Atrial fibrillation in the ICU: Tough AF to Treat, Sick AF to care for…

Peer Reviewed by Dr. Sagar Dave, DO

Every once in a while, it’s a good thing to get down to the nitty gritty of things. I think this is most helpful in common situations. Atrial fibrillation is one of those things to have quickly accessible in your internal brain. In this episode I want to go through some useful studies regarding atrial fibrillation (AF) in the ICU. As usual this is not a how to guide but my synthesis of select articles regarding atrial fibrillation in the ICU. As such this blog is not intended to substitute for medical knowledge by an experienced provider so this is not an authoritative review. It is intended to be an informational supplement that was briefly peer reviewed.  I divided this up into 3 sections. The first is the real down and dirty nitty-gritty painful detail. This is followed by a brief organized summary section ending with an even more abridged algorithm in an attempt to distill it all into a cohesive thought. So, read ahead with caution!  


  • AF Atrial fibrillation
  • CI: Confidence Interval
  • NOAF: New Onset AF
  • AA: Anti-arrhythmic
  • HR: Hazard ratio
  • RR: Risk ratio
  • DCV: Direct Cardioversion
  • EF: Ejection Fraction
  • OR: Odds Ratio
  • NE: Norepinephrine



Causes of AF 

AF risk factors in the critically ill have not been consistently linked to traditional risk factors associated with AF in the ED or community setting (ie, structural and valvular heart disease). It is thought that acute events during critical illness accelerate cardiac remodeling and fibrosis to rapidly produce a susceptible atria (the so-called “atrial substrate”). This allows for the development of sustained AF in as a result of the assault on the body in the ICU by a variety of arrhythmogenic triggers. Accelerated remodeling can occur due to infection and inflammation. Murine and primate models of pneumonia show that bacteria deposit within the myocardium and result in development of atrial fibrosis eve with the treatment with antibiotics. Furthermore, bacteria can alter ion channels gene expression through toxin release [Bosch et al., 2018]. In addition to the bacteria and response to critical illness, we in the intensive care unit further flagellate the heart. Dopamine and epinephrine in particular have chronotropic effects that can lead to increased atrial ectopic discharges triggering new AF. 

 Recall dopamine, in particular in the 2010 SOAP II Trial[a], almost doubled the rate of atrial fibrillation in septic patients (20% vs 11%) [De Backer et al., 2010]. 

Greater illness severity is also associated with the risk of new AF development. Lastly, atrial size on echocardiography is associated with new-onset AF in the ICU, suggesting that iatrogenic atrial pressure/ volume overload may also be important in the development of AF in the critically ill [Bosch et al., 2018].

Risk Factors Associated with AF

The above figure is from a study by Kanje and shows risk factors identified at the onset or immediately before the development of new-onset AF (n = 139)[Kanji et al., 2012].

In a study by Moss of 8356 ICU patients, 10% had new onset atrial fibrillation (NOAF). The strongest associations were acute respiratory failure, advanced age (> 60 yr), and sepsis[b] [Moss et al., 2017]. Weaker but still significant associations were postoperative state, severity of illness, hemorrhage, vasopressor requirement, valvular heart disease, gender, and chronic lung disease [Moss] [Ibid.]. Heart failure, kidney disease, and body mass index (BMI) were not significantly associated with NOAF [Ibid.].

Incidence of NOAF

Walkey[c] in 2011 published a retrospective cohort of a California Database of administrative claims -over 3 million hospitalized adults. Severe sepsis (n = 49,082) occurred in 1.56% of those hospitalizations. New-onset AF occurred in 5.9% of patients with severe sepsis vs 0.65% of patients without severe sepsis [Walkey et al., 2011].

In another study by Walkey in 2014 they identified138,722 sepsis survivors via a Medicare 5% sample. In that group 7% (9,540) had NOAF during sepsis, 24% (33,646) had prior AF, and 69% (95,536) had no AF during sepsis. AF occurred following sepsis hospitalization more commonly among patients with NOAF during sepsis (54.9%) than in patients with no AF during sepsis (15.5%) [Walkey et al., 2014].

In 2020, a study by Fernando found 10% of admissions had NOAF. 22.4% of those NOAF patients went on to have sustained AF lasting longer than 24h [Fernando et al., 2020]. 

Furthermore, we may be missing some AF. Moss performed a retrospective cohort of ICU admissions for NOAF using automated detection (≥ 90 s in 30 min). In 8356 ICU admissions there were 123 (1.5%) documented cases of NOAF. However, they found sub-clinical AF in 626 patients (7.5%) for an overall incidence of any NOAF of 9%. Furthermore, in the Moss study, only 123/749 (16%) were likely persistent [Moss et al., 2017]. 

I’m sure as time goes on and more elderly come into the ICU and technology advances to have minute by minute recordings of vital signs the incidence of AF will continue to rise. 

Hemodynamic instability and AF

This will be the hand waving portion of the day. It is VERY difficult to distinguish instability of AF vs instability of critical illness. In the ICU, incredibly sick patients are “stable” on 0.25 (or more!) mcg/kg/min of NE, 0.03 of epi, 0.03 of vaso and have gotten 4L of fluid.  We have to figure out if there is a driving force that is making the patient unable to come off support and is that driving force AF. In that sense, I submit that “stable”—critically stable or meta-stable—p atient in the ICU has a VERY different connotation (as opposed to denotation) than many might be used to. 

Interestingly, 37% of critically ill patients with NOAF developed immediate hemodynamic instability, 11% exhibited new signs of cardiac ischemia and heart failure [Bosch et al., 2018].

In a study by Kanji et al. those with unstable AF were more likely to be receiving vasopressors/inotropes at the time of AF onset (53% vs 29%), to have decompensated heart failure resulting in pulmonary edema within 24 hours before the onset of AF (18% vs 6%), or to have an initial ventricular response greater than 150 beats per minute within the first 6 hours of AF (35% vs 16%, P = .01) [Kanji] [Kanji et al., 2012]. 

For this reason, maybe looking for new heart failure, a faster rate and increasing need for vasopressor might be helpful (or might not…).

Rates of attempted cardioversion of AF during critical illness are low: in postoperative patients who developed AF, attempted cardioversion resulted in immediate conversion to sinus rhythm (SR) in 71% of patients, but after 1 h, only 43% patients remained in SR, and after 24 h, only 23% patients remained in SR [Bosch] [Bosch et al., 2018]

Side Bar: What is your MAP goal?

Typically, we (stringently) target a goal MAP of 60. However, can a lower MAP goal be tolerated in critically ill patients? While this is subject of much debate one author looked at the elderly patients and the use of a lower MAP goal (60-65mmHg)

Lamantagne performed a multicenter, open-label feasibility RCT of 188 patients and compared lower (60–65 mmHg) to higher (75–80 mmHg) MAP targets and found no difference in SECONDARY outcomes of mortality (28d) or Renal SOFA scores [Lamontagne et al., 2016].

This prompted a follow up RCT by the same investigators.  “The 65 Trial” randomized 2600 patients over age 65 to MAP >60 mmHg or >65mmHg. They found no difference in death (41% vs 44%) and no difference in CRRT (24% in both groups) or urine output. However this endpoint did not lower supraventricular arrhythmias (12 vs 13 episodes) [Lamontagne et al., 2020]. 

[See Blog post:

Side Bar: Is your [radial] arterial line accurate? 

I love putting in a good arterial line but often you will see numbers you cant interpret[d]. Thus, we end up comparing it to something else (like a BP cuff and BTW the MAPs should be within 10 of each other). From the two studies below maybe we should switch out that radial for a femoral arterial line in shocked patients with up trending vasopressor requirements? (A maximal intensity suggestion, I know)

One prospective observational study of 159 patients in septic shock compared simultaneous arterial measurements of radial and femoral lines. Mean difference between radial and femoral MAP was +4.9 mmHg; during high-dose NE (>0.1 mcg/kg/min) NE this increased to +6.2 mmHg (95% CI: -6.0 to +18.3 mmHg). MAP differences > 5 mmHg) occurred in up to 62.2% of patients with high-dose NE therapy [Kim et al., 2013].

A second prospective observation trial of 77 patients in septic shock also comparing simultaneous radial and femoral lines found a difference in 75.4% of cases up to 5 mmHg. Of those, 25% had gradients more than 5 mmHg, 20.4% had the femoral MAP greater than radial MAP and 4% had radial MAP > Femoral MAP. The interval (difference in no direction) ranged from 16 mmHg in the no-NE group, 18 mmHg in the low-NE group, and 19 mmHg in the high-norepinephrine group [Antal et al., 2019].

Is AF a harbinger of Acute MI or Pulmonary Edema

In the study by Kanji [Kanji et al., 2012] of 3081 patients over 1 year in the ICU they found 348 patients (10%) with AF. 4.5% of them had NOAF and 6% had preexisting AF. Acute myocardial infarction occurred for the first time in the 24 hours after AF in 7% (9/139) of the NOAF group and in the preexisting AF group in 4% (8/186). Acute pulmonary edema occurred for the first time in the 24 hours after AF in 4% (6/139) of the NOAF group and in the preexisting AF group in 2% (4/186).

Thus, while a small incidence it is something to consider and not just focus on the rhythm! I’m not sure we need to get troponin on every patient but I do think we take a good look at those ST segments on the ECG and even another reason to not settle for a monitor produced ECG.

Treatment Options

Obviously, this is not an exhaustive list. This is going to be a review of MY go to strategies. As always in medicine there are many options. This is just one person’s journey…

Should we treat atrial fibrillation at all (Do you even cardiovert, brah?!)

Before we actually talk about treatment, do we even need to treat atrial fibrillation in the sick patient? Obviously no one knows the answer to this. From above it does seem some of this is transient and never even diagnosed. However, in a retrospective descriptive cohort study from 2 urban ED’s Scheuermeyer looked at ED patients with atrial fibrillation and an “acute underlying illness” [Scheuermeyer et al., 2015]. They identified patients 416 patients who were divided into those treated for the underlying condition with AF and those treated only for the underlying condition. 135 had rate and/or rhythm control; 281 were not treated for AF  (35% of the treated and 30% of the not treated were diagnosed with sepsis). Of the 135 with AF control 19% had successful rate control and 13% had successful rhythm control. 40% of the treated for AF group had any adverse events; vs 7.1% of those not treated for their AF. Adverse events were divided into major and minor events:

  • 14% of the treated vs 1% of the untreated had major adverse events: hypotension requiring pressors and Intubation
  • 33% of the treated vs 7% of the untreated had minor events: hypotension requiring fluid bolus and bag-valve-mask oxygenation

Direct Cardioversion (DCV)

I love me some electricity! I’m comfortable doing it and we know in the ED setting it is safe and likely associated with shorter ED stays [Stiell et al., 2020]. Since ICU NOAF is not as well studied in the literature it is difficult to distinguish success of amiodarone vs DCV because they are so often used together. So this water is likely pretty muddy and DCV and amiodarone are entangled.

In a study by Kanji, DCV was attempted in 26 (19%) of 139 patients with new-onset AF, (70% had received amiodarone just prior or during DCV). Conversion to sinus for ANY duration occurred in 13/26 (50%) but was maintained for at least 24 hours in only  (27%) of 7/26. By comparison Conversion to sinus for ANY duration in the amiodarone group occurred in 103/116 (88%) but maintained for at least 24 Hours in only 24/116 (20%) [Kanji et al., 2012]. A low yield of DCV appears to be consistent in the only other study of DCV in critically ill. 

Mayr performed DCV in 37 patients. 13 patients (35%) converted to SR, of those 8 patients remained in SR (24%) at 1 hr, 6 patients (16%) at 24 and 5 patients (13.5%) at 48 hrs. Notably, this study used monophonic waveforms and anterolateral placement [Mayr et al., 2003]. It would seem if you are going to cardiovert, do it as early as possible near the onset as success seems to decrease. 

In the category of most unexpected, Blecher found that in cardioversion of AF in the ED, drug use PRIOR to electrical cardioversion reduced the success of electricity. This is OPPOSITE of what is commonly believed that slowing the ventricular response before attempting cardioversion increases the success rate, although there is little evidence to support this. Blecher (part of the Ian Stiell research powerhouse) looked at ED cardioversion for discharge home in 634 patients who underwent attempted cardioversion: 428 electrical, 354 chemical, and 148 required both. They had 378 successful and 50 unsuccessful electrical cardioversions. Medications used included: Beta-blockers (~33%), Sotalol (~10%), Amiodarone (~5%) and Digoxin (~2%). They found that 64% of those failing electrical cardioversion had the ventricular rate slowed before the attempt at electrical cardioversion versus 38.4% of those successfully converted. Thus, more failures at electrical cardioversion had rate control prior! They found rate control and prior attempted chemical cardioversion was associated with decreased likelihood of successful electrical conversion: OR 0.39 (95% CI 0.21–0.74) and 0.28 (95% CI 0.15–0.53)   [Blecher et al., 2012]. A clinically significant OR (Odds Ratio) is considered to be an OR 0.3 or less!

Electrode Positioning in DCV:

In (what I could find as) the only RCT of electrode positioning a study by Kirchhof[e] et al. of PERSISTENT AF, cardioversion was successful in a higher proportion of the anterior-posterior than the anterior-lateral group ([96%] vs [78%]). Cross-over from the anterior-lateral to the anterior-posterior electrode position was successful in 8/12 patients, whereas cross-over in the other direction was not successful (0/2) [Kirchhof et al., 2002].

Other observational trials have shown inconsistent results regarding electrode positions on the success.  In a meta-analysis of 10 trials with 1281 patients the anterior-posterior electrode position had no advantages in terms of success of electrical cardioversion [Zhang] [Zhang et al., 2014].

However, even in this trial they noted the only study without bias is the Kirchoff [Kirchhof et al., 2002] trial so I continue to use the AP position. Also, the AP position to me makes sense in CARDIOVERSION since you want to be across the atria, the anterior lateral position makes sense to me in DEFIBRILLATION since you are across the LV. Impedance of the chest wall is likely a large factor and is likely affected by BMI. You can ask me in person my strategy to overcome high chest wall impedance. It’s shocking!

