Standards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement.

Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).

Sustainable design of pavement systems in highly urbanized context: A lifecycle assessment.

Substantial amount of resources is consumed by pavement systems, which have resulted considerable environmental impacts. Understanding the environmental impacts would provide opportunity for reducing resource consumption and informing decision-makers in the process of designing sustainable pavement. There is a lacking of comprehensive and comparative sustainability assessment of pavement systems in highly urbanized context currently. Therefore, this study aims to design and comprehensively evaluate the environmental performance of the commonly adopted pavement systems in highly urbanized context using lifecycle assessment (LCA) technique through a case in Hong Kong. According to the codes and practices of Hong Kong, two pavement systems including flexible and rigid pavements were designed based on the same road section. After that interviews with structured questionnaire were conducted to collect relevant practical information of pavement construction and maintenance from the relevant professional bodies and experts for the subsequent LCA of such designs. The LCA results reveal that the two mid-point impacts of global warming potential and mineral extraction are 21% and 54% higher for rigid pavement than for flexible pavement. Yet, the end-point results indicate that flexible pavement is associated with 64%, 65%, and 69% higher human health impact, ecosystem quality damage, and resource damage, respectively. Material production and transportation contribute significantly to the total impact in the two pavement systems. For instance, it is about 57% and 97% of the total global warming potential for flexible and rigid pavements, respectively. The overall results demonstrated that 49% higher total impact was found for flexible pavement than rigid pavement. Therefore, the use of more recycled and environmentally friendly materials can potentially enhance the environmental sustainability of both pavement systems. The findings should provide useful information to the design and selection of sustainable pavement structures in resource-scarce highly-urbanized cities.

Successful continuous positive airway pressure treatment reduces skin sympathetic nerve activity in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with cardiovascular diseases and increased sympathetic tone. We previously demonstrated that patients with OSA have increased skin sympathetic nerve activity (SKNA). OBJECTIVE: The purpose of this study was to test the hypothesis that continuous positive airway pressure (CPAP) treatment reduces SKNA. METHODS: The electrocardiogram, SKNA, and polysomnographic recording were recorded simultaneously in 9 patients with OSA. After baseline recording, CPAP titration was performed and the pressure was adjusted gradually for the optimal treatment, defined by reducing the apnea-hypopnea index (AHI) to ≤5/h. Otherwise the treatment was considered suboptimal (AHI > 5/h). Fast Fourier transform analyses were performed to investigate the frequency spectrum of SKNA. RESULTS: There were very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations in SKNA. The HF oscillation matched the frequency of respiration. OSA episodes were more frequently associated with the VLF and LF than with the HF oscillations of SKNA. Compared with baseline, CPAP significantly decreased the arousal index and AHI and increased the minimal and mean oxyhemoglobin levels. Optimal treatment significantly increased the dominant frequency and reduced the heart rate, average SKNA (aSKNA), SKNA burst duration, and total burst area. The dominant frequency negatively correlated with aSKNA. CONCLUSION: VLF, LF, and HF oscillations are observed in human SKNA recordings. Among them, VLF and LF oscillations are associated with OSA while HF oscillations are associated with normal breathing. CPAP therapy reduces aSKNA and shifts the frequency of SKNA oscillation from VLF or LF to HF.

Skin sympathetic nerve activity as a biomarker of fitness.

