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

Geoffrey Kennedy Isbister, MD, FACEM, Leonie A. Calver, PhD, Michael A. Downes, MBBS, FACEM, Colin B. Page, MBBS
Annals of Emergency Medicine
Volume 67, Issue 5, Pages 581-587.e1 (May 2016)
DOI: 10.1016/j.annemergmed.2015.11.028

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

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

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

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

Introduction
The sedation of agitated and aggressive patients in the emergency department (ED) and other acute care areas is a major problem for health care workers. Patients with acute behavioral disturbance may respond to verbal de-escalation or oral sedation, but a substantial proportion of this group requires parenteral sedation and mechanical restraint.1,2,3,4,5 The majority of these patients will be sedated or tranquilized with parenteral sedation with an antipsychotic or benzodiazepine.1,3,4,5,6 In a recent study, only 8% of patients were not sedated with 1 or 2 doses of droperidol, and only 3% after 3 doses.6 However, this small number of patients with acute behavioral disturbance who remain difficult to sedate despite multiple doses of parenteral medications are highly problematic.7 Although such patients are uncommon, they cause a significant disruption and danger to the ED and consume time and resources required for other patients.

There is limited evidence available on the effective management of patients with acute behavioral disturbance when standard approaches to sedation with sedating antipsychotics and benzodiazepines have failed. Clinical practice guidelines do not cover the treatment options to manage repeatedly failed sedation. A number of agents have been suggested, including barbiturates, propofol, sedating antihistamines (diphenhydramine or promethazine), dexmedetomidine, and ketamine,7,8, 9,10 but there is little evidence to support one over another. Some clinicians may simply opt to intubate the patient, which is a last resort, resource intensive, and fraught with potential complications. To our knowledge, no previous studies have explored an alternative management for failed sedation of acute behavioral disturbance.

The success of ketamine for the sedation of out-of-hospital patients11, 12 and those retrieved with psychiatric illness13 suggests it may be a useful medication for difficult-to-sedate patients in the ED. We hypothesized that ketamine may be a safe and useful agent for the management of difficult-to-sedate patients in the ED.

Goals of This Investigation
The aim of the study was to investigate the effectiveness and safety of ketamine in severely agitated and aggressive patients in the ED when other parenteral sedation had failed on at least 2 occasions.

Study Design and Setting
This was a subgroup analysis of difficult-to-sedate patients with severe acute behavioral disturbance, included from the Droperidol or Midazolam1 (DORM II) study,6 a prospective observational study of ED patients with acute behavioral disturbance who required parenteral sedation and physical restraint. Ethics approval was obtained from the Hunter New England Area Health Service Human Research Ethics Committee and the Metro South Health Service District Human Research Ethics Committee to cover all hospitals involved. Patients required immediate sedation for patient and staff safety, and because of the lack of the patients’ decision making capacity, consent was waived because medical treatment was provided as a duty of care.

Both this analysis and DORM II were observational studies of a clinical protocol in which ketamine (this analysis) or droperidol (DORM II) was administered as part of that protocol. They were not clinical trials, so a clinical trials notification was not required. Although this analysis used a subgroup of patients from the DORM II study, it was not simply a retrospective review of the DORM II data. Ketamine was introduced by clinicians at the 2 hospitals in December 2011, with the intention of prospectively analyzing patients who received ketamine.

Patients were included in this analysis from 2 adult metropolitan hospitals of the 6 hospitals involved in the DORM II study.6 These 2 hospitals were used because they are teaching hospitals that have clinical toxicology services providing advice on difficult-to-sedate patients, and the clinician investigators at these 2 hospitals made a decision to use ketamine if droperidol failed. In addition, both hospitals had the highest recruitment rate to DORM II, and in one there was consecutive recruitment of all cases. The first hospital is a medium-sized urban hospital with a tertiary toxicology unit and drug and alcohol service, and has twice the number of patients presenting with acute behavioral disturbance compared with most EDs.5 The second hospital is a large tertiary adult referral hospital with 60,000 presentations each year, has a dedicated toxicology service, and has a similar number of presentations with acute behavioral disturbance.

Selection of Participants
Patients (>16 years) with acute behavioral disturbance were recruited as part of the DORM II study from the 2 EDs if they required physical restraint and parenteral sedation and had a score of 2 to 3 on the Sedation Assessment Tool (Table E1, available online at http://www.annemergmed.com).14
Patients who could be settled (ie, Sedation Assessment Tool score 0 or 1) with verbal de-escalation or oral medication were excluded. Any patients who then remained agitated and aggressive after their initial sedation and received ketamine as additional sedation were included in this analysis. A standardized protocol was used for all patients with acute behavioral disturbance in the 2 EDs, which recommended two 10-mg doses of droperidol. However, in a minority of cases the protocol was not followed, so either fewer doses of droperidol were given or benzodiazepines were used. In some cases, after consultation with the on-call clinical toxicologist a third dose of droperidol was given before ketamine. The aim was to review ketamine as a rescue treatment, so we included all cases in which there was an initial failure of sedative medication. Patients were included from December 2011 until February 2014.

