EKG Challenge No. 7: Young Lady Swooning?

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.



What is your next step?  Please share your thoughts.

Read the Case Conclusion  here

Hippocratic Medicine No.1: Blood Culture or No Blood Culture, That is the Question.

Welcome to the first installment of our new column here at Everyday EBM - Hippocratic Medicine.  

Modeled after the Do No Harm project pioneered at the University of Colorado, the aim of this (hopefully) monthly installment will be on the avoidance of avoidable care i.e. raising awareness for how medical overuse has the potential to do patient harm.   Because every test or intervention we do has the potential for not just benefit but also harm, we should seek that our patients do better because of the care we provide instead of despite it.  

Clinical Scenario: It is a regular day in the emergency department and along with the regular smattering of chest pain rule-outs, vaginal bleeders, and abdominal pain, you have two patients who need to be admitted for IV antibiotics. One has a diffuse cellulitis of the left leg and the other pyelonephritis, unable to tolerate oral meds. Both have an elevated white count but no other SIRS criteria. When giving sign-out, the inpatient medicine team asks for blood cultures on both patients.  Is there any value for blood cultures in patients with cellulitis and pyelonephritis? Does this value outweigh the potential harms?

Literature Review:The ACEP article [1] “The evidence against blood cultures” presented interesting data regarding cost and benefit of blood cultures. According to the article, in 2010 $151 million dollars was spent on blood cultures. Only 4% to 7% of blood cultures were true positives. Alarmingly, blood cultures are almost as likely to give you a false positive as a true one: 40% of all "positive" cultures are false positives. For cellulitis, only 2% of patients are likely to develop a bacteremia and skin infections are almost always due to Staph or Strep. For uncomplicated pyelonephritis, the urine culture is what is used to target treatment, and if blood cultures are positive, it is almost always with the same organism and does not alter treatment course.
 

With regard to their recommendations for pyelonephritis, the ACEP article draws on a retrospective chart review of 212 patients admitted for uncomplicated pyelonephritis [2] . Blood cultures were performed for 105 of these patients, only 16% of which grew out an organism. Of the 11 positive cultures, all but 2 had the same organism that was identified in the urine and no change was made in treatment. The other 2 were found to have a second infectious source for their bacteremia.
 
With regard to cellulitis, a retrospective review of 710 patients admitted for cellulitis, of which 553 had blood cultures drawn. Of these patients, only 11 cultures (2%) were positive [3]. A 2012 review article in the Journal of infection found 7.9% of patients with cellulitis had positive cultures, all with Staph or Strep identified as the source organism [4]. 

These findings are not limited to the adult population [5].  A retrospective cohort study of blood culture results and microbiology laboratory charges for pediatric cases of community-acquired pneumonia and skin/soft tissue infection found that only 9/279 cultures (3.2%) grew an organism and only 5/9 (55%) were deemed to be true positives.  The main subsequent intervention?  Repeat cultures.  4/9 of these were deemed to be false-positives, leading to a smattering repeat cultures, ID consultation, prolonged LOS, and vancomycin initiation:

Table 2 from Parikh et. al. (Ref 5)

But are there clinical indicators that increase the diagnostic or therapeutic yield of blood cultures? The answer is yes. In a 1996 study, SIRS criteria was found to be 96% sensitive for positive blood cultures and this has been corroborated by other studies [6]. This indicates that in the absence of SIRS criteria aka in the absence of sepsis (2 SIRS + a known infectious source) blood cultures are more likely to be false positives than true positives, and do not meet standards for an indicated test.

As alluded to in the pediatric data, we may be doing more harm than good when ordering blood cultures in patients with uncomplicated [or shall we say SIRS(-) ?] pneumonia, cellulitis or UTI. Just like an incidental finding on an imaging study, false positive blood cultures have the power to beget further testing and intervention. Since we have learned above that the results are unlikely to change treatment course, we know that there are limited benefits. But what about the costs?

