Ingrid Berling

Hematologic Effects and Complications of Snake Envenoming

Hematologic abnormalities are the most common effects of snake envenoming globally. Venom-induced consumption coagulopathy (VICC) is the commonest and most important. Other hematologic abnormalities are an anticoagulant coagulopathy and thrombotic microangiopathy. Venom-induced consumption coagulopathy is a venom-induced activation of the clotting pathway by procoagulant toxins, resulting in clotting factor consumption and coagulopathy. The type of procoagulant toxin differs between snakes and can activate prothrombin, factor X, and factor V or consume fibrinogen. The most useful investigation in VICC is a prothrombin time/international normalized ratio. The d-dimer may assist in early diagnosis, but fibrinogen levels often add little in the clinical setting. Bedside investigations would be ideal, but point-of-care testing international normalized ratio and whole blood clotting tests have been shown to be unreliable in VICC. The major complication of VICC is hemorrhage, including intracranial hemorrhage which is often fatal. The role of antivenom in VICC is controversial and may only be beneficial for some types of snakes including Echis spp where the duration of abnormal clotting is reduced from more than a week to 24 to 48 hours. In contrast, antivenom does not appear to speed the recovery of VICC in Australian snake envenoming. Other treatments for VICC include factor replacement, observation and prevention of trauma, and heparin. An Australian study showed that fresh-frozen plasma speeds recovery of VICC, but early use may increase consumption. There is no evidence to support heparin.

Prolonged QT Risk Assessment in Antipsychotic Overdose Using the QT Nomogram

STUDY OBJECTIVE Antipsychotic drugs are frequently reported to cause QT prolongation and torsade de pointes. We aim to investigate the potential risk of torsade de pointes in antipsychotic overdose by assessing the QT interval with the QT nomogram. METHODS All presentations to a toxicology service between January 1987 and May 2013 were reviewed. Admissions with single ingestions of an antipsychotic greater than maximum daily dose were extracted. Demographics, dose, ECG, and outcomes (arrhythmias and death) were obtained. QT intervals in multiple leads were manually measured and the median taken. QT-heart rate (QT-HR) pairs were plotted on the QT nomogram and defined as prolonged if above the abnormal line. The QTcF (Fridericias HR correction) was calculated and compared with dose. RESULTS From 2,356 antipsychotic overdoses, 494 were included. There were no abnormal QT-HR pairs in 4 aripiprazole, 31 pericyazine, 14 trifluoperazine, and 7 haloperidol overdoses. Abnormal QT intervals occurred in 9 of 16 amisulpride overdoses (56%; 95% confidence interval [CI] 31% to 79%), 16 of 57 thioridazine overdoses (28%; 95% CI 17% to 42%), and 5 of 29 chlorpromazine overdoses (17%; 95% CI 7% to 36%). Abnormal QT intervals occurred in 5 of 41 risperidone overdoses (12%; 95% CI 5% to 27%), 10 of 202 quetiapine overdoses (5%; 95% CI 3% to 9%), and 2 of 76 olanzapine overdoses (3%; 95% CI 0.5% to 10%), but there was no correlation between dose and QTcF, and most abnormal QT intervals were at fast HR. An additional 186 single antipsychotic ingestions with noncardiotoxic coingestants had similar proportions of abnormal QT. There was 1 case of torsade de pointes in a thioridazine overdose. CONCLUSION There appeared to be significant risk of QT prolongation with amisulpride and thioridazine overdoses. Although there were abnormal QT intervals for quetiapine, olanzapine, and risperidone overdoses, they were associated with tachycardia and not dose dependent, and so were unlikely to be associated with increased torsade de pointes risk.

