Management Protocols for Sepsis and Septic Shock after Craniotomy: Clinical Outcomes and Survival Analysis

Abstract

Objectives

Central nervous system infections are linked to a substantial rise in perioperative mortality, with postoperative neurosurgical infections being both prevalent and severe. Although the Surviving Sepsis Campaign (SSC) guidelines offer a framework for managing sepsis, their effect on clinical outcomes in neurosurgical patients has yet to be fully explored. The aim of this study was to compare mortality rates and clinical outcomes in neurosurgical patients with sepsis and septic shock treated according to the SSC protocol versus standard care.

Materials and Methods

This single-center retrospective analysis on prospectively acquired data included 159 patients with neurosurgical sepsis and septic shock, divided into two groups: 77 patients managed according to the SSC guidelines and 82 patients receiving standard treatment. Data on baseline characteristics, initial management within the first hour, and 30-day clinical outcomes were collected and analyzed.

Results

The mortality rate was significantly lower in the SSC protocol group. Additionally, intensive care unit (ICU) length of stay was significantly shorter, and the number of ventilator- and vasopressor-free days was significantly higher in the SSC protocol group (p < 0.001). Hydrocortisone use was associated with reduced vasopressor requirements and shorter hospital stays (p = 0.001 and p < 0.001, respectively). Thiamine use was linked to a shorter hospital stay (p = 0.023), while continuous renal replacement therapy significantly reduced vasopressor use (p = 0.013).

Conclusion

Implementing the SSC protocol within the first hour of treatment significantly reduced mortality, shortened ICU length of stay, and increased the number of ventilator- and vasopressor-free days.

Keywords

central nervous system infections - mortality rate - Surviving Sepsis Campaign - sepsis - protocol - perioperative mortality

Introduction

Neurosurgical infections are a major cause of high morbidity and mortality, often resulting in prolonged neurocritical care admissions and mortality rates ranging from 30 to 50%. These infections are more common than other severe surgical complications, such as acute myocardial infarction, perioperative stroke, and massive pulmonary embolism.[1] [2] [3] Neurosurgical infections can progress to sepsis and septic shock, further exacerbating mortality rates.[4] [5] Despite efforts at source control, these infections remain a significant and persistent challenge, underscoring the need for effective monitoring and management strategies. The Surviving Sepsis Campaign (SSC) protocol, endorsed by multiple medical organizations, offers a structured approach to managing sepsis with the goal of improving patient outcomes. Its implementation is especially critical in developing countries, where the prevalence of neurosurgical infections and septic shock is rising.[6] [7] [8] [9] [10] Adherence to sepsis care bundles is crucial and should be incorporated into public health policies. Increased mortality is associated with factors such as advanced age (≥ 60 years), penetrating or perforating head injuries, and comorbidities like diabetes mellitus, as well as the chronic use of steroids or immunosuppressive agents.[11] [12] [13] [14] [15] [16] Early detection and intervention, though challenging, are essential for improving patient outcomes. Sepsis care bundles, as highlighted in critical care guidelines, play a key role in addressing these challenges. Timely administration of appropriate antibiotics within 1 hour of clinical suspicion is vital, as delays in this time-sensitive intervention can significantly increase mortality rates.[17] [18] Research indicates that neurosurgical patients who are not promptly screened for sepsis have a higher incidence of the condition, with 6.5% of patients developing sepsis if screening is delayed beyond 48 hours postprocedure.[19] [20] [21] This study aims to compare mortality rates before and after the implementation of a standardized care bundle for managing neurosurgical sepsis and septic shock.

Materials and Methods

We conducted a single-center retrospective analysis on prospectively acquired data involving 159 patients, divided into two groups: 77 patients managed according to the SSC protocol between April 1, 2021, and January 31, 2024, and 82 patients who received standard care between January 1, 2018, and June 30, 2021, prior to the implementation of the sepsis and septic shock bundle. Data collected included baseline characteristics (age, gender, underlying conditions), time to positive sepsis screening, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, admission diagnoses, infection sources, reasons for craniotomy, and causes of sepsis and septic shock. The preprotocol cohort consisted of all neurosurgical infection patients admitted to the neurocritical care unit ([Fig. 1]).

