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1.  Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS) in Toronto, Canada 
Background
Severe acute respiratory syndrome (SARS) was introduced into Canada by a visitor to Hong Kong who returned to Toronto on Feb. 23, 2003. Transmission to a family member who was later admitted to a community hospital in Toronto led to a large nosocomial outbreak. In this report we summarize the preliminary results of the epidemiological investigation into the transmission of SARS between 128 cases associated with this hospital outbreak.
Methods
We collected epidemiologic data on 128 probable and suspect cases of SARS associated with the hospital outbreak, including those who became infected in hospital and the next generation of illness arising among their contacts. Incubation periods were calculated based on cases with a single known exposure. Transmission chains from the index family to hospital contacts and within the hospital were mapped. Attack rates were calculated for nurses in 3 hospital wards where transmission occurred.
Results
The cases ranged in age from 21 months to 86 years; 60.2% were female. Seventeen deaths were reported (case-fatality rate 13.3%). Of the identified cases, 36.7% were hospital staff. Other cases were household or social contacts of SARS cases (29.6%), hospital patients (14.1%), visitors (14.1%) or other health care workers (5.5%). Of the 128 cases, 120 (93.8%) had documented contact with a SARS case or with a ward where there was a known SARS case. The remaining 8 cases without documented exposure are believed to have had exposure to an unidentified case and remain under investigation. The attack rates among nurses who worked in the emergency department, intensive care unit and coronary care unit ranged from 10.3% to 60.0%. Based on 42 of the 128 cases with a single known contact with a SARS case, the mean incubation period was 5 days (range 2 to 10 days).
Interpretation
Evidence to date suggests that SARS is a severe respiratory illness spread mainly by respiratory droplets. There has been no evidence of further transmission within the hospital after the elapse of 2 full incubation periods (20 days).
PMCID: PMC180651  PMID: 12925421
2.  Statin therapy as prevention against development of acute respiratory distress syndrome: An observational study* 
Critical care medicine  2012;40(5):1470-1477.
Objectives
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (“statins”) have anti-inflammatory properties and are associated with improved outcomes in critically ill patients. We investigated whether previous statin therapy affects outcomes in patients at risk for acute respiratory distress syndrome.
Design
Patients were followed-up for the primary outcome of acute respiratory distress syndrome and secondary outcomes of intensive care unit and 60-day mortality, organ dysfunction, and ventilator-free days in a secondary analysis of a prospective cohort study. Receipt of statin therapy was recorded. Propensity score matching was used to adjust for confounding by indication.
Setting
Intensive care units at a tertiary care academic medical center.
Patients
Critically ill patients (2,743) with acute respiratory distress syndrome risk factors.
Interventions
None.
Measurements and Main Results
Acute respiratory distress syndrome developed in 738 (26%) patients; 413 patients (15%) received a statin within 24 hrs of intensive care unit admission. Those who had received a statin within 24 hrs had a lower rate of development of acute respiratory distress syndrome (odds ratio 0.56; 95% confidence interval 0.43–0.73; p < .0001). After multivariate adjustment for potential confounders, this association remained significant (odds ratio 0.69; 95% confidence interval 0.51–0.92; p = .01). However, after propensity score matching, the association was not statistically significant (odds ratio 0.79; 95% confidence interval 0.57–1.10; p = .16). Statin use was not associated with reduced acute respiratory distress syndrome mortality, organ dysfunction, or ventilator-free days. Results of the study were presented in accordance with STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.
Conclusions
Statin therapy at the time of intensive care unit admission was not associated with a lower rate of development of acute respiratory distress syndrome after matching for patient propensity to receive statins. Statin therapy was not associated with improvements in acute respiratory distress syndrome mortality, organ failure, or days free from mechanical ventilation.
doi:10.1097/CCM.0b013e3182416d7a
PMCID: PMC3939937  PMID: 22430234
ALI/ARDS; critical illness; statin
3.  Identification and containment of an outbreak of SARS in a community hospital 
Background
Severe acute respiratory syndrome (SARS) is continuing to spread around the world. All hospitals must be prepared to care for patients with SARS. Thus, it is important to understand the transmission of this disease in hospitals and to evaluate methods for its containment in health care institutions. We describe how we cared for the first 2 patients with SARS admitted to our 419-bed community hospital in Richmond Hill, Ont., and the response to a SARS outbreak within our institution.
Methods
We collected clinical and epidemiological data about patients and health care workers at our institution who during a 13-day period had a potential unprotected exposure to 2 patients whose signs and symptoms were subsequently identified as meeting the case definition for probable SARS. The index case at our hospital was a patient who was transferred to our intensive care unit (ICU) from a referral hospital on Mar. 16, 2003, where he had been in close proximity to the son of the individual with the first reported case of SARS in Toronto. After 13 days in the ICU, a diagnosis of probable SARS was reached for our index case. Immediately upon diagnosis of our index case, respiratory isolation and barrier precautions were instituted throughout our hospital and maintained for a period of 10 days, which is the estimated maximum incubation period reported for this disease. Aggressive surveillance measures among hospital staff, patients and visitors were also maintained during this time.
Results
During the surveillance period, 15 individuals (10 hospital staff, 3 patients and 2 visitors) were identified as meeting the case definition for probable or suspected SARS, in addition to our index case. All but 1 individual had had direct contact with a symptomatic patient with SARS during the period of unprotected exposure. No additional cases were identified after infection control precautions had been implemented for 8 days. No cases of secondary transmission were identified in the 21 days following the implementation of these precautions at our institution.
Interpretation
SARS can easily be spread by direct personal contact in the hospital setting. We found that the implementation of aggressive infection control measures is effective in preventing further transmission of this disease.
PMCID: PMC155957  PMID: 12771070
4.  Clinical course and management of SARS in health care workers in Toronto: a case series 
Background
Severe acute respiratory syndrome (SARS) has only recently been described. We provide individual patient data on the clinical course, treatment and complications experienced by 14 front-line health care workers and hospital support staff in Toronto who were diagnosed with SARS, and we provide follow-up information for up to 3 weeks after their discharge from hospital.
Methods
As part of the initial response to the SARS outbreak in Toronto, our health care centre was asked to establish a SARS unit for health care workers who were infected. Patients were admitted to this unit and were closely monitored and treated until they were well enough to be discharged. We prospectively compiled information on their clinical course, management and complications and followed them for 3 weeks after discharge.
Results
The 11 women and 3 men described here (mean age 42 [standard deviation {SD} 9] years) were all involved in providing medical or ancillary hospital services to patients who were later found to have SARS. Onset of symptoms in 4 of our patients who could clearly identify only a single contact with a patient with SARS occurred on average 4 (SD 3) days after exposure. For the remaining 10 patients with multiple patient contacts, symptom onset followed exposure by a mean of 3.5 (SD 3) days after their exposure. All patients were treated with ribavirin, and all patients received levofloxacin. Many experienced major complications. Dyspnea was present in 12 patients during their stay in hospital, and all developed abnormalities on chest radiograph; 3 patients developed severe hypoxemia (PaO2 < 50 mm Hg). All patients experienced a drop in hemoglobin. Nine patients had hemolytic anemia. Three patients experienced numbness and tingling in their hands and feet, and 2 developed frank tetany. All 3 had magnesium levels that were less than 0.1 mmol/L. All patients recovered and were discharged home. At a follow-up examination 3 weeks after discharge (5 weeks after onset of illness), all patients were no longer weak but continued to become fatigued easily and had dyspnea on minimal exertion. For 5 patients, chest radiographs still showed residual disease.
Interpretation
SARS is a very serious illness even in healthy, relatively young people. The clinical course in our patients, all of whom met the case definition for SARS (which requires pulmonary involvement), resulted in dyspnea and, in some individuals, severe hypoxemia. Severe hemolytic anemia may be a feature of SARS or may be a complication of therapy, possibly with ribavirin.
PMCID: PMC161610  PMID: 12821618
5.  Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation 
PLoS Medicine  2013;10(12):e1001577.
In this paper, Choi and colleagues analyzed levels of mitochondrial DNA in two prospective observational cohort studies and found that increased mtDNA levels are associated with ICU mortality, and improve risk prediction in medical ICU patients. The data suggests that mtDNA could serve as a viable plasma biomarker in MICU patients.
Background
Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.
Methods and Findings
Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.
Conclusions
Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Intensive care units (ICUs, also known as critical care units) are specialist hospital wards that provide care for people with life-threatening injuries and illnesses. In the US alone, more than 5 million people are admitted to ICUs every year. Different types of ICUs treat different types of problems. Medical ICUs treat patients who, for example, have been poisoned or who have a serious infection such as sepsis (blood poisoning) or severe pneumonia (inflammation of the lungs); trauma ICUs treat patients who have sustained a major injury; cardiac ICUs treat patients who have heart problems; and surgical ICUs treat complications arising from operations. Patients admitted to ICUs require constant medical attention and support from a team of specially trained nurses and physicians to prevent organ injury and to keep their bodies functioning. Monitors, intravenous tubes (to supply essential fluids, nutrients, and drugs), breathing machines, catheters (to drain urine), and other equipment also help to keep ICU patients alive.
Why Was This Study Done?
Although many patients admitted to ICUs recover, others do not. ICU specialists use scoring systems (algorithms) based on clinical signs and physiological measurements to predict their patients' likely outcomes. For example, the APACHE II scoring system uses information on heart and breathing rates, temperature, levels of salts in the blood, and other signs and physiological measurements collected during the first 24 hours in the ICU to predict the patient's risk of death. Existing scoring systems are not perfect, however, and “biomarkers” (molecules in bodily fluids that provide information about a disease state) are needed to improve risk prediction for ICU patients. Here, the researchers investigate whether levels of circulating cell-free mitochondrial DNA (mtDNA) are associated with ICU deaths and whether these levels can be used as a biomarker to improve risk prediction in ICU patients. Mitochondria are cellular structures that produce energy. Levels of mtDNA in the plasma (the liquid part of blood) increase in response to trauma and infection. Moreover, mtDNA activates molecular processes that lead to inflammation and organ injury.
What Did the Researchers Do and Find?
