Mechanistic Rationale and Clinical Efficacy of Hyperbaric Oxygen Therapy in Chronic Neuropathic Pain: An Evidence-Based Narrative Review.

Background: Chronic neuropathic pain is a condition affecting an increasing proportion of the general population and its management requires a comprehensive, multidisciplinary program. A growing body of evidence supports the use of hyperbaric oxygen therapy (HBOT) in several chronic neuropathic pain conditions; however, its role and efficacy remain unclear. Purpose: To summarize current evidence for the mechanistic rationale of HBOT in chronic neuropathic pain conditions and to evaluate its clinical efficacy. Methods: This narrative review was conducted after searching the following databases (Medline, Embase, Cochrane, PsycINFO, the Web of Science, Scopus, ClinicalTrials. gov, WHO ICTRP, and ProQuest Digital Dissertation) from January 1946 to March 2020. Articles published in English that involved either animal or human studies with acute or chronic neuropathic pain evaluating any HBOT-related intervention were included. Results: A total of 2971 citations were identified. A total of 29 studies were included in this review. The mechanisms of action for HBOT use in neuropathic conditions included the primary effects of hyperoxia and edema resolution, as well as the secondary effects pertinent to the production of oxygen and nitrogen reactive species (serving as pain signaling molecules), nitric oxide-dependent release of opioid peptides, and reduction of inflammatory mediators. A robust evidence for HBOT use in the clinical setting was associated with chronic regional pain syndrome and chronic primary bladder pain syndrome. Some evidence supported its use for chronic secondary (peripheral) neuropathic pain including radiation-induced plexus neuropathies, postherpetic neuralgia, and trigeminal neuralgia. Conclusions: HBOT has been shown to have antinociceptive and analgesic effects in animal models of inflammatory, neuropathic, and chronic pain. Human studies demonstrated beneficial effects of HBOT in improving clinical outcomes such as pain scores, pain-related symptoms, and quality of life. A systematic methodology of HBOT application is necessary to confirm its safety and efficacy.

Magnitude and Clinical Predictors of Blood Pressure Changes in Patients Undergoing Hyperbaric Oxygen Therapy: A Retrospective Study.

Hyperbaric oxygen therapy (HBOT) is widely used to treat several pathologies. The hemodynamic changes during HBOT, particularly the magnitude of arterial blood pressure (ABP) increase, are not completely understood. No clinical predictors for HBOT-induced ABP increase have been described. The purpose of this study was to quantify ABP changes in patients undergoing HBOT and to examine their predictors. This retrospective longitudinal cohort study examined 3291 elective HBOT sessions. Non-invasive ABP was recorded before and after each session. The primary outcome was to quantify the HBOT-induced ABP rise. The secondary outcome was to determine the ABP-rise predictors among demographic and clinical variables. Overall, ABP increased significantly after HBOT; this finding was more evident in the hypertensive subgroup compared to the normotensive one (+6 vs. +16.2 mmHg). Clinical predictors of significant post-HBOT ABP change were history of hypertension and pre-session baseline ABP classification. This study demonstrates an absolute HBOT-induced ABP rise. This change is clinically relevant in patients with history of hypertension. A higher baseline ABP seems a risk factor for clinically relevant ABP change. Pre-session ABP should be used clinically as an indicator for strict ABP monitoring during HBOT; future studies are recommended to explore the ABP optimization before starting an HBO treatment.

Sedation Practice in Extracorporeal Membrane Oxygenation-Treated Patients with Acute Respiratory Distress Syndrome: A Retrospective Study.

Our objective was to characterize sedation management in adult patients with severe respiratory distress syndrome (ARDS) treated with venovenous extracorporeal membrane oxygenation (VV-ECMO). We conducted a retrospective chart review of these patients treated at Toronto General Hospital between January 2012 and October 2015. Medications administered (sedative, analgesic, paralytic, and antipsychotic), sedation depth (Sedation Agitation Scale [SAS] score) delirium assessments, and mobilization were recorded daily. Forty-five adults (33 males, median age 47 years; interquartile range [IQR], 35-56]) with ARDS (median PaO2/FiO2 71; IQR 59-83) because of respiratory infection (91%) were treated with VV-ECMO for a median of 11 days (IQR, 7-17). After ECMO initiation, 96% patients were deeply sedated (SAS score < 3) with continuous infusions of midazolam (49%), propofol (18%), or both (29%) and 98% were receiving opioid infusions (93% fentanyl). Patients were deeply sedated for a median of 6 days (IQR, 3-10) after cannulation before transitioning to intermediate or light sedation (SAS score ≥ 3). Before ECMO discontinuation, 77% of surviving patients were intermediately or lightly sedated, 20% were receiving no sedatives, and 9% were receiving no opioids. During ECMO, 58% had positive delirium assessment and 24% experienced agitation (SAS ≥ 6). During ECMO support, 71% received physical therapy that occurred after a median of 7 days (IQR, 4-12) after cannulation. In conclusion, we found that although patients were deeply sedated for a prolonged duration after VV-ECMO initiation, many were able to safely achieve light sedation and active mobilization.

