Quantification of neonatal procedural pain severity: a platform for estimating total pain burden in individual infants

There is increasing evidence that long-term outcomes for infants born prematurely are adversely affected by repeated exposure to noxious procedures. These interventions vary widely, for example, in the extent of damage caused and duration. NICU (neonatal intensive care unit) procedures are therefore likely to each contribute differently to the overall pain burden of individual neonates, ultimately having a different impact on their development. In order for researchers to quantify the procedural pain burden experienced by infants on NICU, we aimed to estimate the pain severity of common NICU procedures using published pain scores. We extracted pain scores over the first minute (pain reactivity) from the literature, using 59 randomized controlled trials for 15 different procedures. Hierarchical cluster analysis of average pain scores resulted in five discrete severity groups; mild (n=1), mild to moderate (n=3), moderate (n=7), severe (n=3) and very severe (n=1). The estimate of the severity of individual procedures provided new insight into infant pain reactivity which is not always directly related to the invasiveness and duration of a procedure; thus both heel lance and skin tape removal are moderately painful procedures. This estimate of procedural pain severity, based on pain reactivity scores, provides a novel platform for retrospective quantification of an individual neonate's pain burden due to NICU procedures. The addition of measures that reflect the recovery from each procedure, such as brain activity and behavioural regulation, would further improve estimates of the pain burden of neonatal intensive care

Computational analysis of firing regularity and burst firing in midbrain dopamine neurons

Dopamine neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) regulate day-to-day activities such as reward-related learning, and motor control. Dysfunction of these neurons is implicated in disorders like Schizophrenia, addiction to drugs, and Parkinson’s disease. Dopamine neurons fire action potentials with variability in inter-spike intervals (ISI) interspersed with bursts of spikes, both firing patterns being a result of co-ordinated action of synaptic inputs and ion channels. Pharmacological inhibition of calcium-activated potassium (SK) channels increases the variability in their firing pattern, sometimes also increasing the number of spikes fired in bursts, indicating that SK channels play an important role in maintaining dopamine neuron firing regularity and burst firing. However, the exact mechanisms underlying these effects are still unclear. We hypothesized that the post-spike after hyperpolarisation (AHP) provided by the SK current controls and standardises the availability of other voltage-gated ion channels, thus timing successive action potentials at regular intervals. Here, I develop a biophysical model of a dopamine neuron incorporating ion channel stochasticity that enabled me to analyse availability of ion channels in multiple states during spiking. Decreased firing regularity is primarily due to a significant decrease in the AHP that in turn resulted in a reduction in the fraction of available voltage-gated sodium channels. Insufficient AHP causes a failure of sodium channels to recover from inactivation and, due to ion channel stochasticity, a variable number of sodium channels are available to fire a spike, in the absence of AHP, thus resulting in an irregular spike train. My model further predicts that inhibition of SK channels results in a depolarisation of action potential threshold along with an increase in its variability, thus suggesting that SK channels regulate spike threshold in midbrain dopamine neurons. Moreover, a quantitative description of action potential features during endogenous burst firing in midbrain dopamine neurons has not been reported, perhaps due to a lack of in vivo whole-cell recordings that can shed light on membrane dynamics. Because we had available in vivo whole-cell recordings from immuno-histochemically identified dopamine neurons in the VTA, I analysed these using mathematical techniques like Principal Components Analysis (PCA) and the stochastic model mentioned above, in order to provide quantitative descriptions of action potential features during the course of endogenous burst firing. I found that the first detectable change in membrane dynamics that perhaps leads to burst firing is a reduction in the AHP mediated by SK channels. This was accompanied by progressive depolarisation of action potential threshold with each spike within the burst due to reduced availability of sodium channels as a result of progressive decrease in recovery from inactivation. This also resulted in a decrease in rate of change of membrane voltage for each successive spike in a burst. Reduction in action potential height that is commonly observed during burst firing can also be explained by the reduced availability of sodium channels. My model predicts that a reduction in A-type potassium channel current during burst firing could facilitate the transient increase in instantaneous firing rate during bursts and the progressive reduction in sodium channel availability results in the cessation of firing, facilitating burst termination in these neurons.Open Acces

Paramedic attitudes and experiences of enrolling patients into the PARAMEDIC-2 adrenaline trial: a qualitative survey within the London Ambulance Service

OBJECTIVES: The aim of this study was to gather the views and experiences of paramedics who participated in a large-scale randomised controlled drug trial and to identify barriers to recruitment. DESIGN: We surveyed paramedics using a questionnaire consisting of a mix of closed and open ended questions. SETTING: The study was conducted within the London Ambulance Service, London, UK. PARTICIPANTS: 150 paramedics who were trained to enrol patients into the PARAMEDIC-2 randomised controlled trial of adrenaline versus placebo in out-of-hospital cardiac arrest and who returned the questionnaire. RESULTS: 98% of study participants felt prehospital research was very important, and 97.3% reported an overall positive experience of being involved in a drug trial. Only 5.3% felt uncomfortable enrolling patients into the trial without prior consent from the patient or a relative. Over one- third (39.3%) identified one or more barriers to patient recruitment, the most common being the attitudes of other staff. CONCLUSION: We found a strong appetite for involvement in prehospital research among paramedics and an understanding of the importance of research that prevailed over the complexities of the trial. This is an important finding demonstrating that potentially ethically controversial research can be undertaken successfully by paramedics in the prehospital environment., https://www.ncbi.nlm.nih.gov/pubmed/31791962. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ DOI: 10.1136/bmjopen-2018-02558

Review of public personnel administration

Background Adrenaline is the primary drug of choice for resuscitation from out-of-hospital cardiac arrest (OHCA). Although adrenaline may increase the chance of achieving return of spontaneous circulation (ROSC), there is limited evidence that repeated doses of adrenaline improves overall survival, and increasing evidence of a detrimental effect on neurological function in survivors. This paper reports the relationship between repeated doses of adrenaline and survival in a cohort of patients attended by the London Ambulance Service in the United Kingdom. Methods A retrospective review of OHCA treated by the London Ambulance Service over a one year period. Patients aged ≥18 years who received one or more doses of adrenaline (1 mg bolus) during resuscitation were included in the analyses. Outcomes described are survival to hospital discharge and survival to one year post-arrest. Results Over the one year study period, 3151 patients received adrenaline during OHCA. A significant inverse relationship was found between increasing cumulative doses of adrenaline and survival both to hospital discharge and one year post-arrest. No patients survived after receiving more than ten adrenaline doses. Conclusion Our study indicates that repeated doses of adrenaline are associated with decreasing odds of survival. There were no survivors amongst patients requiring more than 10 doses of adrenaline

A novel neonatal procedural pain index derived from adult self-report

<div><b>Abstact</b></div><div><b>Objective</b>: This study addresses the gap in our understanding of neonatal procedural pain intensity. We aimed to identify the most commonly performed neonatal procedures, devise a pain ranking of these procedures based on adult pain scores, and develop a new Neonatal Pain Index (NPI).</div><div><b>Design</b>: A retrospective analysis of neonatal procedures and an online literature search of adult procedural pain intensity.</div><div><b>Setting</b>: Neonatal wards in University College London Hospital.</div><div><b>Patients</b>: 138 neonates [23-42 weeks gestational age] for retrospective procedure history. Literature survey of 5405 adults receiving standard care or in control arms of clinical trials for pain ranking.</div><div>Interventions: 11 most common neonatal procedures in a hospital setting.</div><div><b>Main outcome measures</b>: Frequency of neonatal painful procedures. Pain scores derived from adult self-report.</div><div><b>Results</b>: Of 3,728 neonatal procedures, the heel lance was the most common (66%). Of the adult procedures reviewed, nasogastric tube insertion was the most painful (pooled mean score 5.9±2.7 out of 10) while lance was one of the least painful (pooled mean score 2.1±1.5). The adult scores differed from the estimates currently held by most neonatologists. A neonatal pain index (NPI) was developed to grade individual neonatal pain history based on the number of procedures and average adult pain score for each of those procedures.</div><div><b>Conclusion</b>: This systematic approach to neonatal procedural pain, through comparison to a gold standard adult measure, can be used as an index which quantifies the total pain experience of a neonate throughout their hospital admission.</div