Interventions
In the DORM II study, all patients with acute behavioral disturbance were managed with a standardized protocol that included the administration of intramuscular sedation and the assessment of the level of sedation or agitation with the Sedation Assessment Tool.6, 14 The protocol recommended starting with a 10-mg dose of intramuscular droperidol for parenteral sedation, and if the patient is not sedated within 15 minutes a second dose of 10 mg droperidol was given. Patients who were not sedated after 30 minutes were discussed with the on-call clinical toxicologist at each site, and from December 2011 ketamine was used in the majority of cases as the third-line agent. The clinical toxicologists decided on an intramuscular dose of ketamine of 4 to 6 mg/kg, based on intramuscular use in other settings.10,15,16 Rarely, droperidol was not used as the first-line agent. This usually occurred when new junior or training medical staff did not consult the clinical toxicologist. In one case, only a single dose of droperidol was given before ketamine.

All patients were observed in a critical care area and had pulse rate, pulse oximetry, respiratory rate, and blood pressure recorded every 5 minutes for the first 20 minutes and then every 30 minutes for the next 2 to 4 hours. The level of agitation or sedation was measured with the Sedation Assessment Tool score.14 This score is used routinely in both EDs and assesses the degree of agitation or sedation as a score of 3 (physically violent) to –3 (unconscious).

Data Collection and Processing
All observations were recorded on a purpose-designed acute behavioral disturbance chart by the treating medical and nursing staff, which was part of the patient’s medical record. It included patient demographics (age and sex), reason for presentation, method of arrival, drug administration details (dose and timing), sedation scores, vital signs (pulse rate, blood pressure, respiratory rate, and oxygen saturations), and adverse effects. This information was then entered into a relational database (Microsoft Access 2010; Microsoft, Redmond, WA) by a single researcher who collected all cases for DORM II daily for data entry. This researcher identified all cases of ketamine administration prospectively as they were entered into the database.

Primary Data Analysis
The primary outcome for the study was the number of patients who failed to achieve sedation within 120 minutes of ketamine administration or required further sedation within 1 hour of ketamine. A number of other outcomes were included: (1) the time to sedation from the initial onset of acute behavioral disturbance, defined as a decrease in the Sedation Assessment Tool score by 2 levels or a score of zero or less; (2) the time to sedation after the administration of ketamine; and (3) any adverse effects (airway obstruction, oxygen saturation less than 90%, respiratory rate less than 12 breaths/min, new-onset arrhythmia, and systolic blood pressure less than 90 mm Hg). In addition, the change in pulse rate and blood pressure after ketamine administration was measured. Continuous variables were summarized as medians, interquartile ranges (IQRs), and ranges, and dichotomous outcomes were reported with 95% confidence intervals. All analyses and graphics were conducted with GraphPad Prism (version 6.03; GraphPad Software, San Diego, CA).

Results
There were 1,296 patients sedated as part of the DORM II protocol at the 2 hospitals during the 27-month period. Of these, 53 patients (4%) received ketamine as part of their sedation. Four of these patients received ketamine without any previous sedation, leaving 49 patients who received ketamine after the failure of previous parenteral sedation (Figure). Three of the 4 patients were sedated by ketamine, 2 at 10 minutes and 1 at 20 minutes. The fourth patient received only 30 mg ketamine and then a further 30 mg 85 minutes later and did not settle for 5 hours. One of the 4 patients had a dystonic reaction after droperidol, but none had any adverse effects after ketamine.

Flowchart of the patients recruited to DORM II and those included in this subgroup analysis. An estimate of the total number of patients with acute behavioral sedation is included according to the number reported in the DORM study and then randomized to parenteral sedation.
Of the 49 patients, there were 28 men (57%) and the median age was 37 years (range 20 to 82 years). Police were required to assist with the transport of 20 patients to the hospital (41%). Droperidol alone was administered before ketamine in 46 patients (10 mg [1], 10+10 mg [33], 10+10+10 mg [11], and 10+10+5 mg [1]), whereas a combination of droperidol, diazepam, and midazolam was given in 2 patients and midazolam alone in 1 (Table). The median dose of ketamine used was 300 mg (IQR 200 to 400 mg; range 50 to 500 mg).

Table

Five patients (10%; 95% confidence interval 4% to 23%) were not sedated within 120 minutes (1), required additional sedation within 1 hour (1), or both (3). The doses administered in these 5 patients were 100, 150, 150, 200, and 400 mg. One of the 5 patients receiving 200 mg ketamine remained severely agitated for 12 hours (overnight) and was given no further sedation. Unfortunately, the clinical toxicologist was not notified about this patient again until the following morning.
The median time to sedation from the onset of acute behavioral disturbance was 60 minutes (IQR 40 to 140 minutes; range 20 to 540 minutes). The median time to sedation postketamine was 20 minutes (IQR 10 to 30 minutes; range 2 to 500 minutes). Three patients were resedated with ketamine 4 to 24 hours after the initial dose.

There were adverse effects in 3 patients after ketamine (6%). Two patients had vomiting (one treated with intramuscular metoclopramide 10 mg) and the third had an episode of oxygen desaturation to 90% without airway obstruction 40 minutes after ketamine, which immediately responded to oxygen, with no further problems. No patient had laryngeal spasm. One patient developed hypotension before ketamine but after droperidol.

