Long-term isoflurane therapy for refractory bronchospasm associated with herpes simplex pneumonia in a heart transplant patient.

A 47-year-old man with a history of heart transplant was admitted after severe traumatic brain injury and seizures. During mechanical ventilation, the patient developed bronchospasm that severely compromised respiratory function that led to cardiac arrest. After resuscitation, application of isoflurane through the Anaesthetic Conserving Device (AnaConDa) in the ICU successfully treated bronchospasm, provided adequate sedation, and enabled appropriate ventilation and diagnostic bronchoscopy. A subsequent bronchoalveolar lavage revealed a high amount of Herpes simplex DNA. Herpes simplex pneumonia was diagnosed and treated with acyclovir. Isoflurane treatment was applied for twelve days total without side effects on renal and cerebral function. The patient recovered quickly after the termination of sedation. At discharge, he was fully awake without focal neurological deficiency and his long-term outcome was excellent. This case demonstrates that isoflurane is a treatment option in life-threatening cases of bronchospasm and a safe option for long-term sedation.

Improved aetiological diagnosis of ischaemic stroke in a Vascular Medicine Unit--the significance of transesophageal echocardiogram.

BACKGROUND: The TOAST study estimates that 34% of ischaemic strokes are of undetermined aetiology. Improvements in the diagnosis of the pathogenetic mechanism of ischaemic stroke would translate into a better care, in analogy to other fields of vascular and internal medicine. OBJECTIVE: To measure the reduction of undetermined aetiology strokes performing a set of additional diagnostic tests. DESIGN: Consecutive case series with historical controls. SETTING: Internal Medicine Ward with a stroke area (SA) admitting most stroke patients of a large hospital in Italy. SUBJECTS: A total of 179 ischaemic stroke patients admitted to SA in 2004-2005 compared with 105 ischaemic stroke patients admitted to the whole department in 2001. INTERVENTION: To perform more diagnostic tests, including transesophageal echocardiography (TEE), in the greatest possible number of ischaemic stroke inpatients admitted in SA of the Internal Medicine Department, in the years 2004-2005. RESULTS: More diagnostic tests were performed during the study period than in 2001, especially TEE (56% of patients in 2004-2005 vs. 3% of patients in 2001). We observed a significant reduction of undetermined aetiology from 38% in 2001 to 16% in 2004-2005 (p < 0.0001), largely for an increased identification of cases of cardio-embolic mechanism (from 18% to 40%, p = 0.0002). In the years 2004-2005 the fraction of patients on anticoagulant treatment at discharge was 21% vs. 12% in 2001 (p = 0.041). CONCLUSION: Performing more tests, particularly TEE, brought improvements in the aetiological diagnosis of stroke, increasing cardio-embolism diagnosis and anticoagulant treatment.

Ischemic preconditioning attenuates portal venous plasma concentrations of purines following warm liver ischemia in man.

BACKGROUND/AIMS: Degradation of adenine nucleotides to adenosine has been suggested to play a critical role in ischemic preconditioning (IPC). Thus, we questioned in patients undergoing partial hepatectomy whether (i) IPC will increase plasma purine catabolites and whether (ii) formation of purines in response to vascular clamping (Pringle maneuver) can be attenuated by prior IPC. METHODS: 75 patients were randomly assigned to three groups: group I underwent hepatectomy without vascular clamping; group II was subjected to the Pringle maneuver during resection, and group III was preconditioned (10 min ischemia and 10 min reperfusion) prior to the Pringle maneuver for resection. Central, portal venous and arterial plasma concentrations of adenosine, inosine, hypoxanthine and xanthine were determined by high-performance liquid chromatography. RESULTS: Duration of the Pringle maneuver did not differ between patients with or without IPC. Surgery without vascular clamping had only a minor effect on plasma purine concentrations. After IPC, plasma concentrations of purines transiently increased. After the Pringle maneuver alone, purine plasma concentrations were most increased. This strong rise in plasma purines caused by the Pringle maneuver, however, was significantly attenuated by IPC. When portal venous minus arterial concentration difference was calculated for inosine or hypoxanthine, the respective differences became positive in patients subjected to the Pringle maneuver and were completely prevented by preconditioning. CONCLUSION: These data demonstrate that (i) IPC increases formation of adenosine, and that (ii) the unwanted degradation of adenine nucleotides to purines caused by the Pringle maneuver can be attenuated by IPC. Because IPC also induces a decrease of portal venous minus arterial purine plasma concentration differences, IPC might possibly decrease disturbances in the energy metabolism in the intestine as well.

