key: cord-0936898-fzfjxldq
authors: Mokhtari, Ava K.; Maurer, Lydia R.; Christensen, Mathias A.; Moheb, Mohamad El; Naar, Leon; Alser, Osaid; Gaitanidis, Apostolos; Langeveld, Kimberly; Kapoen, Carolijn; Breen, Kerry; Velmahos, George C.; Kaafarani, Haytham M.A.
title: Rhabdomyolysis in Severe COVID-19: male sex, high BMI, and prone positioning confer high risk
date: 2021-04-06
journal: J Surg Res
DOI: 10.1016/j.jss.2021.03.049
sha: c23b0ca6319e8a0205a1f7e469cffd7e84d7fa3e
doc_id: 936898
cord_uid: fzfjxldq

Background: Bedside experience and studies of critically ill patients with coronavirus disease 2019 (COVID-19) indicate COVID-19 to be a devastating multisystem disease. We aim to describe the incidence, associated variables, and outcomes of rhabdomyolysis in critically ill COVID-19 patients. Materials and Methods: Data for all critically ill adult patients (≥18 years old) admitted to the ICU at a large academic medical center with confirmed COVID-19 between March 13, 2020 and April 18, 2020 were prospectively collected. Patients with serum creatine kinase (CK) concentrations greater than 1000 U/L were diagnosed with rhabdomyolysis. Patients were further stratified as having moderate (serum CK concentration 1000-4999 U/L) or severe (serum CK concentration ≥5000 U/L) rhabdomyolysis. Univariate and multivariate analyses were performed to identify outcomes and variables associated with the development of rhabdomyolysis. Results: Of 235 critically ill COVID-19 patients, 114 (48.5%) met diagnostic criteria for rhabdomyolysis. Patients with rhabdomyolysis more often required mechanical ventilation (p-value<0.001), prone positioning (p-value<0.001), pharmacological paralysis (p-value<0.001), renal replacement therapy (p-value=0.010), and extracorporeal membrane oxygenation (ECMO) (p-value=0.025). They also had longer median ICU length of stay (LOS) (p-value<0.001) and hospital LOS (p-value<0.001). No difference in mortality was observed. Male sex, patients with morbid obesity, SOFA score, and prone positioning were independently associated with rhabdomyolysis. Conclusions: Nearly half of critically ill COVID-19 patients in our cohort met diagnostic criteria for rhabdomyolysis. Male sex, morbid obesity, SOFA score, and prone position were independently associated with rhabdomyolysis. Study Type: prognostic

Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) is an enveloped RNA Betacoronavirus that was first observed in China in December 2019. 1, 2 The majority of patients with confirmed SARS-CoV-2 only experience minor symptoms, but a subset of COVID-19 patients can progress to life threatening critical illness. [3] [4] [5] [6] While pulmonary manifestations of the disease are prevalent, front line clinicians are increasingly reporting bedside findings suggestive of systemic manifestations of COVID-19 infection, including neurologic, cardiac, gastrointestinal, hematologic, and renal complications. [7] [8] [9] [10] [11] [12] [13] Rhabdomyolysis is a complex disease ranging from asymptomatic illness with mild elevations in serum creatine kinase (CK) concentration to a severe illness characterized by electrolyte imbalances and acute kidney injury (AKI). 14, 15 A serum CK greater than 1000 U/L is diagnostic, and serum CK concentrations in the severe range (>5000 U/L) have been associated with increased risk for AKI. [15] [16] [17] [18] The incidence of AKI in patients with rhabdomyolysis is estimated to range between 10 and 50%. 17, [19] [20] [21] [22] Although rare, viral etiologies of rhabdomyolysis have been described. [23] [24] [25] [26] A case report characterized rhabdomyolysis associated with a previous Severe Acute Respiratory Syndrome (SARS) outbreak. 27 In addition, case reports describe atypical presentations of SARS-CoV-2 associated rhabdomyolysis in elderly patients. 26, [28] [29] [30] [31] [32] In this study, we report our experience with a high incidence of, and adverse outcomes for rhabdomyolysis in critically ill COVID-19 patients during the pandemic surge in Massachusetts, and investigate potential factors independently associated with developing rhabdomyolysis in this patient population.

