Clinical profile and role of C-reactive protein and lactate dehydrogenase as prognostic marker and comparative efficacy of different pharmacotherapeutic agents in patients with cerebrovascular accident: An observational study.

The current study was conducted to determine the role of C-reactive protein (CRP) and lactate dehydrogenase (LDH) as prognostic-marker and outcomes of different pharmacotherapeutic agents among patients with cerebrovascular accident (CVA). A hospital-based observational study was conducted and patients with CVA admitted were included. Serum-CRP on admission correlated positively with modified Rankin score (mRS) (r = 0.9, P < 0.001) in ischemic stroke, whereas no correlation between serum LDH with mRS (r = 0.1, P = 0.5) was observed. Neither CRP nor LDH was helpful in predicting the outcome in hemorrhagic stroke. The use of Vitamin B12 was associated with favorable outcome in ischemic CVA cases and use of folic acid was associated with favorable outcome among hemorrhagic-CVA patients.

Introduction

C-reactive protein (CRP) is an acute-phase substance which is produced in hepatocytes. It is considered a sensitive predictor of both new onset and recurrent ischemic events.[123] CRP is a potential predictor of future vascular events and a potential prognostic marker following vascular events. There is a paucity of data relating to CRP as prognostic factor in cerebrovascular accident (CVA).[45] CVA is one of the leading causes of death and disability in the elderly population,[6] and the indicators predicting the outcome in such patients are not clearly outlined. About three-quarter of patients with ischemic stroke have elevated levels of CRP.[7] The rise in CRP level may reflect a systemic inflammatory response following stroke and the extent of tissue injury. In animal models of focal cerebral ischemia, it has been noted that CRP increases the secondary brain damage through activating complement system.[8] The information regarding hemorrhagic stroke is also scarce. It has been observed that CRP levels increases shortly after admission and was related to hematoma volume in hemorrhagic stroke which can be attributed to inflammatory response in hematoma.[9] There are several studies which have assessed the role of CRP in the early phases of stroke as a prognostic factor of functional outcome among which most of the studies evaluated only the relation between CRP and mortality with variable results. Some studies found positive association; however, other studies did not.[1011]

Lactate dehydrogenase (LDH) has also been used as inflammatory marker for various inflammatory and neoplastic diseases (lymphoma, breast carcinoma, hepatocellular carcinoma, etc.,). Cerebrospinal fluid (CSF) LDH has been described as a prognostic marker in CVA patients in some studies.[12] Studies on serum LDH as prognostic marker in CVA in isolation or in combination with elevated CRP level have not been reported. Therefore, to bridge the unmet need of early prognostication of stroke patients, we attempt to study the role of CRP and LDH as the prognostic markers and their significance in outcome of CVA patients.

Aim of the study

This study was conducted to assess the etiology, clinical features as well as to estimate CRP and LDH as prognostic markers in patients suffering from cerebrovascular events. The secondary outcome was assessed for the role of intravenous mannitol, Vitamin B12 injection, and oral folic acid supplementation in the outcome of ischemic and haemorrhagic stroke, respectively; which are used as the part of standard of care in stroke patients.

Methods

This study was undertaken among indoor patients admitted in the medicine department of Silchar Medical College and Hospital from July 2020 to May 2021 (No SMC/753 dated Silchar January 20, 2021).

Study design

The present study is a hospital-based, prospective, observational study.

Sample size

Patients admitted in the medicine department of Silchar Medical College and Hospital with cerebrovascular accident who fulfilled the inclusion criteria over a period of 10 months from July 2020 to May 2021were included in the analysis.

Inclusion and exclusion criteria

All symptomatic patients with CVA who will be admitted in the medicine department of Silchar Medical College and Hospital were included in the study. Patients who were excluded from the preview of the study includes (1) patients with multiple sclerosis, intracranial space occupying lesion, meningitis, (2) patients with psychiatric disorder, (3) pregnant and lactating mothers, (4) children <12 years of age, and (5) patients who refused to give consent.

