Incidence of Electrolyte Imbalances Following Traumatic Rhabdomyolysis: A Systematic Review and Meta-Analysis

Rhabdomyolysis, a medical condition caused by the destruction of striated muscle fibers, can have many etiologies, with the most common one being traumatic etiologies, that is, crushing injuries, heavy exertion, and being trapped under rubbles, and so forth. Rhabdomyolysis causes many complications, including acute kidney injury and different electrolyte imbalances, which later can cause cardiac dysrhythmia and even death as a result. This systematic review and meta-analysis investigate the incidence of imbalances of four important electrolytes among patients diagnosed with traumatic rhabdomyolysis. PubMed, Scopus, Web of Science, and Embase databases were searched for any article related to traumatic rhabdomyolysis using keywords related to the topic of our study, excluding case studies and case series. Relevant data were extracted from the included articles, and finally, a meta-analysis was performed on them to calculate the pooled incidence of each electrolyte imbalance. Collectively, 32 articles were included in our study (through the database and citation checking). The following were the pooled incidence of each electrolyte imbalance: hyperkalemia, 31% (95%CI 22%-41%); hypokalemia, 10% (95%CI 4%-17%); hypernatremia, 3% (95%CI 0%-8%); hyponatremia, 23% (95%CI 7%-44%); hypercalcemia, 0% (95%CI 0%-1%); hypocalcemia, 57% (95%CI: 22%-88%); hyperphosphatemia, 33% (95%CI 11%-59%); hypophosphatemia, 4% (95%CI 0%-16%). According to the meta-analyses, the rate of hyperkalemia, hyponatremia, hypocalcemia, and hyperphosphatemia is higher than their counterpart in patients diagnosed with traumatic rhabdomyolysis.


Introduction And Background
Rhabdomyolysis, first described by Dr. Bywaters, involves striated muscle injury, which results in the release of cell contents into the bloodstream [1,2].The incidence of rhabdomyolysis in the United States is estimated to be around 26,000 new cases per year, although the exact frequency is unknown [3].Rhabdomyolysis has many causes, and among the acquired causes, traumatic rhabdomyolysis is the most common [1,2,[4][5][6].
The typical symptoms of rhabdomyolysis, regardless of its cause, include muscular weakness, myalgia, swelling, tenderness, stiffness over the affected area, tea-colored urine, oliguria, or even anuria [7].Upon destruction of myocytes, certain substances such as myoglobin, an iron-containing molecule, and intracellular electrolytes may be released.The release of intracellular electrolytes can cause electrolyte imbalances [2] such as hyperkalemia, hypocalcemia, hyperphosphatemia, and sodium imbalances in these patients [8].Hyperkalemia and hypocalcemia, in particular, can be life-threatening due to their impact on the cardiac conductive system and cause dysrhythmias and even cardiac arrest [5,8].It is reported that necrosis of 100 grams of muscle can increase serum potassium levels by up to 1 mg/dL [5].
Various studies have reported the incidence of electrolyte imbalances among patients diagnosed with traumatic rhabdomyolysis; however, no meta-analysis or systematic review has been conducted on this issue.In this study, we aim to present a systematic review and meta-analysis to determine the incidence of electrolyte imbalances that have been reported to be possible in patients diagnosed with traumatic rhabdomyolysis.

Selection Criteria and Definitions
The primary and secondary screenings were done independently by MAS and AJK, and conflicts were solved by discussion.Rayyan AI tool for screening was used for primary screening [10]; using this tool, authors reviewed the title and abstract of every record that our search yielded.In the secondary screening phase of the study, the full text of the articles was retrieved and reviewed thoroughly.Every study on the subject of traumatic rhabdomyolysis, crush syndrome, and crush injury in which the authors reported the number of patients with any electrolyte imbalance was included.Case series, case studies, articles on rhabdomyolysis with any cause other than trauma, and articles in which the number of patients with electrolyte imbalance wasn't reported were excluded.Following screening, duplicate articles and articles that reported findings from a shared sample were excluded.Rhabdomyolysis was defined as patients having a history of muscle injury accompanied by elevated creatine kinase (CK) level; mild rhabdomyolysis was described as having a blood creatine phosphokinase (CPK) of 300-1000 IU/L on the first day of admission, moderate rhabdomyolysis (crush injury) was defined as having blood CKP level above 1000 IU/L, crush syndrome was defined as having blood raised CPK level accompanied with systemic complication (acute kidney injury (AKI), sepsis, organ failure or respiratory failure) [7].Normal levels for each ion are as follows: serum sodium 135-145 mEq/dL, serum potassium 3.5-5.5 mEq/dL, serum calcium 8.6-10.3mEq/dL, and serum phosphate 2.5-4.5 mEq/dL [11,12].

