Cardiac arrest, add antibiotics to the kitchen sink?

Clinical scenario:

You get a page out for a 55 yo M in cardiac arrest, EMS reports PEA on their arrival, patient has received 3 rounds of epi prior to arrival, patient achieves return of spontaneous circulation (ROSC) after 5 minutes of ACLS while in the ED. When family arrives they report the patient had been feeling unwell for several days and had a significant cough.  No obvious infiltrate was seen on initial chest xray.  The patient's BP is stable on an epi infusion. You admit the patient to the ICU. Your attending requests drawing blood cultures and starting the patient on broad spectrum antibiotics, and cites data stating antibiotics improves mortality in out of hospital cardiac arrest. You perform a brief literature review. 

Literature Review:

Out of hospital cardiac arrest (OHCA) has a very high mortality rate, where approximately only 23% make it to the hospital alive, and 7.6% survive to hospital discharge. (1) The most common etiology of out of hospital cardiac arrest is presumed to be myocardial in origin. However, several retrospective studies indicate that sepsis and bacteremia may also be a significant contributing factor to OHCA. A study by Coba et al in published in 2014 performed a prospective study to identify the incidence of bacteremia in OHCA patients. They enrolled 173 patients, where all patients had two sets of blood cultures drawn, 77 patients met exclusion criteria (trauma, pregnant, pediatric, single positive culture of skin flora). The overall incidence of bacteremia was 37% (65 patients). The most common bacterial species cultured were streptococcus and staphylococcus and Ecoli and klebsiella for gram positive and gram negative bacteria respectively. Bacteremic OHCA patient had significantly higher lactates, lower pH, and more frequent use of vasopressors. Notably the ED survival was significantly lower in the bacteremic patients (25%) compared to nonbacteremic patients (40%). However, 28 day mortality difference was insignificant in bacteremic vs nonbacteremic patients (93.8 vs 92.6%). The figure below by Coba et al lays out the proposed inter-relationships between bacteremia and sudden cardiac arrest. (1)

Proposed association between bacteremic infection and sudden cardiac arrest. From Coba et al.

Although there is very little data examining pre-existing bacteremia in OHCA, there has been a significant amount of research studying infection following ROSC in OHCA. The most commonly cited sources of post ROSC infection are lung possibly from aspiration during arrest, or gut likely from translocation of flora secondary to low flow state during arrest.  Davis et al performed a retrospective analysis on 138 patients admitted to the ICU following OHCA, and showed that 97.8% had at least one positive mark of infection within 72 hours (positive blood culture, consolidation on cxr, CRP greater than 100 or wbc greater than 11 or less than 4 x10^9 ). In this study approximately 38.4% of patients received antibiotics during the first 7 days of their ICU stay. The authors showed that mortality was significantly lower among those receiving antibiotics versus those not receiving antibiotics (56.6% versus 75.3%). However, highest mortality was within the first three days, and for patients who survived to day 3, there was no difference in mortality between those who received antibiotics already and those who had not. (2)

Take home points:

OHCA is typically presumed to be a primary myocardial event, however there is some data to suggest that sepsis is potentially a significantly under reported cause. Furthermore, there is also data to suggest that following ROSC, infection is quite common, and antibiotics may reduce early mortality. However, caution must be taken, as of yet there are no RTC's comparing prophylactic antibiotics versus placebo in OHCA.

Expert Commentary:
Dr. Holthaus one of our own critical care and sepsis guru's was nice enough to provide some of his own thoughts on this topic, and cardiac arrest in general. 

Things we'd like to see examined in future cardiac arrest RCTs:

1) Antibiotics during arrest - push dose, timing, coverage.

2) Propofol - control for this or exclude as a variable since it has been shown to cause some mitochondrial dysfunction and may be thwarting potential resuscitation benefits.

3) Epi dosing - frequency, continue 1mg push dose vs lower dose vs maximum that is less likely to cause or further exacerbate either ischemic or post-inflammatory cardiomyopathy.

4) Vasopressin-Steroid-Epi- for ED arrest. Link to VSE study in JAMA . VSE (vasopresson-steroids-epi) better than Epi alone for in-hospital arrest Vasopressin (20u, q 3-5min, max 100u, w 1 mg epi pushes)-Methypred (40mg IV x1) w better ROSC (84% vs 66%) and better CPC1/2 survival (14% vs 5%).  Major caveat is time to ACLS was very low at 2 min for both which is way faster than many we see in the ED that are frequently >10 min downtime before EMS.  Hypothesis generating, re-hinting at potential beneficial role of vasopressin and steroids for shock (like sepsis). 

