Is insulin intoxication still the perfect crime? Analysis and interpretation of postmortem insulin: review and perspectives in forensic toxicology.

Insulin is an anabolic hormone essential to glucose homeostasis. Insulin therapy, comprising human insulin (HI) or biosynthetic analogs, is critical for the management of type-1 diabetes and many of type-2 diabetes. However, medication error including non-adapted dose and confusion of insulin type, and misuse, such as massive self-administration or with criminal intent, can have lethal consequences. The aim of this paper is to review the state of knowledge of insulin analysis in biological samples and of the interpretation of insulin concentrations in the situation of insulin-related death investigations. Analytic aspects are considered, as quantification can be strongly impacted by methodology. Immunoanalysis, the historical technique, has a prominent role due to its sensitivity and ease of implementation. Recently, liquid chromatography coupled to mass spectrometry has provided indispensable selectivity in forensic contexts, distinguishing HI, analogs, and degradation products. We review the numerous antemortem (dose, associated pathology, injection-to-death interval, etc.) and postmortem parameters (in corpore degradation, in vitro degradation related to hemolysis, etc.) involved in the interpretation of insulin concentration. The interest and limitations of various alternative matrices providing a valuable complement to blood analysis are discussed. Vitreous humor is one of the most interesting, but the low diffusion of insulin in this matrix entails very low concentrations. Injection site analysis is relevant for identifying which type of insulin was administered. Muscle and renal cortex are matrices of particular interest, although additional studies are required. A table containing most case reports of fatal insulin poisoning published, with analytical data, completes this review. A logic diagram is proposed to highlight analytical issues and the main parameters to be considered for the interpretation of blood concentrations. Finally, it remains a challenge to provide reliable biological data and solid interpretation in the context of death related to insulin overdose. However, the progress of analytical tools is making the "perfect crime" ever more difficult to commit.

Pharmacokinetics of insulin disappearance after massive overdosing.

Long-term glucose supplementation is required to prevent hypoglycemia after massive insulin overdosing. We fitted the blood insulin concentration-time profile to the model: I = A·exp(-a·t) + B·exp(-b·t), where I (µU/mL) is the serum/plasma insulin concentration, A (µU/mL) and B (µU/mL) are the peak insulin concentrations of each component, a (time-1) and b (time-1) are the time constants of each component, and t (h) is the time elapsed from the peak of blood insulin level. Additional components were considered as needed. Patient 1 had auto-injected 600 U NovoRapid® 30Mix, and Patient 2 had auto-injected 300 U Novolet®R (regular) and 1,800 U NovoLet®N (NPH). We used the disappearance of therapeutic doses of the respective insulin in healthy individuals as controls, and we obtained parameters by Excel solver. In Patient 1, the parameter values were A = 1490.04 and a = 0.15 for insulin aspart and B = 60.66 and b = 0.04 for protaminated aspart. In Patient 2, the values were A = 784.45 and a = 0.38 for regular insulin and B = 395.84 and b = 0.03 for NPH. Compared with controls, the half-lives (t1/2) for insulin aspart and protaminated aspart were 4 and 2 times longer, respectively, in Patient 1. In Patient 2, the t1/2 for regular and NPH insulin were 2 and 7 times longer than those in the controls, respectively. In conclusion, the t1/2 for insulin was elongated 2 to 7 times after massive overdosing, explaining why glucose supplementation is needed for long periods in these cases.

Treatment of sulfonylurea and insulin overdose.