All adult (≥18 years old) patients with confirmed SARS-CoV-2 infection via reverse transcriptase polymerase chain reaction (RT-PCR) testing of nasopharyngeal swabs and who were admitted to any of 13 pre-existent and surge Intensive Care Units (ICUs) at the largest academic medical center in New England, USA between March 13, 2020 and April 18, 2020 were included. All patients were prospectively followed until July 2, 2020.

A systematic medical record review was performed to collect patient demographics (e.g.

age, sex, race, ethnicity, insurance status), presenting symptoms (e.g. fever, shortness of breath, cough, diarrhea), comorbidities (e.g. hypertension, diabetes mellitus, chronic kidney disease) and severity of illness at ICU admission (e.g. Sequential Organ Failure Assessment or SOFA Score).

Rhabdomyolysis was defined as a serum CK concentration above 1000 U/L. The severity of rhabdomyolysis was categorized by serum CK concentration, with severe rhabdomyolysis defined as serum CK concentrations >5000 U/L. 14, 15, 22 The hospital course and outcome variables included were: the need for dialysis, the need for mechanical ventilation, total number of days on mechanical ventilation, prone positioning, pharmacologic paralysis, extracorporeal membrane oxygenation (ECMO), ICU length of stay (LOS), hospital LOS, systemic complications (e.g. thromboembolic, pulmonary, cardiac, gastronintestinal, renal, neurologic) and mortality. We also collected data on the specific treatment modalities for COVID-19 (e.g. hydroxychlroquine, azithromycin, steroids) and rhabdomyolysis (e.g. statin avoidance or discontinuation, fluid resuscitation, diuresis). times the baseline). 33 Chart review was conducted to identify those patients with AKI with secondary oliguria or anuria. Neurologic complications included stroke, delirium, and seizures.

Descriptive statistics were performed to compare baseline characteristics of rhabdomyolysis and non-rhabdomyolysis patients. Median and inter-quartile ranges (IQR) were recorded for continuous data, while categorical data were summarized using the incidence (actual number) (n) and percentages (cumulative incidence). Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables were compared using Pearson's chi-squared or Fisher's exact test. Univariate and multivariable analyses were performed to identify variables associated with the development of rhabdomyolysis and variables associated with developing AKI in patients with rhabdomyolysis. All covariates with p-values less than 0.2 in the univariate analyses were included in the logistic regression model. Odds ratios (OR) and 95% confidence intervals (CI) following multivariable analyses are reported. 

A sub-analysis was performed in order to determine factors associated with moderate and severe rhabdomyolysis. This was accomplished by first stratifying patients by severity of rhabdomyolysis using serum CK concentration as a surrogate marker for disease severity. Those individuals with a serum CK<1000 U/L were defined as not having rhabdomyolysis, patients with a serum CK concentration between 1000 U/L and 4999 U/L were defined as the "moderate" rhabdomyolysis cohort, and those patients with a serum CK concentration 5000 U/L were defined as the "severe" rhabdomyolysis cohort. An analysis of variance (ANOVA) was performed to characterize the demographic and in-hospital characteristics of these three groups.

A multinomial (polytomous) logistic regression was performed to characterize variables independently associated with moderate and/or severe rhabdomyolysis. Calculations of the relative risk ratios (RRR) were performed to estimate the strength of association between independent and dependent variables in this model.

A detailed review of this project was conducted by the institutional review board (IRB).

This study was granted a waiver for consent/authorization. Following an expedited review, this study was granted IRB approval.

