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Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5).
Chiew, AL, James, LP, Isbister, GK, Pickering, JW, McArdle, K, Chan, BSH, Buckley, NA
Journal of hepatology. 2020;(3):450-462
Abstract
BACKGROUND & AIMS Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.
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Migraine Treatment in Pregnant Women Presenting to Acute Care: A Retrospective Observational Study.
Hamilton, KT, Robbins, MS
Headache. 2019;(2):173-179
Abstract
OBJECTIVE To assess the acute treatment of pregnant women presenting to a hospital with migraine. BACKGROUND Migraine is a common problem in pregnancy; however, migraine treatment is challenging in pregnant women for fears of medication teratogenicity and lack of data in this population. To date, no study has directly explored physician practices for treatment of acute migraine in pregnant women. METHODS We conducted a retrospective chart review of medication administration for pregnant women who presented to an acute care setting with a migraine attack and received neurology consultation between 2009 and 2014. RESULTS We identified 72 pregnant women with migraine who were treated with pain medications. Fifty-one percent (37/72) were in the third trimester of pregnancy, 39% (28/72) in the second trimester, and 10% (7/72) in the first trimester. Thirty-two percent (23/72) had not tried any acute medications at home before coming to the hospital, and 47% (34/72) presented in status migrainosus. Patients received treatment in the hospital for a median of 23 hours (interquartile range = 5-45 hours). The most common medications prescribed were metoclopramide in 74% (53/72) of patients (95% confidence interval [CI] 62-82%) and acetaminophen in 69% (50/72) of patients (95% CI 58-79%). Metoclopramide was administered along with diphenhydramine in 81% (44/53) of patients (95% CI 71-91%). Acetaminophen was the most frequent medicine administered first (53%, 38/72). Patients were often treated with butalbital (35%, 25/72) or opioids (30%, 22/72), which were used as second- or third-line treatments in 29% of patients (20/72). Thirty-eight percent (27/72) received an intravenous (IV) fluid bolus, 24% received IV magnesium (17/72), and 6% (4/72) had peripheral nerve blocks performed. CONCLUSIONS While the majority of pregnant women with acute migraine received medications considered relatively safe in pregnancy, there was variation in treatment choice and sequence. Some acute medications considered potentially hazardous for fetal health and less effective for migraine (opioids and butalbital) were used frequently, whereas other treatments that may have low teratogenic risk (nerve blocks, IV fluid boluses, and triptans) were used less or not at all. These results indicate a need for developing guidelines and protocols to standardize acute treatment of migraine in pregnancy.
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Lack of respiratory depression in paracetamol-codeine combination overdoses.
Heppell, SPE, Isbister, GK
British journal of clinical pharmacology. 2017;(6):1273-1278
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Abstract
AIMS: Codeine containing analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone. METHODS We reviewed deliberate self-poisoning admissions with paracetamol (>2 g) and paracetamol-codeine combinations presenting to a tertiary toxicology unit (1987-2013). Demographic information, clinical effects, treatment (naloxone, length of stay [LOS], mechanical ventilation) were extracted from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression. RESULTS From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12-89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5-20 g). Median LOS was 16 h (IQR: 6.5-27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2-1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1-1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1-2.3%; absolute difference, 0.26%; 95% CI: -0.7-1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3-8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol-codeine group. CONCLUSIONS Paracetamol-codeine combination overdoses are rarely associated with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression.
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Characteristics of the use of cold combination products among older ambulatory patients at the National Hospital Organization Tochigi Medical Center in Japan: a retrospective single-center observational study.
Komagamine, J
BMC research notes. 2017;(1):728
Abstract
OBJECTIVE This study aimed to determine the frequency and characteristics of prescriptions of cold combination products among older ambulatory patients. A retrospective observational study was conducted using electronic medical records. All patients aged 65 years or older who continued visiting internal medicine physicians for at least 1 year were included. The primary outcome was the prescription of cold combination products by any physicians in National Hospital Organization Tochigi Medical Center during a 1-year follow-up. RESULTS Seven hundred fifty-six patients were included. The mean age was 75.4 years, 392 (51.9%) were men, the mean Charlson Comorbidity Index was 1.8, and the mean number of medications was 4.9. The proportion of patients who were prescribed cold combination products during the 1-year follow-up was 6.1% (95% confidence interval 4.4-7.8%). The prescription of cold combination products was not significantly associated with age (p = 0.11) or Charlson Comorbidity Index (p = 0.93) but was associated with an increasing number of medications (p < 0.001). A substantial proportion of older ambulatory patients were exposed to cold combination products during a 1-year follow-up.
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A prospective observational study of a novel 2-phase infusion protocol for the administration of acetylcysteine in paracetamol poisoning.
Isbister, GK, Downes, MA, Mcnamara, K, Berling, I, Whyte, IM, Page, CB
Clinical toxicology (Philadelphia, Pa.). 2016;(2):120-6
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.
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Outpatient, non-antibiotic management in acute uncomplicated diverticulitis: a prospective study.
Isacson, D, Thorisson, A, Andreasson, K, Nikberg, M, Smedh, K, Chabok, A
International journal of colorectal disease. 2015;(9):1229-34
Abstract
PURPOSE The aim of this study was to evaluate outpatient, non-antibiotic management in acute uncomplicated diverticulitis with regard to admissions, complications, and recurrences, within a 3-month follow-up period. METHODS A prospective, observational study in which patients with computer tomography-verified acute uncomplicated diverticulitis were managed as outpatients without antibiotics. The patients kept a personal journal, were contacted daily by a nurse, and then followed up by a surgeon at 1 week and 3 months. RESULTS In total, 155 patients were included, of which 54 were men; the mean age of the patients was 57.4 years. At the time of diagnosis, the mean C-reactive protein and white blood cell count were 73 mg/l and 10.5 × 10(9), respectively, and normalized in the vast majority of patients within the first week. The majority of the patients (97.4%) were managed successfully as outpatients without antibiotics, admissions, or complications. In only four (2.6%) patients, the management failed because of complications in three and deterioration in one. These patients were all treated successfully as inpatients without surgery. Five patients had recurrences and were treated as outpatients without antibiotics. Follow-up colonic investigations revealed cancer in two patients and polyps in 13 patients. CONCLUSION Previous results of low complication rates with the non-antibiotic policy were confirmed. The new policy of outpatient management without antibiotics in acute uncomplicated diverticulitis is now shown to be feasible, well functioning, and safe.
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Paracetamol-codeine compared to ketorolac for pain control in the Emergency Department.
Buccelletti, F, Marsiliani, D, Zuccalà, G, Iacomini, P, Proietti, L, Pola, E, Zirio, G, Genitiempo, M, Marrocco, R, Conti, C, et al
European review for medical and pharmacological sciences. 2014;(20):3139-43
Abstract
OBJECTIVE Paracetamol /codeine has shown a strong analgesic activity in several studies conducted among different kind of subjects, including those with trauma. Nevertheless, its efficacy in patients accessing the Emergency Department (ED) for different kind of pain has never been tested. PATIENTS AND METHODS This is a cross-sectional, observational, prospective, cohort study. Inclusion criteria were patients > 18 year old presenting to the ED for localized traumatic or inflammatory pain involving only extremities. Numeric scale (NRS) was recorded thirty minutes and two hours after the administration of the analgesic therapy, consisting of 15 mg of ketorolac or 1000 mg/60 mg of paracetamol/ codeine, both orally. RESULTS Two-hundred patients were consecutively enrolled; 87 were treated with paracetamol/codeine and 113 with ketorolac. The combination paracetamol/codeine resulted to be not inferior to ketorolac in non-traumatic pain group and trauma group (p = 0.635 and p = 0.482, respectively). Compared to ketorolac, the combination paracetamol/codeine exerted a significantly higher analgesic activity in patients with fractures and muscular pain (p = 0.044) and was more effective in acute pain (p = 0.002), with a significant effect two hours after the administration (p = 0.029). CONCLUSIONS Paracetamol/codeine is equivalent to ketorolac in non-traumatic pain and post-traumatic pain, but is superior in acute pain and in patients with fractures and muscular pain. Those results play in favor of the use of the combination paracetamol/codeine in patients accessing the ED for non-traumatic or traumatic pain of the extremities.