A prospective observational study of a novel 2-phase infusion protocol for the administration of acetylcysteine in paracetamol poisoning

Abstract Context: The current 3-phase acetylcysteine infusion for paracetamol poisoning delivers half the dose over 15–60 min and frequently results in adverse reactions. Objective: We aimed to determine adverse reaction frequency with a modified 2-phase infusion protocol with a longer initial infusion. Materials and methods: A prospective observational study of a modified 2-phase acetylcysteine protocol was undertaken at two hospitals. Acetylcysteine was commenced on admission and ceased if paracetamol concentrations were low-risk (below the nomogram line). The first infusion was 200 mg/kg over 4–9 h based on ingestion time or 4 h for staggered/chronic ingestions. The second infusion was 100 mg/kg over 16 h. Pre-defined outcomes were frequency of adverse reactions (systemic hypersensitivity reactions or gastrointestinal); proportion with alanine transaminase (ALT) > 1000 U/L or abnormal ALT. Results: 654 paracetamol poisonings were treated with the new protocol; median age 29 y (15–98 y); 453 females; 576 acute and 78 staggered/chronic ingestions. In 420 (64%) acetylcysteine was stopped for low-risk paracetamol concentrations. An adverse reaction occurred in 229/654 admissions (35%; 95% CI: 31–39%): 173 (26.5%; 95% CI: 23–30%) only gastrointestinal, 50 (8%; 95% CI: 6–10%) skin only systemic hypersensitivity reactions; and three severe anaphylaxis (0.5%; 95% CI: 0.1–1.5%; all hypotension). Adverse reactions occurred in 111/231 (48%) receiving full treatment compared to 116/420 (28%) in whom the infusion was stopped early (absolute difference 20%; 95% CI: 13–28%; p < 0.0001). In 200 overdoses < 10 g, one had toxic paracetamol concentrations, but 53 developed reactions. Sixteen patients had an ALT > 1000 U/L and 24 an abnormal ALT attributable to paracetamol; all but one had treatment commenced >12 h post-ingestion. Conclusion: A 2-phase acetylcysteine infusion protocol results in a fewer reactions in patients with toxic paracetamol concentrations, but is not justified in patients with low-risk paracetamol concentrations.

Oxycodone overdose causes naloxone responsive coma and QT prolongation

BACKGROUND Although there are limited data on oxycodone overdose, it has been suggested that, in addition to central nervous system (CNS) depression, oxycodone may cause QT prolongation. Given the high prescription rate and increasing use of oxycodone, an understanding of its effects and treatment in overdose is necessary. AIM To investigate the clinical features, electrocardiogram (ECG) parameters and treatment of oxycodone overdose. DESIGN Retrospective review of a clinical database. METHODS One hundred and thirty-seven oxycodone overdoses were identified from admissions to a toxicology unit between January 2001 and May 2011. Demographic information, details of ingestion, clinical effects, ECG parameters [heart rate (HR), QT and QRS], naloxone use and length of stay (LOS) were extracted from a clinical database. QT was measured manually and plotted on a QT nomogram. LOS was extracted for all overdoses over the same period. RESULTS From 137 oxycodone overdoses, 79 (58%) ingested immediate release (IR) and 58 (42%) ingested sustained release (SR) or a combination of IR and SR. The median age was 40 years [interquartile range (IQR): 33-49 years], and 87 were female (64%). The median ingested dose of IR oxycodone was 70 mg (IQR: 40-100, range: 5-200), compared to 240 mg (IQR: 80-530, range: 30-1600) for SR oxycodone. Benzodiazepines were the most frequent co-ingested drug in 52 (38%) cases. No arrhythmias were recorded. Twenty-four patients (18%) had bradycardia of which five had a HR < 50 beats/min. From 116 available ECGs, the median QRS was 95 ms (IQR: 90-102 ms), and there were 20 (17%) abnormal QT-HR pairs. Naloxone boluses were required in 65 admissions (47%), and 34 (25%) required a naloxone infusion. There was higher overall naloxone use with SR and IR + SR (32/58, 55%) compared to IR oxycodone (33/79, 42%). The median LOS was 18 h (IQR: 12-35), which was greater than the median LOS for all toxicology admissions at 15 h (IQR: 8-24) over the same period. Patients requiring a naloxone infusion had an even greater LOS of 36 h (IQR: 20-62 h). CONCLUSION In addition to the expected CNS depression, the opioid oxycodone can cause bradycardia and QT prolongation in overdose. The SR formulation is associated with the use of naloxone infusions and a longer LOS.

