Protocolized reduction of non-resuscitation fluids versus usual care in septic shock patients (REDUSE): a randomized multicentre feasibility trial.

BACKGROUND/PURPOSE: Non-resuscitation fluids constitute the majority of fluid administered for septic shock patients in the intensive care unit (ICU). This multicentre, randomized, feasibility trial was conducted to test the hypothesis that a restrictive protocol targeting non-resuscitation fluids reduces the overall volume administered compared with usual care. METHODS: Adults with septic shock in six Swedish ICUs were randomized within 12 h of ICU admission to receive either protocolized reduction of non-resuscitation fluids or usual care. The primary outcome was the total volume of fluid administered within three days of inclusion. RESULTS: Median (IQR) total volume of fluid in the first three days, was 6008 ml (interquartile range [IQR] 3960-8123) in the restrictive fluid group (n = 44), and 9765 ml (IQR 6804-12,401) in the control group (n = 48); corresponding to a Hodges-Lehmann median difference of 3560 ml [95% confidence interval 1614-5302]; p < 0.001). Outcome data on all-cause mortality, days alive and free of mechanical ventilation and acute kidney injury or ischemic events in the ICU within 90 days of inclusion were recorded in 98/98 (100%), 95/98 (98%) and 95/98 (98%) of participants respectively. Cognition and health-related quality of life at six months were recorded in 39/52 (75%) and 41/52 (79%) of surviving participants, respectively. Ninety out of 134 patients (67%) of eligible patients were randomized, and 15/98 (15%) of the participants experienced at least one protocol violation. CONCLUSION: Protocolized reduction of non-resuscitation fluids in patients with septic shock resulted in a large decrease in fluid administration compared with usual care. A trial using this design to test if reducing non-resuscitation fluids improves outcomes is feasible. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05249088, 18 February 2022. https://clinicaltrials.gov/ct2/show/NCT05249088.

Accuracy of the Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity score and the Nottingham risk score in hip fracture patients in Sweden - A prospective observational study.

BACKGROUND: Little is known about accuracy of common risk prediction scores in elderly patients suffering from hip fractures. The objective of this study was to investigate accuracy of the Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) score, Portsmouth-POSSUM (P-POSSUM) score and the Nottingham Hip Fracture Score (NHFS) for prediction of mortality and morbidity in this patient group. METHODS: This was a prospective single centre observational study on 997 patients suffering out-of-hospital cervical, trochanteric or subtrochanteric fracture of the neck of the femur. Calibration and discrimination was assessed by calculating the ratio of observed to expected events (O:E) and areas under receiver operating characteristics curves (ROC). RESULTS: The 30-day mortality was 6.2% and complications, as defined by POSSUM, occurred in 41% of the patients. Overall O:E ratios for POSSUM, P-POSSUM and NHFS scores for 30-day mortality were 0.90, 0.98, and 0.79 respectively. The models underestimated mortality in the lower risk bands and overestimated mortality in the higher risk bands. In contrast, POSSUM predicted morbidity well with O:E ratios close to unity in most risk bands. The areas under the ROC curves for the scoring systems was 0.60-0.67. CONCLUSION: The POSSUM score and NHFS show moderate calibration and poor discrimination in this cohort. The results suggest that mortality and morbidity in hip fracture patients are largely dependent on factors that are not included in these scores.

Changes in the sublingual microcirculation during major abdominal surgery and post-operative morbidity.

