Exposure Duration Determines ARDS in Nitrobenzene Poisoning

Exposure Duration Determines ARDS in Nitrobenzene Poisoning | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Exposure Duration Determines ARDS in Nitrobenzene Poisoning Min Zhang, Yixun Wang, Gaosheng Zhou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9483104/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract This case report adheres to the CARE 2013 guidelines. Nitrobenzene poisoning is a life-threatening condition characterized by severe methemoglobinemia (MetHb) and potential multi-organ injury. Methylene blue is the standard antidote, but factors predicting progression to acute respiratory distress syndrome (ARDS) remain unclear, and the impact of dermal decontamination timing on clinical outcomes has not been previously elucidated. Two male chemical workers were simultaneously exposed to undiluted, high-concentration nitrobenzene during an industrial accident. Patient 1 underwent immediate complete decontamination (removal of all contaminated clothing and thorough rinsing within 3 minutes), while Patient 2 had prolonged dermal contact (> 2 hours) by continuing work in contaminated trousers. Both patients developed severe MetHb (> 70%) but had drastically different outcomes: Patient 1 recovered without ARDS or renal injury and was discharged on day 15, whereas Patient 2 developed refractory ARDS requiring 12 days of venovenous extracorporeal membrane oxygenation (VV-ECMO) and acute kidney injury (AKI), with discharge on day 30. The divergent outcomes confirm that dermal exposure duration—rather than exposure intensity—is the sole independent determinant of ARDS and multi-organ injury in nitrobenzene poisoning. Prolonged exposure leads to nitrobenzene accumulation in adipose tissue, forming a slow-release toxic depot that sustains oxidative stress and pulmonary endothelial damage. Early therapeutic blood exchange and proactive ECMO consultation improve outcomes in patients with delayed decontamination. Implications : Immediate complete decontamination is an irreplaceable life-saving intervention in lipophilic chemical poisoning. This report provides the first human evidence linking dermal exposure duration to ARDS risk in nitrobenzene poisoning and proposes a preliminary ECMO risk-stratification algorithm. Nitrobenzene Methemoglobinemia ARDS VV-ECMO Decontamination Poisoning Figures Figure 1 Introduction Nitrobenzene is a widely used industrial chemical primarily employed in the synthesis of aniline, pesticides, and pharmaceuticals [ 1 , 2 ] . Human poisoning occurs via inhalation, dermal absorption, or ingestion, with dermal exposure being a common route in occupational settings. Its metabolite, phenylhydroxylamine, is a potent oxidant that converts ferrous hemoglobin (Fe²⁺) to ferric methemoglobin (Fe³⁺), impairing oxygen transport and leading to tissue hypoxia and multi-organ failure [ 3 ] . Severe methemoglobinemia (MetHb > 70%) is a medical emergency requiring urgent intervention. Methylene blue is the first-line antidote for methemoglobinemia, acting as an electron donor to reduce MetHb via NADPH-dependent methemoglobin reductase [ 4 ] . However, methylene blue only targets the effect (MetHb) and does not eliminate the parent nitrobenzene compound. Nitrobenzene is highly lipophilic (log P = 1.85), rapidly partitions into adipose tissue, and undergoes slow re-release [ 5 ] , creating a therapeutic gap: even after successful MetHb reversal, ongoing metabolite generation from adipose-stored nitrobenzene may perpetuate endothelial injury and predispose to delayed ARDS [ 6 ] . Existing literature on nitrobenzene poisoning consists primarily of single-case reports documenting the use of methylene blue, exchange transfusion, or hemoperfusion [ 2 , 5 – 7 ] . No study has isolated the critical determinant distinguishing recoverable from catastrophic poisoning, and the respective roles of exposure intensity versus duration remain undefined. Additionally, the optimal timing of extracorporeal life support (ECMO) in this context has not been addressed. We present a unique natural experiment involving two simultaneous, identical-dose nitrobenzene exposures with divergent outcomes, attributable solely to dermal decontamination duration. This study provides three novel insights: (1) immediate complete decontamination is the most impactful intervention, irreplaceable by subsequent antidotes; (2) prolonged exposure creates a toxic depot rendering methylene blue alone insufficient[8]; and (3) proactive ECMO deployment, based on exposure history rather than ARDS criteria, can prevent progressive respiratory failure. We also propose a preliminary clinical algorithm to guide ECMO consultation in this rare but lethal poisoning. Case Presentation Study Design and Exposure Details This is a comparative observational study of two natural experiments. On March 12, 2025, two previously healthy male workers at a chemical manufacturing facility were simultaneously sprayed with undiluted industrial nitrobenzene (> 99% purity, density 1.205 g/cm³) following an accidental valve activation. Both workers had received identical occupational health education and had immediate access to on-site safety showers. Their post-exposure decontamination behavior was the sole variable, creating a natural experiment to evaluate the impact of dermal contact duration on outcomes. Key baseline characteristics and time intervals are summarized in Table 1 . Table 1 summarizes the baseline characteristics and key time intervals. Feature / Item Case 1 Case 2 Gender Male Male Age 38 years old 44 years old Past Medical History No significant history No significant history Post-Exposure Management Immediately removed all clothing and rinsed with a safety shower Only removed upper garment, continued working in wet pants Symptom Onset 4 hours post-exposure 2 hours post-exposure Initial Symptoms Dizziness, fatigue, cyanotic lips Altered consciousness, severe cyanosis, dyspnea Hospital of Admission Transferred directly to this hospital Initially transferred to a local hospital Time of Hospital Admission 4 hours post-exposure 12 hours post-exposure Mental Status (GCS Score) Comatose, but with purposeful movement in response to pain (E1V1M5) Deep coma, loss of corneal and pupillary reflexes (E1V1M1) Vital Signs Severe cyanosis, SpO₂ 55% (room air) Severe cyanosis, dyspnea, SpO₂ 62% (under mechanical ventilation) Arterial Blood Gas MetHb > 70%, Lactate 6.3 mmol/L MetHb > 70%, Lactate 5.1 mmol/L Imaging Findings Not mentioned Chest X-ray showed bilateral diffuse infiltrates Initial Resuscitation 1. Methylene blue (2 mg/kg) IV 2. Mechanical ventilation 3. Thorough skin washing with running water 4. Vitamin C (1g q8h) Same as Case 1 (Methylene blue 2 mg/kg, Mechanical ventilation, Skin washing, Vitamin C) Blood Purification CRRT + Daily PE + Daily HP (alternating) CVVHDF + PE + HP (alternating) Blood Product Therapy Leukocyte-depleted red blood cell transfusion + Exchange transfusion Leukocyte-depleted red blood cell transfusion + Exchange transfusion Methylene Blue Use Initial 2 mg/kg, repeated doses according to MetHb levels (including reduced dose of 1 mg/kg) Initial 2 mg/kg, repeated doses according to MetHb levels (once daily on days 2 and 3) MetHb Reduction Rate Relatively fast, decreased to 30% within 6 hours of admission Relatively slow, MetHb remained > 70% 1 hour after treatment Major Complications 1. Severe hemolytic anemia (decreased Hb, increased indirect bilirubin) 2. Transiently elevated liver enzymes 1. Severe ARDS (diagnosed on day 6, required VV-ECMO) 2. Acute kidney injury (AKI) Advanced Life Support None Yes (VV-ECMO combined with CRRT) Discontinuation of Blood Purification Approximately 48 hours after admission (when MetHb neared normal levels) 3 days after admission (when MetHb decreased to 9.6%) Discharge Day Day 15 Day 30 Discharge Status Fully recovered and discharged. Renal function not fully recovered (subsequent follow-up showed normalization). Status at Discharge Discharged with full recovery. Early and thorough decontamination is critical. Despite extremely high MetHb, timely management prevented severe pulmonary/renal complications, resulting in a shorter clinical course. Renal function not fully recovered (subsequent follow-up showed normalization). Delayed decontamination and treatment led to continued toxin absorption, causing severe ARDS and AKI, necessitating advanced support like ECMO. The clinical course was prolonged with slower recovery. Patient 1: Immediate Decontamination A 38-year-old male with no prior medical history immediately removed all contaminated clothing and rinsed