Noxious Procedures Research Articles

Pentadecapeptide BPC 157 as Therapy for Inferior Caval Vein Embolization: Recovery of Sodium Laurate-Post-Embolization Syndrome in Rats.

After inferior caval vein embolization therapy, post-embolization syndrome (sodium laurate 10 mg/kg, 0.1 mL into rat inferior caval vein, assessment at 15, 30, 60 min, prime lung lesions, thromboemboli occluding lung vessels), as a severe occlusion/occlusion-like syndrome, might be resolved as a whole by stable gastric pentadecapeptide BPC 157 therapy. At 5 min after laurate injection, stable gastric pentadecapeptide BPC 157 was implemented as therapy (10 µg/kg, 10 ng/kg intraperitoneally or intragastrically). As before, confronted with the occlusion of major vessel(s) or similar noxious procedures, such as rapidly acting Virchow triad circumstances, the particular effect of the therapy (i.e., collateral pathways activation, "bypassing vascular key", i.e., direct blood flow delivery via activation of azygos vein) assisted in the recovery of the vessel/s and counteracted multiorgan failure due to occlusion/occlusion-like syndrome as a whole in the laurate-injected rats. Along with prime lung lesions and thromboemboli occluding lung vessels, post-embolization syndrome rapidly occurred peripherally and centrally as a shared multiorgan and vessel failure, brain, heart, lung, liver, kidney, and gastrointestinal tract lesions, venous hypertension (intracranial (superior sagittal sinus), portal, and caval), aortal hypotension, progressing thrombosis in veins and arteries and stasis, congested and/or failed major veins, and severe ECG disturbances. Whatever the cause, these were all counteracted, eliminated, or attenuated by the application of BPC 157 therapy. As recovery with BPC 157 therapy commonly and rapidly occurred, reversing the collapsed azygos vein to the rescuing collateral pathway might initiate rapid direct blood delivery and start blood flow reorganization. In conclusion, we suggest BPC 157 therapy to resolve further vascular and embolization injuries.

Nociception assessment with videopupillometry in deeply sedated intensive care patients: Discriminative and criterion validations

BackgroundNociceptive assessment in deeply sedated patients is challenging. Validated instruments are lacking for this unresponsive population. Videopupillometry is a promising tool but has not been established in intensive care settings. Aim/ObjectiveTo test the discriminate validity of pupillary dilation reflex (PDR) between non-noxious and noxious procedures for assessing nociception in non-neurological intensive care unit (ICU) patients and to test the criterion validity of pupil dilation using recommended PDR cut-off points to determine nociception. MethodsA single-centre prospective observational study was conducted in medical–surgical ICU patients. Two independent investigators performed videopupillometer measurements during a non-noxious and a noxious procedure, once a day (up to 7 days), when the patient remained deeply sedated (Richmond Agitation–Sedation Scale score: −5 or −4). The non-noxious procedures consisted of a gentle touch on each shoulder and the noxious procedures were endotracheal suctioning or turning onto the side. Bivariable and multivariable general linear mixed models were used to account for multiple measurements in same patients. Sensitivity and specificity, and areas under the curve of the receiver operating characteristic curve were calculated. ResultsSixty patients were included, and 305 sets of 3 measurements (before, during, and after), were performed. PDR was higher during noxious procedures than before (mean difference between noxious and non-noxious procedures = 31.66%). After testing all variables of patient and stimulation characteristics in bivariable models, age and noxious procedures were kept in the multivariable model. Adjusting for age, noxious procedures (coefficient = −15.14 (95% confidence interval = −20.17 to −15.52, p < 0.001) remained the only predictive factor for higher pupil change. Testing recommended cut-offs, a PDR of >12% showed a sensitivity of 65%, and a specificity of 94% for nociception prediction, with an area under the receiver operating curve of 0.828 (95% confidence interval = 0.779–0.877). ConclusionsIn conclusion, PDR is a potentially appropriate measure to assess nociception in deeply sedated ICU patients, and we suggest considering its utility in daily practices. RegistrationThis study was not preregistered in a clinical registry. Tweetable abstractPupillometry may help clinicians to assess nociception in deeply sedated ICU patients.

Stomach perforation-induced general occlusion/occlusion-like syndrome and stable gastric pentadecapeptide BPC 157 therapy effect.

