The effectiveness of tonsillectomy in diagnosing lymphoproliferative disease in pediatric patients after liver transplantation.

OBJECTIVE: To determine the effectiveness of diagnosing forms of lymphoproliferative disease by performing tonsillectomy in pediatric patients who develop symptomatic or asymptomatic tonsillar hypertrophy during immunosuppressive therapy after liver transplantation. DESIGN: Retrospective chart and pathological review. SETTING: Urban tertiary referral children's hospital. MAIN OUTCOME MEASURES: The presence of a pathological stage of lymphoproliferative disease or Epstein-Barr virus (EBV) diagnosed using tonsillar specimens, resulting in a change in therapy. RESULTS: Of 275 pediatric patients who underwent liver transplantation, 13 had tonsillectomy performed with histopathological review of the tonsillar specimens. The specimens from 5 patients (39%) demonstrated pathological changes thought to be consistent with EBV-related changes or a form of lymphoproliferative disease. Histological changes ranged from tonsillar hyperplasia associated with EBV infection to large cell lymphoma. Immunosuppressive therapy was reduced or discontinued, and antiviral therapy was initiated. CONCLUSION: Children who have undergone liver transplantation and develop tonsillar hypertrophy should undergo a diagnostic tonsillectomy, regardless of the clinical presentation, to rule out a form of posttransplant lymphoproliferative disease. Arch Otolaryngol Head Neck Surg. 2000;126:1444-1447

Feasibility of asynchronous independent lung high-frequency oscillatory ventilation in the management of acute hypoxemic respiratory failure: a case report.

OBJECTIVE: To report the first case of the use of asynchronous independent lung high-frequency oscillatory ventilation (AIL-HFOV) in the management of acute hypoxemic respiratory failure in a large pediatric patient with markedly asymmetric lung disease. DESIGN: Case study. SETTING: Tertiary pediatric intensive care unit in a pediatric teaching hospital. PATIENT: A 17-yr-old, 87-kg male patient with trisomy 21 and with respiratory failure and progressive hypoxemia because of pneumonia. INTERVENTIONS: Intubation with a 37-Fr double-lumen endobronchial tube and ventilation with two oscillatory ventilators for a total of 16 days. MEASUREMENTS AND MAIN RESULTS: Hemodynamic data were obtained using a pulmonary artery catheter. Adequate oxygenation and ventilation were readily achieved after institution of AIL-HFOV. The F(IO2)/PaO2 ratio increased from 52 to 224, and the shunt fraction decreased from 40 to 9 after 30 mins of AIL-HFOV. F(IO2) was rapidly reduced from 1.0 to 0.4 on the right lung and to 0.6 on the left lung. Mean arterial pressure was maintained, the cardiac index increased from 3.5 to 5.4 L/min/m2, the systemic vascular resistance index decreased from 1513 to 1225 dyne x sec/cm5 x m2, and the pulmonary vascular resistance index decreased from 723 to 428 dyne x sec/cm5 x m2 without the need for additional fluid boluses or increases in inotropic support. No airleaks developed during the entire hospital stay. CONCLUSIONS: AIL-HFOV improved oxygenation and hemodynamic performance in this large patient. This case demonstrates that it is feasible to use two high-frequency oscillatory ventilators to independently ventilate the lungs of a large patient with markedly asymmetric lung disease. We believe that AIL-HFOV deserves future study and development for the treatment of large patients with acute hypoxemic respiratory failure and asymmetric lung disease when other choices are limited.

Aprotinin in the management of life-threatening bleeding during extracorporeal life support.

Contact with the synthetic surfaces of an extracorporeal circuit induces alterations in vascular components, derangements of the coagulation cascade and a systemic inflammatory response. Aprotinin reduces intraoperative and postoperative bleeding in adults undergoing cardiopulmonary bypass; however, trials in children have not had similar favorable results. While there have been some anecdotal reports, there have been no prospective clinical trials exploring the utility of aprotinin in the prevention of or as a therapy for bleeding while on extracorporeal life support (ECLS). We present a case series on our experience utilizing aprotinin for the treatment of life-threatening bleeding during ECLS. The combination of a loading dose followed by a continuous infusion resulted in significant reduction in blood loss and blood product utilization. This suggests that aprotinin may have clinical efficacy in the management of massive blood loss while on ECLS; however, larger controlled trials will be essential to determine the efficacy and appropriate dosing regimens before widespread use in ECLS can be advocated.

Heart rate variability after acute traumatic brain injury in children.

