RESEARCH PROTOCOL
Association Between Admission C-Reactive Protein Levels and In-Hospital Mortality Among Patients With Acute Stroke: A Prospective Cohort Study
Running title: Admission CRP and Stroke Mortality
[Insert author name(s), department(s), institution(s), and corresponding author details before publication.]
Abstract
Background: Stroke remains a major global cause of death and long-term disability. Inflammatory responses may contribute to brain injury and complications after stroke. C-reactive protein (CRP), an acute-phase inflammatory marker, is readily measured in clinical practice and may provide additional information about prognosis.
Objective: To evaluate the association between CRP levels measured at hospital admission and in-hospital mortality among adults presenting with acute stroke.
Methods: This prospective cohort study is planned in the Department of Medicine at Bakhtawar Amin Hospital, Multan, over six months following the required approvals. The proposed sample comprises 204 adults aged 25–70 years who present within 24 hours of stroke symptom onset and meet the study eligibility criteria. Participants will be grouped according to admission CRP level using the final threshold specified in the approved protocol. The primary outcome will be in-hospital mortality. Secondary outcomes will include intensive care unit (ICU) admission, mechanical ventilation, in-hospital complications, and length of stay. Data will be analysed using descriptive statistics, group comparisons, relative risks with 95% confidence intervals, and a multivariable modified Poisson regression model.
Expected contribution: The study is designed to generate local evidence on whether admission CRP is associated with in-hospital mortality and whether it may contribute to early risk assessment alongside established clinical variables. As this is a protocol, no results or conclusions about the study cohort are available yet.
Keywords: C-reactive protein; CRP; acute stroke; mortality; inflammation; prospective cohort; Pakistan
1. Introduction
Stroke is a major public health challenge and remains among the leading causes of death and disability worldwide. Its consequences extend beyond the initial neurological event: many patients develop complications, require intensive monitoring, or experience persistent functional impairment. The global burden of stroke has continued to increase, reinforcing the need for practical tools that can support early assessment and appropriate use of hospital resources [1].
Inflammation is involved in several processes relevant to cerebrovascular disease, including atherosclerosis, plaque instability, vascular injury, and the response of brain tissue to ischemia. After an acute stroke, systemic inflammatory activity may reflect a combination of pre-existing vascular disease, tissue injury, and complications. These processes can be associated with clinical severity and recovery, although an inflammatory marker alone cannot establish the cause of a patient’s condition [2–4].
C-reactive protein is an acute-phase protein produced in response to inflammatory signalling. It is widely available and comparatively straightforward to measure. Increased CRP after stroke may reflect a systemic inflammatory response, the extent of tissue injury, or an intercurrent infection. This makes CRP a potentially useful adjunct to clinical assessment, but it is not specific to stroke and should be interpreted in the context of symptoms, examination, imaging, and other investigations [4].
A 2023 meta-analysis of 39 studies reported an association between elevated admission high-sensitivity CRP (hs-CRP) and mortality among patients with acute ischemic stroke. The pooled relative risk reported for higher versus lower hs-CRP was 3.84 (95% confidence interval 2.41–6.11) [5]. The findings support further investigation, but differences in patient populations, assays, cut-off values, stroke subtypes, and outcome definitions mean that estimates from previous studies should not be assumed to apply directly to every hospital setting.
2. Rationale for the Study
Although previous research suggests that higher CRP levels may be associated with adverse stroke outcomes, local patient characteristics, disease severity, available treatment pathways, and patterns of complications can influence observed outcomes. Data from Bakhtawar Amin Hospital, Multan, may help describe the relationship in this clinical setting and assess whether admission CRP adds useful prognostic information when considered alongside established clinical factors.
A prospective cohort design allows CRP to be documented at admission and patients to be followed until their hospital outcome is known. By recording demographic characteristics, vascular risk factors, stroke severity, imaging findings, treatments, and complications, the study will also be able to examine whether the CRP–mortality association persists after adjustment for selected covariates.
3. Objective and Hypothesis
Primary objective: To determine the association between CRP levels at admission and in-hospital mortality among patients with acute stroke.
Study hypothesis: In-hospital mortality will be higher among patients with elevated admission CRP than among patients in the comparison CRP group.
4. Materials and Methods
4.1 Study Design, Setting, and Duration
The study is planned as a prospective cohort study in the Department of Medicine at Bakhtawar Amin Hospital, Multan. Recruitment and follow-up are planned over six months after approval of the research synopsis and completion of the required institutional and regulatory procedures.
