Influence of human insulin on symptoms and awareness of hypoglycaemia: a randomised double blind crossover trial.

OBJECTIVE--To investigate the apparent increased risk of severe hypoglycaemia associated with use of human insulin by comparing the pattern of symptoms of hypoglycaemia with human insulin and porcine insulin. DESIGN--Randomised controlled double blind crossover trial of treatment with human insulin and porcine insulin, with two treatment periods of six weeks. SETTING--Diabetes outpatient department of a university teaching hospital in Berne, Switzerland. PATIENTS--44 patients (25 men, 19 women) aged 14 to 60 years, with insulin dependent diabetes mellitus. All patients met the following criteria: receiving treatment with fast acting soluble insulin and long acting protamine insulin; performing multiple daily fingerstick blood glucose self measurements; and had stable glycaemic control with about one mild hypoglycaemic episode a week during the preceding two months. INTERVENTION--Patients were randomised to receive either human or porcine insulin for six weeks and were then changed over to the other type of insulin for a further six weeks. MAIN OUTCOME MEASURE--Questionnaire recording "autonomic" and "neuroglycopenic" symptoms that occurred during hypoglycaemic episodes confirmed by a blood glucose concentration less than or equal to 2.8 mmol/l. RESULTS--Insulin doses and blood glucose, glycated haemoglobin A1c, and fructosamine concentrations were similar during the two treatment periods. 493 questionnaires on hypoglycaemia (234 during treatment with human insulin and 259 during treatment with porcine insulin) were analysed. With human insulin patients were more likely to report lack of concentration (52% v 35%, p = 0.0003) and restlessness (53% v 45%, p = 0.004) and less likely to report hunger (33% v 42%, p = 0.016) than during treatment with porcine insulin. The difference in the pattern of symptoms during the two treatments was similar to that between the 12 patients with a history of recurrent hypoglycaemic coma and the 32 patients without such a history. CONCLUSIONS--The pattern of symptoms associated with human insulin could impair patients'' ability to take appropriate steps to avoid severe hypoglycaemia. Caution should be exercised when transferring patients from animal insulin to human insulin, and a large scale randomised trial of the two types of insulin may be justified.     

Hypothermia: a complication of diabetic ketoacidosis.

During 1969-77, 20 episodes of severe hypothermia occurred in 19 diabetic patients in Nottingham. Thirteen were associated with ketotic hyperosmolar coma, two with lactic acidosis, and one with hypoglycaemia, while in four there was no loss of diabetic control. Ketoacidosis accounted for 11.8% of all admissions for severe accidental hypothermia and was a commoner cause than hypothyroidism (8%). Patients with ketoacidosis were younger and developed hypothermia as often during the summer as during the winter. The metabolic disturbance was characteristic, with severe acidosis (mean pH 7.04), a high blood glucose concentration (mean 56.6 mmol/l; 1020 mg/100 ml), and high plasma osmolality (mean 379.7 mmol (mosmol)/kg). Eight of the 13 episodes proved fatal. Hypothermia may aggravate ketoacidosis and complicate treatment and should be sought in all patients with severe diabetic coma.     

Double blind clinical and laboratory study of hypoglycaemia with human and porcine insulin in diabetic patients reporting hypoglycaemia unawareness after transferring to human insulin.

