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JOURNAL CLUB

JOURNAL CLUB. May 31st. Andrew Prenter ST4 Anaesthetics. Suitable study. Concise. The Question. Library services. Literature search. Potential to change local practice. Original article. Medline. EMBASE. PubMed, Cochrane. Up to Date. Simple definitions. CASP-NET. The Question.

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JOURNAL CLUB

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  1. JOURNAL CLUB May 31st Andrew Prenter ST4 Anaesthetics

  2. Suitable study Concise The Question Library services Literature search Potential to change local practice Original article Medline EMBASE PubMed, Cochrane Up to Date Simple definitions CASP-NET

  3. The Question • 60 yr old man admitted with general lethargy and shortness of breath • Treated for community acquired pneumonia • Under investigation for recurrence of lymphoma • Referred with obtunded conscious level • Found to be in septic shock (low BP, base excess -19, lactate 15, DIC) • Admitted to ITU • Rapidly progressed to maximum noradrenaline doses • ECHO: poor ejection fraction What is the most appropriate inotrope/inotrope combination in his management?

  4. Definitions • Vasopressors are a class of drugs that induce vasoconstriction and thereby elevate MAP. • Inotropes increase cardiac contractility. • Many drugs have both effects. • Alpha -1: vascular walls inducing vasoconstriction • Beta-1: heart inducing increased inotropy and chronotropy • Beta-2: found in blood vessels and stimulation can cause vasodilation • Dopamine: renal, splanchnic, coronary and cerebral vascular beds. Stimulation leads to vasodilation. Second subtype can induce NA release and lead to vasoconstriction?! • So which one/combination to use?

  5. General principles • Vasopressors : MAP <60mmHg with end organ dysfunction due to hypo perfusion. • Volume resuscitation • Repletion of adequate intravascular volume is crucial prior to the initiation of vasopressors • Selection and titration • What is the underlying suspected aetiology? • Hyper dynamic septic shock (“warm sepsis”) • High CI Low SVR– alpha agonists probably most effective such as noradrenaline, phenylephrine. • Hypo dynamic septic shock (“cold sepsis”) • Low CI and low to modest reduction in SVR. • Noradrenaline still reasonable start. What if hypotension persists in this scenario? Do you add adrenaline? How about Dobutamine? Does it matter?

  6. Selected study and bibliographic details: Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial Citation: Lancet, Aug 2007, vol./is. 370/9588(676-684), 0140-6736 (25 Aug 2007) Author(s): AnnaneD.,VignonP.,RenaultA.,BollaertP.-E.,CharpentierC.,MartinC.,TrocheG.,RicardJ.-D.,NitenbergG.,PapazianL.,AzoulayE.,Bellissant E.

  7. Validity • Did this trial address a clearly focussed issue? • Was the assignment of patients to treatments randomised? • Were all of the patients who entered the trial accounted for at the end? • Were patients, health workers and study personnel ‘blind’? • Were the groups similar at the start of the trial? • Aside from experimental intervention were the groups treated equally?

  8. Validity – ‘PICO’ • Population: • 330 patients with septic shock • Intervention given: • Adrenaline infusion (161) • Comparator given: • Noradrenaline plus Dobutamine (169) • Assumption was this group would have improved mortality rates • Previous studies showing deleterious effects of adrenaline • Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) study. 2006. • Effects of dopamine, noradrenaline and adrenaline on the splanchnic circulation in septic shock: which is best? (2003) • Adrenaline impairs splanchnic perfusion in Septic shock (1997) • Outcomes considered: • Mortality at day 28

  9. Validity • 330 patients randomised to treatment groups. • Central randomisation and done blind by an independent 3rd party. • In other words, there was allocation concealment. Potential for bias was low. • Aside from one, all patients entered were followed at the end. • All were analysed in the groups to which they were randomised – ‘intention to treat’ • Funding had no role in running of trial – no conflict • Where the groups equally treated? Not quite! • Other treatments at discretion of individual physicians • Cardiac index measured differently in each ITU Overall a strong start with good methods section, but not perfect

  10. Reliability of results? • Primary end point was day 28 all cause mortality. • Secondary end points: • Mortality at day 7 • Mortality at day 14 • Arterial pH and lactate • SOFA scores • Time to haemodynamic stability (MAP> 70 for 12 hrs) • Time to vasopressor withdrawal • Statistics: • Frequency of fatal events (i.e mortality) compared using the chi squared test. • Relative risks estimated and CI calculated • Cumulative event curves estimated with Kaplan Meier procedure

