Klassen, Stephen A.

COVID-19 convalescent plasma (CCP) was one of the first therapeutic options available for the treatment of SARS-CoV-2 infections and continues to be used selectively for immunosuppressed patients. Given the emergence of novel SARS-CoV-2 variants which are resistant to treatment with available monoclonal antibody (MAb) therapy, CCP remains an important therapeutic consideration.

Background Humans with high O 2 affinity hemoglobin (HAH) have a markedly lower partial pressure of O 2 at which 50% of hemoglobin is saturated (P 50 ) and a leftward shift of the oxy‐hemoglobin dissociation curve. Humans with HAH have attenuated heart rate responses during both acute and chronic hypoxic exposure relative to humans with typical P 50 . Despite the attenuated heart rate responses to hypoxia, there are typically no blood pressure differences found in humans with HAH relative to humans with typical P 50 . Due to the blunted heart rate and normal blood pressure responses to hypoxia in humans with HAH, this study aimed to investigate the impact of HAH on cardiac autonomic function during normoxia and hypoxia. We hypothesized that humans with HAH would have lower cardiac baroreflex sensitivity (cBRS) and heart rate variability (HRV) during normoxia and hypoxia relative to individuals with typical P 50. Methods Nine humans with a HAH mutation (6 female, Age: 40±12yrs, P 50 : 16±1 mmHg) and 12 controls with typical affinity hemoglobin (6 female, Age: 40±10yrs, P 50 : 26±1 mmHg) laid supine for 10‐minutes prior to 20‐minutes of isocapnic hypoxia, titrated to reduce arterial O 2 pressure to ~50 mmHg (Avg. F i O 2 = 11.9±0.0%). Beat‐to‐beat arterial pressures (arterial catheter) and heart rate (electrocardiogram) were continuously recorded. Data were averaged in five‐minute segments starting with the last five minutes of supine normoxic rest. Spontaneous cBRS was quantified using the sequence method. HRV was measured in time and frequency domains. Standard deviation of the RR interval (SDRR) was calculated as the standard deviation of all RR intervals in a data segment. Low frequency (LF) HRV was calculated using Fast Fourier Transformation and assessed as absolute spectral intensity in the LF band (0.04‐0.15Hz). Results Arterial oxygen (P a O 2 ) and carbon dioxide (P a CO 2 ) pressures were not different between humans with HAH and controls during normoxia or isocapnic hypoxia [P a O 2 : (HAH vs. Control): 48±3 vs. 47±2 mmHg, p=0.612; P a CO 2 : (HAH vs. Control): 40±3 vs. 39±1 mmHg, p=0.328] exposure. cBRS was lower in humans with HAH compared to controls in normoxia and throughout isocapnic hypoxia [normoxia (HAH vs. Control): 7±4 vs. 16±10 ms/mmHg; hypoxia minutes 15‐20 (HAH vs. Control): 4±3 vs. 14±11 ms/mmHg; Hb type, p=0.024]. Several metrics of HRV were lower in humans with HAH relative to control (SDRR: Hb type, p≤0.001; LF: Hb type, p=0.030) and HRV was blunted to a similar extent in both groups with hypoxia (SDRR: time effect, p=0.009). Conclusion The findings of this study are twofold. Compared to controls, humans with HAH have: 1) attenuated cardiac baroreflex sensitivity and 2) lower heart rate variability in both normoxia and isocapnic hypoxia.

Discrete physiological stressors differentially affect sympathetic postganglionic neuronal rate-, population-, and temporal-coding strategies. When performing end-expiratory apnea (APN) during graded baroreflex unloading via lower body negative pressure (LBNP): 1) augmented sympathetic neuronal firing probability, 2) recruited larger and previously silent sympathetic postganglionic neurons at ambient and −10 mmHg, but not −40 mmHg LBNP, and 3) reduced neuronal discharge latency similarly across all conditions, independent of the level of baroreflex unloading.

