2009 Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial

Presented by Dr CHU Po Ngai Alvin, ICU, PYNEH, Hong Kong, on 2 June 2009
John F Potter FRCP a , Thompson G Robinson FRCP b, Gary A Ford FRCP d, Amit Mistri MRCP b, Martin James FRCP e, Julia Chernova MSc f, Carol Jagger PhD c ‡The Lancet Neurology, Volume 8, Issue 1, Pages 48 - 56, January 2009
Editor's note: This negative study is underpowered due to difficulty in recruitment, despite the fact that in the calculation for study power and the number of subjects required the assumed difference was already quite large and 1-beta was only 0.8. Results are therefore difficult to comment or apply.

Background: Raised blood pressure is common after acute stroke and is associated with an adverse prognosis. We sought to assess the feasibility, safety, and effects of two regimens for lowering blood pressure in patients who have had a stroke.

Methods: Patients who had cerebral infarction or cerebral haemorrhage and were hypertensive (systolic blood pressure [SBP] >160 mm Hg) were randomly assigned by secure internet central randomisation to receive oral labetalol, lisinopril, or placebo if they were non-dysphagic, or intravenous labetalol, sublingual lisinopril, or placebo if they had dysphagia, within 36 h of symptom onset in this double-blind pilot trial. The doses were titrated up if target blood pressure was not reached. Analysis was by intention to treat. This trial is registered with the National Research Register, number N0484128008.

Read more ...

2009 Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial - The CLOTS Trials Collaboration

The Lancet, Early Online Publication, 27 May 2009 doi:10.1016/S0140-6736(09)60941-7

Background: Deep vein thrombosis (DVT) and pulmonary embolism are common after stroke. In small trials of patients undergoing surgery, graduated compression stockings (GCS) reduce the risk of DVT. National stroke guidelines extrapolating from these trials recommend their use in patients with stroke despite insufficient evidence. We assessed the effectiveness of thigh-length GCS to reduce DVT after stroke.

Read more ...

2009 Seminar: Stress hyperglycaemia

Kathleen M Dungan MD, Prof Susan S Braithwaite MD, Prof Jean-Charles Preiser MD. The Lancet, Volume 373, Issue 9677, Pages 1798 - 1807, 23 May 2009

Results of randomised controlled trials of tight glycaemic control in hospital inpatients might vary with population and disease state. Individualised therapy for different hospital inpatient populations and identification of patients at risk of hyperglycaemia might be needed.

Read more ...

2009 Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial

William D Schweickert MD a, Mark C Pohlman MD b, Anne S Pohlman MSN b, et al. The Lancet, Early Online Publication, 14 May 2009

Background: Long-term complications of critical illness include intensive care unit (ICU)-acquired weakness and neuropsychiatric disease. Immobilisation secondary to sedation might potentiate these problems. We assessed the efficacy of combining daily interruption of sedation with physical and occupational therapy on functional outcomes in patients receiving mechanical ventilation in intensive care.

Read more ...

2009 Review: Intracerebral haemorrhage

The Lancet, Volume 373, Issue 9675, Pages 1632 - 1644, 9 May 2009

Dr Adnan I Qureshi MD a , A David Mendelow FRCS b, Daniel F Hanley MD c
a Zeenat Qureshi Stroke Research Center, Department of Neurology and Neurosurgery, University of Minnesota, MN, Minnesota, USA
b Department of Neurosurgery, University of Newcastle, Newcastle, UK
c Division of Brain Injury Outcomes, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Summary
Intracerebral haemorrhage is an important public health problem leading to high rates of death and disability in adults. Although the number of hospital admissions for intracerebral haemorrhage has increased worldwide in the past 10 years, mortality has not fallen. Results of clinical trials and observational studies suggest that coordinated primary and specialty care is associated with lower mortality than is typical community practice.

Read more ...