Using rat stomach perforation as a prototypic direct lesion applied in cytoprotection research, we focused on the first demonstration of the severe occlusion/ occlusion-like syndrome induced by stomach perforation. The revealed stomach-induced occlusion/occlusion-like syndrome corresponds to the previously described occlusion/occlusion-like syndromes in rats suffering multicausal pathology and shared severe vascular and multiorgan failure. This general point was particularly reviewed. As in all the described occlusion/occlusion-like syndromes with permanent occlusion of major vessels, peripheral and central, and other similar noxious procedures that severely affect endothelium function, the stable gastric pentadecapeptide BPC 157 was resolving therapy. To reveal the stomach perforation-induced general occlusion/occlusion-like syndrome and BPC 157 therapy effect. The procedure included deeply anesthetized rats, complete calvariectomy, laparotomy at 15 min thereafter, and stomach perforation to rapidly induce vascular and multiorgan failure occlusion/occlusion-like syndrome. At 5 min post-perforation time, rats received therapy [BPC 157 (10 µg or 10 ng/kg) or saline (5 mL/kg, 1 mL/rat) (controls)] into the perforated defect in the stomach). Sacrifice was at 15 min or 60 min post-perforation time. Assessment (gross and microscopy; volume) included: Brain swelling, peripheral vessels (azygos vein, superior mesenteric vein, portal vein, inferior caval vein) and heart, other organs lesions (i.e., stomach, defect closing or widening); superior sagittal sinus, and peripherally the portal vein, inferior caval vein, and abdominal aorta blood pressures and clots; electrocardiograms; and bleeding time from the perforation(s). BPC 157 beneficial effects accord with those noted before in the healing of the perforated defect (raised vessel presentation; less bleeding, defect contraction) and occlusion/occlusion-like syndromes counteraction. BPC 157 therapy (into the perforated defect), induced immediate shrinking and contraction of the whole stomach (unlike considerable enlargement by saline application). Accordingly, BPC 157 therapy induced direct blood delivery via the azygos vein, and attenuated/eliminated the intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension. Thrombosis, peripherally (inferior caval vein, portal vein, abdominal aorta) and centrally (superior sagittal sinus) BPC 157 therapy markedly reduced/annihilated. Severe lesions in the brain (swelling, hemorrhage), heart (congestion and arrhythmias), lung (hemorrhage and congestion), and marked congestion in the liver, kidney, and gastrointestinal tract were markedly reduced. We revealed stomach perforation as a severe occlusion/occlusion-like syndrome, peripherally and centrally, and rapid counteraction by BPC 157 therapy. Thereby, further BPC 157 therapy may be warranted.

Innate Vascular Failure by Application of Neuroleptics, Amphetamine, and Domperidone Rapidly Induced Severe Occlusion/Occlusion-like Syndromes in Rats and Stable Gastric Pentadecapeptide BPC 157 as Therapy.

Even before behavioral disturbances, neuroleptics, amphetamine, and domperidone application rapidly emerged severe occlusion/occlusion-like syndrome, shared innate vascular and multiorgan failure in rats, comparable to occlusion/occlusion-like syndrome described with vessel(s) occlusion or similar noxious procedures application. As therapy, i.e., activation of the collateral pathways, "bypassing key" (activated azygos vein pathway, direct blood flow delivery), the stable gastric pentadecapeptide BPC 157 is a novel solution. Recently, BPC 157 therapy particularly counteracted neuroleptic- or L-NAME-induced catalepsy, lithium intoxication, and schizophrenia positive and negative symptoms (amphetamine/methamphetamine/apomorphine/ketamine). In rats with complete calvariectomy, medication (BPC 157 10 µg/kg, 10 ng/kg ip or ig) was given 5 min after distinctive dopamine agents (mg/kg ip) (haloperidol (5), fluphenazine (5), clozapine (10), risperidone (5), olanzapine (10), quetiapine (10), or aripiprazole (10), domperidone (25), amphetamine (10), and combined amphetamine and haloperidol) and assessed at 15 min thereafter. All neuroleptic-, domperidone-, and amphetamine-induced comparable vascular and multiorgan failure severe syndrome was alleviated with BPC 157 therapy as before major vessel(s) occlusion or other similar noxious procedures. Specifically, all severe lesions in the brain (i.e., immediate swelling, hemorrhage), heart (i.e., congestion, arrhythmias), and lung (i.e., congestion, hemorrhage), as well as congestion in the liver, kidney, and gastrointestinal (stomach) tract, were resolved. Intracranial (superior sagittal sinus), portal, and caval hypertension and aortal hypotension were attenuated or eliminated. BPC 157 therapy almost annihilated arterial and venous thrombosis, peripherally and centrally. Thus, rapidly acting Virchow triad circumstances that occur as dopamine central/peripheral antagonists and agonist essential class-points, fully reversed by BPC 157 therapy, might be overwhelming for both neuroleptics and amphetamine.

