Randomised, controlled, feasibility trial comparing vasopressor infusion administered via peripheral cannula versus central venous catheter for critically ill adults: A study protocol.

BACKGROUND: When clinicians need to administer a vasopressor infusion, they are faced with the choice of administration via either peripheral intravenous catheter (PIVC) or central venous catheter (CVC). Vasopressor infusions have traditionally been administered via central venous catheters (CVC) rather than Peripheral Intra Venous Catheters (PIVC), primarily due to concerns of extravasation and resultant tissue injury. This practice is not guided by contemporary randomised controlled trial (RCT) evidence. Observational data suggests safety of vasopressor infusion via PIVC. To address this evidence gap, we have designed the "Vasopressors Infused via Peripheral or Central Access" (VIPCA) RCT. METHODS: The VIPCA trial is a single-centre, feasibility, parallel-group RCT. Eligible critically ill patients requiring a vasopressor infusion will be identified by emergency department (ED) or intensive care unit (ICU) staff and randomised to receive vasopressor infusion via either PIVC or CVC. Primary outcome is feasibility, a composite of recruitment rate, proportion of eligible patients randomised, protocol fidelity, retention and missing data. Primary clinical outcome is days alive and out of hospital up to day-30. Secondary outcomes will include safety and other clinical outcomes, and process and cost measures. Specific aspects of safety related to vasopressor infusions such as extravasation, leakage, device failure, tissue injury and infection will be assessed. DISCUSSION: VIPCA is a feasibility RCT whose outcomes will inform the feasibility and design of a multicentre Phase-3 trial comparing routes of vasopressor delivery. The exploratory economic analysis will provide input data for the full health economic analysis which will accompany any future Phase-3 RCT.

Determining sex-specific preoperative haemoglobin levels associated with intraoperative red blood cell transfusion in cardiac surgery: a retrospective cohort study.

BACKGROUND: Anaemic cardiac surgery patients are at greater risk of intraoperative red blood cell transfusion. This study questions the application of the World Health Organization population-based anaemia thresholds (haemoglobin <120 g L-1 in non-pregnant females and <130 g L-1 in males) as appropriate preoperative optimisation targets for cardiac surgery. METHODS: A retrospective cohort study was conducted on adults ≥18 yr old undergoing cardiopulmonary bypass surgery. Logistic regression was applied to define sex-specific preoperative haemoglobin concentrations with reduced probability of intraoperative red blood cell transfusion for cardiac surgery patients. RESULTS: Data on 4384 male and 1676 female patients were analysed. Binarily stratified multivariable logistic regression odds of receiving intraoperative red blood cell transfusion increased in cardiac surgery patients >45 yr old (odds ratio [OR] 1.84; 95% confidence interval [CI] 1.33-2.55), surgery urgency <30 days (OR 2.03; 95% CI 1.66-2.48), combined coronary artery bypass grafting and valve surgery, or other surgery types (OR 2.24; 95% CI 1.87-2.67), and female sex (OR 1.92; 95% CI 1.62-2.28). The odds decreased by 8.4% with each 1 g L-1 increase in preoperative haemoglobin (OR 0.92; 95% CI 0.91-0.92). Logistic regression predicted females required a preoperative haemoglobin concentration of 133 g L-1 and males 127 g L-1 to have a 15% probability of intraoperative transfusion. CONCLUSIONS: The World Health Organization female anaemia threshold of haemoglobin <120 g L-1 disproportionately disadvantages female cardiac surgery patients. A preoperative haemoglobin concentration ≥130 g L-1 in adult cardiac surgery patients would minimise their overall probability of intraoperative red blood cell transfusion to <15%.

Single-FiO2 lung modelling with machine learning: a computer simulation incorporating volumetric capnography.