5) ED ECMO for cardiac arrest or refractory/severe shock

6) Remote ischemic conditioning immediately after ROSC- 5 min thigh BP tourniquet to >20mmHg above SBP then deflate, repeat 3-4 times, reportedly induces systemic circulation of a protein that blocks CNS/cardiac opening of the "mitochondrial permeability transition pore" which is the final common pathway for ischemic reperfusion injury).  On recent ED ECMO podcast (Shiner-Bellezo) Link to podcast Remote ischemic conditioning 

Personally since everything (ACLS) isn't getting much results, if I can remember to I will do Vasopressin-Methypred-Epi dosing, I am less excited about a lot of epi (ie 3 pushes tells me if they're trending toward making it or not), I've pushed zosyn and then hung vancomycin in a code (after learning about Coba study). I have generally avoided propofol in past because of known myocardial suppression, and now with concern for mitochondrial insult, I just use fentanyl/versed. In addition I  will try thigh remote ischemic reconditioning, and continue targeted temperature management to 33-36C while hoping for ED ECMO (which I think will be the biggest game changer)  

Submitted and Edited by Louis Jamtgaard PGY-3 @Lgaard
Faculty Review by Chris Holthaus

References

 1) Coba V et al. The incidence and significance of bacteremia in out of hospital cardiac arrest.

Resuscitation. 2014 Feb;85(2):196-202. d

2)Davies K et al. Early antibiotics improve survival following out-of hospital cardiac arrest.Resuscitation 2013 May; 84 (5) : 616-9.

Subchorionic Hematoma: incidental finding or early risk?

Clinical Scenario:

A 20 yo G1P0 at 6wk1day by LMP presented with vaginal bleeding.  She had onset of bleeding 1 hour prior to arrival, soaked through 1 pad.  She was seen at her OB earlier that day (prior to onset of bleeding) and had an US which showed +FHR.  Transabdominal and transvaginal ultrasound showed an IUP with +FHR of 120 BPM (image below).  Her beta hCG was 72,813 and she was Rh+.  Hypoechoic material was seen surrounding the gestational sac, consistent with subchorionic bleeding.  The patient was given return precautions and instructed to follow-up with her OB in 48 hours.  You wonder if should have given any specific precautions regarding subchorionic hematoma?

Correcting Acidosis or Just adding CO2?: On Sodium Bicarbonate for Metabolic Acidosis

Clinical Scenario:

You are working in the emergency department when an elderly male is brought in by EMS after being found unresponsive at home with an unknown downtime.  The paramedics report a possible seizure.  His finger stick glucose registers as critical high.  Post-intubation for poor GCS,  his initial labs reveal an ABG of  6.8/20/90 and a lactate of 18.   As you are signing out the patient to the ICU,  the ICU team requests a sodium bicarbonate infusion.  You wonder, will sodium bicarbonate administration improve outcomes or correct acidosis faster when compared to normal saline?

Physiology & Literature Review:
Other than well-defined indications for sodium bicarbonate administration (such as treatment of Na-channel blockade in TCA overdose or to induce alkalinization in salicylate toxicity), one should be skeptical about administering sodium bicarbonate simply for acidosis. On the one hand if a patient is acidotic, it makes intuitive sense that you should try to alkalinize them, which is why sodium bicarbonate has been used so often in the past.  On the other hand, there is evidence to show that administration of sodium bicarbonate shifts the oxygen dissociation curve, increasing hemoglobin affinity to oxygen,  and resulting in paradoxical tissue hypoxia and causes an increase in lactate production. In addition, it causes an intracellular acidosis.  Despite this,  because it tends to be part of the "code cocktail",  it is often administered anyway. 

Rise in EtC02 after bicarb (Dr. Sacchetti video)

The effect of administration of Sodium bicarbonate on the end-tidal CO2 in an intubated patient with severe metabolic acidosis is well demonstrated by  this video by Dr. Alfred Sacchetti. While we disagree in giving a bicarb drip as mentioned in the video, it does demonstrate the acid-base physiology in real time. 

A small randomized-controlled trial published in Critical Care Medicine more than 20 years ago gave either a blinded bolus of saline or sodium bicarbonate to patients with lactic acidosis vasopressor support [1].  They then checked ABGs one hour later.   While sodium bicarbonate did increase the venous bicarb level, improved pH, it did not improve hemodynamics.

Thomboembolic events after cardioversion in afib

Clinical Scenario:
55 year old with past medical history of hypertension presents with sudden onset palpitations and chest pain that awoke him from sleep at midnight.  Patient presents 3 hours later with complaint of palpitations, chest pain, shortness of breath with stable vitals.  EKG demonstrates atrial fibrillation (a.fib).  Patient undergoes successful synchronized cardioversion.

Clinical Question:
In a patient who is electrically cardioverted within 48 hours of symptom onset of new atrial fibrillation, what is the incidence of thromboembolic complications?  Do you still have to anticoagulate?

