The impact of tacrolimus as rescue therapy in children using a double immunosuppressive regimen after heart transplantation.

BACKGROUND: Organ transplant recipients with refractory rejection or intolerance to the prescribed immunosuppressant may respond to rescue therapy with tacrolimus. We sought to evaluate the clinical outcomes of children undergoing heart transplantation who required conversion from a cyclosporine-based, steroid-free therapy to a tacrolimus-based regimen. METHODS: We performed a prospective, observational, cohort study of 28 children who underwent conversion from cyclosporine-based, steroid-free therapy to a tacrolimus-based therapy for refractory or late rejection or intolerance to cyclosporine. RESULTS: There was complete resolution of refractory rejection episodes and adverse side effects in all patients. The incidence rate (×100) of rejection episodes before and after conversion was 7.98 and 2.11, respectively (P ≤ .0001). There was a 25% mortality rate in patients using tacrolimus after a mean period of 60 months after conversion. CONCLUSION: Tacrolimus is effective as rescue therapy for refractory rejection and is a therapeutic option for pediatric patients.

Positive fluid balance is associated with reduced survival in critically ill patients with cancer.

BACKGROUND: There are no studies that describe the impact of the cumulative fluid balance on the outcomes of cancer patients admitted to intensive care units ICUs. The aim of our study was to evaluate the relationship between fluid balance and clinical outcomes in these patients. METHOD: One hundred twenty-two cancer patients were prospectively evaluated for survival during a 30-day period. Univariate (Chi-square, t-test, Mann-Whitney) and multiple logistic regression analyses were used to identify the admission parameters associated with mortality. RESULTS: The mean cumulative fluid balance was significantly higher in non-survivors than in survivors [1675 ml/24 h (471-2921) vs. 887 ml/24 h (104-557), P = 0.017]. We used the area under the curve and the intersection of the sensibility and specificity curves to define a cumulative fluid balance value of 1100 ml/24 h. This value was used in the univariate model. In the multivariate model, the following variables were significantly associated with mortality in cancer patients: the Acute Physiology and Chronic Health Evaluation II score at admission [Odds ratio (OR) 1.15; 95% confidence interval (CI) (1.05-1.26), P = 0.003], the Lung Injury Score at admission [OR 2.23; 95% CI (1.29-3.87), P = 0.004] and a positive fluid balance higher than 1100 ml/24 h at ICU [OR 5.14; 95% CI (1.45-18.24), P = 0.011]. CONCLUSION: A cumulative positive fluid balance higher than 1100 ml/24 h was independently associated with mortality in patients with cancer. These findings highlight the importance of improving the evaluation of these patients' volemic state and indicate that defined goals should be used to guide fluid therapy.

Use of pulse pressure variation to estimate changes in preload during experimental acute normovolemic hemodilution.

BACKGROUND: Acute normovolemic hemodilution (ANH) is an alternative to blood transfusion in surgeries involving blood loss. This experimental study was designed to evaluate whether pulse pressure variation (PPV) would be an adequate tool for monitoring changes in preload during ANH, as assessed by transesophageal echocardiography. METHODS: Twenty-one anesthetized and mechanically ventilated pigs were randomized into three groups: CTL (control), HES (hemodilution with 6% hydroxyethyl starch at a 1:1 ratio) or NS (hemodilution with saline 0.9% at a 3:1 ratio). Hemodilution was performed in animals of groups NS and HES in two stages, with target hematocrits 22% and 15%, achieved at 30-minute intervals. After two hours, 50% of the blood volume withdrawn was transfused and animals were monitored for another hour. Statistical analysis was based on ANOVA for repeated measures followed by multiple comparison test (P<0.05). Pearson's correlations were performed between changes in left ventricular end-diastolic volume (LVEDV) and PPV, central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP). RESULTS: Group NS received a significantly greater amount of fluids during ANH (NS, 900 ± 168 mL vs. HES, 200 ± 50 mL, P<0.05) and presented greater urine output (NS, 2643 ± 1097 mL vs. HES, 641 ± 338 mL, P<0.001). Significant decreases in LVEDV were observed in group NS from completion of ANH until transfusion. In group HES, only increases in LVEDV were observed, at the end of ANH and at transfusion. Such changes in LVEDV (∆LVEDV) were better reflected by changes in PPV (∆PPV, R=-0.62) than changes in CVP (∆CVP, R=0.32) or in PAOP (∆PAOP, R=0.42, respectively). CONCLUSION: Changes in preload during ANH were detected by changes in PPV. ∆PPV was superior to ∆PAOP and ∆CVP to this end.

