Tag Archives: drugs

Stroke thrombolysis outcomes from registry

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

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.

Intranasal ketamine for kids – 1mg / kg?

A small pilot study on a convenience sample of children presenting to the emergency department with acute limb injury pain evaluated the use of intranasal ketamine(1).

Initial dose averaged 0.84 mg/kg and a third of the patients required a top up dose at 15 minutes, resulting in a total dose of about 1.0 mg/kg to provide adequate analgesia by 30 min for most patients. The authors suggest that this could guide investigators on an appropriate dose of IN ketamine for use in clinical trials.

Adverse events were all transient and mild.

Prior to administration, the ketamine was diluted with saline to a total volume of 0.5 mL and was administered as 0.25 mL per nare using a Mucosal Atomiser Device (MAD, Wolfe Tory Medical, Salt Lake City, UT, USA). According to the protocols in my Service, this device requires 0.1 ml to prime its dead space(2). It is unclear whether this factor may have affected the total dose delivered to the patient in this study.

1. Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: A pilot study
Emerg Med Australas. 2013 Apr;25(2):161-7

OBJECTIVE: The present study aims to conduct a pilot study examining the effectiveness of intranasal (IN) ketamine as an analgesic for children in the ED.

METHODS: The present study used an observational study on a convenience sample of paediatric ED patients aged 3-13 years, with moderate to severe (≥6/10) pain from isolated limb injury. IN ketamine was administered at enrolment, with a supplementary dose after 15 min, if required. Primary outcome was change in median pain rating at 30 min. Secondary outcomes included change in median pain rating at 60 min, patient/parent satisfaction, need for additional analgesia and adverse events being reported.

RESULTS: For the 28 children included in the primary analysis, median age was 9 years (interquartile range [IQR] 6-10). Twenty-three (82.1%) were male. Eighteen (64%) received only one dose of IN ketamine (mean dose 0.84 mg/kg), whereas 10 (36%) required a second dose at 15 min (mean for second dose 0.54 mg/kg). The total mean dose for all patients was 1.0 mg/kg (95% CI: 0.92-1.14). The median pain rating decreased from 74.5 mm (IQR 60-85) to 30 mm (IQR 12-51.5) at 30 min (P < 0.001, Mann-Whitney). For the 24 children who contributed data at 60 min, the median pain rating was 25 mm (IQR 4-44). Twenty (83%) subjects were satisfied with their analgesia. Eight (33%) were given additional opioid analgesia and the 28 reported adverse events were all transient and mild.

CONCLUSIONS: In this population, an average dose of 1.0 mg/kg IN ketamine provided adequate analgesia by 30 min for most patients

2. Case report: prehospital use of intranasal ketamine for paediatric burn injury
Emerg Med J. 2011 Apr;28(4):328-9

In this study, the administration of an intravenous ketamine formulation to the nasal mucosa of a paediatric burn victim is described in the prehospital environment. Effective analgesia was achieved without the need for vascular or osseous access. Intranasal ketamine has been previously described for chronic pain and anaesthetic premedication. This case highlights its potential as an option for prehospital analgesia.

Endovascular stroke treatment

Two randomised controlled trials have been published which compare endovascular stroke treatments with intravenous tPA. Both the American Interventional Management of Stroke (IMS) III trial (1) and the Italian SYNTHESIS Expansion trial (2) had Modified Rankin Scores as their primary endpoint. No significant differences in this outcome or in mortality or intracranial haemorrhage rates were found in either trial, and IMS III was terminated early due to futility.

A third trial, from North America, called MR RESCUE, randomised patients within 8 hours after the onset of large vessel, anterior-circulation strokes to undergo mechanical embolectomy or receive standard care(3). No clinical outcome differences were demonstrated.

An accompanying editorial (4) draws the following conclusion:

“The IMS III and SYNTHESIS Expansion studies show that intravenous thrombolysis should continue to be the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset, even if imaging shows an occluded major intracranial artery. Beyond 4.5 hours, the MR RESCUE trial does not provide data supporting the use of endovascular treatment in patients with an ischemic penumbra of any size.”

Many might argue that showing endovascular treatment is equivalent to thrombolysis just means endovascular treatment doesn’t work, because a significant proportion of the emergency medicine community views this as the correct interpretation of a thorough analysis of the stroke thrombolysis literature.

1. Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke
NEJM Feb 8, 2013 Full Text Link

2. Endovascular Treatment for Acute Ischemic Stroke
NEJM Feb 8, 2013 Full Text Link

3. A Trial of Imaging Selection and Endovascular Treatment for Ischemic Stroke
NEJM Feb 8, 2013 Full Text Link

4.Endovascular Treatment for Acute Ischemic Stroke — Still Unproven
NEJM Feb 8, 2013 Full Text Link

Ketamine & cardiovascular stability

I ‘jumped ship’ from etomidate to ketamine for rapid sequence intubation (RSI) in sick patients about seven years ago. Good thing too, since I later moved to Australia where we don’t have etomidate. I’ve been one of the aggressive influences behind my prehospital service’s switch to ketamine as the standard induction agent for prehospital RSI. It’s no secret that I think propofol has no place in RSI in the critically ill.

I love ketamine for its haemodynamic stability compared with other induction agents. In fact, I very rarely see a drop in blood pressure when I use it for RSI even in significantly shocked patients. One should however try to remain open to evidence that disconfirms ones biases, lest we allow science to be replaced by religion. I therefore was interested to read a report of two cases of cardiac arrest following the administration of ketamine for rapid sequence intubation (RSI)(1).


The first case was a 25 year old with septic shock due to an intestinal perforation, with a respiratory rate of 30 ‘labored’ breaths per minute and hypoxaemia prior to intubation with 2mg/kg ketamine who became bradycardic and then had a 10-15 minute PEA arrest after ketamine administration (but prior to intubation). Pre-arrest oxygen saturation and pre-induction blood gases are not reported.

The second case was an 11 year old with septic shock and pneumonia, hypoxaemia, and a severe metabolic acidosis. She arrested with bradycardia then a brief period of asystole one minute after receiving 2.4 mg/kg ketamine with rocuronium for intubation.

Was the ketamine responsible for the arrests? Ketamine usually exhibits a stimulatory effect on the cardiovascular system, through effects which are incompletely understood but include a centrally mediated sympathetic response and probable inhibition of norepinephrine (noradrenaline) reuptake. However ketamine can have a direct depressant effect on cardiac output which is usually overridden by the sympathetic stimulation. In critically ill severely stressed patients the depressant effect may predominate. In a study on 12 critically ill surgical patients, haemodynamic indices were measured using pulmonary artery catheters within 5 minutes of ketamine administration (at a mean of 70 mg)(2). Six patients demonstrated decreases in ventricular contractility, and four had decreases in cardiac output. Mean arterial blood pressure decreased in four patients. The authors commented:

The patients..were septic, hypovolemic, or cirrhotic, and had severe stress preoperatively. It is possible that in these ill patients adrenocortical and catechol stores had been depleted prior to ketamine administration. Alternatively, in the setting of prolonged preoperative stress, there may be resistance to further sympathetic and/or adrenocotical stimulation by ketamine. In either case, preoperative stress may blunt the usual physiologic responses to ketamine, setting the stage for possible adverse effects.

The negative cardiovascular effects of ketamine may also be precipitated by larger doses or repeated doses of ketamine(3).

While this small case series of cardiac arrest following ketamine administration is interesting, we should bear in mind the other possible precipitants of arrest in these patients, which are not all discussed by the authors:

i) Both patients were hypoxaemic prior to induction and their peri-intubation oxygen saturations are not reported. Arrests following bradycardia at the time of induction in the critically ill are frequently related to hypoxaemia.

ii) The second patient had a severe metabolic acidosis and the first – an abdominal sepsis patient with a labored respiratory rate of 30 – very probably did too. A failure to match a patient’s compensatory respiratory alkalosis with hyperventilation after anaesthesia is known to precipitate arrest in acidaemic patients.

iii) Finally, if the ketamine was responsible for the arrests, one should consider that the doses given to these shocked and highly unstable patients were well in excess of what many of us would recommend, and doses in the range of 0.5-1 mg/kg might not have been associated with adverse effects.