We investigated whether machine learning (ML) analysis of ICU monitoring data incorporating volumetric capnography measurements of mean alveolar PCO2 can partition venous admixture (VenAd) into its shunt and low V/Q components without manipulating the inspired oxygen fraction (FiO2). From a 21-compartment ventilation / perfusion (V/Q) model of pulmonary blood flow we generated blood gas and mean alveolar PCO2 data in simulated scenarios with shunt values from 7.3% to 36.5% and a range of FiO2 settings, indirect calorimetry and cardiac output measurements and acid- base and hemoglobin oxygen affinity conditions. A 'deep learning' ML application, trained and validated solely on single FiO2 bedside monitoring data from 14,736 scenarios, then recovered shunt values in 500 test scenarios with true shunt values 'held back'. ML shunt estimates versus true values (n = 500) produced a linear regression model with slope = 0.987, intercept = -0.001 and R2 = 0.999. Kernel density estimate and error plots confirmed close agreement. With corresponding VenAd values calculated from the same bedside data, low V/Q flow can be reported as VenAd-shunt. ML analysis of blood gas, indirect calorimetry, volumetric capnography and cardiac output measurements can quantify pulmonary oxygenation deficits as percentage shunt flow (V/Q = 0) versus percentage low V/Q flow (V/Q > 0). High fidelity reports are possible from analysis of data collected solely at the operating FiO2.

Pulmonary gas exchange evaluated by machine learning: a computer simulation.

Using computer simulation we investigated whether machine learning (ML) analysis of selected ICU monitoring data can quantify pulmonary gas exchange in multi-compartment format. A 21 compartment ventilation/perfusion (V/Q) model of pulmonary blood flow processed 34,551 combinations of cardiac output, hemoglobin concentration, standard P50, base excess, VO2 and VCO2 plus three model-defining parameters: shunt, log SD and mean V/Q. From these inputs the model produced paired arterial blood gases, first with the inspired O2 fraction (FiO2) adjusted to arterial saturation (SaO2) = 0.90, and second with FiO2 increased by 0.1. 'Stacked regressor' ML ensembles were trained/validated on 90% of this dataset. The remainder with shunt, log SD, and mean 'held back' formed the test-set. 'Two-Point' ML estimates of shunt, log SD and mean utilized data from both FiO2 settings. 'Single-Point' estimates used only data from SaO2 = 0.90. From 3454 test gas exchange scenarios, two-point shunt, log SD and mean estimates produced linear regression models versus true values with slopes ~ 1.00, intercepts ~ 0.00 and R2 ~ 1.00. Kernel density and Bland-Altman plots confirmed close agreement. Single-point estimates were less accurate: R2 = 0.77-0.89, slope = 0.991-0.993, intercept = 0.009-0.334. ML applications using blood gas, indirect calorimetry, and cardiac output data can quantify pulmonary gas exchange in terms describing a 20 compartment V/Q model of pulmonary blood flow. High fidelity reports require data from two FiO2 settings.

Respiratory system mechanics, gas exchange, and outcomes in mechanically ventilated patients with COVID-19-related acute respiratory distress syndrome: a systematic review and meta-analysis.

The association of respiratory mechanics, particularly respiratory system static compliance (CRS), with severity of hypoxaemia in patients with COVID-19-related acute respiratory distress syndrome (ARDS) has been widely debated, with some studies reporting distinct ARDS phenotypes based on CRS. Ascertaining whether such phenotypes exist is important, because they might indicate the need for ventilation strategies that differ from those used in patients with ARDS due to other causes. In a systematic review and meta-analysis of studies published between Dec 1, 2019, and March 14, 2022, we evaluated respiratory system mechanics, ventilator parameters, gas exchange parameters, and clinical outcomes in patients with COVID-19-related ARDS. Among 11 356 patients in 37 studies, mean reported CRS, measured close to the time of endotracheal intubation, was 35·8 mL/cm H2O (95% CI 33·9-37·8; I2=96·9%, τ2=32·6). Pooled mean CRS was normally distributed. Increasing ARDS severity (assessed by PaO2/FiO2 ratio as mild, moderate, or severe) was associated with decreasing CRS. We found no evidence for distinct CRS-based clinical phenotypes in patients with COVID-19-related ARDS, and we therefore conclude that no change in conventional lung-protective ventilation strategies is warranted. Future studies should explore the personalisation of mechanical ventilation strategies according to factors including respiratory system mechanics and haemodynamic status in patients with ARDS.

Stress response during early sedation with dexmedetomidine compared with usual-care in ventilated critically ill patients.

