SEPSIS AND SEPTIC SHOCK IN ADULTS: CURRENT CONCEPTS IN PATHOPHYSIOLOGY, DIAGNOSIS, AND INTENSIVE CARE MANAGEMENT

ABSTRACT

Sepsis is a common condition that is associated with persistently high mortality rates and, for those who survive, significant long-term morbidity. Over the past decade, increased awareness of this condition as a result of campaigns and research has increased understanding of the problem among healthcare professionals and lay people and improved patient outcomes. In 2017, the World Health Assembly, together with the WHO, recognized sepsis as a priority global health problem and adopted a resolution aimed at improving its prevention, diagnosis, and treatment.In 2016, an updated definition of sepsis (Sepsis-3) was proposed. It defines sepsis as an infection accompanied by organ dysfunction, assessed using the Sequential Organ Failure Assessment (SOFA) score. Current research is focused on more precise patient stratification, which will enable the development of personalized treatment approaches based on their molecular and biochemical characteristics. An active search is underway for more advanced diagnostic methods that could bring this goal closer, as well as for an effective drug capable of altering the course of the disease and increasing survival. While these goals remain elusive, the greatest promise for improving outcomes lies in high-quality basic treatment, supported by educational initiatives and quality-of-care improvement programs.

АННОТАЦИЯ

Сепсис — это распространённое состояние, связанное с устойчиво высокой смертностью и, для выживших пациентов, значимой долгосрочной заболеваемостью. За последнее десятилетие повышение осведомлённости о данном состоянии благодаря кампаниям и исследованиям улучшило понимание проблемы среди медицинских работников и населения, а также привело к улучшению исходов у пациентов. В 2017 году Всемирная ассамблея здравоохранения совместно с ВОЗ признала сепсис приоритетной глобальной проблемой здравоохранения и приняла резолюцию, направленную на улучшение его профилактики, диагностики и лечения. В 2016 году было предложено обновлённое определение сепсиса (Sepsis-3). Оно определяет сепсис как инфекцию, сопровождающуюся органной дисфункцией, оцениваемой с помощью шкалы SOFA (Sequential Organ Failure Assessment). Современные исследования направлены на более точную стратификацию пациентов, что позволит разрабатывать персонализированные подходы к лечению на основе их молекулярных и биохимических характеристик. Активно ведётся поиск более совершенных методов диагностики, которые могли бы приблизить достижение этой цели, а также эффективного лекарственного средства, способного изменить течение заболевания и повысить выживаемость. Пока эти цели остаются недостижимыми, наибольший потенциал улучшения исходов заключается в качественной базовой терапии, поддерживаемой образовательными инициативами и программами улучшения качества медицинской помощи.

Keywords: Sepsis, septic shock, organ dysfunction, early diagnosis, SOFA score, biomarkers, antimicrobial resistance, intensive care, hemodynamic support, treatment strategies, Kazakhstan healthcare system.

Ключевые слова: сепсис, септический шок, органная дисфункция, ранняя диагностика, шкала SOFA, биомаркеры, антимикробная резистентность, интенсивная терапия, гемодинамическая поддержка, стратегии лечения, система здравоохранения Казахстана.

1. Introduction

Sepsis, according to the Sepsis-3 definition (2016), is a life-threatening condition caused by a disrupted immune response to infection, leading to organ dysfunction and death. It remains a major global problem, with 48.9 million cases and 11 million deaths in 2017. A meta-analysis by Fleischmann-Struzek et al. shows 26.7% mortality and a 46% increase in incidence. Sepsis and septic shock are critical in anesthesiology and intensive care, requiring rapid diagnosis and treatment. The article aims to examine current concepts in the pathophysiology, diagnosis, treatment, anesthesiology, and intensive care of sepsis and septic shock.

2. Aim

This work reviews sepsis and septic shock- etiology, pathophysiology, diagnosis, treatment, antimicrobial resistance, Kazakhstan data, and future personalized therapy.

