R. Ray Morrison

Adenosine Receptors and the Heart: Role in Regulation of Coronary Blood Flow and Cardiac Electrophysiology

Adenosine is an autacoid that plays a critical role in regulating cardiac function, including heart rate, contractility, and coronary flow. In this chapter, current knowledge of the functions and mechanisms of action of coronary flow regulation and electrophysiology will be discussed. Currently, there are four known adenosine receptor (AR) subtypes, namely A(1), A(2A), A(2B), and A(3). All four subtypes are known to regulate coronary flow. In general, A(2A)AR is the predominant receptor subtype responsible for coronary blood flow regulation, which dilates coronary arteries in both an endothelial-dependent and -independent manner. The roles of other ARs and their mechanisms of action will also be discussed. The increasing popularity of gene-modified models with targeted deletion or overexpression of a single AR subtype has helped to elucidate the roles of each receptor subtype. Combining pharmacologic tools with targeted gene deletion of individual AR subtypes has proven invaluable for discriminating the vascular effects unique to the activation of each AR subtype. Adenosine exerts its cardiac electrophysiologic effects mainly through the activation of A(1)AR. This receptor mediates direct as well as indirect effects of adenosine (i.e., anti-beta-adrenergic effects). In supraventricular tissues (atrial myocytes, sinuatrial node and atriovetricular node), adenosine exerts both direct and indirect effects, while it exerts only indirect effects in the ventricle. Adenosine exerts a negative chronotropic effect by suppressing the automaticity of cardiac pacemakers, and a negative dromotropic effect through inhibition of AV-nodal conduction. These effects of adenosine constitute the rationale for its use as a diagnostic and therapeutic agent. In recent years, efforts have been made to develop A(1)R-selective agonists as drug candidates that do not induce vasodilation, which is considered an undesirable effect in the clinical setting.

Changes in outcomes (1996-2004) for pediatric oncology and hematopoietic stem cell transplant patients requiring invasive mechanical ventilation

Objective: To assess the following hypotheses regarding mechanically ventilated pediatric oncology patients, including those receiving hematopoietic stem cell transplant (HSCT) and those not receiving HSCT: 1) outcomes are more favorable for nontransplant oncology patients than for those requiring HSCT; 2) outcomes have improved for both populations over time; and 3) there are factors available during the time of mechanical ventilation that identify patients with a higher likelihood of dying. Design: Retrospective review. Setting: Free-standing, tertiary care, pediatric hematology oncology hospital. Patients: All patients requiring invasive mechanical ventilation with a diagnosis of cancer or following HSCT from January 1996 to December 2004. Interventions: Bivariate and multivariate analysis. Dates of admission were grouped into time periods for analysis: 1996–1998, 1999–2001, and 2002–2004. Measurements and Main Results: There were 401 courses of mechanical ventilation (329 patients) analyzed. Forty-five percent of HSCT admissions (92 of 206) vs. 75% of non-HSCT oncology admissions (146 of 195) were extubated and discharged from the pediatric intensive care unit (p < .0001). Twenty-five percent of HSCT vs. 60% of non-HSCT admissions survived 6 months (p < .0001). Among admissions with an abnormal chest radiograph and a Pao2/Fio2 ratio <200, pediatric intensive care unit survival increased for each successive time period, with 45% of HSCT and 83% of non-HSCT admissions surviving during 2002–2004. In multivariate analysis of all study patients, Pediatric Risk of Mortality scores on the day of intubation, allogeneic HSCT, cardiovascular failure, hepatic failure, neurologic failure, a previous course of mechanical ventilation within 6 months, and the time period intubated were associated with mortality. With the exception of time period, these same variables were associated with mortality in multivariate analysis of only HSCT patients. Conclusions: HSCT patients who require mechanical ventilation have worse outcomes than non-HSCT oncology patients. Outcomes for both groups have improved over time. Allogeneic transplant, higher Pediatric Risk of Mortality scores, need for repeated mechanical ventilation, and concomitant organ system dysfunction are risk factors for death.

Endogenous adenosine increases coronary flow by activation of both A2A and A2B receptors in mice.

To clarify which adenosine receptor subtype(s) are responsible for regulation of coronary flow through endogenous adenosine, coronary vascular responses were examined in isolated hearts from wild-type (WT) and A2A knockout (A2AKO) mice. Adenosine deaminase inhibitor, erythro-9-hydroxy-nonyl-adenine (EHNA), and adenosine kinase inhibitor, iodotubericidine (ITU), were used to examine the effects of endogenous adenosine. Combined infusion of EHNA and ITU in Balb/c hearts produced comparable increases in coronary flow as exerted by exogenous adenosine while they markedly decreased the heart rate, and these effects were reversed by adenosine receptor antagonist, 8-p-sulfophenyl-theophylline (8-SPT). Similarly, EHNA and ITU increased coronary flow in WT hearts to 422% of baseline, whereas this response was reduced to 144% of baseline in A2AKO hearts. Heart rate was equally reduced (approximately 50% of baseline) in both groups. Alloxazine (A2B receptor antagonist) abolished EHNA- and ITU-induced coronary flow in A2AKO hearts without altering the reduced heart rate. Selective A1 receptor antagonist, 8-cyclopentyl-1–1,3-dipropylxanthine (DPCPX), reversed EHNA- and ITU-induced decreases in heart rate without altering the elevated coronary flow. These findings suggest that coronary vascular responses to endogenous adenosine mimic those produced by exogenous adenosine and are mediated at least by activation of both A2A and A2B receptors in isolated mouse hearts.

