Tissue microvascular flow and oxygenation in critically ill patients

PhDThe use of fluid resuscitation and vasoactive agents to optimise global haemodynamics has been demonstrated to improve outcomes in patients undergoing major surgery and in early sepsis. Whether changes in global haemodynamics result in similar improvements in the microcirculation in critically ill patients remains unclear. The aim of this thesis was to investigate the changes in tissue microvascular flow and oxygenation that occur in patients undergoing major surgery and in those with sepsis, and specifically how haemodynamic therapies may affect these changes. The first part of this thesis investigates the treatment pathway of the high risk surgical patient. Analysis of two large health databases was performed and confirmed the existence of a high risk sub-population within the local surgical population. Only about a third of these high-risk patients were admitted to a critical care unit at any stage during their hospital admission. An observational trial was performed examining the relationship between global oxygen delivery, microvascular flow and tissue oxygenation in 25 surgical patients receiving usual care. Data including global haemodynamics, sublingual and cutaneous microvascular flow, and tissue oxygenation were collected before, and for eight hours after surgery. Abnormalities in sublingual microvascular flow were found to be associated with worse outcomes. 4 A randomised controlled study investigating the effects of two goal directed haemodynamic therapy (GDHT) algorithms on tissue microvascular flow and oxygenation compared to central venous pressure guided fluid therapy in 135 perioperative patients was performed. For eight hours after surgery, intravenous fluid therapy was guided by measurements of central venous pressure (CVP group) or stroke volume (SV group). In a third group stroke volume guided fluid therapy was combined with dopexamine (SV & DPX group). In the SV & DPX group, increased global oxygen delivery was associated with improved sublingual and cutaneous microvascular flow. Microvascular flow remained constant in the SV group but deteriorated in the CVP group. Cutaneous PtO2 improved only in the SV & DPX group. There were no differences in complication rates between groups. The importance of derangements in microvascular flow in patients with established sepsis is well recognized. However, little data is available to describe microvascular changes in early sepsis. Observational data were collected in 16 healthy volunteers and within six hours of presentation in 48 patients with sepsis and severe sepsis. Sublingual microvascular flow was impaired in patients with sepsis and severe sepsis compared to healthy volunteers. Greater alterations in flow were seen with increasing severity of illness. The dose-related effects of vasopressor therapy on microvascular flow and tissue oxygenation in sepsis have not been previously fully investigated. The effects of increasing doses of noradrenaline, targeted to achieve successively greater mean arterial pressures, on microvascular flow and tissue oxygenation in 16 patients with septic shock were investigated. Increasing doses of noradrenaline were associated with improvements in 5 global oxygen delivery, cutaneous PtO2 and cutaneous microvascular red blood cell flux. No changes in sublingual microvascular flow were identified. This thesis confirms the existence of a large sub-population of high risk surgical patients. It demonstrates that abnormal microvascular flow in the perioperative period may be associated with poor outcomes. The use of flow guided fluid therapy alongside low dose dopexamine infusion is shown to improve global haemodynamics, microvascular flow and tissue oxygenation in perioperative patients. Microvascular abnormalities are shown to occur in the earliest stages of sepsis with increasing severity of disease being associated with greater changes. Increasing doses of noradrenaline were found to improve global haemodynamics, cutaneous microvascular flow and cutaneous tissue oxygenation in septic shock. Further work is required to investigate the effects of haemodynamic therapies on microvascular flow and organ dysfunction in critically ill patients and the use of the microcirculation as a resuscitation endpoint

Volatile vs Total intravenous Anaesthesia for major non-cardiac surgery: a pragmatic randomised triaL (VITAL)

Background: Improving outcomes after surgery is a major public health research priority for patients, clinicians and the NHS. The greatest burden of perioperative complications, mortality and healthcare costs lies amongst the population of patients aged over 50 years who undergo major non-cardiac surgery. The Volatile vs Total Intravenous Anaesthesia for major non-cardiac surgery (VITAL) trial specifically examines the effect of anaesthetic technique on key patient outcomes: quality of recovery after surgery (quality of recovery after anaesthesia, patient satisfaction and major post-operative complications), survival and patient safety. // Methods: A multi-centre pragmatic efficient randomised trial with health economic evaluation comparing total intravenous anaesthesia with volatile-based anaesthesia in adults (aged 50 and over) undergoing elective major non-cardiac surgery under general anaesthesia. // Discussion: Given the very large number of patients exposed to general anaesthesia every year, even small differences in outcome between the two techniques could result in substantial excess harm. Results from the VITAL trial will ensure patients can benefit from the very safest anaesthesia care, promoting an early return home, reducing healthcare costs and maximising the health benefits of surgical treatments. // Trial registration: ISRCTN62903453. September 09, 2021

Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer.

In this report from the CAPTURE study (NCT03226886), we demonstrate that a third dose of COVID-19 vaccine boosts neutralizing antibody (NAb) and cellular responses in patients with cancer, including those that had undetectable NAb titers (NAbT) following two vaccine doses or for whom NAbT waned. We have noted that one key member of the CAPTURE consortium—Sanjay Popat—was inadvertently not included in the author list. We now include him as a co-author. There are no additional changes to the declaration of interests statement, since Dr. Popat declares no competing conflict of interest. This author list change is now reflected in the online version of this letter

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Summary Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886) we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralising antibody titres (NAbT) using a live virus microneutralization assay against wild-type (WT), Delta, Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titres and T cell responses after the fourth vaccine dose increases compared to those after the third vaccine dose. Patients who received B cell-depleting therapies within 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination

Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer

Summary Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886) we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralising antibody titres (NAbT) using a live virus microneutralization assay against wild-type (WT), Delta, Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titres and T cell responses after the fourth vaccine dose increases compared to those after the third vaccine dose. Patients who received B cell-depleting therapies within 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination

Functional antibody and T-cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707