Ventilatory control in newborn mice prenatally exposed to cocaine

Infants born to mothers who used cocaine during pregnancy are at increased risk for neonatal death and respiratory impairments. Confounding factors such as multiple substance abuse make it difficult to isolate the effects of cocaine. We used a murine model to test the hypothesis that prenatal cocaine exposure may impair ventilatory responses to chemical stimuli in newborns. Seventy-two pregnant mice were randomly assigned to three groups: cocaine (COC), saline (SAL), and untreated (UNT). COC and SAL mice received subcutaneous injections of either 20 mg/kg of cocaine or a saline solution twice a day from gestational days 8-17. Ventilation (V'(E)) and tidal volume (V(T)), both divided by body weight, and breath duration (T(TOT)) were measured using whole-body plethysmography in freely moving COC (n = 47), SAL (n = 123), and UNT (n = 93) pups on postnatal day 2.The comparison between SAL and UNT pups showed significant differences in baseline breathing and in V'(E) responses to hypoxia, suggesting that maternal stress caused by injections affected the development of ventilatory control in pups. Baseline T(TOT) was significantly longer in COC than in SAL pups. V'(E) responses to hypoxia were significantly smaller in COC than in SAL pups (+27 +/- 35% vs. +38 +/- 25%), but V'(E) responses to hypercapnia were similar (29 +/- 15% vs. 25 +/- 23%).Thus, breathing control was impaired by prenatal cocaine exposure, possibly because of abnormal development of neurotransmitter systems, such as the dopamine and serotonin systems.     

The effect of age on prostaglandin E2 stimulation of growth hormone release from cultured rat pituitary cells

Prostaglandin E2 (PGE2) is a potent secretagogue of GH in mature mammals. Although PGs are produced by the fetus and newborn of many species, the ontogeny of PGE2's GH stimulatory effect and the interaction of PGE2 with GHRF in the developing animal are not known. We examined the effects of 0.01-10 microM PGE2 and 0.01-10 nM rat GHRF, alone and in combination, on GH release from cultured pituitary cells of 2-day(d)-old, 7-d-old, 15-d-old, and adult (3- to 4-month-old) male rats (n = 4-7 experiments/age group). The effect of PGE2 on GH release was markedly age dependent. The GH response to all doses of PGE2 over 0.01 microM was greatest in pituitary cells of adult and 15-d-old rats and least in those of 2-d-old pups. PGE2 (0.1 microM) did not cause significant GH release from pituitary cells of 2-d-old pups (110 +/- 3% of control values), but increased that from 7-d-old, 15-d-old, and adult pituitary cells to 126 +/- 8%, 155 +/- 8%, and 156 +/- 9% of respective control values (by analysis of variance: F = 7.28; P less than 0.001). PGE2 (1 microM) increased GH release to 123 +/- 8%, 145 +/- 12%, 259 +/- 24%, and 260 +/- 17% of control values from pituitary cells of these same respective age groups (F = 12.3; P less than 0.001). The highest dose of PGE2 studied (10 microM) yielded similar results. The influence of PGE1 on GH release was also age dependent and similar to that of PGE2. In contrast to PGE2, GHRF stimulated GH release most in pituitary cells of 2-d-old pups and least in those of adults, similar to our previous observations with human GHRF-40. Coincubation with PGE2 and low dose GHRF resulted in partial additivity of GH response in adult rats, but no additivity in newborn pups. These results indicate that in rats, the sensitivity of the somatotroph to PGE2 increases with advancing age after birth. The contrasting developmental patterns of somatotroph sensitivity to PGE2 and GHRF support the concept that these GH secretagogues act, at least in part, by different intracellular mechanisms, which are subject to differential rates of maturation.     

