Roberto Gusinu

Human albumin solution for resuscitation and volume expansion in critically ill patients.

BackgroundHuman albumin solutions are used in a range of medical and surgical problems. Licensed indications are the emergency treatment of shock and other conditions where restoration of blood volume is urgent, burns, and hypoproteinaemia. Human albumin solutions are more expensive than other colloids and crystalloids.ObjectivesTo quantify the effect on mortality of human albumin and plasma protein fraction (PPF) administration in the management of critically ill patients.Search strategyWe searched the Cochrane Injuries Group trials register, Cochrane Central Register of Controlled Trials, Medline, Embase and BIDS Index to Scientific and Technical Proceedings. Reference lists of trials and review articles were checked, and authors of identified trials were, contacted. The search was last updated in August 2004.Selection criteriaRandomised controlled trials comparing albumin/PPF with no albumin/PPF, or with a crystalloid solution, in critically ill patients with hypovolaemia, burns or hypoalbuminaemia.Data collection and analysisWe collected data on the participants, albumin solution used, mortality at the end of follow up, and quality of allocation concealment. Analysis was stratified according to patient type.Main resultsWe found 32 trials meeting the inclusion criteria and reporting death as an outcome. There were 1632 deaths among 8452 trial participants. For hypovolaemia, the relative risk of death following albumin administration was 1.01 (95% confidence interval 0.92–1.10). This estimate was heavily influenced by the results of the SAFE trial, which contributed 91% of the information (based on the weights in the meta-analysis). For burns, the relative risk was 2.40 (1.11–5.19) and for hypoalbuminaemia the relative risk was 1.38 (0.94–2.03). There was no substantial heterogeneity between the trials in the various categories (X2=21.86, df=25, p=0.64). The pooled relative risk of death with albumin administration was 1.04 (0.95–1.13).ConclusionsFor patients with hypovolaemia there is no evidence that albumin reduces mortality when compared with cheaper alternatives such as saline. There is no evidence that albumin reduces mortality in critically ill patients with burns and hypoalbuminaemia. The possibility that there may be highly selected populations of critically ill patients in which albumin may be indicated remains open to question. However, in view of the absence of evidence of a mortality benefit from albumin and the increased cost of albumin compared to alternatives such as saline, it would seem reasonable that albumin should only be used within the context of well concealed and adequately powered randomised controlled trial.Plain language summaryThere is no evidence that giving human albumin to replace lost blood in critically ill or injured people improves survival when compared to giving saline.Trauma, burns or surgery can cause people to lose large amounts of blood. Fluid replacement, giving fluids intravenously (into a vein), is used to help restore blood volume and hopefully reduce the risk of dying. Blood products (including human albumin), non-blood products or combinations can be used. The review of trials found no evidence that albumin reduces the risk of dying. Albumin is very expensive in which case it may be better to use cheaper alternatives such as saline for fluid resuscitation.

Systematic reviews of diagnostic test accuracy and the Cochrane collaboration

Since Cochrane’s Corner focuses on Cochrane systematic reviews, it is important that readers be informed about new publication types within the Cochrane Library (http://www. thecochranelibrary.com), for example systematic reviews of diagnostic test accuracy (DTA). This commentary serves to explain that research on diagnostic test efficacy and impact has recently begun to be based on an expanding set of complex methodological rules. These rules may still be unfamiliar to doctors who rely on and use tests for clinical decisions. A historical perspective

Antibiotic prophylaxis to prevent nosocomial infections in patients in intensive care units: evidence that struggle to convince practising clinicians

BackgroundPneumonia is an important cause of mortality in intensive care units. The incidence of pneumonia in such patients ranges between 7 and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to pneumonia, it has been shown to contribute to mortality in intensive care units independently of other factors that are also strongly associated with such deaths.ObjectivesThe objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care.Search strategyWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2003), which contains the Acute Respiratory Infections (ARI) Group specialised trials register; MEDLINE (January 1966 to September 2003); EMBASE (January 1990 to September 2003); proceedings of scientific meetings and reference lists of articles from January 1984 to December 2002. We also contacted investigators in the field.Selection criteriaRandomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients.Data collection and analysisAt least two reviewers independently extracted data and assessed trial quality.ResultsOverall 36 trials involving 6922 people were included. There was variation in the antibiotics used, patient characteristics and risk of respiratory tract infections and mortality in the control groups. In 17 trials (involving 4295 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 29% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval [CI] 0.29–0.41) and total mortality (odds ratio 0.78, 95% CI 0.68–0.89) in the treated group. On average 5 patients needed to be treated to prevent one infection and 21 patients to prevent one death. In 17 trials (involving 2664 patients) that tested topical antimicrobials alone (or comparing topical plus systemic versus systemic alone) the rates of respiratory tract infections and deaths in the control groups were 30 and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.52,95% CI 0.43–0.63), but not in total mortality (odds ratio 0.97, 95%, CI 0.81–1.16) in the treated group.ConclusionsA combination of topical and systemic prophylactic antibiotics reduces respiratory tract infections and overall mortality in adult patients receiving intensive care. A treatment based on the use of topical prophylaxis alone reduces respiratory infections, but not mortality. The risk of occurrence of resistance as a negative consequence of antibiotic use was appropriately explored only in the most recent trial by de Jonge, which did not show any such effect.

