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The failure of chemoreflexes, arousal, and/or autoresuscitation to asphyxia may underlie some sudden infant death syndrome (SIDS) cases. In Part I, we showed that some SIDS infants had altered 5-hydroxytryptamine (5-HT)2A/Creceptor binding in medullary nuclei supporting chemoreflexes, arousal, and autoresuscitation. Here, using the same dataset, we tested the hypotheses that the prevalence of low 5-HT1Aand/or 5-HT2A/Creceptor binding (defined as levels below the 95% confidence interval of controls—a new approach), and the percentages of nuclei affected are greater in SIDS versus controls, and that the distribution of low binding varied with age of death. The prevalence and percentage of nuclei with low 5-HT1Aand 5-HT2A/Cbinding in SIDS were twice that of controls. The percentage of nuclei with low 5-HT2A/Cbinding was greater in older SIDS infants. In >80% of older SIDS infants, low 5-HT2A/Cbinding characterized the hypoglossal nucleus, vagal dorsal nucleus, nucleus of solitary tract, and nuclei of the olivocerebellar subnetwork (important for blood pressure regulation). Together, our findings from SIDS infants and from animal models of serotonergic dysfunction suggest that some SIDS cases represent a serotonopathy. We present new hypotheses, yet to be tested, about how defects within serotonergic subnetworks may lead to SIDS.

Inland Steel Industries Inc entered into a joint venture with Nippon Steel Corp in 1986 to gain access to new technology and to become competitive in the 1990s. The joint venture was prompted by Inland Steel's study on its international competitive position in the 1980s, which revealed that the organization had both a cost disadvantage and a quality disadvantage when compared to Japanese firms. Japanese corporations were able to produce and ship higher quality sheet steel at a 20% lower cost. Inland Steel then underwent a reorganization, followed by the creation of the joint venture. The success of the joint venture is attributed to common objectives, as well as each organization's need for the other.

BackgroundPreterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury.MethodsRat pups were exposed to IH from P2 to P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20–P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed.ResultsPups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1β at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus, and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr, and Gly/Cr; increases in TCho and GPC in the brainstem; and decreases in NAA/Cho in the hippocampus.ConclusionsWe conclude that early postnatal exposure to IH, similar in magnitude to that experienced in human preterm infants, is associated with evidence for proinflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia.

Industrial engineers have played an important part in the administration and implementation of Inland Steel's margin improvement program. They have worked with department managers to develop specific action plans for margin improvements and to prioritize the plans in terms of their likelihood of success. The program saved the company $75 million in 1982 and $400 million in the three years that followed. Industrial engineers have also taken part in designing incentive plans and job classification changes resulting from the program., IEs Play Key Role In Effort To Revitalize And Rebuild Competitiveness At Inland Steel Company For many years, the steel industry was perhaps the most visible symbol of the United [...]

IMPORTANCE Preterm infants have immature respiratory control and resulting intermittent hypoxia (IH). The extent of IH after stopping routine caffeine treatment and the potential for reducing IH with extended caffeine treatment are unknown. OBJECTIVES To determine (1) the frequency of IH in premature infants after discontinuation of routine caffeine treatment and (2) whether extending caffeine treatment to 40 weeks’ postmenstrual age (PMA) reduces IH. DESIGN, SETTING, AND PARTICIPANTS A prospective randomized clinical study was conducted at 16 neonatal intensive care units in the United States, with an 18-month enrollment period. Preterm infants (<32 weeks’ gestation) previously treated with caffeine were randomized to extended caffeine treatment or usual care (controls) at a PMA of at least 34 weeks but less than 37 weeks. Continuous pulse oximeter recordings were obtained through 40 weeks’ PMA. Oximeter data were analyzed by persons masked to patient group. INTERVENTION Continued treatment with caffeine. MAIN OUTCOMES AND MEASURES Number of IH events and seconds with less than 90% hemoglobin oxygen saturation (Sao2) per hour of recording. RESULTS Our analysis included 95 preterm infants. In control infants, the mean (SD) time at less than 90% Sao2 at 35 and 36 weeks’ PMA was 106.3 (89.0) and 100.1 (114.6) s/h, respectively. The number of IH events decreased significantly from 35 to 39 weeks’ PMA (P = .01). Extended caffeine treatment reduced the mean time at less than 90% Sao2 by 47% (95% CI, −65% to −20%) to 50.9 (48.1) s/h at 35 weeks and by 45% (95% CI, −74% to −17%) to 49.5 (52.1) s/h at 36 weeks. CONCLUSIONS AND RELEVANCE Substantial IH persists after discontinuation of routine caffeine treatment and progressively decreases with increasing PMA. Extended caffeine treatment decreases IH in premature infants. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01875159

Some victims of sudden infant death syndrome have arcuate nucleus abnormalities. The arcuate nucleus may be homologous with ventral medullary structures in the cat known to be involved in the control of breathing and the response to systemic hypercapnia. We refer to putative arcuate homologues in the piglet collectively as the rostral ventral medulla (RVM). We inhibited the RVM in awake and sleeping, chronically instrumented piglets by microdialysis of the GABAAreceptor agonist muscimol. Muscimol dialysis (10 and 40 mM) had no effect on eupnea but caused a significant reduction in the response to hypercapnia during both wakefulness (34.8 ± 8.7 and 30.7 ± 10.1%, respectively) and sleep (36.7 ± 6.7 and 49.5 ± 8.9%, respectively). The effect of muscimol on the CO2response was entirely via a reduction in tidal volume and appeared to be greater during non-rapid-eye-movement sleep. We conclude that the piglet RVM contains neurons of importance in the response to systemic CO2during both wakefulness and non-rapid-eye-movement sleep. We hypothesize that dysfunction of homologous regions in the human infant could lead to impaired ability to respond to hypercapnia, particularly during sleep, which could potentially be involved in the pathogenesis of sudden infant death syndrome.

Airway obstruction at the level of the larynx causes respiratory insufficiency during experimental seizures in spontaneously breathing, anesthetized piglets (T. E. Terndrup and W. E. Fordyce, Pediatr. Res., 38: 61–66, 1995). To investigate further the neural mechanisms of this obstruction, the activities of the phrenic nerve (PH) and the recurrent laryngeal motor branches to the thyroarytenoid (TA) and posterior cricoarytenoid (PCA) muscles were analyzed in 11 anesthetized, vagotomized, paralyzed, and ventilated piglets. After a control recording period, seizures were induced by subcortical penicillin G injections. Compared with baseline conditions, nerve activities became irregular during seizures. Extraneous TA bursts during PH activation were evident in all piglets during seizures. During ictal phases of seizures, the peak integrated activities of the PH and the expiratory component of the PCA, but not TA or inspiratory PCA activities, were significantly decreased compared with interictal phases. During seizures, a significant delay in the onset of the inspiratory component of PCA activation with respect to the onset of the PH was observed. This study helps to explain respiratory impairment during cortical seizures by providing evidence of impaired timing of activation of laryngeal dilator mechanisms and coordination with those activating the diaphragm. Cyclical PH inhibition during high-intensity cortical discharges may provide a secondary mechanism producing respiratory insufficiency during seizures.

ABSTRACT: Newborn infants and animals typically exhibit a paradoxical ventilatory response to hypoxia. The depressive phase of the response has not been adequately explained. It has been suggested that hypoxia may cause the release of inhibitory neuromodulators which depress ventilation. We have postulated that the nucleoside, adenosine, may be involved because 1) it is rapidly released during hypoxia, 2) it depresses ventilation, and 3) theophylline, a competitive inhibitor, has successfully been used to treat apnea of prematurity. Herein we describe the effects of aminophylline on ventilation during hypoxia in the spontaneously breathing newborn piglet administered both rapidly after ventilatory depression has occurred (bolus) and before the onset of hypoxia (pretreatment). Ten percent oxygen breathing produced a typical biphasic ventilatory response. The decrease in minute ventilation was caused by a decrease in both tidal volume and respiratory frequency. The bolus administration of aminophylline reversed the depression in minute ventilation (p < 0.001) by increasing tital volume (p < 0.002). Pretreatment with aminophylline decreased the amount of ventilatory depression (p < 0.05) by preventing a decrease in respiratory frequency. We conclude that aminophylline, an adenosine antagonist, reduces the decrease in ventilation which occurs during hypoxia in the newborn. We speculate that adenosine may play a role in hypoxic ventilatory depression and respiratory control in the newborn.

Alterations in thermoregulatory mechanisms related to sleep state may play an important role in the problems of homeostasis experienced by the premature infant. In the adult, homeothermic regulation of body temperature may be suspended during REM. We measured oxygen consumption (O2) in six premature infants 33–35 wk gestation both at thermoneutrality and during a mild thermal stress to determine whether thermoregulatory responses were intact during REM sleep. All infants were studied under radiant warmers. Skin temperature was allowed to fall 7–8 times during a 6–8 h study period while O2, CO2, heart rate and TcPO2were continuously recorded. Sleep state was scored using EEG, EOG, EMG and behavioral criteria. A total of 1,162 one-min epochs were scored. In all states including REM, O2was significantly higher during the cool periods. The mean increases: 21.5, 23.3, 11.1 and 5.3 for Awake, Indeterminate, REM and NREM respectively. When REM and NREM were compared at thermoneutrality, there was no difference in the O2(8.80 ± 0.11 and 8.93 ± 0.15 cc/kg/min, mean ± S.E., for REM and NREM, respectively). We conclude that in contrast to the adult, active thermoregulation occurs in the premature infant during REM sleep.

Theophylline (T) reduces hypoxic ventilatory depression in newborn pig lets and can enhance the release of catecholamines (CATs) which in turn may stimulate ventilation. To determine if the effect of T on ventilation was due to the release of CATs, we measured plasma CATs and ventilation in two groups of spontaneously breathing newborn piglets <4 days old treated with either T (n=7) or normal saline (NS) (n=6) both during normoxia and hypoxia. The piglets were anesthetized with ketamine and xylazine, intubated and the femoral artery catheterized o Epinephrine (EPI) and norepinephrine (NE) were measured before and 30 minutes after treatment with T (15 mg/kg) or NS. The animals were exposed to 10% oxygen and the CATs remeasured after 5 minutes of hypoxia. Respiratory rate (RR), expiratory flow integrated to minute ventilation (Ve), heart rate and blood pressure were continuously recorded. CATs were assayed by high pressure liquid chromatography with electrochemical detection.Treatment with T during normoxla was associated with an increase in tidal volume. During hypoxia treatment with T prevented the falI in Ve and RR seen in the NS group. EPI and NE increased during hypoxia but there was no difference between the groups at 5 minutes. In our model the increase in CATs observed during hypoxia was not enhanced by T. This is consistent with the hypothesis that some mechanism other than catecholamine release is responsible for the effect of T in reducing neonatal hypoxic respiratory depression.

Positive end-expiratory pressure (PEEP) decreases dynamic respiratory system compliance (Crs) in ventilated infants. As dynamic Crs measurements reflect airway resistance, we utilized a pulse method (J. Appl Physiol. 49:1116) to test the effect of PEEP on static Crs. We measured Crs in 11 infants (gestational age 33±4{mean±S.D.}weeks, weight 2052±704 gms, and study age 29±35 days) with respiratory failure supported with a constant flow ventilator. Flow, transrespiratory pressure, and tidal volume were recorded. We calculated pulse Crs by dividing flow by the slope of the linear portion of the pressure tracing. Static and dynamic Crs were measured by standard methods. Values of Crs were compared from PEEPs of 2.5 to 10.0 cms H2O. At the baseline ventilator settings, pulse and static Crs were similar (b=0.94, r2=90%), and both exceeded dynamic Crs (p<0.005). The effect of PEEP is shown below:Comparing individual regression slopes, pulse Crs decreased uniformly among the infants (F=1.80) from PEEPs of 5.0 to 10.0 cms. PEEPs exceeding 5.0 cms may overdistend the lungs and chest wall of ventilated infants as demonstrated by a decrease in pulse Crs.

Premature infants in single wall incubators covered with “thermal blankets” (TB) made of plastic packing material have large reductions in insensible water loss (IWL) compared to naked infants. We postulated that such reductions in evaporative heat loss would not result in decreases in caloric expenditure if body temperature were maintained by a servo controlled heat source. Using an open circuit technique, we measured oxygen consumption (VO2), carbon dioxide production (VCO2), heart rate (HR), respiratory rate (RR), abdominal skin (Tabd), cheek, thigh, rectal, incubator air, wall, and room air temperature in 10 infants less than 36 weeks gestation and from 2 to 24 days of age both naked and covered with a plastic TB. Tabdwas maintained between 36.2 and 36.8 and rectal temperature between 36.8 and 37.2 °C. in each environment by manual or automatic servo control. A “resting state” was defined using a combination of subjective and objective criteria. The mean values of VO2during the “resting state” were 7.31 and 7.59 cc/kg/min. for naked and covered infants, respectively. Mean values of VCO2, respratory quotient, HR, RR, abdominal, cheek, thigh, and rectal temperatures were essentially identical in both environments. Operant temperatures, however, averaged 0.5 °C. lower when the infants were covered. These data support the hypothesis that decreases in IWL do not necessarily imply reductions in caloric requirements in infants where Tabdis maintained by servo control.

We have previously demonstrated that theophylline, an adenosine antagonist, reduces hypoxic ventilatory depression in the newborn piglet. In order to investigate the possibility that the stimulatory effects of theophylline we observed were due to effects on vagal pulmonary receptors, we compared the effect of theophylline on the hypoxic ventilatory response in intact and vagotomized newborn piglets. Five newborn piglets less than 3 days of age were exposed to 10 % oxygen under three experimental conditions: 1) intact; 2) after vagotomy; and 3) vagotomy + theophylline. Each animal was anesthetized with ketamine and xylazine, intubated, and the femoral artery catheterized. The vagi were identified but left intact prior to the onset of the experiments. Recordings of expiratory flow and integrated volume, EKG, and arterial blood pressure were obtained during six minutes of hypoxia first before and then beginning 30 minutes after vagotomy. Theophylline (15 mg/kg) was then administered over 10 minutes and after 30 minutes the experiment was repeated. The effect of hypoxia on minute ventilation in each of the three conditions is shown in the graph. Vagotomy alone had no effect on the hypoxic ventilatory response. The addition of theophylline, however, resulted in a greater increase above baseline after 6 minutes of hypoxia (38.7 +/−17.3 %) compared to vagotomy alone (19.8 +/− 15.0 %)(p<0.02). The difference in ventilation was due to changes in frequency rather than tidal volume. We conclude that vagal afferents do not influence the newborn hypoxic ventilatory response and that the effects of methyl xanthines on hypoxic ventilatory depression are not mediated by the vagus.