Optimal postoperative pain management after VATS lung resection by thoracic epidural analgesia, continuous paravertebral block or single-shot intercostal nerve block (OPtriAL): study protocol of a three-arm multicentre randomised controlled trial.

BACKGROUND: Adequate pain control after video-assisted thoracoscopic surgery (VATS) for lung resection is important to improve postoperative mobilisation, recovery, and to prevent pulmonary complications. So far, no consensus exists on optimal postoperative pain management after VATS anatomic lung resection. Thoracic epidural analgesia (TEA) is the reference standard for postoperative pain management following VATS. Although the analgesic effect of TEA is clear, it is associated with patient immobilisation, bladder dysfunction and hypotension which may result in delayed recovery and longer hospitalisation. These disadvantages of TEA initiated the development of unilateral regional techniques for pain management. The most frequently used techniques are continuous paravertebral block (PVB) and single-shot intercostal nerve block (ICNB). We hypothesize that using either PVB or ICNB is non-inferior to TEA regarding postoperative pain and superior regarding quality of recovery (QoR). Signifying faster postoperative mobilisation, reduced morbidity and shorter hospitalisation, these techniques may therefore reduce health care costs and improve patient satisfaction. METHODS: This multi-centre randomised study is a three-arm clinical trial comparing PVB, ICNB and TEA in a 1:1:1 ratio for pain (non-inferiority) and QoR (superiority) in 450 adult patients undergoing VATS anatomic lung resection. Patients will not be eligible for inclusion in case of contraindications for TEA, PVB or ICNB, chronic opioid use or if the lung surgeon estimates a high probability that the operation will be performed by thoracotomy. PRIMARY OUTCOMES: (1) the proportion of pain scores ≥ 4 as assessed by the numerical rating scale (NRS) measured during postoperative days (POD) 0-2; and (2) the QoR measured with the QoR-15 questionnaire on POD 1 and 2. Secondary outcome measures are cumulative use of opioids and analgesics, postoperative complications, hospitalisation, patient satisfaction and degree of mobility. DISCUSSION: The results of this trial will impact international guidelines with respect to perioperative care optimization after anatomic lung resection performed through VATS, and will determine the most cost-effective pain strategy and may reduce variability in postoperative pain management. Trial registration The trial is registered at the Netherlands Trial Register (NTR) on February 1st, 2021 (NL9243). The NTR is no longer available since June 24th, 2022 and therefore a revised protocol has been registered at ClinicalTrials.gov on August 5th, 2022 (NCT05491239). PROTOCOL VERSION: version 3 (date 06-05-2022), ethical approval through an amendment (see ethical proof in the Study protocol proof).

Randomised controlled trial to estimate reduction in pain after laparoscopic surgery when using a combination therapy of intraperitoneal normal saline and the pulmonary recruitment manoeuvre.

OBJECTIVE: To evaluate the effect of two manoeuvres at the end of gynaecological laparoscopy on postoperative pain. DESIGN: Randomised controlled trial. SETTING: One teaching and one university hospital in the Netherlands. SAMPLE: Women aged between 18 and 65 years, with American Society of Anaesthesiologists (ASA) classification I-II, scheduled for an elective laparoscopic procedure for a benign gynaecological indication. METHODS: Women were randomly allocated to two groups. In the intervention group, carbon dioxide was removed from the abdomen by a combination treatment of intraperitoneal warm saline and performing a pulmonary recruitment manoeuvre. In the control group, carbon dioxide was removed with gentle abdominal pressure. MAIN OUTCOME MEASURES: Frequency and intensity of post-laparoscopic shoulder pain and pain in the upper abdomen at 8, 24, and 48 hours after surgery. RESULTS: A total of 200 women participated, with 100 in each group. No difference was observed in the occurrence of post-laparoscopic shoulder pain during the first 48 hours after surgery between the intervention group (46%) and the control group (55%). The incidence of abdominal pain was not significantly different between the two groups. The mean visual analogue scale (VAS) scores of participants who reported shoulder pain were not statistically different between the groups. The mean VAS score for abdominal pain at 8 hours after surgery was significantly lower in the intervention group compared with the control group (3.2 versus 4.2, P = 0.02). No difference in pain medication between the groups was observed, nor was there any difference in nausea or vomiting. CONCLUSIONS: Combined intervention of intraperitoneal saline and the pulmonary recruitment manoeuvre does not lower post-laparoscopic shoulder pain. FUNDING: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. TWEETABLE ABSTRACT: PRM with intraperitoneal saline does not influence the incidence and intensity of post-laparoscopic shoulder pain.

