Immunomodulatory drugs in sepsis: a systematic review and meta-analysis.

Dysregulation of the host immune response has a central role in the pathophysiology of sepsis. There has been much interest in immunomodulatory drugs as potential therapeutic adjuncts in sepsis. We conducted a systematic review and meta-analysis of randomised controlled trials evaluating the safety and clinical effectiveness of immunomodulatory drugs as adjuncts to standard care in the treatment of adults with sepsis. Our primary outcomes were serious adverse events and all-cause mortality. Fifty-six unique, eligible randomised controlled trials were identified, assessing a range of interventions including cytokine inhibitors; anti-inflammatories; immune cell stimulators; platelet pathway inhibitors; and complement inhibitors. At 1-month follow-up, the use of cytokine inhibitors was associated with a decreased risk of serious adverse events, based on 11 studies involving 7138 patients (RR (95%CI) 0.95 (0.90-1.00), I2 = 0%). The only immunomodulatory drugs associated with an increased risk of serious adverse events were toll-like receptor 4 antagonists (RR (95%CI) 1.18 (1.04-1.34), I2 = 0% (two trials, 567 patients)). Based on 18 randomised controlled trials, involving 11,075 patients, cytokine inhibitors reduced 1-month mortality (RR (95%CI) 0.88 (0.78-0.98), I2 = 57%). Mortality reduction was also shown in the subgroup of 13 randomised controlled trials that evaluated anti-tumour necrosis factor α interventions (RR (95%CI) 0.93 (0.87-0.99), I2 = 0%). Anti-inflammatory drugs had the largest apparent effect on mortality at 2 months at any dose (two trials, 228 patients, RR (95%CI) 0.64 (0.51-0.80), I2 = 0%) and at 3 months at any dose (three trials involving 277 patients, RR (95%CI) 0.67 (0.55-0.81), I2 = 0%). These data indicate that, except for toll-like receptor 4 antagonists, there is no evidence of safety concerns for the use of immunomodulatory drugs in sepsis, and they may show some short-term mortality benefit for selected drugs.

Analysis of exhaled breath to identify critically ill patients with ventilator-associated pneumonia.

Ventilator-associated pneumonia commonly occurs in critically ill patients. Clinical suspicion results in overuse of antibiotics, which in turn promotes antimicrobial resistance. Detection of volatile organic compounds in the exhaled breath of critically ill patients might allow earlier detection of pneumonia and avoid unnecessary antibiotic prescription. We report a proof of concept study for non-invasive diagnosis of ventilator-associated pneumonia in intensive care (the BRAVo study). Mechanically ventilated critically ill patients commenced on antibiotics for clinical suspicion of ventilator-associated pneumonia were recruited within the first 24 h of treatment. Paired exhaled breath and respiratory tract samples were collected. Exhaled breath was captured on sorbent tubes and then analysed using thermal desorption gas chromatography-mass spectrometry to detect volatile organic compounds. Microbiological culture of a pathogenic bacteria in respiratory tract samples provided confirmation of ventilator-associated pneumonia. Univariable and multivariable analyses of volatile organic compounds were performed to identify potential biomarkers for a 'rule-out' test. Ninety-six participants were enrolled in the trial, with exhaled breath available from 92. Of all compounds tested, the four highest performing candidate biomarkers were benzene, cyclohexanone, pentanol and undecanal with area under the receiver operating characteristic curve ranging from 0.67 to 0.77 and negative predictive values from 85% to 88%. Identified volatile organic compounds in the exhaled breath of mechanically ventilated critically ill patients show promise as a useful non-invasive 'rule-out' test for ventilator-associated pneumonia.

Sugar or salt ("SOS"): A protocol for a UK multicentre randomised trial of mannitol and hypertonic saline in severe traumatic brain injury and intracranial hypertension.

