Clinical Focus

  • Neonatal-Perinatal Medicine

Academic Appointments

Administrative Appointments

  • President, California Association of Neonatologists (2005 - 2006)
  • President, Board of Governors, Stanford University School of Med. Alumni Assoc. (2009 - 2011)
  • National Advisory Board Member, Vermont-Oxford Network NICQ (2007 - Present)
  • Medical Director, Neonatal ICU (2000 - Present)

Professional Education

  • Fellowship:Stanford University School of Medicine Registrar (1989) CA
  • Residency:Stanford University School of Medicine Registrar (1987) CA
  • Internship:Stanford University School of Medicine (1985) CA
  • Medical Education:Stanford University School of Medicine (1984) CA
  • Board Certification: Neonatal-Perinatal Medicine, American Board of Pediatrics (1989)
  • M.D., Stanford University, Medicine (1984)
  • M.S., Mass. Institute of Technology, Nutritional Biochemistry (1979)
  • B.S., Mass. Institute of Technology, Biology (1977)

Research & Scholarship

Current Research and Scholarly Interests

Neonatology, extracorporeal membrane oxygenation, nitric oxide therapy, mechanisms of bilirubin toxicity and brain injury, non-invasive biotechnologies to study cellular and organ metabolism.


2018-19 Courses


All Publications

  • Parental coping in the neonatal intensive care unit. Journal of clinical psychology in medical settings Shaw, R. J., Bernard, R. S., Storfer-Isser, A., Rhine, W., Horwitz, S. M. 2013; 20 (2): 135-142


    Fifty-six mothers of premature infants who participated in a study to reduce symptoms of posttraumatic stress disorder (PTSD) completed the Brief COPE, a self-report inventory of coping mechanisms, the Stanford Acute Stress Reaction Questionnaire to assess acute stress disorder (ASD) and the Davidson Trauma Scale to assess PTSD. 18 % of mothers had baseline ASD while 30 % of mothers met the criteria for PTSD at the 1-month follow-up. Dysfunctional coping as measured by the Brief COPE was positively associated with elevated risk of PTSD in these mothers (RR = 1.09, 95 % CI 1.02-1.15; p = .008). Maternal education was positively associated with PTSD; each year increase in education was associated with a 17 % increase in the relative risk of PTSD at 1 month follow-up (RR = 1.17, 95 % CI 1.02-1.35; p = .03). Results suggest that dysfunctional coping is an important issue to consider in the development of PTSD in parents of premature infants.

    View details for DOI 10.1007/s10880-012-9328-x

    View details for PubMedID 22990746

    View details for PubMedCentralID PMC3578086

  • Impact of an EMR-Based Daily Patient Update Letter on Communication and Parent Engagement in a Neonatal Intensive Care Unit. Journal of participatory medicine Palma, J. P., Keller, H., Godin, M., Wayman, K., Cohen, R. S., Rhine, W. D., Longhurst, C. A. 2012; 4


    To evaluate the impact of using electronic medical record (EMR) data in the form of a daily patient update letter on communication and parent engagement in a level II neonatal intensive care unit (NICU).Parents of babies in a level II NICU were surveyed before and after the introduction of an EMR-generated daily patient update letter, Your Baby's Daily Update (YBDU).Following the introduction of the EMR-generated daily patient update letter, 89% of families reported using YBDU as an information source; 83% of these families found it "very useful", and 96% of them responded that they "always" liked receiving it. Rates of receiving information from the attending physician were not statistically significantly different pre- and post-implementation, 81% and 78%, respectively (p = 1). Though there was no statistically significant improvement in parents' knowledge of individual items regarding the care of their babies, a trend towards statistical significance existed for several items (p <.1), and parents reported feeling more competent to manage information related to the health status of their babies (p =.039).Implementation of an EMR-generated daily patient update letter is feasible, resulted in a trend towards improved communication, and improved at least one aspect of parent engagement-perceived competence to manage information in the NICU.

    View details for PubMedID 23730532

  • Combining hand techniques with electric pumping increases the caloric content of milk in mothers of preterm infants JOURNAL OF PERINATOLOGY Morton, J., Wong, R. J., Hall, J. Y., Pang, W. W., Lai, C. T., Lui, J., Hartmann, P. E., Rhine, W. D. 2012; 32 (10): 791-796


    We previously reported that preterm mothers' milk production can exceed levels of term mothers by using early hand expression and hands-on pumping (HOP) with the highest production (955 ml per day) in frequent users of hand expression. In this study, we compared milk composition between mothers stratified by early hand expression frequency.A total of 67 mothers of infants <31 weeks gestation were instructed on hand expression and HOP. Subjects submitted expression records and 1-ml samples from each pumping session over 24 h once weekly for 8 weeks.78% (52/67) of mothers completed the study. But for Week 1, no compositional differences (despite production differences) were noted between the three groups. Protein and lactose tracked reported norms, but fat and energy of mature milk (Weeks 2-8) exceeded norms, 62.5 g l(-1) per fat and 892.7 cal l(-1) (26.4 cal oz(-1)), respectively.Mothers combining manual techniques with pumping express high levels of fat-rich, calorie-dense milk, unrelated to production differences.

    View details for DOI 10.1038/jp.2011.195

    View details for Web of Science ID 000309519800010

    View details for PubMedID 22222549

  • Improved outcomes with a standardized feeding protocol for very low birth weight infants JOURNAL OF PERINATOLOGY McCallie, K. R., Lee, H. C., Mayer, O., Cohen, R. S., Hintz, S. R., Rhine, W. D. 2011; 31: S61-S67


    The objective of this study was to evaluate the impact of a standardized enteral feeding protocol for very low birth weight (VLBW) infants on nutritional, clinical and growth outcomes.Retrospective analysis of VLBW cohorts 9 months before and after initiation of a standardized feeding protocol consisting of 6-8 days of trophic feedings, followed by an increase of 20 ml/kg/day. The primary outcome was days to reach full enteral feeds defined as 160 ml/kg/day. Secondary outcomes included rates of necrotizing enterocolitis and culture-proven sepsis, days of parenteral nutrition and growth end points.Data were analyzed on 147 VLBW infants who received enteral feedings, 83 before ('Before') and 64 subsequent to ('After') feeding protocol initiation. Extremely low birth weight (ELBW) infants in the After group attained enteral volumes of 120 ml/kg/day (43.9 days Before vs 32.8 days After, P=0.02) and 160 ml/kg/day (48.5 days Before vs 35.8 days After, P=0.02) significantly faster and received significantly fewer days of parenteral nutrition (46.2 days Before vs 31.3 days After, P=0.01). Necrotizing enterocolitis decreased in the After group among VLBW (15/83, 18% Before vs 2/64, 3% After, P=0.005) and ELBW infants (11/31, 35% Before vs 2/26, 8% After, P=0.01). Late-onset sepsis decreased significantly in the After group (26/83, 31% Before vs 6/64, 9% After, P=0.001). Excluding those with weight <3rd percentile at birth, the proportion with weight <3rd percentile at discharge decreased significantly after protocol initiation (35% Before vs 17% After, P=0.03).These data suggest that implementation of a standardized feeding protocol for VLBW infants results in earlier successful enteral feeding without increased rates of major morbidities.

    View details for DOI 10.1038/jp.2010.185

    View details for Web of Science ID 000289236900010

    View details for PubMedID 21448207

  • Brief Cognitive-Behavioral Intervention for Maternal Depression and Trauma in the Neonatal Intensive Care Unit: A Pilot Study JOURNAL OF TRAUMATIC STRESS Bernard, R. S., Williams, S. E., Storfer-Isser, A., Rhine, W., Horwitz, S. M., Koopman, C., Shaw, R. J. 2011; 24 (2): 230-234


    Parents of hospitalized premature infants are at risk for developing psychological symptoms. This randomized controlled pilot study examined the effectiveness of a brief cognitive-behavioral intervention in reducing traumatic and depressive symptoms in mothers 1 month after their infant's discharge from the hospital. Fifty-six mothers were randomly assigned to the intervention or control group. Results showed that mothers experienced high levels of symptoms initially and at follow-up. At follow-up, there was a trend for mothers in the intervention group to report lower levels of depression (p = .06; Cohen's f = .318), but levels of traumatic symptoms were similar for both groups. Brief psychological interventions may reduce depressive symptoms in this population. Estimates of the effect sizes can be used to inform future intervention studies.

    View details for DOI 10.1002/jts.20626

    View details for Web of Science ID 000289528300014

    View details for PubMedID 21438016

  • Combining hand techniques with electric pumping increases milk production in mothers of preterm infants JOURNAL OF PERINATOLOGY Morton, J., Hall, J. Y., Wong, R. J., Thairu, L., Benitz, W. E., Rhine, W. D. 2009; 29 (11): 757-764


    Pump-dependent mothers of preterm infants commonly experience insufficient production. We observed additional milk could be expressed following pumping using hand techniques. We explored the effect on production of hand expression of colostrum and hands-on pumping (HOP) of mature milk.A total of 67 mothers of infants <31 weeks gestation were enrolled and instructed on pumping, hand expression of colostrum and HOP. Expression records for 8 weeks and medical records were used to assess production variables.Seventy-eight percent of the mothers completed the study. Mean daily volumes (MDV) rose to 820 ml per day by week 8 and 955 ml per day in mothers who hand expressed >5 per day in the first 3 days. Week 2 and/or week 8 MDV related to hand expression (P<0.005), maternal age, gestational age, pumping frequency, duration, longest interval between pumpings and HOP (P<0.003). Mothers taught HOP increased MDV (48%) despite pumping less.Mothers of preterm infants may avoid insufficient production by combining hand techniques with pumping.

    View details for DOI 10.1038/jp.2009.87

    View details for Web of Science ID 000271187300009

    View details for PubMedID 19571815

  • A quality improvement project to improve admission temperatures in very low birth weight infants JOURNAL OF PERINATOLOGY Lee, H. C., Ho, Q. T., Rhine, W. D. 2008; 28 (11): 754-758


    To review the results of a quality improvement (QI) project to improve admission temperatures of very low birth weight inborn infants.The neonatal intensive care unit at Lucile Packard Children's Hospital underwent a QI project to address hypothermic preterm newborns by staff education and implementing processes such as polyethylene wraps and chemical warming mattresses. We performed retrospective chart review of all inborn infants with birth weight <1500 g during the 18 months prior to (n=134) and 15 months after (n=170) the implementation period. Temperatures were compared between periods. Multivariable logistic regression was used to account for potential confounding variables. We compared mortality rates and grade 3 or 4 intraventricular hemorrhage rates between periods.The mean temperature rose from 35.4 to 36.2 degrees C (P<0.0001) after the QI project. The improvement was consistent and persisted over a 15-month period. After risk adjustment, the strongest predictor of hypothermia was being born in the period before implementation of the QI project (odds ratio 8.12, 95% confidence interval 4.63, 14.22). Although cesarean delivery was a strong risk factor for hypothermia prior to the project, it was no longer significant after the project. There was no significant difference in death or intraventricular hemorrhage detected between periods.There was a significant improvement in admission temperatures after a QI project, which persisted beyond the initial implementation period. Although there was no difference in mortality or intraventricular hemorrhage rates, we did not have sufficient power to detect small differences in these outcomes.

