Are arterial and venous samples clinically equivalent for the estimation of pH, serum bicarbonate and potassium concentration in critically ill patients?

AIMS: To assess the comparability of venous and arterial samples for pH, bicarbonate and potassium measurements in critically ill patients. METHODS: Simultaneous arterial and venous samples from 206 critically ill patients were analysed in duplicate. Coefficients of variation and 95% limits of agreement were calculated for arterial and venous samples. Bland-Altman plots were constructed to assess agreement between sampling sites. RESULTS: The median (range) of arterial pH, bicarbonate concentrations, potassium concentrations and glucose concentrations were 7.40 (7.01-7.56), 25 (9-41) mmol/l, 4.2 (3.1-6.8) mmol/l and 7.4 (3.0-13.5) mmol/l, respectively. Coefficients of variation for arterial and venous pH were both 0.1%, with bias (95% limits of agreement) of -0.01 (-0.03 to 0.01) for arterial and -0.01 (-0.02 to 0.01) for venous samples. The bias (95% limits of agreement) between arterial and venous samples was 0.03 (-0.02 to 0.08). Coefficients of variation for arterial and venous bicarbonate results were 0.8 and 0.7%, respectively, with bias (95% limits of agreement) of 0 (-0.5 to 0.5) mmol/l for both sample types. The bias (95% limits of agreement) between venous and arterial samples was 0 (-1.3 to 1.3) mmol/l. Coefficients of variation for arterial and venous potassium samples were 0.8 and 1.1%, respectively, with bias (95% limits of agreement) of 0 (-0.1 to 0.1) for both sample types. The bias (95% limits of agreement) between venous and arterial samples was 0.1 (-0.4 to 0.6) mmol/l. CONCLUSIONS: A venous blood sample, analysed on a blood gas machine, is sufficiently reliable to assess pH, bicarbonate and potassium concentrations in critically ill patients, suggesting that venous sampling alone is appropriate in the management of diabetic ketoacidosis.

An account of the quality of life of patients after treatment for non-functioning pituitary tumours.

OBJECTIVE: Studies assessing quality of life in GH-deficient adults have shown varying results. This may be due to a number of factors including varying causes of GH deficiency, the use of radiotherapy in treatment and patient selection. We aimed to assess whether anterior pituitary hormone deficiency or external pituitary radiotherapy influenced the quality of life of patients with non-functioning pituitary tumours. PATIENTS: We studied 48 patients treated and under follow-up for non-functioning pituitary tumours on standard hormone replacement therapy excluding GH. There were 21 females and 27 males with a mean age of 59 +/- 12 years. We also studied 42 control patients who had undergone mastoid surgery and were followed at least annually. There were 17 females and 25 males with a mean age of 61 +/- 14 years. DESIGN: All patients attended a research clinic and completed the Short Form 36 (SF36) and General Well Being Schedule (GWBS) to assess quality of life. Thyroid function tests, IGF1 and IGFBP3 were measured on all patients. Gonadotrophin and cortisol measurements were made on the patients with pituitary disease where appropriate. RESULTS: IGF1 and IGFBP3 levels were lower in the pituitary patients compared with controls: 104 +/- 98 vs 143 +/- 37 micrograms.l (P < 0.0001) and 2.9 +/- 0.75 vs 3.3 +/- 0.52 mg/l (P < 0.004). There were no significant differences in the quality of life scores between the pituitary patients and the control subjects. There was also no difference in quality of life between pituitary patients with two or more hormone deficiencies (n = 29) compared with controls. Patients who had received radiotherapy (n = 18), when compared with controls, had a decreased mental health score using the SF36 71 +/- 21 vs 81 +/- 17 (P < 0.05) and decreased total GWBS score 70 +/- 20 vs 82 +/- 17 (P < 0.05). Subscore analysis of GWBS showed this to be due to depression and decreased control of emotions. CONCLUSIONS: We found that the quality of life of patients treated and under follow up for non-functioning pituitary tumours was similar to that of patients treated by mastoid surgery and under similar follow up. The pituitary patients deficient in two hormones and thus most likely to be GH deficient were also similar to the controls. These results suggest that adding GH replacement in this patient group may not be routinely indicated for improvement in quality of life and needs careful assessment. Patients who had received radiotherapy were more depressed and anxious than controls. Further investigation into the psychological and psychomotor effects of radiotherapy in this group of patients is required.

