To identify the virulence factors responsible for toxic shock syndrome in causative strains submitted by field laboratories throughout the Czech Republic. To detect the production of TSST-1 and staphylococcal enterotoxins, the micro-slide gel diffusion test was initially used and later followed by reverse passive latex agglutination. Currently, the polymerase chain reaction is the preferred tool for the detection of toxin genes as well as genes for other toxins of S. aureus strains: exfoliatins A, B, and D, Panton-Valentine leukocidin, and the mecA and mecC genes responsible for resistance to methicillin/cefoxitin and other beta-lactam antibiotics. A simple form was used to obtain information which confirmed the diagnosis of toxic shock syndrome (A48.3). Over a 42-year period from 1983 to 2025, the toxinogenicity of the causative agent was confirmed in 174 cases of non-menstrual toxic shock syndrome. The TSST-1 toxin (either alone or in combination with enterotoxin) was produced by 60% of the strains studied. Only 40% of the strains were positive for a specific type of enterotoxin. Most strains were methicillin-sensitive, and seven strains (4.0%) were positive for the mecA gene. Genes for Panton-Valentine leukocidin were detected in a single strain. The most common type of staphylococcal infection leading to toxic shock syndrome was pyoderma. Other cases were associated with hospital acquired and post-traumatic wound infections. Of the entire cohort, the disease resulted in death of 38 patients, representing a high case fatality rate of 21.8%. Toxic shock syndrome is a serious staphylococcal disease affecting multiple organs, which can be fatal in severe cases. Given the wide range of symptoms, establishing a clinical diagnosis can sometimes be difficult. It is crucial to recognize the staphylococcal toxin aetiology and initiate early appropriate treatment.
Impaired myocardial contractility is a major contributor to cardiovascular failure during septic shock; however, the underlying mechanisms remain incompletely understood. This study investigated the roles of endothelin and nitric oxide (NO) in cardiac dysfunction using the endothelin receptor antagonist tezosentan and nitric oxide synthase (NOS) inhibitors in an experimental model of endotoxic shock. Endotoxic shock was induced in rats via intraperitoneal injection of lipopolysaccharide (LPS, 1 mg/kg). Hearts were isolated four hours after LPS or saline administration and perfused using a Langendorff apparatus. Myocardial contractility, coronary perfusion pressure, and heart rate were recorded. The effects of tezosentan and NOS inhibitors (Nω-nitro-L-arginine methyl ester [L-NAME], aminoguanidine, and S-methylisothiourea sulfate [AETU]) were assessed by adding these agents to the perfusate. In parallel, atrial and papillary muscle contractility and spontaneous beating rates were evaluated using isolated tissue preparations in in vitro organ bath studies. Baseline myocardial contractility was significantly reduced in LPS-treated perfused hearts compared with controls (3.03 +- 0.25 vs. 4.94 +- 0.39 g, P < 0.05), whereas no significant differences were observed in isolated atrial or papillary muscle preparations. Coronary perfusion pressure was significantly increased in the LPS group (101 +- 6 vs. 79 +- 6 mmHg, P < 0.05). Tezosentan significantly attenuated the LPS-induced reduction in myocardial contractility but did not affect the increase in perfusion pressure. None of the NOS inhibitors altered myocardial contractility or perfusion pressure in LPS-treated hearts. Myocardial contractility impairment in experimental endotoxic shock occurs only in the presence of an intact coronary vasculature and is prevented by endothelin receptor blockade. These findings suggest that vascular endothelium-derived endothelin plays a key role in myocardial depression during endotoxic shock, whereas nitric oxide appears to have a limited contribution in this model.
Gunshot wound survivors are at especially high risk for post-traumatic stress disorder. Early identification of patients at increased risk remains a major clinical challenge. Physiologic markers of injury severity, such as shock index and hypotension, are readily available during initial resuscitation and may help identify patients who could benefit from targeted mental health interventions. This exploratory study evaluates the association between markers of physiologic stress and post-traumatic stress disorder screening outcomes following gunshot wound injury. We retrospectively identified nonfatal gunshot wound patients screened for post-traumatic stress disorder at a single urban level I trauma center. We conducted multivariate Bayesian logistic regression with post-traumatic stress disorder as the binary outcome of interest. Predictor variables included shock index and hypotension, units of blood product transfusion, and demographic information. Our final cohort included 134 patients, of whom 39 (29%) screened positive for post-traumatic stress disorder. Increasing shock index (odds ratio, 1.2; 95% credible interval, 1.02-1.42; posterior probability of odds ratio >1, 99.2%) and the presence of hypotension (odds ratio, 4.0; 95% credible interval, 1.03-17.6; posterior probability of OR >1, 97.7%) were associated with a positive post-traumatic stress disorder diagnosis. Increasing units of blood product transfusion (odds ratio, 0.9; 95% credible interval, 0.77-0.97; posterior probability of OR <1, 99.7%) was associated with a negative post-traumatic stress disorder diagnosis. Increasing shock index and the presence of hypotension predict positive post-traumatic stress disorder screening in gunshot wound patients. These predictors potentially allow for early identification of high-risk patients, informing mental health resource allocation. The present associative findings should be interpreted cautiously and warrant validation in prospective studies.