    View details for DOI 10.1038/jp.2008.92

    View details for Web of Science ID 000260795100005

    View details for PubMedID 18580878

  • Inhaled nitric oxide in the treatment of preterm infants EARLY HUMAN DEVELOPMENT Miller, S. S., Rhine, W. D. 2008; 84 (11): 703-707


    Inhaled nitric oxide (iNO) has been used successfully in select term and near-term infants with respiratory failure. The use of iNO in the premature infant population, however, remains controversial. This article will review some of the current literature regarding the use of iNO in premature infants and discuss current recommendations and future research directions.

    View details for DOI 10.1016/j.earlhumdev.2008.08.005

    View details for Web of Science ID 000261560600002

    View details for PubMedID 18930359

  • Neonatal heparin overdose-a multidisciplinary team approach to medication error prevention. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG Arimura, J., Poole, R. L., Jeng, M., Rhine, W., Sharek, P. 2008; 13 (2): 96-98


    Despite the efforts of many hospitals, system failures can result in medication errors that may be life threatening. During 2006 and 2007, nine neonates received potentially fatal doses of heparin. This paper will review contributing factors to the heparin medication errors and ways to minimize the risk of heparin overdose.

    View details for DOI 10.5863/1551-6776-13.2.96

    View details for PubMedID 23055872

    View details for PubMedCentralID PMC3462065

  • The use of inhaled nitric oxide in the premature infant with respiratory distress syndrome. Minerva pediatrica Van Meurs, K., Hintz, S., Rhine, W., Benitz, W. 2006; 58 (5): 403-422


    The identification of the biologic properties of nitric oxide (NO) is one of the key scientific discoveries of the century, but its potential for treating human disease is yet to be fully realized. NO has a basic role in regulating vascular tone of the pulmonary circulation, and recent animal models have suggested a more wide reaching influence on perinatal lung development. In animal models, NO has effects on lung growth, angiogenesis, airway smooth muscle proliferation, vascular remodeling, surfactant function, inflammation, and pulmonary mechanics. However, despite extensive basic science investigation and completion of several large clinical trials, the role of NO in the treatment of the premature infant with respiratory distress syndrome remains unclear. One must conclude that the interaction of lung immaturity, ventilator and oxygen-induced lung injury, and NO biology in the premature newborn is incompletely understood. Clinical trial results of inhaled NO therapy in the premature infant are accumulating, but the results do not suggest a clear-cut advantage for the population at greatest risk for death and disability. Whether trial design, dose, duration of therapy, or other factors are responsible has not been determined. Further research is needed to answer these questions and more clearly define the population of premature infants who may derive benefit from this new therapy.

    View details for PubMedID 17008853

  • Eliminating nosocomial infections in the NICU: everyone's duty JOURNAL OF PERINATOLOGY Rhine, W. D. 2006; 26 (3): 141-143

    View details for DOI 10.1038/

    View details for Web of Science ID 000241843100001

    View details for PubMedID 16493430

  • Venoarterial versus venovenous extracorporeal membrane oxygenation in congenital diaphragmatic hernia: The Extracorporeal Life Support Organization Registry, 1990-1999 31st Annual Meeting of the Section-on-Surgery of the American-Academy-of-Pediatrics Dimmitt, R. A., Moss, R. L., Rhine, W. D., Benitz, W. E., Henry, M. C., VanMeurs, K. P. W B SAUNDERS CO-ELSEVIER INC. 2001: 1199–1204


    Venoarterial (VA) extracorporeal membrane oxygenation (ECMO) traditionally has been the mode of support used in congenital diaphragmatic hernia (CDH). A few studies report success using venovenous (VV) ECMO. The purpose of this study is to compare outcomes in CDH patients treated with VA and VV.The authors queried the Extracorporeal Life Support Organization Registry for newborns with CDH treated with ECMO from January 1, 1990 through December 31, 1999. They analyzed the pre-ECMO data, ECMO course, and complications.VA was utilized in 2,257 (86%) and VV in 371 (14%) patients. The pre-ECMO status was similar, with greater use of nitric oxide, surfactant, and pressors in VV. Survival rate was similar (58.4% for VV and 52.2% for VA, P =.057). VA was associated with more seizures (12.3% v 6.7%, P =.0024) and cerebral infarction (10.5% v 6.7%, P =.03). Sixty-four treatments were converted from VV to VA (VV-->VA). Survival rate in VV-->VA was not significantly different than VA (43.8% v 52.2%, respectively; P =.23). VV-->VA and VA patients had similar neurologic complications.CDH patients treated with VV and VA have similar survival rates. VA had more neurologic complications. The authors identified no disadvantage to the use of VV as an initial mode of ECMO for CDH, although some infants may need conversion to VA.

    View details for DOI 10.1053/jpsu.2001.25762

    View details for Web of Science ID 000170120300021

    View details for PubMedID 11479856

  • Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): How new treatment modalities have affected ECMO utilization PEDIATRICS Hintz, S. R., Suttner, D. M., Sheehan, A. M., Rhine, W. D., Van Meurs, K. P. 2000; 106 (6): 1339-1343


