Publications by authors named "Darren M Roberts"

122 Publications

Death from severe, refractory methaemoglobinaemia: A case report to illustrate an increasingly frequent manifestation of deliberate self-poisoning.

Emerg Med Australas 2022 Aug 31;34(4):654-655. Epub 2022 May 31.

Clinical Pharmacology and Toxicology, St Vincent's Hospital Sydney, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/1742-6723.14020DOI Listing
August 2022

Life-threatening barium carbonate poisoning managed with intravenous potassium, continuous veno-venous haemodialysis and endoscopic removal of retained ceramic glazes.

Clin Toxicol (Phila) 2022 May 4:1-5. Epub 2022 May 4.

New South Wales Poisons Information Centre, The Children's Hospital Westmead, Westmead, Australia.

Introduction: Barium poisoning is rare but potentially severe. We describe a case of acute barium carbonate poisoning with cardiac arrest, managed with intravenous potassium, dialysis and endoscopic removal of retained ceramic glazes.

Case Report: A 38-year-old woman presented with vomiting 90 min after ingesting 3 cups of barium and strontium carbonate. Initial bloods noted potassium 2.8 mmol/L and creatinine 53 μmol/L. Electrocardiogram demonstrated prolonged corrected QT interval 585msec. Initial management included intravenous potassium. Four hours post-ingestion she developed proximal muscle weakness in upper limbs with a potassium of 2.2 mmol/L. At 15 h post-ingestion she developed profound muscle weakness, polymorphic ventricular tachycardia and cardiac arrest. Treatment included defibrillation, endotracheal intubation and continuous veno-venous haemodialysis (CVVHD) for metabolic derangement and enhanced elimination of barium. Chest X-ray 17 h post-ingestion demonstrated a large radio-opaque mass in the stomach, thought to be the ceramic glaze. Endoscopy removed the retained material 41 h post-ingestion. She was extubated 58 h post-ingestion and CVVHD was ceased on day 3. Serum creatinine peaked at 348 μmol/L on day 7, but normalised by discharge. Biphasic barium concentrations were noted, notably 94 μmol/L on admission, 195 μmol/L at 16 h, 95 μmol/L at 20 h, and 193 μmol/L at 30 h post-ingestion.

Conclusion: In barium poisoning with hypokalaemia, prompt potassium supplementation is required but rebound hyperkalaemia can occur. Endoscopic removal of ceramic glazes may be useful more than 12 h post-ingestion. Consider extracorporeal methods to enhance barium elimination in severe cases.
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http://dx.doi.org/10.1080/15563650.2022.2068424DOI Listing
May 2022

Life-threatening barium carbonate poisoning managed with intravenous potassium, continuous veno-venous haemodialysis and endoscopic removal of retained ceramic glazes.

Clin Toxicol (Phila) 2022 May 4:1-5. Epub 2022 May 4.

New South Wales Poisons Information Centre, The Children's Hospital Westmead, Westmead, Australia.

Introduction: Barium poisoning is rare but potentially severe. We describe a case of acute barium carbonate poisoning with cardiac arrest, managed with intravenous potassium, dialysis and endoscopic removal of retained ceramic glazes.

Case Report: A 38-year-old woman presented with vomiting 90 min after ingesting 3 cups of barium and strontium carbonate. Initial bloods noted potassium 2.8 mmol/L and creatinine 53 μmol/L. Electrocardiogram demonstrated prolonged corrected QT interval 585msec. Initial management included intravenous potassium. Four hours post-ingestion she developed proximal muscle weakness in upper limbs with a potassium of 2.2 mmol/L. At 15 h post-ingestion she developed profound muscle weakness, polymorphic ventricular tachycardia and cardiac arrest. Treatment included defibrillation, endotracheal intubation and continuous veno-venous haemodialysis (CVVHD) for metabolic derangement and enhanced elimination of barium. Chest X-ray 17 h post-ingestion demonstrated a large radio-opaque mass in the stomach, thought to be the ceramic glaze. Endoscopy removed the retained material 41 h post-ingestion. She was extubated 58 h post-ingestion and CVVHD was ceased on day 3. Serum creatinine peaked at 348 μmol/L on day 7, but normalised by discharge. Biphasic barium concentrations were noted, notably 94 μmol/L on admission, 195 μmol/L at 16 h, 95 μmol/L at 20 h, and 193 μmol/L at 30 h post-ingestion.

Conclusion: In barium poisoning with hypokalaemia, prompt potassium supplementation is required but rebound hyperkalaemia can occur. Endoscopic removal of ceramic glazes may be useful more than 12 h post-ingestion. Consider extracorporeal methods to enhance barium elimination in severe cases.
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http://dx.doi.org/10.1080/15563650.2022.2068424DOI Listing
May 2022

The serum glycolate concentration: its prognostic value and its correlation to surrogate markers in ethylene glycol exposures.

Clin Toxicol (Phila) 2022 07 24;60(7):798-807. Epub 2022 Mar 24.

Research Center, CIUSSS du Nord-de-l'île-de-Montréal, University of Montreal, Montreal, QC, Canada.

Context: Ethylene glycol poisoning manifests as metabolic acidemia, acute kidney injury and death. The diagnosis and treatment depend on history and biochemical tests. Glycolate is a key toxic metabolite that impacts prognosis, but assay results are not widely available in a clinically useful timeframe. We quantitated the impact of serum glycolate concentration for prognostication and evaluated whether more readily available biochemical tests are acceptable surrogates for the glycolate concentration.

Objectives: The objectives of this study are to 1) assess the prognostic value of the initial glycolate concentration on the occurrence of AKI or mortality in patients with ethylene glycol exposure (); 2) identify surrogate markers that correlate best with glycolate concentrations ).

