RESUMEN
Cardiac arrest (CA) results in global ischemia-reperfusion injury damaging tissues in the whole body. The landscape of therapeutic interventions in resuscitation medicine has evolved from focusing solely on achieving return of circulation to now exploring options to mitigate brain injury and preserve brain function after CA. CA pathology includes mitochondrial damage and endoplasmic reticulum stress response, increased generation of reactive oxygen species, neuroinflammation, and neuronal excitotoxic death. Current non-pharmacologic therapies, such as therapeutic hypothermia and extracorporeal cardiopulmonary resuscitation, have shown benefits in protecting against ischemic brain injury and improving neurological outcomes post-CA, yet their application is difficult to institute ubiquitously. The current preclinical pharmacopeia to address CA and the resulting brain injury utilizes drugs that often target singular pathways and have been difficult to translate from the bench to the clinic. Furthermore, the limited combination therapies that have been attempted have shown mixed effects in conferring neuroprotection and improving survival post-CA. The global scale of CA damage and its resultant brain injury necessitates the future of CA interventions to simultaneously target multiple pathways and alleviate the hemodynamic, mitochondrial, metabolic, oxidative, and inflammatory processes in the brain. This narrative review seeks to highlight the current field of post-CA neuroprotective pharmaceutical therapies, both singular and combination, and discuss the use of an extensive multi-drug cocktail therapy as a novel approach to treat CA-mediated dysregulation of multiple pathways, enhancing survival, and neuroprotection.
RESUMEN
STUDY OBJECTIVE: To identify whether adding intrathecal ketamine to intrathecal bupivacaine prolongs the time to first analgesic request in adult humans. DESIGN: A meta-analysis of randomized controlled trials in humans. SETTING: The majority of data was obtained in an operating room and postoperative recovery area. PATIENTS: A total of 750 ASA physical status I and II patients were included in the study. Procedures performed include: cesarean section, lower abdominal surgery, lower limb surgery, and urologic surgery. INTERVENTIONS: Databases including PubMed, Embase, Web of Science, and Cochrane were searched. Google Scholar was also queried. Multiple reviewers screened the papers for inclusion. MEASUREMENTS: The primary outcome assessed was time to first analgesic request. Secondary outcomes included onset of sensory blockade, onset of motor blockade, duration of sensory blockade, and duration of motor blockade. Data were extracted to include means, 95% confidence intervals, tests for heterogeneity, and use of the Cochrane Collaboration guidelines to assess for publication bias. MAIN RESULTS: Eleven randomized controlled trials met inclusion criteria. When comparing intrathecal bupivacaine plus ketamine to intrathecal bupivacaine alone, the time to first analgesic request was prolonged (effect size = 58.23 min (95% CI 37.36 to 79.10) p < 0.0001). Secondary outcomes showed the onset time of sensory blockade was shortened (effect size = -0.87 min (95% CI -1.361 to 0.378) p = 0.0005), the onset time of motor blockade was reduced (effect size = -0.88 min (95% CI -1.77 to 0.013) p = 0.05), the duration of sensory blockade was prolonged (effect size = 39.73 min (95% CI 15.97 to 63.50) p = 0.001), and the duration of motor blockade was prolonged (effect size = 4.02 min (95% CI 3.27 to 4.78) p < 0.0001). Studies were shown to have high heterogeneity. Egger tests for all outcomes were non-significant and funnel plots assessing publication bias were all asymmetrical. CONCLUSIONS: The studies analyzed suggest there may be a benefit to using intrathecal ketamine as an adjunct to bupivacaine. Additional studies are warranted to optimize dosing, clarify the safety and efficacy of this intrathecal drug combination, and examine the various ketamine formulations as intrathecal bupivacaine adjuvants.