POstLAparoscopic Reduction of pain By combining intraperitoneal normal salinE And the pulmonary Recruitment maneuver (POLAR BEAR trial). RCT to estimate reduction in pain after laparoscopic surgery when using a combination therapy of intraperitoneal normal saline and the pulmonary recruitment maneuver.

BACKGROUND: Shoulder pain and pain in the upper abdomen are common complaints after laparoscopy, sometimes surpassing the pain at incision sites. The incidence of shoulder pain ranges from 35 to 80%. Post-laparoscopic pain is caused by retention of carbon dioxide in the abdomen, which irritates the phrenic nerve and diaphragm, causing referred pain in the shoulder and in the upper abdomen. A promising strategy to reduce this post-laparoscopic pain is the pulmonary recruitment maneuver, which indirectly increases intraperitoneal pressure and thereby facilitates removal of residual carbon dioxide. An alternative strategy is the infusion of intraperitoneal normal saline. With normal saline infusion, carbon dioxide rises and escapes through the port sites. In addition, normal saline offers a physiologic buffer system to dissolve excess carbon dioxide. METHODS/DESIGN: This multicenter randomized controlled trial is conducted in two teaching hospitals in the Netherlands. Women between 18 and 65 years of age, with an ASA classification of I-II who are scheduled to undergo an elective laparoscopic procedure with benign gynecologic indication can participate. Following informed consent, participants are randomly allocated into two groups at the end of the surgical procedure. In the intervention group, the upper abdomen is filled with normal saline infusion with the patient in the Trendelenburg position. Then the anesthesiologist performs a standardized pulmonary recruitment maneuver with a pressure of 40 cm H2O. The trocar sleeve valves will be left open, so carbon dioxide can escape the abdominal cavity. With the patient in a neutral position the instruments are removed from the abdomen. In the control group, carbon dioxide is removed from the abdominal cavity at the end of surgery, with gentle abdominal pressure and passive exsufflation through the port sites, with open sleeve valves. The primary outcomes are the incidence and intensity of post-laparoscopic pain in the shoulder, upper abdomen and at the operation sites, at 8, 24 and 48 h after surgery. Secondary outcomes are postoperative use of analgesics, nausea, vomiting and pulmonary complications. DISCUSSION: This study may reduce post-laparoscopic pain in women undergoing laparoscopy. TRIAL REGISTRATION: Dutch trial register, number NTR4812 .

Assessment of disease activity in patients with rheumatoid arthritis using optical spectral transmission measurements, a non-invasive imaging technique.

OBJECTIVES: In rheumatoid arthritis (RA), treat-to-target strategies require instruments for valid detection of joint inflammation. Therefore, imaging modalities are increasingly used in clinical practice. Optical spectral transmission (OST) measurements are non-invasive and fast and may therefore have benefits over existing imaging modalities. We tested whether OST could measure disease activity validly in patients with RA. METHODS: In 59 patients with RA and 10 patients with arthralgia, OST, joint counts, Disease Activity Score (DAS) 28 and ultrasonography (US) were performed. Additionally, MRI was performed in patients with DAS28<2.6. We developed and validated within the same cohort an algorithm for detection of joint inflammation by OST with US as reference. RESULTS: At the joint level, OST and US performed similarly inproximal interphalangeal-joints (area under the receiver-operating curve (AUC) of 0.79, p<0.0001) andmetacarpophalangeal joints (AUC 0.78, p<0.0001). Performance was less similar in wrists (AUC 0.62, p=0.006). On the patient level, OST correlated moderately with clinical examination (DAS28 r=0.42, p=0.001), and US scores (r=0.64, p<0.0001). Furthermore, in patients with subclinical and low disease activity, there was a correlation between OST and MRI synovitis score (RAMRIS (Rheumatoid Arthritis MRI Scoring) synovitis), r=0.52, p=0.005. CONCLUSIONS: In this pilot study, OST performed moderately in the detection of joint inflammation in patients with RA. Further studies are needed to determine the diagnostic performance in a new cohort of patients with RA.

