CAP Profiles

Bio

Bio

Dr. Kanwaljeet Anand graduated from M.G.M. Medical College, Indore (India). As a Rhodes Scholar at University of Oxford, he received the D.Phil. degree, followed by post-doctoral fellowship at Harvard Medical School, a categorical Pediatrics residency training at Boston Children’s Hospital and a Critical Care Medicine fellowship at the Massachusetts General Hospital, Boston.
His pioneering research was widely recognized by the Dr. Michael Blacow Award from British Paediatric Association (1986), Pediatric Resident Research Award from American Academy of Pediatrics (1992), the inaugural Young Investigator Award in Pediatric Pain from International Association for Study of Pain (IASP, 1994), the Jeffrey Lawson Award for Children’s Advocacy from American Pain Society (2000), the Windermere Honorary Lectureship Award from Royal College of Paediatrics & Child Health (2004), Joan M. Cranmer “Mentor of the Year” Award (2007) from University of Arkansas, the Nils Rosén von Rosenstein Award* from the Swedish Academy of Medicine (2009), Top Mentor Award, School of Graduate Studies, University of Arkansas for Medical Sciences (2011), the 9th Annual “In Praise of Medicine” Public Address at Erasmus University (2014), the Journées Nationales de Néonatologie 2015 Address at The Pasteur Institute (Paris, France), the Nightingale Excellence Award (2016) from Stanford Children’s Healthcare, and an Honorary Doctorate from University of Örebro, Sweden (2019). Dr. Anand founded the Harmony Health Clinic, the largest charitable medical & dental clinic in Central Arkansas and worked to remove inter-faith conflict throughout the state of Arkansas. The Father Joseph Biltz Award (2007) from the National Conference for Community & Justice (NCCJ) and the Dr. Martin Luther King “Salute to Greatness” Individual Award (2008) from the Governor of Arkansas recognized his commitments to community service.
Dr. Anand is currently Professor of Pediatrics, Anesthesiology, Perioperative & Pain Medicine at Stanford University School of Medicine; he directs the Pain/Stress Neurobiology Lab, the Jackson Vaughan Critical Care Research Fund, and serves as Field Chief Editor for the journal Frontiers in Pediatrics. He has published >275 peer-reviewed articles, edited 9 books or journal issues, and has contributed >65 book chapters and numerous other publications. He is considered a world authority on pain and stress in newborns and the pain management in infants.

Academic Appointments

Honors & Awards

  • Nightingale Excellence Award for Physicians, Stanford Children’s Healthcare System (2016)
  • Elected as Executive Committee Member for the PPRN, the Pediatric Section of the ACTTION Network, Pediatric Pain Research Network (2015)
  • Member, Study Section for STTR Applications, Eunice Kennedy Shriver National Institute for Child Health & Human Development/NIH (2015)
  • Respect for Nursing Award , PICU Nurses and Nursing Leadership, Lucile Packard Children’s Hospital, Palo Alto, CA. (2015)

Contact

    • Tel: (650) 498-6313
    Fax: (650) 736-9186
  • Lisa Higdon Administrative Assistant
    • Tel: 650-497-6602

Links

Research & Scholarship

Current Research and Scholarly Interests

Dr. Anand is a translational clinical researcher who pioneered research on the endocrine-metabolic stress responses of infants undergoing surgery and developed the first-ever scientific rationale for pain perception in early life. This provided a framework for newer methods of pain assessment, numerous clinical trials of analgesia/anesthesia in newborns, infants and older children. His research focus over the past 30+ years has contributed fundamental knowledge about pediatric pain/stress, long-term effects of pain in early life, management of pain, mechanisms for opioid tolerance and withdrawal. Current projects in his laboratory are focused on developing biomarkers for repetitive pain/stress in critically ill children and the mechanisms underlying sedative/anesthetic neurotoxicity in the immature brain. He designed and directed many randomized clinical trials (RCT), including the largest-ever pediatric analgesia trial studying morphine therapy in ventilated preterm neonates. He has extensive experience in clinical and translational research from participating in collaborative networks funded by NIMH, NINDS, or NICHD, a track-record of excellent collaboration across multiple disciplines, while achieving success with large research teams like the Collaborative Pediatric Critical Care Research Network (CPCCRN). He played a leadership roles in CANDLE (Condition Affecting Neuro-Development & Learning in Early infancy) and other activities of the Urban Child Institute and UT Neuroscience Institute. More recently, he led the NeoOpioid Consortium funded by the European Commission, which collected data from 243 NICUs in 18 European countries.

Clinical Trials

  • Assessment of Pain in Newborns and Older Infants (Infant Pain Assessment Study = Recruiting

    Pain assessments in non-verbal, critically ill infants represent an important clinical challenge. Older children or adults can easily express their pain, but infants lack that capability. They frequently experience repetitive acute pain during routine ICU care, but their analgesic management flounders on the horns of a dilemma: (a) failure to treat infant pain leads to immediate clinical instability and potentially long-term physical, behavioral, and cognitive sequelae, vs. (b) strong analgesics may increase risks for medical complications and/or impaired brain growth. Bedside nurses currently assess pain using pain scores, before taking action to ameliorate pain. Pain scores increase nursing workload and provide subjective assessments, rather than objective data for evaluating infant pain. Consequently, infants exposed to skin-breaking procedures, surgery, or other painful conditions often receive variable and inconsistent pain management in the ICU. The investigators aim to develop a multimodal pain assessment system, using sensor fusion and novel machine learning algorithms to provide an objective measure of pain that is context-dependent and rater-independent. This will enhance the quality of pain management in ICUs and allow continuous pain monitoring in real-time.

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  • Electronic Application of a Severe Sepsis Screening Tool and Management Bundle Recruiting

    Thousands of children die from Sepsis following routine infections. Many of these deaths can be prevented with earlier recognition and focused management. No tools are currently available to recognize the signs of early sepsis in children. The investigators have developed a electronic health record-based tool that will recognize children with sepsis early and trigger an alert to their hospital caregivers. The caregivers will be prompted to launch a focused management bundle that can stabilize these children, prevent further deterioration and reduce their chances of sepsis related complications and death. The proposed study will test the validity and effectiveness of this electronic tool in reducing sepsis mortality rates.

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Teaching

2018-19 Courses

Graduate and Fellowship Programs

  • Pediatric Critical Care Medicine (Fellowship Program)

Publications

All Publications

  • Measuring socioeconomic adversity in early life. Acta paediatrica (Oslo, Norway : 1992) Anand, K. J., Rigdon, J., Rovnaghi, C. R., Qin, F., Tembulkar, S., Bush, N., LeWinn, K., Tylavsky, F. A., Davis, R., Barr, D. A., Gotlib, I. H. 2019

    Abstract

    AIM: Early life adversity in leads to enduring effects on physical and mental health, school performance, and other outcomes. We sought to identify potentially modifiable factors leading to socioeconomic adversity in early life.METHODS: We enrolled 1,503 pregnant women aged 16-40 years, without pregnancy complications or pre-existing conditions from Shelby County, Tennessee. Social, familial, and economic variables were analyzed using principal components (PCs) analyses to generate the Socioeconomic Adversity Index (SAI). This was replicated using the National Survey of Children's Health (NSCH). Health and social outcomes were compared across the quintile groups defined by SAI values at the county, state, and national levels.RESULTS: Significant differences occurred across the SAI Quintile-1 to Quintile-5 groups in marital status, household structure, annual income, education, and health insurance. Significantly worse health and social outcomes occurred in the lower vs. higher SAI quintiles, including maternal depression, parental incarceration, child's birthweight, and potential for child abuse. Maternal age and race also differed significantly across the SAI quintiles.CONCLUSION: Modifiable factors contributing to socioeconomic adversity in early life included marital status, household structure, annual income, education, and health insurance. Those exposed to greater socioeconomic adversity as defined by SAI values had significantly worse maternal and child outcomes. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/apa.14715

    View details for PubMedID 30614554

  • Maternal experiences of trauma and hair cortisol in early childhood in a prospective cohort PSYCHONEUROENDOCRINOLOGY Slopen, N., Roberts, A. L., LeWinn, K. Z., Bush, N. R., Rovnaghi, C. R., Tylaysky, F., Anand, K. S. 2018; 98: 168–76

    Abstract

    Maternal trauma can have intergenerational consequences but little is known about whether maternal traumas affect key biological domains associated with mental health in their offspring. The objective of this study was to examine maternal lifetime history of traumatic events through mid-gestation in relation to offspring cortisol production in early childhood.The sample was comprised of 660 children (49.9% Black, 44.4% White) from a longitudinal study of mother-offspring dyads in Shelby County, Tennessee, followed from mid-gestation to child age 4 years (enrolled 2006-2011). Maternal lifetime history of traumatic life events were assessed mid-gestation using the Traumatic Life Events Questionnaire. Total cortisol output among offspring was measured using hair cortisol concentrations at ages 1 to 4 years.Associations of maternal trauma history with child hair cortisol varied by child's age. No association was observed at age 1 or 2. In adjusted regression models, at ages 3 and 4, offspring of mothers in the third (β = 0.99, P < .01), fourth (β=0.72, P < .05), and fifth (β=0.83, P < .01) quintiles of trauma exposure history had elevated (natural log) hair cortisol concentrations, relative to mothers in the lowest quintile (P-trend = 0.003). The associations were not attenuated after adjustment for theorized pathways, including premature birth, maternal postpartum depression, and maternal parenting stress.Maternal lifetime trauma exposures are associated with offspring hair cortisol concentrations. Future research is needed to determine intermediary mechanisms and functional significance of elevated hair cortisol concentration in young children.

    View details for DOI 10.1016/j.psyneuen.2018.08.027

    View details for Web of Science ID 000450381100023

    View details for PubMedID 30170311

  • Pathways from adverse childhood experiences to nervous system dysregulation. (https://www.internalmedicinereview.org/index.php/imr/article/download/773/pdf). Internal Medicine Review Rovnaghi, C. R., Anand, K. J. 2018; 4 (10): 1-20
  • Clinical Profile Associated with Adverse Childhood Experiences: The Advent of Nervous System Dysregulation. Children (Basel, Switzerland) Elbers, J., Rovnaghi, C. R., Golianu, B., Anand, K. J. 2017; 4 (11)

    Abstract

    BACKGROUND: We report the prevalence of children with multiple medical symptoms in a pediatric neurology clinic, describe their symptom profiles, and explore their association with adverse childhood experiences (ACEs).METHODS: We retrospectively reviewed 100 consecutive patients from an outpatient pediatric neurology clinic. Patients were included if they were ≥5 years old and reported ≥4 symptoms that were unexplained for ≥3-months. Symptom profiles across six functional domains were recorded: (1) executive dysfunction, (2) sleep disturbances, (3) autonomic dysregulation, (4) somatization, (5) digestive symptoms, and (6) emotional dysregulation. ACEs were scored for all patients.RESULTS: Seventeen patients reported ≥4 medical symptoms. Somatization, sleep disturbances, and emotional dysregulation occurred in 100% patients, with executive dysfunction (94%), autonomic dysregulation (76%), and digestive problems (71%) in the majority. Forty-two children reported ≥1 ACE, but children with ≥4 symptoms were more likely to report ACEs compared to other children (88% vs. 33%; p < 0.0001) and had a higher median total ACE score (3 vs. 1; p < 0.001).CONCLUSIONS: Children with multiple medical symptoms should be screened for potential exposure to ACEs. A clinical profile of symptoms across multiple functional domains suggests putative neurobiological mechanisms involving stress and nervous system dysregulation that require further study.