In Hospital and 3-Month Mortality and Functional Recovery Rate in Patients Treated for Hip Fracture by a Multidisciplinary Team.

Objectives Medical comorbidities affect outcome in elderly patients with hip fracture. This study was designed to preliminarily evaluate the usefulness of a hip-fracture unit led by an internal medicine specialist. Methods In-hospital and 3-month outcomes in patients with hip fracture were prospectively evaluated in 121 consecutive patients assessed before and followed after surgery by a multidisciplinary team led by internal medicine specialist; 337 consecutive patients were recalled from ICD-9 discharge records and considered for comparison regarding in-hospital mortality. Results In the intervention period, patients treated within 48 hours were 54% vs. 26% in the historical cohort (P<0.0001). In-hospital mortality remained stable at about 2.3 per 1000 person-days. At 3 months, 10.3% of discharged patients had died, though less than 8% of patients developed postoperative complications (mainly pneumonia and respiratory failure). The presence of more than 2 major comorbidities and the loss of 3 or more BADL were independent predictors of death. 50/105 patients recovered previous functional capacity, but no independent predictor of functional recovery could be identified. Mean length of hospital stay significantly decreased in comparison to the historical cohort (13.6± 4.7 vs 17 ± 5 days, p = 0.0001). Combined end-point of mortality and length of hospitalization < 12 days was significantly lower in study period (27 vs 34%, p <0.0132). Conclusions Identification and stabilization of concomitant clinical problems by internal medicine specialists may safely decrease time to surgery in frail subjects with hip fracture. Moreover, integrated perioperative clinical management may shorten hospital stay with no apparent increase in in-hospital mortality and ultimately improve the outcome. These results are to be confirmed by a larger study presently ongoing at our institution.

Heterogeneity and meta-analyses: do study results truly differ?

As the Cochrane Corner hosts analytical comments on Cochrane systematic reviews (SRs), it is important that readers are comfortable in understanding the methodology related to SR science. In the first article in this series, we presented an approach to understand all basic information reported in a meta-analysis graph [1]. In this issue, we cover concepts and tips related to heterogeneity, and whether to combine the results of the studies is appropriate. The decision to meta-analyse or not to meta-analyse studies may appear imponderable to many clinicians. How do authors decide whether patients, interventions and outcomes considered in individual studies are sufficiently similar to be pooled in meta-analyses?

When drug companies select what they want to publish patients are denied relevant therapeutic information

The methodologist’s point of viewGraziella Filippini, Lorenzo Moja, Alessandro LiberatiCochrane ReviewType-1 interferons are recommended as the first-linetreatment of multiple sclerosis (MS) in North Americanand European guidelines [1–3]. The efficacy of interferonson delaying disability progression—the most importantgoal of treatment in this 30–40 year disease—has beenevaluated in one Cochrane Review including five ran-domized, placebo control trials of either interferon beta-1b (two trials), or interferon beta-1a (three trials)involving 1,130 patients with relapsing-remitting MS(RRMS) [4]. From the available data in three of thesetrials, the authors of the review calculated an absolute riskreduction (ARR) of 9% (95% CI: 3.14%) of RRMSpatients who progressed in 2 years. However, when allpatients randomised in the trials were re-analysed bysensitivity analysis (overall 20% of patients had beenexcluded after randomization or were lost to follow-upduring the intervention), statistical significance was lost,providing an ARR of -10% (95% CI -38.18%). At2 years’ follow-up data were not robust or dropoutscompromised interpretation: for instance, in one trialfollow-up data were available on less than 40% of ran-domised patients. The number of patients who hadrelapses during the first 2 years fell significantly in theper protocol analysis (ARR 14%; 95% CI 8.19%), but,again, results were inconclusive after sensitivity analyses.All extended trials’ observations beyond 2 years wereopen, hampering an evaluation of long-term effect of in-terferons in delaying progression of RRMS patients.All individual studies included in this review weresponsored by the pharmaceutical companies producinginterferon beta: the data presented by companies in medicaljournal publications were actually selective reporting ofpatients who adhered to the interferons. This approach isknown as a per protocol analysis (also known as efficacy orexplanatory analysis) which counts the outcomes of thepatients who adhered to the research protocol [5]. Notsurprisingly these patients tended to have a better prognosisas opposed to the patients that had not adhered. Excludingdropouts from the analysis influenced the nature of the finalresults (both in terms of direction and/or magnitude). The

Is thrombolysis for intermediate-risk pulmonary embolism beneficial? The case of Emeritus Professor Crow

