Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study.

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.

The Diagnostic Accuracy of Noninvasive Methods to Measure the Intracranial Pressure: A Systematic Review and Meta-analysis.

BACKGROUND: Although invasive monitoring is the standard method for intracranial pressure (ICP) measurement, it is not without potential for serious complications. Noninvasive methods have been proposed as alternatives to invasive ICP monitoring. The study aimed to investigate the diagnostic accuracy of the currently available noninvasive methods for intracranial hypertension (ICH) monitoring. METHODS: We searched 5 databases for articles evaluating the diagnostic accuracy of noninvasive methods in diagnosing ICH in PubMed, Institute of Science Index, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase. The quantitative analysis was conducted if there were at least 2 studies evaluating a specific method. The accuracy measures included the sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. RESULTS: We included 134 articles. Ultrasonographic optic nerve sheath diameter (US ONSD) had high diagnostic accuracy (estimated sensitivity of 90%; 95% confidence interval [CI], 87-92, estimated specificity of 88%; 95% CI, 84-91) while the magnetic resonance imaging (MRI) ONSD had estimated sensitivity of 77%; 95% CI, 64-87 and estimated specificity of 89%; 95% CI, 84-93, and computed tomography (CT) ONSD had estimated sensitivity of 93%; 95% CI, 90-96 and estimated specificity of 79%; 95% CI, 56-92. All MRI signs had a very high estimated specificity ranging from 90% to 99% but a low estimated sensitivity except for sinus stenosis which had high estimated sensitivity as well as specificity (90%; 95% CI, 75-96 and 96%; 95% CI, 91-99, respectively). Among the physical examination signs, pupillary dilation had a high estimated specificity (86%; 95% CI, 76-93). Other diagnostic tests to be considered included pulsatility index, papilledema, transcranial Doppler, compression or absence of basal cisterns, and ≥10 mm midline shift. Setting the cutoff value of ICH to ≥20 mm Hg instead of values <20 mm Hg was associated with higher sensitivity. Moreover, if the delay between invasive and noninvasive methods was within 1 hour, the MRI ONSD and papilledema had a significantly higher diagnostic accuracy compared to the >1 hour subgroup. CONCLUSIONS: Our study showed several promising tools for diagnosing ICH. Moreover, we demonstrated that using multiple, readily available, noninvasive methods is better than depending on a single sign such as physical examination or CT alone.

Timing of Tracheostomy in Pediatric Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: Tracheostomy is a very common clinical intervention in critically ill adult patients. The indications for tracheostomy procedures in pediatric patients with complex conditions have increased dramatically in recent years, but there are currently no guidelines on the optimal timing of tracheostomy in pediatric patients undergoing prolonged ventilation. DATA SOURCES: We performed a systematic search of the existing literature in MEDLINE via PubMed and Embase databases and the Cochrane Library to identify clinical trials, observational studies, and cohort studies that compare early and late tracheostomy in children. The date of the last search was August 27, 2018. Included articles were subjected to manual searching. STUDY SELECTION: Studies in mechanically ventilated children that compared early with late tracheostomy were included. DATA EXTRACTION: Data were extracted into a spreadsheet and copied into Review Manager 5.3 (The Cochrane Collaboration, Copenhagen, Denmark). DATA SYNTHESIS: Data were meta-analyzed using an inverse variance, random effects model. Continuous outcomes were calculated as mean differences with 95% CIs, and dichotomous outcomes were calculated as Mantel-Haenszel risk ratios with 95% CIs. We included eight studies (10 study arms). These studies were all retrospective cohort studies. Early tracheostomy was associated with significant reductions in mortality, days on mechanical ventilation, and length of intensive care and total hospital stay, although the lack of randomized, controlled trials limits the validity of these findings. Although variance was imputed for some studies, these conclusions did not change after removing these studies from the analysis. CONCLUSIONS: In children on mechanical ventilation, early tracheostomy may improve important medical outcomes. However, our data demonstrate the urgent need for high-quality, randomized controlled trials in the pediatric population.

The validity of central venous to arterial carbon dioxide difference to predict adequate fluid management during living donor liver transplantation. A prospective observational study.

