Transtentorial herniation syndrome from meningococcal meningitis in a young woman: the case for neurocritical care.

We report a case of a previously healthy early adolescent female who presented with meningococcal meningitis. While in hospital, she had marked neurologic deterioration with clinical herniation from malignant cerebral oedema. She was transferred to a neurocritical care centre where she underwent invasive intracranial pressure (ICP) and brain tissue oxygen (PbtO2) monitoring. Early in her course, she demonstrated a compete absence of autoregulation, with pressure passive cerebral blood flow. As a result, maintaining a mean arterial pressure between 50 mm Hg and 60 mm Hg, which ensured adequate cerebral oxygenation, while avoiding increases in ICP. Although her course was initially complicated by bilateral optic neuropathy, she has subsequently made a full neurologic recovery and is now undertaking postsecondary education. This case highlights that access to specialist neurocritical care, guided by neurophysiologic monitoring of ICP and PbtO2, may help improve outcomes, even among those patients with catastrophic cerebral oedema from bacterial meningitis.

Therapeutic hypothermia attenuates physiologic, histologic, and metabolomic markers of injury in a porcine model of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a lung injury characterized by noncardiogenic pulmonary edema and hypoxic respiratory failure. The purpose of this study was to investigate the effects of therapeutic hypothermia on short-term experimental ARDS. Twenty adult female Yorkshire pigs were divided into four groups (n = 5 each): normothermic control (C), normothermic injured (I), hypothermic control (HC), and hypothermic injured (HI). Acute respiratory distress syndrome was induced experimentally via intrapulmonary injection of oleic acid. Target core temperature was achieved in the HI group within 1 h of injury induction. Cardiorespiratory, histologic, cytokine, and metabolomic data were collected on all animals prior to and following injury/sham. All data were collected for approximately 12 h from the beginning of the study until euthanasia. Therapeutic hypothermia reduced injury in the HI compared to the I group (histological injury score = 0.51 ± 0.18 vs. 0.76 ± 0.06; p = 0.02) with no change in gas exchange. All groups expressed distinct phenotypes, with a reduction in pro-inflammatory metabolites, an increase in anti-inflammatory metabolites, and a reduction in inflammatory cytokines observed in the HI group compared to the I group. Changes to respiratory system mechanics in the injured groups were due to increases in lung elastance (E) and resistance (R) (ΔE from pre-injury = 46 ± 14 cmH2 O L-1 , p < 0.0001; ΔR from pre-injury: 3 ± 2 cmH2 O L-1  s- , p = 0.30) rather than changes to the chest wall (ΔE from pre-injury: 0.7 ± 1.6 cmH2 O L-1 , p = 0.99; ΔR from pre-injury: 0.6 ± 0.1 cmH2 O L-1  s- , p = 0.01). Both control groups had no change in respiratory mechanics. In conclusion, therapeutic hypothermia can reduce markers of injury and inflammation associated with experimentally induced short-term ARDS.

Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear-mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)-dependency of CVR and cSMD. Eleven volunteers underwent a steady-state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG -monomethyl-l-arginine (l-NMMA) or volume-matched saline (placebo; single-blinded and counter-balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra-arterial blood pressure and PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ . Paired arterial and jugular venous blood sampling allowed for the determination of trans-cerebral NO2- exchange (ozone-based chemiluminescence). l-NMMA reduced arterial NO2- by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady-state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ ; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. -1.8 ± 8.2 nM/min at 120 s post-CO2 ; P = 0.044) shifted trans-cerebral NO2- exchange towards a greater net release (a negative value indicates release). Although this trans-cerebral NO2- release was abolished by l-NMMA, CVR did not differ between the saline and l-NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l-NMMA impact peak internal carotid artery dilatation during the steady-state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l-NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady-state CVR. Further, our novel transient CO2 test of cSMD is largely NO-dependent and provides an in vivo bioassay of NO-mediated cerebrovascular function in humans. KEY POINTS: Emerging evidence indicates that a transient CO2 stimulus elicits shear-mediated dilatation of the internal carotid artery, termed cerebral shear-mediated dilatation. Whether or not cerebrovascular reactivity to a steady-state CO2 stimulus is NO-dependent remains unclear in humans. During both a steady-state cerebrovascular reactivity test and a transient CO2 test of cerebral shear-mediated dilatation, trans-cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non-selective NO synthase inhibitor NG -monomethyl-l-arginine. NO synthase blockade did not alter cerebrovascular reactivity in the steady-state CO2 test; however, cerebral shear-mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG -monomethyl-l-arginine. NO is not obligatory for cerebrovascular reactivity to CO2 , but is a key contributor to cerebral shear-mediated dilatation.

