Category Archives: PHARM

Prehospital and Retrieval Medicine

Acute Med, All Updates, ICU, PHARM, Resus

Clopidogrel and aspirin for TIA

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A large Chinese trial compared aspirin alone with combination aspirin / clopidogrel in patients who had had a TIA in the previous 24 hours. 90-day stroke outcome was reduced in the combination therapy group without an apparent increase in haemorrhage.
Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack
N Engl J Med. 2013 Jul 4;369(1):11-19
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Background Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone.

Methods In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect.

Results Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group.

Conclusions Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage.

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Acute Med, All Updates, ICU, PHARM, Resus

Family presence during resuscitation

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CPR-iconFamilies allowed to be present during attempted cardiopulmonary resuscitation had improved psychological outcomes at ninety days.
Adult family members of adult patients were studied in this randomized study from France.
Resuscitation team member stress levels and effectiveness of resuscitation did not appear to be affected by family presence.
Family Presence during Cardiopulmonary Resuscitation
N Engl J Med. 2013 Mar 14;368(11):1008-18
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BACKGROUND: The effect of family presence during cardiopulmonary resuscitation (CPR) on the family members themselves and the medical team remains controversial.

METHODS: We enrolled 570 relatives of patients who were in cardiac arrest and were given CPR by 15 prehospital emergency medical service units. The units were randomly assigned either to systematically offer the family member the opportunity to observe CPR (intervention group) or to follow standard practice regarding family presence (control group). The primary end point was the proportion of relatives with post-traumatic stress disorder (PTSD)-related symptoms on day 90. Secondary end points included the presence of anxiety and depression symptoms and the effect of family presence on medical efforts at resuscitation, the well-being of the health care team, and the occurrence of medicolegal claims.

RESULTS: In the intervention group, 211 of 266 relatives (79%) witnessed CPR, as compared with 131 of 304 relatives (43%) in the control group. In the intention-to-treat analysis, the frequency of PTSD-related symptoms was significantly higher in the control group than in the intervention group (adjusted odds ratio, 1.7; 95% confidence interval [CI], 1.2 to 2.5; P=0.004) and among family members who did not witness CPR than among those who did (adjusted odds ratio, 1.6; 95% CI, 1.1 to 2.5; P=0.02). Relatives who did not witness CPR had symptoms of anxiety and depression more frequently than those who did witness CPR. Family-witnessed CPR did not affect resuscitation characteristics, patient survival, or the level of emotional stress in the medical team and did not result in medicolegal claims.

CONCLUSIONS: Family presence during CPR was associated with positive results on psychological variables and did not interfere with medical efforts, increase stress in the health care team, or result in medicolegal conflicts.

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Acute Med, All Updates, PHARM, Resus

Isolated LAFB and outcome

A small study followed up an older cohort of patients with isolated left anterior fascicular block on their ECG (isolated left axis deviation), without clinically manifest cardiovascular disease.

LAFB-litfl
Learn about LAFB at Life In The Fast Lane

LAFB was associated with an increased risk of atrial fibrillation, heart failure and death. LAFB is caused by conduction tissue fibrosis, and is a marker of other left heart fibrosis. The patients did not go on to develop left bundle branch block, and only 2 of 39 required pacing in 10 years, suggesting these outcomes were not due to progression of conduction disease.

Long-term Outcomes of Left Anterior Fascicular Block in the Absence of Overt Cardiovascular Disease
JAMA. 2013 Apr 17;309(15):1587-8

Acute Med, All Updates, PHARM, Resus

5 days of steroids for COPD exacerbation

A randomised trial showed 5 days of oral steroid therapy (40 mg prednisone) was non-inferior to 14 days’ duration in delaying the next exacerbation.
Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial
JAMA. 2013 Jun 5;309(21):2223-31
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IMPORTANCE: International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown.

OBJECTIVE: To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids.

DESIGN, SETTING, AND PATIENTS: REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011.

INTERVENTIONS: Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%.

MAIN OUTCOME AND MEASURE: Time to next exacerbation within 180 days.

RESULTS: Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently.
CONCLUSIONS AND RELEVANCE: In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.

