Resham Baruah

Real-Time Dynamic Carbon Dioxide Administration: A Novel Treatment Strategy for Stabilization of Periodic Breathing With Potential Application to Central Sleep Apnea

OBJECTIVES This study targeted carbon dioxide (CO(2)) oscillations seen in oscillatory ventilation with dynamic pre-emptive CO(2) administration. BACKGROUND Oscillations in end-tidal CO(2) (et-CO(2)) drive the ventilatory oscillations of periodic breathing (PB) and central sleep apnea in heart failure (HF). METHODS Seven healthy volunteers simulated PB, while undergoing dynamic CO(2) administration delivered by an automated algorithm at different concentrations and phases within the PB cycle. The algorithm was then tested in 7 patients with HF and PB. RESULTS In voluntary PB, the greatest reduction (74%, p < 0.0001) in et-CO(2) oscillations was achieved when dynamic CO(2) was delivered at hyperventilation; when delivered at the opposite phase, the amplitude of et-CO(2) oscillations increased (35%, p = 0.001). In HF patients, oscillations in et-CO(2) were reduced by 43% and ventilatory oscillations by 68% (both p < 0.05). During dynamic CO(2) administration, mean et-CO(2) and ventilation levels remained unchanged. Static CO(2) (2%, constant flow) administration also attenuated spontaneous PB in HF patients (p = 0.02) but increased mean et-CO(2) (p = 0.03) and ventilation (by 45%, p = 0.03). CONCLUSIONS Dynamic CO(2) administration, delivered at an appropriate time during PB, can almost eliminate oscillations in et-CO(2) and ventilation. This dynamic approach might be developed to treat central sleep apnea, as well as minimizing undesirable increases in et-CO(2) and ventilation.

Effect of acetazolamide on chemosensitivity, Cheyne-Stokes respiration, and response to effort in patients with heart failure.

Increased chemosensitivity to hypoxia and hypercapnia, together with a prolonged circulatory time, are the main determinants of Cheyne-Stokes (C-S) respiration in heart failure. To evaluate the effect of acetazolamide, a carbonic anhydrase inhibitor, on chemosensitivity and respiratory dynamics in patients with heart failure with C-S respiration, 12 patients (mean age 62 ± 9 years, mean left ventricular ejection fraction 24 ± 9%) and C-S respiration (mean apnea-hypopnea index 23 ± 13) who underwent 4 consecutive days of oral acetazolamide treatment (250 mg twice daily) were enrolled in this study. Assessment of chemosensitivity to hypoxia and hypercapnia, cardiopulmonary stress testing, 24-hour cardiorespiratory polygraphy, and neurohormonal characterization were performed at baseline and at the end of treatment. Acetazolamide improved central apneas (apnea-hypopnea index 23 ± 13 to 15 ± 9, p = 0.012) and the percentage of time spent below an arterial oxyhemoglobin saturation of 90% (16 ± 23% to 10 ± 18%, p = 0.005). Chemosensitivity to hypoxia was blunted (1.03 ± 0.69 to 0.78 ± 0.55 L/min/mm Hg, p = 0.032), while chemosensitivity to hypercapnia increased after acetazolamide (1.27 ± 0.71 to 1.54 ± 0.78 L/min/% arterial oxygen saturation, p = 0.023); patients achieved a lower workload (90 ± 30 to 81 ± 30 W, p <0.001), with no differences in peak oxygen consumption, while there was an increment in the regression slope relating minute ventilation to carbon dioxide output (39 ± 10 to 43 ± 9, p = 0.010). In conclusion, in patients with heart failure, acetazolamide diminishes C-S respiration and improves oxyhemoglobin saturation, likely by decreasing chemosensitivity to hypoxia. However, it is associated with reduced maximal workload achieved during effort and increased chemosensitivity to hypercapnia, inducing a reduction in the ventilatory efficiency.

