The Acute Respiratory Distress Syndrome Network. Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome. N Engl J Med 2000; 342:1301-1308

In a prospective randomized controlled trial of 861 patients with ARDS, mechanical ventilation with a tidal volume of 6 ml/kg IBW and plateau pressure ≤ 30 cmH20 (with a focus on achieving these parameters vs. normalising PaCO2 or pH), in comparison with tidal volume of 12 ml/kg IBW and plateau pressure ≤ 50cm H20, was associated with a 9% absolute mortality decrease (31% vs 40%, P=0.007; NNT=11) and a 2 day increase in ventilator-free days (12±11 vs. 10±11; P=0.007).

Mean tidal volumes on day 1-3 were 6.2 and 11.8mL/kg IBW respectively and plateau pressures 25cmH20 and 33cmH20 respectively. Those involved were allowed to increase the RR within the plateau pressure limits as well as provide bicarbonate for mild-to-moderate acidosis. Introduced the concept of PEEP tables corresponding to rising FiO2.

Finfer. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350(22):2247-56

In a  multicentre (16 ICU’s across Australia and NZ), randomized, double-blind trial comparing 0.9% saline or 4% albumin for fluid resuscitation in 6997 critically ill patients in the ICU, there was no difference in mortality (729 v 726, RR 0.99; 95 CI 0.91 to 1.09; P=0.87), new single-organ and multiple-organ failure (P=0.85), mean (SD) numbers of ICU days (6.2±6.2 v 6.5±6.6, P=0.44), hospital days (15.6±9.6 v 15.3±9.6; P=0.30), days of mechanical ventilation (4.3±5.7 v 4.5±6.1; P=0.74), or days of renal-replacement therapy (0.4±2.0 v 0.5±2.3) respectively. 

Clinicians could decide if their patient needed fluid in the first place supported by fulfillment of at least one objective criterion. Excluded post-cardiac/liver transplant/burns patients. Patients were randomly assigned to 4% albumin or N/saline for fluid boluses. Maintenance fluids, specific replacement fluids, TPN/enteral nutrition and blood products were at clinician discretion. There were similar 8-10% rates of alternative resuscitation fluid provided in each group. The albumin group received significantly less fluid overall than the saline group in 1:1.4 ratio. The albumin group also received 70mL more PRBC in first 2 days of the study period. No difference in MAP. CVP higher in albumin group on each day of study. 

Subgroup analysis identified significant increase in mortality in albumin group with trauma, specifically traumatic brain injury (24.5% mortality vs. 15.1%). There was no difference in trauma subgroup without TBI. The sepsis subgroup was later analysed and showed trend towards benefit with albumin. 

Hebert. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-17

In a prospective randomized controlled trial in Canada comparing a red cell transfusion trigger of 7 g/dL versus 10 g/dl in 838 critically ill resuscitated normovolaemic patient, there was no difference in either total 30 day mortality (18.7% vs 23.3%, P=0.11, respectively) or mortality in those with clinically significant cardiac disease (20.5% vs 22.9%; P=0.69). The restrictive transfusion policy was superior for mortality outcome in patients with APACHE II scores of <20 (8.7% vs 16.1%;P=0.03), in patients < 55 years of age (5.7% vs 13.0%; P=0.02), and during hospitalization (22.2% vs 28.1%;P=0.05).

Clinicians were instructed to give one unit at a time with repeat Hb measurements in between.

The average daily Hb concentration was 85 vs. 107g/L in restrictive and liberal groups respectively. Average 2.6 vs. 5.6 PRBC units given in each group respectively.
33% of the restrictive group received no PRBC vs. 0% of the liberal group.

There was non-compliance of physicians in 4.3% of liberal group and 1.3% of restrictive group. There was no difference in secondary outcomes (vasoactive agents, fluid, daily fluid balance, dialysis, MV and surgical procedures).

Mortality benefit differs to previous studies in those with cardiac disease, however, this may be due to previous studies not investigating the deleterious effects of liberal transfusion as closely.

Nielsen. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. N Engl J Med 2013;369:2197-2206

In a multicenter, randomized, control trial, comparing temperature management at 33°C with 36°C in 939 comatose patients after out-of-hospital cardiac arrest of presumed cardiac cause, there was no difference in mortality at the end of the trial (33°C group 50% vs 36°C group 48%; hazard ratio with 33°C, 1.06; 95% CI 0.89 to 1.28; P = 0.51), 180-day composite of mortality and poor neurological function (54% vs. 52%, respectively; RR 1.02; 95% CI 0.88 to 1.16; P = 0.78), or serious adverse events (93% vs. 90%, respectively; RR 1.03; 95% CI 1.00 to 1.08; P = 0.09).

Two previous trials of patients who remained unconscious after initial shockable rhythm compared targeting 32 – 34 degrees for 12-24 hours vs. standard treatment and found a significant improvement in neurologic function and survival.

This study included all OOHCA of presumed cardiac origin (not just initial shockable rhythm) across 36 ICU’s in Australia over 18 years of age with initial GCS <8.

Exclusion criteria were interval from ROSC to screening for inclusion >240 minutes, unwitnessed arrest with asystole as initial rhythm, suspected or known ICH or stroke and body temperature <30 degrees.

Intervention period lasted 36 hours from time of randomisation. Goal was to attain the target temperature as quickly as possible using ice-cold fluids, ice packs and IV or surface temperature management devices at discretion of sites.

After 28 hours, gradual rewarming to 37 degrees was undertaken in hourly increments of 0.5 degrees. At 36 hours, mandatory sedation was discontinued or tapered. After the initial intervention period, the intention was to keep body temp <37.5 for unconscious patients until 72 hours post-cardiac arrest, with the use of fever control measures at the discretion of sites.

Primary outcome was all-cause mortality at end of trial. Main secondary outcome was composite poor neurological outcome or death as defined by CPC of 3-5 and a modified Rankin score of 4-6 at or around 180 days.

The groups were the same with regard to: 80% shockable vs. 20% non-shockable in both groups; 90% witnessed in both groups; 40% STEMI in both groups.

No harms were identified in the 33 degree group but also all point estimates of benefit were in the direction of the 36 degree group.

Sprung. Hydrocortisone Therapy for Patients with Septic Shock. N Engl J Med 2008;358:111-124

In a multicentre, double-blind, randomized placebo-controlled trial comparing hydrocortisone (50mg IV 6 hourly for 5 days, then tapered to BD then daily up to day 11) with placebo in 499 patients with septic shock, there was no significant difference in 28-day mortality (hydrocortisone group 34.3% vs placebo group 31.5%; P=0.51). Subgroup analyses of 28-day mortality based on response to corticotropin also showed no difference between study groups. Hydrocortisone hastened reversal of shock compared to placebo, however, with more episodes of superinfection, including new sepsis and septic shock (OR 1.37).

Initial study by Schumer showed short course of corticosteroids was beneficial. However, subsequent studies showed increased rates of superinfection-related mortality.

This study evaluated efficacy of low-dose hydrocortisone in a broad-group of septic shock patients, in particular, those who had a response to a corticotropin test.

Inclusion criteria were 18 years and older, admitted to ICU, clinical evidence of infection, evidence of systemic response to infection and the onset of shock within the previous 72 hours (as defined by SBP <90 despite adequate fluid resuscitation or vasopressor requirement for at least 1 hour).

Exclusion criteria were poor prognosis, life expectancy <24 hours, immunosuppression, long-term corticosteroid treatment in last 6 months or short-term use in last 4 weeks.

The definitions were as follows:

Organ-system failure defined as SOFA score 3 or 4.

Reversal of shock defined as SBP >90 without vasopressors for 24 hours.

Superinfection defined as new infection 48 hours or more after initiation of study drug.

The primary endpoint was rate of death at 28 days in patients who did not have a response to corticotropin. Secondary endpoints were rate of death at 28 days in those that did have a response to corticotropin and in all patients, rates of death in ICU and in the hospital, rates of death at 1 year, reversal of organ system failure and duration of stay in ICU and hospital.

Safety outcomes were superinfection, GI bleeding, hyperglycaemia, hypernatraemia, muscular weakness, stroke, acute MI and peripheral ischaemia.

There were similar rates of corticotropin response and etomidate use in both groups.

The ProCESS Investigators. A Randomized Trial of Protocol-Based Care for Early Septic Shock (ProCESS study). New Engl J Med 2014

Following on from Rivers et al., which showed EGDT for sepsis reduced mortality from 45% to 30%, PROCESS aimed to validate the same EGDT protocol 10 years later across 31 hospitals in USA. Inclusion criteria were adults >18yo with suspected sepsis and refractory hypotension or lactate >4. 1351 patients were randomly assigned 1:1:1 to either
1) Protocol-based EGDT as per Rivers et al. including mandatory central venous catheterisation, CVP and ScvO2 monitoring
2) Protocol-based standard care with CVL only if peripheral line inadequate and administration of fluids or vasopressors to target SBP and shock index targets or to improve fluid status or hypoperfusion, or
3) usual care (at discretion of treating clinician).

The protocol-based standard care mandated PRBC delivery if Hb <75g/L as compared to Hct>30% in protocol-based EGDT.

Primary outcome was in-hospital death at 60 days. Secondary outcomes were rate of death at 90 days and cumulative mortality at 90 days and 1 year, duration of cardiovascular failure, renal failure, respiratory failure, hospital/ICU LOS and hospital discharge disposition.

EGDT got 2.8L of fluid in first 6 hours vs. 3.3L in protocol-based standard therapy vs. 2.3L in usual care group. Crystalloids in 96% of patients overall. More vasopressors used in protocolised treatment groups. EGDT received much more dobutamine also compared to the other 2 groups.

There were significantly more dialysis requirements in protocol standard care group and more ICU admission for EGDT care group.

At day 60, mortality rates in each group were 21% (EGDT), 18.2% (protocol standard) and 18.9% (usual care) respectively.

Overall impression is protocolised care is no better than usual care, however, this is after a significant period of EGDT being seen as ‘the standard’.

Maitland. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med 2011;364:2483-2495

Maitland et al performed a stratified (severe hypotension or not), multicenter, randomized control trial, in a resource-limited setting in sub-Saharan Africa, comparing a fluid bolus (20 to 40 ml of 5% albumin or 0.9% saline) with no fluid bolus at admission to hospital in 3,141 children with febrile illness and impaired perfusion, and found fluid bolus therapy was associated with a higher mortality at 48 hours (albumin 10.6%, saline 10.5%, no bolus 7.3%; relative risk bolus therapy versus no bolus 1.45, 95% CI 1.13 to 1.86, P=0.003), and 28 days (12.2%, 12.0% & 8.7%, respectively; RR bolus therapy versus no bolus p=0.004), with similar incidences of pulmonary oedema, increased intracranial pressure (2.6%, 2.2% versus 1.7% P=0.17), and neurological sequela in the three groups (P=0.92).

The standard of care in this region prior to the study was to reserve fluid bolus resuscitation for ‘advanced shock’ and was therefore rarely used.

Stratum A did NOT have severe shock, while Stratum B did (based on age-defined BP cut-offs). The Stratum A group were assigned 1:1:1 to rapid volume expansion over 1 hour with 20mL/kg of N/saline, 20ml/kg 5% albumin or no bolus (control). Children in stratum B received 40mL/kg of either N/saline or 5% albumin. In both strata, if impaired perfusion remained at 1 hour, they received a further 20mL/kg bolus of the same fluid (except the control group). If severe hypotension developed, all groups (including control) received 40mL/kg of study fluid as a bolus.

Bolus volumes rates were relatively conservative owing to lack of ICU facilities in sub-Saharan Africa. Initial boluses were increased to 40mL/kg and 60mL/kg respectively mid-way through the study.

Enrolment ceased at 2995 patients once safety group determined highly unlikely to find superiority of bolus strategy vs. control group and safety concerns in bolus groups.

Enrolment criteria were children 60 days to 12 years old with severe febrile illness complicated by impaired consciousness, respiratory distress, or both, and with impaired perfusion as defined by one or more of cap refill <3 seconds, lower-limb temperature gradient, weak radial pulse or severe tachycardia (age-defined).

Exclusion criteria were severe malnutrition, gastroenteritis, non-infectious shock and conditions for which volulme expansion is contraindicated.

Primary end-point was mortality at 48 hours post-randomisation. Secondary endpoints were mortality at 4 weeks, neurologic sequelae at 4 and 24 weeks, episodes of shock within 48 hours and adverse events.

Only short-term BVM was available as respiratory support.

Only 29 were in Stratum B in total, with 13 in albumin group and 16 in saline group.

Median age 2 years and severe lactic acidosis (lactate >5) was present in 39% of children. Malaria was confirmed in 57% of the cohort.

There was no difference found between the saline and albumin groups in any outcomes. Respiratory failure was relatively rare, suggesting the absence of advanced respiratory support was not a significant contributor to mortality.

No subgroup had benefit from bolus treatment.

The applicability of this study to children in the developed world is questionable given the vastly different underlying pathologies (i.e. not malaria) and the lower overall mortality in the developed world ICU environment.

Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009; 374: 1351-63

In a multicenter, randomized control trial, comparing ongoing conventional mechanical ventilation in a non-ECMO centre with transfer to an ECMO centre for respiratory support with either conventional mechanical ventilation or ECMO in 180 patients with severe hypoxic respiratory failure, ECMO centre management, where only 75% of the transferred patients actually received ECMO, was associated with increased 6-month survival (63% vs. 47%, relative risk 0.69, 95% CI 0.05 to 0.97, P=0.03) and a gain of 0·03 quality-adjusted life-years at 6-months, with a lifetime model predicting the cost per QALY of ECMO to be £19 252 (95% CI 7622—59 200) at a discount rate of 3·5%.

Included eligible adults with reversible (as decided by EMCO clinicians) respiratory failure and failing mechanical ventilation. Patients were excluded if they had been on peak pressures >30 or FiO2 >0.8 for more than 7 days, signs of ICH, contraindications to heparinisation or any contraindication to continued treatment.

Patients were then randomly assigned 1:1 to conventional management (not protocolised but ARDSnet protocol recommended) or consideration for ECMO. Those randomised to ‘ECMO consideration’ were then transferred to the ECMO centre. Those transferred followed a protocolised ARDS management plan and if they did not respond to this after 12 hours they were transferred onto vvECMO. Patients were not transported on ECMO.

180 patients enrolled in total and 75% (68 patients) of those considered for ECMO actually received it. Low-volume, low-pressure ventilation was achieved more commonly and steroids used more commonly in the ‘consideration for ECMO group’ than the conventional care group.

CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010;376:23-32

In a blinded, international, multicenter, randomized control trial, largely in resource limited healthcare systems, comparing administration of tranexamic acid (TXA) within 8 hours of traumatic injury (1g over 10 min, then infusion of 1g over 8 hours) with placebo in 20,211 adult patients, with or at risk of significant haemorrhage (SBP <90 mmHg or HR >110 bpm, or both), TXA was associated with reduced mortality (14.5% versus 16.0%; relative risk 0.91, 95% CI 0.85 to 0.97; p=0.0035), including reduced bleeding-related mortality (4.9% versus 5.7%; RR 0.85, 95% CI 0.76 to 0.96; p=0.0077), despite no difference in requirement for blood transfusions (50.4% vs. 51.3%) or vascular-occlusive events. In a subsequent post hoc analysis, the bleeding-related mortality reduction with TXA was time dependent, and actually reversed with late administration after 3 hours of injury (TXA 4.4% vs. placebo 3.1%, p=0.004). Treatment groups were balanced in all specified characteristics.

Asfar et al. High versus Low Blood-Pressure Target in Patients with Septic Shock (SEPSISPAM study). New Engl J Med 2014;370:1583-1593

Surviving Sepsis Campaign advised target MAP >65 based on low level evidence. There was equipoise regarding MAP targets in those with baseline hypertension or atherosclerosis. SEPSISPAM was a multicentre, randomised open-label trial in France to determine whether targeting MAP 80-85mmHg vs. 65-70mmHg improved 28-day mortality. Patients were stratified at randomisation into baseline chronic hypertension or not.

Inclusion criteria were adults >18yo with refractory septic shock requiring vasopressors. Refractory was defined as lack of response to 30mL/kg resuscitation fluid or as per clinician assessment. Did not include pregnant patients.

Renal replacement therapy was initiated as per protocol.

Vasopressor treatment was then titrated to the target MAP for up to 5 days or until weaned, after which it was up to clinicians. For patients who did not reach target MAP’s, they were analysed on an intention-to-treat basis.

In the high-target group, vasopressors were reduced to maintain MAP 65-70 if adverse events occurred as pre-defined.

Primary outcome was 28 day mortality. Secondary outcomes were 90-day mortality, days alive and free of organ dysfunction by day 28 and hospital/ICU LOS.

The study enrolled 776 patients with ~44% of each group having chronic hypertension. The mean MAP in the low-target group (while lower than the high target group) exceeded 65-70mmHg on each day of the study (closer to 70-75mmHg). The high-target group had a mean MAP of 80-85 throughout the study period.

At 28 days there was no difference in rate of death (~35% in each group). This was also true at 90 days, nor any difference in secondary outcomes except for patients with baseline chronic hypertension requiring more RRT in the low group. This did not alter mortality outcomes.

The high-target group received higher and longer doses of vasopressors but with no difference in overall adverse events. The high target group did have more episodes of AF.

The higher actual mean MAP in both groups maintained a target difference in mean MAP and may reflect the fact that clinicians were reticent to reduce vasopressor infusion rates at MAP’s near the upper limit of the target range. In reality, a pragmatic approach of targeting either MAP would be reasonable, with the knowledge that the actual achieved MAP may differ (likely higher), more RRT may be required if targeting a low MAP in chronic hypertension and that targeting a higher MAP may increase rates of AF.

Chesnut et al. A Trial of Intracranial-Pressure Monitoring in Traumatic Brain Injury. New Engl J Med 2012;367:2471-2481

BEST TRIP study showed ICP monitoring utilised to target ICP <20mmHg vs. conventional therapy to manage based on imaging and clinical examination made no difference to mortality.

Multicentre, randomised control trial in Bolivia and Ecuador (as did not use ICP monitoring as standard care prior to the trial). Inclusion criteria were patients 13 years or older, with GCS 3-8 within 48 hours of injury. Exclusion criteria were GCS of 3 with fixed dilated pupils or unsurvivable injury.

Those patients randomised to ICP monitoring had an intraparenchymal monitor placed as soon as possible with ICP <20mmHg targeted in accordance with TBI guidelines. Drainage of CSF required ventriculostomy placement. The clinical examination and imaging group had care protocolised as per standard care prior to the trial in the trial sites.

Primary outcome was a composite of 21 components measuring survival, duration and level of impaired consciousness, functional status and orientation at 3 months. The overall outcome was the average of the 21 percentiles.

Of 528 eligible patients, 39% were excluded before randomisation. Similar groups at baseline. Only 45% of participants were transported to hospital via ambulance. The median time to arrival to the study centre was 3.1 hours (including both transfers and direct admissions). Prehospital interventions and obs were not available.

The median GCS at randomisation was 4.

49% of participants had localising brain injuries and 43% had Grade III diffuse injury on CT. 33% had mass lesions requiring surgery.

There was greater use of hypertonic saline and mannitol in the clinical group but greater use of high dose barbiturate therapy in the ICP monitored group.

Brings into question the protocol utilised around pressure-monitoring rather than monitoring itself.

Caironi. Albumin Replacement in Patients with Severe Sepsis or Septic Shock. New Engl J Med 2014;370:1412-1421

Following the SAFE trial, where albumin and crystalloid were proven equal in critically ill patient resuscitation and the subsequent post-hoc analysis of this showing a trend towards improved mortality in sepsis, ALBIOS aimed to prove albumin replacement targeting a serum albumin 30g/L + crystalloid versus crystalloid alone would improve outcomes. They showed it made no difference to mortality at 28 days or 90 days.

The study was performed in 100 ICU’s in Italy in adults over 18 years old with severe sepsis. They utilised 20% albumin.

The primary outcome was death at 28 days and principal secondary outcome was death at 90 days.

There were 1818 patients enrolled with similar baseline characteristics. The total amount of fluid delivered across the first 7 days of the protocol did not differ between groups. The serum albumin was significantly higher in the albumin group from day 1 to 28. During the first 7 days, the albumin group had higher MAP and lower heart rates as well as a lower net fluid balance. There was a trend towards improved haemodynamics and reduced vasopressor dose/duration in the albumin group.

Subgroup analysis of those patients who were in septic shock showed a significant improvement in mortality at 90 days.

Russell. Vasopressin versus norepinephrine infusion in patients with septic shock. NEJM 2008;358:877-87

The rationale behind vasopressin use in septic shock stems from relative vasopressin deficiency observed in patients with septic shock and that replacement of this may reduce catecholamine requirements.