There were 43 patients who had a preadministration systolic blood pressure with a median of 130 mm Hg (IQR 115 to 146 mm Hg; range 100 to 195 mm Hg). Blood pressures were measured a median of 15 minutes (2 to 120 minutes) postadministration, with a median change in systolic blood pressure of +5 mm Hg (IQR –3 to 23 mm Hg; range –47 to 38 mm Hg). No patients were hypotensive and 3 patients had a systolic blood pressure greater than 180 mm Hg (181, 183, and 198 mm Hg), but all had blood pressure greater than 140 mm Hg before ketamine (181, 149, and 174 mm Hg). There were 45 patients with pre– and post–pulse rate measurements with a median change of 0 beats/min (IQR –13 to 11 beats/min; range –60 to 30 beats/min).

Limitations
Our study is limited by its sample size. Although ketamine administration was associated with no serious adverse events, larger samples would be required to reliably confirm its safety profile. The study had a relatively small heterogenous patient sample and the inability to prevent the occasional variation in the treatment protocol. Although the majority of patients had 2 administrations of droperidol before ketamine, this was not always the case, with some receiving 1 or 3 doses and some receiving benzodiazepines. However, the aim was to assess ketamine as a rescue medication, not only after droperidol.

There was also some variability in the timing between droperidol doses and ketamine administration. This meant that it is not possible to determine whether the ultimate sedation of the patient was a result of the ketamine, delayed response to the initial medication (mainly droperidol), or both. There is some support for the sedation being due to ketamine because the median total time to sedation (from the initial onset of acute behavioral sedation) was 55 minutes, which is much longer than the median time in the DORM II study of 20 minutes.6
However, the median time to sedation after ketamine administration in this analysis was 20 minutes, the same as the median time to sedation in DORM II, suggesting that the sedation was due to ketamine.

Another potential limitation was that we present a subgroup analysis of patients from the DORM II study, and therefore the outcomes and data collection were designed to assess droperidol and not ketamine. However, after the introduction of ketamine in the 2 hospitals, the investigators planned a priori to prospectively assess the safety and effectiveness of ketamine by using the DORM II study infrastructure.

The study environment of the ED is a limitation of our study, and caution should be exercised in regard to generalizing it to areas that do not have ready access to critical care monitoring and medical staff. It would not be appropriate for ketamine to be used for acute behavioral disturbance on general wards or in psychiatric settings. However, recent reports have demonstrated the safety and effectiveness of ketamine for sedation in other environments, such as out-of-hospital transport, as well as in retrieval of psychotic patients.11,12,13,17,18

Discussion
This study reports the clinical use of ketamine in 49 patients with severe acute behavioral disturbance who could not be sedated with high-dose droperidol or, in a few cases, droperidol and benzodiazepines. Only 10% of the 49 patients could not be sedated within 2 hours or required additional sedation, which is only a very small proportion of the initial 1,296 patients who required sedation. There were only 3 adverse effects, 2 minor and the other easily treated with oxygen.

The major reason for failure of ketamine appeared to be the use of smaller doses, with 4 of 5 patients receiving 200 mg or less. The aim was to use 4 to 6 mg/kg, but in some cases staff decided to administer only half of the dose because of concerns about oversedation. However, larger doses of ketamine are not necessarily associated with oversedation, although they are associated with other adverse effects such as emergence phenomena.19

Although “nightmares” and recovery agitation are commonly reported in adult patients when ketamine has been administered for other indications, this was not reported in our series.16,9 It is possible that it was difficult to distinguish agitation associated with ketamine from the agitation already present in the patient. However, in the majority of cases no more medication was given to the patient after ketamine, and the patient settled for more than an hour and in most cases woke normally. The other concern with ketamine is the well-reported increase in blood pressure and pulse rate after administration. However, in our study there were only minor increases in both after administration. This may be due to an excess of endogenous sympathomimetic substances being present because of the agitation, therefore limiting further release of endogenous monoamines by ketamine. Hopper et al also reported only minor increases in blood pressure and pulse rate.

Benzodiazepines are the other obvious choice for difficult-to-sedate patients. However, there is increasing evidence that benzodiazepines alone 3,21,22 and combinations of benzodiazepines and antipsychotics are associated with higher rates of adverse effects.1,6 Both the DORM and DORM II studies found a higher rate of adverse effects with airway obstruction, oxygen desaturation, and hypotension than antipsychotics alone.1,6  A systematic review found that the addition of a benzodiazepine to haloperidol for psychosis-induced aggression provided no additional benefit but was associated with increased risk of harm.23 The additional use of ketamine after droperidol for difficult-to-sedate patients with severe acute behavioral disturbance appears to provide a safer option in this patient group compared with the combination of droperidol and benzodiazepines.

There is one other recent study of ketamine in the ED by Hopper et al.20 This study reviewed 32 patients given ketamine for acute agitation from 459 patients given ketamine in the ED during a 7-year period. Ketamine was administered intravenously and intramuscularly, and in almost half of the patients it was given without previous sedative medication. The median dose administered intramuscularly was 200 mg, with an IQR of 150 to 200 mg. There was a much higher failure rate in this study, with 16 of 32 patients (50%) requiring further sedation within an hour. The results of this study support our suggestion that lower doses of ketamine are associated with a higher failure rate. In addition, Hopper et al20 reported a similar low adverse event rate.