The takehome points for me are that this report is a helpful reminder that the cardiovascular stimulation-inhibition balance of ketamine may be altered by severe critical illness, and that doses of any induction agent should be significantly reduced in the critically ill patient. In no way does this convince me that I should discard ketamine as my preferred choice for RSI in such patients.

1. Cardiac Arrest Following Ketamine Administration for Rapid Sequence Intubation
J Intensive Care Med. 2012 May 29. [Epub ahead of print]

Given their relative hemodynamic stability, ketamine and etomidate are commonly chosen anesthetic agents for sedation during the endotracheal intubation of critically ill patients. As the use of etomidate has come into question particularly in patients with sepsis, due to its effect of adrenal suppression, there has been a shift in practice with more reliance on ketamine. However, as ketamine relies on a secondary sympathomimetic effect for its cardiovascular stability, cardiovascular and hemodynamic compromise may occur in patients who are catecholamine depleted. We present 2 critically ill patients who experienced cardiac arrest following the administration of ketamine for rapid sequence intubation (RSI). The literature regarding the use of etomidate and ketamine for RSI in critically ill patients is reviewed and options for sedation during endotracheal intubation in this population are discussed.

2. Cardiovascular effects of anesthetic induction with ketamine
Anesth Analg. 1980 May;59(5):355-8

Anesthetic induction with ketamine has been reported to maintain or improve cardiovascular performance in severely ill patients. Using invasive cardiovascular monitoring, we studied physiologic responses to a single dose of ketamine in 12 critically ill patients. Six patient demonstrated decreases in ventricular contractility, and four had decreases in cardiac output. Mean arterial blood pressure decreased in four patients. Pulmonary venous admixture increased in four of six patients, while oxygen consumption decreased in eight of 11 patients. Thus, a single dose of ketamine produced decreases in cardiac and pulmonary performance and in peripheral oxygen transport in this group of patients. It is proposed that in severely ill patients, preoperative stress may alter the usual physiologic responses to ketamine administration, and adverse effects may predominate. Ketamine, therefore, should be used with caution for induction of anesthesia in critically ill and in acutely traumatized patients until additional studies and further information on cardiovascular responses to ketamine are available.

3. A comparison of some cardiorespiratory effects of althesin and ketamine when used for induction of anaesthesia in patients with cardiac disease
Br J Anaesth. 1976 Nov;48(11):1071-81

Cardiorespiratory effects of ketamine and Althesin were measured in two groups of premedicated patients with cardiac disease. The drugs were given in clinically equivalent doses with a second dose administered about 10 min after induction. The first dose of ketamine caused a marked increase in systemic and pulmonary arterial pressure, heart rate, and central venous and wedge pressures and cardiac index. The first dose of Althesin caused a decrease in systemic arterial pressure, central venous pressure, cardiac index and heart work, but little change in heart rate. The second dose of induction agent was administered before the cardiorespiratory effects of the initial dose had resolved. The second dose of Althesin caused changes similar to those following the first dose, but less marked. The changes following the second dose of ketamine were opposite to those following the first dose.

Don’t bronchodilators work in infants?

Inpatient paediatric teams can be scornful when bronchodilators are given by ED staff to wheezing infants, correctly referring to the lack of evidence of clinical benefit(1). There is however a persisting meme out there I’ve heard on a number of occasions that ‘young infants don’t have the receptors so inhaled beta agonists will never work.’ I’d love to know where this comes from.

Apparently, beta 2-receptors are present from the 16th gestational week(2). Pulmonary function testing of ventilated, very-low-birth-weight babies has shown that some consistently responded to beta-agonists whereas others did not(3). A newly published study reports that a quarter of mechanically ventilated infants with bronchiolitis were responders to inhaled albuterol, defined as a reduction in respiratory system resistance more than 30% below baseline(4).

In summary: beta-agonist bronchodilators have not been shown to improve clinical outcomes in wheezing infants. However some infants with some wheezing disorders will show a response in terms of pulmonary function. The receptors are there, and in life-threatening presentations bronchodilators should certainly be considered.

