Immature platelets in patients with Covid-19: association with disease severity.

Coronavirus disease 2019 (Covid-19) is associated with a high incidence of venous and arterial thromboembolic events. Currently, there are no clinical or laboratory markers that predict thrombotic risk. Circulating immature platelets are hyper-reactive platelets, which are associated with arterial thrombotic events. The aim of this study was to assess whether the proportion of circulating immature platelets is associated with disease severity in Covid-19 patients. Patients admitted with Covid-19 disease were prospectively assessed. Immature platelet count (IPC) and immature platelet fraction (IPF) were measured at admission and at additional time points during the hospital course using the Sysmex XN-3000 auto-analyzer. A total of 136 consecutive patients with Covid-19 were recruited [mean age 60 ± 19 years, 49% woman, 56 (41%) had mild-moderate disease and 80 (59%) had severe disease at presentation]. The median IPF% was higher in patients with severe compared to mild-moderate disease [5.8 (3.9-8.7) vs. 4.2 (2.73-6.45), respectively, p = 0.01]. The maximal IPC value was also higher in patients with severe disease [15 (10.03-21.56), vs 10.9 (IQR 6.79-15.62), respectively, p = 0.001]. Increased IPC was associated with increased length of hospital stay. Patients with severe Covid-19 have higher levels of IPF than patients with mild-moderate disease. IPF may serve as a prognostic marker for disease severity in Covid-19 patients.

Immature platelets in patients hospitalized with Covid-19.

Coronavirus disease 2019 (Covid-19) is associated with high incidence of venous and arterial thromboembolic events. Currently, there are no markers to guide antithrombotic therapy in Covid-19. Immature platelets represent a population of hyper-reactive platelets associated with arterial events. This prospective study compared consecutive Covid-19 patients (n = 47, median age = 56 years) to patients with acute myocardial infarction (AMI, n = 100, median age = 59 years) and a group of stable patients with cardiovascular risk factors (n = 64, median age = 68 years). Immature platelet fraction (IPF) and immature platelet count (IPC) were determined by the Sysmex XN-3000 auto-analyzer on admission and at subsequent time-points. IPF% on admission was higher in Covid-19 than the stable group and similar to the AMI group (4.8% [IQR 3.4-6.9], 3.5% [2.7-5.1], 4.55% [3.0-6.75], respectively, p = 0.0053). IPC on admission was also higher in Covid-19 than the stable group and similar to the AMI group (10.8 × 109/L [8.3-18.1], 7.35 × 109/L [5.3-10.5], 10.7 × 109/L [7.7-16.8], respectively, P < 0.0001). The maximal IPF% among the Covid-19 group was higher than the stable group and similar to the AMI group. The maximal IPC in Covid-19 was higher than the maximal IPC in both the stable and AMI groups (COVID-19: 14.4 × 109/L [9.4-20.9], AMI: 10.9 × 109/L [7.6-15.2], P = 0.0035, Stable: 7.55 × 109/L [5.55-10.5], P < 0.0001). Patients with Covid-19 have increased immature platelets indices compared to stable patients with cardiovascular risk factors, and as the disease progresses also compared to AMI patients. The enhanced platelet turnover and reactivity may have a role in the development of thrombotic events in Covid-19 patients.

Placenta-Derived Cell Therapy to Treat Patients With Respiratory Failure Due to Coronavirus Disease 2019.

OBJECTIVES: To determine whether placental cell therapy PLacental eXpanded (PLX)-PAD (Pluristem Therapeutics, Haifa, Israel) may be beneficial to treating critically ill patients suffering from acute respiratory distress syndrome due to coronavirus disease 2019. DESIGN: Retrospective case report of critically ill coronavirus disease 2019 patients treated with PLacental eXpanded (PLX)-PAD from March 26, 2020, to April 4, 2020, with follow-up through May 2, 2020. SETTING: Four hospitals in Israel (Rambam Health Care Campus, Bnai Zion Medical Center, and Samson Assuta Ashdod University Hospital), and Holy Name Medical Center in New Jersey. PATIENTS: Eight critically ill patients on invasive mechanical ventilation, suffering from acute respiratory distress syndrome due to coronavirus disease 2019. INTERVENTIONS: Intramuscular injection of PLacental eXpanded (PLX)-PAD (300 × 106 cells) given as one to two treatments. MEASUREMENTS AND MAIN RESULTS: Mortality, time to discharge, and changes in blood and respiratory variables were monitored during hospitalization to day 17 posttreatment. Of the eight patients treated (median age 55 yr, seven males and one female), five were discharged, two remained hospitalized, and one died. By day 3 postinjection, mean C-reactive protein fell 45% (240.3-131.3 mg/L; p = 0.0019) and fell to 77% by day 5 (56.0 mg/L; p < 0.0001). Pao2/Fio2 improved in 5:8 patients after 24-hour posttreatment, with similar effects 48-hour posttreatment. A decrease in positive end-expiratory pressure and increase in pH were statistically significant between days 0 and 14 (p = 0.0032 and p = 0.00072, respectively). A decrease in hemoglobin was statistically significant for days 0-5 and 0-14 (p = 0.015 and p = 0.0028, respectively), whereas for creatinine, it was statistically significant between days 0 and 14 (p = 0.032). CONCLUSIONS: Improvement in several variables such as C-reactive protein, positive end-expiratory pressure, and Pao2/Fio2 was observed following PLacental eXpanded (PLX)-PAD treatment, suggesting possible therapeutic effect. However, interpretation of the data is limited due to the small sample size, use of concomitant investigational therapies, and the uncontrolled study design. The efficacy of PLacental eXpanded (PLX)-PAD in coronavirus disease 2019 should be further evaluated in a controlled clinical trial.

Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma.

BACKGROUND: We assessed outcome of patients with moderate and severe COVID-19 following treatment with convalescent plasma (CP) and the association with IgG levels in transfused CP. METHODS: A prospective cohort study. Primary outcome was improvement at day 14 defined as alive, not on mechanical ventilation, and moderate, mild, or recovered from COVID-19. Antibody levels in CP units were unknown at the time of treatment. IgG against the spike protein S1 was subsequently measured by ELISA. Neutralizing antibodies titers were determined in a subset. Outcome was assessed in relation to the mean antibody level transfused to the patients (≤4.0 versus >4.0). FINDINGS: Of 49 patients, 11 (22.4%) had moderate, 38 (77.6%) had severe disease, 28 were ventilated. At day 14, 24 (49.0%) patients improved, 9 (18.4%) died, and 13 (26.5%) were ventilated. In 14/98 (14.3%) CP units IgG was < 1.1 (cutoff calibration) and in 60 (61.2%) ≤4.0. IgG level and neutralizing antibody titer were correlated (0.85 p < 0.001). In patients receiving ≤4.0 antibody levels, 11/30 improved (36.7%) versus 13/19 (68.4%) in patients receiving >4.0 odds ratio (OR) 0.267 [95% confidence interval (CI) 0.079-0.905], P = 0.030. In patients diagnosed >10 days prior to treatment, 4/14 (22.4%) improved in the ≤4.0 antibody group, versus 6/7 (85.7%) in the >4.0 antibody group, OR 0.048 (95% CI, 0.004-0.520), P = 0.007. No serious adverse events were reported. INTERPRETATION: Treatment with CP with higher levels of IgG against S1 may benefit patients with moderate and severe COVID-19. IgG against S1 level in CP predicts neutralization antibodies titers.

[THE MORBIDITY AND MORTALITY OF INFLUENZA PATIENTS TREATED AT RAMBAM MEDICAL CENTER INTENSIVE CARE UNIT IN THE YEARS 2009-2014].

INTRODUCTION: Data regarding the characteristics and results of the treatment of patients hospitalized in intensive care units (ICUs) with influenza in Israel are limited. AIMS: We evaluated the characteristics and outcomes of patients treated at Rambam Medical Center at the adult department of critical care medicine for influenza between the years 2009-2014. METHODS: A retrospective cohort study was conducted. Patients were detected by laboratory reports and data were extracted from electronic medical records. RESULTS: The study included 64 patients with laboratory-proven influenza. Median age was 54 years (range 17-83) and symptom duration before admission was 5 days (1-14). The median APACHE-II score at admission was 31.5 and 63.5% were in hemodynamic shock mandating the use of vasopressors. All patients received mechanical ventilation. Inhalation of nitric oxide was needed in a third; 14.3% needed Intra-Pulmonary Percussive Ventilation and steroids were given to 57.1%. ICU mortality was 24/64 (37.5%). Factors significantly associated with mortality were older age, longer length of disease prior to ICU admission, APACHE-II score, septic shock and creatinine. Mortality during the last season was lower than observed during the 2009 pandemia despite increasing severity of illness. CONCLUSIONS: The appearance of a new strain of influenza leads to high morbidity, complications and mortality due to low population immunity. There are no randomized controlled trials evaluating the efficacy of anti-viral drugs and other treatments in severe Influenza with complications. DISCUSSION: The treatment of critically-ill patients with severe influenza is complex, mandates advanced techniques of mechanical ventilation and hemodynamic support. Under intense supportive care most patients with influenza survive.

