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Role of Bicarbonates and Mannitol in Rhabdomyolysis: A Comprehensive Review

Rhabdomyolysis is characterized by rapid muscle breakdown and release of intracellular muscle components into the circulation. Acute renal injury is the most common and fatal complication of rhabdomyolysis. The current literature emphasizes the importance of preventing rhabdomyolysis and finding the benefits of sodium bicarbonates and mannitol in its prevention. A PubMed database search for the keywords "Rhabdomyolysis," "Sodium bicarbonate use in rhabdomyolysis," "Mannitol use in rhabdomyolysis," and a Medical Subject Headings (MeSH) search using the keyword "Rhabdomyolysis; Acute Kidney Injury (Subheading-Prevention and control)" generated 10,005 articles overall. After a thorough application of inclusion/exclusion criteria, 37 relevant studies were selected for this literature study. This analysis demonstrates that aggressive early volume resuscitation with normal saline should continue being the principal focus of therapy, and the use of sodium bicarbonate and mannitol in practical situations is not entirely justified. This article also emphasizes the need for future research on this topic and provides recommendations for future research.


Introduction And Background
Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle constituents into the circulation [1]. Bywaters and Beall first reported it in four crush injury victims after excavating them from the rubble during the London bombing in 1941 [2]. They noticed that dark urine and brown pigmented casts similar to hemoglobin were deposited in the distal tubules of the victims, leading to significant renal impairment. The causes of rhabdomyolysis are multifactorial. The most common causes in adults are illicit drugs/toxins, alcohol abuse, medical drugs, trauma (crush injury), genetic defects, seizures, and metabolic disorders [3]. Acute kidney injury (AKI) is the most severe complication of rhabdomyolysis regardless of the etiology. The incidence ranges from 13% to 50%, depending on the clinical setting and diagnosing criteria [4]. In the Meijer et al. study, the mortality of patients who developed AKI was 59% vs. 22% in patients who did not develop AKI [5]. As exemplified by this study, early recognition of rhabdomyolysis and prevention of AKI should be the cornerstone of treatment.
Many studies have shown that progression to significant renal failure can be avoided via early and aggressive saline infusion [6]. The use of sodium bicarbonate and mannitol to deter the development of AKI in rhabdomyolysis is currently controversial. Some studies propose that patients benefit from sodium bicarbonate and mannitol infusions [7]. However, other recent studies suggest against their use to prevent myoglobinuric renal failure as there is little evidence other than from animal studies, retrospective observational studies, and case series to support their routine use [8,9].
This study's objective is to determine the optimal management and review the effectiveness of sodium bicarbonate and mannitol in the prevention of AKI following rhabdomyolysis. This study also aims to summarise the available evidence on this topic and provide recommendations according to current standards for practical guidelines.

Review Methods
Literature was searched in PubMed with parallel strategies based on Medical Subject Headings (MeSH) subheadings and regular keywords for data collection. Table 1 shows regular and MeSH keywords used for the literature search.   Table 2 shows the total number of articles after applying inclusion/exclusion criteria in the following order.  A single PubMed database search generated 10,005 articles overall. After applying the inclusion-exclusion criteria, only 1283 potentially relevant articles remained. After screening the abstracts of these articles, 120 studies were included in the final analyses as they met our study's title and objectives. Out of these, 37 studies were used as they provided full text and pertinent information for this review.

Complications
Cell destruction promotes leakage of intracellular components causing fatal complications. Immoderate potassium leakage leads to cardiac arrhythmias or cardiac arrest, whereas hypocalcemia is a result of calcium phosphate precipitation with calcification in the necrotic muscle [10][11][12][13][14][15][16][17]. The release of proteases and coagulating cascade from the damaged cell causes hepatic dysfunction and disseminated intravascular coagulation (DIC), respectively. Intracellular fluid accumulation and ischemic changes potentiate the rise in the intracompartmental pressure and cause compartment syndrome to be an early or late complication [11,14].

Pathogenesis of Myoglobin-Induced Acute Kidney Injury
The exact mechanism of AKI in rhabdomyolysis is complex and debatable with the growing evidence. Although the deposition of myoglobin in the renal tubules remains the main insult, the mechanism by which it occurs remains controversial [18].
Myoglobin appears in the urine only when the renal threshold of 0.5 to 1.5 mg of myoglobin per deciliter is exceeded and is grossly visible as reddish-brown (commonly referred to as "teacolored") urine when serum myoglobin levels reach 100 mg per deciliter [4]. Acidic urine and incremented uric acid in the urine can further complicate this effect by precipitating myoglobin upon interacting with Tamm-Horsfall protein, resulting in tubular casts formation and obstruction to urine flow [10]. Intratubular myoglobin, when degraded, releases reactive oxygen species and free radicals, causing direct ischemic tubular damage [10].
Recent studies demonstrate that in pathological conditions, myoglobin oxidized to ferryl state (Fe) exhibits peroxidase properties and leads to lipid peroxidation. Products of lipid peroxidation contribute to AKI by causing renal vasoconstriction, oxidative injury, and tissue damage [18,19]. The current evidence affirms that kidney failure is due to the collective effects of hypovolemia, aciduria, and direct cytotoxicity due to the accumulation of myoglobin [14,[18][19][20]. Many clinical factors like serum creatine kinase (CK), creatinine, potassium, Ca2+, and urine myoglobin level are valued to foretell the risk of acute renal failure (ARF), but there is no consensus on a single factor [14].