Data collection

A detailed clinical history and complete physical and neurological examination was done in all cases. All routine hematological and biochemical investigations such as complete blood count, renal function test, as well as the inflammatory markers such as serum CRP, LDH was evaluated. Noncontrast computed tomography (NCCT) scan of the brain was done in patients. The results for each parameter for the categorical data were represented in numbers and percentages, whereas continuous data were presented as average (mean, standard deviation) which was depicted in tables and figures as per need.

Statistical analysis

Statistical analysis will be carried out by Microsoft Excel/SPSS software. During the analysis of data, continuous variables were compared using the Student t-test, whereas the categorical variables were compared using the Chi-square test and descriptive statistics was used as per need. Differences in distribution will be tested with the Fisher's exact test and X test. P ≤ 0.05 is considered statistically significant.

Results and Observations

This study was a hospital-based, prospective, observational study including 50 patients presenting with cerebrovascular accident in the Department of General Medicine, Silchar Medical College and Hospital from between July 2020 to May 2021. The study participants were investigated by various radiological and biochemical test along with comprehensive clinical examination, and the results were analyzed using the Chi-square test and Student's t-test. In all analysis, a P < 0.05 was considered statistically significant.

The mean age of the study population was 61.68 ± 12.07 years ranging from 30 to 91 years. The patients were classified into two groups according to the NCCT brain at admission: Group A included 28 patients with acute ischemic stroke with mean age (62.81 ± 9.8 years) and Group B included 22 patients with intracerebral hemorrhage with mean age of 60.14 ± 14.5 years. The outcome was measured by modified Rankin score (mRS) and poor outcome was defined as mRS parameter >2. The outcomes were assessed in 7 days after admission by mRS value and showed poor outcome in 22 patients (44%). The mean mRS of the overall patients was 2.96 ± 2.3. Serum CRP level on admission was positively correlated with mRS parameter (r = 0.6, P < 0.001). The demographic characteristics of both groups of the study were almost identical, as shown in Table 1. However, more patients in hemorrhagic stroke group had higher baseline blood pressure value as compared to ischemic stroke group.

Table 1

Baseline characteristics in both ischemic and hemorrhagic cerebrovascular accident groups

	Ischemic CVA (n=28)	Hemorrhagic CVA (n=22)	P
Age (years)	62.89±9.8	60.14±14.5	0.5
Gender, n (%)
Male	19 (67.8)	15 (68.2)	0.5
Female	9 (32.1)	7 (31.8)	0.5
Dyslipidemia, n (%)	23 (82.1)	16 (72.7)	0.4
Systolic BP (mm Hg)	142.14±23.5	156.41±31.6	<0.001
Diastolic BP (mm Hg)	85.29±10.5	91.32±15.3	<0.001
Fundoscopy, n (%)
Papilledema	3 (10.7)	4 (18.2)	0.9
Hypertensive retinopathy	8 (28.5)	9 (40.9)	0.4
Diabetic retinopathy	4 (14.3)	2 (.09)	0.9
Normal	13 (46.4)	7 (31.8)	0.5

CVA=Cerebrovascular accident, BP=Blood pressure

In ischemic stroke serum CRP on admission correlated positively with mRS (r = 0.9, P < 0.001). Mean serum CRP in patients with poor outcome according to mRS parameter was 40 ± 9.2 mg/L, whereas in those with favorable outcome, the mean was 22.64 ± 2.8 mg/L (P < 0.001), as depicted in Table 2, whereas serum LDH has no correlation with mRS (r = 0.1, P = 0.5). In hemorrhagic stroke, there was no correlation between CRP and mRS (r = 0.3, P = 0.165). The mean serum CRP in patients with poor outcome was 9.60 ± 5.9 mg/L, whereas those with favorable outcome, the mean was 2.82 ± 1.90 mg/L (P = 0.165). There was no correlation between serum LDH with mRS parameter (r = 0.03, P = 0.9) in predicting the outcome of CVA patients. On comparing both groups, it was found that CRP was significantly higher in ischemic stroke than in hemorrhagic stroke. CRP was 33.18 ± 11.3 in ischemic stroke compared to 4.36 ± 9.5 in hemorrhagic stroke (P < 0.001).

