Edward Pascoe

Mass spectrometry-based proteomic analysis of urine in acute kidney injury following cardiopulmonary bypass: a nested case-control study.

BACKGROUND The early evolution of acute kidney injury (AKI) in humans is difficult to study noninvasively. We hypothesized that urine proteomics could provide insight into the early pathophysiology of human AKI. STUDY DESIGN A prospective nested case-control study (n = 250) compared serial urinary proteomes of 22 patients with AKI and 22 patients without AKI before, during, and after cardiopulmonary bypass surgery. OUTCOMES AKI was defined as a greater than 50% increase in serum creatinine level, and non-AKI, as less than 10% increase from baseline. MEASUREMENTS Serum creatinine, urine protein-creatinine ratio, neutrophil gelatinase-associated lipocalin (NGAL), alpha1-microglobulin, interferon-inducible protein-10 (IP-10), monokine induced by interferon gamma (Mig), interferon-inducible T cell alpha chemoatractant (I-TAC), interleukin 6 (IL-6), IL-1beta, and IL-10. Urine protein profiling by means of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). RESULTS SELDI-TOF-MS showed intraoperative tubular stress in both groups on arrival to the intensive care unit, evidenced by beta2-microglobulinuria. Non-AKI proteomes returned toward baseline postoperatively. In contrast, AKI proteomes showed a second phase of tubular injury/stress with the reappearance of beta2-microglobulin and multiple unidentified peaks (3 to 5 and 6 to 8 kDa) and the appearance of established tubular injury markers: urinary protein, alpha1-microglobulin, and NGAL. Furthermore, 2 novel peaks (2.43 and 2.78 kDa) were found to be dominant in postoperative non-AKI urine samples. The 2.78-kDa protein was identified as the active 25-amino acid form of hepcidin (hepcidin-25), a key regulator of iron homeostasis. Finally, an inflammatory component of reperfusion injury was evaluated by means of enzyme-linked immunosorbent assay analysis of candidate chemokines (IP-10, I-TAC, and Mig) and cytokines (IL-6, IL-1beta, and IL-10). Of these, IP-10 was upregulated in patients with versus without AKI postoperatively. LIMITATIONS This is an observational study. SELDI-TOF-MS is a semiquantitative technique. CONCLUSIONS Evaluation of human AKI revealed early intraoperative tubular stress in all patients. A second phase of injury observed in patients with AKI may involve IP-10 recruitment of inflammatory cells. The enhancement of hepcidin-25 in patients without AKI may suggest a novel role for iron sequestration in modulating AKI.

The relationship of blood concentrations of rapamycin and cyclosporine to suppression of allograft rejection in a rabbit heterotopic heart transplant model.

Heterotopic heart transplants were performed on 50 New Zealand white rabbits. Groups of 5 rabbits were randomly assigned to receive, through an intravenous route, rapamycin (RAPA) or cyclosporine at the following doses: RAPA (0.05, 0.1, 0.5, and 1.0 mg/kg/day); CsA (5.0, 10.0, and 15.0 mg/kg/day). Drug vehicle and saline controls were also included. Trough blood concentrations were monitored in both RAPA- and CsA-treated groups on a weekly basis throughout the study. Biochemical assessment of renal and liver function was performed at the beginning and end of the study. Animals receiving RAPA exhibited excellent allograft survival; only two animals in the lowest dosage group (0.05 mg/kg/day) rejected their grafts. In contrast, no rejection occurred in the CsA-treated groups. Animals that rejected their grafts were maintained on the drug until the endpoint of the study was reached at 60 days posttransplant to monitor drug induced side-effects. In some instances animals were sacrificed prior to this time due to infectious and other complications. No significant changes in renal or liver function were noted in the RAPA-treated group, while in the group of animals receiving the highest dose of CsA (15.0 mg/kg/day) a significant decrease in creatinine clearance was noted. A correlation was shown to exist between dose and the trough concentrations of both drugs. The whole-blood concentrations of RAPA that resulted in maximal efficacy with minimal toxicity was in the range of 10–60 μg/L. Rabbits having trough whole-blood concentrations of <10 μg/L rejected their grafts. A much wider therapeutic range for CsA (50–300 μg/L) was noted. The results suggest that RAPA is as efficacious as CsA in prevention of allograft rejection in the animal model tested. The therapeutic monitoring of trough blood concentrations of RAPA, as with CsA, may be useful in guiding dosage adjustments to maximize the immunosuppressive efficacy while minimizing drug-induced side-effects.