BACKGROUND: Sedative agents may variably impact the stress response. Dexmedetomidine is a sympatholytic alpha2-adrenergic agonist mainly used as a second-line sedative agent in mechanically ventilated patients. We hypothesised that early sedation with dexmedetomidine as the primary agent would result in a reduced stress response compared to usual sedatives in critically ill ventilated adults. METHODS: This was a prospective sub-study nested within a multi-centre randomised controlled trial of early sedation with dexmedetomidine versus usual care. The primary outcome was the mean group differences in plasma levels of stress response biomarkers measured over 5 days following randomisation. Other hormonal, biological and physiological parameters were collected. Subgroup analyses were planned for patients with proven or suspected sepsis. RESULTS: One hundred and three patients were included in the final analysis. Baseline illness severity (APACHE II score), the proportion of patients receiving propofol and the median dose of propofol received were comparable between groups. More of the usual-care patients received midazolam (57.7% vs 33.3%; p = 0.01) and at higher dose (median (95% interquartile range) 0.46 [0.20-0.93] vs 0.14 [0.08-0.38] mg/kg/day; p < 0.01). The geometric mean (95% CI) plasma level of the stress hormones, adrenaline (0.32 [0.26-0.4] vs 0.38 [0.31-0.48]), noradrenaline (4.27 [3.12-5.85] vs 6.2 [4.6-8.5]), adrenocorticotropic hormone (17.1 [15.1-19.5] vs 18.1 [15.9-20.5]) and cortisol (515 [409-648] vs 618 [491-776)] did not differ between dexmedetomidine and usual-care groups, respectively. There were no significant differences in any other assayed biomarkers or physiological parameters Sensitivity analyses showed no effect of age or sepsis. CONCLUSIONS: Early sedation with dexmedetomidine as the primary sedative agent in mechanically ventilated critically ill adults resulted in comparable changes in physiological and blood-borne parameters associated with the stress-response as with usual-care sedation.

Impact of frailty on clinical outcomes in patients with and without COVID-19 pneumonitis admitted to intensive care units in Australia and New Zealand: a retrospective registry data analysis.

BACKGROUND: It is unclear if the impact of frailty on mortality differs between patients with viral pneumonitis due to COVID-19 or other causes. We aimed to determine if a difference exists between patients with and without COVID-19 pneumonitis. METHODS: This multicentre, retrospective, cohort study using the Australian and New Zealand Intensive Care Society Adult Patient Database included patients aged ≥ 16 years admitted to 153 ICUs between 01/012020 and 12/31/2021 with admission diagnostic codes for viral pneumonia or acute respiratory distress syndrome, and Clinical Frailty Scale (CFS). The primary outcome was hospital mortality. RESULTS: A total of 4620 patients were studied, and 3077 (66.6%) had COVID-19. The patients with COVID-19 were younger (median [IQR] 57.0 [44.7-68.3] vs. 66.1 [52.0-76.2]; p < 0.001) and less frail (median [IQR] CFS 3 [2-4] vs. 4 [3-5]; p < 0.001) than non-COVID-19 patients. The overall hospital mortality was similar between the patients with and without COVID-19 (14.7% vs. 14.9%; p = 0.82). Frailty alone as a predictor of mortality showed only moderate discrimination in differentiating survivors from those who died but was similar between patients with and without COVID-19 (AUROC 0.68 vs. 0.66; p = 0.42). Increasing frailty scores were associated with hospital mortality, after adjusting for Australian and New Zealand Risk of Death score and sex. However, the effect of frailty was similar in patients with and without COVID-19 (OR = 1.29; 95% CI: 1.19-1.41 vs. OR = 1.24; 95% CI: 1.11-1.37). CONCLUSION: The presence of frailty was an independent risk factor for mortality. However, the impact of frailty on outcomes was similar in COVID-19 patients compared to other causes of viral pneumonitis.

Reduction in preterm birth rates during and after the COVID-19 lockdown in Queensland Australia.

BACKGROUND: Preventative strategies for preterm birth are lacking. Recent evidence proposed COVID-19 lockdowns may have contributed to changes in preterm birth. AIMS: To determine the prevalence of preterm birth and birth outcomes during and after the COVID-19 lockdown at the Sunshine Coast University Hospital and the overall state of Queensland, Australia. METHODS: Retrospective cohort analysis of all births in Queensland including the Sunshine Coast University Hospital, during two epochs, April 1-May 31, 2020 (lockdown) and June 1-July 31, 2020 (post-lockdown), compared to antecedent calendar-matched periods in 2018-2019. Prevalence of preterm birth, stillbirth, and late terminations were examined. RESULTS: There were 64 989 births in Queensland from April to July 2018-2020. At the Sunshine Coast University Hospital, there was a significantly higher chance of birth at term during both lockdown (odds ratio (OR) 1.81, 95% CI 1.17, 2.79; P = 0.007) and post-lockdown (OR 2.01, 95% CI 1.27, 3.18; P = 0.003). At the same centre, prevalence of preterm birth was 5.5% (30/547) during lockdown, compared to 9.1% (100/1095) in previous years, a 40.0% relative reduction (P = 0.016). At this centre during lockdown, emergency caesareans concurrently decreased (P < 0.01) and instrumental vaginal births increased (P < 0.01). In Queensland overall, there was a nonsignificant decrease in the prevalence of preterm birth during lockdown. CONCLUSIONS: There is a link between lockdown and a reduction in the prevalence of preterm birth on the Sunshine Coast. The cause is speculative at present, although increased influenza vaccination rates, decreased transmission of infections, and improved air quality may have been favourable in reducing preterm birth. Further research is needed to determine a causal link.

