Hyponatremia associates with poor outcome in metastatic renal cell carcinoma patients treated with everolimus: prognostic impact.

BACKGROUND: The prognostication of metastatic renal cell carcinoma (mRCC) is based on Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classifications. Research has shown that hyponatremia is associated with worse prognosis in cancer. We analyzed the association of hyponatremia and outcome in everolimus-treated mRCC patients. PATIENTS AND METHODS: Baseline and on-treatment (≤12 weeks) sodium in 233 mRCC patients was analyzed using Kaplan-Meier, Cox regression and logistic regression. Baseline sodium was correlated with baseline thrombocyte and neutrophil values. RESULTS: 65 (28%) and 41 (18%) patients had sodium < lower limit of normal (LLN) at baseline and on-treatment, respectively. Baseline sodium < LLN was associated with shorter overall survival (OS) (6.1 vs. 10.3 months; p < .001) and progression-free survival (PFS) (2.8 vs. 3.5 months; p = .04). On-treatment sodium < LLN was associated with shorter OS (5.4 vs. 9.9 months; p < .001) and PFS (2.8 vs. 4.0 months; p < .001). In multivariate analyses adjusted for IMDC factors, baseline and on-treatment sodium < LLN were significantly associated with shorter OS (adjusted HR 1.46 (95% CI 1.04-2.05); p = .02; adjusted HR 1.80 (95% CI 1.23-2.61); p = .002; respectively). On-treatment sodium < LLN was significantly associated with progressive disease (OR 0.23 (95% CI 0.10-0.56); p = .001). A landmark analysis demonstrated that on-treatment hyponatremia was significantly associated with shorter OS and PFS (p = .01 and p = .03, respectively). On-treatment normalization of hyponatremia was associated with improved OS (unadjusted HR 0.61 (95% CI 0.35-0.98); p = .04), as compared to patients with sustained hyponatremia throughout follow-up. CONCLUSIONS: Hyponatremia associates with poor outcome in mRCC patients treated with everolimus. On-treatment normalization of hyponatremia to normal sodium values associates with favorable outcome.

Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma.

BACKGROUND: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. PATIENTS AND METHODS: Eighty-five mRCC patients received everolimus at Helsinki University Hospital (cohort A). Computed tomography (CT) verified pneumonitis was correlated with outcome using Kaplan-Meier, Cox regression and logistic regression. An independent cohort of 148 everolimus treated mRCC patients (cohort B) at Aarhus University Hospital was assessed for validation. RESULTS: In cohort A, CT-verified pneumonitis (N = 29, 34.1%) was associated with improved overall survival (OS) (24.7 versus 8.5 months; P < 0.001), progression-free survival (PFS) (5.5 versus 3.2 months; P = 0.002) and clinical benefit rate (CBR) 57.1% versus 24.1% (P = 0.003). In multivariate analyses pneumonitis was associated with improved OS (hazard ratio [HR], 0.22; 95% confidence interval [CI] 0.12-0.44; P < 0.001), PFS (HR 0.37; 95% CI 0.21-0.66; P = 0.001) and CBR (odds ratio [OR] 4.11; 95% CI 1.42-11.95; P = 0.01). In cohort B, CT-verified pneumonitis (N = 29, 19.6%) was associated with improved OS (12.9 versus 6.0 months; P = 0.02), PFS (6.0 versus 2.8 months; P = 0.02) and CBR (79.3% versus 39.5%; P < 0.001). In multivariate analyses pneumonitis was associated with improved OS (HR 0.58; 95% CI 0.36-0.94; P = 0.03), PFS (HR 0.61; 95% CI 0.39-0.95; P = 0.03) and CBR (OR 5.65; 95% CI 2.10-15.18; P = 0.001). In a combined multivariate analysis (N = 233), with pneumonitis as a time-dependent covariate, CT-verified pneumonitis was associated with longer OS (HR, 0.67; 95% CI 0.46-0.97; P = 0.03). Furthermore, in a landmark analysis, pneumonitis was associated with longer OS (17.4 versus 7.8 months; P = 0.01). CONCLUSIONS: Everolimus-induced pneumonitis is associated with improved outcome in patients with mRCC and may serve as a biomarker of everolimus efficacy.

Peripheral nervous system in gyrate atrophy of the choroid and retina with hyperornithinemia.

