Anesthesia for children with mitochondrial disorders: a national survey and review

Purpose

Mitochondrial diseases are a heterogeneous group of disorders. Patients with such diseases often need general anesthesia for diagnostic procedures and surgery; guidelines are lacking for the anesthetic care of these patients.

Methods

We conducted a survey to investigate the current practices of pediatric anesthesiologists in the US in order to determine and document current practice. The survey consisted of twenty questions, including two demographic questions. A link to the survey was sent via email to members of the Society for Pediatric Anesthesia (2440), and was available online for 14 weeks.

Results

Only 503 completed the survey: a response rate of 20.61 %. Among the responders, 93.2 % had children with mitochondrial disorders among their patients, but only 11 % had institutional guidelines for such cases in place. Among the responders, 80.3 % used the standard nil per os (NPO) status guidelines, while the rest give intravenous dextrose solution once NPO was in effect. Only 18.3 % took precautions for malignant hyperthermia during treatment. The majority of the practitioners chose sevoflurane as the safest inhaled agent for induction and maintenance (89.7 and 78.5 %, respectively). Regional anesthesia was deemed safe by 97.3 % of the responders. Lactated Ringer’s solution was considered safe for these children by 49 %; only 47.8 % used dextrose-containing fluids for fluid replacement. The blood glucose was monitored by 72.7 %, and the majority (85 %) of this monitoring was done in a postanesthesia care unit.

Conclusion

Although the response rate was low, the majority of the responders provide care to these children routinely, so it can be inferred that the results of this survey are the closest published results to the true trend.     

Long-term outcomes following single-bundle transtibial arthroscopic posterior cruciate ligament reconstruction

Purpose

Posterior cruciate ligament (PCL) injury has a reported incidence of 3–20 %. PCL reconstruction is aimed at reducing onset of premature articular degeneration and improving function. Numerous operative techniques have been described with varying degrees of result consistency.

Methods

We evaluated 15 patients treated for isolated primary posterior cruciate ligament injury with a mean follow-up of 4.1 years (range one to nine). Post-reconstruction clinical assessment included the Lysholm and Tegner knee scoring scale, international knee documentation committee (IKDC) ligament evaluation, and KT2000 arthrometer assessment.

Results

On the Lysholm knee score 11 patients (73 %) had excellent results, three patients (20 %) had good results and one patient (7 %) had a poor result. On the Tegner activity score the majority of patients scored 7–8 with a return to high level sports. At the final follow-up, the post-reconstruction IKDC score was normal or nearly normal (A and B) in 14 (93 %) patients, and abnormal (C) in one (7 %) patient. According to KT-2000 arthrometer measurements at final follow-up review, 11 patients (73 %) were rated as normal (A, 0–2 mm), and four patients (27 %) as nearly normal (B, 3–5 mm). These results were independent of age, mechanism of injury, time elapsed to surgical reconstruction, and length of follow-up.

Conclusions

Despite being a technically demanding procedure, the outcomes reported in this study show that single bundle transtibial arthroscopic PCL repair using four strands hamstring autograft provides satisfactory and consistent functional outcomes.     

Blood Pressure Recordings During Hemodialysis Access Interventions: Implications for Acute Management

A retrospective study evaluating the pattern of blood pressure and its related complications before, during, and after percutaneous hemodialysis interventions was performed in patients presenting with asymptomatic hypertension. Hemodialysis patients undergoing percutaneous interventions including tunneled hemodialysis catheter insertion, percutaneous balloon angioplasty and thrombectomy procedure, and stage II hypertension (systolic blood pressure ≥160 mmHg) were included in this analysis. Blood pressure medications were not used while midazolam and fentanyl were routinely administered. Patients were followed for up to 4 weeks to monitor any complications. The mean blood pressure before, during, and after the procedures were 185 ± 18/96 ± 14, 172 ± 22/92 ± 15, and 153 ± 25/87 ± 14, respectively. There was a statistically significant difference between the blood pressure readings before and after the procedure (before = 185 ± 18/96 ± 14, after = 153 ± 25/87 ± 14; p = 0.001). None of the patients had a stroke, myocardial infarction, or acute pulmonary edema before, during, or after the procedure or during the 4‐week follow‐up period. A significant reduction in blood pressure was observed after the procedure without the administration of any antihypertensive medication. These results suggest that the reduction in blood pressure observed after percutaneous dialysis access interventions (particularly in the presence of midazolam and fentanyl) may make it unnecessary to treat asymptomatic hypertension prior to these procedures.     

