Rhabdomyolysis Research Articles

Resistance exercise and nutritional interventions for augmenting sarcopenia outcomes in chronic kidney disease: a narrative review.

Sarcopenia is an age‐related progressive muscle disease characterized by loss of muscle mass, muscle strength and physical performance with high prevalence in chronic kidney disease (CKD). CKD is associated with decreased muscle protein synthesis and muscle breakdown due to a number of factors including, the uremic inflammatory environment of the disease. CKD patients are highly sedentary and at risk of malnutrition which may exacerbate sarcopenia outcomes even further. Short and long‐term exercise and nutritional interventions have been studied and found to have some positive effects on sarcopenia measures in CKD. This narrative review summarized evidence between 2010 and 2020 of resistance exercise (RE) alone or combined with nutritional interventions for improving sarcopenia outcomes in CKD. Due to lack of CKD‐specific sarcopenia measures, the second European Working Group on Sarcopenia in Older People (EWGSOP2) definition has been used to guide the selection of the studies. The literature search identified 14 resistance exercise‐based studies and 5 nutrition plus RE interventional studies. Muscle strength outcomes were increased with longer intervention duration, intervention supervision, and high participant adherence. Data also suggested that CKD patients may require increased RE intensity and progressive loading to obtain detectable results in muscle mass. Unlike muscle strength and muscle mass, physical performance was readily improved by all types of exercise in long or short‐term interventions. Four studies used RE with high‐protein nutritional supplementation. These showed significant benefits on muscle strength and physical performance in dialysis patients while non‐significant results were found in muscle mass. More research is needed to confirm if a combination of RE and vitamin D supplementation could act synergistically to improve muscle strength in CKD. The current evidence on progressive RE for sarcopenia in CKD is encouraging; however, real‐life applications in clinical settings are still very limited. A multidisciplinary patient‐centred approach with regular follow‐up may be most beneficial due to the complexity of sarcopenia in CKD. Long‐term randomized control trials are needed to verify optimal RE prescription and explore safety and efficacy of other nutritional interventions in CKD.

CLINICAL RESEARCH: O.6 Pre-operative exercise and pyrexia as modifying factors in malignant hyperthermia

Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anaesthetics and succinylcholine (SC) characterized by hypercapnia, hypermetabolism and muscle breakdown. MH is commonly caused by mutations in RYR1, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between risk genotypes and actual MH incidence remains unexplained. We hypothesized that MH is a compound event, reflecting a synergistic effect of predisposing genotype, triggering anaesthetic, and exercise and/or pyrexia as modifying factors.

Anabolic effects of oral leucine-rich protein with and without β-hydroxybutyrate on muscle protein metabolism in a novel clinical model of systemic inflammation—a randomized crossover trial

β-lactoglobulin (BLG) stimulates muscle protein synthesis and β-hydroxybutyrate (BHB) inhibits muscle breakdown. Whether combining the 2 can additively attenuate disease-induced muscle loss is unknown. Based on previous observations of anticatabolic effects of protein and ketone bodies during inflammation, and using a novel model combining ongoing systemic inflammation, fasting, and immobilization, we tested whether the anticatabolic muscle response to oral amino acids is altered compared with control conditions, as well as whether coadministration of oral BHB and BLG further improves the muscle anabolic response. Muscle net balance (NBphe) was the primary outcome and intramyocellular signals were assessed. In a randomized crossover design, 8 young men underwent either preconditioning with LPS (prestudy day: 1 ng/kg, study day: 0.5 ng/kg) combined with a 36-h fast and bed rest to mimic catabolic inflammatory disease (CAT) or an overnight fast (control [CTR]) prior to isocaloric nutritional interventions on 3 occasions separated by ∼6 wk (range 42 to 83 d). NBphe increased similarly upon all conditions (interaction P=0.65). From comparable baseline rates, both Rdphe [muscle synthesis, median ratio (95% CI): 0.44 (0.23, 0.86) P=0.017] and Raphe [muscle breakdown, median ratio (95% CI): 0.46 (0.27, 0.78) P=0.005] decreased following BHB+BLG compared with BLG. BLG increased Rdphe more under CAT conditions compared with CTR (interaction P=0.02). CAT increased inflammation, energy expenditure, and lipid oxidation and decreased Rdphe and anabolic signaling [mammalian target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E-binding protein 1 (4EPB1) phosphorylation]. In contrast to our initial hypothesis, NBphe increased similarly following BLG during CAT and CTR conditions; CAT however, specifically stimulated the BLG-mediated increase in protein synthesis, whereas BHB coadministration did not affect NBphe, but distinctly dampened the BLG-induced increase in muscle amino acid fluxes thereby liberating circulating amino acids for anabolic actions elsewhere.

Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases.

Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases.

1679P A double-blind, placebo-controlled, randomized phase IIa trial, evaluating the effect of curcumin for the treatment of cancer anorexia-cachexia syndrome in patients with stage III-IV head and neck cancer (CurChexia)

Cancer anorexia-cachexia syndrome (CAS) is a significant comorbidity in all cancer patients that increase the mortality rate. Almost all head and neck cancer (HNC) patients suffered from this syndrome. CAS causes increased energy expenditure by increased systemic inflammation and decreased energy consumption due to anorexia. This leads to skeleton muscle breakdown and affects the quality of life. Nutritional interventions and cancer treatment are the mainstays to treat this situation. However, a vicious cycle causes CAS to persist, especially in HNC, where tumor location and its treatment interfere with nutritional intervention.

Two Types of Mouse Models for Sarcopenia Research: Senescence Acceleration and Genetic Modification Models.

Sarcopenia leads to loss of skeletal muscle mass, quality, and strength due to aging; it was recently given a disease code (International Classification of Diseases, Tenth Revision, Clinical Modification, M62.84). As a result, in recent years, sarcopenia-related research has increased. In addition, various studies seeking to prevent and treat sarcopenia by identifying the various mechanisms related to the reduction of skeletal muscle properties have been conducted. Previous studies have identified muscle synthesis and breakdown; investigating them has generated evidence for preventing and treating sarcopenia. Mouse models are still the most useful ones for determining mechanisms underlying sarcopenia through correlations and interventions involving specific genes and their phenotypes. Mouse models used to study sarcopenia often induce muscle atrophy by hindlimb unloading, denervation, or immobilization. Though it is less frequently used, the senescence-accelerated mouse can also be useful for sarcopenia research. Herein, we discuss cases where senescence-accelerated and genetically engineered mouse models were used in sarcopenia research and different perspectives to use them.

Symptoms and impacts of ambulatory nonsense mutation Duchenne muscular dystrophy: a qualitative study and the development of a patient-centred conceptual model

BackgroundDuchenne muscular dystrophy is a rare genetic neuromuscular disorder, which can result in early death due to disease progression. Ataluren is indicated for the treatment of nonsense mutation Duchenne muscular dystrophy, in ambulatory individuals aged two years and older. This study explored the symptoms and impacts of nonsense mutation Duchenne muscular dystrophy and experience with ataluren.MethodsQualitative interviews were conducted with caregivers in the UK. Interviews were conducted by telephone, were recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded.ResultsTen interviews were conducted with parents of individuals aged 4–19 years. Key symptoms included muscle weakness and muscle breakdown, which were associated with limitations in physical function and pain. These impacted individuals’ daily activities, social activities and emotional wellbeing. These concepts and relationships were illustrated in a conceptual model, along with positive and negative moderating factors. Experience with ataluren and changes since initiation with treatment were discussed.ConclusionIndividuals with nonsense mutation Duchenne muscular dystrophy experience a range of interrelated symptoms and functional issues which impact their broader health-related quality of life. Treatments which address this high unmet need have the potential to improve the health-related quality of life of these individuals.