UKPDS 21: low prevalence of the mitochondrial transfer RNA gene (tRNA(Leu(UUR))) mutation at position 3243bp in UK Caucasian type 2 diabetic patients.

Some patients with Type 2 (non-insulin-dependent) diabetes mellitus possess a mitochondrial mutation in the tRNA(Leu(UUR)) gene at position 3243 bp. These subjects show a maternal mode of inheritance and often have hearing defects. In French and Japanese populations, this mutation may be present in 1-3% of subjects with a family history of diabetes. We assessed the prevalence of this mutation in newly diagnosed diabetic subjects in the UK white Caucasian population. The 3243 bp mutation was not detected in 500 randomly selected Type 2 diabetic subjects, 50 gestational diabetic subjects, and members of a MODY pedigree. Two of 748 (0.27%) Type 2 diabetic subjects with a family history of diabetes were found to possess the mutation. These subjects had an early age of diagnosis (M 38 years; F 36 years) and were non-obese. The male patient showed evidence of markedly impaired beta-cell function and deafness, while the female was not deaf, had approximately 50% of normal pancreatic function and responded well to diet. The mutation in the tRNA(Leu(UUR)) gene probably occurs in only approximately 0.1-0.2% of white Caucasian Type 2 diabetic patients in the UK.

The Fasting Hyperglycaemia Study: I. Subject identification and recruitment for a non-insulin-dependent diabetes prevention trial.

Subjects at increased risk for developing non-insulin-dependent diabetes mellitus (NIDDM) were encouraged via a public awareness campaign, general practitioners, or a direct approach (in the case of women with previous gestational diabetes) to attend one of three English and two French centers for fasting plasma glucose (FPG) measurement. Of 1,580 subjects (mean +/- SD age, 47 +/- 10 years), 29% were male, 56% had a diabetic relative, 20% had a history of elevated blood glucose or glycosuria, and 9% previously had gestational diabetes. Thirty-one percent (493) had an initial increased fasting glucose ([IFG] 5.5 to 7.7 mmol.L-1), 3% (41) a diabetic fasting glucose ([DFG] > or = 7.8 mmol.L-1), and 66% (1,046) a normal fasting glucose ([NFG] < 5.5 mmol.L-1). Four hundred forty-one of the 493 returned for a second FPG measurement, and 67% (293) of these had a similar value on repeat testing 2 weeks later. A 75-g, 2-hour oral glucose tolerance test (OGTT) in 223 of these subjects showed that 37% (83) had impaired glucose tolerance (IGT), 26% (58) diabetes mellitus (DM), and 37% (82) normal glucose tolerance (NGT). Seven percent of self-referred patients had NIDDM by World Health Organization (WHO) criteria. Eighty-eight percent of those with an initial DFG had an increased glycated hemoglobin (> 6.2%), and 75% an increased fructosamine (> 282 mumol.L-1). While these two glycemic measures provided good discrimination for diabetes, neither were reliable in detecting those with increased but not diabetic FPG values. In conclusion, 293 (19%) of 1,580 self-referred subjects were identified as having persistently increased FPG, and 227 have been entered into a randomized NIDDM prevention trial evaluating healthy-living advice and sulfonylurea therapy.

The Fasting Hyperglycaemia Study: II. Randomized controlled trial of reinforced healthy-living advice in subjects with increased but not diabetic fasting plasma glucose.

Self-referred subjects (N = 227) thought to be at risk of developing non-insulin-dependent diabetes mellitus (NIDDM) and with fasting plasma glucose (FPG) in the range of 5.5 to 7.7 mmol.L-1 on two consecutive tests 2 weeks apart were randomized to reinforced or basic healthy-living advice. They were simultaneously allocated either to a sulfonylurea group or a control group in a two-by-two factorial design. A total of 201 subjects in three English and two French centers completed 1 year's follow-up study. Reinforced advice recommending dietary modification and increased exercise was given every 3 months, and basic advice was given once at the initial visit. Glycemia was monitored by FPG, dietary compliance by body weight and food diaries, and fitness compliance by bicycle ergometer assessment and exercise diaries. Both reinforced and basic advice groups had a significant mean reduction in body weight (1.5 kg) at 3 months, although the weight subsequently returned to baseline. After 1 year, subjects allocated to reinforced advice versus basic advice (1) reported a lower fat intake (34.1% v 35.8%, P = .04) with no difference in lipid profiles, (2) had improved fitness as shown by increased calculated maximal oxygen uptake ([Vo2max] 2.39 v 2.18 L.min-1, P = .007) with no change in insulin sensitivity, (3) showed no change in FPG, glucose tolerance, or hemoglobin A1c (HbA1c), and (4) showed a greater tendency to withdraw from the study (16% v 7%, P = .03). In conclusion, reinforced healthy-living advice given to self-referred subjects with increased FPG did not encourage sufficiently pronounced life-style changes for significantly greater effects on body weight and glycemia in a 1-year study than basic healthy-living advice.