The researchers measured mtDNA levels in the plasma of patients enrolled in two prospective observational cohort studies that monitored the outcomes of ICU patients. In the Brigham and Women's Hospital Registry of Critical Illness study, blood was taken from 200 patients within 24 hours of admission into the hospital's medical ICU. In the Molecular Epidemiology of Acute Respiratory Distress Syndrome study (acute respiratory distress syndrome is a life-threatening inflammatory reaction to lung damage or infection), blood was taken from 243 patients within 48 hours of admission into medical and non-medical ICUs at two other US hospitals. Patients admitted to medical ICUs with a raised mtDNA level (3,200 or more copies of a specific mitochondrial gene per microliter of plasma) had a 7- to 8-fold increased risk of dying within 28 days of admission compared to patients with mtDNA levels of less than 3,200 copies/µl plasma. There was no evidence of an association between raised mtDNA levels and death among patients admitted to non-medical ICUs. The addition of an elevated mtDNA level to a clinical model for risk prediction that included the APACHE II score and biomarkers that are already used to predict ICU outcomes improved the net reclassification index (an indicator of the improvement in risk prediction algorithms offered by new biomarkers) of 28-day mortality among medical ICU patients in both studies.
What Do These Findings Mean?
These findings indicate that raised mtDNA plasma levels are associated with death in medical ICUs and show that, among patients in medical ICUs, measurement of mtDNA plasma levels can improve the prediction of the risk of death from the APACHE II scoring system, even when commonly measured biomarkers are taken into account. These findings do not indicate whether circulating cell-free mtDNA increased because of the underlying severity of illness or whether mtDNA actively contributes to the disease process in medical ICU patients. Moreover, they do not provide any evidence that raised mtDNA levels are associated with an increased risk of death among non-medical (mainly surgical) ICU patients. These findings need to be confirmed in additional patients, but given the relative ease and rapidity of mtDNA measurement, the determination of circulating cell-free mtDNA levels could be a valuable addition to the assessment of patients admitted to medical ICUs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001577.
The UK National Health Service Choices website provides information about intensive care
The Society of Critical Care Medicine provides information for professionals, families, and patients about all aspects of intensive care
MedlinePlus provides links to other resources about intensive care (in English and Spanish)
The UK charity ICUsteps supports patients and their families through recovery from critical illness; its booklet Intensive Care: A Guide for Patients and Families is available in English and ten other languages; its website includes patient experiences and relative experiences of treatment in ICUs
Wikipedia has a page on ICU scoring systems (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001577
PMCID: PMC3876981  PMID: 24391478
6.  Intensive care management of organophosphate insecticide poisoning 
Critical Care  2001;5(4):211-215.
Introduction
Organophosphate (OP) insecticides inhibit both cholinesterase and pseudo-cholinesterase activities. The inhibition of acetylcholinesterase causes accumulation of acetylcholine at synapses, and overstimulation of neurotransmission occurs as a result of this accumulation. The mortality rate of OP poisoning is high. Early diagnosis and appropriate treatment is often life saving. Treatment of OP poisoning consists of intravenous atropine and oximes. The clinical course of OP poisoning may be quite severe and may need intensive care management. We report our experience with the intensive care management of serious OP insecticide poisonings.
Methods
A retrospective study was performed on the patients with OP poisoning followed at our medical intensive care unit. Forty-seven patients were included. Diagnosis was performed from the history taken either from the patient or from the patient's relatives about the agent involved in the exposure. Diagnosis could not be confirmed with serum and red blood cell anticholinesterase levels because these are not performed at our institution. Intravenous atropine and pralidoxime was administered as soon as possible. Pralidoxime could not be given to 16 patients: 2 patients did not receive pralidoxime because they were late admissions and 14 did not receive pralidoxime because the Ministry of Health office was out of stock. Other measures for the treatment were gastric lavage and administration of activated charcoal via nasogastric tube, and cleansing the patient's body with soap and water. The patients were intubated and mechanically ventilated if the patients had respiratory failure, a depressed level of consciousness, which causes an inability to protect the airway, and hemodynamic instability. Mechanical ventilation was performed as synchronized intermittent mandatory ventilation + pressure support mode, either as volume or pressure control. Positive end expiratory pressure was titrated to keep SaO2 above 94% with 40% FIO2. Weaning was performed using either T-tube trials or pressure support weaning. The chi-square test was used for statistical analysis. Data are presented as mean ± standard deviation.
Results
There were 25 female and 22 male patients. Thirty-two (68%) were suicide attempts and 15 (32%) were accidental exposure. The gastrointestinal route was the main route in 44 (93.6%) patients. The mortality rates for the patients who did and did not receive pralidoxime were 32 and 18.7%, respectively, and were not statistically different. The most frequent signs were meiosis, change in mental status, hypersalivation and fasciculations. Ten patients (21.2%) required mechanical ventilation. The mortality rate for the patients who required mechanical ventilation was 50%, but the rate was 21.6% for the patients who were not mechanically ventilated. Intermediate syndrome was observed in 9 (19.1%) patients. Complications were observed in 35 (74.4%) patients. These complications were respiratory failure (14 patients), aspiration pneumonia (10 patients), urinary system infection (6 patients), convulsion (4 patients) and septic shock (1 patient). The duration of the intensive care stay was 5.2 ± 3.0 days.
Discussion
Ingestion of OP compounds for suicidal purposes is a major problem, especially in developing countries. Thirty-two (68%) of our patients used the OP insecticide for suicide. Two patients did not receive pralidoxime because of delayed admission and they were successfully treated with atropine alone. Three of the patients who did not receive pralidoxime because of unavailability died. The mortality rate was no different between the patients treated with pralidoxime or those without pralidoxime. De Silva and coworkers have also reported that the mortality rate was not different between each group. Three patients with intermediate syndrome died due to delay for endotracheal intubation. The average respiratory rate of these patients increased from 22 to 38 breaths/min, which is an important sign of respiratory distress. The nurse to patient ratio was increased after these events. Early recognition of respiratory failure resulting in intubation and mechanical ventilation is a life-saving intervention for patients with OP poisoning. Respiratory failure is the most troublesome complication, which was observed in 35 (74.4%) patients. Patients with OP poisoning may have respiratory failure for many reasons, including aspiration of the gastric content, excessive secretions, pneumonia and septicemia complicating acute respiratory distress syndrome.
Conclusions
OP insecticide poisoning is a serious condition that needs rapid diagnosis and treatment. Since respiratory failure is the major reason for mortality, careful monitoring, appropriate management and early recognition of this complication may decrease the mortality rate among these patients.
PMCID: PMC37406  PMID: 11511334
anticholinesterase; atropine; organophosphate pesticides; poisoning; pralidoxime
7.  Extracorporeal Lung Support Technologies – Bridge to Recovery and Bridge to Lung Transplantation in Adult Patients 
Executive Summary
For cases of acute respiratory distress syndrome (ARDS) and progressive chronic respiratory failure, the first choice or treatment is mechanical ventilation. For decades, this method has been used to support critically ill patients in respiratory failure. Despite its life-saving potential, however, several experimental and clinical studies have suggested that ventilator-induced lung injury can adversely affect the lungs and patient outcomes. Current opinion is that by reducing the pressure and volume of gas delivered to the lungs during mechanical ventilation, the stress applied to the lungs is eased, enabling them to rest and recover. In addition, mechanical ventilation may fail to provide adequate gas exchange, thus patients may suffer from severe hypoxia and hypercapnea. For these reasons, extracorporeal lung support technologies may play an important role in the clinical management of patients with lung failure, allowing not only the transfer of oxygen and carbon dioxide (CO2) but also buying the lungs the time needed to rest and heal.
Objective
The objective of this analysis was to assess the effectiveness, safety, and cost-effectiveness of extracorporeal lung support technologies in the improvement of pulmonary gas exchange and the survival of adult patients with acute pulmonary failure and those with end-stage chronic progressive lung disease as a bridge to lung transplantation (LTx). The application of these technologies in primary graft dysfunction (PGD) after LTx is beyond the scope of this review and is not discussed.
Clinical Applications of Extracorporeal Lung Support
Extracorporeal lung support technologies [i.e., Interventional Lung Assist (ILA) and extracorporeal membrane oxygenation (ECMO)] have been advocated for use in the treatment of patients with respiratory failure. These techniques do not treat the underlying lung condition; rather, they improve gas exchange while enabling the implantation of a protective ventilation strategy to prevent further damage to the lung tissues imposed by the ventilator. As such, extracorporeal lung support technologies have been used in three major lung failure case types:
As a bridge to recovery in acute lung failure – for patients with injured or diseased lungs to give their lungs time to heal and regain normal physiologic function.
As a bridge to LTx – for patients with irreversible end stage lung disease requiring LTx.
As a bridge to recovery after LTx – used as lung support for patients with PGD or severe hypoxemia.
Ex-Vivo Lung Perfusion and Assessment
Recently, the evaluation and reconditioning of donor lungs ex-vivo has been introduced into clinical practice as a method of improving the rate of donor lung utilization. Generally, about 15% to 20% of donor lungs are suitable for LTx, but these figures may increase with the use of ex-vivo lung perfusion. The ex-vivo evaluation and reconditioning of donor lungs is currently performed at the Toronto General Hospital (TGH) and preliminary results have been encouraging (Personal communication, clinical expert, December 17, 2009). If its effectiveness is confirmed, the use of the technique could lead to further expansion of donor organ pools and improvements in post-LTx outcomes.
Extracorporeal Lung support Technologies
ECMO
The ECMO system consists of a centrifugal pump, a membrane oxygenator, inlet and outlet cannulas, and tubing. The exchange of oxygen and CO2 then takes place in the oxygenator, which delivers the reoxygenated blood back into one of the patient’s veins or arteries. Additional ports may be added for haemodialysis or ultrafiltration.
Two different techniques may be used to introduce ECMO: venoarterial and venovenous. In the venoarterial technique, cannulation is through either the femoral artery and the femoral vein, or through the carotid artery and the internal jugular vein. In the venovenous technique cannulation is through both femoral veins or a femoral vein and internal jugular vein; one cannula acts as inflow or arterial line, and the other as an outflow or venous line. Venovenous ECMO will not provide adequate support if a patient has pulmonary hypertension or right heart failure. Problems associated with cannulation during the procedure include bleeding around the cannulation site and limb ischemia distal to the cannulation site.
ILA
Interventional Lung Assist (ILA) is used to remove excess CO2 from the blood of patients in respiratory failure. The system is characterized by a novel, low-resistance gas exchange device with a diffusion membrane composed of polymethylpentene (PMP) fibres. These fibres are woven into a complex configuration that maximizes the exchange of oxygen and CO2 by simple diffusion. The system is also designed to operate without the help of an external pump, though one can be added if higher blood flow is required. The device is then applied across an arteriovenous shunt between the femoral artery and femoral vein. Depending on the size of the arterial cannula used and the mean systemic arterial pressure, a blood flow of up to 2.5 L/min can be achieved (up to 5.5 L/min with an external pump). The cannulation is performed after intravenous administration of heparin.
Recently, the first commercially available extracorporeal membrane ventilator (NovaLung GmbH, Hechingen, Germany) was approved for clinical use by Health Canada for patients in respiratory failure. The system has been used in more than 2,000 patients with various indications in Europe, and was used for the first time in North America at the Toronto General Hospital in 2006.
Evidence-Based Analysis
The research questions addressed in this report are:
Does ILA/ECMO facilitate gas exchange in the lungs of patients with severe respiratory failure?
Does ILA/ECMO improve the survival rate of patients with respiratory failure caused by a range of underlying conditions including patients awaiting LTx?
What are the possible serious adverse events associated with ILA/ECMO therapy?
To address these questions, a systematic literature search was performed on September 28, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 to September 28, 2008. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Studies in which ILA/ECMO was used as a bridge to recovery or bridge to LTx
Studies containing information relevant to the effectiveness and safety of the procedure
Studies including at least five patients
Exclusion Criteria
Studies reporting the use of ILA/ECMO for inter-hospital transfers of critically ill patients
Studies reporting the use of ILA/ECMO in patients during or after LTx
Animal or laboratory studies
Case reports
Outcomes of Interest
Reduction in partial pressure of CO2
Correction of respiratory acidosis
Improvement in partial pressure of oxygen
Improvement in patient survival
Frequency and severity of adverse events
The search yielded 107 citations in Medline and 107 citations in EMBASE. After reviewing the information provided in the titles and abstracts, eight citations were found to meet the study inclusion criteria. One study was then excluded because of an overlap in the study population with a previous study. Reference checking did not produce any additional studies for inclusion. Seven case series studies, all conducted in Germany, were thus included in this review (see Table 1).
Also included is the recently published CESAR trial, a multicentre RCT in the UK in which ECMO was compared with conventional intensive care management. The results of the CESAR trial were published when this review was initiated. In the absence of any other recent RCT on ECMO, the results of this trial were considered for this assessment and no further searches were conducted. A literature search was then conducted for application of ECMO as bridge to LTx patients (January, 1, 2005 to current). A total of 127 citations on this topic were identified and reviewed but none were found to have examined the use of ECMO as bridge to LTx.
Quality of Evidence
To grade the quality of evidence, the grading system formulated by the GRADE working group and adopted by MAS was applied. The GRADE system classifies the quality of a body of evidence as high, moderate, low, or very low according to four key elements: study design, study quality, consistency across studies, and directness.
Results
Trials on ILA
Of the seven studies identified, six involved patients with ARDS caused by a range of underlying conditions; the seventh included only patients awaiting LTx. All studies reported the rate of gas exchange and respiratory mechanics before ILA and for up to 7 days of ILA therapy. Four studies reported the means and standard deviations of blood gas transfer and arterial blood pH, which were used for meta-analysis.
Fischer et al. reported their first experience on the use of ILA as a bridge to LTx. In their study, 12 patients at high urgency status for LTx, who also had severe ventilation refractory hypercapnea and respiratory acidosis, were connected to ILA prior to LTx. Seven patients had a systemic infection or sepsis prior to ILA insertion. Six hours after initiation of ILA, the partial pressure of CO2 in arterial blood significantly decreased (P < .05) and arterial blood pH significantly improved (P < .05) and remained stable for one week (last time point reported). The partial pressure of oxygen in arterial blood improved from 71 mmHg to 83 mmHg 6 hours after insertion of ILA. The ratio of PaO2/FiO2 improved from 135 at baseline to 168 at 24 hours after insertion of ILA but returned to baseline values in the following week.
Trials on ECMO
The UK-based CESAR trial was conducted to assess the effectiveness and cost of ECMO therapy for severe, acute respiratory failure. The trial protocol were published in 2006 and details of the methods used for the economic evaluation were published in 2008. The study itself was a pragmatic trial (similar to a UK trial of neonatal ECMO), in which best standard practice was compared with an ECMO protocol. The trial involved 180 patients with acute but potentially reversible respiratory failure, with each also having a Murray score of ≥ 3.0 or uncompensated hypercapnea at a pH of < 7.2. Enrolled patients were randomized in a 1:1 ratio to receive either conventional ventilation treatment or ECMO while on ventilator. Conventional management included intermittent positive pressure ventilation, high frequency oscillatory ventilation, or both. As a pragmatic trial, a specific management protocol was not followed; rather the treatment centres were advised to follow a low volume low pressure ventilation strategy. A tidal volume of 4 to 8 mL/kg body weight and a plateau pressure of < 30 cm H2O were recommended.
Conclusions
ILA
Bridge to recovery
No RCTs or observational studies compared ILA to other treatment modalities.
Case series have shown that ILA therapy results in significant CO2 removal from arterial blood and correction of respiratory acidosis, as well as an improvement in oxygen transfer.
ILA therapy enabled a lowering of respiratory settings to protect the lungs without causing a negative impact on arterial blood CO2 and arterial blood pH.
The impact of ILA on patient long-term survival cannot be determined through the studies reviewed.
In-hospital mortality across studies ranged from 20% to 65%.
Ischemic complications were the most frequent adverse events following ILA therapy.
Leg amputation is a rare but possible outcome of ILA therapy, having occurred in about 0.9% of patients in these case series. New techniques involving the insertion of additional cannula into the femoral artery to perfuse the leg may lower this rate.
Bridge to LTx
The results of one case series (n=12) showed that ILA effectively removes CO2 from arterial blood and corrects respiratory acidosis in patients with ventilation refractory hypercapnea awaiting a LTx
Eight of the 12 patients (67%) awaiting a LTx were successfully transplanted and one-year survival for those transplanted was 80%
Since all studies are case series, the grade of the evidence for these observations is classified as “LOW”.
ECMO
Bridge to recovery
Based on the results of a pragmatic trial and an intention to treat analysis, referral of patient to an ECMO based centre significantly improves patient survival without disability compared to conventional ventilation. The results of CESAR trial showed that:
For patients with information about disability, survival without severe disability was significantly higher in ECMO arm
Assuming that the three patients in the conventional ventilation arm who did not have information about severe disability were all disabled, the results were also significant.
Assuming that none of these patients were disabled, the results were at borderline significance
A greater, though not statistically significant, proportion of patients in ECMO arm survived.
The rate of serious adverse events was higher among patients in ECMO group
The grade of evidence for the above observations is classified as “HIGH”.
Bridge to LTx
No studies fitting the inclusion criteria were identified.
There is no accurate data on the use of ECMO in patients awaiting LTx.
Economic Analysis
The objective of the economic analysis was to determine the costs associated with extracorporeal lung support technologies for bridge to LTx in adults. A literature search was conducted for which the target population was adults eligible for extracorporeal lung support. The primary analytic perspective was that of the Ministry of Health and Long-Term Care (MOHLTC). Articles published in English and fitting the following inclusion criteria were reviewed:
Full economic evaluations including cost-effectiveness analyses (CEA), cost-utility analyses (CUA), cost-benefit analyses (CBA);
Economic evaluations reporting incremental cost-effectiveness ratios (ICER) i.e. cost per quality adjusted life year (QALY), life years gained (LYG), or cost per event avoided; and
Studies in patients eligible for lung support technologies for to lung transplantation.
The search yielded no articles reporting comparative economic analyses.
Resource Use and Costs
Costs associated with both ILA and ECMO (outlined in Table ES-1) were obtained from the University Health Network (UHN) case costing initiative (personal communication, UHN, January 2010). Consultation with a clinical expert in the field was also conducted to verify resource utilization. The consultant was situated at the UHN in Toronto. The UHN has one ECMO machine, which cost approximately $100,000. The system is 18 years old and is used an average of 3 to 4 times a year with 35 procedures being performed over the last 9 years. The disposable cost per patient associated with ECMO is, on average, $2,200. There is a maintenance cost associated with the machine (not reported by the UHN), which is currently absorbed by the hospital’s biomedical engineering department.
The average capital cost of an ILA device is $7,100 per device, per patient, while the average cost of the reusable pump $65,000. The UHN has performed 16 of these procedures over the last 2.5 years. Similarly, there is a maintenance cost not that was reported by UHN but is absorbed by the hospital’s biomedical engineering department.
Resources Associated with Extracorporeal Lung Support Technologies
Hospital costs associated with ILA were based on the average cost incurred by the hospital for 11 cases performed in the FY 07/08 (personal communication, UHN, January 2010). The resources incurred with this hospital procedure included:
Device and disposables
OR transplant
Surgical ICU
Laboratory work
Medical imaging
Pharmacy
Clinical nutrition
Physiotherapy
Occupational therapy
Speech and language pathology
Social work
The average length of stay in hospital was 61 days for ILA (range: 5 to 164 days) and the average direct cost was $186,000 per case (range: $19,000 to $552,000). This procedure has a high staffing requirement to monitor patients in hospital, driving up the average cost per case.
PMCID: PMC3415698  PMID: 23074408
8.  Prevention of LPS-Induced Acute Lung Injury in Mice by Mesenchymal Stem Cells Overexpressing Angiopoietin 1 
PLoS Medicine  2007;4(9):e269.
Background
The acute respiratory distress syndrome (ARDS), a clinical complication of severe acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. ALI is characterized by disruption of the lung alveolar–capillary membrane barrier and resultant pulmonary edema associated with a proteinaceous alveolar exudate. Current specific treatment strategies for ALI/ARDS are lacking. We hypothesized that mesenchymal stem cells (MSCs), with or without transfection with the vasculoprotective gene angiopoietin 1 (ANGPT1) would have beneficial effects in experimental ALI in mice.
Methods and Findings
Syngeneic MSCs with or without transfection with plasmid containing the human ANGPT1 gene (pANGPT1) were delivered through the right jugular vein of mice 30 min after intratracheal instillation of lipopolysaccharide (LPS) to induce lung injury. Administration of MSCs significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts in bronchoalveolar lavage (BAL) fluid (53%, 95% confidence interval [CI] 7%–101%; and 60%, CI 4%–116%, respectively) as well as reducing levels of proinflammatory cytokines in both BAL fluid and lung parenchymal homogenates. Furthermore, administration of MSCs transfected with pANGPT1 resulted in nearly complete reversal of LPS-induced increases in lung permeability as assessed by reductions in IgM and albumin levels in BAL (96%, CI 6%–185%; and 74%, CI 23%–126%, respectively). Fluorescently tagged MSCs were detected in the lung tissues by confocal microscopy and flow cytometry in both naïve and LPS-injured animals up to 3 d.
Conclusions
Treatment with MSCs alone significantly reduced LPS-induced acute pulmonary inflammation in mice, while administration of pANGPT1-transfected MSCs resulted in a further improvement in both alveolar inflammation and permeability. These results suggest a potential role for cell-based ANGPT1 gene therapy to treat clinical ALI/ARDS.
