Development and pharmacist-mediated use of tools for monitoring atypical antipsychotic-induced side effects related to blood glucose levels.

PURPOSE: Drug side effects often lead to serious outcomes. Administration of second-generation antipsychotics has resulted in diabetic ketoacidosis and diabetic coma leading to death. Therefore, pharmacists are required to collect information on clinical test values, determine the appropriate test timing, and coordinate with doctors for further clinical laboratory orders, all of which are labor-intensive and time-intensive tasks. In this study, we developed a side effect-monitoring tool and aimed to clarify the influence and efficiency of monitoring side effects by using the tool in patients taking atypical antipsychotics in whom it is necessary to check clinical test values such as blood sugar levels. METHODS: We extracted clinical test values for patients treated with second-generation antipsychotics from electronic medical records. The test values are automatically displayed in the side effect grade classification specified by CTCAE ver. 4.0. A database was constructed using scripts to provide alerts for the timing of clinical testing. The pharmacist used this tool to confirm clinical test values for patients taking medication and requested the physician to inspect orders based on the appropriate test timings. RESULTS: The management tool reduced the pharmacists' effort in collecting information on patients' prescription status and test values. It enabled patients to undergo tests at the appropriate time according to the progression of glucose metabolism and allowed for easy monitoring of side effects. CONCLUSIONS: The results suggested that regardless of pharmacists' experience or skill, the introduction of this tool enables centralization of side effect monitoring and can contribute to proper drug use.

Glycated hemoglobin A1c as a risk factor for severe hypoglycemia in pediatric type 1 diabetes.

OBJECTIVE: To assess the risk of severe hypoglycemia related to glycated hemoglobin A1c (HbA1c) levels in a population-based cohort of pediatric type 1 diabetes patients during two time periods since 1995. METHODS: The association between HbA1c levels and severe hypoglycemia (defined as requiring assistance from another person) or hypoglycemic coma (loss of consciousness or seizures) was analyzed by multivariable regression analysis in children and adolescents with type 1 diabetes from the DPV Diabetes Prospective Follow-up in Germany and Austria in 1995-2003 (n = 15 221 patients) and 2004-2012 (n = 22 318 patients). RESULTS: Mean adjusted rates of severe hypoglycemia and hypoglycemic coma decreased from 19.18 [95% confidence interval (CI), 17.95-20.48] and 4.36 (3.93-4.83) per 100 patient-years in 1995-2003 to 15.01 (14.18-15.88) and 2.15 (1.94-2.39) in 2004-2012, respectively (p < 0.001). From the first to the second period, the relative risk (RR) for severe hypoglycemia and hypoglycemic coma per 1% lower HbA1c decreased from 1.22 (1.15-1.30) to 1.06 (1.01-1.12) and from 1.27 (1.15-1.40) to 1.04 (0.94-1.16), respectively. Risk of severe hypoglycemia and coma declined most in patients with HbA1c levels of 6-6.9% (RR 0.70 and 0.43, respectively) and with HbA1c of 7-7.9% (RR 0.63 and 0.38, respectively). Mean HbA1c levels fell from 8.4% in 1995-2003 to 8.2% in 2004-2012, while the use of insulin pumps, short- and long-acting insulin analogs, and glucose monitoring increased (p < 0.001). CONCLUSIONS: In contrast to 1995-2003, low HbA1c has become a minor risk factor for severe hypoglycemia and coma in pediatric patients with type 1 diabetes in the 2004-2012 period.

Clinical and forensic examinations of glycaemic marker methylglyoxal by means of high performance liquid chromatography-tandem mass spectrometry.

