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1.  Post-traumatic pulmonary embolism in the intensive care unit 
Annals of Thoracic Medicine  2011;6(4):199-206.
OBJECTIVE:
To determine the predictive factors, clinical manifestations, and the outcome of patients with post-traumatic pulmonary embolism (PE) admitted in the intensive care unit (ICU).
METHODS:
During a four-year prospective study, a medical committee of six ICU physicians prospectively examined all available data for each trauma patient in order to classify patients according to the level of clinical suspicion of pulmonary thromboembolism. During the study period, all trauma patients admitted to our ICU were classified into two groups. The first group included all patients with confirmed PE; the second group included patients without clinical manifestations of PE. The diagnosis of PE was confirmed either by a high-probability ventilation/perfusion (V/Q) scan or by a spiral computed tomography (CT) scan showing one or more filling defects in the pulmonary artery or its branches.
RESULTS:
During the study period, 1067 trauma patients were admitted in our ICU. The diagnosis of PE was confirmed in 34 patients (3.2%). The mean delay of development of PE was 11.3 ± 9.3 days. Eight patients (24%) developed this complication within five days of ICU admission. On the day of PE diagnosis, the clinical examination showed that 13 patients (38.2%) were hypotensive, 23 (67.7%) had systemic inflammatory response syndrome (SIRS), three (8.8%) had clinical manifestations of deep venous thrombosis (DVT), and 32 (94%) had respiratory distress requiring mechanical ventilation. In our study, intravenous unfractionated heparin was used in 32 cases (94%) and low molecular weight heparin was used in two cases (4%). The mean ICU stay was 31.6 ± 35.7 days and the mean hospital stay was 32.7 ± 35.3 days. The mortality rate in the ICU was 38.2% and the in-hospital mortality rate was 41%. The multivariate analysis showed that factors associated with poor prognosis in the ICU were the presence of circulatory failure (Shock) (Odds ratio (OR) = 9.96) and thrombocytopenia (OR = 32.5).Moreover, comparison between patients with and without PE showed that the predictive factors of PE were: Age > 40 years, a SAPS II score > 25, hypoxemia with PaO2/FiO2 < 200 mmHg, the presence of spine fracture, and the presence of meningeal hemorrhage.
CONCLUSION:
Despite the high frequency of DVT in post-traumatic critically ill patients, symptomatic PE remains, although not frequently observed, because systematic screening is not performed. Factors associated with poor prognosis in the ICU are the presence of circulatory failure (shock) and thrombocytopenia. Predictive factors of PE are: Age > 40 years, a SAPS II score > 25, hypoxemia with PaO2/FiO2 < 200, the presence of a spine fracture, and the presence of meningeal hemorrhage. Prevention is highly warranted.
doi:10.4103/1817-1737.84773
PMCID: PMC3183636  PMID: 21977064
Anticoagulation; ICU; predictive factors; pulmonary embolism; trauma patients
2.  An Economic Evaluation of Venous Thromboembolism Prophylaxis Strategies in Critically Ill Trauma Patients at Risk of Bleeding 
PLoS Medicine  2009;6(6):e1000098.
Using decision analysis, Henry Stelfox and colleagues estimate the cost-effectiveness of three venous thromboembolism prophylaxis strategies in patients with severe traumatic injuries who were also at risk for bleeding complications.
Background
Critically ill trauma patients with severe injuries are at high risk for venous thromboembolism (VTE) and bleeding simultaneously. Currently, the optimal VTE prophylaxis strategy is unknown for trauma patients with a contraindication to pharmacological prophylaxis because of a risk of bleeding.
Methods and Findings
Using decision analysis, we estimated the cost effectiveness of three VTE prophylaxis strategies—pneumatic compression devices (PCDs) and expectant management alone, serial Doppler ultrasound (SDU) screening, and prophylactic insertion of a vena cava filter (VCF)—in trauma patients admitted to an intensive care unit (ICU) with severe injuries who were believed to have a contraindication to pharmacological prophylaxis for up to two weeks because of a risk of major bleeding. Data on the probability of deep vein thrombosis (DVT) and pulmonary embolism (PE), and on the effectiveness of the prophylactic strategies, were taken from observational and randomized controlled studies. The probabilities of in-hospital death, ICU and hospital discharge rates, and resource use were taken from a population-based cohort of trauma patients with severe injuries (injury severity scores >12) admitted to the ICU of a regional trauma centre. The incidence of DVT at 12 weeks was similar for the PCD (14.9%) and SDU (15.0%) strategies, but higher for the VCF (25.7%) strategy. Conversely, the incidence of PE at 12 weeks was highest in the PCD strategy (2.9%), followed by the SDU (1.5%) and VCF (0.3%) strategies. Expected mortality and quality-adjusted life years were nearly identical for all three management strategies. Expected health care costs at 12 weeks were Can$55,831 for the PCD strategy, Can$55,334 for the SDU screening strategy, and Can$57,377 for the VCF strategy, with similar trends noted over a lifetime analysis.
Conclusions
The attributable mortality due to PE in trauma patients with severe injuries is low relative to other causes of mortality. Prophylactic placement of VCF in patients at high risk of VTE who cannot receive pharmacological prophylaxis is expensive and associated with an increased risk of DVT. Compared to the other strategies, SDU screening was associated with better clinical outcomes and lower costs.
Please see later in the article for Editors' Summary
Editors' Summary
Background
For patients who have been seriously injured in an accident or a violent attack (trauma patients), venous thromboembolism (VTE)—the formation of blood clots that limit the flow of blood through the veins—is a frequent and potentially fatal complication. The commonest form of VTE is deep vein thrombosis (DVT). “Distal” DVTs (clots that form in deep veins below the knee) affect about half of patients with severe trauma; “proximal” DVTs (clots that form above the knee) develop in one in five trauma patients. DVTs cause pain and swelling in the affected leg and can leave patients with a painful condition called post-thrombotic syndrome. Worse still, part of the clot can break off and travel to the lungs where it can cause a life-threatening pulmonary embolism (PE). Distal DVTs rarely embolize but, if untreated, half of patients who present with a proximal DVT will develop a PE, and 2%–3% of them will die as a result.
Why Was This Study Done?
VTE is usually prevented by using heparin, a drug that stops blood clotting, but clinicians treating critically ill trauma patients have a dilemma. Many of these patients are at high risk of serious bleeding complications so cannot be given heparin to prevent VTE. Nonpharmacological ways to prevent VTE include the use of pneumatic compression devices to keep the blood moving in the legs (clots often form in patients confined to bed because of the sluggish blood flow in their legs), repeated screening for blood clots using Doppler ultrasound, and the insertion of a “vena cava filter” into the vein that takes blood from the legs to the heart. This last device catches blood clots before they reach the lungs but increases the risk of DVT. Unfortunately, no-one knows which VTE prevention strategy works best in trauma patients who cannot be given heparin. In this study, therefore, the researchers use decision analysis (the systematic evaluation of the most important factors affecting a decision) to estimate the costs and likely clinical outcomes of these strategies.
What Did the Researchers Do and Find?
The researchers used cost and clinical data from patients admitted to a Canadian trauma center with severe head/neck and/or abdomen/pelvis injuries (patients with a high risk of bleeding complications likely to make heparin therapy dangerous for up to two weeks after the injury) to construct a Markov decision analysis model. They then fed published data on the chances of patients developing DVT or PE, and on the effectiveness of the three VTE prevention strategies, into the model to obtain estimates of the costs and clinical outcomes of the strategies at 12 weeks after the injury and over the patients' lifetime. The estimated incidence of DVT at 12 weeks was 15% for the pneumatic compression device and Doppler ultrasound strategies, but 25% for the vena cava filter strategy. By contrast, the estimated incidence of PE was 2.9% with the pneumatic compression device, 1.5% with Doppler ultrasound, but only 0.3% with the vena cava filter. The expected mortality with all three strategies was similar. Finally, the estimated health care costs per patient at 12 weeks were Can$55,334 and Can$55,831 for the Doppler ultrasound and pneumatic compression device strategies, respectively, but Can$57,377 for the vena cava filter strategy; similar trends were seen for lifetime health care costs.