Effects of Pringle manoeuvre and ischaemic preconditioning on haemodynamic stability in patients undergoing elective hepatectomy: a randomized trial.

BACKGROUND: The Pringle manoeuvre and ischaemic preconditioning are applied to prevent blood loss and ischaemia-reperfusion injury, respectively, during liver surgery. In this prospective clinical trial we report on the intraoperative haemodynamic effects of the Pringle manoeuvre alone or in combination with ischaemic preconditioning. METHODS: Patients (n=68) were assigned randomly to three groups: (i) resection with the Pringle manoeuvre; (ii) with ischaemic preconditioning before the Pringle manoeuvre for resection; (iii) without pedicle clamping. RESULTS: Following the Pringle manoeuvre the mean arterial pressure increased transiently, but significantly decreased after unclamping as a result of peripheral vasodilation. Ischaemic preconditioning improved cardiovascular stability by lowering the need for catecholamines after liver reperfusion without affecting the blood sparing benefits of the Pringle manoeuvre. In addition, ischaemic preconditioning protected against reperfusion-induced tissue injury. CONCLUSIONS: Ischaemic preconditioning provides both better intraoperative haemodynamic stability and anti-ischaemic effects thereby allowing us to take full advantage of blood loss reduction by the Pringle manoeuvre.

Cryopreservation of reduced cytochrome C for determination of N-formyl-methionyl-leucyl-phenylalanine-stimulated superoxide anion production in human whole blood.

Various methods are available for measuring the production of reactive oxygen species by phagocytes, but they are limited in their use by the need for their immediate application, cell isolation and of cell-activation by unphysiological stimuli. In addition, after measurement of reactive oxygen metabolites using oxidizing agents, the reduced compounds formed have to be determined during or immediately after their formation. In the present study, an improved cytochrome C assay was investigated which allowed measurements of superoxide anions in whole blood samples following activation of phagocytes by physiological stimuli such as the bacterial tripeptide N-formyl-methionyl-leucyl-phenylalanine (fMLP). The fMLP-stimulated production of superoxide anion (O(2)(-)) showed a sigmoidal-shaped fMLP dose-response curve, and constant O(2)(-) production rates (nmol.1(-1)x10(6) granulocytes) could be determined reliably up to a blood granulocyte concentration of 1 x 10(4) x microl(-1). To allow the determination of reduced cytochrome C later after its formation, the effect of long-term storage at -20 degrees C on the stability of reduced cytochrome C was tested up to 16 weeks. The results obtained show that the determination of reduced cytochrome C in whole blood represents a simple and reliable method. Most importantly, O(2)(-)-reduced cytochrome C can be frozen and stored without any alterations, at least up to 2 weeks. Thus the method seems to be superior to other methods of detection, especially when the experimental conditions do not allow immediate spectrophotometry (e.g. mountain medicine, space medicine). Under such conditions the present assay would allow reliable measurement of reduced cytochrome C, even after weeks of cryopreservation.

Nephrotic-range proteinuria, the major risk factor for early atherosclerosis in juvenile-onset systemic lupus erythematosus.