In ECAT veritas?

The laboratory criteria of the antiphospholipid syndrome include one coagulation assay (lupus anticoagulant [LA]) and two solid phase assays (anticardiolipin [aCL] and anti-ß(2)glycoprotein I antibodies [aß(2)GPI]). External quality control (EQC) surveys show that negative and clearly positive LA samples are classified correctly by about 95% of laboratories. For 'weak' LA there is a wide variability in samples' classification. Furthermore, when a weak LA sample is used in two different EQC surveys more than 50% of laboratories classify it differently. In some surveys weak LA samples were found to be positive for aCL and for aß(2)GPI by a majority of laboratories; the main reason for laboratories which classified these samples as LA negative was a negative result in the mixing test. It is likely that, depending on the sensitivity of the assay, a weak LA cannot be detected anymore after 1:1 dilution of the sample with normal plasma. Therefore, we recommend the use of integrated assays, such as screen/confirm ratios, for the detection of weak LA samples.

A guideline to medical photography: a perspective on digital photography in an orthopaedic setting.

PURPOSE: Quality photographs are essential for clinical documentation, research, and publication in scientific journals and teaching. Oftentimes, non-ideal lighting and a sterile environment restrict the medical photographer, resulting in lower-quality photographs. This article aims to provide a clear and comprehensible guideline for medical photography in an orthopaedic setting. METHODS: This article is based on extensive photographic involvement in operating and laboratory settings, in close collaboration with medical professionals from the Steadman Clinic (Vail, Colorado, USA), Gothenburg University (Göteborg, Sweden) and Erasmus MC (Rotterdam, the Netherlands). Background literature was searched through Google Scholar and PubMed. RESULTS: Three relevant journal articles, and one book on medical photography, were used to write this paper. Seventeen Internet articles were used for background information. CONCLUSION: A relevant, up-to-date and comprehensive guideline to medical photography for medical professionals, with or without photographic experience, is provided. LEVEL OF EVIDENCE: Expert opinion, Level V.

Cardiac assessment of patients with late stage Duchenne muscular dystrophy.

Background. Duchenne muscular dystrophy (DMD) patients used to die mainly from pulmonary problems. However, as advances in respiratory care increase life expectancy, mortality due to cardiomyopathy rises. Echocardiography remains the standard diagnostic modality for cardiomyopathy in DMD patients, but is hampered by scoliosis and poor echocardiographic acoustic windows in adult DMD patients. Multigated cardiac radionuclide ventriculography (MUGA) does not suffer from these limitations. N-terminal proBNP (NTproBNP) has shown to be a diagnostic factor for heart failure. We present our initial experience with plasma NT-proBNP measurement in the routine screening and diagnosis of cardiomyopathy in adult mechanically ventilated DMD patients.Methods. Retrospective study, 13 patients. Echocardiography classified left ventricular (LV) function as preserved or depressed. NT-proBNP was determined using immunoassay. LV ejection fraction (LVEF) was determined using MUGA.Results. Median (range) NT-proBNP was 73 (25 to 463) ng/l. Six patients had an NT-proBNP >125 ng/l. Seven patients showed an LVEF <45% on MUGA. DMD patients with depressed LV function (n=4) as assessed by echocardiography had significantly higher median NT-proBNP than those (n=9) with preserved LV function: 346 (266 to 463) ng/l versus 69 (25 to 257) ng/l (p=0.003). NT-proBNP significantly correlated with depressed LV function on echocardiogram and with LVEF determined by MUGA.Conclusion. Although image quality of MUGA is superior to echocardiography, the combination of echocardiography and NT-proBNP achieves similar results in the evaluation of left ventricular function and is less time consuming and burdensome for our patients. We advise to add NT-proBNP to echocardiography in the routine cardiac assessment of DMD patients. (Neth Heart J 2009;17:232-7.).

