Clinical Course and Interstage Monitoring After the Norwood and Hybrid Procedures for Hypoplastic Left Heart Syndrome

Infants with hypoplastic left heart syndrome (HLHS) are at risk for interstage morbidity and mortality, especially between the first and second surgical stages after the Norwood and hybrid procedures. This study compared the morbidity and mortality of patients treated by either the Norwood or the hybrid procedure for HLHS between the first and second stages who were undergoing interstage monitoring. Between October 2008 and December 2011, 26 infants (14 boys) with HLHS (n = 16) and other univentricular heart malformations with aortic arch anomaly (n = 10) were scheduled for interstage monitoring after Norwood I (n = 12) and hybrid (n = 14) procedures. Three infants (11.5 %) died after first-stage palliation (one hybrid patient and two Norwood patients), and three infants (11.5 %) died after second-stage palliation (two hybrid patients and one Norwood patient) (p = 0.83), all after early second-stage surgery (<90 days). The Norwood I and hybrid procedures did not differ in terms of overall mortality (23 %) (three hybrid and three Norwood patients; p = 1.00). Seven infants (26.9 %) could not be discharged from the hospital due to hemodynamic instability and were referred for early second-stage surgery (<90 days). After the first stage, the invasive reevaluation rate before discharge was high (53.8 %), with cardiac catheterizations for 8 of 14 patients after the hybrid procedure and for 6 of 12 patients after the Norwood procedure (p = 0.69). A total of 11 reinterventions were performed (eight by catheter and three by surgery). Of the eight catheter reinterventions, five were performed for hybrid patients (p = 0.22). For 14 infants, 89 days (range 10–177 days) of interstage monitoring were scheduled. One infant (3.9 %) died during the interstage monitoring. The findings showed a breach of the physiologic criteria for interstage monitoring in seven infants (50 %) after 10 days (range 4–68 days) (five hybrid and two Norwood patients), leading to rehospitalization and catheterization for six patients (four hybrid and two Norwood patients), requiring interventions for two patients (patent arterial duct stent dilation, and atrial septal defect stenting, all for hybrid patients). Overall, three of the seven patients with red flag events of interstage monitoring were candidates for early second-stage surgery. In conclusion, morbidity among infants treated for HLHS remains high, either before or after hospital discharge, emphasizing the need of interstage monitoring programs. Despite retrograde aortic flow in infants with HLHS after the hybrid procedure, the mortality rate was comparable between the two groups. Mortality occurs after early second-stage surgery (<90 days).     

Participation of the Prostaglandins in the Control of Renal Blood Flow during Acute Reduction of Cardiac Output in the Dog

To determine whether renal prostaglandins participate in the regulation of renal blood flow during acute reduction of cardiac output, cardiac venous return was decreased in 17 anesthetized dogs by inflating a balloon placed in the thoracic inferior vena cava. This maneuver decreased cardiac output from 3.69±0.09 liters/min (mean±SEM) to 2.15±0.19 liters/min (P < 0.01) and the mean arterial blood pressure from 132±4 to 111±5 mm Hg (P < 0.01) and increased total peripheral vascular resistance from 37.6±2.5 to 57.9±4.8 arbitrary resistance units (RU) (P < 0.01). In marked contrast, only slight and insignificant decreases in the renal blood flow from 224±16 to 203±19 ml/min and renal vascular resistance from 0.66±0.06 to 0.61±0.05 arbitrary resistance units (ru) were observed during inflation of the balloon. Concomitant with these hemodynamic changes, plasma renin activity and plasma norepinephrine concentration increased significantly in both the arterial and renal venous bloods. Plasma concentration of prostaglandin E₂ in renal venous blood increased from 34±6 to 129±24 pg/ml (P < 0.01). The subsequent administration of indomethacin or meclofenamate had no significant effect on mean arterial pressure, cardiac output, and total peripheral vascular resistance, but reduced renal blood flow from 203±19 to 156±21 ml/min (P < 0.01) and increased renal vascular resistance from 0.61±0.05 to 1.05±0.21 ru (P < 0.01). Simultaneously, the plasma concentration of prostaglandin E₂ in renal venous blood fell from 129±24 to 19±3 pg/ml (P < 0.01). Administration of indomethacin to five dogs without prior obstruction of the inferior vena cava had no effect upon renal blood flow or renal vascular resistance. The results indicate that acute reduction of cardiac output enhances renal renin secretion and the activity of the renal adrenergic nerves as well as renal prostaglandin synthesis without significantly changing renal blood flow or renal vascular resistance. Inhibition of prostaglandin synthesis during acute reduction of cardiac output results in an increased renal vascular resistance and reduced renal blood flow. Accordingly, that data provide evidence that renal prostaglandins counteract in the kidney the vasoconstrictor mechanisms activated during acute reduction of cardiac output.     

Liver and kidney metabolism during prolonged starvation

This study quantifies the concentrations of circulating insulin, growth hormone, glucose, free fatty acids, glycerol, beta-hydroxybutyrate, acetoacetate, and alpha amino nitrogen in 11 obese subjects during prolonged starvation. The sites and estimated rates of gluconeogenesis and ketogenesis after 5-6 wk of fasting were investigated in five of the subjects.Blood glucose and insulin concentrations fell acutely during the 1st 3 days of fasting, and alpha amino nitrogen after 17 days. The concentration of free fatty acids, beta-hydroxybutyrate, and acetoacetate did not reach a plateau until after 17 days.Estimated glucose production at 5-6 wk of starvation is reduced to approximately 86 g/24 hr. Of this amount the liver contributes about one-half and the kidney the remainder. Approximately all of the lactate, pyruvate, glycerol, and amino acid carbons which are removed by liver and kidney are converted into glucose, as evidenced by substrate balances across these organs.     

Influence of high mutation rates on the mechanisms and dynamics of in vitro and in vivo resistance development to single or combined antipseudomonal agents

We studied the mechanisms and dynamics of the development of resistance to ceftazidime (CAZ) alone or combined with tobramycin (TOB) or ciprofloxacin (CIP) in vitro and in vivo (using a mouse model of lung infection with human antibiotic regimens). Pseudomonas aeruginosa strain PAO1 and its hypermutable derivative PAODeltamutS were used, and the results were compared with those previously obtained with CIP, TOB, and CIP plus TOB (CIP-TOB) under the same conditions. An important (200-fold) amplification of the number of resistant mutant cells was documented for PAODeltamutS-infected mice that were under CAZ treatment compared to the number for mice that received placebo, whereas the median number of resistant mutant cells was below the detection limits for mice infected by PAO1. These results were intermediate between the high amplification with CIP (50,000-fold) and the low amplification with TOB (10-fold). All CAZ-resistant single mutant cells selected in vitro or in vivo hyperproduced AmpC. On the other hand, the three combinations studied were found to be highly effective in the prevention of in vivo resistance development in mice infected with PAODeltamutS, although the highest therapeutic efficacy (in terms of mortality and total bacterial load reduction) compared to those of the individual regimens was obtained with CIP-TOB and the lowest was with CAZ-CIP. Nevertheless, mutant cells that were resistant to the three combinations tested were readily selected in vitro for PAODeltamutS (mutation rates from 1.2 x 10(-9) to 5.8 x 10(-11)) but not for PAO1, highlighting the potential risk for antimicrobial resistance development associated with the presence of hypermutable strains, even when combined therapy was used. All five independent CAZ-TOB-resistant PAODeltamutS double mutants studied presented the same resistance mechanism (AmpC hyperproduction plus an aminoglycoside resistance mechanism not related to MexXY), whereas four different combinations of resistance mechanisms were documented for the five CAZ-CIP-resistant double mutants.