Localized deferoxamine injection augments vascularity and improves bony union in pathologic fracture healing after radiotherapy

BackgroundMedically based efforts and alternative treatment strategies to prevent or remediate the corrosive effects of radiotherapy on pathologic fracture healing have failed to produce clear and convincing evidence of success. Establishing an effective pharmacologic option to prevent or treat the development of non-unions in this setting could have immense therapeutic potential. Experimental studies have shown that deferoxamine (DFO), an iron-chelating agent, bolsters vascularity and subsequently enhances normal fracture healing when injected locally into a fracture callus in long bone animal models. Since radiotherapy is known to impede angiogenesis, we hypothesized that the pharmacologic addition of DFO would serve to mitigate the effects of radiotherapy on new vessel formation in vitro and in vivo.Materials and MethodsIn vitro investigation of angiogenesis was conducted utilizing HUVEC cells in Matrigel. Endothelial tubule formation assays were divided into four groups: Control, Radiated, Radiated + Low-Dose DFO and Radiated + High-Dose DFO. Tubule formation was quantified microscopically and video recorded for the four groups simultaneously during the experiment. In vivo, three groups of Sprague–Dawley rats underwent external fixator placement and fracture osteotomy of the left mandible. Two groups received pre-operative fractionated radiotherapy, and one of these groups was treated with DFO after fracture repair. After 40 days, the animals were perfused and imaged with micro-CT to calculate vascular radiomorphometrics.ResultsIn vitro, endothelial tubule formation assays demonstrated that DFO mitigated the deleterious effects of radiation on angiogenesis. Further, high-dose DFO cultures appeared to organize within 2 h of incubation and achieved a robust network that was visibly superior to all other experimental groups in an accelerated fashion. In vivo, animals subjected to a human equivalent dose of radiotherapy (HEDR) and left mandibular fracture demonstrated quantifiably diminished μCT metrics of vascular density, as well as a 75% incidence of associated non-unions. The addition of DFO in this setting markedly improved vascularity as demonstrated with 3D angiographic modeling. In addition, we observed an increased incidence of bony unions in the DFO treated group when compared to radiated fractures without treatment (67% vs. 25% respectively).ConclusionOur data suggest that selectively targeting angiogenesis with localized DFO injections is sufficient to remediate the associated severe vascular diminution resulting from a HEDR. Perhaps the most consequential and clinically relevant finding was the ability to reduce the incidence of non-unions in a model where fracture healing was not routinely observed.     

Assessing the compatibility of primary human hepatocyte culture within porous silk sponges

Donor organ shortages have prompted the development of alternative implantable human liver tissues for patients suffering from end-stage liver failure. Purified silk proteins provide desirable features for generating implantable tissues, including sustainable sourcing from insects/arachnids, biocompatibility, tunable mechanical properties and degradation rates, and low immunogenicity upon implantation. While different cell types were previously cultured for weeks within silk-based scaffolds, it remains unclear whether such scaffolds can be used to culture primary human hepatocytes (PHH) isolated from livers. Therefore, here we assessed the compatibility of PHH culture within porous silk scaffolds that enable diffusion of oxygen/nutrients through the pores. We found that incorporation of type I collagen during the fabrication and/or autoclaving of porous silk scaffolds, as opposed to simple adsorption of collagen onto pre-fabricated silk scaffolds, was necessary to enable robust PHH attachment/function. Scaffolds with small pores (73 ± 25 μm) promoted larger PHH spheroids and consequently higher PHH functions than large pores (235 ± 84 μm) for at least 1 month in culture. Further incorporation of supportive fibroblasts into scaffolds enhanced PHH functions up to 5-fold relative to scaffolds with PHHs alone and 2D co-cultures on plastic. Lastly, encapsulating PHHs within protein hydrogels while housed in the silk scaffold led to higher functions than protein hydrogel-only or silk-only controls. In conclusion, porous silk scaffolds containing extracellular matrix proteins can be used for the culture of PHHs ± supportive non-parenchymal cells, which can be further built on in the future to create optimized silk-based liver tissue surrogates for cell-based therapy.

