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1.  Phenotyping community-acquired pneumonia according to the presence of acute respiratory failure and severe sepsis 
Respiratory Research  2014;15(1):27.
Acute respiratory failure (ARF) and severe sepsis (SS) are possible complications in patients with community-acquired pneumonia (CAP). The aim of the study was to evaluate prevalence, characteristics, risk factors and impact on mortality of hospitalized patients with CAP according to the presence of ARF and SS on admission.
This was a multicenter, observational, prospective study of consecutive CAP patients admitted to three hospitals in Italy, Spain, and Scotland between 2008 and 2010. Three groups of patients were identified: those with neither ARF nor SS (Group A), those with only ARF (Group B) and those with both ARF and SS (Group C) on admission.
Among the 2,145 patients enrolled, 45% belonged to Group A, 36% to Group B and 20% to Group C. Patients in Group C were more severe than patients in Group B. Isolated ARF was correlated with age (p < 0.001), COPD (p < 0.001) and multilobar infiltrates (p < 0.001). The contemporary occurrence of ARF and SS was associated with age (p = 0.002), residency in nursing home (p = 0.007), COPD (p < 0.001), multilobar involvement (p < 0.001) and renal disease (p < 0.001). 4.2% of patients in Group A died, 9.3% in Group B and 26% in Group C, p < 0.001. After adjustment, the presence of only ARF had an OR for in-hospital mortality of 1.85 (p = 0.011) and the presence of both ARF and SS had an OR of 6.32 (p < 0.001).
The identification of ARF and SS on hospital admission can help physicians in classifying CAP patients into three different clinical phenotypes.
PMCID: PMC4015148  PMID: 24593040
Pneumonia; Sepsis; Severe sepsis; Acute respiratory failure; ARDS; CAP; Community-acquired pneumonia; Mortality; Oxygenation
2.  Risk Factors for Renal Failure in Pediatric Patients With Acute Myeloid Leukemia: A Retrospective Cohort Study 
Pediatric blood & cancer  2010;55(4):655-661.
In children receiving treatment for acute myeloid leukemia (AML) there is often concern for the development of acute renal failure (ARF). Despite this, data are limited to define the incidence of ARF in this population. This study aims to evaluate the rate of ARF in AML patients and to delineate the impact of age, race, various co-morbid conditions and antimicrobial agents on the development of ARF.
A cohort of newly diagnosed AML patients from children's hospitals across the United States was identified using the Pediatric Health Information Systems database. Information regarding demographics, discharge diagnoses, pharmaceutical exposures, and hospital resource utilization were collected for each hospitalization for up to 1 year from AML diagnosis. Cox regression analysis was used to define the hazard ratios for development of ARF by demographic variables, co-morbid conditions, and exposure to various antimicrobial agents.
Within 1 year of AML diagnosis, 135 (16.2%) patients were diagnosed with ARF. After adjustment for the presence of co-morbid conditions, the risk for ARF was greater in older patients and in black patients. Vancomycin exposure duration of greater than 48 hr and carbapenem exposure duration greater than 10 days were associated with an increased risk for ARF.
ARF is a relatively common problem in children with AML. Future studies should address the different risks of ARF by age and race. Empiric therapy with potentially nephrotoxic agents did not increase the risk of nephrotoxicity. Patients on prolonged vancomycin therapy should be monitored closely for development of ARF.
PMCID: PMC3909928  PMID: 20533519
antimicrobials; epidemiology; leukemia; pediatrics; renal failure
3.  Polypharmacy in elderly patients at discharge from the acute care hospital 
To investigate correlates of polypharmacy at discharge from wards of general medicine and geriatrics.
2465 patients enrolled in the Gruppo Italiano di Farmacovigilanza nell’Anziano (GIFA) study.
Main outcome measure
Polypharmacy, ie having more than 6 drugs prescribed at discharge.
Data on drugs prescribed at home, during hospital stay, and at discharge were collected according to a validated procedure. Logistic regression analysis was used to identify independent correlates of polypharmacy at discharge. The adherence to current therapeutic guidelines was assessed for selected drugs (digitalis, diuretics, antithrombotics, bronchodilators)
The median number of prescribed drugs was 3.0 before admission and 4.0 at discharge (p < 0.001). Polypharmacy prior to admission (Odds Ratio [OR] 4.32, 95% Confidence Interval [CI] 3.13–5.96), cumulative comorbidity (OR 1.81, 95% CI 1.40–2.32) and selected chronicconditions (diabetes, heart failure, chronic obstructive pulmonary disease, renal insufficiency, and depression) were significant correlates of polypharmacy at discharge. Negative correlate of the outcome was the occurrence of adverse drug reactions prior to admission (OR 0.22, 95% CI 0.09–0.51). The rate of appropriate prescription reached 80% only for antithrombotics either at home or in hospital and at discharge.
Hospitalization increases drug prescription at discharge in elderly patients. Efforts are needed to identify the determinants and to assess the quality of this prescription practice, with the final aim of contrasting polypharmacy.
PMCID: PMC1936300  PMID: 18360627
polypharmacy; elderly; epidemiology; comorbidity
4.  Antipsychotic patterns of use in patients with schizophrenia: polypharmacy versus monotherapy 
BMC Psychiatry  2014;14(1):341.
The objective of this study was to characterize real-world treatment patterns in the prescription of antipsychotic polypharmacy (≥2 concurrent antipsychotics) compared with antipsychotic monotherapy for patients with schizophrenia.
This study was a retrospective claims-based analysis of patients (aged 13–64 years) with schizophrenia belonging to an employer-based health plan. Duration of therapy was measured as the number of treatment days over one year following the initial date of antipsychotic therapy. Discontinuation was defined as a 90-day gap in antipsychotic treatment (or in at least one antipsychotic for the polypharmacy group). Logistic regression analyses were used to predict discontinuation within one year. Ordinary Least Squares (OLS) regressions were used to predict duration of therapy (by type of therapy) when controlling for gender, region, number of somatic and psychiatric comorbidities, Deyo-Charlson comorbidity score, and number of psychiatric and somatic medications.
