Introduction

Rhabdomyolysis is a medical condition characterized by the breakdown of skeletal muscle tissue, leading to the release of intracellular components such as myoglobin, creatine kinase (CK), lactate dehydrogenase (LDH), and electrolytes into the bloodstream [1-3]. This process can trigger systemic complications, ranging from asymptomatic enzyme elevation to life-threatening conditions, including severe electrolyte disturbances, disseminated intravascular coagulation (DIC), and acute kidney injury (AKI) [4-6].

Muscle fiber breakdown results from direct sarcolemmal injury or ATP depletion, which leads to increased intracellular calcium, activation of proteases and phospholipases, and eventual myocyte necrosis [4, 7]. Myoglobin, which is freely filtered by the glomerulus, can precipitate in renal tubules and exert direct cytotoxic effects, contributing to AKI. Additional risk factors for kidney injury include hypovolemia, renal ischemia, and uric acid crystallization, particularly in exertional or heat-induced rhabdomyolysis [6, 8-10].

The etiology of rhabdomyolysis is diverse. Traumatic causes include crush injuries, prolonged immobilization, heavy exertion, and events such as earthquakes [11-13]. Non-traumatic causes encompass medications (e.g., statins), illicit drugs, infections, and metabolic or genetic disorders [3, 4, 8]. Certain populations, including men, African Americans, pediatric patients, and individuals with underlying medical conditions, are at higher risk [3, 8]. Common complications include electrolyte imbalances such as hyperkalemia, hyponatremia, hypocalcemia, and hyperphosphatemia, which are particularly prevalent in traumatic rhabdomyolysis [13].

Diagnosis is primarily laboratory-based, with key markers including elevated serum CK (>5× the upper limit of normal), myoglobin, LDH, aspartate aminotransferase (AST), and potassium; while urinary myoglobin may provide additional evidence [1, 2]. Early recognition and prompt treatment are critical to prevent AKI and other complications. The cornerstone of management is aggressive intravenous fluid resuscitation with isotonic crystalloids to maintain adequate urine output [1, 2, 10]. Although sodium bicarbonate and mannitol have been proposed to prevent kidney injury, evidence supporting their routine use remains limited and controversial [1, 2, 10].

Overall, rhabdomyolysis has a favorable prognosis with early recognition and treatment. However, the development of AKI significantly worsens outcomes, highlighting the importance of timely intervention and careful monitoring [1, 4].

To date, no study has provided definitive evidence that adding sodium bicarbonate to fluid therapy is superior to fluid therapy alone. Given the inconclusive nature of existing literature and the lack of comprehensive analyses, this systematic review and meta-analysis was conducted to determine the role of urine alkalinization in preventing rhabdomyolysis-induced AKI and the need for dialysis.

Materials and Methods

This systematic review and meta-analysis was conducted in accordance with the PRISMA guidelines [14]. The study protocol was registered in PROSPERO (registration number CRD42024502360).

A comprehensive literature search was performed on January 21, 2024, across four databases, including MEDLINE/Pubmed, Scopus, Web of Science, and Embase, to ensure the inclusion of all available relevant research. Key search terms included “rhabdomyolysis”, “crush injury”, “urine alkalization”, “sodium bicarbonate”, and “management”. The complete search strategy for each database is provided in the supplementary data. No time or language restrictions were applied to maximize the scope of the results.

After the search, duplicates were removed using EndNote software (version 20). Two reviewers (AJK and MAS) conducted an initial screening of titles and abstracts against the study eligibility criteria. Irrelevant records were excluded, and any conflicts were resolved through discussion. The same two reviewers then independently performed a full-text assessment of the remaining articles. Studies that did not meet the inclusion criteria were excluded, and any discrepancies were resolved via discussion. Forward and backward citation tracking was performed during the full-text screening; however, no additional relevant articles were identified.

The risk of bias for each included study was independently assessed by the reviewers using the ROBINS-I tool [15]. Any differences in opinion were resolved through discussion. Studies with a critical risk of bias were excluded from the final meta-analysis.

