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Four recent trials compared the strategies of rate control vs rhythm control in patients with atrial fibrillation. All of them found a rate control strategy to be equivalent to a rhythm control strategy in terms of primary outcomes, but the findings may not apply equally to all patients.
BACKGROUND: Cryopreservation of hematopoietic cells with the rate-controlled method is used in the majority of centers. In recent years, there has been a trend toward the simplification of the process. STUDY DESIGN AND METHODS: A simplified method for cryopreservation was developed with 5-percent dimethyl sulfoxide (DMSO) as the sole cryoprotectant without rate-controlled freezing. Experiments were done with progressive concentrations of DMSO, ranging from 0 to 10 percent. With DMSO concentrations from 5- to 10-percent, the best recovery and viability for hematopoietic progenitor cells were observed. Hematopoietic progenitor cells with plasma and 5-percent DMSO were frozen and stored in a -80 degrees C mechanical freezer. Ten patients with solid and hematologic malignancies underwent transplantation with autologous hematopoietic progenitor cells. RESULTS: The median number of transfused mononuclear cells and CD34+ cells was 3.70 (3.1-8.2) x 10(8) per kg and 1.70 (0.8-6.5) x 10(6) per kg, respectively. The median number of transfused colony-forming units-granulocyte-macrophage was 12.45 (3.4-55.3) x 10(4) per kg. All patients showed rapid and sustained engraftment. The mean times to reach a neutrophil count of 0.5 x 10(9) per L and a platelet count of 50 x 10(9) per L were 11.50 +/- 1.70 and 13.90 +/- 3.98 days, respectively. All patients are alive and without transfusion requirements in complete remission 2 to 8 months after transplantation. CONCLUSION: This simplified cryopreservation technique will be useful for institutions without rate-controlled freezing facilities. Moreover, this method diminishes the amount of DMSO infused to patients, as well as its toxicity.
Atrial fibrillation is the most common sustained arrhythmia. Based on multiple large randomized trials, rate control therapy has been shown to be safe and effective and is gaining greater acceptance as a frontline alternative to drugs to maintain sinus rhythm. Adequate rate control can be achieved by atrioventricular nodal blocking agents both in the acute and chronic settings. In refractory patients, other methods such as atrioventricular node ablation can be used to control rate.
STUDY OBJECTIVES: The relative risks and benefits of strategies of rate control vs rhythm control in patients with atrial fibrillation (AF) remain to be fully explored. DESIGN: The How to Treat Chronic Atrial Fibrillation (HOT CAFE) Polish trial was designed to evaluate in a randomized, multicenter, and prospective manner the feasibility and long-term outcomes of rate control vs rhythm control strategies in patients with persistent AF. PATIENTS: Our study population comprised 205 patients (134 men and 71 women; mean [+/- SD] age, 60.8 +/- 11.2 years) with a mean AF duration of 273.7 +/- 112.4 days. The mean observation period was 1.7 +/- 0.4 years. One hundred one patients were randomly assigned to the rate control group and received rate-slowing therapy guided by repeated 24-h Holter monitoring. Direct current cardioversion and atrioventricular junctional ablation with pacemaker placement were alternative nonpharmacologic strategies for patients with tachycardia that was resistant to medical therapy. One hundred four patients were randomized to sinus rhythm restoration and maintenance using serial cardioversion supported by a predefined stepwise antiarrhythmic drug regimen (ie, disopyramide, propafenone, sotalol, and amiodarone). In both groups, thromboembolic prophylaxis followed current guidelines. MEASUREMENTS AND RESULTS: At the end of follow-up, 63.5% of patients in the rhythm control arm remained in sinus rhythm. No significant differences in the composite end point (ie, all-cause mortality, number of thromboembolic events, or major bleeding) were found between the rate control group and the rhythm control group (odds ratio, 1.98; 95% confidence interval, 0.28 to 22.3; p > 0.71). The incidence of hospital admissions was much lower in the rate control arm (12% vs 74%, respectively; p < 0.001). New York Heart Association functional class improved in both study groups, while mean exercise tolerance, as measured by the maximal treadmill workload, improved only in the rhythm control group (5.2 +/- 5.1 vs 7.6 +/- 3.3 metabolic equivalents, respectively; p < 0.001). The rhythm control strategy led to an increased mean left ventricular fractional shortening (29 +/- 7% vs 31 +/- 7%, respectively; p < 0.01). One episode of pulmonary embolism occurred in the rate control group despite oral anticoagulation therapy, while three patients in the rhythm control arm of the study experienced ischemic strokes (not significant). CONCLUSIONS: The Polish HOT CAFE study revealed no significant differences in major end points between the rate control group and the rhythm control group.