The postmortem determination of hyperglycaemic coma is quite difficult because of the lack of morphological findings and the difficult interpretation of biochemical parameters. Methylglyoxal (MG) is a reactive oxoaldehyde, which is mainly derived from glycolysis. An electrospray ionisation liquid chromatography-tandem mass spectrometric procedure for the determination of methylglyoxal in human serum and postmortem blood was developed. It involves protein precipitation with perchloric acid and a derivatisation step with 2,3-diaminonaphthalene. The assay was validated according to international guidelines. Serum samples from diabetics obtained at a diabetes clinic and from non-diabetics were used to assess data about reference concentrations in human serum. The assay showed linearity within the physiological concentrations in serum (5-500 ng/ml). Intraday imprecision at three concentrations was 10.3, 9.2 and 8.3 %, and interday imprecision was 15.3, 14.2 and 9.4 %; the limit of detection was 1.3 ng/ml, and limit of quantification, 3.2 ng/ml. One hundred and eighteen clinical (100 diabetics, 18 non-diabetics) and 98 forensic samples (84 non-diabetics, 14 in a status of hyperglycaemic coma) were measured. During life, diabetics showed significantly (p < 0.001) higher serum concentrations of MG than non-diabetics. After death, concentrations of MG increased significantly (p < 0.001). However, there was no correlation between the sum formula of Traub in vitreous humour and MG femoral blood concentrations (R = 0.237). This indicates that MG concentrations in the deceased cannot distinguish deaths due to a hyperglycaemic coma from other causes of death.

One hundred years ago: the dawning of the insulin era.

The dawn of the insulin era can be placed in 1921, when Banting and Best started their experiments which led, a year later, to the successful treatment of diabetes. They were preceded by the discoveries of the pancreatic cause of diabetes by Minkowski and von Mering in 1889 and of the islets by Paul Langerhans in 1869. The achievement of the first targeted treatment in medical history was a landmark of medical progress. However, it was accompanied by a mixture of human greatness and misery. Genius and recklessness, ambition and deception, camaraderie and rivalry, selflessness and pursuit of glory went along with superficial search of the existing literature, poor planning, faulty interpretation of results, failure to reproduce them, and misquoting of reports from other laboratories. Then as now, such faults surface whenever human nature aims to push forward the boundaries of knowledge and pose a real challenge in today's world, as the scientific method strives to keep healthy in the face of growing anti-scientific feelings.

Evaluation of 1,5-anhydro-d-glucitol in clinical and forensic urine samples.

Because of the lack of characteristic morphological findings post mortem diagnosis of diabetes mellitus and identification of diabetic coma can be complicated. 1,5-Anhydroglucitol (1,5-AG), the 1-deoxy form of glucose, competes with glucose for renal reabsorption. Therefore low serum concentrations of 1,5-AG, reflect hyperglycemic excursions over the prior 1-2 weeks in diabetic patients. Next to clinical applications determination of 1,5-AG can also be used in forensic analysis. To investigate the elimination of 1,5-AG, a liquid chromatographic-mass spectrometric method for the determination of 1,5-AG and creatinine in urine was developed and validated according to international guidelines. To evaluate ante mortem concentrations of 1,5-AG spot urine samples of 30 healthy subjects, 46 type 1 and 46 type 2 diabetic patients were analyzed. 1,5-AG urine concentrations of diabetic patients were significantly (p<0.001) lower (mean: 1.54µg/ml, n=92) compared to concentrations of healthy subjects (mean: 4.76µg/ml, n=30) which led to the idea that 1,5-AG urine concentrations post mortem might help in the interpretation of a diabetic coma post mortem. Urine of 47 deceased non-diabetics, 37 deceased diabetic and 9 cases of diabetic coma were measured. Comparison of blood and urine 1,5-AG concentrations in clinic samples (linear, R2=0.13) and forensic samples (linear, R2=0.02) showed no correlation. Urinary levels of 1,5-AG in deceased diabetic (mean 6.9µg/ml) and in non-diabetic patients (mean 6.3µg/ml) did not show a significant difference (p=0.752). However, urinary 1,5-AG concentrations in deceased due to diabetic coma (mean: 1.7µg/ml) were significantly lower than in non-diabetic (mean: 6.3µg/ml, p=0.039) and lower than in diabetic cases (mean: 4.7µg/ml, p=0.058). The determination of a reliable cut-off for the differentiation of diabetic to diabetic coma cases was not possible. Normalization of urinary 1,5-AG concentrations with the respective creatinine concentrations did not show any gain of information. In clinical (serum) and forensic blood samples a significant difference between all groups could be detected (p<0.05). Comparison of blood and urine 1,5-AG concentrations in clinical samples (linear, R2=0.13) and forensic samples (linear, R2=0.02) showed no correlation.

An assessment of insulin action in hyperosmolar hyperglycemic nonketotic diabetic patients.