Investigators performed a randomised, stratified, multicentre, double-blind trial across Canada, USA and Australia to determine whether vasopressin at 0.01-0.03U/min vs. noradrenaline 5-15mcg/min in addition to open-label vasopressors targeting MAP 65 in septic shock improved mortality. They found no difference in mortality at 28 or 90 days. They found no significant difference in rates of adverse events including organ dysfunction.

Their secondary hypothesis was that benefits would be more pronounced in the more severe septic shock group. In the less severe septic shock group, vasopressin showed mortality benefit but this was not evident in the more severe group.

Inclusion criteria were adults over 16yo with fluid-resistant septic shock (as defined by lack of response to 500mL N/saline or requiring vasopressors (at least 5mcg/min of noradrenaline or equivalent).

Exclusion criteria included severe heart failure or intercurrent myocardial infarction.

Shock was stratified as less severe (NA 5-14mcg/mL) or more severe (>=15mcg/mL).

Blinded vasopressin was started at 0.01U/min and titrated up to 0.03U/min over the first hour vs. blinded NA started at 5mcg/min and uptitrated to 15mcg/min.

The bedside nurses were also allowed to continue open-label vasopressors to maintain a constant MAP of 65-75 (but this target could be altered by attending physicians).

Open-label vasopressors were only uptitrated if target MAP was not reached on maximal study-drug infusion. Tapering of the study drug was only commenced when the target Map had been achieved for 8 hours without any open-label vasopressors.

Of 6229 screened patients, 802 underwent randomisation with 778 included in final primary analysis. BP was similar between groups while HR was significantly lower in the vasopressin group. The rate of noradrenaline infusion was significantly lower in the vasopressin group than the NA group.

There were trends towards higher rates of cardiac arrest in the NA group and digital ischaemia in the vasopressin group, but neither reached statistical significance.

In the less severe shock group, there was a trend towards improved mortality in the vasopressin group at 28 and 90 days. There was no difference noted in the more severe septic shock subgroup.

Specifically, this was NOT a trial of vasopressin in catecholamine-refractory shock, the role in which it is most used.

14. Kumar. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136(5):1237-1248.

This was a retrospective multicentre review aimed at examining the relationship between inappropriate antimicrobial initiation and survival in septic shock. Decisions on ‘appropriateness’ were prespecified based on broad cover of culture-negative sepsis or specifically targeting identified pathogens.

Reviewed 5715 cases of septic shock, with 55% community-acquired vs. 45% nosocomial. 82% had documented infections while 18% were suspected infectious without bacteria isolated or definitive diagnostics. The survival rate between these two groups was similar.

Of the entire group, 4.8% received inappropriate antimicrobials. 21.8% of patients suffered septic shock after inappropriate antimicrobial use. Specifically, pneumonia, intra-abdominal infection, catheter-associated infections and primary bacteraemia showed lower rates of appropriate initial coverage. Fungal organisms showed the lowest rate of appropriate coverage (44%).

Survival to hospital discharge with appropriate vs. inappropriate antibiotic initial therapy were 52% and 10% respectively. In the inappropriate group survival decreased 2.3 fold for pneumonia to 17.6 fold for primary bacteraemia.

15. Bernard. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. N Engl J Med 2002; 346:557-563 

In a multicentre, blinded, randomised, controlled trial in Melbourne, comparing therapeutic hypothermia (33°C, achieved within 2 hours of ROSC and maintained for 12 hours) with normothermia in 77 comatose survivors of out-of-hospital VF cardiac arrest, hypothermia improved survival with a good outcome (49% versus 26%, p=0.046; odds ratio 5.25, 95% CI 1.47 to 18.76, p = 0.011).  

Inclusion criteria were patients with initial VF, successful ROSC and persistent coma. Exclusion criteria were <18yo for men, <50yo for women (due to possibility of pregnancy), cardiogenic shock or possible differentials for coma other than cardiac arrest. Cooling measures were initiated pre-hospital for those randomised to hypothermia. MAP was maintained between 90 and 100mmHg in both arms. All patients received lignocaine bolus (1mg/kg) and infusion (2mg/min over 24 hours). In the ED and ICU, patients assigned to hypothermia had ice packs placed until temperature reached 33 degrees and then removed with temperature maintained at this level for 12 hours. 

The target core temperature in the normothermia arm was 37 degrees and passive rewarming was used if hypothermic on arrival.  

Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, hyperglycemia, with no difference in the frequency of adverse events. 

16. Villanueva. Transfusion Strategies for Acute Upper Gastrointestinal Bleeding. N Engl J Med 2013;368:11-21

Hebert et al. study on restrictive vs. liberal transfusion triggers in critical illness excluded GI bleeds. This study aimed to investigate this group specifically. Performed in Barcelona, they included adults over 18yo with haematemesis, melaena, or both. Exclusion criteria were exsanguination; ACS, symptomatic peripheral vascular disease, stroke, TIA or transfusion in the last 90 days; recent trauma/surgery; lower GI bleeding; and Rockall score of 0 with Hb >120.

The restrictive group had a trigger of 70g/L and target of 70-90g/L. The liberal group had a trigger of 90g/L, with a target range of 90-110g/L. A Hb check was performed after each unit.

All patients underwent emergency gastroscopy within 6 hours.

Primary outcome was rate of death from any cause within the first 45 days. Secondary outcomes were rates of further bleeding and in-hospital complications.

1610 patient screened and 921 patients underwent randomisation. 49% of patients had peptic ulcers and 21% had oesophageal varices.

51% of patients in the restrictive group vs. 14% in the liberal group received NO transfusion. The lowest Hb concentration in the first 24 hours was significantly lower in the restrictive group, as was the mean numbers of units transfused (1.5 vs 3.7). 9% of patients had violation of protocol in the restrictive group vs. 3% of the liberal group.

The total amounts of fluid provided, platelets and FFP delivery were the same between groups.

Restrictive transfusion (70g/L) vs. liberal (90g/L) trigger resulted in improved survival from 9% to 5%. The effect was most significant in Childs-Pugh A and B. Those with Childs-Pugh C had no reduction in mortality. Death was due to associated diseases in the vast majority in both groups. The rate of further bleeding was less in the restrictive group (10% vs. 16%). Again, this effect was not evidence in those with Childs-Pugh C but was apparent in A/B stage disease. The risk of rebleeding trended towards an improvement with the restrictive regime. The overall rate of adverse events was 40% in the restrictive group vs. 48% in the liberal group. Transfusion reactions and pulmonary oedema were more common in the liberal group.

Meyer. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med 2014;370:1402-1411

Multicentre, randomised, double-blind, placebo-controlled trial in adults >18yo with objectively confirmed acute pulmonary embolism, with onset in last 15 days, RV dysfunction confirmed by echo or CT, normotensive and myocardial injury with positive troponin (so called submassive PE).

Those randomised to fibrinolysis received weight-based tenectaplase bolus (30-50mg). IV heparin bolus was administered immediately after randomisation.

All patients were followed up for 30 days for death, haemodynamic collapse, bleeding, stroke, recurrent PE and serious adverse events.

Primary outcome was clinical composite of death from any cause or haemodynamic decompensation within 7 days after randomisation.

1006 patients enrolled.

The primary outcome occurred in 2.6% of the fibrinolysis group vs. 5.6% in the placebo group. Death at 7 days was unchanged between groups however, as it was only haemodynamic decompensation that was reduced in the fibrinolysis group. More patients in the placebo group required open-label rescue fibrinolysis. By day 30, mortality between groups was equal.

Major bleeding occurred in 11.5% of the fibrinolysis group vs. 2.4% of the placebo group. There were 12 strokes (10 haemorrhagic) in the fibrinolysis group vs. 1 in the placebo arm.

There was overall a 2% rate of haemorrhagic stroke and 6.3% rate of major extracranial haemorrhage in the fibrinolysis arm.

The apparent benefit in primary outcome was only evident in the under 75yo age group and did not reach significant in those over 75yo. The rates of ICH were not significantly higher in the over 75yo group.

Suggestion was made in discussion to consider half-dose lysis in the over 75yo age group to potentially reduce bleeding risk despite no significant in this study specifically.

18. The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus Lower Positive End-Expiratory Pressures in Patients with the Acute Respiratory Distress Syndrome. N Engl J Med 2004;351:327-36.

Theorised that higher PEEP levels may reduce the volume of non-aerated lung and may allow achievement of PaO2 values with lower FiO2, thus overall reducing the risk of ventilator-associated lung injury.

There were initially two different FiO2/PEEP tables generated, identified as low and high-PEEP. The lower PEEP table was the same as that used in the original ARDSnet trial. The higher PEEP table initially required a minimum PEEP of 12 for the first 12 hours, but this was mid-study increased to 14cmH20 for 48 hours.

The study was then stopped after 549 patients as deemed to be futile (i.e. likelihood of benefit of higher PEEP was <1%).

The mean PEEP values were 8.3 and 13.2 in each group. Tidal volumes were significantly lower and plateau pressures higher in the PEEP group (but still near 6mL/kg and <30cmH20 respectively).

19. Annane. Corticosteroids in the Treatment of Severe Sepsis and Septic Shock in Adults. JAMA 2009;301(22):2362-2375

Systematic review of the effects of corticosteroids on 28 day survival in severe sepsis and septic shock. Included 13 trials. Showed no significant benefit of corticosteroid treatment on 28 day mortality, ICU mortality or hospital mortality. Specific subgroup analysis of those studies investigating prolonged courses (>5 days) and low-dose (<300mg hydrocortisone equivalent per day) demonstrated significant reduction in all-cause and hospital mortality.

20. Allen. Cerebral Arterial Spasm – A Controlled Trial of Nimodipine in Patients with Subarachnoid Hemorrhage. N Engl J Med 1983; 308:619-624

Prospective, randomised, double-blind, placebo-controlled trial of nimodipine to test its benefit in preventing or altering the severity of neurological deficits due to vasospasm. Inclusion criteria were neurologically normal patients (had to be oriented to person, place and time; or have at most an isolated CN palsy) following confirmed aneurysmal SAH within 96 hours.

Patients aged 15-80yo were included. Nimodipine was dosed at 0.7mg/kg PO bolus then 0.35mg/kg PO q4h for 21 days vs. placebo.

Primary endpoints were the development of a neurological deficit and the severity of the deficit at the end of the treatment period. 121 patients randomised with similar baseline SAH severity (radiological), LOC and recent previous SAH, age, concurrent medical illness and number of aneurysms.

Nimodipine reduced the frequency of severe neurological deficits from spasm. 8 patients in the placebo group had severe deficits at the end of treatment. Vs. 1 patient in the nimodipine group. Rebleeding rates were similar between groups.

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020; 395; 1927-36

Gastrointestinal bleeding carries a case-fatality rate of 10% (upper GI) or 4% (lower GI). Re-bleeding increases the risk of death by four times. HALT-IT was performed across 15 countries (mostly resource-poor) in adults over 18yo who presented with significant bleeding (as defined by risk of bleeding to death, hypotension, tachycardia or signs of shock, or those likely to need transfusion or urgent endoscopy or surgery.

Patients were randomised to either TXA or placebo. TXA was delivered as 1g bolus over 10 minutes followed by maintenance dose of 3g over 24 hours. The primary outcome was death due to bleeding within 5 days of randomisation. Secondary outcomes were death due to bleeding at 24 hours and within 28 days, all-cause and cause-specific mortality at 28 days, surgery or radiological intervention, blood product transfusion, VTE events, seizures, other complications, days in ICU and functional status.

They recruited 12009 patients over 6 years with no difference identified in any primary outcome but an increased risk of VTE events (RR 2.11) and seizures (RR 1.73). Rebleeding rates were also no different.

Commentary was that in GI bleeding patients present later than in trauma/PPH and the contribution of hyperfibrinolysis at this time is unclear.

Rivers. Early goal directed therapy in the treatment of severe sepsis and septic shock. N Eng J Med 2001;345:1368-77

Single centre study in tertiary institution with severe sepsis, septic shock or the sepsis syndrome over 3 years. Had to meet 2/4 SIRS criteria and a SBP <90 after crystalloid fluid challenge of 20-30mL/kg or lactate >4.

Exclusion criteria were age <18, pregnancy, acute stroke, acute MI, APO, status asthmaticus, cardiac dysrhythmias, active GI haemorrhage, seizure, drug overdose, burns, uncured cancer or immunosuppression.

Patients were then managed as standard care (as per a haemodynamic protocol (see Figure 1 below)

Those patients assigned to early goal-directed therapy received a CVL for central venous oxygen saturation with a different protocol for at least 6 hours. SCVO2 monitoring was then ceased and care continued as per usual care pathways.

Figure 1 – Study design

Figure 2 – EGDT protocol

• If MAP >90 -> Nitrates; if MAP <65 -> vasopressors; Dobutamine was the inotrope of choice.

288 patients were screened and 263 patients underwent randomisation.

Those assigned to standard care had shorter ED stay (6.3 vs 8 hours) and baseline characteristics were equal. During the initial 6 hours, the MAP was significantly lower in the standard care group but was still >65. SCVO2 target >70% was achieved in 60% of the standard care group vs. 95% of the EGDT group.

In-hospital, 28 day and 60 day mortality were higher in the standard therapy group (57%) than the EGDT group (42%).

During the initial 6 hours, the EGDT group received more fluid, more inotropes and more PRBC. In the following 7-72 hour period, the standard group caught up in fluids, blood products, vasopressors and pulmonary artery catheterisation.

This led to the broad uptake of the EGDT protocol, which was then compared to the new standard of care in the PROCESS study which found it to be equal.

Kattah JC, Talkad AV, Wang DZ, Hsieh YH, Newman-Toker DE.. “HINTS to diagnose stroke in the acute vestibular syndrome: three-step bedside oculomotor examination more sensitive than early MRI diffusion-weighted imaging.”. Stroke. 2009. 40(11):3504-3510.

Assessed a three-step bedside test for its sensitivity and specificity in comparison to MRI in diagnosing posterior stroke in acute vestibular syndrome. This was a prospective, cross-sectional study of patients presenting with AVS in a single academic centre. Patients with core features of AVS (rapid onset vertigo, nausea, vomiting, unsteady gait, with or without nystagmus) were identified from ED. Patients were also identified through screening patients admitted for cerebellar stroke. Patients all had at least one risk factor for stroke (smoking, HTN, diabetes, recent cervical trauma, hyperlipidaemia, eclampsia, hypercoagulable state or prior stroke/MI). Excluded were patients with previous vertigo with or without auditory symptoms.

The study neuro-ophthalmologist then conducted a neurologic and vestibular examination (including the three-step HINTS).

HINTS was defined as benign (abnormal horizontal head impulse test + direction-fixed horizontal nystagmus) + absent skew) OR dangerous (normal/untestable h-HIT or direction-changing nystagmus or skew deviation).

Screened 121 patients and excluded 19. Mean age of 62yo. 76 of the 101 patients had a central lesion, while 25 and acute peripheral vertigo.

Severe truncal ataxia was only seen with central lesions (34% vs. 0%).

Vertical skew deviation was present in 4% of acute peripheral vertigo, 4% with pure cerebellar lesions and 30% of brainstem structural lesions.

A dangerous HINTS result was 100% sensitive and 96% specific for the presence of a central lesion. By comparison, general neurological signs were 50% sensitive and oculomotor signs 32% sensitive.

MRI was found to be 88% sensitive overall in the first 24-48 hours and 72% sensitive for lateral medullary and lateral pontine infarctions.

The major flaw in the study was the examination being performed by a neuro-ophthalmologist who was not masked to history, general neurological examination or obvious oculomotor issues apart from the HINTS test. Another flaw was the high-risk cohort being studied.

Anderson. Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage. N Eng J Med 2013

International, multicentre, randomised, open-treatment, blinded end-point trial of targeted lower systolic blood pressure (<140mmHg) within first hour post-diagnosis of acute non-traumatic intracerebral haemorrhage as compared to standard care (treatment only if SBP >180mmHg). Patients were included if they had an initial SBP of 150-220mmHg and who had no contraindication to blood pressure lowering within 6 hours of onset of symptoms. Exclusions included GCS 3-5, structural cause for haemorrhage, massive haematoma with poor prognosis, or if early surgery was planned.

Pre-specified treatment protocols differed between region based on availability of medications.

The blood pressure target remained for 7 days. The primary outcome was poor outcome as defined by death or major disability (mRS 3-5) at 90 days. This was then changed to ordinal analysis after large stroke trials utilised this measure.

2839 patients over 4 years were enrolled. The mean systolic pressure at 1 hour in the intensive treatment arm was 150mmHg (33% achieved <140mmHg as targeted) vs. 164mmHg in the standard treatment group.

A decision to withdraw treatment was made in the intensive treatment group more often (75 vs. 46 patients).

There was no statistically significant difference in the primary outcome between groups. Ordinal analysis showed a benefit of intensive treatment with a pooled odds ratio of improvement in mRS to higher score of 0.87.

The number of serious adverse events was also equal between groups. There was no significant difference in the size of the intracerebral haematoma between groups.

He. Effects of Immediate Blood Pressure Reduction on Death and Major Disability in Patients With Acute Ischemic Stroke: The CATIS Randomized Clinical Trial. JAMA 2013

The China Antihypertensive Trial in Acute Ischaemic Stroke (CATIS) was a multicentre RCT testing whether moderate lowering of BP in the first 48 hours post-ischaemic stroke would reduce death and disability at 14 days or hospital discharge, 3-month mortality, major disability and vascular events.

Patients were included if they had confirmed ischaemic stroke within 48 hours of onset, blood pressure of 140-220mmHg. Patients were excluded if SBP >220 or DBP >120 as treatment is recommended by guideline in these groups, severe heart failure, acute MI, AF, aortic dissection, cerebrovascular stenosis, or deep coma.

Patients receiving tPA were also excluded.

Target blood pressure was a reduction by 10-25% within the first 24 hours post-randomisation, SBP <140mmHg and DBP <90mmHg within 7 days and maintaining this target for the duration of hospital stay.

Drugs could be used based on clinician preference. Patients in the control group discontinued their home antihypertensives.

Once discharged patients were prescribed antihypertensives as per guidelines.

Primary outcome was combination of death and major disability (mRS 3-5) at 14 days or at hospital discharge. Later switched to ordinal analysis as per stroke trials.

Of 22 230 screened patients over 4 years, 4071 underwent randomisation. 49% were taking antihypertensives on admission.

Within 24 hours, the mean SBP was reduced by 21 in the treatment group and 12.7 in the control group. At day 7, the mean SBP was 137 in the treatment arm (65.7% achieved <140mmHg) vs. 146.5mmHg in the control group (32.3% had mean SBP <140mmHg).

At day 14, the mean SBP was 135.2 in the treatment group (72% achieved <140mmHg) vs. 143.7 (39.5% with mean SBP <140mmHg) in the control group.

No difference in primary outcome of death or major disability at 14 days or hospital discharge, nor at 3 months follow-up. No difference in ordinal analysis of mRS. No difference in adverse events.

The findings suggest that unless SBP >220mmHg or DBP >120mmHg, there is no benefit to antihypertensive treatment acutely. This does not include patients treated with tPA.

26. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg. 1976;184(3):333-341.

Prospective double-blind RCT on 172 septic shock patients admitted to a surgical service over 8 years in 1967 through to 1975. Patients had to have a positive blood culture for inclusion. Treatment arms were saline, dexamethasone 3mg/kg or methylprednisolone 30mg/kg and could be repeated at 4 hours.

The study was predominantly males. Mortality rates did not differ significantly across the timeframe despite changes in antibiotic regimes and ventilator strategies.

The mortality rate in the saline group was 38.4% vs. 10.4% in the steroid group.

No difference in complications between groups.

27. Andersen. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349(8):733-42

RCT of patients with STEMI to either on-site fibrinolysis or transfer for primary PCI (within 3 hours) in Denmark.

In the fibrinolysis group, failed fibrinolysis (i.e. incomplete resolution or recurrent STEMI) repeat fibrinolysis was attempted before rescue PCI.

Primary endpoint was composite of death from any cause, clinical reinfarction or disabling stroke at 30 days.

Patients had to be over 18 with presence of symptoms for at least 30 minutes but less than 12 hours. Exclusion criteria were CI to fibrinolysis, LBBB, previous CABG, renal failure, diabetes treated with metformin and non-cardiac disease limiting life expectancy <12 months. Also excluded were those with cardiogenic shock, persistent life-threatening arrhythmias, or mechanical ventilation requirement.

Subsets of patients were those that presented to interventional hospitals and those that presented to referral hospitals without PCI capability.

4278 patients were screened for inclusion. At a safety checkpoint, it was deemed the substudy at referral (non-PCI) hospitals showed significant benefit to PCI and the study was ceased.

Median time from onset of symptoms to randomisation was 135 minutes and the median distance to be transferred was 50km. The mean transfer time was 67 minutes to the cath lab. There were no deaths during transport.