Using a mouse model of acute respiratory distress syndrome, Duncan Stewart and colleagues report that rescue with mesenchymal stem cells expressing human angiopoietin 1 can avert lung injury from lipopolysaccharide.
Editors' Summary
Background.
Critically ill people who have had an injury to their lungs, for example through pneumonia, trauma, or an immune response to infection, may end up developing a serious complication in the lung termed acute respiratory distress syndrome (ARDS). In ARDS, inflammation develops in the lung, and fluid builds up in the alveoli (the air sacs resembling “bunches of grapes” at the ends of the network of tubes in the lung). This buildup of fluid prevents oxygen from being carried efficiently from air into the blood; the individual consequently experiences problems breathing and can develop further serious complications, which contribute significantly to the burden of illness among people in intensive care units. The death rate among individuals who do develop ARDS is very high, upward of 30%. Normally, individuals with ARDS are given extra oxygen, and may need a machine to help them breathe; treatments also focus on addressing the underlying causes in each particular patient. However, currently there are very few specific treatments that address ARDS itself.
Why Was This Study Done?
The researchers here wanted to work toward new treatment options for individuals with ARDS. One possible approach involves cells known as mesenchymal stem cells (MSCs). These cells are typically found in the bone marrow and have a property shared by very few other cell types in the body; they are able to carry on dividing and renewing themselves, and can eventually develop into many other types of cell. The researchers already knew that MSCs could become incorporated into injured lungs in mice and develop there into the tissue layers lining the lung. Some interesting work had also been done on a protein called angiopoeitin 1 (ANGPT1), which seemed to play a role in protecting against inflammation in blood vessels. Therefore, there was a strong rationale for carrying out experiments in mice to see if MSCs engineered to produce the ANGPT1 protein might “rescue” lung injury in mice. These experiments would be an initial step toward developing possible new treatments for humans with ARDS.
What Did the Researchers Do and Find?
The researchers used a mouse model to mimic the human ARDS condition. This involved injecting the windpipe of experimental mice with lipopolysaccharide (a substance normally found on the outer surface of bacteria that brings about an immune reaction in the lung). After 30 minutes, the mice were then injected with either salt solution (as a control), the MSCs, or MSCs producing the ANGPT1 protein. The researchers then looked at markers of lung inflammation, the appearance of the lungs under a microscope, and whether the injected MSCs had become incorporated into the lung tissue.
The lipopolysaccharide brought about a large increase in the number of inflammatory cells in the lung fluid, which was reduced in the mice given MSCs. Furthermore, in mice given the MSCs producing ANGPT1 protein, the number of inflammatory cells was reduced to a level similar to that of mice that had not been given lipopolysaccharide. When the researchers looked at the appearance under the microscope of lungs from mice that had been given lipopolysaccharide, they saw signs of inflammation and fluid coming out into the lung air spaces. These signs were reduced among both mice treated with MSCs and those treated with MSCs producing ANGPT1. The researchers also measured the “leakiness” of the lung tissues in lipopolysaccharide-treated mice; MSCs seemed to reduce the leakiness to some extent, and the lungs of mice treated with MSCs producing ANGPT1 were no more leaky than those of mice that had never been injected with lipopolysaccharide. Finally, the MSCs were seen to be incorporated into lung tissue by three days after injection, but after that were lost from the lung.
What Do These Findings Mean?
Previous research done by the same group had shown that fibroblasts producing ANGPT1 could prevent lung injury in rats later given lipopolysaccharide. The experiments reported here go a step further than this, and suggest that MSCs producing ANGPT1 can “rescue” the condition of mouse lungs that had already been given lipopolysaccharide. In addition, treatment with MSCs alone also produced beneficial effects. This opens up a possible new treatment strategy for ARDS in humans. However, it should be emphasized that the animal model used here is not a precise parallel of ARDS in humans, and that more research remains to be done before human studies of this sort could be considered.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040269.
Medline Plus entry on acute respiratory distress syndrome, providing basic information about what ARDS is, its effects, and how it is currently managed
ARDS Network from the US National Heart, Lung, and Blood Institute of the National Institutes of Health; the site provides frequently asked questions about ARDS as well as a list of clinical trials conducted by the network
Information about stem cells from the US National Institutes of Health, including information about the potential uses of stem cells
Wikipedia page about mesenchymal stem cells (note: Wikipedia is an internet encyclopedia anyone can edit)
doi:10.1371/journal.pmed.0040269
PMCID: PMC1961632  PMID: 17803352
9.  Red blood cell transfusions and the risk of acute respiratory distress syndrome among the critically ill: a cohort study 
Critical Care  2007;11(3):R63.
Introduction
Recent data indicate that transfusion of packed red blood cells (pRBCs) may increase the risk for the development of acute respiratory distress syndrome (ARDS) in critically ill patients. Uncertainty remains regarding the strength of this relationship.
Methods
To quantify the association between transfusions and intensive care unit (ICU)-onset ARDS, we performed a cohort study within Crit, a multicenter, prospective, observational study of transfusion practice in the ICU which enrolled 4,892 critically ill patients in 284 ICUs in the United States. Diagnostic criteria for ARDS were prospectively defined, and we focused on subjects without ARDS at admission. The development of ARDS in the ICU served as the primary endpoint.
Results
Among the 4,730 patients without ARDS at admission, 246 (5.2%) developed ARDS in the ICU. At baseline, ARDS cases were younger, more likely to be in a surgical ICU, and more likely to be admitted with pneumonia or sepsis than controls without ARDS. Cases also were more likely to have a serum creatinine of greater than 2.0 mg/dl (23% versus 18%) and a serum albumin of less than or equal to 2.3 g/dl (54% versus 30%) and were more severely ill upon ICU admission as measured by either the APACHE II (Acute Physiology and Chronic Health Evaluation II) or SOFA (Sequential Organ Failure Assessment) score (p < 0.05 for all). Sixty-seven percent and 42% of cases and controls, respectively, had exposure to pRBC transfusions (p < 0.05), and the unadjusted odds ratio (OR) of developing ARDS in transfused patients was 2.74 (95% confidence interval [CI], 2.09 to 3.59; p < 0.0001) compared to those never transfused. After age, baseline severity of illness, admitting diagnosis, and process-of-care factors were adjusted for, the independent relationship between pRBC transfusions and ICU-onset ARDS remained significant (adjusted OR, 2.80; 95% CI, 1.90 to 4.12; p < 0.0001).
Conclusion
Development of ARDS after ICU admission is common, occurring in approximately 5% of critically ill patients. Transfusion of pRBCs is independently associated with the development of ARDS in the ICU.
doi:10.1186/cc5934
PMCID: PMC2206425  PMID: 17553147
10.  Surfactant protein-B polymorphisms and mortality in the acute respiratory distress syndrome* 
Critical care medicine  2008;36(9):2511-2516.
Objective
To determine whether polymorphisms of the surfactant protein B gene may be associated with increased mortality in patients with the acute respiratory distress syndrome.
Design
A prospective cohort study.
Setting
Four adult intensive care units at a tertiary academic medical center.
Patients
Two hundred fourteen white patients who had met criteria for acute respiratory distress syndrome.
Interventions
None.
Measurements and Main Results
Patients were genotyped for a variable nuclear tandem repeat polymorphism in intron 4 of the surfactant protein B gene and the surfactant protein B gene +1580 polymorphism. For the variable nuclear tandem repeat surfactant protein B gene polymorphism, patients were found to have either a homozygous wild-type genotype or a variant genotype consisting of either a heterozygous insertion or deletion polymorphism. Logistic regression was performed to analyze the relationship of the polymorphisms to mortality in patients with acute respiratory distress syndrome. In multivariate analysis, the presence of variable nuclear tandem repeat surfactant protein B gene polymorphism was associated with a 3.51 greater odds of death at 60 days in patients with acute respiratory distress syndrome as compared to those patients with the wild-type genotype (95% confidence interval 1.39-8.88, p = 0.008). There was no association found between the +1580 variant and outcome (p = 0.15).
Conclusions
In this study, the variable nuclear tandem repeat surfactant protein B gene polymorphism in intron 4 is associated with an increased 60 day mortality in acute respiratory distress syndrome after adjusting for age, severity of illness, and other potential confounders. Additional studies in other populations are needed to confirm this finding.
doi:10.1097/CCM.0b013e318183f608
PMCID: PMC3090262  PMID: 18679120
acute respiratory distress syndrome; surfactant; pulmonary; surfactant protein SFTP-B; SFTP-B +1580; genetic polymorphism
11.  Serum activin A and B, and follistatin in critically ill patients with influenza A(H1N1) infection 
BMC Infectious Diseases  2014;14:253.
Background
Activin A and its binding protein follistatin (FS) are increased in inflammatory disorders and sepsis. Overexpression of activin A in the lung causes similar histopathological changes as acute respiratory distress syndrome (ARDS). ARDS and severe respiratory failure are complications of influenza A(H1N1) infection. Interleukin 6 (IL-6), which in experimental studies increases after activin A release, is known to be related to the severity of H1N1 infection. Our aim was to evaluate the levels of activin A, activin B, FS, IL-6 and IL-10 and their association with the severity of respiratory failure in critically ill H1N1 patients.
Methods
A substudy of a prospective, observational cohort of H1N1 patients in Finnish intensive care units (ICU). Clinical information was recorded during ICU treatment, and serum activin A, activin B, FS, IL-6 and IL-10 were measured at admission to ICU and on days 2 and 7.
Results
Blood samples from 29 patients were analysed. At the time of admission to intensive care unit, elevated serum levels above the normal range for respective age group and sex were observed in 44% for activin A, 57% for activin B, and 39% for FS. In 13 of the 29 patients, serial samples at all time points were available and in these the highest activin A, activin B and FS were above the normal range in 85%, 100% and 46% of the patients, respectively. No difference in baseline or highest activin A or activin B was found in patients with or without acute lung injury (ALI) or ARDS (P > 0.05 for all). Peak levels of IL-6 were significantly elevated in ALI/ARDS patients. Peak activin A and activin A/FS were associated with ventilatory support free-days, severity of acute illness and length of ICU stay (P < 0.05 for all).
Conclusions
Higher than normal values of these proteins were common in patients with H1N1 infection but we found no association with the severity of their respiratory failure.
doi:10.1186/1471-2334-14-253
PMCID: PMC4101860  PMID: 24885241
Activin A; Activin B; Follistatin; H1N1 influenza; Acute respiratory distress syndrome; Interleukin 6
12.  Free radical scavengers in anaesthesiology and critical care 
Indian Journal of Anaesthesia  2012;56(3):227-233.