4.2 Sample Size and Sampling Technique
The proposed sample size is 204 participants, with 102 participants planned for each CRP group. The synopsis states that this estimate was calculated using OpenEpi, based on previously reported mortality estimates of 25.2% in the higher-CRP group and 9.4% in the comparison group, with a 95% confidence level and 80% power. Non-probability consecutive sampling will be used to recruit eligible patients presenting during the study period.
4.3 Eligibility Criteria
Inclusion criteria are adults aged 25–70 years, of either sex, presenting with acute stroke within 24 hours of symptom onset, with the diagnosis supported by clinical assessment and brain CT imaging according to the study protocol.
The synopsis excludes patients with evidence of an acute infection at admission, autoimmune disease or chronic inflammatory disorders, major trauma, surgery, burns or myocardial infarction within the preceding four weeks, use of systemic corticosteroids or immunosuppressive therapy, and chronic kidney or liver disease. These criteria are intended to reduce potential sources of distortion in CRP measurement and outcome assessment.
4.4 CRP Measurement and Exposure Classification
Blood samples will be collected at admission using aseptic venipuncture, and CRP will be measured in the study laboratory using standard operating procedures. Participants will be classified into higher-CRP and comparison groups according to the prespecified threshold in the final approved protocol.
For reproducibility, the final manuscript must report the exact cut-off, measurement unit, laboratory assay, and how values at the threshold are classified.
4.5 Data Collection
After written informed consent, baseline information will be recorded using a structured proforma. Demographic and clinical variables will include age, sex, body mass index, smoking status, diabetes mellitus, hypertension, dyslipidaemia, and ischemic heart disease. Stroke-related variables will include time from symptom onset to admission, stroke type (ischemic or hemorrhagic), lesion side and location, admission Glasgow Coma Scale (GCS), National Institutes of Health Stroke Scale (NIHSS) score, modified Rankin Scale, and relevant neuroimaging findings such as cerebral oedema, midline shift, infarction, or hematoma.
Laboratory investigations specified in the synopsis include complete blood count, blood glucose, serum creatinine, coagulation profile, and CRP. Treatment information will include thrombolysis, antiplatelet therapy, anticoagulation, and statin therapy, as applicable to stroke type and institutional practice. Patients will receive standard care according to the hospital’s clinical protocols; the study is observational and does not assign treatment on the basis of CRP status.
4.6 Outcomes
The primary outcome is in-hospital mortality, recorded as death before final hospital disposition. Secondary outcomes are ICU admission, mechanical ventilation, in-hospital complications, and length of hospital stay. Complications listed in the synopsis include aspiration pneumonia, urinary tract infection, pulmonary embolism, deep vein thrombosis, seizures, raised intracranial pressure, and myocardial infarction.
4.7 Statistical Analysis
Data are planned to be analysed using SPSS version 27.0. The distribution of quantitative variables will be assessed using the Shapiro–Wilk test. Normally distributed data will be summarized as means and standard deviations, while categorical variables will be presented as frequencies and percentages. Between-group comparisons will use the independent-samples t-test or Mann–Whitney U test for quantitative variables, and the chi-square test or Fisher’s exact test for categorical variables, as appropriate.
In-hospital mortality will be compared between CRP groups using the chi-square test. Relative risk estimates with 95% confidence intervals will be reported. A modified Poisson regression model will be used to assess the adjusted association between CRP group and mortality, incorporating clinically relevant covariates and variables meeting the protocol’s univariable screening criterion. A two-sided p-value below 0.05 will be considered statistically significant. The final analysis plan should specify the exact covariates and how missing data will be handled before the database is locked.
4.8 Ethical Considerations
The synopsis states that data collection will begin only after approval from the relevant institutional ethical review committee and the College of Physicians and Surgeons Pakistan (CPSP), as applicable. Written informed consent will be obtained from participants, and confidentiality will be maintained. Before publication, the authors should add the relevant ethics committee name, approval reference and date, and any applicable registration details. No approval number should be inserted unless it has actually been issued.
5. Expected Clinical Significance
The study may clarify whether admission CRP is associated with in-hospital mortality in the local cohort. If an association is observed and remains after appropriate adjustment, CRP could be considered as one additional component of early risk assessment alongside stroke severity, vital signs, imaging, comorbidities, and other established clinical information. It may also provide locally relevant information for clinical counselling and planning monitoring needs.