Respiratory effects of gestational intermittent hypoxia in the developing rat

Intermittent hypoxia (IH), one of the hallmarks of obstructive sleep apnea, occurs more frequently during pregnancy. We hypothesized that IH may lead to persistent postnatal changes in respiratory responses to acute hypoxia and may also lead to adverse effects on spatial function learning as revealed by the Morris water maze. To examine this issue, time-pregnant Sprague-Dawley rats were exposed to IH and room air (IHRA; 21 and 10% O2 alternations every 90 seconds) or to normoxia (RARA) until delivery. Ventilatory and metabolic responses to a 20-minute acute hypoxic challenge (10% O2) were conducted at postnatal ages 5, 10, 15, and 30 days. In addition, spatial task learning was assessed in the water maze at 1 and 4 months of age. Normoxic ventilation was higher at all time points in IHRA rats than in RARA rats (p < 0.01). Peak hypoxic ventilatory responses were attenuated in IHRA rats at 5 days of age and hypoxic ventilatory depression was accentuated at this age as well. However, ventilatory equivalents (minute ventilation/oxygen consumption) revealed significant reductions in peak hypoxic ventilatory responses of IHRA rats and hypoxic ventilatory depression at all postnatal ages (p < 0.01). Acquisition and retention of a spatial task were similar in the IHRA and RARA groups at both 1 and 4 months of age. We conclude that gestational intermittent hypoxia elicits long-lasting alterations in the control of breathing. We postulate that such IH-induced respiratory plasticity may create selective vulnerability to hypoxia during development.     

Early recovery of regional left ventricular function after reperfusion in acute myocardial infarction assessed by serial two-dimensional echocardiography

Although global and regional left ventricular (LV) function has been demonstrated to improve after reperfusion in acute myocardial infarction (AMI), the timing of these changes has not been well established. In this study, serial 2-dimensional echocardiography was used to assess regional LV function in 23 patients with AMI in whom reperfusion was accomplished by thrombolysis alone, by coronary angioplasty alone or by both interventions within 6 hours after onset of chest pain. Echocardiograms were performed before or within 6 hours after reperfusion (n = 23) and at 1 (n = 19), 3 (n = 21) and 7 (n = 20) days after reperfusion. Wall motion index and percentage of normally functioning muscle were calculated using a 16-segment scoring system analyzed in blinded fashion without knowledge of patient identity, therapy or time of study. The mean wall motion index improved from 1.78 +/- 0.48 to 1.56 +/- 0.38 at 1 day (n = 19, p less than 0.01), and to 1.48 +/- 0.37 at 3-7 days (p less than 0.01), with no significant difference between 3 days (1.49 +/- 0.39) and 7 days (1.42 +/- 0.30). There was a corresponding improvement in the percentage of normally functioning muscle, from 53 +/- 24% at 6 hours to 62 +/- 20% at 1 day (p less than 0.05) and to 67 +/- 18% at 3-7 days (p less than 0.01), again with no significant difference between 3 days (67 +/- 21) and 7 days (70 +/- 20).(ABSTRACT TRUNCATED AT 250 WORDS)     

Respiratory muscle endurance training in chronic obstructive pulmonary disease: impact on exercise capacity, dyspnea, and quality of life

