovasospasm is regarded as abnormal and prolonged smooth muscle contraction of cerebral arteries; many substances have been involved in the development of cerebral vasospasm following SAH, but the complex mechanism of this arterial narrowing is not yet fully understood
Conclusions
In this study, plasma copeptin level is a useful, complementary tool to predict functional outcome and mortality after aneurysmal subarachnoid hemorrhage.
Key messages
• In the patients with aneurysmal subarachnoid hemorrhage, plasma copeptin level was substantially higher than that in healthy controls.
• Plasma copeptin level was an independent predictor of functional outcome and death after aneurysmal subarachnoid hemorrhage
• Copeptin level was a useful, complementary tool to predict functional outcome and mortality after aneurysmal subarachnoid hemorrhage.
Abbreviations
AUC: areas under the receiver operating characteristics curve; CT: computerized tomography; ELISA: enzyme-linked immunosorbent assay; GOS: Glasgow outcome scale; SAH: subarachnoid hemorrhage; WFNS: World Federation of Neurological Surgeons.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
XDZ and JSC contributed to the design of the study and drafted the manuscript and participated in the laboratory work. JSC, FZ and QCL enrolled the patients. GC and JMZ contributed to data analysis and interpretation of the results. All authors read and approved the final manuscript.