    Over the last decade, several new therapies, including high-frequency oscillatory ventilation (HFOV), exogenous surfactant therapy, and inhaled nitric oxide (iNO), have become available for the treatment of neonatal hypoxemic respiratory failure. The purpose of this retrospective study was to ascertain to what extent these modalities have impacted the use of neonatal extracorporeal membrane oxygenation (ECMO) at our institution.Patients from 2 time periods were evaluated: May 1, 1993 to November 1, 1994 (group 1) and May 1, 1996 to November 1, 1997 (group 2). During the first time period (group 1), HFOV was not consistently used; beractant (Survanta) use for meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), and pneumonia was under investigation; and iNO was not yet available. During the second time period (group 2), HFOV and beractant treatment were considered to be standard therapies, and iNO was available to patients with oxygenation index (OI) >/=25 x 2 at least 30 minutes apart, or on compassionate use basis. Patients were included in the data collection if they met the following entry criteria: 1) OI >15 x 1 within the first 72 hours of admission; 2) EGA >/=35 weeks; 3) diagnosis of MAS, PPHN or sepsis/pneumonia; 4) <5 days of age on admission; and 5) no congenital heart disease, diaphragmatic hernia, or lethal congenital anomaly.Of the 49 patient in group 1, 21 (42.8%) required ECMO therapy. Of these ECMO patients, 14 (66.6%) had received diagnoses of MAS or PPHN. Only 3 of the patients that went on to ECMO received beractant before the initiation of bypass (14.3%). All ECMO patients in group 1 would have met criteria for iNO had it been available. Of all patients in group 1, 18 (36.7%) were treated with HFOV, and 13 (26.5%) received beractant. Of the 47 patients in group 2, only 13 (27.7%) required ECMO therapy (compared with group 1). Of these ECMO patients, only 5 (38.5%) had diagnoses of MAS or PPHN, with the majority of patients (61.5%) requiring ECMO for sepsis/pneumonia, with significant cardiovascular compromise. Only 5 of these ECMO patients, all outborn, did not receive iNO before cannulation because of the severity of their clinical status on admission. Of all patients in group 2, 41 (87.2%) were treated with HFOV (compared with group 1), 42 (89.3%) received beractant (compared with group 1), and 18 (44.7%) received iNO.The results indicate that ECMO was used less frequently when HFOV, beractant and iNO was more commonly used. The differences in treatment modalities used and subsequent use of ECMO were statistically significant. We speculate that, in this patient population, the diagnostic composition of neonatal ECMO patients has changed over time.

    View details for Web of Science ID 000165914800020

    View details for PubMedID 11099586

  • Tc-99m annexin V imaging of neonatal hypoxic brain injury STROKE D'Arceuil, H., Rhine, W., de Crespigny, A., Yenari, M., Tait, J. F., Strauss, W. H., Engelhorn, T., Kastrup, A., Moseley, M., Blankenberg, F. G. 2000; 31 (11): 2692-2699


    Delayed cell loss in neonates after cerebral hypoxic-ischemic injury (HII) is believed to be a major cause of cerebral palsy. In this study, we used radiolabeled annexin V, a marker of delayed cell loss (apoptosis), to image neonatal rabbits suffering from HII.Twenty-two neonatal New Zealand White rabbits had ligation of the right common carotid artery with reduction of inspired oxygen concentration to induce HII. Experimental animals (n=17) were exposed to hypoxia until an ipsilateral hemispheric decrease in the average diffusion coefficient occurred. After reversal of hypoxia and normalization of average diffusion coefficient values, experimental animals were injected with (99m)Tc annexin V. Radionuclide images were recorded 2 hours later.Experimental animals showed no MR evidence of blood-brain barrier breakdown or perfusion abnormalities after hypoxia. Annexin images demonstrated multifocal brain uptake in both hemispheres of experimental but not control animals. Histology of the brains from experimental animals demonstrated scattered pyknotic cortical and hippocampal neurons with cytoplasmic vacuolization of glial cells without evidence of apoptotic nuclei by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Double staining with markers of cell type and exogenous annexin V revealed that annexin V was localized in the cytoplasm of scattered neurons and astrocytes in experimental and, less commonly, control brains in the presence of an intact blood-brain barrier.Apoptosis may develop after HII even in brains that appear normal on diffusion-weighted and perfusion MR. These data suggest a role of radiolabeled annexin V screening of neonates at risk for the development of cerebral palsy.

    View details for Web of Science ID 000165107100026

    View details for PubMedID 11062296

  • Secondary infection presenting as recurrent pulmonary hypertension. Journal of perinatology Hintz, S. R., Benitz, W. E., Halamek, L. P., Van Meurs, K. P., Rhine, W. D. 2000; 20 (4): 262-264


    Primary infection in the neonate, especially group B streptococcal infection, has long been recognized as a cause of persistent pulmonary hypertension of the newborn (PPHN), sometimes requiring treatment with inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO). However, secondary nosocomial infections in the neonatal period have not been widely reported as a cause of severe recurrent pulmonary hypertension (PHTN). We now present two cases of secondary infection in the neonate leading to significant PHTN. In both cases, the infants presented with PPHN soon after birth, requiring transfer to a level 3 neonatal intensive care unit and treatment with high-frequency oscillatory ventilation and iNO. After successful resolution of the initial PPHN, including extubation to nasal cannula, both infants developed signs of severe recurrent PHTN, leading to reintubation, high-frequency oscillatory ventilation and iNO therapy, and consideration of ECMO. In both cases, blood cultures taken at the time of recurrence of PHTN returned positive, one for Staphylococcus epidermidis, the other for methicillin-resistant Staphylococcus aureus. These unusual cases present the possibility of severe recurrent PHTN requiring iNO or ECMO in the setting of secondary infection. We speculate that these infants, although extubated after their first episodes of PHTN, were at risk for recurrence of PHTN due to continued pulmonary vascular reactivity.

