Improved patient selection for cardiac resynchronization therapy by normalization of QRS duration to left ventricular dimension.

AIMS: This study evaluates the relative importance of two components of QRS prolongation, myocardial conduction velocity and travel distance of the electrical wave front (i.e. path length), for the prediction of acute response to cardiac resynchronization therapy (CRT) in left bundle branch block (LBBB) patients. METHODS AND RESULTS: Thirty-two CRT candidates (ejection fraction <35%, LBBB) underwent cardiac magnetic resonance (CMR) imaging to provide detailed information on left ventricular (LV) dimensions. Left ventricular end-diastolic volume (LVEDV) was used as a primary measure for path length, subsequently QRSd was normalized to LV dimension (i.e. QRSd divided by LVEDV) to adjust for conduction path length. Invasive pressure-volume loop analysis at baseline and during CRT was used to assess acute pump function improvement, expressed as LV stroke work (SW) change. During CRT, SW improved by +38 ± 46% (P < 0.001). The baseline LVEDV was positively related to QRSd (R = 0.36, P = 0.044). Despite this association, a paradoxical inverse relation was found between LVEDV and SW improvement during CRT (R = -0.40; P = 0.025). Baseline unadjusted QRSd was found to be unrelated to SW changes during CRT (R = 0.16; P = 0.383), whereas normalized QRSd (QRSd/LVEDV) yielded a strong correlation with CRT response (R = 0.49; P = 0.005). Other measures of LV dimension, including LV length, LV diameter, and LV end-systolic volume, showed similar relations with normalized QRSd and SW improvement. CONCLUSION: Since normalized QRSd reflects myocardial conduction properties, these findings suggest that myocardial conduction velocity rather than increased path length mainly determines response to CRT. Normalizing QRSd to LV dimension might provide a relatively simple method to improve patient selection for CRT.

The influence of right ventricular stimulation on acute response to cardiac resynchronisation therapy.

BACKGROUND: The contribution of right ventricular (RV) stimulation to cardiac resynchronisation therapy (CRT) remains controversial. RV stimulation might be associated with adverse haemodynamic effects, dependent on intrinsic right bundle branch conduction, presence of scar, RV function and other factors which may partly explain non-response to CRT. This study investigates to what degree RV stimulation modulates response to biventricular (BiV) stimulation in CRT candidates and which baseline factors, assessed by cardiac magnetic resonance imaging, determine this modulation. METHODS AND RESULTS: Forty-one patients (24 (59 %) males, 67 ± 10 years, QRS 153 ± 22 ms, 21 (51 %) ischaemic cardiomyopathy, left ventricular (LV) ejection fraction 25 ± 7 %), who successfully underwent temporary stimulation with pacing leads in the RV apex (RVapex) and left ventricular posterolateral (PL) wall were included. Stroke work, assessed by a conductance catheter, was used to assess acute haemodynamic response during baseline conditions and RVapex, PL (LV) and PL+RVapex (BiV) stimulation. Compared with baseline, stroke work improved similarly during LV and BiV stimulation (∆+ 51 ± 42 % and ∆+ 48 ± 47 %, both p < 0.001), but individual response showed substantial differences between LV and BiV stimulation. Multivariate analysis revealed that RV ejection fraction (ß = 1.01, p = 0.02) was an independent predictor for stroke work response during LV stimulation, but not for BiV stimulation. Other parameters, including atrioventricular delay and scar presence and localisation, did not predict stroke work response in CRT. CONCLUSION: The haemodynamic effect of addition of RVapex stimulation to LV stimulation differs widely among patients receiving CRT. Poor RV function is associated with poor response to LV but not BiV stimulation.

Magnetic resonance imaging, pacemakers and implantable cardioverter-defibrillators: current situation and clinical perspective.

New developments and expanding indications have resulted in a significant increase in the number of patients with pacemakers and internal cardioverterdefibrillators (ICDs). Because of its unique capabilities, magnetic resonance imaging (MRI) has become one of the most important imaging modalities for evaluation of the central nervous system, tumours, musculoskeletal disorders and some cardiovascular diseases. As a consequence of these developments, an increasing number of patients with implanted devices meet the standard indications for MRI examination. Due to the presence of potential life-threatening risks and interactions, however, pacemakers and ICDs are currently not approved by the Food and Drug Administration (FDA) for use in an MRI scanner. Despite these limitations and restrictions, a limited but still growing number of studies reporting on the effects and safety issues of MRI and implanted devices have been published. Because physicians will be increasingly confronted with the issue of MRI in patients with implanted devices, this overview is given. The effects of MRI on an implanted pacemaker and/or ICDs and vice versa are described and, based on the current literature, a strategy for safe performance of MRI in these patients is proposed. (Neth Heart J 2010;18:31-7.).