Sedation and Mobilization During Venovenous Extracorporeal Membrane Oxygenation for Acute Respiratory Failure: An International Survey.

OBJECTIVES: To characterize sedation, analgesia, delirium, and mobilization practices in patients supported with venovenous extracorporeal membrane oxygenation for severe acute respiratory failure. DESIGN: Cross-sectional electronic survey administered January 2016 to March 2016. SETTING: Three-hundred ninety-four extracorporeal membrane oxygenation centers registered with the Extracorporeal Life Support Organization. SUBJECTS: Extracorporeal membrane oxygenation medical directors and program coordinators. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed responses from 209 respondents (53%), mostly from academic centers (63%); 41% respondents provide venovenous extracorporeal membrane oxygenation to adults exclusively. Following venovenous extracorporeal membrane oxygenation initiation, 97% respondents administer sedative/analgesic infusions, and the sedation target was "sedated" or "very sedated" for 59%, "calm and cooperative" for 25%, and "unarousable" for 16%. Use of daily sedation interruption and a sedation/analgesia protocol was reported by 51% and 39%, respectively. Midazolam (48%) and propofol (19%) were reported as the most frequently used sedatives; fentanyl (44%) and morphine (20%) the most frequent opioids. Use of a delirium scale was reported by 55% respondents. Physical therapy was reported by 84% respondents, with 41% initiating it within 72 hours after cannulation. Mobilization goals varied from range of motion exercises (81%) to ambulation (22%). The most frequently perceived barriers to mobilization were hemodynamic instability, hypoxemia, and dependency on venovenous extracorporeal membrane oxygenation support. CONCLUSIONS: The majority of respondents reported targeting moderate to deep sedation following cannulation, with the use of sedative and opioid infusions. There is considerable variability surrounding early physical therapy and mobilization goals for patients with acute respiratory failure supported by venovenous extracorporeal membrane oxygenation.

Noninvasive Ventilation in Patients With Hematologic Malignancy.

INTRODUCTION: Noninvasive ventilation (NIV) is commonly used as first-line therapy for immunocompromised patients with acute respiratory failure. However, it may not be appropriate for all patients, as failure of NIV and delayed endotracheal intubation (ETI) may increase mortality. We report our center's experience and outcomes for patients with active hematologic malignancy (HM) treated with NIV. METHODS: We conducted a retrospective study of consecutive patients with HM who were admitted to the intensive care unit (ICU) of Mount Sinai Hospital for acute respiratory failure between January 1, 2010, and May 31, 2015, and were initially treated with NIV. We compared the characteristics of patients who were successfully treated with NIV and avoided intubation and those who failed NIV. RESULTS: Seventy-nine patients (mean age 56 ± 14 years, mean Acute Physiology and Chronic Health Evaluation II score 27 ± 5) with HM were treated with NIV for acute respiratory failure. The etiology of respiratory failure was multifactorial in 31 (39%) patients, with features of pneumonia in 61 (77%) patients, severe sepsis or septic shock in 33 (42%) patients, and pulmonary edema in 24 (30%) patients. The majority of patients were admitted with acute leukemia (n = 60, 76%), 8 (10%) with lymphoma, and 11 (14%) with chronic leukemia, multiple myeloma, or myelodysplastic syndrome. Of the 79 patients treated with NIV, 44 (56%) failed NIV and required ETI, 7 (9%) had a do-not-intubate (DNI) order and died, and 28 (35%) avoided ETI. Compared with patients who avoided ETI, those who failed NIV or had a DNI order and died were more likely to have acute leukemia (84% vs 61%; P = .02) and at baseline had higher Paco2 (39 vs 30; P = .038), higher fraction of inspired oxygen (Fio2) requirements (0.6 vs 0.4; P = .002), and more vasopressor use (31% vs 11%; P = .059). The ICU mortality was 42%; 3-month mortality was 57% overall and was significantly lower in the NIV success patients compared with the NIV failure group (21% vs 74%; P < .001). CONCLUSION: Two-thirds of patients with HM and respiratory failure failed NIV and required ETI, and had high subsequent mortality. Patients who failed NIV had higher Paco2, higher Fio2, and a trend toward more vasopressor use.

Intensive Care Physiotherapy during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome.

RATIONALE: There are limited data on physiotherapy during extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS). OBJECTIVES: We sought to characterize physiotherapy delivered to patients with ARDS supported with ECMO, as well as to evaluate the association of this therapeutic modality with mortality. METHODS: We conducted a retrospective cohort study of all adult patients with ARDS supported with ECMO at our institution between 2010 and 2015. The highest level of daily activity while on ECMO was coded using the ICU Mobility Scale. Through multivariable logistic regression, we evaluated the association between intensive care unit (ICU) physiotherapy and ICU mortality. In an exploratory univariate analysis, we also evaluated factors associated with a higher intensity of ICU rehabilitation while on ECMO. MEASUREMENTS AND MAIN RESULTS: Of 107 patients who underwent ECMO, 61 (57%) had ARDS requiring venovenous ECMO. The ICU physiotherapy team was consulted for 82% (n = 50) of patients. Thirty-nine percent (n = 18) of these patients achieved an activity level of 2 or higher (active exercises in bed), and 17% (n = 8) achieved an activity level 4 or higher (actively sitting over the side of the bed). In an exploratory analysis, consultation with the ICU physiotherapy team was associated with decreased ICU mortality (odds ratio, 0.19; 95% confidence interval, 0.04-0.98). In univariate analysis, severity-of-illness factors differentiated higher-intensity and lower-intensity physiotherapy. CONCLUSIONS: Physiotherapy during ECMO is feasible and safe when performed by an experienced team and executed in stages. Although our study suggests an association with improved ICU mortality, future research is needed to identify potential barriers, optimal timing, dosage, and safety profile.

