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1.  The Assessment of Airway Maneuvers and Interventions in University Canadian Football, Ice Hockey, and Soccer Players 
Journal of Athletic Training  2011;46(2):117-125.
Managing an airway in an unconscious athlete is a lifesaving skill that may be made more difficult by the recent changes in protective equipment. Different airway maneuvers and techniques may be required to help ventilate an unconscious athlete who is wearing full protective equipment.
To assess the effectiveness of different airway maneuvers with football, ice hockey, and soccer players wearing full protective equipment.
Crossover study.
University sports medicine clinic.
Patients or Other Participants:
A total of 146 university varsity athletes, consisting of 62 football, 45 ice hockey, and 39 soccer players.
Athletes were assessed for different airway and physical characteristics. Three investigators then evaluated the effectiveness of different bag-valve-mask (BVM) ventilation techniques in supine athletes who were wearing protective equipment while inline cervical spine immobilization was maintained.
Main Outcome Measure(s):
The effectiveness of 1-person BVM ventilation (1-BVM), 2-person BVM ventilation (2-BVM), and inline immobilization and ventilation (IIV) was judged by each investigator for each athlete using a 4-point rating scale.
All forms of ventilation were least difficult in soccer players and most difficult in football players. When compared with 1-BVM, both 2-BVM and IIV were deemed more effective by all investigators for all athletes. Interference from the helmet and stabilizer were common reasons for difficult ventilation in football and ice hockey players.
Sports medicine professionals should practice and be comfortable with different ventilation techniques for athletes wearing full equipment. The use of a new ventilation technique, termed inline immobilization and ventilation, may be beneficial, especially when the number of responders is limited.
PMCID: PMC3070498  PMID: 21391796
emergency management; ventilation; resuscitation
2.  From Mouth-to-Mouth to Bag-Valve-Mask Ventilation: Evolution and Characteristics of Actual Devices—A Review of the Literature 
BioMed Research International  2014;2014:762053.
Manual ventilation is a vital procedure, which remains difficult to achieve for patients who require ventilatory support. It has to be performed by experienced healthcare providers that are regularly trained for the use of bag-valve-mask (BVM) in emergency situations. We will give in this paper, a historical view on manual ventilation's evolution throughout the last decades and describe the technical characteristics, advantages, and hazards of the main devices currently found in the market. Artificial ventilation has developed progressively and research is still going on to improve the actual devices used. Throughout the past years, a brand-new generation of ventilators was developed, but little was done for manual ventilation. Many adverse outcomes due to faulty valve or misassembly were reported in the literature, as well as some difficulties to ensure efficient insufflation according to usual respiratory parameters. These serious incidents underline the importance of BVM system routine check and especially the unidirectional valve reassembly after sterilization, by only experienced and trained personnel. Single use built-in devices may prevent disassembly problems and are safer than the reusable ones. Through new devices and technical improvements, the safety of BVM might be increased.
PMCID: PMC4058195  PMID: 24971346
3.  End-tidal carbon dioxide monitoring during bag valve ventilation: the use of a new portable device 
For healthcare providers in the prehospital setting, bag-valve mask (BVM) ventilation could be as efficacious and safe as endotracheal intubation. To facilitate the evaluation of efficacious ventilation, capnographs have been further developed into small and convenient devices able to provide end- tidal carbon dioxide (ETCO2). The aim of this study was to investigate whether a new portable device (EMMA™) attached to a ventilation mask would provide ETCO2 values accurate enough to confirm proper BVM ventilation.
A prospective observational trial was conducted in a single level-2 centre. Twenty-two patients under general anaesthesia were manually ventilated. ETCO2 was measured every five minutes with the study device and venous PCO2 (PvCO2) was simultaneously measured for comparison. Bland- Altman plots were used to compare ETCO2, and PvCO2.
The patients were all hemodynamically and respiratory stable during anaesthesia. End-tidal carbon dioxide values were corresponding to venous gases during BVM ventilation under optimal conditions. The bias, the mean of the differences between the two methods (device versus venous blood gases), for time points 1-4 ranges from -1.37 to -1.62.
The portable device, EMMA™ is suitable for determining carbon dioxide in expired air (kPa) as compared to simultaneous samples of PvCO2. It could therefore, be a supportive tool to asses the BVM ventilation in the demanding prehospital and emergency setting.
PMCID: PMC2949667  PMID: 20840740
4.  Safety and Pharmacokinetics of Bevirimat (PA-457), a Novel Inhibitor of Human Immunodeficiency Virus Maturation, in Healthy Volunteers▿  
Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV) maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n = 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n = 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.
PMCID: PMC2043192  PMID: 17576843
5.  A comparison between over-the-head and lateral cardiopulmonary resuscitation with a single rescuer by bag-valve mask 
Saudi Journal of Anaesthesia  2014;8(1):30-37.
mask fixation in the lateral position is difficult during CPR.
the aim of this study is to compare the lateral CPR for the use of bag-valve mask by single paramedic rescuer as well as over-the-head CPR on the chest compression and ventilation on the manikin.
