Therapeutic hypothermia following out-of-hospital cardiac arrest

Another study questioning therapeutic hypothermia has been published following the recent publication of two research studies which resulting in several organisations, including the European Resuscitation Council and ILCOR to issue statements on targeted temperature management.

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

Comparative Effectiveness of Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest: Insight from a Large Data Registry

Therapeutic Hypothermia and Temperature Management. Online Ahead of Print: December 28, 2013

This study was undertaken by the authors to determine the effectiveness of therapeutic hypothermia (TH) after out-of-hospital cardiac arrest (OHCA) among a large cohort of adults in the Cardiac Arrest Registry to Enhance Survival (CARES), with an emphasis on subgroups with a non-shockable first documented rhythm.

All adult index events at participating sites from November 2010 to December 2013 were study eligible. All patient data elements were provided with summary statistics calculated for all patients with and without TH. For multivariate adjustment, a multilevel (i.e., hierarchical), mixed-effects logistic regression (MLR) model was used with hospitals treated as random effects. Propensity score matching (PSM) on both shockable and non-shockable patients was done as a sensitivity analysis. After predefined exclusions, our final sample size was 6369 records for analysis: shockable=2992 (47.0%); asystole=1657 (26.0%); pulseless electrical activity=1249 (19.6%); other unspecified non-shockable=471 (7.4%). Unadjusted differences in neurological status at hospital discharge with and without TH were similar (p=0.295).

After multivariate adjustment, TH had either no association with good neurological status at hospital discharge or that TH was actually associated with worse neurological outcome, particularly in patients with a non-shockable first documented rhythm (i.e., for NS patients, MLR odds ratio for TH=1.444; 95% CI [1.039, 2.006] p=0.029, and OR=1.017, p=0.927 via PSM).

Highlighting the limitations, the authors concluded that when TH is indiscriminately provided to a large population of OHCA survivors with a non-shockable first documented rhythm, evidence for its effectiveness is diminished. The authors suggest more uniform and rigid guidelines for the application of TH.

http://online.liebertpub.com/doi/abs/10.1089/ther.2013.0018

This was published only a month after the European Resuscitation Council issued a statement (https://www.erc.edu/index.php/docLibrary/en/viewDoc/2083/3/) on target temperature management following two studies into the treatment of patients with ROSC after out-of-hospital cardiac arrest (OHCA) arise from these studies, questioning whether:

1. Should ice-cold intravenous fluid continue to be used for inducing hypothermia prehospital?
2. Should the target temperature be 32-34 °C or 36 °C for the management of comatose cardiac arrest survivors with ROSC?

Shortly after the European Resuscitation Council (ERC) released the statement, International Liaison Committee on Resuscitation (ILCOR)  published an advisory statement to guide clinicians on the use of temperature management in post cardiac arrest patients (http://www.ilcor.org/data/TTM-ILCOR-update-Dec-2013.pdf)

According to ILCOR: “A key message from this study is that targeted temperature management (TTM) remains an important component of the post resuscitation care of the unconscious cardiac arrest patient and that similar results were obtained when either 33ºC or 36ºC were selected as target temperature.”

With regard to choosing that temperature to cool your patients, the following advice was issued: ” Pending formal consensus on the optimal temperature, we suggest that clinicians provide post-resuscitation care based on the current treatment recommendations” and “We accept that some clinicians may make a local decision to use a target temperature of 36°C pending this further guidance”. Further formal discussions are being undertaken by ILCOR regarding future decisions on targeted temperature management.

Below are details on the original two studies which sparked the release of the advisory statements:

Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest found no difference in survival when lowering cardiac arrest patients’ temperature to 33 °C vs. 36 °C. [N Engl J Med 2013; 369:2197-2206 December 5, 2013]

Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. The authors objective was to compare two target temperatures, both intended to prevent fever.

METHODS
In an international trial, the authors randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale.

RESULTS
In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar.

CONCLUSIONS
In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C.

http://www.nejm.org/doi/full/10.1056/NEJMoa1310519

Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest: A Randomized Clinical Trial was the second study which resulted in the statement. (JAMA. 2014;311(1):45-52.)

Objective To determine whether prehospital cooling improves outcomes after resuscitation from cardiac arrest in patients with ventricular fibrillation (VF) and without VF.