- Blood cultures increased cost and hospital length of stay: A retrospective study from Ireland [7] compared "cases" of false-positive blood cultures [defined as a single blood culture set positive for micro-organisms commonly thought of as contaminants or multiple blood cultures positive for different organisms] with "controls" matched for comorbidity via the Charlson index with "true negative" blood cultures. They found an overall false positive rate of 4.7%, and that patients with false positive blood cultures stayed in the hospital for 5.4 days ( 95% CI 2.8 - 8.1 days) longer at a cost of $7502.20 more (95% CI: $4,925.80 - $10, 078.60) compared to counterparts matched for diagnosis and comorbidity. A similar study from Brigham and Women's Hospital published in 1991 [8] found essentially the same results (average increased LOS of 4.5 days and increased total cost of $4,385). 


-  Blood cultures increase unnecessary antibiotic use: In addition to adding to hospital length of stay, part of the additional costs incurred by false positive blood cultures are unnecessary antibiotics [8]. 
A prospective, blood culture cohort study [9] evaluated all blood culures positive for skin flora during a three month period at a US medical center.  In this study, they found 59 false positives aka contaminants with Coagulase Negative Staph in 3, 276 collections (compared with 20 cases of "true bacteremia" with the same organism).  Among the 59 patients in the false positive category, 24 (41%) were treated with antimicrobial agents, predominantly vancomycin.  It is unclear from reading the paper if this was a direct result of the positive blood culture, or due to continuation of empiric treatment; however, the results described by Alahmadi [7] and Bates [8] suggest that the culture results are at least in part responsible.  Beyond the aspect of monetary cost alone, there are a number of harms, including renal injury and spread of antibiotic resistance, that make unnecessary antibiotic use particularly troubling.


It has been written [8] that  "The true costs of a blood culture may greatly exceed the costs of the test itself".   How do we change this?  In the same way we make all clinical tests better - by using them in the appropriate situation and maximizing specificity.
 
                I. Decrease blood culture contamination rates:  The nationwide average for blood culture contamination is thought to be in the range of 3-5%.  At our own hospital (BJH), the blood culture contamination rate was within this range, with a rate of 3-4% for the emergency department compared with 1-2% for the ICU for 2014.  Several studies have demonstrated that increased nursing education and standardization of protocols can have significant impact on contamination rates. For example, one study for multiple centers in Sacramento saw a sustained drop from a 12% to 3% after instituting (and intensively educating about) a protocol of chlorhexidine-based skin cleaner and sterile glove technique in which a sterile glove is used for repalpating the site [10].
           
               II.  Use it in the appropriate clinical situation:  If you are admitting a patient with SIRS(-) pneumonia, UTI, or SSTI just don't do it.  However, make sure to send the urine culture before antibiotics (patient has not gone yet?  That's what a straight cath is for!). If the inpatient medicine team asks you to, use it as an opportunity for education.  Floridly septic?  Go ahead.  Think its endocarditis?  Sure.  


Submitted by Alicia Oberle, PGY-3 and Maia Dorsett (@maiadorsett), PGY-3
Reviewed by Ryan Schneider and Stephen Liang. 
Thank you to Maureen Keating and Carey-Ann Burnham of BJC Micro for our own contamination rate data.