Literature review:
Based on the Finnish CardioVersion Study, which included 2,481 patients who had a.fib for less than 48 hours and underwent cardioversion and were NOT started on oral anticoagulation nor peri-procedural heparin, there are certain groups who have higher risks for thromboembolic events.  Of the group as a whole, 0.7% (95% CI 0.5-1.0) had thromboembolic events within 30 days with a median of 2 days and mean of 4.6 days.  The three highest risk factors were female gender (OR 2.1 95% CI 1.1 to 4.0), heart failure (OR 2.9 95% CI 1.1 to 7.2), and diabetes (OR 2.3 with 95% CI 1.1 to 4.9).  Those with no heart failure who were younger than 60 years old had the lowest risk of thromboembolism (0.2%). 

Example of Afib

Hitting the bottle hard, beyond benzos for AWS.

Clinical Scenario:

It’s the age old story, chronic alcoholic evaluated for an unrelated issue, cleared from that issue only to now have developed alcohol withdrawal. The patient in question is a middle aged male with heavy alcohol use history who was transferred from another center for specialist evaluation. After being cleared by the consultant, he is now 24 hours from his last drink and looks decidedly not well. He is tremulous, tachycardic, anxious, and vomiting. You recognize his alcohol withdrawal, but despite treatment, he rapidly worsens requiring very high doses of benzodiazepines and an ICU admission. What adjunct therapies are available for severe alcohol withdrawal?

Synapse in AWS (© 2015 Cynthia Turner cynthiaturner.com)

Alcohol abuse is an exceedingly common problem and alcohol-related ED visits are encountered daily across the country.  Annually, around 500,000 episodes of acute alcohol withdrawal require treatment. The symptoms typically begin to manifest within hours to days after cessation of alcohol and typically peak at 2 – 3 days.  The clinical course of alcohol withdrawal varies widely among patients.  Chronic alcohol use leads to down-regulation of GABA receptors and up-regulation of NMDA glutamate receptors. Additionally, GABA receptor expression is suppressed. In the active drinker, this allows patients to maintain a normal level of consciousness despite blood alcohol levels that would incapacitate a nondrinker. Withdrawal is therefore, associated with a decrease in GABAergic activity and an increase in glutaminergic activity. The increase in excitatory activity and loss of inhibitory activity results in the symptom complex of alcohol withdrawal. Symptoms include autonomic hyperactivity, tremor, insomnia, nausea/vomiting, hallucinations (commonly visual or tactile in addition to auditory), psychomotor agitation, anxiety, generalized tonic-clonic seizures. Benzodiazepines are the standard of care for alcohol withdrawal. Adjunct therapies of old have targeted adrenergic symptoms, not so much the underlying disease. These include beta-blockers and calcium channel blockers. Other more targeted therapies like gabapentin are hindered by prolonged onset of action. Adjuncts that make a bit more sense pharmacologically and are gaining popularity include barbiturates, ketamine, and dexmedotomidine.  Let’s look at some of that data.

EKG Challenge #8 Case Conclusion - The Way to the Heart is through the BRAIN

A middle-aged female is brought in by EMS yelling and thrashing on a stretcher.  Per report, she was found unresponsive next to the couch by her daughter.  She was given 2mg of IM Narcan and woke up a bit and has been agitated ever since.  You just begin your assessment and order some labs before you are pulled away to two Level I traumas and an impending respiratory arrest.  As you head back to the patient's room to complete your assessment, you receive a "critical value" phone call from the chemistry lab.  You are told that your patient has a troponin of 0.65.

After thinking to yourself, "Oh S--- I didn't expect that, not even 100% sure why I ordered it", you realize that you have not yet seen the EKG.  It's not in the chart, so you hurry to her room to find a nurse and security wrestling with  half-naked agitated patient who is trying to stand up on the stretcher and grab on to the light fixture above.  You call your attending and he agrees "that THIS" (turning to the wrestling match) "is not going to work."  You decide to intubate her to facilitate your greatly expanded workup for altered mental status.  Post intubation, you get this EKG:

When you first look at the EKG nothing in particular really jumps out at you.   There are some T wave inversions in I and avL,  as well as a biphasic T wave in V2. Sure that there is something more, you decide to take a moment and go through it systematically.  When you get to examining the intervals, everything on the surface looks fine, but you remember reading on Steve Smith's ECG blog that calculating the QT interval can be tricky (especially for computers) and decide to calculate it yourself:

To calculate the QT interval, you start by drawing a line along the maximum slope of the T wave  and marking where it intersects the isoelectric line.  The distance from the preceding Q wave to this intersection point is the  QT interval :

To calculate the corrected QT (QTc), you  use Barrett's formula and divide the QT interval in milliseconds by the square-root of the preceding RR interval (in seconds).   In the case of our patient, the QTc is 525 ms, prolonged by any standard.

While you are running through your differential for altered mental status + positive troponin + prolonged QT, the patient is taken get a head  CT.  You go with her and recognize the subarachnoid hemorrhage star of death as it appears on the screen of the CT tech in front of you:

Neurosurgery emergently places a ventriculostomy drain and the patient is admitted to the Neuro ICU.   When you go home after your shift, your brain is buzzing, making sleep impossible.  You've heard the term "neurocardiogenic" injury before and decide to look into this interesting brain-heart connection.