Design, Setting, and Participants A randomised clinical trial that assigned adults with prehospital cardiac arrest to standard care with or without prehospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation. Adults in King County, Washington, with prehospital cardiac arrest and resuscitated by paramedics were eligible and 1359 patients (583 with VF and 776 without VF) were randomized between December 15, 2007, and December 7, 2012. Patient follow-up was completed by May 1, 2013. Nearly all of the patients resuscitated from VF and admitted to the hospital received hospital cooling regardless of their randomisation.

Main Outcomes and Measures The primary outcomes were survival to hospital discharge and neurological status at discharge.

Results The intervention decreased mean core temperature by 1.20°C  in patients with VF and by 1.30°C  in patients without VF by hospital arrival and reduced the time to achieve a temperature of less than 34°C by about 1 hour compared with the control group. However, survival to hospital discharge was similar among the intervention and control groups among patients with VF (62.7% vs 64.3%) and among patients without VF (19.2% vs 16.3%). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for either patients with VF (57.5% of cases had full recovery or mild impairment vs 61.9% or those without VF (14.4% of cases vs 13.4% of controls). Overall, the intervention group experienced rearrest in the field more than the control group (26%  vs 21% ), as well as increased diuretic use and pulmonary oedema on first chest x-ray, which resolved within 24 hours after admission.

Conclusion and Relevance Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF.

http://jama.jamanetwork.com/article.aspx?articleid=1778673&resultClick=3

The association between systolic blood pressure on arrival at hospital and outcome in adults surviving from out-of-hospital cardiac arrests of presumed cardiac aetiology

The association between systolic blood pressure on arrival at hospital and outcome in adults surviving from out-of-hospital cardiac arrests of presumed cardiac aetiology

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

Resuscitation. Available online 12 December 2013

The optimal blood pressure target following successful resuscitation from out-of-hospital cardiac arrest (OHCA) is uncertain. This study aimed to explore the association between level of systolic blood pressure (SBP) on arrival at hospital and survival to hospital discharge.

Methods
The authors analysed eligible OHCAs occurring between January 2003 and December 2011 from the Victorian Ambulance Cardiac Arrest Register (VACAR). Inclusion criteria were: adults (≥18 years), presumed cardiac aetiology, not paramedic witnessed, and ROSC at hospital arrival. Multivariate logistic regression models were performed by initial rhythm (shockable/non-shockable) to examine the relationship between SBP at hospital arrival in 10 mmHg increments and survival to hospital discharge. Models were adjusted for known predictors of survival, including duration of arrest.

Results
Of 3620 eligible cases, 14% were hypotensive (SBP < 90 mmHg) on hospital arrival (10% shockable and 19% non-shockable). For patients in shockable rhythms, discharge survival was maximal at 120–129 mmHg (54%), and in the adjusted model (≥120 mmHg as reference) SBP decrements below 90 mmHg were associated with lower survival: 80–89 mmHg AOR = 0.49 (95% CI: 0.24–0.95); <79 mmHg AOR = 0.24 (95% CI: 0.10–0.61); unrecordable AOR = 0.10 (95% CI: 0.04–0.30). In patients found in non-shockable rhythms, SBP was not significant associated with discharge survival (AOR = 1.01, 95% CI: 0.89–1.15).

Conclusions
In an EMS system using intravenous adrenaline and fluids to maintain post-resuscitation SBP at 120 mmHg, hypotension on hospital arrival was relatively uncommon. However, in presumed cardiac OHCA patients with an initial shockable rhythm, SBPs below 90 mmHg was associated with significant lower odds of survival to hospital discharge. This level of hypotension may indicate patients who require more aggressive post-resuscitation blood pressure management.

http://www.sciencedirect.com/science/article/pii/S0300957213008976

Dextrose gel for neonatal hypoglycaemia

Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a randomised, double-blind, placebo-controlled trial

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

The Lancet, Volume 382, Issue 9910, Pages 2077 – 2083, 21 December 2013
Neonatal hypoglycaemia is common, and a preventable cause of brain damage. Dextrose gel is used to reverse hypoglycaemia in individuals with diabetes; however, little evidence exists for its use in babies. The authors aimed to assess whether treatment with dextrose gel was more effective than feeding alone for reversal of neonatal hypoglycaemia in at-risk babies.

Methods

The authors undertook a randomised, double-blind, placebo-controlled trial at a tertiary centre in New Zealand between Dec 1, 2008, and Nov 31, 2010. Babies aged 35—42 weeks’ gestation, younger than 48-h-old, and at risk of hypoglycaemia were randomly assigned (1:1), via computer-generated blocked randomisation, to 40% dextrose gel 200 mg/kg or placebo gel. Randomisation was stratified by maternal diabetes and birthweight. Group allocation was concealed from clinicians, families, and all study investigators. The primary outcome was treatment failure, defined as a blood glucose concentration of less than 2·6 mmol/L after two treatment attempts. Analysis was by intention to treat.