Urinary, biliary and faecal excretion of rocuronium in humans.

The excretion of rocuronium and its potential metabolites was studied in 38 anaesthetized patients, ASA I-III and 21-69 yr old. Rocuronium bromide was administered as an i.v. bolus dose of 0.3 or 0.9 mg kg-1. In Part A of the study, the excretion into urine and bile, and the liver content were studied. Plasma kinetics (n = 19) were similar to those reported previously. Urinary recovery within 48 h after administration was 26 (8)% (mean (SD)) (n = 8) of the dose. In bile obtained from T-drains, the recovery within 48 h was 7 (6)% (n = 11). The rocuronium concentration in bile declined bi-exponentially, with half-lives of 2.3 (0.7) and 16 (11) h respectively (n = 6). In three patients from whom stoma fluid was collected, the amount of rocuronium recovered ranged from 0.04 to 12.0% of the dose. In liver tissue obtained from four patients undergoing hemihepatectomy, the estimated amount of rocuronium at 2-5 h after administration ranged between 6.3 and 13.2% (n = 4). In the second part of the study (Part B), urine and faeces were collected over 4-8 days and the recovery was 27 (13)% and 31 (23)% of the dose respectively (n = 10). In most samples, irrespective of the type of biological material, only small amounts of the metabolite 17-desacetyl-rocuronium was found. The results demonstrate that rocuronium is taken up by the liver and excreted into bile in high concentrations. The faecal and urinary excretion of unchanged rocuronium are the major routes of rocuronium elimination.

A large simple randomized trial of rocuronium versus succinylcholine in rapid-sequence induction of anaesthesia along with propofol.

BACKGROUND: Rocuronium has an onset of action more rapid than other non-depolarizing neuromuscular blocking agents, but it is unclear whether it and succinylcholine give equivalent intubating conditions during rapid-sequence induction of anaesthesia. We performed this study to answer the question--are there clinically relevant differences between the use of rocuronium and succinylcholine to secure acceptable intubating conditions during rapid-sequence induction of anaesthesia with propofol? METHODS: Anaesthesia was induced using propofol 2.5 mg/kg in 349 ASA physical status grade I-IV patients who were undergoing either elective or emergency surgery. Propofol was followed immediately by either rocuronium 0.6 or 1 mg/kg or succinylcholine 1.0 mg/kg (randomly selected). Fifty seconds after the end of muscle relaxant injection laryngoscopy was performed and intubating conditions were graded by an experienced anaesthetist blind to the muscle relaxant allocation. This study design was selected so that a 10% difference in clinically acceptable intubating conditions between drugs would be detectable. RESULTS: In this setting rocuronium 1.0 mg/kg provided superior intubating conditions compared with rocuronium 0.6 mg/kg. The incidence of clinically acceptable intubating conditions with rocuronium 1.0 mg/kg and succinylcholine 1.0 mg/kg was 93.2% and 97.1% respectively, the difference being -3.9% (95% C.I. -9.7% to 1.9%). CONCLUSION: Rocuronium 1.0 mg/kg given along with propofol in a rapid-sequence induction of anaesthesia is clinically equivalent to succinylcholine 1.0 mg/kg.

Comparison of rocuronium and suxamethonium for use during rapid sequence induction of anaesthesia.

This study was designed to compare the tracheal intubating conditions during a rapid sequence induction of anaesthesia using rocuronium 0.6 (n = 61) or 1.0 mg.kg-1 (n = 130) or suxamethonium 1.0 mg.kg-1 (n = 127) as the neuromuscular blocking drugs. Anaesthesia was induced with fentanyl 1-2 micrograms.kg-1 and thiopentone 5 mg.kg-1 (median dose) and intubating conditions were assessed 60s after the administration of the neuromuscular blocking drug by an observer unaware of which drug had been given. Intubating conditions were graded on a three-point scale as excellent, good or poor, the first two being considered clinically acceptable. The study was carried out in two parts. At the end of the first part a comparison between the two doses of rocuronium was carried out when at least 50 patients had been enrolled in each group. The results showed the intubating conditions to be significantly superior with the 1.0 mg.kg-1 dose of rocuronium (p < 0.01). Final comparison between the 1.0 mg.kg-1 doses of rocuronium and suxamethonium showed no significant difference in the incidence of acceptable intubations (96 and 97%, respectively). The incidence of excellent grade of intubations was, however, significantly higher with suxamethonium (80% vs. 65%; p = 0.02). It is concluded that rocuronium 1.0 mg.kg-1 can be used as an alternative to suxamethonium 1.0 mg.kg-1 as part of a rapid sequence induction provided there is no anticipated difficulty in intubation. The clinical duration of this dose of rocuronium is, however, 50-60 min.