CRP should not be treated as a stand-alone decision tool. Because it is a nonspecific inflammatory marker, an elevated result must be interpreted in the wider clinical context. The study is designed to evaluate an association and cannot, by itself, demonstrate that CRP causes mortality or that lowering CRP would improve outcomes.
6. Strengths and Potential Limitations
Potential strengths include prospective data collection, measurement of CRP early after presentation, a prespecified primary outcome, and planned adjustment for selected clinical factors. Recording stroke severity, imaging findings, comorbidities, treatment, and complications may support a more meaningful interpretation of the observed association.
Potential limitations include the single-centre design, non-probability consecutive sampling, the proposed restriction to adults aged 25–70 years, and follow-up limited to the in-hospital period. Residual confounding may remain even after statistical adjustment. CRP is nonspecific, and undetected infection or other inflammatory conditions may affect its level. The study will also require a clearly defined CRP assay, unit, and cut-off to ensure that exposure classification is reproducible.
7. Conclusion
This prospective cohort protocol proposes to investigate the relationship between admission CRP levels and in-hospital mortality among adults with acute stroke at Bakhtawar Amin Hospital, Multan. The planned analysis will compare mortality between CRP groups and assess the association after adjustment for selected clinical factors. The study may contribute local evidence on the potential prognostic role of CRP; however, conclusions about the actual strength or significance of the association must await completion and analysis of the collected data.
Declarations
Ethics approval: Pending/insert the actual approving committee, reference number, and approval date before publication.
Informed consent: The protocol plans to obtain written informed consent from participants.
Funding: [Insert funding source, or state that no external funding was received only if confirmed by the authors.]
Conflicts of interest: [To be completed and confirmed by all authors.]
Data availability: Not applicable at the protocol stage; update after study completion if required.
References
1. Feigin VL, Brainin M, Norrving B, Martins SO, Pandian J, Lindsay P, et al. World Stroke Organization: Global Stroke Fact Sheet 2025. International Journal of Stroke. 2025;20(2):132–144. doi:10.1177/17474930241308142.
2. Puleo MG, Miceli S, Di Chiara T, Pizzo GM, Della Corte V, Simonetta I, et al. Molecular mechanisms of inflammasome in ischemic stroke pathogenesis. Pharmaceuticals. 2022;15(10):1168. doi:10.3390/ph15101168.
3. Gusev E, Sarapultsev A. Atherosclerosis and inflammation: insights from the theory of general pathological processes. International Journal of Molecular Sciences. 2023;24(9):7910. doi:10.3390/ijms24097910.
4. Simats A, Liesz A. Systemic inflammation after stroke: implications for post-stroke comorbidities. EMBO Molecular Medicine. 2022;14(9):e16269. doi:10.15252/emmm.202216269.
5. Chen L, Wang M, Yang C, Wang Y, Hou B. The role of high-sensitivity C-reactive protein serum levels in the prognosis for patients with stroke: a meta-analysis. Frontiers in Neurology. 2023;14:1199814. doi:10.3389/fneur.2023.1199814.
6. Mazaheri S, Reisi E, Poorolajal J, Ghiasian M. C-reactive protein levels and clinical outcomes in stroke patients: a prospective cohort study. Archives of Iranian Medicine. 2018;21(1):8–12.
7. Finck T, Sperl P, Hernandez-Petzsche M, Boeckh-Behrens T, Maegerlein C, Wunderlich S, et al. Inflammation in stroke: initial CRP levels can predict poor outcomes in endovascularly treated stroke patients. Frontiers in Neurology. 2023;14:1167549. doi:10.3389/fneur.2023.1167549.
8. Rizo-Tellez SA, Sekheri M, Filep JG. C-reactive protein: a target for therapy to reduce inflammation. Frontiers in Immunology. 2023;14:1237729. doi:10.3389/fimmu.2023.1237729.
AUTHOR CHECKLIST — NOT PART OF THE ARTICLE
Please resolve these points before publishing the article or submitting the manuscript:
· CRP cut-off and units: the operational definition in the uploaded synopsis states mg/dL, while the cited studies in the background use mg/L. Confirm the correct unit, exact threshold, assay, and the rule for a value exactly equal to 7 with the supervisor, laboratory, and approved protocol.
· Add verified author names, institutional affiliations, and corresponding-author details.
· Enter only confirmed ethics approval details and any applicable registration number; do not invent an approval number.
· Complete funding and conflict-of-interest declarations after confirmation by all authors.
· This is a research protocol draft. A completed original research article will require actual study data, results, and analysis; do not present expected findings as observed results.