Abstract
31R Evaluating our use of methylthioninium chloride (‘Methylene Blue’) for refractory septic shock in a district general hospital
DJ Stubbs, G Singleton, D Sapsford, C Phillips, AD Kane, C Kubitzek and C Swanevelder
32R Use of peripheral metaraminol on the intensive care unit
R Schofield, T Sreelakshmi and S Ridler
33R Ventilator-associated pneumonia on neuro intensive care – Is there a difference?
LM Ruff, A Harkanyi, P Nair and S Larkin
34R Fluid resuscitation of septic patients in Aberdeen Royal Infirmary
C Kaye and A Clarkin
35R Dimethylarginine dimethylaminohydrolase 2 is upregulated by interferon-γ which alters methylarginine metabolism and mediates nitric oxide synthesis by monocytes in ex vivo and in vivo models
S Lambden, S Piper, K Vanezis, J Tomlinson, L Doswett, M Singer and J Leiper
36R The lungs are a major site for uptake of circulating microvesicles during subclinical endotoxaemia
SV Shah, KP O'Dea, S Soni, KC Tatham and M Takata
37R Cost-effectiveness of early, goal-directed, protocolised resuscitation for septic shock
MZ Sadique, RD Grieve, DA Harrison, PR Mouncey, JD Young, KM Rowan and for the ProMISe Trial Investigators
31R Evaluating our use of methylthioninium chloride (‘Methylene Blue’) for refractory septic shock in a district general hospital
DJ Stubbs, G Singleton, D Sapsford, C Phillips, AD Kane, C Kubitzek, C Swanevelder
Department of Anaesthetics, Intensive Care Unit, West Suffolk Hospital, Suffolk, UK
Methylthioninium chloride (Methylene-blue ‘Met-Blue’) is used for treating septic shock but data are limited.1 We retrospectively evaluated Met-Blue use, complications and appropriateness of our current guideline of a 2-h consultant review. (Data are mean ± standard error of the mean unless stated.)
Hospital R&D approval was granted. Thirty-nine patients between 2011 and 2015 were analysed (median age 70 years; interquartile range (IQR): 61.5–72.6). Septic source: peritonitis 13, pneumonia 13, urinary 3, necrotising fasciitis 3, meningitis 1, unknown 6. Intensive care unit mortality was 48.6%.
Thirty-seven (95%) patients received a bolus of 3 mg·kg−1 over 30 min, 29 (78%) of these then received an infusion of 20 mg·h−1 for maximum 48 h. Two patients received an infusion only. Thirty-four (87%) patients received steroids and 23 (59%) haemodia filtration. After initial fluid resuscitation, median fluid input from t = −4 h was 1018 ml (IQR: 610–1484 ml).
Our guideline states that response (e.g. ↑mean arterial pressure, MAP) should be evaluated 2 h after Met-Blue administration. For patients with complete data between t = −1.5 to 0 and t = 0.5 to 2 h, we compared noradrenaline (NA) and MAP values pre- and post-Met-Blue. For MAP, analysis of 31 patients showed overall significant improvement in post-Met-Blue values (66 ± 0.9 vs. 70 ± 1.0 mmHg p = 0.008). For NA, 28 patients were analysed; 16 revealed no dose difference (p > 0.05, unpaired two-tailed t-test). Significant increases occurred in five and decreases in seven. Combined data from these 28 found no significant change in post-Met-Blue NA dose (0.206 ± 0.009 vs. 0.204 ± 0.009 µ·kg−1·min−1 p = 0.85). Figure 1 shows data for NA and MAP from t = −4.5 h to t = + 24 h. MAP:NA ratio (MN-ratio) was plotted; opposing changes in NA and MAP would lead to an increase in this ratio suggesting a positive effect. Best-fit curves for MN-ratio and NA were fitted (‘Plotly’, http://plot.ly). R2 values were >0.90. Resulting equations were differentiated and solved to find inflection points. The NA best-fit curve’s gradient becomes more negative at t = 1.9 h, that for the MN-ratio becomes more positive at t = −0.37 h, consistent with an overall increase in MAP or decrease in NA from this point.
Graph charting pooled data from 39 patients of average mean arterial pressures (MAP), noradrenaline dose (NA) and the ratio between them (MAP:NA ratio MN ratio) at time intervals from 4 h prior to Met-Blue to 24 h post. Error bars are ± SEM. Marked in red is 2-h consultant review period at which point our guideline states to look for a response and decide on continuing treatment as an infusion.
