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February 9, 2009 (New York, New York) - Several research groups have identified new genomic markers in various cohorts that have an association--albeit small--with MI or coronary artery disease (CAD). The work appears as five papers online February 8, 2009 in Nature Genetics, and some of the discoveries are somewhat surprising, say experts.
Dr Nilesh Samani (University of Leicester, UK), who was involved in three of the papers, told heartwire: "The bottom line is that if we take this new research [on top of existing work], we now have at least 10 loci that clearly affect the risk of heart attacks and CAD. This is from a position where, two years ago, we didn't really have any loci we were completely comfortable with. And most of these are [associated with genes] we wouldn't hitherto have suspected of being involved, so this provides new evidence, new pathology, that may be involved in causing heart disease."
Dr Eric Topol (Scripps Translational Research Institute, La Jolla, CA), who was not involved in any of this new research, told heartwire: "Using various cohorts, several new genomic markers have been found without any particular theme on type of gene; the only common thread is that the effect is small: 1.1 to 1.2 odds ratio."
Haplotype Association Study Among Papers Identifying New Loci for MI/CAD
Samani was involved in the work by Dr David-Alexandre Tregouet (University Pierre and Marie Curie, Paris, France) and his team, who have discovered a new gene cluster--SLC22A3-LPAL2-LPA--as a strong susceptibility locus for CAD [1]. The novelty of this paper, says Samani, is that they used "a slightly different technique to look at the data that come out of genomewide association studies [GWAS]." Rather than looking at individual differences in DNA sequence--single nucleotide polymorphisms (SNPs)--the researchers looked at groups of SNPs that are inherited together, known as haplotypes.
"Tregouet has slowly walked across the chromosomes identifying these haplotypes to see whether the signal was better when looking at the haplotype rather than individual SNPs . . . and one region showed very strong evidence, which was apparent in the individual SNP analysis but wasn't strong enough to be definite. By analyzing it in this way [by haplotype], we found evidence that this locus is strongly associated with CAD. So the findings are twofold: first, we identified a new locus; and second, it shows we can extract more information out of GWAS by doing a slightly more sophisticated analysis," Samani asserts.
We can extract more information out of GWAS by doing a slightly more sophisticated analysis.
The second paper that Samani is involved in is by Dr Jeanette Erdmann (University of Lubeck, Germany) and colleagues, who identify a new susceptibility locus for CAD on chromosome 3q22.3 following a three-stage analysis of genomewide data in 1222 German individuals with MI and 1298 controls [2].
Samani explains: "When we did the original genomewide scans, we really looked at the low-hanging fruit--the signals that were very strong--but we knew that, because of the nature of these studies, there was a strong possibility that among the signals that were of moderate significance, there must be some that were definitely genuine. In this new Erdmann paper, we saw some signals that appeared to be stronger when we combined everything together and then took it through to replication in these populations, and we confirmed that this locus was true."
Largest GWAS for MI to Date; No Association of MI With CNVs
Samani is also involved in the international Myocardial Infarction Genetics Consortium research, a GWAS testing SNPs and copy number variants (CNVs) for association with early-onset MI in 2967 cases and 3075 controls and replicated in an independent sample of 19 492 [3].
Our study is the largest GWAS for MI conducted to date [and] the first to comprehensively test whether CNVs are associated with MI.
Corresponding author on the paper, Dr Sekar Kathiresan (Massachusetts General Hospital, Boston, MA), told heartwire: "Our study is the largest GWAS for MI conducted to date [and] the first to comprehensively test whether CNVs are associated with MI."
Kathiresan explained that CNVs are large chunks of DNA that are either deleted or duplicated, and it has been hypothesized that they might be responsible for some of the inherited component of common diseases. They found no evidence in this new study, however, that any CNVs were associated with MI.
They did find that SNPs at nine loci reached significance, three of which were new: 21q22, 6p24, and 2q33. The remaining six had previously been observed, including one at 9p21, which is recognized to be the strongest genetic predictor of early MI discovered to date.
"These nine variants in aggregate identify 20% of the population at 2.25-fold increased risk for MI," says Kathiresan.
Surprising Link Between Eosinophil Count and MI; New Data in Asian Subjects
Probably the most surprising of the new reports is from Dr David F Gudbjartsson (deCODE Genetics, Reykjavik, Iceland) and colleagues, who find a link between a high-eosinophil-count gene and MI [4]. They looked for sequence variants affecting eosinophil counts in the blood of 9392 Icelanders and, using the most significant SNPs identified, they studied them further in 12 118 Europeans and 5212 East Asians.
A variety of the SNPs were associated with asthma and one--a nonsynonymous SNP at 12q24--was significantly associated with MI in six different populations (6650 cases and 40 621 controls).
Topol says the Icelandic paper is "curious," with "the surprise link of a high-eosinophil-count gene and MI. This wasn't at all surprising for atopic asthma, but we would not have expected it to be the case for MI."
This wasn't at all surprising for atopic asthma, but we would not have expected it to be the case for MI.
Finally, Japanese researchers extend on prior work they have conducted. Dr Kouichi Ozaki (Center for Genomic Medicine, RIKEN, Yokohama, Japan) and colleagues have previously reported an association of variants in LGALS2, encoding galectin-2, with MI susceptibility in a case-control association in a Japanese population.
Now, they identify BRCA-1 associated protein (BRAP) as a galectin-2 binding protein and report an association of SNPs in BRAP with MI risk in a large Japanese cohort (OR 1.48, 2475 cases and 2778 controls), with replication in additional Japanese and Taiwanese cohorts [5].
Topol says, "This has been a very interesting series of findings from the group of Ozaki and [Dr Toshihiro] Tanaka over several years."
In conclusion, Topol says that he now believes "there are several pathways that set up a genomic susceptibility to MI. Some are ancestry-specific (such as galectin2-BRAP) and some are unanticipated (eg, eosinophilia). While we see the common phenotype of MI, [it appears] there are many ways to get there at the molecular level."
Tregouet D-A, Konig IR, Erdmann J, et al. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 2009; DOI: 10.1038/ng.314. Available at: http://www.nature.com/ng.
Erdmann J, Grosshennig A, Braund PS, et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat Genet 2009; DOI: 10.1038/ng.307. Available at: http://www.nature.com/ng.
Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 2009; DOI: 10.1038/ng.327. Available at: http://www.nature.com/ng.
Gudbjartsson DF, Bjornsdittir US, Halapi E, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 2009; DOI: 10.1038/ng.323. Available at: http://www.nature.com/ng.
Ozaki K, Sato H, Inoue K, et al. SNPs in BRAP associated with risk of myocardial infarction in Asian populations. Nat Genet 2009; DOI: 10.1038/ng.326. Available at: http://www.nature.com/ng.
Friday, February 13, 2009
Chondroitin May Act as Disease Modifier in Knee Osteoarthritis
NEW YORK (Reuters Health) Feb 09 - Long-term use of prescription-grade chondroitins 4 and 6 sulfate (CS) for treatment of knee osteoarthritis reduces pain and slows joint narrowing, investigators report in the February issue of Arthritis and Rheumatism.
The Study on Osteoarthritis Progression Prevention (STOPP) involved 622 patients in Europe and the US, ages 45-80 years, with primary knee osteoarthritis of the medial tibiofemoral compartment. Mean baseline pain scores were 57 mm on a 100-mm visual analog scale.
Patients were randomly assigned to 2 years of daily treatment with an 800-mg sachet of highly purified CS of bovine origin (n = 309) or identical placebo (n = 313). The per-protocol analysis included 206 and 217 patients, respectively. Radiographs of the target knee were obtained using the Lyon Schuss view and assessed by digital image analysis.
Structural effects and pain relief increased with time in the CS group, lead author Dr. Andre Kahan, at Cochin Hospital in Paris, and colleagues report.
The intent-to-treat analysis at 24 months showed a significantly smaller minimum joint space width loss in the CS group (-0.07 mm vs -0.31 mm; median difference 0.14 mm, p < 0.0001). The authors observed a 33% relative risk reduction for joint narrowing.
In addition, the percentage of patients with radiographic progression of less than 0.25 mm was lower in the CS group (28% vs 41% in the control group, p <0.0005).
The decrease in pain scores also favored CS, with significant differences from placebo between months 1 and 9.
The per-protocol analysis showed a median 0.20 mm difference over 24 months in minimum joint space width loss (p < 0.0001), and better global efficacy scores at 6 months (median 50 vs 35, p = 0.03) associated with CS use.
In the per protocol radiographic analysis, the number of patients needed to treat was 5. In the intent-to-treat analysis, the number needed to treat was 8.
Tolerability was deemed good or very good by more than 90% of subjects, with no significant difference between groups in the frequency of adverse events.
The authors note that because the CS used in the STOPP trial is a prescription drug, the results cannot be generalized to chondroitin products sold as dietary supplements.
"The long-term combined structure-modifying and symptom-modifying effects of CS suggest that it could be a disease-modifying agent in patients with knee osteoarthritis," Dr. Kahan and associates conclude.
The Study on Osteoarthritis Progression Prevention (STOPP) involved 622 patients in Europe and the US, ages 45-80 years, with primary knee osteoarthritis of the medial tibiofemoral compartment. Mean baseline pain scores were 57 mm on a 100-mm visual analog scale.
Patients were randomly assigned to 2 years of daily treatment with an 800-mg sachet of highly purified CS of bovine origin (n = 309) or identical placebo (n = 313). The per-protocol analysis included 206 and 217 patients, respectively. Radiographs of the target knee were obtained using the Lyon Schuss view and assessed by digital image analysis.
