Andrew D. Bersten

Treatment of Severe Cardiogenic Pulmonary Edema with Continuous Positive Airway Pressure Delivered by Face Mask

BACKGROUND Severe cardiogenic pulmonary edema is a frequent cause of respiratory failure, and many patients with this condition require endotracheal intubation and mechanical ventilation. We investigated whether continuous positive airway pressure delivered by means of a face mask had physiologic benefit and would reduce the need for intubation and mechanical ventilation. METHODS We randomly assigned 39 consecutive patients with respiratory failure due to severe cardiogenic pulmonary edema to receive either oxygen alone or oxygen plus continuous positive airway pressure delivered through a face mask. It was not possible to blind the investigators to the assigned treatment. Physiologic measurements were made over the subsequent 24 hours, and the patients were followed to hospital discharge. RESULTS After 30 minutes, both respiratory rate and arterial carbon dioxide tension had decreased more in the patients who received oxygen plus continuous positive airway pressure. The mean (+/- SD) respiratory rate at 30 minutes decreased from 32 +/- 6 to 33 +/- 9 breaths per minute in the patients receiving oxygen alone and from 35 +/- 8 to 27 +/- 6 breaths per minute in those receiving oxygen plus continuous positive airway pressure (P = 0.008); the arterial carbon dioxide tension decreased from 64 +/- 17 to 62 +/- 14 mm Hg in those receiving oxygen alone and from 58 +/- 8 to 46 +/- 4 mm Hg in those receiving oxygen plus continuous positive airway pressure (P less than 0.001). The patients receiving continuous positive airway pressure also had a greater increase in the arterial pH (oxygen alone, from 7.15 +/- 0.11 to 7.18 +/- 0.18; oxygen plus continuous positive airway pressure, from 7.18 +/- 0.08 to 7.28 +/- 0.06; P less than 0.001) and in the ratio of arterial oxygen tension to the fraction of inspired oxygen (oxygen alone, from 136 +/- 44 to 126 +/- 47; oxygen plus continuous positive airway pressure, from 138 +/- 32 to 206 +/- 126; P = 0.01). After 24 hours, however, there were no significant differences between the two treatment groups in any of these respiratory indexes. Seven (35 percent) of the patients who received oxygen alone but none who received oxygen plus continuous positive airway pressure required intubation and mechanical ventilation (P = 0.005). However, no significant difference was found in in-hospital mortality (oxygen alone, 4 of 20 patients; oxygen plus continuous positive airway pressure, 2 of 19; P = 0.36) or the length of the hospital stay. CONCLUSIONS Continuous positive airway pressure delivered by face mask in patients with severe cardiogenic pulmonary edema can result in early physiologic improvement and reduce the need for intubation and mechanical ventilation. This short-term study could not establish whether continuous positive airway pressure has any long-term benefit or whether a larger study would have shown a difference in mortality between the treatment groups.

Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis

Objective To systematically review the efficacy of steroids in the prevention of acute respiratory distress syndrome (ARDS) in critically ill adults, and treatment for established ARDS. Data sources Search of randomised controlled trials (1966-April 2007) of PubMed, Cochrane central register of controlled trials, Cochrane database of systematic reviews, American College of Physicians Journal Club, health technology assessment database, and database of abstracts of reviews of effects. Data extraction Two investigators independently assessed trials for inclusion and extracted data into standardised forms; differences were resolved by consensus. Data synthesis Steroid efficacy was assessed through a Bayesian hierarchical model for comparing the odds of developing ARDS and mortality (both expressed as odds ratio with 95% credible interval) and duration of ventilator free days, assessed as mean difference. Bayesian outcome probabilities were calculated as the probability that the odds ratio would be ≥1 or the probability that the mean difference would be ≥0. Nine randomised trials using variable dose and duration of steroids were identified. Preventive steroids (four studies) were associated with a trend to increase both the odds of patients developing ARDS (odds ratio 1.55, 95% credible interval 0.58 to 4.05; P(odds ratio ≥1)=86.6%), and the risk of mortality in those who subsequently developed ARDS (three studies, odds ratio 1.52, 95% credible interval 0.30 to 5.94; P(odds ratio ≥1)=72.8%). Steroid administration after onset of ARDS (five studies) was associated with a trend towards reduction in mortality (odds ratio 0.62, 95% credible interval 0.23 to 1.26; P(odds ratio ≥1)=6.8%). Steroid therapy increased the number of ventilator free days compared with controls (three studies, mean difference 4.05 days, 95% credible interval 0.22 to 8.71; P(mean difference ≥0)=97.9%). Steroids were not associated with increase in risk of infection. Conclusions A definitive role of corticosteroids in the treatment of ARDS in adults is not established. A possibility of reduced mortality and increased ventilator free days with steroids started after the onset of ARDS was suggested. Preventive steroids possibly increase the incidence of ARDS in critically ill adults.