OBJECTIVE: To evaluate peripheral nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinemia (GA). BACKGROUND: GA is an inborn error of amino acid metabolism caused by mutations in the enzyme ornithine aminotransferase. Patients with GA have hyperornithinemia, progressive centripetal loss of vision, minor CNS abnormalities, and type II muscle fiber atrophy with accumulation of tubular aggregates. The authors previously showed that muscle and brain creatine stores are depleted in the patients with GA. METHODS: The authors searched evidence of peripheral nervous involvement in 40 patients with GA (mean age 31.6 +/- 16.3 years; range 5 to 74 years) by using neurography, quantitative sensory threshold testing, and evoked potential testing. RESULTS: Neurography revealed abnormalities in 21 (53%) of the patients. The abnormalities associated with the severity of the ophthalmologic changes and the age of the patients. With quantitative sensory threshold testing, abnormal large-fiber function was found in seven (18%) and abnormal small-fiber function was found in four (10%) patients. Somatosensory evoked potential and brainstem auditory evoked potential responses were abolished in five patients. CONCLUSIONS: These findings of peripheral nervous system involvement in GA suggest that GA is a systemic disease affecting not only CNS but also the peripheral nervous system.

Ophthalmologic heterogeneity in subjects with gyrate atrophy of choroid and retina harboring the L402P mutation of ornithine aminotransferase.

OBJECTIVE/PURPOSE: To investigate clinical variation in a genetically homogenous group of subjects with gyrate atrophy of choroid and retina with hyperornithinemia (GA). The group was made up of homozygotes and compound heterozygotes for mutation L402P in the ornithine aminotransferase (OAT) gene. DESIGN: Cross-sectional study. PARTICIPANTS: Thirty-five Finnish subjects (18 men) with GA with a mean age of 33 years (range, 5-74 years) carrying the Finnish founder mutation L402P. METHODS: All subjects were examined between 1993 and 1995. The analysis was composed of, in addition to careful clinical evaluation, studies of visual fields with Goldmann perimeter, photographing of the eye fundi, and corneal electroretinography (ERG) recordings. MAIN OUTCOME MEASURES: The changes in eye fundi, visual acuity, cataract changes in the lens, visual field constriction, and ERG responses were determined. RESULTS: Myopia, early cataracts, and highly abnormal ERG were typical for the GA subjects. The changes progressed rather uniformly with age. However, visual acuity, funduscopic findings, and visual fields showed great phenotypic variation. Despite the great interindividual variation, both eyes of each subject were always similarly affected. CONCLUSIONS: This study of 35 subjects with GA carrying a single mutation shows that the ophthalmologic symptoms and findings vary widely. The data also reveal that GA subjects are already affected by severe visual impairment in young adulthood. However, the diagnosis is often made very late.

Pharmacokinetics of amrinone in neonates and infants.

OBJECTIVE: To evaluate the pharmacokinetics of amrinone and its metabolites in neonates and infants after reconstructive surgery for congenital heart disease. DESIGN: Prospective study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Fifteen neonates aged less than 1 month with transposition of the great arteries and 14 infants aged 2 to 6 months with complete atrioventricular septal defect. INTERVENTIONS: Amrinone, loading dose of 2 mg/kg, was administered before weaning from cardiopulmonary bypass, followed by a maintenance infusion of 7.5 microg/kg/min. MEASUREMENTS AND MAIN RESULTS: Blood samples to determine plasma concentrations of amrinone, N-acetylamrinone, and N-glycolylamrinone were drawn before amrinone administration, frequently after the loading dose, every 6 hours during the maintenance infusion, and until 48 hours after the end of the infusion. Amrinone clearance was 2.4 +/- 0.9 mL/kg/min in neonates and 3.2 +/- 1.2 mL/kg/min in infants (p < 0.05). The volume of distribution at steady-state was smaller (p < 0.05) in neonates than in infants. The elimination half-life of amrinone was 10.7 +/- 6.7 hours in neonates and 6.1 +/- 1.4 hours in infants (p < 0.05). There was a linear correlation between the clearance of amrinone and the body surface area (r = 0.67; p < 0.05). The ratio of the plasma concentration of N-acetylamrinone to that of amrinone did not differ between neonates and infants. CONCLUSIONS: Amrinone is eliminated at a slower rate in neonates than in infants. The rate of acetylation of amrinone appears to be similar; the differences in the elimination capacity of amrinone are mainly due to the immature renal function in neonates.

Delayed impairment of cerebral oxygenation after deep hypothermic circulatory arrest in children.