Intravenous paracetamol toxicity in a malnourished child

We present a case of intravenous (IV) paracetamol overdose in a nutritionally malnourished child during hospital admission. A ten-fold IV paracetamol dosing error ocurred, with delayed recognition and treatment resulting in transient hepatotoxicity, with a peak alanine transaminase (ALT) of 1378 IU/L in a 3-year-old child. Our case suggests that hepatotoxicity may occur for lower doses of IV paracetamol compared to oral ingestion, especially in the malnourished, and that a dose less than 150 mg/kg of IV paracetamol should be used to define treatment following overdose in a child with potential nutritional deficiencies.

Mirtazapine overdose is unlikely to cause major toxicity.

Objective. There is limited information on mirtazapine overdose, but cases of severe effects (seizures, serotonin toxicity and coma) have been reported. We aimed to investigate the clinical effects and complications of mirtazapine overdose. Methods. This was an observational case series of mirtazapine overdoses (> 120 mg) identified from admissions to a toxicology unit between January 1987 and August 2013. Demographic information, details of ingestion, clinical effects, ECG parameters (HR, QT and QRS), and length of stay were extracted from a clinical database. Results. From 267 mirtazapine overdoses, there were 89 single-agent mirtazapine ingestions and 178 cases where mirtazapine was taken with at least one other drug. The median age of the 89 single-agent mirtazapine ingestions was 36 years [interquartile range (IQR): 26–49 years; Range: 15–81 years]; 45 were female (51%). The median ingested dose was 420 mg (IQR: 270–750 mg; Range: 150–1350 mg) and 41 patients (46%) had a Glasgow coma score (GCS) < 15, but the minimum GCS was 10. There were no seizures, serotonin toxicity or delirium. Tachycardia occurred in 29 patients (33%) and hypertension in 32 patients (36%). The median QRS was 80 ms (Range: 80–120 ms) and there were no cases with QT prolongation. There were no arrhythmias and no deaths. The median length of stay was 14 h (IQR: 8.8–18.2 h; Range:2.2–75 h). No single-agent mirtazapine patient was admitted to intensive care. The 178 patients taking co-ingestants had more severe toxicity depending on the co-ingested drug. Conclusion. Mirtazapine appears to be relatively benign in overdose, associated with tachycardia, mild hypertension and mild CNS depression not requiring intervention.

Digital Holter measurement of QT prolongation in ziprasidone overdose

Objective. QT prolongation is an important complication in drug overdose, particularly with some antidepressants and antipsychotics. There are problems with the accurate measurement of the QT interval and determining for what QT interval patients should be monitored, because of the risk of torsades des pointes (TdP). We report a case of ziprasidone overdose with QT prolongation, demonstrating different methods of measuring the QT interval. Case report. A 47-year-old female presented after taking 1.2 g of ziprasidone and 250 mg of diazepam. She was taking propranolol and venlafaxine therapeutically. She developed bradycardia and QT prolongation (540 msec). She was transferred to a telemetry bed and observed for 48 h until her QT interval returned to normal (460 msec). QT intervals were extracted from (1) 12-lead digital Holter recordings (gold standard); (2) automated measurements on standard electrocardiograms (ECGs); and (3) manual measurements on standard ECGs, and compared on a QT versus time plot. An abnormal QT was determined based on the QT nomogram. Manual QT measurements showed a clear temporal association between ziprasidone overdose and a long QT, consistent with accurate QT measurements using continuous 12-lead Holter recordings with automatic QT measurements. However, standard automated measurements did not indicate an abnormal QT. Conclusions. Manual measurement of the QT interval appeared to be similar to the more accurate measurement of the QT by automated digital Holter recordings and better than standard automated measurements. Manual QT measurements would be more appropriate in clinical assessment of patients.