2009 Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease

The Lancet Infectious Diseases, Volume 9, Issue 5, Pages 301 - 311, May 2009

Philippe Brouqui MD a , Vincenzo Puro MD b, Francesco M Fusco MD b, Barbara Bannister MSc c, Stephan Schilling MD d, Per Follin MD e, René Gottschalk MD f, Robert Hemmer MD g, Helena C Maltezou MD h, Kristi Ott MD i, Renaat Peleman MD j, Christian Perronne MD k, Gerard Sheehan MD l, Heli Siikamäki MD m, Peter Skinhoj MD n, Giuseppe Ippolito MD b, for the EUNID Working Group‡

Summary
The European Network for Infectious Diseases (EUNID) is a network of clinicians, public health epidemiologists, microbiologists, infection control, and critical-care doctors from the European member states, who are experienced in the management of patients with highly infectious diseases. We aim to develop a consensus recommendation for infection control during clinical management and invasive procedures in such patients.

Read more ...

2009 Lancet Editorial: Swine influenza: how much of a global threat?

Editorial, The Lancet, Early Online Publication, 29 April 2009

On April 27, WHO raised its pandemic alert level from phase 3 to phase 4 after human cases of a novel H1N1 swine influenza A virus spread quickly around the world from its origin in Mexico.

Read more ...

2009 Gram-positive toxic shock syndromes

The Lancet Infectious Diseases, Volume 9, Issue 5, Pages 281 - 290, May 2009

Summary
Toxic shock syndrome (TSS) is an acute, multi-system, toxin-mediated illness, often resulting in multi-organ failure. It represents the most fulminant expression of a spectrum of diseases caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes (group A streptococcus).

Read more ...

2009 Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up

The Lancet Neurology, Volume 8, Issue 5, Pages 427 - 433, May 2009

Andrew J Molyneux FRCR a , Richard SC Kerr FRCS a, Jacqueline Birks MSc b, Najib Ramzi MD a, Julia Yarnold MA a, Mary Sneade BA a, Joan Rischmiller RGN a, for the ISAT collaborators
 

Summary
Background
Our aim was to assess the long-term risks of death, disability, and rebleeding in patients randomly assigned to clipping or endovascular coiling after rupture of an intracranial aneurysm in the follow-up of the International Subarachnoid Aneurysm Trial (ISAT).
Methods
2143 patients with ruptured intracranial aneurysms were enrolled between 1994 and 2002 at 43 neurosurgical centres and randomly assigned to clipping or coiling. Clinical outcomes at 1 year have been previously reported. All UK and some non-UK centres continued long-term follow-up of 2004 patients enrolled in the original cohort. Annual follow-up has been done for a minimum of 6 years and a maximum of 14 years (mean follow-up 9 years). All deaths and rebleeding events were recorded. Analysis of rebleeding was by allocation and by treatment received. ISAT is registered, number ISRCTN49866681.

Read more ...

2009 Effect of whole-body CT during trauma resuscitation on survival: a retrospective, multicentre study

The Lancet, Early Online Publication, 24 March 2009doi:10.1016/S0140-6736(09)60232-4Cite or Link Using DOI

Dr Stefan Huber-Wagner MD a , Rolf Lefering PhD b, Lars-Mikael Qvick MD a, Markus Körner MD c, Michael V Kay a, Prof Klaus-Jürgen Pfeifer PhD c, Prof Maximilian Reiser PhD c, Prof Wolf Mutschler PhD a, Karl-Georg Kanz PhD a, on behalf of the Working Group on Polytrauma of the German Trauma Society‡

Summary

Background
The number of trauma centres using whole-body CT for early assessment of primary trauma is increasing. There is no evidence to suggest that use of whole-body CT has any effect on the outcome of patients with major trauma. We therefore compared the probability of survival in patients with blunt trauma who had whole-body CT during resuscitation with those who had not.

