Super-refractory status epilepticus, rhabdomyolysis, central hyperthermia and cardiomyopathy attributable to spinal anesthesia: a case report and review of literature.

BACKGROUND: There are only six past reports of super-refractory status epilepticus induced by spinal anesthesia. None of those patients have died. Only < 15 mg of bupivacaine was administered to all six of them and to our case. Pathophysiology ensuing such cases remains unclear. CASE PRESENTATION: A 27 year old gravida 2, para 1, mother at 37 weeks of gestation came to the operating theater for an elective cesarean section. She had no significant medical history other than controlled hypothyroidism and one episode of food allergy. Her current pregnancy was uneventful. Her American Society of Anesthesiologists (ASA) grade was 2. She underwent spinal anesthesia and adequate anesthesia was achieved. After 5-7 min she developed a progressive myoclonus. After delivery of a healthy baby, she developed generalized tonic clonic seizures that continued despite the induction of general anesthesia. She had rhabdomyolysis, one brief cardiac arrest and resuscitation, followed by stress cardiomyopathy and central hyperthermia. She died on day four. There were no significant macroscopic or histopathological changes in her brain that explain her super refractory status epilepticus. Heavy bupivacaine samples of the same batch used for this patient were analyzed by two specialized laboratories. National Medicines Quality Assurance Laboratory of Sri Lanka reported that samples failed to confirm United States Pharmacopeia (USP) dextrose specifications and passed other tests. Subsequently, Therapeutic Goods Administration of Australia reported that the drug passed all standard USP quality tests applied to it. Nonetheless, they have detected an unidentified impurity in the medicine. CONCLUSIONS: After reviewing relevant literature, we believe that direct neurotoxicity by bupivacaine is the most probable cause of super-refractory status epilepticus. Super-refractory status epilepticus would have led to her other complications and death. We discuss probable patient factors that would have made her susceptible to neurotoxicity. The impurity in the drug detected by one laboratory also would have contributed to her status epilepticus. We propose several possible mechanisms that would have led to status epilepticus and her death. We discuss the factors that shall guide investigators on future such cases. We suggest ways to minimize similar future incidents. This is an idiosyncratic reaction as well.

Lipid emulsion treatment for local anesthetic systemic toxicity in pediatric patients: A systematic review.

BACKGROUND: Local anesthetic systemic toxicity (LAST) is rare, but fatal; the current widely used treatment is lipid emulsion (LE). The goal of this study was to analyze and review case reports on LE treatment for LAST in pediatric patients. METHODS: We performed a systematic review using case reports on LE treatment for LAST in pediatric patients, searching PubMed and Scopus databases to March 2023 using the following keywords: ("local anesthetic toxicity" OR "local anesthetic systemic toxicity" OR LAST") AND ("newborn" OR "infant" OR "child" OR "children" OR "adolescent" OR "pediatric") AND ("lipid emulsion" OR "Intralipid"). RESULTS: Our search yielded 21 cases, revealing that nearly 43% patients with LAST were less than 1 year old, and most cases were caused by bupivacaine (approximately 67% cases). "Inadvertent intravascular injection" by anesthesiologists and "overdose of local anesthetics" mainly by surgeons were responsible for 52% and 24% cases of LAST, respectively. LAST occurred in the awake state (52%) and under general anesthesia (48%), mainly causing seizures and arrhythmia, respectively. Approximately 55% of patients received LE treatment in <10 minutes after LAST, mainly improving cardiovascular symptoms. A 20% LE (1.5 mL/kg) dose followed by 0.25 mL/kg/minutes dose was frequently used. LE and anticonvulsants were mainly used in the awake state, whereas LE with or without vasopressors was mainly used under general anesthesia. LE treatment led to full recovery from LAST in 20 cases; however, 1 patient died due to underlying disease. CONCLUSION: Consequently, our findings reveal that LE is effective in treating pediatric LAST.

Dose safety and pharmacodynamics of subcutaneous bupivacaine in a novel extended-release microparticle formulation: A phase 1, dose-ascending study in male volunteers.