Computed tomography assessment of lung structure in patients undergoing cardiac surgery with cardiopulmonary bypass

Hypoxemia is a frequent complication after coronary artery bypass graft (CABG) with cardiopulmonary bypass (CPB), usually attributed to atelectasis. Using computed tomography (CT), we investigated postoperative pulmonary alterations and their impact on blood oxygenation. Eighteen non-hypoxemic patients (15 men and 3 women) with normal cardiac function scheduled for CABG under CPB were studied. Hemodynamic measurements and blood samples were obtained before surgery, after intubation, after CPB, at admission to the intensive care unit, and 12, 24, and 48 h after surgery. Pre- and postoperative volumetric thoracic CT scans were acquired under apnea conditions after a spontaneous expiration. Data were analyzed by the paired Student t-test and one-way repeated measures analysis of variance. Mean age was 63 ± 9 years. The PaO2/FiO2 ratio was significantly reduced after anesthesia induction, reaching its nadir after CPB and partially improving 12 h after surgery. Compared to preoperative CT, there was a 31 percent postoperative reduction in pulmonary gas volume (P < 0.001) while tissue volume increased by 19 percent (P < 0.001). Non-aerated lung increased by 253 ± 97 g (P < 0.001), from 3 to 27 percent, after surgery and poorly aerated lung by 72 ± 68 g (P < 0.001), from 24 to 27 percent, while normally aerated lung was reduced by 147 ± 119 g (P < 0.001), from 72 to 46 percent. No correlations (Pearson) were observed between PaO2/FiO2 ratio or shunt fraction at 24 h postoperatively and postoperative lung alterations. The data show that lung structure is profoundly modified after CABG with CPB. Taken together, multiple changes occurring in the lungs contribute to postoperative hypoxemia rather than atelectasis alone.

Computed tomography assessment of lung structure in patients undergoing cardiac surgery with cardiopulmonary bypass.

Hypoxemia is a frequent complication after coronary artery bypass graft (CABG) with cardiopulmonary bypass (CPB), usually attributed to atelectasis. Using computed tomography (CT), we investigated postoperative pulmonary alterations and their impact on blood oxygenation. Eighteen non-hypoxemic patients (15 men and 3 women) with normal cardiac function scheduled for CABG under CPB were studied. Hemodynamic measurements and blood samples were obtained before surgery, after intubation, after CPB, at admission to the intensive care unit, and 12, 24, and 48 h after surgery. Pre- and postoperative volumetric thoracic CT scans were acquired under apnea conditions after a spontaneous expiration. Data were analyzed by the paired Student t-test and one-way repeated measures analysis of variance. Mean age was 63 ± 9 years. The PaO2/FiO2 ratio was significantly reduced after anesthesia induction, reaching its nadir after CPB and partially improving 12 h after surgery. Compared to preoperative CT, there was a 31% postoperative reduction in pulmonary gas volume (P < 0.001) while tissue volume increased by 19% (P < 0.001). Non-aerated lung increased by 253 ± 97 g (P < 0.001), from 3 to 27%, after surgery and poorly aerated lung by 72 ± 68 g (P < 0.001), from 24 to 27%, while normally aerated lung was reduced by 147 ± 119 g (P < 0.001), from 72 to 46%. No correlations (Pearson) were observed between PaO2/FiO2 ratio or shunt fraction at 24 h postoperatively and postoperative lung alterations. The data show that lung structure is profoundly modified after CABG with CPB. Taken together, multiple changes occurring in the lungs contribute to postoperative hypoxemia rather than atelectasis alone.