Free radicals are highly reactive and unstable compounds. These highly reactive molecules cause oxidative damage to cellular components such as DNA, proteins and lipids. They play central role in the mechanism of cell injury and cell death. Free radical scavengers either prevent these reactive species from being formed, or remove them before they can damage vital components of the cell. Oxidative stress defines an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants and scavenger enzymes. Evidence of massive oxidative stress is well established in critical illnesses characterized by tissue ischaemia-reperfusion injury and by an intense systemic inflammatory response such as during sepsis and acute respiratory distress syndrome, acute lung injury. Several clinical trials have been performed in order to reduce oxidative stress by supplementation of antioxidants alone or in combination with standard therapies. Antioxidant supplementation at an early stage of illness may lead to improved therapies in the treatment of critically ill patients. Several intravenous anaesthetic drugs act as reactive oxygen species scavengers. Anaesthetic preconditioning is of particular interest to anaesthesiologist, in which lasting protection of myocardium is elicited by brief exposure to a inhalational anaesthetic agent. These anasthetics may also mediate protective effects in other organs, such as the brain and kidney It is important for the anaesthesiologist to understand the mechanism of damage caused by free radicals and how free radical scavengers work so that this knowledge can be applied to varied pathological conditions. The topic was hand searched in text books and electronically searched from PubMed and Google scholar using text words.
doi:10.4103/0019-5049.98760
PMCID: PMC3425280  PMID: 22923819
Anaesthesiology; antioxidants; critical care; free radicals; oxidative stress
13.  Factors associated with nosocomial SARS-CoV transmission among healthcare workers in Hanoi, Vietnam, 2003 
BMC Public Health  2006;6:207.
Background
In March of 2003, an outbreak of Severe Acute Respiratory Syndrome (SARS) occurred in Northern Vietnam. This outbreak began when a traveler arriving from Hong Kong sought medical care at a small hospital (Hospital A) in Hanoi, initiating a serious and substantial transmission event within the hospital, and subsequent limited spread within the community.
Methods
We surveyed Hospital A personnel for exposure to the index patient and for symptoms of disease during the outbreak. Additionally, serum specimens were collected and assayed for antibody to SARS-associated coronavirus (SARS-CoV) antibody and job-specific attack rates were calculated. A nested case-control analysis was performed to assess risk factors for acquiring SARS-CoV infection.
Results
One hundred and fifty-three of 193 (79.3%) clinical and non-clinical staff consented to participate. Excluding job categories with <3 workers, the highest SARS attack rates occurred among nurses who worked in the outpatient and inpatient general wards (57.1, 47.4%, respectively). Nurses assigned to the operating room/intensive care unit, experienced the lowest attack rates (7.1%) among all clinical staff. Serologic evidence of SARS-CoV infection was detected in 4 individuals, including 2 non-clinical workers, who had not previously been identified as SARS cases; none reported having had fever or cough. Entering the index patient's room and having seen (viewed) the patient were the behaviors associated with highest risk for infection by univariate analysis (odds ratios 20.0, 14.0; 95% confidence intervals 4.1–97.1, 3.6–55.3, respectively).
Conclusion
This study highlights job categories and activities associated with increased risk for SARS-CoV infection and demonstrates that a broad diversity of hospital workers may be vulnerable during an outbreak. These findings may help guide recommendations for the protection of vulnerable occupational groups and may have implications for other respiratory infections such as influenza.
doi:10.1186/1471-2458-6-207
PMCID: PMC1562405  PMID: 16907978
14.  The Spectrum of Intermediate Syndrome Following Acute Organophosphate Poisoning: A Prospective Cohort Study from Sri Lanka 
PLoS Medicine  2008;5(7):e147.
Background
Intermediate syndrome (IMS) is a major cause of death from respiratory failure following acute organophosphate poisoning. The objective of this study was to determine repetitive nerve stimulation (RNS) predictors of IMS that would assist in patient management and clinical research.
Methods and Findings
Seventy-eight consenting symptomatic patients with organophosphate poisoning were assessed prospectively with daily physical examination and RNS. RNS was done on the right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. The study was conducted as a prospective observational cohort study in the Central Province, Sri Lanka. IMS was diagnosed in ten out of 78 patients using a priori clinical diagnostic criteria, and five of them developed respiratory failure. All ten patients showed progressive RNS changes correlating with the severity of IMS. A decrement-increment was observed at intermediate and high frequencies preceding the onset of clinical signs of IMS. As the patient developed clinical signs of IMS, decrement-increment was progressively noted at low and intermediate frequencies and a combination of decrement-increment and repetitive fade or severe decrement was noted at high frequencies. Severe decrement preceded respiratory failure in four patients. Thirty patients developed forme fruste IMS with less severe weakness not progressing to respiratory failure whose RNS was characterized by decrement-increment or a combination of decrement-increment and repetitive fade but never severe decrements.
Conclusions
Characteristic changes in RNS, preceding the development of IMS, help to identify a subgroup of patients at high risk of developing respiratory failure. The forme fruste IMS with the characteristic early changes on RNS indicates that IMS is a spectrum disorder. RNS changes are objective and precede the diagnosis and complications of IMS. Thus they may be useful in clinical management and research.
Jayawardane and colleagues evaluate a cohort of 78 patients with organophosphate poisoning from Sri Lanka, and identify changes in repetitive nerve stimulation that precede, and may help predict, the onset of intermediate syndrome.
Editors' Summary
Background.
Each year, many thousands of deaths around the world are caused by pesticide poisoning. Often, the pesticide involved is an organophosphate. These highly toxic compounds, which are widely used in agriculture, particularly in developing countries, disrupt the transmission of messages from the brain to the body in insect pests and in people. The brain controls body movements by sending electrical impulses along nerve cells (neurons). At the end of the neurons, these impulses are converted into chemical messengers (neurotransmitters), which cross the gap between neurons and muscle cells (the neuromuscular junction) and bind to proteins on the surface of the muscle cells to pass on the brain's message. One important neurotransmitter is acetylcholine. This is used in the part of the nervous system that controls breathing and other automatic vital functions, at neuromuscular junctions, and in parts of the central nervous system. Normally, acetylcholine is quickly broken down after it has delivered its message, but organophosphates disrupt this process and, consequently, affect nerve transmission to muscles. Organophosphate poisoning causes three syndromes. The cholinergic syndrome, which can be fatal, happens soon after organophosphates are swallowed, inhaled, or absorbed through the skin. The intermediate syndrome (IMS), which results in muscle weakness in the limbs, neck, and throat, develops in some patients 24–96 hours after poisoning. Finally, long-term nerve damage sometimes develops 2–3 weeks after poisoning.
Why Was This Study Done?
Although IMS is a major contributor to the illness caused by organophosphate poisoning and can result in respiratory (breathing) failure and death, the functional changes that are associated with IMS (its pathophysiology) are poorly understood. With a better understanding of these changes, it might be possible to find ways to prevent or treat IMS or to predict which patients with IMS are likely to develop respiratory failure. In this study, the researchers make a set of measurements of nerve transmission in a large group of organophosphate-poisoned patients in Sri Lanka to discover more about the pathophysiology of IMS.
What Did the Researchers Do and Find?
Seventy-eight patients with organophosphate poisoning were assessed several times a day for clinical signs of IMS. In addition, nerve transmission was measured daily in the patients using an electrophysiological technique called repetitive nerve stimulation (RNS). For this, a series of small electrical shocks was applied to the certain nerves in the arm and the responses in the muscles that these nerves control were recorded. In the ten study participants who developed IMS, the researchers observed several characteristic changes in their muscle responses to RNS, some of which were seen before the clinical signs of IMS. Other changes in muscle responses to RNS correlated with the development of clear IMS. Most importantly, in the four patients with IMS who developed respiratory failure, an RNS response pattern called severe decrement (a reduced response to the first electrical shock and then no response to the subsequent shocks) was seen before respiratory failure. Finally, there were other characteristic changes in muscle responses to RNS in 30 patients with muscle weakness not severe enough for a diagnosis of IMS (incomplete or “forme fruste” IMS).
What Do These Findings Mean?
These findings indicate that changes in nerve transmission that can be objectively monitored using RNS evolve during the development of IMS. In other words, IMS is a “spectrum” disorder in which the weakness and neuromuscular junction problems caused by organophosphate poisoning gradually progress over time through a series of electrophysiological changes that will sometimes resolve quickly and only in the most severe cases will result in respiratory failure. These findings need to be validated in further studies, particularly since most of the patients in this study had been exposed to a single organophosphate (chlorpyrifos). However, they suggest that the RNS tests might be useful in the clinical management of patients with organophosphate poisoning, particularly since such tests could provide an early warning of impending respiratory failure.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050147.
This study is further discussed in a PLoS Medicine Perspective by Cynthia Aaron
The US Environmental Protection Agency provides information about all aspects of pesticides (in English and Spanish)
Toxtown, an interactive site from the US National Library of Science, provides information on environmental health concerns including exposure to pesticides (in English and Spanish)
The US National Pesticide Information Center provides objective, science-based information about pesticides
MedlinePlus also provides links to information on pesticides (in English and Spanish)
The International Programme on Chemical Safety has information on poisoning prevention and management; its INTOX databank has a description of the cholinergic syndrome
WikiTox is a clinical toxicology resource
doi:10.1371/journal.pmed.0050147
PMCID: PMC2459203  PMID: 18630983
15.  Corticosteroids influence the mortality and morbidity of acute critical illness 
Critical Care  2006;10(4):R101.
Introduction
Use of corticosteroids for adrenal supplementation and attenuation of the inflammatory and immune response is widespread in acute critical illness. The study hypothesis was that exposure to corticosteroids influences the mortality and morbidity in acute critical illness.
Methods
This case–control retrospective study was performed in a single multidisciplinary intensive care unit at a tertiary care institution and consisted of 10,285 critically ill patients admitted between 1 January 1999 and 31 December 2004. Demographics, comorbidities, acute illness characteristics including severity measured by Sequential Organ Failure Assessment, concurrent medications, therapeutic interventions and incidence of infections were obtained from electronic medical records, were examined with multiple regression analysis and were adjusted for propensity of corticosteroid exposure. The primary outcome was hospital death, and the secondary outcome was transfer to a care facility at hospital discharge.
Results
Corticosteroid exposure in 2,632 (26%) patients was characterized by younger age, more females, higher Charlson comorbidity and maximal daily Sequential Organ Failure Assessment scores compared with control patients. Corticosteroids potentiated metabolic and neuromuscular sequels of critical illness with increased requirements for diuretics, insulin, protracted weaning from mechanical ventilation, need for tracheostomy and discharge to a care facility. Early exposure to corticosteroids predisposed to recurrent and late onset of polymicrobial and fungal hospital-acquired infections. Corticosteroids increased the risk for death or disability after adjustments for comorbidities and acute illness characteristics.