Sodium Bicarbonate
An acidic urine environment potentiates myoglobin-induced renal toxicity [10][11][12][13][14]. The basis behind the use of sodium bicarbonate is that it promotes alkalization of the urine and counteracts the process of heme pigment precipitation, thereby decreasing the direct pigment injury [13][14][15][16]. Urine alkalization is also useful in diminishing redox cycling and lipid peroxidation, thus preventing oxidative stress, tubular damage, and renal vasoconstriction [10,17]. Hence, it is believed that urine alkalization, optimizing the pH higher than 6.5, can prevent renal impairment [4]. On the contrary, the evidence is scarce that urine alkalization has a proven clinical benefit over standard saline resuscitation in these patients [6].
A well-observed side effect with bicarbonate therapy in the initial stages of treatment is hypocalcemia. It is also noted that when bicarbonates are used in decompensated respiratory patients or circulatory failure, they can cause hyperosmolar states and paradoxical intracellular acidosis [12,21]. However, no studies have compared it as standard therapy with saline resuscitation alone.

Mannitol
Mannitol is a rapidly acting osmotic diuretic that has many proposed benefits [22]. It works as a renal vasodilator improving glomerular filtration rate. This mechanism leads to diuresis to be beneficial in the excretion of excess myoglobin and the prevention of myoglobin cast formation [22][23][24][25][26]. Mannitol also acts as a free radical scavenger and has an antioxidant effect on renal parenchyma. While some initial studies suggested using mannitol in rhabdomyolysis, most of the evidence presenting mannitol's protective effect comes from animal studies [4]. Further, a few clinical trials and observational studies found no clinical benefit with mannitol [4]. Many studies have observed the paradoxical effect of mannitol as a renal vasoconstrictor when used in higher dosages (>200 g/day), causing osmotic nephrosis [10]. However, many authors support the use of mannitol in rhabdomyolysis-induced renal failure, especially in crush injury victims as mannitol decreases osmotic swelling and edema in the injured muscle cells and helps restore the skeletal muscle function [22,23]. They also recommend that mannitol be administered when saline infusions fail to improve a urine output of more than 300 ml/hr [23], and thus it is practical to initiate treatment with IV fluids and offer mannitol after assessing the urinary response. Frequent monitoring of plasma osmolality and the osmolal gap is needed during mannitol administration, and it should be halted when there is a significant rise in the osmolal gap (>55 mOsm/kg) [10].  and followed by urine alkalization and mannitol therapy [31]. In 2017, Nielsen et al. recognized a significant decrease in the development of acute renal failure of 26% vs. 70% (P=0.008) in patients with CK>10000 u/l with sodium bicarbonate and mannitol added to normal saline compared to patients with normal saline alone, respectively [35].

Why the Need for Revision?
The recent Neilsen et al. study highlights the importance of reassessment on this topic. There is an emerging need to address these topics forthwith, such as a specific clinical biomarker in categorizing rhabdomyolysis and assessing patients for their risk for AKI. The benefit of these agents catered to case specifics such as anuric patients should be evaluated [35]. Also, the appropriate timing for the initiation of therapy and specific parameters for the use of these agents should be determined. There is a demand and need for more multicenter randomized clinical trials to address these issues and provide more evidence. Future research can help practice an evidence-based approach to attain better outcomes and avoid opting for the use of these agents in regular clinical practice.

Limitations
Nonetheless, the findings of this study have to be seen in light of some limitations. Animal studies and literature published in languages other than English were not used in this review.

Conclusions
Rhabdomyolysis is clinically challenging to manage as many medical, social, and environmental factors can contribute to this condition. Acute kidney injury is a fatal insult following rhabdomyolysis, and early identification of the risk factors and interventions to prevention should be the center of treatment for high-risk patients. Considering the historical evidence and theoretical benefits of bicarbonates and mannitol in AKI, it is assumed that these agents are beneficial, which has led to their routine use in standard practice. However, there is ample evidence that these standards of practice need to be revisited. Aggressive early volume resuscitation with normal saline still should be the primary focus of treatment. The use of these agents as a single standard measure is discouraged as they are not superior to saline therapy, as shown by current evidence.