Persistent augmentation of natural-killer- and T-cell-mediated cytotoxicity in peripheral blood mononuclear cells pulsed in vitro with high-dose recombinant interleukin-2 prior to culturing with a low maintenance dose.

The toxicity of high-dose recombinant interleukin-2 (rIL-2) treatment limits its use in tumour therapies. This paper describes in vitro studies of whether a single, peak rIL-2 dose, followed by low maintenance doses, could enhance the cytotoxic potential of peripheral blood mononuclear cells (PBMC) without inducing a significant sustained release of secondary cytokines, known to contribute to undesirable side-effects of therapy. Pre-pulsing of PBMC with high-dose rIL-2 (16,000 IU/ml for 30 min), followed by low-dose (5 IU/ml) maintenance culturing, was found to induce persistent augmentation of cytotoxic activity towards natural-killer(NK)-sensitive and -insensitive tumour targets, as well as increased T-cell-mediated target cell killing. Under these conditions the level of killing was as high as that achieved by higher maintenance doses (20-100 IU/ml). Although not reflected by overexpression of cell surface markers, enhanced activation of cytotoxic capacities by high-dose pre-pulsing remained clearly apparent for at least 12 days of culture. Increased secondary cytokine production (tumour necrosis factor, interleukin-6 and interferon gamma) was only evident during the first 24-72 h after pulsing, and not at later stages of culturing at the low maintenance dose of 5 IU rIL-2/ml. These results may warrant a human phase-1 B study to investigate the in vivo effect of high-dose prepulsing, followed by low-dose maintenance.

The development of anti-interleukin-2 (IL-2) antibodies in cancer patients treated with recombinant IL-2.

Serum samples from 217 cancer patients participating in phase I/II clinical trials were analysed for the development of anti-interleukin-2 (IL-2) antibodies. Patients received recombinant human IL-2 (rIL-2) by continuous intravenous infusion (c.i.v.; n = 86) or by subcutaneous (s.c.) injections (n = 131). Both patient groups developed anti-rIL-2 antibodies as detected by ELISA with similar frequencies and titres: 52% (median titre, 23) and 47% (median titre, 24), respectively. Using an IL-2-dependent T-cell proliferation assay, sera from 5 c.i.v.-treated patients (6%) and 13 s.c.-treated patients (10%) exhibited neutralising activity. Immunoabsorption studies with rIL-2-coated beads, demonstrated that in 8 of 15 patients with neutralising sera, the neutralising activity was correlated with specific anti-rIL-2 immunoglobulin. All 8 patients had received at least two cycles of rIL-2 by s.c. injections. Specific IL-2 neutralising activity affected both recombinant and natural IL-2 in all 8 patients. Development of anti-rIL-2 antibodies, irrespective of whether these exhibited neutralising activity or not, did not affect the frequency or duration of clinical responses.

Evaluation of the safety of recombinant interleukin-2 (rIL-2) and rIL-2 plus 5-fluorouracil (5-FU) in the adjuvant treatment of gastric cancer patients.

Eight patients received either recombinant Interleukin-2 (rIL-2) alone or rIL-2 plus 5-Fluorouracil (5-FU) by constant infusion after undergoing potentially curative surgery for gastric cancer. rIL-2, given at a dose of 18 x 10(6) IU/m2/24 hours, was safely tolerated and only two episodes of WHO grade 3 toxicities occurred, both of which promptly responded to treatment and temporary interruptions of rIL-2 infusions. 5-FU infusions given at 12.5 mg/kg/24 hours did not alter the rebound lymphocytosis seen after completion of rIL-2 infusions. We conclude that the administration of rIL-2 and rIL-2 plus 5-FU to cancer patients recovering from major surgery is safe and well tolerated.

Intravesical therapy of superficial bladder transitional cell carcinoma with tumor necrosis factor-alpha: preliminary report of a phase I-II study.