Methods: A systematic review of the literature was performed using Medline/PubMed, EMBASE, Cochrane library, conference proceedings and reference lists. Human studies reporting measured glycolate concentrations were eligible. Glycolate concentrations were related to categorical clinical outcomes (acute kidney injury, mortality), and correlated with continuous surrogate biochemical measurements (anion gap, base excess, bicarbonate concentration and pH). Receiver operating characteristic curves were constructed to calculate the positive predictive values and the negative predictive values of the threshold glycolate concentrations that predict acute kidney injury and mortality. Further, glycolate concentrations corresponding to 100% negative predictive value for mortality and 95% negative predictive value for acute kidney injury were determined.

Results: Of 1,531 articles identified, 655 were potentially eligible and 32 were included, reflecting 137 cases from 133 patients for the prognostic study and 154 cases from 150 patients for the surrogate study. The median glycolate concentration was 11.2 mmol/L (85.1 mg/dL, range 0-38.0 mmol/L, 0-288.8 mg/dL), 93% of patients were treated with antidotes, 80% received extracorporeal treatments, 49% developed acute kidney injury and 13% died. The glycolate concentration best predicting acute kidney injury was 12.9 mmol/L (98.0 mg/dL, sensitivity 78.5%, specificity 88.1%, positive predictive value 86.4%, negative predictive value 80.9%). The glycolate concentration threshold for a 95% negative predictive value for acute kidney injury was 6.6 mmol/L (50.2 mg/dL, sensitivity 96.9%, specificity 62.7%). The glycolate concentration best predicting mortality was 19.6 mmol/L (149.0 mg/dL, sensitivity 61.1%, specificity 81.4%, positive predictive value 33.3%, negative predictive value 93.2%). The glycolate concentration threshold for a 100% negative predictive value for mortality was 8.3 mmol/L (63.1 mg/dL, sensitivity 100.0%, specificity 35.6%). The glycolate concentration correlated best with the anion gap ( = 0.73), followed by bicarbonate ( = 0.57), pH ( = 0.50) and then base excess ( = 0.25), while there was no correlation between the glycolate and ethylene glycol concentration ( = 0.00). These data can assist clinicians in planning treatments such as extracorporeal treatments and prognostication. Potentially, they may also provide some reassurance regarding when extracorporeal treatments can be delayed while awaiting the results of further testing in patients in whom ethylene glycol poisoning is suspected but not yet confirmed.

Conclusions: This systematic review demonstrates that the glycolate concentration predicts mortality (unlikely if <8 mmol/L [61 mg/dL]). The anion gap is a reasonable surrogate measurement for glycolate concentration in the context of ethylene glycol poisoning. The findings are mainly based on published retrospective data which have various limitations. Further prospective validation studies are of interest.
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http://dx.doi.org/10.1080/15563650.2022.2049811DOI Listing
July 2022

Treating ethylene glycol poisoning with alcohol dehydrogenase inhibition, but without extracorporeal treatments: a systematic review.

Clin Toxicol (Phila) 2022 07 21;60(7):784-797. Epub 2022 Mar 21.

Research Center, CIUSSS du Nord-de-l'île-de-Montréal, University of Montreal, Montreal, QC, Canada.

Context: Ethylene glycol is metabolized to toxic metabolites that cause acute kidney injury, metabolic acidemia, and death. The treatment of patients with ethylene glycol poisoning includes competitively inhibiting alcohol dehydrogenase with ethanol or fomepizole to prevent the formation of toxic metabolites, and extracorporeal treatments such as hemodialysis to remove ethylene glycol and its metabolites. In the absence of significant metabolic acidemia or kidney injury, it is hypothesized that extracorporeal treatments may be obviated without adverse outcomes to the patient if alcohol dehydrogenase inhibitors are used.

Objectives: The objectives of this study are to: (1) identify indicators predicting ADH inhibitor failure in patients with ethylene glycol poisoning treated with either ethanol or fomepizole for whom extracorporeal treatment was not performed (aside from rescue therapy, see below) (), and (2) validate if the anion gap, shown in a previous study to be the best surrogate for the glycolate concentration, is associated with acute kidney injury and mortality ().

Methods: We conducted a systematic review to identify all reported patients with ethylene glycol poisoning treated without extracorporeal treatments but with either fomepizole () or ethanol (). Analyses were performed using both one case per patient and all cases (if multiple events were reported for a single patient). Data were compiled regarding poisoning, biochemistry, and outcomes. Treatment failure was defined as mortality, worsening of acid-base status, extracorporeal treatments used as rescue, or a worsening of kidney or neurological function after alcohol dehydrogenase inhibition was initiated. Also, we performed an analysis of previously described anion gap thresholds to determine if they were associated with outcomes such as acute kidney injury and mortality.

Results: Of 115 publications identified, 96 contained case-level data. A total of 180 cases were identified with ethanol monotherapy, and 231 with fomepizole monotherapy. Therapy failure was noted mostly when marked acidemia and/or acute kidney injury were present prior to therapy, although there were cases of failed ethanol monotherapy with minimal acidemia (suggesting that ethanol dosing and/or monitoring may not have been optimal). Ethylene glycol dose and ethylene glycol concentration were predictive of monotherapy failure for ethanol, but not for fomepizole. In the anion gap study (207 cases), death and progression of acute kidney injury were almost nonexistent when the anion gap was less than 24 mmol/L and mostly observed when the anion gap was greater than 28 mmol/L.

Conclusion: This review suggests that in patients with minimal metabolic acidemia (anion gap <28 mmol/L), fomepizole monotherapy without extracorporeal treatments is safe and effective regardless of the ethylene glycol concentration. Treatment failures were observed with ethanol monotherapy which may relate to transient subtherapeutic ethanol concentrations or very high ethylene glycol concentrations. The results are limited by the retrospective nature of the case reports and series reviewed in this study and require prospective validation.
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http://dx.doi.org/10.1080/15563650.2022.2049810DOI Listing
July 2022

Extracorporeal Treatment for Methotrexate Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup.

Clin J Am Soc Nephrol 2022 04 2;17(4):602-622. Epub 2022 Mar 2.

Pharmacy Department, Verdun Hospital, CIUSSS du Sud-Ouest-de-l'ïle-de-Montréal, University of Montreal, Montreal, Quebec, Canada.

Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflammatory bowel disease. Toxicity from use is associated with severe morbidity and mortality. Rescue treatments include intravenous hydration, folinic acid, and, in some centers, glucarpidase. We conducted systematic reviews of the literature following published EXtracorporeal TReatments In Poisoning (EXTRIP) methods to determine the utility of extracorporeal treatments in the management of methotrexate toxicity. The quality of the evidence and the strength of recommendations (either "strong" or "weak/conditional") were graded according to the GRADE approach. A formal voting process using a modified Delphi method assessed the level of agreement between panelists on the final recommendations. A total of 92 articles met inclusion criteria. Toxicokinetic data were available on 90 patients (89 with impaired kidney function). Methotrexate was considered to be moderately dialyzable by intermittent hemodialysis. Data were available for clinical analysis on 109 patients (high-dose methotrexate [>0.5 g/m]: 91 patients; low-dose [≤0.5 g/m]: 18). Overall mortality in these publications was 19.5% and 26.7% in those with high-dose and low-dose methotrexate-related toxicity, respectively. Although one observational study reported lower mortality in patients treated with glucarpidase compared with those treated with hemodialysis, there were important limitations in the study. For patients with severe methotrexate toxicity receiving standard care, the EXTRIP workgroup: () suggested against extracorporeal treatments when glucarpidase is not administered; () recommended against extracorporeal treatments when glucarpidase is administered; and () recommended against extracorporeal treatments instead of administering glucarpidase. The quality of evidence for these recommendations was very low. Rationales for these recommendations included: () extracorporeal treatments mainly remove drugs in the intravascular compartment, whereas methotrexate rapidly distributes into cells; () extracorporeal treatments remove folinic acid; () in rare cases where fast removal of methotrexate is required, glucarpidase will outperform any extracorporeal treatment; and () extracorporeal treatments do not appear to reduce the incidence and magnitude of methotrexate toxicity.
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http://dx.doi.org/10.2215/CJN.08030621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8993465PMC
April 2022

Extracorporeal Treatment for Methotrexate Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup.

Clin J Am Soc Nephrol 2022 04 2;17(4):602-622. Epub 2022 Mar 2.

Pharmacy Department, Verdun Hospital, CIUSSS du Sud-Ouest-de-l'ïle-de-Montréal, University of Montreal, Montreal, Quebec, Canada.

Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflammatory bowel disease. Toxicity from use is associated with severe morbidity and mortality. Rescue treatments include intravenous hydration, folinic acid, and, in some centers, glucarpidase. We conducted systematic reviews of the literature following published EXtracorporeal TReatments In Poisoning (EXTRIP) methods to determine the utility of extracorporeal treatments in the management of methotrexate toxicity. The quality of the evidence and the strength of recommendations (either "strong" or "weak/conditional") were graded according to the GRADE approach. A formal voting process using a modified Delphi method assessed the level of agreement between panelists on the final recommendations. A total of 92 articles met inclusion criteria. Toxicokinetic data were available on 90 patients (89 with impaired kidney function). Methotrexate was considered to be moderately dialyzable by intermittent hemodialysis. Data were available for clinical analysis on 109 patients (high-dose methotrexate [>0.5 g/m]: 91 patients; low-dose [≤0.5 g/m]: 18). Overall mortality in these publications was 19.5% and 26.7% in those with high-dose and low-dose methotrexate-related toxicity, respectively. Although one observational study reported lower mortality in patients treated with glucarpidase compared with those treated with hemodialysis, there were important limitations in the study. For patients with severe methotrexate toxicity receiving standard care, the EXTRIP workgroup: () suggested against extracorporeal treatments when glucarpidase is not administered; () recommended against extracorporeal treatments when glucarpidase is administered; and () recommended against extracorporeal treatments instead of administering glucarpidase. The quality of evidence for these recommendations was very low. Rationales for these recommendations included: () extracorporeal treatments mainly remove drugs in the intravascular compartment, whereas methotrexate rapidly distributes into cells; () extracorporeal treatments remove folinic acid; () in rare cases where fast removal of methotrexate is required, glucarpidase will outperform any extracorporeal treatment; and () extracorporeal treatments do not appear to reduce the incidence and magnitude of methotrexate toxicity.
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http://dx.doi.org/10.2215/CJN.08030621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8993465PMC
April 2022

Extracorporeal Treatment for Gabapentin and Pregabalin Poisoning: Systematic Review and Recommendations From the EXTRIP Workgroup.

Am J Kidney Dis 2022 01 17;79(1):88-104. Epub 2021 Nov 17.

Research Center, CIUSSS du Nord-de-l'île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, Quebec, Canada. Electronic address:

Toxicity from gabapentin and pregabalin overdose is commonly encountered. Treatment is supportive, and the use of extracorporeal treatments (ECTRs) is controversial. The EXTRIP workgroup conducted systematic reviews of the literature and summarized findings following published methods. Thirty-three articles (30 patient reports and 3 pharmacokinetic studies) met the inclusion criteria. High gabapentinoid extracorporeal clearance (>150mL/min) and short elimination half-life (<5 hours) were reported with hemodialysis. The workgroup assessed gabapentin and pregabalin as "dialyzable" for patients with decreased kidney function (quality of the evidence grade as A and B, respectively). Limited clinical data were available (24 patients with gabapentin toxicity and 7 with pregabalin toxicity received ECTR). Severe toxicity, mortality, and sequelae were rare in cases receiving ECTR and in historical controls receiving standard care alone. No clear clinical benefit from ECTR could be identified although major knowledge gaps were acknowledged, as well as costs and harms of ECTR. The EXTRIP workgroup suggests against performing ECTR in addition to standard care rather than standard care alone (weak recommendation, very low quality of evidence) for gabapentinoid poisoning in patients with normal kidney function. If decreased kidney function and coma requiring mechanical ventilation are present, the workgroup suggests performing ECTR in addition to standard care (weak recommendation, very low quality of evidence).
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http://dx.doi.org/10.1053/j.ajkd.2021.06.027DOI Listing
January 2022

The National Paediatric Medicines Forum: Who we are and what are we doing.