Neurocardiogenic injury is a term used to describe the diverse number of cardiac abnormalities associated with central nervous system disease[1].  Patients with neurovascular emergencies (most notably SAH) can develop subendocardial myocyte damage, global or regional left ventricular systolic dysfunction (incidence of 10-28% in SAH), low-grade troponin elevation (20-40% of patients with SAH), and a diverse number of EKG abnormalities linked to the development of life-threatening cardiac arrythmmias.  Significantly, these occur even in the absence of underlying cardiac disease.  Multiple theories have been proposed for the mechanism of neurocardiogenic injury, the most popular of which postulates that a "catecholamine-surge" leads to myocardial damage.  Others postulate that a wide-spread inflammatory state, such as seen in septic shock -induced myocardial dysfunction, is responsible.  Interestingly, the degree of cardiac injury as measured by troponin level (>0.3 ng/mL) correlates with SAH severity (in terms of Hunt/Hess grading) [2].

With respect to EKG findings specifically, EKG abnormalities are common in the acute phase of neurovascular disorders.  They occur in 60-70% of patients in ICH, 40-70% of patients with SAH, and 15-40% of patients with ischemic stroke [1].  The most common EKG abnormality is QT prolongation, as seen in our patient. QT prolongation may precede sudden death from ventricular arrythmmias among patients with SAH [3].  Other EKG abnormalities in acute stroke include -

1.  Wide, deep and bizarre appearing T wave inversions - The most striking EKG manifestation of CNS disorders are bizarre-appearing, deep and widely splayed T waves usually in the precordial leads [4,6].  Some form of T wave abnormality, including both flattening and inversions, is seen in approximately 15% patients with ischemic stroke and 55% of patients with SAH [1]. While we typically associate T wave inversions with acute myocardial ischemia, the EKG changes can occur even patients with normal coronaries [5].

 EKG from patient with an acute L PCA ischemic stroke. Note marked QT prolongation and bizarre-appearing T wave inversions in V2-V5

2.  U waves - In the original case series by Burch (1954) describing EKG abnormalities in stroke, it was observed that a subset of tracings had U waves even in the absence of hypokalemia [4].  Subsequent studies have found new U waves in 13% - 15% of patients with acute ischemic stroke and SAH [1].  In a subset of these cases, it is possible that some of the prolonged QT observed is actually a form of T-U fusion.

Figure from 4 from Burch (1954) demonstrating U waves in a patient with intracerebral hemorrhage

3.  ST elevation - Some form of ST segment change occurs in approximately 20-30% of patients with stroke.  A small subset of these patients will also have ST elevation (see example below).  While ST elevation can be seen with neurocardiogenic injury, it is still important to consider dissection in patients with cerebral ischemia and ST elevation on their EKG.

EKG from 76 yo male with SAH who subsequently underwent cardiac cath with clean coronaries (Source: Reference 6)

While the EKG changes are interesting,  do they have any clinical significance or prognostic value?  This remains unclear.  Cardiac dysfunction and EKG abnormalities due to neurocardiogenic injury are usually transient, normalizing over days 3-8 post-injury (at least for SAH)[1].  One small retrospective study of only 58 patients attempted to examine whether EKG status was predictive of all cause mortality in SAH [7].  While it was found to correlate strongly with severity of SAH, no independent predictive value was found (see table below).  The EKG, therefore, in addition to the clinical exam, may be an indirect marker of SAH severity associated with increased all-cause mortality.

For the most part, the EKG changes themselves do not require specific treatment, but clinical investigation should include evaluating for other potential causes (i.e. electrolyte abnormalities or true coronary ischemia).  Patients with these changes should have continuous cardiovascular monitoring during the acute period because of the risk of serious arrythmmia.  Despite risk of arrythmmia, these patients benefit from specialized neurocritical care, and belong in a NeuroICU instead of a cardiac care unit.

Submitted by Maia Dorsett (@maiadorsett), PGY-3
Faculty reviewed by Peter Panagos and Douglas Char

Take home points:  Troponin elevation + EKG changes does not automatically point to primary cardiac pathology and can occur even in the absence of underlying cardiac disease.  Remember to consider central nervous system pathology in a patient with altered mental status + EKG changes or elevated troponin.  Because EKG changes can have important clinical effects (such as predisposition to life-threatening arrythmmias), the EKG is an important component of the clinical work-up for CNS disorders. And as always, drug-induced altered mental status should be a diagnosis of exclusion because sometimes people use heroin to treat the worst headache of their life.