Action potentials (APs) of varying sizes and firing probabilities, that are synchronized into bursts of efferent traffic, characterize recordings of muscle sympathetic nerve activity (MSNA). Recent evidence points to ordered recruitment of these APs but the sites of this control remain unknown. This study investigated the role of the paravertebral ganglia in sympathetic AP emission patterns using pharmacological blockade of ganglionic N N ‐nicotinic receptors via trimethaphan camsylate (TM; n = 7 females, 37 ±5 years, 112 ±2/70 ±3 mmHg, 22 ±1 kg/m 2 ). Heart rate (HR; ECG), blood pressure (BP; arterial catheter) and MSNA (microneurography) were recorded during baseline, TM infusion (1–7 mg/min) and Valsalva's manoeuvre. MSNA APs were detected from the filtered raw signal using a wavelet deconstruction approach and were binned in clusters (Scott's rule) based on peak‐to‐peak amplitude (K‐means). In the final minute of MSNA burst detection during TM, HR increased (57 ±11 to 66 ±12 bpm) and mean BP decreased (97 ±7 to 90 ±7 mmHg) (both P < 0.01 compared to baseline). Relative to baseline, TM elicited a progressive reduction in total sympathetic outflow (833 ±458 to 157 ±120 AU/min), characterized by fewer integrated bursts (30 ±14 to 9 ±8 bursts/100 beats) with decaying amplitude (49 ±3 to 31 ±3 AU) (all P < 0.01). Underlying TM‐mediated attenuations in integrated MSNA were reductions in AP incidence (186 ±101 to 29 ±31 AP/100beats) and AP content per integrated burst (7 ±2 to 3 ±1 APs/burst) (all P < 0.01). Compared to baseline, the total number of active AP clusters was reduced with TM (14 ±3 to 9 ±3 AP clusters), resulting in fewer unique clusters per burst (4 ±1 to 3 ±1 AP clusters/burst) (both P < 0.01). Relative to baseline, most participants demonstrated a reduction in the within‐burst firing probability of all AP clusters, with the largest two to six AP clusters ceasing to fire in the last minute before integrated bursting activity was abolished. Following cessation of integrated MSNA bursts, the smallest 6 ±2 sympathetic AP clusters (range: 4 – 8 AP clusters) persisted to fire in an asynchronous pattern (49 ±41 AP/100beats) in all participants. Valsalva's Maneuver did not increase the incidence of these persistent small APs (60 ±42 AP/100beats, P = 0.52), or instigate any larger APs (previously active at baseline) in six of seven participants (6 ±1 total AP clusters, P = 0.30). These data suggest: 1) the paravertebral ganglia may contribute to the heterogeneity in the firing probabilities of varying sized postganglionic sympathetic APs active under baseline conditions, and 2) the presence of non‐synchronized sympathetic APs that express resistance to blockade with trimethaphan. Support or Funding Information Supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada, Discovery Grant #217916‐2013. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Currently, the effect of aging on sympathetic baroreflex control is equivocal, with some studies finding that integrated sympathetic baroreflex threshold gain is not affected by age, and others finding that it is blunted in older compared to young adults. While these studies evaluated the effect of aging on baroreflex control of integrated sympathetic burst frequency, it remains unclear how aging modulates the baroreflex control of postganglionic action potentials (AP). In young adults, the arterial baroreflex exerts non‐uniform control over varying‐sized APs spontaneously firing within bursts of muscle sympathetic nerve activity (MSNA), with the strongest control over medium sized AP clusters, and less control over the smallest and largest APs. Therefore, we tested the hypothesis that resting baroreflex control of AP subpopulations and integrated sympathetic bursts would be blunted in older compared to young adults. Baroreflex threshold relationships for integrated MSNA bursts and the underlying subpopulations of AP clusters (obtained using microneurography and a continuous wavelet transform) were assessed during 5 minutes of supine rest in eleven older (45‐75 years, 5 females) and eleven young (21‐30 years, 5 females) adults. Baroreflex threshold was quantified as the slope of the linear regression between AP probability (%) and MSNA burst probability (%) versus diastolic blood pressure (DBP, mmHg; Finger plethysmography). AP discharge was greater in older compared to young adults (Older: 614 ± 327 spikes/100 beats vs. Young: 211 ± 107 spikes/100 beats, P < 0.001), and the baroreflex control of AP subpopulations was reset towards greater firing probabilities in older adults (group‐by‐cluster effect: P < 0.001). Specifically, the arterial baroreflex threshold gain of medium AP clusters was greater in older compared to young adults (e.g. Cluster 4, Older: ‐7.8 ± 3.1 %/mmHg vs. Young: ‐4.1 ± 2.9 %/mmHg, P = 0.010), whereas the baroreflex threshold gains for the smallest (e.g. Cluster 1, Older: ‐1.2 ± 1.1 %/mmHg vs. Young: ‐0.7 ± 0.4 %/mmHg, P = 0.197) and largest (e.g. Cluster 10, Older: ‐0.5 ± 0.4 %/mmHg vs. Young: ‐0.6 ± 0.6 %/mmHg, P = 0.673) AP clusters were not modified by aging. Additionally, integrated sympathetic burst threshold gain was greater in older compared to young adults (Older: ‐7.9 ± 3.8 %/mmHg vs. Young: ‐3.9 ± 1.8 %/mmHg, P = 0.005), and the operating point was shifted rightward towards a higher DBP (Older: 76 ± 8 mmHg vs. Young: 68 ± 7 mmHg, P = 0.021). Contrary to our hypothesis, the strength of baroreflex control over medium sized AP clusters as well as integrated sympathetic baroreflex threshold gain was greater in this group of older adults compared to young adults.

