Martel ML, Driver BE, Miner JR, Biros MH, Cole JB. Randomized Double-blind Trial of Intramuscular Droperidol, Ziprasidone, and Lorazepam for Acute Undifferentiated Agitation in the Emergency Department. Acad Emerg Med. 2021 Apr;28(4):421-434. doi: 10.1111/acem.14124. Epub 2020 Oct 5. PMID: 32888340.
The answer is still Droperidol however given the small sample size this still needs to be interpreted with caution!
The authors do however state that this confirms “findings from a retrospective chart review of 4,947 patients at our institution sedated with droperidol that demonstrated a 17% rescue sedation rate”.(1) However, “a prospective study from Australia of 1,403 patients receiving droperidol for acute agitation found a higher rescue rate of 31%”.(2)
Calver L, Page CB, Downes MA, et al. The safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department. Ann Emerg Med 2015;66:230–8.e1. 0.1016/j.annemergmed.2015.03.016
Klein LR, Driver BE, Horton G, Scharber S, Martel ML, Cole JB. Rescue sedation when treating acute agitation in the emergency department with intramuscular antipsy- chotics. J Emerg Med 2019;56:484–90.
In residency and med school we are always taught the indications for emergent CRRT as the mnemonic: AEIOU
Acidosis metabolic acidosis with a pH < 7.1 Electrolytes hyperkalemia > 6.5 mEq/L refractory to treatment or rapidly rising levels in potassium Ingestions with dialyzable drug, including salicylates, lithium, isopropanol, methanol, and ethylene glycol (SLIME) Overload volume overload that does not respond to diuresis especially with increased oxygen requirements Uremia causing: uremic bleeding, encephalopathy, pericarditis, and neuropathy
However, in the ICU there has always been a question of how early should we start RRT in the setting of oliguria and BUN not causing symptoms. Initial thoughts were that earlier is better. Today’s infographic focuses on the latest RCT to determine the timing of CRRT. The Bottom Line here is that for the START-AKI TRIAL: Unless there is the emergent a-e-i-o-u’s to start CRRT doing it early does not appear to translate to a mortality benefit. There may be a signal of dialysis dependence at 90 days in this trial. Now we know “Y” we should wait until we have an indication other than the AEIOU’s.
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 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].
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.
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!
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 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.
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 function. The 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].
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!
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:
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)?!
THE BARE MINIMUM
IF a patient becomes grossly unstable obviously resuscitate them.
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
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%)
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.
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
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].
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[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.
[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.
Now usually I don’t go and make wild conjectures and hypotheses. But Im going to discuss a pretty interesting (wild conjecture?) one that on paper seems to make sense to me. Let’s look at the COVID-19 risk factors for who gets severe disease and put them in a molecular and biological framework. If you want you can also skip down and just look at the tables because they sum everything up and then correlates risk factor to molecular basis…The rest is me just talking’. …We will start with the risk factors
Risk Factors of COVID
As with all disease there is usually a group that is particularly susceptible to a particular disease. As information becomes more available we are better able to describe this susceptible population. In the Severe Acute Respiratory Syndrome (SARS) epidemic in 2003 that occurred in Beijing it was noted that those with chronic medical conditions and the elderly had a significantly higher risk of developing SARS1. That outbreak was caused by the SARS-associated coronavirus (SARS-CoV).
Coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the current pandemic. As more time and data accrue it is becoming more clear who may be at risk in this current outbreak of COVID-19. The data thus far is reported from China, Italy and the US, with the majority coming from the devastating effects of the pandemic in Italy. It would appear from the data thus far that once again age and comorbidities play a role in the risk factors of COVID (see Table 1). Those with hypertension (7.3%) and cardiac disease (7.2%) seem to have the highest associations and thus risk. These 2 groups are followed by Diabetes Mellitus (3.3%) (No data specifically distinguishing the two have been reported thus far). Men appear to be more affected by COVID-19 as well. Roughly a 60-40 mix in the confirmed but a 70-30 mix in the cohort from Italy that died (see Table 2 & 3). The age group (see Figure 2) most affected by COVID-19 appears to over-represented by the 70-79, and 80-89-year-old’s. As seen from the Italian data 112 of the 10,026 patients reported to have died were under the age of 50. Twenty-three of that group was less than 40 and of that group 6 were reported to have no co-morbidities.