Hemorrhagic shock remains a leading cause of preventable trauma mortality, yet early identification of physiological decompensation remains challenging because conventional vital signs often remain preserved during compensatory phases. Heart rate variability (HRV) and blood pressure variability (BPV) derived from continuous arterial waveforms reflect dynamic autonomic and hemodynamic regulation and may provide earlier indicators of cardiovascular instability. We investigated whether variability-based physiological markers could stratify hemorrhagic shock severity and whether vagal integrity influences these autonomic signatures. Male Sprague-Dawley rats underwent graded hemorrhagic shock using a delayed fluid resuscitation paradigm and were classified as moderate or severe shock. Animals were assigned to non-vagotomized and subdiaphragmatic vagotomized groups. Heart rate variability and blood pressure variability metrics, respiratory sinus arrhythmia, and indices of vagal and baroreflex regulation were derived from arterial pressure recordings obtained during steady state and the compensatory phase preceding cardiovascular decompensation. Classification performance was evaluated using discriminant and receiver operating characteristic analyses.Progressive hemorrhage was associated with reduced blood pressure variability and increased heart rate variability during compensation. In non-vagotomized animals, high-frequency diastolic blood pressure variability differentiated shock severity. In vagotomized animals, classification depended on a broader combination of autonomic and hemodynamic features. Vagotomy also altered autonomic variability responses and disrupted relationships between baseline heart rate variability and post-resuscitation vascular variability. These findings support further investigation of variability-based physiological monitoring for early detection of hemorrhagic decompensation.
Cardiogenic Shock remains one of the deadliest clinical conditions in the world. Despite technological advances, mortality rates remain unacceptably high. While recently published data in acute myocardial infarction-cardiogenic shock (AMI-CS) suggest improved outcomes with protocolized use of early temporary mechanical circulatory support (tMCS) real-world observational and registry data in both AMI-CS and heart failure-related CS suggest opportunities to improve survival through use of shock teams, early escalation to tMCS and use of hemodynamic and hemometabolic monitoring. Here we review current literature on escalation of care in cardiogenic shock and provide recommendations for optimal escalation through organized systems of care.
Rheumatic mitral stenosis (MS) is the most common form of valvular heart disease worldwide, which could lead to cardiac cirrhosis when associated with severe tricuspid regurgitation. This report presents how we manage patients with cardiogenic obstructive shock due to severe MS complicated by edema but with intravascular volume depletion due to hypoalbuminemia secondary to cardiac cirrhosis. A 66-year-old woman who was previously diagnosed with rheumatic MS was evaluated for refractory dyspnea, shock, and peripheral edema. The examination revealed cardiac cirrhosis and hypoalbuminemia as complications of severe MS. This case highlights the presence of cardiac cirrhosis and hypoalbuminemia, which further exacerbates hemodynamic compromise and complicates the management of congestion in a patient with uncorrected rheumatic MS. In rheumatic MS complicated by severe tricuspid regurgitation, cardiac cirrhosis, and hypoalbuminemia, congestion and shock create a delicate therapeutic balance. Effective management requires careful titration of diuretics and inotropes, close monitoring of end-organ function, and proactive planning for surgical or percutaneous correction of the underlying valvular pathology.
Hemorrhagic shock (HS) remains a leading cause of trauma-related mortality, primarily due to severe hypovolemia and systemic hypoperfusion. These pathophysiological changes may profoundly affect the pharmacokinetics of fentanyl, an opioid widely used for analgesia in trauma care. Previous studies, predominantly based on fixed-pressure shock models, may not adequately reflect clinically relevant hemodynamic conditions. Therefore, we employed a fixed-volume HS model as an alternative approach to reflect hypovolemia-associated perfusion deficits influencing fentanyl disposition. This study aimed to evaluate the pharmacokinetics of fentanyl and its primary metabolite, norfentanyl, in an experimental model of fixed-volume HS. Male Wistar rats were randomly divided into two groups: a control group (C; n = 6) and a fixed-volume hemorrhagic shock group (HS; n = 6). In the HS group, hemorrhage was induced by withdrawal of 30% of the estimated blood volume (EBV) following vascular cannulation. Fentanyl (10 µg/kg) was administered intravenously, and serial blood samples were collected over 60 min. The concentrations of plasma fentanyl and norfentanyl were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Pharmacokinetic parameters were calculated using Phoenix WinNonlin software. Non-compartmental analysis demonstrated significantly increased systemic exposure to fentanyl in the HS group, reflected by higher area under the concentration-time curve (AUC0-∞ and AUC0-t) values, accompanied by a marked reduction in systemic clearance (CL). Mean residence time (MRT) and terminal elimination half-life (t½λz) were significantly prolonged. Compartmental analysis confirmed a more than two-fold increase in fentanyl exposure, driven primarily by reduced clearance and prolonged elimination. In contrast, peak plasma concentrations (Cmax) showed only a borderline increase, and no statistically significant differences were detected in distribution-related parameters. These findings suggest that the major detectable pharmacokinetic changes associated with HS were primarily related to impaired fentanyl elimination. The metabolic conversion ratio (MCR), defined as the ratio of norfentanyl AUC0-t to fentanyl AUC0-t, was lower in the HS group (0.117) compared with controls (0.197). HS significantly alters fentanyl pharmacokinetics in rats by reducing clearance and increasing systemic exposure. The lower norfentanyl-to-fentanyl AUC0-t ratio suggests that HS may also affect metabolite formation or disposition.
The present study was conducted to assess the effects of lycopene (LP) supplementation on antioxidant status, lipid peroxidation, heat-shock proteins, and lipid profile in heat-stressed goat kids. Twenty-one healthy growing Barbari goat kids (4-8 months old) with an average body weight of 9.87 ± 1.09 kg were randomly allocated into three experimental groups, comprising seven animals per group. The activities of superoxide dismutase, catalase, glutathione peroxidase, and total antioxidant capacity increased linearly (P < 0.023) with increasing dietary LP levels. Conversely, concentrations of myeloperoxidase, reactive oxygen species modulator-1, and thiobarbituric acid reactive substances declined linearly (P < 0.001) as LP inclusion in the diet increased. Dietary LP supplementation significantly decreased (P < 0.05) heat shock protein 70, heat shock protein 90, and cortisol concentrations, with the lowest values observed at 100 mg LP/kg DM. Total cholesterol levels were not affected by LP supplementation. However, dietary LP reduced (P < 0.05) low-density lipoprotein cholesterol and triglyceride concentrations, with the most pronounced effect at 100 mg LP/kg DM. High-density lipoprotein cholesterol concentrations were significantly increased (P < 0.05) by LP supplementation, showing the greatest response at 100 mg LP/kg DM. Overall, supplementation of LP at 50 or 100 mg/kg DM improved antioxidant status and modulated the lipid profile by reducing oxidative stress markers, with the highest beneficial response observed at 100 mg LP/kg DM.
Valvular heart disease is an uncommon but high-risk cause of cardiogenic shock requiring rapid, multidisciplinary management aimed at bridging patients to definitive surgical or transcatheter valve intervention. Early comprehensive Doppler echocardiography is essential, as clinical signs may be subtle. Distinguishing decompensated chronic valvular disease from acute unstable lesions guides urgency and treatment strategy. Medical stabilization and mechanical circulatory support vary markedly between stenotic and regurgitant lesions, and standard shock therapies may be harmful in specific contexts. Transcatheter approaches are preferred when feasible, though their expanding use introduces added complexity in cardiac intensive care.
