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Evidence In Intensive Care - Cardiovascular

Systematic reviews or meta-analyses in blue
High impact other trials in red

Atrial fibrillation – new onset
Crit Care Med 2008 vol 36 no. 5
15% of general ICU patients.
X2 increased risk of death (probably reflects underlying disease severity rather than independent risk factor.

Conversion to SR at 12h
Esmolol 80%
Amioderone 60%
Diltiazem 60%
Verapamil 33%
Magnesium 70%

Heterogenicity, trial design and small numbers prevent any recommendation.
3 of 4 studies excluded haemodynamically unstable patients.

Theraputic hypothermia post cardiac arrest
Cochrane review 2009

Up to 40% OOH arrests resuscitated.
Only 20% have good neurological recovery.
Cerebral reperfusion causes injury.

Temp reduced to <35 within 6h of hospital.

Improves mortality and neurological outcome for out of hospital and for those with VF or VT as primary rhythm.

Vasopressin or terlipressin for shock
ESICM not yet published.
No significant mortality benefit.
Reduced noradrenaline dose.
No difference in adverse events.
Therefore safe but no outcome benefit.
NB VASST trial subgroup showed less sick benefited.

Vasopressin in vasodilatory shock: systematic review and meta-analysis
Neto et al. Crit Care 2012, 16:R154
Vasopressin is safe in vasodilatory shock, reduces the need for catecholamines and is associated with reduced mortality.
Numbers dominated by the VASST trial.
Vasopressin increases vascular smooth muscle tone (but causes pulmonary vasodilatation), increases BP, reduces HR and induces diuresis.
High doses cause ischaemia in myocardium, mesenteric circulation and peripheries.
VASST trial showed vasopressin did not reduce mortality compared to norad but may have been underpowered to detect a difference. Possible benefit in patients with less severe septic shock and those on steroids.
Another recent meta-analysis showed no difference (included paediatric trials).
Take home message:
Vasopressin is safe.
Use it as second line to norad but do use it.
Limit the dose to 0.03U/min (1.8U/h)
If pulmonary hypertension +/- RV dysfunction use it as 1st line. (Price et al. Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Critical Care 2010;14:R169.)

Pre-op haemodynamic optimisation
Anaesthesia and analgesia Hamilton et al
Pre-emptive targeted haemodynamic therapy reduced morbidity and mortality overall even in lower risk groups.
Problems:
Control group mortality has significantly decreased over the time of these studies.
Only including the higher quality studies does not show any benefit.


Cardiac arrest

Chest compression only CPR
Lancet 2010;376:1552-57
Increased survival with uninterrupted chest compressions in out of hospital arrests. NNT 41 CVS

Association of prehospital advanced airway management with neurologic outcome and survival in patients with out-of- hospital cardiac arrest.
Hasegawa K et al. JAMA 2013;309:257–266.
Pre-hospital advanced airway management worsened outcome compared with bag mask ventilation.
Possible causes are delay to compressions, delay in oxygenation, too high concentrations of oxygen, high intrathoracic pressure compromising heart function.
Take home message is don’t rush to intubate until conditions are optimal.

Duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study.
Goldberger et al. Lancet 2012
Patients whose resus continued for longer were significantly more likely to achieve ROSC and survive to hospital discharge. Effect increased in those in PEA or asystole. Neurological outcome no different for those resuscitated for longer.
Continuing resus attempts for ‘longer’ should be considered especially in those who may have a reversible cause.

Out of hospital CPR
2 studies in 2010 showing trend towards better outcome in out of hospital arrests if continuous chest compressions without mouth to mouth ventilation.
NEJM 2010;363:423-433 Rea et al
NEJM 210;363:434-442 Svensson et al

Unknown whether in hospital ventilation with O2 and airway skills is better or not.

Effect of adrenaline on survival in out of hospital cardiac arrest.
Jacobs et al. Resuscitation 2011
Adrenaline vs placebo in arrest.
ROSC and admission to hospital improved with adrenaline but no significant improvement in survival to discharge.
Trial was underpowered as many refused to participate (4000 when needed 5000).
Similar trial (IV drug during OOH cardiac arrest JAMA 2009) showed defib without IV drugs resulted in lower ROSC but equal hospital survival.

Trends in survival after in-hospital cardiac arrest.
Girotra et al. N Engl J Med 2012;167:1912–1920.
Mortality and morbidity are decreasing after CPR in hospitalised patients. 14 to 22% 2000-2010.
Longer CPR attempts leads to better outcomes.