Magnesium (Mg)

Don’t you wish sometimes we still lived in that blissful world of medical school and board exams where all cases of appendicitis are in the right lower quadrant, zebras roam freely, and all hypokalemia and hypomagnesima are the cause of AF?! Sadly not even the latter statement is true. 

Lancaster Incidence of AF does not correlate with Potassium (K) or Magnesium (Mg) serum levels. See Text

Lancaster in a study of 2041 post-operative AF (POAF) patients without pre-operative AF looked at just this idea. They found that in 752 patients with POAF patients had higher potassium and magnesium levels than matched patients POAF. Further more they found K, Mg supplementation did not reduce the rate of POAF [Lancaster et al., 2016].

It should be clear that cardiac surgery patients are a slightly different brand of AF but I wouldn’t be surprised to find this is true in the ICU as well. Nevertheless, I will continue to write K>4 and Mg>2 in my notes. 

Although it may be a surprise I do still believe that magnesium is capable of cardioversion in AF. A meta-analysis of magnesium for the prevention of postoperative atrial fibrillation in cardiothoracic patients found an odds ratio of 0.66 (95% CI: 0.51 – 0.87) [Henyan et al., 2005].

In a prospective single arm trial in critically ill patients a “step up” protocol by Sleeswijk of magnesium followed by amiodarone was shown to improve the rate of cardioversion [Sleeswijk et al., 2008]. Sadly this trial looked at only 26 patients. A Mg bolus (0.037 g/kg over 15 minutes) followed by infusion (0.025 g/kg/h) was given to all patients with persistent AF DESPITE correction of K, or Mg. While this is the equivalent of 4g of magnesium in a 100 kg patient, it should be nothing to be concerned about as this is a safe dose in patients with no renal disease and given frequently to OB patients[f]. The INFUSION was cut in half when Mg was >2.0 mmol/L and stopped when Mg >3.0 mmol/L. If no conversion in 1 hour then amiodarone (300 mg over 15 minutes, and infusion of 1200 mg/24 h) was started. The results:

  • 16/29 (55%) patients responded to magnesium alone
  • 11 of the remaining 13 responded to the addition of amiodarone 
  • 27/29 (93%) responded to the combination [Ibid.].

This study looked at the equivalent of 4 g OVER 15 min. Certainly nothing to freak out over. Previous studies have shown a benefit of Mg in patients with AF by increasing the success of pharmacological cardioversion and by decreasing the incidence of postoperative AF [Rajagopalan et al., 2016]. Sadly, the data for magnesium is not of the highest quality. 

Rajagopalan performed an RCT of chronic AF patients showed no difference in cardioversion with or without magnesium (86%). These patients were very different and had chronic AF and were in AF for 3-4 months prior. Even after 4 shocks up to 200J only 86% of these patients cardioverted to SR! As a side note in my favor 2/132 in the mag group converted to SR prior to cardioversion vs none in the placebo group. They found no drop in BP with the magnesium and no adverse events [Ibid.]. This information with other the studies makes me hopeful. 

In my opinion, I like using magnesium especially if it gives me 30 minutes to decided what I want to do and do a second look at the patient! 

Amiodarone for AF

Amiodarone is a very old drug and thus there are numerous different dosing recommendations. 

PDR: Adults Intravenous dosage recommendations [PDR].

  • Initial IV rapid infusion of 150 mg over the first 10 minutes. 
  • And Then 1 mg/min for the next 6 hours (total dose infused = 360 mg).
  • And Then, the infusion rate is lowered to 0.5 mg/min for the next 18 hours (total dose infused = 540 mg). 
  • And Then after the first 24 hours, a maintenance IV infusion of 0.5 mg/minute (720 mg/day) is recommended.
  • No and then! Intravenous amiodarone should not be administered for longer than 3 weeks.  
  • NOTE: The dose of amiodarone may be individualized

Conversion from intravenous to oral therapy [Goldschlager et al., 2000]:

  • If duration of IV infusion was <1 week, the initial oral dose is 800 to 1200 mg/day PO.
  • If 1 to 3 weeks, the initial oral dose is 400 to 800 mg/day PO. 
  • If longer than 3 weeks, the initial oral dose is 300-400 mg/day PO.
  • If there is concern about GI function, both oral and IV therapy should be maintained for a few days

Amiodarone Pharmacology and kinetics (Skip this unless you are feeling particularly nerdy) 

Amiodarone contains 37.3% iodine by weight. It is a Vaughan Williams (remember those) class III antiarrhythmic (AA) but produces activities with each of the 3 other classes as well. Other pharmacologic activities include: systemic/coronary vasodilation, phospholipase inhibition, and inhibition of thyroid hormone metabolism. N-desethyl- amiodarone (DEA), the major metabolite also has antiarrhythmic activity. The half-life of amiodarone is 20-47 days and that of DEA is even longer [Chow, 1996].

Amiodarone Side Effects

In adults, IV (not oral) amiodarone dosage adjustments are not required on the basis of patient age, or renal or hepatic functionThe likelihood of pulmonary fibrosis with short-term use of intravenous amiodarone appears small.There is a reported 3.4% incidence of hepatic enzyme elevations combined with at least possible hepatic dysfunction with IV amiodarone thus it is important to monitor hepatic function. Most studies exclude patients with thyroid dysfunction and it is recommended to check thyroid function once and then at 6 months if the patient is still on amiodarone [Ibid.].

Effects on Thyroid function 

Amiodarone induced hypo/hyper thyroid (AIH) and amiodarone induced thyrotoxicosis can occur (AIT). The prevalence of AIH is as high as 22%. Acutely, there is an increase in TSH (but usually <20 mU/L), an increase in both free and total T4, and a decrease in total and free T3. After 3 months, a new equilibrium is reached, and TSH normalizes. However, T4 will remain high, and T3 will remain low. It is best to avoid checking thyroid function tests during the first 3 months of treatment. Most patients who do not have underlying Hashimoto’s thyroiditis will have resolution after amiodarone is stopped. The prevalence of amiodarone-induced thyrotoxicosis (AIT) is much lower than AIH. AIT can occur quite suddenly and at any time during treatment. AIT is diagnosed based on a suppressed TSH with an elevated free T4. Given the beta- blocking effects of amiodarone, the classic findings of thyroxicosis are often absent. In equivocal cases, a T3 level can be helpful, with an elevated or high normal T3 indicating thyrotoxicosis [Goldschlager et al., 2007].

Pearl: Clinically, the most common findings may be weight loss or a change in warfarin dose.

Amiodarone Mechanism of Action

Interestingly, short term mechanism of action (single dose) mainly produces AV nodal refractoriness and prolongs intranodal conduction interval time, (Class II and IV).  The long-term activity is an increase in the action potential duration in cardiac tissues (Class III). Negative inotropy is the most consistent hemodynamic effect of IV amiodarone. In patients with normal ejection fraction (EF), negative inotropy is usually offset by a decrease in systemic vascular resistance to maintain cardiac output. Thus, patients with left ventricular dysfunction are at greater risk for decrease in cardiac output but this is likely only transient [Kosinski et al., 1984].

Amiodarone Dosing

I find that dosing of amiodarone to be incredibly provider dependent and that is likely due to the extreme variations in patient response to this drug. The pharmacokinetic reason for this is that lasma concentrations of the drug do not correlate well with observed clinical effect because of rapid distribution to tissues and high plasma protein binding [Desai et al., 1997].

A study by Kosinski showed this on the effects of a 300-mg bolus dose over 5 min, followed by a continuous infusion (1000 mg/24 hover 3-5 d) in 12 patients. Patients with the higher EF (>35%) had a small but significant increase in cardiac index following whereas patients with the lower EF (<35%) had a decrease in cardiac index (from 2.1 to 1.7 L/min), MAP and increase PA pressures which after 3-5 days were compensated for by peripheral vasodilation (decreased SVR). Two (out of 6) patients in the low EF group developed hypotension requiring pressors. They recommended a longer infusion for the 300 mg dose in low EF patients [Kosinski et al., 1984]. 

In 1983 a study by in Mexico, Faniel looked at 26 patients admitted to the ICU SPECIFICALLY FOR AF with RVR. They used 3 mg/kg (1983 weights as well) over 3 min vs 5-7.5 mg/kg over 30 min for a total of 1500 mg in 24 hours. 5 were unsuccessful and required cardioversion (4 of these 5 had HR slow to 50 bpm as reason for failure). Mean HR was 140 (55-200). The initial dose was followed immediately by a slow infusion of 600 to 1200 mg/24 h to reach a maximum of 1500 mg administered during the first 24 h. Mean conversion time was 170 min. They saw no hypotension. They noted “The longest reversion times were generally related to situations where small, repeated initial doses had been given. This mode of administration appears less effective than giving the same total amount in a single dose” (175 min vs 240 min, larger vs smaller boluses). They concluded: even if stable reversion is not achieved, then DC shock may be improved by the prior use of amiodarone (we just read above this may not be true). Overall they concluded that there was a good hemodynamic tolerance to their dose of 7 mg/kg over 30 min [Faniel and Schoenfeld, 1983].

In 2004, Hofmann looked at 78 AF patients in a CCU with advanced congestive heart failure or cardiogenic shock (SBP<90). 13 required pressers none were on mechanical circulatory support. Patients were given a single bolus of 450 mg of amiodarone via a PIV (over 1 min?). cardioversion was successful in 40 patients (51.3%) within 24 hours: sinus rhythm occurred in 25 patients (32%) within 30 minutes after amiodarone, and during the following 23.5 hours another 15 patients (19%) reverted to sinus rhythm. They noted “ In two patients, a decrease of systolic blood pressure from 115 to 80 mmHg and from 130 to 100 mmHg occurred within the first 5 minutes, but blood pressure returned to the initial values after 10 and 90 minutes respectively without specific intervention”[Hofmann et al., 2004].

Then in 2006, Hofmann looked at 50 consecutive AF with RVR patients and compared to amiodarone to digoxin. In this trial they excluded patients with SBP <100 and preserved Ejection Fraction (EF). They also looked at 450 mg of amiodarone via a peripheral IV (PIV)[g].  This time specifically stated as a bolus over 1 min. If the ventricular rate was above 100 bpm after 30 min, patients received another 300 mg IV. 28 patients required a second dose of amiodarone. Sinus rhythm conversion occurred quicker in the amiodarone group. SBP fell about 10 mmHg on average after amiodarone. 4 patients require fluid bolus. No prolongation of the QTc interval occurred [Hofmann et al., 2006].

AF: Amiodarone vs All comers

There are not a ton of great studies of drug choices and septic shock

A study by Balik looked 234 patients with septic shock requiring NE for propafenone vs amiodarone vs metoprolol. There were 177 in the amiodarone group, 42 in the propafenone group and 15 in the metoprolol group. The cardioversion rate was: 74% with amiodarone, 89% with propafenone, and 92% with metoprolol. The 28 day mortality was 50% in the Amiodarone group, 40% in the propafenone group, 21% in the metoprolol group. Multivariate analysis demonstrated higher 12-month mortality in amiodarone than in propafenone.  (HR 1.58 95% CI:1.04-2.38; p = 0.03) [Balik et al., 2017].

In this study by Delle Karth of amiodarone vs diltiazem (I can’t leave my ER roots, Kate!) in critically ill patients, they looked at 3 groups of patients in the ICU of 20 patients with Apache scores of 75. Approximately 75% of the groups required mechanical ventilation and catecholamine therapy, thus these were sick patients. The groups were diltiazem (25 mg bolus + 20mg over 24 hrs), amiodarone bolus(300mg), amiodarone bolus + infusion (300 mg+ 45 mg/hr for 24 hours). The primary outcome was a 30% reduction in HR and a secondary outcome was a HR <120. Diltiazem allowed for a 30% HR reduction in 70% of patients and a HR <120 in 100% of patients. Amiodarone bolus only allowed for a 30% HR reduction in 55% of patients and and a HR <120 in 50% of patients. Amiodarone +infusion allowed for a 30% HR reduction in 75% of patients and and a HR <120 in 95% of patients. Hypotension occurred in 6/20 in diltiazem group and 0/20 in either amiodarone group [Delle Karth et al., 2001]. Thus it appears my ED favorite may cause more hypotension in these very sick patients than amiodarone. 

Chapman studied IV procainamide and compared it to Amiodarone in 24 critically ill patients. IV amiodarone (3 mg/kg followed by 10 mg/kg/24 h, with repeat dose of 3 mg/kg at 1 h if no response) or IV procainamide (10 mg/kg at 1 mg/kg/min followed by an infusion of 2-4 mg/min for 24 h, and a repeat dose of 5 mg/kg at 1 h if no response). The patients were recruited from a mixed medical and surgical ICU. Most were on mechanical ventilation (20/24), had sepsis (18/24) and an avg APACHE score of 21. They found conversion to sinus rhythm by 12 h in 10/14 (71%) in the procainamide group and (7/10) (70%) in the amiodarone group. SBP was not significantly different from baseline for either drug [Chapman et al., 1993]. I happen to be a big fan of procainamide in the ED for conversion of AF for discharge home, however, I have not had experience using it in the ICU due to lack of availability. 

Esmolol atrial fibrillation, and Mortality?

In a study of esmolol in patients with septic shock in TACHYCARDIA (avg HR 109) (not due to AF), Brown looked at 7 (yes, 7 patients!…because the other 179 patients were excluded)… Inotropes (not vasopressors) were one of many reasons to stop treatment [Brown et al., 2018]. A review article by Arrigo states “We recommend to start with substances with a low risk profile and short half-life, such as beta blockers (see below), and to escalate to other substance classes such as amiodarone only in cases of contraindications or inefficacy…Our choice is esmolol”. They cite the reason as “[beta blockers] significantly reduces the risk of AF up to 40%, particularly in the [cardiac surgery] postoperative phase”. The recommend a dose of 10–20 mg to reach 1 mg/kg Bolus. If the MAP is >60 mmHg, start infusion at a rate of 0.05 mcg/kg/min and may increase q 30-minute intervals as needed for HR. They recommended use, especially, if a patient was on oral BB prior [Arrigo et al., 2014]. Unfortunately, this review gave no references to support the use of esmolol for NOAF in ICU patients.