The quinary pattern of blast injury.

OBJECTIVE: Bombing is the primary weapon of global terrorism, and it results in a complicated, multidimensional injury pattern. It induces bodily injuries through the well-documented primary, secondary, tertiary, and quaternary mechanisms of blast. Their effects dictate special medical concern and timely implementation of diagnostic and management strategies. Our objective is to report on clinical observations of patients admitted to the Tel Aviv Medical Center following a terrorist bombing. RESULTS: The explosion injured 27 patients, and three died. Four survivors who had been in close proximity to the explosion, as indicated by their eardrum perforation and additional blast injuries, were exposed to the blast wave. They exhibited a unique and immediate hyperinflammatory state, two upon admission to the intensive care unit and two during surgery. This hyperinflammatory state manifested as hyperpyrexia, sweating, low central venous pressure, and positive fluid balance. This state did not correlate with the complexity of injuries sustained by any of the 67 patients admitted to the intensive care unit after previous bombings. CONCLUSION: The patients' hyperinflammatory behavior, unrelated to their injury complexity and severity of trauma, indicates a new injury pattern in explosions, termed the "quinary blast injury pattern." Unconventional materials used in the manufacture of the explosive can partly explain the observed early hyperinflammatory state. Medical personnel caring for blast victims should be aware of this new type of bombing injury.

Terrorist bombing.

Bombings and explosion incidents directed against innocent civilians are the primary instrument of global terror. In the present review we highlight the major observations and lessons learned from these events. Five mechanisms of blast injury are outlined and the different type of injury that they cause is described. Indeed, the consequences of terror bombings differ from those of non-terrorism trauma in severity and complexity of injury, and constitute a new class of casualties that differ from those of conventional trauma. The clinical implications of terror bombing, in treatment dilemmas in the multidimensional injury, ancillary evaluation and handling of terror bombing mass casualty event are highlighted. All this leads to the conclusion that thorough medical preparedness to cope with this new epidemic is required, and that understanding of detonation and blast dynamics and how they correlate with the injury patterns is pivotal for revision of current mass casualty protocols.

The effect of aprotinin in a model of uncontrolled hemorrhagic shock.

BACKGROUND: Aprotinin has been shown to promote clot formation through its antifibrinolytic activity, by inhibiting the plasmin-induced complement activation and by protecting the platelets adhesive surface receptors. It has been successfully used in cardiac and liver transplantation surgery. OBJECTIVE: To evaluate the effect of aprotinin in a model of uncontrolled intra-abdominal bleeding as a basis for its potential use in trauma patients. METHODS: Twenty rats were randomly divided into 2 groups. All animals were operated on and bleeding was induced by transecting 1 lobe of the liver. In the treatment group a single dose of 30,000 U/kg of aprotinin was administered 5 minutes after the injury. The animals were monitored for hemodynamic parameters, blood loss volume, and mortality rates. RESULTS: At 120 minutes from trauma induction a significant difference in mean blood pressure was observed: 67+/-22 mm Hg in the treatment group versus 53+/-28 mm Hg in the control group (P=.04). This difference remained consistent until the end of the experiment. Treatment with aprotinin also resulted in a tendency to an increased survival rate (P=.05) and increased mean survival time: 175+/-46 minutes as compared to 123+/-48 minutes in the controls (P=.027). CONCLUSIONS: Early administration of aprotinin resulted in temporary hemodynamic stabilization and prolonged survival in a model of uncontrolled bleeding. Further studies are needed to establish the possible use of aprotinin in the treatment of trauma patients.

Brain injuries caused by spherical bolts.

OBJECT: Metallic particles contained in antihuman bombs increase the number of fatalities. The ballistics of these particles depends on the explosive that is used, the distance from the explosion, the shape of the particle projected, and the biomechanics of the injured tissue. The authors present their experience with penetrating spherical bolt injuries to the brain. METHODS: The authors retrospectively reviewed clinical and radiological data obtained in eight patients with penetrating spherical bolt injuries to the cranium: four had Glasgow Coma Scale (GCS) scores less than 8 (three died, one from an unrelated injury) and four had a GCS score of 15 (all survived). Two of the latter patients suffered unique anatomical injuries attributed to the distinctive ballistics of spherical bolts: in one patient the bolt penetrated the cavernous sinus causing minimal cranial nerve injury, and in the other patient the bolt lodged in the fourth ventricle causing acute hydrocephalus without other neurological deficits. CONCLUSIONS: Penetrating spherical bolts to the brain may be lethal. Nevertheless, they have unique ballistics that cause highly delineated anatomical damage and minor neurological deficits.

Medical consequences of terrorist bombs containing spherical metal pellets: analysis of a suicide terrorism event.

OBJECTIVE: Various metal objects added to explosives increase and diversify the wounding from bombing; especially favoured are spherical missiles for their special injuring characteristics. Our objective was to study the medical consequences and ballistic effects on human tissue of spherical metal pellets used in terrorist bombings. METHODS: The clinical and forensic data of all bodily injured casualties of a suicide terrorist bombing in a crowded hotel dining room were analysed retrospectively. RESULTS: Of the 250 people at the scene, 164 were injured, with 91 (55.5%) suffering bodily injuries; 30 of them died. The immediately deceased had disseminated tissue damage and their bodies were saturated with steel spheres. Thirty-two immediate survivors sustained severe injuries (Injury Severity Score > or =16), and all suffered tissue penetration by the pellets. Twenty-three (32%) underwent surgery and 15 (21%) required intensive care. CONCLUSIONS: Metal pellets propelled by the explosion enhanced the secondary pattern of injury and injured even patients remote from the origin. Tissue destruction and specific organ injuries among survivors were limited. To evaluate and manage victims of terrorist bombings properly, medical teams should become familiar with these severe injuries.

Somatostatin analogue treatment attenuates histological findings of inflammation and increases mRNA expression of interleukin-1 beta in the articular tissues of rats with ongoing adjuvant-induced arthritis.

OBJECTIVE: Somatostatin is a neuropeptide with modulatory effects on the immune system and the function of synovial cells; it has antiangiogenic and antiproliferative properties. This study aimed to evaluate the clinical, histological, and articular tissue cytokine mRNA response to somostatin treatment in rat adjuvant-induced arthritis (AIA). METHODS: Adjuvant-induced arthritis was induced in a total of 68 Lewis rats by immunization with complete Freund's adjuvant. Twenty-four rats were treated with a long-acting somostatin analogue 14 days after disease induction. Twenty-four untreated rats served as controls. The severity of arthritis was scored weekly for 42 days. In a second experiment, 20 rats (ten treated, ten controls) were killed 21 days after treatment for assessment of joint histopathology and articular tissue cytokine mRNA expression. RESULTS: Somatostatin analogue treatment significantly reduced histological scores of early inflammatory changes and increased articular tissue mRNA expression of interleukin-1 beta (IL-1beta). A trend toward improvement in physical scores of joint inflammation was seen in the treated group. Late destructive changes were not significantly different. CONCLUSION: Treatment with a somostatin analogue attenuated early inflammatory changes in AIA joints and increased mRNA expression of IL-1beta in the articular tissues of rats with ongoing arthritis. Improvement in the physical findings of joint inflammation was mild.

[Trauma education of general surgery residents].

Educating residents in surgery, especially in trauma surgery, and the best way to teach it among the other subspecialties of surgery, is a topic heavily debated in recent literature. Several important factors affecting this learning have changed lately. Many educators have expressed concern about the adequacy of the exposure of surgical residents to surgery and of their ability to care for their patients, with the newly imposed legal constraints on the length of shifts and working hours. Since trauma is inherently unpredictable, residents must spend many hours in the emergency department to become exposed to various types of trauma. Some will only see a small number of trauma patients during their residency, depending on the location of hospital and its commitment to trauma. Furthermore, the operative exposure in trauma has decreased dramatically, with the current trend of non-operative management of blunt splenic and hepatic trauma and conservatism in the management of some stable patients injured by penetrating mechanisms. Similar concerns have also been raised about the exposure of attending surgeons to surgical trauma practice. In most centers in Israel, the trauma patient is managed by a general surgery specialist rather than by a trauma-specialized general surgeon. This may lead to dilution of trauma cases among multiple medical providers and furthermore, to inconsistency in the delivery of care. Consequently, this may effect the education of surgical residents. We therefore suggest a structured curriculum for general surgery residents as well as structural changes in the department of surgery to increase the caseload of general surgeons especially those choosing to specialize in trauma.

The special injury pattern in terrorist bombings.

BACKGROUND: The destructive human consequences of terrorist bombing always challenge the medical system in diagnosis, decision making, and patient management. This injury is produced by multiple injury mechanisms, and departs from the conventional description of trauma complexity. Our objective was to characterize and compare terror-bombing victims with casualties of all other kinds of trauma, and to validate the existence of a different, more complex, injury pattern. STUDY DESIGN: A retrospective cohort study was conducted of patient records from October 2000 through June 2003 in the Israeli National Trauma Registry. All were categorized as victims of terrorist bombings or of nonterror-related trauma. Analysis included age, gender, Injury Severity Score, Glasgow Coma Scale, admission blood pressure, injury complexity, surgical interventions, intensive care and hospital lengths of stay, in-hospital mortality, and disposition. This analysis was extended to Injury Severity Score subgroups. RESULTS: Victims of terrorist bombings (n = 906) were compared with 55,033 casualties of nonterror-related trauma. Bombing resulted in significantly different injury complexity, increased severity, and with more body regions involved. Significantly enhanced use of intensive care, prolonged hospital stay, more surgical interventions, and increased hospital mortality are characteristic of these patients. CONCLUSIONS: Terrorist bombings inflict injury of a distinctly different pattern than other means of trauma. The simultaneous combination of different injury mechanisms in explosions results in a multidimensional injury pattern and a complicated clinical course. Hospital preparedness and medical team awareness to the unique nature of the injuries are mandatory for improving the outcomes of these patients.

Functions and principles in the management of bombing mass casualty incidents: lessons learned at the Tel-Aviv Souraski Medical Center.

Mass casualty incidents (MCI) resulting from terrorist bombings pose special problems and may overwhelm even the most experienced trauma centre. Although role assignments for MCI management and control are documented, we would like to share several aspects that we have found to be crucial for the management of terrorist bombing MCI. Twelve topics and possible answers were brought up and discussed extensively in MCI debriefing sessions in our institution. They were of two main categories: assignments and functions of key personnel, and principles and definitions. The first category includes the Triage Officer, the Medical Director, the Administrative Director, the Head Nurse, the Emergency Medical System Coordinator, the Blood Bank Liaison, and the trauma teams. The second category encompasses the concept of triage hospital, the unidirectional patient flow, ancillary evaluation during MCI, the consultancy, and tertiary survey. All were identified as critical for proper event handling. The integration and implementation of the topics discussed throughout the medical system may enable emergency departments to handle MCI resulting from terrorist bombings better.

Evaluation of inflammatory cytokines as prognostic markers in experimental acute pancreatitis in rats

Background: Early evaluation of the severity of acute pancreatitis requires measurements of many variables. Clinical parameters as well as CT scan have traditionally been used as predictors of severity, and complications. None of them however can predict the outcome early and reliably. Inflammatory cytokines were shown to play an important role in the inflammatory cascade, which occurs early in the course of the disease. The aim of the present study is to evaluate the predictive value of plasma interleukin-6 (IL-6) and interleukin-1 (IL-1) levels in experimental pancreatitis in rats. Methods: Male wistar rats were anesthetized and pancreatitis was induced by intraparenchymal injection of 5% (group 2) and 10% (group 3) sodium taurocholate (TC), resulting in 2 distinct groups of severity. In sham controls (group 1), saline was injected into the pancreas in the same fashion. Blood samples were obtained before and 2, 4, 24, and 96 hours after the induction of pancreatitis and plasma amylase, lipase, LDH, IL-1 and IL-6 levels were measured. Mortality was recorded every 8 hours. Pancreatitis severity was also assessed by histopathology. Results: Four hours after pancreatitis induction, plasma amylase, lipase and LDH levels were markedly increased in the pancreatitis groups. In the sham control group, moderate increases were also observed. No consistent significant difference in amylase, lipase or LDH levels was observed between the groups. At 2 hours from pancreatitis induction, IL-6 levels increased mildly in-groups 1 and 2, and decreased to the baseline levels at 24 hours. In-group 3, the increase in IL-6 levels was significantly higher then in-groups 1 and 2 (p=0.029 and 0.036 respectively), and correlated well with pancreatitis severity as defined by pathology (p=0.01) and mortality rates (p=0.037). No difference in IL-1 levels was observed at 2,4 and 24 hours from induction. At 96 hours IL-1 levels were higher in group 3 then in groups 1 and 2 (p=0.037). Conclusion: IL-6 plasma levels correlated well with the severity of the disease as reflected by the mortality rates and pathological score. IL-6 levels may be a reliable predictor of severity and mortality in acute pancreatitis. This marker can be used as early as 2 hours and up to 24 hours from the beginning of the inflammatory process. IL-1 levels at 96 hours also correlated with pathology, but were not found to predict outcome at the early phases of the disease.

The effect of the somatostatin analogue octreotide on experimental intestinal obstruction in rats

Background: Somatostatin has an inhibitory effect on the endocrine and exocrine secretions of the gut. It may have a beneficial effect in the conservative treatment of intestinal obstruction. The aim of the present study is to investigate the effect of octreotide in mechanical intestinal obstruction in rats. Method: Intestinal obstruction was induced in rats by ligation of a segment of the distal ileum. Animals were treated with the somatostatin analogue octreotide (n=16), or saline (n=16). Eight rats were operated but their intestine was not ligated (n=8) serving as sham controls. Forty eight hours after the operation, the animals were operated upon again and blood samples from the femoral vein were tested for electrolytes, urea, glucose, lactic acid, amylase, ph and bicarbonate. Portal vein blood samples were also obtained and tested for lactic acid and amylase. Results: Intestinal obstruction resulted, after 48 hours, in severe dilatation of bowel loops. A significant increase in plasma levels of urea, amylase and lactic acid was observed. Plasma pH decreased. In blood samples from the portal vein, a significant increase in lactic acid was observed, indicating metabolic acidosis, probably secondary to bowel ischemia. Octreotide treatment, resulted in less acidosis, with concomitant lower urea and lactic acid levels in the plasma and especially in the portal vein. Conclusion: Octreotide treatment may have a beneficial effect in the conservative treatment of selected cases of intestinal obstruction.

Objetivo: A somatostatina tem efeito inibidor nas secrees endcrina e excrina do intestino. Poderß ter efeito benfico no tratamento conservador da obstruo intestinal. O objetivo do presente estudo investigar o efeito do octreotide na obstruo mecnica do intestino delgado de ratos. Mtodo: A obstruo intestinal foi induzida em ratos pela ligadura do segmento distal do ileum. Os animais foram tratados com somatostatina anßloga octreotide (n=16) ou com soluo salina (n=16). Oito ratos foram operados mas o intestino delgado no foi ligado (n=8) servindo como o grupo sham. Quarenta oito horas aps a operao os animais foram re-operados e submetidos a colheita de sangue da veia femoral a fim de verificar os eletrlitos, uria, glicose, ßcido lßtico, amilase, pH e bicarbonato. Obteve-se tambm amostra de sangue da veia porta para verificar os nveis de ßcido lßtico e amilase. Resultados: Aps 48 horas de obstruo houve intensa dilatao das alas intestinais. Observou-se aumento significante dos nveis plasmßticos de uria, amilase e ßcido lßtico. Diminuiu o pH plasmßtico. Observou-se aumento do ßcido lßtico no sangue portal, indicando acidose metablica, provavelmente secundßria a isquemia intestinal. O tratamento com octreotide resultou em menos acidose, com nveis baixos de uria e ßcido lßtico no plasma, e especialmente na veia porta. Concluso: O emprego de octreotide pode ter efeito benfico no tratamento conservador de casos selecionados de obstruo intestinal.