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Background
Decreased level of consciousness in patients can potentially lead to respiratory insufficiency, hypoxemia and aspiration of gastric contents leading to worsening clinical outcomes and potentially death.The Glasgow Coma Score (GCS) provides an objective measurement of a patient's mental status assessing the patient's eyes, vocal response, and motor function.This score is frequently used in the setting of trauma and a score of eight of less is concerning for airway compromised necessitating intubation.In contrast, patients suffering from an acute poisoning event often have a depressed mental status that leads to intubation, a less than benign intervention.Despite the prevalence of poisoning induced intubations, no high level of evidence exists to determine which poisoned patents with decreased mental status require intubation.controls versus 16.4% of the intervention (restricted intubation) group; more controls were admitted to the ICU compared to the intervention group (66.1% v 39.7%).The most common (often only suspected) agents involved (controls %; intervention %, respectively) included alcohol (65.1%; 68.1%), benzodiazepines (40.4%; 38.8%), neuroleptics (28.4%; 19%), and GHB/GBL (10.1%; 12.1%).Compared to routine (control) management, restrictive intubation resulted in lower median ICU stay (0 h [IQR 0-18.5]v 24 h ) and median hospital stay ] v 37 h ).Patients in the restrictive intubation group experienced fewer intubation-associated complications and a 7.8% reduction in rapid onset pneumonia.There were no deaths.

Conclusion
Among the patients enrolled in this study, delaying immediate intubation of suspected poisoned patients with decreased levels of conscious was safe and associated with lower rates of ICU admission and complications.

Critique
Confirmation of poisoning (qualitatively and or quantitatively) was not required.The lack of deaths suggests selection (less sick) bias.The majority of cases involved (suspected) GABA-agonists (including alcohol or GHB) poisoning, which often results in transient clinical effects and might explain the apparent benefit of conservative (restrictive intubation) initial management.

Implication for Toxicologists
Delaying immediate intubation of acute overdose patients with decreased level of consciousness may be appropriate in some patients.More prospective work, involving confirmed overdoses, is required to establish such guidelines.

Background
Veterinary workers may experience lead exposure due to the wearing of lead shielding during radiologic procedures that, compared to human providers, usually involved use of leadcontaining gloves and prolonged use during restraint of the animal during imaging.Damage to the lead shieling is also common in the veterinarian setting.While absorption of lead through skin contact is negligible, there is a risk of dermal-oral contact once lead shielding articles are removed.

Research Questions
Are blood lead levels (BLL) higher in veterinary workers who regularly handle lead shielding compared to veterinary workers who do not?Does the use of disposable gloves under lead gloves reduce dermal lead exposure?

Methods
Non-pregnant workers from a veterinary college were recruited and categorized as "exposed" if they reported any handling of lead shielding in the previous three months, those reporting no handling of lead shield (for three months) were used as controls.A questionnaire was used to assess occupational behaviors (e.g., use of lead and/or disposable gloves) and identify non-occupational lead exposures.Blood was collected and analyzed using a reference range of ≤ 0.48 umol/L for women and 0.72 umol/L for men; the level of detection was 0.01 umol/L (Note: 0.48 umol/L ~ 10 ug/dL).
Hand surface lead levels were tested, using convenience sampling, via wipes of workers' hands immediately before and after wearing lead gloves for radiographs while noting the use (or absence) of disposable gloves under the lead gloves.For control purposes, five sample collecting wipes were removed from the packaging and immediately placed in collection tubes.

