Inappropriate therapy from atrial fibrillation and sinus tachycardia in automated implantable cardioverter defibrillators.

BACKGROUND: Inappropriate therapy from supraventricular tachyarrhythmias (atrial fibrillation [AF] and sinus tachycardia [ST]) in patients with implanted cardioverter defibrillators is a major challenge. We tested the performance of stability algorithms from 3 manufacturers for episodes of inappropriate therapy delivered because of AF and an onset algorithm for all episodes of inappropriate therapy caused by ST. METHODS: Therapy was classified as caused by ventricular tachycardia (VT), ST, or AF from review of stored intracardiac electrograms, history, clinical information, and R-R data before study inception. By using 30 to 60 R-R intervals before therapy, sensitivity and specificity for a family of stability values and percentage of onset values were calculated for each manufacturer and receiver operating characteristic curves generated. RESULTS: Of the 217 patients monitored, 62 (29%) received inappropriate therapy, and 40 had complete R-R information available. Of the 40 patients, 21 patients received therapy for AF, 19 for ST, and 1 patient for noise; 15 (38%) also received appropriate therapy for VT. We analyzed 83 episodes of VT from 18 patients, 94 episodes of AF from 21 patients, and 56 episodes of ST from 19 patients. Specificity, in the clinically relevant sensitivity range of >/=95%, was comparable across manufacturers at about 40%. An onset value of 80% was associated with 91% sensitivity and 95% specificity for the specific algorithm tested. CONCLUSIONS: Inappropriate therapy is a common problem in implantable cardiac defibrillators. The performance of the stability algorithms used to differentiate AF from VT was less than ideal, though comparable across manufacturers. The onset algorithm accurately differentiates ST from VT.

Characterization of prediction in the primate visual smooth pursuit system.

To define predictive behavior and mechanisms in visual smooth pursuit, various target motions were presented to 2 monkeys. Target stimuli included: single sinusoids (1's), triangle waves (T's), sums of 4 nonharmonically related sinusoids (4's), bandpass limited white noise (B's), and wideband white noise (N's). Velocity error was least for 1's, greatest for N's, and intermediate for T's, 4's, and B's. For the bandlimited 4's and B's, monkeys demonstrated the greatest relative amplitude response at the highest frequencies. Predictive mechanisms are classified as short- and long-term, depending on how much past target motion information is employed. The T's and a modification of this stimulus pattern involving a random perturbation were used to test the hypothesis that prediction is based exclusively on short-term signal processing related to target position and its derivatives. The existence of long-term predictive mechanisms in monkey smooth pursuit was unequivocally demonstrated with the use of the latter stimulus.

Dynamical neural network organization of the visual pursuit system.

The central nervous system is a parallel dynamical system which connects sensory input with motor output for the performance of visual tracking. This paper applies elementary control system tools to extend dynamical neural network models to the visual smooth pursuit system. Observed eye position responses to target motions and characteristics of the plant (eye muscles and orbital mechanics) place dynamical constraints on the interposed neural network controller. In the process of constructing a model for the controller, we show two previous pursuit system models, using efference copy and feedforward compensation, are equivalent from an input-output standpoint. We introduce a controller model possessing a potentially highly parallel implementation and offer an example with supporting neural firing rate data. Changes in time delays or other system dynamics are expected to lead to compensatory adaptive changes in the controller. A scheme to noninvasively simulate such changes in system dynamics was developed. Actual physiologic data of adaptive responses to increased time delay is presented as an example of the utility of this parallel controller. Compensatory changes in our parallel controller model are easily predicted. These results suggest a productive interaction between neural network modeling, neurophysiology, and control systems engineering.

Pulmonary and cardiovascular consequences of immediate fixation or conservative management of long-bone fractures.

We randomly assigned patients with multiple trauma who had tibial or femoral fractures to one of two groups--one group received immediate fixation of all fractures, and the second group received conservative orthopedic management, consisting of traction or plaster casts. Studies were conducted twice each day for four days following injury. Mean cardiac index was 1.3 L/min/m2 higher and mean shunt was 5.2% lower in the immediate fixation group compared with the group receiving conservative treatment. Other pulmonary and systemic hemodynamic variables did not differ between the groups. The incidence of fat macroglobules in blood aspirated from the pulmonary capillaries was higher when compared with that in pulmonary arterial blood but was not significantly different between the two treatment groups. Platelet count was significantly lower and fibrinogen concentration was significantly higher in the group receiving immediate fixation. We found no diagnostic significance of the incidence of fat macroglobules in samples of blood aspirated from the pulmonary circulation. We conclude that patients receiving immediate fixation had less pulmonary dysfunction following multiple trauma and long-bone fractures.

Reversal of opsonic deficiency in surgical, trauma, and burn patients by infusion of purified human plasma fibronectin. Correlation with experimental observations.