What Do These Findings Mean?
As with all mathematical models, these findings depend on the data fed into the model and on the assumptions included in it. For example, because data from one Canadian trauma unit were used to construct the model, these findings may not be generalizable. Nevertheless, these findings suggest that, although VTE is common among patients with severe injuries, PE is not a major cause of death among these patients. They also suggest that the use of vena cava filters for VTE prevention in patients who cannot receive heparin should not be routinely used because it is expensive and increases the risk of DVT. Finally, these results suggest that, compared with the other strategies, serial Doppler ultrasound is associated with better clinical outcomes and lower costs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000098.
The US National Heart Lung and Blood Institute provides information (including an animation) on deep vein thrombosis and pulmonary embolism
MedlinePlus provides links to more information about deep vein thrombosis and pulmonary embolism (in several languages)
The UK National Health Service Choices Web site has information on deep vein thrombosis and on embolism (in English and Spanish)
The Eastern Association for the Surgery of Trauma working group document Practice Management Guidelines for the Management of Venous Thromboembolism in Trauma Patients can be downloaded from the Internet
doi:10.1371/journal.pmed.1000098
PMCID: PMC2695771  PMID: 19554085
3.  Does dalteparin PROTECT better than heparin? 
Critical Care  2011;15(6):315.
Expanded abstract
Citation
The PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group: Dalteparin versus Unfractionated Heparin in Critically Ill Patients. N Engl J Med 2011, 364:1305-1314.
Background
It is unclear whether there is a clinically significant advantage to prophylactic low-molecular-weight heparin (LMWH) versus unfractionated heparin (UFH) in mixed medical/surgical critically ill adult patients.
Methods
Objective: To compare once daily dalteparin with twice daily unfractionated heparin for primary prophylaxis of proximal deep venous thrombosis in critically ill adults.
Design: A superiority randomized double-blinded controlled trial from 2006 to 2010 in both medical and surgical ICUs. (ClinicalTrials.gov registration number: NCT00182143)
Setting: Multi-center, international medical and surgical intensive care units (ICUs)
Subjects: Critically ill adults expected to remain in the ICU for at least 3 days.
Intervention: Patients were randomized to either twice daily UFH or daily dalteparin for the duration of ICU admission.
Outcomes: The primary endpoint was proximal leg deep venous thrombosis (DVT), at least three days after randomization, detected on twice weekly screening ultrasound. Secondary endpoints were: any DVT, pulmonary embolism (PE), venous thromboembolism (VTE), death, heparin-induced thrombocytopenia (HIT), major bleeding, and composite death/VTE.
Results
Three thousand seven hundred and forty-six subjects were included in the intention-to-treat analysis. Proximal leg DVT occurred in 96 of 1873 (5.1%) patients randomized to dalteparin versus 109 of 1873 (5.8%) patients randomized to UFH (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P = 0.57). The incidence of PE was 1.3% in the dalteparin group compared to 2.3% in the UFH group (hazard ratio, 0.51; 95% CI, 0.30 to 0.88; P = 0.01). There was no mortality difference and no difference in major bleeding between the two study arms. There was a statistically significant decrease in incidence of HIT in the dalteparin group in the per-protocol analysis, but not in the intention-to-treat analysis.
Limitations
Comparing the incidence of PE was a secondary endpoint and the study was not appropriately powered for this conclusion.
Conclusions
Among critically ill adult patients, dalteparin was not superior to UFH at preventing proximal lower extremity DVTs. There is a suggestion that dalteparin might be superior to UFH at preventing pulmonary embolism but a larger trial is necessary to confirm this result.
doi:10.1186/cc10581
PMCID: PMC3388642  PMID: 22152126
4.  Prevention and diagnosis of venous thromboembolism in critically ill patients: a Canadian survey 
Critical Care  2001;5(6):336-342.
Background
Venous thromboembolism (VTE) confers considerable morbidity and mortality in hospitalized patients, although few studies have focused on the critically ill population. The objective of this study was to understand current approaches to the prevention and diagnosis of deep venous thrombosis (DVT) and pulmonary embolism (PE) among patients in the intensive care unit (ICU).
Design
Mailed self-administered survey of ICU Directors in Canadian university affiliated hospitals.
Results
Of 29 ICU Directors approached, 29 (100%) participated, representing 44 ICUs and 681 ICU beds across Canada. VTE prophylaxis is primarily determined by individual ICU clinicians (20/29, 69.0%) or with a hematology consultation for challenging patients (9/29, 31.0%). Decisions are usually made on a case-by-case basis (18/29, 62.1%) rather than by preprinted orders (5/29, 17.2%), institutional policies (6/29, 20.7%) or formal practice guidelines (2/29, 6.9%). Unfractionated heparin is the predominant VTE prophylactic strategy (29/29, 100.0%) whereas low molecular weight heparin is used less often, primarily for trauma and orthopedic patients. Use of pneumatic compression devices and thromboembolic stockings is variable. Systematic screening for DVT with lower limb ultrasound once or twice weekly was reported by some ICU Directors (7/29, 24.1%) for specific populations. Ultrasound is the most common diagnostic test for DVT; the reference standard of venography is rarely used. Spiral computed tomography chest scans and ventilation–perfusion scans are used more often than pulmonary angiograms for the diagnosis of PE. ICU Directors recommend further studies in the critically ill population to determine the test properties and risk:benefit ratio of VTE investigations, and the most cost-effective methods of prophylaxis in medical–surgical ICU patients.
Interpretation
Unfractionated subcutaneous heparin is the predominant VTE prophylaxis strategy for critically ill patients, although low molecular weight heparin is prescribed for trauma and orthopedic patients. DVT is most often diagnosed by lower limb ultrasound; however, several different tests are used to diagnose PE. Fundamental research in critically ill patients is needed to help make practice evidence-based.
PMCID: PMC83855  PMID: 11737922
critical care; deep venous thrombosis; diagnosis; intensive care unit; prevention; pulmonary embolism; thromboembolism
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.  Safety and efficacy of low-molecular-weight heparins in prophylaxis of deep vein thrombosis in postoperative/ICU patients: A comparative study 
Background:
Venous thromboembolism (VTE), although a very common problem in everyday clinical practice, remains asymptomatic in most cases. Clinical diagnosis helps identify those who are going to have thromboembolic episode. A combination of clinical scoring systems like Wells’ score and D-dimer assay provide a useful diagnostic tool. Trauma (surgical or accidental) and critically ill patients are found to have greatest risk. Enoxaparin and dalteparin are amongst the most common low-molecular-weight heparins (LMWHs) used for deep venous thrombosis (DVT) prophylaxis in such patients.
Aim:
The present study is designed to compare their role in preventing DVT in postoperative or critically ill patients and to determine their relative safety profiles.
Materials and Methods:
The study included 36 critically ill adult patients. All the patients were allocated into three groups of 12 patients each. Group I patients received no prophylaxis, group II received inj. enoxaparin s/c 0.6-0.8 mg/kg twice daily, and group III received inj. dalteparin s/c 125-250 units/kg once daily. Routine investigations and coagulation profile were recorded on admission to intensive care unit (ICU) and at every third day thereafter. Patients were daily assessed for pretest probability of DVT using Wells’ scoring, and D-dimer test was done on the 7th day. Occurrence of any bleeding (visible or occult) was noted, and incidence of DVT was determined in each group using positive results of D-dimer test and the clinical assessment with Wells’ score.
Results:
A significant difference in Wells’ score (P < 0.05) was found between groups I and III on day 5 and day 7. A lower, but insignificant difference in the incidence of DVT was found between the study and control groups. No significant difference in major bleeding or other side effects was found. Better hemodynamic status and arterial blood gases in the study groups may indirectly refer to absence of asymptomatic DVT or silent pulmonary embolism in this group.