Serum Creatinine Measurement Immediately After Cardiac Surgery and Prediction of Acute Kidney Injury

BACKGROUND After heart surgery, acute kidney injury (AKI) confers substantial long-term risk of death and chronic kidney disease. We hypothesized that small changes in serum creatinine (SCr) levels measured within a few hours of exit from the operating room could help discriminate those at low versus high risk of AKI. STUDY DESIGN Prospective cohort of 350 elective cardiac surgery patients (valve or coronary artery bypass grafting) recruited in Winnipeg, Canada. Baseline SCr level was obtained at the preoperative visit 2 weeks before surgery. The postoperative SCr level was drawn within 6 hours of completion of surgery and then daily while the patient was in the hospital. PREDICTOR Immediate (ie, <6 hours) postoperative SCr level change (ΔSCr), categorized as within 10% (reference), decrease >10%, or increase >10% relative to baseline. OUTCOME AKI, defined according to the new KDIGO (Kidney Disease: Improving Global Outcomes) consensus definition as an increase in SCr level >0.3 mg/dL within 48 hours or >1.5 times baseline within 1 week. MEASUREMENTS We compared the C statistic of logistic models with and without inclusion of immediate postoperative ΔSCr. RESULTS After surgery, 176 patients (52%) experienced a decrease >10% in SCr level, 26 (7.4%) experienced an increase >10%, and 143 had ΔSCr within ±10% of baseline. During hospitalization, 53 (14%) developed AKI. Bypass pump time, baseline estimated glomerular filtration rate, and European System for Cardiac Operative Risk Evaluation (euroSCORE) were associated with AKI in a parsimonious base logistic model. Added to the base model, immediate postoperative ΔSCr was associated strongly with subsequent AKI and significantly improved model discrimination over the base model (C statistic, 0.78 [95% CI, 0.71-0.85] vs 0.69 [95% CI, 0.62-0.77]; P < 0.001). A ≥10% SCr level decrease predicted significantly lower AKI risk (OR, 0.37; 95% CI, 0.18-0.76), whereas a ≥10% SCr level increase predicted significantly higher (OR, 6.38; 95% CI, 2.37-17.2) AKI risk compared with the reference category. LIMITATIONS We used a surrogate marker of AKI. External validation of our results is warranted. CONCLUSION In elective cardiac surgery patients, measurement of immediate postoperative ΔSCr improves prediction of AKI.

Nineteen-millimeter prosthetic aortic valves allow normalization of left ventricular mass in elderly women.

BACKGROUND Implantation of small aortic valve prostheses has been reported to be associated with impaired left ventricular (LV) mass regression and incomplete resolution of symptoms although these data have been generated largely with male patients. Therefore we sought to determine the clinical and hemodynamic outcomes of female patients who received a 19-mm aortic valve. METHODS Between May 1995 and December 2000, 38 female patients (average age 73 years, range 42 to 89) underwent isolated aortic valve replacement (AVR; n = 22) or AVR plus coronary artery bypass graft surgery (CABG; n = 16) with a 19-mm aortic prosthesis. The average New York Heart Association (NYHA) class was 3.08 and of the 26 patients who had angina, 47.2% were in CCS class III or IV. Clinical and echocardiographic follow-up was done an average of 33.4 months (8 to 72) after surgery. RESULTS Operative mortality was 10.5%. Overall survival at an average of 33 months was 71.1%. The average NYHA class was 1.52 +/- 0.34 postoperatively (p < 0.001 versus preoperative) and 95% had no anginal symptoms or were in Canadian Cardiovascular Society class I. The LV mass index showed significant regression (114 +/- 11 g/m2 to 89 +/- 9 g/m2, p = 0.001) despite an effective orifice area index (EOAI) of 0.64 +/- 0.09 cm2/m2. CONCLUSIONS Despite a very small EOAI, elderly female patients with 19-mm prosthetic aortic valves can experience a satisfactory improvement in symptoms and normalization of LV mass. This finding suggests that small prosthetic aortic valves continue to have an application in contemporary cardiac surgical practice. The current perception of patient-prosthesis mismatch may need to be reconsidered for select populations.