Dipyridamole enhances ischaemia-induced reactive hyperaemia by increased adenosine receptor stimulation.

BACKGROUND AND PURPOSE: Dipyridamole enhances post-occlusive reactive hyperaemia (PORH) in the human forearm vascular bed. We hypothesize that this effect is completely mediated by increased adenosine receptor stimulation. To test this hypothesis, the effect of caffeine (an adenosine receptor antagonist) on dipyridamole-induced augmentation of PORH was explored. EXPERIMENTAL APPROACH: The forearm vasodilator responses to three increasing periods of forearm ischaemia (2, 5 and 13 min) were determined during placebo infusion. Forty minutes after the last reperfusion period, this procedure was repeated during intra-arterial infusion of dipyridamole (7.4 nmol min(-1) per 100 ml forearm). At least 2 weeks later, this whole procedure was repeated, but now in the presence of caffeine (90 microg min(-1) per 100 ml volume). KEY RESULTS: After 2, 5 and 13 min of ischaemia, the average forearm blood flow increased to 5.6+/-0.7, 9.7+/-1.3 and 34.5+/-2.1 ml min(-1) per 100 ml. After infusion of dipyridamole into the brachial artery, these numbers were significantly increased to 7.7+/-0.8, 12.5+/-1.5 and 41.6+/-3.1 ml min(-1) per 100 ml. This response was abolished by the concomitant infusion of caffeine (6.6+/-0.5, 10.2+/-0.6, 35.1+/-2.2 (caffeine) versus 7.4+/-0.4, 10.5+/-0.6, 33.7+/-2.2 ml min(-1)per 100 ml (caffeine/dipyridamole)). CONCLUSIONS AND IMPLICATIONS: Caffeine prevented the augmenting effect of dipyridamole on PORH. This indicates that dipyridamole-induced augmentation of PORH is mediated via increased adenosine receptor stimulation as a result of elevated extracellular formation of adenosine during ischaemia.

Diagnosis of factor VIII deficiency.

The correct diagnosis of factor VIII deficiency and the assessment of severity of the disease are essential for a patient-tailored treatment strategy. An optimal diagnostic procedure comprises sensitive and specific screening methods and factor VIII activity assays. Different screening reagents show variable characteristics and receiver operator characteristic curves are presented showing the relation between sensitivity and specificity of eleven activated partial thromboplastin time reagents. The details of the three methods for factor VIII activity assay, one-stage and two-stage assay and chromogenic assays, are discussed. The chromogenic assay seems to be more sensitive than the one-stage assay with regard to the detection of severe haemophilia. Discrepant results obtained with one-stage and two-stage assays are reviewed and discussed.

[Summary of the practice guideline 'Atopic dermatitis' (first revision) from the Dutch College of General Practitioners]. / Samenvatting van de standaard 'Constitutioneel eczeem' (eerste herziening) van het Nederlands Huisartsen Genootschap.

The 1996 practice guideline on atopic dermatitis from the Dutch College of General Practitioners has been updated. For diagnosing atopic dermatitis, the use of Williams' criteria is recommended. Testing for food allergy is only useful in case of children under the age of 2 who have other food-related allergic complaints together with dermatitis. In the treatment of atopic dermatitis, keeping the skin in good condition with emollients is essential; furthermore, topical corticosteroids are the therapy of first choice. In case of a severe exacerbation of atopic dermatitis, starting with a class 3 corticosteroid is preferred. In case of frequent recurrences, 'pulse-therapy' is indicated: topical corticosteroids on 2-4 consecutive days per week as maintenance therapy. The role of preparations from tar is marginal. The use of the topical immunomodulators tacrolimus and pimecrolimus in general practice is discouraged.

Quality of factor XI activity testing in North American Specialized Coagulation Laboratories.