Inclusion and Exclusion Criteria

All relevant cohort studies, clinical trials, and case-control studies with appropriate populations, interventions, controls, and outcomes were included. Case reports, case series, animal studies, and review studies were excluded.

The specific characteristics of the population, intervention group, control group, and outcomes are detailed in the following section.

-Population: Adult patients (over 18 years of age) with rhabdomyolysis, irrespective of the cause.

-Intervention: Patients who received urine-alkalizing agents (e.g., sodium bicarbonate or acetazolamide) in addition to fluid therapy. The dosage and mode of administration were not restricted.

-Control: Patients who received fluid therapy alone, without any urine-alkalizing agents.

-Outcomes: Acute renal failure (ARF), AKI, and the need for dialysis.

The ROBINS-I tool was used to assess the risk of bias (ROB) in the included studies. Two reviewers (AJK and MAS) conducted the assessment independently, and any conflicts were resolved through discussion. Studies with a critical risk of bias were excluded. This tool assessed the risk of bias in non-randomized studies of interventions (NRSI) across seven domains. The first three domains differ between NRSI and randomized trials, as randomization protects against biases that occur before the intervention begins. The last four domains had considerable overlap in bias assessment for both NRSI and randomized trials.

The meta-analysis was performed using Stata software (version 17), applying a random-effects model with the DerSimonian‒Laird method. Three outcomes were investigated, and a meta-analysis was conducted for any outcome reported by at least two studies. Heterogeneity was assessed using the Chi squared test and was reported as I² statistic. According to the Cochrane Handbook, there was no need to evaluate publication bias due to the small number of included studies [16].

A sensitivity analysis was performed using the leave-one-out method.

Results

The systematic search initially identified 9,230 articles. After the removal of 1,858 duplicates, 7372 records underwent initial screening based on their titles and abstracts. Following the primary screening, 12 articles were deemed eligible for a full-text review. During the secondary screening, six studies were excluded for the following reasons: one study measured different outcomes, four had significant study design errors, and the full text of one study could not be retrieved. This process resulted in six studies being considered for inclusion (Table 1). Following a risk of bias assessment, one study with a critical risk of bias was excluded, leaving five studies to be included in the final meta-analysis (Figure 1).

Fig. 1. PRISMA flowchart of the included studies

Risk of Bias Assessment

The risk of bias for the six shortlisted studies was assessed using the ROBINS-I tool. The assessment revealed that three studies had a serious risk of bias, and two studies had a moderate risk. One study was judged to have a critical risk of bias and was consequently excluded from the final analysis (Table 2).

Sensitivity Analysis

A sensitivity analysis was conducted using the leave-one-out method across the various outcomes (Figure 2). The results for the dialysis outcome were sensitive to the exclusion of either the Brown or Kim studies. In contrast, no discernible sensitivity was observed for the other two outcomes. This pattern was anticipated, given the limited number of studies, as a small pool of included research increased the susceptibility of the overall results to the influence of individual studies.

Fig. 2. Sensitivity analysis of studies that reported acute kidney injury, need for hemodialysis, and acute renal failure.

Characteristics of the Included Studies

Table 3 provides a comprehensive summary of the characteristics and data from the five studies included in the meta-analysis. Sitzwohl et al., investigated the incidence of AKI and renal failure in 60 patients with a serum myoglobin above 2000 mol/L within 24 hours after trauma [17]. Chendrasekhar et al., performed a retrospective analysis of 23 patients who were entrapped for more than 30 minutes in motor vehicle accidents and had myoglobinuria [18]. Brown et al., reported the incidence of renal failure and the need for dialysis in 382 patients admitted to a trauma intensive care unit (ICU) with serum CK levels above 5000 U/L [19]. Homsi et al., reported acute renal failure in 24 ICU patients with serum CK levels above 5000 U/L [20]. Kim et al., investigated the incidence of AKI and the need for dialysis in 4,077 patients with serum CK levels above 1000 U/L [21].