Hyperoxia post cardiac arrest
JAMA 2010;303:2165-2171 Kilgannon at al
Hyperoxia in post resuscitation care associated with a worse outcome (mortality and functional status) than either normoxia or hypoxia.
Mortality post arrest from reperfusion injury, myocardial stunning and anoxic brain injury.
Hyperoxia causes free radical damage.

PE post trauma
BJA 2010;105:596-602
PE accounts for 12% of trauma deaths.
Causes death later on than other causes.
More common in obese, co-morbidities and increasing severity of injury.

Type of fluid

Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation. A systematic review and meta- analysis.
Zarychanski et al. JAMA. 2013;309:678–688.
38 studies included.
HES associated with a significantly increased risk of mortality and AKI (trials by Boldt removed)

Fluid resuscitation with 6% 130/0.4 starch. Systematic review and meta-analysis
Gattas et al. Anesth Analg 2012
88 papers in 18 journals of Boldts removed. 11 concerned HES 130 0.4
No difference in risk of death.
Studies included acknowledged to be of poor quality so no conclusion could be reached.

Hydroxyethyl starch or saline for fluid resuscitation in intensive care: CHEST
Myburgh et al NEJM 2012;367:1901-1911
7000 patients randomised controlled. HES (voluven) vs saline. Max dose of HES 50ml/kg/day. HES stopped if RRT needed.
Primary outcome death at 90 days. Secondary outcomes AKI and RRT.
No mortality difference (trend to increase death in HES group CI 0.96 -1.18) p = 0.26 and renal failure RR 1.12 p = 0.12).
HES group needed received less fluid (only 90mls).
No differences in HR, MAP, lactate
HES group required more blood products.
More HES patients required RRT and more adverse events (eg pruritis and rash)
Volume of fluid low (526 mls of HES daily average over 4 days). In the 6S trial the average volume of HES was 4000 mls over 3 days. This adds weight to the argument that the toxicity of HES is dose dependent (like in VISEP).

Hydroxyethyl starch 130/0.4 vs Ringer’s acetate in severe sepsis. 6S
NEJM 2012
Multicentre R parallel group T
Up to 33mls/kg per day
798 patients
Significant increase in death at 90 days in HES group (primary outcome)
Significant increase in RRT in HES group (secondary outcome).
Severe bleeding and doubling of creatinine more common with HES but not significant.
90 day follow up.
3L of fluid prior to randomisation (700 starch), no algorithm and no determination of fluid responsiveness.
Amount of fluid given suggests conservative fluid strategy
Survival curves show separation of the curves at 22 days suggesting delayed harm due to tissue accumulation - shows long follow up needed.

Assessment of haemodynamic efficacy and safety of 6% starch 130/0.4 vs 0.9% NaCl in severe sepsis: CRYSTMAS
Crit Care 2012, 16:R94
Multicentre RCT
196 patients
Up to 50mls/kg on day 1 and 25mls/kg 2-4th day.
Less HES used to reach haemodynamic stability (mean difference 330 mls)
Time to reach stability - no significant difference
No difference in total amount of fluid over 4 days, LOS, SOFA, AKI.
No difference in mortality, coag, pruritis (not powered for these)
No algorithm for fluid responsiveness. Used CVP.
Only average of 4 patients per site.
28 day follow up.
Patients receive more fluid before randomisation than afterwards.
Used saline (more acidosis, reduced renal blood flow and perfusion, coag disturbances and interstitial oedema compared to CSL).
Small sample size, limited volume of starch infused and short follow up time mean safety not demonstrated.

HES overall
Cochrane review 2010
Significant increased risk of renal failure overall. RR1.5 (1.2-1.87)
Even greater significant risk of renal failure in sepsis group. RR 1.55 (1.22-1.96).
Non significant risk of requiring RRT overall.
Significant risk of RRT in sepsis group.
Many studies had only 1 day follow-up which is not long enough to identify AKI.
Included positive trials by Boldt with fabricated evidence in favour of HES.
Insufficient data to different molecular weight HES.

HES in critical illness
Open Medicine 2009;3(4):e196-209
Significant risk of requiring RRT in HES group in sepsis or septic shock and kidney transplant recipients from BD donors. Lower 95% CIs all >1.
No mortality difference.
In high quality trials trend towards higher mortality.
4 trials funded by HES manufacturers.
Control solutions were other colloids in many of the trials.
Included trials by Boldt.

Association between a chloride-liberal vs. chloride- restrictive intravenous fluid administration strategy and kidney injury in critically ill adults.
Yunos NM et al. JAMA 2012; 308: 1566–1572.
Chloride restricive fluid strategy associated with significant decrease in AKI and RRT. Also less hypernatraemia and acidosis.
No long term outcome difference.
AKI may be related to chloride induced vasoconstriction and a decrease in GFR mediated by higher distal chloride delivery.
Agrees with another study (Shaw et al. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg 2012;255:821-829) which shoed that 0.9% saline on day of surgery associated with post op complications including AKI.

