Category Archives: CCU Rotation

BNP: Data, Diagnosis and Applications

BNP: Data, Diagnosis and Applications

M Lamberta PGY-3


What are the Biomarkers?

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ACEP Clinical Policy

Natriuretic Peptide (NP) assays gained approval by the FDA around the year 2000 for the evaluation of undifferentiated dyspnea and suspected ADHF.  The first commercially available test detected the biologically active hormone BNP, but many more recent assays also detect the inert Amino-terminal cleavage product of the BNP prohormone: N-Terminal proBNP (NT-proBNP). (Table 1)  Both biomarkers are comparable in their diagnostic accuracy demonstrated by Receiver Operating Characteristic (ROC) curves. 


From 1999 to 2000, Maisel et al. recruited 1,586 participants in the first large multinational randomized control trial (RCT) to evaluate BNP for the diagnosis of heart failure in ED patients presenting with acute dyspnea.[1].  The Breathing Not Properly (BNP) study analyzed a subgroup from this cohort to conclude that adding BNP to clinical judgment would have enhanced diagnostic accuracy from 74% to 81%.  This trial supported BNP as a good rule-out test for Acute Decompensated Heart Failure (ADHF) with a sensitivity of 90% for BNP < 100 pg/mL when compared to the gold standard: blinded assessment of two independent cardiologists.   The authors also argued that BNP ruled-in 14 of the 19 patients that were erroneously diagnosed by clinicians as “CHF improbable,” thereby reducing false negatives from 2% to 0.6%.  The improved sensitivity, however, inevitably reduced specificity to near 74% for a cut-off of BNP ≥100 pg/mL. [2] Furthermore, a secondary analysis pointed out the limited application of this biomarker as clinical judgment seemed to outperform BNP assay when applied to the dyspneic patient at the extremes of pretest probability ie greater than 95% or less than 5% certainty of ADHF. [3] Therefore, a higher rule-in threshold (BNP > 500 pg/mL improved specificity of this assay but also opened up a “gray-zone” in the interpretation of BNP where the test could neither rule-in nor rule-out with good certainty.  

By the mid-2000s, the rule-out and rule-in cut-offs for CHF began to gain modest support by professional organizations including ACEP. [4]  Wang et al. contributed to JAMA’s Rational Clinical Examination series by conducting a meta-analysis of these preceding data in addition to 20 smaller studies on BNP to determine Likelihood ratios for BNP.  The meta-analysis calculated a negative likelihood ratio (LR-) near 0.9 (cut-off <100 pg/mL) again promoting BNP as a strong test to rule-out ADHF.  Yet, comparing BNP to patient history “significant for heart failure” (LR+ 5.8) or  “interstitial edema” on chest X-Ray (LR+ 12), BNP stood as an equivocal test to rule-in HF with LR+ 2.7 (≥100 pg/mL).[5]



In the later 2000s, large RCTs would similarly establish the accuracy of NT-proBNP in ADHF.  The PRIDE (N-Terminal Pro-BNP Investigation of Dyspnea in the Emergency Department) constructed ROC curves to conclude that adding NT-proBNP to the evaluation of patients with dyspnea was superior to clinician-estimated likelihood of CHF alone with area under the curve (AUC) measuring 0.90 for clinician alone versus 0.94 for clinician+NT-proBNP, (p = 0.006).[6]  The Canadian IMPROVE-CHF study affirmed similarly that adding NT-proBNP to clinical judgment alone increased the AUC from 0.83 to 0.90. [7]

Despite showing statistical differences in diagnostic accuracy through Receiver-Operator Characteristic Curves, the application of natriuretic peptides did not appear to add much to clinical judgement at the extremes of pre-test probability, so many began to apply it to patients who were considered intermediate pretest probability  (21% to 79%) or under circumstances of competing diagnoses ie COPD vs PNA vs CHF.  Steinhart et al. attempted to better stratify these “intermediate probability” patients by deriving an algebraic model that capitalized on increased positive likelihood ratios at higher absolute levels of NT-proBNP.  In a validation study, this model appeared to correctly reclassify 44% of the “intermediate” patients to either low risk or high risk.  The strength of this approach is that it provides for practical application of NT-proBNP as a continuous variable rather than just relying on discrete cut-offs, it accounts for age-adjusted variability, and it prompts the clinician to appropriately consider pre-test probability before interpreting the test result.  The weakness lies in the fact that it requires math (yet, an excel model is available for download here), and it does not appear to approve diagnostic accuracy in a majority of cases.  In this study, the model helped to correctly reclassify 10% of the study participants. [8,9]

When NPs came to the scene 15 years ago the hope was that it would be the “super-hero” for the bewildered clinician in the diagnosis of dyspnea, but subsequent trials and meta-analyses gave BNP the persona of  more of a “yes-man” supporting what the clinician already knew and equivocating just as much for cases of “intermediate probability.”    The literature of the last 15 years has elucidated NP test characteristics, confounding variables (Tables 1 and 2), and interpretation, but application of the test still appears rather heterogeneous by anecdote as either a rule-in, rule-out, adjudicator, or prognosticator.   



  • Ruling-in low-probability:  BNP as a rule-in test to diagnose patients who are being treated erroneously for other conditions ie a 65-year-old patient with a history of COPD but no current diagnosis of HF. Rosen even suggests “we abandon the routine obtaining of a BNP level for patients deemed to be having a CHF flare-up, and instead consider it in all dyspnea patients that we don’t believe are having CHF.” [10] This implies a sentiment of screening.  In an older population, where prevalence is higher, it may be a good consideration.
  • Ruling-out high-probability:  As expenditures for heart failure continue to soar, the use of BNP, in concert with other clinical signs and adjunct studies, may have significant application for ruling-out ADHF in known HF patients. This may lead to scoring protocol or institutional decision rules to help identify ED patients who are safe for outpatient management.
  • Adjudicating intermediate risk:  Likely BNP will continue to find application case-by-case by the ED clinician who is interested in detecting the presence of heart strain whether it will change management or not.  Interpretation of BNP should be considered after establishing pre-test probability for the patient, with the knowledge of confounding variables, and can employ tools to interpret the test like that proposed by Steinhart et al. (available for download here).  That said, the same cases of intermediate probability will more likely represent the complex and sicker patients requiring longer hospital stays and extended work-ups and more than half the time the knowledge of BNP will unlikely help to narrow the diagnosis. [9]
  • Prognosticating: Elevated BNP almost always suggests a poor prognosis whether it is used to stratify ADHF, NSTEMI, or PE, but prognosis is often more accurately reflected—and more easily assessed—by patient hemodynamics and renal perfusion. [11,12,13] There is no strong evidence that BNP will consistently help an admitting team in their management, but there is still ongoing research discerning how BNP may help in response-guided therapy and discharge planning.
  • Outcomes: Only a handful of randomized controlled trials have measured changes in outcomes for clinicians who use natriuretic peptide assays in the ED.  Meta-analyses of these trials have shows trends towards decreased cost and length of stay, but no reproducible significant difference in these outcomes or in regards to therapy or mortality.  [14,15]