Additional work of breathing imposed by endotracheal tubes, breathing circuits, and intensive care ventilators

A disadvantage of spontaneous breathing through an endotracheal tube (ETT) and connector attached to a breathing circuit and/or ventilator (breathing device) is an increase in the work of breathing. The work of breathing associated with ETT of 6 to 9-mm diameter and eight breathing devices was determined, using a lung simulator to mimic spontaneous inspiration at flow rates of 20 to 100 L/min and a tidal volume of 500 ml, at both zero end-expiratory pressure (ZEEP) and 10 cm H2O continuous positive airway pressure (CPAP). Work associated with the breathing devices alone (WCIR) ranged from -0.002 kg.m/L (Servo 900-C ventilator, 7-mm ETT, 20 L/min, ZEEP) to 0.1 kg.m/L (continuous flow circuit, 7-mm ETT, 100 L/min, CPAP), the latter representing 196% of the work of normal breathing. When the devices were attached to ETT, total apparatus work (WAPP) ranged from 0.009 kg.m/L (Mapleson-D circuit, 9-mm ETT, 20 L/min, ZEEP) to 0.25 kg.m/L (Drager EV-A, 6-mm ETT, 100 L/min, ZEEP), the latter representing 490% of the work of normal breathing. This additional work imposed by the ETT varied considerably among devices. Spontaneous breathing through modern ventilators, circuits and ETT imposes a burden of increased work, most of which is associated with the presence of the ETT and connector. Whether this burden represents an impediment to the weaning patient, or has training value for the ultimate resumption of unassisted spontaneous ventilation, remains to be determined.

Serum levels of CC16, SP-A and SP-B reflect tobacco-smoke exposure in asymptomatic subjects.

Since the 16-kDa bronchiolar Clara cell protein (CC16) and the alveolar surfactant-associated proteins (SP)-A and -B leak into the circulation when parenchymal health is disturbed, the aim of this study was to determine whether their serum levels could serve as early peripheral markers of tobacco smoke-induced epithelial injury. Sixty-nine (51 yrs (32–54) median (25–75th percentile)) nonsmokers and 54 (42 yrs (31–53)) asymptomatic smokers were enrolled in the study. Serum levels of SP-A did not differ between subjects (270 (208–389) versus 259 (168–392) µg·L−1), however, CC16 levels decreased (10.6 (8.7–14.6) versus 7.6 (6.0–11.2) µg·L−1) and SP-B levels increased (2,529 (2,091–2,943) versus 3,053 (2,613–4,188) µg·L−1) in the smokers. When tobacco smoke exposure, serum creatinine (renal index), age and sex were used as independent variables, CC16 was negatively influenced by cumulative smoking and positively influenced by age. SP-A and -B were negatively influenced by creatinine and positively influenced by cumulative smoking. Serum SP-B was inversely correlated with forced expiratory volume in one second/vital capacity, suggesting an association between obstructive disease and parenchymal lung health. The authors suggest that serum surfactant-associated proteins-A and -B reflect increased alveolocapillary leakage whereas Clara cell secretory protein 16 reflects tobacco smoke-induced Clara cell toxicity. Their evaluation may allow the effects of tobacco smoke on different levels of the respiratory tract, cellular toxicity and epithelial leakage to be distinguished.

Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial

IMPORTANCE Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation. OBJECTIVE To determine the effectiveness of dexmedetomidine when added to standard care in patients with agitated delirium receiving mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium. The study was conducted at 15 intensive care units in Australia and New Zealand from May 2011 until December 2013. Patients with advanced dementia or traumatic brain injury were excluded. INTERVENTIONS Bedside nursing staff administered dexmedetomidine (or placebo) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES Ventilator-free hours in the 7 days following randomization. There were 21 reported secondary outcomes that were defined a priori. RESULTS Of the 74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew consent later and 1 was found to have been randomized incorrectly, leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P < .001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007). CONCLUSIONS AND RELEVANCE Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit, the addition of dexmedetomidine to standard care compared with standard care alone (placebo) resulted in more ventilator-free hours at 7 days. The findings support the use of dexmedetomidine in patients such as these. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01151865.