Settings and Design:
Mazandaran University of Medical Sciences. The design of this study was a randomized cross-over trial.
participants learned a standardized theoretical introduction CPR according to the 2010 guidelines. The total number of chest compressions per two minutes was measured. Total number of correct and wrong ventilation per two minutes was evaluated.
Statistical Analysis:
we used Wilcoxon signed-rank test to analyze the non-normally distributed data in dependence groups A. P-value of more than 0.05 was considered to show statistical significance.
there were 100 participants (45 women and 55 men) who participated in the study from September to March, 2011. The compression and ventilation rate in lateral CPR was lower than OTH CPR. Around 51% of participants had correct chest compression rate more than 90 beats per minute in lateral CPR and 65% of them had equal or more than ten correct ventilations per minute.
in conclusion, this study confirmed that in a simulated CPR model over-the-head position CPR led to a better BLS than the lateral position CPR by a single paramedic student with a BVM device. We also concluded that by this new BVM fixation method on the face of the patients in the lateral position CPR can be a good alternative over-the-head mask fixation by a single trained rescuer.
PMCID: PMC3950449  PMID: 24665237
Bag-valve mask ventilation; lateral CPR; over-the-head CPR; standard CPR; single rescuer
6.  Predicting Bevirimat resistance of HIV-1 from genotype 
BMC Bioinformatics  2010;11:37.
Maturation inhibitors are a new class of antiretroviral drugs. Bevirimat (BVM) was the first substance in this class of inhibitors entering clinical trials. While the inhibitory function of BVM is well established, the molecular mechanisms of action and resistance are not well understood. It is known that mutations in the regions CS p24/p2 and p2 can cause phenotypic resistance to BVM. We have investigated a set of p24/p2 sequences of HIV-1 of known phenotypic resistance to BVM to test whether BVM resistance can be predicted from sequence, and to identify possible molecular mechanisms of BVM resistance in HIV-1.
We used artificial neural networks and random forests with different descriptors for the prediction of BVM resistance. Random forests with hydrophobicity as descriptor performed best and classified the sequences with an area under the Receiver Operating Characteristics (ROC) curve of 0.93 ± 0.001. For the collected data we find that p2 sequence positions 369 to 376 have the highest impact on resistance, with positions 370 and 372 being particularly important. These findings are in partial agreement with other recent studies. Apart from the complex machine learning models we derived a number of simple rules that predict BVM resistance from sequence with surprising accuracy. According to computational predictions based on the data set used, cleavage sites are usually not shifted by resistance mutations. However, we found that resistance mutations could shorten and weaken the α-helix in p2, which hints at a possible resistance mechanism.
We found that BVM resistance of HIV-1 can be predicted well from the sequence of the p2 peptide, which may prove useful for personalized therapy if maturation inhibitors reach clinical practice. Results of secondary structure analysis are compatible with a possible route to BVM resistance in which mutations weaken a six-helix bundle discovered in recent experiments, and thus ease Gag cleavage by the retroviral protease.
PMCID: PMC3224585  PMID: 20089140
7.  Pre-Hospital Intubation Factors and Pneumonia in Trauma Patients 
Surgical Infections  2011;12(5):339-344.
We reported similar rates of ventilator-associated pneumonia (VAP) previously in trauma patients intubated either in a pre-hospital (PH) venue or the emergency department. A subset of PH intubations with continuous quality assessment was re-examined to identify the intubation factors associated with VAP.
The subgroup was derived from an existing data set of consecutive adult trauma patients intubated prior to Level I trauma center admission July 2007–July 2008. Intubation details recorded included bag-valve mask ventilation (BVM) and the presence of material in the airway. The diagnosis of VAP was made preferentially by quantitative bronchoalveolar lavage (BAL) cultures (≥104 colony-forming units indicating infection). Baseline data, injury characteristics, and circumstances of intubation of patients with and without VAP were compared by univariable analysis.
Detailed data were available for 197 patients; 32 (16.2%) developed VAP, on average 6.0±0.7 days after admission. Baseline characteristics were similar in the groups, but diabetes mellitus was more common in the VAP group (4 [12.5%] vs. 5 [3.0%]; p=0.02). There was a higher rate of blunt injury in the VAP patients (28 [87.5%] vs. 106 [64.2%]; p=0.01) and higher injury severity scores (33.1±2.8 vs. 23.0±1.0; p=0.0002) and chest Abbreviated Injury Scores (2.6±0.3 vs. 1.5±0.1; p=0.002). Lower Glasgow Coma Scale scores (7.9±0.9 vs. 9.9±0.4; p=0.04) and greater use of BVM (18 [56.3%] vs. 56 [34.0%]; p=0.02) were observed in patients who developed VAP. Among aspirations, 10 (31.3%) of patients with emesis developed VAP compared with only 4 (12.5%) with blood in the airway (p=0.003).