Findings

Of 514 enrolled babies, 242 (47%) became hypoglycaemic and were randomised. Five babies were randomised in error, leaving 237 for analysis: 118 (50%) in the dextrose group and 119 (50%) in the placebo group. Dextrose gel reduced the frequency of treatment failure compared with placebo (16 [14%] vs 29 [24%]; relative risk 0·57, 95% CI 0·33—0·98; p=0·04). We noted no serious adverse events. Three (3%) babies in the placebo group each had one blood glucose concentration of 0·9 mmol/L. No other adverse events took place.

Interpretation

Treatment with dextrose gel is inexpensive and simple to administer. Dextrose gel should be considered for first-line treatment to manage hypoglycaemia in late preterm and term babies in the first 48 h after birth.

Cognitive appraisals, objectivity and coping in ambulance workers: a pilot study

Cognitive appraisals, objectivity and coping in ambulance workers: a pilot study

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

Emerg Med J 2014;31:41-44

Ambulance workers are regularly exposed to call-outs, which are potentially psychologically traumatic. The ability to remain objective and make adaptive appraisals during call-outs may be beneficial to this at-risk population. This pilot study investigated the links between cognitive appraisals, objectivity and coping in ambulance workers.

Methods Forty-five ambulance workers from the London Ambulance Service, UK, were studied. Trauma exposure, post-traumatic stress disorder and depression symptoms were assessed using self-report measures. Positive and negative appraisals were measured in relation to two previous call-outs: one during which they coped well and one during which they did not.

Results Enhanced coping was associated with making more positive appraisals during the call-out. Better coping was also related to greater levels of objectivity during these call-outs. Coping less well was associated with the use of more negative appraisals during the call-out.

Conclusions Ambulance workers may benefit from psychological interventions, which focus on cognitive reappraisal and enhancing objectivity to improve coping and resilience.

http://emj.bmj.com/content/31/1/41.full.pdf+html (full text article)

Comparison of Bag-Valve-Mask Hand-Sealing Techniques in a Simulated Model

Comparison of Bag-Valve-Mask Hand-Sealing Techniques in a Simulated Model

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

Annals of Emergency Medicine. Volume 63, Issue 1 , Pages 6-12.e3, January 2014

Bag-valve-mask ventilation remains an essential component of airway management. Rescuers continue to use both traditional 1- or 2-handed mask-face sealing techniques, as well as a newer modified 2-handed technique. We compare the efficacy of 1-handed, 2-handed, and modified 2-handed bag-valve-mask technique.

Methods
In this prospective, crossover study, health care providers performed 1-handed, 2-handed, and modified 2-handed bag-valve-mask ventilation on a standardized ventilation model. Subjects performed each technique for 5 minutes, with 3 minutes’ rest between techniques. The primary outcome was expired tidal volume, defined as percentage of total possible expired tidal volume during a 5-minute bout. A specialised inline monitor measured expired tidal volume. The authors compared 2-handed versus modified 2-handed and 2-handed versus 1-handed techniques.

Results
The authors enrolled 52 subjects: 28 (54%) men, 32 (62%) with greater than or equal to 5 actual emergency bag-valve-mask situations. Median expired tidal volume percentage for 1-handed technique was 31%; for 2-handed technique, 85%; and for modified 2-handed technique, 85%. Both 2-handed and modified 2-handed technique resulted in significantly higher median expired tidal volume percentages compared with 1-handed technique. The median expired tidal volume percentages between 2-handed and modified 2-handed techniques did not significantly differ from each other.

Conclusion
In a simulated model, both 2-handed mask-face sealing techniques resulted in higher ventilatory tidal volumes than 1-handed technique. Tidal volumes from 2-handed and modified 2-handed techniques did not differ. Rescuers should perform bag-valve-mask ventilation with 2-handed techniques.

http://www.annemergmed.com/article/S0196-0644(13)00693-8/abstract?elsca1=etoc&elsca2=email&elsca3=0196-0644_201401_63_1&elsca4=emergency_medicine

Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI

Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI

Resuscitation. Volume 85, Issue 1, January 2014, Pages 88–95

To determine if early cardiac catheterisation (CC) is associated with improved survival in comatose patients who are resuscitated after cardiac arrest when electrocardiographic evidence of ST-elevation myocardial infarction (STEMI) is absent.