Inspiratory muscle training may have beneficial effects in certain patients with chronic obstructive pulmonary disease (COPD). Because of the lack of a home training device, normocapnic hyperpnea has rarely been used as a training mode for patients with COPD, and is generally considered unsuitable to large-scale application. To study the effects of hyperpnea training, we randomized 30 patients with COPD and ventilatory limitation to respiratory muscle training (RMT; n = 15) with a new portable device or to breathing exercises with an incentive spirometer (controls; n = 15). Both groups trained twice daily for 15 min for 5 d per week for 8 wk. Training-induced changes were significantly greater in the RMT than in the control group for the following variables: respiratory muscle endurance measured through sustained ventilation (+825 +/- 170 s [mean +/- SEM] versus -27 +/- 61 s, p < 0.001), inspiratory muscle endurance measured through incremental inspiratory threshold loading (+58 +/- 10 g versus +21.7 +/- 9.5 g, p = 0.016), maximal expiratory pressure (+20 +/- 7 cm H(2)O versus -6 +/- 6 cm H(2)O, p = 0.009), 6-min walking distance (+58 +/- 11 m versus +11 +/- 11 m, p = 0.002), V O(2peak) (+2.5 +/- 0.6 ml/kg/min versus -0.3 +/- 0.9 ml/kg/min, p = 0.015), and the SF-12 physical component score (+9.9 +/- 2.7 versus +1.8 +/- 2.4, p = 0.03). Changes in dyspnea, maximal inspiratory pressure, treadmill endurance, and the SF-12 mental component score did not differ significantly between the RMT and control groups. In conclusion, home-based respiratory muscle endurance training with the new device used in this study is feasible and has beneficial effects in subjects with COPD and ventilatory limitation.     

Ventilatory assistance improves exercise endurance in stable congestive heart failure

We postulated that ventilatory assistance during exercise would improve cardiopulmonary function, relieve exertional symptoms, and increase exercise endurance (T(lim)) in patients with chronic congestive heart failure (CHF). After baseline pulmonary function tests, 12 stable patients with advanced CHF (ejection fraction, 24 +/- 3% [mean +/- SEM]) performed constant-load exercise tests at approximately 60% of their predicted maximal oxygen consumption (V O(2)max) while breathing each of control (1 cm H(2)O), continuous positive airway pressure optimized to the maximal tolerable level (CPAP = 4.8 +/- 0.2 cm H(2)O) or inspiratory pressure support (PS = 4.8 +/- 0.2 cm H(2)O), in randomized order. Measurements during exercise included cardioventilatory responses, esophageal pressure (Pes), and Borg ratings of dyspnea and leg discomfort (LD). At a standardized time near end-exercise, PS and CPAP reduced the work of breathing per minute by 39 +/- 8 and 25 +/- 4%, respectively (p < 0. 01). In response to PS: T(lim) increased by 2.8 +/- 0.8 min or 43 +/- 14% (p < 0.01); slopes of LD-time, V O(2)-time, V CO(2)-time, and tidal Pes-time decreased by 24 +/- 10, 20 +/- 11, 28 +/- 8, and 44 +/- 9%, respectively (p < 0.05); dyspnea and other cardioventilatory parameters did not change. CPAP did not significantly alter measured exercise responses. The increase in T(lim) was explained primarily by the decrease in LD- time slopes (r = -0.71, p < 0.001) which, in turn, correlated with the reductions in V O(2)-time (r = 0.61, p < 0.01) and tidal Pes-time (r = 0.52, p < 0.01). in conclusion, ventilatory muscle unloading with PS reduced exertional leg discomfort and increased exercise endurance in patients with stable advanced CHF.     

Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury.

Improved gas exchange has been observed during spontaneous breathing with airway pressure release ventilation (APRV) as compared with controlled mechanical ventilation. This study was designed to determine whether use of APRV with spontaneous breathing as a primary ventilatory support modality better prevents deterioration of cardiopulmonary function than does initial controlled mechanical ventilation in patients at risk for acute respiratory distress syndrome (ARDS). Thirty patients with multiple trauma were randomly assigned to either breathe spontaneously with APRV (APRV Group) (n = 15) or to receive pressure-controlled, time-cycled mechanical ventilation (PCV) for 72 h followed by weaning with APRV (PCV Group) (n = 15). Patients maintained spontaneous breathing during APRV with continuous infusion of sufentanil and midazolam (Ramsay sedation score [RSS] of 3). Absence of spontaneous breathing (PCV Group) was induced with sufentanil and midazolam (RSS of 5) and neuromuscular blockade. Primary use of APRV was associated with increases (p < 0.05) in respiratory system compliance (CRS), arterial oxygen tension (PaO2), cardiac index (CI), and oxygen delivery (DO2), and with reductions (p < 0.05) in venous admixture (QVA/QT), and oxygen extraction. In contrast, patients who received 72 h of PCV had lower CRS, PaO2, CI, DO2, and Q VA/Q T values (p < 0.05) and required higher doses of sufentanil (p < 0.05), midazolam (p < 0.05), noradrenalin (p < 0.05), and dobutamine (p < 0.05). CRS, PaO2), CI and DO2 were lowest (p < 0.05) and Q VA/Q T was highest (p < 0.05) during PCV. Primary use of APRV was consistently associated with a shorter duration of ventilatory support (APRV Group: 15 +/- 2 d [mean +/- SEM]; PCV Group: 21 +/- 2 d) (p < 0.05) and length of intensive care unit (ICU) stay (APRV Group: 23 +/- 2 d; PCV Group: 30 +/- 2 d) (p < 0.05). These findings indicate that maintaining spontaneous breathing during APRV requires less sedation and improves cardiopulmonary function, presumably by recruiting nonventilated lung units, requiring a shorter duration of ventilatory support and ICU stay.     

