Improving Trendelenburg position effectiveness by varying cardiopulmonary bypass flow.

INTRODUCTION: Trendelenburg position (TP) is used to transport gaseous emboli away from the cerebral region during cardiac surgery. However, TP effectiveness has not been fully considered when combined with varying the cardiopulmonary bypass (CPB) flow. This study simulated the supine and TP at different pump flows and assessed the trapped emboli and embolic load entering the aortic arch branch arteries (AABA). METHODS: A computational fluid dynamics (CFD) approach used a centrally cannulated adult patient-specific aorta model replicating a CPB circuit. Air emboli of 0.1 mm, 0.5 mm, and 1.0 mm (n = 700 each) were injected into the aorta placed in the supine position (0°) and the TP (-20°) at 2 L/min and 5 L/min. The number of emboli entering the AABA were compared. An aortic phantom flow experiment was performed to validate air bubble behaviour. RESULTS: TP at 5 L/min had the lowest 0.1 mm mean (±SD) embolic load compared to the supine 2 L/min (55.3 ± 30.8 vs 64.3 ± 35.4). For both the supine and TP, the lower flow of 2 L/min had the highest number of simulated trapped emboli in higher elevated regions than at 5 L/min (541 ± 185 and 548 ± 191 vs 520 ± 159 and 512 ± 174), respectively. The flow experiment demonstrated that 2 L/min promoted bubble coalescence and high amounts of trapped emboli and 5 L/min transported air emboli away from the AABA. CONCLUSIONS: TP effectiveness was improved by using CPB flow to manage air emboli. These results provide insights for predicting emboli behaviour and improving emboli de-airing procedures.

Effect of aortic cannulation depth on air emboli transport during cardiopulmonary bypass: A computational study.

INTRODUCTION: Varying the insertion depth of the aortic cannula during cardiopulmonary bypass (CPB) has been investigated as a strategy to mitigate cerebral emboli, yet its effectiveness associated with CPB flow is not fully understood. We compared different arterial cannula insertion depths and pump flow influencing air microemboli entering the aortic arch branch arteries (AABA). METHODS: A computational approach used a patient-specific aorta model to evaluate four cannula locations at (1) proximal arch, (2) mid arch, (3) distal arch, and (4) descending aorta. We injected 0.1 mm microemboli (N=720) at 2 and 5 L/min and assessed the embolic load and the particle averaged transit times ( entering the AABA. RESULTS: Location 4 had the lowest embolic load (2 L/min: N= 63) and (5 L/min: N= 54) compared to locations 1 to 3 in the range of (N= 118 to 116 at 2 L/min:) and (N= 92 to 146 at 5 L/min). There was no significant difference between 2 L/min and 5 L/min (p = 0.31), despite 5 L/min attaining a lower mean (±standard deviation) than 2 L/min (38.0±23.4 vs 44.5±21.1), respectively. Progressing from location 1 to 4, increased 3.11s -7.40 s at 2 L/min and 1.81s -4.18s at 5 L/min. CONCLUSION: It was demonstrated that the elongated cannula insertion length resulted in lower embolic loads, particularly at a higher flow rate. The numerical results suggest that CPB management could combine active flow variation with improving cannula performance and provide a foundation for a future experimental and clinical investigation to reduce surgical cerebral air microemboli.

Compromised right ventricular contractility in an ovine model of heart transplantation following 24 h donor brain stem death.

