{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T01:28:03Z","timestamp":1773451683798,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Background: In most cases, palliative care is prescribed to adults diagnosed with cancer. The definition of the most suitable therapy for an effective sedation in terminal cancer patients still represents one of the most challenging goals in medical practice. Due to their poor health, the correct dosing of drugs used for deep palliative sedation in terminal cancer patients, often already on polypharmacological therapy, can be extremely complicated, also considering possible drug-to-drug interactions that could lead to an increased risk of overdose and\/or incongruous administration with fatal outcomes. The case of a terminal cancer patient is presented, focusing on the \u201cadequacy\u201d of administered therapy. Materials and Methods: A young male, affected by Ewing sarcoma, attending a palliative care at his own home, died soon after midazolam administration. Toxicological and histological analyses were performed on body fluids and organ fragments. Results and Discussion: Morphological reliefs evidenced a neoplastic mass, composed of lobulated tissue with a lardy, pinkish-gray consistency, extending from the pleural surface to the lung parenchyma, also present at the sacrum region (S1\u2013S5), at the anterior mediastinum level, occupying the entire left pleural cavity, and infiltrating the ipsilateral lung. Metastatic lesions diffused to rachis and lumbar structures. The brain presented edema and congestion. Toxicological analyses evidenced blood midazolam concentrations in the range of 0.931\u20131.690 \u00b5g\/mL, while morphine was between 0.266 and 0.909 \u00b5g\/mL. Death was attributed to cardiorespiratory depression because of a synergic action between morphine and midazolam. The pharmacological interaction between midazolam and morphine is discussed considering the clinical situation of the patient. The opportunity to proceed with midazolam administration is discussed starting from guidelines recommendation. Finally, professional liability outlines are highlighted.<\/jats:p>","DOI":"10.3390\/toxics9120356","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T21:32:40Z","timestamp":1639690360000},"page":"356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Forensic Toxicological and Medico-Legal Evaluation in a Case of Incongruous Drug Administration in Terminal Cancer Patients"],"prefix":"10.3390","volume":"9","author":[{"given":"Pascale","family":"Basilicata","sequence":"first","affiliation":[{"name":"Legal Medicine Section, Department of Advanced Biomedical Science, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pasquale","family":"Giugliano","sequence":"additional","affiliation":[{"name":"Legal Medicine Section, AORN \u201cSant\u2019Anna e San Sebastiano\u201d Caserta, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Vacchiano","sequence":"additional","affiliation":[{"name":"Department of Law, Economics and Mathematical Methods, University of Sannio, 82100 Benevento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Simonelli","sequence":"additional","affiliation":[{"name":"Legal Medicine Section, Department of Advanced Biomedical Science, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossella","family":"Guadagni","sequence":"additional","affiliation":[{"name":"Legal Medicine Section, Department of Advanced Biomedical Science, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Silvestre","sequence":"additional","affiliation":[{"name":"Legal Medicine Section, Department of Advanced Biomedical Science, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4184-5718","authenticated-orcid":false,"given":"Maria","family":"Pieri","sequence":"additional","affiliation":[{"name":"Legal Medicine Section, Department of Advanced Biomedical Science, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1053\/j.seminoncol.2005.02.003","article-title":"Sedation for the relief of refractory symptoms in the imminently dying: A fine intentional line","volume":"32","author":"Levy","year":"2005","journal-title":"Semin. Oncol."},{"key":"ref_2","unstructured":"(2021, October 25). European Charter of Patient\u2019s Rights. Available online: https:\/\/ec.europa.eu\/health\/ph_overview\/co_operation\/mobility\/docs\/health_services_co108_en.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1089\/jpm.2006.0139","article-title":"Palliative sedation therapy in the last weeks of life: A literature review and recommendations for standards","volume":"10","author":"Dean","year":"2007","journal-title":"J. Pall. Med."},{"key":"ref_4","unstructured":"(2021, October 25). Italian Legislative decree No. 38, March 15th, 2010. National Official Gazette No. 65, March 19th, 2010, General Serie. Available online: https:\/\/www.gazzettaufficiale.it\/eli\/gu\/2010\/03\/19\/65\/sg\/pdf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1177\/0300891618792478","article-title":"Consensus document of the Italian Association of Medical Oncology and the Italian Society of Palliative Care on early palliative care","volume":"105","author":"Corsi","year":"2019","journal-title":"Tumor. J."},{"key":"ref_6","unstructured":"Italian Committee for Bioethics (2021, October 25). Deep and Continuous Palliative Sedation in the Imminence of Death, Available online: https:\/\/bioetica.governo.it\/media\/3211\/p122_2016_palliative-sedation_en.pdf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.jpainsymman.2020.09.022","article-title":"Clinican aspects of palliative sedation in prospective studies. A systematic review.","volume":"61","author":"Arantzamendi","year":"2021","journal-title":"J. Pain Symptom Manag."