Conclusion:
The present study suggests that LMWHs, namely, enoxaparin and dalteparin, provide effective means of preventing DVT in high-risk, critically ill or postoperative patients, without causing any significant increase in the risk of bleeding or other side effects. Dalteparin appears to be unaffected by low creatinine clearance as explained by its clearance by a non-saturable mechanism. Still, a more extensive study with larger population is needed to make the outcomes worthwhile.
doi:10.4103/0976-9668.107290
PMCID: PMC3633277  PMID: 23633862
D-dimer; deep vein thrombosis; low-molecular-weight heparin; venous thromboembolism
7.  Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest 
Critical Care  2011;15(2):R90.
Introduction
Hyperoxia has recently been reported as an independent risk factor for mortality in patients resuscitated from cardiac arrest. We examined the independent relationship between hyperoxia and outcomes in such patients.
Methods
We divided patients resuscitated from nontraumatic cardiac arrest from 125 intensive care units (ICUs) into three groups according to worst PaO2 level or alveolar-arterial O2 gradient in the first 24 hours after admission. We defined 'hyperoxia' as PaO2 of 300 mmHg or greater, 'hypoxia/poor O2 transfer' as either PaO2 < 60 mmHg or ratio of PaO2 to fraction of inspired oxygen (FiO2 ) < 300, 'normoxia' as any value between hypoxia and hyperoxia and 'isolated hypoxemia' as PaO2 < 60 mmHg regardless of FiO2. Mortality at hospital discharge was the main outcome measure.
Results
Of 12,108 total patients, 1,285 (10.6%) had hyperoxia, 8,904 (73.5%) had hypoxia/poor O2 transfer, 1,919 (15.9%) had normoxia and 1,168 (9.7%) had isolated hypoxemia (PaO2 < 60 mmHg). The hyperoxia group had higher mortality (754 (59%) of 1,285 patients; 95% confidence interval (95% CI), 56% to 61%) than the normoxia group (911 (47%) of 1,919 patients; 95% CI, 45% to 50%) with a proportional difference of 11% (95% CI, 8% to 15%), but not higher than the hypoxia group (5,303 (60%) of 8,904 patients; 95% CI, 59% to 61%). In a multivariable model controlling for some potential confounders, including illness severity, hyperoxia had an odds ratio for hospital death of 1.2 (95% CI, 1.1 to 1.6). However, once we applied Cox proportional hazards modelling of survival, sensitivity analyses using deciles of hypoxemia, time period matching and hyperoxia defined as PaO2 > 400 mmHg, hyperoxia had no independent association with mortality. Importantly, after adjustment for FiO2 and the relevant covariates, PaO2 was no longer predictive of hospital mortality (P = 0.21).
Conclusions
Among patients admitted to the ICU after cardiac arrest, hyperoxia did not have a robust or consistently reproducible association with mortality. We urge caution in implementing policies of deliberate decreases in FiO2 in these patients.
doi:10.1186/cc10090
PMCID: PMC3219350  PMID: 21385416
8.  Clinically important deep vein thrombosis in the intensive care unit: a survey of intensivists 
Critical Care  2004;8(3):R145-R152.
Introduction
Outside the intensive care unit (ICU), clinically important deep vein thrombosis (DVT) is usually defined as a symptomatic event that leads to objective radiologic confirmation and subsequent treatment. The objective of the present survey is to identify the patient factors and radiologic features of lower limb DVT that intensivists consider more or less likely to make a DVT clinically important in ICU patients.
Methods
Our definition of clinically important DVT was a DVT likely to result in short-term or long-term morbidity or mortality if left untreated, as opposed to a DVT that is unlikely to have important consequences. We asked respondents to indicate the likelihood that patient factors and ultrasonographic features make a DVT clinically important using a five-point scale (from 1 = much less likely to 5 = much more likely).
Results
Of the 71 Canadian intensivists who responded, 70 (99%) rated three patient factors as most likely to make a DVT clinically important: clinical suspicion of pulmonary embolism (mean score 4.6), acute or chronic cardiopulmonary morbidity that might limit a patient's ability to tolerate pulmonary embolism (score 4.5), and leg symptoms (score 4.2). Of the ultrasound features, proximal (score 4.7), large (score 4.2), and totally occlusive (score 3.9) thrombi were considered the three most important.
Conclusion
When labeling a DVT as clinically important, intensivists rely on different patient specific factors and thrombus characteristics than are used to assess the clinical importance of DVT outside the ICU. The clinical importance of DVT is influenced by unique factors such as cardiopulmonary reserve among mechanically ventilated patients.
doi:10.1186/cc2859
PMCID: PMC468908  PMID: 15153243
deep venous thrombosis; pulmonary embolism; ultrasound
9.  Assessment of risk and prophylaxis for deep vein thrombosis and pulmonary embolism in medically ill patients during their early days of hospital stay at a tertiary care center in a developing country 
Aim
Deep vein thrombosis (DVT) and pulmonary thromboembolism (PE) are important causes of morbidity and mortality in medically ill patients. This study was done to assess risk factors and prophylaxis given for DVT and PE in newly admitted medically ill patients during the first two weeks of their hospital stay at a tertiary care center hospital in India.
Methods
All patients within one week of their admission in intensive care unit (ICU) and wards were enrolled in the study after an informed written consent. Patients who had DVT prophylaxis within the past month or any contraindications for DVT prophylaxis were excluded. A structured proforma was designed and effective risk stratification for DVT was done. Patients were followed for up to two weeks to record any changes in the risk categories and document any signs of PE or DVT if present. Any prophylaxis given for DVT or PE was noted.
Results
Seventy-five percent of patients had the highest risk for DVT and PE. Only 12.5% had DVT prophylaxis within the first two days of admission. Within two weeks of admission, 30.8% of patients were discharged, and 16.2% died. 72.6% of the patients still in the wards belonged to the highest risk category. Clinical signs and symptoms of DVT and PE were present in 25.8% and 9.8% of patients, respectively after the second week of admission. 86% of symptomatic patients belonged to the highest risk category initially and none of them received any prophylaxis. 21.6% of the highest risk category patients died within two weeks of their admission. A statistically significant correlation was found between mortality and risk score of the patients for DVT and between lack of prophylaxis and mortality (p < 0.05).
Conclusion
A significant risk for DVT and PE exists in medically ill patients, but only a small proportion of the patients are given prophylaxis. This study underlines the need to aggressively implement DVT risk stratification strategy in medical patients and provide prophylaxis unless contraindicated.
PMCID: PMC2725797  PMID: 19688105
deep venous thrombosis; pulmonary embolism; risk stratification; DVT prophylaxis
10.  Outcome of patients with pulmonary embolism admitted to the intensive care unit 
Annals of Thoracic Medicine  2009;4(1):13-16.
BACKGROUND:
Pulmonary embolism (PE) is an important cause of in-hospital mortality. Many patients are admitted to the intensive care unit (ICU) either due to hemodynamic instability or severe hypoxemia. Few reports have addressed the outcome of patients with PE; however, none were from ICUs in the Middle East.
OBJECTIVES:
To describe the demographics, clinical presentation, risk factors and outcome of patients with PE admitted to the medical ICU and to identify possible factors associated with poor prognosis.
MATERIALS AND METHODS:
Data were collected retrospectively by reviewing the records of patients admitted to the medical ICU with primary diagnosis of PE between January 2001 and June 2007. Demographic, clinical, radiological and therapeutic data were collected on admission to ICU.
RESULTS:
Fifty-six patients (43% females) with PE were admitted to the ICU during the study period. Their mean age was 40.6 ± 10.6 years. Seven patients (12.5%) had massive PE with hemodynamic instability and 15 (26.8%) had submassive PE. The remaining patients were admitted due to severe hypoxemia. Recent surgery followed by obesity were the most common risk factors (55.4 and 28.6%, respectively). Four patients with massive PE received thrombolysis because the remaining three had absolute contraindications. Fatal gastrointestinal bleeding occurred in one patient post thrombolysis. Additionally, two patients with massive PE and five with submassive PE died within 72 h of admission to the ICU, resulting in an overall mortality rate of 14%. Nonsurvivors were older and had a higher prevalence of immobility and cerebrovascular diseases compared with survivors.