Another review article by Bosch also recommends Esmolol as FIRST LINE in AF in critical illness however they also have no evidence for this. They state “Thus, use of BBs to treat arrhythmias during critical illness is a promising area of investigation.” [Bosch et al., 2018].

Although these review articles did not give any evidence for the use of esmolol in AF and the sepsis syndromes, I think much of the reason for these recommendations for esmolol in critically ill patients with AF likely stems from the next two studies we will discuss.  

 An open label Italian  RCT by Morelli looked at septic shock patients WITHOUT AF! 77 patients were randomized to esmolol in septic shock and 77 to usual care. This was a feasibility study so the primary outcome was heart rate. Remember that secondary outcomes are hypothesis generating! They did indeed manage to keep the HR down for their primary outcome. Additionally, they reported a 28d-mortality of 49.4% in the esmolol group vs 80.5% in the control group [Morelli et al., 2013].  Naturally, in 2013 this study made headlines. However, lets check those numbers! That was an 80% mortality in the control group!!! Thus 30% difference… Interestingly they also reported about a 500 ml reduction in fluid administration to the esmolol group. Normally, I hear “Esmolol? That’s a lot of fluid [administered]!” Very interesting indeed. 

While there is no RCT data on AF, septic shock and beta blockers, there is a very large prospective observation trial looking at different rate controlling drugs and their mortality. This one even has a subgroup of septic shock! 

Once again, Walkey performed this interesting observational study of AF and sepsis in 2016. The study was a retrospective cohort of billing data from about 20% of US hospitals. Importantly, we have no idea why the clinician chose the rate control method they did. They looked at 39,693 patients with AF during the first 14 days of hospitalization for sepsis treated with only one rate control drug. They found 36% treated with a calcium channel blocker, 28 % were treated with a beta blocker, 20% with Digoxin and 16% with amiodarone. In a propensity-matched analyses, BBs were associated with lower hospital mortality when compared with CCBs (relative risk [RR], 0.92; 95% CI, 0.86-0.97), digoxin (RR, 0.79; 95% CI, 0.75-0.85), and amiodarone (RR, 0.64; 95% CI, 0.61-0.69). This was similar among subgroups of:  new-onset AF,  preexisting AF, heart failure, vasopressor-dependent shock, or hypertension. Patients with vasopressor infusion/shock were compared. 

  • BBs vs CCBs: shock: RR, 0.86; 95% CI, 0.79-0.94; no shock: RR, 0.98; 95% CI, 0.91-1.06
  • BBs vs Digoxin: shock: RR, 0.79; 95% CI, 0.73-0.86; no shock: RR, 0.80; 95% CI, 0.73-0.88
  • BB vs Amiodarone in shock: RR, 0.64; 95% CI, 0.59-0.69; no shock: RR, 0.73; 95% CI, 0.65-0.81

The percent of patients on vasopressors per drug group was: BB 29%, CCB  26%, Dig 44%, amiodarone 64% [Walkey et al., 2016b]. It should be noted that regardless of how well a propensity matched score is done it can’t isolate bias like an RCT and association does not mean causation, so this needs to be interpreted with caution. On the other hand, if we use the numbers from Walkey and assume a 27% vs 42% mortality in beta blockers vs amiodarone; that gives a Number Needed to Treat of 6 patients to prevent 1 death with amiodarone. Finally, either there is a signal of a mortality benefit with beta blockers or amiodarone is a marker for sicker patients. As an emergency medicine trained person my first thought is for CCB or BB but in the shocked patient many are too hypotensive and I end up having to use amiodarone.  


Digoxin slows heart rate by increasing vagal tone; it is associated with low rates of hypotension but has a narrow therapeutic index. Observational studies show associations between digoxin use and increased mortality. Vagomimetic effects of digoxin may be less effective during critical illnesses characterized by high catecholamine states [Bosch et al., 2018]. Digoxin should not be considered as a first-line option for rate control due to its slow onset of action [Sibley and Muscedere, 2015]. So…no matter what ANYONE[h] says, Digoxin for AF is still a very 1950s Treatment… Hence we wont discuss pharmacology or dosing. 

Does Anything make NOAF better?

McIntyre performed a systematic review and meta-analysis of 23 RCTs with excellent methods and low risk of bias. They found that patients who had vasopressin + catecholamine vasopressor had a lower incidence of AF than did patients not on vasopressin:

  • 24% (136/559) had AF in the catecholamine + vasopressin group
  • 33% (182/554) had AFin the catecholamine only group

They found a risk ratio of 0.77 [95% CI, 0.67 to 0.88] (not something thought to be clinically significant but still statistically significant. Sadly, this study showed no benefit for mortality with vasopressin [215/529 (41%) vs 222/520 (43%)] [McIntyre et al., 2018]. A whopping 40% mortality in this group!

Treatment Duration

            While no one knows how long to keep anti-arrhythmic medications going, Kanji showed 18% of NOAF patients and 62% of patients with preexisting AF who survived to ICU discharge left the ICU in AF [Kanji et al., 2012]. Bosch reported, 70% of patients with new-onset AF and 14% of patients with preexisting AF converted for at least 24 hours within the first 48 hours from the onset of AF[Bosch] [Bosch et al., 2018].

Anticoagulation vs. Stroke Risk

It is unknown if administering anticoagulation in critically ill patients prior to DCCV decreases the risk of thromboembolic events or if there is an optimal timing of anticoagulation prior to DCCV [Ibid.].

In the large study by Walkey in 2014, 138,722 sepsis survivors were identified in a Medicare database. In those with new-onset AF during sepsis compared with those with no AF during sepsis, the NOAF group had a greater 5-year risk of hospitalization for ischemic stroke (5.3% vs 4.7%; HR, 1.22) [Walkey et al., 2014]. That is a 0.6% absolute increase in stroke.

In 2011, Walkey looked at AF, severe sepsis and stroke in the US. In over 49k patients with severe sepsis and NOAF, they found that 2.6% (75/2896) had in hospital stroke as compared to the 0.6%  (306/46,186) without severe AF for an adjusted OR of 2.70 (95% CI, 2.05-3.57; P < .001) [Walkey et al., 2011].

In the Kanji study in Canada, 348 patients and over 2322 cumulative patient days of AF in the ICU, no patients had a documented embolic cerebrovascular event, whereas 5 (9%) of 58 patients who received systemic anticoagulation had a bleeding event that required interruption of anticoagulation and at least 1 blood transfusion [Kanji et al., 2012].

In a 2016 cohort study of 38,582 hospitalized patients with atrial fibrillation and sepsis, Walkey found bleeding events were increased among patients who received anticoagulation (1163 of 13 505 [8.6%]) compared with patients who did not receive anticoagulation (979 of 13 505 [7.2%]). However, those patients did not have a significantly reduced risk of in hospital stroke (1.4%) compared to those receiving of anticoagulation during sepsis compared to those who did (1.3%)[Walkey et al., 2016a]. So bleeding ~1.4% vs stroke 0.1%.

Some recommend starting anticoagulation if the AF is persistent for more than 48 hours [Sibley and Muscedere, 2015]. Others recommend in patients without contraindications to anticoagulation whose AF persists following hospital discharge, anticoagulation should be initiated if moderate to high risk [Bosch et al., 2018]. Currently there is no quality evidence or guideline to guide decision making for atrial fibrillation in the critically ill. Based on this data and the bleeding risk in ICU patients it would seem not surprising that some patients are not started on AC. In fact, in a study in Canada systemic therapeutic anticoagulation was prescribed for 16% (22/139) of patients with new onset AF and 19% (36/186) of patients with preexisting AF while in the ICU [Kanji et al., 2012]. 

Mortality and morbidity associated New onset atrial fibrillation NOAF

In a retrospective analysis by Fernando in 2020 of 6 years of a registry from two Canadian ICUs  10% (1541 of 15014) patients were found have NOAF. These patients did not have a STATISTICALLY significant higher mortality (37.4% vs 29.9%) than patients without AF (OR1.002, p=0.31).  However, NOAF was associated with higher hospital mortality among ICU patients with suspected infection (aOR 1.21 [95% CI 1.08–1.37]), sepsis (aOR 1.24 [95% CI 1.10–1.39]), and septic shock (aOR 1.28 [95% CI 1.14–1.44]). They did have a statistically significant longer ICU stay by 1 day range: [4-14] vs [2-9].

In the 2014 study by Walkey, a multivariable-adjusted hazard ratio compared with patients with no AF during sepsis, those with new-onset AF during sepsis had greater 5-year risks of death (74.8% vs 72.1%; HR, 1.04; 95% CI,1.01-1.07) [Walkey et al., 2014].

In the 2011 study by Walkey comparing patients with severe sepsis with NOAF and severe sepsis without NOAF; they found a greater risks of in-hospital mortality (56% vs. 39%) [Walkey et al., 2011].

In a study IN CHINA, Liu looked at mortality of whether or not patients with AF converted to sinus. They found 503 eligible patients, including 263 patients with no AF and 240 patients with NOAF.  Of the 240 patients with AF, SR was restored in 165 patients, and SR could not be restored in 75 patients. The NOAF that stayed in AF group had the highest in-hospital mortality rate of 61.3% compared with the NOAF that converted to sinus group (26.1%) or the no NOAF (17.5%) group.  Interestingly the group that stayed in AF had higher baseline SOFA scores, APACHE scores, more norepinephrine use, more mechanical ventilation use and more dialysis. The group that has NOAF and stays in AF is likely a sicker group! Also note that a 61% mortality is really high (hopefully this was not confounded by an invisible virus!) [Liu et al., 2016]

Special Populations: Cardiac ICU and Lung Transplant

Until now I have mostly avoided discussing post-operative AF in cardiac surgery patients. I would go through the specifics of post cardiac surgery patients but the following review article does a way better job:

Lung Transplant Patients

Twenty-five per cent (25%) of lung transplantation patients developed atrial flutter or fibrillation, most frequently at day 5–7 post lung transplantation, and more commonly present in older recipients and those with underlying chronic obstructive pulmonary disease (COPD), but not in those with previously noted structural heart disease, or in those undergoing single rather than double lung transplants. Diltiazem can increase tacrolimus concentration and the lung transplant team should be notified to adjust the tacrolimus dose whenever diltiazem is started or stopped [Barnes et al., 2019].

Putting it all together….

So what to do, what to do…

So how do we put all this together? Keep in mind this is MY version of putting it all together (see the algorithm), there are lots of permutations and possibilities. I will also throw back a little Toxicology Bombastus[i] style that THERE IS NO BAD DRUG and only the dose makes the poison!  Well, let’s start at the beginning footnote always good place. Here, again to be sure, we are talking about the ICU patient who is very sick and develops new onset atrial fibrillation. Let’s use a sample case presentation:


Mr. Sic AF presents to your ICU and is admitted via the ED in septic shock. After 24 hours of treatment he is on 0.1 mcg/kg/min of norepinephrine, his map is 65 via a radial arterial line,  his HR is 115 and there is sinus rhythm on the monitor. He suddenly goes in to AF with a rate of 140 and his MAP is 61 now…what do you do wildcat (see corresponding algorithm)?!


  1. IF a patient becomes grossly unstable obviously resuscitate them.
  2. Get a real ECG if they are “stable” (see definition of stable)
    • Be a cardiologist here. Don’t substitute a monitor produced one, not one without a rhythm strip…An honest to god pink shiny papered ECG
  3. Is this rhythm causing additional instability more so than if they did not have AF? 
    • Is this tachycardia (AF or sinus) compensatory for the shock state as opposed to pathological and contributing to the current hemodynamic compromise
    • The atria supply about 25% of cardiac output and myocardial depression is common in sepsis especially in those who die of septic shock [Jardin et al., 1999]
    • Remember that unstable AF is more likely (but not impossible) to present with a HR of >150 (35% vs 16%)
  4. Do they NEED cardioversion?
    • Only cardiovert if you really think they are unstable
    • If you are going to cardiovert your best chance of success is in the first hour of AF. 
    • If you are going to cardiovert use the Anterior posterior placement
    • Remember only about 50% of cardioversion is initially successful and only about 1/3 successfully stay in sinus for 24 hours.
  5. Does this episode of AF need treatment?
    • Risk factors include age>60, chronic lung disease and sepsis [Fernando et al., 2020], [Moss et al., 2017].
    • Treat the underlying illness first if you think the high HR is due to critical illness then consider if the NOAF needs to be treated 
  6. Have the modifiable risk factors been sufficiently optimized?
    • Did you look at the ventricular function with bedside Echo?
    • Is there volume overload that can be optimized?
    • What are the electrolytes?
    • Are they acidotic?
    • Pressors: Avoid epinephrine and, especially, dopamine if possible
    • Can the pressor dose be titrated down without loss of blood pressure goals?
    • Can a lower MAP goal of 60 mmHg be tolerated [Lamontagne et al., 2020].
    • Is that [radial] a-line accurate? [Kim et al., 2013], [Antal et al., 2019].
  7. Give Magnesium[j]
    • I like to have a conversation with my local pharmacists, they are a wealth of knowledge and will let you know what your local hospital “policies” are as far as administration.
    • A small number of patients (but as high as 50%) might convert with this alone.
    • Give about 2g over 15-30 min (not 2 hours!) (consult your local hospital “ethereal” policy).  
    • If you want to give more magnesium then check repeat levels magnesium in a few hours (2-4 hours?)
  8. Choose and administer your anti-arrhythmic of choice
    • There are lots of choices here for the patient and treatment is usually based on personal preference. 
    • In a “stable” blood pressure diltiazem and esmolol are reasonable choices.
    • The aforementioned studies have looked at beta blockers while norepinephrine was infusing but not inotropes) 
    • observational data indicates that beta blockers might have a mortality benefit over amiodarone and digoxin (less so vs. calcium channel blockers) [Walkey et al., 2016b]. 
    • This needs yet to be confirmed in an RCT.
    • In the shocked patient who is on an inotrope or can not risk having more hypotension, amiodarone may be necessary.
    • Consider bolus of 150-450mg over 30 min then an infusion. See the algorithm for dose details.
    • The literature would suggest a 70% of patients but this will decrease by 24 hours and it will be mostly rate controlling. 
    • Amiodarone can initially WORSEN LV function and cardiac output but this will be offset in a few days by a decrease in SVR.
  9. Does the patient need to be anti-coagulated?
    • It would seem from above that less than 20% of patients are given AC to NOAF
    • These patients have a high bleeding risk (9% of those given AC have significant bleeding) so calculate a HAS-BLED score
    • It’s unclear that AC (vs prophylaxis dose) anticoagulation is helpful [Walkey et al., 2016a].
    • Think about it carefully then sleep on it some more before you do…you have time.
  10. These patients are sick AF!
    • The mortality of NOAF who Stay in AF is 40-60%!!!!
    • The mortality of NOAF who go to sinus is 26.1% (vs 18% in those without NOAF)
    • AF is likely a marker of illness as opposed to the cause of it so let the AF serve as a marker of someone who needs to stay on your radar!