References:
1. Lin MP, Schurr JD. Arm Yourself for the “Cultural” Debate: The Evidence Against Blood Cultures. ACEP Now. Sept 2014 Vol 33 Number 9.
2. Pasternak EL, Topink MA. Blood Cultures in Pyelonephritis: do results change therapy? Acad Emerg Med. 2000; 7:1170.
3. Perl B, Gottehrer NP, Raveh D, et. al. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin Infect Dis. 1999; 29:1483-1488.
4. Gunderson CG, Martinello RA. A systematic review of bacteremias in cellulitis and erysipelas. Journal of Infection. 2012 Feb. 
5.Parikh, K., Davis, A. B., & Pavuluri, P. (2014). Do we need this blood culture?. Hospital pediatrics, 4(2), 78-84.
 6. Jones GR, Lowes JA. The systemic inflammatory response syndrome as a predictor of bacteremia and outcome from sepsis. QJM. 1996; 89:515-522. 7. Alahmadi, Y. M., Aldeyab, M. A., McElnay, J. C., Scott, M. G., Darwish Elhajji, F. W., Magee, F. A., ... & Kearney, M. P. (2011). Clinical and economic impact of contaminated blood cultures within the hospital setting. Journal of Hospital Infection, 77(3), 233-236.
8. Bates, D. W., Goldman, L., & Lee, T. H. (1991). Contaminant blood cultures and resource utilization: the true consequences of false-positive results. JAMA, 265(3), 365-369
9. Souvenir, D., Anderson, D. E., Palpant, S., Mroch, H., Askin, S., Anderson, J., ... & Campbell, D. M. (1998). Blood cultures positive for coagulase-negative staphylococci: antisepsis, pseudobacteremia, and therapy of patients. Journal of clinical microbiology, 36(7), 1923-1926.
10. Denno, J., & Gannon, M. (2013). Practical Steps to Lower Blood Culture Contamination Rates in the Emergency Department. Journal of Emergency Nursing, 39(5), 459-464.

Worse after antibiotics: Precipitating endotoxin release?

Clinical Scenario:

A middle-aged female patient presents to the emergency department stating she was diagnosed with a urinary tract infection (UTI) several days ago, but does not feel like her symptoms are improving with the ciprofloxacin and subsequent bactrim given.  She is currently complaining of nausea, vomiting, chills, back pain, and dysuria.  In triage, her vitals are normal (no fever, not tachycardic, normotensive).  On exam, she seems uncomfortable, but is fully alert and orientated and giving you her entire history.  You order a urinalysis with reflex culture, some fluids, and ceftriaxone to be given.

After 2 liters of fluid and the antibiotics, the nurse comes to tell you the patient is now not alert nor orientated, and hypotensive with systolic in the 70s.  She has no rash or wheezing and you don't think that is necessarily anaphylaxis. You look at her labs and see a white blood count of 22.  Her lactate returns at 16.  You pressure bag 3 more liters of NS into her, and on recheck her lactate has risen to 18!  She is intubated for airway protection and you find that her arterial pH is 6.52, with her bicarbonate on her basic metabolic panel below the detectable level (less than 5).  CT abdomen/pelvis without contrast (given creatinine greater than 10) revealed bilateral peri-nephric stranding, suggestive of pyelonephritis without a stone.

Clinical Question:

After she is transferred up the MICU, you wonder what had happened.  How did this woman, who came in talking to you, suddenly deteriorate so quickly?

Since most urinary tract infections in women are caused by E. coli, could it be that the treatment with antibiotics caused a lysis of gram negative cells and release a bolus of endotoxins into the circulatory system that caused circulatory collapse?

Literature review:

The idea of antibiotic therapy used in a rational manner can precipitate adverse reactions.  For example, the Jarisch-Herxheimer reaction with the treatment of syphilis with penicillin causes transient worsening of symptoms as the spirochetes are lysed.  With the high mortality and morbidity of sepsis, researches have been examining if certain antibiotics can precipitate circulatory collapse due to lysis of bacteria.

The lipopolysaccharide (LPS) found in gram negative bacteria cell walls has been implicated as mediating an inflammatory response from the body in gram negative sepsis.  LPS triggered inflammation weakens mitochondrial oxidative phosphorylation (which correlates well with high ScVO2 found in some septic patients).  The LPS also triggers a release of TNF-alpha and other cytokines such as IL-6 from macrophages contributing to septic shock from decreased myocardial contractile force and decreased systemic vascular resistance, which leads subsequently to hypotension.  Experimental models where TNF-alpha have been injected into animals have resulted in hypotension, metabolic acidosis, acute tubular necrosis, and ultimately death.