Methods
In a retrospective, multicentre study, we used the data recorded in the trauma registry of the German Trauma Society to calculate the probability of survival according to the trauma and injury severity score (TRISS), revised injury severity classification (RISC) score, and standardised mortality ratio (SMR, ratio of recorded to expected mortality) for 4621 patients with blunt trauma given whole-body or non-whole-body CT.

Read more ...

2008 Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial

Lancet Neurol. 2008 May;7(5):391-9. Epub 2008 Apr 7

Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, Heeley E, Skulina C, Parsons MW, Kim JS, Tao QL, Li YC, Jiang JD, Tai LW, Zhang JL, Xu E, Cheng Y, Heritier S, Morgenstern LB, Chalmers J; INTERACT Investigators.


BACKGROUND:
There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial.

METHODS:
Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096.

Read more ...

2009 Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study

The Lancet, Early Online Publication, 27 January 2009

Dirk Vlasselaers MD a ‡, Ilse Milants RN a ‡, Lars Desmet MD a ‡, Pieter J Wouters MSc a, Ilse Vanhorebeek PhD a, Ingeborg van den Heuvel MD a, Dieter Mesotten MD a, Michael P Casaer MD a, Geert Meyfroidt MD a, Catherine Ingels MD a, Jan Muller MD a, Sophie Van Cromphaut MD a, Miet Schetz MD a, Prof Greet Van den Berghe MD a 

Summary

Background
Critically ill infants and children often develop hyperglycaemia, which is associated with adverse outcome; however, whether lowering blood glucose concentrations to age-adjusted normal fasting values improves outcome is unknown. We investigated the effect of targeting age-adjusted normoglycaemia with insulin infusion in critically ill infants and children on outcome.
Methods
In a prospective, randomised controlled study, we enrolled 700 critically ill patients, 317 infants (aged <1 year) and 383 children (aged ≥1 year), who were admitted to the paediatric intensive care unit (PICU) of the University Hospital of Leuven, Belgium. Patients were randomly assigned by blinded envelopes to target blood glucose concentrations of 2·8-4·4 mmol/L in infants and 3·9-5·6 mmol/L in children with insulin infusion throughout PICU stay (intensive group [n=349]), or to insulin infusion only to prevent blood glucose from exceeding 11·9 mmol/L (conventional group [n=351]). Patients and laboratory staff were blinded to treatment allocation. Primary endpoints were duration of PICU stay and inflammation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00214916.
Findings
Mean blood glucose concentrations were lower in the intensive group than in the conventional group (infants: 4·8 [SD 1·2] mmol/L vs 6·4 [1·2] mmol/L, p<0·0001; children: 5·3 [1·1] mmol/L vs 8·2 [3·3] mmol/L, p<0·0001). Hypoglycaemia (defined as blood glucose ≤2·2 mmol/L) occurred in 87 (25%) patients in the intensive group (p<0·0001) versus five (1%) patients in the conventional group; hypoglycaemia defined as blood glucose less than 1·7 mmol/L arose in 17 (5%) patients versus three (1%) (p=0·001). Duration of PICU stay was shortest in the intensively treated group (5·51 days [95% CI 4·65-6·37] vs 6·15 days [5·25-7·05], p=0·017). The inflammatory response was attenuated at day 5, as indicated by lower C-reactive protein in the intensive group compared with baseline (-9·75 mg/L [95% CI -19·93 to 0·43] vs 8·97 mg/L [-0·9 to 18·84], p=0·007). The number of patients with extended (>median) stay in PICU was 132 (38%) in the intensive group versus 165 (47%) in the conventional group (p=0·013). Nine (3%) patients died in the intensively treated group versus 20 (6%) in the conventional group (p=0·038).
Interpretation
Targeting of blood glucose concentrations to age-adjusted normal fasting concentrations improved short-term outcome of patients in PICU. The effect on long-term survival, morbidity, and neurocognitive development needs to be investigated.
Funding
Research Foundation (Belgium); Research Fund of the University of Leuven (Belgium) and the EU Information Society Technologies Integrated project "CLINICIP"; and Institute for Science and Technology (Belgium).