BACKGROUND: Heart failure is an inexorably progressive disease with a high mortality, for which heart transplantation (HTx) remains the gold standard treatment. Currently, donor hearts are primarily derived from patients following brain stem death (BSD). BSD causes activation of the sympathetic nervous system, increases endothelin levels, and triggers significant inflammation that together with potential myocardial injury associated with the transplant procedure, may affect contractility of the donor heart. We examined peri-transplant myocardial catecholamine sensitivity and cardiac contractility post-BSD and transplantation in a clinically relevant ovine model. METHODS: Donor sheep underwent BSD (BSD, n = 5) or sham (no BSD) procedures (SHAM, n = 4) and were monitored for 24h prior to heart procurement. Orthotopic HTx was performed on a separate group of donor animals following 24h of BSD (BSD-Tx, n = 6) or SHAM injury (SH-Tx, n = 5). The healthy recipient heart was used as a control (HC, n = 11). A cumulative concentration-effect curve to (-)-noradrenaline (NA) was established using left (LV) and right ventricular (RV) trabeculae to determine ß1-adrenoceptor mediated potency (-logEC50 [(-)-noradrenaline] M) and maximal contractility (Emax). RESULTS: Our data showed reduced basal and maximal (-)-noradrenaline induced contractility of the RV (but not LV) following BSD as well as HTx, regardless of whether the donor heart was exposed to BSD or SHAM. The potency of (-)-noradrenaline was lower in left and right ventricles for BSD-Tx and SH-Tx compared to HC. CONCLUSION: These studies show that the combination of BSD and transplantation are likely to impair contractility of the donor heart, particularly for the RV. For the donor heart, this contractile dysfunction appears to be independent of changes to ß1-adrenoceptor sensitivity. However, altered ß1-adrenoceptor signalling is likely to be involved in post-HTx contractile dysfunction.

High prevalence of Crohn disease and ulcerative colitis among older people in Sydney.

OBJECTIVES: To determine the age-standardised prevalence of inflammatory bowel disease (IBD) in a metropolitan area of Sydney, with a focus on its prevalence among older people. DESIGN, SETTING: Population-based epidemiological study of people with IBD in the City of Canada Bay, a local government area in the inner west of Sydney, during 1 March 2016 - 10 November 2016. PARTICIPANTS: Patients diagnosed with confirmed IBD according to the Copenhagen or revised Porto criteria. MAIN OUTCOME MEASURES: Crude prevalence of IBD, including Crohn disease and ulcerative colitis; age-standardised prevalence of IBD, based on the World Health Organization standard population; prevalence rates among people aged 65 years or more. RESULTS: The median age of 364 people with IBD was 47 years (IQR, 34-62 years); 185 were women (50.8%). The crude IBD prevalence rate was 414 cases (95% CI, 371-456 cases) per 100 000 population; the age-standardised rate was 348 cases (95% CI, 312-385 cases) per 100 000 population. The age-standardised rate for Crohn disease was 166 cases (95% CI, 141-192 cases) per 100 000 population; for ulcerative colitis, 148 cases (95% CI, 124-171 cases) per 100 000 population. The IBD prevalence rate in people aged 65 years or more was 612 cases (95% CI, 564-660 cases) per 100 000, and for those aged 85 years or more, 891 cases (95% CI, 833-949 cases) per 100 000; for people under 65, the rate was 380 cases (95% CI, 342-418 cases) per 100 000. CONCLUSIONS: We found that the prevalence of confirmed IBD in a metropolitan sample was highest among older people. Challenges for managing older patients with IBD include higher rates of comorbid conditions, polypharmacy, and cognitive decline, and the immunosuppressive nature of standard therapies for IBD.

The effect of hyperoxia on inflammation and platelet responses in an ex vivo extracorporeal membrane oxygenation circuit.

Use of extracorporeal membrane oxygenation (ECMO) is expanding, however, it is still associated with significant morbidity and mortality. Activation of inflammatory and innate immune responses and hemostatic alterations contribute to complications. Hyperoxia may play a role in exacerbating these responses. Nine ex vivo ECMO circuits were tested using fresh healthy human whole blood, with two oxygen levels: 21% inspired fraction of oxygen (FiO2 ; mild hyperoxia; n = 5) and 100% FiO2 (severe hyperoxia; n = 4). Serial blood samples were taken for analysis of platelet aggregometry, leukocyte activation, inflammatory, and oxidative stress markers. ECMO resulted in reduced adenosine diphosphate- (P < .05) and thrombin receptor activating peptide-induced (P < .05) platelet aggregation, as well as increasing levels of the neutrophil activation marker, neutrophil elastase (P = .013). Additionally, levels of the inflammatory chemokine interleukin-8 were elevated (P < .05) and the activity of superoxide dismutase, a marker of oxidative stress, was increased (P = .002). Hyperoxia did not augment these responses, with no significant differences detected between mild and severe hyperoxia. Our ex vivo model of ECMO revealed that the circuit itself triggers a pro-inflammatory and oxidative stress response, however, exposure to supra-physiologic oxygen does not amplify that response. Extended-duration studies and inclusion of an endothelial component could be beneficial in characterizing longer term changes.