The most common toxicity associated with sulfonylureas and insulin is hypoglycaemia. The article reviews existing evidence to better guide hypoglycaemia management. Sulfonylureas and insulin have narrow therapeutic indices. Small doses can cause hypoglycaemia, which may be delayed and persistent. All children and adults with intentional overdoses need to be referred for medical assessment and treatment. Unintentional supratherapeutic ingestions can be initially managed at home but if symptomatic or if there is persistent hypoglycaemia require medical referral. Patients often require intensive care and prolonged observation periods. Blood glucose concentrations should be assessed frequently. Asymptomatic children with unintentional sulfonylurea ingestions should be observed for 12 h, except if this would lead to discharge at night when they should be kept until the morning. Prophylactic intravenous dextrose is not recommended. The goal of therapy is to restore and maintain euglycaemia for the duration of the drug's toxic effect. Enteral feeding is recommended in patients who are alert and able to tolerate oral intake. Once insulin or sulfonylurea-induced hypoglycaemia has developed, it should be initially treated with an intravenous dextrose bolus. Following this the mainstay of therapy for insulin-induced hypoglycaemia is intravenous dextrose infusion to maintain the blood glucose concentration between 5.5 and 11 mmol l(-1) . After sulfonylurea-induced hypoglycaemia is initially corrected with intravenous dextrose, the main treatment is octreotide which is administered to prevent insulin secretion and maintain euglycaemia. The observation period varies depending on drug, product formulation and dose. A general guideline is to observe for 12 h after discontinuation of intravenous dextrose and, if applicable, octreotide.

[Research Progress of the Death Caused by Insulin Intoxication].

In recent years, with the sustained increase of the incidence of diabetes in humans and the wider use of exogenous insulin, the cases of inappropriate use and overdose of insulin is growing, even the cases of suicide and homicide using insulin. Through searching the literature at home and abroad about the mechanism, clinical and case report of poisoning and death caused by insulin intoxication, this paper reviews the mechanism, clinical manifestations, pathological changes, and forensic examination.

[Non usual cases of hypoglycaemia--hypoglycaemia factitia]. / Neobvyklé prípady hypoglykémie--hypoglycaemia factitia.

Hypoglycaemia factitia means also in recent time serious diagnostic and therapeutic problem in medical clinical practice, whereby often repeating episodes of serious hypoglycaemia in patients with diabetes mellitus, but also in patients without diabetes mellitus could be very difficult do resolve. First unsuccessful diagnosis implicit from wrong chose of examination algorithm, can lead to unidentified surgical interventions as are laparotomy and pancreatectomy, respectively. Hypoglycaemia factitia is considered to be one of many manifestations of so called Münchhausen's syndrome for that is typical acting of diabetic patient with goal to intentionally making hypoglycaemia or within suicidal attempt of patient on the basis psychological disease with intention to attract attention of surrounding community to himself due to application of insulin or sulfonylurea drugs. Diagnostic and therapeutic process could be in the case of hypoglycaemia factitia extremely difficult as from time side, than from health and also from economical side and that why necessary to approach with maximum responsibility.

Review of the lethal mechanism of insulin poisoning and the characteristic of forensic identification.

Insulin, as the only hypoglycemic hormone in the body, plays a key role in blood sugar control. However, excessive insulin intake can lead to insulin poisoning and even death, which often occurs in clinical and forensic work. At present, some researches on insulin poisoning have been carried out at home and abroad, however, it seems that the mechanism and forensic characteristics of insulin poisoning are not clear and complete. Therefore, in this paper, we reviewed the potential mechanism of insulin poisoning, the methods of insulin detection and the forensic identification of poisoning cases, aiming at providing services for the forensic identification of insulin poisoning.

Use of Intravenous Lipid Emulsion Therapy and Insulin in a Case of Tarka Intoxication.

INTRODUCTION: Tarka (trandolapril/verapamil hydrohloride extended-release) is a fixed-dose combination antihypertensive drug formed from verapamil hydrochloride and trandolapril. Toxicologic manifestations of Tarka overdose are altered mental status, bradycardia, hypotension, atrioventricular block (first-degree), hyperglycemia, metabolic acidosis, and shock. CASE PRESENTATION: We report a case of Tarka toxicity in a 2-year-old girl who presented with altered mental status, cardiogenic shock, hypotension, bradycardia, severe metabolic acidosis, hyperglycemia, and first-degree atrioventricular block. We started fluid resuscitation, epinephrine, norepinephrine, and insulin. Because of the patient's hyperlactatemia and hypotension despite standard therapies, we initiated intravenous lipid emulsion (ILE) therapy, after which her condition improved promptly. DISCUSSION: Tarka overdose may be life-threatening as it can cause cardiogenic shock. In our patient, the regression of lactate elevation in a short time with ILE therapy and the improvement of her general condition highlight the importance of ILE. CONCLUSIONS: ILE is an alternative treatment method for acute lipophilic drug intoxications, such as Tarka.