Fig. 1 Flowchart of patient enrollment and analysis in this study.

The SSC protocol included a 1-hour sepsis care bundle, which comprised blood lactate measurement, blood cultures before initiating empirical antibiotics, appropriate empirical antibiotics, and fluid resuscitation (30 mL/kg). For patients with clinically suspicious, refractory septic shock, intravenous hydrocortisone and glycemic control (80–180 mg/dL) were administered. All patients underwent SOFA score assessments for sepsis screening in line with SSC guidelines, and time to positive screening was recorded.

Measured outcomes included 28-day survival, intensive care unit (ICU) length of stay (LOS), ventilator-free days, and vasopressor-free days. Descriptive statistics, including frequencies and percentages for categorical variables and means with standard deviations (SD) for continuous variables, were used. Independent t-tests and chi-squared tests were applied to compare variables between the two study periods. Statistical significance was defined as p < 0.05.

The study received approval from the Thai Clinical Trials Registry Committee (TCTR20240316003, March 16, 2024) and the Ethics Committee of the Institutional Review Board, Medical Department (IRBRTA 1861/2564). It was conducted in accordance with the Declaration of Helsinki and the Foundation for Human Research Promotion in Thailand. Due to the use of anonymized medical records and aggregate data, written consent was not required, as per the Council for International Organizations of Medical Sciences (CIOMS) Guidelines 2012 and Good Clinical Practice of the International Conference on Harmonization.

Results

The study included 159 patients with neurosurgical sepsis or septic shock, divided into two groups: the protocol group (77 patients) and the usual care group (82 patients). In the protocol group, the mean (SD) age was 69 (12) years, the mean (SD) APACHE II score was 12.6 (1.09), and the mean (SD) SOFA score was 6.29 (0.03). Additionally, 59% (n = 46) were male, and 56% (n = 43) had craniotomy due to emergency neurotrauma. In the usual care group, the mean (SD) age was 61 (15) years, the mean (SD) APACHE II score was 12.9 (1.85), and the mean (SD) SOFA score was 6.2 (0.12). Fifty-one percent (n = 42) were male, and 58.5% (n = 48) had craniotomy due to emergency neurotrauma. Baseline characteristics were comparable between the two groups ([Table 1]), with no statistically significant differences in age, gender, body mass index, underlying conditions (e.g., hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, coronary heart disease, and previous cerebrovascular accident), APACHE II score, SOFA score, serum lactate levels, organ system failures, or specific causes of craniotomy. Hypertension was the most common underlying condition, and emergency neurotrauma was the leading cause of craniotomy. Surgical site infections were the predominant causes of neurosurgical sepsis and septic shock.