1. Ethanol was oxidised more slowly by rats which were given an ethanol dose of 5.1 g/kg than by rats which were given an ethanol dose of 1.4 g/kg. 2. A positive correlation was found between [lactate]/[pyruvate] ratios and rates of ethanol oxidation. 3. Acetaldehyde concentrations varied widely between rats, but in some cases were high enough to influence rates of ethanol oxidation. 4. Liver alcohol dehydrogenase levels were just sufficient to account for ethanol oxidation rates observed in vivo. 5. Pre-administration of a large ethanol dose (6.5 g/kg) did not alter mean [lactate]/[pyruvate] ratios or ethanol oxidation rates during metabolism of test doses of 2.5 g/kg. 6. Injection of pyruvate did not increase rates of ethanol oxidation. 7. The results do not support suggestions that a high-Km ethanol oxidising system plays an important role in vivo, that increased rates of ethanol oxidation can be induced by large, acute ethanol doses or that the rate of NADH reoxidation controls rates of ethanol metabolism. 8. The results support other evidence which has indicated that the level of alcohol dehydrogenase is the major factor limiting rates of ethanol oxidation in vivo.
Patients with cardiac disorders have defective parasympathetic control of heart rate. To evaluate the possibility of similar changes in sympathetic control of heart rate, we compared reflex chronotropic responses to 80 degree upright tilt and nitroglycerin-induced hypotension in 31 cardiac patients and 7 normal individuals before and after partial parasympathetic blockade with atropine. Tilting revealed an attenuation of the normal heart rate increase in patients; the magnitude of this defect was greatest in patients with more severe symptoms (class III) and evidence of left ventricular dysfunction (the heart rate increase averaged 25 plus or minus 3 beats/min in normal subjects, 12 plus or minus 2 beats/min in class I-II patients, and 7 plus or minus 1 beats/min in class III patients). Class III symptoms due to mechanical causes (mitral stenosis), however, were not associated with this defect. A marked reduction in heart rate rise with hypotension was seen only in those class III patients without mitral stenosis (0.4 plus or minus 0.1 beats min-minus 1 mm Hg-minus 1 vs. 3.0 plus or minus 0.5 beats min-minus 1 mm Hg-minus 1 in normal subjects). This abnormality also persisted after atropine administration, thus confirming a defect in the sympathetic as well as the parasympathetic component of baroreceptor-mediated reflex heart rate control in patients with cardiac dysfunction. Infusions of isoproterenol produced equivalent rises in heart rate in patients and normal individuals, excluding a reduction in beta-receptor responsiveness as a cause of impaired sympathetic influence. Norepinephrine depletion, however, is a well-recognized concomitant of cardiac failure. It is possible that the reduction in sympathetically mediated heart rate responses results in part from depletion of the sympathetic neurotransmitter.
Spermatozoa from three species, bovine, ovine, and porcine, were frozen using standard techniques in two controlled-rate cooling machines, a commercial instrument and a custom-built device. Ice crystallisation was induced mechanically by touching the straws with a pre-cooled rod. The sperm samples were stored 24h, and then thawed rapidly and evaluated for motility, viability, and acrosomal integrity in the membrane-intact population. The custom-built controlled-rate cooling machine proved significantly better at all cooling rates for all species. This was particularly evident for the ram and the boar spermatozoa. In general, -30 or -50 degrees C/min were better than -1 degrees C/min, with a slight advantage being evident for -30 degrees C/min. However, this became very apparent for boar spermatozoa. It is clear that the higher cooling rates are necessary for successful freezing of spermatozoa from these species, and that careful control of the cooling rate is essential for maximal recovery of viable and functional cells. This is best achieved when the cooling profile is controlled from within a dummy sample.
We assess whether AV node ablation and pacemaker implantation after discontinuation of effective rate-control medical therapy for chronic atrial fibrillation had a positive impact on quality of life and exercise performance. To assess the possibility of a placebo effect following pacemaker implantation, the study included three groups of patients. Group 1 underwent an echocardiogram, treadmill exercise, and quality of life measurement 1 month prior to and 6 months following AV node ablation and pacemaker implantation associated with discontinuation of rate-control medications. Group 2 underwent AV node ablation and pacemaker implantation without discontinuation of antiarrhythmic rate-control drugs. Group 3 underwent pacemaker implantation without performing AV node ablation and continuing rate-control medical therapy. At the 1- and 6-month evaluation, the patients in group 1 showed a significant improvement of left ventricular ejection fraction, quality of life, and activity scores. The exercise duration and the maximal VO2 consumption, however, did not change significantly. A slight improvement of the quality of life and physical activity scores was observed in the group undergoing AV node ablation without withdrawal of medications. However, no significant changes were observed in the group receiving only the pacemaker without modification of medical therapy and with intact AV node conduction. In conclusion, in patients with chronic atrial fibrillation, discontinuation of effective rate-control medical therapy followed by AV node ablation and permanent pacing appeared to improve quality of life and activity scores despite no change in exercise duration. The improvement observed does not seem to reflect a placebo effect.
The effect and choice of a drug to control heart rate for symptomatic improvement in patients with isolated mitral stenosis with normal sinus rhythm (n = 10) or atrial fibrillation (n = 10) were studied. Digoxin (0.25-0.5 mg daily), metoprolol (50-100 mg twice a day) and verapamil (40-80 mg three times a day) were evaluated for this purpose. An open randomised cross-over design was followed. The efficacy of a drug was evaluated by: (1) subjective improvement on a visual analog scale, and (2) objective improvement on repeated multi-stage symptom-limited treadmill exercise. In patients with sinus rhythm greater than or equal to 50% subjective improvement was seen in 90%, 40% and nil with metoprolol, verapamil and digoxin, respectively. The total work done by these patients was 1008 +/- 541 kpm (control), 2869 +/- 1418 kpm on metoprolol, 2369 +/- 884 kpm on verapamil and 1654 +/- 918 kpm on digoxin. In patients with atrial fibrillation greater than or equal to 50% subjective improvement was seen in 80%, 40% and 30% with verapamil, metoprolol and digoxin, respectively. The total work done by these patients was 555 +/- 232 kpm (control), 1379 +/- 553 kpm on verapamil, 1251 +/- 575 kpm on metoprolol and 716 +/- 340 kpm on digoxin. The degree of improvement on a drug appeared to be a function of its ability to control resting and exercise heart rates in two different rhythms in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Fuzzy theory was applied to the rate control of a cardiac pacemaker which uses two parameters, respiratory rate and temperature, as the parameters for rate regulation. Using 25 fuzzy reasoning rules derived from five mongrel dogs, the pacing rates in three animals were calculated and compared with the intrinsic heart rates. It is concluded that the fuzzy method is well suited for the rate determination of a multi-parameter rate-responsive cardiac pacemaker.
We conducted a randomized prospective study of the cryopreservation of one-cell human embryos, comparing a slow controlled-rate freezing procedure with a rapid cooling procedure by direct plunging into liquid nitrogen. We analysed the numbers of embryos that were recovered immediately after thawing (= recovery), the number of embryos morphologically intact after thawing and subsequent dilution of the cryoprotectants (= survival), the numbers of embryos undergoing further cleavage after 24 h of in-vitro culture (= cleavage) and the implantation of transferred embryos (= children born per frozen-thawed embryo transferred). We demonstrated that the recovery of embryos was greater after slow controlled-rate freezing. Survival was greater after rapid cooling and the number of embryos undergoing further cleavage was higher after slow controlled-rate freezing. Although the birth rate was twice as high after slow controlled-rate freezing as after rapid cooling, this difference was not statistically significant. In conclusion, our results show clearly that for the freezing of one-cell human embryos, slow controlled-rate freezing is more efficient than rapid cooling. Before rapid cooling is used routinely in clinical in-vitro fertilization programmes, its safety and reproducibility must be convincingly demonstrated.
A recent series of randomized prospective clinical trials that compared rate control with rhythm control in patients with atrial fibrillation (AF) found no significant difference in primary outcome between the two strategies. However, these trials lacked clear criteria for defining "successful" rate or rhythm control. Various measures have been used to gauge the success of antiarrhythmic drug therapy, including time to first recurrence of AF, any AF recurrence, AF burden, and a reduction in symptoms. Determining the success of antiarrhythmic therapy can be relatively straightforward by using how patients feel during therapy as a key endpoint. Most patients are satisfied with a major reduction in symptomatic AF episodes and can live comfortably with occasional episodes of AF. For those who are bothered by even infrequent, brief AF episodes, a treatment regimen that eliminates nearly all AF recurrences is required, although often hard to achieve. Catheter ablation may be necessary to achieve a successful outcome in these patients. Suppression of AF in a patient at high risk of stroke does not, however, remove the need for concomitant warfarin therapy. The endpoints of ventricular rate control are not clear, and the recently published rhythm versus rate control trials lacked standard criteria for judging acceptable rate control. One relatively simple method is to try and achieve a 24-hour heart rate that mimics expected normal sinus rhythm. It is important to achieve good rate control to minimize symptoms and the risk of tachycardia-mediated cardiomyopathy.
The present investigation assessed the physiological response patterns which accompany heart-rate control performance, both early and late in training. Six subjects were employed who received six heart-rate control training sessions, half of which were speeding sessions and half of which were slowing. Heart rate, skin resistance, frontalis EMG, systolic and diastolic blood pressure, and respiration rate were continuously recorded throughout all training sessions. Results indicated that the physiological response topography during heart-rate control performance changes from early to late training. Moreover, the changes are different for speeding and slowing performance, suggesting the involvement of different underlying physiological mechanisms in the two tasks.
AIMS: To systematically assess the risk/benefit ratio of a rate-control strategy vs. a rhythm-control strategy in patients with first or recurrent atrial fibrillation (AF). METHODS AND RESULTS: We searched Medline, CENTRAL, and other sources up to September 2004 for randomized trials. Individual and pooled random-effect odd ratios (OR) and 95% confidence intervals (CI) [OR (95% CI)] were calculated for the combined endpoint of all cause death and thromboembolic stroke (CEP), major bleeds (intra and extracranial), and systemic embolism. Number needed to treat (NNT) to avoid one CEP and heterogeneity were also assessed. Five studies enrolling 5239 patients with AF compared rate-control vs. rhythm-control. Average follow-up ranged from 1 to 3.5 years. A rate-control strategy compared with a rhythm-control approach was associated with a significantly reduced risk of CEP [OR 0.84 (0.73, 0.98), P=0.02], and with a trend towards a reduced risk of death [OR 0.87 (0.74, 1.02), P=0.09] and thromboembolic stroke [OR 0.80 (0.6, 1.07), P=0.14]. NNT to save one CEP was 50. There was no significant difference in the risk of major bleeds [OR 1.14 (0.9, 1.45), P=0.28] and systemic embolism [OR 0.93 (0.43, 2.02), P=0.90]. No significant heterogeneity was found in any of the analyses (P>0.1). CONCLUSION: This meta-analysis of 5239 patients with AF indicates that an initial rate-control strategy compared with a rhythm-control one is associated with a better prognosis, thus representing the standard treatment against which to test new therapeutic approaches.
A number of programmable rate-controlled drug delivery technologies have been developed during the last two decades with the aim of regulating the rate of drug delivery, sustaining the duration of therapeutic action and/or targeting the delivery of drug to a specific tissue. As a result, several therapeutically beneficial outcomes can be achieved, such as: (i) controlled delivery of a therapeutic dose at a desirable rate of delivery; (ii) maintenance of drug concentrations within an optimal therapeutic range for prolonged duration of treatment; (iii) maximisation of efficacy-dose relationship; (iv) reduction of adverse effects; (v) minimisation of the need for frequent dose intake; and (vi) enhancement of patient compliance. The treatment of illness can thus be optimised. To gain a better understanding of how to optimise the treatment of illnesses by applying programmable rate-controlled drug delivery technologies, this article reviews the scientific concepts and technical principles behind the development of various programmable rate-controlled drug delivery systems that have been marketed or are under active development. Finally, the roles of these technologies in optimising therapeutic outcomes in nine therapeutic areas are discussed.