Quality Assessment
MAS and AJK independently assessed the quality of the included articles using a modified JBI (Joanna Briggs Institute) critical appraisal tool for prevalence studies [13].The JBI critical appraisal tool questionnaire has nine questions, but we didn't include questions 3, 7, and 8.The reasons for excluding these questions from our assessment and the answers to each question are available in the Appendices.The quality assessment results are available in the Appendices.

Data Extraction
MAS and AJK used a predefined Excel sheet (Microsoft Corporation, Redmond, Washington, United States) to extract data independently.The data extracted were the authors, year of publication, cause of rhabdomyolysis, patient demographic, sample size and the number of patients diagnosed with any electrolyte imbalance, time spent under rubble (in case of earthquake), sampling method, mean blood urea nitrogen (BUN) and creatinine (Cr), and AKI presence.

Statistical Analysis
We did all eight meta-analyses using Stata Statistical Software: Release 18 (2023; StataCorp LLC, College Station, Texas, United States).Based on recently published literature, to perform a meta-analysis of single proportions (prevalence meta-analysis), it is preferred to use transformed data; for this purpose, we opted for the Freeman-Tukey Double Arcsine transformation method [14].Using this method, we transformed raw extracted incidence data into usable effect sizes and calculated corresponding 95%CIs for each study.After preparing our meta-data, we performed meta-analyses using the random effect model (DerSimonian-Laird method) and finally reported back-transformed proportion as pooled incidence for each electrolyte imbalance (Inverse Freeman-Tukey and Clopper-Pearson exact CI).

Results
As shown in Figure 1, our review included 32 records in total.All included studies were retrospective descriptive studies, and their characteristics are shown in Table 1.The sampling method used in all of these articles was the consecutive method.In the following sections, the results of our meta-analysis are presented.

Potassium Imbalance in Patients Diagnosed With Traumatic Rhabdomyolysis
After conducting our search and screening, we found 28 articles that reported the exact number of hyperkalemic patients, while 13 articles reported the number of hypokalemic patients within the studied sample (Tables 2, 3).

Sodium Imbalance in Patients Diagnosed With Traumatic Rhabdomyolysis
After database search and screening, six articles were found to report the exact number of hypernatremic patients and six articles were found to convey the exact number of hyponatremic patients among their studied samples (Tables 4, 5).

Hypernatremia Incidence
Among the articles in which the number of hypernatremic patients was reported, the cause for rhabdomyolysis was heavy exertion in two of them [19,43], and in three of them, the cause of rhabdomyolysis was being trapped under rubble after an earthquake [24,28,30].In all of these studies, serum sodium level was checked on the admission day except for one article.In total, 1585 patients were included in our analysis through these studies.The pooled incidence of hypernatremia among patients with traumatic rhabdomyolysis was calculated to be at 3% (95%CI: 0.00-0.08,heterogeneity I2:89.96%)(Figure 4).References: [19,20,24,28,30,43] Hyponatremia Incidence Six articles reported the number of rhabdomyolysis patients diagnosed with hyponatremia [19,20,24,28,30,43].Three studied traumatic rhabdomyolysis caused by being trapped under rubble after an earthquake [24,28,30], and two articles studied patients with exertional traumatic rhabdomyolysis [19,43].In total, 1585 patients were included in our meta-analysis through the included articles.The pooled incidence of hyponatremia in traumatic rhabdomyolysis patients was calculated to be 23% (95%CI: 0.07-0.43,heterogeneity I2:97.95%)(Figure 5).

Discussion
This review study aimed to investigate the incidence of electrolyte imbalances in traumatic rhabdomyolysis patients.For this purpose, we conducted a systematic review and meta-analysis of previously published original articles, and to the best of our knowledge, this is the first systematic review and meta-analysis that tried to find the incidence of such complications.For the readers' convenience, this section is also divided into four categories, each representing one electrolyte imbalance.