A retrospective study of 29 fatal cases of insulin overdose.

PURPOSE: To summarize recent cases of fatal insulin poisoning both domestically and internationally, thereby offering valuable insights for the forensic identification of insulin overdose cases. METHODS: Literature published since 2000 on fatal insulin overdose were systematically searched and screened. Data encompassing variables such as year, age, sex, cause of death, scene conditions, occupations, medical histories of victims and perpetrators, autopsy timing, dosage and administration methods, forensic pathology, and toxicological analysis, were compiled for rigorous statistical analysis. RESULTS: Among the 29 fatal cases of insulin poisoning, suicides and homicides accounted for 55.2 % and 41.4 %, respectively. Precisely 34.5 % of victims or perpetrators were associated with the medical industry, 27.6 % had diabetes, and 24.1 % had mental illnesses such as depression. Intravenous injection resulted in quicker death than did subcutaneous injection. In some cases, immunohistochemical staining of insulin and protamine at injection sites yielded positive results. The average molar ratio of insulin to C-peptide in post-mortem blood was 13.76 ± 5.167, indicating a significant diagnostic value for insulin poisoning. CONCLUSION: Assessment of cases of fatal insulin overdose should be thorough, incorporating case investigation, scene examination, medical records review, autopsy findings, pathological examinations, and laboratory tests, alongside considering the condition of the body and timing of death autopsy. Using mass spectrometry to detect insulin proves valuable, particularly in cases of poor body preservation.

Multi-modal brain imaging showing brain damage to the orbitofrontal cortex and left hemisphere, in a case of prolonged hypoglycemia-induced transient hemiplegia followed by persistent encephalopathy.

A 21-year-old left-handed male patient was admitted with a 19-h history of coma after substantial insulin injection for suicide attempt. Although the patient recovered from coma 3 days after injury, he experienced transient hemiplegia followed by permanent brain damage. Electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and brain single-photon emission computed tomography (SPECT) identified the localization of this dysfunction, but consistency between clinical symptoms and brain images changed depending on the course of treatment. Transient hemiplegia corresponded to abnormal waveforms on EEG and decreased cerebral blood flow on SPECT, whereas persistent dysfunctions corresponded to abnormal brain regions on MRI and SPECT.

Unintentional use of mistaken insulin products: a retrospective review of poison center data.

BACKGROUND: There are no guidelines for the management of accidental insulin administration. We hypothesized that home monitoring of asymptomatic patients (pts) was safe following unintentionally insulin administration. METHODS: Retrospective review of poison center (PCC) charts from 1/1/2000-12/31/2010 looking for accidental insulin administrations. INCLUSION CRITERIA: pt must be prescribed insulin. Information recorded from charts: pt age/gender, "intended" and "mistaken" insulin formulations/doses, use of oral diabetic agents, management site, Emergency Department (ED) referral, symptoms, blood glucose values, and treatments. Defined outcomes: symptoms (e.g., altered sensorium); hypoglycemia (<60 mg/dL); management site; health care facility (HCF) admission; and death. Multiple logistic regression was used to determine outcome predictors. RESULTS: 652 charts met inclusion criteria. Mean age was 56.4 years; most (58.5%) were women. Most (89%) calls originated from home, 10.7% from a HCF, 0.3% from Emergency Medical Services (EMS). Overall, 397 (60.9%) pts were managed at home. Two pts managed at home were later evaluated by EMS; neither required admission. Symptoms developed in 56 (8.6%) pts. There were no deaths. Only 40 (6.1%) pts were admitted to a HCF; 18 (45%) pts were hypoglycemic. The development of hypoglycemia (odds ratio [OR] 5.94; p < 0.001) and amount of insulin accidentally administered (OR 1.04; p < 0.001) predicted HCF referral. The type and dose of insulin administered did not predict symptoms. CONCLUSIONS: Based on a retrospective analysis of a single PCC's cases, home observation of asymptomatic patients after unintentional administration of a wrong insulin formulation appears safe.

