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.

Lower vs. higher fluid volumes in sepsis-protocol for a systematic review with meta-analysis.

BACKGROUND: Intravenous fluid administration with crystalloids is recommended in the initial management of sepsis. However, the quality of evidence supporting the recommendation on fluid volumes is low, and clinical equipoise exists. Potential benefits of restricting fluid volumes has been suggested, but the overall benefit or harm in patients with sepsis is unknown. Accordingly, we aim to assess patient-important benefits and harms of lower vs. higher fluid volumes in resuscitation of adult patients with sepsis. METHODS/DESIGN: We will conduct a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials comparing different strategies to obtain separation in fluid volumes or balances during resuscitation of adult patients with sepsis. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS and Epistemonikos for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: The outlined systematic review will provide important data on how patient-important outcomes are affected by higher vs. lower resuscitation fluid volumes in adults with sepsis. Using trial sequential analysis to assess the risk of random errors will increase the validity of the summary estimates calculated and help estimate the required information size for future trials.

Association between fluid balance and mortality in patients with septic shock: a post hoc analysis of the TRISS trial.

BACKGROUND: Several studies have shown an association between a positive fluid balance and increased mortality in patients with septic shock. This may have led to a more restrictive use of intravenous fluids. The association between fluid accumulation and mortality in the setting of a more restrictive use of intravenous fluids, however, is uncertain. We therefore aimed to investigate the association between a cumulative fluid balance 3 days after randomization and 90-day mortality in a recent Nordic multicentre cohort of patients with septic shock. METHODS: A post hoc analysis of patients from the Transfusion Requirements in Septic Shock (TRISS) trial treated for 3 days or more in the ICU after randomization. The patients were categorized into four groups depending on their weight-adjusted cumulative fluid balance after 3 days. We performed multivariable Cox regression analysis, adjusting for important prognostics (study site, age, chronic cardiovascular and chronic lung disease, haematologic malignancy, chronic dialysis, source of infection, baseline SOFA score and plasma lactate). RESULTS: The median cumulative fluid balance of the 841 included patients was 2480 ml (IQR 47-5045). The median time from ICU admission to inclusion in the trial was 22 h. The overall 90-day mortality was 52%. There was no statistically significant association between fluid balance 3 days from inclusion and 90-day mortality after the adjustment for the prognostics (P = 0.37). CONCLUSION: In our cohort of patients with septic shock and a comparably low cumulative fluid balance, there was no association between fluid balance and mortality. However, the study design and the limited power preclude strong conclusions. There is an urgent need for high-quality trials assessing the benefit and harm of different fluid volume strategies in patients with septic shock.

Sympathotropic drugs and the distribution of 99mTc-hydroxymethylene diphosphonate. Experimental studies in the mouse.

OBJECTIVE: The uptake of bone-seeking radiopharmaceuticals depends on the blood flow, which is influenced by the sympathetic nervous system. Our aim was to study the effect of sympathomimetic drugs on the distribution of bone-seeking agents. MATERIAL AND METHODS: Various sympathomimetic and beta-blocking drugs were injected in mice at different times in relation to the administration of 99mTc-HDP. Three hours after this, venous blood and various organs were removed and their activities were related to the administered activity. A kinetic study of the whole-body activity retention after administration of terbutaline was also made. RESULTS: The biodistribution of 99mTc-HDP was similar after the administration of sympathomimetics and of beta-antagonists. All drugs gave rise to an increased soft tissue activity and a decreased bone activity, corresponding to a lowered quality of the potential bone scan. Terbutaline gave rise to an increased excretion of 99mTc-HDP. The mechanisms behind the findings cannot be entirely explained. CONCLUSION: Drug interference with the sympathetic nervous system causes undesirable effects on the biodistribution of 99mTc-HDP in the mouse. Studies in humans are necessary to evaluate whether clinical treatment with sympathotropic drugs affects the bone scintigram.

Influence of the phosphate balance on the activity distribution of 99mTc-hydroxy-methylene diphosphonate. Experimental studies in the mouse.

OBJECTIVE: The purpose was to determine whether changes in the phosphate balance have an influence on the distribution of bone-seeking radiopharmaceuticals. MATERIAL AND METHODS: The biodistribution of 99mTc-HDP in mice, intravenously administered under varying conditions, was assessed by removing different organs and estimating their activity in a scintillation counter. Some experiments were also performed with 99mTc-MDP and 99mTc-DPD. RESULTS: After 1 h and 18 h on phosphate-enriched drinking water, the mice showed a strongly increased uptake in all organs/tissues representing background activity and a decrease in the bone uptake. This pattern changed with time. After 6-8 days of phosphate load, we saw a more favourable distribution with a reduction of the background and whole-body activity. Administration of hPTH 1-34 gave rise to an activity distribution similar to that after 6-8 days on phosphate-enriched water. Changing the phosphate balance had less obvious effects on the distribution of 99mTc-MDP and 99mTc-DPD. CONCLUSION: The activity distribution of bone-seeking radiopharmaceuticals in the mouse is affected by the phosphate balance. The mechanism behind this finding is unknown but it may be partially mediated by PTH. It is possible that changes in the phosphate balance, induced by pharmaceuticals or by dietary changes, may affect the image quality at bone scintigraphy.

