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ACEM Independent Literature Review On Thrombolysis for Stroke

26/3/2016

In order to guide Emergency Physicians caring for patients with acute ischaemic stroke, ACEM has initiated an independent analysis of the published scientific literature to evaluate the evidence for administration of thrombolytic therapy in acute ischaemic stroke. The results of this analysis are out and can be downloaded here.

This independent literature review will inform revision of ACEM’s Statement on Intravenous Thrombolysis for Ischaemic Stroke (S129), to be undertaken in 2016. This is likely to support use of thrombolysis for treatment of ischaemic stroke (a significant change from the previous ACEM statement on this topic).

From the Executive Summary and abstract:

Key Findings:

Thrombolytic therapy (with rTPA) administered within 4.5 hours of ischaemic stroke increased the proportion of participants who were essentially back to baseline, as assessed by a modified Rankin Score (mRS) score of 0-1, at 90 days after stroke (odds ratio (OR) 1.58, 95% confidence interval (CI) 1.26 to 1.99). Evidence from the National Institute of Neurological Disorders and Stroke (NINDS) studies indicates that this benefit is sustained in the longer term, i.e. 12 months after treatment (OR=1.7, 95% CI= 1.2 to 2.3).

Treatment within 3 hours of stroke (OR=1.85, 95%CI=1.38 to 2.47), provided a greater advantage for a return to independence (mRS 0-1) than treatment between 3-4.5 hours (OR=1.27, 95%CI=1.01 to 1.60). Timing of treatment within the three hour window had little impact on mortality rates.

Numbers needed to treat (NNT) to achieve functional benefits, as measured by mRS outcome of 0-1, was 10 (i.e. 10 patients needed treatment for one additional good functional outcome).
- Timing of administration alters numbers needed to treat to benefit (NNTB), with around half the number of patients needing to be treated for one to benefit at 3 hours (NNTB = 7, 95% CI = 14 to 5), compared to treatment at 3-4.5 hours (NNTB = 18, 95% CI = 419 to 9).

There was no statistical difference in outcomes in the proportion of patients who were independent, as assessed by a mRS of 0-2 (OR=1.21, 95% CI=0.98 to 1.50). A mRS of 2 implies slight disability but able to look after own affairs without assistance.

Treatment with Alteplase increased the odds of symptomatic intracranial haemorrhage (sICH) during the first week to 10 days following treatment (OR=6.90, 95%CI=2.21 to 21.50) and early death from intracranial haemorrhage (ICH) (OR=7.39, 95% CI=1.93 to 28.29) However heterogeneity in the safety data suggests caution should be applied in the interpretation of these results.
- Numbers needed to harm (NNTH) was 42 for symptomatic intracranial haemorrhage (i.e. 42 patients needed treatment for one to experience sICH), however, with very large confidence intervals (13-119).
- 122 (95% CI = 830 to 30) would need to be treated for one patient to die from ICH.
- The large confidence intervals around these figures should be borne in mind when interpreting the NNT.

Overall the risk of death at 30 days is no different if given thrombolysis or not. Whilst there is a much larger number of symptomatic intra cranial haemorrhages in those patients given thrombolysis, in the non-thrombolysis group the rate of death was the same.

Demographic factors were examined and found no evidence that any of sex, age, ethnicity and comorbidities were predictive of patients who may respond better to rTPA.

Conclusion:

There is evidence that thrombolytic therapy increases the proportion of patients who were back to baseline (mRS 0-1) at 90 days after stroke, however, at a cost of increased intracranial symptomatic haemorrhage.

A mRS of 2 implies slight disability but able to look after own affairs without assistance. If patients are willing to accept this as an outcome from their stroke, there is no evidence that thrombolysis offers any benefits but still carries a significant risk of symptomatic intracranial haemorrhage.

Therefore, discussion with patient and family/carers by the treating clinicians, and informed consent is vital to any decision about use of thrombolytic therapy in stroke.

Danny

Dr Danny Ben-Eli, BSc, MD, FACEM

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Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department

8/3/2016

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Another great study from Geoff Isbister, demonstrating the safety using Ketamine as rescue medication where droperidol or a combination of droperiodol and a benzodiazepine failed. In this prospective observational study, 49 of 1,296 agitated adults failed initial tranquilization attempts (usually with 2 doses of droperidol 10 mg intramuscularly) and received ketamine intramuscularly (median 300 mg). All but 5 were then adequately sedated, with minimal adverse effects.

From the conclusion:
Ketamine appeared effective and did not cause obvious harm in this small sample and is a potential option for patients who have failed previous attempts at sedation. A dose of 4 to 5 mg/kg (IM) is suggested, and doses less than 200 mg are associated with treatment failure.

The study was published ahead of print in the Annals of Emergency Medicine:
http://dx.doi.org/10.1016/j.annemergmed.2015.11.028

The abstract is below.