BACKGROUND: Little is known about perioperative microcirculatory changes during major abdominal surgery, and the main objectives of this study were to evaluate perioperative microcirculatory alterations in this setting, and if changes in microcirculatory parameters are associated with post-operative morbidity and/or with changes in parameters reflecting oxygen delivery. METHODS: Patients scheduled for major abdominal surgery with an estimated Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM) score of > 30 and operation time > 3 h were eligible for inclusion. Perioperative microcirculatory alterations were evaluated in the sublingual mucosa using Sidestream Dark Field (SDF) imaging. Perfused vessel density (PVD), vessel perfusion [microvascular flow index (MFI)], and flow heterogeneity [heterogeneity index (HI)] were analysed. Central venous oxygen saturation (ScvO2) and lactate were measured simultaneously. During a 30-day follow-up period, post-operative complications were registered according to predefined criteria. RESULTS: Forty-two patients with a median P-POSSUM of 33 were included in the study. MFI was higher during anaesthesia than pre- and post-anaesthesia. PVD and HI did not change during the observation period. Lactate and ScvO2 increased during surgery. Perioperative lactate and ScvO2 values were not correlated with microcirculatory parameters. Complications occurred in 16 patients. No differences in microcirculatory parameters were detected between patients with and without complications. CONCLUSIONS: Perioperative changes in the sublingual microcirculatory parameters measured with the SDF-imaging technique appear to be minor, and no association with outcome after major abdominal surgery could be demonstrated. Changes in ScvO2 and serum lactate do not reflect sublingual microcirculatory alterations in this setting.

Rosuvastatin in experimental brain trauma: improved capillary patency but no effect on edema or cerebral blood flow.

BACKGROUND: Microvascular dysfunction, characterized by edema formation secondary to increased blood-brain barrier (BBB) permeability and decreased blood flow, contributes to poor outcome following brain trauma. Recent studies have indicated that statins may counteract edema formation following brain trauma but little is known about other circulatory effects of statins in this setting. The objective of this study was to investigate whether statin treatment improves brain microcirculation early after traumatic brain injury, and whether microvascular effects are associated with altered production of nitric oxide and prostacyclin. METHODS: After fluid percussion injury, rats were randomized to intravenous treatment with 20mg/kg of rosuvastatin or vehicle. Brain edema (wet/dry weight), BBB integrity ((51)Cr-EDTA blood to brain transfer), cerebral blood flow ((14)C-iodoantipyrine autoradiography), and number of perfused cortical capillaries (FITC-albumin fluorescence microscopy), were measured at 4 and 24h. NO and prostacyclin production was estimated from plasma concentration of the degradation products NO2- and NO3- (NOx) and 6-keto-PGF1-alpha, respectively. Sham injured animals were treated with vehicle and analyzed at 4h. RESULTS: Trauma resulted in brain edema, BBB dysfunction, and reduced cortical blood flow, with no effect of statin treatment. Trauma also induced a reduction in the number of perfused capillaries, which was improved by statin treatment. Statin treatment led to increased NOx levels and reduced mean arterial blood pressure. 6-Keto-PGF1-alpha levels tended to increase after trauma, and were significantly reduced by rosuvastatin. CONCLUSIONS: Rosuvastatin treatment may improve microcirculation after traumatic brain injury by preserved patency of cerebral capillaries. This effect is associated with increased NO and reduced prostacyclin production. No effect on brain edema or BBB integrity was found.

Low central venous oxygen saturation in haemodynamically stabilized trauma patients is associated with poor outcome.

BACKGROUND: Central venous oxygen saturation (ScvO(2)) is suggested to reflect the adequacy of oxygen delivery, and the main objective of the present study was to determine whether ScvO(2) is associated with outcome in haemodynamically stabilized trauma patients. METHODS: Haemodynamically unstable trauma patients receiving a central venous line within 1 h of admission were eligible for inclusion in this prospective observational study. The mean arterial pressure (MAP), lactate and ScvO(2) were recorded at inclusion and every 6 h for 36 h or until lactate was <2.0 mmol/l and ScvO(2) was >75% in two consecutive measurements. Patients with a MAP of ≥70 mmHg were considered to be haemodynamically stabilized. The outcome measure was complications defined as infections, delta sequential organ failure assessment score of >0, and mortality. RESULTS: Fifty patients with a median new injury severity score of 27 (17-34) were analysed. Complications occurred in 33 patients. An association between ScvO(2) following resuscitation to MAP ≥70 mmHg and complications was detected with an odds ratio of 0.94 (95% confidence interval; 0.89-0.99). This association was also significant when adjusted for injury severity. The result implies that a low ScvO(2) value is associated with more complications. The optimal cut-off for ScvO(2) to discriminate between patients who did or did not develop complications was found to be 66.5% (56-86%). CONCLUSIONS: These data suggest that low ScvO(2) in haemodynamically stabilized patients is associated with a poor outcome and that ScvO(2) represents a potential endpoint of resuscitation in trauma patients.