Stable Gastric Pentadecapeptide BPC 157 May Recover Brain-Gut Axis and Gut-Brain Axis Function.

Conceptually, a wide beneficial effect, both peripherally and centrally, might have been essential for the harmony of brain-gut and gut-brain axes' function. Seen from the original viewpoint of the gut peptides' significance and brain relation, the favorable stable gastric pentadecapeptide BPC 157 evidence in the brain-gut and gut-brain axes' function might have been presented as a particular interconnected network. These were the behavioral findings (interaction with main systems, anxiolytic, anticonvulsive, antidepressant effect, counteracted catalepsy, and positive and negative schizophrenia symptoms models). Muscle healing and function recovery appeared as the therapeutic effects of BPC 157 on the various muscle disabilities of a multitude of causes, both peripheral and central. Heart failure was counteracted (including arrhythmias and thrombosis), and smooth muscle function recovered. These existed as a multimodal muscle axis impact on muscle function and healing as a function of the brain-gut axis and gut-brain axis as whole. Finally, encephalopathies, acting simultaneously in both the periphery and central nervous system, BPC 157 counteracted stomach and liver lesions and various encephalopathies in NSAIDs and insulin rats. BPC 157 therapy by rapidly activated collateral pathways counteracted the vascular and multiorgan failure concomitant to major vessel occlusion and, similar to noxious procedures, reversed initiated multicausal noxious circuit of the occlusion/occlusion-like syndrome. Severe intracranial (superior sagittal sinus) hypertension, portal and caval hypertensions, and aortal hypotension were attenuated/eliminated. Counteracted were the severe lesions in the brain, lungs, liver, kidney, and gastrointestinal tract. In particular, progressing thrombosis, both peripherally and centrally, and heart arrhythmias and infarction that would consistently occur were fully counteracted and/or almost annihilated. To conclude, we suggest further BPC 157 therapy applications.

A developmental shift in habituation to pain in human neonates

Habituation to recurrent non-threatening or unavoidable noxious stimuli is an important aspect of adaptation to pain. Neonates, especially if preterm, are exposed to repeated noxious procedures during their clinical care. They can mount strong behavioral, autonomic, spinal, and cortical responses to a single noxious stimulus; however, it is not known whether the developing nervous system can adapt to the recurrence of these inputs. Here, we used electroencephalography to investigate changes in cortical microstates (representing the complex sequential processing of noxious inputs) following two consecutive clinically required heel lances in term and preterm infants. We show that stimulus repetition dampens the engagement of initial microstates and associated behavioral and autonomic responses in term infants, while preterm infants do not show signs of habituation. Nevertheless, both groups engage different longer-latency cortical microstates to each lance, which is likely to reflect changes in higher-level stimulus processing with repeated stimulation. These data suggest that while both age groups are capable of encoding contextual differences in pain, the preterm brain does not regulate the initial cortical, behavioral, and autonomic responses to repeated noxious stimuli. Habituation mechanisms to pain are already in place at term age but mature over the equivalent of the last trimester of gestation and are not fully functional in preterm neonates.