OBJECTIVES--To compare awareness of hypoglycaemia and physiological responses to hypoglycaemia with human and porcine insulin in diabetic patients who reported loss of hypoglycaemia awareness after transferring to human insulin. DESIGN--Double blind randomised crossover study of clinical experience and physiological responses during slow fall hypoglycaemic clamping with porcine and human insulin. SETTING--Clinical investigation unit of teaching hospital recruiting from diabetes clinics of five teaching hospitals and one district general hospital. SUBJECTS--17 patients with insulin dependent diabetes mellitus of more than five years'' duration who had reported altered hypoglycaemia awareness within three months of transferring to human insulin. MAIN OUTCOME MEASURES--Glycaemic control and frequency of hypoglycaemic episodes during two months'' treatment with each insulin. Glucose thresholds for physiological and symptomatic responses during clamping. RESULTS--Glycaemic control did not change with either insulin. 136 hypoglycaemic episodes (eight severe) were reported with human insulin and 149 (nine severe) with porcine insulin (95% confidence interval -4 to 2.5, p = 0.63). 20 episodes of biochemical hypoglycaemia occurred with human insulin versus 18 with porcine insulin (-0.8 to 1, p = 0.78). During controlled hypoglycaemia the mean adrenaline response was 138 nmol/l/240 min for both insulins; neurohormonal responses were triggered at 3.0 (SE 0.2) versus 3.1 (0.2) mmol/l of glucose for adrenaline and 2.5 (0.1) versus 2.5 (0.1) mmol/l for subjective awareness. CONCLUSIONS--These data suggest that human insulin per se does not affect the presentation of hypoglycaemia or the neurohumoral, symptomatic, and cognitive function responses to hypoglycaemia in insulin dependent diabetic patients with a history of hypoglycaemia unawareness.     

Monitoring of blood glucose concentration in subjects with hypoglycaemic symptoms during everyday life.

OBJECTIVE--To study the persistence of hypoglycaemic symptoms, changes in blood glucose concentrations, and the relation between reported symptoms and measured blood glucose values in functional hypoglycaemia. DESIGN--Re-evaluation of symptoms in patients admitted consecutively with suspected hypoglycaemia followed by a case-control study. SETTING--The Steno Memorial Hospital in Gentofte, Denmark, which specialises in the diagnosis and treatment of and research on endocrine disorders, including hypoglycaemia. PATIENTS--21 Subjects admitted consecutively with hypoglycaemic symptoms that were relieved by eating in whom insulinoma and other organic disorders presenting with hypoglycaemia had been ruled out. Twelve of these subjects with persistent symptoms entered the case-control study, as did a matched control group. INTERVENTIONS--Four days of monitoring blood glucose concentrations at home, six daily samples being taken in fixed relation to meals by the finger prick method. Extra samples were taken when symptoms occurred. MAIN OUTCOME MEASURES--Blood glucose concentration, glycated haemoglobin concentration, and within subject variation in measured values. RESULTS--After one to three years of observation 19 of the 21 subjects still had symptoms. Six out of 12 subjects experienced hypoglycaemic symptoms during the controlled study. Blood glucose concentration ranged from 3.7 mmol/l to 7.5 mmol/l during these episodes. Changes in blood glucose concentration, mean blood glucose concentrations at each time point, within subject variation in the measured values, and glycated haemoglobin concentration were not significantly different in all patients compared with the control subjects and in patients with symptoms during the study compared with controls. CONCLUSION--Hypoglycaemic symptoms during everyday life in apparently healthy subjects are persistent but are not related to chemical hypoglycaemia.     

Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin: a case control study.

