Surviving the Struggle of COVID-19: Practical Recommendations for Pediatric/Adult Cardiology and Cardiac Surgical Programs in Resource-Limited Settings: a Review.

INTRODUCTION: The primary aim of this systematic review is to provide perioperative strategies to help restore or preserve cardiovascular services under threat from financial and personnel constraints imposed by the coronavirus disease 2019 (COVID-19) pandemic. METHODS: The Medical Literature Analysis and Retrieval System Online, Excerpta Medica dataBASE, Cochrane Central Register of Controlled Trials/CCTR, and Google Scholar were systematically searched using the search terms "(cardiac OR cardiology OR cardiothoracic OR surgery) AND (COVID-19 or coronavirus OR SARS-CoV-2 OR 2019-nCoV OR 2019 novel coronavirus OR pandemic)". Additionally, the webpages of relevant medical societies, including the World Federation Society of Anesthesiologists, the Cardiothoracic Surgery Network, and the Society of Thoracic Surgeons, were screened for relevant information. RESULTS: Whereas cardiac surgery and cardiology practices were reduced by 50-75% during the pandemic, mortality of patients with COVID-19 increased significantly. Healthcare workers are among those at high risk of infection with COVID-19. CONCLUSION: Hospitals must provide maximum protective equipment and training on how to use it to healthcare workers for their mutual protection. Triage management of patients - which accounts for patient's clinical status and risk-factor profile relatable to which services are available during the COVID-19 pandemic - is recommended. A strict reorganization of the hospital resources including preoperative, intraoperative, and postoperative detailed protective measures is necessary to reduce probability of vector contamination, to protect patients and the cardiovascular teams, and to permit safe resumption of cardiological and cardiac surgical activity.

Surviving the Struggle of COVID-19: Practical Recommendations for Pediatric/Adult Cardiology and Cardiac Surgical Programs in Resource-Limited Settings: a Review

ABSTRACT Introduction: The primary aim of this systematic review is to provide perioperative strategies to help restore or preserve cardiovascular services under threat from financial and personnel constraints imposed by the coronavirus disease 2019 (COVID-19) pandemic. Methods: The Medical Literature Analysis and Retrieval System Online, Excerpta Medica dataBASE, Cochrane Central Register of Controlled Trials/CCTR, and Google Scholar were systematically searched using the search terms "(cardiac OR cardiology OR cardiothoracic OR surgery) AND (COVID-19 or coronavirus OR SARS-CoV-2 OR 2019-nCoV OR 2019 novel coronavirus OR pandemic)". Additionally, the webpages of relevant medical societies, including the World Federation Society of Anesthesiologists, the Cardiothoracic Surgery Network, and the Society of Thoracic Surgeons, were screened for relevant information. Results: Whereas cardiac surgery and cardiology practices were reduced by 50-75% during the pandemic, mortality of patients with COVID-19 increased significantly. Healthcare workers are among those at high risk of infection with COVID-19. Conclusion: Hospitals must provide maximum protective equipment and training on how to use it to healthcare workers for their mutual protection. Triage management of patients — which accounts for patient's clinical status and risk-factor profile relatable to which services are available during the COVID-19 pandemic — is recommended. A strict reorganization of the hospital resources including preoperative, intraoperative, and postoperative detailed protective measures is necessary to reduce probability of vector contamination, to protect patients and the cardiovascular teams, and to permit safe resumption of cardiological and cardiac surgical activity.

Preoperative platelet dysfunction predicts blood product transfusion in children undergoing cardiac surgery.

