Dan K. Seilheimer

Insulin resistance is associated with decreased clinical status in cystic fibrosis

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patients was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m2 per minute). Results from the 120 mU/m2 per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 +/- 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 +/- 1.1, patients with CF = 10.2 +/- 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance (r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes.

Proteolysis Associated With Insulin Resistance in Cystic Fibrosis

Objective. We hypothesized that patients with cystic fibrosis (CF) have higher rates of protein breakdown than normal volunteers and that the infusion of insulin would result in less suppression of proteolysis. Methods. Using [1-13C]leucine and a three-step hyperinsulinemic euglycemic clamp, we measured rates of leucine appearance in 29 adult CF patients and 18 matched-control volunteers. The CF patients were characterized by oral glucose tolerance testing and clinical status scoring. Results. The CF patients had significantly increased proteolysis when compared with that of controls (CF, 123 ± 28 μmol/kg/h; controls, 71 ± 15 μmol/kg/h) and rates of proteolysis were significantly different between CF patients with impaired glucose tolerance and diabetes and those CF patients with normal glucose tolerance. Suppression of proteolysis by insulin was less in all CF subgroups than in the controls at peripheral insulin levels of 16 and 29 μU/mL. At peripheral insulin levels of 100 μU/mL, there was no difference in insulin suppression of proteolysis between CF patients and controls. Importantly, basal rates of proteolysis had an inverse relationship with clinical status in CF patients (r = −.76). Conclusions. Our findings indicate that proteolysis is higher in adult CF patients than in controls and that CF patients exhibit resistance to the anabolic effects of insulin on proteolysis. Most significantly, our findings indicate that basal rates of proteolysis inversely correlate with clinical status in CF.

Toxicity of Colistin in Cystic Fibrosis Patients

Pulmonary exacerbations of cystic fibrosis associated with strains of Pseudomonas aeruginosa that are resistant to multiple antibiotics are becoming increasingly common. The search for treatment alternatives continues and may include the reexamination of older antibiotics. Colistin sulfate is a polypeptide antibiotic with good activity against P. aeruginosa. Although its use was largely discontinued in the early 1970s because of reports of frequent renal and neurologic toxicity, intravenous colistin is often prescribed at our institution for patients with P. aeruginosa resistant to multiple-drug therapy. We prospectively monitored 19 patients during 21 courses of colistin therapy to identify the character and incidence of this agents toxicity. Only one case of renal toxicity occurred. Six cases of neurotoxicity occurred, which were characterized by perioral paresthesia, ataxia, or both. The rate of intolerable renal adverse effects secondary to colistin therapy was appreciably lower among these patients than that reported previously for other patients. It appears that intravenous colistin can be considered for cystic fibrosis patients with strains of P. aeruginosa that are resistant to more commonly used antibiotics.

Development of a Health Education Program to Promote the Self-Management of Cystic Fibrosis

The creative challenge of health education for chronic illnesses is the translation of theory-based intervention methods into practical strategies that can be organized into a logical series of learning activities to influence changes in environmental, cognitive, or behavioral factors. A case example describing the development and implementation of a comprehensive health-education intervention for the self-management of cystic fibrosis (CF) is presented. The design of intervention strategies began with an assessment of the educational needs for self-management of CF, followed by specification and validation of particular self-management behaviors. Behavioral and learning objectives then were formulated for each of the self-management behaviors. Constructs from social learning theory considered to be important influences on specified self-management behaviors in CF were identified. Taking into consideration the learning needs of the target population and the practical constraints of the system for providing health care, various intervention methods then were devised based on social learning theory. Lastly, the intervention methods chosen were translated into strategies organized into a series of practical learning activities for CF patients and their families. The process described here should prove useful to others who are planning and developing comprehensive health education programs for self-management of chronic illnesses.

The development of psychiatric symptomatology in patients with cystic fibrosis

Psychiatric symptomatology was compared in 61 cystic fibrosis patients, ages 8 to 15 years, and 36 cystic fibrosis patients, ages 16 to 40 years. When the prevalence of psychiatric symptomatology was compared in the two groups, a developmental pattern emerged: Symptoms of depression and anxiety were more frequent in the older group, while symptoms associated with eating disorders were more frequent in the younger group. Although duration of illness was longer and severity of illness was greater in the older group, these factors were largely unrelated to psychiatric symptomatology in either group. It is hypothesized that younger patients may express psychological distress through less direct means than older patients.