Methods
The authors conducted a retrospective observational study of a prospective cohort of 754 consecutive comatose patients treated with therapeutic hypothermia (TH) following cardiac arrest.

Results
A total of 269 (35.7%) patients had cardiac arrest due to a ventricular arrhythmia without STEMI and were treated with TH. Of these, 122 (45.4%) received CC while comatose (early CC). Acute coronary occlusion was discovered in 26.6% of patients treated with early CC compared to 29.3% of patients treated with late CC (p = 0.381). Patients treated with early CC were more likely to survive to hospital discharge compared to those not treated with CC (65.6% vs. 48.6%; p = 0.017). In a multivariate regression model that included study site, age, bystander CPR, shock on admission, comorbid medical conditions, witnessed arrest, and time to return of spontaneous circulation, early CC was independently associated with a significant reduction in the risk of death (OR 0.35, 95% CI 0.18–0.70, p = 0.003).

Conclusions
In comatose survivors of cardiac arrest without STEMI who are treated with TH, early CC is associated with significantly decreased mortality. The incidence of acute coronary occlusion is high, even when STEMI is not present on the postresuscitation electrocardiogram.

http://www.sciencedirect.com/science/article/pii/S0300957213003961

Survival of resuscitated cardiac arrest patients with STEMI conveyed directly to a Heart Attack Centre

Survival of resuscitated cardiac arrest patients with ST-elevation myocardial infarction (STEMI) conveyed directly to a Heart Attack Centre by ambulance clinicians

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

Resuscitation. Available online 19 September 2013

This study reports survival outcomes for patients resuscitated from out-of-hospital cardiac arrest (OHCA) subsequent to ST-elevation myocardial infarction (STEMI), and who were conveyed directly by ambulance clinicians to a specialist Heart Attack Centre for expert cardiology assessment, angiography and possible percutaneous coronary intervention (PCI).

Methods
This is a retrospective descriptive review of data sourced from the London Ambulance Service’s OHCA registry over a one-year period.

Results

The authors observed excellent survival rates for our cohort of patients with 66% of patients surviving to be discharged from hospital, the majority of whom were still alive after one year. Those who survived tended to be younger, to have had a witnessed arrest in a public place with an initial cardiac rhythm of VF/VT, and to have been transported to the specialist centre more quickly than those who did not.

Conclusion
A system allowing ambulance clinicians to autonomously convey OHCA STEMI patients who achieve a return of spontaneous circulation directly to a Heart Attack Centre is highly effective and yields excellent survival outcomes.

http://www.sciencedirect.com/science/article/pii/S0300957213007326

Should we be establishing heart attack centres, similar to stroke centres, to ensure all patients with heart attacks, including those in cardiac arrest, receive optimum treatment, such as cardiologist review, angiography and PCI, or at least ensuring that our patients are conveyed to hospitals with these facilities?
Achieving a rate of 66% for patients surviving to discharge, with the majority of whom were still alive after one year, could suggest that that this is a good idea.

Evaluation of pre-hospital administration of adrenaline (epinephrine) by EMS for patients with out of hospital cardiac arrest in Japan

Evaluation of pre-hospital administration of adrenaline (epinephrine) by emergency medical services for patients with out of hospital cardiac arrest in Japan: controlled propensity matched retrospective cohort study

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

BMJ 2013; 347

To evaluate the effectiveness of pre-hospital adrenaline (epinephrine) administered by emergency medical services to patients with out of hospital cardiac arrest.

Design Controlled propensity matched retrospective cohort study, in which pairs of patients with or without (control) adrenaline were created with a sequential risk set matching based on time dependent propensity score using Japan’s nationwide registry database of patients with out of hospital cardiac arrest registered between January 2007 and December 2010. Among patients aged 15-94 with out of hospital cardiac arrest witnessed by a bystander, the authors created 1990 pairs of patients with and without adrenaline with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia (VF/VT) and 9058 pairs among those with non-VF/VT. The main outcome measures were overall and neurologically intact survival at one month or at discharge, whichever was earlier.

Results After propensity matching, pre-hospital administration of adrenaline by emergency medical services was associated with a higher proportion of overall survival (17.0% v 13.4%; unadjusted odds ratio 1.34, 95% confidence interval 1.12 to 1.60) but not with neurologically intact survival (6.6% v 6.6%; 1.01, 0.78 to 1.30) among those with VF/VT; and higher proportions of overall survival (4.0% v 2.4%; odds ratio 1.72, 1.45 to 2.04) and neurologically intact survival (0.7% v 0.4%; 1.57, 1.04 to 2.37) among those with non-VF/VT.