Conclusion
Corticosteroids increased the risk for death or disability in critical illness. Hospital-acquired infections and metabolic and neuromuscular sequels of critical illness were exacerbated by corticosteroids. Careful appraisal of the indications for use of corticosteroids is necessary to balance the benefits and risks from exposure in acute critical illness.
doi:10.1186/cc4971
PMCID: PMC1750970  PMID: 16846529
16.  Carbapenem-resistant Acinetobacter ventilator-associated pneumonia: Clinical characteristics and outcome 
Objective:
To study the clinical characteristics and 28-days mortality in patients with ventilator-associated pneumonia (VAP) due to carbapenem-resistant Acinetobacter (CRA).
Design:
Retrospective, observational, cohort study.
Setting:
Intensive care unit (ICU) of a university hospital.
Materials and Methods:
Microbiologically confirmed VAP due to CRA infection.
Intervention:
None.
Results:
Out of 87 patients with VAP due to CRA, 60 (69%) were male; whose median age was 51 years; 73 (84%) patients were medical; 26 (30%) had history of hospitalization in last 3 months; median acute physiology and chronic health evaluation (APACHE) II was 15 and median SOFA 9 at admission; primary reason for ICU admission was respiratory failure (34%); 46 (53%) patients had more than 2 organ failure at ICU admission; median length of ICU stay was 19 days; 66 (76%) patients need vasoactive agents during ICU stay, whereas 55 (63%) patients had renal failure; median duration of mechanical ventilation was 17 days; 22 (25%) patients had acute respiratory distress syndrome (ARDS) during ICU stay; 72 (83%) patients had exposure to carbapenem before inclusion in the study; 33 (38%) patients had same organism at other sites. In the follow-up, 47 (54%) patient survived at 28 days after having VAP; whereas only 40 (46%) patients were discharged from the hospital.
Conclusions:
CRA-VAP has high crude mortality. Advanced age; severity of illness and presence of pneumonia at ICU admission; and presence of shock, ARDS and renal failure have impact on outcome in these patients.
doi:10.4103/0972-5229.117036
PMCID: PMC3777365  PMID: 24082608
Acinetobacter; carbapenem; intensive care unit; ventilator-associated pneumonia
17.  Study protocol: The Improving Care of Acute Lung Injury Patients (ICAP) study 
Critical Care  2005;10(1):R9.
Introduction
The short-term mortality benefit of lower tidal volume ventilation (LTVV) for patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has been demonstrated in a large, multi-center randomized trial. However, the impact of LTVV and other critical care therapies on the longer-term outcomes of ALI/ARDS survivors remains uncertain. The Improving Care of ALI Patients (ICAP) study is a multi-site, prospective cohort study that aims to evaluate the longer-term outcomes of ALI/ARDS survivors with a particular focus on the effect of LTVV and other critical care therapies.
Methods
Consecutive mechanically ventilated ALI/ARDS patients from 11 intensive care units (ICUs) at four hospitals in the city of Baltimore, MD, USA, will be enrolled in a prospective cohort study. Exposures (patient-based, clinical management, and ICU organizational) will be comprehensively collected both at baseline and throughout patients' ICU stay. Outcomes, including mortality, organ impairment, functional status, and quality of life, will be assessed with the use of standardized surveys and testing at 3, 6, 12, and 24 months after ALI/ARDS diagnosis. A multi-faceted retention strategy will be used to minimize participant loss to follow-up.
Results
On the basis of the historical incidence of ALI/ARDS at the study sites, we expect to enroll 520 patients over two years. This projected sample size is more than double that of any published study of long-term outcomes in ALI/ARDS survivors, providing 86% power to detect a relative mortality hazard of 0.70 in patients receiving higher versus lower exposure to LTVV. The projected sample size also provides sufficient power to evaluate the association between a variety of other exposure and outcome variables, including quality of life.
Conclusion
The ICAP study is a novel, prospective cohort study that will build on previous critical care research to improve our understanding of the longer-term impact of ALI/ARDS, LTVV and other aspects of critical care management. Given the paucity of information about the impact of interventions on long-term outcomes for survivors of critical illness, this study can provide important information to inform clinical practice.
doi:10.1186/cc3948
PMCID: PMC1550857  PMID: 16420652
18.  A fresh look at paralytics in the critically ill: real promise and real concern 
Neuromuscular blocking agents (NMBAs), or “paralytics,” often are deployed in the sickest patients in the intensive care unit (ICU) when usual care fails. Despite the publication of guidelines on the use of NMBAs in the ICU in 2002, clinicians have needed more direction to determine which patients would benefit from NMBAs and which patients would be harmed. Recently, new evidence has shown that paralytics hold more promise when used in carefully selected lung injury patients for brief periods of time. When used in early acute respiratory distress syndrome (ARDS), NMBAs assist to establish a lung protective strategy, which leads to improved oxygenation, decreased pulmonary and systemic inflammation, and potentially improved mortality. It also is increasingly recognized that NMBAs can cause harm, particularly critical illness polyneuromyopathy (CIPM), when used for prolonged periods or in septic shock. In this review, we address several practical considerations for clinicians who use NMBAs in their practice. Ultimately, we conclude that NMBAs should be considered a lung protective adjuvant in early ARDS and that clinicians should consider using an alternative NMBA to the aminosteroids in septic shock with less severe lung injury pending further studies.
doi:10.1186/2110-5820-2-43
PMCID: PMC3519794  PMID: 23062076
Neuromuscular blocking agents; Neuromuscular nondepolarizing agents; Polyneuropathies; Respiratory distress syndrome; Adult; Cisatracurium; Status asthmaticus; Shock; Septic
19.  Pro/con clinical debate: Isolation precautions for all intensive care unit patients with methicillin-resistant Staphylococcus aureus colonization are essential 
Critical Care  2004;8(3):153-156.
Antibiotic-resistant bacteria are an increasingly common problem in intensive care units (ICUs), and they are capable of impacting on patient outcome, the ICU's budget and bed availability. This issue, coupled with recent outbreaks of illnesses that pose a direct risk to ICU staff (such as SARS [severe acute respiratory syndrome]), has led to renewed emphasis on infection control measures and practitioners in the ICU. Infection control measures frequently cause clinicians to practice in a more time consuming way. As a result it is not surprising that ensuring compliance with these measures is not always easy, particularly when their benefit is not immediately obvious. In this issue of Critical Care, two experts face off over the need to isolate patients infected with methicillin-resistant Staphylococcus aureus.
doi:10.1186/cc2817
PMCID: PMC468889  PMID: 15153232
hand-washing; infection control; intensive care; isolation; methicillin-resistant Staphylococcus aureus
20.  Adiponectin, retinol-binding protein 4, and leptin in protracted critical illness of pulmonary origin 
Critical Care  2009;13(4):R112.
Introduction
Critically ill patients requiring intensive care uniformly develop insulin resistance. This is most pronounced in patients with sepsis. Recently, several hormones secreted by adipose tissue have been identified to be involved in overall insulin sensitivity in metabolic syndrome-related conditions. However, little is known about these adipokines in critical illness.
Methods
We studied circulating levels of the adipokines adiponectin, retinol-binding protein 4 (RBP4), and leptin during critical illness, and the impact of intensive insulin therapy, a therapy shown to affect insulin sensitivity, in serum samples from prolonged critically ill patients with a respiratory critical illness (n = 318). For comparison, we studied healthy subjects (n = 22) and acutely stressed patients (n = 22).
Results
During acute critical illness, circulating levels of adiponectin, RBP4, and leptin were low. Patients with sepsis had lower levels of leptin and RBP4 than did nonseptic patients. When critical illness was sustained, adipokine levels returned to normal reference values. Insulin therapy enhanced adiponectin, blunted the rise of RBP4, and did not alter leptin levels.
Conclusions
Acute critical illness is associated with immediate, but transiently low serum adipokine levels. Adiponectin and RBP4 are associated with altered insulin resistance in critical illness.
doi:10.1186/cc7956
PMCID: PMC2750156  PMID: 19589139
21.  Effect of widespread restrictions on the use of hospital services during an outbreak of severe acute respiratory syndrome 
Background
Restrictions on the nonurgent use of hospital services were imposed in March 2003 to control an outbreak of severe acute respiratory syndrome (SARS) in Toronto, Ont. We describe the impact of these restrictions on health care utilization and suggest lessons for future epidemics.
Methods
We performed a retrospective population-based study of the Greater Toronto Area (hereafter referred to as Toronto) and unaffected comparison regions (Ottawa and London, Ont.) before, during and after the SARS outbreak (April 2001–March 2004). We determined the adjusted rates of hospital admissions, emergency department and outpatient visits, diagnostic testing and drug prescribing.
Results
During the early and late SARS restriction periods, the rate of overall and medical admissions decreased by 10%–12% in Toronto; there was no change in the comparison regions. The rate of elective surgery in Toronto fell by 22% and 15% during the early and late restriction periods respectively and by 8% in the comparison regions. The admission rates for urgent surgery remained unchanged in all regions; those for some acute serious medical conditions decreased by 15%–21%. The rates of elective cardiac procedures declined by up to 66% in Toronto and by 71% in the comparison regions; the rates of urgent and semi-urgent procedures declined little or increased. High-acuity visits to emergency departments fell by 37% in Toronto, and inter-hospital patient transfers fell by 44% in the circum-Toronto area. Drug prescribing and primary care visits were unchanged in all regions.
Interpretation
The restrictions achieved modest reductions in overall hospital admissions and substantial reductions in the use of elective services. Brief reductions occurred in admissions for some acute serious conditions, high-acuity visits to emergency departments and inter-hospital patient transfers suggesting that access to care for some potentially seriously ill patients was affected.
doi:10.1503/cmaj.061174
PMCID: PMC1891122  PMID: 17576979
22.  Characteristics and outcome of critically ill patients with 2009 H1N1 influenza infection in Syria 
Avicenna Journal of Medicine  2012;2(2):34-37.
Objectives:
To describe the epidemiologic characteristics, clinical features, and outcome of severe cases of 2009 H1N1 influenza A infections who were admitted to the intensive care units (ICUs) in Damascus, Syria.
Materials and Methods:
Retrospectively, we collected clinical data on all patients who were admitted to the ICU with confirmed or suspected diagnosis of severe 2009 H1N1 influenza A with respiratory failure at 4 major tertiary care hospitals in Damascus, Syria. Acute Physiology and Chronic Health Evaluation (APACHE) II system was used to assess the severity of illness within the first 24 h after admission. The outcome was overall hospital mortality.