BACKGROUND: Exercise stress testing is frequently used to expose cardiac arrhythmias. Aerobic exercise conditioning has been used as a nonpharmacologic antiarrhythmic intervention. OBJECTIVE: The purpose of this study was to test the hypothesis that noninvasively recorded skin sympathetic nerve activity (SKNA) is increased during exercise and that SKNA response varies according to fitness levels. METHODS: Oxygen consumption (VO2) and SKNA were recorded in 39 patients undergoing an incremental exercise test. Patients were grouped by 5 levels of fitness based on age, sex, and VO2max. RESULTS: With exercise, all patients had a significant increase in average SKNA (aSKNA) (1.58 ± 1.12 µV to 4.50 ± 3.06 µV, P = .000) and heart rate (HR) (87.40 ± 20.42 bpm to 154.13 ± 16.82 bpm, P = .000). A mixed linear model of aSKNA was used with fixed effects of fitness, exercise time, and recovery time, and random effects of subject level intercept and slopes for exercise time and recovery times. The poor fitness group had significantly higher aSKNA than the other groups (P = .0273). For all subjects studied, aSKNA increased by 5% per minute with progression of exercise and decreased by 15% per minute with progression of recovery. The fitness variable encodes information on both comorbidities and body mass index (BMI). Once fitness level is known, comorbidities and BMI are not significantly associated with aSKNA. In all groups, aSKNA positively correlated with HR (R2 = 0.47 ± 0.23) and VO2 (R2 = 0.68 ± 0.25). CONCLUSION: Fitness level determines the magnitude and time course of SKNA increase during exercise. SKNA may be a useful fitness biomarker in exercise stress testing.

Skin sympathetic nerve activity as a biomarker for neurologic recovery during therapeutic hypothermia for cardiac arrest.

BACKGROUND: Targeted temperature management (TTM) improves neurologic outcome after cardiac arrest. However, better neurologic prognostication is needed. OBJECTIVE: The purpose of this study was to test the hypothesis that noninvasive recording of skin sympathetic nerve activity (SKNA) and its association with heart rate (HR) during TTM may serve as a biomarker of neurologic status. METHODS: SKNA recordings were analyzed from 29 patients undergoing TTM. Patients were grouped based on Clinical Performance Category (CPC) score into group 1 (CPC 1-2) representing a good neurologic outcome and group 2 (CPC 3-5) representing a poor neurologic outcome. RESULTS: Of the 29 study participants, 18 (62%) were deemed to have poor neurologic outcome. At all timepoints, low average skin sympathetic nerve activity (aSKNA) was associated with poor neurologic outcome (odds ratio 22.69; P = .002) and remained significant (P = .03) even when adjusting for presenting clinical factors. The changes in aSKNA and HR during warming in group 1 were significantly correlated (ρ = 0.49; P <.001), even when adjusting for corresponding temperature and mean arterial pressure measurements (P = .017), whereas this correlation was not observed in group 2. Corresponding to high aSKNA, there was increased nerve burst activity during warming in group 1 compared to group 2 (0.739 ± 0.451 vs 0.176 ± 0.231; P = .013). CONCLUSION: Neurologic recovery was retrospectively associated with SKNA. Patients undergoing TTM who did not achieve neurologic recovery were associated with low SKNA and lacked a significant correlation between SKNA and HR. These preliminary results indicate that SKNA may potentially be a useful biomarker to predict neurologic status in patients undergoing TTM.

Recording Intrinsic Nerve Activity at the Sinoatrial Node in Normal Dogs With High-Density Mapping.

BACKGROUND: It is known that autonomic nerve activity controls the sinus rate. However, the coupling between local nerve activity and electrical activation at the sinoatrial node (SAN) remains unclear. We hypothesized that we would be able to record nerve activity at the SAN to investigate if right stellate ganglion (RSG) activation can increase the local intrinsic nerve activity, accelerate sinus rate, and change the earliest activation sites. METHODS: High-density mapping of the epicardial surface of the right atrium including the SAN was performed in 6 dogs during stimulation of the RSG and after RSG stellectomy. A radio transmitter was implanted into 3 additional dogs to record RSG and local nerve activity at the SAN. RESULTS: Heart rate accelerated from 108±4 bpm at baseline to 125±7 bpm after RSG stimulation (P=0.001), and to 132±7 bpm after apamin injection (P<0.001). Both electrical RSG stimulation and apamin injection induced local nerve activity at the SAN with the average amplitudes of 3.60±0.72 and 3.86±0.56 µV, respectively. RSG stellectomy eliminated the local nerve activity and decreased the heart rate. In ambulatory dogs, local nerve activity at the SAN had a significantly higher average Pearson correlation to heart rate (0.72±0.02, P=0.001) than RSG nerve activity to HR (0.45±0.04, P=0.001). CONCLUSIONS: Local intrinsic nerve activity can be recorded at the SAN. Short bursts of these local nerve activities are present before each atrial activation during heart rate acceleration induced by stimulation of the RSG.