OBJECTIVE: To evaluate heart rate variability (HRV) by power spectral analysis of heart rate and its relationship to intracranial pressure (ICP), cerebral perfusion pressure (CPP), and outcomes in children with acute traumatic head injury. DESIGN: Prospective, case series. SETTING: Pediatric intensive care unit in a level II trauma center/children's hospital. SUBJECTS: Fifteen critically ill children with documented acute traumatic brain injury and four control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The normalized total power from 0.04 to 0.15 Hz was used to quantify low-frequency HRV and from 0.15 to 0.40 Hz to quantify high-frequency HRV. The ratio of low- to high-frequency (LF/HF) power was used as a measure of sympathetic modulation of heart rate. The power spectral data from the 5-min samples were averaged over each hour of data collection, and an hourly LF/HF ratio was obtained based on a 60-min electrocardiogram collection (twelve 5-min segments). The daily mean LF/HF ratio was calculated from the hourly LF/HF measurements. We found no linear correlation between the LF/HF ratio and either ICP or CPP (p = NS). There was a significant decrease in the LF/HF ratio when the intracranial pressure was >30 mm Hg (p < .001) or the cerebral perfusion pressure was <40 mm Hg (p < .001). Children with a Glasgow Coma Scale score of 3-4 had a lower LF/HF ratio compared with those who had a Glasgow Coma Scale score of 5-8 (p < .005). Patients who progressed to brain death had a markedly lower LF/HF ratio (p < .001), with a significant decrease after the first 4 hrs of hospitalization. Patients with more favorable outcomes had significantly higher LF/HF ratios. CONCLUSIONS: Our findings suggest that an ICP of >30 mm Hg or a CPP of <40 mm Hg may be associated with marked autonomic dysfunction and poor outcome. We speculate that HRV power spectral analysis may be a useful adjunct in determining the severity of neurologic insult and the prognosis for recovery in children. The LF/HF ratio may be helpful not only in identifying those patients who will progress to brain death but also in predicting which patients will have favorable outcomes.

Predictive value of quantitative PCR-based viral burden analysis for eight human herpesviruses in pediatric solid organ transplant patients.

Human herpesviruses can cause significant morbidity and mortality in pediatric solid organ transplant recipients. It was hypothesized that viral burden quantification by polymerase chain reaction using an internal calibration standard could aid in distinguishing between viral disease and latency. Here we report the results of a 2-year prospective study of 27 pediatric solid organ (liver, kidney, or heart) transplant recipients in which multiple samples were analyzed for levels of all eight human herpesviruses by internal calibration standard-polymerase chain reaction. Herpes simplex viruses 1 and 2, varicella-zoster virus, and Kaposi's sarcoma-associated herpesvirus were not detected in any of these samples. Human herpesvirus types 6 and 7 were detected in half of the patients, but were present at low levels, similar to those found in reference populations. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were detected in 89% and 56% of the patients, respectively. Viral burden analysis suggested distinct patient populations for CMV, with a natural cutoff of 10,000 viral targets/ml blood strongly associated with disease. In some cases, a dramatic increase in CMV levels preceded clinical evidence of disease by several weeks. EBV viral burden was relatively high in the only patient presenting with an EBV syndrome. However, two other patients without evidence of EBV disease had single samples with high EBV burden. Rapid reduction in both EBV and CMV burden occurred with antiviral treatment. These data suggest that viral burden analysis using internal calibration standard-polymerase chain reaction for CMV, and possibly other herpesviruses, is an effective method for monitoring pediatric transplant patients for significant herpesvirus infection and response to therapy.

Improved cyclosporine bioavailability in black pediatric liver transplant recipients after administration of the microemulsion formulation.

Black transplant recipients are associated with low cyclosporine bioavailability, which may contribute to the poorer clinical outcomes observed with these patients. In this analysis, we compared cyclosporine exposure in black (n = 9) and nonblack (n = 18) pediatric maintenance liver transplant recipients by using steady-state pharmacokinetic profiles obtained after administration of the original and microemulsion formulations of cyclosporine. Treatment with the original cyclosporine formulation resulted in lower mean dose-normalized, area under the concentration-versus-time curve values for black compared with nonblack pediatric liver transplant recipients. On conversion to the microemulsion formulation of cyclosporine, black and nonblack patients experienced increases in cyclosporine bioavailability of 102% and 39%, respectively (P =.009 and P =.001). Because the increase in mean bioavailability was substantially greater for blacks, area under the concentration-versus-time curve values for this pediatric subpopulation became similar to those levels obtained for nonblacks receiving the microemulsion formulation for cyclosporine. When patients were further stratified by age, ethnic differences in bioavailability with the original formulation of cyclosporine were most apparent in the 1- to 5-year age group. Conversion to the microemulsion formulation resulted in a 164% increase (P =.05) in bioavailability for black patients within this age group such that, again, these levels became similar to area under the concentration-versus-time curve values obtained for young nonblacks receiving cyclosporine for microemulsion. Improvements in cyclosporine bioavailability after administration of the microemulsion formulation of cyclosporine may translate to improved long-term graft and patient outcomes for black pediatric liver transplant recipients.

Epstein-Barr virus polymerase chain reaction and serology in pediatric post-transplant lymphoproliferative disorder: three-year experience.

To assess whether the semiquantitative peripheral blood Epstein-Barr virus (EBV) polymerase chain reaction (PCR) test correlates with post-transplant lymphoproliferative disorder (LPD), we compiled the results of the test done over a 3-year period ending July 1997. Six hundred seventy-six tests were done on 185 patients. Four hundred-thirty tests (63%) were negative, 167 (25%) were weak positive, 67 (10%) were moderate positive, and 12 (2%) were strong positive. Twelve of the patients developed a lymphoproliferative disorder (LPD) during this time. The EBV PCR tests proximate to the diagnosis of LPD in the 12 patients with EBV-positive LPD were 6 strong positive, 5 moderate positive, 1 weak positive. No patient with LPD had a negative result at diagnosis. Stated another way, 6/12 (50%) of strong-positive PCR tests, 5/67 (7%) moderate-positive tests, and 1/167 (.6%) of weak-positive tests correlated with LPD. Serologic evaluation for EBV done on 7 patients at the time of LPD showed low serologic responses in 5 of the 7 patients. The EBV PCR temporally associated with the serology indicated moderate to large viral burdens. In each patient evaluated serially, the EBV PCR test rose before the diagnosis of LPD and fell with treatment for the disorder. In conclusion, the EBV PCR test may be used as an adjunct to the diagnosis of patients with LPD and may be used to monitor response to therapy for the disorder.

Pharmacokinetics of an oral solution of the microemulsion formulation of cyclosporine in maintenance pediatric liver transplant recipients.

BACKGROUND: A comparison of the oral bioavailability of cyclosporine from the original formulation (CsA) and from the new formulation, cyclosporine for microemulsion (CsA-ME), was made in pediatric maintenance liver transplant patients within two age groups (group 1, ages 1-5 years; group 2, ages 6-17 years) in an open-label, multicenter, randomized crossover trial. All patients were at least 6 months past transplantation and were receiving CsA maintenance therapy. METHODS: In study period 1 (days 1 through 14), patients were administered either CsA or CsA-ME at the same b.i.d. dosage as their maintenance therapy. Upon entry into period 2 (days 15 through 28), patients were converted to the alternate formulation at a 1:1 mg dose ratio. On day 29, all patients returned to the CsA treatment administered at study entry, with follow-up on day 35. Dosage adjustments were not allowed with either CsA or CsA-ME. Twelve-hour pharmacokinetic profiling was performed at the end of periods 1 and 2. RESULTS: Both the mean area under the concentration-versus-time curve and the mean maximum blood concentration of cyclosporine-both normalized for dose-were significantly increased: by 66% and 109%, respectively, in patients receiving CsA-ME compared with those receiving CsA in group 1 and by 39% and 75%, respectively, in group 2. During this study, liver function remained stable, and serum creatinine and blood pressure did not differ significantly between treatment groups. CONCLUSIONS: This study shows increased bioavailability in all patients converted to CsA-ME, with the greatest increase seen in patients with the lowest initial cyclosporine bioavailability. The tolerability was similar between the two formulations during this study.

10 years of pediatric liver transplantation.