OBJECTIVE: To determine the presence of early carotid atherosclerosis and associated risk factors in patients with juvenile-onset systemic lupus erythematosus (SLE). METHODS: The carotid intima-media wall thickness (IMT) was measured by B-mode ultrasound in patients with SLE onset before the age of 16 years and in sex- and age-matched healthy control subjects. Risk factors for atherosclerosis were determined at the time of the ultrasound scan and included traditional cardiovascular and SLE-related risk factors. RESULTS: Twenty-six patients with juvenile-onset SLE and 26 healthy controls were studied. The mean (+/- SD) IMT of the SLE patients was significantly higher than that of the control group (0.57+/-0.05 mm and 0.54+/-0.03 mm, respectively; P = 0.006). The results of IMT measurement were not correlated with the patients' age, disease duration, SLE Disease Activity Index (SLEDAI) score, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (DI) score, laboratory indicators of lupus activity, or cumulative prednisone dose. Patients with nephrotic-range (NR) proteinuria (> or = 3.5 gm/24 hours; n = 6) had a significantly higher IMT than did those without (n = 20) (P = 0.02). Patients with NR proteinuria also had significantly higher SLEDAI scores, SLICC/ACR DI scores, and systolic and diastolic blood pressures, and significantly higher levels of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and fibrinogen. No difference in any of the above variables, including the IMT, was observed when SLE patients without NR proteinuria were compared with healthy controls. CONCLUSION: These patients with juvenile-onset SLE had ultrasonographic evidence of premature atherosclerosis. The risk of early atherosclerosis may be higher in patients with NR proteinuria.

Plasminogen activator inhibitor-1 and carotid intima-media thickening in patients with newly detected primary hypertension.

OBJECTIVE: To investigate the correlation between ultrasonographically evaluated intima-media thickness (IMT) of common carotid artery (CCA) and cardiovascular risk factors for subjects with newly detected, uncomplicated and untreated primary hypertension. METHODS: The study population consisted of 200 subjects (123 men and 77 women, aged 46+/-7.5 years). Blood pressure was measured in the clinical setting and by 24 h noninvasive ambulatory monitoring. Fasting levels of blood glucose, plasma lipids and lipoproteins, fibrinogen and plasminogen activator inhibitor (PAI)-1 were measured. Ultrasound examination included measurement of far-wall intima-media complex of CCA and morphologic evaluation of occurrence of plaques in carotid and femoral bifurcations. RESULTS: The prevalence of greater than normal IMT (mean IMT > or =0.80 mm) was 22%. Significant univariate correlations to the dichotomy between normal and greater than normal mean IMT were detected for age, smoking, level of LDL cholesterol, level of PAI-1 and total ultrasonographic score. Multivariate logistic regression analysis confirmed the associations between greater than normal mean IMT and plasma concentrations of LDL cholesterol and PAI-1 as well as total ultrasonographic score. CONCLUSION: Greater than normal IMT of CCA was more strictly related to other cardiovascular risk factors than it was to blood pressure and was strongly associated with the occurrence of atherosclerotic plaques in carotid and femoral arteries. The role of PAI-1 in intima-media thickening that is emerging suggests that fibrinolytic balance is an important determinant of vessel-wall homeostasis in hypertensive patients.

Carotid intima-media thickening and in vivo LDL oxidation in patients with essential hypertension.

Low density lipoproteins (LDL) from hypertensive patients are more prone to in vitro oxidation and undergo a more pronounced oxidation in vivo. Due to the pro-atherogenic activity of oxidatively modified LDL, the correlation between the carotid intima-media thickening (IMT) and the markers of in vivo LDL oxidation was investigated in hypertensive patients. A cross-sectional study on 101 normocholesterolemic patients with newly diagnosed and untreated essential hypertension was performed. The occurrence of in vivo LDL oxidation was evaluated by measuring the titers of autoantibodies against Cu(2+)-oxidised LDL (oxLDL) and malondialdehyde-derivatised LDL (MDA-LDL). The extent and degree of atherosclerosis and the IMT were measured by means of carotid and femoral ultrasonography with a duplex scanner equipped with a high resolution probe. We did not find significant correlations between in vivo LDL oxidation parameters and the extent of atherosclerotic lesion in the entire group of hypertensive patients. However, a significant direct correlation was detected between the carotid IMT and the titer of autoantibodies against both oxLDL and MDA-LDL in hypertensive patients without advanced atherosclerotic plaques. The results obtained support the hypothesis that enhanced LDL oxidation may be one of the pathophysiological events related to the formation and progression of early atherosclerotic lesions (IMT) in carotid arteries of hypertensive patients.