Of the 4,156 patients, 3,188 received monotherapy and 968 received polypharmacy. Mean age was 40 years (37.8 years for polypharmacy vs 40.3 years for monotherapy, p < 0.001). Within one year, 77% of the polypharmacy group and 54% of the monotherapy group discontinued treatment. The average duration of therapy was 163 [SD = 143] days in the polypharmacy group vs 253 [SD = 147] days in the monotherapy group. In both cohorts, patients <25 years had a higher frequency of discontinuations than those ≥26 years. Age and polypharmacy were independent predictors of treatment duration and discontinuation prior to one year.
One quarter of patients with schizophrenia received antipsychotic polypharmacy. Discontinuation was higher in the polypharmacy group. Age and polypharmacy were significant predictors of treatment discontinuation.
PMCID: PMC4264319  PMID: 25433495
Schizophrenia; Polypharmacy; Claims-based analysis; Patterns of use
5.  Utility of Serum Creatinine, Creatine Kinase and Urinary Myoglobin in Detecting Acute Renal Failure due to Rhabdomyolysis in Trauma and Electrical Burns Patients 
The Indian Journal of Surgery  2012;75(1):17-21.
Rhabdomyolysis due to trauma and burns is an important cause of acute renal failure (ARF) secondary to myoglobinuria. To prevent morbidity and mortality from ARF due to rhabdomyolysis, early detection of ARF by monitoring the biochemical parameters such as serum creatinine, serum creatine kinase (CK), and urinary myoglobin (UM) can be helpful. The aims of the study were (1) to detect ARF due to rhabdomyolysis using serum creatinine, serum CK, and UM in trauma and electrical burn patients (2) to compare utility of these parameters in early prediction of ARF in patients of rhabdomyolysis. A total of 50 patients with trauma and electrical burns were included in the study. Serum creatinine, serum CK, and UM measurements were done at the time of admission and after 48 h. Diagnosis of ARF was made in the patients by Rifle’s criteria. The presence of significant elevation of creatinine, serum CK, and UM at the time of admission and after 48 h was compared in patients developing ARF by Fisher’s exact test. Fifteen of the 50 patients developed ARF as per the defined criteria. Of these, 9 patients (60 %) had raised level of serum creatinine above 1.4 mg% at admission and 14 patients (93.33 %) had CK level >1250 U/L at admission, whereas UM was positive in 6 (40 %) patients. Serum creatinine was significantly raised in all of the 15 ARF patients (100 %) after 48 h of admission and serum CK was raised in 14 of the 15 ARF patients (93.33 %). UM was negative in all the patients after 48 h of admission. Statistical analysis showed that rise in serum CK on admission was significantly increased in patients developing ARF as compared with serum creatinine and UM (P < 0.0001). On admission, CK is a better predictor of ARF due to rhabdomyolysis than creatinine and UM. Initial creatinine is a better predictor of ARF due to rhabdomyolysis than UM. UM assay is not a good investigation for early prediction of ARF in rhabdomyolysis.
PMCID: PMC3585542  PMID: 24426377
Creatine kinase; Urinary myoglobin; Serum creatinine; Acute renal failure; Rhabdomyolysis
6.  Acute renal failure in severe pancreatitis: A population-based study 
Upsala Journal of Medical Sciences  2011;116(2):155-159.
Acute pancreatitis (AP) is a common illness with varied mortality and morbidity. Patients with AP complicated with acute renal failure (ARF) have higher mortality than patients with AP alone. Although ARF has been proposed as a leading mortality cause for AP patients admitted to the ICU, few studies have directly analyzed the relationship between AP and ARF.
We performed a retrospective study using the population-based database from the Taiwan National Health Insurance Research Database (NHIRD). In the period from 1 January 2005 to 31 December 2005, every patient with AP admitted to the ICU was included and assessed for the presence of ARF and mortality risk.
In year 2005, there were a total of 221,101 admissions to the ICU. There were 1,734 patients with AP, of which 261 (15.05%) patients also had a diagnosis of ARF. Compared to sepsis and other critical illness, patients with AP had a higher risk of having a diagnosis of ARF, and patients with both diagnoses had a higher mortality rate in the same ICU hospitalization.
AP is associated with a higher risk of ARF, and, when both conditions exist, a higher risk of mortality is present.
PMCID: PMC3078547  PMID: 21250932
Acute renal failure; intensive care; severe acute pancreatitis
7.  Prevalence of Polypharmacy and Drug Interaction Among Hospitalized Patients: Opportunities and Responsabilities in Pharmaceutical Care 
Materia Socio-Medica  2012;24(2):68-72.
Polypharmacy and drug-related problems (DRPs) have been shown to prevail in hospitalized patients. We evaluated the prevalence of polypharmacy; and investigated relationship between polypharmacy and: symptoms of DRPs, number of drugs and OTC, index of cumulative morbidity, length of exposure to polypharmacy and the number of days of hospital stay among hospitalized patients.
A study was performed in Pharmacies „Eufarm Edal“ Tuzla from 2010 to 2011. Polypharmacy was defined as using ≥ 3 drugs. The total study sample of 226 examiners were interviewed with special constructed questionnaires about DRPs. Experimental study group consisted of hospital patients with polypharmacy (n=166) and control group hospital patients without polypharmacy (n=60). Mann-Whitney test was used to test for significant self-reported symptom differences between groups and cross sectional subgroups, t- test and χ2- test for age, gender and treatment data in hospital.
The prevalence of polypharmacy was 74% among 226 hospitalized patients. The vulnerable age subgroup of hospitalized patients was men and hospitalized patients aged from 46 to 50 years (not geriatric patients). The prevalence of index of cumulative morbidity was 65%. The most common exposures varied by patient age and by hospital type, with various antibiotics, antidepressants, analgesics, sedatives, antihypertensives, flixotide, ranitidine and others. The prevalence of exposure to OTC and self- treatment was 80%. The prevalence of symptoms of drug-related problems were significantly differed among patients of experimental in relationship of control study group patients (P<0.001).