Results:
Eighty patients were admitted to the ICU with severe 2009 H1N1 infection. The mean age was 40.7 years; 69.8% of patients had ≥1 of the risk factors: asthmatics 20%, obesity 23.8%, and pregnancy 5%; and 72.5% had acute lung injury or adult respiratory distress syndrome, 12.5% had viral pneumonia, 42.5% had secondary bacterial pneumonia, and 15% had exacerbation of airflow disease. Mechanical ventilation was required in 73.7% of cases. The mean hospital length of stay was 11.7 days (median 8 days, range 0–77 days, IQR: 5–14 days). The overall mortality rate was 51% for a mean APACHE II score of 15.2 with a predicted mortality of 21% (standardized mortality ratio of 2.4, 95% confidence interval: 1.7–3.2, P value < 0.001).
Conclusion:
Critically ill patients with severe 2009 H1N1 infection in this limited resource country had a much higher mortality rate than the predicted APACHE II mortality rate or when compared with the reported mortality rates for severe cases in other countries during 2009 H1N1 pandemic.
doi:10.4103/2231-0770.99156
PMCID: PMC3507075  PMID: 23210019
Adult respiratory distress syndrome; H1N1; pandemic; Syria
23.  Surviving Critical Illness: The Acute Respiratory Distress Syndrome as Experienced by Patients and Their Caregivers 
Critical care medicine  2009;37(10):2702-2708.
Objective
Survivors of the acute respiratory distress syndrome (ARDS), a systemic critical illness, often report poor quality of life based on responses to standardized questionnaires. However, the experiences of ARDS survivors have not been reported. Our objective was to characterize the effects of critical illness in the daily lives and functioning of ARDS survivors.
Design, Setting, and Patients
We recruited consecutively 31 ARDS survivors and their informal caregivers from medical and surgical intensive care units of an academic medical center and a community hospital. Eight patients died before completing interviews. We conducted semi-structured interviews with 23 ARDS survivors and 24 caregivers three to nine months after ICU admission, stopping enrollment after thematic saturation was reached. Transcripts were analyzed using Colaizzi’s qualitative methodology to identify significant ways in which survivors’ critical illness experience impacted their lives.
Measurements and Main Results
Participants related five key elements of experience as survivors of ARDS: pervasive memories of critical care, day to day impact of new disability, critical illness defining the sense of self, relationship strain and change, and ability to cope with disability. Survivors described remarkable disability that persisted for months. Caregivers’ interviews revealed substantial strain from caregiving responsibilities, as well as frequent symptom minimization by patients.
Conclusions
The diverse and unique experiences of ARDS survivors reflect the global impact of severe critical illness. We have identified symptom domains important to ARDS patients that are not well represented in existing health outcomes measures. These insights may aid the development of targeted interventions to enhance recovery and return of function after ARDS.
doi:10.1097/CCM.0b013e3181b6f64a
PMCID: PMC2771584  PMID: 19865004
Respiratory Distress Syndrome, Adult; Qualitative Research; Quality of Life
24.  Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based analysis was to examine the effectiveness, safety, and cost-effectiveness of noninvasive positive pressure ventilation (NPPV) in the following patient populations: patients with acute respiratory failure (ARF) due to acute exacerbations of chronic obstructive pulmonary disease (COPD); weaning of COPD patients from invasive mechanical ventilation (IMV); and prevention of or treatment of recurrent respiratory failure in COPD patients after extubation from IMV.
Clinical Need and Target Population
Acute Hypercapnic Respiratory Failure
Respiratory failure occurs when the respiratory system cannot oxygenate the blood and/or remove carbon dioxide from the blood. It can be either acute or chronic and is classified as either hypoxemic (type I) or hypercapnic (type II) respiratory failure. Acute hypercapnic respiratory failure frequently occurs in COPD patients experiencing acute exacerbations of COPD, so this is the focus of this evidence-based analysis. Hypercapnic respiratory failure occurs due to a decrease in the drive to breathe, typically due to increased work to breathe in COPD patients.
Technology
There are several treatment options for ARF. Usual medical care (UMC) attempts to facilitate adequate oxygenation and treat the cause of the exacerbation, and typically consists of supplemental oxygen, and a variety of medications such as bronchodilators, corticosteroids, and antibiotics. The failure rate of UMC is high and has been estimated to occur in 10% to 50% of cases.
The alternative is mechanical ventilation, either invasive or noninvasive. Invasive mechanical ventilation involves sedating the patient, creating an artificial airway through endotracheal intubation, and attaching the patient to a ventilator. While this provides airway protection and direct access to drain sputum, it can lead to substantial morbidity, including tracheal injuries and ventilator-associated pneumonia (VAP).
While both positive and negative pressure noninvasive ventilation exists, noninvasive negative pressure ventilation such as the iron lung is no longer in use in Ontario. Noninvasive positive pressure ventilation provides ventilatory support through a facial or nasal mask and reduces inspiratory work. Noninvasive positive pressure ventilation can often be used intermittently for short periods of time to treat respiratory failure, which allows patients to continue to eat, drink, talk, and participate in their own treatment decisions. In addition, patients do not require sedation, airway defence mechanisms and swallowing functions are maintained, trauma to the trachea and larynx are avoided, and the risk for VAP is reduced. Common complications are damage to facial and nasal skin, higher incidence of gastric distension with aspiration risk, sleeping disorders, and conjunctivitis. In addition, NPPV does not allow direct access to the airway to drain secretions and requires patients to cooperate, and due to potential discomfort, compliance and tolerance may be low.
In addition to treating ARF, NPPV can be used to wean patients from IMV through the gradual removal of ventilation support until the patient can breathe spontaneously. Five to 30% of patients have difficultly weaning. Tapering levels of ventilatory support to wean patients from IMV can be achieved using IMV or NPPV. The use of NPPV helps to reduce the risk of VAP by shortening the time the patient is intubated.
Following extubation from IMV, ARF may recur, leading to extubation failure and the need for reintubation, which has been associated with increased risk of nosocomial pneumonia and mortality. To avoid these complications, NPPV has been proposed to help prevent ARF recurrence and/or to treat respiratory failure when it recurs, thereby preventing the need for reintubation.
Research Questions
What is the effectiveness, cost-effectiveness, and safety of NPPV for the treatment of acute hypercapnic respiratory failure due to acute exacerbations of COPD compared with
usual medical care, and
invasive mechanical ventilation?
What is the effectiveness, cost-effectiveness, and safety of NPPV compared with IMV in COPD patients after IMV for the following purposes:
weaning COPD patients from IMV,
preventing ARF in COPD patients after extubation from IMV, and
treating ARF in COPD patients after extubation from IMV?
Research Methods
Literature Search
A literature search was performed on December 3, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), Wiley Cochrane, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Since there were numerous studies that examined the effectiveness of NPPV for the treatment of ARF due to exacerbations of COPD published before 2004, pre-2004 trials which met the inclusion/exclusion criteria for this evidence-based review were identified by hand-searching reference lists of included studies and systematic reviews.
Inclusion Criteria
English language full-reports;
health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials (RCTs);
studies performed exclusively in patients with a diagnosis of COPD or studies performed with patients with a mix of conditions if results are reported for COPD patients separately;
patient population: (Question 1) patients with acute hypercapnic respiratory failure due to an exacerbation of COPD; (Question 2a) COPD patients being weaned from IMV; (Questions 2b and 2c) COPD patients who have been extubated from IMV.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
studies examining noninvasive negative pressure ventilation
studies comparing modes of ventilation
studies comparing patient-ventilation interfaces
studies examining outcomes not listed below, such as physiologic effects including heart rate, arterial blood gases, and blood pressure
Outcomes of Interest
mortality
intubation rates
length of stay (intensive care unit [ICU] and hospital)
health-related quality of life
breathlessness
duration of mechanical ventilation
weaning failure
complications
NPPV tolerance and compliance
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1, otherwise, the results were summarized descriptively. Dichotomous data were pooled into relative risks using random effects models and continuous data were pooled using weighted mean differences with a random effects model. Analyses using data from RCTs were done using intention-to-treat protocols; P values < 0.05 were considered significant. A priori subgroup analyses were planned for severity of respiratory failure, location of treatment (ICU or hospital ward), and mode of ventilation with additional subgroups as needed based on the literature. Post hoc sample size calculations were performed using STATA 10.1.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
NPPV for the Treatment of ARF due to Acute Exacerbations of COPD
NPPV Plus Usual Medical Care Versus Usual Medical Care Alone for First Line Treatment
A total of 1,000 participants were included in 11 RCTs1; the sample size ranged from 23 to 342. The mean age of the participants ranged from approximately 60 to 72 years of age. Based on either the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD stage criteria or the mean percent predicted forced expiratory volume in 1 second (FEV1), 4 of the studies included people with severe COPD, and there was inadequate information to classify the remaining 7 studies by COPD severity. The severity of the respiratory failure was classified into 4 categories using the study population mean pH level as follows: mild (pH ≥ 7.35), moderate (7.30 ≤ pH < 7.35), severe (7.25 ≤ pH < 7.30), and very severe (pH < 7.25). Based on these categories, 3 studies included patients with a mild respiratory failure, 3 with moderate respiratory failure, 4 with severe respiratory failure, and 1 with very severe respiratory failure.
The studies were conducted either in the ICU (3 of 11 studies) or general or respiratory wards (8 of 11 studies) in hospitals, with patients in the NPPV group receiving bilevel positive airway pressure (BiPAP) ventilatory support, except in 2 studies, which used pressure support ventilation and volume cycled ventilation, respectively. Patients received ventilation through nasal, facial, or oronasal masks. All studies specified a protocol or schedule for NPPV delivery, but this varied substantially across the studies. For example, some studies restricted the amount of ventilation per day (e.g., 6 hours per day) and the number of days it was offered (e.g., maximum of 3 days); whereas, other studies provided patients with ventilation for as long as they could tolerate it and recommended it for much longer periods of time (e.g., 7 to 10 days). These differences are an important source of clinical heterogeneity between the studies. In addition to NPPV, all patients in the NPPV group also received UMC. Usual medical care varied between the studies, but common medications included supplemental oxygen, bronchodilators, corticosteroids, antibiotics, diuretics, and respiratory stimulators.
The individual quality of the studies ranged. Common methodological issues included lack of blinding and allocation concealment, and small sample sizes.