The Impact of COVID-19 on Acute Surgical Admissions at the Sunshine Coast University Hospital.

Purpose It has been noted in international literature that acute surgical admissions and number of operations reduced as a result of coronavirus disease2019 (COVID-19). This study assesses the impact of the COVID-19 pandemic on the number of acute surgical admissions, operations, and length of stay (LoS) at the Sunshine Coast University Hospital (SCUH), Queensland, Australia. Methodology A retrospective study was conducted on patients admitted to the Acute Surgical Unit (ASU) during March and April for the years 2018, 2019, and 2020. Admission data for ASU patients in 2018 and 2019 were combined (pre-COVID) and compared with 2020 (COVID) to determine impact of the pandemic on presentations and procedures. Results ASU admissions reduced in 2020 (461 patients) compared with pre-COVID years (mean: 545 patients per year). There was an increase in the number (%) of operations performed in 2020, 175 patients (38%) compared with pre-COVID years, mean 158 patients (29%), p = 0.001. There was a significant decrease in the number (%) of functional presentations in 2020, 29 patients (6.3%) compared with pre-COVID years, mean 105 patients (9.6%), p = 0.04. LoS was not significantly different (52 hours vs. 54 hours, p = 0.11). Conclusion COVID-19 has reduced the absolute number of acute surgical admissions at SCUH. This effectively reduced triage workload. Contrary to the literature, this study did not demonstrate a reduction in the number of operations or change in LoS. These data could be used by health administrators to help with resource allocation during future pandemics.

Characteristics and Outcomes of Patients With Frailty Admitted to ICU With Coronavirus Disease 2019: An Individual Patient Data Meta-Analysis.

Frailty is often used in clinical decision-making for patients with coronavirus disease 2019, yet studies have found a variable influence of frailty on outcomes in those admitted to the ICU. In this individual patient data meta-analysis, we evaluated the characteristics and outcomes across the range of frailty in patients admitted to ICU with coronavirus disease 2019. DATA SOURCES: We contacted the corresponding authors of 16 eligible studies published between December 1, 2019, and February 28, 2021, reporting on patients with confirmed coronavirus disease 2019 admitted to ICU with a documented Clinical Frailty Scale. STUDY SELECTION: Individual patient data were obtained from seven studies with documented Clinical Frailty Scale were included. We classified patients as nonfrail (Clinical Frailty Scale = 1-4) or frail (Clinical Frailty Scale = 5-8). DATA EXTRACTION: We collected patient demographics, Clinical Frailty Scale score, ICU organ supports, and clinically relevant outcomes (ICU and hospital mortality, ICU and hospital length of stays, and discharge destination). The primary outcome was hospital mortality. DATA SYNTHESIS: Of the 2,001 patients admitted to ICU, 388 (19.4%) were frail. Increasing age and Sequential Organ Failure Assessment score, Clinical Frailty Scale score greater than or equal to 4, use of mechanical ventilation, vasopressors, renal replacement therapy, and hyperlactatemia were risk factors for death in a multivariable analysis. Hospital mortality was higher in patients with frailty (65.2% vs 41.8%; p < 0.001), with adjusted mortality increasing with a rising Clinical Frailty Scale score beyond 3. Younger and nonfrail patients were more likely to receive mechanical ventilation. Patients with frailty spent less time on mechanical ventilation (median days [interquartile range], 9 [5-16] vs 11 d [6-18 d]; p = 0.012) and accounted for only 12.3% of total ICU bed days. CONCLUSIONS: Patients with frailty with coronavirus disease 2019 were commonly admitted to ICU and had greater hospital mortality but spent relatively fewer days in ICU when compared with nonfrail patients. Patients with frailty receiving mechanical ventilation were at greater risk of death than patients without frailty.

Hyperlactatemia in diabetic ketoacidosis is common and can be prolonged: lactate time-series from 25 intensive care admissions.

Hyperlactatemia is a documented complication of diabetic ketoacidosis (DKA). Lactate responses during DKA treatment have not been studied and were the focus of this investigation. Blood gas and electrolyte data from 25 DKA admissions to ICU were sequenced over 24 h from the first Emergency Department sample. Hyperlactatemia (> 2 mmol/L) was present in 22 of 25 DKA presentations [mean concentration = 3.2 mmol/L]. In 18 time-series (72%), all concentrations normalized in ≤ 2.6 h (aggregate decay t1/2 = 2.29 h). In the remaining 7 (28%), hyperlactatemia persisted > 12 h. These were females (P = 0.04) with relative anemia (hemoglobin concentrations 131 v 155 g/L; P = 0.004) and lower nadir glucose concentrations (5.2 v 8.0 mmol/L, P = 0.003). Their aggregate glucose decay curve commenced higher (42 mmol/L v 29 mmol/L), descending towards a lower asymptote (8 mmol/L v 11 mmol/L). Tonicity decay showed similar disparities. There was equivalent resolution of metabolic acidosis and similar lengths of stay in both groups. Hyperlactatemia is common in DKA. Resolution is often rapid, but high lactates can persist. Females with high glucose concentrations corrected aggressively are more at risk. Limiting initial hyperglycemia correction to ≥ 11 mmol/L may benefit.

Relationship between coronary microvascular dysfunction and left ventricular diastolic function in patients with chest pain and unobstructed coronary arteries.

BACKGROUD: Diastolic dysfunction (DD) is reported to affect up to 35% of the adult general population. The consequence of progressive DD is heart failure with preserved ejection fraction (HFpEF). Coronary microvascular dysfunction (CMD) has been suggested as one of the pathologic mechanisms leading to HFpEF. We investigated whether there was an association between coronary microvascular function and echocardiographic indices of left ventricular diastolic function at rest in patients with chest pain and unobstructed coronary arteries (CPUCA). METHODS: This retrospective observational study recruited patients referred to cardiology clinics assessment of chest pain who subsequently underwent assessment via CT coronary angiogram (CTA). Coronary microvascular dysfunction was determined by myocardial blood flow reserve (MBFR; <2.0) using myocardial contrast echocardiography. Echocardiographic indices of diastolic function (septal mitral annular e'; septal mitral annular E/e', E/A ratio) were measured from baseline transthoracic echocardiogram. RESULTS: 149 patients (52% men) with a mean age 59.7(9.5) years were recruited. Mean (standard deviation) MBFR was 2.2 (0.51). 37% (55/149) had MBFR < 2.0. Median [interquartile range] septal mitral annular e' velocity and septal mitral annular E/e' were 7.6 cm/s [6.2, 8.9] and 9.5 [7.5, 10.8], respectively. Univariate regression analysis showed only age was a significant predictor of increasing septal mitral annular E/e' (ß = +0.20 95% CI 0.13, +0.28, P < .001) but not MBFR. Multivariable analysis also showed no association between these septal mitral annular E/e' and MBFR after adjustment for cardiovascular risk factors. CONCLUSION: There was no relationship found between echocardiographic indices of left ventricular diastolic function and coronary microvascular function at rest.

A retrospective observational study of sarcopenia and outcomes in critically ill patients.

Frailty assessment in patients admitted to intensive care is often limited using traditional clinical frailty assessment tools. Opportunistic use of contemporary computed tomography (CT) can provide an objective estimate of low skeletal muscle mass (sarcopenia) as a proxy for frailty. The aim of this study was to establish the prevalence of sarcopenia in an Australian intensive care unit (ICU) population and to examine the relationship between sarcopenia and clinical outcomes. We undertook a single centre retrospective study of 1085 adult patients admitted to a single ICU over 12 months. Patients with a contemporary CT scan including the L3 vertebral body were included. Patients were categorised as sarcopenic or non-sarcopenic using previously published data. A total of 279 patients with a mean age of 67 years had an eligible CT scan; 163 (58%) were male. Higher 30-day mortality was associated with the use of CRRT (continuous renal replacement therapy) during the ICU admission (OR 6.84, P < 0.001) and also associated with lower cross-sectional muscle area (odds ratio (OR) 0.98, P = 0.004). Sarcopenia was found to be highly prevalent in this particular Australian ICU population (68%) and associated with older age (68 versus 55 years, P < 0.001), lower body mass index (27 versus 32 kg m-2, P < 0.001), more comorbidities (3 versus 2, P = 0.009), and longer stays in hospital (279 versus 223 h, P = 0.043). As a continuous predictor, lumbar muscle mass was associated with 30-day mortality with and without adjusting for other covariates.