J Paediatr Child Health 2021 Dec 13;57(12):2022-2023. Epub 2021 Oct 13.

Clinical Governance Unit, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/jpc.15789DOI Listing
December 2021

Variability in insulin pharmacokinetics following high-dose insulin therapy.

Clin Toxicol (Phila) 2022 Mar 15;60(3):389-391. Epub 2021 Sep 15.

St Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia.

Introduction: High dose insulin (HDI) therapy for cardiogenic shock from acute poisoning can be complicated by treatable hypoglycemia which persists following poisoning recovery. Glucose requirements post-HDI reflect supraphysiological insulin plasma concentration. A publication reported a patient treated with HDI with plasma insulin concentrations >1000 µU/mL and elimination half-life 10-18 h requiring intravenous glucose replacement for >5 days. We report two cases treated with HDI (Actrapid; soluble or regular insulin) with shorter elimination half-lives.

Case Reports: A man ingesting diltiazem received HDI for approximately 60 h (maximum dose 10 U/kg/h) and supplemental intravenous dextrose for 44 h post-HDI. Post-HDI the maximum measured plasma insulin concentration was 6345 µU/mL and elimination half-life 5.5 h. A man ingesting propranolol received HDI for approximately 12 h (maximum dose 1.5 U/kg/h) and supplemental intravenous dextrose for 4 h post-HDI. Post-HDI the maximum measured plasma insulin concentration was 368 µU/mL and elimination half-life 2.2 h.

Discussion: Markedly different insulin pharmacokinetics post-HDI is observed in two cases and a previously published report, and factors contributing to the interpatient differences are poorly defined. This pharmacokinetic variability impacts on the severity and duration of treatable hypoglycemia post-HDI. Analytical factors impacting on the measured plasma insulin concentrations include appropriate sample dilution and differing analytical specificity for the type of insulin.
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http://dx.doi.org/10.1080/15563650.2021.1967372DOI Listing
March 2022

One-third of people who inject drugs are at risk of incomplete treatment for Staphylococcus aureus bacteraemia: a retrospective medical record review.

Int J Infect Dis 2021 Nov 11;112:63-65. Epub 2021 Sep 11.

St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia; National Centre for Clinical Research on Emerging Drugs, UNSW Sydney, NSW, Australia.

Staphylococcus aureus bacteraemia (SAB) is often a complication of injecting drug use, and is associated with high morbidity and mortality. This article reports the first audit of inpatient parenteral treatment of SAB completion among people who inject drugs (PWID) in Australia. Of 198 patients admitted with SAB, 106 were analysed. Twelve PWID had an inpatient stay <14 days compared with seven non-PWID (34% vs 10%; P=0.002). Sixteen PWID experienced discharge against medical advice compared with zero non-PWID (46% vs 0%; P<0.001). Re-admission to hospital within 28 days was 2.5 times greater among PWID than non-PWID (31% vs 15%; P=0.026). Methadone dose <60 mg/day was associated with premature discharge in opioid-dependent PWID receiving methadone (n=21, 100% vs 31%; P=0.012).
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http://dx.doi.org/10.1016/j.ijid.2021.09.012DOI Listing
November 2021

Reverse Takotsubo Cardiomyopathy Precipitated by Chronic Cocaine and Cannabis Use.

Cardiovasc Toxicol 2021 12 24;21(12):1012-1018. Epub 2021 Aug 24.

Drug Health Services, Royal Prince Alfred Hospital, Level 6, King George V Building, 83-117 Missenden Road, Camperdown, NSW, 2050, Australia.

This case report describes a 31-year-old man with 10 years of cocaine and cannabis dependence who developed reverse Takotsubo cardiomyopathy (rTC), a rare variant of Takotsubo cardiomyopathy. He presented to the Emergency Department (ED) with severe left temporal headache and vomiting which began whilst smoking cannabis and several hours after smoking methamphetamine and using cocaine via insufflation. Computed tomography and angiography of the brain was normal, and the headache resolved with analgesia. Urine drug screen was positive for benzodiazepines, cannabinoids, cocaine, opiates (attributed to morphine administered in ED) and amphetamines. Three hours later he had a seizure and within 10 min developed cardiogenic shock with antero-inferior ST segment depression on electrocardiogram and troponin-T rise to 126 ng/L. Coronary angiography demonstrated normal coronary arteries. Transthoracic echocardiogram demonstrated severely impaired left ventricular (LV) systolic function with ejection fraction 15-20% and hypokinesis sparing the apex. Thyrotoxicosis, nutritional, vasculitic, autoimmune and viral screens were negative. Cardiac magnetic resonance imaging demonstrated severe LV functional impairment with dilated and hypocontractile basal segments, and T2 hyperintensity consistent with myocardial oedema and rTC. He received supportive management. Proposed mechanisms of rTC include catecholamine cardiotoxicity and coronary artery vasospasm. In this case, multiple insults including severe headache, cannabis hyperemesis and cocaine and methamphetamine-induced serotonin toxicity culminated in a drug-induced seizure which led to catecholamine cardiotoxicity resulting in rTC. Clinicians should be cognizant of stress cardiomyopathy as a differential diagnosis in patients with substance use disorders.
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http://dx.doi.org/10.1007/s12012-021-09692-9DOI Listing
December 2021

Kidney dysfunction has a major impact on the effect of idarucizumab for dabigatran reversal.

Eur J Anaesthesiol 2021 09;38(9):1005-1006

From the Department of Renal Medicine, Concord Repatriation General Hospital (AA), Concord Clinical School, Faculty of Medicine and Health, University of Sydney (AA), Drug Health Services and Clinical Pharmacology and Toxicology, Royal Prince Alfred Hospital (AA, NJ, DMR), New South Wales Poisons Information Centre, Sydney Children's Hospital Network (NJ, DMR), Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, New South Wales, Australia (DMR), Department of Renal Medicine and Transplantation, St Vincent's Hospital (DMR) and St Vincent's Clinical School, University of New South Wales, New South Wales, Australia (DMR).

