Ranjit S Chima

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

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Publications (35)124.27 Total impact

  • Critical care medicine 11/2015; 43(12 Suppl 1):104-105. DOI:10.1097/01.ccm.0000474240.41773.9c · 6.31 Impact Factor
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    ABSTRACT: Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplant (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity (CH50), and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined inter-individual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n=18) to patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n=11). In the PK analysis, we found significant inter-patient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, were significant determinants of eculizumab clearance and disease response. Sixty one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared to untreated patients (56% versus 9%, p=0.003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinurina. Our eculizumab dosing algorithm, including pre-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2015; DOI:10.1016/j.bbmt.2015.10.002 · 3.40 Impact Factor
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    ABSTRACT: Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by vision changes, altered mental status, and seizures typically caused by an acute rise in blood pressure. PRES has been reported after hematopoietic stem cell transplant (HSCT) in association with hypertension from calcineurin inhibitors and corticosteroids. The imaging evaluation of PRES after HSCT in children and young adults has not been well described. We performed a retrospective review of all HSCT recipients presenting to the intensive care unit (ICU) with new neurologic symptoms. A neuroradiologist reviewed all radiologic images and compared CT versus MRI findings indicative of diagnosis of PRES. Alternative imaging diagnoses explaining the patients' symptoms were also recorded. Fifty-four transplant recipients were admitted to the ICU with new neurologic symptoms. Thirty nine percent (21/54) of subjects had imaging findings consistent with PRES, 24% (13/54) had imaging findings consistent with an alternative diagnosis, 9% (5/54) had nonspecific finding and 28% (15/54) had no acute imaging findings. PRES was diagnosed at a median of 49 days (IQR 29-94) after HSCT. The presenting symptom for the majority of patients with PRES was seizures (86%), while 14% presented with acute encephalopathy. Ninety five percent of subjects diagnosed with PRES (20/21) underwent a head CT as their initial imaging evaluation. CT scan was diagnostic of PRES in 40% (8/20). Subsequently 16 patients underwent brain MRI with 12 additional patients being diagnosed with PRES on MRI. The median time elapsed between negative CT and a positive MRI examination was 20 hours (range: 3.6 hours to 9 days). CT scan serves as an excellent screening test for acute pathology such as intracranial hemorrhage, however it lacks sensitivity for the diagnosis of PRES. Patients with clinical symptoms suggestive of PRES who have a negative CT, should be treated appropriately for PRES and should undergo MRI of the brain as soon as clinically stable to confirm the diagnosis. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2015; 21(11). DOI:10.1016/j.bbmt.2015.07.023 · 3.40 Impact Factor

  • Biology of Blood and Marrow Transplantation 02/2015; 21(2):S218. DOI:10.1016/j.bbmt.2014.11.335 · 3.40 Impact Factor
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    ABSTRACT: Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.
    Biology of Blood and Marrow Transplantation 02/2015; 21(2):S217-S218. DOI:10.1016/j.bbmt.2014.11.334 · 3.40 Impact Factor

  • Biology of Blood and Marrow Transplantation 02/2015; 21(2):S215-S216. DOI:10.1016/j.bbmt.2014.11.331 · 3.40 Impact Factor
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    ABSTRACT: Pediatric hospital-acquired venous thromboembolism (VTE) is an increasingly prevalent and morbid disease. A multidisciplinary team at a tertiary children's hospital sought to answer the following clinical question: "Among hospitalized adolescents, does risk assessment and stratified VTE prophylaxis compared with no prophylaxis reduce VTE occurrence without an increase in significant adverse effects?" Serial literature searches using key terms were performed in the following databases: Medline, Cochrane Database, CINAHL (Cumulative Index to Nursing and Allied Health), Scopus, EBMR (Evidence Based Medicine Reviews). Pediatric studies were sought preferentially; when pediatric evidence was sparse, adult studies were included. Abstracts and titles were screened, and relevant full articles were reviewed. Studies were rated for quality using a standard rating system. Moderate evidence exists to support VTE risk assessment in adolescents. This evidence comes from pediatric studies that are primarily retrospective in design. The results of the studies are consistent and cite prominent factors such as immobilization and central venous access. There is insufficient evidence to support specific prophylactic strategies in pediatric patients because available pediatric evidence for thromboprophylaxis efficacy and safety is minimal. There is, however, high-quality, consistent evidence demonstrating efficacy and safety of thromboprophylaxis in adults. On the basis of the best available evidence, we propose a strategy for risk assessment and stratified VTE prophylaxis for hospitalized adolescents. This strategy involves assessing risk factors and considering prophylactic measures based on level of risk. We believe this strategy may reduce risk of VTE and appropriately balances the adverse effect profile of mechanical and pharmacologic prophylactic methods. Copyright © 2015 by the American Academy of Pediatrics.
    Hospital Pediatrics 01/2015; 5(1):44-51. DOI:10.1542/hpeds.2014-0044
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    ABSTRACT: Cardiac complications after hematopoietic stem cell transplant (HSCT) can lead to significant morbidity and mortality. Cardiac evaluation during the first 100 days after HSCT is usually performed only if clinically indicated and there are no studies examining if routine screening would be of benefit in this patient population at high risk for tissue injury. We conducted a single center prospective clinical study to screen for cardiac complications in pediatric and young adult patients. One hundred consecutive HSCT patients underwent scheduled echocardiographic screening on day +7 after transplantation, independent of their clinical condition. At least one abnormality was identified in 30% of cases. Seventeen children had a pericardial effusion, 13 elevated right ventricular pressure and 3 reduced left ventricular function. Survival was reduced in children with any echocardiographic abnormality at day 7 (67% vs. 80% in those with and without abnormality, p= 0.073). Moreover, raised right ventricular pressure at day +7 was significantly associated with transplant-associated thrombotic microangiopathy (TA-TMA) (p=0.004), and may indicate early vascular injury in the lungs. These data suggest that echocardiography 7 days after HSCT can detect early cardiac complications of HSCT and may identify early vascular injury associated with TA-TMA.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2014; 21(1). DOI:10.1016/j.bbmt.2014.09.028 · 3.40 Impact Factor
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    ABSTRACT: Transplant-associated thrombotic microangiopathy (TMA) leads to generalized endothelial dysfunction that can progress to multi-organ injury and severe cases are associated with poor outcomes after hematopoietic cell transplantation (HSCT). Identifying patients at highest risk for severe disease is challenging. We prospectively evaluated 100 consecutive HSCT recipients to determine the incidence of moderate and severe TMA and factors associated with poor overall outcomes. Thirty nine subjects (39%) met previously published criteria for TMA. Subjects with TMA had a significantly higher non-relapse mortality (43.6% versus 7.8%, p<0.0001) at 1 year post-HSCT compared to those without TMA. Elevated lactate dehydrogenase, proteinuria on routine urinalysis, and hypertension were the earliest markers of TMA. Proteinuria (>30mg/dL) and evidence of terminal complement activation (elevated sC5b-9) in the blood at the time of TMA diagnosis were associated with very poor survival (<20% at 1-year), while all TMA subjects without proteinuria and a normal sC5b-9 serum concentration survived (p<0.01). Based on these prospective observations, we conclude that severe TMA occurred in 18% of HSCT recipients in our cohort and propose an algorithm to identify the highest risk patients who might benefit from prompt clinical interventions.
    Blood 05/2014; 124(4). DOI:10.1182/blood-2014-03-564997 · 10.45 Impact Factor
  • Katja M Gist · Ranjit S Chima ·

    Critical care medicine 05/2014; 42(5):1317-8. DOI:10.1097/CCM.0000000000000185 · 6.31 Impact Factor
  • Danielle L Webster · Aaron H Gardner · Thomas J Dye · Ranjit S Chima ·
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    ABSTRACT: Human metapneumovirus (hMPV) is a relatively recent addition to the multiplicity of viruses causing respiratory illness in infants and children. Although well described in its ability to cause respiratory illness, there is limited data detailing the association of hMPV with neurologic complications. In this report, we describe 2 toddlers with hMPV infection who presented in status epilepticus and went on to develop respiratory failure. Both patients fully recovered over 2 weeks and were discharged from the hospital with no sequelae. The association between hMPV infection and neurologic complications is increasingly being reported in the literature. Clinicians should be aware of these uncommon manifestations of a common respiratory pathogen and consider testing for hMPV when managing pediatric patients who present with unexplained status epilepticus or encephalitis.
    PEDIATRICS 02/2014; 133(3). DOI:10.1542/peds.2013-0929 · 5.47 Impact Factor
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    ABSTRACT: The insulin sensitizing thiazolidinedione drugs, rosiglitazone and pioglitazone are specific peroxisome proliferator-activated receptor-gamma agonists and reduce pro-inflammatory responses in patients with type 2 diabetes and coronary artery disease, and may be beneficial in sepsis. Sepsis was induced in 8-10-wk-old C57BL/6 mice by cecal ligation and puncture (CLP) with a 22 -g double puncture technique. Mice received an i.p. injection of vehicle (DMSO:PBS) or pioglitazone (20 mg/kg) at 1 h and 6 h after CLP, and were sacrificed at various time points. In sepsis, vehicle-treated mice had hypoglycemia, increased lung injury and increased lung neutrophil infiltration. Pro-inflammatory plasma cytokines were increased, but the plasma adipokine, adiponectin, was decreased in vehicle-treated septic mice. This corresponded with inhibitor κB (IκBα) protein degradation and an increase in NF-κB activity in lung. Pioglitazone treatment improved plasma Glc and adiponectin levels, and decreased pro-inflammatory cytokines. Lung IκBα protein expression increased and corresponded with a decrease in NF-κB activity in the lung from pioglitazone-treated mice. Pioglitazone reduces the inflammatory response in polymicrobial sepsis in part through inhibition of NF-κB and may be a novel therapy in sepsis.
    Innate Immunity 09/2013; 20(5). DOI:10.1177/1753425913501565 · 3.27 Impact Factor
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    ABSTRACT: Pulmonary hypertension (PH) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Given its non-specific clinical presentation it is likely that this clinical entity is under diagnosed after HSCT. Data describing the incidence, risk factors, and etiology of PH in HSCT recipients is minimal. Physicians caring for HSCT recipients should be aware of this severe post-transplant complication since timely diagnosis and treatment may allow improved clinical outcomes. We summarize the pathophysiology, clinical presentation, diagnosis and management of PH in HSCT recipients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2013; 19(11). DOI:10.1016/j.bbmt.2013.07.017 · 3.40 Impact Factor
  • Ranjit S Chima · Kamal Abulebda · Sonata Jodele ·
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    ABSTRACT: Hematopoietic stem cell transplant (SCT) remains a curative option for a variety of malignant and non-malignant disorders in children. Following transplant a proportion of SCT recipients become critically ill and need intensive care. Critical illness may occur in the setting of transplant complications such as graft versus host disease (GVHD), idiopathic pneumonia syndrome (IPS), veno-occlusive disease (VOD) and transplant associated thrombotic microangiopathy (TA-TMA). Hence, familiarity with recent advances in the transplant process and complications is crucial for the intensivist. This article will highlight common complications encountered in the critically ill SCT recipient.
    Pediatric Clinics of North America 06/2013; 60(3):689-707. DOI:10.1016/j.pcl.2013.02.007 · 2.12 Impact Factor
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    ABSTRACT: Deep venous thrombosis (DVT) is being increasingly recognized as a significant issue in children. Despite the low incidence of DVT, the risks of pulmonary embolism and death in children are significant. Post-thrombotic syndrome, a syndrome of chronic venous insufficiency, can have long-term adverse consequences in children and adolescents. Adult studies have shown that catheter-directed therapy can reduce the incidence of post-thrombotic syndrome. Safety of catheter-directed therapy in adolescents has also been demonstrated. These reasons compelled us to institute a pediatric endovascular thrombolysis program at our institute for management of pediatric DVT. We describe the process of developing a multi-disciplinary thrombolysis program involving interventional radiology (pediatric and adult), pediatric hematology, critical care, anesthesia and vascular surgery, and describe the role of each specialty in the development of the program. We also describe our experience with patient selection, endovascular therapy procedure, pre-, intra- and post-procedure monitoring, and follow-up management for endovascular therapy for DVT.
    Pediatric Radiology 03/2013; 43(8). DOI:10.1007/s00247-013-2634-0 · 1.57 Impact Factor
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    Biology of Blood and Marrow Transplantation 02/2013; 19(2):S160. DOI:10.1016/j.bbmt.2012.11.122 · 3.40 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is rarely included in the differential diagnosis of cardiorespiratory failure after pediatric hematopoietic stem cell transplant (HSCT) as the clinical presentation is nonspecific and may mimic other etiologies. The pathogenesis of PAH in HSCT is poorly understood and the diagnosis requires a high degree of suspicion. We describe 5 children diagnosed with PAH after allogeneic HSCT. All 5 patients had prolonged clinical signs of transplantation-associated thrombotic microangiopathy (TA-TMA) when they presented with hypoxemic respiratory failure and evidence of PAH. Four of the 5 patients had echocardiographic evidence of PAH and 1 patient was diagnosed with PAH only on autopsy. PAH was diagnosed a median of 76 days (range, 56-101 days) after a diagnosis of TA-TMA. Despite aggressive medical management, including inhaled nitric oxide, 4 of the 5 patients died. One patient recovered from PAH after 11 months of sildenafil therapy. Three of the 4 deceased patients had an autopsy performed demonstrating severe pulmonary vascular disease consistent with TA-TMA and severe PAH. We conclude that TA-TMA can be associated with significant pulmonary vascular injury presenting as hypoxemic respiratory failure with PAH after HSCT. Pediatric patients with unexplained hypoxemia after HSCT should be evaluated for both transplantation complications, TA-TMA, and PAH, accordingly.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2012; 19(2). DOI:10.1016/j.bbmt.2012.08.022 · 3.40 Impact Factor
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    ABSTRACT: OBJECTIVES:: Survival for hematopoietic stem cell transplant patients requiring pediatric intensive care unit admission may be improving. This study was conducted to review outcomes for patients undergoing hematopoietic stem cell transplantation requiring admission to our pediatric intensive care unit and to identify variables impacting survival. DESIGN:: Retrospective database review. SETTING:: Pediatric intensive care unit and bone marrow transplant service of a children's hospital. PATIENTS:: Patients undergoing hematopoietic stem cell transplantation at our center from July 2004 through June 2010 requiring pediatric intensive care unit admission during the same period. MEASUREMENTS AND MAIN RESULTS:: Thirty-five percent of patients (155 of 448) undergoing hematopoietic stem cell transplantation required 319 admissions over this period. Of these 155 patients, 63% (97 of 155) were discharged alive following their most recent admission with a 100-day survival of 51% (79 of 155). Forty-five percent (69 of 155) of patients were still alive on long-term follow-up. Intubation and mechanical ventilation were required for 57% (88 of 155) of patients, with 39% (34 of 88) of patients surviving their last pediatric intensive care unit admission. Renal support was utilized for 25% (38 of 155) of patients with 34% (13 of 38) survival to pediatric intensive care unit discharge. Admissions surviving to pediatric intensive care unit discharge had significantly lower Pediatric Risk of Mortality II scores, shorter pediatric intensive care unit length of stay, lower utilization of intubation and mechanical ventilation with fewer ventilator days, and lower use of renal support when compared to nonsurvivors. Of note, each prior pediatric intensive care unit admission significantly reduced the odds of pediatric intensive care unit survival. CONCLUSIONS:: We report a 63% survival to pediatric intensive care unit discharge, with 45% surviving at a median follow-up of over 2 yrs for all hematopoietic stem cell transplantation patients admitted to our pediatric intensive care unit over a 6-yr period. Our data suggest improved survival outcomes for this high risk patient population.
    Pediatric Critical Care Medicine 07/2012; 13(6). DOI:10.1097/PCC.0b013e318253c945 · 2.34 Impact Factor
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    Biology of Blood and Marrow Transplantation 02/2012; 18(2):S232. DOI:10.1016/j.bbmt.2011.12.088 · 3.40 Impact Factor
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    ABSTRACT: Hyperglycemia is common in critically ill children and appears to be associated with poor outcomes. However, the incidence of hypoglycemia while attempting glycemic control using an insulin infusion may be as high as 25% and hypoglycemia may be an independent risk factor for mortality in critically ill children. An improvement team developed a guideline for initiation and maintenance of insulin infusions for hyperglycemia in critically ill, nondiabetic patients in the pediatric intensive care unit. The guideline included an insulin infusion algorithm that provided an initiating dose, titration instructions, and discontinuation parameters. Guideline recommendations addressed the frequency of bedside blood glucose monitoring and management of symptomatic hypoglycemia while on insulin infusion. The guideline was implemented in late January 2007 and revised in September 2007. Hypoglycemic events in at-risk patients decreased significantly following implementation of the guideline, from 36% to 3%, despite an increase in the total number of patient days on insulin infusion. The average days between hypoglycemic events increased from 21 to 186. Implementation of a guideline to manage critical illness hyperglycemia in nondiabetic, critically ill pediatric patients resulted in a reduction in hypoglycemic events and a sustained increase in the days between such events.
    Quality management in health care 01/2012; 21(1):20-8. DOI:10.1097/QMH.0b013e318241807c