Disease-related response to inhaled nitric oxide in newborns with severe hypoxaemic respiratory failure

Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10–80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51 ± 21 vs 23 ± 17, P < .0001) or term infants with idiopathic or acute respiratory distress syndrome (45 ± 20 vs 20 ± 17, P < .0001), `idiopathic' PPHN (39 ± 14 vs 14 ± 9, P < .0001), and sepsis (55 ± 25 vs 26 ± 20, P < .0001) provided there was no associated refractory shock. Improvement in oxygenation was less significant and sustained (OI = 41 ± 16 vs 28 ± 18, P < .001) in term neonates with meconium aspiration syndrome and much less (OI = 58 ± 25 vs 46 ± 32, P < .01) in those with congenital diaphragmatic hernia. Only 21 of the 129 term newborns (16%) required extracorporeal membrane oxygenation (57% survival). Survival was significantly associated with the magnitude in the reduction in OI at 30 min of iNO therapy, a gestational age ≥34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants. Received: 24 April 1997 / Accepted in revised form 3 January 1998     

A comparison of intratracheal and intravenous administration of gentamicin during liquid ventilation

Pulmonary absorption of aminoglycosides is poor with intravenous administration, but may be enhanced by direct intratracheal administration of these drugs using perfluorochemical liquid ventilation (LV). To test this hypothesis, gentamicin sulfate was administered to two groups of newborn lambs during LV. Serum and lung tissue levels of gentamicin were compared after either pulmonary intratracheal (IT) or intravenous (IV) routes of administration. Serial serum levels of gentamicin were obtained every 15 min for the 1st h, every 30 min for the 2nd h, and then hourly until sacrifice (maximum 6 h). At sacrifice, representative samples of each lung lobe were homogenized and analyzed for tissue gentamicin content. At 1 h, serum gentamicin levels were similar in both groups: IT administration levels were 3.7 ± 0.55 SE μg/ml and IV levels were 3.5 ± 0.85 SE μg/ml. The peak serum gentamicin level of 4.8 ± 0.8 SE μg/ml for the pulmonary administration group occurred 1.5 h after administration. Lung tissue levels of gentamicin for IT administration (4.04 ± 0.62 SE μg/g) were significantly greater than for IV administration (1.75 ± 0.33 SE μg/g; P < 0.05). There were no significant differences in interlobar gentamicin distribution for either mode of administration. Conclusion Perfluorochemical can be used as a vehicle for intratracheal delivery of antimicrobials. This route provides equivalent serum levels at 1 h, higher lung tissue levels, and uniform interlobar distribution relative to intravenous administration of gentamicin. We speculate that pulmonary administered gentamicin during LV may provide an effective alternative treatment modality in the management of severe neonatal pneumonia. Received: 12 April 1996 and in revised form: 24 July 1996 / Accepted 28 July 1996     

Right Ventricular Diastolic Function After Repair of Tetralogy of Fallot

The objective of this study was quantitate diastolic dysfunction in the postoperative phase of tetralogy of Fallot (TOF) and to correlate it with the type of surgical procedure and clinical parameters. Fifty consecutive patients (mean age, 5.0 years; mean weight, 13.5 kg), operated for TOF during the period November 2004 to May 2005, were prospectively studied [infundibular resection, 23; infundibular resection and transannular patch (TAP), 19; right ventricle→pulmonary artery conduit, 8). Detailed echocardiography was done on postoperative days 3 and 9 with a focus on Doppler indices of right ventricular (RV) function, Antegrade late diastolic flow in the right ventricular outflow tract (RVOT) was taken as the marker of restrictive RV physiology. The previous parameters were correlated to the type of surgery and clinical indices of RV dysfunction. There was no mortality. Twenty-four patients showed restrictive RV physiology. This finding correlated with lower values of E/A ratio (0.98 ± 0.17 vs 1.33 ± 0.49, p < 0.002), tricuspid valve E-wave deceleration time (86.9 ± 21.7 vs 151.4 ± 152 msec, p < 0.05), index of myocardial performance (0.15 ± 0.06 vs 0.26 ± 0.09, p < 0.001), isovolumic relaxation time (19.4 ± 17 vs 39±30 msec, p < 0.009), and a higher central venous pressure (15.1 ± 1.5 vs 12.7 ± 1.9, p < 0.001). Restrictive RV physiology correlated with prolonged intensive case unit (ICU) stay (5.1 ± 3.7 vs 2.8 ± 2 days, p < 0.015), longer duration of inotropic support (108.3 ± 56.2 vs 55.5 ± 28.3 hours, p < 0.02), and higher dosage of diuretics. RV diastolic dysfunction is demonstrable by Doppler echocardiography in the first week following surgery for TOF and tends to be worse with TAP. Restrictive physiology demonstrated by RVOT pulse Doppler predicts longer duration of inotropic support, prolonged ICU stay, and higher dosage of diuretics.     