Aspiration, along with depressed consciousness and greater injury severity, may predispose trauma patients to VAP. Prospective studies should focus on the quality and timing of aspiration relative to intubation to determine if novel interventions can prevent aspiration or decrease the risk of VAP after aspiration.
PMCID: PMC3607967  PMID: 21933010
8.  Manual versus automatic bladder wall thickness measurements: a method comparison study 
World Journal of Urology  2009;27(6):747-753.
To compare repeatability and agreement of conventional ultrasound bladder wall thickness (BWT) measurements with automatically obtained BWT measurements by the BVM 6500 device.
Adult patients with lower urinary tract symptoms, urinary incontinence, or postvoid residual urine were urodynamically assessed. During two subsequent cystometry sessions the infusion pump was temporarily stopped at 150 and 250 ml bladder filling to measure BWT with conventional ultrasound and the BVM 6500 device. For each method and each bladder filling, repeatability and variation was assessed by the method of Bland and Altman.
Fifty unselected patients (30 men, 20 women) aged 21–86 years (median 62.5 years) were prospectively evaluated. Invalid BWT measurements were encountered in 2.1–14% of patients when using the BVM 6500 versus 0% with conventional ultrasound (significant only during the second measurement at 150 ml bladder filling). Mean difference in BWT values between the measurements of one technique was −0.1 to +0.01 mm. Measurement variation between replicate measurements was smaller for conventional ultrasound and the smallest for 250 ml bladder filling. Mean difference between the two techniques was 0.11–0.23 mm and did not differ significantly. The BVM 6500 device was not able to correctly measure BWTs above 4 mm.
Both BWT measurements are repeatable and agree with each other. However, conventional ultrasound measurements have a smaller measurement variance, can measure BWT in all patients, and BWTs above 4 mm.
PMCID: PMC2780620  PMID: 19238399
Bladder wall thickness; Ultrasound; BVM 6500; Repeatability; Accuracy
9.  Feasibility of written instructions in airway management training of laryngeal tube 
Airway management is of essential importance in emergency care. Training and skill retention of endotracheal intubation (ETI) - the technique considered as the "gold standard" -, poses a problem especially among care providers experiencing a low frequency of airway management situations. Therefore, alternative airway devices such as the laryngeal tube (LT) with potentially steeper learning curves have been developed and studied. Our aim was to evaluate in a manikin model the use of LT after no other training than written instructions only.
To evaluate the amount of training required to use the LT in a scenario of airway compromise, we assessed the feasibility of providing written instructions and pictures showing its use to 67 out- and in-hospital emergency care providers attending an Emergency Care conference. The majority of the participants were either nurses or firemen with a median of 5 years' history of work in emergency care.
In this study 55% of all participants inserted the LT on the first attempt without additional instructions. An additional 42% required verbal instructions before successful insertion. Overall, 97% of the participants successfully inserted the LT with two attempts.
In logistic regression analysis, no relationship was detected between background variables (basic education, experience of emergency work, frequency of bag-valve-mask ventilation (BVM) and frequency of ETI) and successful insertion of the LT in less than 30 seconds, ability to maintain normoventilation (7 l/min) and need for further instructions during the test.
We found that in this pilot study majority of emergency care providers could insert LT with one or two attempts with written instructions, pictures and verbal instruction. This may provide an option to simplify the training of airway management with LT.
PMCID: PMC3199246  PMID: 21982179
Airway management; laryngeal tube; training
10.  Post Contrast Susceptibility-Weighted Imaging: A Novel technique for the Detection of Arteriovenous Shunting in Vascular Malformations of the Brain 
To determine the utility of post contrast susceptibility-weighted magnetic resonance imaging (PCSWI) in the evaluation of vascular malformations of the brain (BVM).
Materials and Methods
We retrospectively evaluated PCSWI and digital subtraction angiography (DSA) data from 16 consecutive patients with known or suspected BVM, which had been entered into a prospectively maintained database during a 1-year period. There had been no intervening treatment or change in patients’ symptoms between the PCSWI and DSA studies. The utility of PCSWI in the detection of AVS was compared to that of routine non-contrast susceptibility weighted imaging (SWI), time of flight Magnetic Resonance angiography (TOFMRA) and contrast enhanced Magnetic Resonance angiography (CEMRA) using DSA results as the reference standard. The presence of AVS in PCSWI or SWI sequences was defined by the presence of abnormal signal hyperintensity in the venous structures adjacent to the BVM.
A total of 17 BVMs were identified by DSA (9 newly diagnosed arteriovenous malformations, 3 dural arteriovenous fistulas, 4 treated arteriovenous malformations with residual AVS and 1 complex developmental venous anomaly). PCSWI was 100% sensitive and 100% specific with 100% positive predictive value (PPV) and 100% negative predictive value (NPV) for the detection of AVS in these BVMs. The PCSWI/SWI signal intensity ratio in the most prominent early draining venous structure was 1.2 ± 0.32.