Hyperosmolar solutions are widely used to treat raised intracranial pressure following severe traumatic brain injury. Although mannitol has historically been the most frequently administered, hypertonic saline solutions are increasingly being used. However, definitive evidence regarding their comparative effectiveness is lacking. The Sugar or Salt Trial is a UK randomised, allocation concealed open label multicentre pragmatic trial designed to determine the clinical and cost-effectiveness of hypertonic saline compared with mannitol in the management of patients with severe traumatic brain injury. Patients requiring intensive care unit admission and intracranial pressure monitoring post-traumatic brain injury will be allocated at random to receive equi-osmolar boluses of either mannitol or hypertonic saline following failure of routine first-line measures to control intracranial pressure. The primary outcome for the study will be the Extended Glasgow Outcome Scale assessed at six months after randomisation. Results will inform current clinical practice in the routine use of hyperosmolar therapy as well as assess the impact of potential side effects. Pre-planned longer term clinical and cost effectiveness analyses will further inform the use of these treatments.

Vital signs and estimated blood loss in patients with major trauma: testing the validity of the ATLS classification of hypovolaemic shock.

AIM: The Advanced Trauma Life Support (ATLS) system classifies the severity of shock. The aim of this study is to test the validity of this classification. METHODS: Admission physiology, injury and outcome variables from adult injured patients presenting to hospitals in England and Wales between 1989 and 2007 and stored on the Trauma Audit and Research Network (TARN) database, were studied. For each patient, the blood loss was estimated and patients were divided into four groups based on the estimated blood loss corresponding to the ATLS classes of shock. The median and interquartile ranges (IQR) of the heart rate (HR) systolic blood pressure (SBP), respiratory rate (RR) and Glasgow Coma Score (GCS) were calculated for each group. RESULTS: The median HR rose from 82 beats per minute (BPM) in estimated class 1 shock to 95 BPM in estimated class 4 shock. The median SBP fell from 135 mm Hg to 120 mm Hg. There was no significant change in RR or GCS. CONCLUSION: With increasing estimated blood loss there is a trend to increasing heart rate and a reduction in SBP but not to the degree suggested by the ATLS classification of shock.

Testing the validity of the ATLS classification of hypovolaemic shock.

AIM: The Advanced Trauma Life Support system classifies the severity of shock. The aim of this study is to test the validity of this classification. METHODS: Admission physiology, injury and outcome variables from adult injured patients presenting to hospitals in England and Wales between 1989 and 2007 and stored on the Trauma Audit and Research Network (TARN) database, were studied. Patients were divided into groups representing the four ATLS classes of shock, based on heart rate (HR) systolic blood pressure (SBP), respiratory rate (RR) and Glasgow Coma Score (GCS). The relationships between variables were examined by classifying the cohort by each recorded variable in turn and deriving the median and interquartile range (IQR) of the remaining three variables. Patients with penetrating trauma and major injuries were examined in sub-group analyses. RESULTS: In blunt trauma patients grouped by HR, the median SBP decreased from 128 mmHg in patients with HR<100 BPM to 114 mmHg in those with HR>140 BPM. The median RR increased from 18 to 22 bpm and the GCS reduced from 15 to 14. The median HR in hypotensive patients was 88 BPM compared to 83 BPM in normotensive patients and the RR was the same. When grouped by RR, the HR increased with increasing RR but there were no changes in SBP. CONCLUSION: In trauma patients there is an inter-relationship between derangements of HR, SBP, RR and GCS but not to the same degree as that suggested by the ATLS classification of shock.

Instantaneous versus average wave speed calculation in large mammals under acute hemorrhage.

Arterial blood pressure and velocity pulse wave speed are important biomarkers of arterial stiffness and cardiovascular disease risk in man. Arterial wave speed is usually assessed using pulse wavefront movement over a known finite portion of the arterial tree. In our pilot study we assess a new technique for determining instantaneous wave speed using "wave intensity analysis" of simultaneously recorded high fidelity pressure and velocity waveforms at a single point in the porcine aorta during acute changes in hemodynamic status (hemorrhage). The results, when compared with a traditional wavefront approach over a length of aorta, suggest that the two techniques produce different results that could be explained by the varying properties along the aorta from heart to periphery. We show that instantaneous wave speed can be determined and monitored during acute hemodynamic change using "wave intensity analysis" at one point in the aorta. Furthermore, we uncovered discrepancies between instantaneous and averaged wave speed, which will be important in understanding the integrative physiology of acute cardiovascular perturbations and could have important application in monitoring the progression of chronic cardiovascular diseases.

