Etomidate versus ketamine for emergency endotracheal intubation: a randomized clinical trial.

PURPOSE: Etomidate and ketamine are hemodynamically stable induction agents often used to sedate critically ill patients during emergency endotracheal intubation. In 2015, quality improvement data from our hospital suggested a survival benefit at Day 7 from avoidance of etomidate in critically ill patients during emergency intubation. In this clinical trial, we hypothesized that randomization to ketamine instead of etomidate would be associated with Day 7 survival after emergency endotracheal intubation. METHODS: A prospective, randomized, open-label, parallel assignment, single-center clinical trial performed by an anesthesiology-based Airway Team under emergent circumstances at one high-volume medical center in the United States. 801 critically ill patients requiring emergency intubation were randomly assigned 1:1 by computer-generated, pre-randomized sealed envelopes to receive etomidate (0.2-0.3 mg/kg, n = 400) or ketamine (1-2 mg/kg, n = 401) for sedation prior to intubation. The pre-specified primary endpoint of the trial was Day 7 survival. Secondary endpoints included Day 28 survival. RESULTS: Of the 801 enrolled patients, 396 were analyzed in the etomidate arm, and 395 in the ketamine arm. Day 7 survival was significantly lower in the etomidate arm than in the ketamine arm (77.3% versus 85.1%, difference - 7.8, 95% confidence interval - 13, - 2.4, p = 0.005). Day 28 survival rates for the two groups were not significantly different (etomidate 64.1%, ketamine 66.8%, difference - 2.7, 95% confidence interval - 9.3, 3.9, p = 0.294). CONCLUSION: While the primary outcome of Day 7 survival was greater in patients randomized to ketamine, there was no significant difference in survival by Day 28.

Characterizing the Structural Integrity of Endotracheal Tube Taping Techniques: A Simulation Study.

BACKGROUND: Endotracheal tubes (ETTs) are commonly secured with tape to prevent undesirable tube migration. Many methods of taping have been described, although little has been published comparing various methods of taping to one another. In this study, we evaluated several methods for securing ETTs with tape. We hypothesized a difference in mean peak forces between the methods studied during forced extubation. METHODS: Five methods of securing an ETT with tape were studied in a variety of contexts including cadaver and simulation lab settings. Testing included measurement of peak force (Newton [N]) during forced extubation, durability of taping following mechanical stress, effects of tape length-width variation, and characterization of failure mechanisms. RESULTS: We found several significant differences in mean peak extubation forces between the 5 methods of taping, with mean peak forces during forced extubation ranging from 20 N to 156 N. In separate tests, we found an association between mean peak forces and total surface area as well as geometric configuration of tape on the face. Long thin strips of tape appeared to provide surprising durability against forced extubation, a phenomenon that was associated with minimization of the "peel angle" as tape was removed. CONCLUSIONS: We found evidence of differential structural integrity between the 5 taping methods studied. More generally, we found that increased peak extubation forces were associated with increased total surface area of tape and that minimization of the "peel angle" by lateral application of tape is associated with surprisingly high relative peak extubation forces.

Measuring the cost and effect of current community consultation and public disclosure techniques in emergency care research.

AIM: U.S. federal regulations for research involving exception from informed consent (EFIC) include stipulations for community consultation (CC) and public disclosure (PD) (FDA 21 CFR 50.24). Published descriptions of PD campaigns include letters to community leaders, media outreach, paid advertising, and community meetings. Whether or not these activities provide measurable impact is unknown, as few prior works have evaluated PD activities with probabilistic polling. The aim of this study is to use polling to assess how much public awareness PD efforts generate. METHODS: A 3-month PD campaign similar in scope and scale to PD campaigns described in several recent publications was implemented across a large urban county (pop. 2.55 million). PD included a study website (www.evktrial.org), letters to 300 community leaders/organizations, bilingual media outreach and also phased roll-outs, weeks apart, of newspaper advertisements, mass e-mail messaging, and paid advertising in Facebook® and Twitter® augmented by volunteer social media outreach. During PD we used repeated zip code-targeted online polling via Google Consumer Surveys® to assess community awareness of the proposed EFIC study. RESULTS: Over 3-months all-source exposures to >1 million individuals were estimated, generating ∼5,000 website visits (12-month cumulative, ∼9000). However, general community awareness evaluated through repeated county-wide polling never rose above baseline measurements. CC/PD campaign costs were estimated at $60,000 (USD). CONCLUSION: A PD campaign in scope and scale common for EFIC studies may not provide measurable impact in a community. Investigators, review boards and regulators could consider these findings when re-examining and/or creating policies for PD for EFIC studies.