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[a] This Trial is a classic and a must read!

[b] As we all know there are at least 3 definitions of sepsis over time so the definition of this has changed thus shifting our ability to interpret these studies!

[c] This guy is everywhere in AF and Sepsis! Just check out the references!

[d] Look at those waveforms to make sure they have a dicrotic notch!

[e] No association with Kirchoffs rule of electrical current…and they say the universe has no sense of humor! As a refresher this law states that, for any node (junction) in an electrical circuit, the sum of currents flowing into that node is equal to the sum of currents flowing out of that node

[f] Magnesium: I like to speak with my local pharmacist and see what if any policy there is on mag administration because for some reason the OB floor can give a monitored pt 8g of mag but when I do it there is widespread panic. Still this is not the hill to die on though.

[g] Amiodarone can cause phlebitis and used to require a central line but this is no longer true. 

[h] You know who you are!

[i] Bombastus: Paracelsus born Theophrastus von Hohenheim (full name Philippus Aureolus Theophrastus Bombastus von Hohenheim) (1494 –1541). The father of toxicology! Sola dosis facit venenum “Only the dose makes the poison”

[j] Magnesium: Again know your local practices and staff comfort level. However, this is not a hill to die on.

Quick Hit Article: Difficult vascular access: You know the drill… but do you really know the drill?

Kawano et al. Intraosseous Vascular Access Is Associated With Lower Survival and Neurologic Recovery Among Patients With Out-of-Hospital Cardiac Arrest. Ann Emerg Med. 2018;71:588-596.

This study was a secondary analysis of a large EMS trial conducted in 7 sites in the US and Canada. This is a really interesting study that looks at the association between outcome and IO access. They looked at 12,500 pts with IV access and 660 pts with IO access. The primary outcome measure was favorable neurologic outcome at hospital discharge with a mRS of 0 to 3. In the IO group 24% had rosc, 4% survived to hospital discharge, and 1.5% had a favorable neurological outcome. In the IV group 38% had ROSC, 10% survived, 8% had a favorable neurological outcomes. In the UNADJUSTED propensity matched model IO vs IV access was associated decreased probability of ROSC (25% vs 34%,OR=0.66), survival to discharge (4.5% vs 8.6%, OR=0.5), and favorable neurologic outcome (1.8% vs 5.9%, OR=0.29). The two groups differed in interventions very noticeabley in that the IO group were an almost 15% LESS therapeutic hypothermia and 9% less interventional catheterization. This is JUST AN ASSOCIATION and maybe IO is just a marker of sicker patients, HOWEVER, I think this is enough to allow for an RCT looking directly at this topic.

Difficult IV access in cardiac arrest? Just drill it! Utilize intraosseous vascular access that is. The IO has become the go to for rapid IV access in cardiac arrest patients. We can deliver drugs quickly and not muck around looking for a vein either peripherally or centrally. But are there down stream consequences? Is it REALLY better? This study takes a look at outcomes of non-traumatic cardiac arrest patients who had an IO placed.

This study was a secondary analysis of a publicly available registry conducted in 7 sites in the US and Canada. The original trial looked at the timing of the first analysis for defibrillation and application of an impedance threshold device. The original data was prospectively collected. Exclusion criteria were the typical ones including trauma, prisoners, pregnant, dnr, and hypovolemia. To the study’s benefit the obtained a cohort whose access route was the INTENDED PRIMARY CHOICE and excluded failed attempts at either route of access. The importance of this is that it MIGHT equal out the bias of a sicker patient or delays in care where a failed access attempt delays the care. The primary outcome measure was favorable neurologic outcome at hospital discharge with a mRS of 0 to 3. This is an interesting outcome change point because normally mRS is 0 to 2 is the cutoff in stroke studies. Because out-of-hospital vascular access was not randomly assigned across this cohort, they applied propensity matching to decrease selection bias and unmeasured confounder.
They found after exclusions 13,155 patients with 660 pts (5%) and 12,495 (95%) pts. Note that patients with IO access had a higher proportion of nonshockable initial rhythms, fewer public location and shorter times from call to first provider. In the IO group 24% had rosc, 3.8% survived to hospital discharge, and 1.5% had a favorable neurological outcome. In the IV group 38.3% had ROSC, 10% survived, 7.6% had a favorable neurological outcomes. They found after multiple regression with multivariate analysis that IO access was ASSOCIATED with a DECREASED probability of ROSC [OR 0.6 (CI: 0.49 to 0.74)] and DECREASED favorable neurological outcome [OR 0.24 (CI: 0.13to 0.46)].
They found 1116 patients in the propensity match. In the UNADJUSTED model IO vs IV access was associated decreased probability of ROSC (25% vs 34%,OR=0.66), survival to discharge (4.5% vs 8.6%, OR=0.5), and favorable neurologic outcome (1.8% vs 5.9%, OR=0.29). Looking at the propensity matching these groups for the
Baseline characteristics are quite well matched and markers of their propensity matching were well correlated. They did differ in some ways in the interventions. The very noticeable differences in the IO group were an almost 15% LESS therapeutic hypothermia, 5% less fibrinolytics, and 9% less interventional catheterization.

Although the propensity scoring appears quite well and there were multiple calculations to correct for confounders there are still significant biases. I think foremost the discrepancy between the number of of IO vs IV’s performed is hard to overcome (660 vs 12500). Also there were some big differences in the patients receiving hypothermia and cardiac catheterizations. I still think the data is not definitive for those two interventions but certainly this may be a marker of quality of care and attention to care. Still the OR for survival with favorable neurological outcome is impressively in favor of IV access. It is interesting that some EMS systems used IO as their first line and it would be interesting to know why IO was first line. I also wonder WHY the IO patients got less interventions. Was the IV access the reason or were they initially deemed to be sicker? Also it would be nice to know how long the IO was in and what was the time frame to when it was swapped out for IV access. Lastly, I can’t get away from the thought that sicker patients are going to get IO’s and are going to do worse.

So what’s the bottom line? IO access is critical to establishing vascular access to care for patients (depending on what you think the validity of ACLS drugs are, oh HEY OPALS TRIAL). Maybe IO access is a marker for sicker patients or maybe worse IO access biases providers against the same level of care as those with an IV…We all know the drill… but does it make our patients better? I think this is enough to allow for an RCT looking directly at this topic.

LVAD Complications: A review

This is a nice little review by Dr. Long in Dallas entitled:

B. Long, J. Robertson, A. Koyfman, et al., Left ventricular assist devices and their complications: A review for emergency clinicians, American Journal of Emergency Medicine,


A ventricular assist device (VAD) can be placed into the right, left, or both ventricles thus the patient can have a right ventricular assist device, left ventricular assist device, or biventricular assist device. The goals of these devices include three different strategies: bridge to recovery, bridge to transplantation, or destination therapy (i.e., the patient is unlikely to recover and not a candidate for cardiac transplant). Contraindications to placement include metastatic cancer, irreversible renal/hepatic failure, and CVA with severe neurologic deficits. The LVAD has two basic designs which produce different patterns of perfusion, including the pulsatile and continuous-flow devices. More commonly these days are the non-pulsatile continuous flow devices.

Device Components

The continuous-flow LVAD has several basic parts including: the internal pump an external power source, and a control unit.The specific components of the LVAD include the inflow cannula, pumping chamber, outflow cannula, percutaneous driveline, controller, and power source. The inflow cannula, usually placed in the apex of the left ventricle (LV), provides the route for blood flow from the native LV cavity to the LVAD pumping chamber.

The pumping chamber, the component of the circuit which provides perfusion, is located in different positions depending upon the LVAD model type: the LV apex for the (HeartMate) HMIII and HVAD devices and the subdiaphragmatic space adjacent to the heart for the HMII device. The pumping chamber contains the impeller, a near-friction-less rotor with rotation speeds ranging from 2500 to 9800 rpm; these types of impeller designs can generate blood flow up to 10 L per minute. The outflow cannula provides the conduit back to the patient’s native cardiovascular system and connects the pumping chamber to the ascending aorta,

The percutaneous driveline provides a conduit for the electrical wiring, connecting the pump to the system controller. These wires not only connect the power source to the pump, but they also provide controlling and sensing functions for the LVAD. The driveline is tunneled

subcutaneously from the pump and exits the skin in the anterior abdominal area to connect to the controller. Thus, it is a frequent source of infection in the LVAD patient. The controller performs multiple functions and contains several important components. It controls LVAD functioning, including power source monitoring and regulation, overall system monitoring, data collection, and alarm system function. subcutaneously from the pump and exits the skin in the anterior abdominal area to connect to the controller. Thus, it is a frequent source of infection in the LVAD patient. 


A continuous flow LVAD will not typically produce a palpable pulse on its own, but patients may have enough native ventricular function to produce pulsatile flow and a pulse. A palpable pressure may also be due to pump thrombosis, and thus, it is important to determine if the patient has a palpable pulse at baseline. If a pulse is palpable, a standard sphygmomanometer may detect a blood pressure, which reflects a systolic blood pressure, rather than mean arterial pressure (MAP). If the pulse is not palpable, a pencil Doppler probe should be placed over the radial or brachial artery. The point at which Doppler signal returns corresponds to the MAP for continuous flow devices. If this is unobtainable, an arterial line may be required, which is the most accurate device for monitoring MAP. Invasive arterial monitoring will demonstrate minimal pulse pressure or flat arterial waveform. Caution is recommended in using pulse oximetry, as a low reading commonly reflects a lack of pulsatile flow. However, a normal value may be accurate. 

LVADs, especially those with continuous-flow, are sensitive to afterload and preload. Guidelines recommend maintaining a MAP of 70–90 mm Hg. Acute hypertensive adverse event is associated with MAP N110 mm Hg in patients with continuous flow pumps. The mechanical hum indicates device power and function. Signs of volume overload (extremity edema, ascites, elevated jugular venous pressure) can be due to subacute or chronic right ventricular failure. However, acute dyspnea, pulmonary edema, or hypotension are more commonly due to acute malfunction of the device, such as cannula obstruction or pump thrombosis. The device exit site, which is normally covered with a sterile dressing, and line should be examined with sterile gloves and mask for warmth, erythema, and discharge, which suggest infection. Finally, the patient should be asked if he/she brought the back-up battery and back-up controller. Sustained ventricular dysrhythmias may be due to underlying cardiomyopathy or decompressed left ventricle due to elevated pump speed or right ventricular failure. Patients with an LVAD will typically demonstrate normal sinus rhythm.


Chest radiograph provides important diagnostic information including position and the type of LVAD, as well as the presence or absence of an ICD or pacemaker. Deep space infection of the LVAD components requires assessment with computed tomography (CT). Sustained ventricular dysrhythmias may be due to underlying cardiomyopathy or decompressed left ventricle due to elevated pump speed or right ventricular failure. Patients with an LVAD will typically demonstrate normal sinus rhythm.

Echocardiogram can evaluate cardiac function and assess for complications such as regurgitation, right ventricular failure, and thrombus formation, though thrombi can be difficult to detect on ultrasound alone.  Key components of the assessment include valvular function, inflow/outflow abnormalities, ventricular size and function, and septal position.

Laboratory assessment includes hemoglobin/hematocrit, lactate dehydrogenase (LDH), haptoglobin, free hemoglobin, and coagulation panel. Hemoglobin and hematocrit with type and screen/cross are needed if concern of bleeding is present. Patients with LVADs are anticoagulated with a vitamin K antagonist, with a goal INR of 2–3 well as aspirin. Free hemoglobin and haptoglobin can assess for hemolysis. Elevated LDH >2.5 times the upper limit of normal suggests hemolysis, which is most commonly due to pump thrombosis in an LVAD patient.  Troponin is recommended in patients with new ECG findings, chest pain, or dyspnea. BNP is a sensitive indicator of volume overload in patients with an LVAD and may be elevated in those with new right heart failure or pump thrombosis or malfunction.

Patients should have a controller tag around their waist indicating the type of device, the institution that placed it, and a phone number. Alarms and functional parameters are shown on the external system controller. Pump speed controls flow. Pump power, flow, and speed should be noted, with assessment of alarms and battery. RPMs and pulsatility index must also be evaluated. 

LVAD specific complications:


A suction event is a common LVAD complication and is associated with low flow events, including dysrhythmia, hemorrhage, and other hypovolemic states such as diarrhea or vomiting.  Reduced LV preload results in collapse of the LV and decreased inflow into the LVAD. Low flow, speed, and power will be present on the controller. While bedside US can demonstrate decreased LV volume, this is often difficult in LVAD patients due to poor acoustic windows, and assessment of the LV diameter may assist in evaluating volume status. Treatment requires fluid resuscitation and managing the underlying etiology. With improved preload and intravascular volume, pump speed and flow will improve. 