A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81-52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69-9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52-8.16; P = 0.004) and 4.00 (0.72-24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4-13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490-533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications.

Aseptic meningitis following spinal anaesthesia: An uncommon and challenging diagnosis.

Drug-induced aseptic meningitis (DIAM) or chemical meningitis following spinal anaesthesia has rarely been reported. DIAM is caused by meningeal inflammation due to intrathecally administered drugs or secondary to systemic immunological hypersensitivity. We hereby present a case of a young adult with aseptic meningitis following neuraxial anaesthesia possibly provoked by bupivacaine. The initial cerebrospinal fluid (CSF) picture revealed neutrophilic pleocytosis and normal glycorrhachia. CSF culture was negative. The patient was put on invasive mechanical ventilation and started on intravenous antibiotics. There was a rapid improvement in clinical condition without any residual neurological deficit within the next few days. Aseptic meningitis following neuraxial anaesthesia can be prevented by strict aseptic protocols and careful inspection of visible impurities while administering the intrathecal drug. Detailed history taking, clinical examination, and focused investigations can distinguish between bacterial and chemical meningitis. Appropriate diagnosis of this entity may guide the treatment regimen, reducing hospital stay and cost.

Local anesthetic dosing and toxicity of adult truncal catheters: a narrative review of published practice.

BACKGROUND/IMPORTANCE: Anesthesiologists frequently use truncal catheters for postoperative pain control but with limited characterization of dosing and toxicity. OBJECTIVE: We reviewed the published literature to characterize local anesthetic dosing and toxicity of paravertebral and transversus abdominis plane catheters in adults. EVIDENCE REVIEW: We searched the literature for bupivacaine or ropivacaine infusions in the paravertebral or transversus abdominis space in humans dosed for 24 hours. We evaluated bolus dosing, infusion dosing and cumulative 24-hour dosing in adults. We also identified cases of local anesthetic systemic toxicity and toxic blood levels. FINDINGS: Following screening, we extracted data from 121 and 108 papers for ropivacaine and bupivacaine respectively with a total of 6802 patients. For ropivacaine and bupivacaine, respectively, bolus dose was 1.4 mg/kg (95% CI 0.4 to 3.0, n=2978) and 1.0 mg/kg (95% CI 0.18 to 2.1, n=2724); infusion dose was 0.26 mg/kg/hour (95% CI 0.06 to 0.63, n=3579) and 0.2 mg/kg/hour (95% CI 0.06 to 0.5, n=3199); 24-hour dose was 7.75 mg/kg (95% CI 2.1 to 15.7, n=3579) and 6.0 mg/kg (95% CI 2.1 to 13.6, n=3223). Twenty-four hour doses exceeded the package insert recommended upper limit in 28% (range: 17%-40% based on maximum and minimum patient weights) of ropivacaine infusions and 51% (range: 45%-71%) of bupivacaine infusions. Toxicity occurred in 30 patients and was associated with high 24-hour dose, bilateral catheters, cardiac surgery, cytochrome P-450 inhibitors and hypoalbuminemia. CONCLUSION: Practitioners frequently administer ropivacaine and bupivacaine above the package insert limits, at doses associated with toxicity. Patient safety would benefit from more specific recommendations to limit excessive dose and risk of toxicity.

Local anesthetic dosing and toxicity of pediatric truncal catheters: a narrative review of published practice.