Contrasting effect of different cardiothoracic operations on echocardiographic right ventricular long axis velocities, and implications for interpretation of post-operative values

Background Patients undergoing coronary artery bypass grafting (CABG) experience a reduction in right ventricular long axis velocities post surgery. Objectives We tested whether the phenomenon of right ventricular (RV) long axis velocity decline depends on the chest being opened fully by mid-line sternotomy, pericardial incision, or on the type of operation performed. Method By intraoperative transoesophageal echocardiography (TEE) we recorded serial right ventricular (RV) systolic pulse-wave tissue Doppler velocities during 6 types of elective procedure: 53 CABG surgery, 15 robotic-assisted minimally-invasive CABG (RCABG), 28 aortic valve replacement (AVR), 8 minimally-invasive aortic valve replacement (mini-AVR), 5 mediastinal mass excision, and 1 left atrial myxoma excision. Pre and post operative transthoracic echocardiography (TTE) were also conducted. Results Surgery without substantial opening of the pericardium did not significantly reduce RV systolic velocities (RCABG 13 ± 1.8 versus 12.4 ± 2.7 cm/s post; mini-AVR 11.9 ± 2.3 versus 11.1 ± 2.3 cm/s; mediastinal mass excision 13.9 ± 3.1 versus 13.8 ± 4 cm/s). In contrast, within 5 min of pericardial incision those whose surgery involved full opening of the pericardium had large reductions in RV velocities: 54 ± 11% decline with CABG (11.3 ± 1.9 to 5.1 ± 1.6 cm/s, p < 0.0001), 54 ± 5% with AVR (12.6 ± 1.4 to 5.7 ± 0.6 cm/s, p < 0.001) and 49% with left atrial myxoma excision (11.3 to 15.8 cm/s). This persisted immediately after pericardial opening to the end of surgery (61 ± 11%, p < 0.0001; 58 ± 7%, p < 0.0001; 59% respectively). Conclusions It is full opening of the pericardium, and not cardiac surgery in general, which causes RV long axis decline following cardiac surgery. The impact is immediate (within 5 min) and persistent.

Dynamic CO2 therapy in periodic breathing: a modeling study to determine optimal timing and dosage regimes

We examine the potential to treat unstable ventilatory control (seen in periodic breathing, Cheyne-Stokes respiration, and central sleep apnea) with carefully controlled dynamic administration of supplementary CO2, aiming to reduce ventilatory oscillations with minimum increment in mean CO2. We used a standard mathematical model to explore the consequences of phasic CO2 administration, with different timing and dosing algorithms. We found an optimal time window within the ventilation cycle (covering ∼1/6 of the cycle) during which CO2 delivery reduces ventilatory fluctuations by >95%. Outside that time, therapy is dramatically less effective: indeed, for more than two-thirds of the cycle, therapy increases ventilatory fluctuations >30%. Efficiency of stabilizing ventilation improved when the algorithm gave a graded increase in CO2 dose (by controlling its duration or concentration) for more severe periodic breathing. Combining gradations of duration and concentration further increased efficiency of therapy by 22%. The (undesirable) increment in mean end-tidal CO2 caused was 300 times smaller with dynamic therapy than with static therapy, to achieve the same degree of ventilatory stabilization (0.0005 vs. 0.1710 kPa). The increase in average ventilation was also much smaller with dynamic than static therapy (0.005 vs. 2.015 l/min). We conclude that, if administered dynamically, dramatically smaller quantities of CO2 could be used to reduce periodic breathing, with minimal adverse effects. Algorithms adjusting both duration and concentration in real time would achieve this most efficiently. If developed clinically as a therapy for periodic breathing, this would minimize excess acidosis, hyperventilation, and sympathetic overactivation, compared with static treatment.

The Acute Effects of Changes to AV Delay on BP and Stroke Volume Potential Implications for Design of Pacemaker Optimization Protocols

Background— The AV delay optimization of biventricular pacemakers (cardiac resynchronization therapy) may maximize hemodynamic benefit but consumes specialist time to conduct echocardiographically. Noninvasive BP monitoring is a potentially automatable alternative, but it is unknown whether it gives the same information and similar precision (signal/noise ratio). Moreover, the immediate BP increment on optimization has been reported to decay away: it is unclear whether this is the result of an (undesirable) decrease in stroke volume or a (desirable) compensatory relief of peripheral vasoconstriction. Methods and Results— To discriminate between these alternative mechanisms, we measured simultaneous beat-to-beat stroke volume (flow) using Doppler echocardiography, and BP using finger photoplethysmography, during and after AV delay changes from 40 to 120 ms in 19 subjects with cardiac pacemakers. BP and stroke volume both increased immediately ( P <0.001, within 1 heartbeat). BP showed a clear decline a few seconds later (average rate, −0.65 mm Hg/beat; r =0.95 [95% CI, 0.86–0.98]); in contrast, stroke volume did not decline ( P =0.87). The immediate BP increment correlated strongly with the stroke volume increment ( r =0.74, P <0.001). The signal/noise ratio was 3-fold better for BP than stroke volume (6.8±3.5 versus 2.3±1.4; P <0.001). Conclusions— Improving AV delay immediately increases BP, but the effect begins to decay within a few seconds. Reassuringly, this is because of compensatory vasodilatation rather than reduction in cardiac function. Pacemaker optimization will never be reliable unless there is an adequate signal/noise ratio. Using BP rather than Doppler minimizes noise. The early phase (before vascular compensation) has the richest signal lode.Background— The AV delay optimization of biventricular pacemakers (cardiac resynchronization therapy) may maximize hemodynamic benefit but consumes specialist time to conduct echocardiographically. Noninvasive BP monitoring is a potentially automatable alternative, but it is unknown whether it gives the same information and similar precision (signal/noise ratio). Moreover, the immediate BP increment on optimization has been reported to decay away: it is unclear whether this is the result of an (undesirable) decrease in stroke volume or a (desirable) compensatory relief of peripheral vasoconstriction. Methods and Results— To discriminate between these alternative mechanisms, we measured simultaneous beat-to-beat stroke volume (flow) using Doppler echocardiography, and BP using finger photoplethysmography, during and after AV delay changes from 40 to 120 ms in 19 subjects with cardiac pacemakers. BP and stroke volume both increased immediately (P<0.001, within 1 heartbeat). BP showed a clear decline a few seconds later (average rate, −0.65 mm Hg/beat; r=0.95 [95% CI, 0.86–0.98]); in contrast, stroke volume did not decline (P=0.87). The immediate BP increment correlated strongly with the stroke volume increment (r=0.74, P<0.001). The signal/noise ratio was 3-fold better for BP than stroke volume (6.8±3.5 versus 2.3±1.4; P<0.001). Conclusions— Improving AV delay immediately increases BP, but the effect begins to decay within a few seconds. Reassuringly, this is because of compensatory vasodilatation rather than reduction in cardiac function. Pacemaker optimization will never be reliable unless there is an adequate signal/noise ratio. Using BP rather than Doppler minimizes noise. The early phase (before vascular compensation) has the richest signal lode.

Multinational evaluation of the interpretability of the iterative method of optimisation of AV delay for CRT

BACKGROUND AV delay optimisation of biventricular pacing devices (cardiac resynchronisation therapy, CRT) is performed in trials and recommended by current guidelines. The Doppler echocardiographic iterative method is the most commonly recommended. Yet whether it can be executed reliably has never been tested formally. METHODS 36 multinational specialists, familiar with using the echocardiographic iterative method of CRT optimisation, were shown 20-40 sets of transmitral Doppler traces at 6-8 AV settings and asked to select the optimal AV delay. Unknown to the specialists, some Doppler datasets appeared in duplicate, allowing assessment of both inter and intra-specialist interpretation. RESULTS On the Kappa scale of agreement (1 = perfect agreement, 0 = chance alone), the agreement regarding optimal AV delay between specialists was poor (kappa=0.12 ± 0.08). More importantly, agreement of specialists with themselves (i.e. viewing identical sets of traces, twice) was also poor, with Kappa=0.23 ± 0.07 and mean absolute difference in optimum AV delay of 83 ms between first and second viewing of the same traces. CONCLUSION Iterative AV optimisation is not executed reliably by experts, even in an artificially simplified context where biological variability and variation in image acquisition are eliminated by use of identical traces. This cannot be blamed on insufficient skills of some experts or discordant methods of selecting the optimum, because operators also showed poor agreement with themselves when assessing the same trace. Instead, guidelines should retract any recommendation for this algorithm. Guideline-development processes might usefully begin with a rudimentary check on proposed algorithms, to establish at least minimal credibility.