Effects of L-arginine on cerebral blood flow, microvascular permeability, number of perfused capillaries, and brain water content in the traumatized mouse brain.

It is has been suggested that decreased production of the vasodilatory and anti-aggregative substance NO (nitric oxide) may result in lower cerebral blood flow (CBF) in injured areas of the traumatized brain. The NO-precursor L-arginine has been shown to counteract CBF decreases early after trauma, but microcirculatory and more long-term effects on CBF of L-arginine have not been investigated. In an attempt to analyze effects of L-arginine on the microcirculation in the traumatized brain, the present study was designed to evaluate the effects of L-arginine compared to vehicle (0.9% saline) following a standardized controlled cortical-impact brain trauma in mice. Cerebral blood flow (autoradiography [(14)C]-iodoantipyrine), number of perfused capillaries (FITC-dextran fluorescence technique), brain water content (wet vs. dry weight) and the blood to brain transfer constant K(i) for [(51)Cr]-EDTA were analyzed in the injured and the contralateral cortex. Cortical blood flow in the injured cortex was 0.43+/-0.3 mL/g/min and 0.81+/-0.3 mL/g/min 3 h after trauma in the vehicle and L-arginine groups, respectively (p<0.05), and no treatment effect was seen 24 h after trauma. The number of perfused capillaries decreased following trauma and was unaffected by L-arginine. K(i) increased following trauma and was unaffected by L-arginine. Brain water content was lower in the L-arginine group than in the vehicle group 3 h after trauma and there was no difference between the groups 24 h after trauma. We conclude that L-arginine reduces brain edema formation and improves cortical blood flow in the early phase after a brain trauma, whereas no circulatory effects can be seen after prolonged treatment.

A mouse model for evaluation of capillary perfusion, microvascular permeability, cortical blood flow, and cortical edema in the traumatized brain.

Genetically engineered mice have successfully been used to investigate molecular and cellular mechanisms associated with cell dysfunction following brain trauma. Such animals may also offer a possibility to investigate mechanisms involved in posttraumatic hemodynamic alterations. The objective of the study was to establish a mouse model in which important hemodynamic alterations following trauma could be analyzed. C57/BL6 male mice were subjected to controlled cortical impact injury (CCI) or sham-injury. Distribution of blood flow was estimated by determining number of perfused capillaries using FITC-dextran as an intravascular marker. Cortical blood flow was measured using [(14)C]-iodoantipyrine, brain water content (BWC) was measured using a wet vs. dry weight method, and permeability surface area product (PS) was estimated by the transfer constant for [(51)Cr]-EDTA. Number of perfused capillaries in the contusion area was progressively reduced during the first 24 h following trauma by at most 60% relative to a value of 329 +/- 61/mm(2) in sham-injured animals. Blood flow in the contusion area decreased simultaneously by at most 50% relative to a control value of 1.8 +/- 0.4 mL.min(-1).g(-1), and was reduced further in subregions within the contusion area. BWC in the injured hemisphere increased from 79.3 +/- 0.5% at control to at most 79.9 +/- 0.6% at 24 h post trauma. PS in the injured hemisphere increased by 71% at 3 h post trauma relative to a control value of 0.45 +/- 0.1 microL.min(-1).g(-1), and was close to control at 24 h. The present study demonstrates that brain trauma in addition to a reduction in cortical blood flow, reduces number of perfused capillaries, which most likely affects exchange of nutrients and fluid. The CCI in mouse is likely to be a useful tool to elucidate mechanisms involved in hemodynamic alterations following brain trauma.

