Ketamine: An Update on Cellular and Subcellular Mechanisms with Implications for Clinical Practice.

BACKGROUND: Ketamine is one of the oldest hypnotic agents used to provide an anesthetic agent with analgesic properties and minimal suppressive effects on respiration. The ability of ketamine in modulating glutamatergic (N-methyl D-aspartate) pain receptors has made this anesthetic drug a new option for the management of patients with chronic pain syndromes. Further preclinical and clinical findings suggest ketamine may have wide ranging effects on both cognition and development. Recent advances have revealed an unprecedented role for ketamine in the acute management of depression. OBJECTIVES: The purpose of this review is to integrate a number of basic science, preclinical, and clinical studies with the goal of providing insight into the possible signaling events underlying ketamine's biological effects in pain management, depression, cognition and memory, and neurodevelopment. STUDY DESIGN: Narrative literature review. SETTING: Health science library. METHODS: A comprehensive literature search was performed for the following medical subject headings and keywords (ketamine, anesthesia, pain, analgesia, depression, NMDA receptors) on PubMed, Google Scholar, and Medline from 1966 to the present time. The search was then limited to those in the English language. The full text of the relevant articles were printed and reviewed by all authors. RESULTS: We provided a comprehensive review of the literature that explored the pharmacologic aspects of ketamine from its conception as an anesthetic to its evolution as a drug used for treatment of depression and pain. To address the patient response variability observed in clinical studies, we have provided possible patient-specific factors that could contribute to outcome variability. LIMITATIONS: Like any review, this study was limited by publication bias and missing information on negative studies which were denied publication. CONCLUSIONS: Ketamine, an old anesthetic agent with analgesic properties, is currently being considered for treating patients with chronic pain and depression. The complex pharmacological characteristics of ketamine make this medication a multifaceted therapeutic option in these cases. Key Words: Ketamine, anesthetics, pain, depression, pharmacology.

Digital subtraction angiography versus real-time fluoroscopy for detection of intravascular penetration prior to epidural steroid injections: meta-analysis of prospective studies.

BACKGROUND: Neurological injury is a rare but devastating complication of epidural steroid injections (ESIs) generally thought to arise from neurovascular compromise. The use of real-time fluoroscopy (RTF) with contrast media is the most common preventative measure taken to avoid intravascular penetration. In 2002, it was proposed that digital subtraction angiography (DSA) might be more useful than RTF. Since then, several prospective studies have advocated for its use. OBJECTIVES: As DSA is not currently a "gold standard," a meta-analysis was performed to compare the efficacy of DSA versus RTF for detection of intravascular penetration during ESI. STUDY DESIGN: Meta-analysis of prospective observational studies. METHODS: A targeted Pubmed search was conducted, yielding 49 reports and 4 manuscripts, which were analyzed using Review Manager Software (Rev Man 5.2). Inclusion/exclusion criteria: peer-reviewed prospective reports comparing the sensitivity of DSA to RTF in the same individuals without change in needle position between comparative imaging. Pooled estimate of odds ratios with 95% confidence interval using a random effect model was applied. RESULTS: There were a total of 188 intravascular events from 1,290 ESIs performed. RTF was able to detect 148 events with DSA detecting an additional 40 events missed by RTF. No major neurological complications were reported. DSA had a statistically significant favorable odds ratio over RTF for detection of intravascular penetration during ESI (OR = 1.32 [1.05 - 1.67]; P = 0.02). LIMITATIONS: Although the major methodological aspects of each study assessed in this meta-analysis were quite similar, there were small differences in needle gauge and the selection of secondary outcome measures. Despite attempts to minimize it, concern for operator bias also exists. CONCLUSIONS: DSA had a 32% improvement (OR = 1.32) for detection of intravascular penetration with ESI when compared to RTF. Although this supports advocacy for use of DSA, it also suggests that there is a greater than 30% "missed-events" rate for detection of vascular penetration when using RTF for ESI, which does not correlate with the generally reported cumulative rates of complications (1%). This discrepancy suggests that factors other than vascular events also play a role in complications. Nonetheless, given the evidence, we advocate for the increased use of DSA over RTF for transformational ESIs.