Transfusion-related acute lung injury (TRALI) and anaphylactic shock are rare but life-threatening transfusion-related complications. Differentiating between these conditions during general anesthesia is difficult because subjective symptoms cannot be assessed and intraoperative diagnostic evaluation is limited. A 40-year-old woman undergoing surgery for ovarian cancer under general anesthesia developed acute hypoxemia during transfusion. After completion of the transfusion, she developed sudden hypotension, tachycardia, and generalized erythema, which responded promptly to adrenaline administration. Respiratory failure persisted, and frothy sputum appeared in the endotracheal tube. Postoperative chest radiography showed bilateral pulmonary infiltrates, while echocardiography revealed preserved cardiac function. Anti-human leukocyte antigen (HLA) class I and II antibodies were detected in the transfused fresh frozen plasma, and serum tryptase levels were elevated postoperatively. This case demonstrated overlapping clinical features of TRALI and anaphylactic shock during general anesthesia. Although donor anti-HLA antibodies supported the possibility of TRALI, severe anaphylaxis alone could not be completely excluded as an explanation for the pulmonary edema.
Postcardiotomy shock (PCS) is a complex, high-mortality complication following cardiac surgery, driven by cardiopulmonary bypass-related inflammation, vasoplegia, myocardial dysfunction, and pulmonary hypertension. Conventional shock definitions are poorly applicable to this population; a vasoactive inotropic score greater than 20 to 25 with evidence of hypoperfusion is proposed as a practical operational definition. Overlapping PCS phenotypes (cardiogenic, vasoplegic, obstructive, arrhythmic, mixed) necessitate multimodal hemodynamic profiling incorporating pulmonary artery catheter data, echocardiography, and dynamic perfusion indices. Management focuses on judicious fluid and blood product administration, phenotype-directed inotropes and vasopressors, lung-protective ventilation, and early initiation of temporary mechanical circulatory support.
Preeclampsia (PE) is a serious human pregnancy complication and remains the most complex hypertensive disorder due to its multifactorial nature and multisystemic effects. Despite the incomplete understanding of the PE pathophysiology, it is well-accepted that placental changes in PE are associated with oxidative stress, increasing the excessive production of cytokines and other inflammatory mediators. Thus, agents such as silibinin, a non-toxic natural polyphenolic flavonoid with antioxidant, anti-inflammatory, and hepatoprotective properties could modulate this profile for better disease resolution. This study aimed to investigate the effect of silibinin treatment on Nω-nitro-L-arginine methyl ester (L-NAME)-induced PE in rats, exploring its potential as a preventive anti-inflammatory agent. Pregnant Wistar rats were treated or not during gestation (days 10-19) with L-NAME (70-80 mg/kg/day) in drinking water and with silibinin (100 mg/kg/day, orally) starting on days 0, 7 or 14 of pregnancy. Systolic blood pressure was recorded on gestation days 0 and 20. The rats were euthanized on day 20. Then, we evaluated proteinuria, maternal weight gain, and litter weight. Tumor necrosis factor- alpha (TNF-α), interleukin-1 (IL-1β), IL-6, IL-10, interferon-gamma (IFN-γ), heat shock protein 70 (Hsp70) and NF-κB activity were determined in liver and placenta homogenates. Our findings indicated that silibinin treatment decreased the production of the inflammatory cytokines TNF-α, IL-1β, IFN-γ, and reduced Hsp70 levels in the placenta and liver homogenate. NF-κB activation was also decreased in these organs of silibinin-treated groups, especially in the LN+SB0 and LN+SB7 groups. This study introduces a novel use of silibinin as a preventive agent in a PE-like model that reproduces essential features of human PE, providing physiological relevance to the findings. Overall, our data emphasize the translational potential of silibinin for PE prevention, showing promising effects on key inflammatory and stress-related pathways.
Management of venoarterial-extracorporeal membrane oxygenation for cardiogenic shock requires prompt diagnosis, rapid intervention with individualized cannulation, adherence to clear device and anticoagulation management protocols, and close hemodynamic and end-organ monitoring. Assessment of left ventricular unloading and oxygen delivery is essential to prevent complications such as malperfusion of end organs, limb ischemia, pulmonary edema, and Harlequin (North-South) syndrome. Daily evaluation guides weaning for myocardial recovery and transition to durable support, transplant, or palliative care. Multidisciplinary coordination with critical care clinicians, early involvement of advanced heart failure and transplant teams, and clear communication with families are crucial to align therapy with patient.
We reviewed the case report by Shrestha et al. describing ranitidine-induced anaphylactic shock. Although the clinical management of the case is clearly presented, the report appears to have limited novelty and originality, as similar cases have already been extensively documented in the literature, spanning a wide clinical spectrum from mild hypersensitivity to fatal outcomes. Moreover, while ranitidine has been withdrawn in many high-income countries, it remains in use across numerous low- and middle-income countries, including Nepal. We therefore argue that for such a report to make a meaningful scientific contribution, its discussion should more explicitly address regional pharmacovigilance gaps, disparities in drug regulation, and the responsibility of national regulatory authorities regarding the continued availability of this agent.