While endotoxins are constantly released into the blood stream during bacteria infection, causing patients to feel sick and become febrile, the administration of antibiotics has been shown to precipitate a large release of endotoxins due to lysis of bacteria.  Compared to bound endotoxin, free endotoxin may have up to 50 fold increase in activity. 

Not all antibiotics release endotoxins equally.  Certain beta-lactam antibiotics appear to liberate a greater amount of endotoxin compared to other antibiotics.  The mechanism of action is theorized to be the interaction of beta-lactam antibiotics with the penicillin-binding proteins (PBP) found in bacteria cell walls.  The inhibition of PBP3 specifically seems to cause a decrease in septum formation in dividing cells, causing long filaments to form.  This increase in biomass with subsequent lysis is theorized to be the cause large increase in endotoxin associated with antibiotics that bind specifically to PBP3.  In contrast, antibiotics that bind to PBP2 seem to form more spheroid cells with rapid lysis, leading to decreased endotoxin release.

Periti and colleagues found that aztreonam, piperacillin, ceftazidime, and cefuroxime seem to have high affinities to PBP3.  With increasing concentrations of these antibiotics, they start saturating other PBP sites, causing less filament formations, suggesting that the larger release of endotoxins associated with these antibiotics may be reduced with higher doses of antibiotics.  Ceftriaxone and cefepime appear to have equal affinities for many of the PBPs causing more spheroid cells and less endotoxin release.  Carbapenems such as imipenem and meropenem showed greatest affinity for PBP2.  Many studies have compared imipenem and ceftazidime, generally demonstrating higher release of endotoxin with ceftazidime therapy.  A study by Arditi and colleagues found that ceftriaxone induced a larger endotoxin release and subsequent TNF-alpha release when compared to imipenem, correlating with the theory that imipenem primarily with PBP2 while ceftriaxone has more equal affinity over all binding sites.  Goscinski and colleagues found that in E. coli treated with cefuroxime, there was higher release of endotoxin after the second dose, supporting the theory of filament formation with subsequent lysis.  They also found that the addition of tobramycin reduced the amount of endotoxin released.

Other antibiotics seem to release less endotoxin by various methods.  Polymyxin actually has a binding effect to endotoxins, inhibiting the biological activity of endotoxins.  Some antibiotics lead to the loss of viability in bacteria without lysis and release of endotoxins, such as quinolones.  Gentamicin, tobramycin, and amikacin have even been shown to neutralize the effects of endotoxins.

While studies have clearly shown a link between antibiotics and the release of endotoxins and the effect of endotoxins and cytokines in precipitating an inflammatory response as well as septic shock, it has remained to be seen if this correlates with clinical outcome.  There have been few prospective human studies into the administration of different antibiotics in the treatment of gram negative sepsis.  One pertinent randomized study by Prins and colleagues of urosepsis patients treated with imipenem compared to ceftazidime found a more rapid defervescence with the administration of imipenem.  Endotoxin and cytokine release also increased after administration of ceftazidime compared to no increase in the imipenem group.  However in other physiological measures and mortality, there were no differences between the two study groups.  Another study by Byl and colleagues examined again the difference between imipenem and ceftazidime in human septic patients.  While both antibiotics did appear to induce endotoxin release and increase cytokine production in a small number of patients, there did not seem to be a difference in the two groups.  Both studies found that the endotoxin rise only appreciably happened to a fraction of their study population that were septic. 