The effect of fetal hypoxia on adrenocortical function in the 7-day-old rat

Fetal hypoxia in late gestation is a common cause of postnatal morbidity. The purpose of the present study was to evaluate adrenal function in vivo and in vitro in 7-d-old rat pups previously exposed to normoxia or hypoxia (12% O2) during the last 2-3 d of gestation. Seven-day-old rats exposed to fetal hypoxia had a small, but significant decrease in plasma aldosterone despite no decreases in plasma ACTH or renin activity. There was a small (approx 20%) but significant decrease in the aldosterone and corticosterone response to cAMP in vitro in dispersed cells from 7-d-old pups exposed to fetal hypoxia. The aldosterone, corticosterone, and cAMP response to ACTH, however, was not altered by prior fetal hypoxia. There was also no effect of fetal hypoxia on steroidogenic enzyme expression or zonal dimension in 7-d-old rats. We conclude that fetal hypoxia in late gestation results in a subtle decrease in cAMP-stimulated steroidogenesis. Fetal hypoxia appears to have minimal effects on subsequent adrenal function in the neonatal rat.     

The effect of hypoxia on plasma leptin and insulin in newborn and juvenile rats

Hypoxia leads to a decrease in food intake and attenuated weight gain in rats. The purpose of this study was to measure plasma leptin and insulin in young rats exposed to hypoxia for 7 d as compared to a normoxic control group of the same age. One group was exposed from birth to 7 d of age; the other was exposed from 28 to 35 d of age (weaned at 21 d of age). As expected, body weight was significantly lower in rats of either age exposed to hypoxia for 7 d. Plasma leptin was significantly lower in hypoxic (2.0+/-0.2 ng/mL; n = 41) compared with normoxic (2.6+/-0.3 ng/mL; n = 30) 7-d-old rats. Plasma leptin was also significantly lower in hypoxic (1.1+/-0.1 ng/mL; n = 20) as compared to normoxic (1.5+/-0.1 ng/mL; n = 20) 35-d-old rats. Seven-day-old rats exposed to hypoxia demonstrated significant increases in plasma glucose and insulin whereas 35-d-old rats exhibited a decrease in both variables. We conclude that exposure to hypoxia for 7 d leads to a decrease in body weight and plasma leptin in infant and juvenile rats. The decrease in leptin may be an attempt to reverse hypoxia-induced anorexia.     