In addition to helping to resolve the above mentioned issues, the results from this study could provide baseline information quantifying the problem of drug- related problems among hospitalized patients receiving polypharmacy and contribute to the formulation and implementation of risk management strategies for pharmacists and physicians in primary care health.
PMCID: PMC3633380  PMID: 23678310
polypharmacy; hospitalized patients; index of cumulative; primary pharmaceutical care.
8.  Prognosis and serum creatinine levels in acute renal failure at the time of nephrology consultation: an observational cohort study 
BMC Nephrology  2007;8:14.
The aim of this study is to evaluate the association between acute serum creatinine changes in acute renal failure (ARF), before specialized treatment begins, and in-hospital mortality, recovery of renal function, and overall mortality at 6 months, on an equal degree of ARF severity, using the RIFLE criteria, and comorbid illnesses.
Prospective cohort study of 1008 consecutive patients who had been diagnosed as having ARF, and had been admitted in an university-affiliated hospital over 10 years. Demographic, clinical information and outcomes were measured. After that, 646 patients who had presented enough increment in serum creatinine to qualify for the RIFLE criteria were included for subsequent analysis. The population was divided into two groups using the median serum creatinine change (101%) as the cut-off value. Multivariate non-conditional logistic and linear regression models were used.
A ≥ 101% increment of creatinine respect to its baseline before nephrology consultation was associated with significant increase of in-hospital mortality (35.6% vs. 22.6%, p < 0.001), with an adjusted odds ratio of 1.81 (95% CI: 1.08–3.03). Patients who required continuous renal replacement therapy in the ≥ 101% increment group presented a higher increase of in-hospital mortality (62.7% vs 46.4%, p = 0.048), with an adjusted odds ratio of 2.66 (95% CI: 1.00–7.21). Patients in the ≥ 101% increment group had a higher mean serum creatinine level with respect to their baseline level (114.72% vs. 37.96%) at hospital discharge. This was an adjusted 48.92% (95% CI: 13.05–84.79) more serum creatinine than in the < 101% increment group.
In this cohort, patients who had presented an increment in serum level of creatinine of ≥ 101% with respect to basal values, at the time of nephrology consultation, had increased mortality rates and were discharged from hospital with a more deteriorated renal function than those with similar Liano scoring and the same RIFLE classes, but with a < 101% increment. This finding may provide more information about the factors involved in the prognosis of ARF. Furthermore, the calculation of relative serum creatinine increase could be used as a practical tool to identify those patients at risk, and that would benefit from an intensive therapy.
PMCID: PMC2048940  PMID: 17894896
9.  A positive fluid balance is associated with a worse outcome in patients with acute renal failure 
Critical Care  2008;12(3):R74.
Despite significant improvements in intensive care medicine, the prognosis of acute renal failure (ARF) remains poor, with mortality ranging from 40% to 65%. The aim of the present observational study was to analyze the influence of patient characteristics and fluid balance on the outcome of ARF in intensive care unit (ICU) patients.
The data were extracted from the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a multicenter observational cohort study to which 198 ICUs from 24 European countries contributed. All adult patients admitted to a participating ICU between 1 and 15 May 2002, except those admitted for uncomplicated postoperative surveillance, were eligible for the study. For the purposes of this substudy, patients were divided into two groups according to whether they had ARF. The groups were compared with respect to patient characteristics, fluid balance, and outcome.
Of the 3,147 patients included in the SOAP study, 1,120 (36%) had ARF at some point during their ICU stay. Sixty-day mortality rates were 36% in patients with ARF and 16% in patients without ARF (P < 0.01). Oliguric patients and patients treated with renal replacement therapy (RRT) had higher 60-day mortality rates than patients without oliguria or the need for RRT (41% versus 33% and 52% versus 32%, respectively; P < 0.01). Independent risk factors for 60-day mortality in the patients with ARF were age, Simplified Acute Physiology Score II (SAPS II), heart failure, liver cirrhosis, medical admission, mean fluid balance, and need for mechanical ventilation. Among patients treated with RRT, length of stay and mortality were lower when RRT was started early in the course of the ICU stay.
In this large European multicenter study, a positive fluid balance was an important factor associated with increased 60-day mortality. Outcome among patients treated with RRT was better when RRT was started early in the course of the ICU stay.
PMCID: PMC2481469  PMID: 18533029
10.  Neurodiagnostic Abnormalities in Patients with Acute Renal Failure 
Journal of Clinical Investigation  1978;61(6):1448-1455.
Neurological abnormalities are a major cause of morbidity in patients with renal failure. The pathophysiology of these neurological changes is unclear, and the effects on them of dialysis and return of renal function have not been well studied. Studies were done in 31 patients who had acute renal failure (ARF), all of whom were either treated with dialysis within 5 days or did not survive. Studies on these patients included the electroencephalogram (EEG), motor nerve conduction velocity, and plasma Ca++ and parathyroid hormone (PTH) levels. Studies were done at the time ARF was diagnosed, after stabilization on dialysis, during the diuretic phase of ARF, and 3 mo after recovery from ARF. In 16 patients with acute or chronic renal failure who did not survive and in nine patients without renal disease who died, measurements were made in brain of content of Na+, K+, Cl−, Ca++, Mg++, and water.
In patients with ARF for less than 48 h, despite the fact that there were only modest increases in plasma urea and creatinine, there were striking abnormalities in the EEG. The percent EEG power < 5 Hz±SE was 41±8% (normal = 2±1%), whereas the percent of frequencies > 9 Hz was only 22±6% (normal = 62±3%). These changes were unaffected by dialysis, but became normal with return of renal function and remained normal at 3 mo follow-up. The motor nerve conduction velocity was unaffected by either ARF or dialysis. In patients with ARF, the brain Ca++ was 46.5±3.2 meq/kg dry wt, almost twice the normal value of 26.9±1.0 meq/kg dry wt (P < 0.001). The plasma PTH level was 3.2±0.6 ng/ml (normal < 1.5 ng/ml, P < 0.01). The increased brain Ca++ was not related to an increased plasma (Ca++) (PO4−−−) product (r2 = 0.14, P > 0.05). There was a small but significant decrement in brain Na+ (P < 0.05), but brain water, K+, and Mg++ were unaffected by ARF.