BACKGROUND/IMPORTANCE: Despite over 30 years of use by pediatric anesthesiologists, standardized dosing rates, dosing characteristics, and cases of toxicity of truncal nerve catheters are poorly described. OBJECTIVE: We reviewed the literature to characterize dosing and toxicity of paravertebral and transversus abdominis plane catheters in children (less than 18 years). EVIDENCE REVIEW: We searched for reports of ropivacaine or bupivacaine infusions in the paravertebral and transversus abdominis space intended for 24 hours or more of use in pediatric patients. We evaluated bolus dosing, infusion dosing, and cumulative 24-hour dosing in patients over and under 6 months. We also identified cases of local anesthetic systemic toxicity and toxic blood levels. FINDINGS: Following screening, we extracted data from 46 papers with 945 patients.Bolus dosing was 2.5 mg/kg (median, range 0.6-5.0; n=466) and 1.25 mg/kg (median, range 0.5-2.5; n=294) for ropivacaine and bupivacaine, respectively. Infusion dosing was 0.5 mg/kg/hour (median, range 0.2-0.68; n=521) and 0.33 mg/kg/hour (median, range 0.1-1.0; n=423) for ropivacaine and bupivacaine, respectively, consistent with a dose equivalence of 1.5:1.0. A single case of toxicity was reported, and pharmacokinetic studies reported at least five cases with serum levels above the toxic threshold. CONCLUSIONS: Bolus doses of bupivacaine and ropivacaine frequently comport with expert recommendations. Infusions in patients under 6 months used doses associated with toxicity and toxicity occurred at a rate consistent with single-shot blocks. Pediatric patients would benefit from specific recommendations about ropivacaine and bupivacaine dosing, including age-based dosing, breakthrough dosing, and intermittent bolus dosing.

Local Anesthetic Systemic Toxicity During Transversus Abdominis Plane Block With Liposomal Bupivacaine.

Local anesthetic systemic toxicity (LAST) is a rare but potentially fatal outcome associated with local anesthetic administration. Liposomal bupivacaine (LB; EXPAREL®) is a widely used local anesthetic with extended-release and liposomal formulation that carries an improved cardiac and central nervous system safety profile. However, there is limited data regarding LAST associated with liposomal bupivacaine. Here is described a case of local anesthetic systemic toxicity in a 68-year-old male who presented with obstructing sigmoid adenocarcinoma and underwent open sigmoidectomy with end descending colostomy. The operation was complicated by LAST following transversus abdominis plane block injection with liposomal bupivacaine resulting in cardiac arrest. Return of spontaneous circulation was achieved following advanced cardiac life support and infusion of 20% I.V. fat emulsion. Given the widespread use of local anesthetics, providers must be aware of the pathophysiology, diagnosis, and immediate treatment of LAST.

Protocol for a randomized controlled trial of endoscopic ultrasound guided celiac plexus neurolysis (EUS-CPN) with vs without bupivacaine.

BACKGROUND: Pancreatic cancer is a devastating disease with less than 5% 5-year survival. Inoperable patients often present with pain. Randomized controlled trial have shown that endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) improves pain control. It is usually performed by injecting bupivacaine followed by absolute alcohol around the celiac axis. STUDY DESIGN: Single center, randomized, double blind controlled trial of EUS-CPN with and without bupivacaine in patients with inoperable malignancy (pancreatic or other) involving the celiac plexus. The study was approved by research ethics board with approval number of 2022-9969, 21.151 and registered on ClinicalTrials.gov (NCT04951804). DISCUSSION: We hypothesize that bupivacaine is superfluous and may actually reduce pain control by diluting the neurolytic effect of alcohol. Bupivacaine is also potentially dangerous in that it may produce serious adverse events such as arrythmias and cardiac arrest if inadvertently injected intravascularly. CONCLUSION: This randomized trial is designed to assess whether bupivacaine is of any value during EUS-CPN.

Local anaesthetic systemic toxicity complicating intraoperative intercostal nerve blocks: What do clinicians need to know to prevent similar occurrence?

Local anaesthetic systemic toxicity is a life-threatening adverse event that may occur after administration of local anaesthetics through a variety of routes. Local anaesthetic systemic toxicity is always a potential complication and may occur with all local anaesthetics and in any route of administration. Local anaesthetic systemic toxicity primarily affects the central nervous system and the cardiovascular system and may be fatal. The following is a case of local anaesthetic systemic toxicity complicating surgeon-performed intraoperative intercostal nerve blocks at multiple levels, with a mixture of liposomal bupivacaine and bupivacaine hydrochloride in a patient who underwent video-assisted segmental lung resection for lung cancer under general anaesthesia. Local anaesthetic systemic toxicity presented with seizures and hypotension. The patient was successfully managed and fully recovered. This case illustrates the importance of awareness regarding the prevention, diagnosis and treatment of local anaesthetic systemic toxicity among medical professionals who administer local anaesthetics.