Ureaplasma urealyticum colonization and bronchopulmonary dysplasia: a comparative prospective multicentre study

To determine the role of tracheal colonization at birth with Ureaplasma urealyticum and other pathogenic bacteria with regard to the development of bronchopulmonary dysplasia (BPD), 97 premature infants with very low birth weight (<1500 g) were followed prospectively over 30 days in a multicentre study. Of those infants, 35 were colonized with Ureaplasma urealyticum (group Ia), 22 with other pathogenic bacteria (group Ib) and 40 infants with sterile tracheal aspirates served as controls (group II). Colonization with Ureaplasma urealyticum or with pathogenic bacteria independently increased the risk of developing BPD as compared to the controls (OR 2.55; 95% CI [1.11, 5.87]). Among Ureaplasma urealyticum and bacterial colonized infants, duration of mechanical ventilation and oxygen requirement were significantly longer than among controls (P < 0.05); during the interval of 11 to 35 days of life, every additional day of ventilation significantly increased the risk of BPD (OR 1.22; CI [1.12, 1.32]). The rate of oxygen supplementation, which was similar in both groups during the first 2 weeks of life, was significantly higher among the colonized infants at day 21 (0.38 ± 0.18 and 0.39 ± 0.16 vs 0.31 ± 0.13, P < 0.05) and at day 28 (0.38 ± 0.21 and 0.34 ± 0.15 vs 0.28 ± 0.12, P < 0.05). For infants still ventilated at age of 28 days, Ureaplasma urealyticum and bacterial colonization were associated with a significant higher risk for BPD than for uncolonized controls (OR 5.53; [1.27, 24.02]. Association of Ureaplasma urealyticum and of bacterial colonization and BPD was not weakened after adjustments were made in a multivariate analysis for other significant risk factors. Conclusion Ureaplasma urealyticum colonization is as an important risk factor in the development of bronchopulmonary dysplasia as bacterial colonization even after treatment with surfactant. Received: 23 January 1997 and in revised form: 30 December 1997 / Accepted: 5 January 1998     

Recovery of the Chronically Hypoxic Young Rabbit Heart Reperfused Following No-Flow Ischemia

The objective of this study was to test whether chronically hypoxic immature hearts exhibit greater tolerance to no-flow ischemia than normoxic hearts. Rabbits (N = 36) were raised from birth to 5 weeks of age in either hypoxic (10% O₂/90% N₂) or normoxic (room air) environment. Isolated, isovolumically beating hearts, with a fluid-filled balloon catheter in the left ventricular chamber, were perfused with a well-oxygenated buffer and studied during baseline [30 minutes; perfusion pressure, 60 mmHg; end diastolic pressure (EDP), 5 mmHg], no-flow ischemia (until onset of contracture or for 30 minutes), and Reperfusion (30 minutes; perfusion pressure, 60 mmHg). Time for onset of contracture (TOC) was defined by an increase in balloon pressure of 5 mmHg. The results were as follows: hypoxic vs normoxic: Hct, 56.4 ± 2.5* vs 36.3 ± 0.4%, (right ventricle/left ventricle) weight (dry) ratio, 0.50 ± 0.04* vs 0.28 ± 0.02. Baseline: developed pressure (ΔP), 96 ± 4 vs 93 ± 5 mmHg; coronary flow, 90 ± 10* vs 62 ± 4 ml/min/g_dry. No-flow ischemia: TOC, 12 ± 1* vs 24 ± 2 minutes. All hypoxic (no normoxic) hearts reached peak contracture. Reperfusion: Just after onset of contracture, ΔP, 80 ± 3* vs 67 ± 4 mmHg; EDP, 5 ± 1* vs 13 ± 2 mmHg; after 30 minutes of no-flow ischemia, ΔP, 58 ± 5 vs 46 ± 4 mmHg; EDP, 13 ± 1* vs 24 ± 3 mmHg; lactate release (LR), 0.15 ± 0.01 vs 0.17 ± 0.01 mmol/g_dry, creatine kinase release (CKR), 46 ± 8* vs 242 ± 28 U/g_dry. For hypoxic hearts reperfused after onset of contracture, LR was 0.11 ± 0.03 mmol/g_dry, comparable to that following 30 minutes of no-flow ischemia (*p < 0.05). Rabbit hearts subjected to hypoxia from birth developed ischemic contracture earlier and reached peak contracture, showed no significant increase in LR after onset of contracture, exhibited better recovery of EDP, and had markedly reduced CKR compared to normoxic controls.     