OBJECTIVES: Excessive bleeding can be a problem during or after cardiac surgery. While cardiopulmonary bypass-associated platelet dysfunction is an important inducer of coagulopathy, preoperative platelet dysfunction can also contribute to this bleeding. We investigated the relationship between preoperative platelet dysfunction and transfusion of blood products given to children undergoing cardiac surgery. METHODS: The platelet function analyser test measures platelet function in vitro by aspirating blood through a small standard hole (creating high shear) in a collagen membrane infused with a platelet agonist. The time taken to form a platelet plug is known as closure time and prolonged closure time (CT) indicates platelet dysfunction. Three hundred and thirty-eight children who had undergone surgery with cardiopulmonary bypass between 2008 and 2012 were included. The volume of red blood cells and fresh-frozen plasma transfused was recorded. The relationship between closure time and transfusion requirements was analysed using linear and logistic regression. RESULTS: Patients with prolonged closure time had greater odds of getting red blood cells and fresh-frozen plasma transfusions compared with patients with normal closure time (P <0.01). On univariate analysis, age, weight, haematocrit, cardiopulmonary bypass time, Risk Adjustment for Congenital Heart Surgery score and closure time were associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre (P <0.05). However, when logistic multivariable regression analysis was applied, only age, cardiopulmonary bypass time and closure time remained as significant predictive factors for transfusion. CONCLUSIONS: In children who have undergone cardiac surgery, when age and cardiopulmonary bypass time are accounted for, a prolonged preoperative closure time is significantly associated with increased odds of red blood cells and fresh-frozen plasma transfusion in the operation theatre. This may have implications for planning and utilization of blood products.

Congenital cardiac lesions involving systolic flow abnormalities are associated with platelet dysfunction in children.

BACKGROUND: Shear stress-induced platelet dysfunction (PD) is prevalent among adults with aortic stenosis. Our aim was to determine whether abnormal platelet function was associated with specific congenital cardiac lesions in children. METHODS: The charts of 407 children who had undergone cardiopulmonary bypass and had preoperative platelet function analysis were evaluated. Patients were assigned to 1 of 11 different lesion categories. Platelet dysfunction (PD) was defined as prolonged closure time (CT) as measured with a platelet function analyzer. Odds ratio (OR) estimates for prolonged CT were calculated for each lesion category. Mean CTs were compared with Tukey-Kramer separated means testing. Analysis of variance modeling was used to determine association between hematocrit value and CT. RESULTS: CT in patients with ventricular septal defects (VSD) and right ventricular outflow tract obstruction (RVOTO) lesions was prolonged. OR analysis found that patients with VSDs (OR, 2.46) or RVOTO (OR, 2.88) had at least a 95% probability of an abnormal CT. In contrast, patients with atrial septal defect (ASD), bidirectional Glenn procedure (BDG), and pulmonary insufficiency (PI) had a reduced probability of a prolonged CT (p < 0.05). A similar pattern was seen in parametric analysis comparing mean CTs across lesion categories. A lower preoperative hematocrit value was associated with prolonged CTs across all lesion types (p < 0.05). CONCLUSIONS: PD was common in children with congenital cardiac lesions involving systolic flow abnormalities and was uncommon among children with lesions having diastolic abnormalities. Lower preoperative hematocrit values were associated with prolonged CTs, suggesting subclinical bleeding secondary to excessive platelet shearing.

Fatal carboplatin-induced immune hemolytic anemia in a child with a brain tumor.

Drug-induced immune hemolytic anemia (DIIHA) is an uncommon side effect of pharmacologic intervention. A rare mediator of DIIHA, carboplatin is an agent used to treat many pediatric cancers. We describe here, the first case of fatal carboplatin induced DIIHA in a pediatric patient and a brief review of the literature. Our patient developed acute onset of multi-organ failure with evidence of complement activation, secondary to a drug induced red cell antibody. Early recognition of the systemic insult associated with carboplatin induced hemolytic anemia may allow for future affected patients to receive plasmapheresis, a potentially effective therapy.

The optimal hematocrit.

Nearly 15 million units of packed red blood cells and whole blood are transfused annually in the United States alone. Until recently, the major risks from blood transfusion were thought to be transmission of viral infections, and overall, blood transfusion was believed by most providers to be safe. A safe hemoglobin threshold above which red cell transfusion is clearly unnecessary has not been established. This article addresses the numerous problems that surround the use and consequences of blood transfusion, such as hemoglobin and hematocrit levels, oxygenation, storage time, immunomodulation, infection, and anemia. The relevant literature is comprehensively reviewed.

Use of leukoreduced blood does not reduce infection, organ failure, or mortality following trauma.