Phenotype and Clinical Outcomes of Titin Cardiomyopathy.

Background Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification. Objectives The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM. Methods In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events. Results Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m2 reduction; padjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv+/− groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82). Conclusions In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis.

Induction of oscillatory ventilation pattern using dynamic modulation of heart rate through a pacemaker

For disease states characterized by oscillatory ventilation, an ideal dynamic therapy would apply a counteracting oscillation in ventilation. Modulating respiratory gas transport through the circulation might allow this. We explore the ability of repetitive alternations in heart rate, using a cardiac pacemaker, to elicit oscillations in respiratory variables and discuss the potential for therapeutic exploitation. By incorporating acute cardiac output manipulations into an integrated mathematical model, we observed that a rise in cardiac output should yield a gradual rise in end-tidal CO2 and, subsequently, ventilation. An alternating pattern of cardiac output might, therefore, create oscillations in CO2 and ventilation. We studied the effect of repeated alternations in heart rate of 30 beats/min with periodicity of 60 s, on cardiac output, respiratory gases, and ventilation in 22 subjects with implanted cardiac pacemakers and stable breathing patterns. End-tidal CO2 and ventilation developed consistent oscillations with a period of 60 s during the heart rate alternations, with mean peak-to-trough relative excursions of 8.4 ± 5.0% (P < 0.0001) and 24.4 ± 18.8% (P < 0.0001), respectively. Furthermore, we verified the mathematical prediction that the amplitude of these oscillations would depend on those in cardiac output (r = 0.59, P = 0.001). Repetitive alternations in heart rate can elicit reproducible oscillations in end-tidal CO2 and ventilation. The size of this effect depends on the magnitude of the cardiac output response. Harnessed and timed appropriately, this cardiorespiratory mechanism might be exploited to create an active dynamic responsive pacing algorithm to counteract spontaneous respiratory oscillations, such as those causing apneic breathing disorders.

Fully Automatable, Reproducible, Noninvasive Simple Plethysmographic Optimization: Proof of Concept and Potential for Implantability

Background: Hemodynamic optimization of cardiac resynchronization therapy (CRT) can be achieved reproducibly and—with bulky, nonimplantable equipment—noninvasively. We explored whether a simple photoplethysmogram signal might be used instead.

A systematic approach to designing reliable VV optimization methodology: Assessment of internal validity of echocardiographic, electrocardiographic and haemodynamic optimization of cardiac resynchronization therapy

Background In atrial fibrillation (AF), VV optimization of biventricular pacemakers can be examined in isolation. We used this approach to evaluate internal validity of three VV optimization methods by three criteria. Methods and results Twenty patients (16 men, age 75 ± 7) in AF were optimized, at two paced heart rates, by LVOT VTI (flow), non-invasive arterial pressure, and ECG (minimizing QRS duration). Each optimization method was evaluated for: singularity (unique peak of function), reproducibility of optimum, and biological plausibility of the distribution of optima. The reproducibility (standard deviation of the difference, SDD) of the optimal VV delay was 10 ms for pressure, versus 8 ms (p = ns) for QRS and 34 ms (p < 0.01) for flow. Singularity of optimum was 85% for pressure, 63% for ECG and 45% for flow (Chi2 = 10.9, p < 0.005). The distribution of pressure optima was biologically plausible, with 80% LV pre-excited (p = 0.007). The distributions of ECG (55% LV pre-excitation) and flow (45% LV pre-excitation) optima were no different to random (p = ns). The pressure-derived optimal VV delay is unaffected by the paced rate: SDD between slow and fast heart rate is 9 ms, no different from the reproducibility SDD at both heart rates. Conclusions Using non-invasive arterial pressure, VV delay optimization by parabolic fitting is achievable with good precision, satisfying all 3 criteria of internal validity. VV optimum is unaffected by heart rate. Neither QRS minimization nor LVOT VTI satisfy all validity criteria, and therefore seem weaker candidate modalities for VV optimization. AF, unlinking interventricular from atrioventricular delay, uniquely exposes resynchronization concepts to experimental scrutiny.