Autoimmune heparin-induced thrombocytopenia and venous limb gangrene after aortic dissection repair: in vitro and in vivo effects of intravenous immunoglobulin.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder characterized by heparin-dependent antibodies that activate platelets (PLTs) via PLT FcγIIa receptors. "Autoimmune" HIT (aHIT) indicates a HIT subset where thrombocytopenia progresses or persists despite stopping heparin; aHIT sera activate PLTs strongly even in the absence of heparin (heparin-independent PLT-activating properties). Affected patients are at risk of severe complications, including dual macro- and microvascular thrombosis leading to venous limb gangrene. High-dose intravenous immunoglobulin (IVIG) offers an approach to interrupt heparin-independent PLT-activating effects of aHIT antibodies. CASE REPORT: A 78-year-old male who underwent cardiopulmonary bypass for aortic dissection developed aHIT, disseminated intravascular coagulation, and deep vein thrombosis; progression to venous limb gangrene occurred during partial thromboplastin time (PTT)-adjusted bivalirudin infusion (underdosing from "PTT confounding"). Thrombocytopenia recovered with high-dose IVIG, although the PLT count increase began only after the third dose of a 5-day IVIG regimen (0.4 g/kg/day × 5 days). We reviewed case reports and case series of IVIG for treating HIT, focusing on various IVIG dosing regimens used. RESULTS: Patient serum-induced PLT activation was inhibited in vitro by IVIG in a dose-dependent fashion; inhibition of PLT activation by IVIG was much more marked in the absence of heparin versus the presence of heparin (0.2 U/mL). Our literature review indicated 1 g/kg × 2 IVIG dosing as most common for treating HIT, usually associated with rapid PLT count recovery. CONCLUSION: Our clinical and laboratory observations support dose-dependent efficacy of IVIG for decreasing PLT activation and thus correcting thrombocytopenia in aHIT. Our case experience and literature review suggests dosing of 1 g/kg IVIG × 2 for patients with severe aHIT.

Treatment Outcomes for Right-Sided Endocarditis in Intravenous Drug Users: A Systematic Review and Analysis of Outcomes in a Tertiary Centre.

BACKGROUND: The increasing prevalence of intravenous drug users (IVDU) has resulted in higher incidence of right-sided infective endocarditis (RSIE). However, treatment guidelines for RSIE in IVDU are not well defined. The aim is to evaluate efficacy of different treatment strategies in reducing mortality and to describe treatment outcomes. METHODS: We systematically reviewed the literature using PubMed, Cochrane, CENTRAL, OvidEMBASE, Web of Science, and Medline databases to include prospective studies that compare mortality rates among IVDU with RSIE receiving isolated medical treatment versus those receiving medical-surgical treatment. In conjunction, analysis of 27 RSIE patients (including IVDU) treated at authors' institution was done to supplement the findings. Kaplan-Meier survival rates following hospital admission and cumulative incidence estimates for hospital re-admission were obtained. RESULTS: A total of nine studies (all with low or marginal risk of bias) met inclusion criteria. The prevalence of RSIE among IVDU with infective endocarditis varied from 34% to 100%. Seven studies compared medical versus medical-surgical therapy with less than 30% needing surgery. Mortality was higher in patients receiving surgical therapy. There were 27 RSIE (16 non-IVDU and 11 IVDU) analyzed at the authors' institution. Survival at 30 days, 1 year, and 3 years were 89%, 82%, and 78%, respectively, and repeat hospitalization for recurrent endocarditis were 8%, 17%, and 23%, respectively. CONCLUSIONS: There is paucity around optimal RSIE management strategy for IVDU that can decrease mortality. Surgical management of RSIE may be associated with increased mortality over medical management mainly due to advanced surgical indications.

Human antibody recognition of xenogeneic antigens (NeuGc and Gal) on porcine heart valves: could genetically modified pig heart valves reduce structural valve deterioration?