OBJECTIVE--To examine whether transfer from animal insulin to human insulin is associated with an increased risk of severe hypoglycaemia. DESIGN--Matched case-control study of insulin treated diabetic patients admitted to hospital because of hypoglycaemia during 1984-7, the period when human insulin was introduced into treatment. SETTING--Case admissions and control admissions were obtained from eight public hospitals within the Swiss canton of Berne and a second control group comprised members of the Bernese section of the Swiss Diabetes Association. SUBJECTS--94 patients with insulin treated diabetes with a total of 112 admissions for hypoglycaemia during 1984-7 (case admissions), 182 patients with insulin treated diabetes seen in the same hospitals for reasons other than hypoglycaemia with a total of 225 admissions (control admissions), and 86 insulin treated diabetic patients who were members of the Bernese section of the Swiss Diabetes Association. MAIN OUTCOME MEASURES--Type of insulin used at time of admission, glycaemic control as measured by amount of glycated haemoglobin or glucose concentration; severity of hypoglycaemia. RESULTS--Treatment with human insulin at admission was more common in cases than controls (52/112 (46%) admissions v 77/225 (34%); p = 0.003). 116 out of 129 (90%) of admissions taking human insulin had been transferred from animal insulin, mainly because of non-availability of porcine insulins. The ratio of rate of hypoglycaemia in those taking human insulin to the rate in those taking animal insulin was 2.4 (95% confidence interval 1.3 to 4.4). Other risk factors for hypoglycaemia were a history of hypoglycaemic coma (rate ratio of history to no history 3.8, 2.3 to 6.4) and good glycaemic control (rate ratio of good to poor control 3.9, 1.4 to 7.5). With multivariate analysis the increase in rate ratio associated with use of human insulin rose to 3.0 (1.4 to 6.4). Comparison with the diabetes association controls also showed an increased risk associated with use of human insulin (2.2; 1.1 to 4.8). CONCLUSIONS--Transfer of treatment from animal insulin to human insulin was associated with an increased risk of severe hypoglycaemia. Caution should be exercised when transferring diabetic patients to human insulin. Further studies are required to elucidate why this effect occurs.     

Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy.

OBJECTIVE--To examine the traditional view that unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation in insulin dependent diabetes mellitus are manifestations of autonomic neuropathy. DESIGN--Perspective assessment of unawareness of hypoglycaemia and detailed assessment of autonomic neuropathy in patients with insulin dependent diabetes according to the adequacy of their hypoglycaemic counterregulation. SETTING--One routine diabetic unit in a university teaching hospital. PATIENTS--23 Patients aged 21-52 with insulin dependent diabetes mellitus (seven with symptoms suggesting autonomic neuropathy, nine with a serious clinical problem with hypoglycaemia, and seven without symptoms of autonomic neuropathy and without problems with hypoglycaemia) and 10 controls with a similar age distribution, without a personal or family history of diabetes. MAIN OUTCOME MEASURES--Presence of autonomic neuropathy as assessed with a test of the longest sympathetic fibres (acetylcholine sweatspot test), a pupil test, and a battery of seven cardiovascular autonomic function tests; adequacy of hypoglycaemic glucose counterregulation during a 40 mU/kg/h insulin infusion test; history of unawareness of hypoglycaemia; and response of plasma pancreatic polypeptide during hypoglycaemia, which depends on an intact and responding autonomic innervation of the pancreas. RESULTS--There was little evidence of autonomic neuropathy in either the 12 diabetic patients with a history of unawareness of hypoglycaemia or the seven patients with inadequate hypoglycaemic counterregulation. By contrast, in all seven patients with clear evidence of autonomic neuropathy there was no history of unawareness of hypoglycaemia and in six out of seven there was adequate hypoglycaemic counterregulation. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation were significantly associated (p less than 0.01). The response of plasma pancreatic polypeptide in the diabetic patients with adequate counterregulation but without autonomic neuropathy was not significantly different from that of the controls (change in plasma pancreatic polypeptide 226.8 v 414 pmol/l). The patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response (3.7 pmol/l), but this response was also blunted in the patients with inadequate hypoglycaemic counterregulation (72.4 pmol/l) compared with that of the controls (p less than 0.05). CONCLUSIONS--Unawareness of hypoglycaemia and inadequate glucose counterregulation during hypoglycaemia are related to each other but are not due to autonomic neuropathy. The blunted plasma pancreatic polypeptide responses of the patients with inadequate hypoglycaemic counterregulation may reflect diminished autonomic activity consequent upon reduced responsiveness of a central glucoregulatory centre, rather than classical autonomic neuropathy.     

Comparison of propranolol,metoprolol, and acebutolol on insulin-induced hypoglycaemia.