Table 1 Baseline characteristics between the two groups of patients

	Protocol (n = 77)	Usual care (n = 82)	p-Value
Sex
Male	46 (59%)	42 (51%)	0.23
Age (y)	69 ± 12	61 ± 15	0.16
Body mass index (BMI, kg/m2)	21.7 ± 3.4	21.0 ± 2.1	0.58
Hypertension	48 (62%)	55 (67%)	0.67
Dyslipidemia	22 (28%)	19 (23%)	0.43
Diabetes mellitus	30 (38%)	29 (35%)	0.39
Chronic kidney disease	8 (10.4%)	9 (11%)	1
Coronary artery disease	15 (19.4%)	17 (20.7%)	0.32
Old cerebrovascular accident	7 (9%)	8 (9.7%)	0.900
SOFA score	6.29 ± 0.03	6.2 ± 0.12	0.4
APACHE II score	12.6 ± 1.09	12.9 ± 1.85	0.447
Serum lactate at admission	5.2 ± 0.92	5.50 ± 0.61	0.54
Organ system failure involved
Brain	54 (70%)	62 (75%)	0.500
Brain and extracranial	13 (16.9%)	10 (12.2%)
Causes for craniotomy
Emergency neurotrauma	43 (56%)	48 (58.5%)	0.82
Emergency stroke	16 (20.8%)	14 (17.1%)
Brain tumor	4 (5.2%)	5 (6.1%)
Others	4 (5.2%)	5 (6.1%)
Causes of neurosurgical sepsis and septic shock
Surgical site infection	20 (26%)	24 (29.3%)	0.684
Epidural empyema	18 (23.4%)	21 (25.6%)
Subdural empyema	16 (20.8%)	15 (18.3%)
Intraparenchymal brain abscess	7 (9%)	7 (8.5%)
Others	6 (7.8%)	5 (6.1%)
Frequency of debridement	3 (2,4)	4 (3,5)	0.73
Number of patients who underwent a second surgery	23 (29%)	28 (34%)	0.64
Risk factors for requiring debridement surgery
Diabetes mellitus	25 (32%)	24 (29%)	0.23
On immunosuppression	11 (14%)	13 (16%)	0.47
Timing of the infection after surgery (d)	2.58 ± 1.42	3.17 ± 1.37	0.81
Timing which sepsis progresses to septic shock (d)	1.67 ± 0.53	1.12 ± 0.25	0.62
Types of pathogens identified by bacterial cultures
Staphylococcus aureus	28 (36.4%)	35 (42.7%)	0.27
Coagulase-negative  Staphylococcus	12 (15.6%)	19 (23.2%)	0.14
Pseudomonas aeruginosa	10 (13%)	19 (23.2%)	0.18
Streptococcus pneumoniae	18 (23.4%)	21 (25.6%)	0.85
Enterococcus species	26 (33.8%)	29 (35.4%)	0.82
Propionibacterium acnes	17 (22.1%)	23 (28%)	0.63
Methicillin-resistant  Staphylococcus aureus (MRSA)	8 (10.4%)	10 (12.2%)	0.81
Vancomycin-resistant enterococci (VRE)	5 (6.5%)	7 (8.5%)	0.83
Candida species	4 (5.2%)	6 (7.3%)	0.72
The name(s) of vasopressors used
Norepinephrine	55 (71.4%)	64 (78%)	0.81
Epinephrine	24 (31.2%)	26 (31.7%)	0.92
Vasopressin	12 (15.6%)	14 (17.1%)	0.73
Phenylephrine	4 (5.2%)	6 (7.3%)	0.76
Dosage on hydrocortisone
Dosage on hydrocortisone (milligram per day)	200	200	1
Duration of hydrocortisone usage (d)	3.67 ± 2.31	4.28 ± 2.16	0.65

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; BMI, body mass index; SOFA, Sequential Organ Failure Assessment.

Note: Value presented as mean ± standard deviation (SD) or n (%). p-Value corresponds to independent t-test and chi-square test.

Adherence to sepsis care bundles was higher in the SSC protocol group ([Table 2]). In the usual care group, the mean time to initial fluid resuscitation, vasopressor administration, blood culture and sensitivity, empirical antibiotics, and source control was 1.4 ± 0.73, 2.41 ± 0.58, 3.3 ± 0.5, 3.54 ± 0.6, and 7.3 ± 0.17 hours, respectively. [Table 2] also shows that adherence to the sepsis care bundle led to reduced hospital LOS, treatment costs, and ICU LOS in the protocol group, compared with the usual care group. The protocol group also had more ventilator-free and vasopressor-free days. The overall cost per patient was lower in the SSC protocol group, with a mean cost of 39,741.50 ± 7,954.50 Thai Baht, compared with 57,512.50 ± 1,223.50 Thai Baht in the usual care group.

Table 2 Difference of secondary outcomes between two patient groups

	Protocol (n = 77)	Usual care (n = 82)	p-Value
Initial fluid resuscitation (h)	1 ± 0	1.4 ± 0.73	< 0.001*
Vasopressor (h)	1 ± 0	2.41 ± 0.58	< 0.001*
Culture (h)	1 ± 0	3.3 ± 0.5	< 0.001*
Initiated empirical antibiotics (h)	1 ± 0	3.54 ± 0.6	< 0.001*
Neurosurgical source control (h)	3 ± 1.7	7.3 ± 0.17	< 0.001*
Hospital length of stay (d)	9.27 ± 1.84	13.5 ± 2.6	< 0.001*
Cost of treatment (Thai Bath)	39,741.50 ± 7,954.50	57,512.50 ± 1,223.50	< 0.001*
ICU length of stay (d)	3.47 ± 1.31	11.08 ± 3.45	< 0.001*
Ventilator-free day (d)	4.72 ± 1.61	1.55 ± 0.67	< 0.001*
Vasopressor-free day (d)	5.48 ± 1.39	3 ± 0.7	< 0.001*

Abbreviation: ICU, intensive care unit.