Neonatal Life-Threatening Nonoliguric Hyperkalemia Under Therapeutic Hypothermia

To illustrate our experience with two cases of neonatal life-threatening hyperkalemia during therapeutic hypothermia (TH) despite a normal acid-base status, urine output, and preserved renal function. Clinical cases are presented from Pediatric Intensive Care Unit (PICU) admission to the onset of the hyperkalemia, with related complications and after resolution. Similar cases were not retrieved from a critical review of pertinent literature. Severe hyperkalemia pathophysiology and risk factors have been debated. Two full-term adequate for weight female neonates were admitted to PICU because of perinatal asphyxia who underwent TH. Prenatal history was completely uneventful, nor hereditary genetic conditions were reported; moreover, long-term follow-up ruled out any metabolic or renal disease. Despite an accurate evaluation of previous clinical series and literature on TH and perinatal asphyxia, these hyperkalemic episodes remain unexplained. The hypoxic-ischemic insult may affect multiple organs, mainly central nervous system, heart, lung, and kidneys; acute muscle breakdown and consequent rising of myoglobin may also have a precipitating role in acute kidney failure (AKF) and hyperkalemia. Electrolyte imbalance is a possible finding as a consequence of combined cell injury and AKF. In contrast, an isolated severe hyperkalemia is exceedingly rare in nonoliguric neonates.

The protective mechanism of Klotho gene-modified bone marrow mesenchymal stem cells on acute kidney injury induced by rhabdomyolysis.

BackgroundStudies have shown that the Klotho gene has tremendous potential for future therapeutic purposes in both acute and chronic kidney diseases (CKD). This study aimed to investigate the possible protective mechanisms of the Klotho gene against acute kidney injury (AKI) induced by rhabdomyolysis (RM).MethodsIn this study, bone marrow mesenchymal stem cells (BMSCs) were transfected with recombinant adenoviruses expressing the Klotho gene (BMSCs-Klotho) and by those expressing empty vector (BMSCs-EV). After successful transfection, we tested the proliferation, secretion and migration abilities of the BMSCs-Klotho compared with those of the BMSCs-EV and BMSCs. Then, 30 male C57BL/6 mice were examined, with 6 mice randomly assigned to the control group (PBS injected into the tail vein, CON) or one of the four treatment groups treated with either BMSCs-Klotho (AKI+BMSCs-Klotho), BMSCs-EV (AKI+BMSCs-EV), BMSCs (AKI+BMSCs) or PBS (AKI+PBS) after induction of RM. Seventy-two h after treatment, serum creatinine (SCr) and blood urea nitrogen (BUN) levels were obtained to assess renal function, and renal tissue was obtained to measure kidney tissue damage. Additionally, kidney protective mechanism-related indexes, such as EPO, IGF-1, KIM-1 and HIF-1, were analysed using Western blot analysis and immunohistochemistry.ResultsThe results obtained showed that the proliferation, secretory and migration abilities of the BMSCs were significantly increased after transfection with the Klotho gene. Treatment with BMSCs-Klotho, BMSCs-EV or BMSCs improved renal function compared to treatment with PBS. However, the improvement observed in renal function in the BMSCs-Klotho group was better than that of the other groups. Histological analysis demonstrated that tissue damage was significantly decreased in the mice in the AKI+BMSCs-Klotho, AKI+BMSCs-EV or AKI+BMSCs groups compared to that in the mice in the AKI+PBS group. However, the best recovery was observed in the mice treated with BMSCs-Klotho concomitantly. Furthermore, the expression of protective factors erythropoietin (EPO) and insulin-like growth factor 1 (IGF-1) increased obviously, and the injury biomarkers kidney injury molecule 1 (KIM-1) and hypoxia inducible factor 1 (HIF-1) decreased notably in the group of BMSCs-Klotho, BMSCs-EV and BMSCs. Additionally, the levels of the aforementioned protein indicators in the AKI+BMSCs-Klotho group were not different from those in the CON group.ConclusionKlotho overexpression exerted positive effects on BMSCs and markedly promoted recovery from RM-induced AKI. These findings suggest that the overexpression of the Klotho gene might be a good candidate for further therapy for AKI in clinical trials.

Muscle deteriorations become prominent within 24 hours after admission in severely burned adults.

