Sibilah Breen

Autonomic activity during human sleep as a function of time and sleep stage.

While there is a developing understanding of the influence of sleep on cardiovascular autonomic activity in humans, there remain unresolved issues. In particular, the effect of time within the sleep period, independent of sleep stage, has not been investigated. Further, the influence of sleep on central sympathetic nervous system (SNS) activity is uncertain because results using the major method applicable to humans, the low frequency (LF) component of heart rate variability (HRV), have been contradictory, and because the method itself is open to criticism. Sleep and cardiac activity were measured in 14 young healthy subjects on three nights. Data was analysed in 2‐min epochs. All epochs meeting specified criteria were identified, beginning 2 h before, until 7 h after, sleep onset. Epoch values were allocated to 30‐min bins and during sleep were also classified into stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. The measures of cardiac activity were heart rate (HR), blood pressure (BP), high frequency (HF) and LF components of HRV and pre‐ejection period (PEP). During non‐rapid eye movement (NREM) sleep autonomic balance shifted from sympathetic to parasympathetic dominance, although this appeared to be more because of a shift in parasympathetic nervous system (PNS) activity. Autonomic balance during REM was in general similar to wakefulness. For BP and the HF and LF components the change occurred abruptly at sleep onset and was then constant over time within each stage of sleep, indicating that any change in autonomic balance over the sleep period is a consequence of the changing distribution of sleep stages. Two variables, HR and PEP, did show time effects reflecting a circadian influence over HR and perhaps time asleep affecting PEP. While both the LF component and PEP showed changes consistent with reduced sympathetic tone during sleep, their pattern of change over time differed.

Hypoxemia near mid-gestation has long-term effects on fetal brain development.

We tested the hypotheses that an episode of hypoxemia near mid-gestation in fetal sheep has long-term effects on brain development and that the extent and type of damage is related to the stage of development within a particular brain structure at the time of the hypoxemia. Fetal sheep (n = 8) were made hypoxemic at 90 +/- 2 days (term approximately 147 days) by restricting the maternal blood supply to the placenta for 12 hours (h) using a vascular clamp so as to reduce fetal arterial O2 saturation by 50%-60%. Fetuses were killed 35 days later and the brains analysed histologically and immunohistochemically. Age-matched fetuses (n = 8) were used as controls. Gross brain damage was observed in only 1 fetus, the most acidemic during the period of hypoxemia. There was a reduction of 12% (p < 0.05) in the cross-sectional area of the cerebral cortex in hypoxemic fetuses compared with controls. In lobule 6 of the cerebella of hypoxemic fetuses, significant reductions were seen in (a) the volume density of Purkinje cells (33%), (b) the width of the molecular layer (13%), (c) the area of the inner granule cell layer (13%), (d) the area of the white matter (18%), and (e) the total cross-sectional area (15%). There were also significant reductions in the area of arborization of Purkinje cell dendritic trees (50%), in the branching density (25%), and in the number of dendritic spines (31%). In the ventral hippocampi of hypoxemic fetuses, there was a 36% reduction (p < 0.05) in the volume density of CA1 pyramidal cells and a 50% increase (p < 0.05%) in the number of astrocytes. We conclude that an episode of hypoxemia near mid-gestation reduces neuronal numbers in the hippocampus and cerebellum and probably also in the cerebral cortex. The growth of neural processes in a particular region will be significantly retarded if the hypoxemia occurs at an early stage of the growth of neural processes (e.g. cerebellum) but not if development is well advanced at the time of the insult (e.g. hippocampus). Damage is sustained in the white matter of the cerebral hemispheres if the insult is particularly severe. Together, these deficits could affect neural connectivity and impair postnatal brain function.

Fetal Brain Injury Following Prolonged Hypoxemia and Placental Insufficiency: A Review

It is well-established that severe, acute episodes of hypoxemia can damage the brain before birth, but the effects of more sustained hypoxemia are less well understood. We have used fetal fetal sheep in a series of studies aimed at determining the effects of prolonged hypoxemia, induced by placental insufficiency of differing severity and duration, on fetal brain structure. Restriction of placental, and hence fetal, growth by carunclectomy caused impaired development of neural processes and connections in the hippocampus, cerebellum, and visual cortex; neuronal migration and neuronal numbers did not appear to be affected. Twenty days of placental insufficiency during late gestation induced by umbilicoplacental embolisation also caused abnormalities in brain structure; the cerebellum, which develops late in gestation, was particularly affected. In the cortex, there was evidence of white matter lesions, an increase in the size of capillaries and a proliferation of astroglia. We also examined the effects of shorter periods of hypoxemia (6-12 hr) near mid-gestation on brain structure; fetuses were allowed to recover for 7 or 35 days after the hypoxemic challenge. The major changes were mild focal damage in the cortical white matter, a reduction in the number of Purkinje cells, a delay in the growth of neural processes in the cerebellum and proliferation of blood vessels. The hippocampus was also affected, in particular the areal density of pyramidal cells was reduced. The use of several classes of pharmacological agents with the potential to protect neurons from hypoxemic injury is discussed in relation to the developing brain.

