Protocolised reduction of non-resuscitation fluids versus usual care in patients with septic shock (REDUSE): a protocol for a multicentre feasibility trial.

INTRODUCTION: Administration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care unit (ICU) patients suffering from septic shock. The present trial is designed to test the hypothesis that a protocol targeting this source of fluids can reduce fluid administration compared with usual care. METHODS AND ANALYSIS: The design will be a multicentre, randomised, feasibility trial. Adult patients admitted to ICUs with septic shock will be randomised within 12 hours of admission to receive non-resuscitation fluids either according to a restrictive protocol or to receive usual care. The healthcare providers involved in the care of participants will not be blinded. The participants, outcome assessors at the 6-month follow-up and statisticians will be blinded. Primary outcome will be litres of fluids administered within 3 days of randomisation. Secondary outcomes will be proportion of randomised participants with outcome data on all-cause mortality; days alive and free of mechanical ventilation within 90 days of inclusion; any acute kidney injury and ischaemic events in the ICU (cerebral, cardiac, intestinal or limb ischaemia); proportion of surviving randomised patients who were assessed by European Quality of Life 5-Dimensions 5-Level questionnaire and Montreal Cognitive Assessment; proportion of all eligible patients who were randomised and proportion of participants experiencing at least one protocol violation. ETHICS AND DISSEMINATION: Ethics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05249088.

Intensive care unit burden is associated with increased mortality in critically ill COVID-19 patients.

BACKGROUND: Traditional models to predict intensive care outcomes do not perform well in COVID-19. We undertook a comprehensive study of factors affecting mortality and functional outcome after severe COVID-19. METHODS: In this prospective multicentre cohort study, we enrolled laboratory-confirmed, critically ill COVID-19 patients at six ICUs in the Skåne Region, Sweden, between May 11, 2020, and May 10, 2021. Demographics and clinical data were collected. ICU burden was defined as the total number of ICU-treated COVID-19 patients in the region on admission. Surviving patients had a follow-up at 90 days for assessment of functional outcome using the Glasgow Outcome Scale-Extended (GOSE), an ordinal scale (1-8) with GOSE ≥5 representing a favourable outcome. The primary outcome was 90-day mortality; the secondary outcome was functional outcome at 90 days. RESULTS: Among 498 included patients, 74% were male with a median age of 66 years and a median body mass index (BMI) of 30 kg/m2 . Invasive mechanical ventilation was employed in 72%. Mortality in the ICU, in-hospital and at 90 days was 30%, 38% and 39%, respectively. Mortality increased markedly at age 60 and older. Increasing ICU burden was independently associated with a two-fold increase in mortality. Higher BMI was not associated with increased mortality. Besides age and ICU burden, smoking status, cortisone use, Pa CO2 >7 kPa, and inflammatory markers on admission were independent factors of 90-day mortality. Lower GOSE at 90 days was associated with a longer stay in the ICU. CONCLUSION: In critically ill COVID-19 patients, the 90-day mortality was 39% and increased considerably at age 60 or older. The ICU burden was associated with mortality, whereas a high BMI was not. A longer stay in the ICU was associated with unfavourable functional outcomes at 90 days.

Survey of non-resuscitation fluids administered during septic shock: a multicenter prospective observational study.

