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.

Rivastigmine for the management of anticholinergic delirium.

INTRODUCTION: Anticholinergic agents are commonly taken in overdose, often causing delirium. The spectrum of anticholinergic delirium ranges from mild agitation to severe behavioural disturbance. Physostigmine is an effective treatment for anticholinergic delirium, but its availability is limited. As rivastigmine is readily available, it has been used to manage anticholinergic delirium; however, there is limited research investigating its use. METHOD: This was a retrospective review of patients with anticholinergic delirium treated in two toxicology units with rivastigmine (oral capsule or transdermal patch) from January 2019 to June 2023. The primary outcome was the use of further parenteral treatment (sedation or physostigmine) for delirium post rivastigmine administration. RESULTS: Fifty patients were administered rivastigmine for the management of anticholinergic delirium. The median age was 36 years (interquartile range: 25-49 years) and 27 (54 per cent) were females. Features consistent with anticholinergic toxicity included tachycardia in 44 (88 per cent) and urinary retention requiring catheterisation in 40 (80 per cent). Forty-three patients (86 per cent) were treated with physostigmine before rivastigmine administration. Twenty-two were managed with transdermal rivastigmine (most commonly 9.5 mg/24 hour patch), and 28 with oral rivastigmine 6 mg. Further parenteral sedation and/or physostigmine treatment were required more often in patients given transdermal than oral rivastigmine [16/22 (73 per cent) versus 9/28 (32 per cent), P = 0.010)]. No patients had bradycardia or gastrointestinal symptoms following rivastigmine administration. One patient with a history of epilepsy had a seizure, 1.5 hours post physostigmine administration and 7 hours post transdermal rivastigmine. DISCUSSION: Rivastigmine has been increasingly used for the management of patients with anticholinergic delirium, due to the lack of availability of physostigmine. In this case series, rivastigmine transdermal patch appeared to be less effective than oral rivastigmine capsules, likely due to its slow onset of action and/or insufficient dose. CONCLUSION: Rivastigmine can be used to treat anticholinergic delirium. In our case series oral rivastigmine appeared more effective than transdermal rivastigmine.

Evaluating Clinical Prediction Rules for Bacteremia Detection in the Emergency Department: A Retrospective Review.

BACKGROUND: Bacteremia is a major cause of morbidity. Blood cultures are the gold standard for diagnosing bacteremia. OBJECTIVE: To compare previously published clinical decision rules for predicting a true positive blood culture (bacteremia) in the emergency department. METHODS: Retrospective analysis of medical records of patients who had a blood culture performed in a tertiary hospital emergency department in 2020 (12 months). Positive blood cultures were compared with randomly selected negative blood cultures (1:4 ratio). Blood cultures were analyzed per patient presentation. Clinical data from patient presentations were extracted and appraised against the modified-Shapiro (mShapiro) rule and systemic inflammatory response syndrome (SIRS) criteria to calculate diagnostic accuracy to detect bacteremia. RESULTS: During the study period, 3870 blood cultures were taken from 2921 patients: 476 (12.3%) cultures were positive for bacterial growth, from 421 individual patient presentations (10 excluded as incomplete data). Of included patients, 338 were true positives and 73 contaminates, these were compared with 1446 patients with negative blood culture presentations. Evaluating mShapiro's rule and SIRS criteria to detect bacteremia vs. no bacteremia (negative + contaminated cultures) had a sensitivity of 94.4% (95% confidence interval [CI] 91.4-96.4%) and 84.9% (95% CI 80.7-88.3%), respectively, and a specificity of 37.9% (95% CI 35.5-40.1%) and 33.8% (95% CI 31.5-36.3%), respectively. Both had a high negative predictive value for bacteremia of 96.8% (95% CI 95.1-98.0) and 91.0% (95% CI 88.3-93.1) for mShapiro's rule and SIRS criteria, respectively. CONCLUSIONS: In this cohort, mShapiro's rule performed better than the SIRS criteria at predicting bacteremia.

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.

Intestinal injury in paracetamol overdose (ATOM-8).

