Authors: Huang Jingjie, Wu Bangqi, Qin Peng, Zhang Ziyi, Cheng Yupei, Wang Chaoran, Chen Yuyan, Bai Jing
Categories: Article, Stroke, Acute fever, Intractable fever, Post-stroke fever, Therapy, Diseases, Medical research, Neurology, Risk factors, Signs and symptoms
Source: Scientific Reports
Authors: Huang Jingjie, Wu Bangqi, Qin Peng, Zhang Ziyi, Cheng Yupei, Wang Chaoran, Chen Yuyan, Bai Jing
Fever has long been recognized as one of the earliest clinical indicators of illness and remains a leading reason for seeking medical care worldwide. It is typically classified based on its duration and underlying etiology. In clinical settings, intractable fever is as common as acute fever, particularly in patients with brain injuries. Beyond infectious causes, stroke survivors often experience recurrent intractable fever due to central or neurogenic mechanisms. This study aims to retrospectively investigate the incidence and clinical characteristics of acute and intractable fever in patients undergoing stroke rehabilitation. It explores the associations between these characteristics and the different types of fever. Additionally, the study seeks to identify potential risk factors contributing to the development of intractable fever, aiming to guide clinical management and optimize treatment strategies for stroke-related fever. This study evaluated 1,065 stroke patients in the rehabilitation phase who were admitted to the Neurorehabilitation Center between January 1, 2023, and December 31, 2023. Of these, 230 febrile patients met the inclusion criteria and were included in the analysis, comprising 194 cases of acute fever and 36 cases of intractable fever. Medical records and clinical characteristics were collected, and the data from the two groups of febrile patients were analyzed using t-tests, Mann-Whitney U tests, and chi-square tests. Logistic regression analysis was performed to identify risk factors associated with intractable fever, while receiver operating characteristic (ROC) curves were used to assess the predictive performance of individual and combined risk factors. A p-value of less than 0.05 was considered statistically significant. 15.7% of patients experienced intractable fever, which was significantly associated with brainstem lesions (P < 0.05). Compared to patients with acute fever, those with intractable fever had higher NIHSS scores (33.3% vs. 15.5%, P < 0.05), a greater incidence of consciousness disorders (66.7% vs. 28.9%, P < 0.05), and a higher rate of tracheostomy (55.6% vs. 15.5%, P < 0.05). All patients received antibiotic treatment, and gabapentin was administered to 16 cases. Patients with brainstem lesions were less likely to be treated with gabapentin (37.5% vs. 90%, P < 0.05), while those with intracerebral hemorrhage were more likely to receive gabapentin (87.5% vs. 10%, P < 0.05). Logistic regression analysis revealed that consciousness disorders and tracheostomy status were significant risk factors for intractable fever (P = 0.047, OR 6.691, 95% CI 1.030–43.478; P = 0.021, OR 5.366, 95% CI 1.282–22.465). Brainstem lesions also significantly increased the risk (P = 0.002, OR 9.617, 95% CI 2.277–40.614). Although limited in scope, this retrospective study highlights the increased risk of intractable fever during stroke rehabilitation among patients with consciousness disorders, tracheostomy, and brainstem injuries. The key risk factors identified include higher NIHSS scores, impaired consciousness, tracheostomy status, and brainstem lesions.
Fever plays a significant role in the pathogenesis, clinical manifestations, and outcomes of numerous diseases. It is typically defined as an elevation of body temperature beyond the normal range, triggered by an increase in the body’s core temperature set point. The complexity of fever stems from its multisystemic effects, which are coordinated through endocrine, neural, immune, and behavioral mechanisms^1^. The thermoregulatory center, located in the hypothalamus, contains temperature-sensitive neurons responsible for maintaining thermal homeostasis. When pyrogens disrupt this balance and alter the temperature set point, fever ensues as a physiological response to inflammation and infection^2^. Post-stroke fever is a common occurrence, with approximately 50% of stroke inpatients experiencing fever, most frequently due to infections such as post-stroke pneumonia^3,4^. Generally, symptoms of infectious fever resolve within days to weeks with appropriate antibiotic treatment. However, in cases of severe infection, patients may develop prolonged intractable fever, necessitating extended treatment to alleviate symptoms. Research indicates that both infectious and non-infectious conditions can lead to intractable fever, with an increasing number of studies identifying central fever and neurogenic fever as particularly prevalent in patients with brain injuries^5,6^. Unlike infectious fever and neurogenic fever, central fever lacks definitive diagnostic criteria and is often diagnosed by exclusion, after ruling out other causes of fever^7–9^.