1. Short acting beta agonists for recurrent wheeze in children under 2 years of age
Cochrane Database Syst Rev. 2002;(3):CD002873

BACKGROUND: Wheeze is a common symptom in infancy and is a common cause for both primary care consultations and hospital admission. Beta2-adrenoceptor agonists (b2-agonists) are the most frequently used as bronchodilator but their efficacy is questionable.
OBJECTIVES: To determine the effectiveness of b2-agonist for the treatment of infants with recurrent and persistent wheeze.
SEARCH STRATEGY: Relevant trials were identified using the Cochrane Airways Group database (CENTRAL), Medline and Pubmed. The database search used the following terms: Wheeze or asthma and Infant or Child and Short acting beta-agonist or Salbutamol (variants), Albuterol, Terbutaline (variants), Orciprenaline, Fenoterol

SELECTION CRITERIA: Randomised controlled trials comparing the effect of b2-agonist against placebo in children under 2 years of age who had had two or more previous episodes of wheeze, not related to another form of chronic lung disease.
DATA COLLECTION AND ANALYSIS: Eight studies met the criteria for inclusion in this meta-analysis. The studies investigated patients in three settings: at home (3 studies), in hospital (2 studies) and in the pulmonary function laboratory (3 studies). The main outcome measure was change in respiratory rate except for community based studies where symptom scores were used.

MAIN RESULTS: The studies were markedly heterogeneous and between study comparisons were limited. Improvement in respiratory rate, symptom score and oxygen saturation were noted in one study in the emergency department following two salbutamol nebulisers but this had no impact on hospital admission. There was a reduction in bronchial reactivity following salbutamol. There was no significant benefit from taking regular inhaled salbutamol on symptom scores recorded at home.

REVIEWER’S CONCLUSIONS: There is no clear benefit of using b2-agonists in the management of recurrent wheeze in the first two years of life although there is conflicting evidence. At present, further studies should only be performed if the patient group can be clearly defined and there is a suitable outcome parameter capable of measuring a response.

2. The beta-2-agonists in asthma in infants and young children
Arch Pediatr. 2002 Aug;9 Suppl 3:384s-389s

Beta 2-agonists, by inducing a fast and long relaxation of the bronchial smooth muscle, are considered as the more potent bronchodilators. beta 2-receptors are present from the 16th gestational week, explaining a possible bronchial response in the youngest children. beta 2-agonists do not induce any bronchodilator response in healthy children. Short-acting beta 2-agonists (salbutamol or albuterol, terbutaline) are indicated for asthma attacks, as needed in chronic asthma, and for prevention of symptoms during effort. They are safe and secure. The more efficient route of administration in preschool children is pressurized metered-dose inhaler used with a spacer device. Therefore, whatever the route of inhalation chosen (inhalation, injection, or continuous nebulization in acute asthma attack), more specified indications and doses are needed in young children. Long-acting beta 2-agonists (formoterol, salmeterol) are not authorized in France in children under 4 to 5 years of age depending on the drug used. Because of new oral formulations and recent considerations about their use in asthma attack, instead of short-acting beta 2-agonists, their indication in preschool asthmatic children might be reconsidered.

3. Use of a beta-agonist in ventilated, very-low-birth-weight babies: a longitudinal evaluation
Dev Pharmacol Ther. 1990;15(2):61-7

To determine if there is a specific postnatal (PNA) or postconceptional age (PCA) at which ventilated preterm infants respond to beta-agonists, we evaluated 15 infants with a mean gestational age of 26.5 +/- 1.5 weeks and mean birth weight of 0.89 +/- 0.23 kg who required mechanical ventilation at 10 days of age. Weekly pulmonary function testing (PFT) was performed before and 1 h after administration of albuterol. Taking the group as a whole, as well as individual babies, regression analysis showed no relationship between positive response and either PNA or PCA. Evaluation of individual infants, however, showed that some consistently responded to beta-agonists whereas others did not. We recommend individual PFT to identify those infants who will benefit from use of beta-agonists.

4. Pulmonary mechanics following albuterol therapy in mechanically ventilated infants with bronchiolitis
J Asthma. 2012 Sep;49(7):688-96

BACKGROUND AND AIMS: Bronchiolitis is a common cause of critical illness in infants. Inhaled β(2)-agonist bronchodilators are frequently used as part of treatment, despite unproven effectiveness. The purpose of this study was to describe the physiologic response to these medications in infants intubated and mechanically ventilated for bronchiolitis.