Severe novel influenza A (H1N1) infection in cancer patients.

BACKGROUND: The natural history and consequences of severe H1N1 influenza infection among cancer patients are not yet fully characterized. We describe eight cases of H1N1 infection in cancer patients admitted to the intensive care unit of a referral cancer center. PATIENTS AND METHODS: Clinical data from all patients admitted with acute respiratory failure due to novel viral H1N1 infection were reviewed. Lung tissue was submitted for viral and bacteriological analyses by real-time RT-PCR, and autopsy was conducted on all patients who died. RESULTS: Eight patients were admitted, with ages ranging from 55 to 65 years old. There were five patients with solid organ tumors (62.5%) and three with hematological malignancies (37.5%). Five patients required mechanical ventilation and all died. Four patients had bacterial bronchopneumonia. All deaths occurred due to multiple organ failure. A milder form of lung disease was present in the three cases who survived. Lung tissue analysis was performed in all patients and showed diffuse alveolar damage in most patients. Other lung findings were necrotizing bronchiolitis or extensive hemorrhage. CONCLUSIONS: H1N1 viral infection in patients with cancer can cause severe illness, resulting in acute respiratory distress syndrome and death. More data are needed to identify predictors of unfavorable evolution in these patients.

Lung hyperinflation stimulates the release of inflammatory mediators in spontaneously breathing subjects.

Lung hyperinflation up to vital capacity is used to re-expand collapsed lung areas and to improve gas exchange during general anesthesia. However, it may induce inflammation in normal lungs. The objective of this study was to evaluate the effects of a lung hyperinflation maneuver (LHM) on plasma cytokine release in 10 healthy subjects (age: 26.1 +/- 1.2 years, BMI: 23.8 +/- 3.6 kg/m(2)). LHM was performed applying continuous positive airway pressure (CPAP) with a face mask, increased by 3-cmH(2)O steps up to 20 cmH(2)O every 5 breaths. At CPAP 20 cmH(2)O, an inspiratory pressure of 20 cmH(2)O above CPAP was applied, reaching an airway pressure of 40 cmH(2)O for 10 breaths. CPAP was then decreased stepwise. Blood samples were collected before and 2 and 12 h after LHM. TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, and IL-12 were measured by flow cytometry. Lung hyperinflation significantly increased (P < 0.05) all measured cytokines (TNF-alpha: 1.2 +/- 3.8 vs 6.4 +/- 8.6 pg/mL; IL-1beta: 4.9 +/- 15.6 vs 22.4 +/- 28.4 pg/mL; IL-6: 1.4 +/- 3.3 vs 6.5 +/- 5.6 pg/mL; IL-8: 13.2 +/- 8.8 vs 33.4 +/- 26.4 pg/mL; IL-10: 3.3 +/- 3.3 vs 7.7 +/- 6.5 pg/mL, and IL-12: 3.1 +/- 7.9 vs 9 +/- 11.4 pg/mL), which returned to basal levels 12 h later. A significant correlation was found between changes in pro- (IL-6) and anti-inflammatory (IL-10) cytokines (r = 0.89, P = 0.004). LHM-induced lung stretching was associated with an early inflammatory response in healthy spontaneously breathing subjects.

Effect of cardiopulmonary bypass on the pharmacokinetics of propranolol and atenolol.

The pharmacokinetics of some beta-blockers are altered by cardiopulmonary bypass (CPB). The objective of this study was to compare the effect of coronary artery bypass graft (CABG) surgery employing CPB on the pharmacokinetics of propranolol and atenolol. We studied patients receiving oral propranolol with doses ranging from 80 to 240 mg (N = 11) or atenolol with doses ranging from 25 to 100 mg (N = 8) in the pre- and postoperative period of CABG with moderately hypothermic CPB (32 degrees C). On the day before and on the first day after surgery, blood samples were collected before beta-blocker administration and every 2 h thereafter. Plasma levels were determined using high-performance liquid chromatography and data were treated by pharmacokinetics-modelling. Statistical analysis was performed using ANOVA or the Friedman test, as appropriate, and P < 0.05 was considered to be significant. A prolongation of propranolol biological half-life from 5.41 +/- 0.75 to 11.46 +/- 1.66 h (P = 0.0028) and an increase in propranolol volume of distribution from 8.70 +/- 2.83 to 19.33 +/- 6.52 L/kg (P = 0.0032) were observed after CABG with CPB. No significant changes were observed in either atenolol biological half-life (from 11.20 +/- 1.60 to 11.44 +/- 2.89 h) or atenolol volume of distribution (from 2.90 +/- 0.36 to 3.83 +/- 0.72 L/kg). Total clearance was not changed by surgery. These CPB-induced alterations in propranolol pharmacokinetics may promote unexpected long-lasting effects in the postoperative period while the effects of atenolol were not modified by CPB surgery.