his entire body thoroughly with a safety shower within 3 minutes of nitrobenzene exposure. He developed dizziness, fatigue, and lip cyanosis 4 hours post-exposure and was transferred to our emergency department. On admission (4 hours post-exposure): Glasgow Coma Scale (GCS) E1V1M5; temperature 36.3°C; heart rate 105 beats/min; blood pressure 97/63 mmHg; respiratory rate 19 breaths/min; SpO₂ 55% on room air. Arterial blood gas (ABG) on FiO₂ 0.8: pH 7.35, PaO₂ 344 mmHg, MetHb > 70%, lactate 6.3 mmol/L. Chest radiography and cranial CT were unremarkable. Initial laboratory results: serum creatinine 0.75 mg/dL, ALT 18 U/L, hemoglobin 13.4 g/dL. Interventions Methylene blue: 2 mg/kg IV bolus immediately, repeated at 5 hours (cumulative 4 mg/kg within 6 hours), then 1 mg/kg at 28 hours (total 6 mg/kg over 48 hours). Extracorporeal detoxification: One session each of plasma exchange (PE, 2000 mL fresh frozen plasma), hemoperfusion (HP, HA330 cartridge), and continuous venovenous hemodiafiltration (CVVHDF) initiated on day 1. Therapeutic whole blood exchange: 200 mL leukocyte-depleted red cell transfusion with simultaneous 200 mL phlebotomy at 5 hours and 16 hours. Adjuvant therapy: IV vitamin C 1 g q8h for 72 hours. Clinical Course Cyanosis improved within 1 hour of intervention, but SpO₂ remained 75–79% on FiO₂ 0.8. MetHb declined to 30% at 6 hours, 13% at 16 hours, and < 10% at 28 hours. PE and HP were discontinued at 48 hours. On day 3, hemoglobin dropped to 9.5 g/dL with indirect hyperbilirubinemia (IBIL 3.01 mg/dL), consistent with hemolytic anemia, which was managed with intermittent red cell transfusion. Transaminases peaked on day 5 (ALT 387 U/L, AST 194 U/L) and normalized with hepatoprotective therapy. No pulmonary infiltrates developed during hospitalization. The patient was discharged on day 15 with complete organ recovery. Patient 2: Prolonged Dermal Contact A 44-year-old male with no significant medical history removed only his upper garments and continued working while wearing trousers saturated with nitrobenzene. He reported a “burning sensation” on his lower body but did not leave the worksite. Two hours post-exposure, he developed confusion, severe generalized cyanosis, and dyspnea, and was transferred to a local hospital, where methylene blue (1 mg/kg) was administered and mechanical ventilation initiated. Due to persistent deterioration, he was transferred to our ICU at 12 hours post-exposure. On admission (12 hours post-exposure): Deep coma (GCS E1V1M1) with absent corneal and pupillary reflexes; severe cyanosis; blood pressure 105/72 mmHg on norepinephrine 0.2 µg/kg/min; SpO₂ 62% on FiO₂ 1.0 with PEEP 12 cmH₂O. ABG: pH 7.25, PaO₂ 350 mmHg (FiO₂ 1.0), MetHb > 70%, lactate 5.1 mmol/L. Chest CT revealed bilateral lower lobe ground-glass opacities; cranial CT was normal. Initial laboratory results: serum creatinine 0.84 mg/dL, ALT 45 U/L, hemoglobin 13.8 g/dL. Interventions Methylene blue: 2 mg/kg on admission, repeated at 13 hours, 24 hours, 48 hours, and day 3 (total cumulative dose 10 mg/kg over 72 hours). Extracorporeal detoxification: Alternate-day PE, HP, and CVVHDF from day 1 to day 3. Therapeutic whole blood exchange: Performed at 13 hours, 24 hours, and 48 hours (200 mL each). Adjuvant therapy: IV vitamin C 1 g q8h for 7 days. Clinical Course MetHb declined slowly: 37% at 24 hours, 13.1% at 48 hours, and 9.6% at 72 hours. Hemolytic anemia developed on day 3, with a hemoglobin nadir of 5.3 g/dL on day 5, requiring multiple red cell transfusions. On day 6, despite MetHb < 4%, progressive hypoxemia occurred (PaO₂/FiO₂ ratio 80.8, SpO₂ 60% on FiO₂ 1.0), and chest radiograph showed diffuse bilateral opacities (“white lung”), meeting severe ARDS criteria (Berlin definition). VV-ECMO was initiated via right femoral-jugular cannulation and continued for 6 days. CRRT was continued for AKI, with peak serum creatinine 5.04 mg/dL on day 11. The patient was extubated on day 18 and discharged on day 30. Renal function normalized during outpatient follow-up at 2 months, and serial cranial CTs remained normal. Key Clinical Differences The critical differences between the two patients are summarized in Table 2 , emphasizing that dermal contact duration was the sole variable associated with ARDS, AKI, and the need for ECMO. Table 2 Comparative Clinical Characteristics and Key Time Intervals Variable Patient 1 Patient 2 Age/sex 38/M 44/M Estimated exposed area 90%BSA 90%BSA Time to partial decontamination < 1 min 2 h(upper bod) Time to complete decontamination < 3 min 2 h(lower bod) remained epic Time to first methylene blue 4 h 12 h Cumulative methylene blue (72h) 6 mg/kg 10 mg/kg Time to MetHb < 10% 28 h 72 h ARDS(day 6) No Yes VV-ECMO No Yes(day 6 ~ 12) AKI(KDIGO stage 3) No Yes Hospital stay(days) 15 30 Long-term sequelae None None Dynamic Laboratory and Imaging Changes Dynamic changes in laboratory parameters and pulmonary imaging are illustrated in Fig. 1. Serial measurements of serum creatinine, ALT, AST, total bilirubin, indirect bilirubin, hemoglobin, and MetHb demonstrate the slower recovery and more severe organ injury in Patient 2. Serial chest DR and CT images of Patient 2 show the progression of ARDS and complete resolution by 2 months post-exposure. Discussion Central Finding: Exposure Duration, Not Intensity, Determines Outcome To our knowledge, this is the first reported pair of simultaneous, identical-dose nitrobenzene exposures with directly observed differences in decontamination behavior. This unique natural experiment eliminates confounding variables (e.g., exposure dose, toxin concentration, treatment access) and isolates dermal contact duration as the sole independent determinant of ARDS and multi-organ injury. Patient 1, who decontaminated within minutes, recovered rapidly without pulmonary sequelae, while Patient 2—with prolonged exposure (> 2 hours)—developed protracted MetHb elevation, severe ARDS, and AKI despite identical initial therapy. This observation fundamentally shifts the toxicological paradigm for lipophilic poisonings from dose-dependent to time-dependent injury. Adipose Reservoir Hypothesis: A Mechanistic Explanation Nitrobenzene’s lipophilicity (log P = 1.85) predicts substantial partitioning into adipose tissue. Animal studies have shown that nitrobenzene accumulates rapidly in perirenal and omental fat after intravenous administration, with a terminal elimination half-life exceeding 24 hours [ 9 ] . Human data are limited, but our clinical observations provide compelling indirect evidence for an “adipose reservoir hypothesis”: 1.Delayed MetHb clearance in Patient 2: Despite a higher cumulative methylene blue dose (10 vs. 6 mg/kg), MetHb declined at half the rate of Patient 1. This is inconsistent with first-order elimination and suggests ongoing generation of phenylhydroxylamine from a slowly releasing adipose depot [ 10 ] . 2.Delayed ARDS onset: Patient 2 developed ARDS on day 6, when MetHb was already < 4%. This temporal dissociation between hemoglobin oxidation and lung injury indicates a parallel pathogenic pathway—likely direct pulmonary endothelial toxicity from nitrobenzene or its metabolites released from adipose tissue [ 11 ] . 3.Absence of ARDS in Patient 1: Immediate decontamination prevented significant adipose loading, truncating the toxicokinetic curve before depot formation [ 12 ] . We propose the following mechanistic framework: Prolonged dermal exposure → significant adipose partitioning → sustained slow release of nitrobenzene → persistent oxidative stress → pulmonary endothelial priming → delayed ARDS. This hypothesis is testable, though practical constraints (e.g., lack of serial serum nitrobenzene measurements, difficulty obtaining adipose biopsies in acute settings) limit immediate validation. Methylene Blue: Necessary but Not Sufficient Methylene blue remains the cornerstone of methemoglobinemia management, and both patients ultimately achieved MetHb normalization [ 13 , 14 ] . However, Patient 2’s slow response highlights a critical limitation: methylene blue treats the effect (MetHb) but not the cause (nitrobenzene itself). When a toxic adipose depot exists, repeated methylene blue administration may be required, but this carries risks—high doses (> 7 mg/kg) paradoxically oxidize hemoglobin and exacerbate hemolysis. Patient 1 received 6 mg/kg over 48 hours and developed moderate hemolysis (nadir Hb 9.5 g/dL), while Patient 2 received 10 mg/kg over 72 hours and developed severe hemolysis (nadir Hb 5.3 g/dL). While hemolysis in nitrobenzene poisoning is multifactorial (e.g., direct toxin-induced erythrocyte damage), the dose-dependent contribution of methylene blue cannot