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http://dx.doi.org/10.1097/EJA.0000000000001428DOI Listing
September 2021

Recommendations from the EXTRIP workgroup on extracorporeal treatment for baclofen poisoning.

Kidney Int 2021 10 4;100(4):720-736. Epub 2021 Aug 4.

Emergency Medicine Department, Centre Intégré de Santé et de Services Sociaux (CISSS) de la Montérégie-Centre, Hôpital Charles-LeMoyne, Greenfield Park, Québec, Canada; Academic Emergency Medicine Department, Faculty of Medicine, McGill University, Montréal, Québec, Canada; Centre Antipoison du Québec, Québec, Québec, Canada. Electronic address:

Baclofen toxicity results from intentional self-poisoning (acute baclofen poisoning) or accumulation of therapeutic dose in the setting of impaired kidney function. Standard care includes baclofen discontinuation, respiratory support and seizure treatment. Use of extracorporeal treatments (ECTRs) is controversial. To clarify this, a comprehensive review of the literature on the effect of ECTRs in baclofen toxicity was performed and recommendations following EXTRIP methods were formulated based on 43 studies (1 comparative cohort, 1 aggregate results cohort, 1 pharmacokinetic modeling, and 40 patient reports or series). Toxicokinetic data were available for 20 patients. Baclofen's dialyzability is limited by a high endogenous clearance and a short half-life in patients with normal kidney function. The workgroup assessed baclofen as "Moderately dialyzable" by intermittent hemodialysis for patients with normal kidney function (quality of evidence C) and "Dialyzable" for patients with impaired kidney function (quality of evidence C). Clinical data were available for 25 patients with acute baclofen poisoning and 46 patients with toxicity from therapeutic baclofen in kidney impairment. No deaths or sequelae were reported. Mortality in historical controls was rare. No benefit of ECTR was identified in patients with acute baclofen poisoning. Indirect evidence suggests a benefit of ECTR in reducing the duration of toxic encephalopathy from therapeutic baclofen in kidney impairment. These potential benefits were balanced against added costs and harms related to the insertion of a catheter, the procedure itself, and the potential of baclofen withdrawal. Thus, the EXTRIP workgroup suggests against performing ECTR in addition to standard care for acute baclofen poisoning and suggests performing ECTR in toxicity from therapeutic baclofen in kidney impairment, especially in the presence of coma requiring mechanical ventilation.
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http://dx.doi.org/10.1016/j.kint.2021.07.014DOI Listing
October 2021

Increases in NT-proBNP in the poisoned patient are probably multifactorial.

Clin Toxicol (Phila) 2021 11 26;59(11):1035-1036. Epub 2021 Jul 26.

Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Darlinghurst, Australia.

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http://dx.doi.org/10.1080/15563650.2021.1955915DOI Listing
November 2021

Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup.

Crit Care 2021 06 10;25(1):201. Epub 2021 Jun 10.

Research Center, CIUSSS du Nord-de-L'île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, QC, Canada.

Background: β-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension. Poisoning from BAAs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in BAAs poisoning.

Methods: We conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods.

Results: A total of 76 studies (4 in vitro and 2 animal experiments, 1 pharmacokinetic simulation study, 37 pharmacokinetic studies on patients with end-stage kidney disease, and 32 case reports or case series) met inclusion criteria. Toxicokinetic or pharmacokinetic data were available on 334 patients (including 73 for atenolol, 54 for propranolol, and 17 for sotalol). For intermittent hemodialysis, atenolol, nadolol, practolol, and sotalol were assessed as dialyzable; acebutolol, bisoprolol, and metipranolol were assessed as moderately dialyzable; metoprolol and talinolol were considered slightly dialyzable; and betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol were considered not dialyzable. Data were available for clinical analysis on 37 BAA poisoned patients (including 9 patients for atenolol, 9 for propranolol, and 9 for sotalol), and no reliable comparison between the ECTR cohort and historical controls treated with standard care alone could be performed. The EXTRIP workgroup recommends against using ECTR for patients severely poisoned with propranolol (strong recommendation, very low quality evidence). The workgroup offered no recommendation for ECTR in patients severely poisoned with atenolol or sotalol because of apparent balance of risks and benefits, except for impaired kidney function in which ECTR is suggested (weak recommendation, very low quality of evidence). Indications for ECTR in patients with impaired kidney function include refractory bradycardia and hypotension for atenolol or sotalol poisoning, and recurrent torsade de pointes for sotalol. Although other BAAs were considered dialyzable, clinical data were too limited to develop recommendations.

Conclusions: BAAs have different properties affecting their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol and sotalol were assessed as dialyzable in patients with kidney impairment, and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.
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http://dx.doi.org/10.1186/s13054-021-03585-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194226PMC
June 2021

A case of a markedly elevated dabigatran concentration resistant to the approved dose of idarucizumab.

Intern Med J 2021 Apr;51(4):616-617

Department of Haematology, St Vincent's Hospital, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/imj.15278DOI Listing
April 2021

A cluster of lysergic acid diethylamide (LSD) poisonings following insufflation of a white powder sold as cocaine.

Clin Toxicol (Phila) 2021 Nov 13;59(11):969-974. Epub 2021 Apr 13.

NSW Poisons Information Centre, Sydney Children's Hospitals Network, Westmead, Australia.

Objective: Adulteration, substitution or contamination of illicit substances can have clinically significant implications when other illicit substances are included. Such circumstances can present as clusters of poisonings, including severe toxicity and death following exposure to unexpected illicit substances. We report a cluster of laboratory-confirmed lysergic acid diethylamide (LSD) in a powder that was sold as cocaine and used recreationally.

