Nicholas S. Hill

Non-invasive ventilation in acute respiratory failure

Summary Non-invasive mechanical ventilation has been increasingly used to avoid or serve as an alternative to intubation. Compared with medical therapy, and in some instances with invasive mechanical ventilation, it improves survival and reduces complications in selected patients with acute respiratory failure. The main indications are exacerbation of chronic obstructive pulmonary disease, cardiogenic pulmonary oedema, pulmonary infiltrates in immunocompromised patients, and weaning of previously intubated stable patients with chronic obstructive pulmonary disease. Furthermore, this technique can be used in postoperative patients or those with neurological diseases, to palliate symptoms in terminally ill patients, or to help with bronchoscopy; however further studies are needed in these situations before it can be regarded as first-line treatment. Non-invasive ventilation implemented as an alternative to intubation should be provided in an intensive care or high-dependency unit. When used to prevent intubation in otherwise stable patients it can be safely administered in an adequately staffed and monitored ward.

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension

OBJECTIVES The aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH). BACKGROUND Primary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized. METHODS Echocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone. RESULTS During the mean follow-up period of 36.9 +/- 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis. CONCLUSIONS Pericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation.

Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema

OBJECTIVE To evaluate whether bilevel positive airway pressure, by actively assisting inhalation, more rapidly improves ventilation, acidemia, and dyspnea than continuous positive airway pressure (CPAP) in patients with acute pulmonary edema. DESIGN Randomized, controlled, double-blind trial. SETTING Emergency department in a university hospital. PATIENTS Twenty-seven patients, presenting with acute pulmonary edema, characterized by dyspnea, tachypnea, tachycardia, accessory muscle use, bilateral rales, and typical findings of congestion on a chest radiograph. INTERVENTIONS In addition to standard therapy, 13 patients were randomized to receive nasal CPAP (10 cm H2O), and 14 patients were randomized to receive nasal bilevel positive airway pressure (inspiratory and expiratory positive airway pressures of 15 and 5 cm H2O, respectively) in the spontaneous/timed mode that combines patient flow-triggering and backup time-triggering. MEASUREMENTS AND MAIN RESULTS After 30 mins, significant reductions in breathing frequency (32 +/- 4 to 26 +/- 5 breaths/min), heart rate (110 +/- 21 to 97 +/- 20 beats/min), blood pressure (mean 117 +/- 28 to 92 +/- 18 mm Hg), and Paco2 (56 +/- 15 to 43 +/- 9 torr [7.5 +/- 2 to 5.7 +/- 1.2 kPa]) were observed in the bilevel positive airway pressure group, as were significant improvements in arterial pH and dyspnea scores (p < .05 for all of these parameters). Only breathing frequency improved significantly in the CPAP group (32 +/- 4 to 28 +/- 5 breaths/min, p < .05). At 30 mins; the bilevel positive airway pressure group had greater reductions in Paco2 (p = .057), systolic blood pressure (p = .005), and mean arterial pressure (p = .03) than the CPAP group. The myocardial infarction rate was higher in the bilevel positive airway pressure group (71%) compared with both the CPAP group (31%) and historically matched controls (38%) (p = .05). Duration of ventilator use, intensive care unit and hospital stays, and intubation and mortality rates were similar between the two groups. CONCLUSIONS Bilevel positive airway pressure improves ventilation and vital signs more rapidly than CPAP in patients with acute pulmonary edema. The higher rate of myocardial infarctions associated with the use of bilevel positive airway pressure highlights the need for further studies to clarify its effects on hemodynamics and infarction rates, and to determine optimal pressure settings.

Challenges in end-of-life care in the ICU

The jurors identified numerous problems with end of life in the ICU including variability in practice, inadequate predictive models for death, elusive knowledge of patient preferences, poor communication between staff and surrogates, insufficient or absent training of health-care providers, the use of imprecise and insensitive terminology, and incomplete documentation in the medical records. The jury strongly recommends that research be conducted to improve end-of-life care. The jury advocates a “shared” approach to end-of-life decision-making involving the caregiver team and patient surrogates. Respect for patient autonomy and the intention to honour decisions to decline unwanted treatments should be conveyed to the family. The process is one of negotiation, and the outcome will be determined by the personalities and beliefs of the participants. Ultimately, it is the attending physician’s responsibility, as leader of the health-care team, to decide on the reasonableness of the planned action. In the event of conflict, the ICU team may agree to continue support for a predetermined time. Most conflicts can be resolved. If the conflict persists, however, an ethics consultation may be helpful. Nurses must be involved in the process. The patient must be assured of a pain-free death. The jury of the Consensus Conference subscribes to the moral and legal principles that prohibit administering treatments specifically designed to hasten death. The patient must be given sufficient analgesia to alleviate pain and distress; if such analgesia hastens death, this “double effect” should not detract from the primary aim to ensure comfort.

Efficacy and safety of quetiapine in critically ill patients with delirium: A prospective, multicenter, randomized, double-blind, placebo-controlled pilot study*

Objective: To compare the efficacy and safety of scheduled quetiapine to placebo for the treatment of delirium in critically ill patients requiring as-needed haloperidol. Design: Prospective, randomized, double-blind, placebo-controlled study. Setting: Three academic medical centers. Patients: Thirty-six adult intensive care unit patients with delirium (Intensive Care Delirium Screening Checklist score ≥4), tolerating enteral nutrition, and without a complicating neurologic condition. Interventions: Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 mg every 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs. Study drug was continued until the intensive care unit team discontinued it because of delirium resolution, therapy ≥10 days, or intensive care unit discharge. Measurements and Main Results: Baseline characteristics were similar between the quetiapine (n = 18) and placebo (n = 18) groups. Quetiapine was associated with a shorter time to first resolution of delirium [1.0 (interquartile range [IQR], 0.5–3.0) vs. 4.5 days (IQR, 2.0–7.0; p =.001)], a reduced duration of delirium [36 (IQR, 12–87) vs. 120 hrs (IQR, 60–195; p =.006)], and less agitation (Sedation-Agitation Scale score ≥5) [6 (IQR, 0–38) vs. 36 hrs (IQR, 11–66; p =.02)]. Whereas mortality (11% quetiapine vs. 17%) and intensive care unit length of stay (16 quetiapine vs. 16 days) were similar, subjects treated with quetiapine were more likely to be discharged home or to rehabilitation (89% quetiapine vs. 56%; p =.06). Subjects treated with quetiapine required fewer days of as-needed haloperidol [3 [(IQR, 2–4)] vs. 4 days (IQR, 3–8; p = .05)]. Whereas the incidence of QTc prolongation and extrapyramidal symptoms was similar between groups, more somnolence was observed with quetiapine (22% vs. 11%; p = .66). Conclusions: Quetiapine added to as-needed haloperidol results in faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation. Future studies should evaluate the effect of quetiapine on mortality, resource utilization, post-intensive care unit cognition, and dependency after discharge in a broader group of patients.

Does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? A systematic review.

Context:The results of studies on noninvasive positive pressure ventilation (NPPV) for acute hypoxemic respiratory failure unrelated to cardiogenic pulmonary edema have been inconsistent. Objective:To assess the effect of NPPV on the rate of endotracheal intubation, intensive care unit and hospital length of stay, and mortality for patients with acute hypoxemic respiratory failure not due to cardiogenic pulmonary edema. Data Source:We searched the databases of MEDLINE (1980 to October 2003) and EMBASE (1990 to October 2003). Additional data sources included the Cochrane Library, personal files, abstract proceedings, reference lists of selected articles, and expert contact. Study Selection:We included studies if a) the design was a randomized controlled trial; b) patients had acute hypoxemic respiratory failure not due to cardiogenic pulmonary edema; c) the interventions compared noninvasive ventilation and standard therapy with standard therapy alone; and d) outcomes included need for endotracheal intubation, length of intensive care unit or hospital stay, or intensive care unit or hospital survival. Data Extraction:In duplicate and independently, we abstracted data to evaluate methodological quality and results. Data Synthesis:The addition of NPPV to standard care in the setting of acute hypoxemic respiratory failure reduced the rate of endotracheal intubation (absolute risk reduction 23%, 95% confidence interval 10–35%), ICU length of stay (absolute reduction 2 days, 95% confidence interval 1–3 days), and ICU mortality (absolute risk reduction 17%, 95% confidence interval 8–26%). However, trial results were significantly heterogeneous. Conclusion:Randomized trials suggest that patients with acute hypoxemic respiratory failure are less likely to require endotracheal intubation when NPPV is added to standard therapy. However, the effect on mortality is less clear, and the heterogeneity found among studies suggests that effectiveness varies among different populations. As a result, the literature does not support the routine use of NPPV in all patients with acute hypoxemic respiratory failure.