Impaired pulmonary diffusing capacity and hypoxia in heart failure correlates with central sleep apnea severity

BACKGROUND: Heart failure (HF) is often associated with interstitial pulmonary edema and structural changes, resulting in thickening of the alveolar-capillary membrane and reductions in diffusing capacity of the lung for carbon monoxide (Dlco). Reduced Dlco reflects an impaired efficiency of gas exchange, which may increase plant gain, influence ventilatory control stability, and result in central sleep apnea (CSA). In this study, we test the hypothesis that reductions in Dlco would be associated with increased apnea-hypopnea index (AHI) in patients with CSA. METHODS: Overnight polysomnography, pulmonary function tests, and arterial blood gas analyses were performed in 45 patients with chronic, stable HF. Univariate and multivariate regression analyses were performed in those patients with predominant CSA to test which variables were associated with AHI. RESULTS: Patients had a mean (+/-SD) age of 52.7+/-8.9 years, a mean left ventricular ejection fraction of 26.5+/-9.9%, and a mean AHI of 22.0+/-17.4 events per hour. In CSA patients, Dlco and Pao2 both correlated with total AHI (r=-0.43, p=0.046 and r=-0.53, p=0.011, respectively) and with supine AHI (r=-0.56, p=0.009 and r=-0.60, p=0.004, respectively). In a forward stepwise estimation model, Dlco, Pao2, and body mass index were independent predictors of total AHI, explaining 51% of variability, as was supine AHI, explaining 64% of variability. Dlco and Pao2 accounted for 37% of the variability in total AHI and 49% of the variability in supine AHI. CONCLUSIONS: In patients with HF and CSA, reductions in Dlco and Pao2 are independently associated with respiratory disturbance during sleep. The increase in ventilatory instability may be due to plant gain effects.     

Neonatal exposure to 65% oxygen durably impairs lung architecture and breathing pattern in adult mice

STUDY OBJECTIVE: To test the hypothesis that exposure to hyperoxia during the postnatal period of rapid alveolar multiplication by septation would cause permanent impairments, even with moderate levels of hyperoxia. DESIGN: We exposed mouse pups to 65% O(2) (hyperoxic mice) or normoxia (normoxic mice) during their first postnatal month, and we analyzed lung histology, pulmonary mechanics, blood gas, and breathing pattern during normoxia or in response to chemical stimuli in adulthood, when they reached 7 to 8 months of postnatal age. RESULTS: Hyperoxic mice had fewer and larger alveoli than normoxic mice (number of alveoli per unit surface area of parenchyma, 266 +/- 62/mm(2) vs 578 +/- 77/mm(2), p < 0.0001) [mean +/- SD], the cause being impaired alveolarization (radial alveolar count, 5.8 +/- 0.2 in hyperoxic mice vs 10.5 +/- 0.5 in normoxic mice, p < 0.0001). Respiratory system compliance was higher in hyperoxic mice (0.098 +/- 0.006 mL/cm H(2)O) than in normoxic mice (0.064 +/- 0.006 mL/cm H(2)O, p < 0.016). Baseline tidal volume (VT) and breath duration (TTOT]) measured noninvasively by whole-body plethysmography were larger in hyperoxic mice than in normoxic mice (VT, + 15%, p < 0.01; TTOT, + 12%, p < 0.01). Despite these impairments, blood gas, baseline minute ventilation E, and E responses to hypoxia and hypercapnia were normal in hyperoxic mice, compared with normoxic mice. CONCLUSION: Hyperoxic exposure during lung septation in mice may cause irreversible lung injury and breathing pattern abnormalities in adulthood at O(2) concentrations lower than previously thought. However, ventilatory function and body growth were preserved, and ventilatory function showed no major abnormalities, at least at rest, despite early oxygen-induced injuries.     

Dynamic ventilatory responses in rats: normal development and effects of prenatal nicotine exposure.