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All Updates, ICU, Kids, PHARM, Trauma

Blood products in trauma & survivor bias

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Esky-label.001The observation that patients with haemorrhagic trauma in military and civilian settings do better if they receive coagulation factors and platelets is yet to be replicated in a randomised trial. It has been suggested that the effect may in part be a consequence of survivor bias – ie. that if a patient lives long enough to received some thawed fresh frozen plasma, then they were already more likely to be a survivor and therefore more survivors will be represented in the ‘FFP’ groups vs a ‘no-FFP’ comparison group.
An attempt to eliminate survivor bias was made in the PROMMTT study, which documented the timing of transfusions during active resuscitation and patient outcomes in adult trauma patients who received a transfusion of at least 1 unit of RBCs within 6 hours of admission.
Increased ratios of plasma:RBCs and platelets:RBCs were independently associated with decreased 6-hour mortality, when haemorrhagic death predominated. In the first 6 hours, patients with ratios less than 1:2 were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher.
A prospective trial is underway to identify the optimal ratio of blood products, in the PROPPR study, in which 1:1:1 ratio of plasma:platelets:RBC will be compared with 1:1:2.
The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study
Arch Surg. 2012 Oct 15:1-10
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Objective: To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios.

Design: Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models.

Setting: Ten US level I trauma centers.
Patients: Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group).

Main Outcome Measure: In-hospital mortality.

Results: Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P < .001 for both). In a multivariable time-dependent Cox model, increased ratios of plasma:RBCs (adjusted hazard ratio = 0.31; 95% CI, 0.16-0.58) and platelets:RBCs (adjusted hazard ratio = 0.55; 95% CI, 0.31-0.98) were independently associated with decreased 6-hour mortality, when hemorrhagic death predominated. In the first 6 hours, patients with ratios less than 1:2 were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher. After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from nonhemorrhagic causes prevailed.

Conclusions: Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.

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Acute Med, All Updates, PHARM, Resus

Stroke thrombolysis outcomes from registry

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Data from a large national stroke registry are reported to show that in patients who received tPA, outcomes were worse the later it was given. From a registry of over a million patients, the study group included 58353 patients from 1395 sites treated after emergency department arrival with IV tPA within 4.5 hours of symptom onset. Reported odds ratios were small but statistically significant in this large sample size. There was a 4.9% rate of intracranial haemorrhage.
As there is no comparison with patients who did not receive tPA, one cannot conclude from this study that tPA is either beneficial or harmful. It may however be used as an argument that if you’re working in a centre where the patients are going to get the tPA, it’s advisable not to delay it.
Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke
JAMA. 2013 Jun 19;309(23):2480-8
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IMPORTANCE: Randomized clinical trials suggest the benefit of intravenous tissue-type plasminogen activator (tPA) in acute ischemic stroke is time dependent. However, modest sample sizes have limited characterization of the extent to which onset to treatment (OTT) time influences outcome; and the generalizability of findings to clinical practice is uncertain.

OBJECTIVE: To evaluate the degree to which OTT time is associated with outcome among patients with acute ischemic stroke treated with intraveneous tPA.

DESIGN, SETTING, AND PATIENTS: Data were analyzed from 58,353 patients with acute ischemic stroke treated with tPA within 4.5 hours of symptom onset in 1395 hospitals participating in the Get With The Guidelines-Stroke Program, April 2003 to March 2012.

MAIN OUTCOMES AND MEASURES: Relationship between OTT time and in-hospital mortality, symptomatic intracranial hemorrhage, ambulatory status at discharge, and discharge destination.

RESULTS: Among the 58,353 tPA-treated patients, median age was 72 years, 50.3% were women, median OTT time was 144 minutes (interquartile range, 115-170), 9.3% (5404) had OTT time of 0 to 90 minutes, 77.2% (45,029) had OTT time of 91 to 180 minutes, and 13.6% (7920) had OTT time of 181 to 270 minutes. Median pretreatment National Institutes of Health Stroke Scale documented in 87.7% of patients was 11 (interquartile range, 6-17). Patient factors most strongly associated with shorter OTT included greater stroke severity (odds ratio [OR], 2.8; 95% CI, 2.5-3.1 per 5-point increase), arrival by ambulance (OR, 5.9; 95% CI, 4.5-7.3), and arrival during regular hours (OR, 4.6; 95% CI, 3.8-5.4). Overall, there were 5142 (8.8%) in-hospital deaths, 2873 (4.9%) patients had intracranial hemorrhage, 19,491 (33.4%) patients achieved independent ambulation at hospital discharge, and 22,541 (38.6%) patients were discharged to home. Faster OTT, in 15-minute increments, was associated with reduced in-hospital mortality (OR, 0.96; 95% CI, 0.95-0.98; P < .001), reduced symptomatic intracranial hemorrhage (OR, 0.96; 95% CI, 0.95-0.98; P < .001), increased achievement of independent ambulation at discharge (OR, 1.04; 95% CI, 1.03-1.05; P < .001), and increased discharge to home (OR, 1.03; 95% CI, 1.02-1.04; P < .001).
CONCLUSIONS AND RELEVANCE: In a registry representing US clinical practice, earlier thrombolytic treatment was associated with reduced mortality and symptomatic intracranial hemorrhage, and higher rates of independent ambulation at discharge and discharge to home following acute ischemic stroke. These findings support intensive efforts to accelerate hospital presentation and thrombolytic treatment in patients with stroke.