    View details for DOI 10.3390/children4110098

    View details for PubMedID 29140276

  • Defining pain in newborns: Need for a uniform taxonomy? Acta paediatrica (Oslo, Norway : 1992) Anand, K. J. 2017

    Abstract

    A scientific rationale for applying pain terms such as acute, persistent, prolonged, or chronic pain to newborns was derived from the scientific literature on neonatal pain assessments, previous attempts to define chronic pain, and the clinical and neurophysiological features of neonatal pain. This novel framework incorporates the temporal features, localizing characteristics, and secondary effects of the pain experienced, as well as the behavioral and physiological response patterns of newborns.Although not evidence-based, this framework provides an initial starting point for defining commonly used neonatal pain terms. It will require future revision/refinement based on the accumulating evidence for non-acute pain. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/apa.13936

    View details for PubMedID 28556311

  • Assessment of Continuous Pain in Newborns admitted to NICUs in 18 European Countries. Acta paediatrica Anand, K. J., Eriksson, M., Boyle, E. M., Avila-Alvarez, A., Andersen, R. D., Sarafidis, K., Polkki, T., Matos, C., Lago, P., Papadouri, T., Attard-Montalto, S., Ilmoja, M., Simons, S., Tameliene, R., Van Overmeire, B., Berger, A., Dobrzanska, A., Schroth, M., Bergqvist, L., Courtois, E., Rousseau, J., Carbajal, R. 2017

    Abstract

    Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown.A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission.Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001).Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.

    View details for DOI 10.1111/apa.13810

    View details for PubMedID 28257153

  • Does noninvasive electrical stimulation of acupuncture points reduce heelstick pain in neonates? Acta paediatrica Mitchell, A. J., Hall, R. W., Golianu, B., Yates, C., Williams, D. K., Chang, J., Anand, K. J. 2016

    Abstract

    Noninvasive electrical stimulation at acupuncture points (NESAP) for analgesia is used in children, but has not been widely studied in neonates. The purpose of this study was to determine whether NESAP alone or in combination with sucrose relieved heelstick pain in neonates.Term neonates (n = 162) receiving routine heelsticks for newborn screening were enrolled following parental consent. All infants received facilitated tucking and non-nutritive sucking. Neonates were randomised to standard care, sucrose, NESAP or sucrose plus NESAP. NESAP (3.5 mA, 10 Hz) or sham was administered over four acupuncture points. The Premature Infant Pain Profile (PIPP), heart rate variability (HRV) and salivary cortisol were used to measure heelstick pain.PIPP scores among all four treatment groups increased during heelstick, F (9,119) = 1.95, p = 0.05 and NESAP therapy had no significant effect on PIPP scores. However, PIPP scores from baseline to heelstick increased the most in the two groups not receiving sucrose (p < 0.01). Mean PIPP scores remained below five during the heelstick in all four groups, indicating minimal or no pain. Differences in HRV and salivary cortisol among groups were insignificant.NESAP at 3.5 mA, 10 Hz is not effective in relieving pain during heelsticks in neonates.

    View details for DOI 10.1111/apa.13581

    View details for PubMedID 27607517

    View details for PubMedCentralID PMC5118154

  • Revisiting a dilemma: repetitive pain vs. opioid exposures? ACTA PAEDIATRICA Anand, K. J. 2016; 105 (7): 736-737

    View details for DOI 10.1111/apa.13442

    View details for Web of Science ID 000378565100012

    View details for PubMedID 27272629

  • The validity and reliability of the EValuation of INtervention Scale: preliminary report ACTA PAEDIATRICA Warren, I., Hicks, B., Kleberg, A., Eliahoo, J., Anand, K. J., Hickson, M. 2016; 105 (6): 618-622

    Abstract

    Pain management is a priority for infants receiving neonatal care as they undergo many necessary painful and stressful interventions, which are associated with negative short- or long-term consequences. This study aims to validate the content, and test the reliability, of the EValuation of INtervention Scale (EVIN), which is designed to evaluate the use of widely recommended nonpharmacological strategies to reduce neonatal pain and stress during procedures.The content of the EVIN was validated with multidisciplinary participation (N = 80), and consistency was established via observations on preterm infants (N = 12, at 31-34 weeks' gestation) during interventions in a neonatal unit. A revised scale was tested for inter-rater reliability with observations of invasive (blood sampling, N = 16) and noninvasive (nappy change, N = 18) interventions. The intraclass correlation coefficient (ICC) was used to determine inter-rater reliability. SPSS (PASW Statistics) version 18 was used for analysis.Very good intraclass correlation coefficients (>0.8) for both invasive (0.962) and noninvasive procedures (0.970) were achieved.These results indicate that the EVIN is suitable for the evaluation of nonpharmacological support during painful or stressful interventions.

    View details for DOI 10.1111/apa.13370

    View details for Web of Science ID 000376265400017

    View details for PubMedID 26896153

  • Ketamine exposure during embryogenesis inhibits cellular proliferation in rat fetal cortical neurogenic regions ACTA ANAESTHESIOLOGICA SCANDINAVICA Dong, C., Rovnaghi, C. R., Anand, K. J. 2016; 60 (5): 579-587

    Abstract

    Developmental neurotoxicity of ketamine, an N-methyl-d-aspartate receptor antagonist, must be considered due to its widespread uses for sedation/analgesia/anesthesia in pediatric and obstetric settings. Dose-dependent effects of ketamine on cellular proliferation in the neurogenic regions of rat fetal cortex [ventricular zone (VZ) and subventricular zone (SVZ)] were investigated in this in vivo study.Timed-pregnant Sprague-Dawley rats at embryonic day 17 (E17) were given with different doses of ketamine intraperitoneally (0, 1, 2, 10, 20, 40, and 100 mg/kg). Proliferating cells in the rat fetal brains were labeled by injecting 100 mg/kg of 5-bromo-2'-deoxyuridine (BrdU) intraperitoneally. BrdU-labeled cells were detected by immunostaining methods. The numbers of BrdU-positive cells in VZ and SVZ of rat fetal cortex were employed to quantify proliferation in the developing rat cortex.Ketamine dose-dependently reduced the number of BrdU-positive cells in VZ (P < 0.001) and SVZ (P < 0.001) of the rat fetal cortex. SVZ showed greater susceptibility to ketamine-induced reduction of proliferation in rat fetal cortex, occurring even at clinically relevant doses (2 mg/kg).These data suggest that exposure to ketamine during embryogenesis can dose-dependently inhibit the cellular proliferation in neurogenic regions of the rat fetal cortex.

    View details for DOI 10.1111/aas.12689

    View details for Web of Science ID 000373773700004

    View details for PubMedID 26822861

  • Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial CYTOKINE Schwingshackl, A., Kimura, D., Rovnaghi, C. R., Saravia, J. S., Cormier, S. A., Teng, B., West, A. N., Meduri, U. G., Anand, K. J. 2016; 77: 63-71

    View details for DOI 10.1016/j.cyto.2015.10.007

    View details for Web of Science ID 000366540500009

    View details for PubMedID 26545141

  • Epidemiology and neonatal pain management of heelsticks in intensive care units: EPIPPAIN 2, a prospective observational study. International journal of nursing studies Courtois, E., Droutman, S., Magny, J. F., Merchaoui, Z., Durrmeyer, X., Roussel, C., Biran, V., Eleni, S., Vottier, G., Renolleau, S., Desfrere, L., Castela, F., Boimond, N., Mellah, D., Bolot, P., Coursol, A., Brault, D., Chappuy, H., Cimerman, P., Anand, K. J., Carbajal, R. 2016; 59: 79–88

    Abstract

    Heelstick is the most frequently performed skin-breaking procedure in the neonatal intensive care units (NICUs). There are no large multicenter studies describing the frequency and analgesic approaches used for heelsticks performed in NICUs.To describe the frequency of heelsticks and their analgesic management in newborns in the NICU. To determine the factors associated with the lack of specific preprocedural analgesia for this procedure.EPIPPAIN 2 (Epidemiology of Procedural PAin In Neonates) is a descriptive prospective epidemiologic study.All 16 NICUs in the Paris region in France.All newborns in the NICU with a maximum corrected age of 44 weeks +6 days of gestation on admission who had at least one heelstick during the study period were eligible for the study. The study included 562 newborns.Data on all heelsticks and their corresponding analgesic therapies were prospectively collected. The inclusion period lasted six weeks, from June 2, 2011 to July 12, 2011. Newborns were followed from their admission to the 14th day of their NICU stay or discharge, whichever occurred first.The mean (SD) gestational age was 33.3 (4.4) weeks and duration of participation was 7.5 (4.4) days. The mean (SD; range) of heelsticks per neonate was 16.0 (14.4; 1-86) during the study period. Of the 8995 heelsticks studied, 2379 (26.4%) were performed with continuous analgesia, 5236 (58.2%) with specific preprocedural analgesia. Overall, 6764 (75.2%) heelsticks were performed with analgesia (continuous and/or specific). In a multivariate model, the increased lack of preprocedural analgesia was associated with female sex, term birth, high illness severity, tracheal or noninvasive ventilation, parental absence and use of continuous sedation/analgesia.Heelstick was very frequently performed in NICUs. Although, most heelsticks were performed with analgesia, this was not systematic. The high frequency of this procedure and the known adverse effects of repetitive pain in neonates should encourage the search of safe and effective strategies to reduce their number.

    View details for DOI 10.1016/j.ijnurstu.2016.03.014

    View details for PubMedID 27222453

  • Plasma Biomarker Analysis in Pediatric ARDS: Generating Future Framework from a Pilot Randomized Control Trial of Methylprednisolone: A Framework for Identifying Plasma Biomarkers Related to Clinical Outcomes in Pediatric ARDS. Frontiers in pediatrics Kimura, D., Saravia, J., Rovnaghi, C. R., Meduri, G. U., Schwingshackl, A., Cormier, S. A., Anand, K. J. 2016; 4: 31-?

    Abstract

    Lung injury activates multiple pro-inflammatory pathways, including neutrophils, epithelial, and endothelial injury, and coagulation factors leading to acute respiratory distress syndrome (ARDS). Low-dose methylprednisolone therapy (MPT) improved oxygenation and ventilation in early pediatric ARDS without altering duration of mechanical ventilation or mortality. We evaluated the effects of MPT on biomarkers of endothelial [Ang-2 and soluble intercellular adhesion molecule-1 (sICAM-1)] or epithelial [soluble receptor for activated glycation end products (sRAGE)] injury, neutrophil activation [matrix metalloproteinase-8 (MMP-8)], and coagulation (plasminogen activator inhibitor-1).Double-blind, placebo-controlled randomized trial.Tertiary-care pediatric intensive care unit (ICU).Mechanically ventilated children (0-18 years) with early ARDS.Blood samples were collected on days 0 (before MPT), 7, and 14 during low-dose MPT (n = 17) vs. placebo (n = 18) therapy. The MPT group received a 2-mg/kg loading dose followed by 1 mg/kg/day continuous infusions from days 1 to 7, tapered off over 7 days; placebo group received equivalent amounts of 0.9% saline. We analyzed plasma samples using a multiplex assay for five biomarkers of ARDS. Multiple regression models were constructed to predict associations between changes in biomarkers and the clinical outcomes reported earlier, including P/F ratio on days 8 and 9, plateau pressure on days 1 and 2, PaCO2 on days 2 and 3, racemic epinephrine following extubation, and supplemental oxygen at ICU discharge.No differences occurred in biomarker concentrations between the groups on day 0. On day 7, reduction in MMP-8 levels (p = 0.0016) occurred in the MPT group, whereas increases in sICAM-1 levels (p = 0.0005) occurred in the placebo group (no increases in sICAM-1 in the MPT group). sRAGE levels decreased in both MPT and placebo groups (p < 0.0001) from day 0 to day 7. On day 7, sRAGE levels were positively correlated with MPT group PaO2/FiO2 ratios on day 8 (r = 0.93, p = 0.024). O2 requirements at ICU transfer positively correlated with day 7 MMP-8 (r = 0.85, p = 0.016) and Ang-2 levels (r = 0.79, p = 0.036) in the placebo group and inversely correlated with day 7 sICAM-1 levels (r = -0.91, p = 0.005) in the MPT group.Biomarkers selected from endothelial, epithelial, or intravascular factors can be correlated with clinical endpoints in pediatric ARDS. For example, MPT could reduce neutrophil activation (⇓MMP-8), decrease endothelial injury (⇔sICAM-1), and allow epithelial recovery (⇓sRAGE). Large ARDS clinical trials should develop similar frameworks.https://clinicaltrials.gov, NCT01274260.