Effect of inhaled nitric oxide on intrapulmonary right-to-left-shunting in two rabbit models of saline lavage induced surfactant deficiency and meconium instillation

Marked hypoxia secondary to intrapulmonary right-to-left shunting is a characteristic of respiratory failure in human neonates and can sometimes be complicated by additional extrapulmonary right-to-left shunting. To investigate the effect of inhaled nitric oxide (iNO) on intrapulmonary shunting, two typical pulmonary diseases of the newborn (respiratory distress syndrome and meconium aspiration) were reproduced in 32 mechanically ventilated rabbits weighing approximately 2 kg each. After tracheotomy, catheters were inserted into a jugular vein, a carotid artery and the right ventricle (to measure systolic right ventricular pressure [SRVP] and mixed venous oxygen content for calculation of shunt by Fick equation). Repeated airway lavages (LAV) with normal saline or repeated instillations of a suspension of human meconium (MEC) were continued until both the a/A-ratio was ≤0.14 and a peak inspiratory pressure ≥22 mbar was needed to keep the tidal volume constant at 10 ml/kg of body weight. Measurements of shunt, SRVP, systolic systemic pressure, physiological dead space, tidal volume and a ventilation index were performed before and after completion of lung damage and at 20 and 60 min after administering iNO at 80 ppm. Four groups of rabbits were studied (n = 8 in each group): LAV control and intervention, Mec control and intervention. 60 min after starting iNO, there was a decrease in shunt (LAV: 67.6% ± [SD] 11.3% vs 56.2 ± 16.4, P = 0.05; MEC: 52.6 ± 6.3 vs 44.3 ± 8.3, P < 0.05), in SRVP (LAV: 29.7 mmHg ± 10.1 mmHg vs 20.0 ± 8.2, P < 0.01; MEC: 25.1 ± 4.4 vs 22.3 ± 5.0, P = 0.46) and in dead space (% of tidal volume, LAV: 32.7% ± 10.5% vs 25.9 ± 10.1, P < 0.01; MEC: 26.1 ± 16.6 vs 18.9 ± 10.1, P = 0.05). These results demonstrate that iNO decreases intrapulmonary shunt (as well as SRVP and dead space). We suggest that iNO may be beneficial in human newborns with severe respiratory failure even if no extrapulmonary shunting via ductus or foramen ovale is apparent. Received: 18 March 1997 and revised form 6 September 1997 / Accepted: 7 September 1997     

Respiratory hospitalizations and respiratory syncytial virus prophylaxis in special populations

Palivizumab utilization, compliance, and outcomes were examined in infants with preexisting medical diseases within the Canadian Registry Database (CARESS) to aid in developing guidelines for potential “at-risk” infants in the future. Infants who received ≥1 dose of palivizumab during the 2006–2010 respiratory syncytial virus (RSV) seasons at 29 sites were recruited and utilization, compliance, and outcomes related to respiratory infection/illness (RI) events were collected monthly. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for premature infants ≤35 completed weeks gestational age (GA) who met standard approval criteria (group 1) compared to those with medical disorders (group 2) using Cox proportional hazards regression models with adjustment for potential confounding factors. Of 7,339 registry infants, 4,880 were in group 1 and 952 in group 2, which included those with Down syndrome (20.3%), upper airway anomalies (18.7%), pulmonary diseases (13.3%), and cystic fibrosis (12.3%). Group 2 were older at enrolment (10.2 ± 9.2 vs. 3.5 ± 3.1 months, p < 0.0005), had higher GA (35.9 ± 6.0 vs. 31.0 ± 5.4 weeks, p < 0.0005), and were less compliant with treatment intervals (69.4% vs. 72.6%, p = 0.048). A greater proportion of group 2 infants were hospitalized for RI (9.0% vs. 4.2%, p < 0.0005) and RSV (2.4% vs. 1.3%, p = 0.003) (unadjusted). Being in group 2 was associated with an increased risk of RI (HR = 2.0, 95%CI 1.5–2.5, p < 0.0005), but not RSV hospitalization (HR = 1.6, 95%CI 0.9–2.8, p = 0.106). In infants receiving palivizumab, those with underlying medical disorders, though not currently approved for prophylaxis, are at higher risk for RI events compared with preterm infants. However, risk of RSV hospitalizations is similar.     