Methaemoglobin levels increased significantly after Met-Blue (0.83 ± 0.05% vs. 1.08 ± 0.05%, p = 0.001) but below our 3% threshold for stopping it. Met-Blue did not affect PaO2/FiO2 ratio in population (27.28 ± 2.1 vs. 28.29 ± 2.3, p = 0.75) or pneumonia cases (17.05 ± 1.7 vs. 21.55 ± 2.8 p = 0.15). Three patients were taking drugs predisposing to serotonin syndrome; none had symptoms with Met-Blue.
Following Met-Blue, MAP increased significantly but NA requirements did not change significantly. Further analysis of best-fit curves suggests a response should be seen within our consultant review period of 2-h post-administration. Reassuringly, we found no evidence of complications.
Reference
32R Use of peripheral metaraminol on the intensive care unit
R Schofield, T Sreelakshmi, S Ridler
Department of Anaesthesia, Countess of Chester NHS Foundation Trust, UK
In Mersey and North West region, 67% of intensive care unit’s use metaraminol infusion with 83% of these not having a policy for its use.
We propose a guideline for use of peripheral metaraminol infusion (Figure 1).
References
33R Ventilator-associated pneumonia on neuro intensive care – Is there a difference?
LM Ruff, A Harkanyi1, P Nair, and S Larkin3
1Department of Anaesthesia, University Hospital Aintree, Liverpool, UK
2Department of Anaesthesia and Intensive Care, The Walton Centre, Liverpool, UK
3Department of Microbiology, University Hospital Aintree, Liverpool, UK
Ventilator-associated pneumonia (VAP) is associated with significant morbidity and mortality.1 VAP is defined as pneumonia that occurs after 48–72 h or thereafter following endotracheal intubation.2 It is diagnosed by the presence of new infiltrate on chest X-ray, signs of systematic infection, changes in sputum characteristics and detection of causative agent.2 VAP rates are estimated between 1.2 and 8.5 per 1000 ventilator days depending on the diagnostic definition.3 There is limited data available about the incidence of VAP in neuro intensive care unit (neuro ICU). There is evidence that oral mouth care significantly reduces VAP rate.4,5 In our retrospective audit we determined the VAP rate on our neuro ICU and determine whether introduction of an alternative oral care method affected the VAP rate. We also compared the occurring microorganisms to the results of other ICUs.
Clinical Pulmonary Infection Scores (CPIS) were calculated on all ventilated intensive care patients on a UK Neurosurgical/Neurological Intensive Care Unit. Further information was then collected on ICU patients with a CPIS of greater or equal to six. The patients were split into two groups. The first was a 10-week period prior to introduction of oral care (group 1). The second was an eight-week period after the introduction of a new oral care practice (group 2). The oral care procedure included a tooth brush system with attached closed suctioning with the use of chlorhexidine mouthwash used three times a day. Data were collected retrospectively by case note review. A proforma was completed for each VAP episode and the data analysed.
In group 1, there were 17 patients that met our CPIS criteria, and in group 2, there were five patients. The total number of patient ventilator days for each group was 710 days and 472 days, respectively. The VAP rate was therefore calculated as 23.9 per 1000 ventilator days in group one and 10.6 per 1000 ventilator days in group two. Organisms were isolated from 17 patients (more than one organism is seven patients). The most commonly isolated organisms were Enterobacteriacae (seven cases), Staphylococcus aureus (five), Haemophilus influenzae (four) and Pseudomonas (four).
Our VAP rate appears to be higher than reported rates for general ICUs. VAP rate continues to be a difficult entity to measure accurately and varies with definition/diagnostic criteria. The case mix on neuro ICU compared to general ICU may also impact on VAP rate. Patients often need greater levels of sedation and longer periods of ventilation. The introduction of a new oral care routine appeared to reduce the VAP rate, although we recognise that the small number of cases make meaningful conclusions difficult. The microorganisms isolated were similar to published data, although there was a higher incidence of Haemophilus species and Enterobacteriaceae. The CPIS system has now been added to the patient’s daily observation charts to trigger a clinical review of whether a VAP is present. Further work should assess whether this helps identify VAP cases more accurately.
Acknowledgements
Thanks to Peter Jones (Audit Clerk) at The Walton Centre for assisting in data collection.
