Respiratory measurements and airway clearance device prescription over one year in amyotrophic lateral sclerosis.

Objective: The rates of decline in respiratory measurements, including Peak Cough Flow (PCF) have not been established in Amyotrophic Lateral Sclerosis (ALS). Additionally, optimal prescription of cough adjuncts which aim to increase cough strength are unknown. The primary aim of this study was to quantify declines in respiratory function in ALS using PCF, Sniff Nasal Inspiratory Pressure (SNIP) and Slow Vital Capacity (SVC). Secondary aims were to measure respiratory morbidity, audit the characteristics of those prescribed cough adjuncts, and compare outcomes between treated and untreated cohorts. Methods: A prospective, longitudinal, observational, cohort study evaluated respiratory measures, morbidity, and physical function in ALS patients at three monthly intervals, over one year. Patient and disease characteristics of those prescribed cough adjuncts were profiled at the time of device prescription. Results: one hundred and eight participants with mean age 62.1 ± 11.5 years participated. PCF declined rapidly at a rate of 124.8L/min/year (p < 0.001). SNIP, SVC (%predicted), and ALSFRS-R also declined significantly at rates of 18.72cmH2O, 17.49%, and 9.62 units per year respectively (p < 0.001). Thirty-two (29.6%) patients reported 56 incidences of chest infection and 21 died. Patients prescribed a cough adjunct (44.4%) had significantly lower average PCF, SNIP, SVC percent predicted, and ALSFRS-R (p < 0.001). Conclusions: This study identified a rapid rate of decline in PCF, a similar decline in SNIP, and slower declines in SVC and ALSFRS-R. Cough adjunct prescription was triggered by declining respiratory measures and recommended PCF thresholds, but also by respiratory symptoms. Chest infections were common in patients regardless of cough adjunct prescription and should be closely monitored.

Diseases the doctor (or autoanalyser) says you have got.

Much of modern medical practice involves treating patients with asymptomatic conditions or risk factors which I call 'diseases the doctors says you've got'. These generally asymptomatic conditions, which are usually discovered by screening, include hypertension, hyperlipidaemia, many cases of type 2 diabetes and the post-menopausal state. My argument is that many doctors do not have the interest or inclination to follow such patients. However, persuading them to take their tablets or modify their diets or lifestyles is arguably more difficult than in the 'proper' diseases on which physicians spend most of their training. I suggest that the only way of doing this is to educate and enthuse the patients and find a way to make them as interesting as the cases of the rare diseases we all find so fascinating.

Euglycaemic hyperinsulinaemia does not affect gastric emptying in type I and type II diabetes mellitus.

Hyperglycaemia slows gastric emptying in both normal subjects and patients with diabetes mellitus. The mechanisms mediating this effect, particularly the potential role of insulin, are uncertain. Hyperinsulinaemia has been reported to slow gastric emptying in normal subjects during euglycaemia. The purpose of this study was to evaluate the effect of euglycaemic hyperinsulinaemia on gastric emptying in Type I (insulin-dependent) and Type II (noninsulin-dependent) diabetes mellitus. In six patients with uncomplicated Type I and eight patients with uncomplicated Type II diabetes mellitus, measurements of gastric emptying were done on 2 separate days. No patients had gastrointestinal symptoms or cardiovascular autonomic neuropathy. The insulin infusion rate was 40 mU x m(-2) x min(-1) on one day and 80 mU x m(-2) x min(-1) on the other. Gastric emptying and intragastric meal distribution were measured using a scintigraphic technique for 3 h after ingestion of a mixed solid/liquid meal and results compared with a range established in normal volunteers. In both Type I and Type II patients the serum insulin concentration had no effect on gastric emptying or intragastric meal distribution of solids or liquids. When gastric emptying during insulin infusion rates of 40 mU x m(-2) x min(-1) and 80 mU x m(-2) x min(-1) were compared the solid T50 was 137.8+/-24.6 min vs. 128.7+/-24.3 min and liquid T50 was 36.7+/-19.4 min vs. 40.4+/-15.7 min in the Type I patients; the solid T50 was 94.9+/-19.1 vs. 86.1+/-10.7 min and liquid T50 was 21.8+/-6.9 min vs. 21.8+/-5.9 min in the Type II patients. We conclude that hyperinsulinaemia during euglycaemia has no notable effect on gastric emptying in patients with uncomplicated Type I and Type II diabetes; any effect of insulin on gastric emptying in patients with diabetes is likely to be minimal.