CONCLUSIONS:
The mortality rate of patients with PE admitted to the ICU in our center was comparable to other published studies. Older age, immobility as well as coexistent cerebrovascular diseases were associated with a worse outcome.
doi:10.4103/1817-1737.44779
PMCID: PMC2700473  PMID: 19561916
Intensive care unit; pulmonary embolism; thrombolytic agents
11.  Thromboembolism 
Clinical Evidence  2010;2010:0208.
Introduction
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low-molecular-weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
Key Points
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. About 5% to 15% of people with untreated DVT may die from pulmonary embolism.The risk of recurrence of thromboembolism falls over time, but the risk of bleeding from anticoagulation remains constant.
Oral anticoagulants are considered effective in people with proximal DVT compared with no treatment, although we found few trials. In people with proximal DVT or pulmonary embolism, long-term anticoagulation reduces the risk of recurrence, but high-intensity treatment has shown no benefit. Both approaches increase the risk of major bleeding. Low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin, and may be as effective as oral anticoagulants, although all are associated with some adverse effects.We don't know how effective tapering off of oral anticoagulant agents is compared with stopping abruptly.We don't know whether once-daily LMWH is as effective as twice-daily administration at preventing recurrence. Home treatment may be more effective than hospital-based treatment at preventing recurrence, and equally effective in reducing mortality. Vena cava filters reduce the short-term rate of pulmonary embolism, but they may increase the long-term risk of recurrent DVT.Elastic compression stockings reduce the incidence of post-thrombotic syndrome after a DVT.
In people with isolated calf DVT, anticoagulation with warfarin may reduce the risk of proximal extension, although prolonged treatment seems no more beneficial than short-term treatment.
Anticoagulation may reduce mortality compared with no anticoagulation in people with a pulmonary embolus, but it increases the risk of bleeding. We found few studies that evaluated treatments for pulmonary embolism. LMWH may be as effective and safe as unfractionated heparin.Thrombolysis seems as effective as heparin in treating people with major pulmonary embolism, but it is also associated with adverse effects.The use of computerised decision support may increase the time spent adequately anticoagulated, and reduce thromboembolic events or major haemorrhage, compared with manual dosage calculation.
PMCID: PMC2907619
12.  Thromboembolism 
Clinical Evidence  2011;2011:0208.
Introduction
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. Around 5% to 15% of people with untreated DVT may die from pulmonary embolism. Risk factors for DVT include immobility, surgery (particularly orthopaedic), malignancy, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for proximal DVT? What are the effects of treatments for isolated calf DVT? What are the effects of treatments for pulmonary embolism? What are the effects of interventions on oral anticoagulation management in people with thromboembolism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticoagulation; compression stockings; low molecular weight heparin (short and long term, once or twice daily, and home treatment); oral anticoagulants (short and long term, high intensity, abrupt discontinuation, and computerised decision support); prolonged duration of anticoagulation; thrombolysis; vena cava filters; and warfarin.
Key Points
Deep venous thrombosis (DVT) or pulmonary embolism may occur in almost 2 in 1000 people each year, with up to 25% of those having a recurrence. About 5% to 15% of people with untreated DVT may die from pulmonary embolism.The risk of recurrence of thromboembolism falls over time, but the risk of bleeding from anticoagulation remains constant.
Oral anticoagulants are considered effective in people with proximal DVT compared with no treatment, although we found few trials. In people with proximal DVT or pulmonary embolism, long-term anticoagulation reduces the risk of recurrence, but high-intensity treatment has shown no benefit. Both approaches increase the risk of major bleeding. Low molecular weight heparin (LMWH) is more effective than unfractionated heparin, and may be as effective as oral anticoagulants, although all are associated with some adverse effects.We don't know how effective tapering off of oral anticoagulant agents is compared with stopping abruptly.We don't know whether once-daily LMWH is as effective as twice-daily administration at preventing recurrence. Home treatment may be more effective than hospital-based treatment at preventing recurrence, and equally effective in reducing mortality. Vena cava filters reduce the short-term rate of pulmonary embolism, but they may increase the long-term risk of recurrent DVT.Elastic compression stockings reduce the incidence of post-thrombotic syndrome after a DVT compared with placebo or no treatment.
In people with isolated calf DVT, anticoagulation with warfarin may reduce the risk of proximal extension, although prolonged treatment seems no more beneficial than short-term treatment.
Anticoagulation may reduce mortality compared with no anticoagulation in people with a pulmonary embolus, but it increases the risk of bleeding. We found few studies that evaluated treatments for pulmonary embolism. LMWH may be as effective and safe as unfractionated heparin. Thrombolysis seems as effective as heparin in treating people with major pulmonary embolism, but it is also associated with adverse effects.The use of computerised decision support may increase the time spent adequately anticoagulated, and reduce thromboembolic events or major haemorrhage, compared with manual dosage calculation.
PMCID: PMC3217723  PMID: 21385473
13.  Risk Factors for Severe Outcomes following 2009 Influenza A (H1N1) Infection: A Global Pooled Analysis 
PLoS Medicine  2011;8(7):e1001053.
This study analyzes data from 19 countries (from April 2009 to Jan 2010), comprising some 70,000 hospitalized patients with severe H1N1 infection, to reveal risk factors for severe pandemic influenza, which include chronic illness, cardiac disease, chronic respiratory disease, and diabetes.
Background
Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures.
Methods and Findings
Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5–14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50–64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3).
Conclusions
Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In April 2009, a new strain of influenza A H1N1 was first identified in Mexico and the United States and subsequently spread around the world. In June 2009, the World Health Organization (WHO) declared a pandemic alert phase 6, which continued until August 2010. Throughout the pandemic, WHO and member states gathered information to characterize the patterns of risk associated with the new influenza A H1N1 virus infection and to assess the clinical picture. Although risk factors for severe disease following seasonal influenza infection have been well documented in many countries (for example, pregnancy; chronic medical conditions such as pulmonary, cardiovascular, renal, hepatic, neuromuscular, hematologic, and metabolic disorders; some cognitive conditions; and immunodeficiency), risk factors for severe disease following infection early in the 2009 H1N1 pandemic were largely unknown.
Why Was This Study Done?
Many countries have recently reported data on the association between severe H1N1 influenza and a variety of underlying risk factors, but because these data are presented in different formats, making direct comparisons across countries is difficult, with no clear consensus for some conditions. Therefore, to assess the frequency and distribution of known and new potential risk factors for severe H1N1 infection, this study was conducted to collect data (from 1 April 2009 to 1 January 2010) from surveillance programs of the Ministries of Health or National Public Health Institutes in 19 countries―Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong (special administrative region), Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom.
What Did the Researchers Do and Find?
As part of routine surveillance, countries were asked to provide risk factor data on laboratory-confirmed H1N1 in patients who were admitted to hospital, admitted to the intensive care unit (ICU), or had died because of their infection, using a standardized format. The researchers grouped potential risk conditions into four categories: age, chronic medical illnesses, pregnancy (by trimester), and other conditions that were not previously considered as risk conditions for severe influenza outcomes, such as obesity. For each risk factor (except pregnancy), the researchers calculated the percentage of each group of patients using the total number of cases reported in each severity category (hospitalization, admission to ICU, and death). To evaluate the risk associated with pregnancy, the researchers used the ratio of pregnant women to all women of childbearing age (age 15–49 years) at each level of severity to describe the differences between levels.
The researchers were able to collect data on approximately 70,000 patients requiring hospitalization, 9,700 patients admitted to the ICU, and 2,500 patients who died from H1N1 infection. The proportion of patients with H1N1 with one or more reported chronic conditions increased with severity—the median was 31.1% of hospitalized patients, 52.3% of patients admitted to the ICU, and 61.8% of patients who died. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. The proportion of patients with obesity increased with increasing disease severity—median of 6% of hospitalized patients, 11.3% of patients admitted to the ICU, and 12.0% of all deaths from H1N1.
