Creation and Expansion of a Mixed Patient Intermediate Care Unit to Improve ICU Capacity.

OBJECTIVES: ICU capacity strain is associated with worsened outcomes. Intermediate care units (IMCs) comprise one potential option to offload ICUs while providing appropriate care for intermediate acuity patients, but their impact on ICU capacity has not been thoroughly characterized. The aims of this study are to describe the creation of a medical-surgical IMC and assess how the IMC affected ICU capacity. DESIGN: Descriptive report with retrospective cohort review. SETTING: Six hundred seventy-three-bed tertiary care academic medical center with 77 ICU beds. PATIENTS: Adult inpatients who were admitted to the IMC. INTERVENTIONS: An interdisciplinary working group created an IMC which was located on a general ward. The IMC was staffed by hospitalists and surgeons and supported by critical care consultants. The initial maximum census was three, but this number increased to six in response to heightened critical care demand. IMC admission criteria also expanded to include advanced noninvasive respiratory support defined as patients requiring high-flow nasal cannula, noninvasive positive pressure ventilation, or mechanical ventilation in patients with tracheostomies. MEASUREMENTS AND MAIN RESULTS: The primary outcome entailed the number of ICU bed-days saved. Adverse outcomes, including ICU transfer, intubation, and death, were also recorded. From August 2021 to July 2022, 230 patients were admitted to the IMC. The most frequent IMC indications were respiratory support for medical patients and post-operative care for surgical patients. A total of 1023 ICU bed-days were made available. Most patients were discharged from the IMC to a general ward, while 8% of all patients required transfer to an ICU within 48 hours of admission. Intubation (2%) and death (1%) occurred infrequently within 48 hours of admission. Respiratory support was the indication associated with the most ICU transfers. CONCLUSIONS: Despite a modest daily census, an IMC generated substantial ICU bed capacity during a time of peak critical care demand.

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease.

BACKGROUND: The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS: In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed. RESULTS: A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS: In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).

Inhibition of P-Selectin and PSGL-1 Using Humanized Monoclonal Antibodies Increases the Sensitivity of Multiple Myeloma Cells to Bortezomib.

Multiple myeloma (MM) is a plasma cell malignancy localized in the bone marrow. Despite the introduction of novel therapies majority of MM patients relapse. We have previously shown that inhibition of P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) play a key role in proliferation of MM and using small-molecule inhibitors of P-selectin/PSGL-1 sensitized MM cells to therapy. However, these small-molecule inhibitors had low specificity to P-selectin and showed poor pharmacokinetics. Therefore, we tested blocking of P-selectin and PSGL-1 using functional monoclonal antibodies in order to sensitize MM cells to therapy. We have demonstrated that inhibiting the interaction between MM cells and endothelial and stromal cells decreased proliferation in MM cells and in parallel induced loose-adhesion to the primary tumor site to facilitate egress. At the same time, blocking this interaction in vivo led to MM cells retention in the circulation and delayed homing to the bone marrow, thus exposing MM cells to bortezomib which contributed to reduced tumor growth and better mice survival. This study provides a better understanding of the biology of P-selectin and PSGL-1 and their roles in dissemination and resensitization of MM to treatment.

Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria.

The complement system provides critical immunoprotective and immunoregulatory functions but uncontrolled complement activation can lead to severe pathology. In the rare hemolytic disease paroxysmal nocturnal hemoglobinuria (PNH), somatic mutations result in a deficiency of glycosylphosphatidylinositol-linked surface proteins, including the terminal complement inhibitor CD59, on hematopoietic stem cells. In a dysfunctional bone marrow background, these mutated progenitor blood cells expand and populate the periphery. Deficiency of CD59 on PNH red blood cells results in chronic complement-mediated intravascular hemolysis, a process central to the morbidity and mortality of PNH. A recently developed, humanized monoclonal antibody directed against complement component C5, eculizumab (Soliris; Alexion Pharmaceuticals Inc., Cheshire, CT, USA), blocks the proinflammatory and cytolytic effects of terminal complement activation. The recent approval of eculizumab as a first-in-class complement inhibitor for the treatment of PNH validates the concept of complement inhibition as an effective therapy and provides rationale for investigation of other indications in which complement plays a role.

Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria.

Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n = 195); patients from these studies continued treatment in the current multinational open-label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317).

The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.

BACKGROUND: We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed. RESULTS: Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae. CONCLUSIONS: Eculizumab is an effective therapy for PNH.

Antithrombin reduces monocyte and neutrophil CD11b up regulation in addition to blocking platelet activation during extracorporeal circulation.