Out of a total of 235 critically ill COVID-19 patients, 114 (48.5%) developed rhabdomyolysis, including 90 (79.0%) with moderate (1000-4999 U/L) peak serum CK concentrations, and 24 (21.0%) with severely elevated (>5000 U/L) peak serum CK concentrations. As of the last day of the study, 58 patients had died (24.7%) and 175 (74.5%) were discharged from the hospital; only 2 (0.9%) remained in the hospital on the floor. Table 1 compares the demographic characteristics of patients with and without rhabdomyolysis. Patients with rhabdomyolysis were younger, more often male, and had a higher body mass index (BMI kg/m 2 ). There was no significant difference between the two groups in terms of race, ethnicity, insurance status, smoking history, symptoms on presentation, or SOFA Scores. Patients with rhabdomyolysis also had similar comorbidities to those without rhabdomyolysis, except that they were less likely to have hypertension. Table 1 contains a summary of patient presenting symptoms, comorbid conditions, and median SOFA Score.

When examining admission CK levels, most rhabdomyolysis patients (81%) did not have a serum CK concentration that met minimum criteria for the diagnosis of rhabdomyolysis on admission to the hospital, but instead developed elevated serum CK concentrations later during their admission. The median admission serum CK concentration in patients who developed rhabdomyolysis was significantly higher than in those patients who did not develop rhabdomyolysis, and median peak serum CK concentrations were higher for patients with rhabdomyolysis. Table 2 summarizes admission and peak serum CK concentrations. The median hospital day that patients with rhabdomyolysis reached their peak serum CK concentration was hospital day 6 (3, 9) with the majority of patients reaching peak value by hospital day 7 (Table 2, Figure 1 ). While many patients had a return to a serum CK level below 1000 U/L within three days of peak serum CK concentration, the range of days required to return to normal concentrations was 1 to 23 days. Table 3 characterizes and compares the systemic complications described for patients with and without rhabdomyolysis. 

In the majority of rhabdomyolysis patients, the most common treatment or mitigation strategy was statin avoidance or discontinuation. Of 114 patients with rhabdomyolysis, 24 (21.1%) patients were never initiated on a statin, and 72 (63.2%) patients had their statin discontinued as a result of elevated serum CK concentrations. Fluid resuscitation was provided to 24 (21.1%) patients with rhabdomyolysis, and diuresis was initiated to maintain adequate urine output for 10 (8.8%) rhabdomyolysis patients. Specific treatment strategies for our COVID-19 rhabdomyolysis patient cohort are summarized in Table 3 . Table 4 shows the results of the multivariable analysis identifying variables independently associated with rhabdomyolysis. In summary, male sex, patients with morbid obesity, SOFA score, and prone positioning were independently associated with rhabdomyolysis.

Out of 29 patients who were male, morbidly obese and proned, 26 (89.7%) developed rhabdomyolysis. Supplemental Table 1 indicates all covariates included in the multivariable logistic regression. The results of model diagnostics can be found in Supplemental Table 2 Moderate and severe rhabdomyolysis were defined via serum CK cutoffs of 1000 U/L to 4999 U/L and greater than or equal to 5000 U/L, respectively. Overall, 90 patients were included in the "moderate" rhabdomyolysis cohort, and 24 patients met criteria for "severe" rhabdomyolysis. Following a multinomial logistic regression analysis, male sex, race, a BMI ≥35 kg/m 2 , SOFA score, and prone positioning were identified as variables statistically associated with moderate rhabdomyolysis. This sub-analysis also indicated that patients with a race of "other" (non-white/Asian/Black or African American/American Indian/Alaskan Native and unknown), a BMI ≥35 kg/m 2 , and an elevated SOFA score were independently associated with severe rhabdomyolysis. Prone positioning trended towards significance for being independently associated with severe rhabdomyolysis. Table 4 shows results of the multivariable analysis identifying variables independently associated with developing AKI in all patients diagnosed with AKI following peaking of their serum CK concentration. A sub-analysis of these 33 patients identified male sex as highly associated with AKI in this subpopulation. Supplemental Table 1 indicates all covariates included in the multivariable logistic regression.