BACKGROUND AND AIM: Paracetamol, a widely used medication, is known for its delayed hepatotoxicity in cases of overdose. However, the potential for intestinal toxicity resulting from very high paracetamol concentrations during absorption is not well explored. This study aims to investigate the presence of intestinal toxicity and its correlation with observations in early and late paracetamol toxicity. METHODS: Serial samples of 30 patients with acute paracetamol overdose (> 10 g or 200 mg/kg) were prospectively tested. Markers of enterocyte damage, including plasma intestinal fatty acid binding protein (IFABP) and selected gut-related microRNAs (miR-21, miR-122, miR-194, and miR-215), were analyzed. Sub-analysis was performed on patients presenting with hyperlactatemia defined as a lactate greater than 2 mmol/L within 12 h post ingestion. RESULTS: In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720 µg/L [interquartile range, IQR, 533-1644] vs 270 µg/L [IQR 153-558], P < 0.001). Four patients had early hyperlactatemia and had significantly higher median plasma IFABP compared with those without early hyperlactatemia (3028 µg/L [IQR 1399-3556] vs 574 µg/L [IQR 526-943], P = 0.007). Furthermore, two microRNAs (miR-122 and miR-215) were downregulated in early hyperlactatemia (P = 0.019 and P = 0.006, respectively). Plasma IFABP concentrations correlated with paracetamol concentration (Spearman's r = 0.55) and lactate (r = 0.60). CONCLUSIONS: Paracetamol overdose causes concentration-related intestinal toxicity, and this is a possible explanation for the early hyperlactatemia syndrome. Intestinal toxicity has potential impacts on pharmacokinetics of other agents ingested and on the evolution of hepatotoxicity. Further studies are required to explore the mechanisms and prognostic implications of intestinal toxicity.

Advances in the understanding of acetaminophen toxicity mechanisms: a clinical toxicology perspective.

INTRODUCTION: Acetaminophen (paracetamol) is a commonly used analgesic and antipyretic agent, which is safe in therapeutic doses. Acetaminophen poisoning due to self-harm or repeated supratherapeutic ingestion is a common cause of acute liver injury. Acetylcysteine has been a mainstay of treatment for acetaminophen poisoning for decades and is efficacious if administered early. However, treatment failures occur if administered late, in 'massive' overdoses or in high-risk patients. AREAS COVERED: This review provides an overview of the mechanisms of toxicity of acetaminophen poisoning (metabolic and oxidative phase) and how this relates to the assessment and treatment of the acetaminophen poisoned patient. The review focuses on how these advances offer further insight into the utility of novel biomarkers and the role of proposed adjunct treatments. EXPERT OPINION: Advances in our understanding of acetaminophen toxicity have allowed the development of novel biomarkers and a better understanding of how adjunct treatments may prevent acetaminophen toxicity. Newly proposed adjunct treatments like fomepizole are being increasingly used without robust clinical trials. Novel biomarkers (not yet clinically available) may provide better assessment of these newly proposed adjunct treatments, particularly in clinical trials. These advances in our understanding of acetaminophen toxicity and liver injury hold promise for improved diagnosis and treatment.

Acetaminophen Metabolites on Presentation Following an Acute Acetaminophen Overdose (ATOM-7).

Acetaminophen (APAP) is commonly taken in overdose and can cause acute liver injury via the toxic metabolite NAPQI formed by cytochrome (CYP) P450 pathway. We aimed to evaluate the concentrations of APAP metabolites on presentation following an acute APAP poisoning and whether these predicted the subsequent onset of hepatotoxicity (peak alanine aminotransferase > 1,000 U/L). The Australian Toxicology Monitoring (ATOM) study is a prospective observational study, recruiting via two poison information centers and four toxicology units. Patients following an acute APAP ingestion presenting < 24 hours post-ingestion were recruited. Initial samples were analyzed for APAP metabolites, those measured were the nontoxic glucuronide (APAP-Glu) and sulfate (APAP-Sul) conjugates and NAPQI (toxic metabolite) conjugates APAP-cysteine (APAP-Cys) and APAP-mercapturate (APAP-Mer). The primary outcome was hepatotoxicity. In this study, 200 patients were included, with a median ingested dose of 20 g, 191 received acetylcysteine at median time of 5.8 hours post-ingestion. Twenty-six patients developed hepatotoxicity, one had hepatotoxicity on arrival (excluded from analysis). Those who developed hepatotoxicity had significantly higher total CYP metabolite concentrations: (36.8 µmol/L interquartile range (IQR): 27.8-51.7 vs. 10.8 µmol/L IQR: 6.9-19.5) and these were a greater proportion of total metabolites (5.4%, IQR: 3.8-7.7) vs. 1.7%, IQR: 1.3-2.6, P < 0.001)]. Furthermore, those who developed hepatotoxicity had lower APAP-Sul concentrations (49.1 µmol/L, IQR: 24.7-72.2 vs. 78.7 µmol/L, IQR: 53.6-116.4) and lower percentage of APAP-Sul (6.3%, IQR: 4.6-10.9 vs. 13.1%, IQR, 9.1-20.8, P < 0.001)]. This study found that those who developed hepatotoxicity had higher APAP metabolites derived from CYP pathway and lower sulfation metabolite on presentation. APAP metabolites may be utilized in the future to identify patients who could benefit from increased acetylcysteine or newer adjunct or research therapies.

