Plasma Profiling of Acute Myeloid Leukemia With Fever- and Infection-Related Complications During Chemotherapy-Induced Neutropenia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous and complex blood cancer requiring aggressive treatment. Early identification and prediction of the complications following treatment is vital for effective disease management. AIMS: We explored associations between plasma protein levels and fever- and infection-related complications in 26 AML patients during chemotherapy-induced neutropenia. MATERIAL AND METHODS: Longitudinal plasma profiling was conducted using data-dependent mass spectrometry analysis. RESULTS: Mass spectrometry-based plasma profiling data correlated well with laboratory parameters, including C-reactive protein, and revealed a broader inflammation protein network associated with fever- and infection-related complications. DISCUSSION AND CONCLUSION: These data indicate the potential of longitudinal plasma profiling in AML patients for identifying and predicting complications that may aid in improved disease monitoring and treatment.

Safety and efficacy of human apotransferrin infusion in patients with ß-thalassemia intermedia: the AIM study.

Not available.

Self-perceived oral health in hemato-oncological patients and the relation to quality of life.

PURPOSE: To assess the self-reported oral health and oral health-related quality of life of patients diagnosed with hemato-oncological disease. PATIENTS AND METHODS: Data was collected through a digital questionnaire in collaboration with the Dutch patient organization Hematon. The questionnaires EORTC-QLQ-C30, EORTC-QLQ-OH15, shortened Xerostomia Inventory (XI), and the OHIP-14 were used. RESULTS: Seven hundred five patients were included (52.5% female, mean age 63.2 ± 10.1). The majority was diagnosed more than 2 years ago (86%) and had received treatment (81%) for their disease. Lymphoma, leukemia, and multiple myeloma were the most frequent malignancies. Chemotherapy alone, chemotherapy in combination with targeted therapy or immunotherapy, and myeloablative chemotherapy followed by autologous stem cell transplantation were the most common treatment modalities. The XI identified that 40.5% met the criteria for xerostomia. Other complaints included mouth soreness and sensitivity, gingival pain and bleeding, problems with teeth or with an ill-fitting denture. Despite reporting oral complaints, most patients experienced a rather good OH-QoL. A high xerostomia score led to a significantly lower OH-QoL. Female gender, history of stem cell transplantation, radiation to head and neck, and multiple daily medication use were significant predictors of xerostomia. CONCLUSION: Patients with hematologic malignancies frequently reported a dry mouth and other oral complaints including mouth soreness and sensitivity, gingival pain and bleeding, and problems with teeth. Despite these oral complaints, most patients experienced a relatively good OH-QoL. Future longitudinal studies are needed, and health professionals should have an active role in providing oral supportive care based on patients' individual needs.

Macular neurodegenerative and vascular changes on OCTA in sickle cell disease are not related to its ocular and systemic complications.

PURPOSE: To evaluate macular abnormalities in sickle cell disease (SCD) with OCT-Angiography (OCTA) and to determine associations with sickle cell retinopathy (SCR) and clinical and laboratory characteristics. METHODS: Complete ophthalmic examination was performed in consecutive SCD patients (HbSS, HbSC, HbSß0 or HbSß+ genotype), including fundoscopy and macular SD-OCT/OCTA scans. SCR stage was based on fundoscopic examination (without fluorescein angiography) instead of the Goldberg classification, since fluorescein angiography was only used in case of tentative diagnosis. Medical/ophthalmological history and hematologic characteristics were retrieved from medical records. RESULTS: 249 eyes of 137 patients were analyzed. The mean age was 33.3 ± 12.4 years (range 15-70). Non-proliferative SCR was present in 57 eyes (22.9%) and proliferative SCR in 36 eyes (14.5%). Macular thinning was present in 100 eyes (40.2%) and was associated with lower foveal vessel density (VD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) and with enlargement of the foveal avascular zone (FAZ) area, perimeter and acircularity index (AI). Age and female sex were associated with lower (para)foveal VD in the SCP and DCP. No associations were found between SCR presence/severity and macular thinning or VD. CONCLUSION: Macular abnormalities were common, but did not result in visual impairment. No relation with SCR presence/severity was found. While OCTA-imaging is suitable for detecting maculopathy, it appears to have no diagnostic value in identifying patients at risk for SCR.

Metabolic blood profile and response to treatment with the pyruvate kinase activator mitapivat in patients with sickle cell disease.

Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted p < 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted p < 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.

Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria.

Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.

Azathioprine/hydroxyurea preconditioning prior to nonmyeloablative matched sibling donor hematopoietic stem cell transplantation in adults with sickle cell disease: A prospective observational cohort study.

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease.

ABSTRACT: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Effect of allogeneic hematopoietic stem cell transplantation on sickle cell disease-related organ complications: A systematic review and meta-analysis.

Sickle cell disease (SCD)-related organ complications are a major cause of morbidity and mortality in patients with SCD. We sought to assess whether hematopoietic stem cell transplantation (HSCT) stabilizes, attenuates, or exacerbates organ decline. We performed a systematic review and meta-analysis of trials investigating organ function before and after HSCT in patients with SCD. We searched MEDLINE/PubMed and EMBASE up to September 21, 2023. Continuous data were expressed as standardized mean difference (SMD) and pooled in a weighted inverse-variance random-effects model; binomial data were expressed as risk ratio (RR) using the Mantel-Haenszel random-effects meta-analyses. Of 823 screened studies, 34 were included in this review. Of these, 17 (774 patients, 23.6% adults, 86.3% HLA-identical sibling donor, 56.7% myeloablative conditioning regimen) were included in the meta-analyses. Pulmonary function remained stable. Mean tricuspid regurgitant jet velocity decreased but did not reach statistical significance. In children, estimated glomerular filtration rate decreased (SMD -0.80, p = .01), and the presence of proteinuria increased (RR 2.00, p = <.01), while splenic uptake and phagocytic function improved (RR 0.31, p = <.01; RR 0.23, p = <.01). Cerebral blood flow improved (SMD -1.39, p = <.01), and a low incidence of stroke after transplantation in high-risk patients was found. Retinopathy and avascular osteonecrosis were investigated in only one study, showing no significant changes. While HSCT can improve some SCD-related organ dysfunctions, transplantation-related toxicity may have an adverse effect on others. Future research should focus on identifying individuals with SCD who might benefit most from HSCT and which forms of organ damage are more likely to exacerbate post-transplantation.

Prevalence of autoimmune diseases in patients with sickle cell disease: a single center retrospective analysis.

Not available.

Neutrophils in sickle cell disease: Exploring their potential role as a therapeutic target.

Factors influencing the activation of neutrophils in SCD and the potential neutrophil-mediated ameliorating effects of therapies in SCD.

Cerebral hemodynamics and oxygenation in adult patients with sickle cell disease after stem cell transplantation.

Sickle cell disease (SCD) is characterized by chronic hemolytic anemia associated with impaired cerebral hemodynamics and oxygen metabolism. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for patients with SCD. Whereas normalization of hemoglobin levels and hemolysis markers has been reported after HSCT, its effects on cerebral perfusion and oxygenation in adult SCD patients remain largely unexplored. This study investigated the effects of HSCT on cerebral blood flow (CBF), oxygen delivery, cerebrovascular reserve (CVR), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ) in 17 adult SCD patients (mean age: 25.0 ± 8.0, 6 females) before and after HSCT and 10 healthy ethnicity-matched controls (mean age: 28.0 ± 8.8, 6 females) using MRI. For the CVR assessment, perfusion scans were performed before and after acetazolamide as a vasodilatory stimulus. Following HSCT, gray and white matter (GM and WM) CBF decreased (p < .01), while GM and WM CVR increased (p < .01) compared with the baseline measures. OEF and CMRO2 also increased towards levels in healthy controls (p < .01). The normalization of cerebral perfusion and oxygen metabolism corresponded with a significant increase in hemoglobin levels and decreases in reticulocytes, total bilirubin, and LDH as markers of hemolysis (p < .01). This study shows that HSCT results in the normalization of cerebral perfusion and oxygen metabolism, even in adult patients with SCD. Future follow-up MRI scans will determine whether the observed normalization of cerebral hemodynamics and oxygen metabolism prevents new silent cerebral infarcts.

Hoping for a normal life: Decision-making on hematopoietic stem cell transplantation by patients with a hemoglobinopathy and their caregivers.

BACKGROUND: To provide insight into the perspectives of children and young adults with transfusion-dependent thalassemia and sickle cell disease and their caregivers regarding the decision for hematopoietic stem cell transplantation (HSCT). PROCEDURE: A qualitative longitudinal multicenter study. Data collection consisted of 40 audio-recorded conversations between physicians and families and 77 interviews with patients and/or caregivers related to 27 unique cases, collected at different time points throughout the decision-making process. RESULTS: Conversations and interviews revealed "hoping for a normal life" as an overarching theme, consisting of four main topics: (i) "Building a frame of reference" refers to a process where patients or families try to obtain comprehensive information on HSCT and translate this to their situation to decide. (ii) "Balancing between loss and benefit" reports the process of considering the advantages and disadvantages of continuing with supportive care to treat their disease versus choosing HSCT. (iii) "Experiencing the impact of HSCT" describes the impactfull experience of the HSCT period by those who chose HSCT. (iv) "Balancing again" refers to reflecting on the decision made. CONCLUSIONS: The hope for a normal life guided the decision-making process, described as a constant balance between the impact of the disease and HSCT. A structured approach to explore patients' and caregivers' perspectives on HSCT decision-making is needed, where specifically discussing the impact of the disease and hope for a normal life need to be integrated in the process.

