Can we predict critical care mortality with non-conventional inflammatory markers in SARS-CoV-2 infected patients?

BACKGROUND: Severe COVID-19 disease is associated with multiple organ involvement,then failure and often fatal outcomes.In addition,inflammatory mechanisms and cytokine storms,documented in many COVID-19 patients,are responsible for the progression of the disease and high mortality rates.Inflammatory parameters,such as procalcitonin(PCT) and C-reactive protein(CRP), are widely used in clinical practice. OBJECTIVE: To evaluate the predictive power of non-conventional inflammatory markers regarding mortality risk. METHODS: In our prospective study 52 patients were followed for 5 days after admission to an intensive care unit immediately with severe SARS-CoV-2 infection.We compared leukocyte-,platelet antisedimentation rate (LAR, PAR),neutrophil lymphocyte ratio(NLR), CRP, PCT levels. RESULTS: In non-surviving(NSU) patients LAR remained largely constant from D1 to D4 with a statistically significant drop(p < 0.05) only seen on D5.The NSU group showed statistically significant(p < 0.05) elevated LAR medians on D4 and D5, compared to the SU group.NLR values were continually higher in the non-survivor group.The difference between the SU and NSU groups were statistically significant on every examined day.PAR, CRP and PCT levels didn't show any significant differences between the SU and NSU groups. CONCLUSIONS: In conclusion, this study suggests that LAR and NLR are especially worthy of further investigation as prognostic markers.LAR might be of particular relevance as it is not routinely obtained in current clinical practice.It would seem beneficial to include LAR in data sets to train prognostic artificial intelligence.

Changes of pituitary adenylate cyclase activating polypeptide (PACAP) level in polytrauma patients in the early post-traumatic period.

In polytrauma patients who survive the primary insult, the imbalance between the pro- and anti-inflammatory processes seems to be responsible for life-threatening complications such as sepsis or multiple organ dysfunction syndrome. Measurement of C-reactive protein (CRP) and procalcitonin (PCT) is a standard way for differentiating between infectious (bacterial) and non-infectious inflammation. Monitoring of immune cell functions, like leukocyte anti-sedimentation rate (LAR) can also be useful to diagnose infectious complications. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with well-known immunomodulatory and anti-inflammatory effects. The aim of our study was to determine the changes of PACAP38 levels in polytrauma patients in the early post-traumatic period in intensive care unit and analyse possible correlation of its level with conventional (CRP, PCT) and unconventional (LAR) laboratory parameters. Twenty polytrauma patients were enrolled. Blood samples were taken daily for five days. We observed significant correlation between PACAP38 and CRP levels on day 4 and 5 as well as between PACAP38 and LAR levels all of the days. This could be due to the anti-inflammatory and cytoprotective functions of PACAP38 as part of an endogenous response to the trauma induced systemic inflammatory response syndrome. These significant correlations could have clinical importance in monitoring the dynamic balance of pro- and anti-inflammatory processes in case of polytraumatic patients.

Lack of early platelet and leukocyte activation can indicate complications after major burn injury.

BACKGROUND: Major burn injury causes massive tissue destruction consequently enhanced platelet function and leukocyte-mediated inflammatory response. METHODS: In a prospective, observational study 23 consecutive patients with more than 20% body surface burn injury were followed for five days (T1-T5) after admission to a university intensive care (ICU). Platelet and leukocyte antisedimentation rate (PAR and LAR) was measured by one-hour gravity sedimentation. It detects the percentage of total platelet and leukocyte number crossed the half line of blood sample column, therefore, they can be regarded as cells of decreased specific gravity. We aimed to investigate the time course of PAR and LAR after burn injury, as the trend of platelet and the leukocyte activation in the early post-burn period. RESULTS: Daily mean PAR and LAR values continuously increased in the observation period (T1 to T5). Daily mean PAR and LAR were lower in ICU non-survivors (n = 7) compared to survivors (n = 16) between T2 and T4 (p < 0.05 and p < 0.01). PAR values of septic patients (n = 10) were lower than that of non-septic ones (n = 13, p < 0.01 at T5). CONCLUSIONS: Both PAR and LAR, as novel bedside test can predict septic complications and unfavorable outcome after major burn injury. Further studies with higher sample size are warranted.

Changes of para-, meta- and ortho-tyrosine over time in burned patients.