Use of a Tilting Orthopedic Fracture Table to Facilitate Proper Patient Positioning During Intrathecal Neurolysis With Hyperbaric Phenol: A Case Report.

We describe the case of a 41-year-old woman with metastatic cervical cancer and a large mass eroding into the pelvis and left lumbosacral plexus. The patient had intractable left lower extremity pain refractory to standard therapies, and she elected to undergo intrathecal neurolysis. A diagnostic intrathecal block was performed at the T11-12 interspace followed by intrathecal neurolysis with 6% phenol in glycerin on a subsequent date. During both procedures, we used a tilting radiolucent orthopedic fracture table to maintain strict left lateral-supine positioning. A tilting orthopedic fracture table may be a valuable adjunct to ensure positional stability during intrathecal neurolysis.

Intercostal Nerve Block and Neurolysis for Intractable Cancer Pain.

Management of intractable cancer-associated chest wall pain is difficult once patients have reached dose-limiting side effects of opioids and coanalgesic medications. This case series describes 11 patients with intractable cancer-associated chest wall pain who were treated with a diagnostic intercostal nerve block. Six patients subsequently received chemical neurolysis with phenol using the same approach. No serious adverse events were observed. Radiopaque contrast dye spread into the paravertebral space in all 11 patients, and in 1 patient contrast dye spread into the epidural space. Seven of 11 patients experienced pain relief from the diagnostic blockade. Four of six patients experienced pain relief from the neurolytic blockade. The principal reportable finding from this case series is the observation that contrast dye spread liberally from the intercostal space into other anatomic spaces, even though very small volumes of injectate (less than 5 mL) were used. Definitive evidence of safety and efficacy of intercostal nerve block and neurolysis for cancer pain will require a prospective randomized clinical trial.

How Drug Shortages Affect Clinical Care: The Case of the Surgical Anesthetic Propofol.

BACKGROUND: Periodic drug shortages have become a reality in clinical practice. In 2010, in the context of a nationwide drug shortage, our hospital experienced an abrupt 3-month shortage of the surgical anesthetic propofol. The purpose of this retrospective study was to survey the clinical impact of the abrupt propofol shortage at our hospital and to survey for any change in perioperative mortality. METHODS: A retrospective before-and-after analysis, comparing May through July 2010 (group A, prior to the propofol shortage) to August through October 2010 (group B, during the propofol shortage). RESULTS: In May through July 2010, before the propofol shortage, a majority of patients (80%) received propofol (group A, n = 2,830). In August through October 2010, during the propofol shortage, a majority of patients (81%) received etomidate (group B, n = 3,066). We observed that net usage of etomidate increased by more than 600% in our hospital. Baseline health characteristics and type of surgery were similar between groups A and B. Thirty-day and 2-year mortality were similar between groups A and B. The reported causes and frequency of mortality in groups A and B were also similar. CONCLUSION: The propofol shortage led to an increased usage of etomidate by more than 600%. In spite of that, we did not detect an increase in mortality associated with the increased use of etomidate during a 3-month propofol shortage.

General anesthesia suppresses normal heart rate variability in humans.