Prolonged alveolocapillary barrier damage after acute cardiogenic pulmonary edema

ObjectivesTo determine whether acute cardiogenic pulmonary edema is associated with damage to the alveolocapillary barrier, as evidenced by increased leakage of surfactant specific proteins into the circulation, to document the duration of alveolocapillary barrier damage in this setting, and to explore the role of pulmonary parenchymal inflammation by determining if circulating tumor necrosis factor-&agr; is increased after acute cardiogenic pulmonary edema. DesignProspective, observational study. SettingCritical care, cardiac intensive care, and cardiology wards of a tertiary-care university teaching hospital. PatientsA total of 28 patients presenting with acute cardiogenic pulmonary edema and 13 age-matched normal volunteers. InterventionsCirculating surfactant protein-A and -B and tumor necrosis factor-&agr; were measured on days 0 (presentation), 1, 3, 7, and 14. Clinical markers of pulmonary edema were documented at the same times. Measurements and Main ResultsSurfactant protein-A and -B were elevated on day 0 compared with controls (367 ± 17 ng/mL vs. 303 ± 17 and 3821 ± 266 ng/mL vs. 2747 ± 157 [mean ± sem], p < .05), and although clinical, hemodynamic and radiographic variables improved rapidly (p < .001), surfactant protein-A and -B rose further until day 3 (437 ± 22, p < .001, 4642 ± 353, p < .01). Tumor necrosis factor-&agr; was elevated at presentation (p < .05), doubled by day 1 (6.98 ± 1.36 pg/mL, p < .05), remained elevated on day 3 (5.72 ± 0.96 pg/mL, p < .05), and peak levels were related to chest radiograph extravascular lung water score (rp = 0.64, p = .003). ConclusionsAlthough the initial increase in plasma surfactant protein-A and -B may represent hydrostatic stress failure of the alveolocapillary barrier, the prolonged elevation, when hemodynamic abnormalities have resolved, and the delayed elevation of tumor necrosis factor-&agr; are consistent with pulmonary parenchymal inflammation, which may further damage the alveolocapillary barrier. This prolonged physiologic defect at the alveolocapillary barrier after acute cardiogenic pulmonary edema may partly account for the vulnerability of these patients to recurrent pulmonary fluid accumulation.

Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective

IntroductionCurrent low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.MethodsRCTs were identified (1950-September 2008) by multiple data-base electronic search (MEDLINE via OVID, OVID PreMedline, OVID Embase, Cochrane Central Register of Controlled trials, Cochrane database of systematic reviews, Health Technology Assessment Database and Database of Abstracts of Reviews of Effects) and hand search of references, reviews and scientific society proceedings. Three investigators independently assessed trial inclusion and data extraction into standardised forms; differences resolved by consensus.ResultsCorticosteroid efficacy, compared with control, for hospital-mortality, proportion of patients experiencing shock-resolution, and infective and non-infective complications was assessed using Bayesian random-effects models; expressed as odds ratio (OR, (95% credible-interval)). Bayesian outcome probabilities were calculated as the probability (P) that OR ≥1. Fourteen RCTs were identified. High-dose (>1000 mg hydrocortisone (equivalent) per day) corticosteroid trials were associated with a null (n = 5; OR 0.91(0.31-1.25)) or higher (n = 4, OR 1.46(0.73-2.16), outlier excluded) mortality probability (P = 42.0% and 89.3%, respectively). Low-dose trials (<1000 mg hydrocortisone per day) were associated with a lower (n = 9, OR 0.80(0.40-1.39); n = 8 OR 0.71(0.37-1.10), outlier excluded) mortality probability (20.4% and 5.8%, respectively). OR for shock-resolution was increased in the low dose trials (n = 7; OR 1.20(1.07-4.55); P = 98.2%). Patient responsiveness to corticotrophin stimulation was non-determinant. A high probability of risk-related treatment efficacy (decrease in log-odds mortality with increased control arm risk) was identified by metaregression in the low dose trials (n = 9, slope coefficient -0.49(-1.14, 0.27); P = 92.2%). Odds of complications were not increased with corticosteroids.ConclusionsAlthough a null effect for mortality treatment efficacy of low dose corticosteroid therapy in severe sepsis and septic shock was not excluded, there remained a high probability of treatment efficacy, more so with outlier exclusion. Similarly, although a null effect was not excluded, advantageous effects of low dose steroids had a high probability of dependence upon patient underlying risk. Low dose steroid efficacy was not demonstrated in corticotrophin non-responders. Further large-scale trials appear mandated.

Effect of CPAP on intrinsic PEEP, inspiratory effort, and lung volume in severe stable COPD