PURPOSE: Serious burn injury leads to oxidative stress resulting in production of meta- and ortho-tyrosine, while para-tyrosine is the physiological isoform. Our aim was to investigate the metabolism of these tyrosine isoforms following major burn injury. METHODS: Fifteen patients requiring intensive care were followed for 5 consecutive days after major burn injury. Serum and urine concentrations of para-, meta-, and ortho-tyrosine were measured with high performance liquid chromatography. Fifteen healthy matching individuals were invited as control group. RESULTS: Median serum concentration of normal isoform para-tyrosine decreased in burned patients between days 2 and 5 (p < 0.01). Mean meta-, and ortho-tyrosine levels were significantly higher in patients compared to controls in the same time period (p < 0.05). Renal excretion of para-tyrosine increased significantly in our observation period (p < 0.01). CONCLUSIONS: Pathologic isoforms of tyrosine accumulate in serum meanwhile the level of normal isoform decreases possibly due to belated enhanced renal excretion or, to decreased synthesis after major burn injury.

Cost-effectiveness of anesthesia maintained with sevoflurane or propofol with and without additional monitoring: a prospective, randomized controlled trial.

BACKGROUND: We compared cost-effectiveness of anesthesia maintained with sevoflurane or propofol with and without additional monitoring, in the clinical setting of ear-nose-throat surgery. METHODS: One hundred twenty adult patients were randomized to four groups. In groups SEVO and SEVO+ anesthesia was maintained with sevoflurane, in group SEVO+ with additional bispectral index (BIS) and train-of-four (TOF) monitoring. In groups PROP and PROP+ anesthesia was maintained with propofol, in group PROP+ with additional BIS and TOF monitoring. RESULTS: Total cost of anesthesia per hour was greater in group SEVO+ compared to SEVO [€ 19.95(8.53) vs. 12.15(5.32), p <  0.001], and in group PROP+ compared to PROP (€ 22.11(8.08) vs. 13.23(4.23), p <  0.001]. Time to extubation was shorter in group SEVO+ compared to SEVO [11.1(4.7) vs. 14.5(3.9) min, p = 0.002], and in PROP+ compared to PROP [12.6(5.4) vs. 15.2(4.7) min, p <  0.001]. Postoperatively, arterial blood pressure returned to its initial values sooner in groups SEVO+ and PROP+. CONCLUSIONS: Our study demonstrated that the use of BIS and TOF monitoring decreased the total cost of anesthesia drugs and hastened postoperative recovery. However, in our circumstances, these were associated with higher disposables costs. Detailed cost analysis and further investigations are needed to identify patient populations who would benefit most from additional monitoring. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02920749 . Retrospectively registered (date of registration September 2016).

Can leukocyte antisedimentation rate (LAR) predict septic complications and critical care survival early in polytrauma and burn victims?

BACKGROUND: In polytrauma and burn injury Systemic Inflammatory Response Syndrome (SIRS) develops. SIRS is presented in many hospitalized patients, including those who never develop infection or sepsis. Both in SIRS and sepsis the leukocyte activation occurs. In acute phase reaction leukocytes' upward flotation i.e. leukocyte antisedimentation rate (LAR) can indicate infectious origin. OBJECTIVE: To evaluate the predictive power of LAR, serum C-reactive protein (CRP) and procalcitonin (PCT) levels regarding mortality risk and development of septic complications. METHODS: In a prospective, observational study, 36 patients were followed for 5 days (T1-T5) after admission to a critical care unit immediately with severe polytrauma or burn injury. Eleven patients developed septic complications, their LAR, CRP and PCT levels were analyzed before and after 3 days of sepsis was declared. RESULTS: Ten patients died due to septic complications. In survivors LAR at T1 (p < 0.001) and T2 (p < 0.001) as well as CRP at T1 (p < 0.05) were significantly higher compared to controls and non survivors. In septic patients LAR (p < 0.05) and CRP (p < 0.05) showed a significant drop one day before sepsis was declared. PCT levels failed to predict this. CONCLUSIONS: Drop in LAR and CRP levels may be warning signs regarding the onset of septic complications after severe polytrauma and burn injury.

Dynamic changes of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 after burn injury.