INTRODUCTION: The performance of factor XI activity (FXI) by laboratories in the North American Specialized Coagulation Laboratory Association proficiency testing program was analyzed. METHODS: Over 10 years (2003-2013), 80 samples were distributed; 33-55 laboratories participated per exercise providing 3833 total responses. Analysis was performed on numeric results and qualitative classification of results. RESULTS: The sample FXI levels ranged from 3.8 to 154.0 IU/dL. The overall interlaboratory average coefficient of variation (CV%) was 17.5%; the CV was higher for a sample with low (3.8 IU/dL) FXI. Results were correctly classified as abnormal (100%) for a sample with 3.8 IU/dL FXI and normal/borderline normal (97.7%) for 45 samples with 80 to < 140 IU/dL FXI. The classification was heterogeneous for samples with FXI of 50 to < 80 IU/dL. Six specimens were repeat-tested from 2007 to 2013. The mean FXI was not significantly different in laboratories using the same method on both exercises, suggesting good intralaboratory precision over time. Univariate analysis of data from 2011 to 2012 did not find a consistent significant difference among the activators, analyzers, calibrators, and FXI-deficient plasmas. CONCLUSION: Laboratories generally performed well in assessment of FXI based on interlaboratory precision when FXI >30 IU/dL and on classification of samples with very low or normal FXI.

Food choice in hyperthyroidism: potential influence of the autonomic nervous system and brain serotonin precursor availability.

We explored energy and macronutrient intake in patients with Graves' hyperthyroidism. We specifically hypothesized that hyperthyroidism is associated with increased appetite for carbohydrates, because of enhanced sympathetic tone and diminished serotonin mediated neurotransmission in the brain. To test this hypothesis, we measured food intake by dietary history and food selected for lunch in the laboratory in 14 patients with Graves' hyperthyroidism. Twenty-four-hour catecholamine excretion was used as a measure of activity of the sympathetic nervous system (SNS) and the plasma [Trp]/[NAA] ratio was measured to estimate (rate limiting) precursor availability for brain 5-hydroxytryptamine synthesis. All measurements were repeated after the subjects had been treated to establish euthyroidism. In addition, the effects of nonselective beta-adrenoceptor blockade upon these parameters were studied to evaluate the influence of beta-adrenergic hyperactivity on food intake. Hyperthyroidism was marked by increased SNS activity and reduced plasma [Trp]/[NAA] ratio. Accordingly, energy intake was considerably and significantly increased in hyper vs. euthyroidism, which was fully attributable to enhanced carbohydrate consumption, as protein and fat intake were not affected. These results suggest that hyperthyroidism alters the neurophysiology of food intake regulation. Increased SNS activity and reduced Trp precursor availability for 5-hydroxytryptamine synthesis in the brain may drive the marked hyperphagia and craving for carbohydrates that appears to characterize hyperthyroid patients. Because propranolol did not affect food intake in hyperthyroidism, the potential effect of catecholamines on food intake might be mediated by alpha-adrenoceptors.

The long-term within- and between-laboratory variability for assay of antithrombin, and proteins C and S: results derived from the external quality assessment program for thrombophilia screening of the ECAT Foundation.

A stable laboratory performance is important for comparability and transferability of laboratory data both within and between laboratories. The lack of a reference system within hemostasis hampers laboratories in establishing their laboratory performance over a prolonged period of time. Therefore, based on data from an external quality assessment program, we evaluated the between laboratory variation (CVBETWEEN) and the long-term within-laboratory variation (LCVa) for antithrombin, and proteins C and S. We evaluated the CVBETWEEN for the period 1996-2001, including the results of 64-240 laboratories from 23 different surveys (protein S activity 15 surveys). We observed a quite high CVBETWEEN and a broad range for each analyte. The CVBETWEEN was significantly higher for antithrombin and protein S for samples with low levels similar to heterozygous deficiencies. We also evaluated the LCVa, including the results of 136 laboratories. The lowest LCVa[median and 95% content interval (CI)] was observed for antithrombin (7.6%; 3.6-35.5%), intermediate values for protein C activity and antigen (8.6%; 3.5-25.3% and 10.8%; 4.8-33.1%, respectively) and highest values for the protein S variables (13.4%; 6.4-50.6% for total protein S antigen, 14.1%; 6.5-79.1% for free protein S antigen and 17.2%; 7.2-84.3% for protein S activity). We concluded that the main reason for the high CVBETWEEN is the long-term within-laboratory variability. Application of linear regression on data of an external quality assessment program is a useful model to demonstrate per analyte per laboratory the long-term variability (LCVa). It is concluded that improvement of the long-term within-laboratory test performance is the first priority in hemostasis to yield important improvements in the comparability and transferability of laboratory data.

