Suren Soghomonyan

Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review

Introduction: The use of opioids has been increasing in operating room and intensive care unit to provide perioperative analgesia as well as stable hemodynamics. However, many authors have suggested that the use of opioids is associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) in experimental studies and clinical observations in dose and/or time dependent exposure even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management during anesthesia as well as in the intensive care units because of its rapid onset and offset. Objectives: Search of the available literature to assess remifentanil AOT and OIH based on available published data. Methods: We reviewed articles analyzing remifentanil AOT and OIH, and focused our literature search on evidence based information. Experimental and clinical studies were identified using electronic searches of Medline (PubMed, Ovid, Springer, and Elsevier, ClinicalKey). Results: Our results showed that the development of remifentanil AOT and OIH is a clinically significant phenomenon requiring further research. Discussions and Conclusions: AOT – defined as an increase in the required opioid dose to maintain adequate analgesia, and OIH – defined as decreased pain threshold after chronic opioid treatment, should be suspected with any unexplained pain report unassociated with the disease progression. The clinical significance of these findings was evaluated taking into account multiple methodological issues including the dose and duration of opioids administration, the different infusion mode, the co-administrated anesthetic drug’s effect, method assessing pain sensitivity, and the repetitive and potentially tissue damaging nature of the stimuli used to determine the threshold during opioid infusion. Future studies need to investigate the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process.

Enteric Glial Cells: A New Frontier in Neurogastroenterology and Clinical Target for Inflammatory Bowel Diseases

Abstract:The word “glia” is derived from the Greek word “&ggr;&lgr;o&igr;&agr;,” glue of the enteric nervous system, and for many years, enteric glial cells (EGCs) were believed to provide mainly structural support. However, EGCs as astrocytes in the central nervous system may serve a much more vital and active role in the enteric nervous system, and in homeostatic regulation of gastrointestinal functions. The emphasis of this review will be on emerging concepts supported by basic, translational, and/or clinical studies, implicating EGCs in neuron-to-glial (neuroglial) communication, motility, interactions with other cells in the gut microenvironment, infection, and inflammatory bowel diseases. The concept of the “reactive glial phenotype” is explored as it relates to inflammatory bowel diseases, bacterial and viral infections, postoperative ileus, functional gastrointestinal disorders, and motility disorders. The main theme of this review is that EGCs are emerging as a new frontier in neurogastroenterology and a potential therapeutic target. New technological innovations in neuroimaging techniques are facilitating progress in the field, and an update is provided on exciting new translational studies. Gaps in our knowledge are discussed for further research. Restoring normal EGC function may prove to be an efficient strategy to dampen inflammation. Probiotics, palmitoylethanolamide (peroxisome proliferator-activated receptor–&agr;), interleukin-1 antagonists (anakinra), and interventions acting on nitric oxide, receptor for advanced glycation end products, S100B, or purinergic signaling pathways are relevant clinical targets on EGCs with therapeutic potential.

Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review.

The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans.

Mechanosensory Signaling in Enterochromaffin Cells and 5-HT Release: Potential Implications for Gut Inflammation

Enterochromaffin (EC) cells synthesize 95% of the body 5-HT and release 5-HT in response to mechanical or chemical stimulation. EC cell 5-HT has physiological effects on gut motility, secretion and visceral sensation. Abnormal regulation of 5-HT occurs in gastrointestinal disorders and Inflammatory Bowel Diseases (IBD) where 5-HT may represent a key player in the pathogenesis of intestinal inflammation. The focus of this review is on mechanism(s) involved in EC cell “mechanosensation” and critical gaps in our knowledge for future research. Much of our knowledge and concepts are from a human BON cell model of EC, although more recent work has included other cell lines, native EC cells from mouse and human and intact mucosa. EC cells are “mechanosensors” that respond to physical forces generated during peristaltic activity by translating the mechanical stimulus (MS) into an intracellular biochemical response leading to 5-HT and ATP release. The emerging picture of mechanosensation includes Piezo 2 channels, caveolin-rich microdomains, and tight regulation of 5-HT release by purines. The “purinergic hypothesis” is that MS releases purines to act in an autocrine/paracrine manner to activate excitatory (P2Y1, P2Y4, P2Y6, and A2A/A2B) or inhibitory (P2Y12, A1, and A3) receptors to regulate 5-HT release. MS activates a P2Y1/Gαq/PLC/IP3-IP3R/SERCA Ca2+signaling pathway, an A2A/A2B–Gs/AC/cAMP-PKA signaling pathway, an ATP-gated P2X3 channel, and an inhibitory P2Y12-Gi/o/AC-cAMP pathway. In human IBD, P2X3 is down regulated and A2B is up regulated in EC cells, but the pathophysiological consequences of abnormal mechanosensory or purinergic 5-HT signaling remain unknown. EC cell mechanosensation remains poorly understood.

