Risk Stratification of QTc Prolongation in Critically Ill Patients Receiving Antipsychotics for the Management of Delirium Symptoms.

BACKGROUND: Patients experiencing significant agitation or perceptual disturbances related to delirium in an intensive care setting may benefit from short-term treatment with an antipsychotic medication. Some antipsychotic medications may prolong the QTc interval, which increases the risk of potentially fatal ventricular arrhythmias. In this targeted review, we describe the evidence regarding the relationships between antipsychotic medications and QTc prolongation and practical methods for monitoring the QTc interval and mitigating arrhythmia risk. METHODS: Searches of PubMed and Cochrane Library were performed to identify studies, published before February 2023, investigating the relationships between antipsychotic medications and QTc prolongation or arrhythmias. RESULTS: Most antipsychotic medications commonly used for the management of delirium symptoms (eg, intravenous haloperidol, olanzapine, quetiapine) cause a moderate degree of QTc prolongation. Among other antipsychotics, those most likely to cause QTc prolongation are iloperidone and ziprasidone, while aripiprazole and lurasidone appear to have minimal risk for QTc prolongation. Genetic vulnerabilities, female sex, older age, pre-existing cardiovascular disease, electrolyte abnormalities, and non-psychiatric medications also increase the risk of QTc prolongation. For individuals at risk of QTc prolongation, it is essential to measure the QTc interval accurately and consistently and consider medication adjustments if needed. CONCLUSIONS: Antipsychotic medications are one of many risk factors for QTc prolongation. When managing agitation related to delirium, it is imperative to assess an individual patient's risk for QTc prolongation and to choose a medication and monitoring strategy commensurate to the risks. In intensive care settings, we recommend regular ECG monitoring, using a linear regression formula to correct for heart rate. If substantial QTc prolongation (eg, QTc > 500 msec) is present, a change in pharmacologic treatment can be considered, though a particular medication may still be warranted if the risks of discontinuation (eg, extreme agitation, removal of invasive monitoring devices) outweigh the risks of arrhythmias. AIMS: This review aims to summarize the current literature on relationships between antipsychotic medications and QTc prolongation and to make practical clinical recommendations towards the approach of antipsychotic medication use for the management of delirium-related agitation and perceptual disturbances in intensive care settings.

C-L Case Conference: Torsades de Pointes in a Patient With Lifelong Medical Trauma, COVID-19, Remdesivir, Citalopram, Quetiapine, and Hemodialysis.

We present a case of Torsades de Pointes (TdP) in a patient with COVID-19 infection and multiple TdP risk factors including QT-interval prolongation, hemodialysis, bradycardia, and treatment with remdesivir, citalopram, and quetiapine. The case was complicated by post-resuscitation anxiety superimposed on a history of medical trauma since childhood. Top experts in the field of consultation-liaison psychiatry, trauma informed care, and cardiac electrophysiology provide perspectives on this case with a review of the literature. Key teaching topics include identification of TdP risk factors in patients with a complex illness; the necessity for prompt electrophysiology consultation in clinical scenarios with high risk for TdP; and the approach to patients with medical trauma using a trauma-informed lens. We highlight the contributions of COVID-19, the pharmacokinetics of QT-interval-prolonging psychotropic medications, the risks of hemodialysis, and the role of remdesivir-induced bradycardia in this first reported case of TdP in a patient treated with remdesivir.

Development and Pilot of a Process for Regularly Sharing Summary Patient Safety Data.

OBJECTIVE: Dissemination of patient safety data is key to understanding safety events and improving the quality of patient care. However, there is limited guidance on how psychiatry residency programs can create a supportive environment in which to disclose and discuss such information. The authors developed and piloted a resident-led Patient Safety Presentation process at an Accreditation Council for Graduate Medical Education-accredited psychiatry residency program, sharing patient safety data while enhancing residents' education and engagement in patient safety. METHODS: From September 2020 through February 2021, the authors convened a workgroup of psychiatry residents and faculty members to devise and conduct the presentation process. The process consisted of an introductory hour-long training of residents in patient safety concepts, followed a week later by the presentation by two psychiatry residents. The authors evaluated the pilot presentation process using pre- and post-presentation resident surveys. RESULTS: The introductory training and the Patient Safety Presentation were included into the didactic schedules of all 32 program residents. Twenty (62.5%) and 17 (53.1%) residents completed the pre- and post-presentation surveys, respectively. Improvements were seen in residents' knowledge regarding the medical center's patient safety practices and perspectives on patient safety practices. On the post-presentation survey, all 17 residents reported overall satisfaction with the presentation. CONCLUSIONS: The piloted Patient Safety Presentation process increased psychiatry residents' knowledge of and engagement in patient safety. The development and pilot of the presentation process serve as an illustrative case study for other residency programs that are aspiring to grow this aspect of their curriculum.

"Doctor" Badge Promotes Accurate Role Identification and Reduces Gender-Based Aggressions in Female Resident Physicians.

OBJECTIVE: Role misidentification among hospital staff is common. Female resident physicians are more likely to be misidentified as non-physicians. This study utilized a pre-post examination to determine if the usage of a "doctor" badge by resident physicians at a Veterans Affairs Medical Center influences role identification, gender-based aggressions, and workplace experience. METHODS: Twenty-six psychiatry residents at the Veterans Affairs Boston Healthcare System participated in a voluntary, anonymous electronic pre-survey in December 2020 and post-survey in March 2021 to report their experiences with role identification and gender-based aggressions before and after the implementation of a "doctor" badge. RESULTS: Females were significantly more likely than males to report role misidentification (x2(1)=10.8, p=0.001). Females were significantly more likely to experience gender-based aggressions compared to males (x2(1)=19.5, p<0.001). Compared to pre-intervention, females who wore the badge were significantly less likely to be misidentified (x2(1)=9.6, p=0.002). There was no significance when comparing males who were misidentified pre- to post-intervention (x2(1)=1.1, p=0.294). Compared to pre-intervention, females who wore the badge were significantly less likely to experience gender-based aggressions (x2(1)=17.3, p=<0.001). Compared to pre-intervention, there was no significant change in gender-based aggressions for males who wore the badge (x2(1)=1.05, p=0.306). CONCLUSIONS: Female residents were more likely than male residents to report role misidentification. Usage of the "doctor" badge resulted in improved role identification and a reduction in gender-based aggressions for females, but not males. "Doctor" badges can improve role identification, gender-based aggressions, workplace experience, patient communication, and care.

Assessment of QTc and Risk of Torsades de Pointes in Ventricular Conduction Delay and Pacing: A Review of the Literature and Call to Action.

BACKGROUND: Assessment of the heart rate-corrected QT-interval on the 12-lead electrocardiogram when prescribing medications known to increase the risk of Torsades de Pointes has become a common part of consultation-liaison psychiatry practice. OBJECTIVES: Highlighted by a patient who experienced psychiatric decompensation due to inaccurate interpretation of QTc prolongation in the setting of a wide QRS complex, we aimed to describe the approach to QTc interpretation in patients with ventricular conduction delay. METHODS: We reviewed the current literature on the approach to assessment of prolonged repolarization in patients with ventricular conduction delay due to bundle branch block (BBB) and ventricular pacing. RESULTS: Physicians of any specialty may perform initial electrocardiogram interpretation and should be proficient in the definition, recognition, and understanding of the basic pathophysiology of electrocardiographic abnormalities. We discuss current approaches to assessment of the QT-interval in patients with a wide QRS complex due to bundle branch block and ventricular pacing, including bivariate QTc modification, univariate QT-interval modifications, and use of the JT-interval. CONCLUSIONS: The QT-interval is prolonged ipso facto in patients with a wide QRS complex from ventricular conduction delay/ventricular pacing and must be adjusted for QRS duration. Multiple formulae have been proposed to account for wide QRS complex in this setting with no single universally accepted methodology. We suggest the use of either the Bogossian formula or JT-interval followed by Hodges or Framingham heart-rate correction to adjust for a wide QRS complex. It is critical that the C-L psychiatrist be able to identify a wide QRS complex on the electrocardiogram, understand implications for accurate assessment of prolonged depolarization, and apply an appropriate correction methodology.

What the Psychiatrist Needs to Know About Ventricular Assist Devices: A Comprehensive Review.

BACKGROUND: The number of patients with end-stage heart failure using mechanical circulatory support has dramatically increased over the past decade. Left ventricular assist devices, the most common type of mechanical circulatory support, can be used as a bridge to transplant, destination therapy, and as a bridge to recovery. As this patient population continues to grow, consultation-liaison psychiatrists will become increasingly involved in their care. A thorough biopsychosocial assessment is required to ensure adequate recognition and management of medical, psychiatric, social, and ethical challenges posed by this population. METHODS: We performed a literature review to identify key issues relevant to the practice of consultation-liaison psychiatrists. RESULTS: General functioning of left ventricular assist devices, device types, system components, life with a left ventricular assist device, preoperative evaluation, treatment of psychiatric comorbidities, and end-of-life decision-making are discussed. CONCLUSIONS: Consultation-liaison psychiatrists need to be familiar with the high prevalence of psychopathology in patients implanted with left ventricular assist devices. A detailed biopsychosocial formulation is required to adequately identify and, if possible, resolve a myriad of medical, psychiatric, social, and ethical challenges presented by this population. Future efforts should accurately identify and report specific psychiatric disorders and adverse events within this cohort.

Trichotillomania and Trauma: Dissociation and Alexithymia in a Case of Pregnancy Denial.

Pregnancy denial is rare yet reported and is often the result of complex psychosocial circumstances. We present an unusual case of pregnancy denial associated directly with both remote and ongoing trauma. A woman suddenly gave birth to a child in a hospital while visiting her other daughter, resulting in emergent labor and delivery as well as social work and psychiatric evaluation. Various atypical findings were noted, including pathological hair-pulling, alexithymia, indifference, and pregnancy denial. We offer a biopsychosocial conceptualization of the case, commenting on various possible processes including dissociation. The case also explores current states of knowledge regarding the interaction between impulse control disorders such as trichotillomania, dissociation, and trauma, with a call for future clinical and investigational attention to these interactions.

Protected from torsades de pointes? What psychiatrists need to know about pacemakers and defibrillators.

BACKGROUND: Consultation-liaison (C-L) psychiatrists are frequently asked to initiate and manage psychotropic drugs, some of which can delay cardiac repolarization, prolong the QT interval, and increase the risk of torsades de pointes (TdP). This task is complicated by the growing number of patients with cardiovascular implantable electronic devices (CIED) [i.e., permanent pacemakers (PPM), implantable cardioverter defibrillators (ICD), and cardiac resynchronization therapy devices (CRT)]. The precise protective role of CIEDs in the prevention and treatment of TdP is not well-defined. METHODS: We review practical tips for assessment of the QT interval in patients with paced rhythms, as well as the basic operative principles of CIEDs. We examine the available clinical evidence for the use of CIEDs in patients at risk for TdP. RESULTS: Most CIEDs have a pacing function that, when utilized appropriately, can offer partial protection against TdP by prevention of bradycardia. Defibrillators deliver shocks and are reasonably effective at terminating TdP; however, recurrent shocks are common and are associated with significant physical and psychological morbidity. CONCLUSIONS: CIEDs are important tools in the management of drug-induced ventricular arrhythmias in spite of significant limitations. The C-L psychiatrist should remain vigilant in recognizing and managing patients at risk for TdP, and refrain from over-reliance on CIEDs regardless of type or settings. Ultimately, the presence of a CIED should serve as a marker of increased risk of TdP.

A unified sample preparation protocol for proteomic and genomic profiling of cervical swabs to identify biomarkers for cervical cancer screening.

Cervical cancer screening is ideally suited for the development of biomarkers due to the ease of tissue acquisition and the well-established histological transitions. Furthermore, cell and biologic fluid obtained from cervix samples undergo specific molecular changes that can be profiled. However, the ideal manner and techniques for preparing cervical samples remains to be determined. To address this critical issue a patient screening protein and nucleic acid collection protocol was established. RNAlater was used to collect the samples followed by proteomic methods to identify proteins that were differentially expressed in normal cervical epithelial versus cervical cancer cells. Three hundred ninety spots were identified via 2-D DIGE that were expressed at either higher or lower levels (>three-fold) in cervical cancer samples. These proteomic results were compared to genes in a cDNA microarray analysis of microdissected neoplastic cervical specimens to identify overlapping patterns of expression. The most frequent pathways represented by the combined dataset were: cell cycle: G2/M DNA damage checkpoint regulation; aryl hydrocarbon receptor signaling; p53 signaling; cell cycle: G1/S checkpoint regulation; and the ER stress pathway. HNRPA2B1 was identified as a biomarker candidate with increased expression in cancer compared to normal cervix and validated by Western blot.

Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates.

This study is the first comprehensive, integrated approach to examine grade-specific changes in gene expression along the entire neoplastic spectrum of cervical intraepithelial neoplasia (CIN) in the process of cervical carcinogenesis. This was accomplished by identifying gene expression signatures of disease progression using cDNA microarrays to analyze RNA from laser-captured microdissected epithelium and underlying stroma from normal cervix, graded CINs, cancer, and patient-matched normal cervical tissues. A separate set of samples were subsequently validated using a linear mixed model that is ideal to control for interpatient gene expression profile variation, such as age and race. These validated genes were ultimately used to propose a genomically based model of the early events in cervical neoplastic transformation. In this model, the CIN 1 transition coincides with a proproliferative/immunosuppression gene signature in the epithelium that probably represents the epithelial response to human papillomavirus infection. The CIN 2 transition coincides with a proangiogenic signature, suggesting a cooperative signaling interaction between stroma and tumor cells. Finally, the CIN 3 and squamous cell carcinoma antigen transition coincide with a proinvasive gene signature that may be a response to epithelial tumor cell overcrowding. This work strongly suggests that premalignant cells experience a series of microenvironmental stresses at the epithelium/stroma cell interface that must be overcome to progress into a transformed phenotype and identifies the order of these events in vivo and their association with specific CIN transitions.

Identification of chromosomal alterations important in the development of cervical intraepithelial neoplasia and invasive carcinoma using alignment of DNA microarray data.

OBJECTIVE: To use microarray data to reveal regions of potential chromosomal loss or gain important in cervical intraepithelial neoplasia (CIN) and invasive cervical cancer by identifying mRNA expression biases in contiguous chromosomal regions. METHODS: Data from three RNA expression microarray experiments were used: one primary experiment using cDNA arrays profiling gene expression in cervical epithelium from viral cytopathic effect to invasive cancer, one experiment using Affymetrix arrays profiling gene expression in invasive cancerous cervical epithelium, and one experiment using Affymetrix arrays profiling gene expression in CIN cervical biopsy specimens. Gene expression was aligned along chromosomes to reveal regions of significant chromosomal imbalance. Regions showing significant gain or loss and verified in more than one experiment are presented here. RT-PCR was performed to validate expression of one gene in a region. RESULTS: Gain of 3q was detected from the CIN II (P=0.018), CIN III (P=0.005), and invasive cancer (P=0.0002) cDNA arrays, and gain of 12q was detected from the CIN (P=0.05) and invasive cancer (P=0.05) Affymetrix arrays. Loss of 6p was detected from the CIN III (P=0.004) cDNA arrays and invasive cancer (P=0.05) Affymetrix arrays. Loss of 4q was detected from the invasive cancer (P=0.04) cDNA arrays and invasive cancer (P=0.05) Affymetrix arrays. RAN, located in the region of gain on 12q24.3, was overexpressed in CIN and invasive cancer. CONCLUSIONS: Alignment of microarray expression data by chromosomes can be used to estimate regions of potential chromosomal aberration and identify differentially expressed genes important in the development of CIN and invasive cancer.

IGSF4 promoter methylation and expression silencing in human cervical cancer.

OBJECTIVES: Functional assays of tumor suppression and loss of heterozygosity point to a tumor suppressor gene (TSG) for cervical cancer (CC) on chromosome 11q23. We evaluated IGSF4, a putative TSG located in the region, for promoter methylation and gene silencing in CC cell lines and cervical tissues. METHODS: IGSF4 expression was detected by both RT-PCR and Northern blot analysis. Methylation maps of the IGSF4 promoter region were generated for 11 CC cell lines based upon bisulfite-genomic sequencing, using seven nested-PCR primer sets covering 97 CpG sites. Methylation fingerprints in primary cervical tissues were evaluated by denaturing high performance liquid chromatography. RESULTS: A 4.4-kb mRNA was seen in cell lines, consistent with the RT-PCR results for both cell lines and primary cervical tissue. IGSF4 was expressed in 6/11 cell lines, 6/8 CC tissues and in all seven normal cervical epithelia. In the cell lines, IGSF4 silencing was associated with promoter hypermethylation. The methylation status in the region covering the -18 to -2 CpG sites correlated most strongly with expression, pointing to the existence of an unmethylated core in the IGSF4 promoter in cell lines expressing IGSF4. This unmethylated core spans approximately 180 bp and is immediately upstream of the ATG site. In primary tissues, methylation was detected in 15/23 (65%) CC specimens but in none of seven normal cervical epithelia. CONCLUSIONS: Our data strongly suggest that IGSF4 is a TSG and that gene silencing by aberrant hypermethylation may contribute to the development of CC.

The effect of DNA damage on the formation of protein/DNA complexes.

Many cellular functions including gene expression and chromosome structure are highly dependent upon the precise recognition and binding of specific DNA elements by regulatory and structural proteins. DNA damage that alters protein/DNA interactions therefore has the potential to disrupt normal cellular functions including proliferation. As a model to examine the interaction of proteins with damaged DNA, the binding of AP-1 transcription factor to cognate DNA elements with 8-oxoadenine, 8-oxoguanine and abasic sites was studied by gel mobility shift analysis. Of the three types of DNA damage only 8-oxoadenine was without effect on AP-1 binding. A single 8-oxoguanine could partially inhibit AP-1 binding when located at specific positions within and even adjacent to the conserved AP-1 binding sequence. Abasic site damage also demonstrated a position effect but with more overall inhibition. When 8-oxoguanine and abasic sites were combined to model the multiple damage sites produced by ionizing radiation there was a cumulative loss of AP-1 binding that appeared to be synergistic. These results suggest protein/DNA interactions can be quite sensitive to the site, degree, and type of DNA damage, even relatively minor modifications.