John N Kheir

Boston Children's Hospital, Boston, Massachusetts, United States

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Publications (12)26.85 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tissue hypoxia is a final common pathway that leads to cellular injury and death in a number of critical illnesses. Intravenous injections of self-assembling, lipid-based oxygen microbubbles (LOMs) can be used to deliver oxygen gas, preventing organ injury and death from systemic hypoxemia. However, current formulations exhibit high polydispersity indices (which may lead to microvascular obstruction) and poor shelf-lives, limiting the translational capacity of LOMs. In this study, we report our efforts to optimize LOM formulations using a mixture response surface methodology (mRSM). We study the effect of changing excipient proportions (the independent variables) on microbubble diameter and product loss (the dependent variables). By using mRSM analysis, the experimental data were fit using a reduced Scheffé linear mixture model. We demonstrate that formulations manufactured from 1,2-distearoyl-sn-glycero-3-phosphocholine, corn syrup, and water produce micron-sized microbubbles with low polydispersity indices, and decreased product loss (relative to previously described formulations) when stored at room temperature over a 30-day period. Optimized LOMs were subsequently tested for their oxygen-releasing ability and found to have similar release kinetics as prior formulations. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2014.
    Journal of Biomedical Materials Research Part B Applied Biomaterials 01/2014; · 2.31 Impact Factor
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    ABSTRACT: Gas-filled microbubbles have been developed as ultrasound contrast and drug delivery agents. Microbubbles can be produced by processing surfactants using sonication, mechanical agitation, microfluidic devices, or homogenization. Recently, lipid-based oxygen microbubbles (LOMs) have been designed to deliver oxygen intravenously during medical emergencies, reversing life-threatening hypoxemia, and preventing subsequent organ injury, cardiac arrest, and death. We present methods for scaled-up production of highly oxygenated microbubbles using a closed-loop high-shear homogenizer. The process can produce 2 L of concentrated LOMs (90% by volume) in 90 min. Resulting bubbles have a mean diameter of ~2 μm, and a rheologic profile consistent with that of blood when diluted to 60 volume %. This technique produces LOMs in high capacity and with high oxygen purity, suggesting that this technique may be useful for translational research labs.
    Journal of visualized experiments : JoVE. 01/2014;
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    ABSTRACT: Self-assembling, concentrated, lipid-based oxygen microparticles (LOMs) have been developed to administer oxygen gas when injected intravenously, preventing organ injury and death from systemic hypoxemia in animal models. Distinct from blood substitutes, LOMs are a one-way oxygen carrier designed to rescue patients who experience life-threatening hypoxemia, as caused by airway obstruction or severe lung injury. Here, we describe methods to manufacture large quantities of LOMs using an in-line, recycling, high-shear homogenizer, which can create up to 4 liters of microparticle emulsion in 10 minutes, with particles containing a median diameter of 0.93 microns and 60 volume% of gas phase. Using this process, we screen 30 combinations of commonly used excipients for their ability to form stable LOMs. LOMs composed of DSPC and cholesterol in a 1:1 molar ratio are stable for a 100 day observation period, and the number of particles exceeding 10 microns in diameter does not increase over time. When mixed with blood in vitro, LOMs fully oxygenate blood within 3.95 seconds of contact, and do not cause hemolysis or complement activation. LOMs can be manufactured in bulk by high shear homogenization, and appear to have a stability and size profile which merit further testing.
    Advanced healthcare materials. 03/2013;
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    ABSTRACT: BACKGROUND. Lung recruitment maneuvers are frequently used in the treatment of children with lung injury. Here, we describe a pilot study to compare the acute effects of two commonly used lung recruitment maneuvers on lung volume, gas exchange and hemodynamic profiles in children with acute lung injury (ALI). METHODS. In a prospective, non-randomized, cross-over pilot study, n=10 intubated pediatric patients with lung injury sequentially underwent (1) a period of observation, (2) a sustained inflation (SI) maneuver of 40 cm H(2)O for 40 seconds and open lung ventilation, (3) a staircase recruitment strategy (SRS) which utilized 5 cm H(2)O increments in airway pressure from a starting plateau pressure of 30 cm H(2)O and PEEP of 15 cm H(2)O, (4) a downwards PEEP titration and (5) a one hour period of observation with PEEP set 2 cm H(2)O above closing PEEP. RESULTS. Arterial blood gases, lung mechanics, hemodynamics and functional residual capacity were recorded following each phase of the study and following each increment of the SRS. Both SI and SRS were effective in raising arterial oxygen tension and functional residual capacity. During the SRS maneuver, we noted significant increases in dead space ventilation, a decrease in CO(2) elimination, an increase in arterial carbon dioxide tension and a decrease in compliance of the respiratory system (Crs). Lung recruitment was not sustained following the decremental PEEP titration. CONCLUSIONS. SRS is effective in opening the lung in children with early ALI, and is hemodynamically well tolerated. However, attention must be paid to carbon dioxide tension during the SRS. Even minutes following lung recruitment, lungs may derecruit when PEEP is lowered beyond the closing pressure.