The relative risk reduction in composite outcome at PCI hospital was 45% and at referral hospitals was 40%. This was driven by a 75% overall reduction in reinfarction in the PCI group and there was not a difference in death or stroke rates.

Webb. Percutaneous coronary intervention for cardiogenic shock. JACC 2003;42(8):1380–1386

Patients in cardiogenic shock within 36 hours of MI were randomised within 12 hours of diagnosis of shock to either medical management or emergency revascularisation via PCI or surgery. 302 patients were enrolled with 132 patients underwent attempted revascularisation, with 48 CABG and 84 PCI attempts. 8 patients subsequently underwent CABG after PCI.

The median time from MI to shock diagnosis was 5.1 hours and MI to PCI was 11 hours.

Emergency revascularisation showed a significant mortality benefit at 1 year but actual results for the medical arm were unclear. This study also pre-dated modern stents (had balloons mostly).

29. Kilgannon. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010;303:2165–2171

Retrospective analysis of post-ROSC patients who survived to ICU and whether hyperoxia (PaO2 >300) was associated with lower survival to hospital discharge.

Patients were older than 17yo, with non-traumatic cardiac arrest and CPR prior to ICU arrival. Of 6326 analysed patients, 18% were in the hyperoxia group, 63% in the hypoxia group (PaO2 <60) and 19% in the normoxia group (PaO2 60-300).

Mortality in the hyperoxia group was 63%, hypoxia group 57% and normoxia group 45%. After controlling for a predefined set of confounders, hyperoxia remained a significant predictor of death. Additionally, hyperoxia was associated with a lower likelihood of independent functional status on discharge.

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. Perkins G.D. et al. New England Journal of Medicine 2018

Observational studies had shown adrenaline increased ROSC but with risk of worsened neurological outcome. ILCOR then decided to undertake this research comparing adrenaline or placebo every 3-5 minutes in OOHCA in adults over 16yo. Patients were excluded if they had received adrenaline prior to arrival of a trial paramedic, cardiac arrest for anaphylaxis or asthma, or pregnant.

The primary outcome was rate of survival at 30 days with secondary outcomes of rate of survival to hospital admission, hospital and ICU LOS, rate of survival at hospital discharge and at 3 months, and neurological outcome at hospital discharge and at 3 months. Survival with favourable neurological outcome was defined as an mRS of 3 or less.

Of 10 623 patients screened, 76% were deemed eligible. Most exclusions were due to receipt of adrenaline prior to trial paramedic arrival. 4000 in each group were then randomised. The median time to ambulance arrival was 6.6 minutes and to trial drug administration was 13.8 minutes.

Adrenaline group showed pre-hospital ROSC rate of 36.3% vs. 11.7% and proportion transported to hospital was 50% vs. 30%.

Survival at 30 days was 3.2% in adrenaline group vs. 2.4% in placebo group. There was no difference in favourable neurological outcome between the two groups (2.2% and 1.9% respectively). Severe neurological impairment (mRS 4-5) was seen in 31% of adrenaline group and 17.8% of placebo group.

ffect of intravenous corticosteroids on death within 14 days in 10 008 adults with clinically significant head injury: randomised placebo-controlled trial. Roberts et al for the CRASH trial collaborators. Lancet 2004; 364:1321-28

International RCT of early methylprednisolone infusion over 48 hours for TBI on risk of death and disability. Adults over 16 were included if randomised <8 hours post-injury and GCS 14 or less. Primary outcome was death from any cause at 2 weeks and death or disability at 6 months. Recruitment was ceased after 10 008 patients randomised. There was a 21% mortality rate in the steroid group vs. 18% for placebo (p = 0.0001). 6 month follow-up favoured placebo for mortality and severe disability.

Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH – 3): a randomised, placebo-controlled trial. The CRASH-3 trial collaborators. The Lancet, 2019

RCT of TXA dosing as per CRASH-2 for adults with TBI and no major extracranial bleeding within 3 hours and GCS 12 or lower with ICH on CT.

Mortality 18.5% in TXA group vs. 19.8% in placebo group

Not statistically significant

Statistically significant reduction of mortality in mild-moderate group but not severe group

No evidence of adverse events

Really just proves safe to give in multitrauma with head injuries.

Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI)”. Lancet. 1 (8478): 397–402. 1986

Consensus in 1983 was that intracoronary streptokinase was of benefit in acute MI within 24 hours of presentation. This trial aimed to compared IV streptokinase vs. standard care as per individual CCU’s. If the policy of the CCU was to anticoagulate, then this was performed with/without streptokinase accordingly.

Patients were eligible if had chest pain and ST elevation or depression of 1mm or more in any limb lead and/or 2mm or more in any praecordial lead AND if they were admitted to CCU within 12 hours of symptom onset.

Only 13 and 14% of patients received antiplatelets in this trial respectively.

There 11806 patients randomised in 176 CCU’s in Italy. Mortality in the streptokinase group was 10.7% vs. 13% in the control group across all ages and gender. This benefit existed only in the <9 hours subgroup and was greater the more rapidly streptokinase was administered. In the 9-12 hour group, mortality was actually higher in the streptokinase group at 15.8% vs. 13.6%.

Patients with anterior and multiple-site infarcts did best with streptokinase while those with lateral infarcts and ST depression did worse than the control group (non-significant).

Adverse incidents were rare.

Boersma E; Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J. 2006 Apr;27(7):779-88

The primary endpoint of this meta-analysis was all-cause mortality at 30 days. This looked at all randomised trials from 1990 until 2002 comparing primary PCI with fibrinolysis in AMI.

22 trials met inclusion criteria.

Overall 3383 patients had fibrinolysis and 3380 primary PCI. The median presentation delay was 142 minutes in both groups. The time from randomisation to the start of either intervention was not altered by the length of time from symptom onset. From this it is evident, the time from randomisation to fibrinolysis was far shorter at 19 minutes vs. 76min, with a calculated PCI delay of 55 minutes.

The overall mortality rate was 6.6% at 30 days. The 30-day mortality rate for fibrinolysis was 7.9% and 5.3% for primary PCI.

In those randomised to fibrinolysis, the 30-day mortality increased two-fold as presentation delay increased from <1 hour to >6 hours.

The treatment effect benefited primary PCI in all subgroups. The absolute mortality reduction increased from 1.7% in patients randomised within 1 hour of symptom onset, to 4.2% for those randomised after 6 hours.

35. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003 Jan 4;361(9351):13-20.

Another analysis of the RCT’s of IV fibrinolysis vs. primary PCI in 2003. Inclusion criteria differed between studies but was ‘typically’ ST elevation of 1mm or more in two contiguous leads or a LBBB. Included both streptokinase and fibrin-specific (much higher numbers). Included trials with stents in primary PCI.

Overall patients assigned to primary PCI showed a benefit in terms of overall mortality, non-fatal reinfarction and combined death, non-fatal reinfarction or stroke.

Major bleeding was increased in the primary PCI group (7%) vs. fibrinolysis (5%).

For trials specifically looking at in-hospital fibrinolysis vs. emergent transfer for primary PCI, despite an average delay of 39 minutes, primary PCI was beneficial in terms of non-fatal reinfarction and combined endpoint of death, non-fatal reinfarction or stroke but was NOT beneficial with regard to all-cause mortality.

Six AJ, Backus BE, Kelder JC. Chest pain in the emergency room: value of the HEART score. Neth Heart J. 2008;16(6):191-196.

Study undertaken at community hospital in the Netherlands. Inclusion criteria were all patients who presented with chest pain to ED without STEMI. Study authors then analysed the charts to assign scores as per the HEART score to each case.

Primary endpoints were acute MI, PCI, CABG and death + Combined AMI, PCI, CABG, Death.

Over 3 months, 122 patients were included. 24.1% of patients reached one or more endpoints. AMI in 13.3%, PCI in 11.6%, CABG in 5% and death in 1.6%.

The average HEART score for this with any endpoint reached was 6.51 vs. 3.71 if no endpoint reached.

The only independent risk factor predictors of the combined outcome were hx of HTN, family hx and hx of peripheral artery disease.

The independent predefined HEART elements that predicted the combined outcome were history, ECG abnormalities and Tn.

Found a HEART score of 0-3 indicated a 2.5% risk of combined outcome, 4-6 had a 20.3% risk of combined outcome and 7 or more a 72.7% risk of combined outcome.

Mahler SA, Riley RF, Hiestand BC, Russell GB, Hoekstra JW, Lefebvre CW, Nicks BA, Cline DM, Askew KL, Elliott SB, Herrington DM, Burke GL, Miller CD. The HEART Pathway randomized trial: identifying emergency department patients with acute chest pain for early discharge. Circ Cardiovasc Qual Outcomes. 2015 Mar;8(2):195-203.

Randomised prospective study of the HEART pathway to determine whether it can meaningfully reduce objective cardiac testing, increase early discharges and reduce index hospital LOS compared to usual care (American College of Cardiology Guideline) while maintaining high sensitivity and NPV of >99% for MACE.

Single institution study in North Carolina using sensitive Tn (not high-sensitive).

Patients were over 21 years old with symptoms suggestive of ACS as evidenced by an ECG and troponin being ordered. Ineligible patients were those with new STE, hypotension, life expectancy <1 year or a noncardiac illness requiring admission.

Had Tn at 0 and 3 hours and low-risk HEART score of 0-3 were discharged should they prove negative without further testing (but encouraged to follow-up with their primary care provider).

Those with high-risk HEART scores were admitted to Cardiology.

Enrolled 282 patients with 141 in each arm. Of those randomised to the HEART pathway, 46.8% were classified as low risk and 53.2% as high-risk. These patients had an objective cardiac testing rate at 30 days of 56.7% compared with 68.8% in the usual care group.

Early discharge occurred in 39.7% of the HEART arm vs. 18.4% in the usual care group.

Median LOS in the HEART group was 9.9 hours vs. 21.9 hours in the usual care group.

Within the HEART arm, 2.8% of patients had repeat cardiac ED visits vs. 4.3% in the usual care arm but this did not reach statistical significance.

No patients identified as low risk in the HEART arm had missed MACE during the 30 day follow-up period or an index or non-index event.

Perfect adherence to the HEART pathway would have increased the early discharge rate to 46.8% without any missed MACE.

Prior to this study the HEART score had been studied in over 6000 patients and shown a NPV for MACE at 6 weeks >98%. The HEART pathway has even higher sensitivity than this owing to serial troponin inclusion.

Cullen L, Mueller C, Parsonage WA, Wildi K, Greenslade JH, Twerenbold R, Aldous S, Meller B, Tate JR, Reichlin T, Hammett CJ, Zellweger C, Ungerer JPJ, Rubini Gimenez M, Troughton R, Murray K, Brown AFT, Mueller M, George P, Mosimann T, Flaws DF, Reiter M, Lamanna A, Haaf P, Pemberton CJ, Richards AM, Chu K, Reid CM, Peacock WF, Jaffe AS, Florkowski C, Deely JM, Than M. Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary syndrome. J Am Coll Cardiol. 2013 Oct 1;62(14):1242-1249.

Aimed to internally and externally validate hsTn assays with an accelerated diagnostic protocol (ADP) for patients with possible ACS. The ADAPT cohort included patients consecutively recruited to two urban ED’s in Brisbane and Christchurch. The APACE cohort was a multicentre, multinational subset who presented with symptoms suggestive of AMI in the last 12 hours.

In both cohorts, usual care consisted of objective cardiac testing for all patients with raised troponins and/or ECG findings of ischaemia.

The primary endpoint was MACE at 30 days (as defined by death, cardiac arrest, AMI, emergency revascularisation, cardiogenic shock, ventricular arrhythmia requiring intervention and high-degree AV block requiring intervention).

hsTn samples taken at 0 and 2 hours were not used in clinical decision making but rather were analysed post-hoc.

Two ADP’s were analysed:

TIMI 0, ECG and hsTn at 0 and 2 hours

TIMI 0 or 1, ECG and hsTn at 0 and 2 hours

39-41% of patients could be classified as low risk with TIMI 0 or 1 with 0.6-0.8% rate of MACE at 30 days (NPV >99%).

If TIMI 0 was used as a the cut-off for low risk, the number of low-risk patients reduced to 19-25%.

Systematic reviews had shown heparin in addition to antiplatelets reduced the risk of death or myocardial infarction by up to 50% compared to antiplatelets alone. This effect was almost entirely powered by recurrent MI as opposed to death.

Included 8 studies and 3118 patients. The incidence of death was 0.9% in placebo vs. 0.7% in the heparin group. This did not reach statistical significance but the study was self-reportedly underpowered to detect a chance in such a rare event.

Heparins were superior to placebo in recurrent myocardial infarction with rates of 4.8% in the placebo group and 1.9% in the heparin group (RR 0.40).

There was a trend towards more major bleeding (>20g/L drop in Hb or transfusion requirement) in the heparin group but this did not reach statistical significance.

Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Baharoglu. Lancet 2016; 387:2605–2613

Patients on antiplatelets who go on to suffer spontaneous ICH show a 27% increased odds of death compared to patients not on antiplatelets. This multicentre, open-label RCT examined platelet transfusion in adults over 18 who suffered a spontaneous supratentorial ICH, with a GCS of 8-15, within 6 hours of symptom onset and 90 minutes of brain imaging, who were on either aspirin, clopidogrel or dipyramidole for at least 7 days prior and who had an mRS 0-1 pre-haemorrhage.

Exclusion criteria were epidural/subdural haemorrhage, underlying vascular abnormality, planned surgical evacuation within 24 hours, intraventricular blood, known use of warfarin, coagulopathy, known thrombocytopaenia or palliative.

Participants on a COX-inhibitor (aspirin), with or without adenosine reuptake inhibitor, received one platelet concentrate (5U), whereas participants on ADP receptor inhibitors (clopidogrel), with or without another antiplatelet drug, received two platelet concentrates.

The primary endpoint was difference in functional outcome at 3 months (mRS). Initially this was to be a defined set mRS of 4-6 at 3 months but this was changed to ordinal analysis at 3 months. There were 97 patients in the platelet transfusion group and 93 in the standard group.

Platelet transfusion showed a shift towards death or dependence at 3 months vs. standard care (crude common OR 1.84; statistically significant).

More participants in the platelet transfusion group had poor outcome (mRS 4-6) at 3 months than standard care.

Intracerebral haemorrhage growth at 24 hours was unchanged between groups and there was no difference in outcomes between those that received platelets within 3 hours vs. 3-6 hours from symptom onset.

The majority of patients were on aspirin vs. clopidogrel, so it is difficult to know if findings are generalisable to any antiplatelet.

Kudenchuk PJ et al. Amiodarone, Lidocaine, or Placeboe in Out-of-Hospital Cardiac Arrest. NEJM 2016.

In previously controlled trials, amiodarone was shown to improve ROSC and survival to hospital admission, as compared to placebo or lignocaine in OOHCA.

This study aimed to determine if these agents improved neurological outcome or survival to hospital discharge.

Across 10 USA sites, adults with non-traumatic OOHCA and shock-refractory VF or pulseless VT (defined as continued or recurrent) were randomised to 300mg amiodarone, 120mg of lignocaine or saline (half-dose if <45kg). Another supplemental dose of 150mg amiodarone, 60mg lignocaine or saline was delivered if VF or pVT was persistent. Further amiodarone or lignocaine could not be given pre-hospital after this.

The primary outcome was survival to hospital discharge. Secondary outcomes were survival with favourable neurological status at discharge (mRS 3 or less).

Of 38000 screened patients, 7051 had shock-refractory VF or pVT and were potentially eligible. 4653 patients then had the trial kit actually opened with ~1500 in each group.

Rates of survival to hospital discharge (20-25%) and survival with favourable neurological outcome (17-18%) were similar between all groups.

In subgroup analysis, patients with witnessed arrest had higher rates of survival to hospital discharge if given active drugs vs. placebo (28% vs. 22%). Adverse events did not significantly differ.

Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest. N Engl J Med 2008; 359:2651-2662.

Previous RCT showed no benefit to lysis for PEA. This study aimed to determine whether thrombolysis during CPR could improve survival in adults with witnessed OOHCA of presumed cardiac origin.

Exclusion criteria were presumed non-cardiac cause of arrest, known internal bleeding, neurologic impairment, coagulation disorders, pregnancy and hypersensitivity to tenectaplase. Open-label use of thrombolysis for presumed PE was allowed.

For patients undergoing primary PCI within 12 hours, glycoprotein IIb/IIIa antagonists were not permitted and the use of antiplatelets was discouraged unless mandatory.

Patients with PEA or asystole as their initial rhythm were randomised immediately, while those with shockable rhythms were randomised after 3 failed shocks. Weight-based tenectaplase was then provided vs. placebo. CPR was then continued for at least 30 minutes. Heparin use was not allowed during the pre-hospital phase and discouraged until hospital admission.

Primary endpoint was 30 day survival; secondary endpoints were hospital admission, ROSC, 24-hour survival, survival to hospital discharge and neurological outcome of surviving patients (cerebral performance category 1-5).

Interim safety analysis then excluded patients with asystole as their initial rhythm owing to a 30-day survival rate of <1%.

A formal futility analysis was then performed and the trial ceased after 1050 patients were enrolled.

There were no significant differences between groups in terms of 30-day survival nor secondary outcomes. ICH occurred more frequently in the lysis group at 2.7% vs. 0.4%.

43. FLORALI: High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. Frat. NEJM 2015; first published on line on May 17th 2015

Adults admitted to ICU with all four of the following criteria were randomised:

RR >25

P:F <300 while patient was on O2 flow >10L/min for at least 15 min

PaCO2 <45

Absence of chronic respiratory failure

Exclusion criteria were PaCO2 >45, exacerbation of asthma or chronic respiratory failure, APO, severe neutropaenia, haemodynamic instability, use of vasopressors, GCS 12 or less, contraindications to NIV, urgent need for intubation or DNR order.

Patients were randomised to HFNP, standard oxygen therapy or NIV.

The standard group received oxygen via NRBM at flow of at least 10L/min with the rate adjusted to maintain SpO2 >92% until the patient recovered or was intubated.

The HFNP group received 50L/min at FiO2 1.0 initially then titrated to SpO2 >92%. The patient could be switched to the standard arm after 2 days.

The NIV group received face mask pressure support to attain Vt 7-10mL/kg, with initial PEEP 2-10cmH20. The minimal required duration was 8 hours per day for 2 calendar days. Patients received HFNP between NIV sessions as above.

The primary outcome was intubation within 28 days of randomisation. Pre-specified criteria for intubation were defined:

Haemodynamic instability, deterioration in neurological status, persistent or worsening respiratory failure as defined by at least 2 of: RR >40, high work of breathing, copious tracheal secretions, pH <7.35, SpO2 <90% for more than 5 minutes or poor response to oxygenation techniques.

In both the HFNP and standard arms, a trial of NIV was allowed at the discretion of the physician.

2500 patients were screened across 2 years, with 525 eligible patients randomised ( ~100 in each group). Most patients had CAP.

The intubation rates at 28 days were 38% (HFNP), 47% (standard) and 50% (NIV) (p=0.18).

The intervals between enrolment and intubation did not differ significantly.

The hazard ratio for death at 90 days or in ICU was 2.01 for standard care vs. HFNP and 2.5 for NIV vs. HFNP.

There was significant heterogeneity between those with P:F <200 and >200. Those with P:F <200 showed significantly lower intubation rates in the HFNP than the other two groups.

Overall HFNP showed benefit in terms of ICU and 90 day mortality without significant reduction in intubation rates (although a trend was apparent).

Douglas PS, et al. “Outcomes of anatomical versus functional testing for coronary artery disease”. The New England Journal of Medicine. 2015. 372(14):1291-1300

Computed tomographic coronary angiography (CTCA) is thought to have the potential to reduce unnecessary invasive testing and improve outcomes, owing to higher ‘accuracy’ compared to functional testing, and unique ability to demonstrate prognostically important non-obstructive coronary artery disease.

PROMISE compared health outcomes in patients who underwent anatomical vs. functional testing for new symptoms suggestive of coronary artery disease requiring further testing.

Symptomatic outpatients without diagnosed CAD whose physicians believed warranted non-urgent, non-invasive cardiovascular testing for suspected CAD were eligible. The study included men over 54 and women over 64 as well as men over 44 and women over 49 with at least one CVD risk factor.

Exclusion criteria were unstable haemodynamics or arrhythmias, evaluation for CAD in last 12 months, hx of CAD or clinically significant heart disease.

Functional testing type was determined by the treating clinician and included exercise ECG, nuclear stress testing and stress echocardiography.

Primary endpoint was composite endpoint of major cardiovascular events including death from any cause, MI, hospitalisation for unstable angina and major complications of cardiovascular procedures or diagnostic testing.

Secondary endpoints also included invasive catheterisation showing no obstructive CAD at 90 days.

10003 patients were enrolled. Of all patients that underwent functional testing, 67% had nuclear stress testing, 22% stress echo and 10% exercise ECG. CTCA were positive in 10.7% and 11.7% of functional tests.