The major difference between our study and that by Hopper et al20 was that ketamine was not administered as part of a standardized sedation protocol. Our study was undertaken as part of a much larger study of more than 1,000 patients requiring parenteral sedation. The majority of the patients were sedated with droperidol, which was safe and effective.6 We then focused on the small group of patients who were not sedated, and this study now provides evidence that ketamine is an appropriate third-line agent to be used in these patients. There is one recent study of 5 adolescents (aged 14 to 18 years) who were sedated with intramuscular or intravenous ketamine, which again had similar outcomes. Ketamine was administered initially in some cases or after other attempts had failed.

There are an increasing number of studies of ketamine use in the out-of-hospital setting for agitated and difficult-to-sedate patients.11,12,17,18 These include a variety of reasons to sedate, most commonly trauma, and a mixture of intravenous and intramuscular use. These studies provide further support for the safety of ketamine. However, a significant proportion of patients receiving out-of-hospital ketamine have to be intubated on arrival to the ED.12

Ketamine appears to be a reasonable third-line agent in the sedation of patients with acute behavioral disturbance. The recommended dose is 4 to 6 mg/kg, which should be administered intramuscularly in a critical care area. Further research is required to define its use in settings outside of the ED for severe behavioral disturbance.

The authors acknowledge the staff of the Calvary Mater Newcastle and Princess Alexandra Emergency Departments.

Appendix




References: http://www.annemergmed.com/article/S0196-0644(15)01562-0/fulltext#sec1




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Virtual Journal Club June 2016 Test Questions (CME available through Allina CME)

1.   1  This article notes that evidence is limited regarding the use of a second line agent when sedating antipsychotics and benzodiazepines have failed. Which of the following agents have been suggested:

a.      barbiturates

b.     propofol

c.      sedating antihistamines

d.     dexmedetomidate

e.      ketamine

f.       all of the above

2.     2 True or False: The aim of this study was to investigate the effectiveness and safety of ketamine in severely agitated and aggressive patients in the ED when other parenteral sedation had failed on at least 2 occasions. 

3.     3 This study was a subgroup analysis of the  __________ study.

a.      STORM I

b.     DORM II

c.      FORM III

d.     NORM IV

4.     4 The dose of Ketamine used was ___ to ___ mg/kg administered intramuscularly.

a.      1, 2

b.     2, 4

c.      3, 9

d.     4, 6   

e.      0, Infinity

5.     5 The following were reported as adverse reactions to ketamine in this study:

                  

a.      Vomiting

b.     Oxygen desaturation

c.      Laryngeal spasm

d.     Hypotension

e.      a and c

A prospective validation of the HEART score for chest pain patients at the emergency department

B.E. Backus, A.J. Six, J.C. Kelder , M.A.R. Bosschaert, E.G. Mast, A. Mosterd, R.F. Veldkamp, A.J. Wardeh, R. Tio, R. Braam, S.H.J. Monnink, R. van Tooren, T.P. Mast, F. van den Akker, M.J.M. Cramer, J.M. Poldervaart, A.W. Hoes, P.A. Doevendans

International Journal of Cardiology

18 January 2013

Abstract

Background:

The focus of the diagnostic process in chest pain patients at the emergency department is to identify both low and high risk patients for an acute coronary syndrome (ACS). The HEART score was designed to facilitate this process. This study is a prospective validation of the HEART score. 

Methods: 

A total of 2440 unselected patients presented with chest pain at the cardiac emergency department of ten participating hospitals in The Netherlands. The HEART score was assessed as soon as the first lab results and ECG were obtained. Primary endpoint was the occurrence of major adverse cardiac events (MACE) within 6 weeks. Secondary endpoints were (i) the occurrence of AMI and death, (ii) ACS and (iii) the performance of a coronary angiogram. The performance of the HEART score was compared with the TIMI and GRACE scores. 

Results: 

Low HEART scores (values 0–3) were calculated in 36.4% of the patients. MACE occurred in 1.7%. In patients with HEART scores 4–6, MACE was diagnosed in 16.6%. In patients with high HEART scores (values 7–10), MACE occurred in 50.1%. The c-statistic of the HEART score (0.83) is significantly higher than the c-statistic of TIMI (0.75)and GRACE (0.70) respectively (pb0.0001). 

Conclusion: 

The HEART score provides the clinician with a quick and reliable predictor of outcome, without computer-required calculating. Low HEART scores (0–3), exclude short-term MACE with >98% certainty. In these patients one might consider reserved policies. In patients with high HEART scores (7–10) the high risk of MACE may indicate more aggressive policies.

Introduction

Chest pain is the most common reason for admitting patients to the cardiac emergency department [[1], [2]]. The first challenge in these patients is to identify those with acute coronary syndrome (ACS). This diagnostic process should be quick and efficient, since the prognosis improves dramatically when ACS patients receive targeted treatment as early as possible [3]. In today's practice, approximately 80% of chest pain patients have no clear ACS at presentation [4]. Clinicians tend to postpone the decision making process and to admit these patients for clinical observation, meanwhile treating the patients as an ACS. Consequently, over diagnosis and unnecessary treatment are common, resulting in redundant patient burden and high cost. In order to improve risk stratification of all cause chest patients at the emergency department and to place relative arguments for ACS into perspective, we designed the HEART score. (Table 1).