Skin Sympathetic Nerve Activity and the Short-Term QT Interval Variability in Patients With Electrical Storm.

Background: Skin sympathetic nerve activity (SKNA) and QT interval variability are known to be associated with ventricular arrhythmias. However, the relationship between the two remains unclear. Objective: The aim was to test the hypothesis that SKNA bursts are associated with greater short-term variability of the QT interval (STVQT) in patients with electrical storm (ES) or coronary heart disease without arrhythmias (CHD) than in healthy volunteers (HV). Methods: We simultaneously recorded the ECG and SKNA during sinus rhythm in patients with ES (N = 10) and CHD (N = 8) and during cold-water pressor test in HV (N = 12). The QT and QTc intervals were manually marked and calculated within the ECG. The STVQT was calculated and compared to episodes of SKNA burst and non-bursting activity. Results: The SKNA burst threshold for ES and HV was 1.06 ± 1.07 and 1.88 ± 1.09 µV, respectively (p = 0.011). During SKNA baseline and burst, the QT/QTc intervals and STVQT for ES and CHD were significantly higher than those of the HV. In all subjects, SKNA bursts were associated with an increased STVQT (from 6.43 ± 2.99 to 9.40 ± 5.12 ms, p = 0.002 for ES; from 9.48 ± 4.40 to 12.8 ± 5.26 ms, p = 0.016 for CHD; and from 3.81 ± 0.73 to 4.49 ± 1.24 ms, p = 0.016 for HV). The magnitude of increased STVQT in ES (3.33 ± 3.06 ms) and CHD (3.34 ± 2.34 ms) was both higher than that of the HV (0.68 ± 0.84 ms, p = 0.047 and p = 0.020). Conclusion: Compared to non-bursting activity, SKNA bursts were associated with a larger increase in the QTc interval and STVQT in patients with heart disease than in HV.

The frequency spectrum of sympathetic nerve activity and arrhythmogenicity in ambulatory dogs.

BACKGROUND: Sympathetic nerve activity, heart rate (HR), and blood pressure (BP) all have very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations. OBJECTIVE: The purpose of this study was to test the hypothesis that the frequency spectra of subcutaneous nerve activity (ScNA), stellate ganglion nerve activity (SGNA), HR, and BP are important to cardiac arrhythmogenesis. METHODS: We used radiotransmitters to record SGNA, ScNA, HR, and BP in 6 ambulatory dogs and determined the dominant frequency and paroxysmal atrial tachyarrhythmias (PATs) episodes in 3-minute windows over a 24-hour period. RESULTS: The frequency spectra determined in ScNA reflected that in SGNA. HF oscillations were present in both ScNA and SGNA at all time but could be overshadowed by the much larger LF and VLF burst activities. The dominant frequency could occur in any of the 3 frequency bands. There were circadian variations with more frequent occurrences of HF oscillations at night. HF oscillations in HR and BP matched HF oscillations in SGNA and ScNA. PATs occurred only when dominant frequencies of SGNA and ScNA were in the LF and VLF bands. CONCLUSION: HF oscillations in BP and HR correlate with HF oscillations in sympathetic nerve activity and are present at all time. HF oscillations can be overshadowed by the much larger LF and VLF burst activities. PATs occur only when LF or VLF, but not when HF, is the dominant frequency. The frequency spectra determined in ScNA reflect that in SGNA.

