Clinical Trials

On fluid resuscitation
1. SPLIT (2015) Effect of a buffered crystalloid solution vs saline on acute kidney
injury among patients in the intensive care unit: the SPLIT
randomised clinical trial

Bottom line - Among patients receiving crystalloid fluid therapy in

the ICU, use of a buffered crystalloid compared with saline did not
reduce the risk of AKI.

2. SAFE (2004) SAFE: A Comparison of Albumin and Saline for Fluid Resuscitation
in the Intensive Care Unit

Bottom line – Albumin and saline result in similar clinical

outcomes when administered in ICU patients for volume
resuscitation, except for those with TBI who do worse with
albumin
3. ALBIOS (2014) Albumin Replacement in Patients with Severe Sepsis or Septic
Shock
Albumin Italian
Outcome Sepsis Bottom line – Among patients with severe sepsis/septic shock,
daily administration of albumin tomaintain serum albumin ≥ 3
g/dL was NOT associated with reduction in all-cause mortality at
28 days when compared to no albumin
*4. SMART (2018) Balanced Crystalloids versus Saline in Critically Ill Adults
SMART-MED
SMART-SURG Bottom line – Among medical/surgical ICU patients, balanced
crystalloid (LR, plasma Lyte) reduce the rate of death, need for
renal replacement therapy, or persistent renal dysfunction, when
compare to normal saline
*5. SALT-ED (2018) Balanced Crystalloids versus Saline in Noncritically Ill Adults

Saline against Bottom line – Among non-critically ill ED patents, initial dluid
LR/Plasma-Lyte in resuscitation with balanced crystalloid (LR, plasma LYTE) does NOT
ED reduce the duration of hospitalization when compared to the
isotonic crystalloid (NS). However balanced crystalloid use is
associated with reduction in major adverse kidney-related events
6. FEAST (2011) Mortality after Fluid Bolus in African Children with Severe
Infection
Fluid Expansion as
Supportive Therapy Bottom line – Among Sub-Saharan African children meeting a
particular definition of shock, saline and albumin resuscitation
appears to increase mortality when compared to a no-bolus
strategy
7. 6S (2012) Hydroxyethyl Starch 130/0.42 versus Ringer's Acetate in Severe
Sepsis
6% HES 130/0.42 in
Ringer’s acetate Bottom line - Patients with severe sepsis who received fluid
group (Tetraspan resuscitation with hydroxyethyl starch compared with Ringer’s
6%) vs Ringer’s acetate had a higher risk of death within 90 days and were more
acetate group likely to receive renal replacement therapy
 Clinical Trials

8. VISEP (2008) Intensive insulin therapy and pentastarch [hydroxyethyl starch (HES)]
resuscitation in severe
The Efficacy of sepsis
Volume Bottom line - In patients with severe sepsis and septic shock, both
Substitution and intensive insulin therapy and HES are harmful as compared to
Insulin Therapy in conventional insulin therapy and Ringer's lactate, respectively.
Severe Sepsis
9. CHEST (2016) Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive
Care

Bottom line - In patients in the ICU, there was no significant

difference in 90-day mortality between patients resuscitated with
6% HES (130/0.4) or saline. However, more patients who received
resuscitation with HES were treated with renal-replacement
therapy.
*10. CRISTAL Effects of fluid resuscitation with colloids vs. crystalloids on
(2013) mortality in critically ill patients presenting with hypovolemic
shock
Colloids vs Bottom line – Among ICU patients with hypovolemic shock there
Crystalloid for the was NO mortality benefit at 28 days with colloid over crystalloid
Resuscitation of for fluid resuscitation
the critically Ill
Note:
a. SALT ED and SMART trials are two recent landmark trials which further discuss on
the never-ending debate between normal saline vs balanced crystalloid
b. FEAST, 6S and VISEP trials are among the trials which showed evidence of harm in
using colloid for sepsis patients, hence our current practice of avoiding it
11. BICARB-ICU (2018) Sodium bicarbonate therapy for patients with severe metabolic
acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-
label, randomised controlled, phase 3 trial
Bottom line -
 In patients with severe metabolic acidaemia, sodium bicarbonate
treatment had NO effect on the primary composite outcome (ie,
mortality by day 28 or the presence of at least one organ failure
at day 7)
 In a subgroup of patients with acute kidney injury, sodium
bicarbonate treatment did decrease the composite outcome and
28 day mortality although this may represent a type I error based
on the outlined limitations of the study
 This study will reassure clinicians that already use sodium
bicarbonate for correcting metabolic acidaemia, that this may
delay and/or reduce the requirement for RRT. Equally, for those
that opt to avoid sodium bicarbonate, there is no compelling
evidence to change practice
On sepsis
Early goal-directed therapy (EGDT) – River trial (2001)
Severe sepsis and septic shock patients → arterial and central line with Continuous Central
Venous O2 Saturation (ScvO2) monitoring with goals of
1. CVP 8-12 mmHg, achieved with fluid boluses
2. MAP >65 mmHg, add on vasopressor if necessary
3. ScvO2 >70%, achieved with RBC transfusions (to maintain HCT of 30) and
dobutamine if necessary
4. UOP > 0.5mL/kg/hr
 Clinical Trials