Thus, in patients with ARF for less than 48 h, the EEG is grossly abnormal and there are elevated levels of PTH in plasma. The PTH appears to have a direct effect on the brain, resulting in an increased brain Ca++ content. The EEG abnormalities are unaffected by dialysis, but they become normal with return of renal function and remain normal after 3 mo follow-up. Thus, PTH may be a major uremic toxin, demonstrating evidence for central nervous system toxicity when there are only minimal abnormalities of other biochemical markers of ARF.
PMCID: PMC372670  PMID: 659607
11.  Polypharmacy and Potentially Inappropriate Medication Use as the Precipitating Factor in Readmissions to the Hospital 
Background and Aim:
Readmission to the hospital within 30 days of discharge from the hospital is a common occurrence. Congestive heart failure is the most common cause of readmissions in the hospital. We hypothesized that irrespective of the admission diagnosis polypharmacy and potentially inappropriate use of medications (PIM) leads to readmissions within 30 days of discharge from the hospital.
Materials and Methods:
A retrospective study was carried out by reviewing the hospital records of 414 patients who were readmitted to the hospital within 30 days of discharge from the hospital between January 2008 and December 2009. The data was stratified to see which patients were on polypharmacy and/or on PIM. Polypharmacy was defined as use of more than 5 medications. PIM was defined as per the modified Beers criteria. Day 0 was defined as the day of discharge and day1 was defined as the day-after Admission to the hospital. Statistical analysis was carried out using a two-way analysis of variance (ANOVA) on the data to see if polypharmacy and/or PIM was related to readmission within 30 days of discharge irrespective of admission diagnosis.
Polypharmacy was related to hospital readmission at day 1 and day 0, however inappropriate drug use was found to be not related at any day. Polypharmacy and PIM combined had a positive correlation to readmission only on days 1 and 0 and it was statistically significant. The use of minimal and appropriate use of drugs was statistically significant compared to polypharmacy and PIM use.
Polypharmacy and PIM are under recognized cause of readmissions to the hospital.
PMCID: PMC3894035  PMID: 24479078
Adverse drug reactions; Beer's Criteria; geriatric population; polypharmacy; potentially inappropriate medications; readmission
12.  Antipsychotics Prescribing Patterns of Patients with Schizophrenia Admitted to Korean General Hospital Psychiatric Unit: 2001 to 2008 
Although the standard of treatment for schizophrenia is antipsychotic monotherapy, overall psychotropic polypharmacy including antipsychotic polypharmacy is increasingly practiced by clinicians. However, there are very few studies that assess the prescription patterns of psychotropic drugs for patients with schizophrenia in Korea. The objective of this study is to describe changes in prescription patterns with respect to antipsychotic polypharmacy and overall psychotropic polypharmacy.
In this retrospective study, we reviewed all psychotropic drugs prescribed at the time of discharge for patients diagnosed as having schizophrenia (DSM-IV criteria) who entered a psychiatric unit of a Korean general hospital from 2001 to 2008. These included a total of 467 patients.
Of the 467 patients in this study, 205 (43.9%) were discharged with antipsychotic monotherapy and the rest, 262 (56.1%), were discharged with a polypharmacy regimen. A total of 9% of the studied patients received more than two antipsychotic drugs. The most frequent combination of antipsychotics was clozapine and aripiprazole, followed by clozapine and amisulpride, and risperidone and olanzapine. The ratio of patients discharged with a polypharmacy regimen including antipsychotic polypharmacy increased from 2001 to 2008. In relation to the mean dose of all antipsychotic drugs at the time of discharge, mean length of hospital stay and mean initial global assessment of functioning scores on admission statistically significant differences were not detected between both monotherapy and polypharmacy groups.
The main finding of this study is that polypharmacy with antipsychotics and other psychotropic medicines increased in our psychiatric unit from 2001 to 2008. The rates of antipsychotic polypharmacy in our study were less than those described in our literature review.
PMCID: PMC3568650  PMID: 23430568
Schizophrenia; Antipsychotic monotherapy; Polypharmacy
13.  Muscle protein turnover and glucose uptake in acutely uremic rats. Effects of insulin and the duration of renal insufficiency. 
Journal of Clinical Investigation  1983;72(3):836-845.
Acute renal failure (ARF) in rats is associated with increased amino acid release from peripheral tissues and insulin resistance. To study whether abnormal protein and carbohydrate metabolism are linked in ARF, the effects of insulin on net muscle protein degradation (T) and on glucose uptake were measured in the perfused hindquarters of paired ARF and sham-operated (SO) rats. The basal rate of T increased 40% after 24 and 98% after 48 h of ARF. Insulin was less effective in decreasing T in ARF (-79% SO vs. -22% ARF 24 h and -64% SO vs. -23% ARF 48 h; P less than 0.01). Protein synthesis (PS) and protein degradation (PD) were measured independently in incubated epitrochlearis muscles; the increase in T after 24 h of ARF was due specifically to increased PD, while PS was unchanged. At this stage, insulin was less effective in decreasing PD in ARF (-10% ARF vs. -23% SO; P less than 0.02), although PS responded normally. After 48 h of ARF, the further increment in T was caused by the additional appearance of depressed basal and insulin-stimulated PS. This was confirmed in the perfused hindquarter (26 +/- 3 ARF vs. 38 +/- 3 SO, basal; 54 +/- 5 ARF vs 73 +/- 7 SO, insulin-stimulated, nmol phenylalanine/g per h; P less than 0.05). Although basal glucose uptake by hindquarters of ARF and SO rats was comparable, insulin-stimulated glucose uptake was 33% less at 24 and 44% less after 48 h of ARF. After 48 h of ARF, lactate and alanine release were increased and net glycogen synthesis in muscle was depressed. These abnormalities were even more apparent in the presence of insulin. Inefficient glucose utilization, estimated as the ratio of lactate release to glucose uptake, was correlated with T (r = +0.78; P less than 0.001). In conclusion, after 24 h of ARF, both increased PD and altered glucose utilization could be detected. After 48 h of ARF, T increased further because PS was depressed. At this time, glucose utilization was clearly abnormal and the results suggest that abnormal net protein degradation in ARF may be a consequence of defective glucose utilization.