Meta-Analysis

Odds ratios were used to assess the efficacy of adding urine alkalizing agents to fluid therapy for rhabdomyolysis by comparing the intervention and control groups (Figure 3). The results revealed that the intervention group did not exhibit a significant improvement in any of the measured outcomes compared to the control group. Specifically, statistical analysis indicated no significant differences between the groups for the need for dialysis (OR: 4.25; 95% CI: 0-3.8e⁺⁰⁷; p=0.25) or the occurrence of AKI (OR: 1.26; 95% CI: 0.86-1.84, p=0.36).

Fig. 3. Odds ratio and heterogeneity in comparing the effect of urine alkalinization with fluid therapy alone on the prevention of acute kidney injury, the need for hemodialysis, and acute renal failure in patients with rhabdomyolysis

Heterogeneity Analysis

Heterogeneity was examined using the Chi squared test, and the results are reported as the I² statistic (Figure 3). For the outcome of AKI, the I² value of 55.54% indicated moderate heterogeneity, which may stem from differences in population age, diverse underlying causes of rhabdomyolysis, various comorbidities, and an undisclosed duration of treatment initiation. For the need for dialysis, a substantial I² of 95.58% suggested significant heterogeneity, likely due to causes similar to those for AKI. In contrast, acute renal failure (ARF) exhibited an I² of 0%, indicating no notable heterogeneity. Due to the observed heterogeneity and the limited number of included studies (fewer than 10), a subgroup analysis was not performed, in accordance with the Cochrane Handbook recommendations [16].

Discussion

This study is the first systematic review and meta-analysis to specifically investigate the effect of urine alkalinization on preventing AKI in patients with rhabdomyolysis. To ensure a comprehensive review of the available literature, we developed an inclusive search strategy that did not apply time or language filters.

The utility of urine alkalinization for preventing AKI in rhabdomyolysis patients has remained uncertain in previous research. Some studies suggested a potential benefit. For instance, an animal study by Özgüç et al., indicated that a hypertonic saline-dextran solution could effectively prevent oxidant damage and restore tissue blood flow in experimental rhabdomyolysis. However, the same study noted that a combination of 0.9% saline, sodium bicarbonate, and mannitol seemed to be superior to hypertonic saline and dextran in reducing oxidant injury. They concluded that further investigation is required to understand the effects of solute overload and metabolic acidosis resulting from hypertonic saline-dextran resuscitation on renal function in this context [22]. Supporting a potential role in humans, a study by Nielsen et al., involving 77 patients with CK levels exceeding 10,000 U/L, concluded that supplementing fluid therapy with bicarbonate and mannitol helped to prevent acute renal dysfunction [23].

In contrast, other evidence disputed the benefit of urine alkalinization. One study concluded that there was no significant difference between urine alkalinization and fluid therapy for treating patients with rhabdomyolysis. In their case series, Tazmini et al., reported that urinary alkalization did not yield significantly different outcomes from fluid therapy alone in individuals with exercise-induced rhabdomyolysis [24].

Furthermore, some guidelines explicitly recommend against the practice. Kodadek et al., recommended against the use of bicarbonate and urine alkalinization. They concluded that, due to limitations in the available clinical studies—such as inadequate control groups, inconsistent outcome definitions, retrospective designs, and low statistical power—the use of sodium bicarbonate or diuretics for preventing AKI in patients with rhabdomyolysis is not recommended [2].

Previous systematic reviews concluded that the effectiveness of urine alkalinization remained uncertain. For instance, Manspeaker et al., highlighted that the efficacy of treating exertional rhabdomyolysis (ER) was unclear due to variations in study types and methodologies. They noted that intravenous fluid replacement, predominantly with normal saline, is the common practice to reduce CK levels and myoglobinuria, with sodium bicarbonate or chloride sometimes added as an adjunct [25]. Additionally, in another study, Somagutta et al., concluded that aggressive early volume resuscitation using normal saline was the cornerstone of rhabdomyolysis management. Based on their findings, they questioned the practical utility of sodium bicarbonate and mannitol and emphasized the need for more robust future research to inform definitive recommendations [26].