HEART was not developed from a database as modern scores often are. The HEART score was based on clinical experience and medical literature and designed to be as easy to use as the Apgar score for newborns [5]. HEART is an acronym of its components: History, ECG, Age, Risk factors and Troponin. Each of these may be scored with 0, 1 or 2 points. We retrospectively evaluated the HEART score in two smaller studies and obtained promising results [[6], [7]]. This resulted in the prospective study in 2440 patients at 10 sites described in this paper. We compared the performance of the HEART score with other scoring systems, such as TIMI [8]and GRACE [[9], [10], [11]], although both have been designed for risk stratification of patients with proven ACS and not for the chest pain population at the emergency department.

Methods

2.1. Participants

This study was performed at ten hospitals in the Netherlands. Participating hospitals and numbers of included patients are listed in Appendix A. Any patient admitted to the (cardiac) emergency department due to chest pain irrespective of age, pre-hospital suspicions and previous medical treatment was eligible. Patients presenting with only dyspnea or palpitations were not included. Only patients presenting to the emergency department were eligible for the study. Typically, patients with chest pain and signifi- cant ST segment elevations on the ECG during transportation in the ambulance were immediately taken to the nearest available coronary intervention room in the area and, consequently, not presented at the emergency department. Therefore, patients with ST-elevation acute myocardial infarction (STEMI) were only exceptionally included in this study. The ethics committees of all participating hospitals approved the study. As this was an observational non-intervention study, informed consent procedures were waived. However, patients were informed of the registration of data and the follow up policy.

2.2. Data acquisition and management

Emergency department residents of participating hospitals were instructed carefully about the admission Case Report Form (CRF) and interpretation of the elements of patient history. The resident entered the initial patient data in writing on the admission CRF, upon arrival of the patient. The CRF consisted of separate entries for classical elements of patient history, cardiovascular risk factors, medication, physical examination and past medical history.

Laboratory values, including troponin I or T levels, were collected throughout the study period, starting with the moment of admission and typically repeated with 6 h intervals. According to the original study design the measured troponin values were interpreted according to local lab standards and reference values (see Appendix A). Only the troponin value of the first blood sample was used for the HEART score calculation. High sensitive troponin was not used at any participating hospital at the time of the study conduct.

A copy of the admission ECG was added to the study files. The ECG was blindly reviewed and classified afterwards by independent, experienced cardiologists, according to the Minnesota criteria [12]. In case of disagreement, a third cardiologist was consulted. A secured web based database was built for this study. An algorithm was devised to calculate the TIMI [8], GRACE [9–11] and HEART [6,7] scores automatically from the admission data, without interpretations by the investigators.

2.3. HEART score criteria

The HEART score was calculated on admission data only. Data acquired more than 1 h after presentation were ignored for score calculations. For specific explanation of each HEART element, please see previous publications [6,7].

2.4. Follow-up

Follow up data were retrieved from digital and written patient records, including discharge letters, revascularization reports and any other relevant documentation. In a few cases where follow-up data were not available from hospital records, the patient or their general practitioner was called to obtain information on their condition, hospital admissions, myocardial infarction and revascularization.

2.5. Outcomes

The diagnosis of acute myocardial infarction (AMI) was made according the applicable guidelines when the protocol was written, the joint ESC-ACCF-AHA-WHF task force for the redefinition of myocardial infarction [13], and consisted of a rise and fall of troponin values with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia. Within the diagnosis of AMI, distinction was made between either: ST-elevation myocardial infarction (STEMI), de- fined as a syndrome consisting of a rise and fall of troponin values as described above, typical patient history and transient ST segment elevations on the consecutive 12 lead ECGs, or non ST-elevation myocardial infarction (NSTEMI), defined as a syndrome consisting of a rise and fall of troponin values as described above, typical patient history and persistent or transient ST-segment depression or T-wave inversion, flat T-waves, pseudo-normalization of T-waves, or no changes at presentation.

In case of rises of troponin levels without evidence of myocardial ischemia or in case of non-availability of data the case was discussed in the adjudication committee where a final diagnosis was made according to the guidelines [3,13,14].

Percutaneous coronary intervention (PCI) was defined as any therapeutic catheter intervention in the coronary arteries. Coronary artery bypass graft (CABG) surgery was defined as any cardiac surgery in which coronary arteries were operated on. The primary endpoint in this study was the occurrence of a major adverse cardiac event (MACE), within six weeks of initial presentation. MACE consists of: AMI, PCI, CABG, coronary angiography revealing procedurally correctable stenosis managed conservatively, and death due to any cause. Coronary angiography revealing procedurally correctable stenosis managed conservatively was defined as significant coronary stenosis thought to be the cause of the chest pain, but revascularization was withheld for reasons of co-morbidity or risk of complications.