Oxygen gradient ektacytometry-derived biomarkers are associated with acute complications in sickle cell disease.

ABSTRACT: We investigated the potential of the point of sickling (PoS; the pO2 tension at which red cells start to sickle), determined by oxygen gradient ektacytometry to serve as a biomarker associated with the incidence of acute sickle cell disease-related complications in 177 children and 50 adults. In the pediatric cohort, for every 10 mmHg increase in PoS reflecting a greater likelihood of sickling, the likelihood of an individual experiencing >1 type of acute complication increased; the adjusted odds ratio (aOR) was 1.65. For every 0.1 increase in minimum elongation index (EImin; reflecting improved red blood cell deformability at hypoxia), the aOR was 0.50. In the adult cohort, for every 10 mmHg increase in PoS, we found an aOR of 3.00, although this was not significant after correcting for multiple testing. There was a trend for an association between higher PoS and greater likelihood of vaso-occlusive episodes (VOEs; children aOR, 1.35; adults aOR, 2.22). In children, only EImin was associated with VOEs (aOR, 0.68). When data of both cohorts were pooled, significant associations with PoS and/or EImin were found for all acute complications, independently and when >1 type of acute complication was assessed. These findings indicate that oxygen gradient ektacytometry generates novel biomarkers and provides a rationale for further development of these biomarkers in the assessment of clinical severity, evaluation of novel therapies, and as surrogate clinical trial end points. These biomarkers may be useful in assessing efficacy of novel therapies like pyruvate kinase activators, voxelotor, and L-glutamine.

One-year safety and efficacy of mitapivat in sickle cell disease: follow-up results of a phase 2, open-label study.

Targeting the primary pathogenic event of sickle cell disease (SCD), the polymerization of sickle hemoglobin (HbS), may prevent downstream clinical events. Mitapivat, an oral pyruvate kinase (PK) activator, has therapeutic potential by increasing adenosine triphosphate (ATP) and decreasing 2,3-diphosphoglycerate (2,3-DPG), a glycolytic red blood cell (RBC) intermediate. In the previously reported 8-week dose-finding period of this phase 2, investigator-initiated, open-label study, mitapivat was well tolerated and showed efficacy in SCD. Here, the 1-year fixed-dose extension period is reported in which 9 of 10 included patients (90%) aged ≥16 years with SCD (HbSS, HbS/ß0, or HbS/ß+) continued with mitapivat. Mostly mild treatment-emergent adverse events (AEs) (most commonly, transaminase increase and headache) were still reported. Apart from the reported nontreatment-related serious AE (SAE) of a urinary tract infection in the dose-finding period, 1 nontreatment-related SAE occurred in the fixed-dose extension period in a patient who died of massive pulmonary embolism due to COVID-19. Importantly, sustained improvement in Hb level (mean increase, 1.1 ± 0.7 g/dL; P = .0014) was seen, which was accompanied by decreases in markers of hemolysis. In addition, the annualized rate of vaso-occlusive events reduced significantly from a historic baseline of 1.33 ± 1.32 to 0.64 ± 0.87 (P = .0489) when combining the dose-finding period and fixed-dose extension period. Cellularly, the ATP:2,3-DPG ratio and Hb-oxygen affinity significantly increased and RBC sickling (point of sickling) nonsignificantly reduced. Overall, this study demonstrated 1-year safety and efficacy of treatment with mitapivat in SCD, supporting further evaluation in ongoing phase 2/3 study (RISE UP, NCT05031780). This trial was registered at https://www.clinicaltrialsregister.eu/ as NL8517 and EudraCT 2019-003438-18.

Not Everything Is as It Seems: A Case Series and Overview of Diseases Mimicking Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare heterogeneous disease in which treatment must be initiated early to prevent irreversible organ damage and death. There are several diseases that can mimic AAV, even in the presence of positive ANCA serology and/or histological evidence of vasculitis, as demonstrated in this case series. We reflect on the diagnostic approach of patients with AAV and provide an overview of AAV-mimicking diseases that can be considered in patients with atypical disease presentation or course.