Continuous-flow LVADs place patients at high risk of thrombosis, which may originate in the pump or the components such as the inflow or outflow cannula. Types of pump thrombi include acute catastrophic red thrombi entrapped within a fibrin mesh and white thrombi rich in platelets. Red thrombi form at the inlet and outlet areas due to blood stasis, while white thrombi typically form on the pump surface and are associated with turbulent flow. Thrombosis can result in pump dysfunction, hemolysis, emboli, stroke, and death, but patients with thrombosis present with a variety of symptoms due to these potential complications, ranging from no symptoms to cardiac arrest and death. On examination, evidence of hemolysis may be present with scleral icterus, dark urine, and fatigue. Serum LDH is typically >2.5 times normal. Urinalysis may demonstrate hematuria. Other important laboratory assessments include hemoglobin, free hemoglobin, haptoglobin, and coagulation panel. Thrombolysis may be required if patients are hemodynamically unstable. Emergent surgical pump exchange may be needed if the pump stops, the patient is unstable, or if alarms are present. 


Mechanical failure is the second most common cause of death in LVAD patients and may result from several different issues. Pump failure is the most important life-threatening complication requiring immediate care. The controller may demonstrate low flow, low voltage, and power loss. A low flow alarm should always be evaluated by first checking the power. Physicians should auscultate over the LVAD and evaluate for disconnected leads and cannula issues such as kinking or obstruction. A disconnected lead should be reconnected. However, if auscultation reveals no pump activity but all leads are in place, the clinician must assess power and power leads. If all leads are connected, the pump can be reset. If a power lead is not connected to the batteries or unit cable, the cable disconnect advisory will alarm and demonstrate a flashing symbol.  However, if the device has been off for over an hour and the patient is stable, consultation with the LVAD specialist is required, as the device should not be immediately restarted due to high risk of thromboembolic events. In the setting of hemodynamic instability, the device should be restarted immediately no matter the duration of stoppage, with continuous anticoagulation. If the clinician and/or LVAD specialist cannot restart the LVAD, pump exchange is needed, which requires discussion with the LVAD specialist and surgeon. For patients with inadequate perfusion and hemodynamic instability without an alarm activated, resuscitation with IV fluids and standard ACLS protocol is needed.

LVAD-associated complications 


Patients with LVAD are at elevated bleeding risk. Bleeding can occur from several sources: pump connections, grafts in the conduits, and most commonly, mucosal surfaces such as the gastrointestinal (GI) tract. GI bleeding affects 15–30% of patients with an LVAD. Bleeding in the immediate postoperative period is often due to hepatic congestion associated with severe heart failure and the effects of extracorporeal circulation of the bypass machine. Patients may also develop an acquired form of von Willebrand factor (vWF) disease due to the high shear stress associated with LVAD circulation resulting in cleavage and deficiency of vWF. Bleeding in elderly patients with acquired vWF is more severe. Resuscitation of patients with significant hemorrhage with LVAD includes product replacement and reversal agent administration. However, reversing anticoagulation should be weighed with the risk of thrombotic complications, and consultation with the LVAD. Lesions are typically treated with coagulation or clips. Due to the risk of sensitization and reducing the success of heart transplant, blood product transfusion should not be reflexive in patients who are hemodynamically hemodynamically stable. Leukoreduced and irradiated blood products are recommended if available. Octreotide has demonstrated efficacy in LVAD-related GI bleeding in several studies. Desmopressin can be provided, which is a synthetic analogue of vasopressin, or infusion of vWF concentrates. Discussion of platelet transfusion is needed with the LVAD specialist if the patient is thrombocytopenic and bleeding, as well as those with severe hemorrhage.


Ischemic and hemorrhagic stroke can result in poor outcomes and demonstrate a prevalence of 6.8% and 8.4%, respectively. There is an increased risk with every 5 mm Hg increase in systolic blood pressure. The ENDURANCE trial found a lower stroke rate with MAP 90 mm Hg, with patients receiving close blood pressure control demonstrating a 24.7% reduction in total neurologic events and 50% decrease in hemorrhagic stroke rate. Acute ischemic stroke more commonly affects the right cerebral hemisphere in patients with an LVAD. 


Patients with an LVAD are at high risk of sepsis, with rates of infection approaching over 42% in the first year post-implant, usually 2 weeks to 2 months. The driveline and VAD pump pocket are the most common infectious sites, with 80% of driveline infections occurring in the first 30 days of transplant. The system controller may demonstrate a high-flow alarm with distributive shock due to loss of vascular tone. LVAD-related infections include those that may occur in patients without an LVAD, but occur with greater frequency in LVAD patients such as mediastinitis, endocarditis, and bacteremia.  Non-LVAD infections include pneumonia, Clostridium difficile infection, and urinary tract infection (UTI). Within the first 3 months post implantation, the most common sources of infection typically include catheters, pneumonia, and C. difficile, while later sources of infection are more commonly related to the device.  Only half of patients will demonstrate fever, leukocytosis, or meet criteria for systemic inflammatory response syndrome. Discussion with the LVAD specialist and cardiothoracic surgery is recommended.  Deep infections typically require surgical debridement, while persistent bacteremia may require removal and implantation of a new device. 

RV Failure

RV failure is a major cause of morbidity and mortality, occurring in 15–40% of patients. Late onset right heart failure is increasingly being reported with RV dysfunction, ventricular dysrhythmias, pulmonary hypertension, tricuspid regurgitation, and device thrombosis or malfunction. This can result in reduced preload to the LV, decreasing LVAD flows and triggering a low-flow alarm. RV failure may result in elevated liver function tests, creatinine, and lactic acid. RV failure requires inotropes and/or vasopressors, pulmonary vasodilators, and LVAD specialist consultation. Patients may require careful fluid resuscitation, with 250 mL boluses. 

Ventricular Dysrhythmias

Patients may tolerate severe ventricular dysrhythmias with minimal symptoms due to the LVAD producing adequate cardiac output to meet end organ perfusion despite poor venous return. Patients often have an ICD prior to LVAD placement. Dysrhythmias may eventually result in compromised blood flow and can also contribute to RV dysfunction, suction events, thrombus formation, and poor perfusion. The controller will demonstrate low flow in patients with hypotension due to the dysrhythmia.

Aortic Regurgitation

Aortic regurgitation (AR) may develop de novo in up to 25% of patients after LVAD placement. AR more commonly occurs in patients with a closed aortic valve compared to patients in whom the valve frequently opens. AR results in decreased LVAD efficacy and may require modifications in pump speed, managed by the LVAD specialist. Patients may require aortic valve replacement.


Standard procedures for resuscitation are recommended as needed. Hypotension in LVAD patients is defined by MAP <60 mm Hg. Patients who are conscious should be assessed with history and examination, with close assessment of volume and perfusion status. ECG and bedside echocardiogram are vital components of the assessment, with analysis of LVAD components. Patients who are unresponsive and hypotensive require external chest compressions. Literature suggests no cases of dislodgement during cardiopulmonary resuscitation (CPR). If the patient has a MAP N<50 mm Hg or end tidal CO2 <20 mm Hg with a device possessing an audible hum, perfusion is likely adequate, and compressions are not necessary MAP <50 mm Hg without an audible hum in the unresponsive patient is associated with compromised perfusion and requires chest compressions at the same depth and frequency as in those without an LVAD. Defibrillation should be performed for unstable ventricular dysrhythmia. The pads should be placed distant from the pump, and if an ICD is present, the pads should not be placed directly over the ICD. In patients with adequate perfusion and respiration but who remain unconscious, evaluate for hypoglycemia, stroke, hypoxia, sedation, and coma.


Chest thoracostomy with chest tube placement in the setting of trauma with pneumothorax and/or hemothorax is recommended, but clinicians must avoid the driveline. Arterial line placement can be beneficial, and US guidance is recommended. Pericardiocentesis should be avoided due to risk of serious device complications, but it is recommended in the case of pericardial tamponade with hemodynamic compromise.





ST segment elevation in aVR is probably NOT a STEMI…BUT, damn, are they sick!

There I said it. Well Ok I’ve been saying it for a while. But say this to a room full of doctors and you might be ostracized! Well there has been mounting evidence that would argue aVR ST elevation is not an acute STEMI/ STEMI equivalent for a while now. I think this article clinches it for me. However, just because its not a STEMI equivalent doesn’t mean they are ok, nor does it mean we should forget about aVR…


In this blinded retrospective review of 99 patients with ST elevation in aVR (STE-aVR) and multi-lead ST depression, only 10% had a definite culprit lesion,  none had left main or LAD occlusions, and 40% had no disease or mild to moderate disease on PCI. However, this group had an overall in-hospital mortality of 31% compared with 6% in a matched conventional STEMI group. Patients with aVR ST elevation represent a very sick cohort of patients who need critical care and a workup for why they are having poor diffuse coronary perfusion.


This was a retrospective study with actually quite good blinding and decent methods that looked at 854 consecutive STEMI activations in a 35 month period. They identified 99 patients with ST elevation in aVR (STE-aVR) and multi-lead ST depression in the final analysis. Cardiologists reading the ECGs and catheterizations were blinded to the study outcome. The primary outcome was the number of patients presenting with STE-aVR and multilead ST depression who had an acutely occluded culprit coronary artery on PCI. Secondary outcomes were number of patients who presented with cardiac arrest, and survival-to-hospital discharge compared to the non-aVR ST elevation STEMI population. None of these 99 patients had ST elevation in 2 contiguous leads (STEMI definition). Of the original 99, 79 underwent PCI. Interestingly the 20 that did not undergo PCI were a very sick population including known severe coronary artery disease on recent coronary angiogram, neurological emergency, obvious extra-cardiac etiology for arrest, and very long down time with poor prognosis. Of the 79 patients that had PCI, 8 (10%) had evidence of a definite, acute, thrombotic, culprit coronary occlusion but none had an acutely occluded left main or left anterior descending coronary artery. 19 of these 79 had angiographically normal vessels and 40% of them had either no disease or only mild to moderate disease on PCI. However, these were a pretty sick group though: 47 developed respiratory failure, 15 developed cardiogenic shock , 48 developed acute kidney injury( 9 of them requiring hemodialysis), and 36 patients underwent in-hospital coronary revascularization (29 PCI and 7 CABG). Wow are these a sick cohort! Those with STE-aVR had a 31% in- hospital mortality, whereas those with a non-aVR STEMI had a 6.2% in-hospital mortality (p <0.00001)! The presence of a critical medical condition or severe multivessel subocclusive disease with intact distal flow was the most common etiology for this ECG finding. This emphasizes working up these patients for the underlying issue. These patients don’t likely need immediate PCI of a culprit lesion they likely need resuscitation and eventually treatment by a multi-specialty heart team for their multi-vessel disease.


Harhash, A et al. aVR ST Segment Elevation: Acute STEMI or Not? Incidence of an Acute Coronary Occlusion. The American Journal of Medicine (2019) 000:1−9. PMID: 30639554. DOI: 10.1016/j.amjmed.2018.12.021

Recent Recommendations in Neonatal Resuscitation 2019 UPDATE

Sometimes we need a reminder and update on the basics… Your Welcome..

Recent Recommendations and Emerging Science in Neonatal Resuscitation. Pediatr Clin N Am 66 (2019) 309–320.

– The 2017 NRP guidelines recommend a 30- to 60-second delay in clamping in all term and preterm infants not requiring resuscitation.

– If the placental circulation is disrupted (e.g., placental abruption), the cord should be clamped immediately. Investigators found that delayed clamping reduced mortality before discharge.

– Another option is to clamp and cut a long segment of the cord immediately after birth and then milk the cord. The major advantage of either method of cord milking is that the newborn can be passed to the awaiting resuscitation team without delay while preserving the receipt of the placental transfusion.
– Delivery room temperatures should be at 23 C to 25 C (74 F–77 F).

– Suctioning of newborns should be performed only if the airway is obstructed or if PPV is needed.
– In nonvigorous infants born through meconium-stained amniotic fluid (MSAF), current recommendations include only intubation and endotracheal suctioning for those who need it for ventilation or airway obstruction.

– It is recommended that room air (21% O2 at sea level) be used at the initiation of resuscitation in infants born at 35 weeks gestation.

– Failing to reach SpO2 of 80% at 5 minutes was associated with adverse outcomes including intraventricular hemorrhage, and risk of death was significantly increased with time to reach SpO2 80%.
– Endotracheal intubation is indicated for ineffective or prolonged positive pressure ventilation (PPV) or for special circumstances such as an abnormal airway anatomy.

– Chest compressions are indicated when heart rate remains less than 60 beats/min after at least 30 seconds of PPV. When chest compressions begin, supplemental O2 may be increased until the heart rate recovers and weaned rapidly afterward.
– Epinephrine is indicated when the heart rate is <60 beats/min after 60 seconds of chest compressions coordinated with PPV using 100% O2

Cardiac Arrest in Pregnancy: An 2019 UPDATE

Sometimes we need a reminder and update on the basics… Your Welcome..

Cardiac arrest in pregnancy. SEMINARS IN PERINATOLOGY 42(2018)33–38.

– The maternal heart rate increases by 20–30% or 15–20 beats per minute

– Cardiac output increases by 30–50% or 1.8 L per minute with the uterus receiving approximately 17% of maternal cardiac output in the third trimester.

– The diaphragm elevates by up to 4 cm in the third trimester causing decreased chest compliance

– Functional residual capacity decreases by up to 25% in the supine position at term.

– Pregnant patients experience mild respiratory alkalosis.


– Aortocaval compression (ACC) needs to be addressed during cardiac arrest management.

– The American Heart Association recommends manual left uterine displacement (LUD) throughout resuscitative efforts and during perimortem cesarean section until delivery of the infant.

– In the past, ACC was addressed by placing the patient in a tilt; however, this is no longer recommended.

– Numerous studies have shown that maternal tilt decreases efficacy of chest compressions, which hinders resuscitative efforts.

– Successful manual LUD can be performed from the patient’s right and left side.

– From the right side, the uterus is pushed upward and leftward to relieve pressure from the maternal vessels.

– Care should be ensured that the uterus is not inadvertently pushed down.


