Development Of Multisystem Organ Failure Research Articles

Antishear Therapy for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Follow-up Study.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening conditions best approached with multidisciplinary burn-equivalent care. There is a lack of consensus on wound management, in particular, whether to debride detached epidermis. Our center instituted "antishear" wound therapy 35 years ago, where detached skin is left in situ as a biologic dressing and a standardized protocol avoids shear forces to prevent further desquamation. Our center's initial results showed outcomes comparable to SCORTEN predictions, but advancements in burn critical care necessitate a reevaluation of the antishear approach. A retrospective chart review was conducted for all patients admitted between June 2004 and May 2020 with a dermatologist-confirmed diagnosis of SJS/TEN (N = 51). All patients were treated with burn-equivalent critical care and antishear wound therapy. Standardized mortality ratios were calculated using the established SCORTEN, and newly developed ABCD-10, prediction models. Mean SCORTEN, ABCD-10, and %TBSA were 2.6, 2.0, and 28%. Overall mortality was 22%; SCORTEN score (P < .001), ABCD-10 score (P < .01), %TBSA involved (P = .02), and development of multisystem organ failure (P < .001) correlated with increased mortality. Cohort-wide standardized mortality based on ABCD-10 was 1.18 (P = .79). Standardized mortality based on SCORTEN was 0.62 (P = .20) and 0.77 (P = .15) for patients with scores ≤3 and >3; across the cohort it was 0.71 (P = .11), representing a 29% mortality reduction. Incorporating the antishear approach as part of burn-equivalent care for SJS/TENs led to outcomes comparable to those predicted for surgical debridement via SCORTEN. However, the antishear approach has the advantage of avoiding painful dressing changes, sedation, and general anesthesia required for surgical debridement.

538 Antishear Therapy for Toxic Epidermal Necrolysis: A Follow-up Study

Abstract Introduction Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are life-threatening dermatologic conditions, which are best approached by a multidisciplinary team practicing burn-equivalent care. There is a lack of consensus on wound management in these patients, in particular whether to debride detached epidermis. Our center instituted “antishear” wound therapy thirty-five years ago, where detached skin is left in situ as a biologic dressing. A standardized protocol aims to avoid shear forces to prevent further desquamation of involved areas. In this study, we follow-up on our outcomes with antishear therapy during the latter half of our center’s experience. Methods A retrospective chart review was conducted for all patients admitted between July 2004 – May 2020 with a Dermatologist-confirmed diagnosis of SJS/TEN. Patients admitted with non-SJS/TEN dermatologic diagnoses and those treated outside of the burn center were excluded. All patients were treated with burn-equivalent critical care and antishear wound therapy. Data was characterized by demographics, inciting agent, total body surface area (%TBSA) affected, hospital course, and any administered systemic therapy. Univariate regression was performed to identify factors that increased mortality. Standardized mortality ratios were calculated at each SCORTEN level and in aggregate. Results Of the 51 patients that met inclusion criteria, 10 (20%), 22 (43%), and 19 (37%) developed SJS (&amp;lt; 10% TBSA), SJS/TEN overlap (10%-30% TBSA), and TEN (&amp;gt;30% TBSA) respectively. Mean SCORTEN (day 3) and %TBSA were 2.6 and 28%, respectively. Overall mortality was 22%; SCORTEN (p&amp;lt; 0.001), %TBSA involvement (p&amp;lt; 0.02), and development of multi-system organ failure (p&amp;lt; 0.001) correlated with increased mortality. No mortality was observed for patients with a SCORTEN ≤2. Patients with SCORTEN scores of ≤3 and &amp;gt;3 had standardized mortality ratios of 0.63 (p=0.21) and 0.78 (p=0.17), respectively, representing 37% and 22% reductions in mortality. The standardized mortality ratio across the entire cohort was 0.73 (p=0.14), representing a 23% reduction in mortality. Conclusions Incorporating the antishear approach as part of burn-equivalent care in SJS/TENS patients is an effective alternative with equivalent mortality outcomes compared to SCORTEN predictions. Standardized mortality ratios were lower for patients with SCORTEN ≤3 and SCORTEN &amp;gt;3, but limited sample size reduced ability to show statistical significance.