In a review by Holzheimer, he found that clinical significance of antibiotic-induced endotoxin release has only been documented in a few clinical disorders such as meningitis and urosepsis.  In a prospective study by Mignon and colleagues in septic patients in an ICU, there was no significant increase in endotoxin levels after initiation of empiric antibiotic therapy however there was clinical deterioration in 42% of patients 4 hours after antibiotic administration, which correlated with higher endotoxin levels when compared to stable septic patients.  Maskin and colleagues randomized 24 gram-negative septic patients between imipenem and ceftazidime.  All patients showed high levels of LPS, TNF-alpha, and IL-6 compared to controls.  TNF-alpha concentrations were higher in patients treated with ceftazidime compared to imipenem, however LPS and other cytokine production was not significantly different.  Many of these studies were limited by small sample sizes as well as sepsis caused by a wide variety of bacteria.

Severe sepsis is a difficult disease to deal with in the emergency department due to the uncertainty of source combined with the multiple comorbidities of the patient.  It requires fluid resuscitation as well as the quick administration of antibiotics.  While it seems that some antibiotics may precipitate circulatory collapse due to release of endotoxins and subsequent increased production of cytokines in a small subset of patients, there have been no large, randomized studies demonstrating a mortality difference in regard to selection of a specific antibiotic.

Take home points:

-Certain antibiotics cause a greater release of endotoxins and cytokines compared to others, possibly correlated with circulatory collapse

-No large, prospective studies have demonstrated an advantage to selecting certain class of antibiotics over another

  

References:

1. Arditi M, Kabat William, Yogev R. Anitibiotic-Induced Bacterial Killing Stimulates Tumor Necrosis Factor-alpha release in whole blood. J Infect Dis 1993;167:240-4.

2. Byl B, Clevenbergh P, Kentos A, Jacobs F, Marchant A, Vincent JL, Thys JP. Ceftazidime and Imipenem-Induced Endotoxin Release. Eur J Clin Microbiol Infect Dis 2001;20:804-807.

3. Goscinski G, Tano E, Lowdin E, Sjolin J. Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: higher release after the second dose. Journal of Antimicrobial Chemotherapy. 2007;60(2):328-333.

4. Holzheimer RG. Antibiotic Induced Endotoxin Release and Clinical Sepsis: a Review. Journal of Chemotherapy 2001;13:159-172.

5. Kirikae T, Nakano M, Morrison DC. Antibiotic-Induced Endotoxin Release from Bacteria and Its Clinical Significance. Microbiol Immuno 1997;41(4)285-294.

6. Lepper PM, Held TK, Schneider EM, Bolke E, Gerlach H, Trautmann M. Clinical implications of antibiotic-induced endotoxin release in septic shock. Intensive Care Medicine 2002;28:824-833.

7. Maskin B, Fontan PA, Spinedi EG, Gammella D, Badolati A. Evaluation of endotoxin release and cytokine production induced by antibiotics in patients with Gram-negative nosocomial pneumonia. Critical Care Medicine. 2002;30(2):349-354.

8. Mignon F, Piagnerelli M, Van Nuffelen M, Vincent JL. Effect of empiric antibiotic treatment on plasma endotoxin activity in septic patients.

9. Periti P, Mazzei T. New criteria for selecting the proper antimicrobial chemotherapy for severe sepsis and septic shock. International Journal of Antimicrobial Agents. 1999;12(2):97-105.

10. Prins JM, van Agtmael MA, Kuijper EJ, van Deventer SJ, Speelman P. Antibiotic-induced endotoxin release in patients with Gram-negative urosepsis: a double-blind study comparing imipenem and ceftazidime. J Infect Dis 1995. 172:886–891

Submitted by Steven Hung (@DocHungER), PGY-2

Faculty reviewed by Richard Griffey

EKG Challenge No. 6 Case Conclusion - Them Dirty Drugs

You are working the day shift at Children's Hospital when you get a medical control call from EMS.  They responded to a call for "altered behavior" at a house to find a partially-clothed and confused teenage boy who was discovered "talking nonsense" by his parents in the living room that morning.  They call you because the patient is somewhat "agitated" and just won't stop picking at every line and piece of equipment.  They want your okay to give him some versed to chill him out.  You agree to 2 mg of IV versed and await his arrival in the emergency department.

