A cross-sectional study on serum uric acid as an early marker in predicting the mortality and morbidity in patients with sepsis

Introduction

Sepsis represents a medical emergency characterized by a dysregulated host response to infection, ultimately leading to acute organ dysfunction. It is a grave condition accompanied by systemic inflammation affecting the entire body. Consequently, many patients in intensive care units (ICUs) experience varying degrees of ischemic-perfusion injury and inflammation during hospitalization. Sepsis, in essence, embodies the response of multiple organ systems to infection, with manifestations typically involving the fulfillment of two or more of the systemic inflammatory response syndrome (SIRS) criteria in response to an infection.^1–3

During sepsis, various changes occur at multiple levels within the body. One such change involves alterations in various markers that serve as early indicators of inflammation and, by extension, sepsis. In this context, the present study aims to investigate serum uric acid as a potential marker of inflammation and sepsis.⁴ Organ dysfunction, a hallmark of sepsis, is identified by an acute change in the Sequential Organ Failure Assessment (SOFA) score, typically a score increases of two points or more. Despite advances in understanding sepsis, its underlying pathophysiology, and the development of monitoring and resuscitative tools, sepsis remains a prominent cause of morbidity and mortality among critically ill patients.⁵

In the United States alone, the annual incidence of severe sepsis and septic shock reaches up to 300 cases per 100,000 people. The economic burden of sepsis on healthcare is substantial, accounting for over $20 million, equivalent to approximately 5.2% of total hospital costs in 2011. Globally, the epidemiological impact of sepsis is challenging to quantify precisely. Still, it is estimated that more than 30 million individuals are affected by sepsis annually worldwide, potentially resulting in six million deaths yearly.⁶

Severe sepsis is characterized by sepsis in conjunction with organ dysfunction, hypoperfusion, or hypotension, which may include indicators such as lactic acidosis, oliguria, or an acute alteration in mental status. According to the Third International Consensus, sepsis is defined as a life-threatening dysfunction of organ systems caused by the dysregulation of the host response to infection.⁷ The “Sepsis-3” clinical criteria for sepsis mandate the presence of suspected infection and acute organ dysfunction, defined as an increase by two or more points from baseline (if known) on the SOFA score.¹

Clinical prompts such as the quick Sequential Organ Failure Assessment (qSOFA) and the National Early Warning Score (NEWS) have been proposed to enhance the early identification of infected patients. qSOFA assigns one point each for systolic hypotension (≤100 mmHg), tachypnea (≥22 breaths/min), or altered mentation, with a qSOFA score of ≥2 points indicating a predictive value for sepsis akin to more intricate organ dysfunction assessments.⁸ Conversely, NEWS is an aggregate scoring system based on six physiological parameters: respiratory rate, oxygen saturation, systolic blood pressure, heart rate, altered mentation, and temperature.⁸ Organ dysfunction is identified as a change in the SOFA score of two points or more concerning the infection, and a SOFA score of two points or more implies an approximate 10% mortality risk in patients suspected of infection.¹

Patients with suspected infection are rapidly identified as having poor outcomes, especially in emergency departments or ward settings, if they exhibit at least two of the following criteria, which constitute the quick SOFA (qSOFA) score: respiratory rate of 22/min or higher, altered mentation/sensorium, or systolic blood pressure of 100 mmHg or lower.⁹

Sepsis shock is a subset of sepsis characterized by profound circulatory and cellular/metabolic abnormalities that significantly elevate mortality risk compared to sepsis alone. Clinically, patients with septic shock are identified by their need for vasopressor therapy to maintain a mean arterial pressure of ≥65 mm Hg and a serum lactate level exceeding 2 mmol/L (>18 mg/dL) after appropriate fluid resuscitation. This condition is associated with hospital mortality rates exceeding 40%.¹⁰

Method

Discussion

Despite being included within the broader category of sepsis, Septic shock varies in its application as a criterion for patient enrolment across clinical trials, observational studies, and quality improvement initiatives. To provide clarity, the proposed septic shock criteria encompass sepsis and vasopressor therapy to elevate mean arterial pressure to ≥65 mmHg and a serum lactate concentration >2.0 mmol/L following adequate fluid resuscitation.¹⁵ Notably, mortality rates related to sepsis, as reported by the Surviving Sepsis Campaign in 2012, exhibited disparities, with Europe recording approximately 41% and the United States 28.3%. However, these discrepancies disappeared when adjusted for disease severity, underscoring the impact of patient characteristics on sepsis mortality rates.¹⁶