References:
1. Kopelnik, A., & Zaroff, J. G. (2006). Neurocardiogenic injury in neurovascular disorders. Critical care clinics, 22(4), 733-752.
2. Hravnak, M., Frangiskakis, J. M., Crago, E. A., Chang, Y., Tanabe, M., Gorcsan, J., & Horowitz, M. B. (2009). Elevated cardiac troponin I and relationship to persistence of electrocardiographic and echocardiographic abnormalities after aneurysmal subarachnoid hemorrhage. Stroke, 40(11), 3478-3484.
3.Oppenheimer, S. M., Cechetto, D. F., & Hachinski, V. C. (1990). Cerebrogenic cardiac arrhythmias: cerebral electrocardiographic influences and their role in sudden death. Archives of Neurology, 47(5), 513-519.
4.Burch, G. E., Meyers, R., & Abildskov, J. A. (1954). A new electrocardiographic pattern observed in cerebrovascular accidents. Circulation, 9(5), 719-723.
5.Cropp, G. J., & Manning, G. W. (1960). Electrocardiographic changes simulating myocardial ischemia and infarction associated with spontaneous intracranial hemorrhage. Circulation, 22(1), 25-38.
6. Catanzaro, J. N., Meraj, P. M., Zheng, S., Bloom, G., Roethel, M., & Makaryus, A. N. (2008). Electrocardiographic T-wave changes underlying acute cardiac and cerebral events. The American journal of emergency medicine, 26(6), 716-720.
7. Zaroff, J. G., Rordorf, G. A., Newell, J. B., Ogilvy, C. S., & Levinson, J. R. (1999). Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery, 44(1), 34-39.

Droperidol the psycho dropper or heart stopper?

Clinical Scenario:
You are working a typical EM-1 shift loaded full of psychiatric patients, EMS brings you another agitated male with a history of schizophrenia. He is shouting absurdities and threatening staff members.  The RN glances over at you, 5/2 doc? You're feeling a little different today and order 10mg of droperidol IM. The drug is administered and the patient calms down. With pride you present the patient to your attending. Your attending is alarmed and immediately requests an EKG and places the patient on a cardiac monitor and tells you the patient is in imminent danger of converting into torsades de pointes (TdP) secondary to prolonged QT.  You perform a rapid review of the literature.

EKG Challenge #8: Altered with an Elevated Troponin ...

A middle-aged female is brought in by EMS yelling and thrashing on a stretcher.  Per report, she was found unresponsive next to the couch by her daughter.  She was given 2mg of IM Narcan and woke up a bit and has been agitated ever since.  You just begin your assessment and order some labs before you are pulled away to two Level I traumas and an impending respiratory arrest.  As you head back to the patient's room to complete your assessment, you receive a "critical value" phone call from the chemistry lab.  You are told that your patient has a troponin of 0.65.

After thinking to yourself, "Oh S--- I didn't expect that, not even 100% sure why I ordered it", you realize that you have not yet seen the EKG.  It's not in the chart, so you hurry to her room to find a nurse and security wrestling with  half-naked agitated patient who is trying to stand up on the stretcher and grab on to the light fixture above.  You call your attending and he agrees "that THIS" (turning to the wrestling match) "is not going to work."  You decide to intubate her to facilitate your greatly expanded workup for altered mental status.  Post intubation, you get this EKG:

Read the case conclusion here.

Brought in By Ambulance #5: Chemical Takedown - IM Ketamine for Prehospital Restraint

Clinical scenario: You are working the overnight shift in the Emergency Department (ED) when a pre-arrival for "agitation" pops up on the board.  You see EMS roll by with several police officers and decide that you should follow.  On the stretcher lies a partially clothed, basically unresponsive patient who is maintaining a respiratory rate of 10 and oxygen saturation of 88% on room air.  As you quickly slap on the oxygen, check the patient's response to pain with a sternal rub, see an end-tidal CO2 reading of 35, and contemplate intubation, EMS starts to provide their signout.  The paramedics responded to a call for "altered behavior" and were confronted with a psychotic, agitated, diaphoretic patient who would likely fit the description of Excited Delirium Syndrome (ExDS).  The patient quickly ran at and jumped on a paramedic.  The paramedics, fire department, and police restrained the patient who required multiple doses of Haldol and Ativan to facilitate transport.  As you further assess the patient, you wonder, "is there a better way to chemically restrain a patient that maximizes the safety of EMS providers and patients?".  As the patient's sats improve to 98%, you realize that you have some time to think. You have recently heard about prehospital use of IM ketamine for just this purpose and decide to review the evidence.

Practical exercise:  Calculate the IM Ketamine dose to takedown the Incredible Hulk.

Literature Review:
In 2011, the term "Excited Delirium Syndrome (ExDS)" was coined to describe the clinical syndrome referred to in different venues as "agitated delirium", "excited delirium", or "Sudden Death in Custody Syndrome".   The American College of Emergency Physicians (ACEP) convened a task force to define the spectrum of the syndrome which has the following clinical features [1,2]:

                   - hyper-aggressive or bizarre behavior, including lack of clothing
                   - lack of sensitivity to pain
                   - hyperthermia
                   - diaphoresis
                   - attraction to light or shiny objects

The exact etiology of ExDS is unknown, but there is a strong association with pre-existing psychiatric disease (in particular, schizophrenia) and drugs of abuse (cocaine, methamphetamine, and PCP) [2].