Anatomical changes in descending serotonergic projections from the rostral ventromedial medulla to the spinal dorsal horn following repetitive neonatal painful procedures

AbstractExcessive noxious stimulation during the critical neonatal period impacts the nociceptive network lasting into adulthood. As descending serotonergic projections from the rostral ventromedial medulla (RVM) to the spinal dorsal horn develop postnatally, this study aims to investigate the long‐term effect of repetitive neonatal procedural pain on the descending serotonergic RVM–spinal dorsal horn network. A well‐established rat model of repetitive noxious procedures is used in which neonatal rats received four noxious needle pricks or tactile stimulation with a cotton swab per day in the left hind paw from day of birth to postnatal Day 7. Control animals were left undisturbed. When animals reached adulthood, tissue was collected for quantitative immunohistochemical analysis of serotonin (5‐hydroxytryptamine, 5‐HT) in the RVM and spinal dorsal horn. Both repetitive noxious and tactile procedures in the neonate decreased the 5‐HT staining intensity in the adult ipsilateral but not contralateral spinal dorsal horn. Repetitive neonatal noxious procedures resulted in an increased area covered with 5‐HT staining in the adult RVM ipsilateral to the side of injury, whereas repetitive neonatal tactile stimulation resulted in increased 5‐HT staining intensity in both the ipsi‐ and contralateral RVM. The number of 5‐HT cells in adult RVM is unaffected by neonatal conditions. This detailed anatomical study shows that not only neonatal noxious procedures but also repetitive tactile procedures result in long‐lasting anatomical changes of the descending serotonergic system within the RVM and spinal dorsal horn. Future studies should investigate whether these anatomical changes translate to functional differences in descending serotonergic modulation after neonatal adverse experiences.

781 Multimodal Virtual Reality Encouragement

IntroductionBurn units’ nurses develop creative methods to mitigate unpleasant experiences. Peer reviewed research has affirmed that non-pharmacological stimuli can distract patients from noxious procedures. Therefore, novel virtual reality was introduced as a nurse-driven modality to improve patient care. Multiple approaches encouraged staff utilization of this exciting, yet unfamiliar, technology.MethodsA needs assessment concluded that patients experience moderate pain and some anxiety during wound care - indicating an opportunity to explore virtual reality. The virtual reality headset was introduced to nurses via in-services to encourage hands-on experience. The following month, an interactive “VR Superstars” poster was developed as a visual cue to motivate nurses to attempt the new product. Whenever a nurse used the device with a patient, a star sticker was applied next to his/her name. Next, a resource binder was created: This binder included the device protocol, patient inclusion criteria, educational handouts to assist staff with introduction to patients, and surveys. Biweekly emails encouraged virtual reality use and acknowledged staff members who proactively utilized it. The multidisciplinary team also discussed virtual reality at daily rounds.ResultsTo assess virtual reality’s effectiveness, patients completed surveys after each use. At the end of the first month, staff implemented virtual reality only three times - as identified by the number of surveys. Upon completion of the multi-modal staff encouragement, virtual reality use doubled. By the third month, nurses implemented the technology on six occasions within the month.ConclusionsThe multi-modal approach ultimately familiarized nurses. These techniques contributed to increasing staff experience, thereby improving staff confidence to utilize a new product. As exposure increased, nurses reported more excitement to introduce the product to patients. Due to the implementation of multiple motivators, nurses are more readily implementing an intervention to benefit a patient’s experience.

Analysis of the educational needs of nurses in the neonatal intensive care unit for developmental supportive care

Purpose: This study used a descriptive investigative design to identify educational needs for developmental supportive care for the purpose of establishing a developmental supportive care education program for nurses in neonatal intensive care units. Methods: A survey was conducted on 93 nurses working in neonatal intensive care units located in a metropolitan area, and the collected data were analyzed using descriptive statistics and a paired t-test with the SPSS 25.0 program. For the purpose of analyzing educational needs, we further analyzed data through an importance-performance analysis (IPA) and the Borich needs assessment and the locus for focus models. Results: The average importance of the developmental supportive care of nurses in neonatal intensive care units was 3.74±0.78 out of 5, and the average performance was 3.46±0.81 out of 5. A t-test on the difference between the IPA and Borich needs assessment showed the highest educational need in the categories of ‘individualized care’, and ‘I serve on the Developmental Care Committee at my institution’. In addition, according to the results of deriving the priorities of educational needs using the Borich needs assessment and the locus for focus model, the highest priority was ‘I provide appropriate pain management when noxious procedures are necessary’. Conclusion: These findings can be used as basic data to design a developmental supportive care program suitable for nurses in neonatal intensive care units to meet the educational needs for developmental supportive care.