The role of metformin on vitamin B12 deficiency: a meta-analysis review.

Metformin is the only biguanide oral hypoglycemic drug, that is used to treat patients with type-2 diabetes mellitus. There are some reports of metformin being associated with decreased serum levels of vitamin B12 (VB12). The objective of this study is to systematically analyze the impact of metformin on the frequency of VB12 deficiency and serum levels of VB12. A search of various databases provided 18 retrospective cohort studies and 11 randomized controlled trials. Pooled estimates of odds ratio with 95% confidence interval using random effect model were conducted. Studies were examined for heterogeneity, publication bias and sensitivity analysis. Separate analysis of randomized control trials (RCTs) including both low-risk and high-risk bias was also conducted. 29 studies were selected with a total of 8,089 patients. 19 studies were rated intermediate or high quality. Primary outcome suggested increased incidence of VB12 deficiency in metformin group (OR = 2.45, 95% CI 1.74-3.44, P < 0.0001.) Heterogeneity was relatively high (I(2) = 53%), with minor publication bias. Secondary outcome suggested lower serum VB12 concentrations in metformin group (Mean difference = -65.8, 95% CI -78.1 to -53.6 pmol/L, P < 0.00001) with high heterogeneity (I(2) = 98%,) and low publication bias. RCTs analysis of low-and high-risk group revealed similar trends. We conclude that metformin treatment is significantly associated with an increase in incidence of VB12 deficiency and reduced serum VB12 levels.

Adjuvant hyaluronidase to epidural steroid improves the quality of analgesia in failed back surgery syndrome: a prospective randomized clinical trial.

BACKGROUND: Management of low back pain after spinal surgeries is one of the most challenging problems in pain medicine. Transforaminal lumbar epidural steroid injection has been used with inconsistent response. Most patients require multiple and frequent injections due to high recurrence of back pain. OBJECTIVE: To find out whether the addition of hyaluronidase to the epidural injectate affects the quality and duration of analgesia in patients with low back pain secondary to failed back surgery syndrome. STUDY DESIGN: Prospective randomized trial. METHODS: The study was registered in the Government Clinical Trial registry and the protocol was reviewed and approved by the institutional review board. After obtaining an informed consent, 25 patients with low back pain due to failed back syndrome were randomly assigned to receive a transforaminal epidural injection of hyaluronidase 1500 IU (HYL) or normal saline (NSL) to a mixture of bupivacaine 0.5% (1 mL) and triamcinolone 40 mg (1 mL) in a double-blind fashion. An interventional pain specialist using fluoroscopic guidance performed all epidural injections. The patients received a comprehensive neurological examination by a non-interventional pain specialist who was blinded to the treatment during their follow-up visits, scheduled one, 2, and 4 weeks after the intervention. Numerical pain scores, analgesic requirement, and satisfaction scores were recorded during every visit. RESULTS: There was no difference in demographic data between the 2 groups. Pain scores and total analgesic requirement were significantly lower in the HYL group at 2 and 4 weeks after blockade (P < 0.01). Patient satisfaction was higher in the HYL group. LIMITATIONS: The study was limited by a relatively small sample size. CONCLUSION: We conclude that adding hyaluronidase to the epidural injectate was effective in the management of chronic low back pain in patients with failed back surgery syndrome demonstrated over a period of 4 weeks.

Cardiac output monitoring devices: an analytic review.

To evaluate cardiac output (CO), both invasive and semi-invasive monitors are used in critical care medicine. The pulmonary artery catheter is an invasive tool to assess CO with the major criticism that the level of its invasiveness is not supported by an improvement in patients' outcomes. The interest in a lesser invasive techniques is high. Therefore, alternative techniques have been developed recently, and are used frequently in critical care medicine. Cardiac output can be monitored continuously by different devices that analyze the stroke volume and CO. The purpose of this review is to understand these new technologies and their applications and limitations.