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.

Intravenous anti-P. aeruginosa IgY-antibodies do not decrease pulmonary bacterial concentrations in a porcine model of ventilator-associated pneumonia.

Ventilator associated pneumonia (VAP) caused by P. aeruginosa is a cause of morbidity and mortality in critically ill patients. The spread of pathogens with anti-microbial resistance mandates the investigation of novel therapies. Specific polyclonal anti-P. aeruginosa IgY-antibodies (Pa-IgY) might be effective for VAP caused by P. aeruginosa. The objective of this study was to investigate if intravenous Pa-IgY decreases the lower airway concentration of P. aeruginosa in VAP. We used a double blind randomized placebo controlled porcine model of VAP caused by P. aeruginosa. Eighteen pigs were randomized to either receive intravenous Pa-IgY or placebo. Repeated registration of physiological parameters and sampling was performed for 27 h. Concentration of P. aeruginosa in BAL-cultures was similar in both groups with 104.97 ± 102.09 CFU/mL in the intervention group vs 104.37 ± 102.62 CFU/mL in the control group at the end of the experiment. The intervention group had higher heart rate, cardiac index, oxygen delivery and arterial oxygen tension/fraction of inspired oxygen-ratio, but lower plasma lactate and blood hemoglobin levels than the control group. In summary, in an anesthetized and mechanically ventilated porcine model of VAP, Pa-IgY at the dose used did not decrease concentrations of P. aeruginosa in the lower airways.

Urinary cytokines correlate with acute kidney injury in critically ill COVID-19 patients.

BACKGROUND: Acute kidney injury is common in COVID-19 patients admitted to the ICU. Urinary biomarkers are a non-invasive way of assaying renal damage, and so far, urinary cytokines are not fully investigated. The current study aimed to assess urinary cytokine levels in COVID-19 patients. METHODS: Urine was collected from COVID-19 patients (n = 29) in intensive care and compared to a preoperative group of patients (n = 9) with no critical illness. 92 urinary cytokines were analyzed in multiplex using the Olink Target 96 inflammation panel and compared to clinical characteristics, and urinary markers of kidney injury. RESULTS: There were strong correlations between proinflammatory cytokines and between urinary cytokines and urinary kidney injury markers in 29 COVID-19 patients. Several cytokines were correlated to kidney injury, 31 cytokines to AKI stage and 19 cytokines correlated to maximal creatinine. CONCLUSIONS: Urinary inflammatory cytokines from a wide range of immune cell lineages were significantly upregulated during COVID-19 and the upregulation correlated with acute kidney injury as well as urinary markers of kidney tissue damage.

Inadequate prophylactic effect of low-molecular weight heparin in critically ill COVID-19 patients.

PURPOSE: The aim of this study was to investigate potential markers of coagulopathy and the effects of thromboprophylaxis with low-molecular-weight heparin (LMWH) on thromboelastography (TEG) and anti-factor Xa in critically ill COVID-19 patients. MATERIAL AND METHODS: We conducted a prospective study in 31 consecutive adult intensive care unit (ICU) patients. TEG with and without heparinase and anti-factor Xa analysis were performed. Standard thromboprophylaxis was given with dalteparin (75-100 IU/kg subcutaneously). RESULTS: Five patients (16%) had symptomatic thromboembolic events. All patients had a maximum amplitude (MA) > 65 mm and 13 (42%) had MA > 72 mm at some point during ICU stay. Anti-factor Xa activity were below the target range in 23% of the patients and above target range in 46% of patients. There was no significant correlation between dalteparin dose and anti-factor Xa activity. CONCLUSIONS: Patients with COVID-19 have hypercoagulability with high MA on TEG. The effect of LMWH on thromboembolic disease, anti-factor Xa activity and TEG was variable and could not be reliably predicted. This indicates that standard prophylactic doses of LMWH may be insufficient. Monitoring coagulation and the LMWH effect is important in patients with COVID-19 but interpreting the results in relation to risk of thromboembolic disease poses difficulties.

Correction to: Inhalation of specific anti-Pseudomonas aeruginosa IgY antibodies transiently decreases P. aeruginosa colonization of the airway in mechanically ventilated piglets.

Following publication of the original article [1], the authors flagged that an incorrect piece of data is given in the Materials and Methods section of the article.