3. Etiology and Risk factors

Sepsis occurs when a pathogenic insult triggers an inappropriate and exaggerated host response which results in tissue injury and organ dysfunction. Although nearly any pathogen can trigger the cascade, bacteria remain the most common etiologic agents. Gram-negative bacteria including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are common culprits, with Gram-positive bacteria including Staphylococcus aureus and Streptococcus pneumoniae contributing a major portion to the global burden. Opportunistic fungi, particularly Candida species, have emerged as pathogenically significant in immunocompromised patients or those with a prolonged course of severe illness. Viral causes like influenza and recently SARS-CoV-2 also cause sepsis but account for a minority of cases.

The clinical syndromes by which sepsis in occurs are varied, but worldwide, pneumonia is always the primary cause. Severe intraperitoneal infections, device-related or native bloodstream infections, and complicated urinary tract infections also account for significant percentages. Skin and soft-tissue infections, especially necrotizing fasciitis and infected post-surgical wounds, are fewer but can rapidly develop into septic shock.

Not all patients who are exposed to infection are equally at risk. Progressive age and early life confer added vulnerability, a manifestation of immunosenescence and host defense immaturity. A wide array of chronic illnesses—diabetes, chronic kidney disease, cirrhosis, congestive heart failure, and chronic lung disease—contribute further to breakdown. Acquired immunosuppression due to HIV, cytotoxic therapy, organ transplant, or long-term corticosteroid and biologic use are other modifiers of risk. Nutritional deficiency, frailty, and prior episodes of sepsis have also been implicated in worse outcomes.

Healthcare-related exposures amplify risk through the creation of sites for colonization and invasion. Prolonged hospitalization, large doses of surgery, and the placement of invasive devices such as central venous catheters, urinary catheters, and endotracheal tubes are all known to contribute. ICU admission, mechanical ventilation, and intense exposure to exogenous antibiotics predispose to multidrug-resistant organism colonization/infection with a correlation for poorer clinical outcome. Delay in the administration of appropriate antimicrobial therapy, pathogenic virulence during invasion, and the risk for polymicrobial infection also increase the risk of septic shock and mortality.

3. Pathophysiology of Sepsis

A modern understanding of the pathophysiology of sepsis is impossible without analyzing the mechanisms of inflammation, both local and systemic. Normally, inflammation is a localized, immune-regulated response to damaging factors aimed at eliminating pathogens, limiting the focus of infection, and repairing tissues. At the same time, cellular and humoral defense mechanisms are activated, which ensures recovery. However, with massive aggression — infectious, traumatic, or burn — the inflammatory process goes beyond the local and becomes generalized. Such a systemic response is accompanied by a violation of the functions of vital organs and can lead to the development of sepsis and multiple organ failure. This condition is known as systemic inflammatory response syndrome (SIRS).

Inflammation begins with local reactions, but as it progresses, it involves the integration of various regulatory systems of the body. The protective response includes: the reaction of the central nervous system and neuroendocrine mechanisms that regulate hemodynamics and metabolism; non—specific immune reactions such as phagocytosis, chemotaxis and complement activation; as well as the synthesis of inflammatory mediators - cytokines. The latter play a key role in triggering and developing an inflammatory response. They are produced by activated monocytes, macrophages, neutrophils, lymphocytes and endothelial cells, with Kupffer liver cells of particular importance, which make up more than 70% of all macrophages in the body and remove microorganisms, toxins and decomposition products.

Cytokines are divided into five main classes: interleukins (pro- and anti-inflammatory), tumor necrosis factors (TNF), lymphocyte growth and differentiation factors, granulocyte and macrophage colony stimulators, and mesenchymal cell growth factors. Under physiological conditions, their secretion is minimal and ensures the interaction of cells of the immune system. With inflammation, their production increases dramatically. A balanced ratio of pro- and anti-inflammatory cytokines ensures a limited and controlled nature of inflammation, but when this balance is disturbed, an excessive systemic response develops.

Excessive production of cytokines transforms them from protective factors into aggressive ones, causing tissue damage and intensifying the inflammatory process. The systemic inflammatory response becomes self-sustaining and can progress to sepsis, multiple organ failure, and septic shock. The vascular endothelium plays a central role in this process: it not only participates in the production of mediators, but also regulates the interaction between immune cells and tissues, promotes the directed migration of leukocytes to the lesion site and coordinates the inflammatory response.