Infants of smoking mothers are at increased risk of SIDS, one cause of which is thought to be due to impaired ventilatory responses. We tested the hypotheses that prenatal nicotine exposure impairs the development of dynamic carotid chemoreceptor-driven ventilatory responses, and reduces the ability to lower metabolic rate in hypoxia. Osmotic minipumps were implanted into 20 pregnant rats at day 3 of gestation to deliver nicotine (6 mg/kg per day free base) or saline for 4 weeks. Minute ventilation was recorded breath by breath in rat pups at 3, 8 and 18 days (n = 6, 8 and 6) postnatal in response to 5-sec challenges of 100% O2 (Dejours test) and 5% O2 + 5% CO2. Carotid sinus nerve (CSN) responses to hypoxia and CO2 were recorded from 22 control and 17 nicotine-exposed preparations at ages between 3-20 days. Oxygen consumption (V(O)2) was measured in groups of pups at 3 days (n = 7 each for nicotine and control) and 8 days (n = 5 each for nicotine and control) in room air and 10% O2. There was no detectable effect of nicotine exposure on the development of CSN responses. Ventilatory responses to 5% O2-5% CO2 increased with age but did not differ between nicotine and control groups. Ventilatory responses to 100% O2 were unaffected by nicotine exposure at 8 and 18 days. However, the 3-day nicotine group showed no significant response to 100% O2 whereas V(E) was significantly reduced in the control group by 100% O2. There was no significant effect of nicotine exposure on the ability to reduce oxygen consumption in hypoxia at 3 or 8 days, but at 3 days, baseline (room air) variability in oxygen consumption was greater in the nicotine group. We conclude that nicotine exposure appears to result in abnormal ventilatory responses to withdrawal of baseline peripheral chemoreceptor drive during a period of early postnatal life. We speculate that a transient abnormality could contribute to a period of instability and increased vulnerability to challenges.     

Hypercapnic and hypoxic ventilatory responses in parents and siblings of children with congenital central hypoventilation syndrome

Children with congenital central hypoventilation syndrome (CCHS) have abnormal ventilatory responses to metabolic stimuli. As there is a genetically determined component of chemoreceptor sensitivity, parents and siblings of children with CCHS may also have blunted ventilatory responses to hypercapnea and hypoxia. To test this, we studied hypercapnic ventilatory responses and hypoxic ventilatory responses in six mothers, four fathers, and five siblings (6 to 49 yr of age) of seven children with CCHS and compared them with 15 age- and sex-matched control subjects (5 to 47 yr of age). Pulmonary function tests were not different between relatives of children with CCHS and control subjects. To measure hypercapnic ventilatory responses, subjects rebreathed 5% CO2/95% O2 until PACO2 reached 60 to 70 mm Hg. To measure hypoxic ventilatory responses (L/min/% SaO2), subjects rebreathed 14% O2/7% CO2/balance N2 at mixed venous PCO2 until SaO2 fell to 75%. All tests were completed in less than 4 min. Instantaneous minute ventilation, mean inspiratory flow (tidal volume/inspiratory time), and respiratory timing (inspiratory timing/total respiratory cycle timing) were calculated on a breath-by-breath basis. Hypercapnic ventilatory responses were 1.97 +/- 0.32 L/min/mm Hg PACO2 in children with CCHS relatives and 2.23 +/- 0.23 L/min/mm Hg PACO2 in control subjects. Hypoxic ventilatory responses were -1.99 +/- 0.37 L/min/% SaO2 in the relatives and -1.54 +/- 0.25 L/min/% SaO2 in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of betaxolol on the hemodynamic, gas exchange, and cardiac output response to exercise in chronic atrial fibrillation