be ignored. We recommend that in patients with delayed decontamination, methylene blue be dosed based on MetHb trends rather than a fixed schedule, with alternative detoxification strategies (e.g., blood exchange) prioritized once MetHb falls below 20%. Therapeutic Blood Exchange: Underutilized and Undervalued Whole blood exchange directly removes erythrocytes containing both MetHb and nitrobenzene-adducted hemoglobin, making it a critical intervention for severe poisoning. Singh et al.’s systematic review confirmed its efficacy in refractory methemoglobinemia [ 15 ] . In our study, each 200 mL exchange was followed by an immediate 10–15% absolute reduction in MetHb in both patients. In Patient 2, three exchanges over 48 hours accelerated MetHb clearance despite ongoing toxin release from the adipose depot. We advocate for earlier and more aggressive use of therapeutic blood exchange in severe nitrobenzene poisoning, particularly in the following scenarios: (1) initial MetHb > 70%; (2) blunted response to methylene blue (< 20% MetHb reduction within 2 hours); (3) suspected G6PD deficiency; (4) evidence of ongoing hemolysis. Exchange transfusion should be initiated concurrently with, not after, methylene blue administration. VV-ECMO: From Rescue Therapy to Proactive Strategy Patient 2 developed severe ARDS on day 6, requiring 12 days of VV-ECMO support. Crucially, bilateral pulmonary infiltrates were already present on admission CT, indicating that lung injury began early but remained clinically silent until a cumulative toxicity threshold was crossed. This raises a key clinical question: Should we wait for ARDS to manifest before initiating ECMO? In traditional critical care, ECMO is reserved for refractory hypoxemia after failed conventional ventilation. However, in poisonings with known delayed toxicity (e.g., nitrobenzene), this “wait-and-fail” approach may squander the window of opportunity. Nitrobenzene-induced endothelial injury is not instantly reversible; by the time PaO₂/FiO₂ falls below 100, widespread capillary leakage and alveolar damage may already be irreversible. We propose a proactive, risk-stratified approach to ECMO consultation in nitrobenzene poisoning—the Nitrobenzene ECMO Eligibility Score (NEES), which requires prospective validation: Nitrobenzene ECMO Eligibility Score (NEES) – Proposal for Validation Criteria Points Dermal contact > 2 hours without complete decontamination 2 Initial MetHb > 70% 1 MetHb < 20%reduction at 4 hours post-methylene blue 1 Bilateral infiltrates on admission CT 2 PaO₂/FiO₂<200 on FiO₂ 1.0, PEEP ≥ 10 2 Total ≥ 4: consider early ECMO consultation Patient 2 would have scored 6 (2 + 1+1 + 2+0). Patient 1 scored 1. This algorithm requires prospective validation but provides a structured framework for clinical decision-making in an otherwise anecdotal field. Plasma Exchange and Hemoperfusion: Unresolved Questions We utilized PE and HP based on theoretical rationale: removal of protein-bound toxins and inflammatory mediators. However, nitrobenzene is predominantly hemoglobin-bound (only 10–15% plasma protein binding), making the incremental benefit of PE beyond blood exchange questionable. HP with HA330 cartridge has been reported in nitrobenzene poisoning, but its efficacy cannot be dissociated from concurrent interventions (e.g., blood exchange, methylene blue). We explicitly acknowledge that this report does not provide evidence for the independent efficacy of PE or HP. Their use should be considered exploratory, and future research should prioritize blood exchange and early decontamination over complex extracorporeal cocktails. Implications for Occupational Health and Emergency Preparedness These two cases deliver a stark public health message: personal protective equipment and immediate decontamination are irreplaceable by advanced hospital therapy. Patient 1 survived without ECMO and was discharged in 15 days; Patient 2 required 30 days of hospitalization and ECMO support. The difference was not access to intensive care, but access to a safety shower and prompt decontamination. For chemical plants handling lipophilic toxins, we recommend: (1) a mandatory buddy system to ensure complete decontamination; (2) a low threshold for hospital referral following any skin contact with nitrobenzene; (3) pre-arranged transfer protocols with regional ECMO centers. First responders must also be protected, as contaminated clothing is a source of secondary exposure—no secondary cases occurred in our study due to standard precautions. What This Case Adds to the Literature This report provides the first direct human evidence linking dermal exposure duration to ARDS risk in nitrobenzene poisoning. It proposes the “adipose reservoir hypothesis” as a mechanistic framework for delayed toxicity and introduces a preliminary ECMO risk-stratification algorithm. Additionally, it highlights the critical importance of immediate decontamination and the limitations of methylene blue alone in patients with prolonged exposure. Limitations This is a comparative observational study of two cases, not a controlled trial. Causality cannot be definitively proven, and unmeasured confounders may exist. Serum nitrobenzene concentrations were not available to quantify toxin exposure and clearance. The proposed NEES score is preliminary and requires external validation. We cannot exclude the possibility of occult inhalation exposure in Patient 2, though his work practice (wearing saturated trousers with upper body decontaminated) suggests dermal absorption was the dominant route. Despite these limitations, the natural experimental design—identical exposure, same environment, different decontamination behavior—provides the strongest possible human evidence short of a randomized trial, which is neither feasible nor ethical in this context. Conclusions In simultaneous, identical-dose nitrobenzene poisoning, dermal contact duration is the sole independent predictor of ARDS and multi-organ failure. Immediate complete decontamination is the most powerful life-saving intervention and must be prioritized in occupational safety protocols. For patients with delayed decontamination (> 2 hours), methylene blue alone is insufficient; therapeutic blood exchange should be initiated early, and VV-ECMO should be considered proactively in those with admission pulmonary infiltrates and slow MetHb clearance [ 13 , 16 ] . The adipose reservoir hypothesis provides a mechanistic framework for understanding delayed toxicity in lipophilic poisonings. We call for a prospective registry to validate the proposed NEES algorithm and further refine clinical management. Declarations Ethics approval and consent to participate The present study was approved by the Medical Ethics Committee of Yichang Central People’s Hospital (Approval No. 2025-352-01). Written informed consent was obtained from both patients prior to their participation in the case study. Consent for publication Written informed consent was obtained from both patients for publication of this case report and any accompanying images. A copy of the consent form is available for review by the Editor-in-Chief. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution M Z and Yx W drafted the manuscript and contributed equally as co-first authors. M Z and Gs Z designed the study, collected clinical data, and revised the manuscript. Gs Z conceived the study, supervised patient management, and finalized the manuscript. All authors approved the final version and agree to be accountable for all aspects of the work. Acknowledgement We thank the nursing staff of the Yichang Central People’s Hospital ICU for their exceptional care of these patients. We also acknowledge the occupational health team at the referring chemical plant for providing detailed exposure histories. Data availability All relevant data are presented in the manuscript. Raw clinical data are available from the corresponding author upon reasonable request. References Agency for Toxic Substances and Disease Registry. Toxicological profile for nitrobenzene. Atlanta, GA: ATSDR; 2024. Ivek I, Knotek T, Ivičić T, et al. Methemoglobinemia - a case report and literature review. Acta Clin Croat. 2022;61:93–8. Ludlow JT, Wilkerson RG, Nappe TM. In: StatPearls, editor. Methemoglobinemia. Treasure Island, FL: StatPearls Publishing; 2025. Rothenberg R, Biary R, Hoffman RS. Effectiveness and tolerability of methylthioninium chloride (methylene blue) for the treatment of methemoglobinemia: Twenty-four years of experience at a single poison center. Clin Toxicol (Phila). 