Methods: The Prescription, Recreational and Illicit Substance Evaluation (PRISE) program established by the New South Wales Ministry of Health includes State-based hospital toxicology services, Poisons Information Centre, Forensic & Analytical Science Service and emergency services to identify clusters of severe and unusual toxicity associated with substance use. PRISE criteria include a known cluster (geographically or situationally related) of people with acute severe toxicity, especially when accompanied by a toxidrome that is inconsistent with the history of exposure. A timely comprehensive drug screen and quantification is performed in eligible cases and the results are related to the clinical features. The need for a public health response is then considered. Four individuals inhaled a white powder that was sold as cocaine and developed severe toxicity that was not consistent with cocaine which prompted transfer to hospital for further management.

Results: LSD was confirmed in four subjects, and the concentrations in 3 of the individuals were 0.04-0.06 mg/L which are among the highest reported in the literature. Common clinical features were hallucinations, agitation, vomiting, sedation, hypertension, and mydriasis. One subject required intubation and admission to the intensive care unit, two required overnight admission, and the fourth was discharged following oral diazepam after observation. No subject suffered persistent injury.

Conclusions: A close working relationship between pre-hospital emergency services, hospital-based clinical services, public health authorities, and analytical laboratories appears to be advantageous. Favourable clinical outcomes are observed from LSD poisoning despite high exposures with good supportive care.
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http://dx.doi.org/10.1080/15563650.2021.1904140DOI Listing
November 2021

Extracorporeal treatments for isoniazid poisoning: Systematic review and recommendations from the EXTRIP workgroup.

Pharmacotherapy 2021 05 3;41(5):463-478. Epub 2021 Apr 3.

Research Center, CIUSSS du Nord-de-l'île-de-Montréal, University of Montreal, Montreal, Quebec, Canada.

Isoniazid toxicity from self-poisoning or dosing errors remains common in regions of the world where tuberculosis is prevalent. Although the treatment of isoniazid poisoning is centered on supportive care and pyridoxine administration, extracorporeal treatments (ECTRs), such as hemodialysis, have been advocated to enhance elimination of isoniazid. No systematic reviews or evidence-based recommendations currently exist on the benefit of ECTRs for isoniazid poisoning. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup systematically collected and rated the available evidence on the effect of and indications for ECTRs in cases of isoniazid poisoning. We conducted a systematic review of the literature, screened studies, extracted data on study characteristics, outcomes, and measurement characteristics, summarized findings, and formulated recommendations following published EXTRIP methods. Forty-three studies (two animal studies, 34 patient reports or patient series, and seven pharmacokinetic studies) met inclusion criteria. Toxicokinetic or pharmacokinetic analysis was available for 60 patients, most treated with hemodialysis (n = 38). The workgroup assessed isoniazid as "Moderately Dialyzable" by hemodialysis for patients with normal kidney function (quality of evidence = C) and "Dialyzable" by hemodialysis for patients with impaired kidney function (quality of evidence = A). Clinical data for ECTR in isoniazid poisoning were available for 40 patients. Mortality of the cohort was 12.5%. Historical controls who received modern standard care including appropriately dosed pyridoxine generally had excellent outcomes. No benefit could be extrapolated from ECTR, although there was evidence of added costs and harms related to the double lumen catheter insertion, the extracorporeal procedure itself, and the extracorporeal removal of pyridoxine. The EXTRIP workgroup suggests against performing ECTR in addition to standard care (weak recommendation, very low quality of evidence) in patients with isoniazid poisoning. If standard dose pyridoxine cannot be administered, we suggest performing ECTR only in patients with seizures refractory to GABA receptor agonists (weak recommendation, very low quality of evidence).
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http://dx.doi.org/10.1002/phar.2519DOI Listing
May 2021

Poor relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) and level of consciousness following intentional ingestion of eucalyptus oil.

Clin Toxicol (Phila) 2021 11 1;59(11):1033-1034. Epub 2021 Mar 1.

Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Darlinghurst, Australia.

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http://dx.doi.org/10.1080/15563650.2021.1887884DOI Listing
November 2021

Extracorporeal treatment for calcium channel blocker poisoning: systematic review and recommendations from the EXTRIP workgroup.

Clin Toxicol (Phila) 2021 May 8;59(5):361-375. Epub 2021 Feb 8.

Research Center, CIUSSS du Nord-de-l'île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, QC, Canada.

Background: Calcium channel blockers (CCBs) are commonly used to treat conditions such as arterial hypertension and supraventricular dysrhythmias. Poisoning from these drugs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in the management of CCB poisoning.

Methods: We conducted systematic reviews of the literature, screened studies, extracted data, summarized findings, and formulated recommendations following published EXTRIP methods.

Results: A total of 83 publications (6 and 1 animal experiments, 55 case reports or case series, 19 pharmacokinetic studies, 1 cohort study and 1 systematic review) met inclusion criteria regarding the effect of ECTR. Toxicokinetic or pharmacokinetic data were available on 210 patients (including 32 for amlodipine, 20 for diltiazem, and 52 for verapamil). Regardless of the ECTR used, amlodipine, bepridil, diltiazem, felodipine, isradipine, mibefradil, nifedipine, nisoldipine, and verapamil were considered not dialyzable, with variable levels of evidence, while no dialyzability grading was possible for nicardipine and nitrendipine. Data were available for clinical analysis on 78 CCB poisoned patients (including 32 patients for amlodipine, 16 for diltiazem, and 23 for verapamil). Standard care (including high dose insulin euglycemic therapy) was not systematically administered. Clinical data did not suggest an improvement in outcomes with ECTR. Consequently, the EXTRIP workgroup recommends against using ECTR in addition to standard care for patients severely poisoned with either amlodipine, diltiazem or verapamil (strong recommendations, very low quality of the evidence (1D)). There were insufficient clinical data to draft recommendation for other CCBs, although the workgroup acknowledged the low dialyzability from, and lack of biological plausibility for, ECTR.

Conclusions: Both dialyzability and clinical data do not support a clinical benefit from ECTRs for CCB poisoning. The EXTRIP workgroup recommends against using extracorporeal methods to enhance the elimination of amlodipine, diltiazem, and verapamil in patients with severe poisoning.
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http://dx.doi.org/10.1080/15563650.2020.1870123DOI Listing
May 2021

Managing hyperuricemia and gout in chronic kidney disease: a clinical conundrum.

Curr Opin Nephrol Hypertens 2021 03;30(2):245-251

Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital.

Purpose Of Review: There is controversy regarding the impact of hyperuricemia on the progression of chronic kidney disease (CKD), and gout remains sub optimally managed in this population. We discuss the prescribing of drugs for the treatment of gout in patients with CKD.

Recent Findings: There is a lack of consensus from expert guidelines, and prescribers have concerns regarding the risk of adverse reactions from medicines used to treat gout. These situations appear to contribute to suboptimal management of gout in this cohort. Recent data have challenged the role of urate lowering therapy (ULT) in the management of asymptomatic hyperuricemia in CKD.

Summary: ULT should be commenced in all patients with severe, recurrent disease, tophaceous gout and evidence of joint damage. Most international guidelines recommend a treat-to-target approach for the management of gout. In CKD, ULT should be started at low dose with up titration adjusted to serum urate levels, rather than being based on the creatinine clearance. If patients fail first-line therapy, alternative agents are utilized, the specific agent depending on ease of access, burden of disease and other comorbidities. This approach should be incorporated into routine practice to ensure optimal treatment of gout in CKD. More research is required to investigate whether treatment of asymptomatic hyperuricemia has clinical benefits.
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http://dx.doi.org/10.1097/MNH.0000000000000691DOI Listing
March 2021

Evaluation of a Pilot Vancomycin Precision Dosing Advisory Service on Target Exposure Attainment Using an Interrupted Time Series Analysis.

Clin Pharmacol Ther 2021 01 5;109(1):212-221. Epub 2020 Dec 5.

Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, New South Wales, Australia.

This study evaluated the ability of a pilot therapeutic drug monitoring (TDM) Advisory Service to facilitate vancomycin therapeutic target attainment within a real-world clinical setting. The Service provided area under the concentration-time curve (AUC)-guided vancomycin dose recommendations, using Bayesian forecasting software and clinical expertise, to prescribers at an Australian hospital. A retrospective audit of intravenous vancomycin therapy (> 48 hours) in adults (≥ 18 years old) was undertaken over a 54-month period to evaluate attainment of established vancomycin pharmacokinetic/pharmacodynamic targets (AUC over 24 hours / minimum inhibitory concentration: 400-600) before (36-month period) and after (18-month period) Service implementation. Interrupted time series analysis was employed to evaluate monthly measures of the median proportion of therapy spent within the target range. Indices of time to target attainment were also assessed before and after Service implementation. The final cohort comprised 1,142 courses of vancomycin (816 patients); 835 courses (596 patients) and 307 courses (220 patients) administered before and after Service implementation, respectively. Prior to piloting the Service, the median proportion of time in the target range was 40.1% (95% CI, 34.3-46.0%); this increased by 10.4% (95% CI, 1.2-19.6%, P = 0.03) after the Service, and was sustained throughout the post-Service evaluation period. Post-Service target attainment at 48-72 hours after initiation of therapy was increased (7.8%, 95% CI, 1.3-14.3%, P = 0.02). The findings of this study provide evidence that a consultative TDM Service can facilitate attainment of vancomycin therapeutic targets; however, optimization of the Service may further improve the use of vancomycin.
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http://dx.doi.org/10.1002/cpt.2113DOI Listing
January 2021

Extracorporeal Treatment for Chloroquine, Hydroxychloroquine, and Quinine Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup.

J Am Soc Nephrol 2020 10 22;31(10):2475-2489. Epub 2020 Sep 22.

Research Center, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, Quebec, Canada

Background: Although chloroquine, hydroxychloroquine, and quinine are used for a range of medical conditions, recent research suggested a potential role in treating COVID-19. The resultant increase in prescribing was accompanied by an increase in adverse events, including severe toxicity and death. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup sought to determine the effect of and indications for extracorporeal treatments in cases of poisoning with these drugs.

Methods: We conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods.

Results: A total of 44 studies (three studies, two animal studies, 28 patient reports or patient series, and 11 pharmacokinetic studies) met inclusion criteria regarding the effect of extracorporeal treatments. Toxicokinetic or pharmacokinetic analysis was available for 61 patients (13 chloroquine, three hydroxychloroquine, and 45 quinine). Clinical data were available for analysis from 38 patients, including 12 with chloroquine toxicity, one with hydroxychloroquine toxicity, and 25 with quinine toxicity. All three drugs were classified as non-dialyzable (not amenable to clinically significant removal by extracorporeal treatments). The available data do not support using extracorporeal treatments in addition to standard care for patients severely poisoned with either chloroquine or quinine (strong recommendation, very low quality of evidence). Although hydroxychloroquine was assessed as being non-dialyzable, the clinical evidence was not sufficient to support a formal recommendation regarding the use of extracorporeal treatments for this drug.

Conclusions: On the basis of our systematic review and analysis, the EXTRIP workgroup recommends against using extracorporeal methods to enhance elimination of these drugs in patients with severe chloroquine or quinine poisoning.
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http://dx.doi.org/10.1681/ASN.2020050564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609009PMC
October 2020

Management of proteinuria: blockade of the renin-angiotensin-aldosterone system.

Aust Prescr 2020 08 3;43(4):121-125. Epub 2020 Aug 3.

Drug Health Services and Clinical Pharmacology and Toxicology, Royal Prince Alfred Hospital, Sydney.