Thrombin generation induced by the intrinsic or extrinsic coagulation pathway is accelerated by streptokinase, independently of plasminogen.

Thrombolytic therapy paradoxically induces the formation of fibrinopeptide A, fibrin degradation products and thrombin-antithrombin complexes, indicating thrombin generation. Part of the mechanism of this thrombin generation under the influence of thrombolytic agents was unraveled in this study. We measured thrombin with a chromogenic substrate at several time intervals after recalcification of citrated plasma which had been preincubated with urokinase, streptokinase, recombinant tissue plasminogen activator (rt-PA) or recombinant single-chain urokinase-type plasminogen activator (rscu-PA). Thrombin generation induced by the addition of thromboplastin together with calcium (extrinsic pathway) was greatly accelerated in the presence of streptokinase (from about 7 to 2 min), and to a lesser extent in the presence of urokinase, rt-PA or rscu-PA. Similar effects were seen after the addition of calcium to the plasma containing the thrombolytic agent and preincubated with partial thromboplastin (intrinsic pathway). Hirudin quenched the conversion of the chromogenic substrate completely, confirming that thrombin was the active enzyme. Aprotinine did not affect the results, and the effect of streptokinase was also observed in plasminogen-depleted plasma. We conclude that streptokinase, and to a lesser extent other thrombolytic agents, activate the prothrombinase complex directly or indirectly through a calcium-dependent mechanism, independently of plasminogen, with a resulting acceleration of thrombin generation.

Lupus anticoagulant testing in Europe: an analysis of results from the first European Concerted Action on Thrombophilia (ECAT) survey using plasmas spiked with monoclonal antibodies against human beta2-glycoprotein I.

Lupus anticoagulants (LA) are immunoglobulins directed to either prothrombin or Beta-2-glycoprotein 1(beta1GPI) bound to phospholipids. Most patients with LA have both beta2GPI- and prothrombin-dependent antibodies. Several recent reports have shown that LA is more strongly associated with thrombosis than anticardiolipin antibodies (aCL). Therefore, an accurate detection of LA is of utmost importance in patients suspected of an antiphospholipid syndrome. We recently raised a series of murine monoclonal antibodies against human Beta-2-glycoprotein I (beta2GPI) with LA activity similar to affinity purified human beta2GPI-dependent LAs. A normal plasma pool, and the same pool spiked with LA positive anti-beta2GPI antibodies at two potency levels, were used as materials in an external quality assessment scheme organised by the European Concerted Action on Thrombosis (ECAT). Fifty nine laboratories participating in this trial were asked to test for the presence of a LA in the 3 samples submitted. The majority (82%) of the participants found the high potency LA sample to be positive. Only 37% of the laboratories considered the weak potency LA sample to be positive. The submission of a normal sample, a weakly positive sample and a clearly positive sample enabled us to compare the relative LA responsiveness of the different screening assays used. Clotting time ratios varied from 0.81 to 3.28 for sample B and from 0.66 to 5.32 for sample D. In general, the highest clotting time ratios were found with the dilute prothrombin time (dPT), the dilute Russell Viper Venom time (dRVVT) and the Kaolin Clotting time. The most frequently used screening tests were the aPTT and the dRVVT. With the various assay systems, LA responsiveness varied largely according to the reagents used. For the beta2GPI-dependent LA used in this study, PTT LA clearly showed the highest responsiveness among the aPTT reagents and Innovin among the dPT reagents. The present study also shows that many laboratories still rely on poorly responsive screening assays for their LA tests. Other laboratories rely on sensitive and more specific integrated test systems based on a sensitive screening assay with a low phospholipid content and a confirmatory test employing high phospholipid concentrations. The most used integrated system was dRVVT based. However, also here the LA responsiveness was largely reagent dependent. In conclusion, many laboratories still rely on poorly responsive screening assays by which weakly positive LA samples are misdiagnosed. LA positive anti-beta2GPI moabs have a potential for the unlimited production of LA control specimens, that may help hemostasis laboratories choose more LA responsive assay systems and to assess intralaboratory precision of their LA testing.

