Management of late onset urea cycle disorders-a remaining challenge for the intensivist?

BACKGROUND: Hyperammonemia caused by a disorder of the urea cycle is a rare cause of metabolic encephalopathy that may be underdiagnosed by the adult intensivists because of its rarity. Urea cycle disorders are autosomal recessive diseases except for ornithine transcarbamylase deficiency (OTCD) that is X-linked. Optimal treatment is crucial to improve prognosis. Main body We systematically reviewed cases reported in the literature on hyperammonemia in adulthood. We used the US National Library of Medicine Pubmed search engine since 2009. The two main causes are ornithine transcarbamylase deficiency followed by type II citrullinemia. Diagnosis by the intensivist remains very challenging therefore delaying treatment and putting patients at risk of fatal cerebral edema. Treatment consists in adapted nutrition, scavenging agents and dialysis. As adults are more susceptible to hyperammonemia, emergent hemodialysis is mandatory before referral to a reference center if ammonia levels are above 200 µmol/l as the risk of cerebral edema is then above 55%. Definitive therapy in urea cycle abnormalities is liver transplantation. CONCLUSION: Awareness of urea cycle disorders in adults intensive care units can optimize early management and accordingly dramatically improve prognosis. By preventing hyperammonemia to induce brain edema and herniation leading to death.

A case report of serious haemolysis in a glucose-6-phosphate dehydrogenase-deficient COVID-19 patient receiving hydroxychloroquine.

While the COVID-19 epidemic occurred since December 2019, as of end April 2020, no treatment has been validated or invalidated by accurate clinical trials. Use of hydroxychloroquine has been popularised on mass media and put forward as a valid treatment option without strong evidence of efficacy. Hydroxychloroquine (HCQ) has its own side effects, some of which are very serious like acute haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. Side effects may be worse than the disease itself. Belgian national treatment guidelines recommend the use of HCQ in mild to severe COVID-19 disease. As opinions, politics, media and beliefs are governing COVID-19 therapy, performance of randomised controlled blinded clinical trials became difficult. Results of sound clinical trials are eagerly awaited. We report a case of acute haemolysis leading to admission in intensive care unit and renal failure in a patient with uncovered G6PD deficiency.

Potassium disorders in pediatric emergency department: Clinical spectrum and management.

INTRODUCTION: Potassium abnormalities are frequent in intensive care but their incidence in the emergency department is unknown. AIM: We describe the spectrum of potassium abnormalities in our tertiary-level pediatric emergency department. METHODS: Retrospective case-control study of all the patients admitted to a single-center tertiary emergency department over a 2.5-year period. We compared patients with hypokalemia (<3.0mEq/L) and patients with hyperkalemia (>6.0mEq/L) against a normal randomized population recruited on a 3:1 ratio with potassium levels between 3.5 and 5mEq/L. RESULTS: Between January 1, 2013 and August 31, 2016 we admitted 108,209 patients to our emergency department. A total of 9342 blood samples were tested and the following potassium measurements were found: 60 cases of hypokalemia (2.8±0.2mEq/L) and 55 cases of hyperkalemia (6.4±0.6mEq/L). In total, 200 patients with normokalemia were recruited (4.1±0.3mEq/L). The main causes of the disorders were non-specific: lower respiratory tract infection (23%) and fracture (15%) for hypokalemia, lower respiratory tract (21.8%) and ear-nose-throat infections (20.0%) for hyperkalemia. Patients with hyperkalemia had an elevated creatinine level (0.72±1.6 vs. 0.40±0.16mg/dL, P<0.0001) with lower bicarbonate (19.4±3.8 vs. 21.8±2.8mmol/L, P=0.0001) and higher phosphorus levels (1.95±0.6 vs. 1.42±0.27mg/dL, P=0.0001). Patients with hypokalemia had an elevated creatinine level (0.66±0.71 vs. 0.40±0.16mg/dL, P<0.0001) and a lower phosphorus level (1.12±0.31 vs. 1.42±0.27mg/dL, P=0.0001). We did not observe significant differences in pH, PCO2, base excess and lactate, or in the mean duration of hospitalization in general wards and pediatric intensive care units according to the PIM and PRISM scores. DISCUSSION: Dyskalemia is rare in emergency department patients: 0.64% for hypokalemia and 0.58% for hyperkalemia. This condition could be explained by a degree of renal failure due to transient volume disturbance. The main mechanism is dehydration due to digestive losses, polypnea in young patients, and poor intake. In the case of hypokalemia, poor intake and digestive losses could be the main explanation. These disorders resolve easily with feeding or perfusion and do not impair development. CONCLUSION: Dyskalemia is rare in emergency department patients and is easily resolved with feeding or perfusion. A plausible etiological mechanism is a transient volume disturbance. Dyskalemia is not predictive of poor development in the emergency pediatric population.

Variation of Cognitive Function During a Short Stay at Hypobaric Hypoxia Chamber (Altitude: 3842 M).

OBJECTIVE: To observe the effects of a fast-acute ascent to high altitude on brain cognitive function and transcranial doppler parameters in order to understand the physiological countermeasures of hypoxia. METHODS: 17 high-altitude-naïve male subjects (mean age was 26.3 ± 8.1 years) participated in the study. We measured Critical Flicker Fusion Frequency (CFFF), blood oxygen saturation, Psychology Experiment Building (PEBL) including three tests (Modified Math Processing Task, Perceptual Vigilance Task, and Time Estimation Task), as well as Cerebral Blood Flow index (CBFi), mean cerebral artery Systolic and diastolic velocities, Cerebral Pulsatility index (CPi), and heart Rate. All were measured at sea level, at least 1 h after arrival at the hypobaric hypoxia equivalent of 3842 m and 1 h after return to sea level. RESULTS: Under acute exposure to hypobaric hypoxic conditions, significant decrease in CFFF [42.1 ± 1 vs. 43.5 ± 1.7 Hz at sea level (asl), p < 0.01], CBFi (611 ± 51 vs. 665 ± 71 asl, p < 0.01) and blood oxygen saturation (83 ± 4% vs. 98 ± 1% asl, p < 0.001) as compared to pre-ascent values were observed. Physiological countermeasures to hypoxia could be involved as there was no significant change in neuropsychometric tests, Systolic and Diastolic velocities and CPi. A significant increase in Heart Rate (81 ± 15 bpm vs. 66 ± 15 bpm asl, p < 0.001) was observed. All parameters returned to their basal values 1 h after regaining sea level. CONCLUSION: Hypoxia results in a decrease in CFFF, CBFi and oxygen saturation and in an increase in heart rate. As it decreased, Cerebral Blood Flow index does not seem to be the physiological measurement of choice to hypoxia explaining the maintenance of cognitive performance after acute exposure to hypobaric hypoxia and requires further investigation. Cerebral oxygen delivery and extraction could be one of the underlying mechanisms.

Fatal multiple coronary involvements in a young woman with systemic lupus erythematosus.

We report a rare case of fulminant congestive heart failure with fatal outcome in a 21-year-old girl with systemic lupus erythematosus (SLE). A young woman was admitted in the intensive care unit for pericardial tamponade associated with disseminated coagulopathy and refractory shock secondary to multiple coronary aneurysms. Post-mortem examination revealed significant multiple coronary lesions with aneurysms of the interventricular and right coronary arteries, responsible of muscular necrosis, thrombosis of the coronary sinus, and significant pericardial infiltration with hemorrhagic fluid. We describe a refractory cardiac failure with extensive coronary artery involvements, which is very uncommon in young patients with SLE: few cases have been previously described in the literature. We report a rare case of fulminant congestive heart failure with fatal outcome in a young woman with SLE related to extensive coronary involvements.

The "normobaric oxygen paradox": a new tool for the anesthetist?

Hypoxia is the natural trigger for endogenous EPO production but recently the use of intermittent hyperoxia to stimulate EPO has been postulated and this phenomenon has been called the "normobaric oxygen paradox" (NOP). The "NOP" is a mechanism by which oxygen regulates the expression of the Hypoxia Inducible Factor 1 alpha (HIF-1α). The HIF-1α-depending gene regulation is responsible for many different genetic expressions including EPO and VEGF. It has been proposed that relative changes of oxygen availability rather than steady state hypoxic or hyperoxic conditions, play an important role in HIF transcriptional effects. According to this hypothesis, the cell interprets the return to normoxia after a hyperoxic event as an oxygen shortage, and induces HIF-1-regulated gene synthesis, including EPO. Being both a hormone and a cytokine, the actual actions of EPO are complex; its clinical utility has been postulated for neuroprotection and cardioprotection. The precise level of inspired oxygen and the exact timeframe for its iterative administration are not totally known. N-Acetyl-L-Cysteine (NAC) supplementation has been shown to help. All the reported data demonstrate how hyperoxic and hypoxic states can potentially be manipulated if oxygen is been considered as a multifaceted molecule more than just a gas.

Nitric oxide-related endothelial changes in breath-hold and scuba divers.

OBJECTIVE: Scuba and breath-hold divers are compared to investigate whether endothelial response changes are similar despite different exposure(s) to hyperoxia. DESIGN: 14 divers (nine scuba and five breath-holding) performed either one scuba dive (25m/25 minutes) or successive breath-hold dives at a depth of 20 meters, adding up to 25 minutes of immersion time in a diving pool. Flow-mediated dilation (FMD) was measured using echography. Peripheral post-occlusion reactive hyperemia (PORH) was assessed by digital plethysmography and plasmatic nitric oxide (NO) concentration using a nitrate/nitrite colorimetric assay kit. RESULTS: The FMD decreased in both groups. PORH was reduced in scuba divers but increased in breath-hold divers. No difference in circulating NO was observed for the scuba group. Opposingly, an increase in circulating NO was observed for the breath-hold group. CONCLUSION: Some cardiovascular effects can be explained by interaction between NO and superoxide anion during both types of diving ending to less NO availability and reducing FMD. The increased circulating NO in the breath-hold group can be caused by physical exercise. The opposite effects found between FMD and PORH in the breath-hold group can be assimilated to a greater responsiveness to circulating NO in small arteries than in large arteries.

Pulsed high oxygen induces a hypoxic-like response in human umbilical endothelial cells and in humans.

It has been proposed that relative changes of oxygen availability, rather than steady-state hypoxic or hyperoxic conditions, play an important role in hypoxia-inducible factor (HIF) transcriptional effects. According to this hypothesis describing the "normobaric oxygen paradox", normoxia following a hyperoxic event is sensed by tissues as an oxygen shortage, upregulating HIF-1 activity. With the aim of confirming, at cellular and at functional level, that normoxia following a hyperoxic event is "interpreted" as a hypoxic event, we report a combination of experiments addressing the effects of an intermittent increase of oxygen concentration on HIF-1 levels and the activity level of specific oxygen-modulated proteins in cultured human umbilical vein endothelial cells and the effects of hemoglobin levels after intermittent breathing of normobaric high (100%) and low (15%) oxygen in vivo in humans. Our experiments confirm that, during recovery after hyperoxia, an increase of HIF expression occurs in human umbilical vein endothelial cells, associated with an increase of matrix metalloproteinases activity. These data suggest that endothelial cells "interpret" the return to normoxia after hyperoxia as a hypoxic stimulus. At functional level, our data show that breathing both 15 and 100% oxygen 30 min every other day for a period of 10 days induces an increase of hemoglobin levels in humans. This effect was enhanced after the cessation of the oxygen breathing. These results indicate that a sudden decrease in tissue oxygen tension after hyperoxia may act as a trigger for erythropoietin synthesis, thus corroborating the hypothesis that "relative" hypoxia is a potent stimulator of HIF-mediated gene expressions.

The normobaric oxygen paradox: a novel way to administer oxygen as an adjuvant treatment for cancer?

The "normobaric oxygen paradox" is a dual mechanism by which oxygen regulates the expression of the Hypoxia Inducible Factor 1 alpha (HIF-1α). The HIF-1α-depending gene regulation is responsible for many different genetic expressions including EPO and VEGF that are usually expressed in parallel. First, VEGF under-expression could decrease tumor angiogenesis leading to a decrease in tumor growth or even apoptosis of cancer cells. Second, induction of EPO-expression can provide cytoprotection. Altogether, this could be deleterious for cancer cells while helping non-malignant cells (at least neural and cardiac) cells to be protected from the side effects of chemotherapy. Eventually, HIF induction could boost immune response by inflammatory cells, increasing their antitumor activity.