At 25 months follow-up (median), there was no difference between primary endpoint rates of 3.3% of the CTCA group and 3% of the functional group.

At 90 days, 12.2% of the CTCA group underwent cardiac catheterisation vs. 8.1% of the functional testing group.

27.9% of the CTCA group who underwent cardiac catheterisation showed no obstructive CAD vs. 52.5% of the functional testing group who underwent cardiac catheterisation. Overall 3.4% of the CTCA group underwent cardiac cath showing no obstructive CAD vs. 4.3% of the functional group.

Revascularisation was performed in 6.2% of the CTCA group at 90 days vs. 3.2% of the functional group.

Although more patients underwent cardiac cath in the CTCA group, and more patients underwent revascularisation in the CTCA group, this was not a trial end point.

Newby DE, et al. “Coronary CT Angiography and 5-Year Risk of Myocardial Infarction”. The New England Journal of Medicine. 2018. 379(10):924-933

This study analysed the 5 year long-term outcome of the original SCOT-HEART trial of CTCA use in Cardiology clinics. It originally showed that CTCA use clarified diagnosis, altered subsequent management and resulted in better clinical outcomes.

Patients 18-75 years old who were referred to Cardiology with stable chest pain for investigation were included. All patients underwent routine clinical evaluation including potential exercise ECG. Patients were then randomised to standard care + CTCA vs. standard care alone.

Patients with any coronary artery disease or higher risk profile (in the standard care group) were prompted to have preventative therapies initiated.

Clinical endpoints were death (cardiovascular death, non-cardiovascular death, death from coronary artery disease and death from any cause), MI and stroke.

The primary end point was death from coronary artery disease or non-fatal MI at 5 years.

Rates of invasive catheterisation and revascularisation were obtained.

4146 patients recruited over 4 years.

Patients assigned to CTCA were more likely to receive preventative therapies (19.4% vs. 14.7%) and anti-anginal prescription (13% vs. 10%).

There was no difference at 5 years in frequency of catheterisation (23-24% in each group). A trend early on of increased catheterisation in the CTCA group did not persist at 5 years. The CTCA group were also less likely to undergo revascularisation (HR 0.59).

The primary endpoint was lower in the CTCA group (2.3%) vs. standard care (3.9%), driven primarily by lower rate of non-fatal MI.

The overall conclusion was that CTCA use provided a more accurate diagnosis, allowing targeted treatment to be initiated (medical optimisation and appropriate revascularisation) and subsequent fewer primary endpoint events.

Among patients in the CTCA group, 50% of subsequent MI occurred in patients without obstructive disease at baseline. In PROMISE, 2/3 of subsequent MI were in patients without obstructive disease at baseline. Preventative treatment was not mandated in PROMISE.

The data suggested that 63 CTCA would have to be performed to prevent 1 fatal or non-fatal MI at 5 years.

46. ARISE: Australasian Resuscitation In Sepsis Evaluation Randomised Controlled Trial. ARISE Investigators. NEJM Oct 1 2014

Rivers showed significant benefit of EGDT initiated in ED for severe sepsis. ProCESS showed no survival benefit as compared to usual care. This study aimed to validate ProCESS and PROMISE outside of the US in a multicentre international setting.

Patients over 18 who met eligibility criteria within 6 hours of ED arrival were screened. Eligible patients had suspected or confirmed infection, two or more SIRS criteria met and evidence of refractory hypotension/hypoperfusion. First dose of antimicrobial was mandated before randomisation.

Patients received either usual care (which did not involve protocolised care or SCVo2 monitoring) or EGDT. Specifically, SCVO2 monitoring was not allowed for the 6 hour trial intervention period. The EGDT algorithm was the same as Rivers et al. and went for 6 hours.

Over 6 years and 51 centres, 1600 patients were enrolled and randomised. Groups were similar at baseline. The volume of resuscitation fluid was higher in the EGDT group at 1.9L vs. 1.7L and more patients received vasopressors, PRBC and dobutamine. MAP was higher in the EGDT group at 6 hours.

By 90 days, death from any cause was equal between groups at 19%.

A Gray, S Goodacre, D Newby, M Masson, F Sampson and J Nicholl on behalf of the 3CPO triallists. Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema. New England Journal of Medicine. (2008);359:24-33.

Large RCT of patients with APO to determine whether NIV improves survival and whether BiPAP is superior to CPAP.

CPAP was commenced at 5cmH20 and increased to a maximum of 15. BiPAP was started at IPAP 8 and EPAP 4 with increased to maximum IPAP of 20 and EPAP of 10.

The supplemental oxygen group received oxygen to reach Spo2 >92%. All participants received therapy designated for at least 2 hours.

The primary endpoint between NIV and standard oxygen therapy was death at 7 days. The primary endpoint between BiPAP and CPAP was death at 7 days or tracheal intubation at 7 days.

There was no significant difference in primary outcome between NIV and standard oxygen therapy. There was no significant difference in composite primary endpoint between CPAP and BiPAP.

There was no relationship between MI and either CPAP or BiPAP.

There was also no benefit in intubation rates between NIV and standard oxygen therapy.

de Gans J, van de Beek D; European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002 Nov 14;347(20):1549-56.

Previous studies had shown benefit in children with H. influenzae type b meningitis with respect to hearing loss and suggested a benefit in pneumococcal meningitis in children.

This study aimed to prove benefit in adults with suspected meningitis who had not been treated with antibiotics within the prior 48 hours. Patients were randomised to dexamethasone 10mg q6h for 4 days 15-20 minutes before or at the same time as antibiotic administration vs. placebo.

Primary outcome was Glasgow Outcome Scale at 8 weeks, with favourable outcome defined as score of 5 and unfavourable score of 1-4. Secondary outcomes were death, focal neurology, hearing loss, GI bleed, fungal infection, herpes zoster and hyperglycaemia. Subgroup analysis was performed for different pathogens.

There were 301 patients enrolled. Both groups were similar.

At 8 weeks, 15% in the dex group and 25% in the placebo group had unfavourable neurological outcome. In those with pneumococcal meningitis, 26% in the dex group and 52% in the placebo group had unfavourable outcome. This was not seen in the N. meningitidis subgroup (albeit a smaller cohort).

Death occurred in 7% of the dex group and 15% of the placebo group; 14% and 34% respectively in the pneumococcal group.

There was no benefit seen in terms of hearing loss.

One concern is that the study required CSF sampling for enrolment, which meant only those with LP performed prior to antibiotics could be included. This effectively excluded anyone receiving on-spec antibiotics prior to LP.

SAFE: A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit. The SAFE Study Investigators. N Engl J Med 2004; 351:1905-1908.

SAFE compared albumin and saline resuscitation fluids on mortality in heterogenous population of ICU patients. This found no significant difference in outcome. It was shown that albumin increased mortality in a subgroup of patients with TBI.

A post-hoc follow-up study was then performed of those patients within SAFE who had TBI.

TBI was defined as trauma with GCS 13 or less on arrival and an abnormality on CT brain.

Primary outcome measures were mortality rate and functional neurological outcome 24 months after randomisation. There were ~250 patients in each group randomised to albumin or saline. Baseline TBI severity, haemodynamics and variables specific to brain injury were similar between groups. During the first 48 hours, the albumin group received significantly less volume than saline group but this was not apparent after 48 hours. No difference in mean systolic pressure or heart rate over the first 4 days. Mean CVP was higher in the albumin group during the first 24 hours. No significant difference in raised ICP between groups.

Death occurred at 24 months in 33% of the albumin group and 20% of the saline group. In those with severe TBI, 41% of the albumin group died vs. 22% of the saline group. This was mostly in the first 21 days post-randomisation. Favourable neurological outcome was seen in 47% of the albumin group vs. 60% of the saline group, however, this was predominantly due to death.

The mechanism for this difference is unclear.

CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trial. Lancet, The, 2015-06-13, Volume 385, Issue 9985, Pages 2383-2391

CTCA sensitivity 89% and specificity 96% for detection of coronary artery disease. Earlier studies had shown its use from ED in patients with ‘low risk chest pain’ could improve decision making but increase downstream testing and healthcare costs without any benefit on cardiovascular outcomes. It had not been studied in a Cardiology clinic situation in patients with stable chest pain.

This open-label, parallel-group, randomised control trial recruited adults referred by a GP to a Cardiology clinic with stable suspected angina. All patients underwent routine assessment, including symptom-limited exercise ECG if appropriate. Patients were then randomised to standard care + coronary calcium score and CTCA vs. standard care alone.

Primary endpoint was proportion of patients diagnosed with angina secondary to coronary artery disease at 6 weeks. Long-term outcomes were death, MI, revascularisation, admission for chest pain, cerebrovascular disease, and peripheral vascular disease.

4146 patients were enrolled (9849 screened) across 12 centres in Scotland. Most patients underwent stress exercise ECG prior to randomisation.

63% of the CTCA group had coronary artery disease, 38% non-obstructive and 25% obstructive coronary artery disease.

This increased the certainty but reduced the frequency of the diagnosis of angina due to coronary artery disease.

Overall, the 6 week diagnosis of CAD changed in 27% of the CTCA group vs. 1% of the standard care group.

Changes in the diagnosis were then associated with changes in planned investigations in 15% of the CTCA group vs. 1% of the standard care group. The CTCA group subsequently underwent more invasive angiography, changes in preventative medications and antianginal medications. CTCA was not associated with increased coronary revascularisation.

Angina stability and frequency was significantly reduced after randomisation in both groups equally. CTCA was not associated with any significant reduction in coronary artery disease death or non-fatal MI.

Dumas F, Bougouin W, Geri G, Lamhaut L, Rosencher J, Pène F, Chiche JD, Varenne O, Carli P, Jouven X, Mira JP, Spaulding C, Cariou A. Emergency Percutaneous Coronary Intervention in Post-Cardiac Arrest Patients Without ST-Segment Elevation Pattern: Insights From the PROCAT II Registry. JACC Cardiovasc Interv. 2016 May 23;9(10):1011-8.

Previous studies had shown rates of acute coronary occlusion of 21-53% in those without ST elevation on post-ROSC ECG after OOHCA. The authors had previously shown a rate of 26% in those without ST elevation vs. 74% in patients with ST elevation.

This study aimed to investigate an immediate invasive strategy in OOHCA without ST elevation on the post-ROSC ECG. In Paris, regardless of ECG findings, in those without obvious non-cardiac cause for arrest, all patients are taken directly to cath lab.

695 patients were analysed from the PROCAT registry who met inclusion criteria of no extra-cardiac cause and no ST elevation on post-ROSC ECG. Initial shockable rhythm was seen in 62% of these patients.

39% of patients had non-specific ST/T wave changes, 26% with conduction disturbances, 20% a normal ECG pattern and 15% other (SVT/AF).

Emergent angiography identified at least 1 significant lesion in 58% of patients. A culprit lesion was found in 29% of patients.

The overall favourable outcome rate (Cerebral performance category 1 or 2) in this group of OOHCA patients was 36%.

Those patients treated with successful PCI had a better outcome (favourable in 43%) compared to those in whom angiography was not followed by emergent PCI (33%).

After adjustment, emergent successful PCI was associated with better outcome.

Shockable rhythm at EMS arrival was the strongest predictor of an acute coronary occlusion requiring early PCI, with male gender and older age also predictive.

IST Collaborative Group. “The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke”. The Lancet. 1997. 349(9065):1569-1581.

Designed to assess the separate and combined effects of SC heparin and aspirin in acute stroke. Inclusion criteria were adults with an acute stroke in the last 48 hours, no evidence of ICH or contraindications. Non-comatose patients could receive treatment prior to CT if there was a delay to imaging.

Half of the patients were randomised to SC UFH (1/4 5000IU BD and ¼ 12500IU BD) and half allocated to ‘avoid heparin’. Half of all patients were randomised to aspirin 300mg daily and half to ‘avoid aspirin’.

Treatment was continued for 14 days or until discharge from hospital, whichever was shorter. At discharge, all clinicians were advised to consider long-term aspirin continuance.

Follow-up at 6 months was either via telephone or outpatient visit. The primary outcomes were death from any cause at 14 days and death or dependency (needing help with ADL’s) at 6 months.

Secondary outcomes were symptomatic ICH, ischaemic stroke within 14 days, major extracranial haemorrhage, death at 6 months, dependence at 6 months.

19345 patients were randomised over 3 years. The median time to randomisation was 19 hours and 67% had a CT scan before randomisation. 4% of patients never had a CT scan.

Heparin vs. no heparin

No significant change in death of any cause at 14 days but significant increase in death caused by haemorrhagic stroke and extracranial bleeding.

Significant reduction in recurrent stroke at 14 days but offset completely by increased haemorrhagic stroke

No significant increase in death at 6 months

Less evidence of hazard with moderate dose vs. high-dose but still no benefit

Aspirin vs. no aspirin

No significant reduction in death of any cause at 14 days

Significantly fewer ischaemic strokes at 14 days with no increase in haemorrhagic stroke

Significant increase in extracranial bleeding

No change in death of any cause at 6 months

28% reduction of 14 day stroke and 9% reduction in combined outcome of nonfatal stroke or death

Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM; FASTER Investigators. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007 Nov;6(11):961-9.

Designed to assess, in a factorial design, whether clopidogrel and statin, if started within 24 hours of symptom onset and continued for 90 days would reduce the risk of stroke after TIA or minor stroke.

All patients received aspirin 81mg daily with an initial 162mg load and then randomly assigned to either placebo or clopidogrel (300mg load and 75mg daily) and to placebo or simvastatin 40mg daily).

3101 patients were screened and 396 patients were actually enrolled. Exclusion criteria included age <40, pure sensory/ataxia, currently on non-aspirin antiplatelet/anticoagulation/NSAID, presumed cardioembolic source, concomitant ACS, pre-morbid mRS >= 3, uncontrolled HTN, contraindications).

The trial was ceased for poor enrolment and was unable to reach statistical significance. It acted as a pilot to promote further study.

Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013 Jul 4;369(1):11-9.

Approximately 10-20% of TIA patients suffer a recurrent stroke within 3 months, most within the first 2 days. Previous large-scale trials of DAPT for secondary stroke prevention had not shown benefit. However, these trials did not study DAPT initiation in the acute phase and few TIA patients. The FASTER trial showed a trend towards benefit.

This trial in adults over 40 with high-risk TIA (ABCD >=4) or acute minor stroke (NIHSS <=3) with treatment initiation within 24 hours of onset of symptoms. Exclusion criteria were intracranial haemorrhage, isolated sensory/visual/vertigo symptoms, a clear indication for anticoagulation or contraindication to DAPT.

All patients received aspirin but half of patients were randomised to clopidogrel in addition. Those in the clopidogrel-aspirin arm received aspirin and clopidogrel for 21 days then clopidogrel only until day 90. Those in the aspirin arm received aspirin only for 90 days.

The primary outcome was incidence of stroke at 90 days.

41000 patients were screened and 5170 enrolled. 30% of patients were TIA. DAPT for 21 days reduced the risk of stroke from 11.7 to 8.2%. Fatal or disabling stroke was reduced in the DAPT group from 6.8 to 5.2%. Haemorrhagic stroke occurred equally at 0.3%.

Moderate or severe haemorrhage occurred equally in both groups at 0.3%.

Nearly half of the patients were enrolled within 12 hours, which likely contributed to the success of the DAPT intervention.

Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018 Jul 19;379(3):215-225.

Validation of the CHANCE trial in an international cohort. Adults over 18 who could undergo randomisation within 12 hours of symptom onset with acute ischaemic stroke (NIHSS <=3) or a high-risk TIA (ABCD2 >=4) and no evidence of haemorrhage on cerebral imaging. Patients were excluded if they had isolated sensory change, visual changes or disequilibrium. Patients were randomised 1:1 to DAPT (Clopidogrel + aspirin) or aspirin only (+ placebo) for 90 days.

Primary outcome was composite of ischaemic stroke, MI or death from ischaemic vascular causes. Primary safety outcome was major haemorrhage.

The trial was discontinued after major haemorrhage safety endpoint was reached in the DAPT group. A reduction in ischaemic events was noted but was outweighed by the haemorrhage risk (approximately 15 less strokes per 1000 treated and 5 extra haemorrhages with unclear disability as a result).

Overall it is thought the CHANCE trial regime of 21 days of DAPT may provide most benefit with least risk of harm.

National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-7. doi: 10.1056/NEJM199512143332401.

Two part study of r-tPA for acute ischaemic stroke within 3 hours of onset. Part I tested whether tPA resulted in early improvement at 24 hours (complete resolution or improvement in NIHSS score of 4 or more) with stratification by time to tPA (0-90, 91-180 and 0-180 minutes).

Part 2 tested if this improvement was maintained at 3 months in terms of proportion with minimal or no symptoms (combination NIHSS <=1, mRS <=1, GOS of 1 and 95-100 on Barthel index).

Inclusion criteria were clear time of onset, measurable deficit on NIHSS, and no ICH. Exclusion criteria were usual tPA contraindications. In addition, patients had baseline platelet counts and prothrombin times measured (unlike current practice) and were excluded if ‘aggressive’ treatment was required to maintain SBP <185mmHg/DBP <110mmHg.

Treating clinicians were told to maintain BP within target range for at least 24 hours and antiplatelet/anticoagulants were withheld for 24 hours post-thrombolysis.

Over 4 years, 624 patients were enrolled. In part 1, there was no statistically significant difference between groups in neurological improvement/resolution at 24 hours.

In part 2, the number of patients with favourable outcomes at 3 months was higher in the tPA group (OR 1.7 with 12% absolute increase in number of patients achieving this).

No significant difference in mortality between groups.

Symptomatic ICH during the first 36 hours with 8 /144 in Part 1 and 12/168 in Part 2 tPA groups vs. 0/147 and 2/165 in the placebo group. Overall 60% of the symptomatic ICH died.

Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29.

Analysis of NINDS and combined analysis of 6 other randomised trials showed benefit up to 4.5 hours for thrombolysis with OR 1.4 in the 3-4.5 hour subgroup. ECASS III served as a randomised trial of thrombolysis at 3-4.5 hours. Anticoagulation and antiplatelet therapy was prohibited for 24 hours (aside from DVT prophylactic SC heparin). The primary efficacy endpoint was disability at day 90 as assessed by mRS, dichotomised as favourable (0 or 1) or unfavourable (2-6). The secondary efficacy endpoint was combination favourable outcome on NIHSS, Barthel index, GOS and mRS.

52.4% of the tPA group had favourable neurological outcome as compared to 45.2% of the placebo group (OR 1.34). The overall distribution of scores on the mRS scale also showed statistically significant benefit.

Overall mortality was 7.7% in the tPA group vs. 8.4% of the placebo group.

ICH occurred in 27% of the tPA group and 17.6% of the placebo group. Symptomatic ICH (defined as being determined to be the predominant cause of neurological deterioration) occurred in 2.4% of the tPA group and 0.3% of the placebo group.

IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, Arauz A. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012 Jun 23;379(9834):2352-63. doi: 10.1016/S0140-6736(12)60768-5. Epub 2012 May 23. Erratum in: Lancet. 2012 Aug 25;380(9843):730.

Cochrane review showed IV rt-PA significantly improved survival free of disability despite 3% excess of fatal intracranial haemorrhage. The review also suggested treatment up to 6 hours may prove beneficial. This trial had the objectives of testing use in patients of all ages (most trials excluded patients over 80) and up to 6 hours.

Had an initial double-blind pilot phase followed by an open-label phase without complete blinding.

In the open phase, patients randomised to the no tPA arm received aspirin immediately (vs. no antiplatelets in the pilot phase for 24 hours). The primary outcome was patients alive and independent as measured by Oxford Handicap Scale (OHS), a commonly used variant of the mRS. Patients with OHS 0-2 were classed as independent and the statistical plan specified an ordinal analysis of OHS score at 6 months be performed.

Overall recruited less than half pre-planned number and was not powered for the primary outcome. It was still three times larger than any previous thrombolysis trial.

53% of patients were older than 80 years old. The mean time from onset to thrombolysis was 4.2 hours. At 6 months, 37% of the tPA group and 35% of the control group were independent (not significant). Secondary ordinal analysis showed favourable shift in distribution of OHS scores at 6 months with treatment. tPA was associated with an increase in symptomatic ICH (7% vs 1%).

There was an initial increase in death from tPA (in first 7 days) but this equalled out over 6 months.

In subgroup analysis, treatment seemed at lease equally efficacious in those over 80yo.

This is another example of a negative study that then had a positive secondary outcome (ordinal analysis).

Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015 Jan 1;372(1):11-20.

Evidence had shown IV alteplase was less effective at clearing proximal clots. Intra-arterial therapy was thought to be a promising alternative (local tPA delivery or thrombectomy). MR CLEAN assessed whether usual care + intra-arterial therapy vs. usual care alone would be more effective in patients with proximal intracerebral arterial occlusion (confirmed on imaging) within 6 hours of onset.