MATERIALS AND METHODS: We conducted a prospective trial of albuterol treatment in infants intubated and mechanically ventilated for bronchiolitis. Before and for 30 minutes following inhaled albuterol treatment, sequential assessments of pulmonary mechanics were determined using the interrupter technique on repeated consecutive breaths.

RESULTS: Fifty-four infants were enrolled. The median age was 44 days (25-75%; interquartile range (IQR) 29-74 days), mean hospital length of stay (LOS) was 18.3 ± 13.3 days, mean ICU LOS was 11.3 ± 6.4 days, and mean duration of mechanical ventilation was 8.5 ± 3.5 days. Fifty percent (n = 27) of the infants were male, 81% (n = 44) had public insurance, 80% (n = 41) were Caucasian, and 39% (n = 21) were Hispanic. Fourteen of the 54 (26%) had reduction in respiratory system resistance (Rrs) that was more than 30% below baseline, and were defined as responders to albuterol. Response to albuterol was not associated with demographic factors or hospitalization outcomes such as LOS or duration of mechanical ventilation. However, increased Rrs, prematurity, and non-Hispanic ethnicity were associated with increased LOS.

CONCLUSIONS: In this population of mechanically ventilated infants with bronchiolitis, relatively few had a reduction in pulmonary resistance in response to inhaled albuterol therapy. This response was not associated with improvements in outcomes.

Thrombolytic Therapy in Unstable Patients with PE

Most of us would give strong consideration to giving thrombolytics to patients with massive pulmonary embolism (PE), which is in keeping with many guidelines. Some physicians remain reluctant to do so, often citing the lack of good evidence. It is true that large scale RCTs have not been done in this population. The authors of this recent retrospective study state:

There are no definitive trials that prove the value of thrombolytic therapy in unstable patients with pulmonary embolism. It is extremely remote that a randomized controlled trial will be performed in the future. We therefore analyzed the database of the Nationwide Inpatient Sample to test the hypothesis that thrombolytic therapy reduces case fatality rate in unstable patients with acute pulmonary embolism.

They demonstrate a striking difference in mortality when thrombolysis is given to unstable patients with PE, which is further reduced with the addition of a vena cava filter. ‘Unstable’ was defined as having a listed code for shock or ventilator dependence.

Associated comorbid conditions were more often present in those who did not receive thrombolytic therapy than in those who did. However in their discussion the authors add:

Although unstable patients who received thrombolytic therapy had fewer comorbid conditions than those who did not, this would not explain the difference in case fatality rate because unstable patients with a primary diagnosis of pulmonary embolism and none of the comorbid conditions…also showed a lower case fatality rate with thrombolytic therapy. Therefore, differences in comorbid conditions in this group were eliminated as a possible cause of the lower case fatality rate in unstable patients who received thrombolytic therapy.

They round off their conclusion with:

Despite the marked reduction of case fatality rate with thrombolytic therapy in unstable patients, only 30% of unstable patients received it, and the proportion receiving thrombolytic therapy is diminishing. On the basis of these data, thrombolytic therapy in combination with a vena cava filter in unstable patients with acute pulmonary embolism seems indicated.

Many thanks to Dr Daniel Horner for highlighting this paper.

BACKGROUND: Data are sparse and inconsistent regarding whether thrombolytic therapy reduces case fatality rate in unstable patients with acute pulmonary embolism. We tested the hypothesis that thrombolytic therapy reduces case fatality rate in such patients.

METHODS: In-hospital all-cause case fatality rate according to treatment was determined in unstable patients with pulmonary embolism who were discharged from short-stay hospitals throughout the United States from 1999 to 2008 by using data from the Nationwide Inpatient Sample. Unstable patients were in shock or ventilator dependent.

RESULTS: Among unstable patients with pulmonary embolism, 21,390 of 72,230 (30%) received thrombolytic therapy. In-hospital all-cause case fatality rate in unstable patients with thrombolytic therapy was 3105 of 21,390 (15%) versus 23,820 of 50,840 (47%) without thrombolytic therapy (P< .0001). All-cause case fatality rate in unstable patients with thrombolytic therapy plus a vena cava filter was 505 of 6630 (7.6%) versus 4260 of 12,850 (33%) with a filter alone (P<.0001). Case fatality rate attributable to pulmonary embolism in unstable patients was 820 of 9810 (8.4%) with thrombolytic therapy versus 1080 of 2600 (42%) with no thrombolytic therapy (P<.0001). Case fatality rate attributable to pulmonary embolism in unstable patients with thrombolytic therapy plus vena cava filter was 70 of 2590 (2.7%) versus 160 of 600 (27%) with a filter alone (P<.0001).