Most importantly,  ExDS conveys a high risk of mortality, in the realm of 10% [1,2].  The exact cause of death is not completely clear, but is thought to arise from severe acidosis or hyperkalemia, and is usually the end result of physical struggle or restraint.  Agitated, combative patients also pose a risk to prehospital providers.  Follow this link to watch a video of ExDS from presentation to death. 

Multiple pharmacologic therapies for chemical restraint of patients with ExDS have been suggested, from anti-psychotics, to benzodiazepines to the dissociative drug, ketamine:

Table 2 from Vilke et. al (Ref 3).

Anti-psychotics and benzodiazepines have long delays to peak effect when given via the IM route, in the realm of 15-30 minutes.  Because of its relatively rapid onset,  there has more widespread  prehospital of IM ketamine for chemical restraint of ExDS.

Several studies have attempted to examine the efficacy of ketamine for prehospital management of ExDS.  Anecdotal evidence for the effectiveness of prehospital ketamine came from initial case series and has been adopted into EMS protocols for extreme agitation [4,5].  These initial case series also highlighted the potential adverse effects of the drug, including hypersalivation, laryngospasm, and hypoxia (at least in the doses used ~ 5 mg/kg IM).

After the initial case series were reported, a pilot, retrospective study of prehospital ketamine for ExDS was published in the Western Journal of Emergency Medicine [6].  In this study, the authors reviewed the paramedic run sheets for 52 violent and agitated patients who were given a single 4 mg/kg dose of IM ketamine  The average time to sedation and medical control was approximately 2 minutes. At the 4 mg/kg IM dosage,  3/52 patients developed respiratory depression, two of whom were intubated.  In each of these cases, the patients had received IV midazolam in conjunction ketamine to prevent emergence reaction.  The authors concluded that "ketamine may be safely and effectively used by trained paramedics following a specific protocol."  A major caveat to this study is that the authors did not examine what happened later in the emergency department.  Interestingly, a previously published case series of 13 patients found that of the three patients who developed respiratory distress, two did so only after arrival to the ED while one patient arrived with ventilation being assisted by EMS [5].  In none of these cases was the impending respiratory distress documented in the prearrival note, suggesting that 6% may be a gross underestimation of the true incidence of respiratory complications. 

Another outcome measure for respiratory complication is by examining incidence of intubation after the patients arrive in the emergency department.  A recent retrospective study published in the American Journal of Emergency Medicine examined the correlation between ketamine dosage and need for intubation [7].  They reviewed the prehospital and emergency department records for 51 consecutive patients who were administered ketamine for prehospital chemical restraint.  Fourteen (29%) of patients required intubation.  Of note, none of these patients were intubated in the field.  Patients who were intubated were administered a significantly higher ketamine dose (6.16 +/- 1.62 mg/kg) than those who were not (4.90 +/- 1.54 mg/kg).  It is not clear what proportion of patients were intubated as a side-effect of the ketamine as opposed to facilitation of  medical care in the emergency department.  It was specifically noted that two of the patients were intubated because of "recurrent agitation and need for additional sedation" and one patient was intubated to facilitate medical workup (a lumbar puncture).  The mortality rate for these patients was not documented, but 71% of the patients were admitted to the hospital, primarily on medical (55%) rather than psychiatric (14%) services.

A final consideration is whether ketamine interacts at all with the psychiatric disorders that underlie some cases of ExDS.  Ketamine acts as an NMDA-receptor antagonist, thereby causing a deficiency in glutamate-mediated

Ketamine chemical structure (wiki)

neurotransmission [8] .   Because PCP and ketamine-abuse can model some aspects of schizophrenia, some have postulated that some aspects of schizophrenia are due to defects in glutamate-mediated neurotransmission.  Indeed, in one study they found that CSF from schizophrenic patients had lower glutamate content when compared with controls [9].  While the "glutamate hypothesis of schizophrenia" remains controversial, because a subset of ExDS syndrome patients have psychotic disorders, one might be concerned that ketamine could have an adverse effect on the underlying psychiatric disease, although this does not appear to have been directly studied anywhere and there are no reports in the limited literature regarding ketamine administration for chemical restraint.

Take Home Points:  ExDS is a syndrome with a high rate of mortality. IM Ketamine is a promising treatment for the prehospital realm because of its rapid time of onset (~2-5 min).  Providers administering ketamine need to have heightened awareness and ability to handle potential respiratory complications, including respiratory depression and laryngospasm.  The long-term effects of single dose ketamine administration in patients with underlying psychiatric diagnoses is unclear.