Randomised, open-label, blinded end-point evaluation was performed in patients over 18. Patients had confirmed occlusion of the distal intracranial internal carotid, M1/M2, A1/A2 and NIHSS >=2.

Primary outcome was score on mRS at 90 days with a score of 2 or less defining functional independence. Secondary outcomes were NIHSS at 24 hours and 5 and 7 days or discharge if earlier, QoL and Barthel index all dichotomised. Follow-up was via telephone.

Ordinal analysis was then performed to analyse a shift in mRS score.

502 patients in 16 Dutch centres were randomised.

Of those randomised to intraarterial therapy, 84% underwent mechanical thrombectomy with retrievable stents in 82%.

The adjusted common OR of 1.67 for a shift in mRS outcome at 90 days with an adjusted OR of 2.16 for functional independence. Overall an excellent outcome (mRS 0-1) was seen in 11.6% of the intra-arterial group vs. 6% of usual care. Functional independence was seen in 32.6% of intra-arterial group and 19.1% of the usual care group.

There was no significant difference in adverse events or mortality. Down-stream embolization occurred in 8.6% of the intraarterial group vs. 1.7% of the usual care group.

Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, Yavagal DR, Ribo M, Cognard C, Hanel RA, Sila CA, Hassan AE, Millan M, Levy EI, Mitchell P, Chen M, English JD, Shah QA, Silver FL, Pereira VM, Mehta BP, Baxter BW, Abraham MG, Cardona P, Veznedaroglu E, Hellinger FR, Feng L, Kirmani JF, Lopes DK, Jankowitz BT, Frankel MR, Costalat V, Vora NA, Yoo AJ, Malik AM, Furlan AJ, Rubiera M, Aghaebrahim A, Olivot JM, Tekle WG, Shields R, Graves T, Lewis RJ, Smith WS, Liebeskind DS, Saver JL, Jovin TG; DAWN Trial Investigators. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11-21.

Previous studies had shown benefit of endovascular thrombectomy up to 6 hours and that benefit reduced with time from symptom onset. The DAWN trial compared usual care + endovascular therapy vs. usual care for patients 6-24 hours from onset who had a mismatch between clinical deficit and infarct.

Open-label but blinded outcome measure.

Patients were eligible if they had evidence of occlusion of the intracranial internal carotid artery, M1, or both, on CTA or MRA.

Group A were >=80yo, had NIHSS 10 or higher with infarct volume <21mL;
Group B were <80yo, NIHSS 10 or higher with infarct volume <31mL;
Group C were <80yo, NIHSS 20 or higher with infarct volume 31-51mL.

Infarct volume was measured on DW-MRI or CT perfusion.

Had to have prestroke mRS 0-1 and no evidence of infarction >1/3 of MCA territory.

One quarter of patients had phone follow-up and the rest in-person.

The first primary endpoint was mean score for disability on a utility-weighted mRS at 90 days based on patient- and clinician-scored weighting.

The second primary endpoint was rate of functional independence (mRS 0-2) at 90 days.

There were 107 patients randomised to thrombectomy and 99 to control group. The median NIHSS was 17 and median infarct volume ~8mL. The median interval to randomisation was ~13 hours. Thrombectomy showed an improvement of 2.0 points (1.1-3.0) on the utility-weight mRS at 90 days with a posterior probability of superiority >0.999). Functional independence was achieved in 49% of thrombectomy group vs. 13% of usual care.

There was no difference in safety outcomes.

Overall NNT for lower disability = 2 and NNT for functional independence = 2.8

Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation. 1994 Apr;89(4):1545-56.

Aimed to investigate the clinical outcomes comparing thrombolytic therapy and of an early invasive strategy for NSTEMI. Included 1473 patients with chest pain lasting 5min to 6 hours within the last 24 hours with ECG evidence of ischaemia OR previously confirmed coronary artery disease (previous MI or angiography). All patients received usual care (except aspirin was withheld until second day).

2×2 study of tPA (max 80mg) vs. placebo and early invasive vs. early conservative strategy.

Early invasive meant angiography at 18-48 hours post-randomisation with angioplasty performed if deemed suitable.

The early conservative arm received catheterisation only after failure of initial therapy as defined by chest pain with ECG changes, ECG changes alone, unsatisfactory result on the predischarge stress thalium test, representation after discharge with ischaemic rest pain or moderate-severe angina after hospital discharge despite maximal anti-anginal therapy and a positive symptom-limited ETT.

The primary endpoint for tPA vs. placebo was unfavourable outcome (death, non-fatal MI or failure of initial therapy) at 6 weeks.

The primary endpoint of the early invasive vs. conservative arms was death, postrandomisation MI or an unsatisfactory ETT at 6 weeks.

There was no significant difference in primary outcome for tPA vs. placebo (unfavourable outcome in 54% and 55% respectively). Specifically, MI occurred in 7.4% of tPA and 4.9% of placebo group.

0.55% of the tPA group suffered ICH vs. none in the placebo group.

Patients with unstable angina showed worse outcomes with tPA while those with NSTEMI (CK positive) showed equal results.

There was no significant difference in primary outcome between the early invasive vs. conservative arms.

Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. Albers et Al, N Engl J Med 2018; 378:708-718 DOI: 10.1056/NEJMoa1713973

Trial tested hypothesis that patients likely to have salvageable brain tissue as identified on perfusion imaging who underwent endovascular clot retrieval 6-16 hours after last seen well would have better functional outcomes that standard medical therapy. Performed at 38 centres in the US. Specifically, patients were eligible if infarct core <70mL and ratio of infarct:penumbra >1.8 and absolute volume of potentially reversible penumbra of >15mL. CT or MRI perfusion could be utilised. Only intracranial carotid and M1 lesions were included.

Primary efficacy outcome was ordinal score on mRS at day 90 on either in-person or phone follow-up.

Trial was halted after efficacy setpoint was reached early. 182 patients were randomised at that point 1:1 medical vs. ECT.

ECT showed more favourable distribution of mRS at 90 days and functional independence rates of 45% vs. 17% in the medical group. Mortality was 14% in the ECT group vs. 26% in the medical group.

This trial included patients with larger core infarcts and milder stroke symptoms than DAWN.

Sreedharan A, Martin J, Leontiadis GI, Dorward S, Howden CW, Forman D, Moayyedi P. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD005415.

Systematic review of all studies comparing PPI with another acid-lowering agent, placebo or no treatment in the setting of upper GI bleeding. Results showed no significant benefit in terms of mortality, rebleeding, requirement for surgery, blood transfusion requirements, presence of blood in the stomach on endoscopy, proportion of patients with active bleeding on endoscopy or hospital LOS.

There was a significant reduction in stigmata of recent bleeding on endoscopy and requirement for haemostatic endoscopy therapy on the index endoscopy.

van der Pol LM, Tromeur C, Bistervels IM, Ni Ainle F, van Bemmel T, Bertoletti L, Couturaud F, van Dooren YPA, Elias A, Faber LM, Hofstee HMA, van der Hulle T, Kruip MJHA, Maignan M, Mairuhu ATA, Middeldorp S, Nijkeuter M, Roy PM, Sanchez O, Schmidt J, Ten Wolde M, Klok FA, Huisman MV; Artemis Study Investigators. Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism. N Engl J Med. 2019 Mar 21;380(12):1139-1149. doi: 10.1056/NEJMoa1813865. PMID: 30893534.

The YEARS study assessed the diagnostic YEARS algorithm in men and women showing a VTE incidence at 3 months of 0.61% in those in whom it had been ruled out, with 14% lower rates of CTPA vs. conventional algorithms. There were very few pregnant patients in this cohort. This was a prospective study to evaluate a modified version of this in pregnant women with suspected PE.

Patients were then followed up for 3 months for VTE or complications. Primary outcome was cumulative incidence of symptomatic VTE, with confirmatory objective tests, during 3 month follow-up of the subgroup in whom VTE had been ruled out. The secondary outcome was the proportion of patients in whom CTPA was not indicated to safely rule out PE. The results of this analysis were then compared to a hypothetical scenario in which all patients underwent CTPA or VQ scanning.

Total 510 consecutive pregnant patients were screened with 498 enrolled. 46% were in their third trimester. Half met at least on YEARS criterion. Total prevalence of PE at baseline was 4% including 4/20 with DVT. There was patient who did not undergo CTPA who subsequently was diagnosed with VTE (popliteal DVT on day 90). In a worst-case scenario in which all patients lost to follow-up subsequently developed VTE, the rate would be 0.42%.

Avoidance of CTPA was possible in 65% of first-trimester mothers, 46% of second-trimester and 32% of third-trimester. This is likely due to the physiological rise in D-dimer throughout pregnancy.

Van der Hulle T, Cheung WY, Kooij S, et al. Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study. Lancet. 2017

Post-hoc analysis of the Well’s criteria found three factors to be most predictive -> Clinical signs of DVT, haemoptysis and whether PE was thought to be the most likely diagnosis. The YEARS algorithm was developed around these to enable reduced CTPA utilisation while maintaining safety.

This was a prospective, multicentre study over 2 years in the Netherlands. Patients with clinically suspected acute PE (first or recurrent) over 18 years old were enrolled. Clinicians were not blinded to the D-dimer result before deciding if ‘PE was most likely diagnosis’, as is often the case in clinical practice.

The primary outcome was 3 month incidence of symptomatic VTE in the overall population and in those managed with and without CTPA performed.

The secondary outcome was comparing rates of CTPA with YEARS algorithm vs. theoretical proportions if two-level Well’s and D-dimer cut-off of 500ng/mL were utilised. Finally, they compared the efficacy to an age-adjusted D-dimer cut-off.

There 3616 patients screened and 3465 enrolled. PE was detected in 13% of those enrolled.

Of the 85% in whom the YEARS algorithm ruled out PE, 18 patients were diagnosed at 3 months with VTE (0.61%), with fatal PE in 0.20%. In a worst-case scenario in which all patients lost to follow-up suffered VTE, the 3-month incidence would have been 0.78%.

The rate of CTPA was 13% lower than standard two-level Well’s + fixed D-dimer cut-off algorithm and 8.7% less than standard two-level well’s with age-adjusted D-dimer.

These rates of subsequent VTE at 3 months including fatal VTE are similar to and less than previous studies of conventional algorithms.

Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D, Forgie M, Kovacs G, Ward J, Kovacs MJ. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med. 2001 Jul 17;135(2):98-107. doi: 10.7326/0003-4819-135-2-200107170-00010. PMID: 11453709.

This study was the validation study in an ED setting of the original Wells’ criteria for PE pre-test probability incorporating a D-dimer. Performed in 4 hospital ED’s in Ottawa over 12 months.

Well’s score:

3 points – Clinical signs and symptoms of DVT

1.5 points – HR >100

1.5 points – Immobilisation for 3 or more days or surgery in last 4 weeks

1.5 points – Previous VTE

point – Haemoptysis

point – Malignancy treated in last 6 months

points – PE as or more likely than alternative diagnoses

Low pre-test = <2

Moderate pre-test = 2-6.0

High pre-test = >6.0

Utilised VQ scanning for definitive diagnosis of PE and duplex USS for DVT diagnosis.

Included 946 patients with 16 lost to follow-up. 9.5% rate of PE (40% of high-risk group; 16% of moderate-risk group and 1.3% of low-risk group).

No patients with PE ruled out died in the follow-up period and 2 patients had a PE diagnosed in the follow-up period after rule out with negative D-dimer +- lower limb duplex ultrasonography.

NPV of D-dimer in low-risk group was 99.5%.

Kruip MJ, Söhne M, Nijkeuter M, Kwakkel-Van Erp HM, Tick LW, Halkes SJ, Prins MH, Kramer MH, Huisman MV, Büller HR, Leebeek FW; Christopher Study Investigators. A simple diagnostic strategy in hospitalized patients with clinically suspected pulmonary embolism. J Intern Med. 2006 Nov;260(5):459-66. doi: 10.1111/j.1365-2796.2006.01709.x. PMID: 17040252.

Assessed safety of a two-level clinical decision-rule based on Well’s criteria for hospitalised patients with clinically suspected PE. Performed across 12 teaching hospitals in the Netherlands with an original Well’s score of >4 deemed likely and 4 or below as unlikely.

In the low-risk group, a D-dimer was utilised to rule out VTE. All other patients underwent CTPA.

The study followed-up patients for 3 months. Of 605 patients, 48% were deemed unlikely and 52% likely. Of those deemed unlikely with subsequent negative D-dimer there were no PE diagnosed during the follow-up period.

Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, Kovacs G, Mitchell M, Lewandowski B, Kovacs MJ. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003 Sep 25;349(13):1227-35. doi: 10.1056/NEJMoa023153. PMID: 14507948.

Study group had previously shown the safety of a CDR incorporating D-dimer testing for DVT in an ED population. They then hypothesised that use of D-dimer testing in patients with suspected DVT would reduce the need for ultrasound imaging and rule out DVT in a higher proportion of patients on the day of presentation, while not compromising safety, as reflected in the three-month follow-up data.

Well’s score was calculated as follows:

Consecutive patients were then randomised to either USS imaging alone or D-dimer testing. Those in the D-dimer group then underwent USS if deemed likely or if D-dimer positive.

There were no VTE in the three months of follow-up in those with DVT ruled out by the algorithm incorporating D-dimer testing and 2 subsequent DVT in the no D-dimer group in whom USS was negative.

There were 1096 eligible patients randomised, with DVT rates of around 16% in each group.

Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A, Rutschmann OT, Sanchez O, Jaffrelot M, Trinh-Duc A, Le Gall C, Moustafa F, Principe A, Van Houten AA, Ten Wolde M, Douma RA, Hazelaar G, Erkens PM, Van Kralingen KW, Grootenboers MJ, Durian MF, Cheung YW, Meyer G, Bounameaux H, Huisman MV, Kamphuisen PW, Le Gal G. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA. 2014 Mar 19;311(11):1117-24. doi: 10.1001/jama.2014.2135. Erratum in: JAMA. 2014 Apr 23-30;311(16):1694. PMID: 24643601.

Previous studies had shown D-dimer cut-off of 500mcg/L was able to rule out PE in 60% of patients under 40 but only 5% over 80. This study prospectively validated an age-adjusted cut-off of Age x 10 in patients 50 years and older. Performed across 4 countries in Europe, the study looked at consecutive patients presenting to ED with suspected PE and excluded those with PE suspicion raised after 24 hours of admission, renal impairment (eGFR< 30), anticoagulated, life-expectancy <3 months and/or pregnancy. They utilised the revised Geneva score or 2-level Well’s (Christopher study) with subsequent D-dimer testing in the low-risk group.

Over 3 years, 3346 patients were included in the study. Among the 2898 patients deemed low-risk, 39.8% had a negative age-adjusted D-dimer. The use of the age-adjusted D-dimer resulted in an 11.6% absolute increase in the proportion of negative D-dimers and subsequent reduction in CTPA/VQ utilisation.

The three-month VTE risk in the low-risk group with D-dimer <500 was 0.1%.

1 patient with D-dimer between 500 and age-adjusted cut-off had a subsequent non-fatal PE (0.3%).

Kline JA, Courtney DM, Kabrhel C, Moore CL, Smithline HA, Plewa MC, Richman PB, O’Neil BJ, Nordenholz K. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost. 2008 May;6(5):772-80. doi: 10.1111/j.1538-7836.2008.02944.x. Epub 2008 Mar 3. PMID: 18318689.

The study group derived the PERC criteria (below) to define a very low risk cohort of patients with low clinical gestalt and PERC negative that had a pretest probability of PE less than the testing threshold. This was a prospective analysis across the USA and NZ to determine if the outcome frequency (i.e. posterior probability) of VTE at 45 days was below 2% (upper limit of 95% CI).

Patients were only deemed very low risk if they met clinical gestalt VTE risk of <15% + none of 8 PERC criteria:

Age>49yo

HR >99

SpO2 <95% on room air

Haemoptysis

Exogenous oestrogen

Prior VTE

Recent surgery or trauma in past 4 weeks

Unilateral leg swelling?

There were 8138 patients enrolled from 12213 eligible patients. There were 513 VTE diagnosed during the index ED visit and a further 47 patients after discharge. The measured incidence of VTE in the clinical gestalt groups (<15%, 15-40% and >40%) were 3.0%, 10.4% and 31.1% respectively. This suggests clinicians overestimate the clinical probability of VTE in all risk groups.

24% of patients were PERC negative. The false-negative rate in this group was 1.2% (0.8-1.8%) for VTE and 1.3% (0.8-1.9%) for combined VTE and death from any cause.

20% of the cohort were very low risk (PERC negative and clinical gestalt <15%). Of this group, the false-negative rate was 0.9% (0.5-1.5%) for VTE and 1.0% (0.6-1.6%) for combined VTE or death from any cause.

Zondag W, Mos IC, Creemers-Schild D, Hoogerbrugge AD, Dekkers OM, Dolsma J, Eijsvogel M, Faber LM, Hofstee HM, Hovens MM, Jonkers GJ, van Kralingen KW, Kruip MJ, Vlasveld T, de Vreede MJ, Huisman MV; Hestia Study Investigators. Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost. 2011 Aug;9(8):1500-7. doi: 10.1111/j.1538-7836.2011.04388.x. PMID: 21645235.

Prospective multicentre study of criteria for outpatient management of PE to determine rates of recurrence, major bleeding and mortality.

Utilised LMWH then warfarin for at least 3 months.

Patients not meeting any exclusion criteria underwent outpatient therapy (single-arm study with no comparator)

Exclusion criteria were as follows:

Haemodynamically unstable (SBP <100 and HR >100

Thrombolysis or embolectomy necessary

Active bleeding or high risk of bleeding (GI bleeding in last 14 days, stroke <4 weeks ago, surgery <2 weeks ago, bleeding disorder, thrombocytopaenia <75, SBP >180 or DBP >110)

PE diagnosed during anticoagulant treatment

Severe pain needing IV pain relief for >24 hours

Medical or social reasons for admission

CrCl <30

Severe liver impairment

Pregnant

Documented hx of HIT

Primary endpoint was proven recurrent VTE during 3 month follow-up.

Secondary endpoints were major bleeding and death within 3 months.

Recruited 581 consecutive patients with 338 deemed eligible for outpatient therapy.

The mean duration of hospital admission in the outpatient group was 19 hours as compared to 7 days admission being the historical comparator.

2 patients had major bleeding complications (one fatal ICH and one a large abdominal wall haematoma).

Clinically relevant non-major bleeding complications occurred in 15 patients (5.1%)

2 other fatalities occurred from progressive metastatic cancer.

This study was a single-arm study with no contemporary comparator. It shows relative safety of a selected outpatient regime but does not equate to an RCT.

Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, Bouvaist H, Couturaud F, Dellas C, Duerschmied D, Empen K, Ferrari E, Galiè N, Jiménez D, Kostrubiec M, Kozak M, Kupatt C, Lang IM, Lankeit M, Meneveau N, Palazzini M, Pruszczyk P, Rugolotto M, Salvi A, Sanchez O, Schellong S, Sobkowicz B, Meyer G. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol. 2017 Mar 28;69(12):1536-1544. doi: 10.1016/j.jacc.2016.12.039. PMID: 28335835.

28 PEITHO sites consented to obtain 2 year follow-up data. There was no significant difference in overall mortality rate (~19.2% in each group). Similar rates of persistent symptoms were described in each cohort (36% in fibrinolysis arm vs. 30% in placebo arm; p=0.23).

There was no significant difference in echocardiographic features of residual pulmonary hypertension or RV dysfunction (~40% in each group).

Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; “MOPETT” Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013 Jan 15;111(2):273-7. doi: 10.1016/j.amjcard.2012.09.027. Epub 2012 Oct 24. PMID: 23102885.

Study undertaken to assess efficacy of low-dose tPA on pulmonary artery systolic pressure in patients with ‘moderate PE’ at 28 months.

Enrolled 121 patients with moderate PE defined as:

• CTPA involvement of >70% thrombus in 2 or more lobar or main pulmonary arteries OR a high probability VQ scan with mismatch in 2 or more lobes.
• Minimum of 2 or more new signs or symptoms including chest pain, RR >22, HR>90, dyspnoea, cough, SpO2 <95% on RA, JVP >12.

Primary endpoints were development of pulmonary hypertension on echo and composite endpoint of pulmonary HTN and recurrent PE at intermediate-term follow-up.

Secondary endpoints were mortality, duration of hospital stay, recurrent PE, bleeding index at hospital discharge and composite endpoint of mortality + recurrent PE.

The dose of tPA used was <50% of standard dose (100mg)

There were a total of 121 patients randomised. Safe-dose (aka low-dose tPA) was shown to reduce pulmonary artery pressure at 48 hours, 6 months and 28 months +-5 months from ~45 to ~30 (statistically significant).

