Daily Ards Research Analysis

Acute respiratory distress syndrome (ARDS) is present in >10% of all people admitted to critical care and is associated with severe morbidity and mortality. Despite more than half a century since its first description, no efficacious pharmacological therapies have been developed, and little progress has been made in improving clinical outcomes. Neutrophils are the principal drivers of ARDS, with their priming and subsequent aberrant downstream functions, including interleukin (IL) 1β and IL-18 secretion, central to the disease pathogenesis. The dominant pathways through which IL-1β and IL-18 are believed to be elaborated are multimeric protein structures called inflammasomes that consist of sensor proteins, adaptor proteins and an effector enzyme. The inflammasome's initial activation depends on one of a variety of damage-associated (DAMP) or pathogen-associated (PAMP) molecular patterns. However, once activated, a common downstream inflammatory pathway is initiated regardless of the specific DAMP or PAMP involved. Several inflammasomes exist in humans. The nucleotide-binding domain leucine-rich repeat (NLR) family, pyrin domain-containing 3 (NLRP3), inflammasome is the best described in the context of ARDS and is known to be activated in both infective and sterile cases. The NLR family, caspase activation and recruitment domain-containing 4 (NLRC4) and absent in melanoma 2 (AIM2) inflammasomes have also been implicated in various ARDS settings, as have inflammasome-independent pathways. Further work is required to understand human biology as much of our knowledge is extrapolated from rodent experimental models. Experimental lung injury models have demonstrated beneficial responses to inflammasome, IL-1β and IL-18 blockade. However, findings have yet to be successfully translated into humans with ARDS, likely due to an underappreciation of the central role of the neutrophil inflammasome. A thorough understanding of inflammasome pathways is vital for critical care clinicians and researchers and for the development of beneficial therapies. In this review, we describe the central role of the inflammasome in the development of ARDS and its potential for immunomodulation, highlighting key areas for future research.

Malignant hyperthermia is a pharmacogenetic disorder that manifests clinically as a hypermetabolic crisis when a patient with a mutation in the ryanodine or dihydropyridine receptor genes is exposed to neuromuscular blocking agents. Depolarizing neuromuscular agents are known to cause malignant hyperthermia, but cases caused by nondepolarizing agents are rarely reported. We present a case consistent with malignant hyperthermia after receipt of cisatracurium, a nondepolarizing anesthetic agent. A 57-year-old male patient presented with shortness of breath and increased edema of the lower extremities, found to be clinically volume overloaded. Respiratory status did not improve with diuresis and non-invasive ventilation. He developed severe acute respiratory distress syndrome necessitating endotracheal intubation and ventilation. The patient was beginning to clinically recover when he went into several instances of cardiopulmonary arrest with the eventual return of circulation. An intravenous infusion of cisatracurium was initiated to improve ventilation, and the patient's core temperature rose to 109 degrees F shortly thereafter. Dantrolene was given with an improvement in temperature just before the patient's family opted for comfort measures. Based on our analysis using the Naranjo score for adverse drug reactions, cisatracurium was the probable culprit for the development of malignant hyperthermia. The development of malignant hyperthermia in response to non-depolarizing neuromuscular blockers is a very rare phenomenon but should remain on the list of differential diagnoses in the setting of rapid rise in temperature so that dantrolene may be administered as quickly as possible.

RATIONALE: Stüve-Wiedemann syndrome (SWS) is a rare, severe autosomal recessive disorder (#OMIM 601559) caused by pathogenic variants in the LIFR gene. It is characterized by skeletal dysplasia and dysautonomia and carries a high mortality rate in infancy, which decreases significantly after the age of 2. Detailed case descriptions enhance understanding of this rare condition. PATIENT CONCERNS: We report a male, full-term infant born to consanguineous Yemeni parents with no family history of genetic disorders. Prenatal ultrasound revealed short, bowed long bones suggestive of skeletal dysplasia. At 12 hours of age, the infant developed respiratory distress, poor sucking, and an agitated cry. At 48 hours, he experienced unexplained hyperthermia, and a comprehensive septic workup was negative. DIAGNOSES: Initial findings included generalized hypotonia, hyporeflexia, and dysmorphic features (micrognathia, camptodactyly, short, and bowed limbs). Radiographic imaging revealed skeletal abnormalities. Whole exome sequencing identified a novel homozygous pathogenic variant in the LIFR gene (c.2257dup p.(Arg753Lysfs*20)), confirming the diagnosis of autosomal recessive SWS type 1. INTERVENTIONS: The infant was admitted to the neonatal intensive care unit, received nasal oxygen support, and was managed with orogastric tube feeding due to poor sucking and swallowing. OUTCOMES: At 5 months, the infant remains dependent on orogastric tube feeding, with less frequent hyperthermic episodes. LESSONS: SWS is a rare genetic disorder with a wide phenotypic spectrum. Early recognition and multidisciplinary management are crucial to addressing the high mortality risk associated with dysautonomia in infancy. Case reports of novel variants contribute to a deeper understanding of SWS and highlight the importance of tailored clinical care for improved outcomes.