2.6. Secondary endpoints

Secondary endpoints were: (i) the six-week occurrence of AMI and death, (ii) the diagnosis of ACS within three months after presentation. The spectrum of ACS was described according to the definitions in the guideline for non-ST-segment elevation acute coronary syndrome [3,14] and consisted of: definite ACS, defined as: STEMI or NSTEMI (as defined above), or suspected ACS, defined as: likely to be an ACS based on typical patient history consistent with unstable angina and/or ST segment depression or T wave inversion or significant stenosis at coronary angiography, but without a rise of troponin levels, (iii) the performance of coronary angiography within three months after presentation.

2.7. Statistical analysis

Statistical analysis was performed with R (Version 2.9; The R foundation for Statistical Computing, Vienna, Austria) [15]. Descriptive statistics are given as average+/−SD, percentage or Kaplan–Meier cumulative event-free curve. Differences between groups were assessed by means of the Student's t-test when normally distributed. For scalar data we used the Fisher's exact test, or for ordinal data the Cochran–Armitage Trend Test.

The probability of reaching an endpoint was calculated as the percentage of cases with an endpoint within a given category. The area under the receiver operator characteristic curve (c-statistic) was computed in order to give a measure of diagnostic discriminative strength, combining sensitivity and specificity, especially for non-binomial variables. The DeLong's test was used for testing two correlated ROC curves. Statistical significance was defined as pb0.05 two-sided.

Results

3.1. Study population

The patient inclusion period lasted from October 2008 to November 2009. The patient flow in the HEART study is given in Fig. 1. A total of 2440 patients were included. Seven patients (0.3%) were nonevaluable due to invalid data on admission. In another 45 cases (1.8%) the 6-week follow up was incomplete. The study population consisted of the remainder of 2388 patients with a follow up duration of 222+/−127 days (mean+/−SD). The total follow up duration of the entire study group was 1449 patient years. Patient characteristics of the study group are presented in Table 2.

(Figure 1). Patient flow in the HEART score validation study. AMI= acute myocardial infarction. CABG=coronary artery bypass graft. PCI=percutaneous coronary intervention. MACE=major adverse coronary events.

3.2 Primary end points

Of a total of 2388 patients 407 (17.0%) were diagnosed with MACE within 6 weeks: AMI was diagnosed in 155 patients (6.4%), 251 patients (10.5%) underwent PCI, 67 patients (2.8%) had a CABG and 44 patients (1.8%) had coronary angiography revealing procedurally correctable stenosis managed conservatively. Sixteen patients (0.7%) died within 6 weeks after presentation. Thirteen patients died of a cardiac cause: 1 patient in the low-risk HEART group, 5 in the intermediate-risk HEART group and 7 in the high-risk HEART group. Three of these 16 patients died due to non-cardiovascular causes. Altogether, 533 MACE occurred in 407 patients: an average of 1.30 events/MACE patient.

3.3. Diagnosis at admission

On admission, the 2388 patients that were analyzed were diagnosed as follows: 419 (17.5%) acute coronary syndrome, 144 (6.0%) AMI of which 2 died at the ED, 230 (9.6%) stable angina, 68 (2.8%) rhythm, 90 (3.8%) other cardiac diseases, 106 (4.4%) gastro-esophagitis, 347 (14.5%) other non-cardiac diagnoses, 984 (41.2%) with atypical/undifferentiated chest pain. Eventually 142/155 AMIs (91.6%) were diagnosed at presentation: 110 NSTEMI, 18 STEMI and 14 recent AMI (onset 12–48 h before presentation). Mean duration of time to AMI was 0.3 days (range 0–17). 165/407 (40.8%) of MACE were reached upon presentation. Mean duration of time to MACE was 5.6 days (range 0–41). Mean time to PCI 6.9 days (0–41), mean time to CABG 12.1 (1–39) days and mean time to death 13.6 days (1–33). The time elapsed between arrival of the patient and the occurrence of MACE is given in Fig. 2.

3.4. The HEART score

The numerical distribution of the HEART score's five elements in the groups with or without endpoints is shown in Table 3. The five elements of the HEART score differed significantly between the groups with and without MACE. The average HEART score was 3.96+/−2.0 in the non-MACE group and 6.54+/−1.7 in the MACE group. The c-statistic of the HEART score in the entire study group was 0.83. The HEART score retained its discriminative ability in three relevant subgroups: in diabetics the event rate was 81/440 with a c-statistic of 0.78 (non-diabetic 0.84), in females (event rate 116/1016) the c-statistic was 0.83 (males 0.82) and in elderly over the age of 75 (event rate 101/490) the c-statistic was 0.73 (age≤75 0.86).

(Figure 2):

Kaplan–Meier curves for the occurrence of major adverse cardiac events.

The five elements of the HEART score differed significantly between the groups with and without MACE. The average HEART score was 3.96+/−2.0 in the non-MACE group and 6.54+/−1.7 in the MACE group.

The c-statistic of the HEART score in the entire study group was 0.83. The HEART score retained its discriminative ability in three relevant subgroups: in diabetics the event rate was 81/440 with a c-statistic of 0.78 (non-diabetic 0.84), in females (event rate 116/1016) the c-statistic was 0.83 (males 0.82) and in elderly over the age of 75 (event rate 101/490) the c-statistic was 0.73 (age≤75 0.86).

The c-statistic of troponin only was 0.70. With addition of the ECG the c-statistic improved significantly to a value 0.78, with a likelihood ration test p-value of <0.001. This combination of troponin plus ECG only had a significantly poorer performance as compared with the complete HEART score (p<0.001).