Hyperthrombotic Milieu in COVID-19 Patients.

COVID-19 infection has protean systemic manifestations. Experience from previous coronavirus outbreaks, including the current SARS-CoV-2, has shown an augmented risk of thrombosis of both macrovasculature and microvasculature. The former involves both arterial and venous beds manifesting as stroke, acute coronary syndrome and venous thromboembolic events. The microvascular thrombosis is an underappreciated complication of SARS-CoV-2 infection with profound implications on the development of multisystem organ failure. The telltale signs of perpetual on-going coagulation and fibrinolytic cascades underscore the presence of diffuse endothelial damage in the patients with COVID-19. These parameters serve as strong predictors of mortality. While summarizing the alterations of various components of thrombosis in patients with COVID-19, this review points to the emerging evidence that implicates the prominent role of the extrinsic coagulation cascade in COVID-19-related coagulopathy. These mechanisms are triggered by widespread endothelial cell damage (endotheliopathy), the dominant driver of macro- and micro-vascular thrombosis in these patients. We also summarize other mediators of thrombosis, clinically relevant nuances such as the occurrence of thromboembolic events despite thromboprophylaxis (breakthrough thrombosis), current understanding of systemic anticoagulation therapy and its risk–benefit ratio. We conclude by emphasizing a need to probe COVID-19-specific mechanisms of thrombosis to develop better risk markers and safer therapeutic targets.

Concurrent RVAD Improves Survival for Patients with RV Failure at the Time of LVAD Implantation

Right ventricular (RV) failure is associated with poor outcomes after left ventricular assist device (LVAD) placement. This can be treated with a temporary right ventricular assist device (RVAD), which ideally should be placed before the development of multisystem organ failure. The purpose of this study was to determine if there is any outcome difference in patients who underwent early or concurrent RVAD as compared to delayed RVAD implantation. Via retrospective chart review, 32 patients who received temporary RVAD (30 CentriMag and 2 Protek Duo) were identified between 1/2013 and 7/2018. Subjects were divided into two groups as concurrent RVAD placement (defined as RVAD at the time of LVAD implantation) versus delayed RVAD placement (defined as an RVAD placed at any time after leaving the operating room for the LVAD implant). Survival, ICU and total length of stay (LOS), and total number of days on RVAD were compared utilizing Chi-square and two tailed t-test. Patients in the concurrent RVAD group had higher preoperative central venous pressure (p = 0.037). Survival rate at three months (χ² = 6.647, p 0.010) and one year (χ² = 3.983, p 0.046) was statistically significantly better among patients who received concurrent LVAD. ICU LOS, total hospital LOS, and number of days on RVAD were not statistically significant between the two groups. Concurrent placement of a temporary RVAD for patients with RV failure at the time of LVAD implantation improves short- and long-term survival post LVAD implantation as compared to a delayed RVAD approach.

Critical care management of the patient with cirrhosis awaiting liver transplant in the intensive care unit.

Patients with cirrhosis who are awaiting liver transplantation (LT) are at high risk for developing critical illnesses. Current liver allocation policies that dictate a "sickest first" approach coupled with a mismatch between need and availability of organs result in longer wait times, and thus, patients are becoming increasingly ill while awaiting organ transplantation. Even patients with well-compensated cirrhosis may suffer acute deterioration; the syndrome of acute-on-chronic liver failure (ACLF) results in multisystem organ dysfunction and a marked increase in associated short-term morbidity and mortality. For patients on transplant waiting lists, the development of multisystem organ failure may eliminate candidacy for transplant by virtue of being "too sick" to safely undergo transplantation surgery. The goals of intensive care management of patients suffering ACLF are to rapidly recognize and treat inciting events (eg, infection and bleeding) and to aggressively support failing organ systems to ensure that patients may successfully undergo LT. Management of the critically ill ACLF patient awaiting transplantation is best accomplished by multidisciplinary teams with expertise in critical care and transplant medicine. Such teams are well suited to address the needs of this unique patient population and to identify patients who may be too ill to proceed to transplantation surgery. The focus of this review is to identify the common complications of ACLF and to describe our approach management in critically ill patients awaiting LT in our centers. Liver Transplantation 23 1465-1476 2017 AASLD.

Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling.

A patient’s recovery from lung inflammatory injury or development of multi-system organ failure is determined by the host’s ability to resolve inflammation and repair tissue damage, both of which require the clearance of apoptotic neutrophils by macrophages (efferocytosis). Here, we investigated the effects of isoflurane on macrophage efferocytosis and resolution of lung inflammatory injury. Treatment of murine bone marrow-derived macrophages (BMDMs) or alveolar macrophages with isoflurane dramatically enhanced phagocytosis of apoptotic neutrophils. Isoflurane significantly increased the surface expression of the receptor tyrosine kinase Mer in macrophages, but markedly decreased the levels of a soluble form of Mer protein in the medium. Isoflurane treatment also caused a decrease in a disintegrin and metalloproteinase 17 (ADAM17) on the cell surface and a concomitant increase in its cytoplasmic fraction. These responses induced by isoflurane were completely reversed by a pharmacological inhibitor or genetic deletion of AMP-activated protein kinase (AMPK). In a mouse model of lipopolysaccharide-induced lung injury, isoflurane accelerated the recovery of lung inflammation and injury that was coupled with an increase in the number of alveolar macrophages containing apoptotic bodies. In alveolar macrophage-depleted mice, administration of isoflurane-pretreated BMDMs facilitated resolution of lung inflammation following lipopolysaccharide challenge. Thus, isoflurane promoted resolution of lipopolysaccharide-induced lung inflammatory injury via enhancement of macrophage efferocytosis. Increased macrophage efferocytosis following isoflurane treatment correlates with upregulation of Mer surface expression through AMPK-mediated blockade of ADAM17 trafficking to the cell membrane.

High intravascular tissue factor-but not extracellular microvesicles-in septic patients is associated with a high SAPS II score.

BackgroundSepsis is associated with coagulation abnormalities, and a high content of intravascular tissue factor (TF) may contribute to the development of multisystem organ failure. Circulating microvesicles (MVs) are increased during sepsis and characterized by their phosphatidylserine content. It is unclear whether MVs—as a part of the host response to the infection—are beneficial or rather contribute to systemic complications in sepsis. In the present prospective clinical pilot study, we investigated whether plasma TF and MVs are associated with the risk of multiple organ failure and mortality.MethodsThirty patients diagnosed with sepsis, severe sepsis, or septic shock were enrolled and classified as 19 survivors and 11 non-survivors. Blood samples were collected on the day of admission and then daily for up to 2 weeks. MVs and TF were quantified in plasma by ELISA.ResultsNon-survivors had significantly higher TF concentrations on day 3 compared to survivors. Logistic regression analysis revealed that patients with high amounts of TF had significantly increased risk for severity of disease, according to high Simplified Acute Physiology Score II (SAPS II) scores (odds ratio 18.7). In contrast, a higher content of phosphatidylserine-rich MVs were apparently associated with a lower risk for mortality and multiple organ failure, although this was only a trend and the odds ratios were not significant.ConclusionsThis study showed that a high amount of TF in septic patients is significantly associated with increased risk for disease severity, according to a high SAPS II score. Quantification of total MVs in plasma, independent from their cell origin, might be indicative for the outcome of patients in sepsis.

The survival of monocytes infected by human cytomegalovirus is dependent on a unique signalsome induced during entry.

