Extracorporeal membrane oxygenation: experience in an adult medical ICU

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a technology that can provide extracorporeal gas exchange to patients with severe pulmonary or cardiac dysfunction. We report on our clinical experience with ECMO in critically ill patients. METHODS: We performed a retrospective analysis of 23 patients treated with ECMO in a medical intensive care unit in a tertiary referral academic centre. RESULTS: 13 patients were considered immunocompetent and 10 were immunocompromised when extracorporeal membrane oxygenation was started. 16 patients presented with acute respiratory distress syndrome (ARDS), 2 patients had intractable cardiac failure, and 5 patients had combined respiratory and cardiac failure. In 16 patients, a veno-venous bypass was constructed; in 7 patients, the initial bypass was venoarterial. 11 patients survived. In 2 patients technical complications were fatal. CONCLUSIONS: Our data indicate that patients with community-acquired pneumonia and no underlying disease will benefit most from this technique. However, long-term survival is possible in immunocompromised patients. Venoarterial bypass can carry a higher risk for technical complications. Increasing experience apparently also reduces the risk of technical complications.     

Arterial-wave reflections are increased in heart failure patients with a left-ventricular assist device

BACKGROUND: Chronic heart failure (HF) is associated with increased central arterial pulse-wave reflections, which may contribute to increased myocardial oxygen demand. Although the treatment of HF via left-ventricular assist device (LVAD) placement has recently become widespread, the effects of LVAD therapy on central arterial pulse-wave reflections are unknown. METHODS: Central aortic pulse-wave analysis was performed on patients with end-stage HF awaiting cardiac transplantation and on healthy age-matched controls using the SphygmoCor (Akor Medical, Sydney, Australia) system. Arterial pulse-wave data were compared between patients receiving LVAD support versus those receiving intravenous inotropic drugs and healthy control patients. RESULTS: Five patients on LVAD support were compared with 10 patients on inotropic drugs and 10 healthy control patients. Aortic augmented pressure and the aortic augmentation index (AI(a)) were higher in LVAD patients compared with inotrope and control patients, despite similar brachial and aortic blood pressures between groups. The AI(a) was significantly higher in LVAD patients than in patients on inotropic drugs (28.2% +/- 10% v 7.9% +/- 9%, P < or = .01). Additionally, there was a significantly higher aortic systolic tension time index, an index of left-ventricular myocardial oxygen demand, in the LVAD group compared with the inotrope group (2655 +/- 298 mm Hg/sec/min v 1748 +/- 303 mm Hg/sec/min, P < .01). CONCLUSIONS: Central arterial pressure-wave reflection is increased in end-stage HF patients on LVAD support compared with those on inotropic drugs, leading to an increase in aortic augmented pressure, AI(a), and systolic tension time index. The AI(a) is also higher in LVAD patients than in healthy controls. This increased central arterial-wave reflection places an additional hemodynamic load on the LVAD device and may have relevance to the medical management of patients after LVAD placement and to the longevity of the LVAD device itself.     

A randomized, controlled trial of the reciprocating procedure device for local anesthesia

The purpose of this study was to determine whether the new reciprocating procedure device (RPD) is superior to the conventional syringe for the administration of local anesthesia. There were 209 local lidocaine anesthesia procedures randomized between the RDP and the conventional syringe. Outcome measures included administration time, anesthesia pain, procedure pain, and operator satisfaction. The RPD significantly reduced anesthesia administration time by 49% (RPD: 0.68 +/- 0.59 min, Syringe: 1.32 +/- 1.01 min, p < 0.001, 95% confidence interval [CI] for % reduction: 36%-60%), reduced anesthesia pain by 27% (RPD visual analog pain scale score: 4.05 +/- 2.64; Syringe: 5.55 +/- 3.00; p < 0.001, 95% CI 14%-38%), reduced significant procedure pain by 74% (p < 0.001, 95% CI 60%-87%), and improved physician satisfaction by 63% (p < 0.001, 95% CI 53%-74%). The RPD markedly reduces the pain associated with lidocaine anesthesia administration, reduces administration time, and maintains the effectiveness of local anesthesia. The RPD is superior to and significantly more effective than the conventional syringe for the administration of local lidocaine anesthesia.     

