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Bench-to-bedside review: Treating acid–base abnormalities in the intensive care unit – the role of buffers


The recognition and management of acid–base disorders is a commonplace activity for intensivists. Despite the frequency with which non-bicarbonate-losing forms of metabolic acidosis such as lactic acidosis occurs in critically ill patients, treatment is controversial. This article describes the properties of several buffering agents and reviews the evidence for their clinical efficacy. The evidence supporting and refuting attempts to correct arterial pH through the administration of currently available buffers is presented.


Acidemia occurs commonly in critically ill patients. Certain acidoses have specific remedies, for example insulin for the patient with diabetic ketoacidosis, or fomepizole for the treatment of methanol intoxication. However, the optimal management of other forms of acidosis, such as lactic acidosis from sepsis, is controversial. Specifically, it is unclear for many of these disorders whether it is appropriate to attempt to correct arterial pH through the administration of sodium bicarbonate or other 'buffering' agents, while efforts to treat the underlying cause of the acidosis proceed apace. Similarly, whether pH should be corrected in patients with hypercapnea as a result of lung protective strategies of mechanical ventilation is unknown. Herein we describe the properties of several buffering agents and review the evidence for their clinical efficacy. We do not discuss the administration of sodium bicarbonate to patients with bicarbonate-losing metabolic acidoses such as occurs with diarrhea or renal tubular acidosis – a practice that enjoys widespread acceptance. Similarly, the role of buffering agents in treating intoxication is beyond the scope of the present review.

What is the harm associated with low pH?

Because we understand poorly both the effects of an elevated arterial H+concentration ([H+]) as well as the effects of attempting to correct it, deciding whether to administer a buffering agent such as sodium bicarbonate to patients with non-bicarbonate-losing forms of metabolic acidosis is difficult. Proponents of such an approach typically argue along the following lines [1].

  • An elevated arterial [H+], in and of itself, is harmful.

  • The administration of buffer X intravenously will lower the arterial [H+].

  • Lowering the [H+] with buffer X confers clinical benefit.

  • Any adverse effects of buffer X will be outweighed by its benefit.

We first consider the evidence supporting the first assertion. The remaining ones are discussed below in the context of each individual agent.

What are the effects of an elevated [H+]?

Because protein function is sensitive to the [H+] of its environment, an increase in arterial [H+] might be expected to have important detrimental effects on a host of bodily functions. However, it is unclear to what extent the arterial blood pH reflects the intracellular pH, which seems likely to be more relevant. By way of example, consider the effect of decreasing blood flow to a tissue by 50%. According to the Fick relationship the arterial–venous partial CO2 tension (PCO2) difference will double, assuming that local CO2 production is constant. This will have the effect of raising the tissue PCO2 and lowering its pH; however, the arterial PCO2 and pH are unchanged and hence do not reveal the abnormality. The meaning of an individual arterial blood pH is further limited when one considers the diversity of microcirculations and tissue metabolisms throughout the body. The effects of the elevated [H+] may also be difficult to separate from the effects of the accompanying anion; lactate buffered to a pH of 7.4, for example, causes a decrease in cardiac contractility in animal models [2]. Finally, discerning the effect of an elevated [H+] from that of the underlying process causing the acidosis – hypoperfusion, sepsis, or diabetic ketoacidosis for example – is difficult.

Nevertheless, lowering the arterial pH has rather convincingly been shown to cause a decrease in cardiac contractility. This effect has been demonstrated in isolated [3, 4] and whole animal heart preparations [5, 6], as well as in excised human ventricular muscle [7]. The net influence of acidosis on the cardiovascular system is complicated, however, by concomitant stimulation of the sympathetic–adrenal axis. As a result, acidemia has been shown to increase cardiac output and pulmonary artery pressure, whereas pulmonary vascular resistance is not changed [8]. The responsiveness of adrenergic receptors to circulating catecholamines is decreased [911], and the load tolerance of the right ventricle is reduced [12]. It is unclear whether resuscitability from induced ventricular fibrillation is impaired [1315]. Fewer patients with an arterial pH below 7.1 have been studied, making it difficult to draw any conclusions. Both respiratory and metabolic acidoses appear to have similar effects, although the effects of respiratory acidosis are more rapid, presumably because of rapid diffusion of CO2 across cell membranes.

Acute hypercapnea causes a decrease in diaphragmatic contractility and endurance time [16], along with an increase in cerebral blood flow. In fact, acute elevation in PCO2 to more than 70 mmHg may cause loss of consciousness and seizures [17]. In contrast, more gradual elevations in PCO2 are well tolerated, as exhibited by patients with chronic obstructive pulmonary disease. Broad clinical experience with the application of lung protective strategies of mechanical ventilation in patients with acute lung injury (ALI) and status asthmaticus suggests that modest acidemia (typically pH 7.15–7.30, PCO2 50–70 mmHg) is remarkably well tolerated. In general, patients with so-called permissive hypercapnea have a decrease in systemic vascular resistance, an increase in heart rate, cardiac output, oxygen delivery, mean pulmonary artery pressure, and mixed venous oxygen saturation, and unchanged mean arterial pressure and pulmonary vascular resistance.

The effects of acidosis may differ according to type and magnitude. Disparate effects of three types of extracellular acidosis – inorganic, respiratory, and lactic – on left ventricular function in isolated rabbit hearts have been described [18]. Lactic acidosis caused a significant increase in the time to peak left ventricular pressure while retarding ventricular relaxation, reinforcing the concept that lactate ions have an independent effect on myocardial function. Different types and severity of acidosis may also induce different patterns of inflammatory response. For example, murine macrophage-like cells stimulated with lipopolysaccharide exhibited an essentially proinflammatory response when the media contained hydrochloric acid, but an anti-inflammatory response when the media contained lactic acid [19]. Furthermore, hydrochloric acid infusion decreased the blood pressure in septic rats in a dose dependent manner, but whereas rats with moderately severe acidosis (standard base excess of 5–10 mEq/l) had increased plasma nitrate/nitrite levels, rats with severe acidosis did not [20].

Are there beneficial effects to an elevation in [H+] in critical illness?

Interesting data are emerging regarding potential protective effects of acidosis, particularly hypercapnic acidosis, in various experimental models. Acidosis has been shown to protect cells in a variety of organs (heart, lung, brain, and liver) against injury from a number of insults, including hypoxia [2125]. In contrast, hypocapnic alkalosis worsened ischemia–reperfusion ALI in isolated rabbit lungs [26], whereas hypercapnic and metabolic acidosis afforded protection [27]. Buffering the hypercapnic acidosis attenuated the protection conferred. Similarly, rabbits ventilated with injurious tidal volumes exhibited less ALI histologically when hypercapnea was present [28]. A protective effect of hypercapnea on the development of ALI has also been demonstrated for an experimental model of extrapulmonary ALI in which rats were subjected to splanchnic ischemia–reperfusion injury [29]. Hypercapnic acidosis was effective at attenuating endotoxin-induced ALI in an in vivo rat model [30]; in fact, both prophylactic and therapeutic hypercapnic acidosis ameliorated lung injury. Conceivably, reducing cells' mechanical work (e.g. in cardiac cells) and metabolic demand during hypoxia may protect them from ischemia.

Interestingly, the ARDS Network trial [31], which demonstrated reduced mortality in ALI and acute respiratory distress syndrome (ARDS) using a protocol employing low tidal ventilation, allowed for sodium bicarbonate infusion for acidemia. Whether this therapy had any effect, either negative or positive, on patient outcome is unclear.

In summary, the negative impact of an elevated arterial [H+] is frequently difficult to discern. We consider the evidence for and against the administration of different buffering agents within the context of each agent below.

Buffering agents

Buffers have conventionally been defined in acid–base chemistry as substances that allow a solution to 'resist' changes in pH in response to administration of H+. Problems exist with this definition, however. First, as discussed below, may cause conventionally defined buffers such as NaHCO3- an increase in arterial [H+] in certain circumstances when they are administered intravenously, while Stewart [32] demonstrated that a solution containing weak acids (buffers) – such as blood containing albumin – 'resists' changes in [H+] much less effectively than the same solution without any weak acid. Also, the use of the term 'buffer' obscures the unique mechanisms of each agent. Neverthess, because of its widespread use, we employ the term buffer to refer to any agent whose intent is to raise the arterial pH when given intravenously.

Sodium bicarbonate

Does sodium bicarbonate lower the arterial [H+]?

The effects of sodium bicarbonate infusion can be understood within the following context. Although the Henderson equation ([H+] = 24 × PCO2/[HCO3-]) accurately describes the dissociation equilibrium for carbonic acid, it is misleading to assume that [HCO3-] is an independent determinant of [H+]. In fact, the independent determinants of [H+] in the blood are the strong ion difference [SID], the total concentration of weak acids [Atot], and the PCO2 [32]. Weak acids [Atot] include substances such as albumin and PO4-, change relatively little acutely, and have little impact on [H+]. Strong ions are those that dissociate fully (or nearly so) in aqueous solutions, such as Na+ and Cl-. Because they are fully dissociated, strong ions do not participate in chemical reactions in blood like weak ions (such as H+ or HCO3-) do. Because they do not react chemically, all that matters (for acid–base purposes) is the net difference in their charges.

The [SID] is defined as the difference between the sum of the major cations (Na+, K+, Ca2+, Mg2+) and the sum of the major anions (Cl-, SO4-, lactate) in the blood. [SID] is so important because the difference in charges affects how much water will dissociate into the charged species H+ and OH- (i.e. [SID] is the major determinant of pH).

The arterial [HCO3-] and pH depend simply and quite inextricably on the [SID], [Atot], and PCO2. The intravenous infusion of sodium bicarbonate solution typically lowers arterial [H+] (raising the pH) through an increase in [SID]. This occurs because Na+ is a strong cation whereas HCO3- is not, but rather reacts with [H+] to create CO2. When ventilation is not limited, the excess CO2 that is produced can be eliminated, and arterial pH is increased so that most [5, 3336], but not all [37, 38], whole animal studies have shown an increase in arterial pH when sodium bicarbonate is administered. Additionally, two prospective, randomized controlled trials conducted in mechanically ventilated patients with lactic acidosis [39, 40] demonstrated that sodium bicarbonate given intravenously causes a modest increase in arterial pH. When ventilation is fixed, however, as commonly occurs in mechanically ventilated patients, the effect of sodium bicarbonate may be to lower arterial pH, as was seen in patients ventilated with a lung protective strategy [41].

However, evidence supporting an increase in arterial pH with bicarbonate infusion does not alone support its use for the treatment of acidosis. First, bicarbonate infusion has been shown to stimulate the production of lactate in animal models of hypoxic lactic acidosis [34, 38], phenformin-induced lactic acidosis [37], hemorrhagic shock [35], and diabetic ketoacidosis [36, 42]. As mentioned above, lactate is itself a strong anion, which may have independent negative effects on cardiac contractility [2]. Furthermore, the effects of bicarbonate administration on intracellular pH are far from clear. Because CO2 diffuses readily across cell membranes, sodium bicarbonate administration may cause a decrease in intracellular pH. In fact, the findings of cellular and whole animal model studies examining the effects of bicarbonate infusion on intracellular pH are variable, with intracellular [H+] rising [36], falling [37, 38, 4348], not changing [4, 14, 34, 35], or either rising or falling depending on the buffer used [49, 50]. Two studies of normal volunteers using very different experimental designs have investigated the effect of bicarbonate on intracellular pH using magnetic resonance spectroscopy. In one study [51] bicarbonate attenuated the decrease in intracellular muscle pH during exercise induced metabolic acidosis while raising the arterial pH and PCO2. In the other study [46] sodium bicarbonate caused a fall in brain pH.

The effect of bicarbonate on intracellular pH may depend on the extracellular nonbicarbonate buffering capacity [52]. In this model, bicarbonate reacts with H+ to form H2O and CO2 (reaction 1). The abrupt decrease in [H+] caused by reaction 1 causes the dissociation of [H+] from nonbicarbonate buffer (back titration of the buffer), which in turn reacts with bicarbonate to produce more CO2. Finally, the CO2 diffuses readily into cells, decreasing intracellular pH (an effect that may be minimized by intracellular bicarbonate buffer).

Does sodium bicarbonate confer any beneficial effects?

In general, whole animal studies fail to demonstrate any hemodynamic benefit of sodium bicarbonate therapy over isotonic saline [5, 33, 34, 37, 38, 53, 54]. Additionally, two randomized controlled trials of sodium bicarbonate therapy in patients with lactic acidosis [39, 40] found no benefit from this therapy over sodium chloride in improving global hemodynamics or the cardiovascular response to infused catecholamines.

The effects of sodium bicarbonate therapy in patients with permissive hypercapnea have received little study, notwithstanding the inclusion of sodium bicarbonate in the aforementioned ARDS Network low tidal volume protocol [31]. One small, uncontrolled study of patients receiving lung protective ventilation for ALI showed a decrease in arterial pH with bicarbonate therapy [41]. No benefit from sodium bicarbonate has been found in the management of diabetic ketoacidosis [55, 56].


Intravenous sodium bicarbonate may decrease the arterial [H+] when ventilation is not limited, but its effect on intra-cellular pH is unclear. Perhaps more importantly, no clinical benefit from sodium bicarbonate has been demonstrated in the setting of lactic or ketoacidosis, but volume overload, hyperosmolarity [57], and a decrease in ionized calcium [40] are known to complicate its use.


Carbicarb is an equimolar mixture of sodium bicarbonate and sodium carbonate that is not currently available clinically. Carbicarb raises the [SID] (lowering the arterial [H+]) far more [33, 34, 43, 58] and boosts the PCO2 far less [33, 34, 45] than does sodium bicarbonate when given intravenously to animals with metabolic acidosis. If the inability of sodium bicarbonate to demonstrate a benefit in patients with non-bicarbonate-wasting forms of metabolic acidosis is due to increased CO2 generation, then carbicarb should be a superior agent. In fact, although carbicarb more consistently lowers intracellular [H+] [34, 43, 45], studies of its effects on hemodynamics have yielded conflicting findings [4, 33, 34, 43]. This agent deserves further study.


Tris-hydroxymethyl aminomethane (THAM) is a weak alkali (pK = 7.8) that reduces arterial [H+] without producing CO2. Because it penetrates cells easily, it also reduces intracellular [H+]. Protonated THAM is excreted by the kidneys.

Although THAM has been commercially available for some time and has seen considerable use outside North America, there are few studies of its efficacy. THAM incompletely buffered metabolic acidosis but significantly improved contractility and relaxation in an isolated blood perfused rabbit heart model [59]. The combination of THAM and sodium bicarbonate perfectly buffered acidosis without modifying CO2, resulting in a significant improvement in contractility. Weber and colleagues [60] studied the effect of THAM on systemic hemodynamics in 12 patients with ARDS in whom permissive hypercapnea was induced with a target CO2 of 80 mmHg. Hypercapnea had the following effects on hemodynamics in control patients, in whom no attempt was made to correct the pH: reduced systemic vascular resistance, mean arterial pressure and myocardial contractility, and increased cardiac output and pulmonary artery pressure. Patients who received THAM experienced significantly less myocardial depression when compared with control patients, whereas the effects of hypercapnea on mean arterial pressure and mean pulmonary artery pressure were ameliorated. Administration of THAM to 10 patients with acidosis and ALI caused significant improvements in arterial pH and base deficit, as well as a decrease in CO2 that was not adequately explained by the effects of ventilation [41].

Whether it is even desirable to 'buffer' hypercapnea in ALI and hypoperfusion states is unclear, as discussed above. THAM also has potentially serious side effects, including hypoglycemia, hyperkalemia, extravasation related necrosis, and, in neonates, hepatic necrosis [61]. Nevertheless, THAM is an interesting agent that deserves further study, including as a potential therapy for patients with lactic acidosis.

Alternative agents for lactic acidosis


Conceivably, the lactic acidosis of sepsis may be due in part to impaired pyruvate oxidation. The pyruvate dehydrogenase complex is a key regulator of carbohydrate metabolism. This complex is inactivated by a pyruvate dehydrogenase kinase that may be activated by sepsis [62], leading to pyruvate accumulation and subsequently an increase in lactate. Dichloroacetate stimulates pyruvate kinase, increasing the oxidation of pyruvate to acetyl coenzyme A.

Initial studies of dichloroacetate in animals and humans were indeed promising, demonstrating that dichloroacetate effectively reduced arterial [H+] and lactate levels [6365]. There has been one large, randomized, placebo-controlled trial of dichloroacetate in patients with lactic acidosis due to sepsis, cardiogenic shock, or massive hemorrhage. Although dichloroacetate reduced the arterial blood lactate concentration and improved the arterial pH, it had no effect on hemodynamics or survival [66]. Further studies of dichloroacetate in other patient populations and using different dosing schedules are warranted. Currently, this therapy is investigational.


Patients with lactic acidosis due to thiamine deficiency (beri beri) may respond promptly to its administration. Patients at risk include those with chronic alcoholism, malignancy, chronic illness, and short bowel syndrome. Lactic acidosis may also develop in HIV infected patients receiving nucleoside analog reverse transcriptase inhibitors [67]. This disorder is thought to represent drug induced mitochondrial dysfunction, and there are anecdotal reports of improvement with thiamine [68]. Although thiamine is an essential cofactor for pyruvate dehydrogenase, its utility in sepsis with lactic acidosis has not been studied.

Volume expanders and acid–base disorders

Considerable debate exists regarding the relative merits of sodium chloride, lactated Ringer's solution, or various colloid solutions in the resuscitation of patients in shock. The different chemical compositions of these fluids translate into different acid–base consequences. For example, infusing large volumes of normal saline intravenously lowers the [SID] (because the [SID] of saline is zero), raising [H+] (and lowering pH). Whether the 'dilutional acidosis' that results is harmful, inconsequential, or even protective to the patient is unclear. Lactated Ringer's solution also has an [SID] of zero but, because lactate is metabolized in the liver (assuming adequate hepatic perfusion and function), the effect is similar to infusing a fluid with a positive [SID]. Whether this might be advantageous is not known. New formulations of colloids have been investigated; in an animal model of septic shock, volume expansion with Hextend (Bio Time, Inc., Berkeley, CA, USA) – a synthetic colloid in a balanced electrolyte solution that does not produce metabolic acidosis in humans – conferred longer survival when compared with 0.9% normal saline [69].

Conceivably, the differing effects of various volume expanders on acid–base status may be important clinically, but it is the authors' view that considerably more work remains to be done in this area before volume expanders other than normal saline can be recommended. A detailed analysis of this subject is beyond the scope of the present review.

When should I administer a buffering agent?

The lack of evidence supporting buffer therapy in human acidosis makes it difficult to provide explicit recommendations. Currently, it is unclear whether it is ever advantageous to administer a buffering agent to a patient with lactic acidosis or ketoacidosis. In fact, we do not recommend administration of sodium bicarbonate to patients with lactic acidosis, regardless of the pH. This includes lactic acidosis caused by hypoperfusion, sepsis, mitochondrial dysfunction, or liver failure, or in the setting of cardiopulmonary bypass. If the decision is made to administer sodium bicarbonate, then slow infusion is preferable and objective measures of benefit (or harm) should be sought. Further study into the efficacy of alternative buffering agents such as THAM and carbicarb is merited.

In patients with severe hyperchloremic metabolic acidosis from diarrhea or renal tubular acidosis, the administration of sodium bicarbonate is reasonable. Whether a patient will benefit from this therapy is difficult to predict and probably depends on the clinical circumstance. Patients with critical respiratory compromise, who cannot easily compensate for acidemia, could also benefit. Nevertheless, we find these patients to be quite rare. In the much more common circumstance of modest hyperchloremic acidosis, attempting treatment with buffers is unlikely to be helpful and may serve to distract the clinician from addressing the underlying problem.

When buffer therapy is given its effect can be monitored by serial determination of arterial blood pH, PCO2, and serum anion gap corrected for albumin concentration. Failure to correct for the nearly ubiquitous hypoalbuminemia present in the critically ill introduces a systematic error in the detection of unidentified anions such as lactate or ketoacids [70]. An alternative approach is to calculate the strong ion gap, but this requires measurement of albumin and phosphate concentrations as well as a little more mathematics, and this may be too cumbersome for regular clinical use.


Acidemia has both harmful and beneficial biological effects. Sodium bicarbonate is generally ineffective in raising pH when ventilation is limited, as in patients with ARDS. Even when alkalinizing agents can correct the pH, evidence of efficacy is lacking. Thus, these treatments should not be considered standard therapy in patients with organic acidoses, such as lactic acidosis. Rather, attention should be directed toward correcting the underlying basis for the acidosis. Alternative buffer agents, such as tromethamine, offer potential advantages over sodium bicarbonate, but clinical trials in humans are lacking.



acute lung injury


acute respiratory distress syndrome


total concentration of weak acids


H+ concentration


partial CO2 tension


strong ion difference


tris-hydroxymethyl aminomethane.


  1. Forsythe SM, Schmidt GA: Sodium bicarbonate for the treatment of lactic acidosis. Chest 2000, 117: 260-267. 10.1378/chest.117.1.260

    Article  CAS  PubMed  Google Scholar 

  2. Yatani A, Fujino T, Kinoshita K, Goto M: Excess lactate modulates ionic currents and tension components in frog atrial muscle. J Mol Cell Cardiol 1981, 13: 147-161. 10.1016/0022-2828(81)90212-1

    Article  CAS  PubMed  Google Scholar 

  3. Poole-Wilson PA, Langer GA: Effect of pH on ionic exchange and function in rat and rabbit myocardium. Am J Physiol 1975, 229: 570-581.

    CAS  PubMed  Google Scholar 

  4. Shapiro JI: Functional and metabolic responses of isolated hearts to acidosis: effects of sodium bicarbonate and Carbicarb. Am J Physiol 1990, 258: H1835-H1839.

    CAS  PubMed  Google Scholar 

  5. Cooper DJ, Herbertson MJ, Werner HA, Walley KR: Bicarbonate does not increase left ventricular contractility during L-lactic academia in pigs. Am Rev Respir Dis 1993, 148: 317-322.

    Article  CAS  PubMed  Google Scholar 

  6. Wildenthal K, Mierzwiak DS, Myers RW, Mitchell JH: Effects of acute lactic acidosis on left ventricular performance. Am J Physiol 1968, 214: 1352-1359.

    CAS  PubMed  Google Scholar 

  7. Cingolani HE, Faulkner SL, Mattiazzi AR, Bender HW, Graham TP Jr: Depression of human myocardial contractility with 'respiratory' and 'metabolic' acidosis. Surgery 1975, 77: 427-432.

    CAS  PubMed  Google Scholar 

  8. Thorens J-B, Jolliet P, Ritz M, Chevrolet JC: Effects of rapid permissive hypercapnia on hemodynamics, gas exchange, and oxygen transport and consumption during mechanical ventilation for the acute respiratory distress syndrome. Intensive Care Med 1996, 22: 182-191.

    Article  CAS  PubMed  Google Scholar 

  9. Nakanishi T, Okuda H, Kamata K, Seguchi M, Nakazawa M, Takao A: Influence of acidosis on inotropic effect of catecholamines in newborn rabbit hearts. Am J Physiol 1987, 253: H1441-H1448.

    CAS  PubMed  Google Scholar 

  10. Marsh JD, Margolis TI, Kim D: Mechanism of diminished contractile response to catecholamines duringacidosis. Am J Physiol 1988, 254: H20-H27.

    CAS  PubMed  Google Scholar 

  11. Campbell GS, Houle DB, Crisp NW Jr, Weil MH, Brown EB Jr: Depressed response to intravenous sympathicomimetic agents in humans during acidosis. Dis Chest 1958, 33: 18-22.

    Article  CAS  PubMed  Google Scholar 

  12. Rose CE Jr, Benthuysen KV, Jackson JT, Tucker CE, Kaiser DL, Grover RF, Weil JV: Right ventricular performance during increased afterload impaired by hypercapnicacidosis in conscious dogs. Circ Res 1983, 52: 76-84.

    Article  PubMed  Google Scholar 

  13. von Planta I, Weil MH, von Planta M, Gazmuri RJ, Duggal C: Hypercarbic acidosis reduces cardiac resuscitability. Crit Care Med 1991, 19: 1177-1182.

    Article  CAS  PubMed  Google Scholar 

  14. Kette F, Weil MH, von Planta M, Gazmuri RJ, Rackow EC: Buffer agents do not reverse intramyocardial acidosis during cardiac resuscitation. Circulation 1990, 81: 1660-1666.

    Article  CAS  PubMed  Google Scholar 

  15. Kerber RE, Pandian NG, Hoyt R, Jensen SR, Koyanagi S, Grayzel J, Kieso R: Effect of ischemia, hypertrophy, hypoxia, acidosis, and alkalosis on canine defibrillation. Am J Physiol 1983, 244: H825-H831.

    CAS  PubMed  Google Scholar 

  16. Juan G, Calverley P, Talamo C, Schnader J, Roussos C: Effect of carbon dioxide on diaphragmatic function in human beings. N Engl J 1984, 310: 874-879.

    Article  CAS  Google Scholar 

  17. Barnett VT, Schmidt GA: Acid-base disorders. In Principles of Critical Care 2 Edition (Edited by: Hall JB, Schmidt GA, Wood LDH). New York: McGraw-Hill 1998, 1169-1181.

    Google Scholar 

  18. Berger DS, Fellner SK, Robinson KA, Vlasica K, Godoy IE, Shroff SG: Disparate effects of three types of extracellular acidosis on left ventricular function. Am J Physiol 1999, 276: H582-H594.

    CAS  PubMed  Google Scholar 

  19. Kellum JA, Song M, Li J: Lactic, and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 2004, 286: R686-R692. 10.1152/ajpregu.00564.2003

    Article  CAS  PubMed  Google Scholar 

  20. Kellum JA, Song M, Venkataraman R: Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest 2004, 125: 243-248. 10.1378/chest.125.1.243

    Article  CAS  PubMed  Google Scholar 

  21. Bonventre JV, Cheung JY: Effects of metabolic acidosis on viability of cells exposed to anoxia. Am J Physiol 1985, 249: C149-C159.

    CAS  PubMed  Google Scholar 

  22. Preckel B, Schlack W, Obal D, Barthel H, Ebel D, Grunert S, Thamer V: Effect of acidotic blood reperfusion on reperfusion injury after coronary artery occlusion in the dog heart. J Cardiovascular Pharmacol 1998, 31: 179-186. 10.1097/00005344-199802000-00002

    Article  CAS  Google Scholar 

  23. Kitakaze M, Takashima S, Funaya H, Minamino T, Node K, Shinozaki Y, Mori H, Hori M: Temporary acidosis during reperfusion limits myocardial infarct size in dogs. Am J Physiol 1997, 272: H2071-H2078.

    CAS  PubMed  Google Scholar 

  24. Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM: Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Pediatrics 1995, 95: 868-874.

    CAS  PubMed  Google Scholar 

  25. Nomura F, Aoki M, Forbess JM, Mayer JE: Effects of hypercarbic acidotic reperfusion on recovery of myocardial function after cardioplegic ischemia in neonatal lambs. Circulation 1994, 90: 321-327.

    Google Scholar 

  26. Laffey JG, Engelberts D, Kavanagh BP: Injurious effects of hypocapnic alkalosis in the isolated lung. Am J Respir Crit Care Med 2000, 162: 399-405.

    Article  CAS  PubMed  Google Scholar 

  27. Laffey JG, Engelberts D, Kavanagh BP: Buffering hypercapnic acidosis worsens acute lung injury. Am J Respir Crit Care Med 2000, 161: 141-146.

    Article  CAS  PubMed  Google Scholar 

  28. Sinclair SE, Kregenow DA, Lamm WJ, Starr IR, Chi EY, Hlastala MP: Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med 2002, 166: 403-408. 10.1164/rccm.200112-117OC

    Article  PubMed  Google Scholar 

  29. Laffey JG, Jankov RP, Engelberts D, Tanswell AK, Post M, Lindsay T, Mullen JB, Romaschin A, Stephens D, McKerlie C, Kavanagh BP: Effects of therapeutic hypercapnia on mesenteric ischemia-reperfusion injury. Am J Respir Crit Care Med 2003, 168: 1383-1390. 10.1164/rccm.2108078

    Article  PubMed  Google Scholar 

  30. Laffey JG, Honan D, Hopkins N, Hyvelin J-M, Boylan JF, McLoughlin P: Hypercapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit Care Med 2004, 169: 46-56. 10.1164/rccm.200205-394OC

    Article  PubMed  Google Scholar 

  31. The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000, 342: 1301-1308. 10.1056/NEJM200005043421801

    Article  Google Scholar 

  32. Stewart PA: How to Understand Acid–base: a Quantitative Acid-base Primer for Biology and Medicine New York: Elsevier 1981.

    Google Scholar 

  33. Benjamin E, Oropello JM, Abalos AM, Hannon EM, Wang JK, Fischer E, Iberti TJ: Effects of acid base correction on hemodynamics, oxygen dynamics, and resuscitability in severe canine hemorrhagic shock. Crit Care Med 1994, 22: 1616-1623.

    Article  CAS  PubMed  Google Scholar 

  34. Rhee KH, Toro LO, McDonald GG, Nunnally RL, Levin DL: Carbicarb, sodium bicarbonate, and sodium chloride in hypoxic lactic acidosis: effect on arterial blood gases, lactate concentrations, hemodynamic variables, and myocardial intracellular pH. Chest 1993, 104: 913-918.

    Article  CAS  PubMed  Google Scholar 

  35. Beech JS, Nolan KM, Iles RA, Cohen RD, Williams SC, Evans SJ: The effects of sodium bicarbonate and a mixture of sodium bicarbonate and carbonate (Carbicarb) on skeletal muscle pH and hemodynamic status in rats with hypovolemic shock. Metabolism 1994, 43: 518-522. 10.1016/0026-0495(94)90087-6

    Article  CAS  PubMed  Google Scholar 

  36. Beech JS, Williams SCR, Iles RA, Cohen RD, Nolan KM, Evans SJ, Going TC: Haemodynamic and metabolic effects in diabetic ketoacidosis in rats of treatment with sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate. Diabetologia 1995, 38: 889-898. 10.1007/s001250050368

    Article  CAS  PubMed  Google Scholar 

  37. Arieff AI, Leach W, Park R, Lazarowitz VC: Systemic effects of NaHCO 3 in experimental lactic acidosis in dogs. Am J Physiol 1982, 242: F586-F591.

    CAS  PubMed  Google Scholar 

  38. Graf H, Leach W, Arieff AI: Metabolic effets of NaHCO 3 in hypoxic lactic acidosis in dogs. Am J Physiol 1985, 249: F630-F635.

    CAS  PubMed  Google Scholar 

  39. Mathieu D, Neviere R, Billard V, Fleyfel M, Wattel F: Effects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study. Crit Care Med 1991, 19: 1352-1356.

    Article  CAS  PubMed  Google Scholar 

  40. Cooper DJ, Walley KR, Wiggs BR, Russell JA: Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis: a prospective, controlled clinical study. Ann Intern Med 1990, 112: 492-498.

    Article  CAS  PubMed  Google Scholar 

  41. Kallet RH, Jasmer RM, Luce JM, Lin LH, Marks JD: The treatment of acidosis in acute lung injury with tris-hydroxymethyl aminomethane (THAM). Am J Respir Crit Care Med 2000, 161: 1149-1153.

    Article  CAS  PubMed  Google Scholar 

  42. Bureau MA, Begin R, Berthiaume Y, Shapcott D, Khoury K, Gagnon N: Cerebral hypoxia from bicarbonate infusion in diabetic acidosis. J Pediatr 1980, 96: 968-973.

    Article  CAS  PubMed  Google Scholar 

  43. Bersin RM, Arieff AI: Improved hemodynamic function during hypoxia with carbicarb, a new agent for the management of acidosis. Circulation 1988, 77: 227-233.

    Article  CAS  PubMed  Google Scholar 

  44. Shapiro JI, Whalen M, Kucera R, Kindig N, Filley G, Chan L: Brain pH responses to sodium bicarbonate and carbicarb during systemic acidosis. Am J Physiol 1989, 25: H1316-H1321.

    Google Scholar 

  45. Shapiro JI, Whalen M, Chan L: Hemodynamic and hepatic pH responses to sodium bicarbonate and carbicarb during systemic acidosis. Magnetic Res Med 1990, 16: 403-410.

    Article  CAS  Google Scholar 

  46. Nakashima K, Yamashita T, Kashiwagi S, Nakayama N, Kitahara T, Ito H: The effect of sodium bicarbonate on CBF and intracellular pH in man: stable Xe-CT and 31P-MRS. Acta Neurol Scand Suppl 1996, 166: 96-98.

    Article  CAS  PubMed  Google Scholar 

  47. Bjerneroth G, Sammeli O, Li YC, Wiklund L: Effects of alkaline buffers on cytoplasmic pH in lymphocytes. Crit Care Med 1994, 22: 1550-1556.

    Article  CAS  PubMed  Google Scholar 

  48. Ritter JM, Doktor HS, Benjamin N: Paradoxical effect of bicarbonate on cytoplasmic pH. Lancet 1990, 335: 1243-1246. 10.1016/0140-6736(90)91305-T

    Article  CAS  PubMed  Google Scholar 

  49. Goldsmith DJA, Forni LG, Hilton PJ: Bicarbonate therapy and intracellular acidosis. Clin Sci 1997, 93: 593-598.

    Article  CAS  PubMed  Google Scholar 

  50. Levraut J, Labib Y, Chave S, Payan P, Raucoules-Aime M, Grimaud D: Effect of sodium bicarbonate on intracellular pH under different buffering conditions. Kidney Int 1996, 49: 1262-1267.

    Article  CAS  PubMed  Google Scholar 

  51. Nielsen HB, Hein L, Svendsen LB, Secher NH, Quistorff B: Bicarbonate attenuates intracellular acidosis. Acta Anaesthesiol Scand 2002, 46: 579-584. 10.1034/j.1399-6576.2002.460516.x

    Article  CAS  PubMed  Google Scholar 

  52. Levraut J, Giunti C, Ciebiera J-P, de Sousa G, Ramhani R, Payan P, Grimaud D: Initial effect of sodium bicarbonate on intracellular pH depends on the extracellular nonbicarbonate buffering capacity. Crit Care Med 2001, 29: 1033-1039. 10.1097/00003246-200105000-00032

    Article  CAS  PubMed  Google Scholar 

  53. Tanaka M, Nishikawa T, Mizutani T: Normovolemic hemodilution attenuates cardiac depression induced by sodium bicarbonate in canine metabolic acidosis. Br J Anaesth 1996, 77: 408-412.

