Mark T. Gladwin

Cannulation of the internal jugular vein: is postprocedural chest radiography always necessary?

OBJECTIVESnTo determine whether clinical features can be used in a decision rule to prospectively identify a subgroup of internal jugular catheter placements that are correctly positioned and free from mechanical complications, thus obviating the need for routine postprocedural chest radiographs in selected patients.nnnDESIGNnProspective cohort study.nnnSETTINGnTertiary care teaching hospital.nnnPATIENTSnA total of 107 consecutive patients who presented to our catheter service for internal jugular catheter insertion because of clinical indications between November 1995 and April 1996. Exclusion criteria were mechanical ventilation, an altered mental status, an age of <15 years, and a height of <152 cm.nnnINTERVENTIONSnRight or left internal jugular vein catheter placement followed by a postprocedural chest radiograph.nnnMEASUREMENTSnThe operating physician completed a detailed questionnaire for each catheter insertion, designed to detect potential complications and to predict the necessity, or lack of necessity, for a postprocedural chest radiograph. The questionnaire documented patient characteristics, the number of needle passes, difficulty establishing access, operator experience, poor anatomical landmarks, number of previous catheter placements, resistance to wire or catheter advancement, resistance to aspiration of blood or flushing of the catheter ports, sensations in the ear, chest, or arm, and development of signs or symptoms suggestive of pneumothorax. After catheter insertion, chest radiographs were obtained to assess for mechanical complications and malpositioned catheters.nnnMAIN RESULTSnIn 46 cases, the decision rule predicted either a complication or a malposition and, thus, the need for a chest radiograph. In 61 cases, neither was predicted (no chest radiograph was needed). Radiographs confirmed one complication (pneumothorax) and 15 catheter tip malpositions (nine in the right atrium and six in the right axillary vein). Among the 46 cases predicted to have a potential complication or malposition, there were one actual complication (pneumothorax) and six actual malpositions (three axillary vein malpositions and three right atrial malpositions). The positive predictive value of this decision rule is 15%. Among the 61 cases predicted to be free from complications or malpositions and not to require a postprocedural chest radiograph, there were nine unexpected malpositions (three axillary vein malpositions and six right atrial malpositions). The negative predictive value is 85%. The overall sensitivity of the decision rule for detecting complications and malpositions is 44%, and the specificity is 55%.nnnCONCLUSIONSnIn experienced hands, internal jugular venous catheterization is a safe procedure. However, the incidence of axillary vein or right atrial catheter malposition is 14%, and clinical factors alone will not reliably identify malpositioned catheters. Chest radiographs are necessary to ensure correct internal jugular catheter position.

Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy

&NA; Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States. The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality rate ranging from 1 to 3%. A significant number of patients who survive CO poisoning suffer from long‐term neurological and affective sequelae. The neurologic deficits do not necessarily correlate with blood CO levels but likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart. Long‐term neurocognitive deficits occur in 15‐40% of patients, whereas approximately one‐third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction. Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy. Management of these patients requires the identification of accompanying drug ingestions, especially in the setting of intentional poisoning, fire‐related toxic gas exposures, and inhalational injuries. Conventional therapy is limited to normobaric and hyperbaric oxygen, with no available antidotal therapy. Although hyperbaric oxygen significantly reduces the permanent neurological and affective effects of CO poisoning, a portion of survivors still have substantial morbidity. There has been some early success in therapies targeting the downstream inflammatory and oxidative effects of CO poisoning. New methods to directly target the toxic effect of CO, such as CO scavenging agents, are currently under development.

Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning

A mutant five-coordinate neuroglobin with a very high carbon monoxide binding affinity acts as an antidote to bind and eliminate CO. Antidote for an invisible foe We cannot see it, taste it, or smell it. Nevertheless, carbon monoxide is a deadly poison; it is a frequent cause of poisoning all over the world. This gaseous product of incomplete combustion displaces the oxygen molecules carried by hemoglobin throughout the body, thereby starving tissues of oxygen and causing death. Now, Azarov et al. have reengineered neuroglobin, a hemoglobin-like protein from the brain, so that it binds carbon monoxide more quickly and tightly than does hemoglobin. When CO-poisoned mice are infused with the artificial neuroglobin, it scavenges the CO, freeing hemoglobin to perform its oxygen delivery duty. The engineered neuroglobin ensures the survival of CO-poisoned mice. The half-life of CO in human red blood cells treated with neuroglobin is only 25 s, compared with a published half-life of 20 min with hyberbaric oxygen, the best treatment currently available. Engineered globins show encouraging promise as antidotes for this lethal gas. Carbon monoxide (CO) is a leading cause of poisoning deaths worldwide, with no available antidotal therapy. We introduce a potential treatment paradigm for CO poisoning, based on near-irreversible binding of CO by an engineered human neuroglobin (Ngb). Ngb is a six-coordinate hemoprotein, with the heme iron coordinated by two histidine residues. We mutated the distal histidine to glutamine (H64Q) and substituted three surface cysteines with less reactive amino acids to form a five-coordinate heme protein (Ngb-H64Q-CCC). This molecule exhibited an unusually high affinity for gaseous ligands, with a P50 (partial pressure of O2 at which hemoglobin is half-saturated) value for oxygen of 0.015 mmHg. Ngb-H64Q-CCC bound CO about 500 times more strongly than did hemoglobin. Incubation of Ngb-H64Q-CCC with 100% CO-saturated hemoglobin, either cell-free or encapsulated in human red blood cells, reduced the half-life of carboxyhemoglobin to 0.11 and 0.41 min, respectively, from ≥200 min when the hemoglobin or red blood cells were exposed only to air. Infusion of Ngb-H64Q-CCC to CO-poisoned mice enhanced CO removal from red blood cells, restored heart rate and blood pressure, increased survival, and was followed by rapid renal elimination of CO-bound Ngb-H64Q-CCC. Heme-based scavenger molecules with very high CO binding affinity, such as our mutant five-coordinate Ngb, are potential antidotes for CO poisoning by virtue of their ability to bind and eliminate CO.

Pulmonary vascular disease in the setting of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is defined as clinical features of heart failure, ideally with biomarker evidence such as elevated plasma natriuretic peptide levels, in the setting of an ejection fraction (EF) greater than 50% and imaging evidence of diastolic left ventricular dysfunction [1,2]. In the absence of cardiac imaging or invasive hemodynamics, this is a clinical syndrome that is often indistinguishable from heart failure with reduced ejection fraction (HFrEF). HFpEF and HFrEF present with a cadre of comparable signs and symptoms including jugular venous distention, pulmonary rales on auscultation, breathlessness, orthopnea, exercise intolerance, exertional dyspnea, fatigue and peripheral edema. HFpEF accounts for at least half of all diagnoses of heart failure [1,2]. Pulmonary hypertension (PH) is a common complication of HFpEF that is linked to worse disease morbidity and mortality. In fact, mortality has been linked to increases in the intrinsic pulmonary vascular resistance in the setting of increased left ventricular end diastolic pressure, characterized hemodynamically by rises in the transpulmonary pressure gradient, pulmonary vascular resistance or diastolic pressure gradient. Despite being the most common form of PH, there are no approved therapies for the treatment of PH secondary to HFpEF. This review will summarize the hemodynamic classifications of PH in the setting of HFpEF, mechanisms of disease, the potential contribution of pulmonary vascular disease to poor outcomes in patients with HFpEF, and new approaches to therapy.

Sleep phenotype in the Townes mouse model of sickle cell disease

PurposePatients with sickle cell disease (SCD) regularly experience abnormal sleep, characterized by frequent arousals and reduced total sleep time. However, obstructive sleep apnea syndrome (OSAS) is a common comorbidity of SCD, making it unclear whether the disease per se is impacting sleep, or sleep disruption is secondary to the presence of OSAS. Thus, we assessed sleep, independent of OSAS, using a mouse model of SCD.MethodsSleep was compared between 10-to-12-week-old Townes knockout-transgenic mice with the sickle cell phenotype SS (nu2009=u20096) and Townes mice with sickle cell trait AS (nu2009=u20096; control). The mice underwent chronic polysomnographic electrode implantation (4EEG/2EMG) to assess sleep architecture.ResultsThe SS mice had significantly lower hemoglobin concentration compared to control AS mice (7.3u2009±u20091.3 vs. 12.9u2009±u20091.7xa0g/dL; pu2009<u20090.01), consistent with the expected SCD phenotype. SS mice exhibited significantly decreased total NREM sleep time (45.0u2009±u20090.7 vs. 53.0u2009±u20091.3% 24xa0h sleep time; pu2009<u20090.01), but no change in total REM sleep time compared to the AS mice. The SS mice took longer to resume sleep after a wake period compared to the AS mice (3.2u2009±u20090.3xa0min vs. 1.9u2009±u20090.2xa0min; pu2009<u20090.05). Unexpectedly, SS mice experienced fewer arousals compared to AS mice (19.0u2009±u20090.9 vs. 23.3u2009±u20092.1 arousals/h of sleep; pu2009=u20090.031).ConclusionsThe presence of decreased total NREM sleep associated with reduced arousals, in the absence of OSAS, suggests a distinctive underlying sleep phenotype in a mouse model of SCD.

Experimental intravascular hemolysis induces hemodynamic and pathological pulmonary hypertension: association with accelerated purine metabolism

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive administration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200u2009mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1u2009±u20091.1, 41.5u2009±u20090.5 and 85.1u2009±u20095.9 in untreated, HAB treated and SU+HAB treated rats, respectively). In rats, repetitive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted.

Biomarker signatures of sickle cell disease severity

Identifying sickle cell disease patients at high risk of complications could lead to personalized treatment and better prognosis but despite many advances prediction of the clinical course of these patients remains elusive. We propose a system-type approach to discover profiles of multiple, common biomarkers that correlate with morbidity and mortality in sickle cell disease. We used cluster analysis to discover 17 signatures of 17 common circulating biomarkers in 2320 participants of the Cooperative Study of Sickle Cell Disease, and evaluated the association of these signatures with risk for stroke, pain, leg ulceration, acute chest syndrome, avascular necrosis, seizure, death, and trend of fetal hemoglobin and hemolysis using longitudinally collected data. The analysis shows that some of the signatures are associated with reduced risk for complications, while others are associated with increased risk for complications. We also show that these signatures repeat in two more contemporary studies of sickle cell disease and correlate with recently discovered biomarkers of pulmonary vascular disease. With replication and further study, these biomarker signatures could become an important and affordable precision medicine tool to aid treatment and management of the disease.

A 53-Year-Old Woman with Severe Carbon Monoxide Poisoning

A 60-year-old woman with amedical history of depression, anxiety, and prior suicide attempts presented after being found unconscious in an enclosed garage with the car engine running. Carbon monoxide (CO) levels in the garage were in the range of 120 ppm at the time of her discovery, and the duration of her exposure was unknown. She required intubation in the field for airway protection. On arrival in the emergency room, her heart rate was 120–130 beats per minute and her blood pressure was 78/57 mm Hg. Her initial arterial blood gas analysis was notable for a pH of 7.32, PCO2 of 33 mm Hg, PO2 of 380 mm Hg, bicarbonate of 16 mEq/L, and a carboxyhemoglobin level of 24.0%, which decreased to 1.3% after 5 hours of 100% oxygen administration. Due to her initial clinical instability, including her ongoing need for mechanical ventilation, hyperbaric oxygen therapy was not initiated. Labs were notable for lactate 4.5 mmol/L, anion gap of 16, and toxicology screen negative for volatile alcohols, ethanol, acetaminophen, or salicylate. Complete blood count was within normal limits, and urine drug screen was only positive for benzodiazepines. Her initial troponin level was 0.98 ng/ml (normal ,0.012 ng/ml), and her ECG was notable only for sinus tachycardia.