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. Neonatal intensive care unit (NICU) procedures are therefore likely to each contribute differently to the overall pain burden of individual neonates, ultimately having a different impact on their development. 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 5 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.

Adult spinal opioid receptor μ1 expression after incision is altered by early life repetitive tactile and noxious procedures in rats.

ABSTRACTClinical and experimental data suggests that noxious stimulation at critical stages of development results in long‐term changes on nociceptive processing in later life. Here, we use an established, well‐documented rat model of repetitive noxious procedures closely mimicking the clinical situation in the NICU. In order to understand molecular changes underlying the long‐term consequences of repetitive stimulation of the developing nociceptive system the present study aims to analyze the presence of the µ‐opioid‐receptor‐1 (OPRM1). Neonatal rats received either four needle pricks per day in the left hind‐paw from postnatal day 0–7 as a model of procedural pain in infancy. Control pups were handled in the same way but were instead tactile stimulated, or were left undisturbed. At the age of 8 weeks, all animals received an ipsilateral hind‐paw incision as a model for post‐operative pain, and mechanical sensitivity was tested at multiple time‐points. Before, and 1 or 5 days post‐incision, spinal cord tissue was collected for immunostaining of opioid receptor OPRM1. Semi‐quantitative immunocytochemical analysis of superficial laminae in lumbar spinal dorsal horn revealed that: (1) early life repetitive tactile or noxious procedures do not alter baseline levels of OPRM1 staining intensity and (2) early life repetitive tactile or noxious procedures lead to a decrease in OPRM1 staining intensity 5 days after incision in adulthood compared to undisturbed controls. We conclude that early life repetitive tactile or noxious procedures affect the intensity of OPRM1‐immunoreactivity in the lumbar superficial spinal cord dorsal horn after adulthood injury, without affecting baseline intensity. © 2018 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 417–426, 2018

Is Less Noise, Light and Parental/Caregiver Stress in the Neonatal Intensive Care Unit Better for Neonates?

In utero sensory stimuli and interaction with the environment strongly influence early phases of fetal and infant development. Extremely premature infants are subjected to noxious procedures and routine monitoring, in addition to exposure to excessive light and noise, which disturb the natural sleep cycle and induce stress. Non-invasive ventilation, measures to prevent sepsis, and human milk feeding improve short-term and long-term neurodevelopmental outcomes in premature infants. To preserve brain function, and to improve quality of life and long-term neurodevelopmental outcomes, the focus now is on the neonatal intensive care unit (NICU) environment and its impact on the infant during hospital stay. The objectives of this write-up are to understand the effects of environmental factors, including lighting and noise in the NICU, on sensory development of the infant, the need to decrease parental and caregiver stress, and to review existing literature, local policies and recommendations.

Mapping of pain circuitry in early post-natal development using manganese-enhanced MRI in rats

Premature or ill full-term infants are subject to a number of noxious procedures as part of their necessary medical care. Although we know that human infants show neural changes in response to such procedures, we know little of the sensory or affective brain circuitry activated by pain. In rodent models, the focus has been on spinal cord and, more recently, midbrain and medulla. The present study assesses activation of brain circuits using manganese-enhanced magnetic resonance imaging (MEMRI). Uptake of manganese, a paramagnetic contrast agent that is transported across active synapses and along axons, was measured in response to a hindpaw injection of dilute formalin in 12-day-old rat pups, the age at which rats begin to show aversion learning and which is roughly the equivalent of full-term human infants. Formalin induced the oft-reported biphasic response at this age and induced a conditioned aversion to cues associated with its injection, thus demonstrating the aversiveness of the stimulation. Morphometric analyses, structural equation modeling and co-expression analysis showed that limbic and sensory paths were activated, the most prominent of which were the prefrontal and anterior cingulate cortices, nucleus accumbens, amygdala, hypothalamus, several brainstem structures, and the cerebellum. Therefore, both sensory and affective circuits, which are activated by pain in the adult, can also be activated by noxious stimulation in 12-day-old rat pups.

Changing Balance of Spinal Cord Excitability and Nociceptive Brain Activity in Early Human Development

SummaryIn adults, nociceptive reflexes and behavioral responses are modulated by a network of brain regions via descending projections to the spinal dorsal horn [1]. Coordinated responses to noxious inputs manifest from a balance of descending facilitation and inhibition. In contrast, young infants display exaggerated and uncoordinated limb reflexes [2]. Our understanding of nociceptive processing in the infant brain has been advanced by the use of electrophysiological and hemodynamic imaging [3, 4, 5, 6]. From approximately 35 weeks’ gestation, nociceptive-specific patterns of brain activity emerge [7], whereas prior to this, non-specific bursts of activity occur in response to noxious, tactile, visual, and auditory stimulation [7, 8, 9, 10]. During the preterm period, refinement of spinal cord excitability is also observed: reflex duration shortens, response threshold increases, and improved discrimination between tactile and noxious events occurs [2, 11, 12]. However, the development of descending modulation in human infants remains relatively unexplored. In 40 infants aged 28–42 weeks’ gestation, we examined the relationship between nociceptive brain activity and spinal reflex withdrawal activity in response to a clinically essential noxious procedure. Nociceptive-specific brain activity increases in magnitude with gestational age, whereas reflex withdrawal activity decreases in magnitude, duration, and latency across the same developmental period. By recording brain and spinal cord activity in the same infants, we demonstrate that the maturation of nociceptive brain activity is concomitant with the refinement of noxious-evoked limb reflexes. We postulate that, consistent with studies in animals, infant reflexes are influenced by the development of top-down inhibitory modulation from maturing subcortical and cortical brain networks.

The cortical response to a noxious procedure changes over time in preterm infants

The aim of the study was to investigate whether cortical response to a repeated noxious procedure may change over time in preterm infants. Possible reasons for change are: (1) advancing maturation of central nervous system; and (2) increasing experience with noxious procedures during hospital stay. Sixteen preterm infants were recruited, with a postmenstrual age (PMA) ranging between 29 and 36 weeks. Newborns were assessed during a heel-prick procedure, once a week for at least 3 consecutive times. Multichannel near-infrared spectroscopy was used to detect cortical activation, by measuring increase in cortical oxy-haemoglobin (HbO2). Parietal, temporal, and posterior frontal areas were monitored bilaterally. By regression analysis, we studied the effect of (1) increasing PMA and (2) increasing number of heel pricks, on the magnitude of cortical activation. We observed a bilateral nociceptive event-related activation of the posterior frontal cortex, mainly contralateral to the side pricked. Additionally, we found a significant positive effect of PMA, as HbO2 progressively increased in the posterior frontal cortex (P < 0.001), bilaterally, over time. Conversely, the degree of cortical activation decreased as the number of noxious events increased (P < 0.002). We conclude the following: (1) Preterm newborns showed a significant activation of the posterior frontal cortex in association with noxious stimuli; (2) Cortical activation was progressively greater with increasing PMA; (3) There was an inverse relationship between cortical activation and the number of heel pricks. We speculate that such findings may be due to both endogenous cortical maturation and experience-dependent neuroplasticity of the developing brain (eg, synaptogenesis, synaptic pruning).

Pain in fish: Weighing the evidence

The target article by Key (2016) examines whether fish have brain structures capable of mediating pain perception and consciousness, functions known to depend on the neocortex in humans. He concludes, as others have concluded (Rose 2002, 2007; Rose et al. 2014), that such functions are impossible for fish brains. This conclusion has been met with hypothetical assertions by others to the effect that functions of pain and consciousness may well be possible through unknown alternate neural processes. Key's argument would be bolstered by consideration of other neurological as well as behavioral evidence, which shows that sharks and ray are fishes that have no nociceptive afferents and that bony fishes, although they have A delta nociceptors, are extremely deficient in C fibers, the most abundant nociceptor in mammals. In addition, behavioral studies of surgery, angling and other putatively noxious procedures show that fish don't behave as if they suffer from pain.

Modeling Respiratory Depression Induced by Remifentanil and Propofol during Sedation and Analgesia Using a Continuous Noninvasive Measurement of pCO2.