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This study aimed to evaluate the predictive value of serum presepsin, proadrenomedullin, and interleukin-6 levels for prognosis and mortality in patients diagnosed as having sepsis in the emergency department. This prospective observational cohort study was conducted with patients diagnosed as having sepsis in the emergency department of a tertiary university hospital. The study analyzed the patients' demographic characteristics, comorbidities, source of sepsis, biomarker levels, treatments, microbial culture results, and 30-day mortality. Blood samples were collected upon the patients' admission to the emergency department. Patients with septic shock had significantly higher serum interleukin-6 levels (363.2 pg/mL) than those with sepsis (140.6 pg/mL; P = .003). In contrast, proadrenomedullin levels were significantly lower in patients with septic shock (0.27 pmol/mL) than those with sepsis (0.48 pmol/mL; P = .02). Although presepsin levels were higher in the septic shock group (178.3 ng/L vs 156.9 ng/L), this difference was not statistically significant (P = .81). However, in multivariable analysis, none of the biomarkers remained independent predictors after adjustment for clinical confounders. Interleukin-6 levels were also significantly higher in nonsurvivors than survivors (363.2 pg/mL vs 195.5 pg/mL; P = .046). In receiver operating characteristic analysis, interleukin-6 (area under the curve, 0.701), proadrenomedullin (area under the curve, 0.658), and procalcitonin (area under the curve, 0.625) demonstrated moderate predictive ability for septic shock. Interleukin-6, presepsin, and proadrenomedullin may provide supportive diagnostic and prognostic information in patients with sepsis and septic shock in the emergency department. However, none of these biomarkers remained independent prognostic predictors after adjustment for clinical confounders. Further studies are needed to better clarify their clinical utility and prognostic role.
The Microaxial Flow Pump (MFP) is a miniaturised rotary pump that aspirates blood from the left ventricle and expels it into the ascending aorta. It unloads the left ventricle and increases mean arterial pressure and cardiac output. MFP is most commonly utilised in cardiogenic shock, for protected percutaneous coronary intervention (PCI), and for ventricular offloading in veno-arterial extracorporeal membrane oxygenation (VA-ECMO). We conducted a retrospective review of all patients who underwent MFP insertion at John Hunter Hospital, Australia. Categorical data are represented as counts and percentages, with continuous variables described as means with standard deviations. Twenty-three MFP devices were inserted between September 2020 and May 2024. Five (22%) were for protected PCI, three (13%) for venting with VA-ECMO (ECPELLA), and 15 (65%) for acute coronary syndrome (ACS) and cardiogenic shock. The median age for the overall cohort was 62 years, with a 74% male predominance. Eighty percent of the protected PCI cohort were elective outpatient procedures, and there were no deaths in this cohort. The mortality in the ECPELLA group was 67%. Thirteen (87%) of the patients with cardiogenic shock presented with an anterior infarct, and 53% had cardiac arrest on admission. The overall morality in the cardiogenic shock cohort was 40%. Complications in this cohort included limb ischaemia in four patients (17%) and site bleeding in seven patients (30%). Four patients (17%) required vascular surgery intervention. Our initial experience showed the use of MFP in a tertiary centre was safe and feasible, allowing progression from protected percutaneous intervention to acute cardiogenic shock.