Potassium Imbalances (Hyperkalemia and Hypokalemia)
The incidence of hyperkalemia in patients with traumatic rhabdomyolysis was found to be 31% (95%CI: 22%-41%, heterogeneity I2:97.64%).The incidence of hypokalemia among these patients was 10% (95%CI 4%-17%, heterogeneity I2 94.3%).The high degree of heterogeneity among studies included in prevalence metaanalysis has been investigated in many articles; Migliavaca et al. reviewed 134 prevalence meta-analysis articles and found that a high degree of heterogeneity is usual in such studies [14].High I2 does not necessarily translate into true high heterogeneity among the included articles; the median of I2 of these 134 articles was 96.6% [14].Authors have also suggested that the best way to interpret prevalence data is to discuss and explain the results with regard to what was being expected before conducting the analysis and also account for all the articles that had the highest deviation from the calculated pooled prevalence, so we tried to discuss and explain the results with this rationale.
The higher incidence of hyperkalemia among these patients compared to hypokalemia is aligned with and can be justified according to the pathogenesis of rhabdomyolysis, the process in which contents of myocytes such as potassium and phosphorus get released into the bloodstream [2,6].Among the included articles, four articles reported a lower number of hyperkalemic patients comparatively [19,22,23,43]; three of these articles were about traumatic rhabdomyolysis due to heavy exertion [19,22,43].Many articles state that profuse sweating during heavy exercise without replacing the lost fluid may lead to hypokalemia since electrolytes are being excreted with sweating.It is only reasonable to expect a lower incidence of hyperkalemia in this situation.One study found that the incidence of hypokalemia in a 116-patient cohort increased after exertion to 21% [47].One of the main reasons for this occurrence is that following exertion, due to intravascular loss, the Renin-Aldosterine-angiotensin axis gets activated, causing kidneys to increase sodium reabsorption in exchange for increased potassium excretion.This mechanism eventually leads to a decrease in serum potassium, which can be an excuse for the low number of hyperkalemic patients in these three articles [5].

Stewart et al.'s study that investigated the incidence of hyperkalemia among victims of the Afghanistan and
Iraq wars is another one in which the number of hyperkalemic patients reported was lower compared to pooled incidence [23].In this study, several causes may have led to a low reported number of hyperkalemia patients.First, they defined hyperkalemia as having a serum potassium level of more than 6 mEq/dL instead of a widely used 5.5 mEq/dL cut-off.Secondly, they only investigated the victims who could survive long enough to make it to the hospital, so there may have been patients who died and were hyperkalemic.Based on the study design, when victims were being taken to the hospital in Germany (from Iraq or Afghanistan), they may have received initial therapy if they had had any signs of electrolyte imbalance.Since they reported the serum potassium level obtained within three days of the victim's hospital admission, electrolyte imbalances may have been corrected due to fluid therapy before blood tests.
Among the studies, one by An [46]  hyperkalemic patients.The authors of these two studies investigated serum potassium levels of traumatic rhabdomyolysis patients diagnosed with crush syndrome and AKI, and since AKI can itself lead to hyperkalemia, the high number of hyperkalemic patients can contribute to this.Furthermore, Guner and Oncu reported the highest recorded serum potassium levels in these patients during their hospital stay [27].
The incidence of hypokalemia in traumatic rhabdomyolysis after conducting a meta-analysis was found to be 8% (95%CI 1%-18%, heterogeneity I2:98.12%).According to the hypokalemia incidence meta-analysis forest plot diagram, Mao et al.'s study reported the highest number of hypokalemic patients [19].They studied patients who developed traumatic rhabdomyolysis after severe exertion.As mentioned earlier, we can witness the loss of electrolytes such as potassium and other ions due to isotonic water loss.Furthermore, after conducting a leave-one-out meta-analysis, if this study gets omitted, the pooled incidence will be 3%, indicating that it had the most effect on our analysis.