Skin sympathetic nerve activity in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased cardiac arrhythmia and sudden cardiac death. We recently developed a new method (neuECG) to noninvasively measure electrocardiogram and skin sympathetic nerve activity (SKNA). OBJECTIVE: The purpose of this study was to test the hypothesis that SKNA measured during sleep study is higher in patients with OSA than in those without OSA. METHODS: We prospectively recorded neuECG and polysomnography in 26 patients undergoing a sleep study. Sleep stages were scored into rapid eye movement (REM), and non-REM sleep stages 1 (N1), 2 (N2), and 3 (N3). Average voltage of skin sympathetic nerve activity (aSKNA) and SKNA burst area were calculated for quantification. Apnea/hypopnea index (AHI) >5 per hour was used to diagnose OSA. RESULTS: There was a positive correlation (r = 0.549; P = .018) between SKNA burst area and the arousal index in OSA but not in the control group. aSKNA during sleep was 0.61 ± 0.09 µV in OSA patients (n = 18) and 0.53 ± 0.04 µV in control patients (n = 8; P = .025). Burst area was 3.26 (1.90-4.47) µV·s/min in OSA patients and 1.31 (0.67-1.94) µV·s/min in control (P = .047). More apparent differences were found during N2, when the burst area in OSA (3.06 [1.46-5.52] µV·s/min) was much higher than that of the control (0.89 [0.79-1.65] µV·s/min; P = .03). CONCLUSION: OSA patients have higher SKNA activity than control patients, with the most pronounced differences observed during N2. Arousal at the end of apnea episodes is associated with large SKNA bursts. Overlaps of aSKNA and SKNA burst area between groups suggest that not all OSA patients have increased sympathetic tone.

Simultaneous noninvasive recording of electrocardiogram and skin sympathetic nerve activity (neuECG).

neuECG, the simultaneous noninvasive recording of ECG and skin sympathetic nerve activity (SKNA), directly records sympathetic nerve activity over a long period of time. It can be used to measure sympathetic tone in healthy subjects and in subjects with non-cardiovascular diseases. The electrical activity that can be measured on the surface of the skin originates from the heart, the muscle or nerve structures. Because the frequency content of nerve activity falls in a higher frequency range than that of the ECG and myopotential, it is possible to use high-pass or band-pass filtering to specifically isolate the SKNA. neuECG is voltage calibrated and does not require invasive procedures to impale electrodes in nerves and thus has advantages over microneurography. Here, we present a protocol that takes <10 min to set up. The neuECG can be continuously recorded over a 24-h period or longer. We also describe methods to efficiently analyze neuECG from humans using commercially available hardware and software to facilitate adoption of this technology in clinical research.

Subcutaneous nerve stimulation reduces sympathetic nerve activity in ambulatory dogs with myocardial infarction.

BACKGROUND: Subcutaneous nerve stimulation (ScNS) remodels the stellate ganglion and reduces stellate ganglion nerve activity (SGNA) in dogs. Acute myocardial infarction (MI) increases SGNA through nerve sprouting. OBJECTIVE: The purpose of this study was to test the hypothesis that ScNS remodels the stellate ganglion and reduces SGNA in ambulatory dogs with acute MI. METHODS: In the experimental group, a radio transmitter was implanted during the first sterile surgery to record nerve activity and an electrocardiogram, followed by a second sterile surgery to create MI. Dogs then underwent ScNS for 2 months. The average SGNA (aSGNA) was compared with that in a historical control group (n = 9), with acute MI monitored for 2 months without ScNS. RESULTS: In the experimental group, the baseline aSGNA and heart rate were 4.08±0.35 µV and 98±12 beats/min, respectively. They increased within 1 week after MI to 6.91±1.91 µV (P=.007) and 107±10 beats/min (P=.028), respectively. ScNS reduced aSGNA to 3.46±0.44 µV (P<.039) and 2.14±0.50 µV (P<.001) at 4 and 8 weeks, respectively, after MI. In comparison, aSGNA at 4 and 8 weeks in dogs with MI but no ScNS was 8.26±6.31 µV (P=.005) and 10.82±7.86 µV (P=0002), respectively. Immunostaining showed confluent areas of remodeling in bilateral stellate ganglia and a high percentage of tyrosine hydroxylase-negative ganglion cells. Terminal deoxynucleotidyl transferase dUTP nick end labeling was positive in 26.61%±11.54% of ganglion cells in the left stellate ganglion and 15.94%±3.62% of ganglion cells in the right stellate ganglion. CONCLUSION: ScNS remodels the stellate ganglion, reduces SGNA, and suppresses cardiac nerve sprouting after acute MI.

