Gary D. Ceneviva

Hemodynamic Support in Fluid-refractory Pediatric Septic Shock

Objective. Assess outcome in children treated with inotrope, vasopressor, and/or vasodilator therapy for reversal of fluid-refractory and persistent septic shock. Design. Survey; case series. Setting. Three pediatric hospitals. Patients. Fifty consecutive patients with fluid-refractory septic shock with a pulmonary artery catheter within 6 hours of resuscitation. Interventions. Patients were categorized according to hemodynamic state and use of inotrope, vasopressor, and/or vasodilator therapy to maintain cardiac index (CI) >3.3 L/min/m2 and systemic vascular resistance >800 dyne-sec/cm 5 /m 2 to reverse shock. Outcome Measures. Hemodynamic state, response to class of cardiovascular therapy, and mortality. Results. After fluid resuscitation, 58% of the children had a low CI and responded to inotropic therapy with or without a vasodilator (group I), 20% had a high CI and low systemic vascular resistance and responded to vasopressor therapy alone (group II), and 22% had both vascular and cardiac dysfunction and responded to combined vasopressor and inotropic therapy (group III). Shock persisted in 36% of the children. Of the children in group I, 50% needed the addition of a vasodilator, and in group II, 50% of children needed the addition of an inotrope for evolving myocardial dysfunction. Four children showed a complete change in hemodynamic state and responded to a switch from inotrope to vasopressor therapy or vice versa. The overall 28-day survival rate was 80% (group I, 72%; group II, 90%; group III, 91%). Conclusions. Unlike adults, children with fluid-refractory shock are frequently hypodynamic and respond to inotrope and vasodilator therapy. Because hemodynamic states are heterogeneous and change with time, an incorrect cardiovascular therapeutic regimen should be suspected in any child with persistent shock. Outcome can be improved compared with historical literature.

Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells

Our group recently reported that cultured sheep pulmonary artery endothelial cells (SPAECs) became resistant to lipopolysaccharide (LPS)-induced apoptosis several days after constitutive synthesis of nitric oxide (NO) after adenoviral (Ad) transfer of inducible NO synthase (iNOS) or exposure to the NO donor S-nitroso-N-acetylpenicillamine (SNAP) (E. Tzeng, Y.-M. Kim, B. R. Pitt, A. Lizonova, I. Kovesdi, and T. R. Billiar. Surgery 122: 255-263, 1997). In the present study, we confirmed this observation by establishing stable transfectants after retroviral gene transfer [replication-deficient retrovirus (DFG)] of human iNOS (DFG-iNOS) SPAECs and then used all three approaches (Ad, DFG, and SNAP) to determine underlying mechanisms of this phenomenon. Continuous endogenous production of NO in itself did not cause apoptosis as assessed by phase-contrast microscopy, nuclear morphology, and internucleosomal DNA fragmentation. Prolonged (72-96 h) synthesis of NO, however, after DFG- or replication-deficient adenovirus (Ad. CMV)-iNOS or SNAP (100 microM, 96 h) inhibited LPS-induced apoptosis. The kinetics of such protection suggested that NO may be inducing other gene products. Ad-mediated transfer of manganese superoxide dismutase (MnSOD) decreased the sensitivity of wild-type SPAECs to LPS-induced apoptosis. MnSOD, however, was not induced in an NG-monomethyl-L-arginine (L-NMMA)-sensitive time-dependent fashion after Ad.CMV-iNOS. Other inducible genes that may be affected by NO and that may protect against potential oxidant-mediated LPS-induced apoptosis including 70-kDa heat shock protein, heme oxygenase-1, metallothionein, and Bcl-2 also were not elevated in an L-NMMA-sensitive, time-dependent fashion. Although the candidate gene product underlying NO-induced protection remains unclear, we did note that prolonged synthesis of NO inhibited LPS-induced activation of an interleukin-1beta-converting enzyme-like cysteine protease (cysteine protease protein-32-like) in a dithiothreitol-sensitive fashion, suggesting that S-nitrosylation of an important downstream target of convergence of apoptotic signals may contribute to the sensitivity of SPAECs to LPS.Our group recently reported that cultured sheep pulmonary artery endothelial cells (SPAECs) became resistant to lipopolysaccharide (LPS)-induced apoptosis several days after constitutive synthesis of nitric oxide (NO) after adenoviral (Ad) transfer of inducible NO synthase (iNOS) or exposure to the NO donor S-nitroso- N-acetylpenicillamine (SNAP) (E. Tzeng, Y.-M. Kim, B. R. Pitt, A. Lizonova, I. Kovesdi, and T. R. Billiar. Surgery 122: 255-263, 1997). In the present study, we confirmed this observation by establishing stable transfectants after retroviral gene transfer [replication-deficient retrovirus (DFG)] of human iNOS (DFG-iNOS) SPAECs and then used all three approaches (Ad, DFG, and SNAP) to determine underlying mechanisms of this phenomenon. Continuous endogenous production of NO in itself did not cause apoptosis as assessed by phase-contrast microscopy, nuclear morphology, and internucleosomal DNA fragmentation. Prolonged (72-96 h) synthesis of NO, however, after DFG- or replication-deficient adenovirus (Ad.CMV)-iNOS or SNAP (100 μM, 96 h) inhibited LPS-induced apoptosis. The kinetics of such protection suggested that NO may be inducing other gene products. Ad-mediated transfer of manganese superoxide dismutase (MnSOD) decreased the sensitivity of wild-type SPAECs to LPS-induced apoptosis. MnSOD, however, was not induced in an N G-monomethyl-l-arginine (l-NMMA)-sensitive time-dependent fashion after Ad.CMV-iNOS. Other inducible genes that may be affected by NO and that may protect against potential oxidant-mediated LPS-induced apoptosis including 70-kDa heat shock protein, heme oxygenase-1, metallothionein, and Bcl-2 also were not elevated in an l-NMMA-sensitive, time-dependent fashion. Although the candidate gene product underlying NO-induced protection remains unclear, we did note that prolonged synthesis of NO inhibited LPS-induced activation of an interleukin-1β-converting enzyme-like cysteine protease (cysteine protease protein-32-like) in a dithiothreitol-sensitive fashion, suggesting that S-nitrosylation of an important downstream target of convergence of apoptotic signals may contribute to the sensitivity of SPAECs to LPS.

Palivizumab prophylaxis to prevent respiratory syncytial virus mortality after pediatric bone marrow transplantation: a decision analysis model.

Objective Palivizumab, a monoclonal antibody against respiratory syncytial virus (RSV), has been demonstrated to be safe and effective in young children, but evidence is lacking as to whether palivizumab is effective in preventing RSV-induced morbidity and mortality in children who are immunosuppressed after bone marrow transplantation (BMT). As a randomized, double-blind, placebo-controlled trial is lacking, we chose to examine this issue with the use of decision analysis methodology. Methods A decision tree was designed to determine mortality from RSV-related lung disease in children who received palivizumab after BMT. Probabilities were derived by meta-analysis methodology on the basis of the available literature. Sensitivity analyses were performed across a broad range of biologically plausible probabilities to judge the robustness of the results of the model. Results The model revealed that there is a 10% increase in survival in BMT patients who receive palivizumab. The absolute survival rate increased from 83% to 92%. A practitioner would need to treat 12 children to save 1 post-BMT child from dying from RSV-related lung disease. Conclusions Decision analysis modeling demonstrates a decrease in mortality in pediatric BMT patients with the addition of palivizumab to protect against RSV-related lung disease. A well-designed, randomized controlled trial is necessary.

Magnesium sulfate for control of muscle rigidity and spasms and avoidance of mechanical ventilation in pediatric tetanus.