BACKGROUND: beta-blockade controls the ventricular response to exercise in chronic atrial fibrillation (AF), but the effects of beta-blockers on exercise capacity in AF have been debated. METHODS: Twelve men with AF (65+/-8 years) participated in a randomized, double-blind, placebo-controlled study of betaxolol (20 mg daily). Patients underwent maximal exercise testing with ventilatory gas exchange analysis, and a separate, submaximal test (50% of maximum) during which cardiac output was measured by a CO2 rebreathing technique. RESULTS: After betaxolol therapy, heart rate was reduced both at rest (92+/-27 vs 62+/-12 beats/min; p < 0.001) and at peak exercise (173+/-22 vs 116+/-24 beats/min; p < 0.001). Maximal oxygen uptake (VO2) was reduced by 19% after betaxolol (21.8+/-5.3 with placebo vs 17.6+/-5.1 mL/kg/min with betaxolol; p < 0.05), with similar reductions observed for maximal exercise time, minute ventilation, and CO2 production. VO2 was reduced by a similar extent (19%) at the ventilatory threshold. Submaximal cardiac output was reduced by 15% during betaxolol therapy (12.9+/-2.3 vs 10.9+/-1.3 L/min; p < 0.05), and stroke volume was higher (88.0+/-21 vs 105.6+/-19 mL/beat; p < 0.05). CONCLUSION: Betaxolol therapy in patients with AF effectively controlled the ventricular rate at rest and during exercise, but also caused considerable reductions in maximal VO2 and cardiac output during exercise. The observed increase in stroke volume could not adequately compensate for reduced heart rate to maintain VO2 during exercise.     

Caerulein stimulates pancreatic secretory response in conscious newborn rats

The aim of our study was to measure age-dependent, caerulein-stimulated pancreatic enzyme secretion of conscious CFY suckling rats without pancreatic duct cannulation. Pancreatic secretory response was expressed as the decrease in specific enzyme (trypsin, amylase) activity compared to saline-injected control. The study was performed in three phases. In 10-d-old conscious newborn rats, single 1 and 3 micrograms/kg sc doses of caerulein induced significant decreases in specific trypsin (42 and 47%) and amylase (34 and 33%) activity 15 min after the caerulein injection; the same doses injected at 0 and 30 min evoked a similar decrease 90 min after the first injection. The 0.5 microgram/kg dose was ineffective. In 10-d-old anesthetized rats, the 90-min-decrease in total pancreatic trypsin activity, induced by graded doses (1,3,10, and 30 micrograms/kg) of caerulein, was compared to the 90-min output of trypsin in their bile-pancreatic juice. Each of the applied doses induced significant change in the total trypsin activity both in the pancreas (-33-57%) and juice (+21 +/- 49%) and its decrease in the gland corresponded quantitatively well (r = 0.52; p less than 0.01) to the increase in the simultaneous 90-min trypsin output. The age- and dose-dependent pancreatic response of 3-, 5-, 10-, and 20-d-old conscious rats was investigated under the effect of 1,3,10, and 30 micrograms/kg sc doses of caerulein injected at 0 and 30 min. In 3-d-old rats, the 10 and 30 micrograms/kg and in 20-d-old rats, the 1 and 3 micrograms/kg doses were effective, whereas in 5- and 10-d-old rats each caerulein dose applied evoked a significant decrease in pancreatic-specific trypsin activity. Conclusion: The pancreas of newborn rats is in vivo less sensitive to caerulein between postnatal d 3 and 10 than in already weaned rats.     

Passive motion of the extremities modifies alveolar ventilation during sleep in patients with congenital central hypoventilation syndrome

Passive motion of lower extremities (PMLE) elicits significant increases in alveolar ventilation (V A) in awake children with congenital central hypoventilation syndrome (CCHS), who have absent or near absent ventilatory responses to hypercapnia. We hypothesized that PMLE would improve V A during non-rapid eye movement (NREM) sleep. To study this, six patients with CCHS (0.2 to 7 yr of age) were disconnected from mechanical ventilatory support during Stage III-IV NREM, and their feet were passively moved at the ankle, either manually or with a motorized device strapped to their feet at 40 to 50 strokes/min. Holding of the feet without motion served as control (C). From a total of 74 successful trials not associated with sleep state changes, PET(CO(2)) decreased from 58.9 +/- 3.5 to 40.9 +/- 2.6 mm Hg with PMLE (n = 58; p < 0.001), whereas end-tidal carbon dioxide (PET(CO(2))) increased in C (n = 16; 58.8 +/- 3.1 to 60.3 +/- 3.7 mm Hg; PMLE versus C: p < 0.001). PMLE increased respiratory frequency from 10.2 +/- 1.9 to 21.2 +/- 2.7 breaths/min (p < 0.0001). We conclude that PMLE during NREM increases V A possibly via activation of mechanoreceptor-afferent pathways rather than by respiratory entrainment. We speculate that such effect may provide future noninvasive ventilatory support strategies in patients with CCHS and mild phenotypic expression of their disease.     