PCSWI appears to be superior to SWI, TOFMRA and CEMRA in detecting AVS in BVMs and may be useful in the initial diagnosis and follow-up of patients with BVMs.
PMCID: PMC3202078  PMID: 21940964
Susceptibility-weighted imaging (SWI); Arteriovenous shunting; Arteriovenous malformation (AVM); Developmental venous anomalies (DVA)
11.  Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457) ▿ †  
Journal of Virology  2009;83(10):4884-4894.
The maturation inhibitor bevirimat [3-O-(3′,3′dimethysuccinyl)betulinic acid; BVM; also known as PA-457 or DSB] potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking protease (PR)-mediated cleavage at the junction between capsid (CA) and spacer peptide 1 (SP1) in Gag. We previously isolated a panel of single-amino-acid substitutions that confer resistance to BVM in vitro (C. S. Adamson, S. D. Ablan, I. Boeras, R. Goila-Gaur, F. Soheilian, K. Nagashima, F. Li, K. Salzwedel, M. Sakalian, C. T. Wild, and E. O. Freed, J. Virol. 80:10957-10971, 2006). The BVM resistance mutations cluster at or near the CA-SP1 cleavage site. Because BVM likely will be used clinically in patients harboring viruses resistant to PR inhibitors (PIs), in this study we evaluated the interplay between a PI-resistant (PIR) PR and the BVM resistance mutations in Gag. As expected, the PIR mutations had no effect on inhibition by BVM; however, we observed general processing defects and a slight delay in viral replication in Jurkat T cells associated with the PIR mutations, even in the absence of compound. When combined, most BVM resistance and PIR mutations acted additively to impair viral replication, particularly in the presence of BVM. The BVM-resistant mutant SP1-A1V was an exception, as it supported robust replication in the context of either wild-type (WT) or PIR PR, even at high BVM concentrations. Significantly, the emergence of BVM resistance was delayed in the context of the PIR PR, and the SP1-A1V mutation was acquired most frequently with either WT or PIR PR. These results suggest that resistance to BVM is less likely to emerge in patients who have failed PIs than in patients who are PI naïve. We predict that the SP1-A1V substitution is the most likely to emerge in vivo, as this mutant replicates robustly independently of PR mutations or BVM. These findings offer insights into the effect of PIR mutations on the evolution of BVM resistance in PI-experienced patients.
PMCID: PMC2682084  PMID: 19279107
12.  Emergency airway management by non-anaesthesia house officers—a comparison of three strategies 
Objectives—The purpose of this study was to determine effects of different airway devices and tidal volumes on lung ventilation and gastric inflation in an unprotected airway.
Methods—Thirty one non-anaesthesia house officers volunteered for the study, and ventilated a bench model simulating an unintubated respiratory arrest patient with bag-valve-facemask, laryngeal mask airway, and combitube using paediatric and adult self inflating bags.
Results—The paediatric versus adult self inflating bag resulted with the laryngeal mask airway and combitube in significantly (p<0.001) lower mean (SEM) lung tidal volumes (376 (30) v 653 (47) ml, and 368 (28) v 727 (53) ml, respectively). Gastric inflation was zero with the combitube; and 0 (0) v 8 (3) ml with the laryngeal mask airway with low versus large tidal volumes. The paediatric versus adult self inflating bag with the bag-valve-facemask resulted in comparable lung tidal volumes (245 (19) v 271 (33) ml; p=NS); but significantly (p<0.001) lower gastric tidal volume (149 (11) v 272 (24) ml).
Conclusions—The paediatric self inflating bag may be an option to reduce the risk of gastric inflation when using the laryngeal mask airway, and especially, the bag-valve-facemask. Both the laryngeal mask airway and combitube proved to be valid alternatives for the bag-valve-facemask in this experimental model.
PMCID: PMC1725532  PMID: 11300206
13.  The comparison of Proseal laryngeal mask airway and endotracheal tube in patients undergoing laparoscopic surgeries under general anaesthesia 
Indian Journal of Anaesthesia  2011;55(2):129-134.
