These routinely used in clinical histopathology can be successfully used for this purpose, as we demonstrated in the second case [ 16 ]. In routine forensic practice, usually antemortem blood samples of the victim, who sometimes is hospitalized before the death, are unavailable for forensic toxicologists, so they can analyze only postmortem biological material taken during autopsy and nonbiological specimens revealed at the crime scene, like syringes, ampoules, vials, or remnants of the infusion solution and tubings [ 24 , 25 , 26 ].
What is important from the medicolegal point of view is that the interpretation of insulin levels in the postmortem biological material is difficult and still in doubt [ 27 , 28 , 29 , 30 , 31 ]. The number of published papers dealing with this problem is relatively low. The time of survival after insulin injection depends on many different factors: type of insulin differentiated onset of action and insulin half-life , method of administration injection or insulin infusion pump , anatomical localization of injection sites on the body different rate of absorption , etc.
It certainly influences the insulin levels detected in the postmortem biological material. Unfortunately, in the forensic practice, investigators usually do not know that time, because the cadavers not infrequently are found after a long time since death at an advanced stage of late postmortem changes, for example, when the victim lived alone or the killer committed suicide [ 21 ].
Additionally, insulin determination in postmortem blood has a low diagnostic and testimonial value, mainly because of ongoing thanatochemical processes of autolysis and putrefaction [ 8 , 24 ]. The main barrier that prevents receiving correct and trustworthy results of insulin determinations in postmortem blood with radioimmunological methods is the blood hemolysis rupturing of red blood cells and the release of their contents into surrounding plasma.
This fact was confirmed in the literature and by our own studies performed in the Department of Forensic Medicine and Forensic Toxicology in Katowice [ 32 , 33 ]. Fortunately, insulin crosses the blood-retinal barrier and may be identified in the VH, which is generally very valuable alternative material for many different chemical-toxicological analyses [ 34 , 35 ]. The advantage of this material is that it is easy to obtain during typical forensic autopsy.
Another advantage is anatomical isolation, useful especially in the case of advanced autolytic and putrefactive changes in corpore.
It has also a very low cell count, so there is a small postmortem metabolism of glucose and other substances by surviving cells. In Thevis et al. This was a significant advance in postmortem biochemistry. In our department, we have analyzed material consisted of 93 samples of vitreous humor taken during forensic autopsies. Analysis revealed that in 86 vitreous humor samples The concentration of insulin in vitreous humor was determined only in seven cases range of results, 1.
We have described above one of these cases, where insulin was used to commit suicide [ 15 ]. The IRMA method is known as sensitive, specific, and relatively cheap in comparison to modern methods, but it requires adequate apparatus for the measurement of radioactivity and some experience in its interpretation. It is worth knowing that the studies on insulin determination using antibody-radiolabeled antigen reaction in the late s were the beginning of a new medical discipline—radioimmunology [ 36 ].
Until the introduction of radioimmunoassay RIA , death caused by insulin overdose was extremely difficult to prove [ 4 ]. In , Palmiere et al. Regardless of the method used in toxicological investigation, an analytically confirmed higher level of insulin in the vitreous humor plays an important and even a decisive role in structuring the final medicolegal opinion about the cause of death.
An interesting observation, so far unused in the forensic practice, is an increase in the expression of certain genes stimulated by insulin, especially in hyperinsulinemic conditions.
This is a potentially promising area for further research. An example might be the changes of neuropeptide Y NPY gene expression and its release during hypoglycemic stress. Han et al. They have concluded that these results suggest that NPY may play a role in insulin-induced hypertension. Another example can be increased vascular resistance in the equine digit and overexpression of endothelin-1 ET-1 in the laminar tissue due to the short-term hyperinsulinemia [ 39 ].
An overdose of insulin is a potential life-threatening condition and requires urgent medical attention [ 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. The clinical manifestations of hypoglycemia occur when the blood glucose level is less than 2. Symptomatology includes two groups of symptoms. The first one is caused by stimulation of the autonomic nervous system and includes profuse sweating, anxiety, tremor, and hunger.