Neurogenic fever is primarily associated with dysfunction of the autonomic nervous system and is often characterized by paroxysmal hypertension, fever, tachycardia, tachypnea, dilated pupils, agitation, and extensor posturing^10,11^. In contrast, central fever is related to disruptions in temperature regulation systems, such as the brainstem and hypothalamus^12–14^. Due to the absence of clear diagnostic markers and typical clinical symptoms, central fever is easily overlooked. Clinically, we have observed that the causes of fever in stroke patients are multifaceted, often involving a combination of infectious and central factors. While fever during the acute phase of stroke is well-documented, fever in the rehabilitation phase also deserves attention. In addition to acute fever, some stroke patients experience recurrent episodes of intractable fever during rehabilitation^15–17^. Although laboratory and imaging findings in these patients may indicate infection, targeted antibiotic treatments often fail to produce significant improvements, with fever symptoms frequently recurring^18^. This suggests that the fever in these cases may not be purely infectious in nature. A deeper understanding of fever is essential for the accurate diagnosis, treatment, and management of various diseases. This study aims to review the onset characteristics and treatment regimens of patients with intractable fever, analyze potential causes and risk factors, and contribute to a more comprehensive understanding, diagnosis, and treatment of this condition.
We conducted a retrospective review of electronic medical records and identified 230 stroke patients who experienced fever during their treatment at the Neurology Rehabilitation Center between January 1, 2023, and December 31, 2023. Among these, 36 patients were definitively diagnosed with intractable fever through real-time temperature monitoring. All eligible patients were included in this study. Data were extracted from electronic medical records using standardized forms designed for data collection and analysis. These forms captured demographic information, relevant medical history, patient consciousness and tracheostomy status, discharge outcomes, the duration and frequency of fever episodes, antibiotic usage, and the involvement of any lesions. In clinical practice, we observed that patients with intractable fever often failed to show significant improvement in body temperature despite undergoing multiple courses of antibiotics. However, upon administration of gabapentin, these patients exhibited a rapid reduction in fever. Based on this clinical observation, we included an analysis of the effect of gabapentin on body temperature within the intractable fever group as part of this study.
The inclusion criteria for this study comprised patients admitted to our rehabilitation center between January 1, 2023, and December 31, 2023, who were diagnosed with either ischemic or hemorrhagic stroke and exhibited signs of fever during hospitalization. Patients aged 18 years or older were eligible for inclusion. These patients were divided into two groups based on the duration and frequency of the acute fever group and the intractable fever group. The intractable fever group included patients who experienced a fever of ≥ 37.5 °C with a total frequency of recurrent episodes ≥ 3 times and a total fever duration of ≥ 21 days. In contrast, the acute fever group consisted of patients with a fever of ≥ 37.5 °C, a total fever frequency of ≥ 1 episode, and a total fever duration of ≤ 14 days. Patients who did not meet these inclusion criteria or had incomplete data were excluded from the study (see Fig. 1).
Fig. 1Screening Process Flowchart.
Statistical analyses were conducted using SPSS (version 25.0) and Microsoft Excel. Descriptive statistics were employed to summarize patient characteristics, including mean, standard deviation (SD), median, interquartile range (IQR), frequency, and corresponding percentages. Given that variables such as age, NIHSS score, number of lesion areas, and the number of antibiotic types used did not follow a normal distribution, the median (IQR) was selected to describe these continuous variables. For categorical variables, such as gender, age groups, stroke types, NIHSS score categories, lesion areas and extent, history of atrial fibrillation, history of myocardial ischemia/infarction, tracheostomy status, level of consciousness, deep vein thrombosis assessment, infection history, and discharge outcomes, absolute frequencies were deemed more suitable to provide a clear representation of category distributions. Additionally, since the proportion of missing values in the dataset was minimal, their exclusion had a negligible impact on the overall analysis. Therefore, this study addressed missing data by removing the incomplete records. Group differences were analyzed after assessing the normality of data distribution using the Kolmogorov-Smirnov test. Patient-reported outcome measures were utilized to evaluate treatment outcomes, with rank-sum tests employed for the analysis. For numerical variables, Student’s tt-test was used for normally distributed data, while the Mann-Whitney U test was applied for non-normally distributed data. Categorical variables were analyzed using the chi-square test. A binary logistic regression model was used to assess the association between each variable and the development of intractable fever. Odds ratios (ORs), 95% confidence intervals (CIs), and p-values were calculated to interpret the results. Receiver operating characteristic (ROC) curves were employed to evaluate the relationships between age, NIHSS score, number of lesions, antibiotic usage, and the combined effect of these indicators on the development of intractable fever in febrile patients. A two-tailed p-value of less than 0.05 was considered statistically significant.