[Acute poisonings and organ donation--case reports and literature review]. / Ostre zatrucia a donacja narzadów--opis przypadkow i przeglad pismiennictwa.

Poland is one of the European countries where serious problem of shortage of organ donors is observed. Organ donation from victims following fatal acute intoxications is extremely rare, and there's only several such case reports published in Poland. There's a need to establish guidelines of instrumental confirmatory tests of brain death determination according to acute poisonings. Authors present two cases of poisoned donors following acute poisonings with drugs. Current opinions concerning poisoned patients as a potential organ donors are also described. Case 1: A 36-years old male poisoned intentionally with insulin was admitted to Toxicology Department in Poznan. Patient was unconscious (GCS:3), hypoglycemic (glycaemia: 0). In 3rd day of treatment brain death was determined using clinical tests and instrumental confirmatory test (transcranial Doppler ultrasonography). Both kidneys were procured for transplantation. Case 2: A 23-years old male after prehospital sudden cardiac arrest in the course of suicidal carbamazepine intoxication was admitted to Toxicology Department. During whole hospitalization patient was unconscious, unresponsive to the pain (GCS:3), with circulatory and respiratory insufficiency. Despite intense treatment and decrease of carbamazepine level to therapeutic values there were no signs of patient recovery on the 9th day of treatment. After brain death determination patient was qualified as a kidneys and liver donor. Each patient diagnosed of brain death in the course of acute intoxication should be considered as a potential organ donor. Brain death determination in poisoned patients requires consultation by clinical toxicologist to exclude influence of neurotoxic xenobiotics on the central nervous system. Standards of instrumental confirmatory tests in victims following fatal poisonings should be established. Introduction of guidelines concerning donors intensive care procedures that allows successful organ procurement. All organ donations and transplantations from poisoned donors should be registered in national and/or international databases to provide an exchange of experiences and improve understanding of such cases.

Disorders of glucose metabolism: post mortem analyses in forensic cases--part II.

In continuation to part I, a literature review is presented concerning biochemical problems of forensic post mortem cases of unclear hyperglycaemia or hypoglycaemia. Clinical parameters for this purpose were recently reviewed. Particular attention was paid to the detection of diabetic ketoacidosis, of hyperosmolar coma, insulinoma, insulin-induced or oral diabetic-induced hypoglycaemia. The second part of the review discusses the analytes ketone bodies, synthetic insulins, human insulin, C-peptide, proinsulin and insulin antibodies. Special interest is given to post mortem matrices for those analytes to reference concentrations, stability data, analytic interferences and analytical procedures which should be used in toxicological laboratories willing to detect diabetic metabolism disorders after death.

Unintentional therapeutic errors involving insulin in the ambulatory setting reported to poison centers.

BACKGROUND: Adverse drug events in the ambulatory care setting are not uncommon and can cause significant morbidity. Little research has been published on the management of adverse drug events involving insulin in the outpatient setting. OBJECTIVE: To analyze data on patients with unintentional therapeutic errors involving insulin managed by 9 regional poison control centers. METHODS: A retrospective search was performed for all records involving insulin at 9 poison centers, covering the population of 4 states for the years 2000-2009. A subgroup of the study population was selected with a reason for exposure of "unintentional-therapeutic error." RESULTS: There were 3819 insulin exposures reported, with an increase in the annual incidence of insulin exposures of 279% (from 170 to 645 patients/year) and a mean annual increase of 18%. Of the insulin exposures, 2584 were unintentional therapeutic errors (68%). The percentage of all insulin exposures that were unintentional therapeutic errors increased progressively, from 41% to 78%. There was a 495% increase in annual incidence of unintentional therapeutic errors involving insulin, with a mean annual increase of 28%. Unintentional therapeutic errors involving insulin occurred primarily in adults >40 years (73%), with 63% occurring in women. There was a pronounced increase in unintentional therapeutic errors involving insulin in the later evening hours, with 71% occurring between 1800 and 2400 and reaching a peak at 2200. The majority (n = 1803; 70%) of patients were managed in a non-health-care facility location, primarily their own residence. CONCLUSIONS: This is the first report of an increasing trend of insulin-related unintentional therapeutic errors in the ambulatory setting. Our study highlights a number of striking features, including: (1) a consistent and dramatic increase of unintentional therapeutic errors involving insulin over the 10-year period, (2) a high incidence of unintentional therapeutic errors involving insulin in the late evening hours, and (3) a high incidence of unintentional therapeutic errors involving insulin involving adults >40 years and females. With their 24/7 availability, poison centers appear to be an increasingly important resource for patients experiencing unintentional therapeutic errors involving insulin.