Structural effects and pain relief increased with time in the CS group, lead author Dr. Andre Kahan, at Cochin Hospital in Paris, and colleagues report.
The intent-to-treat analysis at 24 months showed a significantly smaller minimum joint space width loss in the CS group (-0.07 mm vs -0.31 mm; median difference 0.14 mm, p < 0.0001). The authors observed a 33% relative risk reduction for joint narrowing.
In addition, the percentage of patients with radiographic progression of less than 0.25 mm was lower in the CS group (28% vs 41% in the control group, p <0.0005).
The decrease in pain scores also favored CS, with significant differences from placebo between months 1 and 9.
The per-protocol analysis showed a median 0.20 mm difference over 24 months in minimum joint space width loss (p < 0.0001), and better global efficacy scores at 6 months (median 50 vs 35, p = 0.03) associated with CS use.
In the per protocol radiographic analysis, the number of patients needed to treat was 5. In the intent-to-treat analysis, the number needed to treat was 8.
Tolerability was deemed good or very good by more than 90% of subjects, with no significant difference between groups in the frequency of adverse events.
The authors note that because the CS used in the STOPP trial is a prescription drug, the results cannot be generalized to chondroitin products sold as dietary supplements.
"The long-term combined structure-modifying and symptom-modifying effects of CS suggest that it could be a disease-modifying agent in patients with knee osteoarthritis," Dr. Kahan and associates conclude.
Infliximab May Prevent Crohn's Disease Recurrence After Surgery
NEW YORK (Reuters Health) Feb 09 - Treatment with infliximab may help prevent endoscopic and histologic recurrence of Crohn's disease following ileal resection, according to a report in the February issue of Gastroenterology.
The results provide "a rationale for aggressive postoperative chemoprevention with biologic therapy," lead author Dr. Miguel Regueiro, from the University of Pittsburgh Medical Center, said in a statement. "We are encouraged by our findings," he added, "which warrant future study of the duration of post-operative infliximab maintenance and appropriate endoscopic follow-up."
The study featured 24 patients who were randomized to receive infliximab (5 mg/kg IV) or placebo after ileal resection, starting within 4 weeks of surgery and continued for 1 year. The main endpoint was the proportion of patients with endoscopic recurrence at 1 year.
Just 1 of 11 patients (9.1%) in the infliximab group had endoscopic recurrence, compared with 11 of 13 patients (84.6%) in the control group, the authors found (p = 0.0006).
The histologic recurrence rate at 1 year was also lower in the infliximab group: 27.3% vs. 84.6% (p = 0.01). The clinical remission rate was non-significantly higher in the infliximab group: 80.0% vs. 53.8%.
Rates of adverse events did not differ between the study groups, the authors note.
"In our practice, we now consider patients with a high risk for postoperative recurrence of Crohn's disease, such as ileal penetrating disease and recurrent resective surgery, for postoperative infliximab prophylaxis," the investigators conclude.
The results provide "a rationale for aggressive postoperative chemoprevention with biologic therapy," lead author Dr. Miguel Regueiro, from the University of Pittsburgh Medical Center, said in a statement. "We are encouraged by our findings," he added, "which warrant future study of the duration of post-operative infliximab maintenance and appropriate endoscopic follow-up."
The study featured 24 patients who were randomized to receive infliximab (5 mg/kg IV) or placebo after ileal resection, starting within 4 weeks of surgery and continued for 1 year. The main endpoint was the proportion of patients with endoscopic recurrence at 1 year.
Just 1 of 11 patients (9.1%) in the infliximab group had endoscopic recurrence, compared with 11 of 13 patients (84.6%) in the control group, the authors found (p = 0.0006).
The histologic recurrence rate at 1 year was also lower in the infliximab group: 27.3% vs. 84.6% (p = 0.01). The clinical remission rate was non-significantly higher in the infliximab group: 80.0% vs. 53.8%.
Rates of adverse events did not differ between the study groups, the authors note.
"In our practice, we now consider patients with a high risk for postoperative recurrence of Crohn's disease, such as ileal penetrating disease and recurrent resective surgery, for postoperative infliximab prophylaxis," the investigators conclude.
Lower Limb Orthotics Improve Balance and Gait After Stroke
NEW YORK (Reuters Health) Feb 09 - Ankle and foot splints can improve balance, ambulation and mobility in the immediate post-stroke period, according to British researchers.
This finding is the result of a Cochrane Review undertaken by the researchers to study the effects of upper and lower limb orthotic devices in patients with nonprogressive brain lesions. The review was published online by the Cochrane Database of Systematic Reviews on January 21 in Issue 1 for 2009.
Dr. Sarah F. Tyson of the University of Salford and Dr. Ruth M. Kent of the University of Leeds identified 14 randomized controlled trials, parallel or crossover, that compared use of an orthosis plus normal management with normal management alone, or use of an orthosis with no treatment, normal care, or placebo. The 14 trials involved 429 participants.
The British team found that the "overall effect of lower limb orthoses on walking disability (speed), walking impairment (step/stride length) and balance impairment (weight distribution in standing) was significant and beneficial."
In a press release, Dr. Tyson noted that "traditionally, physiotherapists have been reluctant to prescribe" lower limb splints to stroke patients." However, she added, "Views have been slowly shifting in the last few years."
On the other hand, the review found no effect from wrist splints on patients' ability to use the arm, range of wrist, finger or thumb motion, or pain. "This result was also surprising, as the use of orthotics to prevent contractures...is thought to be very important in restoring use of the arm after stroke," Dr. Tyson said, but she pointed out that this finding was based on only three studies.
The studies all looked only at the short-term, immediate effects of orthotics. The long-term effects - good or bad - are unknown.
Even so, Dr. Tyson told Reuters Health, "I would use an ankle-foot orthotic and I would not limit it to a specific time period at this point. I would use it for as long as (the patient) had a problem."
"The current evidence suggests that a wrist and finger orthotic is of no help to reduce pain, limit flexibility or reduce contractures at the wrist, fingers or thumb to promote movement in the hand and use of the arm," Dr. Tyson added. "Further research needs to be done to establish whether they are of any use at all."
This finding is the result of a Cochrane Review undertaken by the researchers to study the effects of upper and lower limb orthotic devices in patients with nonprogressive brain lesions. The review was published online by the Cochrane Database of Systematic Reviews on January 21 in Issue 1 for 2009.
Dr. Sarah F. Tyson of the University of Salford and Dr. Ruth M. Kent of the University of Leeds identified 14 randomized controlled trials, parallel or crossover, that compared use of an orthosis plus normal management with normal management alone, or use of an orthosis with no treatment, normal care, or placebo. The 14 trials involved 429 participants.
The British team found that the "overall effect of lower limb orthoses on walking disability (speed), walking impairment (step/stride length) and balance impairment (weight distribution in standing) was significant and beneficial."
In a press release, Dr. Tyson noted that "traditionally, physiotherapists have been reluctant to prescribe" lower limb splints to stroke patients." However, she added, "Views have been slowly shifting in the last few years."
On the other hand, the review found no effect from wrist splints on patients' ability to use the arm, range of wrist, finger or thumb motion, or pain. "This result was also surprising, as the use of orthotics to prevent contractures...is thought to be very important in restoring use of the arm after stroke," Dr. Tyson said, but she pointed out that this finding was based on only three studies.
The studies all looked only at the short-term, immediate effects of orthotics. The long-term effects - good or bad - are unknown.
Even so, Dr. Tyson told Reuters Health, "I would use an ankle-foot orthotic and I would not limit it to a specific time period at this point. I would use it for as long as (the patient) had a problem."
"The current evidence suggests that a wrist and finger orthotic is of no help to reduce pain, limit flexibility or reduce contractures at the wrist, fingers or thumb to promote movement in the hand and use of the arm," Dr. Tyson added. "Further research needs to be done to establish whether they are of any use at all."
Multivitamin Use: No Effect on Cancers or CVD in Women
February 10, 2009 (Seattle, Washington) — Multivitamin use has no influence on the risk of common cancers, cardiovascular disease, or overall mortality, according to a new analysis of more than 160 000 women participating in the Women's Health Initiative (WHI) clinical trials [1]. Dr Marian L Neuhouser (Fred Hutchinson Cancer Research Center, Seattle, WA) and colleagues report their findings in the February 9, 2009 issue of the Archives of Internal Medicine.
"The main message of our study is that postmenopausal women who take a multivitamin don't increase their risk for cancer or cardiovascular disease, but they don't decrease it either," Neuhouser told heartwire. "These multivitamins are having no effect with regard to these particular disease outcomes."
"Consumers need to decide if they want to continue this practice if they are taking [multivitamins] in order to prevent getting cancer or CVD," she added. "There may be other preventive practices that are better than taking a vitamin supplement, and their money is probably better spent on buying fruit and vegetables or increasing physical activity."
"These Pills Are of Little Value"
The study included 161 808 participants from the WHI; detailed data were collected on multivitamin use at baseline and follow-up time points, with enrollment occurring between 1993 and 1998 and a median follow-up period of around eight years. Nearly half of the participants (41.5%) reported using multivitamins on a regular basis.
Disease end points were collected through 2005 and included cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary, and lung; CVD (myocardial infarction, stroke, and venous thromboembolism); and total mortality.