Rates of pulmonary hypertension at the end of the 28 months follow-up were 16% (tPA group) and 63% (placebo group).

There were 0 major bleeding sequelae in either group and no significant different in mortality. Symptoms were not assessed.

WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017 May 27;389(10084):2105-2116. doi: 10.1016/S0140-6736(17)30638-4. Epub 2017 Apr 26. Erratum in: Lancet. 2017 May 27;389(10084):2104. PMID: 28456509; PMCID: PMC5446563.

International randomised, double-blind, placebo controlled trial of TXA in women over 16 years old with clinical diagnosis of post-partum haemorrhage defined as >500mL (post-vaginal birth), >1000mL (post-C/S) or any amount deemed to compromise haemodynamic stability.

Patients were randomised to TXA 1g in 100mL saline over 100 min vs. placebo. If bleeding continued after 30 min or stopped and restarted within 24 hours, a second dose of TXA or placebo could be given.

Primary outcome was composite of death from all cause or hysterectomy within 42 days of randomisation. Death was also assessed separately.

Death from bleeding was a secondary outcome specifically. Other secondary outcomes were thromboembolic events (DVT, PE, MI, stroke) and specific surgical interventions.

Across 6 years, 20 000 patients were randomised. There were a total of 483 maternal deaths, 72% of which were due to bleeding.

Risk of death due to bleeding was 1.5% (TXA) vs. 1.9% (placebo) [p=0.045]. Deaths from other causes were no different.

The benefit was only seen in the group given TXA within 3 hours of giving birth. The risk of hysterectomy was not reduced by TXA use. The incidence of thromboembolic complications was no different between groups.

The Magpie Trial Collaborative Group

Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial.

Lancet. 2002; 359: 1877-1890

Initial question was whether magnesium sulfate, as a prophylactic anticonvulsant for women with pre-eclampsia, reduced the risk of eclampsia. Subsequent analysis looked at adverse effects on mother and baby and the disease severity at which benefits outweigh any apparent risks.

Women were eligible if they had pre-eclampsia and there was uncertainty around the use of MgSO4.

Eligibility criteria were:

Woman had not given birth or was <24 hours post-partum

SBP >140 or DBP >90 on at least 2 occasions

Proteinuria 1+ or more

Women with oliguria had half-dose MgSO4 provided.

Eligible women then were randomly allocated to either MgSO4 or placebo.

Standard treatment was a loading dose then 24 hour infusion of agent.

Loading dose was 4g MgSO4 (16mmol) or placebo over 10-15min followed by infusion of 1g(4mmol)/hr for 24 hours.

Reflexes and respiratory rate were monitored every 30 minutes and urine output measured hourly.

If eclampsia ensued, open-label MgSO4 was delivered (4g (16mmol) if no previous MgSO4 or 2g (8mmol) if had been loaded with MgSO4.

Primary outcomes were eclampsia, death of the baby before discharge from hospital (if randomised before delivery).

Maternal death was not a primary outcome owing to inadequate power.

Secondary outcomes were serious maternal morbidity, toxicity, side effects, complications of labour and delivery (if randomised before delivery) and LOS.

Women were also classified at entry into subgroups: severity, imminent eclampsia, gestational age, previous anticonvulsant use in last 48 hours, and whether they had already given birth.

Severe pre-eclampsia was defined as:

DBP >110 or SBP >170 and proteinuria 3+ or more OR

DBP >100 or SBP >150 and proteinuria 2+ or more and at least 2 signs or symptoms of imminent eclampsia

Imminent eclampsia was defined as 2 or more signs or symptoms of imminent eclampsia regardless of hypertension or proteinuria:

Severe headaches

Epigastric pain

Blurred vision

Hyperreflexia

Overall 10 141 women were randomised across 33 countries.

The significant beneficial effect on incidence of eclampsia was apparent in all subgroups aside from those randomised after delivery, those that had received an anticonvulsant before randomisation and those in low perinatal mortality countries.

Overall eclamptic seizures occurred in 0.9% of the MgSO4 group vs. 1.9% of the placebo group, a NNT of 91. The NNT in severe pre-eclampsia was 63.

While the MgSO4 group had higher rates of minor adverse effects, serious morbidity was unchanged.

There was no clinically useful reduction in antihypertensive use.

Kuppermann N, Holmes JF, Dayan PS, Hoyle JD Jr, Atabaki SM, Holubkov R, Nadel FM, Monroe D, Stanley RM, Borgialli DA, Badawy MK, Schunk JE, Quayle KS, Mahajan P, Lichenstein R, Lillis KA, Tunik MG, Jacobs ES, Callahan JM, Gorelick MH, Glass TF, Lee LK, Bachman MC, Cooper A, Powell EC, Gerardi MJ, Melville KA, Muizelaar JP, Wisner DH, Zuspan SJ, Dean JM, Wootton-Gorges SL; Pediatric Emergency Care Applied Research Network (PECARN). Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009 Oct 3;374(9696):1160-70. doi: 10.1016/S0140-6736(09)61558-0. Epub 2009 Sep 14. Erratum in: Lancet. 2014 Jan 25;383(9914):308. PMID: 19758692.

Prospective cohort study of 42412 children <18 to US Emergency Departments within 24 hours of traumatic head injury with GCS 14 or greater.

Children with trivial mechanisms were excluded e.g. ground-level falls, walking or running into objects and no signs/symptoms of head trauma other than scalp abrasions/lacerations.

Patients were excluded if they had penetrating trauma, known brain tumors or pre-existing neurological disorders.

Showed clinically significant brain injury in 0.9% of patients as defined by death, neurosurgical intervention, intubation >24 hours or admission 2 or more nights with CT evidence of TBI.

Overall 0.1% underwent neurosurgery.

Severe mechanism of injury was defined as: MVA with patient ejection, death or another passenger, or rollover; pedestrian or cyclist without helmet struck by motorised vehicle; falls >1.5m for children 2 and older or >0.9m for children under 2; head struck by high-impact object.

Altered mental status was defined as: GCS <15, agitation, sleepiness, slow responses or repetitive questioning.

CT scans were obtained in 35.3% of patients overall; 31% in children under 2 and 37% of children over 2 years old.

In the group <2yo the PECARN pathway was 100% sensitive (2/10 000).

In the group >2yo the PECARN pathway was 96.8% sensitive.

Has since been shown in validation studies to have 100% sensitivity (albeit with a predominance of CT vs. observation in the lower risk patients).

Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. CochraneDatabaseofSystematicReviews 2014, Issue 6. Art. No.: CD001266.

Across 30 trials and 1992 infants, the authors found no evidence of benefit, even in those with strong FHx of atopy. This included no improvement in oxygenation, reduction in hospitalisation, LOS or time to resolution.

Fernandes RM, Bialy LM, Vandermeer B, Tjosvold L, Plint AC, Patel H, Johnson DW, Klassen TP, Hartling L. Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD004878.

Across 17 trials and 2596 individuals, glucocorticoid use made no difference in admission rate, LOS, clinical score or re-admission.

Kuppermann N, Ghetti S, Schunk JE, Stoner MJ, Rewers A, McManemy JK, Myers SR, Nigrovic LE, Garro A, Brown KM, Quayle KS, Trainor JL, Tzimenatos L, Bennett JE, DePiero AD, Kwok MY, Perry CS 3rd, Olsen CS, Casper TC, Dean JM, Glaser NS; PECARN DKA FLUID Study Group. Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis. N Engl J Med. 2018 Jun 14;378(24):2275-2287. doi: 10.1056/NEJMoa1716816. PMID: 29897851; PMCID: PMC6051773.

Clinically apparent brain injury is seen in 0.5-0.9% of paediatric DKA patients. These injuries manifest as sudden neurological decline with significant morbidity and mortality. Previous treatment protocols advocated for slow IV fluid administration, with the rationale that sudden decreases in serum osmolality would contribute to cerebral oedema. The authors investigated the outcomes of specific fluid regimeson neurological outcome in paediatric DKA.

This was enacted across 13 sites (PECARN collaborators) in the US in a 2-by-2 factorial design: 0.9% vs. 0.45% saline + rapid vs. slow

Rapid: Half fluid deficit replaced in 12 hours + maintenance. Remainder of deficit replaced over subsequent 24 hours.

Both received initial 10mL/kg 0.9% saline bolus x 2. Assumed 10% deficit.

Slow: Deficit + maintenance evenly over 48 hours

Both groups were assumed to have a 5% fluid deficit and both received 10mL/kg 0.9% saline bolus x 1

The authors found no difference in number of episodes of GCS <14, clinically apparent brain injury or amnesia. Importantly, only 10% of population were under 6yo which are the main group at risk of cerebral oedema.

Holcomb JB, del Junco DJ, Fox EE, Wade CE, Cohen MJ, Schreiber MA, Alarcon LH, Bai Y, Brasel KJ, Bulger EM, Cotton BA, Matijevic N, Muskat P, Myers JG, Phelan HA, White CE, Zhang J, Rahbar MH; PROMMTT Study Group. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013 Feb;148(2):127-36. doi: 10.1001/2013.jamasurg.387. PMID: 23560283; PMCID: PMC3740072.

Across 10 trauma centres, this was a prospective observational study to describe the blood components provided to severe trauma patients and their subsequent outcomes (with a view to eliminating survival bias – whereby the question becomes did the patient survive because of specific ratios or did the patient receive certain treatment only because they survived long enough to receive it).

Patients were included if they received: Highest level trauma alert, age 16 or older, transfused at least 1U PRBC in first 6 hours.

Exclusion criteria were: Transfers, declared dead within 30 minutes of admission, >5 min CPR prior to or within 30 minutes of admission, prisoners, burn injuries >20% BSA, inhalational injuries, or pregnant.

There were no changes made to clinical practice.

Data was collected on 12560 patients, of whom 11 315 were deemed ineligible. Only 1245 remained to meet criteria for analysis. Of these, 905 were transfused at least 3 units PRBC and therefore met analysis criteria. Overall in-hospital mortality was 21% for all 1245 transfused patients and 25% for those in the analysis cohort.

The median time to haemorrhagic death was 2.6 hours.

Higher plasma and platelet ratios early in resuscitation associated with reduced mortality in patients receiving at least 3U of PRBC over 24 hours. Ratios <1:2 were 3-4 times more likely to die than ratios of 1:1 or higher. The protective association with higher ratios was more apparent in the first 30 min to 6 hours and became non-significant after 24 hours.

Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel KJ, Bulger EM, Callcut RA, Cohen MJ, Cotton BA, Fabian TC, Inaba K, Kerby JD, Muskat P, O’Keeffe T, Rizoli S, Robinson BR, Scalea TM, Schreiber MA, Stein DM, Weinberg JA, Callum JL, Hess JR, Matijevic N, Miller CN, Pittet JF, Hoyt DB, Pearson GD, Leroux B, van Belle G; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015 Feb 3;313(5):471-82. doi: 10.1001/jama.2015.12. PMID: 25647203; PMCID: PMC4374744.

First large randomised multicentre study with survival as a primary endpoint. Compared a 1:1:1 (RBC:platelet:FFP) transfusion ratio to 2:1:1 in trauma patients who were predicted receive a massive transfusion.

The containers for the 1:1:1 group contained 6U PRBC, 6U FFP and 1 unit pooled platelets (6 donor units).

Transfusions were performed in the order: Platelets first, then alternating PRBC and FFP.

Transfusion of blood products was stopped when clinically indicated irrespective of use.

Enrolled patients were severely injured for highest level trauma activation at Level 1 centres in the US. Inclusion criteria were receipt of 1U or more of PRBC either pre-hospital or within 1 hour of arrival and prediction of ABC score of 2 or greater.

The primary outcomes were absolute percentage difference in 24 hour and 30-day mortality.

Ancillary outcomes were time to haemostasis, number and type of products used from randomisation until haemostasis, number and type of products used after haemostasis up to 24 hours, complications, LOS, major surgical procedures and functional status at discharge or 30 days.

From 14 313 highest-level trauma activations across the sites, 680 patients were randomised with no differences in baseline characteristics.

The median ISS was 26 and 75% of patients underwent haemorrhage control within 2 hours of admission.

There were no significant differences in mortality at 24 hours (12.7% in 1:1:1 vs. 17% in 2:1:1) nor at 30 days. However, exsanguination was less likely and more patients achieved haemostasis in the 1:1:1 group. Taken together with the PROMMTT trial, this would suggest a 1:1:1 is a safe and effective ratio for severe trauma with haemorrhagic shock.

Rodriguez, RM et al. Derivation and validation of two decision instruments for selective chest CT in blunt trauma: a multicenter prospective observational study (NEXUS Chest CT). PLoS Med. 2015 Oct 6;12(10)

Authors sought to derive and validate two clinical decision rules to help prevent unnecessary CT chest imaging in trauma.

The first rule (CT-All) was designed to have high sensitivity for all thoracic injuries seen on chest CT and the second (CT-Major) was designed for high sensitivity for major injuries, while accepting of a small miss rate for minor injuries (in order to maximise specificity).

Conducted across 8 Level 1 trauma centres in the US.

Inclusion criteria were over 14 years old, presenting to ED for blunt trauma within 6 hours and either CXR or CT ordered in the ED. All imaging decisions were at the discretion of the treating clinician.

Injuries defined as major included: Great vessel injury (any), ruptured diaphragm (any), pneumothorax requiring evacuation, haemothorax requiring evacuation, sternal fracture requiring operative intervention, multiple rib fractures requiring surgical procedure or epidural nerve block, pulmonary contusion requiring ventilatory support within 24 hours, thoracic spine fracture requiring surgical intervention, scapular fracture requiring surgical intervention, mediastinal or pericardial haematoma requiring drainage procedure, oesophageal injury requiring surgical intervention or tracheal/bronchial injury requiring surgical intervention.

Injuries defined as minor clinical significance included all of the above not requiring surgical intervention or any great vessel or ruptured diaphragm.

There were 11477 patients enrolled with median ISS of 5.

In the derivation cohort of 6000 patients, 31.2% had both CXR and CT chest. Of these, 7.7% had clinically major injury and 34.7% had injuries of minor or no clinical significance.

In the validation cohort of 5475 patients, 48% had both CXR and CT chest, with 4.6% suffering major injury and 26.9% suffering major or minor clinical injury.

Recursive partitioning provided the following DI Factors of sufficient predictive value for inclusion:

Specifically, abnormal CXR was defined as any thoracic injury or widened mediastinum and rapid deceleration defined as fall >6.1m or MVA >64.4km/hr with sudden deceleration.

Clinicians seeking to rule out only those injuries requiring surgical intervention, the CT chest – Major CDI is recommended by the authors owing to its equal sensitivity for major injuries and enhanced specificity (37%), thereby sparing more patients from potentially harmful radiation exposure/resource utilisation.

Interestingly, of all great vessel injuries (21 in total), 1/3 had no rapid deceleration mechanism and 1/3 had a normal CXR.

The application of this rule has not been universal, primarily due to the somewhat subjective classification of certain injuries as ‘minor’ and the lower 95% CI of sensitivity of 95%, potentially exposing patients to up to a 5% risk of missed major injury.

Walker SP, Barratt SL, Thompson J, Maskell NA. Conservative Management in Traumatic Pneumothoraces: An Observational Study. Chest. 2018 Apr;153(4):946-953. doi: 10.1016/j.chest.2017.10.015. Epub 2017 Nov 15. PMID: 29080710.

Observational study of traumatic pneumothorax treatment in 602 cases over 4 years in the UK. This was from a screened trauma population of 3771 patients (17% PTX rate).

The mean ISS was 26 (very severe).

Current guidelines (ATLS) suggests chest tube placement for all traumatic pneumothoraces with the caveat that asymptomatic pneumothoraces can be managed by observation and aspiration at the treating physicians discretion. It does mandate chest drain placement if undergoing ventilatory support or general anaesthesia.

Occult pneumothoraces (visible only on CT and asymptomatic) make up 75% of all traumatic pneumothoraces.

Total of 325 patients underwent intervention vs. 277 conservative. Of those treated conservatively, 90% did not require subsequent intervention. Of these, 90% underwent initial NIV.

There were 25 failed conservative Mx

Those managed conservatively had significantly smaller (5.5mm vs. 22mm) with majority <10mm. There was no significant difference in failure rate of conservative treatment in PPV vs. no PPV.

The size of pneumothorax (5.3 vs. 8.2mm – so generally small)/MOI/rib fractures/clinical condition/surgery/ISS were not significantly associated with failure of conservative Mx

The presence of haemothorax >2cm was associated with hazard ratio of 4.08 for failed conservative management.

Further prospective study is required to validate these findings but suggests occult pneumothoraces, occult haemothoraces (<2cm) and minimally symptomatic patients may be suitable for conservative management in an observed environment.

Brown SGA, Ball EL, Perrin K, Asha SE, Braithwaite I, Egerton-Warburton D, Jones PG, Keijzers G, Kinnear FB, Kwan BCH, Lam KV, Lee YCG, Nowitz M, Read CA, Simpson G, Smith JA, Summers QA, Weatherall M, Beasley R; PSP Investigators. Conservative versus Interventional Treatment for Spontaneous Pneumothorax. N Engl J Med. 2020 Jan 30;382(5):405-415. doi: 10.1056/NEJMoa1910775. PMID: 31995686.

Spontaneous pneumothorax occurs in 140 per million per year in the UK, with 1/3 being primary. Historical cohort studies had shown the safety of conservative management in those without physiological stress, however, this was the first prospective study.

This was a multicentre, prospective, randomised, open-label, non-inferiority trial of conservative primary spontaneous pneumothorax (PSP) management across 39 sites in Australia and NZ. Patients were eligible if aged 14-50yo, with unilateral PSP of 32% or more (Collins method; sum of interpleural distances >6cm). Patients were then assigned 1:1 to interventional management (<=12 Fr small bore Seldinger catheter insertion attached to underwater seal without suction) vs. conservative.

In the interventional group, at 1 hour a repeat CXR was performed. If the drain stopped bubbling and lung had re-expanded, the stop cock was closed and a repeat CXR performed 4 hours later. If patients condition was stable and lung had not re-collapsed, the drain was removed and patient discharged. If pneumothorax recurred the stopcock was opened and patient admitted.

In the conservative group patients were observed for a minimum of 4 hours before repeat CXR. If not requiring supplemental O2 and mobilising, patients were discharged. Interventions were allowed if: clinically significant symptoms persisted despite analgesia, chest pain/dyspnoea preventing mobilisation, patient unwilling to continue with conservative management, SBP <90, HR > SBP, RR >30 or SpO2 <90% on room air), or repeat CXR showing enlarging PTX along with physiological instability. Subsequent interventions were then at the discretion of the treating clinician.

Supplemental oxygen for SpO2 <92% and analgesia were given to all patients.

The primary non-inferiority outcome was complete radiographic resolution of PSP within 8 weeks.

Secondary outcomes were pneumothorax recurrence (ipsilateral), serious adverse events, hospital LOS, number of invasive procedures, number of days off work, persistent air leak (>72 hours) and patient satisfaction.

Total of 316 patients over 6 years. 85% of the conservative arm did not undergo intervention. 94% of the intervention group underwent intervention, with 6.5% declining.

Overall showed modest but statistically fragile evidence that conservative management was non-inferior to interventional management of moderate-to-large PSP for radiographic resolution at 8 weeks. The time to complete resolution did not significantly differ, and the conservative group had shorter hospital LOS, less adverse events and less recurrence.

Stiell IG, Wells GA, Vandemheen K, Clement C, Lesiuk H, Laupacis A, McKnight RD, Verbeek R, Brison R, Cass D, Eisenhauer ME, Greenberg G, Worthington J. The Canadian CT Head Rule for patients with minor head injury. Lancet. 2001 May 5;357(9266):1391-6. doi: 10.1016/s0140-6736(00)04561-x. PMID: 11356436.

Prospective cohort study in Canadian ED’s of patients who presented with acute minor head injury. Eligible patients had blunt trauma to the head resulting in witnessed LOC, definite amnesia, or witnessed disorientation; initial ED GCS 13 or higher, and injury in the last 24 hours.

Exclusion criteria: Under 16yo, minimal head injury (no LOC, amnesia or disorientation), no clear history of trauma, obvious penetrating injury, acute focal neurology, unstable vital signs associated with major trauma, seizure pre-ED assessment, bleeding disorder, oral anticoagulants, repeat presentation or were pregnant.

Primary outcome was need for neurosurgical intervention and secondary outcome was clinically important brain injury on CT.

Need for NSx intervention was defined as either death within 7 days secondary to head injury or need for craniotomy/evacuation/ICP monitoring/intubation for head injury.

Clinically important brain injury was defined as any acute brain injury revealed on CT and which would normally require admission and neurosurgical follow-up. All injuries considered clinically important unless neurologically intact and only one of the following: solitary contusion <5mm in diameter; localised SAH <1mm thick; smear subdural haematoma <4mm thick; isolated pneumocephaly; closed depressed skull fracture not through the inner table.