CONCLUSION: In-hospital all-cause case fatality rate and case fatality rate attributable to pulmonary embolism in unstable patients was lower in those who received thrombolytic therapy. Thrombolytic therapy resulted in a lower case fatality rate than using vena cava filters alone, and the combination resulted in an even lower case fatality rate. Thrombolytic therapy in combination with a vena cava filter in unstable patients with acute pulmonary embolism seems indicated.

Thrombolytic Therapy in Unstable Patients with Acute Pulmonary Embolism: Saves Lives but Underused
Am J Med. 2012 May;125(5):465-70

Nitrate bolus in acute heart failure

Despite intravenous nitrate boluses being used in original studies demonstrating benefit in acute heart failure1,2, I regularly meet reluctance from both physicians and nurses in the emergency department to give them.

Their resistance seems to be based on a concern for inducing hypotension, and they prefer to ‘titrate up’ an infusion.

iv nitrate options include nitroglycerin (GTN), and isosorbide dinitrate (ISDN). Studies have used ISDN 4mg every 4 mins, ISDN 3mg every 5 mins, and GTN 2mg every 3 mins3.

There are a number of reasons to avoid starting with a low rate infusion in a sick heart failure patient.

Matthew Reed highlighted cannula size as an important factor4:

If a GTN infusion is commenced at a rate of 1 ml/h, a critically unwell patient with a large cannula—for example, a grey cannula (16G) — will have to wait over 6 min for the drug to enter the body. This compares with 1.5 min for a pink cannula (20G) at the same infusion rate. If a large-diameter cannula is chosen for these patients, then a fast initial infusion rate should also be chosen to ensure that the GTN begins to act quickly.

Alistair Steel subsequently pointed out further reasons to avoid slow infusions5:

(1) mechanical slack within an infusion device may mean an infusion set at 1 ml/h will take many minutes for the driver to contact and advance the syringe plunger. For this reason, infusions should be purged before patient connection.

(2) the pharmacokinetics of the drug should be considered. At low infusion rates it will take significant time for a steady state to be achieved (a drug such as GTN, with a half-life of 2 min, would require 10 min to achieve steady state). For clinical effects to be seen quickly, a bolus should be given before commencing infusions.

(3) the use of 1 ml/h infusions (8 µg/min using a 0.5% solution) may be excessively cautious – the British National Formulary recommends a therapeutic dose range from 10 to 200 µg/min. Furthermore, there is emerging evidence that, when used for decompensated heart failure, higher doses of GTN are associated with more favourable outcomes.

(4) at low infusion rates any obstruction in the intravenous system will take a proportionally longer time to become apparent, as it will take longer for the pressure to build up and trigger the syringe pump’s high pressure alarm.

Now a recent study confirms such a regimen can be used safely in the elderly. ISDN 3mg bolus treatment was not associated with higher rates of hypotension in the elderly population treated for heart failure in the emergency department. Despite a small study and a retrospective design, this lends support to the practice of iv bolus nitrate therapy for acute heart failure, even in the elderly.

1. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema
Lancet. 1998 Feb 7;351(9100):389-93

2. High-doses intravenous isosorbide dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema
J Am Coll Cardiol. 2000 Sep;36(3):832-7 Free Full Text

3. Managing acute pulmonary oedema with high or standard dose nitrate
Emerg Med J. 2009 May;26(5):357-8

4. Administering a glyceryl trinitrate infusion: big is not always best
Emerg Med J 2007;24:423-424

5. Administering a glyceryl trinitrate infusion: faster is better than slower
Emerg Med J. 2008 Jan;25(1):60

6. Isosorbide dinitrate bolus for heart failure in elderly emergency patients: a retrospective study
Eur J Emerg Med. 2011 Oct;18(5):272-5

Ventilated patients better able to communicate pain with dexmedetomidine

A multicentre European trial on intensive care units showed dexmedetomidine was non-inferior to midazolam or propofol in achieving target sedation levels, but patients were better able to communicate pain compared with midazolam and propofol. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam, but not compared with propofol.