The methodologist’s point of viewAlessandro Squizzato, Lorenzo MojaYou are the attending physician on duty at the EmergencyDepartment, when John Crow, a 69-year-old EmeritusProfessor of cardiology comes with acute dyspnoea [1].The day before he started complaining a right leg oedemaand pain, he said. While starting to collect other clinicaldata and requiring tests you remember that time you metDr. Crow on a luxurious conference. Was he the onesupporting prescription of hormone replacement therapy towomen on the mistaken basis that this would reduce therisk of heart? Dr. Crow’s blood pressure is 120/80 mmHg.Spiral computed tomography shows emboli in more than50% of pulmonary vessels and a right ventricularenlargement. Blood troponin level is elevated and echo-cardiography confirm right ventricular enlargement.The resident on duty, who is just back from an inter-national meeting on venous thromboembolic diseases, isaware of the recently published European Society ofCardiology (ESC) guidelines and of the American Collegeof Chest Physicians (ACCP) on this topic that suggest thatabsolute indications for thrombolysis are: massive pul-monary embolism with persistent hypotension or shock[2, 3]. This is not your case. Your colleague reportsthat thrombolysis may be an option in selected cases ofsub-massive pulmonary embolism (PE) defined as normalblood pressure and right ventricular dysfunction [2, 3]. Thisis your case. Indeed, before discussing with this decla-mated patient the convenient therapeutic strategy, you needto clarify the advantages and the risks of adding throm-bolysis to heparin, which is your reference therapy. Youhave a look at the Cochrane Library and downloadthe systematic review entitled Thrombolytic therapy forpulmonary embolism [4].The Cochrane’s point of view: a systematic reviewOverall 679 patients were enrolled in 8 included random-ised controlled trials [4]. Different types of thrombolysis—alteplase, urokinase, streptokinase—were used and werecompared with heparin alone. All trials excluded patientswith high-risk PE, i.e. shock or persistent hypotension. Fiveof the eight trials had well reported and satisfactorymethodological quality. Clinically sound outcomes wereinconclusive: death rate odds ratio (OR) 0.89 [95% confi-dence interval (CI) 0.4–1.78]; major haemorrhagic eventsOR 1.61 (95 CI 0.91–2.86). Thrombolytics improved somesecondary outcomes—hemodynamic outcomes, perfusion

Commercial dressings for burns versus sweet ancient remedy.

In the heart of your house, one foggy evening, you are cooking what all the world should repute as a memorable dinner; you invited some new colleagues from the hospital, which makes you feel slightly nervous. While thinking about the last table decorations you look into the oven at the big pan. Food needs your attention. You take a spoon and start to stir the ingredients but... inadvertently you burn yourself. There are few minutes before the guests will start to ring your door. What you should do? There are two options: the first deals with the home remedy, a natural cure, and it requires you to open your cupboard (looking for honey); the second deals with modern marketed drugs and it requires you to go to the nearest pharmacy to buy a dressing. The solution deals with the comparative efficacy of these medicines. Which should be better? The latest issue of the Cochrane Database of Systematic Reviews offers two topical reviews dealing with this subject. In the first study, honey is evaluated for wound healing [1], and in the other, different dressings are studied for their healing properties [2]. Doctors and consumers are increasingly demanding more separation between marketing campaign to sustain products, superstition, myth remedies and evidence. In other words, the community is calling for disentanglement of evidence and folkloristic practice: these disentanglements regard both conventional medicines and nature’s drugs. The results of these disentanglements sometimes are surprising.

Measuring the impact of evidence: the Cochrane systematic review of organised stroke care

In 2007, the first commentary hosted by this Cochrane’s Corner focussed on stroke units and discussed the principle that a valid combination of results from a series of unbiased primary studies can provide influential information that would not be otherwise available by individual studies [1]. We now present a case study of the role played by the stroke unit Cochrane review in the complicated process that led to changes in clinical practice and health policy. Our hypothesis is that the theoretical and pragmatic value of this systematic review goes beyond the mere increase in the number of patients considered in one study: robust results from a methodologically sound systematic review including trials performed in different setting and with different standards can increase the applicability of the conclusion.

Rimonabant for overweight and “metabolic syndrome”: the attempt to supersize disease and risk by pharmaceutical marketing

A Cochrane systematic review explored the potential role of rimonabant for overweight and obesity [1]. On the basis of surrogate outcomes reported in the included RCTs, rimonabant has been a candidate (by its producer) to act as a pleiotropic agent for the entire cardiovascular risk spectrum. Is this compelling evidence to consider rimonabant the new panacea for the ‘‘metabolic syndrome’’ or are we facing another attempt of disease mongering by a new market frontier? Rimonabant has been shown to reduce food intake, appetite and body weight in overweight or obese people. Four randomized controlled trials (RIO-Europe [2], RIONorth America [3], RIO-diabetes [4], RIO-lipids [5]) evaluated rimonabant 20 mg versus rimonabant 5 mg versus placebo. All interventions were given over 1 year and included the addition of a hypocaloric diet. All trials were designed, conducted and reported with the contribution of Sanofi-Aventis drug company. The Cochrane review (‘‘Rimonabant for overweight and obesity’’) [1] includes evidence from these four trials.