Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Thromboelastometry and Platelet Function during Acclimatization to High Altitude.

Interaction between hypoxia and coagulation is important given the increased risk of thrombotic diseases in chronically hypoxic patients who reside at sea level and in residents at high altitude. Hypoxia alters the proteome of platelets favouring a prothrombotic phenotype, but studies of activation and consumption of specific coagulation factors in hypoxic humans have yielded conflicting results. We tested blood from 63 healthy lowland volunteers acclimatizing to high altitude (5,200 m) using thromboelastometry and assays of platelet function to examine the effects of hypoxia on haemostasis. Using data from two separate cohorts of patients following identical ascent profiles, we detected a significant delay in clot formation, but increased clot strength by day 7 at 5,200 m. The latter finding may be accounted for by the significant rise in platelet count and fibrinogen concentration that occurred during acclimatization. Platelet function assays revealed evidence of platelet hyper-reactivity, with shortened PFA-100 closure times and increased platelet aggregation in response to adenosine diphosphate. Post-expedition results were consistent with the normalization of coagulation following descent to sea level. These robust findings indicate that hypoxia increases platelet reactivity and, with the exception of the paradoxical delay in thromboelastometry clotting time, suggest a prothrombotic phenotype at altitude. Further work to elucidate the mechanism of platelet activation in hypoxia will be important and could impact upon the management of patients with acute or chronic hypoxic respiratory diseases who are at risk of thrombotic events.

Contemporary outcomes of open repair of thoracoabdominal aortic aneurysm in young patients.

BACKGROUND: Endovascular technology now permits total endovascular thoracoabdominal aortic aneurysm (TAAA) repair with high volume centres reporting encouraging results. The long-term durability of such stent grafts is unknown, leading to concerns regarding their use in younger patients. This study reports contemporary outcomes of open repair in young patients. METHODS: Outcomes for patients age 60 or younger undergoing open TAAA repair between June 1999 and August 2013 with prospective collected data were analysed retrospectively. RESULTS: Thirty-seven patients (31 men, 84%) with a median age of 56 (range 22-60) were identified with a median TAAA diameter of 6.9 cm (range 5.6-11). Aneurysm aetiology included degenerative change (18), dilation of chronic dissection (10), connective tissue disease (7) and mycotic degeneration (2). Crawford Type IV TAAA were most commonly treated (17), followed by Type II (10), Type III (7) and Type I (3). Two (5%) patients died in hospital, one from multiple organ failure and one from respiratory failure. Three patients (8%) developed temporary paraplegia, all of whom made a complete recovery and 4 (11%) patients required temporary renal replacement therapy. Median critical care stay was 5 days (range 2-28) with an in-hospital stay of 14 days (range 7-83). During a median follow-up of 72 months (range 13-171), no patient subsequently required any further aneurysm related surgical or radiological intervention. The mean (SEM) survival time was 138.5 (11) months. The 5 year survival was 79.7% (8.3) including early deaths, with no aneurysm related complications. CONCLUSIONS: The outcome of open TAAA repair in patients aged less than 60 years is favorable. It is against these results that evolving endovascular interventions must be compared.

Rotational thrombolelastometry produces potentially clinical useful results within 10 min in bleeding emergency department patients: the DEUCE study.

OBJECTIVES AND BACKGROUND: For the first time in the Emergency Department (ED), to assess the use of rotational thromboelastometry (ROTEM) in patients presenting with all-cause haemodynamic shock, specifically (a) to establish whether a 5- min (A5) or a 10-min result (A10) is accurate compared with a final maximum clot firmness (MCF) result; (b) to compare time to A10 and formal laboratory coagulation result; (c) to assess whether bleeding ED trauma, gastrointestinal and aortic aneurysm patients are coagulopathic according to ROTEM; and (d) to compare ROTEM results with formal laboratory coagulation parameters. METHODS: Patients presenting to the ED in haemodynamic shock were recruited. A citrated coagulation sample was taken and once a ROTEM researcher arrived in the ED, was subjected to ROTEM analysis. RESULTS: Between 28 September 2010 and 31 August 2011, 40 patients were recruited (15 gastrointestinal bleeds, 20 major trauma cases and five ruptured abdominal aortic aneurysms). A10 and MCF correlated well (κ=0.98); A5 and MCF correlated less well (κ=0.91). The mean time to result (SD) was 57 (28) min for the formal laboratory coagulation result and 50 (45) min for the ROTEM A10 result (including delay to start of analysis). Seven patients were coagulopathic on ROTEM. CONCLUSION: Eighteen percent of bleeding ED patients are coagulopathic using ROTEM including 25% of trauma patients. A 10-min ROTEM clot firmness (A10) is an excellent surrogate for MCF and allows a result to be obtained earlier than formal laboratory results and potentially within 10 min of the patient arriving in the ED.