Differences between brain and rectal temperatures during routine critical care of patients with severe traumatic brain injury.

Theoretical models suggest that small differences only exist between brain and body temperature in health. Once the brain is injured, brain temperature is generally regarded to rise above body temperature. However, since reports of the magnitude of the temperature gradient between brain and body vary, it is still not clear whether conventional body temperature monitoring accurately predicts brain temperature at all times. In this prospective, descriptive study, 20 adults with severe primary brain trauma were studied during their stay in the neurointensive care unit. Brain temperature ranged from 33.4 to 39.9 degrees C. Comparisons between paired brain and rectal temperature measurements revealed no evidence of a systematic difference [mean difference -0.04 degrees C (range -0.13 to 0.05 degrees C, 95% CI), p = 0.39]. Contrary to popular belief, brain temperature did not exceed systemic temperature in this relatively homogeneous patient series. The mean values masked inconsistent and unpredictable individual brain-rectal temperature differences (range 1.8 to -2.9 degrees C) and reversal of the brain-body temperature gradient occurred in some patients. Brain temperature could not be predicted from body temperature at all times.

Estimation of errors in determining intrathoracic blood volume using thermal dilution in pigs with acute lung injury and haemorrhage.

BACKGROUND: Global end diastolic volume (GEDV) has a constant and predictable relationship to intrathoracic blood volume (ITBV). The present study assesses the difference between ITBV derived from GEDV and ITBV measured directly in pigs with acute lung injury (ALI) and mild haemorrhage. METHODS: We caused ALI in 12 anaesthetized pigs by i.v. injection of oleic acid and removed 10% of estimated blood volume. EVLW, GEDV, ITBV (COLD; Pulsion Medical Systems), Pa(o(2))/Fi(o(2)), lung compliance and haemodynamic variables were measured at baseline (time 0) and at 30 and 120 min. All animals were volume-resuscitated, followed by measurements at 180 min. A linear equation estimated from the 44 pairs of ITBV and GEDV values in 11 animals was applied iteratively to the four GEDV measurements in the 12th animal, enabling 48 comparisons between measured (ITBVm) and derived ITBV (ITBVd) to be made. RESULTS: Increase in extravascular lung water index (EVLWi) was associated with significant pulmonary hypertension, worsening of oxygenation and compliance (repeated measures ANOVA; P<0.05). There was good within-subject correlation and agreement between ITBV(m) and ITBV(d) (r=0.72, mean bias 0.8 ml; sd 32 ml). Mean error in deriving ITBV from GEDV was 4.5%. (sd 4.2%; range 0.05-19%). There were no significant differences in errors in the presence of small (up to 10%) deficits in blood volume (F=1.0; P=0.41). CONCLUSIONS: ITBV estimated by thermodilution alone is comparable to measurements made by the thermo-dye dilution technique in the presence of pulmonary hypertension and mild deficits in total blood volume.

Effects of sustained post-traumatic shock and initial fluid resuscitation on extravascular lung water content and pulmonary vascular pressures in a porcine model of shock.