Hydration does not influence the image quality in bone scintigraphy: an investigation using 99Tcm-HDP.

We investigated the possibility that the increased diuresis caused by hydration leads to enhanced renal excretion of radiotracer and thereby increases the target-to-background activity ratio and improves the image quality in bone scintigraphy. The study was carried out using paired comparisons in 10 healthy volunteers. Whole-body antero-posterior and postero-anterior acquisitions were obtained for 4 h after the administration of 99Tcm-hydroxymethylene diphosphonate with and without hydration. The bone-to-soft tissue activity ratio was semi-quantified by comparing regions of interest acquired from geometrical means of the acquisitions. Hydration was performed by slowly drinking 1.5 litres of water after administration of the tracer. Hydration induced a slight enhancement of excretion of the activity, but it had no effect on the bone-to-soft tissue activity ratio, nor did it influence image quality. We conclude that hydration could be avoided when it is cumbersome for the patient. However, as hydration reduces the radiation dose to the urinary bladder wall, which is the critical organ, hydration should be maintained in younger patients.

Activity in the gastrointestinal tract after administration of bone-seeking radiopharmaceuticals. Experimental studies in mice.

PURPOSE: To test the possibility that (radio)activity of non-pertechnetate nature is excreted into the gastrointestinal tract at bone scintigraphy. MATERIAL AND METHODS: The distribution of a bone-seeking radiopharmaceutical (99mTc-HDP) was studied in an experimental mouse system by dissecting different organs and assessing their activity with a gamma-counter. RESULTS: A comparison of the activity of the submandibular glands, which are assumed to accumulate only pertechnetate, and the gastrointestinal tract showed that a significant fraction of the activity excreted into the gastrointestinal tract did not consist of pertechnetate. Part of the excretion took place in the stomach. It was not connected to a specific bone-seeking agent or 99Mo/99mTc generator. Nor did it increase with time between make-up and injection. The excretion of the non-pertechnetate activity was reduced by cimetidine and omeprazole. These gastric-secretion blocking drugs did not reduce excretion of pertechnetate or significantly affect the general distribution of the radiopharmaceutical. CONCLUSION: There is a significant excretion of non-pertechnetate activity in the gastrointestinal tract. Part of this may be caused by excretion of the undegraded radiopharmaceutical by the stomach mucosa.

Hypercycles versus parasites in the origin of life: model dependence in spatial hypercycle systems.

Spatial hypercycle systems can be modelled by means of cellular automata or partial differential equations. In either model, two dimensional spirals or clusters can be formed. Different models give rise to slightly different spatial structures, but the response to parasites is fundamentally different: In cellular automata the hypercycle is resistant to parasites that are fatal in a partial differential equations model. In three dimensions scroll rings correspond to the two dimensional spirals. Numerical simulations on a partial differential equations model indicate that the scroll rings are unstable: The contract by a power law and disappear. Therefore, in three dimensions clusters seem to be the best candidate for the hypercycle resistant to parasites.

Disturbances of fluid balance reduce the image quality of bone scintigraphy. Experimental studies in mice.

The effects of hydration, dehydration and osmotic diuresis on the activity distribution of bone-seeking radiopharmaceuticals have been studied in an experimental mouse system. It was found that any change of the water balance impairs the activity distribution of the radiolabelled phosphonate in the potential bone scintigraphic image. The findings suggest that in order to maintain image quality, elderly patients should not be instructed to drink a large volume of fluid after the administration of a bone-seeking radiopharmaceutical. Further investigations, though, have to be performed in humans.

Intron evolution: a statistical comparison of two models.

The two most frequently occurring explanations for the existence and distribution of introns in the genes of different species are: (1) introns are remnants of the original genetic material. (2) Introns were introduced during evolution. We construct mathematical models corresponding to these two explanations, and calculate the probabilities that the intron distribution in genes from different species coding for actin, alpha-tubulin, triosephosphate isomerase and superoxide dismutase are described by these models. In both models, the branch lengths as well as the structure of the corresponding evolutionary tree is taken into account. Every branch in the evolutionary tree is assumed to have its own individual rate of loss of introns for the first model and rate of gain of introns for the second model. These rate constants are estimated from the actual number of introns. Using the rate constants we stimulate the intron evolution and calculate the probabilities that the actual intron arrangements are produced. The results for actin and alpha-tubulin, which are the two genes we have the most data for, favor the model corresponding conjecture (1), i.e. the idea that introns are old. This contradicts the results from an earlier attempt to model intron evolution where almost the same data was used (Dibb & Newman, 1989, EMBO J. 8, 2015-2021).