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1093\/annonc\/mdl373","article-title":"International Association for Hospice and Palliative Care list of essential medicines for palliative care","volume":"18","year":"2007","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1002\/bdd.1830","article-title":"A physiologically based pharmacokinetic (PBPK) approach to evaluate pharmacokinetics in patients with cancer","volume":"34","author":"Cheeti","year":"2013","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1177\/0269216313477177","article-title":"Palliative care research: Lessons learned by our team over the last 25 years","volume":"27","author":"Bruera","year":"2013","journal-title":"Palliat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1080\/17425255.2016.1179281","article-title":"Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol","volume":"12","author":"Franken","year":"2016","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/bcpt.12655","article-title":"The Pharmacology and Toxicology of the \u2018Holy Trinity\u2019","volume":"120","author":"Horsfall","year":"2017","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.forsciint.2017.07.006","article-title":"Postmortem blood sampling-Comparison of drug concentrations at different sample sites","volume":"278","author":"Zilg","year":"2017","journal-title":"Forensic Sci. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.forsciint.2019.05.003","article-title":"Application of a chemiluminescence immunoassay system and GC\/MS for toxicological investigations on skeletonized human remains","volume":"300","author":"Basilicata","year":"2019","journal-title":"Forensic Sci. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8566","DOI":"10.1021\/ac201905q","article-title":"Screening of several drugs of abuse in Italian workplace drug testing: Performances comparison of an on-site screening tests and a Fluorescence Polarization ImmunoAssay-based device","volume":"83","author":"Basilicata","year":"2011","journal-title":"Anal. Chem."},{"key":"ref_16","first-page":"1509","article-title":"Il dato chimico-tossicologico post-mortale: Avvelenamento o non avvelenamento?","volume":"4","author":"Basilicata","year":"2019","journal-title":"Riv. Ital. Med. Leg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/s12024-010-9150-4","article-title":"Postmortem toxicology","volume":"6","author":"Skopp","year":"2010","journal-title":"Forensic Sci. Med. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S0952-8180(02)00428-2","article-title":"Accidental overdose of midazolam as intramuscular premedication","volume":"14","author":"Nishiyama","year":"2002","journal-title":"J. Clin. Anesth."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/jep.12228","article-title":"Reducing risk of overdose with midazolam injection in adults: An evaluation of change in clinical practice to improve patient safety in England","volume":"21","author":"Flood","year":"2015","journal-title":"J. Eval. Clin. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121","DOI":"10.4172\/2472-1026.1000121","article-title":"Revisit of a rare death by overdosed midazolam: A forensic pathological perspective","volume":"3","author":"Wang","year":"2018","journal-title":"J. Forensic Med."},{"key":"ref_21","unstructured":"Katzung, B.G., Trevor, A.J., and Kruidering-Hall, M. (2014). Basic and Clinical Pharmacology, McGraw-Hill. [13th ed.]."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1056\/NEJM198308113090607","article-title":"Current status of benzodiazepines (first of two parts)","volume":"309","author":"Greenblatt","year":"1983","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1017\/S1478951514000200","article-title":"Palliative sedation for cancer patients included in a home care program: A retrospective study","volume":"13","author":"Gonzalez","year":"2015","journal-title":"Pall. Supp. Care"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1177\/0269216309359996","article-title":"At-home palliative sedation for end-of-life cancer patients","volume":"24","author":"Bruera","year":"2010","journal-title":"Pall. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s00520-009-0632-4","article-title":"Efficacy and safety of deep, continuous palliative sedation at home: A retrospective, single-institution study","volume":"18","author":"Porzio","year":"2010","journal-title":"Supp. Care Cancer"},{"key":"ref_26","first-page":"1","article-title":"Midazolam: An essential palliative care drug","volume":"14","author":"Prommer","year":"2020","journal-title":"Palliat. Care Soc. Pract."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0885-3924(98)00066-9","article-title":"Sedation for uncontrolled symptoms in a South African hospice","volume":"16","author":"Fainsinger","year":"1988","journal-title":"J. Pain Symptom Manag."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.jpainsymman.2010.07.013","article-title":"Palliative sedation in patients with advanced cancer followed at home: A systematic review","volume":"41","author":"Mercadante","year":"2011","journal-title":"J. Pain Sym. Man."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1177\/1049909115572991","article-title":"Palliative sedation at the end of life: Patterns of use in an Israeli hospice","volume":"33","author":"Azoulay","year":"2016","journal-title":"Am. J. Hosp. Palliat. Care"},{"key":"ref_30","unstructured":"Italian Constitutional Court (2021, October 25). Sentence No 249\/2019. Available online: https:\/\/www.cortecostituzionale.it\/actionSchedaPronuncia.do?anno=2019&numero=242."},{"key":"ref_31","first-page":"242","article-title":"Practical guide to palliative sedation","volume":"4","author":"Cowan","year":"2002","journal-title":"Pall. Med."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/9\/12\/356\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:50:05Z","timestamp":1760169005000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/9\/12\/356"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,16]]},"references-count":31,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["toxics9120356"],"URL":"https:\/\/doi.org\/10.3390\/toxics9120356","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,16]]}}}