Inhalation of specific anti-Pseudomonas aeruginosa IgY antibodies transiently decreases P. aeruginosa colonization of the airway in mechanically ventilated piglets.

BACKGROUND: P. aeruginosa is a pathogen frequently resistant to antibiotics and a common cause of ventilator-associated pneumonia (VAP). Non-antibiotic strategies to prevent or treat VAP are therefore of major interest. Specific polyclonal avian IgY antibodies have previously been shown to be effective against pneumonia caused by P. aeruginosa in rodents and against P. aeruginosa airway colonization in patients. OBJECTIVES: To study the effect of specific polyclonal anti-P. aeruginosa IgY antibodies (Pa-IgY) on colonization of the airways in a porcine model. METHOD: The pigs were anesthetized, mechanically ventilated, and subject to invasive hemodynamic monitoring and allocated to either receive 109 CFU nebulized P. aeruginosa (control, n = 6) or 109 CFU nebulized P. aeruginosa + 200 mg Pa-IgY antibodies (intervention, n = 6). Physiological measurement, blood samples, and tracheal cultures were then secured regularly for 27 h, after which the pigs were sacrificed and lung biopsies were cultured. RESULTS: After nebulization, tracheal growth of P. aeruginosa increased in both groups during the experiment, but with lower growth in the Pa-IgY-treated group during the experiment (p = 0.02). Tracheal growth was 4.6 × 103 (9.1 × 102-3.1 × 104) vs. 4.8 × 104 (7.5 × 103-1.4 × 105) CFU/mL in the intervention group vs. the control group at 1 h and 5.0 × 100 (0.0 × 100-3.8 × 102) vs. 3.3 × 104 (8.0 × 103-1.4 × 105) CFU/mL at 12 h in the same groups. During this time, growth in the intervention vs. control group was one to two orders of ten lower. After 12 h, the treatment effect disappeared and bacterial growth increased in both groups. The intervention group had lower body temperature and cardiac index and higher static compliance compared to the control group. CONCLUSION: In this porcine model, Pa-IgY antibodies lessen bacterial colonization of the airways.

Impact of resuscitation fluid bag size availability on volume of fluid administration in the intensive care unit.

BACKGROUND: Iatrogenic fluid overload is associated with increased mortality in the intensive care unit (ICU). Decisions on fluid therapy may, at times, be based on other factors than physiological endpoints. We hypothesized that because of psychological factors volume of available fluid bags would affect the amount of resuscitation fluid administered to ICU patients. METHODS: We performed a prospective intervention cross-over study at 3 Swedish ICUs by replacing the standard resuscitation fluid bag of Ringer's Acetate 1000 mL with 500 mL bags (intervention group) for 5 separate months and then compared it with the standard bag size for 5 months (control group). Primary endpoint was the amount of Ringer's Acetate per patient during ICU stay. Secondary endpoints were differences between the groups in cumulative fluid balance and change in body weight, hemoglobin and creatinine levels, urine output, acute kidney failure (measured as the need for renal replacement therapy, RRT) and 90-day mortality. RESULTS: Six hundred and thirty-five ICU patients were included (291 in the intervention group, 344 in the control group). There was no difference in the amount of resuscitation fluid per patient during the ICU stay (2200 mL [1000-4500 median IQR] vs 2245 mL [1000-5630 median IQR]), RRT rate (11 vs 9%), 90-day mortality (11 vs 10%) or total fluid balance between the groups. The daily amount of Ringer's acetate administered per day was lower in the intervention group (1040 (280-2000) vs 1520 (460-3000) mL; P = .03). CONCLUSIONS: The amount of resuscitation fluid administered to ICU patients was not affected by the size of the available fluid bags. However, altering fluid bag size could have influenced fluid prescription behavior.

The impact of hydrocortisone treatment on neutrophil gelatinase-associated lipocalin release in porcine endotoxemic shock.

