Prospective longitudinal observational study of the macro and micro haemodynamic responses to septic shock in the renal and systemic circulations: a protocol for the MICROSHOCK - RENAL study.

Septic acute kidney injury (AKI) is the most common complication of septic shock and increases mortality. A large body of experimental data suggests alterations in renal perfusion occur, but this is yet to be fully assessed in humans. The aim of the current study is to observe the macro and microcirculations in both the systemic and renal circulations in a cohort of patients with early septic shock. Single-centre, prospective, longitudinal, observational study of 50 patients with septic shock. Renal microcirculatory assessment will be performed with contrast-enhanced ultrasound, the sublingual microcirculation assessed with incident dark field microscopy and transthoracic echocardiography used to assess global flow. Patients will be enrolled as soon as possible after admission to the intensive care unit and then at +24,+48 and +96 hours. Blood samples of circulatory and renal biomarkers will be collected. Sample groups will be defined by the presence or absence of AKI and then subclassified by the severity (Kidney Disease Improving Global Outcomes (KDIGO) criteria), variables will be compared within and between groups over time. Research Ethics Committee (REC) approval has been granted for this study by Yorkshire and the Humber, Leeds West Research Ethics Committee (18/YH/0371) and due to the nature of the patients enrolled with septic shock, capacity for informed consent is likely to be lacking. Therefore, a personal consultee (friend or relative) will be consulted or a nominated consultee (clinician) in their absence. After capacity is regained, consent will then be sought from the patient in accordance with the Mental Capacity Act, UK (2005). This consent process has been approved following REC review. Results will be published in a relevant peer-reviewed journal and presented at academic meetings.

Watchorn J ，Huang D ，Hopkins P ，Bramham K ，Hutchings S ... -  《BMJ Open》

Observational study of the effects of traumatic injury, haemorrhagic shock and resuscitation on the microcirculation: a protocol for the MICROSHOCK study.

The microcirculation is the physiological site of oxygen and substrate exchange. Its effectiveness during circulatory shock is vital for the perfusion of tissues, and has a bearing on subsequent organ function and prognosis. Microcirculatory dysfunction following traumatic haemorrhagic shock (THS) has been understudied compared with other pathologies such as sepsis. The aim of the MICROSHOCK study is to investigate changes seen in the microcirculation of patients following THS, and to assess its response to resuscitation. A greater understanding of the behaviour and mechanisms of microcirculatory dysfunction in this context may direct future avenues of goal-directed resuscitation for these patients. This multicentre prospective longitudinal observational study includes patients who present as an emergency with THS. Microcirculatory parameters are recorded using sublingual incident dark field microscopy alongside measurements of global flow (oesophageal Doppler and transthoracic echocardiography). Patients are enrolled into the study as soon as feasible after they arrive in hospital, and then at subsequent daily time points. Blood samples are taken for investigation into the mechanisms of microcirculatory dysfunction. Sequential Organ Failure Assessment scores will be analysed with microcirculatory parameters to determine whether they correlate with greater fidelity than more conventional, global circulatory parameters. Research Ethics Committee approval has been granted for this study (Reference: 14/YH/0078). Owing to the nature of THS, capacity for informed consent will be absent on patient enrolment. This will be addressed according to the Mental Health Capacity Act 2005. The physician in charge of the patient's care (nominated consultee) may consent on behalf of the patient. Consent will also be sought from a personal consultee (close relative or friend). After capacity is regained, the participant will be asked for their consent. Results will be submitted for publication in peer-reviewed journal format and presented at relevant academic meetings. NCT02111109; Pre-results.

Hutchings S ，Naumann DN ，Harris T ，Wendon J ，Midwinter MJ ... -  《BMJ Open》

The REPERFUSE study protocol: The effects of vasopressor therapy on renal perfusion in patients with septic shock-A mechanistically focused randomised control trial.

Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI, renal cortical perfusion is deficient despite normal macrovascular organ blood flow. This intra-renal perfusion abnormality may be amenable to pharmacological manipulation, which may offer mechanistic insight into the pathophysiology of septic AKI. The aim of the current study is to investigate the effects of vasopressin and angiotensin II on renal microcirculatory perfusion in a cohort of patients with septic shock. In this single centre, mechanistically focussed, randomised controlled study, 45 patients with septic shock will be randomly allocated to either of the study vasopressors (vasopressin or angiotensin II) or standard therapy (norepinephrine). Infusions will be titrated to maintain a mean arterial pressure (MAP) target set by the attending clinician. Renal microcirculatory assessment will be performed for the cortex and medulla using contrast-enhanced ultrasound (CEUS) and urinary oxygen tension (pO2), respectively. Renal macrovascular flow will be assessed via renal artery ultrasound. Measurement of systemic macrovascular flow will be performed through transthoracic echocardiography (TTE) and microvascular flow via sublingual incident dark field (IDF) video microscopy. Measures will be taken at baseline, +1 and +24hrs following infusion of the study drug commencing. Blood and urine samples will also be collected at the measurement time points. Longitudinal data will be compared between groups and over time. Vasopressors are integral to the management of patients with septic shock. This study aims to further understanding of the relationship between this therapy, renal perfusion and the development of AKI. In addition, using CEUS and urinary pO2, we hope to build a more complete picture of renal perfusion in septic shock by interrogation of the constituent parts of the kidney. Results will be published in peer-reviewed journals and presented at academic meetings. The REPERFUSE study was registered on Clinical Trials.gov (NCT06234592) on the 30th Jan 24.