The human heart normally exhibits robust beat-to-beat heart rate variability (HRV). The loss of this variability is associated with pathology, including disease states such as congestive heart failure (CHF). The effect of general anesthesia on intrinsic HRV is unknown. In this prospective, observational study we enrolled 100 human subjects having elective major surgical procedures under general anesthesia. We recorded continuous heart rate data via continuous electrocardiogram before, during, and after anesthesia, and we assessed HRV of the R-R intervals. We assessed HRV using several common metrics including Detrended Fluctuation Analysis (DFA), Multifractal Analysis, and Multiscale Entropy Analysis. Each of these analyses was done in each of the four clinical phases for each study subject over the course of 24 h: Before anesthesia, during anesthesia, early recovery, and late recovery. On average, we observed a loss of variability on the aforementioned metrics that appeared to correspond to the state of general anesthesia. Following the conclusion of anesthesia, most study subjects appeared to regain their normal HRV, although this did not occur immediately. The resumption of normal HRV was especially delayed on DFA. Qualitatively, the reduction in HRV under anesthesia appears similar to the reduction in HRV observed in CHF. These observations will need to be validated in future studies, and the broader clinical implications of these observations, if any, are unknown.

Intercostal administration of liposomal bupivacaine as a prognostic nerve block prior to phenol neurolysis for intractable chest wall pain.

Inadequate pain relief from systemic medications is common in patients with advanced malignancy. Chest wall pain secondary to tumor involvement of chest wall structures can be challenging to manage with systemic medications, and occasionally patients benefit from interventional procedures such as intercostal nerve blocks and neurolysis. In this report, the authors describe the case of a 58-year-old woman with advanced non-small cell lung cancer with tumor invasion into the third thoracic rib. After reaching maximum tolerated doses of transdermal fentanyl, oral hydromorphone, and oral ketamine, the patient elected for intercostal nerve blockade and neurolysis. Prognostic nerve blockade was performed using liposomal bupivacaine administered via intercostal approach. This formulation of bupivacaine provided an excellent prognostic blockade, which lasted for approximately 96 hours. This extended period of time allowed the patient to fully evaluate the prognostic blockade, prior to proceeding with neurolysis with phenol. This case suggests that liposomal bupivacaine may be a valuable adjunctive agent for prognostic blockade prior to neurolysis for cancer pain.

Combined ultrasound and fluoroscopic guidance for radiofrequency ablation of the obturator nerve for intractable cancer-associated hip pain.

Management of pain from skeletal metastases is notoriously difficult. Case reports and case series have described radiofrequency ablation of the obturator nerve branches to the femoral head for treatment of intractable hip pain. Ablation of the obturator branches to the femoral head is technically difficult because of bony and vascular anatomy, including close proximity of the femoral vessels. Here we present the case of a 79-year-old woman with intractable right hip pain and inability to ambulate secondary to metastatic non-small cell lung cancer in the femoral head and acetabulum, treated with thermal radiofrequency ablation of the obturator and femoral nerve branches to the femoral head. Ablation of the obturator nerve was done via anterior placement of the radiofrequency needle under combined ultrasound and fluoroscopic guidance, passing the radiofrequency needle between the femoral artery and femoral vein. Real-time ultrasound guidance was used to avoid vascular puncture. Thermal radiofrequency ablation resulted in sustained pain relief, and resumption in the ability of the patient to ambulate. From this case we suggest that an anterior approach to the obturator nerve branches to the femoral head may be technically feasible using combined ultrasound and fluoroscopic guidance to avoid vascular puncture.

Using pulsed radiofrequency ablation to treat pain associated with a tumor involving the brachial plexus.