A paper which changed clinical practice (slowly). Jacob Holler on potassium deficiency in diabetic acidosis (1946).

It is often said that the introduction of insulin into clinical medicine made a 'dramatic' difference to the mortality resulting from diabetic coma. This is true in the sense that before 1922 it was almost uniformly fatal, but until the 1950s the mortality in many large hospitals was as high as 30-50%. Often autopsy did not establish a cause of death. Many may have been a result of hypokalaemia, a complication which was not recognized until 1946; in that year in the Journal of the American Medical Association, Jacob Holler described a patient who developed respiratory paralysis 12h into treatment that, after several hours in an iron lung, was cured by potassium infusion. In the 5 years after Holler's paper there were many reports of deaths resulting from hypokalaemia, as well as several 'near misses', but clinicians were extremely cautious about early replacement probably, as an editorialist in The Lancet suggested, because 'the frightening effects of intravenous injections of potassium made clinicians reluctant to believe in a lack of potassium as a cause of trouble, except in very rare conditions such as familial periodic paralysis'. It had been known since 1923 that insulin lowered serum potassium, but this was not of great interest because the symptoms of hypokalaemia were not known. Also, potassium was not an electrolyte with which clinicians were familiar. Until the introduction of flame photometry in 1950, it was only measured in research studies as chemical methods took several hours to complete.

The effect of single doses of pramlintide on gastric emptying of two meals in men with IDDM.

In a previous study we have shown that an intravenous infusion of pramlintide (an analogue of human amylin) delayed gastric emptying, but the dose of pramlintide was supraphysiological in relation to the amylin response to food in non-diabetic subjects. The purpose of this study was to examine the dose response relationship of subcutaneous injections of pramlintide on gastric emptying and to determine whether administration of the drug before one meal has an impact on the subsequent meal. Eleven men with insulin-dependent diabetes mellitus were studied in a double-blind, randomised, four-way crossover design. None had autonomic neuropathy. Euglycaemia was maintained overnight before the study day. At -30 min the patients self-injected their usual morning insulin and at -15 min they injected the study drug (either placebo or 30, 60 or 90 microg pramlintide) subcutaneously. At 0 min they ate a standard meal consisting of a pancake, labelled with 99mTc, and a milkshake containing 3-ortho-methylglucose (3-OMG). Gastric emptying images were obtained for the next 8 h. At 240 min the subjects ate a similar meal, but on this occasion the pancake was labelled with (111)In. All three doses of pramlintide delayed emptying of the solid component of the first meal (p < 0.004) with no significant difference between the drug doses. There were no differences between placebo and pramlintide after the second meal. All three doses of pramlintide resulted in a prolongation in the time to peak plasma 3-OMG level (p < 0.0001) after the first meal but there was no difference after the second meal.

Effect of euglycaemic hyperinsulinaemia on gastric emptying and gastrointestinal hormone responses in normal subjects.

