Duration Of Sepsis Research Articles

Beyond survival: understanding post-intensive care syndrome.

Post-intensive care syndrome (PICS) refers to persistent or new onset physical, mental, and neurocognitive complications that can occur following a stay in the intensive care unit. PICS encompasses muscle weakness; neuropathy; cognitive deficits including memory, executive, and attention impairments; post-traumatic stress disorder; and other mood disorders. PICS can last long after hospital admission and can cause significant physical, emotional, and financial stress for patients and their families. Several modifiable risk factors, such as duration of sepsis, delirium, and mechanical ventilation, are associated with PICS. However, due to limited awareness about PICS, these factors are often overlooked. The objective of this paper is to highlight the pathophysiology, clinical features, diagnostic methods, and available preventive and treatment options for PICS.

AQP3 and AQP9-Contrary Players in Sepsis?

Sepsis involves an immunological systemic response to a microbial pathogenic insult, leading to a cascade of interconnected biochemical, cellular, and organ-organ interaction networks. Potential drug targets can depict aquaporins, as they are involved in immunological processes. In immune cells, AQP3 and AQP9 are of special interest. In this study, we tested the hypothesis that these aquaporins are expressed in the blood cells of septic patients and impact sepsis survival. Clinical data, routine laboratory parameters, and blood samples from septic patients were analyzed on day 1 and day 8 after sepsis diagnosis. AQP expression and cytokine serum concentrations were measured. AQP3 mRNA expression increased over the duration of sepsis and was correlated with lymphocyte count. High AQP3 expression was associated with increased survival. In contrast, AQP9 expression was not altered during sepsis and was correlated with neutrophil count, and low levels of AQP9 were associated with increased survival. Furthermore, AQP9 expression was an independent risk factor for sepsis lethality. In conclusion, AQP3 and AQP9 may play contrary roles in the pathophysiology of sepsis, and these results suggest that AQP9 may be a novel drug target in sepsis and, concurrently, a valuable biomarker of the disease.

Variable Levels of Oxytocin During Sepsis: The Role of Oxytocin in Sepsis Pathophysiology.

Although the role of oxytocin in the pathophysiology of sepsis is still unknown, rising preclinical evidence suggests that oxytocin is possibly involved. However, no direct clinical studies have measured the levels of oxytocin during sepsis. In this preliminary study, the serum oxytocin levels were evaluated throughout the duration of sepsis. Twenty-two male patients over 18 years of age with a SOFA score of 2 points or more who were admitted to the ICU were included. Patients with a history of neuroendocrine, psychiatric, and neurologic disorders, cancer, an infection caused by COVID-19, shock due to reasons other than sepsis, a history of psychiatric or neurologic medication use, and those who died during the study were excluded. The main endpoint included the measurement of serum oxytocin levels using radioimmunoassay at 6, 24, and 48 h of the ICU admission. Mean serum oxytocin level was higher at 6 h of ICU admission (41.27 ± 13.14 ng/L) than after 24 and 48 h of ICU admission (22.63 ± 5.75 and 20.97 ± 7.61 ng/L respectively) (P-value < .001). Our study, while reporting increased serum oxytocin levels in the initial phase of sepsis and decline afterward, supports the possible contribution of oxytocin in the pathophysiology of sepsis. Given that oxytocin seems to modulate the innate immune system, future investigations are necessary to assess the potential role of oxytocin in the pathophysiology of sepsis.

Evidence-based rationale for low dose nivolumab in critically ill patients with sepsis-induced immunosuppression.

A substantial part of critically ill patients suffer from sepsis-induced immunosuppression. Reversal of immunosuppression through PD-1 checkpoint inhibition has been proposed as a treatment strategy to overcome immunosuppression in these patients. The PD-1 inhibitor nivolumab, currently used in treatment of cancer, has been evaluated in phase I/II studies in patients with sepsis, demonstrating tolerability and signs of clinical efficacy. No proper dose finding was performed in these studies and, after a single high dose of 480 mg or 960 mg nivolumab, PD-1 inhibition persisted beyond 90 days in the majority of cases. As the duration of sepsis is ~7-10 days, prolonged PD-1 inhibition may unnecessarily induce longer-term immune-related side effects. Based on previously published pharmacokinetic and pharmacodynamic data of nivolumab, a thorough in silico dose finding study for nivolumab in critically ill patients was performed. We found that volume of distribution and clearance of nivolumab were not higher in patients with sepsis compared to the cancer population for which nivolumab is currently approved and showed profound variability. We found that with a single dose of 20 mg nivolumab, the PD-1 receptor occupancy is predicted to stay above the 90% threshold for a median of 23 days (90% prediction interval of 7-78 days). We propose to investigate this dose in critically ill patients as a potential safe and cost-effective pharmacotherapeutic intervention to treat sepsis-induced immunosuppression.