The Shortened Infusion Time of Intravenous Ibuprofen Part 1: A Multicenter, Open-label, Surveillance Trial to Evaluate Safety and Efficacy

PURPOSE The main purpose of the study was to determine the safety profile and efficacy of intravenous ibuprofen administered over 5 to 10 minutes for the treatment of pain or fever in hospitalized patients. Current evidence supports the use of intravenous infusions of ibuprofen to control pain and reduce the opioid requirements associated with surgical pain. Current dosing guidelines recommend that the drug be administered over 30 minutes. However, a more rapid infusion might yield additional benefits. The safety profile and efficacy of a shortened infusion time requires additional study. METHODS This was a Phase IV multicenter, open-label, surveillance clinical study. Thirteen clinical centers located in the United States enrolled a total of 150 adult hospitalized patients with pain or fever. Patients experiencing pain received 800 mg intravenous ibuprofen infused over 5 to 10 minutes every 6 hours for up to 24 hours (4 doses) and patients experiencing fever received 400 mg intravenous ibuprofen infused over 5 to 10 minutes every 4 hours for up to 24 hours (6 doses). Vital signs, adverse events, and pain scores were assessed. The exclusion criteria included inadequate intravenous access; patients younger than 18 years of age; history of allergy or hypersensitivity to any component of intravenous ibuprofen, aspirin, or other nonsteroid anti-inflammatory drugs; active hemorrhage or clinically significant bleeding; pregnancy or nursing; and patients in the perioperative period in the setting of coronary artery bypass graft surgery. FINDINGS Adverse events were reported for 43 of 150 patients (29%). The most common adverse events experienced by patients were infusion site pain in 22 of 150 patients (15%) and flatulence (8 of 150 [5%]). Four patients (3%) discontinued the study drug due to infusion-site pain. In the patients experiencing fever, temperature decreased from baseline over 4 hours (mean [SD] reduction of 1.5 [1.25]°F). In patients experiencing pain, patient-reported visual analog scale scores decreased from baseline over 4 hours (mean [SD] reduction of 27.1 [31.29] mm). IMPLICATIONS The study demonstrates that more rapid administration of intravenous ibuprofen is well tolerated and supports intravenous ibuprofen as an effective treatment for pain and fever in hospitalized patients.

The Shortened Infusion Time of Intravenous Ibuprofen, Part 2: A Multicenter, Open-label, Surgical Surveillance Trial to Evaluate Safety

PURPOSE The literature and clinical data support the use of intravenous (IV) infusions of ibuprofen to control pain and reduce the opioid requirements associated with surgical pain. According to current guidelines, IV ibuprofen can be administered via a slow IV infusion performed during a 30-minute period. Although recent studies indicate that more rapid infusions may yield additional benefits for patients, the safety of such an approach needs further evaluation. The main purpose of this study was to determine the safety of single and multiple doses of IV ibuprofen (800 mg) administered over 5 to 10 minutes at the induction of anesthesia and after the surgical procedure for the treatment of postoperative pain. METHODS This was a Phase IV, multicenter, open-label, clinical surveillance study. It was conducted at 21 hospitals in the United States, and 300 adult hospitalized patients undergoing surgery were enrolled. The exclusion criteria for the study were: inadequate IV access; hypersensitivity to any component of IV ibuprofen, aspirin, or related products; and any active, clinically significant bleeding. Also excluded were patients who had taken NSAIDs <6 hours before administration of IV ibuprofen; pregnant or breastfeeding female patients; and patients in the perioperative period of coronary artery bypass graft surgery. Patients received 800 mg of IV ibuprofen administered over 5 to 10 minutes preoperatively. Vital signs, adverse events, and pain scores were assessed. FINDINGS Approximately 22% (65 of 300) of patients reported adverse events (serious and nonserious). The most common adverse event was infusion site pain (34 of 300 [11%]). No deaths were reported. Nine subjects reported serious adverse events, 8 of which occurred during the first 6 hours. All serious events reported were judged unrelated to ibuprofen. Of the 300 total patients, 2 (0.67%) discontinued the study drug due to an adverse event (1 patient discontinued the study because of infusion site pain, and 1 patient withdrew due to a hypersensitivity reaction after drug administration). IMPLICATIONS Our study found that IV ibuprofen infused over 5 to 10 minutes at induction of anesthesia is a safe administration option for surgical patients. ClinicalTrials.gov identifier: NCT01334957.

Anesthesia and evoked responses in neurosurgery

Intraoperative evoked potential (EP) monitoring has become a routine part of operative neurosurgical procedures. The theoretical, technical, and clinical aspects of various EPs have been extensively characterized and significant clinical experience has been accumulated with this modality of neuromonitoring. Successful EP monitoring requires an adequate understanding of how anesthetic drugs and physiological variations affect EP signals and how to improve the sensitivity of neuromonitoring through appropriate drug selection and administration. Unlike intraoperative electroencephalography (EEG), EP signals are much smaller in amplitude (0.1–20 mcV) and indistinguishable from background noise. In order to extract the EP signal from the underlying EEG noise, multiple stimulations with summation and frequency filtering are necessary (Freye, 2005; Moller, 2011). EPs are highly sensitive to fluctuations in physiological parameters such as peripheral and core body temperature, arterial blood pressure, hematocrit etc. They are also susceptible to various general anesthetic agents and other drugs frequently given during surgery. The effects of general anesthetics on intraoperative EP depend on the mode of evoked response and the pharmacological characteristics of administered anesthetic drugs. Evoked responses that travel via polysynaptic pathways, such as visual EP are significantly more susceptible to the anesthesia and surgery when compared to EPs with fewer synapses in their pathway. In general, inhalational anesthetics are more potent suppressants of EP than intravenous agents (Banoub et al., 2003; Moller, 2011). Combinations of inhalational agents, as occurs with the addition of nitrous oxide, potentiate the suppressive effects of anesthesia even further. Despite their suppressive effects on EPs, inhalational anesthetics have obvious advantages for use during neurosurgery because they are easily titratable to provide stable anesthetic conditions. Lower doses of inhalational anesthetics (0.5–0.8 MAC depending on type of the evoked response) have been successfully applied during neurosurgical interventions and neurophysiological monitoring without compromising the quality of monitoring. Balanced general anesthesia with low doses of inhalational agents combined with low-dose constant infusions of remifentanil (0.05 mcg/kg/min), propofol (50 mcg/kg/min), or dexmedetomidine (0.003–0.005 mcg/kg/min) may be recommended when EP monitoring is anticipated. Such an approach will provide stable anesthesia and reduce the incidence of adverse events encountered occasionally during total intravenous anesthesia such as patient movement and awareness. Sevoflurane has low solubility compared with other inhalation anesthetics and thus is eliminated rapidly, minimizing its effects during monitoring later in the case (Sloan T, as cited in Fulkerson et al., 2011). Using sevoflurane as an induction agent, Fulkerson and colleagues were able to successfully monitor the intraoperative motor EPs in young children (less than 3 years) undergoing neurosurgical spinal procedures (Fulkerson et al., 2011). We believe that other inhalational anesthetics with low blood solubility (desflurane) may uneventfully be used for anesthesia induction and will be compatible with intraoperative neurophysiological monitoring. Anesthetics used for intravenous anesthesia, with a few exceptions, produce a dose-dependent suppressive effect on EP. Unlike the other intravenous hypnotics, etomidate, and ketamine tend to increase the SSEP amplitudes (Banoub et al., 2003). Further studies will be required to evaluate whether the use of various concentrations of these anesthetics during neurosurgical interventions suppress EP equally when different modalities of EP are being monitored. Opioids, in general, do not affect the quality of intraoperative EP monitoring. However, their mild suppressive effects are proportional to lipophilicity. When infused at higher doses, remifentanil causes a 20–80% decline in P37 peak amplitude of SSEP and a mild (<10%) increase in latency (Asouhidou et al., 2010). Midazolam and other benzodiazepines moderately suppress the intraoperative EP (Banoub et al., 2003), and their use, whenever possible, should be avoided. Benzodiazepine-induced EP suppression is less pronounced compared to inhalational agents. Dexmedetomidine, a relatively new hypnotic characterized by selective alpha-2 adrenergic antagonism, can be safely used to supplement general anesthesia during EP monitoring (Tobias et al., 2008). Intravenous lidocaine (1.5 mg/kg/h) is also a useful adjunct to general anesthesia with EP monitoring due to its ability to reduce anesthetic requirements, stabilize the cardiovascular parameters and decrease the incidence of patient movement during surgery (Sloan et al., 2014). Monitoring of motor EPs during surgery requires special caution, as they are more sensitive to anesthetics and muscle relaxants (Kunisawa et al., 2004; Lotto et al., 2004). Anesthetic conditions optimized for motor EP monitoring are suitable for SSEP registration as well (Pajewski et al., 2007). Although, partial muscle relaxation can be used for motor EP monitoring during surgery (Moller, 2011; Kim et al., 2013), most practitioners refrain from using muscle relaxants after tracheal intubation. In addition to selection of the most suitable anesthetics, their mode of administration is also an important factor that influences the quality of EP monitoring. During procedures requiring EP monitoring, steady infusion rates and stable concentrations of inhalational agents are preferred. Administration of drugs in bolus doses and variations in anesthesia level can negatively impact the quality of signal and cause EP suppression indistinguishable from changes triggered by surgical trauma (van Dongen et al., 1999; Lotto et al., 2004; Pajewski et al., 2007; Tobias et al., 2008; Deipolyi et al., 2011). During lengthy neurosurgical procedures, gradual attenuation of the EP signal may occur. This signal degradation is not related to the dose of anesthetics and is proportional to the length of anesthesia. This phenomenon is more frequently seen in younger patient populations and those with spinal cord pathology (Yang et al., 2012; Macdonald et al., 2013). The exact mechanisms underlying signal degradation are currently not well understood. Intraoperative monitoring of evoked responses can be successfully utilized to reduce the rate of inadvertent trauma to the nervous structures during neurosurgical procedures. Their interpretation requires profound knowledge of neurophysiology, comprehension of the surgical procedure and an understanding of the effects that general anesthesia and physiological changes may have on signal quality. Intraoperative neuromonitoring is one of the areas of medicine where team approach is a crucial prerequisite to obtain meaningful results. During neurosurgical procedures, a variety of general and local anesthetics are used, and many of them can substantially affect or even completely eliminate the EP signal. The possibility of anesthesia-related signal suppression and the influence of physiological changes on EP must be considered in order to avoid such effects. Drugs with minimal interference on neurophysiological monitoring should be used preferentially, and attempts made to keep the anesthetic concentrations, temperature, and other physiological variables constant. Maintaining steady state concentrations of an appropriately selected balanced anesthetic will reduce the incidence of false positive results and assist in the prevention of surgical trauma and ischemic damage during neurosurgical interventions. Appropriate drug selection, meticulous drug administration and minimization of physiological variation can improve patient safety by optimizing EP signal monitoring in patients undergoing neurological surgery.

Tension Pneumothorax During Surgery for Thoracic Spine Stabilization in Prone Position: A Case Report and Review of Literature

The intraoperative progression of a simple or occult pneumothorax into a tension pneumothorax can be a devastating clinical scenario. Routine use of prophylactic thoracostomy prior to anesthesia and initiation of controlled ventilation in patients with simple or occult pneumothorax remains controversial. We report the case of a 75-year-old trauma patient with an insignificant pneumothorax on the right who developed an intraoperative tension pneumothorax on the left side while undergoing thoracic spine stabilization surgery in the prone position. Management of an intraoperative tension pneumothorax requires prompt recognition and treatment; however, the prone position presents an additional challenge of readily accessing the standard anatomic sites for pleural puncture and air drainage.

Innovative Approaches To The Management of Acute Arterial Hypertension - Clevidipine Butyrate

Acute arterial hypertension is one of the major concerns in many clinical settings including but not limited to operating room, intensive care and emergency care units. Perioperative hypertension is one of the major reasons for cancellation of elective surgeries, and also increases the perioperative morbidity. We would like to discuss pathophysiology, evaluation of the patients with acute hypertension, management of these patients and future considerations of the current intravenous antihypertensive medications.

The Role of Permissive and Induced Hypotension in Current Neuroanesthesia Practice

Background Induced hypotension (IH) had been used for decades in neurosurgery to reduce the risk for intraoperative blood loss and decrease blood replacement. More recently, this method fell out of favor because of concerns for cerebral and other end-organ ischemia and worse treatment outcomes. Other contributing factors to the decline in its popularity include improvements in microsurgical technique, widespread use of endovascular procedures, and advances in blood conservation and transfusion protocols. Permissive hypotension (PH) is still being used occasionally in neurosurgery; however, its role in current anesthesia practice remains unclear. Our objective was to describe contemporary utilization of IH and PH (collectively called PH) in clinical practice among members of the Society for Neuroscience in Anesthesiology and Critical Care (SNACC). Methods A questionnaire was developed and distributed among SNACC members that addressed practice patterns related to the use of PH. The responses were analyzed based on the number of individuals who responded to each specific question. Results Of 72 respondents, 67.6% reported over 10 years of clinical experience, while 15.5% reported 5–10 years of post-training experience. The respondents admitted to providing anesthesia for 300 (median) neurosurgical cases per year. PH was applied most commonly during open interventions on cerebral aneurysms (50.8%) and arteriovenous malformations (46%). Seventy-three percent of respondents were not aware of any complications in their practice attributable to PH. Conclusion PH is still being used in neuroanesthesia practice by some providers. Further research is justified to clarify the risks and benefits of PH in modern neuroanesthesia practice.