Severe burn injury results in profound catabolic deterioration. Although burn-related catabolism has been well stated, it is unclear when the catabolic response begins. This study characterized acute changes of muscle protein breakdown at the admission and the day after in severely burned adults. Twelve patients (43 ± 19 years old) with 40% ± 21% total body surface area burns were prospectively enrolled into an observational study approved by institutional review board. Urinary samples were collected on admission day and the day after (day 1). Patient demographic and clinical data of vital signs, blood gas and chemistry, and coagulation status were collected. Catabolic changes of muscle breakdown were quantified by urinary excretion of 3-methylhisitidine, determined by gas chromatography and mass spectrometry analysis. Compared with admission day, burned patients had elevated mean ± SD arterial pressure (from 90 ± 5 mm Hg to 108 ± 7 mm Hg) and heart rate (from 102 ± 7 beats per minute to 119 ± 4 beats per minute both p < 0.05) after 24 hours. Their 24-hour urinary output was 1,586 ± 813 mL at admission day to 1,911 ± 1,048 mL on day 1. The 24-hour urea excretion was elevated from 172 ± 101 mg/kg per day at admission day to 302 ± 183 mg/kg per day on day 1 (both p < 0.05), with no change in creatinine excretion. Urinary 3-methylhisitidine excretion increased from 0.75 ± 0.74 mg/kg per day at admission to 1.14 ± 0.86 mg/kg per day on day 1 (p < 0.05). The estimated skeletal muscle protein breakdown was increased from 1.1 ± 1.0 g/kg per day at admission day to 1.6 ± 1.2 g/kg per day on day 1 (p < 0.05). There were no changes in prothrombin time, activated partial thromboplastin time, or platelets. In severely burned patients, catabolic muscle protein breakdown is elevated within 24 hours after admission and before changes in coagulation. These findings suggest that early interventions may be needed to effectively attenuate the catabolic responses in burn patients. Prospective and observational study, level II.

Pathogenesis of arrhythmogenic cardiomyopathy: role of inflammation.

Arrhythmogenic cardiomyopathy (AC) is an inherited disease characterized by progressive breakdown of heart muscle, myocardial tissue death, and fibrofatty replacement. In most cases of AC, the primary lesion occurs in one of the genes encoding desmosomal proteins, disruption of which increases membrane fragility at the intercalated disc. Disrupted, exposed desmosomal proteins also serve as epitopes that can trigger an autoimmune reaction. Damage to cell membranes and autoimmunity provoke myocardial inflammation, a key feature in early stages of the disease. In several preclinical models, targeting inflammation has been shown to blunt disease progression, but translation to the clinic has been sparse. Here we review current understanding of inflammatory pathways and how they interact with injured tissue and the immune system in AC. We further discuss the potential role of immunomodulatory therapies in AC.

Exogenous Biological Renal Support Improves Kidney Function in Mice With Rhabdomyolysis-Induced Acute Kidney Injury.

Background: Rhabdomyolysis (RM) is a clinical syndrome characterized by breakdown of skeletal muscle fibers and release of their contents into the circulation. Myoglobin-induced acute kidney injury (AKI) is one of the most severe complications of RM. Based on our previous research, exogenous biological renal support alleviates renal ischemia–reperfusion injury in elderly mice. This study aimed to determine whether exogenous biological renal support promotes renal recovery from RM-induced AKI and to preliminarily explore the mechanisms involved.Methods: A parabiosis animal model was established to investigate the effects of exogenous biological renal support on RM-induced AKI. Mice were divided into three groups: the control group (in which mice were injected with sterile saline), the RM group (in which mice were injected with 8 mL/kg glycerol), and the parabiosis + RM group (in which recipient mice were injected with glycerol 3 weeks after parabiosis model establishment). Blood samples and kidney tissue were collected for further processing 48 h after RM induction. Bioinformatics analysis was conducted via Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, functional enrichment analysis, and clustering analysis.Results: No mice died within 48 h after the procedure. Exogenous biological renal support attenuated the histological and functional deterioration in mice with RM-induced AKI. Bioinformatics analysis identified key pathways and proteins involved in this process. We further demonstrated that exogenous biological renal support ameliorated AKI through multiple mechanisms, including by suppressing the complement system; attenuating oxidative stress, inflammation, and cell death; and increasing proliferation.Conclusions: Exogenous biological renal support provided by parabiosis can improve renal function in RM-induced AKI by suppressing the complement system; decreasing oxidative stress, inflammation, and cell death; and promoting tubular cell proliferation. Our study provides basic research evidence for the use of bioartificial kidneys to treat RM-induced AKI.

Postprandial muscle protein synthesis rate is unaffected by 20-day habituation to a high protein intake: a randomized controlled, crossover trial.