2008 Thrombolysis with alteplase 3-4·5 h after acute ischaemic stroke (SITS-ISTR): an observational study

The Lancet, Volume 372, Issue 9646, Pages 1303 - 1309, 11 October 2008

Prof Nils Wahlgren MD a , Niaz Ahmed MD a, Prof Antoni Dávalos MD b, Prof Werner Hacke MD c, Mónica Millán MD b, Keith Muir MD d, Risto O Roine MD f, Prof Danilo Toni MD g, Prof Kennedy R Lees FRCP e, for the SITS investigators

Summary

Background
Intravenous alteplase is approved for use within 3 h of ischaemic stroke onset, although a meta-analysis of randomised controlled trials suggests treatment benefit up to 4·5 h. We compared outcome in patients treated between 3 h and 4·5 h versus those treated within 3 h, who were recorded in the in the Safe Implementation of Treatments in Stroke (SITS), a prospective internet-based audit of the International Stroke Thrombolysis Registry (ISTR).
Methods
We compared 664 patients presenting with ischaemic stroke and given intravenous altepase (0·9 mg/kg total dose) between 3 h and 4·5 h with 11 865 patients treated within 3 h. All patients were otherwise compliant with European summary of product characteristics criteria and had been documented in the international stroke treatment registry between Dec 25, 2002, and Nov 15, 2007. Outcome measures were symptomatic intracerebral haemorrhage within 24 h (haemorrhage type 2 associated with National Institutes of Health Stroke Scale [NIHSS] ≥4 points deterioration), and mortality and independence (modified Rankin scale of 0-2) at 3 months.
Findings
In the 3-4·5-h cohort, treatment was started at a median of 55 min later after symptom onset (195 min [IQR 187-210] vs 140 min [115-165], p<0·0001), median age was 3 years younger (65 years [55-73] vs 68 years [58-74], p<0·0001), and stroke severity was lower (NIHSS score 11 [7-16] vs 12 [8-17], p<0·0001) than in the 3-h cohort. We recorded no significant differences between the 3-4·5-h cohort and the within 3-h cohort for any outcome measure-rate of symptomatic intracerebral haemorrhage: 2·2% (14 of 649) versus 1·6% (183 of 11 681) (odds ratio [OR] 1·18 [95% CI 0·89-1·55], p=0·24; adjusted OR 1·32 [1·00-1·75], p=0·052); mortality: 12·7% (70 of 551) versus 12·2% (1263 of 10 368) (OR 1·02 [0·90-1·17]; p=0·72; adjusted OR 1·15 [1·00-1·33]; p=0·053); and independence: 58·0% (314 of 541) versus 56·3% (5756 of 10231) (OR 1·04 [0·95-1·13], p=0·42; adjusted OR 0·93 [0·84-1·03], p=0·18).
Interpretation
Alteplase remains safe when given at 3-4·5 h after ischaemic stroke, offering an opportunity for patients who cannot be treated within the standard 3-h timeframe.
Funding
Boehringer-Ingelheim, European Union Public Health Executive Authority.

2007 Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial

Articles
The Lancet, Volume 370, Issue 9588, Pages 676 - 684, 25 August 2007

Prof Djillali Annane MD a , Prof Philippe Vignon MD b, Alain Renault PhD c, Prof Pierre-Edouard Bollaert MD d, Claire Charpentier MD e, Prof Claude Martin MD f, Gilles Troché MD g, Prof Jean-Damien Ricard MD h, Gérard Nitenberg MD i, Prof Laurent Papazian MD j, Prof Elie Azoulay MD k, Prof Eric Bellissant MD l, for the CATS Study Group‡