    View details for DOI 10.3389/fped.2016.00031

    View details for PubMedID 27066464

  • Research as a Standard of Care in the PICU PEDIATRIC CRITICAL CARE MEDICINE Zimmerman, J. J., Anand, K. J., Meert, K. L., Willson, D. F., Newth, C. J., Harrison, R., Carcillo, J. A., Berger, J., Jenkins, T. L., Nicholson, C., Dean, J. M. 2016; 17 (1): E13-E21

    Abstract

    Excellence in clinical care coupled with basic and applied research reflects the maturation of a medical subspecialty, advances that field, and provides objective data for identifying best practices. PICUs are uniquely suited for conducting translational and clinical research. In addition, multiple investigations have reported that a majority of parents are interested in their children's participation in clinical research, even when the research offers no direct benefit to their child. However, such activity may generate ethical conflict with bedside care providers trying to acutely identify the best approach for an individual critically ill child. Ultimately, this conflict may diminish enthusiasm for the generation of scientific evidence that supports the application of evidence-based medicine into PICU clinical standard work. Accordingly this review endeavors to provide an overview of current state PICU clinical research strengths, liabilities, opportunities, and barriers and contrast this with an established pediatric hematology-oncology iterative research model that constitutes a learning healthcare system.Narrative review of medical literature published in English.Currently, most PICU therapy is not evidence based. Developing a learning healthcare system in the PICU integrates clinical research into usual practice and fosters a culture of evidence-based learning and continual care improvement. As PICU mortality has significantly decreased, identification and validation of patient-centered, clinically relevant research outcome measures other than mortality is essential for future clinical trial design. Because most pediatric critical illness may be classified as rare diseases, participation in research networks will facilitate iterative, collaborative, multiinstitutional investigations that over time identify the best practices to improve PICU outcomes. Despite real ethical challenges, critically ill children and their families should have the opportunity to participate in translational/clinical research whenever feasible.

    View details for DOI 10.1097/PCC.0000000000000562

    View details for Web of Science ID 000367745900002

    View details for PubMedID 26513203

  • Methodological Considerations for Hair Cortisol Measurements in Children THERAPEUTIC DRUG MONITORING Slominski, R., Rovnaghi, C. R., Anand, K. J. 2015; 37 (6): 812-820

    Abstract

    Hair cortisol levels are used increasingly as a measure for chronic stress in young children. We propose modifications to the current methods used for hair cortisol analysis to more accurately determine reference ranges for hair cortisol across different populations and age groups.The authors compared standard (finely cutting hair) versus milled methods for hair processing (n = 16), developed a 4-step extraction process for hair protein and cortisol (n = 16), and compared liquid chromatography-mass spectrometry (LC-MS) versus enzyme-linked immunosorbent assays (ELISAs) for measuring hair cortisol (n = 28). The extraction process included sequential incubations in methanol and acetone, repeated twice. Hair protein was measured through spectrophotometric ratios at 260/280 nm to indicate the hair dissolution state using a BioTek plate reader and dedicated software. Hair cortisol was measured using an ELISA assay kit. Individual (n = 13), pooled hair samples (n = 12) with high, intermediate, and low cortisol values, and the ELISA assay internal standards (n = 3) were also evaluated by LC-MS.Milled and standard methods showed highly correlated hair cortisol (rs = 0.951, P < 0.0001) and protein values (rs = 0.902, P = 0.0002), although higher yields of cortisol and protein were obtained from the standard method in 13 of 16 and 14 of 16 samples, respectively (P < 0.05). Four sequential extractions yielded additional amounts of protein (36.5%, 27.5%, 30.5%, 3.1%) and cortisol (45.4%, 31.1%, 15.1%, 0.04%) from hair samples. Cortisol values measured by LC-MS and ELISA were correlated (rs = 0.737; P < 0.0001), although cortisol levels [median (interquartile range)] detected in the same samples by LC-MS [38.7 (14.4-136) ng/mL] were lower than that by ELISA [172.2 (67.9-1051) ng/mL]. LC-MS also detected cortisone, which comprised of 13.4% (3.7%-25.9%) of the steroids detected.Methodological studies suggest that finely cutting hair with sequential incubations in methanol and acetone, repeated twice, extracts greater yields of cortisol than does milled hair. Based on these findings, at least 3 incubations may be required to extract most of the cortisol in human hair samples. In addition, ELISA-based assays showed greater sensitivity for measuring hair cortisol levels than LC-MS-based assays.

    View details for DOI 10.1097/FTD.0000000000000209

    View details for Web of Science ID 000365594600017

    View details for PubMedID 25811341

  • Long-Acting Opioids for Treating Neonatal Abstinence Syndrome A High Price for a Short Stay? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Peltz, G., Anand, K. J. 2015; 314 (19): 2023-2024

    View details for DOI 10.1001/jama.2015.13537

    View details for Web of Science ID 000364764200013

    View details for PubMedID 26469386

  • Corticosteroids in pediatric ARDS: all cards on the table INTENSIVE CARE MEDICINE Schwingshackl, A., Meduri, G. U., Kimura, D., Cormier, S. A., Anand, K. J. 2015; 41 (11): 2036-2037

    View details for DOI 10.1007/s00134-015-4027-3

    View details for Web of Science ID 000361829900043

    View details for PubMedID 26359160

  • Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study LANCET RESPIRATORY MEDICINE Carbajal, R., Eriksson, M., Courtois, E., Boyle, E., Avila-Alvarez, A., Andersen, R. D., Sarafidis, K., Polkki, T., Matos, C., Lago, P., Papadouri, T., Montalto, S. A., Ilmoja, M., Simons, S., Tameliene, R., Van Overmeire, B., Berger, A., Dobrzanska, A., Schroth, M., Bergqvist, L., Lagercrantz, H., Anand, K. J. 2015; 3 (10): 796-812

    Abstract

    Neonates who are in pain or are stressed during care in the intensive care unit (ICU) are often given sedation or analgesia. We investigated the current use of sedation or analgesia in neonatal ICUs (NICUs) in European countries.EUROPAIN (EUROpean Pain Audit In Neonates) was a prospective cohort study of the management of sedation and analgesia in patients in NICUs. All neonates admitted to NICUs during 1 month were included in this study. Data on demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal syndromes were gathered during the first 28 days of admission to NICUs. Multivariable linear regression models and propensity scores were used to assess the association between duration of tracheal ventilation (TV) and exposure to opioids, sedatives-hypnotics, or general anaesthetics in neonates (O-SH-GA). This study is registered with ClinicalTrials.gov, number NCT01694745.From Oct 1, 2012, to June 30, 2013, 6680 neonates were enrolled in 243 NICUs in 18 European countries. Mean gestational age of these neonates was 35.0 weeks (SD 4.6) and birthweight was 2384 g (1007). 2142 (32%) neonates were given TV, 1496 (22%) non-invasive ventilation (NIV), and 3042 (46%) were kept on spontaneous ventilation (SV). 1746 (82%), 266 (18%), and 282 (9%) neonates in the TV, NIV, and SV groups, respectively, were given sedation or analgesia as a continuous infusion, intermittent doses, or both (p<0.0001). In the participating NICUs, the median use of sedation or analgesia was 89.3% (70.0-100) for neonates in the TV group. Opioids were given to 1764 (26%) of 6680 neonates and to 1589 (74%) of 2142 neonates in the TV group. Midazolam was given to 576 (9%) of 6680 neonates and 536 (25%) neonates of 2142 neonates in the TV group. 542 (25%) neonates in the TV group were given neuromuscular blockers, which were administered as continuous infusions to 146 (7%) of these neonates. Pain assessments were recorded in 1250 (58%) of 2138, 672 (45%) of 1493, and 916 (30%) of 3017 neonates in the TV, NIV, and SV groups, respectively (p<0.0001). In the univariate analysis, neonates given O-SH-GA in the TV group needed a longer duration of TV than did those who were not given O-SH-GA (mean 136.2 h [SD 173.1] vs 39.8 h [94.7] h; p<0.0001). Multivariable and propensity score analyses confirmed this association (p<0.0001).Wide variations in sedation and analgesia practices occur between NICUs and countries. Widespread use of O-SH-GA in intubated neonates might prolong their need for mechanical ventilation, but further research is needed to investigate the therapeutic and adverse effects of O-SH-GA in neonates, and to develop new and safe approaches for sedation and analgesia.European Community's Seventh Framework Programme.

    View details for DOI 10.1016/S2213-2600(15)00331-8

    View details for Web of Science ID 000362452900023

    View details for PubMedID 26420017

  • Pediatric Intensive Care Unit Mortality Among Latino Children Before and After a Multilevel Health Care Delivery Intervention JAMA PEDIATRICS Anand, K. J., Sepanski, R. J., Giles, K., Shah, S. H., Juarez, P. D. 2015; 169 (4): 383-390

    Abstract

    Research on health equity has focused on documenting health care disparities or understanding factors leading to disparities, but limited efforts have focused on reducing health care disparities in children. Latino children have increased prevalence of acute and chronic conditions; they have limited access and other barriers to high-quality health care, including intensive care.To determine whether pediatric intensive care unit mortality can be reduced by a multilevel health care delivery intervention.Observational study of factors associated with pediatric intensive care unit mortality at a tertiary care metropolitan children's hospital in Memphis, Tennessee. Participants were children younger than 18 years discharged from the pediatric intensive care unit during the 3-year preintervention period of 2007 to 2009 (n = 3891) and 3-year postintervention period of 2010 to 2012 (n = 4179).Multilevel health care intervention to address the increased odds of mortality among Latino children.The odds of mortality were analyzed over the 3-year preintervention period (2007-2009) using multivariable logistic regressions to control for age, sex, race/ethnicity, severity of illness, major diagnostic categories, diagnosed infections, and insurance status. Data from the postintervention period (2010-2012) were analyzed similarly to measure the effect of changes in health care delivery.Unadjusted mortality rates for white, African American, and Latino children in 2007 to 2009 were 3.3%, 3.3%, and 8.6%, respectively. After controlling for covariates, no differences in the odds of mortality were observed between white children and African American children (odds ratio [OR], 1.0; 95% CI, 0.6-1.7; P = .97), but Latino children had 3.7-fold (95% CI, 1.8-7.5; P < .001) higher odds of mortality. A multilevel and multidisciplinary intervention was launched to address these differences. In the postintervention period, unadjusted mortality rates for white, African American, and Latino children were 3.6%, 3.2%, and 4.0%, respectively, with no differences observed after adjustment for covariates (OR, 0.7; 95% CI, 0.2-2.1; P = .49). The odds of mortality decreased between the preintervention period and postintervention period for Latino children (OR, 0.24; 95% CI, 0.06-0.88; P = .03) but remained unchanged for white and African American children (OR, 1.02; 95% CI, 0.73-1.43; P = .90).Latino children had higher odds of mortality, even after controlling for age, sex, severity of illness, insurance status, and other covariates. These differences disappeared after culturally and linguistically sensitive interventions at multiple levels. Local multilevel interventions can reduce the effect of health care inequities on clinical outcomes, without requiring major changes in health care policy.