During the last decade more researchers have argued in favor of an increased protein intake for older adults. However, there is a lack of knowledge on the long-term effects of conforming to such a high protein intake with regards to the basal and postprandial muscle protein turnover. The purpose of this study was to compare the postprandial synthesis response in muscle proteins, and the abundance of directly incorporated food-derived amino acids following habituation to high vs. recommended level of protein intake. In a double blinded crossover intervention 11 older male participants (66.6 ± 1.7years of age) were habituated for 20days to a recommended protein (RP) intake (1.1g protein/kg lean body mass (LBM)/day) and a high protein (HP) intake (> 2.1g protein/kg LBM/day). Following each habituation period, intrinsically labelled proteins were ingested as part of a mixed meal to determine the incorporation of meal protein-derived amino acids into myofibrillar proteins. Furthermore, the myofibrillar fractional synthesis rate (FSR) and amino acid kinetics across the leg were determined using gold standard stable isotope tracer methodologies. RT qPCR was used to assess the expression of markers related to muscle proteinsynthesis and breakdown. No impact of habituation was observed on skeletal muscle amino acid or protein kinetics. However, the shunting of amino acids directly from artery to vein was on average 2.9 [Formula: see text]mol/min higher following habituation to HP compared to RP. In older males, habituation to a higher than the currently recommended protein intake did not demonstrate any adaptions in the muscle protein turnover or markers hereof when subjected to an intake of an identical mixed meal. Journal number NCT02587156, Clinicaltrials.org. Date of registration: October 27th, 2015.

A rare case of ectopic ACTH syndrome with rhabdomyolysis

BackgroundManifestations of hypokalaemia in ectopic adrenocorticotropic hormonesyndrome(EAS) vary from mild muscle weakness to life-threatening arrhythmia. Herein, we present a rare case of EAS with concomitant rhabdomyolysis(RM) as a result of intractable hypokalaemia.Case presentationA 64-year-old man was admitted for limb weakness and facial hyperpigmentation for 2 weeks. Lab tests revealed intractable hypokalaemia (lowest at 1.8 mmol/L) and metabolic alkalosis. The diagnosis of RM was based on a creatine kinase(CK)level of 5 times the upper limit. The elevated CK and myohemoglobin (Mb) levels returned to within the normal range after the alleviation of hypokalaemia. The patient was diagnosed with ACTH-dependent Cushing’s syndrome (CS) based on unsuppressed serum cortisol after a low-dose dexamethasone suppression test(LDDST) and remarkably elevated ACTH levels. The diagnosis of EAS was made based on the results of a high-dose dexamethasone suppression test(HDDST) and bilateral inferior petrosal sinus sampling(BIPSS). Multiple lymph nodes in the left supraclavicular fossa, right root of neck, mediastinum and bilateral hili of the lung were found with abnormal uptake of 68Ga-DOTA-NOC. Mediastinoscopic lymph node biopsy was performed. The pathological diagnosis was small-cell and large-cell neuroendocrine carcinoma with positive ACTH staining. The patient was prescribed mifepristone and received one cycle of chemotherapy. The patient could not tolerate subsequent chemotherapy and died of dyscrasia.ConclusionsRM is a rare complication of EAS with insidious onset and atypical clinical manifestations. Serum potassium levels should be vigilantly monitored to avoid RM in EAS.