Summary

Background
International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done. We aimed to compare the efficacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock.
Methods
This prospective, multicentre, randomised, double-blind study was done in 330 patients with septic shock admitted to one of 19 participating intensive care units in France. Participants were assigned to receive epinephrine (n=161) or norepinephrine plus dobutamine (n=169), which were titrated to maintain mean blood pressure at 70 mm Hg or more. The primary outcome was 28-day all-cause mortality. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148278.
Findings
There were no patients lost to follow-up; one patient withdrew consent after 3 days. At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p=0·31; relative risk 0·86, 95% CI 0·65-1·14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs 75 [44%] deaths, p=0·69), at hospital discharge (84 [52%] vs 82 [49%], p=0·51), and by day 90 (84 [52%] vs 85 [50%], p=0·73), time to haemodynamic success (log-rank p=0·67), time to vasopressor withdrawal (log-rank p=0·09), and time course of SOFA score. Rates of serious adverse events were also similar.
Interpretation
There is no evidence for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock.

2008 Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial

Articles
The Lancet, Volume 371, Issue 9607, Pages 126 - 134, 12 January 2008


Dr Timothy D Girard MD c d , John P Kress MD g, Barry D Fuchs MD h, Jason WW Thomason MD c, William D Schweickert MD g, Brenda T Pun RN c, Darren B Taichman MD h, Jan G Dunn RN b, Anne S Pohlman RN g, Paul A Kinniry MD h, James C Jackson PsyD c d, Angelo E Canonico MD a, Prof Richard W Light MD c, Ayumi K Shintani PhD e, Jennifer L Thompson MPH e, Sharon M Gordon PsyD d f, Prof Jesse B Hall MD g, Prof Robert S Dittus MD d f, Prof Gordon R Bernard MD c, Prof E Wesley Ely MD c d f
Summary

Background
Approaches to removal of sedation and mechanical ventilation for critically ill patients vary widely. Our aim was to assess a protocol that paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs).
Methods
In four tertiary-care hospitals, we randomly assigned 336 mechanically ventilated patients in intensive care to management with a daily SAT followed by an SBT (intervention group; n=168) or with sedation per usual care plus a daily SBT (control group; n=168). The primary endpoint was time breathing without assistance. Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00097630.
Findings
One patient in the intervention group did not begin their assigned treatment protocol because of withdrawal of consent and thus was excluded from analyses and lost to follow-up. Seven patients in the control group discontinued their assigned protocol, and two of these patients were lost to follow-up. Patients in the intervention group spent more days breathing without assistance during the 28-day study period than did those in the control group (14·7 days vs 11·6 days; mean difference 3·1 days, 95% CI 0·7 to 5·6; p=0·02) and were discharged from intensive care (median time in intensive care 9·1 days vs 12·9 days; p=0·01) and the hospital earlier (median time in the hospital 14·9 days vs 19·2 days; p=0·04). More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 6·0% difference, 95% CI 0·6% to 11·8%; p=0·03), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 1·2% difference, 95% CI -5·2% to 2·5%; p=0·47), as were total reintubation rates (13·8% vs 12·5%; 1·3% difference, 95% CI -8·6% to 6·1%; p=0·73). At any instant during the year after enrolment, patients in the intervention group were less likely to die than were patients in the control group (HR 0·68, 95% CI 0·50 to 0·92; p=0·01). For every seven patients treated with the intervention, one life was saved (number needed to treat was 7·4, 95% CI 4·2 to 35·5).
Interpretation
Our results suggest that a wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches and should become routine practice.

2008 Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis

Articles
The Lancet, Volume 372, Issue 9638, Pages 554 - 561, 16 August 2008 <Previous Article|Next Article>doi:10.1016/S0140-6736(08)60958-7Cite or Link Using DOI
Editors' note: Despite more frequent use of cardiopulmonary resuscitation (CPR), sudden cardiac arrest still has a low survival rate. Extracorporeal life-support in cardiac arrest uses a percutaneous system that incorporates the rapid initiation of femoral-femoral venoarterial cardiopulmonary bypass by a trained vascular-access team, followed by the extracorporeal maintenance of circulation until an effective cardiac output has been achieved. In this study, extracorporeal CPR was superior to conventional CPR in terms of short-tem and long-term survival.