Clean the skin: Reducing blood culture contamination in the emergency department.

OBJECTIVE: To determine whether blood culture contamination (BCC) rates could be decreased in the ED by an educational programme. METHODS: Educational intervention focusing on a 1-min venepuncture cleaning time and providing a larger chlorhexidine alcohol swab. BCC rates were examined retrospectively 12-month pre-, and 9-month post-intervention. RESULTS: Six thousand nine hundred and fifty-three blood cultures were collected over the study period. The BCC rate was 2.4% pre-intervention versus 1.8% post-intervention, with no significant difference in BCC rates (Z-score = 1.862, P = 0.063). CONCLUSION: This educational intervention focusing on skin clean time did not significantly decrease BCC rates in a setting of an already low (<3%) BCC rate.

Tapentadol exposures and poisonings in Australia.

INTRODUCTION: Tapentadol is an atypical opioid with mu-receptor affinity and noradrenaline reuptake inhibition approved for use in Australia in 2011. However, data on tapentadol poisoning are scarce. OBJECTIVES: To investigate tapentadol poisonings and related deaths in Australia. METHODS: We performed a retrospective review of tapentadol poisonings from New South Wales Poisons Information Centre (NSWPIC) and three toxicology units in Australia. The National Coronial Information System (NCIS) database was searched to determine the number of tapentadol-related deaths. RESULTS: Between 2016 and 2020, 220 tapentadol calls were made to NSWPIC, with a 4.5-fold increase in tapentadol exposure calls. The median dose ingested was 575 mg (IQR: 300-1163 mg). Most overdoses included co-ingestions (75%), especially benzodiazepines (26%) and opioids (25%). From Jan 2016 to Dec 2021, 107 patients presented to the three toxicology units with tapentadol poisoning. The median dose ingested was 500 mg (IQR: 200-1400 mg). Most patients took co-ingestants (84%), including benzodiazepines (40%) and opioids (32%). Naloxone was administered in 39 patients (36%), 10 (9%) were intubated and the median length of stay was 18 h (IQR: 9-30). Thirty-five tapentadol-related deaths were recorded within NCIS between Jan 2015 and Oct 2021 with a median age of 51 years (IQR: 42-61 years). CONCLUSION: There are increasing tapentadol poisonings and deaths reported to the NSWPIC, three toxicology units, and NCIS in Australia. Most tapentadol poisonings were taken with benzodiazepines and/or other opioids.

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.

Delayed Acetaminophen Absorption Resulting in Acute Liver Failure.

Introduction. Acetaminophen is a common medication involved in deliberate and accidental self-poisoning. The acetaminophen treatment nomogram is used to guide acetylcysteine treatment. It is rare to develop hepatotoxicity with an initial acetaminophen concentration below the nomogram line. We present a case of acetaminophen ingestion with an initial concentration below the nomogram line that developed hepatic failure, due to a delayed peak acetaminophen concentration secondary to coingesting medications that slow gastric emptying. Case Report. A 43-year-old (55 kg) female presented after ingesting an unknown quantity of acetaminophen, clonidine, and alcohol. Her acetaminophen level was 41 mg/L (256 µmol/L) at 4.5 h post-ingestion, well below the nomogram line, and ALT was 25 U/L. Hence, acetylcysteine was not commenced. She was intubated for decreased level of conscious. A repeat acetaminophen level 4 h later was 39 mg/L (242 µmol/L), still below the nomogram line. She was extubated 24 h later.At 38 h post-ingestion she developed abdominal pain, the repeat acetaminophen level was 85 mg/L (560 µmol/L), ALT was 489 U/L, and acetylcysteine was commenced. The patient developed hepatic failure with a peak ALT of 7009 U/L and INR of 7.5 but made a full recovery. It was discovered that she had ingested a combination acetaminophen product containing dextromethorphan and chlorphenamine. Acetaminophen metabolites were measured, including nontoxic glucuronide and sulfate conjugates and toxic cytochrome P450 (CYP) metabolites. The metabolite data demonstrated increasing CYP metabolites in occurrence with the delayed acetaminophen peak concentration. Discussion. Opioids and antimuscarinic agents are known to delay gastric emptying and clonidine may also have contributed. These coingested medications resulted in delayed acetaminophen absorption. This case highlights the issue of altered pharmacokinetics when patients coingest gut slowing agents.