  

3.5. HEART, TIMI and GRACE scores

Average values of the HEART, TIMI and GRACE scores in groups with and without MACE are given in Table 4. All scores differed considerably between the group free from MACE and the group with MACE. Fig. 3 illustrates the relation between the scores (on the x-axis) and the risk of MACE within 6 weeks after initial presentation (on the y-axis).

(Figure 3) Probability of reaching a MACE related to the three risk scores.

Only for the purpose of comparing graphs we divided the TIMI and GRACE scores in deciles in order to achieve the same distribution as the HEART score on the x-axis. All other computations were made with the original values.

Only for the purpose of comparing graphs we divided the TIMI and GRACE scores in deciles in order to achieve the same distribution as the HEART score on the x-axis. All other computations were made with the original values.

Comparison of the c-statistics as represented in Table 4 shows a value of 0.83 for the HEART score, 0.75 for TIMI and 0.70 for GRACE. The HEART score performed significantly better (p<0.001) as compared with TIMI and GRACE.

3.7. Predictive values of intermediate scores

The intermediate risk boundaries for all scores were set at a risk of MACE between 5 and 40%.In the group with TIMI scores of 2–5, which accounted for 62.7% of the study population, 350/1497 (23.4%) had a MACE. The 85.7% of the patients who had GRACE scores >60 had MACE in 389/2012 (19.3%) of the cases. The group with an intermediate HEART score (values 4–6) represents 46.1% of the study population. Six-week MACE occurred in 183/1101 (16.6%) of these patients.

3.8. Predictive values of high scores

Only the TIMI and HEART scores reached a high risk level, defined as a risk of MACE>40%. MACE occurred in 34/80 patients (42.5%) where TIMI scores were 6–7. The group with a high HEART score (7–10) represents 17.5% of the study population; six-week MACE occurred in 209/417 (50.1%) of those patients.

3.9. Secondary endpoints 

A total of 164/2388 (6.9%) patients had an AMI (n= 155) or died (n=16) within six weeks. The c-statistics for the occurrence of AMI or death of HEART, TIMI and GRACE are 0.82, 0.70 and 0.71 respectively (p<0.0001). An ACS within three months after presentation was diagnosed in 536 patients (22.4%); 501 of these 536 ACS (93.4%) were already diagnosed during primary admission. The c-statistics for the occurrence of ACS shows a value of 0.86 for the HEART score, 0.78 for TIMI and 0.72 for GRACE (p<0.0001).

Coronary angiography within three months was performed in 578 patients (24.2%). In 93 (16.2%) of these cases this diagnostic procedure was performed during primary admission. The results were: 58 (10.0%) normal coronaries, 104 (17.9%) non-significant stenosis, 44 (7.6%) significant stenosis with conservative treatment, 361 (62.4%) significant stenosis requiring revascularization and 11 (1.9%) were unclassified. The HEART score was 3.9+/−2.0 in the group with no catheterization in the first three months and 6.0+/−1.8 in the group with a catheterization in the first three months (p<0.001).

Discussion

The use of the HEART score for chest pain patients at the emergency department provides the clinician with a reliable predictor of outcome, very soon after the arrival of the patient, based on already available clinical data and without computer-required calculating.

The favorable results of this large prospective validation study con- firm our previous retrospective evaluation studies [6,7]. A c-statistic of 0.83 for the HEART score indicates a good to excellent ability to discriminate all cause chest pain patients at the emergency department for their risk of MACE. Each element of the HEART score adds value significantly in statistical terms. The HEART score facilitates communication, and it can be used as a guidance to correctly place patients into low, intermediate and high risk groups. In addition, it closely follows clinical thinking. Less complex guidelines for clinical practice can be formulated when advised policies are based on a HEART score stratification.

Several risk scores for ACS have been published [16]. The most reputable of these are the TIMI [8] and GRACE [9–11] scores. Both were developed for risk stratification of patients admitted to the coronary care unit with an ACS, and may take observations at arbitrarily chosen points in time into account. Although not designed for this purpose, these scores are commonly applied and are recommended in European and American guidelines3 at the emergency department for the whole range of chest pain patients, both in practice and in science [1,4,17,18]. Different from this, the HEART score was specifically designed for the much broader chest pain population at the emergency department. HEART is based on admission data only, typically complete within 1 h. This score is now validated in a prospective manner.

Neither the TIMI nor the GRACE score appreciates the specificity of patient history (anamnesis), even though clinicians rely heavily on this and guidelines advise to use patient history for making a diagnosis [3,14,19,20]. Some other scores, such as PURSUIT [21], FRISC [22] and SRI [23] are less specific and to some extent outdated, as troponin levels are not part of it; therefore, these are not reported in this paper.

The GRACE score is a well-validated prediction model of death in ACS patients. A practical disadvantage of the GRACE score is that it can only be calculated by means of a computer. Although it was not designed for making or excluding the ACS diagnosis in an unselected chest pain population, we applied the GRACE score in the chest pain setting at the emergency department. We found that the points given for ‘age’ accounted for 50.0+/−18.3% of the total number of GRACE points. Not surprisingly, higher age is related to higher mortality rates. The predominantly age based GRACE score assesses the risk of death of patients in the coronary care unit (CCU). Whether the GRACE score helps the clinician to choose the right treatment option in the ED is questionable.