Hypoxic vasoconstriction increases with postnatal age in lungs from newborn rabbits

Previous studies on the pressor response of the newborn pulmonary circulation to hypoxia have used intact animals and have reported conflicting results. Some have found an increase in responsiveness with increasing age; others have found a decrease. To circumvent many problems inherent in studies of pulmonary vascular reactivity in intact animals, we have developed methods for studying isolated, blood-perfused lungs from newborn rabbits. These methods have been used to study the influence of postnatal age on hypoxic pulmonary vasoconstriction. Two sets of experiments were performed. In the first, a stimulus response curve for hypoxic pulmonary vasoconstriction was constructed, using lungs from 19 rabbit pups that were 3-8 days old. At a constant blood flow, pulmonary artery pressure increased progressively as alveolar oxygen tension decreased so that the maximum increase from baseline (29.4 +/- 4.7%) occurred at PIO2 = 0. The pressor response to hypoxia was highly reproducible, and the entire system remained stable for over 2-3 hours. In the second set of experiments, we compared the pulmonary vascular response to hypoxia obtained using lungs from an additional 21 pups that were 3-8 days old with that obtained using lungs from 23 pups that were 10-14 days old. In response to the same hypoxic stimulus, pulmonary artery pressure increased more in lungs from older rabbit pups (56 +/- 4%) than in lungs from younger rabbit pups (34 +/- 7%) (p less than 0.001). We conclude that isolated perfused lungs from newborn rabbits exhibit a reproducible pressor response to alveolar hypoxia and that this response increases as a function of postnatal age.     

The effect of rebreathing CO2 on ventilation and diaphragmatic electromyography in newborn infants

We tested the hypothesis of whether the reduced ventilatory response to CO2 in preterm as compared to term infants is related to primary central unresponsiveness, or to mechanical impairment of the respiratory pump. Eleven preterm (n = 19; gestational age 32 +/- 0.4 wk) and 14 term (n = 24; GA 40 +/- 0.3 wk) infants were studied. Minute integrated diaphragmatic activity EMGDi X f), and mean inspiratory diaphragmatic activity (EMGDi/TI), were used as indices of central output. After 3 min breathing 21% O2 (control), infants rebreathed from a bag containing 5% CO2 in 40% O2 for 2 to 3 minutes. We measured VE, VT, f, VT/TI. Sleep states were monitored. Preterm infants had a decreased ventilatory response to CO2 both in quiet sleep (QS) (0.0379 +/- 0.067 vs 0.505 +/- 0.032 L . (min . kg . kPa PACO2)-1; P less than 0.04) and in active sleep (AS) (0.210 +/- 0.032 vs 0.331 +/- 0.048 L . (min . kg . kPa PACO2)-1; P less than 0.04). The decrease in response primarily was a function of a lack of increase in tidal volume with CO2 in QS and a lack of increase in f in AS. Parallel to these changes there were significant correlations between the increases in EMGDi X f and VE with inhaled CO2 (r = 0.75; P less than 0.001); VT and EMGDi (r = 0.63; P less than 0.01); and between the increases in EMGDi/TI and VT/TI with inhaled CO2 (r = 0.64; P less than 0.001). The results suggest that ventilatory response to CO2 is (1) correlated highly with diaphragmatic indices of central output; (2) less in active than in quiet sleep; (3) less in preterm than in term infants. We conclude that despite their increased chest wall compliance, preterm infant respond less to CO2 because of central unresponsiveness.