Acidosis and Sodium Bicarbonate Therapy
Dr James Cooper FRACP, FFICANZA
Acidosis is thought to have adverse physiological effects and critically ill patients who develop acidosis generally have an increased risk of death. Consequently, therapies to correct acidosis, usually sodium bicarbonate infusions for metabolic acidosis, have been widely used. In recent years, however, this approach has changed.
Firstly, although the underlying condition causing acidosis may be life threatening, the acidosis itself is now recognised to be a much less significant problem. Next, the cause of the acidosis is important. Different types of acidosis have different causes, different physiological effects and therefore different managements. Finally, the major therapy available for metabolic acidosis, sodium bicarbonate, has significant side effects which limit its clinical usefulness. New therapies for metabolic acidosis are being investigated, but appear to hold little immediate promise for improving patient outcome.
This paper will outline the adverse effects of acidosis, describe the side effects of sodium bicarbonate and the new therapies which may be useful for acidosis and describe management principles for patients with each of the main sub-types of acidosis.
Adverse Effects Of Acidosis
Depressed myocardial contractility
Clinical concern about decreased myocardial contractility resulting from acidosis is often the primary reason for treatment with sodium bicarbonate. However, the only evidence to support this practice is derived from in vitro and animal studies in which the physiology is different from that found in humans. In many cases, acidoses that are more severe than those found in living patients have been studied and anaesthetic agents (such as pentobarbital), which accumulate unpredictably and depress myocardial contractility, have been used at the same time. Different types of acidosis (respiratory, hydrochloric, ammonium chloride and others) have been lumped together, whereas they each may have different effects. Finally, the techniques used to measure changes in myocardial contractility in large animals have improved markedly in recent years and older studies have used assessment techniques which are now known to be unreliable in vivo.
Recent studies using sophisticated measures of left ventricular (LV) function in large animals with lactic acidosis 1,2 have concluded that lactic acidosis of the severity usually seen in critically ill patients (arterial pH 7.00 - 7.10) has a measurable, but small, depressant effect upon LV contractility. This depression is overridden by the effects of catecholamines. It is known that plasma catecholamine concentrations are high in patients with stress, shock and acidosis, and in those receiving catecholamine infusions. By contrast, respiratory acidosis, (arterial pH 7.09) has two competing effects on the heart 3 Although LV contractility is decreased by pure respiratory acidosis, the overall effect on cardiac function is an increase in cardiac output, because of the effects of catecholamines and because of the decrease in afterload resulting from hypercapnic vasodilatation.
In patients with acidosis and an arterial pH of about 7.10, the decrease in myocardial contractility caused by the acidosis itself is, therefore, likely to be of little clinical significance and usually negated by catecholamine effects. Critically ill patients with acidosis often have severely depressed cardiac function, but there are many other possible causes in these patients apart from acidosis. A great deal of evidence in recent years indicates that the true causes of depressed myocardial contractility during shock and acidosis are the actions of cytokines (tumour necrosis factor and interleukins) and the phospholipids (platelet activating factor), which are released during shock and which cause most of the known physiological disturbances in patients with shock 4,5,6
Decreased catecholamine efficacy
It is often said that acidosis blunts the myocardial response to catecholamines. This is suggested by in vitro studies in which decreased catecholamine efficacy was documented during severe acidosis. Although the effect of acidosis upon catecholamine efficacy has not been studied extensively in large animals, the evidence suggests that the myocardial response to catecholamines is relatively normal above an arterial pH of 6.90. This question has only recently been studied in humans. The findings in patients with lactic acidosis 2 and in others with mixed respiratory and metabolic acidosis from asthma 7 showed that catecholamine efficacy did not improve when acidosis was corrected, suggesting that this is not an important clinical problem.
Severe acidosis can cause arrhythmias and reduce the arrhythmia threshold. The arterial pH at which arrhythmias become likely varies in different species and in different clinical settings. The threshhold arterial pH at which arrhythmias develop in humans is not known, but clinical experience suggests that it is below 7.00. Patients with diabetic ketoacidosis and those with lactic acidosis following grand mal seizures (no underlying cardiac problems) rarely have arrhythmias despite an initial arterial pH of 6.80 - 6.90.
Acidosis is a well-recognised cause of pulmonary vasoconstriction. In patients who have shock, acidosis, and pulmonary hypertension, however, it is unknown to what extent pulmonary vasoconstriction is caused by acidosis or by other factors (including cytokines and leukotrienes) circulating during shock. Furthermore, it is not clear whether pulmonary vasoconstriction is an important clinical problem in these patients in the absence of significant underlying cardiac disease. Acidaemic pulmonary vasoconstriction requires further study because of its potentially adverse effects on myocardial function.
Sodium bicarbonate is the only therapy commonly used to treat metabolic acidosis in patients outside clinical trials. In most patients, bicarbonate is used with the intention of reversing cardiovascular complications thought to be caused by acidosis. At other times, bicarbonate has been infused because it was considered to be a simple, benign therapy and probably beneficial to all patients with acidosis. Clinical situations in which bicarbonate has been used include cardiac arrest, lactic acidosis associated with shock, diabetic ketoacidosis, respiratory acidosis during "permissive hypercapnia", renal failure and bicarbonate losing states. However in many of these clinical situations, bicarbonate is no longer recommended, because its efficacy has not been confirmed in clinical studies and because its side effects are significant.
Side Effects Of Bicarbonate Therapy
Hypertonicity and hyperosmolality
Sodium bicarbonate is used clinically as an 8.4% solution (1 mmol/ml). This solution is both hypertonic and hyperosmolar. Hypertonic sodium solutions have direct effects upon myocardial cell function, either increasing or decreasing LV contractility, depending upon the rate of infusion 8,9. This is the reason why bicarbonate solutions should always be infused slowly. The same concern applies to carbicarb, a compound which is being investigated as a bicarbonate alternative and which is also presented as a hypertonic solution 10. A second problem is that hyperosmolar solutions redirect fluid from extravascular to intravascular sites, thereby increasing myocardial preload. The clinical effect of increased preload will depend upon the patient's intravascular volume, vascular tone and myocardial function. The effect on cardiac output in an individual patient will be unpredictable and, in some patients, left ventricular failure can be precipitated.
Hypercapnia and intracellular acidosis
Carbon dioxide diffuses rapidly across cell membranes, and therefore an acute elevation in PCO2 increases intracellular acidosis. This effect has been reported in a number of different models. Infused bicarbonate ions combine with hydrogen ions and release CO2, which may acutely worsen intracellular acidosis. Healthy humans hyperventilate in response to hypercapnia and maintain an arterial PCO2 within normal limits. Many critically ill patients with shock and acidosis are sedated and mechanically ventilated with a fixed minute volume. They are unable to eliminate an increased CO2 load. These patients have increased arterial and mixed venous PCO2 during bicarbonate infusions 11. Patients with cardiac arrest have elevated mixed venous PCO2 because decreased cardiac output impairs CO2 elimination 12. In these patients, infusion of bicarbonate is associated with further increases in mixed venous PCO2 13,14 Myocardial intracellular acidosis and cellular function may, therefore, be paradoxically worsened during bicarbonate therapy 15,16.
Sodium bicarbonate infusions decrease plasma ionised calcium concentration, both by increasing pH (increasing the binding between calcium ions and albumin) and by chelating calcium 17. This effect is most marked in patients who already have ionised hypocalcaemia; many patients with lactic acidosis fall into this category 11. Ionised hypocalcaemia decreases myocardial contractility 18 and bicarbonate administration may paradoxically decrease myocardial contractility in some patients with acidosis, by this mechanism 18,11
Decreased oxygen delivery
Acidosis shifts the haemoglobin oxygen dissociation curve to the right. This favours oxygen unloading to tissues and is likely to be beneficial in patients who have impaired oxygen delivery associated with shock. By increasing pH, sodium bicarbonate shifts the dissociation curve leftward and may remove this physiological compensation. Tissue oxygen delivery may therefore be impaired in these patients. Bicarbonate impairs myocardial and systemic oxygen delivery when infused to cause alkalosis in patients with heart disease 19. The importance of this effect in patients with acidosis is uncertain.
If a condition causing lactic acidosis is later reversed (for example when patients with cardiac arrest are resuscitated) accumulated lactate is metabolised to bicarbonate. If bicarbonate has been infused earlier to increase pH in these patients, metabolic alkalosis occurs during recovery 20. Metabolic alkalosis impairs tissue oxygen delivery and is associated with increased mortality in survivors of cardiopulmonary resuscitation.
Increased lactate production
This paradoxical effect of bicarbonate infusions during acidosis has been well described in animals 21. It occurs because acidosis slows a rate-limiting enzyme in the glycolytic pathway (phosphofructokinase) and thereby slows lactate production during anaerobic metabolism 22. If acidosis is reversed but the cause of anaerobic metabolism is not corrected, then hepatic lactate production is accelerated.
Adverse effects of acidosis have probably been overstated and are usually due to other factors in critically ill patients. Most evidence suggests that the adverse effects of acidosis are not seen with an arterial pH at or above 7.00 - 7.10. Acidosis may be considered a useful marker of the disease process causing tissue hypoxia, rather than a major cause of physiological derangement. Sodium bicarbonate has important detrimental side effects which mean that it should be infused slowly and that benefits are unlikely, except in very severe acidosis.
Sub-Types Of Acidosis - Management Principles
Optimum management of patients with severe diabetic ketoacidosis includes insulin infusion, intravascular and intracellular fluid resuscitation and early treatment of the precipitating condition. Sodium bicarbonate does not improve any aspect of patient management and recovery is usual regardless of the initial arterial pH (often 6.80 - 7.00). Two well designed, prospective clinical studies 23,24 have concluded that bicarbonate does not have any measurable beneficial effects when infused during diabetic ketoacidosis. It also delays the clearance of important metabolites (ketones, lactate) and normalisation of the lactate/pyruvate ratio. Bicarbonate is therefore not indicated in patients with diabetic ketoacidosis who have an arterial pH of greater than 6.80.
Acidosis during cardiac arrest is predominantly lactic acidosis resulting from decreased tissue oxygen delivery, in turn, caused by the decreased cardiac output. During cardiac arrest and cardiopulmonary resuscitation (CPR), cardiac output is mainly determined by mechanical factors and is not improved by bicarbonate therapy. In patients with cardiac arrest, drugs must be infused rapidly. As a consequence, the adverse side effects of bicarbonate (hypertonicity, acute hypercapnia, and ionised hypocalcaemia) are maximised. Bicarbonate does not improve the defibrillation threshold or outcome in animal models of cardiac arrest. Bicarbonate was 'de-emphasised' by the American Heart Association in its 1986 ACLS guidelines for the treatment of cardiac arrest and was further restricted in 1993. This progressive change in policy, away from recommending bicarbonate administration during cardiac arrest, has followed studies in which bicarbonate failed to improve myocardial pH or outcome in animals with cardiac arrest 13 and other studies in which patients receiving rapid bicarbonate infusions during cardiac arrest were noted to have very high mixed venous PCO2 14.
The interventions which improve outcome during cardiac arrest are early defibrillation and adrenaline administration. Oxygen therapy and effective CPR are also likely to improve oxygen delivery. In patients with cardiac arrest, bicarbonate is not indicated, and is probably detrimental.
In critically ill patients, lactic acidosis is usually the result of impaired tissue perfusion (shock) which increases lactate production. Lactic acidosis is worsened when patients also have impaired lactate metabolism, commonly as a result of liver disease.
Bicarbonate administration does not improve LV contractility during lactic acidosis caused by hypovolaemic shock 25 or lactic acid infusion 2. Furthermore, in two prospective controlled clinical studies of Intensive Care Unit patients with severe lactic acidosis, bicarbonate had no measurable beneficial effects upon haemodynamics. In the first of these to be published 11, 14 patients had severe lactic acidosis predominantly caused by septic shock. In this study, the only changes in haemodynamics found after bicarbonate infusion were also seen after an equimolar hypertonic saline control infusion and were due to the acute effects of the hypertonic solution. No haemodynamic changes could be attributed to increased arterial pH. Patients in this study were mechanically hyperventilated and had a mean arterial pH of 7.20. In the subset of patients with the most severe acidosis (mean arterial pH 7.10), the findings were similar. Important side effects of bicarbonate administration included arterial and mixed venous hypercapnia and ionised hypocalcaemia. In this study, patients were receiving catecholamine infusions and, because bicarbonate infusion did not improve haemodynamics, it also did not alter the cardiovascular response to circulating catecholamines. The second study from a different group, but using an almost identical study design, confirmed in 10 critically ill patients with a similar degree of lactic acidosis (mean arterial pH 7.16) that bicarbonate had no measurable beneficial haemodynamic effects 26. In both studies, the mortality rate of patients with severe lactic acidosis was about 90%, despite the bicarbonate infusions.
Critically ill patients with lactic acidosis not caused by hypovolaemia clearly have a high mortality rate. These patients have impaired cardiac function and are usually receiving inotropic drug infusions to maintain blood pressure and cardiac output. The apparent lack of benefit of bicarbonate therapy in this setting may be because acidosis (pH about 7.10) does not have important adverse effects upon cardiovascular function, because the effects of acidosis are overridden by catecholamines, or because bicarbonate benefits are negated by side effects.
Overall, if the cause of lactic acidosis is not identified and rapidly corrected, then patient mortality is extremely high regardless of supportive therapies, including those for acidosis.
It should be remembered that in some patients, when tissue perfusion is restored by initial therapy, lactic acidosis may worsen before improving. This is probably caused by washout of acidaemic blood from previously vasoconstricted sites. Thus, although acidosis is often a useful marker of tissue perfusion and of adequacy of therapy, it must be used in conjunction with other clinical signs.
The major alternatives to sodium bicarbonate for treatment of lactic acidosis are THAM, carbicarb and dichloroacetate. THAM (or TRIS) is a non-CO2-generating buffer which has been available for many years and which has no advantages over bicarbonate in either animals or patients. Carbicarb is a combination of sodium carbonate and sodium bicarbonate which also does not generate additional CO2. In animal studies, carbicarb is better tolerated than bicarbonate and appears to be superior as far as correction of intracellular acidosis is concerned. Like bicarbonate, carbicarb is a hypertonic solution and must be infused slowly to minimise side effects (10). Carbicarb is not beneficial in animal models of cardiac arrest, probably because acidosis is not an important factor determining outcome in this setting. Carbicarb has not been studied in patients with lactic acidosis, but it is likely that side effects would be less than with bicarbonate. However, it seems that carbicarb is unlikely to improve outcome in critically ill patients with lactic acidosis because, in most cases, acidosis is a consequence rather than the cause of cardiovascular dysfunction. Dichloroacetate (DCA) is not a buffer, but increases the activity of pyruvate dehydrogenase and thereby decreases lactate production and increases lactate clearance. DCA effectively increases arterial pH and decreases blood lactate concentrations in patients with lactic acidosis 27. However, in the two largest (uncontrolled) clinical studies, DCA had no effect upon mortality rate 27,28. In these studies, all patients died within a few days. These results strongly suggest that, in patients with lactic acidosis the acidosis, itself is not an important determinant of outcome and should not be a focus of therapy. Clearly the underlying disease process determines the very poor outcome in critically ill patients with lactic acidosis. Diagnosis and therapy should be focussed with urgency on that process.
Respiratory Acidosis And Permissive Hypercapnia
In most circumstances, respiratory acidosis is best treated either by stimulating respiratory drive or by mechanical ventilation. However, in recent years there has been increasing recognition that in some patients requiring mechanical ventilation particularly for asthma and Adult Respiratory Distress Syndrome, the side effects of mechanical ventilation may be minimised by intentional hypoventilation. In patients with acute severe asthma, hypoventilation minimises dynamic hyperinflation and prevents barotrauma and cardiovascular compromise 29 .In patients with ARDS, progressive lung injury is now recognised to be aggravated by high inflation volumes and pressures and appears to be minimised by therapeutic hypoventilation 30. Hypoventilation, however, causes respiratory acidosis and it is controversial at this time whether respiratory acidosis in these patients should be managed with bicarbonate infusions to increase arterial pH.
Because CO2 rapidly crosses cell membranes, acute hypercapnia rapidly decreases intracellular pH. However intracellular compensation is rapid, and arterial acidaemia may markedly overestimate intracellular acidosis in patients. Furthermore renal correction of extracellular pH occurs gradually and increases arterial pH over several days despite persistent hypercapnia. Hypercapnic acidosis in animals is associated with decreased myocardial contractility but increased cardiac output because of the actions of catecholamines and hypercapnic vasodilatation 3. Case reports suggest that very severe hypercapnic acidosis is surprisingly well tolerated 31.
In seven mechanically ventilated patients with acute severe asthma and acidosis (PCO2 70 mmHg, arterial pH 7.20), the effects of bicarbonate infusion on cardiovascular and respiratory function were assessed in a prospective controlled study 7. These patients had both respiratory and metabolic acidosis. All patients had small increases in blood lactate concentrations, in addition to hypercapnia. Despite acidosis, there was no evidence of cardiac compromise. Indeed, cardiac indices were increased to about twice normal and right ventricular ejection fractions were high. Actions of catecholamines and hypercapnic vasodilatation probably explain these findings. Bicarbonate infusion did not improve cardiac function or improve resolution of bronchospasm (an indicator of catecholamine efficacy). However, bicarbonate administration decreased pulmonary artery pressures and may therefore be useful in selected patients with severe acidaemic pulmonary vasoconstriction and right heart failure.
Acute Renal Failure
Acidosis associated with acute renal failure is best treated with early dialysis. A number of techniques are successful. Gradual techniques (continuous arteriovenous haemofiltration, CAVH; continuous venovenous haemodiafiltration, CVVHD) are more effective and better tolerated in unstable critically ill patients than is intermittent haemodialysis. Bicarbonate (rather than lactate or acetate) based replacement fluids are effective in patients who also have increased blood lactate concentrations. Renal failure is a cause of acidosis for which an effective (although supportive) therapy is available and many patients do well.
Patients with bicarbonate loss from kidneys or enteric fistulae may develop metabolic acidosis. Management is not controversial and includes both bicarbonate and electrolyte infusions to replace past and ongoing losses.