  1. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347:161-167.
  2. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416–22
  3. Schwam E. B-type natriuretic peptide for diagnosis of heart failure in emergency department patients: a critical appraisal. Acad Emerg Med. 2004;11:(6)686-91.
  4. Silvers SM, Howell JM, Kosowsky JM, Rokos IC, Jagoda AS. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med 2007;49:627–69. (BNP Clinical Policy)
  5. Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA 2005;294:1944–56
  6. Januzzi JL Jr, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Am J Cardiol. 2005;95:948-954.
  7. Moe GW, Howlett J, Januzzi JL, Zowall H, for the Canadian Multicenter Improved Management of Patients With Congestive Heart Failure (IMPROVE-CHF) Study Investigators. N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study. Circulation 2007;115:3103–10
  8. Emergency Medicine Journal Club. Does BNP Augment Acue Decompensated CHF ED Management. WUSM-St. Louis. Journal Club November, 2009.
  9. Steinhart B, Thorpe KE, Bayoumi AM, Moe G, Januzzi JL, Mazer CD. Improving the diagnosis of acute heart failure using a validated prediction model. J Am Coll Cardiol 2009;54:1515–21.
  10. Carpenter CR, Keim SM, Worster A, Rosen P, BEEM (Best Evidence in Emergency Medicine). BRAIN NATRIURETIC PEPTIDE IN THE EVALUATION OF EMERGENCY DEPARTMENT DYSPNEA: IS THERE A ROLE? The Journal of Emergency Medicine. 2012;42(2):197-205.
  11. Heeschen C, Hamm CW, Mitrovic V, et al. N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes. Circulation. 2004 Nov 16. 110(20):3206-12.
  12. Binder L, Pieske B, Olschewski M, et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation. 2005 Sep 13.
  13. Singer AJ, Birkhahn RH, Guss D, et al. Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT II): a randomized controlled trial of the effect of serial B-type natriuretic peptide testing on patient management. Circ Heart Fail 2009;2:287–93.
  14. Trinquart L, Ray P, Riou B, Teixeira A. Natriuretic peptide testing in EDs for managing acute dyspnea: a meta-analysis. Am J Emerg Med. 2011;29:(7)757-67
  15. Lam LL, Cameron PA, Schneider HG, et al. Meta-analysis: effect of B-type natriuretic peptide testing on clinical outcomes in patients with acute dyspnea in the emergency setting. Ann Intern Med 2010; 153: 728−735.



LB Daniels, AS Maisel. Natriuretic Peptides. J Am Coll Cardiol. 2007 Dec 18. 50(25): 2357-68. (Tables 1-2)


Continued Reading

JM Kosowsky, JL Chan. Acutely Decompensated Heart Failure: Diagnostic and Therapeutic Strategies. EB Medicine Review (2006).

Mueller TT. Head-to-head comparison of the diagnostic utility of BNP and NT-proBNP in symptomatic and asymptomatic structural heart disease.. Clinica chimica acta. 2004-03;341:41-48.


Cancel the Cath Lab Activation; Its only an NSTEMI

By Andrew Barbera, PGY3

Who Needs a Cath?


63 year old male with history of HTN, OA s/p R hip replacement, PTSD was BIBEMS after syncopal event. Pt states that evening he felt acute general weakness when he was on the subway. The weakness worsened when he got off the subway and was walking in the street. He then developed acute severe SOB and he stopped and rested himself on the trunk of a car. Pt then lost consciousness and awoke in the ambulance. Pt stated upon awakening he was alert and oriented. Pt denied CP, palpitations, diaphoresis or dizziness before passing out or during initial ED evaluation. Pt also denied any recent exercise intolerance, recent chest pain, orthopnea or additional symptoms. Pt reported normal stress test done 6 months ago at VA for unknown reason. Initial EMS ekg showed sinus rhythm, slight left axis deviation, LBBB with 0.5 mm ST depression II, III, avF, I, aVL. Repeat EKG on ED presentation showed NSR, slight left axis deviation, with no ST-T depression/elevations or rhythm issues. Pt had received 162mg of asa by ems prior to ED arrival. During ED evaluation pt developed an episode of acute, moderate, left sided, pressure like CP. Pt was given sublingual nitro and morphine with full resolution within 45 min. Repeat EKG during this episode showed NSR, comparing the previous one, new TWI in III and aVF. Pt’s initial troponin was negative at 0.021, but repeat troponin was positive at 3.37. Cardiology was consulted. Pt diagnosed with NSTEMI. Cardiology at the time declined emergent transfer for coronary cath, and wanted to optimize the patient on medical management. Pt was loaded with 600mg of Plavix and heparin bolus and drip was started. Pt was transferred to CCU for additional medical management and cardiac monitoring.


CCU course pt remained chest pain free, serial EKG’s remained unchanged and pt had serial troponins that were down trending. Pt was additionally risk stratified with ECHO for wall motion abnormalities (hypokinesis) and LVEF and found to be normal. Pt was optimized on medical management with metoprolol, atorvastatin, Plavix and asa. Pt was discharged home with close cardiology follow up.


This made me think what are the indications for cardiac revascularization (aggressive) vs. medical management (conservative) in pts with NSTEMI. According to the 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction, Pt’s with NSTEMI who have signs of persistent angina or electrical and or hemodynamic instability should receive early cardiac revascularization.[1] Pt’s with acute decreased LVEF (40% or less) or signs of heart failure should also be considered for early cardiac revascularization. Additionally pts with any signs of continued or repeat ischemia, or new serious arrhythmia.[2]

Additionally there are several randomized trials including FRISC II, TACTICS-TIMI 18, both of which showed a significant lower rate of primary end point of death or repeat MI, especially in high risk individuals. [3]


In summary it seems that high-risk patients with NSTEMI/Unstable angina should undergo early cardiac revascularization. Patients with signs and symptoms of ongoing or repeat ischemia have better outcomes after reperfusion vs. conservative therapy, along with patients who have failed medical therapy. Pts that are lower risk for repeat or continued ischemia may have greater risk/benefit from the conservative medical management.



[1] Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association . Circulation 2011:2022–2060.

[2] Unstable Angina Treatment & Management. Unstable Angina Treatment & Management: Approach Considerations, Initial Medical Management, Further Medical Management. Available at: Accessed September 2016.

[3] Kumar A, Cannon CP. Acute coronary syndromes: diagnosis and management, part I. Mayo Clin Proc. 2009;84(10):917-38.

Why Not Dobutamine?

Why Not Dobutamine?

PGY3 Neil McCormack


A patient rolls into the emergency room. You don’t need this. You’ve got a lot of other patients. This patient however is in shock. They are hypotensive and with a decreased mental status. You need to give them something and the attending asks what vasopressors you would like. “Why not dobutamine” the intern asks. With a sigh and a heavy eye roll you turn away. But… Why not dobutamine?



Dobutamine            Dobutamine is a synthetic catecholamine used primarily for cardiac stress testing outside of the hypotensive patient (8). This is due to the positive inotropic effects it plays on the heart. Dobutamine acts via a 3:1 selective agonist effect on β1 and β2 receptors respectively. This causes increased contractility of the heart (9). There is, however, a side effect of reflexive decrease in systemic vascular resistance (SVR) causing potential for worsening of hypotension. This is not seen in higher doses of dobutamine and the reason for this is because of dobutamine’s partial α1 agonist effect (9). Given this information, we can intuitively think that giving dobutamine would be a good option for use in a hypotensive patient. But what does the literature say?