Iron metabolism in burned children

The administration of iron supplementation in children with burns has been a subject of controversy. Recent studies argue against its use in the acute phase of stress. To assess whether iron metabolism parameters show significant differences in the acute phase and the recovery phase of burn, 21 patients (age range: 17 months to 13 years) with burns of more than 10% of body surface who had not received blood transfusions or iron supplementation were studied. Sideraemia, ferritin, transferrin, transferrin saturation index (TSI) and C-reactive protein (CRP) were assessed both in the acute and the recovery phase after burn. Sideraemia, transferrin, and TSI were significantly lower in the acute than in the recovery phase (17.3 ± 3 vs 53.8 ± 6.6 μg/dL, 190.5 ± 15 vs 287.9 ± 14.3 mg/dL and 7.7 ± 1.3 vs 15.4 ± 1.6%, P < 0.0001, P < 0.001 and P = 0.0006, respectively) while plasma ferritin and CRP were significantly higher (84.7 ± 8.8 vs 43.1 ± 8.5 ng/mL and 9.5 ± 1.5 vs 0.7 ± 0.2 mg/dL, P = 0.016 and P < 0.0001, respectively). When the above parameters were analysed based on age (≤ 2 years, >2 years), the observed differences persisted. Conclusion Hyposideraemia is a frequent finding in the acute phase of paediatric burns and is accompanied by increased ferritin levels and decreased transferrin concentrations. The low iron values tend to recover without the use of iron supplementation suggesting an endogenous block of iron release in the acute phase and indicates that iron therapy should be not recommended in the initial period of stress of the burned patient. Received: 12 March 1998 / Accepted in revised form: 2 September 1998     

Phototherapy for neonatal hyperbilirubinemia affects cytokine production by peripheral blood mononuclear cells

The capacity of peripheral blood mononuclear cells (PBMC) to produce interleukin (IL) IL-1β, IL-2, IL-3, IL-6, IL-10 and tumor necrosis factor-α (TNFα) was examined in term newborns with hyperbilirubinemia after 24 hours' exposure to phototherapy (wave length 425–475 nm). The results were compared with those from untreated neonates. Fifty newborns spontaneously delivered at term were included in the study. Blood samples were collected from 20 newborns before and 24 h after phototherapy. The control group consisted of 30 neonates examined on two consecutive days. PBMC isolated from blood samples were incubated in vitro for cytokine production. The concentration of cytokines in the supernatants was tested using ELISA kits (for IL-1β, IL-6, IL-10 and TNFα), or by bioassays (for IL-2 and IL-3). Phototherapy caused a 70% increase in IL-2 secretion (123 ± 27 vs 208 ± 30 units/ml, P < 0.01) and 56% in IL-10 production (1.07 ± 0.19 vs 1.67 ± 0.33 ng/ml, P < 0.03), whereas the spontaneous secretion of IL-1β was reduced by 43% (13.7 ± 2.3 vs 7.3 ± 1.7 ng/ml, P < 0.02). In the control group the secretion of these cytokines was similar on the two consecutive days and did not differ significantly from secretion in the other group before phototherapy. On the other hand, lipopolysaccharide induced TNFα production was higher on the second day in the two groups of newborns irrespective of phototherapy (388 ± 58 vs 683 ± 88 pg/ml, P < 0.001, in the control group and 384 ± 75 vs 588 ± 91, P < 0.05, before and after phototherapy). The synthesis of IL-3 and IL-6 did not change significantly between the two days of the study. The results demonstrate that in addition to the well-known positive effect of phototherapy on the neonate serum bilirubin level, this treatment affects the function of the immune system in newborns via alterations in cytokine production. Received: 4 September 1997 / Accepted: 14 February 1998     