BACKGROUND: Glutaraldehyde-fixed bioprosthetic heart valves (GBHVs) derived from wild-type (WT, genetically unmodified) pigs are widely used clinically for heart valve replacement. There is evidence that their failure is related to an immune response. The use of valves from genetically engineered pigs that do not express specific pig antigens may prolong GBHV survival. Our aims were to determine (i) expression of Gal and NeuGc on heart (aortic and pulmonary) valves and pericardium of WT, α1,3-galactosyltransferase gene knockout (GTKO) and GTKO/N-glycolylneuraminic acid gene-knockout (GTKO/NeuGcKO) pigs in comparison with three different commercially available GBHVs and (ii) to determine human antibody binding to these tissues. METHODS: Wild-type, GTKO/CD46, and GTKO/CD46/NeuGcKO pig valves and pericardium were tested (i) fresh and (ii) after fixation with glutaraldehyde (0.02%, 0.2%, 2%). Sections of GBHVs, fresh and fixed valves, and pericardium were stained for Gal and NeuGc expression, and for human IgM and IgG antibody binding. RESULTS: Gal and NeuGc expression was high on all GBHVs and WT pig valves/pericardium, but was absent after antigen-specific-knockout. There was no difference in antigen expression or antibody binding among WT aortic, pulmonary valves, and pericardium as well as GBHVs. Glutaraldehyde fixation did not alter expression of Gal or NeuGc. After incubation with human serum, human IgM and IgG bound to all GBHVs and WT pig valves/pericardium. Valves from GTKO/CD46 pigs and, particularly, GTKO/CD46/NeuGcKO pigs (with/without glutaraldehyde fixation) showed less IgM and IgG binding. CONCLUSION: Compared to WT pigs, GTKO/CD46/NeuGcKO pigs would be preferable sources of GBHVs, because the absence of Gal/NeuGc expression reduces human antibody binding.

Recurrent Seizures Following Cardiac Surgery: Risk Factors and Outcomes in a Historical Cohort Study.

OBJECTIVES: To determine the risk factors for and outcomes after recurrent seizures (RS) in patients following cardiac surgery. DESIGN: A historical cohort study. SETTING: A single-center university teaching hospital. PARTICIPANTS: Cardiac surgery patients from April 2003 to September 2010 experiencing postoperative seizures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were divided into an isolated seizure group and an RS group. Risk factors for RS were determined using logistic regression. Intermediate-term follow-up was conducted by phone. Of 7,280 consecutive patients undergoing cardiac surgery, 61 (0.8%) experienced postoperative seizure and 36 (59%) of those experienced at least 1 recurrence. Of these, 32 (89%) experienced RS within 24 hours of the first seizure, and 29 (81%) had grand mal seizures. Preoperative creatinine ≥120 µmol/L (p = 0.02), time until first seizure occurred (≤4 hours; p = 0.01), and procedures involving the thoracic aorta were associated with RS (R(2) = 0.53, p<0.05). Patients with RS had longer intensive care unit stays (5.3 v 2.9 days, p = 0.03) and longer mechanical ventilation duration (53.3 v 15.0 hours, p = 0.01). At a median follow-up of 21 months for the RS group and 16 months for the isolated seizure group, restrictions, anticonvulsant use, morbidity, and mortality were similar between patients with isolated versus recurrent seizures. CONCLUSIONS: Higher preoperative creatinine, thoracic aortic surgery, and early seizure onset were associated with RS after cardiac surgery. When compared to isolated seizures, recurrence per se was not associated with significantly increased long-term morbidity or mortality.

Bioprosthetic heart valves of the future.

Glutaraldehyde-fixed bioprosthetic heart valves (GBHVs), derived from pigs or cows, undergo structural valve deterioration (SVD) over time, with calcification and eventual failure. It is generally accepted that SVD is due to chemical processes between glutaraldehyde and free calcium ions in the blood. Valve companies have made significant progress in decreasing SVD from calcification through various valve chemical treatments. However, there are still groups of patients (e.g., children and young adults) that have accelerated SVD of GBHV. Unfortunately, these patients are not ideal patients for valve replacement with mechanical heart valve prostheses as they are at high long-term risk from complications of the mandatory anticoagulation that is required. Thus, there is no "ideal" heart valve replacement for children and young adults. GBHVs represent a form of xenotransplantation, and there is increasing evidence that SVD seen in these valves is at least in part associated with xenograft rejection. We review the evidence that suggests that xenograft rejection of GBHVs is occurring, and that calcification of the valve may be related to this rejection. Furthermore, we review recent research into the transplantation of live porcine organs in non-human primates that may be applicable to GBHVs and consider the potential use of genetically modified pigs as sources of bioprosthetic heart valves.

Design of the rivaroxaban for heparin-induced thrombocytopenia study.

Rivaroxaban is an ideal potential candidate for treatment of heparin-induced thrombocytopenia (HIT) because it is administered orally by fixed dosing, requires no laboratory monitoring and is effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study evaluating the incidence of new symptomatic venous and arterial thromboembolism in patients with suspected or confirmed HIT who are treated with rivaroxaban. Methodological challenges faced in the design of this study include heterogeneity of the patient population, differences in the baseline risk of thrombosis and bleeding dependent on whether HIT is confirmed or just suspected, and heterogeneity in laboratory confirmation of HIT. The rationale for how these challenges were addressed and the final design of the Rivaroxaban for HIT study is reviewed.