Results
A total of 61 subjects were enrolled, some of whom participated in both the BLL and hand wipe study.Of the 55 completing the exposure survey, 16 (26% of all subjects) reported non-occupational lead expose (e.g., home remodeling, firing range, soldering).A total of 53 workers were evaluated for BLL, 28 exposed and 25 controls.The median BLL for both groups was 0.03 umol/L; the ranges being 0.01-0.09umol/L for controls and 0.01-0.39umol/L for exposed.
For the hand wipe experiment, 51 samples were collected from 21 workers before and after the use of lead gloves and showed a significantly lower lead amount present before (median 2.71 ug; range 0.27-41.5)compared to after (median 13.77 ug; 0.28-2337.09)glove use (p<0.001).Those not wearing disposable gloves (n=26) had significantly more lead on their hands compared to those wearing disposable gloves (median 869.65 ug; range 8.8-2337.09 v median 5.47 ug; range 0.28-44.31, respectively [p<0.001]).
Eighteen participants reported handling lead shielding earlier in the day and before donning gloves; their median lead (wipe) level was significantly higher than those not handling lead shielding prior to glove use: 6.08 ug (range 1.53-24.36)v. 1.36 ug (range 0.27-41.4);p<0.001.

Conclusions
Use of lead shielding during veterinarian work is associated with lead exposure.The use of disposable gloves while working with/using lead shielding can significantly reduce this lead exposure.

Critique
Many important variables were addressed via questionnaire, introducing potential bias.Although acknowledged by the authors, dermal lead exposure (without dermal-tooral transmission) is of limited clinical importance.Related to this, the effects of hand washing were not evaluated.Not all participants answered the survey or engaged in both the BLL and hand wipe aspects of the study.

Implication for Toxicologists
Understanding occupational lead (and other) exposures must include evaluation of workplace duties and practices, and well as individuals' potential non-occupational exposure.Use of lead shielding during medical imaging is a source of potential lead exposure, use of appropriate personal protective equipment (i.e., disposable gloves) and hand washing should be encouraged.

Background
Angiotensin II (AT2) was approved for the treatment of distributive shock in 2017 after the Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) trial demonstrated significant improvement in blood pressures of patients receiving AT2 for catecholamine-refractory shock vs. placebo.While this study did not find a difference in mortality, and the invasive methods employed are impractical in most institutions, AT2 is increasingly used for rescue therapy for refractory shock in fashions inconsistent with the original study.Since publication, subgroup analyses of the ATHOS-3 data have shown mortality reductions in select subgroups, but the study overall was underpowered for mortality conclusions to be made.A retrospective study of 147 patients also showed no mortality reduction with the addition of AT2 as a third line vasopressor, but it too was underpowered.With the appeal of AT2 for distributive shock accelerating its use, given its unique mechanism and receptors, resolution of its association with mortality should be determined via an adequately powered study.

Research Question
Does the addition of AT2 improve 30-day mortality in patients with severe, refractory shock requiring high doses of vasopressors?

Methods
This was a retrospective cohort study of patients admitted with shock to the ICU of a university-based health system between 2016 and 2022.The primary outcome measure was all-cause 30-day mortality, comparing patients receiving any combination of norepinephrine, epinephrine, phenylephrine, vasopressin, or dopamine to those patients additionally receiving AT2.It was noted that AT2 was typically used only for shock refractory to the other listed vasopressors.All adult patients receiving vasopressors were initially included, however patients receiving AT2 initiated in the operating room were excluded.Patients receiving AT2 were then matched to controls based on norepinephrine equivalent (NE) doses at the time AT2 was initiated.The control group was further divided into historical and concurrent controls, defined by vasopressors being administered before or after AT2 became available on March 14, 2018.Baseline characteristics were obtained within 24 h of enrollment and mean arterial pressure (MAP) and Sequential Organ Failure Assessment (SOFA) scores were calculated for five days post-enrollment.Etiology of shock was determined by preset criteria as either septic, hemorrhagic, vasoplegic without sepsis, or other.Secondary outcomes included 90-day mortality and post-enrollment initiation of renal replacement therapy (RRT) and mechanical ventilation.Tertiary outcomes included mortality-adjusted SOFA scores (MA-SOFA), ventilator-free days, and major thrombotic events within 30 days (defined as venous thromboembolism, acute coronary syndrome, mesenteric ischemia, or stroke).Standard exploratory data analysis, univariate comparison with standardized differences (SDiff) and chi-square and independent t tests, and multivariate analysis were performed.The Generalized Estimating Equation method was used to mortality on multivariate analysis, creating the possibility of residual confounding despite the analytical methods.The study methods did not control for AT2 or other vasopressor dosing and the mean maximum AT2 dose (35.2 ng/kg/ min) was less than half the approved maximum initial dose (80 ng/kg/min).Altogether, potential variability in practice could lead to underestimation of benefit or adverse effects from AT2.The NE equivalent dosing during and after the observation period were not reported, leaving to question any benefit from AT2 regarding dose reduction of other vasopressors.Finally, the study only examined AT2 as salvage therapy for refractory shock; further studies are needed to determine the role for AT2 as a second-or first-line agent.