A global study on sepsis mortality rates has revealed that India experiences significantly higher mortality rates from septic shock and sepsis syndrome—life-threatening responses to infections—compared to other South Asian countries, except Afghanistan. The study indicated sepsis death rates of 213 per 100,000 people in India, 206 in Pakistan, 183 in Nepal, 136 in Bangladesh, 109 in Bhutan, 69 in Sri Lanka, and 27 in the Maldives, while Afghanistan recorded 285.¹⁷

Throughout the 20th century, numerous experiments and clinical trials highlighted the critical role of the host’s immune response in sepsis signs and symptoms. However, the heterogeneity of sepsis presented considerable challenges in its recognition, treatment, and study.¹⁸ Bacterial infections are the most common cause of sepsis but can also result from fungal, parasitic, or viral infections. Infections can originate from various sites or organs within the body, including the abdomen (e.g., appendicitis, peritonitis), central nervous system (e.g., meningitis, spinal cord infections), lungs (e.g., pneumonia), or the urinary tract, particularly in cases involving indwelling urinary catheters.¹⁹

The risk of sepsis varies with age, being higher in individuals over 65 years old, young children, and pregnant women. People with comorbidities such as other infections, hypertension, diabetes, lung diseases, cancer, kidney diseases, immunocompromised individuals, those with prolonged hospital stays, severe injuries, large burns, or extensive wounds are also at greater risk. Indwelling catheters, such as IV cannulas, urinary catheters, or endotracheal tubes, further elevate the risk.²⁰

Routine diagnostic investigations for sepsis include a Complete Blood Count (CBC), blood culture, urine culture, and blood sugar assessment. Various markers are employed for prognosis and early diagnosis of sepsis, including C-reactive protein (CRP), procalcitonin, serum lactate levels, serum albumin levels, and the serum lactate-to-albumin ratio. Additionally, newer markers with distinct prognostic and diagnostic value for acute infections include soluble triggering receptors expressed on myeloid cells-1 (sTREM-1), soluble urokinase-type plasminogen receptor (suPAR), proadrenomedullin (pro-ADM), and presepsin.²¹

Lactic acid represents the product of anaerobic glucose or carbohydrate metabolism in tissues. The normal serum lactate level ranges from 0.5 to 1 mmol/L. Patients with terminal illnesses typically exhibit normal serum lactate levels of less than 2 mmol/L. Hyperlactatemia, defined as a persistent mild to moderate increase in levels up to 2-4 mmol/L, holds promise as a potentially valuable biomarker, offering prognostic insights in critically ill patients.²² Albumin, constituting most of the plasma protein and synthesized primarily in the liver, accounts for two-thirds of the total protein content in the blood. Any reduction in albumin due to diminished synthesis or losses significantly disrupts intravascular oncotic pressure, leading to edema. Therefore, serum albumin emerges as an ideal prognostic indicator.²³

In humans, uric acid is the product of purine catabolism due to the absence of uricase, which converts uric acid into the more soluble allantoin. Xanthine oxidase is the enzyme responsible for uric acid formation. It is estimated that approximately 70% of uric acid is excreted by the kidneys, while the remaining 30% is excreted through the gastrointestinal tract. Uric acid is predominantly found in the form of the urate anion under physiological pH conditions. It is easily filtered by the glomerulus and reabsorbed by proximal tubular cells in the kidney. The normal uric acid range is 3.4 to 7.2 mg/dL in males and 2.4 to 6.1 mg/dL in females. Hyperuricemia is a well-recognized phenomenon characterized by elevated uric acid levels and accumulation due to overproduction, underexcretion, or a combination of both. Elevated uric acid levels have recently been observed in chronic kidney disease, hypertension, hyperinsulinemia, atherosclerosis, obstructive pulmonary diseases, and chronic heart failure. Elevated uric acid levels can result in acute inflammation of renal epithelial cells due to uric acid crystal precipitation, even without crystal formation. Hyperuricemia can also cause endothelial dysfunction, afferent renal arteriolopathy, tubulointerstitial fibrosis, and systemic inflammation, activating various inflammatory transcription factors and cytokine production.²⁴