To our knowledge, this is the first comprehensive study reporting on rhabdomyolysis in a large prospective cohort of critically ill COVID-19 patients. Nearly half of our patient population developed rhabdomyolysis. Male patients with morbid obesity and who were placed into prone positioning were significantly more likely to develop rhabdomyolysis. Whether rhabdomyolysis in our study was the result of critical illness per se, or was directly related to the COVID-19 infection itself remains unclear, warranting further studies. We also recognize that an additional diagnostic consideration in patients with elevated serum CK concentrations is viral myositis, which by itself is a known etiology of rhabdomyolysis. However, as the pandemic continues to dramatically unfold in many countries across the world and across many US states, we believe that sharing our experience could be helpful to front line health care providers taking care of critically ill COVID-19 patients.

Prone positioning is an important strategy used to increase alveolar recruitment and promote increased gas exchange and oxygenation in patients with ARDS. 34 Prone positioning is associated with decreased mortality in patients with severe ARDS, and as such early prone positioning is recommended for COVID-19 patients with ARDS and worsening hypoxemia. 35, 36 While our data does not examine the risks and benefits of prone positioning in this vulnerable patient population, it does suggest the need for close monitoring of CK levels in mechanically ventilated and proned COVID-19 patients, especially when other variables characterized as being independently associated with rhabdomyolysis are present, such as male sex and/or morbid obesity. This will allow for early identification and intervention for patients with rising CK levels. The interplay between sex, obesity, prone positioning and rhabdomyolysis warrants further investigation.

The most common etiologies of rhabdomyolysis, such as crush injuries, drug toxicity, extreme physical exertion, metabolic myopathies, crush syndromes (traumatic or from immobilization), viral infection, and electrolyte disorders, are often easily identifiable. 15, 19, 21, 37, 38 However, critically ill patients with confirmed COVID-19 have a wide spectrum of sequelae secondary to viral infection, including but not limited to coagulopathy, thrombotic events, hematologic complications, cardiac dysfunction, sepsis, shock, liver dysfunction, mesenteric ischemia, severe renal dysfunction, pulmonary dysfunction, and encephalopathy, that could have resulted in rhabdomyolysis. 7, 10, [39] [40] [41] [42] [43] The vast majority of patients critically ill with COVID-19 in the ICU were administered Propofol during their ICU admission, and although unlikely, Propofol Infusion Syndrome (PRIS) is a potential precipitant of rhabdomyolysis in our patient population.

Critical illness with numerous concomitant systemic manifestations, multiple medication administration, and high rates of pharmacologic paralysis make identification of a primary etiology for rhabdomyolysis in our cohort challenging; in fact, the etiology is most likely multifactorial. Additionally, fluid balance and the potential for inadequate resuscitation may be another complicating factor in the development of rhabdomyolysis in our cohort. However, the pathophysiology of COVID-19 remains incompletely elucidated, and as such, a direct impact of the SARS-CoV-2 virus on the musculoskeletal system cannot be definitely ruled out. To aid in the early identification, management, and mitigation of rhabdomyolysis, we recommend trending serum CK concentrations throughout ICU admission, particularly for patients with any one of the aforementioned variables found to be associated with rhabdomyolysis in our cohort of critically ill COVID-19 patients.