Noninvasive Positive Pressure Ventilation To Treat Respiratory Failure

Use of noninvasive positive pressure ventilation, the delivery of positive pressure mechanical ventilation to the lungs without endotracheal intubation, is increasing among patients with acute and chronic respiratory failure, mainly because of its convenience, lower cost, and morbidity-sparing potential compared with standard invasive positive pressure ventilation. The technique requires a positive pressure mechanical ventilator, usually portable, connected by tubing to an interface device that directs airflow into the nose, mouth, or both. It differs from nasal continuous positive pressure, which does not provide ventilatory assistance but instead applies a sustained positive pressure through the nose [1]. Noninvasive positive pressure ventilation, on the other hand, delivers intermittent positive airway pressure through the upper airway and actively assists ventilation. Noninvasive positive pressure ventilation through the mouth has been used to assist ventilation in patients with chronic respiratory failure at some centers for several decades [2, 3] but was not widely used until newer, more comfortable interfaces were developed and physician experience increased. When the widely available and better-tolerated nasal continuous positive airway pressure masks introduced during the mid 1980s to treat obstructive sleep apnea [1] were found to be effective in delivering noninvasive positive pressure ventilation, use of noninvasive positive pressure ventilation increased rapidly. Methods The primary approach for the review was search of the MEDLINE database for the past 20 years using the key words respiratory failure and mechanical ventilation. Studies using noninvasive ventilation techniques to manage acute or chronic respiratory failure were selected for analysis. This database was supplemented by searching the tables of contents of recently published issues of respiratory journals and by scanning the reference sections of papers identified in the MEDLINE search. Case reports were excluded, but all other original studies describing the use of noninvasive positive pressure ventilation in acute or chronic respiratory failure were reviewed. Because of the paucity of randomized, controlled studies, uncontrolled cohort studies were not excluded. Selection criteria, numbers of patients, diagnoses, types of ventilatory techniques used, duration of use, and outcomes, including changes in gas exchange and pulmonary functions, symptom relief, and success rates were extracted and tabulated, and complication rates were noted. Although variability and inadequacy of study design precluded meta-analysis of many of the studies, they were all reviewed critically and weaknesses in the existing database were identified. Conclusions relating to the use of noninvasive positive pressure ventilation were drawn whenever possible, and areas needing further investigation were highlighted. Historical Perspective Early mechanical ventilators were first described in the late 1700s. They consisted of various noninvasive devices that applied positive pressure to the upper airway through a bellows type of apparatus or through negative or positive pressure applied externally to the chest, back, or abdomen [4-8]. These early ventilators typically were powered manually and had varied success as acute resuscitators of infants and drowning victims [5]. Techniques for sustained ventilatory support awaited the wide availability of electricity, the development of electric motors, and the need for more pa tients with chronic respiratory failure. This need arose during the polio epidemics of the 1920s through the 1950s, when various noninvasive ventilators, such as the rocking bed [9, 10], and negative pressure devices, such as the iron lung [11], poncho-wrap, and tortoise shell ventilators [12-14], were developed. These ventilators successfully supported many survivors of the polio epidemics who had chronic respiratory insufficiency, sometimes for decades [10, 12-16]. During the early 1960s, however, control of the polio epidemics with the Salk and Sabin vaccines and the concomitant proliferation of positive pressure ventilation through endotracheal intubation caused a marked decrease in noninvasive ventilator use [17-19]. Interest in noninvasive ventilators resurged during the early 1980s when intermittent use (mostly nocturnal) of negative pressure ventilators was found to reverse daytime gas exchange abnormalities and symptoms of chronic hypoventilation in patients with severe kyphoscoliosis and other neuromuscular diseases, including muscular dystrophy, multiple sclerosis, and the postpolio syndrome [20-24]. Unfortunately, these body ventilators have several limitations, including bulkiness, lack of portability, difficult application in severely disabled patients, and the tendency to cause musculoskeletal discomfort [16]. Frequent and severe oxygen desaturation caused by transient upper airway obstruction during sleep in certain patients using