Pericapsular nerve group block in hip arthroplasty: A prospective randomized trial.

OBJECTIVES: This study aimed to evaluate the analgesic effect of the ultrasound-guided pericapsular nerve group (PENG) block in hip arthroplasty (HA) surgery. DESIGN: A prospective double-blinded, randomized study. SETTING: Tertiary institutional clinical care. PARTICIPANTS: Fifty patients, more than 50 years old of both genders, were chosen according to the American Society of Anesthesiologists classification, with physical status I-III, and scheduled for unilateral HA surgeries. INTERVENTIONS: Patients were randomized to receive either a sham PENG block with 20 mL of normal saline (control group) or a PENG block with 20 mL of bupivacaine 0.25 percent (PENG group). MAIN OUTCOME MEASURES: From the onset of the first request for rescue opioid analgesia, preoperative pain scores before and after block (at rest and with a raised straight leg), the incidence of quadriceps weakness after the block, intraoperative fentanyl consumption, post-operative pain scores, and morphine consumption, besides the presence and frequency of adverse events, were recorded. RESULTS: The patients undergoing PENG block with bupivacaine had prolonged durations before the first analgesic request, lower perioperative pain scores, less intraoperative rescue fentanyl, and less post-operative morphine consumption than the control group, with nonsignificant motor weakness after the block and similar adverse events. CONCLUSIONS: The PENG block provided effective perioperative analgesia for HA with prolonged duration of analgesia, nonsignificant motor effects, reduced perioperative opioids consumption, and no major side effects.

Retrospective evaluation of the effects of traditional interscalene block alone versus combined with superior truncus block-associated diaphragm paralysis during arthroscopic shoulder surgery.

OBJECTIVES: The aim of this study was to investigate the effects of traditional interscalene block (ISB) alone and ISB combined with superior truncus block (STB)-associated diaphragm paralysis evaluated by ultrasound, duration of analgesia, and rate of complication in patients undergoing arthroscopic shoulder surgery. PATIENTS AND METHODS: Between January 2020 and December 2022, a total of 285 patients (158 males, 127 females; mean age: 48.0±15.1 years; range, 18 to 80 years) who underwent arthroscopic shoulder surgery under ISB, either alone or combined with STB, were retrospectively analyzed. The patients were operated under ISB alone using 30 mL 0.5% bupivacaine (n=140) or ISB using 10 mL (n=67) or 5 mL 0.5% bupivacaine (n=78) combined with STB using 20 mL 0.5% bupivacaine. Ultrasound reports of all patients' diaphragm function were also retrieved. Duration of analgesia, need for additional analgesics, and the type of analgesic drugs, and evaluations of patient and surgeon satisfactions were evaluated. Degree of diaphragm paralysis considered as complete (≥75%), partial (25.1 to 74.9%) and no paralysis (≤25%) were evaluated for comparison between the block types. RESULTS: The patients underwent operation due to rotator cuff rupture (n=218) or Bankart (n=67). Duration of analgesia, need for additional analgesia, and the type of analgesic drugs used were comparable between the block types. The most common complication was Horner syndrome (n=96, 33.68%) which was significantly lower in ISB (5 mL) +STB (20 mL) than the others (17.9% vs. 41.4% and 37.3%, p=0.002). The ISB (5 mL bupivacaine 0.5%) + STB (20 mL bupivacaine 0.5%) resulted in less complete diaphragm paralysis with adequate surgical anesthesia not requiring general anesthesia. CONCLUSION: The ISB using 5 mL of 0.5% bupivacaine + STB instead of traditional ISB alone can be preferred due to the low rate of complete hemi-diaphragm paralysis with adequate surgical anesthesia/analgesia and high patient and surgeon satisfaction.

Postoperative injectable opioid use and incidence of surgical site complications after use of liposomal bupivacaine in canine gastrointestinal foreign body surgery.

