Effects of transcranial direct current stimulation and transcranial random noise stimulation on working memory and task-related EEG in major depressive disorder.

OBJECTIVE: To compare effects of transcranial direct current stimulation (tDCS) and transcranial random noise stimulation with a direct-current offset (tRNS + DC-offset) on working memory (WM) performance and task-related electroencephalography (EEG) in individuals with Major Depressive Disorder (MDD). METHODS: Using a sham-controlled, parallel-groups design, 49 participants with MDD received either anodal tDCS (N = 16), high-frequency tRNS + DC-offset (N = 16), or sham stimulation (N = 17) to the left dorsolateral prefrontal cortex (DLPFC) for 20-minutes. The Sternberg WM task was completed with concurrent EEG recording before and at 5- and 25-minutes post-stimulation. Event-related synchronisation/desynchronisation (ERS/ERD) was calculated for theta, upper alpha, and gamma oscillations during WM encoding and maintenance. RESULTS: tDCS significantly increased parieto-occipital upper alpha ERS/ERD during WM maintenance, observed on EEG recorded 5- and 25-minutes post-stimulation. tRNS + DC-offset did not significantly alter WM-related oscillatory activity when compared to sham stimulation. Neither tDCS nor tRNS + DC-offset improved WM performance to a significantly greater degree than sham stimulation. CONCLUSIONS: Although tDCS induced persistent effects on WM-related oscillatory activity, neither tDCS nor tRNS + DC-offset enhanced WM performance in MDD. SIGNIFICANCE: This reflects the first sham-controlled comparison of tDCS and tRNS + DC-offset in MDD. These findings directly contrast with evidence of tRNS-induced enhancements in WM in healthy individuals.

Understanding the Barriers and Facilitators to Employment for People with Bipolar Disorder.

People with Bipolar Disorder (BD) consistently report a desire for employment; however, this is not reflected in employment figures. Individuals' perceptions of barriers to employment, along with endorsement of facilitators to employment remain under-investigated. We aimed to address this limitation by: (i) first examining differences in employed versus unemployed individuals (demographic, clinical, functioning); then (ii) identifying barriers and/or facilitators to employment, perception of same, and subsequent impact on employment. We assessed demographics, functioning, and illness-related characteristics in 35 participants with BD (19 employed, 16 unemployed). Participants were asked to indicate perception of common barriers and facilitators to employment. Groups did not differ regarding demographic or clinical variables. High levels of absenteeism, termination of last role and commonly perceived barriers were attributed to mental ill-health. 93.3% of unemployed participants reportedly desired employment, and more perceived barriers were observed in the unemployed group. Identified facilitators included increased support and flexible work strategies. A comprehensive understanding of perceptions of limiting and helpful factors related to employment for people with BD was obtained. These findings have implications for service provision, encouraging targeted discussion, and tailored treatment approaches to individual's unique perceptions of factors related to employment.

Norepinephrine release may play a critical role in the Warburg effect: an integrative model of tumorigenesis.

Many cancer cells share the property of carrying out markedly elevated rates of glycolysis to generate energy even in the presence of sufficient oxygen, and this is known as the Warburg effect. In recent years, there has been a resurgence of interest in the Warburg effect, as the field of oncology has amassed evidence that cellular metabolism may play a prominent role in many neoplasms. Largely in the past decade, another prominent and perhaps surprising factor has emerged in the cancer literature: the catecholamine molecules, epinephrine (adrenaline) and norepinephrine (noradrenaline), appear to play a role in tumorigenesis and metastasis. The drug propranolol, which blocks beta adrenergic receptors, may be therapeutic in human angiosarcoma, melanoma, and ovarian cancer. The current paper synthesizes these older and more recent findings, in an attempt to unify the major factors that contribute to tumorigenesis. This paper suggests that in addition to the direct interaction of catecholamine signaling with genetic risk factors (including mutagenesis), it interacts with environmental factors such as hypertension, obesity, unhealthy dietary components, physical inactivity, substance abuse, and mental or emotional stress, to promote the Warburg effect by facilitating glucose availability through suppression of pancreatic insulin release. Further, it proposes that many cancer cells synthesize and release catecholamines to activate their own receptors in an autocrine fashion. In summary, catecholamines are an important "new" factor in cancer that may interface with both genetics and environmental factors to alter the Warburg effect and modulate tumorigenesis.

Hypoxaemia during recovery after surgery for colorectal cancer: a prospective observational study.

Episodic and ongoing hypoxaemia are well-described after surgery, but, to date, no studies have investigated the occurrence of episodic hypoxaemia following minimally-invasive colorectal surgery performed in an enhanced recovery setting. We aimed to describe the occurrence of postoperative hypoxaemia after minimally-invasive surgery in an enhanced recovery setting, and the association with morphine use, incision site, fluid intake and troponin increase. We performed a prospective observational study of 85 patients undergoing minimally-invasive surgery for colorectal cancer between 25 August 2016 and 17 August 2017. We applied a pulse oximeter with a measurement rate of 1 Hz immediately after surgery either until discharge or until two days after surgery, and recorded the oxygen saturation. We measured troponin I during the first four days after surgery, or until discharge. The median (IQR [range]) length of stay was 3 (2-4 [1-38]) days. Thirty-six percent of patients spent more than 1 h below an oxygen saturation of 90% (4.2% of the day), and with a median (IQR [range]) proportion of 1.3 (0.2-11.1 [0.0-21.4])% of the day spent with an oxygen saturation below 88%. We found no associations between time spent below an oxygen saturation of 88% and morphine use (p = 0.215), fluid intake (p = 0.446), complications (p = 0.808) or extraction site (p = 0.623). Postoperative increases in troponin I were associated both with time spent below an oxygen saturation of 88% (p = 0.026) and hypopnoea episodes (p = 0.003). Even with minimally-invasive surgery and enhanced recovery after surgery, episodic hypoxaemia and hypopnoea episodes are common, but are not associated with morphine use, fluid intake or incision site. Further studies should investigate the relationship between hypoxaemia and troponin increase.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age.

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean = 35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 µg, transdermal estradiol 100 µg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 µg than 100 µg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 µg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.

Durable fear memories require PSD-95.

Traumatic fear memories are highly durable but also dynamic, undergoing repeated reactivation and rehearsal over time. Although overly persistent fear memories underlie anxiety disorders, such as posttraumatic stress disorder, the key neural and molecular mechanisms underlying fear memory durability remain unclear. Postsynaptic density 95 (PSD-95) is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory. Using a loss-of-function mutant mouse lacking the guanylate kinase domain of PSD-95 (PSD-95(GK)), we analyzed the contribution of PSD-95 to fear memory formation and retrieval, and sought to identify the neural basis of PSD-95-mediated memory maintenance using ex vivo immediate-early gene mapping, in vivo neuronal recordings and viral-mediated knockdown (KD) approaches. We show that PSD-95 is dispensable for the formation and expression of recent fear memories, but essential for the formation of precise and flexible fear memories and for the maintenance of memories at remote time points. The failure of PSD-95(GK) mice to retrieve remote cued fear memory was associated with hypoactivation of the infralimbic (IL) cortex (but not the anterior cingulate cortex (ACC) or prelimbic cortex), reduced IL single-unit firing and bursting, and attenuated IL gamma and theta oscillations. Adeno-associated virus-mediated PSD-95 KD in the IL, but not the ACC, was sufficient to impair recent fear extinction and remote fear memory, and remodel IL dendritic spines. Collectively, these data identify PSD-95 in the IL as a critical mechanism supporting the durability of fear memories over time. These preclinical findings have implications for developing novel approaches to treating trauma-based anxiety disorders that target the weakening of overly persistent fear memories.

Neurobiological mechanisms of repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex in depression: a systematic review.

Depression is one of the most prevalent mental illnesses worldwide and a leading cause of disability, especially in the setting of treatment resistance. In recent years, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative strategy for treatment-resistant depression and its clinical efficacy has been investigated intensively across the world. However, the underlying neurobiological mechanisms of the antidepressant effect of rTMS are still not fully understood. This review aims to systematically synthesize the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996-2014), Embase (1980-2014) and PsycINFO (1806-2014) were searched under set terms. Three authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. Of 1647 articles identified, 66 studies met both inclusion and exclusion criteria. rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limits the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggest that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology as well as blood flow and activity in the brain in a frequency-dependent manner. More research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.

Clozapine-induced myocarditis, a widely overlooked adverse reaction.

OBJECTIVE: We review the published cases of clozapine-induced myocarditis and describe reasons for the higher incidence in Australia (>1%) than elsewhere (<0.1%). METHOD: Medline was searched to September 2014 using 'clozapine' as the sole term. RESULTS: A total of around 250 cases of clozapine-induced myocarditis have been published. Fever among patients commencing clozapine has been reported internationally, and very few of these cases were investigated for myocarditis. The time to onset of fever is consistent with its being part of a prodrome of undiagnosed myocarditis, and the risk factors are similar to those for myocarditis. In more severe cases, clozapine is discontinued, avoiding fatalities which may occur with myocarditis. Furthermore, cases of sudden death and respiratory illness may well have been undiagnosed myocarditis. The diagnosis of myocarditis is confounded by the non-specific nature of the signs and symptoms, and it depends on appropriate investigations being conducted at the time of myocardial involvement or, for fatal cases, the affected area of the myocardium being sampled for histology. CONCLUSION: It is likely that the incidence of myocarditis is around 3%. Implementation of monitoring procedures will increase case ascertainment and result in more patients benefiting from this valuable medication.

The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.

Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.

Quality of life in bipolar and schizoaffective disorder--a naturalistic approach.

PURPOSE: The aim of this study was to evaluate the health-related quality of life (HRQoL) in bipolar type I (BD I) and schizoaffective (SQA) patients during a 2-year period in a naturalistic study. METHODS: This study was based on the data generated by the Bipolar Comprehensive Outcome Study, a prospective, non-interventional, observational study of participants with BD I and SQA disorder. Mixed-Model Repeated Measures Analysis was used to analyze changes in the SF-36 and EQ-5D. RESULTS: Participants exhibited low health status at baseline with SF-36 mean scores of 46.7±10.5 and 36.9±12.9 (best imaginable health=100, normal population≈50) for physical and mental components, respectively. No significant differences were found between the ratings of the BD I and SQA patients on HRQoL. The SF-36 SMC improved significantly over 24 months although SPC scores remained consistent across the study. On the whole, the lowest SMC score was observed among the depressed patients (38.20), followed by the patients with a mixed state (39.01) and the manic patients (39.83). LIMITATIONS: The observational design may have limited the causal relationships and the generalizability within the current findings. CONCLUSIONS: HRQoL was significantly impaired in all stages of BD and SQA when compared to the general population. The impairment of HRQoL was most pronounced in the depressed state, followed by the mixed state and then the manic state. The euthymic patients showed the least impairment. In addition, patients showed a global improvement in their mental health satisfaction over the 2 years follow up period.

Antibacterial validation of electrogenerated hypochlorite using carbon-based electrodes.

UNLABELLED: This proof-of-concept study explores the novel use of carbon-based electrodes for the electrochemical generation of hypochlorite and compares the antimicrobial efficacy against commercial hypochlorite solution. Antimicrobial concentrations of hypochlorite were generated using pad-printed carbon and carbon fibre electrodes, yielding up to 0·027% hypochlorite in 60 min and 0·1% hypochlorite in 15 min, respectively, in a nondivided assembly. The minimum inhibitory concentration (MIC) of the electrogenerated hypochlorite produced using carbon fibre electrodes was established for four medically important bacteria (Pseudomonas aeruginosa and Staphylococcus aureus approx. 0·025%, Escherichia coli and Enterococcus faecalis approx. 0·012%) and found to be in agreement with those determined using commercial hypochlorite solution. Therefore, carbon-based electrodes, particularly carbon fibre, have proven effective for the generation of antimicrobial concentrations of hypochlorite. The similarity of the MIC values to commercial hypochlorite solutions suggests that the antimicrobial efficacy is derived from the quantified hypochlorite generated and not due to marked cogeneration of reactive oxygen species, as identified for other assemblies. As such, the application of carbon electrodes may be suitable for the local production of hypochlorite for healthcare antisepsis. SIGNIFICANCE AND IMPACT OF THE STUDY: Carbon fibre electrodes can rapidly generate antimicrobial concentrations of hypochlorite; as such, these cheap and commercially available electrodes are proposed for the local production of hypochlorite for healthcare antisepsis. Importantly, the antimicrobial properties of the electrochemically generated hypochlorite mirror those of commercial hypochlorite, suggesting this is not enhanced by the cogeneration of reactive oxygen species. This illustrates the potential use of disposable carbon electrodes for localized small-volume production of hypochlorite for surface and skin cleansing, and opens a broader scope of research into the exploitation of carbon electrodes for this application.

Virtual airway simulation to improve dexterity among novices performing fibreoptic intubation.

We developed a virtual reality software application (iLarynx) using built-in accelerometer properties of the iPhone(®) or iPad(®) (Apple Inc., Cupertino, CA, USA) that mimics hand movements for the performance of fibreoptic skills. Twenty novice medical students were randomly assigned to virtual airway training with the iLarynx software or no additional training. Eight out of the 10 subjects in the standard training group had at least one failed (> 120 s) attempt compared with two out of the 10 participants in the iLarynx group (p = 0.01). There were a total of 24 failed attempts in the standard training group and four in the iLarynx group (p < 0.005). Cusum analysis demonstrated continued group improvement in the iLarynx, but not in the standard training group. Virtual airway simulation using freely available software on a smartphone/tablet device improves dexterity among novices performing upper airway endoscopy.

Equal remission rates and reduced length of hospital stay with twice-daily repetitive transcranial magnetic stimulation (rTMS) for major depression - A large naturalistic retrospective cohort association study.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is a level 1a evidence-based treatment for major depression, but high cost of care and limited effectiveness in naturalistic cohorts have been lingering criticisms. This naturalistic, retrospective cohort analysis compares the effect of once and twice daily treatment protocols of rTMS using quality assurance data collected at an Australian private psychiatric hospital. METHODS: A total of 210 inpatients self-selected into two groups receiving up to 30 sessions of either daily (n = 101) or twice daily (n = 109) 10 Hz rTMS to the left dorsolateral prefrontal cortex (DLPFC). The a priori primary outcome measure was remission rate as measured by pre and post treatment HAMD-17 scores. Length of hospital stay was a secondary post hoc outcome adopted due to the importance to cost of acute psychiatric care. RESULTS: Remission rates were similar across groups, with 44.9% and 45.4% for twice daily and daily rTMS groups respectively, although these may be confounded by patient expectations, other treatments and medication changes given the naturalistic setting. The length of hospital stay was 10.11 days and 18.44 days for twice daily and daily rTMS respectively - the twice daily rTMS length of hospital stay was 45.1% shorter 95% CI [38.7% - 51.56%]. Dropout rates were high; Twenty-seven (24.77%) twice daily participants dropped out before 20 sessions were completed, and 35 (34.65%) of daily participants. CONCLUSIONS: Twice daily 10 Hz left sided rTMS remission outcomes were similar to traditional once daily rTMS but required a shorter length of hospital stay. This finding has substantial cost of care implications. If these findings are independently replicated, twice daily rTMS may become the standard of care for inpatient rTMS.

Introducing RELAX: An automated pre-processing pipeline for cleaning EEG data - Part 1: Algorithm and application to oscillations.

OBJECTIVE: Electroencephalographic (EEG) data are often contaminated with non-neural artifacts which can confound experimental results. Current artifact cleaning approaches often require costly manual input. Our aim was to provide a fully automated EEG cleaning pipeline that addresses all artifact types and improves measurement of EEG outcomes METHODS: We developed RELAX (the Reduction of Electroencephalographic Artifacts). RELAX cleans continuous data using Multi-channel Wiener filtering [MWF] and/or wavelet enhanced independent component analysis [wICA] applied to artifacts identified by ICLabel [wICA_ICLabel]). Several versions of RELAX were compared using three datasets (N = 213, 60 and 23 respectively) against six commonly used pipelines across a range of artifact cleaning metrics, including measures of remaining blink and muscle activity, and the variance explained by experimental manipulations after cleaning. RESULTS: RELAX with MWF and wICA_ICLabel showed amongst the best performance at cleaning blink and muscle artifacts while preserving neural signal. RELAX with wICA_ICLabel only may perform better at differentiating alpha oscillations between working memory conditions. CONCLUSIONS: RELAX provides automated, objective and high-performing EEG cleaning, is easy to use, and freely available on GitHub. SIGNIFICANCE: We recommend RELAX for data cleaning across EEG studies to reduce artifact confounds, improve outcome measurement and improve inter-study consistency.

RELAX part 2: A fully automated EEG data cleaning algorithm that is applicable to Event-Related-Potentials.

OBJECTIVE: Electroencephalography (EEG) is often used to examine neural activity time-locked to stimuli presentation, referred to as Event-Related Potentials (ERP). However, EEG is influenced by non-neural artifacts, which can confound ERP comparisons. Artifact cleaning reduces artifacts, but often requires time-consuming manual decisions. Most automated methods filter frequencies <1 Hz out of the data, so are not recommended for ERPs (which contain frequencies <1 Hz). Our aim was to test the RELAX (Reduction of Electroencephalographic Artifacts) pre-processing pipeline for use on ERP data. METHODS: The cleaning performance of multiple versions of RELAX were compared to four commonly used EEG cleaning pipelines across both artifact cleaning metrics and the amount of variance in ERPs explained by different conditions in a Go-Nogo task. Results RELAX with Multi-channel Wiener Filtering (MWF) and wavelet-enhanced independent component analysis applied to artifacts identified with ICLabel (wICA_ICLabel) cleaned data most effectively and produced amongst the most dependable ERP estimates. RELAX with wICA_ICLabel only or MWF_only may detect effects better for some ERPs. CONCLUSIONS: RELAX shows high artifact cleaning performance even when data is high-pass filtered at 0.25 Hz (applicable to ERP analyses). SIGNIFICANCE: RELAX is easy to implement via EEGLAB in MATLAB and freely available on GitHub. Given its performance and objectivity we recommend RELAX to improve artifact cleaning and consistency across ERP research.

A randomized trial comparing repetitive transcranial magnetic stimulation given 3 days/week and 5 days/week for the treatment of major depression: is efficacy related to the duration of treatment or the number of treatments?