A phase I-II trial of intravesical immunotherapy with tumor necrosis factor (TNF)-alpha in 24 patients affected by superficial bladder tumors is herein presented. Of these, 11 patients were submitted, at weekly intervals, after complete TUR, to 8 instillations of TNF-alpha at increasing doses from 50 to 600 micrograms. Tolerability was excellent, even at the highest dose. In a second group of 13 patients with a histologically proved papillary marker lesion, TNF-alpha was instilled at weekly intervals at the dose of 500 micrograms for 8 weeks. Three complete responses (23%) were obtained.

Continuous infusion of recombinant interleukin-2 with or without autologous lymphokine activated killer cells for the treatment of advanced renal cell carcinoma.

Data have been analysed for 327 patients with advanced renal cell carcinoma receiving a continuous infusion of recombinant interleukin 2 (rIL-2) alone (225 patients) or rIL-2 plus lymphokine activated killer (LAK) cells (102) on a normal oncology ward. Eligibility criteria were uniform across protocols, all patients having advanced progressive disease, but with an ambulatory performance status. The baseline characteristics of patients receiving rIL-2 alone did not differ significantly from those receiving LAK, with the exception that the LAK treated patients had a better performance status. Despite similar treatment intensity, toxicity was more severe in the patients receiving LAK. The addition of LAK did not lead to higher response rates or to prolonged response duration, progression-free survival or survival. This review confirms the activity of rIL-2 for the treatment of advanced renal cell carcinoma and demonstrates that the addition of LAK cells does not lead to increased efficacy.

Sequential dacarbazine chemotherapy followed by recombinant interleukin-2 in metastatic melanoma. A pilot multicentre phase I-II study.

Between April 1988 and August 1989, 30 melanoma patients were entered in a multicentre Phase II study of dacarbazine (DTIC) 850 mg/m2 i.v. bolus on day 1, and recombinant interleukin-2 (rIL-2) (Cetus) 18 x 10(6) IU/m2/day i.v. continuous infusion on days 4-9. Six treatment cycles were given: the first two at an interval of 13 days, and further cycles at intervals of 20 days. Twenty patients are currently evaluable for toxicity and 18 for response. Two of these patients presented with metastatic intraocular melanoma. Median age was 48 years (range 18-83), and median Karnofsky index was 100 (range 80-100). Four patients had received prior radiotherapy and one had received prior immunotherapy. Seventeen patients received two cycles of treatment and nine patients received three or more cycles. Four patients responded (22%): two complete remissions and two partial remissions. Stable disease was seen in six patients (33%). Responses occurred in the lung, skin, spleen and lymph nodes. Seventy-five percent of the patients received the full dose of rIL-2 during cycle 1, whilst only 2 out of 9 (22%) received the planned dose on the third cycle. Rebound lymphocytosis of 5.3 x 10(3)/L (range 1.2-18.1) occurred 24-48 h after rIL-2, but was not predictive for response. Currently, there is no evidence that pretreatment with DTIC impacts negatively on the rIL-2-stimulated lymphocyte proliferation. The toxicity profile of this treatment regimen did not differ significantly from that already described for similar regimens of rIL-2. However, in this interim analysis, there was a trend for a higher percentage of patients (25%) to experience severe weight gain (greater than 10%). This study shows that this treatment regimen is active in metastatic melanoma, with acceptable toxicity. Further research will focus on using other chemotherapeutic agents and/or other biological response modifiers (e.g. interferons, tumour necrosis factor) in combination with rIL-2.

Increase of enkephalin and decrease of substance P immunoreactivity in the dorsal and ventral striatum of the rat after midbrain 6-hydroxydopamine lesions.

Unilateral 6-hydroxydopamine lesions of the mesostriatal dopaminergic system in the rat resulted in a decrease of substance P-immunoreactivity in the ventral striatum, and in a heterogeneously distributed increase of enkephalin-immunoreactivity in the dorsal and ventral striatum and the globus pallidus. The respective decrease and increase are caused by a lower or higher staining intensity of the peptidergic fibers, whereas no changes were found in the cell bodies.

[The presence of antibodies to IBR/IPV virus in cattle in the environs of Leyden (author's transl)]. / Het voorkomen van antistoffen tegen I.B.R./I.P.V. bij runderen in de omgeving van Leiden

The appearance of IBR among cattle in the environs of Leyden is reported. Possible explanations of local differences in the incidence of IBR and possible effects on IBR immunisation of cattle in these areas are referred to in the discussion.