With a massive bacterial load, hyperactivation of macrophages and neutrophils leads to an excess of mediators, endothelial damage, the development of microthrombosis, vasodilation and hypotension. Increased permeability of the vascular wall causes edema and hypovolemia, microcirculation and blood supply to organs and tissues are disrupted, and their dysfunction develops. Metabolic shifts include the transition to an anaerobic type of metabolism, a decrease in ATP synthesis, the development of metabolic acidosis, cellular edema and disruption of ion pumps, which further exacerbates multiple organ disorders.

The pathological process from SIRS to sepsis has a stepwise character. There are three stages of SIRS:A local reaction is the production of mediators in the focus of inflammation, aimed at destroying pathogens.The systemic response is a controlled release of mediators into the bloodstream, activation of an acute–phase reaction. Generalization is the loss of control over the balance of mediators, the development of immunosuppression and multiple organ failure.

4. Diagnosis of Sepsis

SOFA score identifies Sequential Organ Failure Assessment in six systems, created in 1996. The scale evaluates the dysfunction of six organ systems: respiratory, coagulation, hepatic, cardiovascular, neurological, renal, for each of which 0-4 points are assigned. [Table 1]

Figure 1. Sequential Organ Failure Assessment score (SOFA)

qSOFA scale is simplified organ dysfunction risk assessment. It is used to predict the threat of organ dysfunction and death in critically ill patients. The qSOFA scale includes only three characteristics, for each of which 1 point is awarded. [Table 2]

• respiratory rate ≥ 22 per minute
• systolic blood pressure < 100 mmHg
• presence of consciousness

Figure 2. qSOFA score

Clinical tools called Early Warning Scores are intended to notify healthcare professionals of a clinical decline that is about to occur. This decline is frequently, but not always, linked to the development of sepsis. Their popularity has grown significantly since they were first introduced approximately ten years ago.

The NEWS system is a widely recognized clinical early warning system. It relies on seven clinical indicators, yielding a total score ranging from 0 to 20. Patients with aggregate scores of 4 or lower are deemed to be at “low risk,” while those with NEWS scores of 5 or 6, or any individual parameter scoring 3, are classified as being at “medium risk.” A NEWS score of 7 or higher indicates that a patient is at “high risk,” necessitating constant vital sign monitoring and potential transfer to an acute care unit, high dependency unit, or ICU. It is important to highlight that NEWS scores below 7 can still indicate potential clinical issues. [Table 3]

Figure 3. National Early Warning Score

Biomarkers are often used to help doctors diagnose, track, and assess the risk level in patients who have sepsis or septic shock.

Presepsin, also known as sCD14-ST, is a soluble part of the CD14 protein, helps the body recognize harmful molecules from pathogens and starts the body's first line of defense.Since presepsin levels rise early in sepsis and are mostly linked to bacterial infections, it is a marker for diagnosing sepsis and assessing a patient's risk.

When there's an acute infection or inflammation, the liver makes a protein called C-reactive protein (CRP). CRP levels can go up to 300 mg/L within two days. In a healthy person, CRP levels are usually below 3 mg/L.

Procalcitonin (PCT) can be a helpful tool in managing the use of antibiotics properly. During a bacterial infection, PCT levels rise quickly.

Instrumental diagnostics

Chest X-ray shows fluid in the pleural spaces, lung tissue with infiltrates, and signs of pulmonary edema, which are typical of pleuropneumonia or ARDS.

ECG results may show irregular heart rhythms, conduction issues, or signs of myocarditis.

An abdominal ultrasound should check for free fluid, an enlarged liver, spleen, blocked bile ducts, liver damage, and pancreatitis. It should also look for the original or secondary infection source.

A kidney and retroperitoneal ultrasound should check for kidney abnormalities, as part of looking for possible infection sources.

Echocardiography or echocardiocopy is used to check for structural heart problems to help distinguish between different heart diseases.