Metoprolol and acebutolol, two supposedly cardio-selective beta-adrenergic recptor blocking agents, were tested in healthy volunteers against propranolol, a non-selective drug, for their effect on blood glucose levels during insulin-induced hypoglycaemia. There was not significant difference between propranolol and metoprolol, which both potentiated the initial hypoglycaemic action of the insulin and delayed the return to normoglycaemia. Acebutolol, even though potentiating the initial hypoglycaemia, did not possess a significant delaying effect. A similar trial should be undertaken in diabetics to determine with certainty the safety of such drugs in diabetes mellitus.     

Intensified conventional insulin treatment and neuropsychological impairment.

OBJECTIVE--To assess whether intensified insulin treatment, with an increased frequency of hypoglycaemic episodes, leads to cognitive deterioration. DESIGN--Prospective randomised trial of intensified conventional treatment and standard treatment. SETTING--Outpatient clinic for patients with insulin dependent diabetes. SUBJECTS--96 patients with insulin dependent diabetes, high blood glucose concentrations, and non-proliferative retinopathy were randomised to intensified conventional treatment (n = 44) or standard treatment (n = 52). MAIN OUTCOME MEASURES--Glycated haemoglobin concentration (metabolic control); the number of hypoglycaemic episodes reported by patients at each visit; results of computerised neuropsychological tests performed at entry and after five years. RESULTS--Mean glycated haemoglobin concentration during the study was 7.2% (SE 0.1%) with intensified conventional treatment and 8.7 (0.1%) with standard treatment (p less than 0.001). During five years 34 (77%, 95% confidence interval 53% to 100%) of the patients given intensified treatment and 29 (56%, 36% to 75%) of the others had at least one episode of serious hypoglycaemia (p less than 0.05). The intensified conventional treatment group had a mean of 1.1 episodes of serious hypoglycaemia per patient per year compared with 0.4 episodes in the standard treatment group. Results of the neuropsychological tests were similar in the two groups after five years. CONCLUSIONS--Intensified conventional insulin treatment led to lower blood glucose concentrations and a higher frequency of hypoglycaemic episodes, but patients showed no signs of cognitive deterioration.     

Effects of self poisoning with maprotiline.

Self poisoning with maprotiline was studied in 41 patients (43 episodes) consecutively admitted to an intensive care unit. Thirty five patients had taken more than one drug or alcohol. Fifteen patients were in coma grade III or IV; 17 patients were still not conscious after 24 hours in the intensive care unit. Among six patients given ventilation the mean duration of ventilation in the five who recovered was 36 hours. Three patients had a cardiorespiratory arrest, and one patient died. Twenty eight patients had a QRS interval of 100 ms or more, and 15 patients had seizures. In six patients seizures were precipitated by physostigmine. Cardiotoxicity after overdosage of maprotiline is equal to if not greater than that found after overdosage of conventional tricyclic antidepressants. Overdosage of maprotiline is more often associated with seizures than overdosage with tricyclic antidepressants. Physostigmine further increases the risk of seizures and should not be used in cases of overdosage of maprotiline.     

Prognosis after cardiac arrest based on age and duration of coma.

In an attempt to determine the relation between duration of coma and neurologic recovery following cardiac resuscitation 163 survivors of cardiac arrest from Winnipeg, Manitoba and Aarhus, Denmark were studied. The age of the patients did not influence the outcome. Of the 153 patients who had awakened from the coma within 24 hours, only 11 suffered brain damage, compared with all of the 10 patients who wakened after 24 hours. The three who wakened after 72 hours had severe brain damage and required permanent care in an institution. It was concluded that recovery of communicative brain function is unlikely if coma persists longer than 72 hours after cardiac arrest and that full recovery cannot be expected after 24 hours of coma.     

Factors contributing to mortality in paracetamol-induced hepatic failure.