There have been a few studies that look at the use and effectiveness of dobutamine in the setting of hypotension (1, 2, 9, 10, 12, 13). Partially due to the α1 partial agonist effect, dobutamine is not a first line recommended treatment option alone in patients with septic or hypovolemic shock (3, 4, 9). It has been proposed as a first line treatment for sepsis patients if used in conjunction with another vasopressor (example: norepinephrine) to prevent the reflexive SVR decrease and hypotension. In the absence of using multiple vasopressors, dopamine and norepinephrine have been listed as the first line drugs of choice for septic shock patients. According to the “Surviving Sepsis” guidelines (3, 4), norepinephrine is the first line vasopressor of choice for sepsis patients. However, dobutamine is the recommended inotropic agent to be used in combination to improve cardiac output (without going to supranormal levels of cardiac output) (3).



But what if this patient has a bad heart? The evidence for use of dobutamine in patients with cardiogenic shock is more favorable (7, 12, 14). Patients who need inotropic support primarily are recommended to undergo dobutamine therapy as their vasopressor of choice in the beginning. This is due to the positive effect that dobutamine has on the contractility of the heart muscle itself. It has been shown as well that dobutamine appears to have a more favorable effect on right ventricular (RV) contractility than on left ventricular (LV) though it is effective in both settings (14). The downside of dobutamine alone is, as mentioned, it is only a partial α1 agonist and thus, if the blood pressure does not respond to the increased inotropic effects, a second line agent will need to be added. In a trial looking at epinephrine vs dobutamine/norepinephrine, there was no difference in the overall outcomes of patients but the epinephrine patients had more side effects (including arrhythmias).

What does all this mean? Well what this means is that the intern may have, in fact, been correct to suggest that we use dobutamine for our now hypotensive patient. It all depends on the suspected cause (IE: cardiogenic vs septic vs other causes of hypotension). It is important to keep in mind, though, that unless this patient has a purely cardiogenic cause (such as severe heart failure), they may also require a second pressure support in order to maintain a healthy blood pressure.



1) Bangash, Mansoor N, Ming-Li Kong, and Rupert M Pearse. “Use of Inotropes and Vasopressor Agents in Critically Ill Patients.” British Journal of Pharmacology 165, no. 7 (April 2012): 2015–33. doi:10.1111/j.1476-5381.2011.01588.x.

2) Beale, Richard J., Steven M. Hollenberg, Jean-Louis Vincent, and Joseph E. Parrillo. “Vasopressor and Inotropic Support in Septic Shock: An Evidence-Based Review.” Critical Care Medicine 32, no. 11 Suppl (November 2004): S455–65.

3) Campaign, Surviving Sepsis. “Leitlinienempfehlungen Zur Sepsistherapie.” Sepsis Und MODS, 2015, 377.

4) Dellinger, R. Phillip, Mitchell M. Levy, Jean M. Carlet, Julian Bion, Margaret M. Parker, Roman Jaeschke, Konrad Reinhart, et al. “Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008.” Critical Care Medicine 36, no. 1 (January 2008): 296–327. doi:10.1097/01.CCM.0000298158.12101.41.

5) Huang, Xuan, Shu Lei, Mei-fei Zhu, Rong-lin Jiang, Li-quan Huang, Guo-lian Xia, and Yi-hui Zhi. “Levosimendan versus Dobutamine in Critically Ill Patients: A Meta-Analysis of Randomized Controlled Trials.” Journal of Zhejiang University. Science. B 14, no. 5 (May 2013): 400–415. doi:10.1631/jzus.B1200290.

6) Levy, Bruno, Pierre Perez, Jessica Perny, Carine Thivilier, and Alain Gerard. “Comparison of Norepinephrine-Dobutamine to Epinephrine for Hemodynamics, Lactate Metabolism, and Organ Function Variables in Cardiogenic Shock. A Prospective, Randomized Pilot Study.” Critical Care Medicine 39, no. 3 (March 2011): 450–55. doi:10.1097/CCM.0b013e3181ffe0eb.

7) Lewis, Tyler, Caitlin Aberle, Diana Esaian, and John Papadopoulos. “EFFICACY AND SAFETY OF MILRINONE VERSUS DOBUTAMINE IN CARDIOGENIC SHOCK.” Critical Care Medicine 43, no. 12 Suppl 1 (December 2015): 34. doi:10.1097/01.ccm.0000473960.43621.41.

8) Miller, Todd D., J. Wells Askew, and Nandan S. Anavekar. “Noninvasive Stress Testing for Coronary Artery Disease.” Heart Failure Clinics 12, no. 1 (January 2016): 65–82. doi:10.1016/j.hfc.2015.08.006.

9) Müllner, M., B. Urbanek, C. Havel, H. Losert, F. Waechter, and G. Gamper. “Vasopressors for Shock.” The Cochrane Database of Systematic Reviews, no. 3 (2004): CD003709. doi:10.1002/14651858.CD003709.pub2.

10) Rudis, M. I., M. A. Basha, and B. J. Zarowitz. “Is It Time to Reposition Vasopressors and Inotropes in Sepsis?” Critical Care Medicine 24, no. 3 (March 1996): 525–37.

11) Smith, Maria A. “Use of Vasopressors in the Treatment of Cardiac Arrest.” Critical Care Nursing Clinics of North America 17, no. 1 (March 2005): 71–75, xi. doi:10.1016/j.ccell.2004.09.010.

12) Steltzer, H., P. Simon, A. N. Owen, M. Thalmann, and A. F. Hammerle. “The Effects of Dobutamine Therapy in Critically Ill Patients Measured by Transoesophageal Echocardiography and Intracardiac Monitoring.” Anaesthesia 49, no. 5 (May 1994): 432–37.

13) “Vasopressors and Inotropes in Shock.pdf,” n.d.

14) Vincent, J. L., C. Reuse, and R. J. Kahn. “Effects on Right Ventricular Function of a Change from Dopamine to Dobutamine in Critically Ill Patients.” Critical Care Medicine 16, no. 7 (July 1988): 659–62.


Which came first: the AFib or the MI?

Which came first: the atrial fibrillation or the MI?

Anna Meyendorff, MD PGY-3

(Image from:


Initial Presentation:

77yo AA F hx HTN, DM, CVA, former smoker presenting with chest pain. Symptoms started 24 hours prior to ED presentation while watching TV. Pain was epigastric/lower sternal, 10/10, nonradiating. Associated with SOB, but not nausea, vomiting, or diaphoresis.

Initial vitals: BP 125/61   P 114   R 21   T 98.4   95% on RA   FS 377


Initial EKG showing afib with RVR with 2mm ST elevations in III and aVF and possible small ST depressions in I, avL. Given diltiazem 20mg IVP with conversion to sinus rhythm, but not resolution of pain. Repeat EKG showing continued ST elevation in the inferior leads, so MEHEART (STEMI code) was activated by ED. Pt given aspirin, plavix, heparin IV bolus. Chest pain resolved by time of cardiology evaluation, so decision made not to proceed with transfer for immediate cardiac cath because symptoms resolved and presentation “unconvincing for STEMI” (per cardiology). In addition, lab results revealed that patient was in renal failure, further increasing the risk of dye infusion. Initial troponin was 5 (normal range <0.09). Pt was admitted to the CCU with dx: NSTEMI, plan for medical management with heparin drip.


