CCP Podcast 061: Papers of the Month: March 2017

 January 8

by Jonathan Downham

Three more papers of the month for us to peruse. This time Gavin (@DentonGavin) and I are also joined by Sean Munnelly (@seanmunn).

The CLASSIC trial.

Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Hjortrup et al.  Intensive Care Med. 2016 Nov;42(11):1695-1705. Epub 2016 Sep 30.

Clinical Question.

In patient with septic shock, does the use of a restrictive approach to fluid resuscitation compared to a liberal approach, reduce the resuscitation fluid volume received.


  • Randomised controlled trial carried out between 2014-2015.
  • Multi-centre, multi-national trial.
  • Computer allocation, with web-based, centralised
  • randomisation system.
  • 1:1 allocation
  • Non-blinded to clinicians, allocation blinded to statistician.
  • 150 patients were required to provide 80% power to detect 1.7L difference in the volume of resuscitation fluid administered. n=151 enrolled.


  • Scandinavian intensive care units in Denmark and Finland.
  • 9 intensive care units.


  • Adults over 18 years in intensive care.

Inclusion criteria:

  • Sepsis as defined by the surviving sepsis campaign SIRS criteria.
  • HR <140, systolic <90, lactate more >4 or need for vasopressors for less than 12hs preceding ITU admission.
  • Patients must have received at least 30ml/Kg fluid resuscitation and ongoing need for vasopressor infusion.
  • Use of colloid was not allowed.
  • Resuscitation fluid could be Ringer’s lactate or 0.9% saline.


  • 250-500ml of crystalloid boluses were administered for 4 signs of severe hypo-perfusion, lactate >4, MAP <50 despite increases in noradrenaline, skin mottling above the knee cap or mottling score >2,  oligurea (but only for the first 2hrs after randomisation).
  • Repeated boluses could be given depending on the response to the 4 criteria.
  • A fluid bolus was not mandated for any of the 4 criteria.


  • The control group could receive fluid boluses of crystaloid based on dynamic or static haemodynamic measures as long as variables improved.


  • A co-primary outcome of: the volume of resuscitation fluid given for circulatory impairment in the first 5 days following randomisation and the volume of resuscitation fluid given for the duration of the intensive care stay.
  • Secondary outcomes included the TOTAL fluid volume received in the first 5 days following randomisation and the duration of the ITU stay.

Primary outcome:

  • There was a significantly significant fluid resuscitation volume difference in the first 5 days, 1.2L p= 0.001.
  • There was a 1.4L total fluid resuscitation volume difference over the course of the intensive care stay p=0.001.

Secondary outcomes:

  • In terms of the total fluid volume received, there was only a difference of 500ml over the course of the ITU stay, this was not statistically significant p=0.6.
  • Further exploratory data provided, non-showed a statistically significant difference.

Authors’ Conclusions:

  • It is feasible to conduct a trial that restricts fluid resuscitation volume in patients with septic shock.


  • Randomised multi-centre trial.
  • Separation of volume between patients, although it is not clear if this is meaningful


  • Un-blinded, but not really feasible in this context.
  • Primary outcome not patient centered.
  • 36% of the intervention group had protocol violations, high lighting that it is difficult to stop clinicians wanting to give fluid. This may restrict the feasibility of conducting a meaningful trial.
  • The total fluid volume difference between groups was only 500ml. This may meaning fluid restriction of resuscitation volumes may be circumvented by administration of maintenance fluids.

The Bottom Line.


  • This study demonstrates that it is difficult to restrict clinicians from violating research protocols where the intervention is to restrict fluid resuscitation.


 Effect of Intensive vs Moderate Alveolar Recruitment Strategies Added to Lung-Protective Ventilation on Post operative Pulmonary Complications   

Is there any extra benefit to applying more intensive alveolar recruitment strategies for high-risk surgical patients already receiving perioperative small tidal volumes and protective lung ventilation?

Design: Randomised Clinical Trial

Setting: Single Center RCT performed at the Heart Institute from the University of Sao Paulo Brazil

Population: Patients aged 18-80– undergoing elective CABG or cardiac valve surgery were assessed for elegibility —-  had hypoxemia as defined P:F ratio as 250mmHg

Inclusion criteria: Immediate postoperative period of myocardial revascularization and/or heart valve surgery (aortic and/or mitral)  • Age > 18 years and < 80 years • No previous pulmonary disease • Left ventricular ejection fraction > 35% • Body mass index < 40 kg/m2 • Oxygen index (PaO2/FiO2) < 250 • Corrected volemic status (negative raising legs mean arterial pressure [MAP]  variation < 10%)  • Written informed consent

Exclusion criteria:      MAP < 60mmHg   • Noradrenaline > 2 micrograms/Kg/min • Acute arrhythmias • Bleeding associated to hemodynamic instability • Need of re-surgery and/or mechanical circulatory assistance • Suspicion of neurological alteration • Chest tube with persistent air leak

Intervention: Intensive Alveolar Recruitment Group  Recruitment with opening pressures of 45 cmH2O in the airways, followed by  ventilation with PEEP = 13 cmH2O, during 4 hours of protective mechanical ventilation with VT = 6 mL/kg/ibw.