Accurate prediction of fluid responsiveness is essential in managing circulatory shock. While passive leg raising (PLR) is recommended in international guidelines, its diagnostic validity depends critically on the monitoring modality used to detect hemodynamic responses. In resource-limited settings, manual blood pressure measurement remains the predominant available technology, yet its adequacy for PLR interpretation has not been rigorously evaluated in an adequately powered study with an independent reference standard. To compare the diagnostic accuracy of manual pulse pressure change (ΔPP%) versus continuous flow monitoring (USCOM-1 A, ΔSV%) for predicting fluid responsiveness during PLR in intensive care unit (ICU) patients with undifferentiated shock, using echocardiographic cardiac output assessment as an independent reference standard. Prospective single-center diagnostic accuracy study enrolling consecutive ICU patients with undifferentiated shock at Sina Educational and Medical Center, Tehran, Iran (2020-2021). A standardized PLR protocol was performed with simultaneous blinded measurements by three independent operators: manual blood pressure via calibrated sphygmomanometer, continuous flow monitoring via USCOM-1 A, and echocardiographic velocity-time integral (VTI) measurement as the reference standard. Fluid responsiveness was defined as ≥ 15% cardiac output increase following 500 mL crystalloid challenge. Primary outcome was area under the receiver operating characteristic curve (AUC). The study followed Standards for Reporting Diagnostic Accuracy Studies (STARD) 2015 guidelines (Ethics approval: IR.SBMU.PHARMACY.REC.1399.316). Of 124 patients analyzed (mean age 58.1 ± 19.8 years, 65.3% female), 58 (46.8%) were fluid responders. Continuous flow monitoring demonstrated acceptable diagnostic accuracy (AUC 0.712, 95% confidence interval [CI] 0.622-0.802; sensitivity 81.0%; specificity 61.8%; negative predictive value [NPV] 79.2%). Manual pulse pressure demonstrated significantly inferior discrimination (AUC 0.601, 95%CI 0.502-0.700; DeLong test P = 0.029) with critically low sensitivity (32.8%) and clinically inadequate NPV (57.8%). Bootstrap-corrected performance estimates confirmed the robustness of findings (USCOM AUC 0.708; Manual pulse pressure [PP] AUC 0.596). Mean pulse pressure remained essentially unchanged during PLR (+ 0.4 ± 4.6 mmHg, P = 0.287) despite significant proportional increases in both systolic (+ 3.7%) and diastolic (+ 5.6%) pressures, and despite echocardiographically confirmed stroke volume augmentation (left ventricular outflow tract [LVOT] VTI + 15.9%). The correlation between ΔPP% and ΔSV% was weak (r = 0.39, R²=0.15). Baseline method comparison between USCOM-derived and echocardiography-derived cardiac output showed low paired bias, although the percentage error exceeded the conventional interchangeability threshold, supporting interpretation of USCOM as a directional flow-monitoring index rather than a fully interchangeable substitute for echocardiography. In this single-center study, manual pulse pressure demonstrated insufficient sensitivity (32.8%) and inadequate NPV (57.8%) for reliable fluid responsiveness prediction during PLR. Our findings suggest it should be interpreted with considerable caution, particularly when the test result is negative. Continuous flow monitoring provides superior and clinically acceptable diagnostic accuracy when available, although USCOM should be interpreted as a directional flow-monitoring index rather than a fully interchangeable substitute for echocardiographic cardiac output measurement. The proportional pressure increase phenomenon provides a mechanistic explanation for this diagnostic limitation. These findings require multicenter validation before definitive practice recommendations can be issued.
Persistent urban-rural disparities in emergency medical service (EMS) demand constitute a core challenge to global public health equity. Existing research focuses predominantly on static comparisons of demand scale, with limited systematic analysis of spatiotemporal dynamics, shock responsiveness, and heterogeneous driving mechanisms across urban and rural EMS systems. Conventional one-size-fits-all regression models further widen the gap between academic findings and on-the-ground EMS operations. Taking Ningbo, China as the case, we defined urban and rural units in full alignment with official EMS response zoning. Using 189,506 validated dispatch records from October 2022 to September 2025 (spanning the exogenous shock of China's COVID-19 policy adjustment), we applied a sequential framework integrating global negative binomial regression (GNBR) and geographically weighted regression (GWR) to compare spatiotemporal patterns and identify system-specific demand drivers. Urban EMS demand showed strong positive spatial autocorrelation (Global Moran's I = 0.47, p < 0.01) with contiguous high-demand clusters, and exhibited marked volatility across monthly, diurnal, and weekly scales alongside high sensitivity to policy shocks. Rural EMS demand displayed weak spatial autocorrelation (Global Moran's I = 0.25, p < 0.01) with scattered small-scale agglomeration, and maintained stable temporal patterns decoupled from external disruptions. Driving mechanisms differed structurally: urban demand was driven primarily by population aging and built environment intensity with significant spatial nonstationarity, while rural demand was shaped by traffic accessibility, localized service hubs, and terrain conditions. Based on these findings, we formalize two distinct EMS demand patterns: spatiotemporal coupling in urban areas and spatiotemporal independence in rural areas. This study advances theoretical understanding of urban-rural EMS demand heterogeneity beyond superficial scale comparisons. The practice-aligned sequential modeling framework provides a scalable analytical approach for heterogeneous health service research, and delivers evidence for targeted EMS planning, optimized resource allocation, and improved healthcare equity.