Danny

Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department

Geoffrey Kennedy Isbister, MD, FACEM*; Leonie A. Calver, PhD; Michael A. Downes, MBBS, FACEM; Colin B. Page, MBBS

Study objective: We investigate the effectiveness and safety of ketamine to sedate patients with severe acute behavioral disturbance who have failed previous attempts at sedation.

Methods: This was a prospective study of patients given ketamine for sedation who had failed previous sedation attempts. Patients with severe acute behavioral disturbance requiring parenteral sedation were treated with a standardized sedation protocol including droperidol. Demographics, drug dose, observations, and adverse effects were recorded. The primary outcome was the number of patients who failed to sedate within 120 minutes of ketamine administration or requiring further sedation within 1 hour.

Results: Forty-nine patients from 2 hospitals were administered rescue ketamine during 27 months; median age was 37 years (range 20-82 years); 28 were men. Police were involved with 20 patients. Previous sedation included droperidol (10 mg; 1), droperidol (10þ10 mg; 33), droperidol (10þ10þ5 mg; 1), droperidol (10þ10þ10 mg; 11), and combinations of droperidol and benzodiazepines (2) and midazolam alone (1). The median dose of ketamine was 300 mg (range 50 to 500 mg). Five patients (10%; 95% confidence interval 4% to 23%) were not sedated within 120 minutes or required additional sedation within 1 hour. Four of 5 patients received 200 mg or less. Median time to sedation postketamine was 20 minutes (interquartile range 10 to 30 minutes; 2 to 500 minutes). Three patients (6%) had adverse effects, 2 had vomiting, and a third had a transient oxygen desaturation to 90% after ketamine that responded to oxygen.

Conclusion: Ketamine appeared effective and did not cause obvious harm in this small sample and is a potential option for patients who have failed previous attempts at sedation. A dose of 4 to 5 mg/kg is suggested, and doses less than 200 mg are associated with treatment failure. [Ann Emerg Med. 2016;-:1-7.]

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SIRS - Out, SOFA - In: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

1/3/2016

3 Comments

Hi All,

For some time there has been growing evidence that the current definition of sepsis and septic shock is inaccurate. In fact, 1 in 8 patients admitted to critical care units in Australia and New Zealand with infection and new organ failure did not have the requisite minimum of 2 SIRS criteria to fulfil the definition of sepsis and had protracted courses with significant morbidity and mortality (Kaukonen et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629-1638).

The new definitions of Sepsis and Septic Shock were published in this week’s JAMA. These were written by a taskforce with expertise in sepsis pathobiology, clinical trials, and epidemiology which was was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. They are titled: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

The article is attached and can be downloaded here (open access).

Key points:

Concepts of Sepsis:

Sepsis is the primary cause of death from infection, especially if not recognised and treated promptly. Its recognition mandates urgent attention.
Sepsis is a syndrome shaped by pathogen factors and host factors (eg, sex, race and other genetic determinants, age, comorbidities, environment) with characteristics that evolve over time. What differentiates sepsis from infection is an aberrant or dysregulated host response and the presence of organ dysfunction.
Sepsis-induced organ dysfunction may be occult; therefore, its presence should be considered in any patient presenting with infection. Conversely, unrecognized infection may be the cause of new-onset organ dysfunction. Any unexplained organ dysfunction should thus raise the possibility of underlying infection.
The clinical and biological phenotype of sepsis can be modified by preexisting acute illness, long-standing comorbidities, medication, and interventions.
Specific infections may result in local organ dysfunction without generating a dysregulated systemic host response.

New Terms and Definitions:

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.
Organ dysfunction can be identified as an acute change in total SOFA score 2 points consequent to the infection.
The baseline SOFA score can be assumed to be zero in patients not known to have preexisting organ dysfunction.
A SOFA score 2 reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection. Even patients presenting with modest dysfunction can deteriorate further, emphasizing the seriousness of this condition and the need for prompt and appropriate intervention, if not already being instituted.
In lay terms, sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs.
Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be promptly identified at the bedside with qSOFA, ie, alteration in mental status, systolic blood pressure 100 mm Hg, or respiratory rate 22/min.
Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.
Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP 65 mm Hg and having a serum lactate level
>2 mmol/L (18 mg/dL) despite adequate volume resuscitation. With these criteria, hospital mortality is in excess of 40%.

The SOFA (Sequential [Sepsis-Related] Organ Failure Assessment) Score:

qSOFA (Quick SOFA) Criteria:

Respiratory rate 22/min
Altered mentation
Systolic blood pressure 100 mm Hg

Operationalization of Clinical Criteria Identifying Patients With Sepsis and Septic Shock:

Danny

Dr Danny Ben-Eli, BSc, MD, FACEM
Emergency Physician | Monash Medical Centre | Monash Health

3 Comments

ACEM Independent Literature Review On Thrombolysis for Stroke

Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department

SIRS - Out, SOFA - In: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

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