PMCID: PMC1129248  PMID: 6350366
14.  Early non-invasive ventilation for acute respiratory failure in immunocompromised patients (IVNIctus): study protocol for a multicenter randomized controlled trial 
Trials  2014;15(1):372.
Acute respiratory failure (ARF) remains the leading reason for intensive care unit (ICU) admission of immunocompromised patients. In the most severe cases, high-flow oxygen therapy may fail to ensure adequate gas exchange, and mechanical ventilation (MV) must be used. This scenario is associated with high mortality rates of 40 to 60%, depending on the cause of ARF and type of immune deficiency. The use of non-invasive ventilation (NIV) in this situation has been criticized as potentially delaying the initiation of optimal treatment. In contrast, early NIV used prophylactically in patients with ARF who do not meet the criteria for invasive MV (IMV) may obviate the need for IMV, thereby decreasing the morbidity and mortality rates. We aim to demonstrate that a management strategy including early NIV decreases 28-day mortality rates compared to oxygen therapy alone in immunocompromised patients with ARF.
This is a multicenter parallel-group randomized controlled trial comparing early NIV to oxygen therapy alone in immunocompromised patients with ARF. All immunocompromised adult patients admitted to admission for ARF are eligible for randomization. Patient with ARF onset more than 72 hours earlier or ARF related to cardiogenic pulmonary edema or hypercapnia, or with a need for immediate endotracheal intubation or other organ failure are not eligible.
After inclusion patient are allocated to receive early NIV (intervention arm) or oxygen therapy only (control arm).
We plan to enroll 374 patients in 29 ICUs. An interim analysis is planned after the inclusion of 187 patients. The main objective is to demonstrate early NIV increases survival as compared to oxygen therapy alone. Other outcomes include the need of IMV, organ failure evolution, nosocomial infections rate, 6 months survival.
This study is expected to demonstrate an improved 28-day survival in immunocompromised patients managed with early NIV.
Trial registration
Registration number: NCT01915719. Registered on 26 July 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-372) contains supplementary material, which is available to authorized users.
PMCID: PMC4190291  PMID: 25257210
Non-invasive ventilation; Immunocompromised patient; Acute respiratory failure
15.  Cost prediction of antipsychotic medication of psychiatric disorder using artificial neural network model 
Antipsychotic monotherapy or polypharmacy (concurrent use of two or more antipsychotics) are used for treating patients with psychiatric disorders (PDs). Usually, antipsychotic monotherapy has a lower cost than polypharmacy. This study aimed to predict the cost of antipsychotic medications (AM) of psychiatric patients in Iran.
Materials and Methods:
For this purpose, 790 patients with PDs who were discharged between June and September 2010 were selected from Razi Psychiatric Hospital, Tehran, Iran. For cost prediction of AM of PD, neural network (NN) and multiple linear regression (MLR) models were used. Analysis of data was performed with R 2.15.1 software.
Mean ± standard deviation (SD) of the duration of hospitalization (days) in patients who were on monotherapy and polypharmacy was 31.19 ± 15.55 and 36.69 ± 15.93, respectively (P < 0.001). Mean and median costs of medication for monotherapy (n = 507) were $8.25 and $6.23 and for polypharmacy (n =192) were $13.30 and $9.48, respectively (P = 0.001). The important variables for cost prediction of AM were duration of hospitalization, type of treatment, and type of psychiatric ward in the MLR model, and duration of hospitalization, type of diagnosed disorder, type of treatment, age, Chlorpromazine dosage, and duration of disorder in the NN model.
Our findings showed that the artificial NN (ANN) model can be used as a flexible model for cost prediction of AM.
PMCID: PMC3872587  PMID: 24381622
Linear regression; neural networks; psychiatric disorders; treatment cost
16.  Noninvasive positive pressure ventilation in acute respiratory failure due to COPD vs other causes: Effectiveness and predictors of failure in a respiratory ICU in North India 
To determine the effectiveness of noninvasive positive pressure ventilation (NIPPV), and the factors predicting failure of NIPPV in acute respiratory failure (ARF) due to chronic obstructive pulmonary disease (COPD) versus other causes of ARF.
Patients and methods
This was a prospective observational study and all patients with ARF requiring NIPPV over a one-and-a-half year period were enrolled in the study. We recorded the etiology of ARF and prospectively collected the data for heart rate, respiratory rate, arterial blood gases (pH, partial pressure of oxygen in the arterial blood [PaO2], partial pressure of carbon dioxide in arterial blood [PaCO2]) at baseline, one and four hours. The patients were further classified into two groups based on the etiology of ARF as COPD–ARF and ARF due to other causes. The primary outcome was the need for endotracheal intubation during the intensive care unit (ICU) stay.
During the study period, 248 patients were admitted in the ICU and of these 63 (25.4%; 24, COPD–ARF, 39, ARF due to other causes; 40 male and 23 female patients; mean [standard deviation] age of 45.7 [16.6] years) patients were initiated on NIPPV. Patients with ARF secondary to COPD were older, had higher APACHE II scores, lower respiratory rates, levels compared to other causes of ARF. After one hour there was lower pH and higher PaCO2 levels with increase a significant decrease in respiratory rate and heart rate and decline in PaCO2 levels in patients successfully managed with NIPPV. However, there was no in pH and PaO2 difference in improvement of clinical and blood gas parameters between the two groups except at one hour which was significantly the rate of decline of pH at one and four hours and PaCO2 faster in the COPD group. NIPPV failures were significantly higher in ARF due to other causes (15/39) than in ARF–COPD (3/24) (p = 0.03). The mean ICU and hospital stay and the hospital mortality were similar in the two groups. In the multivariate logistic regression model (after and adjusting for gender, APACHE II scores and improvement in respiratory rate, pH, PaO2 at one hour) only the etiology of ARF, ie, ARF–COPD, was associated with a decreased PaCO2 risk of NIPPV failure (odds ratio 0.23; 95% confidence interval, 0.58–0.9).