    View details for DOI 10.1001/jamapediatrics.2014.3789

    View details for Web of Science ID 000354995600022

    View details for PubMedID 25706478

  • Double-blind, placebo-controlled pilot randomized trial of methylprednisolone infusion in pediatric acute respiratory distress syndrome. Pediatric critical care medicine Drago, B. B., Kimura, D., Rovnaghi, C. R., Schwingshackl, A., Rayburn, M., Meduri, G. U., Anand, K. J. 2015; 16 (3): e74-81

    Abstract

    Low-dose methylprednisolone therapy in adults with early acute respiratory distress syndrome reduces systemic inflammation, duration of mechanical ventilation, and ICU length of stay. We report a pilot randomized trial of glucocorticoid treatment in early pediatric acute respiratory distress syndrome.Double-blind, placebo-controlled randomized clinical trial.Le Bonheur Children's Hospital, Memphis, TN.Children (0-18 yr) with acute respiratory distress syndrome undergoing mechanical ventilation.Patients were randomly assigned to steroid or placebo groups within 72 hours of intubation. IV methylprednisolone administered as loading dose (2 mg/kg) and continuous infusions (1 mg/kg/d) on days 1-7 and then tapered over days 8-14. Both groups were ventilated according to the Acute Respiratory Distress Syndrome Network protocol modified for children. Daily surveillance was performed for adverse effects.Thirty-five patients were randomized to the steroid (n = 17, no death) and placebo groups (n = 18, two deaths). No differences occurred in length of mechanical ventilation, ICU stay, hospital stay, or mortality between the two groups. At baseline, higher plateau pressures (p = 0.006) and lower Pediatric Logistic Organ Dysfunction scores (p = 0.04) occurred in the steroid group; other characteristics were similar. Despite higher plateau pressures on days 1 (p = 0.006) and 2 (p = 0.025) due to poorer lung compliance in the steroid group, they had lower PaCO2 values on days 2 (p = 0.009) and 3 (p = 0.014), higher pH values on day 2 (p = 0.018), and higher PaO2/FIO2 ratios on days 8 (p = 0.047) and 9 (p = 0.002) compared with the placebo group. Fewer patients in the steroid group required treatment for postextubation stridor (p = 0.04) or supplemental oxygen at ICU transfer (p = 0.012). Steroid therapy was not associated with detectable adverse effects.This study demonstrates the feasibility of administering low-dose glucocorticoid therapy and measuring clinically relevant outcomes in pediatric acute respiratory distress syndrome. Changes in oxygenation and/or ventilation are consistent with early acute respiratory distress syndrome pathophysiology and results of similar clinical trials in adults. We propose and design a larger randomized trial to define the role of glucocorticoid therapy in pediatric acute respiratory distress syndrome.

    View details for DOI 10.1097/PCC.0000000000000349

    View details for PubMedID 25634565

  • Clinical risk factors for central line-associated venous thrombosis in children. Frontiers in pediatrics Shah, S. H., West, A. N., Sepanski, R. J., Hannah, D., May, W. N., Anand, K. J. 2015; 3: 35-?

    Abstract

    Identifying risk factors related to central venous line (CVL) placement could potentially minimize central line-associated venous thrombosis (CLAVT). We sought to identify the clinical factors associated with CLAVT in children.Over a 3-year period, 3733 CVLs were placed at a tertiary-care children's hospital. Data were extracted from the electronic medical records of patients with clinical signs and symptoms of venous thromboembolism, diagnosed using Doppler ultrasonography and/or echocardiography. Statistical analyses examined differences in CLAVT occurrence between groups based on patient and CVL characteristics (type, brand, placement site, and hospital unit).Femoral CVL placement was associated with greater risk for developing CLAVT (OR 11.1, 95% CI 3.9-31.6, p < 0.0001). CVLs placed in the NICU were also associated with increased CLAVT occurrence (OR 5.3, 95% CI 2.1-13.2, p = 0.0003). CVL brand was also significantly associated with risk of CLAVT events.Retrospective analyses identified femoral CVL placement and catheter type as independent risk factors for CLAVT, suggesting increased risks due to mechanical reasons. Placement of CVLs in the NICU also led to an increased risk of CLAVT, suggesting that small infants are at increased risk of thrombotic events. Alternative strategies for CVL placement, thromboprophylaxis, and earlier diagnosis may be important for reducing CLAVT events.

    View details for DOI 10.3389/fped.2015.00035

    View details for PubMedID 26000265

  • Pain Management in Newborns CLINICS IN PERINATOLOGY Hall, R. W., Anand, K. J. 2014; 41 (4): 895-?

    Abstract

    As a standard of care for preterm/term newborns effective pain management may improve their clinical and neurodevelopmental outcomes. Neonatal pain is assessed using context-specific, validated, and objective pain methods, despite the limitations of currently available tools. Therapeutic approaches reducing invasive procedures and using pharmacologic, behavioral, or environmental measures are used to manage neonatal pain. Nonpharmacologic approaches like kangaroo care, facilitated tucking, non-nutritive sucking, sucrose, and others can be used for procedural pain or adjunctive therapy. Local/topical anesthetics, opioids, NSAIDs/acetaminophen and other sedative/anesthetic agents can be incorporated into NICU protocols for managing moderate/severe pain or distress in all newborns.

    View details for DOI 10.1016/j.clp.2014.08.010

    View details for Web of Science ID 000346216900011

    View details for PubMedID 25459780

  • Chronic Pain in the Newborn Toward a Definition CLINICAL JOURNAL OF PAIN van Ganzewinkel, C., Anand, K. J., Kramer, B. W., Andriessen, P. 2014; 30 (11): 970-977

    Abstract

    Chronic pain is poorly addressed in neonatal pain research. We aimed at contributing to define the concept of chronic pain in the newborn.We designed a Web-based, 3-round Delphi survey. We invited an international panel of experts (health care providers and parents) in the fields of neonatology and neonatal pain to participate.In the first round, participants (n=189) answered 3 open-ended questions: (1) define chronic pain in your own words, (2) what are the possible causes, and (3) which signs and symptoms are used to diagnose chronic pain? The answers were categorized and summarized into 437 statements, which were valued by the participants (n=189) on a 5-point Likert scale. In the second round, the remaining participants (n=72) were asked to reflect on 65 selected statements with a mode or median ≥4 or mean ≥3.75. These threshold values provided the opportunity to reach consensus in the following round. In the third round, the remaining participants (n=33) were provided with the group and individual responses. This process resulted in 23 statements with mode, mean, and median of ≥4, on which the participants reached consensus.Although several etiologic factors were defined, no useful diagnostic criterion could be identified. The survey resulted in a description of chronic pain in the newborn. Identifying chronic pain is clinically relevant because it interferes with growth, prolongs hospitalization, leads to altered pain perception, and impairs cognitive and behavioral development.

    View details for DOI 10.1097/AJP.0000000000000056

    View details for Web of Science ID 000343247000006

    View details for PubMedID 24296909

  • Ketamine Affects the Neurogenesis of Rat Fetal Neural Stem Progenitor Cells via the PI3K/Akt-p27 Signaling Pathway BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY Dong, C., Rovnaghi, C. R., Anand, K. J. 2014; 101 (5): 355-363

    Abstract

    Ketamine is widely used as an anesthetic, analgesic, or sedative in pediatric patients. We reported that ketamine alters the normal neurogenesis of rat fetal neural stem progenitor cells (NSPCs) in the developing brain, but the underlying mechanisms remain unknown. The PI3K-PKB/Akt (phosphatidylinositide 3-kinase/protein kinase B) signaling pathway plays many important roles in cell survival, apoptosis, and proliferation. We hypothesized that PI3K-PKB/Akt signaling may be involved in ketamine-altered neurogenesis of cultured NSPCs in vitro. NSPCs were isolated from Sprague-Dawley rat fetuses on gestational day 17. 5-bromo-2'-deoxyuridine (BrdU) incorporation, Ki67 staining, and differentiation tests were utilized to identify primary cultured NSPCs. Immunofluorescent staining was used to detect Akt expression, whereas Western blots measured phosphorylated Akt and p27 expression in NSPCs exposed to different treatments. We report that cultured NSPCs had properties of neurogenesis: proliferation and neural differentiation. PKB/Akt was expressed in cultured rat fetal cortical NSPCs. Ketamine inhibited the phosphorylation of Akt and further enhanced p27 expression in cultured NSPCs. All ketamine-induced PI3K/Akt signaling changes could be recovered by N-methyl-d-aspartate (NMDA) receptor agonist, NMDA. These data suggest that the inhibition of PI3K/Akt-p27 signaling may be involved in ketamine-induced neurotoxicity in the developing brain, whereas excitatory NMDA receptor activation may reverse these effects.

    View details for DOI 10.1002/bdrb.21119

    View details for Web of Science ID 000344449800002

    View details for PubMedID 25231110

  • A Single Nucleotide Polymorphism in the Corticotropin Receptor Gene Is Associated With a Blunted Cortisol Response During Pediatric Critical Illness PEDIATRIC CRITICAL CARE MEDICINE Jardine, D., Emond, M., Meert, K. L., Harrison, R., Carcillo, J. A., Anand, K. J., Berger, J., Newth, C. J., Willson, D. F., Nicholson, C., Dean, J. M., Zimmerman, J. J. 2014; 15 (8): 698-705

    Abstract

    The cortisol response during critical illness varies widely among patients. Our objective was to examine single nucleotide polymorphisms in candidate genes regulating cortisol synthesis, metabolism, and activity to determine if genetic differences were associated with variability in the cortisol response among critically ill children.This was a prospective observational study employing tag single nucleotide polymorphism methodology to examine genetic contributions to the variability of the cortisol response in critical illness. Thirty-one candidate genes and 31 ancestry markers were examined.Patients were enrolled from seven pediatric critical care units that constitute the Eunice Kennedy Shriver Collaborative Pediatric Critical Care Research Network.Critically ill children (n = 92), age 40 weeks gestation to 18 years old, were enrolled.Blood samples were obtained from all patients for serum cortisol measurements and DNA isolation. Demographic and illness severity data were collected.Single nucleotide polymorphisms were tested for association with serum free cortisol concentrations in context of higher illness severity as quantified by Pediatric Risk of Mortality III score greater than 7. A single nucleotide polymorphism (rs1941088) in the MC2R gene was strongly associated (p = 0.0005) with a low free cortisol response to critical illness. Patients with the AA genotype were over seven times more likely to have a low free cortisol response to critical illness than those with a GG genotype. Patients with the GA genotype exhibited an intermediate free cortisol response to critical illness.The A allele at rs1941088 in the MC2R gene, which encodes the adrenocorticotropic hormone (corticotropin, ACTH) receptor, is associated with a low cortisol response in critically ill children. These data provide evidence for a genetic basis for a portion of the variability in cortisol production during critical illness. Independent replication of these findings will be important and could facilitate development of personalized treatment for patients with a low cortisol response to severe illness.