Has been debunked by “below” trails, d/t

CVP and ScvO2 monitoring does NOT appear useful to target aggressively in early
resuscitation period
CVP has been known to poorly correlate with blood volume in critically ill patients since
1984
Transfusion to maintain ScvO2 lead to excessive transfusions : TRICC trail (1999)
1. ProCESS (2014) A Randomized Trial of Protocol-Based Care for Early Septic Shock

Protocolized Care Bottom line – Among patient with early septic shock, there was
for Early Septic NO difference in all-cause-in-hospital mortality at 60 days with
Shock management driven by early goal-directed therapy (EGDT), a
novel protocol-based therapy (standard therapy), or usual care
2. ProMISe (2015) Trial of Early, Goal-Directed Resuscitation for Septic Shock

UK-based Bottom line – in this multicenter trial of patients with severe

Protocolised sepsis and septic shock, EGDT did NOT improve mortality at 90
Management in days compared to standard therapy including IV fluids and
sepsis vasopressors
3. ARISE (2014) Goal-Directed Resuscitation for Patients with Early Septic Shock

Australian Bottom line – Among patients with severe sepsis or septic shock
Resuscitation in presenting to ED, EGDT did NOT reduce all-cause mortality at 90
Sepsis Evaluation days when compared to usual care
4. TRISS (2014) Lower versus Higher Hemoglobin Threshold for Transfusion in
Septic Shock
Transfusion
Requirements in Bottom line – Patient with septic shock who underwent
Septic Shock transfusion at a Hb threshold of 7 /dL (restrictive transfusion
strategy) had similar mortality at 90 days but used 50% fewer unit
of blood compared with those who underwent transfusion at Hb
threshold of 9 g/dL (liberal transfusion strategy)
5. CORTICUS (2008) CORTICUS: Hydrocortisone Therapy for Patients with Septic Shock

Bottom line – Hydrocortisone hasten the reversal of shock but

does NOT confer a survival benefit among patients with septic
shock

Steroid in septic shock remain controversial.

Increase in infections rate
Corticosteroid should NOT be used routinely in adult patient with
septic shock
 Clinical Trials

6. ADRENAL (2018) Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

Bottom line – In patient with septic shock on mechanical

ventilation and receiving vasopressor, a WEEK of hydrocortisone
200mg/day DID NOT reduce 90 days mortality but may be
associated with faster time for reversal of shock, time to extubate,
length of ICU stay, and blood transfusion

2016 Surviving Sepsis Campaign – suggest IV hydrocortisone if

hemodynamic CANNOT be stabilize using fluids and vasopressors
7. SEPSISPAM High versus Low Blood-Pressure Target in Patients with Septic
(2014) Shock

Sepsis and Mean Bottom line – For patient with septic shock, a goal MAP of 80-85
Arterial Pressure mmHg does NOT reduce all-cause mortality in 28 days when
compared to goal of 65-75 mmHg
The higher the MAP goal was associated with reduction of rates of
renal dysfunction for patient with a history of chronic
hypertension

2016 Surviving Sepsis Campaign – suggest maintaining MAP of 65

- 75 mmHg
8. NICE-SUGAR Intensive versus Conventional Glucose Control in Critically Ill
(2009) Patients

Normoglycemia in Bottom line – In medical ICU patients, intensive glycemic control

ICU and Surviving 4.4 – 6.1 mmol/L lead to more deaths compare to conventional
Using Glucose control (target <10 mmol/L)
Algorithm
Regulation 2016 Surviving Sepsis Campaign – sugar control <10 mmol/L
9. VASST (2008) Vasopressin versus Norepinephrine Infusion in Patients with
Septic Shock
Vasopressin and
Septic Shock Trail Bottom line – Among patient with septic shock on a
catecholamine vasopressor, additional low dose vasopressin
(ADH) did NOT reduce all-cause mortality at 28 days when
compared to addition of epinephrine
10. SOAP II (2010) The use of catecholamine (dopamine vs norepinephrine) in septic
shock
Sepsis Occurrence
in Acutely Ill Bottom line – In treatment of shock, norepinephrine and
Patients dopamine compare similarly with respect to 28 days mortality,
but dopamine is a/w an increase risk or arrhythmias
Note:

a. ProCESS, ProMISe and ARISE trials are also known as sepsis trilogy, which
debunked the concept of EGDT by Rivers et al

