Robert J. DiGeronimo

A 22-year experience in global transport extracorporeal membrane oxygenation

BACKGROUND/PURPOSE Transport extracorporeal membrane oxygenation (ECMO) is currently available at 12 centers. We report a 22-year experience from the only facility providing global transport ECMO. Indications for transport ECMO include lack of ECMO services, inability to transport conventionally, inability to wean from cardiopulmonary bypass, extracorporeal cardiopulmonary resuscitation, and need to move a patient on ECMO for specialized services such as organ transplantation. METHODS Retrospective database review of children undergoing inhouse and transport ECMO from 1985 to 2007. RESULTS Sixty-eight children underwent transport ECMO. Fifty-six were transported on ECMO into our facility. The remaining 12 were moved between 2 outside locations. Ground vehicles and fixed-wing aircraft were used. Distance transported was 8 to 7500 miles (13-12070 km), mean 1380 miles (2220 km). There were 116 inhouse ECMO runs. No child died during transport. Survival to discharge after transport ECMO was 65% (44/68) and, for inhouse ECMO, was 70% (81/116). CONCLUSIONS Transport ECMO is feasible and effective, with survival rates comparable to inhouse ECMO. We have used transport ECMO to help children at non-ECMO centers with pulmonary failure who have not improved with inhaled nitric oxide and high-frequency ventilation. We have also transported a child after extracorporeal cardiopulmonary resuscitation, which may represent an emerging indication for transport ECMO. Transport ECMO often is the only option for children too unstable for conventional transport or those already on ECMO and requiring a specialized service at another facility, such as organ transplantation.

Remodeling of the tight junction during recovery from exposure to hydrogen peroxide in kidney epithelial cells

Renal ischemia-reperfusion injury results in oxidative stress-induced alterations in barrier function. Activation of the mitogen-activated protein (MAP) kinase pathway during recovery from oxidative stress may be an effector of oxidant-induced tight junction reorganization. We hypothesized that tight junction composition and barrier function would be perturbed during recovery from oxidative stress. We developed a model of short-term H(2)O(2) exposure followed by recovery using Madin Darby canine kidney (MDCK II) cells. H(2)O(2) perturbs barrier function without a significant cytotoxic effect except in significant doses. ERK-1/2 and p38, both enzymes of the MAP kinase pathway, were activated within minutes of exposure to H(2)O(2). Transient exposure to H(2)O(2) produced a biphasic response in the transepithelial electrical resistance (TER). An initial drop in TER at 6 h was followed by a significant increase at 24 h. Inhibition of ERK-1/2 activation attenuated the increase in TER observed at 24 h. Expression of occludin initially decreased, followed by partial recovery at 24 h. In contrast, claudin-1 levels decreased and failed to recover at 24 h. Claudin-2 levels were markedly decreased at 24 h; however, inhibition of ERK-1/2 activation was protective. Occludin and claudin-1 localization at the apical membrane on immunofluorescence images was fragmented at 6 h after H(2)O(2) exposure with subsequent recovery of appropriate localization by 24 h. MDCK II cell recovery after H(2)O(2) exposure is associated with functional and structural modifications of the tight junction that are mediated in part by activation of the MAP kinase enzymes ERK-1/2 and p38.

Brain preservation with selective cerebral perfusion for operations requiring circulatory arrest: protection at 25 °C is similar to 18 °C with shorter operating times