Need for Endotracheal Intubation
Eleven studies reported the need for endotracheal intubation as an outcome. The pooled results showed a significant reduction in the need for endotracheal intubation in the NPPV plus UMC group compared with the UMC alone group (relative risk [RR], 0.38; 95% confidence interval [CI], 0.28−0.50). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Inhospital Mortality
Nine studies reported inhospital mortality as an outcome. The pooled results showed a significant reduction in inhospital mortality in the NPPV plus UMC group compared with the UMC group (RR, 0.53; 95% CI, 0.35−0.81). When subgrouped by severity of respiratory failure, the results remained significant for the moderate and severe respiratory failure groups.
GRADE: moderate
Hospital Length of Stay
Eleven studies reported hospital length of stay (LOS) as an outcome. The pooled results showed a significant decrease in the mean length of stay for the NPPV plus UMC group compared with the UMC alone group (weighted mean difference [WMD], −2.68 days; 95% CI, −4.41 to −0.94 days). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Complications
Five studies reported complications. Common complications in the NPPV plus UMC group included pneumonia, gastrointestinal disorders or bleeds, skin abrasions, eye irritation, gastric insufflation, and sepsis. Similar complications were observed in the UMC group including pneumonia, sepsis, gastrointestinal disorders or bleeds, pneumothorax, and complicated endotracheal intubations. Many of the more serious complications in both groups occurred in those patients who required endotracheal intubation. Three of the studies compared complications in the NPPV plus UMC and UMC groups. While the data could not be pooled, overall, the NPPV plus UMC group experienced fewer complications than the UMC group.
GRADE: low
Tolerance/Compliance
Eight studies reported patient tolerance or compliance with NPPV as an outcome. NPPV intolerance ranged from 5% to 29%. NPPV tolerance was generally higher for patients with more severe respiratory failure. Compliance with the NPPV protocol was reported by 2 studies, which showed compliance decreases over time, even over short periods such as 3 days.
NPPV Versus IMV for the Treatment of Patients Who Failed Usual Medical Care
A total of 205 participants were included in 2 studies; the sample sizes of these studies were 49 and 156. The mean age of the patients was 71 to 73 years of age in 1 study, and the median age was 54 to 58 years of age in the second study. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, patients in 1 study had very severe COPD. The COPD severity could not be classified in the second study. Both studies had study populations with a mean pH less than 7.23, which was classified as very severe respiratory failure in this analysis. One study enrolled patients with ARF due to acute exacerbations of COPD who had failed medical therapy. The patient population was not clearly defined in the second study, and it was not clear whether they had to have failed medical therapy before entry into the study.
Both studies were conducted in the ICU. Patients in the NPPV group received BiPAP ventilatory support through nasal or full facial masks. Patients in the IMV group received pressure support ventilation.
Common methodological issues included small sample size, lack of blinding, and unclear methods of randomization and allocation concealment. Due to the uncertainty about whether both studies included the same patient population and substantial differences in the direction and significance of the results, the results of the studies were not pooled.
Mortality
Both studies reported ICU mortality. Neither study showed a significant difference in ICU mortality between the NPPV and IMV groups, but 1 study showed a higher mortality rate in the NPPV group (21.7% vs. 11.5%) while the other study showed a lower mortality rate in the NPPV group (5.1% vs. 6.4%). One study reported 1-year mortality and showed a nonsignificant reduction in mortality in the NPPV group compared with the IMV group (26.1% vs. 46.1%).
GRADE: low to very low
Intensive Care Unit Length of Stay
Both studies reported LOS in the ICU. The results were inconsistent. One study showed a statistically significant shorter LOS in the NPPV group compared with the IMV group (5 ± 1.35 days vs. 9.29 ± 3 days; P < 0.001); whereas, the other study showed a nonsignificantly longer LOS in the NPPV group compared with the IMV group (22 ± 19 days vs. 21 ± 20 days; P = 0.86).
GRADE: very low
Duration of Mechanical Ventilation
Both studies reported the duration of mechanical ventilation (including both invasive and noninvasive ventilation). The results were inconsistent. One study showed a statistically significant shorter duration of mechanical ventilation in the NPPV group compared with the IMV group (3.92 ± 1.08 days vs. 7.17 ± 2.22 days; P < 0.001); whereas, the other study showed a nonsignificantly longer duration of mechanical ventilation in the NPPV group compared with the IMV group (16 ± 19 days vs. 15 ± 21 days; P = 0.86). GRADE: very low
Complications
Both studies reported ventilator-associated pneumonia and tracheotomies. Both showed a reduction in ventilator-associated pneumonia in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 34.6%, P = 0.07; and 6.4% vs. 37.2%, P < 0.001, respectively). Similarly, both studies showed a reduction in tracheotomies in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 23.1%, P = 0.29; and 6.4% vs. 34.6%; P < 0.001).
GRADE: very low
Other Outcomes
One of the studies followed patients for 12 months. At the end of follow-up, patients in the NPPV group had a significantly lower rate of needing de novo oxygen supplementation at home. In addition, the IMV group experienced significant increases in functional limitations due to COPD, while no increase was seen in the NPPV group. Finally, no significant differences were observed for hospital readmissions, ICU readmissions, and patients with an open tracheotomy, between the NPPV and IMV groups.
NPPV for Weaning COPD Patients From IMV
A total of 80 participants were included in the 2 RCTs; the sample sizes of the studies were 30 and 50 patients. The mean age of the participants ranged from 58 to 69 years of age. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, both studies included patients with very severe COPD. Both studies also included patients with very severe respiratory failure (mean pH of the study populations was less than 7.23). Chronic obstructive pulmonary disease patients receiving IMV were enrolled in the study if they failed a T-piece weaning trial (spontaneous breathing test), so they could not be directly extubated from IMV.
Both studies were conducted in the ICU. Patients in the NPPV group received weaning using either BiPAP or pressure support ventilation NPPV through a face mask, and patients in the IMV weaning group received pressure support ventilation. In both cases, weaning was achieved by tapering the ventilation level.
The individual quality of the studies ranged. Common methodological problems included unclear randomization methods and allocation concealment, lack of blinding, and small sample size.
Mortality
Both studies reported mortality as an outcome. The pooled results showed a significant reduction in ICU mortality in the NPPV group compared with the IMV group (RR, 0.47; 95% CI, 0.23−0.97; P = 0.04).
GRADE: moderate
Intensive Care Unit Length of Stay
Both studies reported ICU LOS as an outcome. The pooled results showed a nonsignificant reduction in ICU LOS in the NPPV group compared with the IMV group (WMD, −5.21 days; 95% CI, −11.60 to 1.18 days).
GRADE: low
Duration of Mechanical Ventilation
Both studies reported duration of mechanical ventilation (including both invasive and noninvasive ventilation) as an outcome. The pooled results showed a nonsignificant reduction in duration of mechanical ventilation (WMD, −3.55 days; 95% CI, −8.55 to 1.44 days).
GRADE: low
Nosocomial Pneumonia
Both studies reported nosocominal pneumonia as an outcome. The pooled results showed a significant reduction in nosocomial pneumonia in the NPPV group compared with the IMV group (RR, 0.14; 95% CI, 0.03−0.71; P = 0.02).
GRADE: moderate
Weaning Failure
One study reported a significant reduction in weaning failure in the NPPV group compared with the IMV group, but the results were not reported in the publication. In this study, 1 of 25 patients in the NPPV group and 2 of 25 patients in the IMV group could not be weaned after 60 days in the ICU.
NPPV After Extubation of COPD Patients From IMV
The literature was reviewed to identify studies examining the effectiveness of NPPV compared with UMC in preventing recurrence of ARF after extubation from IMV or treating acute ARF which has recurred after extubation from IMV. No studies that included only COPD patients or reported results for COPD patients separately were identified for the prevention of ARF postextubation.
One study was identified for the treatment of ARF in COPD patients that recurred within 48 hours of extubation from IMV. This study included 221 patients, of whom 23 had COPD. A post hoc subgroup analysis was conducted examining the rate of reintubation in the COPD patients only. A nonsignificant reduction in the rate of reintubation was observed in the NPPV group compared with the UMC group (7 of 14 patients vs. 6 of 9 patients, P = 0.67). GRADE: low
Conclusions
NPPV Plus UMC Versus UMC Alone for First Line Treatment of ARF due to Acute Exacerbations of COPD
Moderate quality of evidence showed that compared with UMC, NPPV plus UMC significantly reduced the need for endotracheal intubation, inhospital mortality, and the mean length of hospital stay.
Low quality of evidence showed a lower rate of complications in the NPPV plus UMC group compared with the UMC group.
NPPV Versus IMV for the Treatment of ARF in Patients Who Have Failed UMC
Due to inconsistent and low to very low quality of evidence, there was insufficient evidence to draw conclusions on the comparison of NPPV versus IMV for patients who failed UMC.
NPPV for Weaning COPD Patients From IMV
Moderate quality of evidence showed that weaning COPD patients from IMV using NPPV results in significant reductions in mortality, nosocomial pneumonia, and weaning failure compared with weaning with IMV.
Low quality of evidence showed a nonsignificant reduction in the mean LOS and mean duration of mechanical ventilation in the NPPV group compared with the IMV group.
NPPV for the Treatment of ARF in COPD Patients After Extubation From IMV
Low quality of evidence showed a nonsignificant reduction in the rate of reintubation in the NPPV group compared with the UMC group; however, there was inadequate evidence to draw conclusions on the effectiveness of NPPV for the treatment of ARF in COPD patients after extubation from IMV
PMCID: PMC3384377  PMID: 23074436
25.  Bench-to-bedside review: Outcome predictions for critically ill patients in the emergency department 
Critical Care  2005;9(4):376-383.
The escalating number of emergency department (ED) visits, length of stay, and hospital overcrowding have been associated with an increasing number of critically ill patients cared for in the ED. Existing physiologic scoring systems have traditionally been used for outcome prediction, clinical research, quality of care analysis, and benchmarking in the intensive care unit (ICU) environment. However, there is limited experience with scoring systems in the ED, while early and aggressive intervention in critically ill patients in the ED is becoming increasingly important. Development and implementation of physiologic scoring systems specific to this setting is potentially useful in the early recognition and prognostication of illness severity. A few existing ICU physiologic scoring systems have been applied in the ED, with some success. Other ED specific scoring systems have been developed for various applications: recognition of patients at risk for infection; prediction of mortality after critical care transport; prediction of in-hospital mortality after admission; assessment of prehospital therapeutic efficacy; screening for severe acute respiratory syndrome; and prediction of pediatric hospital admission. Further efforts at developing unique physiologic assessment methodologies for use in the ED will improve quality of patient care, aid in resource allocation, improve prognostic accuracy, and objectively measure the impact of early intervention in the ED.
doi:10.1186/cc3518
PMCID: PMC1269432  PMID: 16137387

Results 1-25 (726494)