The global impact of Aspergillus infection on COPD.

BACKGROUND: Advanced chronic obstructive pulmonary disease (COPD) often leads to hospitalisation and invasive aspergillosis (IA) is a serious complication. Aspergillus sensitisation may worsen symptoms in COPD. METHODS: We identified published papers between January 2000 and May 2019 with > 50 subjects and GOLD criteria for grade II, III or IV (FEV1/FVC < 70% and FEV1 < 80%) using standardised criteria in multiple countries, to re-estimate the prevalence of COPD. Hospitalised COPD patients develop IA in 1.3-3.9%, based on positive cultures of Aspergillus spp. and radiological findings. Given limited data on per-patient annual hospitalisation rates, we assumed a conservative 10.5% estimate. Annual IA mortality in COPD was estimated using the literature rates of 43-72%. A separate literature search assessed the impact of Aspergillus sensitisation on severity of COPD (by FEV1). RESULTS: We re-estimated the global prevalence of COPD GOLD stages II-IV at 552,300,599 people (7.39% of the population) with 339,206,893 (8.58%) in Asia, 85,278,783 (8.52%) in the Americas, 64,298,051 (5.37%) in Africa, 59,484,329 (7.77%) in Europe and 4,032,543 (10.86%) in Oceania. An estimated 57,991,563 (10.5%) people with COPD are admitted to hospital annually and of these 753,073 (1.3%) - 2,272,322 (3.9%) develop IA and 540,451-977,082 deaths are predicted annually. Aspergillus sensitisation prevalence in COPD was 13.6% (7.0-18.3%) and not related to lower predicted FEV1% (P > 0.05). CONCLUSIONS: The prevalence of COPD is much higher than previously estimated. Overall COPD mortality may be higher than estimated and IA probably contributes to many deaths. Improved rapid diagnosis of IA using culture and non-culture based techniques is required in COPD hospital admissions to reduce mortality.

Aortic cannula orientation and flow impacts embolic trajectories: computational cardiopulmonary bypass.

INTRODUCTION: Emboli events are associated with the aortic cannula insertion and final position in the ascending aorta. However, the impact of subtle changes in aortic cannula movement and flow influencing embolic transport throughout the aortic arch is not well understood. The present study evaluated the aortic cannula's outflow and orientation effect on emboli entering the aortic branch arteries. METHODS: A simplified aortic computational model was anteriorly cannulated in the distal ascending aorta with a 21-French straight aortic cannula, and two orientations were analysed by injecting gaseous and solid emboli at pump flows 2, 3 and 5 L/minute. The first aortic cannula orientation (forward flow cannula) was directed towards the lesser curvature. The second aortic cannula orientation (rear flow cannula) was tilted slightly backwards by 15°, providing flow in the retrograde direction. RESULTS: Forward flow cannula produced a primary arch flow, whereas rear flow cannula produced a secondary arch flow resulting in four times longer emboli arch resident times than forward flow cannula. The rear flow cannula had the highest percentage of gaseous emboli entering the brachiocephalic artery of 8%, 12% and 36% (at 2, 3 and 5 L/minute, respectively). Rear flow cannula provided a positive aortic branch arterial flow at all pump flows, whereas at forward flow cannula, the brachiocephalic artery experienced retrograde flows of -1.0% (3 L/minute) and -4.0% (5 L/minute), with the left common carotid -0.23% (5 L/minute). No significant number of solid emboli entered the aortic branch arteries. CONCLUSION: This numerical study illustrated distinct trajectory behaviours between gaseous and solid emboli where slight changes in aortic cannula orientation influenced idealised emboli direction with higher pump flows magnifying the effects.

Full-Spectrum Endoscopy Improves Surveillance for Dysplasia in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) increase the risk of colorectal cancer. Surveillance colonoscopy with chromoendoscopy is recommended, but conventional forward-viewing colonoscopy (FVC) detects dysplasia with low levels of sensitivity. Full-spectrum endoscopy (FUSE) incorporates 2 additional lateral cameras to the forward camera of the colonoscope, allowing endoscopists to view behind folds and in blind spots, which might increase dysplasia detection. We compared FUSE vs FVC in the detection of dysplasia in patients with IBDs. METHODS: We performed a prospective, randomized, cross-over, tandem colonoscopy study comparing FVC vs FUSE in 52 subjects with IBD undergoing surveillance for neoplasia in Australia (23 with Crohn's colitis, 29 with ulcerative colitis; median age, 45.0 y; 60% male; mean IBD duration, 16.4 y). All subjects met national IBD surveillance inclusion criteria; 27 were assigned randomly to groups that underwent FVC followed by FUSE, and 25 were assigned to groups that underwent FUSE followed by FVC. All procedures were performed from February 2014 through December 2015. Random biopsy specimens were collected and visible lesions were collected; all were analyzed histologically. The primary end point was dysplasia missed by the first colonoscopy detected by the second colonoscopy. Dysplasia was diagnosed by an expert gastrointestinal pathologist blinded to the colonoscope allocation in consensus with a second expert pathologist. RESULTS: FVC missed 71.4% of dysplastic lesions per lesion whereas FUSE missed 25.0% per lesion (P = .0001); FVC missed 75.0% of dysplastic lesions per subject and FUSE missed 25.0% per subject (P = .046). FUSE identified a mean of 0.37 dysplastic lesions and FVC identified a mean of 0.13 dysplastic lesions (P = .044). The total colonoscopy times were similar (21.2 min for FUSE vs 19.1 min for FVC; P = .32), but withdrawal time was significantly longer for FUSE (15.8 min) than for FVC (12.0 min) (P = .03). Correcting for per-unit withdrawal time, the mean dysplasia miss rate per subject was significantly lower for FUSE (0.19) than for FVC (0.83; P < .0001). Targeted tissue acquisition identified significantly more dysplastic lesions than random biopsies (P < .0001). CONCLUSIONS: In a prospective cross-over study of IBD patients undergoing surveillance colonoscopy, we found panoramic views obtained by full-spectrum endoscopy increased the number of dysplastic lesions detected, compared with conventional forward-viewing colonoscopy. Trial no: ACTRN12616000047493.

The 10-nm chromatin fiber and its relationship to interphase chromosome organization.

A chromosome is a single long DNA molecule assembled along its length with nucleosomes and proteins. During interphase, a mammalian chromosome exists as a highly organized supramolecular globule in the nucleus. Here, we discuss new insights into how genomic DNA is packaged and organized within interphase chromosomes. Our emphasis is on the structural principles that underlie chromosome organization, with a particular focus on the intrinsic contributions of the 10-nm chromatin fiber, but not the regular 30-nm fiber. We hypothesize that the hierarchical globular organization of an interphase chromosome is fundamentally established by the self-interacting properties of a 10-nm zig-zag array of nucleosomes, while histone post-translational modifications, histone variants, and chromatin-associated proteins serve to mold generic chromatin domains into specific structural and functional entities.

Unplanned Autotransplantation for Complex Multi-Valve Replacement in a Super Morbid Obese Female: The Challenge of Intraoperative Decision Making.

Cardiac autotransplantation is a rare technique typically reserved for the treatment of malignant tumors of the left atrium and left ventricle. Even when well planned, it conveys a high risk to the patient. This report discusses the intraoperative progression to an unplanned autotransplant for mitral valve repair while considering some decision making processes that cardiac surgeons make.

Evidence of altered haemostasis in an ovine model of venovenous extracorporeal membrane oxygenation support.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality used in the management of cardiopulmonary failure that is refractory to conventional medical and surgical therapies. The major problems clinicians face are bleeding and clotting, which can occur simultaneously. To discern the impact of pulmonary injury and ECMO on the host's haemostatic response, we developed an ovine model of smoke-induced acute lung injury (S-ALI) and ECMO. The aims of this study were to determine if the ECMO circuit itself altered haemostasis and if this was augmented in a host with pulmonary injury. METHODS: Twenty-seven South African meat merino/Border Leicester Cross ewes underwent instrumentation. Animals received either sham injury (n = 12) or S-ALI (n = 15). Control animal groups consisted of healthy controls (ventilation only for 24 h) (n = 4), ECMO controls (ECMO only for 24 h) (n = 8) and S-ALI controls (S-ALI but no ECMO for 24 h) (n = 7). The test group comprised S-ALI sheep placed on ECMO (S-ALI + ECMO for 24 h) (n = 8). Serial blood samples were taken for rotational thromboelastometry, platelet aggregometry and routine coagulation laboratory tests. Animals were continuously monitored for haemodynamic, fluid and electrolyte balances and temperature. Pressure-controlled intermittent mandatory ventilation was used, and mean arterial pressure was augmented by protocolised use of pressors, inotropes and balanced fluid resuscitation to maintain mean arterial pressure >65 mmHg. RESULTS: Rotational thromboelastometry, platelet aggregometry and routine coagulation laboratory tests demonstrated that S-ALI and ECMO independently induced changes to platelet function, delayed clot formation and reduced clot firmness. This effect was augmented with the combination of S-ALI and ECMO, with evidence of increased collagen-induced platelet aggregation as well as changes in factor VIII (FVIII), factor XII and fibrinogen levels. CONCLUSIONS: The introduction of an ECMO circuit itself increases collagen-induced platelet aggregation, decreases FVIII and von Willebrand factor, and induces a transient decrease in fibrinogen levels and function in the first 24 h. These changes to haemostasis are amplified when a host with a pre-existing pulmonary injury is placed on ECMO. Because patients are often on ECMO for extended periods, longer-duration studies are required to characterise ECMO-induced haemostatic changes over the long term. The utility of point-of-care tests for guiding haemostatic management during ECMO also warrants further exploration.

Inflammation and lung injury in an ovine model of extracorporeal membrane oxygenation support.

Extracorporeal membrane oxygenation (ECMO) is a life-saving treatment for patients with severe refractory cardiorespiratory failure. Exposure to the ECMO circuit is thought to trigger/exacerbate inflammation. Determining whether inflammation is the result of the patients' underlying pathologies or the ECMO circuit is difficult. To discern how different insults contribute to the inflammatory response, we developed an ovine model of lung injury and ECMO to investigate the impact of smoke-induced lung injury and ECMO in isolation and cumulatively on pulmonary and circulating inflammatory cells, cytokines, and tissue remodeling. Sheep receiving either smoke-induced acute lung injury (S-ALI) or sham injury were placed on veno-venous (VV) ECMO lasting either 2 or 24 h, with controls receiving conventional ventilation only. Lung tissue, bronchoalveolar fluid, and plasma were analyzed by RT-PCR, immunohistochemical staining, and zymography to assess inflammatory cells, cytokines, and matrix metalloproteinases. Pulmonary compliance decreased in sheep with S-ALI placed on ECMO with increased numbers of infiltrating neutrophils, monocytes, and alveolar macrophages compared with controls. Infiltration of neutrophils was also observed with S-ALI alone. RT-PCR studies showed higher expression of matrix metalloproteinases 2 and 9 in S-ALI plus ECMO, whereas IL-6 was elevated at 2 h. Zymography revealed higher levels of matrix metalloproteinase 2. Circulating plasma levels of IL-6 were elevated 1-2 h after commencement of ECMO alone. These data show that the inflammatory response is enhanced when a host with preexisting pulmonary injury is placed on ECMO, with increased infiltration of neutrophils and macrophages, the release of inflammatory cytokines, and upregulation of matrix metalloproteinases.

The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology.

Extracorporeal membrane oxygenation (ECMO) is a technology capable of providing short-term mechanical support to the heart, lungs or both. Over the last decade, the number of centres offering ECMO has grown rapidly. At the same time, the indications for its use have also been broadened. In part, this trend has been supported by advances in circuit design and in cannulation techniques. Despite the widespread adoption of extracorporeal life support techniques, the use of ECMO remains associated with significant morbidity and mortality. A complication witnessed during ECMO is the inflammatory response to extracorporeal circulation. This reaction shares similarities with the systemic inflammatory response syndrome (SIRS) and has been well-documented in relation to cardiopulmonary bypass. The exposure of a patient's blood to the non-endothelialised surface of the ECMO circuit results in the widespread activation of the innate immune system; if unchecked this may result in inflammation and organ injury. Here, we review the pathophysiology of the inflammatory response to ECMO, highlighting the complex interactions between arms of the innate immune response, the endothelium and coagulation. An understanding of the processes involved may guide the design of therapies and strategies aimed at ameliorating inflammation during ECMO. Likewise, an appreciation of the potentially deleterious inflammatory effects of ECMO may assist those weighing the risks and benefits of therapy.