References
34R Fluid resuscitation of septic patients in Aberdeen Royal Infirmary
C Kaye, A Clarkin
Intensive Care Unit, Aberdeen Royal Infirmary, Aberdeen, Scotland
Three questions were then asked:
Type of fluid Volume of fluid administered before considering adding vasoactive support Goals of treatment
Twenty-six (62%) used Hartmann’s Solution, 12 (29%) used 0.9% saline and four (9.5%) used a mixture of colloid and crystalloid. No respondents chose to use purely colloids, albumin or dextrose.
Fluid volumes ranged from 1 L to 6 L (median 2 L). Sixty-five percent (26) identified a volume within 500 ml of the target (2.5 L).
Comparing against the SSC guidelines, four respondents identified the suggested treatment goals, apart from SCVO2. When ignoring central venous pressure (CVP), 10 respondents identified the remaining goals.
Although CVP measurement was unpopular among the respondents, this may reflect the increasing evidence against CVP in fluid resuscitation.2 However, even when excluding CVP and SCVO2, less than 25% identified the remaining goals of treatment. Patient care could be improved with increased awareness of the SCC bundle.
References
35R Dimethylarginine dimethylaminohydrolase 2 is upregulated by interferon-γ which alters methylarginine metabolism and mediates nitric oxide synthesis by monocytes in ex vivo and in vivo models
S Lambden1, S Piper1, K Vanezis1, J Tomlinson1, L Doswett1, M Singer2 and J Leiper1
1Nitric Oxide Signalling Group, Clinical Sciences Centre, MRC, Hammersmith Hospital, London, UK
2Bloomsbury Institute for Intensive Care, UCL, London, UK
Cell culture: The murine macrophage cell line (RAW 264.7) was used to assess the impact of differing pro-inflammatory stimuli on NO synthesis and its endogenous regulators. Sections of the human DDAH2 promoter region were inserted by electroporation into these cells to facilitate identification of potential activation sites.
Ex vivo model: Peritoneal macrophages were isolated from wild-type C57Bl6 mice, and from mice deficient in monocyte DDAH2 (DDAH2MΦ-) developed using the LoxP Cre recombinase model and their flox/flox controls (DDAH2flox/flox). The impact of differing stimuli on NO synthesis and its regulation were compared in these two groups.
In vivo model: DDAH2MΦ- mice and their DDAH2flox/flox littermate controls underwent intraperitoneal injection of polyinositic polycytidylic acid (Poly I:C), a viral ‘mimic’. Indwelling radiofrequency monitoring of body temperature and terminal blood sampling at 6 h was undertaken to establish the role of monocyte DDAH2 in the systemic response to this stimulus.
Monocyte synthesis of ADMA, expression of the regulatory enzyme DDAH2 and NO production were measured using mass spectrometry, quantitative PCR and chemiluminescent techniques, respectively.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was part funded by a project grant from the Royal College of Anaesthetists.
Proposed use of peripheral metaraminol.
References
36R The lungs are a major site for uptake of circulating microvesicles during subclinical endotoxaemia
SV Shah1,2, KP O'Dea1,2, S Soni1,2, KC Tatham1,2 and M Takata1,2
1Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea, UK
2Westminster Hospital, London, UK
Microvesicles (MVs) are membrane-enclosed particles released from activated or dying cells, which represent an emerging pathway of long-range intercellular communication, and may play an important role in the pathophysiology of sepsis.1 Organ uptake of circulating MVs is critical in determining their role in the propagation of systemic inflammation, and under normal conditions has been ascribed mainly to the liver but also to the lungs and spleen.2,3 We previously demonstrated that during subclinical endotoxaemia, uptake of microbial particles (yeast, bacteria) in the lungs is enhanced by ‘marginated’ monocytes and neutrophils within the pulmonary microcirculation.4 We hypothesised that such inflammatory priming would similarly result in significant increases in capture of MVs by the lungs, with implications for sepsis-related lung injury. We therefore examined cellular uptake of MVs in different organs in mice with and without subclinical endotoxaemia.
MVs were obtained from J774A.1 macrophages, by stimulation with ATP (3 mM) for 30 min and isolation by differential centrifugation. MVs were labelled with the fluorescent membrane-intercalating dye, DiD (Ex 644 nm; Em 665 nm) and injected intravenously (i.v.) into control untreated C57BL/6 mice, or mice pre-treated with low-dose lipopolysaccharide (LPS) (20 ng, i.v. 2 h). After 1 h, mice were sacrificed and single cell suspensions prepared from the lungs, liver and spleen for flow cytometric analysis of leukocyte and endothelial cell-associated DiD-fluorescence.