Our results suggest that the majority of patients did not present to the ED with rhabdomyolysis, but rather developed rhabdomyolysis during their ICU admission. Many of these patients had concomitant AKI. Multiple theories to explain AKI as a complication of rhabdomyolysis exist, including a direct toxic effect of myoglobin on tubular cells, tubular obstruction by myoglobin, or changes in glomerular filtration rate secondary to ischemic changes to the kidneys resulting from the release of vasoconstrictive mediators. 17, 44 In addition, some reports suggest that SARS-CoV-2 may cause direct damage to kidneys. Postmortem pathologic examination of kidney damage in 26 patients with severe COVID-19 characterized extensive acute tubular and endothelial injury with evidence of direct parenchymal, tubular, epithelial, and podocyte viral infection. 11 Another recent study by Naar et al reported that nearly 3 in 4 critically ill COVID-19 patients develop AKI during their ICU stay. 45 Their analysis also identified a significantly higher mortality rate in patients with AKI. In our study, the median hospital day of peak serum CK concentration was day six, while the median hospital day of AKI diagnosis was on the first day of hospitalization, suggesting that rhabdomyolysis is unlikely to be the sole or even the primary etiology behind AKI for the majority of patients. Still, nearly one third of rhabdomyolysis patients developed AKI after peaking of serum CK concentrations, and as such, early identification and management of rhabdomyolysis in COVID-19 patients may help prevent further decline in renal function, and potentially decrease AKI-related mortality. Close monitoring of renal specific laboratory values should be made in the male patient, as male sex was independently associated with AKI following rhabdomyolysis.

This study has a few limitations. First, this is a single institutional experience with potentially limited generalizability. Second, the use of serum CK concentration alone without additional confirmatory tests (e.g. myoglobin in urine, muscle biopsy) to diagnose rhabdomyolysis may have led to overdiagnosis of rhabdomyolysis. Due to inconsistent and limited recordings of serum CK-MM (muscle breakdown) levels in this cohort, our capacity to confirm that elevated serum CK concentrations was secondary to skeletal muscle breakdown was not possible. Additionally, future investigations should focus on parsing out the potential role of fluid under-resuscitation in the development of rhabdomyolysis in critically ill COVID-19

patients. The occurrence of AKI in many patients prior to rhabdomyolysis limits our ability to clearly decipher the renal impairment that can be attributed to rhabdomyolysis. Future efforts should focus on characterizing the link between rhabdomyolysis and worsening renal impairment. Lastly, longer-term and post-ICU follow up for our cohort is a natural next-step, and we are planning to undertake additional chart review to capture these data to assess the long-term impact of rhabdomyolysis and AKI on renal function in critically-ill subjects who recover from COVID-19.

In this large cohort of critically ill COVID-19 patients, nearly half developed rhabdomyolysis. We found male patients who were obese and underwent prone positioning to have a particularly high incidence of rhabdomyolysis, warranting close observation and a low threshold for diagnostic consideration of rhabdomyolysis in this cohort. Additionally, we were able to characterize shared and unique variables associated with moderate and severe rhabdomyolysis in our cohort, including male sex, race, morbid obesity, SOFA score, and prone positioning. Further studies are warranted to confirm our findings, but healthcare providers on the front lines need to be aware of this complication in order to prevent it and mitigate its adverse effects. Table 1 . Demographic characterization, presenting symptomology, comorbidities, illness severity, treatment strategies, and hospital outcomes of patients with and without rhabdomyolysis Abbreviations: (1) interquartile range (IQR), (2) body mass index (kg/m 2 ) (BMI), (3) congestive heart failure (CHF), (4) chronic obstructive pulmonary disease (COPD), (5) Sequential Organ Failure Assessment Score (SOFA), (6) nonsteroidal anti-inflammatory drugs (NSAIDS), (7) extracorporeal membrane oxygenation (ECMO), (8) Intensive care unit (ICU), (9) length of stay (LOS) *SOFA Score was calculated at time of admission to the ICU Table 2 . Characterization of serum CK concentration and renal function in COVID-19 ICU patients Abbreviations: (1) creatine kinase (CK), (2) Inter-quartile range (IQR), (3) acute kidney injury (AKI) Table 3 . Implemented treatment strategies and hospital complications.

Abbreviations: (1) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), (2) Extracorporeal Membrane Oxygenation (ECMO) Table 4 . Adjusted multivariable analysis (logistic regression) for identification of variables independently associated with rhabdomyolysis and AKI. *Rhabdomyolysis multivariable analysis was performed on 235 patients to identify variables independently associated with rhabdomyolysis in this population. **AKI multivariable analysis was performed on 33 patients diagnosed with AKI following peaking of serum CK (U/L) concentration. Abbreviations: (1) body mass index (BMI), (2) sequential organ failure assessment (SOFA), (3) acute kidney injury (AKI)

Mohamad El Moheb: MELMOHEB@mgh

Osaid Alser: OALSER@mgh

Apostolos Gaitanidis: AGAITANIDIS@mgh

Velmahos: GVELMAHOS@mgh

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Rhabdomyolysis associated with acute renal failure in patients with severe acute respiratory syndrome: Severe Acute Respiratory Syndrome

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State

Gastrointestinal Complications in Critically Ill Patients with COVID-19

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19

Kidney involvement in COVID-19 and rationale for extracorporeal therapies

Multiorgan and Renal Tropism of SARS-CoV-2

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Is there a role for tissue plasminogen activator as a novel treatment for refractory COVID-19 associated acute respiratory distress syndrome?: J Trauma Acute Care Surg

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Beyond muscle destruction: a systematic review of rhabdomyolysis for clinical practice

Rhabdomyolysis: pathogenesis, diagnosis, and treatment

Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features

Factors Predictive of Acute Renal Failure in Rhabdomyolysis

Preventing Renal Failure in Patients with Rhabdomyolysis: Do Bicarbonate and Mannitol Make a Difference?

Rhabdomyolysis and Acute Kidney Injury

Pathogenesis and treatment of renal dysfunction in rhabdomyolysis

Rhabdomyolysis: an evaluation of 475 hospitalized patients

An observational study on rhabdomyolysis in the intensive care unit. Exploring its risk factors and main complication: acute kidney injury

Influenza A induced rhabdomyolysis resulting in extensive compartment syndrome

Rhabdomyolysis and lower extremity compartment syndrome due to influenza B virus

Acute Rhabdomyolysis and Renal Failure in HIV-Infected Patients: Risk Factors, Presentation, and Pathophysiology

Rhabdomyolysis in a Patient With Coronavirus Disease

Rhabdomyolysis associated with probable SARS

Weakness and elevated creatinine kinase as the initial presentation of coronavirus disease 2019 (COVID-19)

Rhabdomyolysis as Potential Late Complication Associated with COVID-19

Rhabdomyolysis as a manifestation of a severe case of COVID-19: A case report

Rhabdomyolysis as an initial presentation in a patient diagnosed with COVID-19

Rhabdomyolysis as the main manifestation of coronavirus disease 2019

Clinical Practice Guideline for Acute Kidney Injury (AKI) 2012. Acute Kidney Injury (AKI)

Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome

Prone Positioning in Severe Acute Respiratory Distress Syndrome

Treatment for severe acute respiratory distress syndrome from COVID-19

Bench-to-bedside Review: Rhabdomyolysis --An Overview for Clinicians

Management of acute kidney injury in patients with COVID-19

Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy. Cureus

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Liver injury in COVID-19: management and challenges

Coagulation abnormalities and thrombosis in patients with COVID-19

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

Acute renal failure and rhabdomyolysis

Acute Kidney Injury in Critically-Ill Patients With COVID-19: A Single-Center Experience of 206 Consecutive Patients

Authors declare no funding or conflicts of interest

0.035 *Rhabdomyolysis multivariable analysis was performed on 235 patients to identify variables independently associated with rhabdomyolysis in this population. **AKI multivariable analysis was performed on 33 patients diagnosed with AKI following peaking of serum CK (U/L) concentration. Abbreviations: (1) body mass index (BMI), (2) sequential organ failure assessment (SOFA), (3) acute kidney injury (AKI)