A Case of Rhabdomyolysis in a Patient With Hashimoto’s Thyroiditis

Introduction: Hashimoto’s thyroiditis (HT) is an autoimmune disease that presents with musculoskeletal symptoms like proximal muscle weakness, stiffness, pain or cramps in the majority of patients. Rhabdomyolysis which is a breakdown of the skeletal muscles, is a rare but serious manifestation of hypothyroidism and if occurs, it is usually related to trauma, strenuous exercise or use of statins. We report a patient with unrecognized Hashimoto’s thyroiditis who presented with severe rhabdomyolysis without reported history of strenuous exercise, seizures or statin use and surprisingly, He did not have any complications from rhabdomyolysis like electrolytes abnormalities or acute kidney injury. Case Report: A 56-year-old man with no reported past medical history who presented with severe generalized weakness, bilateral leg pain, and recurrent falls for three months. He also reported constipation, fatigue and dry skin. Denied any prior personal or family history of thyroid disease, seizure disorder, statin use, trauma or tick bite. He was afebrile with a heart rate of 80 beats/minute, a blood pressure of 126/71mmHg. Initial laboratory testing showed normal metabolic panel, elevated thyroid stimulating hormone 30.6 uIU/mL (Range 0.27-4.2 uIU/mL), FT4 0.1 ng/dL (Range 0.93-1.7ng/dL), TPO Ab 300IU/mL (N<43IU/mL), Creatine Kinase (CK) level 10,000U/L (N<200U/L), ESR 27 mm/Hr (N<20mm/Hr) and Lactate Dehydrogenase 621U/L (N <225U/L). A muscle biopsy was done to rule out polymyositis as a cause of his severe muscle pain, weakness and tenderness and it was negative. Patient was diagnosed with HT with associated rhabdomyolysis after excluding other causes of rhabdomyolysis. Supportive treatment with intravenous fluids and Levothyroxine were initiated and resulted in dramatic clinical improvement. Conclusion: Rhabdomyolysis is a rare but potentially a serious complication of hypothyroidism. Screening for hypothyroidism in patients with elevated muscle enzymes should be considered, as early diagnosis and prompt treatment of hypothyroidism is essential to prevent rhabdomyolysis and its consequences like acute kidney disease and electrolytes abnormalities. Appropriate fluid resuscitation is the mainstay therapy for AKI prevention and should be initiated in a timely manner. Key Words: HT: Hashimoto’s Thyroiditis, ESR: Erythrocyte Sedimentation Rate, TPO Ab: Thyroid Peroxidase Antibody, TSH: Thyroid Stimulating Hormone, FT4: Free Thyroxine level, AKI: Acute Kidney Injury.

A Rare Case of Rhabdomyolysis in a Patient With Pembrolizumab Induced Hypothyroidism

Introduction: Although reported in previous literature, Rhabdomyolysis due to hypothyroidism,without an obvious precipitating factor, is rare. We report a case of severe hypothyroidism leading torhabdomyolysis. Case Report: A 70-year-old man with a history of progressive weakness, myalgia x1 month, statinallergy, pancreatic adenocarcinoma, metastatic melanoma, and acquired hypothyroidism afterreceiving Pembrolizumab for 6 months. He was non-adherent to the levothyroxine, prescribed 1month before hospitalization. He presented to the ED after slipping from his bed onto the floor in aseating position and being unable to get up due to his weakness. Initially, he was afebrile, hypoxic,tachypneic, tachycardic, hypotensive, lethargic, oriented x2, and had a global muscular weakness. Labs were significant for CK of 10,180 (n < 166 IU/L), TSH 136.18(n 0.34-5.6 mU/L), FT4 < 0.25 (n0.6-1.10 ng/dl), FT3 1.4 (n 2.5-3.9 Pg/ml), AKI, leukocytosis, abnormal electrolytes and LFTs. IV fluidsand antibiotics failed to improve the patient’s clinical status in 48 hours. He was started on IVthyroxine and stress steroids with improved weakness and overall clinical picture. Discussion: 4.6 % of people have hypothyroidism per the United States National Health andNutrition Examination Survey. Rhabdomyolysis is defined as the rapid breakdown of skeletal muscle,which may also develop due to hypothyroidism. Most patients with hypothyroidism who developrhabdomyolysis are found to have a clear precipitating risk factor, such as the use of statins orstrenuous exercise. Still, none of these risk factors were present in this case. Our patient acquiredhypothyroidism after a few months of receiving Immunotherapy. It is reported that hypothyroidismoccurs in (9% to 18%) of patients receiving Pembrolizumab. Although the patient was prescribedthyroid replacement therapy, he was not adherent to the medication for 1 month prior topresentation. Although mechanical injury is reported to cause elevated CK levels, mostrhabdomyolysis cases are related to crush injuries. We believe that the fall was probably related tohis progressive generalized weakness due to his noncompliance with medical therapy leading tomyxedema coma and rhabdomyolysis. Conclusion: Screening for hypothyroidism in patients with elevated muscle enzymes should behighly considered since an early diagnosis. Prompt treatment of hypothyroidism is essential toprevent rhabdomyolysis and its consequence.

