Author: Charles Murchison, MD (EM Resident Physician, SUNY Downstate/Kings County Emergency Medicine) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

This article will not attempt to wade into the pathophysiology of acid-base disorders. From reading the nephrology literature, it seems that this topic is more closely akin to theoretical physics than the sturdy biochemistry I learned in college. Researchers can’t even agree on how to define acidosis, much less what causes it or how to measure or name it. Is it just HCO 3 and CO 2 ? Were Henderson and Hasselbach wrong, and it’s actually a strong ion difference? Were the surgeons right all along, and it’s all about the base deficit? The best advice would be to pick a way of thinking about it, read about it, understand it well, and during your next shift when an acid-base question comes up, clear your throat, gather everyone around, and 20 seconds into speaking realize that you have no idea what you’re talking about, you completely forgot everything you read, and you do not in any way understand acid-base physiology.

Then go sit back down. And be comforted by the fact that nobody does. And if someone claims they do, they are lying. Because nobody does.

So, with that start, let’s see if we can steady ourselves by grabbing onto some more sturdy, well-established ideas.

Acidosis is bad. Correct?

The answer is: maybe?

One of the main arguments for acidosis being harmful is that it is thought to decrease cardiac output. This has been born out in several in vitro studies, showing decreased contractility of isolated cardiac myocytes in an acidemic environment (1,2,3). However, the clinical application of this data is suspect. As mentioned, these are in vitro studies examining isolated cells of various animals, including rats, rabbits, turtles, guinea pigs and even trout. The reductions in contractility are minor – around 25% – and mostly occur at an extremely low pH: 6.5 to 6.8 (1,2,3).

Another proposed reason for acidosis being harmful is that it diminishes response to catecholamines, both among cardiac myocytes and the systemic vasculature, which theoretically could contribute to decreased cardiac output and hypotension (4,5,6). However, studies again found that most depressed function comes at an extremely low pH, and in vivo the effect of decreased catecholamine responsiveness is more or less offset by increased catecholamine production during acidemic states (4,5,6).

So in the laboratory, extreme acidosis probably causes small reductions in cardiac myocyte contractility. But what about in alive human beings?

There are two places where the effects of acidosis have been studied in humans. One is in exercise physiology, where lactic acidosis is a natural response to exercise. The other is in patients with ARDS, where a lung-protective strategy of mechanical ventilation is used. The low tidal volumes associated with a lung-protective strategy of ventilation result in a permissive hypercapnia, and thus a permissive respiratory acidosis.

Exercise Physiology

Studies measuring pH during exercise on a stationary cycle show ranges as low as 7.1 with a lactate > 12.0 mmol/L in healthy subjects. Evaluation of skeletal muscle at low pH shows some decreased contractility; however, other physiologic factors likely play a greater role in this decreased contractility than the acidosis itself (7,8,9). It would make sense that exercise-induced acidosis should not cause dysfunction of cardiac and skeletal muscle, as this would make it really hard for humans to survive. Why would we develop an evolutionary response where upon initiation of physical activity our body enters a dysfunctional state in which our heart and muscles stop working? It’s actually the opposite. Acidosis appears to be beneficial during exertion. Look at the Bohr effect, where lower pH shifts the hemoglobin binding curve, and red blood cells offload more O 2 for hypoxic tissues. In this situation, acidosis is beneficial, not harmful.

ARDS

In the ARDS trials, the use of a lung protective ventilation strategy has clearly led to improved outcomes (10,11). This strategy of using lower tidal volumes has secondarily led to intubated ICU patients living with a respiratory acidosis, due to the permissive hypercapnia associated with low tidal volumes. The mortality benefit in the lung protective strategy of ventilation persists despite the resulting low pH. It should be noted that in the ICU, acidosis is often buffered with sodium bicarbonate infusion when pH drops very low, i.e. below 7.15, although it is not clear if this changes outcomes (12).

In summary, the basis for the theory that acidosis is bad for you comes primarily from in vitro experiments on isolated cells at a very low pH. On the other hand, evidence in living humans suggests mild to moderate acidosis does not have deleterious effects and is potentially beneficial. So why would we correct acidosis at all? Well, as mentioned above, the decreased contractility of cardiac myocytes was only seen at severely low pH, so perhaps this is where the bicarbonate infusion will help. Exercise induced acidosis was not harmful in healthy patients, but can we generalize this to the typical emergency room or ICU patient? And in our ICU patients with ARDS in whom permissive hypercapnia was well tolerated, perhaps there was such a substantial mortality benefit from using low tidal volumes that it masked any negative effects of the resulting hypercapneic acidosis. As you can imagine, a significant number of confounders are present in studies including patients with ARDS. It is hard to extrapolate evidence from one population to another, so let’s look into specific causes of acidosis and whether or not sodium bicarbonate administration is beneficial.

How does sodium bicarbonate work in correcting acidosis?