Several studies have shown that hyperglycaemia slows gastric emptying in normal subjects and patients with diabetes mellitus but whether hyperinsulinaemia per se has an effect remains debatable. In the present study we have assessed the effect of hyperinsulinaemia on gastric emptying of a solid and liquid meal in normal subjects. Ten men were studied three times in random order. After an overnight fast, subjects were infused with 0.9% NaCl on two occasions and on the third with insulin, at 40 mU x m(-2) x min(-1) with 20% glucose simultaneously to maintain euglycaemia. Steady-state glucose infusion rate was ensured before the subjects ate a standard meal of a pancake labelled with 99mTc and milkshake labelled with (111)In-DTPA. Gamma-scintigraphic images were then obtained every 20 min for the next 3 h. There were no significant differences between the mean half-emptying times (T50) of the solid and liquid during the two saline infusions (129.6 +/- 28.5 vs 128.4 +/- 23.8 min for the solid and 25.4 +/- 7.0 vs 34.7 +/- 18.0 min for the liquid, mean +/- SD). Hyperinsulinaemia delayed both solid (mean T50 149.6 +/- 30.7, p = 0.031) and liquid emptying (mean T50 39.8 +/- 13.9, p = 0.042). There were no significant differences in the cholecystokinin and glucagon-like peptide 1 responses to the meal during either saline or insulin infusions. There was a tendency towards a greater insulin response to the meal during the hyperinsulinaemic study. Thus, hyperinsulinaemia delayed emptying of both the solid and liquid components of the meal.

Intravenous lactate prevents cerebral dysfunction during hypoglycaemia in insulin-dependent diabetes mellitus.

1. Intravenous lactate prevents cerebral dysfunction during hypoglycaemia in healthy volunteers. This study examines whether this also occurs in insulin-dependent diabetes. Changes in four-choice reaction time, auditory brain stem response, and P300 latency were used as measures of cerebral function. 2. Ten subjects were studied twice at least 4 weeks apart. Blood glucose was maintained between 5 and 8 mmol/l for 1 h before starting a 60 m-unit min-1 m-2 stepped hyperinsulinaemic clamp, achieving blood glucose concentrations of 4.5, 3.3 and 2.5 mmol/l. At one visit, 40 mumol min-1 kg-1 sodium lactate was infused, and at the other, normal saline. Cerebral function was measured at each blood glucose concentration. 3. Blood lactate rose to 3.32 +/- 0.06 mmol/l during lactate infusion compared with 0.9 +/- 0.03 mmol/l during saline infusion. Compared with the results at 4.5 mmol/l there were no significant changes at 3.3 mmol/l in any measure of cerebral function at either visit. At 2.5 mmol/l a significant increase in reaction time and P300 latency occurred with saline [mean change 33.1 +/- 8.6 ms (P < 0.01) and 30.1 +/- 9.2 ms (P < 0.01) respectively] but not lactate [mean change -5.9 +/- 3.7 ms (P > 0.05) and -6 +/- 7.6 ms (P > 0.05) respectively]. No significant changes occurred in auditory brain stem response. The catecholamine response to hypoglycaemia was attenuated by lactate (P < 0.05 for adrenaline and noradrenaline). 4. Thus intravenous lactate prevents cerebral dysfunction during hypoglycaemia in insulin-dependent diabetes.

Well-being, cerebral function, and physical fatigue after nocturnal hypoglycemia in IDDM.

OBJECTIVE: This study assessed the effect of nocturnal hypoglycemia on well-being cerebral function, and physical fatigue the next day in 10 subjects with IDDM. RESEARCH DESIGN AND METHODS: After an exercise test to determine work-loads corresponding to 30 and 60% VO2max, volunteers were studied twice, 4 weeks apart. Blood glucose was lowered one night to 2.3-2.7 mmol/l for 1 h, and at the control visit, hypoglycemia was avoided. The next morning, well-being was assessed using the minor symptom evaluation profile (MSEP), and cerebral function was assessed with the paced auditory serial addition test, the digit symbol substitution test, trail making part B, four-choice reaction time, and auditory P300 latency. Subjects then exercised at predetermined workloads corresponding to 30% VO2max for 30 min and 60% VO2max until exhaustion. Fatigue was assessed every 10 min using the Borg scale for rating of perceived exertion. RESULTS: All three components of the MSEP scored higher (indicating more symptoms) after the hypoglycemic night compared with the control night (P < 0.01 contentment, sleep; P < 0.001 vitality). None of the cerebral function tests performed the next day was affected by hypoglycemia. Exercise capacity was similar at both visits, but subjects were more fatigued after the hypoglycemic night (P < 0.01, analysis of variance). There were no differences in potassium, catecholamine, glucose, or lactate concentrations between visits either before or during exercise. CONCLUSIONS: One hour of hypoglycemia at night affects a subject's sense of well-being, but not cerebral function, the next day. The greater fatigue after the hypoglycemic night cannot be explained by the biochemical parameters measured.