2025;63:284–91. Yu G, Li Y, Cui S, et al. Two cases of methaemoglobinaemia and haemolysis due to poisoning after skin absorption of 4-chloro-1-nitrobenzene. Clin Toxicol (Phila). 2022;60:970–3. Zhao L, Jian T, Shi L, et al. Case report: Methemoglobinemia caused by nitrobenzene poisoning. 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Removal of inflammatory factors and prognosis of patients with septic shock complicated with acute kidney injury by hemodiafiltration combined with HA330-II hemoperfusion. Ther Apher Dial. 2024;28:460–6. Agrawal A, Gutch M, Arora R, Jain N. Acute cardiogenic pulmonary oedema with multiorgan dysfunction—still to learn more about nitrobenzene poisoning. BMJ Case Rep. 2011;2011:bcr1020115026. Singh P, Rakesh K, Agarwal R, et al. Therapeutic whole blood exchange in the management of methaemoglobinemia: Case series and systematic review of literature. Transfus Med. 2020;30:231–9. Seshadri SY, Tb H. Acute methemoglobinemia due to crop-flowering stimulant (nitrobenzene) poisoning: A case report. Cureus. 2023;15:e47766. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9483104","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":633641327,"identity":"a25b93ce-64fb-47b7-b967-45add47c63d0","order_by":0,"name":"Min Zhang","email":"","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Zhang","suffix":""},{"id":633641328,"identity":"5331d567-93f2-4f6b-8ff1-142bd5529c12","order_by":1,"name":"Yixun Wang","email":"","orcid":"","institution":"China Three Gorges University","correspondingAuthor":false,"prefix":"","firstName":"Yixun","middleName":"","lastName":"Wang","suffix":""},{"id":633641329,"identity":"442f7d43-6947-4221-8edb-5f7e3c1fe723","order_by":2,"name":"Gaosheng Zhou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYHACNiC24WFjbz5w4MMP4rWkyfHxHEs8OLOHeC2HjeUkcowPc7ARoV7e//izBx/bmBPbGHI+HGbgYZDnFzuAX4vhjYR0w5ltbEAtZzccLrBgMJw5O4GAlhkMx6R523gS2xh7NxyewcOQYHCbkJb+g21ALRKJbcw8Dw7zsBGhRZ4hmQ2oxcCYjY2HgTgtBhJpbJIzziXIsfGwGQADWYKwX+T7jz+T+FD2n0d+/uPHHz78sJHnlyZkywFUvgR+5WBbGgirGQWjYBSMgpEOAKWxQpv8Az6AAAAAAElFTkSuQmCC","orcid":"","institution":"Yichang Central People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Gaosheng","middleName":"","lastName":"Zhou","suffix":""}],"badges":[],"createdAt":"2026-04-21 10:54:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9483104/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9483104/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108735999,"identity":"c2d46253-1ab2-42b1-9a15-9667f48a67f0","added_by":"auto","created_at":"2026-05-07 20:10:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":891787,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDynamic Changes in Laboratory Parameters and Pulmonary Imaging in Two Patients with Nitrobenzene Poisoning\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.1.png","url":"https://assets-eu.researchsquare.com/files/rs-9483104/v1/ca8ab5ebf55dc5ca76b1288d.png"},{"id":108807312,"identity":"fc25929e-f649-441c-ba67-b6292d699309","added_by":"auto","created_at":"2026-05-08 15:30:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1151844,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9483104/v1/9e5fb593-1060-437a-abf7-e360d168a31d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eExposure Duration Determines ARDS in Nitrobenzene Poisoning\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNitrobenzene is a widely used industrial chemical primarily employed in the synthesis of aniline, pesticides, and pharmaceuticals\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Human poisoning occurs via inhalation, dermal absorption, or ingestion, with dermal exposure being a common route in occupational settings. Its metabolite, phenylhydroxylamine, is a potent oxidant that converts ferrous hemoglobin (Fe\u0026sup2;⁺) to ferric methemoglobin (Fe\u0026sup3;⁺), impairing oxygen transport and leading to tissue hypoxia and multi-organ failure\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Severe methemoglobinemia (MetHb\u0026thinsp;\u0026gt;\u0026thinsp;70%) is a medical emergency requiring urgent intervention.\u003c/p\u003e \u003cp\u003eMethylene blue is the first-line antidote for methemoglobinemia, acting as an electron donor to reduce MetHb via NADPH-dependent methemoglobin reductase\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. However, methylene blue only targets the effect (MetHb) and does not eliminate the parent nitrobenzene compound. Nitrobenzene is highly lipophilic (log P\u0026thinsp;=\u0026thinsp;1.85), rapidly partitions into adipose tissue, and undergoes slow re-release\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, creating a therapeutic gap: even after successful MetHb reversal, ongoing metabolite generation from adipose-stored nitrobenzene may perpetuate endothelial injury and predispose to delayed ARDS\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eExisting literature on nitrobenzene poisoning consists primarily of single-case reports documenting the use of methylene blue, exchange transfusion, or hemoperfusion\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. No study has isolated the critical determinant distinguishing recoverable from catastrophic poisoning, and the respective roles of exposure intensity versus duration remain undefined. Additionally, the optimal timing of extracorporeal life support (ECMO) in this context has not been addressed.\u003c/p\u003e \u003cp\u003eWe present a unique natural experiment involving two simultaneous, identical-dose nitrobenzene exposures with divergent outcomes, attributable solely to dermal decontamination duration. This study provides three novel insights: (1) immediate complete decontamination is the most impactful intervention, irreplaceable by subsequent antidotes; (2) prolonged exposure creates a toxic depot rendering methylene blue alone insufficient[8]; and (3) proactive ECMO deployment, based on exposure history rather than ARDS criteria, can prevent progressive respiratory failure. We also propose a preliminary clinical algorithm to guide ECMO consultation in this rare but lethal poisoning.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Design and Exposure Details\u003c/h2\u003e\n \u003cp\u003eThis is a comparative observational study of two natural experiments. On March 12, 2025, two previously healthy male workers at a chemical manufacturing facility were simultaneously sprayed with undiluted industrial nitrobenzene (\u0026gt;\u0026thinsp;99% purity, density 1.205 g/cm\u0026sup3;) following an accidental valve activation. Both workers had received identical occupational health education and had immediate access to on-site safety showers. Their post-exposure decontamination behavior was the sole variable, creating a natural experiment to evaluate the impact of dermal contact duration on outcomes. Key baseline characteristics and time intervals are summarized in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u0026nbsp;\u003c/p\u003e\n \u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003esummarizes the baseline characteristics and key time intervals.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eFeature / Item\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eCase 1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eCase 2\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e38 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e44 years old\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003ePast Medical History\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eNo significant history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eNo significant history\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003ePost-Exposure Management\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eImmediately removed all clothing and rinsed with a safety shower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eOnly removed upper garment, continued working in wet pants\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSymptom Onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e4 hours post-exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e2 hours post-exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eInitial Symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eDizziness, fatigue, cyanotic lips\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eAltered consciousness, severe cyanosis, dyspnea\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eHospital of Admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eTransferred directly to this hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eInitially transferred to a local hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eTime of Hospital Admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e4 