Circulating Iron in Patients with Sickle Cell Disease Mediates the Release of Neutrophil Extracellular Traps.

Introduction: Neutrophils promote chronic inflammation and release neutrophil extracellular traps (NETs) that can drive inflammatory responses. Inflammation influences progression of sickle cell disease (SCD), and a role for NETs has been suggested in the onset of vaso-occlusive crisis (VOC). We aimed to identify factors in the circulation of these patients that provoke NET release, with a focus on triggers associated with hemolysis. Methods: Paired serum and plasma samples during VOC and steady state of 18 SCD patients (HbSS/HbSß0-thal and HbSC/HbSß+-thal) were collected. Cell-free heme, hemopexin, and labile plasma iron have been measured in the plasma samples of the SCD patients. NETs formation by human neutrophils from healthy donors induced by serum of SCD patients was studied using confocal microscopy and staining for extracellular DNA using Sytox, followed by quantification of surface coverage using ImageJ. Results: Eighteen patients paired samples obtained during VOC and steady state were available (11 HbSS/HbSß0-thal and 7 HbSC/HbSß+-thal). We observed high levels of systemic heme and iron, concomitant with low levels of the heme-scavenger hemopexin in sera of patients with SCD, both during VOC and in steady state. In our in vitro experiments, neutrophils released NETs when exposed to sera from SCD patients. The release of NETs was associated with high levels of circulating iron in these sera. Although hemin triggered NET formation in vitro, addition of hemopexin to scavenge heme did not suppress NET release in SCD sera. By contrast, the iron scavengers deferoxamine and apotransferrin attenuated NET formation in a significant proportion of SCD sera. Discussion: Our results suggest that redox-active iron in the circulation of non-transfusion-dependent SCD patients activates neutrophils to release NETs, and hence, exerts a direct pro-inflammatory effect. Thus, we propose that chelation of iron requires further investigation as a therapeutic strategy in SCD.

ATG versus PTCy in matched unrelated donor haematopoietic stem cell transplantations with non-myeloablative conditioning.

Graft-versus-host disease (GvHD) is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT). Both anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are used as lymphocyte-depleting strategies, yet a systematic comparison of transplantation outcomes between these two methods in matched unrelated donors (MUD) transplantations with non-myeloablative conditioning (NMC) is lacking. Adult patients with haematological malignancies who had undergone MUD HSCT with NMC regimens between 2014 and 2021 at 2 centres in Amsterdam (ATG: n = 95, PTCy: n = 90), were included in this retrospective study. Patient characteristics were comparable between the groups. The cumulative incidence of acute GvHD grade II-IV was 48% in the ATG group compared to 21% in the PTCy group (p < 0.001). The 3-year moderate/severe chronic GvHD was similar in both groups (p = 0.69). While the relapse rate was comparable between the groups (ATG 31% vs. PTCy 34%, p = 0.94), non-relapse mortality tended to be higher in the ATG group (17% vs. 9%, p = 0.069). Overall survival was similar in both groups (p = 0.12). In conclusion, PTCy-based regimens resulted in a significantly lower rate of acute GvHD than ATG-containing regimens in MUD transplantations with NMC. Whether PTCy results in improved overall survival as compared to ATG needs to be elucidated in larger prospective studies.

A multimodal pain protocol for treatment of vaso-occlusive crisis in patients with sickle cell disease: Implementation and evaluation.

OBJECTIVES: Pain management during a vaso-occlusive crisis (VOC) for patients with sickle cell disease (SCD) remains a major challenge and strongly depends on opioids. We developed a multimodality pain protocol for rapid, opioid-sparing pain treatment of VOC and evaluated its feasibility. METHODS: Patients were included for evaluation if they were ≥18 years, diagnosed with SCD and visited the emergency department (ED) because of VOC between July 2018 and December 2020. Primary evaluation outcome was the feasibility of multimodal pain analgesia (i.e., the use of at least two analgesics with different underlying mechanisms of action). RESULTS: A total of 131 SCD patients visited the ED because of VOC with a total of 550 ED presentations, of which 377 were eventually hospitalised. A total of 508 (92.4%) ED presentations and 374 (99.2%) hospital admissions received multimodal pain treatment. Time to first administration of an opioid was median [IQR] 34.0 [21.0-62.0] minutes. CONCLUSION: The implementation of a pain protocol using multimodal analgesia for VOC in patients with SCD appeared to be feasible and facilitated rapid administration of opioids. Controlled trials are needed to investigate the effectiveness of multimodal analgesia on pain and should focus on patient reported outcome measures.