Skin sympathetic nerve activity as a biomarker for syncopal episodes during a tilt table test.

BACKGROUND: Autonomic imbalance is the proposed mechanism of syncope during a tilt table test (TTT). We have recently demonstrated that skin sympathetic nerve activity (SKNA) can be noninvasively recorded using electrocardiographic electrodes. OBJECTIVE: The purpose of this study was to test the hypothesis that increased SKNA activation precedes tilt-induced syncope. METHODS: We studied 50 patients with a history of neurocardiogenic syncope undergoing a TTT. The recorded signals were band-pass filtered at 500-1000 Hz to analyze nerve activity. RESULTS: The average SKNA (aSKNA) value at baseline was 1.38 ± 0.38 µV in patients without syncope and 1.42 ± 0.52 µV in patients with syncope (P = .77). On upright tilt, aSKNA was 1.34 ± 0.40 µV in patients who did not have syncope and 1.39 ± 0.43 µV in patients who had syncope (P = .65). In all 14 patients with syncope, there was a surge of SKNA before an initial increase in heart rate followed by bradycardia, hypotension, and syncope. The peak aSKNA immediately (<1 minute) before syncope was significantly higher than baseline aSKNA (2.63 ± 1.22 vs 1.39 ± 0.43 µV; P = .0005). After syncope, patients were immediately placed in the supine position and aSKNA dropped significantly to 1.26 ± 0.43 µV; (P = .0004). The heart rate variability during the TTT shows a significant increase in parasympathetic tone during syncope (low-frequency/high-frequency ratio: 7.15 vs 2.21; P = .04). CONCLUSION: Patients with syncope do not have elevated sympathetic tone at baseline or during the TTT except immediately before syncope when there is a transient surge of SKNA followed by sympathetic withdrawal along with parasympathetic surge.

Skin sympathetic nerve activity and ventricular rate control during atrial fibrillation.

BACKGROUND: The relationship between the ventricular rate (VR) during atrial fibrillation (AF) and skin sympathetic nerve activity (SKNA) remains unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that SKNA bursts accelerate VR during AF. METHODS: We simultaneously recorded electrocardiogram and SKNA in 8 patients (median age 66.0 years [interquartile range {IQR} 59.0-77.0 years]; 4 men [50%]) with 30 paroxysmal AF episodes (all >10-minute long) and 12 patients (73.0 years [IQR 60.5-80.0 years]; 6 men [50%]) with persistent AF. The average amplitude of SKNA (aSKNA [µV]) during AF was analyzed in 1-minute windows and binned, showing 2 Gaussian distributions. We used the mean + 3SD of the first Gaussian distribution as the threshold that separates burst from baseline (nonburst) SKNA. All 1-minute aSKNA values above the threshold were detected, and the area between aSKNA and baseline of every 1 minute was calculated and added as burst area. RESULTS: VR was higher during SKNA bursts than during the nonburst period (103 beats/min [IQR 83-113 beats/min] vs 88 beats/min [IQR 76-101 beats/min], respectively; P = .003). In the highest quartile of the burst area during persistent AF, the scatterplot of maximal aSKNA and VR during each SKNA burst shows higher aSKNA and VR. The overall estimate of the correlation between maximal VR and aSKNA during bursts show a positive correlation in the highest quartile of the burst area (0.64; 95% confidence interval 0.54-0.74; P < .0001). CONCLUSION: SKNA bursts are associated with VR acceleration. These SKNA bursts may be new therapeutic targets for rate control during AF.