On arrival, the patient has a dry mouth, dilated pupils, and speaks some unclear, but seemingly pleasant gibberish.  Mom, through her tears, tells you the patient takes no medications but has "experimented with drugs" in the past.  There is radio silence when you listen for bowel sounds and your ungloved hand meets a dry axilla, confirming the clinical picture of an anticholingeric toxidrome.  Noting his heart rate in the 140's, you decide that it is prudent to get an EKG:

You carefully assess the EKG and review it systematically:
          Rate - tachycardic, regular
          Rhythm - sinus (clear p waves in the lateral leads)
          Axis - Right axis deviation
          Intervals - the QRS is wide (> 100 ms in toxicology), with normal QTc
          Other - Incomplete RBBB (see lead V1) with tall R' in avR

Together, these findings are indicative of Na-channel blockade, the hallmark of which is a widened QRS due to delay of phase 0 depolarization of the cardiac action potential:

Image source: Hollowell et. al. (2005)

Interestingly, the right heart seems to be more sensitive to Na-channel blockade as evidenced by the common finding of RBBB and Right axis deviation in Na-channel blocker toxicity [Ref 1].  This is corroborated by the association of RBBB with Brugada syndrome, which is due to a genetic defect in the SCN5a Na channel.

When you think of the toxicologic differential for anticholinergic toxicity with Na channel blockade, benadryl and TCAs are at the top of your list. Given the widened QRS and overall clinical picture, you administer Sodium bicarbonate and the patient's QRS narrows.  He is admitted to the hospital and has full resolution of all symptoms by morning.  Once awake, he admits to taking "a lot" of benadryl because he was having trouble sleeping.

While we use diphenhydramine for blockade of the histamine H1 receptor, it is a dirty drug that has  blocks both muskarinic acetylcholine receptors and voltage-gated Na channels as well [Ref 2].  This patient's clinical presentation - altered, dry, and tachycardic - is secondary to development of an anticholinergic toxidrome.  The abnormal EKG findings - right axis deviation, widened QRS, R' in avR - are due to Na-channel blockade.

It is important to be familiar with the EKG findings of pharmacologic Na-channel blockade because it is a property of many medications, including both cardiac and non-cardiac drugs.  See the table below from Kolecki & Curry  (1997) [Ref 3] for some common examples:

Because of the importance of Na influx at essentially every stage of  heart beat generation,  the cardiac effects of Na-channel blockade can have a number of manifestations, the unifying theme of which is a widened QRS [Ref 1, 3]:

(1) Intraventricular conduction defects - Na-channel blockade slows propagation of the action potential, which is manifested as a widened QRS, and occasionally this takes on the pattern of recognized bundle branch blocks. At extreme overdoses, the QRS can widen to a sine wave morphology.  If the action potential is completely blocked, this is manifested as asystole.

EKG for patient with cocaine overdose with 1st degree AV block, bradycardia, and markedly wide QRS; Source: Ref 7

With regard to the definition of widened QRS, it is important to note that unlike the standard definition of  > 120 ms, the QRS is considered wide in toxicology when it exceeds 100 ms.  This is rooted in part in a prospective study of 49 patients with TCA overdose that examined the correlation between QRS duration and risk of seizure and/or ventricular arrythmmia [Ref 4].  It was found that in acute tricyclic overdoses, seizures occurred "at any QRS duration of 0.10s or longer (p <.05) but ventricular arrythmmias were seen only with QRS duration of 0.16 seconds or longer (p < 0.0005)."  This finding for TCA overdose has been generalized to the management of all Na-channel blocker overdoses. Therefore, in our patient above, with an initial QRS of 117 ms, there may be cause for concern.

(2) Ventricular Arrythmmias - ventricular arrythmmias occur in Na-channel blockade by a variety of mechanisms. One proposed mechanism is that intraventricular conduction is slowed to a point at which unidirectional block and re-entry tachycardias can develop.  A second mechanism has to do with the fact that many Na channel blockers also block K channels (i.e. all group 1A anti-arrythmmics).  K blockade is associated with QT prolongation, thereby putting patients at risk for torsades.