This study was approved by the Ethics Committee of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine. As this is a retrospective study, the Ethics Committee of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine waived the requirement for informed consent. The study aims to enhance the understanding of risk factors related to stroke-associated fever. All data were obtained from existing medical records and were anonymized and de-identified. Data handling strictly complied with data protection regulations, without involving any identifiable patient information or direct contact with participants. All procedures adhered to the ethical standards of the national research committee and followed the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Our research team obtained administrative permission to access the data used in this study.
Between January 2023 and December 2023, a total of 1,065 patients were admitted. Of these, 835 were excluded because they either did not exhibit fever symptoms during hospitalization or had primary diagnoses unrelated to stroke. Ultimately, 230 patients met the inclusion criteria and were included in the final analysis. Among them, 98 patients (42.6%) were diagnosed with hemorrhagic stroke, 120 (52.2%) with ischemic stroke, and 10 (5.2%) with both ischemic and hemorrhagic strokes. The mean age was 66.56 ± 11.70 years, and 156 patients (67.8%) were male. More than half of the patients (60.9%) were classified as elderly. The most common lesion locations were the basal ganglia (72.2%) and cortical areas (62.6%), with extensive lesion sizes reported in 47.8% of cases. Infection was the most frequent cause of fever (83.5%). The median NIHSS score at admission was 13 (interquartile range [IQR] 8–23). Additionally, 12 patients (5.2%) were diagnosed with atrial fibrillation, 10 (4.3%) with myocardial infarction, and 32 (13.9%) with myocardial ischemia. Consciousness disorders were observed in 80 patients (34.8%), and 50 patients (21.7%) had undergone a tracheostomy. Table 1 presents the characteristics of the acute fever and intractable fever groups. Patients with intractable fever had significantly more brainstem lesions compared to those with acute fever (P < 0.05). The median NIHSS score at admission for acute fever patients was 11 (IQR 8–23), whereas for intractable fever patients, it was 20 (IQR 13–27). A greater proportion of intractable fever patients had moderate to severe NIHSS scores (33.3% vs. 15.5%, P < 0.05), while mild NIHSS scores were more common in the acute fever group (21.6% vs. 0.0%, P < 0.05). This indicates that patients in the intractable fever group were in more severe condition at admission compared to those in the acute fever group (NIHSS 20 vs. 11, P < 0.05). Furthermore, patients with intractable fever were more likely to have consciousness disorders (66.7% vs. 28.9%, P < 0.05) and tracheostomy status (55.6% vs. 15.5%, P < 0.05) compared to acute fever patients. The intractable fever group also had a significantly higher median number of antibiotics used, with a median of 3 (IQR 2–4) compared to 1 (IQR 1–2) in the acute fever group. Regarding discharge outcomes, two patients in the acute fever group showed no improvement in fever symptoms, and two died during hospitalization. In the intractable fever group, four patients failed to show improvement in fever symptoms. Analysis of various variables, including age, gender, age stratification, stroke type, history of atrial fibrillation, myocardial infarction, myocardial ischemia, infection, lesion size, number of affected lesion areas, and discharge outcomes, revealed no statistically significant differences (P > 0.05).