BACKGROUND: A key feature of sepsis is systemic inflammatory activation that could be counteracted by steroids. In this experimental model of systemic inflammation, we sought to investigate whether septic neutrophil activation, evaluated by the plasma levels of neutrophil gelatinase-associated protein (NGAL), is modulated by the timing of hydrocortisone treatment. METHODS: Sixteen anesthetized pigs were allocated to one of four equally sized groups. Three of these groups received endotoxin at 2 µg × kg-1 × h-1 for 6 h so as to induce endotoxemic shock. Hydrocortisone (5 mg × kg-1) was administered intravenously before endotoxemic challenge, or at the onset of endotoxemic shock. Endotoxemic pigs not receiving hydrocortisone and non-endotoxemic pigs served as control groups. Physiologic variables, hematology, and biochemistry, including plasma NGAL, were measured repeatedly. RESULTS: Hydrocortisone treatment prior to endotoxemia attenuated some inflammatory, hematological, circulatory, and metabolic manifestations of shock (i.e., higher white blood cell count, higher mean arterial pressure, lower heart rate and mean pulmonary arterial pressure, higher left ventricular stroke work index, higher base excess). Endotoxemic shock increased plasma NGAL (p < 0.001). In pigs given hydrocortisone before the endotoxin infusion, plasma NGAL was lower as compared to those given hydrocortisone at endotoxemic shock (p < 0.05). Plasma NGAL levels correlated inversely to neutrophil granulocyte counts (rho = -0.65) but not to urine output (rho = -0.10) at the end of the experiment. CONCLUSIONS: The increase in plasma NGAL is counteracted by hydrocortisone administration prior to endotoxemia; concomitantly, this treatment was associated with less expressed circulatory derangement. Urine NGAL did not differ between the groups, suggesting that the NGAL response was not primarily related to kidney injury.

Intraosseous and intravenous administration of antibiotics yields comparable plasma concentrations during experimental septic shock.

BACKGROUND: We aimed to investigate whether comparable antibiotic concentrations could be reached with intraosseous and intravenous administration during septic shock. METHODS: In this randomized, prospective experimental study conducted at an animal research laboratory at the University Hospital of Uppsala, eight anesthetized pigs, weighing 21.2 to 29.1 kg (mean: 25.2 ± 2.3 kg), received endotoxin infusion at 4 µg/kg/h for 6 h. At the onset of clinical shock, alternatively after 3 h of endotoxemia, they received 75 mg/kg of cefotaxime and 7 mg/kg of gentamicin either in a proximal tibial intraosseous catheter or in a peripheral intravenous catheter. Mixed venous samples were taken after 5, 15, 30, 60, 120 and 180 min and analyzed for antibiotic concentrations. RESULTS: For both antibiotics, plasma concentrations after intraosseous and intravenous administration followed similar curves throughout the observation period, and peak concentrations were comparable. Mean concentration area under the curve (AUC mg × h/l) for cefotaxime was 108.1 ± 19.5 after intraosseous and 116.5 ± 11.1 after intravenous administration; ratio 0.93, (95% CI 0.71-1.19). Mean AUC for gentamicin was 28.1 ± 6.8 for intraosseous and 32.2 ± 3.5 for intravenous administration; ratio 0.87 (95% CI 0.62-1.19). CONCLUSIONS: In this porcine septic shock model, intraosseous and intravenous administration of gentamicin and cefotaxime yielded comparable concentrations. In an emergency, intraosseous administration of these antibiotics may be considered in severe infections when venous access is difficult.

Hemodynamic management of septic shock.

We present a review of the hemodynamic management of septic shock. Although substantial amount of evidence is present in this area, most key decisions on the management of these patients remain dependent on physiological reasoning and on pathophysiological principles rather than randomized controlled trials. During primary (early) resuscitation, restoration of adequate arterial pressure and cardiac output using fluids and vasopressor and/or inotropic drugs is guided by basic hemodynamic monitoring and physical examination in the emergency department. When more advanced level of monitoring is present in these patients, i.e. during secondary resuscitation (later phase in the emergency department and in the ICU), hemodynamic management can be guided by more advanced measurements of the macrocirculation. Our understanding of the microcirculation in septic shock is limited and reliable therapeutic modalities to optimize it do not yet exist. No specific hemodynamic treatment strategy, be it medications including fluids, monitoring devices or treatment algorithms has yet been proved to improve outcome. Moreover, there is virtually no data on the optimal management of the resolution phase of septic shock. Despite these gaps in knowledge, the data from observational studies and trials suggests that mortality in septic shock has been generally decreasing during the last decade.

Effect of perfusion pressure on the splanchnic circulation after CPB: a pilot study.