Fifty patients with fulminant hepatic failure from paracetamol overdose were reviewed retrospectively to determine whether there had been any avoidable delays in treatment with protective agents, or other preventable factors which could contribute to the high mortality. Only nine were admitted to the local hospital early enough (within 12 hours) to benefit from protective agents, and only three of these were treated. Treatment was delayed in two patients while the results of plasma paracetamol concentrations were awaited. Signs of grade 3 hepatic encephalopathy were never found until 72 hours after the overdose, and sudden deterioration in consciousness at an earlier stage was due either to the sedative effects of drugs or to hypoglycaemia, which in one patient went unrecognised for 24 hours. A rapid deterioration in prothrombin time, which became prolonged by at least 25 seconds at 48 hours, preceded the onset of grade 3 encephalopathy, and this is the time at which transfer should be arranged to avoid the danger of brain-stem coning. This occurred more rapidly in those transferred at a later stage of their illness.     

Characteristics of the rat behavior following single and multiple exposures of the hypoglycemic insulin doses]

Rats behaviour in the "open field" changed in 2 hrs after a single episode of hypoglycaemia was abolished with glucose whereas no changes occurred in their stereotyped behaviour and intraspecies interaction. In 24 hrs quantitative parameters of the "open field" behaviour normalised although the behaviour still had an altered structure. At the same time, amphetamine-induced stereotyped behaviour's indices became reduced. These and other findings suggest some deeper behavioural changes in rats during their recovery from repeated hypoglycaemic episodes and absence of synchronisation of the insulin effects.     

High incidence of hypoglycaemia in African patients treated with intravenous quinine for severe malaria.

Changes in plasma glucose and insulin concentrations were monitored over 24 hours in 28 African patients receiving quinine intravenously in an average dose of 8.5 mg base/kg over one hour eight hourly for severe malaria. The patients (nine children and 19 adults) were moderately undernourished; none was pregnant or had renal insufficiency. Plasma insulin concentrations rose during the infusion and then declined. Plasma glucose concentrations were decreased at two, three, and four hours after the start of the infusion. Insulin: glucose ratios were raised between half an hour and two hours after the start of the infusion. The three infusions of quinine increased plasma insulin concentrations in a similar way. In nine patients, including four children, plasma glucose concentrations fell below 2.8 mmol/l on one or two occasions. At the time of the hypoglycaemia plasma insulin concentrations were inappropriately high as shown by a consistent and often considerable increase in the insulin:glucose ratio. Hypoglycaemia that may pass unnoticed in comatose patients is thus a common complication of treating severe malaria with quinine, in particular in children. Its high incidence calls for attentive monitoring and preventive measures.     

How long should patients with suspected myocardial infarction be under observation in hospital?

Out of 368 patients admitted to hospital for chest pain and suspected acute myocardial infarction, 267 were discharged within 24 hours on the basis of the clinical picture, electrocardiogram, and serum activities of aspartate transaminase, alpha-hydroxybutyrate dehydrogenase, and creatine phosphokinase. The patients were followed up for 28 days, during which 17 were readmitted, two of them twice and one three times. Two of the patients were readmitted with non-fatal acute myocardial infarction, and two died. The patients had been primarily divided into two groups: those admitted with presumably non-coronary chest pain (77 patients) formed group 1 and those with obvious coronary chest pain (190 patients) group 2. Both deaths occurred in patients in group 2 but the incidences of events during the follow-up period were otherwise similar in the two groups, and some patients in both groups may have had small acute myocardial infarctions when first admitted. The decision to keep in hospital or discharge a patient with chest pain of recent onset can be made within 24 hours of admission. To discharge the patient acute myocardial infarction need not necessarily be excluded and conventional tests are enough to enable a decision to be made.     