The effects of body positioning on sucking behaviour in sick neonates

Some infants show better oxygenation in the prone position compared to the supine position while they are bottle-fed; however, the reason for this phenomenon is not clear. The purpose of this study was to obtain a better understanding of the effects of body position on the oral feeding performance, i.e. the sucking pressure, frequency, efficiency, and ventilation. A total of 14 infants (12 full-term, 2 preterm), who often showed O₂ desaturation (SpO₂ < 90) during oral feeding, were enrolled in the study. The infants were fed either in the supine position or in the prone position throughout feeding. Oxygen saturation was recorded with a pulse oxymeter. The sucking pressure was measured with a 1 mm I.D. silicone tube inserted into the artificial nipple. The ventilation volume during bottle feeding was measured with a pneumotachograph. The prone position resulted in better oxygenation (97.2 ± 0.6% prone, 92.5 ± 0.9% supine, P < 0.05) and larger tidal volume (6.4 ± 0.8 ml/kg prone and 4.9 ± 0.6 ml/kg supine, P < 0.05), although the minute ventilation during bottle-feeding was not different from that in the supine position. In the prone position, the sucking pressure and frequency were higher and the duration of each suck was shorter. Conclusion Sucking in the prone position may to some extent reduce disadvantages of oral feeding on ventilation. Received: 18 January 2000 / Accepted: 9 May 2000     

The number and function of circulating endothelial progenitor cells in patients with Kawasaki disease

Kawasaki disease (KD) is associated with coronary artery injury. Studies have shown that the endothelial progenitor cell (EPC) participates in the process of arterial repair. Data have been reported that the number of EPC increased significantly in the subacute phase of KD. However, until now, there are no data about the functions of EPC in KD patients. The present study was designed to further investigate the number and functions of EPC in KD. Ten KD patients in the acute phase and ten healthy volunteers were recruited and attributed to the KD group and control group, respectively. The circulating CD34/kinase insert domain-containing receptor double positive cells were evaluated in the two groups using flow cytometry. In vitro assays were used to measure the functions of EPC, including proliferation, adhesion, and migration activities. The plasma levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and high sensitivity C-reactive protein (hs-CRP) were also assessed in both groups. The number of EPC in the KD group was significantly higher than that of the control group (0.021 ± 0.007% vs. 0.014 ± 0.003%, P < 0.05). The migratory response of EPC was significantly decreased in the KD group, compared with that of the control group (5.50 ± 1.78 vs. 3.40 ± 1.35 cells/high power field, P < 0.01). Similarly, the proliferative and adhesive activities of EPC in the KD group were also decreased (0.47 ± 0.08 vs. 0.66 ± 0.07, P < 0.01; 6.5 ± 2.12 vs. 11.2 ± 2.04 cells/high power field, P < 0.01). The plasma NO, TNF-α, and hs-CRP levels in the KD group were higher than those of the control group (54.10 ± 11.78 vs. 38.80 ± 11.10 μmol/l, P < 0.01; 48.20 ± 7.42 vs. 37.00 ± 11.12 pg/ml, P < 0.05; 87.10 ± 30.18 vs. 5.30 ± 3.37 mg/l, P < 0.01). The number of circulating EPC positively correlated with the level of NO (r = 0.92, P < 0.001), and the functions of EPC negatively correlated with the levels of TNF-α and hs-CRP, respectively. In Kawasaki disease, the number of EPC was enhanced and the functions of EPC were attenuated. The two-way regulation of circulating EPC in KD patients may be associated with the disorders of cytokines or messengers in KD patients.     

Evaluation of postoperative pulmonary regurgitation after surgical repair of tetralogy of Fallot: comparison between Doppler echocardiography and MR velocity mapping

Background Pulmonary regurgitation is a common finding in patients after correction of tetralogy of Fallot (TOF). Right ventricular impairment and even ventricular arrhythmia have been ascribed to pulmonary valve insufficiency (PI), which is therefore an important issue in follow-up examinations. Objective To compare PI measured by echocardiography (ECHO) with data provided by cardiac MRI (CMR). Materials and methods We studied 54 selected patients (18 female; median age 14.0 years, range 3.8–53.4 years) after surgical correction of TOF. To quantify pulmonary regurgitant fraction (PRF) by CMR, flow velocity mapping was performed. On Doppler ECHO, length, width and localization of regurgitant flow was measured. The severity of PI was categorized as mild, moderate or severe and compared to the data obtained by CMR. Results On CMR the mean PRF was 29.2 ± 13.4%. Patients with a transannular patch had a significantly higher PRF (39.9 ± 11.6%) than patients with an intact annular ring (23.6 ± 11.4%). Differentiation by Doppler ECHO between the categories mild, moderate and severe PI was confirmed by significant differences in PRF measured by CMR (mild vs. moderate P < 0.04; moderate vs. severe P < 0.014; mild vs. severe P < 0.001). Furthermore, PRF correlated with right ventricular end diastolic volume index (r = 0.45, P < 0.01) and right ventricular end systolic volume index (r = 0.39, P < 0.01). Conclusion Doppler ECHO can estimate the severity of PI after repair of TOF with acceptable results compared to CMR flow measurement. In univariate analysis there is only a weak influence of PRF on right ventricular volume.     