A lung CT scan is used to check for pulmonary embolism, pneumonia, or ARDS.

In cases where sepsis is suspected, it is recommended to collect samples for microbiological testing, including biological media, after the diagnosis of sepsis, especially before starting antibacterial treatment.

5. Principles of Intensive Therapy

5.1. Early Recognition and Initial Management Golden hour concept. Fluid resuscitation. Early antibiotics.

Three factors known as quick sequential organ failure assessment, or qSOFA (table 1), were created in 2016 to forecast death in patients with suspected or confirmed sepsis. 2. Glasgow Coma Score < 15, respiration rate ≥ 22 breaths/minute, and systolic blood pressure ≤ 100 mmHg are the three variables. A patient is considered qSOFA positive if two or more factors are present at any one moment. Compared to other screening techniques like SIRS, NEWS, or MEWS, studies have demonstrated that qSOFA is a superior predictor of death in patients with suspected or confirmed sepsis. High sensitivity is the aim of a screening tool, not death prediction, so that physicians can find patients with the disease process of interest.

Algorithm for Early Recognition and Initial Management of Sepsis in Adults

Step 1: Suspected Sepsis Identification

Any patient who satisfies two or more SIRS criteria [Table 3]or in whom an infection is suspected—especially in immunocompromised individuals—should be suspected of having sepsis.

Step 2: Preliminary Clinical Evaluation

Table 1.

SIRS criteria

To identify the most likely cause of infection or sepsis, quickly conduct a clinical evaluation.

Determine the hemodynamic status and acquire baseline tests, such as:

Lactate in blood

Blood cultures from a minimum of two locations, including indwelling central venous catheters in the event that an infection linked to the catheter is suspected

Comprehensive metabolic panel (CMP), urine with reflex culture, and CBC with differential

Step 3: Early Treatment with Antimicrobials

Broad-spectrum intravenous antibiotics that target probable bacteria based on clinical presentation and local resistance trends should be started as soon as blood cultures are obtained.

Step 4: Hypoperfusion Assessment

Check for tissue hypoperfusion symptoms [Table 4]:

Mean arterial pressure (MAP) < 65 mmHg, systolic blood pressure > 40 mmHg below baseline, or systolic blood pressure < 90 mmHg

Lactate in serum ≥ 4 mmol/L

Table 2.

Values

Step 5:

Give an initial intravenous bolus of 30 mL/kg of isotonic crystalloid solution (such as lactated Ringer's) as soon as feasible if hypoperfusion is present.

Repeat the measurement in three hours if the initial lactate level is greater than 4 mmol/L.

Step 6: Evaluation Following Fluid Administration

To determine fluid responsiveness and hemodynamic state, conduct a physical examination.

To evaluate the success of resuscitation, repeat serum lactate.

Step 7: Support for Vasopressors

If, following early fluid resuscitation, the patient's hemodynamic instability persists:

To keep the MAP at or above 65 mmHg, start vasopressor treatment.

The suggested order is:

Norepinephrine is the first line.

Vasopressin is the second line.

Epinephrine is the third line.

Give more intravenous fluids as necessary if the patient is still fluid sensitive.

Step 8: Continuous Management and Monitoring

Maintain regular evaluations of organ function, lactate levels, hemodynamic condition, and treatment response.

Adapt antimicrobial treatment in light of clinical development and microbiological findings.

5.2. Hemodynamic Support

Core Principle

The goal is to restore tissue perfusion, not just to achieve a target blood pressure. The target Mean Arterial Pressure (MAP) is approximately 65 mmHg.

2. Essential Medications

Vasopressors:

Norepinephrine is the first-line agent. It provides potent vasoconstriction with minimal tachycardia.

Vasopressin is added to norepinephrine to reduce its required dose.

Epinephrine is a rescue agent but increases the risk of arrhythmias.

Inotropes:

Dobutamine is the primary choice for septic cardiomyopathy to improve cardiac contractility.

3. Critical Monitoring & Diagnosis

Essential Monitoring: Arterial catheter for continuous MAP measurement; lactate clearance.

Key Diagnostic Tool: Bedside echocardiography for rapid assessment of cardiac function and fluid status.