    View details for DOI 10.1097/PCC.0000000000000193

    View details for Web of Science ID 000343049200006

    View details for PubMedID 25055195

  • Pediatric critical care: grand challenges for a glowing future. Frontiers in pediatrics Anand, K. J. 2014; 2: 35-?

    View details for DOI 10.3389/fped.2014.00035

    View details for PubMedID 24818121

  • Eight Years Later, Are We Still Hurting Newborn Infants? NEONATOLOGY Roofthooft, D. W., Simons, S. H., Anand, K. J., Tibboel, D., van Dijk, M. 2014; 105 (3): 218-226

    Abstract

    To study whether new pharmacological and nonpharmacological guidelines lowered numbers of painful procedures in neonates and changed the amount and frequency of analgesic therapy as compared to the results of our previous study in 2001.A prospective observational study.Level III NICU of the Erasmus MC-Sophia Children's Hospital, Rotterdam.Neonates admitted at postnatal ages less than 3 days with length of stay at least 72 h.Number of all potentially painful procedures and analgesic therapy recorded at the bedside during the first 14 days of NICU stay.A total number of 21,076 procedures were performed in the 175 neonates studied during 1,730 patient-days (mean 12.2). The mean number of painful procedures per neonate per day was 11.4 (SD 5.7), significantly lower than the number of 14.3 (SD 4.0) in 2001 (p < 0.001). The use of analgesics was 36.6% compared to 60.3% in 2001. Sixty-three percent of all peripheral arterial line insertions failed versus 37.5% in 2001 and 9.1% venipunctures failed versus 21% in 2001.The mean number of painful procedures per NICU patient per day declined. Nonpharmacological pain- or stress-reducing strategies like NIDCAP and sucrose were fully embedded in our pain management. As further reduction of the number of painful procedures is unlikely, we should apply more nonpharmacological interventions and explore newer pharmacological agents.

    View details for DOI 10.1159/000357207

    View details for Web of Science ID 000333321100010

    View details for PubMedID 24503902

  • Early Adversity, Socioemotional Development, and Stress in Urban 1-Year-Old Children JOURNAL OF PEDIATRICS Palmer, F. B., Anand, K. J., Graff, J. C., Murphy, L. E., Qu, Y., Voelgyi, E., Rovnaghi, C. R., Moore, A., Tran, Q. T., Tylavsky, F. A. 2013; 163 (6): 1733-U291

    Abstract

    To determine demographic, maternal, and child factors associated with socioemotional (SE) problems and chronic stress in 1-year-old children.This was a prospective, longitudinal, community-based study, which followed mother-infant dyads (n = 1070; representative of race, education, and income status of Memphis/Shelby County, Tennessee) from midgestation into early childhood. Child SE development was measured using the Brief Infant-Toddler Social and Emotional Assessment in all 1097 1-year-olds. Chronic stress was assessed by hair cortisol in a subsample of 1-year-olds (n = 297). Multivariate regression models were developed to predict SE problems and hair cortisol levels.More black mothers than white mothers reported SE problems in their 1-year-olds (32.9% vs 10.2%; P < .001). In multivariate regression, SE problems in blacks were predicted by lower maternal education, greater parenting stress and maternal psychological distress, and higher cyclothymic personality score. In whites, predictors of SE problems were Medicaid insurance, higher maternal depression score at 1 year, greater parenting stress and maternal psychological distress, higher dysthymic personality score, and male sex. SE problem scores were associated with higher hair cortisol levels (P = .01). Blacks had higher hair cortisol levels than whites (P < .001). In the entire subsample, increased hair cortisol levels were associated with higher parenting stress (P = .001), lower maternal depression score (P = .01), lower birth length (P < .001), and greater length at 1 year of age (P = .003).Differences in maternal education, insurance, mental health, and early stress may disrupt SE development in children. Complex relationships between hair cortisol level in 1-year-olds and maternal parenting stress and depression symptoms suggest dysregulation of the child's hypothalamic-pituitary-adrenal axis.

    View details for DOI 10.1016/j.jpeds.2013.08.030

    View details for Web of Science ID 000327543200042

    View details for PubMedID 24070827

  • Pain Panacea for Opiophobia in Infants? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Anand, K. J. 2013; 309 (2): 183-184

    View details for DOI 10.1001/jama.2012.208359

    View details for Web of Science ID 000313517000028

    View details for PubMedID 23299611

  • A comparison of critical care research funding and the financial burden of critical illness in the United States CRITICAL CARE MEDICINE Coopersmith, C. M., Wunsch, H., Fink, M. P., Linde-Zwirble, W. T., Olsen, K. M., Sommers, M. S., Anand, K. J., Tchorz, K. M., Angus, D. C., Deutschman, C. S. 2012; 40 (4): 1072-1079

    Abstract

    To estimate federal dollars spent on critical care research, the cost of providing critical care, and to determine whether the percentage of federal research dollars spent on critical care research is commensurate with the financial burden of critical care.The National Institutes of Health Computer Retrieval of Information on Scientific Projects database was queried to identify funded grants whose title or abstract contained a key word potentially related to critical care. Each grant identified was analyzed by two reviewers (three if the analysis was discordant) to subjectively determine whether it was definitely, possibly, or definitely not related to critical care. Hospital and total costs of critical care were estimated from the Premier Database, state discharge data, and Medicare data. To estimate healthcare expenditures associated with caring for critically ill patients, total costs were calculated as the combination of hospitalization costs that included critical illness as well as additional costs in the year after hospital discharge.Of 19,257 grants funded by the National Institutes of Health, 332 (1.7%) were definitely related to critical care and a maximum of 1212 (6.3%) grants were possibly related to critical care. Between 17.4% and 39.0% of total hospital costs were spent on critical care, and a total of between $121 and $263 billion was estimated to be spent on patients who required intensive care. This represents 5.2% to 11.2%, respectively, of total U.S. healthcare spending.The proportion of research dollars spent on critical care is lower than the percentage of healthcare expenditures related to critical illness.

    View details for DOI 10.1097/CCM.0b013e31823c8d03

    View details for Web of Science ID 000301813700004

    View details for PubMedID 22202712

  • Pediatric Analgesic Clinical Trial Designs, Measures, and Extrapolation: Report of an FDA Scientific Workshop PEDIATRICS Berde, C. B., Walco, G. A., Krane, E. J., Anand, K. J., Aranda, J. V., Craig, K. D., Dampier, C. D., Finkel, J. C., Grabois, M., Johnston, C., Lantos, J., Lebel, A., Maxwell, L. G., McGrath, P., Oberlander, T. F., Schanberg, L. E., Stevens, B., Taddio, A., von Baeyer, C. L., Yaster, M., Zempsky, W. T. 2012; 129 (2): 354-364

    Abstract

    Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

    View details for DOI 10.1542/peds.2010-3591

    View details for Web of Science ID 000300395100058

    View details for PubMedID 22250028

  • Response to letter to the Editor. Acta paediatrica (Oslo, Norway : 1992) Rovnaghi, C. R., Tembulkar, S., Rigdon, J., Anand, K. J. 2019

    Abstract

    We agree with Dr. Meyer (1) that socioeconomic disparities are far from being solved and, in fact, US disparities have increased in the past decade. Most studies on socioeconomic status attempt to disentangle specific factors mediating the inequities linked with poor health outcomes. Because of complex interactions between individual factors, we proposed a socioeconomic adversity index (SAI) combining such factors in the US(2). This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/apa.14768

    View details for PubMedID 30825246

  • Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations PAIN Walco, G. A., Kopecky, E. A., Weisman, S. J., Stinson, J., Stevens, B., Desjardins, P. J., Berde, C. B., Krane, E. J., Anand, K. S., Yaster, M., Dampier, C. D., Dworkin, R. H., Gilron, I., Lynn, A. M., Maxwell, L. G., Raja, S., Schachtel, B., Turk, D. C. 2018; 159 (2): 193–205

    Abstract

    Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts - neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts. (216 words).

    View details for DOI 10.1097/j.pain.0000000000001104

    View details for Web of Science ID 000428999000003

    View details for PubMedID 29140927

    View details for PubMedCentralID PMC5949239

  • Editorial: Work-Life Balance: Essential or Ephemeral? FRONTIERS IN PEDIATRICS Schwingshackl, A., Anand, K. J. 2017; 5

    View details for DOI 10.3389/fped.2017.00108

    View details for Web of Science ID 000401578500005

    View details for PubMedID 28540286

    View details for PubMedCentralID PMC5423898

  • Editorial: ARDS: Reaching for the Horizon FRONTIERS IN PEDIATRICS McGuire, J. K., Schwingshackl, A., Anand, K. J. 2017; 5

    View details for DOI 10.3389/fped.2017.00100

    View details for Web of Science ID 000401576900001

    View details for PubMedID 28555176

    View details for PubMedCentralID PMC5430045

  • Sedation and analgesia practices at Italian neonatal intensive care units: results from the EUROPAIN study. Italian journal of pediatrics Lago, P., Frigo, A. C., Baraldi, E., Pozzato, R., Courtois, E., Rambaud, J., Anand, K. J., Carbajal, R. 2017; 43 (1): 26-?

    Abstract

    We aimed to examine current bedside analgesia/sedation (A/S) and pain assessment (PA) practices in Italian neonatal intensive care units (NICUs) in relation to the findings of an epidemiological European study and recently-introduced national guidelines.We analyzed the Italian data from the EUROPAIN (EUROpean-Pain-Audit-In-Neonates) prospective observational study on A/S practices that involved 6680 newborns admitted to tertiary-level NICUs in 18 European countries. Demographics, type of assisted ventilation, type and mode of A/S administration and PA were analyzed. Multivariate linear regression models were used to identify factors predicting A/S and PA practices.From October 1(st), 2012 to June 30(th), 2013, thirty Italian NICUs gathered data on 422 newborn: 131 on invasive ventilation (IV); 150 on noninvasive ventilation (NIV); and 141 on spontaneous ventilation (SV). A/S was documented for 35.3% of all infants admitted (86.3% IV; 17.3% NIV; 7.1% SV [p = 0.0001]), and varied considerably between NICUs (as reported in other European countries). Strong analgesics were used in 32.5% of cases, sedatives in 10.2%, mild analgesics in 3.8%. Fentanyl was used in 78.6% of cases, morphine in 8.4%, neuromuscular blockers in 5.3%, midazolam in 22.1%. The performance of PA was documented in 67.5% of all newborn (85.5% IV; 67.3% NIV; 51.1% SV [p = 0.001]). Illness severity, type of ventilation, bedside PA, and number of NICU beds were all factors associated with A/S use on multivariate analysis, while gestational age ≤ 32 weeks, and type of ventilation and presence of a pain team were associated with PA.We documented a generally widespread, but still highly variable use of A/S and PA at Italian NICUs, despite the diffusion of national guidelines. There is an urgent need to improve routine PA to enable customized pain and stress control (and prevention) in all infants.Clinical Trials.gov # NCT01694745 .