Note: Value presented as mean ± standard deviation (SD). or n (%). p-Value corresponds to Independent t-test and chi-square test.

The asterisk “*” indicates a statistically significant difference compared to baseline values (p < 0.05).

Primary and Secondary Outcomes

Period effect analysis ([Table 2]) showed that hospital and ICU LOSs were significantly shorter in the protocol group compared with the usual care group (13.5 ± 2.6 vs. 9.27 ± 1.84 days and 11.08 ± 3.45 vs. 3.47 ± 1.31 days, p < 0.001). The protocol group also had significantly more ventilator-free days (4.72 ± 1.61 vs. 1.55 ± 0.67 days) and vasopressor-free days (5.48 ± 1.39 vs. 3.0 ± 0.7 days, p < 0.001). After applying the neurosurgical sepsis and septic shock care bundle, 28-day survival rate significantly increased in the protocol group (p < 0.001, 95% confidence interval 19.45–20.85) ([Table 3], [Fig. 2]).

Table 3 Primary outcome in medians for survival time between the two groups of neurosurgical sepsis and septic shock

	Median time	95% confidence interval
	(d)	Lower bound	Upper bound
No protocol	15	14.57	15.63
Protocol	20	19.45	20.85
Overall	18	17.25	18.75

Note: Value presented as median, p-value analyzed using the Kaplan–Meier survival estimates.

Fig. 2 Kaplan–Meier survival estimates in medians for 28-day survival rate between the two groups. Value presented as median, p-value analyzed using the Kaplan–Meier survival estimates.

The SSC protocol, which defined early interventions such as fluid resuscitation, vasopressor use, blood cultures, empirical antibiotics, and source control, was associated with improved outcomes. The adjunct therapies used within the protocol, including intravenous hydrocortisone, thiamine, and continuous renal replacement therapy (CRRT), demonstrated significant benefits. Hydrocortisone reduced vasopressor requirements and hospital LOS, thiamine shortened hospital stays (p = 0.023), and CRRT reduced vasopressor use (p = 0.013) ([Table 4]). These findings suggest that implementing the SSC protocol improves clinical outcomes and reduces costs compared with usual care.

Table 4 Multilevel mixed-effects linear regression analysis of secondary outcomes in protocol groups (n = 77) compared with usual care

Intervention in protocol group	N (%)	Difference in vasopressor-free day		Difference in hospital length of stay		Difference in ICU length of stay
		Mean (95% CI)	p-Value	Mean (95% CI)	p-Value	Mean (95% CI)	p-Value
Hydrocortisone	43 (55.8)	−0.51 (−0.82, −0.2)	0.001*	−1.63 (−2.5, −0.75)	< 0.001*	−0.72 (−1.61, 0.17)	0.112
Thiamine	22 (28.6)	0.26 (−0.06, 0.57)	0.111	1.04 (0.14, 1.93)	0.023*	0.73 (−0.18, 1.63)	0.114
Vitamin C	10 (13)	−0.13 (−0.44, 0.18)	0.418	−0.85 (−1.73, 0.04)	0.061	−0.78 (−1.67, 0.12)	0.088
CRRT	5 (6.5)	−0.46 (N0.82, −0.1)	0.013*	0.08 (−0.95, 1.12)	0.874	0.14 (−0.9, 1.18)	0.794

Abbreviations: CI, confidence interval; CRRT, continuous renal replacement therapy; ICU, intensive care unit.

Note: Value presented as median, p-value analyzed using multilevel mixed-effects linear regression analysis.

The asterisk “*” indicates a statistically significant difference compared to baseline values (p < 0.05).