negative pressure ventilators is the greatest concern [25-27]. Switching to noninvasive positive pressure ventilators from negative pressure ventilators ameliorates oxygen desaturation [26] and improves portability and ease of application. These advantages compared with other noninvasive forms of ventilation have increased the use of noninvasive positive pressure ventilation. Invasive positive pressure ventilation was first introduced during the late 1800s and early 1900s [28] but was not extensively used for ventilatory support until the late 1950s and 1960s, when experience using anesthesia for surgery led to the development of positive pressure ventilators that reliably delivered preset pressures and volumes. These early positive pressure ventilators were used almost exclusively with artificial airways [18]. Noninvasive administration of intermittent positive pressure became popular during the 1950s through the 1970s for several respiratory disorders with the use of intermittent positive pressure breathing through a mouthpiece [29, 30]. Although some early studies showed that intermittent positive pressure breathing could transiently reverse carbon dioxide narcosis in patients with acute respiratory failure [31, 32], successes were inconsistent [33], and intermittent positive pressure breathing became used primarily to deliver aerosolized bronchodilator medication. It fell into disfavor after several studies, including a National Institutes of Healthsponsored multicenter trial [30], found no benefit of intermittent positive pressure breathing compared with standard nebulizer therapy for patients with chronic obstructive pulmonary disease exacerbations. During the 1960s and 1970s, a few centers used noninvasive positive pressure ventilation to provide ventilatory support to patients with chronic respiratory failure using lip seals or facial masks as interfaces [2, 3], but the technique required cooperative, motivated patients and considerable patience and coaching from medical staff. In 1981, Sullivan and colleagues [1] described nasal continuous positive airway pressure used as a pneumatic splint to maintain upper airway patency in patients with obstructive sleep apnea and, several years later, relatively comfortable nasal masks became commercially available. During the mid-1980s, investigators began applying intermittent positive pressure ventilation through nasal interfaces and rapidly discovered that it augmented ventilation in patients with chronic respiratory failure, particularly during sleep [26, 34-43]. Patients also seemed to adapt to these more readily than to previously available interfaces. Most recently, small, relatively inexpensive, easily portable ventilators were developed to be used specifically with noninvasive positive pressure ventilation using a nasal mask [44-47] (Figure 1). Application of noninvasive positive pressure ventilation has been tested in patients with many varieties of acute [48-57] and chronic [34-43] respiratory failure, as an aid to weaning after bouts of acute respiratory failure [58], in obstructive sleep apnea unresponsive to high nasal continuous positive airway pressure [47], and in patients having difficulty after extubation [53]. Figure 1. A typical noninvasive positive pressure ventilation system using a nasal mask and a portable pressure-limited ventilator. Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure For the past several decades, acute respiratory failure has been treated primarily with positive pressure ventilation through endotracheal intubation. To avoid endotracheal intubation and its attendant complications [59], investigators recently began administering noninvasive positive pressure ventilation to selected patients with acute respiratory failure. The theoretical advantages of this approach are to improve patient comfort; to reduce the need for sedation; to avoid the complications of endotracheal intubation, including upper airway trauma, sinusitis, otitis, and nosocomial pneumonia [59]; and to maintain airway defense, speech, and swallowing. Of course, limitations exist, including the need for patient cooperation; the lack of direct access to the airway, which could promote mucus plugging or atelectasis in patients with copious secretions; facial skin ulcers caused by mask pressure; and aerophagia. Noninvasive positive pressure ventilation has been tested in several uncontrolled series [50-56], in a study with historically matched controls [49], and in one randomized, controlled trial [57], as listed in Table 1. Table 1. Studies on the Use of Noninvasive Positive Pressure Ventilation in Acute Respiratory Failure* Several interfaces and ventilator modes have been used to deliver noninvasive positive pressure ventilation to patients with acute respiratory failure (Table 1), including facial masks covering both the nose and mouth [49-51] and nasal masks [52-57]. Ventilator modes were pressure-limited [49-51, 53] and volume-cont

Pulmonary complications of chronic neuromuscular diseases and their management.