Sodium Imbalances (Hypernatremia and Hyponatremia)
incidence of hypernatremia in traumatic rhabdomyolysis patients was 3% (95%CI 0%-8%, heterogeneity I2:89.96).The incidence of hyponatremia in these patients was 23% (95%CI 7%-43%, heterogeneity I2:97.95).As for the low reported number of hypernatremic patients and, accordingly, rare encounters of physicians with hypernatremia in traumatic rhabdomyolysis patients, there haven't been many articles explaining how rhabdomyolysis can cause hypernatremia; however, according to forest plot of hypernatremia incidence, Safari et al. [24] and Zhang et al. [28] reported the highest number of hypernatremia among studied patients.In both articles, the authors studied patients who developed rhabdomyolysis after being trapped under rubble due to an earthquake.In this situation, patients may be under rubble for a long time before they get rescued and may lose water (insensible water loss).They also may be bleeding, which may eventually lead to vasopressin secretion (some studies have stated that in these situations, there is stress-induced secretion of vasopressin), which may cause hypernatremia [24].In contrast, there are multiple explanations and reasons for hyponatremia in traumatic rhabdomyolysis.In rhabdomyolysis following myocyte damage, cell membrane functionality gets disrupted, resulting in an influx of sodium ions into cells, which draws water in (third-spacing) [5].On the other hand, the stress of being trapped under rubble promotes vasopressin secretion, which enhances water resorption in the kidneys.Above all, myoglobin toxicity in kidneys may cause acute renal failure, leading to water overload due to the kidney's inability to excrete water.All of the mentioned reasons may eventually lead to hyponatremia.With all that in mind, two of the included studies reported a lower incidence of hyponatremia among their studied population (Sinert et al. [43] and Mao et al. [19]).The cause of rhabdomyolysis in both of these studies was heavy exertion.We can assume muscle injury isn't as severe in these populations as it is in patients with multiple limb injuries due to being trapped under rubble, so we can conclude less severe trauma may cause less severe complications as well since injured muscle mass directly influences the amount of third-spacing [48].

Calcium Imbalances (Hypercalcemia and Hypocalcemia)
The incidence of hypercalcemia among the patients was found to be 0% (95%CI 0%-1%, heterogeneity I2:48.37%).However, the incidence of hypocalcemia was quite high at 57% (95%CI 22%-88%, heterogeneity I2:99.45%).Medical literature provides several explanations for hypocalcemia in rhabdomyolysis patients, especially during the early stages of the disease.Firstly, the damage inflicted on muscle cell membranes (sarcolemma) causes a loss of cell membrane selective permeability, and calcium ions influx into cells, leading to a decrease in serum calcium level.Secondly, phosphate ions leak into the extracellular space, which binds to free calcium ions, augmenting renal calcium excretion.Thirdly, free calcium can bind to phosphates in damaged muscle tissue and deposit in that area.Fourthly, due to probable AKI, the production of active vitamin D3 may be interrupted, leading to decreased renal calcium reabsorption.Finally, some studies suggest that bone response to parathyroid hormone is altered in these patients, which may further worsen hypocalcemia.Of the articles included, the studies by Sinert et al. [43] and Lim et al. [15] reported the lowest number of hypocalcemic patients.This can be attributed to the fact that the degree of hypocalcemia in patients with rhabdomyolysis is closely linked to the amount of damaged muscle tissue.The studies mentioned showed that the cause of traumatic rhabdomyolysis in these patients was excessive exertion, which means that it is logical to have a lower number of hypocalcemic patients compared to other causes of traumatic rhabdomyolysis since the total injured muscle is usually less [2,5,7].

Phosphate Imbalances (Hyperphosphatemia and Hypophosphatemia)
Among investigated electrolyte imbalances, the number of patients diagnosed with phosphate imbalance was the lowest.With that being said, the incidence of hyperphosphatemia was 33% (95%CI 11%-59%, heterogeneity I2:97.6%) and the incidence of hypophosphatemia among these patients was 4% (95%CI 0%-16%, heterogeneity I2:88.73%).The pathophysiological mechanism behind this disease can justify the higher incidence of hyperphosphatemia among patients diagnosed with traumatic rhabdomyolysis since phosphate is an intracellular ion (intracellular anion).Thus, upon muscular damage, logically, it gets released into the stream, raising serum phosphate levels [5].
To sum up, hyperkalemia, hyponatremia, hypocalcemia, and hyperphosphatemia are more common among traumatic rhabdomyolysis patients.However, diagnosing traumatic rhabdomyolysis is not straightforward, as there is no agreed-upon diagnostic method.Different CPK cut-offs were used in different studies (500, 1000, and 5000), and some physicians relied on clinical symptoms to diagnose rhabdomyolysis.Additionally, various definitions of electrolyte imbalances were used, and not all patients could be investigated due to the emergency nature of the disease.Despite these limitations, we made an effort to be as inclusive and comprehensive as possible by reviewing all relevant articles

Limitations
It is important to note that our study has a few limitations.Firstly, during our primary review, we found that many studies reported the mean serum value of electrolytes for patients instead of the number of patients with imbalanced electrolyte levels.This limited the number of articles we could include in our analysis.Secondly, we were unable to include any prospective studies in our analysis because there were none on traumatic rhabdomyolysis, likely due to the urgent nature of the condition.Another limitation is that some of the included studies had small sample sizes, which can result in high heterogeneity and CIs.This issue is to be expected, as the authors of these studies did their best to include as many patients as possible within the limited resources of an emergency setting.Additionally, some patients with mild injuries may not have been evaluated or tested for electrolyte imbalances and, hence, were not included in the study.This could explain the smaller sample sizes in some of the articles.