    View details for PubMedID 10879342

  • Sonography, CT, and MR imaging: A prospective comparison of neonates with suspected intracranial ischemia and hemorrhage AMERICAN JOURNAL OF NEURORADIOLOGY Blankenberg, F. G., Loh, N. N., Bracci, P., D'Arceuil, H. E., Rhine, W. D., Norbash, A. M., Lane, B., Berg, A., Person, B., Coutant, M., Enzmann, D. R. 2000; 21 (1): 213-218


    Sonography, CT, and MR imaging are commonly used to screen for neonatal intracranial ischemia and hemorrhage, yet few studies have attempted to determine which imaging technique is best suited for this purpose. The goals of this study were to compare sonography with CT and MR imaging prospectively for the detection of intracranial ischemia or hemorrhage and to determine the prognostic value(s) of neuroimaging in neonates suspected of having hypoxic-ischemic injury (HII).Forty-seven neonates underwent CT (n = 26) or MR imaging (n = 24) or both (n = 3) within the first month of life for suspected HII. Sonography was performed according to research protocol within an average of 14.4 +/- 9.6 hours of CT or MR imaging. A kappa analysis of interobserver agreement was conducted using three independent observers. Infants underwent neurodevelopmental assessment at ages 2 months (n = 47) and 2 years (n = 26).CT and MR imaging had significantly higher interobserver agreement (P < .001) for cortical HII and germinal matrix hemorrhage (GMH) (Grades I and II) compared with sonography. MR imaging and CT revealed 25 instances of HII compared with 13 identified by sonography. MR imaging and CT also revealed 10 instances of intraparenchymal hemorrhage (>1 cm, including Grade IV GMH) compared with sonography, which depicted five. The negative predictive values of neuroimaging, irrespective of technique used, were 53.3% and 58.8% at the 2-month and 2-year follow-up examinations, respectively.CT and MR imaging have significantly better interobserver agreement for cortical HII and GMH/intraventricular hemorrhage and can reveal more instances of intraparenchymal hemorrhage compared with sonography. The absence of neuroimaging findings on sonograms, CT scans, or MR images does not rule out later neurologic dysfunction.

    View details for Web of Science ID 000085055900042

    View details for PubMedID 10669253

  • Serial magnetic resonance diffusion and hemodynamic imaging in a neonatal rabbit model of hypoxic-ischemic encephalopathy NMR IN BIOMEDICINE D'Arceuil, H. E., de Crespigny, A. J., Rother, J., Moseley, M., Rhine, W. 1999; 12 (8): 505-514


    Dynamic changes in relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were investigated, using high speed magnetic resonance imaging (MRI) in an acute neonatal rabbit model of hypoxic-ischemic encephalopathy (HIE). Serial rCBV imaging used a magnetic susceptibility blood pool contrast agent. Interleaved ADC and rCBV images were acquired with 9 s temporal resolution. Rabbits received unilateral common carotid artery (CCA) ligation followed by hypoxia. rCBV increased bilaterally within 1-2 min after the onset of hypoxia. A biphasic ADC decline was observed: a slowly declining phase (84 +/- 18% of baseline) followed by a rapid, focal drop to 55 +/- 8% of baseline in the ipsilateral cortex, which was paralleled by a rapid focal rCBV drop to 70 +/- 17% of baseline. ADC decline generally began in a small region of ipsilateral cortex and spread over the ipsilateral cortex, ipsilateral subcortical tissue and contralateral cortex. The initial ADC drop usually preceded the initial rCBV drop by approximately 60 s, however at later timepoints rCBV decline sometimes preceded ADC decline. Upon normoxia, rCBV recovered to about baseline values while ADC recovered to baseline or above. This method provides a sensitive means of non-invasively visualizing acute hemodynamic- and metabolic-related changes in HIE with good temporal and spatial resolution.

    View details for Web of Science ID 000085232300004

    View details for PubMedID 10668043

  • Bilirubin toxicity and differentiation of cultured astrocytes. Journal of perinatology Rhine, W. D., SCHMITTER, S. P., Yu, A. C., Eng, L. F., Stevenson, D. K. 1999; 19 (3): 206-211


    To study the toxicity of bilirubin in primary cultures of newborn rat cerebral cortical astrocytes.Primary cultures of newborn rat astrocytes were incubated at bilirubin concentrations of 0, 1, 5, 10, 25, 50, 100, 200, and 2000 microM, at a bilirubin:albumin molar ratio of 1.7. Bilirubin toxicity was determined by changes in cellular morphology, trypan blue staining, and lactate dehydrogenase (LDH) release into the culture medium at various times of incubation. To determine if differentiation of astrocytes affects bilirubin toxicity, cultures were treated with dibutyryl cyclic adenosine monophosphate.All three indices of toxicity showed a bilirubin concentration dependence. LDH release in experimental cultures was significantly elevated (p < 0.05) above that of control cultures by 24 hours at bilirubin concentrations of > or = 100 microM. The absolute amount of LDH release differed significantly between the 200 and 2000 microM cultures from 1.5 to 24 hours, after which duration of exposure appeared to take over and all cultures approached maximum. LDH release for the lower concentrations all reached maximum by 120 hours, except for the 1 microM cultures, which showed no significant elevation above control throughout the study period. At 100 and 200 microM bilirubin, LDH release by untreated cells was significantly higher (p < 0.05) than release by treated cells by 36 hours.Undifferentiated astrocytes appeared to be more sensitive to bilirubin toxicity, which may correlate with the greater susceptibility of newborns to kernicteric injury. Studies with primary astrocyte culture may provide insight into how bilirubin sensitivity changes with brain development as well as the cellular and biochemical mechanisms of bilirubin encephalopathy.

