Search

Objective: Blood transfusions are given to approximately one-fifth of patients undergoing elective lumbar spine surgery, and previous studies have shown that transfusions are accompanied by increased complications and additional costs. One method for decreasing transfusions is administration of tranexamic acid (TXA). The authors sought to evaluate whether the cost of TXA is offset by the decrease in blood utilization in lumbar spine surgery patients., Methods: The authors retrospectively reviewed patients who underwent elective lumbar or thoracolumbar surgery for degenerative conditions at a tertiary care center between 2016 and 2018. Patients who received intraoperative TXA (TXA patients) were matched with patients who did not receive TXA (non-TXA patients) by age, sex, BMI, ASA (American Society of Anesthesiologists) physical status class, and surgical invasiveness score. Primary endpoints were intraoperative blood loss, number of packed red blood cell (PRBC) units transfused, and total hemostasis costs, defined as the sum of TXA costs and blood transfusion costs throughout the hospital stay. A subanalysis was then performed by substratifying both cohorts into short-length (1-4 levels) and long-length (5-8 levels) spinal constructs., Results: Of the 1353 patients who met inclusion criteria, 68 TXA patients were matched to 68 non-TXA patients. Patients in the TXA group had significantly decreased mean intraoperative blood loss (1039 vs 1437 mL, p = 0.01). There were no differences between the patient groups in the total costs of blood transfusion and TXA (p = 0.5). When the 2 patient groups were substratified by length of construct, the long-length construct group showed a significant net cost savings of $328.69 per patient in the TXA group (p = 0.027). This result was attributable to the finding that patients undergoing long-length construct surgeries who were given TXA received a lower amount of PRBC units throughout their hospital stay (2.4 vs 4.0, p = 0.007)., Conclusions: TXA use was associated with decreased intraoperative blood loss and significant reductions in total hemostasis costs for patients undergoing surgery on more than 4 levels. Furthermore, the use of TXA in patients who received short constructs led to no additional net costs. With the increasing emphasis put on value-based care interventions, use of TXA may represent one mechanism for decreasing total care costs, particularly in the cases of larger spine constructs.

Objectives: To review the neurocritical care aspects of patients supported by extracorporeal membrane oxygenation, including cerebral physiology, neurologic monitoring, use of sedatives and anti-seizure medications, and prevalence and management of extracorporeal membrane oxygenation associated brain injury., Data Sources: PubMed database search using relevant search terms related to neurologic complications, neurocritical care management, and brain injury management in patients with extracorporeal membrane oxygenation., Study Selection: Articles included original investigations, review articles, consensus statements and guidelines., Data Extraction: A detailed review of publications performed and relevant publications were summarized., Data Synthesis: We found no practice guidelines or management strategies for the neurocritical care of extracorporeal membrane oxygenation patients. Such patients are at high risk for hypoxic-ischemic brain injury, intracranial hemorrhage, cerebral edema, and brain death. Improving clinical outcomes will depend on better defining the neurologic complications and underlying pathophysiology that are specific to extracorporeal membrane oxygenation. Currently, insufficient understanding of the pathophysiology of neurologic complications prevents us from addressing their etiologies with specific, targeted monitoring techniques and interventions., Conclusions: A large knowledge gap exists in our understanding and treatment of extracorporeal membrane oxygenation-related neurologic complications. A systematic and multidisciplinary approach is needed to reduce the prevalence of these complications and to better manage the neurologic sequelae of extracorporeal membrane oxygenation in a way that will improve patient outcomes.

Purpose: Optimization of antifungal therapy with voriconazole can be challenging due to inter- and intrapatient variability in voriconazole pharmacokinetics (PK). In this case, we introduce challenges in voriconazole therapy due to drug-drug interactions, autoinduction, and saturable metabolism., Summary: A 32-year-old male on chronic prednisone developed central nervous system (CNS) aspergillosis. He was started on high-dose intravenous (IV) voriconazole 8.5 mg/kg every 12 hours due to concerns for lasting induction effects of recent rifampin therapy. The initial voriconazole trough was 2 μg/mL. Frequent dose adjustments were made to maintain the therapeutic trough goal. On day 24 of voriconazole therapy, his trough was undetectable on IV voriconazole 5.5 mg/kg every 12 hours. His dose was escalated to 8.5 mg/kg every 12 hours to avoid subtherapeutic levels and therapeutic failure. On day 48, his trough level was 1.1 μg/mL on the same dose. His regimen was changed to 6.5 mg/kg every 8 hours at this point. Sixteen days after this regimen on day 74 of voriconazole therapy, his trough was 27.2 μg/mL indicating saturable PK of voriconazole in the absence of interacting drugs., Conclusion: Our findings highlight the unpredictable PK of voriconazole and reinforce the importance of continuous therapeutic drug monitoring in critically ill patients.

Purpose: The purpose of this analysis is to assess the effect of antiepileptics (AEDs) on seizure prevention and short and long term functional outcomes in patients with acute intracerebral hemorrhage., Method: The meta-analysis was conducted using the PRISMA guidelines. A literature search was performed of the PubMed, the Cochrane Library, and EMBASE databases. Search terms included "Anticonvulsants", "Intracerebral Hemorrhage", and related subject headings. Articles were screened and included if they were full-text and in English. Articles that did not perform multivariate regression were not included. Overall effect size was evaluated with forest plots and publication bias was assessed with the Begg's and Egger's tests., Results: A total of 3912 articles were identified during the initial review. After screening, 54 articles remained for full review and 6 articles were included in the final analysis. No significant association between the use of AEDs after ICH and functional outcome (OR 1.53 [95%CI: 0.81-2.88] P = 0.18, I 2  = 81.7%). Only one study evaluated the effect AEDs had in preventing post-ICH seizures., Conclusions: The use of prophylactic AEDs was not associated with improved short and long outcomes after acute ICH. This analysis supports the 2015 AHA/ASA recommendation against prophylactic AEDs (class III; level of evidence b)., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Rapid administration of hypertonic saline 23.4% is crucial in treatment of herniation syndromes. Hypertonic 23.4% saline must be administered via a central line. In cases where central line access is difficult to obtain and leads to delay in therapy, placement of intraosseous access can be lifesaving., Main Body: The purpose of this case series is to describe the use of intraosseous administration of 23.4% saline in critically ill patients and to assess feasibility., Conclusion: Intraosseous administration of 23.4% saline in 6 adult patients with neurological emergencies was feasible and should be considered in cases where obtaining intravenous access is time consuming.

Purpose of Review: To discuss recent updates in fluid management and use of hyperosmolar therapy in neurocritical care., Recent Findings: Maintaining euvolemia with crystalloids seems to be the recommended fluid resuscitation for neurocritical care patients. Buffered crystalloids have been shown to reduce hyperchloremia in patients with subarachnoid hemorrhage without causing hyponatremia or hypo-osmolality. In addition, in patients with traumatic brain injury, buffered solutions reduce the incidence of hyperchloremic acidosis but are not associated with intracranial pressure (ICP) alteration. Both mannitol and hypertonic saline are established as effective hyperosmolar agents to control ICP. Both agents have been shown to control ICP, but their effects on neurologic outcomes are unclear. A recent surge in preference for using hypertonic saline as a hyperosmolar agent is based on few studies without strong evidence., Summary: Fluid resuscitation with crystalloids seems to be reasonable in this setting although no recommendations can be made regarding type of crystalloids. Based on current evidence, elevated ICP can be effectively reduced by either hypertonic saline or mannitol.

Status epilepticus (SE) has a high mortality rate and is one of the most common neurologic emergencies. Fast progression of this neurologic emergency and lack of response to traditional antiepileptic drugs (AEDs) in most cases has challenged clinicians to use new agents. This article evaluates the efficacy and safety of AEDs released to the market after 2000 for SE, refractory status epilepticus (RSE), and super-refractory status epilepticus (SRSE). The PubMed database was searched for clinical trials published between January 2000 and July 2018 using the search terms status epilepticus, refractory status epilepticus, super refractory status epilepticus, brivaracetam, clobazam, cannabidiol, eslicarbazepine, lacosamide, perampanel, rufinamide, stiripentol, and zonisamide. Trials that evaluated these agents in adults with SE, RSE, and SRSE were included. Brivaracetam use was identified in two retrospective reviews with success rates of 27% and 57%. One unsuccessful case report of cannabidiol use in SE was found. Four clobazam studies were identified in SE and RSE with success rates ranging from 25-100%. No evidence for the use of eslicarbazepine and zonisamide was found. Using the search terms for lacosamide identified 38 articles: 1 systematic review, 5 prospective studies, 15 retrospective reviews, and 17 case reports. Success rates and dosing varied, but studies that included focal or partial types of SE showed higher success rates. Five articles were identified regarding perampanel use in this setting. Three were retrospective reviews with success rates ranging from 17-60%, and two were case reports. Only one case report regarding the use of rufinamide was found; rufinamide titrated up to 4.4 mg/day allowed discontinuation of barbiturate and clobazam. One case report and two case series of stiripentol were found with reported efficacy between 60% and 100% in SRSE. Evidence is currently insufficient to support the use of these agents in this setting., (© 2019 Pharmacotherapy Publications, Inc.)

Background: The incidence of seizures in intensive care units ranges from 3.3% to 34%. It is therefore often necessary to initiate or continue anticonvulsant drugs in this setting. When a new anticonvulsant is initiated, drug factors, such as onset of action and side effects, and patient factors, such as age, renal, and hepatic function, should be taken into account. It is important to note that the altered physiology of critically ill patients as well as pharmacological and nonpharmacological interventions such as renal replacement therapy, extracorporeal membrane oxygenation, and target temperature management may lead to therapeutic failure or toxicity. This may be even more challenging with the availability of newer antiepileptics where the evidence for their use in critically ill patients is limited., Main Body: This article reviews the pharmacokinetics and pharmacodynamics of antiepileptics as well as application of these principles when dosing antiepileptics and monitoring serum levels in critically ill patients. The selection of the most appropriate anticonvulsant to treat seizure and status epileptics as well as the prophylactic use of these agents in this setting are also discussed. Drug-drug interactions and the effect of nonpharmacological interventions such as renal replacement therapy, plasma exchange, and extracorporeal membrane oxygenation on anticonvulsant removal are also included., Conclusion: Optimal management of antiepileptic drugs in the intensive care unit is challenging given altered physiology, polypharmacy, and nonpharmacological interventions, and requires a multidisciplinary approach where appropriate and timely assessment, diagnosis, treatment, and monitoring plans are in place.

Purpose of Review: Pain management in neurocritical care is a subject often avoided because of concerns over the side-effects of analgesics and the potential to cause additional neurological injury with treatment. The sedation and hypercapnia caused by opioids have been feared to mask the neurological examination and contribute to elevations in intracranial pressure. Nevertheless, increasing attention to patient satisfaction has sparked a resurgence in pain management. As opioids have remained at the core of analgesic therapy, the increasing attention to pain has contributed to a growing epidemic of opioid dependence. In this review, we summarize the most recent literature regarding opioids and their alternatives in the treatment of acute pain in patients receiving neurocritical care., Recent Findings: Studies on pain management in neurocritical care continue to explore nonopioid analgesics as part of a multimodal strategy aimed at decreasing overall opioid consumption. Agents including local anesthetics, acetaminophen, ketamine, gabapentinoids, and dexmedetomidine continue to demonstrate efficacy. In addition, the prolonged longitudinal course of many recent trials has also revealed more about the transition from acute to chronic pain following hospitalization., Summary: In an era of increasing attention to patient satisfaction mitigated by growing concerns over the harms imposed by opioids, alternative analgesic therapies are being investigated with promising results.

Background: Refractory status epilepticus (RSE) has a high mortality rate and is often difficult to treat. When traditional therapies fail ketamine may be considered. There are limited reports of adverse cardiac events with the use of ketamine for RSE and no reports of cardiac arrest in this context., Objective: Evaluate the occurrence of cardiac arrhythmias associated with the use of ketamine for RSE., Methods: Retrospective chart review of nine patients who underwent ketamine infusion for RSE., Results: Etiology of refractory status epilepticus included autoimmune/infectious process (Zeiler et al., 2014), ischemic stroke (Bleck, 2005) and subarachnoid hemorrhage (Bleck, 2005). Of the nine patients who received ketamine, two had documented cardiac events; one remained clinically stable and the other developed multiple arrhythmias, including recurrent episodes of asystole. Once ketamine was discontinued the latter patient stabilized with the addition of anti arrhythmic therapy., Conclusion: Ketamine is utilized to treat refractory status epilepticus, but should be used with caution in patients with subarachnoid hemorrhage, as there may be an increased risk of life threatening arrhythmias and cardiac arrest., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The cessation (ischemia) and restoration (reperfusion) of cerebral blood flow after cardiac arrest (CA) induce inflammatory processes that can result in additional brain injury. Therapeutic hypothermia (TH) has been proven as a brain protective strategy after CA. In this article, the underlying pathophysiology of ischemia-reperfusion brain injury with emphasis on the role of inflammatory mechanisms is reviewed. Potential targets for immunomodulatory treatments and relevant effects of TH are also discussed. Further studies are needed to delineate the complex pathophysiology and interactions among different components of immune response after CA and identify appropriate targets for clinical investigations., Competing Interests: There are no conflicts of interest.

Drug-drug interactions (DDIs) are common and avoidable complications that are associated with poor patient outcomes. Neurocritical care patients may be at particular risk for DDIs due to alterations in pharmacokinetic profiles and exposure to medications with a high DDI risk. This review describes the principles of DDI pharmacology, common and severe DDIs in Neurocritical care, and recommendations to minimize adverse outcomes. A review of published literature was performed using PubMed by searching for 'Drug Interaction' and several high DDI risk and common neurocritical care medications. Key medication classes included anticoagulants, antimicrobials, antiepileptics, antihypertensives, sedatives, and selective serotonin reuptake inhibitors. Additional literature was also reviewed to determine the risk in neurocritical care and potential therapeutic alternatives. Clinicians should be aware of interactions in this setting, the long-term complications, and therapeutic alternatives.

Purpose: The frequency with which atypical antipsychotics initiated in the intensive care unit (ICU) is unknown. While there is lack of evidence to support the exact duration of treatment, antipsychotics should not be continued chronically for agitation and psychosis related to critical illness. The objective of this study was to determine whether atypical antipsychotics initiated in the ICU at a large tertiary academic medical center were continued after hospital discharge. Safety outcomes were also assessed., Materials: A total of 1023 patients who received atypical antipsychotics during ICU stay were identified. Patients were assessed in a pseudo-randomized fashion until a sample of 191 patients was reached. After review of the exclusion criteria, the final study population was 100 patients. When antipsychotics were discontinued, progress notes were reviewed to identify the reason for discontinuation. Safety outcomes were assessed based on physician documentation in the medical charts., Results: Atypical antipsychotics were continued in 23% of patients. Atypical antipsychotics were discontinued in 1 patient due to QTc prolongation., Conclusions: Atypical antipsychotics initiated in the ICU are frequently continued after hospital discharge. Given the known risks associated with extended therapy, initiatives are needed to prevent inappropriate continuation.

Background: Maternal and fetal Low Density Lipoprotein-Cholesterol (LDL-C) concentrations are compromised in intrauterine growth restriction (IUGR). Generally, LDL-C catabolism is under control of PCSK9 by binding to the LDL-receptor leading to its degradation. Hence, we hypothesized a role for PCSK9 in the modulation of lipid metabolism and placental transport in IUGR., Methods: 172 women, 70 IUGR and 102 controls were included in the study. Maternal and fetal serum PCSK9 levels and lipid profiles including LDL-C were measured. Placental LDL-receptor and PCSK9 expressions were estimated by tissue microarray immunohistochemistry, and analyzed by two blinded observers using an immunoreactivity score. Non-parametric tests and multivariate regression analyses were used for statistical estimations., Results: PCSK9 levels in the maternal and fetal compartment independently predicted LDL-C levels (maternal compartment: adjusted R 2  = 0.2526; coefficient b i  = 0.0938, standard error s bi =0.0217, r partial  = 0.4420, t-value = 4.323, p < 0.0001; fetal compartment: adjusted R 2  = 0.2929; b i  = 0.1156, s bi =0.020, r partial  = 0.5494, t-value = 5.81, p < 0.0001). We did not find significant differences in maternal PCSK9 concentrations between IUGR and controls. However, we found lower fetal serum PCSK9 concentrations in IUGR than in controls (IUGR median 137.1 ng/mL (95% CI 94.8-160.0) vs. controls 176.8 (154.6-202.5), p = 0.0005). When subgrouping according to early onset, late onset IUGR, and fetal gender differences remained consistent only for male neonates born before 34 weeks of gestation. In the placenta we found no correlation between PCSK9 and LDL-receptor expression patterns. However, the LDL-receptor was significantly upregulated in IUGR when compared to controls (p = 0.0063)., Conclusions: Our results suggest that PCSK9 play a role in impaired fetal growth by controlling fetal LDL-C metabolism, which seems to be dependent on gestational age and fetal gender. This underlines the need to identify subgroups of IUGR that may benefit from individualized and gender-specific pharmacotherapy in future studies.

Significance: The endothelium regulates vessel dilation and constriction, balances hemostasis, and inhibits thrombosis. In addition, pro- and anti-angiogenic molecules orchestrate proliferation, survival, and migration of endothelial cells. Regulation of all these processes requires fine-tuning of signaling pathways, which can easily be tricked into running the opposite direction when exogenous or endogenous signals get out of hand. Surprisingly, some critical regulators of physiological endothelial functions can turn malicious by mere alternative splicing, leading to the expression of protein isoforms with opposite functions., Recent Advances: While reviewing the evidence of alternative splicing on cellular physiology, it became evident that expression of splice factors and their activities are regulated by externally triggered signaling cascades. Furthermore, genome-wide identification of RNA-binding sites of splicing regulatory proteins now offer a glimpse into the splicing code responsible for alternative splicing of molecules regulating endothelial functions., Critical Issues: Due to the constantly growing number of transcript and protein isoforms, it will become more and more important to identify and characterize all transcripts and proteins regulating endothelial cell functions. One critical issue will be a non-ambiguous nomenclature to keep consistency throughout different laboratories., Future Directions: RNA-deep sequencing focusing on exon-exon junction needs to more reliably identify alternative splicing events combined with functional analyses that will uncover more splice variants contributing to or inhibiting proper endothelial functions. In addition, understanding the signals mediating alternative splicing and its regulation might allow us to derive new strategies to preserve endothelial function by suppressing or upregulating specific protein isoforms. Antioxid. Redox Signal. 22, 1212-1229.

Objective: Sister-of-Mammalian Grainyhead (SOM) is a member of the Grainyhead family of transcription factors. In humans, 3 isoforms are derived from differential first exon usage and alternative splicing and differ only in their N terminal domain. SOM2, the only variant also present in mouse, induces endothelial cell migration and protects against apoptosis. The functions of the human specific isoforms SOM1 and SOM3 have not yet been investigated. Therefore we wanted to elucidate their functions in endothelial cells., Approach and Results: Overexpression of SOM1 in primary human endothelial cells induced migration, phosphorylation of Akt1 and endothelial nitric oxide synthase, and protected against apoptosis, whereas SOM3 had opposite effects; isoform-specific knockdowns confirmed the disparate effects on apoptosis. After reporter assays demonstrated that both are active transcription factors, microarray analyses revealed that they induce different target genes, which could explain the different cellular effects. Overexpression of SOM3 in zebrafish embryos resulted in increased lethality and severe deformations, whereas SOM1 had no deleterious effect., Conclusions: Our data demonstrate that the splice variant-derived isoforms SOM1 and SOM3 induce opposing effects in primary human endothelial cells and in a whole animal model, most likely through the induction of different target genes.