BACKGROUND: Leukoreduced (LR) blood has been demonstrated to reduce morbidity and mortality in high-risk surgical patients, but not in trauma patients. The objective of the present study was to determine the effect of LR blood on morbidity and mortality. We hypothesized that the use of LR blood does not improve outcome in trauma patients. METHODS: This study was a retrospective cohort analysis of trauma patients transfused at a level 1 Trauma Center from 2001 to 2004. Between 2002 and 2003, LR blood was transfused. Prior to that time and subsequent to it, non-leukoreduced (NLR) blood was transfused. This created two historical comparison groups. Data collected included patient demographics, units of blood transfused, intensive care unit (ICU) and hospital days, ventilator days, injury severity score (ISS), mortality, presence of acute respiratory distress syndrome (ARDS), and infectious complications. A multiple organ dysfunction syndrome (MODS) score was calculated. RESULTS: The distribution of patients was as follows: 284 patients received only NLR blood, 153 received only LR blood, and 58 received at least one unit of each. The mean ISS was similar (NLR: 26, LR: 24; P > 0.1). No differences were seen between groups in units transfused (6.2 vs. 5.5), number of ICU days (8.2 vs. 9.0), number of hospital days (16.9 vs. 18.6), number of ventilator days (6.1 vs. 5.7), incidence of ARDS (8.3% vs. 8.5%), MODS score (5.5 vs. 5.9), mortality rate (15.1% vs. 15.7%), or infection rate (36% vs. 30%) (P > 0.1). CONCLUSIONS: This study represents the largest series comparing trauma patients who received either LR or standard blood transfusions. The use of LR blood does not improve outcome in trauma patients.

gammaA/gamma' fibrinogen inhibits thrombin-induced platelet aggregation.

The minor gammaA/gamma' fibrinogen isoform contains a high affinity binding site for thrombin exosite II that is lacking in the major gammaA/gammaA fibrinogen isoform. We therefore investigated the biological consequences of the gamma' chain binding to thrombin. Thrombin-induced platelet aggregation was inhibited by gammaA/gamma' fibrinogen. Carboxyl terminal peptide fragment gamma'410-427 from the gamma' chain was also inhibitory, with an IC(50) of approximately 200 microM in whole plasma. Deletion of the peptide from either the amino or carboxyl end significantly decreased inhibition. In contrast to thrombin-induced platelet aggregation, aggregation induced by epinephrine, ADP, arachidonic acid, or SFLLRN peptide showed little inhibition by the gamma' peptide. The inhibition of thrombin-induced platelet aggregation was not due to direct inhibition of the thrombin active site, since cleavage of a small peptidyl substrate was 91% of normal even in the presence of 1 mM gamma'410-427. The gamma'410-427 peptide blocked platelet adhesion to immobilized thrombin under both static and flow conditions, blocked soluble thrombin binding to platelet GPIbalpha, and inhibited PAR1 cleavage by thrombin. These results suggest that the gamma' chain of fibrinogen inhibits thrombin-induced platelet aggregation by binding to thrombin exosite II. Thrombin that is bound to the gamma' chain is thereby prevented from activating platelets, while retaining its amidolytic activity.

Hemorrhagic disease of the newborn despite vitamin K prophylaxis at birth.

Late hemorrhagic disease of the newborn (HDN) presents 0.5-6 months after birth with mucocutaneous and intracranial bleeding. We describe here two cases of late HDN in infants who received vitamin K. The first case is a previously healthy breastfed male who received one dose of oral vitamin K at birth and developed an intracranial hemorrhage 5 weeks later. He was treated with intravenous vitamin K and recombinant factor VIIa prior to emergent craniectomy. An unrelated infant presented at 5 months of age with diarrhea and easy bruising despite IM vitamin K at birth. These cases illustrate the morbidity associated with late HDN.

Fibrinogen gamma' chain carboxy terminal peptide selectively inhibits the intrinsic coagulation pathway.