Over the follow-up period, there were 9619 cases of cancer, 8751 CVD events, and 9865 deaths reported. Multivariate adjusted analyses revealed no association of multivitamin use with risk of any cancer (hazard ratio, 0.98), CVD (HR, 0.96), or total mortality (HR, 1.02).
Neuhouser said there was no particular positive (or negative) trend for any individual cancer or CVD end point, with the exception of "a slightly decreased risk for MI in those who took stress multivitamins--the ones that have high doses of B vitamins, vitamin C, zinc, and selenium--but because there were so few cases in this group, only 64 MIs among all these women, it's a little bit hard to draw a firm conclusion, so we didn't want to draw particular attention to this," she noted.
"The evidence is accumulating that these are pills of little value," she said, referring to recent neutral results from trials with multivitamins in men--the US-based SELECT trial and the Physician's Health Study 2--that were not available when her manuscript was submitted.
No Policing of the Supplements Industry
Neuhouser also criticizes the deregulation of the supplement industry that occurred in the US in the early 1990s with the introduction of the Dietary Supplement and Health Education Act. "The FDA has a small amount of jurisdiction, but it's an unfunded mandate and their meager budget means they don't really have any policing power over this," she noted.
"We have entire aisles in our grocery stores, with all kinds of vitamins, minerals, and so forth. Some are generic or store brand and so not that expensive, but some are extremely expensive. I hate to have consumers spending money on something that may not help them at all, when they could probably better spend it on healthy foods," she concluded.
"The main message of our study is that postmenopausal women who take a multivitamin don't increase their risk for cancer or cardiovascular disease, but they don't decrease it either," Neuhouser told heartwire. "These multivitamins are having no effect with regard to these particular disease outcomes."
"Consumers need to decide if they want to continue this practice if they are taking [multivitamins] in order to prevent getting cancer or CVD," she added. "There may be other preventive practices that are better than taking a vitamin supplement, and their money is probably better spent on buying fruit and vegetables or increasing physical activity."
"These Pills Are of Little Value"
The study included 161 808 participants from the WHI; detailed data were collected on multivitamin use at baseline and follow-up time points, with enrollment occurring between 1993 and 1998 and a median follow-up period of around eight years. Nearly half of the participants (41.5%) reported using multivitamins on a regular basis.
Disease end points were collected through 2005 and included cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary, and lung; CVD (myocardial infarction, stroke, and venous thromboembolism); and total mortality.
Over the follow-up period, there were 9619 cases of cancer, 8751 CVD events, and 9865 deaths reported. Multivariate adjusted analyses revealed no association of multivitamin use with risk of any cancer (hazard ratio, 0.98), CVD (HR, 0.96), or total mortality (HR, 1.02).
Neuhouser said there was no particular positive (or negative) trend for any individual cancer or CVD end point, with the exception of "a slightly decreased risk for MI in those who took stress multivitamins--the ones that have high doses of B vitamins, vitamin C, zinc, and selenium--but because there were so few cases in this group, only 64 MIs among all these women, it's a little bit hard to draw a firm conclusion, so we didn't want to draw particular attention to this," she noted.
"The evidence is accumulating that these are pills of little value," she said, referring to recent neutral results from trials with multivitamins in men--the US-based SELECT trial and the Physician's Health Study 2--that were not available when her manuscript was submitted.
No Policing of the Supplements Industry
Neuhouser also criticizes the deregulation of the supplement industry that occurred in the US in the early 1990s with the introduction of the Dietary Supplement and Health Education Act. "The FDA has a small amount of jurisdiction, but it's an unfunded mandate and their meager budget means they don't really have any policing power over this," she noted.
"We have entire aisles in our grocery stores, with all kinds of vitamins, minerals, and so forth. Some are generic or store brand and so not that expensive, but some are extremely expensive. I hate to have consumers spending money on something that may not help them at all, when they could probably better spend it on healthy foods," she concluded.
Lower Sedation, Frequent Wakening of ICU Patients Minimizes Long-Term Cognitive Impairment
February 3, 2009 (Nashville, Tennessee) — Late-breaking results of the Awakening and Breathing Controlled (ABC) trial, presented here at the Society of Critical Care Medicine 38th Critical Care Congress, show that cognitive function is better if the patient is wakened early and frequently during a stay in the intensive care unit (ICU).
"The thinking has been that if the patient is heavily sedated, then he [or she] won't remember the experience and that will be less traumatized. In fact, it appears that the opposite is true," James C. Jackson, PsyD, of the ICU Delirium and Cognitive Impairment Study Group of the Vanderbilt Center for Health Services Research, in Nashville, Tennessee, told meeting attendees as he presented the findings of the ABC trial.
The ABC trial involved 93 ICU patients randomized to daily attempts to halt sedation (spontaneous awakening trials, or SAT) combined with daily assessments of patients while they are breathing on their own (spontaneous breathing trials, or SBT, also called the wake-up-and-breathe protocol) and 94 patients randomized to a control group undergoing daily spontaneous wakening and usual care.
Baseline characteristics and severity of illness were similar in the 2 groups. Cognitive function, posttraumatic stress disorder (PTSD), and depression were assessed at discharge, and at 3 months and 12 months after discharge.
"We conducted a full neuropsychological battery, including a range of memory types," Dr. Jackson explained. Cognitive performance was scored on a 4-point scale, with 0 for no impairment, 1 for mild-to-moderate impairment, 2 for severe cognitive dysfunction, and 3 for death.
Median number of ventilation-free days in the hospital was 15 in the study group and 12 in the control group. Median number of days to ICU discharge was 9 in the study group and 13 in the control group. Days to hospital discharge was 15 in the study group and 19 in the control group.
There was no difference between the 2 groups in incidence of PTSD, but there were few cases, overall. There was no difference in the incidence of depression, but the incidence was high in both groups, ranging from 50% to 60% at 12 months, Dr. Jackson reported.
"ABC was associated with improved cognitive function at all time points compared with controls, and the difference was statistically significant at all time points," he announced.
The odds ratio was 2.13 for good long-term cognitive function with SAT-SBT, compared with SAT and usual care (P = .01).
"This is the first direct evidence that intervention [and early arousal] significantly improves neurological outcome at 1 year and that prolonged sedation is independently associated with impaired brain function . . ., with impairment seen in the avoidance domain, primarily . . . . These patients really don't want to go back to the hospital," Dr. Jackson told Medscape Critical Care.
There is a strong association between heavy sedation and an increased risk of delirium," Richard R. Riker, MD, director of critical care research at Maine Medical Center, in Portland, said in an interview after Dr. Jackson's presentation.
"Delirium appears to be an independent factor for an adverse outcome," Dr. Riker said. "We don't know the reason behind that at this point. We do know that infection rates are 2-fold higher if delirium is present . . . . There may be a neutropenic effect somehow involved."
"The culture of the ICU should change," Dr. Jackson added. "The concept of keeping the patient down should be considered an antiquated concept."
Dr. Riker receives support from Aspect Medical Systems Inc., AstraZeneca, Eli Lilly, Hospira, and Takeda. Dr. Jackson has disclosed no relevant financial relationships
"The thinking has been that if the patient is heavily sedated, then he [or she] won't remember the experience and that will be less traumatized. In fact, it appears that the opposite is true," James C. Jackson, PsyD, of the ICU Delirium and Cognitive Impairment Study Group of the Vanderbilt Center for Health Services Research, in Nashville, Tennessee, told meeting attendees as he presented the findings of the ABC trial.
The ABC trial involved 93 ICU patients randomized to daily attempts to halt sedation (spontaneous awakening trials, or SAT) combined with daily assessments of patients while they are breathing on their own (spontaneous breathing trials, or SBT, also called the wake-up-and-breathe protocol) and 94 patients randomized to a control group undergoing daily spontaneous wakening and usual care.
Baseline characteristics and severity of illness were similar in the 2 groups. Cognitive function, posttraumatic stress disorder (PTSD), and depression were assessed at discharge, and at 3 months and 12 months after discharge.
"We conducted a full neuropsychological battery, including a range of memory types," Dr. Jackson explained. Cognitive performance was scored on a 4-point scale, with 0 for no impairment, 1 for mild-to-moderate impairment, 2 for severe cognitive dysfunction, and 3 for death.
Median number of ventilation-free days in the hospital was 15 in the study group and 12 in the control group. Median number of days to ICU discharge was 9 in the study group and 13 in the control group. Days to hospital discharge was 15 in the study group and 19 in the control group.
There was no difference between the 2 groups in incidence of PTSD, but there were few cases, overall. There was no difference in the incidence of depression, but the incidence was high in both groups, ranging from 50% to 60% at 12 months, Dr. Jackson reported.
"ABC was associated with improved cognitive function at all time points compared with controls, and the difference was statistically significant at all time points," he announced.
The odds ratio was 2.13 for good long-term cognitive function with SAT-SBT, compared with SAT and usual care (P = .01).
"This is the first direct evidence that intervention [and early arousal] significantly improves neurological outcome at 1 year and that prolonged sedation is independently associated with impaired brain function . . ., with impairment seen in the avoidance domain, primarily . . . . These patients really don't want to go back to the hospital," Dr. Jackson told Medscape Critical Care.
There is a strong association between heavy sedation and an increased risk of delirium," Richard R. Riker, MD, director of critical care research at Maine Medical Center, in Portland, said in an interview after Dr. Jackson's presentation.
