Abstract: Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%] , − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation.

Abstract: In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. Methods For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. Results We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p  = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p  = 0.47) or history of chronic hypertension ( n  = 126 [63.0%] vs. n  = 153 [66.8%]; p  = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p  = 0.76). Conclusions The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

Abstract: Vasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective of the Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65) trial is to ascertain the effect of permissive hypotension (vasopressor titration to achieve MAP 60–65 mm Hg) versus usual care on biomarkers of organ injury in hypotensive patients aged ≥65 years. Methods and analysis OVATION-65 is an allocation-concealed randomised trial in 7 Canadian hospitals. Eligible patients are ≥65 years of age, in an ICU with vasodilatory hypotension, receiving vasopressors for ≤12 hours to maintain MAP ≥65 mm Hg during or after adequate fluid resuscitation, and expected to receive vasopressors for ≥6 additional hours. Patients are excluded for any of the following: active treatment for spinal cord or acute brain injury; vasopressors given solely for bleeding, ventricular failure or postcardiopulmonary bypass vasoplegia; withdrawal of life-sustaining treatments expected within 48 hours; death perceived as imminent; previous enrolment in OVATION-65; organ transplant within the last year; receiving extracorporeal life support or lack of physician equipoise. Patients are randomised to permissive hypotension versus usual care for up to 28 days. The primary outcome is high-sensitivity troponin T, a biomarker of cardiac injury, on day 3. Secondary outcomes include biomarkers of injury to other organs (brain, liver, intestine, skeletal muscle); lactate (a biomarker of global tissue dysoxia); resource utilisation; adverse events; mortality (90 days and 6 months) and cognitive function (6 months). Assessors of biomarkers, mortality and cognitive function are blinded to allocation. Ethics and dissemination This protocol has been approved at all sites. Consent is obtained from the eligible patient, the substitute decision-maker if the patient is incapable, or in a deferred fashion where permitted. End-of-grant dissemination plans include presentations, publications and social media platforms and discussion forums. Trial registration number NCT03431181 .

Abstract: Introduction: We present a case report of posterior reversible leukoencephalopathy syndrome (PRES) following transarterial chemoembolization (TACE) of liver metastasis of an intestinal neuroendocrine tumour.Case presentation: A 62-year-old female was evaluated for progressive bilateral vision loss following transarterial chemoembolization (TACE) of hepatic metastasis of a midgut carcinoid tumour with cisplatin. Vital signs were remarkable for significant hypertension (170-210/85-110) since having undergone TACE (baseline BP 136/74), despite pre-procedure administration of octreotide. Blood pressure failed to correct with administration of amlodipine, hydralazine, captopril and labetalol infusion but responded promptly to octreotide infusion. Magnetic resonance imaging showed findings compatible with PRES. The patient’s vision gradually corrected to her baseline over 2 days. Conclusion: TACE for neuroendocrine tumours can be complicated by carcinoid crisis despite pre-administration of octreotide. Rarely, this may present as a hypertensive emergency of which PRES is a manifestation. Prompt recognition and treatment with high dose octreotide are important and can avoid permanent neurological injury in patients.RésuméIntroduction : Il s’agit d’une étude de cas de syndrome de leuco encéphalopathie réversible postérieure (SERP) consécutive à la chimioembolisation transartérielle (CETA) d’une métastase hépatique d’une tumeur neuro-endocrinine intestinale.Présentation du dossier: Une femme de 62 ans est évaluée pour une perte de vision bilatérale progressive à la suite de la chimioembolisation transartérielle (CETA) de métastases hépatiques d’une tumeur du tube digestif effectuée au moyen du cisplatine. Les signes vitaux sont remarquables malgré une hypertension importante (170-210/85-110) depuis la CETA (p.a. de base 136/74) et l’administration d’octréotide préalable à l’intervention. La pression artérielle ne s’est pas corrigée avec l’administration d’amlodipine, d’hydralazine, de captopril et de labétalol en perfusion, mais a répondu promptement à l’octréotide en perfusion. Une imagerie par résonnance magnétique a fourni des résultats compatibles avec un diagnostic de SERP. La vision de la patiente s’est graduellement corrigée pour revenir à son état habituel en deux jours.Conclusion : Dans le cas de tumeurs neuro-endocriniennes, la CETA peut être compliquée d’une crise carcinoïde malgré l’administration d’octréotide au préalable. Cette condition peut, quoique rarement, représenter une urgence hypertensive dont le SERP est une manifestation. L’identification rapide de la condition et un traitement à l’aide d’octréotide à dose élevée sont de la plus haute importance et peuvent éviter des dommages neurologiques permanents.Carcinoid syndrome is a syndrome classically consisting of diarrhea, paroxysms of cutaneous flushing with or without hypotension and bronchospasm arising most frequently in the setting of hepatic metastases originating from midgut carcinoid tumours. However, these neuroendocrine tumours can synthesize a wide variety of polypeptides, prostaglandins, and biogenic amines and hence present atypical clinical manifestations such as pellagra, abdominal pain, right-sided heart failure from valvular lesions and paroxysmal hypertension. Tumour manipulation may result in a massive influx of hormones into the systemic vasculature, potentially resulting in life threatening swings in blood pressure, cardiac arrhythmias and bronchoconstriction, even in patients without liver metastases or preoperative carcinoid syndrome.1 We present a case report of hypertensive emergency presenting as posterior reversible leukoencephalopathy syndrome (PRES) after transarterial chemoembolization (TACE) of a hepatic metastasis of carcinoid tumour.Case PresentationA 62-year-old caucasian female was evaluated on the surgical ward for progressive bilateral vision loss about 10 hours following transarterial chemoembolization (TACE) of a hepatic metastasis of a midgut carcinoid tumour (Figure 1, Figure 2) with Lipiodol and cisplatin. Premedication with octreotide 100 mcg subcutaneously and dexamethasone 8 mg IV pre-procedure was given, and post-procedure orders were given for dexamethasone 4 mg bid, ondansetron as needed and D5% NaCl 0.45% at a rate of 150 mL/h. The rest of her past medical history was unremarkable, specifically without history of hypertension, cerebrovascular disease, or clinical manifestations of carcinoid syndrome prior to admission. She had undergone two intra-abdominal surgeries without complication. Her usual medication was limited to inhaled glycopyrronium and indacaterol. Figure 1. Axial computed tomography scan of hepatic metastasis. A mass is visible in hepatic parenchyma corresponding to a metastasis of the midgut carcinoid tumour. Figure 2. Fluroscopic image of transarterial chemoembolization of hepatic metastasis. Upon evaluation, the patient was somnolent but otherwise well oriented. Eye exam confirmed bilateral 0/20 vision though pupils were 4 mm and reactive. On motor exam, the patient had diffuse hyperreflexia with upgoing plantar reflexes but without focal weakness. Chart review was remarkable for blood pressures ranging from 170-210/85-110 since TACE (pre-procedure blood pressure 136/74). A presumptive diagnosis of PRES due to cisplatin was made.Initial cerebral computed tomography scan was suspicious for a right occipital sub-cortical hypodensity of 3 cm, possibly of ischemic nature. IV fluids were discontinued (NaCl 0.9% at a rate of 250 mL/h) and anti-hypertensive agents were begun. After failure of improvement of blood pressure or symptoms despite amlodipine, hydralazine, labetalol, and captopril, a diagnosis of carcinoid crisis was suspected and octreotide 300mcg IV bolus followed by an infusion of 50 mcg/h was started. The suspected diagnosis of carcinoid crisis was later confirmed by 24h urinary 5-HIAA dosing at 141.4 umol/day (normal 0–42, previously within normal limits pre-operatively). Serum chromogranin A was also elevated at 138.2 ug/L (normal 0–82), compatible with a neuroendocrine tumour.Characteristic changes of PRES were seen on cerebral magnetic resonance imaging (MRI) (Figure 3) including predominantly sub-cortical hyperintensities in the bilateral parietal and occipital lobes on T2 and FLAIR sequences which were also hyperintense on diffusion-weighted imaging (DWI), likely from T2 shine through, and apparent diffusion coefficient (ADC) maps without restricted diffusion, hence confirming the finding of vasogenic edema compatible with PRES. Figure 3. FLAIR sequence, axial slice, cerebral magnetic resonance imaging. Subcortical hyperintensies in the bilateral occipital lobes reflecting vasogenic edema of the visual white matter tracts are seen. The patient’s blood pressure and her visual symptoms progressively normalized over 48 hours. On last follow-up 1 month after procedure, vital signs were normal (blood pressure 115/54) and vision was normal.DiscussionCarcinoid tumours are classically described as slow growing, mainly affecting the gastrointestinal (GI) tract. They are known to internists mainly for their capability to produce the carcinoid syndrome. However, only about 25% of carcinoids actually produce the mediators which produce the carcinoid syndrome and less than 10% of patients actually develop the carcinoid syndrome.2 The syndrome usually presents when midgut carcinoids metastasize to the liver, hence bypassing hepatic metabolism. Typical symptoms include secretory diarrhea (80%) and flushing of the head, neck, and upper torso (90%) which may be associated with hypotension and tachycardia. Less frequent manifestations are right heart failure due to carcinoid valve disease (30%), bronchospasm (15%) and pellagra (5%). 3 The classic triad of flushing, diarrhea and wheezing is infrequently found. Foregut (e.g., bronchial) and extra-digestive midgut (e.g., ovarian) bypass the liver and may result carcinoid syndrome without hepatic metastasis, although symptoms are usually atypical in these cases.Perioperative carci noid crisis occurs in 10–30% of patients undergoing operative resection. Absence of preoperative carcinoid syndrome decreases the risk of carcinoid crisis, however it may still occur.1 This has led to the recommendation by some that patients be premedicated with somatostatin analogues to block bioactive peptide release and action, with or without other hormone antagonists (e.g., anti-histamines).3 However, the benefit of octreotide prophylaxis has been questioned by other studies.1 Once a carcinoid crisis has occurred, bolus doses of 25–500 mcg and intravenous infusions at rates of 