TABLE 1. Comorbidities of reported COVID patients
# CasesN= 10473a
Number DiedN= 10336b
%Total of Deaths
Immune Suppression/Cancer/ Organ transplant
a # of Cases from references: 2–5, Italy contributed 10,026 cases of patients who died
b # Died from references: 2, 5
c of 10,272 cases reported
d of only 10,135 cases reported
Table 2. Number and Percent of Men and Women having Confirmed COVID-19 infection
Table 3. Number and Percent of Men and Women Died in Italian cohort
Figure 1. Number of patients who died by age group. This data is based solely on the Italian2 reported cohort of 10,026 patients who died.
Now for the molecular basis!
Lets go back in time, long before anyone ever associated a corona virus with an incredibly severe pandemic. Before this, we in the medical field new it as “The common cold”. So how did something go from being a common cold to the second worst pandemic the world has ever seen? (1918-1919 Flu killed an estimated 50 million people*- as of today 4/3 COVID-19 has been confirmed in >1 Million people and has taken just over 53 thousand lives)?
The “common cold” coronaviruses that we used to be able to test for came in such flavors HCoV-229E, HCoV-NL63, HCoV-OC43 (HCoV = Human Corona virus). They caused only self-limiting upper respiratory tract infections (about 30% of the common colds) 1. We never, really, bothered to make any treatments for the diseases they caused because as a 1994 study said “the presence of side-effects in treating such a mild illness is…unacceptable” 1.
Something has definitely changed. You might be surprised to know that we actually do understand what has changed since these OG corona viruses and the 2003 SARS (we now call SARS-CoV-1).
The “corona” of corona virus gets its name from spikes on the outer edge of the virus that give it a crown-like appearance (SEE THE FEATURED IMAGE ON THIS PAGE). Those spikes are how it gets into the cell. Now, in this rendition of SARS-CoV-2, those spikes sting…
In a paper so important it made it into NATURE, Li in 2003 found that SARS (CoV-1) used the ACE2 receptor to facilitate viral entry into humans2. Sound familiar? ACE inhibitors have been used to control hypertension for years and ACE inhibition is key in the treatment of cardiovascular disorders.
Interestingly, although we have known about ACE for a long time, ACE2 was only discovered in 20003 and its discovery has been “noteworthy and might be categorized as a Classic”4. The reason for this is it has “changed our simplistic vertical concept about the renin-angiotensin-system (RAS) by pointing out the presence of dual functions of the RAS with opposing effects in cardiovascular biology”4. We now know A LOT about ACE2 (SEE FIGURE BELOW FOR BIOCHEMICAL PATHWAY). ACE2 prevents the formation of the vasopressor angiotensin II. Interestingly, the gene for this enzyme, ACE2, maps to the X chromosome in humans. Thus the male species have less ACE2 than women do. Also interesting to note is that we start out life with a high amount of ACE2 and then ACE2 becomes down regulated and decreases with age. Thus older males have the least amount of ACE2 5! (Really starting to sound like a correlation here with risk factors!). We know that ACE2 is an essential regulator of heart function6. We also know that ACE2 is abundantly present in humans in the epithelia of the lung, small intestine, and vascular endothelium which may provide routes of entry for the SARS-CoV 7. With the SARS epidemic in 2003 we also learned a lot about SARS-CoV. We found that the CoV-1 bound tightly to ACE2 much more tightly than the corona viruses of old did. In fact now we know that SARS-CoV-2 even more efficiently recognizes and binds to ACE2 which may explain it enhanced ability to be transmitted from person to 8.
So how does that translate into such severe disease? Well for that we dive deeper into ACE2. Crackower in his article in Nature created knock-out mice that could not express ACE2. The loss of ACE2 did not alter blood-pressure but did impair cardiac function causing:
Mild thinning of the left ventricle and severe reduction in contractility but without fibrosis or hypertrophy of the heart. The damage was more similar to that seen with myocardial stunning, which is reversible and also suggested a role for ACE2 in mediating a response to cardiac ischemia.