Prediction of recovery time from hypoglycemia in patients with insulin overdose.

Insulin overdose results in prolonged hypoglycemia. We hypothesized that if a huge amount of insulin is subcutaneously injected, the duration of hypoglycemia depends on the dose of insulin rather than the type of insulin. We conducted a literature review of insulin overdose and 33 cases were included in this study. We assessed the correlation between recovery time from hypoglycemia and insulin dose. As a result, there was a significant correlation between recovery time from hypoglycemia and insulin dose (r=0.88, p<0.0001) and this correlation was expressed as y=0.045x; where y is time (h) and x is insulin dose (U), corresponding to that if 1000 U insulin is injected, hypoglycemia will persist for ~45 h. This equation may be useful to predict the duration of glucose supplementation for treatment of insulin overdose.

Detection of intact insulin analogues in post-mortem vitreous humour-Application to forensic toxicology casework.

The application of proteomic techniques to forensic science widens the range of analytical capabilities available to forensic laboratories when answering complex toxicology problems. Currently, these techniques are underutilised in post-mortem toxicology because of the historic focus on smaller (<1,000 amu) drug molecules. Definitive confirmation of an insulin overdose by analysis of post-mortem biological matrices is rare and challenging, however can assist coronial investigations pertaining to accidental or intentional overdoses in both diabetic and nondiabetic populations. A semiautomated micro-solid phase extraction paired with mass spectrometry-based insulin methodology was developed and validated for routine use in a Forensic Coronial Toxicology Laboratory. This resulting work reports the first Australian cases where synthetic insulins were confirmed by mass spectrometry in the vitreous humour of Type 1 diabetics who intentionally or accidentally overdosed on their prescription medication glargine and aspart. The detection of glargine M1 in Case 1, aspart in Case 2 and glargine M1 was indicated in Case 3. This paper highlights advancements in forensic coronial toxicology and the promising potential of proteomic analysis in a forensic context.

Pediatric condition falsification (Munchausen syndrome by Proxy) as a continuum of maternal factitious disorder (Munchausen syndrome).

Pediatric condition falsification (PCF), also known as Munchausen syndrome by Proxy or Medical Child Abuse, is a somewhat rare form of child abuse and neglect. Its association with a history of adult factitious disorder (AFD) or Munchausen syndrome in the perpetrator is also well known. Exogenous insulin injection to cause hypoglycemia both in the context of PCF and AFD has been reported in the literature. However, the coexistence of both conditions via insulin injection in the same family has not been reported in the literature. This paper presents a family, in which the mother was diagnosed with AFD and her three children with PCF perpetrated by their mother via exogenous insulin injection.

A Case Involving Massive Insulin Overdose: Direct and Indirect Conditions Requiring Extended Management of Serum Potassium.