Aims to compare the efficacy of Proseal laryngeal mask airway(PLMA) and endotracheal tube (ETT) in patients undergoing laparoscopic surgeries under general anaesthesia. This prospective randomised study was conducted on 60 adult patients, 30 each in two groups, of ASA I-II who were posted for laparoscopic procedures under general anaesthesia. After preoxygenation, anaesthesia was induced with propofol, fentanyl and vecuronium. PLMA or ETT was inserted and cuff inflated. Nasogastric tube (NGT) was passed in all patients. Anaesthesia was maintained with N2 O, O2, halothane and vecuronium. Ventilation was set at 8 ml/kg and respiratory rate of 12/min. The attempts and time taken for insertion of devices, haemodynamic changes, oxygenation, ventilation and intraoperative and postoperative laryngopharyngeal morbidity (LPM) were noted. There was no failed insertion of devices. Time taken for successful passage of NGT was 9.77 s (6-16 s) and 11.5 s (8-17 s) for groups P and E, respectively. There were no statistically significant differences in oxygen saturation (SpO2) or end-tidal carbon dioxide (EtCO2) between the two groups before or during peritoneal insufflation. Median (range) airway pressure at which oropharyngeal leak occurred during the leak test with PLMA was 35 (24-40) cm of H2O. There was no case of inadequate ventilation, regurgitation, or aspiration recorded. No significant difference in laryngopharyngeal morbidity was noted. A properly positionedPLMA proved to be a suitable and safe alternative to ETT for airway management in elective fasted, adult patients undergoing laparoscopic surgeries. It provided equally effective pulmonary ventilation despite high airway pressures without gastric distention, regurgitation, and aspiration.
PMCID: PMC3106384  PMID: 21712868
Endotracheal tube; IPPV; laparoscopy; oropharyngeal seal pressure; Proseal LMA
14.  Effects of preoxygenation with the three minutes tidal volume breathing technique in the elderly 
Korean Journal of Anesthesiology  2010;58(4):369-373.
Preoxygenation with tidal volume breathing for 3 min is commonly used technique. An end tidal expiratory oxygen concentration greater than 90% is considerd to be adequate for preoxygenation. The aim of this study was to check the effects of preoxygenation on elderly patients through the comparison with young patients during the 3 min tidal volume breathing technique.
Sixty patients from ASA class I or II who were scheduled for elective orthopedic general surgery were divided into an elderly (>65 yr) group and a control (25-65 yr) group. Patients were instructed in the technique of preoxygenation. Preoxygenation was accomplished with an appropriately sized face mask connected to an anesthesia machine with 100% oxygen during 3 min with patients in both groups. Expired O2, CO2 concentration and oxygen saturation were recorded simultaneously for 3 min.
The elderly group showed significantly lower end tidal oxygen concentration than the control group from 50 sec to the end of study (180 sec) with the 3 min tidal volume breathing technique (P < 0.05). In 180 sec, the control group had over 90% (91.5%) end tidal oxygen concentration, but in the elderly group end tidal oxygen concentration could not reach 90% (86.2%). In oxygen saturation, the elderly group showed a significantly lower level until 40 sec from the start of study, and then two groups showed a similar levels of oxygen saturation until the end of study.
End tidal oxygen concentration did not reach 90% in 180 sec in the elderly group during preoxygenation with the 3 min tidal volume breathing technique.
PMCID: PMC2876858  PMID: 20508794
Elderly; Mask; Oxygen concentration; Preoxygenation; 3 min tidal volume breathing
15.  Accuracy of Susceptibility-Weighted Imaging for the Detection of Arteriovenous Shunting in Vascular Malformations of the Brain 
Background and Purpose
To determine the accuracy of susceptibility-weighted magnetic resonance imaging (SWI) for the detection of arteriovenous shunting (AVS) in vascular malformations of the brain (BVM).
We retrospectively identified 60 patients who had been evaluated for known or suspected BVM by both SWI and digital subtraction angiography (DSA), without intervening treatment, during a 3-year period. SWI images were retrospectively assessed by two independent reviewers for the presence of AVS as determined by the presence of signal hyperintensity within a venous structure in the vicinity of the BVM. Discrepancies were resolved by consensus among a panel of three neuroradiologists. Accuracy parameters of SWI for the detection of AVS were calculated utilizing DSA as the reference standard.
A total of 80 BVMs were identified in the 60 patients included in our study. Of the 29 BVMs with AVS on DSA, 14 were untreated AVMs, 10 were previously-treated AVMs, and 5 were untreated dural arteriovenous fistulas. Overall, SWI was 93% sensitive and 98% specific for the detection of AVS in BVMs, with excellent inter-observer agreement (kappa 0.94). In the 14 previously-treated AVMs, SWI was 100% sensitive and specific for the detection of AVS. In the 28 BVMs associated with intracerebral hemorrhage, SWI was 100% sensitive and 96% specific for the detection of AVS.
SWI is accurate for the detection of arteriovenous shunting in vascular malformations of the brain and, for some patients, SWI may offer a non-invasive alternative to angiography in screening for or follow-up of treated BVMs.
PMCID: PMC3092781  PMID: 21088245
Susceptibility-weighted imaging (SWI); Arteriovenous shunting; Arteriovenous malformation (AVM); Developmental venous anomalies (DVA)
16.  A Single Polymorphism in HIV-1 Subtype C SP1 Is Sufficient To Confer Natural Resistance to the Maturation Inhibitor Bevirimat ▿ 
3-O-(3′,3′-Dimethylsuccinyl) betulinic acid (DSB), also known as PA-457, bevirimat (BVM), or MPC-4326, is a novel HIV-1 maturation inhibitor. Unlike protease inhibitors, BVM blocks the cleavage of the Gag capsid precursor (CA-SP1) to mature capsid (CA) protein, resulting in the release of immature, noninfectious viral particles. Despite the novel mechanism of action and initial progress made in small-scale clinical trials, further development of bevirimat has encountered unexpected challenges, because patients whose viruses contain genetic polymorphisms in the Gag SP1 (positions 6 to 8) protein do not generally respond well to BVM treatment. To better define the role of amino acid residues in the HIV-1 Gag SP1 protein that are involved in natural polymorphisms to confer resistance to the HIV-1 maturation inhibitor BVM, a series of Gag SP1 chimeras involving BVM-sensitive (subtype B) and BVM-resistant (subtype C) viruses was generated and characterized for sensitivity to BVM. We show that SP1 residue 7 of the Gag protein is a primary determinant of SP1 polymorphism-associated drug resistance to BVM.
PMCID: PMC3122462  PMID: 21502630
17.  Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 
PLoS Medicine  2009;6(8):e1000132.
In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.
Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.
Methods and Findings
We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.
Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.
Please see later in the article for the Editors' Summary
Editors' Summary
About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.
Why Was This Study Done?
Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.
What Did the Researchers Do and Find?
At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.
What Do These Findings Mean?
These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)
The UK National Heath Service also provides information for patients about sleep apnea
MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)
More information on the Sleep Heart Health Study is available
PMCID: PMC2722083  PMID: 19688045
18.  The incidence of oxygen desaturation during rapid sequence induction and intubation 
Rapid sequence induction and intubation (RSII) is an emergency airway management technique for patients with a risk of pulmonary aspiration. It involves preoxygenation, administration of predetermined doses of induction and paralytic drugs, avoidance of mask ventilation, and laryngoscopy followed by tracheal intubation and keeping cricoid pressure applied till endotracheal tube cuff be inflated. Oxygen desaturation has been seen during RSII. We assessed the incidence of oxygen desaturation during RSII.
An institution-based observational study was conducted from March 3 to May 4, 2014 in our hospital. All patients who were operated upon under general anesthesia with RSII during the study period were included. A checklist was prepared for data collection.
A total of 153 patients were included in this study with a response rate of 91.6%. Appropriate drugs for RSII, equipments for RSII, equipments for difficult intubation, suction machine with a catheter, a monitor and an oxygen backup such as ambu bag were not prepared for 41 (26.8%), 50 (32.7%), 51 (33.3%), 38 (24.8%) and 25 (16.3%) patients respectively. Cricoid pressure was not applied at all for 17 (11.1%) patients and 53 (34.6%) patients were ventilated after induction of anesthesia but before intubation and endotracheal cuff inflation. A total of 55 (35.9%) patients desaturated during RSII (SPO2<95%). The minimum, maximum and mean oxygen desaturations were 26%, 94% and 70.9% respectively. The oxygen desaturation was in the range of <50%, 50%–64%, 65%–74%, 75%–84%, 85%–89 % and 90%–94% for 6 (3.9%), 7 (4.6%), 5 (3.3%), 10 (6.5%), 13 (8.5%) and 14 (9.2%) patients respectively.
The incidence of oxygen desaturation during RSII was high in our hospital. Preoperative patient optimization and training about the techniques of RSII should be emphasized.
PMCID: PMC4272932  PMID: 25548602
General anesthesia; Rapid sequence induction and intubation; Oxygen desaturation
19.  The Contribution of Malglycemia to Mortality among Allogeneic Hematopoietic Cell Transplant Recipients 
Allogeneic hematopoietic cell transplantation (HCT) continues to be associated with substantial rates of non-relapse mortality (NRM). Numerous factors influence glucose metabolism among HCT recipients. We hypothesized that “malglycemia”, defined as hyperglycemia, hypoglycemia or increased glycemic variability, is associated with increased mortality in HCT patients.
In a retrospective cohort study, Cox regression was used to assess the association of malglycemia after transplant with day 200 NRM.
66,062 blood glucose (BG) measurements from 1175 adult allogeneic HCT recipients between 2000 and 2005 at the Fred Hutchinson Cancer Research Center were evaluated (median 0.55 values per patient-day, range 0.09-3.62). Overall, there were 215 cases of NRM by day 200 post-HCT and 601 deaths from any cause throughout observation. After adjustment for previously identified factors associated with NRM, all three components of malglycemia were associated with increased NRM when individually modeled as time-dependent covariates. Specifically, the hazard ratio for death was 1.93 for BG>200 mg/dl (p=0.0009) and 2.78 for BG>300 (p=0.0004) compared with BG 101-150 mg/dl. A minimum BG ≤ 89 was associated with a risk of day 200 NRM 2.17-times that of a minimum BG > 89 (p<0.0001). The upper quartile of glucose variability was associated with a 14.57-fold increase in risk of NRM by day 200 relative to the first quartile (p<0.0001).
These retrospective data indicate that malglycemia is associated with mortality following HCT. The applicability of these findings to other situations and whether correcting malglycemia in HCT can lead to reductions in mortality remain to be determined.
PMCID: PMC3181426  PMID: 19203725
Hyperglycemia; Hypoglycemia; Glycemic Variability; Hematopoietic Cell Transplant; Infection; Mortality
20.  Acute Pulmonary Vasodilator Testing With Inhaled Treprostinil in Children With Pulmonary Arterial Hypertension 
Pediatric cardiology  2012;34(4):1006-1012.
Acute pulmonary vasodilator testing (AVT) is essential to determining the initial therapy for children with pulmonary arterial hypertension (PAH). This study aimed to report the initial experience with inhaled treprostinil used for AVT in children with PAH and to evaluate the hemodynamic change after inhaled treprostinil compared with inhaled nitric oxide. This prospective cohort study was designed for 13 children who underwent AVT with inhaled treprostinil or oxygen plus inhaled nitric oxide (iNO) during catheterization. Inhaled treprostinil was delivered during cardiac catheterization by adapting the Optineb ultrasonic nebulizer via either a flow-inflating bag or the manual mode of the anesthesia system. The median age of the patients was 10 years (range 4–17 years). The etiologies of PAH included idiopathic PAH and associated PAH. All the patients tolerated inhaled treprostinil without marked clinical worsening and received six or nine breaths (36 or 54 µg) of treprostinil. The median of the total treprostinil doses was 1.53 µg/kg (range 0.71–2.89 µg/kg). Inhaled treprostinil was administrated via an endotracheal tube (n = 8), anesthesia mask (n = 3), or laryngeal mask airway (n = 2). Inhaled nitric oxide (iNO) and inhaled treprostinil significantly decreased the mean pulmonary artery pressure and the pulmonary vascular resistance index compared with baseline. Three adverse events were reported after inhaled treprostinil, including cough and mild to moderate hypotension with higher doses. All adverse events resolved without any intervention. This study report is the first to describe the use of inhaled treprostinil for AVT in children with PAH. In this small pediatric cohort, inhaled treprostinil was effectively delivered and well tolerated and may be useful for AVT.
PMCID: PMC3608847  PMID: 23184020
Acute pulmonary vasodilator testing; Children; Iloprost; Inhaled treprostinil; Nitric oxide; Pulmonary arterial hypertension
21.  HIV-1 Maturation Inhibitor Bevirimat Stabilizes the Immature Gag Lattice ▿ †  
Journal of Virology  2010;85(4):1420-1428.
Maturation of nascent virions, a key step in retroviral replication, involves cleavage of the Gag polyprotein by the viral protease into its matrix (MA), capsid (CA), and nucleocapsid (NC) components and their subsequent reorganization. Bevirimat (BVM) defines a new class of antiviral drugs termed maturation inhibitors. BVM acts by blocking the final cleavage event in Gag processing, the separation of CA from its C-terminal spacer peptide 1 (SP1). Prior evidence suggests that BVM binds to Gag assembled in immature virions, preventing the protease from accessing the CA-SP1 cleavage site. To investigate this hypothesis, we used cryo-electron tomography to examine the structures of (noninfectious) HIV-1 viral particles isolated from BVM-treated cells. We find that these particles contain an incomplete shell of density underlying the viral envelope, with a hexagonal honeycomb structure similar to the Gag lattice of immature HIV but lacking the innermost, NC-related, layer. We conclude that the shell represents a remnant of the immature Gag lattice that has been processed, except at the CA-SP1 sites, but has remained largely intact. We also compared BVM-treated particles with virions formed by the mutant CA5, in which cleavage between CA and SP1 is also blocked. Here, we find a thinner CA-related shell with no visible evidence of honeycomb organization, indicative of an altered conformation and further suggesting that binding of BVM stabilizes the immature lattice. In both cases, the observed failure to assemble mature capsids correlates with the loss of infectivity.
PMCID: PMC3028903  PMID: 21106735
22.  Neonatal resuscitation 2: an evaluation of manual ventilation devices and face masks 
Background: The key to successful neonatal resuscitation is effective ventilation. Little evidence exists to guide clinicians in their choice of manual ventilation device or face mask. The expiratory tidal volume measured at the mask (VTE(mask)) is a good estimate of the tidal volume delivered during simulated neonatal resuscitation.
Aim: To compare the efficacy of (a) the Laerdal infant resuscitator and the Neopuff infant resuscitator, used with (b) round and anatomically shaped masks in a model of neonatal resuscitation.
Methods: Thirty four participants gave positive pressure ventilation to a mannequin at specified pressures with each of the four device-mask combinations. Flow, inspiratory tidal volume at the face mask (VTI(mask)), VTE(mask), and airway pressure were recorded. Leakage from the mask was calculated from VTI(mask) and VTE(mask).