Proteinuria, in particular albuminuria, is a potentially significant modifiable risk factor for cardiovascular disease and the progression of kidney disease. Current treatment guidelines for albuminuria recommend a single renin–angiotensin–aldosterone inhibitor. This can be an ACE inhibitor or an angiotensin receptor antagonist. The routine use of combined renin–angiotensin–aldosterone inhibition for albuminuria is not supported by current evidence. Combination therapy is associated with higher rates of adverse events such as hyperkalaemia and progressive renal impairment.
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http://dx.doi.org/10.18773/austprescr.2020.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450775PMC
August 2020

COVID-19 and the quality use of medicines: evidence, risks and fads.

Aust Prescr 2020 Jun 8;43(3):78-80. Epub 2020 May 8.

Departments of Clinical Pharmacology and Toxicology, and Renal Medicine and Transplantation, St Vincent's Hospital, Sydney.

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http://dx.doi.org/10.18773/austprescr.2020.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358054PMC
June 2020

Assessing the effect of extracorporeal treatments for lithium poisoning.

Br J Clin Pharmacol 2021 01 5;87(1):214-215. Epub 2020 Jun 5.

Departments of Clinical Pharmacology, Toxicology and Renal Medicine, St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia.

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http://dx.doi.org/10.1111/bcp.14367DOI Listing
January 2021

Estimating renal function for patients in wheelchairs.

Aust Prescr 2020 Apr 1;43(2):67. Epub 2020 Apr 1.

Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney.

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http://dx.doi.org/10.18773/austprescr.2020.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186273PMC
April 2020

Antiemetic drugs: what to prescribe and when.

Aust Prescr 2020 04 1;43(2):49-56. Epub 2020 Apr 1.

Drug Health Services and Clinical Pharmacology and Toxicology, Royal Prince Alfred Hospital, Sydney.

Nausea and vomiting are common symptoms with many possible causes, including the adverse effects of drugs. If a drug is indicated, the cause guides the choice of antiemetic drug The main antiemetic classes include antagonists of the serotonin, dopamine, histamine, muscarinic and neurokinin systems, corticosteroids and benzodiazepines. Some antiemetics appear more effective for specific indications Serotonin and neurokinin antagonists, such as ondansetron and aprepitant, are highly effective in treating chemotherapy-induced nausea and vomiting. Metoclopramide and antihistamines are first-line options for nausea and vomiting in pregnancy Serotonin antagonists and some dopamine antagonists, such as metoclopramide, can prolong the QT interval on the ECG. Dopamine antagonists can cause extrapyramidal adverse effects, particularly in children
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http://dx.doi.org/10.18773/austprescr.2020.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186277PMC
April 2020

Incomplete responses to the recommended dose of idarucizumab: a systematic review and pharmacokinetic analysis.

Clin Toxicol (Phila) 2020 Aug 8;58(8):789-800. Epub 2020 Apr 8.

Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, Australia.

Dabigatran, a direct thrombin inhibitor, is 80% renally eliminated and demonstrates multi-compartmental pharmacokinetics. Idarucizumab is a monoclonal antibody that reverses dabigatran-induced anticoagulation and displays single compartment pharmacokinetics, with a smaller volume of distribution and shorter elimination half-life than dabigatran. These differences in pharmacokinetics mean that redistribution of dabigatran from peripheral compartments can occur after idarucizumab has been eliminated, resulting in rebound in the dabigatran plasma concentration and treatment failure. Clinical experience notes failure of a single idarucizumab 5 g dose to fully reverse coagulopathy in certain patients. To identify factors predisposing to an incomplete response to the standard idarucizumab 5 g dose. A systematic literature search in PubMed using terms "dabigatran" and "idarucizumab" covering 2015 to October 2019 identified 387 entries. Titles and abstracts were screened initially, followed by full text review and data extraction from 97 eligible articles. Data extracted included clinical information, dabigatran concentrations, coagulation results, idarucizumab dosage and patient outcomes. Pharmacokinetic simulations were conducted using a two-compartment model to predict the likelihood that acute or chronic kidney disease will contribute to an incomplete reversal of dabigatran-induced anticoagulation. Of 240 published cases receiving idarucizumab, 33 reported dabigatran concentration rebound, within a median time of 22 h. From 231 cases reporting idarucizumab dose, 10 received repeated administration due to a rebound in dabigatran concentrations. Baseline dabigatran concentrations >228 ng/mL were more likely to experience a rebound post-idarucizumab to >30 ng/mL (detectable). For baseline dabigatran >488 ng/mL, the concentration rebounded to >75 ng/mL (therapeutic). Idarucizumab is expected to neutralise a maximum plasma dabigatran concentration of 980 ng/mL, but most likely a lesser amount. Pharmacokinetic modelling suggests, for patients taking dabigatran 150 mg twice daily, an incomplete response to 5 g idarucizumab is predicted after approximately 72 h dosing when GFR less than 30 mL/min (25% of normal), and after 36 h with severely impaired renal function (GFR 6 mL/min; GFR 5% of normal). Idarucizumab has neutralised dabigatran following deliberate self-poisoning with dabigatran in a limited number of cases, even in the absence of bleeding. There are insufficient data regarding the use of idarucizumab as part of standard supportive care in this context. The dilute thrombin time can be used to determine the dabigatran concentration, but other more standard coagulation assays are less precise. A normal aPTT largely excludes dabigatran. We suggest performing coagulation assays and dabigatran concentrations every 6 h for a minimum of 36 h after idarucizumab administration to detect a rebound in dabigatran. This is particularly necessary in patients with glomerular filtration rate <30 mL/min or those with a plasma dabigatran concentration exceeding approximately 500 ng/mL. If a rebound in dabigatran is noted, then repeat administration of idarucizumab 5 g can be considered for reversal of recurrent coagulopathy if clinically indicated. The use of idarucizumab for reversal of dabigatran is complex and requires consideration of clinical circumstances and laboratory investigations. Monitoring post-idarucizumab may be required in acute or chronic kidney disease to detect a rebound in dabigatran concentration and the need for additional doses of idarucizumab.
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http://dx.doi.org/10.1080/15563650.2020.1743846DOI Listing
August 2020
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