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All Updates, ICU, Kids, PHARM, Resus, Trauma

Thenar eminence based medicine

A recent study showed superior effectiveness of one bag-mask ventilation style over another in novice providers. The technique recommended is the thenar eminence grip, in which downward pressure is applied with the thenar eminences while the four fingers of each hand pull the jaw upwards toward the mask.

Interestingly, in their crossover study in which the thenar emininence (TE) technique was compared with the traditionally taught ‘CE’ technique, they demonstrated a ‘sequence effect’. If subjects did TE first, they maintained good tidal volumes when doing CE. However if they did CE first, they achieved poor tidal volumes which were markedly improved when switching to TE.

The authors suggest: “A possible explanation for this sequence effect is that the TE grip is superior. When one used the TE grip first, he or she was more likely to learn how a good tidal volume “feels” and then more likely to apply good technique with the EC grip.“.

Some of us have been practicing and teaching this technique for a while. None have put it better than the brilliant Reuben Strayer of EM Updates in this excellent short video:

Emergency Ventilation in 11 Minutes from reuben strayer on Vimeo.

Efficacy of facemask ventilation techniques in novice providers
J Clin Anesth. 2013 May;25(3):193-7

STUDY OBJECTIVE: To determine which of two facemask grip techniques for two-person facemask ventilation was more effective in novice clinicians, the traditional E-C clamp (EC) grip or a thenar eminence (TE) technique.

DESIGN: Prospective, randomized, crossover comparison study.

SETTING: Operating room of a university hospital.

SUBJECTS: 60 novice clinicians (medical and paramedic students).

MEASUREMENTS: Subjects were assigned to perform, in a random order, each of the two mask-grip techniques on consenting ASA physical status 1, 2, and 3 patients undergoing elective general anesthesia while the ventilator delivered a fixed 500 mL tidal volume (VT). In a crossover manner, subjects performed each facemask ventilation technique (EC and TE) for one minute (12 breaths/min). The primary outcome was the mean expired VT compared between techniques. As a secondary outcome, we examined mean peak inspiratory pressure (PIP).

MAIN RESULTS: The TE grip provided greater expired VT (379 mL vs 269 mL), with a mean difference of 110 mL (P < 0.0001; 95% CI: 65, 157). Using the EC grip first had an average VT improvement of 200 mL after crossover to the TE grip (95% CI: 134, 267). When the TE grip was used first, mean VTs were greater than for EC by 24 mL (95% CI: -25, 74). When considering only the first 12 breaths delivered (prior to crossover), the TE grip resulted in mean VTs of 339 mL vs 221 mL for the EC grip (P = 0.0128; 95% CI: 26, 209). There was no significant difference in PIP values using the two grips: the TE mean (SD) was 14.2 (7.0) cm H2O, and the EC mean (SD) was 13.5 (9.0) cm H2O (P = 0.49).

CONCLUSIONS: The TE facemask ventilation grip results in improved ventilation over the EC grip in the hands of novice providers.

All Updates, ICU, Kids, PHARM, Resus, Trauma

RSI haemodynamics in the field

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intubated-prehosp-vol-iconThe noxious stimulus of laryngoscopy & tracheal intubation can precipitate hypertension, tachycardia, and intracranial pressure elevation, risking exacerbation of brain injury or haemorrhage. Physicians from an English Helicopter Emergency Medical Service examined the response of heart rate and blood pressure to prehospital rapid sequence intubation (RSI). While a retrospective study, the haemodynamic data were prospectively recorded and documented using standard monitor printouts, and time of intubation could be accurately determined by the onset of capnography recordings. Their standardised system documents blood pressure recordings every three minutes. Etomidate and suxamethonium were used for RSI.
They report their findings:


A hypertensive response occurred in 79% (70/89) of patients. MAP exceeded the upper limit of estimated intact cerebral autoregulation (150 mmHg) in 18% (16/89) of cases and 9% (8/89) of patients had a greater than 100% increase in MAP and/or SBP. A single hypotensive response occurred. A tachycardic response occurred in 58% (64/110) of patients and bradycardia was induced in one.