Vocal Cord Paralysis After Thoracic Aortic Surgery: Incidence and Impact on Clinical Outcomes

BACKGROUND Vocal cord paralysis (VCP) is a serious complication associated with thoracic aortic surgery; however, there is a paucity of literature regarding the incidence and impact of VCP on postoperative outcomes. We sought to determine the incidence of VCP and its impact on clinical outcomes in patients who underwent thoracic aortic repair at our center. METHODS A retrospective chart review was conducted on all patients who underwent thoracic aortic surgery between January 2009 and September 2012. RESULTS A total of 259 patients underwent a thoracic aortic procedure during the study period. Vocal cord paralysis was diagnosed in 12 (5%) patients, a median of 6 [3 to 21] days after extubation. The incidence was 1%, 0%, 20%, and 25% in those undergoing an open ascending, hemiarch, total arch, or descending aortic procedure, respectively. Patients with VCP had an increased incidence of pneumonia (58% vs 17%, p = 0.003), readmission to the intensive care unit for respiratory failure (17% vs 2%, p = 0.047), and longer hospital length of stay (18 [11 to 43] days versus 9 [6 to 15] days, p = 0.002). A propensity-matched analysis confirmed a higher incidence of pneumonia (58% vs 17%, p = 0.020) and longer hospital length of stay (18 [11 to 43] vs 10 [7 to 14] days, p = 0.015) in patients suffering VCP. CONCLUSIONS Vocal cord paralysis is a common complication in patients undergoing open surgery of the aortic arch and descending aorta, and is associated with significant morbidity. Further research may be warranted to determine if early fiberoptic examination and consideration of a vocal cord medialization procedure may mitigate the morbidity associated with VCP.

High-dose thiopentone for open-chamber cardiac surgery: a retrospective review.

PurposeHigh-dose thiopentone has been reported to reduce the incidence of neurological dysfunction after open-chamber cardiac surgery. However, this technique delays trachéal extubation and increases requirements for inotropic support after cardiopulmonary bypass. As a quality assurance measure to determine the safety of high-dose thiopentone, we reviewed the records of all patients undergoing elective, open-chamber surgery at our institution between 1st March, 1987 and 31st Dec, 1989.MethodsThe charts of 236 patients were reviewed retrospectively, and 227 met our inclusion criteria. The perioperative characteristics of patients anaesthetized with thiopentone (Group T, n = 80) were compared with those of patients anaesthetized with opioids (Group O, n = 147).ResultsAnaesthetic technique was chosen by the attending anaesthetist. In Group T (n = 80) thiopentone 38.1 ± 11.8 mg· kg−1 was infused to produce electroencephalographic burst-suppression during bypass. Moderate hypothermia and arterial line filtration were used during bypass. The groups did not differ with respect to demographics, type of surgery, or conduct of bypass. There were no strokes in Group T and 4 in Group O (P = NS). The time to extubation was prolonged in Group T compared with Group O(39 ±51 vs 27 ± 24 h, P = 0.014), as was the duration of slay in intensive care (66 ± 56 vs 51 ± 29 h, P = 0.010). Thiopentone did not increase the need for inotropic or mechanical support after bypass, ln-hospital mortality was lower in Group T than in Group O (1.2% vs 9.5%, P= 0.034).ConclusionsHigh-dose thiopentone delays extubation after open-chamber procedures. However, the technique appears safe, and further prospective investigation is justifiable.RésuméObjectifOn a rapporté que les doses élevés de thiopentone diminuaient l’incidence de la dysfonction neurologique après la chirurgie à coeur ouvert. Cependant, cette méthode retarde l’extubation de la trachée et augmente le besoin de soutien inotrope après la circulation extracorporelle. Comme mesure d’assurance-qualité effectuée pour déterminer la sécurité du thiopentone à haute dose, nous avons révisé les dossiers de tous les patients de notre institution opérés pour une chirurgie à coeur ouvert entre le premier mars 1987 et le 31 décembre 1989.MéthodesLes dossiers de 236 patients ont été révisés rétrospectivement et 227 ont rencontré nos critères d’admissibilité. Les caractéristiques périopératoires des patients anesthésiés au thiopentone (groupe T, n = 80) ont été comparées à celles des patients anesthésiés aux morphiniques (groupe O, n = 147).RésultatsLa technique anesthésique était choisie par l’anesthésiste responsable. Dans le groupe T, le thiopentone 38,1 ± 11.8 mg· kg−1 était perfusé de façon à produire un burst suppression électroencéphalographique pendant la circulation extracorporelle (CEC). Aucun accident cérébrovasculaire n’est survenu dans le groupe T mais il y en a eu quatre dans le groupe O. L’intubation a été. prolongée dans le groupe T comparativement au groupe O (39 ± 51 vs 27 ± 24 h, P = 0,014) de même que la durée du séjour à l’unité des soins intensifs. Le thiopentone n’a pas augmenté le besoin de support inotrope ou mécanique après la CEC. La mortalité intrahospitalière était plus basse dans le groupe T que dans le groupe O (1,2% vs 9,5%, P = 0,034).ConclusionsLes doses élevées de thiopentone retardent l’extubation après les interventions à coeur ouvert. Cependant, la technique semble sùre, ce qui justifie des recherches ultérieures.