CCU #1 course:

Overnight, patient developed worsening chest pain. Evidence of CHF/fluid overload on exam (crackles at lung bases, peripheral edema, JVD). Was given lasix 80mg IVP and started on nitro drip, without resolution of CP. She developed worsening respiratory distress requiring initiation of BIPAP. Serial troponins uptrending from initial (5) to 37 to 96. Creatinine worsened from 2.3 to 2.8. Repeat EKG revealed dynamic EKG changes with more pronounced inferior ST elevations and ST depressions in V3-V6. Pt transferred to interventional cardiology center for immediate catheterization for inferior wall STEMI.


CCU #2 course:

Cath revealed 100% circumflex occlusion and successful PCI with placement of DES. Elevated filling pressures also noted (LVEDP 35mmHg, PCWP 18mmHg), consistent with cardiogenic shock. Post-cath, pt improved and was weaned off nitro and lasix drips. Echo revealed inferolateral and inferior wall akinesis with LVEF 45%. Overnight after cath, patient noted on telemetry to be in afib with RVR (110s-140s), but was asymptomatic. She was loaded with amiodarone for rate and rhythm control. Creatinine continued to uptrend (6.7 on HD#5), urine output diminished; renal consult suspected combination of toxic AVN (contrast-induced) plus hemodynamic insults from afib, decompensated CHF, and acute MI. Discussion ongoing regarding initiation of hemodialysis at the time of this post.



So, this case got me thinking. Was the atrial fibrillation noted initially somehow related to the MI? If so, did one cause the other? Which came first?

Numerous studies have demonstrated that myocardial infarction increases risk of afib. Atrial fibrillation is common in the periinfarction period; it occurs in 6-21% of patients, usually in the first 72 hours post-MI. Development of afib in this window carries increased 30-day mortality as well as long-term mortality. Afib during acute MI can be caused by multiple factors, but is most commonly caused by atrial stretching from elevated pressure secondary to heart failure. It can also rarely be secondary to atrial ischemia or infarction, pericarditis, or atherosclerosis of the vessels supplying the SA and AV nodes. (1, 2)


New studies have been published, including several in 2015, documenting the opposite relationship: that atrial fibrillation increases risk of MI, though the mechanism is poorly understood. Soliman et al published a prospective cohort study in JAMA in January 2014. Analysis of 23,928 adult subjects without heart disease (the REGARDS cohort) over median 4.5 years demonstrated that afib conferred a nearly 2-fold increased risk of MI. Even after adjusting for smoking status, hypertension, diabetes, hyperlipidemia, BMI, aspirin use, and more risk factors, these results remained significant (Hazard Ratio 1.70 [95% CI, 1.26–2.30]). Even more interesting, the subgroup analysis also demonstrated a higher risk in women vs men (HR 2.16 vs 1.39) and in blacks vs whites (HR 2.53 vs 1.26). Recall that the patient in the case example above was both black and female. Unlike sex and race, age was not found to change the risk. Limitations of the study included lack of tracking how this risk develops over time after developing afib. It also did not evaluate asians, hispanics, or other racial groups, potentially limiting result generalizability. (3)


A second study was published by Soliman in Circulation in May 2015 with the goal of further elucidating the cause of the previously noted findings and evaluating their findings with a time variable. The study considered 14,462 participants (the ARIC cohort) over 21.6 years (median). They found that the mean time from afib diagnosis to MI was 4.82 years (median 3.35). The incidence of MI in those with afib was nearly 3-fold higher than those without afib (Incidence rate ratio 2.93), and after adjustments for cardiovascular risk factors nearly 2-fold (1.63). They replicated the findings from the previous study for women vs men (IRR 3.75 vs 2.27, P<0.001), and suggested the same in blacks vs whites (HR 2.05 vs 1.52), without statistical significance (P=0.16). In further subgroup analysis by type of MI, they found afib to be associated with increased risk of NSTEMI (HR 1.80), but not STEMI. NSTEMI is usually caused by a nonocclusive thrombus, while STEMI is usually caused by a complete arterial occlusion. According to the authors, the association with only NSTEMI suggests that direct coronary thromboembolization (the mechanism by which afib leads to stroke) is not the primary mechanism by which afib leads to MI. One proposed mechanism suggests the afib-induced prothrombotic risk (from platelet activation, inflammation, and endothelial dysfunction). An alternative mechanism proposes a rapid ventricular rate (afib with RVR) leading to demand ischemia (NSTEMI). (4)


An editorial in the same issue of Circulation includes the following figure as a graphic for understanding the interaction between these two entities. (5)

pasted image 0

Patients found with new onset atrial fibrillation in the emergency department are often admitted for initiation of anticoagulation therapy with the primary goal of preventing stroke. Atrial fibrillation increases stroke risk by 4-5 fold. Based on the newly emerging evidence, it bears noting that these patients also carry a ~2 fold increased risk for MI. More studies must be performed to evaluate whether this risk should alter the standard management of newly diagnosed atrial fibrillation. What medication regimen is optimal for both MI and CVA prevention?



(1)Angeli FF. Atrial fibrillation and mortality in patients with acute myocardial infarction: a systematic overview and meta-analysis. Current cardiology reports. 2012-10;14:601-610.


(2)Schmitt JJ. Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications.. European Heart Journal. 2009-05;30:1038-1045.


(3)Soliman EE. Atrial fibrillation and the risk of myocardial infarction. JAMA internal medicine. 2014-01;174:107.


(4)Soliman EE. Atrial Fibrillation and Risk of ST-Segment-Elevation Versus Non-ST-Segment-Elevation Myocardial Infarction: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation (New York, N.Y.). 2015-05;131:1843-1850.


(5)Vermond RR. Does myocardial infarction beget atrial fibrillation and atrial fibrillation beget myocardial infarction?. Circulation (New York, N.Y.). 2015-05;131:1824-1826.


Stephanie Haimowitz, PGY3


AS is a 43 yo F, on OCPs for menorrhagia, h/o recent left ACL tear and as a result decreased ambulation x3 weeks, p/w SOB, worse on exertion x2 weeks but acutely worsening on the day of presentation. On the day of presentation, the patient complained of an episode of acutely worsening dyspnea, now occurring at rest and associated with lightheadedness, chest pressure, and diaphoresis.

On Exam, the patient was mildly tachycardic with an O2 sat of 98% on RA at rest. She appeared to be breathing comfortably, although at times noted to take shallow breaths, and the remainder of her exam was unremarkable.

Labs were notable for an elevated troponin of 0.302. EKG showed sinus tach with a ventricular rate of 106 and an incomplete RBBB. CT w/PE protocol showed large bilateral pulmonary emboli in both the right and left main pulmonary arteries with extension into segmental and subsegmental branches, as well as flattening of the interventricular septum with dilatation of the right ventricle.


The patient was started on a heparin drip and admitted to the CCU for hemodynamic monitoring and catheter directed thrombolysis via EKOS, which uses ultrasound to enhance the effects of catheter directed thrombolysis. The patient underwent the endovascular intervention with improvement in her symptoms and repeat echo showed improved RV function. She was switched to Lovenox and discharged home on xarelto.

