Defining The Difficult-To-Sedate Clinical Phenotype In Critically Ill Children

Each year thousands of critically-ill children receive sedation to help them tolerate intensive care therapies. A significant number of these children do not respond as expected to appropriately dosed sedation and remain agitated for some period, leading to iatrogenic injury and increased stress, as well as increased resource use. Children who remain under-sedated despite optimal therapy are considered “difficult-to-sedate”, but, to date, little data have been available to support an accurate description of this group of children. Recent attention to heterogeneity of treatment effect has spurred the development of clinical phenotypes that describe subgroups of patients within a disease process who differ in their clinical attributes and responses to therapy. Defining the difficult-to-sedate clinical phenotype in critically ill children is important because it will allow the use of sedation therapy targeted to the unique clinical, physiological, and developmental characteristics of the child. The three papers developed in this dissertation study explored the concept of the difficult-to-sedate child clinical phenotype. A comprehensive review of the literature identified the lack of an operational definition and identified factors contributing to the clinical phenotype. These factors were used to develop an initial operational definition and to construct a conceptual model. Expert critical care clinicians validated the elements of the operational definition through an assessment of face and content validity and proposed additional factors for inclusion in the model. A refined definition was tested using data from the RESTORE study. Characteristics identified through latent class and classification and regression tree analysis were consistent with the conceptual model proposed. Decreasing the ambiguity that currently exists around the concept of the difficult-to-sedate child clinical phenotype is a major achievement of this study. A clear operational definition of the concept promotes its consistent measurement and facilitates future investigation, and allows useful comparisons across studies. The conceptual model and operational definition require further investigation and refinement, as well as prospective validation by other investigators. This study suggests that a clinically meaningful population of difficult-to-sedate children requiring mechanical ventilation for a critical illness exists. Documentation of this phenotype promotes the development of evidence to support best practices in the care of these children

Acceptability, feasibility, and preliminary clinical usefulness of Bispectral index (BIS) monitoring in UK palliative care patients

Background Bispectral index (BIS) is a technology using electroencephalographic (EEG) readings to assess levels of consciousness in patients undergoing general anaesthesia in the operating room where it has been shown to improve patient care and outcomes. Few previous studies have investigated BIS use in palliative care patients receiving sedative medication and none of these have been conducted in the United Kingdom (UK). Aim To explore the acceptability, feasibility, and preliminary clinical usefulness of BIS monitoring in adult UK palliative care patients. Methods Three empirical studies were undertaken to meet the research aim: (1) a qualitative study exploring the perceptions of patients, current patient relatives, and bereaved relatives regarding the possible use of BIS in palliative care, (2) an exploratory study of BIS monitoring in adult hospice inpatients, and (3) a further qualitative study investigating patients', relatives', and hospice clinicians' direct experiences of BIS monitoring. Qualitative data were analysed using the framework method. Quantitative data were analysed using descriptive statistics, correlation coefficients, and the Wilcoxon signed-rank test. Results Ten palliative care patients, four current patient relatives, and eleven bereaved relatives participated in study (1). Forty hospice inpatients were monitored with BIS for study (2). Ten patients, two relatives, and ten clinicians participated in study (3). Findings suggest that conducting research with BIS in UK hospice inpatients is feasible and acceptable to key stakeholders. There was insufficient evidence to support the clinical usefulness of BIS monitoring in this population, probably due to a relatively small sample consisting of patients who were predominantly alert and responsive. Conclusion This research is the first to explore the use of BIS in the UK palliative care context. Findings from this work support the feasibility and acceptability of BIS as a research tool. Further research is needed to determine the clinical usefulness of BIS in palliative care

Pharmacokinetic/pharmacodynamic modelling to optimize the dose of analgesics and sedatives in children

Analgesic and sedative drugs are mostly used in an “off label” fashion in children. The pharmacokinetic-pharmacodymamic (PK/PD) approach is useful in order to determine the dose-concentration-response relationship and therefore the optimal dose regimens in different populations. However, this approach has not been fully explored for all analgesics and sedatives. This is mostly due to the complex and multidimentional nature of pain, making it challenging to evaluate objectively their effect particularly in neonates and infants. Hence, there is an important need for PK/PD studies in pain and sedation. This thesis focuses on analysing clinical trial results on specific areas that lack good quality PK/PD data in order to optimise the dose of analgesic and sedative agents in children. The studies described in this thesis aimed to address the following questions: what is the optimal dose of fentanyl for procedural pain in preterm infants (NEOFENT study); what is the adequate dose regimen of fentanyl and clonidine to provide an adequate pain and sedation management in asphyxiated newborns receiving hypothermic treatment (SANNI study); and finally what is the optimal dose of clonidine and midazolam in the PICU (CloSed study). In order to address these questions, PK and PK/PD models were developed in order to describe the relationship between drug concentration and analagesic/sedative effect using pain and sedation scores. These models were used to define target concentrations and perform simulations to determine the optimal dose. The results of the NEOFENT study showed that three genetic variants had a significant influence on the fentanyl clearance and suggested an IV dose of 2 µg/kg for procedural pain in preterm infants. The results of the SANNI analysis showed that the hypothermic treatment significantly decreased the clearance of both fentanyl and clondine. Finally, the models developed for the CloSed and SANNI studies suggested that the dose routinely prescribed in clinical practice should be increased in order to provide an adequate pain and sedation management