Assessing Fluid Responsiveness: Dynamic indices (e.g., pulse pressure variation, passive leg raise test) are preferred over static pressure measurements.

Conclusion: Effective management requires a combination of norepinephrine (for vascular tone) and dobutamine (for cardiac support), guided by advanced monitoring for individualized therapy.

5.3. Organ Support

Sepsis and septic shock are critical conditions that frequently lead to multiple organ failure. Alongside source control and antimicrobial treatment, a fundamental aspect of intensive care unit (ICU) management is organ support, which focuses on preserving essential physiological functions until the underlying infection is managed. Key elements of organ support consist of mechanical ventilation, renal replacement therapy (RRT), and corticosteroid administration for specific cases of refractory shock.

Mechanical Ventilation

Serious sepsis frequently involves difficulties with breathing, typically due to acute respiratory distress syndrome (ARDS), which stems from widespread inflammation and leaky blood vessels. Patients commonly require assistance with breathing machines to ensure adequate oxygen and ease their respiratory burden. The main approach focuses on gentle ventilation employing smaller breaths—roughly 6 mL per kilogram of estimated body mass—and keeping airway pressure under 30 cm H₂O to limit damage to the lungs. Suitable amounts of continuous positive airway pressure (CPAP) stop air sacs from deflating, while placing individuals with considerable to intense ARDS on their stomachs may improve how well they absorb oxygen. Comfort and synchronization with the machine are improved through calming medication and pain management, though excessive drowsiness must be avoided.

Renal Replacement Therapy (RRT)

Acute kidney injury (AKI) occurs frequently in septic patients due to hypoperfusion, inflammation, and direct toxic effects of circulating mediators. When kidney function deteriorates significantly, RRT is initiated to maintain homeostasis.

The decision to start RRT is based on clinical and laboratory findings rather than strict numerical thresholds. Common indications include refractory hyperkalemia, severe metabolic acidosis, uremic complications such as encephalopathy or pericarditis, and fluid overload unresponsive to diuretics.

 In hemodynamically unstable patients, continuous renal replacement therapy (CRRT) is often preferred because it provides gradual fluid and solute removal, which is better tolerated. In more stable patients, intermittent hemodialysis may be appropriate.

 The timing of initiation remains individualized, as studies have shown mixed results regarding early versus delayed RRT. Clinicians must weigh the risks and benefits based on the patient’s overall condition and response to initial resuscitation.

Corticosteroids

Some patients with septic shock develop relative adrenal insufficiency, also known as critical illness-related corticosteroid insufficiency (CIRCI). This condition leads to poor vascular tone and reduced responsiveness to vasopressors.
Corticosteroids, most commonly hydrocortisone, are recommended for patients whose shock persists despite adequate fluid resuscitation and high-dose vasopressor therapy. The typical regimen is hydrocortisone 200 mg per day, either as a continuous infusion or divided into multiple doses.

Routine administration of corticosteroids to all patients with sepsis is not advised, as studies show that benefits are mostly seen in cases of refractory shock. When used, corticosteroids should be tapered as the patient stabilizes, and clinicians should monitor for adverse effects such as hyperglycemia, secondary infections, and gastrointestinal bleeding.

5.4. Novel and Adjunctive Therapies

Early recognition of septic shock and prompt administration of appropriate antibiotics remain the cornerstones of sepsis care. Despite advances in critical care, mortality remains high. Many additional treatments have been explored, but their effectiveness is still uncertain. Differences in patient populations and inconsistent study results make it challenging to draw firm conclusions, which is why researchers continue to evaluate the rationale and practical use of these therapies.

A wide range of adjunctive approaches has been studied alongside standard care—antibiotics, fluids, and vasopressors. Corticosteroids, particularly low-dose hydrocortisone, are among the most commonly examined. They often help reverse shock faster and reduce vasopressor requirements, though their impact on survival is unclear. For this reason, corticosteroids are usually reserved for patients with persistent hypotension.