Effect of isotretinoin on endogenous tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) in humans.

The effect of isotretinoin on fibrinolysis was investigated in 10 healthy, male volunteers in a randomized, double-blind, crossover-designed study. Isotretinoin (40 mg) was administered in the morning and in the evening for 5 days. t-PA, u-PA and PAI-1 antigen and activity in plasma were measured every morning at 9 a.m. on days 1 to 4 and every 3 hours over 24 hours on day 5. Isotretinoin treatment had no significant stimulatory effect on endogenous t-PA antigen and activity in morning plasma samples nor on their circadian variation. Also, u-PA antigen levels did not change after isotretinoin treatment. Mean PAI-1 antigen and PAI activity in 9 a.m. plasma samples were non-significantly higher during isotretinoin than during placebo treatment. After treatment with isotretinoin a significant rise of fasting triglyceride plasma levels was observed as compared to placebo. The study shows that isotretinoin has no clinically significant effect on endogenous fibrinolysis.

Activation products of the haemostatic system in coronary, cerebrovascular and peripheral arterial disease.

To determine the presence of a 'hypercoagulable state' as assessed by indices of thrombin and plasmin generation and of the amount of fibrin that is lysed, in patients with stable coronary, cerebral and peripheral arterial disease a population-based cross-sectional study was performed. From a population-based cohort comprising 7983 men and women aged 55 years and over, we randomly selected 127 subjects with a history of myocardial infarction, 124 with a history of stroke and/or transient ischemic attack, 131 patients with peripheral arterial disease and 263 control subjects in the same age group without arterial disease. Subjects using anticoagulant drugs were not selected. F1+2, TAT, and PAP were not associated with a history of cardiovascular events, nor with peripheral arterial disease. In contrast, positive associations were found for D-Dimer. Mean D-Dimer level was 40 microg/l (95% CI 35, 44) in control subjects; 53 microg/l (47, 61) in those with a history of myocardial infarction and 51 microg/l (45, 58) in those with a history of stroke and or transient ischemic attack. D-Dimer increased gradually with increasing severity of peripheral atherosclerosis; a decrease in ankle/arm systolic blood pressure ratio of 0.1 was associated with an increase in D-Dimer of 3.9 microg/l (p<0.01). This was more pronounced in subjects with higher F1+2, TAT and PAP concentration. In conclusion, the markers of onset of coagulation F1+2, TAT and PAP are not associated with the presence of arterial disease, but increased levels of these markers are necessary for the positive association between D-Dimer and arterial disease.

ATP-induced vasodilation in human skeletal muscle.

1. The purine nucleotide adenosine-5'-triphosphate (ATP) exerts pronounced effects on the cardiovascular system. The mechanism of action of the vasodilator response to ATP in humans has not been elucidated yet. The proposed endothelium-derived relaxing factors (EDRFs) were studied in a series of experiments, using the perfused forearm technique. 2. Adenosine 5'-triphosphate (0.2, 0.6, 6 and 20 nmol dl(-1) forearm volume min(-1)) evoked a dose-dependent forearm vasodilator response, which could not be inhibited by separate infusion of the nonselective COX inhibitor indomethacin (5 microg dl(-1) min(-1), n=10), the blocker of Na(+)/K(+)-ATPase ouabain (0.2 microg dl(-1) min(-1), n=8), the blocker of K(Ca) channels tetraethylammonium chloride (TEA, 0.1 microg dl(-1) min(-1), n=10), nor by the K(ATP)-channel blocker glibenclamide (2 microg dl(-1) min(-1), n=10). All blockers, except glibenclamide, caused a significant increase in baseline vascular tone. The obtained results might be due to compensatory actions of unblocked EDRFs. Combined infusion of TEA, indomethacin and l-NMMA (n=6) significantly increased the baseline forearm vascular resistance. The ATP-induced relative decreases in forearm vascular resistance were 48+/-5, 67+/-3, 88+/-2, and 92+/-2% in the absence and 23+/-7, 62+/-4, 89+/-2, and 93+/-1% in the presence of the combination of TEA, indomethacin and l-NMMA (P<0.05, repeated-measures ANOVA, n=6). A similar inhibition was obtained for sodium nitroprusside (SNP, P<0.05 repeated-measures ANOVA, n=6), indicating a nonspecific interaction due to the blocker-induced vasoconstriction. 3. ATP-induced vasodilation in the human forearm cannot be inhibited by separate infusion of indomethacin, ouabain, glibenclamide or TEA, or by a combined infusion of TEA, indomethacin, and l-NMMA. Endothelium-independent mechanisms and involvement of unblocked EDRFs, such as CO, might play a role, and call for further studies.