hours post-exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e12 hours post-exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eMental Status (GCS Score)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eComatose, but with purposeful movement in response to pain (E1V1M5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eDeep coma, loss of corneal and pupillary reflexes (E1V1M1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eVital Signs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eSevere cyanosis, SpO₂ 55% (room air)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eSevere cyanosis, dyspnea, SpO₂ 62% (under mechanical ventilation)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eArterial Blood Gas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eMetHb\u0026thinsp;\u0026gt;\u0026thinsp;70%, Lactate 6.3 mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eMetHb\u0026thinsp;\u0026gt;\u0026thinsp;70%, Lactate 5.1 mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eImaging Findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eNot mentioned\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eChest X-ray showed bilateral diffuse infiltrates\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eInitial Resuscitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1. Methylene blue (2 mg/kg) IV\u003c/p\u003e\n \u003cp\u003e2. Mechanical ventilation\u003c/p\u003e\n \u003cp\u003e3. Thorough skin washing with running water\u003c/p\u003e\n \u003cp\u003e4. Vitamin C (1g q8h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eSame as Case 1 (Methylene blue 2 mg/kg, Mechanical ventilation, Skin washing, Vitamin C)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eBlood Purification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eCRRT\u0026thinsp;+\u0026thinsp;Daily PE\u0026thinsp;+\u0026thinsp;Daily HP (alternating)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eCVVHDF\u0026thinsp;+\u0026thinsp;PE\u0026thinsp;+\u0026thinsp;HP (alternating)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eBlood Product Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eLeukocyte-depleted red blood cell transfusion\u0026thinsp;+\u0026thinsp;Exchange transfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eLeukocyte-depleted red blood cell transfusion\u0026thinsp;+\u0026thinsp;Exchange transfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eMethylene Blue Use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eInitial 2 mg/kg, repeated doses according to MetHb levels (including reduced dose of 1 mg/kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eInitial 2 mg/kg, repeated doses according to MetHb levels (once daily on days 2 and 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eMetHb Reduction Rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eRelatively fast, decreased to 30% within 6 hours of admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eRelatively slow, MetHb remained\u0026thinsp;\u0026gt;\u0026thinsp;70% 1 hour after treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eMajor Complications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e1. Severe hemolytic anemia (decreased Hb, increased indirect bilirubin)\u003c/p\u003e\n \u003cp\u003e2. Transiently elevated liver enzymes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e1. Severe ARDS (diagnosed on day 6, required VV-ECMO)\u003c/p\u003e\n \u003cp\u003e2. Acute kidney injury (AKI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAdvanced Life Support\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eYes (VV-ECMO combined with CRRT)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eDiscontinuation of Blood Purification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eApproximately 48 hours after admission (when MetHb neared normal levels)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e3 days after admission (when MetHb decreased to 9.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eDischarge Day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eDay 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eDay 30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eDischarge Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eFully recovered and discharged.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eRenal function not fully recovered (subsequent follow-up showed normalization).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eStatus at Discharge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eDischarged with full recovery. Early and thorough decontamination is critical. Despite extremely high MetHb, timely management prevented severe pulmonary/renal complications, resulting in a shorter clinical course.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eRenal function not fully recovered (subsequent follow-up showed normalization). Delayed decontamination and treatment led to continued toxin absorption, causing severe ARDS and AKI, necessitating advanced support like ECMO. The clinical course was prolonged with slower recovery.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003ePatient 1: Immediate Decontamination\u003c/h3\u003e\n\u003cp\u003eA 38-year-old male with no prior medical history immediately removed all contaminated clothing and rinsed his entire body thoroughly with a safety shower within 3 minutes of nitrobenzene exposure. He developed dizziness, fatigue, and lip cyanosis 4 hours post-exposure and was transferred to our emergency department.\u003c/p\u003e\n\u003cp\u003eOn admission (4 hours post-exposure): Glasgow Coma Scale (GCS) E1V1M5; temperature 36.3\u0026deg;C; heart rate 105 beats/min; blood pressure 97/63 mmHg; respiratory rate 19 breaths/min; SpO₂ 55% on room air. Arterial blood gas (ABG) on FiO₂ 0.8: pH 7.35, PaO₂ 344 mmHg, MetHb\u0026thinsp;\u0026gt;\u0026thinsp;70%, lactate 6.3 mmol/L. Chest radiography and cranial CT were unremarkable. Initial laboratory results: serum creatinine 0.75 mg/dL, ALT 18 U/L, hemoglobin 13.4 g/dL.\u003c/p\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eMethylene blue: 2 mg/kg IV bolus immediately, repeated at 5 hours (cumulative 4 mg/kg within 6 hours), then 1 mg/kg at 28 hours (total 6 mg/kg over 48 hours).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eExtracorporeal detoxification: One session each of plasma exchange (PE, 2000 mL fresh frozen plasma), hemoperfusion (HP, HA330 cartridge), and continuous venovenous hemodiafiltration (CVVHDF) initiated on day 1.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eTherapeutic whole blood exchange: 200 mL leukocyte-depleted red cell transfusion with simultaneous 200 mL phlebotomy at 5 hours and 16 hours.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eAdjuvant therapy: IV vitamin C 1 g q8h for 72 hours.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3\u003eClinical Course\u003c/h3\u003e\n\u003cp\u003eCyanosis improved within 1 hour of intervention, but SpO₂ remained 75\u0026ndash;79% on FiO₂ 0.8. MetHb declined to 30% at 6 hours, 13% at 16 hours, and \u0026lt;\u0026thinsp;10% at 28 hours. PE and HP were discontinued at 48 hours. On day 3, hemoglobin dropped to 9.5 g/dL with indirect hyperbilirubinemia (IBIL 3.01 mg/dL), consistent with hemolytic anemia, which was managed with intermittent red cell transfusion. Transaminases peaked on day 5 (ALT 387 U/L, AST 194 U/L) and normalized with hepatoprotective therapy. No pulmonary infiltrates developed during hospitalization. The patient was discharged on day 15 with complete organ recovery.\u003c/p\u003e\n\u003ch3\u003ePatient 2: Prolonged Dermal Contact\u003c/h3\u003e\n\u003cp\u003eA 44-year-old male with no significant medical history removed only his upper garments and continued working while wearing trousers saturated with nitrobenzene. He reported a \u0026ldquo;burning sensation\u0026rdquo; on his lower body but did not leave the worksite. Two hours post-exposure, he developed confusion, severe generalized cyanosis, and dyspnea, and was transferred to a local hospital, where methylene blue (1 mg/kg) was administered and mechanical ventilation initiated. Due to persistent deterioration, he was transferred to our ICU at 12 hours post-exposure.\u003c/p\u003e\n\u003cp\u003eOn admission (12 hours post-exposure): Deep coma (GCS E1V1M1) with absent corneal and pupillary reflexes; severe cyanosis; blood pressure 105/72 mmHg on norepinephrine 0.2 \u0026micro;g/kg/min; SpO₂ 62% on FiO₂ 1.0 with PEEP 12 cmH₂O. ABG: pH 7.25, PaO₂ 350 mmHg (FiO₂ 1.0), MetHb\u0026thinsp;\u0026gt;\u0026thinsp;70%, lactate 5.1 mmol/L. Chest CT revealed bilateral lower lobe ground-glass opacities; cranial CT was normal. Initial laboratory results: serum creatinine 0.84 mg/dL, ALT 45 U/L, hemoglobin 13.8 g/dL.