OBJECTIVE: To compare postoperative analgesic use and postoperative complications between dogs that received liposomal bupivacaine (LB) during surgical gastrointestinal foreign body (GIFB) removal and those that did not. STUDY DESIGN: Retrospective study. ANIMALS: Two hundred five dogs. METHODS: Medical records for all dogs with GIFB removal at the Purdue University Veterinary Hospital between May 2017 and August 2021 were searched. Incomplete records and dogs with less than 2 weeks' veterinary follow up were excluded. Data collected included: patient information, time until surgery, intraoperative findings, surgical data (including perforation at time of surgery, linear vs. solid, enterotomy vs. enterectomy), use of LB (including time and manner of administration), time to extubation after surgery, in-hospital postoperative analgesic use and duration, and postoperative complications. Fentanyl was noted as used/not used, quantified as mean hourly rate over 12 h intervals. All analyses were performed using commercial statistical software with p < .05 as the significance level. RESULTS: Dogs that received LB were heavier (n = 65, median 28.5 kg) than those that did not (n = 140, median 24.4 kg) (p = .005). Postoperative fentanyl use (p < .05 between 13 and 72 h) and hourly rates (p < .05 between 13 and 48 h) were less, and postoperative time in the intensive care unit (ICU) (p < .001) and hospital were shorter (p < .001) in dogs receiving LB. Postoperative wound complications were seen in 7/65 dogs (10.8%, 95% CI = 4.4-21.0%) with LB and 4/140 (2.9%, 95% CI = 0.8-7.2%) without LB (p = .039). CONCLUSION: Use of LB was associated with reduced postoperative analgesic use, and shortened ICU and hospital stay but also with wound complications. CLINICAL SIGNIFICANCE: Caution should be used when using LB in (clean) contaminated surgeries.

Anesthesia characteristic of an algorithm of bupivacaine dose based on height in caesarean section under spinal anesthesia: a retrospective cohort study.

BACKGROUND: An algorithm of bupivacaine dose based on height is applied to reduce maternal hypotension in caesarean section under spinal anesthesia. This study is designed to further verify whether the algorithm of bupivacaine dose based on height is suitable. METHODS: The parturients were grouped according to height. The comparison of anesthesia characteristic among subgroups was carried out. The univariate and multivariate binary logistic regressions were executed to reanalyze the interference factor for the anesthesia characteristic. RESULTS: When the dose of bupivacaine was adjusted by using the height based dosing algorithm, except for weight (P < 0.05), other general data did not present statistical changes with height (P > 0.05); the incidences of complications, characteristics of sensory or motor block, quality of anesthesia and neonatal outcome were of no statistical difference among parturients with different heights (P > 0.05); the height, weight and body mass index were not related with maternal hypotension (P > 0.05). When the dose of bupivacaine is constant, except for weight and body mass index (P > 0.05), the height was the independent risk factor for maternal hypotension (P < 0.05). CONCLUSIONS: Except for weight and body mass index, the height has an influence on the bupivacaine dose. It is reasonable that the bupivacaine dose is adjusted by using this dosing algorithm based on height. TRIAL REGISTRATION: This study was registered at http://clinicaltrials.gov (13/04/2018, NCT03497364).

The use of liposomal bupivacaine in fracture surgery: a review.

Historically, opioids have played a major role in the treatment of postoperative pain in orthopedic surgery. A multitude of adverse events have been associated with opioid use and alternative approaches to pain relief are being investigated, with particular focus on multimodal pain management regimens. Liposomal bupivacaine (EXPAREL) is a component of some multimodal regimens. This formulation of bupivacaine encapsulates the local anesthetic into a multivesicular liposome to theoretically deliver a consistent amount of drug for up to 72 hours. Although the use of liposomal bupivacaine has been studied in many areas of orthopedics, there is little evidence evaluating its use in patients with fractures. This systematic review of the available data identified a total of eight studies evaluating the use of liposomal bupivacaine in patients with fractures. Overall, these studies demonstrated mixed results. Three studies found no difference in postoperative pain scores on postoperative days 1-4, while two studies found significantly lower pain scores on the day of surgery. Three of the studies evaluated the quantity of narcotic consumption postoperatively and failed to find a significant difference between control groups and groups treated with liposomal bupivacaine. Further, significant variability in comparison groups and study designs made interpretation of the available data difficult. Given this lack of clear evidence, there is a need for prospective, randomized clinical trials focused on fully evaluating the use of liposomal bupivacaine in fracture patients. At present, clinicians should maintain a healthy skepticism and rely on their own interpretation of the available data before widely implementing the use of liposomal bupivacaine.