Chronic neuromuscular diseases may affect all major respiratory muscles groups including inspiratory, expiratory, and bulbar, and respiratory complications are the major cause of morbidity and mortality. Untreated, many of these diseases lead inexorably to hypercapnic respiratory failure, precipitated in some cases by chronic aspiration and secretion retention or pneumonia, related to impairment of cough and swallowing mechanisms. Many measures are helpful including inhibition of salivation, cough‐assist techniques, devices to enhance communication, and physical therapy. In addition, ventilatory assistance is an important part of disease management for patients with advanced neuromuscular disease. Because of its comfort, convenience, and portability advantages, noninvasive positive pressure ventilation (NPPV) has become the modality of first choice for most patients. Patients to receive NPPV should be selected using consensus guidelines, and initiation should be gradual to maximize the chances for success. Attention should be paid to individual preferences for interfaces and early identification of cough impairment that necessitates the use of cough‐assist devices. For patients considered unsuitable for noninvasive ventilation, invasive mechanical ventilation should be considered, but only after a frank but compassionate discussion between the patient, family, physician, and other caregivers. Muscle Nerve 29: 5–27, 2004

Outcomes of patients with do-not-intubate orders treated with noninvasive ventilation

Objective:To determine whether diagnosis and bedside observations predict outcomes of patients who have declined intubation but accept noninvasive positive pressure ventilation (NPPV) to treat their respiratory failure. Design:Prospective multiple-center cohort trial. Setting:Two teaching hospitals and two community-based hospitals in southeastern New England from January through October 1999. Patients:All patients receiving NPPV for acute respiratory failure were screened and enrolled if they had a written do-not-intubate (DNI) order. Interventions:Patients were begun on NPPV with mean inspiratory and expiratory pressures of 13.4 ± 0.3 and 5.0 ± 1 cm H2O, respectively. Respiratory therapists recorded demographic information, blood gases, and ventilator type and settings, and they made bedside assessments of cough strength, presence of airway secretions, awake state, and agitation. Patients were followed until discharge for duration of NPPV, survival status, and disposition. Measurements and Main Results:Of 1,211 screened patients, 114 had a DNI status and were enrolled into the study. Of these, 49 (43%) survived to discharge. Age, gender, location in a community vs. teaching hospital, and initial pH and Pao2 did not affect survival, but a higher baseline Paco2 was associated with a favorable odds ratios for survival to discharge. Diagnosis was an important determinant of survival, with congestive heart failure patients having significantly better survival rates than those with chronic obstructive pulmonary disease, cancer, pneumonia, or other diagnoses. A stronger cough and being awake were also associated with increased probability of survival. Conclusion:Patients with respiratory failure and a DNI status have a high overall mortality rate when treated with NPPV, but those with diagnoses such as congestive heart failure or chronic obstructive pulmonary disease, who have a strong cough, or who are awake have better prognoses. These data should be useful when counseling DNI patients and their families on use of NPPV.

Molecular basis for antagonism between PDGF and the TGFβ family of signalling pathways by control of miR-24 expression

Modulation of the vascular smooth‐muscle‐cell (vSMC) phenotype from a quiescent ‘contractile’ phenotype to a proliferative ‘synthetic’ phenotype has been implicated in vascular injury repair, as well as pathogenesis of vascular proliferative diseases. Both bone morphogenetic protein (BMP) and transforming growth factor‐β (TGFβ)‐signalling pathways promote a contractile phenotype, while the platelet‐derived growth factor‐BB (PDGF‐BB)‐signalling pathway promotes a switch to the synthetic phenotype. Here we show that PDGF‐BB induces microRNA‐24 (miR‐24), which in turn leads to downregulation of Tribbles‐like protein‐3 (Trb3). Repression of Trb3 coincides with reduced expression of Smad proteins and decrease in BMP and TGFβ signalling, promoting a synthetic phenotype in vSMCs. Inhibition of miR‐24 by antisense oligonuclotides abrogates the downregulation of Trb3 as well as pro‐synthetic activity of the PDGF‐signalling pathway. Thus, this study provides a molecular basis for the antagonism between the PDGF and TGFβ pathways, and its effect on the control of the vSMC phenotype.