Objective To describe the use of intravenous magnesium sulfate for the control of muscle spasms and severe generalized rigidity in a child with moderate to severe tetanus without the need for prolonged deep sedation, mechanical ventilation, or neuromuscular blockade. Design Case report. Setting Pediatric intensive care unit in a tertiary care, university-based children’s hospital. Interventions A continuous infusion of magnesium sulfate. Measurements and Main Results We describe a 12-yr-old child with moderate to severe tetanus who was treated with a continuous infusion of magnesium sulfate to control painful muscle spasms and severe generalized rigidity initially refractory to moderate sedation. Muscle spasms and severe generalized rigidity were improved with magnesium sulfate. No adverse effects associated with the use of magnesium sulfate were noted during the monitoring of cardiovascular and respiratory function, reflexes, and serum magnesium concentrations. Conclusions An infusion of magnesium sulfate can be utilized to treat muscle spasms and severe generalized rigidity without the need for deep sedation, mechanical ventilation, or neuromuscular blockade. We recommend that magnesium sulfate be considered in the armamentarium of therapeutics utilized to treat muscle spasms and rigidity associated with tetanus, provided the patient’s neurologic, cardiovascular, and respiratory status can be closely monitored in the pediatric intensive care unit.

Care goals and decisions for children referred to a pediatric palliative care program.

OBJECTIVE To describe goals of care for children with complex, life-limiting conditions and to assess the variables that may influence these goals. METHODS Goals of care were elicited from the parents and children with complex, life-limiting conditions during initial palliative care consultation. Data abstracted included: diagnoses, demographics, time from diagnosis until initial palliative care consult, spirituality status, resuscitative status, and disposition at discharge. Goals of care were categorized into one of four quality-of-life domains: 1) physical health and independence, 2) psychological and spiritual, 3) social, and 4) environment. Summary statistics were prepared and comparisons were made between the four categories of goals. Descriptive statistics were utilized to explore potential associations with a decision to pursue full medical support. RESULTS One hundred and forty goals of care were obtained from 50 patients/parents. The median patient age was 4.6 years. Thirty-seven patients had significant cognitive delay/impairment. Neuromuscular disorders accounted for more than half of the diagnoses. Forty-nine patients identified at least one goal pertaining to physical health and independence. This was significantly more than any other category (p < 0.0001). Thirty-three of the 50 patients (66%) opted for full medical support at the time of initial consult. CONCLUSIONS Children with complex, life-limiting conditions and their families referred to a palliative care service commonly verbalize goals related to health maintenance and independence. Anticipating this expectation may foster communication and improve patient care.

Jading in the pediatric intensive care unit: Implications for healthcare providers of medically complex children.

Objective: To discuss the phenomenon of jading within the context of the pediatric intensive care unit. Design: Drawing from their experience, the authors describe and then discuss a clinical scenario readily recognizable by pediatric intensive care unit practitioners: a child whose care requires the expenditure of a large amount of energy and resources, provides seemingly little reward, and leads to jading of the PICU staff. Conclusion: Jading describes a process of exhaustion whereby apathy, cynicism, and callousness replace the drive to be responsive, to make a difference, and to care. The issue of jading has become an increasing area of concern in the pediatric intensive care unit, due in part to recurring, prolonged admissions, combined with the perception, at times, that continued medical care is fruitless. With a better understanding of the phenomenon of jading, and by reconsidering their own responses, pediatric intensive care unit practitioners can avoid becoming jaded.

Safety and efficacy of sedation with propofol for transoesophageal echocardiography in children in an outpatient setting

BACKGROUND Transoesophageal echocardiography has become a powerful tool in the diagnosis and management of children with congenital cardiac malformations. Unlike adults, children will not tolerate transoesophageal echocardiography under light sedation. This study was undertaken, therefore, to evaluate the safety and efficacy of deep sedation with propofol for transoesophageal echocardiography in children examined in an outpatient setting. METHODS This is a retrospective study of patients undergoing transoesophageal echocardiography with propofol given in bolus aliquots to achieve a level of sedation adequate to insert the transoesophageal echocardiographic probe and maintain sedation throughout the procedure. RESULTS We included a total of 118 patients, 57% being male, with a mean age of 12.9 years. Adequate sedation was achieved using a mean propofol dose of 8.3 milligrams per kilogram, with the dose per kilogram decreasing concomitant with increasing weight of the patient. Patients less than two years of age were intubated for the procedure. There were no clinically significant changes in cardiac function or haemodynamics. Non-intubated patients received supplemental oxygen prior to, or just after, the onset of sedation, with transient hypoxaemia observed in one-fifth. Complications were rare, with minor problems occurring in 7.6%, and major ones in 4%. CONCLUSIONS Transoesophageal echocardiography can be performed on an outpatient basis in children with a wide spectrum of congenital cardiac malformations, and propofol is an ideal sedative agent in this setting. Although not common, preparations must be made for significant haemodynamic and respiratory complications. In our study, we intubated all the children under 2 years of age.