\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eInterventions\u003c/h2\u003e\n \u003cul\u003e\n \u003cli\u003e\n \u003cp\u003eMethylene blue: 2 mg/kg on admission, repeated at 13 hours, 24 hours, 48 hours, and day 3 (total cumulative dose 10 mg/kg over 72 hours).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eExtracorporeal detoxification: Alternate-day PE, HP, and CVVHDF from day 1 to day 3.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eTherapeutic whole blood exchange: Performed at 13 hours, 24 hours, and 48 hours (200 mL each).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eAdjuvant therapy: IV vitamin C 1 g q8h for 7 days.\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ul\u003e\n\u003c/div\u003e\n\u003ch3\u003eClinical Course\u003c/h3\u003e\n\u003cp\u003eMetHb declined slowly: 37% at 24 hours, 13.1% at 48 hours, and 9.6% at 72 hours. Hemolytic anemia developed on day 3, with a hemoglobin nadir of 5.3 g/dL on day 5, requiring multiple red cell transfusions. On day 6, despite MetHb\u0026thinsp;\u0026lt;\u0026thinsp;4%, progressive hypoxemia occurred (PaO₂/FiO₂ ratio 80.8, SpO₂ 60% on FiO₂ 1.0), and chest radiograph showed diffuse bilateral opacities (\u0026ldquo;white lung\u0026rdquo;), meeting severe ARDS criteria (Berlin definition). VV-ECMO was initiated via right femoral-jugular cannulation and continued for 6 days. CRRT was continued for AKI, with peak serum creatinine 5.04 mg/dL on day 11. The patient was extubated on day 18 and discharged on day 30. Renal function normalized during outpatient follow-up at 2 months, and serial cranial CTs remained normal.\u003c/p\u003e\n\u003ch3\u003eKey Clinical Differences\u003c/h3\u003e\n\u003cp\u003eThe critical differences between the two patients are summarized in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, emphasizing that dermal contact duration was the sole variable associated with ARDS, AKI, and the need for ECMO.\u0026nbsp;\u003c/p\u003e\n\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparative Clinical Characteristics and Key Time Intervals\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003ePatient 1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003ePatient 2\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAge/sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e38/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e44/M\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eEstimated exposed area\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e90%BSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e90%BSA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eTime to partial decontamination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;1 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e2 h(upper bod)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eTime to complete decontamination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;3 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e2 h(lower bod) remained epic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eTime to first methylene blue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e4 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e12 h\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCumulative methylene blue (72h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e6 mg/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e10 mg/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eTime to MetHb\u0026thinsp;\u0026lt;\u0026thinsp;10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e28 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e72 h\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eARDS(day 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eVV-ECMO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eYes(day 6\u0026thinsp;~\u0026thinsp;12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eAKI(KDIGO stage 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eHospital stay(days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eLong-term sequelae\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eDynamic Laboratory and Imaging Changes\u003c/h2\u003e\n \u003cp\u003eDynamic changes in laboratory parameters and pulmonary imaging are illustrated in Fig. 1. Serial measurements of serum creatinine, ALT, AST, total bilirubin, indirect bilirubin, hemoglobin, and MetHb demonstrate the slower recovery and more severe organ injury in Patient 2. Serial chest DR and CT images of Patient 2 show the progression of ARDS and complete resolution by 2 months post-exposure.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eCentral Finding: Exposure Duration, Not Intensity, Determines Outcome\u003c/h2\u003e\n \u003cp\u003eTo our knowledge, this is the first reported pair of simultaneous, identical-dose nitrobenzene exposures with directly observed differences in decontamination behavior. This unique natural experiment eliminates confounding variables (e.g., exposure dose, toxin concentration, treatment access) and isolates dermal contact duration as the sole independent determinant of ARDS and multi-organ injury. Patient 1, who decontaminated within minutes, recovered rapidly without pulmonary sequelae, while Patient 2\u0026mdash;with prolonged exposure (\u0026gt;\u0026thinsp;2 hours)\u0026mdash;developed protracted MetHb elevation, severe ARDS, and AKI despite identical initial therapy. This observation fundamentally shifts the toxicological paradigm for lipophilic poisonings from dose-dependent to time-dependent injury.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eAdipose Reservoir Hypothesis: A Mechanistic Explanation\u003c/h2\u003e\n \u003cp\u003eNitrobenzene\u0026rsquo;s lipophilicity (log P\u0026thinsp;=\u0026thinsp;1.85) predicts substantial partitioning into adipose tissue. Animal studies have shown that nitrobenzene accumulates rapidly in perirenal and omental fat after intravenous administration, with a terminal elimination half-life exceeding 24 hours\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Human data are limited, but our clinical observations provide compelling indirect evidence for an \u0026ldquo;adipose reservoir hypothesis\u0026rdquo;:\u003c/p\u003e\n \u003cp\u003e1.Delayed MetHb clearance in Patient 2: Despite a higher cumulative methylene blue dose (10 vs. 6 mg/kg), MetHb declined at half the rate of Patient 1. This is inconsistent with first-order elimination and suggests ongoing generation of phenylhydroxylamine from a slowly releasing adipose depot\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003e2.Delayed ARDS onset: Patient 2 developed ARDS on day 6, when MetHb was already\u0026thinsp;\u0026lt;\u0026thinsp;4%. This temporal dissociation between hemoglobin oxidation and lung injury indicates a parallel pathogenic pathway\u0026mdash;likely direct pulmonary endothelial toxicity from nitrobenzene or its metabolites released from adipose tissue\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003e3.Absence of ARDS in Patient 1: Immediate decontamination prevented significant adipose loading, truncating the toxicokinetic curve before depot formation\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eWe propose the following mechanistic framework: Prolonged dermal exposure \u0026rarr; significant adipose partitioning \u0026rarr; sustained slow release of nitrobenzene \u0026rarr; persistent oxidative stress \u0026rarr; pulmonary endothelial priming \u0026rarr; delayed ARDS. This hypothesis is testable, though practical constraints (e.g., lack of serial serum nitrobenzene measurements, difficulty obtaining adipose biopsies in acute settings) limit immediate validation.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eMethylene Blue: Necessary but Not Sufficient\u003c/h2\u003e\n \u003cp\u003eMethylene blue remains the cornerstone of methemoglobinemia management, and both patients ultimately achieved MetHb normalization\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. However, Patient 2\u0026rsquo;s slow response highlights a critical limitation: methylene blue treats the effect (MetHb) but not the cause (nitrobenzene itself). When a toxic adipose depot exists, repeated methylene blue administration may be required, but this carries risks\u0026mdash;high doses (\u0026gt;\u0026thinsp;7 mg/kg) paradoxically oxidize hemoglobin and exacerbate hemolysis.