Presence of autoantibodies against oxidatively modified low-density lipoprotein in essential hypertension: a biochemical signature of an enhanced in vivo low-density lipoprotein oxidation.

OBJECTIVE: We have previously reported that low-density lipoproteins (LDL) isolated from patients with essential hypertension are more susceptible to in vitro oxidation than lipoproteins isolated from normotensive control subjects. In the present study we investigated the occurrence of in vivo LDL oxidation in hypertensive patients. DESIGN: The presence of antioxidatively modified LDL autoantibodies was taken as a suitable index of in vivo LDL oxidation because, after oxidative modifications, LDL express antigenic epitopes that elicit an immune response. The antibody titres were measured in plasma from untreated patients with newly diagnosed essential hypertension. METHODS: An enzyme-linked immunosorbent assay method was employed, using native LDL, Cu(2+)-oxidized LDL and malondialdehyde-derivatized LDL (MDA-LDL) as antigens. Human serum albumin and MDA human serum albumin were also used to monitor cross-reactivity with other oxidized molecules. The antibody titre was expressed as the ratio between anti-modified and anti-native antigen absolute values. RESULTS: The patients with essential hypertension had an antibody ratio significantly higher than control subjects with respect to anti-Cu(2+)-oxidized LDL immunoglobulins G and M, and with respect to anti-MDA-LDL immunoglobulins G and M. A significant positive correlation was found between anti-MDA-LDL and anti-Cu(2+)-oxidized LDL antibody titres. The anti-MDA human serum albumin antibody titre was not different in the two groups of patients. An inverse correlation was detected between the anti-MDA-LDL immunoglobulin M titre and the age of the patients. CONCLUSIONS: The results obtained are consistent with the view that, during the early phases of hypertension development, LDL undergo in vivo oxidation that is mirrored by the generation of autoantibodies against epitopes of oxidized LDL. The oxidation process appears specific for LDL and might be relevant both for the progression of hypertension and for the development of the atherosclerosis that often complicates hypertension itself.

[Autoantibodies against oxidised low density lipoproteins in patients with coronary disease]. / Autoanticorps contre les lipoprotéines de basse densité oxydées chez des patients coronariens.

OBJECTIVES: Evidence has been obtained indicating that oxidation of low-density lipoproteins (LDL) plays a relevant role in the pathogenesis of atherosclerosis and it has been proposed that, due to the antigenic properties of oxidized LDL, the anti-oxLDL antibody titre could represent a useful index of in vivo LDL oxidation. METHODS: Sixty-nine control subjects and 64 patients scheduled for selective coronary revascularization were investigated before surgery. RESULTS: The coronary disease patients had a higher level of total plasma cholesterol, LDL cholesterol and triglycerides, and a lower level of HDL cholesterol. Plasma anti-oxLDL antibody titre was measured as the ratio of antibody binding to CuSO4-oxidised LDL versus native LDL. The antibody ratio was higher in coronary patients as compared with control subjects (1.56 +/- 0.5 vs 1.0 +/- 0.3, p < 0.01). A ratio higher than 1.34 (mean of controls +/- one standard deviation) was present in 60% of the coronary patients. Subclass analysis indicated that the presence of diabetes mellitus and hypercholesterolaemia (but not of hypertension, generalized arteriosclerosis, myocardial infarction and cigarette smoking) increased the anti-oxLDL antibody ratio to 1.72 +/- 0.4 and 1.68 +/- 0.3 respectively. CONCLUSION: The results obtained indicate that a) a high titre of anti-oxLDL antibodies is present in plasma of patients with coronary atherosclerosis, b) in these patients LDL oxidation takes place in vivo and probably plays a critical role in the development and progression of atherosclerosis.