Left ventricle output and mean arterial blood pressure in preterm infants during the 1st day of life

The objective was to assess the contribution of left ventricular output (LVO) in determining low mean arterial blood pressure (MABP) in preterm infants admitted to the neonatal intensive care unit. Doppler echocardiography was prospectively performed on a cohort of 17 consecutive infants with low MABP (<30 mmHg) and on 17 consecutive control subjects (range: 600–1520 g; 27–30.7 weeks gestation). The median haematocrit was 42.5% in the low MABP group versus 49.4% in the control group (P < 0.01). The index of resistance to the LVO (RILV = MABP:LVO ratio) was lower in the low MABP group (98 vs 156 mmHg · l⁻¹ · kg⁻¹ · min⁻¹; P < 0.05). An analysis of the low MABP group regarding LVO revealed that a subgroup of four infants had LVO <10th percentile (185 ml · kg⁻¹ · min⁻¹) with a high RILV (>90th percentile: 226 mmHg · l⁻¹ · kg⁻¹ ·  min⁻¹) for three of the infants. The remaining 13 infants had LVO >10th percentile and a shortening fraction >25th percentile. In this subgroup, a high proportion of infants (9/13 vs 2/17, P < 0.01) had low RILV (<10th percentile: 96 mmHg · l⁻¹ · kg⁻¹ · min⁻¹) and the incidence of haemodynamically significant patent ductus arteriosus was higher than in the control group (10/13 vs 4/17, P < 0.01). Conclusion Left ventricular output, index of resistance to left ventricular output and patent ductus arteriosus status are important to consider in evaluating mean arterial blood pressure during early postnatal life in preterm infants. Low mean arterial blood pressure is frequently associated with normal or high left ventricular output, low index of resistance to left ventricular output and significant patent ductus arteriosus. Received: 10 November 1998 and in revised form: 8 February 1999 / Accepted: 9 February 1999     

Effect of elective antibiotic therapy on resting energy expenditure and inflammation in cystic fibrosis

Cystic fibrosis (CF) patients often present with malnutrition which may partly be due to increased resting energy expenditure (REE) secondary to inflammation. Both REE and tumour necrosis factor-alpha (TNF-α), as other markers of inflammation, are elevated during respiratory exacerbations and decrease after antibiotic treatment. However, the effect of antibiotic therapy on REE and inflammation in patients without respiratory exacerbation is not known. The aim of our study was to determine the effect of such an elective antibiotic therapy on REE, TNF-α, and other serum markers of inflammation. Twelve CF patients 5F/7M, age 15.9 ± 6.1 years, weight for height ratio 89 ± 8% without clinically obvious exacerbation and treated by intravenous antibiotics were studied. Both before (D0) and after (D14) treatment, pulmonary function tests were performed. REE was measured by indirect calorimetry and blood taken to measure inflammation parameters. Body weight increased by 1.1 kg from D0 to D14 (P < 0.001), composed of 0.3 kg fat mass and 0.8 kg fat-free mass (FFM). The forced expiratory volume at 1 s increased from 43 ± 15% of predicted at D0 to 51 ± 15% of predicted at D14 (P < 0.01). Mean REE was 41.1 ± 7.6 kcal/kg FFM per day at D0 and did not change significantly at D14 (40.6 ± 8.5 kcal/kg FFM per day). Serum markers of inflammation decreased from D0 to D14: C-reactive protein 17 ± 17 mg/l to 4 ± 7 mg/l (P < 0.05), elastase 62 ± 29 μg/l to 45 ± 18 μg/l (P < 0.02), orosomucoid acid 1.25 ± 0.11 g/l to 0.80 ± 0.15 g/l (P < 0.001), and TNF-α 37 ± 14 pg/ml to 29 ± 6 pg/ml (P = 0.05). Individual values showed a correlation between changes in REE and in TNF-α (P < 0.02). Conclusion The contribution of inflammation to energy expenditure is possible but appears to be minimal in cystic fibrosis patients treated by antibiotics on a regular basis in the absence of clinically obvious exacerbation. Received: 6 August 1998 and in revised form: 23 November 1998 / Accepted: 23 November 1998     

A Prospective Analysis of the Incidence and Risk Factors Associated with Junctional Ectopic Tachycardia Following Surgery for Congenital Heart Disease