Table 2

Association between level of C-reactive protein and outcome

Parameter	Ischemic stroke		Hemorrhagic stroke
	CRP mg/L (mean±SD)	P	CRP mg/L (mean±SD)	P
Poor outcome	40±9.2	<0.001	9.6±5.9	0.165
Favorable outcome	22.64±2.8		2.82±1.9

Poor or favorable outcome was decided on the basis of mRS score (mRS score >2 was taken as indicator of poor outcome). mRS=Modified Rankin score, CRP=C-reactive protein

All patients were managed as per standard protocol used for stroke patients in our institute. On analyzing the pharmacological treatment received by the patients in our study, intravenous mannitol was found not to be associated with significant difference in outcome between ischemic and hemorrhagic stroke. On the other hand, intravenous Vitamin B12 injection use was associated with improved outcome in ischemic stroke, whereas folic acid supplementation led to better outcome in hemorrhagic stroke patients, as shown in Table 3.

Table 3

Association between pharmacological treatment on outcome in both groups of cerebrovascular accident

Parameters	Poor outcome	Favourable outcome	P
Ischemic (n=28) Poor outcome: n=17, Favorable outcome n=11
Mannitol	7/17	9/11	0.576
Tab Vitamin B12	8/17	11/11	0.003
Tab folic acid	4/17	6/11	0.094
Hemorrhagic (n=22) Poor outcome: n=5, Favorable outcome n=17
Mannitol	3/5	7/17	0.457
Tab Vitamin B12	2/5	4/17	0.467
Tab folic acid	2/5	17/17	0.001

Poor outcome was defined as mRS score >2. mRS=Modified Rankin score

Discussion

Stroke is one of the leading causes of death in developed and developing countries. Stroke induces systemic inflammatory response through mobilizing and migration of peripheral immune cells into the brain. It has been observed in Rotterdam study, that high CRP is associated with the risk of future stroke, although it is not beneficial for individual stroke outcome prediction.[13] On the contrary, it was observed that high level of CRP is associated with increased risk of ischemic stroke and transient ischemic attack (TIA) in a study done in Framingham.[3] An association between high CRP and stroke presentation, outcomes and future vascular events were found in CVA patients in other studies.[241415161718]

The measurement of CSF LDH was found to be significantly high in newborn infants with perinatal ischemia. The longer half-life of LDH in CSF and high intracellular concentration explain the high LDH sensitivity in cerebral ischemia. It has been observed in several studies that the value of LDH measured within 8 h of stoke was significantly higher in patients with neurological deficits in comparison to TIA.[192021] In a study done by Shoaeb et al., it was found that serum CRP predicts the outcome in ischemic stroke not in hemorrhagic stroke and it also had positive correlation with mRS value in ischemic stroke.[22] Elevated CRP level was associated with higher incidence of ischemic stroke but not with hemorrhagic stroke was also reported by a retrospective study done in Japan[23] which is echoed similarly in our study. In another study done by Parakh et al.,[12] no correlation was noted between serum LDH and both ischemic as well as hemorrhagic stroke and its outcome, which was in concordance with the present study.

Among acute stroke patients who received intravenous mannitol treatment as per routine management; no significant difference in outcome was observed between infarct and hemorrhagic stroke. In a previous study, intravenous mannitol when used in acute stroke was found be safe but not associated with improved short term outcome.[24] Patients with hemorrhagic stroke had better outcome with folic acid supplementation, whereas patients with acute stroke with infarct who received intravenous Vitamin B12 had good outcome. This was in concordance with a previous study which observed reduced serum Vitamin B12 level in ischemic stroke and low folic acid level in hemorrhagic stroke patients, respectively.[25]

Conclusion

In the current study, we found that serum CRP level was positively correlated with the outcome of ischemic stroke but not with hemorrhagic stroke and serum LDH had no correlation with the outcome of both ischemic and hemorrhagic stroke. Thus, CRP concentration can be used as a screening investigation for determining the severity of ischemic stroke.

Ethical consideration

The study was undertaken with due clearance from the ethical committee of our institute which follows the Helsinki guidelines for research. Informed consent was obtained from patients or attendant before the inclusion in our study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.