Stephen Brett

A Pilot-controlled Study Of A Polymyxin B-immobilized Hemoperfusion Cartridge In Patients With Severe Sepsis Secondary To Intra-abdominal Infection

Endotoxin is an important pathogenic trigger for sepsis. The polymyxin B-immobilized endotoxin removal hemoperfusion cartridge, Toraymyxin (hereafter PMX), has been shown to remove endotoxin in preclinical and open-label clinical studies. In a multicenter, open-label, pilot, randomized, controlled study conducted in the intensive care unit in six academic medical centers in Europe, 36 postsurgical patients with severe sepsis or septic shock secondary to intra-abdominal infection were randomized to PMX treatment of 2 h (n = 17) or standard therapy (n = 19). PMX was well tolerated and showed no significant side effects. There were no statistically significant differences in the change in endotoxin levels from baseline to 6 to 8 h after treatment or to 24 h after treatment between the two groups. There was also no significant difference in the change in interleukin (IL)-6 levels from baseline to 6 to 8 h after treatment or to 24 h after treatment between the two groups. Patients treated with PMX demonstrated significant increases in cardiac index (CI; P = 0.012 and 0.032 at days 1 and 2, respectively), left ventricular stroke work index (LVSWI, P = 0.015 at day 2), and oxygen delivery index (DO2I, P = 0.007 at day 2) compared with the controls. The need for continuous renal replacement therapy (CRRT) after study entry was reduced in the PMX group (P = 0.043). There was no significant difference between the groups in organ dysfunction as assessed by the Sequential Organ Failure Assessment (SOFA) scores from day 0 (baseline) to day 6. Treatment using the PMX cartridge is safe and may improve cardiac and renal dysfunction due to sepsis or septic shock. Further studies are needed to prove this effectiveness.

An exploration of social and economic outcome and associated health-related quality of life after critical illness in general intensive care unit survivors: a 12-month follow-up study.

IntroductionThe socio-economic impact of critical illnesses on patients and their families in Europe has yet to be determined. The aim of this exploratory study was to estimate changes in family circumstances, social and economic stability, care requirements and access to health services for patients during their first 12 months after ICU discharge.MethodsMulti-center questionnaire-based study of survivors of critical illness at 6 and 12 months after ICU discharge.ResultsData for 293 consenting patients who spent greater than 48 hours in one of 22 UK ICUs were obtained at 6 and 12 months post-ICU discharge. There was little evidence of a change in accommodation or relationship status between pre-admission and 12 months following discharge from an ICU. A negative impact on family income was reported by 33% of all patients at 6 months and 28% at 12 months. There was nearly a 50% reduction in the number of patients who reported employment as their sole source of income at 12 months (19% to 11%) compared with pre-admission. One quarter of patients reported themselves in need of care assistance at 6 months and 22% at 12 months. The majority of care was provided by family members (80% and 78%, respectively), for half of whom there was a negative impact on employment. Amongst all patients receiving care, 26% reported requiring greater than 50 hours a week. Following discharge, 79% of patients reported attending their primary care physician and 44% had seen a community nurse. Mobility problems nearly doubled between pre-admission and 6 months (32% to 64%). Furthermore, 73% reported moderate or severe pain at 12 months and 44% remained significantly anxious or depressed.ConclusionsSurvivors of critical illness in the UK face a negative impact on employment and commonly have a care requirement after discharge from hospital. This has a corresponding negative impact on family income. The majority of the care required is provided by family members. This effect was apparent by 6 months and had not materially improved by 12 months. This exploratory study has identified the potential for a significant socio-economic burden following critical illness.

MANNOSE-BINDING LECTIN POLYMORPHISMS IN SEVERE SEPSIS: RELATIONSHIP TO LEVELS, INCIDENCE, AND OUTCOME

Mannose-binding lectin (MBL) genetic polymorphisms result in deficiency of the encoded protein and increased susceptibility to infection, especially in children and the immunocompromised. The objective of this study was to investigate the relationship between MBL-2 exon 1 and promoter −221 polymorphisms, plasma levels of the encoded protein, and the incidence and outcome of severe sepsis and septic shock. One hundred seventy-four white adult patients with severe sepsis or septic shock were recruited in a prospective multicenter study across eight intensive care units in the South of England, UK. Genotype and haplotype frequencies were compared between normal population controls and patients, and between survivors and nonsurvivors. Plasma levels of encoded protein were related to genotype and outcome. The exon 1 polymorphisms (A/O or O/O) were significantly more common in the patients with severe sepsis and septic shock than in normal healthy adults (54.6% vs. 39.7%, P = 0.001), and there was a significant difference in haplotype frequency between controls and septic patients (P < 0.0001). There was no significant difference in MBL-2 genotype or haplotype frequency between survivors and nonsurvivors. There was a strong relationship between MBL-2 haplotype and plasma MBL concentration (P < 0.001). Individual plasma levels were variable and increased between days 1 and 7. The mortality rate was higher in those with MBL levels <1000 μg/L than in those patients with levels >1000 μg/L (47.2 vs. 22.2%, P = 0.05). We conclude that genetic polymorphisms resulting in mannose-binding lectin deficiency are associated with increased susceptibility to sepsis. The close relationship between polymorphic variants and plasma MBL concentration persists during sepsis but individual levels vary widely. Lower circulating MBL levels are associated with a poor outcome.

Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality

Objective To assess the efficacy and safety of pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of baseline hypoalbuminaemia) in critically unwell adults with sepsis of any severity. Design Systematic review and meta-analysis of randomised clinical trials, with trial sequential analysis, subgroup, and meta-regression analyses. Data sources PubMed, PubMed Central, Web of Science (includes Medline, Conference Proceedings Citation Index, Data Citation Index, Chinese Science Citation Database, CAB abstracts, Derwent Innovations Index), OvidSP (includes Embase, Ovid Medline, HMIC, PsycINFO, Maternity and Infant Care, Transport Database), Cochrane Library, clinicaltrials.gov, controlled-trials.com, online material, relevant conference proceedings, hand searching of reference lists, and contact with authors as necessary. Eligibility criteria Prospective randomised clinical trials of adults with sepsis of any severity (with or without baseline hypoalbuminaemia) in critical or intensive care who received pooled human albumin solutions as part of fluid volume expansion and resuscitation (with or without improvement of hypoalbuminaemia) compared with those who received control fluids (crystalloid or colloid), were included if all-cause mortality outcome data were available. No restriction of language, date, publication status, or primary study endpoint was applied. Data extraction Two reviewers independently assessed articles for inclusion, extracted data to assess risk of bias, trial methods, patients, interventions, comparisons, and outcome. The relative risk of all-cause mortality was calculated using a random effects model accounting for clinical heterogeneity. Primary outcome measure All-cause mortality at final follow-up. Results Eighteen articles reporting on 16 primary clinical trials that included 4190 adults in critical or intensive care with sepsis, severe sepsis, or septic shock. A median of 70.0 g daily of pooled human albumin was received over a median of 3 days by adults with a median age of 60.8 years as part of fluid volume expansion and resuscitation, with or without correction of hypoalbuminaemia. The relative risk of death was similar between albumin groups (that received a median of 175 g in total) and control fluid groups (relative risk 0.94; 95% confidence interval 0.87 to 1.01; P=0.11; I2=0%). Trial sequential analysis corrected the 95% confidence interval for random error (0.85 to 1.02; D2=0%). Eighty eight per cent of the required information size (meta-analysis sample size) of 4894 patients was achieved, and the cumulative effect size measure (z score) entered the futility area, supporting the notion of no relative benefit of albumin (GRADE quality of evidence was moderate). Evidence of no difference was also found when albumin was compared with crystalloid fluid (relative risk 0.93; 0.86 to 1.01; P=0.07; I2=0%) in 3878 patents (GRADE quality of evidence was high; 79.9% of required information size) or colloid fluids in 299 patients (relative risk 1.04; 0.79 to 1.38; P=0.76; I2=0%) (GRADE quality of evidence was very low; 5.8% of required information size). When studies at high risk of bias were excluded in a predefined subgroup analysis, the finding of no mortality benefit remained, and the cumulative z score was just outside the boundary of futility. Overall, the meta-analysis was robust to sensitivity, subgroup, meta-regression, and trial sequential analyses. Conclusions In this analysis, human albumin solutions as part of fluid volume expansion and resuscitation for critically unwell adults with sepsis of any severity (with or without baseline hypoalbuminaemia) were not robustly effective at reducing all-cause mortality. Albumin seems to be safe in this setting, as a signal towards harm was not detected, but this analysis does not support a recommendation for use.