Outcomes of hematopoietic stem cell transplant patients who received continuous renal replacement therapy in a pediatric oncology intensive care unit

Objectives: To assess the long-term benefits of continuous renal replacement therapy (CRRT) in this patient population and to analyze factors associated with survival. Hematopoietic stem cell transplantation is being utilized as curative therapy for a variety of disorders. However, organ dysfunction is commonly associated with this therapy. Continuous renal replacement therapy (CRRT) is increasingly being used in the treatment of this multiorgan dysfunction. Design: Retrospective cohort study. Setting: A free-standing, tertiary care, pediatric oncology hospital. Patients: Twenty-nine allogeneic hematopoietic stem cell transplantation patients who underwent 33 courses of CRRT in the intensive care unit between January 2003 and December 2007. Interventions: Cox proportional hazards regressions models were used to examine the relationship between demographic and clinical variables and length of survival. Measurements and Main Results: The median length of survival post CRRT initiation was 31 days; only one patient survived >6 mos. Factors associated with increased risk of death included: higher bilirubin and blood urea nitrogen levels before and at 48 hrs into CRRT, lower Pao2/Fio2 ratios at 48 hrs of CRRT, and higher C-reactive protein levels, as well as lower absolute neutrophil counts at CRRT end. Conclusion: In this single-center study, CRRT was not associated with long-term survival in pediatric allogeneic hematopoietic stem cell transplantation patients. Clinical data exist, both before and during CRRT, that may be associated with length of survival. Lower C-reactive protein levels at CRRT end were associated with longer survival, suggesting that the ability to attenuate inflammation during CRRT may afford a survival advantage. These findings require confirmation in a prospective study. (Pediatr Crit Care Med 2010; 11:699–706)

Effect of cardiac A1 adenosine receptor overexpression on sarcoplasmic reticulum function

OBJECTIVE We investigated the effect of A(1) adenosine receptor overexpression, which has been reported to increase myocardial tolerance to ischemia-reperfusion injury, on sarcoplasmic reticulum (SR) Ca(2+) handling. METHODS Transgenic mouse hearts (approximately 300-fold A(1) adenosine receptor overexpression) and wild-type mouse hearts were perfused in the Langendorff mode and subjected either to 80 min of aerobic perfusion or to 30 min of aerobic perfusion, 20 min of global ischemia and 30 min of reperfusion. The hearts were then homogenized and used to assay SR oxalate-supported 45Ca(2+) uptake and [3H]-ryanodine binding. RESULTS Transgenic hearts showed increased resistance to ischemia-reperfusion, as shown by lower diastolic tension (1.5 +/- 0.2 vs. 2.6 +/- 0.1 g, P<0.05) and higher recovery of developed tension (45 +/- 3 vs. 30 +/- 4% of the baseline, P<0.05) following ischemia-reperfusion. Under baseline conditions, oxalate-supported 45Ca(2+) uptake was lower in transgenic hearts, owing to reduced V(max) (10.6 +/- 2.0 vs. 17.8 +/- 2.7 nmol/min per mg of protein, P<0.05), and the difference was preserved after ischemia-reperfusion (10.0 +/- 1.0 vs. 15.7 +/- 2.5 nmol/min per mg of protein, P<0.05). No significant difference in [3H]-ryanodine binding was observed. CONCLUSIONS A(1) adenosine receptor overexpression is associated with a decreased rate of active Ca(2+) transport into the SR. We hypothesize that changes in SR function may cause a depletion of the SR Ca(2+) pool, which might protect from ischemic injury by delaying the development of cytosolic Ca(2+) overload during ischemia.