Context Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α2-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.

Objective To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients’ interaction with nursing care.

Design, Setting, and Patients Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251).

Interventions Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials.

Main Outcome Measures For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients’ ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223).

Results Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients’ interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001).

Conclusions Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients’ ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine.

Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials
JAMA. 2012 Mar 21;307(11):1151-60

Prehospital IM midazolam for seizures

Intramuscular midazolam is at least as safe and effective as intravenous lorazepam for the prehospital management of status epilepticus. In his blog EM Literature of Note, Dr Ryan Radecki looks forward to a similar trial comparing nasal midazolam, which would reduce the risk from injections. Read his full critique here. Buccal midazolam 0.5 mg/kg is of course also an option, as described in the Advanced Paediatric Life Support manual:

If using the buccal route, draw up the higher dose (0.5mg) of the IV preparation using a needle (to avoid any fragments of glass from the ampoule) and after removing the needle, inject the drug into the buccal area between the lower bottom lip and the gum margin at the side of the mouth. Buccal midazolam is twice as effective as rectal diazepam, but both drugs produce the same level and degree of respiratory depression.

BACKGROUND: Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route.

METHODS: This double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults in status epilepticus treated by paramedics. Subjects whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived were given the study medication by either intramuscular autoinjector or intravenous infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that intramuscular midazolam was noninferior to intravenous lorazepam by a margin of 10 percentage points.

RESULTS: At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscular-midazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups.

CONCLUSIONS: For subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, ClinicalTrials.gov NCT00809146.).

Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus
N Engl J Med. 2012 Feb 16;366(7):591-600

Enoxaparin beats heparin for PCI

This is of interest to those of us in retrieval medicine, for logistic reasons: an infusion of heparin can be an unnecessary hassle during transport, especially if a subcutaneous injection prior to retrieval is a satisfactory alternative. This systematic review and meta-analysis shows enoxaparin appears to be superior to unfractionated heparin in reducing mortality and bleeding outcomes during percutaneous coronary intervention. This applies particularly to patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction

OBJECTIVE: To determine the efficacy and safety of enoxaparin compared with unfractionated heparin during percutaneous coronary intervention.

DESIGN: Systematic review and meta-analysis.

DATA SOURCES: Medline and Cochrane database of systematic reviews, January 1996 to May 2011.

STUDY SELECTION: Randomised and non-randomised studies comparing enoxaparin with unfractionated heparin during percutaneous coronary intervention and reporting on both mortality (efficacy end point) and major bleeding (safety end point) outcomes.

DATA EXTRACTION: Sample size, characteristics, and outcomes, extracted independently and analysed.

DATA SYNTHESIS: 23 trials representing 30 966 patients were identified, including 10 243 patients (33.1%) undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction, 8750 (28.2%) undergoing secondary percutaneous coronary intervention after fibrinolysis, and 11 973 (38.7%) with non-ST elevation acute coronary syndrome or stable patients scheduled for percutaneous coronary intervention. A total of 13 943 patients (45.0%) received enoxaparin and 17 023 (55.0%) unfractionated heparin. Enoxaparin was associated with significant reductions in death (relative risk 0.66, 95% confidence interval 0.57 to 0.76; P<0.001), the composite of death or myocardial infarction (0.68, 0.57 to 0.81; P<0.001), and complications of myocardial infarction (0.75, 0.6 to 0.85; P<0.001), and a reduction in incidence of major bleeding (0.80, 0.68 to 0.95; P=0.009). In patients who underwent primary percutaneous coronary intervention, the reduction in death (0.52, 0.42 to 0.64; P<0.001) was particularly significant and associated with a reduction in major bleeding (0.72, 0.56 to 0.93; P=0.01).

CONCLUSION: Enoxaparin seems to be superior to unfractionated heparin in reducing mortality and bleeding outcomes during percutaneous coronary intervention and particularly in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction.

Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis

BMJ. 2012 Feb 3;344:e553