BACKGROUND Hypothermic circulatory arrest (HCA) is employed for aortic arch and other complex operations, often with selective cerebral perfusion (SCP). Our previous work has demonstrated real-time evidence of improved brain protection using SCP at 18 degrees C. The purpose of this study was to evaluate the utility of SCP at warmer temperatures (25 degrees C) and its impact on operating times. METHODS Piglets undergoing cardiopulmonary bypass (CPB) and 60 min of HCA were assigned to three groups: 18 degrees C without SCP, 18 degrees C with SCP and 25 degrees C with SCP (n=8 animals per group). CPB flows were 100 ml kg(-1) min(-1) using pH-stat management. SCP flows were 10 ml kg(-1) min(-1) via the innominate artery. Cerebral oxygenation was monitored using NIRS (near-infrared spectroscopy). A microdialysis probe placed into the cerebral cortex had samples collected every 15 min. Animals were recovered for 4h after separation from CPB. All data are presented as mean+/-standard deviation (SD; p<0.05, significant). RESULTS Cerebral oxygenation was preserved during deep and tepid HCA with SCP, in contrast to deep HCA without SCP (p<0.05). Deep HCA at 18 degrees C without SCP resulted in significantly elevated brain lactate (p<0.01) and glycerol (p<0.01), while the energy substrates glucose (p<0.001) and pyruvate (p<0.001) were significantly depleted. These derangements were prevented with SCP at 18 degrees C and 25 degrees C. The lactate/pyruvate ratio (L/P) was profoundly elevated following HCA alone (p<0.001) and remained persistently elevated throughout recovery (p<0.05). Piglets given SCP during HCA at 18 degrees C and 25 degrees C maintained baseline L/P ratios. Mean operating times were significantly shorter in the 25 degrees C group compared to both 18 degrees C groups (p<0.05) without evidence of significant acidemia. CONCLUSION HCA results in cerebral hypoxia, energy depletion and ischaemic injury, which are attenuated with the use of SCP at both 18 degrees C and 25 degrees C. Procedures performed at 25 degrees C had significantly shorter operating times while preserving end organs.

Correlation of brain tissue oxygen tension with cerebral near infrared spectroscopy and mixed venous oxygen saturation during extracorporeal membrane oxygenation

The aim of this prospective, animal study was to compare brain tissue oxygen tension (PbtO2) with cerebral near infrared spectroscopy (NIRS) and mixed venous oxygen saturation (SVO2) during venoarterial extracorporeal membrane oxygenation (VA ECMO) in a porcine model. This was accomplished using twelve immature piglets with surgically implanted catheters placed in the superficial cerebral cortex to measure brain PbtO2 and microdialysis metabolites. The NIRS sensor was placed overlying the forehead to measure cerebral regional saturation index (rSO2i) while SVO2 was measured directly from the ECMO circuit. Animals were placed on VA ECMO followed by an initial period of stabilization, after which they were subjected to graded hypoxia and recovery. Our results revealed that rSO2i and SVO2 correlated only marginally with PbtO2 (R2=0.32 and R2=0.26, respectively) while the correlation between rSO2i and SVO 2 was significantly stronger (R2=0.59). Cerebral metabolites and rSO2i were significantly altered during attenuation of PbtO 2, p<0.05). A subset of animals, following exposure to hypoxia, experienced markedly delayed recovery of both rSO2i and PbtO 2 despite rapid normalization of SVO2. Upon further analysis, these animals had significantly lower blood pressure (p=0.001), lower serum pH (p=0.01), and higher serum lactate (p=0.02). Additionally, in this subgroup, rSO2i correlated better with PbtO2 (R2=0.76). These findings suggest that, in our ECMO model, rSO2i and SVO 2 correlate reasonably well with each other, but not necessarily with brain PbtO2 and that NIRS-derived rSO2i may more accurately reflect cerebral tissue hypoxia in sicker animals.

Distribution of corticotropin releasing hormone in the fetus, newborn, juvenile, and adult baboon.

Corticotropin releasing hormone (CRH) has previously been identified in extrahypothalamic tissues and may act in a paracrine fashion within these tissues. To date, CRH production and its role in the fetus and newborn have not been investigated. The aim of this study was to explore the distribution and ontogeny of CRH in extrahypothalamic tissues of the fetus, newborn, juvenile, and adult baboon. Pituitary, adrenal, kidney, liver, and lung tissues from baboons at 125 d gestation, 140 d gestation, 185 d gestation (term), juveniles, and adults were obtained at necropsy. The tissues were quantified for protein and immunoreactive CRH was determined by a RIA. CRH levels were normalized to the protein content of each tissue. CRH was present in all tissues and varied over a 100-fold range according to tissue type. The highest concentration of CRH was found in the pituitary, which did not differ with the gestation and/or age of the animal. In the lung tissues of 125- and 140-d gestation animals, CRH was greater than the term, juvenile, and adult lung (p < 0.02). CRH in the adrenal gland of the 125-d samples was greater than the other four ages tested (p < 0.02). Liver CRH levels were higher in the term animals compared with the juvenile baboons. Our study documents the existence of CRH in extrahypothalamic tissues of the baboon from 125 d of gestation to adulthood. Given its presence and distribution, we speculate that CRH may exert ongoing paracrine and/or autocrine actions in these tissues from the time of intrauterine life throughout adulthood.