Inhibition of Rho kinase decreases hydraulic and protein microvascular permeability in cat skeletal muscle.

Rho-associated kinases are involved in regulation of actin-myosin contractility and the organization of the actin cytoskeleton in both endothelial and smooth muscle cells. By influencing the contraction of the intraendothelial filaments, Rho kinases may affect the size of the interendothelial gaps and thereby influence microvascular permeability. The aim of the study was therefore to investigate whether Rho kinases influence hydraulic and protein microvascular permeability. The study was performed on the autoperfused cat skeletal muscle. A capillary filtration coefficient (CFC) technique was used to evaluate changes in hydraulic permeability, and protein permeability was evaluated by estimation of the change in the reflection coefficient for albumin. In the first part of each experiment, the effects on CFC of three doses of the Rho kinase inhibitor Y-27632 of about 0.35, 0.70, and 1.05 microg/h per ml plasma flow were determined. There was a reduction in CFC at the lowest dose, and a tendency to further reduction at the higher doses used, reaching a decrease in CFC of 20%. The effects on CFC of the high and the middle dose did not differ. The reflection coefficient for albumin was increased by 31% following infusion of the highest dose of Y-27632. We conclude that hydraulic and protein microvascular permeability increase by Rho kinase activation, and that Rho kinase is involved in regulation of microvascular permeability.

Capillary filtration coefficient is independent of number of perfused capillaries in cat skeletal muscle.

The capillary filtration coefficient (CFC) is assumed to reflect both microvascular hydraulic conductivity and the number of perfused capillaries at a given moment (precapillary sphincter activity). Estimation of hydraulic conductivity in vivo with the CFC method has therefore been performed under conditions of unchanged vascular tone and metabolic influence. There are studies, however, that did not show any change in CFC after changes in vascular tone and metabolic influence, and these studies indicate that CFC may not be influenced by alteration in the number of perfused capillaries. The present study reexamined to what extent CFC in a pressure-controlled preparation depends on the vascular tone and number of perfused capillaries by analyzing how CFC is influenced by 1) vasoconstriction, 2) increase in metabolic influence by decrease in arterial blood pressure, and 3) occlusion of precapillary microvessels by arterial infusion of microspheres. CFC was calculated from the filtration rate induced by a fixed decrease in tissue pressure. Vascular tone was increased in two steps by norepinephrine (n = 7) or angiotensin II (n = 6), causing a blood flow reduction from 7.2 +/- 0.8 to at most 2.7 +/- 0.2 ml x min(-1) x 100 g(-1) (P < 0.05). The decrease in arterial pressure reduced blood flow from 4.8 +/- 0.4 to 1.40 +/- 0.1 ml x min(-1) x 100 g(-1) (n = 6). Vascular resistance increased to 990 +/- 260% of control after the infusion of microspheres (n = 6). CFC was not significantly altered from control after any of the experimental interventions. We conclude that CFC under these conditions is independent of the vascular tone and number of perfused capillaries and that variation in CFC reflects variation in microvascular hydraulic conductivity.

Infusion of prostacyclin following experimental brain injury in the rat reduces cortical lesion volume.