Plasma concentrations of levobupivacaine in neonates during caudal epidural analgesia maintained over 48 hours.

BACKGROUND: Differences in neonatal pharmacokinetics are known to cause systemic accumulation of levobupivacaine with adverse effects during epidural analgesia. Therefore, it is not recommended to surpass 48 hours of administration in neonates. Free and total levobupivacaine levels are considered as predictors of toxicity. OBJECTIVE: The aim of the LEVON pilot study was to detect the accumulation of levobupivacaine during epidural analgesia exceeding 48 hours in neonates. METHODS: Ten neonates received a loading dose of levobupivacaine (1.25 mg/kg) followed by a continuous infusion (0.2 mg/kg/hour) epidurally. Free and total levobupivacaine concentrations were measured 0.5, 1, 6, 12, 36, 72 and 144 hours after the start of infusion. Cumulative doses of levobupivacaine, pain scores and clinical signs of toxicity were used for assessing efficacy and safety. RESULTS: The median concentrations of total levobupivacaine were 586.0, 563.0, 837.5, 957.0, 1930.0, 708.5 and 357.5 ng/ml. The median concentrations of free levobupivacaine were 4.0, 3.6, 5.5, 3.6, 5.5, 0.8 and 0.0 ng/ml. Three patients reached concerning concentrations of total levobupivacaine. Levels of free levobupivacaine remained low. No signs of toxicity were observed. CONCLUSION: Caudal epidural analgesia with levobupivacaine lasting longer than 48 hours appears to be safe providing that free levobupivacaine levels are below the presumed threshold for toxicity (Tab. 1, Fig. 1, Ref. 29). Text in PDF www.elis.sk Keywords: free levobupivacaine, total levobupivacaine, neonate, caudal continuous epidural analgesia, postoperative pain.

Electroacupuncture alleviates multifidus muscle injury by modulating mitochondrial function and Ca2+ uptake.

Multifidus muscles maintain the stability of the lumbar spine and play a crucial role in the pathogenesis of nonspecific lower back pain. Previous studies have shown that electroacupuncture (EA) can relieve the symptoms of low back pain and reduce injury to the lumbar multifidus muscles. In this study, a rat model of lumbar multifidus muscle injury was established by 0.05% bupivacaine injection and subsequently treated with EA at bilateral "Weizhong" (BL40) acupoints. Disruption of the function and structure of multifidus muscles, increased cytosolic Ca2+ in multifidus myocytes, and reduced mitochondrial fission and ATP production were observed in the model group. Additionally, increased expression of the mitochondrial calcium uniporter (MCU) promoted mitochondrial reuptake of Ca2+ , reversing the excessive increase in cytoplasmic Ca2+ . However, the excessive increase in MCU not only aggravated the increased cytoplasmic Ca2+ but also decreased the expression of the mitochondrial division proteins dynamin-related protein 1 (Drp1) and mitochondrial fission factor (MFF). EA inhibited the overexpression of MCU, promoted mitochondrial reuptake of Ca2+ , and reversed cytosolic Ca2+ overload. Furthermore, EA regulated the expression of the mitochondrial fission proteins Drp1 and MFF and promoted the production of ATP, helping the recovery of mitochondrial function after multifidus injury. Therefore, EA can protect against bupivacaine-induced mitochondrial dysfunction, possibly by attenuating MCU overexpression in the inner mitochondrial membrane and reducing Ca2+ overloading in muscle cells, thereby protecting mitochondrial function and maintaining the normal energy demand of muscle cells.