Conclusions Pre-hospital administration of adrenaline by emergency medical services improves the long term outcome in patients with out of hospital cardiac arrest, although the absolute increase of neurologically intact survival was minimal.

http://www.bmj.com/content/347/bmj.f6829?etoc= (full text article)

Exercise-related out-of-hospital cardiac arrest in the general population: incidence and prognosis

Exercise-related out-of-hospital cardiac arrest in the general population: incidence and prognosis

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

Eur Heart J (2013) 34 (47): 3616-3623.

Although regular physical activity has beneficial cardiovascular effects, exercise can trigger an acute cardiac event. We aimed to determine the incidence and prognosis of exercise-related out-of-hospital cardiac arrest (OHCA) in the general population.

Methods and results The authors prospectively collected all OHCAs in persons aged 10–90 years from January 2006 to January 2009 in the Dutch province North Holland. The relation between exercise during or within 1 h before OHCA and outcome was analysed using multivariable logistic regression, adjusted for age, gender, location, bystander witness, bystander cardiopulmonary resuscitation (CPR), automated external defibrillator (AED) use, initial rhythm, and Emergency Medical System response time. Of 2524 OHCAs, 143 (5.7%) were exercise related (7 ≤35 years, 93% men). Exercise-related OHCA incidence was 2.1 per 100 000 person-years overall and 0.3 per 100 000 person-years in those ≤35 years. Survival after exercise-related OHCA was distinctly better than after non-exercise related OHCA (46.2 vs. 17.2%) [unadjusted odds ratio (OR) 4.12; 95%CI 2.92–5.82; P < 0.001], even after adjustment for abovementioned variables (OR 2.63; 95%CI, 1.23–5.54; P = 0.01). In the 69 victims aged ≤35 years, exercise was not associated with better survival: 14.3 vs. 17.7% in non-exercise-related OHCA (OR 0.77; 95%CI 0.08–7.08;P = 0.82).

Conclusion Exercise-related OHCA has a low incidence, particularly in the young. Cardiac arrests occurring during or shortly after exercise carry a markedly better prognosis than non-exercise-related arrests in persons >35 years. This study establishes the favourable outcome of exercise-related OHCA and should have direct implications for public health programs to prevent exercise-related sudden death.

http://eurheartj.oxfordjournals.org/content/34/47/3616.abstract.html?etoc

Effect of prehospital cardiac catheterisation lab activation

Effect of Prehospital Cardiac Catheterization Lab Activation on Door-to-Balloon Time, Mortality, and False-Positive Activation

© Gary Wilson/ Pre-hospital Research Forum

© Gary Wilson/ Pre-hospital Research Forum

Prehospital Emergency Care January-March 2014, Vol. 18, No. 1 , Pages 68-75

Reperfusion of ST elevation myocardial infarction (STEMI) is most effective when performed early. Notification of the cardiac catheterization laboratory (cath lab) prior to hospital arrival based on paramedic-performed ECGs has been proposed as a strategy to decrease time to reperfusion and mortality. The purpose of this study was to compare the effects of cath lab activation prior to patient arrival versus activation after arrival at the emergency department (ED). 

Methods. The authors performed a retrospective cohort study (n = 1933 cases) using Los Angeles County STEMI database from May 1, 2008 through August 31, 2009. The database includes patients arriving at a STEMI Receiving Center (SRC) by ambulance who were diagnosed with STEMI either before or after hospital arrival. We compared the cohort of patients with prehospital cath lab activation to those activated from the ED within 5 minutes of first ED ECG. Outcomes measured were mortality, door-to-balloon time, percent door-to-balloon time <90 min, and percentage of false-positive activations. 

Results. Prehospital cath lab activations had mean door-to-balloon times 14 minutes shorter (95% CI 11–17), in-hospital mortality 1.5% higher (95% CI −1.0–5.2), and false-positive activation 7.8%, (95% CI 2.7–13.3) higher than ED activation. For prehospital activation, 93% (95% CI 91–94%) met a door-to-balloon target of 90 minutes versus 85% (95% CI 80–88%) for ED activations. 

Conclusion. Prehospital cath lab activation based on the prehospital ECG was associated with decreased door-to-balloon times but did not affect hospital mortality. False-positive activation was common and occurred more often with prehospital STEMI diagnosis.

http://informahealthcare.com/doi/abs/10.3109/10903127.2013.836263