Pain associated with cancer is often difficult to treat, even more so when tumors involve peripheral nerves. Therapy is complex and often requires a multimodal approach that can include medications, radiation, and interventional techniques. These components are utilized with variable success, but are also limited by known complications or adverse effects. We present the case of a 53-year-old woman with a metastatic axillary tumor that involved her brachial plexus. Attempts to control her pain with medication were unsuccessful despite escalation and use of adjunct agents. She was not deemed to be a surgical candidate due to the size and location of the tumor. Radiation was discussed but, obviously, would not work immediately. Our team decided to employ a brachial plexus catheter for continuous nerve block, which provided almost complete relief of pain. Since her pain was deemed to be of peripheral etiology, pulsed radiofrequency ablation of her brachial plexus was used for more long-term pain relief. The patient responded very well with minimal pain issues and no apparent complications. On follow-up, the patient had good relief for almost 2 months. Pulsed radiofrequency is a poorly understood technology that has increasing evidence for certain pain conditions; however, for cancer and peripheral nerves the evidence is slim to none. Our case presents a successful use for pain management of a brachial plexopathy due to a tumor. We propose that pulsed radiofrequency may present a non-neurodestructive pain management technique for tumors involving peripheral nerves, though more data is definitely needed.

Hyperbaric oxygen therapy and cerebral ischemia: neuroprotective mechanisms.

INTRODUCTION: Numerous studies have demonstrated a protective effect of hyperbaric oxygen therapy in experimental ischemic brain injury, and many physiological and molecular mechanisms of hyperbaric oxygen therapy-related neuroprotection have been identified. METHODS: Review of articles pertaining to hyperbaric oxygen therapy and cerebral ischemia in the National Library of Medicine and National Institutes of Health database, emphasizing mechanisms of hyperbaric oxygen therapy-related neuroprotection. RESULTS: Hyperbaric oxygen therapy has been shown to ameliorate brain injury in a variety of animal models including focal cerebral ischemia, global cerebral ischemia, neonatal hypoxia-ischemia and subarachnoid hemorrhage. Small human trials of hyperbaric oxygen therapy in focal ischemia have not shown benefit, although one trial of hyperbaric oxygen therapy before cardiopulmonary bypass demonstrated improved neuropsychological and inflammatory outcomes with hyperbaric oxygen therapy. Hyperbaric oxygen therapy is associated with improved cerebral oxygenation, reduced blood-brain barrier breakdown, decreased inflammation, reduced cerebral edema, decreased intracranial pressure, reduced oxidative burden, reduced metabolic derangement, decreased apoptotic cell death and increased neural regeneration. CONCLUSION: On a molecular level, hyperbaric oxygen therapy leads to activation of ion channels, inhibition of hypoxia inducible factor-1alpha, up-regulation of Bcl-2, inhibition of MMP-9, decreased cyclooxygenase-2 activity, decreased myeloperoxidase activity, up-regulation of superoxide dismutase and inhibition of Nogo-A (an endogenous growth-inhibitory factor). Ongoing research will continue to describe the mechanisms of hyperbaric oxygen therapy-related neuroprotection, and possibly expand hyperbaric oxygen therapy use clinically.

Neuroprotective effect of volatile anesthetic agents: molecular mechanisms.

INTRODUCTION: Intra-operative cerebral ischemia can be catastrophic, and volatile anesthetic agents have been recognized for their potential neuroprotective properties since the 1960s. In this review, we examine the neuroprotective effects of five volatile anesthetic agents in current or recent clinical use: isoflurane, sevoflurane, desflurane, halothane and enflurane. METHODS: A review of publications in the National Library of Medicine and National Institutes of Health database from 1970 to 2007 was conducted. RESULTS: Volatile anesthetic agents have been shown to be neuroprotective in multiple animal works of ischemic brain injury. Short-term neuroprotection (<1 week post-ischemia) in experimental cerebral ischemia has been reported in multiple works, although long-term neuroprotection (> or = 1 week post-ischemia) remains controversial. Comparison works have not demonstrated superiority of one specific volatile agent over another in experimental models of brain injury. Relatively few human works have examined the protective effects of volatile anesthetic agents and conclusive evidence of a neuroprotective effect has yet to emerge from human works. CONCLUSION: Proposed mechanisms related to the neuroprotective effect of volatile anesthetic agents include activation of ATP-dependent potassium channels, up-regulation of nitric oxide synthase, reduction of excitotoxic stressors and cerebral metabolic rate, augmentation of peri-ischemic cerebral blood flow and up-regulation of antiapoptotic factors including MAP kinases.