Conclusions
Our meta-analyses and reviews have shown that there is a logical correlation between electrolyte imbalances and traumatic rhabdomyolysis in patients.It has been observed that certain electrolyte imbalances are more prevalent in patients diagnosed with traumatic rhabdomyolysis in the early stages of the disease.This has been attributed to the fact that patients were tested during the early phase of their disease in most of the studies.The most common electrolyte imbalances in these patients include hypocalcemia (57%), hyperkalemia (31%), hyperphosphatemia (33%), and hyponatremia (23%).Conversely, electrolyte imbalances such as hypokalemia (10%), hypernatremia (3%), hypophosphatemia (4%), and hypercalcemia (in the early stages) (0%) are less prevalent and almost rare to encounter.
It is important to note that traumatic rhabdomyolysis caused by being trapped under the rubble is much more severe than traumatic rhabdomyolysis caused by exertion.Therefore, electrolyte imbalances were observed to be less common among patients who developed traumatic rhabdomyolysis after a session of heavy exertion.This is because the occurrence of complications of diseases is directly related to the severity of diseases.

JBI critical appraisal checklist for studies reporting prevalence data
Note: Questions 3, 7, and 8 were not utilized Question 1: Was the sample frame appropriate to address the target population?Patients diagnosed with traumatic rhabdomyolysis (of any etiology), crush syndrome, and crush injury Question 2: Were study participants sampled in an appropriate way?The method used for sampling should be census or consecutive Question 3: Was the sample size adequate?Given the emergency nature of the disease, we didn't incorporate this question in our risk of bias assessment, nevertheless, we excluded articles that included less than 10 patients Question 4: Were the study subjects and the setting described in detail?Age, sex, cause of rhabdomyolysis, and the country should be stated Question 5: Was the data analysis conducted with sufficient coverage of the identified sample?
Question 6: Were valid methods used for the identification of the condition?

FIGURE 1 :
FIGURE 1: Flowchart of selection process based on Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines.

FIGURE 4 :
FIGURE 4: Meta-analysis on rate of hypernatremia in studies including patients diagnosed with traumatic rhabdomyolysis.

FIGURE 6 :
FIGURE 6: Meta-analysis on rate of hypercalcemia in studies including patients diagnosed with traumatic rhabdomyolysis.

FIGURE 8 :FIGURE 9 :
FIGURE 8: Meta-analysis on rate of hyperphosphatemia in studies including patients diagnosed with traumatic rhabdomyolysis.

TABLE 1 : Characteristics of included studies
N/M: not mentioned, RD: retrospective descriptive study

TABLE 3 : Articles reporting the number of hypokalemic patients among traumatic rhabdomyolysis patients
# : number of hypernatremic patients TUR: trapped under rubble; HE: heavy exercise

TABLE 5 : Articles reporting the number of hyponatremic patients among traumatic rhabdomyolysis patients
# : number of hyponatremic patients TUR: trapped under rubble; HE: heavy exercise; HS: heat stroke

TABLE 7 : Articles reporting the number of hypocalcemic patients among traumatic rhabdomyolysis patients
# : number of hypocalcemic patients TUR: trapped under rubble; HE: heavy exercise; HS: heat stroke

TABLE 9 : Articles reporting the number of hyperphosphatemic patients among traumatic rhabdomyolysis patients
# : number of hyperphosphatemic patients TUR: trapped under rubble; HE: heavy exercise

TABLE 11 : Results of risk-of-bias assessment
Question 1: appropriate sample frame, Question 2: sampling method, Question 4: study subjects' description, Question 5: coverage of the identified sample, Question 6: valid method used in diagnosis of rhabdomyolysis, Question 6*: valid method used in diagnosis of electrolyte imbalance, Question 9: adequate response rate.
5 mEq/dL, Serum sodium normal range 135-145 mEq/dL, Serum calcium normal range 8.6-10.3mEq/dL, Serum phosphate normal range 2.5-4.5 mEq/dL Question 7: Was the condition measured in a standard, reliable way for all participants?Overlap with question 9 (was not utilized) Question 8: Was there appropriate statistical analysis?Since we just extracted the number of patients diagnosed with electrolyte imbalance and the total number of patients, this question wasn't applicable.Question 9: Was the response rate adequate, and if not, was the low response rate managed appropriately?