Hemodynamic effects of PEEP in a porcine model of HCl-induced mild acute lung injury.

BACKGROUND: Positive end-expiratory pressure (PEEP) and sustained inspiratory insufflations (SI) during acute lung injury (ALI) are suggested to improve oxygenation and respiratory mechanics. We aimed to investigate the hemodynamic effects of PEEP with and without alveolar recruiting maneuver in a mild ALI model induced by inhalation of hydrochloric acid. METHODS: Thirty-two pigs were randomly allocated into four groups (Control-PEEP, Control-SI, ALI-PEEP and ALI-SI). ALI was induced by intratracheal instillation of hydrochloric acid. PEEP values were progressively increased and decreased from 5, 10, 15 and 20 cmH2O in all groups. Three SIs maneuvers of 30 cmH2O for 20 s were applied to the assignable groups between each PEEP level. Transesophageal echocardiography (TEE), global hemodynamics, oxygenation indexes and gastric tonometry were measured 5 min after the maneuvers had been concluded and at each established value of PEEP (5, 10, 15 and 20 cmH2O). RESULTS: The cardiac index, ejection fraction and end-diastolic volume of right ventricle were significantly (P < 0.001) decreased with PEEP in both Control and ALI groups. Left ventricle echocardiography showed a significant decrease in end-diastolic volume at 20 cmH2O of PEEP (P < 0.001). SIs did not exert any significant hemodynamic effects either early (after 5 min) or late (after 3 h). CONCLUSIONS: In a mild ALI model induced by inhalation of hydrochloric acid, significant hemodynamic impairment characterized by cardiac function deterioration occurred during PEEP increment, but SI, probably due to low applied values (30 cmH2O), did not exert further negative hemodynamic effects. PEEP should be used cautiously in ALI caused by acid gastric content inhalation.

Comparative study of pressure- and volume-controlled ventilation on pulse pressure variation in a model of hypovolaemia in rabbits.

BACKGROUND AND OBJECTIVE: Dynamic indices represented by systolic pressure variation and pulse pressure variation have been demonstrated to be more accurate than filling pressures in predicting fluid responsiveness. However, the literature is scarce concerning the impact of different ventilatory modes on these indices. We hypothesized that systolic pressure variation or pulse pressure variation could be affected differently by volume-controlled ventilation and pressure-controlled ventilation in an experimental model, during normovolaemia and hypovolaemia. METHOD: Thirty-two anaesthetized rabbits were randomly allocated into four groups according to ventilatory modality and volaemic status where G1-ConPCV was the pressure-controlled ventilation control group, G2-HemPCV was associated with haemorrhage, G3-ConVCV was the volume-controlled ventilation control group and G4-HemVCV was associated with haemorrhage. In the haemorrhage groups, blood was removed in two stages: 15% of the estimated blood volume withdrawal at M1, and, 30 min later, an additional 15% at M2. Data were submitted to analysis of variance for repeated measures; a value of P < 0.05 was considered to be statistically significant. RESULTS: At M0 (baseline), no significant differences were observed among groups. At M1, dynamic parameters differed significantly among the control and hypovolaemic groups (P < 0.05) but not between ventilation modes. However, when 30% of the estimated blood volume was removed (M2), dynamic parameters became significantly higher in animals under volume-controlled ventilation when compared with those under pressure-controlled ventilation. CONCLUSIONS: Under normovolaemia and moderate haemorrhage, dynamic parameters were not influenced by either ventilatory modalities. However, in the second stage of haemorrhage (30%), animals in volume-controlled ventilation presented higher values of systolic pressure variation and pulse pressure variation when compared with those submitted to pressure-controlled ventilation.