Background: Intrinsic positive end expiratory pressure (PEEPi) constitutes an inspiratory threshold load on the respiratory muscles, increasing work of breathing. The role of continuous positive airway pressure (CPAP) in alleviating PEEPi in patients with severe stable chronic obstructive pulmonary disease is uncertain. This study examined the effect of CPAP on the inspiratory threshold load, muscle effort, and lung volume in this patient group. Methods: Nine patients were studied at baseline and with CPAP increasing in increments of 1 cm H2O to a maximum of 10 cm H2O. Breathing pattern and minute ventilation (V̇i), dynamic PEEPi, expiratory muscle activity, diaphragmatic (PTPdi/min) and oesophageal (PTPoes/min) pressure-time product per minute, integrated diaphragmatic (EMGdi) and intercostal EMG (EMGic) and end expiratory lung volume (EELV) were measured. Results: Expiratory muscle activity was present at baseline in one subject. In the remaining eight, PEEPi was reduced from a mean (SE) of 2.9 (0.6) cm H2O to 0.9 (0.1) cm H2O (p<0.05). In two subjects expiratory muscle activity contributed to PEEPi at higher pressures. There were no changes in respiratory pattern but V̇i increased from 9.2 (0.6) l/min to 10.7 (1.1) l/min (p<0.05). EMGdi remained stable while EMGic increased significantly. PTPoes/min decreased, although this did not reach statistical significance. PTPdi/min decreased significantly from 242.1 (32.1) cm H2O.s/min to 112.9 (21.7) cm H2O.s/min). EELV increased by 1.1 (0.3) l (p<0.01). Conclusion: High levels of CPAP reduce PEEPi and indices of muscle effort in patients with severe stable COPD, but only at the expense of substantial increases in lung volume.

The efficacy of loop diuretics in acute renal failure: assessment using Bayesian evidence synthesis techniques.

Objective:To quantify the therapeutic efficacy of loop diuretics in acute renal failure using Bayesian evidence synthesis, because despite widespread use, the role of diuretics is controversial. Data Source:Randomized controlled trials or nonrandomized studies, 1966 to January 2007, identified from MEDLINE and EMBASE databases and manual bibliographic search. Study Selection:Studies with assessable predefined end points, exclusive of those pertaining to acute renal failure prophylaxis or chronic renal failure. Data Extraction:Data extraction was performed jointly by the first two authors; independent study assessment was via standard checklist, unblinded. Data Synthesis:The primary outcome was mortality; secondary outcomes were time to renal function normalization and total number of dialyses. Bayesian hierarchical random effects estimates of treatment effects were determined as risk ratio for mortality, incidence rate ratio for dialysis number, and mean difference for continuous measures. Bayesian outcome probabilities were calculated as probability (P) that risk ratio or incidence rate ratio of loop diuretics >1 and probability that mean difference >0. Five randomized controlled trials and eight nonrandomized studies were identified. Loop diuretics were not associated with decreased mortality in either randomized controlled trials or nonrandomized studies: overall risk ratio 1.10; 95% credible interval 0.85, 1.42; P (risk ratio >1) = 83.8%. The oliguric period was decreased by loop diuretics: overall mean difference −7.70 days; 95% credible interval −12.51, −2.08; P (mean difference >0) = 0.7%. Although the dialysis rate credible interval, loop diuretics vs. control, spanned unity (incidence rate ratio 0.71; 95% credible interval 0.47, 1.06), the probability that the incidence rate ratio exceeded unity indicated a substantial benefit: P (incidence rate ratio >1 = 4.1%. Uremic duration was not substantially different, loop diuretics vs. control: overall mean difference −1.54 days; 95% credible interval −5.62, 2.46; P [mean difference >0] = 17.8%). Conclusions:Loop diuretics were not associated with improved survival benefit in acute renal failure, despite reduction in oliguric period and high probability of a significant reduction in dialysis numbers. Further studies to clarify this dichotomy appear mandated.

Factors affecting sleep quality of patients in intensive care unit

INTRODUCTION Sleep disturbance is a frequently overlooked complication of intensive care unit (ICU) stay. AIM To evaluate sleep quality among patients admitted to ICU and investigate environmental and non-environmental factors that affect sleep quality in ICU. METHODS Over a 22-month period, we consecutively recruited patients who spent ≥ 2 nights post-endotracheal extubation in ICU and who were orientated to time, place, and person on the day of discharge. Self-reported sleep quality, according to a modified Freedman questionnaire, which provided data on self-reported ICU sleep quality in ICU and environmental factors affecting sleep quality in the ICU, were collected. We also investigated non-environmental factors, such as severity of illness, ICU interventions, and medications that can affect sleep quality. RESULTS Fifty males and 50 females were recruited with a mean (± SD) age of 65.1 ± 15.2 years. APACHE II score at admission to ICU was 18.1 ± 7.5 with duration of stay 6.7 ± 6.5days. Self-reported sleep quality score at home (1 = worst; 10 = best) was 7.0 ± 2.2; this decreased to 4.0 ± 1.7 during their stay in ICU (p < 0.001). In multivariate analysis with APACHE III as severity of illness (R(2) = 0.25), factors [exp(b)(95% CI), p value] which significantly affected sleep in ICU were sex [0.37(0.19-0.72), p < 0.01], age and sex interaction [1.02(1.01-1.03), p < 0.01], bedside phone [0.92(0.87-0.97), p < 0.01], prior quality of sleep at home [1.30(1.05-1.62), p = 0.02], and use of steroids [0.82(0.69-0.98), p = 0.03] during the stay in ICU. CONCLUSION Reduced sleep quality is a common problem in ICU with a multifactorial etiology.