Perioperative platelet and monocyte activation in patients with critical limb ischemia.

BACKGROUND: Patients with critical limb ischemia (CLI) have a high rate of adverse cardiovascular events, particularly when undergoing surgery. We sought to determine the effect of surgery and vascular disease on platelet and monocyte activation in vivo in patients with CLI. METHODS: An observational, cross-sectional study was performed at a tertiary referral hospital in the southeast of Scotland. Platelet and monocyte activation were measured in whole blood in patients with CLI scheduled for infrainguinal bypass and compared with matched healthy controls, patients with chronic intermittent claudication, patients with acute myocardial infarction, and those undergoing arthroplasty (n = 30 per group). Platelet and monocyte activation were quantified using flow cytometric assessment of platelet-monocyte aggregation, platelet P-selectin expression, platelet-derived microparticles, and monocyte CD40 and CD11b expression. RESULTS: Compared with those with intermittent claudication, subjects with CLI had increased platelet-monocyte aggregates (41.7% +/- 12.2% vs 32.6% +/- 8.5%, respectively), platelet microparticles (178.7 +/- 106.9 vs 116.9 +/- 53.4), and monocyte CD40 expression (70.0% +/- 12.2% vs 52.4% +/- 15.2%; P < .001 for all). Indeed, these levels were equivalent (P-selectin, 4.4% +/- 2.0% vs 4.9% +/- 2.2%; P > .05) or higher (platelet-monocyte aggregation, 41.7% +/- 12.2% vs 33.6% +/- 7.0%; P < .05; platelet microparticles, 178.7 +/- 106.9 vs 114.4 +/- 55.0/microL; P < .05) than in patients with acute myocardial infarction. All platelet and monocyte activation markers remained elevated throughout the perioperative period in patients with CLI (P < .01) but not those undergoing arthroplasty. CONCLUSIONS: Patients undergoing surgery for CLI have the highest level of in vivo platelet and monocyte activation, and these persist throughout the perioperative period. Additional antiplatelet therapy may be of benefit in protecting vascular patients with more severe disease during this period of increased risk.

Randomized controlled trial of dual antiplatelet therapy in patients undergoing surgery for critical limb ischemia.

BACKGROUND AND OBJECTIVE: Patients with critical limb ischemia have a perioperative cardiovascular morbidity comparable to patients with acute coronary syndromes. We hypothesized that perioperative dual antiplatelet therapy would improve biomarkers of atherothrombosis without causing unacceptable bleeding in patients undergoing surgery for critical limb ischemia. METHODS: In a double-blind randomized controlled trial, 108 patients undergoing infrainguinal revascularization or amputation for critical limb ischemia were maintained on aspirin (75 mg daily) and randomized to clopidogrel (600 mg prior to surgery, and 75 mg daily for 3 days; n = 50) or matched placebo (n = 58). Platelet activation and myocardial injury were assessed by flow cytometry and plasma troponin concentrations, respectively. RESULTS: Clopidogrel reduced platelet-monocyte aggregation before surgery (38%-30%; P = 0.007). This was sustained in the postoperative period (P = 0.0019). There were 18 troponin-positive events (8 [16.0%] clopidogrel vs. 10 [17.2%] placebo; relative risk [RR]: 0.93, 95% confidence interval [CI]: 0.39-2.17; P = 0.86). Half of troponin-positive events occurred preoperatively with clopidogrel causing a greater decline in troponin concentrations (P < 0.001). There was no increase in major life-threatening bleeding (7 [14%] vs. 6 [10%]; RR: 1.4, 95% CI: 0.49-3.76; P = 0.56) or minor bleeding (17 [34%] vs. 12 [21%]; RR 1.64, 95% CI: 0.87-3.1; P = 0.12), although blood transfusions were increased (28% vs. 12.6%, RR: 2.3, 95% CI: 1.0-5.29; P = 0.037). CONCLUSIONS: In patients with critical limb ischemia, perioperative dual antiplatelet therapy reduces biomarkers of atherothrombosis without causing unacceptable bleeding. Large-scale randomized controlled trials are needed to establish whether dual antiplatelet therapy improves clinical outcome in high-risk patients undergoing vascular surgery.