    View details for PubMedID 10685223

  • Strategy for lipid suppression in lactate imaging using STIR-DQCT: A study of hypoxic-ischemic brain injury MAGNETIC RESONANCE IN MEDICINE Nakai, T., Rhine, W. D., Okada, T., Stevenson, D. K., Spielman, D. M. 1998; 40 (4): 629-632


    In vivo lactate detection using gradient enhanced double quantum coherence transfer (DQCT) was significantly improved by addition of short-time-inversion-recovery (STIR). Phantom studies demonstrated lipid suppression down to the background noise level with 33% loss of lactate signal. In vivo studies using a rabbit model of hypoxic and unilateral-ischemic brain injury showed reduction down to 29 +/- 11% in lipids with inversion times between 140 and 170 ms. Lactate signals on the ischemic side were 51 +/- 53% higher than the nonischemic side at the peak of hypoxia. STIR-DQCT can be a useful robust method of obtaining metabolic maps of lactate in vivo.

    View details for Web of Science ID 000076080900015

    View details for PubMedID 9771580

  • Diffusion and perfusion magnetic resonance imaging of the evolution of hypoxic ischemic encephalopathy in the neonatal rabbit JOURNAL OF MAGNETIC RESONANCE IMAGING D'Arceuil, H. E., de Crespigny, A. J., Rother, J., Seri, S., Moseley, M. E., Stevenson, D. K., Rhine, W. 1998; 8 (4): 820-828


    Hypoxic-ischemic encephalopathy (HIE) can result from neonatal asphyxia, the pathophysiology of which is poorly understood. We studied the acute evolution of this disease, using magnetic resonance imaging in an established animal model. HIE was induced in neonatal rabbits by a combination of common carotid artery (CCA) ligation and hypoxia. Serial diffusion and perfusion-weighted magnetic resonance images were acquired before, during, and after the hypoxic interval. Focal areas of decreased apparent diffusion coefficient (ADC) were detected initially in the cortex ipsilateral to CCA ligation within 62 +/- 48 min from the onset of hypoxia. Subsequently, these areas of decreased ADC spread to the subcortical white matter, basal ganglia (ipsilateral side), and then to the contralateral side. Corresponding perfusion-weighted images showed relative cerebral blood volume deficits which closely matched those regions of ADC change. Our results show that MRI diffusion and perfusion-weighted imaging can detect acute cell swelling post-hypoxia in this HIE model.

    View details for Web of Science ID 000080143600010

    View details for PubMedID 9702883

  • Congenital diaphragmatic hernia associated with aortic coarctation 29th Annual Meeting of the Canadian-Association-of-Paediatric-Surgeons Eghtesady, P., Skarsgard, E. D., Smith, B. M., Robbins, R. C., Wexler, L., Rhine, W. D. W B SAUNDERS CO-ELSEVIER INC. 1998: 943–45


    Congenital diaphragmatic hernia (CDH) may be associated with other anomalies, most frequently cardiovascular in nature. Despite fetal echocardiography, diagnosis of an accompanying cardiac malformation often is not made until after birth and sometimes not until after extracorporeal membrane oxygenation (ECMO) has been instituted. Aortic coarctation associated with CDH may occur as an isolated, surgically correctable malformation or it may be a component of the usually fatal left heart "hypoplasia" or "smallness" syndrome. The authors present two cases of aortic coarctation associated with CDH requiring ECMO that illustrate the management challenges of these coincident diagnosis. In one case, the accompanying coarctation was suspected and required precannulation angiography for confirmation, whereas in the other case, the diagnosis of coarctation was not made until after ECMO cannulation. Depending on its anatomic location and severity, an aortic coarctation associated with life-threatening CDH may limit the physiological efficacy of venoarterial ECMO. Furthermore, arterial cannulation for extracorporeal support requires that flow through the remaining carotid artery be maintained during aortic reconstruction, which may prove difficult for lesions best treated by subclavian flap angioplasty. When the diagnosis of coincident aortic coarctation and CDH is suspected or proven before institution of extracorporeal support, serious consideration should be given to venovenous bypass, because this may provide better postductal oxygenation and facilitate aortic repair with the option of left carotid artery inflow occlusion.

    View details for Web of Science ID 000074327400034

    View details for PubMedID 9660236

  • Response of premature infants with severe respiratory failure to inhaled nitric oxide. Preemie NO Collaborative Group. Pediatric pulmonology Van Meurs, K. P., Rhine, W. D., Asselin, J. M., Durand, D. J. 1997; 24 (5): 319-323


    Elevated pulmonary vascular resistance is seen in premature infants with severe respiratory distress syndrome (RDS). Inhaled nitric oxide (NO) has been shown to decrease pulmonary vascular resistance and to improve oxygenation in some patients with respiratory failure. The purpose of this study was to determine whether premature infants with severe RDS would respond to inhaled NO with an improvement in oxygenation. Eleven premature infants (mean gestational age 29.8 weeks) with severe respiratory failure caused by RDS were treated with NO in four concentrations [1, 5, 10, 20 parts per million (ppm) NO] and with placebo (0 ppm NO). Arterial blood gas measurements were drawn immediately before and at the end of each of the 15-minute treatments and were used to determine the arterial/alveolar oxygen ratio (PaO2/PAO2). Ten of the 11 infants had a greater than 25% increase in PaO2/PAO2. Five of the 11 had a greater than 50% increase in PaO2/PAO2. Despite normal cranial ultrasound imaging prior to NO, 3 infants had intracranial hemorrhage (ICH) noted on their first ultrasound scan after this brief period of NO treatment, and 4 additional infants developed ICH later during their hospitalization. No infant had significant elevations of methemoglobin concentrations after the total 60-minute exposure to NO. NO may be an effective method of improving oxygenation in infants with severe RDS. The disturbing incidence of ICH in this small group of infants needs to be carefully evaluated before considering routine use or NO for preterm infants.