The minor gammaA/gamma' isoform of fibrinogen contains a high affinity binding site for thrombin exosite II that is lacking in the major fibrinogen isoform, gammaA/gammaA fibrinogen. The biological consequences of gamma' chain binding to thrombin were therefore investigated. Coagulation assays, thrombin activity assays, and a primate thrombosis model were used to characterize the biological effects of the gamma' 410-427 peptide. The gamma' peptide had little effect on thrombin cleavage of the small peptidyl substrate tosyl-glycyl-prolyl-arginine-4-nitranilide acetate. However, in vitro assays demonstrated that the gamma' peptide inhibited thrombin cleavage of larger proteinaceous substrates, including fibrinogen and factor VIII. The gamma' peptide inhibited the activated partial thromboplastin time in plasma and showed greater inhibition of activated partial thromboplastin time assays than prothrombin time assays, consistent with the inhibition of factor VIII cleavage. Studies in a baboon thrombosis model showed that the gamma' 410-427 peptide inhibited fibrin-rich thrombus formation (typical of venous thrombi) and, to a lesser extent, platelet-rich thrombus formation (typical of arterial thrombi). These results indicate that binding of thrombin exosite II by the gamma' peptide has selective effects on the intrinsic pathway.

Clinical outcomes of palliative surgery including a systemic-to-pulmonary artery shunt in infants with cyanotic congenital heart disease: does aspirin make a difference?

BACKGROUND: Aspirin (ASA) often is used to prevent thrombosis in infants with congenital heart disease after placement of a systemic-to-pulmonary artery shunt, but its effect on outcomes is unknown. METHODS AND RESULTS: The present multicenter study prospectively collected data on 1-year postoperative rates of death, shunt thrombosis, or hospitalization age <4 months for bidirectional Glenn/hemi-Fontan surgery in 1004 infants. The use and dose of ASA were recorded. Kaplan-Meier event rates were calculated for each event and the composite outcome, and a Cox regression model was constructed for time to event. Model terms were ASA use and type of surgery, with adjustment for age at surgery. Diagnoses were hypoplastic left heart syndrome (n=346), tricuspid atresia (n=103), tetralogy of Fallot (n=127), pulmonary atresia (n=177), heterotaxy syndrome (n=38), and other (n=213). There were 344 shunts placed without cardiopulmonary bypass (closed shunt), 287 shunts with bypass (open shunt), 323 Norwood procedures, and 50 Sano procedures. Overall, 80% of patients received ASA. One-year postoperative events rates were high: 38% for the composite end point, 26% for death, and 12% for shunt thrombosis. After the exclusion of patients with early mortality, patients receiving ASA had a lower risk of shunt thrombosis (hazard ratio, 0.13; P=0.008) and death (closed shunt: hazard ratio, 0.41, P=0.057; open shunt: hazard ratio, 0.10, P<0.001; Norwood: hazard ratio, 0.34, P<0.001; Sano: hazard ratio, 0.68, P=NS) compared with those not receiving ASA. CONCLUSIONS: The morbidity and mortality for infants after surgical placement of a systemic-to-pulmonary artery shunt are high. ASA appears to lower the risk of death and shunt thrombosis in the present observational study.

Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is a form of posttransfusion acute pulmonary insufficiency that has been linked to the infusion of biologic response modifiers (BRMs), including antileukocyte antibodies and lipids. Soluble CD40 ligand (sCD40L) is a platelet-derived proinflammatory mediator that accumulates during platelet storage. We hypothesized that human polymorpho-nuclear leukocytes (PMNs) express CD40, CD40 ligation rapidly primes PMNs, and sCD40L induces PMN-mediated cytotoxicity of human pulmonary microvascular endothelial cells (HMVECs). Levels of sCD40L were measured in blood components and in platelet concentrates (PCs) implicated in TRALI or control PCs that did not elicit a transfusion reaction. All blood components contained higher levels of sCD40L than fresh plasma, with apheresis PCs evidencing the highest concentration of sCD40L followed by PCs from whole blood, whole blood, and packed red blood cells (PRBCs). PCs implicated in TRALI reactions contained significantly higher sCD40L levels than control PCs. PMNs express functional CD40 on the plasma membrane, and recombinant sCD40L (10 ng/mL-1 mug/mL) rapidly (5 minutes) primed the PMN oxidase. Soluble CD40L promoted PMN-mediated cytotoxicity of HMVECs as the second event in a 2-event in vitro model of TRALI. We concluded that sCD40L, which accumulates during blood component storage, has the capacity to activate adherent PMNs, causing endothelial damage and possibly TRALI in predisposed patients.

Recognition and management of heparin-induced thrombocytopenia in pediatric cardiopulmonary bypass patients.