BACKGROUND: The impact of different blood pressure targets is unknown for post cardiac surgery patient in the intensive care unit. We, therefore, investigated the effects of a mean arterial pressure (MAP) target of 65 or 85 mmHg on splanchnic oxygenation, metabolic function, cytokine regulation and gastric tonometry after cardiopulmonary bypass. METHODS: Sixteen patients were randomized to the HLH group (high-low-high) where MAP of 85-65-85 mmHg was targeted or the LHL group where MAP 65-85-65 mmHg was targeted with norepinephrine infusion. RESULTS: MAP targets were achieved in all patients at all timepoints (64 ± 3, 84 ± 4; 65 ± 5, LHL group; vs. 84 ± 3; 66 ± 2; 85 ± 5 mmHg, HLH group). At corresponding timepoints, hepatic venous saturation was 41 ± 15%; 58 ± 24%; 56 ± 21% in the LHL group vs. 50 ± 19%; 43 ± 20%; 41 ± 18% in the HLH group (P<0.05). No changes were observed in cardiac output, global or trans-splanchnic lactate levels and cytokine levels or in gastric tonometry CO2. CONCLUSION: Achieving a MAP target of 85 mmHg by means of norepinephrine infusion after CPB appears safe for the splanchnic circulation.

Analysis of intraosseous samples in endotoxemic shock--an experimental study in the anaesthetised pig.

BACKGROUND: Intraosseous (IO) access is used in emergency situations to allow rapid initiation of treatment. IO access is also sometimes used for blood sampling, although data on accuracy of such sampling in critical illness are limited. There is also a potential risk that bone marrow fragments in IO samples may damage laboratory equipment. It is ethically questionable to perform a simultaneous comparison between IO and arterial/venous sampling in critically ill humans. We have, thus, studied the analytical performance of IO sampling in a porcine septic shock model using a cartridge-based analyser. METHODS: Eight pigs with endotoxin-induced septic shock were sampled hourly for 6 h, and analysed for blood gases, acid base status, haemoglobin, glucose and lactate using point of care instruments. Samples were taken from three IO cannulae (tibia bilaterally, one with infusion, and humerus), one arterial and one venous. An interaction test was used to assess changes in agreement between methods over time. Bland­Altman plots were constructed to study bias between methods. RESULTS: There were, to a varying extent, differences between IO and arterial/venous levels for all studied variables, but agreement did not change significantly during the experiment. A general finding was a large dispersion of differences between methods. CONCLUSIONS: IO sample values should be treated with caution in this setting but may add useful information to the clinical picture. The tibia or humerus may be used for sampling. IO infusion decreases agreement, thus sampling during infusion should be avoided.

Pilot alternating treatment design study of the splanchnic metabolic effects of two mean arterial pressure targets during cardiopulmonary bypass.

BACKGROUND: The arterial pressure target for optimal splanchnic function during cardiopulmonary bypass (CPB) is uncertain. Thus, we aimed to compare the effects of two different arterial pressure targets during CPB on trans-splanchnic oxygenation, acid-base regulation, and splanchnic interleukin-6 (IL-6) and interleukin-10 (IL-10) flux. METHODS: Sixteen patients undergoing cardiac surgery with CPB in a university affiliated hospital were subjected to a prospective alternating treatment design interventional study. We measured arterial and hepatic vein blood gases, electrolytes, IL-6, and IL-10 while targeting a mean arterial pressure (MAP) of between 60 and 65 mm Hg for 30 min, a MAP of between 80 and 85 mm Hg for 30 min (using norepinephrine infusion), and finally 60-65 mm Hg MAP target for 30 min. RESULTS: The MAP targets were achieved in all patients [65 (4), 84 (4), and 64 (3) mm Hg, respectively; P<0.001] with a greater dose of norepinephrine infusion during the higher MAP target (P<0.001). With longer time on CPB, hepatic vein O2 saturation decreased, while magnesium, lactate, glucose, IL-6, and IL-10 increased independent of MAP target. The decrease in hepatic vein saturation was greater as the temperature increased (re-warming). Overall, there was trans-splanchnic oxygen, chloride, lactate, and IL-6 removal during CPB (P<0.001) and carbon dioxide, bicarbonate, glucose, and IL-10 release (P<0.001). Such removal or release was not affected by the MAP target. CONCLUSIONS: Targeting of a higher MAP during CPB by means of norepinephrine infusion did not affect splanchnic oxygenation, splanchnic acid-base regulation, or splanchnic IL-6 or IL-10 fluxes. Australian and New Zealand Clinical Trial Registry ACTRN 12611001107910.