BACKGROUND: The temporal evolution of lung injury following post-traumatic shock is poorly understood. In the present study we have tested the hypothesis that manifestations of pulmonary vascular dysfunction may be demonstrable within the first hour after the onset of shock. METHODS: Twenty-nine anaesthetized pigs (mean weight 27.4 kg; (SD) 3.2) were randomly allocated to three groups: control (C, n=9), shock resuscitated with either NaCl 0.9% (S, n=10), or 4% gelatine (G, n=10). Shock was maintained for 1 h followed by fluid resuscitation with either normal saline or 4% gelatine solution. Cardiac output (CO), mean arterial pressure (MAP), mixed venous saturation (Sv(O(2))), blood lactate concentration, mean pulmonary artery pressure (MPAP), MPAP/MAP, pulmonary vascular resistance (PVR), extravascular lung water index (EVLWi), Pa(O(2))/FI(O(2)), venous admixture (Q(.)(S)/Q(.)(T)), and dynamic lung compliance (C(dyn)) were measured at baseline, beginning of shock phase, end of shock phase, and post-resuscitation. RESULTS: At the end of volume resuscitation CO was restored to control values in both shock groups. MAP remained significantly below control values (95% CI: C=70-95, S=28-52, G=45-69 mm Hg) in both shock groups. MPAP/MAP was significantly greater in both shock groups at the end of the shock phase (95% CI; C=0.15-0.24, S=0.28-0.38, G=0.32-0.42) and at the post-resuscitation phase (95% CI: C=0.12-0.30, S=0.43-0.61, G=0.32-0.49) indicating the presence of relative pulmonary hypertension. This was associated with a significant increase in PVR in Group S (F=3.9; P<0.05). There were no significant changes in Pa(O(2))/FI(O(2)), Q(.)(S)/Q(.)(T), EVLWi, or C(dyn). In a small cohort of animals a measurable increase in EVLWi (>30%) and reduction in C(dyn) (>10%) were observed. CONCLUSIONS: Pulmonary vascular injury manifesting as relative pulmonary hypertension and increased PVR may occur within the first hour after the onset of shock. These changes may not be accompanied by overt changes in oxygenation, compliance, or EVLWi. Br J Anaesth 2003; 91: 224-32

Monitoring the circulatory responses of shocked patients during fluid resuscitation in the emergency department.

OBJECTIVES: To assess the feasibility of constructing left ventricular response curves non-invasively during the fluid resuscitation of critically ill patients in the emergency department (ED) using a portable suprasternal Doppler ultrasound (PSSDU) device. DESIGN: Prospective case series. SETTING: Emergency department, Catholic University of Leuven, Belgium. PATIENTS: Shocked patients in the ED were diagnosed by predefined criteria. Only those thought to require standardised intravenous colloid challenges were observed i. e., sequential boluses of 3.5 ml/kg/10 min titrated against changes in stroke distance (Doppler surrogate for left ventricular stroke volume). RESULTS: A total of 50 shocked patients were studied. Stroke distance was measurable in 45 patients. 35 patients were fluid responders in terms of stroke distance. Group mean stroke distance increased during resuscitation (8.6 +/- 4.1 cm to 19.5 +/- 4.6 cm, P < 0.001) and then reached a plateau value (19.6 +/- 4.6 cm, P = 0.488). No response to fluid was seen in nine patients of which eight had severe sepsis. Alternative therapeutic approaches increased stroke distance for all of these patients. Evidence for right ventricular dysfunction was found as a cause for fluid non-response in the majority of patients with sepsis. CONCLUSIONS: Previous experimental work has shown that changes in central blood flow can be derived using the PSSDU device. This clinical feasibility study suggests that the PSSDU can help tailor haemodynamic therapy for an individual patient and give an early indication of treatment failure in the ED.

Cyclic neutropenia--unusual cause of acute abdomen. Report of a case.

Cyclic neutropenia, a rare blood disorder, may be complicated by spontaneous necrosis of the cecum and ascending colon. We describe one such case, where a staged surgical approach achieved a successful outcome. The importance of recognition of this disorder is stressed, since this allows both performance of appropriate surgery and consultation with hematologic colleagues.

An objective analysis of an accident flying squad.

An objective evaluation of an accident flying squad, in relation to trauma call-outs during a six month period, was performed using the Injury Severity Score and the recently described Revised TRISS methodology. We have demonstrated improvement in patient survival for those trauma cases treated at the scene. This has not been previously documented. Objective evaluation of these squads in relation to medical emergencies is even more difficult. The profile of these call-outs is described. (11.1%) of those treated at the scene for cardiac arrest survived to leave hospital. Ventricular fibrillation was the primary arrhythmia recorded in this group of survivors. This supports the vogue for extended ambulance personnel training.