\u003c/p\u003e\n \u003cp\u003ePatient 1 received 6 mg/kg over 48 hours and developed moderate hemolysis (nadir Hb 9.5 g/dL), while Patient 2 received 10 mg/kg over 72 hours and developed severe hemolysis (nadir Hb 5.3 g/dL). While hemolysis in nitrobenzene poisoning is multifactorial (e.g., direct toxin-induced erythrocyte damage), the dose-dependent contribution of methylene blue cannot be ignored. We recommend that in patients with delayed decontamination, methylene blue be dosed based on MetHb trends rather than a fixed schedule, with alternative detoxification strategies (e.g., blood exchange) prioritized once MetHb falls below 20%.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eTherapeutic Blood Exchange: Underutilized and Undervalued\u003c/h2\u003e\n \u003cp\u003eWhole blood exchange directly removes erythrocytes containing both MetHb and nitrobenzene-adducted hemoglobin, making it a critical intervention for severe poisoning. Singh et al.\u0026rsquo;s systematic review confirmed its efficacy in refractory methemoglobinemia\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. In our study, each 200 mL exchange was followed by an immediate 10\u0026ndash;15% absolute reduction in MetHb in both patients. In Patient 2, three exchanges over 48 hours accelerated MetHb clearance despite ongoing toxin release from the adipose depot.\u003c/p\u003e\n \u003cp\u003eWe advocate for earlier and more aggressive use of therapeutic blood exchange in severe nitrobenzene poisoning, particularly in the following scenarios: (1) initial MetHb\u0026thinsp;\u0026gt;\u0026thinsp;70%; (2) blunted response to methylene blue (\u0026lt;\u0026thinsp;20% MetHb reduction within 2 hours); (3) suspected G6PD deficiency; (4) evidence of ongoing hemolysis. Exchange transfusion should be initiated concurrently with, not after, methylene blue administration.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eVV-ECMO: From Rescue Therapy to Proactive Strategy\u003c/h2\u003e\n \u003cp\u003ePatient 2 developed severe ARDS on day 6, requiring 12 days of VV-ECMO support. Crucially, bilateral pulmonary infiltrates were already present on admission CT, indicating that lung injury began early but remained clinically silent until a cumulative toxicity threshold was crossed. This raises a key clinical question: Should we wait for ARDS to manifest before initiating ECMO?\u003c/p\u003e\n \u003cp\u003eIn traditional critical care, ECMO is reserved for refractory hypoxemia after failed conventional ventilation. However, in poisonings with known delayed toxicity (e.g., nitrobenzene), this \u0026ldquo;wait-and-fail\u0026rdquo; approach may squander the window of opportunity. Nitrobenzene-induced endothelial injury is not instantly reversible; by the time PaO₂/FiO₂ falls below 100, widespread capillary leakage and alveolar damage may already be irreversible.\u003c/p\u003e\n \u003cp\u003eWe propose a proactive, risk-stratified approach to ECMO consultation in nitrobenzene poisoning\u0026mdash;the Nitrobenzene ECMO Eligibility Score (NEES), which requires prospective validation:\u003c/p\u003e\n \u003cp\u003eNitrobenzene ECMO Eligibility Score (NEES) \u0026ndash; Proposal for Validation\u003c/p\u003e\n \u003ctable float=\"No\" id=\"Tabd\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCriteria\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003ePoints\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eDermal contact\u0026thinsp;\u0026gt;\u0026thinsp;2 hours without complete decontamination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eInitial MetHb\u0026thinsp;\u0026gt;\u0026thinsp;70%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eMetHb\u0026thinsp;\u0026lt;\u0026thinsp;20%reduction at 4 hours post-methylene blue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eBilateral infiltrates on admission CT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003ePaO₂/FiO₂\u0026lt;200 on FiO₂ 1.0, PEEP\u0026thinsp;\u0026ge;\u0026thinsp;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003cstrong\u003e\n \u003cp\u003eTotal\u0026thinsp;\u0026ge;\u0026thinsp;4: consider early ECMO consultation\u003c/p\u003e\n \u003c/strong\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003ePatient 2 would have scored 6 (2\u0026thinsp;+\u0026thinsp;1+1\u0026thinsp;+\u0026thinsp;2+0). Patient 1 scored 1. This algorithm requires prospective validation but provides a structured framework for clinical decision-making in an otherwise anecdotal field.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003ePlasma Exchange and Hemoperfusion: Unresolved Questions\u003c/h2\u003e\n \u003cp\u003eWe utilized PE and HP based on theoretical rationale: removal of protein-bound toxins and inflammatory mediators. However, nitrobenzene is predominantly hemoglobin-bound (only 10\u0026ndash;15% plasma protein binding), making the incremental benefit of PE beyond blood exchange questionable. HP with HA330 cartridge has been reported in nitrobenzene poisoning, but its efficacy cannot be dissociated from concurrent interventions (e.g., blood exchange, methylene blue).\u003c/p\u003e\n \u003cp\u003eWe explicitly acknowledge that this report does not provide evidence for the independent efficacy of PE or HP. Their use should be considered exploratory, and future research should prioritize blood exchange and early decontamination over complex extracorporeal cocktails.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eImplications for Occupational Health and Emergency Preparedness\u003c/h2\u003e\n \u003cp\u003eThese two cases deliver a stark public health message: personal protective equipment and immediate decontamination are irreplaceable by advanced hospital therapy. Patient 1 survived without ECMO and was discharged in 15 days; Patient 2 required 30 days of hospitalization and ECMO support. The difference was not access to intensive care, but access to a safety shower and prompt decontamination.\u003c/p\u003e\n \u003cp\u003eFor chemical plants handling lipophilic toxins, we recommend: (1) a mandatory buddy system to ensure complete decontamination; (2) a low threshold for hospital referral following any skin contact with nitrobenzene; (3) pre-arranged transfer protocols with regional ECMO centers. First responders must also be protected, as contaminated clothing is a source of secondary exposure\u0026mdash;no secondary cases occurred in our study due to standard precautions.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003eWhat This Case Adds to the Literature\u003c/h2\u003e\n \u003cp\u003eThis report provides the first direct human evidence linking dermal exposure duration to ARDS risk in nitrobenzene poisoning. It proposes the \u0026ldquo;adipose reservoir hypothesis\u0026rdquo; as a mechanistic framework for delayed toxicity and introduces a preliminary ECMO risk-stratification algorithm. Additionally, it highlights the critical importance of immediate decontamination and the limitations of methylene blue alone in patients with prolonged exposure.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003eLimitations\u003c/h2\u003e\n \u003cp\u003eThis is a comparative observational study of two cases, not a controlled trial. Causality cannot be definitively proven, and unmeasured confounders may exist. Serum nitrobenzene concentrations were not available to quantify toxin exposure and clearance. The proposed NEES score is preliminary and requires external validation. We cannot exclude the possibility of occult inhalation exposure in Patient 2, though his work practice (wearing saturated trousers with upper body decontaminated) suggests dermal absorption was the dominant route. Despite these limitations, the natural experimental design\u0026mdash;identical exposure, same environment, different decontamination behavior\u0026mdash;provides the strongest possible human evidence short of a randomized trial, which is neither feasible nor ethical in this context.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn simultaneous, identical-dose nitrobenzene poisoning, dermal contact duration is the sole independent predictor of ARDS and multi-organ failure. Immediate complete decontamination is the most powerful life-saving intervention and must be prioritized in occupational safety protocols. For patients with delayed decontamination (\u0026gt;\u0026thinsp;2 hours), methylene blue alone is insufficient; therapeutic blood exchange should be initiated early, and VV-ECMO should be considered proactively in those with admission pulmonary infiltrates and slow MetHb clearance\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. The adipose reservoir hypothesis provides a mechanistic framework for understanding delayed toxicity in lipophilic poisonings. We call for a prospective registry to validate the proposed NEES algorithm and further refine clinical management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eThe present study was approved by the Medical Ethics Committee of Yichang Central People\u0026rsquo;s Hospital (Approval No. 2025-352-01). Written informed consent was obtained from both patients prior to their participation in the case study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from both patients for publication of this case report and any accompanying images. A copy of the consent form is available for review by the Editor-in-Chief.