Hydrogen gas is ineffective in moderate and severe neonatal hypoxia-ischemia rat models.

Hydrogen gas (H(2)) has been shown to ameliorate brain injury in experimental adult rat focal ischemia and in a mild neonatal hypoxia-ischemia (HI, 90 min hypoxia) rat model. In this study we tested H(2) in moderate (120 min hypoxia) and severe (150 min hypoxia) neonatal HI rat models. We hypothesized that H(2) would improve outcomes after neonatal HI by scavenging free radicals. Two hundred (200) unsexed Sprague-Dawley rats at day 10 of life (p10) underwent neonatal HI with the Rice-Vannucci model. Multiple treatment protocols were studied, including pre-ischemic treatment, intra-ischemic treatment, and post-ischemic treatment (Sham n=32, HI n=82, HI+H(2)n=86). We also tested H(2) in middle cerebral artery occlusion (MCAO) in adult rats (MCAO n=9, MCAO+H(2)n=7) for comparison. Analysis at 24 h included infarction volume, measurement of brain concentration of malondialdehyde (MDA) (an end-product of lipid peroxidation), daily weight, Nissl histology, and mortality. In moderate and severe neonatal HI models, hydrogen gas therapy (2.9% concentration H(2)) was not associated with decreased volume of infarction or decreased concentration of MDA. H(2) gas pretreatment (2.9%) was associated with increased infarction volume in neonatal HI. In MCAO in adult rats, H(2) gas therapy demonstrated a trend of beneficial effect. Exposure of H(2) gas to non-ischemic neonates resulted in a significant increase in brain concentration of MDA. We conclude that 2.9% H(2) gas therapy does not ameliorate moderate to severe ischemic damage in neonatal hypoxia-ischemia.

Role of histamine in brain protection in surgical brain injury in mice.

Surgical resection of brain tissue is associated with tissue damage at the resection margin. Studies of ischemic brain injury in rodents have shown that administration of L-histidine and thioperamide reduces ischemic tissue loss, in part by inhibition of apoptotic cell death. In this study we tested administration of L-histidine and thioperamide in surgical brain injury in mice. Mice were randomized to one of three groups: Sham surgery (n=18), surgical brain injury without treatment (SBI) (n=33), and surgical brain injury with combined l-histidine and thioperamide treatment (SBI+H) (n=29). Surgical brain injury was induced via right frontal craniotomy with resection of the right frontal lobe. L-histidine (1000 mg/kg) and thioperamide (5 mg/kg) were administered to the SBI+H group immediately following surgical resection. Postoperative assessment included neurobehavioral scores, Evans blue measurement of blood-brain barrier breakdown, brain water content, Nissl histology, and immunohistochemistry for IgG and cleaved caspase 3. Postoperative findings included equivalent neurobehavioral outcomes at 24 and 72 h in the SBI and SBI+H groups, similar histological outcomes between SBI and SBI+H, and similar qualitative staining for cleaved caspase 3. SBI+H had increased BBB breakdown on Evans blue analysis and a trend towards increased brain edema which was significant at 72 h. We conclude that combined treatment with l-histidine and thioperamide leads to increased BBB breakdown and brain edema in surgical brain injury.

The effect of 2-methoxyestradiol, a HIF-1 alpha inhibitor, in global cerebral ischemia in rats.