Metabolic resuscitation with vitamin C, thiamine, and hydrocortisone (“HAT therapy”) initially appeared promising, but trials such as CITRUS-ALI, VITAMINS, and LOVIT did not demonstrate a clear survival benefit. Vitamin D supplementation and thiamine alone can improve physiological measures, like lactate clearance, but have not shown consistent mortality reduction.

Immune dysfunction and prompting exploration of immunomodulatory strategies are owing to sepsis. Intravenous immunoglobulins, including IgM-enriched formulations, show mixed results, sometimes benefiting patients with low immunoglobulin levels. Emerging therapies—interferon-γ, interleukin-7, and PD-1/PD-L1 inhibitors reverse immune suppression.

It is believed that coagulation abnormalities are common in sepsis. Recombinant activated protein C was withdrawn due to inconsistent efficacy and bleeding risk. Antithrombin and heparin continue to be investigated, especially in sepsis-induced coagulopathy, but are not standard treatments.

Extracorporeal blood purification techniques—polymyxin B hemoperfusion, cytokine adsorption (CytoSorb), and high-volume hemofiltration—may improve short-term hemodynamics, but trials like EUPHRATES show no clear survival advantage. Plasma exchange is limited to select toxin-mediated cases.

Angiotensin II has emerged as a rescue vasopressor, improving blood pressure and reducing catecholamine needs, though survival benefit is unproven. Beta-blockers such as esmolol can manage persistent tachycardia but require careful selection. Mitochondria-targeted therapies, including coenzyme Q10 and melatonin, show early promise but remain experimental.

In summary, many adjunctive therapies improve physiological parameters, but none consistently reduce mortality. Currently, corticosteroids and angiotensin II are selectively supported, while most other interventions remain investigational and need further research..

6. Discussion

The diagnosis of sepsis remains one of the major challenges in clinical medicine. Despite international definitions and novel criteria, the early recognition of sepsis is still hindered by the nonspecific nature of clinical symptoms and overlap with other inflammatory conditions. Furthermore, conventional microbiological cultures are limited by their turnaround time and frequent negativity in patients with prior antimicrobial exposure. These diagnostic limitations are also observed in Kazakhstan, where access to advanced fast laboratories is uneven, which delays definitive recognition.

Timely and effective treatment is complicated by the global rise of antimicrobial resistance (AMR), which is also evident in Kazakhstan. According to the national analysis of antibiotic consumption from 2019–2023, there is a moderate increase in use of broad-spectrum agents that raise concerns about empiric therapy efficacy. While Kazakhstan has adopted an AMR National Action Plan in line with WHO guidance, stewardship implementation remains heterogeneous. This affects sepsis care directly, as delayed or inadequate empiric antibiotic coverage is directly associated with increased mortality.

Outcome differences across regions of Kazakhstan is another highlighted challenge. Neonatal and infant sepsis studies reveal variability in mortality rates between regions, and areas such as Karaganda reporting higher burdens. These disparities likely reflect differences in healthcare infrastructure, timeliness of intervention, availability of intensive care resources, and local AMR patterns. Addressing these inequities requires both targeted resource allocation and standardized implementation of national sepsis protocols.

Looking forward, several directions hold promise for improving sepsis outcomes in Kazakhstan. Biomarker panels and multi-marker algorithms may improve diagnostic accuracy by identifying sepsis phenotypes more reliably than single markers. Precision medicine approaches, including sepsis subtyping, could facilitate personalized treatment strategies, aligning specific therapies with patient endotypes. Integration of artificial intelligence and decision-support tools to analyze clinical and laboratory data could also enhance early recognition.

8. Conclusion

Sepsis and septic shock remain conditions with a high burden of morbidity and mortality worldwide. Their complex pathophysiology, nonspecific clinical presentation, and limitations of available diagnostic methods make early recognition extremely difficult. Timely treatment is further challenged by the growing problem of antimicrobial resistance, which is also observed in Kazakhstan. Analysis of national data shows that outcomes vary between different regions, reflecting inequalities in healthcare resources and access to intensive care. At the same time, modern research gives new perspectives for improving patient care. Biomarker panels, rapid microbiological and molecular diagnostics, and precision medicine approaches open opportunities for more individualized and effective therapy. For Kazakhstan, it is important to strengthen antimicrobial stewardship, ensure equal access to intensive care services, and gradually integrate innovative technologies into daily clinical practice. These steps can contribute to reducing mortality from sepsis and improving the quality of medical care at the national level.