Submitted by Maia Dorsett (@maiadorsett), PGY-3
Faculty Reviewed by H. Phil Moy

References:
1. Vilke, G. M., DeBard, M. L., Chan, T. C., Ho, J. D., Dawes, D. M., Hall, C., ... & Bozeman, W. P. (2012). Excited delirium syndrome (ExDS): defining based on a review of the literature. The Journal of emergency medicine, 43(5), 897-905.
2. Vilke, G. M., Payne-James, J., & Karch, S. B. (2012). Excited delirium syndrome (ExDS): redefining an old diagnosis. Journal of forensic and legal medicine, 19(1), 7-11.
3. Vilke, G. M., Bozeman, W. P., Dawes, D. M., DeMers, G., & Wilson, M. P. (2012). Excited delirium syndrome (ExDS): treatment options and considerations. Journal of forensic and legal medicine, 19(3), 117-121.
4. Ho, J. D., Smith, S. W., Nystrom, P. C., Dawes, D. M., Orozco, B. S., Cole, J. B., & Heegaard, W. G. (2013). Successful management of excited delirium syndrome with prehospital ketamine: two case examples. Prehospital Emergency Care, 17(2), 274-279.
5.Burnett, A. M., Salzman, J. G., Griffith, K. R., Kroeger, B., & Frascone, R. J. (2012). The emergency department experience with prehospital ketamine: a case series of 13 patients. Prehospital Emergency Care, 16(4), 553-559.
6. Scheppke, K. A., Braghiroli, J., Shalaby, M., & Chait, R. (2014). Prehospital use of IM ketamine for sedation of violent and agitated patients. Western Journal of Emergency Medicine, 15(7), 736.
7. Burnett, A. M., Peterson, B. K., Stellpflug, S. J., Engebretsen, K. M., Glasrud, K. J., Marks, J., & Frascone, R. J. (2014). The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. The American journal of emergency medicine.
8. Murray, R. M., Paparelli, A., Morrison, P. D., Marconi, A., & Di Forti, M. (2013). What can we learn about schizophrenia from studying the human model, drug‐induced psychosis?. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 162(7), 661-670.
9.  Kim, J. S., Kornhuber, H. H., Schmid-Burgk, W., & Holzmüller, B. (1980). Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neuroscience letters, 20(3), 379-382.

EKG Challenge No. 7 Case Conclusion - Not Everything is a Medical Mystery

A 22-year-old female with no past medical history presents to the Emergency Department after a syncopal episode at home. She reports feeling lightheaded and then noticed her heart was pounding, prior to passing out. Her mother caught her, and she came to in "about a minute." She was brought to the ED by EMS. On further history, she stated she had not eaten anything today and had just gotten back from a jog outside when she began to feel lightheaded. She had a few similar episodes in the past when she has had blood drawn. Now she feels slightly weak but otherwise back to normal. Fingerstick glucose is normal, as well as CBC, BMP, and U/A. Her pregnancy test is negative. Her EKG is below.


You review the EKG and are at first concerned about the T wave abnormalities in the V1 - V3.  Your colleague (ahem, attending) then looks over your shoulder and states, "well looks like she might have persistent juvenile T wave inversion". 

Persistent Juvenile T wave Inversion is a benign finding found predominantly in young females [1, 2].  Prior to birth, the right heart must pump against high pulmonary pressures, causing it to be thicker and stronger than the pediatric left heart. Pediatric EKGs often reflect this with right axis deviation and anterior t-wave inversion.  Right axis deviation should resolve before early adolescence, but in some individuals the pattern of precordial T wave inversion persists (hence the name).  The EKG findings of Persistent Juvenile T wave inversion?  Per Amal Mattu (see Mattu's ECG case of the week and Ref 3]:

Shallow and asymmetric T wave abnormalities in V1-V3 (either inversions or biphasic T waves). 
 
From our patient:

Is there any clinical significance to persistent Juvenile T wave inversion and is there anything that we should do about it?  The answer is probably no.  A recent Finnish study [4] recorded EKGs of 10,000 middle-aged patients and then collected morbidity and mortality data for 30 years. 0.5% of patients were found to have anterior t-wave inversion on their baseline EKG. No adverse outcomes were associated with anterior t-wave inversions. A Turkish study [2] evaluated the correlation between anterior T wave inversions in adulthood and risk factors for cardiovascular disease.  No correlation was found in male subjects (where anterior T wave inversions were rare), but women with anterior T wave inversions were more likely to have a lower SBP and a higher incidence of Type 2 Diabetes.  It is unclear whether these findings have any clinical significance or are the product of a shotgun approach to identifying correlations.  However, an Italian study [5] of nearly 3000 peri- and post-pubertal children (age range 8-18) found t-wave inversion to be present in 158 (5.8%), with a significant decline after puberty. These children underwent echocardiography and 4 were diagnosed with cardiomyopathy [including arrhythmogenic right ventricular cardiomyopathy (n=3) and hypertrophic cardiomyopathy (n=1)]. This study recommended further testing for post-pubertal patients with persistent anterior t-wave inversion.

Our patient?  She was diagnosed with vasovagal syncope and was discharged to home.  This was likely an appropriate disposition given the clinical history (although some would have considered an echo per the studies above), which brings up an important point:

                                Always interpret the EKG within the clinical context.