    Respiratory care 12/2012; · 2.03 Impact Factor
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    ABSTRACT: We have developed an injectable foam suspension containing self-assembling, lipid-based microparticles encapsulating a core of pure oxygen gas for intravenous injection. Prototype suspensions were manufactured to contain between 50 and 90 ml of oxygen gas per deciliter of suspension. Particle size was polydisperse, with a mean particle diameter between 2 and 4 μm. When mixed with human blood ex vivo, oxygen transfer from 70 volume % microparticles was complete within 4 s. When the microparticles were infused by intravenous injection into hypoxemic rabbits, arterial saturations increased within seconds to near-normal levels; this was followed by a decrease in oxygen tensions after stopping the infusions. The particles were also infused into rabbits undergoing 15 min of complete tracheal occlusion. Oxygen microparticles significantly decreased the degree of hypoxemia in these rabbits, and the incidence of cardiac arrest and organ injury was reduced compared to controls. The ability to administer oxygen and other gases directly to the bloodstream may represent a technique for short-term rescue of profoundly hypoxemic patients, to selectively augment oxygen delivery to at-risk organs, or for novel diagnostic techniques. Furthermore, the ability to titrate gas infusions rapidly may minimize oxygen-related toxicity.
    Science translational medicine 06/2012; 4(140):140ra88. · 10.76 Impact Factor
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    ABSTRACT: : To describe the resolution of regional atelectasis and the development of regional lung overdistension during a lung-recruitment protocol in children with acute lung injury. : Prospective interventional trial. : Pediatric intensive care unit. : Ten children with early (<72 hrs) acute lung injury. : Sustained inflation maneuver (positive airway pressure of 40 cm H2O for 40 secs), followed by a stepwise recruitment maneuver (escalating plateau pressures by 5 cm H2O every 15 mins) until physiologic lung recruitment, defined by PaO2 + PaCO2 ≥400 mm Hg, was achieved. Regional lung volumes and mechanics were measured using electrical impedance tomography. : Patients that responded to the stepwise lung-recruitment maneuver had atelectasis in 54% of the dependent lung regions, while nonresponders had atelectasis in 10% of the dependent lung regions (p = .032). In the pressure step preceding physiologic lung recruitment, a significant reversal of atelectasis occurred in 17% of the dependent lung regions (p = .016). Stepwise recruitment overdistended 8% of the dependent lung regions in responders, but 58% of the same regions in nonresponders (p < .001). Lung compliance in dependent lung regions increased in responders, while compliance in nonresponders did not improve. In contrast to the stepwise recruitment maneuver, the sustained inflation did not produce significant changes in atelectasis or oxygenation: atelectasis was only reversed in 12% of the lung (p = .122), and there was only a modest improvement in oxygenation (27 ± 14 mm Hg, p = .088). : Reversal of atelectasis in the most dependent lung region preceded improvements in gas exchange during a stepwise lung-recruitment strategy. Lung recruitment of dependent lung areas was accompanied by considerable overdistension of nondependent lung regions. Larger amounts of atelectasis in dependent lung areas were associated with a positive response to a stepwise lung-recruitment maneuver.
    Pediatric Critical Care Medicine 05/2012; 13(5):509-15. · 2.35 Impact Factor
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    ABSTRACT: Neosaxitoxin (NeoSTX) is a potent site-1 sodium-channel blocker being developed as a local anesthetic. Doses of 100 μg have been used by local infiltration in anesthetized adult humans without adverse effect. We hypothesized that similar doses could cause significant respiratory, neuromuscular, and cardiovascular impairment and sought to test this hypothesis in sheep. Procedures were approved by the Institutional Animal Care and Use Committee. In neuromuscular/respiratory experiments, 33 intubated, isoflurane-anesthetized sheep were randomized to 6 NeoSTX treatment groups: saline control, 1 μg/kg subcutaneous (SC), 1 μg/kg intravenous (IV), 2 μg/kg SC, 2 μg/kg SC with bupivacaine 0.25%, and 3 μg/kg SC. Primary outcome measures were doxapram-stimulated inspired volume (DSIV) and quantitative limb acceleration. In cardiovascular experiments, 8 sheep received escalating IV doses of NeoSTX (1, 2, and 3 μg), with hemodynamic and electrocardiographic measurements. Data were analyzed using repeated-measures analysis of variance with post hoc Bonferroni-corrected comparisons. NeoSTX 1 μg/kg IV and SC produced no significant reduction in DSIV or limb acceleration compared with baseline. NeoSTX 2 μg/kg SC produced clinically mild reduction in twitch and DSIV; animals recovered well postoperatively. Coadministration of bupivacaine did not worsen these effects. NeoSTX 3 μg/kg produced severe and prolonged impairment of DSIV and limb acceleration. Escalating IV doses of NeoSTX produced mild decrements in heart rate, systemic arterial pressure, and systemic vascular resistance; cardiac output was maintained. Transient interventricular conduction delay occurred without cardiac arrest or ventricular ectopy. In our sheep model, neuromuscular, respiratory, and cardiovascular effects of NeoSTX were dose dependent and mild using the dose range anticipated for clinical use.