References:

1. Kilinc Toker A, Kose S, Turken M. Comparison of SOFA Score, SIRS, qSOFA, and qSOFA + L Criteria in the Diagnosis and Prognosis of Sepsis. Eurasian J Med. https://pmc.ncbi.nlm.nih.gov/articles/PMC7929579/
2. Doyle D. Clinical Early Warning Scores: New Clinical Tools in Evolution . Open Anesthesia J, 2018; 12:. http://dx.doi.org/10.2174/2589645801812010026
3. Siddiqui E, Jokhio AA, Raheem A, Waheed S, Hashmatullah S. The Utility of Early Warning Score in Adults Presenting With Sepsis in the Emergency Department of a Low Resource Setting. Cureus. https://pmc.ncbi.nlm.nih.gov/articles/PMC7406184/
4. Anush MM, Ashok VK, Sarma RI, Pillai SK. Role of C-reactive Protein as an Indicator for Determining the Outcome of Sepsis. Indian J Crit Care Med. https://pmc.ncbi.nlm.nih.gov/articles/PMC6481256/
5. Vijayan AL, Vanimaya, Ravindran S, Saikant R, Lakshmi S, Kartik R, G M. Procalcitonin: a promising diagnostic marker for sepsis and antibiotic therapy. J Intensive Care. https://pmc.ncbi.nlm.nih.gov/articles/PMC5543591/
6. Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C. M., French, C., & Levy, M. M. (2021). Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock 2021. Critical Care Medicine, 49(11), e1063–e1143. https://doi.org/10.1097/CCM.0000000000005337
7. The ARDS Network. (2000). Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine, 342(18), 1301–1308. https://doi.org/10.1056/NEJM200005043421801
8. Gaudry, S., Hajage, D., Schortgen, F., Martin-Lefevre, L., Pons, B., Boulet, E., & Dreyfuss, D. (2016). Initiation strategies for renal-replacement therapy in the intensive care unit. New England Journal of Medicine, 375(2), 122–133. https://doi.org/10.1056/NEJMoa1603017
9. Venkatesh, B., Finfer, S., Cohen, J., Rajbhandari, D., Arabi, Y., Bellomo, R., ... & Myburgh, J. (2018). Adjunctive glucocorticoid therapy in patients with septic shock. New England Journal of Medicine, 378(9), 797–808. https://doi.org/10.1056/NEJMoa1705835
10. Annane, D., Renault, A., Brun-Buisson, C., Megarbane, B., Quenot, J. P., Siami, S., ... & Vignon, P. (2018). Hydrocortisone plus fludrocortisone for adults with septic shock. New England Journal of Medicine, 378(9), 809–818. https://doi.org/10.1056/NEJMoa1705716
11. Zhang, W., Li, S., Liu, Y., Lu, J., Chen, J., Chen, L., ... & Wang, X. (2024). Adjunctive therapies in sepsis: Multidisciplinary consensus statement. Journal of Anesthesia, Analgesia and Critical Care, 4, 65. https://doi.org/10.1186/s44158-024-00165-3
12. Atkinson, T. M., & Watanabe, E. (2014). Adjunctive therapies in sepsis: An evidence-based review. Critical Care Clinics, 30(3), 843–868. https://doi.org/10.1016/j.ccc.2014.03.011
13. Dellinger, R. P., Bagshaw, S. M., Antonelli, M., Foster, D., Klein, D. J., Marshall, J. C., ... & Vincent, J. L. (2004). Adjunctive therapies in sepsis: An evidence-based review. Critical Care Medicine, 32(11 Suppl), S571–S575. https://www.researchgate.net/publication/8183975_Adjunctive_therapies_in_sepsis_An_evidence-based_review
14. Kellum, J. A., & Mehta, R. L. (2014). Therapeutic interventions for sepsis: Blood purification. Pediatric Critical Care Medicine, 15(4 Suppl 1), S63–S68. https://pmc.ncbi.nlm.nih.gov/articles/instance/6530767/pdf/10-3233-PIC-14112.pdf
