Kavitha Muthiah

Background: Drug interactions involving immunosuppressants can compromise transplant outcomes. Although repeated ketamine administration induces hepatic enzymes in experimental models, clinical reports of induced clearance of cytochrome P450 (CYP) substrates are lacking. Continuous subcutaneous ketamine infusions are increasingly used for acute pain management. We present a case of difficult‐to‐maintain tacrolimus and sirolimus concentrations in the context of subcutaneous ketamine infusion for acute pain management. Methods: A 55‐year‐old male heart transplant recipient received continuous subcutaneous ketamine (5.2–10.4 mg/h) for pain management following lower limb thrombectomy. Tacrolimus and sirolimus concentrations were monitored throughout hospitalization and rehabilitation. Population pharmacokinetic modeling with Bayesian estimation characterized temporal clearance changes, incorporating inter‐occasion variability across six periods (pre‐, during‐, and weekly post‐ketamine administration for 4 weeks). Results: Following ketamine initiation, tacrolimus and sirolimus concentrations remained subtherapeutic despite dose escalations of 1.8‐fold and 5‐fold, respectively. Pharmacokinetic modeling revealed approximately 2‐fold clearance increases during ketamine administration, peaking 1 week after initiation. Following ketamine discontinuation, tacrolimus and sirolimus concentrations progressively increased over 3 weeks, consistent with enzyme induction and recovery. Drug Interaction Probability Scale assessment indicated probable interaction (score + 5). Brief concomitant flucloxacillin use may have contributed to the observed changes. Conclusions: This case provides preliminary evidence of potential interaction between ketamine and CYP3A4‐metabolized immunosuppressants. Clinicians should consider increased therapeutic drug monitoring when using ketamine with narrow therapeutic range medications, continuing approximately 3 weeks post‐discontinuation.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has failed to demonstrate mortality benefit in randomised controlled trials of cardiogenic shock. We aimed to determine whether a novel ‘Hemi-ECMO’ configuration, involving aortic occlusion to isolate the left ventricle from the VA-ECMO circuit, improves cardiac haemodynamics. We utilised a pulsatile biventricular mock circulatory loop with variable contractility to compare standard VA-ECMO with Hemi-ECMO support under left ventricular or biventricular failure conditions. When averaged across all pump speeds, mean left atrial pressure was significantly reduced with Hemi-ECMO compared to VA-ECMO (21.11 ± 1.32 mmHg vs. 26.53 ± 0.87 mmHg, p < 0.001), with more pronounced benefit at higher pump speeds. Aortic ejection increased with Hemi-ECMO at higher pump speeds: 0.14 ± 0.03 vs. 0.00 ± 0.00 L/min (p = 0.002) at 3000 revolutions per minute (RPM). Aortic ejection was greater with Hemi-ECMO in the descending aorta compared to the ascending aorta position (0.27 ± 0.03 L/min vs. 0.17 ± 0.05 L/min, p = 0.015). In conclusion, Hemi-ECMO demonstrates significant haemodynamic advantages in severe cardiogenic shock, including reductions in mean left atrial pressure and increases in aortic ejection, with greater benefits when positioned in the descending aorta. Further in vivo studies are warranted to assess clinical viability.

Background: Protein-losing enteropathy (PLE) is seen in up to 15% of patients with Fontan circulation and has important nutritional, immunologic, and haemodynamic consequences especially in the context of advanced heart failure. Midodrine, an alpha-1-receptor agonist, increases lymphatic tone, mitigating leak of lymph into the bowel, and has been shown to have clinical and biochemical benefit in patients with Fontan failure. Case summary: A young woman with Fontan circulation, end-stage heart failure, and PLE developed progressive hypoalbuminaemia, deconditioning, and frailty prohibitive to transplantation candidacy. Three months after commencing oral midodrine therapy, she experienced normalization of her serum albumin and improvements in her oedema, exercise tolerance, and frailty enabling candidacy and eventual successful heart transplantation. Discussion: The development of PLE in patients with Fontan circulations is an indication for cardiac transplantation, but there are often significant barriers due to the many complications. We performed a comprehensive Medline search, and this is the first case demonstrating the use of midodrine to bridge a frail patient with PLE and advanced Fontan heart failure to heart transplantation candidacy and eventual transplant.