There are many factors to consider when choosing the appropriate treatment modality for a patient with a PE. In a well-appearing hemodynamically stable patient with evidence of a peripheral or subsegmental PE, anticoagulation with either heparin, a low molecular weight heparin such as lovenox, or one of the newer factor Xa inhibitor oral agents is the most common treatment modality. Factors to consider when deciding whether to escalate treatment include hemodynamic instability, evidence of right heart strain, a large central thrombus on CT, and overall clinical appearance.

While this patient was hemodynamically stable, she had clear evidence of right heart strain (e.g. troponemia, dilated right ventricle, flattening of interventricular septum, and McConnell’s sign- diminished RV systolic function with sparing of the apical wall seen here), and large bilateral pulmonary emboli on CT scan. The RV dysfunction seen on echo is often considered to be predictive of a poor short-term prognosis, thus warranting more aggressive therapeutic measures.[1]

The decision was made to use ultrasound enhanced catheter directed fibrinolysis.

The SEATTLE II Study, published in August of this year, investigated the efficacy of this technique. The use of full dose systemic thrombolysis has fallen out of favor over the past few years due to the risks of severe bleeding and intracranial hemorrhage. By using the ultrasound guided catheter directed approach, a lower dose of thrombolytic can be used because it is injected adjacent to the PE. The study was a single-arm, multicenter design with the inclusion criteria of a proximal PE, age >18, PE symptom duration <14 days, and RV/LV diameter ratio >0.9 on CT. A total of 150 patients were enrolled at 22 sites across the US, at urban, non-urban, teaching, and non-teaching hospitals. The primary outcome was a change in RV/LV diameter ratio pre and post procedure. The primary safety outcome was major bleeding within 72 hours of initiation of therapy. Major bleeding was defined as either intracranial hemorrhage or bleeding causing hemodynamic compromise and requiring intervention such as blood transfusion. Patients enrolled in the study had a mean difference RV/LV diameter of 0.42. There were 16 major bleeding events, however none of these were intracranial hemorrhage.[2]

The most glaring limitation of the study was the lack of a comparator group, such as full dose systemic fibrinolysis, half dose systemic fibrinolysis, or a/c alone. Thus, while the results of the study appear promising, additional comparative clinical studies are necessary to help define the role of ultrasound facilitated catheter directed fibrinolysis in the treatment of acute PE.




[1] 14.Grifoni S, Olivotto I, Cecchini P, et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000; 101:2817.

[2] Piazza, Gregory, Benjamin Hohlfelder, Michael R. Jaff, Kenneth Ouriel, Tod C. Engelhardt, Keith M. Sterling, Noah J. Jones, John C. Gurley, Rohit Bhatheja, Robert J. Kennedy, Nilesh Goswami, Kannan Natarajan, John Rundback, Immad R. Sadiq, Stephen K. Liu, Narinder Bhalla, M. Laiq Raja, Barry S. Weinstock, Jacob Cynamon, Fakhir F. Elmasri, Mark J. Garcia, Mark Kumar, Juan Ayerdi, Peter Soukas, William Kuo, Ping-Yu Liu, and Samuel Z. Goldhaber. “A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism.”JACC: Cardiovascular Interventions 8.10 (2015): 1382-392. Web.

Goodbye MONA? Oxygen in AMI

Goodbye MONA?

From: Best Mona Lisa Parodies @

Dr. Mayuri Patel PGY3

CC: Chest pain and Shortness of breath

HPI: 72F w/ PMHx of Rheumatic fever (s/p AVR repair 9 years prior), pHTN, hFrEF (EF 30%), HLD, DVT (on coumadin) s/p IVC filter BIBEMS for progressive DOE over 1 month. Prior to arrival to ED, pt developed substernal chest pain radiating to jaw associated with diaphoresis and nausea. EMS placed patient on NRB.

Triage VS afebrile BP 129/85 HR 74 RR 24 02 96%RA

General: awake, mild distress, oriented to person, place and time


Pulm: CTA – b/l

Abd: +bs, soft, nt/nd

Ext: 2+ pulses, no cyanosis or edema

EKG – Sinus rhythm, HR 74, STE II, III, aVF with reciprocal changes

Troponin – 12; CPK – 377


MEHEART was activated, patient transferred to Weiler for cardiac catheterization.

Patient given Heparin 5000 Units, NTG Sl, Plavix 600mg, ASA 162mg. En route to Weiler hospital, pt placed on 2L NC.

Hospital course:

Cardiac cath showed mild coronary artery disease for the left ventricle. The 1st acute marginal artery to the right ventricle occluded (possibly culprit). Intervention – medical management.

Patient was admitted to telemetry s/p cardiac cath. ECHO showed dilated left ventricle, EF 20-25%. Patient was elevated by heart failure team for ICD placement, because patient met NYS Class IIa criteria. Patient opted for medical management instead of ICD placement. Patient was evaluated for LifeVest and discharged after medical management.


Traditionally, we are taught that administration of high flow oxygen is the standard of care for patients presenting with cardiac emergencies. However, where does this dogma come from? The earliest evidence comes from 1900, when Steele observed that oxygen relieved pain during episodes of angina pectoris(1). The evidence for this observation came in 1928, when the cause of angina was attributed to hypoxia of the myocardium (2).

It is indeed a strange phenomena that our current day practices are based on studies in early 1900s. There have been multiple subsequent studies showing the harmful effects of oxygen. In 1950, Russek et al. showed that administration of 100% oxygen prolonged EKG changes during exercise tolerance testing and had no effect on anginal pain (3). A 1964 study reported that breathing high concentrations of oxygen (85% to 90%) for at least 30 minutes in the first 24 hours after MI resulted in decreased heart rate, reduced cardiac output, and increased systemic vascular resistance (4). In the following year, a study by Thomas et al. showed that giving 40% oxygen for 20 minutes to patients following MI resulted in a 17% decrease in cardiac output and a 5% rise in arterial blood pressure (5). Certainly not an ideal situation after an AMI. In 1969, a study by Neill showed that in “normal subjects” the availability of oxygen for myocardial metabolism was not affected until arterial oxygen saturation falls as low as 50% (6). However, in patients with CAD, myocardial ischemia was observed in some patients when oxygen saturation fell below 85%. In a subset of patients with triple-vessel disease, 6 minutes of high-flow oxygen reduced coronary blood flow sufficiently to induce myocardial ischemia (7).


The first randomized, double blinded controlled trial of oxygen therapy was conducted in 1976. The study randomized 200 consecutive patients thought to have MI to treatment with oxygen (given via medium concentration mask at 6L/min) or air for the first 24 hours. Patients with CHF, chronic pulmonary disease, or breathlessness from any cause other than AMI were excluded. The group receiving oxygen therapy had a higher level of serum aspartate aminotransferase level than the group receiving room air, indicating greater myocardial damage. Forty-three patients were excluded post-hoc when the diagnosis of MI was revoked. There was a mortality rate of 11% (9/80) in the oxygen group vs. 4% (3/77) in the air group, but this did not achieve statistical significance. The relative risk of mortality in oxygen group 2.9 (95% CI 0.81-10.3; P=0.08). The authors concluded that the results are suggestive of “deleterious effect” of oxygen and that administration of it in patients with uncomplicated MI is not beneficial (8).