PURPOSE: Pediatric liver transplantation is an accepted therapy for end-stage liver disease, but little long-term data exist. METHODS: From October 1984 to October 1994, 202 patients underwent a total of 225 liver transplantations. There were 98 boys and 104 girls, the average age was 5.1 +/- 4.9 (range, 0.2 to 19.1) years. Thirty (16%) were under 1 year of age. The diseases that required transplantation included biliary atresia (BA) (45%), metabolic liver disease (MLD) (9.9%), acute hepatic failure (6.9%), and Alagille's syndrome (AS) (5.4%). Originally the immunosuppression was cyclosporine- and steroid-based; the later regimens also included azathioprine and antilymphocyte preparations. All reported survival rates were derived from life-table analysis. RESULTS: The patient survival rates at 1, 5, and 10 years were 76%, 70%, and 61%; the retransplantation rate was 11%. The respective graft survival rates were 71%, 63%, and 59%. There were 60 deaths; 48 (81%) occurred in the first year. These first-year deaths were from sepsis (20; 42%), central nervous system problems (5; 11%), intraoperative complications (4; 8%), lymphoproliferative disease (LPD) (2; 4%), rejection (2; 4%), primary nonfunction (2; 4%), and miscellaneous other causes (7; 15%). There were 12 deaths after the first year, from LPD (3; 25%), sepsis (1; 8%), rejection (2; 18%), cancer (1; 9%), secondary hepatic failure (1; 9%), cerebral vascular accident (1; 9%), or pre- or postoperative complications (3; 25%). Compared with the overall survival rate, patients with MLD had a better chance of survival (83%; P <.012) than did those with AS (45%; P < .001). The 5- and 10-year survival rates for patients with BA were 61% and 58%. Over the past 2 years, the survival rate has increased (87% v 72%; P < .05) as early septic deaths have decreased (from 2.6 to 1.0 per year). CONCLUSION: Liver transplantation is effective treatment for end-stage liver disease. Decreasing the number of early septic deaths has improved the chance of survival, and better diagnosis and treatment of LPD would improve the late survival rate.

Influence of referring physicians on interventions by a pediatric and neonatal critical care transport team.

The objective of this study was to determine the influence of: a) pediatrician versus nonpediatrician referrals on a transport team's therapeutic interventions and b) referring physician's year of graduation on interventions performed by the transport team. From November 1987 through December 1989 we prospectively compared the therapeutic interventions performed by the critical care transport team on newborns and pediatric patients with the referring physician's specialty and year of graduation. The transport team (critical care physician [PL3 or greater], registered respiratory therapist, critical care nurse), recorded all therapeutic interventions, including both procedural and pharmacologic, for 213 newborn and 149 consecutive pediatric transports. Referring physicians were categorized as pediatricians and nonpediatricians. Data were analyzed by analysis of variance, chi2, or linear regression. All patients were admitted to either the pediatric or the neonatal intensive care unit, and over 80% of both age groups received assisted ventilation. Newborns referred by nonpediatricians required significantly more procedural interventions (2.64 vs 1.91, P = 0.016) than those referred by pediatricians. The opposite relationship was observed among pediatric patients in that children referred by pediatricians received more frequent intervention (P = 0.008) than those referred by nonpediatricians. There was a significant inverse relationship between the referring physicians year of medical school graduation and the number of therapeutic interventions (total interventions = 6.17 - 0.040 x graduation year, P = 0.01) and procedural interventions (procedural interventions = 3.54 - 0.024 x graduation year, P = 0.01). We found that the referring physicians' medical training affected the number of interventions their patients received. Similarly, patients were likely to receive more interventions if the referral physicians training was not recent. These data have educational implications and support the concepts of continuing medical education, recertification, and maintenance of skills among physicians providing care to critically ill newborns and pediatric patients.

Pediatric and neonatal critical care transport: a comparison of therapeutic interventions.

OBJECTIVE: To compare the therapeutic interventions provided to newborn and pediatric patients by a dedicated combined neonatal pediatric critical care transport team. METHOD: From November 1987 through December 1989 we prospectively compared the number of therapeutic interventions performed by the critical care transport team on newborns and pediatric patients. The transport team (critical care physician [PL3 or greater], pediatric respiratory therapist, critical care nurse), recorded all therapeutic interventions, including both procedural and pharmacologic, for 213 newborn and 149 pediatric consecutive transports. Data were analyzed by analysis of variance or chi 2 statistic. RESULTS: All patients were admitted to either the pediatric or the neonatal intensive care unit, and over 80% of both age groups received assisted ventilation. Newborns commonly suffered from respiratory diseases (159/213), while pediatric patients suffered from respiratory (52/149), central nervous system (28/149), and traumatic conditions (37/149). Airway maintenance procedural interventions (intubation, ventilation) were the commonest in both groups, although more frequent in neonates. Neonates received antibiotics and morphine (P < 0.05) while pediatric patients received anticonvulsants and respiratory drugs (P < 0.05) more frequently. Newborns received significantly more interventions than pediatric patients (average 3.56 vs 2.93, P < 0.05). Newborns also received significantly more procedural interventions (2.06 vs 1.36, P = < 0.05) including intubation (34.7% vs 15.4%, P < 0.05) and the initiation of mechanical ventilation (38% vs 22%, P < 0.05). CONCLUSION: Overall, newborns received more interventions, including intubation, and ventilation from the transport team than did pediatric patients. Our data suggest that combined pediatric neonatal transport teams should be prepared to intervene in a wide range of conditions from preterm respiratory distress to the multiply traumatized adolescent.