Porcine bioprosthetic heart valves: The next generation.

There have been significant advances in organ xenotransplantation (cross-species transplantation), especially in the development of genetically engineered pigs, but clinical trials of solid organ transplants are still a time away. However, there is a form of pig-to-human xenotransplantation that has been taking place since the 1960s-bioprosthetic heart valve (BHV) replacement. Recently, there has been increasing evidence that, despite glutaraldehyde fixation of BHVs, there is a significant immune reaction to the valves, leading to calcification, rapid structural deterioration, and failure, particularly in young patients who have a more vigorous immune system and metabolism than the elderly. However, it is the young patients who would most benefit from such BHVs because these avoid the complications associated with the lifelong anticoagulation required with mechanical valves. In this review, we examine pathologic and immunohistochemical reports of failed BHVs that suggest that there is an immune response to these valves. Small animal studies that link the development of calcification and BHV failure to the immune response are reviewed. We draw parallels between the problems of glutaraldehyde-fixed tissue xenotransplantation and those currently being faced in live organ xenotransplantation. Finally, we discuss the advances being made in the production of genetically modified pigs and the evidence that these pigs may become a source of BHVs that can be used worldwide to treat valvular heart disease in children and young adults (for whom there is no ideal valve replacement in existence today). The design of a BHV that is resistant to the host's immune response would be a major step forward in cardiac surgery.

Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors.

BACKGROUND: Seizures after cardiac surgery are a serious complication. The antifibrinolytic agent tranexamic acid (TA), which has known proconvulsant properties, may be associated with postoperative seizures. We sought to determine the association between TA and other risk factors for seizures after cardiac surgery. METHODS AND RESULTS: We analyzed a database of consecutive cardiac surgery patients (April 2003 to December 2009) using multivariable logistic regression analysis to assess for seizure risk factors. Seizures occurred in 56 of 5,958 patients (0.94%). TA use was associated with an increased risk of seizures (odds ratio 7.4, 95% confidence interval 2.8-19.3; P < 0.001). Multivariable logistic regression analysis revealed that the following factors were significantly associated with seizures: TA exposure; Acute Physiology, Age, and Chronic Health Evaluation (APACHE) II score > 20; preoperative cardiac arrest; preoperative neurological disease; open chamber surgery; cardiopulmonary bypass time > 150 min; and previous cardiac surgery. Seizures occurred at a median of 5.3 hr (interquartile range 2.4-15.1 hr) after the end of surgery. In all, 58.1% were grand mal, 14.5% were associated with a stroke, and 58.1% recurred in hospital. Altogether, 48.3% of the patients were able to discontinue anticonvulsant medications prior to discharge. Compared to the non-seizure group, seizure patients had an increased rate of postoperative neurological complications, defined as delirium and/or stroke (3.2% vs 19.6%, P < 0.001), increased intensive care unit (ICU) length of stay (1.0 vs 4.7 days, P < 0.001), and increased ICU mortality (1.4 % vs 9.7 %, P = 0.001). CONCLUSIONS: Our data suggest that multiple risk factors, including TA, are associated with seizures after cardiac surgery. Thus, the TA dose may be a readily modifiable risk factor for postoperative seizures.

Delirium definition influences prediction of functional survival in patients one-year postcardiac surgery.

BACKGROUND: Delirium after cardiac surgery is associated with prolonged intensive care unit (ICU) and hospital length of stay and elevated rates of mortality. The Society of Thoracic Surgery National Database (STS-ND) includes delirium in routine data collection but restricts its definition to hyperactive symptoms. The objective is to determine whether the Confusion Assessment Method for ICU (CAM-ICU), which includes hypo- and hyperactive symptoms, is associated with improved prediction of poor 1-year functional survival following cardiac surgery. METHODS: Clinical and administrative databases were used to determine the influence of postoperative delirium on 1-year poor functional survival, defined as being institutionalized or deceased at 1 year. Patients experiencing postoperative delirium using the STS-ND definition (2007-2009) were compared with patients with delirium identified by the CAM-ICU (2010-2012). A propensity score match was undertaken, and multivariable Cox proportional hazards regression models were generated to determine risk of poor 1-year functional survival. RESULTS: There were 2756 and 2236 patients in the STS-ND and CAM-ICU cohorts, respectively. Propensity matching resulted in a cohort of 1835 patients (82.1% matched). The overall rate of delirium in the matched study population was 7.6% in the STS-ND cohort and 13.0% in the CAM-ICU cohort (P < .001). Delirium in the CAM-ICU cohort was independently associated with poor 1-year functional survival (hazard ratio, 2.58; 95% confidence interval, 1.20-5.54; P = .02); delirium in the STS-ND cohort was not associated with poor 1-year functional survival (hazard ratio, 0.92; 95% confidence interval, 0.49-1.71; P = .79). CONCLUSIONS: A systematic screening tool identifies postoperative delirium with improved prediction of poor 1-year functional survival following cardiac surgery.

The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration.

Bioprosthetic heart valves (BHVs) are commonly used to replace severely diseased heart valves but their susceptibility to structural valve degeneration (SVD) limits their use in young patients. We hypothesized that antibodies against immunogenic glycans present on BHVs, particularly antibodies against the xenoantigens galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc), could mediate their deterioration through calcification. We established a large longitudinal prospective international cohort of patients (n = 1668, 34 ± 43 months of follow-up (0.1-182); 4,998 blood samples) to investigate the hemodynamics and immune responses associated with BHVs up to 15 years after aortic valve replacement. Early signs of SVD appeared in <5% of BHV recipients within 2 years. The levels of both anti-αGal and anti-Neu5Gc IgGs significantly increased one month after BHV implantation. The levels of these IgGs declined thereafter but anti-αGal IgG levels declined significantly faster in control patients compared to BHV recipients. Neu5Gc, anti-Neu5Gc IgG and complement deposition were found in calcified BHVs at much higher levels than in calcified native aortic valves. Moreover, in mice, anti-Neu5Gc antibodies were unable to promote calcium deposition on subcutaneously implanted BHV tissue engineered to lack αGal and Neu5Gc antigens. These results indicate that BHVs manufactured using donor tissues deficient in αGal and Neu5Gc could be less prone to immune-mediated deterioration and have improved durability.

Determining relevant cortisol concentrations in critically ill patients.

The importance of adrenal function to survival in critically ill patients has been established; however, identifying the best method to diagnose adrenal insufficiency has been problematic. Multiple methods of determining adrenal function have been developed, each with its advantages and disadvantages. Serum-free cortisol levels are probably the most accurate, although obtaining this result is technically demanding. Cohen and colleagues investigated the feasibility of measuring tissue cortisol levels in burn patients and whether tissue cortisol levels could be used as a surrogate for plasma-free cortisol levels.

Extracorporeal lung support for patients who had severe respiratory failure secondary to influenza A (H1N1) 2009 infection in Canada.

BACKGROUND: From March to July 2009, influenza A (H1N1) 2009 (H1N1-2009) virus emerged as a major cause of respiratory failure that required mechanical ventilation. A small proportion of patients who had this condition developed severe respiratory failure that was unresponsive to conventional therapeutic interventions. In this report, we describe characteristics, treatment, and outcomes of critically ill patients in Canada who had H1N1-2009 infection and were treated with extracorporeal lung support (ECLS). METHODS: We report the findings of a case series of six patients supported with ECLS who were included in a cohort study of critically ill patients with confirmed H1N1-2009 infection. The patients were treated in Canadian adult and pediatric intensive care units (ICUs) from April 16, 2009 to August 12, 2009. We describe the nested sample treated with ECLS and compare it with the larger sample. RESULTS: During the study period, 168 patients in Canada were admitted to ICUs for severe respiratory failure due to confirmed H1N1-2009 infection. Due to profound hypoxemia unresponsive to conventional therapeutic interventions, six (3.6%) of these patients were treated with ECLS in four ICUs. Four patients were treated with veno-venous pump-driven extracorporeal membrane oxygenation (vv-ECMO), and two patients were treated with pumpless lung assist (NovaLung iLA). The mean duration of support was 15 days. Four of the six patients survived (66.6%), one of the surviving patients was supported with iLA and the other three surviving patients were supported with ECMO. The two deaths were due to multiorgan failure, which occurred while the patients were on ECLS. INTERPRETATION: Extracorporeal lung support may be an effective treatment for patients who have H1N1-2009 infection and refractory hypoxemia. Survival of these patients treated with ECLS is similar to that reported for patients who have acute respiratory distress syndrome of other etiologies and are treated with ECMO.

Studying Xenograft Rejection of Bioprosthetic Heart Valves.