OXIDATIVE METABOLISM OF THE CEREBRAL CORTEX OF THE RAT IN SEVERE INSULIN-INDUCED HYPOGLYCAEMIA

—Measurements were made of organic phosphates, carbohydrate substrates, amino acids and ammonia in the cerebral cortex, as well as of cerebral blood flow and of cerebral metabolic rate for oxygen and glucose in rats that developed an isoelectric EEG pattern (‘coma’) during insulin-induced hypoglycaemia. The results were compared to those obtained in control animals, as well as in hypoglycaemic animals with an EEG pattern of slow waves and polyspikes. In animals with slow waves and polyspikes, there was a decrease in all citric acid cycle intermediates except succinate and oxaloacetate, and a decrease in the pool size of intermediates. In animals that had an isoelectric EEG for 5–15 min, there were further decreases in citrate, isocitrate, α-ketoglutarate, malate and fumarate, but since the concentration of succinate (and oxaloacetate) increased, the pool size remained the same. In isoelectric animals, the results revealed extensive utilization of amino acids by both transamination and deamination reactions. However, since glycogen had disappeared and the amino acid pattern was constant after the first 5 min of isoelectric EEG, further oxidation must have occurred at the expense of non-carbohydrate, non-amino acid substrates. There were two- to three-fold increases in cerebral blood flow in animals with slow waves and polyspikes and in animals with isoelectric EEG, and no decrease in the cerebral metabolic rate for oxygen. Since less than half of the oxygen consumption could be accounted for in terms of glucose extraction, the data indicate that severe hypoglycaemia is associated with extensive oxidation of endogenous substrates other than carbohydrates and free acids.     

Unawareness of hypoglycemia by insulin-dependent diabetics

After several years of insulin therapy, about 20% of insulin-dependent diabetics have little or no perception of hypoglycaemia because of a loss of the adrenergic warning symptoms. This defect, poorly correlated with the presence of autonomic neuropathy, has been classically explained by a defect in the catecholamine secretion. We compared the hormonal counterregulation during hypoglycaemia induced by subcutaneous injection of insulin in 7 insulin-dependent diabetics with poor perception of hypoglycaemia and experiencing repeated episodes of severe hypoglycaemia (group A) and 7 insulin-treated diabetics with very good perception of hypoglycaemia and not experiencing severe hypoglycaemia (group B). Groups A and B were similar in terms of age, duration of diabetes, HbA1c level and degenerative complications. The glucagon levels were identical and non-reactive in the two groups. The basal levels and secretion peaks of adrenaline, noradrenaline, growth hormone and cortisol were similar between the two groups, but there was a significant delay in secretion in group A with a blood glucose threshold of adrenergic secretion of between 3.1 +/- 0.5 and 1.6 +/- 0.2 mmoles/l in group A and between 4.6 +/- 0.3 and 3.2 +/- 0.2 mmoles/l in group B (P less than 0.05). This delayed secretion could be explained by desensitisation of the hypothalamic glucostat and could be due to the frequency and/or severity of hypoglycaemic episodes.     

Repeated hypoglycemia and cognitive decline. A case report

OBJECTIVE: Diabetes mellitus has a high incidence in general population and goes by high morbidity by specific micro vascular pathology in the retina, renal glomerul and peripheral nerves. In type 1 DM, intensive therapy can prevent or delay the development of long-term complications associated with DM but hypoglycaemia especially severe hypoglycaemia defined, as a low blood glucose resulting in stupor, seizure, or unconsciousness that precludes self-treatment is a serious threat. Hypoglycaemia that may preferentially harm neurons in the medial temporal region, specifically the hippocampus, is a potential danger for the brain cognitive function which several studies failed to detect any significant effects, whereas others indicated an influence on it. A young diabetic case presented here with severe cognitive defect. Great number of severe hypoglycaemic or hyperglycaemic attacks and convulsion episodes were described in his medical history. RESULTS and CONCLUSION: Neuroradiologic findings on CT and MRI, pointed that global cerebral atrophy that is incompatible with his age. Brain perfusion studies (SPECT, (99m)Tc-labeled HMPAO) also showed that there were severe perfusion defects at superior temporal region and less perfusion defects at gyrus cingulum in frontal region. These regions are related with memory processing. Severe cognitive defect in this patient seems to be closely related these changes and no another reason was found to explain except the repeated severe hypoglycaemic episodes.     