  11. Results – Primary Outcome • Primary Outcome: Mortality at day 28 • Absolute difference in mortality of 6%. • RR 0.86 • 95% Confidence interval 0.65-1.21 • p= 0.31 • So fairly wide CI containing 1 • Hence whilst there was a difference it was not significant

  12. Survival from randomisation until day 90

  13. Results – Secondary Outcomes • No significant difference at day 7 or day 14 • Day 7 (RR 0.81 CI 0.54-1.21; p=0.31) • Day 14 (RR 0.75 CI 0.54-1.04; p=0.08) • Arterial pH and lactate • pH significantly lower in adrenaline group. • day 1 (p=0.0001) • day 2 (p=0.0008) • day 3 (p=0.0019) • day 4 (p=0.0007) • Lactate also significantly increased in adrenaline only group at day 1 (p=0.0003)

  14. Results – Secondary Outcomes • SOFA scores improved over time in both groups to same extent. • Time to haemodynamic stability and inotrope withdrawal • No significant differences

  15. Kaplan Meier plots of time to haemodynamic success (A) and inotrope withdrawal (B)

  16. Results No significant difference in side effects potentially linked to catecholamine use

  17. Results: Key Findings • No evidence for a difference in all cause mortality in either the short or long term between the groups. • No evidence for a difference in terms of delay in haemodynamic stabilisation, resolution of organ dysfunction or adverse events. • The expected benefit and reduced mortality of a Dobutamine/noradrenaline approach was not found • Adrenaline was just as beneficial in terms of mortality reduction but did increase likelihood of acidosis and elevated lactate levels • Does this matter overall if mortality no different?

  18. Relevance – can the results help locally? • Patients similar to our patients • All clinically important outcomes were considered • However, lack of significant difference means unlikely to change practice • Would one inotrope be more cost effective than two? • £5672 (NA/dobutamine) vs £5439 (adrenaline) • Do we need further evidence to answer our question? • No significant trials looking at inotropes in sepsis and decompensated heart failure - our patient. I think this trial was close though. • Surely logical that Dobutamine remains inotrope of choice in this setting? • Were is the evidence? Perhaps my search was flawed?

  19. Context – Surviving sepsis • Inotropic Therapy 1. A trial of Dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressors (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypo perfusion, despite achieving adequate intravascular volume and adequate MAP (grade 1C). C “Unclear or conflicting scientific evidence”

  20. Strengths & Weaknesses

  21. More Context • A comparison of epinephrine and norepinephrine in critically ill patients. Intensive care medicine 2008 • Very similar findings, no difference in overall mortality but metabolic derangement common with adrenaline. • DOBUPRESS group. British Journal Anaesthesia 2008. • Terlipressin can have noradrenaline sparing effect and along with dobutamine can help reduce noradrenaline requirements • Vasopressin vs Noradrenaline infusion in patients with septic shock. NEJM 2008. • Low dose vasopressin did not reduce mortality rates as compared with noradrenaline in patients with septic shock

  22. Summary and Conclusions • There is no evidence for a difference in efficacy and safety between adrenaline alone and noradrenaline plus dobutamine for management of septic shock • Validity: • the results are valid • Reliability: • Sample size not large enough to determine if absolute differences were real • Variability in how two groups were treated (Cardiac index measurement, use of other treatments) • Relevance: • Probably wont change local practise • Why not just use single drug – adrenaline, and tolerate short term metabolic derangements knowing outcome will be no different? • Cheaper? • Less need to monitor cardiac index • Single drug and not two • Less equipment etc

  23. Questions? Problems with study? CASP-NET Library services The Question Original article Potential to change local practice Medline, EMBASE Literature search Concise Simple definitions Suitable study Literature search

  24. References • Library services/Victoria! • Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial • Lancet, Aug 2007, vol./is. 370/9588(676-684), • AnnaneD.,VignonP.,RenaultA.,BollaertP.-E.,Charpentier C.,Martin C.,TrocheG.,RicardJ.-D.,NitenbergG.,PapazianL.,AzoulayE.,Bellissant E.

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