Electromuscular Incapacitation Current Induced Neuromuscular Tissue Injury.

Electrical stun devices (ESDs) serve a basic role in law enforcement and provide an alternative to lethal options for target control by causing electromuscular incapacitation (EMI). A fundamental concern is the adverse health consequences associated with their use. The capability of EMI electric field pulses to disrupt skeletal muscle cells (i.e. rhabdomyolysis) was investigated over the operational range commonly used in commercial EMI devices. Functional and structural alteration and recovery of muscle and nerve tissue were assessed. In an anesthetized swine model, the left thigh was exposed to 2 min of electrical pulses, using a commercially available ESD or a custom-made EMI signal power amplifier. Serum creatinine phosphokinase (CPK), troponin, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels were monitored intermittently for 6 h post-EMI exposure. A standard external cardiac defibrillator served as a positive control. Muscle and nerve tissue histology adjacent to the EMI contacts were examined. Post-EMI shock skeletal muscle function was evaluated by analyzing the compound muscle action potentials (CMAPs) of the rectus femoris muscle. Maximal energy cardiac defibrillator pulses resulted in rhabdomyolysis and marked elevation of CPK, LDH, and AST 6 h post-shock. EMI field pulses resulted in the animals developing transient acidosis. CMAP amplitudes decreased approximately 50% after EMI and recovered to near-normal levels within 6 h. Within 6 h post-EMI exposure, blood CPK was mildly increased, LDH was normal, and no arrhythmia was observed. Minimal rhabdomyolysis was produced by the EMI pulses. These results suggest that EMI exposure is unlikely to cause extremity rhabdomyolysis in normal individuals. Bioelectromagnetics. © 2020 Bioelectromagnetics Society.

Bodybuilding supplements leading to copper toxicity, encephalopathy, fulminant hepatic failure and rhabdomyolysis.

Millions of people worldwide use nutritional and dietary supplements, such as vitamins and minerals. These and other performance-enhancing substances are also used by high school, college, and professional athletes, bodybuilders, and amateur sports enthusiasts. The constituents of these supplements and their metabolites may be harmful and not listed on the product label. We present a case report of a 32-year-old bodybuilder using myriad nutritional, performance-enhancing, and weight-loss supplements with life-threatening encephalopathy, hepatic failure, rhabdomyolysis, and copper toxicity mimicking Wilson's disease. Emergency physicians and nurses should be aware of these potential deleterious effects and inquire about supplement use by patients with unexplained multiorgan failure. Family, friends, or acquaintances should be asked to bring the actual products to the hospital for analysis.

Curcumin-Loaded Nanoparticles Protect Against Rhabdomyolysis-Induced Acute Kidney Injury.

BACKGROUND/AIMS: Rhabdomyolysis (RM) is a potentially life-threatening condition that results from the breakdown of muscle and consequent release of toxic compounds into circulation. The most common and severe complication of RM is acute kidney injury (AKI). This study aimed to evaluate the efficacy and mechanisms of action of curcumin-loaded nanoparticles (Cur-NP) for treatment of RM-induced AKI. METHODS: Curcumin-NP was synthesized using the nanocarrier distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) to achieve a prolonged and constant drug release profile compared with the curcumin-free group. The anti-AKI effects of Curcumin-NP were examined both in vitro (myoglobin-treated renal tubular epithelial HK-2 cells) and in vivo (glycerol-induced AKI model). RESULTS: Our results indicated that Curcumin-NP reversed oxidative stress, growth inhibition and cell apoptosis accompanied with down-regulation of apoptotic markers Caspase-3 and GRP-78 in vitro. In vivo studies revealed enhanced AKI treatment efficacy with Curcumin-NP as characterized by reduced serum creatine phosphokinase (CPK), creatinine (Cr) and urea and less severe histological damage in renal tubules. In addition, kidney tissues from Curcumin-NP-treated AKI rats exhibited reduced oxidative stress, apoptosis, and cleaved Capase-3 and GRP-78 expression. CONCLUSION: Our results suggest that nanoparticle-loaded curcumin enhances treatment efficacy for RM-induced AKI both in vitro and in vivo.

Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial.

BACKGROUND: Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight-carbon fatty acid triglyceride, in patients with LC-FAODs. METHODS: A double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis. RESULTS: Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p = 0.046) while experiencing a 20% (p = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups. CONCLUSIONS: C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01379625.

When Nutraceuticals Reinforce Drugs Side Effects: A Case Report.