Acute behavioural disturbance associated with phenibut purchased via an internet supplier

Abstract Context. Toxicity from recreational substances marketed for other purposes is a well-documented clinical entity. We present two cases of phenibut toxicity procured via the internet. Case Details. A 20-year-old female presented to the emergency department (ED) having used phenibut the prior day. The main finding was a decreased level of consciousness, however when roused she became delirious. Supportive care only was required with no specific intervention. The patient made a full recovery over a 24-hour period and admitted to use of phenibut purchased online. Plasma phenibut concentration was 29.7 μg/ml. A 38-year-old male presented to ED with an agitated delirium. The prior evening he had used tetrahydrocannabinol or THC, alcohol and phenibut, the latter purchased via the internet. His behavioural state had a suboptimal response to parenteral sedation. He was subsequently intubated for airway protection in the context of ongoing sedation to optimally manage his behavioural state. Post extubation the next morning he admitted using phenibut. Plasma phenibut concentration was 36.5 μg/ml. Discussion. Altered mental status was the predominant manifestation of phenibut toxicity in these cases. Clinicians to be aware of how phenibut toxicity may present as the internet has widened access to such substances.

The Half RR Rule: A Poor Rule of Thumb and Not a Risk Assessment Tool for QT Interval Prolongation.

OBJECTIVES Measuring the QT interval on an electrocardiogram (ECG) is integral to risk assessment of Torsade de Pointes (TdP). This study aimed to investigate the accuracy of the 1/2 RR rule as a risk assessment tool for drug-induced TdP, comparing it to the QT nomogram, Bazetts corrected QT (QTcB), and Fridericias corrected QT (QTcF). METHODS The authors calculated sensitivity and specificity of the 1/2 RR rule using a published data set of 129 cases of drug-induced TdP and 316 controls (noncardiotoxic overdoses), compared to the QT nomogram, QTcB > 500 msec and QTcF > 500 msec. To further determine the value of the 1/2 RR rule, its observed positive, and negative agreement were calculated when compared to the QT nomogram for determining an abnormal QT in eight samples of different drugs in overdose. RESULTS The sensitivity and specificity of the 1/2 RR rule were 88% (95% confidence interval [CI] = 80% to 93%) and 53% (95% CI = 47% to 58%), respectively, compared to the QT nomogram (sensitivity = 97%, 95% CI = 92% to 99%; specificity = 99%, 95% CI = 97% to 100%). It was also less sensitive than QTcB > 500 msec and had a lower specificity than QTcB > 500 msec and QTcF > 500 msec. In drug overdose patients, the 1/2 RR rule had poor observed agreement averaging 41%, which was mainly due to poor positive agreement, except for amisulpride where there was good agreement. CONCLUSIONS The 1/2 RR rule was not as sensitive as the QT nomogram or QTcB > 500 msec for drug-induced TdP. It had poor positive agreement in almost all overdose patients, resulting in over half of patients receiving unnecessary cardiac monitoring and repeat ECGs.

Catecholamine-induced cardiomyopathy resulting from life-threatening funnel-web spider envenoming.

Wepresent twocasesof cardiomyopathy in life-threatening funnel-webspider envenoming.A33-yearoldman bitten by amale Sydney funnel-web spider developed autonomic and neuromuscular excess, pulmonary oedema, hypotension and cardiogenic shock. Hewas treatedwith antivenom, dobutamine, noradrenaline and high-dose insulin, and recovered over 4 days. Echocardiograms showed severe systolic dysfunction, andhigh catecholamineconcentrationsweremeasured in his blood. A 13-year-old girl developed cardiogenic shock after a funnel-web spider bite, confirmed on echocardiogram treated with antivenom and dobutamine. Funnel-web spider envenoming appears to cause catecholamineinduced cardiomyopathy and cardiogenic pulmonary oedema resulting from catecholamine excess. Antivenom did not reverse the cardiomyopathy.