Myocardial Calcification Caused by Secondary Hyperparathyroidism Due to Dietary Deficiency of Calcium and Vitamin D

A 6-year-old girl presented with respiratory distress. Chest radiographs exhibited calcifications in the mediastinum. Further imaging revealed extensive cardiac calcifications on computed tomography of the chest. The laboratory parameters were consistent with findings of secondary hyperparathyroidism. Detailed review of her dietary history revealed a prolonged history of dietary deficiency of calcium and vitamin D. Treatment consisted of adequate daily replacement of calcium and ergocalciferol. On follow-up, her parathyroid hormone level was significantly reduced and substantially reduced cardiac calcifications were seen on echocardiogram. Pediatric cardiologists must be aware of this potentially fatal but treatable disease in children with cardiac calcifications unexplained by other causes.

A prospective assessment of the effect of aminophylline therapy on urine output and inflammation in critically ill children.

Background: Aminophylline, an established bronchodilator, is also purported to be an effective diuretic and anti-inflammatory agent. However, the data to support these contentions are scant. We conducted a prospective, open-label, single arm, single center study to assess the hypothesis that aminophylline increases urine output and decreases inflammation in critically ill children. Methods: Children less than 18 years of age admitted to the pediatric intensive care unit who were prescribed aminophylline over a 24-h period were eligible for study. The use and dosing of aminophylline was independent of the study and was at the discretion of the clinical team. Data analyzed consisted of demographics, diagnoses, medications, and markers of pulmonary function, renal function, and inflammation. Data were collected at baseline and at 24-h after aminophylline initiation with primary outcomes of change in urine output and inflammatory cytokine concentrations. Results: Thirty-five patients were studied. Urine output increased significantly with aminophylline use [median increase 0.5 mL/kg/h (IQR: −0.3, 1.3), p = 0.05] while blood urea nitrogen and creatinine concentrations remained unchanged. Among patients with elevated C-reactive protein concentrations, levels of both interleukin-6 (IL-6) and IL-10 decreased at 24 h of aminophylline therapy. There were no significant differences in pulmonary compliance or resistance among patients invasively ventilated at both time points. Side effects of aminophylline were detected in 7 of 35 patients. Conclusion: Although no definitive conclusions can be drawn from this study, aminophylline may be a useful diuretic and effective anti-inflammatory medication in critically ill children. Given the incidence of side effects, the small sample size and the uncontrolled study design, further study is needed to inform the appropriate use of aminophylline in these children.

Dexmedetomidine for Sedation during Withdrawal of Support

Agents used to control end-of-life suffering are associated with troublesome side effects. The use of dexmedetomidine for sedation during withdrawal of support in pediatrics is not yet described. An adolescent female with progressive and irreversible pulmonary deterioration was admitted. Despite weeks of therapy, she did not tolerate weaning of supplemental oxygen or continuous bilevel positive airway pressure. Given her condition and the perception that she was suffering, the family requested withdrawal of support. Despite opioids and benzodiazepines, she appeared to be uncomfortable after support was withdrawn. Ketamine was initiated. Relief from ketamine was brief, and its use was associated with a “wide-eyed” look that was distressing to the family. Ketamine was discontinued and a dexmedetomidine infusion was initiated. The patients level of comfort improved greatly. The child died peacefully 24 hours after initiating dexmedetomidine from her underlying disease rather than the effects of the sedative.