Infusion of sodium bicarbonate – NaHCO 3 – works by directly buffering H+ions. HCO 3 combines with H+to form H 2 CO 3 – carbonic acid – which then splits into H 2 O and CO 2 . The CO 2 is ventilated off. Therefore, it really functions by changing your metabolic acidosis to a respiratory acidosis. As long as you can adequately ventilate off the CO 2 that bicarbonate therapy creates, your acidosis will improve. Conversely, if a patient already has a functional respiratory acidosis, the addition of more CO 2 to the picture is not going to help them, and will actually make their acidosis worse. So, adequate ventilation is 100% necessary for sodium bicarbonate to work.

There are a few inherent negative effects of sodium bicarbonate therapy. Studies have found rapid bicarbonate administration will cause a paradoxical worsening intracellular acidosis, despite alkalinization of the extracellular fluid (13). This is from an imbalance in CO 2 across cell membranes. As mentioned earlier, bicarbonate administration will take the H+in your blood and convert it to H 2 CO 3 , which then quickly breaks down to H 2 O and CO 2 . So there is a time where your extracellular CO 2 rapidly rises before you can ventilate it off. That rapid increase in CO 2 diffuses almost instantly across cell membranes, where the reverse reaction occurs – CO 2 + H 2 O leads to increased H+in the cell – thus creating an intracellular acidosis.

Sodium bicarbonate is also a huge load of sodium which can create hypernatremia and hyperosmolality, expanding the extracellular circulating volume (ECV) quickly. One dose of the sodium bicarbonate often found in crash carts – 50 mL or 50 meq of 8.4% sodium bicarbonate – will raise the Na by 1.0 meq and increase ECV by 250 mL.

So with that background, let’s look at the clinical evidence.

Cardiac Arrest

The theory behind using sodium bicarbonate in cardiac arrest seems to be that the severe acidosis resulting from global hypoperfusion causes decreased responsiveness to catecholamines – i.e. your epinephrine pushes won’t work – and an increased risk of dysrhythmias – i.e. that VF won’t quit. However, again, these theoretical harms of acidosis are primarily based on animal and in vitro studies. When you look at the human trials studying the use of sodium bicarbonate in cardiac arrest, they show no benefit and even possible harm (14). To date there are only two RCTs using sodium bicarbonate in cardiac arrest, and both showed no benefit (15,16).

The first trial was a randomized, double-blind, placebo-controlled study of 500 patients 16 years or older with out-of-hospital cardiac arrest – asystole or VF refractory to the first defibrillation. They found no difference in outcomes between patients who did and did not receive buffer therapy.

The second trial was also a randomized, double-blind, placebo-controlled study of out-of-hospital cardiac arrest, this time with 874 patients (16). They studied a similar cohort of patients, including patients over 18 years old with cardiac arrest refractory to defibrillation. They found no difference in their primary outcome between patients who did and did not received bicarbonate.

There are some issues with this study. First, the primary outcome of the trial was having a pulse on ED arrival, which is not a patient-centered outcome. In the trial (16), about 14% of patients arrived to the ED with pulses, meaning they achieved the primary outcome. But if you look at the data from around the world, the percentage of patients with meaningfulsurvival after out of hospital cardiac arrest is 7-9% (17,18). So ⅓ or ½ of the patients with a supposed good outcome in this study likely did not go on to meaningful survival. And if the primary outcome is not meaningful, it’s hard to know how to interpret the rest of the data.

The second problem is the headline finding in this study. Vukmir et al report patients with prolonged cardiac arrest had better survival if they received bicarbonate therapy (16). They found this outcome in a subgroup analysis of patients with prolonged downtime i.e. cardiac arrest for 15 minutes prior to CPR. However on close inspection, this is misleading. How did they get to their conclusion? Let’s look at the numbers.

Vukmir et al report that giving sodium bicarbonate to patients who had prolonged downtime more than doubled their chance of survival from 15% to 33% (16). Those numbers alone should raise suspicion. They are saying that 33% of patients in one cohort who did not receive CPR for over 15 minutes survived. That’s better than their total survival numbers of 14%. So according to their conclusion, it was beneficial to have been dead for more than 15 minutes before CPR. It doubled the chance of survival. In comparison, though it reports a longer-term outcome, a study of 30,000 patients with out of hospital cardiac arrest found that among patients in whom CPR was initiated after 15 minutes, 30-day survival was 0.5-1.0% (19).

Obviously, something is not right here. It turns out Vukmir et al misinterpreted the numbers. Among survivors, they saw that twice as many people with a prolonged downtime received bicarbonate (red box to the right). They then incorrectly concluded that giving bicarb to patients with prolonged downtime doubled chance of survival. But everyone in the group survived. How can you say bicarb increases your chance of survival if nobody died? The correct interpretation of this data is: patients with prolonged downtime are twice as likely to receive bicarbonate therapy.

