Kalpalatha K. Guntupalli

Aerosolized Surfactant in Adults with Sepsis-Induced Acute Respiratory Distress Syndrome

BACKGROUND Patients with acute respiratory distress syndrome (ARDS) have a deficiency of surfactant. Surfactant replacement improves physiologic function in such patients, and preliminary data suggest that it may improve survival. METHODS We conducted a prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 725 patients with sepsis-induced ARDS. Patients were stratified according to the risk of death at base line (indicated by their score on the Acute Physiological and Chronic Health Evaluation [APACHE III] index) and randomly assigned to receive either continuously administered synthetic surfactant (13.5 mg of dipalmitoylphosphatidylcholine per milliliter, 364 patients) or placebo (o.45 percent saline; 361 patients) in aerosolized form for up to five days. RESULTS The demographic and physiologic characteristics of the two treatment groups were similar at base line. The mean (+/- SD) age was 50 +/- 17 years in the surfactant group and 53 +/- 18 years in the placebo group, and the mean APACHE III scores at randomization were 70.4 +/- 25 and 70.5 +/- 25, respectively. Hemodynamic measures, measures of oxygenation, duration of mechanical ventilation, and length of stay in intensive care unit did not differ significantly in the two groups. Survival at 30 days was 60 percent for both groups. Survival was similar in the groups when analyzed according to APACHE III score, cause of death, time of onset and severity of ARDS, presence or absence of documented sepsis, underlying disease, whether or not there was a do-not-resuscitate order, and medical center. Increased secretions were significantly more frequent in the surfactant group; the rates of other complications were similar in the two groups. CONCLUSIONS The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function.

An open-label dose escalation study of the nitric oxide synthase inhibitor, NG-methyl-L-arginine hydrochloride (546C88), in patients with septic shock

ObjectiveTo assess the effects of the nitric oxide synthase inhibitor, 546C88, in patients with septic shock and to evaluate the range of dose rates that sustain mean arterial pressure (MAP) of >or=to70 mmHg.DesignMulticenter, open-label, uncontrolled, dose range finding study.SettingTen intensive c

Burnout in the internist-intensivist

ObjectivesCaring for acutely ill patients imposes significant demands on physicians. The environment and stresses of the ICU may lead to the burnout syndrome. The purpose of this study was to evaluate the prevalence of burnout among internal medicine intensivists and the contributing factors present in ICU practice.DesignMailed survey utilizing the Maslach Burnout Inventory (MBI). Increasing burnout has been shown to be associated with low levels on personal achievement and high scores on depersonalization and emotional exhaustion.SubjectsRandom sample of members of the Internal Medicine Section of the Society of Critical Care Medicine.Measurements and main results248 people responded: 220 (88.7%) males and 28 females. Mean age of all respondents was 41.6±6.7 years. The majority (58.1%) worked in large hospitals (>400 beds); 55.6% devoted more than 50% of their time to critical care. The emotional exhaustion subscale of the MBI averaged 22.2±9.5, with a third of respondents scoring in the high range. The depersonalization score averaged 7.1±5.1%, with 20.4% of respondents scoring in the high range. Similarly personal achievement subscores were poor, with a mean value of 30.9±6.4%, with 59% scoring in the low range. High levels of emotional exhaustion were associated with anticipating leaving critical care before retirement.ConclusionsBurnout as measured by the MBI appears to be common in internal medicine intensivists. High levels of emotional exhaustion and depersonalization are related not only to patient care issues but also to a poor support system.

Cardiovascular effects of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002).