What causes the deleterious effects of oxygen therapy? It is theorized that reactive oxygen species are responsible for vasoconstriction. This was shown by McNulty et al. in 2007 in patients with AMI. The study showed that breathing 100% oxygen for 10 minutes increased vascular resistance in the LAD by 23% (9). Interestingly, this increase could be prevented by co-administration of the antioxidant ascorbic acid. The diameter of the large conduit coronary arteries was not appreciably affected, suggesting that vasoconstriction occurs at the level of the myocardial microcirculation.

A Cochrane review in 2013 meta-analyzed available studies on oxygen therapy in patients with AMI. Combing the 4 randomized controlled trials (430 patients with 17 deaths) generated a relative risk of mortality of 2.11 (95% CI 0.78 to 5.68) in participants with confirmed AMI. The authors concluded that due to the small number of deaths, it could be a chance occurrence (10).

The AVOID trial from Australia might be the last straw in the age-old dogma of oxygen for AMI. It is a prospective, multicenter trial with both pre-hospital and in-hospital treatment comparing oxygen (8L/min) with air. It included patients that met STEMI criteria, had symptoms for less than 12 hours and initial 02 saturation >94%. Exclusion criteria included 02 saturations <94%, AMS, and oxygen administration prior to randomization. Primary end points for the study were infarct size measured by Troponin T (TnT) and CK-MB. Secondary endpoints were recurrent myocardial infarction, cardiac arrhythmia and myocardial infarct size assessed by cardiac magnetic resonance (CMR) imaging at 6 months. There were 638 patients randomized, of which 441 were confirmed STEMI who underwent primary endpoint analysis (218 in oxygen group vs. 223 in no oxygen group). The baseline characteristics were similar except for 38% in the oxygen group had anterior infract vs. 33 % in no oxygen group. There was a statistically significant increase in mean CK-MB, however mean TnT was similar. There was an increase in the rate of recurrent myocardial infarction in the oxygen group compared to the no oxygen group (5.5% vs. 0.9%, P=0.006) along with increase in frequency of cardiac arrhythmia (40.4% vs. 31.4%; P=0.05). At 6 months, the oxygen group (139 patients) had an increase in myocardial infarct size on CMR (20.3grams vs. 13.1grams; P=0.04) (11).

The AVOID trail concludes that supplemental oxygen in normoxic STEMI patients increased myocardial injury along with cardiac arrhythmia, and recurrent MI. It was also associated with larger myocardial infarct size. However, the study is not without its flaws. The use of 02 at 8L/min seems excessive and could account for the differences. Also, patients in no oxygen group were given oxygen either during catheterization or in the hospital stay (if 02 saturation dropped below 94%).

Where do we go from here? It seems that every patient who arrives via EMS with complaint of chest pain is placed on a NRB. The literature does not support this notion, and we may in fact be doing disservice to our patients. If there is to be a change in practice, it has to come from both pre-hospital setting as well as ED. There is no denying the importance of oxygen in patients who are hypoxic and having AMI. However, for normoxic patients it might be prudent to stay away from oxygen.


  1. Steele C. Severe angina pectoris relieved by oxygen inhalations. BMJ1900, 2:1568.
  2. Keefer CS, Resnik WH. Angina pectoris: a syndrome caused by anoxemia of the myocardium. Arch Intern Med 1928, 41:769-807.
  3. Russek HI, Regan FD, Naegele CF. One hundred percent oxygen in the treatment of acute myocardial infarction and severe angina pectoris. JAMA 1950, 144:373-375.
  4. MacKenzie GJ, Flenley DC, Taylor SH, McDonald AH, Stanton HP, Donald KW. Circulatory and respiratory studies in myocardial infarction and cardiogenic shock. Lancet 1964, 2:825-832.
  5. Thomas M, Malmcroma R, Shillingford J. Haemodynamic effects of oxygen in myocardial infarction. Brit Heart J 1965,27:401-407.
  6. Neill WA. Effects of arterial hypoxemia and hyperoxia on oxygen availability for myocardial metabolism: patients with and without coronary artery disease. Am J Cardiol 1969, 24:166-171.
  7. Bourassa MG, Campeau L, Bois MA, Rico O. The effects of inhalation of 100 percent oxygen on myocardial lactate metabolism in coronary heart disease. Am J Cardiol 1969, 24:172-177.
  8. Rawles JM, Kenmure AC:Controlled trial of oxygen in uncomplicated myocardial infarction. Br Med J 1976, 1:1121-1123.
  9. McNulty PH, Robertson BJ, Tulli MA, Hess J, Harach LA, Scott S, Sinoway LI. Effect of hyperoxemia and vitamin C on coronary blood flow in patients with ischemic heart disease. J Appl Physiol 2007, 102:2040-2045.
  10. Cabello JB, Burls A, Emparanza JI, Bayliss S, Quinn T:Oxygen therapy for acute myocardial infarction. Cochrane Database Syst Rev2013, 8:
  11. Stub D, Smith K, Bernard S, Bray JE, Stephenson M, Cameron P, Meredith I, Kaye DM: A randomized controlled trial of oxygen therapy in acute myocardial infarction Air Verses Oxygen In myocarDial infarction study (AVOID Study). American Heart Journal 2012, Volume 163, Issue 3, 339 – 345.e1.





July 2014 CCU Rotation


Anthony Clarke, PGY3

July 2014


A 38 year-old obese male  active smoker with history of Asthma, Hypertension, Hyperlipidemia, poorly controlled Type II Diabetes, Acute Tubular Necrosis, and Pancreatitis who  presented with non-radiating, sub-sternal crushing chest pain for 1 hour. The patient described his pain as pressure as if someone was sitting on his chest. He also endorsed nausea,diaphoresis and complained of dyspnea on exertion for about 6 hours prior to his chest pain. On review of systems he denied syncope, drug or alcohol use. He was given sublingual nitroglycerin by EMS which did not alleviate his  chest pain.


In ED patient was seen to be  pale, clammy, appeared to be in moderate to severe distress. His vitals were 137/92, 82, 96.5, 20, 100% 2LNC.  His cardiac and lung exams were unremarkable.


EKG: ST elevations in leads II, III, AVF, V4, V5, V6. ST depressions in leads I and AVL.

Right sided EKG: ST elevations in leads V3R, V4R, and V5R

RCA infarct (click to left to view EKG)

STEMI code activated and patient received Aspirin 325mg, Heparin bolus of 5000U, Clopidogrel 600mg, Metoprolol 25 mg PO and 5mg IVP. Patient was then transferred to cath lab.



Troponin-T 3.93 NG/mL

CPK 2376

Hospital Course

Intervention Lab:
6 French RFA Access
Catherization showed 100% mid RCA , 70% proximal RCA, 70% ostium cux, 50% mid LAD, 70% distal LAD and 60% OM1 occlusions.
Patient received angioplasty and PCI with DES (drug-eluting stents) at mid and proximal RCA.
LVgram showed inferior wall akinesis with LVEF of 50% (mildly reduced)

CCU course

Patient tolerated procedure well and was sent to the CCU for post STEMI management after obtaining 3 DES stents in his mid and proximal RCA. He remained hemodynamically stable and his chest pain had resolved. CXR showed no acute process. He had down-trending cardiac enzymes after an initial increase and his renal function appeared to be normal. Patient has a history of AKI so caution was taken with medications such as ACE-I. Pt was placed on his PO ACE-I and metformin after discharge due to recent dye loading and history of renal injury. He was medically stabilized in the CCU with aspirin 81mg qd, clopidogrel 75mg qd, metoprolol 25mg q12 hrs, and atorvastatin 80 mg qhs. He received in-patient smoking cessation, nutrition, cardiac and diabetic counseling and was discharged with cardiac rehabilitation and follow-up appointments with cardiology, nephrology and primary care.