NIPPV is more effective in preventing endotracheal intubation in ARF due to COPD than other causes, and the etiology of ARF is an important predictor of NIPPV failure.
PMCID: PMC2650588  PMID: 19281088
noninvasive ventilation; noninvasive positive pressure ventilation; acute respiratory failure; chronic obstructive pulmonary disease; CPAP; bilevel positive airway pressure; pneumonia; ALI; ARDS
17.  Importance of Neutrophil Gelatinase-Associated Lipocalin in Differential Diagnosis of Acute and Chronic Renal Failure 
Neutrophil Gelatinase-associated Lipocalin (NGAL) protein is easily detected in the blood and urine soon after acute renal injury. NGAL gains features of an early, sensitive and noninvasive biomarker for acute renal injury. Recent evidences suggest that its expression is also increased in CRF reflecting the severity of disease.
In the present study, we aimed to investigate whether blood NGAL level plays a role in the differential diagnosis of acute and chronic renal failure.
Patients and Methods:
This was a prospective case-control study. Fifty patients presented to emergency department with acute renal failure (ARF), 30 with chronic renal failure (CRF) and 20 healthy individuals as control group were included in this study. Blood pH, HCO3-, BUN, creatinine and potassium values were evaluated in all patients. Blood NGAL values were evaluated in all groups. BUN, serum creatinine and NGAL values were statistically compared between patients and controls.
Median NGAL levels in patients was 304.50 (29), and 60 (0) in control, which was statistically significant between the two groups (Z = -6.477, P < 0.001). The median NGAL values were 261.50 ± 291 in ARF group and 428.50 ± 294 in CRF group. There was a significant difference in NGAL level between ARF and CRF groups (Z = -2.52, P = 0.012). Median BUN values were 153.46 ± 82.47 in ARF group and 169.40 ± 93.94 in CRF group. There was no significant difference in BUN value between ARF and CRF groups (P > 0.05). Median creatinine values were 2.84 ± 2.95 in ARF group and 4.78 ± 4.32 in CRF group. In serum creatinine values, a significant difference was found between ARF and CRF groups (P < 0.05).
Serum NGAL levels of ARF and CRF patients were significantly higher than healthy individuals. In addition, NGAL values of patients with CRF were significantly higher than those of ARF. Serum NGAL values can be used to detect renal injury and differentiate ARF and CRF.
PMCID: PMC4222006  PMID: 25389480
Renal Failure; Chronic; Acute; NGAL Protein
18.  Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics 
BMC Psychiatry  2005;5:26.
Antipsychotic monotherapy is recognized as the treatment of choice for patients with schizophrenia. Simultaneous treatment with multiple antipsychotics (polypharmacy) is suggested by some expert consensus guidelines as the last resort after exhausting monotherapy alternatives. This study assessed the annual rate and duration of antipsychotic monotherapy and its inverse, antipsychotic polypharmacy, among schizophrenia patients initiated on commonly used atypical antipsychotic medications.
Data were drawn from a large prospective naturalistic study of patients treated for schizophrenia-spectrum disorders, conducted 7/1997–9/2003. Analyses focused on patients (N = 796) who were initiated during the study on olanzapine (N = 405), quetiapine (N = 115), or risperidone (N = 276). The percentage of patients with monotherapy on the index antipsychotic over the 1-year post initiation, and the cumulative number of days on monotherapy were calculated for all patients and for each of the 3 atypical antipsychotic treatment groups. Analyses employed repeated measures generalized linear models and non-parametric bootstrap re-sampling, controlling for patient characteristics.
During the 1-year period, only a third (35.7%) of the patients were treated predominately with monotherapy (>300 days). Most patients (57.7%) had at least one prolonged period of antipsychotic polypharmacy (>60 consecutive days). Patients averaged 195.5 days on monotherapy, 155.7 days on polypharmacy, and 13.9 days without antipsychotic therapy. Olanzapine-initiated patients were significantly more likely to be on monotherapy with the initiating antipsychotic during the 1-year post initiation compared to risperidone (p = .043) or quetiapine (p = .002). The number of monotherapy days was significantly greater for olanzapine than quetiapine (p < .001), but not for olanzapine versus risperidone, or for risperidone versus quetiapine-initiated patients.
Despite guidelines recommending the use of polypharmacy only as a last resort, the use of antipsychotic polypharmacy for prolonged periods is very common during the treatment of schizophrenia patients in usual care settings. In addition, in this non-randomized naturalistic observational study, the most commonly used atypical antipsychotics significantly differed on the rate and duration of antipsychotic monotherapy. Reasons for and the impact of the predominant use of polypharmacy will require further study.
PMCID: PMC1156914  PMID: 15921508
19.  Pre-injury polypharmacy as a predictor of outcomes in trauma patients 
One of the hallmarks of modern medicine is the improving management of chronic health conditions. Long-term control of chronic disease entails increasing utilization of multiple medications and resultant polypharmacy. The goal of this study is to improve our understanding of the impact of polypharmacy on outcomes in trauma patients 45 years and older.
Materials and Methods:
Patients of age ≥45 years were identified from a Level I trauma center institutional registry. Detailed review of patient records included the following variables: Home medications, comorbid conditions, injury severity score (ISS), Glasgow coma scale (GCS), morbidity, mortality, hospital length of stay (LOS), intensive care unit (ICU) LOS, functional outcome measures (FOM), and discharge destination. Polypharmacy was defined by the number of medications: 0–4 (minor), 5–9 (major), or ≥10 (severe). Age- and ISS-adjusted analysis of variance and multivariate analyses were performed for these groups. Comorbidity–polypharmacy score (CPS) was defined as the number of pre-admission medications plus comorbidities. Statistical significance was set at alpha = 0.05.