Of note, 97 of the 115 patients had injuries that included head trauma.
The authors note that opioids are often co-administered during in-hospital RSI and that this may offset the haemodynamic stimulation, while possible increasing the complexity of the procedure in the prehospital environment. They have modified their pre-hospital anaesthesia standard operating procedure to include the use of an opioid and will report the associated outcomes and complication rates ‘in due course’.
This is interesting and important stuff, and something we should all be looking at in our respective prehospital critical care services.
The haemodynamic response to pre-hospital RSI in injured patients
Injury. 2013 May;44(5):618-23
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BACKGROUND: Laryngoscopy and tracheal intubation provoke a marked sympathetic response, potentially harmful in patients with cerebral or cardiovascular pathology or haemorrhage. Standard pre-hospital rapid sequence induction of anaesthesia (RSI) does not incorporate agents that attenuate this response. It is not known if a clinically significant response occurs following pre-hospital RSI or what proportion of injured patients requiring the intervention are potentially at risk in this setting.

METHODS: We performed a retrospective analysis of 115 consecutive pre-hospital RSI’s performed on trauma patients in a physician-led Helicopter Emergency Medical Service. Primary outcome was the acute haemodynamic response to the procedure. A clinically significant response was defined as a greater than 20% change from baseline recordings during laryngoscopy and intubation.

RESULTS: Laryngoscopy and intubation provoked a hypertensive response in 79% of cases. Almost one-in-ten patients experienced a greater than 100% increase in mean arterial pressure (MAP) and/or systolic blood pressure (SBP). The mean (95% CI) increase in SBP was 41(31-51) mmHg and MAP was 30(23-37) mmHg. Conditions leaving the patient vulnerable to secondary injury from a hypertensive response were common.

CONCLUSIONS: Laryngoscopy and tracheal intubation, following a standard pre-hospital RSI, commonly induced a clinically significant hypertensive response in the trauma patients studied. We believe that, although this technique is effective in securing the pre-hospital trauma airway, it is poor at attenuating adverse physiological effects that may be detrimental in this patient group.

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All Updates, ICU, PHARM, Resus

Awake intubation

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I had some fun today getting intubated.
We used the Ambu aScope 2 and the Greater Sydney Area HEMS equipment and approach to airway management. I didn’t receive an antisialogogue or any analgesia or sedation.
The big learning point for me was how hard it was to anaesthetise the posterior part of my nasal cavity and nasopharynx. I thought the worst part would be any stimulation of my vocal cords or trachea with lidocaine or instrumentation, but this really was fine. Nebulised 2% lidocaine (the strongest concentration we have), atomised lidocaine (using a mucosal atomiser), and co-phenylcaine spray weren’t sufficient. I can see why people use pastes or gel to maintain mucosal contact while the lidocaine takes effect, but we don’t have those (yet). The best solution came from hooking up oxygen tubing to an iv cannula via a three way tap. Oxygen was run through at 2 l/min and lidocaine injected via the the three way tap. This enabled an atomised spray to be directed right onto the area concerned, and made the insertion of the nasotracheal tube more tolerable – although still unpleasant.
crazed-nutter-sm
The fact I could be intubated awake with reasonable topicalisation suggests most patients should tolerate it perhaps after even an analgesic dose of ketamine, eg. 30-40 mg in an adult. I suspect full dissocation would not be required, which is good for cooperation (“stick your tongue out sir”). I appreciate there are better agents, such as remifentanil or dexmedetomidine, but my area of interest is the retrieval setting – where I have neither the luxury of using these agents nor that of calling for anaesthetic back up.
Thanks to HEMS physicians Emily Stimson, Nirosha De Zoysa, Felicity Day, Chloe Tetlow, and Fergal McCourt for making it fun and safe.
Here’s the video:

Twitter has been helpful in gathering some advice, particularly from @DocJohnHinds: