The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action.

Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1R1074H and PHF5AY36C The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action (MOA). Using several related chemical probes, we validate the pose of the compound and support their substrate competitive MOA by comparing their activity against both strong and weak pre-mRNA substrates. Finally, we present functional data and structure-activity relationship (SAR) on the PHF5AR38C mutation that sensitizes cells to some chemical probes but not others. Developing small molecule splicing modulators represents a promising therapeutic approach for a variety of diseases, and this work provides a significant step in enabling structure-based drug design for these elaborate natural products. Importantly, this work also demonstrates that the utilization of cryo-EM in drug discovery is coming of age.

Navigating methotrexate toxicity: Examining the therapeutic roles of folinic acid and glucarpidase.

Methotrexate (MTX) toxicity varies depending on factors such as dosing frequency (acute or repeated), dosage (low or high) and the administration route (oral, parenteral or intrathecal). Renal impairment can trigger or exacerbate MTX toxicity. Acute oral low-dose MTX (LDMTX) overdoses seldom lead to toxicity due to the saturable maximal bioavailable dose, but toxicity risks increase with repeated low doses (>3 days), high-dose MTX (HDMTX) or intrathecal poisoning. Folinic acid shares MTX transporters in the gut and cells and bypasses the MTX-induced dihydrofolate reductase inhibition. The required folinic acid dosage differs for low-dose and high-dose MTX toxicities. Acute LDMTX poisoning rarely requires folinic acid, while chronic LDMTX poisoning needs low-dose folinic acid until cellular function is restored. In HDMTX toxicities, early intravenous folinic acid administration is recommended, with dose and duration being guided by MTX concentrations and clinical improvement. In intrathecal MTX poisoning, folinic acid should be administered intravenously. Glucarpidase, a recombinant bacterial enzyme, has a high affinity for MTX and folate analogues in the intravascular or intrathecal systems. It decreases serum MTX concentrations by 90%-95% within 15 min. Its primary indication is for intrathecal MTX poisoning. It is rarely indicated in HDMTX toxicity unless patients have renal injury. However, there is no literature evidence supporting its use in HDMTX poisoning. Its use is limited by its significant cost and lack of availability. Haemodialysis can be potentially useful for MTX removal in cases where glucarpidase is not available. Additionally, fluid hydration, renal support and urine alkalinization are important adjunctive therapies for managing MTX toxicities.

Home Therapies to Neutralize Button Battery Injury in a Porcine Esophageal Model.

STUDY OBJECTIVE: Button battery ingestion can cause alkaline esophageal injury. There is interest in first-aid household products to neutralize the injury. The objective was to investigate which household products are effective at reducing button battery injury. METHODS: Two cadaveric porcine experiments were performed. Experiment 1 utilized esophageal mucosal segments. A button battery (3VCR2032) was placed onto the mucosa, and substances (saline control, honey, jam, orange juice, yogurt, milk, and cola) were applied every 10 minutes for 6 applications. Tissue pH was measured every 10 minutes, and macroscopic ulceration size was assessed at 120 minutes. Experiment 2 used an intact esophageal model with a battery inserted into the lumen and jam, honey, and saline irrigation as per experiment 1. Tissue pH, macroscopic and histopathology changes were evaluated at 60, 90 and 120 minutes. RESULTS: In experiment 1, only honey and jam had a lower mean tissue pH at 120 minutes (8.0 [standard deviation [SD] 0.9, n=12] and 7.1 [SD 1.7, n=12], respectively) compared to saline solution 11.9 (SD 0.6, n=6, P<.0001). Both honey (0.24 cm2, SD 0.17) and jam (0.37 cm2, SD 0.40) had smaller mean areas of ulceration compared to saline solution (3.90 cm2, SD 1.03, P<.0001). In experiment 2, honey and jam had significantly lower mean tissue pH at all timepoints compared to saline solution. Histologic changes were evident at 60 minutes in the saline group, whereas honey and jam exhibited no or minimal changes until 120 minutes. CONCLUSIONS: Honey and jam were able to neutralize injury caused by a button battery resulting in a smaller area of ulceration. Jam should be further explored as a possible first-aid option as an alternative to honey in suspected button battery ingestion prior to definitive management.

Case series profile of olanzapine post-injection delirium/sedation syndrome.

Olanzapine pamoate is an intramuscular depot injection for the treatment of schizophrenia. Approximately 1.4% of patients develop a serious adverse event called post-injection delirium/sedation syndrome (PDSS), characterised by drowsiness, anticholinergic and extrapyramidal symptoms. The objective is to investigate olanzapine PDSS presentations including clinical features and treatment approach. This is a retrospective review of olanzapine PDSS patients from three toxicology units and the NSW Poisons Information Centre between 2017 and 2022. Adult patients were included if they had intramuscular olanzapine then developed PDSS criteria. Clinical symptoms, treatment, timing and length of symptoms were extracted into a preformatted Excel database. There were 18 patients included in the series, with a median age of 49 years (interquartile range [IQR]: 38-58) and male predominance (89%). Median onset time post injection was 30 min (IQR: 11-38). PDSS symptoms predominate with drowsiness, confusion and dysarthria. Median length of symptoms was 24 h (IQR: 20-54). Most common treatment included supportive care without any pharmacological intervention (n = 10), benzodiazepine (n = 4) and benztropine (n = 3). In one case, bromocriptine and physostigmine followed by oral rivastigmine were given to manage antidopaminergic and anticholinergic symptoms respectively. This proposed treatment combination could potentially alleviate some of the symptoms but needs further studies to validate the findings. In conclusion, this case series supports the characterisation of PDSS symptomology predominantly being anticholinergic with similar onset (<1 h) and duration (<72 h). Bromocriptine is proposed to manage PDSS if patients develop severe dopamine blockade and physostigmine followed by rivastigmine for anticholinergic delirium.

Prescribing trend of tapentadol in a Sydney local health district.

AIMS: Tapentadol, an opioid with mu-opioid receptor agonism and noradrenaline reuptake inhibition, has been increasingly used in Australia since 2011. However, data on hospital prescribing trends and indications are scarce. This study aimed to investigate hospital prescribing trends of tapentadol, oxycodone and tramadol in a Sydney local health district (LHD) and the indications for tapentadol hospital prescriptions in an Australian tertiary hospital. METHODS: We analysed 5-year patient dispensing for tapentadol, oxycodone and tramadol from four hospitals in a Sydney LHD with data expressed as oral morphine equivalents (OME). We also conducted a retrospective review of 140 and 54 patients prescribed tapentadol at a tertiary hospital's surgical and spinal units in 2020. RESULTS: Over 5 years in the Sydney LHD, there was a 19.5% reduction in total dispensing of these opioids from 1 225 210 to 986 477.5 OME milligrams. Decreases were specifically for oxycodone (-37.8% immediate-release, -65.2% sustained-release) and tramadol (-74.6% immediate-release, -70.1% sustained-release). Contrastingly, hospital prescriptions of tapentadol immediate-release increased by 223.2% between 2018-19 and 2020-21 while sustained-release increased by 17.9% from 2016-17 to 2020-21. By 2020-21, tapentadol overtook oxycodone to become the most prescribed opioid in the Sydney LHD (51.4%). At the hospital's surgical units, 137 (97.9%) patients were prescribed tapentadol for acute post-operative pain with the majority (54.0%) prescribed both immediate-release and sustained-release tapentadol, while 71.1% were prescribed for neuropathic pain in the spinal units. CONCLUSION: In a Sydney LHD, tapentadol prescriptions increased significantly to become the preferred opioid analgesic. At the hospital's surgical units, off-label prescriptions of tapentadol sustained-release for acute post-operative pain were observed.

Optimising alkalinisation and its effect on QRS narrowing in tricyclic antidepressant poisoning.

AIMS: The objectives were to determine the effect of NaHCO3 and/or mechanical ventilation on the biochemical profile and serum alkalinisation in tricyclic antidepressant (TCA) poisoning and investigate the impact of effective alkalinisation therapy on the QRS interval in TCA poisoning. METHODS: This was a retrospective review of TCA poisonings from three Australian toxicology units and a poisons information centre (Jan 2013 to Jan 2019). We included patients with TCA toxicity who ingested>10 mg/kg or had clinically significant toxicities consistent with TCA poisoning, and analysed patients' clinical, electrocardiogram and biochemical data. RESULTS: Of 210 patients, 84 received NaHCO3 and ventilation (dual therapy), 12 NaHCO3 , 46 ventilation and 68 supportive care treatment. When compared with single/supportive groups, patients who received dual therapy had taken a significantly higher median dose of TCA (1.5 g vs1.3 g, P < .001), a longer median maximum QRS interval (124 ms, interquartile ranges [IQR] 108-138 vs106 ms, IQR 98-115, P < .001) and were more likely to have seizures (14% vs3%, P = .006) and arrhythmias (17% vs1%, P < .001). The dual therapy group demonstrated greater increases in serum pH (median 0.11, IQR 0.04-0.17) compared to the single/supportive therapy group (median 0.03, IQR -0.01-0.09, p < .001). A greater proportion of patients reached the target pH 7.45-7.55 in the dual therapy group (59%) compared to the single/supportive therapy group (10%) (P < .001). For each 100 mmol bolus of NaHCO3 given, the median increase in serum sodium was 2.5 mmol/L (IQR 1.5-4.0). QRS narrowing occurred twice as quickly in the dual therapy vs single/supportive therapy group. CONCLUSIONS: A combination of NaHCO3 and mechanical ventilation was most effective in achieving serum alkalinisation and was associated with a more rapid narrowing of the QRS interval. We advise that the maximal dose of NaHCO3 should be <400 mmol (6 mmol/kg).

Just 'nanging' around - harmful nitrous oxide use: a retrospective case series and review of Internet searches, social media posts and the coroner's database.

BACKGROUND: The chronic recreational inhalation of nitrous oxide (N2 O) 'nanging', can have adverse neurological and psychiatric effects. AIM: To evaluate cases of chronic N2 O use presenting to two hospitals, as well as to evaluate nationally N2 O deaths reported to the coroner and trends in Internet searches and social media posts related to N2 O. METHODS: Retrospective review of two toxicology units, from July 2017 to October 2020, of patients presenting with chronic N2 O use and neurological and/or psychiatric symptoms. We evaluated 10 years (2010-2019) of Internet search and social media trends involving N2 O and the National Coronial Information System (NCIS) database for deaths across Australia. RESULTS: Twenty-two patients were identified: median age 22 years, half female, 17 Asian background and 15 students. Presentations included decreased mobility or unsteady gait (n = 15) and psychiatric symptoms (n = 5). The median reported bulb use/day was 300 (interquartile range (IQR): 200-370), for a median of 6 months (IQR: 3-24). On magnetic resonance imaging, 10/18 had subacute combined degeneration of the spinal cord and 7/7 sensorimotor neuropathy on nerve conduction studies. All received high-dose intramuscular vitamin B12 and 11 methionine. Despite prolonged rehabilitation, nine required walking aids on discharge. Since 2017, social media posts and Internet searches for N2 O increased rapidly, the latter mostly directed at obtaining N2 O canisters. From the NCIS, 36 deaths were identified, 12 unintentional (recreational drug use), 20 intentional self-harm and 4 traumatic. CONCLUSION: We report a case series of symptomatic chronic N2 O use, many with ongoing neurological sequelae. Furthermore, a sharp increase in Internet searches to obtain N2 O cannisters was noted. Education of high-risk student groups on the long-term sequelae is important.

Machine read frontal QRS-T angle and QTc is no substitute for manual measurement of QTc in pro-arrhythmic drug overdose.

INTRODUCTION: To investigate whether there is an association between the blocking of cardiac potassium channels, which is characterised by a prolonged QTc interval and the frontal QRS-T angle after overdose by QT prolonging drugs. METHODS: We obtained patient medical records associated with QT prolonging drugs from 3 different hospitals: the Calvary Mater Newcastle Hospital (CMNH), Royal Prince Alfred Hospital (RPAH) and Prince of Wales Hospital (POWH). RPAH and POWH admissions were taken between 4/01/2017 to 1/11/2019, and CMNH admissions were taken between 4/01/2013 to 24/06/2018. Demographic information and details of overdose were collected. All admission ECGs were manually measured. Linear regression was used to assess the relationship between various QTc formulas and the frontal QRS-T angle. A Bland-Altman plot was used to examine agreement between manual and machine QT intervals. RESULTS: 144 patients met the inclusion criteria for analysis. None of the patients developed torsades de pointes (TdP). There was no linear association between the QRS-T angle and the various QTc formulas (For QRS-T angle: QTcRTH: p = 0.76, QTcB: p = 0.83, QTcFri: p = 0.90, QTcFra: p = 0.13, QTcH: p = 0.97; For square root transformation of the QRS-T angle: QTcRTH: p = 0.18, QTcB: p = 0.33, QTcFri: p = 0.95, QTcFra: p = 0.47, QTcH: p = 0.33). Agreement between machine and manual QT measurements was low. CONCLUSIONS: The frontal QRS-T angle cannot substitute the QTc in assessing the blockage of cardiac potassium channels in drug induced long QT syndrome. We also support the consensus that despite the availability of machine measurements of the QT interval, manual measurements should also be performed.

Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5).

BACKGROUND & AIMS: Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS: We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS: Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION: Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY: Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION: Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.

Haemodialysis for lithium poisoning: Translating EXTRIP recommendations into practical guidelines.

OBJECTIVES: This study aimed to determine the impact on practice of applying the Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup criteria to lithium toxicity. METHOD: We retrospectively examined the medical records of patients from three hospitals who presented with chronic or acute on chronic lithium poisoning with a lithium concentration ≥1.3 mmol/L (2008-2018). We determined which criteria were met by patients and their subsequent course. We developed and validated a method to predict if lithium concentration would be >1mmol/L at 36 hours. RESULTS: There were 111 acute on chronic and 250 chronic lithium toxic patients. Nine patients (2.5%) were treated with haemodialysis. Six chronic patients had neurological sequelae. The "estimated lithium concentration at 36 hours > 1 mmol/L" criterion required pharmacokinetic calculations. A simple nomogram was developed using Estimated Glomerular Filtration Rate (eGFR) and lithium concentration. For chronic toxicity, the nomogram would have correctly predicted lithium concentration >1.4 mmol/L at 36 hours in all except two patients. If EXTRIP criteria were followed, dialysis would have been instituted for 211 patients (58%). However, only 51 patients with chronic toxicity fulfilled both a concentration and a clinical criterion. Late neurological sequelae were observed in five out of six patients who fulfilled a concentration and a clinical criterion on admission, with the sixth meeting these criteria shortly after admission. CONCLUSIONS: The EXTRIP criteria are too broad, but minor modifications allow haemodialysis to be targeted to those most at risk of sequelae. Most acute on chronic poisonings do not need haemodialysis, but it might shorten hospital stay in those with very high concentrations. The nomogram accurately predicts the fall in lithium concentration for chronic poisoning.

Seasonal and temperature effect on serum lithium concentrations.

BACKGROUND: Lithium remains the gold standard treatment for bipolar disorder. However, it has a very narrow therapeutic index (0.6-0.8 mmol/L). It has been suggested that high environmental temperature can lead to dehydration, elevated plasma lithium concentration and then lithium toxicity. OBJECTIVES: We aimed to investigate the effect of seasonal and short-term changes in temperature on serum lithium concentrations in Sydney, Australia. METHODS: We retrospectively analysed data from all patients who had serum lithium concentrations taken from the Prince of Wales and Sutherland Hospitals between 2008 and 2018. Temperature data came from the Bureau of Meteorology. We examined correlations between lithium concentrations and the preceding 5 days maximum temperatures, month and season. We also performed a longitudinal analysis of the effect of temperature and seasons within selected patients who had repeated levels. RESULTS: A total of 11,912 serum lithium concentrations from 2493 patients were analysed. There was no significant association between higher lithium concentration and preceding higher temperatures (r = -0.008, p = 0.399). There was also no important seasonal or monthly variation, across all patients or in the smaller cohort with longitudinal data (n = 123, r = 0.008, 95% confidence interval: [-0.04, 0.06]). CONCLUSION: There were no clinically important differences in serum lithium concentration related to seasons, months or temperatures, which suggests that patients on lithium are able to adequately maintain hydration during hot weather in Sydney.

Comparison of Wells and YEARS clinical decision rules with D-dimer for low-risk pulmonary embolus patients.

BACKGROUND: Assessment of pulmonary embolism (PE) remains a diagnostic and investigative burden to emergency departments. The decision of which D-dimer cut-off to use in low-risk patients remains controversial. AIMS: To compare the sensitivity and specificity of varying D-dimer cut-offs in the diagnosis of PE for Wells low-risk patients. METHODS: Retrospective review of patients presenting to a tertiary emergency department over 42 months who had a D-dimer performed for PE risk stratification. Wells scores were calculated for each patient, those with Wells score of ≤4 ('PE unlikely') were analysed. Four D-dimer thresholds were compared, including traditional threshold (≥0.5 µg/mL), age-adjusted (≥age in years × 0.01 µg/mL), doubled-traditional threshold and YEARS criteria. RESULTS: During the study period, 2291 D-dimers were ordered for suspected PE, of which 2125 were low risk for PE. Of these low-risk patients 46 (2.2%) were found to have a PE. The sensitivity and specificity for each D-dimer threshold were traditional threshold (95.6% and 65.6%), age-adjusted (93.5% and 71.7%), doubled traditional (69.6% and 85.5%) and YEARS criteria (80.4% and 84.0%). Utilising an age-adjusted threshold, YEARS criteria or doubled-traditional threshold would have resulted in 70, 217 and 245 fewer imaging investigations. CONCLUSIONS: The prevalence of PE in this low-risk cohort was very low. Utilising an age-adjusted D-dimer would have reduced imaging tests performed while maintaining good sensitivity. Although The YEARS criteria and doubled-traditional threshold would have reduced scanning considerably both had sensitivities of less than 90%.

Pharmacological treatment of cardiac glycoside poisoning.

Cardiac glycosides are an important cause of poisoning, reflecting their widespread clinical usage and presence in natural sources. Poisoning can manifest as varying degrees of toxicity. Predominant clinical features include gastrointestinal signs, bradycardia and heart block. Death occurs from ventricular fibrillation or tachycardia. A wide range of treatments have been used, the more common including activated charcoal, atropine, ß-adrenoceptor agonists, temporary pacing, anti-digoxin Fab and magnesium, and more novel agents include fructose-1,6-diphosphate (clinical trial in progress) and anticalin. However, even in the case of those treatments that have been in use for decades, there is debate regarding their efficacy, the indications and dosage that optimizes outcomes. This contributes to variability in use across the world. Another factor influencing usage is access. Barriers to access include the requirement for transfer to a specialized centre (for example, to receive temporary pacing) or financial resources (for example, anti-digoxin Fab in resource poor countries). Recent data suggest that existing methods for calculating the dose of anti-digoxin Fab in digoxin poisoning overstate the dose required, and that its efficacy may be minimal in patients with chronic digoxin poisoning. Cheaper and effective medicines are required, in particular for the treatment of yellow oleander poisoning which is problematic in resource poor countries.

The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department.

STUDY OBJECTIVE: We investigate the safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department (ED). METHODS: This was a prospective observational study in 6 EDs (August 2009 to April 2013). Adult patients requiring parenteral sedation for acute behavioral disturbance received droperidol 10 mg. If this did not sedate the patient within 15 minutes, further sedation was allowed but droperidol 10 mg was recommended as part of a sedation protocol. The primary outcome was the proportion of patients with an abnormal QT interval, defined by the at-risk line on the QT nomogram. Secondary outcomes were effectiveness determined by the time to sedation measured on the Sedation Assessment Tool, use of additional sedation, adverse events, and injury to staff or patients. RESULTS: There were 1,009 patients with an ECG performed within 2 hours of droperidol administration, with a median dose of 10 mg (interquartile range [IQR]10 to 17.5 mg). Thirteen of the 1,009 patients had an abnormal QT (1.3%; 95% confidence interval 0.7% to 2.3%), but 7 of these had another cause attributed for prolonged QT (methadone, escitalopram, amiodarone, or preexisting). In 1,403 patients sedated with a median total dose of droperidol of 10 mg (IQR 10 to 20 mg), the median time to sedation was 20 minutes (IQR 10 to 30 minutes) and 97% were sedated within 120 minutes. Additional sedation was required for 435 patients (31.0%; 95% confidence interval 28.6% to 33.5%). Adverse events occurred in 70 patients (5%) and oversedation without complications in 109 (8%), the latter more common for patients receiving benzodiazepines as additional sedation (16/109 [15%]). There were no cases of torsades de pointes. Injuries occurred in 34 staff members and 4 patients. CONCLUSION: The study supports the use of high-dose droperidol as a safe sedating agent for patients with acute behavioral disturbance in the ED. There is no evidence of increased risk for QT prolongation with the doses used in this study.

Common pitfalls in the use of hypertonic sodium bicarbonate for cardiac toxic drug poisonings.

BACKGROUND: Hypertonic sodium bicarbonate is advocated for the treatment of sodium channel blocker poisoning, but its efficacy varies amongst different sodium channel blockers. This Commentary addresses common pitfalls and appropriate usage of hypertonic sodium bicarbonate therapy in cardiotoxic drug poisonings. SODIUM BICARBONATE WORKS SYNERGISTICALLY WITH HYPERVENTILATION: Serum alkalinization is best achieved by the synergistic effect of hypertonic sodium bicarbonate and hyperventilation (PCO2 ∼ 30-35 mmHg [0.47-0.6 kPa]). This reduces the dose of sodium bicarbonate required to achieve serum alkalinization (pH ∼ 7.45-7.55) and avoids adverse effects from excessive doses of hypertonic sodium bicarbonate. VARIABILITY IN RESPONSE TO SODIUM BICARBONATE TREATMENT: Tricyclic antidepressant poisoning responds well to sodium bicarbonate therapy, but many other sodium channel blockers may not. For instance, drugs that block the intercellular gap junctions, such as bupropion, do not respond well to alkalinization. For sodium channel blocker poisonings in which the expected response is unknown, a bolus of 1-2 mmol/kg sodium bicarbonate can be used to assess the response to alkalinization. SODIUM BICARBONATE CAN EXACERBATE TOXICITY FROM DRUGS ACTING ON MULTIPLE CARDIAC CHANNELS: Hypertonic sodium bicarbonate can cause electrolyte abnormalities such as hypokalaemia and hypocalcaemia, leading to QT interval prolongation and torsade de pointes in poisonings with drugs that have mixed sodium and potassium cardiac channel properties, such as hydroxychloroquine and flecainide. THE GOAL FOR HYPERTONIC SODIUM BICARBONATE IS TO ACHIEVE THE ALKALINIZATION TARGET (∼PH 7.5), NOT COMPLETE CORRECTION OF QRS COMPLEX PROLONGATION: Excessive doses of hypertonic sodium bicarbonate commonly occur if it is administered until the QRS complex duration is < 100 ms. A prolonged QRS complex duration is not specific for sodium channel blocker toxicity. Some sodium channel blockers do not respond, and even when there is a response, it takes a few hours for the QRS complex duration to return completely to normal. In addition, QRS complex prolongation can be due to a rate-dependent bundle branch block. So, no further doses should be given after achieving serum alkalinization (pH ∼ 7.45-7.55). MAXIMAL DOSING FOR HYPERTONIC SODIUM BICARBONATE: A further strategy to avoid overdosing patients with hypertonic sodium bicarbonate is to set maximum doses. Exceeding 6 mmol/kg is likely to cause hypernatremia, fluid overload, metabolic alkalosis, and cerebral oedema in many patients and potentially be lethal. RECOMMENDATION FOR THE USE OF HYPERTONIC SODIUM BICARBONATE IN SODIUM CHANNEL BLOCKER POISONING: We propose that hypertonic sodium bicarbonate therapy be used in patients with sodium channel blocker poisoning who have clinically significant toxicities such as seizures, shock (systolic blood pressure < 90 mmHg, mean arterial pressure <65 mmHg) or ventricular dysrhythmia. We recommend initial bolus dosing of hypertonic sodium bicarbonate of 1-2 mmol/kg, which can be repeated if the patient remains unstable, up to a maximum dose of 6 mmol/kg. This is recommended to be administered in conjunction with mechanical ventilation and hyperventilation to achieve serum alkalinization (PCO2∼30-35 mmHg [4-4.7 kPa]) and a pH of ∼7.45-7.55. With repeated bolus doses of hypertonic sodium bicarbonate, it is imperative to monitor and correct potassium and sodium abnormalities and observe changes in serum pH and on the electrocardiogram. CONCLUSIONS: Hypertonic sodium bicarbonate is an effective antidote for certain sodium channel blocker poisonings, such as tricyclic antidepressants, and when used in appropriate dosing, it works synergistically with hyperventilation to achieve serum alkalinization and to reduce sodium channel blockade. However, there are many pitfalls that can lead to excessive sodium bicarbonate therapy and severe adverse effects.

