Antipsychotics in the Treatment of Delirium in Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To conduct a systematic review and meta-analysis assessing whether the use of antipsychotic medications in critically ill adult patients with delirium impacts patient-important outcomes. DATA SOURCES: A medical librarian searched Ovid MEDLINE, EMBASE, APA PsycInfo, and Wiley's Cochrane Library as well as clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform up to November 2023. STUDY SELECTION: Independently and in duplicate, reviewers screened abstracts and titles for eligibility, then full text of qualifying studies. We included parallel-group randomized controlled trials (RCTs) that included critically ill adult patients with delirium. The intervention group was required to receive antipsychotic medications at any dose, whereas the control group received usual care or placebo. DATA EXTRACTION: Reviewers extracted data independently and in duplicate using a piloted abstraction form. Statistical analyses were conducted using RevMan software (version 5.4). DATA SYNTHESIS: Five RCTs ( n = 1750) met eligibility criteria. The use of antipsychotic medications compared with placebo did not increase the number of delirium- or coma-free days (mean difference 0.90 d; 95% CI, -0.32 to 2.12; moderate certainty), nor did it result in a difference in mortality, duration of mechanical ventilation, ICU, or hospital length of stay. The use of antipsychotics did not result in an increased risk of adverse events (risk ratio 1.27; 95% CI, 0.71-2.30; high certainty). Subgroup analysis of typical versus atypical antipsychotics did not identify any subgroup effect for any outcome. CONCLUSIONS: In conclusion, our systematic review and meta-analysis demonstrated with moderate certainty that there is no difference in delirium- or coma-free days when delirious critically ill adults are treated with antipsychotic medications. Further studies in the subset of patients with hyperactive delirium may be of benefit.

Introducing helmet non-invasive ventilation during COVID-19 pandemic: Early experience of two centres.

Purpose: The helmet is a novel interface for delivering non-invasive ventilation (NIV). We conducted a case series to characterize introduction of the helmet interface in both COVID and non-COVID patients at two-centres. Methods: We enrolled all patients with respiratory failure admitted to the Juravinski Hospital (Hamilton, Canada) and St. Joseph's Health Center (Syracuse, New York) between November 1, 2020 and June 30, 2021 who used the helmet interface (Intersurgical StarMed) as part of this introduction into clinical practice. We collected patient demographics, reason for respiratory failure, NIV settings, device-related complications and outcomes. We report respiratory therapist's initial experiences with the helmet using descriptive results. Results: We included 16 patients with a mean age of 64.3 ± 10.9 years. The most common etiology for respiratory failure was pneumonia (81.3%). The median duration of NIV during the ICU admission was 67.5 (15.3, 80.8) hours, with a mean maximum PS of 13.9 ± 6.6 cm H2O and a mean maximum PEEP of 10.4 ± 5.1 cm H20. Three patients (18.7%) did not tolerate the helmet. Ten (62.5%) patients ultimately required intubation, and 7 (43.4%) patients died while in the ICU. The most common reason for intubation was worsening hypoxia (70%). No adverse events related to the helmet were recorded. Conclusion: Over the 8-month period of this study, we found that the helmet was well tolerated in over 80% of patients, although, more than half ultimately required intubation. Randomized controlled trials with this device are required to fully assess the efficacy of this interface.

Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies.

BACKGROUND: Benzodiazepine use is associated with delirium, and guidelines recommend avoiding them in older and critically ill patients. Their perioperative use remains common because of perceived benefits. METHODS: We searched CENTRAL, MEDLINE, CINAHL, PsycInfo, and Web of Science from inception to June 2021. Pairs of reviewers identified randomised controlled trials and prospective observational studies comparing perioperative use of benzodiazepines with other agents or placebo in patients undergoing surgery. Two reviewers independently abstracted data, which we combined using a random-effects model. Our primary outcomes were delirium, intraoperative awareness, and mortality. RESULTS: We included 34 randomised controlled trials (n=4354) and nine observational studies (n=3309). Observational studies were considered separately. Perioperative benzodiazepines did not increase the risk of delirium (n=1352; risk ratio [RR] 1.43; 95% confidence interval [CI]: 0.9-2.27; I2=72%; P=0.13; very low-quality evidence). Use of benzodiazepines instead of dexmedetomidine did, however, increase the risk of delirium (five studies; n=429; RR 1.83; 95% CI: 1.24-2.72; I2=13%; P=0.002). Perioperative benzodiazepine use decreased the risk of intraoperative awareness (n=2245; RR 0.26; 95% CI: 0.12-0.58; I2=35%; P=0.001; very low-quality evidence). When considering non-events, perioperative benzodiazepine use increased the probability of not having intraoperative awareness (RR 1.07; 95% CI: 1.01-1.13; I2=98%; P=0.03; very low-quality evidence). Mortality was reported by one randomised controlled trial (n=800; RR 0.90; 95% CI: 0.20-3.1; P=0.80; very low quality). CONCLUSIONS: In this systematic review and meta-analysis, perioperative benzodiazepine use did not increase postoperative delirium and decreased intraoperative awareness. Previously observed relationships of benzodiazepine use with delirium could be explained by comparisons with dexmedetomidine. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42019128144.

