High-dose antithrombin III in severe sepsis. A randomized controlled trial ▸

Background:

The authors set out to determine if high dose antithrombin III (administered within six hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.

Methods:

The KyberSept Trial was conducted from March 1997 to January 2000. It was a double blind placebo controlled, multicentre (211 contributing centres in 19 countries) phase three clinical trial. There was a total of 2314 adult patients randomised into two equal groups to receive 30 000 IU of intravenous antithrombin III over four days or a placebo of 1% human albumin. The main outcome measure was all cause mortality at 28 days after start of study medication. Secondary efficacy criteria were survival time, length of intensive care stay, and occurrence of new organ dysfunction within seven days.

Results:

Overall mortality at 28 days in the antithrombin III treatment group was 38.9% compared with 38.7% in the placebo group (p=0.94). Secondary end points did not differ between the groups. In the subgroup of patients who did not receive concomitant heparin during the four day treatment phase (n=698), the 28 day mortality was non-significantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (p=0.8). Interestingly, this trend became significant after 90 days (n=686; 44.9% for antithrombin III group compared with 52.5% for placebo group; p=0.03). Bleeding incidence was significantly increased in the patients who received high dose antithrombin III and concomitant heparin (23.8% for antithrombin III compared with 13.5% for placebo group; p<0.001).

Conclusion:

The results of this study indicate that high dose administration of antithrombin III in combination with heparin to severely septic patients offers no mortality advantage over standard care.

Comment:

This large multicentre clinical trial disappointingly failed to show a survival advantage in severely septic patients treated with high dose antithrombin III in combination with, over standard care for sepsis. It has noted a trend to increased survival in those not receiving concomitant heparin, and this may be worthy of further research. Interestingly antithrombin III levels at baseline, although strongly predictive for 28 day mortality, did not interfere with the main treatment effect of antithrombin III compared with placebo. As the authors acknowledge, the levels of antithrombin III achieved during the study were less than that which they had hypothesised would be necessary to achieve maximum benefits in the severely septic population (mean of 180% of normal antithrombin physiological concentrations achieved compared with mean of 200% to 250% desired). This may mean that with higher concentrations of antithrombin III, the results may have been different.

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The Canadian c-spine rule for radiography in alert and stable trauma patients ▸

Background:

The authors aimed to derive a clinical decision rule that is highly sensitive for detecting acute cervical spine injury and will allow emergency physicians to be more selective in their use of radiography in alert and stable trauma patients.

Method:

This was a prospective cohort study conducted from October 1996 to April 1999 in which a convenience sample of 8924 adult patients with stable vital signs and a Glasgow Coma Score of 15/15 and a history of blunt trauma to the head and neck were evaluated for 20 standardised clinical findings before radiography. The main outcome measure was clinically important cervical spine injury, evaluated by plain radiography, computed tomography, and a structured follow up telephone interview. The clinical decision rule was derived using κ coefficient, logistic regression analysis, and χ² recursive partitioning techniques.

Results:

A total of 151 (1.7%) of the study sample had important cervical spine injury defined as any fracture, dislocation, or ligamentous instability demonstrated by diagnostic imaging. The resultant model and final Canadian cervical spine rule comprises three main questions. Firstly, is there any high risk factor present that mandates radiography (that is, age >65 years, a dangerous mechanism, or paraesthesiae in extremities)? Secondly, is there any low risk factor present that permits safe assessment of range of motion (that is, simple rear end motor vehicle collision, sitting position in the emergency department, ambulatory at any time since injury, delayed onset of neck pain, or absence of midline cervical spine tenderness)? Thirdly, is the patient able to actively rotate the neck 45 degrees to left and right? The Canadian cervical spine rule by cross validation had 100% sensitivity (95% confidence intervals (CI), 98% to 100%) and 42.5% specificity (95% CI 40% to 44%) for identifying 151 clinically important cervical spine injuries. The potential radiography ordering rate would be 58.2%.

Conclusion:

If the derived Canadian cervical spine rule is prospectively validated in other cohorts, it will have the potential to significantly reduce practice variation and inefficiency in the use of cervical spine radiography.

Comment:

This Canadian group of researchers show no sign of losing interest in the development of clinical decision rules! This study may represent a significant advance in the routine investigation of cervical spine trauma. It is eight times bigger than the previous largest derivation study conducted with regard to potential cervical spine injury. Limitations of the study included the fact that there were 3281 eligible patients who were not enrolled. Apparently, their characteristics were similar to the enrolled patients, but interestingly they had a higher incidence of cervical spine injury (3.2% v 2.0%).

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Antipyretic efficacy of an initial 30-mg/kg loading dose of acetaminophen versus a 15-mg/kg maintenance dose ▸

Background:

In the knowledge that the antipyretic efficacy is dose dependent, and that there are theoretical benefits in reducing high temperatures in sick children, the authors determined to examine the antipyretic effects of two doses of acetaminophen (paracetamol).