Table 1Clinical characteristics of patients.CharacteristicsAcute fever groupIntractable fever groupTotalP valueCase19436230Gender0.664 Female64 (33.0%)10 (27.8%)74 (32.2%) Male130 (67.0%)26 (72.2%)156 (67.8%) Age M(IQR)68 (61–74)68 (58–74)68(60–73)0.669Age Stratification0.668 Young (18–39)6 (3.1%)2 (5.6%)8 (3.5%) Middle-aged (40–59)34 (17.5)8 (22.2%)42 (18.3%) Elderly (60–75)118 (60.8%)22 (61.1%)140 (60.9%) Very Elderly (> 75)36 (18.6%)4 (11.1%)40 (17.4%)Stroke Type0.344 Cerebral Hemorrhage82 (42.3%)16 (44.4%)98 (42.6%) Cerebral Infarction104 (53.6%)16 (44.4%)120 (52.2%) Cerebral Infarction + Cerebral Hemorrhage8 (4.1%)4 (11.2%)12 (5.2%) NIHSS Score M(IQR)11 (8–23)20 (13–27)13(8–23)0.004NIHSS Score Level0.034 Mild 0–642 (21.6%)42 (18.3%) Moderate 7–1572 (37.1%)10 (27.8%)82 (35.7%) Moderately Severe 16–2030 (15.5%)12 (33.3%)42 (18.3%) Severe 21–4250 (25.8%)14 (38.9%)64 (27.8%)Lesion Area Cerebral Cortex128 (66.0%)16 (44.4%)144 (62.6%)0.083 Centrum Semiovale18 (9.3%)2 (5.6%)20 (8.7%)0.953 Basal Ganglia144 (74.2%)22 (61.1%)166 (72.2%)0.254 Thalamus46 (23.7%)12 (33.3%)58 (25.2%)0.570 Brainstem36 (18.6%)24 (66.7%)60 (26.1%)< 0.05* Cerebellum4 (2.1%)4 (11.1%)8 (3.5%)0.115 Number of Lesions Involved M(IQR)2 (1–2)2 (1–3)2 (1–2)0.843Lesion Range1.000 Dot-like12 (6.2%)2 (5.6%)14 (6.1%) Dot-patchy78 (40.2%)14 (38.8%)92 (40.0%) Large Patchy92 (47.4%)18 (50.0%)110(47.8%) Extensive12 (6.2%)2 (5.6%)14 (6.1%)Admission ECG Atrial Fibrillation10 (5.2%)2 (5.6%)12 (5.2%)1.000 Myocardial Ischemia26 (13.4%)6 (16.7%)32 (13.9%)1.000 Myocardial Infarction6 (3.1%)4 (11.1%)10 (4.3%)0.174 Consciousness Impairment56 (28.9%)24 (66.7%)80 (34.8%)0.002* Tracheotomy Status30 (15.5%)20 (55.6%)50 (21.7%)0.001DVTs Evaluation Abnormal D-dimer&FDP40(20.6%)34(94.4%)74(32.2%) History of Infection156 (80.4%)36 (100%)192 (83.5%)0.087 Antibiotic Count M(IQR)1 (1–2)3 (2–4)1 (1–2)< 0.05Discharge Outcome0.059 Improved (Afebrile)190 (98.0%)32 (88.9%)222 (96.5%) Unimproved (Still febrile)2 (1.0%)4 (11.1%)6 (2.6%) Death2 (1.0%)2 (0.9%)The data include demographic and clinical characteristics of all included patients. The percentages in parentheses represent the proportion of individuals.P-value indicates statistical differences between patients with acute fever and intractable fever, *P < 0.05.M (IQR) represents median (interquartile range).Lesion range was categorized based on descriptions of lesions in cranial CT or MR reports.
As shown in Table 2, the results revealed that the proportion of brainstem lesions was significantly higher in the group not receiving gabapentin compared to the group that did receive gabapentin (90% vs. 37.5%, P < 0.05), with the brainstem being the most frequently affected area in the non-gabapentin group. Furthermore, gabapentin use was significantly more prevalent among patients with cerebral hemorrhage (87.5% vs. 10%, P < 0.05). However, no significant differences were observed between the two groups regarding the total duration of fever, total frequency of fever, antibiotic usage, or discharge outcomes.