Neuromuscular Blockade in the 21st Century Management of the Critically Ill Patient.

Neuromuscular blockings agents (NMBAs) have a controversial role in the ventilatory and medical management of critical illness. The clinical concern surrounding NMBA-induced complications stems from evidence presented in the 2002 clinical practice guidelines, but new evidence from subsequent randomized trials and studies provides a more optimistic outlook about the application of NMBAs in the ICU. Furthermore, changes in the delivery of critical care, such as protocolized care pathways, minimizing or interrupting sedation, increased monitoring techniques, and overall improvements in reducing immobility, have created a modern, 21st century ICU environment whereby NMBAs may be administered safely. In this article we start with a review of the mechanism of action, side effects, and pharmacology of commonly used NMBAs. We then address the rationale for NMBA use for an expanding number of indications (endotracheal intubation, acute respiratory distress syndrome, status asthmaticus, increased intracranial and intra-abdominal pressure, and therapeutic hypothermia after cardiac arrest), with an emphasis on NMBA use in facilitating lung-protective ventilation for respiratory failure. We end with an appraisal over the importance of monitoring depth of paralysis and the concerns of complications, such as prolonged skeletal muscle weakness. In the context of adequate sedation and analgesia, monitored NMBA use (continuous or bolus administration) can be considered for the small number of clinical indications in critically ill patients for which evidence currently exists.

GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self-administering rats.

Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA-mediated potentiation of AMPA receptors in this region may be part of the neural circuits of drug relapse.

Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats.

Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self-administering rats, but not in those of drug-naïve and sucrose self-administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal.

D1 dopamine receptor-mediated LTP at GABA synapses encodes motivation to self-administer cocaine in rats.

Enhanced motivation to take drugs is a central characteristic of addiction, yet the neural underpinning of this maladaptive behavior is still largely unknown. Here, we report a D1-like dopamine receptor (DRD1)-mediated long-term potentiation of GABAA-IPSCs (D1-LTPGABA) in the oval bed nucleus of the stria terminalis that was positively correlated with motivation to self-administer cocaine in rats. Likewise, in vivo intra-oval bed nucleus of the stria terminalis DRD1 pharmacological blockade reduced lever pressing for cocaine more effectively in rats showing enhanced motivation toward cocaine. D1-LTPGABA resulted from enhanced function and expression of G-protein-independent DRD1 coupled to c-Src tyrosine kinases and required local release of neurotensin. There was no D1-LTPGABA in rats that self-administered sucrose, in those with limited cocaine self-administration experience, or in those that received cocaine passively (yoked). Therefore, our study reveals a novel neurophysiological mechanism contributing to individual motivation to self-administer cocaine, a critical psychobiological element of compulsive drug use and addiction.

A switch in the neuromodulatory effects of dopamine in the oval bed nucleus of the stria terminalis associated with cocaine self-administration in rats.

Chronic exposure to drugs of abuse alters brain reward circuits and produces functional changes in the dopamine (DA) system. However, it is not known whether these changes are directly related to drug-driven behaviors or whether they simply are adaptive responses to long-term drug exposure. Here, we combined the rat model of cocaine self-administration with brain slice electrophysiology to identify drug-use related alterations in the neuromodulatory effects of DA in the oval bed nucleus of the stria terminalis (ovBST), a robust DA terminal field. Long-Evans rats self-administered cocaine intravenously (0.75 mg/kg/injection) for an average of 15 d, on reward-lean or -rich schedules of reinforcement. Brain slice recordings conducted 20 h after the last self-administration session revealed a reversal of the neuromodulatory effect of DA on GABA(A)-IPSCs. Specifically, the effect of DA switched from a D2-mediated decrease in drug-naive rats to a D1-receptor-mediated increase in GABA(A)-IPSC in cocaine self-administering rats. Furthermore, the switch in DA modulation of GABA(A)-IPSC remained after a 30 d withdrawal period. In contrast, this switch was not observed after the acquisition phase of cocaine self-administration, when rats received cocaine passively, or in rats maintaining sucrose self-administration. Therefore, our study reveals a reversal in the effects of DA on inhibitory transmission, from reduction to enhancement, in the ovBST of cocaine self-administering rats. This change was unique to voluntary intake of cocaine and maintained after a withdrawal period, suggesting a mechanism underlying the maintenance of cocaine self-administration and perhaps craving during drug-free periods.