(3) Bradydysrhythmias - Bradydysrhythmias in the context of Na-channel overdose are thought to occur secondary to Na-blockade at the pacemaker cells.  Bradycardia is rare (but very ominous) in the context of overdose with agents, such as benadryl or TCAs, that also have tachycardia-inducing anticholingeric activity.  Propanolol, a beta-blocker with Na-channel blocking activity, causes bradycardia by beta-blockade as well.

                                                  Ionic currents underlying depolarization at the SA node
                                     Image source: http://www.nataliescasebook.com/tag/cardiac-action-potentials

With regard to treatment, the mainstay is sodium bicarbonate, which has been demonstrated to narrow the QRS in Na-channel blockade secondary to diphenhydramine overdose [Ref 1, 5].  Sodium bicarbonate should be titrated to effect on the QRS.  It is generally recommended that initial boluses of 1 Amp of Sodium bicarbonate at a time be administered until the QRS narrows. Following this, one can consider starting a drip (3 ampules of sodium bicarbonate in 1L D5W infusing at twice the patient's maintenance rate) with close attention paid to the patient's potassium to prevent development of hypokalemia [Ref 1].  As the antidote effects of Sodium bicarbonate have more to do with the Sodium hypertonicity than alkalinization, hypertonic saline can also be considered (and actually works better in a swine model of TCA toxicity) [Ref 6].  Administration of physostigmine can reverse the clinical findings of anticholinergic toxicity, but should be used with caution in patients with a widened QRS, as reversal of anticholingeric tachycardia can unmask Na channel blockade at the pacemaker cells, leading to bradycardia, heart block, and cardiovascular collapse.


Take Home Points -
- If the QRS is wide (> 100 ms) in your overdose patient, they may have Na-channel blockade and Sodium bicarbonate should be considered for treatment.
- All that electrophysiology you learned in medical school does have clinical relevance.
- Clinical syndrome + EKG will likely lead you to the right treatment pathway:

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Agent	Clinical Presentation	EKG effects	Treatment
Antihistamines	Anticholingeric toxidrome: Delirium, mydriasis, anhydrosis, urinary retention, reduced GI motility, tachycardia	Tachycardia, QRS widening, Right axis deviation, tall R' in avR; can progress to bradyarthmmia, heart block, and asystole in large overdose	Sodium bicarbonate;                                                     Consider physostigmine (use with caution with widened QRS)
TCAs	Anticholingeric toxidrome+ hypotension + seizure		Sodium bicarbonate
Cocaine	Sympathomimetic toxidrome: hypertension, tachycardia, agitation, diaphoresis	Wide complex dysrhthmmias, heart block,  ST elevation/depression [Ref 7]	Benzodiazepines; Sodium bicarbonate if widened QRS
Propanolol	Hypotension, bradycardia, seizures	Bradycardia, QRS complex widening	Intralipid

References

[1] Hollowell, H., Mattu, A., Perron, A. D., Holstege, C., & Brady, W. J. (2005). Wide-complex tachycardia: beyond the traditional differential diagnosis of ventricular tachycardia vs supraventricular tachycardia with aberrant conduction. The American journal of emergency medicine, 23(7), 876-889.
[2] Jang, D. H., Manini, A. F., Trueger, N. S., Duque, D., Nestor, N. B., Nelson, L. S., & Hoffman, R. S. (2010). Status epilepticus and wide-complex tachycardia secondary to diphenhydramine overdose. Clinical Toxicology, 48(9), 945-948.
[3] Kolecki, P. F., & Curry, S. C. (1997). Poisoning by sodium channel blocking agents. Critical care clinics, 13(4), 829-848.