Table 2Analysis of Gabapentin intervention on body temperature in the intractable Fever Group.CharacteristicsNon-Gabapentin groupGabapentin groupP valueCases2016Stroke type0.001* Ischemic Stroke16 (80%) Hemorrhagic Stroke2 (10%)14 (87.5%) Ischemic Stroke + Hemorrhagic Stroke2 (10%)2 (12.5%)Primary lesion area Cerebral Cortex12 (60%)4 (25%)0.188 Centrum Semiovale2 (10%)01.000 Basal Ganglia12 (60%)10 (62.5%)1.000 Thalamic Region10 (50%)2 (12.5%)0.152 Brainstem18 (90%)6 (37.5%)0.043* Cerebellar Region4 (20%)00.477 Total Duration of Fever28.5 (26−48.25)28.5 (24.5–30)0.475 Total Frequency of Fever7.3 ± 4.5969.75 ± 4.5590.660 Number of Antibiotics Used3 (2–4)3 (2–6)0.681Discharge outcome0.192 Improved (Afebrile)1616 Unimproved (Intractable Fever)4 Deceased**P* < 0.05.
This study initially conducted descriptive analysis and statistical testing between the two groups to preliminarily screen all predictor variables, incorporating those with p < 0.05 into the multivariable logistic regression model. Additionally, variables considered potentially relevant to the occurrence of intractable fever based on previous studies or clinical experience (such as age, gender, lesion extent, number of affected lesions, and history of atrial fibrillation or myocardial infarction) were also included in the model. This study employed a multivariable logistic regression model, incorporating all candidate predictor variables into a single analysis to evaluate each variable’s independent impact on outcomes. To control for potential confounding factors, all possible confounders, such as age, gender, number of affected lesions, and lesion extent, were simultaneously included in the regression model. The binary logistic regression analysis yielded the following key a higher NIHSS score at admission was significantly associated with an increased risk of intractable fever (P = 0.013, OR 1.074, 95% CI 1.015–1.136), suggesting that stroke severity is an important risk factor. Additionally, patients with impaired consciousness and those who underwent tracheostomy were at a notably higher risk of developing intractable fever (P = 0.046, OR 6.691, 95% CI 1.030-43.478; P = 0.021, OR 5.366, 95% CI 1.282–22.465). Specifically, impaired consciousness was associated with a nearly 6.7-fold higher risk compared to patients with normal consciousness. This may be due to autonomic dysfunction impairing thermoregulation in patients with consciousness disorders. Similarly, patients who underwent tracheostomy faced a 5.4-fold higher risk of intractable fever compared to those without tracheostomy, potentially due to increased infection risk, ventilation issues, or inflammation affecting thermoregulatory centers. However, it is important to note that while the ORs for impaired consciousness and tracheostomy were relatively high, the 95% CIs were wide, indicating some degree of uncertainty in these estimates. This may be attributed to the limited sample size or individual patient variability. Further analysis revealed that patients with brainstem lesions had a significantly higher likelihood of developing intractable fever (P = 0.002, OR 9.617, 95% CI 2.277–40.614), likely related to autonomic dysregulation caused by brainstem dysfunction. Additionally, patients who required more frequent antibiotic use were also at increased risk (P < 0.05, OR 4.132, 95% CI 1.885–9.058). This finding suggests that extensive antibiotic use may influence thermoregulation through various mechanisms, including persistent infections due to antibiotic resistance, enhanced inflammatory responses from gut microbiota disruption, or immune system dysregulation induced by the medication itself.
However, no significant associations were observed with variables such as age, gender, stroke type, lesion extent, history of atrial fibrillation, myocardial infarction, myocardial ischemia, or the number of lesion areas. Detailed results are provided in Table 3.
Table 3Analysis of binary logistic regression model assessing the probability of developing intractable fever based on fever status.VariableP valueORCILowerUpperAge0.675Gender0.346Stroke Type0.658Admission NIHSS Score0.0131.0741.0151.136Number of Affected Lesions0.064Lesion extent0.137History of Atrial Fibrillation0.557History of Myocardial Ischemia0.262History of Myocardial Infarction0.146Consciousness Impairment0.0476.6911.03043.478Tracheostomy Status0.0215.3661.28222.465Lesion area Cerebral Cortex0.323 Basal Ganglia0.429 Thalamus0.907 Brainstem0.0029.6172.27740.614 Number of Antibiotics Used< 0.054.1321.8859.058OR* odds ratio, CI confidence interval.*P < 0.05.
We generated ROC curves and calculated the area under the curve (AUC) values to evaluate the relationship between age, NIHSS score, number of primary lesions, antibiotic usage, and the development of intractable fever in febrile patients. The ROC curves are shown in Fig. 2. The AUC for the NIHSS score in predicting intractable fever was 0.716, indicating moderate discriminative ability. The optimal cutoff value was determined to be 10.5, with a sensitivity of 1 and a specificity of 0.474, resulting in a Youden index of 0.474. For antibiotic usage, the AUC was 0.893, reflecting high discriminative ability. The optimal cutoff value was 2.5, with a sensitivity of 0.722 and a specificity of 0.918, yielding a Youden index of 0.64. When all four indicators (age, NIHSS score, number of primary lesions, and antibiotic usage) were combined to predict the development of intractable fever, the AUC reached 0.910, demonstrating excellent discriminative ability. The optimal cutoff value was 0.16, with a sensitivity of 0.889 and a specificity of 0.845, producing a Youden index of 0.734.
Fig. 2Evaluation Model of Associated Indicators for the Development of Intractable Fever in Febrile Patients.
Fever is a common occurrence following ischemic or hemorrhagic stroke and is associated with poorer clinical outcomes^17,19^. In this study, we assessed the demographic and clinical data, stroke characteristics, risk factors, treatment strategies, and predictors for the development of intractable fever in stroke patients who presented with fever. We compared these findings with those of patients experiencing acute fever. Our results indicate that, even after adjusting for variables such as age, gender, stroke type, lesion location, history of atrial fibrillation, myocardial infarction, ischemia, and the number of affected lesion areas, there remains an increased risk of developing intractable fever in febrile stroke patients. Additionally, higher NIHSS scores, brainstem injury, altered consciousness, and tracheostomy status were significantly associated with the occurrence of intractable fever. The relationship between the quantity of antibiotic usage and the risk of intractable fever remains unclear, though some studies have suggested a link between antibiotic use and hyperthermia^20^.
Similar to other international studies, we analyzed the risk factors for fever in stroke patients^21,22^. However, our study focused primarily on stroke patients in the rehabilitation phase and further classified fever, with particular emphasis on intractable fever. Additionally, we examined the progression of fever to intractable fever in stroke patients. It is well-established that the likelihood and severity of infection increase with stroke severity, and as infection severity increases, so does the severity of fever^23,24^. Although our logistic regression analysis showed a significant correlation between stroke severity and the incidence of intractable fever, the odds ratio (OR) was modest and approached 1. This could be attributed to different thresholds in other studies or the relatively small sample size in our study. Current research indicates that elevated temperatures and recurrent fever in intubated patients are often linked to aspiration and lung infections^25,26^. A higher NIHSS score, reflecting the severity of neurological deficits, is correlated with post-stroke infections or pneumonia^27,28^, suggesting that the increased risk of intractable fever in patients with higher NIHSS scores may result from both central mechanisms and infections. There is limited literature documenting the direct relationship between consciousness disorders and intractable fever. However, stroke patients with consciousness disorders often suffer from subarachnoid hemorrhage or intracerebral hemorrhage. Numerous studies indicate that these patient groups are particularly prone to intractable fever^6,8^, possibly due to elevated intracranial pressure or a shift in the third ventricle, which can compress the hypothalamus or temperature regulation centers^29,30^. Our study also found a significant correlation between brainstem injury and the incidence of intractable fever. Previous research has identified brainstem hemorrhage as a common cause of hyperthermia, particularly central fever^16,31^. Although all intractable fever patients in our study exhibited infection markers, we cannot rule out the involvement of central factors. Clinically, we observed that some patients with intractable fever did not show temperature improvement despite treatment with broad-spectrum antibiotics, antipyretics, or physical cooling measures. However, after gabapentin was introduced into the treatment regimen, body temperatures returned to normal. The decision to use gabapentin was based on the location of the lesions in the brainstem and hypothalamus, which play a crucial role in temperature regulation, with the hypothalamus being the central regulator of body temperature^14,16^. In patients with cerebral hemorrhage, abnormal electrical excitability and stimulation occur in the lesion area, particularly when the lesion is in the brainstem or basal ganglia-thalamus region. This may lead to increased sensitivity of the temperature regulation system to inflammatory responses, resulting in recurrent temperature fluctuations. This hypothesis aligns with an international study that proposed a bidirectional relationship between fever and hematoma enlargement^32^. Just as higher temperatures may contribute to hematoma growth, larger hematomas may cause a rise in temperature, potentially due to the damage they inflict on thermoregulatory brain structures or the extension of the hematoma into the ventricle, leading to hypothalamic damage^33^. Gabapentin, known for inhibiting abnormal neuronal discharges, was incorporated into the treatment regimen. The typical dosage starts with 0.3 g of gabapentin twice daily on the first day, increasing to 0.3 g three times daily from the second day onward. Unfortunately, in our analysis, the use of gabapentin did not show a significant correlation with fever duration, frequency, or discharge outcomes. This may be partly due to the small sample size, and the clinical results could be coincidental. Nevertheless, this is an intriguing observation that warrants further clinical investigation.