A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation.

Persistent pain has been reported in up to 80% of patients after limb amputation. The mechanisms are not fully understood, but nerve injury during amputation is important, with evidence for the crucial involvement of the spinal N-methyl d-aspartate (NMDA) receptor in central changes. The study objective was to assess the effect of pre-emptively modulating sensory input with epidural ketamine (an NMDA antagonist) on post-amputation pain and sensory processing. The study recruited 53 patients undergoing lower limb amputation who received a combined intrathecal/epidural anaesthetic for surgery followed by a randomised epidural infusion (Group K received racemic ketamine and bupivacaine; Group S received saline and bupivacaine). Neither general anaesthesia nor opioids were used during the peri-operative period. Pain characteristics were assessed for 12 months. The primary endpoint was incidence and severity of post-amputation pain. Persistent pain at one year was much less in both groups than in comparable studies, with no significant difference between groups (Group K=21% (3/14) and 50% (7/14); and Group S=33% (5/15) and 40% (6/15) for stump and phantom pain, respectively). Post-operative analgesia was significantly better in Group K, with reduced stump sensitivity. The intrathecal/epidural technique used, with peri-operative sensory attenuation, may have reduced ongoing sensitisation, reducing the overall incidence of persistent pain. The improved short-term analgesia and reduced mechanical sensitivity in Group K may reflect acute effects of ketamine on central sensitisation. Longer term effects on mood were detected in Group K that requires further study.

Automatic CPAP compared with conventional treatment for episodic hypoxemia and sleep disturbance after major abdominal surgery.

BACKGROUND: After major surgery, analgesia with opioids can cause obstructive apnea and intermittent hypoxemia, probably from loss of upper airway control. Since this resembles the obstructive sleep apnea syndrome, we tested the possibility that nasal continuous positive airway pressure (nCPAP) would reduce episodes of reduced oxygen saturation and sleep disruption. Because oxygen therapy is frequent after surgery, we also assessed the effect of oxygen on sleep disruption. METHODS: We recruited 48 patients about to have major abdominal surgery. We present data for 34 patients: 27 who received patient-controlled intravenous morphine and 7 who received epidural opioid. Treatment was randomized to either nCPAP or conventional therapy with an oxygen mask. Alternate periods of administration of air and 35% oxygen were used in both groups. If the oxygen saturation as measured by pulse oximetry was consistently <90% on air, the patient was withdrawn from the study. We measured sleep, arousals, oxygenation, episodes of desaturation, and disturbances of respiration. Values are given as median and quartiles. RESULTS: The median proportion of time awake was 65% (45-79%) among control patients and 74% (55-87%) among those undergoing nCPAP. Oxygen administration did not affect the sleep pattern. The median frequency of arousals per hour of sleep was very similar in each group: during air breathing from nCPAP, 125 (76-187), and during air breathing by mask, 116 (84-187). Oxygen therapy had no effect. Oxygenation and hypoxemic events were not improved by nCPAP. Oxygen therapy improved oxygenation and reduced but did not eliminate episodes of desaturation. CONCLUSIONS: Nasal CPAP does not improve sleep and oxygenation or reduce hypoxemic events in the first night after major abdominal surgery.