BACKGROUND: The indication, composition and timing of administration of non-resuscitation fluid in septic shock have so far received little attention and accordingly the potential to reduce this source of fluid is unknown. The objective of the study was to quantify and characterize non-resuscitation fluid administered to patients with septic shock. METHODS: This prospective observational study was performed in eight intensive care units in Sweden and Canada during 4 months in 2018. Adult patients with septic shock within 24 h of admission to the intensive care unit were eligible for inclusion. Non-resuscitation fluids were defined as fluids other than colloids, blood products and crystalloids at a rate ≥ 5 ml/kg/h. Indication, volume and type of fluid were recorded during the first 5 days after admission. A maximum of 30 patients could be included per centre. To estimate the potential to reduce administration of non-resuscitation fluid, a pragmatic "restrictive" protocol for administration of non-resuscitation fluids was devised based on the most restrictive practice already in place for non-resuscitation fluids at any of the participating centres. Data are presented as median (interquartile range [IQR]). RESULTS: A total of 200 patients were included in the study and the 30-day mortality was 35%. Patients received a total of 7870 (4060-12,340) ml of non-resuscitation fluids and 2820 (1430-4580) of resuscitation fluids during the observation period. Median volumes of non-resuscitation and resuscitation fluids were similar at day 1 (1620 [710-2320] and 1590 [520-3000]) ml, respectively) and non-resuscitation fluids represented the largest source of fluid from day 2 and onwards after admission to the ICU. Vehicles for drugs such as vasoactive drugs and antibiotics constituted the largest fraction of non-resuscitation fluids (2400 [1270-4030] ml) during the 5-day observation period. Modelling suggested that volume of non-resuscitation fluids could be reduced by 2840 (1270-4900) ml during the first 5 days of admission to the ICU, mainly through reducing maintenance fluids. CONCLUSIONS: Non-resuscitation fluids constitute the major fraction of fluids administered in the ICU to patients suffering from septic shock and may represent the largest modifiable target to reduce fluid overload.

Blood-brain barrier permeability following traumatic brain injury.

BACKGROUND: Brain edema and intracranial hypertension is deleterious after traumatic brain injury (TBI), but the underlying pathophysiology is complex and poorly understood. One major subject of controversy is the time course and extent of blood-brain barrier (BBB) dysfunction following trauma, and previous studies in humans have only provided semi-quantitative data. The objective of the present study was therefore to quantify changes in BBB-permeability in the early course of TBI, when brain edema is still evolving. METHODS: Sixteen non-consecutive brain trauma patients and two controls were included. Following i.v. injection of iohexol and CT perfusion scans, patients were scanned eight times from 4 to 25 minutes. Blood to brain transfer constant (Ki) for iohexol (molecular weight 821 D), reflecting permeability and available area for diffusion, was calculated offline by Patlak plot analysis of the enhancement curves of intracerebral large venous vessels and pericontusional brain parenchyma. RESULTS: In non-ischemic tissue surrounding contusions and hematomas Ki was increased 2- to 10-fold compared to normal tissue, reaching maximal values of 0.5 mL/min/100 g. In non-injured areas and in controls Ki was about 0.06 mL/min/100 g. The increase was more pronounced in the most severely injured patients, and was detectable within 24 hours after trauma and up to five days after. CONCLUSIONS: Our results suggest that traumatic brain injury is associated with early focal increases in small molecular BBB-permeability. The results indicate that in the injured brain, capillary hydrostatic and oncotic pressures may influence edema formation.

Intracranial pressure following resuscitation with albumin or saline in a cat model of meningitis.

OBJECTIVE: To compare the intracranial pressure after resuscitation to normovolemia by using 20% albumin or normal saline in a cat model of meningitis. DESIGN: Prospective, randomized animal study. SETTING: University hospital laboratory. SUBJECTS: Twenty adult, male cats. INTERVENTIONS: Meningitis was induced by intrathecal injection of Escherichia coli-derived lipopolysaccharide (0.8 × 10 units/kg). Four hours after the lipopolysaccharide injection, the animals were randomized to intravenous treatment with 0.4 mL/kg/hr of 20% albumin or 7.5 mL/kg/hr of 0.9% sodium chloride for 6 hrs (n = 7 per group). A control group receiving lipopolysaccharide but no fluid was also studied (n = 6). MEASUREMENTS AND MAIN RESULTS: Effects on intracranial pressure, mean arterial pressure, plasma volume (I-albumin technique), plasma oncotic pressure, and brain metabolism via cerebral interstitial lactate/pyruvate ratio and glycerol and glucose levels (microdialysis technique) were evaluated. Plasma volume decreased by approximately 20% and intracranial pressure increased from 10 to approximately 20 mm Hg at 4 hrs after the lipopolysaccharide injection. Six hours later, plasma volume had returned to baseline in both fluid groups while there was a further reduction in the control group. Intracranial pressure was higher in the saline group than in the albumin and control groups and was 25.8 ± 2.8 mm Hg, 18.3 ± 0.6 mm Hg, and 20.4 ± 1.7 mm Hg, respectively. Plasma oncotic pressure was higher in the albumin group than in the saline and control groups. Mean arterial pressure and microdialysis data were within normal range and did not differ among the groups. CONCLUSIONS: The results showed that the choice of resuscitation fluid may influence intracranial pressure in meningitis. The lower intracranial pressure in the colloid group may be explained by a higher plasma oncotic pressure and less fluid distribution to the brain interstitium.