– The most common cause of maternal mortality is venous thromboembolism followed by preeclampsia and eclampsia.

– In an analysis of cardiac arrest in pregnancy in the United States the most common causes of arrest were hemorrhage, heart failure, amniotic fluid embolism, and sepsis.


– Chest compressions are performed in the same manner as for non-pregnant patients with a rate of 100–120 compressions per minute and a depth of at least 2 in with minimal interruptions.

–  The most recent guidance state that hand placement for chest compressions should be in the center of the chest on the lower portion of the sternum in the same manner as for non-pregnant patients.

Bag-mask ventilation with 100% oxygen with a rate of at least 15 L/min should be initiated immediately with a compression–ventilation ratio of 30:2.

– Early defibrillation should be provided when appropriate, and modifications in shock energy are not indicated. Studies have shown that transthoracic impedance is unchanged in pregnant patients. Providers should not delay or withhold defibrillation due to concerns for fetal safety. During defibrillation, a minimal amount of energy is transferred to the fetus, and it is safe to defibrillate a patient at any stage of pregnancy.

– Since airway management is more challenging, intubation should be attempted by the most experienced provider available with the use of a smaller endotracheal tube with a 6.0–7.0mm inner diameter to increase the likelihood of successful intubation.

– Medical therapy for cardiac arrest in pregnancy is no different than for non-pregnant patients.

– Medications do not require dose alterations, and no medication should be withheld due to concerns for fetal teratogenicity.

– During active CPR, the AHA guidelines recommend against fetal assessment, and all fetal monitors should be removed from the patient. The goal of CPR is to restore circulation in the pregnant patient. Evaluating the fetal heart rate is not helpful at this time and can interfere with maternal resuscitative efforts.
– PMCD should be initiated after 4 min of failed resuscitative efforts with the goal of delivery within 5 min of initiation of resuscitative efforts.

– As a caveat, if the mother has clearly non-survivable injuries, it is not necessary to wait to begin the PMCD. Transfer to the operating room is not recommended.

– With regards to technique for cesarean section, both vertical and Pfannenstiel incisions are acceptable and are at the discretion of the obstetrician. If the underlying arrest is secondary to trauma, a vertical incision is preferred given that it provides better visualization of the abdomen.
– If restoration of spontaneous circulation (ROSC) has been achieved without undergoing a PMCD, the patient should immediately be placed in the full left lateral decubitus position.

– The 2015 AHA guidelines now state that pregnancy is not an absolute contraindication, and therapeutic hypothermia can be considered on an individual basis.






  1. An increase by 4-6-mmol/L [Na] is sufficient to reverse most serious manifestations of acute hyponatremia.
  2. Increase [Na] no more than 10 mEq/L in 24 hour period in pts with LOW RISK Osmotic Demyelination syndrome
  3. Increase [Na] no more than 8 mEq/L in 24 hour period in pts with HIGH RISK Osmotic Demyelination syndrome (ODS).
  4. PTS at HIGH RISK of ODS (mnemonic CHAMP):
    1. Cirhosis
    2. Hypokalemia
    3. Alcoholism
    4. Malnutrition
    5. Plasma Serum sodium <105


  1. For our purposes the only cause of cerebral edema and neurological causes of hyponatremia are the hypotonic (low osmolar) hyponatremia causes.
  2. IF neurological symptoms are present and hypotonic hyponatremia is presumed or confirmed then 150 ml of 3% (3ml/kg) over 20 min
  3. Check serum sodium after 20 min while repeating an infusion of 150 ml of 3% over 20 min IF symptoms persist.
  4. GOAL: Target goal of 5 mmol/L increase in serum Na is achieved


  1. As long as the patient is not hypovolemic AND the SEVERE symptoms are treated then
  2. Use the smallest volume of NS until specific causes are found
  3. Limit the increase in Serum Na to a total of 10 mEq/L[g]in the first 24hr and an additional 8 mEq/L during every 24hr there after until serum sodium reaches a goal of 130 mmol.
  4. Check Serum sodium concentration after 6 hour and after 12 hr and then daily until Na has stabilized.
  5. A sudden increase in urine output to >100ml/h signals increased risk of overly rapid rise in serum sodium concentration


To calculate the anticipated increase of Serum sodium by infused saline:

Screen Shot 2018-12-24 at 5.51.42 AMWhere:

  • Infused Na = 154 if Normal Saline or 513 if 3% hypertonic saline
  • Total Body water (TBW) = Wt x 0.6 if male
  • Total Body water (TBW) = Wt x 0.5 if female
  • Total Body water (TBW) = Wt x 0.5 if elderly (>65) male
  • Total Body water (TBW) = Wt x 0.45 if elderly (>65) female

Example: 70 kg young female with severe cerebral symptoms is given a 3 ml/kg bolus of 3% NaCl (Na=
513 mEq/L) and Serum Na = 108

Infuse Na                   = 513 mEq/L (hypertonic)

Volume infused         = 0.003 L/kg x 70 kg = 0.14 L

Serum Na                   = 108

TBW                            = 70×0.5 (young female) = 35L

Screen Shot 2018-12-24 at 6.33.33 AM

 Final serum Na = 111


  1. BEER POTOMANIA 15 (BOX 1 from algorithm)
    1. NPO except medications for 24 h
    2. No IVFs unless symptomatic
    3. Prescribe IVFs in finite amounts if needed
    4. Serum sodium every 2 h

    5. S Na increase < 10 mEq/L in first 24 h
    6. S Na increase < 18 mEq/L in first 48 h
    7. Re-lower serum sodium levels if necessary
    8. Give all IV medications in D5W

    9. If caloric intake is needed, use D5W.
  2. HYPERVOLEMIC causes (BOX 2 from algorithm)
    1. Recommend against treatment with the sole purpose of aim of increasing the serum sodium concentration in mild or moderate hyponatraemia.
    2. Fluid restriction (<1.5-1.0L/d or 500ml/d less than the Urine output) to prevent further fluid overload.
    3. Recommend against vasopressin receptor antagonists.
    4. Recommend against demeclocycline.
  3. HYPOVOLEMIC (BOX 3/4 from algorithm)
    1. It is recommended to restore volume with i.v. 0.9% saline or a balanced crystalloid solution at 0.5–1.0 ml/kg per h
    2. In case of hemodynamic instability, the need for rapid fluid resuscitation overrides the risk of an overly rapid increase in serum sodium concentration
    3. In these patients restoring volume will suppress vasopressin secretion causing electrolyte-free water excretion to increase. Therefore, these patients are at high risk of an overly rapid increase in serum sodium concentration. Sudden increases in urine output can act as a warning signal that overly rapid correction of hyponatremia is imminent.
  4. EUVOLEMIA HYPOTHYROIDISM (BOX 5 from algorithm)
    1. Unless severe (i.e. myexedma or TSH >50 mIU/mL), other causes of hyponatremia should be sought rather than hypothyroidism. 

    2. Unless the patient has hyponatremic encephalopathy, primary treatment of hyponatremia should consist of thyroid hormone replacement at standard weight-based doses; several days may be needed to normalize the serum Na. 

  5. SIADH (BOX 6 from algorithm)
    1. In moderate or profound hyponatraemia, restricting fluid intake should be first-line treatment.
    2. In moderate or profound hyponatraemia, the following are equal be second-line treatments: increasing solute intake with 0.25–0.50 g/kg per day of urea or a combination of low-dose loop diuretics and oral sodium chloride.
    3. In moderate or profound hyponatraemia, we recommend against lithium or demeclocycline.
    4. In moderate or severe hyponatraemia, we do not recommend vasopressin receptor antagonists.
  6. Cerebral Salt Wasting (Box 7 from algorithm)16 17
    1. CSW is a volume-depleted state
    2. Depending on the severity isotonic or hypertonic solutions are indicated.
    3. Additionally, sodium tablets up to 12 g/d may be used can be combined with the IVF
    4. Once euvolemia is achieved, the goal of therapy is to prevent volume depletion by matching the urinary output.
    5. Fludrocortisone has also been used for the treatment of CSW at doses of 0.1 to 1 mg/d (stimulating reabsorption of sodium and water)
    6. The most common adverse effect associated with fludrocortisone was hypokalemia in up to 73% of patients.


  1. Fluid restriction is first line treatment
  2. Urea[h]/loop diuretics are equal second line treatments


  1. Prompt intervention for re-lowering the serum sodium concentration if it increases >10 mmol/l during the first 24 h or >8 mmol/l in any 24 h thereafter
  2. We recommend discontinuing the ongoing active treatment.
  3. Consulting an expert to discuss if it is appropriate to start an infusion of 10 ml/kg body weight of electrolyte-free water (e.g. glucose solutions) over 1 h under strict monitoring of urine output and fluid balance.
  4. We recommend consulting an expert to discuss if it is appropriate to add i.v. desmopressin 2 mg, with the understanding that this should not be repeated more frequently than every 8 h.


Chances are if you are reading this you have probably seen a case or two of hyponatremia. Well, defining hyponatremia isn’t really hard. In fact treating acute symptomatic hyponatremia isn’t that hard either. So what makes this electrolyte disturbance so painful? It’s the over abundance of math, renal physiology and lack of organization that exists within the literature; enough to make doctors have flashbacks of their USMLE days. Fear not friends, we are going to make this simple and painless. Unless simple and painless are not your thing, then I have for you the sadist’s ball gag equivalent of math in the optional section to appease even the most vicious of IM attendings. No more google-ing 40 different articles to treat that hyponatremic patient, everything in one neat package! So lets get to it!

            First off some definitions:


Classification Definition Comment
Hyponatremia <136  
Moderate 125-135  
Severe/Profound <125 Profound in UK
Acute vs Chronic Time of development (48 hr cutoff)


Usually unknown
Tonicity Dealing with osmolarity There can be unaccounted osmoles (EtOH)
Hypotonic Hypo-osmolar Type of hyponatremia
Volemia Dealing with the pt volume status Difficult to asses clinically.

Table 1. Classification of Hyponatremia (US units: mEq/L) 1, 2

So far, not horrible; Right?


We need to talk about epidemiology not because every chapter on any disease starts out this way but because it will help us down the road. So lets push on. Hyponatremia is probably the most common electrolyte abnormality3.  Based on studies from the first half of the 2000’s the incidence[a]of hyponatremia is about 30-40% of admitted patients worldwide. The largest amount were found in the ICU with hyponatremia <125 mEq being an independent predictor of mortality. Values <126 mEq/L and < 116 mEq/L were found in about 6% and 1% of the patients, respectively4. In ED populations it is obviously lower than in admitted patients. ED based studies outside the US found a prevalence of  3-5% for all adults but 10-17% in those patients age 65 and older. These studies also found an increase in hyponatremia for both groups during the summer months 1-2% greater than the above numbers 5, 6. In the geriatric population 78% of episodes of hyponatremia were precipitated by increased fluid intake, administered orally or as intravenous hypotonic fluid. Finally, up to 17% of chronic alcoholic patients had hyponatremia secondary to Beer Potomania[b]

OPTIONAL: OsmolaLity or OsmolaRity?

To jump back a bit we should define osmolaLity and osmolaRity. Osmolality (with an “L”) is a measure of the osmoles per kilogram (Osm/Kg),  osmolarity (with an “R”) is defined as the number of osmoles per liter (L) (Osm/L). Don’t worry we don’t have to know how many kg our patients are to calculate their osmolality. If the L and the R were flipped it would probably be easier to remember but lets just remember that the L is for weight and the R is for volume. This is important because we calculate osmolaRity but measure osmolaLity so we should keep track of the units. If you want to not be accurate then you don’t have to worry because we are dealing with water in the body, so we can approximate osmolaLity to equal the osmolaRity[c].


Figuring out the differential our patients have for their hyponatremia is probably the most difficult part of this diagnosis. However, here is where I am going to try (or at least try to try) to simplify it.

Click Here for the Hyponatremia Algorithm: Hyponatremia 2.0-3

In order to decide the reason for the hyponatremia in our patients we need to have a starting point. We used to talk about volume status as the starting point but this makes things too difficult furthermore the reliability of volume status by clinical exam is less than accurate. Instead we are going to start with the osmolality.



The first branch point into our differential diagnosis is figuring out what is the serum osmolality (tonicity). We can do this two ways: order an extra lab value of serum osmoles (not usually part of “first round of orders”) or we can estimate (oh thank god!) a serum olsmolarity. To do this we us the formula:

Serum Osm [mmol/L]= 2[Na+] + Glucose + Bun               (Equation 1)

This probably looks a bit strange to US doctors since it’s missing some numbers. That’s because we don’t use [mmol/L] in the US, instead we use the crazy units of  [mEq/L]. So to go from mmol to mEq (or mg same thing for our purposes) we have to divide the molecules by their molecular weight. In fact, any good British child will tell you to convert their glucose to US values by dividing by 18![d]So now our formula becomes the familiar:

Serum Osm [mEq/L]= 2[Na+] + Glucose/18 + Bun/2.8    (Equation 2)


To estimate the serum osmolarity [mEq/L] use the formula:

2[Na+] + Glucose/18 + Bun/2.8


How good is this formula for estimating serum osmoles? When equation 1 (also referred to as the Smithline-Gardner formula) is compared to the mean measured osmolality in healthy patients it gives an osmolal gap (OG, i.e the difference between calculated and measured Osm) close to zero and an SD of 4 mmol/L. When applied to patients in which an osmolality was clinically indicated (i.e where it would theoretically matter) the variability in the OG is approximately +/- 7 mmol/L. This held true as long as ethanol was not adulterating the sample7. Remember that ethanol will contribute to serum osmolarity and will need to be divided by 3.78. Thus equation 2 (in the US) is proposed to be adopted by all clinicians and laboratories along with a “fudge” factor of +/- 10 mmol/L for the gap7. To really get the most accurate answer here you would likely have to order a serum osmoles but it would appear that this estimation holds up pretty well to start treatment.


Only true (hypotonic) hyponatremia matters so exclude other causes.

The normal human plasma osmolality is 275-300 mOsm/Kg9. Therefore, we need to see if we have hypertonic or isotonic hyponatremia. Hypertonic (also called Translocational or redistributive hyponatremia) causes include: hyperglycemia[e], mannitol, and sometimes a contrast load.  Isotonic (also called Pseudo or normo-osmolal hyponatremia) causes include: hyperlipidemia and hyperproteinemia. Once we have excluded these causes by a value of <275 mOsm/kg then we can say that we have a true hypotonic or hypo-osmolar hyponatremia.


Calculate the serum osmolarity. If it is <275 mOsm/Kg then the causes are “true” or hypotonic causes1which can truly cause symptomatic hyponatremia.


The normal response to hyponatremia is marked suppression of ADH secretion, resulting in the excretion of maximally dilute urine with an osmolality below 100 mOsm/kg and a specific gravity ≤1.003. Vasopressin (ADH) levels are what really differentiates the type of hyponatremia at this point. The first type will have high vasopressin levels and high urine Osm with low Na.  Here high vasopressin causes inability to excrete water and consists of the classic 3 groups of hyponatremia: hypovolemic, euvolemic and hypervolemic. The second type will have low serum vasopressin levels and typically low urine osmolality. Thus, mechanisms other than vasopressin are responsible. These types includes: chronic renal failure, psychiatric disorders, potomania, and low solute load excreted in the urine. However we can’t measure Vasopressin (ADH) so we use low osm and low sodium to represent this group. Values above 100 mOsm/kg indicate an inability to normally excrete free water, most commonly because of persistent secretion of ADH. Therefor the urine osmolality can help us. Once again we have 2 options to determine osmolality: order it or to estimate it. 


To jump back a bit to med school physiology lets understand what ADH does. ADH (Vasopressin) is released from the posterior pituitary. It does this in response to 2 motivating factors: 1. Low Blood pressure via Angiotensin II released from the kidney and activating the V2 receptor; 2. High plasma osmolality (Hypertonicity) either by too little water or too many solutes. Once ADH is release it works on the principal cells in the collecting duct to stimulate aqauporin-2 channels to be inserted on the collecting duct to reabsorb more water back into the blood. So ADH “ADDs H20″ to the plasma. Thus in the algorithm when there is low URINE osmolality this must mean that ADH is not working and is “ADH independent”


The normal response to hyponatremia causes a urine osmolality below 100 mOsm/kg. To estimate the urine Osm from the urine we can use the Urine specific gravity (USG) and the following equation:

            UOsm = (USG -1) x 25,000                         Equation 311.


So if the urine Osm are calculated and less than 100 mOsm/kg then it is likely that a relative excess water intake is the umbrella cause of the hypotonic hyponatremia1. Thus the differential includes: Primary polydipsia, beer potomania, water dilution in formulas of infants, tap water enemas in infants, or very low sodium intake. Again this is because the normal response to hyponatremia is suppression of ADH, resulting in the excretion of a very dilute urine If that’s the case you are done and all you need to do is fluid restrict! We will speak more about beer potomania later on since it deserves special attention.

            TAKE HOME POINT: UOsm <100 implies water excess


If urine osmolality > 100 mOsm/kg then likely there is impairment of the renal concentrating ability. Now, it gets a little more complicated. *At this point more lab testing will likely be needed. My feeling is if you are going to order a urine sodium, you might as well order everything at once[f]. At this point I recommend ordering:

Serum:  cortisol, Osmoles, TSH, Uric acid

Urine:  creatinine, potassium, sodium, Uric acid,


In a study by Imran, 504 urine specimens from patients on whom a simultaneously drawn USG and an osmolality were available were examined. They found good linear correlation between USG and Urine Osm when measured either by reagent strip or refractometry. Urine samples were divided into ‘‘clean’’ and ‘‘pathological’’ urines. Pathologic urines on reagent strip included: glucose, ketones, urobilinogen, bilirubin, and protein and ketones, bilirubin, and urobilinogen, for samples measured using refractometry. The study found that pathological urines did not correlate as well to urine Osm as the non-pathological12.  In another study of only hyponatremic patients it was found that USG has a linear relationship with measured urine osmolality in patients with hyponatremia. A multiplying factor of 20-33 is better than 30-40 in predicting urine osmolality of most patients with hyponatremia11. The commonly used formula to predict UOsm from USG uses a multiply of 30 but from the above two studies it would appear that multiplying by 25 gives a closer approximation and less likely to overestimate.  Hence equation 3.

STEP 4: URINE Na <30 mEq/L

If urine sodium concentration ≤ 30 mmol/L, then most likely low effective arterial volume (see below optional section on What the hell does “low effective arterial volume” mean) is the cause of the hypotonic hyponatraemia. Really what we have to focus on here is whether the patient has HYPERvolumic or HYPOvolemic causes. The cutoff of urine sodium of 30 is randomly picked based on studies and is used by guidelines2. Using a cutoff of <30 suggests the above diagnoses and diuretics wont affect this diagnosis1.

OPTIONAL: What the hell does “low effective arterial volume” mean

Early observations in patients with cardiac failure demonstrated renal sodium and water retention that resulted in an increase in extracellular fluid (ECF) volume and edema. This degree of sodium and water retention in normal individuals would lead to an increase in renal sodium and water excretion, yet the reverse occurs in patients with heart failure. A similar sequence of events occurs in patients with cirrhosis and pregnancy. Renal sodium and water retention in edematous disorders continued to be perplexing. A term for sodium and water retention in edematous disorders was proposed to be due to a decrease in “effective blood volume” rather than “total blood volume”. For many years, however, this enigmatic term, which was used to explain sodium and water retention in patients with heart failure or cirrhosis, was never defined.  Use of the term “decreased effective blood volume” can be considered outdated and be replaced by “arterial under-filling.” However, use of the term persists in clinical medicine, as “decreased effective arterial blood volume”13.


Although I said before that determining clinical volume status is more difficult at this stage the causes of hyponatremia from hypovolemic and hypervolemic reasons should be more obvious. Hypervolemic causes would include: CHF, Cirrhosis, and Nephrotic syndrome. Hypovolemic causes would include: Diarrhea and vomiting, third spacing, diuretics. It should be noted that a third cause of low urine sodium is very low sodium intake but this is rare in western diets. Also know there are insufficient data to suggest that increasing serum sodium concentration improves patient-important outcomes in moderate hyponatraemia with expanded extracellular fluid volume, in cirrhosis or heart failure.



If the urine sodium is >30 mEq/L then one needs to consider if the patient is on diuretics. When I say diuretics I’m mostly refering to Thiazide and Thiazide-like diuretics. Potassium sparing diuretics can contribute to hyponatremia but less so. Loop diuretics are much less likely to cause hyponatremia.  In fact diuretics can cause a urine sodium of <30 mEq/L also but we will touch on how to differentiate this as well.  If the patient is NOT on diuretics then again we must decide if the patient has hypovolemia or Euvolemia


Determining volume status in this category may be more subtlebut hypovolemia should be more obvious than euvolemia in this group. Thus, if by clinical exam, the patient is hypovolemic then the causes include: vomiting, primary adrenal insufficiency and renal/cerebral salt wasting.Determining euvolemia is much more subtle, however, if the ECF is normal by clinical exam then the causes include: SIADH, secondary adrenal insufficiency, and hypothyroidism (realistically unless hypothyroidism is severe such as myxedema or TSH >50 mIU/mL, then other causes of hyponatremia should be considered10). 


As I said above the big problem at this branch point is that determining whether a patient is euvolemic or not can be very difficult. Additionally the treatments of SIADH and salt wasting are differentbecause of fluid restricting patients with SIADH as opposed to administering salt and water in salt wasting14. One way to differentiate this is by the fractional excretion of uric acid (urate). FEurate is normally 4%–11%and will stay normal in the excess water states with low urine osmoles because the concentrating ability is preserved (BOX 1 conditions). If the FEurate is <4%, it is consistent with pre-renal (BOX 2,3,4 conditions) including volume depleted states or edematous states such as CHF, cirrhosis, nephrotic syndrome,and pre-eclampsia.


Distinguishing these two can be very different because the only real difference is that in salt wasting there is a decrease in volume. However, the treatments are very different. The FEurate is especially helpful in distinguishing these two entities. In SIADH and Salt wasting (either cerebral or renal) FEurate is increased to >11% while the sodium is low. However, they can be differentiated after correction of the sodiumto >130. In SIADH, correction of hyponatremia will normalize FEurate to <11%, however in salt wasting the FEurate will still be inceased to>11%. One important caviat is that for the FEurate to be valid the patients serum creatinine must be <1.5 mg/dL14.


Essential criteria

  • Effective serum osmolality < 275 mOsm/kg 

  • Urine osmolality > 100 mOsm/kg at some level of decreased effective osmolality

  • Clinical euvolaemia 

  • Urine sodium concentration > 30 mmol/L with normal salt and water intake 

  • Absence of adrenal, thyroid, pituitary or renal insufficiency 

  • No recent use of diuretic agents 

Supplemental criteria

  • Serum uric acid < 0.24 mmol/L (< 4 mg/dL) 

  • Serum urea < 3.6 mmol/L (< 21.6 mg/dL)

  • Failure to correct hyponatraemia after 0.9% saline infusion 

  • Fractional sodium excretion > 0.5% 

  • Fractional urea excretion > 55% 

  • Fractional uric acid excretion > 12%
Correction of hyponatremia through fluid restriction


Fractional Excretion Of Sodium FENa

It is calculated byScreen Shot 2018-12-24 at 5.51.21 AM         

In patients with normal renal function and hyponatremia cut off for FENa is <0.1%.

<0.1%- hypovolemic hyponatremia

>0.1%- hypervolemic and normovolemic hyponatremia.


In hyponatremia due to SIADH, the blood urea nitrogen (BUN) is usually less than 5 mg/dL. However, as urea excretion decreases with aging the absence of a low BUN cannot be used to exclude SIADH in older patients10.

 Fractional Excretion of Uric Acid14

This is calculated as:   Screen Shot 2018-12-24 at 5.51.28 AM     

FEUrate <4% implies: Volume Depletion Addison’s Disease Edematous states, CHF

  Cirrhosis, Nephrotic syndrome

FEUrate 4-11% implies: psychogenic polydipsia

FEUrate >11% implies: HCTZ, Salt Wasting

After normalization of Na to >130 FEurate will be <11% in SIADH and >11% in Salt wasting


Cases of a hypoosmolal (Hypotonic) syndrome in beer drinkers were first described in 1972. Up to 17% of chronic alcoholic patients had hyponatremia.  Although not consistently reported in patients with beer potomania, low urine osmolality on admission laboratory test results was not a consistent finding. In addition to the history of excess beer drinking, often a recent history of binge drinking or illness was present.  This may potentially precipitate a rapid decrease in serum sodium levels. The maximum urinary dilution capability is 50 mOsm/L, a large amount of water (>20 L) must be ingested under normal situations to overwhelm the capacity for urinary dilution. For example, if the patient excretes only 100 mOsm/d, greater than 2 L of fluid intake with a urinary dilution capability of 50 mOsm/L will result in net water retention and subsequently hyponatremia. Patients with beer potomania have a history of significant beer drinking, often long term, in conjunction with a poor diet. The net result is very low osmole intake because beer has very little sodium and no protein, but has some calories that prevent endogenous protein breakdown (urea generation). Because the obligatory solute loss in a day is approximately 250 mOsm in these patients, with a urinary dilution capability of 50 mOsm/L, water intake greater than 5 L (or 14 cans of beer) results in hyponatremia. The net effect is an excess of free water without the solute for diuresis. ADH levels are expected to be suppressed in patients with beer potomania. The low ADH levels limit free-water reuptake in the collecting tubules of the kidney and explain why these patients have brisk diuresis when solute is presented. Sodium chloride in IV fluids is a common source of the solute load while hospitalized. Urine osmolality on recheck after the solute is introduced is low in these patients because of the low ADH levels. Based on a solute concentration of 308 mEq/L (154×2) in 0.9NaCl solution and the kidney’s diluting ability of 50 mOsm/L, significant diuresis can occur with 1 L of NS solution in the setting of a low-ADH state. This water diuresis can produce large increases in serum sodium levels in a short period. Attempting to replace this with electrolyte-free water to prevent a rapid increase in sodium levels can be difficult. Beer potomania is unusual because the cause of hyponatremia is multifactorial, including low osmole intake. Furthermore, as these patients convert to a low ADH state, the rate of correction may be dramatic.  One study found that 18% of patients presenting with beer potomania developed ODS. Three large retrospective reviews of patients who presented with symptomatic severe hyponatremia found no benefit to aggressive correction of chronic hyponatremia. If the patient is asymptomatic, fluid restriction and monitoring the patient despite the degree of hyponatremia is the recommended approach. If the serum sodium level increase occurs at a rate that will exceed the desired goal, D5W infusion should be started to match urine output. The D5W rate can be adjusted every 2 hours based on serum sodium level change. If serum sodium levels increase to greater than either the 24- or 48-hour goals, D5W rate should be increased to decrease the serum sodium level to the recommended goal. Desmopressin may be considered if diuresis occurs at an excessive rate that the infused D5W is unable to match; based upon the current rate of serum sodium level change, the goal will be exceeded despite D5W; the goal has been already been exceeded; or last, symptoms of ODS develop15. A large rise in serum Na after infusion of a test volume of isotonic saline suggests the presence of hypovolemia. 