BACKGROUND: Patients undergoing cardiac surgery requiring cardiopulmonary bypass develop a systemic inflammatory reaction. Antithrombin III (AT) has anticoagulant effects but also shows evidence of anti-inflammatory activity. The aim of this study was to examine whether exogenous AT could reduce white blood cell activation (CD11b up regulation or elastase release), in addition to inhibiting platelet (PLT) activation and fibrin generation, during simulated cardiopulmonary bypass (sCPB), undertaken in the absence of endothelium. STUDY DESIGN AND METHODS: sCPB was carried out with minimally heparinized (2 U/mL) human blood for 90 minutes in controls and with supplementation by low-dose (1 U/mL) and high-dose (5 U/mL) AT. RESULTS: High-dose AT blunted thrombin generation during sCPB (prothrombin fragment 1.2); both doses significantly inhibited thrombin activity (fibrinopeptide A). Complement activation (C3a and C5b-9) was unaffected by AT. High-dose AT inhibited PLT activation (P-selectin expression and P-selectin-dependent monocyte-PLT conjugate formation). AT supplementation at the higher dose significantly abrogated monocyte and neutrophil CD11b up regulation and neutrophil elastase release. CONCLUSION: In addition to anticoagulant and anti-PLT effects, pharmacologic AT doses significantly blunted monocyte and neutrophil CD11b up regulation and neutrophil elastase release during sCPB, independent of endothelial effects. These data provide evidence for the direct anti-inflammatory activity of AT that has clinical relevance for CPB complications.

Concerning the mechanism of pexelizumab's benefit in acute myocardial infarction.

BACKGROUND: The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial previously demonstrated an unexpected dose-dependent reduction in 90-day mortality after bolus/infusion of pexelizumab despite no reduction in the primary end point of myocardial infarction (MI) size. We examined whether the mortality benefit was related to established modulators of clinical benefit such as baseline demographics, time to treatment from symptom onset, myocardial perfusion post-percutaneous coronary intervention (PCI), and extent of ST resolution. METHODS AND RESULTS: Eight hundred fourteen patients were randomized into 3 groups; (1) placebo, (2) pexelizumab bolus 2.0 mg/kg and placebo infusion for 20 hours, and (3) pexelizumab bolus 2.0 and 0.05 mg/kg per hour infusion for 20 hours commencing 4 hours after the bolus. Subjects presented with ST elevation MI within 6 hours of symptom onset and underwent PCI, creatine kinase (CK), and CK-MB measurements taken sequentially to define CK-MB area under the curve (AUC) and sequential ECG's defined ST resolution and QRS infarct size. Whereas mortality for both placebo and bolus pexelizumab groups rose during later time after presentation, it remained low and did not change appreciably during the 6-hour randomization window when patients received pexelizumab bolus infusion. Amplification of the mortality benefit was evident in patients with the highest quartile of hemodynamic compromise, that is, heart rate > or = 90 beat/min and systolic blood pressure < or = 118 mm Hg (3.2% vs 11.3% P = .004). A significant interaction between treatment assignment and hemodynamic status (P = .013) existed after adjusting for age, race, and MI location. Clinical benefit was not related to infarct size, extent of ST elevation, or evidence of angiographic or electrocardiographic reperfusion. CONCLUSIONS: These data raise the possibility that the clinical benefit of pexelizumab is mediated through novel pathways such as reduction in apoptosis or other mechanisms.

Prognostic significance of blood markers of inflammation in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty and effects of pexelizumab, a C5 inhibitor: a substudy of the COMMA trial.

AIMS: Pexelizumab, a monoclonal antibody inhibiting C5, reduced 90 day mortality and shock in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial without apparent reductions in infarct size. Inflammation is a critical component of ST-elevation myocardial infarction (STEMI); this substudy examines prognostic values of selected markers and treatment effects. METHODS AND RESULTS: C-reactive protein, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha) serum levels were assessed in 337 patients enrolled in either the placebo or the pexelizumab 24 h infusion group. Higher C-reactive protein and IL-6 levels at baseline, 24 h, and 72 h were strongly associated with increased subsequent death (P<0.002 at baseline and 24 h, P<0.02 at 72 h); and all baseline marker levels with death or cardiogenic shock (P<0.03) within 90 days. C-reactive protein and IL-6 levels were similar at baseline, but significantly lower 24 h later with pexelizumab, when compared with placebo (17.1 vs. 25.5 mg/L, P=0.03 and 51.0 vs. 63.8 pg/mL, P=0.04, respectively). At 72 h, corresponding levels were similar, whereas TNF-alpha was slightly higher (P=0.04) in the treated group. CONCLUSION: Inflammation markers and their serial changes predict death and shock in patients with STEMI undergoing primary angioplasty. Pexelizumab reduced C-reactive protein and IL-6, suggesting treatment benefits mediated through anti-inflammatory effects.

