David A Harrison

Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial

BACKGROUND Over the past 30 years the pulmonary artery catheter (PAC) has become a widely used haemodynamic monitoring device in the management of critically ill patients, though doubts exist about its safety. Our aim was, therefore, to ascertain whether hospital mortality is reduced in critically ill patients when they are managed with a PAC. METHODS We did a randomised controlled trial to which we enrolled 1041 patients from 65 UK intensive care units. We assigned individuals to management with (n=519) or without (n=522) a PAC. The timing of insertion and subsequent clinical management were at the discretion of the treating clinician. Intensive care units decided a priori to have the option of using an alternative cardiac output-monitoring device in control patients. FINDINGS 1014 patients were eligible for analysis. We noted no difference in hospital mortality between patients managed with or without a PAC (68% [346 of 506] vs 66% [333 of 507], p=0.39; adjusted hazard ratio 1.09, 95% CI 0.94-1.27). We noted complications associated with insertion of a PAC in 46 of 486 individuals in whom the device was placed, none of which was fatal. INTERPRETATION Our findings indicate no clear evidence of benefit or harm by managing critically ill patients with a PAC. Efficacy studies are needed to ascertain whether management protocols involving PAC use can result in improved outcomes in specific groups if these devices are not to become a redundant technology.

Trial of early, goal-directed resuscitation for septic shock.

BACKGROUND Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. METHODS We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. RESULTS We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. CONCLUSIONS In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).

Referral to an Extracorporeal Membrane Oxygenation Center and Mortality Among Patients With Severe 2009 Influenza A(H1N1)

CONTEXT Extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients with severe acute respiratory distress syndrome (ARDS), but its role has remained controversial. ECMO was used to treat patients with ARDS during the 2009 influenza A(H1N1) pandemic. OBJECTIVE To compare the hospital mortality of patients with H1N1-related ARDS referred, accepted, and transferred for ECMO with matched patients who were not referred for ECMO. DESIGN, SETTING, AND PATIENTS A cohort study in which ECMO-referred patients were defined as all patients with H1N1-related ARDS who were referred, accepted, and transferred to 1 of the 4 adult ECMO centers in the United Kingdom during the H1N1 pandemic in winter 2009-2010. The ECMO-referred patients and the non-ECMO-referred patients were matched using data from a concurrent, longitudinal cohort study (Swine Flu Triage study) of critically ill patients with suspected or confirmed H1N1. Detailed demographic, physiological, and comorbidity data were used in 3 different matching techniques (individual matching, propensity score matching, and GenMatch matching). MAIN OUTCOME MEASURE Survival to hospital discharge analyzed according to the intention-to-treat principle. RESULTS Of 80 ECMO-referred patients, 69 received ECMO (86.3%) and 22 died (27.5%) prior to discharge from the hospital. From a pool of 1756 patients, there were 59 matched pairs of ECMO-referred patients and non-ECMO-referred patients identified using individual matching, 75 matched pairs identified using propensity score matching, and 75 matched pairs identified using GenMatch matching. The hospital mortality rate was 23.7% for ECMO-referred patients vs 52.5% for non-ECMO-referred patients (relative risk [RR], 0.45 [95% CI, 0.26-0.79]; P = .006) when individual matching was used; 24.0% vs 46.7%, respectively (RR, 0.51 [95% CI, 0.31-0.81]; P = .008) when propensity score matching was used; and 24.0% vs 50.7%, respectively (RR, 0.47 [95% CI, 0.31-0.72]; P = .001) when GenMatch matching was used. The results were robust to sensitivity analyses, including amending the inclusion criteria and restricting the location where the non-ECMO-referred patients were treated. CONCLUSION For patients with H1N1-related ARDS, referral and transfer to an ECMO center was associated with lower hospital mortality compared with matched non-ECMO-referred patients.

Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review

IMPORTANCE Small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm. OBJECTIVE To evaluate the clinical effectiveness of a perioperative, cardiac output-guided hemodynamic therapy algorithm. DESIGN, SETTING, AND PARTICIPANTS OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014. INTERVENTIONS Patients were randomly assigned to a cardiac output-guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366). MAIN OUTCOMES AND MEASURES The primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care-free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay. RESULTS Baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, -0.3% to 13.9%]; P = .07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]). CONCLUSIONS AND RELEVANCE In a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output-guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rates. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN04386758.