Comparison of fluid infusion rates among peripheral intravenous and humerus, femur, malleolus, and tibial intraosseous sites in normovolemic and hypovolemic piglets.

STUDY OBJECTIVES: To compare infusion rates from various intraosseous sites (tibial, medial malleolar, distal femoral, and humeral) and at a peripheral IV site under gravity and pressure flow in normovolemic and hypovolemic states. DESIGN AND SETTING: A piglet model was used to assess rates of infusion under varying conditions in a university hospital animal laboratory. Analysis of variance was used to evaluate site differences. PARTICIPANTS: Twenty-three Yorkshire-Landrace mix pigs (weight, 12 to 23 kg) were studied. INTERVENTIONS: Animals were anesthetized and intubated before cannulation with 18-gauge bone marrow needles at intraosseous sites and 22-gauge Teflon catheters in peripheral vessels. Infusion rates under gravity and 300 mm Hg pressure were determined. Infusion rates under similar conditions were repeated in hypovolemic animals with acute bleeding of 25 mL/kg. MEASUREMENTS AND MAIN RESULTS: Mean infusion rates (mL/min) for gravity versus 300 mm Hg pressure in normovolemic pigs were 13.1 versus 40.9 for peripheral IV, 11.1 versus 41.3 for humerus, 9.3 versus 29.5 for femur, 8.2 versus 24.1 for malleolus, and 4.3 versus 17.0 for tibia. Hypovolemia resulted in average decreased rates of 32%. Infusion rates were significantly different between sites and between normovolemia and hypovolemia (P = .0001). CONCLUSION: Intravenous access is the most efficacious method of acute volume replacement. Intraosseous sites differ in the infusion rates obtained--descending order is humerus, femur, malleolus, and tibia, but each is a reasonable alternative for short-term vascular access.

Relationship of cross-brain oxygen content difference, cerebral blood flow, and metabolic rate to neurologic outcome after near-drowning.

We evaluated the relationship of global cerebral blood flow, cross-brain oxygen content difference, cerebral metabolic rate for oxygen, intracranial pressure, and cerebral perfusion pressure to functional neurologic outcome in 12 comatose children on 2 consecutive days after near-drowning. Five children survived with functional neurologic outcome; five died and two survived with severe neurologic damage. Children who survived with functional neurologic outcome had a significantly higher cross-brain oxygen content difference (7.89 +/- 2.62 vs 3.91 +/- 1.59 ml/dl; p = 0.028) at 24 hours and a higher cerebral metabolic rate for oxygen 48 hours after admission (3.19 +/- 2.86 vs 0.96 +/- 0.45 ml/100 gm per minute; p = 0.030) compared with those who died or survived in a damaged state. There were no significant differences in global cerebral blood flow, intracranial pressure, and cerebral perfusion pressure between groups at either 24 or 48 hours. Our preliminary data suggest that a higher cross-brain content difference value is an important early variable associated with functional neurologic recovery after near-drowning. However, a single cross-brain oxygen content difference value must be interpreted with caution because considerable variability may occur among patient groups.

Intraosseous infusion rates: comparison of various intraosseous sites versus peripheral intravenous sites in normovolemic and hypovolemic pigs - abstract

The tibial intraosseous (IO) site is useful for vascular access in paediatric resuscitation. However, alternate IO sites need to be considered for use in patients with lower extremity and abdominal trauma, and in those requiring multiple infusions. The infusion rates were determined at tibial, medial malleolar, distal femoral and humeral IO sites and at a peripheral intravenous (IV) site in 23 normovolemic and hypovolemic anaesthetised pigs (12 - 23 kg). IO cannulation was established with 18 gauge bone marrow needles and in peripheral vessels with ww gauge teflon catheters. Hypovolemia was established by acutely bleeding 2 mi/kg. Infusion rates were determined in random order under gravity and 300/mm Hg pressure. The infusion rates obtained (table given) were significantly different (MANOVA p = 0.0001) for gravity vs 300 mm Hg. Our study suggested 1) IV access is the most efficacious infusion method for volume resuscitation; 2) IO sites differ in the infusion rates obtained; 3) IO infusions provide reasonable alternatives for short-term vascular access (AU)