Rapid haemodilution accelerates hypertonicity resolution in diabetic ketoacidosis: data from 25 intensive care admissions.

BACKGROUND: Clinically apparent cerebral oedema during diabetic ketoacidosis (DKA) is rare and more common in children and young adults. Subclinical oedema with mild brain dysfunction is more frequent, with unknown long term effects. Rapid tonicity changes may be a factor although not well studied. Guidelines recommend capping hypertonicity resolution at ≤ 3 mOsmol/kg/h. OBJECTIVES: To audit current DKA management in the emergency department (ED) and in the intensive care unit (ICU) for tonicity benchmark compliance, and to determine interactions between plasma tonicity, plasma glucose concentrations and blood haemoglobin concentrations. METHODS: Twenty-five adult DKA admissions from ED to ICU were studied retrospectively. Blood gas and electrolyte data were sequenced for 24 hours from first ED blood sample. RESULTS: Sampling was frequent (median, 11 times per day; range, 6-26). Tonicity reduction was largely accomplished by the first ICU blood sample and exceeded 3 mOsmol/ kg/h in 72% of admissions. Correlation with haemoglobin reduction (haemodilution) rates exceeded correlation with glucose rates (R2 = 0.52 v 0.38). In benchmark noncompliant admissions, haemodilution was more rapid (6.1 g/L/h v 2.1 g/L/h; P = 0.001). Although also true of glucose reduction (4.5 mmol/L/h v 2.2 mmol/L/h; P = 0.007), there was no interaction between haemodilution and glucose reduction (R2 = 0.09). CONCLUSIONS: Major tonicity reductions often exceeding guidelines were common by ICU admission. Correcting DKA-induced hypertonicity at ≤ 3 mOsmol/kg/h requires controlled hyperglycaemia correction and, based on our data, avoidance of high fluid replacement rates; for example, sufficient to reduce haemoglobin concentrations by > 3 g/L/h, unless there is evidence of intravascular hypovolaemia.

Unintended Consequences: Fluid Resuscitation Worsens Shock in an Ovine Model of Endotoxemia.

RATIONALE: Fluid resuscitation is widely considered a life-saving intervention in septic shock; however, recent evidence has brought both its safety and efficacy in sepsis into question. OBJECTIVES: In this study, we sought to compare fluid resuscitation with vasopressors with the use of vasopressors alone in a hyperdynamic model of ovine endotoxemia. METHODS: Endotoxemic shock was induced in 16 sheep, after which they received fluid resuscitation with 40 ml/kg of 0.9% saline or commenced hemodynamic support with protocolized noradrenaline and vasopressin. Microdialysis catheters were inserted into the arterial circulation, heart, brain, kidney, and liver to monitor local metabolism. Blood samples were recovered to measure serum inflammatory cytokines, creatinine, troponin, atrial natriuretic peptide, brain natriuretic peptide, and hyaluronan. All animals were monitored and supported for 12 hours after fluid resuscitation. MEASUREMENTS AND MAIN RESULTS: After resuscitation, animals that received fluid resuscitation required significantly more noradrenaline to maintain the same mean arterial pressure in the subsequent 12 hours (68.9 mg vs. 39.6 mg; P = 0.04). Serum cytokines were similar between groups. Atrial natriuretic peptide increased significantly after fluid resuscitation compared with that observed in animals managed without fluid resuscitation (335 ng/ml [256-382] vs. 233 ng/ml [144-292]; P = 0.04). Cross-sectional time-series analysis showed that the rate of increase of the glycocalyx glycosaminoglycan hyaluronan was greater in the fluid-resuscitated group over the course of the study (P = 0.02). CONCLUSIONS: Fluid resuscitation resulted in a paradoxical increase in vasopressor requirement. Additionally, it did not result in improvements in any of the measured microcirculatory- or organ-specific markers measured. The increase in vasopressor requirement may have been due to endothelial/glycocalyx damage secondary to atrial natriuretic peptide-mediated glycocalyx shedding.