Elimination of antiviral defense by viral RNase III

Sweet potato (Ipomoea batatas) is an important subsistence and famine reserve crop grown in developing countries where Sweet potato chlorotic stunt virus (SPCSV; Closteroviridae), a single-stranded RNA (ssRNA) crinivirus, synergizes unrelated viruses in co-infected sweet potato plants. The most severe disease and yield losses are caused by co-infection with SPCSV and a potyvirus, Sweet potato feathery mottle virus (SPFMV; Potyviridae). Potyviruses synergize unrelated viruses by suppression of RNA silencing with the P1/HC-Pro polyprotein; however, the SPCSV-SPFMV synergism is unusual in that the potyvirus is the beneficiary. Our data show that transformation of an SPFMV-resistant sweet potato variety with the double-stranded RNA (dsRNA)-specific class 1 RNA endoribonuclease III (RNase3) of SPCSV broke down resistance to SPFMV, leading to high accumulation of SPFMV antigen and severe disease symptoms similar to the synergism in plants co-infected with SPCSV and SPFMV. RNase3-transgenic sweet potatoes also accumulated higher concentrations of 2 other unrelated viruses and developed more severe symptoms than non-transgenic plants. In leaves, RNase3 suppressed ssRNA-induced gene silencing (RNAi) in an endonuclease activity-dependent manner. It cleaved synthetic double-stranded small interfering RNAs (siRNAs) of 21, 22, and 24 bp in vitro to products of approximately 14 bp that are inactive in RNAi. It also affected total siRNA isolated from SPFMV-infected sweet potato plants, suggesting a viral mechanism for suppression of RNAi by cleavage of siRNA. Results implicate RNase3 in suppression of antiviral defense in sweet potato plants and reveal RNase3 as a protein that mediates viral synergism with several unrelated viruses, a function previously described only for P1/HC-Pro.     

Immunocytochemical identification of DNA adducts, O6-methylguanine and 7-methylguanine, in respiratory and other tissues of rat, mouse and Syrian hamster exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

The present paper reports about an immunocytochemical inventoryof the cell types involved in the metabolic activation of thetobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) to a DNA methylating metabolite. The formation and distributionof the methylated DNA bases O⁶-methylguanine (O⁶-meGua) and7-methylguanine (7-MeGua) were studied in respiratory tissues,oesophagus, liver, kidneys, pancreas, small intestine, colonand prostate of rat, mouse and hamster 6 h after treatment witha single dose of 30 mg NNK/kg. The tissue-and cell-specificdistribution of O⁶-meGua- and 7-meGua-specific nuclear stainingshowed the same patterns and were remarkably similar in rat,mouse and hamster in spite of the diverging spectra of NNK-inducedtumours in these species. In nasal tissue, a target for NNK-inducedtumourigenesis in rat and hamster, but not in mouse, adduct-specificnuclear staining was observed in all three species in sustentacularcells, Bowman glands, respiratory epithelial cells and serousglands. Both methylated DNA bases were also observed in basalcells of the olfactory epithelium of rat and (occasionally)hamster, but not in those of the mouse. In the trachea, a targetfor NNK-induced tumourigenesis in hamster only, substantialadduct-specific nuclear staining was found in basal epithelialand glandular cells of the hamster; in the same cells of ratand mouse only a weak nuclear staining was found. In the lung,a common target for NNK-induced tumourigenesis, the formationof O⁶-meGua and 7-meGua was restricted predominantly to bronchialand proximal bronchiolar epithelium. Nuclear staining in therat was occasionally found in alveolar cells and was also observedin hepatocytes. In the three species investigated, O⁶-meGua-and 7-MeGua-specific nuclear staining was found in target andnon-target tissues. Apparently, and in analogy with resultsobtained in other studies, the species-specific organotropyfor tumour formation of NNK is not exclusively determined byDNA methylation. Expanding methylation data with literaturedata on factors considered to be involved in tumour formation,namely proliferation, toxicity and DNA repair among others,still did not lead to a satisfactory explanation for the species-specificorganotropy observed. Additional factors (yet to be identified),need to be taken into account in order to explain (and predict)tumourigenic effects induced by monofunctional methylating agents.     

Localization of DNA adducts formed in the nasal cavity of the rat by the tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK)

The tissue localization of the DNA adducts O6- and 7-methylguanine induced in the nasal cavity by the nicotine-derived carcinogen 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK, 30 mg/kg intraperitoneally) has been investigated immunocytochemically in male Sprague-Dawley rats. Adduct-specific nuclear staining, indicative of the metabolic activation of NNK to a methylating compound, was observed in both respiratory and olfactory mucosa. In the respiratory epithelium, strong staining was generally observed in areas devoid of goblet cells. Less intense staining was observed both in the serous gland cells and their efferent ducts in the respiratory submucosa, whereas the mucous gland cells were unstained. In the olfactory mucosa, the sustentacular and basal cells of the olfactory epithelium were moderately stained; staining varied substantially from site to site. No DNA adduct was detected in the olfactory cells. Strong nuclear staining, similar to that in the respiratory mucosa, was observed in the cells of the Bowman glands of the olfactory submucosa. A similar distribution of methylated DNA bases in nasal tissues has been observed in rats after exposure to other N-nitrosamines and in Syrian hamsters after exposure to NNK. This finding may indicate that in man the same cell types undergo DNA adduct formation after exposure to NNK and other N-nitrosamines.     