[4]Boehnert, M. T., & Lovejoy Jr, F. H. (1985). Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. New England Journal of Medicine, 313(8), 474-479.
[5] Sharma, A. N., Hexdall, A. H., Chang, E. K., Nelson, L. S., & Hoffman, R. S. (2003). Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. The American journal of emergency medicine, 21(3), 212-215.
[6]McCabe, J. L., Cobaugh, D. J., Menegazzi, J. J., & Fata, J. (1998). Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Annals of emergency medicine, 32(3), 329-333.
[7] Kerns II, W., Garvey, L., & Owens, J. (1997). Cocaine-induced wide complex dysrhythmia. The Journal of emergency medicine, 15(3), 321-329.



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

Let it Flow: Tamsulosin For Kidney Stone Expulsion

Clinical Scenario:
A middle- aged man with no significant past medical history presents with acute onset right flank pain.  A CT renal stone protocol scan finds a 4 mm kidney stone.  You provide hydration and pain control, and soon the patient starts to feel better.  As you are preparing to discharge the person, what is the evidence that tamsulosin helps with stone expulsion?

Image source: modified from gopixpic.com

Literature review:

A 2014 meta-analysis published in the Canadian Journal of Emergency Medicine [Ref 1] selected 22 studies which were all randomized, had radiologic confirmation of renal stone, and compared tamsulosin (mostly 0.4mg daily) against placebo with standard therapy given to all patients (NSAIDs, hydration, and/or opioids).  The primary outcome was percent of spontaneous passage of distal ureterolithiasis of less than or equal to 10mm, while secondary outcomes evaluated mean time to expulsion, complications/side effects, and impact of varying stone size on expulsion.  Many of the studies had a high risk of bias secondary to poor descriptions of the randomization process.  Of the 22 studies, there was an overall suggested benefit for stones less than or equal to 5mm (RR 1.50 95% CI 1.31-1.71) and among the studies that were double-blind and randomized there was a suggested benefit (1.22 95% CI 1.06-1.41).  However, of the studies that were considered to have low risk of bias, there was no statistically significant relation between tamsulosin and expulsion (RR 1.15 95% CI 0.92-1.47). Thirteen studies analyzed mean time to expulsion of distal stones, and it was found that tamsulosin decreased expulsion time by 3.33 days.  There did not seem to be a significant association for the number of hospitalizations, urology consults, or average number of pain episodes with the use of tamsulosin.  Again, when limited to studies with low risk of bias, there was no significant gain in mean time to expulsion with tamsulosin.  The most common side effects were orthostatic hypotension and retrograde ejaculations.

A 2014 meta-analysis published by the Cochrane Database [Ref 2] presented data more in favor of the use of tamsulosin.  Tamsulosin had better rate of expulsion (RR 1.48, 95% CI 1.32 to 1.67, P < 0.00001) as well as time to expulsion with 2.91 days shorter when compared to control (95% CI -4.00 to -1.81, P < 0.00001).  It did not significantly affect pain scoring, but slightly reduced the number of pain episodes.  Patients using tamsulosin were more likely to experience side effects compared to standard therapy and placebo including dizziness, palpitations, headache, retrograde ejaculations, fatigue, and postural hypotension.

Take Home:
-Tamsulosin seems to shorten time to expulsion of kidney stones
-Tamsulosin does not reduce pain from kidney stones
-Most common side effects are orthostatic hypotension and retrograde ejaculations

References:
1. Malo C, Audette-Côté JS, Emond M, Turgeon AF. Tamsulosin for treatment of unilateral distal ureterolithiasis: a systematic review and meta-analysis. CJEM. 2014 May 1;16(3):229-42.
2. Campschroer T, Zhu Y, Duijvesz D, Grobbee DE, Lock MT. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014 Apr 2;4:CD008509.

Submitted by Lydia Luangruangrong, PGY-3.

Edited by  Steven Hung (@DocHungER), PGY-2

Faculty reviewed by Joan Noelker