50–150 mcg/h have been effective in case reports and case series, with higher doses being potentially required in patients on maintenance octreotide therapy or with carcinoid heart disease.4Despite a lack of data comparing it to surgical management, transarterial chemoembolization (TACE).5 is a frequent management strategy for patients with liver metastases, especially when patients present with hormonal symptoms and multiple metastases preclude resection. Rates of complication from TACE are difficult to estimate ranging from 0 to 100%, likely due to variable definitions and reporting. Only one study reported on the incidence of post embolization carcinoid crisis,6 with 2 of 12 patients developing the complication. Both had a history of carcinoid syndrome and had been premedicated with octreotide 200 mcg SC before procedure and q8h afterward. One group7 did report a patient who developed transient cortical blindness following TACE which possibly could have been due to PRES.PRES is a syndrome of failure of cerebral blood pressure autoregulation with acute onset elevations of blood pressure from baseline and a combination of altered level of consciousness, visual symptoms, headache and seizures.8 Blood pressure is often only moderately elevated, though significantly above the patient’s baseline. Etiologies are varied but include cytotoxic chemotherapy, eclampsia and other causes of hypertensive emergency. It was originally felt that the patient’s PRES was due to the cisplatin received during TACE with contribution from dexamethasone and iatrogenic fluid overload (NaCl 0.9% at 150 mL/h had been running for several hours) as she had no history of carcinoid syndrome, had been premedicated and had no other findings associated with the disease. However, her lack of response to standard anti-hypertensives and prompt response to octreotide suggest carcinoid crisis as the cause.Neuroimaging with MRI confirms the diagnosis. Findings are compatible with symmetrical white matter edema in the posterior cerebral hemispheres, particularly the parieto-occipital regions. The cortex, basal ganglia, brainstem, and cerebellar may also be involved though less so than the subcortical white matter, while anterior cortical involvement is seen only with the most severe cases. Importantly, the distribution is not confined to a single vascular territory. Classically lesions appear as punctate or confluent areas of hyperintensity on T2 and FLAIR sequences.9 DWI usually shows hypo or iso-intense signal (though sometimes mildly hyperintense from T2 shine through) while ADC maps show increased signal, thus distinguishing PRES from ischemic stroke. With prompt recognition and management, full recovery over a period of days to weeks can be expected.  ConclusionsCarcinoid crisis is a well-known and dreaded complication of surgical manipulation of carcinoid tumours. Transarterial chemoembolization of these tumours may also result in carcinoid crisis and our report suggests that pre-procedure carcinoid syndrome is not a prerequisite for this. Presentation may be atypical, as it was in our patient, and so clinical suspicion should be high. When suspected, prompt management with octreotide and other supportive therapies should be instituted.Key Points1. Patients undergoing transarterial chemoembolization for carcinoid tumour metastases are at risk for carcinoid crisis, even if they have been premedicated with octreotide and have no history of carcinoid syndrome.2. Carcinoid crisis may present as hypertensive crisis rather than hypotension, and may give rise to PRES.References1. Condron ME, Pommier SJ, Pommier RF. Continuous infusion of octreotide combined with perioperative octreotide bolus does not prevent intraoperative carcinoid crisis. Surgery 2016;159:358–67.2. Van Der Lely AJ, Herder WWd. Carcinoid syndrome: diagnosis and medical management. Arquivos Brasileiros de Endocrinologia & Metabologia 2005;49:850–60.3. Mancuso K, Kaye AD, Boudreaux JP, et al. Carcinoid syndrome and perioperative anesthetic considerations. J Clin Anesth 2011;23:329–41.4. Seymour N, Sawh SC. Mega-dose intravenous octreotide for the treatment of carcinoid crisis: a systematic review. Can J Anesth/J can d'anesthés2013;60:492–9.5. Kennedy A, Bester L, Salem R, Sharma RA, Parks RW, Ruszniewski P. Role of hepatic intra‐arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET‐Liver‐Metastases Consensus Conference. HPB 2015;17:29–37.6. Maire F, Lombard-Bohas C, O’Toole D, et al. Hepatic arterial embolization versus chemoembolization in the treatment of liver metastases from well-differentiated midgut endocrine tumours: a prospective randomized study. Neuroendocrinology 2012;96:294–300.7. Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumours. Cancer 2005;104:1590–602.8. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494–500.9. Pedraza R, Marik PE, Varon J. Posterior reversible encephalopathy syndrome: a review. Crit Care Shock 2009;12:135–43.

Abstract: We report a case of propofol infusion syndrome (PRIS) in a young female treated for status epilepticus. In this case, PRIS rapidly evolved to full cardiovascular collapse despite aggressive supportive care in the intensive care unit, as well as prompt discontinuation of the offending agent. She progressed to refractory cardiac arrest requiring emergent initiation of venoarterial extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation (CPR). She regained a perfusing rhythm after prolonged ( 〉 8 hours) asystole, was weaned off ECMO and eventually all life support, and was discharged to home. We also present a review of the available literature on the use of ECMO for PRIS.