Inflammatory Bowel Disease Environmental Risk Factors: A Population-Based Case-Control Study of Middle Eastern Migration to Australia.

BACKGROUND & AIMS: The incidences of the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC) are increasing, indicating gene-environment interactions. Migrants from low-IBD-prevalence countries to a high-prevalence country may help identify the relative contribution of environmental risk factors compared with native Caucasians. METHODS: This prospective case-control study evaluated IBD environmental risk factors of Middle Eastern migrants (MEM) in Australia compared with matched Caucasian IBD subjects, MEM controls, Caucasian controls, and controls in the Middle East using adjusted odds ratios (aOR). RESULTS: A total of 795 subjects were recruited: 154 MEM cases (75 CD; 79 UC), 153 MEM controls, 162 Caucasian cases (85 CD; 77 UC), 173 Caucasian controls, and 153 controls in Lebanon. Smoking increased CD risk in MEM and Caucasians and reduced UC risk in Caucasians (aOR, 0.77; 95% CI, 0.41-0.98) but not MEM (aOR, 1.45; 95% CI, 0.80-2.62). Antibiotic use reduced the risk of MEM CD (aOR, 0.27; 95% CI, 0.11-0.67) and UC (aOR, 0.38; 95% CI, 0.18-0.80), but increased the risk in Caucasians (CD: aOR, 5.24; 95% CI, 2.13-12.90; and UC: aOR, 6.82; 95% CI, 2.67-17.38). Most hygiene markers (rural dwelling, pet ownership, pet feeding, and farm animal contact) reduced CD and UC risk in MEM (P < .05). In contrast, in Caucasians these hygiene markers lacked significance. Other significant risk factors include IBD family history, appendectomy, tonsillectomy, and breastfeeding. CONCLUSIONS: Differential IBD environmental risk factors exist between migrants and native Caucasians, indicating a dynamic interplay between environmental factors and IBD risk for immigrants that is distinct to those factors most relevant in native Caucasians.

Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study.

INTRODUCTION: Vital drugs may be degraded or sequestered in extracorporeal membrane oxygenation (ECMO) circuits, with lipophilic drugs considered to be particularly vulnerable. However, the circuit effects on protein-bound drugs have not been fully elucidated. The aim of this experimental study was to investigate the influence of plasma protein binding on drug disposition in ex vivo ECMO circuits. METHODS: Four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators and were used. The circuits were primed with crystalloid, albumin and fresh human whole blood and maintained at a physiological pH and temperature for 24 hours. After baseline sampling, known quantities of study drugs (ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin and thiopentone) were injected into the circuit to achieve therapeutic concentrations. Equivalent doses of these drugs were also injected into four polypropylene jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the controls and the ECMO circuits over 24 hours, and the concentrations of the study drugs were quantified using validated chromatographic assays. A regression model was constructed to examine the relationship between circuit drug recovery as the dependent variable and protein binding and partition coefficient (a measure of lipophilicity) as explanatory variables. RESULTS: Four hundred eighty samples were analysed. There was no significant loss of any study drugs in the controls over 24 hours. The average drug recoveries from the ECMO circuits at 24 hours were as follows: ciprofloxacin 96%, linezolid 91%, fluconazole 91%, ceftriaxone 80%, caspofungin 56% and thiopentone 12%. There was a significant reduction of ceftriaxone (P = 0.01), caspofungin (P = 0.01) and thiopentone (P = 0.008) concentrations in the ECMO circuit at 24 hours. Both protein binding and partition coefficient were highly significant, with the model possessing a high coefficient of determination (R (2) = 0.88, P <0.001). CONCLUSIONS: Recovery of the highly protein-bound drugs ceftriaxone, caspofungin and thiopentone was significantly lower in the ECMO circuits at 24 hours. For drugs with similar lipophilicity, the extent of protein binding may determine circuit drug loss. Future clinical population pharmacokinetic studies should initially be focused on drugs with greater lipophilicity and protein binding, and therapeutic drug monitoring should be strongly considered with the use of such drugs.