Effects of anesthetic and sedative agents on sympathetic nerve activity.

BACKGROUND: The effects of sedative and anesthetic agents on sympathetic nerve activity (SNA) are poorly understood. OBJECTIVE: The purpose of this study was to determine the effects of commonly used sedative and anesthetic agents on SNA in ambulatory dogs and humans. METHODS: We implanted radiotransmitters in 6 dogs to record stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (ScNA), and blood pressure (BP). After recovery, we injected dexmedetomidine (3 µg/kg), morphine (0.1 mg/kg), hydromorphone (0.05 mg/kg), and midazolam (0.1 mg/kg) on different days. We also studied 12 human patients (10 male; age 68.0 ± 9.1 years old) undergoing cardioversion for atrial fibrillation with propofol (0.77 ± 0.18 mg/kg) or methohexital (0.65 mg/kg) anesthesia. Skin sympathetic nerve activity (SKNA) and electrocardiogram were recorded during the study. RESULTS: SGNA and ScNA were significantly suppressed immediately after administration of dexmedetomidine (P = .000 and P = .000, respectively), morphine (P = .011 and P = .014, respectively), and hydromorphone (P = .000 and P = .012, respectively), along with decreased BP and heart rate (HR) (P <.001 for each). Midazolam had no significant effect on SGNA and ScNA (P = .248 and P = .149, respectively) but increased HR (P = .015) and decreased BP (P = .004) in ambulatory dogs. In patients undergoing cardioversion, bolus propofol administration significantly suppressed SKNA (from 1.11 ± 0.25 µV to 0.77 ± 0.15 µV; P = .001), and the effects lasted for at least 10 minutes after the final cardioversion shock. Methohexital decreased chest SKNA from 1.59 ± 0.45 µV to 1.22 ± 0.58 µV (P = .000) and arm SKNA from 0.76 ± 0.43 µV to 0.55 ± 0.07 µV (P = .001). The effects lasted for at least 10 minutes after the cardioversion shock. CONCLUSION: Propofol, methohexital, dexmedetomidine, morphine, and hydromorphone suppressed, but midazolam had no significant effects on, SNA.

Subcutaneous nerve stimulation for rate control in ambulatory dogs with persistent atrial fibrillation.

BACKGROUND: Subcutaneous nerve stimulation (ScNS) damages the stellate ganglion and improves rhythm control of atrial fibrillation (AF) in ambulatory dogs. OBJECTIVE: The purpose of this study was to test the hypothesis that thoracic ScNS can improve rate control in persistent AF. METHODS: We created persistent AF in 13 dogs and randomly assigned them to ScNS (n = 6) and sham control (n = 7) groups. 18F-2-Fluoro-2-deoxyglucose positron emission tomography/magnetic resonance imaging of the brain stem was performed at baseline and at the end of the study. RESULTS: The average stellate ganglion nerve activity reduced from 4.00 ± 1.68 µV after the induction of persistent AF to 1.72 ± 0.42 µV (P = .032) after ScNS. In contrast, the average stellate ganglion nerve activity increased from 3.01 ± 1.26 µV during AF to 5.52 ± 2.69 µV after sham stimulation (P = .023). The mean ventricular rate during persistent AF reduced from 149 ± 36 to 84 ± 16 beats/min (P = .011) in the ScNS group, but no changes were observed in the sham control group. The left ventricular ejection fraction remained unchanged in the ScNS group but reduced significantly in the sham control group. Immunostaining showed damaged ganglion cells in bilateral stellate ganglia and increased brain stem glial cell reaction in the ScNS group but not in the control group. The 18F-2-fluoro-2-deoxyglucose uptake in the pons and medulla was significantly (P = .011) higher in the ScNS group than the sham control group at the end of the study. CONCLUSION: Thoracic ScNS causes neural remodeling in the brain stem and stellate ganglia, controls the ventricular rate, and preserves the left ventricular ejection fraction in ambulatory dogs with persistent AF.