Effects on brain edema of crystalloid and albumin fluid resuscitation after brain trauma and hemorrhage in the rat.

BACKGROUND: It has been hypothesized that resuscitation with crystalloids after brain trauma increases brain edema compared with colloids, but previous studies on the subject have been inconclusive. To test this hypothesis, the authors compared groups resuscitated with either colloid or crystalloid. METHODS: After fluid percussion injury, rats were subjected to a controlled hemorrhage of 20 ml/kg and were randomized to 5% albumin at 20 ml/kg (A20), isotonic Ringer's acetate at 50 ml/kg (C50), or 90 ml/kg (C90). After 3 or 24 h, water content in the injured cortex was determined using a wet/dry weight method. Blood volume was calculated from plasma volume, measured by 125I-albumin dilution, and hematocrit. Oncotic pressure and osmolality were measured with osmometers. RESULTS: At 3 h, blood volume was equal in the A20 and C90 groups and lower in the C50 group. Oncotic pressure was reduced by 35-40% in the crystalloid groups and unchanged in the albumin group. Cortical water content in the A20 group was lower than in the C90 group (81.3 +/- 0.5% vs. 82.1 +/- 1.1%, P < 0.05), but it was not different from the C50 group (81.8 +/- 1.1%). At 24 h, oncotic pressure and blood volume were normalized in all groups, and cortical water content was significantly lower in the albumin group than in the crystalloid groups. Osmolality and arterial pressure were equal in all groups throughout the experiment. CONCLUSIONS: When given to the same intravascular volume expansion, isotonic crystalloids caused greater posttraumatic brain edema than 5% albumin at 3 and 24 h after trauma.

Prostacyclin reduces elevation of intracranial pressure and plasma volume loss in lipopolysaccharide-induced meningitis in the cat.

BACKGROUND: Severe meningitis may compromise cerebral perfusion through increases in intracranial pressure (ICP) and through hypovolemia caused by a general inflammation with systemic plasma leakage. From its antiaggregative/antiadhesive and permeability-reducing properties, prostacyclin (PGI2) is a potential adjuvant treatment in meningitis, but previously published data have been ambiguous. The objective of this study was to evaluate the effects of PGI2 on meningitis on ICP, plasma volume, blood pressure, and cerebral oxidative metabolism. METHODS: Meningitis was induced by intrathecal injection of lipopolysaccharide (LPS, 0.8 x 10 units/kg) in cats. Four hours after the injection, the animals were randomized to intravenous treatment with either low-dose PGI2 (1 ng/kg/min) or the vehicle for 6 hours (n = 7 in each group). No LPS and no PGI2 or vehicle was given to three cats (sham group). Effects of treatment on ICP, mean arterial pressure, plasma volume (I-albumin technique), and brain tissue lactate/pyruvate ratio (microdialysis technique) were evaluated. RESULTS: ICP increased from 10.0 mm Hg +/- 1.3 mm Hg and 10.8 mm Hg +/- 1.7 mm Hg to 19.9 mm Hg +/- 1.7 mm Hg and 19.6 mm Hg +/- 3.3 mm Hg in the PGI2 and the vehicle group, respectively, 4 hours after the LPS injection (not significant). ICP increased further to 21.8 mm Hg +/- 4.5 mm Hg and to 25.8 mm Hg +/- 6.0 mm Hg after treatment for 6 hours with PGI2 or vehicle, respectively (p < 0.05). There was no significant difference in arterial pressure between groups. Plasma volume loss was less in the PGI2 group than in the vehicle group at the end of the experiment and urine production and arterial oxygenation was higher in the PGI2 group. Lactate/pyruvate ratio was within the normal range in all groups. CONCLUSION: Low-dose PGI2 may be a beneficial adjuvant therapy for meningitis by reducing elevation of ICP and plasma volume loss.