    Article  CAS  PubMed  Google Scholar 

  54. Tanaka M, Nishikawa T: Acute haemodynamic effects of sodium bicarbonate administration in respiratory and metabolic acidosis in anaesthetized dogs. Anaesth Intensive Care 1997, 25: 615-620.

    CAS  PubMed  Google Scholar 

  55. Lever E, Jaspan JB: Sodium bicarbonate therapy in severe diabetic ketoacidosis. Am J Med 1983, 75: 263-268. 10.1016/0002-9343(83)91203-2

    Article  CAS  PubMed  Google Scholar 

  56. Morris LR, Murphy MB, Kitabchi AE: Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med 1986, 105: 836-840.

    Article  CAS  PubMed  Google Scholar 

  57. Mattar JA, Weil MH, Shubin H, Stein L: Cardiac arrest in the critically ill: II. Hyperosmolal states following cardiac arrest. Am J Med 1974, 56: 162-168. 10.1016/0002-9343(74)90593-2

    Article  CAS  PubMed  Google Scholar 

  58. Sun JH, Filley GF, Hord K, Kindig NB, Bartle EJ: Carbicarb: an effective substitute for NaHCO3 for the treatment of acidosis. Surgery 1987, 5: 835-839.

    Google Scholar 

  59. Sirieix D, Delayance S, Paris M, Massonnet-Castel S, Carpentier A, Baron J-F: Tris-hydroxymethyl aminomethane and sodium bicarbonate to buffer metabolic acidosis in an isolated heart model. Am J Respir Crit Care Med 1997, 155: 957-963.

    Article  CAS  PubMed  Google Scholar 

  60. Weber T, Tschernich H, Sitzwohl C, Ullrich R, Germann P, Zimpfer M, Sladen RN, Huemer G: Tromethamine buffer modifies the depressant effect of permissive hypercapnia on myocardial contractility in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2000, 162: 1361-1365.

    Article  CAS  PubMed  Google Scholar 

  61. Adrogue HJ, Madias NE: Management of life-threatening acid–base disorders. N Engl J Med 1998, 338: 26-34. 10.1056/NEJM199801013380106

    Article  CAS  PubMed  Google Scholar 

  62. Vary TC: Increased pyruvate dehydrogenase kinase activity in response to sepsis. Am J Physiol 1991, 260: E669-E674.

    CAS  PubMed  Google Scholar 

  63. Park R, Arieff AI: Treatment of lactic acidosis with dichloroacetate in dogs. J Clin Invest 1982, 70: 853-862.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Stacpoole PW, Lorenz AC, Thomas RG, Harman EM: Dichloroacetate in the treatment of lactic acidosis. Ann Intern Med 1988, 108: 58-63.

    Article  CAS  PubMed  Google Scholar 

  65. Stacpoole PW, Harman EM, Curry SH, Baumgartner TG, Misbin RI: Treatment of lactic acidosis with dichloroacetate. N Engl J Med 1983, 309: 390-399.

    Article  CAS  PubMed  Google Scholar 

  66. Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S, Lachin JM, Lorenz A, Schneider SH, Siegel JH, Summer WR, Thompson D, Wolfe CL, Zorovich B, the DCA Lactic Acidosis Study Group: A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. N Engl J Med 1992, 327: 1564-1569.

    Article  CAS  PubMed  Google Scholar 

  67. Falco V, Rodriguez D, Ribera E, Martinez E, Miro JM, Domingo P, Diazaraque R, Arribas JR, Gonzalez-Garcia JJ, Montero F, Sanchez L, Pahissa A: Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: report of 12 cases and review of the literature. Clin Infect Dis 2002, 34: 838-846. 10.1086/339041

    Article  PubMed  Google Scholar 

  68. Schramm C, Wanitschke R, Galle PR: Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis. Eur J Anaesthesiol 1999, 16: 733-735. 10.1046/j.1365-2346.1999.00586.x

    Article  CAS  PubMed  Google Scholar 

  69. Kellum JA: Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved short-term survival and acid-base balance with Hextend compared with saline. Crit Care Med 2002, 30: 300-305. 10.1097/00003246-200202000-00006

    Article  PubMed  Google Scholar 

  70. Fencl V, Jabor A, Kazda A, Figge J: Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 2000, 162: 2246-2251.

    Article  CAS  PubMed  Google Scholar 

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Gehlbach, B.K., Schmidt, G.A. Bench-to-bedside review: Treating acid–base abnormalities in the intensive care unit – the role of buffers. Crit Care 8, 259 (2004).

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  • acid-base
  • acidosis
  • bicarbonate
  • buffer
  • tromethamine