INTRODUCTION: Nutraceutical is a term applied for a plethora of products ranging from isolated nutrients, herbal products to dietary supplements and recently, the interest for a nutraceutical approach to lipid and metabolic disorders is growing. Patients with metabolic conditions seem to appreciate a therapeutic management that does not involve drug treatment, particularly for the side effects due to statins, a class of drug used for lipid disorders. Statins directly induce skeletal muscle injury and in the elderly patients, under polytherapy treatments, this risk relies to an increase in adverse drug reactions due to drug interactions. CASE DESCRIPTION: Herein we report a 70-year-old woman under polytherapy who developed rhabdomyolysis after starting the administration of a dietary supplement containing monacolin K. Using the Drug Interaction Probability Scale, we postulated that rhabdomyolysis was possibly related to a drug interaction between sertraline, rosuvastatin and monacolin K. These treatments were discontinued leading to a remission of both clinical symptoms and biochemical parameters. CONCLUSION: This case report highlights how pharmacological treatment must be periodically reassessed, since elderly people could take drugs by themselves when they donot need.

Mitochondrial bioenergetics deregulation caused by long-chain 3-hydroxy fatty acids accumulating in LCHAD and MTP deficiencies in rat brain: a possible role of mPTP opening as a pathomechanism in these disorders?

Long-chain 3-hydroxylated fatty acids (LCHFA) accumulate in long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies. Affected patients usually present severe neonatal symptoms involving cardiac and hepatic functions, although long-term neurological abnormalities are also commonly observed. Since the underlying mechanisms of brain damage are practically unknown and have not been properly investigated, we studied the effects of LCHFA on important parameters of mitochondrial homeostasis in isolated mitochondria from cerebral cortex of developing rats. 3-Hydroxytetradecanoic acid (3 HTA) reduced mitochondrial membrane potential, NAD(P)H levels, Ca(2+) retention capacity and ATP content, besides inducing swelling, cytochrome c release and H2O2 production in Ca(2+)-loaded mitochondrial preparations. We also found that cyclosporine A plus ADP, as well as ruthenium red, a Ca(2+) uptake blocker, prevented these effects, suggesting the involvement of the mitochondrial permeability transition pore (mPTP) and an important role for Ca(2+), respectively. 3-Hydroxydodecanoic and 3-hydroxypalmitic acids, that also accumulate in LCHAD and MTP deficiencies, similarly induced mitochondrial swelling and decreased ATP content, but to a variable degree pending on the size of their carbon chain. It is proposed that mPTP opening induced by LCHFA disrupts brain bioenergetics and may contribute at least partly to explain the neurologic dysfunction observed in patients affected by LCHAD and MTP deficiencies.

Selenium inhibits renal oxidation and inflammation but not acute kidney injury in an animal model of rhabdomyolysis.

UNLABELLED: Acute kidney injury (AKI) is a manifestation of rhabdomyolysis (RM). Extracellular myoglobin accumulating in the kidney after RM promotes oxidative damage, which is implicated in AKI. AIM: To test whether selenium (Se) supplementation diminishes AKI and improves renal function. RESULTS: Dietary selenite increased Se in the renal cortex, as demonstrated by X-ray fluorescence microscopy. Experimental RM-stimulated AKI as judged by increased urinary protein/creatinine, clusterin, and kidney injury molecule-1 (KIM-1), decreased creatinine clearance (CCr), increased plasma urea, and damage to renal tubules. Concentrations of cholesterylester (hydro)peroxides and F2-isoprostanes increased in plasma and renal tissues after RM, while aortic and renal cyclic guanidine monophosphate (cGMP; marker of nitric oxide (NO) bioavailability) decreased. Renal superoxide dismutase-1, phospho-P65, TNFα gene, MCP-1 protein, and the 3-chloro-tyrosine/tyrosine ratio (Cl-Tyr/Tyr; marker of neutrophil activation) all increased after RM. Dietary Se significantly decreased renal lipid oxidation, phospho-P65, TNFα gene expression, MCP-1 and Cl-Tyr/Tyr, improved NO bioavailability in aorta but not in the renal microvasculature, and inhibited proteinuria. However, CCr, plasma urea and creatinine, urinary clusterin, and histopathological assessment of AKI remained unchanged. Except for the Se++ group, renal angiotensin-receptor-1/2 gene/protein expression increased after RM with parallel increases in MEK1/2 inhibitor-sensitive MAPkinase (ERK) activity. INNOVATION: We employed synchrotron radiation to identify Se distribution in kidneys, in addition to assessing reno-protection after RM. CONCLUSION: Se treatment has some potential as a therapeutic for AKI as it inhibits oxidative damage and inflammation and decreases proteinuria, albeit histopathological changes to the kidney and some plasma and urinary markers of AKI remain unaffected after RM.

Sivelestat improves outcome of crush injury by inhibiting high-mobility group box 1 in rats.