ObjectiveTo assess the hemodynamic effects of the nitric oxide synthase inhibitor 546C88 in patients with septic shock, although this was not a stated aim of the protocol. The predefined primary efficacy objective of the protocol was resolution of shock determined at the end of a 72-hr treatment period. DesignMulticentered, randomized, placebo-controlled, safety and efficacy study. SettingForty-eight intensive care units in Europe, North America, and Australia. PatientsA total of 312 patients with septic shock diagnosed within 24 hr before randomization. InterventionsPatients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). Measurements and Main ResultsRequirement for vasopressors, systemic and pulmonary hemodynamics, indices of oxygen transport, and plasma concentrations of arginine and nitrate were assessed over time. The median mean arterial pressure for both groups was maintained ≥70 mm Hg. There was an early increase in systemic and pulmonary vascular tone and oxygen extraction, whereas both cardiac index and oxygen delivery decreased for patients in the 546C88 cohort. Although these parameters subsequently returned toward baseline values, the observed differences between the treatment groups, except for pulmonary vascular resistance and oxygen extraction, persisted throughout the treatment period, despite a reduced requirement for vasopressors in the 546C88 cohort. These changes were associated with a reduction in plasma nitrate concentrations, which were elevated in both groups before the start of therapy. ConclusionsThe nitric oxide synthase inhibitor 546C88 can reduce the elevated plasma nitrate concentrations observed in patients with septic shock. In this study, treatment with 546C88 for up to 72 hrs was associated with an increase in vascular tone and a reduction in both cardiac index and oxygen delivery. The successful maintenance of a target mean arterial blood pressure ≥70 mm Hg was achieved with a reduction in the requirement for, or withdrawal of, conventional inotropic vasoconstrictor agents (i.e., dopamine and norepinephrine). There were no substantive untoward consequences accompanying these hemodynamic effects. An international, randomized, double-blind, placebo-controlled phase III study has since been conducted in patients with septic shock. Recruitment into the study was discontinued due to the emergence of increased mortality in the 546C88-treated group.

Metered-Dose Inhalers: Do Health Care Providers Know What to Teach?

OBJECTIVE The specific aim of this investigation was to evaluate the proficiency of health care providers and patients in the proper use of metered-dose inhalers. DESIGN, SETTING, AND PARTICIPANTS Health care providers, which include house staff, nurses, and respiratory care practitioners who provide care to patients with asthma in the primary general medicine clinic or the pulmonary medicine clinic of a university-county hospital in which patients were referred, were surveyed and assigned a performance score regarding the knowledge base of the appropriate use of metered-dose inhalers. Patients who attended the primary care general medicine and pulmonary subspecialty clinic were also assessed as to their proficiency in the use of metered-dose inhalers. RESULTS A significant percentage of patients had a poor understanding of the technique used with the metered-dose inhaler. House staff and nursing staff were also less proficient in the proper use of the metered-dose inhaler. The respiratory care practitioners were the most knowledgeable of the health care providers. CONCLUSIONS This study confirms that a large percentage of patients use metered-dose inhalers improperly. It also demonstrates a significant lack of understanding by health care providers of the proper use of metered-dose inhalers. Furthermore, this study supports the use of respiratory care practitioners in the outpatient setting, since they were the most proficient among all the health care providers in the proper use of metered-dose inhalers.

Arginine, citrulline and nitric oxide metabolism in sepsis.

Arginine has vasodilatory effects, via its conversion by NO synthase into NO, and immunomodulatory actions which play important roles in sepsis. Protein breakdown affects arginine availability and the release of asymmetric dimethylarginine, an inhibitor of NO synthase, may therefore affect NO synthesis in patients with sepsis. The objective of the present study was to investigate whole-body in vivo arginine and citrulline metabolism and NO synthesis rates, and their relationship to protein breakdown in patients with sepsis or septic shock and in healthy volunteers. Endogenous leucine flux, an index of whole-body protein breakdown rate, was measured in 13 critically ill patients with sepsis or septic shock and seven healthy controls using an intravenous infusion of [1-13C]leucine. Arginine flux, citrulline flux and the rate of conversion of arginine into citrulline (an index of NO synthesis) were measured with intravenous infusions of [15N2]guanidino-arginine and [5,5-2H2]citrulline. Plasma concentrations of nitrite plus nitrate, arginine, citrulline and asymmetric dimethylarginine were measured. Compared with controls, patients had a higher leucine flux and higher NO metabolites, but arginine flux, plasma asymmetric dimethylarginine concentration and the rate of NO synthesis were not different. Citrulline flux and plasma arginine and citrulline were lower in patients than in controls. Arginine production was positively correlated with the protein breakdown rate. Whole-body arginine production and NO synthesis were similar in patients with sepsis and septic shock and healthy controls. Despite increased proteolysis in sepsis, there is a decreased arginine plasma concentration, suggesting inadequate de novo synthesis secondary to decreased citrulline production.

Genome-wide association study of smoking behaviours in patients with COPD

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78×10−5 for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.

Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia

IntroductionAminoglycosides aerosolization might achieve better diffusion into the alveolar compartment than intravenous use. The objective of this multicenter study was to evaluate aerosol-delivered amikacin penetration into the alveolar epithelial lining fluid (ELF) using a new vibrating mesh nebulizer (Pulmonary Drug Delivery System (PDDS), Nektar Therapeutics), which delivers high doses to the lungs.MethodsNebulized amikacin (400 mg bid) was delivered to the lungs of 28 mechanically ventilated patients with Gram-negative VAP for 7-14 days, adjunctive to intravenous therapy. On treatment day 3, 30 minutes after completing aerosol delivery, all the patients underwent bronchoalveolar lavage in the infection-involved area and the ELF amikacin concentration was determined. The same day, urine and serum amikacin concentrations were determined at different time points.ResultsMedian (range) ELF amikacin and maximum serum amikacin concentrations were 976.1 (135.7-16127.6) and 0.9 (0.62-1.73) μg/mL, respectively. The median total amount of amikacin excreted in urine during the first and second 12-hour collection on day 3 were 19 (12.21-28) and 21.2 (14.1-29.98) μg, respectively. During the study period, daily through amikacin measurements were below the level of nephrotoxicity. Sixty-four unexpected adverse events were reported, among which 2 were deemed possibly due to nebulized amikacin: one episode of worsening renal failure, and one episode of bronchospasm.ConclusionsPDDS delivery of aerosolized amikacin achieved very high aminoglycoside concentrations in ELF from radiography-controlled infection-involved zones, while maintaining safe serum amikacin concentrations. The ELF concentrations always exceeded the amikacin minimum inhibitory concentrations for Gram-negative microorganisms usually responsible for these pneumonias. The clinical impact of amikacin delivery with this system remains to be determined.Trial RegistrationClinicalTrials.gov Identifier: NCT01021436.

Angioedema : the role of ACE inhibitors and factors associated with poor clinical outcome

Objective: We sought to study the prevalence of angiotensin-converting enzyme (ACE) inhibitors, a cause of angioedema, and investigate any association between clinical findings at the time of presentation and clinical outcome. Design and setting: Retrospective review of the charts of all patients presenting with angioedema to the emergency department at our tertiary referral teaching hospital or clinics over a 4-year period. The charts were reviewed for documentation of chief complaint(s), physical findings, medical treatment, need for laryngoscopy and/or endotracheal intubation, triage, and probable etiology. Results: Of the 40 patients presenting with angioedema in this study, 15 cases were caused by ACE inhibitors. They were the most common cause of angioedema, accounting for 38 % of all cases. The incidence of ACE inhibitor-induced angioedema is estimated to be 0.14 %. More patients with angioedema secondary to ACE inhibitors had complaints of odynophagia (p < 0.02), whereas only patients with non-ACE inhibitor causes of angioedema presented with pruritus (p < 0.02). Furthermore, patients presenting with an acute reaction within 24 h of exposure to the causative agent were more likely to require inpatient monitoring (p < 0.05). Both odynophagia and edema of the tongue were significant predictors for undergoing laryngoscopy (p < 0.001 and p < 0.02, respectively) and admission to the hospital (p < 0.05). Conclusion: ACE inhibitors are the number one cause of acute angioedema in this tertiary referral teaching hospital. Odynophagia and tongue swelling at the time of presentation had significant implications for diagnostic intervention and admission to the hospital.

Use of sedatives, opioids, and neuromuscular blocking agents in patients with acute lung injury and acute respiratory distress syndrome

Objective:The use of sedatives, opioids, and neuromuscular blocking agents (NMBAs) may delay weaning and prolong intensive care unit length of stay. We hypothesized that in patients on higher positive end-expiratory pressure (PEEP), sedatives, opioids, and NMBAs are used in a higher proportion of patients and in higher doses and that the use of these medications is associated with prolongation of weaning and mortality. Design:Retrospective analysis. Setting:The ALVEOLI trial. Patients:Five hundred forty-nine patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) who were enrolled in the ALVEOLI trial. Interventions:We analyzed prospectively collected data regarding the impact of sedatives, opioids, and NMBAs in ALI/ARDS patients on duration of mechanical ventilation, time to weaning landmarks, and mortality. Measurements and Main Results:Sedatives and opioids were used in >80% of the patients in similar proportion in the two groups. The use of sedatives and opioids, but not the use of NMBAs, was associated with longer time on mechanical ventilation and an increased time to achieve a 2-hr spontaneous breathing trial (p < .0001). Sedatives were also associated with increased time to achieve unassisted breathing. NMBAs were used for a short period of time, in a higher proportion of patients in the lower PEEP group, and for a longer time (0.23 days). Conclusions:Sedatives and opioids use was similar in the higher and lower PEEP groups. The use of sedatives and opioids, but not NMBAs, was associated with a longer time to achieve important weaning landmarks.