Maturity-onset diabetes of the young: a clinical history.

A mild form of diabetes in young people was recognized in the pre-insulin era but was forgotten, probably because of Joslin's dictum that all young people with diabetes should have insulin as a safeguard against complications. After the introduction of sulphonylureas in the 1950s it was found, most notably by Fajans and Conn at the University of Michigan, that tolbutamide could improve or normalize carbohydrate tolerance in some young non-obese mildly diabetic patients. These experiments were not primarily of genetic interest because diabetes was regarded as homogeneous with young and old patients forming part of the same continuum. The question was whether treatment could prevent young subjects with mild diabetes progressing to a total loss of insulin reserve. By 1973, Fajans had shown that the carbohydrate intolerance of 45 patients diagnosed under age 25 had not progressed after up to 16 years on sulphonylureas. Nearly all (43 out of 45) these subjects had a first degree relative with diabetes. In 1974, under the title 'Mild familial diabetes with dominant inheritance' Tattersall described three families in which diabetes, although diagnosed in adolescence, could be treated with sulphonylureas over 40 years later and was dominantly inherited. Collaboration between Fajans and Tattersall established that 'chemical' diabetes in Michigan was also predominantly inherited and distinct from classical 'juvenile-onset' diabetes. In Paris in 1973 Lestradet also described a non-insulin-dependent form of childhood diabetes and later established that it was dominantly inherited. In 1974, Tattersall and Fajans coined the acronym MODY which was defined as 'fasting hyperglycaemia diagnosed under age 25 which could be treated without insulin for more than two years'.

Frederick Pavy (1829-1911) and his opposition to the glycogenic theory of Claude Bernard.

For more than 50 years the Guy's Hospital physician Frederick Pavy (1829-1911) attempted to discredit the theory of his erstwhile teacher, Claude Bernard, that liver glycogen was broken down to supply sugar to the systemic circulation. His opposition was driven by his clinical perceptions and was based on two assumptions: the first was that the kidney was a simple filter through which small molecules would diffuse, so that sugar had to be prevented from reaching the systemic circulation. For Pavy, the liver was the barrier. The second was teleological: he could not believe that nature would operate in what he saw as a defective way, i.e. converting sugar into glycogen and then back again. At the beginning of his long working life Pavy regarded himself as a physiologist and was critical of the stagnancy of English physiology which was kept afloat by amateurs like himself in whatever time they could spare from busy private practice. At the end he came to see his own view of carbohydrate metabolism as symbolic of the schism between responsible clinicians (himself) and irresponsible daydreaming physiologists (his opponents).

Brittle diabetes revisited: the Third Arnold Bloom Memorial Lecture.