The second one is caused by progressive dysfunction of the central nervous system CNS due to neuroglycopenia and includes nausea, headache, dizziness, blurred vision, abnormal intellectual processes, behavioral disturbances, and finally loss of consciousness, convulsions, and death. The most optimal place of the treatment is clinical toxicology ward, but patients who are overdosed with insulin can be also treated in typical intensive care units or in less serious cases—in general internal wards.
Physiologically for every molecule of insulin formed, a corresponding molecule of C-peptide is formed. However, it should be remembered that C-peptide is very unstable in postmortem blood [ 4 ]. Treatment of hypoglycemia is initially based on the securing of basic vital functions breathing and circulation. Subsequently, infusions of glucose solution adjusted to the current blood glucose levels are used. Depending on the clinical situation, other drugs are administered s.
In the past such specific methods of treatment and management have been reported as excision of insulin injection site or the use of artificial pancreas [ 48 , 49 , 50 ]. Fisher's exact tests and nonparametric tests were used for between-group comparisons. Correlations were quantified using Pearson's linear correlation coefficient. The predicted proportion of unfavorable outcomes was assumed to follow the logistic model.
The step selection was based on the maximum likelihood ratio. Over a 6-year period, 25 patients 14 females and 11 male, age 46 [36 to 58] years and SAPS II score 25 [19 to 51] were admitted in our ICU because of intentional insulin poisoning.
Rapid-acting insulin injected amount [ to ] IU was involved in 14 out of 25 patients, while intermediate-acting or slow-acting insulin [ to 1,] IU was used by 13 out of 25 patients. Two patients self-injected both insulin types.
The interval between insulin self-injection and pre-hospital glucose administration was 2. The temperature was At the scene, the capillary glucose concentration was 1. Six patients were mechanically ventilated for persistent coma despite correction of hypoglycaemia. On ICU admission, the blood glucose was 5. The total amount of infused glucose was to 1, g. The total duration of glucose infusion was 32 12 to 68 hours. Two patients developed an acute respiratory distress syndrome confirmed by pulmonary wedge pressure measurements.
Final outcome was favourable in 21 out of 25 patients Table 1. Two patients died in the ICU, following withholding and withdrawal of life-sustaining treatments because of severe hypoglycaemic encephalopathy, associated in one case with a terminal phase cancer. Two other patients suffered from significant neurological sequelae at ICU discharge CPC 3 , including cognitive and memory impairments. In the patient who died on day 85 with a severe hypoglycaemia-related encephalopathy, fast fluid-attenuated inversion recovery magnetic resonance imaging showed disseminated hypersignals in the cerebral gray matter at day 3 Figure 1.
Interestingly, all these signal abnormalities disappeared on day 30, whereas marked cerebral atrophy was observed and neurological disabilities persisted.
A stepwise multiple regression logistic regression model showed that a delay between insulin injection and first medical treatment in excess of 6 hours OR MRI findings in hypoglycemia-related encephalopathy. Cerebral fast fluid-attenuated inversion recovery magnetic resonance imaging MRI in a patient suffering from a severe hypoglycaemia-related encephalopathy on day 3 after deliberate insulin self-poisoning.
The disseminated hypersignals of the cerebral gray matter plain arrows disappeared on day 30, whereas neurological impairments persisted. Delay from insulin self-injection to pre-hospital management versus duration of ICU stay. Shown is the correlation between the delay from insulin self-injection to pre-hospital management and the duration of intensive care unit ICU stay in 22 cases of insulin self-poisoning.
Duration of glucose infusion versus self-injected insulin dose. Shown is the correlation between the duration of glucose infusion and the self-injected insulin dose in 25 cases of insulin self-poisoning. The duration of ICU stay was 3 3 to 7 days. The decrease in exogenous insulin concentrations using a semi-logarithmic scale was linear, exhibiting first-order kinetics Figure 4. The terminal half-life was 3.
Despite the widespread use of insulin, overdoses are infrequently reported. In comparison, sulfonylureas are the most frequently identified antidiabetic agent in human poisonings [ 11 ]. Insulin causes the greatest number of major and serious problems, whereas biguanides lead to most deaths. In our study, which included 25 patients admitted to our ICU because of severe insulin self-poisoning, four patients developed significant sequelae that resulted in two deaths.