Method:

They compared an initial dose of 30 mg/kg acetaminophen (loading dose) compared with a “standard” 15 mg/kg (maintenance) dose. The study was a double blind, parallel group, randomised clinical trial. Altogether 121 children ranging in age from 4 months to 9 years (weighing 4 kg to 26 kg) and with a rectal temperature between 39°C and 40.5°C were assigned to one of the dose groups. Children were excluded from the study if they had already taken temperature altering drugs or antibiotics or were likely to require antibiotics during the first four hours after being enrolled. Other exclusion criteria were the presence of hepatic, renal or neurological disease or previous febrile convulsions. Vomiting and hypersensitivity to acetaminophen were also exclusion criteria.

Results:

In an “intention to treat analysis”, the children in the 30 mg/kg group had a significantly quicker reduction in temperature to below 38.5°C (110 +/− 94 minutes v 139 +/− 113 minutes). The loading dose group also had a significantly higher maximum temperature decrease (2.3 +/− 0.7°C v 1.7 +/− 0.6°C). The temperature in the group receiving 30 mg/kg loading dose stayed below 38.5°C significantly longer than the group receiving 15 mg/kg (250 +/− 92 minutes v 185 +/− 121 minutes, respectively). There was no statistically significant difference in adverse events (hyperthermia, hypothermia, vomiting) reporting between the two groups.

Conclusions:

This study suggests that an initial loading dose (30 mg/kg) of acetaminophen in children with fever may be more efficient than giving a maintenance dose (15 mg/kg) initially.

Comment:

This study confirms what one would think intuitively, namely that a larger dose of acetaminophen would bring down temperature more quickly and for longer than a smaller dose. The authors postulate that this more effective use of acetaminophen could help decrease the “irrational, untested use of combined, alternating antipyretic drug administration (ibuprofen or aspirin with acetaminophen).” They do not explain why they regard combination therapy as irrational, except that, of course, there are very few practising emergency physicians who would use aspirin in this age group for its antipyretic properties.

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Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial ▸

This prospective randomised, multicentre, double blind, aspirin controlled trial tested the safety and efficacy of treatment with high dose tinzaparin (487 patients), medium dose tinzaparin (508 patients), or aspirin (491 patients) started within 48 hours of acute ischaemic stroke and given for up to 10 days. Outcomes assessed at the end of treatment included neurological deterioration, having a recurrent stroke, symptomatic deep venous thrombosis, or pulmonary embolus and death. There were no differences in the frequency of recurrent stroke or neurological deterioration between the three groups. Tinzaparin was associated with a lower frequency of deep vein thrombosis than was aspirin, an effect that was significant in the high dose group. However, the rate of symptomatic intracranial haemorrhage was significantly higher among patients assigned high dose tinzaparin than in those assigned aspirin, and was more common in those treated within 24 hours of stroke onset. This large multicentre study involving 10 European countries and Canada is the largest study into the use of low molecular weight heparin in acute stroke to date. The findings are applicable to emergency medicine. Despite some study limitations, such as possibly over liberal inclusion criteria, variation in time of starting treatment and possibly inappropriate dosage regimens, the study has failed to show any improvement in the proportion of acute stroke patients achieving independence with either medium or high dose tinzaparin as compared with aspirin.

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Does the presence of ultrasound really affect computed tomographic scan use? A prospective randomized trial of ultrasound in trauma ▸

The ability to perform abdominal ultrasound examination is highly regarded by a small but growing proportion of emergency physicians. This prospective study was aimed at increasing the evidence base of the effect of the performance of abdominal ultrasound in emergency departments on the management of patients who had sustained blunt trauma. The authors aimed to ascertain whether or not the availability of ultrasound would affect clinical decision making as evidenced through abdominal computed tomographic (CT) use in blunt multiple trauma patients. Altogether 215 patients aged between 18 and 75 years who presented to the emergency department with blunt trauma while a physician who was “ultrasound-credentialed” was on duty were randomised either to receive or not to receive abdominal ultrasound. The primary outcome variable was abdominal CT scan use between the ultrasound and control group. Of the 104 patients in the ultrasound group, 37 (36%) had an abdominal CT scan obtained versus 54 (52%) of 104 in the control group, giving a mean difference in proportions of 15.9% (p<0.02). In the ultrasound group there were 12 true positive examinations, 88 true negative examinations, three false negative examinations, and one false positive examination. This gave a sensitivity of 80% and a specificity of 98%, and a positive predictive value of 92% and a negative predictive value of 96%. The authors concluded that routine use of abdominal ultrasound in blunt trauma reduced the use of abdominal CT. The results may have been biased because of the non-consecutive enrolment of patients, although it is hard to see how the authors could have avoided this. Given that the primary outcome was the use of abdominal CT, the failure of the authors to determine the reasons the surgeons decided to obtain CT could be viewed as a major oversight.