Abstract HCMV infection of immunocompromised individuals often leads to multi-system organ failure. The development of multi-system organ failure is dependent on the ability of HCMV to spread to peripheral organs, which is mediated by blood monocytes. We have previously shown HCMV to extend the short 48hr lifespan of monocytes. Mechanistically, HCMV upregulated cellular myeloid leukemia sequence 1 (Mcl-1) and heat shock protein 27 (HSP27), to block the proteolytic cleavages necessary for the formation of active caspase 3. We now show that, compared to other myeloid survival factors, HCMV infection more efficiently upregulates Mcl-1 and the only survival factor to rapidly induce HSP27. These observations, suggest a unique virus specific mechanism of induction; thus, we examined receptor: ligand signaling events, since viral anti-apoptotic proteins are not expressed until differentiation into macrophages is complete. We determined that HCMV-induced EGFR/PI3K/AKT signaling increased the transcription of both Mcl-1 and HSP27. Yet, protein expression of Mcl-1 and HSP27 is increased via the gH/aVb3/src and the gB/EGFR pathways, respectively. To address this discrepancy between transcripts and protein we evaluated the effects of HCMV on the translation of Mcl-1 and HSP27. Indeed, we found, in contrast to myeloid survival factors, HCMV stimulated the translation of Mcl-1 and HSP27. Overall, these data indicate that inhibition of apoptosis by HCMV is through the unique signaling regulation of Mcl-1 and HSP27; ensuring short-lived monocyte survival past the normal 48hr viability checkpoint, a key event necessary for viral dissemination.

Urgent chemotherapy in hematological patients in the ICU.

Over the past decades, survival of critically ill hematological patients has dramatically improved, and these patients are more frequently referred to the ICU for intensive treatment, including a rising need for administering anticancer-therapy in this setting. The scarce literature on this subject provides evidence for feasibility of administering chemotherapy in the ICU, with expected ICU survival of 60-70%, and one in three patients surviving at least 1 year after discharge. We summarize the recent evidence concerning outcome, dosing and indications of chemotherapy in the ICU, and provide practical guidelines for some special oncological situations. Anticancer-therapy in the ICU is feasible and no longer futile as long as it is initiated in a selected, well-informed patient population with reasonable prognostic expectations. Accurate recognition of organ failure and early referral to the ICU for both supportive care and timely administration of chemotherapy is recommended before the development of multisystem organ failure.

Analysis of ventilator induced lung injury impact in lung and cardiac tissue in a murine model

Mechanical ventilation (MV) with high tidal volumes (Vt) leads to enormous biophysical lung damage, both in patients and in experimental animal models. From a biological point of view, however, the inflammatory response triggered by high Vt-MV and its association with the development of multisystem organ failure is still under study.

Near infrared spectroscopy for evaluation of skeletal muscle tissue oxygenation in different types of shock

Clinical examination is non-invasive, but has well-recognized limitations in detecting compensated and uncompensated low flow states and their severity.This paper describes the principles of near infra-red spectroscopy (NIRS) and the basis for its proposed use, in hypovolaemic, cardiogenic and septic shock, for assessing global and regional tissue oxygenation. The vascular occlusion test is explained. Limitations of NIRS, current controversies, and what is necessary in the future to make this technology a part of the initial and ongoing assessment of a patient, are discussed as well. The ultimate goal of such techniques is to prevent miss-assessment and inadequate resuscitation of patients, two major initiators in the development of multisystem organ failure and death.

Near-infrared spectroscopy for evaluation of global and skeletal muscle tissue oxygenation

Non-invasive clinical examination has well-recognized limitations in detecting compensated and uncompensated low flow states and their severity. This paper describes the principles of near-infrared absorption spectroscopy (NIRS) and the basis for its proposed use in heart failure/cardiogenic and septic shock to assess global and regional tissue oxygenation. The vascular occlusion test is explained. Limitations of NIRS, current controversies, and what is necessary in the future to make this technology a part of the initial and ongoing assessment of a patient are also discussed. The ultimate goal of such techniques is to prevent miss-assessment and inadequate resuscitation of patients, two major factors in the development of multisystem organ failure and death.

Outcomes of previously healthy pediatric patients with fulminant sepsis‐induced multisystem organ failure receiving therapeutic plasma exchange

Fulminant sepsis-induced multisystem organ failure (MSOF) in pediatric patients carries substantial morbidity and mortality. Therapeutic plasma exchange (TPE) has been reported to be beneficial in sepsis-induced MSOF. We evaluated the outcomes of previously healthy children with fulminant sepsis-induced MSOF receiving TPE. Previously healthy pediatric ICU patients who underwent TPE for MSOF due to fulminant bacterial sepsis were retrospectively reviewed. Eleven patients (three females and eight males) with age ranging 8 months to 14 years were identified (eight meningococcemia and three other infections). All patients received daily TPE with fresh frozen plasma (FFP) as replacement fluid. Organ failure index (OFI-maximum score = 6) was assessed daily for 7 days. A median of 4 TPE (1-14) were performed. Improvements in organ function and platelet count occurred in most patients with 2-4 TPE treatments. All 10 patients who were alive had reduced OFI to 2 by day 7 of initial TPE and were all fully recovered (survival rate = 10/11, 91%). The only death occurred in a patient who died the same day after his first TPE treatment, which was initiated 24 h after development of MSOF. The 10 survivors underwent early initiation of TPE (median 5.3 h) after the onset of MSOF. > TPE may contribute to a better outcome in previously healthy pediatric patients with fulminant sepsis-induced MSOF, especially if instituted early in the course of multiorgan failure.

Comparison of the effect of aminophylline and low PEEP vs. high PEEP on EGF concentration in critically ill patients with ALI/ARDS

Acute respiratory distress syndrome (ARDS) remains a serious, often fatal, condition, despite progress in modern critical care treatment. Cytokines play important roles in the pathogenesis of the syndrome, although their roles in the evaluation and outcome have not been clearly elucidated yet. We tested whether serum concentration of epidermal growth factor (EGF), as one of the important inflammatory mediators, changes with time and administration of mechanical ventilation and aminophylline. Thirty patients [mean (SD): age = 56.6 (17.4) years] with ARDS were enrolled. After diagnosis based on inclusion and exclusion criteria, the patients were intubated and mechanically ventilated. Two hours after ventilation with definite positive end-expiratory pressure (PEEP), aminophylline with a specific dose was started. Serum samples were obtained at five time points of 0, 2, 2.5, 4 and 8 h post-starting PEEP. Serum EGF concentration decreased after mechanical ventilation with PEEP (P < 0.05). The serum EGF concentrations 8 h after intervention was statistically lower in the low PEEP group than in the high PEEP group. The Acute Physiology and Chronic Health Evaluation (APACHE) Pi score and PaO2/FiO2 improved significantly after 8 h (P < 0.05). Beneficial effects of mechanical ventilation and aminophylline on APACHE Pi score and PaO2/FiO2 influence serum EGF levels. These findings may have relevance to the development of multisystem organ failure.

CD40 contributes to lethality in acute sepsis: in vivo role for CD40 in innate immunity.

Sepsis induces an early inflammatory cascade initiated by the innate immune response. This often results in the development of multisystem organ failure. We examined the role of CD40, a costimulatory molecule that is integral in adaptive immunity, by using a murine model of polymicrobial sepsis. CD40 knockout (KO) mice had delayed death and improved survival after cecal ligation and puncture (CLP). In addition, they had less remote organ injury as manifested by reduced pulmonary capillary leakage. The improvements in survival and remote organ dysfunction in CD40 KO mice were associated with reduced interleukin-6 (IL-6) and IL-10 levels in serum and bronchoalveolar lavage fluid compared to the levels in wild-type (WT) controls. Furthermore, in contrast to WT mice, CD40 KO mice had no induction of the Th1 cytokines IL-12 and gamma interferon in serum or lungs after CLP. The alterations in cytokine production in CD40 KO mice were associated with similar changes in transcription factor activity. After CLP, CD40 KO mice had attenuated activation of nuclear factor kappaB and signal transducer and activator of transcription 3 in both the lung and the liver. Finally, WT mice had increased expression of CD40 on their alveolar macrophages. These data highlight the importance of CD40 activation in the innate immune response during polymicrobial sepsis and the subsequent development of remote organ dysfunction.

TNF-alpha increases sensitivity to LPS in chronically catheterized rats.

Patients with severe trauma injury are transiently exposed to increased serum concentrations of tumor necrosis factor-alpha (TNF-alpha). These patients are susceptible to the development of multisystem organ failure (MSOF) triggered by subsequent exposure to bacterial toxins either via infection or increased intestinal permeability. We simulated the cytokine response of trauma by infusing 0.8 or 8.0 microg/kg of TNF-alpha (priming dose) into chronically catheterized rats. After 48 h, rats were challenged with endotoxin [lipopolysaccharide (LPS); 10 or 1,000 microg/kg]. Animals primed with either dose of TNF-alpha and then challenged with 1,000 microg/kg of LPS demonstrated significantly increased mortality, mean peak serum concentrations of interferon-gamma (IFN-gamma), and blood lactate concentrations (P < 0.05) compared with nonprimed animals. Mean peak serum concentrations of IFN-gamma and blood lactate concentrations were increased after challenge with 10 microg/kg of LPS only in animals primed with 8.0 microg/kg of TNF-alpha. Priming with TNF-alpha did not increase mortality after challenge with 10 microg/kg of LPS. These data suggest that both TNF-alpha release and the subsequent exposure to bacterial toxins mediate the pathophysiological progression from trauma to subsequent MSOF.

Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome.

We examined the hypothesis that injurious ventilatory strategies (large tidal volume [VT] and/or low positive end-expiratory pressure [PEEP]) would increase release of inflammatory mediators into the lung and into the systemic circulation in a lung injury model. Lung injury was induced in 40 anesthetized paralyzed Sprague-Dawley rats (350 +/- 2 g) by hydrochloric acid instillation (pH 1.5, 2.5 ml/kg). Rats were then randomized into five groups (n = 8): (1) high-volume zero PEEP (HVZP): VT, 16 ml/ kg; (2) high-volume PEEP (HVP): VT, 16 ml/kg, PEEP, 5 cm H2O; (3) low-volume zero PEEP (LVZP): VT, 9 ml/kg; (4) low-volume PEEP (LVP): VT, 9 ml/kg, PEEP, 5 cm H2O; (5) same settings as (4) plus a recruitment maneuver performed every hour (LVPR). Respiratory rate was adjusted to maintain normocapnia and fraction of inspired oxygen (FIO2) was 1. Cytokine concentrations (tumor necrosis factor-alpha [TNF-alpha] and macrophage inflammatory protein-2 [MIP-2]) were measured by ELISA. All animals in the LVZP group died before the end of the experiment. After 4 h of ventilation, the HVZP group had similar lung fluid TNF-alpha concentrations compared with the HVP group: 1,861 +/- 333 pg/ml versus 1,259 +/- 189 pg/ml; and much higher serum concentrations: 692 +/- 74 pg/ml versus 102 +/- 31 pg/ml (p < 0.05). An identical pattern was found for MIP-2. These results suggest that the particular ventilatory strategy can affect the release of cytokines into the systemic circulation, a finding that may have relevance for the development of multisystem organ failure.

Monitoring tissue oxygenation in the critically ill

Because occult tissue hypoxia may contribute to the development of multisystem organ failure, monitoring of tissue oxygenation is an important goal of critical care. This has been accomplished most commonly by assessment of global (whole body) oxygenation. However, no global parameter provides a sufficient, reliable assessment of adequacy of global oxygenation for routine clinical application. In addition, such measurements do not reflect local oxygenation. A number of regional techniques have been devised, but none is well enough developed to be recommended. Finally, no method of tissue oxygenation assessment has been tested in a randomized, controlled trial to determine its effects on patient outcome.

Etiology and treatment of acquired coagulopathies in the critically ill patient

Excessive bleeding frequently complicates the care of critically-ill patients. Except in the case of trauma or in patients with known coagulopathies (e.g., hemophilia), the bleeding is generally not directly related to the illness that results in admission to the intensive care unit. In general, the causes of the bleeding can be divided into 3 categories: consumptive coagulopathies (e.g., DIC), bleeding related to ``hepatic issues'' (i.e., liver dysfunction, vitamin K deficiency), and iatrogenic causes. This review will discuss the more common causes of bleeding in the critically-ill patient and outline diagnostic and treatment approaches for these patients. New experimental data linking activation of the coagulation and inflammatory systems with the development of multisystem organ failure is briefly discussed.

Adult respiratory distress syndrome

This review discusses basic research into the etiologic mechanisms of the adult respiratory distress syndrome (ARDS), as well as therapeutic strategies directed at mechanisms of disease and supportive strategies involving mechanical ventilation and hemodynamic management. The concept of O, supply/delivery in ARDS, and its possible contribution to the development of multisystem organ failure (MOF), is briefly discussed.