    View details for PubMedID 9407564

  • Hemopericardium from coronary artery laceration complicating extracorporeal membrane oxygenation. Journal of perinatology Rhine, W. D., Hartman, G. E., Shochat, S. J., Benitz, W. E., Van Meurs, K. P. 1997; 17 (3): 189-192


    We report the clinical course and successful surgical treatment of hemopericardium resulting from coronary artery (CA) laceration in two patients with congenital diaphragmatic hernia (CDH) undergoing extracorporeal membrane oxygenation (ECMO) bypass.Retrospective case review.Two neonates with CDH had needle aspiration for either pneumothorax or pericardial effusion before initiation of ECMO. While on bypass, progressive hemopericardium led to narrow pulse pressure and decreased venous return that limited bypass flow. Widened cardiac silhouette on chest radiographs suggested hemopericardium; echocardiography was confirmatory in one case. The underlying diagnosis of CA laceration was made during pericardiotomy and treated with surgical patching.Pre-ECMO history of cardiothoracic needle aspiration is important because complications such as hemothorax or hemopericardium may arise once ECMO bypass is initiated. Inadvertent CA laceration may lead to acute hemopericardium, compromising venous drainage. However, CA laceration can be successfully repaired while the patient is on bypass.

    View details for PubMedID 9210072

  • Nitrovasodilator therapy for severe respiratory distress syndrome. Journal of perinatology Benitz, W. E., Rhine, W. D., Van Meurs, K. P., Stevenson, D. K. 1996; 16 (6): 443-448


    Improved gas exchange in infants with severe respiratory distress syndrome has been reported in association with infusion of nitroprusside and during inhalation of nitric oxide. To evaluate the association between nitrovasodilator therapy and clinical improvement in premature neonates with severe respiratory distress syndrome, we reviewed the courses of 22 infants with severe respiratory distress syndrome who were treated with sodium nitroprusside for at least 24 hours. These infants had birth weights of 2049 +/- 828 gm (range 720 to 3430 gm), gestational ages of 32.5 +/- 3.5 weeks (range 25 to 38 weeks), high ventilator settings before treatment (FIO2 of 100%, peak inspiratory pressures of 37.8 +/- 6.1 cm H2O [range 30 to 50 cm H2O], and mean airway pressures of 18.0 +/- 3.3 cm H2O [range 12.3 to 26 cm H2O]), and low pretreatment PaO2 of 49.3 +/- 9.4 mm Hg (range 27 to 69 mm Hg). Baseline oxygenation indexes were 39.4 +/- 12.1 (range 18.6 to 66.7). Nitroprusside infusion was temporally associated with increased PaO2, decreased PaCO2, and reduced oxygenation index. Potentially beneficial changes were inconsistent in infants with pulmonary interstitial emphysema and were greatest in infants treated with end-expiratory pressures of at least 4 cm H2O. These observations provide a basis for the hypothesis that nitrovasodilator therapy produces improvement in gas exchange in premature infants with severe respiratory distress syndrome.

    View details for PubMedID 8979182

  • A model for detecting early metabolic changes in neonatal asphyxia by 1H-MRS JOURNAL OF MAGNETIC RESONANCE IMAGING Nakai, T., Rhine, W. D., Enzmann, D. R., Stevenson, D. K., Spielman, D. M. 1996; 6 (3): 445-452


    In newborn rabbits, the early cerebral metabolic changes caused by hypoxic-ischemic (H-I) insult was examined by using volume localized 1H-MRS (STEAM). Partial ischemia was caused by unilateral carotid artery ligation, and hypoxia was induced by 10% oxygen inspiration for 150 minutes. Lactate immediately increased after hypoxia induction and almost disappeared 120 to 150 minutes after removal of hypoxia in both H-I and hypoxia-only experiments. Lactate production correlated well with decrease of the blood oxygen saturation. More lactate was produced on ischemic side 50 minutes post-hypoxia induction in H-I study. Ischemia alone did not cause any significant lactate production. Lactate caused by hypoxia can be dynamically monitored by localized 1H-MRS. Existence of regional ischemia can induce greater anaerobic glycolysis and may affect the pattern of brain injury under hypoxia. 1H-MRS is a sensitive tool to detect the acute metabolic change caused by H-I insult.

    View details for Web of Science ID A1996UM58400004

    View details for PubMedID 8724409

  • NEONATAL JAUNDICE - WHAT NOW CLINICAL PEDIATRICS Dennery, P. A., Rhine, W. D., Stevenson, D. K. 1995; 34 (2): 103-107

    View details for Web of Science ID A1995QH23900007

    View details for PubMedID 7729104

  • LOBAR LUNG TRANSPLANTATION AS A TREATMENT FOR CONGENITAL DIAPHRAGMATIC-HERNIA JOURNAL OF PEDIATRIC SURGERY VanMeurs, K. P., Rhine, W. D., Benitz, W. E., Shochat, S. J., Hartman, G. E., Sheehan, A. M., Starnes, V. A. 1994; 29 (12): 1557-1560


    The mortality rate for infants severely affected with congenital diaphragmatic hernia (CDH) remains high despite significant advances in surgical and neonatal intensive care including delayed repair and extracorporeal membrane oxygenation (ECMO). Because of the increasingly successful experience with single-lung transplantation in adults; this approach has been suggested as a potential treatment for CDH infants with unsalvageable pulmonary hypoplasia. The authors report on a newborn female infant who was the product of a pregnancy complicated by polyhydramnios. At birth, she was found to have a right-sided CDH and initially was treated with preoperative ECMO, followed by delayed surgical repair. Despite the CDH repair and apparent resolution of pulmonary hypertension, the infant's condition deteriorated gradually after decannulation, and escalating ventilator settings were required as well as neuromuscular paralysis and pressor support because of progressive hypoxemia and hypercarbia. A lung transplant was performed 8 days after decannulation, using the right lung obtained from a 6-week-old donor. The right middle lobe was excised because of the size discrepancy between the donor and recipient. After transplantation, the patient was found to have duodenal stenosis and gastroesophageal reflux, which required duodenoduodenostomy and fundoplication. The patient was discharged from the hospital 90 days posttransplantation, at 3 1/2 months of age. Currently she is 24 months old and doing well except for poor growth. This case shows the feasibility of single-lung transplantation for infants with CDH, and the potential use of ECMO as a temporary bridge to transplantation. Lobar lung transplantation allowed for less stringent size constraints for the donor lung.