Our understanding of altered neuro‐cardiovascular control following long‐duration inactivity via head‐down bed rest (HDBR) is incomplete. Here, we retrospectively analyzed two long‐duration HDBR studies, including female (n=17; 32±5 years) and male (n=16; 29±7 years) cohorts, to determine whether HDBR 1) alters spontaneous cardiovagal baroreflex sensitivity (cBRS) similarly between males and females and 2) alters spontaneous baroreflex control of muscle sympathetic action potentials (AP) in males. Heart rate (HR; electrocardiogram) and arterial blood pressure (BP; finger‐plethysmography) were continuously measured during 5‐minutes of supine rest prior to and following 60‐days bed rest in a ‐6° head‐down position. Spontaneous cBRS was assessed by the relationship between R‐R interval and systolic BP analyzed using the linear regression sequence method. Recordings of multi‐unit muscle sympathetic nerve activity (peroneal microneurography) were obtained and a continuous wavelet transform detected APs which were grouped into AP clusters with similar morphology (n=10, all males). Baroreflex threshold for AP cluster discharge was assessed by linear regression analysis of the relationship between AP cluster discharge probability and diastolic BP. No change in resting HR (64±9 versus 66±9 /min, P=0.12) or mean BP (91.2±9.0 versus 90.6±9.2 mmHg, P=0.73) occurred after HDBR. Reductions in cBRS after HDBR (‐4.1±9.4 ms/mmHg, Time effect: P<0.01) were similar between males and females (Time‐by‐Sex effect: P=0.51) and not related to changes in total blood volume (r 2 =0.045, P=0.24). Grouped AP clusters demonstrated heterogenous arterial baroreflex threshold gain according to AP cluster morphology (Cluster effect: P<0.01) which was unaltered following HDBR (Time‐by‐Cluster effect: P=0.43). In summary, males and females similarly attenuate cBRS following 60‐days of HDBR and novel evidence indicates HDBR does not alter spontaneous baroreflex control of muscle sympathetic APs in males.

Background: The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA. Methods: We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data. Results: CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = −0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021. Conclusions: A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths. Funding: There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.

AbstractIn the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID‐19), including among patients with innate or acquired immunosuppression. However, the association between COVID‐19‐associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched‐control registry study of 143 COVID‐19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID‐19 patients with immunosuppression. We review clinical features and treatment protocols of COVID‐19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID‐19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune‐deficient and immune‐suppressed patients with COVID‐19 warrants further investigation.