Feasibility of perflutren microsphere contrast transthoracic echocardiography in the visualization of ventricular endocardium during venovenous extracorporeal membrane oxygenation in a validated ovine model.

BACKGROUND: Transthoracic echocardiography (TTE) during extra corporeal membrane oxygenation (ECMO) is important but can be technically challenging. Contrast-specific TTE can improve imaging in suboptimal studies. These contrast microspheres are hydrodynamically labile structures. This study assessed the feasibility of contrast echocardiography (CE) during venovenous (VV) ECMO in a validated ovine model. METHOD: Twenty-four sheep were commenced on VV ECMO. Parasternal long-axis (Plax) and short-axis (Psax) views were obtained pre- and postcontrast while on VV ECMO. Endocardial definition scores (EDS) per segment were graded: 1 = good, 2 = suboptimal 3 = not seen. Endocardial border definition score index (EBDSI) was calculated for each view. Endocardial length (EL) in the Plax view for the left ventricle (LV) and right ventricle (RV) was measured. RESULTS: Summation EDS data for the LV and RV for unenhanced TTE (UE) versus CE TTE imaging: EDS 1 = 289 versus 346, EDS 2 = 38 versus 10, EDS 3 = 33 versus 4, respectively. Wilcoxon matched-pairs rank-sign tests showed a significant ranking difference (improvement) pre- and postcontrast for the LV (P < 0.0001), RV (P < 0.0001) and combined ventricular data (P < 0.0001). EBDSI for CE TTE was significantly lower than UE TTE for the LV (1.05 ± 0.17 vs. 1.22 ± 0.38, P = 0.0004) and RV (1.06 ± 0.22 vs. 1.42 ± 0.47, P = 0.0.0006) respectively. Visualized EL was significantly longer in CE versus UE for both the LV (58.6 ± 11.0 mm vs. 47.4 ± 11.7 mm, P < 0.0001) and the RV (52.3 ± 8.6 mm vs. 36.0 ± 13.1 mm, P < 0.0001), respectively. CONCLUSIONS: Despite exposure to destructive hydrodynamic forces, CE is a feasible technique in an ovine ECMO model. CE results in significantly improved EDS and increased EL.

Long-term follow-up reveals low incidence of colorectal cancer, but frequent need for resection, among Australian patients with inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease can require surgical resection and also lead to colorectal cancer (CRC). We investigated the cumulative incidence of resection surgeries and CRC among patients with ulcerative colitis (UC) or Crohn's disease (CD). METHODS: We analyzed data from a cohort of patients who participated in an inflammatory bowel disease study (504 with UC and 377 with CD) at 2 academic medical centers in Sydney, Australia from 1977 to 1992 (before the development of biologic therapies). We collected follow-up data on surgeries and development of CRC from hospital and community medical records or via direct contact with patients during a median time period of 14 years. Cumulative incidences of resection surgeries and CRC were calculated by competing risk survival analysis. RESULTS: Among patients with UC, CRC developed in 24, for a cumulative incidence of 1% at 10 years (95% confidence interval [CI], 0%-2%), 3% at 20 years (95% CI, 1%-5%), and 7% at 30 years (95% CI, 4%-10%). Their cumulative incidence of colectomy was 15% at 10 years (95% CI, 11%-19%), 26% at 20 years (95% CI, 21%-30%), and 31% at 30 years (95% CI, 25%-36%). Among patients with CD, 5 of 327 with colon disease developed CRC, with a cumulative incidence of CRC of 1% at 10 years (95% CI, 0%-2%), 1% at 20 years (95% CI, 0%-2%), and 2% at 30 years (95% CI, 0%-4%). Among all patients with CD, the cumulative incidence of resection was 32% at 5 years (95% CI, 27%-37%), 43% at 10 years (95% CI, 37%-49%), and 53% at 15 years (95% CI, 46%-58%). Of these 168 subjects, 42% required a second resection within 15 years of the first surgery (95% CI, 33%-50%). CONCLUSIONS: Patients with UC have a low incidence of CRC during a 30-year period (7% or less); the incidence among patients with CD is even lower. However, almost one-third of patients with UC and about 50% of those with CD will require surgery.