BACKGROUND: Cryobiologic variables responsible for cell injuries and freezing techniques applicable in medical cryopractice should be revised and/or reengineered for minimizing cryoinjuries and maximizing cell recovery. In this study, the efficacy of different cryopreservation protocols based on platelet (PLT) recovery was evaluated. STUDY DESIGN AND METHODS: PLTs (n = 33) were prepared from whole-blood units. Cell count and viability, PLT morphologic score (PMS), and hypotonic shock response were determined. PLT surface antigens were measured by flow cytometry. Controlled-rate (with compensated fusion heat) and uncontrolled-rate freezing methods combined with 6 percent dimethyl sulfoxide were used. RESULTS: PLT recovery was superior in the controlled-rate setting (91.0 +/- 5.5 vs. 86.0 +/- 6.5; p < 0.05). PMS was significantly better in controlled-rate freezing (p < 0.01). GPIb/CD42b expression was reduced in both freezing groups versus control. GP140/CD62p expression was significantly (p < 0.05) lower in the controlled-rate group and in both frozen groups was significantly higher than in the control groups. CONCLUSION: The use of strictly equalized (1 degrees C/min) controlled-rate freezing, combined with an intensified cooling rate (2 degrees C/min) during the liquid-to-solid-phase transition period, allows advanced quantitative and qualitative PLT recovery, even though the minor intergroup differences for some variables were observed.
Standardization of protocols for processing peripheral blood stem cells (PBSC) will be important for multiinstitutional studies. For this reason, a strategy was developed utilizing the small volume collection chamber (SVCC) in the Fenwal CS-3000 PLUS Blood Cell Separator and cryopreservation without a rate controller in medium containing pentastarch. Use of the SVCC allows for a small extracorporeal volume, extraction of a minimal number of platelets, and a high efficiency of mononuclear cell (MNC) removal. Advantages of the pentastarch cryopreservation technique include reduction in technician time compared to controlled rate cryopreservation and use of lower concentrations in DMSO. Clinical studies using the SVCC and pentastarch technique demonstrate that these goals have been accomplished. Furthermore, patients transplanted with cells that were processed by this technique engrafted faster and were discharged sooner than patients receiving autologous bone marrow transplants.
UNLABELLED: Our sub study was designed to analyze the cost effectiveness of two alternative treatment strategies with a view to improved allocation of the limited therapeutic resources. To that effect we conducted detailed analysis of the related costs and other relevant data collected in the course of the HOT CAFE study. METHODS: The prospective costs related to 205 patients randomly assigned to rhythm or rate control were traced over a 12 month period. Since, both strategies produced similar clinical outcomes a cost minimization analysis was undertaken. The cost of diagnostic and treatment procedures, including hospitalization, outpatient visits, drugs and physicians consultations were estimated for both groups. RESULTS: The study population comprised 205 patients (mean age 60.8 year; 35% females). A hundred and one patients were randomly assigned to the rate control group with the pharmacological heart rate frequency optimization treatment combined with Holter monitoring. A hundred and four patients were randomized to sinus rhythm (SR) restoration with its subsequent maintenance with sequential antiarrhythmic drug treatment. There was no significant difference in the composite primary end-point (all-cause mortality, number of thromboembolic and major bleeding events). The hospital admissions rate was significantly higher in the rhythm control than the rate control arm (202 vs. 5, respectively). The conservative strategy involving pharmacological ventricular rate control proved to be less costly than rhythm control (1225 euros vs. 2526 euros; p<0.001). The main cost driver behind the established difference was the cardioversion related hospitalization. CONCLUSIONS: The cost effectiveness appraisal seems to have supported the rate control strategy as less costly due to the lower hospitalization rate as a major cost carrier.