Host and fungal factors both contribute to cryptococcosis-associated hyperammonemia (cryptammonia).

Cryptococcus neoformans and Cryptococcus gattii are both known urease producers and have the potential to cause hyperammonemia. We hypothesized that the risk of hyperammonemia is increased by renal failure, burden of cryptococcal infection, and fungal strain characteristics. We performed a retrospective review of plasma ammonia levels in patients with cryptococcal infections. Risk factors for hyperammonemia were statistically compared between patients with and without hyperammonemia (>53 µmol/L). Cryptococcal cells from three patients included in the study were recovered from our biorepository. Strain characteristics including urease activity, ammonia production, growth curves, microscopy, melanin production, and M13 molecular typing were analyzed and compared with a wild-type (WT) C. neoformans strain. We included 29 patients, of whom 37.9% had hyperammonemia, 59% had disseminated cryptococcal infection (DCI), and 41% had isolated central nervous system infection. Thirty-eight percent of patients had renal failure and 28% had liver disease. Renal failure was associated with 4.4 times (95% confidence interval [CI] 1.5, 13.0) higher risk of hyperammonemia. This risk was higher in DCIs (RR 6.2, 95% CI 1.0, 40.2) versus isolated cryptococcal meningitis (RR 2.5, 95% CI, 0.40, 16.0). Liver disease and cryptococcal titers were not associated with hyperammonemia. C. neoformans from one patient with extreme hyperammonemia demonstrated a 4- to 5-fold increase in extracellular urease activity, slow growth, enlarged cell size phenotypes, and diminished virulence factors. Hyperammonemia was strongly associated with renal failure in individuals with DCI, surpassing associations with liver failure or cryptococcal titers. However, profound hyperammonemia in one patient was attributable to high levels of urease secretion unique to that cryptococcal strain. Prospective studies are crucial to exploring the significance of this association.IMPORTANCECryptococcus produces and secretes the urease enzyme to facilitate its colonization of the host. Urease breaks down urea into ammonia, overwhelming the liver's detoxification process and leading to hyperammonemia in some hosts. This underrecognized complication exacerbates organ dysfunction alongside the infection. Our study investigated this intricate relationship, uncovering a strong association between the development of hyperammonemia and renal failure in patients with cryptococcal infections, particularly those with disseminated infections. We also explore mechanisms underlying increased urease activity, specifically in strains associated with extreme hyperammonemia. Our discoveries provide a foundation for advancing research into cryptococcal metabolism and identifying therapeutic targets to enhance patient outcomes.

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH and contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 12 females) treated with IT nicardipine every 6 hours (n=8) or every 8 hours (n=8), which were subject to high-performance liquid chromatography for measurement of its CSF concentration. Our popPK analysis showed that the CSF PK of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time, with reliable parameter estimates (relative standard error < 50%). The intracranial pressure influenced both the total clearance and the central volume. Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.

A Case of "Cryptammonia": Disseminated Cryptococcal Infection Generating Profound Hyperammonemia in a Liver Transplant Recipient.

Mycoplasma and Ureaplasma infections have been described as a cause of hyperammonemia syndrome leading to devastating neurological injury in the post-transplant period, most commonly in lung transplant recipients. The occurrence of significant hyperammonemia caused by other urease-producing organisms remains unclear. We describe a case of disseminated cryptococcosis presenting with profound hyperammonemia in a 55-year-old orthotopic liver transplant recipient. Through a process of elimination, other potential causes for hyperammonemia were excluded revealing a probable association between hyperammonemia and disseminated cryptococcosis.

Retinopathy and Systemic Disease Morbidity in Severe COVID-19.

PURPOSE: To assess the prevalence of retinopathy and its association with systemic morbidity and laboratory indices of coagulation and inflammatory dysfunction in severe COVID-19. DESIGN: Retrospective, observational cohort study. METHODS: Adult patients hospitalized with severe COVID-19 who underwent ophthalmic examination from April to July 2020 were reviewed. Retinopathy was defined as one of the following: 1) Retinal hemorrhage; 2) Cotton wool spots; 3) Retinal vascular occlusion. We analyzed medical comorbidities, sequential organ failure assessment (SOFA) scores, clinical outcomes, and laboratory values for their association with retinopathy. RESULTS: Thirty-seven patients with severe COVID-19 were reviewed, the majority of whom were female (n = 23, 62%), Black (n = 26, 69%), and admitted to the intensive care unit (n = 35, 95%). Fourteen patients had retinopathy (38%) with retinal hemorrhage in 7 (19%), cotton wool spots in 8 (22%), and a branch retinal artery occlusion in 1 (3%) patient. Patients with retinopathy had higher SOFA scores than those without retinopathy (8.0 vs. 5.3, p = .03), higher rates of respiratory failure requiring invasive mechanical ventilation and shock requiring vasopressors (p < .01). Peak D-dimer levels were 28,971 ng/mL in patients with retinopathy compared to 12,575 ng/mL in those without retinopathy (p = .03). Peak CRP was higher in patients with cotton wool spots versus those without cotton wool spots (354 mg/dL vs. 268 mg/dL, p = .03). Multivariate logistic regression modeling showed an increased risk of retinopathy with higher peak D-dimers (aOR 1.32, 95% CI 1.01-1.73, p = .04) and male sex (aOR 9.6, 95% CI 1.2-75.5, p = .04). CONCLUSION: Retinopathy in severe COVID-19 was associated with greater systemic disease morbidity involving multiple organs. Given its association with coagulopathy and inflammation, retinopathy may offer insight into disease pathogenesis in patients with severe COVID-19.

Extracorporeal Devices.

Extracorporeal liver support (ECLS) emerged from the need stabilize high-acuity liver failure patients with the highest risk of death. The goal is to optimize the hemodynamic, neurologic, and biochemical parameters in preparation for transplantation or to facilitate spontaneous recovery. Patients with acute liver failure and acute-on-chronic liver failure stand to benefit from these devices, especially because they have lost many of the primary functions of the liver, including detoxifying the blood of various endogenous and exogenous substances, manufacturing circulating proteins, secreting bile, and storing energy. Existing ECLS devices are designed to mimic some of these functions.

Hyperchloremia Is Associated With Acute Kidney Injury in Patients With Subarachnoid Hemorrhage.

OBJECTIVE: To assess the prevalence of acute kidney injury in patients with subarachnoid hemorrhage patients. DESIGN: Retrospective analysis of all subarachnoid hemorrhage admissions. SETTINGS: Neurocritical care unit. PATIENTS: All patients with a diagnosis of subarachnoid hemorrhage between 2009 and 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,267 patients included in this cohort, 16.7% developed acute kidney injury, as defined by Kidney Disease Improving Global Outcome criteria (changes in creatinine only). Compared to patients without acute kidney injury, patients with acute kidney injury had a higher prevalence of diabetes mellitus (21.2% vs 9.8%; p < 0.001) and hypertension (70.3% vs 50.5%; p < 0.001) and presented with higher admission creatinine concentrations (1.21 ± 0.09 vs 0.81 ± 0.01 mg/dL [mean ± SD], respectively; p < 0.001). Patients with acute kidney injury also had higher mean serum chloride and sodium concentrations during their ICU stay (113.4 ± 0.6 vs 107.1 ± 0.2 mmol/L and 143.3 ± 0.4 vs 138.8 ± 0.1 mmol/L, respectively; p < 0.001 for both), but similar chloride exposure. The mortality rate was also significantly higher in patients with acute kidney injury (28.3% vs 6.1% in the non-acute kidney injury group [p < 0.001]). Logistic regression analysis revealed that only male gender (odds ratio, 1.82; 95% CI, 1.28-2.59), hypertension (odds ratio, 1.64; 95% CI, 1.11-2.43), diabetes mellitus (odds ratio, 1.88; 95% CI, 1.19-2.99), abnormal baseline creatinine (odds ratio, 2.48; 95% CI, 1.59-3.88), and increase in mean serum chloride concentration (per 10 mmol/L; odds ratio, 7.39; 95% CI, 3.44-18.23), but not sodium, were associated with development of acute kidney injury. Kidney recovery was noted in 78.8% of the cases. Recovery reduced mortality compared to non-recovering subgroup (18.6% and 64.4%, respectively; p < 0.001). CONCLUSIONS: Critically ill patients with subarachnoid hemorrhage show a strong association between hyperchloremia and acute kidney injury as well as acute kidney injury and mortality.

Hepatic Encephalopathy-the Old and the New.

Hepatic encephalopathy occurs ubiquitously in all causes of advanced liver failure, however, its implications on mortality diverge and vary depending upon acuity and severity of liver failure. This associated mortality has decreased in subsets of liver failure over the last 20 years. Aside from liver transplantation, this improvement is not attributable to a single intervention but likely to a combination of practical advances in critical care management. Misconceptions surrounding many facets of hepatic encephalopathy exists due to heterogeneity in presentation, pathophysiology and outcome. This review is intended to highlight the important concepts, rationales and strategies for managing hepatic encephalopathy.

Emerging strategies for the treatment of patients with acute hepatic failure.

PURPOSE OF REVIEW: The objective of this article is to review the latest developments related to the treatment of patients with acute liver failure (ALF). RECENT FINDINGS: As the treatment of ALF has evolved, there is an increasing recognition regarding the risk of intracranial hypertension related to advanced hepatic encephalopathy. Therefore, there is an enhanced emphasis on neuromonitoring and therapies targeting intracranial hypertension. Also, new evidence implicates systemic proinflammatory cytokines as an etiology for the development of multiorgan system dysfunction in ALF; the recent finding of a survival benefit in ALF with high-volume plasmapheresis further supports this theory. SUMMARY: Advances in the critical care management of ALF have translated to a substantial decrease in mortality related to this disease process. The extrapolation of therapies from general neurocritical care to the treatment of ALF-induced intracranial hypertension has resulted in improved neurologic outcomes. In addition, recognition of the systemic inflammatory response and multiorgan dysfunction in ALF has guided current treatment recommendations, and will provide avenues for future research endeavors. With respect to extracorporeal liver support systems, further randomized studies are required to assess their efficacy in ALF, with attention to nonsurvival end points such as bridging to liver transplantation.

Clinical predictors of significant findings on head computed tomographic angiography.

BACKGROUND: Although head computed tomographic angiography (CTA) is a sensitive tool for the evaluation of neurological symptoms in the emergency department (ED), little is known about which clinical signs predict significant CTA findings. OBJECTIVES: To identify clinical factors that predict significant findings on head CTA in patients presenting to the ED with neurological complaints. METHODS: Retrospective chart review of consecutive adult patients undergoing head CTA over a 6-month period in an urban, tertiary care ED with an annual volume of 76,000. Significant head CTA findings were defined as clinically significant neurological abnormalities undetected by previous imaging studies. Demographics, chief complaint, results of the neurological examinations (NE), and head non-contrast computed tomography (CT) results were used as predictors of significant head CTA. All predictors with a univariate p < 0.2 using Pearson's chi-squared were entered stepwise into a multivariable logistic regression including odds ratios (OR), with inclusion restricted to p < 0.05. RESULTS: Chart review yielded 456 cases; 215 (47%) were male. Mean age was 62 (SD 20) years. There were 189 patients (41%) with abnormal CTAs. Multivariable logistic regression indicated five variables that predicted a clinically significant CTA: abnormal CT (OR 3.72), chief complaint of subarachnoid hemorrhage-type headache (OR 2.30), and motor deficit (OR 2.23), visual deficit (OR 2.23), and other focal deficit (OR 2.18) on NE. A chief complaint of trauma (OR 0.23) predicted a normal CTA. CONCLUSIONS: Specific historical and focal neurological findings are useful for predicting clinically significant findings on head CTA.

Evaluating the diagnostic capacity of a single-question neuropathy screen (SQNS) in HIV positive Zambian adults.

A single-question neuropathy screen (SQNS) is routinely included in the enrolment data for people commencing antiretroviral therapy in publically funded clinics in Zambia. The authors assessed the sensitivity, specificity, positive and negative predictive value of this SQNS against the Brief Peripheral Neuropathy Screen (BPSN) in detecting HIV-associated sensory neuropathy in patients recruited from a rural and an urban hospital in Zambia. The SQNS was asked followed by conduct of the BPNS by the neurology resident assisted by a Zambian healthcare worker/translator. 77 patients (48 (62.3%) urban and 29 (37.7%) rural) were enrolled. 13 subjects were excluded due to altered mental status. The mean age was 33.7 years (range 15-53 years; SD±7.81). The SQNS was 95.7% sensitive and 80.0% specific, with 88.2% positive predictive value and 92.3% negative predictive value. Age, geographical location, gender and WHO stage were all unrelated to the performance of the SQNS (p>0.05). Despite its reliance on symptoms alone, this study suggests that the SQNS may be a valid research tool for identifying HIV-associated neuropathy among advanced stage HIV patients in Zambia.