Background.: Coronary allograft vasculopathy (CAV) remains a significant cause of morbidity and mortality after heart transplantation. The use of aspirin for CAV prophylaxis has recently garnered interest as a possible therapeutic adjunct in this setting. Methods.: This 2-center retrospective cohort study included 372 patients who underwent heart transplantation between January 2009 and March 2018 and were stratified according to the commencement of aspirin during their index transplant admission. The primary outcome was the development of moderate or severe CAV (International Society for Heart and Lung Transplantation grade ≥2) at surveillance coronary angiography. Secondary endpoints included mortality at follow-up. Results.: There were no differences in age, sex, and cause of heart failure. In the early aspirin group, the preponderant risk factors included use of ventricular assist devices, pretransplant smoking, and mild or moderate rejection. Multivariable analyses to assess for independent predictors of CAV development and mortality demonstrated that aspirin was associated with reduced mortality (adjusted hazard ratio = 0.19; 95% confidence interval, 0.08-0.47, P < 0.01) and a trend toward a protective effect against the development of moderate or severe CAV (adjusted hazard ratio = 0.24; 95% confidence interval, 0.54-1.19; P = 0.08). Conclusions.: In this retrospective risk-adjusted 2-center cohort study, early aspirin administration was associated with reduced risk of death and a trend toward a protective effect against CAV development. These findings warrant validation in prospective randomized trials.

Background: Subaortic pannus formation complicates bioprosthetic aortic valve (AV) replacement. We report an extreme case in a continuous-flow left ventricular assist device (LVAD) patient. Case summary: A 49-year-old Caucasian female with dilated cardiomyopathy was bridged to transplant with a HeartWare Ventricular Assist Device (Medtronic). Duration of support was prolonged, 6 years & 7 months, due to allosensitization requiring desensitization. Pump thrombosis occurred 2 years & 4 months post-LVAD requiring alteplase thrombolysis. The patient underwent bioprosthetic AV replacement 3 years & 10 months post-LVAD for symptomatic aortic incompetence. Transthoracic echocardiography (TTE) performed 1 year and 2 years post-bioprosthetic AV replacement repeatedly demonstrated an AV closed during all cardiac cycles without incompetence and nil flow through the left ventricular outflow tract (LVOT). Following transplant, analysis of explanted heart revealed a fused AV. A pannus adherent to the underside of the AV had formed across the entire AV outlet, with complete obliteration of LVOT. This subaortic pannus was not visualized on previous TTE. Histologically, the pannus consisted of hypocellular fibrous tissue with chronic inflammatory cells, spindle histiocytes, and myofibroblasts scattered throughout the loose fibromyxoid stroma, the latter highlighted on CD68 immunohistochemical stain (IHC). Partial endothelialization on the pannus surface was highlighted on ERG and CD31 IHC. Neither calcification nor signs of acute inflammation were noted. In contrast to previous cases, there was no evidence of associated thrombus macroscopically or microscopically. Discussion: Prolonged LVAD support may facilitate subaortic pannus following bioprosthetic AV replacement due to AV closure and altered transvalvular flow. Due to the parallel LVAD circulation, subaortic pannus may develop asymptomatically, without haemodynamic compromise, allowing progression to total LVOT obstruction. This requires consideration prior to LVAD explantation in bridge-to-recovery patients.

Background: The impact of continuous flow resulting from contemporary left ventricular assist devices (LVAD) on renal vascular physiology is unknown. Renal resistive index (RRI) reflects arterial compliance, as well as renal vascular resistance, contributed by afferent and efferent arteriolar tone, the renal interstitium as well as renal venous pressures.Methods: Prospective, single center study with renal Doppler evaluation at baseline (pre‐implant) and at 3‐months support. Outcomes assessed include need for post‐operative renal replacement therapy (RRT), worsening renal function (WRF) defined as persistent increase from pre‐implant KDIGO chronic kidney disease stage, right ventricular (RV) failure, and survival to transplantation.Results: Pre‐implant RRI did not predict cardiorenal outcomes including right heart failure, need for renal replacement therapy or worsening renal function. Post‐implant RRI was significantly lower than pre‐implant RRI, with a distinct Doppler waveform characteristic of continuous flow. Post‐implant renal end‐diastolic velocity, but not RRI, correlated strongly with LVAD flow (Spearman rho −0.99, p < 0.001), with trend toward correlation with mean arterial pressure (Spearman's rho 0.63, p = 0.129). There was a negative correlation between post‐implant RRI and mean pulmonary artery pressure (Spearman's rho −0.81, p = 0.049), likely driven by elevated pulmonary capillary wedge pressure (Spearman's rho −0.83, p = 0.058).Conclusion: The hemodynamic contributors to RRI in LVAD supported patients are complex. Higher mean pulmonary artery and pulmonary capillary wedge pressures seen in lower RRI may reflect a smaller difference in systolic and diastolic flow. Future simultaneous Doppler assessment of the LVAD outflow graft and RRI may help understand the hemodynamic interactions contributing to this index.