Influence of octreotide (SMS 201-995) and insulin administration on the course of blood pressure after an oral glucose load in hypertensive elderly subjects.

Pretreatment with a somatostatin analogue, octreotide (SMS 201-995), prevents postprandial blood pressure reduction in the elderly. We hypothesized that this beneficial effect on blood pressure is caused by an octreotide-induced suppression of insulin secretion. We studied the effects of octreotide and insulin administration on the course of blood pressure after oral glucose loading in 10 healthy hypertensive old persons (mean age 73 +/- 3 years). Octreotide was given in a dose of 50 micrograms subcutaneously (sc) (time = -30 minutes). Insulin was given sc in a dose of 0.3 U/kg body weight (time = -10 minutes) and glucose was given orally in a dose of 75 g in 300 mL water (time = 0 minutes). Plasma insulin concentrations remained essentially unchanged after placebo and rose to a maximum level of 58 +/- 6 mU/L following insulin administration. The course of blood pressure was not different following glucose loading with high or low plasma insulin levels. These data indicate that the effects of octreotide on postprandial blood pressure reduction in the elderly are unrelated to the inhibition of insulin secretion.

Beneficial effect of a moderately energy-restricted diet on fibrinolytic factors in non-obese men.

Impaired fibrinolytic activity has been reported in the elderly and is thought to play a role in the etiology of cardiovascular disease, one of the leading causes of death in most Western countries. Since restriction of energy intake has been demonstrated to act beneficially on the aging process in a variety of species, we studied the effect of a 10-week moderately energy-restricted (ER) regimen (80% of habitual) on plasminogen activator inhibitor (PAI) activity, PAI-1 antigen, tissue plasminogen activator (tPA) activity, and tPA antigen in non-obese, middle-aged men. Moreover, the relationship between these fibrinolytic markers and glucose tolerance was investigated. Weight loss in the ER group (n = 16) was considerable (-7.4 +/- 1.7 kg, P < .001). Subjects in the control group (n = 8) also lost some weight (-2.1 +/- 1.5 kg, P < .01). Fasting glucose levels decreased in the ER group (-0.31 +/- 0.48 mmol/L, P < .05), which was correlated with the extent of weight loss (P < .01). Baseline insulin levels at 2 hours after an oral glucose load correlated with baseline PAI activity (P < .001) and PAI-1 antigen levels (P < .001). PAI activity decreased in the ER group (-2.94 +/- 2.90 IU/mL, P < .001), particularly in subjects with a high baseline PAI activity (> 9 IU/mL). Furthermore, energy restriction led to decreased PAI-1 antigen concentration (P < .05), a nonsignificant increase in tPA activity, and a decrease in tPA antigen concentration (P < .001). All these changes were more clear in subjects with a high baseline PAI activity. These results suggest that 10 weeks of moderate energy- restriction has a profibrinolytic effect in non-obese, middle-aged men, at least in subjects with higher baseline PAI activity (> 9 IU/mL). Moreover, in line with the suggestion that high PAI activity goes together with insulin resistance, a relationship between insulin concentration after a glucose load and PAI activity was found.