Is Antimicrobial Dosing Adjustment Associated with Better Outcomes in Patients with Severe Obesity and Bloodstream Infections? An Exploratory Study.

The impact of adjusted treatment on clinical outcomes in patients with severe obesity is unclear. This study included adults with severe obesity admitted for bloodstream infections between 2005 and 2015. The patients were grouped according to the percentage of the appropriateness of the dosage of their antimicrobial treatment: 80–100% = good, 20–79% = moderate, and 0–19% = poor. The association between antimicrobial adjustment and a composite of unfavourable outcomes [intensive care unit stay ≥72 h, duration of sepsis >3 days, length of stay ≥7 days or all-cause 30-day mortality] was assessed using logistic regression. Of 110 included episodes, the adjustment was rated good in 47 (43%) episodes, moderate in 31 (28%), and poor in 32 (29%). Older age, Pitt bacteremia score ≥2, sepsis on day 1, and infection site were independent risk factors for unfavourable outcomes. The level of appropriateness was not associated with unfavourable outcomes. The number of antimicrobials, consultation with an infectious disease specialist, blood urea nitrogen 7–10.9 mmol/L, and hemodialysis were significantly associated with adjusted antimicrobial dosing. While the severity of the infection had a substantial impact on the measured outcomes, we did not find an association between dosing optimization and better outcomes.

Peptide-based formula versus standard-based polymeric formula for critically ill children: is it superior for patients’ tolerance?

IntroductionMalnutrition affects 50% of hospitalized children and 25–70% of critically ill children. Enteral tube feeding is generally considered the preferred modality for critically ill pediatric patients. Clinical advantages of using peptide-based formulas are still controversial in critically ill children. The aim of this study was to compare the effect of a peptide-based formula versus a standard polymeric formula on feeding tolerance and whether this will affect the outcome among critically ill children.Material and methodsThis single blind case control study was conducted on 180 randomly selected critically ill children in the pediatric critical care unit (PICU) of Ain Shams University. Patients were divided into 2 groups: a group receiving a standard polymeric formula (group 1; 90 patients) and a group receiving a peptide-based formula (group II; 90 patients). Nutritional requirements, days to reach full enteral feeding, feeding intolerance symptoms and anthropometric measurements were recorded for all patients at admission together with their pediatric risk of mortality score (PRISM). Length of PICU stay, occurrence of sepsis together with survival were analyzed at discharge as outcome measures.ResultsPatients receiving a peptide-based formula showed a significant decrease in feeding interruptions and abdominal distention (p < 0.000), reached full enteral feeding faster (2.60 ±0.74 days versus 5.36 ±1.00 days in patients received polymeric standard formula; p < 0.001) and improved weight gain (p < 0.028). Moreover, duration of sepsis was significantly shorter (p < 0.045), but no difference in mortality was recorded between patient groups.ConclusionsPeptide-based formula feeding was better tolerated than standard polymeric formula feeding in critically ill pediatric patients. However, the choice of patients receiving the peptide-based formula needs to be further evaluated.

Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure

Context Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. Objectives To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. Design, Setting, and Participants Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections. Main Outcome Measures Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Results The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28–stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P Conclusions Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.

Oxygen consumption of human peripheral blood mononuclear cells in severe human sepsis*

During sepsis, after an initial stimulation immune cells down-regulate their functions, leading to a state of immunosuppression. Because the mechanisms of such down-regulation are unclear, we investigated the hypothesis of an energetic failure of immune cells to participate in immune dysfunction. Cohort of septic shock patients to study peripheral blood mononuclear cells (PBMCs) biological energy in comparison to healthy volunteer cells. Critical care unit and laboratory, university hospital. Eighteen severe sepsis or septic shock patients and 32 healthy volunteers. Ex vivo measurement of oxygen consumption in PBMCs taken from patients. The PBMCs' mitochondrial oxidative phosphorylation was investigated using adenosine diphosphate stimulation. The plasma factors implication was tested, using healthy cells incubated in septic plasma, or septic cells incubated in healthy plasma, at different time points of sepsis. The relationship between monocyte human leukocyte antigen-DR expression and bioenergetic results was tested. Baseline oxygen consumption was higher in septic PBMCs (p < .01), with an attenuated response to adenosine diphosphate stimulation (p < .01). Oxygen consumption of healthy PBMCs incubated in septic plasma mimicked the septic cell response, with amplitude depending on the duration of sepsis (days 0-28). Septic cells incubated in healthy plasma partially recovered normal patterns. Septic plasma incubation increased the fraction of decoupling oxygen consumption (p = .021). A relationship between oxygen consumption (baseline or adenosine diphosphate stimulated) and human leukocyte antigen-DR expression was observed for incubation with plasma sampled at different time points of septic shock. Energetic failure of PBMCs in sepsis may be a factor associated with the modulation of immune response and human leukocyte antigen-DR phenotype, partially driven by plasma factors.