This study was designed to evaluate the incidence and risk factors associated with the occurrence of junctional ectopic tachycardia (JET) in patients after congenital heart surgery. We prospectively analyzed cardiac rhythm status in 336 consecutive patients undergoing surgery for congenital heart disease at our institution during a 1-year period. The incidence of JET was 8% (27/336). Repairs with the highest incidence of JET were arterial switch operation (3/13, 23%), atrioventricular (AV) canal repair (4/19, 21%), and Norwood repair (2/10, 20%). Compared to patients with no arrhythmias, patients with JET were more likely to be younger (2.75 ± 2.44 vs 5.38 ± 7.25 years, p < 0.01), have had longer cardiopulmonary bypass times (126 ± 50 vs 85 ± 73, p < 0.01), and have a higher inotrope score (6.26 ± 7.55 vs 2.41 ± 8.11, p < 0.01). By multivariate analysis, ischemic time was the only factor associated with JET [odds ratio, 1.01 (confidence interval, 1.005–1.02); p = 0.0014). The presence of JET did not correlate with electrolyte abnormalities. JET is not necessarily related to surgery near the His bundle or hypomagnesemia. Longer ischemic time is the best predictor of JET. Patients undergoing arterial switch operation, AV canal repair, and Norwood repair are at highest risk of postoperative JET and should be considered for prophylactic therapy.     

An old drug for use in the prevention of sudden infant unexpected death due to vagal hypertonia

Reflex vagal hypertonia (RVH) has been identified as a possible cause of sudden unexpected death in infants during the first year of life. Homatropine methylbromide (HM) is an anticholinergic drug known to inhibit muscarinic acetylcholine receptors, thus affecting the parasympathetic nervous system. The aim of the present study was to investigate the effects of HM on 24-h Holter electrocardiographic signs of RVH (pre-HM treatment vs post-HM treatment; post-HM treatment vs a control group of healthy infants). A total of 50 patients (mean age, 6.1 ± 2.7 months; 28 males, 22 females; 12 born pre-term) affected by RVH were enrolled in the study. Pre-HM treatment vs post-HM treatment: statistically significant differences were detected for higher heart rate, lower heart rate, mean heart rate, longer sinusal pause, presence of advanced atrio-ventricular blocks, and systolic blood pressure (p < 0.001, p < 0.00001, p < 0.02, p < 0.00001, p < 0.05, and p < 0.04, respectively). A statistically significant correlation was revealed between HM-administered dose and both average heart rate and systolic blood pressure (r = 0.93, p < 0.0001; r = 0.94, p < 0.0001, respectively). No significant differences were detected between post-HM treatment electrocardiographic data and those of the control group. By antagonizing action of the vagus nerve of the parasympathetic system on the heart, thus increasing cardiac frequency, HM treatment appears to feature a good safety profile and be highly effective in preventing transient infantile hypervagotonia, the potential cause of several cases of sudden unexpected death during the first year of life.     

Down syndrome patients with pulmonary hypertension have elevated plasma levels of asymmetric dimethylarginine

Down syndrome (DS) patients have an increased risk of developing pulmonary hypertension (PH). Increased plasma levels of asymmetric dimethylarginine (ADMA) may contribute to vascular dysfunction in adults with idiopathic pulmonary hypertension. Our goal was to test the hypothesis that DS patients with PH have higher plasma levels of ADMA than DS patients without PH. DS patients with definitive PH (n = 6) and DS patients with no evidence of PH (n = 12) were studied. Plasma levels of arginine, ADMA, and nitrite/nitrate (NOx; stable metabolites of nitric oxide (NO)) were measured. Plasma arginine concentration was lower (p < 0.05) in PH patients (23 ± 11 μM) versus non-PH patients (46 ± 24 μM). Plasma ADMA concentration was higher (p < 0.005) in PH patients (18.0 ± 4.2 μM) versus non-PH patients (8.6 ± 5.9 μM). Plasma NOx was lower (p < 0.05) in PH patients (4.5 ± 1.7 μM) versus non-PH patients (8.5 ± 7.3 μM). These results are consistent with ADMA contributing to lower NO production in DS patients with PH and suggest that ADMA levels may be a potential biomarker for PH in DS patients.     

