A six-month randomized controlled trial of exercise and pyridostigmine in the treatment of fibromyalgia.

OBJECTIVE: A subset of fibromyalgia (FM) patients have a dysfunctional hypothalamic-pituitary-insulin-like growth factor 1 (IGF-1) axis, as evidenced by low serum levels of IGF-1 and a reduced growth hormone (GH) response to physiologic stimuli. There is evidence that pyridostigmine (PYD) improves the acute response of GH to exercise in FM patients. The purpose of this study was to evaluate the clinical effectiveness of 6 months of PYD and group exercise on FM symptoms. METHODS: FM patients were randomized to 1 of the following 4 groups: PYD plus exercise, PYD plus diet recall but no exercise, placebo plus exercise, and placebo plus diet recall but no exercise. The primary outcome measures were the visual analog scale (VAS) score for pain, tender point count, and total myalgic score. Secondary outcome measures were the total score on the Fibromyalgia Impact Questionnaire (FIQ) and FIQ VAS scores for individual symptoms (fatigue, poor sleep, stiffness, and anxiety), as well as quality of life (QOL) and physical fitness (lower body strength/endurance, upper and lower body flexibility, balance, and time on the treadmill). RESULTS: A total of 165 FM patients completed baseline measurements; 154 (93.3%) completed the study. The combination of PYD and exercise did not improve pain scores. PYD groups showed a significant improvement in sleep and anxiety in those who completed the study and in QOL in those who complied with the therapeutic regimen as compared with the placebo groups. Compared with the nonexercise groups, the 2 exercise groups demonstrated improvement in fatigue and fitness. PYD was generally well tolerated. CONCLUSION: Neither the combination of PYD plus supervised exercise nor either treatment alone yielded improvement in most FM symptoms. However, PYD did improve anxiety and sleep, and exercise improved fatigue and fitness. We speculate that PYD may have improved vagal tone, thus benefiting sleep and anxiety; this notion warrants further study.

Conversion of big endothelin-1 and characterization of its contractile effects on isolated human placental arteries.

OBJECTIVES: To study the conversion of human big endothelin-1 (bigET-1) to endothelin-1 (ET-1) and to characterize contractile ET-1 receptors in human placental arteries. METHODS: BigET-1 was incubated with artery membranes and the formation of ET-1 was investigated. ET-1 and bigET-1-induced contractile responses were studied in the absence or presence of the metalloprotease inhibitor phosphoramidon, the ET(A)-receptor antagonist BQ 123, or the ETB-receptor antagonists IRL 1038 and RES 701-1. RESULTS: The artery membranes hydrolysed bigET-1 to ET-1 through a partly phosphoramidon-sensitive pathway. The contractile responses to ET-1 and bigET-1 were similar, with pEC50% values of 8.1 +/- 0.2 and 7.8 +/- 0.1, respectively (NS; n = 17). Phosphoramidon decreased pEC50% for bigET-1-evoked contractions (p < 0.05; n = 8), without affecting the response to ET-1. A Schild plot of BQ 123 effects on ET-1 and bigET-1-induced contractions resulted in identical pA2 values and a slope of 0.56 +/- 0.2 and 0.47 +/- 0.01, respectively. IRL 1038 and RES 701-1 did not affect the contractile responses. CONCLUSION: BigET-1-evoked contractions in isolated human placental arteries depend on a rapid and metalloprotease-dependent hydrolytic conversion to ET-1, which in turn causes a, mainly ETA-receptor-mediated, contraction.

Hydrolysis of big endothelin-1 by a serine protease in the membrane fraction of human lung.

The hydrolysis of human big endothelin 1-38 (bigET-1) was investigated in the membrane fractions from three human lung specimens. The hydrolysis products were identified by HPLC or by amino acid analysis, peptide sequencing and mass spectrometry, and the contractile effects of synthetic bigET-1, synthetic ET-1 and the major metabolite were tested on isolated rabbit pulmonary arteries. The dominating hydrolysis product was identified as bigET1-31, formed by a chymostatin-sensitive enzyme. Soybean trypsin inhibitor also suppressed bigET1-31 formation, while two other serine protease inhibitors, 3,4-dichloroisocoumarin and aprotinin, had no (or a limited) inhibitory effect. Through a partly phosphoramidon-sensitive enzymatic activity, endothelin-1 (ET-1) was formed independently of bigET1-31. On isolated pulmonary arteries, bigET1-31 had a contractile effect similar to that of synthetic bigET-1, with pEC50% values of 7.3 +/- 0.1 (n = 6) and 7.1 +/- 0.1 (n = 8), respectively. The pEC50% value of ET-1 was 9.2 +/- 0.3 (n = 6). These results indicate that human pulmonary membranes, besides hydrolysing bigET-1 to ET-1, also express serine protease activity that is responsible for the formation of the biologically active product, bigET1-31.

Contractile effect of big endothelin-1 and its conversion to endothelin-1 in rabbit cerebral arteries.

The effect of big endothelin-1 (big ET-1) and its conversion to endothelin-1 (ET-1) in rabbit cerebral arteries were examined. Big ET-1 and ET-1 induced concentration-dependent contractions in the basilar artery; ET-1 was approximately 8 times more potent than big ET-1. The metalloprotease inhibitor phosphoramidon (30 mumol/l) almost abolished the contractile response to big ET-1, whereas the ET-1-induced contraction was unaffected. Removal of the endothelium did not attenuate the big ET-1-induced contraction. ET-1 was approximately 14 times more potent than endothelin-3 (ET-3) to elicit contraction. The contractions induced by big ET-1, ET-1 and ET-3 were all inhibited by ET(A) receptor antagonist BQ 123 (3 mumol/l). The ET(B) receptor antagonist IRL 1038 (3 mumol/l) had no effect on the contractile responses to big ET-1 and ET-1, but produced a small inhibition of the ET-3-induced contraction. Formation of ET-1 was demonstrated in membrane fractions of cerebral arteries incubated with big ET-1 as measured by high pressure liquid chromatography followed by radioimmunoassay. These results suggest that externally applied big ET-1 is converted to ET-1 by a phosphoramidon-sensitive "endothelin converting enzyme" present in the vascular smooth muscle cells. The ET-1 formed subsequently mediates the big ET-1-induced contraction by activation of mainly ET(A) receptors, although a small contribution of ET(B) receptors cannot be excluded.

An audit programme for central venous catheter-associated infections.

Central venous catheters (CVC) are commonly associated with both localized and systemic infection. This paper describes an audit programme which was designed to review clinical practice associated with the insertion and subsequent care of CVC and their possible relationship to the development of infection. The programme was produced by a joint working group of the Hospital Infection Society and the Research Unit of the Royal College of Physicians and is subdivided into an audit of hospital practices and patient management associated with the use of CVC. It consists of a number of questions designed to evaluate all areas of CVC use, including the assessment of the incidence of associated local and systemic infection. Use of the questionnaire should allow policies for CVC insertion and care to be reviewed thereby, facilitating improvements, which may in turn reduce the incidence of infection associated with CVC.

Guidelines for good practice in central venous catheterization. Hospital Infection Society and the Research Unit of the Royal College of Physicians.

Central venous catheters (CVC) are commonly used in clinical practice and are associated with several complications, including early and late onset infection. In these guidelines, an outline of good practice for the use of CVC and the prevention of associated infections is presented. Definitions of both localized and systemic catheter-related sepsis are given. Subsequent good practice in relation to the insertion of CVC, including patient preparation, planned duration of catheterization, catheter materials and design of the CVC, are presented. Skin fixation and insertion site care, including the use of dressings and administration sets, as well as an approach to flow obstructions, are also reviewed. The clinical and microbiological diagnosis of catheter-related sepsis and its treatment is next presented. Finally, guidelines for CVC removal and replacement are given. The guidelines are designed to facilitate the development of good practice in the use of CVC, allowing appropriate protocols to be formulated and to reduce infection risk.

Bedside measurement of intra-abdominal pressure (IAP) via an indwelling naso-gastric tube: clinical validation of the technique.

OBJECTIVES: To compare measurements of intraabdominal pressure (IAP) via a naso-gastric tube with the previously validated technique of IAP measurement via a urinary bladder catheter. To examine an association between elevated IAP and oliguric acute renal failure. DESIGN: Simultaneous paired measurements of gastric and urinary bladder pressures in supine patients. SETTING: The general intensive care units of two London hospitals. PATIENTS: 141 Paired measurements of intragastric and urinary bladder pressures were obtained in 26 general intensive care patients. MEASUREMENTS AND RESULTS: With the patient lying supine, 50 ml of sterile water were instilled via manometer tubing into the stomach and bladder following drainage of each viscera. The mid-axillary line was used as the zero reference, and cavity pressures noted in centimeters of water (cmH2O) at end expiration. The results were compared using the technique of Bland and Altman. RESULTS: Gastric pressure may be approximately 2.5 cmH2O above or below urinary bladder pressure. Manometric measurement of the gastric pressure via a naso-gastric tube provides a simple, reliable, non-invasive technique of IAP measurement. IAP should be regularly monitored in patients with abdominal distension at risk of acute renal failure.

Chloroquine poisoning: ventricular fibrillation following 'trivial' overdose in a child.

A 13-year-old boy was admitted to hospital 45 min after the ingestion of approximately 750 mg of chloroquine base. A few minutes after gastric lavage with warm water he developed ventricular fibrillation from which he was promptly resuscitated. The plasma concentration of chloroquine was 4.2 mumol/l; significantly lower than the concentrations previously associated with a fatal outcome in adults. The clinical and electrocardiographic effects of chloroquine poisoning are discussed, and the literature reviewed regarding the role of specific management with diazepam and adrenaline infusions. A period of twenty four hours electrocardiographic (ECG) monitoring and pulse oximetry in an intensive care unit is advocated for all patient with ECG changes following chloroquine overdose.

Management of patients with shock and sepsis.

The pathophysiology of shock associated with sepsis in complex, but granulocyte activation and production of toxic oxygen radicals, is of major importance in producing endothelial cell injury. Multiple organ failure including a reversible cardiomyopathy with impairment of left ventricular ejection fraction, are known factors complicating, and in the latter, perpetuating, shock. When treating the severely shocked patient, a systolic pressure of 100 mmHg and a PaO2 of greater than 8 kPa (60 mmHg) should be aimed for. Non-response to oxygenation, respiratory support, volume, and metabolic control, may be an indication for insertion of a thermodilution catheter into the right heart, so that cardiac output can be measured and oxygen delivery maintained above 10 mmol/kg/min. Where, by manipulation of respiratory indices and inotropic support, achievement of this level is not possible, the prognosis is grave. Antibiotic therapy is discussed, therapy being instituted if at all possible once the haemodynamic state has been improved.

Sedating ventilated asthmatics: etomidate reconsidered.

The use of etomidate and fentanyl infusions to sedate four asthmatics who required artificial ventilation and were receiving high dose steroids is described. The non-asthmatic patients who had not received steroids were also given etomidate combined with either fentanyl or alfentanil by infusion. Use of this sedative technique was suspended in June 1983, following reports of excess mortality associated with the long-term administration of etomidate. Retrospective measurements of plasma cortisols were subnormal in 5 of the 10 patients who did not receive steroids and remained low 12 hours after discontinuation of the infusion in two cases. All the asthmatics survived, but two of the non-asthmatic patients died. Despite its adverse effects, we still feel there may be a place for etomidate infusion in selected asthmatic patients, provided that steroid replacement is given.

Cardiac arrest in near-term pregnancy.

This case study emphasises the multiple factors that may be involved in the precipitation of electromechanical dissociation, which are compounded by additional problems that relate to pregnancy. It reinforces the value of the tracheal route for drug administration when a central vein is not cannulated and stresses the importance of posture and early consideration of Caesarean section in the pre-term gravid patient who has sustained a cardiac arrest.

Prostacyclin deficiency in a young woman with recurrent thrombosis.

A young woman with recurrent deep venous thromboses and spontaneous abortions was studied. She suffered an ovarian infarction followed by aortic thrombosis and renal failure. Evidence for deficient prostacyclin production was found and she responded to treatment with a prostacyclin infusion. This syndrome is identical with that seen in women with the lupus anticoagulant, but the lupus anticoagulant was not detected and no other cause was identified.

Serum morphine levels. A comparison between continuous subcutaneous infusion and continuous intravenous infusion in postoperative patients.

A study was undertaken to compare continuous subcutaneous infusions of morphine with continuous intravenous infusions in patients whose lungs were mechanically ventilated for 24 hours postoperatively. Serum morphine levels were measured after the end of surgery and at 6, 12, 18 and 24 hours in nine patients receiving continuous subcutaneous morphine and in four patients receiving continuous intravenous morphine given at the same rate. At 6, 12, 18 and 24 hours the means of serum morphine levels in the intravenous group were 20 ng/ml, 17.75 ng/ml, 18.5 ng/ml and 18 ng/ml, respectively, the corresponding figures in the subcutaneous group being 23.2 ng/ml, 20 ng/ml, 20.7 ng/ml and 20 ng/ml. For the intravenous route the mean dose of supplementary analgesia was 14 mg of phenoperidine in the first 24 postoperative hours, whereas for the subcutaneous route the mean dose was 11.66 mg. The differences in the serum morphine levels and in the requirements of phenoperidine were not statistically significant. We conclude that a continuous subcutaneous infusion of morphine is a simple and effective means of achieving postoperative analgesia.

Iatrogenic nondiabetic hyperosmolar states.

Four cases of the iatrogenic nondiabetic hyperosmolar state are presented. The clinical presentation, biochemical findings and management are discussed. No hypertonic solution should be infused at a rate above the level of patient tolerance; irrigation of a hollow viscus with a hypertonic solution should be avoided, and salt should not be used as an emetic. Patients under stress are particularly prone to this condition, largely because of the high circulating cortisol levels. The use of corticosteroids, salt-containing solutions in excess of patient requirements, water depletion and intravenous nutrition in the absence of careful biochemical monitoring, are all factors which may precipitate the hyperosmolar state in the critically ill.