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A randomized comparison of helium-oxygen mixture (Heliox) and racemic epinephrine for treatment of moderate to severe croup ▸

It is always encouraging to find medical research based upon the application of the laws of physics into clinical practice. The authors of this paper set out to investigate the possible extension of the clinical use of helium, a gas with very low viscosity. They aimed to compare the additive effects of a helium-oxygen mixture (Heliox) or racemic epinephrine on modified Taussig croup scores in children with moderate to severe croup treated with humidified oxygen and 0.6 mg/kg of intramuscular dexamethasone. Thirty three patients were enrolled, with 29 undergoing final analysis, in this prospective, randomised, double blind study conducted in an urban level 1 trauma centre. The children ranged in age from 6 months to 3 years. The inclusion criteria were moderate to severe croup, which included hoarseness, barking cough, and stridor with a history of a recent upper respiratory tract infection and a specified croup score. Patients were excluded if the symptoms or signs were consistent with another cause of stridor. The patients were computer randomised to racemic epinephrine or a blend of 70% helium: 30% oxygen mixture via mask or tent house at a flow rate of 10 to 12 l/min. The principal outcome measure was the change in croup score. The overall results using repeat measures analysis of variance revealed no significant differences in croup score at the end of the observation period (p=0.13). This is the first report of a double blind, randomised study comparing the effects of racemic epinephrine and Heliox in children with acute viral croup. The practical difficulties in undertaking this type of research should not be underestimated, but because of the relatively small numbers of participants, the study was not powered to detect small differences between groups. Also, the choice of change in croup scores as the principal outcome measure means that the results of the study could have been influenced by observer bias.

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Acute rupture of tendo Achillis. A prospective randomised study of comparison between surgical and non-surgical treatment ▸

Debate continues as to how Achilles tendon ruptures should be treated. This prospective, multicentre study randomised 112 patients (ranging in age from 16 to 65 years) to either surgical repair (59 patients) or conservative management (53 patients). The characteristics of the patients were similar in both groups (p>0.05). The period of follow up was two years. Re-rupture after non-surgical treatment occurred in 11 patients (20.8%) compared with just one patient (1.7%) after operation (p=0.0013). The time before return to work in the surgical group was 54.9 days (range 0 to 197) compared with 73.4 days (range 0 to 250) in the conservative group. Patient satisfaction was higher in the surgically treated group. Patients in the surgically treated group recovered 87% of their strength at one year, compared with 90% in the non-surgical group. The authors argue that given the high re-rupture rate, conservative management is not acceptable management in active people aged less than 65 years. This well conducted and detailed study from Sweden is a useful addition to the literature, but is unlikely to be the final word on this controversial subject.

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Fetal deaths related to maternal injury ▸

This three year retrospective descriptive study of fetal death certificates in 16 US states sets out to determine the reported rate of traumatic fetal deaths and the types of trauma responsible. A total of 240 traumatic fetal injury deaths attributable to maternal injury at 20 weeks gestation or later were identified (3.7 deaths per 100 000 live births). Surprisingly perhaps, given the increasing publicity given to firearm injuries in the US, the leading mechanism was road traffic collisions (82% of cases), with firearm injuries only accounting for 6% (and falls for 3%). It was notable that in three states, road traffic collision related fetal death rates exceeded road traffic related infant death rates. A peak rate of 9.3 fetal deaths per 100 000 live births was observed among younger women (15–19 year olds). Interestingly, the authors noted that “most mothers survive the trauma that kills the fetus”. Their findings do not enable significant conclusions to be drawn regarding how these fetal deaths may be prevented, highlighting the need for further research.

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Prognostic value of a normal or nonspecific initial electrocardiogram in acute myocardial infarction ▸

This six year observational study aimed to compare the inhospital mortality among patients with acute myocardial infarction (AMI) who have normal or non-specific electrocardiograms (ECGs) with that of patients who have diagnostic ECGs. A massive 391 208 patients with AMI were studied. A logistic regression model was constructed using a propensity score for ECG findings and data on demographics, medical history, diagnostic procedures, and treatment to determine the independent prognostic value of a normal or non-specific initial ECG. In the normal, non-specific, and diagnostic ECG groups, the inhospital mortality rates were 5.7%, 8.7%, and 11.5% respectively. This large well conducted multicentre study confirms that patients with a diagnostic ECG had higher rates of mortality and serious complications in hospital. However, there was also a substantial mortality rate in those with initially normal ECGs. Patients with AMI who present with a normal ECG were less often treated with aspirin, heparin, and β blockers. This study is further evidence of the important role of biomarkers of myocardial necrosis in diagnosing AMI.

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Comparative analysis of multiple-casualty incident triage algorithms ▸

This paper attempts to discover the best triage system for a major incident by retrospectively relating triage prioritisation of 1144 consecutive trauma victims to a resource based definition of severe injury. The authors readily acknowledge that the form of triage system that performed best for them may not do so prospectively in an actual major incident. They point out that the study population was all adults and that their findings would not necessarily apply to an incident involving children. They also acknowledge that the performance of triage algorithms may vary with injury mechanism. Their findings that the motor component of the Glasgow Coma Scale and systolic blood pressure are the variables most predictive of injury severity are hardly surprising and are consistent with the large quantities of published data.

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Genital injury: is it significant? A review of the literature ▸

Although more strictly the domain of forensic medical examiners (police surgeons), emergency physicians will occasionally find themselves having to provide an opinion regarding the nature and causation of genital injuries. This review can be recommended as a useful overview of a difficult area, in which much work remains to be done.

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