What Do These Findings Mean?
These findings show that risk factors for severe H1N1 infection are similar to those for seasonal influenza, with some notable differences: a substantial proportion of people with severe and fatal cases of H1N1 had pre-existing chronic illness, which indicates that the presence of chronic illness increases the likelihood of death. Cardiac disease, chronic respiratory disease, and diabetes are important risk factors for severe disease that will be especially relevant for countries with high rates of these illnesses. Approximately 2/3 of hospitalized people and 40% of people who died from H1N1 infection did not have any identified pre-existing chronic illness, but this study was not able to comprehensively assess how many of these cases had other risk factors, such as pregnancy, obesity, smoking, and alcohol misuse. Because of large differences between countries, the role of risk factors such as obesity and pregnancy need further study—although there is sufficient evidence to support vaccination and early intervention for pregnant women. Overall, the findings of this study reinforce the need to identify and target high-risk groups for interventions such as immunization, early medical advice, and use of antiviral medications.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001053.
WHO provides a Global Alert and Response (GAR) with updates on a number of influenza-related topics
The US Centers for Disease Control and Prevention provides information on risk factors and H1N1
doi:10.1371/journal.pmed.1001053
PMCID: PMC3130021  PMID: 21750667
14.  Patient-Centered Research 
PURPOSE
To validate the Canadian clinical probability tool and utility of bedside rapid D-dimer testing using SimpliRed® among patients with suspected acute deep-vein thrombosis (DVT) in an emergency room setting.
METHODS
Consecutive patients with clinically suspected DVT in a leg and no past history of symptomatic DVT were evaluated in the UC Davis emergency room by emergency room staff using the clinical probability tool developed by Wells and colleagues [Lancet,1997; 350:1795], which was provided on a one page form. After completing the form, each patient underwent venous ultrasound (US) imaging, whole blood D-dimer testing using SimpliRed®, and D-dimer measurement using a sensitive ELISA technique. All patients were followed for 3 months. Diagnosis of thromboembolism required objective confirmation of DVT using US or venography, or confirmation of pulmonary embolism using a high-probability lung scan or pulmonary arteriography.
RESULTS
Of 102 patients who were evaluated, 17 (17%) were diagnosed as having DVT initially; none of the 85 in whom DVT was excluded developed thromboembolism within 3 months. Ten of 17 (59%, CI 36%–82%) who met criteria for ‘high-probability’, 6 of 44 (13%, CI 5%–21%) with ‘intermediate probability’ and 1 of 41 (2.4%, CI 0.5%–7%) with ‘low probability’ had objectively confirmed DVT. This compares to published values of 49%, 14% and 3%, respectively, from two Canadian emergency rooms. Forty-one of the 102 (40%) patients had an ‘alternate diagnosis as likely or greater than DVT’, which lowered the probability of DVT by one or more levels in 35 (85%) cases. Thirty-eight of the 41 (93%) patients with an ‘alternate diagnosis’ did not have DVT; the 3 who did have DVT were thought to have cellulitis (n = 2) or knee hyperextension (n = 1). The negative predictive value of the SimpliRed rapid D-dimer test was 100%, 100% and 71% (5 of 7) in the low, intermediate and high probability groups. Both ‘false negative’ SimpliRed®tests had normal levels of D-dimer using a sensitive ELISA method, and careful re-review of the US studies revealed findings consistent with subacute or chronic DVT.
CONCLUSION
The Canadian probability tool for DVT appears to be a valid instrument in our emergency department. Similarly, we documented the high negative predictive value of bedside D-dimer (SimpliRed®) testing among patients classified as ‘low’ or ‘intermediate’ probability for having DVT, as reported in the literature. Radiographic misinterpretation of subacute or chronic DVT as acute DVT may partially explain the lower negative predictive value of SimpliRed® testing in patients with high clinical probability of having DVT.
doi:10.1046/j.1525-1497.2000.15200-10.x
PMCID: PMC1495734
15.  MORTALITY-ADJUSTED DURATION OF MECHANICAL VENTILATION IN CRITICALLY ILL CHILDREN WITH SYMPTOMATIC CENTRAL VENOUS LINE-RELATED DEEP VENOUS THROMBOSIS 
Critical care medicine  2011;39(5):1151-1156.
Objective
To determine the association between symptomatic central venous line (CVL) related deep venous thrombosis (DVT) and a mortality-adjusted measure of duration of mechanical ventilation (MV) in critically ill children with CVL.
Design
Retrospective matched cohort study.
Setting
11 pediatric ICUs across the United States.
Patients
Twenty-nine index critically ill children with CVL-related DVT from a previous prospective observational study on symptomatic venous thromboembolism (VTE) were compared to 116 control children with CVL without VTE. Each index patient was matched to 4 control patients based on age group, disease category, severity of illness score and number of days in the ICU prior to CVL insertion.
Interventions
None.
Measurements and Main Results
Index patients were appropriately matched to control patients, with similar characteristics between the 2 groups. Index patients had fewer ventilator free days (VFD i.e. days alive and breathing unassisted within 28 days after CVL insertion) compared to matched control patients (16.8±11.5 days versus 22.3±4.9 days, P=.040). Index patients also had less ICU free days (ICUFD i.e. days alive and discharged from the ICU within 28 days after CVL insertion) (9.8±9.9 days versus 17.9±5.7 days, P<.001). Durations of MV (17.6±40.6 days versus 5.2±5.5 days, P=.236) and ICU stay (38.1±61.7 days versus 11.9±10.9 days, P=.011) were longer in index patients. The mortality rate was statistically similar between the 2 groups.
Conclusions
The presence of symptomatic CVL-related DVT is associated with worse outcomes, particularly fewer VFD, in critically ill children. The causal relationship that DVT leads to impairment in lung function and delays weaning from MV and discharge from the ICU needs to be proven prospectively. VFD is a possible alternative outcome measure for future DVT studies.
doi:10.1097/CCM.0b013e31820eb8a1
PMCID: PMC3101274  PMID: 21336130
Venous thromboembolism; mortality; intensive care unit; catheter; pediatrics; outcome; critical care
16.  Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors 
Critical Care  2008;12(2):R32.
Background
Critically ill patients with renal insufficiency are predisposed to both deep vein thrombosis (DVT) and bleeding. The objective of the present study was to evaluate the prevalence, incidence and predictors of DVT and the incidence of bleeding in intensive care unit (ICU) patients with estimated creatinine clearance <30 ml/min.
Methods
In a multicenter, open-label, prospective cohort study of critically ill patients with severe acute or chronic renal insufficiency or dialysis receiving subcutaneous dalteparin 5,000 IU once daily, we estimated the prevalence of proximal DVT by screening compression venous ultrasound of the lower limbs within 48 hours of ICU admission. DVT incidence was assessed on twice-weekly ultrasound testing. We estimated the incidence of major and minor bleeding by daily clinical assessments. We used Cox proportional hazards regression to identify independent predictors of both DVT and major bleeding.
Results
Of 156 patients with a mean (standard deviation) creatinine clearance of 18.9 (6.5) ml/min, 18 had DVT or pulmonary embolism within 48 hours of ICU admission, died or were discharged before ultrasound testing – leaving 138 evaluable patients who received at least one dose of dalteparin. The median duration of dalteparin administration was 7 days (interquartile range, 4 to 12 days). DVT developed in seven patients (5.1%; 95% confidence interval, 2.5 to 10.1). The only independent risk factor for DVT was an elevated baseline Acute Physiology and Chronic Health Evaluation II score (hazard ratio for 10-point increase, 2.25; 95% confidence interval, 1.03 to 4.91). Major bleeding developed in 10 patients (7.2%; 95% confidence interval, 4.0 to 12.8), all with trough anti-activated factor X levels ≤ 0.18 IU/ml. Independent risk factors for major bleeding were aspirin use (hazard ratio, 6.30; 95% confidence interval, 1.35 to 29.4) and a high International Normalized Ratio (hazard ratio for 0.5-unit increase, 1.68; 95% confidence interval, 1.07 to 2.66).
Conclusion
In ICU patients with renal insufficiency, the incidence of DVT and major bleeding are considerable but appear related to patient comorbidities rather than to an inadequate or excessive anticoagulant from thromboprophylaxis with dalteparin.
Clinical Trial Registration
Number NCT00138099.
doi:10.1186/cc6810
PMCID: PMC2447552  PMID: 18315876
17.  Should C-reactive protein concentration at ICU discharge be used as a prognostic marker? 
BMC Anesthesiology  2010;10:17.
Background
About one third of hospital mortality in critically ill patients occurs after Intensive Care Unit (ICU) discharge. Some authors have recently hypothesized that unresolved or latent inflammation and sepsis may be an important factor that contributes to death following successful discharge from the ICU.
Aim
The aim of our study was to determine the ability of the clinical and inflammatory markers at ICU discharge to predict post-ICU mortality.
Methods
A prospective observational cohort study was conducted during a 14-month period in an 8 bed polyvalent ICU. Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score, Therapeutic Intervention Scoring System-28 (TISS-28), C-reactive protein (CRP), white cell count (WCC) and body temperature of the day of ICU discharge were collected from patients who survived their first ICU admission.
Results
During this period 156 patients were discharged alive from the ICU. A total of 29 patients (18.6%) died after ICU discharge. There were no differences in clinical and demographic characteristics between survivors and nonsurvivors. C-reactive protein levels at ICU discharge were not significantly different between survivors and nonsurvivors. The area under receiver operating characteristics curves of APACHE II, SAPS II, SOFA, TISS-28, CRP, WCC and body temperature at ICU discharge as prognostic markers of hospital death were 0.76 (95% confidence interval (CI) 0.67-0.86); 0.75 (95% CI 0.66-0.85); 0.72 (95% CI 0.62-0.83); 0.64 (95% CI 0.52-0.77); 0.55 (95% CI 0.43-0.67); 0.55 (95% CI 0.42-0.66) and 0.54 (95% CI 0.44-0.67) respectively. The hospital mortality rate of the patients with CRP <5, 5-10, >10 mg/dL was 15.1%, 16.1% and 33.3% respectively (p = NS).
Conclusions
At ICU discharge serum CRP concentration was a poor marker of post-ICU prognosis. Post-ICU death appears to be unrelated to the persistent inflammatory response.
doi:10.1186/1471-2253-10-17
PMCID: PMC2954920  PMID: 20875120
18.  Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients 
Critical Care  2008;12(6):R156.
Introduction
The aim of this study was to investigate whether in-hospital mortality was associated with the administered fraction of oxygen in inspired air (FiO2) and achieved arterial partial pressure of oxygen (PaO2).
Methods
This was a retrospective, observational study on data from the first 24 h after admission from 36,307 consecutive patients admitted to 50 Dutch intensive care units (ICUs) and treated with mechanical ventilation. Oxygenation data from all admission days were analysed in a subset of 3,322 patients in 5 ICUs.
Results
Mean PaO2 and FiO2 in the first 24 h after ICU admission were 13.2 kPa (standard deviation (SD) 6.5) and 50% (SD 20%) respectively. Mean PaO2 and FiO2 from all admission days were 12.4 kPa (SD 5.5) and 53% (SD 18). Focusing on oxygenation in the first 24 h of admission, in-hospital mortality was shown to be linearly related to FiO2 value and had a U-shaped relationship with PaO2 (both lower and higher PaO2 values were associated with a higher mortality), independent of each other and of Simplified Acute Physiology Score (SAPS) II, age, admission type, reduced Glasgow Coma Scale (GCS) score, and individual ICU. Focusing on the entire ICU stay, in-hospital mortality was independently associated with mean FiO2 during ICU stay and with the lower two quintiles of mean PaO2 value during ICU stay.
Conclusions
Actually achieved PaO2 values in ICU patients in The Netherlands are higher than generally recommended in the literature. High FiO2, and both low PaO2 and high PaO2 in the first 24 h after admission are independently associated with in-hospital mortality in ICU patients. Future research should study whether this association is causal or merely a reflection of differences in severity of illness insufficiently corrected for in the multivariate analysis.
doi:10.1186/cc7150
PMCID: PMC2646321  PMID: 19077208
19.  Clinical characteristics and outcomes of patients with acute myelogenous leukemia admitted to intensive care: a case-control study 
BMC Cancer  2010;10:516.
Background
There is limited epidemiologic data on patients with acute myelogenous (myeloid) leukemia (AML) requiring life-sustaining therapies in the intensive care unit (ICU). Our objectives were to describe the clinical characteristics and outcomes in critically ill AML patients.
Methods
This was a retrospective case-control study. Cases were defined as adult patients with a primary diagnosis of AML admitted to ICU at the University of Alberta Hospital between January 1st 2002 and June 30th 2008. Each case was matched by age, sex, and illness severity (ICU only) to two control groups: hospitalized AML controls, and non-AML ICU controls. Data were extracted on demographics, course of hospitalization, and clinical outcomes.
Results
In total, 45 AML patients with available data were admitted to ICU. Mean (SD) age was 54.8 (13.1) years and 28.9% were female. Primary diagnoses were sepsis (32.6%) and respiratory failure (37.3%). Mean (SD) APACHE II score was 30.3 (10.3), SOFA score 12.6 (4.0) with 62.2% receiving mechanical ventilation, 55.6% vasoactive therapy, and 26.7% renal replacement therapy. Crude in-hospital, 90-day and 1-year mortality was 44.4%, 51.1% and 71.1%, respectively. AML cases had significantly higher adjusted-hazards of death (HR 2.23; 95% CI, 1.38-3.60, p = 0.001) compared to both non-AML ICU controls (HR 1.69; 95% CI, 1.11-2.58, p = 0.02) and hospitalized AML controls (OR 1.0, reference variable). Factors associated with ICU mortality by univariate analysis included older age, AML subtype, higher baseline SOFA score, no change or an increase in early SOFA score, shock, vasoactive therapy and mechanical ventilation. Active chemotherapy in ICU was associated with lower mortality.
Conclusions
AML patients may represent a minority of all critically ill admissions; however, are not uncommonly supported in ICU. These AML patients are characterized by high illness severity, multi-organ dysfunction, and high treatment intensity and have a higher risk of death when compared with matched hospitalized AML or non-AML ICU controls. The absence of early improvement in organ failure may be a useful predictor for mortality for AML patients admitted to ICU.
doi:10.1186/1471-2407-10-516
PMCID: PMC2955611  PMID: 20920175
20.  Anti-Xa activity after subcutaneous administration of dalteparin in ICU patients with and without subcutaneous oedema: a pilot study 
Critical Care  2006;10(3):R93.
Introduction
Intensive care unit (ICU) patients often suffer from subcutaneous oedema, due to administration of large fluid volumes and the underlying pathophysiological condition. It is unknown whether the presence of subcutaneous oedema impairs the absorption of dalteparin, a low molecular weight heparin, when it is given by subcutaneous administration for venous thromboembolism prophylaxis. The objective of this study is to compare the anti-Xa activity of dalteparin after subcutaneous administration in ICU patients with and without subcutaneous oedema.
Methods
This non-randomized open parallel group follow-up pilot study was conducted in two mixed medical-surgical intensive care units at two teaching hospitals. Seven ICU patients with subcutaneous oedema (index group) and seven ICU patients without subcutaneous oedema (reference group) were studied. Anti-Xa activity was determined at 0, 3, 4, 6, 8, 12 and 24 hours after subcutaneous administration of 2,500 IU dalteparin. Plasma concentrations of factor anti-Xa activity were measured using a chromogenic factor Xa inhibition assay.
Results
The characteristics of the index group were: age, 58 years; male/female ratio, 5/2; body mass index at admission, 23.4 kg/m2 (at study day, 30.6 kg/m2). The characteristics of the reference group were: age, 49 years; male/female ratio, 6/1; body mass index at admission, 24.8 kg/m2 (at study day, 25.0 kg/m2). In the index group, creatinine clearance was lower compared to the reference group (71 versus 131 ml/minute, p = 0.003). Sequential organ failure assessment score did not differ between index and reference groups (4 versus 5). Mean arterial pressure was comparable between index and reference groups (91 versus 95 mmHg) and within the normal range. The mean Cmax value was not different between ICU patients with and without subcutaneous oedema (0.15 ± 0.02 versus 0.14 ± 0.02 IU/ml, p = 0.34). In the index group, the mean AUC(0–24 h) value was slightly higher compared with the reference group (1.50 ± 0.31 versus 1.15 ± 0.25 h·IU/ml, p = 0.31). This difference was not significant.
Conclusion
In this pilot study, there was no clinically relevant difference in anti-Xa activity after subcutaneous administration of 2,500 IU dalteparin for venous thromboembolism prophylaxis between ICU patients with and without subcutaneous oedema. Critically ill patients seem to have lower anti-Xa activity levels than healthy volunteers.
doi:10.1186/cc4952
PMCID: PMC1550968  PMID: 16790078
21.  Case mix, outcome and activity for patients admitted to intensive care units requiring chronic renal dialysis: a secondary analysis of the ICNARC Case Mix Programme Database 
Critical Care  2007;11(2):R50.
Introduction
This report describes the case mix, outcome and activity for admissions to intensive care units (ICUs) of patients who require prior chronic renal dialysis for end-stage renal failure (ESRF), and investigates the effect of case mix factors on outcome.
Methods
This was a secondary analysis of a high-quality clinical database, namely the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database, which includes 276,731 admissions to 170 adult ICUs across England, Wales and Northern Ireland from 1995 to 2004.
Results
During the eight year study period, 1.3% (n = 3,420) of all patients admitted to ICU were receiving chronic renal dialysis before ICU admission. This represents an estimated ICU utilization of six admissions (32 bed-days) per 100 dialysis patient-years. The ESRF group was younger (mean age 57.3 years versus 59.5 years) and more likely to be male (60.2% versus 57.9%) than those without ESRF. Acute Physiology and Chronic Health Evaluation II score and Acute Physiology Score revealed greater severity of illness on admission in patients with ESRF (mean 24.7 versus 16.6 and 17.2 versus 12.6, respectively). Length of stay in ICU was comparable between groups (median 1.9 days versus 1.8 days) and ICU mortality was only slightly elevated in the ESRF group (26.3% versus 20.8%). However, the ESRF group had protracted overall hospital stay (median 25 days versus 17 days), and increased hospital mortality (45.3% versus 31.2%) and ICU readmission (9.0% vs. 4.7%). Multiple logistic regression analysis adjusted for case mix identified the increased hospital mortality to be associated with increasing age, emergency surgery and nonsurgical cases, cardiopulmonary resuscitation before ICU admission and extremes of physiological norms. The adjusted odds ratio for ultimate hospital mortality associated with chronic renal dialysis was 1.24 (95% confidence interval 1.13 to 1.37).
Conclusion
Patients with ESRF admitted to UK ICUs are more likely to be male and younger, with a medical cause of admission, and to have greater severity of illness than the non-ESRF population. Outcomes on the ICU were comparable between the two groups, but those patients with ESRF had greater readmission rates, prolonged post-ICU hospital stay and increased post-ICU hospital mortality. This study is by far the largest comparative outcome analysis to date in patients with ESRF admitted to the ICU. It may help to inform clinical decision-making and resource requirements for this patient population.
doi:10.1186/cc5785
PMCID: PMC2206479  PMID: 17451605
22.  Survival Analysis of 314 Episodes of Sepsis in Medical Intensive Care Unit in University Hospital: Impact of Intensive Care Unit Performance and Antimicrobial Therapy 
Croatian medical journal  2006;47(3):385-397.
Aim
To evaluate epidemiology of sepsis in medical intensive care unit (ICU) in an university hospital, and the impact of ICU performance and appropriate empirical antibiotic therapy on survival of septic patients.
Methods
Observational, partly prospective study conducted over 6 years assessed all patients meeting the criteria for sepsis at ICU admission at the Sisters of Mercy Hospital in Zagreb. Clinical presentation of sepsis was defined according to 2001 International Sepsis Definitions Conference. Demographic data, admission category, source of infection, severity of sepsis, ICU or hospital stay and outcome, ICU performance, and appropriateness of empirical antibiotic therapy were analyzed.
Results
The analysis included 314 of 5022 (6.3%) patients admitted to ICU during the study period. There were 176 (56.1%) ICU survivors. At the ICU admission, sepsis was present in 100 (31.8%), severe sepsis in 89 (28.6%), and septic shock in 125 (39.8%) patients with mortality rates 17%, 33.7%, 72.1%, respectively. During ICU treatment, 244 (77.7%) patients developed at least one organ dysfunction syndrome. Of 138 (43.9%) patients who met the criteria for septic shock, 107 (75.4) were non-survivors (P<0.001). Factors associated with in-ICU mortality were acquisition of sepsis at another department (odds ratio [OR] 0.06; 95% confidence interval [CI], 0.02-0.19), winter season (OR 0.42; 0.20-0.89), limited mobility (OR 0.28; 0.14-0.59), ICU length of stay (OR 0.82; 0.75-0.91), sepsis-related organ failure assessment (SOFA) score on day 1 (OR 0.80; 0.72-0.89), history of global heart failure (OR 0.33; 0.16-0.67), chronic obstructive pulmonary disease (COPD)-connected respiratory failure (OR 0.50; 0.27-0.93), septic shock present during ICU treatment (OR 0.03; 0.01-0.10), and negative blood culture at admission (OR 2.60; 0.81-6.23). Microbiological documentation of sepsis was obtained in 235 (74.8%) patients. Urinary tract infections were present in 168 (53.5%) patients, followed by skin or soft tissue infections in 58 (18.5%) and lower respiratory tract infections in 44 (14.0%) patients. Lower respiratory tract as focus of sepsis was connected with worse outcome (P<0.001). Empirical antibiotic treatment was considered adequate in 107 (60.8%) survivors and 42 (30.4%) non-survivors. Patients treated with adequate empirical antibiotic therapy had significantly higher survival time in hospital (log-rank, P = 0.001).
Conclusion
The mortality rate of sepsis was unacceptably high. The odds for poor outcome increased with acquisition of sepsis at another department, winter season, limited mobility, higher SOFA score on day 1, history of chronic global heart failure, COPD-connected respiratory failure, and septic shock present during ICU treatment, whereas longer ICU length of stay, positive blood culture, and adequate empirical antibiotic therapy were protective factors.
PMCID: PMC2080418  PMID: 16758516
23.  A cohort study on the incidence and outcome of pulmonary embolism in trauma and orthopedic patients 
BMC Medicine  2014;12:39.
Background
This study aims to determine the incidence of pulmonary embolism (PE) in trauma and orthopedic patients within a regional tertiary referral center and its association with the pattern of injury, type of treatment, co-morbidities, thromboprophylaxis and mortality.
Methods
All patients admitted to our institution between January 2010 and December 2011, for acute trauma or elective orthopedic procedures, were eligible to participate in this study. Our cohort was formed by identifying all patients with clinical features of PE who underwent Computed Tomography-Pulmonary Angiogram (CT-PA) to confirm or exclude the clinical suspicion of PE, within six months after the injury or the surgical procedure.
Case notes and electronic databases were reviewed retrospectively to identify each patient’s venous thromboembolism (VTE) risk factors, type of treatment, thromboprophylaxis and mortality.