PROTOCOL OF SEDATION AND ANTAGONISM (DEXMEDETOMIDINE-ATIPAMEZOLE) TO PERFORM DIAGNOSTIC ANALGESIA IN FRACTIOUS HORSES : PRELIMINARY STUDY

Purpose of the work: To assess the applicability of a new protocol of sedation and antagonism using dexmedetomidine (DEX) and atipamezole (ATZ) to perform diagnostic analgesia in fractious horses. Materials and methods: Six fractious horses (3 geldings and 3 mares) undergoing lameness investigation that required diagnostic analgesia were recruited. All the horses were admitted two days before the beginning of the study. During this period heart rate (HR), respiratory rate (RR), height of the head from the ground, mucous membranes colour, capillary refill time (CRT) and temperature were recorded. All the horses were sedated with DEX 2.5-5\u3bcg/kg and after 20 min ATZ 5\u3bcg/kg was administered. The degree of sedation was assessed using the visual analogue scale (VAS) and the numerical rating scale (NRS). The FC, FR, TRC were assessed at 3, 5, 10 and 15 min after both sedation and ATZ administration. Statistical analysis: The physiological parameters were analysed using ANOVA whereas Wilcoxon test was used for the sedation scales. Results: The values of HR and RR were significantly different after administration of DEX and ATZ at 3 and 5 min respectively. Statistical significance was also appreciated for height of the head from the ground, ataxia, tactile stimuli and visual stimuli. Ataxia and height of the head from the ground were improved starting from 3 min after administration of ATZ. Conclusion and clinical relevance: The protocol was successful in all cases, however in two patients ataxia was not completely abolished after ATZ administration. There is a potential for the protocol to be used in the everyday practice. However diffusion of the local anaesthetic after block must be born in mind

Don't be afraid! Population PK-PD modeling as the basis for individualized dosing in children and critically ill

The overall goal was to develop individualized dosing guidelines for the sedatives propofol and midazolam in infants and in critically ill patients, on the basis of population pharmacokinetic-pharmacodynamic (PK-PD) modeling. Both under- and oversedation significantly and adversely affects patient outcome. Due to the high intra- and interindividual variability in dose requirements dosing is complicated. In this thesis the interindividual variability in response has been examined by covariate analysis. In this analysis the effects of bodyweight, cardiac function, severity of illness and liver blood flow and the unexplained interindividual variability have been characterized. It was shown that infants require higher doses of propofol because of differences in pharmacokinetics rather than pharmacodynamics. When comparing the results of the PK-PD model of propofol and midazolam in infants, propofol is preferred over midazolam because of the lower interindividual variability in pharmacodynamics compared to midazolam. In critically ill patients severity of the illness was found to be a major determinant of the level of sedation, with lower propofol dosing requirements with increasing severity of illness. The PK-PD models can be used as a basis for individualized dosing of propofol and midazolam, which is essential for optimizing the quality of sedation in clinical practice and will improve patients__ outcome.UBL - phd migration 201

Delirium screening in the intensive care unit using emerging QEEG techniques : A pilot study

This work was supported by an Alzheimer’s Society grant (project grant number AS-PG-14-039 to BP) and a British Journal of Anaesthesia / Royal College of Anaesthetists funded John Snow Anaesthesia iBSc Award (to AH).Peer reviewedPublisher PD

Analgesia and/or anaesthesia during piglet castration–part I: efficacy of farm protocols in pain management

Pain alleviation associated with surgical castration of piglets is a debated welfare issue. The present study compares the effect of different protocols involving analgesia and/or anaesthesia or sedation suitable under field conditions, with the aim to alleviate pain due to castration in piglets. A randomised within-litter design, with 50 replicates, compared 7 treatments applied 10 min before castration: HAND: positive control, handling only; CTRL: negative control, physiological saline, i.m.; MEL: meloxicam, i.m.; AZA: azaperone, i.m.; PROC: local anaesthesia with procaine and adrenaline, subcutaneously; AZA-MEL: joint administration of azaperone and meloxicam; PROC-MEL: procaine and meloxicam. Efficacy of pain relief was assessed during a 180 min period after castration by serum cortisol and glycaemia, algometry and behaviour. CTRL, AZA, PROC and AZA-MEL piglets showed an increase in cortisol concentration 60 min after castration compared to HAND. Both groups with azaperone (AZA and AZA-MEL) developed concentrations even higher than CTRL (p .05). CRTL and PROC piglets reacted to the algometer at an average lower pressure than HAND (p =.03), differently to the other treatments that showed similar skin sensitivity to HAND (p >.05). No differences in glycaemia and behaviour were observed among treatments. The results suggest that using meloxicam alone might offer a promising option in reducing the expression of pain-related parameters in piglets after surgical castration, however, it appears more efficient when used alone than in association with the anaesthetic agents tested. Procaine administered alone and azaperone seems unsuited to the purpose considered.HIGHLIGHTS Meloxicam used alone is suggested for reducing the expression of pain-related parameters in piglets after surgical castration; When a protocol using procaine is used on the farm during piglets castration, the association with meloxicam reduces some pain-related indicators; Procaine administered alone and azaperone seems unsuited to manage pain after surgical castration of piglets