Severe crush injury is associated with high mortality because of resulting hyperkalemia in early phase and multiorgan dysfunction in later phase. In this study, we investigated the effects of sivelestat administration 1 h before reperfusion on the outcome of crush injury. Crush injury was induced by 6 h of direct compression to both hindlimbs of anesthetized rats with blocks weighing 3.5 kg each side, followed by 3 h of reperfusion. Rats were randomly assigned to three groups. In the control group, rats were infused with normal saline at 1 mL/kg per hour throughout the experiment without compression. Rats in the positive control group were compressed for 6 h, followed by fluid resuscitation initiated 1 h before release with normal saline. The infusion rate was increased from 1 to 10 mL/kg per hour and continued for 4 h. Rats in the treated group underwent the same procedures as in the positive control group, but sivelestat was added to normal saline (concentration was adjusted to infuse 10 mg/kg per hour) during fluid resuscitation (for 4 h). Treatment with sivelestat significantly improved survival rate with P = 0.032. This was accompanied by lower serum high-mobility group box 1 (HMGB1) levels after 3-h reperfusion, attenuated lung injury (assessed using hematoxylin-eosin stain), and suppression of HMGB1 expression in the lung and the liver. These results suggest that treatment with sivelestat improves the outcome of crush injury, likely by inhibiting HMGB1 in rats.

Preventive effects of hyperbaric oxygen treatment on glycerol-induced myoglobinuric acute renal failure in rats.

Myoglobinuric acute renal failure (ARF) is a uremic syndrome caused by traumatic or non-traumatic skeletal muscle breakdown and intracellular elements that are released into the bloodstream. We hypothesized that hyperbaric oxygen (HBO) therapy could be beneficial in the treatment of myoglobinuric ARF caused by rhabdomyolysis. A total of 32 rats were used in the study. The rats were divided into four groups: control, control+hyperbaric oxygen (control+HBO), ARF, and ARF+hyperbaric oxygen (ARF+HBO). Glycerol (8 ml/kg) was injected into the hind legs of each of the rats in ARF and ARF+HBO groups. 2.5 atmospheric absolute HBO was applied to the rats in the control+HBO and ARF+HBO groups for 90 min on two consecutive days. Plasma urea, creatinine, sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, creatinine kinase and urine creatinine and sodium were examined. Creatinine clearance and fractional sodium excretion could then be calculated. Superoxide dismutase, catalase, glutathione and malondialdehyde (MDA) levels were assessed in renal tissue. Tissue samples were evaluated by Hematoxylin-eosin, PCNA and TUNEL staining histopathologically. MDA levels were found to be significantly decreased whereas SOD and CAT were twofold higher in the ARF+HBO group compared to the ARF group. Renal function tests were ameliorated by HBO therapy. Semiquantitative evaluation of histopathological findings indicated that necrosis and cast formation was decreased by HBO therapy and TUNEL staining showed that apoptosis was inhibited. PCNA staining showed that HBO therapy did not increase regeneration. Ultimately, we conclude that, in accordance with our hypothesis, HBO could be beneficial in the treatment of myoglobinuric ARF.

Hypokalemic rhabdomyolysis in a child with Gitelman's syndrome.

We report here the first published case of a pediatric patient with Gitelman's syndrome (GS) in whom hypokalemia-associated rhabdomyolysis developed. A 13-year-old girl was admitted with weakness of the extremities, walking difficulty and calf pain. Laboratory data showed a serum potassium level of 2.1 mmol/l and a serum creatinine phosphokinase level of 1,248 IU/l plus myoglobinemia. The presence of normomagnesemia was the basis for a genetic analysis of the thiazide-sensitive sodium chloride cotransporter gene, which revealed compound heterozygous mutations in this gene. Prompt fluid expansion and potassium supplementation led to regression of the muscle symptoms. Hypokalemia can be a rare cause of rhabdomyolysis in patients with GS, even in childhood. We emphasize that genetic analysis is advisable to determine whether the suspicion of GS is warranted.

Rhabdomyolysis in response to weight-loss herbal medicine.

The authors report rhabdomyolysis following the ingestion of weight-loss herbal medicine in an otherwise healthy 54-year-old woman. Three hours after ingestion of the herbal medicine, the patient suffered chest pain that continued for 2 hours and resolved gradually. Laboratory investigation showed the presence of rhabdomyolysis with peak serum creatine kinase (CK) of 1028 IU/L, which gradually decreased and normalized after the herbal medicine was discontinued. The pharmacological effects of the active ingredients of the herbal medicine, ma huang (ephedrine), guarana (active alkaloid caffeine), chitosan, Gymnena sylvestre, Garcinia cambogia (50% hydroxycitric acid), and chromium, are discussed, and similar case reports are reviewed. The elevation of CK in this case is of concern, as it may denote that muscle breakdown may be one of the mechanisms of weight loss in these herbal remedies. Further studies are needed to investigate their effects on muscle bulk or CK. Physicians should be aware of the potential side effects of many herbal medicines. It may be advisable to measure serum CK enzyme for patients who admit using weight-loss herbs.