Global cerebral ischemia is an important clinical problem with few effective treatments. The hippocampus, which is important for memory, is especially vulnerable during global ischemia. Brain-specific knockout of hypoxia inducible factor-1 alpha (HIF-1 alpha) has been shown to be protective in focal ischemia in vivo. 2-methoxyestradiol (2ME2) is a natural metabolite of estrogen that is known to inhibit HIF-1 alpha. We tested 2ME2 in a rat model of global cerebral ischemia. Global ischemia was induced with the two-vessel occlusion model (2VO) which entailed hemorrhagic hypotension to a mean arterial pressure of 38-42 mmHg with simultaneous bilateral common carotid artery occlusion for 8 minutes. Sprague-Dawley rats (male, 280-350 g) were randomly assigned to three groups: global ischemia (GI, n=17), global ischemia with 2ME2 treatment (GI + 2ME2, n=17) and sham surgery (sham, n=12). 2ME2 treatment (15 mg/kg in 1% DMSO) was rendered 10 minutes after reperfusion. Rats in the GI and sham groups received similar doses of the DMSO solvent. Rats were killed 24 hours, 72 hours and 7 days after reperfusion. Quantitative CA1 hippocampal cell counts demonstrated significantly lower cell survival in the GI + 2ME2 group compared to either the GI or sham groups, in spite of a statistically significant reduction in HIF-1 alpha by Western blotting analysis of the GI + 2ME2 group. We conclude that 2ME2 worsens outcomes after global ischemia in rats.

Inhibition of Src tyrosine kinase and effect on outcomes in a new in vivo model of surgically induced brain injury.

OBJECT: Brain tissue at the periphery of a neurosurgical resection site is vulnerable to injury by a variety of mechanisms including direct trauma, edema, hemorrhage, retractor stretch, and electrocautery. The goal in the present study was to develop an in vivo model of surgically induced brain injury and to test an Src tyrosine kinase inhibitor for neuroprotective properties in this model. METHODS: The authors developed a new surgically induced brain injury model in rats. This model involves resection of part of the frontal lobe. Sprague-Dawley male rats weighing between 300 and 350 g were divided randomly into four groups: Group 1, surgical injury with vehicle treatment; Group 2, surgical injury after treatment with PP1 (an Src tyrosine kinase inhibitor with known neuroprotective properties); Group 3, sham surgery; and Group 4, control. Postoperative assessment included blood-brain barrier (BBB) permeability studies, and histological, immunohistochemical, and Western blot analyses. The authors found that surgical injury caused localized edema and disruption of the BBB compared with findings in the sham surgery group. Treatment with PP1 was associated with decreased edema, decreased breakdown of the BBB, decreased expression of both vascular endothelial growth factor and phosphorylated extracellular signal-regulated kinase 1 and 2, and preservation of ZO-1 expression. CONCLUSIONS: In this study the authors describe a simple and reproducible in vivo animal model of surgically induced brain injury. Pretreatment with PP1 results in improved outcomes in this model, which suggests a possible role for Src tyrosine kinase inhibitors as preoperative therapy for planned neurosurgical procedures.

Granulocyte-colony stimulating factor inhibits apoptotic neuron loss after neonatal hypoxia-ischemia in rats.

Neonatal hypoxia-ischemia (HI) is an important clinical problem with few effective treatments. Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has been shown to be neuroprotective in focal ischemia in vivo and is currently in phase I/II clinical trials for ischemic stroke in humans. We tested G-CSF in a rat model of neonatal hypoxia-ischemia in postnatal day 7 unsexed rat pups. Three groups of animals were used: hypoxia-ischemia (HI, n=67), hypoxia-ischemia with G-CSF treatment (HI+G, n=65), and healthy control (C, n=53). G-CSF (50 microg/kg, subcutaneous) was administered 1 h after HI and given on four subsequent days (five total injections). Animals were euthanized 24 h, 1, 2, and 3 weeks after HI. Assessment included brain weight, histology, immunohistochemistry, and Western blotting. G-CSF treatment was associated with improved quantitative brain weight and qualitative Nissl histology after hypoxia-ischemia. TUNEL demonstrated reduced apoptosis in group HI+G. Western blot demonstrated decreased expression of Bax and cleaved caspase-3 in group HI+G. G-CSF treatment was also associated with increased expression of STAT3, Bcl-2, and Pim-1, all of which may have participated in the anti-apoptotic effect of the drug. We conclude that G-CSF ameliorates hypoxic-ischemic brain injury and that this may occur in part by an inhibition of apoptotic cell death.