The Fasting Hyperglycaemia Study: III. Randomized controlled trial of sulfonylurea therapy in subjects with increased but not diabetic fasting plasma glucose.

Self-referred subjects (N = 227) thought to be at increased risk of developing diabetes who had fasting plasma glucose (FPG) values in the range of 5.5 to 7.7 mmol.L-1 on two consecutive occasions 2 weeks apart were randomized to sulfonylurea therapy (gliclazide, < or = 160 mg.d-1) or to a control group allocated either to double-blind placebo or to no tablets. Subjects were randomly allocated also to reinforced or basic healthy-living advice in a factorial design. A total of 201 subjects have been evaluated for 1 year in three English and two French hospital outpatient centers. Those allocated to sulfonylurea had a significant (P < .001) reduction in median FPG compared with the control group (6.0 mmol.L-1 to 5.6 mmol.L-1, P < .001, v 6.0 mmol.L-1 to 6.0 mmol.L-1, NS). Median hemoglobin A1c (HbA1c) also improved (P < .0002; 5.8% to 5.6%, P < .001, v 5.7% to 5.6%, NS), as did mean beta-cell function (62% to 70%, P < .01, v 62% to 61%, NS). Mean body weight was unchanged in subjects allocated to sulfonylurea (81.7 kg to 82.4 kg, NS), but decreased in the control group (81.6 kg to 80.4 kg, P < .01). More subjects in the sulfonylurea group versus the control group reported one or more minor symptoms of hypoglycemia over 1 year (50% v 24%, P < .0001). Only two subjects reported major hypoglycemic episodes requiring assistance, both of whom were taking sulfonylurea. Insulin sensitivity did not change between groups. Sulfonylurea therapy with gliclazide improved glycemic control and beta-cell function significantly in subjects with increased but not diabetic FPG levels. The study is being extended to determine whether sulfonylurea therapy prevents progression to non-insulin-dependent diabetes mellitus (NIDDM).

High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population.

A high proportion of the female patients who are members of maturity onset diabetes of the young (MODY) pedigrees, and whose diabetes mellitus is due to a glucokinase mutation, originally presented with gestational diabetes. To establish whether glucokinase mutations could be a common cause of gestational diabetes, we studied 50 subjects who presented with gestational diabetes and on follow-up had hyperglycaemia (5.5-10.0 mmol/l). Screening for glucokinase mutations using single-stranded conformational polymorphism (SSCP) analysis detected a missense mutation at position 299 (Gly299-->Arg) in three subjects. As two pedigrees in the Oxford area had the same glucokinase mutation, we suspected the role of a founder-effect, and carried out pedigree extension, haplotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area. One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects with the mutation were found to have the Z + 4/2 (GCK1/ GCK2) haplotype, suggesting that the observed high prevalence of the Gly299-->Arg glucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglycaemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which remains undetected unless pregnancy occurs.

Prevalence of diabetes mellitus and impaired glucose tolerance in parents of women with gestational diabetes.

Nuclear families of non-insulin-dependent diabetic (NIDDM) patients are uncommon, as usually one or both parents have died. In order to aid identification of complete nuclear families, we have ascertained the disease process at a younger age by studying subjects with previous gestational diabetes. One hundred women who had had gestational diabetes, age (+/- SD) 38 (6) years, were screened by fasting plasma glucose (fpg). Sixty-one were found to have either fasting hyperglycaemia (5.5 < or = fpg < 7.8 mmol/l) or diabetes. Of these women 35 had both parents alive and the parents of 14 of these women agreed to the assessment of their metabolism by a continuous infusion of glucose with model assessment (CIGMA). Seven probands had impaired glucose tolerance (IGT) and seven were diabetic. They were age 35 (4) years and had body mass index (BMI) 26 (5) kg/m2. The parents were aged 62 (6) years and had BMI 29 (6) kg/m2 and their affection status was defined as presence of glucose intolerance (fpg or post-infusion achieved plasma glucose level > 2 SD of an age and obesity matched population). In the 14 families, five probands (36%) had neither parent affected, six (43%) had one parent affected and three (21%) had both parents affected. Only three probands had a parent with diabetes as defined by World Health Organisation criteria. We conclude that the study of women who have had gestational diabetes allows detection of probands with diabetes or impared glucose tolerance, who have both parents available for study.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced microvascular hyperaemia in subjects at risk of developing type 2 (non-insulin-dependent) diabetes mellitus.