The patient in the case was a young to middle aged male with multiple cardiovascular risk factors who presented with an acute inferior STEMI. The patient had ST elevations in inferior leads with reciprocal changes of ST depressions in lateral leads, which makes the primary affected artery more likely RCA than LCX. The patient also had a right-sided EKG (not shown above) that had ST elevations in V3R-V5R, which is an indicator of right ventricular (RV) injury. Isolated RV infarcts are rare but they can appear in up to 40% of inferior STEMIs. Patients with RV infarcts can become susceptible to severe hypotension and shock in the setting of preload reducing agents such as nitroglycerin due to the poor RV contractility. This patient was given nitroglycerin in the field, which did not relieve his chest pain but also did not appear to induce  enough reduction in his preload to manifest clinically in his blood pressure. However, care should be taken with the use of nitroglycerin in the management of chest pain if RV involvement is a concern. R sided EKG’s can help to affirm your concerns.

The association of profound hypotension or shock with the use of nitroglycerin in right ventricular involvement in acute myocardial infarction (AMI) has been well documented. Ferguson, et al showed in 1989 that 15 out of 20 patients with documented inferior AMI that received nitroglycerin and became hypotensive had evidence of RV involvement. Meanwhile 18 out of 20 patients with documented inferior AMI that received nitroglycerin and did not become hypotensive had no evidence of RV involvement. The EKG criteria used for this study for RV involvement was 1 mm or greater elevation in at least two right-sided precordial leads. Another association was shown with further analysis showing that 20 out of 28 patients with inferior AMI and RV involvement developed hypotension after administration of nitroglycerin. In addition to using R-sided EKGs, there are clinical findings that may suggest possible RV involvement and prompt caution for the use of nitroglycerin. These patients often look sicker and may initially present with hypotension and signs of R heart failure such as JVD with clear lungs or paradoxical rise of JVP on inspiration (Kussmaul’s sign).

If hypotension ensues the first course of action should be to increase the preload with volume. Patients who are not responsive to volume resuscitation may benefit from vasopressor support, a reduction of RV after-load (nitric oxide, normalization of L atrial pressure) and early re-perfusion.

Another complication which may be encountered in inferior MIs are various arrhythmias especially sinus bradycardia and high degree heart blocks. This is secondary to the fact the RCA supplies the sinus node in approximately 50% of the population and posterior descending branch supplies AV node. Fortunately, sinus bradycardia is often transient and typically improves with atropine. High second-degree and third-degree heart blocks also occur and rarely require permanent pacemakers. Most heart blocks resolve completely after re-perfusion.

Post myocardial infarction cardiac care will have the largest reduction in morbidity and mortality with a multifactorial approach. Patient education is paramount in helping them instill lifestyle modifications and medication adherence. Counseling for weight loss, smoking cessation, diet and exercise regimen are indispensable. Many of these components are incorporated in cardiac rehab, which have shown lower the risk of cardiac death by 25%. Recommended medication therapy for post MI include aspirin, beta-blockers, ACE-I, statins with a thienopyridine such as ticlopidine or clopidogrel for 12 months if stents are used and consideration for eplerenone for patients with L ventricular dysfunction.


1. Antiplatelet therapy after placement of a drug-eluting stent: a review of efficacy and safety studies.
2. Cardiac Rehabilitation

3. Right Ventricular Infarction 

4. Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular.

5. Significance of nitroglycerin-induced hypotension with inferior wall acute myocardial infarction.

6. Chapter 6:Right Ventricular Infarction.

7. tWithTheGuidelines-HF/ACE-InhibitorsBeta-Blockers-Underutilized-for-Heart- Attack-PatientsUCM_313643_Article.jsp. ACE Inhibitors/Beta Blockers Underutilized for Heart Attack Patients.

8. infarction-a-survey-of-uk-current-practice. Lifestyle advice and drug therapy post-myocardial infarction: a survey of UK current practice.

9. Berger, PB and Ryan, TJ. Inferior myocardial infarction. High-risk subgroups. Circulation. 1990. 81:401-4

10.The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal. 2003. 24, 28–66

Is Bicarbonate ever Indicated in DKA? – Dr. E. Sosa

Diabetic ketoacidosis (DKA) is characterized by hyperglycemia, elevated serum ketones, and metabolic acidosis. To explain briefly, this disorder results from dysfunctional glucose metabolism in the context of insulin underproduction and/or insensitivity. Unable to utilize glucose, cells begin to consume fatty acids via anaerobic metabolism, leading to the buildup of acidic ketone bodies and other electrolyte abnormalities. Some common precipitants of this acutely life-threatening condition include infection and noncompliance with insulin therapy in known diabetics. DKA is often how new-onset diabetics initially present, but it can also be found in patients with acute pancreatitis, MI, and CVA. Nevertheless, the complexity of metabolic derangements that come with DKA can be formidable to manage, regardless of the precipitating insult.1

Resuscitation of a DKA patient involves aggressive fluid replacement and insulin administration, all while continuously managing sodium, potassium, chloride, phosphate, and bicarbonate shifts. For this review, we will focus on the management of low bicarbonate levels in metabolic acidosis. Since bicarbonate will be very low in severe cases, many physicians treat this metabolic acidosis with intravenous sodium bicarbonate, hoping to reverse the acidosis more quickly. However, this practice is controversial.2

There are three major adverse effects to consider when using bicarbonate:
1) When given continuously, the acidemic drive to blow off CO2 via hyperventilation is blunted. In the hypercapnic state that results, CO2 crosses the blood-brain barrier preferentially, leading to a paradoxical drop in cerebral pH and neurologic deterioration.3
2) It can actually slow ketone clearance by about 6 hours, causing a more refractory acidosis. Animal studies suggest that bicarbonate induces hepatic ketogenesis.4,5,6
3) The use of bicarbonate might help close the anion gap, but may simultaneously delay correction of the acidosis (low HCO3). This occurs because, while ketones are excreted in the urine, they are naturally excreted with an equal amount of protons when they are excreted with hydrogen or ammonium. Meanwhile, some of the ketoacids will be metabolized to regenerate some of the lost HCO3. This process both closes the anion gap and corrects the acidosis. On the other hand, when bicarbonate is used ketones are excreted with sodium and potassium, which are considered bicarbonate precursors. This process leads to a paradoxical loss of potential bicarbonate, as well as a hyperchloremic non-anion-gap metabolic acidosis. Interestingly, this does not happen in ESRD patients, since they cannot excrete excessive amounts of urinary ketones and bicarbonate precursors.7,8,9,10,11

Based on anecdotal evidence, the pH threshold for administration of bicarbonate had been as high as <7.2 for some physicians in the past.  In 2006 and 2009, the American Diabetes Association (ADA) lowered its pH threshold for IV bicarbonate in DKA from <7.0 to <6.9, respectively.  This was based on the facts that results were varied in studies on patients with a pH >7.0, that there is a paucity of data demonstrating its effect in patients with a pH <7.0, and that there is no published data on patients with a pH <6.85.1,12

In general, the literature supporting the use of bicarbonate in DKA is weak. The body of literature includes mostly case-control and retrospective cohort studies. There are a total of three single- or double-blinded randomized controlled trials (RCT), all of which had sample sizes in the double digits.4,6,13 Pediatric studies tend to look at the risk of cerebral edema, whereas adult studies have not.14,15,16,17 There have been no RCTs in pediatric populations.