Comprehensive Immune Profiling of a Kidney Transplant Recipient With Peri-Operative SARS-CoV-2 Infection: A Case Report.

To date there is limited data on the immune profile and outcomes of solid organ transplant recipients who encounter COVID-19 infection early post-transplant. Here we present a unique case where the kidney recipient's transplant surgery coincided with a positive SARS-CoV-2 test and the patient subsequently developed symptomatic COVID-19 perioperatively. We performed comprehensive immunological monitoring of cellular, proteomic, and serological changes during the first 4 critical months post-infection. We showed that continuation of basiliximab induction and maintenance of triple immunosuppression did not significantly impair the host's ability to mount a robust immune response against symptomatic COVID-19 infection diagnosed within the first week post-transplant.

Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post-Cardiac Arrest.

[Figure: see text].

Duraplasty in Traumatic Thoracic Spinal Cord Injury: Impact on Spinal Cord Hemodynamics, Tissue Metabolism, Histology, and Behavioral Recovery Using a Porcine Model.

After acute traumatic spinal cord injury (SCI), the spinal cord can swell to fill the subarachnoid space and become compressed by the surrounding dura. In a porcine model of SCI, we performed a duraplasty to expand the subarachnoid space around the injured spinal cord and evaluated how this influenced acute intraparenchymal hemodynamic and metabolic responses, in addition to histological and behavioral recovery. Female Yucatan pigs underwent a T10 SCI, with or without duraplasty. Using microsensors implanted into the spinal cord parenchyma, changes in blood flow (ΔSCBF), oxygenation (ΔPO2), and spinal cord pressure (ΔSCP) during and after SCI were monitored, alongside metabolic responses. Behavioral recovery was tested weekly using the Porcine Injury Behavior Scale (PTIBS). Thereafter, spinal cords were harvested for tissue sparing analyses. In both duraplasty and non-animals, the ΔSCP increased ∼5 mm Hg in the first 6 h post-injury. After this, the SCP appeared to be slightly reduced in the duraplasty animals, although the group differences were not statistically significant after controlling for injury severity in terms of impact force. During the first seven days post-SCI, the ΔSCBF or ΔPO2 values were not different between the duraplasty and control animals. Over 12 weeks, there was no improvement in hindlimb locomotion as assessed by PTIBS scores and no reduction in tissue damage at the injury site in the duraplasty animals. In our porcine model of SCI, duraplasty did not provide any clear evidence of long-term behavioral or tissue sparing benefit after SCI.

Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome.

Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 receptor (sIL-6R) in IL-6 trans-signaling and how understanding the IL-6:sIL-6R axis might help define and treat COVID-19 cytokine storm syndrome.

Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes.

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

The Association of Inflammatory Cytokines in the Pulmonary Pathophysiology of Respiratory Failure in Critically Ill Patients With Coronavirus Disease 2019.