"Delirium appears to be an independent factor for an adverse outcome," Dr. Riker said. "We don't know the reason behind that at this point. We do know that infection rates are 2-fold higher if delirium is present . . . . There may be a neutropenic effect somehow involved."
"The culture of the ICU should change," Dr. Jackson added. "The concept of keeping the patient down should be considered an antiquated concept."
Dr. Riker receives support from Aspect Medical Systems Inc., AstraZeneca, Eli Lilly, Hospira, and Takeda. Dr. Jackson has disclosed no relevant financial relationships
High-Dose Statins Reduce Mortality in Sepsis Patients
February 4, 2009 (Nashville, Tennessee) — Current use of moderate to high doses of statins for patients hospitalized with sepsis was associated with a mortality risk reduction of more than 20%, compared with patients not taking statins, investigators reported here at the Society of Critical Care Medicine 38th Critical Care Congress.
Results of a retrospective review of 25,587 patients 50 years and older who were hospitalized with sepsis between 1999 and 2004 were presented by Ahmed I. Shah, MD, from the Department of Cardiology at Kaiser Permanente Los Angeles Medical Center, in California. The group was approximately half men and half women, and the mean age was 72 years.
Dr. Shah's team divided patients into 3 groups, according to statin use: current users, who were taking a statin before and on the day of hospitalization; remote users, who had taken a statin 2 or more months before hospitalization, but not afterward; and never users, who had not taken a statin for at least 1 year before admission.
Current users were divided into a low-dose group and a high-dose group. Low dose was defined as lovastatin 40 mg or less daily, simvastatin 10 mg or less daily, and atorvastatin 10 mg or less daily.
Of the cohort, 70% were never users, 11% were remote users, and 19% were current users. Of the current users, approximately half were on low doses and half were on moderate to high doses. Current users were more severely ill and had more comorbidities than never users.
Patients were followed for up to 12 months after admission or until death. Twelve-month mortality rates were calculated.
The adjusted hazard ratios for all-cause mortality were:
0.83 (0.76–0.91; P < .0001) for current users vs never users;
0.76 (0.72–0.81; P < .0001) for current users vs remote users;
0.87 (0.79–0.96; P < .009) for low-dose users vs never users;
0.79 (0.72–0.88; P < .0001) for high-dose users vs never users; and
0.90 (0.83–0.99; P < .03) for high-dose vs low-dose users.
"In hospitalized septic patients, current high-dose statin use is associated with a statistically significantly lower rate of 1-year mortality," Dr. Shah told meeting attendees. However, he emphasized that this was a retrospective review and not a prospective interventional study.
"This has become a very hot area for research over the past 5 to 6 years, but most of the data are like this," Robert Duncan Hite, MD, FCCP, associate professor of medicine and director of the Medical Intensive Care and Critical Care Research Section on Pulmonary, Critical Care, Allergy and Immunologic Disease at Wake Forest University School of Medicine, in Winston-Salem, North Carolina, told Medscape Critical Care in an interview after Dr. Shah's presentation.
These are "retrospective analyses of large databases in which the use of statins is examined but cannot be controlled for other important variables that might explain differences in outcomes," Dr. Hite said.
"There are several prospective, randomized, blinded trials currently ongoing around the world. Even once those [results] are available, and assuming they prove to be successful, we will still not know whether all statins [are] of equal benefit and what the optimal dose is," he pointed out. "Since statins are not without toxicity and little is known about the metabolism of statins in sepsis, dosing will have to be considered carefully."
Dr. Hite concluded: "For now, I would not recommend that statins be initiated in a septic patient, but it is reasonable to continue statins in a septic patient previously taking a statin. This is a change that I and many others have made in their practice over the past few years as a result of data similar to the data provided by this study.
Drs. Shah and Hite have disclosed no relevant financial relationships.
Results of a retrospective review of 25,587 patients 50 years and older who were hospitalized with sepsis between 1999 and 2004 were presented by Ahmed I. Shah, MD, from the Department of Cardiology at Kaiser Permanente Los Angeles Medical Center, in California. The group was approximately half men and half women, and the mean age was 72 years.
Dr. Shah's team divided patients into 3 groups, according to statin use: current users, who were taking a statin before and on the day of hospitalization; remote users, who had taken a statin 2 or more months before hospitalization, but not afterward; and never users, who had not taken a statin for at least 1 year before admission.
Current users were divided into a low-dose group and a high-dose group. Low dose was defined as lovastatin 40 mg or less daily, simvastatin 10 mg or less daily, and atorvastatin 10 mg or less daily.
Of the cohort, 70% were never users, 11% were remote users, and 19% were current users. Of the current users, approximately half were on low doses and half were on moderate to high doses. Current users were more severely ill and had more comorbidities than never users.
Patients were followed for up to 12 months after admission or until death. Twelve-month mortality rates were calculated.
The adjusted hazard ratios for all-cause mortality were:
0.83 (0.76–0.91; P < .0001) for current users vs never users;
0.76 (0.72–0.81; P < .0001) for current users vs remote users;
0.87 (0.79–0.96; P < .009) for low-dose users vs never users;
0.79 (0.72–0.88; P < .0001) for high-dose users vs never users; and
0.90 (0.83–0.99; P < .03) for high-dose vs low-dose users.
"In hospitalized septic patients, current high-dose statin use is associated with a statistically significantly lower rate of 1-year mortality," Dr. Shah told meeting attendees. However, he emphasized that this was a retrospective review and not a prospective interventional study.
"This has become a very hot area for research over the past 5 to 6 years, but most of the data are like this," Robert Duncan Hite, MD, FCCP, associate professor of medicine and director of the Medical Intensive Care and Critical Care Research Section on Pulmonary, Critical Care, Allergy and Immunologic Disease at Wake Forest University School of Medicine, in Winston-Salem, North Carolina, told Medscape Critical Care in an interview after Dr. Shah's presentation.
These are "retrospective analyses of large databases in which the use of statins is examined but cannot be controlled for other important variables that might explain differences in outcomes," Dr. Hite said.
"There are several prospective, randomized, blinded trials currently ongoing around the world. Even once those [results] are available, and assuming they prove to be successful, we will still not know whether all statins [are] of equal benefit and what the optimal dose is," he pointed out. "Since statins are not without toxicity and little is known about the metabolism of statins in sepsis, dosing will have to be considered carefully."
Dr. Hite concluded: "For now, I would not recommend that statins be initiated in a septic patient, but it is reasonable to continue statins in a septic patient previously taking a statin. This is a change that I and many others have made in their practice over the past few years as a result of data similar to the data provided by this study.
Drs. Shah and Hite have disclosed no relevant financial relationships.
Non-Smokers Are More Prone to Pulmonary Oedema Than Smokers During Acute Coronary Syndrome
Introduction:
Patients of acute coronary syndrome (ACS) often get admitted in the coronary care unit (CCU) with varied degree of left ventricle dysfunction, low cardiac output, low tissue perfusion and cardiogenic shock. These patients are thus vulnerable to develop backpressure changes on pulmonary bed presenting as the pulmonary oedema[1-3] and the associated ventilation perfusion mismatch.[4,5] These changes predispose patients to varied degree of hypoxaemia, metabolic acidosis and the compensatory respiratory alkalosis.[6] These factors together are likely to cast changes in the arterial blood gas (ABG) depending upon the extent of cardiac insult and the compensatory response. As smoking is a predisposing factor to coronary artery disease,[7] a significant number of ACS patients might be chronic smokers as well. Short-term better outcome of active smokers 'smokers paradox' during ACS has been reported.[8,9] Based on the data of national registry, the paradox was correlated with younger age, more men smokers and with fewer cardiovascular risk factors such as hypertension or diabetes.[8,9] However, the phenomenon was not fully explained by the measured covariates. Chronic smoking is associated with airway-alveolar changes in smokers[10] than in the non-smoker. We hypothesise that the smoking related lung changes might show different clinical presentation during ACS than that of non-smoker. As we have not come across any such report after extensive literature search, we prospectively compared clinical presentation of ACS patients in terms of being chronic smoker or the non-smokers.
Patients included were aged from 48 to 82 years (median 60 years). Patients in two study groups were demographically similar in terms of their age, gender, distribution, weight, height and body surface area . The non-smoker patients (group 1) had significantly (p <> 0.05). However, non-smokers (group 1) had significant (p < 0.01) tachycardia (101 ± 26 bpm) and the lower urine output at similar creatinine levels than the smokers (group 2) .
In the background of maintaining target SpO2 (≥ 95%) by oxygen inhalation and active respiratory support, the difference between PaO2 in two groups was statistically insignificant (p > 0.05), but the calculated PaO2/FiO2 ratio (201 ± 44) in non-smokers was significantly (p < 0.0001) lower than in the smokers (296 ± 110). Although blood pH was normal in both the groups, the significant (p < 0.001) metabolic acidosis (bicarbonate; 19 ± 4.3 mmol/l, base deficit; -5.1 ± 4.8, and higher lactate; 2.1 ± 0.72 mmol/l) was noteworthy amongst non-smokers with compensatory hypocarbia (28 ± 2.9 mmHg) than the smokers (PaCO2- 38 ± 5.7 mmHg and HCO3- 24 ± 4.9 mmol/l) . Incidence of active respiratory support (29%) and inotropes used (32%) was significantly lower in smokers (group 2) than in non-smokers (group 1) during ACS. Although the in-hospital mortality was higher in non-smokers (21%) than in the smokers (11%), the difference could not attain statistical significance .