The TIMI score, which was designed about 15 years ago for identifying high-risk ACS patients who benefit most from aggressive anti-clotting agents, is relatively easy to calculate. However, it is quite rough as it allows only binary choices, thus ignoring the fact that many variables have a ‘grey area.’ Than and co-investigators applied the TIMI score for the broad chest pain population at the cardiac emergency departments of 14 hospitals in 9 countries in the AsiaPacific region [4]. In their prospective multi-center study 9.8% of the patients had a TIMI score= 0 assessed after 2 h and those patients had a 4-week risk of MACE of 0.9%. In our study at 10 sites in the Netherlands 36.4% of the patients had HEART scores 0–3 within 1 h, indicating a 6-week risk of MACE of 1.7%. Although the comparison is hampered to some extent by differences in end point definitions, we believe that the approach in the Pacific study may benefit signifi- cantly from the replacement of the TIMI score by the HEART score [24].

When comparing the GRACE, TIMI and HEART in terms of predictive values for low- and high-risk, and the c-statistics, we conclude that the HEART score is the best score for the group of all cause chest pain patients at the emergency department and that GRACE and TIMI should be reserved for ACS patients in the CCU.

As the purpose of the study was to validate the HEART score in daily practice, the study protocol stipulated to use all measurements, reference values and interpretations according to local standards. This held true for the cut off values of troponin measurements. In practice this resulted in differences in cut-off values for the same test in between participating sites in some cases. Consequently, some patients with slightly elevated troponins may have received somewhat different classifications depending on the hospital where they were enrolled. However, this influence is minimal and we considered it not appropriate to make retrospective changes in the study protocol.

Other than in randomized trials, loss to follow up is an inevitable reality in an observational study at the emergency department: occasional visitors occur and they are sometimes hard to track afterwards. Our clinical review of the characteristics showed that the 45 patients lost to follow up (1.8% of the entire study population) were relatively young visitors with low likelihood of disease.

The HEART score gives immediate direction to the treatment policy. Over one third of our patients had HEART scores 0–3, with a risk of MACE of 1.7%. This observation may be a firm basis to omit redundant diagnostic and treatment steps and move into the direction of quick discharge. This issue was also addressed recently by Mahler and coworkers [25]. In a retrospective study in low-risk chest pain patients from North Carolina (USA) they found a 0.6% risk of MACE in 904 patients with HEART scores≤3. The authors state “… the HEART score could substantially reduce cardiac testing in a population with low pretest probability of ACS”. These conclusions were further supported by their other recent article in this journal, where HEART with 0 and 3 h serial troponin after presentation “identified 20% (95% CI 18–23%) for early discharge with 99% (95% CI 97–100%) sensitivity for ACS. The HEART score had a net reclassification improvement of 10% (95% CI 8–12%) versus unstructured assessment and 19% (95% CI 17–21%) versus the North American Chest Pain Rule” [26,27].

The group of high-risk patients (HEART scores 7–10) in our study concerns 17.5% of the entire study population. With a risk of MACE of 50.1% in these patients quick coronary intervention should be warranted according to studies by others [16,28–30]. Obviously, the early direction given by the HEART score should not prevent the treating physicians from further clinical thinking. In many patients the observation should continue for some more hours, with repeated troponins and ECGs, in order to confirm initial findings.

In conclusion, the HEART score for chest pain patients at the emergency department provides the clinician with a quick and reliable predictor of outcome shortly after arrival of the patient, without computer-required calculating. Low HEART scores (0–3), occurring in one third of the patients, exclude short-term MACE with >98% certainty. In these patients one might consider reserved policies. In patients with high HEART scores (7–10) the high risk of MACE may indicate more aggressive policies.

Appendix A:

Table A1. Participating hospitals, principal investigators and numbers of patients in the study

Table A2. Reference values troponin

References: http://www.internationaljournalofcardiology.com/article/S0167-5273(13)00315-X/fulltext

Questions:

1. The HEART score is a decision tool intended to help clinicians predict outcome in chest pain patients.  It is based on which for the following considerations for risk stratification?

1. History
2. ECG findings
3. Age
4. Risk factors
5. Troponin levels
6. All of the above

2. True or False: The  authors report that the HEART score was based on clinical experience and medical literature; and designed to be as easy to use as the Apgar score for newborns.

3. Endpoints in this study were defined as Major Adverse Cardiac Event (MACE) and consisted of which of the following:

1. acute myocardial infarction (AMI)
2. percutaneous coronary intervention (PCI)
3. coronary artery bypass graft (CABG)
4. death
5. All of the above

4. In the group with low HEART score (0-3), six week MACE occurred in ____ of ____ patients which equaled ____%

1. 15; 2440; 1.7
2. 419; 870; 55
3. 15; 870; 1.7
4. 1; 3900; 0.001

5. When comparing “c-statistics” the HEART score performed significantly better (p<0.001) as compared with the following popular scoring tool(s).

1. GRACE
2. KELLY
3. TIMI
4. LASSIE
5. a and c