Consistent with this, in a large study assessing outcomes following enquiries regarding insulin overdose recorded in a regional poison unit [ 3 ], full recovery occurred in Hypoglycaemic encephalopathy is the most feared consequence of self-poisoning with insulin. The cortex, caudate, putamen and hippocampus are considered to be most vulnerable to hypoglycaemia.
Selective regional brain vulnerability is related to differences in glucose content, glucose influx, amino acid distribution and inhibition of cerebral protein synthesis. Diffusion-weighted magnetic resonance imaging is therefore an excellent tool for evaluating patients who have self-poisoned with insulin, because it has the ability to detect cytotoxic damage early and can demonstrate as in one of our patients heterogeneous high intensity areas in both cortex and subcortex [ 12 ].
Prognostic factors in insulin poisoning are subject to debate. It is generally accepted that the severity of intoxication should be assessed based on clinical findings rather than on any speculated amount of self-injected insulin [ 1 , 13 ]. Interestingly, as in our study, the dose and type of insulin were found to be closely related to the duration but not to the severity of hypoglycaemia [ 1 , 13 , 15 ].
It should be noted that patients may become hypoglycaemic much later than predicted based on the conventional duration of action of insulin preparations [ 7 ]. The cause of the dissociation between large doses of insulin and the severity of subsequent hypoglycaemia remains unclear [ 16 ]. In addition to activation of counter-regulatory mechanisms, a rate-limiting system appears to be involved in the blood glucose response to plasma insulin level, which is not affected by increased circulating insulin [ 16 , 17 ].
This is supported by the comparable efficacy between low-dose and conventional high-dose insulin therapy in diabetic ketosis [ 18 ]. Moreover, in diabetic patients who are chronically exposed to high levels of insulin, saturation of or decreased insulin receptors alters the response of blood glucose to circulating insulin [ 16 ].
It has also been hypothesized that there is a delayed dissociation of insulin bound to antibodies in vivo , but this is considered rather unlikely [ 16 ]. In contrast, duration of hypoglycaemia is usually much longer than predicted based on the commonly accepted kinetics of insulin absorption and action, whereas the degree of hypoglycaemia may not be so profound, especially in patients who have diabetes [ 7 ].
Some diabetic patients have defects in counter-regulatory hormone secretion, resulting in impaired recovery from insulin-induced hypoglycaemia [ 19 ]. In other cases, hypoglycaemia induces a reduction in peripheral circulation, limiting the absorption of the subcutaneously self-injected insulin [ 7 ]. Study of the kinetics of self-injected insulin is difficult, particularly in nondiabetic patients, because of the presence of endogenous insulin. Thus, in order to interpret accurately the insulin levels and to study the disappearance of exogenous insulin from circulation, we used the level of peptide C a cleavage product of endogenous pro-insulin as a surrogate, the value of which has previously been demonstrated [ 6 , 20 ].
We considered the existence of suppressed C-peptide immunoreactivity and a molar ratio of insulin to C-peptide of less than 1 unity to represent assurance of reliable measurement of exogenous insulin [ 21 ].
The kinetics of insulin follow a multi-compartmental course, with a terminal plasma half-life of 10 to 20 minutes [ 22 ]. Insulin metabolism is dependent on hepatic and renal functions, with a small contribution made by muscle and adipose tissue [ 14 ]. Using a non-compartmental analysis in a case of insulin intoxication in a type 1 diabetic patient, Shibutani and Ogawa [ 17 ] found an elimination half-life of 6.
In another insulin-poisoned type 1 diabetic patient, Fasching and coworkers [ 23 ] identified a biphasic slow decline, with apparent half-lives of 4 hours and 10 hours for the two successive phases, respectively. In our patients, we identified late half-lives ranging from 0. The kinetics of insulin are characterized by a large intra-individuals and inter-individual variability [ 13 ]. In acute poisoning, insulin levels reflect various delays in insulin activity, including delayed absorption from the injection site and possibly prolonged clearance of absorbed insulin.