Results: A total of 10 780 inflations were recorded and analysed. Peak inspiratory pressure targets were achieved equally with the Laerdal and Neopuff resuscitators. Positive end expiratory pressure was delivered with the Neopuff but not the Laerdal device. Despite similar peak pressures, VTE(mask) varied widely. Mask leakage was large for each combination of device and mask. There were no differences between the masks.
Conclusion: During face mask ventilation of a neonatal resuscitation mannequin, there are large leaks around the face mask. Airway pressure is a poor proxy for volume delivered during positive pressure ventilation through a mask.
PMCID: PMC1721950  PMID: 15871989
23.  Clinical review: Helmet and non-invasive mechanical ventilation in critically ill patients 
Critical Care  2013;17(2):223.
Non-invasive mechanical ventilation (NIV) has proved to be an excellent technique in selected critically ill patients with different forms of acute respiratory failure. However, NIV can fail on account of the severity of the disease and technical problems, particularly at the interface. The helmet could be an alternative interface compared to face mask to improve NIV success. We performed a clinical review to investigate the main physiological and clinical studies assessing the efficacy and related issues of NIV delivered with a helmet. A computerized search strategy of MEDLINE/PubMed (January 2000 to May 2012) and EMBASE (January 2000 to May 2012) was conducted limiting the search to retrospective, prospective, nonrandomized and randomized trials. We analyzed 152 studies from which 33 were selected, 12 physiological and 21 clinical (879 patients). The physiological studies showed that NIV with helmet could predispose to CO2 rebreathing and increase the patients' ventilator asynchrony. The main indications for NIV were acute cardiogenic pulmonary edema, hypoxemic acute respiratory failure (community-acquired pneumonia, postoperative and immunocompromised patients) and hypercapnic acute respiratory failure. In 9 of the 21 studies the helmet was compared to a face mask during either continous positive airway pressure or pressure support ventilation. In eight studies oxygenation was similar in the two groups, while the intubation rate was similar in four and lower in three studies for the helmet group compared to face mask group. The outcome was similar in six studies. The tolerance was better with the helmet in six of the studies. Although these data are limited, NIV delivered by helmet could be a safe alternative to the face mask in patients with acute respiratory failure.
PMCID: PMC3672531  PMID: 23680299
24.  Comparison of intubation conditions and apnea time after anesthesia induction with propofol/remifentanil combined with or without small dose of succinylcholine 
Background: Many scholars are seeking for an anesthesia induction regimen to meet the requirements of both intubation and instant recovery of spontaneous breathing in case of “cannot intubate, cannot ventilate” to prevent severe consequences. This study aims to investigate whether the combination use of remifentanil 1 μg/kg and small dose of succinylcholine (0.6 mg/kg) is superior to single use of remifentanil 1.5 μg/kg in improving intubation conditions and shortening apnea time under anesthesia induction with propofol. Methods: Sixty patients undergoing selective gynecological laparoscopic operation under general anesthesia were included into the prospective randomized controlled trial. After sufficient preoxygenation, all patients received propofol for anesthesia induction, and patients in group S were managed with remifentanil 1 μg/kg and succinylcholine 0.6 mg/kg, while those in group C were treated with remifentanil 1.5 μg/kg and normal saline. Tracheal intubation was conducted 60 s later, and mechanical ventilation was not performed until spontaneous breathing emerged. The intubation conditions were evaluated, and the apnea time between induction and breathing recovery was recorded. Results: One patient (3.70%) in group S was graded as poor in intubation conditions, which was significantly fewer than 12 patients in group C (P<0.001). There was no significant difference in apnea time between two groups (245.50 ± 53.71 vs 251.12 ± 70.71, P=0.750). No patient experienced hypoxic event with SpO2<90% before recovery of spontaneous breathing. Conclusions: Compared with single use of remifentanil 1.5 μg/kg, the combination use of remifentanil 1 μg/kg and succinylcholine 0.6 mg/kg may offer better intubation conditions and may not prolong apnea time under anesthesia induction with propofol 2 mg/kg.
PMCID: PMC3931593  PMID: 24600494
Endotracheal intubation; apnea time; small-dose succinylcholine; remifentanil
25.  Conditioning with Treosulfan and Fludarabine Followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies 
In this prospective study 60 patients of median age 46 (range 5–60) years, with acute myeloid leukemia (AML; n=44), acute lymphoblastic leukemia (ALL; n=3), or myelodysplastic syndrome (MDS; n=13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine combination. Most patients were considered at high risk for relapse or non-relapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m2/day (n=5) or 14 g/m2/day (n=55) on days -6 to -4, and fludarabine (30 mg/m2/day) on days -6 to -2, followed by infusion of marrow (n=7) or peripheral blood stem cells (n=53) from HLA-identical siblings (n=30) or unrelated donors (n=30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival for all patients was 58% and 88% for patients without high risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/fludarabine regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/fludarabine to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.
PMCID: PMC2974965  PMID: 20685259

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