Results
Out of 18,151 patients admitted during the study period only 85 (0.47%) patients developed PE (positive CT-PA) (24 underwent elective surgery and 61 sustained acute trauma). Of these, only 76% of the patients received thromboprophylaxis. Hypertension, obesity and cardiovascular disease were the most commonly identifiable risk factors. In 39% of the cases, PE was diagnosed during the in-hospital stay. The median time of PE diagnosis, from the date of injury or the surgical intervention was 23 days (range 1 to 312). The overall mortality rate was 0.07% (13/18,151), but for those who developed PE it was 15.29% (13/85). Concomitant deep venous thrombosis (DVT) was identified in 33.3% of patients. The presence of two or more co-morbidities was significantly associated with the incidence of mortality (unadjusted odds ratio (OR) = 3.52, 95% confidence interval (CI) (1.34, 18.99), P = 0.034). Although there was also a similar clinical effect size for polytrauma injury on mortality (unadjusted OR = 1.90 (0.38, 9.54), P = 0.218), evidence was not statistically significant for this factor.
Conclusions
The incidence of VTE was comparable to previously reported rates, whereas the mortality rate was lower. Our local protocols that comply with the National Institute for Health and Clinical Excellence (NICE) guidelines in the UK appear to be effective in preventing VTE and reducing mortality in trauma and orthopedic patients.
doi:10.1186/1741-7015-12-39
PMCID: PMC3996019  PMID: 24589368
Pulmonary embolism; Deep venous thrombosis; Trauma; Orthopedic surgery; Arthroplasty; Mortality; Incidence
24.  Sex-and age-based differences in the delivery and outcomes of critical care 
Background
Previous studies have suggested that a patient's sex may influence the provision and outcomes of critical care. Our objective was to determine whether sex and age are associated with differences in admission practices, processes of care and clinical outcomes for critically ill patients.
Methods
We used a retrospective cohort of 466 792 patients, including 24 778 critically ill patients, admitted consecutively to adult hospitals in Ontario between Jan. 1, 2001, and Dec. 31, 2002. We measured associations between sex and age and admission to the intensive care unit (ICU); use of mechanical ventilation, dialysis or pulmonary artery catheterization; length of stay in the ICU and hospital; and death in the ICU, hospital and 1 year after admission.
Results
Of the 466 792 patients admitted to hospital, more were women than men (57.0% v. 43.0% for all admissions, p < 0.001; 50.1% v. 49.9% for nonobstetric admissions, p < 0.001). However, fewer women than men were admitted to ICUs (39.9% v. 60.1%, p < 0.001); this difference was most pronounced among older patients (age ≥ 50 years). After adjustment for admission diagnoses and comorbidities, older women were less likely than older men to receive care in an ICU setting (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.66–0.71). After adjustment for illness severity, older women were also less likely than older men to receive mechanical ventilation (OR 0.91, 95% CI 0.81– 0.97) or pulmonary artery catheterization (OR 0.80, 95% CI 0.73– 0.88). Despite older men and women having similar severity of illness on ICU admission, women received ICU care for a slightly shorter duration yet had a longer length of stay in hospital (mean 18.3 v. 16.9 days; p = 0.006). After adjustment for differences in comorbidities, source of admission, ICU admission diagnosis and illness severity, older women had a slightly greater risk of death in the ICU (hazard ratio 1.20, 95% CI 1.10–1.31) and in hospital (hazard ratio 1.08, 95% CI 1.00–1.16) than did older men.
Interpretation
Among patients 50 years or older, women appear less likely than men to be admitted to an ICU and to receive selected life-supporting treatments and more likely than men to die after critical illness. Differences in presentation of critical illness, decision-making or unmeasured confounding factors may contribute to these findings.
doi:10.1503/cmaj.071112
PMCID: PMC2096494  PMID: 18003954
25.  Long-Term Oxygen Therapy for 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 health technology assessment was to determine the effectiveness, cost-effectiveness, and safety of long-term oxygen therapy (LTOT) for chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Oxygen therapy is used in patients with COPD with hypoxemia, or very low blood oxygen levels, because they may have difficulty obtaining sufficient oxygen from inspired air.
Technology
Long-term oxygen therapy is extended use of oxygen. Oxygen therapy is delivered as a gas from an oxygen source. Different oxygen sources are: 1) oxygen concentrators, electrical units delivering oxygen converted from room air; 2) liquid oxygen systems, which deliver gaseous oxygen stored as liquid in a tank; and 3) oxygen cylinders, which contain compressed gaseous oxygen. All are available in portable versions. Oxygen is breathed in through a nasal cannula or through a mask covering the mouth and nose. The treating clinician determines the flow rate, duration of use, method of administration, and oxygen source according to individual patient needs. Two landmark randomized controlled trials (RCTs) of patients with COPD established the role of LTOT in COPD. Questions regarding the use of LTOT, however, still remain.
Research Question
What is the effectiveness, cost-effectiveness, and safety of LTOT compared with no LTOT in patients with COPD, who are stratified by severity of hypoxemia?
Research Methods
Literature Search
Search Strategy
A literature search was performed on September 8, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, the Cochrane Library, and INAHTA for studies published from January 1, 2007 to September 8, 2010.
A single clinical epidemiologist reviewed the abstracts, obtained full-text articles for studies meeting the eligibility criteria, and examined reference lists for additional relevant studies not identified through the literature search. A second clinical epidemiologist and then a group of epidemiologists reviewed articles with an unknown eligibility until consensus was established.
Inclusion Criteria
patients with mild, moderate, or severe hypoxemia;
English-language articles published between January 1, 2007 and September 8, 2010;
journal articles reporting on effectiveness, cost-effectiveness, or safety for the comparison of interest;
clearly described study design and methods;
health technology assessments, systematic reviews, RCTs, or prospective cohort observational studies;
any type of observational study for the evaluation of safety.
Exclusion Criteria
no hypoxemia
non-English papers
animal or in vitro studies
case reports, case series, or case-case studies
studies comparing different oxygen therapy regimens
studies on nocturnal oxygen therapy
studies on short-burst, palliative, or ambulatory oxygen (supplemental oxygen during exercise or activities of daily living)
Outcomes of Interest
mortality/survival
hospitalizations
readmissions
forced expiratory volume in 1 second (FEV1)
forced vital capacity (FVC)
FEV1/FVC
pulmonary hypertension
arterial partial pressure of oxygen (PaO2)
arterial partial pressure of carbon dioxide (PaCO2)
end-exercise dyspnea score
endurance time
health-related quality of life
Note: Outcomes of interest were formulated according to existing studies, with arterial pressure of oxygen and carbon dioxide as surrogate outcomes.
Summary of Findings
Conclusions
Based on low quality of evidence, LTOT (~ 15 hours/day) decreases all-cause mortality in patients with COPD who have severe hypoxemia (PaO2 ~ 50 mm Hg) and heart failure.
The effect for all-cause mortality had borderline statistical significance when the control group was no LTOT: one study.
Based on low quality of evidence, there is no beneficial effect of LTOT on all-cause mortality at 3 and 7 years in patients with COPD who have mild-to-moderate hypoxemia (PaO2 ~ 59-65 mm Hg)1
Based on very low quality of evidence, there is some suggestion that LTOT may have a beneficial effect over time on FEV1 and PaCO2 in patients with COPD who have severe hypoxemia and heart failure: improved methods are needed.
Based on very low quality of evidence, there is no beneficial effect of LTOT on lung function or exercise factors in patients with COPD who have mild-to-moderate hypoxemia, whether survivors or nonsurvivors are assessed.
Based on low to very low quality of evidence, LTOT does not prevent readmissions in patients with COPD who have severe hypoxemia. Limited data suggest LTOT increases the risk of hospitalizations.
Limited work has been performed evaluating the safety of LTOT by severity of hypoxemia.
Based on low to very low quality of evidence, LTOT may have a beneficial effect over time on health-related quality of life in patients with COPD who have severe hypoxemia. Limited work using disease-specific instruments has been performed.
Ethical constraints of not providing LTOT to eligible patients with COPD prohibit future studies from examining LTOT outcomes in an ideal way.
PMCID: PMC3384376  PMID: 23074435

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