Discussion

This study evaluated the benefits of the SSC care bundle in managing neurosurgical infections within the neurosurgical ICU. Our primary finding was that implementing the SSC care bundle significantly improved patient survival compared with usual care, with a reduction in the duration of treatment for neurosurgical infections. This supports previous studies that have shown similar benefits from the SSC bundle.[22] [23] The potential differences in the interval between the index surgery and the onset of sepsis or septic shock between the two groups, a few key aspects include study design and groups, we define the two groups that are comparing based on different treatments, risk factors, surgical types, or patient demographics. To clarify these factors helps in understanding what might influence the timing of sepsis or septic shock onset. Time interval analysis, the interval between the index surgery and the occurrence of sepsis or septic shock can be measured in days or hours, depending on the severity and the nature of the surgical procedure. A few considerations would include: early-onset sepsis, some groups may develop sepsis or septic shock early (within hours to a day or two postsurgery) due to factors like intraoperative contamination, high-risk surgical procedures, or compromised immune systems. Late-onset sepsis: other groups may experience sepsis or septic shock several days or even weeks after surgery, potentially due to factors such as delayed wound infections, hospital-acquired infections, or other postoperative complications. Potential explanations for differences: to observe differences in the time to sepsis or septic shock, several factors could be at play including surgical factors—different types of surgery may carry different risks for infection based on the invasiveness, contamination risk, or type of surgical site. Patient factors: comorbid conditions like diabetes, immunosuppression, or obesity could affect the immune response, influencing how quickly sepsis or septic shock develops. Postoperative care: variations in the management of postoperative care, including antibiotic prophylaxis, wound care, and monitoring, could result in differences in the timing of sepsis. Infection source: whether the infection originated from a surgical site, catheter-related infection, or another source could also influence the timing of onset. Clinical implications: early recognition—if one group shows an earlier onset of sepsis or septic shock, early recognition and intervention could be crucial in improving outcomes for that group. Preventative measures: identifying any factors associated with a delayed onset of sepsis (e.g., late detection of infections) could guide preventative measures, like enhanced monitoring or targeted interventions for high-risk patients. The interval between index surgery and the onset of sepsis or septic shock can provide important insights into the risks associated with surgery and postoperative care. If there are significant differences between the two groups, understanding the underlying reasons for those differences (whether surgical, patient-related, or due to care protocols) can help guide improvements in clinical practice to prevent or manage infections more effectively. Statistical analysis will be essential to confirm whether the observed differences are statistically significant and to identify any factors that may contribute to the variation in timing. Kaplan–Meier survival estimates for early-stage neurosurgical sepsis indicated that median survival times were comparable between the two groups, suggesting that the SSC protocol did not significantly impact mortality rates during the early stages of sepsis. However, early fluid resuscitation was crucial for restoring adequate tissue perfusion, a key factor in improving survival in neurosurgical infections and sepsis.

Previous studies have shown that supraphysiologic oxygen delivery, such as hyperoxia, does not improve outcomes and may even increase mortality rates.[24] [25] Effective management of neurosurgical sepsis requires source control,[26] which involves draining intra- and extracranial fluid collections, removing necrotic tissue, and addressing foreign bodies. These interventions are particularly important in both the early and late stages of infection. While surgical intervention is often necessary, maintaining stable hemodynamics is critical. In emergencies like subdural empyema and brain abscesses near the ventricle, prompt surgical intervention is essential. Cerebrospinal infections are a major cause of poor prognosis in postneurosurgery patients, as delays in neurological recovery often lead to prolonged hospital stays and can result in disability or death.[27] In the literature, postneurosurgery cerebrospinal infections are commonly attributed to pathogens such as Staphylococcus aureus, Propionibacterium acnes, and coagulase-negative Staphylococcus.[28] [29]