Cloxacillin versus vancomycin for presumed late-onset sepsis in the Neonatal Intensive Care Unit and the impact upon outcome of coagulase negative staphylococcal bacteremia: a retrospective cohort study

BackgroundCoagulase negative staphylococcus (CONS) is the main cause of late-onset sepsis in Neonatal Intensive Care Units (NICU). Although CONS rarely causes fulminant sepsis, vancomycin is frequently used as empiric therapy. Indiscriminate use of vancomycin has been linked to the emergence of vancomycin resistant organisms. The objective of this study was to compare duration of CONS sepsis and mortality before and after implementation of a policy of selective vancomycin use and compare use of vancomycin between the 2 time periods.MethodsA retrospective study was conducted of infants ≥4 days old, experiencing signs of sepsis with a first positive blood culture for CONS, during two 12-month periods. Late-onset sepsis was treated empirically with vancomycin and gentamicin during period 1, and cloxacillin and gentamicin during period 2. The confidence interval method was used to assess non-inferiority of the outcomes between the two study groups.ResultsThere were 45 episodes of CONS sepsis during period 1 and 37 during period 2. Duration of sepsis was similar between periods (hazard ratio of 1.00, 95%CI: 0.64, 1.57). One death during period 2 was possibly related to CONS sepsis versus none in period 1. Vancomycin was used in 97.8% of episodes in period 1 versus 81.1% of episodes in period 2.ConclusionAlthough we failed to show non-inferiority of duration of sepsis in the cloxacillin and gentamicin group compared to the vancomycin and gentamicin group, duration of sepsis was clinically similar. Restricting vancomycin for confirmed cases of CONS sepsis resistant to oxacillin appears effective and safe, and significantly reduces vancomycin use in the NICU.

Sepsis and catecholamine support are the major risk factors for critical illness polyneuropathy after open heart surgery'.

Critical illness polyneuropathy (CIP) remains a problem after open heart surgery. Recently, we reported about a retrospectively performed study pointing out that sepsis, the application of higher amounts of catecholamines and intervention such as chronic venovenous hemodiafiltration may be involved in the onset of CIP. A prospectively performed study is presented in order to evaluate the significance of risk factors initially after open heart surgery. From June 1997 until September 1998, patients undergoing open heart surgery and being ventilated beyond 3 days were prospectively enrolled in the study and underwent a standard protocol of electromyographic investigation in order to determine CIP. Several items were recorded: amount of catecholamines, serum levels of urea, creatinine, albumin, and glucose. The duration of sepsis and chronic venovenous hemodiafiltration were reevaluated. Additionally the age, the left ventricular end-diastolic pressure prior to the operation, the time of ICU stay and the time of ventilatory support were compared. Within the observation period, 37 adult patients could be enrolled in the study, whereas 12 patients did develop CIP and 7 patients did not. Patients developing CIP required significantly different amounts of epinephrine (0.17 +/- 0.02 vs. 0.09 +/- 0.01 mg/kg/day, p < 0.05, t-test) higher amounts of norepinephrine (0.06 +/- 0.02 vs. 0.02 +/- 0.01 mg/kg/day, p<0.05, t-test), and lesser dosages of dobutamine (2.2 +/- 0.5 vs. 4.9 +/- 0.7, p<0.05, t-test). After cardiac surgery, the plasma levels of urea was initially significantly elevated in patients developing CIP (127.4 +/- 10.5 vs 97.3 +/- 18.5, p<0.05, t-test) Patients suffering from CIP stayed significantly longer in the ICU (40.3 +/- 11.7 vs. 19.6 +/- 11.3 days, p < 0.05 t-test) with an extended time of ventilator support. (769.6 +/- 05.0 vs 295.0 +/- 134.0 hours, p<0.05, t-test). Patients of the CIP group were suffering significant longer from sepsis than patients without CIP. Sepsis and catecholamine support and an increased level of urea were associated with the development of CIP. The prevention of sepsis and a modulation of the catecholamine support in order to improve microcirculatory flow may reduce the onset of CIP in patients undergoing open heart surgery.