Too much of a good thing: Bicarbonate toxicity following treatment of sodium channel blocker overdose.

Although sodium bicarbonate can be a life-saving antidote for patients with overdoses resulting in sodium channel blockade, there has been a concerning rise in cases referred to the Poisons Information Centre where inappropriately large doses of bicarbonate have been used resulting in iatrogenic harm. We present a series of three clinical cases where excessive bicarbonate was used to treat poisonings and discuss our approach to managing cardiotoxicity secondary to sodium channel blockade. Serial blood gas analysis should be performed when using bicarbonate to ensure pH targets are met and severe alkalaemia, hypernatraemia and hypokalaemia are avoided. We encourage clinicians to contact the Poisons Information Centre (13 11 26) or their local clinical toxicologist when managing patients with life-threatening sodium channel blockade.

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).

Population pharmacokinetics of immediate-release and modified-release paracetamol and its major metabolites in a supratherapeutic dosing study.

OBJECTIVES: Overdose with paracetamol modified-release (MR) formulation, a bilayer tablet containing 69% slow-release component, has been increasing since its introduction to the market. However, little evidence exists for the management of MR paracetamol overdose. We aimed to develop a population pharmacokinetic (PK) model for immediate-release (IR) and MR paracetamol and its major metabolism, and quantitatively understand the formulation difference in toxicity assessment based on the nomogram line. METHODS: Data from a cross-over study design in nine healthy volunteers administered a single supratherapeutic oral dose (80 mg/kg) of either IR and MR paracetamol were available from a published study. Plasma concentrations for paracetamol and its metabolites glucuronide (APAPG) and sulfate conjugate (APAPS) for both formulations were measured and analysed with population pharmacokinetic (PK) method using NONMEM. Toxicity in both formulations was assessed by comparing the simulated paracetamol concentrations under different paracetamol dose levels with the 150 mg/L nomograms. The difference in the assessment was compared between the two formulations. RESULTS: Paracetamol concentrations for the IR formulation were described with a two-compartment model with first-order input and a lag time. The delayed time-course of MR paracetamol concentrations was best captured by a parallel absorption model in which the slow-release component was a serial zero-order then the first-order process. The formation of APAPG was linear, while APAPS concentrations were best fitted by a Michaelis-Menten process. The relative bioavailability of MR paracetamol compared to IR (FMR/IR) was estimated as 0.81. The simulated probability of making different toxicity assessments based on nomogram line was increased with dose levels and was as high as 14.6% after 22 g IR or MR paracetamol ingested. CONCLUSIONS: A joint parent-metabolite model to describe time-course profiles of both IR and MR paracetamol and its metabolites APAPG and APAPS concentrations was developed. Simulations from the model showed that toxicity assessment based on the 150 mg/L nomograms is not suitable in MR paracetamol overdoses.

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.

The serotonin toxidrome: shortfalls of current diagnostic criteria for related syndromes.