To see if there is a survival benefit, you will have to look at what happened to the people who did not survive. We re-analyzed the data, taking the patients with prolonged downtime and comparing survival vs no survival with bicarb vs no bicarb (red box to the left). Using the more appropriate Fisher’s exact test, we found a p-value of 0.1 (not statistically significant) – meaning there is no difference in survival in the subgroup of patients with prolonged arrest. So, aside from the issue of titling a paper with the result of subgroup analysis, the trial’s main conclusion is also inaccurate. In fact, the 2015 AHA ACLS guidelines state “sodium bicarbonate should not be used routinely in cardiac arrest”, unless you suspect arrest from TCA overdose or hyperkalemia (20).

In conclusion, will I be using sodium bicarbonate in cardiac arrest anymore? No.

Takeaways:

The evidence for acidosis being harmful is primarily based on in vitro studies. Clinical data show acidosis may not be as harmful as we think. Sodium bicarbonate therapy creates excess CO2 which must be quickly exhaled. If a patient is not adequately ventilating they will become more acidotic when given sodium bicarbonate therapy. There are only two clinical trials on using sodium bicarbonate in cardiac arrest, both show no benefit. The AHA no longer recommends its use in ACLS.

References/Further Reading:

Orchard CH, Kentish JC. Effects of changes of pH on the contractile function of cardiac muscle. Am J Physiol. 1990 Jun;258(6 Pt 1):C967-81. Tang WC et al. Reversible impairment of myocardial contractility due to hypercarbic acidosis in the isolated perfused rat heart. Crit Care Med. 1991 Feb;19(2):218-24. EA Beierholm et al. Effects of acid-base changes, hypoxia, and catecholamines on ventricular performance. American Journal of Physiology. 1975 228(5): 1555-1561. Leitch SP et al. Interactive effects of K+, acidosis, and catecholamines on isolated rabbit heart: implications for exercise. J Appl Physiol (1985). 1994 Sep;77(3):1164-71. Tajimi K et al. Plasma catecholamine levels and hemodynamic responses of severely acidotic dogs to dopamine infusion. Crit Care Med. 1983 Oct;11(10):817-9. Chen LQ et al. Role of H+ and alpha 2-receptors in escape from sympathetic vasoconstriction. Am J Physiol. 1991 Sep;261(3 Pt 2):H868-73. E B Cady et al. Changes in force and intracellular metabolites during fatigue of human skeletal muscle. J Physiol. 1989 Nov; 418: 311–325. Degroot M et al. Dissociation of [H+] from fatigue in human muscle detected by high time resolution 31P-NMR. Muscle Nerve. 1993 Jan;16(1):91-8. Westerblad, Håkan. Acidosis Is Not a Significant Cause of Skeletal Muscle Fatigue. Medicine & Science in Sports & Exercise: November 2016 – Volume 48 – Issue 11 – p 2339–2342. McIntyre RC Jr et al. Cardiopulmonary effects of permissive hypercapnia in the management of adult respiratory distress syndrome. J Trauma. 1994 Sep;37(3):433-8. Peltekova V et al. Hypercapnic acidosis in ventilator-induced lung injury. Intensive Care Med. 2010 May;36(5):869-78. doi: 10.1007/s00134-010-1787-7. Laffey JG et al. Buffering hypercapnic acidosis worsens acute lung injury. Am J Respir Crit Care Med. 2000 Jan;161(1):141-6. Goldsmith DJ et al. Bicarbonate therapy and intracellular acidosis. Clin Sci (Lond). 1997 Dec;93(6):593-8. Dimitrios Velissaris et al. Use of Sodium Bicarbonate in Cardiac Arrest: Current Guidelines and Literature Review. J Clin Med Res. 2016 Apr; 8(4): 277–283. Dybvik T et al. Buffer therapy during out-of-hospital cardiopulmonary resuscitation. Resuscitation. 1995 Apr;29(2):89-95. Vukmir RB et al. Sodium bicarbonate improves outcome in prolonged prehospital cardiac arrest. Am J Emerg Med. 2006 Mar;24(2):156-61. Malta Hansen C et al. Association of Bystander and First-Responder Intervention With Survival After Out-of-Hospital Cardiac Arrest in North Carolina, 2010-2013. JAMA. 2015 Jul 21;314(3):255-64. doi: 10.1001/jama.2015.7938. Berdowski J et al. Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation. 2010 Nov;81(11):1479-87. doi: 10.1016/j.resuscitation.2010.08.006. Epub 2010 Sep 9. Hasselqvist-Ax, Ingela et al. Early Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest. N Engl J Med 2015; 372:2307-2315 DOI: 10.1056/NEJMoa1405796 Neumar RW et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010 Nov 2;122(18 Suppl 3):S729-67. doi: 10.1161/CIRCULATIONAHA.110.970988.