Intravenous hydrocortisone significantly reduced the need for vasopressors and shortened hospital LOS. This effect is attributed to hydrocortisone's role in managing critical illness-related corticosteroid insufficiency, which is common in severe sepsis and septic shock. By improving corticosteroid levels, hydrocortisone reduces vasopressor requirements and shortens hospital stays. Additionally, intravenous thiamine, administered at a dose of 200 mg twice daily, significantly reduced hospital LOS. Thiamine aids in lactate clearance and supports the resolution of sepsis and septic shock. CRRT also played a role in reducing vasopressor use by addressing metabolic acidosis, a major contributor to refractory septic shock. In the protocol group, CRRT was administered to five patients who met specific criteria for acute kidney injury (AKI) and refractory shock. Outcomes were compared with those who received standard care or intermittent dialysis. The results showed a significant improvement in renal function recovery and 28-day survival in patients who received CRRT. However, the small sample size limits the statistical power of these findings, warranting caution in generalizing the results. The potential benefits of CRRT in patients with refractory septic shock are focusing on its impact on vasopressor use, renal function, and survival outcomes. Vasopressor reduction: CRRT is used to address metabolic acidosis, which is a significant issue in patients with septic shock. By correcting the acidosis, CRRT can improve the body's overall hemodynamic status, potentially reducing the need for vasopressors (medications used to constrict blood vessels and raise blood pressure). This could be a key clinical benefit in treating patients with refractory septic shock, who often require high doses of vasopressors. In this study, CRRT was specifically administered to five patients in the protocol group who met certain criteria for AKI and refractory shock. This means that only those with more severe conditions were included in the CRRT treatment group, making the results more relevant for critically ill patients. Comparative analysis: the outcomes in the CRRT group were compared with those who received either standard care (which might not include dialysis) or intermittent dialysis. This comparison helps assess the relative effectiveness of CRRT versus other treatments in terms of clinical outcomes like renal function recovery and survival. The results showed that patients who received CRRT had a significant improvement in both renal function recovery and 28-day survival rates compared with those who received standard care or intermittent dialysis. This suggests that CRRT may be more effective than other methods in these critically ill patients. Despite these promising results, it is important to note that the study involved a small number of patients (only five in the CRRT group). A small sample size can limit the statistical power of the findings, meaning that it may be difficult to conclude with certainty that CRRT is truly effective, or whether the observed benefits could have occurred by chance. Larger studies are needed to validate these findings and provide more robust evidence. While CRRT appears to have positive effects in terms of improving renal function and survival in these critically ill patients, the small sample size means the results should be interpreted cautiously, and more research is necessary to confirm these findings.

Conclusion

The care bundle for neurosurgical sepsis and septic shock was effective in reducing mortality and decreasing both ventilator and vasopressor use. Additionally, specific adjunctive therapies contributed to improved outcomes. Intravenous hydrocortisone significantly reduced the need for vasopressors and shortened the hospital LOS. Intravenous thiamine led to a notable reduction in hospital LOS. Furthermore, CRRT effectively decreased the requirement for vasopressors.

Conflict of Interest

None declared.

Acknowledgments

The authors would like to express their gratitude to the staff of the neurosurgical and medical intensive care units for their support and for providing the resources necessary to conduct this study. The authors also extend their thanks to their colleagues for their encouragement throughout the research process.

Note

This original article has not been previously published, nor has it been presented to another journal for consideration.

Authors' Contributions

P.B.: Project administration and coordination, wrote the original draft of the manuscript, participated in the review process, and data curation. P.B., S.S., and P.F.: Data curation, wrote the original draft of the manuscript, participated in the review process, and data curation. P.B. and K.U.: Data curation and formal analysis of the research. P.B.: Participated in the review process. P.F. and K.U.: Project administration, coordination, and participated in the review process. All the authors have read and approved the final manuscript.

Ethical Approval

The study received approval from the Thai Clinical Trials Registry Committee (TCTR20240316003, March 16, 2024) and the Ethics Committee of the Institutional Review Board, Medical Department (IRBRTA 1861/2564). It was conducted in accordance with the Declaration of Helsinki and the Foundation for Human Research Promotion in Thailand. Due to the use of anonymized medical records and aggregate data, written consent was not required, as per the CIOMS Guidelines 2012 and Good Clinical Practice of the International Conference on Harmonization.

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Publication History

Article published online:
01 May 2025