Attenuation of cytogenetic damage by 2-mercaptoethanesulfonate in cultured human lymphocytes exposed to cyclophosphamide and its reactive metabolites

Cyclophosphamide (CP) is metabolized to the reactive intermediates, phosphoramide mustard (PAM) and acrolein (AC), which have generally different molecular binding targets. Sodium 2-mercaptoethanesulfonic acid (MESNA) has been used clinically to alleviate hemorrhagic cystitis caused by CP chemotherapy, has exhibited anticarcinogenic effects in rats exposed to CP during a long-term bioassay, and acts in the urogenital tract by reacting with 4'-OH-CP and AC. The purpose of this study was to: (a) compare the relative abilities of PAM and AC to induce cytogenetic damage and cytotoxicity in cultured human lymphocytes; (b) assess the efficacy of MESNA to attenuate the cytogenetic damage and cytotoxicity induced by CP, AC, PAM, and diethyl-4'-hydroperoxycyclophosphamide (DEHP-CP), an activated AC-generating compound; and (c) determine if concanavalin A-stimulated T-lymphocytes, which differentiate into suppressor cells upon lectin activation, exhibit any heightened cytogenetic sensitivity compared to a variety of cultured mammalian cells during exposure to PAM or AC as reported by other investigators. Purified mononuclear leukocytes were stimulated with concanavalin A and exposed to CP (0.5-2.0 mM) without an exogenous activation system, AC (0.001-40.0 microM), PAM (0.0014-27.1 microM), or DEHP-CP (0.1-100.0 microM) in the presence or absence of MESNA (1, 5, or 10 mM). All four compounds induced significant concentration-related increases in the SCE frequency, but only PAM was clastogenic. On an induced SCE/microM basis, PAM was about 130 and 193 times more potent than were DEHP-CP and AC, respectively. MESNA protected against the cytogenetic damage and cytotoxicity induced by the four compounds, but it was particularly effective against AC and DEHP-CP by abolishing SCE induction completely. SCEs and chromosome aberrations differed considerably in their induction kinetics in lymphocytes exposed to PAM, and these disparities suggested an uncoupling of the two phenomena. Although SCE induction was not consistently associated with cytotoxicity with the four agents, chromosome aberration induction coincided with an inhibition of cell cycle kinetics in PAM-treated cells. The exceptionally high SCE frequency of up to 21 times baseline in cells exposed to PAM indicates that T-suppressor lymphocytes stimulated with concanavalin A may be particularly sensitive to the DNA-damaging effects of PAM. Finally, these data suggest that the anticarcinogenicity of MESNA correlates with its ability to attenuate cytogenetic damage and cytotoxicity induced by reactive CP metabolites.     

Radial artery tonometry demonstrates arterial stiffness in children with type 1 diabetes

OBJECTIVE: To determine if children with type 1 diabetes have increased arterial stiffness by estimating augmentation index with the simple noninvasive technique of radial artery tonometry. RESEARCH DESIGN AND METHODS: We studied 98 type 1 diabetic children and 57 healthy control subjects, ages 10-18 years, matched for age, sex, race, and BMI, generating 43 matched pairs. Radial artery tonometry was performed, and blood was collected for analysis of fasting lipids, HbA1c, glucose, and cytokines in all children. RESULTS: Children with diabetes had a significantly higher augmentation index corrected to a heart rate of 75 (AI75) than their matched control subjects. Mean AI75 in type 1 diabetic subjects was 1.11 +/- 10.15 versus -3.32 +/- 10.36 in control subjects. The case-control difference was 5.20 +/- 11.02 (P=0.0031). CONCLUSIONS: Children with type 1 diabetes have increased arterial stiffness compared with healthy control subjects. Radial artery tonometry is a simple noninvasive technique that could be added to the armamentarium of tests used to provide cardiovascular risk stratification in children with type 1 diabetes.     

Development and validation of a Pneumocystis jirovecii real-time polymerase chain reaction assay for diagnosis of Pneumocystis pneumonia

BACKGROUND:Pneumocystis jirovecii (PJ), a pathogenic fungus, causes severe interstitial Pneumocystis pneumonia (PCP) among immunocompromised patients. A laboratory-developed real-time polyermase chain reaction (PCR) assay was validated for PJ detection to improve diagnosis of PCP.METHODS:Forty stored bronchoalveolar lavage (BAL) samples (20 known PJ positive [PJ+] and 20 known PJ negative [PJ−]) were initially tested using the molecular assay. Ninety-two sequentially collected BAL samples were then analyzed using an immunofluorescence assay (IFA) and secondarily tested using the PJ real-time PCR assay. Discrepant results were resolved by retesting BAL samples using another real-time PCR assay with a different target. PJ real-time PCR assay performance was compared with the existing gold standard (ie, IFA) and a modified gold standard, in which a true positive was defined as a sample that tested positive in two of three methods in a patient suspected to have PCP.RESULTS:Ninety of 132 (68%) BAL fluid samples were collected from immunocompromised patients. Thirteen of 92 (14%) BALs collected were PJ+ when tested using IFA. A total of 40 BAL samples were PJ+ in the present study including: all IFA positive samples (n=13); all referred PJ+ BAL samples (n=20); and seven additional BAL samples that were IFA negative, but positive using the modified gold standard. Compared with IFA, the PJ real-time PCR had sensitivity, specificity, and positive and negative predictive values of 100%, 91%, 65% and 100%, respectively. Compared with the modified gold standard, PJ real-time PCR had a sensitivity, specificity, and positive and negative predictive values of 100%.CONCLUSION:PJ real-time PCR improved detection of PJ in immunocompromised patients.