The post hoc analysis for observed difference between the mean values of PaO2/FiO2 in two groups for the small sample size revealed power (1-beta) 99% for the two tailed α-probability (0.05) and the power of observed difference in rate of respiratory support for the two groups was 93% at alpha error probability 80% for the sample size in our study.
Discussion:
The present study demonstrates that during similar degree of ACS, the non-smoker patients developed higher degree of pulmonary oedema (higher chest x-ray score, AaDpO2 and lower PaO2/FiO2), metabolic acidosis (higher lactate levels and base deficit) with compensatory hypocarbia than the smokers. Risk estimates suggested that the non-smokers were three times more at risk for active respiratory support to maintain SpO2 > 95% and the inotropes to maintain mean arterial pressure (MAP) ≥ 60 mmHg than the smokers during ACS.
Normally, there is continuous exchange of liquid, colloid and solutes between the vascular bed and interstitium.[13,14] Studies have shown that during ACS, patients develop depressed myocardial contractility with segmental motion abnormalities[2,15] and the back pressure effect on lung vasculature.[3] The increased left atrial pressure model for cardiogenic oedema on rat demonstrated increased fluid flux from the lung vasculature with decreased reabsorption[16] thus predisposing patients to pulmonary oedema during ACS. Lymphatic drainage plays a significant role to control extracellular fluid accumulation.[17] Pulmonary oedema, however, will develop once the lymphatic drainage is overwhelmed by the fluid accumulation in the interstitial compartment and the alveoli.[18,19] A redistribution of the pulmonary flow with prominent pulmonary vasculature in upper lobes of the lungs with increasing left atrium (LA) pressure and the pulmonary oedema is reported approximately at 22-25 mmHg of wedge pressure.[16] Chest x-ray score has a strong correlation between the extravascular lung water and the left ventricular dynamics after MI.[4,18-21] Although we did not measure LA pressure, we observed higher chest x-ray scores and hypoxaemia in our patients during ACS. However, the chest x-ray scores being higher in non-smokers suggested a higher degree of pulmonary oedema in non-smokers than in the smokers during similar degree of cardiac insult.
Besides backpressure changes during ACS, the anatomical shape of alveoli also plays an important role in the accumulation of liquid in alveoli. The small radius of curvature at the corners puts-in greater local recoil pressure and more negative interstitial pressure than at the greater radii of curvature of alveoli. The resultant readily transfer of liquid at the junctions of smaller radii alveoli and the compliant loose interstitial space will favour fluid accumulation in normal lungs of non-smokers[22] and the oedema. The oedema in due course will result in hypoxaemia, associated poor tissue oxygen delivery, lactic acidosis and the compensatory hypocapnoea. As hypocapnoea per se is also reported to be injurious to the lungs,[23] non-smokers with significant hypocapnoea than smokers during ACS will perpetuate more to the lung injury and the extra lung water accumulation than the smokers, who had hypercarbia. The hypercarbia in smokers is related to lung changes affecting gas exchange because of gas trapping, mismatched ventilation perfusion with large areas of dead space ventilation and inefficient carbon dioxide elimination.[24]
Chronic smoking, associated with loss of alveolar shape and size because of fibrosis, shall make these patients less prone to accumulate fluid in interstitial compartment and the alveoli. These alveolar changes in turn shall also distort parenchymal vasculature and sequel pulmonary hypertension,[25] in turn stimulating lymphatic drainage and the greater tolerance for higher pulmonary artery (PA) pressure and decreased lung water accumulation. The Smokers are reported with reduced diffusing capacity of the lung for carbon monoxide (Dlco)[26] as a result of the loss of alveolar-capillary surface area[27] and the reduced expiratory flow, particularly at these low lung volumes, reduces the breathing reserve to make them vulnerable for hypoxaemia and hypercarbia. However, the hypoxaemia in smokers is exquisitely sensitive to low concentrations of oxygen supplementation.[24] We too found a significantly higher arterial oxygen levels in smokers on oxygen supplementation than in non-smokers.
It has also been reported that the functional residual capacity is reduced during ACS, and the closing capacity moves higher into the tidal volume range leading to larger low (V/Q) regions and hypoxaemia, despite no change in closing volume.[5] So, both smokers and non-smokers are vulnerable to develop hypoxaemia, but improvement was more in smokers on O2 inhalation than in non-smokers. Thus, the existing literature formed a basis to explain the observed higher degree of pulmonary oedema in non-smokers than in the smokers during ACS.
Although the number of patients in this cohort was small, it has prospectively analysed the observations in the randomly selected patients and the post hoc power analysis revealed 99% power for the detected difference in hypoxaemia. Besides smaller size, the in-hospital mortality was also higher in our patients than the advanced centres and it could be related to the lack of advanced investigative and therapeutic modalities such as coronary angiography and the angioplasty to match the treatment profile. However, for a similar kind of therapeutic facilities and protocol, the lower mortality in smokers than in the non-smokers was significant and comparable with the studies reporting 'smoker's paradox' for the in-hospital mortality for the comparable age group.[8]
The role of smoking in the short-term prognosis is still not very clear and some investigators have shown that the habitual smokers suffering from ACS tend to be younger, male, with less diffuse coronary artery disease and the fewer comorbidities compared with non-smokers.[8,28,29] In our study also, the smokers were predominantly male but did not differ significantly in terms of age (smokers - 62 ± 11.1 years vs. non-smokers - 63 ± 11.0 years) or the comorbidities. All large-scale randomised trials powered to detect significant differences because of the large number of the participants have failed to address the reason for the smoker's paradox. However, we are able to demonstrate a phenomenon not studied so far could also be an added significant factor for the reported 'smoker's paradox'. As we did not measure pulmonary artery wedge pressure and the prior to ACS lung function test reports were not available in first time admitted patients or patients were incapable of performing lung function test in CCU, it should taken as the limitation in our study. In our cohort, some of the observation like tachycardia in non-smokers was related to the frequent need of inotropes in non-smokers than in smokers. Our observation of higher haematocrit in smokers is related to hypercarbic state in these patients.
In summary, the term 'smoker's paradox' for better early outcome in cigarette smoking patients during ACS does not seem to be fully justifying, as smoking predisposes patients to hypercoagulable state, impaired endothelium-dependent dilatation[30] and excessive catecholamine secretion induced life threatening cardiac arrhythmias.[31] It can lead to a misunderstanding by the public for smoking. In the wake of observed greater risk of pulmonary oedema in non-smokers, our conclusion stands that an early active respiratory support in non-smokers presenting with ACS. To fully understand the outcome of this study, a detailed physiological study on gas exchange needed to be performed.
Patients of acute coronary syndrome (ACS) often get admitted in the coronary care unit (CCU) with varied degree of left ventricle dysfunction, low cardiac output, low tissue perfusion and cardiogenic shock. These patients are thus vulnerable to develop backpressure changes on pulmonary bed presenting as the pulmonary oedema[1-3] and the associated ventilation perfusion mismatch.[4,5] These changes predispose patients to varied degree of hypoxaemia, metabolic acidosis and the compensatory respiratory alkalosis.[6] These factors together are likely to cast changes in the arterial blood gas (ABG) depending upon the extent of cardiac insult and the compensatory response. As smoking is a predisposing factor to coronary artery disease,[7] a significant number of ACS patients might be chronic smokers as well. Short-term better outcome of active smokers 'smokers paradox' during ACS has been reported.[8,9] Based on the data of national registry, the paradox was correlated with younger age, more men smokers and with fewer cardiovascular risk factors such as hypertension or diabetes.[8,9] However, the phenomenon was not fully explained by the measured covariates. Chronic smoking is associated with airway-alveolar changes in smokers[10] than in the non-smoker. We hypothesise that the smoking related lung changes might show different clinical presentation during ACS than that of non-smoker. As we have not come across any such report after extensive literature search, we prospectively compared clinical presentation of ACS patients in terms of being chronic smoker or the non-smokers.
Patients included were aged from 48 to 82 years (median 60 years). Patients in two study groups were demographically similar in terms of their age, gender, distribution, weight, height and body surface area . The non-smoker patients (group 1) had significantly (p <> 0.05). However, non-smokers (group 1) had significant (p < 0.01) tachycardia (101 ± 26 bpm) and the lower urine output at similar creatinine levels than the smokers (group 2) .
In the background of maintaining target SpO2 (≥ 95%) by oxygen inhalation and active respiratory support, the difference between PaO2 in two groups was statistically insignificant (p > 0.05), but the calculated PaO2/FiO2 ratio (201 ± 44) in non-smokers was significantly (p < 0.0001) lower than in the smokers (296 ± 110). Although blood pH was normal in both the groups, the significant (p < 0.001) metabolic acidosis (bicarbonate; 19 ± 4.3 mmol/l, base deficit; -5.1 ± 4.8, and higher lactate; 2.1 ± 0.72 mmol/l) was noteworthy amongst non-smokers with compensatory hypocarbia (28 ± 2.9 mmHg) than the smokers (PaCO2- 38 ± 5.7 mmHg and HCO3- 24 ± 4.9 mmol/l) . Incidence of active respiratory support (29%) and inotropes used (32%) was significantly lower in smokers (group 2) than in non-smokers (group 1) during ACS. Although the in-hospital mortality was higher in non-smokers (21%) than in the smokers (11%), the difference could not attain statistical significance .
The post hoc analysis for observed difference between the mean values of PaO2/FiO2 in two groups for the small sample size revealed power (1-beta) 99% for the two tailed α-probability (0.05) and the power of observed difference in rate of respiratory support for the two groups was 93% at alpha error probability 80% for the sample size in our study.
Discussion:
The present study demonstrates that during similar degree of ACS, the non-smoker patients developed higher degree of pulmonary oedema (higher chest x-ray score, AaDpO2 and lower PaO2/FiO2), metabolic acidosis (higher lactate levels and base deficit) with compensatory hypocarbia than the smokers. Risk estimates suggested that the non-smokers were three times more at risk for active respiratory support to maintain SpO2 > 95% and the inotropes to maintain mean arterial pressure (MAP) ≥ 60 mmHg than the smokers during ACS.
Normally, there is continuous exchange of liquid, colloid and solutes between the vascular bed and interstitium.[13,14] Studies have shown that during ACS, patients develop depressed myocardial contractility with segmental motion abnormalities[2,15] and the back pressure effect on lung vasculature.[3] The increased left atrial pressure model for cardiogenic oedema on rat demonstrated increased fluid flux from the lung vasculature with decreased reabsorption[16] thus predisposing patients to pulmonary oedema during ACS. Lymphatic drainage plays a significant role to control extracellular fluid accumulation.[17] Pulmonary oedema, however, will develop once the lymphatic drainage is overwhelmed by the fluid accumulation in the interstitial compartment and the alveoli.[18,19] A redistribution of the pulmonary flow with prominent pulmonary vasculature in upper lobes of the lungs with increasing left atrium (LA) pressure and the pulmonary oedema is reported approximately at 22-25 mmHg of wedge pressure.[16] Chest x-ray score has a strong correlation between the extravascular lung water and the left ventricular dynamics after MI.[4,18-21] Although we did not measure LA pressure, we observed higher chest x-ray scores and hypoxaemia in our patients during ACS. However, the chest x-ray scores being higher in non-smokers suggested a higher degree of pulmonary oedema in non-smokers than in the smokers during similar degree of cardiac insult.
Besides backpressure changes during ACS, the anatomical shape of alveoli also plays an important role in the accumulation of liquid in alveoli. The small radius of curvature at the corners puts-in greater local recoil pressure and more negative interstitial pressure than at the greater radii of curvature of alveoli. The resultant readily transfer of liquid at the junctions of smaller radii alveoli and the compliant loose interstitial space will favour fluid accumulation in normal lungs of non-smokers[22] and the oedema. The oedema in due course will result in hypoxaemia, associated poor tissue oxygen delivery, lactic acidosis and the compensatory hypocapnoea. As hypocapnoea per se is also reported to be injurious to the lungs,[23] non-smokers with significant hypocapnoea than smokers during ACS will perpetuate more to the lung injury and the extra lung water accumulation than the smokers, who had hypercarbia. The hypercarbia in smokers is related to lung changes affecting gas exchange because of gas trapping, mismatched ventilation perfusion with large areas of dead space ventilation and inefficient carbon dioxide elimination.[24]
Chronic smoking, associated with loss of alveolar shape and size because of fibrosis, shall make these patients less prone to accumulate fluid in interstitial compartment and the alveoli. These alveolar changes in turn shall also distort parenchymal vasculature and sequel pulmonary hypertension,[25] in turn stimulating lymphatic drainage and the greater tolerance for higher pulmonary artery (PA) pressure and decreased lung water accumulation. The Smokers are reported with reduced diffusing capacity of the lung for carbon monoxide (Dlco)[26] as a result of the loss of alveolar-capillary surface area[27] and the reduced expiratory flow, particularly at these low lung volumes, reduces the breathing reserve to make them vulnerable for hypoxaemia and hypercarbia. However, the hypoxaemia in smokers is exquisitely sensitive to low concentrations of oxygen supplementation.[24] We too found a significantly higher arterial oxygen levels in smokers on oxygen supplementation than in non-smokers.
It has also been reported that the functional residual capacity is reduced during ACS, and the closing capacity moves higher into the tidal volume range leading to larger low (V/Q) regions and hypoxaemia, despite no change in closing volume.[5] So, both smokers and non-smokers are vulnerable to develop hypoxaemia, but improvement was more in smokers on O2 inhalation than in non-smokers. Thus, the existing literature formed a basis to explain the observed higher degree of pulmonary oedema in non-smokers than in the smokers during ACS.
Although the number of patients in this cohort was small, it has prospectively analysed the observations in the randomly selected patients and the post hoc power analysis revealed 99% power for the detected difference in hypoxaemia. Besides smaller size, the in-hospital mortality was also higher in our patients than the advanced centres and it could be related to the lack of advanced investigative and therapeutic modalities such as coronary angiography and the angioplasty to match the treatment profile. However, for a similar kind of therapeutic facilities and protocol, the lower mortality in smokers than in the non-smokers was significant and comparable with the studies reporting 'smoker's paradox' for the in-hospital mortality for the comparable age group.[8]
The role of smoking in the short-term prognosis is still not very clear and some investigators have shown that the habitual smokers suffering from ACS tend to be younger, male, with less diffuse coronary artery disease and the fewer comorbidities compared with non-smokers.[8,28,29] In our study also, the smokers were predominantly male but did not differ significantly in terms of age (smokers - 62 ± 11.1 years vs. non-smokers - 63 ± 11.0 years) or the comorbidities. All large-scale randomised trials powered to detect significant differences because of the large number of the participants have failed to address the reason for the smoker's paradox. However, we are able to demonstrate a phenomenon not studied so far could also be an added significant factor for the reported 'smoker's paradox'. As we did not measure pulmonary artery wedge pressure and the prior to ACS lung function test reports were not available in first time admitted patients or patients were incapable of performing lung function test in CCU, it should taken as the limitation in our study. In our cohort, some of the observation like tachycardia in non-smokers was related to the frequent need of inotropes in non-smokers than in smokers. Our observation of higher haematocrit in smokers is related to hypercarbic state in these patients.
In summary, the term 'smoker's paradox' for better early outcome in cigarette smoking patients during ACS does not seem to be fully justifying, as smoking predisposes patients to hypercoagulable state, impaired endothelium-dependent dilatation[30] and excessive catecholamine secretion induced life threatening cardiac arrhythmias.[31] It can lead to a misunderstanding by the public for smoking. In the wake of observed greater risk of pulmonary oedema in non-smokers, our conclusion stands that an early active respiratory support in non-smokers presenting with ACS. To fully understand the outcome of this study, a detailed physiological study on gas exchange needed to be performed.
oral care reduce the ventilator associated pneumonia
Ventilator-associated pneumonia (VAP) is a preventable secondary consequence of intubation and mechanical ventilation. VAP is pneumonia that develops in an intubated patient after 48 hours or more of mechanical ventilator support. Mechanically ventilated patients in neurologic and other intensive care units (ICUs) are at an increased risk of VAP due to factors such as decreased level of consciousness; dry, open mouth; and microaspiration of secretions. VAP can be prevented by initiating interventions from the Institute of Healthcare Improvement's VAP bundle, including (a) elevating the head of the bed of ventilated patients to 30˚, (b) preventing venous thromboembolism through use of sequential compression devices or anticoagulation, (c) administering gastric acid histamine2 blockers, (d) practicing good hand hygiene, (e) initiating early mobilization, and (f) performing daily sedation interruption at 10 am to evaluate neurologic status. The one intervention not included in the IHI bundle is oral hygiene. The purpose of this project is to support the premise that oral care, including timed toothbrushing, combined with the VAP bundle can mitigate and prevent the occurrence of VAP.
In ventilated patients, the normal defense system of the body, including the cilia in the nose and protective mucus, are circumvented, allowing the patient's mouth to be colonized with pathogenic bacteria such as Pseudomonas, Acinetobacter, and Methicillin-resistant Staphylococcus aureus (MRSA) within 24 hours of admission to an ICU (El-Solh et al., 2004; Rello, 2005). Mechanically ventilated neurointensive care patients are at an increased risk for VAP due to factors such as decreased level of consciousness and inability to protect the airway (Cohn & Fulton, 2006; Kollef et al., 2006). Neurologic patients with decreased level of consciousness or low Glasgow Coma Scale scores are prone to aspiration due to an unprotected airway and inability to swallow properly. Interventions for lowering intracranial pressure (ICP), such as raising the head of the bed, are a positive influence on prevention of VAP, whereas limited mobility because of ICP monitors, ventriculostomies, and disease processes such as spinal cord injury, can negatively affect VAP-prevention techniques (Cocanour et al., 2005). In addition, because it is difficult to temporarily stop sedation in neurologic patients who have increased ICP, the cessation of daily sedation cannot be used to prevent VAP in these patients. Other risk factors include gastric distension, presence of gastric or duodenal tubes, and trauma or chronic obstructive pulmonary disease (Harris & Miller, 2000).
Meticulous mouth care is crucial for preventing VAP. Rincón-Ferrari and colleagues (2004) found that in head-injured patients, 40%–60% of the gram-negative bacilli found were due to endogenous lung colonization after aspiration of oropharyngeal secretions. Twenty percent to forty percent of these bacteria were Staphylococcus aureus, and more than half of the Staphylococcus aureus were methicillin-resistant. This type of staphylococcus is exogenous, usually originating from the hands (Mori et al., 2006).
Studies have shown that patients can become colonized with pathogenic bacteria within 24 hours of admission to a critical care unit (Garcia, Jendresky, & Colbert, 2004; Sole, Poalillo, Byers, & Ludy, 2002). The oral cavity and its components—especially dental plaque—are the perfect media in which bacteria can colonize (Garcia et al.).