BACKGROUND: To assess the validity of central and pulmonary veno-arterial CO2 gradients to predict fluid responsiveness and to guide fluid management during liver transplantation. METHODS: In adult recipients (ASA III to IV) scheduled for liver transplantation, intraoperative fluid management was guided by pulse pressure variations (PPV). PPV of ≥15% (Fluid Responding Status-FRS) indicated fluid resuscitation with 250 ml albumin 5% boluses repeated as required to restore PPV to < 15% (Fluid non-Responding Status-FnRS). Simultaneous blood samples from central venous and pulmonary artery catheters (PAC) were sent to calculate central venous to arterial CO2 gap [C(v-a) CO2 gap] and pulmonary venous to arterial CO2 gap [Pulm(p-a) CO2 gap]. CO and lactate were also measured. RESULTS: Sixty seven data points were recorded (20 FRS and 47 FnRS). The discriminative ability of central and pulmonary CO2 gaps between the two states (FRS and FnRS) was poor with AUC of ROC of 0.698 and 0.570 respectively. Central CO2 gap was significantly higher in FRS than FnRS (P = 0.016), with no difference in the pulmonary CO2 gap between both states. The central and Pulmonary CO2 gaps are weakly correlated to PPV [r = 0.291, (P = 0.017) and r = 0.367, (P = 0.002) respectively]. There was no correlation between both CO2 gaps and both CO and lactate. CONCLUSION: Central and the Pulmonary CO2 gaps cannot be used as valid tools to predict fluid responsiveness or to guide fluid management during liver transplantation. CO2 gaps also do not correlate well with the changes in PPV or CO. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03123172 . Registered on 31-march-2017.

Effect of ultrafiltration on extravascular lung water assessed by lung ultrasound in children undergoing cardiac surgery: a randomized prospective study.

BACKGROUND: Increased lung water and the resultant atelectasis are significant pulmonary complications after cardiopulmonary bypass (CPB) in children undergoing cardiac surgery; these complications are observed after CPB than after anaesthesia alone. Ultrafiltration has been shown to decrease total body water and postoperative blood loss and improve the alveolar to arterial oxygen gradient and pulmonary compliance. This study investigated whether conventional ultrafiltration during CPB in paediatric heart surgeries influences post-bypass extravascular lung water (EVLW) assessed by lung ultrasound (LUS). METHODS: This randomized controlled study included 60 patients with congenital heart disease (ASA II-III), aged 1 to 48 months, with a body weight > 3 kg. Conventional ultrafiltration targeting a haematocrit (HCT) level of 28% was performed on the ultrafiltration group, while the control group did not receive ultrafiltration. LUS scores were recorded at baseline and at the end of surgery. The PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen), urine output, and haemodynamic parameters were also recorded. RESULTS: LUS scores were comparable between the two groups both at baseline (p = 0.92) and at the end of surgery (p = 0.95); however, within the same group, the scores at the end of surgery significantly differed from their baseline values in both the ultrafiltration (p = 0.01) and non-ultrafiltration groups (p = 0.02). The baseline PaO2/FiO2 ratio was comparable between both groups. at the end of surgery, The PaO2/FiO2 ratio increased in the ultrafiltration group compared to that in the non-ultrafiltration group, albeit insignificant (p = 0.16). no correlation between the PaO2/FiO2 ratio and LUS score was found at baseline (r = - 0.21, p = 0.31). On the other hand, post-surgical measurements were negatively correlated (r = - 0.41, p = 0.045). CONCLUSION: Conventional ultrafiltration did not alter the EVLW when assessed by LUS and oxygenation state. Similarly, ultrafiltration did not affect the urea and creatinine levels, intensive care unit (ICU) stays, ventilation days, or mortality. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03146143 registered on 29-April-2017.

Mitral Valve Compression Induced Hypoxemia After Left Ventricular Assist Device Surgery: A Case Report.

Blood flow obstruction of left ventricular assist device (LVAD) is not uncommon. Causes of flow obstructions could be prepump, intrapump, and postpump. Clinical and echocardiographic parameters of LVAD obstruction vary substantially, ranging from being completely asymptomatic with unchanged functional status, normal filling pressures to frank cardiogenic shock. In the current case report, we present hypoxemia as an early presentation of LVAD inflow obstruction in the early postimplantation period in the absence of respiratory cause for hypoxemia.

Effect of Dexmedetomidine Infusion on Sublingual Microcirculation in Patients Undergoing On-Pump Coronary Artery Bypass Graft Surgery: A Prospective Randomized Trial.