Porous silk scaffolds hybridized with extracellular matrix proteins are useful for culture of primary human hepatocytes ± supportive non-parenchymal cells.     

Pharmacokinetic considerations for use of artemisinin-based combination therapies against falciparum malaria in different ethnic populations

Introduction: Artemisinin-based combination therapy (ACT) is used extensively as first-line treatment for uncomplicated falciparum malaria. There has been no rigorous assessment of the potential for racial/ethnic differences in the pharmacokinetic properties of ACTs that might influence their efficacy.

Areas covered: A comprehensive literature search was performed that identified 72 publications in which the geographical origin of the patients could be ascertained and the key pharmacokinetic parameters maximum drug concentration (C_max), area under the plasma concentration-time curve (AUC) and elimination half-life (t_½β) were available for one or more of the five WHO-recommended ACTs (artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine and artesunate-sulfadoxine-pyrimethamine). Comparisons of each of the three pharmacokinetic parameters of interest were made by drug (artemisinin derivative and long half-life partner), race/ethnicity (African, Asian, Caucasian, Melanesian, South American) and patient categories based on age and pregnancy status.

Expert opinion: The review identified no evidence of a clinically significant influence of race/ethnicity on the pharmacokinetic properties of the nine component drugs in the five ACTs currently recommended by WHO for first-line treatment of uncomplicated falciparum malaria. This provides reassurance for health workers in malaria-endemic regions that ACTs can be given in recommended doses with the expectation of adequate blood concentrations regardless of race/ethnicity.     

Evaluating acellular versus cellular perfusate composition during prolonged ex vivo lung perfusion after initial cold ischaemia for 24 hours

Normothermic ex vivo lung perfusion (EVLP) has developed as a powerful technique to evaluate particularly marginal donor lungs prior to transplantation. In this study, acellular and cellular perfusate compositions were compared in an identical experimental setting as no consensus has been reached on a preferred technique yet. Porcine lungs underwent EVLP for 12 h on the basis of an acellular or a cellular perfusate composition after 24 h of cold ischaemia as defined organ stress. During perfusion, haemodynamic and respiratory parameters were monitored. After EVLP, the lung condition was assessed by light and transmission electron microscopy. Aerodynamic parameters did not show significant differences between groups and remained within the in vivo range during EVLP. Mean oxygenation indices were 491 ± 39 in the acellular group and 513 ± 53 in the cellular group. Groups only differed significantly in terms of higher pulmonary artery pressure and vascular resistance in the cellular group. Lung histology and ultrastructure were largely well preserved after prolonged EVLP and showed only minor structural alterations which were similarly present in both groups. Prolonged acellular and cellular EVLP for 12 h are both feasible with lungs prechallenged by ischaemic organ stress. Physiological and ultrastructural analysis showed no superiority of either acellular or cellular perfusate composition.     

Augmentation of Transient Donor Cell Chimerism and Alloantigen‐Specific Regulation of Lung Transplants in Miniature Swine

Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex–mismatched single lung transplantation was performed in 28 minipigs followed by a 28‐day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low‐dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4⁺CD25^high+ T cell frequencies were detected in peripheral blood associated with decreased interferon‐γ production of leukocytes. Secondary third‐party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third‐party splenocytes or donor splenocyte protein extracts. While animals treated with third‐party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third‐party, splenocyte infusions may develop long‐term donor‐specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells.