Steven S. Robertson

Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery

BACKGROUND Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.).

Development of sucking rhythm in preterm infants

We studied the ontogeny and temporal organization of non-nutritive sucking during active sleep in 6 healthy preterm infants (mean birthweight 1.1 kg (range 0.8-1.3 kg) gestational age 28.6 weeks (range 26-30 w] from 30 to 35 weeks of post-menstrual (PM) age. Recognizable rhythmical sucking bursts were recorded at 28 weeks in one infant and by 31-33 weeks in the others. Results were analyzed for the periods 30-31, 32-33 and 34-35 PM weeks. The number of bursts/min increased with age, while the duration of each burst was stable (mean 4.1 s). The pause between bursts decreased. Sucking pace within bursts increased with age which resulted in an increase in the overall rate of sucking. The coefficient of variation (CV) for intersuck time within bursts and for interburst time was computed to examine the stability of the sucking rhythm. For intersuck time the CV was relatively low and constant across ages. However, for interburst time CV was relatively large across ages. Thus, there appears to be a stability of the intraburst sucking rhythm from 30 weeks of gestation, whereas the interburst rhythm is less regular. This documentation of temporal organization in sucking from 30 weeks is one of the earliest indications of an intrinsic rhythm in human behavior.

Early randomized intervention with high-frequency jet ventilation in respiratory distress syndrome

To determine whether early use of high-frequency jet ventilation reduces neonatal mortality or pulmonary morbidity rates, we randomly selected 42 infants with clinical and radiographic evidence of severe respiratory distress syndrome to receive either high-frequency jet ventilation or conventional ventilation. Separate sequential analyses (two-sided, alpha = 0.05, power = 0.95 to detect 85:15 advantage) were performed for mortality rates, air leaks, bronchopulmonary dysplasia, intraventricular hemorrhage, and assignment crossover, and a combined analysis was performed, with death overriding other outcome variables. Enrollment was completed when the combined analysis reached the sequential design boundary indicating no treatment difference. Mortality rates (19% among infants receiving high-frequency jet ventilation vs 24% among infants receiving conventional ventilation), the incidence of air leaks (48% vs 52%), bronchopulmonary dysplasia (39% vs 41%), and intraventricular hemorrhage (33% vs 43%), and assignment crossovers (14% vs 24%) did not differs significantly between the treatment groups. We conclude that early use of high-frequency jet ventilation does not prevent or substantially reduce mortality or morbidity rates associated with assisted ventilation.

Blood pressure and heart rate in the ovine fetus: ontogenic changes and effects of fetal adrenalectomy

Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109-114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120-126, 127-133, and 134-140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 μg/min) was infused intravenously in four ADX fetuses from day 7postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 ± 3.2 ng/ml (mean ± SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109-114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120-126, 127-133, and 134-140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 microgram/min) was infused intravenously in four ADX fetuses from day 7 postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 +/- 3.2 ng/ml (mean +/- SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.

Child care setting affects salivary cortisol and antibody secretion in young children

Elevated afternoon levels of cortisol have been found repeatedly in children during child care. However, it is unclear whether these elevations have any consequences. Because physiologic stress systems and the immune system are functionally linked, we examined the relationship between salivary cortisol concentration and antibody secretion across the day at home and in child care, and their relationships with parent-reported illnesses. Salivary antibody provides a critical line of defense against pathogens entering via the mouth, but little is known about its diurnal rhythm in young children or the effect of different environmental contexts. Saliva samples were taken at approximately 10:30 a.m., 3:30 p.m. and 8:00 p.m. on two child care and two home days in a sample of 65 3-5-year-old children attending very high quality, full time child care centers. Results indicated that (1) a rising cortisol profile at child care, driven by higher afternoon levels, predicted lower antibody levels on the subsequent weekend, (2) higher cortisol on weekend days was related to greater parent-reported illness, and (3) a declining daily pattern in sIgA was evident on weekend and child care days for older preschoolers, but only on weekend days for younger preschoolers. The results suggest that elevated cortisol in children during child care may be related to both lowered antibody levels and greater illness frequency.

The Integration of Body Movement and Attention in Young Infants

The normal development of adaptive behavior in humans depends on the integration of visual attention and body movement, yet little is known about the initial state of movement-attention coupling at the beginning of postnatal life. We studied 1- and 3-month-old infants during extended periods of visual exploration and found that spontaneous shifts of gaze are preceded by rapid changes in general body movement. The results reveal a tight link between motor activation and overt attention on a time scale of seconds or less. This link undergoes substantial developmental change in the first few weeks after birth. During that time, phasic motor activation may play a key role in visual exploration by helping to unlock gaze when the environment is unchanging.

The neural control of cyclic motor activity in the fetal rat (Rattus norvegicus).

The spontaneous behavior of rat fetuses (in a saline bath with fetal-placental-uterine connections intact) was observed directly for 30 minutes on Day 20 of gestation. Rearleg and nonrearleg movements from fetuses with a mid-thoracic spinal cord transection or sham operation were analyzed for cyclic organization. Oscillations in rearleg activity occurred at the same frequency in fetuses with spinal cord transections (0.74 cycle/min) and sham-operated fetuses (0.72 cycle/min). However, oscillations in nonrearleg activity were much slower in the fetuses with spinal cord transections (0.30 vs. 0.77 cycle/min). Other characteristics of the cyclic patterns in motor activity were unaffected. The findings demonstrate 1) the caudal half of the spinal cord can generate cyclic output in the absence of descending input from the brain, 2) there is no single timing center, and 3) rostral sources are slower.

Movement–attention coupling in infancy and attention problems in childhood

Adaptive behavior requires the integration of body movement and attention. Therefore, individual differences in integration of movement and attention during infancy may have significance for development. We contacted families whose 8‐year‐old children (n=26; 16 females, 10 males; mean age 8y 2mo, SD 8mo) participated in a previous study of movement‐attention coupling at 1 or 3 months of age, to assess parent‐reported attention or hyperactivity problems using the Child Behavior Checklist and Diagnostic and Statistical Manual of Mental Disorders (4th edn) criteria. Parent‐reported attention problems at 8 years of age were associated with less suppression of body movement at onset of looking, and greater rebound of body movement following its initial suppression at 3 months, but not at 1 month. Parent‐reported hyperactivity was not related to any of the infant movement–attention measures. Results suggests that the dynamic integration of movement and attention early in life may have functional significance for the development of attention problems in childhood.

Embodied infant attention

Does real time coupling between mental and physical activity early in development have functional significance? To address this question, we examined the habituation of visual attention and the subsequent response to change in two groups of 3-month-olds with different patterns of movement-attention coupling. In suppressors, the typical decrease in body movement at the onset of looks persists into the looks. In rebounders, the initial decrease is more transient and movement quickly returns above baseline. Suppressors and rebounders did not differ on measures of looking during habituation, but when the stimulus changed rebounders looked more than suppressors. When it did not change, they looked less. In addition, during habituation rebounders spent more time looking away from the stimulus. Rapid motor reactivation soon after gaze locks onto a target, characteristic of rebounders, may influence visual foraging and the response to change by keeping attention near a threshold of engagement.

Structure and irregularity in the spontaneous behavior of young infants

Persistent, irregular fluctuations in spontaneous motor activity are common in the young of many vertebrate species, but whether the irregularity is intrinsic to the dynamics of motor activation or the result of random perturbations is not known. Analysis of the second-by-second variation in the general body movement of awake human infants 1 and 3 months after birth revealed low dimensional structure in the characteristically irregular motor activity and exponential rates of divergence of initially similar states of motor activation. Results support the conclusion that irregularity is an intrinsic property of the dynamics of motor activation involving relatively few effective degrees of freedom and raise questions about the advantages or disadvantages of irregularity built into early behavioral organization.