Hemophagocytic syndrome associated with extracerebral toxoplasmosis in an HIV-infected patient.

Hemophagocytic syndrome (HPS) is a clinical entity that combines non-specific clinical and biological features. The diagnosis is usually confirmed by a bone marrow examination. HPS may be primary or secondary to a malignancy or to an infectious or autoimmune disease. Since it was first described, various agents have been implicated, including viruses, bacteria, and parasites. In HIV patients, many cases occur with lymphoma or with a variety of opportunistic infections due to CMV, HHV8, Pneumocystis carinii, Mycobacterium tuberculosis, MAC, toxoplasmosis, and even pneumococcus. We report here a case of an AIDS patient presenting a HPS secondary to an extracerebral form of systemic toxoplasmosis that was only revealed by specific PCR in tissue other than the CNS.

Prevention of external ventricular drain--related ventriculitis.

OBJECTIVE: The purpose of this study was to test if a reduction of external ventricular drains (EVD) related ventriculitis could be achieved by a strict protocol of care and if protocol violation was associated with a higher incidence of EVD-related ventriculitis. METHODS: A written protocol for EVD insertion, nursing and surveillance was implemented. A retrospective comparison of EVD-related ventriculitis incidence was performed between control (161 EVD in 131 patients) and study periods (216 EVD in 175 patients). Risk factor analysis was performed in patients in whom an EVD was inserted during the study period including the relationship between protocol compliance and ventriculitis. A score for the number of protocol violations (absence of hair clipping, absence of a tunnelled EVD, absence of shampooing, incorrect dressing change, inappropriate CSF bag or tap samplings and EVD manipulation) was established for each patient. RESULTS: Incidence of patient-related ventriculitis decreased from 12.2% (1999) down to 5.7% (p<0.05) as well as incidence of EVD-related ventriculitis (9.9% vs 4.6%, p<0.05). During the study period, the only statistically significant risk factors for infection were CSF leak and protocol violations. The mean protocol violation score was 4 times higher in the infected versus the non-infected patients (p<0.0001). Patients with a violation score of 0 or 1 had no infection (EVD duration 2 to 42 days). CONCLUSION: EVD can be left safely, as long as needed, provided that meticulous care is taken for EVD insertion and nursing. EVD duration seems to have no effect on infection incidence.

Empirical treatment of adult postsurgical nosocomial meningitis.

BACKGROUND: The combination of cefotaxime and fosfomycin (CTX-FOS) has been proposed in France for the empirical treatment of postoperative nosocomial meningitis since the late 1980s. The purpose of this work was to evaluate this strategy today, as well as other possible treatments. METHODS: Each patient undergoing a neurosurgical procedure was prospectively included in a database designed for the surveillance of surgical site infection (SSI). For each meningitis detected, we analysed the in vitro susceptibility of the causative micro-organisms to cefotaxime alone (CTX), cefotaxime-fosfomycin (CTX-FOS), vancomycin (VAN) and cefotaxime-vancomycin (CTX-VAN) combinations. The patient population was divided into two groups according to the presence or absence of CSF shunting material. FINDINGS: 116 patients had had a postoperative meningitis/ventriculitis during the last 36 months, among 6447 patients undergoing neurosurgery in our department (1.8%). Ten patients had aseptic meningitis (8.6%). Overall sensitivity to CTX was 69.8%, as compared to 77.3% with CTX-FOS combination (NS). This result was due to a large proportion of fosfomycin resistant cocci in our population. The CTX-VAN combination increased the overall in vitro susceptibility up to 91.5%, but the benefit of this combination was only significant in CSF shunting material patients. In these latter patients, VAN was as effective as CTX-FOS combination. INTERPRETATION: CTX-FOS combination is no longer the best choice for empirical treatment of post neurosurgical meningitis. CTX alone can be safely used in patients without a CSF shunt; in those with either a ventriculostomy or a CSF shunt associated ventriculitis, a CTX-VAN combination could improve treatment efficacy, provided that high doses of vancomycin are used to ensure correct CSF diffusion.