15. Khanna, A., English, S. W., Wang, X. S., Ham, K., Tumlin, J., Szerlip, H., ... & Tumlin, J. A. (2017). Angiotensin II for the treatment of vasodilatory shock. The New England Journal of Medicine, 377(5), 419–430. https://doi.org/10.1056/NEJMoa1704154
16. Fowler, A. A., Truwit, J. D., Hite, R. D., Morris, P. E., DeWilde, C., Priday, A., ... & Fisher, B. (2019). Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial. JAMA, 322(13), 1261–1270. https://doi.org/10.1001/jama.2019.11825
17. Fujii, T., Luethi, N., Young, P. J., Frei, D. R., Eastwood, G. M., French, C. J., ... & Venkatesh, B. (2020). Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: The VITAMINS randomized clinical trial. JAMA, 323(5), 423–431. https://doi.org/10.1001/jama.2019.22176
18. Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):762-774. doi:10.1001/jama.2016.0288 [PMC free article] [PubMed] [CrossRef]
19. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Critical Care Medicine. 2014;42(8):1749-1755. doi:10.1097/CCM.0000000000000330 [PubMed] [CrossRef]
20. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596. [PubMed]
21. Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. Journal of Medicine. 2017;376(23):2235-2244. doi:10.1056/NEJMoa1703058 [PMC free article] [PubMed] [CrossRef] https://www.ncbi.nlm.nih.gov/books/NBK598311/
22. Milano PK, Desai SA, Eiting EA, Hofmann EF, Lam CN, Menchine M. Sepsis Bundle Adherence Is Associated with Improved Survival in Severe Sepsis or Septic Shock. Journal of Emergency Medicine. 2018;19(5):774-781. doi:10.5811/westjem.2018.7.37651 [PMC free article] [PubMed] [CrossRef] https://pmc.ncbi.nlm.nih.gov/articles/PMC8160230/#B117
23. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. Jama. (2012) 307:2526–33. 10.1001/jama.2012.5669 [DOI] [PubMed] [Google Scholar]
24. Iscimen R, Cartin-Ceba R, Yilmaz M, Khan H, Hubmayr RD, Afessa B, et al. Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care Med. (2008) 36:1518–22. 10.1097/CCM.0b013e31816fc2c0 [DOI] [PubMed] [Google Scholar]
25. Francis SE, Holden H, Holt CM, Duff GW. Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol. (1998) 30:215–23. 10.1006/jmcc.1997.0592 [DOI] [PubMed] [Google Scholar]
26. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063–e1143. [https://www.sccm.org/clinical-resources/guidelines/guidelines/surviving-sepsis-guidelines-2021]
27. Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodynamic monitoring. Intensive Care Med. 2014;40:1795–1815.[https://pmc.ncbi.nlm.nih.gov/articles/PMC4239778]
28. Vieillard-Baron A, Cecconi M. Hemodynamic monitoring in sepsis: current practice and future directions. Crit Care. 2022;26:229.[https://ccforum.biomedcentral.com/articles/10.1186/s13054-022-04173-z]
29. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362:779–789.[https://pmc.ncbi.nlm.nih.gov/articles/PMC5953246]
30. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–810.[https://pmc.ncbi.nlm.nih.gov/articles/PMC5953246]
31. Akhmetova, A., Dauletbayeva, A., & Ospanova, Z. (2025). Assessment of outpatient antibiotic prescribing trends in Kazakhstan: 2019–2023 data. Journal of Global Antimicrobial Resistance, 33, 15–22.
32. Semenova, Y., Sadvakasova, K., Zholdasbekova, A., Mailybayeva, Z., Sadykova, A., Shved, N., & Tuleuova, N. (2025). Analysis of national antibiotic consumption in Kazakhstan between 2019 and 2023. BMC Infectious Diseases, 25(1), 112. https://doi.org/10.1186/s12879-025-10428-2