Metabolic effects of the combination of captopril and hydrochlorothiazide in hypertensive subjects.

The medium-term (16 weeks) effects of the combination of captopril and hydrochlorothiazide (HCTZ) on some metabolic indexes, particularly on plasma lipoproteins, were evaluated in 20 mild to moderate hypertensive outpatients. After a 4-week wash-out period, the subjects were given one tablet of a new commercially available fixed combination once/daily (i.e., captopril 50 mg + HCTZ 25 mg). The dose could be titrated to a maximum of one tablet twice daily according to individual blood pressure responses. Both systolic and diastolic blood pressure significantly decreased at week 4 and showed a further decrease thereafter; the rate of responders (diastolic blood pressure at or below 90 mm Hg at the end of the study) was very high (90%). The only metabolic change was a small though significant increase in HDL cholesterol (P less than .05), almost entirely due to an increase in the denser HDL3 subfraction. The atherogenic fractions, namely total cholesterol, LDL cholesterol, and apoprotein B, showed no significant changes. Plasma triglycerides underwent a transient increase at week 8 (P less than .05) but thereafter fell. Plasma glucose, creatinine, uric acid, and potassium were unchanged. The fixed combination of captopril and HCTZ seems highly effective in lowering blood pressure and seems devoid of untoward metabolic effects. Its overall impact on the coronary risk profile in hypertensive subjects seems therefore to be favorable.

Increase in plasma HDL-cholesterol in hypertensive patients treated with enalapril.

The effects of enalapril on plasma lipoproteins were evaluated in an open study of 12 normolipidemic outpatients with mild-to-moderate essential hypertension (World Health Organization stages I and II). After a two-week washout period, during which placebo was given, the patients received 20 to 40 mg/day of enalapril for 16 weeks. Treatment with enalapril was associated with significant increases in levels of HDL cholesterol (mean, 23%; P less than 0.001) and apoprotein A (mean, 11%; P less than 0.01), largely because of the increase in the subfraction HDL2 (mean, 43%; P less than 0.001), although the subfraction HDL3 also rose (mean, 14%; P less than 0.005). Total cholesterol and LDL cholesterol levels did not change, whereas triglycerides decreased significantly (mean, 26%; P less than 0.001). Apoprotein B was unchanged. Unlike diuretics and most beta-blockers, enalapril favorably affects plasma lipoprotein levels, thus improving the overall cardiovascular risk in hypertensive patients.

Effect of mepindolol on serum lipids.

In view of the postulated association between plasma lipids and the development of atherosclerosis, there is growing interest in the effects of beta blockers on plasma lipids. This study was undertaken to investigate whether a nonselective beta blocker, such as mepindolol, which possesses intrinsic sympathomimetic activity, causes significant changes in serum lipids, particularly in their ditribution among the different lipoproteins. Eighteen healthy subjects, twelve males and six females, were given mepindolol orally, daily doses of 0.2 mg/kg averaging 10-15 mg. Pre- and post-treatment fasting total serum cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were evaulated; the ratio LDL cholesterol/HDL cholesterol was also calculated. Total cholesterol did not change significantly after treatment with mepindolol (- 1.9 mg%), whereas a small and nonsignificant decrease was observed in LDL cholesterol (- 6 mg%); no change was found in HDL cholesterol (- 0. mg%). Serum triglycerides showed a significant increase (+ 20.9 mg%, p less than 0.01). Thus, the most prominent effect of even a short period of treatment with mepindolol is a net increase in serum triglyceride levels. It must be remembered that high triglyceride levels do not constitute a cardiovascular risk factor. On the other hand, no significant changes in total cholesterol, HDL and LDL cholesterol, and in LDL cholesterol/HDL cholesterol ratio were observed. The results of this study show that mepindolol, unlike other beta-blocking agents, does not affect cholesterol concentration and distribution among the lipoproteins. In particular it does not reduce HDL cholesterol, which is currently assumed to be inversely related to the development of atherosclerosis.