OBJECTIVES: Cardiac surgery is characterized by attenuation of microcirculatory perfusion. Dexmedetomidine has been proved to attenuate the microcirculatory derangements evoked by experimental sepsis. The authors investigated the effects of dexmedetomidine infusion on sublingual microcirculation in patients undergoing on-pump coronary artery bypass graft (CABG) surgery. DESIGN: Prospective, randomized blinded study. SETTINGS: Tertiary university hospital. PARTICIPANTS: A total of 70 adults undergoing elective on-pump CABG surgery. INTERVENTION: After a standard general anesthesia, participants were allocated randomly to receive either propofol continuous intravenous infusion, 50 to 70 µg/kg/min, or propofol infusion, 50 to 70 µg/kg/min plus dexmedetomidine infusion, 0.5 µg/kg/h, during cardiopulmonary bypass. Microcirculation was studied with side-stream dark field imaging at 3 times: immediately before starting bypass (T0), 30 minutes after initiation of bypass (T1), and 30 minutes after weaning from bypass (T2). MEASUREMENTS AND MAIN RESULTS: Microvascular flow index was significantly higher in the dexmedetomidine group at T2 compared to the control group (2.20 ± 0.29 and 1.47 ± 0.30, respectively; p = 0.001). The perfused vessel density was significantly higher in the dexmedetomidine group at T2 compared to the control group (6.1 [3-8.9] mm/mm² and 3.3 [2.2-4.3] mm/mm², respectively; p = 0.01). The total vascular density was significantly higher in the dexmedetomidine group compared to the control group at T1 and T2 (9.9 [7.8-12.6] mm/mm² v 7.4 [6.1-9] mm/mm², p = 0.005; and 9.27 ± 2.27 mm/mm² v 7.24 ± 1.66 mm/mm², p = 0.003, respectively). CONCLUSION: This trial demonstrated that dexmedetomidine infusion improved sublingual microcirculation indices in patients undergoing on-pump CABG surgery.

Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache: A Randomized Controlled Trial.

BACKGROUND: Postdural puncture headache (PDPH) lacks a standard evidence-based treatment. A patient treated with neostigmine for severe PDPH prompted this study. METHODS: This randomized, controlled, double-blind study compared neostigmine and atropine (n = 41) versus a saline placebo (n = 44) for treating PDPH in addition to conservative management of 85 patients with hydration and analgesics. The primary outcome was a visual analog scale score of ≤3 at 6, 12, 24, 36, 48, and 72 hours after intervention. Secondary outcomes were the need for an epidural blood patch, neck stiffness, nausea, and vomiting. Patients received either neostigmine 20 µg/kg and atropine 10 µg/kg or an equal volume of saline. RESULTS: Visual analog scale scores were significantly better (P< .001) with neostigmine/atropine than with saline treatment at all time intervals after intervention. No patients in the neostigmine/atropine group needed epidural blood patch compared with 7 (15.9%) in the placebo group (P< .001). Patients required no >2 doses of neostigmine/atropine. There were no between-group differences in neck stiffness, nausea, or vomiting. Complications including abdominal cramps, muscle twitches, and urinary bladder hyperactivity occurred only in the neostigmine/atropine group (P< .001). CONCLUSIONS: Neostigmine/atropine was effective in treating PDPH after only 2 doses. Neostigmine can pass the choroid plexus but not the blood-brain barrier. The central effects of both drugs influence both cerebrospinal fluid secretion and cerebral vascular tone, which are the primary pathophysiological changes in PDPH. The results are consistent with previous studies and clinical reports of neostigmine activity.

Comparative Study Between Conventional Fasting Versus Overnight Infusion of Lipid or Carbohydrate on Insulin and Free Fatty Acids in Obese Patients Undergoing Elective On-pump Coronary Artery Bypass Grafting. A Prospective Randomized Trial.