Cognitive impairment following sedative overdose.

INTRODUCTION: Patients with sedative overdose may have residual cognitive impairment at the time they are deemed medically cleared for discharge. Impairment could affect the performance of high-risk activities, including driving. The Trail Making Test is an alpha-numeric assessment that can be performed at the bedside to assess cognitive function. We examined whether there were differences in cognitive function when medically cleared between patients that overdosed on sedative and non-sedative drugs. METHODS: A prospective, observational study assessed cognitive function using the Trail Making Test between 2018 and 2021. Patients (16 years and greater) completed testing upon medical clearance if they spoke English and had no previous neurological injury. Continuous covariates were compared using t-tests or Mann-Whitney U tests and multiple linear regression; binary variables were modelled using logistic regression. RESULTS: Of 171 patients enrolled, 111 (65 per cent) had sedative overdose; they were older (median 32.1 versus 22.2 years) and more likely to be male (58.6 per cent versus 36.7 per cent). Benzodiazepines and paracetamol were the commonest drug overdoses. Patients with sedative overdose performed worse on Trail Making Test part A (37.0 versus 33.1 seconds, P = 0.017) and Trail Making Test part B (112.4 versus 81.5 seconds, P = 0.004). Multiple linear regression analysis indicated that patient age (P < 0.001, 1.7 seconds slower per year, 95 per cent confidence interval: 0.9-2.6 seconds) and perception of recovery (P = 0.006, 36.4 seconds slower if perceived not recovered, 95 per cent confidence interval: 10.8-62.0 seconds) were also associated with Trail Making Test part B times. Patients with sedative overdose were more likely to be admitted to the intensive care unit (Odds Ratio: 4.9, 95 percent confidence interval: 1.1-22.0; P = 0.04). DISCUSSION: Our results are broadly in keeping with previously published work, but include a wider range of drug overdose scenarios (polypharmacy and recreational drugs). While patients demonstrated some perception of their cognitive impairment, our model could not reliably be used to provide individual discharge advice. The study design did not allow us to prove causation of cognitive impairment, or to make comparison between the strength of an overdose to the trail making test time. CONCLUSIONS: Trail Making Test results suggested that patients who had sedative drug overdoses may have significant cognitive deficits even when medically cleared. Risk of harm may be minimised with advice to avoid high-risk activities such as driving. More profound impacts seen on the Trail Making Test part B than A may mean higher-order thinking is more affected than simple cognitive function.