A total of 323 patients were examined (mean age 62.3 years, 56.1% males, median ISS 9). Study patients were using an average of 4.74 pre-injury medications, with the number of medications per patient increasing from 3.39 for the 45–54 years age group to 5.68 for the 75+ year age group. Age- and ISS-adjusted mortality was similar in the three polypharmacy groups. In multivariate analysis only age and ISS were independently predictive of mortality. Increasing polypharmacy was associated with more comorbidities, lower arrival GCS, more complications, and lower FOM scores for self-feeding and expression-communication. In addition, hospital and ICU LOS were longer for patients with severe polypharmacy. Multivariate analysis shows age, female gender, total number of injuries, number of complications, and CPS are independently associated with discharge to a facility (all, P < 0.02).
Over 40% of trauma patients 45 years and older were receiving 5 or more medications at the time of their injury. Although these patients do not appear to have higher mortality, they are at increased risk for complications, lower functional outcomes, and longer hospital and intensive care stays. CPS may be useful when quantifying the severity of associated comorbid conditions in the context of traumatic injury and warrants further investigation.
PMCID: PMC3249840  PMID: 22229132
Comorbid conditions; outcome prediction; polypharmacy; trauma outcomes
20.  Acute respiratory failure in kidney transplant recipients: a multicenter study 
Critical Care  2011;15(2):R91.
Data on pulmonary complications in renal transplant recipients are scarce. The aim of this study was to evaluate acute respiratory failure (ARF) in renal transplant recipients.
We conducted a retrospective observational study in nine transplant centers of consecutive kidney transplant recipients admitted to the intensive care unit (ICU) for ARF from 2000 to 2008.
Of 6,819 kidney transplant recipients, 452 (6.6%) required ICU admission, including 200 admitted for ARF. Fifteen (7.5%) of these patients had combined kidney-pancreas transplantations. The most common causes of ARF were bacterial pneumonia (35.5%), cardiogenic pulmonary edema (24.5%) and extrapulmonary acute respiratory distress syndrome (ARDS) (15.5%). Pneumocystis pneumonia occurred in 11.5% of patients. Mechanical ventilation was used in 93 patients (46.5%), vasopressors were used in 82 patients (41%) and dialysis was administered in 104 patients (52%). Both the in-hospital and 90-day mortality rates were 22.5%. Among the 155 day 90 survivors, 115 patients (74.2%) were dialysis-free, including 75 patients (65.2%) who recovered prior renal function. Factors independently associated with in-hospital mortality were shock at admission (odds ratio (OR) 8.70, 95% confidence interval (95% CI) 3.25 to 23.29), opportunistic fungal infection (OR 7.08, 95% CI 2.32 to 21.60) and bacterial infection (OR 2.53, 95% CI 1.07 to 5.96). Five factors were independently associated with day 90 dialysis-free survival: renal Sequential Organ Failure Assessment (SOFA) score on day 1 (OR 0.68/SOFA point, 95% CI 0.52 to 0.88), bacterial infection (OR 0.43, 95% CI 0.21 to 0.90), three or four quadrants involved on chest X-ray (OR 0.44, 95% CI 0.21 to 0.91), time from hospital to ICU admission (OR 0.98/day, 95% CI 0.95 to 0.99) and oxygen flow at admission (OR 0.93/liter, 95% CI 0.86 to 0.99).
In kidney transplant recipients, ARF is associated with high mortality and graft loss rates. Increased Pneumocystis and bacterial prophylaxis might improve these outcomes. Early ICU admission might prevent graft loss.
PMCID: PMC3219351  PMID: 21385434
21.  p14ARF expression in invasive breast cancers and ductal carcinoma in situ – relationships to p53 and Hdm2 
Breast Cancer Research  2004;6(5):R571-R585.
p14ARF stabilises nuclear p53, with a variable expression of p14ARF mRNA in breast cancers. In vitro, nuclear p14ARF binds Hdm2 to block Hdm2-dependent nucleocytoplasmic shuttling of p53, which is required before cytoplasmic degradation of p53. p14ARF is negatively regulated by p53 and through p53-independent pathways. No studies have yet examined levels of p14ARF protein expression in breast cancer and their relationship to Hdm2/p53 immunoreactivity or subcellular localisation. Previously, immunohistochemical expression of cytoplasmic p14ARF, p53 and Hdm2 has been described. HER-2 (c-erbB2/neu) predicts prognosis and interacts with the p14ARF/Hdm2 pathway to inactivate p14ARF and to influence Hdm2 activity and localisation. This study examined p14ARF and p53/Hdm2 expression and subcellular localisation by using immunohistochemistry in a series of invasive ductal breast cancers (IDCs) with concomitant ductal carcinoma in situ (DCIS), to evaluate whether findings in vitro were related to clinicopathological parameters such as HER-2 and their effect on patient outcome.
The 4C6 anti-p14ARF monoclonal antibody and Dako Envision Plus system were used to evaluate p14ARF expression in 103 patients; p53/Hdm2 staining was performed.
p14ARF was evaluable in 96 patients, with nuclear p14ARF expression (modified Quick-score ≥ 3) in 79% (n = 76) of IDCs and in associated DCIS in 74 patients. Cytoplasmic p14ARF was detectable in 23 breast cancers. Nuclear and cytoplasmic p14ARF showed no correlation with p53 subcellular immunoreactivity. Increasing levels of cytoplasmic p14ARF were associated with nuclear and cytoplasmic Hdm2 expression (P < 0.001). Subcellular ARF expression was not associated with clinicopathological parameters, and although not an independent prognosticator, these preliminary findings suggest that cytoplasmic p14ARF might be associated with a better overall survival (P = 0.09; log rank). The association between HER-2 positivity and nuclear p14ARF (P = 0.038), as well as nuclear Hdm2 (P = 0.019), reflects the in vitro findings of HER-2 interaction with the ARF/Hdm2 pathway. Cytoplasmic p53 and Hdm2 expression might have biological implications, through an association of cytoplasmic p53 with increased tumour proliferation (P = 0.005), and an improved overall survival (P = 0.002, log rank) in cytoplasmic Hdm2-expressing tumours, that independently predict favourable overall survival (P = 0.02) and disease-free survival (P = 0.03).