Effect of growth hormone therapy in burn patients on conservative treatment

Evaluation of growth hormone therapy in burns is limited and none is reported from developing countries where burns still carry high mortality. We analysed serial observations on the clinical and biochemical profiles in 13 patients with second and third degree burns who received recombinant human growth hormone (rhGH) (0.5 IU/kg body wt) for 2 weeks in addition to standard conservative treatment and in 9 patients who were managed with standard conservative treatment only. The two groups of patients had burns, comparable in extent and severity. Additional rhGH treatment resulted in improved wound healing ( p<0.001), delayed separation of eschars ( p<0.01), increase in haemoglobin ( p<0.05), serum albumin ( p<0.01), calcium ( p<0.05), phosphorus ( p<0.001), glomerular filtration rate ( p<0.05) and 7 fold elevation in IGF-1. Also, a reduction in weight loss ( p<0.01), nitrogen production rate ( p<0.05), catabolic index ( p<0.01), duration of sepsis ( p<0.01) and hospital stay by 40% ( p<0.01) was noted with rhGH therapy. Transient hypercalcemia (3 patients), albuminuria (2 patients) and elevated blood glucose (one patient) were noted in the rhGH treated group not necessitating any specific therapy. Mortality in rhGH treatment group was 8.3% compared to 44.5% in the “no rhGH” treatment group. These observations suggest significant benefits of short term rhGH treatment in burn patients on conservative management.

Critical illness myopathy and neuropathy

SummaryBackground Critically ill patients may develop muscle weakness or paralysis during the course of sepsis and multiple-organ failure. We studied peripheral nerve and muscle disorders (NMD) in comatose patients.Methods Comatose patients who developed paralysis associated with absent deep-tendon reflexes had electroneuromyography (ENMG) and muscle-nerve biopsy specimens taken. Onset and duration of sepsis, multiple-organ dysfunction and failure, biochemical alterations, and drugs potentially interfering with nerve-muscle function were recorded.Findings 24 patients became quadriparetic or quadriplegic; muscle changes were found in 23. Axonal neuropathy was found in eight of 22 patients examined. All patients had prolonged sepsis and multiple-organ dysfunction, but only 14 had multiple-organ failure. Drugs such as steroids, neuromuscular-blocking agents, and aminoglycosides were not responsible for paresis, and the part played by hyperglycaemia and hypoalbuminaemia is uncertain. Attending physicians predicted a fatal outcome in all cases, although six of seven survivors fully recovered within 115-210 days from the onset of paralysis.Interpretation Comatose patients may become completely paralysed because of NMD. The diagnosis is important to avoid unnecessary investigations and unreasonably pessimistic prognosis. ENMG is essential for the diagnosis and for planning further clinical management. Biopsy needs to be done only when it is necessary to properly classify NMD.

Mixed-Function Oxidase Activity in Sepsis

Hepatic dysfunction is a major contributor to death in multiple organ system failure. To evaluate whether this dysfunction increases with the length of sepsis, we studied the effect of fulminant CLP peritonitis with hyperoxia on mixed-function oxidase-MFO (cytochrome P450 content and activity) and lipid peroxidation in rat livers. Livers were harvested at 18, 21, 24, and 27 hr, homogenized, and microsomal fractions prepared. Cytochrome P450 concentration was determined by assay and P450 activity was determined by the metabolism of ethoxyresorufin and ethoxycoumarin. Lipid peroxidation was estimated by measuring malondialdehyde content. Septic rats showed decreases in P450 levels and activity, which worsened with duration of sepsis. These decreases were partially lessened by hyperoxia. Although there was a trend toward increased lipid peroxidation, this effect was not statistically significant. This study suggests that while MFO content and activity decrease with sepsis, these decreases do not appear to be related to the production of oxygen-derived free radicals. Furthermore, hyperoxia actually appears to have a protective role in this instance.

Gunshot wounds of the tarsal joints

Gunshot wounds of the tarsal joints have unsatisfactory results with prolonged conservative therapeutic methods. One hundred two cases of missile wounds of the tarsal joints are presented, nine of which terminated in amputation. Seventeen patients have normal painless motion; ankylosis has occurred in thirty-seven, and thirty-nine patients have painful limited motion. Only 53 per cent of the 102 patients have painless weight-bearing extremities. The prognosis of wounds of multiple tarsal joints is more guarded for normal painless gait than wounds limited to an individual tarsal joint. Fragmentation wounds have a higher incidence of infection than wounds due to small arms time. The duration of sepsis has decreased with modern antibiotics and current surgical technics. Amputation of the involved extremity should be performed only if bony loss or sepsis is so severe as to necessitate the procedure. A painful joint with limited motion is more disabling than an ankylosed joint, and an early decision concerning surgical arthrodesis should be made.