Respiratory depression is a common adverse effect of propofol and remifentanil. We aimed to develop a model for respiratory depressant effects of propofol with remifentanil in patients undergoing endoscopy with sedation. Data were available for 136 patients undergoing endoscopy with sedation. Participants randomly received infusions of propofol and remifentanil. Predicted plasma concentrations, outputted by infusion pumps, were available. Transcutaneous arterial pressure of carbon dioxide (pCO2) was measured. Data were analyzed using nonlinear mixed-effects modeling methods. Covariate relationships were investigated for age, noxious stimuli (endoscopy tube insertion), and A118G genotype for the µ-opioid receptor (OPRM1). Participants had a median (range) age of 64.0 (25.0-88.0) years, weight of 70.0 (35.0-98.0) kg, and height of 164.0 (147.0-190.0) cm. Seven percent were recessive homozygous for OPRM1 polymorphism. An indirect-effect model with a "modulator" compartment best described pCO2 data (P < 0.001) over a direct-effect model. Remifentanil inhibited pCO2 removal with an IC50 of 1.13 ng/ml and first-order rate constant (ke 0) of 0.28 minute(-1). Propofol affected the modulator compartment with an IC50 of 4.97 µg/ml (no effect-site compartment). Propofol IC50 and remifentanil ke 0 were reduced with increasing age. Noxious stimuli and genotype were not significant covariates. An indirect-effect model with a rebound mechanism can describe remifentanil- and propofol-induced changes in pCO2 in patients undergoing noxious procedures. The model may be useful for identifying optimal dosing schedules for these drugs in a combination that provides adequate sedation but avoids respiratory depression.

The relevance of pupillometry for evaluation of analgesia before noxious procedures in the intensive care unit.

Many patients in the intensive care unit are unable to communicate verbally. Accurately predicting whether such patients will exhibit painful behaviors during noxious procedures and assessing the adequacy of analgesia during those procedures is a challenge. In addition to observational pain assessment tools such as the Behavioral Pain Scale, physiologic indicators such as the pupillary response have been proposed. The pupil is innervated by both divisions of the autonomic nervous system and is affected by pain and analgesic medications. We evaluated the pupillary response to a light stimulus before noxious procedures as a method to predict pain during the procedure. We correlated different aspects of the pupillary light reflex with established strategies for pain assessment to evaluate the adequacy of analgesia before surgical dressing changes performed in the intensive care unit in patients with cellulitis associated with mediastinitis or not. We found that a percentage of variation in pupil size >19% predicted the presence of pain as assessed by a Behavioral Pain Scale score of >3 with a sensitivity of 100% (95% confidence interval, 100%-100%) and a specificity of 77% (95% confidence interval, 54%-100%). In patients unable to communicate verbally, pupillometry may potentially guide caregivers to adjust analgesia before noxious procedures.

Is Two Better Than One? Anticipation of a Favorable Hemodynamic Profile by Combining the Hypnotic Drugs for Induction of Anesthesia.

Is Two Better Than One? Anticipation of a Favorable Hemodynamic Profile by Combining the Hypnotic Drugs for Induction of Anesthesia.

Noxious stimulation in children receiving general anaesthesia evokes an increase in delta frequency brain activity

More than 235,000children/year in the UK receive general anaesthesia, but it is unknown whether nociceptive stimuli alter cortical brain activity in anaesthetised children. Time-locked electroencephalogram (EEG) responses to experimental tactile stimuli, experimental noxious stimuli, and clinically required cannulation were examined in 51 children (ages 1–12years) under sevoflurane monoanaesthesia. Based on a pilot study (n=12), we hypothesised that noxious stimulation in children receiving sevoflurane monoanaesthesia would evoke an increase in delta activity. This was tested in an independent sample of children (n=39), where a subset (n=11) had topical local anaesthetic applied prior to stimulation. A novel method of time-locking the stimuli to the EEG recording was developed using an event detection interface and high-speed camera. Clinical cannulation evoked a significant increase (34.2±8.3%) in delta activity (P=0.042), without concomitant changes in heart rate or reflex withdrawal, which was not observed when local anaesthetic was applied (P=0.30). Experimental tactile (P=0.012) and noxious (P=0.0099) stimulation also evoked significant increases in delta activity, but the magnitude of the response was graded with stimulus intensity, with the greatest increase evoked by cannulation. We demonstrate that experimental and clinically essential noxious procedures, undertaken in anaesthetised children, alter the pattern of EEG activity, that this response can be inhibited by local anaesthetic, and that this measure is more sensitive than other physiological indicators of nociception. This technique provides the possibility that sensitivity to noxious stimuli during anaesthesia could be investigated in other clinical populations.