Compared with usual use of insulin, which is completely absorbed within 24 hours, time to peak concentration is delayed, suggesting slow absorption from the injected site.
Several factors may alter insulin kinetics, resulting in prolonged elimination and consequently prolonged duration of action. Large volumes of self-injected insulin solution may cause a 'depot effect', resulting in a significant reduction in local blood flow caused by compression of tissues at the injection site.
In diabetic patients, absorption is also delayed if local lipodystrophy caused by repeated injections is present. Circulating antibodies against insulin as well as impaired renal and hepatic function may also alter insulin clearance.
We used the glucose infusion rate as a surrogate marker of the severity of hypoglycaemia. In the six patients the maximal glucose infusion rate was associated with a wide range of insulin concentrations, suggesting a saturable toxic mechanism at these high concentrations.
Consistent with this, insulin-stimulated glucose flux is a saturable, receptor-mediated process with a nonlinear dose-effect curve [ 25 , 26 ]. The range of insulin concentrations accompanied by a decrease in glucose infusion rate was highly variable, enhancing the weak prognostic value of circulating insulin concentration. In contrast, the rate of glucose infusion decreased only when plasma insulin concentrations dropped dramatically.
Our findings clearly demonstrate that prompt recognition and adequate treatment of the hypoglycaemic events is the key to achieving a successful outcome. Whether there is any correlation between amounts of administered glucose and self-administered insulin is subject to debate [ 7 , 13 ]. As stated above, insulin level is not related to the severity of hypoglycaemia.
These were managed with oral glucose, IM glucagon, and further dextrose boluses. Blood electrolytes and pH were monitored throughout. Insulin overdoses are relatively common and often occur with an excess of other drugs or alcohol which can enhance its action. Overdoses can result in persistent hypoglycaemia, liver enzyme derangement, electrolyte abnormalities, and neurological damage. Overall mortality is 2. A year-old man was brought to the Emergency Department after a deliberate huge overdose of long-acting Levemir insulin following an argument with his partner.
He reported injecting units at multiple points on his chest, abdomen, and upper thighs. No discarded drug packets were found around him. He was brought to hospital by ambulance two hours after his overdose when his partner found him unconscious. He was in full-time employment and lived with his partner. He was a lifelong nonsmoker and denied any illicit drug use or excessive alcohol consumption. He also denied previous deliberate self-harm or suicide attempts.
Physical observations were stable and he was apyrexial. Initial capillary blood glucose was 2. Physical examination, including a full neurological assessment, was unremarkable. A normal ECG was recorded. His initial arterial blood gas on 15L oxygen showed: pH 7. Bloods on admission were Na , K 3. Subsequent bloods showed a corrected calcium of 2. After 12 hours, intermittent hypoglycaemic episodes persisted. Throughout treatment, there was close monitoring of potassium, magnesium, and phosphate levels, along with regular arterial blood gases to monitor pH.
Insulin and C-peptide levels were not checked on this occasion. He experienced his last hypoglycaemic episode 41 hours after taking the overdose and dextrose infusions were continued for 62 hours in total. Metformin was restarted 10 hours after stopping the dextrose infusion.
Insulin overdoses are an increasing clinical problem in the Emergency Department [ 1 ]; however, reports of massive overdoses in the literature remain scarce. Other overdoses were units of lispro and units of glargine in a patient [ 3 ], units of NPH insulin in a patient [ 4 ] and units regular insulin and units NPH insulin in a patient [ 5 ]. A case of units of overdose of insulin glargine was also reported.
In this case the effects of the Insulin glargine lingered for up to 84 hours after dose [ 6 ]. It should be noted that insulin overdoses can also be because medical staff have mistakenly given a high dose. Insulin overdose is associated with multiple side effects including neurological damage, electrolyte abnormalities hypokalemia, hypomagnesaemia, and hypophosphatemia , severe hypoglycaemic episodes, and liver enzyme derangement [ 8 ]. Von Mach et al.
Prognosis is poorer in patients who are admitted unconscious 12 hours after overdose. Russell et al. Levemir is a long-acting insulin which delivers a constant level of insulin between meals.
0コメント