McDonald R ，Watchorn J ，Mehta R ，Ostermann M ，Hutchings S ... -  《PLoS One》

Decreased renal cortical perfusion, independent of changes in renal blood flow and sublingual microcirculatory impairment, is associated with the severity of acute kidney injury in patients with septic shock.

Reduced renal perfusion has been implicated in the development of septic AKI. However, the relative contributions of macro- and microcirculatory blood flow and the extent to which impaired perfusion is an intrinsic renal phenomenon or part of a wider systemic shock state remains unclear. Single-centre prospective longitudinal observational study was carried out. Assessments were made at Day 0, 1, 2 and 4 after ICU admission of renal cortical perfusion in 50 patients with septic shock and ten healthy volunteers using contrast-enhanced ultrasound (CEUS). Contemporaneous measurements were made using transthoracic echocardiography of cardiac output. Renal artery blood flow was calculated using velocity time integral and vessel diameter. Assessment of the sublingual microcirculation was made using handheld video microscopy. Patients were classified based on the degree of AKI: severe = KDIGO 3 v non-severe = KDIGO 0-2. At study enrolment, patients with severe AKI (37/50) had prolonged CEUS mean transit time (mTT) (10.2 vs. 5.5 s, p < 0.05), and reduced wash-in rate (WiR) (409 vs. 1203 au, p < 0.05) and perfusion index (PI) (485 vs. 1758 au, p < 0.05); differences persisted throughout the entire study. Conversely, there were no differences in either cardiac index, renal blood flow or renal resistive index. Sublingual microcirculatory variables were not significantly different between groups at study enrolment or at any subsequent time point. Although lactate was higher in the severe AKI group at study enrolment, these differences did not persist, and there were no differences in either ScvO2 or ScvCO2-SaCO2 between groups. Patients with severe AKI received higher doses of noradrenaline (0.34 vs. 0.21mcg/kg/min, p < 0.05). Linear regression analysis showed no correlation between mTT and cardiac index (R-0.18) or microcirculatory flow index (R-0.16). Renal cortical hypoperfusion is a persistent feature in critically ill septic patients who develop AKI and does not appear to be caused by reductions in macrovascular renal blood flow or cardiac output. Cortical hypoperfusion appears not be associated with changes in the sublingual microcirculation, raising the possibility of a specific renal pathogenesis that may be amenable to therapeutic intervention. Trial Registration Clinical Trials.gov NCT03713307 , 19 Oct 2018.

Watchorn J ，Huang D ，Bramham K ，Hutchings S ... -  《CRITICAL CARE》

Protocol for a prospective observational study on the association of variables obtained by contrast-enhanced ultrasonography and sepsis-associated acute kidney injury.

Sepsis commonly results in acute kidney injury (AKI), whereas about 50% of AKI cases are due to sepsis. Sepsis-associated acute kidney injury (SA-AKI) increases morbidity and mortality especially among critically ill patients. This study aims to monitor renal microcirculation perfusion during sepsis using contrast-enhanced ultrasonography (CEUS), and to explore whether CEUS is useful for predicting the development of SA-AKI. This prospective observational study will enrol patients who were diagnosed with sepsis-3 definition. The total of septic or septic shock patients were stratified into AKI (including stages 1, 2 and 3) and non-AKI groups according to Kidney Disease Improving Global Outcomes criteria on days 0, 1, 2 and 7 after admission to the emergency intensive care unit, meanwhile, the CEUS technique will be performed to monitor renal microcirculation perfusion. A multivariable model including all CEUS variables were expected to create for predicting the development of AKI during sepsis. Ultrasonography results, demographic information, therapeutic interventions, survival outcomes, laboratory and other clinical datas will also be collected for further analysis. The study protocol was approved on 2 August 2017 by the Ethics Committee of Sir Run Run Shaw Hospital (Zhejiang University Medical College) (approval number: 2016C91401). The results will be published in a peer-reviewed journal and shared with the worldwide medical community within 2 years after the start of the recruitment. ISRCTN14728986.

Liu N ，Zhang Z ，Hong Y ，Li B ，Cai H ，Zhao H ，Dai J ，Liu L ，Qian X ，Jin Q ... -  《BMJ Open》