Changes in appetite related gut hormones in intensive care unit patients: a pilot cohort study

IntroductionThe nutritional status of patients in the intensive care unit (ICU) appears to decline not only during their stay in the ICU but also after discharge from the ICU. Recent evidence suggests that gut released peptides, such as ghrelin and peptide YY (PYY) regulate the initiation and termination of meals and could play a role in the altered eating behaviour of sick patients. The aim of this study was to assess the patterns of ghrelin and PYY levels during the stay of ICU patients in hospital.MethodsSixteen ICU patients (60 ± 4.7 years, body mass index (BMI) 28.1 ± 1.7 kg/m2 (mean ± standard error of the mean)) underwent fasting blood sample collections on days 1, 3, 5, 14, 21 and 28 of their stay at Hammersmith and Charing Cross Hospitals. Changes in appetite and biochemical and anthropometric markers of nutritional status were recorded. A comparison was made to a group of 36 healthy volunteers matched for age and BMI (54.3 ± 2.9 years, p = 0.3; BMI 25.8 ± 0.8 kg/m2p = 0.2).ResultsCompared to healthy subjects, ICU patients exhibited a significantly lower level of ghrelin (day one 297.8 ± 76.3 versus 827.2 ± 78.7 pmol/l, p < 0.001) during their stay in the ICU. This tended to rise to the normal level during the last three weeks of hospital stay. Conversely, ICU patients showed a significantly higher level of PYY (day one 31.5 ± 9.6 versus 11.3 ± 1.0 pmol/l, p < 0.05) throughout their stay in the ICU and on the ward, with a downward trend to the normal level during the last three weeks of stay.ConclusionsResults from our study show high levels of PYY and low levels of ghrelin in ICU patients compared to healthy controls. There appears to be a relationship between the level of these gut hormones and nutritional intake.

Production of nitric oxide during surgery involving cardiopulmonary bypass

OBJECTIVES Surgery involving cardiopulmonary bypass induces an inflammatory response due to the contact of blood with the extracorporeal circuit. In some patients, this inflammatory response leads to multiple organ failure and death. Inflammatory states may increase the production of nitric oxide, either by increasing the activity of constitutive enzyme systems or by inducing of inflammation-specific systems. We hypothesized that surgery involving cardiopulmonary bypass would increase the production of nitric oxide in association with the inflammatory response. DESIGN Prospective, single center, observational study. SETTING University-affiliated, tertiary referral cardiothoracic center. PATIENTS Eleven adult patients undergoing routine myocardial revascularization. INTERVENTIONS Surgery for myocardial revascularization. MEASUREMENTS AND MAIN RESULTS Observations were made after induction of anesthesia, before bypass, after completion of the bypass, and on return to the recovery area. Parameters measured included hemodynamics, exhaled nitric oxide concentrations, plasma nitrate/nitrite concentration, plasma and bronchoalveolar lavage myeloperoxidase concentrations, and protein carbonyl conversion. All patients survived surgery. Oxygenation index fell significantly after bypass. Plasma myeloperoxidase increased significantly during the study period. Plasma carbonyl conversion also increased, although not significantly. Plasma nitrate/nitrite and airway nitric oxide concentrations did not change through the course of the study. CONCLUSION Surgery involving cardiopulmonary bypass induced a demonstrable inflammatory response, but this response was not associated with increased nitric oxide production.

The interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial.

Objectives:Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock. Design:Prospective open-label randomized controlled pilot trial. Setting:Four adult ICUs in London teaching hospitals. Patients:Sixty-one adult patients who had septic shock. Interventions:Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6–12 and 24–36 hours after hydrocortisone/placebo administration. Measurements and Main Results:Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1–5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32–0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, –32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups. Conclusions:Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids.

Exercise rehabilitation following hospital discharge in survivors of critical illness: an integrative review.

Although clinical trials have shown benefit from early rehabilitation within the ICU, rehabilitation of patients following critical illness is increasingly acknowledged as an area of clinical importance. However, despite recommendations from published guidelines for rehabilitation to continue following hospital discharge, there is limited evidence to underpin practice during this intermediate stage of recovery. Those patients with ICU-acquired weakness on discharge from the ICU are most likely to benefit from ongoing rehabilitation. Despite this, screening based on strength alone may fail to account for the associated level of physical functioning, which may not correlate with muscle strength, nor address non-physical complications of critical illness. The aim of this review was to consider which patients are likely to require rehabilitation following critical illness and to perform an integrative review of the available evidence of content and nature of exercise rehabilitation programmes for survivors of critical illness following hospital discharge. Literature databases and clinical trials registries were searched using appropriate terms and groups of terms. Inclusion criteria specified the reporting of rehabilitation programmes for patients following critical illness post-hospital discharge. Ten items, including data from published studies and protocols from trial registries, were included. Because of the variability in study methodology and inadequate level of detail of reported exercise prescription, at present there can be no clear recommendations for clinical practice from this review. As this area of clinical practice remains in its relative infancy, further evidence is required both to identify which patients are most likely to benefit and to determine the optimum content and format of exercise rehabilitation programmes for patients following critical illness post-hospital discharge.