Selenoprotein synthesis and side-effects of statins.

Statins are possibly the most effective drugs for the prevention and treatment of hypercholesterolaemia and coronary heart disease. They are generally well tolerated, however, they do cause some unusual side-effects with potentially severe consequences, most prominently myopathy or rhabdomyolysis and polyneuropathy. We noted that the pattern of side-effects associated with statins resembles the pathology of selenium deficiency, and postulated that the mechanism lay in a well established, but often overlooked, biochemical pathway--the isopentenylation of selenocysteine-tRNA([Ser]Sec). A negative effect of statins on selenoprotein synthesis does seem to explain many of the enigmatic effects and side-effects of statins, in particular, statin-induced myopathy.

Myoglobin clearance and removal during continuous venovenous hemofiltration.

Myoglobin has a relatively high molecular weight of 17,000 Da and is poorly cleared by dialysis (diffusion). However, elimination of myoglobin might be enhanced by an epuration modality based on convection for solute clearances. We present a single case of myoglobin-induced renal failure (peak creatine kinase level: 313,500 IU/l) treated by continuous venovenous hemofiltration (CVVH). Our purpose was to evaluate the efficiency of such a modality using an ultrafiltration rate of 2 to 3 l/h for myoglobin removal and clearance. The hemofilter was a 0.9 m(2) polyacrylonitrile (AN69) membrane Multiflow-100 (Hospal-Gambro, St-Leonard, Canada) and the blood flow rate was maintained at 150 ml/min by an AK-10 pump (Hospal-Gambro, St-Leonard, Canada). The ultrafiltration bag was placed 60 cm below the hemofilter and was free of pump control or suction device. Serum myoglobin concentration was 92,000 microg/l at CVVH initiation and dropped to 28,600 microg/l after 18 h of the continuous modality. The mean sieving coefficient for myoglobin was 0.6 during the first 9 h of therapy and this decreased to 0.4 during the following 7 h. Mean clearance of myoglobin was 22 ml/min, decreasing to 14 ml/min during corresponding periods, while the mean ultrafiltration rates were relatively stable at 2,153 +/- 148 ml/h and 2,074 +/- 85 ml/h, respectively. In contrast to myoglobin, the sieving coefficeint for urea, creatinine, and phosphorus remained stable at 1.0 during the first 16 h of CVVH. More than 700 mg of myoglobin were removed by CVVH during the entire treatment. In conclusion, considerable amounts of myoglobin can be removed by an extracorporeal modality allowing important convective fluxes and middle molecule clearances, such as CVVH at a rate of 2 to 3 l/h using an AN69 hemofilter. If myoglobin clearance had been maintained at 22 ml/min, 32 l of serum would have been cleared per day. However, the sieving coefficient of myoglobin decreased over time, probably as a consequence of protein coating and/or blood clotting of the hemofilter. Whereas myoglobin can be removed by CVVH, it remains unknown at this point if such a modality, applied early, can alter or shorten the course of myoglobinuric acute renal failure.

Acute pancreatitis and rhabdomyolysis: a new association.

Fourteen cases of acute severe pancreatitis complicated by non-traumatic rhabdomyolysis are described and compared to case controls. Pancreatitis of various aetiologies was confirmed by surgical diagnosis, laparotomy, abdominal paracentesis, CAT scan and post mortem. Pancreatitis was severe with a high Ranson prognostic score (7.4 +/- 0.5 vs controls 1.9 +/- 0.4, p less than 0.001), longer ICU admission and a mortality of 79%. Rhabdomyolysis occurred two to 19 days after the onset of pancreatitis (with a median CPK peak at 6.5 days) and was accompanied by multiple organ failure in 93% of cases. Severe rhabdomyolysis and myoglobinuric renal failure occurred in three patients out of 12 with acute renal failure. Hypocalcaemia was common (93%), severe (with a mean minimum value of 1.79 +/- 0.07 vs 2.34 +/- 0.04mmol/L, p less than 0.01) and prolonged (remaining abnormal for 5.2 +/- 0.8 vs 0.07 +/- 0.07 days, p less than 0.001). Intravenous calcium supplements were required in 50% of patients. Plasma phosphate, potassium, urate and anion gap were elevated (all p less than 0.05) and accompanying clinical features included fever, ascites, leucocytosis, hypoalbuminaemia and abnormal liver function tests. Rhabdomyolysis is associated with acute several pancreatitis, appearing as a late phenomenon in the context of severe prolonged hypocalcaemia, multiple organ failure and a poor outcome.