The American Association of Critical-Care Nurses published an evidence-based practice alert in 2006 that offered guidelines for oral care of the mechanically ventilated patient. In addition, Grap and Munro (2004) and Collard and Saint (2004) recommended raising the head of the bed to an elevation of 30˚ to 40˚, using endotracheal tubes that have a dorsal lumen above the endotracheal cuff, and sporadically changing ventilator circuits.
Grap and Munro (2004) presented supporting evidence indicating that critically ill patients who are intubated for more than 24 hours are at higher risk for VAP, and therefore, mouth care and oral health should be an important part of nursing care. Current literature identified a problem with adequate oral care in the intubated patient that included the definition and quantification of oral care (Fourrier et al., 2000). Bergmans and colleagues (2001) provided evidence that prevention of bacterial colonization of the oropharynx is the key to preventing VAP. The Centers for Disease Control and Prevention guidelines (Tablan, Anderson, Besser, Bridges, & Hajjeh, 2004) determined that the primary route of bacterial entry into the lungs is through the oropharynx during episodes of microaspiration.
Several studies (El-Solh et al., 2004; Schleder et al., 2002; Shinn, 2004) have verified that removing bacteria from the oropharynx requires the removal of dental plaque, and the only way to remove the plaque is with toothbrushing. Pearson and Hutton (2002) and others found that the majority of nurses use a soft Toothette® instead of toothbrushing and that the Toothettes do not remove plaque as effectively as toothbrushes; consequently, oral bacteria can proliferate (Baker, 2007; Binkley, Furr, Carrico, & McCurren, 2004).
Pearson and Hutton (2002) completed a controlled trial that compared the ability of foam swabs and toothbrushes to remove dental plaque and to quantify any differences. They concluded that toothbrushing skills must be taught to nurses and clinical support staff. Schleder (2003) reviewed the pathogenesis of bacteria; identified risk factors, including colonization of the oropharynx; and recommended the following approaches:
Use good oral hygiene, including toothbrushing, on all patients.
Implement oral-hygiene assessments and intervention strategies for all patients at risk for developing VAP.
Pathophysiology:Decontaminate devices that come into contact with the respiratory tract.
Implement the hand-hygiene guidelines released by the CDC in 2003. The guidelines include decontaminating hands by washing them with antimicrobial soap and water or by using an alcohol-based, waterless antiseptic agent if hands are not visibly contaminated. In addition, gloves should be worn when handling respiratory secretions or objects contaminated with the respiratory secretions of any patient (Schleder, 2003; Tablan et al., 2004).
Grap, Munro, Ashtiani, and Bryant (2003) have substantiated the need to standardize oral care for a variety of reasons, the most compelling of which is to prevent or lower VAP rates in mechanically ventilated patients. Oral care is not only part of a standard of care that lowers infection rates by removing plaque-harboring organisms, but is also a comfort care issue (Fourrier et al., 2000; Munro & Grap, 2004). Using evidence-based outcomes and research, the CDC and its Hospital Infection Control Practices Advisory Committee have developed a set of guidelines for VAP prevention that are beneficial for any institution. The guidelines include preferential use of orotracheal tubes over nasotracheal tubes, use of endotracheal tubes with a dorsal lumen to allow drainage, elevating the head of the bed to 30˚ or 40˚, routinely verifying placement of feeding tubes, and preventing or modulating oropharyngeal colonization with implementation of a comprehensive oral hygiene program (Dodek et al., 2004; Tablan et al., 2004).
Implementation of the VAP Bundle: The VAP bundle was implemented over a period of 2 years and included (a) elevating the head of the bed of ventilated patients to 30˚, (b) preventing venous thromboembolism with the use of sequential compression devices or anticoagulation, (c) administering gastric acid histamine2 (H2) blockers, (d) practicing good hand hygiene, (e) initiating early mobilization, and (f) performing daily sedation interruption at 10 am for evaluating neurologic status. Other precautions also were initiated and include the following: (a) the practice of universal gloving was observed (i.e., as staff in all hard-wire units enter a patient's room [after having meticulously washed their hands], they put on gloves. At the bedside, they used hand sanitizer.), (b) in-services regarding VAP and its consequences were held on all shifts and weekends, and (c) dual lumen endotracheal tubes were implemented.
The first intervention in the bundle was to keep the head of the bed above 30˚ in intubated patients (Shorr & Kollef, 2005). When the head of the bed is flat, more secretions can pool in the back of the airway, become colonized, and then aspirate into the lungs (Safdar, Crnich, & Maki, 2006). In conjunction with in-services about VAP, posters with a picture of a 30˚ angle showing what the height of the head of the bed should be were put up at patients' bedsides.
The next pieces of the bundle that were put into place were hand washing and gloving. Universal gloving requires any staff member walking into a patient's room to put on gloves as they enter. Sinks are available in the front of every room in critical care, so in-services were held on all shifts to encourage universal gloving, as well as frequent hand washing before and after putting on gloves, before and after suctioning, and before and after touching ventilator equipment or coming into contact with patients' respiratory secretions. In addition, alcohol-based hand sanitizer dispensers were placed outside all rooms and around the units.
The third intervention was to increase mobility. Rehabilitation services staff were intimately involved with nursing and respiratory personnel to develop an activity flow sheet and protocols for progressive ambulation. Every patient admitted to critical care received a physical and occupational therapy screen within 24 hours and then received appropriate rehabilitation services, even if those included only range of motion services. Even intubated patients without contraindications such as back injury were encouraged to sit on the edge of the bed or to try to ambulate a few steps with the assistance of ceiling lifts.
Daily sedation interruption (i.e., a "sedation vacation") was the fourth part of the bundle incorporated into our policy. A multidisciplinary group including pharmacists, intensivists, and nurses met over several months to develop a system to ensure a daily sedation reprieve for mechanically ventilated patients (Simmons-Trau, Cenek, Counterman, Hockenbury, & Litwiller, 2004). If a patient was on a sedative drip, it was turned off at 10 am every morning to allow the patient to wake up to a level whereby he or she could be assessed neurologically. The Richmond Agitation Sedation Scale (RASS) was used to measure the level of sedation. After the patient reached the predetermined score on the RASS, the drip was then restarted at 75% of the rate. This decreased side effects of the drugs, prevented oversedation, allowed the patient to wake up sooner, and allowed the doctors to assess the patient's neurologic status more accurately.
In addition to the other bundle recommendations, a dual lumen endotracheal tube (ETT) was introduced. Dual lumen ETTs are much more expensive than ordinary endotracheal tubes ($14 versus $1), but some studies have shown that the dual lumen ETT's extra subglottic port decreases VAP by as much as 20%–40%, thereby decreasing the overall costs associated with VAP (Shorr & O'Malley, 2001; Smulders, van der Hoeven, Weers-Pothoff, & Vandenbroucke-Grauls, 2002). Although the dual lumen ETTs have an extra port for subglottic secretions, and some hospitals use continuous suction, our hospital did not have any of the low-volume, low-pressure suction the manufacturer suggested (Hijazi & Al-Ansari, 2004). Nurses and respiratory therapists devised a plan to have only respiratory suction from the port with a 10-ml syringe every 2 hours with ventilator checks. These endotracheal tubes were enthusiastically accepted by the staff and placed on all emergency carts.
The final portion of the bundle was the use of H2 blockers or sucralfate to prevent ulcers, as well as preventive measures against deep vein thrombosis (Berriel-Cass, Adkins, Jones, & Fakih, 2006; Collard, Saint, & Matthay, 2003). Fortunately, our institution had been following current guidelines, so it was not necessary to take further action with ulcer and DVT prevention.
Summery:VAP is a preventable and expensive nosocomial disease. Literature has covered its pathophysiology and the myriad reasons that patients develop VAP, but solid evidence that supports nursing interventions has not been forthcoming. Oral-care interventions have been suggested as a preventive technique, but there are few evidence-based studies that report exactly how and when to perform oral care. A multidisciplinary approach (Salahuddin et al., 2004) is the most efficient and efficacious way to effect change in a system; such an approach was used to implement the timed oral-care and toothbrushing regimen to change nursing practice. This study changed nursing practice, saved lives, and saved more than $724,000 for Summa in 2006, as indicated in the 2007 Summa financial scorecard. The study showed that the simple nursing intervention of brushing the teeth three times a day and using the IHI VAP bundle can be powerful tools for preventing VAP.
In ventilated patients, the normal defense system of the body, including the cilia in the nose and protective mucus, are circumvented, allowing the patient's mouth to be colonized with pathogenic bacteria such as Pseudomonas, Acinetobacter, and Methicillin-resistant Staphylococcus aureus (MRSA) within 24 hours of admission to an ICU (El-Solh et al., 2004; Rello, 2005). Mechanically ventilated neurointensive care patients are at an increased risk for VAP due to factors such as decreased level of consciousness and inability to protect the airway (Cohn & Fulton, 2006; Kollef et al., 2006). Neurologic patients with decreased level of consciousness or low Glasgow Coma Scale scores are prone to aspiration due to an unprotected airway and inability to swallow properly. Interventions for lowering intracranial pressure (ICP), such as raising the head of the bed, are a positive influence on prevention of VAP, whereas limited mobility because of ICP monitors, ventriculostomies, and disease processes such as spinal cord injury, can negatively affect VAP-prevention techniques (Cocanour et al., 2005). In addition, because it is difficult to temporarily stop sedation in neurologic patients who have increased ICP, the cessation of daily sedation cannot be used to prevent VAP in these patients. Other risk factors include gastric distension, presence of gastric or duodenal tubes, and trauma or chronic obstructive pulmonary disease (Harris & Miller, 2000).
