Blood volume and albumin transudation in critically ill COVID-19 patients

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. To the Editor: The SARS-CoV-2 infection (COVID-19) in critically ill patients presents as a viral pneumonia and inflammation affecting the endothelium [1] with unclear consequences for fluid leakage to the extravascular space. Nevertheless, the adapted Surviving Sepsis Guidelines advocate a conservative fluid strategy [2]. By using a radiolabeled albumin tracer, the total blood volume (TBV), red blood cell volume (RBCV), plasma volume (PV), and the albumin transudation rate (ATR) can be measured [3]. In six mechanically ventilated patients (admitted March/April 2020), the TBV was measured [4] as advanced hemodynamic monitoring was not used, and the volume status was unclear. The volumes measured were corrected for the ideal body weight of a corresponding healthy individual, and deviations were calculated. The results of only the TBV, RBCV, and PV were communicated with the treatment team. We retrospectively analyzed these data together with the ATR. Albumin transudation rate is presented as a numeric value with 0.0025 (0.25%/min exiting the circulation) serving as the normal reference threshold. We report absolute variation (values at admission minus value at day of measurement for each case), and dayindexed values, calculated by dividing the absolute variation by the number of days in the ICU. We performed univariate regression between albumin transudation and variables of interest. In the multivariate regression, we tested variables that showed statistical significance in the univariate analysis and other that did not reach the significance threshold but had clinical relevance. Data are expressed as mean ± 1 standard deviation unless otherwise indicated. A p value of equal or less than 0.05 was considered significant. None of the patients was diagnosed with a secondary infection the days before the measurement. Age of the patients was 66 ± 11 year with a mean weight of 86.3 ± 15.7 kg. Only one patient did not have any comorbidity on admission where the most frequent comorbidity was diabetes (four patients, two in combination with hypertension). Four patients died, all of whom developed complete renal failure. At the time of measurement, all patients had stable hemodynamics only one patient received vasopressor support (norepinephrine 0.42 mcg/kg/min). Results are shown in Table 1. Three of the four clinically hypervolemic patients (assessed by fluid balance and extend of peripheral edema), TBV showed a decreased value from ideal body weight. The median ATR was 0.46%/min (range 0.12– 0.82). There was a strong linear relationship between the day of admission and ATR (R2 = 0.99, P < 0.0001) and a curve linear relationship with the deviation of the TBV (R2 = 0.63, p < 0.03) (Fig. 1). In an exploratory multivariate regression model, we found TBV deviation (p = 0.022) and net fluid balance since admission (p = 0.018) and CRP at day of measurement (p = 0.043) to explain 99% of the variation in ATR. Although endothelial damage is believed to be an important part of COVID-19 and related to the severity of illness [5] and aggregates of red and white blood cells in the microcirculation have been reported [6], extensive capillary leakage has not been reported before. As a nosocomial bacterial infection had not been confirmed in any of the patients, the severity of COVID-19 and the Open Access


To the Editor:
The SARS-CoV-2 infection (COVID-19) in critically ill patients presents as a viral pneumonia and inflammation affecting the endothelium [1] with unclear consequences for fluid leakage to the extravascular space. Nevertheless, the adapted Surviving Sepsis Guidelines advocate a conservative fluid strategy [2]. By using a radiolabeled albumin tracer, the total blood volume (TBV), red blood cell volume (RBCV), plasma volume (PV), and the albumin transudation rate (ATR) can be measured [3]. In six mechanically ventilated patients (admitted March/April 2020), the TBV was measured [4] as advanced hemodynamic monitoring was not used, and the volume status was unclear. The volumes measured were corrected for the ideal body weight of a corresponding healthy individual, and deviations were calculated. The results of only the TBV, RBCV, and PV were communicated with the treatment team.
We retrospectively analyzed these data together with the ATR. Albumin transudation rate is presented as a numeric value with 0.0025 (0.25%/min exiting the circulation) serving as the normal reference threshold. We report absolute variation (values at admission minus value at day of measurement for each case), and dayindexed values, calculated by dividing the absolute variation by the number of days in the ICU. We performed univariate regression between albumin transudation and variables of interest. In the multivariate regression, we tested variables that showed statistical significance in the univariate analysis and other that did not reach the significance threshold but had clinical relevance. Data are expressed as mean ± 1 standard deviation unless otherwise indicated. A p value of equal or less than 0.05 was considered significant. None of the patients was diagnosed with a secondary infection the days before the measurement. Age of the patients was 66 ± 11 year with a mean weight of 86.3 ± 15.7 kg. Only one patient did not have any comorbidity on admission where the most frequent comorbidity was diabetes (four patients, two in combination with hypertension). Four patients died, all of whom developed complete renal failure. At the time of measurement, all patients had stable hemodynamics only one patient received vasopressor support (norepinephrine 0.42 mcg/kg/min). Results are shown in Table 1. Three of the four clinically hypervolemic patients (assessed by fluid balance and extend of peripheral edema), TBV showed a decreased value from ideal body weight. The median ATR was 0.46%/min (range 0.12-0.82). There was a strong linear relationship between the day of admission and ATR (R 2 = 0.99, P < 0.0001) and a curve linear relationship with the deviation of the TBV (R 2 = 0.63, p < 0.03) (Fig. 1).
In an exploratory multivariate regression model, we found TBV deviation (p = 0.022) and net fluid balance since admission (p = 0.018) and CRP at day of measurement (p = 0.043) to explain 99% of the variation in ATR.
Although endothelial damage is believed to be an important part of COVID-19 and related to the severity of illness [5] and aggregates of red and white blood cells in the microcirculation have been reported [6], extensive capillary leakage has not been reported before. As a nosocomial bacterial infection had not been confirmed in any of the patients, the severity of COVID-19 and the Open Access  systemic inflammatory response could be a more likely explanation. This vascular leakage could result in tissue edema and ultimately organ dysfunction as seen in these patients. Although this may suggest a role for the use of specific fluids (such as colloids) in this disease, our current data do not allow such recommendation. Given the only one-time measurement results should be interpreted with caution. This study could be seen as a unique exploratory study in COVID-19 patients.
We have therefore initiated a multicenter prospective study to improve our understanding of blood volume and vascular leakage in critically ill COVID-19 patients (NCT04517695).