In control mice, MV uptake occurred primarily in the liver by Kupffer cells and to a lesser degree by endothelial cells (Figure 1(a)). In the lungs, uptake was limited to intravascular lung-marginated monocytes (Figure 1(b)), although at much lower levels than in Kupffer cells. Subclinical endotoxaemia enhanced Ly-6Chigh monocyte subset margination to the lungs and liver, and resulted in substantial increases (∼3-fold) in their uptake of MVs. By contrast, uptake levels remained low in lung Ly-6Clow monocytes, neutrophils and endothelial cells, while in the liver, Kupffer and endothelial cell uptake was substantially reduced. MV capture in the spleen was negligible in control and endotoxaemic mice. To investigate these findings further, we performed experiments in ex vivo isolated perfused lungs from LPS-pre-treated mice. Preliminary results indicated a similar in vivo pattern of MV uptake, with DiD-fluorescence limited mainly to Ly-6Chigh monocytes.
These findings indicate that MV-cell interactions within the vasculature are dynamic, with subclinical systemic inflammation resulting in a significant redistribution of MV uptake from the hepatic to the pulmonary microcirculation. This could have important implications for the propagation of organ injury during sepsis.
Flow cytometric analysis of cell-associated DiD-flourescence in the liver (a) and lungs (b) of normal (white bars, n = 4) and LPS pre-treated (grey bars, n = 4) mice. DiD-fluorescent macrophage MVs were prepared in vitro and then administered systemically via i.v tail injection. After 1 h, organs were harvested and processed to allow quantification of MV uptake at the single cell level. Values refer to median fluorescence intensity of DiD (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt), [*p < 0.05, **p < 0.01, dotted line represents background cell autofluorescence in non-LPS pre-treated mice which did not receive a MV injection (n = 4)].
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funded by the Chelsea and Westminster Health Charity.
References
37R Cost-effectiveness of early, goal-directed, protocolised resuscitation for septic shock
MZ Sadique1, RD Grieve1, DA Harrison2, PR Mouncey2, JD Young3, KM Rowan2 and for the ProMISe Trial Investigators
1Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK
2Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, UK
3Nuffield Division of Anaesthetics, University of Oxford, Oxford, UK
Early, goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with septic shock. However, three recent, large, multicentre randomised controlled trials have shown no difference in clinical outcomes1–3 or in cost-effectiveness at 90 days3 compared with usual resuscitation. The aim of the study was to evaluate the cost-effectiveness of EGDT versus usual resuscitation at one year and over the lifetime for patients with septic shock presenting to emergency departments in England.
We undertook a cost-effectiveness analysis (CEA) using data from a large, pragmatic, multi-centre randomised controlled trial, the ProMISe trial, which recruited patients from 56 emergency departments in England.3 Resource use and outcome data on 1243 trial patients were used to report cost-effectiveness at one year and to project lifetime cost-effectiveness. The CEA used information on health-related quality of life at 90 days and at one year combined with information on vital status to report Quality-Adjusted Life Years (QALYs). Each QALY was valued using the NICE recommended threshold of willingness-to-pay (£20,000 per QALY) in conjunction with the costs of each intervention to report the incremental net monetary benefits (INB) of EGDT versus usual care.
At one year following randomisation, a slightly higher proportion of patients in the EGDT group were alive compared with the usual resuscitation group (334/558 (59.9%) versus 325/558 (58.2%)). However, the net effect of patients in the EGDT group having higher survival, but lower average health-related quality of life, resulted in similar one-year QALYs between the treatment groups (mean difference 0.002, 95% confidence interval (CI) − 0.036 to 0.040). The mean total cost was higher for patients in the EGDT group, with an incremental cost of £764 (95% CI − £1,402 to 2,930). Hence, the incremental net benefit for EGDT versus usual resuscitation was negative at − £725 (95% CI − £3,000 to £1,550). The probability that EGDT is cost-effective, at the recommended threshold of £20,000 per QALY, was below 30%. Cost-effectiveness results were similar when extrapolated to the lifetime (INB − £1,446, 95% CI − £8,102 to £5,210).
For adult patients presenting to the emergency department with septic shock, EGDT is unlikely to be cost-effective compared with usual resuscitation.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NIHR Health Technology Assessment Programme (07/37/47).