A few studies showed an initial improvement in acidosis in the short-term when bicarbonate was used, but they did not demonstrate any sustained benefit beyond a couple of hours. These studies also showed paradoxical worsening of ketonemia in these patients.6,13 Other studies showed that patients who received bicarbonate also needed more potassium supplementation and gained no advantage in terms of hemodynamic stability.13,18,19 One study actually showed a slower rate of lactate clearance in patients who received bicarbonate, implying impaired tissue oxygenation.6 In studies where cerebrospinal fluid (CSF) was analyzed, the bicarbonate group actually demonstrated mild decreases in CSF pH and increases in CSF PCO2, reflecting the rapid transport and accumulation of CO2 across the blood brain barrier.4,20,21 And even in pediatrics, the trend leans toward an increased risk of cerebral edema in the bicarbonate groups.14,15,16

No studies have ever shown any significant difference in mortality, length of hospital stays, neurologic recovery, insulin requirements, or improvement of hyperglycemia. No difference has been shown between slow isotonic infusions vs. small concentrated intermittent boluses, with regard to risk of rapid pH/osmolality changes 4,6,13,18,19,22,23. What we do know is that giving bicarbonate can lead to harm in the form of refractory acidosis, worsened tissue hypoxia, paradoxical CNS acidosis and neurologic decline, and cerebral edema in children.

In summary, since patients routinely recover from DKA with fluids and insulin1,5,14,18, the use of bicarbonate in DKA remains controversial and is explicitly not recommended by some experts.2  The literature simply does not provide convincing evidence of its clinical benefit.  Still, the ADA guidelines say it should be applied in DKA when the pH is below 6.9, despite no evidence to support this recommendation.  But as with any medical debate, clinical equipoise comes into play, and there are a few circumstances in which giving bicarbonate may make theoretical sense.  Those include: 1) patients with a pH below 7.0, in whom decreased cardiac contractility and vasodilatation may be impairing tissue perfusion, and 2) patients with severe hyperkalemia, and 3) patients with coma.  In any case in which bicarbonate is used, it should be discontinued once the pH rises above 7.0.3,24,25  In these special cases, the answer lies with weighing the risks and benefits.

1. Kitabchi AE, Umpierrez GE, Miles JM, & Fisher JN. (2009). Hyperglycemic crises in adult patients with diabetes. Diabetes Care, 32(7), 1335-1343.
2. Chansky ME, Lubkin CL. Chapter 220. Diabetic Ketoacidosis. In: Tintinalli JE, Stapczynski JS, Cline DM, Ma OJ, Cydulka RK, Meckler GD, eds.Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 7th ed. New York: McGraw-Hill; 2011.
3. Narins RG, Cohen JJ. Bicarbonate therapy for organic acidosis: the case for its continued use. Ann Intern Med. 1987;106(4):615.
4. Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med. 1986;105(6):836.
5. Okuda Y, Adrogue HJ, Field JB, Nohara H, Yamashita K. Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis. J Clin Endocrinol Metab. 1996;81(1):314.
6. Hale PJ, Crase J, Nattrass M. Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis. Br Med J (Clin Res Ed). 1984;289(6451):1035.
7. Adrogué HJ, Eknoyan G, Suki WK. Diabetic ketoacidosis: role of the kidney in the acid-base homeostasis re-evaluated. Kidney Int. 1984;25(4):591.
8. Adrogué HJ, Wilson H, Boyd AE 3rd, Suki WN, Eknoyan G. Plasma acid-base patterns in diabetic ketoacidosis. N Engl J Med. 1982;307(26):1603.
9. Owen OE, Licht JH, Sapir DG. Renal function and effects of partial rehydration during diabetic ketoacidosis. Diabetes. 1981;30(6):510.
10. Oh MS, Carroll HJ, Goldstein DA, Fein IA. Hyperchloremic acidosis during the recovery phase of diabetic ketosis. Ann Intern Med. 1978;89(6):925.
11. Oh MS, Carroll HJ, Uribarri J. Mechanism of normochloremic and hyperchloremic acidosis in diabetic ketoacidosis. Nephron. 1990;54(1):1.
12. Chua HR, Schneider A, and Bellomo R. Bicarbonate in diabetic ketoacidosis – a systematic review. Annals of Intensive Care 2011, 1:23.
13. Gamba G, Oseguera J, Castrejon M, Gomez-Perez FJ. Bicarbonate therapy in severe diabetic ketoacidosis. A double blind, randomized, placebo controlled trial. Revista de Investigacion Clinica 1991, 43:234-238.
14. Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. New England Journal of Medicine 2001, 344:264-269.
15. Lawrence SE, Cummings EA, Gaboury I, Daneman D. Population-based study of incidence and risk factors for cerebral edema in pediatric diabetic ketoacidosis. Journal of Pediatrics 2005, 146:688-692.
16. Edge JA, Jakes RW, Roy Y, Hawkins M, Winter D, Ford-Adams ME, Murphy NP, Bergomi A, Widmer B, Dunger DB. The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children. Diabetologia 2006, 49:2002-2009.
17. Edge JA, Roy Y, Bergomi A, Murphy NP, Ford-Adams ME, Ong KK, Dunger DB. Conscious level in children with diabetic ketoacidosis is related to severity of acidosis and not to blood glucose concentration. Pediatric Diabetes 2006, 7:11-15.
18. Viallon A, Zeni F, Lafond P, Venet C, Tardy B, Page Y, Bertrand JC. Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med. 1999;27(12):2690.
19. Lever E, Jaspan JB. Sodium bicarbonate therapy in severe diabetic ketoacidosis. Am J Med. 1983;75(2):263.
20. Assal JP, Aoki TT, Manzano FM, Kozak GP. Metabolic effects of sodium bicarbonate in management of diabetic ketoacidosis. Diabetes 1974, 23:405-411.
21. Ohman JL, Marliss EB, Aoki TT, Munichoodappa CS, Khanna VV, Kozak GP. The cerebrospinal fluid in diabetic ketoacidosis. N Engl J Med 1971, 284:283-290.
22. Duhon B, Attridge RL, Franco-Martinez AC, Maxwell PR, Hughes DW. Intravenous Sodium Bicarbonate Therapy in Severely Acidotic Diabetic Ketoacidosis. Ann Pharmacother 2013;47:970-5.
23. Lutterman JA, Adriaansen AA, van ‘t Laar A. Treatment of severe diabetic ketoacidosis. A comparative study of two methods. Diabetologia 1979;17:17-21.
24. DeFronzo RA, Matzuda M, Barret E. Diabetic ketoacidosis: a combined metabolic-nephrologic approach to therapy. Diabetes Rev. 1994; 2:209.
25. Fraley DS, Adler S. Correction of hyperkalemia by bicarbonate despite constant blood pH. Kidney Int. 1977;12(5):354.