Catheter management across patients with hematologic malignancies and catheter-related blood stream infections: a systematic review.

Catheter-related bloodstream infection (CRBSI) can lead to ICU admission in patients with hematologic malignancy (HM). Variability exists in the management of catheters given the need for long-term access and co-existing thrombocytopenia or coagulopathy. We conducted a systematic review to evaluate catheter management in patients with CRBSI. Literature searches were conducted up to December 20, 2021 across MEDLINE, EMBASE, CENTRAL, CINAHL, and PubMed. Observational studies and RCTs of adults (> 16) with HM were included. Our primary outcome was mortality and secondary outcomes included infection recurrence and ICU admission. We identified 23 studies (N = 2026 patients), of which 22 were observational. Across the 12 studies (N = 801) that reported on bacterial organisms, 528 (65.9%) were gram positive, and 273 (34.1%) were gram negative. Catheters were removed in 1266 (62%) and retained in 760 (38%) patients. Removal was associated with a mean 30-day mortality of 13.14% (SD 9.12; 90/685) and reinfection rate of 5.49% (SD 2.88; 22/401) compared to 39.23% (SD 14.58; 122/311) and 10.75% (SD 21.07; 10/93), respectively, if retained. Catheter retention may be associated with a higher risk of mortality and infection recurrence. Further prospective research should assess catheter management in this population, including potential harms associated with retention.

Internal jugular vein ultrasound for the diagnosis of hypovolemia and hypervolemia in acutely ill adults: a systematic review and meta-analysis.

Accurate volume status assessments allow physicians to rapidly implement therapeutic measures in acutely unwell patients. However, existing bedside diagnostic tools are often unreliable for assessing intravascular volume. We searched PUBMED, EMBASE, CENTRAL, and Web of Science for English language articles without date restrictions on January 20, 2022. Studies reporting the diagnostic accuracy of IJV-US for hypovolemia and/or hypervolemia in an acute care setting were screened for inclusion. We included studies using any method of IJV-US assessment as the index test, compared against any reference standard. We fitted hierarchical summary receiver operating characteristic (HSROC) models for meta-analysis of diagnostic test accuracy, separately for hypovolemia and hypervolemia. Two reviewers independently extracted data and assessed risk of bias using QUADAS-2. We assessed certainty of evidence using the GRADE approach. A total of 26 studies were included, of which 19 studies (956 patients) examined IJV-US for hypovolemia and 13 studies (672 patients) examined IJV-US for hypervolemia. For the diagnosis of hypovolemia, IJV-US had a pooled sensitivity of 0.82 (95% CI 0.76 to 0.87; moderate-certainty evidence) and specificity of 0.82 (95% CI 0.73 to 0.88; moderate-certainty evidence). Measurement of IJV collapsibility indices had higher diagnostic accuracy (sensitivity 0.85, 95% CI 0.80 to 0.89; specificity 0.78, 95% CI 0.64 to 0.88) than static IJV indices (sensitivity 0.73, 95% CI 0.60 to 0.82; specificity 0.70, 95% CI 0.48 to 0.86). For the diagnosis of hypervolemia, IJV-US had a pooled sensitivity of 0.84 (95% CI 0.70 to 0.92; moderate-certainty evidence) and specificity of 0.70 (95% CI 0.55 to 0.82; very low-certainty evidence). IJV-US has moderate sensitivity and specificity for the diagnosis of hypervolemia and hypovolemia. Randomized controlled trials are needed to determine the role of IJV-US for guiding therapeutic interventions aimed at optimizing volume status.