Millions of patients with valvular heart disease have benefitted from heart valve replacement since the procedure was first introduced in the 1960s; however, there are still many patients who get early structural valve deterioration (SVD) of their bioprosthetic heart valves (BHV). BHV are porcine, bovine, or equine tissues that have been glutaraldehyde fixed to preserve the tissue and presumably make the tissue immunologically inert. These glutaraldehyde-fixed BHV with anti-calcification treatments last long periods of time in older adults but develop early SVD in younger patients. The consensus at present is that the early SVD in younger patients is due to more "wear and tear" of the valves and higher calcium turnover in younger patients. However, as younger patients likely have a more robust immune system than older adults, there is a new hypothesis that BHV xenografts may undergo xenograft rejection, and this may contribute to the early SVD seen in younger patients.At present, the technology to noninvasively study in vivo whether an implanted BHV in a human patient is undergoing rejection is not available. Thus, a small animal discordant xenotransplant model in young rodents (to match the young patient getting a pig/bovine/equine BHV) was developed to study whether the hypothesis that glutaraldehyde-fixed BHV undergo xenograft rejection had any merit. In this chapter, we describe our model and its merits and the results of our investigations. Our work provides clear evidence of xenograft rejection in glutaraldehyde-fixed tissue, and our small animal model offers an opportunity to study this process in detail.

Long-term non-institutionalized survival and rehospitalization after surgical aortic and mitral valve replacements in a large provincial cardiac surgery centre.

OBJECTIVES: Long-term quality of life following open surgical valve replacement is an increasingly important outcome to patients and their caregivers. This study examines non-institutionalized survival and rehospitalization within our surgical aortic valve replacement (AVR) and mitral valve replacement (MVR) populations. METHODS: A retrospective single-centre study of all consecutive open surgical valve replacements between 1995 and 2014 was undertaken. Clinical data were linked to provincial administrative data for 3219 patients who underwent AVR, MVR or double (aortic and mitral) valve replacement with or without concomitant coronary artery bypass grafting (CABG). Non-institutionalized survival and cumulative incidence of rehospitalization was examined up to 15 years. RESULTS: Follow-up was complete for 96.9% of the 2146 patients who underwent AVR ± CABG (66.7% of the overall cohort), 878 who underwent MVR ± CABG (27.3%) and 195 who underwent double (aortic and mitral) valve replacement ± CABG (6.0%) with a median follow-up time of 5.6 years. Overall non-institutionalized survival was 35.4% at 15 years, and the cumulative incidence of rehospitalization was 34.4%, 63.2% and 87.0% at 1, 5 and 15 years, respectively, without significant differences between valve procedure cohorts. Both non-institutionalized survival and cumulative incidence of rehospitalization improved in more recent eras, despite increasing age and comorbidities. CONCLUSIONS: Non-institutionalized survival and rehospitalization data for up to 15 years suggest good functional outcomes long after surgical AVR and/or MVR. Continued improvements are seen in these metrics over the past 2 decades. This provides a unique insight into the quality of life after surgical valve replacement in the ageing demographics with valvular heart disease.

Glutaraldehyde-fixed bioprosthetic heart valve conduits calcify and fail from xenograft rejection.

BACKGROUND: Glutaraldehyde fixation (G-F) decreases but likely does not eliminate the antigenicity of bioprosthetic heart valves. Rejection (with secondary dystrophic calcification) may be why G-F xenograft valves fail, especially in young patients, who are more immunocompetent than the elderly. Therefore, we sought to determine whether rejection of G-F xenograft occurs and to correlate this with graft calcification. METHODS AND RESULTS: Ascending aortas/valves (from rats [syngeneic] or guinea pigs [xenogeneic]) were transplanted (fresh or after 48 hour of G-F) into the infrarenal aortas of young rat recipients for 20 days. A xenogeneic group was also treated with steroids until graft harvest. The valves and media/adventitia were scored blindly for inflammation (0 to 4). Percent graft infiltration by T cells/macrophages was determined (immunohistochemistry), and rat IgG ELISAs were performed. There was >3 times more valve inflammation, >10 times more valve T-cell/macrophage infiltrate, and >3 times antibody rise in the G-F xenogeneic groups compared with the fresh syngeneic or the G-F syngeneic groups (P<0.05). There was >2 times more adventitial inflammation and T-cell/macrophage infiltrate in the xenogeneic groups (P<0.05). Steroid treatment decreased inflammation and antibody rise in the xenogeneic groups (P<0.05). Correlation analysis revealed media/adventitia inflammation (P=0.02) and percent macrophage (P=0.01) infiltration to be predictors of calcification. CONCLUSIONS: G-F xenografts have cellular/humoral rejection and calcify secondarily.