    View details for DOI 10.1186/s13052-017-0343-2

    View details for PubMedID 28270167

    View details for PubMedCentralID PMC5341165

  • Consequences of prenatal opioid use for newborns ACTA PAEDIATRICA Anand, K. J., Campbell-Yeo, M. 2015; 104 (11): 1066-1069

    Abstract

    One-third of childbearing women take prescription opioids, previously occurring only in 6-7% of pregnant women. Prenatal opioid exposures may cause birth defects, altered brain development and neonatal abstinence syndrome (NAS). NAS incidence increased fourfold and length of stay increased from 13 to 19 days over 10 years (2004-2013), leading to sevenfold increases in NICU days due to NAS. Initial data suggest that recent NAS increases have resulted from increased use of prescription opioids rather than illicit drugs.Paediatricians will have to manage the consequences of prenatal opioid exposures, as the offspring often have complex medical and social issues associated with these families.

    View details for DOI 10.1111/apa.13121

    View details for Web of Science ID 000363866200017

    View details for PubMedID 26174725

  • Sedation and analgesia practices among Spanish neonatal intensive care units ANALES DE PEDIATRIA Avila-Alvarez, A., Carbajal, R., Courtois, E., Pertega-Diaz, S., Muniz-Garcia, J., Anand, K. J. 2015; 83 (2): 75-84

    Abstract

    Pain management and sedation is a priority in neonatal intensive care units. A study was designed with the aim of determining current clinical practice as regards sedation and analgesia in neonatal intensive care units in Spain, as well as to identify factors associated with the use of sedative and analgesic drugs.A multicenter, observational, longitudinal and prospective study.Thirty neonatal units participated and included 468 neonates. Of these, 198 (42,3%) received sedatives or analgesics. A total of 19 different drugs were used during the study period, and the most used was fentanyl. Only fentanyl, midazolam, morphine and paracetamol were used in at least 20% of the neonates who received sedatives and/or analgesics. In infusions, 14 different drug prescriptions were used, with the most frequent being fentanyl and the combination of fentanyl and midazolam. The variables associated with receiving sedation and/or analgesia were, to have required invasive ventilation (P<.001; OR=23.79), a CRIB score >3 (P=.023; OR=2.26), the existence of pain evaluation guides in the unit (P<.001; OR=3.82), and a pain leader (P=.034; OR=2.35).Almost half of the neonates admitted to intensive care units receive sedatives or analgesics. There is significant variation between Spanish neonatal units as regards sedation and analgesia prescribing. Our results provide evidence on the "state of the art", and could serve as the basis of preparing clinical practice guidelines at a national level.

    View details for DOI 10.1016/j.anpedi.2015.03.017

    View details for Web of Science ID 000361502100002

    View details for PubMedID 25979386

  • Inverse Relationship between Cardio-Ankle Vascular Index and Body Mass Index in Healthy Children JOURNAL OF PEDIATRICS Philip, R., Alpert, B. S., Schwingshackl, A., Huang, X., Blakely, D., Rovnaghi, C. R., Tran, Q. T., Velasquez, A., Arevalo, A., Anand, K. J. 2015; 167 (2): 361-?

    Abstract

    To establish reference scores for cardio-ankle vascular index (CAVI), a noninvasive measure of vascular function, which reflects the stiffness of arteries, in healthy children, to test for racial and ethnic differences, and to compare CAVI scores between overweight and normal weight children.Subjects included 292 children aged 10-18 years: 100 non-Hispanic whites, 89 non-Hispanic blacks, and 103 Hispanics. Subjects were grouped as normal weight (body mass index [BMI] <85th percentile for age) and overweight (BMI >85th percentile for age). Blood pressure (BP) and CAVI scores were measured in all subjects.After controlling for age, sex, and BMI, normal weight black males had a higher CAVI score (indicating stiffer arteries) in comparison with Hispanic males and white males (5.53 ± 0.15 vs 5.13 ± 0.15 vs 5.02 ± 0.15, P = .04). BMI had an inverse association on the CAVI score (r = -0.335, P < .0001). In multivariable analysis, BMI and average CAVI scores were significant predictors of each other (R(2) = 0.37, P < .0001, R(2) = 0.21, P < .0001). There was no significant correlation between CAVI scores and resting BP values, confirming that CAVI scores were independent of concurrent BP values.Significant differences in vascular function exist among ethnic groups of children. Overweight children had lower CAVI scores, suggestive of vascular adaptation to obesity in early life. CAVI, by providing a noninvasive measure of vascular health, may help identify children at increased risk for cardiovascular disease.

    View details for DOI 10.1016/j.jpeds.2015.04.042

    View details for Web of Science ID 000362455300031

    View details for PubMedID 26003881

  • [Sedation and analgesia for neonates in NICUs across Europe]. Archives de pe´diatrie : organe officiel de la Socie´te franc¸aise de pe´diatrie Carbajal, R., Eriksson, M., Courtois, E., Anand, K. J. 2015; 22 (5): 95-96

    View details for DOI 10.1016/S0929-693X(15)30048-8

    View details for PubMedID 26112539

  • [Clinical assessment of pain in Spanish Neonatal Intensive Care Units]. Anales de pediatria (Barcelona, Spain : 2003) Avila-Alvarez, A., Carbajal, R., Courtois, E., Pertega-Diaz, S., Anand, K. J., Muñiz-Garcia, J. 2015

    Abstract

    Clinical scales are currently the best method to assess pain in the neonate, given the impossibility of self-report in this age group. A study is designed with the aim of determining the current practices as regards the clinical assessment of pain in Spanish Neonatal Units and the factors associated with the use of clinical scales.A prospective longitudinal observational study was conducted. A total of 30 Units participated and 468 neonates were included.Only 13 Units (43.3%) had pain assessment protocols. Pain was evaluated with a scale in 78 neonates (16.7%, 95% CI; 13.1-20.1) and the mean number of pain assessments per patient and per day was 2.3 (Standard Deviation; 4.8), with a median of 0.75. Of the total number of 7,189 patient-days studied, there was at least one pain assessment in 654 (9.1%). No pain assessment was performed with a clinical scale on any patient in 20 (66.7%) Units. Among those that did, a wide variation was observed in the percentage of patients in whom pain was assessed, as well as in the scales used. The CRIES (C-Crying; R-Requires increased oxygen administration; I-Increased vital signs; E-Expression; S-Sleeplessness) scale was that used in most Units. In the multivariate analysis, only invasive mechanical ventilation was associated with receiving a pain assessment with a scale (OR 1.46, P=.042).The majority of neonates admitted into Intensive Care in Spain do not receive a pain assessment. Many units still do not routinely use clinical scales, and there is a wide variation between those that do use them. These results could serve as a basis for preparing national guidelines as regards pain in the neonate.

    View details for DOI 10.1016/j.anpedi.2015.09.019

    View details for PubMedID 26553356

  • Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants ACTA PAEDIATRICA van Ganzewinkel, C., Derijks, L., Anand, K. J., Van Lingen, R. A., Neef, C., Kramer, B. W., Andriessen, P. 2014; 103 (6): 612-617

    Abstract

    The therapeutic options available to treat neonatal pain are limited, and one alternative for nonopioid systemic treatment is paracetamol. However, pharmacokinetic data from prolonged administration of intravenous paracetamol in neonates are limited. The aim of this study was to present pharmacokinetics after multiple dose of intravenous paracetamol in very preterm infants of <32 weeks' gestation.Fifteen very preterm infants received five, six-hourly doses of intravenous paracetamol (7.5 mg/kg). Blood samples were taken to measure paracetamol, glutathione and hepatic function, together with urine samples for paracetamol metabolites.A two-compartment pharmacokinetic model gave the best fit for all individual patients and resulted in a predictable pharmacokinetic profile. The estimated pharmacokinetic population parameters were volume of distribution 0.764 ± 0.225 L/kg, elimination rate constant (ke ) 0.117 ± 0.091/h and intercompartment rate constants k12 0.607 ± 0.734/h and k21 1.105 ± 0.762/h.Our study found that multiple doses of intravenous paracetamol resulted in a predictable pharmacokinetic profile in very preterm infants. Increases in postmenstrual age and weight were associated with increased clearance. No evidence of hepatotoxicity was found.

    View details for DOI 10.1111/apa.12638

    View details for Web of Science ID 000335754700017

    View details for PubMedID 24654967

  • Interpretation of Cortisol Concentrations and Reference Intervals from the CALIPER Database CLINICAL CHEMISTRY Rovnaghi, C. R., Kala, A. F., Allen, S. L., Anand, K. J. 2014; 60 (2): 418-419

    View details for DOI 10.1373/clinchem.2013.212944

    View details for Web of Science ID 000335146300021

    View details for PubMedID 24363368

  • Does neonatal pain management in intensive care units differ between night and day? An observational study BMJ OPEN Guedj, R., Danan, C., Daoud, P., Zupan, V., Renolleau, S., Zana, E., Aizenfisz, S., Lapillonne, A., de Saint Blanquat, L., Granier, M., Durand, P., Castela, F., Coursol, A., Hubert, P., Cimerman, P., Anand, K. J., Khoshnood, B., Carbajal, R. 2014; 4 (2)

    Abstract

    To determine whether analgesic use for painful procedures performed in neonates in the neonatal intensive care unit (NICU) differs during nights and days and during each of the 6 h period of the day.Conducted as part of the prospective observational Epidemiology of Painful Procedures in Neonates study which was designed to collect in real time and around-the-clock bedside data on all painful or stressful procedures.13 NICUs and paediatric intensive care units in the Paris Region, France.All 430 neonates admitted to the participating units during a 6-week period between September 2005 and January 2006.During the first 14 days of admission, data were collected on all painful procedures and analgesic therapy. The five most frequent procedures representing 38 012 of all 42 413 (90%) painful procedures were analysed.Observational study.We compared the use of specific analgesic for procedures performed during each of the 6 h period of a day: morning (7:00 to 12:59), afternoon, early night and late night and during daytime (morning+afternoon) and night-time (early night+late night).7724 of 38 012 (20.3%) painful procedures were carried out with a specific analgesic treatment. For morning, afternoon, early night and late night, respectively, the use of analgesic was 25.8%, 18.9%, 18.3% and 18%. The relative reduction of analgesia was 18.3%, p<0.01, between daytime and night-time and 28.8%, p<0.001, between morning and the rest of the day. Parental presence, nurses on 8 h shifts and written protocols for analgesia were associated with a decrease in this difference.The substantial differences in the use of analgesics around-the-clock may be questioned on quality of care grounds.

    View details for DOI 10.1136/bmjopen-2013-004086

    View details for Web of Science ID 000334459100006

    View details for PubMedID 24556241

  • Repetitive neonatal pain and neurocognitive abilities in ex-preterm children PAIN Anand, K. J., Palmer, F. B., Papanicolaou, A. C. 2013; 154 (10): 1899-1901

    View details for DOI 10.1016/j.pain.2013.06.027

    View details for Web of Science ID 000324475500001

    View details for PubMedID 23792285

  • Physicians' Conceptualization of "Closure" as a Benefit of Physician-Parent Follow-up Meetings after a Child's Death in the Pediatric Intensive Care Unit JOURNAL OF PALLIATIVE CARE Eggly, S., Meert, K. L., Berger, J., Zimmerman, J., Anand, K. J., Newth, C. J., Harrison, R., Carcillo, J., Dean, J. M., Willson, D. F., Nicholson, C. 2013; 29 (2): 69-75

    Abstract

    We examined physicians' conceptualization of closure as a benefit of follow-up meetings with bereaved parents. The frequency of use and the meaning of the word "closure" were analyzed in transcripts of interviews with 67 critical care physicians affiliated with the Collaborative Pediatric Critical Care Research Network. In all, 38 physicians (57 percent) used the word "closure" at least once (median: 2; range: 1 to 7), for a total of 86 times. Physicians indicated that closure is a process or trajectory rather than an achievable goal. They also indicated that parents and physicians can move toward closure by gaining a better understanding of the causes and circumstances of the death and by reconnecting with, or resolving relationships between, parents and health professionals. Physicians suggested that a primary reason to conduct follow-up meetings is that such meetings offer parents and physicians an opportunity to move toward closure. Future research should attempt to determine whether followup meetings reduce the negative effects of bereavement for parents and physicians.