Variation in critical care services across North America and Western Europe

Objective:Critical care represents a large percentage of healthcare spending in developed countries. Yet, little is known regarding international variation in critical care services. We sought to understand differences in critical care delivery by comparing data on the distribution of services in eight countries. Design:Retrospective review of existing national administrative data. We identified sources of data in each country to provide information on acute care hospitals and beds, intensive care units and beds, intensive care admissions, and definitions of intensive care beds. Data were all referenced and from as close to 2005 as possible. Setting:United States, France, United Kingdom, Canada, Belgium, Germany, The Netherlands, and Spain. Patients:Not available. Interventions:None. Measurements and Main Results:No standard definition existed for acute care hospital or intensive care unit beds across countries. Hospital beds varied three-fold from 221/100,000 population in the United States to 593/100,000 in Germany. Adult intensive care unit beds also ranged seven-fold from 3.3/100,000 population in the United Kingdom to 24.0/100,000 in Germany. Volume of intensive care unit admissions per year varied ten-fold from 216/100,000 population in the United Kingdom to 2353/100,000 in Germany. The ratio of intensive care unit beds to hospital beds was highly correlated across all countries except the United States (r = .90). There was minimal correlation between the number of intensive care unit beds per capita and health care spending per capita (r = .45), but high inverse correlation between intensive care unit beds and hospital mortality for intensive care unit patients across countries (r = −.82). Conclusions:Absolute critical care services vary dramatically between countries with wide differences in both numbers of beds and volume of admissions. The number of intensive care unit beds per capita is not strongly correlated with overall health expenditure, but does correlate strongly with mortality. These findings demonstrate the need for critical care data from all countries, as they are essential for interpretation of studies, and policy decisions regarding critical care services.

Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database.

Using a retrospective analysis of the Intensive Care National Audit and Research Centre Case Mix Programme Database (ICNARC CMPD), we have summarised the characteristics and outcomes for mechanically ventilated patients admitted to UK intensive care units (ICUs) after cardiac arrest. Descriptive statistics on case mix, physiology, treatment, service delivery, outcome and activity were described separately for community cardiac arrest, in‐hospital cardiac arrest (peri‐operative) and in‐hospital cardiac arrest (not peri‐operative). The impact on outcome of several patient characteristics and physiological values were analysed using multivariable logistic regression. Mechanically ventilated survivors of cardiac arrest accounted for 24 132 (5.8%) of all admissions to the 174 ICUs in the ICNARC CMP. Of these, 10 347 (42.9%) survived to leave the ICU and 6778 (28.6%) survived to acute hospital discharge. The ICNARC model gives much better discrimination than APACHE II for predicting hospital mortality after admission to ICU following cardiac arrest: the predicted hospital mortality based on the APACHE II and ICNARC model was 41.9% and 79.7%, respectively.

The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database

IntroductionTo evaluate the impact of recent evidence-based treatments for severe sepsis in routine clinical care requires an understanding of the underlying epidemiology, particularly with regard to trends over time. We interrogated a high quality clinical database to examine trends in the incidence and mortality of severe sepsis over a nine-year period.MethodsAdmissions with severe sepsis occurring at any time within 24 hours of admission to critical care were identified to an established methodology using raw physiological data from the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database, containing data from 343,860 admissions to 172 adult, general critical care units in England, Wales and Northern Ireland between December 1995 and January 2005. Generalised linear models were used to assess changes in the incidence, case mix, outcomes and activity of these admissions.ResultsIn total, 92,672 admissions (27.0%) were identified as having severe sepsis in the first 24 hours following admission. The percentage of admissions with severe sepsis during the first 24 hours rose from 23.5% in 1996 to 28.7% in 2004. This represents an increase from an estimated 18,500 to 31,000 admissions to all 240 adult, general critical care units in England, Wales and Northern Ireland. Hospital mortality for admissions with severe sepsis decreased from 48.3% in 1996 to 44.7% in 2004, but the total number of deaths increased from an estimated 9,000 to 14,000. The treated incidence of severe sepsis per 100,000 population rose from 46 in 1996 to 66 in 2003, with the associated number of hospital deaths per 100,000 population rising from 23 to 30.ConclusionThe population incidence of critical care admission with severe sepsis during the first 24 hours and associated hospital deaths are increasing. These baseline data provide essential information to those wishing to evaluate the introduction of the Surviving Sepsis Campaign care bundles in UK hospitals.