    View details for Web of Science ID A1994PW61200018

    View details for PubMedID 7877027



    Computed tomography scans of the head and early neurodevelopmental assessment (Bayley Scales of Infant development) were recorded for 24 surviving infants who received venovenous extracorporeal membrane oxygenation and were compared with those of infants treated with venoarterial bypass matched by diagnosis and oxygenation index before extracorporeal membrane oxygenation. A comparable neuroradiographic and early neurodevelopmental outcome was documented for survivors of venoarterial and venovenous extracorporeal membrane oxygenation.

    View details for Web of Science ID A1994PA95200025

    View details for PubMedID 8040782



    Detection of blood-brain barrier (BBB) opening in neonates has required invasive methods not clinically applicable. We set out to develop a noninvasive approach to detect such opening.Wistar rats were studied using MRI with Gd-DTPA contrast before and after injection of hyperosmotic solutions known to produce barrier opening. Arabinose was given via right carotid artery to produce unilateral barrier opening; urea was given via tail vein to produce bilateral opening; controls received normal saline. Next, all animals received Gd-DTPA via tail vein.Animals receiving carotid hyperosmotic injections showed increased signal in the ipsilateral brain hemisphere; those receiving venous hyperosmotic injections showed increased signal bilaterally. Similar increases were not found prior to administration of hyperosmotic agent or in saline controls. In both cases, barrier opening was detectable using the relative partitioning of Gd-DTPA between intrabarrier and extrabarrier structures, even in the absence of a hemispheric control.We conclude that MRI with Gd-DTPA contrast allows noninvasive detection of BBB opening in the rat.

    View details for Web of Science ID A1993LM74900008

    View details for PubMedID 8331226

  • ANTICOAGULATION THERAPY ADVISER - A DECISION-SUPPORT SYSTEM FOR HEPARIN-THERAPY DURING ECMO 16th Annual Symposium on Computer Applications in Medical Care Peverini, R. L., Sale, M., Rhine, W. D., Fagan, L. M., Lenert, L. A. MCGRAW-HILL BOOK CO. 1993: 567–578
  • Where should the hemofiltration circuit be placed in relation to the extracorporeal membrane oxygenation circuit? ASAIO journal Yorgin, P. D., Kirpekar, R., Rhine, W. D. 1992; 38 (4): 801-803


    Patients requiring extracorporeal membrane oxygenation (ECMO) frequently experience hypervolemia and metabolic abnormalities that can be effectively managed by hemofiltration. Although several options for hemofiltration circuit placement exist, some may have the disadvantage of recirculation or shunting of poorly oxygenated blood to the patient. Attachment of the entire hemofiltration circuit to the pre-ECMO pump region is described. Despite the absence of pump generated pressure and a low blood flow rate, effective hemofiltration and diafiltration were achieved. This article examines whether placement of the hemofiltration circuit proximal to the ECMO pump has advantages over other hemofiltration circuit placements.

    View details for PubMedID 1450474

  • Anticoagulation therapy advisor: a decision-support system for heparin therapy during ECMO. Proceedings / the ... Annual Symposium on Computer Application [sic] in Medical Care. Symposium on Computer Applications in Medical Care Peverini, R. L., Sale, M., Rhine, W. D., Fagan, L. M., Lenert, L. A. 1992: 567-571


    We present a case study describing our development of a mathematical model to control a clinical parameter in a patient--in this case, the degree of anticoagulation during extracorporeal membrane oxygenation (ECMO) support. During ECMO therapy, an anticoagulant agent (heparin) is administered to prevent thrombosis. Under- or over-coagulation can have grave consequences. To improve control of anticoagulation, we developed a pharmacokinetic-pharmacodynamic (PK-PD) model that predicts activated clotting times (ACT) using the NONMEM program. We then integrated this model into a decision-support system, and validated it with an independent data set. The population model had a mean absolute error of prediction for ACT values of 33.5 seconds, with a mean bias in estimation of -14.3 seconds. Individualization of model-parameter estimates using nonlinear regression improved the absolute error prediction to 25.5 seconds, and lowered the mean bias to -3.1 seconds. The PK-PD model is coupled with software for heuristic interpretation of model results to provide a complete environment for the management of anticoagulation.

    View details for PubMedID 1482937

  • Fatal postoperative Legionella pneumonia in a newborn. Journal of perinatology Greene, K. A., Rhine, W. D., Starnes, V. A., Ariagno, R. L. 1990; 10 (2): 183-184


    This is a case of postoperative Legionella pneumonia in a full-term infant with hypoplastic left heart syndrome. The infant had an uncomplicated prenatal history, normal vaginal delivery, Apgars of 8 at 1 and 5 minutes, but was cyanotic at birth. At 3 days of age she had a stage 1 Norwood surgical procedure to palliate her congenital heart disease. A synthetic patch was placed over the thoracic midline because of difficulty in reapposing the sternum. Peritoneal dialysis was used to manage renal failure. At 20 days of age she had disseminated intravascular coagulopathy and pneumonia associated with sepsis. Four days later she died. Legionella pneumophila serogroup 1 was isolated from a lung culture taken at autopsy.

    View details for PubMedID 2358903