Now it gets more interesting, because ACE2 also protects us from lung injury!9 In 2011 it was found that the development of ARDS is determined by the balance between ACE and ACE2 activity within the lung10. This study found that treating ACE2 knockout mice with either the by product of ACE2 (Ang1-7) or losartan (which in animal models has been shown to be lung protective but also causes sever drops in blood pressure in those with bp dysregulation such as the kind that occurs in sepsis), resulted in higher values of PaO2 in models of ARDS. They also found that in models of ARDS ACE activity was enhanced, whereas ACE2 activity was reduced in bronchoalveolar lavage fluid. Yang et al. found that an abundance of ACE2 enhanced disease severity in a mouse model of SARS-CoV-1 infection. They introduced the human gene for angiotensin-converting enzyme 2 (hACE2) into these mice. The mice had more severe pulmonary lesions, interstitial hemorrhage, and replicated more efficiently in these mice. CoV-1 had more openings in these mice to enter into. They also found other changes such as desquamation, and vasculitis in these mice. 11.
Thus, ACE2 is not only the entry receptor of the virus but also protects from lung injury. Because CoV-2 binds to it, it essentially becomes nonfunctional and can’t participate in lung repair. So SARS-CoV-2 may have become more infectious because the virus inhibits a lung protective pathway! SARS-CoV likely results in ACE2 downregulation through binding of SARS-CoV Spike protein to ACE2. It has been shown in many animal models that ACE2 is an inhibitor of lung injury. This scenario would explain how this family member of the common cold coronaviruses has turned into a worldwide pandemic. Indeed, this information is all being used in looking for treatments (drugs and vaccines) to subdue this emergency12.
We can even hypothesize further because all this becomes very interesting in the setting of ACEI’s and ARB in the treatment of hypertension. In a study by Burchill, the effect of Ramipril in combination with losartan was investigated. They found that despite ACE inhibition there was no down regulation of ACE2. Thus while it is still to early to tell one could hypothesize that the hypertension medications we take really shouldn’t affect CoV-2—but only time will tell. It is also interesting to consider the issue of ibuprofen. In a study by Qiao, the effects of ibuprofen on ACE2 were investigated in diabetic rats. It was found that Ibuprofen could blunt the cardiac fibrosis in diabetic rats by enhancement of the ACE2! Now obviously there have been “reports” of people saying not to take ibuprofen in CoV-2. In no way does this say one way or the other. What this should do is remind us that CORRELATION IS NOT CAUSATION. We have animal data that suggests ibuprofen is protective by increasing ACE2 and we have small observational data that suggests ibuprofen may be associated with worse disease. This is not the first time ibuprofen has been associated with worse respiratory disease. In 2016 a study reported an ASSOCIATION between NSAIDs and empyema with an adjusted odds ratio of 2.79 (CI 1.4-5.58, P = .004) 13. Again this is an ASSOCIATION and should make us skeptical UNTIL WE SEE A RANDOMIZED CONTROLLED TRIAL to adjust for confounders. However, certainly titles like “Is It Time to Dump the Ibuprofen From Your Medicine Cabinet?” should be met with extreme skepticism.
So to sum up here are the key points and their associated molecular mechanisms
Table 4. RISK FACTORS AND MOLECULAR CORRELATIONS
COVID-19 (CoV-2) has higher transmission and higher virulence
Spike protein of CoV-2 binds ACE2 more tightly than CoV-1 and infinitely tighter than “the common cold”
COVID-19 occurs in men more than women
ACE2 is carried on the X chromosome
COVID-19 occurs in older adults than younger adults
ACE2 is down regulated with age
COVID-19 causes acute lung injury and ARDS
ACE2 is protective of lung injury and is unavailable because of binding to viral spike particles
COVID-19 causes myocardial injury
Lack of ACE2 causes myocardial dysfunction without fibrosis or hypertrophy
3. Donoghue M, Hsieh F, Baronas E et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87: E1-9.https://www.ncbi.nlm.nih.gov/pubmed/10969042
7. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631-637.https://www.ncbi.nlm.nih.gov/pubmed/15141377
8. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020; 94: https://www.ncbi.nlm.nih.gov/pubmed/31996437
10. Wösten-van Asperen RM, Lutter R, Specht PA et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol. 2011; 225: 618-627.https://www.ncbi.nlm.nih.gov/pubmed/22009550
12. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine. 2020; 46: 586-590.http://dx.doi.org/10.1007/s00134-020-05985-9
13. Le Bourgeois M, Ferroni A, Leruez-Ville M et al. Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study. J Pediatr. 2016; 175: 47-53.e3.https://www.ncbi.nlm.nih.gov/pubmed/27339249