    View details for Web of Science ID 000321412100002

    View details for PubMedID 23923469

  • Developmental neurotoxicity of ketamine in pediatric clinical use TOXICOLOGY LETTERS Dong, C., Anand, K. J. 2013; 220 (1): 53-60

    Abstract

    Ketamine is widely used as an anesthetic, analgesic, and sedative in pediatric clinical practice and it is also listed as an illicit drug by most countries. Recent in vivo and in vitro animal studies have confirmed that ketamine can induce neuronal cell death in the immature brain, resulting from widespread neuronal apoptosis. These effects can disturb normal development further altering the structure and functions of the brain. Our recent studies further indicate that ketamine can alter neurogenesis from neural stem progenitor cells in the developing brain. Taken together, these findings identify a novel complication associated with ketamine use in premature infants, term newborns, and pregnant women. Recent data on the developmental neurotoxicity of ketamine are reviewed with proposed future directions for evaluating the safety of ketamine in these patient populations.

    View details for DOI 10.1016/j.toxlet.2013.03.030

    View details for Web of Science ID 000319449300007

    View details for PubMedID 23566897

  • The Role of the Data and Safety Monitoring Board in a Clinical Trial: The CRISIS Study PEDIATRIC CRITICAL CARE MEDICINE Holubkov, R., Casper, T. C., Dean, J. M., Anand, K. J., Zimmerman, J., Meert, K. L., Newth, C. J., Berger, J., Harrison, R., Willson, D. F., Nicholson, C. 2013; 14 (4): 374-383

    Abstract

    Randomized clinical trials are commonly overseen by a Data and Safety Monitoring Board comprised of experts in medicine, ethics, and biostatistics. Data and Safety Monitoring Board responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. Data and Safety Monitoring Board decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate Data and Safety Monitoring Board oversight into the design, monitoring, and reporting of randomized trials.Case study, narrative review.The Data and Safety Monitoring Board's role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described.The National Institutes of Health-appointed CRISIS Data and Safety Monitoring Board was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested Data and Safety Monitoring Board interim review before opening CRISIS to children below 1 yr of age. The first interim analysis found higher 28-day mortality in one treatment arm. The Data and Safety Monitoring Board maintained trial closure to younger children and requested a second interim data review 6 months later. At this second meeting, mortality was no longer of concern, whereas a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the Data and Safety Monitoring Board elected to examine conditional power and unmask treatment arm identities. On finding somewhat greater efficacy in the placebo arm, the Data and Safety Monitoring Board recommended stopping CRISIS due to futility.The design and operating procedures of a multicenter randomized trial must consider a pivotal Data and Safety Monitoring Board role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The Data and Safety Monitoring Board must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups.

    View details for DOI 10.1097/PCC.0b013e318274568c

    View details for Web of Science ID 000318680000011

    View details for PubMedID 23392377

  • Baseline Serum Concentrations of Zinc, Selenium, and Prolactin in Critically III Children PEDIATRIC CRITICAL CARE MEDICINE Heidemann, S. M., Holubkov, R., Meert, K. L., Dean, J. M., Berger, J., Bell, M., Anand, K. J., Zimmerman, J., Newth, C. J., Harrison, R., Willson, D. F., Nicholson, C., Carcillo, J. 2013; 14 (4): E202-E206

    Abstract

    To describe serum concentrations of zinc, selenium, and prolactin in critically ill children within 72 hours of PICU admission, and to investigate relationships between these immunomodulators and lymphopenia.An analysis of baseline data collected as part of the multicenter Critical Illness Stress Induced Immune Suppression (CRISIS) Prevention Trial.PICUs affiliated with the Collaborative Pediatric Critical Care Research Network.All children enrolled in the CRISIS Prevention Trial that had baseline serum samples available for analysis.None.Of 293 critically ill children enrolled in the CRISIS Prevention Trial, 284 had baseline serum samples analyzed for prolactin concentration, 280 for zinc concentration, and 278 for selenium concentration within 72 hours of PICU admission. Lymphocyte counts were available for 235 children. Zinc levels ranged from nondetectable (< 0.1 μg/mL) to 2.87 μg/mL (mean 0.46 μg/mL and median 0.44 μg/mL) and were below the normal reference range for 235 (83.9%) children. Selenium levels ranged from 26 to 145 ng/mL (mean 75.4 ng/mL and median 74.5 ng/mL) and were below the normal range for 156 (56.1%) children. Prolactin levels ranged from nondetectable (< 1 ng/mL) to 88 ng/mL (mean 12.2 ng/mL and median 10 ng/mL). Hypoprolactinemia was present in 68 (23.9%) children. Lymphopenia was more likely in children with zinc levels below normal than those with zinc levels within or above the normal range (82 of 193 [42.5%] vs. 10 of 39 [25.6%], p = 0.0498). Neither selenium nor prolactin concentrations were associated with lymphopenia (p = 1.0 and p = 0.72, respectively).Serum concentrations of zinc, selenium, and prolactin are often low in critically ill children early after PICU admission. Low serum zinc levels are associated with lymphopenia, whereas low selenium and prolactin levels are not. The implications of these findings and the mechanisms by which they occur merit further study.

    View details for DOI 10.1097/PCC.0b013e31827200f5

    View details for Web of Science ID 000318680000006

    View details for PubMedID 23392368

  • Severe acute asthma exacerbation in children: a stepwise approach for escalating therapy in a pediatric intensive care unit. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG Nievas, I. F., Anand, K. J. 2013; 18 (2): 88-104

    Abstract

    An increasing prevalence of pediatric asthma has led to increasing burdens of critical illness in children with severe acute asthma exacerbations, often leading to respiratory distress, progressive hypoxia, and respiratory failure. We review the definitions, epidemiology, pathophysiology, and clinical manifestations of severe acute asthma, with a view to developing an evidence-based, stepwise approach for escalating therapy in these patients.Subject headings related to asthma, status asthmaticus, critical asthma, and drug therapy were used in a MEDLINE search (1980-2012), supplemented by a manual search of personal files, references cited in the reviewed articles, and treatment algorithms developed within Le Bonheur Children's Hospital.Patients with asthma require continuous monitoring of their cardiorespiratory status via noninvasive or invasive devices, with serial clinical examinations, objective scoring of asthma severity (using an objective pediatric asthma score), and appropriate diagnostic tests. All patients are treated with β-agonists, ipratropium, and steroids (intravenous preferable over oral preparations). Patients with worsening clinical status should be progressively treated with continuous β-agonists, intravenous magnesium, helium-oxygen mixtures, intravenous terbutaline and/or aminophylline, coupled with high-flow oxygen and non-invasive ventilation to limit the work of breathing, hypoxemia, and possibly hypercarbia. Sedation with low-dose ketamine (with or without benzodiazepines) infusions may allow better toleration of non-invasive ventilation and may also prepare the patient for tracheal intubation and mechanical ventilation, if indicated by a worsening clinical status.Severe asthma can be a devastating illness in children, but most patients can be managed by using serial objective assessments and the stepwise clinical approach outlined herein. Following multidisciplinary education and training, this approach was successfully implemented in a tertiary-care, metropolitan children's hospital.

    View details for DOI 10.5863/1551-6776-18.2.88

    View details for PubMedID 23798903

  • Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? Pain de Graaf, J., van Lingen, R. A., Valkenburg, A. J., Weisglas-Kuperus, N., Groot Jebbink, L., Wijnberg-Williams, B., Anand, K. J., Tibboel, D., van Dijk, M. 2013; 154 (3): 449-458

    Abstract

    Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.

    View details for DOI 10.1016/j.pain.2012.12.006

    View details for PubMedID 23352760

  • Opioid Analgesia in Mechanically Ventilated Children: Results From the Multicenter Measuring Opioid Tolerance Induced by Fentanyl Study PEDIATRIC CRITICAL CARE MEDICINE Anand, K. J., Clark, A. E., Willson, D. F., Berger, J., Meert, K. L., Zimmerman, J. J., Harrison, R., Carcillo, J. A., Newth, C. J., Bisping, S., Holubkov, R., Dean, J. M., Nicholson, C. E. 2013; 14 (1): 27-36

    Abstract

    To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit.Prospective, observational study with 100% accrual of eligible patients.Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network.Four hundred nineteen children treated with morphine or fentanyl infusions.None.Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03).Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.

    View details for DOI 10.1097/PCC.0b013e318253c80e

    View details for Web of Science ID 000313352200010

    View details for PubMedID 23132396

  • Ketamine alters the neurogenesis of rat cortical neural stem progenitor cells CRITICAL CARE MEDICINE Dong, C., Rovnaghi, C. R., Anand, K. J. 2012; 40 (8): 2407-2416

    Abstract

    High doses or prolonged exposure to ketamine increase neuronal apoptosis in the developing brain, although effects on neural stem progenitor cells remain unexplored. This study investigated dose- and time-dependent responses to ketamine on cell death and neurogenesis in cultured rat fetal cortical neural stem progenitor cells.Laboratory-based study.University research laboratory.Sprague-Dawley rats.Neural stem progenitor cells were isolated from the cortex of Sprague-Dawley rat fetuses on embryonic day 17. In dose-response experiments, cultured neural stem progenitor cells were exposed to different concentrations of ketamine (0-100 µM) for 24 hrs. In time-course experiments, neural stem progenitor cells cultures were exposed to 10 µM ketamine for different durations (0-48 hrs).Apoptosis and necrosis in neural stem progenitor cells were assessed using activated caspase-3 immunostaining and lactate dehydrogenase assays, respectively. Proliferative changes in neural stem progenitor cells were detected using bromo-deoxyuridine incorporation and Ki67 immunostaining. Neuronal differentiation was assessed using Tuj-1 immunostaining. Cultured neural stem progenitor cells were resistant to apoptosis and necrosis following all concentrations and durations of ketamine exposure tested. Ketamine inhibited proliferation with decreased numbers of bromo-deoxyuridine-positive cells following ketamine exposure to 100 µM for 24 hrs (p<.005) or 10 µM for 48 hrs (p< .01), and reduced numbers of Ki67-positive cells following exposure to ketamine concentration>10 µM for 24 hrs (p<.001) or at 10 µM for 48 hrs (p<.01). Ketamine enhanced neuronal differentiation, with all ketamine concentrations increasing Tuj-1-positive neurons (p<.001) after 24-hrs of exposure. This also occurred with all exposures to 10 µM ketamine for >8 hrs (p<.001).Clinically relevant concentrations of ketamine do not induce cell death in neural stem progenitor cells via apoptosis or necrosis. Ketamine alters the proliferation and increases the neuronal differentiation of neural stem progenitor cells isolated from the rat neocortex. These studies imply that ketamine exposure during fetal or neonatal life may alter neurogenesis and subsequent brain development.