Dexmedetomidine vs other sedatives in critically ill mechanically ventilated adults: a systematic review and meta-analysis of randomized trials.

Conventional gabaminergic sedatives such as benzodiazepines and propofol are commonly used in mechanically ventilated patients in the intensive care unit (ICU). Dexmedetomidine is an alternative sedative that may achieve lighter sedation, reduce delirium, and provide analgesia. Our objective was to perform a comprehensive systematic review summarizing the large body of evidence, determining if dexmedetomidine reduces delirium compared to conventional sedatives. We searched MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov and the WHO ICTRP from inception to October 2021. Independent pairs of reviewers identified randomized clinical trials comparing dexmedetomidine to other sedatives for mechanically ventilated adults in the ICU. We conducted meta-analyses using random-effects models. The results were reported as relative risks (RRs) for binary outcomes and mean differences (MDs) for continuous outcomes, with corresponding 95% confidence intervals (CIs). In total, 77 randomized trials (n = 11,997) were included. Compared to other sedatives, dexmedetomidine reduced the risk of delirium (RR 0.67, 95% CI 0.55 to 0.81; moderate certainty), the duration of mechanical ventilation (MD - 1.8 h, 95% CI - 2.89 to - 0.71; low certainty), and ICU length of stay (MD - 0.32 days, 95% CI - 0.42 to - 0.22; low certainty). Dexmedetomidine use increased the risk of bradycardia (RR 2.39, 95% CI 1.82 to 3.13; moderate certainty) and hypotension (RR 1.32, 95% CI 1.07 to 1.63; low certainty). In mechanically ventilated adults, the use of dexmedetomidine compared to other sedatives, resulted in a lower risk of delirium, and a modest reduction in duration of mechanical ventilation and ICU stay, but increased the risks of bradycardia and hypotension.

Venous and arterial thrombosis in COVID-19: An updated narrative review.

Hospitalized patients with coronavirus disease 2019 (COVID-19), particularly those admitted to the intensive care unit (ICU) are at high risk of morbidity and mortality. Several observational studies have described hemostatic derangements and thrombotic complications in patients with COVID-19. The aim of this review article is to summarize the current evidence on pathologic findings, pathophysiology, coagulation and hemostatic abnormalities, D-dimer's role in prognostication epidemiology and risk factors of thrombotic complications, and the role of prophylactic and therapeutic anticoagulation in patients with COVID-19. While existing evidence is limited in quality, COVID-19 appears to increase micro-and macro-vascular thrombosis rates in hospitalized and critically ill patients, which may contribute to the burden of disease. D-dimer can be used for risk stratification of hospitalized patients, but its role to guide anticoagulation therapy remains unclear. Evidence of higher quality is needed to address the role of therapeutic anticoagulation or high-intensity venous thromboembolism prophylaxis in COVID-19 patients. TAKE-HOME POINTS.

Secondary Infection Risk in Patients With Severe COVID-19 Pneumonia Treated With Tocilizumab.

BACKGROUND: Severe SARS-CoV-2 (COVID) pneumonia is characterized by marked inflammation. Current guidelines recommend the addition of the tocilizumab to dexamethasone in critically ill patients. In randomized trials, the use of tocilizumab was not associated with a statistically significant increased risk of secondary infections but concerns remain. STUDY QUESTION: Do patients with severe COVID pneumonia treated with tocilizumab experienced high rates of secondary infection. STUDY DESIGN: We performed a retrospective electronic chart review of patients with COVID pneumonia who received tocilizumab and dexamethasone (n = 62) from January 2021 to October 2021 and compared them with a cohort of patients (n = 49) who received only dexamethasone and admitted from July 2020 to December 2020 (before institutional use of tocilizumab). Patients received tocilizumab only if they had acute hypoxic respiratory failure and were felt to be clinically worsening. Patients were deemed to have a secondary infection only if a diagnosis of infection was confirmed via positive cultures. RESULTS: Sixty-six patients received tocilizumab; of which, 30 (45.5%) subsequently had culture-positive secondary infections compared with 24.5% of controls. Thirty-one patients (47.0%) who received tocilizumab died by the time of analysis, 14 (45.2%) of whom had a secondary infection. Gram-negative bacterial infections predominated, followed by fungal infections. Patients who received tocilizumab had over twice as many gram-negative pneumonias (30.3% vs. 14.3%). CONCLUSIONS: Patients with severe COVID pneumonia treated with tocilizumab experienced high rates of secondary infection. Although the benefit of tocilizumab in reducing mortality is well-established and almost certainly outweighs secondary infection risks, we question if the "real-world" infection rates are much higher than those reported in trials or if the infection risk could be mitigated with dose reductions in tocilizumab without losing the mortality benefit. Further study into the infection risk, and risk-benefit analysis of dose adjustments, of tocilizumab in the critical care setting is warranted.

The Usefulness of the Rapid Shallow Breathing Index in Predicting Successful Extubation: A Systematic Review and Meta-analysis.

BACKGROUND: Clinicians use several measures to ascertain whether individual patients will tolerate liberation from mechanical ventilation, including the rapid shallow breathing index (RSBI). RESEARCH QUESTION: Given varied use of different thresholds, patient populations, and measurement characteristics, how well does RSBI predict successful extubation? STUDY DESIGN AND METHODS: We searched six databases from inception through September 2019 and selected studies reporting the accuracy of RSBI in the prediction of successful extubation. We extracted study data and assessed quality independently and in duplicate. RESULTS: We included 48 studies involving RSBI measurements of 10,946 patients. Pooled sensitivity for RSBI of < 105 in predicting extubation success was moderate (0.83 [95% CI, 0.78-0.87], moderate certainty), whereas specificity was poor (0.58 [95% CI, 0.49-0.66], moderate certainty) with diagnostic ORs (DORs) of 5.91 (95% CI, 4.09-8.52). RSBI thresholds of < 80 or 80 to 105 yielded similar sensitivity, specificity, and DOR. These findings were consistent across multiple subgroup analyses reflecting different patient characteristics and operational differences in RSBI measurement. INTERPRETATION: As a stand-alone test, the RSBI has moderate sensitivity and poor specificity for predicting extubation success. Future research should evaluate its role as a permissive criterion to undergo a spontaneous breathing trial (SBT) for patients who are at intermediate pretest probability of passing an SBT. TRIAL REGISTRY: PROSPERO; No.: CRD42020149196; URL: www.crd.york.ac.uk/prospero/.

The role of eosinophils in sepsis and acute respiratory distress syndrome: a scoping review.

PURPOSE: Septic shock and acute respiratory distress syndrome (ARDS) are characterized by a dysregulated immune host response that may respond to steroid therapy. Eosinophils contribute to type 2 inflammation that often responds to steroid therapy; their role in immune dysregulation and outcomes in sepsis and ARDS is unclear. SOURCE: A systematic search of Cochrane Library, MEDLINE, and EMBASE was performed from inception to 9 September 2020. The search comprised the following terms: eosinophils, sepsis, septic shock, and ARDS. Two reviewers independently screened abstracts and texts and extracted data on disease severity and clinical outcomes. PRINCIPAL FINDINGS: Thirty-nine studies were identified: 30 evaluated serum eosinophil count in sepsis, one evaluated eosinophil activity in sepsis, three assessed bronchoalveolar lavage (BAL) eosinophil count in ARDS, four assessed eosinophil activity in ARDS, and one assessed peripheral eosinophil count in ARDS. Eleven studies showed an association between eosinopenia and sepsis, and eight studies found persistent eosinopenia at > 48 hr of intensive care unit admission to predict mortality and readmission in septic patients. Three studies found BAL eosinophil count to be low in ARDS, although one found that levels rose in late-phase ARDS. Three studies found eosinophil activity markers in BAL to be high in ARDS and correlate with ARDS severity. CONCLUSION: Persistent peripheral eosinopenia is a marker of bacterial sepsis and is independently associated with poor outcomes. Bronchoalveolar lavage eosinophil counts are low in early-phase ARDS, but increase in late-phase ARDS, while elevated markers of eosinophil activity correlate with ARDS severity. Further studies understanding the mechanisms leading to eosinopenia in sepsis and increased eosinophil activity in ARDS are needed.

RéSUMé: OBJECTIF: Le choc septique et le syndrome de détresse respiratoire aiguë (SDRA, ARDS en anglais) se caractérisent par une réponse immunitaire dérégulée chez l'hôte qui pourrait répondre à une corticothérapie. Les éosinophiles contribuent à l'inflammation de type 2, laquelle répond souvent à la corticothérapie; leur rôle dans la dérégulation immunitaire et les devenirs en cas de sepsis et de SDRA n'est pas clair. SOURCE: Une recherche systématique dans les bases de données Cochrane Library, MEDLINE et EMBASE a été réalisée de leur création au 9 septembre 2020. La recherche comprenait les termes suivants : éosinophiles, sepsis, choc septique et SDRA. Deux réviseurs ont examiné de manière indépendante les résumés et textes et ont extrait les données décrivant la gravité de la maladie et les devenirs cliniques. CONSTATATIONS PRINCIPALES: Trente-neuf études ont été identifiées : 30 études portaient sur le décompte d'éosinophiles sériques lors de sepsis, une étude examinait l'activité des éosinophiles dans un contexte de sepsis, trois ont évalué le décompte d'éosinophiles par lavage bronchoalvéolaire (LBA) dans les cas de SDRA, quatre ont examiné l'activité des éosinophiles dans le SDRA, et une a évalué le décompte d'éosinophiles périphériques dans les cas de SDRA. Onze études ont montré une association entre l'éosinopénie et le sepsis, et huit études ont remarqué qu'une éosinopédie persistante pour plus de 48 heures après l'admission à l'unité de soins intensifs était un prédicteur de mortalité et de réadmission chez les patients septiques. Trois études ont révélé que le nombre d'éosinophiles dans un LBA était faible en cas de SDRA, bien qu'une étude ait constaté que les taux augmentaient dans les SDRA de phase tardive. Trois études ont révélé que les marqueurs d'activité éosinophilique dans les LBA étaient élevés dans les cas de SDRA et étaient corrélés à la gravité du SDRA. CONCLUSION: L'éosinopénie périphérique persistante est un marqueur de sepsis bactérien et est indépendamment associée à de mauvais pronostics. Les décomptes d'éosinophiles dans les lavages bronchoalvéolaires sont bas dans les cas de SDRA en phase précoce, mais augmentent dans le SDRA en phase tardive, alors que des marqueurs élevés d'activité éosinophilique sont corrélés à la sévérité du SDRA. D'autres études visant à comprendre les mécanismes menant à l'éosinopénie dans le sepsis et à l'augmentation de l'activité éosinophilique dans le SDRA sont nécessaires.

Safety and Efficacy of Dexmedetomidine in Acutely Ill Adults Requiring Noninvasive Ventilation: A Systematic Review and Meta-analysis of Randomized Trials.

BACKGROUND: Although clinical studies have evaluated dexmedetomidine as a strategy to improve noninvasive ventilation (NIV) comfort and tolerance in patients with acute respiratory failure (ARF), their results have not been summarized. RESEARCH QUESTION: Does dexmedetomidine, when compared with another sedative or placebo, reduce the risk of delirium, mortality, need for intubation and mechanical ventilation, or ICU length of stay (LOS) in adults with ARF initiated on NIV in the ICU? STUDY DESIGN AND METHODS: We electronically searched MEDLINE, EMBASE, and the Cochrane Library from inception through July 31, 2020, for randomized clinical trials (RCTs). We calculated pooled relative risks (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes with the corresponding 95% CIs using a random-effect model. RESULTS: Twelve RCTs were included in our final analysis (n = 738 patients). The use of dexmedetomidine, compared with other sedation strategies or placebo, reduced the risk of intubation (RR, 0.54; 95% CI, 0.41-0.71; moderate certainty), delirium (RR, 0.34; 95% CI, 0.22-0.54; moderate certainty), and ICU LOS (MD, -2.40 days; 95% CI, -3.51 to -1.29 days; low certainty). Use of dexmedetomidine was associated with an increased risk of bradycardia (RR, 2.80; 95% CI, 1.92-4.07; moderate certainty) and hypotension (RR, 1.98; 95% CI, 1.32-2.98; moderate certainty). INTERPRETATION: Compared with any sedation strategy or placebo, dexmedetomidine reduced the risk of delirium and the need for mechanical ventilation while increasing the risk of bradycardia and hypotension. The results are limited by imprecision, and further large RCTs are needed. TRIAL REGISTRY: PROSPERO; No.: 175086; URL: www.crd.york.ac.uk/prospero/.

Experiences of Bereaved Family Members Receiving Commemorative Paintings: A Qualitative Study.

Importance: Although family members of patients who die in the intensive care unit commonly experience long-term psychological distress, end-of-life bereavement support programs for such relatives are uncommon. Whether art influences the grief experience of families is largely unexplored. Objective: To explore the influence of personalized paintings created to honor deceased critically ill patients on family members' bereavement experience. Design, Setting, and Participants: A qualitative descriptive analysis was conducted of semistructured interviews of grieving relatives who received a painting after the death of their loved one. The deceased patients were from a 21-bed medical-surgical intensive care unit. Eleven families were invited to receive a painting, of whom 1 family declined. A total of 22 family members of 10 patients who died in the intensive care unit were interviewed in the study between July 11, 2017, and May 19, 2019. Interventions: Patients were enrolled in an end-of-life care program that elicits and implements wishes of patients and their families to bring peace during the dying process. Selected families of 10 decedents were invited to receive a painting to honor their loved one 1 to 10 months after the patient's death. Using details about the patient's life story, the artist created individualized paintings to commemorate each patient. Main Outcomes and Measures: The experiences of family members receiving a personalized painting and its reported influence on their grieving experience. Results: The family members of 10 decedents (mean [SD] age, 60 [14] years; 5 women [50%]; 8 White patients [80%]) were interviewed. The central theme of art to facilitate healing was illustrated through the following domains: the cocreation process, painting narratives, postmortem connections, and legacy. The process of cocreating the paintings with the artist and family members involved reminiscing, storytelling, and creativity. Family members emphasized the role of art to facilitate healing, exemplified through connections with images portrayed that deeply resonated with memories of their loved one. Participants indicated that the paintings validated that the patient was remembered, helped families feel less alone during a time of grief, honored the loved one's life, and enhanced connections between family members and clinicians. Conclusions and Relevance: This qualitative study's findings suggest that the creation of personalized paintings commemorating the lives of patients may help foster legacy and postmortem connections with clinicians and may help family members in their healing process.

Gene splicing of an invertebrate beta subunit (LCavß) in the N-terminal and HOOK domains and its regulation of LCav1 and LCav2 calcium channels.

The accessory beta subunit (Ca(v)ß) of calcium channels first appear in the same genome as Ca(v)1 L-type calcium channels in single-celled coanoflagellates. The complexity of this relationship expanded in vertebrates to include four different possible Ca(v)ß subunits (ß1, ß2, ß3, ß4) which associate with four Ca(v)1 channel isoforms (Ca(v)1.1 to Ca(v)1.4) and three Ca(v)2 channel isoforms (Ca(v)2.1 to Ca(v)2.3). Here we assess the fundamentally-shared features of the Ca(v)ß subunit in an invertebrate model (pond snail Lymnaea stagnalis) that bears only three homologous genes: (LCa(v)1, LCa(v)2, and LCa(v)ß). Invertebrate Ca(v)ß subunits (in flatworms, snails, squid and honeybees) slow the inactivation kinetics of Ca(v)2 channels, and they do so with variable N-termini and lacking the canonical palmitoylation residues of the vertebrate ß2a subunit. Alternative splicing of exon 7 of the HOOK domain is a primary determinant of a slow inactivation kinetics imparted by the invertebrate LCa(v)ß subunit. LCa(v)ß will also slow the inactivation kinetics of LCa(v)3 T-type channels, but this is likely not physiologically relevant in vivo. Variable N-termini have little influence on the voltage-dependent inactivation kinetics of differing invertebrate Ca(v)ß subunits, but the expression pattern of N-terminal splice isoforms appears to be highly tissue specific. Molluscan LCa(v)ß subunits have an N-terminal "A" isoform (coded by exons: 1a and 1b) that structurally resembles the muscle specific variant of vertebrate ß1a subunit, and has a broad mRNA expression profile in brain, heart, muscle and glands. A more variable "B" N-terminus (exon 2) in the exon position of mammalian ß3 and has a more brain-centric mRNA expression pattern. Lastly, we suggest that the facilitation of closed-state inactivation (e.g. observed in Ca(v)2.2 and Ca(v)ß3 subunit combinations) is a specialization in vertebrates, because neither snail subunit (LCa(v)2 nor LCa(v)ß) appears to be compatible with this observed property.