Complications of gastroesophageal reflux in patients with cystic fibrosis.

Seven patients with cystic fibrosis who had complications of gastroesophageal reflux including abdominal pain, peptic esophagitis, upper gastrointestinal hemorrhage, and esophageal stricture are described. We believe that these are gastrointestinal complications of CF and that they may be responsible for significant morbidity. The mechanical influence of a depressed diaphragm caused by hyperinflation, along with increased abdominal pressure with chronic coughing, may contribute to GER in CF. Early detection and treatment are important not only to prevent esophageal complications but also to increase the quality of life by relief of pain and by avoiding the resultant decrease in appetite, which can contribute to malnutrition.

Self-management of cystic fibrosis : a structural model for educational and behavioral variables

One hundred and ninety-nine patients and their primary caregivers at two metropolitan cystic fibrosis centers participated in a clinical trial to evaluate the effectiveness of a health education program designed to help improve self-management skills for the care of CF. The baseline data from the study was used to test a structural model that hypothesized the relationship between educational, behavioral, and health status variables. Controlling for the effects of all other variables, including demographic, self-efficacy (confidence in being able to perform a behavior) was the most important educational factor predicting self-management behavior for monitoring and treating respiratory problems. Knowledge about the management of CF was only related to the ability of caretakers to apply coping skills to problems associated with CF. The more caretakers reported performing monitoring behaviors the more likely they were to report performing self-management treatment behaviors. The findings suggest that educational interventions that focus on increased knowledge alone are not likely to be effective in improving self-management behavior for CF. Based on the structural model analyses, it is recommended that educational programs for CF patients and families address increased self-efficacy and improved monitoring skills to influence the improvement of self-management treatment for CF.

A retrospective study of growth hormone use in adolescents with cystic fibrosis.

Objectives Studies of growth hormone (GH) effectiveness in prepubertal children with cystic fibrosis (CF) have been published previously. We present a retrospective study of GH treatment in adolescents with CF.

Serum leptin and igf-i levels in cystic fibrosis

The role of leptin in states of negative energy balance such as cystic fibrosis (CF) has not been explored. We hypothesized that leptin levels in patients with CF would be low due to correlation with body weight. Despite the importance of IGF-I in normal growth and anabolism, there are few data on IGF-I in CF. We studied 27 CF patients (25+/-5 yrs, 57+/-9 kg, 10M/17F) and 12 control subjects (25+/-4 yrs, 57+/-9 kg, 6M/6F). Each subject underwent analysis of lean body mass (LBM) and percent body fat by dual-energy x-ray absorptiometry (DEXA). Serum leptin and IGF-I levels were measured by radioimmunoassay. Serum leptin levels were similar both in CF and in controls (CF=5.3+/-4.1 ng/ml, C=4.4+/-3.6ng/ml; p=0.3), and there was no difference in percent body fat between the two groups (CF=26+/-13%, C=21+/-7%; p=0.3). Leptin levels were significantly lower in CF males than females corresponding to lower fat levels in males in both CF and controls. Leptin levels were positively correlated with percent body fat both in CF and controls (CF: r=0.8; p=0.01, CONTROL: r=0.8; p =0.2). Serum IGF-I levels were significantly lower in CF patients than in controls (CF=1.13+/-0.41 ng/ml, C=6.72+/-3.62 ng/ml; p=<0.01). We conclude that the physiological regulation of leptin is maintained in relation to body fat even in chronic illness and that the negative energy balance in CF is not caused by high leptin levels.

Pharmacokinetics of Ibuprofen in Patients with Cystic Fibrosis

Study Objectives. To determine the pharmacokinetic disposition of high doses of ibuprofen in patients with cystic fibrosis (CF), and to evaluate the reliability of intrapatient dosage adjustments to achieve recommended peak ibuprofen plasma concentrations.