In 1934 the Chicago physician R.T. Woodyatt suggested that 'The history of diabetes has been marked by recurrence of certain ideas which decline and disappear; only to go through a similar cycle again in an altered form in a new generation'. This has been particularly true of the concept of brittle diabetes which Woodyatt himself introduced in the 1930s. He never wrote a paper on the subject but contemporaries understood it to refer to excessive fluctuations of blood sugar which could not be explained by patient or physician errors; the cardinal feature was unpredictability and unexpected hypoglycaemic reactions. Also in the 1930s, practitioners of the newly formed psychosomatic movement took an interest in the effect of emotional factors on the course of diabetes and, in particular, patients who were 'difficult' or 'refractory'. What marked 'difficult' patients was that they did not follow their doctor's instructions or had recurrent diabetic ketoacidosis. By the 1950s the question was whether there were two distinct groups of patients; one whose lability could be cured by adjusting insulin, diet, and exercise, and another whose lability had an emotional origin. Did proponents of the organic school have patients (unreported) in whom lability had an obvious emotional cause or, conversely, were the psychosocial problems which the psychiatrists unearthed a consequence rather than a cause of the instability? My experience with a patient with factitious hypoglycaemia which remained undetected for weeks in a clinical research unit suggested that neither close observation nor screening by a psychiatrist could rule out factitious disease. Therefore in 1977 I suggested that the definition of brittle diabetes should be a patient whose life was 'constantly disrupted by episodes of hypo- or hyperglycaemia, whatever their cause'. This was widely accepted and there was a subtle shift towards regarding brittle diabetes as synonymous with recurrent ketoacidosis. In the 1980s two English and one American group investigated large series of such patients, using new methods to try to uncover a biochemical basis such as defective insulin absorption, accelerated degradation at insulin injection sites, and inappropriate secretion of various counterregulatory hormones. Most of these patients were young overweight women and the eventual conclusion was that in most the instability was self-induced. In the 1980s recurrent, often warningless, hypoglycaemia was recognized as a problem in its own right but in this new generation was reborn as a problem of insulin pharmacokinetics as Woodyatt originally conceived it.

Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM.

Pramlintide, a human amylin analogue, reduces hyperglycaemia after meals in patients with insulin-dependent diabetes mellitus (IDDM). We investigated whether this was due to delayed gastric emptying. Eight men with uncomplicated IDDM were studied twice in a randomised, double-blind crossover design. Euglycaemia was maintained overnight by intravenous infusion of glucose and/or insulin and the following morning a 5-h infusion of pramlintide 25 micrograms/h or placebo was started at 08.00 hours. At 08.30 hours the patients injected their normal morning insulin dose subcutaneously and 30 min later ate a meal (600 kcal, 50% carbohydrate) of which the solid component was labelled with Technetium-99 m and the liquid with Indium-111 to quantify gastric emptying. Gamma-scintigraphic images were obtained every 20 min for the next 4 h. Insulin and glucose were infused as necessary to maintain blood glucose levels within 3 mmol/l of the pre-meal value. Compared to placebo, pramlintide significantly delayed emptying of both liquid (median lag time 69 vs 7.5 min) and solid (median lag time 150 vs 44.5 min) components of the meal. Pramlintide delayed gastric emptying so much that t50 values could not be calculated for solid or liquid. Amylin agonists such as pramlintide may, therefore, be of value in improving glycaemic control in IDDM by modifying gastric emptying.

The effect of intravenous lactate on cerebral function during hypoglycaemia.

Any factor which protects the brain against hypoglycaemia induced cerebral dysfunction could have important therapeutic implications for intensive insulin therapy. This study tested the hypothesis that intravenous lactate protects cerebral function during hypoglycaemia. Four choice reaction time, Auditory Brain Stem Response (ABR), and P300 latency were used as measures of cerebral function. Nine healthy volunteers (six female) underwent two stepped hyperinsulinaemic clamps at least 4 weeks apart, achieving blood glucose levels of 4.5, 3.3, and 2.5 mmol l-1. On one occasion 40 mumol kg-1 min-1 sodium lactate was infused, and on the other, normal saline. Cerebral function tests were measured at each glucose level. At 3.3 mmol l-1, there was a significant slowing of four choice reaction time with saline (p < 0.02) but not with lactate; no changes in P300 latency or ABR occurred on either occasion. At 2.5 mmol l-1 results from all three tests deteriorated significantly during saline infusion (p < 0.001 reaction time, p < 0.02 ABR and p < 0.05 P300), but not lactate. Lactate infusion was associated with a reduction in noradrenaline (p < 0.05), adrenaline (p < 0.05), and growth hormone (p < 0.02) responses at a glucose of 2.5 mmol l-1. These results support the hypothesis that intravenous lactate protects cerebral function during hypoglycaemia.