BACKGROUND: Clinical studies of deep hypothermic circulatory arrest (DHCA) have focused only on the immediate postoperative period. However, experimental findings suggest impairment of cerebral oxygenation at 2 to 8 hours after reperfusion. METHODS: In 10 children who had DHCA for heart operations, transcerebral differences of hemoglobin oxygen saturation and plasma hypoxanthine, xanthine, and lactoferrin concentrations were measured in concurrently obtained cerebral venous, arterial, and mixed venous samples up to 10 hours postoperatively. RESULTS: Compared with preoperative levels (57% +/- 7%), cerebral venous oxygen saturation was not significantly reduced until 2 hours (44% +/- 6%) and 6 hours (42% +/- 5%) after DHCA (p < 0.05). A statistically significant transcerebral (ie, cerebral vein versus artery) concentration difference of hypoxanthine was observed at 30 minutes (3.6 +/- 0.9 micromol/L), 1 hour (3.4 +/- 1.1 micromol/L), and 2 hours (3.1 +/- 0.8 micromol/L) after DHCA but not preoperatively (0.4 +/- 0.2 micromol/L). A transcerebral concentration difference of lactoferrin occurred 30 minutes after DHCA (196 +/- 70 microg/mL) but not preoperatively (16 +/- 20 microg/mL). CONCLUSIONS: Cerebral venous oxygen saturation of hemoglobin decreased as late as 2 to 6 hours after DHCA, in association with impaired cerebral energy status. Neutrophil activation in the cerebral circulation occurred 30 minutes after reperfusion.

Amrinone versus dopamine and nitroglycerin in neonates after arterial switch operation for transposition of the great arteries.

OBJECTIVE: To compare the efficacy and safety of amrinone and a combination of dopamine and nitroglycerin in neonates after reconstructive surgery for transposition of the great arteries. DESIGN: A prospective, randomized, double-blind study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Thirty-five neonates with transposition of the great arteries. INTERVENTIONS: A loading dose of amrinone, 2 mg/kg, followed by a maintenance infusion of 7.5 microg/kg/min, were administered to 16 neonates before separation from cardiopulmonary bypass. The remaining 19 patients were administered a combination of dopamine, 5 microg/kg/min, and nitroglycerin, 1 microg/kg/min. An open-label epinephrine infusion was administered in both groups as required. MEASUREMENTS AND MAIN RESULTS: The circulatory state of the patients was evaluated from 4 to 18 hours after cardiopulmonary bypass. The systemic blood flow index, calculated using the Fick principle, was higher in the amrinone group (1.7+/-0.5 L/min/m2 [mean +/- SD]) compared with the dopamine-nitroglycerin group (1.4+/-0.4 L/min/m2; p < 0.04). The systemic vascular resistance in the amrinone group was lower (26+/-8 Wood units x m2) than in the dopamine-nitroglycerin group (35+/-12 Wood units x m2; p < 0.02). The oxygen extraction ratio was higher in the dopamine-nitroglycerin group (0.34+/-0.08) compared with the amrinone group (0.28+/-0.06; p < 0.02). Lower platelet counts were observed in the amrinone group, but no difference in hemorrhagic complications was seen between the groups. CONCLUSION: With the dosage regimen used, supplemented with epinephrine, amrinone provides a higher cardiac output and more favorable oxygen dynamics than a combination of dopamine and nitroglycerin.

Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect.

OBJECTIVES: To compare the effectiveness and safety of amrinone and a combination of dopamine and nitroglycerin in infants after reconstructive surgery for congenital heart disease. DESIGN: A prospective, randomized, double-blind study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Thirty-two infants with complete atrioventricular septal defect. INTERVENTIONS: Amrinone loading dose, 2 mg/kg, followed by a maintenance infusion, 7.5 micrograms/kg/min, was given to 17 infants before separation from cardiopulmonary bypass. The remaining 15 patients received a combination of dopamine, 5 micrograms/kg/min, and nitroglycerin, 1 microgram/kg/min. MEASUREMENTS AND MAIN RESULTS: The circulatory state of the patients was evaluated from 4 to 18 hours after cardiopulmonary bypass. The systemic blood flow index, calculated using the Fick principle, was higher in the amrinone group (2.5 +/- 0.7 L/min/m2) compared with the dopamine-nitroglycerin group (2.0 +/- 0.6 L/min/m2, mean +/- SD). The pulmonary blood flow index in the amrinone group was higher (2.9 +/- 0.6 L/min/m2) than in the dopamine-nitroglycerin group (2.2 +/- 0.6 L/min/m2); no significant difference was noted in the mean pulmonary artery pressure. The oxygen extraction ratio was higher in the dopamine-nitroglycerin group (0.41 +/- 0.07) compared with the amrinone group (0.34 +/- 0.08). Despite lower platelet counts in the amrinone group, no hemorrhagic complications were seen in any patient. CONCLUSIONS: With this dosage regimen, amrinone provides a higher cardiac output, more favorable oxygen dynamics, and lower pulmonary vascular resistance than dopamine and nitroglycerin.