On trauma
Clinical Trials

1. CRASH 2 (2010) Effects of tranexamic acid on death, vascular occlusive events,

and blood transfusion in trauma patients with significant
TXA – amino acid : haemorrhage (CRASH-2): a randomised, placebo-controlled trial
Lysine analogue
Bottom line – TXA improve survival when administered early
(within 1 hour) in trauma with known or suspected significant
hemorrhage

1.5% absolute reduction of mortality

Delayed (>3 hour) administration a/w increase bleeding deaths

No difference in rate of vascular occlusive events

2. CRASH 3 (2019) CRASH-3 - Effects of tranexamic acid on death, disability, vascular
occlusive events and other morbidities in patients with acute
1g over 10 minutes traumatic brain injury (CRASH – 3): a randomised, placebo-
followed by IV controlled trial
infusion of 1g over Bottom line - TXA safe in TBI and that treatment within three
8 hours hours reduces head injury associated deaths

1.7% absolute reduction of mortality

When baseline GCS was used in a regression analysis found

evidence that TXA is more effective in less severely injured
patients (mild – moderate TBI) and among patients with reactive
pupils head injury-related deaths were reduced with TXA

NO statistical difference in head injury death within 28 days

The risk of vascular occlusive events and seizures was similar in

the tranexamic acid and placebo groups

Suggest for TXA

 Early treatment (<3hrs)
 Mild to moderate (GCS 9 – 15)
 ICH on baseline head CT
3. NASCIS 1/2/3 Methylprednisolone in the management of spinal cord injuries

National Acute SCI NO RCT data suggesting that steroid is effective in SCI d/t the complexity
Study and different/mechanism/severity of SCI
1 (1984)
2 (1990) Hallmark study used to justify steroid use in SCI showed minimal
3 (1997) neurologic improvements and likely worsen ICU outcomes (4-fold
increase in the incidence of acute pneumonia, ventilator days, and
Intensive Care Unit (ICU) length of stay)

All three NASCIS studies demonstrated increased risk of adverse

events in the steroid-treated populations. Though high-dose
steroid treatment may be safe in other patient populations,
caution should be exercised in the setting of acute traumatic SCI
given the data from NASCIS.
 Clinical Trials

4. REACT 2 (2016) REACT 2: Immediate total-body CT scanning versus conventional

imaging and selective CT scanning in patients with severe
trauma: a randomised controlled trial

Bottom line - Diagnosing patients with an immediate total-body CT

scan does not reduce in-hospital mortality compared with the
standard radiological work-up. Because of the increased radiation
dose, future research should focus on the selection of patients who
will benefit from immediate total-body CT.
On ventilation
1. ARDSNet ARDSnet: Ventilation with Lower Tidal Volumes as Compared
(2000) with Traditional Tidal Volumes for Acute Lung Injury and the
a.k.a Acute Respiratory Distress Syndrome (ARMA)
ARMA
Bottom line – In patient with ARDS, low tidal volume ventilation
Acute (initial 6 mls/kg PBW-predicted body weight) [lung-protective
Respiratory stratergy] had lower mortality and more ventilator-free days
Distress
Syndrome Lung-protective ventilation strategy – goal plateau pressure
Network (Pplat) 25-30 mmHg
2. LOVS (2008) Ventilation Strategy Using Low Tidal Volumes, Recruitment
Maneuvers, and High Positive End-Expiratory Pressure (open-lung
Control Experi
mental
approach) for Acute Lung Injury and Acute Respiratory Distress
VT 6 6 Syndrome
Pplat <30 <40 Bottom line - For patients with acute lung injury and acute
PEEP Conve- higher
ntional respiratory distress syndrome, a multifaceted protocolized
ventilation strategy designed to recruit and open the lung
resulted in no significant difference in all-cause hospital mortality
or barotrauma compared with an established low-tidal-volume
protocolized ventilation strategy. This “open-lung” strategy did
appear to improve secondary end points related to hypoxemia
and use of rescue therapies.

Lower rates of refractory hypoxemia and death related to

refractory hypoxemia

“Rescue therapies” (including prone ventilation, inhaled nitric

oxide, high-frequency oscillation, jet ventilation, or
extracorporeal membrane oxygenation).

3. ALVEOLI Higher versus Lower Positive End-Expiratory Pressures in Patients

(2004) with the Acute Respiratory Distress Syndrome

Bottom line - patients with acute lung injury and ARDS who
receive mechanical ventilation with a tidal-volume goal of 6 ml per
kilogram of predicted body weight and an end-inspiratory plateau-
pressure limit of 30 cm of water, clinical outcomes are similar
whether lower or higher PEEP levels are used
Clinical Trials

4. EXPRESS Positive end-expiratory pressure setting in adults with acute lung

(2008) injury and acute respiratory distress syndrome: a randomized
controlled trial

Bottom line - A strategy for setting PEEP aimed at increasing

alveolar recruitment while limiting hyperinflation did not
significantly reduce mortality. However, it did improve lung
function and reduced the duration of mechanical ventilation and
the duration of organ failure.

Control (minimal Experimental (increase

distention strategy) recruitment strategy)
VT 6 6
PEEP Moderate(5-9 Higher to reach Pplat of
mmHg) 28-30 cm H2O

5. 3CPO (2009) Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema

A multicenter randomised controlled trial of the use of continuous

positive airway pressure and non-invasive positive pressure
ventilation in the early treatment of patients presenting to the
emergency department with severe acute cardiogenic pulmonary
oedema: the 3CPO trial
Bottom line - Non-invasive ventilatory support delivered by either
CPAP or NIPPV safely provides earlier improvement and resolution
of breathlessness, respiratory distress and metabolic abnormality.
However, this does NOT translate into improved short- or longer-
term survival.

We recommend that CPAP or NIPPV should be considered as

adjunctive therapy in patients with severe acute cardiogenic
pulmonary oedema in the presence of severe respiratory distress
or when there is a failure to improve with pharmacological
therapy.
6. ART Effect of Lung Recruitment and Titrated Positive End-Expiratory
(2017) Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute
Respiratory Distress Syndrome: A Randomized Clinical Trial

Bottom line - This trial confirms that protective lung ventilation is

the standard of care for moderate-to-severe ARDS and that an
open lung approach with recruitment manoeuvres should not be
used routinely.

The increased mortality due to the intervention in this study is

statistically fragile and may lack external validity to other settings
Specific subgroups of ARDS patients may benefit from OLA
ventilation with recruitment manoeuvres (e.g. adequately
resuscitated patients with PEEP-responsive ARDS and few other
risk factors for barotrauma or haemodynamic collapse) but
identification of such subroups is uncertain, the evidence for
 Clinical Trials

benefit is weak, and there is risk of harm to patients as found in

the ART trial

7. HACOR Predicting NIV failure in hypoxemic patients: the HACOR score

Note:

a. ARDSNet trial is the landmark trial which formed the basis of our low tidal volume
strategy in Lung Protective Strategy
b. LOVS, EXPRESS, ALVEOLI trials all showed no difference in mortality between low
vs high peep but with improved oxygenation (LOVS), and more ventilator +
organ
failure free days (EXPRESS)

On vasopressor
1. SOAP 2 Comparison of Dopamine and Norepinephrine in the Treatment of
Shock

2. VASST Vasopressin versus Norepinephrine Infusion in Patients with

Septic Shock

On cardiovascular disease / management

1. OASIS 5 Comparison of Fondaparinux and Enoxaparin in Acute Coronary
Syndromes
2. OASIS 6 Effects of fondaparinux on mortality and reinfarction in patients
with acute ST-segment elevation myocardial infarction: the
OASIS- 6 randomized trial

3. CURE Effects of Clopidogrel in Addition to Aspirin in Patients with Acute

Coronary Syndromes without ST-Segment Elevation

4. PLATO Ticagrelor versus Clopidogrel in Patients with Acute Coronary

Syndromes

5. TREAT Ticagrelor in Patients With ST-Elevation Myocardial Infarction

Treated With Pharmacological Thrombolysis - TREAT

6. AVOID Air Versus Oxygen in ST-Segment Elevation Myocardial Infarction

7. DETOX-AMI Oxygen therapy in suspected acute myocardial infarction
 Clinical Trials

8. PEITHO Fibrinolysis for Patients with Intermediate-Risk Pulmonary

Embolism

9. DOSE Diuretic Strategies in Patients with Acute Decompensated Heart

Failure

Misc
1. REVERT The REVERT Trial: A Modified Valsalva Maneuver to Convert SVT

2. TRICC A multicenter, randomized, controlled clinical trial of transfusion

requirements in critical care
3. AMACING Prophylactic hydration to protect renal function from
intravascular iodinated contrast material in patients at high risk
of contrast-induced nephropathy

4. HALT-IT HALT-IT - tranexamic acid for the treatment of gastrointestinal

bleeding

Note:
a. HALT-IT trial finding is still yet to come out

Disclaimer:
The list is absolutely not perfect and did not cover every aspect of emergency
medicine. This is just my personal list based on my encounters during my Mmed
years (teachings from EPs and seniors; during rounds and classes, and some random
posts by selected websites; such as RebelEM etc). I would recommend the registrars
to read on these just to supplement and solidify our knowledge, but trust me, u can
still pass your final exam even without knowing all this, insyaAllah  Have fun
reading!

PS: please add on and modify accordingly as u see fit. Some trials are old ones, so do
update the list if you guys found something more recent.