Target Temperature Control in Patients with Burns

Severe burns lead to a persistent hypermetabolic response of the organism with significantly increased resting energy turnover, multi-organ dysfunction, muscle breakdown and increased risk of infection. Elevated core and skin temperatures are characteristic. A further increase in the metabolic rate can be triggered by heat losses, for which these patients are particularly predisposed due to high heat dissipation via evaporation of moisture and impairment of the thermoregulatory and insulating properties of the burnt skin. This is especially true in all treatment situations with exposure to large, uncovered skin surfaces, such as primary care, dressing changes in the intensive care unit and surgery with extensive sterile operating field. It has been shown that hypothermia is associated with numerous risks for the burn patient. Consistent heat management with measurement of the core body temperature and application of external and internal heat protection measures is recommended. Traditionally, an increase in room temperature is used here. However, this effective measure is limited by the resilience of the intensive care practitioners and the surgeons. To avoid perioperative hypothermia, strict surgical planning with limitation of the duration of surgery and close intraoperative communication about the risk of hypothermia are of particular importance.The differentiation between accepted temperature increase and infectious fever is often only possible by the inclusion of further examination findings. The criterion for sepsis is a temperature above 39 °C or below 36.5 °C.

Exertional Heat Stroke Causes Long‐Term Satellite Cell Dysfunction and Delayed Muscle Repair

Exertional heat stroke (EHS) is an acute life-threatening event that appears to lead to long-term health problems such as cardiovascular disease and immunosuppression. However, how skeletal muscle (SKM) is affected in the long term by EHS is not well understood. One well-known acute effect of EHS on SKM is rhabdomyolysis (RM), caused by SKM damage. To regain muscle function, this damage requires an effective muscle repair response, which is likely to include a robust contribution of progenitor satellite cell (SCs). We hypothesized that SCs display EHS-induced phenotype changes that contribute to a delay in the muscle repair process. Purpose To determine whether EHS exposure alters SC phenotype after 30 d of recovery in mice and to evaluate whether this impairs muscle repair. Methods Thirty-two female mice were either subjected to a standardized EHS protocol using a forced running wheel (environmental temp: 37.5°C, 40% humidity) or a matched exercise control trial (EXC)(22.5°C). The EHS mice achieved peak core temps of ~42.2°C accompanied by transient loss of consciousness. Mice were sacrificed at 30 d of recovery. In one cohort (N=8/group), SKM was collected to isolate SCs for quantification of proliferation patterns every 24 h over 96 h and to determine their myogenic ability. Of the eight EHS SC isolations, three were unable to proliferate at all following isolation, a response not seen in any control SC populations. Since a significant portion of the samples did not respond, we used a nominal stratification classification for statistical analysis. In a second cohort, SKM was collected to sequence mRNA and perform Western protein analyses. Results EHS SCs were found to proliferate significantly less than EXC SCs at the 72 h & 96 h time points (P=0.0273); however, the ability to differentiate into myotubes was not different. mRNA analysis of EHS gastroc elucidated a robust, ongoing oxidative muscle transcriptional process at 30 d that included upregulation of such genes as Myh6, Myh7, Atp2a2, Casq2, Tnnc1, Tnnt1, and Tnni1. This response was not seen in isoforms associated with fast glycolytic muscle genes. The mRNA encoding embryonic myosin, Myh3, was found upregulated, an indicator of muscle regeneration. The protein encoded by adult oxidative myosin (Myh7) was found to be significantly less in EHS muscle (P<0.01), whereas Myh4 protein was not different and Myh3 was undetectable in either group. Conclusions SC proliferation following 30 d of recovery from a single incidence of EHS is significantly attenuated in female mice. This phenomenon has the potential to hinder the renewal of the SC pool, following depletion, and leading to delayed muscle repair. This delay may be apparent in EHS muscle through significantly lower Myh7 protein in EHS muscle and an ongoing oxidative gene transcription program.