Fibrinolysis, antithrombin III, and protein C in neonates during cardiac operations.

Fibrinolysis and coagulation were studied in 10 neonates undergoing cardiac operations for congenital heart defects. Coagulation was activated during cardiopulmonary bypass as evidenced by highly increased prothrombin fragment 1 + 2 levels compared with preoperative values. Prothrombin fragment 1 + 2 levels remained elevated until postoperative day 3. Unlike coagulation, fibrinolysis was not activated during cardiopulmonary bypass but did show late activation on postoperative day 3, as evidenced by elevated levels of the fibrin degradation product D-dimer. Lack of fibrinolytic activation during bypass and its appearance on postoperative day 3 were partly explained by changes observed in tissue plasminogen activator and its inhibitor. During bypass, levels of tissue plasminogen activator and its inhibitor increased by 3.4-fold and 3.2-fold, respectively. In the postoperative period, levels of plasminogen activator inhibitor normalized rapidly whereas tissue plasminogen activator remained elevated, resulting in late fibrinolytic activation on postoperative day 3. In accordance with elevated prothrombin fragment 1 + 2, platelet count, antithrombin III, protein C, prothrombin, and factor VII were decreased on postoperative day 2, indicating ongoing consumptive coagulopathy. Nine patients had antithrombin III and six had protein C levels below age-specific normal ranges, consistent with an acquired deficiency state. Three had central venous thrombosis by postoperative day 4 or 5. In all three, thrombosis was preceded by antithrombin III deficiency, protein C deficiency, and highly elevated plasminogen activator inhibitor (3.7 to 37 times the mean of the other patients) on postoperative days 1 to 3. In conclusion, cardiopulmonary bypass in neonates caused rapid and profound alterations in the coagulation and fibrinolytic systems and initiated consumptive coagulopathy lasting until at least postoperative day 3. Thrombophilic abnormalities in antithrombin III, protein C, and fibrinolysis were frequently found and were associated with serious thrombotic complications.

Regional generation of free oxygen radicals during cardiopulmonary bypass in children.

Studies on free radical generation during cardiopulmonary bypass have focused mainly on the heart and the lungs. However, low pumping pressure, nonpulsatile perfusion, and hypothermia affect the entire circulation, resulting in decreased splanchnic blood flow, increased intestinal permeability, and endotoxemia. To evaluate regional phenomena, we studied 16 children undergoing cardiopulmonary bypass. Free radical production, granulocyte activation, and hypoxanthine metabolism were assessed separately in the circulations drained by the inferior and superior venae cavae, as well as in the oxygenator. Three minutes after the onset of cardiopulmonary bypass, significant gradients between the inferior vena cava and the arterial line of the oxygenator existed in malondialdehyde (+0.60 +/- 0.12 mumol/L, lactoferrin (+18.21 +/- 7.65 micrograms/L), myeloperoxidase (+53.75 +/- 16.50 micrograms/L), hypoxanthine (-0.62 +/- 0.15 mumol/L), and urate (+8.87 +/- 4.03 mumol/L). These gradients decreased in parallel with decreasing body temperature. Except for a transient gradient in malondialdehyde at 3 minutes after the onset of cardiopulmonary bypass (+0.23 +/- 0.08 mumol/L), no changes were detected between the superior vena cava and the arterial line. In the oxygenator, granulocyte activation was observed only after aortic declamping. We conclude that during cardiopulmonary bypass, significant free radical generation, granulocyte activation, hypoxanthine elimination, and urate production take place in the region drained by the inferior vena cava. In the oxygenator, granulocyte activation occurs only after aortic declamping.

Bleeding and use of blood products after heart operations in infants.