Plasma fibronectin deficiency has been documented in critically ill surgical, trauma, and burn patients. Human plasma fibronectin was isolated by gelatin-Sepharose affinity chromatography and evaluated with respect to its opsonic activity following pasteurization, its in vivo clearance kinetics, and its short-term influence on cardiovascular hemodynamics in postoperative septic sheep. Six patients with low plasma fibronectin levels were also evaluated with respect to temporal changes of immunoreactive fibronectin and opsonic activity following infusion of fibronectin at a dose calculated to elevate the plasma fibronectin level to 400 micrograms/ml. With utilization of three different in vitro radioisotopic phagocytic assays, i.e., liver slice assay, peritoneal macrophage monolayer assay, and Kupffer cell monolayer assay, retention of opsonic activity by fibronectin following pasteurization was documented. The normal biphasic kinetics associated with plasma clearance of fibronectin were also not altered by pasteurization. In postoperative septic sheep with hemodynamic instability, intravenous infusion of 500 mg of purified human fibronectin initiated no abnormal hemodynamic response. Indeed, as compared with placebo, the infusion of fibronectin into the postoperative septic sheep resulted in a more stable systemic vascular resistance and pulmonary vascular resistance with a higher arterial pressure. It also elevated immunoreactive fibronectin levels (p less than 0.05) and increased opsonic activity (p less than 0.05). Surgical, trauma, and burn patients (ages 18 to 80 years) with low plasma fibronectin levels (160 to 236 micrograms/ml) manifested no disturbance in cardiovascular, respiratory, or hematologic parameters following fibronectin infusion (590 to 988 mg per patient), but did display an early increase of opsonic activity. This standardized, pasteurized, and opsonically active preparation of purified human plasma fibronectin (5.0 mg/ml after reconstitution) has utility for future randomized clinical trials in injured patients with sepsis.

Clearance from the vascular compartment of endogenously labelled plasma fibronectin.

Plasma fibronectin is a large molecular weight glycoprotein which may have both opsonic and structural adhesive roles. Fibronectin deficiency has been documented in patients especially early after trauma or burn as well as during sepsis following injury. In this study, the disappearance of fibronectin from the blood was studied in rats utilizing plasma fibronectin metabolically labelled with 75Se-selenomethionine. After injection of 75Se-selenomethionine, the maximum specific activity of endogenously labelled plasma fibronectin, the observed at 4 hours. Thereafter, it declined in a non-monoexponential fashion in association with depletion of the precursor. Labelled 75Se fibronectin was purified from donor rat plasma by gelatin-sepharose affinity chromatography. It retained its electrophoretic mobility, gelatin adherence, and opsonic activity similar to that of unlabelled plasma fibronectin. Following intravenous injection of 75Se plasma fibronectin, its disappearance from plasma manifested two phases. The first was an initial fast disappearance of a small amount of fibronectin, reflecting distribution between plasma and interstitial compartments. The second was a slower disappearance phase with a half-time (T 1/2) of at least 15 hours. Infusion of gelatin-coated particles, which are rapidly cleared by RE cells in the liver and spleen, enhanced the disappearance of 75Se fibronectin from the plasma. These data suggest that the normal rate of fibronectin disappearance from the vascular space is quite fast. Utilization of this experimental approach may provide valuable data on fibronectin kinetics as influenced by trauma and burn.

Mechanism of acute depletion of plasma fibronectin following thermal injury in rats. Appearance of a gelatinlike ligand in plasma.

Plasma fibronectin was depleted within 15 min following sublethal burn, followed by partial recovery at 8 h and complete restoration by 24 h in anesthetized rats. Radiolabeled 75Se-plasma fibronectin, injected intravenously before burn, was rapidly sequestered in burn skin as well as the liver. Fibronectin levels at 2 h postburn as detected by immunoassay vs. 75Se-plasma fibronectin indicated that more fibronectin was in the plasma than detected by electroimmunoassay. Crossed immunoelectrophoretic analysis of fibronectin in early postburn plasma demonstrated a reduced electrophoretic mobility of the fibronectin antigen. Addition of heparin or fibrin, both of which have affinity for fibronectin, to normal plasma was unable to reproduce this altered fibronectin electrophoretic pattern. In contrast, addition of gelatin or native collagen to normal plasma reproduced the abnormal electrophoretic pattern of fibronectin seen in burn plasma. Extracts of burned skin, but not extracts of normal skin, when added to normal plasma, elicited a similar altered electrophoretic pattern for fibronectin. By gel filtration, fibronectin in burn plasma had an apparent molecular weight approximately 40% greater than that observed in normal plasma. These data suggest the release into the blood of a gelatinlike ligand from burned skin, which complexes with plasma fibronectin. Thus, fibronectin deficiency acutely postburn appears mediated by (a) its accumulation at the site of burn injury; (b) its removal from the circulation by the liver; and (c) its presence in the plasma in a form that is less detectable by immunoassay.

Kinetics of endogenously labeled plasma fibronectin: incorporation into tissues.

Fibronectin exists in a soluble form in plasma and lymph as well as in a relatively insoluble form in tissues. The disappearance of endogenously labeled fibronectin from plasma and its subsequent extravascular localization was studied over a 38-h period in normal rats (350-400 g) utilizing plasma fibronectin labeled in vivo with 75Se-selenomethionine. For comparative analysis, 125I-albumin was utilized in these dual isotopic experiments. After the simultaneous injection of 75Se plasma fibronectin (20 nCi) and 125I-albumin (2 microCi), all measured tissues demonstrated accumulation of both radiolabeled proteins in extravascular sites. Plasma fibronectin demonstrated a rather specific and high affinity for liver and spleen, which are enriched with reticuloendothelial cells. Albumin manifested the expected washout from extravascular sites, whereas fibronectin primarily displayed retention in tissues. The plasma disappearance of 75Se-labeled fibronectin was well described by two exponentials: an early phase with a half time of 0.52 h and a later phase with a half time of 21 h. To account for tissue retention of labeled fibronectin, a two-compartment kinetics model was required that included loss from the extravascular exchangeable compartment. Analysis of the disappearance kinetics and fibronectin distribution allowed estimation of the fractional turnover rate, pool size, and mean residence time. Accordingly the total rate of loss for plasma fibronectin was 0.51-0.54 mg/h. The calculated pool size of the soluble form of fibronectin was 15.5-16.3 mg. The mean residence time for exchangeable fibronectin was 29.6-29.9 h. These findings suggest that plasma fibronectin can be incorporated within the insoluble pool of fibronectin in tissues.