Characterization of skin sympathetic nerve activity in patients with cardiomyopathy and ventricular arrhythmia.

BACKGROUND: Heightened sympathetic nerve activity is associated with occurrence of ventricular arrhythmia (VA). OBJECTIVE: To investigate the association of skin sympathetic nerve activity (SKNA) and VA occurrence. METHODS: We prospectively enrolled 65 patients with severe cardiomyopathy. Of these, 39 had recent sustained VA episodes (VA-1 group), 11 had intractable VA undergoing sedation with general anesthesia (VA-2 group), and 15 had no known history of VA (VA-Ctrl group). All patients had simultaneous SKNA and electrocardiogram recording. SKNA was assessed using an average value (aSKNA), a variable value (vSKNA), and the number of bursts of SKNA (bSKNA). RESULTS: The VA-1 group had higher aSKNA and vSKNA compared with the VA-Ctrl group (aSKNA: 1.41 ± 0.53 µV vs 0.98 ± 0.41 µV, P = .003; vSKNA: 0.52 ± 0.22 µV vs 0.30 ± 0.16 µV, P < .001) and the VA-2 group (aSKNA: 0.83 ± 0.22 µV, P < .001; vSKNA: 0.23 ± 0.11 µV; P < .001). Although the VA-2 group had more VA episodes than the VA-1 group (median, 5 vs 2; P = .01), their SKNA was the lowest among the 3 groups. Multivariate Cox regression analysis showed that a higher aSKNA at baseline was an independent predictor of lower VA recurrence rate during a 417 ± 279-day follow-up (hazard ratio, 0.325; 95% confidence interval [CI], 0.119-0.883; P = .03). A >15% reduction in aSKNA after therapy was associated with a lower subsequent VA event rate (hazard ratio, 0.222; 95% CI, 0.057-0.864; P = .03). CONCLUSION: Patients with VA had increased SKNA as compared with control. Both SKNA and sustained VA could be suppressed by general anesthesia. The aSKNA at baseline was an independent predictor of VA recurrence.

Antiarrhythmic and proarrhythmic effects of subcutaneous nerve stimulation in ambulatory dogs.

BACKGROUND: High output subcutaneous nerve stimulation (ScNS) remodels the stellate ganglia and suppresses cardiac arrhythmia. OBJECTIVE: The purpose of this study was to test the hypothesis that long duration low output ScNS causes cardiac nerve sprouting and increases plasma norepinephrine concentration and the duration of paroxysmal atrial tachycardia (PAT) in ambulatory dogs. METHODS: We prospectively randomized 22 dogs (11 males and 11 females) into 5 different output groups for 2 months of ScNS: 0 mA (sham) (n = 6), 0.25 mA (n = 4), 1.5 mA (n = 4), 2.5 mA (n = 4), and 3.5 mA (n = 4). RESULTS: As compared with baseline, the changes in the durations of PAT episodes per 48 hours were significantly different among different groups (sham, -5.0 ± 9.5 seconds; 0.25 mA, 95.5 ± 71.0 seconds; 1.5 mA, -99.3 ± 39.6 seconds; 2.5 mA, -155.3 ± 87.8 seconds; and 3.5 mA, -76.3 ± 44.8 seconds; P < .001). The 3.5 mA group had a greater reduction in sinus heart rate than did the sham group (-29.8 ± 15.0 beats/min vs -14.5 ± 3.0 beats/min; P = .038). Immunohistochemical studies showed that the 0.25 mA group had a significantly increased while 2.5 mA and 3.5 mA stimulation had significantly reduced growth-associated protein 43 nerve densities in both atria and ventricles. The plasma norepinephrine concentrations in the 0.25 mA group was 5063.0 ± 4366.0 pg/mL, which was significantly higher than that in the other groups of dogs (739.3 ± 946.3; P = .009). There were no significant differences in the effects of simulation between males and females. CONCLUSION: In ambulatory dogs, low output ScNS causes cardiac nerve sprouting and increases plasma norepinephrine concentration and the duration of PAT episodes while high output ScNS is antiarrhythmic.