Pulse pressure variation as a tool to detect hypovolaemia during pneumoperitoneum.

BACKGROUND: Pulse pressure variation (DeltaPP) and systolic pressure variation (SPV) induced by mechanical ventilation have been proposed to detect hypovolaemia and guide fluid therapy. During laparoscopic surgery, chest compliance is decreased by pneumoperitoneum. This may affect the value of SPV and DeltaPP as indicators of intravascular volume status. Thereby, we investigated the effects of pneumoperitoneum and hypovolaemia on SPV and DeltaPP. METHODS: We measured DeltaPP, SPV and the inspiratory (Deltaup) and expiratory (Deltadown) components of SPV, at baseline, during pneumoperitoneum, during pneumoperitoneum and hypovolaemia and after the return to baseline conditions, in 11 mechanically ventilated rabbits. Pneumoperitoneum was induced by inflating the abdomen with carbon dioxide, and hypovolaemia was induced by controlled haemorrhage. RESULTS: Pneumoperitoneum induced an increase in SPV from 8.5 +/- 1.6 to 13.3 +/- 2.6 mmHg (+56%, P < 0.05) as a result of an increase in Deltaup from 2.0 +/- 1.0 to 6.7 +/- 2.1 mmHg (+236%, P < 0.05), but no significant change in Deltadown, nor in DeltaPP. Haemorrhage induced a significant (P < 0.05) increase in SPV from 13.3 +/- 2.6 to 19.9 +/- 3.7 mmHg (+50%), in Deltadown from 6.6 +/- 3.3 to 14.0 +/- 4.9 mmHg (+112%) and in DeltaPP from 11.1 +/- 4.8 to 24.9 +/- 9.8% (+124%) but no change in Deltaup. All parameters returned to baseline values after blood re-infusion and abdominal deflation. CONCLUSIONS: SPV is modified by haemorrhage but it is also influenced by pneumoperitoneum. In contrast, DeltaPP is modified by haemorrhage but not by pneumoperitoneum. These findings suggest that DeltaPP should be used preferentially instead of SPV to detect hypovolaemia and guide fluid therapy during laparoscopic surgery.

Hydroxyethyl starch is superior to lactated Ringer as a replacement fluid in a pig model of acute normovolaemic haemodilution.

BACKGROUND: Tissue tolerance to oxygen privation during acute normovolaemic haemodilution with different fluids remains unclear. We tested the hypothesis that hydroxyethyl starch (HES) is superior to lactated Ringer's solution in pigs for preserving tissue perfusion during acute normovolaemic haemodilution. METHODS: Twenty-four animals were randomized into control, lactated Ringer's solution and HES groups. All groups, except the control, underwent acute normovolaemic haemodilution. Haemodynamics, oxygen parameter indices, global anaerobic metabolic markers, echocardiographic parameters, gastric tonometry and serum osmolarity were monitored at baseline, immediately after (0 min) and 60 and 120 min after the end of haemodilution. Myocardial, liver, stomach and intestine samples were collected for further evaluation. RESULTS: Cardiac and oxygen parameter index responses to acute normovolaemic haemodilution were comparable. However, the increment in cardiac index, stroke volume index, and left ventricular stroke work index were more sustained in the starch group. In the lactated Ringer's group, gastric pH decreased significantly and was accompanied by a significant increase in lactate. Myocardial ultrastructure was better preserved in the starch group. The other tissue samples presented no change. CONCLUSIONS: In this model of ANH, the starch group had a superior haemodynamic response. Minor loss of myocardial cellular integrity and preserved gastric pHi reinforce these findings.

Apolipoprotein E4 genotype increases the risk of postoperative cognitive dysfunction in patients undergoing coronary artery bypass graft surgery.

AIM: The aim of this study was to investigate the association between the presence of ApoE4 and the incidence of postoperative cognitive dysfunction (POCD) after cardiac surgery. METHODS: Eighty-seven adult patients undergoing elective coronary artery bypass graft surgery were observed prospectively at a university tertiary care hospital. All patients were evaluated with the Mini-Mental State Examination (MMSE) and the Glasgow Coma Scale (GCS) for cognitive function and mental status preoperatively, 24 h after surgery and at postoperative day 6. Patients were genotyped for the ApoE polymorphism. The association between ApoE genotype and MMSE evolution was studied by using repeated measures ANOVA. RESULTS: Both the presence of at least one ApoE4 allele and POCD were verified in 21.8% of subjects. The presence of the ApoE4 allele was significantly associated with a worse MMSE score evolution (P=0.04). CONCLUSION: This study suggests an association between ApoE4 and early POCD, but further studies are needed to clarify a causative association. Such new studies should include a more homogenous patient sample and a longer follow-up.

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery.

The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB), resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 +/- 8 years, mean weight 75.4 +/- 11.9 kg and mean body surface area 1.83 +/- 0.19 m(2)), receiving propranolol before surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95% CI = 3.9-6.9) to 10.6 h (95% CI = 8.2-14.7; P < 0.01) and an increase in volume of distribution from 4.9 (95% CI = 3.2-14.3) to 8.3 l/kg (95% CI = 6.5-32.1; P < 0.05), while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6) vs 10.7 ml min(-1) kg(-1) (95% CI = 7.7-26.6; NS) after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

Systemic availability of prophylactic cefuroxime in patients submitted to coronary artery bypass grafting with cardiopulmonary bypass.

Cardiopulmonary bypass and hypothermia (HCPB) is a procedure commonly used during heart surgery, representing a risk factor for the patient by promoting extensive haemodilution and profound physiological changes. Cefuroxime is used for the prevention of infection following heart surgery, and several dose schemes have been suggested for prophylaxis with cefuroxime. The objective of the present study was to assess, in a comparative manner, the systemic availability of cefuroxime administered intravascularly as a bolus dose of 1.5 g to 17 patients having heart surgery with or without HCPB. Plasma cefuroxime concentrations were determined by high-pressure liquid chromatography-UV, and the following values, expressed as medians, were obtained for the study group compared with controls: 69.1 vs. 62.7 mg/L (1st h), 35.8 vs. 26.0mg/L (3rd h), 14.6 vs. 8.7 mg/L (6th h, P<0.05), 6.1 vs. 3.0mg/L (9th h, P<0.05) and 2.6 vs. 1.0mg/L (12th h, P<0.05). Despite the differences recorded during the study period as a consequence of HCPB, low antibiotic concentrations were found as early as 6h post dose for both groups investigated. Thus, the low systemic availability of cefuroxime after the administration of a 1.5-g dose may not protect against postoperative infections. The data obtained permit us to recommend a change in the dose scheme in order to maintain adequate plasma levels of cefuroxime.

Effects of low doses of inhaled nitric oxide combined with oxygen for the evaluation of pulmonary vascular reactivity in patients with pulmonary hypertension.

The purpose of this study was to evaluate the hemodynamic effects of inhaled nitric oxide in oxygen (NO + O2) in patients with pulmonary hypertension. Eighteen patients (median age 31.5 months) with pulmonary hypertension inhaled through a mask 100% O2 and 20 parts per million NO + inspired O2 fraction (FiO2) at 0.4. Hemodynamic measurements were made at baseline and after O2 and NO + O2 administration. The pulmonary vascular resistance index decreased after inhalation of O2 and NO + O2 (p = 0.0018 and p = 0.0003, respectively), the decrease being significantly greater after NO + O2 (p = 0.0311). Concerning the transpulmonary pressure gradient, a reduction occurred in values after O2 and NO + O2 inhalation when compared with baseline values (p = 0.0014 and p = 0.0008). In patients with congenital heart disease, an increase occurred in pulmonary blood flow after O2 (p = 0.0089) and NO + O2 (p = 0.0019) compared with baseline values, and an increase also occurred in the pulmonary/systemic blood flow ratio after NO + O2 (p = 0.0017). The main side effect related to NO + O2 was pulmonary congestion in 3 patients. Low doses of NO combined with O2 demonstrated a selective pulmonary vasodilator response in patients with pulmonary hypertension. Despite its use for testing pulmonary reactivity, inhalation of NO + O2 should be carefully administered because of the potential risk of pulmonary congestion.