Identification of brainstem neurons responding to hypoxia in fetal and newborn sheep.

Hypoxia causes a reversible decrease in the level of respiratory, oculomotor and postural muscle activity in fetal sheep, an effect not seen in newborn lambs. We have used Fos immunohistochemistry to identify neurons which are activated by hypoxia and which may mediate this motor inhibition in the fetus. Pregnant sheep of either 117 or 138 days gestation were made hypoxic by allowing them to breathe 8-9% O2 for 2 h. Compared to age-matched control fetuses, hypoxia caused a significant increase in Fos-immunoreactivity in several medullary nuclei including the nucleus tractus solitarius, lateral reticular nucleus and the rostral ventrolateral medulla and also in the lateral parabrachial nucleus, locus coeruleus and subcoeruleus region in the pons. Hypoxia in newborn lambs, 7-18 days old, resulted in Fos staining in the same medullary and pontine nuclei with the exception of the subcoeruleus region which was devoid of Fos-immunoreactivity. In newborn lambs in which the carotid sinus nerves had been sectioned bilaterally, Fos-immunoreactivity was increased in the nucleus tractus solitarius in the medulla and in the locus coeruleus, lateral parabrachial and Kölliker-Fuse nuclei in the pons when compared to intact control newborn lambs. When carotid sinus nerve denervated-lambs were subjected to hypoxia the pattern of Fos-ir was similar to the pattern seen in the denervated control lambs but in addition staining was present in the subcoeruleus. These results suggest that a specific set of pontine neurons are activated by low oxygen levels in the fetus but not in the newborn lamb in the presence of an intact innervation from the carotid sinus. We hypothesise that: (a) in the fetus hypoxia activates neurons in the region of the subcoeruleus and this causes cessation of breathing movements and muscle atonia; and (b) that after birth stimulation of the carotid chemoreceptors by hypoxia normally inhibits activation of these subcoeruleus neurons.

The fetal brainstem is relatively spared from injury following intrauterine hypoxemia

Our aim was to test the hypothesis that the fetal brainstem is relatively spared, compared to other brain regions, from hypoxia-induced damage. We have used established experimental models of acute and chronic intrauterine compromise in sheep to mimic conditions that can arise in human pregnancy. The acute insult was 12 h of placental insufficiency induced by restricted utero-placental blood flow at 90 days of gestation (term approximately 147 days). Five weeks after this insult (n=7 fetuses) there was no overt damage to the brainstem nor were there alterations to the blood vessel morphology, volume of the medulla or of medullary nuclei compared to controls (n=8). This regimen is known to have significant effects on the forebrain and cerebellum. The chronic insult was induced in five fetuses via embolisation of the umbilico-placental circulation from 120 to 140 days of gestation. An additional three fetuses were found to be spontaneously hypoxemic (SH) immediately after surgery. At 140 days, in brainstems of all chronically hypoxemic fetuses compared to controls (n=8), there was an increase (P<0.05) in the percentage of neuropil occupied by blood vessels and abnormal myelin in the most severely SH fetus but no other morphological or neurochemical alterations. This regimen is known to cause marked damage to the cerebral hemispheres and to a lesser extent to the cerebellum. We suggest that the absence of marked structural or neurochemical alterations in the brainstem is most likely due to the maintenance of oxygen delivery to the brainstem during fetal hypoxemia.

The development of diurnal rhythmicity in fetal suprachiasmatic neurons as demonstrated by Fos immunohistochemistry

Using Fos immunohistochemistry as a marker of cellular activity, we have shown that neurons in the suprachiasmatic nucleus of fetal sheep are active by 75 days gestation. From at least 90 days gestation (term is 146 days), these neurons are more active during the day (12.00) than at night (03.00) when pregnant ewes are exposed to a 12-h light-dark cycle with lights on at 07.00. The day-night difference in Fos immunoreactivity persisted when the lighting schedule was extended by 8 h to 03.00, although neurons were now more active at 03.00 than they were in fetuses maintained on the normal light-dark cycle. When ewes were maintained in constant light from 133 to 138 days, the day-night difference in Fos immunoreactivity in the fetal suprachiasmatic nucleus was abolished, suggesting that diurnal activity of the fetal suprachiasmatic nucleus is maintained by a signal related to the external lighting regime. In a twin pregnancy where one fetus was optically enucleated at 100 days gestation, the density of Fos-immunoreactive neurons in the suprachiasmatic nucleus during the day at 138 days was similar to the unoperated twin. This suggests that the effects of dim light in the uterus on the fetal retina do not account for the high level of Fos immunoreactivity in the suprachiasmatic nucleus in the daytime. We propose that a chemical messenger of maternal origin, possibly melatonin, suppresses the activity of fetal suprachiasmatic neurons during the night, and that fetal suprachiasmatic neurons have endogenous activity which is expressed fully during the daytime.

Benefits of remote real-time side-effect monitoring systems for patients receiving cancer treatment

In Australia, the incidence of cancer diagnoses is rising along with an aging population. Cancer treatments, such as chemotherapy, are increasingly being provided in the ambulatory care setting. Cancer treatments are commonly associated with distressing and serious side-effects and patients often struggle to manage these themselves without specialized real-time support. Unlike chronic disease populations, few systems for the remote real-time monitoring of cancer patients have been reported. However, several prototype systems have been developed and have received favorable reports. This review aimed to identify and detail systems that reported statistical analyses of changes in patient clinical outcomes, health care system usage or health economic analyses. Five papers were identified that met these criteria. There was wide variation in the design of the monitoring systems in terms of data input method, clinician alerting and response, groups of patients targeted and clinical outcomes measured. The majority of studies had significant methodological weaknesses. These included no control group comparisons, small sample sizes, poor documentation of clinical interventions or measures of adherence to the monitoring systems. In spite of the limitations, promising results emerged in terms of improved clinical outcomes (e.g. pain, depression, fatigue). Health care system usage was assessed in two papers with inconsistent results. No studies included health economic analyses. The diversity in systems described, outcomes measured and methodological issues all limited between-study comparisons. Given the acceptability of remote monitoring and the promising outcomes from the few studies analyzing patient or health care system outcomes, future research is needed to rigorously trial these systems to enable greater patient support and safety in the ambulatory setting.

Cancer patient and clinician acceptability and feasibility of a supportive care screening and referral process.

Incorporating supportive care into routine cancer care is an increasing priority for the multi‐disciplinary team with growing evidence of its importance to patient‐centred care. How to design and deliver a process which is appropriate for patients, clinicians and health services in rural areas needs further investigation.

Mobile Health Intervention to Increase Oral Cancer Therapy Adherence in Patients With Chronic Myeloid Leukemia (The REMIND System): Clinical Feasibility and Acceptability Assessment

Background Optimal dosing of oral tyrosine kinase inhibitor therapy is critical to treatment success and survival of patients with chronic myeloid leukemia (CML). Drug intolerance secondary to toxicities and nonadherence are significant factors in treatment failure. Objective The objective of this study was to develop and pilot-test the clinical feasibility and acceptability of a mobile health system (REMIND) to increase oral drug adherence and patient symptom self-management among people with CML (chronic phase). Methods A multifaceted intervention was iteratively developed using the intervention development framework by Schofield and Chambers, consisting of defining the patient problem and iteratively refining the intervention. The clinical feasibility and acceptability were examined via patient and intervention nurse interviews, which were audiotaped, transcribed, and deductively content analyzed. Results The intervention comprised 2 synergistically operating elements: (1) daily medication reminders and routine assessment of side effects with evidence-based self-care advice delivered in real time and (2) question prompt list (QPL) questions and routinely collected individual patient adherence and side effect profile data used to shape nurses’ consultations, which employed motivational interviewing to support adoption of self-management behaviors. A total of 4 consultations and daily alerts and advice were delivered over 10 weeks. In total, 58% (10/17) of patients and 2 nurses participated in the pilot study. Patients reported several benefits of the intervention: help in establishing medication routines, resolution of symptom uncertainty, increased awareness of self-care, and informed decision making. Nurses also endorsed the intervention: it assisted in establishing pill-taking routines and patients developing effective solutions to adherence challenges. Conclusions The REMIND system with nurse support was usable and acceptable to both patients and nurses. It has the potential to improve adherence and side-effect management and should be further evaluated.

The experiences of patients with advanced cancer and caregivers presenting to Emergency Departments: A qualitative study

Background: Despite being a common event in the course of an advanced cancer illness, there is little understanding of patients’ perceptions of hospital Emergency Department presentations. Aim: To explore the experiences and perceptions of Emergency Departments held by patients with advanced cancer and their informal caregivers. Design: Cross-sectional study involving semi-structured interviews with advanced cancer patients and their informal caregivers. Qualitative data analysis was underpinned by a phenomenological approach utilising a data-driven inductive thematic frame. Setting/participants: In total, 19 patients with advanced cancer who presented to Emergency Departments in the previous 6 months and 10 informal caregivers from an Australian public hospital and community palliative care service were interviewed. Results: Patients reported that Emergency Department presentations were largely prompted by worsening symptoms or were a means to expedite hospital admission, with many instructed to attend by their health care provider. The experience in the Emergency Department was described as a time of anxiety and uncertainty with concerns over communication, the general environment and delays in the symptom management highlighted. Long waits were common. Despite this, patients described relief at receiving care. While the Emergency Department was viewed as a safety net for the health system, many believed advanced cancer patients should have alternative options. Conclusion: Relatively simple changes of regular communication updates and early symptom relief would improve patient experience of Emergency Department care. However, since an Emergency Department presentation is frequently serving as a default to access medical care, a significant re-orientation of the health care system is required to meet patient needs.