Trial of the Route of Early Nutritional Support in Critically Ill Adults

BACKGROUND Uncertainty exists about the most effective route for delivery of early nutritional support in critically ill adults. We hypothesized that delivery through the parenteral route is superior to that through the enteral route. METHODS We conducted a pragmatic, randomized trial involving adults with an unplanned admission to one of 33 English intensive care units. We randomly assigned patients who could be fed through either the parenteral or the enteral route to a delivery route, with nutritional support initiated within 36 hours after admission and continued for up to 5 days. The primary outcome was all-cause mortality at 30 days. RESULTS We enrolled 2400 patients; 2388 (99.5%) were included in the analysis (1191 in the parenteral group and 1197 in the enteral group). By 30 days, 393 of 1188 patients (33.1%) in the parenteral group and 409 of 1195 patients (34.2%) in the enteral group had died (relative risk in parenteral group, 0.97; 95% confidence interval, 0.86 to 1.08; P=0.57). There were significant reductions in the parenteral group, as compared with the enteral group, in rates of hypoglycemia (44 patients [3.7%] vs. 74 patients [6.2%]; P=0.006) and vomiting (100 patients [8.4%] vs. 194 patients [16.2%]; P<0.001). There were no significant differences between the parenteral group and the enteral group in the mean number of treated infectious complications (0.22 vs. 0.21; P=0.72), 90-day mortality (442 of 1184 patients [37.3%] vs. 464 of 1188 patients [39.1%], P=0.40), in rates of 14 other secondary outcomes, or in rates of adverse events. Caloric intake was similar in the two groups, with the target intake not achieved in most patients. CONCLUSIONS We found no significant difference in 30-day mortality associated with the route of delivery of early nutritional support in critically ill adults. (Funded by the United Kingdom National Institute for Health Research; CALORIES Current Controlled Trials number, ISRCTN17386141.).

Recalibration of risk prediction models in a large multicenter cohort of admissions to adult, general critical care units in the United Kingdom.

Objective:To assess the performance of published risk prediction models in common use in adult critical care in the United Kingdom and to recalibrate these models in a large representative database of critical care admissions. Design:Prospective cohort study. Setting:A total of 163 adult general critical care units in England, Wales, and Northern Ireland, during the period of December 1995 to August 2003. Patients:A total of 231,930 admissions, of which 141,106 met inclusion criteria and had sufficient data recorded for all risk prediction models. Interventions:None. Measurements and Main Results:The published versions of the Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE II UK, APACHE III, Simplified Acute Physiology Score (SAPS) II, and Mortality Probability Models (MPM) II were evaluated for discrimination and calibration by means of a combination of appropriate statistical measures recommended by an expert steering committee. All models showed good discrimination (the c index varied from 0.803 to 0.832) but imperfect calibration. Recalibration of the models, which was performed by both the Cox method and re-estimating coefficients, led to improved discrimination and calibration, although all models still showed significant departures from perfect calibration. Conclusions:Risk prediction models developed in another country require validation and recalibration before being used to provide risk-adjusted outcomes within a new country setting. Periodic reassessment is beneficial to ensure calibration is maintained.

A new risk prediction model for critical care: The Intensive Care National Audit & Research Centre (ICNARC) model*

Objective:To develop a new model to improve risk prediction for admissions to adult critical care units in the UK. Design:Prospective cohort study. Setting:The setting was 163 adult, general critical care units in England, Wales, and Northern Ireland, December 1995 to August 2003. Patients:Patients were 216,626 critical care admissions. Interventions:None. Measurements and Main Results:The performance of different approaches to modeling physiologic measurements was evaluated, and the best methods were selected to produce a new physiology score. This physiology score was combined with other information relating to the critical care admission—age, diagnostic category, source of admission, and cardiopulmonary resuscitation before admission—to develop a risk prediction model. Modeling interactions between diagnostic category and physiology score enabled the inclusion of groups of admissions that are frequently excluded from risk prediction models. The new model showed good discrimination (mean c index 0.870) and fit (mean Shapiro’s R 0.665, mean Brier’s score 0.132) in 200 repeated validation samples and performed well when compared with recalibrated versions of existing published risk prediction models in the cohort of patients eligible for all models. The hypothesis of perfect fit was rejected for all models, including the Intensive Care National Audit & Research Centre (ICNARC) model, as is to be expected in such a large cohort. Conclusions:The ICNARC model demonstrated better discrimination and overall fit than existing risk prediction models, even following recalibration of these models. We recommend it be used to replace previously published models for risk adjustment in the UK.