The effect of insulin treatment on the rate of decline of plasma glucose concentration was determined in nine patients with hyperosmolar hyperglycemic nonketosis [HHNK; mean plasma glucose, 999 +/- 59 (+/- SEM) mg/dl] and in six normal subjects rendered hyperglycemic by a combined infusion of somatostatin and glucose (mean plasma glucose, 653 +/- 28 mg/dl). Both the fractional glucose turnover and the half-time of the fall in plasma glucose during low dose (5-10 U/h) insulin treatment were reduced 10-fold (P less than 0.001) in the diabetic patients compared with the hyperglycemic normal subjects. In the hyperosmolar patients, the mean glucose clearance during insulin treatment was only 7% that in the normal subjects (P less than 0.001). The rate of plasma glucose decline in our hyperosmolar patients after hydration and insulin administration was 80 +/- 7 mg/dl X h. This decline is comparable to the results reported in other series, although in striking contrast to the 508 +/- 32 mg/dl X h decline in normal subjects (P less than 0.001). Our findings do not support the clinical impression that HHNK patients are insulin sensitive. We conclude that marked resistance to infused insulin delays the correction of hyperglycemia during treatment of HHNK and suggest that resistance to the normal basal insulin levels encountered in some HHNK patients may contribute in part to the development of the hyperosmolar state.

Hyperosmolar hyperglycemic nonketotic syndrome. Report of 22 cases and brief review.

In a series of 22 patients with the hyperosmolar hyperglycemic nonketotic syndrome managed during a five-year period in a community hospital setting, 21 patients were known to be diabetic and only six patients were in coma. The overall mortality was 36.3 percent, and seven of the eight deaths were explained by associated nonmetabolic causes. In this study, hyperosmolarity was not related to coma or to final outcome of treatment. Patients were managed with relatively small amounts of fluid, and the type of fluid used did not influence the final outcome.

Determinants of glucose and ketoacid concentrations in acutely hyperglycemic diabetic patients.

Diabetic hyperosmolar coma is a syndrome of marked hyperglycemia and minimal ketoacidosis. In general, the serum glucose concentrations are not predictive of the serum ketoacid concentrations in acutely decompensated diabetes. The endocrine factors that modulate glucose concentrations may be different from those that modulate ketoacid concentrations in patients with acutely decompensated diabetes. To test this hypothesis, regression analysis was used to determine the endocrine and metabolic characteristics that correlated with serum concentrations of glucose and ketoacids in 26 diabetic patients with spontaneous, acute hyperglycemia. All patients had a serum glucose level greater than 390 mg/dl, and ketoacid levels were from 0.17 to 25.5 mM. Multiple regression analysis showed that increased serum glucose concentrations correlated with increased plasma glucagon levels (p = 0.0007, r2 = 0.45), but with no other factors. Increased total ketoacid levels (acetoacetate plus 3-hydroxybutyrate) correlated with increased free fatty acid levels (p = 0.0001), decreased C-peptide levels (p = 0.002), and increased body mass index (p = 0.002) (r2 = 0.72). Body mass index only correlated with ketoacid levels, when it was analyzed with C-peptide and free fatty acid levels. A model is proposed that predicts the serum glucose and ketoacid concentrations in patients with acutely decompensated diabetes. Glucagon modulates the serum glucose concentration in these patients with an absolute or relative insulin deficiency. Total serum ketoacid levels are determined by the serum free fatty acid concentration, residual pancreatic insulin secretion (as reflected by C-peptide), and the patient's body habitus. This model allows for the marked hyperglycemia and minimal ketosis of diabetic nonketotic hyperosmolar coma, as well as the glucose and ketoacid concentrations in other presentations of acutely decompensated diabetes.

Prognostic factors in the diabetic hyperosmolar state.

To evaluate the current outcome of patients hospitalized with diabetic hyperosmolar state (DHS), we retrospectively studied 135 patients admitted to two general hospitals over an 11-year period. Mortality was 17%. Patients who died had a mean age of 77 years, compared to 68 years for the survivors (P = 0.008). They were also more likely to be nursing home residents (48 versus 23%, P = 0.01). Additionally, mean serum osmolality was significantly higher among those who died (383 versus 358 mosm/L, P less than 0.0001) as was blood urea nitrogen (81.3 versus 62.3 mg/dl, P = 0.006) and sodium (148 versus 137.4 mEq/L, P less than 0.001). However, mean glucose level and anion gap were similar among patients who died and patients who survived (1068 versus 1092 mg%; 23 versus 24 mEq/L, respectively). The presence of a chronic disease or an acute comorbid illness was not associated with mortality. Diminished physiologic reserve, attendant comorbidity, or functional disability may explain the effect of age and nursing home residence. High osmolality may indicate a greater water deficit and a more advanced stage of DHS at the time of diagnosis.

The diagnostic value of postmortem blood glucose determinations in cases of diabetes mellitus.

In 24 cases of death in diabetic coma the peripheral venous blood showed glucose levels exceeding 3.5 mg/ml (mean value 7.76 mg/ml). In a control material of deaths of other causes the blood glucose was usually low and often zero, and all values were well below the lower limit of the diabetic concentrations. The acetone contents of the diabetic blood varied widely and were of limited diagnostic value. We conclude that glucose concentrations above 3.5 mg/ml in the peripheral blood indicate that death occurred in diabetic coma.

Diabetic ketoacidosis--a study of 33 episodes.

Twenty-six patients presenting with 33 episodes of Diabetic Ketoacidosis (DKA) and managed on a protocol oriented system were analysed. Diabetes mellitus was newly diagnosed at presentation in 18% of the 33 episodes. The presenting symptoms were polyuria and polydipsia (58%), nausea and vomiting (52%), change in sensorium (24%), hyperventilation (24%), and abdominal pain (18%). The main clinical findings at admission were dehydration (97%), acidotic respiration (67%), coma and confusion (61%), a clinically detectable source of sepsis (49%), fever (33%) and hypotension (9%). Blood sugar levels at admission ranged between 351 mg/dl and 1200 mg/dl (mean = 633 mg/dl). The mean serum potassium at diagnosis was 5.1 mmol/l and the mean calculated serum osmolality was 320 mOsm/kg. The mean serum osmolality was higher in those with disturbed conscious level. Infections, particularly those of the urogenital tract, were the main precipitating cause for the DKA. Only 12 of the 19 patients with sepsis had fever. Eight of the episodes were attributed to patients' non-compliance with insulin. Four patients died during the 33 hospitalisations, giving a mortality rate of 10%. Death occurred despite glucose control and stabilisation of the ketoacidotic state and was due to uncontrolled septicaemia. The mean duration of hospitalisation was 11 days. The ketoacidosis state was reversed after a mean duration of 9.5 hours, with an average soluble insulin requirement per patient of 52.4 units.

[Intracranial hypertension in severe diabetic ketoacidosis with coma. Two cases]. / Hypertension intracrânienne au cours de l'acidocétose diabétique grave avec coma. Deux observations.

We observed two cases of severe diabetic ketoacidosis with coma and shock. In one case, coma was present at admission and in the second occurred within 15 hours. In both cases, intracranial hypertension was confirmed with an extradural captor. These findings are in agreement with observations of brain oedema in diabetic ketoacidosis with coma. Clinical data suggest that brain oedema may occur after a latency period but that clinical expression is much more rare, perhaps favoured by treatment (excessive rehydratation, alkalinization, too sharp drop in blood glucose level). In our cases, despite major fluid infusion, shock persisted requiring norepinephrine. This shock could have been the expression of the severe ketoacidosis or have resulted from an underlying infection. In case of sudden onset coma, a regularly encountered manifestation of brain oedema, respiratory assistance and mannitol infusion must be instituted rapidly. With this type of management, it should be possible to improve the severe prognosis of brain oedema in diabetic ketoacidosis.

[Diabetic ketoacidosis (causes, clinico-biochemical correlations and terminology problems)]. / Diabeticheskii ketoatsidoz (prichiny, kliniko-biokhimicheskie sopostavleniia, voprosy terminologii).

The clinical and biochemical data obtained in 85 patients with diabetic ketoacidosis (DKA) are presented. DKA is an acute exacerbation of diabetes, a characteristic clinico-biochemical syndrome including increasing thirst, polyuria, adynamia, dryness of the skin and mucous membranes, anorexia, nausea, vomiting, occasionally abdominal pain, Kussmaul's breath, acetone odour in the exhaled air, circulatory collapse, prerenal azotemia, stupor, coma. Glycemia level exceeds 19 mmol/l, blood pH over 7.3. The disease is marked by neutrophilic leukocytosis, blood count shift to the left, elevated blood content of creatinine and urea. It was established that the degree of consciousness abnormality does not always correlate with the degree of the clinico-biochemical manifestations of DKA. During DKA, coma occurs relatively seldom (5.9%). It is suggested to use the term "diabetic ketoacidosis", incipient or marked, indicating the degree of consciousness abnormality (stupor, coma).

[Experience with the treatment of diabetic coma]. / Opyt lecheniia diabeticheskoi komy.

To investigate the effect of low-dose versus high-dose insulin treatment of Kussmaul's coma, the authors treated 2 groups of relevant patients. Group I treated with low-dose insulin in combination with other therapeutic measures achieved a progressive decrease of glycemia within 8 hours. Complications were not registered. Group II on high-dose insulin scheme exhibited a drop in blood sugar resultant in hypoglycemia in 4, hypotonia in 2, brain edema in 1 patient. The absence of complications, availability and simplicity support the advantages of the low-dose regime which is now widely introduced into clinical practice.

[The postmortem assessment of glycemia by the levels of blood glucose and glycosylated hemoglobin]. / Posmertnaia otsenka glikemii po urovniu gliukozy i glikozilirovannogo gemoglobina krovi.

The results of cadaveric blood investigation in order to diagnose glycemia directly before death are presented. During the analysis of the whole blood glucose concentration was determined by glucose oxidase method as well as percentage of glycosylated Hb was determined by colorimetric method by colour reaction with thyobarbituric acid. On the basis of the results obtained conclusion was made about failure in use of glucose concentration for medicolegal purposes. Estimation of glycosylated Hb content was suggested as criterion for glycemia detection.

Detection of diabetic metabolism disorders post-mortem--forensic case reports on cause of death hyperglycaemia.

Diabetic coma is the most severe form of hyperglycaemic metabolic disorders. The post-mortem diagnosis of this disorder of glucose metabolism can be difficult and vague due to a lack of characteristic morphological findings. Six death cases caused by diabetic coma are described with special focus on biochemical (and histological) findings. The possible glycaemia markers glucose, lactate, HbA1c, fructosamine, anhydroglucitol, and ketone bodies were measured and the usefulness of these parameters is evaluated and discussed. Estimations of glucose concentrations in vitreous humour or cerebrospinal fluid and of ketone bodies in blood or other matrices are obligatory while measurements of HbA1c, fructosamine, or anhydroglucitol can only provide additional information on the long-term adjustment of diabetes in the deceased. Lactate concentrations (addition of glucose and lactate levels to form the sum formula of Traub) do not give more information than the glucose concentration itself and can be therefore omitted.

Clinical and forensic examinations of glycemic marker 1,5-anhydroglucitol by means of high performance liquid chromatography tandem mass spectrometry.

Postmortem diagnosis of diabetes and a diabetic coma can be difficult because of the lack of characteristic morphological findings. 1,5-Anhydroglucitol (1,5-AG), the 1-deoxy form of glucose, competes with glucose for reabsorption in the kidneys. Therefore, diabetics with a permanent hyperglycemia show significantly lower serum concentrations of 1,5-AG than non-diabetics. A liquid chromatography-mass spectrometric method for the determination of 1,5-AG in serum and postmortem blood was developed and validated according to international guidelines. Linearity was given between 1 µg/ml and 50 µg/ml. Recovery rates ranged between 70.8% and 89.8%, the limit of quantification of the procedure was 0.20 µg/ml, limit of quantification was 0.55 µg/ml. Serum of 199 diabetics and 116 non-diabetics and femoral blood of 31 diabetic and 27 non-diabetic deceased was measured. Average concentrations were significantly (p<0.001) higher in non-diabetics compared to diabetics ante and postmortem. Seven of the diabetics may have died because of a hyperglycemic coma indicated by a sum formula of Traub>450 mg/dl. 1,5-AG average concentrations in these deceased were not significantly different to diabetics which did not die because of a diabetic coma. Concentrations of 1,5-AG give a hint for not well controlled diabetes antemortem and postmortem and can be assumed as an additional and alternative information postmortem to the measurement of HbA1c or fructosamine.