Did not mandate universal CT for all patients as this was not the standard of care. All enrolled patients were followed up at 14 days by telephone with no clinically important brain injury defined as: headache absent or mild; no memory/concentration problems; no seizure/focal motor problems; returned to normal work/duties. If patients did not meet these criteria and had not undergone CT they were recalled to undergo imaging.

Over 3 years, 3121 patients were enrolled, with 100% undergoing assessment for the primary outcome measure (need for NSx intervention) and 67% undergoing imaging to measure the secondary outcome measure (ciTBI).

Those who did not undergo imaging were all attempted to be followed-up at 14 days. A further 363 eligible patients were not enrolled or analysed as they did not undergo imaging and were not available for 14 day follow-up.

Overall, 44 patients underwent neurosurgical intervention and four patients died of their head injuries. 254 patients (8%) were judged to have ciTBI. An additional 94 patients (4%) had clinically insignificant brain injuries as defined above.

All primary predictor variables underwent univariate analysis, with subsequent recursive partitioning to define a list of variables to enter the Canadian CT head rule algorithm.

These were defined into high-risk and medium-risk variables.

High-risk (for neurosurgical intervention)

GCS <15 at 2 hours of injury

Suspected open or depressed skull fracture

Any sign of basal skull fracture

Vomiting 2 or more episodes

Age 65 or over

Medium-risk (for brain injury on CT)

Amnesia before impact >30 min

Dangerous mechanism (pedestrian struck by motorised vehicle, occupant ejected from motor vehicle, fall >3 feet or five stairs)

The decision rule showed 100% sensitivity (95% CI 92-100%) and 68.7% specificity (67-70%) for neurosurgical intervention.

The rule showed 98.4% sensitivity (95% CI 96-99%) and 49.6% specificity (95% CI 48-51%) for ciTBI.

Stiell IG, Wells GA, Vandemheen KL, Clement CM, Lesiuk H, De Maio VJ, Laupacis A, Schull M, McKnight RD, Verbeek R, Brison R, Cass D, Dreyer J, Eisenhauer MA, Greenberg GH, MacPhail I, Morrison L, Reardon M, Worthington J. The Canadian C-spine rule for radiography in alert and stable trauma patients. JAMA. 2001 Oct 17;286(15):1841-8. doi: 10.1001/jama.286.15.1841. PMID: 11597285.

Following NEXUS validation (sensitivity 99.6% but specificity only 12.9%), the Canadian group undertook a prospective cohort study over 10 Canadian ED sites of a CDR for C-spine injury. Eligibility criteria for enrolment were patients at risk of C-spine injury either due to neck pain from any mechanism of injury, or because they had no neck pain but all of the following: some visible injury above the clavicles, had not been ambulatory, and had a dangerous mechanism of injury. Patients also had to be alert (GCS 15) and stable (SBP >90, RR 10-24).

Exclusion criteria were: Age under 16, minor injuries, GCS <15, grossly abnormal vital signs, injured >48 hours previously, penetrating trauma, acute paralysis, known vertebral disease, representation or were pregnant.

The primary outcome measure was clinically important cervical spine injury, defined as any fracture, dislocation, or ligamentous instability demonstrated by imaging.

All C-spine injuries were defined as clinically important unless patient was neurologically intact and had 1 of 4 injuries: isolated avulsion fracture of an osteophyte, isolated fracture of a transverse process not involving a facet joint, isolated fracture of a spinous fracture not involving the lamina, simple compression fracture involving <25% of the vertebral body height.

After clinical examination, patients underwent plain X-ray of the C-spine according to the judgement of the treating clinician.

The authors did not mandate radiography for all patients due to this not being standard of care. Patients who did not undergo imaging were followed up via telephone and were designated as no clinically important cervical spine injury if meeting the following criteria: Neck pain rated as none or mild, restriction of neck movement rated as mild or none, use of a cervical collar not required and neck injury not prevented return to usual duties.

Patients who could not be reached were excluded from analysis.

Variables found to be both reliable and strongly associated with the outcome measure then underwent recursive partitioning to identify those that together gained the most sensitivity.

Over 3 years, 12 782 eligible patients were examined with 8924 enrolled. 577 patients were excluded as could not be followed up after not undergoing imaging. 68.9% of included patients underwent C-spine radiography and 31.1% underwent 14 day follow-up. Overall 151 (1.7%) had ciCSI. An additional 28 (0.3%) had clinically unimportant C-spine injuries.

The final Canadian C-spine Rule incorporated 3 questions:

Any High-risk factor (Age 65 or over, dangerous mechanism, paraesthesias in extremities)

Any low-risk factor (simple rear-end MVC, sitting position in ED, ambulatory at any time, delayed onset of neck pain, absence of midline C-spine tenderness)

Able to actively rotate neck 45 degrees left/right

Dangerous mechanism was defined by fall >1m/5 stairs, axial load to head, MVC >100km/hr/rollover/ejection, motorised recreational vehicles, bicycle collision.

Simple rear-end excluded being pushed into traffic, hit by bus/large truck, rollover, hit by high-speed vehicle.

The overall sensitivity was 100% (98-100%) and specificity 42.5% (40-44%) for ciCSI.

Sierink JC, Treskes K, Edwards MJ, Beuker BJ, den Hartog D, Hohmann J, Dijkgraaf MG, Luitse JS, Beenen LF, Hollmann MW, Goslings JC; REACT-2 study group. Immediate total-body CT scanning versus conventional imaging and selective CT scanning in patients with severe trauma (REACT-2): a randomised controlled trial. Lancet. 2016 Aug 13;388(10045):673-83. doi: 10.1016/S0140-6736(16)30932-1. Epub 2016 Jun 28. PMID: 27371185.

Previous retrospective studies of whole-body CT in trauma used a definition of polytrauma as ISS >16. The authors performed a prospective randomised control trial of whole-body CT versus selective CT imaging on patients with severe trauma as defined by: Unstable OR suspected severe injuries OR severe mechanism (fall >3m, ejection, death of occupant, severely injured other patient, wedged/trapped chest or abdomen) that could be identified at triage in the ED.

Crucially, the multidetector CT was in the resus room or adjacent.

The primary endpoint was in-hospital mortality. Secondary endpoints were 24-hr mortality, 30-day mortality, clinically relevant time intervals during resuscitation (total imaging time, time to diagnosis of life-threatening injuries and total time spent in trauma room), duration of stay and number of ventilation days for patients admitted to ICU, radiation exposure, complications, number of patients who received at least 1U PRBC and hospital costs.

Safety outcomes were the assessment of serious adverse events.

Over 3 years, 5475 patients were assessed, 3860 excluded and 1403 enrolled. A further 203 patients were excluded after randomisation. Finally, 541 patients and 542 patients underwent whole-body CT and standard workup respectively.

Both groups had very high overall mortality (6-8% at 24 hours), with no difference in 24 hour or 30-day mortality between groups. There was a significant reduction in whole-body CT in time to diagnosis of life-threatening injuries and reduced overall ED LOS.

Crucially, 46% of selective group ended up with a whole-body CT anyway in sequential selective scanning of all body regions. The difference in total radiation exposure was very small (20.9mSv vs. 20.6mSv in selective imaging). There were 3 serious adverse events in the whole-body CT group and 1 in the standard care group.

Hutchinson PJ, Kolias AG, Timofeev IS, Corteen EA, Czosnyka M, Timothy J, Anderson I, Bulters DO, Belli A, Eynon CA, Wadley J, Mendelow AD, Mitchell PM, Wilson MH, Critchley G, Sahuquillo J, Unterberg A, Servadei F, Teasdale GM, Pickard JD, Menon DK, Murray GD, Kirkpatrick PJ; RESCUEicp Trial Collaborators. Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension. N Engl J Med. 2016 Sep 22;375(12):1119-30. doi: 10.1056/NEJMoa1605215. Epub 2016 Sep 7. PMID: 27602507.

DECRA trial assessed decompressive craniectomy as a second-tier approach after failure of first-line agents in management of raised intracranial pressure in traumatic brain injury. The authors found patients undergoing this procedure had worse outcomes.

RESCUEicp was a prospective randomised trial of decompressive craniectomy as a last-tier intervention for refractory raised intracranial pressure.

Patients were randomised to ongoing medical management or decompressive craniectomy (unilateral for large mass lesions or bifrontal decompressive craniectomy for diffuse oedema). Patients were aged between 10 and 65yo, had a TBI with abnormal CT, an ICP monitor and ICP >25mmHg for 1-12 hours despite first and second-tier measures.

Tier one measures were sedation, analgesia, head elevation +- paralysis. Other targets were CPP >60mmHg, normothermia, normoglycaemia, PaCO2 34-38 and SpO2 >97%.

Second-tier measures were ventriculostomy (if EVD not already inserted), pharmacological BP augmentation, osmotherapy, PaCO2 30-34mmHg and therapeutic hypothermia.

Barbiturates could be added as a final step in those randomised to continued medical management.

Primary outcome measure was extended Glasgow Outcome Scale (GOS-E) at 6 months.

Secondary outcomes were GOS-E at 12 and 24 months, mortality at 6, 12 and 24 months, GCS at discharge and assessment of ICP control.

Over 10 years, the authors enrolled 409 patients from 2008 that were screened.

Similar numbers in each group received optional stage 1 and 2 measures. In the medical group, 82% received barbiturate infusions. Decompressive craniectomy was performed in 37% of the medical group (cross-over).

Overall, decompressive craniectomy resulted in reduced mortality at 6 months (26.9% vs. 48.9%) and 12 months (30.4% vs. 52%) and increased vegetative state at 6 months (8.5 vs 2.1%) and 12 months (6.2% vs. 1.7%).

A modified intention-to-treat analysis with ordinal regression showed a shift towards improved functional outcome at 12 months but was not statistically robust. It is clear that the survival benefit of DECRA results in both increased numbers of individuals with functional independence and severe disability with no clear way to prognosticate on an individual basis what a patient’s fate may be.

Cooper DJ, Rosenfeld JV, Murray L, Arabi YM, Davies AR, D’Urso P, Kossmann T, Ponsford J, Seppelt I, Reilly P, Wolfe R; DECRA Trial Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011 Apr 21;364(16):1493-502. doi: 10.1056/NEJMoa1102077. Epub 2011 Mar 25. Erratum in: N Engl J Med. 2011 Nov 24;365(21):2040. PMID: 21434843.

This was a multicentre, randomised control trial of bifrontotemporoparietal decompressive craniectomy in adults under 60yo with TBI in whom first-tier therapies failed to reduce ICP.

Over 8 years, 15 ICU’s in Australia and New Zealand enrolled patients.

Refractory ICP was defined as ICP >20mmHg for >15 minutes (continuous or intermittent) in a 1 hour period despite optimised first-tier interventions (sedation, CO2 normalisation, mannitol, hypertonic saline, paralysis and EVD drainage).

Patients were randomised to ongoing medical management or decompressive craniectomy.

The primary outcome was altered during the study to an ordinal analysis of Extended-Glasgow Outcome Scale (GOS-E).

Of 3478 patients screened, 155 were enrolled. Baseline characteristics between groups were similar aside from less patients in the decompressive group having reactive pupils.

The assigned treatment was delivered in 96% of all patients with 15 patients (18%) from the standard care group undergoing DECRA as a life-saving intervention.

At 6 months, the GOS-E was worse in the craniectomy group (median score 3 vs. 4; OR for worse functional outcome 1.84).

Mortality was unchanged between groups.

Isbister GK, Page CB, Buckley NA, Fatovich DM, Pascu O, MacDonald SP, Calver LA, Brown SG; RAVE Investigators. Randomized controlled trial of intravenous antivenom versus placebo for latrodectism: the second Redback Antivenom Evaluation (RAVE-II) study. Ann Emerg Med. 2014 Dec;64(6):620-8.e2. doi: 10.1016/j.annemergmed.2014.06.006. Epub 2014 Jul 3. PMID: 24999282.

Prospective placebo controlled trial of redback spider antivenom in patients with moderate to severe lactodectism. The primary outcome was clinically significant reduction in pain 2 hours after trial drug delivery. Second primary outcome was resolution of systemic features at 2 hours.

All patients received analgesia as per protocol.

Redback spider bites were identified based on patient or clinician diagnosis or a clinical syndrome consistent with red back spider envenoming.

Patients received either 2 vials of antivenom IV or placebo over 20 minutes. After the 2 hour endpoint, antivenom could be given open-label at physician discretion.

Pain was assessed using a verbal numeric rating scale. Patients were also followed up by telephone for 6 weeks to assess any adverse events including serum sickness.

227 patients were recruited with 224 randomised. 34% of patients had systemic effects.

There was no significant difference in pain reduction at 2 hours, resolution of systemic symptoms at 2 hours, analgesia use or serum sickness.

Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010 Oct;56(4):392-401.e1. doi: 10.1016/j.annemergmed.2010.05.037. PMID: 20868907.

This study aimed to determine if IM use of midazolam, droperidol, or both, results in shorter duration of violent and acute behavioural disturbance episode defined by the duration of security staff involvement. The authors performed a blinded randomised control trial over 1 year of patients that failed to de-escalate with verbal or show-of-force interventions or failed to consent to oral/IV treatment.

Trial drug consisted of 2 vials of either: 2 x 5mg droperidol, 2x5mg midazolam or 5mg drop + 5mg midazolam.

All patients were managed in a critical care space with continuous cardiac monitoring, pulse oximetry and NIBP monitoring for the first 6 hours.

Obs were done every 5 minutes for the first 30 minutes then q15min for next 90 minutes, then hourly until 6 hours. All patients received an ECG at 30 minutes, 1 hour and 4 hours after drug delivery. Treating clinicians could decide on further sedation/antipsychotic delivery but were encouraged to wait at least 10 minutes owing to IM dosing of trial drugs.

No staff involved in the study were aware of the primary outcome being time of security personnel attendance.

91 patients were randomised across 12 months (of 223 ED presentations of acute behavioural disturbance).

The median duration of ABD was 20 minutes (droperidol alone), 24 minutes (midazolam alone) and 25 minutes (combination). This did not meet statistical significance.

The hazard ratio for additional sedation for midazolam alone was 2.31 vs. droperidol.

Drug-related adverse events were more likely in the midazolam alone group (28% vs. 6% of droperidol and 7% of combined) and all sedative-related events in the droperidol group occurred after additional sedation was provided.

Abnormal QT-HR pairings occurred in equal numbers from droperidol/midazolam/combined groups.

Overall impression was that droperidol alone was safer, required less subsequent sedation and was equally efficacious with regard to time to security staff stand-down.

Calver L, Page CB, Downes MA, Chan B, Kinnear F, Wheatley L, Spain D, Isbister GK. The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2015 Sep;66(3):230-238.e1. doi: 10.1016/j.annemergmed.2015.03.016. Epub 2015 Apr 15. PMID: 25890395.

Specifically aimed at investigating the frequency of QT prolongation, Torsades de pointes, other adverse events and the effectiveness of droperidol for sedation in the acute behaviourally disturbed patient.

Prospective multicentre study of ABD patients who refused oral medications and were a risk to themselves or others.

A protocol was introduced to each ED involved mandating droperidol 10mg IM or IV, with repeat dosing at 15 minutes if failed to reach SAT score of 0. Beyond this, further sedation was at the discretion of treating clinicians. Patients were managed in critical care areas as per DORM I.

The primary outcome was the proportion of patients with an abnormal QT-HR pair (above the ‘at-risk’ line on the QT nomogram) in a 2 hour period post-droperidol.

1403 patients had complete data sets for analysis over 5 years.

13/1009 patients had an abnormal QT, with only 6 having no other reason for QT prolongation. There were no cases of TdeP. The median time to sedation was 20 minutes. 49 patients failed to become sedated. 31% required more than one dose of droperidol.

Oversedation (SAT -3) occurred in 7.8% of patients and these patients were more likely to have received supplementary benzodiazepines.

Hypotension occurred in 28 patients, desaturation in 22 patients, airway obstruction in 8 patients with 1 patient intubated.

Overall, the study showed routine ECG’s for patients receiving droperidol are not necessary, a starting dose of 10mg is more effective and as safe as any lower dose and further confirmed the risks of oversedation with benzodiazepine use.

Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet. 2000 Oct 14;356(9238):1318-21. doi: 10.1016/S0140-6736(00)02816-6. PMID: 11073021.

Development and validation of a risk score to assess whether patients presenting with upper GI bleeding will require admission for treatment to manage their bleeding.

Rockall scores were previously derived to calculate risk of death or rebleeding. The authors of the Blatchford score determined that risk of requiring intervention was more practical.

The prospective validation study allowed development of a ROC curve for the Blatchford score as compared to the Rockall admission and post-endoscopy scores to compare the discrimination between patients who needed clinical intervention and those that did not.

The score components below were included in the logistic regression model with a ROC AUC of 0.92, higher than that for Rockall admission and post-endoscopy scores.

The tool allowed patients to be classified as low-risk with 99% sensitivity for requiring treatment if all of the following:

BUN <6.5 mmol/L

Hb >130 (men) or >120 (women)

SBP >110

HR <100

Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern Med. 2014;174(11):1755-1762. doi:10.1001/jamainternmed.2014.4056

Guidelines suggest IV bolus then continuous infusion of pantoprazole for 72 hours is recommended for high-risk endoscopic findings in bleeding ulcer management.

In vitro data had suggested that a gastric pH of >6 was required for clot formation and stability. Meta-analysis of RCT’s found this PPI regime compared to placebo showed a significant reduction in further bleeding, surgery and mortality among high-risk bleeding ulcers after endoscopic therapy.

A meta-analysis of intermittent PPI therapy vs. placebo also showed a significant reduction in further bleeding in patients with high-risk bleeding ulcers after endoscopic therapy.

This was a systematic review and meta-analysis comparing intermittent regimes with continuous infusions of PPI after successful endoscopic therapy in patients with bleeding ulcers.

There were 10 full-text articles included in the analysis.

Overall found that intermittent dosing was non-inferior to continuous infusion for rebleeding within 7 (primary outcome), 3 and 30 days. This cannot be interpreted that bolus dosing is superior however. Unfortunately, a variety of bolus dosing regimes were utilised across studies, with the authors advising high-dose (80mg) BD IV with further study into oral effectiveness.

Bellani G, Laffey JG, Pham T, Madotto F, Fan E, Brochard L, Esteban A, Gattinoni L, Bumbasirevic V, Piquilloud L, van Haren F, Larsson A, McAuley DF, Bauer PR, Arabi YM, Ranieri M, Antonelli M, Rubenfeld GD, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group. Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study. Am J Respir Crit Care Med. 2017 Jan 1;195(1):67-77. doi: 10.1164/rccm.201606-1306OC. PMID: 27753501.

Initial use of NIV in ARDS was in selected immunocompromised patients, often with malignancy, who had very poor outcomes with the use of invasive ventilation strategies. Since then, NIV use has increased in non-immunocompromised patients with ARDS, however, the cohort that are predicted to gain the most from this strategy is unclear.

The primary concerns around NIV use in this group are potential delay to intubation and potentially worse overall outcomes.

The LUNG SAFE trial was a prospective observation, international, multicentre cohort study, of which this was a subgroup analysis.

Patients were defined as ARDS if P/F <300 while receiving NIV or MV with at least PEEP of 5 and new pulmonary infiltrates on radiography. Patients were classified as NIV patients if they received NIV on Day 1 or 2 following fulfillment of ARDS criteria.

Those patients that went from NIV to MV before 48 hours from enrolment were classified as MV.

NIV failure was defined as the need to switch from NIV to MV after day 1 and day 2 of NIV.

18% of patients received NIV on Day 1, with 15.5% managed with NIV on Day 1 and 2 (the study population).

CPAP was used in 28.8% of the NIV group with the rest on pressure-cycled modes.

Increasing ARDS severity (based on P/F ratio groups) was significantly associated with failure of NIV.

The use of NIV did not differ between ARDS severity groups.

NIV patients tended to be older, have lower non-pulmonary SOFA scores, higher prevalence of chronic renal failure, CCF and COPD. Clinician recognition of ARDS was significantly lower in the NIV group.

NIV had a 37.5% failure rate with higher non-pulmonary SOFA score, lower P/F ratio and percentage increase in PaCO2 over the first 2 days to be independently associated with failure.

Factors associated with death in the NIV group included CHF, haematological/neoplastic disease, chronic liver disease, age, ARDS severity, total RR and non-pulmonary SOFA score.

Adjusted mortality analysis showed NIV was associated with increased ICU (but not hospital) mortality in those with PF <150 (severe).

Success rates of NIV in ARDS were 78% (mild), 58% (moderate) and 53% (severe) in keeping with previous studies and highlighting the incongruence of equal use of NIV across severity groups in this observational study.

Interestingly, NIV failure was associated with a greater risk of death than severe ARDS managed with invasive ventilation.