Contribution of the blood glucose level in perinatal asphyxia

This is a comparative study between 60 asphyxiated newborns (cases) and 60 normal neonates (controls) in respect of their plasma glucose and uric acid levels and also their clinical and neurological status. The mean plasma glucose level was significantly lower (35.1 ± 11.4 mg/dl vs. 56.9 ± 5.5 mg/dl; P < 0.001) and the mean serum uric acid level was higher (8.0 ± 1.2 mg/dl vs. 4.5 ± 0.83 mg/dl; P < 0.001) in the asphyxiated group when compared to the controls. Within the perinatal asphyxia group, the plasma glucose level and Apgar scores showed a significant positive linear correlation (r = 0.740, P < 0.001), whereas a significant negative linear correlation was observed between the glucose level and different stages of hypoxic ischemic encephalopathy (HIE) (r = −0.875, P < 0.001). Although a strong positive linear correlation was found between uric acid and HIE stages (r = 0.734, P ≤ 0.001), the linear correlation between uric acid and Apgar scores (r = −0.885, P < 0.001) and uric acid and the plasma glucose level (r = −0.725, P < 0.001) were found to be significantly negative among the cases. Conclusion: The severity of encephalopathy and cellular damage varies with the severity of hypoglycemia.     

Cardiovascular impairment in children,adolescents, and young adults with type 1 diabetes mellitus (T1DM)

Left ventricular (LV) function was assessed in 42 patients (mean age ± SD, 18.45 ± 3.76 years; 17 males) with type I diabetes mellitus (T1DM; mean duration 9.89 years) and in 43 healthy controls (mean age ± SD, 18.27 ± 3.36 years; 18 males). Systolic, diastolic cardiac function and LV dimensions were assessed using M-mode and Doppler echocardiography. Neural autonomic function was assessed by measuring RR variation during deep breathing, Valsava maneuver, 30/15 ratio, and blood pressure response to standing. Fractional shortening, peak velocity of early ventricular filling (E wave), peak velocity of LV filling (A wave), E/A ratio, deceleration time, isovolumic relaxation time, LV dimensions (interventricular septum, posterior wall thickness, end diastolic diameter [EDD] and systolic diameter [ESD]) were all comparable between patients with T1DM and controls. However, in 11 T1DM patients with microalbuminuria and/or retinopathy, EDD, ESD, E/A ratio, and E wave were all lower (p = 0.0011, p = 0.019, p = 0.0011, and p = 0.030, respectively) while, A wave, heart rate, and diastolic blood pressure were all higher (p = 0.008, p = 0.0024 and p = 0.004, respectively) compared to matched for age and sex controls. Furthermore, in six of the 11 T1DM patients with microangiopathy who had E/A <1.12 (<2 SD of the control mean), significant and marginally significant correlations were found between E/A ratio and the duration of the disease as well as the mean HbA1c of the last year (r = –0.38, p = 0.011 and r =  –0.287, p = 0.064, respectively). In conclusion, it has been found that impairment of diastolic, but not systolic, LV function can be detected early in young patients with T1DM and microangiopathy.     

Left Ventricular Function in Patients with Transposition of the Great Arteries Operated with Atrial Switch

In patients operated with atrial switch for transposition of the great arteries (TGA), the left ventricle (LV) supports the pulmonary circulation and is thus pressure unloaded. Evaluation of LV function in this setting is of importance, as LV functional abnormalities have been documented and might contribute to development of symptoms. The ventricular contraction pattern in 14 Senning-operated TGA patients and 14 healthy controls was studied using tissue Doppler and magnetic resonance imaging. In the subpulmonary LV free wall, longitudinal strain was greater than circumferential strain (−23.6 ± 3.6% vs. −19.1 ± 3.2%, p = 0.002) as in the normal right ventricle (RV) (−30.7 ± 3.3% vs. −15.8 ± 1.3%, p < 0.001), but opposite to findings in the normal LV (−16.5 ± 1.7% vs. −25.7 ± 3.1%, p < 0.001). Subpulmonary strain and strain rate values were intermediate between those in the normal LV and RV. Ventricular free-wall torsion was reduced in the subpulmonary LV compared with both the normal LV (5.7 ± 3.2° vs. 16.7 ± 5.6°, p < 0.001) and RV (5.7 ± 3.2° vs. 11.4 ± 2.6°, p < 0.05). Furthermore, early diastolic filling of the subpulmonary LV differed from that of the normal LV. The subpulmonary LV displayed predominantly longitudinal shortening, as did its functional counterpart, the normal RV. However, the degree and rate of both longitudinal and circumferential shortening were intermediate between those of the normal LV and RV. This could represent a partial adaptation to the reduced pressure load. Decreased ventricular torsion and diastolic abnormalities might indicate subclinical ventricular dysfunction.