Clinical Outcomes of Children Receiving Intensive Cardiopulmonary Support During Hematopoietic Stem Cell Transplant

Objective: We investigated the short-term and 1-year clinical outcomes of 129 children who received intensive cardiopulmonary support during hematopoietic stem cell transplant. Intensive cardiopulmonary support was defined as receiving at least one of the following interventions: continuous positive pressure ventilation, dopamine infusion greater than or equal to 10 mcg/kg/minute, or the use of any other vasoactive infusion. Duration of intensive cardiopulmonary support, survival to hospital discharge, and predictors of these outcome variables were compared with 387 hematopoietic stem cell transplant patients who did not receive intensive support during the same period. We also report the 1-year survival; presence of chronic graft-versus-host disease; and renal, cardiac, and pulmonary function for all patients. Design: A multicenter retrospective cohort study. Setting: The ICU and hematopoietic stem cell transplant unit of nine pediatric tertiary care centers. Patients: Children undergoing hematopoietic stem cell transplant who required intensive cardiopulmonary support. Interventions: None. Results: Predictors of the need for intensive support included unrelated donor allogeneic transplant, glomerular filtration rate less than 85 mL/minute/1.73 m2, and nonmalignant disease as the indication for transplant. The survival to discontinuation of intensive support for all patients was 62% and 58% for patients who received invasive mechanical ventilatory support. The duration of mechanical ventilation was not predictive of survival. Predictors of intensive support mortality included macroscopic bleeding, engraftment, and pediatric logistic organ dysfunction score greater than one in two domains. Survival to hospital discharge was 50% for the intensive support group and 99% for the nonintensive support group. Overall 1-year survival was 40% in the intensive support population and 65% in the nonintensive support group. There were no significant differences in the survival, rates of chronic graft-versus-host disease, creatinine, forced expiratory volume in 1-minute, cardiac shortening fraction, or performance status in intensive and nonintensive support patients who survived to hospital discharge. Conclusion: Intensive cardiopulmonary support plays an important and potentially life-saving role in the care of pediatric stem cell transplant patients. Survivors of intensive support do not have compromised 1-year survival or organ function compared with children who did not receive intensive support.

Impact of continuous renal replacement therapy on oxygenation in children with acute lung injury after allogeneic hematopoietic stem cell transplantation

Acute lung injury (ALI) continues to carry a high mortality rate in children after allogeneic hematopoietic stem cell transplant (HSCT). Continuous renal replacement therapy (CRRT) is often used for these patients for various indications including renal failure and fluid overload, and may have a beneficial effect on oxygenation and survival. Therefore, we sought to determine the effect of CRRT on oxygenation in mechanically ventilated pediatric allogeneic HSCT patients with ALI, and to document survival to intensive care unit discharge in this at‐risk population receiving both mechanical ventilation and CRRT.

Continuous venovenous hemodiafiltration in hypernatremic hyperglycemic nonketotic coma

Abstract. Rapid changes in serum sodium concentration can result in adverse neurological outcome. The gradual correction of hypernatremia in the setting of acute renal failure can be difficult to achieve. We describe an obese female teenager who presented with severe hypernatremia, hyperosmolar hyperglycemic nonketotic coma, acute renal failure, and rhabdomyolysis. Her hypernatremia and other serum chemistries were gradually corrected by repeatedly adjusting the dialysate electrolyte composition used during continuous venovenous hemodiafiltration. She had a full recovery of her renal function. She does not have clinical neurological sequelae from hypernatremia during a 1-year follow-up period.

Protection from Doxorubicin-Induced Cardiomyopathy Using the Modified Anthracycline N-Benzyladriamycin-14-valerate (AD 198)

The anthracycline doxorubicin (Dox) is an effective antitumor agent. However, its use is limited because of its toxicity in the heart. N-Benzyladriamycin-14-valerate (AD 198) is a modified anthracycline with antitumor efficacy similar to that of Dox, but with significantly less cardiotoxicity and potentially cardioprotective elements. In the present study, we investigated the possibility of in vivo protective effects of low-dose AD 198 against Dox-induced cardiomyopathy. To do this, rats were divided into four groups: vehicle, Dox (20 mg/kg; single injection day 1), AD 198 (0.3 mg/kg per injection; injections on days 1, 2, and 3), or a combination treatment of Dox + AD 198. Seventy-two hours after beginning treatment, hearts from the Dox group had decreased phosphorylation of AMP kinase and troponin I and reduced poly(ADP-ribose) polymerase, β-tubulin, and serum albumin expression. Dox also increased the phosphorylation of phospholamban and expression of inducible nitric-oxide synthase in hearts. Each of these Dox-induced molecular changes was attenuated in the Dox + AD 198 group. In addition, excised hearts from rats treated with Dox had a 25% decrease in left ventricular developed pressure (LVDP) and a higher than normal increase in LVDP when perfused with a high extracellular Ca2+ solution. The Dox-induced decrease in baseline LVDP and hyper-responsiveness to [Ca2+] was not observed in hearts from the Dox + AD 198 group. Thus Dox, with well established and efficient antitumor protocols, in combination with low levels of AD 198, to counter anthracycline cardiotoxicity, may be a promising next step in chemotherapy.

Severe H1N1-associated acute respiratory failure in immunocompromised children†

Severe pandemic influenza A (H1N1) infection can lead to acute respiratory failure (ARF) with associated high mortality. Children with malignancy may be at higher risk of H1N1‐associated ARF because of underlying primary disease or immunosuppression associated with chemotherapy.