Mechanical ventilation down-regulates surfactant protein a and keratinocyte growth factor expression in premature rabbits

Surfactant-associated proteins (SP-A, SP-B, and SP-C) are critical for the endogenous function of surfactant. Keratinocyte growth factor (KGF) and vascular endothelial growth factor (VEGF) are key regulators of lung development. The objective of this study was to evaluate the effects of early mechanical ventilation on the expression of these important regulatory proteins in a preterm rabbit model. Premature fetuses were delivered at 29 d of gestation and randomized to necropsy at birth, i.e. no ventilation (NV), spontaneous breathing (SB), or mechanical ventilation (MV) for 16 h. MV animals were further randomized to treatment with dexamethasone (dex). Our findings showed that SB rabbits increased their expression of SP-A mRNA and protein after birth compared with NV controls. MV significantly attenuated this response in the absence of dex. Exposure to dex elevated SP-B mRNA expression in both SB and MV rabbits. KGF protein levels were markedly increased in SB animals compared with MV counterparts. VEGF levels were similar in SB and MV animals, but were significantly increased compared with NV controls. These data suggest that MV alters surfactant-associated protein and growth factor expression, which may contribute to injury in the developing lung.

Ventricular peritoneal shunt infection resulting from group B streptococcus.

Objective: To report, to our knowledge, the first case of a ventricular peritoneal shunt infection by group B streptococcus occurring in infancy. Design: Descriptive case report. Setting: Neonatal intensive care unit in a tertiary referral military hospital. Patient: A 3-month-old, former preterm infant with a case of postoperative ventricular peritoneal shunt infection by group B streptococcus occurring in infancy. Interventions: The infant’s shunt infection was treated with a prolonged course of antibiotics, shunt removal, and eventual shunt replacement. He developed a persistently enlarging third ventricular region cyst, which ultimately required endoscopic surgical fenestration. Measurements and Main Results: Currently, at 25 months of age, the patient has some moderate developmental delays but is otherwise healthy and making progress with no evidence of any recurrent infection Conclusions: Group B streptococcus should be considered as a potential pathogen in ventricular peritoneal shunt infections in infants even outside of the immediate neonatal period. Providers caring for infants should be especially cognizant of the potential risk for nosocomial infections in former premature neonates, especially following high-risk surgical procedures. Prompt recognition of ventricular peritoneal shunt infections and management to include early shunt removal and appropriate antibiotic coverage are recommended in an effort to optimize outcome.

Effects of moderate versus deep hypothermic circulatory arrest and selective cerebral perfusion on cerebrospinal fluid proteomic profiles in a piglet model of cardiopulmonary bypass.

OBJECTIVE Our objective was to compare protein profiles of cerebrospinal fluid between control animals and those subjected to cardiopulmonary bypass after moderate versus deep hypothermic circulatory arrest with selective cerebral perfusion. METHODS Immature Yorkshire piglets were assigned to one of four study groups: (1) deep hypothermic circulatory arrest at 18 degrees C, (2) deep hypothermic circulatory arrest at 18 degrees C with selective cerebral perfusion, (3) moderate hypothermic circulatory arrest at 25 degrees C with selective cerebral perfusion, or (4) age-matched control animals without surgery. Animals undergoing cardiopulmonary bypass were cooled to their assigned group temperature and exposed to 1 hour of hypothermic circulatory arrest. After arrest, animals were rewarmed, weaned off bypass, and allowed to recover for 4 hours. Cerebrospinal fluid collected from surgical animals after the recovery period was compared with cerebrospinal fluid from controls by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Protein spectra were analyzed for differences between groups by Mann-Whitney U test and false discovery rate analysis. RESULTS Baseline and postbypass physiologic parameters were similar in all surgical groups. A total of 194 protein peaks were detected. Compared with controls, groups 1, 2, and 3 had 64, 100, and 13 peaks that were significantly different, respectively (P < .05). Three of these peaks were present in all three groups. Cerebrospinal fluid protein profiles in animals undergoing cardiopulmonary bypass with moderate hypothermic circulatory arrest (group 3) were more similar to controls than either of the groups subjected to deep hypothermia. CONCLUSIONS The mass spectra of cerebrospinal fluid proteins are altered in piglets exposed to cardiopulmonary bypass and hypothermic circulatory arrest. Moderate hypothermic circulatory arrest (25 degrees C) with selective cerebral perfusion compared with deep hypothermic circulatory arrest (18 degrees C) is associated with fewer changes in cerebrospinal fluid proteins, when compared with nonbypass controls.

Comparison of the Sensormedics 3100A and Bronchotron transporter in a neonatal piglet ARDS model.

The Sensormedics® 3100A (Cardinal Health, Dublin, OH) (HFOV) and the Bronchotron® (Percussionaire, Sandpoint, ID) (HFPV) are high‐frequency ventilation devices used to support neonatal respiratory failure; however, a comparison of the devices, with respect to gas exchange at similar ventilator settings, has not been previously studied. Thus, we compared the ability of HFOV to that of HFPV to provide oxygenation and ventilation during acute lung injury in a newborn animal model. Using a saline lung lavage model, 12 neonatal piglets were randomized to initial support with either the HFOV or HFPV with settings adjusted to achieve PaCO2 of 45–60 mmHg. After stabilization, ventilator settings and arterial blood gases were serially recorded for 30 min. Animals were then crossed over to the alternative device set to deliver the same Vt, MAP, and F for an additional 30 min with the same parameters recorded. We found that the ΔP needed to generate adequate Vt on HFPV (35 ± 7 cmH2O) trended higher versus HFOV (31 ± 7 cmH2O P = 0.09) when the devices were matched for Vt, F, and MAP. No significant differences in ventilation (PaCO2 = 50 ± 10.7 mmHg vs. 46 ± 10 mmHg, P = 0.22) or oxygenation (PaO2 = 150 ± 76 mmHg vs. 149 ± 107 mmHg, P = 0.57) between the devices were found. We conclude that HFPV ventilates and oxygenates as well as HFOV at equivalent ventilator settings. HFPV may require larger ΔPs to generate equivalent Vt. Pediatr Pulmonol. 2009; 44:693–700.

Early neonatal research at Wilford Hall US Air Force Medical Center.

* Abbreviations: AFB — : Air Force Base ECMO — : extracorporeal membrane oxygenation HFOV — : high-frequency oscillatory ventilation HFV — : high frequency ventilation IMV — : intermittent mandatory ventilation PEEP — : positive end-expiratory pressure RDS — : respiratory distress syndrome USAF — : US Air Force The beginning of the many contributions to the field of neonatology originating from Wilford Hall Air Force Medical Center began when Robert deLemos, MD (Col, retired US Air Force [USAF]), was assigned to Lackland Air Force Base (AFB) in the summer of 1969. When Dr deLemos came to Texas, he was the first and only fully trained Air Force neonatologist at a time when neonatal medicine was still just in its infancy. Although surfactant deficiency had been described as the cause of hyaline membrane disease by Dr Avery in her landmark article published in 1959, surfactant replacement therapy in premature infants did not begin until the 1980s after the work of Dr Fujiwara et al was reported in Lancet .1,2 Morbidity and mortality remained high in premature infants, especially in those under 1500 g with respiratory distress syndrome (RDS). Reports published in the 1960s and 1970s described early attempts at the use of mechanical ventilation to rescue neonates with respiratory failure, but ventilator options were limited and devices were not widely available, resulting in minimal success.3,4 Given this backdrop, the story of the accomplishments of a relatively small group of military neonatologists led by Dr deLemos takes on added historical significance. Some of the most important initial work completed by Dr deLemos and his colleagues centered on their efforts to improve respiratory support and cardiovascular monitoring in the critically ill neonate. In the late 1960s and early 1970s, physiologic monitoring of the neonate was very difficult. Blood pressure could only be accurately obtained by using indwelling arterial lines. Ventilators in this time period only provided flow during the inspiratory cycle. If patients breathed between ventilator breaths, they were rebreathing their own exhaled gas contributing to impaired ventilation and oxygenation. In neonates this required mechanical … Address correspondence to Robert J. DiGeronimo, MD (Col, retired US Air Force), 295 Chipeta Way, Salt Lake City, UT 84158-1289. E-mail: robert.digeronimo{at}hsc.utah.edu