If this EKG had been obtained because of high clinical suspicion for ischemia or pulmonary embolism, the precordial T wave inversions would be significantly more concerning. As an emergency physician, it is important to be aware of the differential diagnosis and implications for different T wave morphologies.

In the context of chest pain,  precordial biphasic t-waves can be concerning in adult patients, particularly in the setting of chest pain [3]. T wave changes can be associated with ischemia or infarct.  In ACS, the T-waves are classically symmetric and concave (see Figure blow) and in contrast to persistent juvenile T wave inversion, more likely to extend to V4-V6.   It is particularly important for emergency physicians and EMS providers to familiarize themselves with Wellen's syndrome, which is characterized by inverted or biphasic t-waves in leads V2-V3 [6].  Wellen's syndrome is associated with a nearly occlusive lesion in the LAD .  Patients present with a history of chest pain and when the EKG is recorded during a pain free period, the anterior t-waves are seen. Cardiac enzymes may be slightly elevated or normal.  If you diagnose a patient with Wellen's syndrome, Cardiology should be consulted emergently for possible catheterization. Emergency physicians should be wary of ordering stress tests for patients with chest pain, normal troponins and anterior t-wave inversion, as this could lead to complete LAD occlusion and death in a patient with Wellens syndrome.

Anterior T wave inversions are also seen in patients with pulmonary embolism, although these after often associated with T wave inversions in the inferior leads as well. 

Precordial T wave inversions are also seen in the baseline EKGs of patients prone to life threatening arrythmmias, which may initially present as syncope.  These have been previously reviewed in a post on the can't miss EKG findings in syncope, but we will briefly touch on them here.
   -  Brugada syndrome [7] is characterized by RBBB and abnormal ST waves in the anterior leads, including t-wave inversion in Brugada syndrome type 1.  Brugada syndrome is associated with a mutation in a cardiac sodium channel, which creates a variation in ventricular repolarization. There are three types of Brugada syndrome, and each type is associated with different t-wave morphology (see Fig).  Although the exact pathophysiology is not known, this channelopathy can also lead to sudden onset ventricular fibrillation or tachycardia.
 - Arrhythmogenic right ventricular dysplasia [8] could also present with t-wave inversion in anterior leads.  Arrhythmogenic right ventricular dysplasia (or cardiomyopathy) is characterized by fibro-fatty replacement of the right ventricular myocardium, and is associated with ventricular arrhythmias. EKG findings can include depolarization and/or repolarization changes in the right ventricular leads, including anterior t-wave inversion.


Take Home Points:  Anterior t-wave inversion is common in children. In adult (females) it can be a normal variant.  However, in the right clinical context, it also be associated with sudden death, PE, or myocardial ischemia, and therefore may merit further evaluation, particularly in patients with chest pain or suspicion for arrhythmia.

Submitted by Laura Wallace (@labellalaura), PGY-3
Edited by Maia Dorsett (@maiadorsett), PGY-3
Faculty Reviewed by Evan Schwarz


References:
1. Assali, A. R., Khamaysi, N., & Birnbaum, Y. (1997). Juvenile ECG pattern in adult black Arabs. Journal of electrocardiology, 30(2), 87-90.
2. Onat, T., Onat, A., & Can, G. (2008). Negative T wave in chest lead V1: relation to sex and future cardiovascular risk factors. Turk Kardiyol Dern Ars, 36(8), 513-518.
3. Hayden, G. E., Brady, W. J., Perron, A. D., Somers, M. P., & Mattu, A. (2002). Electrocardiographic T-wave inversion: differential diagnosis in the chest pain patient. The American journal of emergency medicine, 20(3), 252-262.
4. Aro, A. L., Anttonen, O., Tikkanen, J. T., Junttila, M. J., Kerola, T., Rissanen, H. A., ... & Huikuri, H. V. (2012). Prevalence and prognostic significance of T-wave inversions in right precordial leads of a 12-lead electrocardiogram in the middle-aged subjects. Circulation, 125(21), 2572-2577.
5. Migliore, F., Zorzi, A., Michieli, P., Marra, M. P., Siciliano, M., Rigato, I., ... & Corrado, D. (2012). Prevalence of cardiomyopathy in Italian asymptomatic children with electrocardiographic T-wave inversion at preparticipation screening. Circulation, 125(3), 529-538.
6. Mead, N. E., & O'Keefe, K. P. (2009). Wellen's syndrome: An ominous EKG pattern. Journal of Emergencies, Trauma and Shock, 2(3), 206.
7. Berne, P. (2012). Brugada syndrome. Circ J, 76(7), 1563-71.
8. Corrado, D., Buja, G., Basso, C., & Thiene, G. (2000). Clinical diagnosis and management strategies in arrhythmogenic right ventricular cardiomyopathy. Journal of electrocardiology, 33, 49-55.