Endothelial-derived prostacyclin is an important regulator of microvascular function, and its main actions are inhibition of platelet/leukocyte aggregation and adhesion, and vasodilation. Disturbances in endothelial integrity following traumatic brain injury (TBI) may result in insufficient prostacyclin production and participate in the pathophysiological sequelae of brain injury. The objective of this study was to evaluate the potential therapeutic effects of a low-dose prostacyclin infusion on cortical lesion volume, CA3 neuron survival and functional outcome following TBI in the rat. Anesthetized animals (sodium pentobarbital, 60 mg/kg, i.p.) were subjected to a lateral fluid percussion brain injury (2.5 atm) or sham injury. Following TBI, animals were randomized to receive a constant infusion of either prostacyclin (1 ng/kg x min(-1) i.v.) or vehicle over 48 h. All sham animals received vehicle (n = 6). Evaluation of neuromotor function, lesion volume, and CA3 neuronal loss was performed blindly. By 7 days postinjury, cortical lesion volume was significantly reduced by 43% in the prostacyclin-treated group as compared to the vehicle treated group (p < 0.01; n = 12 prostacyclin, n = 12 vehicle). No differences were observed in neuromotor function (48 h and 7 days following TBI), or in hippocampal cell loss (7 days following TBI) between the prostacyclin- and vehicle-treated groups. We conclude that prostacyclin in a low dose reduces loss of neocortical neurons following TBI and may be a potential clinical therapeutic agent to reduce neuronal cell death associated with brain trauma.

Dextran, gelatin, and hydroxyethyl starch do not affect permeability for albumin in cat skeletal muscle.

OBJECTIVE: To evaluate the effects of the three commercially available colloid solutions, 6% dextran 70, 6% hydroxyethyl starch (HES) 200/0.5, and 3.5% urea-linked gelatin on permeability for human albumin in a skeletal muscle in vivo model by evaluating their effects on the reflection coefficient for albumin. DESIGN: Controlled laboratory study. SETTING: University research laboratory. SUBJECTS: Eighteen adult cats. INTERVENTIONS: The autoperfused and denervated calf muscles of the cat hindlimb were placed in a plethysmograph. The transvascular fluid absorption induced by an increase in the colloid osmotic pressure following a fixed intravenous bolus of human albumin was analyzed, first before start of, and then during an intra-arterial infusion to, the muscle preparation of the synthetic colloid to be analyzed. Capillary filtration coefficient as a measure of microvascular fluid permeability (conductance) was analyzed before and after start of the synthetic colloid. MEASUREMENTS AND MAIN RESULTS: Arterial blood flow, arterial and venous blood pressures, total vascular resistance, tissue volume changes, capillary filtration coefficient, and plasma volume were measured before and during the colloid infusion. According to the Starling fluid equilibrium, the ratio between the reflection coefficients for albumin on two occasions (before and after infusion of the synthetic colloid) can be calculated from the maximum osmotic absorption rates induced by a fixed intravenous bolus infusion of albumin and from the capillary filtration coefficients. Obtained data were adjusted for different plasma volume at the two occasions. We found that none of the three synthetic colloids analyzed had any significant effect on the reflection coefficient for albumin. CONCLUSION: An effect on albumin microvascular permeability of the synthetic colloids dextran 70, HES 200/0.5, and urea-linked gelatin could not be shown by a method analyzing their effect on the reflection coefficient for albumin.

Microdialysis-based long-term measurements of energy-related metabolites in the rat brain following a fluid percussion trauma.

The aim of the study was to evaluate an experimental approach based on a fluid percussion rat trauma model in combination with the microdialysis technique for the analysis of cerebral interstitial biochemical alterations following head trauma, and to test the hypothesis that the previously observed acute accumulation of lactate and increase in the lactate pyruvate ratio may persist for several days following trauma. We analyzed how lactate, pyruvate, and glucose were altered in the cortex adjacent to the contusion and in the contralateral side of the brain following a traumatic brain injury. The results were compared with those from sham-operated animals. The lactate concentration in the cortex adjacent to the contusion was 0.73 +/- 0.13 mmol/L and 0.71 +/- 0.08 mmol/L 24 and 48 h posttrauma, respectively, and 0.42 +/- 0.07 mmol/L in the sham group (p < 0.05). The lactate/pyruvate ratio of 18.3 +/- 2.3 in the cortex adjacent to the contusion 24 h posttrauma was higher than corresponding value of 10.3 +/- 1.5 in the sham group (p < 0.05). The lactate/pyruvate ratio 48 h posttrauma did not differ from that in the sham group. Interstitial glucose in the cortex adjacent to the contusion and the sham group were similar. Microdialysis measurements from the contralateral side did not differ from those in the sham group. We conclude that the previously observed acute alterations in brain metabolism persist for at least 48 h posttrauma. Further, the measured parameters from the contralateral side can be used as controls since they did not differ from the sham group. Combining microdialysis with a fluid percussion trauma model may be a tool to explore secondary brain injury mechanisms and evaluate new therapies for the treatment of traumatic brain injury.