Control: Moderate Alveolar Recruitment Recruitment with opening pressures of 20 cmH2O in the airways, followed by ventilation with PEEP = 8 cmH2O, during 4 hours of protective mechanical ventilation with 574 VT = 6 mL/kg/ibw.  After a stabilizing period of four hours of controlled mechanical ventilation, the  patients will follow the routine weaning protocol and physiotherapy protocol of the institution



Primary outcome: Severity of pulmonary complications in the post-operative period [Time Frame: Participants will be followed for the duration of hospital stay, an expected average stay of 12 days after surgery]. Score of pulmonary complications adapted from previous publications 1,2 , with 5 degrees, where the higher one means death before hospital discharge, and degree (4) means the need of mechanical ventilation for more than 48 hours after surgery or after reintubation. The comparison will use this ordinal variable, representing the highest score achieved during the post-operative period

Secondary outcomes: Length of ICU stay—-Length of hospital stay [Time Frame: From the day of surgery up to Hospital 598 discharge, an expected average of 12 days, and maximum censoring at day 28 after surgery] — Incidence of barotrauma [Time Frame: Five days after surgery] Confirmed by X-ray. Test with logistic regression. Hospital mortality [Time Frame: From the day of surgery up to Hospital discharge or death, an expected average of 12 days, with no maximum censoring] Deaths occurred during hospital stay, tested with logistic regression

Authors’ Conclusions :  Among patients with hypoxemia after cardiac surgery, the use of an intensive alveolar recruitment strategy compared with a moderate recruitment strategy resulted in less severe pulmonary complications during the hospital stay.

Strengths: Homogenous group of patients with relatively healthy lungs.
Credible attempt to control variance
Extremely well matched samples
After extubation clinical staff were blinded to the patient
Intention to treat was maintained

Weaknesses: Single Centre..
Homogenous group of patients with relatively healthy lungs difficult to apply to general population
Very specific group of patients on periop bypass
Fluid balance was not included or controlled
Sedation was not protocolized


The Bottom Line: Pretty narrow patient set with a specific insult. However, the application of an aggressive recruitment manoeuvre with exposure to high levels of PEEP combined with LPV was a safe and potentially beneficial approach in the management of this patient group.

Improving Hospital Survival and Reducing Brain Dysfunction at Seven California Community Hospitals: Implementing PAD Guidelines Via the ABCDEF Bundle in 6,064 Patients*Mary Ann Barnes-Daly, MS, RN, CCRN, DC1; Gary Phillips, MAS2; E. Wesley Ely, MD, MPH, FCCM3,4 Critical Care Medicine



  1. Assess and manage pain
  2. Both spontaneous awakening trials and spontaneous breathing trials.
  3. Choice of sedation and analgesia
  4. Delirium monitoring and management
  5. Early mobility and exercise
  6. Family engagement and empowerment


Developed to help implement PAD guidelines.

A prospective cohort quality improvement initiative- seven community hospitals.

Aim of the study was to examine relationship between ABCDEF bundle compliance and outcomes including hospital survival and delirium free and coma free days.

ABCDEF bundles were implemented for every patient for every day.

Use the guidelines of with some depth provided in the paper.

All elements had to be fulfilled for the bundle to have been complete.



  • Active ethanol/drug withdrawal
  • Open abdomen
  • Significant haemodynamic/respiratory instability
  • New coronary ischaemia
  • Therapeutic NMB
  • Intubation within previous 6 hours without stabilisation

6064 patients included in the study, one quarter of which were on mechanical ventilation at some point.

Patients not receiving MV on a particular day and those who never received MV would not be eligible for the A,B or C elements of the bundles on those days.


2 models used

  1. Relative difference in the bundle effect on overall patient group
  2. Relative difference in bundle effect on patients who were or were not transitioned to palliative care.


For every 10% increase in total bundle compliance, patients had a 7% higher odds of hospital survival.

For every 10% increase in partial bundle compliance, patients had a 15% higher hospital survival.

When patients who received palliative care were removed from the calculations then those figures were 12% and 23% respectively.



Total bundle compliance- for every 10% increase in compliance there was a 2% increase in DFCFDs.



Compliance with the bundle was independently associated with better patient survival, more days alive and free of delirium and coma.

These findings help up even when the bundle was not implemented completely.

This study was complementary to previous studies in particular Belas etal, which was a CDC and prevention led quality improvement initiative  where in 51 hospitals all demonstrated improvement implementing some of the elements of the bundle.

There are some criticisms that implementing the bundle is difficult as it has so many parts making lasting change difficult.

The training involved, before actual implementation of the bundle, was felt to be very beneficial in and of itself.

The use of dedicated team members felt to be very important.



Lacked strict protocols used in RCTs

Data collectors were invested in the performance of their units and colleagues/


“the strength of the experience lies in the fact that it was not an RCT. This real world experience can and should lend confidence to may hospitals that want to implement the PAD guidelines.”


Interview Questions for Advanced Critical Care Practitioners

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