Prognostic usefulness of white blood cell count and temperature in acute myocardial infarction (from the CARDINAL Trial).

White blood cell (WBC) count and temperature are 2 global measures of inflammation that are systematically gathered and easily identifiable in a clinical setting, unlike many other markers of inflammation being investigated in patients with coronary artery disease. The prognostic usefulness of the WBC count and temperature were evaluated in a large acute myocardial infarction trial, the Complement And ReDuction of INfarct size after Angioplasty or Lytics program. Baseline and serial measurements of WBC counts and temperature were correlated with infarct size and clinical outcome.

Pharmacologic C5-complement suppression reduces blood loss during on-pump cardiac surgery.

BACKGROUND: Inflammation contributes to morbidity following on-pump cardiac surgery. Complement activation during cardiopulmonary bypass has been associated with the postoperative bleeding and tissue injury. This study examines the pharmacology and impact on blood loss of complement C5 suppression with pexelizumab in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: Pexelizumab, a humanized monoclonal antibody single-chain fragment that binds to the human C5 complement component, was studied in a Phase II multicentered clinical trial. CABG (n = 800) and CABG with concomitant valve surgery (n = 114) patients were evaluated. Patients were randomized to either: pexelizumab bolus (2.0 mg/kg) + placebo infusion; pexelizumab bolus (2.0 mg/kg) + pexelizumab infusion (0.05 mg/kg/hour for 24 hours); or placebo bolus + placebo infusion. Pharmacology, chest tube drainage, and transfusion requirements were assessed. RESULTS: Mean maximum pexelizumab serum concentration was similar for bolus and bolus + infusion-treated patients. Complement-dependent serum hemolytic activity was completely suppressed within 1 hour following pexelizumab bolus, however, suppression was maintained for a longer duration in the bolus + infusion compared to the bolus-only treated patients. A reduction in chest tube drainage was observed for all pexelizumab-treated patients, although transfusion of blood products was similar across all study groups. CONCLUSION: Pexelizumab administration inhibits complement-dependent hemolytic activity and is associated with a reduction in postoperative chest tube drainage in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Further, clinical studies are needed to assess the value of complement attenuation in this setting.

Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial.

CONTEXT: Inflammation and ischemia-reperfusion injury during coronary artery bypass graft (CABG) surgery requiring cardiopulmonary bypass are associated with postoperative myocardial infarction (MI) and mortality. OBJECTIVE: To determine the efficacy and safety of pexelizumab, a C5 complement inhibitor, in reducing perioperative MI and mortality in CABG surgery. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial, including 3099 patients (> or = 18 years) undergoing CABG surgery with or without valve surgery at 205 hospitals in North America and Western Europe from January 2002 to February 2003. INTERVENTIONS: Patients were randomly assigned to receive intravenous pexelizumab (2.0 mg/kg bolus plus 0.05 mg/kg per hour for 24 hours; n = 1553) or placebo (n = 1546) 10 minutes before undergoing the procedure. MAIN OUTCOME MEASURES: The primary composite end point was the incidence of death or MI within 30 days of randomization in those undergoing CABG surgery only (n = 2746). Secondary analyses included the intent-to-treat analyses of death or MI composite at days 4 and 30 in all 3099 study patients. RESULTS: After 30 days, 134 (9.8%) of 1373 of patients receiving pexelizumab vs 161 (11.8%) of 1359 of patients receiving placebo (relative risk, 0.82; 95% confidence interval, 0.66-1.02; P =.07) died or experienced MI in the CABG surgery only population. In the intent-to-treat analyses, 178 (11.5%) of 1547 patients receiving pexelizumab vs 215 (14.0%) of 1535 receiving placebo died or experienced MI (relative risk, 0.82; 95% confidence interval, 0.68-0.99; P =.03). The trial was not powered to detect a reduction in mortality alone. CONCLUSIONS: Compared with placebo, pexelizumab was not associated with a significant reduction in the risk of the composite end point of death or MI in 2746 patients who had undergone CABG surgery only but was associated with a statistically significant risk reduction 30 days after the procedure among all 3099 patients undergoing CABG with or without valve surgery.

Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass.