Repeated exposure to unfractionated heparin is the rule in many congenital heart disease patients. Heparin-induced thrombocytopenia occurs in 1% to 3% of adult cardiac surgeries, and carries high thrombotic morbidity (38% to 81%) and mortality (approximately 28%). Although heparin-induced thrombocytopenia appears to be infrequent in pediatric patients, particularly neonates, our evolving experience suggests postcardiopulmonary bypass congenital heart disease patients may be at increased risk. Diagnostic and therapeutic challenges include frequency of thrombocytopenia after cardiopulmonary bypass, imperfect laboratory testing, lack of established dosing of alternative anticoagulants (such as argatroban and lepirudin), and increased anticoagulant-related bleeding in young children.

Cardiopulmonary bypass using argatroban as an anticoagulant for a 6.0-kg pediatric patient.

A patient was born with transposition of the great arteries, double-outlet right ventricle, interrupted aortic arch, and a ventricular septal defect and underwent a Damus-Kaye-Stansel procedure with a modified Blalock-Taussig shunt at 14 days old. Three months later, this patient presented with hypoxia and bradycardia was found to have a thrombus present in the main pulmonary artery extending to right pulmonary artery. After initiation of thrombolytic therapy, the patient became severely hypoxic and required the institution of extracorporeal membrane oxygenation. As the result of unknown heparin resistance independent of adequate antithrombin III levels, argatroban therapy was used to achieve desired anticoagulation. The patient was taken to the operating room and converted to conventional cardiopulmonary bypass once adequate activated clotting times were achieved using argatroban. This case report summarizes the use of argatroban as an anticoagulant for a 6.0-kg pediatric patient undergoing cardiopulmonary bypass.

Heparin-induced thrombocytopenia in neonates.

Heparin-induced thrombocytopenia (HIT), an immune-mediated response to heparin administration, has been recognized in adults for some time, but only recently recognized in neonates and children. HIT Type I is a mild, self-limiting condition. HIT type II is a severe immune reaction to heparin that leads to thrombocytopenia and often thromboembolic complications. The incidence of HIT Type II is 2-5 percent in adults on heparin products and may be as high in neonates and children. The mortality rate from HIT in adults is 7-30 percent and is unknown but potentially high in newborns as well. The cardinal sign of HIT is a drop in platelet count by 50 percent or platelet counts below 70,000-100,000/mm3. This drop usually occurs five to ten days after the first exposure to heparin. Treatment is immediate cessation of all heparin therapy and initiation of alternative anticoagulants, especially the direct thrombin inhibitors lepirudin and argatroban. This article reviews the literature on HIT and presents a case of neonatal HIT following heart surgery.

Transfusion-related acute lung injury and the ICU.

Transfusion-related acute lung injury (TRALI) has been the leading cause of transfusion-related deaths reported to the United States Food and Drug Administration for three consecutive years. Although traditionally TRALI has been viewed as having a one event pathogenesis (passive donor anti-leukocyte antibody interacting with a cognate antigen on the recipients leukocytes), emerging evidence suggests that TRALI is a multifactorial syndrome, and a true two-event subtype of ALI. Both recipient predisposition and biological response modifiers, generated during storage of cellular blood products, appear to play major pathogenetic roles. This review highlights recent advances in our knowledge of the pathophysiology of TRALI and recent progress towards a consensus definition of TRALI. It also guides the reader as to the recognition, investigation, and clinical management of TRALI.

Sustained engraftment post bone marrow transplant despite anti-platelet antibodies in Glanzmann thrombasthenia.

BACKGROUND: Patients with Glanzmann thrombasthenia (GT) have normal platelet counts but abnormal platelet aggregation and carry the risk of life-threatening bleeding. We report three patients who received bone marrow transplantation (BMT) for type I GT and discuss the risk and management of anti-platelet antibodies. PATIENTS AND RESULTS: Diagnosis of GT was made through abnormal platelet aggregation studies or the absence of GPIIb/IIIa by flow cytometry. All patients had severe bleeding requiring multiple red blood cell transfusions. One patient received an unrelated donor transplant and two received matched sibling donor transplants following conditioning therapy with busulfan, cyclophosphamide, and fludarabine. Two patients developed an anti-platelet antibody, treated in one with intravenous immune globulin (IVIG). Engraftment of white blood cells and platelets was achieved on day +13 to +14 and +17 to +25, respectively. Complete donor chimerism and GPIIb/IIIa+ platelets are sustained at +22 to +30 months post transplant. CONCLUSIONS: In summary, patients with GT and history of severe hemorrhage can be cured with BMT, but the presence of anti-platelet antibodies should be sought and platelet transfusions minimized prior to transplant. IVIG may be helpful in cases of refractory immune thrombocytopenia related to anti-platelet antibodies. Improvement in transplant-related complications with current transplant regimens allows consideration of BMT for life-threatening non-malignant disorders such as GT.

Transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is a life-threatening adverse effect of transfusion that is occurring at increasing incidence in the United States and that, in the past 2 reporting years, has been the leading cause of transfusion-related death. TRALI and acute lung injury (ALI) share a common clinical definition except that TRALI is temporally and mechanistically related to the transfusion of blood/blood components. In prospective studies, 2 patient groups, 1 requiring cardiac surgery and 1 with hematologic malignancies and undergoing induction chemotherapy, were predisposed. Two different etiologies have been proposed. The first is a single antibody-mediated event involving the transfusion of anti-HLA class I and class II or antigranulocyte antibodies into patients whose leukocytes express the cognate antigens. The second is a 2-event model: the first event is the clinical condition of the patient resulting in pulmonary endothelial activation and neutrophil sequestration, and the second event is the transfusion of a biologic response modifier (including lipids or antibodies) that activates these adherent polymorphonuclear leukocytes (PMNs), resulting in endothelial damage, capillary leak, and TRALI. These hypotheses are discussed, as are the animal models and human studies that provide the experimental and clinical relevance. Prevention, treatment, and a proposed definition of TRALI, especially in the context of ALI, are also examined.

Argatroban usage for anticoagulation for ECMO on a post-cardiac patient with heparin-induced thrombocytopenia.

We report a post-Norwood Stage I patient requiring ECMO support using Argatroban as an anticoagulant following diagnosis of heparin-induced thrombocytopenia (HIT). A 2.6 kg female was born with hypoplastic left heart syndrome and underwent a Norwood Stage I operation on day 4 of life. The patient weaned off cardiopulmonary bypass with no complications and was routinely placed on a ventricular assist device (VAD) for 3 days. Heparin was infused at a rate of 16-32 IU/ kg/h to maintain an ACT of 160-180 seconds. Two days after VAD termination, the patient was placed on continuous veno-veno hemofiltration (CVVH). Shortly after CVVH, the patient was diagnosed with HIT and placed on an Argatroban infusion. Five days later, a VAD and subsequent ECMO was used because of decreasing left ventricular function, gross body edema, and poor renal function. This case report summarizes the use of Argatroban during VAD and ECMO support for a patient diagnosed with HIT.

Heparin-induced thrombocytopenia (HIT) in pediatric cardiac surgery: an emerging cause of morbidity and mortality.

Unfractionated heparin (UFH) is immunogenic, and heparin-dependent antibodies can be demonstrated 5 to 10 days postoperatively in 25% to 50% of adult postcardiac surgery patients. In a minority of these cases (1% to 3% if UFH is continued longer than 1 week) these antibodies strongly activate platelets, causing thrombocytopenia and massive thrombin generation (HIT syndrome). HIT is an intensely procoagulant disorder, and in adult cardiac surgery patients carries both significant thrombotic morbidity (38% to 81%) and mortality (28%). Despite the ubiquitous use of UFH in pediatric intensive care units, and the repeated and sustained exposures to UFH in neonates and young children with congenital heart disease, HIT has been infrequently recognized and reported in this patient population. However, emerging experience at our institution and elsewhere suggests that HIT is significantly under-recognized in pediatric congenital heart disease patients, and may in fact have an incidence and associated thrombotic morbidity and mortality in this patient group comparable to that seen in adult cardiac surgery patients. This article will review HIT in pediatric patients with congenital heart disease and emphasize the special challenges posed in clinical recognition, laboratory diagnosis, and treatment of HIT in this patient group. We will also outline our experience with the off-label use of the direct thrombin inhibitor, argatroban, in pediatric patients with HIT.