JOURNAL CLUB

JOURNAL CLUB

Andrew Prenter ST4 Anaesthetics

May 31st

Concise

Potential to change local practice

Original article

The Question

Suitable study

Simple definitions

Literature search

Medline EMBASE

PubMed,Cochrane

Up to Date

CASP-NET

Library services

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?

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?

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?

Your current search history Database("Inotropes" AND "Heart failure").ti,ab EMBASE, MEDLINE

1 [Limit to: (Publication Types Article)] EMBASE, MEDLINE2 [Limit to: (Languages English) and Publication Year 2005-Current and (Publication Types Article)]

EMBASE, MEDLINE

"sepsis".ti,ab [Limit to: (Languages English) and Publication Year 2005-Current and (Publication Types Article)]

EMBASE, MEDLINE

1 AND 4 [Limit to: (Languages English) and Publication Year 2005-Current and (Publication Types Article)]

EMBASE, MEDLINE

"dobutamine".ti,ab [Limit to: (Languages English) and Publication Year 2005-Current and (Publication Types Article)]

EMBASE, MEDLINE

"intensive care".ti,ab [Limit to: (Languages English) and Publication Year 2005-Current and (Publication Types Article)]

EMBASE, MEDLINE

6 AND 7 [Limit to: (Languages English) and Publication Year 2005-Current and (Publication Types Article)]

EMBASE, MEDLINE

"septic shock".ti,ab [Limit to: (Languages English) and Publication Year 2005-Current and (Publication Types Article)]

EMBASE, MEDLINE

6 AND 7 AND 9 [Limit to: (Languages English) and Publication Year 2005-Current and (Publication Types Article)]

EMBASE, MEDLINE

Selected study and bibliographic details:Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trialCitation:Lancet, Aug 2007, vol./is. 370/9588(676-684), 0140-6736 (25 Aug 2007)Author(s):Annane D.,Vignon P.,Renault A.,Bollaert P.-E.,Charpentier C.,Martin C.,Troche G.,Ricard J.-D.,Nitenberg G.,Papazian L.,Azoulay E.,Bellissant E.

Validity

1. Did this trial address a clearly focussed issue?2. Was the assignment of patients to treatments

randomised?3. Were all of the patients who entered the trial

accounted for at the end?4. Were patients, health workers and study personnel

‘blind’?5. Were the groups similar at the start of the trial?6. Aside from experimental intervention were the groups

treated equally?

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

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

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

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

Survival from randomisation until day 90

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)

Results – Secondary Outcomes

• SOFA scores improved over time in both groups to same extent.

• Time to haemodynamic stability and inotrope withdrawal– No significant differences

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

ResultsNo significant difference in side effects potentially linked to catecholamine use

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?

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?

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”

Strengths & WeaknessesStrengths Weaknesses

•Sound methodology •Didn't have a clear null hypothesis•Asked a question and placed it in context

•Assumption was there would be a 60% mortality in adrenaline group

•Conducted a randomised blinded study •Aside from inotropes all other treatment at ‘discretion of ITU physician’

•No loss to follow up •Variability in Cardiac Index measurements

•Independent of external influence •Influence of steroids and APC

•Knew, before they started, that they could never statistically prove any absolute difference between the groups (numbers not enough)

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

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

Original article

Literature search

The Question

ConcisePotential to change local practice

CASP-NET

Medline, EMBASE

Library services

Suitable studySimple definitions

Literature searchQuestions?Problems with study?

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), – Annane D.,Vignon P.,Renault A.,Bollaert P.-

E.,Charpentier C.,Martin C.,Troche G.,Ricard J.-D.,Nitenberg G.,Papazian L.,Azoulay E.,Bellissant E.