    Regional anesthesia and pain medicine 03/2012; 37(2):152-8. · 4.16 Impact Factor
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    ABSTRACT: A detailed study is presented on the synthesis and characterization of purely oxygen-filled microbubbles (OMBs) stabilized by phospholipids. Microbubbles with a diameter of less than 10 μm were generated and concentrated to >50 vol % in saline. The lipid acyl chain length had little effect on the size distribution but profoundly affected the foam stability. For example, OMBs stabilized by dipalmitoyl phosphatidylcholine (DPPC) degraded over 3 weeks, but OMBs stabilized with distearoyl phosphatidylcholine (DSPC) retained over half of their initially encapsulated gas. Interestingly, the polydisperse size distribution remained nearly constant as the foam slowly broke down. Injection into an undersaturated solution led to the immediate release of the oxygen gas core. Injectable gas delivery by OMBs may find use in a variety of medical and industrial fields.
    Langmuir 10/2010; 26(20):15726-9. · 4.38 Impact Factor
  • American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans; 05/2010
  • American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans; 05/2010
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    ABSTRACT: The pathology of posterior reversible encephalopathy syndrome (PRES) is undefined, since it is rarely fatal and is biopsied in only exceptional circumstances. We describe rapidly progressive PRES following stem cell transplant for acute lymphoblastic leukemia. After development of altered mental status, this 8-year-old girl had T2 prolongation of the white matter in a posterior-dominant distribution, eventually developing cerebellar edema, hemorrhage, hydrocephalus, and herniation. Despite surgical and medical management, she died 36 hours later. At autopsy, the occipital and cerebellar white matter and focal occipital cortical gray matter showed a spectrum of microvascular changes, including dilated perivascular spaces containing proteinaceous exudates and macrophages, as well as fibrinoid necrosis and acute hemorrhage, in a distribution corresponding to the neuroimaging abnormalities and reminiscent of those seen in patients with acute hypertensive encephalopathy. Of note, similar microvascular changes were not seen in the kidney or other systemic sites. Thus, the findings indicate a brain-specific microvascular compromise as the substrate of PRES, at least in the rare instance of cases progressing to fatal outcome.
    Pediatric and Developmental Pathology 02/2010; 13(5):397-403. · 0.86 Impact Factor
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    ABSTRACT: Gases are a class biologically active species that are normally transported to the blood by the lungs. Examples include oxygen and other metabolites, as well as nitrous oxide and other anesthetics. But what happens when the lungs are not functioning adequately? Respiratory distress syndrome and other forms of lung injury can result in acute hypoxia, which can rapidly lead to severe morbidity and mortality. Extracorporeal membrane oxygenation (ECMO) currently is the standard clinical treatment for acute hypoxia, but the technique is cumbersome and problematic for certain patient populations, including infants. A means of directly injecting oxygen into the bloodstream, thus precluding the need for an extracorporeal loop, is highly desired in the critical care setting. Such a technology could augment or even replace ECMO for some cases. The approach we have taken is to use oxygen-filled microbubbles for direct intravenous oxygenation. Microbubbles are 0.1 to 10 micron diameter gas spheres, coated and stabilized by a lipid monolayer shell, and surrounded by an aqueous medium. Results will be presented which show that oxygen microbubbles can be reproducibly generated and concentrated to 70 vol%. A dose-response relationship was measured for microbubble suspensions combined in vitro with venous blood. The oxygen carrying and release capability is strongly dependent on lipid composition. Lipids above their main phase transition temperatures do not encapsulate oxygen for meaningful time scales. Those in the gel phase encapsulate and release oxygen efficiently, and an optimum composition was found. Phenomena governing microbubble dissolution in blood will be discussed, including modeling of gas exchange kinetics and excess lipid collapse and shedding. Preliminary results are promising and suggest improvements for future testing in vivo.
    2008 AIChE Annual Meeting; 11/2008