Abnormalities of microvascular function may be important in the pathogenesis of diabetic microangiopathy. As such changes are already present at diagnosis in patients with Type 2 (non-insulin-dependent) diabetes mellitus, subjects at risk of developing the disease, who had elevated fasting plasma glucose concentrations below the diabetic range, were studied. The maximal microvascular hyperaemic response to local heating was determined in the feet of 11 subjects with fasting hyperglycaemia and 11 age- and sex-matched control subjects. There was reduced maximal hyperaemia in the subjects with fasting hyperglycaemia (1.01 [0.71-1.57]V, median and range), when compared to control subjects (1.41 [1.32-2.13]V, p < 0.001). It is unlikely that this limited vasodilation is a result of the mild degree of hyperglycaemia observed in the subjects included in this study. Further studies are therefore required to address the possible mechanisms of limited microvascular reactivity in subjects at risk of developing Type 2 diabetes.

Hyperglycaemic progression in subjects with impaired glucose tolerance: association with decline in beta cell function.

Impaired glucose tolerance is associated with an increased risk of Type 2 diabetes. This prospective cohort study has examined the variables associated with hyperglycaemic progression in order to elucidate the aetiology of this deterioration. The 5 mg glucose.kg ideal body weight.min-1 continuous infusion of glucose with model assessment (CIGMA) test was used to quantitate glucose tolerance, beta cell function, and insulin sensitivity. Twenty-two Caucasian subjects who had impaired glucose tolerance identified on two separate tests underwent repeat testing after a median period of 24 months. At follow-up, 2 of the 22 subjects (9%) had Type 2 diabetes, 18 (82%) had impaired glucose tolerance, and 2 (9%) were normoglycaemic. The fasting and achieved (60-min) glucose levels were significantly higher at follow-up (mean +/- SD) (5.7 +/- 0.8 vs 5.5 +/- 0.5 mmol l-1, p = 0.029 and 10.0 +/- 0.9 vs 9.6 +/- 0.6 mmol l-1, p = 0.021, respectively), and beta cell function was significantly lower (median and interquartile range): 75% (50-93%) vs 90% (70-135%), p = 0.009. The changes in fasting plasma glucose were found to correlate with change in body mass index (rs = 0.46, p = 0.03). We conclude that impaired glucose tolerance is associated with decline in beta cell function, and denotes substantial risk of hyperglycaemic progression. Randomized controlled trials are warranted to determine whether exercise programmes, dietary advice, and attentive follow-up and effective preventive strategies for subjects with impaired glucose tolerance.

What happens to defaulters from a diabetic clinic?

The annual rate at which patients defaulted from follow up at the Wolverhampton diabetic clinic between 1971 and 1981 was 4.1% overall and 3.5% in white patients. In 1982 a study was started to discover what happened to white patients, born after 1919, who defaulted from the hospital clinic. There were 162 defaulters, of whom 19 had died. Of the remaining 143 patients, 19 were attending another hospital diabetic clinic, 22 had moved out of the area, and 28 refused to participate in the study. Seventy four agreed to participate: 39 were treated with diet, 15 with oral hypoglycaemic agents, and 20 with insulin. They were matched for sex, age, treatment, and duration of diabetes with patients attending the clinic. Non-insulin dependent defaulters were significantly more overweight at diagnosis (40% v 25%; p less than 0.05) and remained more obese. They developed significantly higher diastolic blood pressure (94 v 86 mm Hg; p less than 0.02) and higher haemoglobin A1 (HbA1) concentrations (11.7% v 8.4%; p less than 0.01). They had significantly more neuropathy at reassessment (15 v 6 out of 54; p less than 0.05) and a greater incidence of new retinopathy (p less than 0.02), which correlated with their higher diastolic blood pressures (p less than 0.01) and HbA1 concentration (p less than 0.02). In defaulters who were treated with insulin only the prevalence of neuropathy was significantly different from that in controls (p less than 0.05). Defaulters received minimal medical supervision and suffered greater morbidity than regular attenders at the clinic.