Double-blinded, randomised, placebo-controlled trial of convalescent plasma for COVID-19: analyses by neutralising antibodies homologous to recipients' variants.

INTRODUCTION: Convalescent plasma (CP) emerged as potential treatment for COVID-19 early in the pandemic. While efficacy in hospitalised patients has been lacklustre, CP may be beneficial at the first stages of disease. Despite multiple new variants emerging, no trials have involved analyses on variant-specific antibody titres of CP. METHODS: We recruited hospitalised COVID-19 patients within 10 days of symptom onset and, employing a double-blinded approach, randomised them to receive 200 ml convalescent plasma with high (HCP) or low (LCP) neutralising antibody (NAb) titre against the ancestral strain (Wuhan-like variant) or placebo in 1:1:1 ratio. Primary endpoints comprised intubation, corticosteroids for symptom aggravation, and safety assessed as serious adverse events. For a preplanned ad hoc analysis, the patients were regrouped by infused CP's NAb titers to variants infecting the recipients i.e. by titres of homologous HCP (hHCP) or LCP (hLCP). RESULTS: Of the 57 patients, 18 received HCP, 19 LCP and 20 placebo, all groups smaller than planned. No significant differences were found for primary endpoints. In ad hoc analysis, hHCPrecipients needed significantly less respiratory support, and appeared to be given corticosteroids less frequently (1/14; 7.1%) than those receiving hLCP (9/23; 39.1%) or placebo (8/20; 40%), (p = 0.077). DISCUSSION: Our double-blinded, placebo-controlled CP therapy trial remained underpowered and does not allow any firm conclusions for early-stage hospitalised COVID-19 patients. Interestingly, however, regrouping by homologous - recipients' variant-specific - CP titres suggested benefits for hHCP. We encourage similar re-analysis of ongoing/previous larger CP studies. TRIAL REGISTRATION: ClinTrials.gov identifier: NCT0473040.

Tissue expansion and skin circulation. Simultaneous monitoring by laser Doppler flowmetry and transcutaneous oximetry.

The skin circulation was examined in nine patients during filling of their breast expander prostheses. Despite the high expansion pressure, which was increased above the systolic blood pressure, the overlying skin showed good circulation both clinically and when measured with a laser Doppler flowmeter and a transcutaneous oximeter. We conclude that the expansion was therefore directed to the tissues between the expander and the skin--that is, the fibrous capsule surrounding the prosthesis. Nine subcutaneous tissue expanders located in different anatomical regions were overfilled to a pressure at which all skin circulation ceased. Sufficient saline was then removed to allow skin circulation to return. Oxygenation of the skin ceased at a relatively low pressure when measured by transcutaneous oximetry, whereas when the skin circulation was measured with a laser Doppler flowmeter it did not disappear until the expander pressure had been raised appreciably above that level.

Accelerated tissue expansion with the "overfilling" technique.

Temporary overexpansion of the tissues at each filling session increased the actual inflation volume by about 59 percent. This shortened the process of tissue expansion considerably. "Overexpansion" means that the pressure in the expander is increased to a point where the dermal capillary flow is zero or the patient experiences so much discomfort that inflation cannot be carried out any further. The pressure in the expander is thereafter gradually decreased by taking out saline until both the capillary refill and all other clinical criteria are sufficient for safe dermal circulation. Comparison of the expander volume at the final pressure to the initial filling volume at the same pressure before the "overfilling" confirmed an average gain of about 59 percent in 14 patients.

Tissue expander injection dome leakage.

Injection dome leakage was found to be the cause for partial disappearance of the saline solution injected into some tissue expanders. When the injection domes of 22 consecutively removed tissue expanders were checked, we found that the average leakage pressure of these was 32 mmHg, with a range of 8 to 110 mmHg. When the patients were lying on their expanders, the weight of the corresponding body part caused intraluminal pressures of up to 90 mmHg in their expanders. Following removal of the expanders, the total leakage was calculated quantitatively and found to be maximally over 50 percent of the injected volume in some instances. The leakage flow through the injection dome in seven consecutively removed expanders was checked at pressures of 25, 50, and 75 mmHg over 30 minutes and was found to be slow. The possibility of injection dome leakage should be kept in mind, however, as a potential complication under unfavorable conditions. At the same time, we want to emphasize that in most instances tissue expanders function quite well and in predictable ways.

Validity of laser Doppler flowmetry for measuring the effect of the tissue expander pressure on skin circulation. Simultaneous measurement of tissue pressure and laser Doppler flowmetry.

Intermittent Laser Doppler Flowmetry (LDF) was used in five patients to measure changes in the dermal blood flow when changing intraluminal pressures in tissue expanders (TE). In another patient, continuous monitoring of the intraluminal pressure in the TE and simultaneous LDF was used. Our finding is that LDF is a suitable method for the registration of reactions in dermal circulation, caused by TE pressure changes. A statistically significant association between the changes of the LDF values and the intraluminal pressure in the TE was observed.

The rabbit ear pedicle flap. A new model for evaluating factors affecting the circulation in flaps.

Laser Doppler flowmetry and transcutaneous oximetry were compared regarding their speed and accuracy in detecting occlusion of the artery of an experimental rabbit ear pedicle flap. The laser Doppler flowmeter showed a significant decrease in flow and the transcutaneous oximeter showed a significant decrease in oxygen tension within one minute after occlusion of the artery. A significant increase in flow was observed within one minute, and a significant increase in oxygen tension readings was observed one minute after the artery was opened. A steady state after opening the artery was reached sooner for the laser Doppler flowmeter readings. This study suggests that laser Doppler flowmetry and transcutaneous oximetry are equally fast and accurate in detecting changes in blood flow to a pedicle graft. These methods also have equally good reproducibility. Repeated clampings within a 30 min period did not affect the measured parameters.