Cerebral Oximetry During Cardiac Arrest: A Multicenter Study of Neurologic Outcomes and Survival.

Objectives: Cardiac arrest is associated with morbidity and mortality because of cerebral ischemia. Therefore, we tested the hypothesis that higher regional cerebral oxygenation during resuscitation is associated with improved return of spontaneous circulation, survival, and neurologic outcomes at hospital discharge. We further examined the validity of regional cerebral oxygenation as a test to predict these outcomes. Design: Multicenter prospective study of in-hospital cardiac arrest. Setting: Five medical centers in the United States and the United Kingdom. Patients: Inclusion criteria are as follows: in-hospital cardiac arrest, age 18 years old or older, and prolonged cardiopulmonary resuscitation greater than or equal to 5 minutes. Patients were recruited consecutively during working hours between August 2011 and September 2014. Survival with a favorable neurologic outcome was defined as a cerebral performance category 1–2. Interventions: Cerebral oximetry monitoring. Measurements and Main Results: Among 504 in-hospital cardiac arrest events, 183 (36%) met inclusion criteria. Overall, 62 of 183 (33.9%) achieved return of spontaneous circulation, whereas 13 of 183 (7.1%) achieved cerebral performance category 1–2 at discharge. Higher mean ± SD regional cerebral oxygenation was associated with return of spontaneous circulation versus no return of spontaneous circulation (51.8% ± 11.2% vs 40.9% ± 12.3%) and cerebral performance category 1–2 versus cerebral performance category 3–5 (56.1% ± 10.0% vs 43.8% ± 12.8%) (both p < 0.001). Mean regional cerebral oxygenation during the last 5 minutes of cardiopulmonary resuscitation best predicted the return of spontaneous circulation (area under the curve, 0.76; 95% CI, 0.69–0.83); regional cerebral oxygenation greater than or equal to 25% provided 100% sensitivity (95% CI, 94–100) and 100% negative predictive value (95% CI, 79–100); regional cerebral oxygenation greater than or equal to 65% provided 99% specificity (95% CI, 95–100) and 93% positive predictive value (95% CI, 66–100) for return of spontaneous circulation. Time with regional cerebral oxygenation greater than 50% during cardiopulmonary resuscitation best predicted cerebral performance category 1–2 (area under the curve, 0.79; 95% CI, 0.70–0.88). Specifically, greater than or equal to 60% cardiopulmonary resuscitation time with regional cerebral oxygenation greater than 50% provided 77% sensitivity (95% CI,:46–95), 72% specificity (95% CI, 65–79), and 98% negative predictive value (95% CI, 93–100) for cerebral performance category 1–2. Conclusions: Cerebral oximetry allows real-time, noninvasive cerebral oxygenation monitoring during cardiopulmonary resuscitation. Higher cerebral oxygenation during cardiopulmonary resuscitation is associated with return of spontaneous circulation and neurologically favorable survival to hospital discharge. Achieving higher regional cerebral oxygenation during resuscitation may optimize the chances of cardiac arrest favorable outcomes.

Priorities for Future Intensive Care Research in the UK: Results of a James Lind Alliance Priority Setting Partnership

This James Lind Alliance (JLA) Priority Setting Partnership aimed to identify and prioritise unanswered questions about adult intensive care that are important to people who have been critically ill, their families, and the health professionals who care for them. Consensus techniques (modified Delphi and Nominal Group) were used to generate suggestions using online and postal surveys. Following verification and iterative editorial review, research topics were constructed from these suggestions. These topics were presented in a second online and postal survey for rating. A Nominal Group of 21 clinicians, patients and family representatives subsequently met to rank the most important research topics and produce a prioritised list. The project was coordinated by a representative Steering Group and independently overseen by the JLA. The initial survey and review of the literature generated over 1,300 suggestions. Preliminary editing and verification permitted us to encapsulate these suggestions within 151 research topics. Iterative review by members of the Steering Group produced 37 topic statements, subsequently rated by participants. Using the mode to determine importance, 19 topics were presented to the group from which a ‘top three’ intensive care research priorities were identified and a further nine topics were prioritised. By applying and adapting the JLA methodology to focus on an area of care rather than to a single disease, we have provided a means to ensure that patients, their families and professionals materially contribute to the prioritisation of intensive care research in the UK.