Skin sympathetic nerve activity and the temporal clustering of cardiac arrhythmias.

BACKGROUND: Simultaneous noninvasively recorded skin sympathetic nerve activity (SKNA) and electrocardiogram (neuECG) can be used to estimate cardiac sympathetic tone. We tested the hypothesis that large and prolonged SKNA bursts are associated with temporal clustering arrhythmias. METHODS: We recorded neuECG in 10 patients (69 ± 10 years old) with atrial fibrillation (AF) episodes and in 6 patients (50 ± 13 years old) with ventricular tachycardia (VT) or fibrillation (VF) episodes. Clustering was defined by an arrhythmic episode followed within 1 minute by spontaneous recurrences of the same arrhythmia. The neuECG signals were bandpass filtered between 500-1000 Hz to display SKNA. RESULTS: There were 22 AF clusters, including 231 AF episodes from 6 patients, and 9 VT/VF clusters, including 99 VT/VF episodes from 3 patients. A total duration of SKNA bursts associated with AF was longer than that during sinus rhythm (78.9 min/hour [interquartile range (IQR) 17.5-201.3] vs. 16.3 min/hour [IQR 14.5-18.5], P = 0.022). The burst amplitude associated with AF in clustering patients was significantly higher than that in nonclustering patients (1.54 µV [IQR 1.35-1.89], n = 114, vs. 1.20 µV [IQR 1.05-1.42], n = 21, P < 0.001). The SKNA bursts associated with VT/VF clusters lasted 9.3 ± 3.1 minutes, with peaks that averaged 1.13 ± 0.38 µV as compared with 0.79 ± 0.11 µV at baseline (P = 0.041). CONCLUSION: Large and sustained sympathetic nerve activities are associated with the temporal clustering of AF and VT/VF. FUNDING: This study was supported in part by NIH grants R42DA043391 (THE), R56 HL71140, TR002208-01, R01 HL139829 (PSC), a Charles Fisch Cardiovascular Research Award endowed by Suzanne B. Knoebel of the Krannert Institute of Cardiology (TK and THE), a Medtronic-Zipes Endowment, and the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative (PSC).

Effects of Stellate Ganglion Cryoablation on Subcutaneous Nerve Activity and Atrial Tachyarrhythmias in a Canine Model of Pacing-Induced Heart Failure.

OBJECTIVES: This study aimed to test the hypothesis that subcutaneous nerve activity (SCNA) can adequately estimate the cardiac sympathetic tone and the effects of cryoablation of the stellate ganglion in dogs with pacing-induced heart failure (HF). BACKGROUND: Recording of SCNA is a new method to estimate sympathetic tone in dogs. HF is known to increase sympathetic tone and atrial arrhythmias. METHODS: Twelve dogs with pacing-induced HF were studied using implanted radiotransmitters to record the stellate ganglia nerve activity (SGNA), vagal nerve activity, and SCNA. Of these, 6 dogs (ablation group) underwent bilateral stellate ganglia cryoablation before the rapid ventricular pacing; the remaining 6 dogs (control group) had rapid ventricular pacing only. In both groups, SCNA was compared with SGNA and the occurrence of arrhythmias. RESULTS: SCNA invariably increased before the 360 identified atrial tachyarrhythmia episodes in the 6 control dogs before and after HF induction. SCNA and SGNA correlated in all dogs with an average correlation coefficient of 0.64 (95% confidence interval: 0.58 to 0.70). Cryoablation of bilateral stellate ganglia significantly reduced SCNA from 0.34 ± 0.033 µV to 0.25 ± 0.028 µV (p = 0.03) and eliminated all atrial tachyarrhythmias. CONCLUSIONS: SCNA can be used to estimate cardiac sympathetic tone in dogs with pacing-induced HF. Cryoablation of the stellate ganglia reduced SCNA and arrhythmia vulnerability.