Music Intervention to Prevent Delirium among Older Patients Admitted to a Trauma Intensive Care Unit and a Trauma Orthopedic Unit

abstract: Greater than half of older adults who are admitted to an acute care setting experience delirium with an estimated cost between four to twenty billion dollars annually in the United States. As a strategy to address the gap between research and practice, this feasibility study used the Roy Adaptation Model to provide a theoretical perspective for intervention design and evaluation, with a focus on modifying contextual stimuli in a Trauma Intensive Care and a Trauma Orthopedic Unit setting. The study sample included older hospitalized patients in a Trauma Intensive Care and a Trauma Orthopedic setting where there is a greater incidence for delirium. Study participants included two groups, with one group assigned to receive either a music intervention or usual care. The music intervention included pre-recorded music, delivered using an iPod player with soft headsets, with music self-selected from a collection of music compositions with musical elements of slow tempo and simple repetitive rhythm that influence delirium prevention. For the proposed study a music intervention dose included intervention delivery for 60 minutes, twice a day, over a three day period following admission. Physiologic variables measured included systolic blood pressure, diastolic blood pressure, heart rate, and respiratory rate, which were electronically monitored every four hours for the study. The Confusion Assessment Method was used as a screening tool to identify delirium in the admitted patients. Specific aims of this feasibility study were to (a) examine the feasibility of a music intervention designed to prevent delirium among older adults, and (b) evaluate the effects of a music intervention designed to prevent delirium among older adults. Findings indicate there was a significant music group by time interaction effect which suggests that change over time was different for the music and usual care group.Dissertation/ThesisDoctoral Dissertation Nursing and Healthcare Innovation 201

A Critical Examination of Sedation Withdrawal Assessment in Children.

Background Sedation withdrawal is one of the terms used to describe the behavioural response to stopping or reducing sedative drugs in physically dependent patients. Withdrawal behaviours differ according to the drug involved and may be unpleasant and interfere with recovery. Recognition of sedation withdrawal is challenging due to differences in patient presentation and may be further complicated by the patient’s condition and concomitant drug therapy. Overall Aim of the full thesis To improve the accuracy of sedation withdrawal assessment in critically ill children. Objectives and Methods A mixed methods interactive approach comprising six studies. Study 1 evaluates the psychometric properties of the Sedation Withdrawal Score, Studies 2 and 3 examine the complexities/challenges of withdrawal assessment by critiquing existing tool validation studies, A further three studies examine the nurse and parent perspectives of sedation withdrawal assessment in critically ill children. Study 4 investigates how nurses use a sedation withdrawal tool, Studies 5 and 6 investigate what behavioural signs parents recognise and ascertain parents’ willingness to participate in withdrawal assessments. Key findings Nurses found withdrawal behaviours difficult to interpret in critically ill children and there were differences in how these behaviours were construed. Parents identified a broader range of behaviours than included in existing tools. Most parents were eager to participate in the assessment. The elusive theoretical basis for the existing approach to withdrawal assessment may account for the lack of a standardisation and poor accuracy of the current tools. A model of the causal relationship between dependence and withdrawal is proposed. Recommendations The model identifies the diagnostic criteria upon which a definition for Pediatric Withdrawal Syndrome may be based. These criteria also provide a novel framework for withdrawal assessment. Focussing on the shared diagnostic criteria and including the parent perspective of the child’s behaviours may aid the assessment and support decision-making

The Impact of Parameter Identification Methods on Drug Therapy Control in an Intensive Care Unit

This paper investigates the impact of fast parameter identification methods, which do not require any forward simulations, on model-based glucose control, using retrospective data in the Christchurch Hospital Intensive Care Unit. The integral-based identification method has been previously clinically validated and extensively applied in a number of biomedical applications; and is a crucial element in the presented model-based therapeutics approach. Common non-linear regression and gradient descent approaches are too computationally intense and not suitable for the glucose control applications presented. The main focus in this paper is on better characterizing and understanding the importance of the integral in the formulation and the effect it has on model-based drug therapy control. As a comparison, a potentially more natural derivative formulation which has the same computation speed advantages is investigated, and is shown to go unstable with respect to modelling error which is always present clinically. The integral method remains robust