    View details for DOI 10.1097/CCM.0b013e318253563c

    View details for Web of Science ID 000306604900019

    View details for PubMedID 22635046

  • Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: A pilot randomized, double-blind, placebo-controlled trial PEDIATRIC CRITICAL CARE MEDICINE Bhutta, A. T., Schmitz, M. L., Swearingen, C., James, L. P., Wardbegnoche, W. L., Lindquist, D. M., Glasier, C. M., Tuzcu, V., Prodhan, P., Dyamenahalli, U., Imamura, M., Jaquiss, R. D., Anand, K. J. 2012; 13 (3): 328-337

    Abstract

    Infants are potentially more susceptible to cell death mediated via glutamate excitotoxicity attributed to cardiopulmonary bypass. We hypothesized that ketamine, via N-methyl D-aspartate receptor blockade and anti-inflammatory effects, would reduce central nervous system injury during cardiopulmonary bypass.We randomized 24 infants, without chromosomal abnormalities, to receive ketamine (2 mg/kg, n = 13) or placebo (saline, n = 11) before cardiopulmonary bypass for repair of ventricular septal defects. Plasma markers of inflammation and central nervous system injury were compared at the end of surgery, and 6, 24, and 48 hrs after surgery. Magnetic resonance imaging and spectroscopy before cardiopulmonary bypass and at the time of hospital discharge were performed in a subset of cases and controls (n = 5 in each group). Cerebral hemodynamics were monitored postoperatively using near-infrared spectroscopy, and neurodevelopmental outcomes were assessed using Bayley Scales of Infant Development-II before and 2-3 wks after surgery.Statistically significant differences were noted in preoperative inspired oxygen levels, intraoperative cooling and postoperative temperature, respiratory rate, platelet count, and bicarbonate levels. The peak concentration of C-reactive protein was lower in cases compared to controls at 24 hrs (p = .048) and 48 hrs (p = .001). No significant differences were noted in the expression of various cytokines, chemokines, S100, and neuron-specific enolase between the cases and controls. Magnetic resonance imaging with spectroscopy studies showed that ketamine administration led to a significant decrease in choline and glutamate plus glutamine/creatine in frontal white matter. No statistically significant differences occurred between pre- and postoperative Bayley Scales of Infant Development-II scores.We did not find any evidence for neuroprotection or neurotoxicity in our pilot study. A large, adequately powered randomized control trial is needed to discern the central nervous system effect of ketamine on the developing brain. brain.The trial is registered at www.ClinicalTrials.gov, NCT00556361.

    View details for DOI 10.1097/PCC.0b013e31822f18f9

    View details for Web of Science ID 000303984800024

    View details for PubMedID 21926656

  • The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial PEDIATRIC CRITICAL CARE MEDICINE Carcillo, J. A., Dean, J. M., Holubkov, R., Berger, J., Meert, K. L., Anand, K. J., Zimmerman, J., Newth, C. J., Harrison, R., Burr, J., Willson, D. F., Nicholson, C. 2012; 13 (2): 165-173

    Abstract

    Nosocomial infection/sepsis occurs in up to 40% of children requiring long-term intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and/or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein, would reduce the occurrence of nosocomial infection/sepsis in this at-risk population.Randomized, double-blinded, comparative effectiveness trial.Eight pediatric intensive care units in the National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network.Two hundred ninety-three long-term intensive care patients (age 1-17 yrs) expected to require >72 hrs of invasive care.Patients were stratified according to immunocompromised status and center and then were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide (n = 149), or daily enteral whey protein (n = 144) and intravenous saline for up to 28 days of intensive care unit stay. The primary end point was time to development of nosocomial sepsis/infection. The analysis was intention to treat.There were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection/sepsis (median whey protein 13.2 days vs. zinc, selenium, glutamine, and intravenous metoclopramide 12.1 days; p = .29 by log-rank test) or the rate of nosocomial infection/sepsis (4.83/100 days whey protein vs. 4.99/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection/sepsis with zinc, selenium, glutamine, and intravenous metoclopramide in this immunocompromised group (6.09/100 days whey protein vs. 1.57/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .011).Compared with whey protein supplementation, zinc, selenium, glutamine, and intravenous metoclopramide conferred no advantage in the immune-competent population. Further evaluation of zinc, selenium, glutamine, and intravenous metoclopramide supplementation is warranted in the immunocompromised long-term pediatric intensive care unit patient.

    View details for DOI 10.1097/PCC.0b013e31823896ae

    View details for Web of Science ID 000301230100019

    View details for PubMedID 22079954

  • Oral Sucrose and "Facilitated Tucking" for Repeated Pain Relief in Preterms: A Randomized Controlled Trial PEDIATRICS Cignacco, E. L., Sellam, G., Stoffel, L., Gerull, R., Nelle, M., Anand, K. J., Engberg, S. 2012; 129 (2): 299-308

    Abstract

    To test the comparative effectiveness of 2 nonpharmacologic pain-relieving interventions administered alone or in combination across time for repeated heel sticks in preterm infants.A multicenter randomized controlled trial in 3 NICUs in Switzerland compared the effectiveness of oral sucrose, facilitated tucking (FT), and a combination of both interventions in preterm infants between 24 and 32 weeks of gestation. Data were collected during the first 14 days of their NICU stay. Three phases (baseline, heel stick, recovery) of 5 heel stick procedures were videotaped for each infant. Four independent experienced nurses blinded to the heel stick phase rated 1055 video sequences presented in random order by using the Bernese Pain Scale for Neonates, a validated pain tool.Seventy-one infants were included in the study. Interrater reliability was high for the total Bernese Pain Scale for Neonates score (Cronbach's α: 0.90-0.95). FT alone was significantly less effective in relieving repeated procedural pain (P < .002) than sucrose (0.2 mL/kg). FT in combination with sucrose seemed to have added value in the recovery phase with lower pain scores (P = .003) compared with both the single-treatment groups. There were no significant differences in pain responses across gestational ages.Sucrose with and without FT had pain-relieving effects even in preterm infants of <32 weeks of gestation having repeated pain exposures. These interventions remained effective during repeated heel sticks across time. FT was not as effective and cannot be recommended as a nonpharmacologic pain relief intervention for repeated pain exposure.

    View details for DOI 10.1542/peds.2011-1879

    View details for Web of Science ID 000300395100052

    View details for PubMedID 22232305

  • A pilot study of preemptive morphine analgesia in preterm neonates: Effects on head circumference, social behavior, and response latencies in early childhood NEUROTOXICOLOGY AND TERATOLOGY Ferguson, S. A., Ward, W. L., Paule, M. G., Hall, R. W., Anand, K. J. 2012; 34 (1): 47-55

    Abstract

    Use of preemptive analgesia in Neonatal Intensive Care Units is recommended for severe and/or invasive procedures. However, the potential long-term consequences of such analgesia, which may be prolonged, are only beginning to be studied. In this pilot study, a subset of subjects previously enrolled in the Neurological Outcomes and Preemptive Analgesia in Neonates (NEOPAIN) trial was assessed at early childhood. These ex-preterm infants (born at 23-32 weeks of gestational age) required intubation within 72 h postpartum and were randomized to receive either preemptive morphine analgesia (maximum of 14 days) or placebo within 8h post-intubation. At 5-7 years of age, neuropsychological outcomes, morphometrics, adaptive behavior, parent-rated behavior, motivation, and short-term memory were measured. Although overall IQ and academic achievement did not differ between the morphine treated (n=14) and placebo (n=5) groups, preemptive morphine analgesia was associated with distinct differences in other outcome variables. Head circumference of morphine treated children was approximately 7% smaller (Cohen'sd: 2.83, effect size large) and body weight was approximately 4% less (Cohen'sd: 0.81, effect size large); however, height did not differ. In the short-term memory task (delayed matching to sample), morphine treated children exhibited significantly longer choice response latencies than placebo children (3.86±0.33 and 2.71±0.24 s, respectively) (p<0.03) and completed approximately 27% less of the task than placebo children (Cohen'sd: 0.96, effect size large). Parents described morphine treated children as having more social problems, an effect specific to creating and maintaining friendships (Cohen'sd: -0.83, effect size large). Despite the small sample size and the preliminary nature of this study, these results are strongly suggestive of long-lasting effects of preemptive morphine analgesia. A larger investigation with more comprehensive assessments of some of these key features will enable a more complete understanding of the relationship between preemptive morphine treatment and long-term neurocognitive, behavioral, and adaptive outcomes.

    View details for DOI 10.1016/j.ntt.2011.10.008

    View details for Web of Science ID 000301037100006

    View details for PubMedID 22094261

  • Neonatal pain assessment in Sweden - a fifteen-year follow up ACTA PAEDIATRICA Gradin, M., Eriksson, M. 2011; 100 (2): 204-208

    Abstract

    It has been proposed that a systematic pain assessment increases the awareness of the need to treat and prevent pain, and most international and national neonatal pain guidelines state that pain assessment should be performed in a systematic way. National surveys show a wide variation in compliance to these guidelines.A survey to all Swedish neonatal units was performed in 1993, 1998, 2003 and 2008, concerning the use of, and need for, pain assessment tools.The number of units that tried to assess pain increased from 64% in 1993 to 83% in 2008. Forty-four per cent of these used a structured method in 2003, compared to three per cent in 1998. The most common pain indicator was facial actions.The proportion of neonatal units that reported the use of a structured pain assessment tool has increased significantly from 1993 to 2008. There is a need for better evidence for the relation between the implementation of pain guidelines and the actual performance of pain assessment.

    View details for DOI 10.1111/j.1651-2227.2010.01996.x

    View details for Web of Science ID 000285971100011

    View details for PubMedID 20804461

  • Comparison at 32-37 weeks postconception of infants born 1983-1989 and 1995-2004 on the neurobehavioral assessment of the preterm infant INFANCY Brown, J. V., Bakeman, R., Sampers, J. S., Korner, A. F., Constantinou, J. C., Anand, K. J. 2008; 13 (4): 393-409

    View details for DOI 10.1080/15250000802188743

    View details for Web of Science ID 000258330300005

  • Non-pharmacological techniques for pain management in neonates SEMINARS IN PERINATOLOGY Golianu, B., Krane, E., Seybold, J., Almgren, C., Anand, K. J. 2007; 31 (5): 318-322

    Abstract

    Significant progress in understanding the physiology, clinical correlates, and consequences of neonatal pain have resulted in greater attention to pain management during neonatal intensive care. A number of nonpharmacological therapies have been investigated, including nonnutritive sucking, with and without sucrose use, swaddling or facilitated tucking, kangaroo care, music therapy, and multi-sensorial stimulation. Although the efficacy of these approaches is clearly evident, they cannot provide analgesia for moderate or severe pain in the neonate. Further, some of these therapies cannot be effectively applied to all populations of critically ill neonates. Acupuncture, an ancient practice in Chinese medicine, has gained increasing popularity for symptom control among adults and older children. Acupuncture may provide an effective nonpharmacological approach for the treatment of pain in neonates, even moderate or severe pain, and should be considered for inclusion in a graduated multidisciplinary algorithm for neonatal pain management.

    View details for DOI 10.1053/j.semperi.2007.07.007

    View details for Web of Science ID 000250093900008

    View details for PubMedID 17905187