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been shown to be an effective treatment for depression. However, there has been little research to determine optimal parameters for treatment. METHOD: This study compared two rTMS treatment regimes for the treatment of major depression. Seventy-seven participants were randomized to either spaced or daily treatment. Spaced rTMS was given 3 days/week for 6 weeks (18 treatments in total) and daily rTMS was given 5 days/week for 4 weeks (20 treatments in total). All participants were assessed at baseline and after 4 weeks of treatment. Participants in the spaced treatment group were also assessed after 6 weeks of treatment. All participants were treated at 110% of the resting motor threshold with high-frequency rTMS (10 Hz) to the left dorsolateral prefrontal cortex (DLPFC) followed by low-frequency rTMS to the right DLPFC. RESULTS: Participants in the daily treatment group showed more improvement by week 4 than those in the spaced treatment group; however, both groups had similar improvement by treatment completion. There was significant improvement in both groups in ratings of depression and anxiety, with no significant differences between groups. CONCLUSIONS: Our study indicates that the efficacy of rTMS is related to the number of treatments given and that spacing the treatments neither improves nor reduces efficacy.

Metastatic pheochromocytoma and paraganglioma: focus on therapeutics.

Metastatic pheochromocytomas and paragangliomas are rare and challenging tumors. The tumor burden, combined with excessive catecholamine production, predispose to a broad spectrum of complications that range from spinal cord compression to any organ damage, all of which may lead to decreased quality of life and overall survival. Current therapies include surgery, systemic chemotherapy and radiopharmaceutical agents. Surgery is often a preferred therapy because it may cure or allow a long-term remission in patients with locoregional or isolated resectable distant metastases. Additionally, surgery can palliate symptoms related to tumor burden or catecholamine excess. However, in patients for whom surgery is not an option, systemic chemotherapy and radiopharmaceutical agents are preferred options. Systemic chemotherapy and radiopharmaceutical agents such as 131I-Metaiodobenzylguanidine (131I-MIBG) may cause partial responses or stabilization of disease with better blood pressure control and symptomatic and performance status improvement. However, as these therapies are only palliative, patients' quality of life and personal preferences should always be considered. The recognition of molecular pathways involved in the pheochromocytoma and paraganglioma tumorigenesis has driven the development of new therapeutic options. Agents such as tyrosine kinase, MAPK, PI3K, or hypoxia inducible factor inhibitors, alone or in combination, may represent novel therapeutic strategies that could be evaluated in prospective clinical trials. Transcriptional profiling and the development of personalized cancer medicine will help to pave the way for more specific therapeutic approaches and combinations.

Proteinuria in metastatic pheochromocytoma is associated with an increased risk of Acute Respiratory Distress Syndrome, spontaneously or after therapy with 131I-meta-iodobenzylguanidine (131I-MIBG).

Acute Respiratory Distress Syndrome (ARDS) has been reported rarely in pheochromocytoma, occurring spontaneously or after therapy with 131I-meta-iodobenzylguanidine (131I-MIBG). Our objective was to determine whether proteinuria is associated with an increased risk of ARDS. This was a retrospective analysis of a prospective cohort study of 64 patients with metastatic pheochromocytoma or paraganglioma treated with 131I-MIBG on institutional protocols. Proteinuria was defined as at least one urinalysis positive for at least trace protein within 1 month prior to 131I-MIBG or within 1 month prior to spontaneous ARDS. Proportions were compared using Fisher's exact test. Urinalyses within the defined time period were available for 48 patients, 8 of whom had proteinuria. Of the 8 patients with proteinuria, 5 developed ARDS: 3 within 10 days following 131I-MIBG, two 6 months following 131I-MIBG. Both patients who developed ARDS 6 months after 131I-MIBG had proteinuria within 1 month before apparently spontaneous ARDS. None of the 40 patients whose urinalyses were all negative for protein developed ARDS. None of the 16 patients with missing urinalyses developed ARDS. Patients with antecedent proteinuria were more likely to develop ARDS than those without proteinuria (63% vs. 0%; p<0.0001). The following variables were not significantly associated with ARDS: 131I-MIBG activities administered, number of 131I-MIBG administrations, age, hypertension, or secretion of catecholamines or metanephrines. In patients with metastatic pheochromocytoma or paraganglioma, proteinuria is associated with ARDS and urine protein should be examined prior to administering 131I-MIBG.