Implication for Toxicologists
AT2 should be considered as adjunctive treatment for refractory shock once first-line agents (e.g., norepinephrine) have been appropriately titrated for effect.Of note, similar to other vasopressors, the vasoconstrictive effects of AT2 are dependent upon functioning L-type calcium channels in vascular smooth muscle cells.

Background
Acetaminophen-induced nephrotoxicity (APAP-N) has been observed in humans (and animal studies) in both acute and chronic supratherapeutic ingestions, manifesting in 1-2% of patients.The pathophysiology and clinical course of the resultant renal insufficiency may differ from APAPinduced hepatotoxicity; the causative and protective effects of N-acetylcysteine (NAC) on APAP-N are unknown.

Research Questions
What is known about the pathophysiology and clinical features of renal insufficiency in the setting of acute APAP toxicity?How should APAP-N be managed?

Methods
This narrative review discussed several aspects of acute renal insufficiency in the setting of APAP toxicity, including possible pharmacologic and pathophysiologic mechanisms, histopathology, reported clinical manifestations and course, test the hypothesis, that AT2 exposure did not affect 30-day mortality, to account for correlation amongst repeated observations.Results from ATHOS-3 were used to determine a total of 594 patients, 198 AT2 patients with two controls for each, were necessary to achieve 90% power for determining a similar difference in mortality.

Results
A total of 271 patients receiving AT2 were included in the study group, with 542 matched (concurrent and historical) controls.The mean patient age was 61 (+/-16) years and most were male (60%) and white (81%).Pre-enrollment NE equivalent dosing was comparable between AT2 and controls, with SDiff (effect size) of 0.004.The median duration of AT2 treatment was 0.7 (interquartile range, 0.2-1.9)days.The 30-day mortality was similar between the AT2 and control groups (60% vs. 56%; SDiff = 0.079; p = 0.292).The 90-day mortality was also similar for AT2 and controls (65% vs. 63%; SDiff = 0.058; p = 0.440).Baseline higher SOFA scores, lower MAPs, and a diagnosis of septic shock were all significantly more prominent in the AT2 group.This group also had significantly higher creatinine levels, higher rates of chronic illness, and were more likely to have already received mechanical ventilation or RRT at enrollment.After accounting for these baseline characteristics, no association was found between AT2 and the primary outcome or any of the secondary and tertiary outcomes.Thirty-day mortality was associated with several factors including older age, higher baseline NE equivalent doses, higher lactate, and RRT prior to enrollment.Higher MAP at enrollment and postoperative state were associated with decreased 30-and 90-day mortality.

Conclusion
AT2 was not associated with improved mortality or organ dysfunction when used as salvage therapy for patients with severe shock, nor was it associated with an increase in adverse events.

Critique
Unlike ATHOS-3 and other prior studies, this retrospective cohort study was sufficiently powered to detect a mortality difference.However, a large proportion of patients were diagnosed with septic shock.While logistic regression did not show an association between AT2 and mortality in septic patients, the AT2 patients were significantly older with more diagnostic results and interventions typically associated with worsened disease states.Most of these baseline characteristics were associated with higher 30-and 90-day patients receiving NAC for APAP-N, and animal studies have failed to show a protective effect from NAC.

Conclusion
APAP-N occasionally occurs after supratherapeutic APAP ingestion and can occur in the absence of hepatotoxicity.It typically follows a pattern similar to ATN and, while most patients make a full recovery, temporary HD may be necessary.NAC has not been shown to prevent or improve nephrotoxicity; further research is needed.

Critique
Utilizing a case report for illustration, this review article presents a thorough review of the clinical manifestations and pathophysiology of APAP-N.The review includes clinically relevant data and discussion of the correlation between APAP-N and dose, as well as the overall lack of evidence supporting NAC for prevention or treatment in the absence of hepatotoxicity.While there are limitations of summary reviews, the conclusions from this article continue to prevail since its publication 16 years ago, as demonstrated in the 2023 Consensus statement by ACMT, AACT, America's Poison Centers, and the Canadian Association of Poison Centers.

Implication for Toxicologists
This article remains a comprehensive resource on APAP-N for both insight and clinical guidance.Recent literature has suggested a possible protective role for 4-methylpyrazole in APAP-N but further research is needed.The breadth of data continues to support the futility of NAC and other interventions for the treatment or prevention of APAP-N.
Funding Open access funding provided by the Carolinas Consortium.

Conflict of Interest
The authors have received no funding for this article and report no conflicts of interest.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/.relationship to other variables (e.g., dose and degree of hepatotoxicity), and management.A single case report was used to present data and recommendations along with references to human and animal studies, case reports, and retrospective poison center reviews.

Results
The single case report involved a 47-year-old woman with a history of fibromyalgia and gastric bypass but no history of alcohol use disorder or renal insufficiency, who was found by family with altered mentation and recent reported ingestion of nine grams of APAP over two days.She presented with lethargy, tachycardia (HR 112) and tachypnea (RR 32); significant laboratory results included an APAP concentration of 12 mcg/ml, AST 5,409 u/L, ALT 1,085 u/L, creatinine of 0.9 mg/dL, and a urine drug screen positive for marijuana and opiates; she had no hematuria, proteinuria or ketonuria.Oral NAC was started but she developed fulminant hepatic failure with coagulopathy (INR 5.1), hypoglycemia, and an AST of 11,840 u/L on hospital day (HD) three.She was intubated for persistent obtundation, and creatinine increased to 2.3 mg/dL with BUN of 10 mg/ dL; repeat APAP concentration was 2 mcg/mL.Creatinine continued to rise and peaked at 8.1 ng/dL on HD12.She ultimately required multiple days of hemodialysis (HD) but was extubated and ultimately discharged on HD27, at which time her creatinine had improved to 1.3 mg/dL.
Animal studies have demonstrated that NAPQI is formed via CYP 2E1 in nephrocytes during excess APAP exposure, exerting similar toxic effects to that of the liver once glutathione is depleted.Other potential mechanisms of APAP-N include NAPQI formation via prostaglandin endoperoxidase synthetase, seen in both animal and human studies, as well as animal studies revealing the formation of p-aminophenol via N-deacetylase, a free radical precursor.Regardless of mechanism, renal biopsies in humans have shown that the proximal tubule is the most prominent site of toxic effects, resulting in a histopathologic pattern consistent with acute tubular necrosis (ATN).Human case reports have shown that this ATN-like renal injury, similar to hepatic injury, is more likely to occur in those at risk for CYP 2E1 upregulation or glutathione depletion.Interestingly, and with unclear reason, adolescents and young adults may also be more at risk.In these case reports, most cases of APAP-N began between two and five days post-exposure, with creatinine levels peaking at an average of seven days and returning to baseline in most cases within a month.Retrospective studies from poison centers reported almost a third of patients who developed renal insufficiency had no evidence, at the time, of liver injury.Case reports and retrospective studies have not shown a difference in peak creatinine levels among