Recent studies have suggested that postoperative bleeding is decreased in pediatric heart operations if fresh whole blood instead of blood component therapy is used for postoperative transfusions. Because this is in contrast to our practice to use whole blood for only the priming of the cardiopulmonary bypass circuit and then to use blood components for additional transfusion requirements, it was our interest to analyze the bleeding complications and the use of blood products after heart operations in infants. The patient records of the 73 infants operated on in 1992 were reviewed. The chest tube drainage varied from 3 to 51 ml/kg per 6 hours (mean 10 ml/kg) and it did not correlate with any of the tested clinical or laboratory parameters. One infant underwent reoperation because of surgical bleeding. Disseminated intravascular coagulation developed in another patient. Sixty-eight patients (93%) needed red blood cell supplementation. Sixty-eight percent of patients between 1 month and 1 year old could be treated without any other postoperative transfusion except for red blood cell supplementation. In contrast, in the neonates, platelet concentrates or fresh frozen plasma, or both, were used in 61% of the patients. In addition to the known immaturity of the hemostatic system, the increased need for platelet concentrates in the neonates was attributed to longer cardiopulmonary bypass time, deeper hypothermia in association with circulatory arrest, larger dosages of heparin, and more extensive plasma dilution during cardiopulmonary bypass. In conclusion, a low rate of bleeding complications and acceptably low general blood loss can be achieved postoperatively with blood component therapy.

Prenatal muscle relaxation in congenital diaphragmatic hernia.

An infant with congenital diaphragmatic hernia was given 2 mg vecuronium bromide intramuscularly in utero 40 min before vaginal delivery at 40 weeks gestation. At birth the infant had complete muscle relaxation, which facilitated decompression of the bowel and surgical correction. Prenatal muscle relaxation may improve the care of infants with congenital diaphragmatic hernia.

Oxygen consumption following pediatric cardiac surgery.

Metabolic responses during recovery from cardiac operations for various congenital heart defects were studied in 30 mechanically ventilated pediatric patients in two groups: infants 1 year or less (group I) and children more than 1 year old (group II). Oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured using a pediatric metabolic monitor intermittently after induction of anesthesia, after skin closure, 2 to 4 hours postoperatively, and on the first postoperative morning in the pediatric intensive care unit. Energy expenditure and respiratory quotient were determined from respiratory gas measurements. Rectal and skin temperatures and hemodynamic variables were recorded at the same time. VO2 increased during rewarming 2 to 4 hours after the operation by 12 +/- 15% in group I and by 24 +/- 19% in group II, while rectal temperature increased by 2.0 +/- 1.2 degrees C and 1.8 +/- 1.4 degrees C, respectively. No further increase in VO2 occurred until the first postoperative morning. A hypermetabolic response was not seen in all cases despite marked thermal changes. High-dose fentanyl anesthesia partly explains the low responses. On the other hand, low cardiac output may also compromise oxygen supply. Sixty-three percent of infants were treated for cardiac failure before surgery and 75% needed inotropic support immediately after the operation. Low central venous oxyhemoglobin saturation values (ScvO2 < 60%) were observed during rewarming, indicating an increase in oxygen extraction secondary to an increased oxygen demand in the brain during recovery from anesthesia, and a low cardiac output or delayed restoration of cerebral blood flow after CPB and deep hypothermia.

Renal transplantation in children with emphasis on young patients.

We report the results of 41 consecutive renal transplantations performed on 39 children (median age 2.7 years). Twenty-six recipients were less than 5 years old. Twenty-one recipients (13 under the age of 5 years) received cadaver (CAD) grafts. All grafts except 2 were from adult donors and were placed extraperitoneally. Patients were on triple immunosuppression (cyclosporine plus azathioprine plus methylprednisolone). Mean follow-up time was 2.3 years. No vascular and only one ureteral complication was seen. Acute tubular necrosis occurred in 3 patients (7.3%). No grafts were lost due to acute rejection. Three-year patient survival and 1-year graft survival were 100%. The overall 3-year actuarial graft survival was 86%. Three-year survival of grafts from living-related donors (LRD) was 92% and that of CAD grafts 75%. In recipients younger than 5 years, 3-year LRD graft survival was '89% and CAD graft survival 73%. No significant differences in graft survival between recipients of different age groups or between LRD and CAD grafts were found. We conclude that results of renal transplantation in children under 5 years of age are comparable to those of older children, even using CAD grafts, when adult donors and triple immunosuppression are used.

Metabolic effects of corrective surgery in infants and children with congenital heart defects.

We have measured oxygen consumption and carbon dioxide production by indirect calorimetry in 25 infants and children immediately before and after surgical correction of congenital cardiac malformations. Surgical correction of the cardiac defect caused a decrease in oxygen consumption towards normal. Greatly increased oxygen consumption values were observed before surgery in the infants with a large left-to-right intracardiac shunt and heart failure and the highest reduction in metabolic rate, up to 43%, was observed in these infants. The results indicate that corrective surgery for congenital cardiac malformations reduces the load on the cardiopulmonary system immediately after operation.