Donor heart ischemic time can be extended beyond 9 hours using hypothermic machine perfusion in sheep.

BACKGROUND: The global shortage of donor hearts available for transplantation is a major problem for the treatment of end-stage heart failure. The ischemic time for donor hearts using traditional preservation by standard static cold storage (SCS) is limited to approximately 4 hours, beyond which the risk for primary graft dysfunction (PGD) significantly increases. Hypothermic machine perfusion (HMP) of donor hearts has been proposed to safely extend ischemic time without increasing the risk of PGD. METHODS: Using our sheep model of 24 hours brain death (BD) followed by orthotopic heart transplantation (HTx), we examined post-transplant outcomes in recipients following donor heart preservation by HMP for 8 hours, compared to donor heart preservation for 2 hours by either SCS or HMP. RESULTS: Following HTx, all HMP recipients (both 2 hours and 8 hours groups) survived to the end of the study (6 hours after transplantation and successful weaning from cardiopulmonary bypass), required less vasoactive support for hemodynamic stability, and exhibited superior metabolic, fluid status and inflammatory profiles compared to SCS recipients. Contractile function and cardiac damage (troponin I release and histological assessment) was comparable between groups. CONCLUSIONS: Overall, compared to current clinical SCS, recipient outcomes following transplantation are not adversely impacted by extending HMP to 8 hours. These results have important implications for clinical transplantation where longer ischemic times may be required (e.g., complex surgical cases, transport across long distances). Additionally, HMP may allow safe preservation of "marginal" donor hearts that are more susceptible to myocardial injury and facilitate increased utilization of these hearts for transplantation.

Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is a supportive therapy, with its success dependent on effective drug therapy that reverses the pathology and/or normalizes physiology. However, the circuit that sustains life can also sequester life-saving drugs, thereby compromising the role of ECMO as a temporary support device. This ex vivo study was designed to determine the degree of sequestration of commonly used antibiotics, sedatives and analgesics in ECMO circuits. METHODS: Four identical ECMO circuits were set up as per the standard protocol for adult patients on ECMO. The circuits were primed with crystalloid and albumin, followed by fresh human whole blood, and were maintained at a physiological pH and temperature for 24 hours. After baseline sampling, fentanyl, morphine, midazolam, meropenem and vancomycin were injected into the circuit at therapeutic concentrations. Equivalent doses of these drugs were also injected into four polyvinylchloride jars containing fresh human whole blood for drug stability testing. Serial blood samples were collected from the ECMO circuits and the controls over 24 hours and the concentrations of the study drugs were quantified using validated assays. RESULTS: Four hundred samples were analyzed. All study drugs, except meropenem, were chemically stable. The average drug recoveries from the ECMO circuits and the controls at 24 hours relative to baseline, respectively, were fentanyl 3% and 82%, morphine 103% and 97%, midazolam 13% and 100%, meropenem 20% and 42%, vancomycin 90% and 99%. There was a significant loss of fentanyl (p = 0.0005), midazolam (p = 0.01) and meropenem (p = 0.006) in the ECMO circuit at 24 hours. There was no significant circuit loss of vancomycin at 24 hours (p = 0.26). CONCLUSIONS: Sequestration of drugs in the circuit has implications on both the choice and dosing of some drugs prescribed during ECMO. Sequestration of lipophilic drugs such as fentanyl and midazolam appears significant and may in part explain the increased dosing requirements of these drugs during ECMO. Meropenem sequestration is also problematic and these data support a more frequent administration during ECMO.

The appearance of pili annulati following alopecia areata.

Pili annulati is a rare autosomal-dominant hair shaft abnormality. It is characterized by alternating light and dark bands along the shaft due to air-filled cavities within the cortex of the hair shaft. Alopecia areata has been previously described as a common association with pili annulati, with improvement in alopecia areata coinciding with resolution of pili annulati. We report the case of a patient with a history of alopecia areata and alopecia universalis who developed the characteristic banded hair of pili annulati upon resolution of her alopecia areata. We provide direct microscopic examination of postregrowth hairs compared to normal and cross-polarized light microscopy.