OBJECTIVES: Postoperative insulin resistance represents a major component of postoperative metabolic disorder. The authors compared the effects of preoperative infusion of lipid emulsion or carbohydrate to conventional preoperative fasting on postoperative insulin and free fatty acid (FFA) levels. DESIGN: A prospective randomized double-blinded study. SETTINGS: Tertiary university hospital. PARTICIPANTS: Sixty-three patients undergoing coronary artery bypass grafting. INTERVENTION: Participants were randomized into 3 equal groups. Group G received 500 mL of glucose 10% (50 g glucose). Group L received 100 mL of 2% lipid emulsion (soybean 30%, medium chain triglycerides (TG) 30%, olive oil 25%, fish oil 15%, and 20 mg vitamin E). Group C fasted overnight except for clear fluids allowed until 4 hours preoperatively. Serum insulin at the start of infusion (T1), 1-hour preinduction (T2), on admission to the intensive care unit (T3), after 24 hours of admission (T4), and after 48 hours of admission (T5), and FFA at T1 and T2 were measured. Serum very-low-density lipoprotein (VLDL), serum TG, and blood sugar were all measured (T1-T4). Bypass time, ischemic time, need for inotropic support, and length of intensive care unit stay also were measured. MEASUREMENTS AND MAIN RESULTS: At the end of infusion FFAs were significantly lower in the L group (1.1 ± 0.76 mg/dL) compared with G (1.64 ± 0.85 mg/dL) and C groups (1.48 ± 0.76 mg/dL). Insulin levels were significantly lower in the L group compared with levels in the G and C groups at T2, T3, and T4. Also, TG, VLDL, and random blood sugar levels decreased significantly at T2, T3, and T4 in the L group compared with the other 2 groups and compared with baseline value within the same group. CONCLUSION: Preoperative lipid infusion lowered postoperative FFA, insulin, TG, VLDL, and random blood sugar in obese patients undergoing coronary artery bypass grafting surgeries.

Impact of immediate versus delayed tracheal extubation on length of ICU stay of cardiac surgical patients, a randomized trial.

INTRODUCTION: Ultra-fast track anaesthesia aims at immediate extubation of cardiac surgical patients at the end of the operation. This study compares the effect of ultrafast track anesthesia versus continued postoperative mechanical ventilation on the intensive care unit length of stay. METHODS: Fifty-two elective adult patients were randomly allocated into ultrafast track anaesthesia and conventional groups by computer-generated random numbers. Redo operations, pre-operative intubation, uncontrolled diabetes, shock/left ventricular ejection fraction < 45%, pulmonary artery systolic pressure >55mmHg, creatinine clearance -1, haemodynamic instability, or those with concerns of postoperative bleeding were excluded. Pre- and intra-operative management was similar and Logistic EuroSCORE II was calculated for all. Intra-operatively, haemodynamic parameters, urine output, oxygen saturation, arterial blood gas analysis, 5-lead electrocardiogram, operative bypass- and cross-clamp time, and opioid consumption were collected. Postoperatively, patients were compared during their intensive care unit stay. Data were analysed by χ²/Fischer exact, unpaired student's t-test, univariate two-group repeated measures with post hoc Dunnett's test, and Mann-Whitney U tests as appropriate. p < 0.05 was considered significant. RESULTS: Patients were comparable regarding their peri-operative characteristics and EuroSCORE. The intensive care unit stay was shorter in the ultrafast track anaesthesia group [57.4 (18.6) vs. 95 (33.6) h. p < 0.001], without increasing postoperative renal, respiratory complications rate or reopening rate. CONCLUSIONS: In this single center study, ultrafast track anaesthesia decreased intensive care unit stay without increasing the rate of post-operative complications.

Combined lidocaine 1% and hydroxypropyl methylcellulose 2.25% as a single anesthetic/ viscoelastic agent in phacoemulsification.

PURPOSE: To evaluate the use of a mixture of hydroxypropyl methylcellulose 2.25% (HPMC) and lidocaine 1% (final concentrations) as a single viscoelastic/anesthetic agent to achieve proper anesthesia and viscoelastic properties during phacoemulsification. SETTINGS: Department of Ophthalmology, Cairo University, Cairo, Egypt. METHODS: This prospective randomized study comprised 70 eyes having routine phacoemulsification. Patients had the HPMC-lidocaine mixture (n = 35) or pure HPMC 2.25% (n = 35) injected before capsulorhexis and again before intraocular lens implantation. The results were evaluated by a pain/discomfort score postoperatively. RESULTS: The difference in medians of the overall intraoperative pain/discomfort scores between the 2 groups was not statistically significant. However, mild pain/discomfort was reported by 60.0% in the pure HPMC group and by 31.4% in the HPMC-lidocaine mixture group. Moderate pain/discomfort was reported by 28.6% and 5.7%, respectively. The difference between the 2 groups was statistically significant (P =.001). CONCLUSION: The use of a mixture of HPMC 2.25% and lidocaine 1% rather than a regular viscoelastic agent resulted in clinically and statistically significantly reduced pain/discomfort during phacoemulsification.