Heart transplantation in neonates and children. Intermediate-term results.

OBJECTIVE: To assess intermediate-term outcome in children who have undergone orthotopic heart transplantation. METHODS: We carried out a longitudinal and prospective study between October '92 and June '99 comprising 20 patients with ages ranging from 12 days to 7 years (mean of 2.8 years). We employed a double immunosuppression protocol with cyclosporine and azathioprine and induction therapy with polyclonal antithymocyte serum. Survival and complications resulting from the immunosuppression protocol were analyzed. RESULTS: The double immunosuppression protocol and the induction therapy with polyclonal antithymocyte serum resulted in an actuarial survival curve of 90% and 78.2% at 1 and 6 years, respectively, with a mean follow-up period of 3.6 years. One patient died due to acute rejection 40 days after transplantation; another patient died 2 years after transplantation due to lymphoproliferative disorder; a third patient died because of primary failure of the graft; and a fourth patient died due to bronchopneumonia. The major complications were as follows: acute rejection, infection, nephrotoxicity, and systemic hypertension. The means of rejection and infection episodes per patient were 2.9 and 3.4, respectively. After one year of transplantation, a slight reduction in the creatinine clearance and systemic hypertension were observed in 7 (38.9%) patients. CONCLUSION: Heart transplantation made life possible for those patients with complex congenital heart diseases and cardiomyopathies in refractory congestive heart failure constituting a therapeutical option for this group of patients in the terminal phase.

A micromethod for quantitation of debrisoquine and 4-hydroxydebrisoquine in urine by liquid chromatography.

We describe a new simple, selective and sensitive micromethod based on HPLC and fluorescence detection to measure debrisoquine (D) and 4-hydroxydebrisoquine (4-OHD) in urine for the investigation of xenobiotic metabolism by debrisoquine hydroxylase (CYP2D6). Four hundred microl of urine was required for the analysis of D and 4-OHD. Peaks were eluted at 8.3 min (4-OHD), 14.0 min (D) and 16.6 min for the internal standard, metoprolol (20 microg/ml). The 5-microm CN-reverse-phase column (Shimpack, 250 x 4.6 mm) was eluted with a mobile phase consisting of 0.25 M acetate buffer, pH 5.0, and acetonitrile (9:1, v/v) at 0.7 ml/min with detection at lambdaexcitation = 210 nm and lambdaemission = 290 nm. The method, validated on the basis of measurements of spiked urine, presented 3 ng/ml (D) and 6 ng/ml (4-OHD) sensitivity, 390-6240 ng/ml (D) and 750-12000 ng/ml (4-OHD) linearity, and 5.7/8.2% (D) and 5.3/8.2% (4-OHD) intra/interassay precision. The method was validated using urine of a healthy Caucasian volunteer who received one 10-mg tablet of Declinax(R), po, in the morning after an overnight fast. Urine samples (diuresis of 4 or 6 h) were collected from zero to 24 h. The urinary excretion of D and 4-OHD, Fel (0-24 h), i.e., fraction of dose administered and excreted into urine, was 6.4% and 31.9%, respectively. The hydroxylation capacity index reported as metabolic ratio was 0.18 (D/4-OHD) for the person investigated and can be compared to reference limits of >12.5 for poor metabolizers (PM) and <12.5 for extensive metabolizers (EM). In parallel, the recovery ratio (RR), another hydroxylation capacity index, was 0.85 (4-OHD: SigmaD + 4-OHD) versus reference limits of RR <0.12 for PM and RR >0. 12 for EM. The healthy volunteer was considered to be an extensive metabolizer on the basis of the debrisoquine test.