Non-invasive positive pressure ventilation for treatment ofrespiratory failure due to severe acute exacerbations of asthma(Review)Lim WJ, Mohammed Akram R, Carson KV, Mysore S, Labiszewski NA, Wedzicha JA, Rowe BH,Smith BJ

NIV has been postulated to be beneficial in asthma through a direct bronchodilating effect and improved alveolar recruitment through ePEEP matching iPEEP, improved flow through atelectatic regions, improved VQ matching and reduced work of breathing.

5 studies met inclusion criteria that were subsequently analysed. Four of the five studies utilised BiPAP and one CPAP.

The studies could not show any real benefit of NIV in terms of primary outcomes (mortality and tracheal intubation). In general, NIV showed favourable outcomes in most secondary outcomes (length of hospital stay and lung function parameters).

Needs more research for standard of care to be adopted.

Non-invasive positive pressure ventilation for treatment ofrespiratory failure due to exacerbations of chronic obstructivepulmonary disease (Review)Ram FSF, Picot J, Lightowler J, Wedzicha JA

In severe COAD, hyperinflation places respiratory muscles at mechanical disadvantage with function close to their maximum capacity. Ensuing tissue acidosis further impedes function leading to downward spiral of ventilation and fatigue. NIV enhances ventilation by offloading ventilatory musculature allowing recovery from respiratory failure.

This Cochrane review analysed 14 studies with significant improvement shown for treatment failure (NNT = 5), treatment failure in both pH <7.30 and >7.30 subgroups, mortality (48% relative risk reduction; NTT = 10) and intubation (60% relative risk reduction; NNT = 4).

Hospital LOS was also shorter in the NIV group by 3.24 days with decreased complications of care.

Non-invasive positive pressure ventilation (CPAP or bilevel NPPV)for cardiogenic pulmonary oedema (Review)Vital FMR, Ladeira MT, Atallah ÁN

In cardiogenic APO, back pressure on the pulmonary circulation results in extravasation of fluid into the alveoli, dilution of surfactant, reduced compliance and increased effort of breathing. Oedema fluid remains dependent, with VQ mismatching and resultant redistribution of blood flow to upper lobes. Resulting sympathetic nervous system activation results in tachycardia, hypertension, peripheral vasoconstriction and diaphoresis.

The goals of NIV in APO are to improve oxygenation, reduce the effort of breathing and increase cardiac output. CPAP achieves these ends by maintaining positive pressure throughout the respiratory cycle and preventing alveolar collapse at end-expiration. CPAP increases lung compliance and decreases the effort of breathing while reducing preload and afterload. CPAP improves oxygenation by increasing the functional residual capacity of the lungs, reducing intrapulmonary shunt and increasing mean airway pressure throughout the respiratory cycle.

32 studies were analysed in this review with 10 comparing CPAP and 8 comparing BiPAP to standard medical care.

Overall NIV (BiPAP or CPAP) in APO resulted in reduced risk of hospital mortality (RR 0.66), intubation (RR 0.52) with no increase in myocardial infarction but an increased risk of treatment intolerance.

When comparing CPAP specifically with standard medical care, mortality and intubation rates were both reduced. When specifically looking at BiPAP vs. standard medical care, no significant benefits were identified, although the data was less robust. The incidence of MI was not significantly different between NIV and SMC, CPAP and SMC or BiPAP and SMC.

Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988 Aug 13;2(8607):349-60. PMID: 2899772.

Assessed the separate and combined benefits of IV streptokinase and PO aspirin in 17 187 patients with suspected MI. Half of all patients were randomised to streptokinase and half to matching placebo. Half of all patients were randomised to aspirin (162.5mg PO) and half to matching placebo.

Patients were eligible if thought to be within 24 hours of onset of suspected MI and to have no clear contraindication for streptokinase or aspirin.

ECG subgroups were as follows:

For the aspirin vs. placebo analysis, vascular mortality at 5 weeks showed a 23% relative risk reduction (9.4% vs. 11.8% respectively). This was apparent across the vast majority of subgroups (Male/female, age, HR, ECG subgroup). Bleeds requiring transfusion were seen equally across groups (0.4% of each). Minor bleeds were more common in the aspirin group (0.6% vs. 0.2%).

Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002 Nov 20;288(19):2411-20. doi: 10.1001/jama.288.19.2411. Erratum in: JAMA. 2003 Feb 26;289(8):987. PMID: 12435254.

Most appropriate duration of DAPT following PCI had not been prospectively studied with arbitrary 4 weeks prior to this. The PCI-CURE study showed DAPT for mean of 9 months after PCI resulted in an overall 31% relative reduction in the risk of cardiovascular death, myocardial infarction and stroke.

This study was designed to assess the efficacy and safety of 1 year of DAPT (aspirin+ clopidogrel) and the efficacy and safety of a loading dose of clopidogrel prior to elective PCI.

All patients received loading dose aspirin + loading clopidogrel 300mg (or placebo) prior to PCI then both groups received DAPT for 4 weeks. After 4 weeks, the pre-treatment group continued to receive DAPT while the no-pre-treatment group received aspirin + placebo. This was continued for 12 months.

The primary outcome was composite of death, MI and stroke at 1 year. Another primary outcome was 28 day death, MI or urgent target revascularisation.

Continuation of DAPT for 12 months was associated with a 26.9% reduction in relative risk of combined endpoint of death, MI or stroke at 1 year.

Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502. doi: 10.1056/NEJMoa010746. Erratum in: N Engl J Med 2001 Dec 6;345(23):1716. Erratum in: N Engl J Med 2001 Nov 15;345(20):1506. PMID: 11519503.

Randomised placebo controlled double-blind trial comparing clopidogrel with placebo in patients with NSTEMI. All patients received aspirin plus clopidogrel/placebo for mean 9 months. The first primary outcome of death from cardiovascular causes, nonfatal MI or stroke at 1 year was seen in 9.3% of the clopidogrel group vs. 11.4% of the placebo group with recurrent MI driving most of this difference. Major and minor bleeding were more common in the clopidogrel group 3.7% vs. 2.7% in placebo, and 5.1% vs. 2.4% respectively, while life-threatening bleeding occurred in 2.2% of the clopidogrel group and 1.8% of placebo group (non-significant).

Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005 Mar 24;352(12):1179-89. doi: 10.1056/NEJMoa050522. Epub 2005 Mar 9. PMID: 15758000.

Authors enrolled patients 75yo and under with STEMI undergoing fibrinolysis and aspirin therapy to clopidogrel or placebo.

3491 patients were recruited if pain within 12 hours and STEMI on ECG. Patients received either clopidogrel 300mg load then 75mg daily or placebo.

The primary efficacy endpoint was composite of occluded infarct-related artery (TIMI 0 or 1) on angiography, death from any cause before angiography or recurrent MI before angiography (surrogate markers of failed reperfusion).

For patients who did not undergo angiography, primary endpoint was death or recurrent MI by day 8 or hospital discharge.

The primary safety endpoint was major bleeding by the end of day of angiography, or if angiography not performed, by day 8 or hospital discharge.

There was an absolute reduction in the primary composite efficacy endpoint of 6.7% from 21.7 to 15% with clopidogrel. The greatest effect was on rate of occluded culprit artery (18.4% to 11.7%). There was no significant increase in major bleeding.

Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005 Nov 5;366(9497):1607-21. doi: 10.1016/S0140-6736(05)67660-X. PMID: 16271642.

Confirmed results of CLARITY in a large Chinese cohort of 45 852 patients showing 9% proportional reduction in death reinfarction or stroke with no significant increase in major bleeding.

Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327. Epub 2009 Aug 30. PMID: 19717846.

Concerns around clopidogrel prodrug activation, variable platelet inhibition and potential bleeding risks raised the option of an alternative antiplatelet for use in NSTEMI/STEMI.

Ticagrelor, a reversible and direct-acting oral antagonist of ADP P2Y12, was considered a viable alternative.

The authors designed a multicentre, prospective, randomised double-blind trial to compare the two agents in ACS patients with onset of symptoms in prior 24 hours. Any predilection for bradycardia was an exclusion criterion.

18624 patients were recruited over 2 years with the primary endpoint of time to first occurrence of composite of death from vascular causes, myocardial infarction or stroke occurring in 9.8% of the ticagrelor group vs. 11.7% of the clopidogrel group at 12 months.

Rates of major bleeding were equal, however, fatal intracranial bleeding was more common in the ticagrelor group (0.1% vs. 0.01%). Dyspnoea was significantly more common in the ticagrelor group (13.8% vs. 7.8%). Ventricular pauses 3 sec or more were also more common in the ticagrelor group (5.8% vs. 3.6%) in the first week but the rate of syncope and pacemaker insertion was equal.

Sgarbossa EB, Pinski SL, Barbagelata A, Underwood DA, Gates KB, Topol EJ, Califf RM, Wagner GS. Electrocardiographic diagnosis of evolving acute myocardial infarction in the presence of left bundle-branch block. GUSTO-1 (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) Investigators. N Engl J Med. 1996 Feb 22;334(8):481-7. doi: 10.1056/NEJM199602223340801. Erratum in: N Engl J Med 1996 Apr 4;334(14):931. PMID: 8559200.

Authors compared a study group (with confirmed MI) with a control group of patients all with LBBB. Prospectively, the optimal cut-off of ST segment changes was determined to be the most sensitive at which 90% specificity for MI could be attained. Those criteria which showed univariate analysis statistical significance were then entered into a stepwise logistic regression to predict acute MI. A scoring system was then developed based on the coefficients of the logistic model on a scale of 0 to 5. The diagnostic model developed was then tested on a validation cohort of 45 patients with acute chest pain and LBBB.

The derivation cohort had 131 patients with MI (study group) which identified 3 criteria that were independent predictors of acute MI:

Concordant ST segment elevation >1mm = 5 points

ST segment depression >1mm in lead V1, 2 or 3 = 3 points

Discordant ST segment elevation >5mm = 2 points

A score of at least showed sensitivity of 36-78% but specificity of 90-96%.

Smith SW, Dodd KW, Henry TD, Dvorak DM, Pearce LA. Diagnosis of ST-elevation myocardial infarction in the presence of left bundle branch block with the ST-elevation to S-wave ratio in a modified Sgarbossa rule. Ann Emerg Med. 2012 Dec;60(6):766-76. doi: 10.1016/j.annemergmed.2012.07.119. Epub 2012 Aug 31. Erratum in: Ann Emerg Med. 2013 Oct;62(4):302. PMID: 22939607.

A previous systematic review found Sgarbossa score of 3 or higher showed a specificity of 98%, but sensitivity of only 20%. All of the validation studies included used CK(MB) as their criterion of acute MI rather than angiographic coronary occlusion.

The authors of the modified Sgarbossa aimed to evaluate the Sgarbossa rule in patients with confirmed acute coronary occlusion on angiography and improve on the test characteristics.

They tested 5 versions of Sgarbossa criteria with the most sensitive and specific identified as:

Concordant ST elevation >1mm in 1 or more leads

Concordant ST depression >1mm in 1 or more leads of V1-3

Excessively discordant ST elevation >1mm and >25% of the depth of the preceding S wave in 1 or more leads

Overall showed 100% sensitivity and 88% specificity for angiographically-confirmed acute coronary occlusion.

Validation studies have since shown 80% sensitivity and 99% specificity.

Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16. doi: 10.1056/NEJMoa070829. Epub 2007 Mar 26. PMID: 17387127.

Authors aimed to identify wheter PCI altered outcomes in stable angina.

They examined 2287 patients across 50 centres

Inclusion criteria were:

Stable CAD with >70% stenosis in at least one proximal epicardial coronary vessel AND

Objective evidence of myocardial ischaemia

Positive stress

Stenosis >80% with classic angina on provocative testing

Exclusion criteria included:

Persistent Class IV angina despite medical therapy

Markedly positive stress test (substantial ST depression or hypotension in Stage 1 of Bruce Protocol)

Refractory heart failure

Cardiogenic shock

EF <30%

Revascularisation in last 6 months

Unsuitable coronary anatomy

The primary outcomes were death and non-fatal MI over 2.5-7 years. Composite secondary outcomes were Death, MI and/or stroke.

There was no significant difference in either primary or secondary outcomes. Importantly, medical optimisation was undertaken by both groups including antiplatelets, long-acting metoprolol/amlodipine/ISMN, lisinopril/losartan, simvastatin +- ezetimibe and lifestyle counselling.

Possible issues included 85% male patients, highly monitored optimal medical therapy and mostly bare metal stents utilised.

Thomas S, Gokhale R, Boden WE, Devereaux PJ. A meta-analysis of randomized controlled trials comparing percutaneous coronary intervention with medical therapy in stable angina pectoris. Can J Cardiol. 2013 Apr;29(4):472-82. doi: 10.1016/j.cjca.2012.07.010. Epub 2012 Sep 23. PMID: 23010084.

Systematic review of prospective randomised trials of PCI vs. OMT (optimal medical therapy) in patients with stable angina. Across 10 studies with 6752 patients included found no significant reduction in death, non-fatal MI, unplanned revascularisation or angina.

Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE, Chaitman BR, Senior R, López-Sendón J, Alexander KP, Lopes RD, Shaw LJ, Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G, Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A, Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S, Mavromichalis S, Kirby R, Jeffries NO, Harrell FE Jr, Rockhold FW, Broderick S, Ferguson TB Jr, Williams DO, Harrington RA, Stone GW, Rosenberg Y; ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020 Apr 9;382(15):1395-1407. doi: 10.1056/NEJMoa1915922. Epub 2020 Mar 30. PMID: 32227755; PMCID: PMC7263833.

Designed to assess efficacy of adding cardiac catheterisation to optimal medical therapy for those with moderate to severe inducible ischaemia (on stress tests) and stable coronary artery disease.

Most enrolled patients underwent CT coronary angiography to rule out non-obstructive CAD and left main disease.

Patients were randomised 1:1 to either medical therapy, angiography +- revascularisation if indicated OR initial conservative strategy with PCI only for failed medical therapy.

Primary outcome was composite of death from cardiovascular causes, MI or hospitalisation for unstable angina, heart failure or resuscitated cardiac arrest.

The key secondary outcomes were composite of death from cardiovascular causes or MI and angina-related quality of life. Over 6 years, 8518 patients were enrolled and 5179 underwent randomisation.

Early 3.5 year interim follow-up showed no difference in CV events between initial invasive therapy group vs. conservative therapy.

Al-Lamee R, Thompson D, Dehbi HM, Sen S, Tang K, Davies J, Keeble T, Mielewczik M, Kaprielian R, Malik IS, Nijjer SS, Petraco R, Cook C, Ahmad Y, Howard J, Baker C, Sharp A, Gerber R, Talwar S, Assomull R, Mayet J, Wensel R, Collier D, Shun-Shin M, Thom SA, Davies JE, Francis DP; ORBITA investigators. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet. 2018 Jan 6;391(10115):31-40. doi: 10.1016/S0140-6736(17)32714-9. Epub 2017 Nov 2. Erratum in: Lancet. 2018 Jan 6;391(10115):30. PMID: 29103656.

Studied PCI vs. placebo for stable angina in a blinded sham-procedure RCT.

Exclusion criteria:

50% stenosis in another vessel

ACS

Left main CAD

Severe LV impairment

All patients had 6 week medical optimisation prior with minimum weekly phone Cardiology Consult, home BP and pulse monitoring and a target of at least 2 anti-anginals per patient.

At 6 week post-randomisation follow-up there were no significant difference in:

Exercise time

Time to 1mm ST depression on exercise

Angina

Quality of life

The study did not look at long-term symptom control, MI and/or mortality given only 6 week follow-up time frame.

The presumed pathological explanation for this was that microvascular pathology may explain anginal symptomatology. Needs external validation.

Perry JJ et al. Sensitivity of Computed Tomography Performed Within Six Hours of Onset of Headache for Diagnosis of Subarachnoid Haemorrhage: Prospective Cohort Study. BMJ 2011; 343: d4277.

Prospective multicentre cohort study across 11 centres in Canada over 9 years. Enrolled patients 15 years and over with non-traumatic acute headache or with syncope associated with headache and underwent emergent CT imaging as part of their diagnostic workup. Alert was defined as GCS 15 and acute defined as maximum intensity in under 1 year. Patients with previous SAH or known aneurysms were excluded.

Subarachnoid haemorrhage was deemed present if any subarachnoid blood visible on CT; visible xanthochromia on CSF; or red cells >5×10^6/L in the final tube of CSF AND an aneurysm on angiography.

The study utilised the final sign-off radiology report from the Neuroradiologist (or local radiologist who regularly reported on head CT) with patients managed based on initial report from registrar or ED physician interpretation.

Many patients did NOT undergo subsequent LP after normal head CT (as usual local practice was followed). Patients were therefore followed-up for 6 months to ascertain their outcome.

3212 patients were enrolled with a SAH rate of 7.7%. 50% underwent LP after negative CT.

For all study patients, the sensitivity of head CT for SAH was 92.9%, specificity 100%.

The sensitivity was 100% (95%CI 97-100%) for patients who underwent CT head within 6 hours of headache onset.

Dupont SA, Wijdicks EF, Manno EM, Rabinstein AA. Thunderclap headache and normal computed tomographic results: value of cerebrospinal fluid analysis. Mayo Clin Proc. 2008 Dec;83(12):1326-31. doi: 10.1016/S0025-6196(11)60780-5. PMID: 19046551.

Conventional angiography carries morbidity and mortality risks of 4.2% and 0.06% respectively. As such, the sensitivity and specificity of xanthochromia on CSF samples is a crucial piece of information to accurately determine which patients warrant this invasive testing.

A retrospective review of all thunderclap headache presentations with negative CT and who had undergone a lumbar puncture at a single ED over 10 years was conducted.

Xanthochromia detection was by visual inspection. Data analysis was limited to 152 patients with 23% refusing LP. Of the remaining 117 patients, 18 had positive xanthochromia with ruptured cerebral aneurysm identified in 13 of these patients. Of the 99 patients that had non-xanthochromic CSF, 35% underwent an additional MR-A with no aneurysms identified. One patient was later found to have a ruptured MCA aneurysm (xanthochromia testing had been performed at 9 hours).

Sensitivity of xanthochromia was found to be 93% and specificity 95%.

Kearon, Clive, de Wit, Kerstin, Parpia, Sameer, Schulman, Sam, Afilalo, Marc, Hirsch, Andrew, Spencer, Frederick A, Sharma, Sangita, D’Aragon, Frédérick, Deshaies, Jean-François, Le Gal, Gregoire, Lazo-Langner, Alejandro, Wu, Cynthia, Rudd-Scott, Lisa, Bates, Shannon M, & Julian, Jim A. (2019). Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability. The New England Journal of Medicine, 381(22), 2125–2134.

Tested the strategy of ruling out PE in outpatients with a low Well’s score and D-dimer less than 1000ng/mL and in those with moderate pre-test probability and a D-dimer <500ng/mL. Patients who presented to either ED or outpatient clinics with suspected PE were potentially eligible. Low-risk Well’s was defined as scores 0-4.0, moderate risk 4.5-6.0 and high-risk >6.0. Pregnant patients were excluded.

Only those with low-risk Well’s and D-dimer >1000, moderate-risk Well’s and D-dimer >500 or high-risk Well’s underwent CTPA.

Study outcomes were assessed at 90 days either over phone or in person. The primary outcome was symptomatic, objectively confirmed VTE (DVT or PE). 2056 patients were registered with 87% low-risk Well’s, 10.8% moderate and 2.3% high-risk. None of the low or moderate risk Well’s patients that had a negative D-dimer suffered VTE in follow-up.

Bickell WH, Wall MJ Jr, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994 Oct 27;331(17):1105-9. doi: 10.1056/NEJM199410273311701. PMID: 7935634.

Tested the hypothesis that the survival of hypotensive patients after penetrating torso trauma would be improved if fluid resuscitation was restricted until the time of operative intervention. Patients were eligible if over 16 years old with either gunshot or stab wounds to the torso, SBP <90 at the time of paramedic measurement. Pregnant women were excluded.

Patients were assigned to immediate resuscitation vs. delayed resuscitation groups. The immediate group received IV Ringer’s lactate rapidly en route to hospital and in the trauma centre. They could also receive blood products in the ED as indicated. In the delayed group, crystalloids and blood products were only delivered after arrival at the operating theatre and general anaesthesia initiated.

1069 patients were enrolled with 309 enrolled to immediate resuscitation and 289 to delayed resuscitation. Groups were well-matched.

The immediate resuscitation group had higher SBP by arrival to ED, lower Hb, lower Plt count and longer PT/APTT.

The mean volume administered pre-hospital to the immediate group was 870mL vs. 92mL in the delayed group. Mean volumes in ED were 1608mL and 293mL respectively.

The two groups then received similar amounts of fluid and blood products in theatre.

The overall rate of survival was higher in the delayed group at 70% vs. 62% in immediate group.