OBJECTIVES: The majority of coronavirus disease 2019 mortality and morbidity is attributable to respiratory failure from severe acute respiratory syndrome coronavirus 2 infection. The pathogenesis underpinning coronavirus disease 2019-induced respiratory failure may be attributable to a dysregulated host immune response. Our objective was to investigate the pathophysiological relationship between proinflammatory cytokines and respiratory failure in severe coronavirus disease 2019. DESIGN: Multicenter prospective observational study. SETTING: ICU. PATIENTS: Critically ill patients with coronavirus disease 2019 and noncoronavirus disease 2019 critically ill patients with respiratory failure (ICU control group). INTERVENTIONS: Daily measurement of serum inflammatory cytokines. MEASUREMENTS AND MAIN RESULTS: Demographics, comorbidities, clinical, physiologic, and laboratory data were collected daily. Daily serum samples were drawn for measurements of interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor-α. Pulmonary outcomes were the ratio of Pao2/Fio2 and static lung compliance. Twenty-six patients with coronavirus disease 2019 and 22 ICU controls were enrolled. Of the patients with coronavirus disease 2019, 58% developed acute respiratory distress syndrome, 62% required mechanical ventilation, 12% underwent extracorporeal membrane oxygenation, and 23% died. A negative correlation between interleukin-6 and Pao2/Fio2 (rho, -0.531; p = 0.0052) and static lung compliance (rho, -0.579; p = 0.033) was found selectively in the coronavirus disease 2019 group. Diagnosis of acute respiratory distress syndrome was associated with significantly elevated serum interleukin-6 and interleukin-1ß on the day of diagnosis. CONCLUSIONS: The inverse relationship between serum interleukin-6 and Pao2/Fio2 and static lung compliance is specific to severe acute respiratory syndrome coronavirus 2 infection in critically ill patients with respiratory failure. Similar observations were not found with interleukin-ß or tumor necrosis factor-α.

Effects of Prone Position and Positive End-Expiratory Pressure on Noninvasive Estimators of ICP: A Pilot Study.

BACKGROUND: Prone positioning and positive end-expiratory pressure can improve pulmonary gas exchange and respiratory mechanics. However, they may be associated with the development of intracranial hypertension. Intracranial pressure (ICP) can be noninvasively estimated from the sonographic measurement of the optic nerve sheath diameter (ONSD) and from the transcranial Doppler analysis of the pulsatility (ICPPI) and the diastolic component (ICPFVd) of the velocity waveform. METHODS: The effect of the prone positioning and positive end-expiratory pressure on ONSD, ICPFVd, and ICPPI was assessed in a prospective study of 30 patients undergoing spine surgery. One-way repeated measures analysis of variance, fixed-effect multivariate regression models, and receiver operating characteristic analyses were used to analyze numerical data. RESULTS: The mean values of ONSD, ICPFVd, and ICPPI significantly increased after change from supine to prone position. Receiver operating characteristic analyses demonstrated that, among the noninvasive methods, the mean ONSD measure had the greatest area under the curve signifying it is the most effective in distinguishing a hypothetical change in ICP between supine and prone positioning (0.86±0.034 [0.79 to 0.92]). A cutoff of 0.43 cm was found to be a best separator of ONSD value between supine and prone with a specificity of 75.0 and a sensitivity of 86.7. CONCLUSIONS: Noninvasive ICP estimation may be useful in patients at risk of developing intracranial hypertension who require prone positioning.

Extracorporeal membrane oxygenation for adult respiratory distress syndrome in trauma patients: A case series and systematic literature review.

BACKGROUND: Venovenous extracorporeal membrane oxygenation (vv-ECMO) is an established salvage therapy for severe respiratory failure, and may provide an alternative form of treatment for trauma-induced adult respiratory distress syndrome (ARDS) when conventional treatments have failed. The need for systemic anticoagulation is a relative contraindication for patients with bleeding risks, especially in multitraumatic injury. METHODS: We describe a case series of four trauma patients with ARDS who were managed with ECMO admitted to the neuro critical care unit at Addenbrooke's Hospital, Cambridge (UK), from January 2000 to January 2016. We performed a systematic review of the available literature to investigate the safety and efficacy of vv-ECMO in posttraumatic ARDS, focusing on the use of different anticoagulation strategies and risk of bleeding on patients with multiple injuries. RESULTS: Thirty-one patients were included. A heparin bolus was given in 16 cases. Eleven patients developed complications during treatment with ECMO with three cases of major bleeding. In all documented cases of bleeding a bolus and infusion of heparin was administered, aiming for an activated clotting time (ACT) target longer than 150 seconds. Two patients treated with heparin-free ECMO developed thromboembolic complications. Four patients died, and death was never directly or indirectly related to use of ECMO. CONCLUSION: vv-ECMO can be lifesaving in respiratory failure. Our experience and our literature review suggest that vv-ECMO should be considered as a rescue treatment for the management of severe hypoxemic respiratory failure secondary to ARDS in trauma patients.For patients with a high risk of bleeding, the use of ECMO with no initial anticoagulation could be considered a valid option. For patients with a moderate risk of bleeding, use of a heparin infusion keeping an ACT target shorter than 150 seconds can be appropriate. LEVEL OF EVIDENCE: Therapeutic study, level V.