516 Higher Risk of Acute Kidney Injury in Burn Patients with Rhabdomyolysis

Abstract Introduction Rhabdomyolysis, a rapid breakdown of damaged skeletal muscle, is a serious complication known to occur in approximately 1% of burn patients. Muscle breakdown products can accumulate in the renal tubules leading to acute kidney injury (AKI) and increased deaths. Burn-associated factors such as under-resuscitation, infection, and nephrotoxic drugs likely increase incidence of AKI in those with rhabdomyolysis after burn. Other variables such as age, sex, and pre-existing conditions may also be implicated in this relationship. We investigated whether burn patients with rhabdomyolysis are at greater risk of developing AKI than others with rhabdomyolysis. Methods TriNetX, a global health research network, was accessed in September 2020 to create three patient cohorts with a combination of rhabdomyolysis and burns. Data from years 2000 to 2020 from 38 health care organizations was used. Cohort 1 included burned patients who developed rhabdomyolysis within 14 days after injury. Cohort 2 were those with rhabdomyolysis who did not suffer a burn within 14 days prior to diagnosis. Cohort 3 included burned patients who did not develop rhabdomyolysis within 14 days of the burn. Burn diagnosis was identified by ICD-10 codes T20-25, T26-28, or T30-32; rhabdomyolysis was identified with M62.82. We identified 699 patients in Cohort 1. Propensity score matching was done to Cohorts 2 and 3 to balance similar demographics and pre-existing conditions to Cohort 1. Cohorts were then compared to assess the risk of developing AKI (N17) within 14 days of the initial event. Results Cohort 1 had a mean age at incidence of 48.4±19.8; 552 patients were male and 146 were female. 154 patients with hypertensive diseases, 66 with diabetes mellitus, 41 with chronic kidney disease, and 51 overweight or obese patients were identified. Matched Cohorts 2 and 3 had the same number of patients and similar demographics and pre-existing conditions as Cohort 1. 391 of 699 burn patients with rhabdomyolysis (56%), 293 of 699 non-burn patients with rhabdomyolysis (42%), and 23 of 699 burn patients without rhabdomyolysis (3%) developed AKI within 14 days. The risk ratio difference for developing AKI between burn patients and non-burn patients with rhabdomyolysis was 14.02% with a 95% CI of 8.831–19.209% (&amp;lt; 0.0001 p-value) and between burn patients with and without rhabdomyolysis was 52.647% with a 95% CI of 48.736–56.557% (&amp;lt; 0.0001 p-value). The odds ratios for developing AKI were 1.759 and 37.312, respectively. Conclusions We found the risk of developing AKI in burn patients with rhabdomyolysis to be significantly augmented compared to non-burn patients with rhabdomyolysis or burn patients without rhabdomyolysis.

Interpretable Machine Learning Model for Early Prediction of Mortality in ICU Patients with Rhabdomyolysis.

Rhabdomyolysis (RM) is a complex set of clinical syndromes that involves the rapid dissolution of skeletal muscles. Mortality from RM is approximately 10%. This study aimed to develop an interpretable and generalizable model for early mortality prediction in RM patients. Retrospective analyses were performed on two electronic medical record databases: the eICU Collaborative Research Database and the Medical Information Mart for Intensive Care III database. We extracted data from the first 24 h after patient ICU admission. Data from the two data sets were merged for further analysis. The merged data sets were randomly divided, with 70% used for training and 30% for validation. We used the machine learning model extreme gradient boosting (XGBoost) with the Shapley additive explanation method to conduct early and interpretable predictions of patient mortality. Five typical evaluation indexes were adopted to develop a generalizable model. In total, 938 patients with RM were eligible for this analysis. The area under the receiver operating characteristic curve (AUC) of the XGBoost model in predicting hospital mortality was 0.871, the sensitivity was 0.885, the specificity was 0.816, the accuracy was 0.915, and the F1 score was 0.624. The XGBoost model performance was superior to that of other models (logistic regression, AUC = 0.862; support vector machine, AUC = 0.843; random forest, AUC = 0.825; and naive Bayesian, AUC = 0.805) and clinical scores (Sequential Organ Failure Assessment, AUC = 0.747; Acute Physiology Score III, AUC = 0.721). Although the XGBoost model is still not great from an absolute performance perspective, it provides better predictive performance than other models for estimating the mortality of patients with RM based on patient characteristics in the first 24 h of admission to the ICU.