The risk of bias was assessed using the ROBINS-I tool, which is specifically designed for non-randomized studies. This was appropriate as none of the identified articles were large randomized clinical trials. Given the limited number of studies available, those with a moderate or serious risk of bias were included in the meta-analysis. However, any study with a critical risk of bias was excluded. It is important to note that a low risk of bias was not anticipated, given the non-randomized nature of all included studies. To enhance the generalizability of our findings, a random-effects meta-analysis model was employed. While the minimum recommended number of studies for such an analysis is five, it is crucial to acknowledge the limitations of this research. The most significant limitation is the small number of articles included. Consequently, the results of this meta-analysis should be interpreted with caution.

Several limitations must be considered when interpreting our findings. For each outcome that was investigated, a maximum of three studies were included in the meta-analysis, which restricted the statistical power and generalizability of the findings. Furthermore, the methodological rigor of the included studies varied. Only one study measured urine pH to confirm the effect of the intervention, while most others prescribed medication to alkalize the urine without verifying its efficacy. It is also important to note that the evidence is confined to intravenous sodium bicarbonate; other alkalinizing agents, such as acetazolamide, or other forms of administration, such as oral administration, were not examined.

Significant clinical heterogeneity was also present. The treatment protocols in the reviewed studies differed considerably in the volume and type of fluid therapy administered. Although the target urine output was relatively consistent, typically aiming for between 1 mL/Kg/min and 3 mg/Kg/h, the methods to achieve it varied. While fluid therapy was the cornerstone, some protocols included diuretics, such as mannitol or furosemide. The types of diuretics used were not uniform across studies, and crucially, most studies differentiated between those who received sodium bicarbonate alone and those who received it simultaneously with a diuretic. Additionally, the diagnostic methods for rhabdomyolysis itself were inconsistent. Given these limitations, further randomized clinical trials with well-defined populations and standardized protocols are necessary to definitively explore the impact of urine alkalinization on preventing renal failure in patients with rhabdomyolysis.

The interpretation of these findings must be approached with caution due to the limited number of studies available for the meta-analysis. Each outcome was investigated in a maximum of three studies, which restricted the generalizability of the results. A significant methodological limitation was the lack of consistent verification of the intervention’s effect; while one study assessed urine pH, it provided no details, and the other studies did not explore this aspect at all. Furthermore, the scope of this review was confined to intravenous sodium bicarbonate, leaving the effects of alternative alkalinizing agents, such as acetazolamide, or other routes of administration, such as the oral route, unexamined. Clinical heterogeneity was also substantial, as the studies employed varying criteria to define rhabdomyolysis, AKI, and ARF. Treatment protocols exhibited significant disparities in the volume and type of fluid therapy, and the diuretics used alongside bicarbonate were not consistent. Critically, most studies did not distinguish between patients who received sodium bicarbonate concurrently with diuretics and those who received bicarbonate alone.

According to this systematic review and meta-analysis, the co-administration of sodium bicarbonate with fluid therapy did not confer significant protection against AKI, ARF, or the need for dialysis in patients with rhabdomyolysis when compared to fluid therapy alone. Thus, we do not recommend the routine administration of sodium bicarbonate to these patients in the absence of a separate indication, such as metabolic acidosis. To establish more definitive evidence, future research should prioritize conducting large randomized clinical trials with well-defined patient populations.

Declaration

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Conflict of Interest: None declared.

Funding and support: None.

Authors’ Contribution: SS: Conceptualization, study design, searched the databases, screened the records for eligibility, assessed the quality of the studies, and data extraction; IN: Study design; MAS: Searched the databases, screened the records for eligibility, assessed the quality of the studies, and data extraction; AJK: Provided the primary draft, study design, searched the databases, screened the records for eligibility, assessed the quality of the studies, data extraction, data analyses, and supervision; MAS: Provided the primary draft; AS: Data analyses; SHA: Provided the primary draft. All the authors have read and approved the final version of the manuscript.

Acknowledgment: Not applicable.

Data availability: The data underlying this article are available in the article and its online supplementary material.