Yih-Sharng Chen MD a ‡, Jou-Wei Lin MD d ‡, Hsi-Yu Yu MD a, Wen-Je Ko MD a, Jih-Shuin Jerng MD b, Wei-Tien Chang MD c, Wen-Jone Chen MD b, Shu-Chien Huang MD a, Nai-Hsin Chi MD a, Chih-Hsien Wang MD a, Li-Chin Chen RN b, Pi-Ru Tsai RN a, Sheoi-Shen Wang MD a, Juey-Jen Hwang MD b d, Fang-Yue Lin MD a
Summary

Background
Extracorporeal life-support as an adjunct to cardiac resuscitation has shown encouraging outcomes in patients with cardiac arrest. However, there is little evidence about the benefit of the procedure compared with conventional cardiopulmonary resuscitation (CPR), especially when continued for more than 10 min. We aimed to assess whether extracorporeal CPR was better than conventional CPR for patients with in-hospital cardiac arrest of cardiac origin.
Methods
We did a 3-year prospective observational study on the use of extracorporeal life-support for patients aged 18-75 years with witnessed in-hospital cardiac arrest of cardiac origin undergoing CPR of more than 10 min compared with patients receiving conventional CPR. A matching process based on propensity-score was done to equalise potential prognostic factors in both groups, and to formulate a balanced 1:1 matched cohort study. The primary endpoint was survival to hospital discharge, and analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00173615.
Findings
Of the 975 patients with in-hospital cardiac arrest events who underwent CPR for longer than 10 min, 113 were enrolled in the conventional CPR group and 59 were enrolled in the extracorporeal CPR group. Unmatched patients who underwent extracorporeal CPR had a higher survival rate to discharge (log-rank p<0·0001) and a better 1-year survival than those who received conventional CPR (log rank p=0·007). Between the propensity-score matched groups, there was still a significant difference in survival to discharge (hazard ratio [HR] 0·51, 95% CI 0·35-0·74, p<0·0001), 30-day survival (HR 0·47, 95% CI 0·28-0·77, p=0·003), and 1-year survival (HR 0·53, 95% CI 0·33-0·83, p=0·006) favouring extracorporeal CPR over conventional CPR.
Interpretation
Extracorporeal CPR had a short-term and long-term survival benefit over conventional CPR in patients with in-hospital cardiac arrest of cardiac origin.
Funding
National Science Council, Taiwan.

2002 Association between mitochondrial dysfunction and severity and outcome of septic shock

Mechanisms of Disease
The Lancet, Volume 360, Issue 9328, Pages 219 - 223, 20 July 2002 <Previous Article|Next Article>doi:10.1016/S0140-6736(02)09459-XCite or Link Using DOI

David Brealey MRCP a, Michael Brand PhD a, Iain Hargreaves PhD b, Simon Heales MRCPath b, John Land MRCPath b, Ryszard Smolenski PhD c, Nathan A Davies PhD d, Prof Chris E Cooper PhD d, Prof Mervyn Singer FRCP a
Summary