INTRODUCTION: Serotonin syndrome (toxicity) describes adverse drug effects from toxic amounts of intra-synaptic central nervous system serotonin. A wide range of drugs have been implicated to cause serotonin toxicity, not all justifiably. The plausible agents all have a final common pathway resulting in a substantial increase in central nervous system serotonergic neurotransmission. Serotonin toxicity is characterized by neuromuscular excitation, mental status changes, and autonomic dysregulation. Signs and symptoms represent a spectrum of toxicity (mild to life-threatening) related to increasing serotonin concentrations. As there is no consensus on the threshold for "toxicity" or diagnostic criteria, the true incidence of serotonin toxicity is unknown. The incidence in overdose is easier to quantify and is reasonably common in serotonergic antidepressant overdoses. In a large case series of overdoses, moderate serotonin toxicity occurred in 14% of poisonings with a selective serotonin reuptake inhibitor. While half those ingesting a monoamine oxidase inhibitor in combination with a serotonergic agent in overdose exhibit at least moderately severe serotonin toxicity. In contrast, the incidence of serotonin toxicity in those on therapeutic serotonergic agents appears to be very low. OBJECTIVES: To provide a narrative review of the current diagnostic criteria, utilizing case reports of fatalities to evaluate how many meet the various diagnostic criteria and propose practical solutions to resolve controversies in diagnosis. METHODS: A review of serotonin toxicity diagnostic criteria in the English literature was completed by searching Embase and PubMed from January 1990 to July 2021 for the keywords "serotonin syndrome/toxicity" paired with "diagnostic criteria" or "diagnosis." Also, fatal cases of serotonin toxicity identified from a recent systematic review were independently examined to determine what diagnostic criteria were met and whether serotonin toxicity or another cause was most likely. REVIEW OF DIAGNOSIS CRITERIA: Serotonin toxicity is a clinical diagnosis, four diagnostic criteria (Sternbach, Serotonin Syndrome Scale, Radomski, and Hunter) have been proposed. However, the Serotonin Syndrome Scale has not been validated in patients with serotonin toxicity and only utilized in those on a serotonergic agent. The remaining three criteria are utilized more widely but have undergone little refinement or validation. REVIEW OF FATAL CASES: Shortfalls with diagnostic criteria can be illustrated by examining case fatalities. Of 55 fatal cases reviewed, 12 (22%) were unlikely to be serotonin toxicity. Sternbach and Radomski criteria were met by 25 (45%), 20 (36%) had insufficient data reported and 10 (18%) met an exclusion criterion. Few had sufficient information reported to determine whether Hunter Criteria were met, with only 13 (24%) documented as meeting the criteria, the remaining 42 (76%) had insufficient data. RESOLVING SHORTFALLS IN CURRENT DIAGNOSTIC CRITERIA: As serotonin toxicity is a clinical diagnosis, issues arise when basing the diagnosis on symptom criteria alone, without considering whether the drug/s ingested increase central nervous system serotonin or whether there is an alternative diagnosis. This has resulted in case reports and government warnings for drugs that cannot plausibly cause significant serotonin toxicity (e.g., ondansetron and antipsychotics). We propose when assessing for a serotonin toxidrome, both the causative agent(s) and clinical scenario is considered to determine the likelihood of serotonin toxicity. Then the clinical features assessed, those with a moderate to high prior probability (e.g., serotonergic drug-drug interaction, overdose, recent initiation or increase in dose of serotonergic agent/s) could be diagnosed based on the Hunter criteria. However, those with a low probability (e.g., stable therapeutic doses of a serotonergic agent) require more specific and stringent criteria. Finally, we propose a minimum dataset for case reports/series of serotonin toxicity. CONCLUSIONS: More complete and accurate reporting of serotonin toxicity cases is required in the future, to avoid further misleading associations that are physiologically implausible.

The relationship between admission glucose and lactate with critical illness amongst adult patients presenting to the emergency department.

AIM: Our aim was to determine the relationship between glucose and lactate amongst adult patients admitted to hospital via the emergency department. METHOD: We performed a cross-sectional observational study of 2541 patients admitted via the emergency department who had an admission glucose and lactate measurement available. RESULTS: 23% of the whole cohort had a diagnosis of diabetes. Glucose and lactate were predictors of the primary outcome of critical illness defined as composite of intensive care unit (ICU) admission or in-hospital death. In the multivariable analysis, lactate but not glucose remained an independent predictor of ICU/in hospital death in the group without diabetes. In the diabetes group, both glucose and lactate remained independent predictors of ICU admission/ in-hospital death. CONCLUSIONS: Hyperglycaemia and hyperlactataemia are part of the metabolic response to critical illness. Lactate and a diagnosis of diabetes modify the relationship between glycaemia and critical illness.