Left ventricular pseudoaneurysm: The role of multimodality cardiac imaging

A 71-year-old man presented with an inferior ST elevation myocardial infarction. Coronary angiography demonstrated 99% occlusion of the proximal right coronary artery. A posterior wall pseudoaneurysm was incidentally observed on left ventriculography (arrows; Figure 1A). Transthoracic echocardiography revealed a site of rupture in the posterior left ventricular (LV) wall measuring 36 mm in width, communicating with a large, thrombus-free pseudoaneurysm (asterisks; Figure 1B). Cardiac magnetic resonance imaging (MRI) confirmed the presence of an aneurysmal dilation along the basal inferolateral wall with a mouth orifice of 36 mm in diameter and 36 mm deep (arrows; Figure 1C). A rim of delayed enhancement around the aneurysm could have represented either a full-thickness myocardial scar or an enhancing pericardium containing a false aneurysm, although the location was of concern for the latter (arrows; Figure 1D). At surgery, following resection of the aneurysmal sac (Figure 1E), an examination of the interior of the LV wall revealed a zone of transition from healthy-appearing myocardium to thinned scarred myocardium, followed by a thinner fibrous edge, which was compatible with the diagnosis of a pseudoaneurysm. Pathological examination demonstrated organizing fibrous tissue (Figure 1F). The lack of LV wall was consistent with the diagnosis of a pseudoaneurysm. Figure 1) Ao Aorta; LA Left atrium; LV Left ventricle; RV Right ventricle LV pseudoaneurysms develop when myocardial rupture is contained by pericardial adhesions or scar tissue (1). In contrast, true LV aneurysms form following myocardial infarction as a result of scar formation and thinning of the myocardial wall. Echocardiography, left ventriculography and cardiac MRI are complementary imaging modalities used to distinguish theses two entities. Cardiac MRI, with its higher spatial resolution, is more sensitive and specific for the diagnosis of a pseudoaneurysm than transthoracic echocardiography (2). The absence of delayed enhancement findings of myocardial elements within the sac of the aneurysm on cardiac MRI, and the presence of delayed enhancement of the pericardium, is highly suggestive of a pseudoaneurysm (2). In some cases, however, such as in the present patient, differentiation of a delayed enhancement of the myocardium from an adjacent pericardium may be challenging, leading to an incorrect diagnosis because an enhancing pericardium containing a pseudoaneurysm can mimic an infarcted myocardium (2). Hence, surgical assessment and pathological evaluation is occasionally imperative to make a definitive diagnosis.

An unusual presentation of left ventricular free wall rupture

Left ventricular free wall rupture (LVFWR) is one of the most lethal complications following myocardial infarction. It accounts for approximately 12% to 21% of all in-hospital deaths following myocardial infarction. The majority of patients die shortly after LVFWR from instantaneous pericardial tamponade and hemodynamic collapse. However, up to one-third of cases are subacute in nature, allowing limited time for emergent surgical repair to prevent sudden death. A high index of suspicion and timely use of diagnostic tests are important in recognizing cases. The present report describes the case of a 69-year-old man who initially presented with acute pericardial tamponade and was subsequently diagnosed with LVFWR in the operating room as the cause of his hemopericardium. The pathology, diagnosis and management of LVFWR are reviewed.

Cardioembolic source of ST-segment elevation myocardial infarction.

![Figure][1] [![Graphic][3] ][3] A 29-year-old man with antiphospholipid syndrome presented with an acute inferior ST-segment elevation myocardial infarction (A) . Cardiac catheterization confirmed distal embolic occlusion of the third obtuse marginal branch of the circumflex coronary