Growth hormone,prolactin, and corticosteroid responses to insulin hypoglycaemia in alcoholics

Plasma growth hormone (GH), prolactin, and corticosteroid responses to insulin-induced hypoglycaemia were studied in 24 men with progressive alcoholism who had been abstinent for two to seven days. Ten normal healthy subjects (five men, five women) served as controls for comparing GH and prolactin responses, while cortisol responses were studied in a further six male controls. Blood samples were taken at intervals after an injection of soluble insulin (0·1 U/kg body weight). All patients developed adequate hypoglycaemia (blood glucose <2·2 mmol/l (<39·6 mg/100 ml)) and nine had impaired GH responses (peak concentration <10 mU/1). Prolactin concentrations fell or remained unchanged in nine patients, eight of whom also had impaired GH responses. In seven patients corticosteroid concentrations decreased from basal concentrations, and six of these patients had impaired GH responses. All three hormone responses were impaired in several patients, and significant correlations were found between the GH and prolactin responses at 45 and 60 minutes. GH response was not correlated with age, duration of drinking, duration of alcoholism, or admitted alcohol intake. GH responses were significantly lower in patients who had the most severe withdrawal symptoms. Our observations of impaired stress responses in some recently abstinent alcoholics may have important implications for the management of alcohol withdrawal syndrome.     

Single extra-amniotic injection of prostaglandin E2 in viscous gel to induce mid-trimester abortion.

In a preliminary study a single extra-amniotic injection of 1.5 mg of prostaglandin E-2 incorporated into an aqueous viscous gel was given to 24 patients aborted within 24 hours, and the mean induction-abortion interval (plus or minus S.E. of mean) was 13.5 plus or minus 1.5 hours. Vomiting occurred in seven patients, and transient severe uterine cramps, pallor, nausea, and shivering occurred in one patient immediately after injection. Complete abortion occurred in 20patients. A delay in the time taken to abort seemed to be associated with an immediate and rapid rise in uterine tone after the injection which required prompt analgesia; this probably reflected rapid decidual absorption and dissolution of the prostaglandins away from their site of action. The degree of distention of the catheter-retaining balloon did not influence abortion times.     

Myxedema coma of both primary and secondary origin, with non-classic presentation and extremely elevated creatine kinase.

Myxedema coma is a rare, often fatal endocrine emergency that concerns elderly patients with long-standing primary hypothyroidism; myxedema coma of central origin is exceedingly rare. Here, we report a 37-year-old woman in whom classical symptoms of hypothyroidism had been absent. Six years earlier, she had severe obstetric hemorrhage and, shortly after, two subsequent episodes of pericardial effusion. On the day of admission, pericardiocentesis was performed for the third episode of pericardial effusion. Because of the subsequent grave arrhythmias and unconsciousness, she was transferred to our ICU. Prior to the endocrine consultation, a silent myocardial infarction had been suspected, based on the extremely high serum levels of creatine kinase (CK) and isoenzyme CK-MB. However, based on thyroid sonography, pituitary computed tomography, elevated titers of antithyroid antibodies and pituitary stimulation tests, the final diagnosis was myxedema coma of dual origin: an atrophic variant of Hashimoto's thyroiditis and post-necrotic pituitary atrophy (Sheehan syndrome). Substitutive therapy caused a prompt clinical amelioration and normalization of CK levels. Our patient is the first case of myxedema coma of double etiology, and illustrates how its presentation deviates markedly from the one endocrinologists and physicians at ICU are prepared to encounter. In addition, cardiac problems as those of our patient should not discourage from substitutive treatment (using L-thyroxine and the gastrointestinal route of absorption), if the age is relatively low.