In our study, we did not specifically analyze the relationship between fever and mortality. However, there was one case of mortality in the acute fever group, involving a patient with cerebral hemorrhage. Previous meta-analyses have explored the connection between fever and cerebral hemorrhage, revealing an increased mortality rate among cerebral hemorrhage patients with fever, though no significant impact on adverse functional outcomes was observed^33^. While our findings support the association between impaired consciousness, tracheostomy status, brainstem injury, and NIHSS score with the likelihood of developing intractable fever, further research is needed to confirm these relationships. Notably, the overall proportion of fever patients in our study (21.9%) was relatively low compared to other international studies^4^. Nevertheless, our results consistently highlight a significant correlation between high fever and factors such as initial stroke severity, lesion location, tube insertion, and swallowing disorders (tracheostomy status)^21^.
Based on the above analysis, although all intractable fever patients in our study showed signs of infection, we believe that the etiology of intractable fever in stroke patients cannot be solely attributed to infectious causes. Central factors should also be considered, particularly in cases of cerebral hemorrhage involving the brainstem and basal ganglia-thalamus regions. These central influences, often overlooked in clinical practice, may play a critical role in the development of intractable fever.
This study has several limitations. First, the retrospective design may introduce unknown confounding factors and cannot fully eliminate information bias. The analysis could be influenced by incomplete data records or inconsistencies in variable definitions. Additionally, retrospective studies are prone to selection bias, being limited to existing records and capable of analyzing only available information. This constraint may exclude relevant variables, thereby affecting the accuracy of the results and the comprehensiveness of the conclusions. Furthermore, the inability to establish a clear temporal sequence is a notable limitation of retrospective studies, restricting causal inferences and allowing only the description of correlations between variables. Second, the relatively small sample size may limit the robustness and generalizability of the findings. On one hand, it could lead to an overestimation or underestimation of the effects of certain predictor variables and fail to adequately represent rare events. On the other hand, the results from a small sample may not be representative of a broader patient population. Finally, although a significant association was identified between antibiotic use and intractable fever, it remains unclear whether antibiotic use is a cause or a consequence. This ambiguity complicates the interpretation of the causal relationship between antibiotics and intractable fever.
In conclusion, this study demonstrates that altered consciousness, tracheostomy status, brainstem lesions, and higher NIHSS scores are significantly associated with an increased likelihood of developing intractable fever among stroke patients with fever. Independent predictors of post-stroke intractable fever may include higher NIHSS scores, impaired consciousness, tracheostomy status, and brainstem injuries. However, due to the small sample size and retrospective design, the generalizability of these findings may be limited. While these results provide valuable clinical insights, future large-scale, multicenter, prospective studies are needed to validate these conclusions and further explore the underlying mechanisms.
Notably, nearly 50% of patients with intractable fever, particularly those with intracerebral hemorrhage, received gabapentin treatment—a significantly higher proportion compared to patients with acute fever. Clinically, it is essential to differentiate between various types of fever, such as neurogenic, central, or infectious fever, as well as acute, subacute, or intractable fever. Although antibiotics, antipyretics (such as brompheniramine, acetaminophen, ibuprofen, loratadine, aspirin), and physical cooling remain the primary strategies for fever management, the intriguing finding regarding gabapentin’s use in treating intractable central fever warrants further investigation. Nevertheless, its clinical efficacy requires additional research and validation.