Effect of tidal volume and positive end-expiratory pressure on expiratory time constants in experimental lung injury.

We utilized a multicompartment model to describe the effects of changes in tidal volume (VT) and positive end-expiratory pressure (PEEP) on lung emptying during passive deflation before and after experimental lung injury. Expiratory time constants (τE) were determined by partitioning the expiratory flow-volume (V˙EV) curve into multiple discrete segments and individually calculating τE for each segment. Under all conditions of PEEP and VT, τE increased throughout expiration both before and after injury. Segmented τE values increased throughout expiration with a slope that was different than zero (P < 0. 01). On average, τE increased by 45.08 msec per segment. When an interaction between injury status and τE segment was included in the model, it was significant (P < 0.05), indicating that later segments had higher τE values post injury than early τE segments. Higher PEEP and VT values were associated with higher τE values. No evidence was found for an interaction between injury status and VT, or PEEP. The current experiment confirms previous observations that τE values are smaller in subjects with injured lungs when compared to controls. We are the first to demonstrate changes in the pattern of τE before and after injury when examined with a multiple compartment model. Finally, increases in PEEP or VT increased τE throughout expiration, but did not appear to have effects that differed between the uninjured and injured state.

c-MYC antisense phosphosphorodiamidate morpholino oligomer inhibits lung metastasis in a murine tumor model.

BACKGROUND: c-MYC amplification and overexpression has been correlated with progression and chemotherapy resistance in lung cancer. AVI-4126, a neutral antisense phosphorodiamidate morpholino oligomer (PMO) has been identified to specifically inhibit c-MYC expression in multiple disease models and identified in Phase I clinical studies to be safe and bioavailable in solid tumors. The present study evaluates AVI-4126 on the development of lung metastasis in the LLC1 syngeneic murine tumor model. Further, this is the first study to show in vivo mis-splicing of c-MYC post-AVI-4126 treatment. METHODS AND RESULTS: Subcutaneous administration of AVI-4126 at local tumor site (50 microg/day) for 3 cycles of 5 days a week starting day 1 post-tumor cell implantation showed significantly decreased tumor burden, number of tumorlets formed in the lung in comparison to saline or control PMO treatment groups, although no significant reduction of the subcutaneous tumor was observed. AVI-4126 treated lung had markedly reduced mitotic activity but higher rate of apoptosis compared to the controls. HPLC-based analysis of tumor and lung lysates confirmed the presence of intact PMO. In addition to decrease in c-MYC expression, a moderate reduction in the levels of MMP-9 mRNA, a pro-angiogenic extracellular matrix protein postulated to be involved in extravasation of cells from the localized tumor or implantation into the distant metastatic site was observed in the LLC1 tumor tissue of AVI-4126 treated animals. CONCLUSIONS: The study results are significant in the development of novel anti-tumoral therapeutic strategies directed to c-MYC-overexpressing tumors and establish AVI-4126 as a strong clinical candidate for metastatic disease.

Vascular surgery training, exposure, and knowledge during general surgery residency: implications for the future.

BACKGROUND: Vascular surgery (VS) has been removed from the Canadian general surgery (GS) objectives and has become a primary certificate specialty in the United States, leaving its status in GS uncertain. The purpose of this study was to determine GS residents' perceived competence in VS and to assess their knowledge of VS. METHODS: GS residents at a university-based program answered (1) a survey of attitudes and experience in VS and (2) a short-answer examination to assess fundamental vascular knowledge. RESULTS: Twenty-nine of 35 residents participated (83%). Residents reported being inadequately trained in 10 of 13 procedures surveyed despite 6 of these being reported as essential. Although 26 of 29 residents reported an intention to perform vascular procedures, none planned on pursuing a fellowship. The mean examination score was 47%. CONCLUSIONS: Despite mandatory VS rotations, GS residents feel inadequately trained in VS and have marginal knowledge. Current trainees may lack the skills and abilities to deal with vascular emergencies.