Lothar Huebsch

Continuous Multi-Parameter Heart Rate Variability Analysis Heralds Onset of Sepsis in Adults

Background Early diagnosis of sepsis enables timely resuscitation and antibiotics and prevents subsequent morbidity and mortality. Clinical approaches relying on point-in-time analysis of vital signs or lab values are often insensitive, non-specific and late diagnostic markers of sepsis. Exploring otherwise hidden information within intervals-in-time, heart rate variability (HRV) has been documented to be both altered in the presence of sepsis, and correlated with its severity. We hypothesized that by continuously tracking individual patient HRV over time in patients as they develop sepsis, we would demonstrate reduced HRV in association with the onset of sepsis. Methodology/Principal Findings We monitored heart rate continuously in adult bone marrow transplant (BMT) patients (n = 21) beginning a day before their BMT and continuing until recovery or withdrawal (12±4 days). We characterized HRV continuously over time with a panel of time, frequency, complexity, and scale-invariant domain techniques. We defined baseline HRV as mean variability for the first 24 h of monitoring and studied individual and population average percentage change (from baseline) over time in diverse HRV metrics, in comparison with the time of clinical diagnosis and treatment of sepsis (defined as systemic inflammatory response syndrome along with clinically suspected infection requiring treatment). Of the 21 patients enrolled, 4 patients withdrew, leaving 17 patients who completed the study. Fourteen patients developed sepsis requiring antibiotic therapy, whereas 3 did not. On average, for 12 out of 14 infected patients, a significant (25%) reduction prior to the clinical diagnosis and treatment of sepsis was observed in standard deviation, root mean square successive difference, sample and multiscale entropy, fast Fourier transform, detrended fluctuation analysis, and wavelet variability metrics. For infected patients (n = 14), wavelet HRV demonstrated a 25% drop from baseline 35 h prior to sepsis on average. For 3 out of 3 non-infected patients, all measures, except root mean square successive difference and entropy, showed no significant reduction. Significant correlation was present amongst these HRV metrics for the entire population. Conclusions/Significance Continuous HRV monitoring is feasible in ambulatory patients, demonstrates significant HRV alteration in individual patients in association with, and prior to clinical diagnosis and treatment of sepsis, and merits further investigation as a means of providing early warning of sepsis.

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

BACKGROUND Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. METHODS We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. FINDINGS Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. INTERPRETATION We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their diseases aggressive nature. FUNDING Multiple Sclerosis Scientific Research Foundation.

Incidence of symptomatic venous thromboembolism following hematopoietic stem cell transplantation

Summary.  Background: The incidence of symptomatic venous thromboembolism (VTE) following hematopoietic stem cell transplantation (HSCT) is not well described, particularly with increased use of ambulatory care in the transplant setting. Methods: A retrospective analysis involving 589 patients (382 autologous HSCT, 207 allogeneic HSCT) undergoing transplantation between 2000 and 2005 in a single Canadian institution was undertaken to identify the incidence of proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) in HSCT patients. Results: The total 1‐year incidence of symptomatic VTE was 3.7% [95% confidence interval (CI) 2.5–5.6]. Among the HSCT patients, 7/589 (1.2%, 95% CI 0.6–2.4) developed symptomatic non‐catheter‐related VTE following HSCT (four PE and three DVT). All VTE events occurred after hematopoietic engraftment. Patients undergoing autologous HSCT did not receive thromboprophylaxis, whereas most patients undergoing allogeneic HSCT (79.7%) received enoxaparin 20 mg daily for the prevention of veno‐occlusive disease of the liver, starting 6 ± 3 days before transplantation for a mean of 22 ± 14 days. Conclusion: HSCT patients have a high incidence of VTE. Thromboprophylaxis should potentially be considered in these patients. However, future studies assessing the risk and benefits of thromboprophylaxis are needed in this specific population.

A randomized trial of granulocyte colony-stimulating factor (Neupogen) starting day 1 vs day 7 post-autologous stem cell transplantation

The purpose of the study was to evaluate the effect of delayed granulocyte colony-stimulating factor (G-CSF) use on hematopoietic recovery post-autologous peripheral blood progenitor cell (PBPC) transplantation. Patients were randomized to begin G-CSF on day +1 or day +7 post transplantation. Thirty-seven patients with lymphoma or myeloma undergoing high-dose therapy and autologous PBPC rescue were randomized to daily subcutaneous G-CSF beginning on day +1 or day +7 post-transplant. Patients ⩽70 kg received 300 μg/day and >70 kg 480 μg/day. All patients were reinfused with PBPCs with a CD34+ cell count >2.0 × 106/kg. Baseline characteristics of age, sex and CD34+ cell count were similar between the two arms, the median CD34+ cell count being 5.87 × 106/kg in the day +1 group and 7.70 × 106/kg in the day +7 group (P = 0.7). The median time to reach a neutrophil count of >0.5 × 109/l was 9 days in the day +1 arm and 10 days in the day +7 arm, a difference which was not statistically significant (P = 0.68). Similarly, there was no difference in median days to platelet recovery >20 000 × 109/l, which was 10 days in the day +1 arm and 11 days in the day +7 arm (P = 0.83). There was also no significant difference in the median duration of febrile neutropenia (4 vs 6 days; P = 0.7), intravenous antibiotic use (7 vs 8 days; P = 0.54) or median number of red blood cell transfusions (4 vs 7 units; P = 0.82) between the two arms. Median length of hospital stay was 11 days post-PBPC reinfusion in both groups. The median number of G-CSF injections used was 8 in the day +1 group and 3 in the day +7 group (P < 0.0001). there is no significant difference in time to neutrophil or platelet recovery when g-csf is initiated on day +7 compared to day +1 post-autologous pbpc transplantation. there is also no difference in number of febrile neutropenic or antibiotic days, number of red blood cell transfusions or length of hospital stay. the number of doses of g-csf used per transplant is significantly reduced with delayed initiation, resulting in a significant reduction in drug costs. for patients with an adequately mobilized pbpc graft, the initiation of g-csf can be delayed until day +7 post-pbpc reinfusion.

Utility of Comorbidity Assessment in Predicting Transplantation-Related Toxicity Following Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Patients with coexisting medical problems may suffer increased toxicity and reduced quality of life after autologous hematopoietic stem cell transplantation (HSCT). The benefit of high-dose therapy for some patients with multiple myeloma (MM) is debatable. Decision tools that aid in identifying those patients with MM most suited for autologous HSCT may avoid the risk of excess toxicity. An objective assessment of comorbidities was performed in 126 patients with MM undergoing autologous HSCT using the Charlson comorbidity index (CCI), the hematopoietic cell transplantation comorbidity index (HCT-CI), and a modified pretransplantation assessment of mortality (mPAM) to determine the strength of association with increased transplantation-related toxicity and increased length of hospital stay (LOS). Any comorbidity scored using the CCI or HCT-CI (score > 0) was associated with an increased number of organ systems with serious toxicity (at least grade 2 toxicity using the Seattle criteria), an increased total sum of toxicity grades for all organs, and prolonged LOS. An mPAM score > or = 24 was associated with increased LOS. When considering autologous HSCT for a patient with MM, assessment of comorbidities using the CCI or HCT-CI may assist in predicting the risk of transplantation-related toxicity as an adjunct to physician judgment and patient preference.

Autologous Blood and Marrow Transplantation in Patients 60 Years and Older

Although many hematologic malignancies are more common in older patients, autologous blood and marrow transplantation (ABMT) has traditionally been restricted to patients younger than 60 years because of concerns that older patients would be either unable to provide a graft or unable to tolerate the therapy. From June 1995 to May 1998, 30 patients > or = 60 years underwent ABMT at our institution for low-grade lymphoma (4 patients), relapsed intermediate-grade lymphoma (17 patients), or multiple myeloma (9 patients). The median patient age was 62.5 years (range 60-73). Pretransplantation conditioning regimens were CBV (cyclophosphamide, BCNU [carmustine], etoposide) or BEAM (carmustine, etoposide, cytarabine, melphalan) for intermediate-grade lymphoma patients and melphalan 140 mg/m2 + etoposide 60 mg/kg + total body irradiation 500 cGy for the others. The rescue product was bone marrow (BM; 4 patients), peripheral blood stem cells (PBSC; 23 patients), or BM+PBSC (3 patients). The median number of CD34+ cells/kg infused was 3.60 x 10(6) (range 0.53-31.0), by the International Society for Hematotherapy and Graft Engineering method. The treatment-related mortality at day 100 and at 6 months was 10% and 16.7%, respectively. The median days to neutrophil > 0.5 x 10(9)/L was 11 (range 9-25) and platelets > 20 x 10(9)/L was 16 (range 6-70). Three patients died of infection (days 26, 27, and 38), and 1 died of an intracranial hemorrhage related to persistent thrombocytopenia (day 130). Bearman regimen-related toxicity was moderate, with most toxicities < or = grade 2. Seven patients developed significant gut toxicity: 4 patients with Clostridium difficile colitis and 3 patients with neutropenic enterocolitis. Depressive symptoms and signs were noted in 4 patients. Three male patients developed decreased gonadal function after transplantation. These transplantations accounted for 997 patient days, of which 266 days (27%) were in the outpatient BMT program--a smaller percentage than in patients < 60 years (56%, P = .002). Twenty patients are alive 153 to > or = 1224 days after transplantation. ABMT in patients > or = 60 years of age is feasible. Further studies addressing supportive care particular to older patients and comparisons of ABMT with traditional approaches to multiple myeloma and relapsed non-Hodgkins lymphoma in older patients are needed. Further work to identify elderly patients most likely to benefit from this approach is also required.

Performing allogeneic and autologous hematopoietic SCT in the outpatient setting: effects on infectious complications and early transplant outcomes

This retrospective single-center study compared the incidence, spectrum and effect of infections in 1045 consecutive allogeneic (allo) and autologous (auto) hematopoietic SCT (HSCT) performed between 1995 and 2006 in the inpatient (IP) or outpatient (OP) setting. We analyzed 374 allo-HSCT (196 IP and 178 OP) and 671 auto-HSCT (163 IP and 508 OP). The incidence of infection was lower both in auto-OP (25% OP vs 33% IP, P=0.042) and allo-OP cohorts (42.7% OP vs 55.6% IP, P=0.012). The mean number of infections per transplant was lower in both auto-OP (0.39 OP vs 0.57 IP, P=0.05) and in allo-OP cohorts (0.78 OP vs 1.09 IP, P=0.018). The 100-day non-relapse mortality (NRM) for OP auto-HSCT was 4.72% and for IP 3.95% (P=0.68). The 100-day NRM for OP allo-HSCT was lower at 14.1% than it was for IP at 22.6% (P=0.041). Time to onset of first infection and spectrum of infections was similar in all groups. We conclude that performing allo- and auto-HSCT in the OP setting results in short-term outcomes, including infections complications that are comparable to the standard IP setting.

Contaminating tumour cells in autologous PBSC grafts do not influence survival or relapse following transplant for multiple myeloma or B-cell non-Hodgkin's lymphoma

Relapsed disease remains a major obstacle following autologous haematopoietic SCT (HSCT) for non-Hodgkins lymphoma (NHL) and multiple myeloma (MM). Studies regarding the importance of detectable tumour cells in PBSC collections have been inconclusive. Patients undergoing autologous HSCT for NHL and MM between 2001 and 2006 were enrolled (n=158). PBSC grafts were assessed for clonal IgH CDR3 gene rearrangements using qualitative semi-nested PCR. In comparison to patients with PCR-positive PBSC grafts, patients negative for detectable disease had no improvement in overall survival (OS) or PFS for MM (P=0.91 and 0.91) or NHL (P=0.82 and 0.85). Further, no significant difference in OS was observed between patients with PCR-positive compared with PCR-negative PBSC grafts with aggressive NHL histology (P=0.74) or indolent disease (P=0.29). Patients with contaminating tumour cells in autologous PBSCs do not have worsened OS or PFS in MM or NHL. Tumour cells detected by sensitive molecular methods in PBSC collections may be distinct from cells contaminating marrow and appear to have limited utility in identifying patients with MM and B-cell NHL who would benefit from purging strategies.

Cost analysis of the introduction of PBPC for autologous transplantation: effect of switching from bone marrow (BM) to peripheral blood progenitor cells (PBPC).

Increasingly, PBPC instead of BM are used for autologous transplantation. Limited data exist on the economic effects of this change. Using a resource-based utilization model we prospectively determined the costs of 48 autologous transplants (eight BM, 17 BM + PBPC, 23 PBPC), isolating the post-reinfusion period (day 0 to discharge) to better determine the effect of the rescue product. Length of stay post-reinfusion was significantly shorter in patients receiving PBPC (median 13 days) or BM + PBPC (median 14 days) vs BM alone (median 20 days) (P < 0.01). accordingly, transplant admission costs were less in the pbpc groups (pbpc

Combined intraommaya methotrexate, cytosine arabinoside, hydrocortisone and thio-TEPA for meningeal involvement by malignancies

22089, bm + pbpc