Meticulous mouth care is crucial for preventing VAP. Rincón-Ferrari and colleagues (2004) found that in head-injured patients, 40%–60% of the gram-negative bacilli found were due to endogenous lung colonization after aspiration of oropharyngeal secretions. Twenty percent to forty percent of these bacteria were Staphylococcus aureus, and more than half of the Staphylococcus aureus were methicillin-resistant. This type of staphylococcus is exogenous, usually originating from the hands (Mori et al., 2006).
Studies have shown that patients can become colonized with pathogenic bacteria within 24 hours of admission to a critical care unit (Garcia, Jendresky, & Colbert, 2004; Sole, Poalillo, Byers, & Ludy, 2002). The oral cavity and its components—especially dental plaque—are the perfect media in which bacteria can colonize (Garcia et al.).
The American Association of Critical-Care Nurses published an evidence-based practice alert in 2006 that offered guidelines for oral care of the mechanically ventilated patient. In addition, Grap and Munro (2004) and Collard and Saint (2004) recommended raising the head of the bed to an elevation of 30˚ to 40˚, using endotracheal tubes that have a dorsal lumen above the endotracheal cuff, and sporadically changing ventilator circuits.
Grap and Munro (2004) presented supporting evidence indicating that critically ill patients who are intubated for more than 24 hours are at higher risk for VAP, and therefore, mouth care and oral health should be an important part of nursing care. Current literature identified a problem with adequate oral care in the intubated patient that included the definition and quantification of oral care (Fourrier et al., 2000). Bergmans and colleagues (2001) provided evidence that prevention of bacterial colonization of the oropharynx is the key to preventing VAP. The Centers for Disease Control and Prevention guidelines (Tablan, Anderson, Besser, Bridges, & Hajjeh, 2004) determined that the primary route of bacterial entry into the lungs is through the oropharynx during episodes of microaspiration.
Several studies (El-Solh et al., 2004; Schleder et al., 2002; Shinn, 2004) have verified that removing bacteria from the oropharynx requires the removal of dental plaque, and the only way to remove the plaque is with toothbrushing. Pearson and Hutton (2002) and others found that the majority of nurses use a soft Toothette® instead of toothbrushing and that the Toothettes do not remove plaque as effectively as toothbrushes; consequently, oral bacteria can proliferate (Baker, 2007; Binkley, Furr, Carrico, & McCurren, 2004).
Pearson and Hutton (2002) completed a controlled trial that compared the ability of foam swabs and toothbrushes to remove dental plaque and to quantify any differences. They concluded that toothbrushing skills must be taught to nurses and clinical support staff. Schleder (2003) reviewed the pathogenesis of bacteria; identified risk factors, including colonization of the oropharynx; and recommended the following approaches:
Use good oral hygiene, including toothbrushing, on all patients.
Implement oral-hygiene assessments and intervention strategies for all patients at risk for developing VAP.
Pathophysiology:Decontaminate devices that come into contact with the respiratory tract.
Implement the hand-hygiene guidelines released by the CDC in 2003. The guidelines include decontaminating hands by washing them with antimicrobial soap and water or by using an alcohol-based, waterless antiseptic agent if hands are not visibly contaminated. In addition, gloves should be worn when handling respiratory secretions or objects contaminated with the respiratory secretions of any patient (Schleder, 2003; Tablan et al., 2004).
Grap, Munro, Ashtiani, and Bryant (2003) have substantiated the need to standardize oral care for a variety of reasons, the most compelling of which is to prevent or lower VAP rates in mechanically ventilated patients. Oral care is not only part of a standard of care that lowers infection rates by removing plaque-harboring organisms, but is also a comfort care issue (Fourrier et al., 2000; Munro & Grap, 2004). Using evidence-based outcomes and research, the CDC and its Hospital Infection Control Practices Advisory Committee have developed a set of guidelines for VAP prevention that are beneficial for any institution. The guidelines include preferential use of orotracheal tubes over nasotracheal tubes, use of endotracheal tubes with a dorsal lumen to allow drainage, elevating the head of the bed to 30˚ or 40˚, routinely verifying placement of feeding tubes, and preventing or modulating oropharyngeal colonization with implementation of a comprehensive oral hygiene program (Dodek et al., 2004; Tablan et al., 2004).
Implementation of the VAP Bundle: The VAP bundle was implemented over a period of 2 years and included (a) elevating the head of the bed of ventilated patients to 30˚, (b) preventing venous thromboembolism with the use of sequential compression devices or anticoagulation, (c) administering gastric acid histamine2 (H2) blockers, (d) practicing good hand hygiene, (e) initiating early mobilization, and (f) performing daily sedation interruption at 10 am for evaluating neurologic status. Other precautions also were initiated and include the following: (a) the practice of universal gloving was observed (i.e., as staff in all hard-wire units enter a patient's room [after having meticulously washed their hands], they put on gloves. At the bedside, they used hand sanitizer.), (b) in-services regarding VAP and its consequences were held on all shifts and weekends, and (c) dual lumen endotracheal tubes were implemented.
The first intervention in the bundle was to keep the head of the bed above 30˚ in intubated patients (Shorr & Kollef, 2005). When the head of the bed is flat, more secretions can pool in the back of the airway, become colonized, and then aspirate into the lungs (Safdar, Crnich, & Maki, 2006). In conjunction with in-services about VAP, posters with a picture of a 30˚ angle showing what the height of the head of the bed should be were put up at patients' bedsides.
The next pieces of the bundle that were put into place were hand washing and gloving. Universal gloving requires any staff member walking into a patient's room to put on gloves as they enter. Sinks are available in the front of every room in critical care, so in-services were held on all shifts to encourage universal gloving, as well as frequent hand washing before and after putting on gloves, before and after suctioning, and before and after touching ventilator equipment or coming into contact with patients' respiratory secretions. In addition, alcohol-based hand sanitizer dispensers were placed outside all rooms and around the units.
The third intervention was to increase mobility. Rehabilitation services staff were intimately involved with nursing and respiratory personnel to develop an activity flow sheet and protocols for progressive ambulation. Every patient admitted to critical care received a physical and occupational therapy screen within 24 hours and then received appropriate rehabilitation services, even if those included only range of motion services. Even intubated patients without contraindications such as back injury were encouraged to sit on the edge of the bed or to try to ambulate a few steps with the assistance of ceiling lifts.
Daily sedation interruption (i.e., a "sedation vacation") was the fourth part of the bundle incorporated into our policy. A multidisciplinary group including pharmacists, intensivists, and nurses met over several months to develop a system to ensure a daily sedation reprieve for mechanically ventilated patients (Simmons-Trau, Cenek, Counterman, Hockenbury, & Litwiller, 2004). If a patient was on a sedative drip, it was turned off at 10 am every morning to allow the patient to wake up to a level whereby he or she could be assessed neurologically. The Richmond Agitation Sedation Scale (RASS) was used to measure the level of sedation. After the patient reached the predetermined score on the RASS, the drip was then restarted at 75% of the rate. This decreased side effects of the drugs, prevented oversedation, allowed the patient to wake up sooner, and allowed the doctors to assess the patient's neurologic status more accurately.
In addition to the other bundle recommendations, a dual lumen endotracheal tube (ETT) was introduced. Dual lumen ETTs are much more expensive than ordinary endotracheal tubes ($14 versus $1), but some studies have shown that the dual lumen ETT's extra subglottic port decreases VAP by as much as 20%–40%, thereby decreasing the overall costs associated with VAP (Shorr & O'Malley, 2001; Smulders, van der Hoeven, Weers-Pothoff, & Vandenbroucke-Grauls, 2002). Although the dual lumen ETTs have an extra port for subglottic secretions, and some hospitals use continuous suction, our hospital did not have any of the low-volume, low-pressure suction the manufacturer suggested (Hijazi & Al-Ansari, 2004). Nurses and respiratory therapists devised a plan to have only respiratory suction from the port with a 10-ml syringe every 2 hours with ventilator checks. These endotracheal tubes were enthusiastically accepted by the staff and placed on all emergency carts.
The final portion of the bundle was the use of H2 blockers or sucralfate to prevent ulcers, as well as preventive measures against deep vein thrombosis (Berriel-Cass, Adkins, Jones, & Fakih, 2006; Collard, Saint, & Matthay, 2003). Fortunately, our institution had been following current guidelines, so it was not necessary to take further action with ulcer and DVT prevention.
Summery:VAP is a preventable and expensive nosocomial disease. Literature has covered its pathophysiology and the myriad reasons that patients develop VAP, but solid evidence that supports nursing interventions has not been forthcoming. Oral-care interventions have been suggested as a preventive technique, but there are few evidence-based studies that report exactly how and when to perform oral care. A multidisciplinary approach (Salahuddin et al., 2004) is the most efficient and efficacious way to effect change in a system; such an approach was used to implement the timed oral-care and toothbrushing regimen to change nursing practice. This study changed nursing practice, saved lives, and saved more than $724,000 for Summa in 2006, as indicated in the 2007 Summa financial scorecard. The study showed that the simple nursing intervention of brushing the teeth three times a day and using the IHI VAP bundle can be powerful tools for preventing VAP.
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