Background
Sepsis-induced multiple organ failure is the major cause of mortality and morbidity in critically ill patients. However, the precise mechanisms by which this dysfunction is caused remain to be elucidated. We and others have shown raised tissue oxygen tensions in septic animals and human beings, suggesting reduced ability of the organs to use oxygen. Because ATP production by mitochondrial oxidative phosphorylation accounts for more than 90% of total oxygen consumption, we postulated that mitochondrial dysfunction results in organ failure, possibly due to nitric oxide, which is known to inhibit mitochondrial respiration in vitro and is produced in excess in sepsis.
Methods
We did skeletal muscle biopsies on 28 critically ill septic patients within 24 h of admission to intensive care, and on nine control patients undergoing elective hip surgery. The biopsy samples were analysed for respiratory-chain activity (complexes I-IV), ATP concentration, reduced glutathione (an intracellular antioxidant) concentration, and nitrite/nitrate concentrations (a marker of nitric oxide production).
Findings
Skeletal muscle ATP concentrations were significantly lower in the 12 patients with sepsis who subsequently died than in the 16 septic patients who survived (p=0·0003) and in controls (p=0·05). Complex I activity had a significant inverse correlation with norepinephrine requirements (a proxy for shock severity, p=0·0003) and nitrite/nitrate concentrations (p=0·0004), and a significant positive correlation with concentrations of reduced glutathione (p=0·006) and ATP (p=0·03).
Interpretation
In septic patients, we found an association between nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction, and decreased ATP concentrations that relate to organ failure and eventual outcome. These data implicate bioenergetic failure as an important pathophysiological mechanism underlying multiorgan dysfunction.

2003 Stimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes

Mechanisms of Disease
The Lancet, Volume 361, Issue 9352, Pages 130 - 135, 11 January 2003

Dr Mark Lyte PhD a b , Primrose PE Freestone PhD c, Christopher P Neal MB c, Barton A Olson BA a, Richard D Haigh PhD c, Roger Bayston FRCPath d, Peter H Williams PhD c

Summary

Background
Bacterial colonisation of indwelling medical devices by coagulase-negative staphylococci is a prevalent risk in intensive-care units. Factors determining biofilm formation and progression to catheter-related infection are incompletely understood. We postulated that administration of inotropic agents via indwelling intravenous catheters may stimulate growth and formation of biofilms by Staphylococcus epidermidis.
Methods
Inocula representing physiologically relevant infecting doses of S epidermidis were incubated in a minimum medium supplemented with fresh human plasma in the presence or absence of pharmacological concentrations of norepinephrine or dobutamine. Biofilm formation on polystyrene and medical-grade silicone was examined. After incubation, cultures were assessed for growth and formation of biofilms by colony counting and scanning electronmicroscopy. The production of exopolysaccharide, a major constituent of S epidermidis biofilms, was also assessed by use of immunofluorescence microscopy.
Findings
Incubation of S epidermidis with catecholamine inotropes in the presence of human plasma resulted in a significant increase in growth compared with control on both polystyrene and silicone surfaces, with pronounced increases in biofilm formation as visualised by scanning electronmicroscopy. Experiments with transferrin labelled with radioactive iron showed the ability of catecholamine inotropes to facilitate acquisition of iron by S epidermidis. Immunofluorescence microscopy revealed extensive exopolysaccharide production associated with S epidermidis biofilms.
Interpretation
The ability of catecholamine inotropic drugs to stimulate bacterial proliferation and biofilm formation may be an aetiological factor in the development of intravascular catheter colonisation and catheter-related infection. The removal of iron from transferrin for subsequent use by S epidermidis is a possible mechanism by which catecholamine inotropes stimulate bacterial growth as biofilms.

2003 Ventilator-associated lung injury

Review
The Lancet, Volume 361, Issue 9354, Pages 332 - 340, 25 January 2003


Liao Pinhu MSc a, Thomas Whitehead MRCP d, Prof Timothy Evans DSc b e, Dr Mark Griffiths c e
Summary

Mechanical ventilation is indispensable in support of patients with respiratory failure who are critically ill. However, use of this technique has adverse effects, including increased risk of pneumonia, impaired cardiac performance, and difficulties associated with sedation and paralysis. Moreover, application of pressure to the lung, whether positive or negative, can cause damage known as ventilator-associated lung injury (VALI). Despite difficulties in distinguishing the effects of mechanical ventilation from those of the underlying disorder, VALI greatly assists patients with the most severe form of lung injury, acute respiratory distress syndrome (ARDS). Moreover, modification of mechanical ventilation so that VALI is kept to a minimum improves survival of patients with ARDS. Here, we outline the effects of mechanical ventilation on injured lungs and explore the underlying mechanisms.