Albumin for fluid resus
Crit Care Med 2011
Albumin binds drugs, is a transporter of active molecules, is a free radical scavenger, inhibits PLT aggregation and maintains colloid oncotic pressure.
Significant reduction in mortality with albumin.
Still significant with Boldts studies removed.
Improvement significant with dilute albumin (4 or 5%) but not with 20%.

Discussion
Observational data from another study suggest hyperoncotic albumin (20%) may be harmful.
Unpublished data from a recent trial with 20% albumin with severe sepsis that did not demonstrate a benefit.
Albumin is expensive.
Need results from more trials to justify its use. 3 ongoing trials at time of this review (2011)

Amount of fluid

Observational fluid balance study on the RENAL trial data
CCM 2012;40:1753-1760
Positive fluid balance at initiation of RRT is associated with an increased risk of death (than neutral or negative) - adjusted for illness severity.
Positive fluid balance associated with increased RRT and ICU and hospital LOS.
Risk increased with amount of fluid overload.
Agrees with other studies:
SOAP Crit Care 2008 - +ve balance and oliguria with AKI increased mortality.
PICARD Kidney Int 2009 - significant survival difference in patients with, compared to without, fluid overload at initiation of RRT. Duration of fluid overload while on RRT correlated with risk. Mortality was lower when fluid overload was corrected with RRT than with those who who finished RRT with >10% fluid accumulation.
ARDSnet - trend to higher mortality in patients with positive fluid balance with more need for RRT.

What should we do?
Discontinue fluids (salty ones) as soon as not fluid responsive, aim for neutral or negative balance as soon as haemodynamics allow, reassess on a regular basis.

Restrictive vs standard fluids in AAA repair
Ann Surg 2009;250:28-34
Less major complications in restrictive group
Small number of patients so data fragile – only one more complication in restricted group or one less in standard group then results would be non significant.
The non anatomical 3rd space is a myth
As always fluid status should be optimised and no more

Fluid boluses in children with sepsis
NEJM 2011;364:2483-2495
Mortality in compensated shock (severe hypotension all got fluid) increased in those with fluid boluses (1 group saline, 1 group albumin). Pulmonary oedema and ICP not different.
Should be noted that high proportion of the children had malaria and/or anaemia so different population from developed world.

Hypotensive resus in theatre for trauma surgery.
J Trauma 2011;70:652-663
Crap study see ICMonitor.
No difference in MAP between the 2 groups.
‘High’ MAP cohort had significantly more blunt trauma.

Influence of fluid therapy on prognosis of acute pancreatitis
De-Madaria E et al. Am J Gastro 2011;106:1843-1850
Those receiving >4L had more organ failure, more resp failure, more AKI and more peripancreatic fluid collections.
Discussion:
Work of Shires in 60s popularised erroneous 3rd space.
Conservative fluids shown to not worsen or improve outcome. Improved outcome in surgical patients J Am Coll Surg 2009, fast track colonic surgery BJA 2007, ARDSnet NEJM 2006.
Why should xs fluid be detrimental?
Abdo compartment syndrome
Pulmonary oedema
Starlings concept of endothelium has been revised to the double barrier concept with the glycocalyx - this regulates permeability, cell adhesion and inflammation. In the presence of hypervolaemia, ANP destroys the glycocalyx. In combination with SIRS this may be lethal.
Goldilocks analogy - not too little, not too much but just right - only Goldilocks knows.


ECMO

CESAR - Lancet 2009
On an intention to treat basis no significant difference in mortality (only 75% referred for ECMO actually received it).
Significantly less death or disability at 6 months (primary endpoint) in ECMO arm.
LOS x2 in ECMO group.
Costs were x2 in ECMO group.
ECMO group received more steroids and 17% had MARS.
High rates of liver dysfunction and intracranial haemorrhage in ECMO group.
Conventional arm did not have a standardised protocol.
93% of those in ECMO centre treated with lung protective ventilation compared to 70% elsewhere.
ECMO survival rate (63%) compares with ARDSnet lung protective trial of 60%.
So, safety demonstrated but at significant cost.


Other

Haemodynamic impact of PEEP in ARDS.
Fougeres. Crit Care Med 2010;38:802-807

PEEP elevation decreased cardiac index
PLR at high PEEP

• Increased ventricular diastolic areas and R atrial pressure
• Decreased pulm vasc res
• Increase CI