Nuclear p14ARF expression is similar in IDCs and DCIS and is associated with Hdm2 immunoreactivity. Nuclear p14ARF and Hdm2 might be regulated by HER-2. Clearly, our findings in vivo suggest a complexity of p14ARF/Hdm2 and p53 pathways in which consideration of cytoplasmic p14ARF and Hdm2 might have tumorigenic implications.
PMCID: PMC549173  PMID: 15318938
ARF protein; ductal carcinoma in situ; Hdm2; HER-2; immunohistochemistry
22.  Extracorporeal membrane oxygenation in adult patients with hematologic malignancies and severe acute respiratory failure 
Critical Care  2014;18(1):R20.
Acute respiratory failure (ARF) is the main reason for intensive care unit (ICU) admissions in patients with hematologic malignancies (HMs). We report the first series of adult patients with ARF and HMs treated with extracorporeal membrane oxygenation (ECMO).
This is a retrospective cohort study of 14 patients with HMs (aggressive non-Hodgkin lymphoma (NHL) n = 5; highly aggressive NHL, that is acute lymphoblastic leukemia or Burkitt lymphoma, n = 5; Hodgkin lymphoma, n = 2; acute myeloid leukemia, n = 1; multiple myeloma, n = 1) receiving ECMO support because of ARF (all data as medians and interquartile ranges; age, 32 years (22 to 51 years); simplified acute physiology score II (SAPS II): 51 (42 to 65)). Etiology of ARF was pneumonia (n = 10), thoracic manifestation of NHL (n = 2), sepsis of nonpulmonary origin (n = 1), and transfusion-related acute lung injury (n = 1). Diagnosis of HM was established during ECMO in four patients, and five first received (immuno-) chemotherapy on ECMO.
Before ECMO, the PaO2/FiO2 ratio was 60 (53 to 65), (3.3 to 3.7). Three patients received venoarterial ECMO because of acute circulatory failure in addition to ARF; all other patients received venovenous ECMO. All patients needed vasopressors, and five needed hemofiltration. Thrombocytopenia occurred in all patients (lowest platelet count was 20 (11 to 21) G/L). Five major bleeding events were noted. ECMO duration was 8.5 (4 to 16) days. ICU and hospital survival was 50%. All survivors were alive at follow-up (36 (10 to 58) months); five patients were in complete remission, one in partial remission, and one had relapsed.
ECMO therapy is feasible in selected patients with HMs and ARF and can be associated with long-term disease-free survival.
PMCID: PMC4055976  PMID: 24443905
23.  Drug-related problems in hospitalized patients on polypharmacy: the influence of age and gender 
Drug-related problems (DRPs) have been shown to prevail in hospitalized patients, and polypharmacy and increasing age have been identified as two important risk factors.
We investigated the occurrence of DRPs and adverse drug reactions (ADRs) amongst hospitalized patients prescribed polypharmacy, and the association of advanced age and female gender.
A retrospective cross-sectional study was performed in an acute-care hospital in Singapore. Only patients prescribed polypharmacy were included. Mann-Whitney test was used to test for significant difference between the age and gender of patients and their risk of acquiring DRPs. The relative risks of developing DRP and ADR for geriatric patients and female patients were estimated.
Of 347 patients prescribed polypharmacy (43% female and 58.2% geriatrics), no statistical correlations were observed between age and gender with developing DRPs. An increased number of medications was associated with higher risk for patients with DRPs on admission (p = 0.001), but not for inpatients with DRPs (p = 0.119). Results from patients with ADRs showed that the relative risk (RR) of geriatrics prescribed polypharmacy and major polypharmacy (10 and more drugs) were 1.01 and 1.23, respectively. Female patients had a RR of 0.79 compared with male patients in developing ADRs.
Results showed that among patients with polypharmacy, age and gender may not be as important as number of drugs prescribed as predictors of experiencing a DRP. A similar trend was observed in the development of ADRs.
PMCID: PMC1661606  PMID: 18360542
polypharmacy; drug-related problems; adverse drug reactions; geriatrics
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:
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:
For more information on the economic analysis, please visit the PATH website:
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:
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.
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
intubation rates
length of stay (intensive care unit [ICU] and hospital)
health-related quality of life
duration of mechanical ventilation
weaning failure
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
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
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.
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
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.
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
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.  Postpartum acute renal failure: a multicenter study of risk factors in patients admitted to ICU 
Even in developed countries, severe specific pregnancy complications may occur in the immediate postpartum period and require admission to the ICU. The characteristics and risk factors of acute renal failure (ARF) induced by these complications and their treatments are not well known.
We performed a retrospective multicenter study in three intensive care departments linked to level III maternity wards in the north of France. All patients admitted to ICU for postpartum complications over a 5-year period (2008 to 2012) were included. Clinical and biological data, delivery characteristics, type of complications, and treatments were compared by univariate and multivariate analyses according to the occurrence and severity of ARF.
One hundred eighty-two patients admitted to ICU for postpartum complications were included in the study. Sixty-eight patients (37%) developed an ARF: 49 with a low or medium severity and 19 with a severe ARF requiring renal replacement therapy. Hemolysis, elevated liver enzyme, and low platelet count (HELLP) syndrome on its own (p = 0.047) or combined with postpartum haemorrhage (p = 0.003), previous treatment by hyperoncotic albumin infusion (p = 0.001) and blockade of fibrinolysis by tranexamic acid (p = 0.03), was associated with secondary ARF. By multivariate analysis, the only independent factors were the association of HELLP syndrome with postpartum haemorrhage and the use of hyperoncotic albumin infusion.
HELLP syndrome associated with postpartum haemorrhage induces a high risk of ARF in the complicated postpartum setting. A particular attention should be given to treatments that could worsen the kidney function in that situation.
PMCID: PMC4273687  PMID: 25593752
Pregnancy; Postpartum complications; Intensive care; Acute renal failure; HELLP syndrome; Postpartum haemorrhage; Hyperoncotic albumin; Tranexamic acid

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