Day 4 vs. day 12 G-CSF administration following reduced intensity peripheral blood allogeneic stem cell transplant.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis. METHODS: We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017-2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis. RESULTS: Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19-32) with day + 4 initiation vs. 24 days (21-30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups. CONCLUSION: Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.

Clinical and In Vitro Evidence That Subclinical Hemolysis Contributes to LVAD Thrombosis.

BACKGROUND: Recent data suggest that hemolysis contributes to left ventricular assist device (LVAD) thrombosis, but the mechanism is unknown. In a clinical study, we measured plasma free hemoglobin (pfHgb) and the incidence of LVAD thrombosis. In an in vitro study, we examined biophysical relationships between shear stress, pfHgb and von Willebrand factor (vWF) metabolism toward understanding mechanisms of LVAD thrombosis. METHODS: In the clinical study, blood samples were obtained from continuous-flow LVAD patients (n = 30). Plasma free hemoglobin was measured via enzyme-linked immunosorbent assay. Plasma lactate dehydrogenase (LDH) was measured with a fluorimetric assay. In the in vitro study, to investigate mechanism, human plasma (n = 10) was exposed to LVAD-like shear stress (175 dyne/cm2) with and without free hemoglobin (30 mg/dL). ADAMTS-13 (the vWF protease) activity was quantified with Förster resonance energy transfer. vWF size was quantified with immunoblotting. vWF clotting function was quantified with an enzyme-linked immunosorbent assay. RESULTS: In the clinical study, LVAD support caused subclinical hemolysis. In all patients, LDH increased significantly from 213 ± 9 U/L to 366 ± 31 U/L at 10 days of support (p < 0.0001) and remained significantly elevated at 280 ± 18 U/L at 1 month of support (p < 0.01). In 21 patients that did not develop LVAD thrombosis, pfHgb increased early but decreased over time (pre-LVAD: 5.2 ± 0.8 mg/dL; 1 week: 19.8 ± 4.4 mg/dL, p < 0.01; 3 months: 9.3 ± 2.2 mg/dL, p = 0.07). In 9 patients that developed LVAD thrombosis, pfHgb was significantly elevated versus patients without thrombosis before (p < 0.001) and after 3 months (p < 0.05) of support (pre-LVAD: 20.2 ± 6.3 mg/dL; 1 week: 17.3 ± 3.7 mg/dL; 3 months: 21.5 ± 7.8 mg/dL). Similarly, after 3 months, patients that did not develop LVAD thrombosis had an LDH of 271 ± 28 U/L, whereas patients that later developed LVAD thrombosis had a significantly higher LDH of 625 ± 210 U/L (p = 0.02). In the in vitro study, shear stress degraded vWF similarly to an LVAD. Free hemoglobin inhibited ADAMTS-13 activity during shear stress (633 ± 27 ng/mL to 565 ± 24 ng/mL; p < 0.001). vWF was thereby protected from degradation, 4 vWF fragments decreased significantly (p ≤ 0.05), and vWF clotting function increased (1.15 ± 0.09 U/mL to 1.29 ± 0.09 U/mL, p = 0.06). CONCLUSIONS: These are the first data to demonstrate mechanistic relationships between subclinical hemolysis and a procoagulant state during continuous-flow LVAD support. Patients with high pfHgb and LDH were more likely to develop LVAD thrombosis. In vitro experiments demonstrated that free hemoglobin inhibited ADAMTS-13, protected vWF from degradation, increased vWF clotting function, and created a procoagulant state. As such, pfHgb may be a clinical target to prevent LVAD thrombosis.

Pain, Agitation, and Delirium Guidelines: Interprofessional Perspectives to Translate the Evidence.

BACKGROUND: Societal guidelines exist for the management of pain, agitation, and delirium (PAD) in critically ill patients. This contemporary practice aims for a more awake and interactive patient. Institutions are challenged to translate the interrelated multivariable concepts of PAD into daily clinical practice and to demonstrate improvement in quality outcomes. An interdisciplinary goal-directed approach shows outcomes in high-acuity surgical critical care during the early stages of implementation. METHODS: This study was a prospective preintervention and postintervention design. A formal PAD clinical practice guideline targeting standardized assessment and "light" levels of sedation was instituted. All mechanically ventilated patients admitted to a 24-bed surgical intensive care unit (ICU) at an academic medical center during a 6-month period were included (3 months before and 3 months after implementation). Sedation and agitation were measured using the Richmond Agitation Sedation Scale (RASS), pain measured using a Behavioral or Numeric Pain Scale (NPS/BPS), and delirium using the Confusion Assessment Method for the Intensive Care Unit. Total ventilator days with exposure to continuous opioid or sedative infusions and total ICU days where the patient received a physical activity session exercising out of bed were recorded. RESULTS: There were 106 patients (54 at preintervention and 52 at postintervention). Mean percentage of RASS scores between 0 to -1 increased from 38% to 50% postintervention (P < .02). Mean percentage of NPS/BPS scores within the goal range (<5 for BPS and <3 for NPS) remained stable, 86% to 83% (P = .16). There was a decrease in use of continuous narcotic infusions for mechanically ventilated patients. This was reported as mean percentage of total ventilator days with a continuous opioid infusing: 65% before implementation versus 47% after implementation (P < .01). Mean percentage of ICU days with physical activity sessions increased from 24% to 41% (P < .001). Overall mean ventilator-free days and ICU length of stay were 5.4 to 4.5 days (P = .29) and 11.75 to 9.5 days (P = .20), respectively. CONCLUSION: Measureable patient outcomes are achievable in the early stages of PAD guideline initiatives and can inform future systems-level organizational change. Pain, agitation, and delirium assessment tools form the foundation for clinical implementation and evaluation. High-acuity surgical critical care patients can achieve more time at goal RASS, decreased ventilator days, and less exposure to continuous opioid infusions, all while maintaining stable analgesia.