Prostacyclin reduces microvascular fluid conductivity in cat skeletal muscle through opening of ATP-dependent potassium channels.

Prostacyclin is suggested to reduce microvascular permeability, but the cellular mechanisms mediating this response in the microvascular endothelial cells are still unknown. Considering that prostacyclin relaxes vascular smooth muscle cells via opening of ATP-dependent potassium channels, and opening of ATP-dependent potassium channels in the endothelial cells is suggested to influence microvascular permeability, this study was designed to test (1) if ATP-dependent potassium channels are involved in the regulation of microvascular hydraulic permeability, (2) if the permeability-reducing effect of prostacyclin is mediated through opening of ATP-dependent potassium channels, and (3) if cAMP is involved in this process. An autoperfused cat calf hindlimb was used as experimental model, and microvascular hydraulic permeability (conductivity) was estimated by a capillary filtration coefficient (CFC) technique. The potassium channel opener PCO-400 (0.5 microg x min(-1) per 100 g muscle, intra-arterially), prostacyclin (1 ng x min(-1) per kg body weight, intravenously) and the cAMP analogue dibutyryl-cAMP (24 microg x min(-1) per 100 g muscle, intra-arterially), decreased CFC to 77, 72 and 69% compared to control, respectively (p < 0.01). The decrease in CFC obtained by these substances was completely restituted after the start of a simultaneous infusion of the ATP-dependent potassium channel blocker glibenclamide (6 microg x min(-1) per 100 g muscle, intra-arterially; p < 0.01). Infusion of glibenclamide alone increased CFC to 107% of control (p < 0.05). In conclusion, the ATP-dependent potassium channels contribute to the regulation of microvascular hydraulic conductivity, and the prostacyclin permeability-reducing effect may act through this mechanism via increase in intracellular cAMP.

Supersensitivity in rat micro-arteries after short-term denervation.

Contractile responses to phenylephrine and high-K+ were investigated in vitro in microvascular preparations from the rat medial plantar artery, a branch from the saphenous artery, obtained after short-term denervation in vivo. Two groups of animals were studied: (1) animals undergoing surgical resection of the saphenous nerve, and (2) animals undergoing surgical resection of both the sciatic and saphenous nerves. The animals were operated on one side only. Microvascular preparations (diameter about 325 microns) were obtained 10 days after surgery. Vessels from the non-operated side served as controls. Immunocytochemistry showed a decreased number of both neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) immunoreactive nerve fibres in vessels after resection of the saphenous nerve only. Resection of both the saphenous and the sciatic nerve caused a complete loss of immunoreactive nerve fibres. Mechanical measurements were performed using a wire myograph. In vessels subjected to resection of the saphenous nerve the sensitivity to phenylephrine was similar to controls. Vessels denervated by resection of both the saphenous and sciatic nerves showed significant increases in phenylephrine and potassium sensitivity. When depolarized in high-K+ solution the denervated vessels showed an increased sensitivity to extracellular Ca2+. The results show that complete short-term denervation of the rat medial plantar artery in vivo causes a pronounced supersensitivity in the vascular smooth muscle. The supersensitivity appears not to be restricted to the sympathetic alpha-receptors but also associated with changes in the cellular excitation-contraction coupling. Such altered reactivity of the vascular smooth muscle may contribute to vascular disturbances observed in vivo after nerve damage or surgical denervation.