  1. Spasovski G, Vanholder R, Allolio B et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant 2014; 29 Suppl 2, i1-i39.
  2. Hoorn EJ, Zietse R. Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines. J Am Soc Nephrol 2017; 28, 1340-1349.
  3. Anderson RJ, Chung HM, Kluge R, Schrier RW. Hyponatremia: a prospective analysis of its epidemiology and the pathogenetic role of vasopressin. Ann Intern Med 1985; 102, 164-168.
  4. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med 2006; 119, S30-5.
  5. Giordano M, Ciarambino T, Castellino P et al. Seasonal variations of hyponatremia in the emergency department: Age-related changes. Am J Emerg Med 2017; 35, 749-752.
  6. Imai N, Osako K, Kaneshiro N, Shibagaki Y. Seasonal prevalence of hyponatremia in the emergency department: impact of age. BMC Emerg Med 2018; 18, 41.
  7. Choy KW, Wijeratne N, Lu ZX, Doery JC. Harmonisation of Osmolal Gap – Can We Use a Common Formula. Clin Biochem Rev 2016; 37, 113-119.
  8. Purssell RA, Pudek M, Brubacher J, Abu-Laban RB. Derivation and validation of a formula to calculate the contribution of ethanol to the osmolal gap. Ann Emerg Med 2001; 38, 653-659.
  9. Plasma osmolality. Wikipedia
  10. Sahay M, Sahay R. Hyponatremia: A practical approach. Indian J Endocrinol Metab 2014; 18, 760-771.
  11. Sumethkula V, Choojitaromb K, Ingsathitc A, Radinahamed P. The Correlation between Urine Specific Gravity and Urine Osmolality in Patients with Hyponatremia. nternational Journal of Sciences: Basic and Applied Research (IJSBAR) 2017; 31, 181-189.
  12. Imran S, Eva G, Christopher S, Flynn E, Henner D. Is specific gravity a good estimate of urine osmolality. J Clin Lab Anal 2010; 24, 426-430.
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[a]Incidence Incidence is the rate of new cases of the disease. Prevalence is the actual number of cases alive or the accumulation of the incidences over a period of time. 

[b]Poto – drinking alcohol; mania – excessively

[c]Well really Osmolarity = Osmolality x 0.995 but who is counting.

[d]I was literally once told this by one of my really smart 8 yo Type I diabetic patient from the UK who told me how to convert mEq/L to mmol/L for his glucometer readings!

[e]Remember: each mg increase in blood glucose above 100 mg/dl decreases the serum sodium by 1.6 meq/l. This is negligible when blood sugar is less than 300 mg/dl. When serum triglycerides are above 100 mg/dl, for every 500 mg/dl rise in serum triglycerides, fall in serum sodium will be about 1.0 mEq/L. When serum protein is above 8 gm/dl, for every 1 gm/dl rise in serum protein, fall in serum sodium will be about 4.0 mEq/L10.

[f]This is the Shriki-EM Mantra

[g]US guidelines recommend a limit of 6-8 but this is based on limited data.

[h]As a means of increasing solute intake, daily intake of 0.25–0.50 g/kg urea can be used. The bitter taste can be reduced by the following recipe in Sachets:  10 g urea + 2 g NaHCO3 + 1.5g citric acid + 200 mg sucrose to be dissolved in 50–100 ml water.  Alternately using a commercially available urea powder drink mix (Ure-Na by Nephcentric)2

Aspirin for All Comer Chest Pain: Is it Naughty or Nice

Screen Shot 2018-12-04 at 2.35.59 AM.png

Like it or not,  we do a fair amount of primary care medicine in the emergency department. Therefore, we need to know some of the basics about primary care.  One of the most fundamental concepts is the use of aspirin for prevention of MI either before the first one (primary) OR after (secondary) your patient has had a heart attack or stroke. Spoiler alert… 2018 was not a good year for aspirin. It would seem our beloved miracle drug has not been able to escape the rigors of time and medical reversal; much as we have seen with so many other treatments in medicine. Don’t panic, using our beloved aspirin during and after an acute MI hasn’t changed (see you don’t even need a towel!). But whom in the ED, do we need to discharge on a daily aspirin? How good is aspirin in the PRIMARY prevention of cardiovascular disease? Well the holiday season of 2018 has gifted us with 3 trials to help us answer these burning questions.


     First a little back story. I was born at a very young age…oh sorry not my back-story, the aspirin in prevention back-story. To understand the controversy we need to define a few terms. The first is MACE, which stands for major adverse cardiac events defined as MI (aka myocardial infraction, aka heart attack), stroke, and vascular death (and sometimes arrhythmias are thrown in to the definition as well). MACE is what separates the terms Primary prevention from Secondary Prevention. The people without MACE are the people we are PRIMARILY trying to prevent bad things from happening. If they HAVE had MACE then we are trying to SECONDARILY prevent a repeat of bad things. As I said above the role of aspirin has been well established in SECONDARY prevention (i.e. prior MI). This was established by the famous Antithrombotic Trialists’ Collaboration in 2009 in over 200,000 patients. The use of aspirin in the PRIMARY prevention however has been somewhat controversial despite 30 years of studies! The harm from aspirin is mostly due bleeding and over the years we have had better and better medications to treat vascular pathology (specifically statins, neuropathy and myopathy aside).

     OK so now that we are again confident that aspirin is great SECONDARILY (once you have a heart attack), we need to figure out if it is useful for PRIMARILY preventing heart attacks (BEFORE you have one). Below we discuss the THREE trials that help us figure this out.

     The first trial we will discuss is the ARRIVE trial. ARRIVE was done in seven countries, including the US mostly in primary care offices. Eligible patients were either males aged 55 years and older with >1 risk factors or females aged 60 years and older with >2 risk factors. The study also checks all the usual boxes for doing a study the right way including randomized, double blind, placebo-controlled, multicenter, and intention to treat analysis. Patients had a moderate vascular risk but NO MACE, so all primary prevention and were randomized to get aspirin or placebo. The primary outcome was a time to event analysis for the composite of who did get MACE. GI bleeding was the major safety outcomes. They enrolled about 12,500 pts and randomized about 6300 to each group. For the primary outcome of MACE the aspirin group had 4.3% vs. 4.5% MACE (HR of 0.8-1.1; p=0.6). For the GI bleeding outcome aspirin had 0.97% vs. 0.46% in the placebo group (HR 2.11, 1.36–3.28; p=0·0007). So, aspirin had no difference in MACE but doubled the bleeding.

     In order to see if we can find a subgroup of people the MIGHT benefit with primary prevention of aspirin we turn to the ASCEND trial. This jolly good UK trial looked specifically at diabetics for primary prevention. They enrolled men and women at least 40 yo who had a diagnosis of diabetes and followed them for 7 years. The primary outcome, which was modified DURING recruitment (naughty, naughty!) was MACE and the primary safety outcome was any major bleeding (ICH, GI, etc.). The trial was a randomized, placebo controlled and intention to treat study.  The trial included 15000 pts. and randomized 7740 to each group (I know that math doesn’t add up but work with me here). For the primary outcome of MACE, the study found a 1% benefit to aspirin overall, with 8.5% for aspirin and 9.6% for placebo (RR of 0.88 with p=0.01). However, that 1% difference occurred only in the first 3 years (2.6% vs. 3.5%) but after 3 years there was no further difference (2.7% vs. 2.7%). The “any” major bleeding risk however was 4.1% in the aspirin group and 3.2 in the placebo group (RR 1.29 with p=0.003). So even if we don’t look at these groups by year (and the subgroups were NOT pre-specified so we shouldn’t – More naughtiness!); the benefit to aspirin for primary prevention was 1% and the harm was 1% making it a wash. This looks like a job for shared decision making in the first 3 years…

     The last study we will discuss looks at another at risk group, the elderly. The ASPREE trial involved men and women from Australia and the United States who were 70 years of age or older (or ≥65 years of age among minorities in the United States). Again this was a randomized controlled trial of aspirin or placebo of approximately 19,000 (only 2500 from the US) “relatively healthy” elderly people who were followed for about 5 years. The primary end point was disability-free survival, which was defined as survival free from dementia or persistent physical disability. The primary composite end point was derived from the first end-point events of death, dementia, and persistent physical disability. Of note the trial was stopped early because “it was extremely unlikely that continuation of the trial intervention would reveal a benefit with regard to the primary end point”. Unfortunately, this trial makes the naughty list for listing two primary outcomes “The primary end point was disability-free survival… The primary composite end point was derived from the first end-point events of death, dementia, and persistent physical disability”. Then they go on to mistakenly list not survival but mortality. About 9500 were allocated to each group. They list “any cause of death” as 5.9% with aspirin and 5.2 with placebo, so no difference. They list CV disease including stroke as 1.0% for aspirin vs 1.2% for placebo. They list major hemorrhage as 0.3% for aspirin and 0.3% for placebo. They also go on to say in the abstract that there were more cancer related deaths in the aspirin group but that isn’t really an appropriate conclusion since we don’t even know if this is an a priori secondary outcome or just statistical jujitsu after the fact.

So to summarize these three large trials: ARRIVE had no change in MACE but increased bleeding; ASCEND had a decrease in MACE but with an equal and opposite increase in bleeding; and ASPREE had no change in mortality, no change in MACE and no change in bleeding. So does the patient with chest pain but without MACE get an aspirin forthright?

I would say no to that…and to all a good night!


1. Gaziano, J. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 2018; 392: 1036–46.

2. Bowman, L. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med 2018;379: 1529-39.
 ASCEND Study Collaborative Group.

3. McNeil
J. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med 2018;379: 1519-28.
 ASPREE Investigator Group

Quick Hit Article #12: Should you stay or Should you go for syncope

Syncope Admissions.jpg

Anderson. Trends in Hospitalization, Readmission, and Diagnostic Testing of Patients Presenting to the Emergency Department With Syncope. Ann Emerg Med. 2018;72:523-532


Although this study doesn’t tell you who should be admitted it does nicely show the mortality, albeit inpatient only, and some interesting facts about admitted syncope patients.

This was a retrospective epidemiology study of syncope-related ED visits and hospitalizations using the National Emergency Department Sample from 2006 to 2014 and State Inpatient Databases and Emergency Department Databases from 2009 and 2013. Primary outcomes were annual incidence rates of syncope ED visits and subsequent hospitalizations, and rates of hospitalization, observation, 30-day revisits, and diagnostic testing comparing 2009 with 2013.  From 2006 to 2014, they identified 15,154,920 ED visits for syncope. Annual rates of ED visits increased from 643 to 771 per 100,000 adults, whereas hospitalizations declined from 36.3% to 24.7%.  The proportion of ED visits resulting in hospital admission decreased 12.1% between 2009 and 2013, whereas the proportion of ED visits resulting in observation care increased by 7.7%. There was no significant change in 30-day ED revisit rates for syncope (1.9 vs 1.8) and no change for all cause ED revisits (14.9% vs 15.0%) after presentation. The frequency of advanced cardiac testing increased from 13.8% to 17.0%, and neuroimaging increased from 40.6% to 44.3%. In hospital mortality was similar in both groups as well at 0.7% vs 0.9%

QUICK HIT ARTICLE #10: How Low Should you Go? BP lowering without hypertensive emergency

Miller, JB. Cerebrovascular risks with rapid blood pressure lowering in the absence of hypertensive emergency. Am J Emerg Med. 2018 Aug 21. pii: S0735-6757(18)30690-9. doi: 10.1016/j.ajem.2018.08.052.

There are not many studies of affects of blood pressure lowering on ED patients in the absence of end organ disease. This one is an interesting one and should give cause before lowering blood pressure for the sake of a number.


This was a non-randomized trial of 39 patients with out of control BP who had their blood pressure lowered not for end organ disease but for the sake of the number being too high. The primary outcome was measure of cerebral blood flow. One of the secondary outcomes was the number of adverse events in the groups with their blood pressure lowered. There was no difference in the primary outcome, however 5% of patients developed adverse events including stroke and altered mental status when their SBP was lowered by >25%. The practice of lowering BP for the sake of the number being too high is not recommended and can cause harm as seen in this study.


This was a prospective quasi-experimental(1) study occurring in a single academic emergency department. A convenience sample of patients presenting to the ED with severely elevated BP (SBP >180 mmHg) were included if the treating clinician was going to give them medications to lower blood pressure DESPITE not having end organ damage. In other words these were patient with “hypertensive urgency” and not hypertensive EMERGENCY. To evaluate these patients the investigators decided to use transcranial doppler (TCD) to measure cerebral blood flow and determine if lowering the bp acute resulted if decreases in cerebral blood flow. In other words does lowering blood pressure in those who have chronically elevated blood pressure cause problems. The primary outcome was the change in middle cerebral artery (MCA) mean cerebral blood flow (CBF) before and after blood pressure lowering medications (paired samples). In order to detect a 10% relative change in CBF a sample size of 38 patients was obtained for an 80% power. The inclusion and exclusion criteria are listed below in the table. Secondary outcomes were the rate of adverse neurological effects and comparison of patients that had intensive (≥25%) drop in MAP versus those with modest BP reductions. The study recruited 48 patients but 9 were excluded leaving 39 patients. There was an average drop in SBP of -38 mmHg ((95% CI −49 to −27) and MAP of −27 (95% CI−36 to −20) mmHg representing an overall reduction of BP by 18%. For the primary outcome there was no difference in the 2 groups in reference to the CBF (a difference of -5 cm/s). There were no differences in any of the secondary outcomes involving TCD measurements. However, interestingly there were 2 patients with adverse events; one with a reversible stroke like syndrome after a reduction in SBP by54% and one with reversible altered mental status after an 29% reduction in SBP. Both of these adverse events occurred after TCD measurements were completed. This gives the incidence of adverse events as 5% in this group. Also both patients had their adverse events after second attempt at lowering BP. Unfortunately, the authors do not give mention to what drugs were administered. I think this study is actually pretty telling. If you try to lower BP too aggressively in patients without end organ damage you are going to adversely affect some of them. I think this really gets back to my point of what makes a great physician: knowing when to not just do something, but stand there. Maybe we need to change the term “conventional wisdom” to “conventional ignorance”.

A SIDE OF STATISTICAL SWOL: The Quasi-experimental study.

Remember there are 2 basic types of studies observation and experimental. The prototypical experimental study is the randomized controlled trial. A quasi-experimental study is one where you have a controlled trial without the randomization. Another name for this is the non-equivalent group controlled design (NECGD). I like this name better because it says in the name that without randomization the groups will be not be equivalent. Therefore, this is not a trial to determine cause-effect relationships. The typical statistics used in RCT’s may not be sufficient to determine significance here because there is bias between the groups. Usually analysis of co-variance with adjustments are used to determine if the groups are different.