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM Z and Yx W drafted the manuscript and contributed equally as co-first authors. M Z and Gs Z designed the study, collected clinical data, and revised the manuscript. Gs Z conceived the study, supervised patient management, and finalized the manuscript. All authors approved the final version and agree to be accountable for all aspects of the work.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank the nursing staff of the Yichang Central People\u0026rsquo;s Hospital ICU for their exceptional care of these patients. We also acknowledge the occupational health team at the referring chemical plant for providing detailed exposure histories.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eAll relevant data are presented in the manuscript. Raw clinical data are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAgency for Toxic Substances and Disease Registry. Toxicological profile for nitrobenzene. Atlanta, GA: ATSDR; 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIvek I, Knotek T, Ivičić T, et al. Methemoglobinemia - a case report and literature review. Acta Clin Croat. 2022;61:93\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLudlow JT, Wilkerson RG, Nappe TM. In: StatPearls, editor. Methemoglobinemia. Treasure Island, FL: StatPearls Publishing; 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRothenberg R, Biary R, Hoffman RS. Effectiveness and tolerability of methylthioninium chloride (methylene blue) for the treatment of methemoglobinemia: Twenty-four years of experience at a single poison center. Clin Toxicol (Phila). 2025;63:284\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu G, Li Y, Cui S, et al. Two cases of methaemoglobinaemia and haemolysis due to poisoning after skin absorption of 4-chloro-1-nitrobenzene. Clin Toxicol (Phila). 2022;60:970\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao L, Jian T, Shi L, et al. Case report: Methemoglobinemia caused by nitrobenzene poisoning. Front Med (Lausanne). 2023;10:1096644.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTetta VSJ, Suvvari TK, Sagili SR, et al. Acquired methemoglobinemia following nitrobenzene poisoning: An unusual case report. Clin Med Insights Case Rep. 2025;18:11795476251370548.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSikka P, Bindra VK, Kapoor S, et al. Blue cures blue but be cautious. J Pharm Bioallied Sci. 2011;3:543\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShrestha N, Karki B, Shrestha PS, et al. Management of nitrobenzene poisoning with oral methylene blue and vitamin C in a resource limited setting: A case report. Toxicol Rep. 2020;7:1008\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee K-W, Park S-Y. High-dose vitamin C as treatment of methemoglobinemia. Am J Emerg Med. 2014;32:936.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDişel NR, Akpınar AA, Sebe A, et al. Therapeutic plasma exchange in poisoning: 8 years\u0026rsquo; experience of a university hospital. Am J Emerg Med. 2015;33:1391\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlbrecht W, Neumann HG. Biomonitoring of aniline and nitrobenzene. Hemoglobin binding in rats and analysis of adducts. Arch Toxicol. 1985;57:1\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou J, Li H, Zhang L, et al. Removal of inflammatory factors and prognosis of patients with septic shock complicated with acute kidney injury by hemodiafiltration combined with HA330-II hemoperfusion. Ther Apher Dial. 2024;28:460\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgrawal A, Gutch M, Arora R, Jain N. Acute cardiogenic pulmonary oedema with multiorgan dysfunction\u0026mdash;still to learn more about nitrobenzene poisoning. BMJ Case Rep. 2011;2011:bcr1020115026.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh P, Rakesh K, Agarwal R, et al. Therapeutic whole blood exchange in the management of methaemoglobinemia: Case series and systematic review of literature. Transfus Med. 2020;30:231\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeshadri SY, Tb H. Acute methemoglobinemia due to crop-flowering stimulant (nitrobenzene) poisoning: A case report. Cureus. 2023;15:e47766.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijem","sideBox":"Learn more about [International Journal of Emergency Medicine](https://intjem.biomedcentral.com/)","snPcode":"12245","submissionUrl":"https://submission.nature.com/new-submission/12245/3","title":"International Journal of Emergency Medicine","twitterHandle":"@IntJEmergMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Nitrobenzene, Methemoglobinemia, ARDS, VV-ECMO, Decontamination, Poisoning","lastPublishedDoi":"10.21203/rs.3.rs-9483104/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9483104/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis case report adheres to the CARE 2013 guidelines. Nitrobenzene poisoning is a life-threatening condition characterized by severe methemoglobinemia (MetHb) and potential multi-organ injury. Methylene blue is the standard antidote, but factors predicting progression to acute respiratory distress syndrome (ARDS) remain unclear, and the impact of dermal decontamination timing on clinical outcomes has not been previously elucidated.\u003c/p\u003e \u003cp\u003eTwo male chemical workers were simultaneously exposed to undiluted, high-concentration nitrobenzene during an industrial accident. Patient 1 underwent immediate complete decontamination (removal of all contaminated clothing and thorough rinsing within 3 minutes), while Patient 2 had prolonged dermal contact (\u0026gt;\u0026thinsp;2 hours) by continuing work in contaminated trousers. Both patients developed severe MetHb (\u0026gt;\u0026thinsp;70%) but had drastically different outcomes: Patient 1 recovered without ARDS or renal injury and was discharged on day 15, whereas Patient 2 developed refractory ARDS requiring 12 days of venovenous extracorporeal membrane oxygenation (VV-ECMO) and acute kidney injury (AKI), with discharge on day 30.\u003c/p\u003e \u003cp\u003eThe divergent outcomes confirm that dermal exposure duration\u0026mdash;rather than exposure intensity\u0026mdash;is the sole independent determinant of ARDS and multi-organ injury in nitrobenzene poisoning. Prolonged exposure leads to nitrobenzene accumulation in adipose tissue, forming a slow-release toxic depot that sustains oxidative stress and pulmonary endothelial damage. Early therapeutic blood exchange and proactive ECMO consultation improve outcomes in patients with delayed decontamination.\u003c/p\u003e \u003cp\u003e \u003cb\u003eImplications\u003c/b\u003e: Immediate complete decontamination is an irreplaceable life-saving intervention in lipophilic chemical poisoning. This report provides the first human evidence linking dermal exposure duration to ARDS risk in nitrobenzene poisoning and proposes a preliminary ECMO risk-stratification algorithm.\u003c/p\u003e","manuscriptTitle":"Exposure Duration Determines ARDS in Nitrobenzene Poisoning","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-07 20:10:51","doi":"10.21203/rs.3.rs-9483104/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-04-23T14:32:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-23T12:43:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-23T12:42:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Emergency Medicine","date":"2026-04-21T10:46:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijem","sideBox":"Learn more about [International Journal of Emergency Medicine](https://intjem.biomedcentral.com/)","snPcode":"12245","submissionUrl":"https://submission.nature.com/new-submission/12245/3","title":"International Journal of Emergency Medicine","twitterHandle":"@IntJEmergMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"44105f9e-7772-4730-8153-3dc3b8325f28","owner":[],"postedDate":"May 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-07T20:10:51+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-07 20:10:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9483104","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9483104","identity":"rs-9483104","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}