BACKGROUND Insulin lowers not only blood glucose levels but also serum potassium levels by driving potassium into the cells. Hypokalemia can occur during aggressive treatment of hypoglycemia in patients with insulin overdose and is a well-documented clinical phenomenon; however, there are no studies describing delayed hyperkalemia occurring after initial treatment in patients with insulin overdose. CASE REPORT A 23-year-old male with a history of type 2 diabetes mellitus and self-medicating with insulin, attempted suicide by subcutaneously injecting 2100 units of insulin. He was admitted to our emergency department due to recurrent hypoglycemia. Continuous administration of 50% glucose and potassium via a central venous catheter was performed to maintain his glucose levels above 80 mg/dL and serum potassium level between 3.5 and 4.0 mEq/L. Because his serum potassium level exceeded 4.5 mEq/L at day 3 after admission, the dosage was adjusted accordingly. After his serum potassium level declined to 3.0 mEq/L, his potassium level abruptly increased to 6.0 mEq/L at day 5 after admission. The patient was placed on a potassium-restricted diet and administered furosemide. Potassium infusion was also discontinued. After serum potassium levels returned to the normal range without interventional therapies, the patient was discharged to home on day 14. CONCLUSIONS In cases of high-dose insulin overdose, management of hyperkalemia following recovery from hypoglycemia is a critical aspect of patient management. Conservative administration of potassium to correct initial hypokalemia may be considered in patients with high-dose insulin overdose.

Lantus overdose: case presentation and management options.

Insulin glargine (Lantus, Aventis Pharmaceuticals, Bridgewater, NJ) is a long-acting once-daily dosed form of insulin intended to maintain a constant baseline insulin level. As a relatively new medication, there is limited experience in overdoses of Lantus. We present a case of a 37-year-old male insulin-dependent diabetic presenting with refractory hypoglycemia secondary to an intentional overdose of Lantus insulin to illustrate the varied management concerns in overdoses of long-acting insulins. The patient was managed with oral intake, intravenous dextrose bolus, peripheral 10% dextrose solution, 25% dextrose sliding scale via central line, and psychiatry evaluation for suicide attempt. Other potential treatments discussed for possible use with long-acting insulin overdoses include incision and drainage of the injection site, glucagon, and octreotide.

Attempted suicide by massive insulin injection: a case report and review of the literature.

The authors present a case of an 80-year-old man, non-diabetic, who attempted suicide by injecting himself subcutaneously with 10,000 units of Humulin R and 6000 units of Humulin N. Administration of dextrose intravenously was required for 13 days to maintain the capillary blood glucose within the range of 100-180 mg/dl. Hyponatremia, hypokalemia, hypophosphatemia, and elevated liver enzymes were also seen after massive insulin injection. Glucose requirement index was established to demonstrate the trend of glucose requirement during hospitalization. He recovered completely without any complication after monitoring blood glucose and titrating intravenous glucose carefully for two weeks. Current literature about how to manage insulin overdose was reviewed in the present article.

A Systematic Review on Insulin Overdose Cases: Clinical Course, Complications and Treatment Options.

A large overdose of insulin is a serious health matter. Information concerning administration and duration of intravenous (IV) glucose, other treatment options or complications besides hypoglycaemia following large insulin overdoses is not readily apparent from the literature. A systematic search, compilation and review of case reports on insulin overdoses, published 1986-2017, was performed in PubMed, EMBASE, Cochrane and PROSPERO databases. Of 1523 published articles, 45 cases of insulin overdoses were included with a total median insulin dose of 900 international units (IU) (range 26-4800 IU). Hospitalization occurred in 44 cases with a median hospitalization duration of 94 hr (range 12-721 hr), and one-third (n = 15) admitted to the intensive care unit. First-line treatment was IV glucose treatment in 95% of cases. Treatment options besides IV glucose that were reported beneficial included glucagon IV or intramuscular (IM), octreotide IV or IM, surgical excision, hydrocortisone IV and oral intake of complex carbohydrates. Prevalent complications were intermittent cerebral impairment (73%), hypokalaemia (49%), other electrolyte disturbances (42%), and hepatic disturbances (7%) and cardiac toxicity (e.g. cardiac arrhythmia) (9%). Long-term consequences were one case of lasting hypoglycaemic encephalopathy and one death. In conclusion, following large insulin overdoses, in-hospital admission and treatment with IV glucose may be needed for up to a week. Monitoring of electrolytes and hepatic and cardiac functions seems important. Several experimental treatment options may be considered in addition to glucose administration. With appropriate pre- and in-hospital treatment, cases with severe hypoglycaemia and neurologic complications may have a favourable outcome.