BACKGROUND: During cardiac surgery requiring cardiopulmonary bypass, pro-inflammatory complement pathways are activated by exposure of blood to bio-incompatible surfaces of the extracorporeal circuit and reperfusion of ischemic organs. Complement activation promotes the generation of additional inflammatory mediators thereby exacerbating tissue injury. We examined the safety and efficacy of a C5 complement inhibitor for attenuating inflammation-mediated cardiovascular dysfunction in cardiac surgical patients undergoing cardiopulmonary bypass. METHODS: Pexelizumab (Alexion Pharmaceuticals, Inc, Cheshire, CT), a recombinant, single-chain, anti-C5 monoclonal antibody, was evaluated in a randomized, double-blinded, placebo-controlled, multicenter trial that involved 914 patients undergoing coronary artery bypass grafting with or without valve surgery requiring cardiopulmonary bypass. RESULTS: Pexelizumab was administered intravenously as a bolus (2.0 mg/kg) or bolus plus infusion (2.0 mg/kg plus 0.05 mg/kg/h for 24 hours), and inhibited complement activation. There were no statistically significant differences between placebo-treated and pexelizumab-treated patients in the primary endpoint (composite of death, or new Q-wave, or non-Q-wave [myocardial-specific isoform of creatine kinase > 60 ng/mL] myocardial infarction, or left ventricular dysfunction, or new central nervous system deficit). However, post hoc analysis revealed a reduction in the composite of death or myocardial infarction (myocardial-specific isoform of creatine kinase >/= 100 ng/mL) for the isolated coronary artery bypass grafting, bolus plus infusion subgroup on POD 4 (p = 0.007) and on POD 30 (p = 0.004). CONCLUSIONS: Pexelizumab had no statistically significant effect on the primary endpoint. However, the reduction in death or myocardial infarction (myocardial-specific isoform of creatine kinase >/= 100 ng/mL) as revealed in the post hoc analysis in the isolated coronary artery bypass grafting bolus plus infusion subpopulation, suggests that further investigation of anti-C5 therapy for ameliorating complement-mediated inflammation and myocardial injury is warranted.

Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) arises from a somatic mutation of the PIG-A gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system. We tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components, in patients with PNH. METHODS: Eleven transfusion-dependent patients with PNH received infusions of eculizumab (600 mg) every week for four weeks, followed one week later by a 900-mg dose and then by 900 mg every other week through week 12. Clinical and biochemical indicators of hemolysis were measured throughout the trial. RESULTS: Mean lactate dehydrogenase levels decreased from 3111 IU per liter before treatment to 594 IU per liter during treatment (P=0.002). The mean percentage of PNH type III erythrocytes increased from 36.7 percent of the total erythrocyte population to 59.2 percent (P=0.005). The mean and median transfusion rates decreased from 2.1 and 1.8 units per patient per month to 0.6 and 0.0 units per patient per month, respectively (P=0.003 for the comparison of the median rates). Episodes of hemoglobinuria were reduced by 96 percent (P<0.001), and measurements of the quality of life improved significantly. CONCLUSIONS: Eculizumab is safe and well tolerated in patients with PNH. This antibody against terminal complement protein C5 reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH.

Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial.

BACKGROUND: Complement, activated during myocardial ischemia and reperfusion, causes myocardial damage through multiple processes. The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial was performed to determine the effect of pexelizumab, a C5 complement inhibitor, on infarct size in patients with ST-segment-elevation myocardial infarction (MI) undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: In COMMA, 960 patients with MI (20% isolated inferior MI) were randomized to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus and 0.05-mg/kg per h infusion for 20 hours. Infarct size by creatine kinase-MB area under the curve, the primary outcome, did not differ significantly between groups (placebo median, 4393; bolus pexelizumab, 4526; bolus plus infusion pexelizumab, 4713 [ng/mL] x h; P=0.89 for bolus versus placebo; P=0.76 for bolus plus infusion versus placebo), nor did the composite of 90-day death, new or worsening heart failure, shock, or stroke (placebo, 11.1%; bolus, 10.7%; bolus plus infusion, 8.5%). The ninety-day mortality rate was significantly lower with pexelizumab bolus plus infusion (1.8% versus 5.9% with placebo; nominal P=0.014); the bolus-only group had an intermediate mortality rate (4.2%). CONCLUSIONS: In patients with ST-elevation MI undergoing percutaneous coronary intervention, pexelizumab had no measurable effect on infarct size. However, the significant reduction in mortality suggests that pexelizumab may benefit patients through alternative novel mechanisms and provides impetus for additional investigation.