PURPOSE: Severe burn is a life-threatening condition. Many trials discuss the role of matrix metalloproteinases and tissue inhibitor of metalloproteinases in diseases generating systemic inflammatory response syndrome, and in some, their prognostic importance has been established. We aimed to describe the time courses of the aforementioned system and to evaluate the difference between survivors and nonsurvivors in burns. MATERIALS: Thirty-one patients were enrolled. Blood samples were collected on admission and on the 5 consecutive days. Circulating matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) have been measured. Healthy individuals were invited as controls. RESULTS: Tissue inhibitor of metalloproteinase 1 increased in the burn group (P < .001) by day 2 and remained elevated thereafter. Plasma MMP-9 and MMP-9/TIMP-1 were already elevated on admission (P < .001) and decreased in tendency thereafter. In burned patients, significantly lower MMP-9 were noted on days 4 to 6 as MMP-9/TIMP-1 were also lower on days 3 to 6 (P < .01) compared with controls. We experienced difference regarding survival on days 5 and 6 by TIMP-1 (P < .05). CONCLUSIONS: Our research is the first follow-up study elucidating the dynamic changes of MMP-9-TIMP-1 system in severe burns. Alteration of MMP-9-TIMP-1 balance might influence systemic inflammatory response and related mortality. Matrix metalloproteinase 9 might be a good injury marker in burns after an extensive trial.

Plasma somatostatin-like immunoreactivity increases in the plasma of septic patients and rats with systemic inflammatory reaction: experimental evidence for its sensory origin and protective role.

Alterations of somatostatin-like immunoreactivity (SST-LI) in the plasma of 11 systemic inflammatory response syndrome (SIRS) patients were investigated in correlation with cytokines, adhesion molecules and coagulation markers repeatedly during 4 days. The origin and role of SST were studied in the cecum ligation and puncture (CLP) rat SIRS model. Capsaicin-sensitive peptidergic sensory nerves were defunctionalized by resiniferatoxin (RTX) pretreatment 2 weeks earlier, in a separate group animals were treated with the somatostatin receptor antagonist cyclo-somatostatin (C-SOM). Plasma SST-LI significantly elevated in septic patients compared to healthy volunteers during the whole 4-day period. Significantly decreased Horowitz score showed severe lung injury, increased plasma C-reactive protein and procalcitonin confirmed SIRS. Soluble P-selectin, tissue plasminogen activator and the interleukin 8 and monocyte chemotactic protein-1 significantly increased, interleukin 6 and soluble CD40 ligand did not change, and soluble Vascular Adhesion Molecule-1 decreased. SST-LI significantly increased in rats both in the plasma and the lung 6h after CLP compared to sham-operation. After RTX pretreatment SST-LI was not altered in intact animals, but the SIRS-induced elevation was absent. Lung MPO activity significantly increased 6h following CLP compared to sham operation, which was significantly higher both after RTX-desensitization and C-SOM-treatment. Most non-pretreated operated rats survived the 6h, but 60% of the RTX-pretreated ones died showing a significantly worse survival. This is the first comprehensive study in humans and animal experiments providing evidence that SST is released from the activated peptidergic sensory nerves. It gets into the bloodstream and mediates a potent endogenous protective mechanism.

Surgery and sepsis increase somatostatin-like immunoreactivity in the human plasma.

We have previously shown in animals that somatostatin released from capsaicin-sensitive afferents in response to inflammation and tissue damage exerts systemic anti-nociceptive and anti-inflammatory actions. Since peptidergic sensory innervation of the airways and the joints are particularly dense, we aimed at investigating the alterations of plasma somatostatin-like immunoreactivity (SST-LI) in response to thoracic and orthopedic surgery, as well as sepsis. Thoracotomy, video-assisted thoracoscopy, hip and knee endoprosthesis were performed under general anesthesia. Blood was taken before, during and after the surgical procedures, as well as at admission and every consecutive morning from septic patients receiving exclusively total parenteral nutrition. SST-LI was determined from the plasma with specific and sensitive radioimmunoassay developed in our laboratory. Plasma SST-LI in healthy volunteers and preoperatively was 8-12fmol/ml. Both thoracotomy and thoracoscopy significantly increased SST-LI by 55-60% at the end of the procedures when the thoracic cavity and the skin were closed. Hip endoprosthesis implantation elevated SST-LI by 30% after skin incision, which increased further to 55% by the time the surgery was completed. In contrast, knee operations performed under tourniquet did not alter SST-LI in the systemic circulation. SST-LI was almost 3-fold higher in the plasma of septic patients than in healthy volunteers. This human study revealed that thoracic/hip surgery and sepsis elevate SST-LI in the systemic circulation, presumably by inducing its release from sensory fibres. It is concluded, that the endogenous protective mechanism mediated by neural somatostatin, which has been evidenced in animals, is likely to operate in patients.